© Copyright 2013
Richard P. Rucker
Copper-Catalyzed Reactions of Organoboron Compounds
Richard P. Rucker
A dissertation
submitted in partial fulfillment of the
requirements for the degree of:
Doctor of Philosophy
University of Washington
2013
Reading Committee:
Prof. Gojko Lalic, Chair
Prof. Forrest Michael
Prof. D. Michael Heinekey
Program Authorized to Offer Degree:
Department of Chemistry
University of Washington
Abstract
Copper-Catalyzed Reactions of Organoboron Compounds
Richard P. Rucker
Chairperson of the Supervisory Committee:
Professor Gojko Lalic
Department of Chemistry
The discovery, development, scope, and mechanistic studies of three new coppercatalyzed transformations of organoboron compounds are described herein. Specifically,
Chapter 1 details the development and scope of the first general method for SN2’selective substitution of primary allylic chlorides using aryl boronic esters as
nucleophiles.
The formal anti-Markovnikov hydroamination of 9-alkyl-9-BBN
derivatives, which are conveniently prepared from the hydroboration of terminal alkenes,
to give tertiary alkyl amines is discussed in Chapter 2.
Chapter 3 describes the
development, scope, and mechanistic studies of the copper-catalyzed electrophilic
amination of aryl boronic esters and its application to the synthesis of hindered N,Ndialkyl anilines.
Table of Contents
List of Schemes ................................................................................................................. iii
List of Figures................................................................................................................... iv
List of Tables ..................................................................................................................... v
List of Abbreviations ....................................................................................................... vi
Chapter 1 – Copper-catalyzed Regioselective Substitution of Allylic Chlorides by
Organoboron Compounds1 .............................................................................................. 1
Section 1 . Introduction ............................................................................................... 1
Section 2 . Results......................................................................................................... 7
1.2.a . Scope of Aryl Boronic Esters ....................................................................... 8
1.2.b . Scope of Allylic Chlorides .......................................................................... 9
1.2.c . Allylic Alkylation and Allylic Alkenylation ............................................. 11
Section 3 . Mechanism ............................................................................................... 11
Section 4 . Conclusion ................................................................................................. 15
Section 5 . Experimental............................................................................................ 16
1.5.a . Allylic arylation: ....................................................................................... 17
1.5.b . Allylic alkenylation:.................................................................................. 26
1.5.c . Allylic alkylation:...................................................................................... 27
1.5.d . Synthesis of aryl boronic esters: ............................................................... 28
1.5.e . Synthesis of allylic chlorides: ................................................................... 30
Allylic Alcohols: ............................................................................................... 30
Allylic Chlorides: .............................................................................................. 32
1.5.f . Synthesis of (IMes)Cu(4-methylbenzene) complex (Equation 5): ............ 35
1.5.g . Stoichiometric Reaction of (IMes)Cu(4-methylbenzene) with (E)-2hexenyl-1-chloride (Equation 6) ........................................................................... 36
1.5.h . Catalyst synthesis:..................................................................................... 37
Section 6 . References to Chapter 1 ........................................................................... 39
Chapter 2 – Copper-Catalyzed Electrophilic Amination of Alkyl Boranes: Formal
anti-Markovnikov Hydroamination of Terminal Alkenes1 ........................................ 41
Section 1 . Introduction and Context ....................................................................... 41
Section 2 . Reaction Discovery and Optimization ................................................... 47
2.2.a . Identification of electrophilic nitrogen source .......................................... 47
Section 3 . Reaction scope.......................................................................................... 53
Section 4 . Mechanism ............................................................................................... 55
Section 5 . Conclusion ................................................................................................ 57
Section 6 : Experimental ............................................................................................ 58
General .............................................................................................................. 58
i
2.6.b . Reaction Optimization ............................................................................... 59
2.6.c . Reactions of O-benzoyl-N,N-dibenzyl hydroxylamine with sodium tertpentoxide and lithium tert-butoxide. ..................................................................... 61
2.6.d . Hydroamination of Terminal Alkenes ....................................................... 62
2.6.e . Synthesis of O-benzoyl-N,N-hydroxylamines ........................................... 78
2.6.f . Synthesis of IMesCu(Et) 2.32 ................................................................... 81
Section 7 . References to Chapter 2 ........................................................................... 84
Chapter 3 – Copper-Catalyzed Electrophilic Amination of Aryl Boronic Esters:
Synthesis of Hindered Anilines1..................................................................................... 87
Section 1 . Introduction .............................................................................................. 87
Section 2 . Discovery and Optimization .................................................................... 89
Section 3 . Scope ......................................................................................................... 92
Section 4 . Mechanism ................................................................................................ 94
Section 5 . Conclusion ............................................................................................... 100
Section 6 . Experimental........................................................................................... 102
3.6.a . Reaction Optimization ............................................................................ 103
Note on Preparation of XantPhosCu-OtBu from XantPhos and (Cu-OtBu)4: 104
Reactions of O-benzoyl-N,N-dialkyl hydroxylamine with sodium tert-butoxide
and lithium tert-butoxide (Table 3.2).............................................................. 108
3.6.b . Amination of Aryl Boronic Esters ........................................................... 108
General procedure using alkoxides: ................................................................ 108
General procedure using CsF:......................................................................... 109
3.6.c . Synthesis of O-benzoyl-N,N-dialkyl hydroxylamines ............................ 126
General: ........................................................................................................... 126
3.6.d . Stoichiometric Reactions of Organocopper Complexes ......................... 134
Preparation of XantPhosCu-(4-Me)Ph (3.37): ................................................ 134
With XantPhosCu-(4-Me)Ph: ......................................................................... 135
With IMesCu-(4-Me)Ph:17 .............................................................................. 136
3.6.e . Reaction Rate as a Function of Added Equivalents of Sodium tertButoxide .............................................................................................................. 137
Reactions a – c (Figure 3.2): ........................................................................... 137
Reaction d (Figure 3.2): .................................................................................. 138
Section 7 : References to Chapter 3 ........................................................................ 139
Appendix A: Crystallographic Data for IMesCuEt (2.32, Chapter 2) ..................... 141
Appendix B: Crystallographic Data for XantphosCu-(4-Me)Ph (3.37, Chapter 3) 152
ii
List of Schemes
Scheme 1.1. ......................................................................................................................... 1
Scheme 1.2. ......................................................................................................................... 5
Scheme 1.3. ......................................................................................................................... 7
Scheme 1.4 ........................................................................................................................ 11
Scheme 1.5 ........................................................................................................................ 12
Scheme 1.6 ........................................................................................................................ 13
Scheme 1.7 ........................................................................................................................ 14
Scheme 2.1 ........................................................................................................................ 42
Scheme 2.2 ........................................................................................................................ 43
Scheme 2.3 ........................................................................................................................ 44
Scheme 2.4 ........................................................................................................................ 45
Scheme 2.5 ........................................................................................................................ 46
Scheme 2.6 ........................................................................................................................ 48
Scheme 2.7 ........................................................................................................................ 50
Scheme 2.8 ........................................................................................................................ 55
Scheme 2.9 ........................................................................................................................ 57
Scheme 3.1 ........................................................................................................................ 87
Scheme 3.2 ........................................................................................................................ 89
Scheme 3.3 ........................................................................................................................ 94
Scheme 3.4 ........................................................................................................................ 95
Scheme 3.5 ........................................................................................................................ 97
Scheme 3.6 ........................................................................................................................ 97
iii
List of Figures
Figure 2.1. ORTEP of IMesCu(Et) (selected hydrogen atoms omitted for clarity) with
thermal ellipsoids drawn at 50% probability level. .................................................. 56
Figure 3.1 Ellipsoid Drawing of XantphosCu-(4-Me)Ph (3.37) (hydrogen atoms omitted
for clarity). ................................................................................................................ 96
Figure 3.2 Effect of superstoichiometric amount of NaOtBu on product yield............... 99
iv
List of Tables
Table 1.1. ............................................................................................................................ 4
Table 1.2 ............................................................................................................................. 8
Table 1.3 ............................................................................................................................. 9
Table 1.4 ........................................................................................................................... 10
Table 2.1 ........................................................................................................................... 49
Table 2.2 ........................................................................................................................... 51
Table 2.3 ........................................................................................................................... 53
Table 2.4 ........................................................................................................................... 54
Table 2.5 ........................................................................................................................... 62
Table 3.1 ........................................................................................................................... 90
Table 3.2 ........................................................................................................................... 91
Table 3.3 ........................................................................................................................... 93
Table 3.4 ......................................................................................................................... 105
Table 3.5 ......................................................................................................................... 107
v
List of Abbreviations
Ac:
Acetyl
Ad:
Adamantyl
Ar:
Aryl
BBN:
Borabicyclo[3.3.1]nonane
Bn:
Benzyl
Boc:
tert-Butyloxycarbonyl
Bz:
Benzyl
C:
Celsius
Cy:
Cyclohexyl
DNB:
1,3-dinitrobenzene
E+:
Electrophile
eg:
ethylene glycol
eq:
Equation
equiv:
Equivalent
ESI-MS:
Electrospray ionization mass spectrometry
Et:
Ethyl
FTIR:
Fourier transform infrared spectroscopy
h:
Hour
HRMS:
High resolution mass spectrometry
Hz:
Hertz
ICy:
1,3-Bis-dicyclohexyl imidazolium
IMes:
1,3-Bis-(2,4,6-trimethylphenyl)imidazolium
iPr:
isopropyl
IPr:
1,3-Bis-(2,6-diisopropylphenyl)imidazolium
L:
Ligand
Me:
Methyl
Mes:
2,4,6-trimethylphenyl
MHz:
Megahertz
mol:
Mole
mp:
Melting point
ND:
Not determined
neop:
neopentylglycol
NHC:
N-heterocyclic carbene
NMR:
Nuclear magnetic resonance
Abbreviations for NMR splitting patterns
s:
singlet
d:
doublet
t:
triplet
q:
quartet
p:
pentet
m:
multiplet
br:
broad
vi
Nu:
OTs:
Ph:
pin:
ppm:
rt:
tBu:
tPent:
TBS:
THF:
TIPS:
TLC:
TMB:
TMS:
tol:
Ts:
Xantphos:
Nucleophile
p-Toluenesulfonate
Phenyl
pinacol
parts per million
room temperature
tert-butyl
tert-pentyl
tert-butyldimethylsilyl
Tetrahydrofuran
Triisopropylsilyl
Thin layer chromatography
1,3,5-trimethoxybenzene
Trimethylsilyl
Tolyl
p-Toluenesulfonyl
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
vii
Acknowledgements
I am deeply indebted to many people whom without their support this work would
not have been possible. First, I would like to thank my brother, Victor C. Rucker, Ph.D.,
who first introduced me to chemistry while I was in high school and whose counsel
throughout the years has proven invaluable. Victor, you have always been there for me;
for that, my gratitude cannot be expressed. Without the support and love of my father,
Perry C. Rucker, I would never have realized my full potential. Dad, I cannot thank you
enough for all of your sacrifices and encouragement you gave me, even during our
family’s most tumultuous days. My oldest brother, Perry C. Rucker, Jr., through his hard
work and efforts, showed me that any goal is obtainable.
Second, I would like to thank Prof. Gojko Lalic, my advisor at the University of
Washington, for his patience, persistence, and exceptional technical capability and work
ethic. Gojko, you are not only my advisor, but also a role model and an inspiration. In
addition, I must thank my coworkers at the University of Washington, all of whom are
not only excellent researchers, but also good friends. I will continue to value your
friendship throughout the years ahead.
I would also like to give thanks to Prof. Debra D. Dolliver, who enabled my
understanding of organic chemistry through her clarity of instruction and gave me the
opportunity to perform research in her laboratory.
Lastly, I cannot thank Alicia F. McGhee enough for her love, support,
encouragement, and friendship during my entire graduate school career. Alicia, you are
the most important person in my life, and I love you.
viii
Dedication
This work is dedicated to the memory of my loving mother,
Debra I. McGregor Rucker
ix
1
Chapter 1 – Copper-catalyzed Regioselective Substitution of
Allylic Chlorides by Organoboron Compounds1
Section 1. Introduction
The substitution of allylic electrophiles by carbon and heteroatom-based
nucleophiles has been a subject of intense interest for almost a century.
In this
transformation, bond formation between the electrophile and nucleophile can occur at the
α carbon—SN2—or at the γ carbon—SN2’ (See Scheme 1). The uncatalyzed reactions of
allylic electrophiles with most nucleophiles yield products with little regioselectivity.2 In
particular, the regiocontrol of allylic substitution with anionic, carbon-based (hard)
nucleophiles to generate primarily the SN2’-selective product is difficult.3
Scheme 1.1.
It has been known for over 40 years that the addition of stoichiometric or catalytic
amounts of transition-metal salts can influence the regioselectivity of nucleophilic
substitution of allylic electrophiles to such an extent that the SN2 or SN2’-substituted
product can be accessed selectively.4 Today, allylic substitution reactions have been
developed which are catalyzed by a number of transition metals.5 For soft (heteroatombased) nucleophiles, the palladium-catalyzed allylic substitution reactions are historically
the most well-developed and include the robust, SN2’-selective Tsuji-Trost reaction.6
Unfortunately, efforts to extend palladium-based systems to include harder nucleophiles
7
(i.e., carbon-based nucleophiles) have typically afforded the linear SN2-product.
2
As a
result, researchers in the field have investigated other transition metals for possible
solutions to address this unmet challenge.
To this end, the pioneering discovery by Crabbe and coworkers that
stoichiometric amounts of dimethyl lithium cuprate—an anionic copper(I) salt—could
promote the SN2’-selective alkylation of allylic acetates introduced a new approach for
carbon-carbon bond formation and regiocontrolled elaboration of allylic substrates.8 As
the interest in developing these types of reactions continued to increase, improvements in
efficiency were realized by Goering,9 who employed catalytic copper salts in conjunction
with Grignard reagents, and Bäckvall and van Koten, who in 1995 introduced a system
using a chiral thiolate as a ligand for the promotion of an asymmetric, SN2’-selective
alkylation of allylic acetates.10 Since these seminal contributions, the copper-catalyzed
allylic alkylation reaction has matured into a widely-used synthetic method for the
regioselective substitution of allylic electrophiles by sp3-based carbon nucleophiles, such
as Grignard, organolithium, and organozinc reagents.11
In contrast, the analogous substitution reactions of allylic electrophiles by sp2based carbon nucleophiles (allylic arylation and allylic alkenylation) are comparatively
underdeveloped; specifically, most reactions are not regioselective and give mixtures of
linear (SN2) and branched (SN2’) products. Before our research in this arena began, there
existed only Hoveyda’s 2008 report of a general, copper-catalyzed SN2’-selective
alkenylation of allylic phosphates using alkenylalane nucleophiles.12 The inability to
exert regiocontrol in the substitution of allylic substrates by sp2-based organometallic
3
reagents has been noted in the literature as a limitation of this methodology for over 20
years.13 The lack of regiocontrol in allylic substitution has been attributed in part to two
factors: First, the reactivity of sp2-based nucleophiles is lower than their sp3-based
counterparts (support for this can be found by comparing the pKa’s of the carbanions
under consideration); and second, the reactivity of the organocopper intermediates
obtained upon treatment of a copper salt with a nucleophile are inherently different.
The difference in reactivity of sp2- and sp3-based nucleophiles in copper-catalyzed
allylic substitution reactions was studied by Bäckvall, who proposed on the basis of
systematic changes in solvent, temperature, catalyst loading, and addition time of the
nucleophile that two discrete organocopper intermediates can exist and each is
responsible for formation of a different regioisomer.14 An SN2’-selective reaction can be
achieved by using reaction conditions that promote the formation of a monoaryl copper(I)
nucleophilic intermediate, whereas reaction conditions which promote the formation of
an anionic diaryl cuprate are unselective for either regioisomer. Specifically, Bäckvall
demonstrated that stoichiometric reactions of pre-formed monoaryl cuprates with allylic
chlorides are SN2’-selective, whereas the pre-formed diaryl cuprates are not
regioselective (Entries 1 and 2, Table 1). Furthermore, an increase in SN2’-selectivity
was observed when the aryl Grignard reagent was added slowly to the solution (Entries
3—5, Table 1). The authors demonstrated that, by using a high catalyst loading, long
addition time of the aryl Grignard reagent, and performing the reaction at room
temperature, all of which encourage the formation of monoaryl copper(I) complexes, “a
4
certain degree of regiocontrol” can be achieved, with SN2’: SN2 selectivity averaging at
about 10:1.14b
Table 1.1.
An alternate explanation for the difference in the regioselectivity of homocuprate
and heterocuprate complexes was proposed by Nakamura,15 who examined the reaction
coordinates of homo- and heterocuprates with allyl acetate using computational analysis.
On the basis of these studies, Nakamura proposed that reaction of dimethyl lithium
cuprate, a homocuprate, with allyl acetate, will result in a nonregioselective reaction, thus
providing a theoretically-derived verification of experimental observations. In contrast,
reaction of the heterocuprate MeCu(Cl)Li with allyl acetate was calculated to favor
formation of the γ-substituted product due to the differences in transition-state energies of
the diastereomeric organocopper (III) complexes formed upon oxidative addition of the
heterocuprate into the allylic substrate. This effect is a consequence of the in-phase
mixing of C=C π* and C-LG σ* (LG = acetate for this study) orbitals to create a new,
5
mixed LUMO, which is more extended on the carbon γ to the leaving group and is lower
in energy than the C=C π* and C-LG σ* orbitals themselves.16 Computational studies
also indicated that, as a result of the electronic differences of the two ligands bound to a
heterocuprate, the Cu 3dxz orbital—the HOMO—is desymmetrized, with the quadrant
trans to the less σ-donating ligand having a larger coefficient and capable of in-phase
mixing with the more extended portion of the LUMO of the allylic electrophile. As a
result of these two effects, heterocuprates prefer to undergo oxidative addition with the
allylic substrate such that the in-phase mixing of the Cu 3dxz orbital component trans to
the weaker σ-donating ligand occurs with the mixed and more pronounced LUMO
component of the allylic electrophile on the γ carbon. Consequently, the regioselectivity
of allylic substitution using a heterocuprate can, at least qualitatively, be predicted by
considering the relative trans effect (σ-donor ability) of the heterocuprate’s two different
ligands.15,17 In this specific case, the stronger σ-donating group, in this case a methyl
substituent, prefers to be trans to the α carbon of the allylic electrophile; whereas the
weaker σ-donating chloride ligand prefers to be trans to the γ carbon. Due to these
stereoelectronic effects, the SN2’ product is released upon reductive elimination.
Scheme 1.2.
6
Even with this experimental and theoretical insight, by 2010 there still existed no
general method for the regioselective substitution of primary allylic electrophiles by aryl
nucleophiles, although a few examples employing special substrates or reaction
conditions were known.
For instance, Hoveyda found that vinylsilane electrophiles
bearing a longer γ(carbon)-silicon bond could participate in allylic arylation by diarylzinc
nucleophiles to give the SN2’ product selectively.5a In addition, Tomioka noted that
cinnamyl bromides, together with some aliphatic allylic bromides, could undergo a
highly SN2’-selective substitution by electron-rich aryl Grignard reagents if they were
added slowly to the reaction mixture at low temperatures.5b,5c Although these are highly
selective transformations, they rely on special substrates and reaction conditions; as such,
their utility is limited.
Another common feature of copper-catalyzed allylic arylation reactions is the use
of highly reactive organometallic reagents as nucleophilic carbon sources. Such reagents
are known to promote the formation of diaryl cuprates, which are directly responsible for
a nonregioselective substitution reaction (Scheme 3, eq. 1).14b We reasoned that the
formation of diaryl cuprates could be prevented if less reactive arylboronic esters were
used as nucleophiles (Scheme 3, eq 2).
This approach is particularly appealing
considering the availability, stability, and excellent functional group compatibility of
arylboronic esters.18 Furthermore, when we started the project there were no examples of
organoboron compounds being used in copper-catalyzed allylic alkylation or arylation
reactions.
7
Scheme 1.3.
Section 2. Results
In preliminary screening experiments, we discovered that the SN2′-selective
addition of 1.2 to 1-chloro-2-hexene (1.1) can be achieved using copper(I) complexes
1.4—1.7 as catalysts in the presence of a stoichiometric amount of potassium tertbutoxide (KOtBu). The best SN2′ selectivity, as determined by GC analysis of the crude
reaction mixture, was obtained with 1.4, while catalysts 1.5—1.7 provided a higher rate
and lower selectivity. Both the alkoxide and the copper catalyst were necessary for an
efficient reaction. Interestingly, allylic arylation of 1.1 with phenyl Grignard and 1.4 as a
catalyst resulted in exclusive formation of the product of SN2 reaction, in agreement with
previously published results.19
In the process of reaction optimization, we discovered that the highest selectivity
is obtained with readily available 1.8 as a catalyst in 1,4-dioxane (Table 2, entry 5).
Among the alkali tert-butoxides, potassium alkoxide provided the highest yield. With
electron-poor boronic esters, such as 1.3, both sodium and potassium alkoxides could be
successfully used, with slightly better selectivity obtained with sodium alkoxide (Table 1,
entries 9 and 10). Overall, the best results were obtained using reaction conditions
8
described in entry 8 for electron-rich boronic esters and in entry 10 for electron-poor
boronic esters.
Table 1.2
Me
O
Me
Cl
+
1.1
1.0 equiv
Ar
Me
B
Me
O
Me
1.2-1.3
Ar B(pin)
1.25 equiv
Ar
NHC-CuX cat. 1.4-1.8
1.0 equiv MOtBu,
solvent, 45 C, 24 h
Me
1.9 - 1.10
Ar = Aryl
entry
Ar
NHC-CuX
mol%
MOtBu
solvent
SN2':SN2a
yield (%)a
1
1.2
1.4
10
KOtBu
THF
20:1
99
2
1.2
1.5
10
KOtBu
THF
8:1
99
3
1.2
1.6
10
KOtBu
THF
8:1
99
4
1.2
1.7
10
KOtBu
THF
3:1
94
5
1.2
1.8
10
KOtBu
1,4-dioxane
42:1
92
6
1.2
1.8
10
NaOtBu
1,4-dioxane
50:1
30
7
1.2
1.8
10
LiOtBu
1,4-dioxane
35:1
6
8
1.2
1.8
5
KOtBu
1,4-dioxane
48:1
98
9
1.3
1.8
5
KOtBu
1,4-dioxane
18:1
91
10
1.3
1.8
5
NaOtBu
1,4-dioxane
20:1
95
Me
R
N
N
CuX
NHC-CuX
a
R
1.4: R = 2,4,6-Me3C6H2, X = Cl
1.5: R = Me, X = Cl
1.6: R = cyclohexyl, X = Cl
1.7: R = adamantyl, X = Cl
1.8: R = 2,4,6-Me3C6H2, X = OtBu
O
X
O
1.2: X = Me
1.3: X = formyl
Me
B
Me
Me
Determined by GC analysis.
1.2.a. Scope of Aryl Boronic Esters
With the optimized reaction conditions in hand, we explored the reactivity of
various aryl boronic esters. The reaction can be successfully performed in the presence of
a variety of functional groups, including formyl and nitro groups, which are not
compatible with previously described copper-catalyzed allylic substitution reactions (1.10
9
and 1.13—1.14, Table 2). Furthermore, we observed a direct correlation between the
electron-donating ability of the aryl substituents and the regioselectivity of substitution.
Steric properties of the boronic ester, on the other hand, had little effect on the reaction
outcome, as demonstrated by the reaction of the ortho,ortho-disubstituted arylboronic
ester with allylic chloride 1.1 to give product 1.16.
Table 1.3
1.2.b. Scope of Allylic Chlorides
The scope of the allylic arylation was further explored in reactions with a variety
of allylic chlorides. It was discovered that both E- and Z-substituted electrophiles can be
10
used in the reaction with similar success (Table 4, 1.17). Azides (Table 4, 1.20), nitriles
(1.19), chlorides (1.18), and TBS-protected alcohols are all compatible with the reaction
conditions, further demonstrating the exceptional functional group tolerance of the
reaction. Finally, cyclic and aryl-substituted allylic chlorides are also suitable substrates
for allylic arylation (Table 4, 1.21—1.23).
Table 1.4
Ar
R1
Me
O
R
Cl
Ar
+
Me
IMesCuOtBu (5 mol%),
NaOtPent (1.0 equiv);
Me
1,4-dioxane, 45 C, 24 h
B
O
1.0 equiv
Me
1.25 equiv
R1
R
Cl
TBSO
CO2Me
1.17
from E-chloride:
32:1 SN2':SN2, 91% yield
CO2Me
1.18
from Z-chloride:
20:1 SN2':SN2, 90% yield
from Z-chloride:
21:1 SN2':SN2, 94% yield
N3
NC
1.19
21:1 SN2':SN2
92% yield
CO2Me
1.22
17:1 SN2':SN2
90% yield
1.20
33:1 SN2':SN2
90% yield
CO2Me
CO2Me
1.21
30:1 SN2':SN2
64% yield
MeO
OMe
1.23
15:1 SN2':SN2
85% yielda
Reactions were performed on a 0.5 mmol scale. Yields are of isolated product.
tert-butoxide was used.
a
1.0 equiv of potassium
CO2Me
11
1.2.c. Allylic Alkylation and Allylic Alkenylation
In addition to allylic arylation, we discovered that organoboron reagents can also
be used as nucleophiles in copper-catalyzed alkenylation and alkylation of primary allylic
electrophiles. With pentenyl boronic ester (1.24), the alkenylation product (1.25) is
obtained in good yield and excellent selectivity (Scheme 4, eq. 3). Allylic alkylation, on
the other hand, can be accomplished using trialkylboranes formed in situ from an alkene
such as 1.26 and 9-BBN (Scheme 4, eq 4). The hydroboration-allylic alkylation sequence
allows highly efficient and selective one-pot coupling of terminal alkenes and allylic
chlorides to give products such as 1.27.
Scheme 1.4
Section 3. Mechanism
In an attempt to provide a better understanding of the source of the observed SN2′
selectivity, we studied the mechanism of the reaction, with the catalytic cycle presented
in Scheme 5 as a working hypothesis. We were able to isolate the product of
12
transmetallation (1.28) from a stoichiometric reaction of 1.8 and 1.2 (Scheme 5, eq 5) and
provide direct evidence for transmetallation from boron to copper(I) alkoxide.20 The
isolation of 1.28 also allowed us to investigate the potential role of this complex in the
second step of the proposed catalytic cycle.
Scheme 1.5
A stoichiometric reaction of 1.28 and 1.1 resulted in the formation of the expected
product within seconds, in good yield and with selectivity comparable to that obtained in
a catalytic reaction (Scheme 1.5, eq 6). Furthermore, 1.28 is a competent catalyst and can
be used instead of 1.8. Together, these results support the idea that the aryl copper
intermediate is the reactive nucleophile responsible for the selectivity observed in
13
catalytic reactions. Finally, in the last step of the catalytic cycle, copper(I) alkoxide is
regenerated from copper(I) chloride and potassium tert-butoxide in a well-precedented
transformation.21
Scheme 1.6
Two other electron-deficient monoaryl copper(I) complexes, 1.29 and 1.30, were
also prepared in a manner analogous to 1.28 in order to study the influence of electronics
on the regioselectivity of the second step of our proposed catalytic cycle. Interestingly,
the stoichiometric reactions of these complexes with (E)-2-hexenyl chloride 1.1 indicated
that the intrinsic SN2’-selectivity of these systems is diminished, when compared to the
more electron-rich copper complex 1.28, to such an extent that a non-regioselective
reaction results (compare Scheme 6, equations 7 and 9 with Scheme 5, equation 6).
However, when a catalytic amount of either copper-aryl complex 1.29 or 1.30 is
employed, a moderately SN2’-selective arylation of allylic chloride 1.1 is observed
(compare equations 8 and 10 with equations 7 and 9, Scheme 6). The cause of this
interesting dichotomy is unknown and warrants further investigation.
14
In light of the observed high SN2’-selectivity of arylation of a variety of primary
allylic electrophiles, the formation of a diaryl cuprate and its participation as a
nucleophile using the catalytic conditions described in Tables 1.3 and Table 1.4 does not
seem likely. However, we were interested in the possibility that formation of either a
Scheme 1.7
Me
O
1.)
Mes
1.31
N
Cu
Me
Me
Me/H
B
O
Me/H
Me
Me
1,4-dioxane, 45 C, 10 min;
+
N
Mes
1.28 (1.0 equiv)
2.)
Me
Cl
Me
1.1 (2.0 equiv)
Me
Molar Ratio
of Me/H
SN2'
SN2
Me (1.9)
3.3
11.6
1
H (1.32)
1
16.4
1
Me
Me
Cl
1.1 (1.0 equiv)
1.) 1.31 (1.2 equiv), 1,4-dioxane,
45 C, 10 min;
Me
+
2.) 1.28 (0.1 equiv), 10 min
Me
Me
SN2'
SN2
13.3
1
No f ormation of 1.32 (crossover product)
diaryl homocuprate or a diaryl(pinacolato)borate could occur through reaction of an
NHC-ligated copper(I) aryl complex with an aryl boronic ester. To test this possibility,
we performed the crossover experiment shown at the top of Scheme 1.7, in which an
equimolar amount of IMesCu-(4-Me)Ph complex 1.28 was premixed with phenyl
boronic(pinacolato)ester 1.31 before addition of allylic chloride 1.1.
The crossover
products 1.9 and 1.32, corresponding to transfer of the tolyl and phenyl groups,
respectively, were obtained in a 3.3:1 molar ratio with SN2’-selectivity that was
15
attenuated to that observed in a catalytic reaction using either aryl boronic ester alone.
However, in a subsequent experiment, we established that product formation through
oxidative addition of a catalytic amount of IMesCu-(4-Me)Ph 1.28 into electrophile 1.1
and reductive elimination occurs much faster than the process(es) leading to crossover
product formation (bottom of Scheme 1.7); therefore, the formation of either a diaryl
cuprate or diarylborate should not be of significant concern when using the catalytic
conditions described in Tables 1.3 and 1.4.
Section 4. Conclusion
In conclusion, we have developed the first general SN2′-selective allylic arylation
reaction using a copper(I) catalyst and aryl boronic esters as nucleophiles. The reaction
has a broad substrate scope and can be performed in the presence of a variety of
functional groups including formyl, carbomethoxy, nitrilo, azido, chloro, bromo, and
nitro groups.
Each step of our proposed catalytic cycle has been supported with
experimental evidence, including the preparation and isolation of neutral monoaryl
copper(I) complexes formed by transmetallation with aryl boronic esters, as well as the
demonstration of these complexes’ inherent preference for substitution to give either the
SN2’ or SN2 product in stoichiometric reactions with allylic chlorides.
Finally, the
development of this reaction was essential to providing the groundwork for a future
asymmetric variant.22
16
Section 5. Experimental
General:
All reactions were performed under a nitrogen atmosphere, using flame-dried glassware
unless otherwise indicated. Column chromatography was performed on a Biotage Iso1SV flash purification system using silica gel (Agela Technologies Inc., 60Å, 40-60 µm,
230-400 mesh). Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum RX I
spectrometer. IR peak absorbencies are represented as follows: s = strong, m = medium,
w = weak, br = broad. 1H and
13
C NMR spectra were recorded on a Bruker AV-300 or
AV-500 spectrometer. 1H NMR chemical shifts (δ) are reported in parts per million
(ppm) downfield of TMS and are referenced relative to residual CHCl3 (7.26 ppm) or
C6D6 (7.16 ppm).
13
C chemical shifts are reported in parts per million downfield of TMS
and are referenced to the carbon resonance of the solvent (CDCl3: δ 77.2 ppm). Data are
represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet), integration, and coupling constants in Hertz (Hz). Mass spectra
were collected on a JEOL HX-110 Mass spectrometer, a Bruker Esquire 1100 Liquid
Chromatograph – Ion Trap Mass Spectrometer or a Hewlett Packard 5971A Gas
Chromatograph – Mass Spectrometer. Regioselectivity was determined by GC analysis
using a Shimadzu GC-2010 with a flame ionization detector and a SHRXI-5MS column
(15 m, 0.25 mm inner diameter, 0.25 µm film thickness). The following temperature
program was used: 2 min @ 60 °C, 13 °C/min to 160 °C, 30 °C/min to 250 °C, 5.5 min
@ 250 °C. Materials THF, CH2Cl2, Et2O and toluene were degassed and dried on
columns of neutral alumina. 1,4-dioxane was distilled from purple Na/benzophenone
ketyl, and stored over 4Å molecular sieves. Deuterated solvents were purchased from
17
Cambridge Isotope Laboratories, Inc. 1,4-Dioxane-d and THF-d were distilled from
8
8
purple Na/benzophenone ketyl. All other deuterated solvents were degassed and dried
over 4Å molecular sieves. Commercial reagents were purchased from Sigma-Aldrich
Co., VWR international, LLC., or STREM Chemicals, Inc., and were used as received.
