Synthesis of tertiary alkyl amines from terminal alkenes: Copper-catalyzed amination of alkyl boranes

Article abstract of DOI:10.1021/ja3023829

A method for highly selective anti-Markovnikov hydroamination of terminal alkenes is reported. The one-pot procedure involves hydroboration of the alkene followed by a novel electrophilic amination of the alkyl borane catalyzed by an NHC-Cu complex. Terminal alkenes are successfully transformed into tertiary alkyl amines in the presence of a variety of functional groups in yields ranging from 80 to 97% with excellent regioselectivity. Results of a preliminary study of the reaction mechanism are also described.

Full text of DOI:10.1021/ja3023829

Communication
pubs.acs.org/JACS
Synthesis of Tertiary Alkyl Amines from Terminal Alkenes: Copper-
Catalyzed Amination of Alkyl Boranes
Richard P. Rucker, Aaron M. Whittaker, Hester Dang, and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
secondary amines from alkenes.18 Finally, none of the existing
procedures for anti-Markovnikov hydroamination allows the
preparation of tertiary alkyl amines from alkenes.
In this communication, we report a one-pot procedure for
the highly regioselective synthesis of tertiary alkyl amines from
terminal alkenes (eq 1). We describe the reaction development
ABSTRACT: A method for highly selective anti-Markov-
nikov hydroamination of terminal alkenes is reported. The
one-pot procedure involves hydroboration of the alkene
followed by a novel electrophilic amination of the alkyl
borane catalyzed by an NHC−Cu complex. Terminal
alkenes are successfully transformed into tertiary alkyl
amines in the presence of a variety of functional groups in
yields ranging from 80 to 97% with excellent regiose-
lectivity. Results of a preliminary study of the reaction
mechanism are also described.
and exploration of the substrate scope together with the results
of our preliminary study of the reaction mechanism.
mines are ubiquitous among biologically active small
We recently reported a catalytic method for the synthesis of
hindered anilines featuring copper-catalyzed electrophilic
amination of aryl boronic esters.19 At the same time, we were
exploring the possibility that the analogous copper-catalyzed
amination of alkyl boranes could be used to achieve a direct
synthesis of tertiary alkyl amines from alkenes. To test this idea,
we decided to explore the hydroamination of 4-phenyl-1-
butene (1) using 9-borabicyclo[3.3.1]nonane (9-BBN) as a
hydroboration reagent and O-benzoyl-N,N-dibenzylhydroxyl-
amine 2 as the electrophilic source of nitrogen.20 On the basis
of our experience with copper-catalyzed transformations of
organoboron compounds,21 we chose ICyCuCl (ICy = 1,3-
dicyclohexylimidazol-2-ylidene) as a catalyst and sodium tert-
butoxide as a base additive. The hydroboration of the alkene
was performed in 1,4-dioxane at 60 °C, after which all of the
components required for the electrophilic amination were
simply added to the reaction flask. Under these reaction
conditions, the hydroamination product was obtained in 16%
yield (Table 1, entry 1),22 while an imine was identified as the
major product. A control experiment confirmed the fast
formation of this imine by the reaction of the electrophile 2
with sodium tert-butoxide.23 We found the electrophile
decomposition to be significantly slower in the presence of
lithium tert-butoxide in noncoordinating solvents such as
benzene (4% conversion after 2 h at 45 °C).24 Consistent
with this finding, the yield of the hydroamination product
obtained in the catalytic reaction significantly increased when
lithium tert-butoxide was used together with pentane as the
solvent (Table 1, entry 4).
A
molecules, and their synthesis is one of the most common
and important synthetic tasks.1 In practice, amino groups are
usually introduced into organic molecules by transformations of
carbonyl compounds, amides, or alkyl electrophiles (halides or
sulfonates).2 Considerable effort has been devoted to broad-
ening the scope of alkyl amine precursors by the development
of methods for direct amination of other common functional
groups. In this context, hydroamination of alkenes, which
would allow direct preparation of alkyl amines from alkenes,
has received a lot of attention as a highly desirable
transformation.3
Despite the great progress made in developing hydro-
amination reactions,4−7 control of the regioselectivity is still a
major problem. Particularly challenging has been the develop-
ment of anti-Markovnikov hydroamination of simple alkenes.
In metal-catalyzed hydroamination reactions, anti-Markovnikov
selectivity has been observed only with special substrates, such
as activated alkenes8 and styrenes.9 Control of the regiose-
lectivity has also been a major problem in amination methods
based on free radical and pericyclic additions, developed by
Studer10 and Beauchemin.11
