Enantio- and regioselective CuH-catalyzed hydroamination of alkenes

Article abstract of DOI:10.1021/ja4092819

A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes has been developed using diethoxymethylsilane and esters of hydroxylamines. The process tolerates a wide variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched amines. In addition, aliphatic alkenes coupled to generate exclusively the anti-Markovnikov hydroamination products.

Full text of DOI:10.1021/ja4092819

Communication
pubs.acs.org/JACS
Enantio- and Regioselective CuH-Catalyzed Hydroamination of
Alkenes
Shaolin Zhu, Nootaree Niljianskul, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
portion (asymmetric) of this chemistry by Hirano and Miura
was reported.2a
ABSTRACT: A highly enantio- and regioselective copper-
catalyzed hydroamination reaction of alkenes has been
developed using diethoxymethylsilane and esters of
hydroxylamines. The process tolerates a wide variety of
substituted styrenes, including trans-, cis-, and β,β-
disubstituted styrenes, to yield α-branched amines. In
addition, aliphatic alkenes coupled to generate exclusively
the anti-Markovnikov hydroamination products.
ydroamination, the direct formation of a C−N bond by
Hthe formal addition of an amine to an alkene, is a
powerful synthetic procedure with the potential to gain access
to amine products which are widely featured in pharmaceuti-
cally active compounds.1 Although great progress has been
made in the field of late transition metal-catalyzed hydro-
amination,2 several challenges still exist. For example, the
intermolecular process requires activated alkenes such as vinyl
arenes.2a,i,h or acrylic acid derivatives,2c while asymmetric
variants are limited to the addition of aryl amines to simple
β-unsubstituted styrene derivatives and achieve only moderate
levels of enantiomeric excess.2a,3 In addition, there are limited
methods available to obtain the anti-Markovnikov product in
hydroamination reactions of aliphatic amines.4 Thus, there
remains a need for the development of asymmetric hydro-
amination reactions that tolerate a wide variety of substitution
patterns on the alkene component and proceed with high regio-
and enantioselectivity.
Over the past decade, our laboratory has reported several
examples of asymmetric reactions involving copper−hydride
(CuH) intermediates.5a−e We postulated that this CuH strategy
could serve as a platform for the hydroamination of alkenes (eq
1). In our approach for asymmetric intermolecular hydro-
amination, we propose that insertion of an alkene (1, 4) into a
chiral ligand-bound LCu(I)H species (I) would form an alkyl-
copper complex (II) (Figure 1).6 Subsequent oxidative addition
of an electrophilic amine source, such as a hydroxylamine 2,7
followed by reductive elimination, would form the C−N bond
enantioselectively. The copper(I) species generated would then
undergo transmetalation with an external hydride-transfer
reagent to re-form I.10 This mechanism (Figure 1) comes in
a straightforward manner from a combination of our previous
work in two areas.5a,11 Herein, we report a mild copper-
catalyzed hydroamination strategy using a chiral copper catalyst
with a broad substrate scope. We note that toward the end of
our work, a paper describing a method similar to the first
Figure 1. Proposed catalytic cycle for CuH-catalyzed hydroamination
of alkenes.
We began our investigation by attempting the hydro-
amination of styrene (1a) using readily available Cu(OAc)2
and easily accessible O-benzoylhydroxylamine 2a (Table 1).
Various ligands and hydride-transfer reagents were tested. We
were able to achieve the desired cross-coupled products in up
to 74% ee using polymethylhydrosiloxane (PMHS) or
diethoxymethylsilane (DEMS) in conjunction with the
commercially available ligand BINAP (L1) (entries 2 and 3).
DEMS generated the desired product in the highest yield
(entry 3), and thus was chosen as the hydride-transfer reagent
of choice in the examination of other chiral ligands (entries 4−
8). We were able to realize up to 97% ee when using (R)-
Received: September 7, 2013
Published: October 9, 2013
© 2013 American Chemical Society
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Communication
a
Table 1. Reaction Optimization
Table 2. Scope of Different Styrene Derivatives
a
entry Cu(OAc)2 (mol%) hydride reagent
L
yield 4a (%) ee (%)
b
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
2
HBpin
PMHS
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
L1
L1
L1
L2
L3
L4
L5
L5
2
40
64
83
99
99
99
97
nd
−74
−73
−65
−95
79
97
c
97
a
b
GC yields with dodecane as the internal standard. Not determined.
c