1.5.a. Allylic arylation:
General arylation procedure:
In a glove box, a scintillation vial was charged with a stir bar. To the vial was added
boronic ester (1.25 equiv, 0.625 mmol), tert-butoxide (as specified in Tables X and X)
(1.00 equiv, 0.500 mmol), and 1,4-dioxane (2.0 mL).After 10 minutes, IMesCuO-tertbutoxide (0.05 equiv, 0.025 mmol), dissolved in 0.5 mL of 1,4-dioxane, was added, and
the mixture was stirred for another 10 min at ambient temperature. The allylic chloride
was added (1.00 equiv, 0.500 mmol) in one portion and the scintillation vial was heated
to 45 °C for 24 h. The vial was removed from the glove box, diluted with Et2O, filtered
through a plug of silica, concentrated in vacuo, and the crude reaction mixture was
purified by silica gel chromatography.
Me
Me
1-(hex-1-en-3-yl)-4-methylbenzene (1.9)
Compound was isolated as a colorless oil (73.8 mg, 85% yield, 60:1 mixture of isomers)
after purification by silica gel column using hexanes as an eluent. 1H NMR (300 MHz,
18
C6D6) δ 7.11 – 6.92 (m, 4H), 5.93 (ddd, J = 17.6, 10.3, 7.4 Hz, 1H), 5.15 – 4.84 (m, 2H),
3.17 (q, J = 7.4 Hz, 1H), 2.15 (s, 3H), 1.63 (m, 2H), 1.36 – 1.09 (m, 2H), 0.84 (t, J = 7.3
Hz, 3H);
13
C NMR (125 MHz, CDCl3) δ 142.9, 141.8, 135.6, 129.2, 127.6, 113.7, 49.3,
37.8, 21.1, 20.8, 14.1. HRMS calculated for [M]+ 174.1409, found 174.1410. FTIR (neat,
cm-1): 3079 (w), 2927 (m), 1637 (m), 1513 (m), 1111 (w), 814 (m).
O
Me
4-(hex-1-en-3-yl)benzaldehyde (1.10)
Compound was isolated as a light yellow oil (91.7 mg, 97% yield, 20:1 mixture of
isomers) after purification by silica gel column chromatography (5 →15%
EtOAc/hexanes). Major isomer; 1H NMR (300 MHz, C6D6) δ 9.71 (s, 1H), 7.56 (d, J =
8.3 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 5.71 (ddd, J = 17.1, 10.3, 7.6 Hz, 1H), 5.02 – 4.73
(m, 2H), 3.03 (m, 1H), 1.51 – 1.39 (m, 2H), 1.18 – 0.99 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H);
13
C NMR (125 MHz, CDCl3) δ 192.4, 152.4, 141.6, 135, 130.4, 128.7, 115.3, 50.2, 37.8,
21.0, 14.3. HRMS calculated for [M+H]+ 189.1279, found 189.1281. FTIR (neat, cm-1):
3081 (w), 2930 (m), 2733 (m), 1703 (s), 1576 (m), 1108 (w), 828 (m).
OMe
Me
1-(hex-1-en-3-yl)-4-methoxybenzene (1.11)
19
Compound was isolated as a colorless oil (80.6 mg, 85% yield, 58:1 mixture of isomers)
after purification by silica gel column chromatography (5 →20% EtOAc/hexanes). Major
isomer; 1H NMR (500 MHz, C6D6) δ 7.03 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H),
5.92 (ddd, J = 17.4, 10.3, 7.3 Hz, 1H), 5.01 (m, 2H), 3.34 (s, 3H), 3.15 (m, 1H), 1.65 –
1.58 (m, 2H), 1.39 – 1.12 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 158.1, 143.0, 136.8, 128.6, 113.9, 113.6, 55.3, 48.8, 37.8, 20.7, 14.1. HRMS calculated
for [M+H]+191.1434, found 191.1437. FTIR (thin film, cm-1): 3077 (w), 2872 (m), 1636
(m), 1512 (s), 1249 (s), 1038 (m), 829 (m).
CF3
Me
1-(hex-1-en-3-yl)-4-(trifluoromethyl)benzene (1.12)
Compound was isolated as a colorless oil (85.5 mg, 75% yield, 24:1 mixture of isomers)
after purification by silica gel column chromatography (0 →15% EtOAc/hexanes). Major
isomer; 1H NMR (500 MHz, C6D6) δ 7.35 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H),
5.80 – 5.55 (m, 1H), 5.03 – 4.73 (m, 1H), 3.11 – 2.86 (m, 1H), 1.55 – 1.34 (m, 1H), 1.24
– 0.96 (m, 1H), 0.79 (t, J = 7.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.9 (d, J = 1.0
Hz), 141.6, 128.6 (q, J = 32.3 Hz), 128.1, 125.5 (q, J = 3.7 Hz), 124.5 (q, J = 271.8 Hz),
114.8 (s), 49.6, 37.6, 20.7, 14.1. HRMS calculated for [M]+228.1128, found 228.1130.
FTIR (thin film, cm-1): 3082 (w), 2931 (m), 1327 (s), 1126 (m), 1609 (m), 917 (m), 839
(m).
20
1-(hex-1-en-3-yl)-4-nitrobenzene (1.13)
Compound was isolated as a light yellow oil (94.3 mg, 92% yield, 13:1 mixture of
isomers) after purification by silica gel column chromatography (5 →20%
EtOAc/hexanes). Major isomer; 1H NMR (500 MHz, C6D6) δ 7.84 (d, J = 8.7 Hz, 2H),
6.67 (d, J = 8.7 Hz, 2H), 5.59 (ddd, J = 17.6, 10.2, 7.6 Hz, 1H), 4.87 (m, 2H), 2.92 (m,
1H), 1.43 – 1.27 (m, 2H), 1.13 – 0.93 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 152.5, 140.7, 128.4, 123.7, 115.4, 49.5, 37.4, 20.5, 13.9. HRMS
calculated for [M+H]+ 206.1179, found 206.1183. FTIR (thin film, cm-1): 3080 (w), 2932
(m), 1637 (m), 1519 (s), 1346 (s), 1110 (m), 919 (m), 853 (m).
1-(hex-1-en-3-yl)-3-nitrobenzene (1.14)
Compound was isolated as a light yellow oil (67.7 mg, 66% yield, 10:1 mixture of
isomers) after purification by silica gel column chromatography (10 →20%
EtOAc/hexanes). Major isomer; 1H NMR (500 MHz, C6D6) δ 7.95 (s, 1H), 7.79 – 7.66 (d,
1H), 6.95 (d, J = 7.6 Hz, 1H), 6.78 (t, J = 7.9 Hz, 1H), 5.67 – 5.48 (m, 1H), 4.87 (m, 2H),
2.95 (m, 1H), 1.36 (m, 2H), 1.17 – 0.90 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (125
MHz, C6D6) δ 148.9, 146.7, 141.1, 133.6, 129.2, 122.6, 121.4, 115.1, 49.4, 37.5, 20.7,
21
14.0. HRMS calculated for [M+H] 206.1179, found 206.1186. FTIR (thin film, cm-1):
+
3080 (w), 2931 (m), 1638 (m), 1530 (s), 1350 (s), 923 (m), 806 (m).
1-bromo-4-(hex-1-en-3-yl)benzene (1.15)
Compound was isolated as a colorless oil (92.4 mg, 78% yield, 32:1 mixture of isomers)
after purification by silica gel column chromatography using hexanes as an eluent. Major
isomer; 1H NMR (300 MHz, CDCl3) δ 7.25 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.3 Hz, 2H),
5.81 – 5.59 (m, 1H), 4.97 – 4.82 (m, 2H), 2.95 (m, 1H), 1.55 – 1.32 (m, 2H), 1.21 – 0.91
(m, 2H), 0.78 (t, J = 7.3 Hz, 3H);
13
C NMR (75 MHz, CDCl3) δ 143.7, 142.1, 131.8,
129.7, 120.2, 114.2, 49.3, 37.7, 20.8, 14.1. HRMS calculated for [M]+ 238.0357, found
238.0362. FTIR (thin film, cm-1): 3079 (w), 2929 (m), 1637 (m), 1488 (m), 1106 (w),
1011 (m), 824 (m).
2-(hex-1-en-3-yl)-1,3-dimethylbenzene (1.16)
Compound was isolated as a colorless oil (79.9 mg, 85% yield, 24:1 mixture of isomers)
after purification by silica gel column chromatography (0 →20% benzene/hexanes). 1H
NMR (500 MHz, C6D6) δ 7.02 - 6.92 (m, 3H), 6.01 (ddd, J = 17.3, 10.4, 5.0 Hz, 1H),
4.95 (m, 2H), 3.82 – 3.71 (m, 1H), 2.23 (s, 6H), 1.78 – 1.64 (m, 2H), 1.30 – 1.01 (m, 2H),
0.80 (t, J = 7.3 Hz, 3H);
13
22
C NMR (125 MHz, CDCl3) δ 141.0, 140.6, 136.8, 126.0,
113.8, 44.0, 35.3, 21.7, 21.5, 14.4. HRMS calculated for [M]+ 188.1567, found 188.1566.
FTIR (thin film, cm-1): 3075(w), 2931 (m), 1633 (m), 910 (m), 768 (m).
Methyl 4-(5-((tert-butyldimethylsilyl)oxy)pent-1-en-3-yl)benzoate (1.17)
Compound was isolated as a colorless oil (157.5 mg, 94% yield, 32:1 mixture of isomers,
from Z alkene) (152.1 mg, 91%, 21:1 mixture of isomers, from E alkene) after
purification by silica gel column chromatography (0 →10% EtOAc in hexanes). Major
isomer; 1H NMR (500 MHz, C6D6) δ 8.13 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H),
5.77 (ddd, J = 17.5, 10.2, 7.5 Hz, 1H), 5.01 – 4.91 (m, 2H), 3.58 – 3.43 (m, 5H), 3.39 (dt,
J = 10.0, 6.4 Hz, 1H), 1.80 (m, 2H), 0.96 (s, 9H), -0.01 (d, J = 5.4 Hz, 6H);
13
C NMR
(125 MHz, CDCl3) δ 167.2, 149.6, 141.2, 129.9, 128.3, 127.9, 115.0, 60.5, 52.1, 45.8,
38.0, 26.0, 18.4, -5.3. HRMS calculated for [M+H]+ 335.2041, found 335.2029. FTIR
(neat, cm-1): 3081 (w), 3000 (w), 2953 (s),1725 (s), 1610 (m), 1278 (s), 1104 (s), 834 (s)
755 (m).
Methyl 4-(6-chlorohex-1-en-3-yl)benzoate (1.18)
23
Compound was isolated as a colorless oil (106.1 mg, 90% yield, 20:1 mixture of isomers)
after purification by silica gel column chromatography (30 →80% benzene in hexanes).
Major isomer; 1H NMR (300 MHz, C6D6) δ 8.11 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.2 Hz,
2H), 5.64 (ddd, J = 17.1, 10.3, 7.6 Hz, 1H), 5.00 – 4.74 (m, 2H), 3.53 (s, 3H) 3.03 (t, J =
6.4 Hz, 2H), 2.91 (q, J = 7.4 Hz, 1H), 1.62 – 1.17 (m, 4H); 13C NMR (125 MHz, CDCl3)
δ 167.0, 149.3, 140.9, 130.0, 128.5, 127.7, 115.3, 52.1, 49.3, 44.9, 32.4, 30.6. HRMS
calculated for [M+H]+ 253.0996, found 253.1002. FTIR (neat, cm-1):3082 (w), 3000 (w),
2953 (m),1722 (s), 1609 (m), 1436 (m), 1280 (s), 912 (s), 733 (s).
Methyl 4-(7-cyanohept-1-en-3-yl)benzoate (1.19)
Compound was isolated as a colorless oil (118.4 mg, 92% yield, 21:1 mixture of isomers)
after purification by silica gel column chromatography (10 →40% EtOAc in hexanes).
Major isomer; 1H NMR (300 MHz, C6D6) δ 8.16 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.3 Hz,
2H), 5.81 – 5.54 (m, 1H), 4.98 – 4.80 (m, 2H), 3.52 (s, 3H), 2.76 – 2.98 (m, 1H), 1.38 –
1.09 (m, 4H), 1.06 – 0.69 (m, 4H);
13
C NMR (125 MHz, CDCl3) δ 167.0, 149.4, 140.9,
130.0, 128.4, 127.6, 119.6, 115.2, 52.1, 49.7, 34.4, 26.7, 25.3, 17.1. HRMS calculated for
[M+H]+ 244.1338, found 244.1333. FTIR (neat, cm-1):3075 (w), 3000 (w), 2947 (m),
2241 (m), 1721(s), 1609 (m), 1435 (m), 1281 (s), 919 (m).
24
Methyl 4-(7-azidohept-1-en-3-yl)benzoate (1.20)
Compound was isolated as a light yellow oil (123.6 mg, 90% yield, 33:1 mixture of
isomers) after purification by silica gel column chromatography (30 →80% benzene in
hexanes). Major isomer; 1H NMR (300 MHz, C6D6) δ 8.16 (d, J = 8.3 Hz, 2H), 6.97 (d, J
= 8.2 Hz, 2H), 5.83 – 5.55 (m, 1H), 5.00 – 4.82 (m, 2H), 3.52 (s, 3H), 2.95 (m, 1H), 2.59
(t, J = 6.8 Hz, 2H), 1.34 (m, 2H), 1.23 – 0.78 (m, 4H);
13
C NMR (125 MHz, CDCl3) δ
167.1, 149.6, 141.2, 130.0, 128.4, 127.7, 115.1, 52.1, 51.3, 49.9, 34.9, 28.8, 24.7. HRMS
calculated for [M+H]+274.1553, found 274.1557. FTIR (neat, cm-1):3079 (w), 2940 (m),
2095 (s), 1721 (s), 1609 (m), 1435 (m), 1279 (s).
Methyl 4-(2-methylenecyclopentyl)benzoate (1.21)
Compound was isolated as a white solid (69.1 mg, 64% yield, 30:1 mixture of isomers)
after purification by silica gel column chromatography (0 →10% EtOAc in benzene). mp
38 °C. Major isomer; 1H NMR (300 MHz, C6D6) δ 8.15 (d, J = 8.4 Hz, 2H), 7.06 (d, J =
8.3 Hz, 2H), 4.97 (d, J = 2.0 Hz, 1H), 4.60 (d, J = 2.0 Hz, 1H), 3.52 (s, 3H), 3.32 (t, J =
7.4 Hz, 1H), 2.47 – 2.15 (m, 2H), 1.95 – 1.77 (m, 1H), 1.65 – 1.26 (m, 3H);
13
C NMR
(125 MHz, CDCl3) δ 167.3, 156.0, 150.8, 129.8, 128.4, 128.1, 107.8, 52.1, 51.3, 36.6,
25
33.6, 24.9. HRMS calculated for [M+H] 217.1227, found 217.1236. FTIR (thin film,
+
cm-1): 3054 (w), 2987 (m), 1717 (s), 1610 (m), 1422 (m), 1265 (s), 896 (s).
Methyl 4-(1-phenylallyl)benzoate (1.22)
Compound was isolated as a clear liquid (114.2 mg, 90% yield, 17:1 mixture of isomers)
after purification by silica gel column chromatography (0 →20% benzene in
hexanes).Major isomer; 1H NMR (300 MHz, C6D6) δ 8.18 (d, J = 8.3 Hz, 2H), 7.35 –
6.95 (m, 7H), 6.18 (ddd, J = 17.2, 10.2, 7.2 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.97 (d, J
= 17.2 Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 3.61 (s, 3H);
13
C NMR (75 MHz, CDCl3) δ
167.06, 148.71, 142.54, 139.89, 129.82, 128.72, 128.62, 128.39, 126.71, 117.06, 54.98,
52.07. HRMS calculated for [M+H]+ 253.1229, found 253.1232. FTIR (thin film, cm-1):
3061 (w), 3028 (w), 2952 (m), 1723 (s), 1610 (m), 1436 (m), 1281 (s), 1112.8 (s), 701.7
(m).
4,4`-(prop-2-ene-1,1-diyl)bis(methoxybenzene) (1.23)
Compound was isolated as a clear liquid (108.3 mg, 85% yield, 15:1mixture of isomers)
after purification by silica gel column chromatography (0 →20% benzene in hexanes).
Major isomer; 1H NMR (300 MHz, CDCl3) δ 7.13 – 6.99 (m, 4H), 6.85 – 6.71 (m, 4H),
26
6.24 (ddd, J = 17.1, 10.1, 7.0 Hz, 1H), 5.13 (d, J = 10.1 Hz, 1H), 4.97 (d, J = 17.1 Hz,
1H), 4.58 (d, J = 7.0 Hz, 1H), 3.39 – 3.21 (s, 6H);
13
C NMR (75 MHz, C6D6) δ 158.79,
141.93, 136.09, 129.97, 115.70, 114.20, 54.81, 53.83. HRMS calculated for [M+H]+
254.1306, found 254.1308. FTIR (thin film, cm-1): 3054 (m), 3005 (m), 2958 (m), 1636
(m), 1035 (s), 739 (s).
1.5.b. Allylic alkenylation:
(E)-tert-butyldimethyl((4-vinylnon-5-en-1-yl)oxy)silane (1.25)
In a glove box, a scintillation vial was charged with a stir bar. To the vial was added (E)4,4,5,5-tetramethyl-2-(pent-1-en-1-yl)-1,3,2-dioxaborolane (1.25 equiv, 139 µL 0.625
mmol), sodium-tert-pentoxide (1.00 equiv, 55.0 mg, 0.500 mmol), and 1,4-dioxane (2.0
mL). The resulting solution was allowed to stir at 45 °C for 10 minutes. After 10 minutes,
IMesCuO-t-Bu (0.05 equiv, 11.0 mg, 0.025 mmol) in 0.5 mL 1,4-dioxane was added and
the mixture stirred for another 10 min at ambient temperature. (E)-tert-butyl((5chloropent-3-en-1-yl)oxy)dimethylsilane was added (1.00 equiv,118 mg, 0.500 mmol) in
one portion and the scintillation vial was heated to45 °C for 24 h. The vial was removed
from the glove box, and the reaction mixture was diluted with Et2O, filtered through a
plug of silica, concentrated in vacuo and purified by silica gel chromatography.
Compound was isolated as a colorless oil (116.2 mg, 86% yield) after purification by
silica gel column chromatography (0 →10% benzene/hexanes). 1H NMR (300 MHz,
C6D6) δ 5.85 (ddd, J = 17.3, 10.2, 7.2 Hz, 1H), 5.68 – 5.33 (m, 2H), 5.27 – 4.93 (m, 2H),
27
3.72 (t, J = 6.4 Hz, 2H), 3.22 – 2.91 (m, 1H),2.10 – 1.97 (m, 2H), 1.90 – 1.62 (m, 2H),
1.51 – 1.35 (m, 2H), 1.09 (s, 9H), 0.96 (t, J = 7.3 Hz, 3H), 0.17 (s, 6H); 13C NMR (125
MHz, C6D6) δ 142.2, 133.1, 130.9, 114.0, 61.1, 43.5, 38.2,35.2, 26.3, 23.1, 18.6, 13.9, 5.0. HRMS calculated for [M+H]+ 269.2295, found 269.2298. FTIR (neat, cm-1): 3080
(w), 2859 (m), 1637 (m), 1102 (m), 969 (m).
1.5.c. Allylic alkylation:
(5-vinyloctyl)benzene (1.27)
In a glove box, a scintillation vialwas charged with a stir bar. To the vial was added but3-en-1-ylbenzene (1.25 equiv, 83.0 mg, 0.625 mmol), 9-Borabicyclo[3.3.1]nonane dimer
(0.63 equiv, 152 mg, 0.313 mmol), and 1,4-dioxane (0.5 mL). The resulting solution was
stirred at 60 °C for 4 h. After 4 h, the solution was transferred to a scintillation vial
containing IMesCuOt-Bu (0.05 equiv, 11.0 mg, 0.025 mmol), sodium-tert-pentoxide
(1.00 equiv, 56.0 mg, 0.50 mmol), and 1,4-dioxane (2.0 mL). The resulting solution was
allowed to stir at25 °C for 10 minutes, and then (E)-2-hexenyl-1-chloride (1.00 equiv,
65.9 µL, 0.50 mmol) was added. The resulting solution was allowed to stir at 60 °C for
24 h. The vial was removed from the glove box, the reaction mixture was diluted with
Et2O, filtered through a plug of silica, and concentrated in vacuo. Compound was
isolated as a colorless oil (89.0 mg, 82% yield, 32:1 mixture of isomers) after purification
by silica gel chromatography (0 →20% benzene/hexanes). Major isomer; 1H NMR (300
MHz, CDCl3) δ 7.51 – 7.01 (m, 5H), 5.57 (ddd, J = 16.9, 10.3, 8.9 Hz, 1H), 5.16 – 4.95
28
(m, 2H), 2.61 (t, J = 7.7 Hz, 2H), 2.13 – 1.91 (m, 1H), 1.80 – 1.55 (m, 2H), 1.52 – 1.14
(m, 8H), 0.99 (t, J = 6.8 Hz, 3H);
13
C NMR (75 MHz, CDCl3) δ 143.5, 142.9, 128.4,
128.2, 125.6, 113.9, 43.8, 37.3, 36.1, 34.9, 31.7, 27.0, 20.3, 14.2. HRMS calculated for
[M]+216.1879, found 216.1876. FTIR (neat, cm-1): 3064 (w), 2857 (m), 1639 (m), 956
(m), 745, (m), 698 (s).
1.5.d. Synthesis of aryl boronic esters:
A flame-dried round bottom flask was charged with a stir bar and allowed to cool under
N2. Into the flask was added aryl boronic acid (1.0 equiv) and diol (1.0 equiv). Benzene
was added (0.2 M solution of boronic acid) and the resulting solution was heated at the
reflux for 1 h or until water layer separated. The solution was allowed to cool and
MgSO4 (0.5 equiv) was added. The solution was filtered, and the solvent volume was
reduced by half under reduced pressure. The resulting solution was transferred to a
separatory funnel and anequal volume of pentane was added. The organic layer was
washed three times with H2O, dried over MgSO4and filtered. Removal of the solvent
under reduced pressure afforded the aryl boronic ester.
4,4,5,5-tetramethyl-2-p-tolyl-[1,3,2]dioxaborolane
29
Compound was isolated as a white solid (2.596 g, 85% yield). Spectral data matches the
previously reported values.23 1H NMR (300 MHz, C6D6) δ 8.13 (d, J = 7.9 Hz, 2H), 7.05
(dd, J = 8.1, 0.6 Hz, 2H), 2.06 (s, 3H), 1.13 (s, 12H).
4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzaldehyde
Compound was isolated as a white solid (5.112 g, 86% yield). Spectral data matches the
previously reported values.24 1H NMR (300 MHz, C6D6) δ 9.64 (s, 1H), 8.05 (dd, J = 8.0,
3.0 Hz, 2H), 7.57 (dd, J = 8.2, 3.0 Hz, 2H), 1.08 (s, 12H).
2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane
Compound was isolated as a colorless oil (1.912 g, 82% yield). Spectral data matches the
previously reported values.25 1H NMR (300 MHz, C6D6) δ 8.16 (d, J = 8.3 Hz, 2H), 6.84
(d, J = 8.3 Hz, 2H), 3.22 (s, 3H), 1.15 (s, 12H).
2-(4-bromophenyl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane
Compound was isolated as a white solid (2.733 g, 94% yield). Spectral data matches the
previously reported values.25 1H NMR (300 MHz, C6D6) δ 7.79 (d, J = 8.3 Hz, 2H), 7.31
(d, J = 8.3 Hz, 2H), 1.07 (s, 12H).
30
4,4,5,5-tetramethyl-2-(4-nitrophenyl)-[1,3,2]dioxaborolane
Compound was isolated as a yellow solid (538.8 mg, 72% yield). Spectral data matches
the previously reported values.26 1H NMR (300 MHz, C6D6) δ 7.82 (m, 4H), 1.05 (s,
12H).
1.5.e. Synthesis of allylic chlorides:
(E)-5-((tert-butyldimethylsilyl)oxy)pent-2-en-1-ol,27 (Z)-6-chloro-hex-2-en-1-ol,28 (E)-7chlorohept-2-en-1-ol,29 (E)-8-hydroxyoct-6-enenitrile,30 (E)-1-chlorohex-2-ene,31 (Z)tert-butyl((5-chloropent-3-en-1-yl)oxy)dimethylsilane,32
1-(chloromethyl)cyclopent-1-
ene,31 and (E)-1-(3-chloroprop-1-en-1-yl)-4-methoxybenzene33 were all synthesized
according to literature proce-dures, and 1H NMR data match literature values.
Allylic Alcohols:
(E)-5-((tert-butyldimethylsilyl)oxy)pent-2-en-1-ol
Compound was isolated as a colorless oil (1.570g, 82% yield) together with minor
impurities containing TBS group.
1
H NMR (300 MHz, CDCl3) δ 5.74 – 5.66 (m, 2H),
4.11 – 4.07 (m, 2H), 3.65 (t, J = 7.1 Hz, 2H), 2.31 – 2.24 (m, 2H), 1.34 (t, J = 5.8 Hz,
1H), 0.89 (s, 9H), 0.05 (s, 6H).
31
(Z)-6-chloro-hex-2-en-1-ol
Compound was isolated as a colorless oil (2.000 g, 93% yield). 1H NMR (CDCl3) δ 5.68
(dt,J = 6.6, 9.9 Hz, 1H),5.47 (dt, J = 6.6, 10.7 Hz, 1H), 4.23 (d,J = 6.4 Hz, 2H), 3.56 (t, J
= 7.1 Hz, 2H), 2.88 (s, 1 H), 2.13 – 2.47 (m, 2 H), 1.67 – 2.06 (m,2 H).
(E)-7-chlorohept-2-en-1-ol
Compound was isolated as a colorless oil (4.638 g, 53% yield).
1
H NMR (300 MHz,
CDCl3) δ 5.86 – 5.53 (m, 2H), 4.24 – 3.88 (m, 2H), 3.54 (t, J = 6.6 Hz, 2H), 2.16 – 1.97
(m, 2H), 1.88 – 1.68 (m, 2H), 1.61 – 1.47 (m, 2H), 1.29 (s, 1H).
(E)-8-hydroxyoct-6-enenitrile
Compound was isolated as a colorless liquid (1.351 g, 71% yield). 1H NMR (300 MHz,
CDCl3) δ 5.85 – 5.47 (m, 2H), 4.03 – 4.17 (m, 2H), 2.35 (t, J = 6.9 Hz, 2H), 2.24 – 1.91
(m, 2H), 1.80 – 1.40 (m, 4H), 1.33 (s, 1H).
(E)-7-azidohept-2-en-1-ol
To a solution of 6-chloro-(2E)-heptene-1-ol (1.00 equiv, 1.00 mL, 6.817 mmol) in dry
DMSO (14.0 mL) was added sodium iodide (0.10 equiv, 102.2 mg, 0.682 mmol)
followed by sodium azide (2.00 equiv, 886.3 mg, 13.60 mmol). The reaction mixture was
32
vigorously stirred for 16 h at 45 °C then cooled to room temperature, diluted with Et2O,
and washed with H2O. The combined organic layers were washed with brine, dried over
MgSO4 and concentrated in vacuo. The crude reaction mixture was purified by silica gel
column chromatography (20 →50% EtOAc/hexanes) and 6-azido-(2E)-hexen-1-ol was
obtained as a light yellow oil (903.1 g, 85% yield). 1H NMR (300 MHz, C6D6) δ 5.56 –
5.24 (m, 2H), 3.77 – 3.89 (m, 2H), 2.65 (t, J = 6.4 Hz, 2H), 1.66 – 1.82 (m, 2H), 1.25 –
0.98 (m, 4H), 0.77 (s, 1H).
13
C NMR (126 MHz, CDCl3) δ 132.3, 129.7, 63.7, 51.4, 31.7,
28.4, 26.2. ESI-MS (MeOH, m/z):178.1 [M+Na]+. FTIR (neat, cm-1): 3342 (m br), 2936
(m), 2097 (s), 1089 (m), 971 (m).
Allylic Chlorides:
General:
The allylic chlorides were synthesized according to a modified literature procedure:27
Dimethyl sulfide (2.00 equiv) was added over 10 min to a flame dried flask containing Nchlorosuccinimide (2.00 equiv) in dry CH2Cl2 at 0 °C. The milky white solution was
stirred for 1 h then cooled to -20 °C, and the allylic alcohol (1.00 equiv) in dry CH2Cl2
was added dropwise over 30 min. The reaction mixture was allowed to warm to 0 °C and
after 2 h was allowed to warm to 25 °C. After complete consumption of the alcohol,
solvent was removed in vacuo, and the crude mixture was diluted with pentane and
washed with H2O. The aqueous layer was extracted with pentane and the combined
organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was
removed under reduced pressure. The product was passed through a plug of silica using a
mixture of pentane and ethyl acetate as an eluent to afford the pure allylic chloride.
33
(E)-1-chlorohex-2-ene (1.1)
Compound was isolated as a colorless liquid (1.841 g, 92% yield). 1H NMR (300 MHz,
CDCl3) δ 5.77 (m, 1H), 5.69 – 5.53 (m, 1H), 4.03 (dd, J = 6.9, 0.8 Hz, 2H), 2.04 (m, 2H),
1.51 – 1.31 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).
(E)-tert-butyl((5-chloropent-3-en-1-yl)oxy)dimethylsilane
Compound was isolated as a colorless liquid (1.327 g, 92% yield). 1H NMR (300 MHz,
C6D6) δ 5.55 – 5.34 (m, 2H), 3.62 (d, J = 5.9 Hz, 2H), 3.42 (t, J = 6.5 Hz, 2H), 2.09 –
1.97 (m, 2H), 0.96 (s, 9H), 0.02 (s, 6H).
13
C NMR (126 MHz, CDCl3) δ 132.6, 127.9,
62.5, 45.4, 35.8, 26.1, 18.5, -5.1. ESI-MS (MeOH, m/z): 257.1 [M+Na]+. FTIR (neat,
cm-1): 3038 (w), 2956 (s), 1668 (w), 1472 (m) 1256 (m), 1104 (s), 837 (s).
(Z)-tert-butyl((6-chlorohex-4-en-1-yl)oxy)dimethylsilane
Compound was isolated as a colorless liquid (1.458 g, 89% yield). 1H NMR (300 MHz,
C6D6) δ 5.58 – 5.32 (m, 2H), 3.62 (d, J = 5.9 Hz, 2H), 3.42 (t, J = 6.5 Hz, 2H), 2.12 –
1.97 (m, 2H), 0.96 (s, 9H), 0.02 (s, 6H).
34
(Z)-1,6-dichlorohex-2-ene
Compound was isolated as a colorless liquid (1.635 g, 73% yield) after filtration through
a plug of silica using pentane as an eluent.
1
H NMR (300 MHz, C6D6) δ 5.41 (dtt, J =
10.6, 7.8, 1.5 Hz, 1H), 5.05 (dt, J = 10.6, 7.7 Hz, 1H), 3.67 (d, J = 7.8 Hz, 2H), 2.96 (t, J
= 6.5 Hz, 2H), 1.82 – 1.67 (m, 2H), 1.35 – 1.23 (m, 2H). 13C NMR (126 MHz, CDCl3) δ
133.2, 127.0, 44.3, 39.3, 31.9, 24.3. (GC-MS, EI, m/z): 152 [M]+. FTIR (neat, cm-1):
3027 (m), 2959 (s), 1653(m), 1251 (s), 756 (s), 650 (s).
(E)-8-chlorooct-6-enitrile
Compound was isolated as a colorless liquid (927.8 mg, 78% yield) after filtration
through a plug of silica using 20% EtOAc in hexane as an eluent. 1H NMR (300 MHz,
C6D6) δ 5.47 – 4.95 (m, 2H), 3.61 (d, J = 6.5 Hz, 2H), 1.53 – 1.41 (m, 2H), 1.33 (t, J =
6.8 Hz, 2H), 1.00 – 0.73 (m, 4H).
13
C NMR (126 MHz, CDCl3) δ 134.6, 127.0, 119.6,
45.2, 31.1, 27.7, 24.7, 17.0. HRMS calculated for [M+Na]+180.0550, found 180.0546.
FTIR (neat, cm-1): 3036 (m), 2939 (s), 2247 (m), 1666 (m), 1251 (m), 969 (s), 674 (m).
(E)-7-azido-1-chlorohept-2-ene
Compound was isolated as a light yellow liquid (639.7 mg, 93% yield) after filtration
through a plug of silica using 10% EtOAc in hexane as an eluent. 1H NMR (300 MHz,
C6D6) δ 5.44 – 5.12 (m, 2H), 3.61 (d, J = 5.8 Hz, 2H), 2.60 (t, J = 6.6 Hz, 2H), 1.63 –
1.53 (m, 2H), 1.17 – 0.87 (m, 4H).
13
35
C NMR (126 MHz, CDCl3) δ 135.2, 126.7, 51.4,
45.4, 31.6, 28.4, 26.0. HRMS calculated for [M]+ 172.0636, found 172.0673. FTIR (neat,
cm-1): 3035 (w), 2939 (m), 2097 (s), 1666 (w), 1251 (m), 968 (m), 676 (m).
1-(chloromethyl)cyclopent-1-ene
Compound was isolated as a colorless oil (816.2 mg, 86% yield).