The best results in anti-Markovnikov hydroamination to date
have been achieved using a hydroboration−amination
sequence. Primary amines can be prepared using procedures
developed by Brown12 and Kabalka.13 Secondary amines can be
prepared from boronic esters after conversion to trifluorobo-
rates, followed by a reaction with excess Lewis acid (BF3 or
SnCl4) and alkyl azide.14,15 Unfortunately, while these methods
are still the best option for anti-Markovnikov hydroamination
of alkenes because of their exquisite regioselectivity, they often
provide the amination products in low yield (<50% based on
the alkene).16,17 Furthermore, strong Lewis acids are usually
used for the reaction of organoboron compounds with azides,
and this method has rarely been used for the synthesis of
Unfortunately, with a variety of electrophilies, we observed
an alternative decomposition pathway under these reaction
Received: March 11, 2012
Published: April 2, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
a
Table 1. Development of the Hydroamination Procedure
Table 2. Hydroamination of Terminal Alkenes
a
1 (1.0 equiv), R2N−OBz (1.3 equiv, 0.2 M), MOt-Bu (1.3 equiv).
1,3-dicyclohexylimidazol-2-ylidene; 9-BBN 9-
ICy
=
=
b
c
borabicyclo[3.3.1]nonane. Determined by GC. R2N−OBz was
d
added over 6 h. The reaction was conducted at 60 °C. R2N−OBZ
was added over 3 h. Toluene was used as the solvent in the
e
hydroboration reaction. The reaction was conducted at 60 °C. R2N−
OBz (1.1 equiv) and LiOt-Bu (1.1 equiv), 0.05 M concentration.
conditions. For example, the reaction with 3 provided no
hydroamination product and instead resulted in almost
quantitative formation of tert-butyl benzoate (Table 1, entry
5). 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 6). Using toluene led to a further increase
in the yield of the desired product (Table 1, entry 7). However,
the formation of a small amount of toluene amination
product25 complicated the purification of the desired amine.
Finally, 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.
a
Alkene (0.50 mmol), 9-BBN (0.5 mmol), R2N−OBz (0.55 mmol),
and t-BuOLi (0.55 mmol) in 10 mL of toluene. R2N−OBz was added
over 4 h. Yields of isolated products are shown, unless otherwise
noted. Benzene was used as the solvent. GC yield. After purification,
the corresponding aldehyde was isolated in 92% yield. 2.5 mol %
b
c
d
e
catalyst was used. GC yield. The isolated yield was 72%.
Scheme 1. Proposed Mechanism
The optimized reaction conditions and purification proce-
dure proved to be quite general (Table 2). 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 4−8). Equally good results were
obtained in the preparation of acyclic amines, including
sterically hindered N,N-diisopropyl-N-alkyl amines (9−13).
Even the highly hindered N-alkyl-2,2,6,6-tetramethylpiperidine
18 could be formed in 86% yield. The synthesis of such
hindered trialkyl amines is not only impossible to achieve using
the existing hydroamination methods but is also difficult to
accomplish using the standard reductive amination or alkylation
reactions.26 Finally, in all of these examples, only the product of
anti-Markovnikov hydroamination was formed.27
intermediate.29 Finally, copper tert-butoxide is regenerated in
a reaction with lithium alkoxide.30 The most intriguing aspect
of the proposed mechanism is the presence of a neutral
copper(I) alkyl intermediate in a reaction performed at a
relatively high temperature. Such complexes are known to
decompose quickly above −35 °C,31 and to the best of our
knowledge, there are no examples of fully characterized neutral
copper(I) alkyl complexes containing β-hydrogen substituents.
While similar intermediates have previously been proposed in
copper-catalyzed reactions of alkyl boranes,28a,21a there is little
experimental evidence for their involvement.
We propose that the amination of alkyl boron compounds
proceeds according to the mechanism shown in Scheme 1. The
reaction involves transmetalation from boron to copper21,28
followed by electrophilic amination of the alkylcopper
In an effort to explore the role of copper(I) alkyl complexes
in the amination reaction, we prepared IMesCuEt (19) by
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Journal of the American Chemical Society
Communication
Notes
addition of ethyllithium to IMesCuCl at low temperature. To
our surprise, 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 1). We discovered that the complex is
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
For financial support we thank the University of Washington.
Professor Forrest Michael is gratefully acknowledged for helpful
discussions and suggestions.
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Figure 1. ORTEP of IMesCuEt (19) at 50% probability. Selected H
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
lalic@chem.washington.edu
■
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