Reaction was carried out at 40 °C.
DTBM-SEGPHOS (L5) as the ligand (entry 7). Further
optimization revealed that the reaction proceeds with low
catalyst loading (2 mol%) at 40 °C (entry 8), without
diminishing the yield or enantioselectivity. The reaction
exclusively generated an α-branched amine, which is consistent
with the proposed catalytic cycle (Figure 1) because the
hydride migration from the copper catalyst to the alkene would
generate the more stable α-bond Cu species.12
With an optimized protocol in hand, we then explored the
substrate scope with respect to the styrene component (Table
2). This hydroamination tolerates a variety of substituents on
the aryl ring of styrene (3b−g). The reaction also works
efficiently with both trans- and cis-β-substituted styrenes (3h−
o). Even hindered β,β-disubstituted styrenes undergo hydro-
amination in high yield and ee in this reaction (3p,q). Notably,
the hydroamination of β,β-disubstituted styrene 1q gave the
product 3q as a single diastereomer.
We next explored the use of other amine electrophiles in this
reaction. We found that this reaction is applicable to several
alkyl- and dialkyl-N-OBz amines (Table 3). N-(OBz)azepane
and other heterocyclic-N-OBz amines also furnished the
respective hydroamination products in high yields and
enantioselectivities.
a
Isolated yields (average of two runs). 2 (1 mmol), O-benzoyl-N,N-
dibenzylhydroxylamine (1.2 mmol), Cu(OAc)2 (2 mol%), (R)-
DTBM-SEGPHOS (2.2 mol%), DEMS (2 mmol), THF (0.5 M), 40
°C, up to 36 h. Cu(OAc)2 (4 mol%), (R)-DTBM-SEGPHOS (4.4
mol%). THF (1 M).
b
c
a
Table 3. Scope of Amine Electrophiles with Styrene
Since hydroamination of unactivated alkenes remains a
challenge, we examined whether the developed protocol would
be applicable with aliphatic alkenes.4b We found that terminal
aliphatic alkenes could be effectively hydroaminated under the
same conditions (Tables 4 and 5). In every case, the reaction
exclusively produces the anti-Markovnikov products. This
protocol tolerated alkenes containing a primary alkyl bromide
(5c), an epoxide (5g), and was compatible with alkenes
containing a tosylamine (5d), an amide (5e), a pyridine (5f), a
tert-butyldimethylsilyl ether (5i), and ones with geminal
substituents (5h,i). Additionally, a number of amine electro-
philes, including the sterically hindered tetramethylpiperidine
N-OBz (5m), cross-coupled efficiently. Our hypothesis for the
a
Isolated yields (average of two runs). 2 (1 mmol), hydroxylamine
(1.2 mmol), Cu(OAc)2 (2 mol%), (R)-DTBM-SEGPHOS (2.2 mol
%), DEMS (2 mmol), THF (1 M), 40 °C, up to 36 h. THF (0.5 M).
b
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Journal of the American Chemical Society
Communication
a
Table 4. Hydroamination of Terminal Aliphatic Alkenes
Scheme 2. Large-Scale Hydroamination Reaction of β-
Substituted Styrene
able to lower the catalyst loading to 1 mol% with no decrease in
the yield or enantioselectivity.
In summary, we have reported a mild method for
synthesizing chiral tertiary amines by employing an asymmetric
copper-catalyzed hydroamination. Substitution occurs in a
regioselective manner to generate a C−N bond at the α-
position of styrene derivatives. This method has been shown to
be compatible with various substituted styrene derivatives, and
styrenes with β-substitution. Additionally, this method allows
the development of copper-catalyzed anti-Markovnikov hydro-
aminations of terminal aliphatic alkenes. We are currently
investigating the asymmetric version of internal aliphatic alkene
hydroamination, which will be reported in due course.
a
Isolated yields (average of two runs). 2 (1 mmol), O-benzoyl-N,N-
dibenzylhydroxylamine (1.2 mmol), Cu(OAc)2 (2 mol%),
( )-DTBM-SEGPHOS (2.2 mol%), DEMS (2 mmol), THF (0.5
ASSOCIATED CONTENT
b
■
M), 40 °C, up to 36 h. THF (1 M).
S
* Supporting Information
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Table 5. Scope of Amine Electrophiles with 4-Phenyl-1-
butene
a
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institutes of Health under award number GM58160.
We thank Phillip J. Milner and Dr. Daniel T. Cohen for their
advice in the preparation of this manuscript.
a
Isolated yields (average of two runs). 2 (1 mmol), hydroxylamine
(1.2 mmol), Cu(OAc)2 (2 mol%), ( )-DTBM-SEGPHOS (2.2 mol
b
%), DEMS (2 mmol), THF (0.5 M), 40 °C, up to 36 h. Cu(OAc)2 (4
mol%), ( )-DTBM-SEGPHOS (4.4 mol%) were used.
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Scheme 1. Anti-Markovnikov Hydroamination of Aliphatic
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Journal of the American Chemical Society
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