1
H NMR (300 MHz,
CDCl3) δ 5.69 – 5.78 (m, 1H), 4.15 (d, J = 0.8 Hz, 2H), 2.49 – 2.29 (m, 4H), 2.04 – 1.85
(m, 2H).
(E)-1-(3-chloroprop-1-en-1-yl)-4-methoxybenzene
Compound was isolated as a colorless oil (1.053g, 95% yield).
1
H NMR (300 MHz,
CDCl3) δ 7.15 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 6.33 (d, J = 15.6 Hz, 1H),
6.11 – 5.86 (m, 1H), 3.89 (d, J = 7.2 Hz, 2H), 3.38 (s, 3H).
1.5.f. Synthesis of (IMes)Cu(4-methylbenzene) complex (Equation 5):
(IMes)Cu(4-methylbenzene)
(4-methylbenzene)[1,3-dihydro-1,3-bis(2,4,6-trimethylphenyl)-2H-imidazol-2ylidene]-Copper (1.28)
36
A 100 mL Schlenk flask was charged with a stir bar and flame-dried under vacuum. The
flask was then transferred into a glove box and was charged with IMesCuO-tert-butoxide
(1.1 equiv, 1.00 g, 2.27 mmol) and tolyl boronic(pinacolato) ester (1.0 equiv, 0.45 g, 2.06
mmol). Toluene was added (50 mL, 0.05 M). The resulting solution was heated to 60 °C
for 16 h and then filtered over a pad of Celite. The solvent was then removed in vacuo
until cloudy. An equal volume of pentane was added, and the flask was placed into the
-20 °C freezer. After 24 h, the filtrate was removed by pipette and the crystals isolated by
vacuum filtration. The crystals were then washed with pentane and transferred into a
scintillation vial charged with a stir bar. Isooctane was added and the solution was
vigorously stirred at room temperature for 0.5 h. The isooctane was then removed in
vacuo. This process was repeated twice to yield the desired product as a white solid
(575.5 mg, 61% yield). 1H NMR (500 MHz, 1,4-dioxane-d8) δ 7.22 (s, 2H), 7.07 (s, 4H),
6.80 (d, J = 7.4 Hz, 2H), 6.54 (d, J = 7.3 Hz, 2H), 2.35 (s, 6H), 2.17 (s, 12H), 2.04 (s,
3H);
13
C NMR (75 MHz, THF-d8) δ 184.5, 162.5, 140.8, 139.7, 137.2, 135.8, 131.9,
130.1, 126.8, 123.2, 21.8, 21.4, 18.4. The same compound was independently prepared
by addition of 4-MePhMgBr to IMesCuCl. Attempts to obtain HRMS were not
successful.
1.5.g. Stoichiometric Reaction of (IMes)Cu(4-methylbenzene) with (E)-2-hexenyl-1chloride (Equation 6)
In a glove box, a 1 dram vial was charged with a stir bar. To the vial was added (E)-2hexenyl-1-chloride (1.00 equiv, 6.6 µL, 0.05 mmol) and internal standard 1,3,5trimethoxybenzene (TMB) in 1,4-dioxane (0.25 mL). Separately, a solution of
37
(IMes)Cu(4-methylbenzene) (1.00 equiv, 23.0 mg, 0.05 mmol) in 1,4-dioxane (0.25 mL)
was prepared. The solution of (IMes)Cu(4-methylbenzene)was added to a 1 dram vial
containing (E)-2-hexenyl chloride and the resulting solution was stirred at 45 °C. After 5
minutes, an aliquot of the reaction analyzed by GC indicated complete conversion of (E)2-hexenyl chloride. The arylation product was obtained in 79% yield (determined by GC
analysis) as a mixture of isomers.
1.5.h. Catalyst synthesis:
Mes
N
Cu Ot Bu
N
Mes
Mes = 2,4,6-trimethylphenyl
IMesCuO-tert-butoxide (1.8)
(t-butoxy)[1,3-dihydro-1,3-bis(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene]Copper
A 200 mL Schlenk flask was charged with a stir bar and flame-dried under vacuum. The
flask was then transferred into a glove box and was charged with1,3-bis-(2,4,6trimethylphenyl)-imidazolium chloride (IMes-chloride salt) (1.00 equiv, 3.41 g, 10.0
mmol), copper-tert-butoxide tetramer (CuO-tert-Bu)4(0.25 equiv, 1.37 g, 2.50 mmol),
and sodium tert-butoxide (NaO- tert -Bu) (1.00 equiv, 0.96 g, 10.0 mmol). With vigorous
stirring, THF was added in one portion (0.1 M, 100.0 mL). The resulting pale-orange
solution was allowed to stir at room temperature for 4 h. The flask was taken out of the
glovebox and the solvent was removed in vacuo. The flask was transferred to the glove
38
box and the solid scraped and suspended in toluene. The resulting solution was filtered
over a pad of Celite, and the pad was washed with two portions of toluene. The solvent
was removed in vacuo to yield the product as a pale yellow solid (4.08 g, 92% yield). 1H
NMR (300 MHz, C6D6) δ 6.71 (s, 4H), 5.97 (s, 2H), 2.11 (s, 6H), 1.95 (s, 12H), 1.38 (s,
9H); 13C NMR (125 MHz, THF-d8) δ 182.3, 139.7, 137.3, 135.9, 130.0, 123.2, 36.8, 21.3,
18.2.
39
Section 6. References to Chapter 1
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Magid, R. M. Tetrahedron 1980, 36, 1901.
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Consiglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 1.
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Tetrahedron Lett. 1985, 26, 3259; (k) Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.;
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Chem. Soc. 2009, 131; (o) Lautens, M.; Dockendorff, M. C.; Fagnou, K.; Malicki, M.
Org. Lett. 2002, 4, 1311.
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Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
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Rona, P.; Tokes, L.; Tremble, J.; Crabbe, P. Chem. Commun. 1969, 43.
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Tseng, C. C.; Paisley, S. D.; Goering, H. L. J. Org. Chem. 1986, 51, 2884.
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Koten, G. v. Tetrahedron Lett. 1995, 36, 3059.
(11) (a) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev.
2008, 108, 2796; (b) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765; (c)
Geurts, K.; Fletcher, S. P.; van Zijl, A. W.; Minnaard, A. J.; Feringa, B. L. Pure Appl.
Chem. 2008, 80, 1025.
(12) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown, M. K.; Hoveyda, A. H. J. Am.
Chem. Soc. 2008, 130, 446.
(13) (a) Arai, M.; Lipshutz, B. H.; Nakamura, E. Tetrahedron 1992, 48, 5709; (b)
Lipshutz, B. H.; Elsworth, E. L.; Siahaan, T. J. J. Am. Chem. Soc. 1989, 111, 1351.
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Bäckvall, J.-E.; Persson, E. S. M.; Bombrun, A. J. Org. Chem. 1994, 59, 4126; (c)
Bäckvall, J.-E.; Séllen, M. J. Chem. Soc., Chem. Commun. 1987, 827.
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40
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41
Chapter 2 – Copper-Catalyzed Electrophilic Amination of Alkyl
Boranes: Formal anti-Markovnikov Hydroamination of
Terminal Alkenes1
Section 1. Introduction and Context
The synthesis of alkyl amines is one of the most important and common tasks
encountered in the preparation of biologically active molecules.2 A recent analysis of
reactions used in pharmaceutical industry suggests that this task is almost exclusively
accomplished by either reductive amination of carbonyl compounds, or by substitution of
alkyl halides or sulfonates.3 The synthesis of alkyl amines from most other precursors
usually requires functional group interconversion, followed by amination using one of the
two standard methods. As a result, the development of new reactions for direct amination
of other functional groups has attracted a lot of attention as a way to facilitate the
synthesis of alkyl amines.4
Alkenes are particularly attractive as synthetic precursors.
They are readily
available and have orthogonal reactivity to that of polar functional groups found in
biologically active molecules. The most direct approach to obtain alkyl amines from
alkenes is by addition of an amine across an alkene double bond.5 This transformation
has been the focus of numerous studies ever since initial reports of metal-catalyzed
hydroamination under mild conditions appeared more than two decades ago.6 Today,
intramolecular hydroamination can be accomplished with a broad substrate scope and
with a number of different catalysts.7,8 Intermolecular hydroamination is significantly
42
less developed, with most successful examples being focused on the formation of the
Markovnikov hydroamination product.6a,9,10 The formation of the other regioisomer, the
anti-Markovnikov product, still represents a major synthetic challenge.11
For
many
transition
metal-catalyzed
hydroamination
reactions,
regiodetermining step is alkene insertion into a metal-amido bond.5a
the
In a recent
computational study of a rhodium-catalyzed propene hydroamination, Hartwig and
coworkers found that alkene (1,2)-insertion to give the Markovnikov product was both
kinetically and thermodynamically preferred over (2,1)-insertion.12
underlines
the
difficulties
in
developing
metal-catalyzed
This finding
anti-Markovnikov
hydroamination of alkenes.
Despite these challenges, there are several examples of the anti-Markovnikov
hydroamination of alkenes.
In a seminal contribution, Tobin Marks described the
lanthanide-catalyzed intermolecular hydroamination of vinylarenes and vinylsilanes with
alkyl amines to give linear (anti-Markovnikov) products (Scheme 1).13 The origin of
regioselectivity is attributed to directing effects of the aryl group during alkene insertion
into the metal-amido bond.7c,14 For simple alkenes, however, Markovnikov selectivity
(1,2-insertion) is observed.
Scheme 2.1
15
Following observations by Beller and coworkers,
43
Hartwig developed a
rhodium-catalyzed anti-Markovnikov hydroamination of para-substituted vinylarenes
with secondary amines.16 Using a ruthenium catalyst, the same group was able to extend
the scope to other vinylarenes and cyclic and acyclic secondary amines (Scheme 2).17
Detailed mechanistic studies revealed that the ruthenium catalyst activates the arene
towards nucleophilic attack through η6-κ1-coordination.18
Therefore, the selective
formation of linear (anti-Markovnikov) amine products in this case is mechanistically
related to well-documented Michael-type additions of nucleophiles to activated alkenes.19
An alternative approach to Michael-type additions involves activation of amine
nucleophiles.
For instance, Gunnoe and coworkers developed the copper-catalyzed
addition of anilines to electron-deficient vinylarenes, in which the nucleophilicity of the
amine is increased through formation of a metal-amide complex.20
Scheme 2.2
Notwithstanding these contributions, it is apparent that transition-metal catalyzed
alkene hydroamination to give anti-Markovnikov amines remains underdeveloped. In
each of the above cases, anti-Markovnikov selectivity is observed only with activated
alkenes, such as styrene or trimethylsilyl-substituted alkenes, or with uncommon
instances of catalyst coordination and substrate or amine activation. These limitations,
together with the requirement that an excess of alkene must be used in these
44
transformations, limits their utility. Furthermore, none of the existing procedures for
transition metal-catalyzed, anti-Markovnikov hydroamination allows the preparation of
acyclic, tertiary alkyl amines from alkenes.
Scheme 2.3
In view of the difficulties inherent to direct hydroamination of unactivated
alkenes, other methods have been developed for the transformation of alkenes into
amines.
Stüder and coworkers developed a radical-transfer approach for the
transformation of a variety of alkenes into primary and secondary Boc-protected amines
(Scheme 2.4).21 The regiochemistry of this process is determined by the relative stability
of the isomeric alkyl radical intermediates formed in radical addition to the alkene. The
group of Beauchemin has developed an intermolecular hydroamination of styrene
derivatives and strained alkenes with unsubstituted and N-alkyl hydroxylamine (Scheme
3).22 In this reaction, moderate to high anti-Markovnikov selectivity was observed with
electron-poor alkenes.
45
Scheme 2.4
Traditionally, the anti-Markovnikov hydrofunctionalization of alkenes is achieved
by hydroboration and functionalization of the resulting alkyl borane. The classic example
is the hydroboration/oxidation sequence, developed by H.C. Brown. This transformation
is a robust, highly efficient, and practical method for the conversion of a variety of
alkenes to alcohols with excellent regioselectivity.23
Although less developed, the
analogous hydroboration/amination sequence is still the most reliable and regioselective
route to anti-Markovnikov hydroamination products.
In this reaction, a variety of
primary and secondary, but not tertiary, amines can be prepared. Specifically, primary
amines can be generated by the use of chloramine, hydroxylamine-O-sulfonic acid, or
ammonium hydroxide.24 Unlike alkene hydration, alkene amination to give primary
amines is inefficient. Most conditions allow amination of at most two alkyl groups of a
trialkyl borane, limiting the yield based on the alkene to 67% (top of Scheme 4).24b
Similar problems in organoboron chemistry are usually solved by using bulky, nonmigrating groups on the borane, e.g., dicyclohexyl borane or 9-borabicyclo[3.3.1]nonane
(9-BBN).
In hydroboration/amination, however, this approach is ineffective as the
46
migration of secondary alkyl groups is faster than the migration of primary alkyl
groups (bottom of Scheme 4).24b,25 Methyl groups, on the other hand, have no significant
migratory aptitude, and dimethylborane has been used to accomplish an efficient
conversion of alkenes to primary amines.24b Unfortunately, the complex synthesis of this
reagent has precluded its wider use in synthetic chemistry.26
Scheme 2.5
Secondary amines can be prepared by hydroboration followed by amination using
primary organoazides;
27
this is usually accomplished in the presence of excess Lewis
acid (BF3 or SiCl4).28 Good yields of secondary amine products can be obtained using
dichloroborane as the alkene hydroborating reagent.25b,29 D.S. Matteson and coworkers
have developed a related approach in which enantioenriched alkyl boronic esters are first
converted into potassium trifluoroalkylborates en route to secondary amines by the action
of potassium hydrogenfluoride and tetrachlorosilane.30
Overall, even though the hydroboration/amination sequence does provide
excellent regioselectivity, it is rarely used in organic synthesis. Not only is the use of
organoazides impractical, but many synthetic procedures are incompatible with strong
Lewis acids used in the synthesis of secondary amines. Furthermore, the scope of
47
hydroboration/amination is limited to the synthesis of primary and secondary amines.
However, the greatest obstacle to the development of a practical hydroboration/amination
sequence that remained was the inefficient amination of alkyl boranes.
We were intrigued by the possibility that transition metal catalysis could be used
to facilitate the amination of alkyl boranes and allow the development of an efficient
hydroboration/amination sequence.31
because
we
had
already
This approach was especially appealing to us
demonstrated
the
utility
of
organoboron—copper
transmetallation to affect the highly SN2’-selective substitution of allylic chlorides by
alkyl boranes,32 in addition to other recent reports.33 The key steps in these reactions are
transmetallation from boron to copper followed by reaction of the organocopper
intermediate with an electrophile.34 By following the same strategy, our approach to
amination of organoboron compounds would involve transmetallation from boron to
copper, followed by well-precedented electrophilic amination of the organocopper
intermediate.35,36
Section 2. Reaction Discovery and Optimization
2.2.a. Identification of electrophilic nitrogen source
Our
first
challenge
was
to
identify
an
appropriate
electrophile
for
functionalization of the proposed alkyl copper intermediate. Based on our experience
with NHC-Cu complexes (NHC = N-heterocyclic carbene) as catalysts in reactions of
organoboron compounds, we decided to explore the reactivity of 2.137 in stoichiometric
reactions with reagents used in electrophilic amination of organometallic nucleophiles.
In reactions with more reactive electrophiles,38,35b,35c,39 such as N,N-dibenzyl chloramine
(2.2), we observed complete conversion of 2.1, and the formation of a small amount (7%)
48
of the amination product that could not account for the disappearance of 2.1 (Scheme
2.6, equation 1).
Scheme 2.6
More insight into reactivity of chloramine 2.2 was obtained from its reaction with
2.3 (Scheme 2.6, equation 2), in which the oxidative homocoupling product 4,4’dimethyl-1,1’-biphenyl was obtained in 70% yield. Gratifyingly, in a reaction with Obenzoyl-N,N-dibenzylhydroxylamine (2.4) the desired amination was obtained in 99%
yield (Scheme 2.6, equation 1). O-benzoyl-N,N-dialkylhydroxylamines such as 2.4 are
readily available35c,40 and have previously been used in copper-catalyzed electrophilic
amination of organozinc and Grignard reagents.35b,35c
2.2.b. Initial optimization with O-benzoyl-N,N-dibenzylhydroxylamine
Having identified suitable electrophiles for amination of NHC-Cu alkyl
complexes, we turned our attention to the development of copper-catalyzed amination of
alkyl boranes, and its application in the hydroamination of terminal alkenes. We first
explored the electrophilic amination of the 9-alkyl-9-BBN derivative, prepared by
hydroboration of 4-phenyl-1-butene (2.5), with 9-BBN. Hydroboration was performed in
49
1,4-dioxane at 60 °C for 12 h, after which all of the components required for
electrophilic amination were added to the reaction flask.
In a catalytic reaction
performed under conditions previously used by us in the alkylation of allylic chlorides by
alkyl boranes,32 the hydroamination product using 2.4 was obtained in less than 5% yield
(Table 1, entry 1). However, a catalyst screen identified ICyCuCl as the best catalyst,
providing the desired product in 16% yield (entry 2).
Table 2.1
Analysis of the crude reaction mixtures obtained in catalytic reactions indicated
complete consumption of the electrophile and the formation of a single major product.
After column chromatography, we isolated a significant amount of benzaldehyde, which
50
suggested that the major product of the reaction might be the imine formed by
elimination of benzoate from O-benzoylhydroxylamine 2.4.
Control experiments confirmed a fast formation of the imine 2.6 in a reaction of
the electrophile 2.4 with sodium tert-pentoxide at room temperature (Scheme 2.7,
equation 3 conditions a). While the elimination reaction was slower in the presence of
alkyl borane (t1/2 ~ 10 min, conditions b), it still effectively competed with the desired
electrophilic amination.
Further experiments revealed that the consumption of the
electrophile was significantly slower with use of lithium tert-butoxide (t1/2 ~ 120 min,
conditions c).
The deleterious consumption of 2.4 could be further attenuated if a
noncoordinating solvent, such as benzene, was used (5% conversion after 2 h, conditions
d), possibly due to the lower solubility of lithium tert-butoxide in this medium.
Scheme 2.7
Guided by the results of control experiments, we were able to significantly
improve the yield of the hydroamination product. In a catalytic reaction performed with
lithium tert-butoxide instead of sodium tert-pentoxide, the desired product was obtained
in 56% yield (Table 2.1, entry 4). Further improvement was achieved by addition of
pentane to a hydroboration reaction performed in 1,4-dioxane (entry 5). Under these new
conditions, ICyCuCl remained superior to other copper(I) catalysts and was chosen to be
51
used in further optimization of the reaction (Table 2.1, compare entry 5 with entries
6—9). After further modification, the highest yield was obtained when 1.3 equivalents of
both the electrophile and alkoxide were used in the reaction (entry 10), providing the
desired product as a single regioisomer in 97% yield.
Hydroamination of Alkenes by O-benzoyl-N,N-dibenzylhydroxylamine
These conditions were found to catalyze the formal hydroamination of a number
of monosubstituted terminal alkenes to give benzyl-protected primary amines (Table 2.2,
2.7—2.12). Electrophile 2.4 could be used in conjunction with a sterically demanding
tert-butyl substituent on the alkene partner to give 2.8, as well as in reactions with 2,2disubstituted alkenes to form products such as 2.11 and 2.13 without decrease in yield.
Furthermore, benzyl-protected secondary amines such as 2.15 could also be prepared by
this method.
Table 2.2
52
2.2.c: Optimization of Hydroamination Reaction for Other O-benzoylhydroxylamines
Unfortunately,
with
a
variety
of
other
electrophiles,
such
as
4-
benzoyloxymorpholine 2.16, we observed an alternative decomposition pathway under
these reaction conditions. For example, the reaction with 2.6 provided no hydroamination
product and instead resulted in almost quantitative formation of tert-butyl benzoate
(Table 2.3, entry 1). To prevent the decomposition of 3 during the course of the reaction,
we added the electrophile over a 6 h period and observed the formation of the
hydroamination product in 52% yield (Table 1, entry 2). After further experimentation, it
was determined that a co-solvent was unnecessary to the reaction efficiency (compare
entries 2—5). A good yield of the product was achieved through use of toluene as
solvent at 0.35 M (Table 2.3, entry 4). However, the formation of a small amount of
toluene amination product41 complicated the purification of the desired amine when the
reaction was conducted at this concentration.
After further dilution of the reaction
mixture and adjustment of addition time, a 99% yield of the hydroamination product was
obtained when 1.1 equiv of electrophile was added to a relatively dilute reaction mixture
(0.05 M in alkyl borane) over 3 h at 60 °C (entry 8). In view of the difficulties often
encountered in the purification of tertiary alkyl amines, it is important to note that these
reaction conditions allowed pure hydroamination products to be isolated by an acid−base
extraction.
53
Table 2.3
Section 3. Reaction scope.
The optimized reaction conditions and purification procedure proved to be quite
general (Table 2.4). The highly selective anti-Markovnikov hydroamination of alkenes
could be accomplished in the presence of esters, acetals, nitriles, aryl bromides, aryl
chlorides, Boc-protected amines, and silyl and alkyl ethers.
The procedure could be used to prepare morpholine, piperidine, pyrrolidine,
piperazine, and decahydroquinoline derivatives (compounds 2.17−2.21). Equally good
results were obtained in the preparation of acyclic amines, including sterically hindered
N,N-diisopropyl-N-alkyl amines (2.22—2.29) and the adamantyl-substituted amine 2.30.
Even the highly hindered N-alkyl-2,2,6,6-tetramethylpiperidine 2.31 could be formed in
54
86% yield. The synthesis of such hindered trialkyl amines is not only impossible to
achieve using the existing hydroamination methods but is also quite difficult to
accomplish using standard reductive amination or alkylation techniques.42
Finally,
GC/MS analysis of the crude reaction mixture indicated that, for all of these examples,
only the product of anti-Markovnikov hydroamination was formed.
Table 2.4
R2N-OBz (1.1 equiv),
LiOt Bu (1.1 equiv),
ICyCuCl (5 mol%);
9-BBN
(1.0 equiv);
R1
toluene
60 °C, 12 h
B
1
R
NR2
toluene,
60 °C, 4-8 h
1.0 equiv
Me
O
R1
Boc
Et
N
N
Bn
Bn
N
2.17: 94% yield
N
2.18: 84% yield
Me
N
Bn
2.20: 94% yield
2.19: 91% yield
Me
Me
Bn
Me
Me
O
H
N
Me
N
OTIPS Me
Me
N
H
Bn
2.21: 97%
Me
yieldb
Me
2.22: 80%
yieldb
2.23: 80% yield
O
Me
Me
Me
Bn
N
NC
2
Ar
Me
Me
2.24: Ar = 4-MeOPh 84% yield
2.25: Ar = 4-BrPh 84% yield
Me
Me
O
N
OMe
8
Bn
Me
N
N
Me
Me
O
8
2.26: 95% yieldb,c
Me
Me
Cl
Bn
2.27: 92% yielde
Me
2.28: 90% yieldb
nPr
Me
N
N
MeO2C
2.29: 94% yield
d
Me
Me
Me
N
Me
Bn
Me
2.30: 83% yield
b
2.31: 86% yield
aAlkene (0.50 mmol), 9-BBN (0.5 mmol), R2N-OBz (0.55 mmol), and t-BuOLi (0.55 mmol) in 10 mL of toluene. R N OBz
2
was added over 4 h. Yields of isolated products are shown, unless otherwise noted. bBenzene was used as the
solvent. cGC yield. After purification, the corresponding aldehyde was isolated in 92% yield. d 2.5 mol % catalyst was
used. eGC yield. The isolated yield was 72%.
55
Section 4. Mechanism
We propose that the amination of alkyl boron compounds proceeds according to
the mechanism shown in Scheme 2.8. The reaction involves transmetallation from boron
to copper32,33h followed by electrophilic amination of the alkylcopper intermediate.35d
Finally, copper tert-butoxide is regenerated in a reaction with lithium tert-butoxide.43
The most intriguing aspect of the proposed mechanism is the presence of a neutral alkyl
copper(I) intermediate in a reaction performed at a relatively high temperature. Such
complexes are known to decompose quickly above −35°C,44 and to the best of our
knowledge, there are no examples of fully characterized neutral alkyl copper(I)
complexes containing β-hydrogen substituents. While similar intermediates have also
previously been proposed in copper-catalyzed reactions of alkyl boranes,33e,33h there is
little experimental evidence for their involvement.
Scheme 2.8
In an effort to explore the role of alkyl copper(I) complexes in the amination
reaction, we prepared IMesCuEt (2.32) by addition of ethyllithium to IMesCuCl at low
56
temperature. We were able not only to isolate the IMesCuEt complex, albeit in low
yield (37%), but also to characterize it by X-ray diffraction (Figure 2.1). We discovered
that the complex is stable in benzene for at least 4 h at 60°C if kept in the dark. However,
it decomposes quite readily at room temperature upon exposure to light (∼50%
conversion after 4 h).
Figure 2.1. ORTEP of IMesCu(Et) (selected hydrogen atoms omitted for clarity) with thermal
ellipsoids drawn at 50% probability level.
We also showed that IMesCuEt reacts at 45°C with electrophile 2.4 to produce
the expected amination product in 71% yield (eq 4 in Scheme 2.9). Furthermore, when
2.32 was used as the catalyst in the hydroamination of 2.5, the desired product was
obtained in 91% yield (eq 5 in Scheme 2.9). The results of these experiments provide
support for the proposed participation of neutral alkyl copper(I) complexes in the
catalytic amination of alkyl boron compounds.
57
Scheme 2.9
Section 5. Conclusion
In conclusion, we have developed a one-pot hydroamination procedure that
allows the direct formation of tertiary alkyl amines from terminal alkenes as a single
regioisomer. The method is compatible with a wide variety of functional groups and can
be used to prepare a range of both cyclic and acyclic amines. Furthermore, the procedure
can be used to prepare highly sterically hindered amines that can be challenging to
prepare even by well-established methods such as reductive amination and alkylation.
The products of these reactions are isolated in analytical purity by use of a simple
acid/base extraction. Finally, we have prepared and characterized a stable alkyl copper(I)
complex capable of β-hydride elimination and also provided experimental evidence that
supports their proposed role as intermediates in the formal anti-Markovnikov
hydroamination reaction.
58
Section 6: Experimental
General
All reactions were performed under a nitrogen atmosphere with flame-dried
glassware, using standard Schlenk techniques, or in a glove box (Nexus II from Vacuum
Atmospheres). Column chromatography was performed using a Biotage Iso-1SV flash
purification system with silica gel from Agela Technologies Inc. (60Å, 40-60 µm, 230400 mesh). Ion Exchange Chromatography was performed using analytical grade cation
exchange resin from sulfonic acid functionalized styrene (Bio-Rad Laboratories, 200-400
mesh, 5.2 meq/g). Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum RX I
spectrometer. IR peak absorbencies are represented as follows: s = strong, m = medium,
w = weak, br = broad. 1H- and 13C-NMR spectra were recorded on a Bruker AV-300 or
AV-500 spectrometer. 1H NMR chemical shifts (δ) are reported in parts per million
(ppm) downfield of TMS and are referenced relative to residual proteated solvent peak
(CDCl3 (7.26 ppm), C6D6 (7.16 ppm), or CD2Cl2 (5.32 ppm)).
13
C chemical shifts are
reported in parts per million downfield of TMS and are referenced to the carbon
resonance of the solvent (CDCl3: δ 77.2 ppm, C6D6: δ 128.1 ppm, CD2Cl2: δ 54.0 ppm).
Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), integration, and coupling constants in Hertz (Hz).
Mass spectra were collected on a JEOL HX-110 mass spectrometer. GC analysis was
performed on a Shimadzu GC-2010 instrument with a flame ionization detector and a
SHRXI-5MS column (15 m, 0.25 mm inner diameter, 0.25 µm film thickness). The
following temperature program was used: 2 min @ 60 °C, 13 °C/min to 160 °C, 30
°C/min to 250 °C, 5.5 min @ 250 °C.
59
Materials
Toluene and benzene were degassed and dried by passing through columns of neutral
alumina. 1,4-dioxane was distilled from purple Na/benzophenone ketyl and stored over
4Å molecular sieves. All other solvents were used as received. Deuterated solvents were
purchased from Cambridge Isotope Laboratories, Inc. Deuterated solvents were degassed
and dried over 4Å molecular sieves before use. Commercial reagents were purchased
from Sigma-Aldrich Co., VWR International, LLC., TCI Chemicals USA, or STREM
Chemicals,
Inc.,
and
were
used
as
received,
except
for
9-BBN
(9-
borabicyclo[3.3.1]nonane) dimer, which was recrystallized from dimethoxyethane
(glyme).
O-benzoyl-N,N-dialkyl hydroxylamines were synthesized according to a literature
procedure.45 Terminal alkenes were all commercially available with the exception of
triisopropyl(pent-4-en-1-yloxyl)silane,46
bromo-4-(but-3-en-1-yl)benzene,47a
1-(but-3-en-1-yl)-4-methoxybenzene,47
and
1-
2-(2-(pent-4-en-1-yloxy)phenyl)-1,3-
dioxolane,48 which were prepared according to literature procedures.
2.6.b. Reaction Optimization
Hydroboration of Terminal Alkenes
In a glove box, a 1 dram vial was charged with a stir bar. To the vial was added 9-BBN
dimer (0.50 equiv), alkene (1.00 equiv), and solvent. The vial was capped and heated at
60 ̊C with stirring for 12 h.
Using O-benzoyl-N,N-dibenzylhydroxylamine
In a glove box, 4-phenylbut-1-ene (1.00 equiv, 0.017 mL, 0.110 mmol) was subjected to
the standard hydroboration conditions described above using 9-BBN dimer (0.50 equiv,
60
13.4 mg, 0.055 mmol), n-dodecane as internal standard, and 1,4-dioxane (0.20 mL,
[alkene] = 0.55 M). After 12 h at 60 ̊C, the reaction vial was allowed to reach room
temperature, and MOtBu (M = Na, K, Li; 1.00 equiv, 0.110 mmol), copper catalyst (0.05
equiv, 0.006 mmol), O-benzoyl-N,N-dibenzyl hydroxylamine (1.00 equiv, 36.2 mg, 0.110
mmol), 1,4-dioxane (0.075 ml) and the reaction co-solvent (0.275 ml) were added as
indicated in Table 2.1. The vial was capped and stirred at 45 °C for 6 h. Yield of the
desired product was determined by gas chromatography using n-dodecane as an internal
standard.
Using 4-benzoyloxymorpholine
For all optimization reactions, 4-phenylbut-1-ene (1.00 equiv, 0.060 mL, 0.400 mmol)
was subjected to the standard hydroboration conditions described above using 9-BBN
dimer (0.50 equiv, 48.8 mg, 0.400 mmol) and solvent (1.00 mL, 0.40 M). After 12 h at
60 ̊C, the dram vial was allowed to reach room temperature, and the contents were
transferred to a 15 mL Schlenk tube. To the resulting solution was added lithium tertbutoxide (1.3 equiv, 41.6 mg, 0.520 mmol), ICyCuCl (0.05 equiv, 6.6 mg, 0.020 mmol),
and solvent. Separately, a stock solution of the electrophile was prepared (0.400 mL of
reaction co-solvent) and taken up in a gas-tight syringe (500 µL size). The Schenk tube
assembly was put on the manifold using standard air-free techniques. The electrophile
was added over the period indicated in Table 2.3 to the stirred reaction mixture at 60 °C.
After addition of the electrophile, the reaction was stopped and allowed to cool to room
temperature. The crude product was isolated by diluting the reaction mixture with ether
(5 mL) and then washing with aqueous saturated NaHCO3 solution. The aqueous layer
was then extracted with diethyl ether (2 x 10 mL), and the combined organic fractions
61
were dried over sodium sulfate. After filtering, 1,3-dinitrobenzene was added as an
internal standard to the ether solution, and the yield of the product was determined by GC
analysis of an aliquot of this solution.
2.6.c. Reactions of O-benzoyl-N,N-dibenzyl hydroxylamine with sodium tert-pentoxide
and lithium tert-butoxide.
For the following reactions, conversion of O-benzoyl-N,N-dibenzyl hydroxylamine was
determined by 1H-NMR using 1,3,5-trimethoxybenzene as an internal standard.
To
obtain data for each time point in Table 2.5, aliquots (0.05 mL) were withdrawn from the
reaction mixture and were diluted to 0.50 mL with benzene-d6.
Entries 1, 4, and 6: In a glove box, a 1 dram vial was charged with a stir bar. To the vial
was added either LiOtBu or NaOtBu (1.00 equiv, 0.110 mmol), 1,3,5-trimethoxybenzene
as an internal standard, and 1,4-dioxane-d8 (0.35 mL). To the resulting mixture was
added O-benzoyl-N,N-dibenzyl hydroxylamine (1.00 equiv, 0.110 mmol) and 1,4dioxane-d8 (0.15 mL). The resulting mixture was capped and heated to 45 ̊C under
stirring.
Entries 2 and 7: The reactions were set up exactly as described for Entries 1 and 4 except
that ICyCuCl catalyst (0.05 equiv, 0.006 mmol) was added before addition of O-benzoylN,N-dibenzyl hydroxylamine.
Entries 3, 5, and 8: In a glove box, a 1 dram vial was charged with a stir bar. To the vial
was added 9-BBN dimer (0.50 equiv, 13.4 mg, 0.055 mmol) , 4-phenyl-but-1-ene (1.00
-2
62
8
equiv, 1.65x10 mL, 0.110 mmol), and 1,4-dioxane-d (0.20 mL, 0.5 M). The vial was
heated at 60 ̊C for 12 h and then cooled to room temperature. To the resulting solution
was added either LiOtBu or NaOtBu (1.00 equiv, 0.110 mmol), 1,3,5-trimethoxybenzene,
O-benzoyl-N,N-dibenzyl hydroxylamine (1.00 equiv, 0.110 mmol) and 1,4-dioxane-d8
(0.30 mL). The resulting mixture was capped and heated to 45 ̊C with stirring
Table 2.5
Cy
N
CuCl
B
+
Ph
N
+
3
MOtBu
(1.00 equiv)
Bn2N-OBz (1.00 equiv)
Bn
Ph
1,4-dioxane-d 8, 45 °C
N
4
Cy
Entrya
ICyCuCl
(mol%)
9-(4-phenylbutyl)-9borabicyclo[3.3.1]nonane
(equiv)
M
10
30
60
120
1020
1
0
0
Li
7
14
37
53
100
2
5
0
Li
35
50
61
71
100
3
0
1.00
Li
2
17
32
49
100
4b
0
0
Li
0
NA
NA
5
NA
5b
0
1.00
Li
0
NA
NA
2
NA
6
0
0
Na
93
100
100
100
100
7
5
0
Na
100
100
100
100
100
8
0
1.00
Na
50
67
74
81
100
a All
reaction concentrations are 0.2 M.
b
% conversion of Bn2N-OBz (min)
Benzene-d 6 was used as reaction solvent.
2.6.d. Hydroamination of Terminal Alkenes
Using O-benzoyl-N,N-dibenzylhydroxylamine:
General procedure:
In a glove box, a scintillation vial was charged with a stir bar. To the vial was added 9BBN dimer (0.50 equiv, 61.0 mg 0.250 mmol), 1,4-dioxane (1.00 mL), and the alkene
(1.00 equiv, 0.500 mmol). After 12 h at 60 °C, the reaction mixture was cooled to room
63
t
temperature, and LiO Bu (1.00 equiv, 40.0 mg, 0.500 mmol), ICyCuCl (0.05 equiv,
8.3 mg, 0.003 mmol) and pentane (1.25 mL) were added with stirring. After 10 min, the
O-benzoyl-N,N-dialkyl hydroxylamine (1.05 equiv, 0.530 mmol) was added to the vial
together with 1,4-dioxane (0.25 mL). The reaction mixture was stirred at 45 °C for 3 h,
at which time another portion of LiOtBu (0.30 equiv, 12.0 mg, 0.150 mmol) and Obenzoyl-N,N-dialkyl hydroxylamine (0.25 equiv, 0.130 mmol) were added. The reaction
mixture were stirred for an additional 3 h at 45 °C, then diluted in diethyl ether, and
filtered through a plug of silica using diethyl ether as the eluent. The solvent was
removed under reduced pressure, and the crude product was purified by silica gel
chromatography.
N,N-dibenzyl-4-phenylbutan-1-amine
Compound was isolated as a colorless oil (147.5 mg, 90% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 15%
Et2O/hexanes over 7 CV). 1H NMR (300 MHz, C6D6) δ 7.37 (d, J = 7.4 Hz, 4H), 7.28 –
6.90 (m, 11H), 3.41 (s, 4H), 2.52 – 2.27 (m, 4H), 1.60 – 1.26 (m, 4H).
13
C NMR (125
MHz, C6D6) δ 142.8, 140.4, 129.1, 128.8, 128.6, 128.5, 127.2, 126.0, 58.8, 53.3, 35.9,
29.2, 26.9. HRMS calculated for [M]+ 330.2212, found 330.2217. FTIR (neat, cm-1):
3084(w), 2933(m), 1494(m), 1452(m), 1028(w).
64
N,N-dibenzyloctan-1-amine (2.7)
Compound was isolated as a colorless oil (147.8 mg, 96% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 10%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.41 (d, J = 7.0 Hz, 4H), 7.31 –
7.04 (m, 6H), 3.48 (s, 4H), 2.40 (t, J = 7.1 Hz, 2H), 1.45 (m, 2H), 1.35 – 1.09 (m, 10H),
0.90 (t, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 140.2, 128.9, 128.3, 126.8, 58.4,
53.6, 32.0, 29.6, 29.5, 27.4, 27.1, 22.8, 14.3. ESI-MS calculated for [M+H]+ 310.2, found
310.3. FTIR (neat, cm-1): 3062(w), 3026(w), 2926(s), 1494(w), 1452(m), 1367(w).
N,N-dibenzyl-3,3-dimethylbutan-1-amine (2.8)
Compound was isolated as a colorless oil (121.7 mg, 86% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 15%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.41 (d, J = 7.1 Hz, 4H), 7.28 –
7.04 (m, 6H), 3.49 (s, 4H), 2.49 – 2.41 (m, 2H), 1.48 – 1.41 (m, 2H), 0.77 (s, 9H).
13
C
NMR (125 MHz, CDCl3) δ 140.2, 128.9, 128.3, 126.9, 58.3, 49.4, 40.4, 30.0, 29.6. ESIMS calculated for [M+H]+ 282.2, found 282.3. FTIR (neat, cm-1): 3062(w), 3027(w),
2954(s), 1493(w), 1452(m), 1364(m).
65
N,N-dibenzyl-1-cyclopentylmethanamine (2.14)
Compound was isolated as a colorless oil (118.9 mg, 85% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 10%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.40 (d, J = 7.3 Hz, 4H), 7.25 –
7.09 (m, 6H), 3.45 (s, 4H), 2.26 (d, J = 7.6 Hz, 2H), 2.09 – 1.94 (m, 1H), 1.74 – 1.61 (m,
2H), 1.46 – 1.37 (m, 4H), 1.22 – 1.02 (m, 2H).
13
C NMR (125 MHz, CDCl3) δ 140.3,
128.9, 128.2, 126.8, 59.5, 58.7, 38.0, 31.1, 25.1. ESI-MS calculated for [M+H]+ 268.2,
found 268.2. FTIR (neat, cm-1): 3061(w), 3026(m), 2948(s), 1494(m), 1451(m), 1369(w).
N,N-dibenzyl-2-cyclohexylethanamine (2.11)
Compound was isolated as a colorless oil (124.8 mg, 81% yield) after purification by
silica gel column chromatography (0 → 5% Et2O/hexanes over 6 CV).
1
H NMR (300
MHz, C6D6) δ 7.41 (d, J = 7.4 Hz, 4H), 7.26 – 7.07 (m, 6H), 3.48 (s, 4H), 2.42 (t, J = 7.4
Hz, 2H), 1.46 – 1.66 (m, 5H), 1.42 – 1.30 (m, 2H), 1.26 – 1.04 (m, 4H), 0.90 – 0.61 (m,
2H).
13
C NMR (125 MHz, CDCl3) δ 140.2, 128.9, 128.2, 126.8, 58.4, 51.1, 35.8, 34.7,
66
33.6, 26.8, 26.5. ESI-MS calculated for [M+H] 308.2, found 308.4. FTIR (neat, cm ):
+
-1
3061(w), 3026(m), 2920(s), 2849(s), 1494(m), 1450(m), 1366(w).
N-benzyl-N-butyl-4-phenylbutan-1-amine (2.15)
Compound was isolated as a colorless oil (111.9 mg, 76% yield) after purification by
silica gel column chromatography (0 → 5% Et2O/hexanes over 6 CV).
1
H NMR (300
MHz, C6D6) δ 7.38 (d, J = 7.3 Hz, 2H), 7.25 – 7.06 (m, 8H), 3.42 (s, 2H), 2.46 (t, J = 7.5
Hz, 2H), 2.40 – 2.26 (m, 4H), 1.65 – 1.49 (m, 2H), 1.49 – 1.32 (m, 4H), 1.34 – 1.18 (m,
2H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 142.8, 140.4, 129.0, 128.6,
128.4, 128.2, 126.7, 125.7, 58.8, 53.7, 53.6, 35.9, 29.4, 29.3, 26.8, 20.7, 14.2. ESI-MS
calculated for [M+H]+ 296.2, found 296.2. FTIR (neat, cm-1): 3025(w), 2930(s), 2795(w),
1494(m), 1453(m).
N,N-dibenzyl -4-(4-methoxyphenyl)butan-1-amine (2.10)
Compound was isolated as a colorless oil (168.8 mg, 94% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 5%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.39 (d, J = 7.4 Hz, 4H), 7.28 –
7.05 (m, 6H), 6.96 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.43 (s, 4H), 3.34 (s,
13
67
3H), 2.43 – 2.29 (m, 4H), 1.58 – 1.39 (m, 4H). C NMR (125 MHz, CDCl3) δ 157.7,
140.2, 134.9, 129.4, 128.9, 128.3, 126.9, 113.8, 58.5, 55.4, 53.2, 34.8, 29.2, 26.6. ESIMS calculated for [M+H]+ 360.5, found 360.4. FTIR (neat, cm-1): 3026(w), 2934(m),
2795(w), 1511(s), 1494(m), 1256(s), 1038(m).
N,N-dibenzyl -2-methylpentan-1-amine (2.13)
Compound was isolated as a colorless oil (136.5 mg, 97% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 5%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.39 (d, J = 7.2 Hz, 4H), 7.21 (t,
J = 7.4 Hz, 4H), 7.10 (t, J = 7.3 Hz, 2H), 3.52 (d, J = 13.6 Hz, 2H), 3.35 (d, J = 13.6 Hz,
2H), 2.17 (ddd, J = 20.3, 12.3, 7.3 Hz, 2H), 1.75 – 1.55 (m, 1H), 1.37 – 1.13 (m, 3H),
0.99 – 0.81 (m, 7H).
13
C NMR (125 MHz, CD2Cl2) δ 140.6, 129.3, 128.4, 127.0, 61.3,
59.2, 37.6, 31.1, 20.3, 18.4, 14.6. ESI-MS calculated for [M+H]+ 282.2, found 282.3.
FTIR (neat, cm-1): 3062(w), 3027(w), 2955(s), 1494(m), 1452(m), 1372(m).
N,N-dibenzyl-5-((triisopropylsilyl)oxy)pentan-1-amine (2.9)
68
Compound was isolated as a colorless oil (189.1 mg, 86% yield) after purification by
silica gel column chromatography (0 → 30% benzene/hexanes over 3 CV, then 0 → 5%
Et2O/hexanes over 6 CV). 1H NMR (300 MHz, C6D6) δ 7.40 (d, J = 7.3 Hz, 4H), 7.21 (t,
J = 7.4 Hz, 4H), 7.10 (t, J = 7.3 Hz, 2H), 3.57 (t, J = 6.1 Hz, 2H), 3.44 (s, 4H), 2.37 (t, J
= 6.9 Hz, 2H), 1.50 – 1.29 (m, 6H), 1.20 – 1.05 (m, 21H). 13C NMR (125 MHz, CDCl3) δ
140.2, 128.9, 128.3, 126.8, 63.5, 58.4, 53.6, 33.1, 27.1, 23.8, 18.2, 12.2. ESI-MS
calculated for [M+H]+ 440.3, found 440.6. FTIR (neat, cm-1): 3027(w), 2941(s), 2864(s),
1494(m), 1426(m), 1106(s), 909(m).
Using cyclic and acyclic O-benzoyl-N,N-dialkylhydroxylamines:
General procedure:
In a glove box, a one-dram vial was charged with a stir bar. To the vial was added 9BBN dimer (0.50 equiv, 48.8 mg 0.200 mmol), toluene (1.00 mL, 0.40 M), and the
alkene (1.00 equiv, 0.400 mmol). After 12 h at 60 °C, the reaction mixture was cooled to
room temperature and transferred to a 15 mL Schlenk tube.
To the resulting solution
was added lithium tert-butoxide (1.10 equiv, 35.2 mg, 0.440 mmol), ICyCuCl (0.05
equiv, 6.6 mg, 0.020 mmol), and toluene (6.60 mL, 7.60 mL total volume, 0.05 M).
Separately, a stock solution of the electrophile was prepared (0.400 mL of reaction cosolvent) and taken up in a gas-tight syringe (500 µL size). The Schenk tube assembly
was put on the manifold using standard air-free techniques. The electrophile was added
over 4 h to the stirred reaction mixture at 60 °C. After addition of the electrophile, the
reaction was allowed to stir at 60 °C and the consumption of electrophile was monitored
by tlc. Upon complete consumption of the electrophile, the reaction was cooled to room
69
temperature. The crude product was isolated by diluting the reaction mixture with
ether (5 mL) and then washing with aqueous saturated NaHCO3 solution. The aqueous
layer was then extracted with diethyl ether (2 x 10 mL), and the combined organic
fractions were dried over sodium sulfate. After filtration and removal of the solvent
under reduced pressure, the crude product was obtained as an oil, which was further
purified according to one of the following three procedures:
Purification Procedure A: Acid/Base Extraction
The crude product was transferred to a 60 mL separatory funnel using 2.5 mL portions of
diethyl ether and hexane (5 mL total volume). The organic layer was extracted three
times with 5 mL of a 3 M aqueous HCl solution. The organic layer was discarded. The
pH of the aqueous layer was adjusted by dropwise addition of an aqueous 3 M NaOH
solution until pH 10 was achieved. The resulting solution was then extracted three times
with 10 mL portions of dichloromethane. The organic extracts were washed with 5 mL
of saturated brine and then dried over sodium sulfate. Upon filtration and removal of
solvent, the purified tertiary amine product was obtained as an oil.
Purification Procedure B:
Acid-sensitive functional groups, such as the tert-butyl
carbamate (BOC)-protected amine used in product 8, and the tris(isopropyl)siloxy
(TIPS)-protected alcohol used in product 9, require the substitution of a weaker acid in
place of aqueous HCl. This is readily accomplished by use of an aqueous 3 M sodium
acetate and acetic acid solution buffered at pH 4. The purification procedure is identical
to A except for this substitution.
70
Purification Procedure C: Ion-Exchange Chromatography
The crude product was loaded on the cation exchange resin (200 mg resin/mmol product)
using MeOH. The resin was subsequently washed with 4 CV of 2% dichloromethane in
MeOH, then with 4 CV of 20% Et3N in MeOH to elute the product.
4-(4-phenylbutyl)morpholine (2.17)
Compounds was isolated as a colorless oil (82.8 mg, 94% yield) after purification by ion
exchange chromatography. Reaction time was 4 h. 1H NMR (300 MHz, CDCl3) δ 7.46 –
7.30 (m, 2H), 7.30 – 7.10 (m, 3H), 3.88 – 3.65 (m, 4H), 2.70 (t, J = 7.5 Hz, 2H), 2.59 –
2.32 (m, 6H), 1.84 – 1.45 (m, 4H).
13
C NMR (125 MHz, CDCl3) δ 142.5, 128.5, 128.4,
125.8, 67.1, 59.1, 53.9, 35.9, 29.4, 26.3. HR-MS calculated for [M+H]+ 220.1701, found
220.1693. FTIR (neat, cm-1): 3083(w), 3024(w), 2935(s), 1603(w), 1453(s), 1118(s).
2-methyl-1-(4-phenylbutyl)pyrrolidine (2.18)
Compound was isolated as a colorless oil (73.1 mg, 84% yield) after purification by ion
exchange chromatography. Reaction time was 3 h. 1H NMR (300 MHz, MeOD) δ 7.39
71
– 7.05 (m, 5H), 3.24 – 3.00 (m, 1H), 2.94 – 2.73 (m, 1H), 2.64 (t, J = 6.8 Hz, 2H), 2.49
– 2.25 (m, 1H), 2.25 – 1.85 (m, 3H), 1.87 –3 1.34 (m, 7H), 1.11 (d, J = 6.2 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 142.7, 128.6, 128.4, 125.8, 60.5, 54.2, 54.1, 36.0, 32.8, 29.8,
28.5, 21.7, 19.0. HRMS calculated for [M+H]+ 218.1908, found 218.1915. FTIR (neat,
cm-1): 3062(w), 3025(w), 2936(s), 1603(w), 1453(s), 1374(m), 746(s).
2-ethyl-1-(4-phenylbutyl)piperidine (2.19)
Compound was isolated as a colorless oil (89.6 mg, 91% yield) after acid base extraction
A. Reaction time was 3 h. 1H NMR (300 MHz, MeOD) δ 7.43 – 7.00 (m, 5H), 2.96 –
2.80 (m, 1H), 2.79 – 2.57 (m, 3H), 2.57 – 2.42 (m, 1H), 2.42 – 2.15 (m, 2H), 1.82 – 1.44
(m, 9H), 1.44 – 1.21 (m, 3H), 0.87 (t, J = 7.5 Hz, 3H).
13
C NMR (126 MHz, MeOD) δ
142.1, 128.1, 128.0, 125.4, 61.7, 52.8, 51.7, 35.3, 29.2, 28.7, 24.5, 23.8, 23.2, 23.0, 9.2.
HRMS calculated for [M+H]+ 246.2221, found 246.2215. FTIR (neat, cm-1): 3054(w),
2933(s), 1734(m), 1437(s), 1265(s), 738(s).
1-(4-phenylbutyl)decahydroquinoline (2.21)
Compound was isolated as a colorless oil (105.8 mg, 97% yield) after purification by
acid/base extraction A. Reaction time was 4 h. 1H NMR (300 MHz, C6D6) δ 7.33 – 7.18
(m, 2H), 7.15 – 7.05 (m, 3H), 2.93 – 2.82 (m, 1H), 2.78 – 2.60 (m, 1H), 2.52 (t, J = 7.5
72
Hz, 2H), 2.35 – 2.12 (m, 1H), 2.12 – 1.94 (m, 2H), 1.83 – 1.31 (m, 11H), 1.30 – 1.05
(m, 4H), 1.06 – 0.76 (m, 2H).
13
C NMR (125 MHz, C6D6) δ 143.0, 128.8, 128.6, 126.0,
66.8, 54.2, 52.9, 42.6, 36.3, 33.6, 33.3, 30.9, 29.9, 26.6, 26.5, 26.2, 26.0. HR-MS
calculated for [M+H]+ 272.2378, found 272.2378. FTIR (neat, cm-1): 3062(w), 3026(m),
2921(s), 1603(w), 1447(m), 1239(m), 698(s).
tert-butyl 4-(4-phenylbutyl)piperazine-1-carboxylate (2.20)
Compound was isolated as a pale yellow oil (119.7 mg, 94% yield) after purification by
acid/base extraction B. Reaction time was 4 h.
1
H NMR (500 MHz, CDCl3) δ 7.22 –
7.13 (m, 2H), 7.07 (t, J = 7.1 Hz, 3H), 3.38 – 3.25 (m, 4H), 2.52 (t, J = 7.6 Hz, 2H), 2.36
– 2.13 (m, 6H), 1.60 – 1.39 (m, 4H), 1.35 (s, 9H).
13
C NMR (125 MHz, C6D6) δ 154.7,
142.8, 128.7, 128.7, 126.1, 79.0, 58.5, 53.3, 46.2, 44.6, 43.7, 36.1, 29.4, 28.5, 26.7. HRMS calculated for [M+H]+ 319.2385, found 319.2392. FTIR (neat, cm-1): 3062(w),
3026(m), 2933(s), 1688(s), 1442(m), 1247(m), 1171(m), 1123(m), 1006(m).
N,N-diisopropyl-3-((triisopropylsilyl)oxy)propan-1-amine (2.22)
Compound was isolated as a pale yellow oil (101.0 mg, 80% yield) after purification by
acid/base extraction B. Reaction time was 6 h. 1H NMR (300 MHz, C6D6) δ 3.74 (t, J =
73
6.2 Hz, 2H), 3.07 – 2.85 (m, 2H), 2.68 – 2.47 (m, 2H), 1.80 – 1.65 (m, 2H), 1.21 –
1.10 (m, 21H), 1.00 (d, J = 6.6 Hz, 12H).
13
C NMR (125 MHz, C6D6) δ 70.7, 62.0, 48.5,
41.6, 34.8, 32.4, 26.7, 22.5, 21.0, 18.4, 12.4. HR-MS calculated for [M+H]+ 316.3035,
found 316.3045. FTIR (neat, cm-1): 2962(s), 2865(s), 1464(m), 1106(s).
methyl 11-(diisopropylamino)undecanoate (2.23)
Compound was isolated as a colorless oil (96.8 mg, 81% yield) after purification by
acid/base extraction A. Reaction time was 6 h.
1
H NMR (300 MHz, C6D6) δ 3.46 (s,
3H), 3.15 – 2.97 (m, 2H), 2.60 – 2.41 (m, 2H), 2.30 – 2.15 (m, 2H), 1.79 – 1.54 (m, 4H),
1.47 – 1.18 (m, 12H), 1.10 (d, J = 6.6 Hz, 12H).
13
C NMR (125 MHz, C6D6) δ 173.3,
50.9, 48.3, 45.1, 34.2, 31.7, 30.2, 30.1, 29.9, 29.7, 29.5, 28.2, 27.8, 25.3, 21.1. HR-MS
calculated for [M+H]+ 300.2902, found 300.2913. FTIR (neat, cm-1): 2928(s), 2855(m),
1743(s), 1465(m), 1204(m), 1172(m).
N,N-diisopropyl-4-(4-methoxylphenyl)butan-1-amine (2.24)
Compound was isolated as a pale yellow oil (88.7 mg, 84% yield) after purification by
acid/base extraction A. Reaction time was 4 h. 1H NMR (300 MHz, C6D6) δ 7.06 (d, J =
8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 3.34 (s, 3H), 2.92 (hept, J = 6.6 Hz, 2H), 2.55 (t, J
74
= 7.6 Hz, 2H), 2.38 (t, J = 7.1 Hz, 2H), 1.73 – 1.55 (m, 2H), 1.54 – 1.35 (m, 2H), 0.97
(d, J = 6.6 Hz, 12H).
13
C NMR (125 MHz, C6D6) δ 158.5, 135.1, 129.6, 114.2, 54.8,
48.1, 44.7, 35.5, 30.9, 29.8, 21.0.
HR-MS calculated for [M+H]+ 264.2327, found
264.2339. FTIR (neat, cm-1): 3033(w), 2962(s), 1751(w), 1465(m), 1245(s), 1039(m).
4-(4-bromophenyl)-N,N-diisopropylbutan-1-amine (2.25)
Compound was isolated as a pale yellow oil (104.7 mg, 84% yield) after purification by
acid/base extraction A. Reaction time was 4 h. 1H NMR (300 MHz, C6D6) δ 7.27 (d, J =
8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 2.99 – 2.76 (m, 2H), 2.39 – 2.21 (m, 4H), 1.53 –
1.26 (m, 4H), 0.95 (d, J = 6.6 Hz, 12H).
13
C NMR (125 MHz, C6D6) δ 142.0, 131.6,
130.5, 119.8, 48.1, 44.6, 35.6, 30.7, 29.2, 21.0. HR-MS calculated for [M+H]+ 312.1326,
found 312.1320. FTIR (neat, cm-1): 3035(w), 2963(s), 1892(w), 1751(w), 1488(m),
1072(m), 1011(m), 829(m), 677(m).
2-((5-(diisopropylamino)pentyl)oxy)benzaldehyde (2.26)
Compound was isolated as a colorless oil (123.9 mg, 92% yield) after purification by
acid/base extraction A. Reaction time was 5 h. 1H NMR (300 MHz, CDCl3) δ 10.52 (d,
J = 0.8 Hz, 1H), 7.83 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (ddd, J = 8.4, 7.3, 1.9 Hz, 1H), 7.10
75
– 6.89 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 3.10 – 2.90 (m, 2H), 2.40 (s, 2H), 2.11 – 1.77
(m, 2H), 1.48 (d, J = 7.1 Hz, 4H), 1.00 (d, J = 6.6 Hz, 12H).
13
C NMR (125 MHz,
CDCl3) δ 190.1, 161.7, 136.0, 128.3, 125.0, 120.6, 112.6, 68.6, 48.5, 45.2, 31.3, 29.2,
24.0, 20.8. HR-MS calculated for [M+H]+ 292.2276, found 292.2281. FTIR (neat, cm-1):
3076(w), 2952(s), 2811(w), 2758(w), 1694(s), 1458(m), 1243(m), 1042(m).
MeOOC
Me
N
Ph
Ph
methyl 4-(3-(benzyl(4-phenylbutyl)amino)butyl)benzoate (2.29)
Compound was isolated as a colorless oil (161.0 mg, 94% yield) after purification by
column chromatography (0-30% ethyl acetate in hexanes over 8 CV). Reaction time was
4 h. 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 7.1 Hz, 2H),
7.27 – 7.19 (m, 4H), 7.16 – 7.07 (m, 4H), 6.95 (d, J = 8.3 Hz, 2H), 3.60 – 3.52 (m, 4H),
3.21 (d, J = 13.9 Hz, 1H), 2.75 – 2.54 (m, 2H), 2.43 – 2.35 (m, 4H), 2.28 – 2.14 (m, 1H),
1.70 – 1.25 (m, 6H), 0.80 (d, J = 6.6 Hz, 3H).
13
C NMR (126 MHz, CDCl3) δ 167.2,
148.7, 142.7, 141.3, 129.7, 128.7, 128.5, 128.4, 128.3, 128.1, 127.6, 126.6, 125.6, 54.1,
53.4, 52.0, 49.1, 35.9, 35.8, 33.4, 29.2, 28.3, 13.5. HRMS calculated for [M+H]+
430.2746, found 430.2735. FTIR (neat, cm-1): 3061(w), 3026(w), 2929(s), 1721(s),
1609(m), 1453(m), 1279(s), 738(m).
76
Me
Me
N
Ph
Me
CN
4-(3-(isopropyl(4-phenylbutyl)amino)butyl)benzonitrile (2.28)
Compound was isolated as a colorless oil (124.8 mg, 90% yield) after acid/base
extraction A. Reaction time was 8 h. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz,
2H), 7.27 – 7.16 (m, 7H), 3.15 – 2.90 (m, 1H), 2.82 – 2.75 (m, 2H), 2.67 – 2.32 (m, 5H),
1.78 – 1.32 (m, 6H), 1.12 – 0.90 (m, 9H).
13
C NMR (75 MHz, CDCl3) δ 149.3, 142.9,
132.2, 129.3, 128.5, 128.4, 125.8, 119.4, 109.4, 51.9, 48.0, 44.4, 37.6, 36.1, 34.0, 30.1,
29.5, 22.7, 19.6, 17.5. HRMS calculated for [M+H]+ 349.2643, found 349.2646. FTIR
(neat, cm-1): 3086(w), 2961(s), 2226(m), 1606(s), 1453(s), 1152(m), 737(m).
N-(4-(3-chlorophenyl)butan-2-yl)-N-isopropyl-4-phenylbutan-1-amine (2.27)
Compound was isolated as a colorless oil (108.6 mg, 76% yield) after purification by
column chromatography (0-20% MeOH in CH2Cl2 over 8 CV with 0.1% acetic acid as an
additive) followed by acid/base extraction A. Reaction time was 6 h.
1
H NMR (300
MHz, CDCl3) δ 7.30 – 7.27 (m, 2H), 7.21 – 7.10 (m, 5H), 6.96 – 6.90 (m, 2H), 2.92 –
2.86 (m, 1H), 2.78 – 2.54 (m, 4H), 2.48 – 2.24 (m, 3H), 1.86 – 1.24 (m, 6H), 1.01 (d, J =
6.7 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H).
13
C NMR (126 MHz,
77
MeOD) δ 146.6, 143.9, 135.0, 130.8, 129.5, 129.4, 129.3, 127.8, 126.7, 126.6, 53.3,
49.5, 45.8, 38.3, 36.9, 31.0, 30.5, 22.5, 20.1, 17.4.
HRMS calculated for [M+H]+
358.2301, found 358.2296. FTIR (neat, cm-1): 3062(w), 2961(s), 1597(m), 1453(m),
1079(w), 908(s), 733(s).
N-(2-cyclohexylethyl)-N-propyladamantan-1-amine (2.30)
Compound was isolated as a colorless oil which solidified upon standing (101.2 mg, 83%
yield) after acid/base extraction A. Reaction time was 4 h. 1H NMR (300 MHz, C6D6) δ
2.66 – 2.54 (m, 2H), 2.54 – 2.39 (m, 2H), 2.02 (s, 3H), 1.85 – 1.39 (m, 20H), 1.39 – 1.10
(m, 3H), 1.04 – 0.84 (m, 5H).
13
C NMR (125 MHz, CDCl3) δ 50.5, 46.2, 40.0, 37.0,
36.8, 36.5, 33.7, 29.8, 29.7, 26.8, 26.5, 12.1, 12.0. ESI-MS calculated for [M+H]+ 304.3,
found 304.3. FTIR (neat, cm-1): 2917(s), 2849(s), 1447(m), 1084(s) 1154(m).
2,2,6,6-tetramethyl-1-(4-phenylbutyl)piperidine (2.31)
Compound was isolated as a colorless oil (93.7 mg, 86% yield) after purification by
acid/base extraction A. Reaction time was 4 h. 1H NMR (300 MHz, C6D6) δ 7.25 – 7.13
(m, 2H), 7.13 – 7.04 (m, 3H), 2.53 (t, J = 7.4 Hz, 2H), 2.45 – 2.25 (m, 2H), 1.69 – 1.28
(m, 10H), 1.01 (s, 12H).
13
78
C NMR (125 MHz, C6D6) δ 143.1, 128.7, 128.6, 126.0,
54.5, 45.3, 41.6, 36.4, 36.1, 29.7, 27.7, 18.2. HRMS calculated for [M]+ 274.2535, found
274.2527. FTIR (neat, cm-1): 3082(w), 2928(s), 1377(m), 1262(m), 1129(m).
2.6.e. Synthesis of O-benzoyl-N,N-hydroxylamines
General:
The O-benzoyl-N,N-dialkyl hydroxylamines were synthesized according to a modified
literature procedure.35c
To an oven-dried reaction flask under nitrogen was added
potassium hydrogen phosphate (1.50 equiv) and benzoyl peroxide (1.00 equiv) followed
by DMF (1.0 M). With vigorous stirring, the secondary amine (2.00 equiv) was added,
and the resulting mixture stirred for 24 h at 25 °C. Distilled water was added, and the
mixture was stirred until all solids were dissolved. Ethyl acetate was added, and the
organic layer was extracted with sodium hydroxide (0.1 M). The organic layer was
separated, and the aqueous layer was extracted twice more with ethyl acetate. The
organic layers were then combined, washed with water and brine, dried over MgSO4, and
concentrated. The crude product was purified as indicated below.
O-benzoyl-N,N-dibenzylhydroxylamine
Compound was isolated as a white solid (1740.1 mg, 73% yield) after recrystallization
from hexanes. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.1, 2H), 7.52 – 7.21 (m, 13H),
79
13
4.21 (s, 4H). C NMR (125 MHz, CDCl3) δ 165.0, 136.1, 133.0, 129.5, 129.4, 128.5,
128.4, 127.8, 62.2.
O-benzoyl-N-benzyl-N-butylhydroxylamine
Compound was isolated as a colorless oil (1031.0 mg, 74% yield) after purification by
silica gel chromatography (0 → 20% Et2O/hexanes). 1H NMR (500 MHz, C6D6) δ 8.03
(d, J = 7.1 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H), 7.12 (t, J = 7.6 Hz, 2H), 7.06 – 6.96 (m,
4H), 3.98 (s, 2H), 2.83 (t, J = 7.1 Hz, 2H), 1.58 – 1.45 (m, 2H), 1.36 – 1.26 (m, 2H), 0.77
(t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.3, 135.9, 133.0, 129.7, 129.5,
128.5, 128.4, 127.9, 127.7, 63.6, 58.4, 29.1, 20.5, 14.0. ESI-MS calculated for [M+H]+
284.2, found 284.4. FTIR (neat, cm-1): 3063(w), 2958(m), 2871(w), 1743(s), 1451(m),
1246(s), 1062 (m).
Me
N
OBz
2-ethylpiperidin-1-yl benzoate
Compound was isolated as a colorless oil (880.0 mg, 78% yield) after purification by
column chromatography (0-20% ethyl acetate in hexanes over 8 CV).
1
H NMR (500
MHz, CDCl3) δ 8.14 (d, J = 7.1 Hz, 2H), 7.15 – 6.95 (m, 3H), 3.60 – 3.49 (m, 1H), 2.46 –
2.62 (m, 2H), 1.73 – 1.28 (m, 8H), 1.03 – 0.77 (d, J = 36.1 Hz, 3H). 13C NMR (126 MHz,
80
CDCl3) δ 165.0, 132.9, 129.6, 129.4, 128.4, 68.1, 58.1, 30.0, 25.9, 25.5, 23.7, 9.6.
HRMS calculated for [M+H]+ 234.1494, found 234.1493. FTIR (neat, cm-1): 3062(w),
2938(s), 1740(s), 1451(m), 1244(s), 708(s).
O-benzoyl-N-(4-(4-cyanophenyl)butan-2-yl)-N-isopropylhydroxylamine
Compound was isolated as a colorless oil (1443.3 mg, 53% yield) after removal of the
amine through ion exchange chromatography followed by purification by column
chromatography (0-20% diethyl ether in hexanes). 1H NMR (300 MHz, C6D6) δ 8.11 (d,
J = 8.2, 2H), 7.15 – 6.95 (m, 5H), 6.83 (d, J = 8.0 Hz, 2H), 3.16 – 3.02 (m, 2H), 2.92 –
2.60 (m, 1H), 2.74 – 2.54 (m, 1H), 1.75 – 1.43 (m, 1H), 1.44 – 1.28 (m, 1H), 1.08 (d, J =
6.2 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.2 Hz, 3H).
13
C NMR (126 MHz,
CDCl3) δ 166.1, 148.3, 133.1, 132.1, 129.5, 129.4, 128.5, 128.3, 119.1, 109.5, 57.0, 53.7,
53.5, 36.4, 32.7, 20.6, 12.5. HRMS calculated for [M+H]+ 337.1916, found 337.1899.
FTIR (neat, cm-1): 3062(w), 2977(s), 2226(m), 1743(s), 1606(w), 1245(s), 709(s).
O-benzoyl-N-(adamantan-1-yl)-N-propylhydroxylamine
81
Compound was isolated as a colorless oil (683.8 mg, 37% yield), which solidified upon
standing, after purification by column chromatography (0 – 10% Et2O in hexanes).
1
H
NMR (300 MHz, CDCl3) δ 8.10 – 7.99 (m, 2H), 7.60 – 7.53 (m, 1H), 7.44 (t, J = 7.5 Hz,
2H), 2.99 – 2.86 (m, 2H), 2.10 (s, 3H), 1.90 – 1.80 (m, 6H), 1.71 – 1.59 (m, 6H), 1.57 –
1.45 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).
13
C NMR (125 MHz, C6D6) δ 165.6, 132.8, 130.6,
129.8, 128.7, 60.2, 51.7, 38.6, 36.9, 29.7, 21.6, 12.1. ESI-MS calculated for [M+Na]+
336.2, found 336.2. FTIR (neat, cm-1): 3045(m), 2911(s), 1739(s), 1265(s), 740(s).
2.6.f. Synthesis of IMesCu(Et) 2.32
IMesCu(Et) (2.32)
(ethyl)[1,2-dihydro-1,3-bis(2,4,6-trimethylphenyl)-2H-imidazol-2-ylidene]-Copper
The title compound was synthesized according to a modified literature procedure.37 A 15
mL Schlenk bomb was charged with a stir bar and flame-dried under vacuum. The flask
was then transferred into a glove box and IMesCuCl (1.0 equiv, 400 mg, 1.0 mmol)
followed by THF (8.0 mL, 0.1 M) were added. Out of the glove box, the flask was cooled
to -78 °C at which point ethyl lithium (1.0 equiv, 2.0 mL, 1.0 mmol) was added dropwise
over 30 min. The reaction was allowed to stir for 1 h before warming to 0 °C. The
reaction was transferred into the glove box and stirred at 20 °C for 10 min, and then the
mixture was filtered through a pad of celite. The solvent was then removed in vacuo
followed by addition of toluene (10 mL) to the dark brown solid; the resulting slurry was
stirred for 10 min before 20 mL of pentane was added. This mixture was filtered through
a pad of celite and concentrated in vacuo to dryness. The resulting brown solid was taken
up in THF (ca. 5 mL) and pentane was added until the solution became cloudy (ca. 20
82
mL). The mixture was filtered through a pad of celite to give a transparent solution and
a white powder upon concentration (144 mg, 37% yield). 1H NMR (500 MHz, C6D6) δ
6.86 (s, 4H), 6.16 (s, 2H), 2.21 (s, 6H), 2.17 (s, 12H), 1.80 (t, J = 8.0 Hz, 3H), 0.70 (q, J
= 8.0 Hz, 2H). 13C NMR (126 MHz, THF-d8) δ 183.9, 138.3, 136.2, 134.7, 128.8, 121.5,
20.2, 17.2, 13.4, 0.6. Crystals suitable for x-ray analysis were obtained by vapor diffusion
of pentane into a saturated solution of THF. Upon exposure of a solution of IMesCu(Et)
in C6D6 to ambient light at 25 °C in a sealed NMR tube, 50% decomposition was
observed after 4 h. The decomposition was monitored by 1HNMR signatures indicative of
the disappearance of the ethyl signals of 2.32 and the appearance of signals
corresponding to ethane. At 60 °C in a sealed NMR tube protected from light, no
decomposition of IMesCuEt was observed after 4 h. However, complete decomposition
occurred after 24 h.
Stoichiometric Reaction of IMesCu(Et):
In a glove box, a 1 dram vial was charged with a stir bar. To the vial was added Obenzoyl-N,N-dibenzyl hydroxylamine (1.50 equiv, 11.7 mg, 0.037 mmol) and 1,4dioxane-d8 (0.25 mL). Separately, to a shell vial was added IMesCu-Et (1.0 equiv, 9.8
mg, 0.025 mmol) and 1,4-dioxane-d8 (0.25 mL). The resulting solution was then added
dropwise
over
10
min
to
the
reaction
vial
containing
O-benzoyl-N,N-
dibenzylhydroxylamine with stirring at 45 ̊C. After 1 h 1,3,5-trimethoxybenzene as
internal standard was added and the reaction yield was determined by NMR comparison
against 1,3,5-trimethoxybenzene.
83
Hydroamination of 4-phenylbut-1-ene using IMesCu(Et) as a catalyst:
In a glove box, a one-dram vial was charged with a stir bar. To the vial was added 9BBN dimer (0.50 equiv, 12.2 mg 0.050 mmol), toluene (0.20 mL, 0.40 M), and phenyl
butene (1.00 equiv, 13.2 mg, 0.100 mmol). After 12 h at 60 °C, the reaction mixture was
cooled to room temperature and lithium tert-butoxide (1.10 equiv, 8.8 mg, 0.110 mmol),
O-benzoyl-N,N-dibenzyl hydroxylamine (1.10 equiv, 24.3 mg, 0.110 mmol), and toluene
(1.3 mL) were added. Finally IMesCuEt (0.050 equiv, 2.0 mg, 0.005 mmol) in toluene
(0.5 mL, 2.0 mL total) was added dropwise over 1 min at 60 °C. The reaction vial was
capped and allowed to stir at 60 °C for 4 h before 1,3,5-trimethoxybenzene as internal
standard was added and the reaction yield was determined by GC analysis.
84
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(45) Rucker, R. P. W., A. M.; Dang, H.; Lalic, G. Angew. Chem., Int. Ed. Engl. 2012,
124, 4019.
(46) (a) Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 13366; (b)
Phukan, P.; Bauer, M.; Maier, M. E. Synthesis 2003, 9, 1324.
(47) (a) Molander, G. A.; Sandrock, D. L. J. Am. Chem. Soc. 2008, 130, 15792; (b)
Datta, S.; Chang, C.-L.; Yeh, K.-L.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 9294.
(48) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932.
87
Chapter 3 – Copper-Catalyzed Electrophilic Amination of Aryl
Boronic Esters: Synthesis of Hindered Anilines1
Section 1. Introduction
The synthesis of aromatic and heteroaromatic amines has attracted considerable
attention in the last two decades, chiefly as a result of the numerous applications of these
compounds in the pharmaceutical industry and medicinal chemistry.2 The development
of several transition metal-catalyzed couplings of aryl halides with amines3 has provided
a practical method for synthesis of a wide range of anilines.4
In particular, the
palladium-catalyzed Buchwald-Hartwig coupling is a powerful and commonly-used
reaction in synthetic chemistry. However, some important challenges remain.
For
example, bromo- and iodo-substituted anilines cannot be prepared directly using these
methods.
More importantly, the preparation of hindered anilines is still a major
challenge.5 This is illustrated by the low yield obtained in a palladium-catalyzed double
N-arylation of a tert-butyl amine derivative en route to (±)-Murrayazoline (equation 1),6
as well as in the total synthesis of (+)-Psychotetramine described by Baran and
coworkers.7
Scheme 3.1
The methods currently available for preparing hindered anilines require the
formation of highly reactive intermediates, such as benzynes8 or organometallic
9-10
reagents.
88
The most general of these reactions, by Knochel and coworkers, involves
oxidative coupling of organometallic reagents with hindered lithium amides in the
presence of stoichiometric amounts of copper.9b In a rare instance of catalytic synthesis
of hindered anilines, Berman and Johnson reported three examples of the electrophilic
amination of aryl zinc reagents by hindered electrophiles.9a,11 A common feature of the
procedures reported by the groups of Johnson and Knochel is that a significant excess (≥2
equivalents) of one of the coupling components is necessary. Furthermore, both methods
require a stoichiometric amount of a Grignard, aryl lithium, or aryl zinc reagent.
Aryl boronic acids and their derivatives offer significant advantages over the
organometallic reagents currently used in synthesis of hindered anilines. They are stable,
readily available, and compatible with a wide range of functional groups. However,
previous attempts by Berman and Johnson9a and others12 to develop electrophilic
amination of these compounds have been unsuccessful. A related oxidative amination of
organoboron reagents developed by Lam,13 Chan,14 and Evans15 is highly sensitive to
steric properties of amine substrates and cannot be used for the synthesis of hindered
anilines. This limitation is apparent when examining the yields of aniline products
obtained in the series of copper-catalyzed reactions utilizing the cyclic amine 1,4-dioxa8-azaspiro[4.5]decane with increasingly sterically-hindered aryl boronic acids (Scheme
3.2).16
89
Scheme 3.2
Herein, we describe a catalytic method for the synthesis of hindered anilines from
aryl and heteroaryl boronic esters compatible with a wide range of functional groups,
including aryl iodides and bromides.
Section 2. Discovery and Optimization
In an initial experiment, we explored the reactivity of aryl boronic ester 3.3 and 4benzoyloxymorpholine 3.1 in the presence of sodium tert-butoxide and IMesCuOtBu as a
catalyst.17 Upon full conversion of the electrophile, the desired aniline was obtained in
less than 5% yield (Table 3.1, entry 1).
We speculated that the low yield of the aniline was a consequence of slow
transmetallation of the aryl boronic ester. Indeed, reactions with ethylene glycol (3.4)
and neopentyl glycol (3.5) esters, which are known to undergo transmetallation faster
than the corresponding pinacol esters,18 provided the aniline product in 16 and 72% yield,
respectively (Table 3.1, entry 2 and 3).
In a catalyst screen performed with boronic ester 3.5 and electrophile 3.1, we
identified XantphosCuO-tBu, a complex prepared from Xantphos ligand and
(CuO-tBu)4,19 as the best catalyst. In a reaction using this catalyst in 1,4-dioxane as
solvent, the desired aniline was obtained in 99% yield (Table 3.1, entry 4).
Unfortunately, a reaction with the more hindered boronic ester 3.6 resulted in the
90
formation of the desired aniline in only 8% yield, together with 83% yield of tert-butyl
benzoate (Table 3.1, entry 5).
Table 3.1
Ar
B(OR)2
BzONR2
+
LCuOt-Bu (5 mol %)
MOt-Bu, solvent
Ar
NR2
ArB(OR)2
L
M
solvent
yieldb
1.
3.3
IMes
Na
THF
<5%
2.
3.4
IMes
Na
THF
16%
3.5
IMes
Na
THF
72%
entry a
BzONR2
O
3.
N
OBz
c
3.5
Xantphos
Na
1,4-dioxane
99%
5.
3.6
Xantphos
Na
1,4-dioxane
8%
6.
3.6
Xantphos
Li
1,4-dioxane
56%
3.6
Xantphos
Li
toluene
74%
3.6
Xantphos
Li
toluene
81%
3.6
Xantphos
Li
isooctane
94%
4.
3.1
7.
Me
Me
8.d
Me
9.e
3.2
N
Me
OBz
a
ArB(OR)2 (1.2 equiv), BzONR2 (1.0 equiv), MOt-Bu (1.0 equiv), 25 °C, 12 h. b determined by
GC. c Catalyst was formed in situ from Xatphos and (CuOt-Bu)4. d Reaction performed at 45
°C. e 60 °C, 1.0 M. Toluene used to prepare the catalyst. OBz = O-benzoyl (OC(O)Ph)
IMes
Me
Me
Me
Me
Me
Me
Me
Me
N
N
Ar
Ar
O
O
O
O
O
O
(Ar=2,4,6-trimethylphenyl)
B
B
B
O
O
Me Me
B
Me
Me
Me
3.3
3.4
Me
O
Me
3.5
3.6
PPh2
PPh2
Xantphos
In fact, a control experiment revealed that tert-butylbenzoate forms in nearly
quantitative yield in a reaction of 4-benzoyloxymorpholine (3.1) with sodium tertbutoxide after only 10 minutes at room temperature (Table 3.2, entry 1). However, we
found that the background reaction of the electrophile with an alkoxide can be suppressed
if less reactive lithium tert-butoxide is used (Table 3.2, entry 2). When this change was
implemented along with the use of a non-coordinating solvent, a further decrease in the
91
rate of decomposition of 3.1 was observed (Table 3.2, entry 3). Interestingly, the
formation of tert-butyl benzoate could be completely suppressed when using these
conditions
with
the
sterically-hindered
electrophile
O-benzoyl-N,N-
diisopropylhydroxylamine 3.2 (Table 3.2, entry 4); however, when more sodium tertbutoxide was used, the rate of consumption of 3.2 was more pronounced (result not
shown).
Table 3.2
Consistent with the above findings, a reaction with boronic ester 3.6 and
electrophile 3.1 performed in toluene and using lithium tert-butoxide afforded the desired
aniline in 74% yield (Table 3.1, entry 7). The same conditions could also be used to
prepare highly hindered N,N-diisopropyl-2,6-dimethylaniline from boronic ester 3.6 and
electrophile 3.2 (Table 3.1, entry 8). Finally, the best result (94% yield) was obtained
when this reaction was performed in a concentrated isooctane solution using catalyst
prepared from Xantphos and (CuOtBu)4 in toluene (Table 3.1, entry 9).
92
Section 3. Scope
The optimized reaction conditions proved to be remarkably general. We found
that reactions with diisopropylamine-derived electrophile 3.2 could be performed in the
presence of a number of functional groups, including formyl, carbomethoxy, nitro,
methoxy, trifluoromethyl, iodo, and bromo groups (Table 3.3, 3.7 and 3.9—3.12). As the
synthesis of anilines 3.16 and 3.17 suggest, hindered boronic esters are well-tolerated in
the reaction.
In addition, a variety of heteroaromatic boronic esters, including 2-
chloropyridine-3-boronic ester, can also be used as nucleophiles (Table 2, compounds
3.18—3.21). In most reactions, 2.5 mol % of the catalyst was sufficient to accomplish
the full conversion in less than 12 h, while the sterically hindered boronic esters required
a higher catalyst loading. Finally, as the synthesis of 3.8 demonstrates, the reaction can
be successfully performed on a 5 mmol scale.
To establish the full scope of the amination reaction, we explored the reactivity of
various electrophiles. O-benzoyl hydroxylamines derived from common cyclic amines,
such as pyrrole, piperidine, morpholine, piperazine, and decahydroisoquinoline can be
used in the reaction (3.23—3.25 and 3.30—3.31).
Electrophiles bearing functional
groups, such as nitro, carbomethoxy, bromo and chloro groups, are also viable substrates
and provide the aniline products in excellent yields (3.26—3.29). The steric properties of
an electrophile have no significant effect on the outcome of the reaction. Even a highly
hindered electrophile derived from 2,2,6,6-tetramethylpiperidine could be coupled with
nitrophenyl boronic ester in 87% yield, and the 2-methylphenyl boronic ester provided
3.33 in 60% yield. The preparation of 3.33 is especially notable, as it is the most
hindered aniline prepared to date through either catalytic or stoichiometric techniques.
93
Table 3.3
R3
O
Ar
Me
+
B
R2
Me
O
X
OMeb 3.7 85%
3.8 82%
Clc
CO2Me 3.9 89%
CHO 3.10 94%
3.11 82%
I
Br 3.12 84%
Cl
X
i-Pr2N
i-Pr2N
Cl
Me
R1
N
O2N
3.13 84%
CF3
CO2Et
CF3
3.15 85%
i-Pr2N
i-Pr2N
N
i-Pr2N
S
3.18b 87%
3.19b 88%
O
3.20d 87%
i-Pr
i-Pr2N
R1
N
Ar
3.14 88%
Me
R
i-Pr2N
i-Pr2N
i-Pr2N
3.17b 94%
R2
LiOtBu (1.0 equiv)
isooctane, 60 °C
N
3.16 80%
R3
(CuOtBu)4 (0.625 mol%)
Xantphos (2.5 mol%)
OBz
1.0 equiv
R1-4 = alkyl, aryl, H
1.2 equiv
Ar-B(neop)
i-Pr2N
R
i-Pr
N
N
X
N
Cl
Me
Me
Me
d
X = Br 3.28 92%
Cl 3.29d 81%
3.22 95%
3.21d 78%
MeO2C
O2N
H
Me
Me
Ph
N
N
H
N
NO2
3.26d
80%
3.27d
Br
87%
Cl
3.30 95%
O
N
N
N
Me
3.23 81%
Boc
Br
3.31d 90%
Me
N
Me
Br
3.24 80%
Me
Me
N
N
Me
Me
3.25 76%
Me
N
Me
3.32 95%
Me
Me
NO2
Me
3.33d 60%
a
Reactions performed on 0.5 mmol scale. Yields of isolated products are reported. neop = neopentyl glycol.
5 mol% of the catalyst were used. c The reaction was performed on a 5 mmol scale. d 2.5 mol% of the
catalyst were used at 45 °C. OBz = O-benzoyl.
b
An extension of the substrate scope could be achieved if lithium tert-butoxide is
replaced with CsF. This change was particularly beneficial in coupling hindered boronic
94
esters with less-hindered electrophiles (Scheme 3.3, equation 3). Furthermore, CsF
allowed the reaction to be performed in the presence of acidic functional groups, as
demonstrated by the reaction of 4-hydroxypiperidine-derived electrophile 3.35 to give
3.36 shown in equation 4 (Scheme 3.3). Under the conditions using alkoxide, both of
these products were obtained in less than 20% isolated yield. Finally, the extremely
hindered aniline 3.33 could be prepared in 89% yield using this procedure (Scheme 3.3,
equation 5).
Scheme 3.3
Section 4. Mechanism
We propose that the amination reaction proceeds according to the mechanism
shown in Scheme 2. The reaction involves transmetallation from boron to copper, with
subsequent electrophilic amination of the aryl copper intermediate. Finally, the reactive
copper alkoxide is regenerated with lithium alkoxide.
95
Scheme 3.4
While the transmetallation of aryl boronic esters with NHC-ligated copper
complexes is known to result in monomeric, neutral arylcopper(I) intermediates which
can be characterized,17,20 to the best of our knowledge there are no examples of the
corresponding phosphine-ligated arylcopper(I) complexes which have been prepared and
isolated through any analogous transmetallation processes.21 We were able to isolate and
characterize by x-ray diffraction XantphosCu-(4-Me)Ph 3.37, the product of
transmetallation of XantphosCuOtBu with 4-tolyl (neopentyl)boronic ester 3.5 (Equation
6). The isolation of this bidentate phosphine-ligated arylcopper(I) complex provides
evidence that organoboron—copper transmetallation can also be used to prepare
monomeric, isolable phosphine-ligated aryl copper(I) complexes analogous to those
supported by NHC ligands and stands as the only example of a monomeric arylcopper(I)
complex supported by a bidentate phosphine ligand.22
96
Figure 3.1 Ellipsoid Drawing of XantphosCu-(4-Me)Ph (3.37) (hydrogen atoms omitted for clarity).
Although the transmetallation of organoboron compounds with catalytic amounts
of late transition metals such as palladium,23 rhodium,24 ruthenium,25 gold,26 and others27
has been extensively described, the exact mechanism of organoboron—copper
transmetallation remains a subject of debate.28 Transmetallation of the organoboron
compound with copper has been proposed to occur through either the neutral
organoborane, in a process called σ-bond metathesis (top of Scheme 3.5).20,29
Alternatively, organoboron—copper transmetallation has been proposed to occur through
a reaction analogous to nucleophilic substitution by the anionic organoborate onto the
copper center (bottom of Scheme 35).30 To further complicate matters, it is now well-
31
established that a significant amount of organoborate can exist in solution
97
due to
rapid equilibrium with the neutral organoborane27,32 in many conditions which utilize
basic additives in conjunction with organoboron compounds.
Scheme 3.5
To test the possibility of transmetallation occurring through an anionic
organoborate rather than the neutral organoborane, we subjected borate ester 3.38, which
cannot have a significant equilibrium with its neutral borane in solution, to amination
using the 4-benzoyloxymorpholine electrophile 3.1 under standard catalytic conditions in
the presence and absence of lithium tert-butoxide. In both cases, none of the desired
product was detected by GC analysis of the crude reaction mixture, and in the reaction
with added alkoxide, the electrophile was completely consumed within 6 h. These results
are consistent with transmetallation occurring through the neutral organoborane..
Scheme 3.6
98
We also examined the efficiency of catalytic amination of electrophile 3.2 in
reactions which utilized superstoichoimetric amounts of sodium tert-butoxide as the
additive used to assist catalyst turnover. In these reactions, the formation of organoborate
through reaction of the organoboron compound with alkoxide occurs quickly; this
organoborate is in equilibrium with the neutral organoboron compound and is expected to
further favor the formation of organoborate as more equivalents of sodium alkoxide are
added.18a,23 In a reaction using the optimal molar ratio of tolyl(neopentyl)boronic ester
and sodium tert-butoxide (1.2 equiv of boronic ester to 1.0 equiv of alkoxide), the
reaction proceeded efficiently to give the product in quantitative yield (conditions a,
Figure 3.2). However, in a subsequent reaction using 1.6 equiv of alkoxide, only 82% of
the desired product was obtained, with full conversion of the electrophile observed
(conditions b, Figure 3.2).
During the course of monitoring this experiment, the
electrophile was shown to undergo steady decomposition during the first hour of the
reaction with no significant amount of product formation observed.
In fact, the
consumption of electrophile was even more pronounced when 2.0 equiv of the alkoxide
was used (approx. 50%, conditions c, Figure 3.2), and less than 5% of product formation
was observed within the first hour of this reaction. Taken together, these experiments
indicate that organoborate formation is significant when a reactive alkoxide, such as
sodium tert-butoxide, is used in superstoichiometric amounts relative to the
tolyl(neopentyl)boronic ester. As importantly, however, is the observation that product
formation under conditions b and c is suppressed until a significant amount of the
alkoxide has been consumed in side reactions with the electrophile (approx. 18%
conversion of 3.2, condition b; approx. 50% conversion of 3.2, condition c).
Interestingly,
we
found
that,
by
simply
adding
an
extra
equivalent
99
of
tolyl(neopentyl)boronic ester to the reaction described by conditions c after one hour, the
desired reaction pathway became dominant again, due now to the presence of an excess
molar amount of boronic ester to alkoxide (conditions d, Figure 3.2), which allows
transmetallation of the copper(I) alkoxide with the neutral organoborane to occur. In the
reactions using conditions c and conditions d, product formation is initially sluggish due
to rapid reaction of the neutral tolyl(neopentyl)boronic ester with alkoxide to form an
organoborate, which cannot undergo transmetallation with copper(I) alkoxide.
Figure 3.2 Effect of superstoichiometric amount of NaOtBu on product yield.
100
We next focused our attention on the electrophilic amination of the putative
aryl copper intermediate. In a stoichiometric reaction of electrophile 3.2 with Xantphossupported copper aryl complex (3.37), the desired aniline was obtained in 89% yield
(Equation 7). A similar result was obtained with IMes-supported arylcopper(I) complex
(3.39),14 which resulted in a 73% yield of aniline in less than 60 minutes at 25 °C
(Equation 8). In addition, when used as a catalyst, both 3.37 and 3.39 provided results
indistinguishable from those obtained using either XantphosCuOtBu or IMesCuOtBu
catalyst in the amination of 3.2 with tolyl(neopentyl)boronic ester (IMesCuOtBu is an
effective
catalyst
for
the
amination
of
substrates
with
less-hindered
aryl(neopentyl)boronic esters).
Section 5. Conclusion
In conclusion, we have developed a mild copper-catalyzed reaction for the
synthesis of sterically hindered anilines from aryl and heteroaryl boronic esters. This
method allowed us to prepare some of the most hindered anilines ever made.
Furthermore, the new method is compatible with a wide range of functional groups,
including chloro, bromo, iodo, carbomethoxy, nitro, hydroxyl, formyl, and methoxy, and
can be used to prepare a wide variety of heteroaromatic amines. Furthermore, the
isolation and characterization of 3.37 represents the first example of a monomeric
101
bidentate phosphine-ligated aryl copper(I) complex.
We anticipate that the
exceptionally broad substrate scope and reliability of this new procedure, together with
the availability of a wide variety of aryl boronic esters, will make it a useful option for
the synthesis of hindered anilines.
102
Section 6. Experimental
General
All reactions were performed under a nitrogen atmosphere with flame-dried glassware,
using standard Schlenk techniques, or in a glove box (Nexus II from Vacuum
Atmospheres). Column chromatography was performed using a Biotage Iso-1SV flash
purification system with silica gel from Agela Technologies Inc. (60Å, 40-60 µm, 230400 mesh). Ion Exchange Chromatography was performed using analytical grade cation
exchange resin from sulfonic acid functionalized styrene (Bio-Rad Laboratories, 200-400
mesh, 5.2 meq/g). General method for purification by ion exchange chromatography is as
follows: crude product was adsorbed on the cation exchange resin (200 mg resin/mmol
product) using MeOH, and the resin was subsequently washed with 10%
dichloromethane in MeOH over 4 CV, then 10% Et3N in MeOH over 4 CV to elute the
product. Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum RX I
spectrometer. IR peak absorbencies are represented as follows: s = strong, m = medium,
w = weak, br = broad. 1H- and 13C-NMR spectra were recorded on a Bruker AV-300 or
AV-500 spectrometer. 1H NMR chemical shifts (δ) are reported in parts per million
(ppm) downfield of TMS and are referenced relative to residual proteated solvent peak
(CDCl3 (7.26 ppm), C6D6 (7.16 ppm), or CD2Cl2 (5.32 ppm)).
13
C chemical shifts are
reported in parts per million downfield of TMS and are referenced to the carbon
resonance of the solvent (CDCl3: δ 77.2 ppm, C6D6: δ 128.1 ppm, CD2Cl2: δ 54.0 ppm,
CD3CN: δ 1.3 ppm). Data are represented as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, hept = heptet, m = multiplet), integration, and
coupling constants in Hertz (Hz). Mass spectra were collected on a JEOL HX-110 mass
103
spectrometer. GC analysis was performed on a Shimadzu GC-2010 instrument with a
flame ionization detector and a SHRXI-5MS column (15 m, 0.25 mm inner diameter,
0.25 µm film thickness). The following temperature program was used: 2 min @ 60 °C,
13 °C/min to 160 °C, 30 °C/min to 250 °C, 5.5 min @ 250 °C.
Materials
THF, CH2Cl2, diethyl ether, and toluene were degassed and dried by passing through
columns of neutral alumina. 1,4-dioxane was distilled from purple Na/benzophenone
ketyl and stored over 4Å molecular sieves. Deuterated solvents were purchased from
Cambridge Isotope Laboratories, Inc. Deuterated solvents were degassed and dried over
4Å molecular sieves before use. Commercial reagents were purchased from SigmaAldrich Co., VWR International, LLC., or STREM Chemicals, Inc., and were used as
received. Aryl boronic esters were prepared according to a literature procedure.33
3.6.a. Reaction Optimization
General:
All optimization reactions were performed in a glove box. A 1-dram vial was charged
with a stir bar. To the vial was added alkoxide additive (1.00 equiv), aryl boronic ester
(1.20 equiv), copper catalyst (0.05 equiv), n-dodecane (0.10 equiv), and solvent (0.1 M).
To the resulting mixture was added O-benzoyl-N,N-dialkyl hydroxylamine (1.00 equiv).
The reaction vial was capped and stirred for 24 h with heating at the indicated
temperature. Product yield was determined by GC comparison against n-dodecane as an
internal standard.
Optimization of the aryl boronic ester backbone (Entries 1 – 3, Table 3.4):
104
Reactions were conducted according to the General Procedure using IMesCu-OtBu
(0.003 mmol, 1.1 mg), Na-OtBu (0.050 mmol, 4.8 mg), and either 4,4,5,5-tetramethyl-2(p-tolyl)-1,3,2-dioxaborolane (0.060 mmol, 13.8 mg), 2-(p-tolyl)-1,3,2-dioxaborolane
(0.060 mmol, 9.7 mg), or 5,5-dimethyl-2-(p-tolyl)-1,3,2-dioxaborinane (0.060 mmol,
12.2 mg) with THF as solvent (0.5 mL).
To the resulting solution was added 4-
benzoyloxymorpholine (0.050 mmol, 10.4 mg). Reactions were heated at 25 °C with
stirring for 24 h.
Optimization of the catalyst (Entries 4 – 12, Table 3.4):
Reactions were conducted according to the General Procedure using the indicated copper
catalysts (0.003 mmol), Na-OtBu (0.050 mmol, 4.8 mg), and dimethyl-2-(p-tolyl)-1,3,2dioxaborinane (0.060 mmol, 12.2 mg) with THF as solvent (0.5 mL). To the resulting
solution was added 4-benzoyloxymorpholine (0.050 mmol, 10.4 mg). Reactions were
heated at 25 °C with stirring for 24 h.
Note on Preparation of XantPhosCu-OtBu from XantPhos and (Cu-OtBu)4:
In a glove box, a 1-dram reaction vial was charged with a stir bar. To the vial was added
Cu-OtBu tetramer (0.25 equiv), XantPhos ligand (1.00 equiv) and solvent (0.1 M). The
resulting mixture was allowed to stir at 45°C for 0.5 h. The mixture was used as a stock
solution of the catalyst.
Optimization of the solvent (Entries 13 – 15, Table 3.4):
Reactions were conducted according to the General Procedure using XantPhosCu-OtBu
(0.003 mmol, 25 µL of a 0.1 M stock solution), Na-OtBu (0.050 mmol, 4.8 mg), and 2(p-tolyl)-5,5-dimethyl-1,3,2-dioxaborinane (0.060 mmol, 12.4 mg) with either diethyl
105
ether, dichloromethane, or 1,4-dioxane as solvent (0.475 mL).
To the resulting
mixture was added 4-benzoyloxymorpholine (0.050 mmol, 10.4 mg). Reactions were
heated at 25 °C with stirring for 24 h.
Table 3.4
LnCu X (5 mol%),
sodium t-butoxide (1.0 equiv)
4-benzoyloxymorpholine (1.0 equiv)
(4-Me)Ph
B(OR)2
1.2 equiv
a
N
Me
O
Solvent (0.1 M),
25 C, 24 h
Entry
(4 Me)Ph B(OR)2
LnCu Xa
Solvent
Yield
1
3.1
IMesCu-OtBu
THF
<5
2
3.2
IMesCu-OtBu
THF
16
3
3.3
IMesCu-OtBu
THF
72
4
3.3
CyIBoxCu-Cl
THF
<1
5
3.3
IMeCu-Cl
THF
<1
6
3.3
ICyCu-OtBu
THF
<1
7
3.3
ItBuCu-Cl
THF
48
8
3.3
IAdCu-Cl
THF
60
9
3.3
IPrCu-OtBu
THF
0
10
3.3
tBuBipyCu-OtBu
THF
52
11
3.3
dppeCu-OtBu
THF
0
12
3.3
XantPhosCu-OtBu
THF
92
13
3.3
XantPhosCu-OtBu
diethyl ether
5
14
3.3
XantPhosCu-OtBu
DCM
0
15
3.3
XantPhosCu-OtBu
1,4-dioxane
99
XantPhosCu-OtBu is formed in situ from (Cu-OtBu)4 and XantPhos.
Me
IMes R = 2,4,6-trimethylphenyl
Me
R
N
N
N
O
PPh2
XantPhos
PPh2
tBu
t-BuBipy
tBu
N
R
IMe
R = Methyl
ICy
R = cyclohexyl
ItBu
R = t-butyl
IAd
R = adamantyl
IPr
R = 2,6-diisopropylphenyl
106
Optimization of solvent, alkoxide additive, and concentration with 2-(2,6dimethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (Table 3.5):
With 4-benzoyloxymorpholine:
Reactions were conducted according to the General Procedure using XantPhosCu-OtBu
(0.003 mmol, 25 µL of a 0.1 M stock solution prepared in either 1,4-dioxane or toluene),
Na-OtBu (0.050 mmol, 4.8 mg) or Li-OtBu (0.050 mmol, 4.0 mg), and 2-(2,6dimethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (0.06 mmol, 13.1 mg) with either 1,4dioxane or toluene as solvent (0.475 mL).
To the resulting mixture was added 4-
benzoyloxymorpholine (0.050 mmol, 10.4 mg). The reaction vial was capped and stirred
for 24 h at the indicated temperature.
With O-benzoyl-N,N-diisopropyl hydroxylamine:
Reactions were conducted according to the General Procedure using XantPhosCu-OtBu
(0.003 mmol, 25 µL of a 0.1 M stock solution prepared in toluene), Li-OtBu (0.050
mmol, 4.0 mg), and 2-(2,6-dimethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane (0.06
mmol, 13.1 mg) with either toluene or isooctane as solvent (0.475 mL). To the resulting
mixture was added O-benzoyl-N,N-diisopropyl hydroxylamine (0.050 mmol, 11.1 mg).
The reaction vial was capped and stirred for 24 h at the indicated temperature.
Optimization of Concentration with O-benzoyl-N,N-diisopropyl hydroxylamine and
isooctane:
The 0.5 M scale reaction (Table 3.5, entry 5) was conducted according to the General
Procedure using XantPhosCu-OtBu (0.010 mmol, 100 µL of a 0.1 M stock solution
prepared in toluene), Na-OtBu (0.200 mmol, 16.0 mg), and 2-(2,6-dimethylphenyl)-5,5dimethyl-1,3,2-dioxaborinane (0.240 mmol, 52.3 mg) with isooctane as solvent (0.3 mL,
107
0.5 M) The 1.0 M scale reaction (Table 3.5, entry 6) was conducted according to the
General Procedure using XantPhosCu-OtBu (0.010 mmol, 40 µL of a 0.25 M stock
solution prepared in toluene), Na-OtBu (0.200 mmol, 16.0 mg), and 2-(2,6dimethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane
(0.240
mmol,
52.3
mg)
with
isooctane as solvent (0.16 mL, 1.0 M). To the resulting mixture for both entries was
added O-benzoyl-N,N-diisopropyl hydroxylamine (0.200 mmol, 44.3 mg). The reaction
vial was capped and heated to 60 °C with stirring for 24 h.
Table 3.5
Me
O
Me
+
B
R1OM
Me
O
Me
XantPhosCu-OtBu (5 mol%),
R2N-OBz (1.0 equiv)
R 2N
Solvent, 45 °C, 24 h
Me
Me
Entrya
R2N-OBz
1b
2
O
OBz
N
3
4
5c
6c
a
Me
Me
Me
N
OBz
Me
R1OM
Solvent
Concentration (M)
Yield
NaO-tBu
1,4-dioxane
0.1
8
LiO-tBu
1,4-dioxane
0.1
56
LiO-tBu
toluene
0.1
74
LiO-tBu
toluene
0.1
81
LiO-tBu
toluene/isooctane
0.5
87
LiO-tBu
toluene/isooctane
(1:1)
1.0
94
Reactions conducted with 1.2 equiv of boronic ester and 1.0 equiv of ROM. XantPhosCu-OtBu is
formed in situ from (Cu-OtBu)4 and XantPhos. b Reaction is conducted at 25 °C and electrophile
is completely consumed within 3 h. c Reaction conducted at 60 °C and toluene is used to prepare
XantPhosCu-OtBu catalyst.
108
Reactions of O-benzoyl-N,N-dialkyl hydroxylamine with sodium tert-butoxide and
lithium tert-butoxide (Table 3.2).
In a glove box, a 1 dram vial was charged with a stir bar. To the vial was added either
Li-OtBu or Na-OtBu (1.00 equiv, 0.100 mmol), and 1,3,5-trimethoxybenzene as an
internal standard.
To the resulting mixture was added O-benzoyl-N,N-dialkyl
hydroxylamine (1.00 equiv, 0.100 mmol) and solvent (0.50 mL). The resulting mixture
was capped and heated at 45 °C with stirring. Conversion of O-benzoyl-N,N-dialkyl
hydroxylamine was determined by
1
H-NMR using 1,3,5-trimethoxybenzene as an
internal standard. To obtain data for each time point in Table S3, aliquots (0.05 mL)
were withdrawn from the reaction mixture and were diluted to 0.50 mL with benzene-d6.
3.6.b. Amination of Aryl Boronic Esters
General procedure using alkoxides:
In a glove box, a dram vial was charged with a stir bar. To the vial was added Cu-OtBu
tetramer (0.025 equiv, 1.7 mg, 0.0125 mmol), xantphos (0.025 equiv, 7.2 mg, 0.0125
mmol), and toluene (100 µL). After stirring for 30 min at 25 °C, the mixture was
transferred to a dram vial containing the boronic ester (1.20 equiv, 0.600 mmol), Li-OtBu
(1.00 equiv, 40.0 mg, 0.500 mmol), O-benzoyl-N,N-dialkyl hydroxylamine (1.00 equiv,
0.500 mmol), and isooctane (300 µL). An additional 100 µL of isooctane was used to
rinse the dram vial containing the catalyst into the reaction vial. The mixture was allowed
to stir at the specified temperature until complete conversion of the hydroxylamine by
TLC. The mixture was then diluted in dichloromethane (2 mL), and filtered through a
silica plug using successively dichloromethane (5 mL) and then diethyl ether (5 mL) as
109
an eluent. The solvent was removed under reduced pressure, and the crude product
was purified by silica gel chromatography or ion exchange chromatography.
General procedure using CsF:
In a glove box, a dram vial was charged with a stir bar. To the vial was added Cu-OtBu
tetramer (0.025 equiv, 1.7 mg, 0.0125 mmol), xantphos (0.025 equiv, 7.2 mg, 0.0125
mmol), and toluene (100 µL). After stirring for 30 min at 25 °C, the mixture was
transferred to a dram vial containing the boronic ester (1.20 equiv, 0.600 mmol), CsF
(5.00 equiv, 379.7 mg, 2.500 mmol), O-benzoyl-N,N-dialkyl hydroxylamine (1.00 equiv,
0.500 mmol), and toluene (400 µL). The mixture was allowed to stir at 60 °C for 72 h.
The mixture was then diluted in dichloromethane (2 mL), and filtered through a silica
plug using successively dichloromethane (5 mL) and then diethyl ether (5 mL) as an
eluent. The solvent was removed under reduced pressure, and the crude product was
purified by silica gel chromatography.
N,N-diisopropyl-4-methoxyaniline (3.7)
Compound was isolated as a yellow oil (105.6 mg, 85% yield) after purification by ion
exchange chromatography. 1H NMR (500 MHz, CD2Cl2) δ 6.94 (d, J = 9.1 Hz, 1H), 6.77
(d, J = 9.0 Hz, 1H), 3.60 – 3.46 (m, 1H), 1.02 (d, J = 6.5 Hz, 6H 13C NMR (126 MHz,
110
CDCl3) δ 155.5, 140.6, 127.6, 113.4, 55.5, 48.6, 21.4.. ESI-MS calculated for [M]
+
207.3, found 207.1. FTIR (neat, cm-1): 3037(m), 2971(s), 1464(m), 1359(m), 1286(m),
1241(s).
4-chloro-N,N-diisopropylaniline (3.8)
Compound was isolated as a colorless oil (870.4 mg, 82% yield) after purification by
silica gel column chromatography (0 → 5% Et2O/hexanes over 7 CV). 1H NMR (300
MHz, CDCl3) δ 7.14 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.73 (sept, J = 6.7 Hz,
2H), 1.19 (d, J = 6.7 Hz, 12H). 13C NMR (75 MHz, CDCl3) δ 146.7, 128.3, 123.1, 120.4,
47.7, 21.3. ESI-MS calculated for [M+H]+ 212.1, found 212.1.
FTIR (neat, cm-1):
3051(m), 2972(s), 1595(m), 1499(s), 1265(s), 740(s).
methyl 4-(diisopropylamino)benzoate (3.9)
Compound was isolated as a white solid (104.8 mg, 89% yield) after purification by silica
gel column chromatography (0 → 10% ethyl acetate/hexanes over 7 CV).
1
H NMR (300
111
MHz, CDCl3) δ 7.84 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 9.2 Hz, 1H), 4.00 – 3.86 (m,
1H), 3.84 (s, 1H), 1.30 (d, J = 6.9 Hz, 7H). 13C NMR (126 MHz, CDCl3) δ 147.3, 131.3,
120.6, 110.2, 47.8, 21.4. ESI-MS calculated for [M]+ 235.3, found 235.1. FTIR (neat,
cm-1): 2971(s), 2875(m), 2251(m), 1705(s), 1605(s), 1434(s), 1278(s).
4-(diisopropylamino)benzaldehyde (3.10)
Compound was isolated as a yellow oil (106.0 mg, 94% yield) after purification by silica
gel column chromatography (0 → 10% ethyl acetate/hexanes over 6 CV). 1H NMR (300
MHz, CD2Cl2) δ 9.67 (s, 1H), 7.64 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 4.00
(hept, J = 6.8 Hz, 2H), 1.33 (d, J = 6.9 Hz, 12H).
13
C NMR (126 MHz, CD2Cl2) δ 190.1,
153.6, 131.7, 125.5, 114.6, 48.3, 21.1. ESI-MS calculated for [M]+ 205.3, found 205.1.
FTIR (neat, cm-1): 2972(s), 2930(s), 2872(m), 2853(m), 1867(w), 1681(s), 1423(s).
4-iodo-N,N-diisopropylaniline (3.11)
112
Compound was isolated as a white-pink solid (125.0 mg, 83% yield) after purification
by silica gel column chromatography (0 → 10% ethyl acetate/hexanes over 8 CV). 1H
NMR (300 MHz, CDCl3) δ 7.42 (d, J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.76 (hept,
J = 6.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 12H).
13
C NMR (126 MHz, CD2Cl2) δ 148.5, 137.6,
120.4, 78.4, 48.1, 21.5. ESI-MS calculated for [M]+ 303.2, found 303. FTIR (neat, cm-):
3047(w), 2970(s), 2873(m), 2611(w), 1582(s), 1495(s), 1367(s), 1328(s), 1288(s),
591(w), 553(m).
4-bromo-N,N-diisopropylaniline (3.12)
Compound was isolated as off white solid (107.6 mg, 84% yield) after purification by
silica gel column chromatography (0 → 10% ethyl acetate/hexanes over 6 CV). 1H NMR
(300 MHz, C6D6) δ 7.27 (d, J = 9.1 Hz, 2H), 6.51 (d, J = 9.1 Hz, 2H), 3.32 (hept, J = 6.7
Hz, 2H), 0.91 (d, J = 6.7 Hz, 12H). 13C NMR (126 MHz, CDCl3) δ 147.3, 131.3, 120.6,
110.2, 47.8, 21.4. ESI-MS calculated for [M+H]+ 257.2, found 257. FTIR (neat, cm-1):
3038(w), 2970(s), 2872(m), 2612(w), 1588(s), 1496(s), 1367(s), 1287(s), 732(m).
113
N,N-diisopropylnaphthalen-2-amine (3.13)
Compound was isolated as a yellow oil (94.9 mg, 84% yield) after purification by ion
exchange chromatography.
1
H NMR (300 MHz, CDCl3) δ 7.82 – 7.57 (m, 3H), 7.46 –
7.33 (m, 1H), 7.32 – 7.17 (m, 2H), 7.16 (d, J = 2.1 Hz, 1H), 3.90 (hept, J = 6.6 Hz, 2H),
1.30 (d, J = 6.7 Hz, 12H).
13
C NMR (126 MHz, CD2Cl2) δ 147.0, 135.4, 128.0, 127.9,
127.7, 126.7, 126.3, 122.7, 122.1, 112.8, 48.3, 21.8. ESI-MS calculated for [M]+ 227.3,
found 227.1. FTIR (neat, cm-1): 3053(s), 2970(s), 1823(w), 1627(s), 1388(s), 1283(s),
1236(s), 1147(s), 1016(m).
ethyl 4-(diisopropylamino)-3-nitrobenzoate (3.14)
Compound was isolated as a orange oil (129.0 mg, 88% yield) after purification by silica
gel column chromatography (0 → 15% ethyl acetate/hexanes over 9 CV).
1
H NMR (300
MHz, C6D6) δ 8.18 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.5
Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.22 (hept, J = 6.6 Hz, 2H), 0.96 (t, J = 7.1 Hz, 3H),
0.88 (d, J = 6.6 Hz, 12H).
13
C NMR (126 MHz, CD3CN) δ 165.4, 150.4, 146.6, 132.4,
+
114
130.2, 126.8, 125.7, 62.2, 51.4, 21.7, 14.5. ESI-MS calculated for [M] 294.4, found
FTIR (neat, cm-1): 3690(w), 3053(s), 2985(s), 2684(w), 1719(m), 1610(m),
294.1.
1367(w).
N,N-diisopropyl-3,5-bis(trifluoromethyl)aniline (3.15)
Compound was isolated as a yellow oil (133.6 mg, 85% yield) after purification by silica
gel column chromatography (0 → 5% ethyl acetate/hexanes over 9 CV). 1H NMR (300
MHz, C6D6) δ 7.28 (s, 1H), 7.11 (s, 2H), 3.26 (hept, J = 6.8 Hz, 2H), 0.80 (d, J = 6.8 Hz,
12H).
13
C NMR (126 MHz, CD2Cl2) δ 149.5, 132.2 (q, J = 32.2 Hz), 124.7 (q, J = 272.4
Hz), 115.5, 109.3 (dt, J = 7.8, 3.8 Hz), 48.5, 21.3. ESI-MS calculated for [M]+ 313.3,
found 313.1. FTIR (neat, cm-1): 3054(m), 2976(s), 1615(s), 1550(w), 1488(s), 1429(s),
1361(s), 1276(s), 1179(s), 1130(s).
2,6-dichloro-N,N-diisopropylaniline (3.16)
Compound was isolated as a white solid (98.8 mg, 80% yield) after purification by silica
gel column chromatography (100% hexanes over 3 CV).
1
H NMR (300 MHz, CD2Cl2) δ
115
7.36 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 2.5, 8.2 Hz, 1H), 3.50
(hept, J = 6.4 Hz, 2H), 1.02 (d, J = 6.5 Hz, 12H).
13
C NMR (126 MHz, CD2Cl2) δ 147.3,
132.0, 131.1, 126.8, 50.7, 21.3. ESI-MS calculated for [M]+ 246.2, found 246. FTIR
(neat, cm-1): 3052(m), 2971(s), 1577(s), 1463(s), 1381(s), 1264(s), 1131(m), 1092(m),
742(s).
N,N-diisopropyl-2,6-dimethylaniline (3.17)
Compound was isolated as a yellow oil (96.7 mg, 94% yield) after purification by ion
exchange chromatography.
1
H NMR (500 MHz, CD2Cl2) δ 7.02 – 6.96 (m, 2H), 6.96 –
6.90 (m, 1H), 3.55 (hept, J = 6.6 Hz, 2H), 2.26 (s, 6H), 1.02 (d, J = 6.4 Hz, 12H).
13
C
NMR (126 MHz, CD2Cl2) δ 147.0, 141.4, 128.3, 125.4, 50.2, 23.7, 20.7. ESI-MS
calculated for [M+H]+ 206.3, found 206.1. FTIR (neat, cm-1): 4197(w), 3054(s), 2987(s),
2855(m), 2855(w), 2305(m), 1422(m), 1266(s),
N,N-diisopropylpyrimidin-5-amine (3.18)
116
Compound was isolated as a yellow solid (77.8 mg, 87% yield) after purification by
silica gel column chromatography (0 → 30% ethyl acetate/hexanes over 12 CV).
1
H
NMR (300 MHz, CD2Cl2) δ 8.45 (s, 1H), 8.29 (s, 1H), 3.84 (hept, J = 6.8 Hz, 1H), 1.27
(d, J = 6.8 Hz, 6H).
13
C NMR (126 MHz, CD3CN) δ 147.9, 144.6, 48.0, 21.0. [M+H]+
180.3, found 180.1. FTIR (neat, cm-1 3052(s), 2985(s), 2886(m), 2688(w), 1367(w),
1264(s).
N,N-diisopropylthiophen-3-amine (3.19)
Compound was isolated as a yellow brown oil (80.8 mg, 88% yield) after purification by
silica gel column chromatography (0 → 10% diethyl ether/hexanes over 6 CV). 1H NMR
(300 MHz, C6D6) δ 6.89 (dd, J = 5.2, 3.1 Hz, 1H), 6.72 (dd, J = 5.2, 1.5 Hz, 1H), 6.06
(dd, J = 3.1, 1.5 Hz, 1H), 3.34 (hept, J = 6.7 Hz, 2H), 0.99 (d, J = 6.7 Hz, 12H).
13
C
NMR (126 MHz, CD3CN) δ 148.9, 124.2, 124.0, 102.6, 49.2, 21.4. ESI-MS calculated
for [M+H]+ 183.3, found 183.1. FTIR (neat, cm-1): 3052(s), 2971(s), 2871(m), 1537(s),
1264(s), 1126(m).
117
N,N-diisopropylbenzofuran-2-amine (3.20)
Compound was isolated as a light orange solid (95.0 mg, 87% yield) after purification by
silica gel column chromatography (0 → 5% ethyl acetate/hexanes over 6 CV). 1H NMR
(300 MHz, CD2Cl2) δ 7.20 (d, J = 7.7 Hz, 2H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.95 – 6.82
(m, 1H), 5.34 (s, 1H), 3.76 (hept, J = 6.6 Hz, 2H), 1.30 (d, J = 6.8 Hz, 12H).
13
C NMR
(126 MHz, CD3CN) δ 161.5, 151.0, 132.3, 123.5, 119.9, 118.0, 109.9, 79.7, 49.1, 21.4.
ESI-MS calculated for [M]+ 217.3, found 217.1. FTIR (neat, cm-1): 3853(s), 2984(s),
2305(m), 1581(s), 1368(m), 1264(s), 1130(m).
2-chloro-N,N-diisopropylpyridin-3-amine (3.21)
Compound was isolated as a yellow oil (82.4 mg, 78% yield) after purification by silica
gel column chromatography (0 → 10% ethyl acetate/hexanes over 8 CV). 1H NMR (500
MHz, C6D6) δ 7.98 (dd, J = 4.5, 1.7 Hz, 1H), 7.04 (dd, J = 7.8, 1.8 Hz, 1H), 6.51 (dd, J =
7.8, 4.6 Hz, 1H), 3.28 (hept, J = 6.6 Hz, 2H), 0.89 (d, J = 6.5 Hz, 12H).
13
C NMR (126
MHz, CD3CN) δ 155.2, 146.7, 142.9, 141.2, 123.5, 51.0, 21.5. ESI-MS calculated for
[M+H]+ 213.7, found 213.
1265(s).
FTIR (neat, cm-1): 3053(s), 2974(s), 1443(m), 1398(s),
118
N-cyclohexyl-N-isopropyl-2-methylaniline (3.22)
Compound was isolated as a yellow oil (110.0 mg, 95% yield) after purification by ion
exchange chromatography. 1H NMR (300 MHz, CD3CN) δ 7.26 – 7.18 (m, 2H), 7.12 –
7.00 (m, 2H), 3.53 (hept, J = 6.8 Hz, 1H), 3.06 (tt, J = 10.7, 3.3 Hz, 1H), 2.14 (s, 3H),
1.90 – 1.80 (m, 2H), 1.74 – 1.59 (m, 2H), 1.59 – 1.48 (m, 1H), 1.37 – 1.10 (m, 2H), 1.04
(ddd, J = 15.4, 9.4, 3.3 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H).
13
C NMR (126 MHz, CD2Cl2)
δ 147.5, 140.8, 130.7, 130.3, 125.8, 125.3, 59.4, 49.8, 32.1, 26.9, 26.5, 21.4, 19.4. ESIMS calculated for [M]+ 231.4, found 231.2.
FTIR (neat, cm-1): 3052(m), 2931(s),
1379(m), 1361(w), 1264(s), 1109(m), 1066(w).
4-(4-bromophenyl)morpholine (3.23)
Compound was isolated as a white solid (98.1 mg, 81% yield) after purification by silica
gel column chromatography (0 → 17% ethyl acetate/hexanes over 8 CV). 1H NMR (300
MHz, CD2Cl2) δ 7.35 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 9.1 Hz, 1H), 3.91 – 3.66 (m, 2H),
3.21 – 2.94 (m, 2H).
13
C NMR (126 MHz, CD2Cl2) δ 151.1, 132.4, 117.7, 112.2, 67.3,
49.6.
+
ESI-MS calculated for [M+H] 242.1, found 242.9.
-1
119
FTIR (neat, cm ):
3684(w), 3053(s), 2986(s), 1494(m), 1265(s), 522(w).
1-(4-bromophenyl)piperidine (3.24)
Compound was isolated as a white solid (96.2 mg, 80% yield) after purification by ion
exchange chromatography. 1H NMR (500 MHz, CD2Cl2) δ 7.30 (d, J = 9.1 Hz, 2H), 6.79
(d, J = 9.1 Hz, 2H), 3.15 – 3.08 (m, 4H), 1.71 – 1.64 (dt, J = 11.2, 5.6 Hz, 4H), 1.62 –
1.54 (m, 2H).
13
C NMR (126 MHz, CD2Cl2) δ 151.86 (s), 132.18 (s), 118.33 (s), 111.01
(s), 54.22 (s), 54.12 – 54.05 (m), 53.89 (d, J = 27.2 Hz), 50.75 (s), 26.26 (s), 24.77 (s).
ESI-MS calculated for [M]+ 240.1, found 240. FTIR (neat, cm-1): 3053(s), 2986(s),
2940(s), 1856(m), 2827(m), 2305(s), 1588(m), 1421(s), 1264(s), 1130(m), 895(s).
tert-butyl 4-(o-tolyl)piperazine-1-carboxylate (3.25)
120
Compound was isolated as a yellow solid (105.2 mg, 76% yield) after purification by
silica gel column chromatography (0 → 10% ethyl acetate/hexanes over 6 CV). 1H NMR
(300 MHz, MeOD) δ 7.25 – 7.11 (m, 2H), 7.03 – 6.77 (m, 2H), 3.61 – 3.54 (m, 2H), 2.98
– 2.56 (m, 2H), 2.31 (s, 3H), 1.49 (s, 9H).
13
C NMR (126 MHz, CD3CN) δ 155.5, 152.5,
133.5, 131.9, 127.6, 124.3, 120.1, 80.0, 52.6, 28.5, 21.8, 17.9. ESI-MS calculated for
[M]+ 276.4, found 276.
FTIR (neat, cm-1): 3053(s), 2984(m), 2053(m), 1685(m),
1366(m), 1265(s), 1171(m).
Br
N
Me
O2N
4-bromo-N-cyclohexyl-N-(4-(4-nitrophenyl)butan-2-yl)aniline (3.26)
Compound was isolated as a yellow oil (86.8 mg, 80% yield) after purification by silica
gel column chromatography (0 → 15% ethyl acetate/hexanes over 9 CV). 1H NMR (500
MHz, CDCl3) δ 8.01 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.6 Hz,
2H), 6.66 (d, J = 9.0 Hz, 2H), 3.48 – 3.39 (m, 1H), 3.19 – 3.09 (m, 1H), 2.59 (t, J = 8.1
Hz, 2H), 1.92 – 1.82 (m, 1H), 1.79 – 1.63 (m, 5H), 1.59 – 1.52 (m, 1H), 1.42 – 1.35 (m,
2H), 1.25 – 1.14 (m, 5H), 1.05 – 0.95 (m, 1H).
13
C NMR (126 MHz, CDCl3) δ 150.2,
147.4, 146.4, 131.4, 129.1, 123.7, 121.0, 110.7, 58.7, 52.1, 37.2, 33.6, 32.8, 31.9, 26.3,
26.0, 25.9, 19.8. ESI-MS calculated for [M+H]+ 431.1, found 431.3. FTIR (neat, cm-1):
3053(m), 2988(w), 1420(w), 1267(s), 918(s).
121
methyl 4-(3-(benzyl(4-chlorophenyl)amino)butyl)benzoate (3.27)
Compound was isolated as a colorless oil (178.2 mg, 87% yield) after purification by
silica gel column chromatography (0 → 20% ethyl acetate/hexanes over 8 CV), then ion
exchange chromatography. 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz, 2H), 7.34
– 7.16 (m, 5H), 7.11 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 6.55 (d, J = 9.1 Hz,
2H), 4.38 (s, 2H), 3.98 (dq, J = 13.6, 6.7 Hz, 1H), 3.89 (s, 3H), 2.69 (t, J = 7.9 Hz, 2H),
1.99 – 1.91 (m, 1H), 1.83 – 1.74 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H).
13
C NMR (126 MHz,
CDCl3) δ 167.1, 147.9, 147.3, 139.6, 129.8, 128.9, 128.6, 128.4, 128.1, 126.8, 126.5,
121.7, 115.2, 53.6, 52.0, 48.4, 36.2, 33.4, 17.8. ESI-MS calculated for [M+H]+ 408.2,
found 408.3. FTIR (neat, cm-1): 3053(m), 2986(w), 1718(s), 1496(m), 1265(s), 738(s).
N-(4-(3-bromophenyl)butan-2-yl)-N-isopropyl-4-methylaniline (3.28)
Compound was isolated as a colorless oil (166.3 mg, 92% yield) after purification by
silica gel column chromatography (0 → 5% Et2O/hexanes over 9 CV).
1
H NMR (300
MHz, CDCl3) δ 7.29 – 7.18 (m, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H),
122
6.79 – 6.70 (m, 2H), 3.50 – 3.36 (m, 1H), 3.28 – 3.17 (m, 1H), 2.49 – 2.29 (m, 2H),
2.21 (s, 3H), 1.78 – 1.65 (m 1H), 1.47 – 1.34 (m, 1H), 1.16 – 0.91 (m, 9H).
13
C NMR
(126 MHz, CDCl3) δ 145.7, 145.0, 131.5, 129.9, 129.1, 128.9, 128.7, 127.1, 122.5, 121.0,
52.2, 48.4, 37.7, 33.2, 22.6, 21.4, 20.6, 19.2. ESI-MS calculated for [M+H]+ 360.1,
found 360.5. FTIR (neat, cm-1): 3047(w), 2968(m), 1514(m), 1265(s), 739(s).
N-(4-(3-chlorophenyl)butan-2-yl)-N-isopropyl-4-methylaniline (3.29)
Compound was isolated as a colorless oil (128.9 mg, 81% yield) after purification by
silica gel column chromatography (0 → 15% ethyl acetate/hexanes over 7 CV, then 0 →
5% Et2O/hexanes over 7 CV. 1H NMR (300 MHz, C6D6) δ 7.19 (s, 1H), 7.17 – 7.09 (m,
3H), 6.97 (d, J = 8.5 Hz, 2H), 6.91 (t, J = 7.7 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 3.52 (dq,
J = 13.2, 6.6 Hz, 1H), 3.38 – 3.30 (m, 1H), 2.53 – 2.46 (m, 2H), 2.31 (s, 3H), 1.81 (tdd, J
= 10.2, 8.8, 5.8 Hz, 1H), 1.59 – 1.45 (m, 1H), 1.25 – 1.00 (m, 9H).
13
C NMR (126 MHz,
CDCl3) δ 145.7, 144.7, 134.1, 129.5, 129.1, 128.6, 128.0, 127.8, 127.6, 126.6, 125.9,
121.0, 52.2, 48.4, 37.6, 33.2, 22.5, 21.5, 20.5, 19.1. ESI-MS calculated for [M+H]+
315.2, found 315.3. FTIR (neat, cm-1): 3054(m), 2987(w), 1419(w), 1265(s), 741(s).
123
(4aR,8aS)-1-(4-nitrophenyl)decahydroquinoline (3.30)
Compound was isolated as a yellow solid (123.7 mg, 95% yield) after purification by
silica gel column chromatography (0 → 4% ethyl acetate/hexanes over 4 CV). 1H NMR
(300 MHz, C6D6) δ 8.03 (d, J = 9.3 Hz, 2H), 6.32 (d, J = 9.3 Hz, 2H), 2.94 – 2.92 (m,
2H), 2.84 – 2.58 (m, 1H), 2.34 (td, J = 10.6, 3.0 Hz, 1H), 1.77 – 1.22 (m, 6H), 1.22 – 0.95
(m, 3H), 0.95 – 0.63 (m, 3H).
13
C NMR (126 MHz, CD2Cl2) δ 155.51 (s), 138.25 (s),
126.18 (s), 114.54 (s), 64.96 (s), 54.22 (s), 54.00 (s), 53.78 (s), 44.08 (s), 40.12 (s), 33.72
(s), 30.55 (s), 27.70 (s), 26.75 (s), 25.77 (s), 23.54 (s). ESI-MS calculated for [M+H]+
260.3, found 260.1. FTIR (neat, cm-1): 3053(m), 2986(m), 2934(m), 1594(m), 1421(m),
1312(m), 1264(s), 1113(w), 895(m), 705(s).
2-methyl-1-(p-tolyl)pyrrolidine (3.31)
Compound was isolated as a colorless oil (79.1 mg, 90% yield) after purification by silica
gel column chromatography (0 → 5% ethyl acetate/hexanes over 8 CV). 1H NMR (300
MHz, C6D6) δ 7.13 (d, J = 8.7 Hz, 2H), 6.56 (d, J = 8.5 Hz, 2H), 3.80 – 3.49 (m, 1H),
3.13 (dt, J = 12.4, 6.1 Hz, 1H), 2.88 (dt, J = 14.6, 6.9 Hz, 1H), 2.28 (s, 3H), 1.74 – 1.57
(m, 2H), 1.55 – 1.42 (m, 1H), 1.32 – 1.18 (m, 1H), 0.98 (d, J = 6.2 Hz, 3H).
13
124
C
NMR (126 MHz, CDCl3) δ 145.4, 129.7, 124.3, 112.0, 53.8, 48.5, 33.2, 23.4, 20.3, 19.6.
ESI-MS calculated for [M+H]+ 176.1, found 176.1.
FTIR (neat, cm-1): 3053(m),
2985(w), 1521(w), 1265(s).
2,2,6,6-tetramethyl-1-(4-nitrophenyl)piperidine (3.32)
Compound was isolated as a yellow oil (114.3 mg, 87% yield) after purification by silica
gel column chromatography (100% hexanes over 2CV). 1H NMR (300 MHz, CDCl3) δ
8.14 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 1.74 (ddd, J = 11.3, 8.1, 3.2 Hz, 2H),
1.67 – 1.46 (m,4H), 1.32 – 1.14 (m, 2H), 1.03 (s,12H).13C NMR (126 MHz, CDCl3) δ
154.51, 145.69, 134.75, 123.21, 54.72, 42.14, 29.81, 18.27. ESI-MS calculated for [M]+
262.4, found 262.1. FTIR (neat, cm-1): 3085(w), 2968(s), 2869(m), 1586(s), 1345(s),
1277(s), 1174(m), 1130(s), 1036(m),
2,2,6,6-tetramethyl-1-(o-tolyl)piperidine (3.33)
125
Compound was isolated as a yellow oil (102.9 mg, 89% yield) after purification by
silica gel column chromatography (100% hexanes over 2 CV).
1
H NMR (300 MHz,
C6D6) δ 7.34 – 7.27 (m, 1H), 7.21 (dd, J = 5.5, 3.8 Hz, 1H), 7.10 – 7.01 (m, 2H), 2.37 (s,
3H), 1.93 – 1.71 (m, 1H), 1.70 – 1.42 (m, 5H), 1.25 (s, 6H), 0.79 (s, 6H).
13
C NMR (75
MHz, C6D6) δ 145.9, 141.5, 132.4, 130.9, 125.8, 125.5, 55.3, 42.4, 32.0, 25.7, 19.9, 19.0.
ESI-MS calculated for [M]+ 231.4, found 231.2. FTIR (neat, cm-1): 3053(s), 2971(s),
1486(m), 1349(m), 1265(s), 895(m).
4-(2,5-dichlorophenyl)morpholine (3.34)
Compound was isolated as a colorless oil (105.8 mg, 91% yield) after purification by
silica gel column chromatography (0 → 5% Et2O/hexanes over 7 CV). 1H NMR (500
MHz, CDCl3) δ 6.90 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.61 (dd, J = 8.4, 2.1
Hz, 1H), 3.64 – 3.43 (m, 4H), 2.60 – 2.36 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 150.0,
133.2, 131.5, 127.0, 123.7, 120.8, 67.0, 51.5. ESI-MS calculated for [M+H]+ 232.0,
found 232.1. FTIR (neat, cm-1): 3054(s), 2986(m), 1421(w), 1265(s), 736(s).
126
4-hydroxy-1-(4-chlorophenyl)piperidine (3.36)
Compound was isolated as white needles (79.2 mg, 75% yield) after purification by silica
gel column chromatography (40 → 70% Et2O/hexanes over 7 CV). 1H NMR (300 MHz,
C6D6) δ 7.13 (d, J = 9.1 Hz, 2H), 6.43 (d, J = 9.0 Hz, 2H), 3.29 (dtt, J = 12.6, 8.4, 4.0 Hz,
1H), 3.15 – 2.97 (m, 2H), 2.39 (ddd, J = 12.6, 9.6, 3.2 Hz, 2H), 1.61 – 1.41 (m, 2H), 1.36
– 1.21 (m, 2H), 0.66 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 150.0, 129.1, 124.4, 117.8,
67.8, 47.4, 34.1. ESI-MS calculated for [M]+ 212.2, found 212.3. FTIR (neat, cm-1):
3404(br), 2951(m), 1635(br), 1495(s), 1041(s), 733(s).
3.6.c. Synthesis of O-benzoyl-N,N-dialkyl hydroxylamines
General:
The O-benzoyl-N,N-dialkyl hydroxylamines were synthesized according to a modified
literature procedure.10a To a reaction flask under nitrogen was added potassium hydrogen
phosphate (5.00 equiv) and benzoyl peroxide (1.20 equiv), followed by DMF (1.0 M).
With vigorous stirring, the secondary amine (1.00 equiv) was added, and the resulting
mixture stirred for 25 °C until complete conversion of the amine as indicated by TLC.
The solids were filtered off through a plug of silica using diethyl ether as the eluent. The
127
organics were concentrated and the crude product was purified by silica gel
chromatography or ion exchange chromatography.
4-benzoyloxymorpholine (3.1)
Compound was isolated as a white solid (2942.1 mg, 71% yield) after purification by
silica gel column chromatography (0 → 50% diethyl ether/hexanes over 9 CV).
1
H
NMR (300 MHz, CDCl3) δ 8.20 – 7.80 (m, 2H), 7.57 (dd, J = 10.5, 4.4 Hz, 1H), 7.45 (t, J
= 7.5 Hz,2H), 4.08 – 3.76 (m, 4H), 3.46 (d, J = 9.9 Hz, 2H), 3.05 (t, J = 10.7 Hz, 2H
13
C
NMR (126 MHz, CDCl3) δ 164.59, 133.23, 129.47, 129.20, 128.49, 65.87, 57.02. ESIMS calculated for [M]+ 207.2, found 207. FTIR (neat, cm-1): 3053(s), 2986(s), 2858(m)
1691(m), 1264(s), 1160(w), 895(m).
O-benzoyl-N,N-diisopropylhydroxylamine (3.2)
Compound was isolated as a light colored yellow oil which solidifies into a white
crystalline product (1992.1 mg, 60% yield) after purification by silica gel column
chromatography (0 → 20% ethyl acetate/hexanes over 9 CV). 1H 1H NMR (300 MHz,
CDCl3) δ 8.14 – 7.92 (m, 2H), 7.57 (dd, J = 10.4, 4.4 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H),
3.85 – 2.97 (m, 2H), 1.17 (d, J = 6.4 Hz, 12H).
13
C NMR (126 MHz, CDCl3) δ 166.33,
128
132.98, 129.61, 129.46, 128.48, 53.60, 19.97, 17.67. ESI-MS calculated for [M]
+
221.3, found 221.1. FTIR (neat, cm-1): 3053(s), 2984(s), 2939.8(m), 1737(s), 1601(w),
1584(w), 1421(s), 1384(m), 1264(s), 1025(s), 895(s), 746(s).
O-benzoyl-N-cyclohexyl-N-isopropylhydroxylamine (S1)
Compound was isolated as a white solid (991.7 mg, 40% yield) after purification by silica
gel column chromatography (0 → 15% ethyl acetate/hexanes over 9CV). 1H NMR (300
MHz, CDCl3) δ 8.11 – 7.94 (m, 2H), 7.64 – 7.52 (m, 1H), 7.50 – 7.38 (m, 2H), 3.72 –
3.33 (m, 1H), 3.27 – 2.83 (m, 1H), 1.85 (dd, J = 33.2, 11.2 Hz, 4H), 1.63 (d, J = 11.6 Hz,
1H), 1.52 – 0.94 (m, 11H).
13
C NMR (126 MHz, CDCl3) δ 166.39, 133.02, 129.71,
129.55, 128.54, 61.88, 52.69, 30.10, 28.78, 26.01, 25.35. ESI-MS calculated for [M]+
261.4, found 261. FTIR (neat, cm-1): 3053(s), 2986(s), 2684(m), 1710(m), 1601(w),
1266(s), 1158(w), 1082(w), 1063(w), 894(s), 743(s).
piperidin-1-yl benzoate (S2)
Compound was isolated as a white solid (2627.0 mg, 64% yield) after purification by
silica gel column chromatography (0 → 20% diethyl ether/hexanes over 9CV). 1H NMR
(300 MHz, CDCl3) δ 8.07 – 7.87 (m, 2H), 7.61 – 7.51 (m, 1H), 7.49 – 7.36 (m, 2H), 3.62
129
– 3.35 (m, 2H), 2.78 (m, J = 8.9, 8.3 Hz, 2H), 1.97 – 1.77 (m, 4H), 1.75 – 1.54 (m,
1H), 1.45 – 0.94 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 164.85, 133.01, 129.78, 129.52,
128.46, 77.16, 57.63, 25.09, 23.44. ESI-MS calculated for [M]+ 205.3, found 205. FTIR
(neat, cm-1): 3943(w), 3053(s), 2985(s), 1732(s), 1421(m), 1264(s), 1177(w), 1068(m),
1016(m), 895(m),745(s).
tert-butyl 4-(benzoyloxy)piperazine-1-carboxylate (S3)
Compound was isolated as a white solid (1166.6 mg, 71% yield) after purification by
silica gel column chromatography (0 → 20% ethyl acetate/hexanes over 9 CV). 1H NMR
(300 MHz, CDCl3) δ 8.25 – 7.77 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz,
2H), 4.05 (s, 2H), 3.53 – 3.26 (m, 4H), 2.92 (s, 2H), 1.48 (s, 9H).
13
C NMR (126 MHz,
CDCl3) δ 163.99, 153.96, 132.81, 129.03, 128.78, 128.09, 79.65, 55.45, 41.56, 28.00.
[M+H]+ 307.4, found 307.8. FTIR (neat, cm-1): 3053(s), 2986(s), 2938(m), 2857(w),
2830(w), 2684(m), 1739(m), 1601(w), 1421(s), 1265(s).
BzO
N
Me
O2N
O-benzoyl-N-cyclohexyl-N-(4-(4-nitrophenyl)butan-2-yl)hydroxylamine (S4)
130
Compound was isolated as a colorless oil (235.0 mg, 29% yield) after purification by
silica gel column chromatography (0 → 15% Et2O/hexanes over 7 CV, then 0 → 30%
ethyl acetate/hexanes over 7 CV), then ion exchange chromatography.
1
H NMR (300
MHz, CDCl3) δ 8.10 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.45 (dd, J = 7.6, 8.4 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 3.42 – 3.21 (m, 1H), 3.16 –
2.95 (m, 2H), 2.95 – 2.70 (m, 1H), 1.94 – 1.69 (m, 4H), 1.69 – 1.49 (m, 3H), 1.44 – 1.14
(m, 8H).
13
C NMR (126 MHz, C6D6) δ 166.5, 151.1, 146.7, 133.5, 130.0, 129.8, 129.6,
128.9, 124.0, 62.0, 56.5, 31.0, 30.7, 26.2, 25.3, 25.1, 24.9. ESI-MS calculated for
[M+H]+ 397.2, found 397.2. FTIR (neat, cm-1): 2984(m), 2940(w), 1738(s), 1448(m),
1374(s), 1245(s), 908(s).
methyl 4-(3-((benzoyloxy)(benzyl)amino)butyl)benzoate (S5)
Compound was isolated as a colorless oil (1151.4 mg, 75% yield) after purification by
silica gel column chromatography (0 → 15% Et2O/hexanes over 9 CV).
1
H NMR (300
MHz, CDCl3) δ 7.95 – 7.85 (m, 4H), 7.59 – 7.50 (m, 1H), 7.48 – 7.37 (m, 4H), 7.33 –
7.23 (m, 3H), 7.19 (d, J = 8.2 Hz, 2H), 4.27 (d, J = 13.2 Hz, 1H), 4.09 (d, J = 13.2 Hz,
1H), 3.87 (s, 3H), 3.24 – 3.02 (m, 1H), 2.95 – 2.80 (m, 2H), 2.08 – 1.87 (m, 1H), 1.79 –
1.63 (m, 1H), 1.30 (d, J = 6.5 Hz, 3H).
13
C NMR (126 MHz, CDCl3) δ 167.2, 165.2,
148.0, 136.4, 132.9, 129.7, 129.5, 129.3, 128.6, 128.5, 128.4, 128.3, 127.7, 127.6, 59.3,
+
131
58.9, 51.9, 35.7, 32.6, 14.1. ESI-MS calculated for [M] 440.2, found 440.3. FTIR
(neat, cm-1): 3030(w), 2949(m), 1742(s), 1720(s), 1279(s).
O-benzoyl-N-(4-(3-bromophenyl)butan-2-yl)-N-isopropylhydroxylamine (S6)
Compound was isolated as a colorless oil (486.0 mg, 67% yield) after purification by
silica gel column chromatography (0 → 10% Et2O/hexanes over 7 CV), then ion
exchange chromatography. 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.57
(t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.34 (s, 1H), 7.32 – 7.27 (m, 1H), 7.11 (d, J =
4.9 Hz, 2H), 3.43 – 3.38 (m, 1H), 3.23 (dt, J = 12.6, 6.3 Hz, 1H), 2.86 – 2.72 (m, 2H),
1.93 – 1.84 (m, 1H), 1.70 – 1.60 (m, 2H), 1.20 (d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.2 Hz,
6H).
13
C NMR (126 MHz, C6D6) δ 166.6, 145.2, 133.4, 132.0, 130.3, 130.0, 129.7,129.3,
128.9, 127.6, 122.8, 57.4, 54.1, 32.6, 20.8. ESI-MS calculated for [M+H]+ 390.1, found
390.2. FTIR (neat, cm-1): 2979(m), 2876(w), 1739(s), 1451(m), 1257(s), 910(s).
132
O-benzoyl-N-(4-(3-chlorophenyl)butan-2-yl)-N-isopropylhydroxylamine (S7)
Compound was isolated as a colorless oil (612.2 mg, 80% yield) after purification by
silica gel column chromatography (0 → 10% Et2O/hexanes over 7 CV).
1
H NMR (500
MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz,
2H), 7.27 – 7.01 (m, 4H), 3.53 – 3.30 (m, 1H), 3.23 (dt, J = 12.6, 6.3 Hz, 1H), 2.85 – 2.75
(m, 2H), 1.94 – 1.83 (m, 1H), 1.69 – 1.58 (m, 1H), 1.20 (d, J = 6.3 Hz, 3H), 1.13 (d, J =
6.2 Hz, 6H).
13
C NMR (126 MHz, CDCl3) δ 166.1, 144.5, 134.0, 133.0, 129.6, 129.4,
128.7, 128.5, 126.8, 125.9, 57.1, 53.7, 32.2, 20.4. ESI-MS calculated for [M+Na]+ 368.5,
found 368.2. FTIR (neat, cm-1): 2979(m), 2875(w), 1740(s), 1451(m), 1256(s), 908(s).
(4aR,8aS)-octahydroquinolin-1(2H)-yl benzoate (S8)
Compound was isolated as a white solid (1829.4 mg, 54% yield) after purification by
silica gel column chromatography (0 → 10% ethyl acetate/hexanes with 3% toluene as an
additive over 9 CV). 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 7.1 Hz, 2H), 7.56 (t, J =
7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 3.58 (d, J = 9.5 Hz, 1H), 2.88 – 2.60 (m, 1H), 2.42
(t, J = 10.2 Hz, 1H), 1.97 (dt, J = 16.4, 11.6 Hz, 2H), 1.83 – 1.44 (m,6H), 1.46 – 0.90 (m,
5H).
13
C NMR (126 MHz, CDCl3) δ 165.26, 132.95, 129.66, 129.52, 128.45, 77.16,
71.71, 58.11, 41.36, 32.59, 31.39, 29.93, 25.78, 24.91, 24.68. ESI-MS calculated for
[M+H]+ 260.3, found 261.
FTIR (neat, cm-1): 3049(s), 2982(s), 1738(s), 1603(w),
1424(m), 1262(s), 1024(w), 704(s).
133
2-methylpyrrolidin-1-yl benzoate (S9)
Compound was isolated as a colorless oil (529.4 mg, 56% yield) after purification by
silica gel column chromatography (0 → 30% ethyl acetate/hexanes over 7 CV), then ion
exchange chromatography. 1H NMR (300 MHz, C6D6) δ 8.10 (d, J = 6.8 Hz, 2H), 7.12 –
6.98 (m, 3H), 3.65 – 3.40 (m, 1H), 3.22 – 2.92 (m, 1H), 2.74 (dt, J = 19.1, 8.7 Hz, 1H),
1.65 – 1.36 (m, 3H), 1.33 – 1.17 (m, 1H), 1.14 (d, J = 6.3 Hz, 3H).
13
C NMR (126 MHz,
CDCl3) δ 165.5, 132.9, 129.6, 129.5, 128.4, 63.7, 56.3, 28.8, 20.5, 17.9. ESI-MS
calculated for [M+Na]+ 228.1, found 228.1.
FTIR (neat, cm-1): 3054(s), 2986(m),
1734(m), 1420(m), 1265(s).
2,2,6,6-tetramethylpiperidin-1-yl benzoate (S10)
Compound was isolated as a white solid (2522.0 mg, 64% yield) after purification by
silica gel column chromatography (0 → 10% ethyl acetate/hexanes over 8 CV). 1H NMR
(300 MHz, CDCl3) δ 8.20 – 7.95 (m, 2H), 7.62 – 7.54 (m, 1H), 7.46 (t, J = 7.5 Hz, 2H),
1.63 (ddd, J = 46.5, 29.7, 11.6 Hz, 6H), 1.28 (s, 6H), 1.12 (s, 6H).
13
C NMR (126 MHz,
CDCl3) δ 166.57, 133.04, 129.95, 129.78, 128.65, 77.16, 60.62, 39.27, 32.18, 21.05,
17.21. ESI-MS calculated for [M]+ 261.4, found 261.1. FTIR (neat, cm-1): 3944(w),
134
3053(s), 2983(m), 2304(w), 1742(s), 1584(w), 1450(m), 1380(w), 1264(s), 1084(m),
1065(m), 1025(m).
4-hydroxy piperidin-1-yl benzoate (3.35)
Compound was isolated as a white powder (759.0 mg, 79% yield) after purification by
silica gel column chromatography (50 → 80% ethyl acetate/hexanes over 8 CV). 1H
NMR (500 MHz, CDCl3) δ 8.01 (s, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H),
3.92 (s, 1H), 3.63 - 3.52 (m, 1H), 3.39- 3.22 (m, 2H), 2.94 - 2.83 (m, 1H), 2.16 - 2.00 (m,
2H), 1.94 - 1.82 (m, 2H), 1.54 - 1.45 (m, 1H). 13C NMR (126 MHz, C6D6) δ 164.9, 133.1,
129.4, 128.4, 67.1, 63.8, 54.3, 52.1, 33.0, 31.5. ESI-MS calculated for [M+Na]+ 244.1,
found 244.1. FTIR (neat, cm-1): 3417(br), 3057(m), 2952(s), 1734(s), 1601(w), 1450(m),
1258(s), 1063(m).
3.6.d. Stoichiometric Reactions of Organocopper Complexes
Preparation of XantPhosCu-(4-Me)Ph (3.37):
The reaction was performed according to a modified literature procedure.17 A
scintillation vial was charged with a stir bar. To the vial was added copper tert-butoxide
tetramer (0.25 equiv, 0.125 mmol, 68.3 mg) and XantPhos (1.00 equiv, 0.500 mmol,
289.3 mg), and toluene (4.0 mL). The resulting solution was capped and stirred at 60 °C
135
for 1 h. After cooling to room temperature, 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2dioxaborolane (1.00 equiv, 0.5 mmol, 109.1 mg) was added to the stirred heterogeneous
mixture as a solution in toluene (1.0 mL, 0.1 M final concentration). The reaction vial
was capped and allowed to stir at 30 °C for 1 h. Within 5 minutes of addition of tolyl
boronic ester, the heterogenous mixture turned into a homogeneous solution. After 0.5 h
of stirring, the homogeneous solution became a heterogeneous mixture with a large
amount of precipitate. After 1 h of stirring, this precipitate was filtered and rinsed
thoroughly with pentane (10 mL) and cold diethyl ether (3 x 2 mL portions) to afford
XantPhosCu-(4-Me)Ph as a pale yellow solid (233.0 mg, 63.5% yield).
1
H NMR (500
MHz, CD2Cl2) δ 7.54 (s, 2H), 7.48 – 7.18 (m, 26 H), 7.11 (s, 2 H), 3.92 (s, 1H), 6.74 (d, J
= 6.9 Hz, 2 H), 6.60 (s, 2 H), 2.19 (s, 3 H), 1.67 (s, 6 H). 13C NMR (125 MHz, CD2Cl2) δ
155.8, 143.2, 142.0, 138.0, 134.4, 133.4, 132.0, 130.0, 129.0, 128.5, 128.4, 128.2, 127.2,
125.0, 121.9, 28.4, 21.6.
31
P NMR (202 MHz, CD2Cl2) δ -16.49 (s).
With XantPhosCu-(4-Me)Ph:
A 1-dram reaction vial was charged with a stir bar. To the vial was added XantPhosCu(4-Me)Ph (1.00 equiv, 0.050 mmol, 36.7 mg) and toluene (0.25 mL). To a shell vial was
added O-benzoyl-N,N-diisopropylhydroxylamine (1.00 equiv, 0.050 mmol, 11.1 mg),
dodecane as an internal standard, and toluene (0.25 mL).
The solution containing
hydroxylamine was withdrawn and added to the stirred solution of XantPhosCu-(4-
136
Me)Ph over one minute. The vial was capped and stirred at 25 °C for 2 h. After 1 h,
GC analysis using dodecane as an internal standard indicated the yield of N,Ndiisopropyl-4-methylaniline was 89%. The yield of desired product had increased to
97% within 2 h. The reaction was finished within 2 h. This complex was also substituted
for XantPhosCu-O-t-butoxide as a catalyst in a reaction using O-benzoyl-N,N-diisopropyl
hydroxylamine and tolyl(neopentyl)boronic ester under the conditions described in Table
S1 (Entry 15). After 24 h reaction time, a 93% yield of product was obtained.
With IMesCu-(4-Me)Ph:17
A 1-dram vial was charged with a stir bar. To the vial was added O-benzoyl-N,Ndiisopropylhydroxylamine (1.00 equiv, 0.100 mmol, 22.1 mg), 1,3,5-trimethoxybenzene,
and toluene (0.2 mL). To a shell vial was added IMesCu-(4-Me)Ph (1.00 equiv, 0.100
mmol, 45.9 mg) and toluene (0.2 mL). This solution was then added over 1 min to the
stirred solution of O-benzoyl-N,N-diisopropylhydroxylamine and the shell vial rinsed
with toluene (0.1 mL). The reaction vial was capped and stirred at 25 °C. Yield of N,Ndiisopropyl-4-methylaniline was determined by GC using 1,3,5-trimethoxybenzene as an
internal standard. The reaction was completed within 1 h.
This complex was also
substituted for IMesCu-O-t-butoxide as a catalyst in a reaction using O-benzoyl-N,Ndiisopropyl hydroxylamine and tolyl(neopentyl)boronic ester under the conditions
137
described in Table S1 (Entry 15). After 24 h reaction time, an 82% yield of product
was obtained in this catalytic reaction.
3.6.e. Reaction Rate as a Function of Added Equivalents of Sodium tert-Butoxide
Reactions a – c (Figure 3.2):
All reactions were performed in a glove box. A 1-dram reaction vial was charged with a
stir bar.
To the vial were added 2-(p-tolyl)-5,5-dimethyl-1,3,2-dioxaborinane (1.20
equiv, 0.120 mmol, 24.5 mg), XantPhosCu-O-t-butoxide (0.05 equiv, 0.005 mmol, 50 µL
of a 0.1 M stock solution prepared in benzene-d6), 1,3,5-trimethoxybenzene as an internal
standard, varying amounts of sodium tert-butoxide (a: 1.00 equiv, b: 1.60, and c: 2.00
equiv) and 950 µL of benzene-d6. To the resulting homogeneous solution was added Obenzoyl-N,N-diisopropyl hydroxylamine (1.00 equiv, 0.10 mmol, 22.1 mg), and the
reaction vial was capped and heated to 25 °C with stirring. To obtain data for product
yield and the conversion of O-benzoyl-N,N-diisopropyl hydroxylamine, 50 µL of the
stirred solution was diluted to 500 µL with benzene-d6 and the extent of conversion was
determined by 1H-NMR. To determine the yield of N,N-diisopropyl-4-methylaniline34
(indicated as a – b in Graph S1 below), 200 µL of this NMR solution was filtered
through a pipette tip with 2 cm of silica and eluted directly into a GC vial with 2 mL of
1:1 (v:v) dichloromethane:ethyl acetate solution. 1,3,5-trimethoxybenzene was used as
an internal standard for both GC and 1H NMR analysis.
138
Reaction d (Figure 3.2):
To demonstrate that catalytic activity can be restored when excess base is present, the
reaction with 2.00 equivalents of sodium t-butoxide was repeated. After 1 h, 2-(p-tolyl)5,5-dimethyl-1,3,2-dioxaborinane (1.00 equiv, 0.100 mmol, 20.4 mg in addition to the
amount already present initially) was added and the reaction was stirred at 25 °C. Yield
of N,N-diisopropyl-4-methylaniline (indicated as d in the Graph S1 below) was
determined by filtering reaction aliquots through a pipette tip with 2 cm of silica, using 2
mL of a 1:1 (v:v) dichloromethane:ethyl acetate solution as an eluent, and then analyzing
the reaction mixture by GC.
139
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141
Appendix A: Crystallographic Data for IMesCuEt (2.32,
Chapter 2)
Table 1. Crystal data and structure refinement for aw06177_0m.
Identification code
aw06177_0m
Empirical formula
C27 H37 Cu N2 O
Formula weight
469.13
Temperature
100(2) K
Wavelength
0.71073 Å
Crystal system
Triclinic
Space group
P 1
Unit cell dimensions
a = 8.4829(5) Å
α= 102.238(4)°.
b = 11.4784(6) Å
β= 98.112(4)°.
c = 14.0410(8) Å
γ = 107.368(4)°.
Volume
1244.20(12) Å3
Z
2
Density (calculated)
1.252 Mg/m3
Absorption coefficient
0.898 mm-1
F(000)
500
Crystal size
0.32 x 0.25 x 0.10 mm3
Theta range for data collection
1.93 to 33.25°.
Index ranges
-12<=h<=13, -17<=k<=17, -20<=l<=21
Reflections collected
25392
Independent reflections
9527 [R(int) = 0.0514]
Completeness to theta = 25.00°
100.0 %
Max. and min. transmission
0.9156 and 0.7621
Refinement method
Full-matrix least-squares on F2
Data / restraints / parameters
9527 / 0 / 287
Goodness-of-fit on F2
1.009
Final R indices [I>2sigma(I)]
R1 = 0.0487, wR2 = 0.0856
R indices (all data)
R1 = 0.1012, wR2 = 0.1017
Largest diff. peak and hole
0.529 and -0.577 e.Å-3
142
Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)
for aw06177_0m. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
C(1)
6083(2)
7074(2)
8044(1)
13(1)
C(2)
3623(2)
6191(2)
8497(1)
18(1)
C(3)
4235(2)
7424(2)
8999(2)
18(1)
C(4)
6744(2)
9267(2)
9070(1)
13(1)
C(5)
7718(2)
9735(2)
10040(1)
15(1)
C(6)
8688(2)
11018(2)
10358(1)
16(1)
C(7)
8681(2)
11813(2)
9744(1)
16(1)
C(8)
7660(2)
11313(2)
8782(1)
17(1)
C(9)
6678(2)
10036(2)
8430(1)
15(1)
C(10)
5565(3)
9501(2)
7395(2)
25(1)
C(11)
7731(3)
8904(2)
10737(2)
22(1)
C(12)
9728(2)
13200(2)
10109(2)
23(1)
C(13)
4548(2)
4792(2)
7261(1)
14(1)
C(14)
4985(2)
3890(2)
7653(1)
17(1)
C(15)
4699(2)
2715(2)
6999(2)
19(1)
C(16)
4000(2)
2442(2)
5987(1)
18(1)
C(17)
3568(2)
3368(2)
5626(1)
18(1)
C(18)
3824(2)
4555(2)
6251(1)
16(1)
C(19)
3330(2)
5538(2)
5847(2)
22(1)
C(20)
5731(3)
4152(2)
8745(2)
27(1)
C(21)
3724(3)
1169(2)
5298(2)
28(1)
C(22)
9859(2)
7446(2)
6782(2)
20(1)
C(23)
10576(3)
8652(2)
6454(2)
31(1)
C(24)
9294(3)
4222(2)
7041(2)
36(1)
C(25)
8825(3)
3236(2)
6050(2)
39(1)
C(26)
8996(3)
2076(2)
6330(2)
32(1)
C(27)
10323(2)
2644(2)
7286(2)
25(1)
N(1)
4762(2)
5993(1)
7925(1)
14(1)
N(2)
5728(2)
7945(1)
8716(1)
13(1)
Cu(1)
7945(1)
7271(1)
7407(1)
15(1)
143
O(1)
9986(2)
3728(1)
Table 3. Bond lengths [Å] and angles [°] for aw06177_0m.
_____________________________________________________
C(1)-N(2)
1.357(2)
C(1)-N(1)
1.360(2)
C(1)-Cu(1)
1.9022(18)
C(2)-C(3)
1.343(3)
C(2)-N(1)
1.380(2)
C(2)-H(2)
0.9500
C(3)-N(2)
1.382(2)
C(3)-H(3)
0.9500
C(4)-C(5)
1.391(2)
C(4)-C(9)
1.393(3)
C(4)-N(2)
1.440(2)
C(5)-C(6)
1.392(2)
C(5)-C(11)
1.506(3)
C(6)-C(7)
1.382(3)
C(6)-H(6)
0.9500
C(7)-C(8)
1.396(3)
C(7)-C(12)
1.506(2)
C(8)-C(9)
1.391(2)
C(8)-H(8)
0.9500
C(9)-C(10)
1.506(3)
C(10)-H(10A)
0.9800
C(10)-H(10B)
0.9800
C(10)-H(10C)
0.9800
C(11)-H(11A)
0.9800
C(11)-H(11B)
0.9800
C(11)-H(11C)
0.9800
C(12)-H(12A)
0.9800
C(12)-H(12B)
0.9800
C(12)-H(12C)
0.9800
C(13)-C(14)
1.388(3)
C(13)-C(18)
1.397(3)
7784(1)
33(1)
144
C(13)-N(1)
1.436(2)
C(14)-C(15)
1.392(3)
C(14)-C(20)
1.503(3)
C(15)-C(16)
1.390(3)
C(15)-H(15)
0.9500
C(16)-C(17)
1.389(3)
C(16)-C(21)
1.503(3)
C(17)-C(18)
1.391(3)
C(17)-H(17)
0.9500
C(18)-C(19)
1.503(3)
C(19)-H(19A)
0.9800
C(19)-H(19B)
0.9800
C(19)-H(19C)
0.9800
C(20)-H(20A)
0.9800
C(20)-H(20B)
0.9800
C(20)-H(20C)
0.9800
C(21)-H(21A)
0.9800
C(21)-H(21B)
0.9800
C(21)-H(21C)
0.9800
C(22)-C(23)
1.531(3)
C(22)-Cu(1)
1.9303(19)
C(22)-H(22A)
0.9900
C(22)-H(22B)
0.9900
C(23)-H(23A)
0.9800
C(23)-H(23B)
0.9800
C(23)-H(23C)
0.9800
C(24)-O(1)
1.426(3)
C(24)-C(25)
1.511(4)
C(24)-H(24A)
0.9900
C(24)-H(24B)
0.9900
C(25)-C(26)
1.507(3)
C(25)-H(25A)
0.9900
C(25)-H(25B)
0.9900
C(26)-C(27)
1.503(3)
C(26)-H(26A)
0.9900
145
C(26)-H(26B)
0.9900
C(27)-O(1)
1.421(3)
C(27)-H(27A)
0.9900
C(27)-H(27B)
0.9900
N(2)-C(1)-N(1)
102.89(15)
N(2)-C(1)-Cu(1)
129.69(12)
N(1)-C(1)-Cu(1)
127.42(13)
C(3)-C(2)-N(1)
106.33(16)
C(3)-C(2)-H(2)
126.8
N(1)-C(2)-H(2)
126.8
C(2)-C(3)-N(2)
106.55(16)
C(2)-C(3)-H(3)
126.7
N(2)-C(3)-H(3)
126.7
C(5)-C(4)-C(9)
122.55(16)
C(5)-C(4)-N(2)
119.08(16)
C(9)-C(4)-N(2)
118.35(15)
C(4)-C(5)-C(6)
117.57(17)
C(4)-C(5)-C(11)
122.06(16)
C(6)-C(5)-C(11)
120.37(16)
C(7)-C(6)-C(5)
121.90(17)
C(7)-C(6)-H(6)
119.0
C(5)-C(6)-H(6)
119.0
C(6)-C(7)-C(8)
118.80(16)
C(6)-C(7)-C(12)
120.88(17)
C(8)-C(7)-C(12)
120.31(17)
C(9)-C(8)-C(7)
121.36(18)
C(9)-C(8)-H(8)
119.3
C(7)-C(8)-H(8)
119.3
C(8)-C(9)-C(4)
117.79(16)
C(8)-C(9)-C(10)
121.27(17)
C(4)-C(9)-C(10)
120.94(16)
C(9)-C(10)-H(10A)
109.5
C(9)-C(10)-H(10B)
109.5
H(10A)-C(10)-H(10B)
109.5
146
C(9)-C(10)-H(10C)
109.5
H(10A)-C(10)-H(10C)
109.5
H(10B)-C(10)-H(10C)
109.5
C(5)-C(11)-H(11A)
109.5
C(5)-C(11)-H(11B)
109.5
H(11A)-C(11)-H(11B)
109.5
C(5)-C(11)-H(11C)
109.5
H(11A)-C(11)-H(11C)
109.5
H(11B)-C(11)-H(11C)
109.5
C(7)-C(12)-H(12A)
109.5
C(7)-C(12)-H(12B)
109.5
H(12A)-C(12)-H(12B)
109.5
C(7)-C(12)-H(12C)
109.5
H(12A)-C(12)-H(12C)
109.5
H(12B)-C(12)-H(12C)
109.5
C(14)-C(13)-C(18)
122.56(16)
C(14)-C(13)-N(1)
118.92(16)
C(18)-C(13)-N(1)
118.44(16)
C(13)-C(14)-C(15)
117.72(17)
C(13)-C(14)-C(20)
121.86(17)
C(15)-C(14)-C(20)
120.42(17)
C(16)-C(15)-C(14)
121.69(18)
C(16)-C(15)-H(15)
119.2
C(14)-C(15)-H(15)
119.2
C(17)-C(16)-C(15)
118.79(17)
C(17)-C(16)-C(21)
120.77(18)
C(15)-C(16)-C(21)
120.44(18)
C(16)-C(17)-C(18)
121.61(17)
C(16)-C(17)-H(17)
119.2
C(18)-C(17)-H(17)
119.2
C(17)-C(18)-C(13)
117.63(17)
C(17)-C(18)-C(19)
120.73(17)
C(13)-C(18)-C(19)
121.64(17)
C(18)-C(19)-H(19A)
109.5
C(18)-C(19)-H(19B)
109.5
147
H(19A)-C(19)-H(19B)
109.5
C(18)-C(19)-H(19C)
109.5
H(19A)-C(19)-H(19C)
109.5
H(19B)-C(19)-H(19C)
109.5
C(14)-C(20)-H(20A)
109.5
C(14)-C(20)-H(20B)
109.5
H(20A)-C(20)-H(20B)
109.5
C(14)-C(20)-H(20C)
109.5
H(20A)-C(20)-H(20C)
109.5
H(20B)-C(20)-H(20C)
109.5
C(16)-C(21)-H(21A)
109.5
C(16)-C(21)-H(21B)
109.5
H(21A)-C(21)-H(21B)
109.5
C(16)-C(21)-H(21C)
109.5
H(21A)-C(21)-H(21C)
109.5
H(21B)-C(21)-H(21C)
109.5
C(23)-C(22)-Cu(1)
118.71(15)
C(23)-C(22)-H(22A)
107.6
Cu(1)-C(22)-H(22A)
107.6
C(23)-C(22)-H(22B)
107.6
Cu(1)-C(22)-H(22B)
107.6
H(22A)-C(22)-H(22B)
107.1
C(22)-C(23)-H(23A)
109.5
C(22)-C(23)-H(23B)
109.5
H(23A)-C(23)-H(23B)
109.5
C(22)-C(23)-H(23C)
109.5
H(23A)-C(23)-H(23C)
109.5
H(23B)-C(23)-H(23C)
109.5
O(1)-C(24)-C(25)
107.72(19)
O(1)-C(24)-H(24A)
110.2
C(25)-C(24)-H(24A)
110.2
O(1)-C(24)-H(24B)
110.2
C(25)-C(24)-H(24B)
110.2
H(24A)-C(24)-H(24B)
108.5
C(26)-C(25)-C(24)
103.87(19)
148
C(26)-C(25)-H(25A)
111.0
C(24)-C(25)-H(25A)
111.0
C(26)-C(25)-H(25B)
111.0
C(24)-C(25)-H(25B)
111.0
H(25A)-C(25)-H(25B)
109.0
C(27)-C(26)-C(25)
102.16(18)
C(27)-C(26)-H(26A)
111.3
C(25)-C(26)-H(26A)
111.3
C(27)-C(26)-H(26B)
111.3
C(25)-C(26)-H(26B)
111.3
H(26A)-C(26)-H(26B)
109.2
O(1)-C(27)-C(26)
105.13(17)
O(1)-C(27)-H(27A)
110.7
C(26)-C(27)-H(27A)
110.7
O(1)-C(27)-H(27B)
110.7
C(26)-C(27)-H(27B)
110.7
H(27A)-C(27)-H(27B)
108.8
C(1)-N(1)-C(2)
112.19(15)
C(1)-N(1)-C(13)
124.12(15)
C(2)-N(1)-C(13)
123.68(15)
C(1)-N(2)-C(3)
112.05(15)
C(1)-N(2)-C(4)
124.41(15)
C(3)-N(2)-C(4)
123.50(15)
C(1)-Cu(1)-C(22)
178.44(9)
C(27)-O(1)-C(24)
107.75(17)
_____________________________________________________________
Symmetry transformations used to generate equivalent atoms:
149
Table 4. Anisotropic displacement parameters (Å2x 103)for aw06177_0m. The anisotropic
displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ]
______________________________________________________________________________
U11
U22
U33
U23
U13
U12
______________________________________________________________________________
C(1)
14(1)
11(1)
13(1)
2(1)
2(1)
5(1)
C(2)
15(1)
18(1)
21(1)
4(1)
9(1)
5(1)
C(3)
17(1)
18(1)
21(1)
3(1)
11(1)
7(1)
C(4)
13(1)
11(1)
16(1)
2(1)
5(1)
5(1)
C(5)
16(1)
16(1)
14(1)
2(1)
6(1)
8(1)
C(6)
15(1)
19(1)
14(1)
-1(1)
3(1)
7(1)
C(7)
14(1)
13(1)
19(1)
0(1)
7(1)
5(1)
C(8)
18(1)
14(1)
19(1)
5(1)
7(1)
6(1)
C(9)
16(1)
15(1)
14(1)
2(1)
4(1)
7(1)
C(10)
33(1)
18(1)
19(1)
3(1)
-4(1)
6(1)
C(11)
28(1)
21(1)
17(1)
6(1)
4(1)
10(1)
C(12)
22(1)
16(1)
26(1)
1(1)
6(1)
3(1)
C(13)
13(1)
12(1)
16(1)
1(1)
5(1)
4(1)
C(14)
18(1)
16(1)
16(1)
3(1)
3(1)
6(1)
C(15)
21(1)
16(1)
20(1)
2(1)
3(1)
9(1)
C(16)
19(1)
16(1)
18(1)
-2(1)
6(1)
6(1)
C(17)
19(1)
21(1)
12(1)
1(1)
4(1)
5(1)
C(18)
14(1)
17(1)
16(1)
5(1)
6(1)
3(1)
C(19)
25(1)
21(1)
19(1)
7(1)
3(1)
6(1)
C(20)
39(1)
22(1)
19(1)
3(1)
-3(1)
13(1)
C(21)
34(1)
21(1)
25(1)
-4(1)
3(1)
12(1)
C(22)
18(1)
27(1)
14(1)
3(1)
6(1)
7(1)
C(23)
24(1)
36(1)
26(1)
7(1)
8(1)
1(1)
C(24)
26(1)
30(1)
58(2)
18(1)
13(1)
12(1)
C(25)
31(1)
51(2)
37(2)
27(1)
5(1)
9(1)
C(26)
34(1)
27(1)
25(1)
3(1)
9(1)
-2(1)
C(27)
20(1)
26(1)
32(1)
13(1)
8(1)
7(1)
N(1)
15(1)
12(1)
14(1)
2(1)
6(1)
5(1)
N(2)
15(1)
12(1)
14(1)
3(1)
6(1)
5(1)
Cu(1)
14(1)
15(1)
13(1)
2(1)
5(1)
4(1)
150
O(1)
51(1)
22(1)
23(1)
5(1)
10(1)
7(1)
Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103)
for aw06177_0m.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
H(2)
2608
5577
8530
22
H(3)
3739
7853
9459
21
H(6)
9374
11356
11015
20
H(8)
7636
11856
8359
20
H(10A)
5590
10190
7082
38
H(10B)
4401
9069
7437
38
H(10C)
5979
8895
6994
38
H(11A)
6767
8838
11059
33
H(11B)
8787
9274
11248
33
H(11C)
7646
8057
10358
33
H(12A)
8982
13700
10219
35
H(12B)
10357
13446
9608
35
H(12C)
10525
13356
10737
35
H(15)
4989
2083
7252
23
H(17)
3085
3186
4936
22
H(19A)
2546
5810
6216
33
H(19B)
2777
5176
5138
33
H(19C)
4344
6269
5923
33
H(20A)
6685
4953
8963
41
H(20B)
6129
3462
8854
41
H(20C)
4867
4212
9129
41
H(21A)
2965
1056
4666
42
H(21B)
3216
501
5608
42
H(21C)
4813
1120
5171
42
H(22A)
10787
7372
7252
24
H(22B)
9533
6715
6186
24
H(23A)
9704
8719
5952
46
151
H(23B)
11554
8616
6167
46
H(23C)
10929
9393
7033
46
H(24A)
10137
5018
7013
43
H(24B)
8279
4407
7201
43
H(25A)
7650
3074
5701
46
H(25B)
9603
3508
5614
46
H(26A)
7915
1544
6437
38
H(26B)
9374
1561
5811
38
H(27A)
10237
2034
7696
30
H(27B)
11471
2889
7146
30
________________________________________________________________________________
152
Appendix B: Crystallographic Data for XantphosCu-(4Me)Ph (3.37, Chapter 3)
Table 1. Crystal data and structure refinement for xcutol_0m.
Identification code
xcutol_0m
Empirical formula
C48 H43 Cl4 Cu O P2
Formula weight
903.10
Temperature
100(2) K
Wavelength
0.71073 Å
Crystal system
Triclinic
Space group
P1
Unit cell dimensions
a = 9.5374(9) Å
α= 84.293(4)°.
b = 10.6287(9) Å
β= 70.845(4)°.
c = 11.2535(10) Å
γ = 75.681(5)°.
Volume
1043.92(16)
Z
1
Density (calculated)
1.437 Mg/m3
Absorption coefficient
0.893 mm-1
F(000)
466
Crystal size
0.10 x 0.08 x 0.06 mm3
Theta range for data collection
1.92 to 28.33°.
Index ranges
-12<=h<=12, -14<=k<=14, -15<=l<=14
Reflections collected
44905
Independent reflections
10359 [R(int) = 0.0457]
Completeness to theta = 25.00°
99.9 %
Max. and min. transmission
0.9484 and 0.9160
Refinement method
Full-matrix least-squares on F2
Data / restraints / parameters
10359 / 3 / 508
Goodness-of-fit on
F2
Å3
1.021
Final R indices [I>2sigma(I)]
R1 = 0.0347, wR2 = 0.0805
R indices (all data)
R1 = 0.0416, wR2 = 0.0840
Absolute structure parameter
0.004(7)
Largest diff. peak and hole
0.602 and -0.464 e.Å-3
153
Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)
for xcutol_0m. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
C(1)
-193(3)
2977(3)
11603(2)
17(1)
C(2)
699(3)
2258(3)
12313(2)
19(1)
C(3)
86(3)
1693(3)
13503(2)
22(1)
C(4)
-1469(3)
1825(3)
14026(2)
23(1)
C(5)
-2382(3)
2509(3)
13338(3)
24(1)
C(6)
-1764(3)
3065(3)
12163(2)
20(1)
C(7)
-2144(4)
1251(4)
15295(3)
39(1)
C(8)
-1763(3)
3164(2)
8676(2)
13(1)
C(9)
-407(3)
2208(2)
8330(2)
12(1)
C(10)
-533(3)
945(2)
8217(2)
17(1)
C(11)
-1947(3)
682(2)
8432(2)
17(1)
C(12)
-3270(3)
1653(3)
8786(2)
17(1)
C(13)
-3196(3)
2926(2)
8916(2)
15(1)
C(14)
-4591(3)
4080(3)
9252(2)
17(1)
C(15)
-4251(3)
5035(2)
9992(2)
13(1)
C(16)
-5362(3)
5821(3)
10934(2)
16(1)
C(17)
-4970(3)
6704(3)
11536(2)
18(1)
C(18)
-3482(3)
6835(2)
11196(2)
15(1)
C(19)
-2335(3)
6057(2)
10254(2)
14(1)
C(20)
-2770(3)
5177(2)
9686(2)
11(1)
C(21)
-4736(3)
4751(3)
8007(3)
27(1)
C(22)
-6037(3)
3624(3)
9997(3)
29(1)
C(23)
151(3)
6934(2)
8394(2)
13(1)
C(24)
-689(3)
7070(2)
7560(2)
17(1)
C(25)
-217(3)
7669(3)
6396(2)
20(1)
C(26)
1109(3)
8113(3)
6038(2)
21(1)
C(27)
1969(3)
7967(2)
6852(2)
19(1)
C(28)
1473(3)
7393(2)
8029(2)
14(1)
C(29)
-162(3)
6994(2)
11020(2)
13(1)
C(30)
-539(3)
8352(2)
10967(2)
15(1)
154
C(31)
-373(3)
9058(3)
11873(2)
19(1)
C(32)
154(3)
8413(3)
12822(2)
20(1)
C(33)
510(3)
7076(3)
12895(2)
20(1)
C(35)
355(3)
6366(3)
11990(2)
17(1)
C(36)
2077(3)
3220(2)
6617(2)
14(1)
C(37)
2635(3)
4340(2)
6405(2)
18(1)
C(38)
3271(3)
4783(3)
5183(2)
23(1)
C(39)
3345(3)
4115(3)
4172(2)
22(1)
C(40)
2754(3)
3006(3)
4371(2)
23(1)
C(41)
2118(3)
2573(3)
5577(2)
19(1)
C(42)
2685(3)
1086(2)
8296(2)
14(1)
C(43)
4000(3)
605(2)
7337(2)
18(1)
C(44)
5000(3)
-542(3)
7501(3)
21(1)
C(45)
4698(3)
-1231(3)
8632(3)
23(1)
C(46)
3382(3)
-739(3)
9604(3)
24(1)
C(47)
2392(3)
408(3)
9442(2)
20(1)
C(48)
7542(4)
5201(3)
4639(3)
37(1)
C(49)
5600(4)
61(3)
3289(3)
36(1)
O(1)
-1611(2)
4413(2)
8772(2)
13(1)
P(1)
-301(1)
5983(1)
9860(1)
11(1)
P(2)
1360(1)
2650(1)
8235(1)
11(1)
Cl(1)
8937(1)
4814(1)
5374(1)
43(1)
Cl(2)
6474(1)
6824(1)
4913(1)
56(1)
Cl(3)
5779(1)
673(1)
1741(1)
44(1)
Cl(4)
3985(1)
-572(1)
3924(1)
42(1)
Cu(1)
597(1)
3828(1)
9978(1)
14(1)
________________________________________________________________________________
155
Table 3. Bond lengths [Å] and angles [°] for xcutol_0m.
_____________________________________________________
C(1)-C(2)
1.396(4)
C(1)-C(6)
1.405(4)
C(1)-Cu(1)
1.958(3)
C(2)-C(3)
1.413(4)
C(2)-H(2)
0.9500
C(3)-C(4)
1.381(4)
C(3)-H(3)
0.9500
C(4)-C(5)
1.379(4)
C(4)-C(7)
1.498(4)
C(5)-C(6)
1.396(4)
C(5)-H(5)
0.9500
C(6)-H(6)
0.9500
C(7)-H(7A)
0.9800
C(7)-H(7B)
0.9800
C(7)-H(7C)
0.9800
C(8)-C(13)
1.386(4)
C(8)-O(1)
1.389(3)
C(8)-C(9)
1.398(3)
C(9)-C(10)
1.398(3)
C(9)-P(2)
1.827(2)
C(10)-C(11)
1.383(4)
C(10)-H(10)
0.9500
C(11)-C(12)
1.387(4)
C(11)-H(11)
0.9500
C(12)-C(13)
1.396(3)
C(12)-H(12)
0.9500
C(13)-C(14)
1.540(3)
C(14)-C(22)
1.527(4)
C(14)-C(15)
1.528(3)
C(14)-C(21)
1.540(4)
C(15)-C(20)
1.383(3)
C(15)-C(16)
1.395(3)
C(16)-C(17)
1.395(4)
156
C(16)-H(16)
0.9500
C(17)-C(18)
1.382(4)
C(17)-H(17)
0.9500
C(18)-C(19)
1.403(3)
C(18)-H(18)
0.9500
C(19)-C(20)
1.394(3)
C(19)-P(1)
1.826(3)
C(20)-O(1)
1.383(3)
C(21)-H(21A)
0.9800
C(21)-H(21B)
0.9800
C(21)-H(21C)
0.9800
C(22)-H(22A)
0.9800
C(22)-H(22B)
0.9800
C(22)-H(22C)
0.9800
C(23)-C(28)
1.386(3)
C(23)-C(24)
1.397(4)
C(23)-P(1)
1.830(2)
C(24)-C(25)
1.383(4)
C(24)-H(24)
0.9500
C(25)-C(26)
1.382(4)
C(25)-H(25)
0.9500
C(26)-C(27)
1.392(4)
C(26)-H(26)
0.9500
C(27)-C(28)
1.387(4)
C(27)-H(27)
0.9500
C(28)-H(28)
0.9500
C(29)-C(35)
1.388(3)
C(29)-C(30)
1.399(3)
C(29)-P(1)
1.827(2)
C(30)-C(31)
1.394(3)
C(30)-H(30)
0.9500
C(31)-C(32)
1.379(4)
C(31)-H(31)
0.9500
C(32)-C(33)
1.377(4)
C(32)-H(32)
0.9500
157
C(33)-C(35)
1.392(3)
C(33)-H(33)
0.9500
C(35)-H(35)
0.9500
C(36)-C(37)
1.389(4)
C(36)-C(41)
1.401(3)
C(36)-P(2)
1.822(3)
C(37)-C(38)
1.395(4)
C(37)-H(37)
0.9500
C(38)-C(39)
1.373(4)
C(38)-H(38)
0.9500
C(39)-C(40)
1.396(4)
C(39)-H(39)
0.9500
C(40)-C(41)
1.377(4)
C(40)-H(40)
0.9500
C(41)-H(41)
0.9500
C(42)-C(43)
1.379(3)
C(42)-C(47)
1.393(4)
C(42)-P(2)
1.833(2)
C(43)-C(44)
1.387(4)
C(43)-H(43)
0.9500
C(44)-C(45)
1.385(4)
C(44)-H(44)
0.9500
C(45)-C(46)
1.391(4)
C(45)-H(45)
0.9500
C(46)-C(47)
1.382(4)
C(46)-H(46)
0.9500
C(47)-H(47)
0.9500
C(48)-Cl(1)
1.734(4)
C(48)-Cl(2)
1.772(4)
C(48)-H(48A)
0.9900
C(48)-H(48B)
0.9900
C(49)-Cl(4)
1.741(3)
C(49)-Cl(3)
1.767(3)
C(49)-H(49A)
0.9900
C(49)-H(49B)
0.9900
158
P(1)-Cu(1)
2.2455(7)
P(2)-Cu(1)
2.2461(6)
C(2)-C(1)-C(6)
114.0(2)
C(2)-C(1)-Cu(1)
124.9(2)
C(6)-C(1)-Cu(1)
121.1(2)
C(1)-C(2)-C(3)
123.4(2)
C(1)-C(2)-H(2)
118.3
C(3)-C(2)-H(2)
118.3
C(4)-C(3)-C(2)
120.5(3)
C(4)-C(3)-H(3)
119.7
C(2)-C(3)-H(3)
119.7
C(5)-C(4)-C(3)
117.6(2)
C(5)-C(4)-C(7)
121.1(3)
C(3)-C(4)-C(7)
121.3(3)
C(4)-C(5)-C(6)
121.5(3)
C(4)-C(5)-H(5)
119.3
C(6)-C(5)-H(5)
119.3
C(5)-C(6)-C(1)
123.0(3)
C(5)-C(6)-H(6)
118.5
C(1)-C(6)-H(6)
118.5
C(4)-C(7)-H(7A)
109.5
C(4)-C(7)-H(7B)
109.5
H(7A)-C(7)-H(7B)
109.5
C(4)-C(7)-H(7C)
109.5
H(7A)-C(7)-H(7C)
109.5
H(7B)-C(7)-H(7C)
109.5
C(13)-C(8)-O(1)
120.1(2)
C(13)-C(8)-C(9)
123.9(2)
O(1)-C(8)-C(9)
116.0(2)
C(10)-C(9)-C(8)
116.9(2)
C(10)-C(9)-P(2)
124.60(19)
C(8)-C(9)-P(2)
118.06(18)
C(11)-C(10)-C(9)
120.4(2)
C(11)-C(10)-H(10)
119.8
159
C(9)-C(10)-H(10)
119.8
C(10)-C(11)-C(12)
121.1(2)
C(10)-C(11)-H(11)
119.4
C(12)-C(11)-H(11)
119.4
C(11)-C(12)-C(13)
120.3(2)
C(11)-C(12)-H(12)
119.9
C(13)-C(12)-H(12)
119.9
C(8)-C(13)-C(12)
117.4(2)
C(8)-C(13)-C(14)
118.4(2)
C(12)-C(13)-C(14)
124.2(2)
C(22)-C(14)-C(15)
111.9(2)
C(22)-C(14)-C(21)
110.7(2)
C(15)-C(14)-C(21)
108.2(2)
C(22)-C(14)-C(13)
111.1(2)
C(15)-C(14)-C(13)
107.6(2)
C(21)-C(14)-C(13)
107.2(2)
C(20)-C(15)-C(16)
117.3(2)
C(20)-C(15)-C(14)
118.8(2)
C(16)-C(15)-C(14)
123.9(2)
C(15)-C(16)-C(17)
120.5(2)
C(15)-C(16)-H(16)
119.7
C(17)-C(16)-H(16)
119.7
C(18)-C(17)-C(16)
120.7(2)
C(18)-C(17)-H(17)
119.6
C(16)-C(17)-H(17)
119.6
C(17)-C(18)-C(19)
120.3(2)
C(17)-C(18)-H(18)
119.9
C(19)-C(18)-H(18)
119.9
C(20)-C(19)-C(18)
117.2(2)
C(20)-C(19)-P(1)
117.87(17)
C(18)-C(19)-P(1)
124.47(19)
C(15)-C(20)-O(1)
120.2(2)
C(15)-C(20)-C(19)
123.9(2)
O(1)-C(20)-C(19)
115.8(2)
C(14)-C(21)-H(21A)
109.5
160
C(14)-C(21)-H(21B)
109.5
H(21A)-C(21)-H(21B)
109.5
C(14)-C(21)-H(21C)
109.5
H(21A)-C(21)-H(21C)
109.5
H(21B)-C(21)-H(21C)
109.5
C(14)-C(22)-H(22A)
109.5
C(14)-C(22)-H(22B)
109.5
H(22A)-C(22)-H(22B)
109.5
C(14)-C(22)-H(22C)
109.5
H(22A)-C(22)-H(22C)
109.5
H(22B)-C(22)-H(22C)
109.5
C(28)-C(23)-C(24)
119.0(2)
C(28)-C(23)-P(1)
118.68(19)
C(24)-C(23)-P(1)
121.84(19)
C(25)-C(24)-C(23)
120.4(2)
C(25)-C(24)-H(24)
119.8
C(23)-C(24)-H(24)
119.8
C(26)-C(25)-C(24)
120.1(3)
C(26)-C(25)-H(25)
119.9
C(24)-C(25)-H(25)
119.9
C(25)-C(26)-C(27)
120.1(2)
C(25)-C(26)-H(26)
120.0
C(27)-C(26)-H(26)
120.0
C(28)-C(27)-C(26)
119.6(2)
C(28)-C(27)-H(27)
120.2
C(26)-C(27)-H(27)
120.2
C(23)-C(28)-C(27)
120.8(2)
C(23)-C(28)-H(28)
119.6
C(27)-C(28)-H(28)
119.6
C(35)-C(29)-C(30)
119.2(2)
C(35)-C(29)-P(1)
117.46(19)
C(30)-C(29)-P(1)
123.31(19)
C(31)-C(30)-C(29)
120.0(2)
C(31)-C(30)-H(30)
120.0
C(29)-C(30)-H(30)
120.0
161
C(32)-C(31)-C(30)
119.8(2)
C(32)-C(31)-H(31)
120.1
C(30)-C(31)-H(31)
120.1
C(33)-C(32)-C(31)
120.9(2)
C(33)-C(32)-H(32)
119.6
C(31)-C(32)-H(32)
119.6
C(32)-C(33)-C(35)
119.6(2)
C(32)-C(33)-H(33)
120.2
C(35)-C(33)-H(33)
120.2
C(29)-C(35)-C(33)
120.5(2)
C(29)-C(35)-H(35)
119.7
C(33)-C(35)-H(35)
119.7
C(37)-C(36)-C(41)
118.4(2)
C(37)-C(36)-P(2)
118.29(18)
C(41)-C(36)-P(2)
123.26(19)
C(36)-C(37)-C(38)
120.8(2)
C(36)-C(37)-H(37)
119.6
C(38)-C(37)-H(37)
119.6
C(39)-C(38)-C(37)
120.1(2)
C(39)-C(38)-H(38)
120.0
C(37)-C(38)-H(38)
120.0
C(38)-C(39)-C(40)
119.8(2)
C(38)-C(39)-H(39)
120.1
C(40)-C(39)-H(39)
120.1
C(41)-C(40)-C(39)
120.1(2)
C(41)-C(40)-H(40)
120.0
C(39)-C(40)-H(40)
120.0
C(40)-C(41)-C(36)
120.8(2)
C(40)-C(41)-H(41)
119.6
C(36)-C(41)-H(41)
119.6
C(43)-C(42)-C(47)
118.6(2)
C(43)-C(42)-P(2)
124.77(19)
C(47)-C(42)-P(2)
116.34(19)
C(42)-C(43)-C(44)
120.9(2)
C(42)-C(43)-H(43)
119.6
162
C(44)-C(43)-H(43)
119.6
C(45)-C(44)-C(43)
120.7(2)
C(45)-C(44)-H(44)
119.7
C(43)-C(44)-H(44)
119.7
C(44)-C(45)-C(46)
118.5(2)
C(44)-C(45)-H(45)
120.7
C(46)-C(45)-H(45)
120.7
C(47)-C(46)-C(45)
120.7(3)
C(47)-C(46)-H(46)
119.6
C(45)-C(46)-H(46)
119.6
C(46)-C(47)-C(42)
120.6(2)
C(46)-C(47)-H(47)
119.7
C(42)-C(47)-H(47)
119.7
Cl(1)-C(48)-Cl(2)
111.98(17)
Cl(1)-C(48)-H(48A)
109.2
Cl(2)-C(48)-H(48A)
109.2
Cl(1)-C(48)-H(48B)
109.2
Cl(2)-C(48)-H(48B)
109.2
H(48A)-C(48)-H(48B)
107.9
Cl(4)-C(49)-Cl(3)
111.70(19)
Cl(4)-C(49)-H(49A)
109.3
Cl(3)-C(49)-H(49A)
109.3
Cl(4)-C(49)-H(49B)
109.3
Cl(3)-C(49)-H(49B)
109.3
H(49A)-C(49)-H(49B)
107.9
C(20)-O(1)-C(8)
116.20(18)
C(19)-P(1)-C(29)
104.95(11)
C(19)-P(1)-C(23)
104.19(11)
C(29)-P(1)-C(23)
103.75(11)
C(19)-P(1)-Cu(1)
100.19(8)
C(29)-P(1)-Cu(1)
118.14(8)
C(23)-P(1)-Cu(1)
123.24(8)
C(36)-P(2)-C(9)
104.61(11)
C(36)-P(2)-C(42)
103.75(11)
C(9)-P(2)-C(42)
103.99(11)
163
C(36)-P(2)-Cu(1)
126.63(8)
C(9)-P(2)-Cu(1)
100.93(7)
C(42)-P(2)-Cu(1)
114.35(8)
C(1)-Cu(1)-P(1)
116.44(8)
C(1)-Cu(1)-P(2)
117.96(8)
P(1)-Cu(1)-P(2)
119.25(2)
_____________________________________________________________
Symmetry transformations used to generate equivalent atoms:
Table 4. Anisotropic displacement parameters (Å2x 103)for xcutol_0m. The anisotropic
displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ]
______________________________________________________________________________
U11
U22
U33
U23
U13
U12
______________________________________________________________________________
C(1)
23(1)
13(1)
15(1)
-1(1)
-4(1)
-5(1)
C(2)
18(1)
24(1)
18(1)
-1(1)
-7(1)
-9(1)
C(3)
28(2)
24(1)
19(1)
6(1)
-12(1)
-11(1)
C(4)
32(2)
20(1)
17(1)
2(1)
-4(1)
-11(1)
C(5)
15(1)
24(2)
27(1)
1(1)
0(1)
-4(1)
C(6)
24(1)
17(1)
22(1)
7(1)
-12(1)
-9(1)
C(7)
40(2)
50(2)
24(2)
11(1)
-2(1)
-20(2)
C(8)
14(1)
10(1)
14(1)
-1(1)
-5(1)
-3(1)
C(9)
13(1)
14(1)
8(1)
-1(1)
-4(1)
-2(1)
C(10)
21(1)
11(1)
16(1)
-2(1)
-7(1)
1(1)
C(11)
24(1)
14(1)
16(1)
-2(1)
-8(1)
-6(1)
C(12)
20(1)
19(1)
14(1)
-1(1)
-6(1)
-9(1)
C(13)
16(1)
16(1)
12(1)
0(1)
-6(1)
-3(1)
C(14)
13(1)
18(1)
21(1)
-1(1)
-7(1)
-3(1)
C(15)
12(1)
13(1)
15(1)
3(1)
-6(1)
-2(1)
C(16)
10(1)
16(1)
18(1)
2(1)
-2(1)
-1(1)
C(17)
15(1)
19(1)
16(1)
-4(1)
0(1)
-1(1)
C(18)
17(1)
13(1)
15(1)
-2(1)
-4(1)
-3(1)
C(19)
14(1)
13(1)
12(1)
3(1)
-4(1)
-3(1)
C(20)
12(1)
7(1)
12(1)
1(1)
-4(1)
0(1)
C(21)
27(2)
27(2)
29(2)
-5(1)
-19(1)
5(1)
C(22)
10(1)
30(2)
47(2)
-11(1)
-6(1)
-6(1)
164
C(23)
16(1)
10(1)
11(1)
-3(1)
-3(1)
-1(1)
C(24)
17(1)
16(1)
17(1)
-2(1)
-5(1)
-3(1)
C(25)
24(1)
16(1)
19(1)
2(1)
-7(1)
-3(1)
C(26)
29(2)
17(1)
14(1)
5(1)
-5(1)
-7(1)
C(27)
18(1)
16(1)
21(1)
-1(1)
-2(1)
-8(1)
C(28)
15(1)
12(1)
15(1)
-1(1)
-4(1)
-1(1)
C(29)
9(1)
17(1)
13(1)
0(1)
-3(1)
-4(1)
C(30)
18(1)
16(1)
11(1)
0(1)
-3(1)
-5(1)
C(31)
22(1)
19(1)
18(1)
-4(1)
-1(1)
-10(1)
C(32)
23(1)
25(1)
16(1)
-5(1)
-6(1)
-10(1)
C(33)
20(1)
25(1)
15(1)
-1(1)
-6(1)
-5(1)
C(35)
15(1)
19(1)
14(1)
-1(1)
-3(1)
-2(1)
C(36)
11(1)
15(1)
14(1)
-2(1)
-5(1)
-2(1)
C(37)
14(1)
15(1)
21(1)
-2(1)
-3(1)
-1(1)
C(38)
20(1)
19(1)
26(1)
7(1)
-4(1)
-6(1)
C(39)
20(1)
28(2)
15(1)
8(1)
-4(1)
-4(1)
C(40)
26(2)
30(2)
14(1)
-2(1)
-7(1)
-7(1)
C(41)
20(1)
21(1)
17(1)
-3(1)
-4(1)
-7(1)
C(42)
15(1)
11(1)
17(1)
1(1)
-8(1)
-4(1)
C(43)
14(1)
15(1)
22(1)
0(1)
-4(1)
-1(1)
C(44)
12(1)
17(1)
26(1)
1(1)
1(1)
0(1)
C(45)
18(1)
15(1)
33(2)
2(1)
-10(1)
1(1)
C(46)
25(1)
20(1)
23(1)
6(1)
-9(1)
-2(1)
C(47)
19(1)
20(1)
19(1)
1(1)
-3(1)
-2(1)
C(48)
43(2)
37(2)
36(2)
-6(2)
-11(2)
-16(2)
C(49)
32(2)
41(2)
34(2)
4(1)
-10(1)
-10(2)
O(1)
10(1)
11(1)
15(1)
-2(1)
-2(1)
-1(1)
P(1)
12(1)
10(1)
12(1)
0(1)
-4(1)
-2(1)
P(2)
11(1)
11(1)
11(1)
-1(1)
-4(1)
-1(1)
Cl(1)
32(1)
38(1)
54(1)
5(1)
-12(1)
-2(1)
Cl(2)
37(1)
39(1)
85(1)
19(1)
-19(1)
-4(1)
Cl(3)
46(1)
48(1)
28(1)
10(1)
-6(1)
-3(1)
Cl(4)
34(1)
34(1)
47(1)
0(1)
1(1)
-10(1)
Cu(1)
16(1)
13(1)
13(1)
0(1)
-5(1)
-3(1)
______________________________________________________________________________
165
Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103)
for xcutol_0m.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
H(2)
1775
2144
11978
23
H(3)
748
1219
13947
26
H(5)
-3455
2603
13671
29
H(6)
-2437
3525
11723
24
H(7A)
-2198
359
15202
59
H(7B)
-3171
1772
15693
59
H(7C)
-1502
1247
15822
59
H(10)
358
264
7990
20
H(11)
-2012
-177
8337
20
H(12)
-4232
1451
8941
20
H(16)
-6393
5755
11167
19
H(17)
-5735
7222
12188
22
H(18)
-3235
7454
11600
18
H(21A)
-5621
5488
8186
41
H(21B)
-4867
4130
7487
41
H(21C)
-3811
5061
7557
41
H(22A)
-6920
4363
10132
43
H(22B)
-5953
3258
10811
43
H(22C)
-6168
2958
9524
43
H(24)
-1589
6749
7794
20
H(25)
-806
7774
5841
23
H(26)
1435
8519
5236
25
H(27)
2890
8260
6603
22
H(28)
2046
7312
8593
17
H(30)
-907
8793
10314
18
H(31)
-623
9980
11836
23
H(32)
273
8897
13434
24
H(33)
859
6641
13560
23
H(35)
605
5444
12036
20
166
H(37)
2583
4809
7100
21
H(38)
3653
5548
5050
27
H(39)
3796
4407
3340
26
H(40)
2791
2550
3672
27
H(41)
1702
1827
5705
23
H(43)
4225
1065
6555
21
H(44)
5901
-858
6831
25
H(45)
5374
-2023
8742
27
H(46)
3160
-1196
10389
28
H(47)
1505
737
10119
24
H(48A)
6846
4603
4952
45
H(48B)
8030
5076
3722
45
H(49A)
6517
-627
3282
43
H(49B)
5541
768
3827
43
________________________________________________________________________________
167
Vita
Richard P. Rucker was born and raised in southeastern Louisiana. After finishing
high school, Richard obtained a B.S. in Chemistry from Louisiana State University in
Baton Rouge, LA. During his undergraduate career, Richard first participated in organic
chemistry
research
by
exploring
the
synthesis
and
characterization
alkoxybenzimidazoyl azides for possible use in click-chemistry applications.
of
N-
Later,
Richard studied materials chemistry, where he synthesized and characterized
monodisperse, core-shell nanoparticles for multifunctional materials applications. For
this work, Richard received the Department of Chemistry’s Outstanding Undergraduate
Research Award at Louisiana State University in 2008. During the last three years of his
undergraduate career, Richard was a Quality Control Technician and later a Research and
Development Intern for Waterbury Companies, Inc., where he studied the formulation of
new aerosolized emulsions for applications in the professional pesticide industry, as well
as developed GC methods for quantification of active ingredients per EPA regulations.
After graduating from LSU, Richard moved to the University of Washington in Seattle
and began his graduate career with Prof. Gojko Lalic. There, he contributed to the
development of several new copper-catalyzed transformations useful for organic
synthesis. After receiving his Ph.D. in November 2013, Richard will begin a postdoctoral fellowship with Prof. Michael Organ at York University in Toronto, Canada.
There, Richard will prepare highly reactive organopalladium complexes and study their
electronic properties through a combination of spectroscopic, computational, and
experimental techniques.
Richard Rucker