Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Imines Enabled by Ligand-Controlled Chemoselective Hydrocupration

Article abstract of DOI:10.1021/jacs.6b06299

The copper-catalyzed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions at ambient temperature. This process features the use of styrenes as latent carbanion equivalents via the intermediacy of catalytically generated benzylcopper derivatives, providing an effective means for accessing highly enantiomerically enriched amines bearing contiguous stereocenters. Mechanistic studies shed light on the origin of the preferential styrene hydrocupration in the presence of an imine with the Ph-BPE-derived copper catalyst.

Full text of DOI:10.1021/jacs.6b06299

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Communication
Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles
to Imines Enabled by Ligand-Controlled Chemoselective Hydrocupration
Yang Yang, Ian B. Perry, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06299 • Publication Date (Web): 25 Jul 2016
Downloaded from http://pubs.acs.org on July 25, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
Copper-Catalyzed Enantioselective Addition of Styrene-
Derived Nucleophiles to Imines Enabled by Ligand-Controlled
Chemoselective Hydrocupration
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Yang Yang, Ian B. Perry and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139
Supporting Information Placeholder
ABSTRACT: The copper-catalyzed intermolecular enanti-
oselective addition of styrenes to imines has been achieved
under mild conditions at ambient temperature. This process
features the use of styrenes as latent carbanion equivalents
via the intermediacy of catalytically generated benzylcopper
derivatives, providing an effective means for accessing highly
enantiomerically enriched amines bearing contiguous stereo-
centers. Mechanistic studies shed light on the origin of the
preferential styrene hydrocupration in the presence of an
imine with the Ph-BPE-derived copper catalyst.
ceptionally successful for the enantioselective addition to
6
aldehydes, only a few examples of asymmetric addition to
7
imines have been reported. Furthermore, the intermolecu-
lar, enantioselective coupling of less active olefins such as
styrenes to imines is rare.8
(A) Our Previous Work: Stereoselective Indoline Synthesis12a
Me
L*CuH catalyst
Ar
N
Ar
N
H
(B) Proposed Intermolecular Styrene-Imine Coupling: Catalytic Cycle
R3Si OtBu
R1
L*Cu
H
X
I
II
R3Si
IX
H
R1
Catalytic Enantioselective
Addition of Styrene-Derived
Nucleophiles to Imines
CuL*
L*Cu OtBu
Enantiomerically enriched amines constitute essential
structural elements in a variety of pharmaceutically im-
portant small molecule therapeutics. Consequently, general
VIII
III
R1
1
P(O)Ph2
R2
NHP(O)Ph2
N
R1
methods for the synthesis of amines in optically pure form
has long been regarded as an important objective for synthet-
R3
R3
R2
R2
R3
t-BuOH
VI
IV
VII
1
N
ic organic chemists. Among the numerous techniques avail-
L*Cu
P(O)Ph2
able, asymmetric hydrogenation1 and biocatalysis are of-
,2
1,3
V
(C) Hydrocupration Chemoselectivity
R'
R1
PG
L*Cu
PG
R'
ten employed. However, the addition of carbon nucleophiles
N
N
+
L*Cu
H
L*Cu
H
4
+
to prochiral imines, particularly Ellman’s chiral tert-
Ph
styrene
Ph
CuL*
R
R'
imine
R
4
a
butylsulfinimines, often represents the method of choice
for the preparation of free or protected chiral primary
amines.
How to selectively hydrometalate a styrene in the presence of an imine?
Figure 1. Copper-Catalyzed Enantioselective Addition of Sty-
rene-Derived Nucleophiles to Imines
The need to utilize stoichiometric quantities of an organ-
ometallic reagent and the chiral auxiliary is a limitation of
these processes. Additionally, the use of highly basic and nu-
cleophilic organometallic compounds such as organomagne-
sium and organozinc reagents decreases the functional group
compatibility of these methods. Moreover, one or multiple
additional synthetic operations are usually required to pre-
pare an organometallic reagent from an organic halide or an
unsaturated hydrocarbon. In this context, the use of abun-
dant or easily accessible olefins as latent carbanion equiva-
lents for asymmetric nucleophilic addition to imines could
obviate these problems. In recent years, Krische has pio-
neered the use of polyunsaturated olefins as latent carbon
nucleophiles for carbonyl additions using noble metal cata-
In 2013, our group initiated a research program aimed at
developing copper(I) hydride catalysis9 as a general plat-
form for accessing enantiomerically enriched organocopper
intermediates from easily available olefin precursors. By cap-
turing the catalytically generated organocopper species with
electrophilic aminating reagents, our laboratory and Hirano
and Miura11 have independently developed a new approach
for the enantioselective hydroamination of olefins. More
recently, we have also demonstrated the feasibility of engag-
,10
1
0
ing organocopper intermediates in carbon-carbon bond
12,13
forming processes.
In particular, we reported a CuH-
catalyzed intramolecular addition of styrene-derived organo-
copper species to N-arylimines for the enantioselective syn-
5
lysts (Rh, Ru and Ir). While these processes have been ex-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
thesis of indolines (Figure 1(A)),12a as well as an enantiose-
lective intermolecular coupling of (poly)unsaturated olefins
O
R
R
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
SO2Ph
H
Ph
PAr2
PAr2
P
N
N
P
1
2e
and ketones. We note that Shibasaki and Lam have each
previously devised elegant copper-catalyzed protocols for the
enantioselective reductive Mannich reaction.14 We recently
wondered whether our previously reported intramolecular
cyclization of iminostyrenes could be extended to a more
broadly applicable method for the coupling of readily availa-
ble styrenes and N-protected imines. As illustrated in Figure
1(B), the enantioselective addition of a phosphine-ligated
copper catalyst (I) across the double bond of styrene II
would furnish a transient benzylcopper intermediate (III).15
Nucleophilic addition of benzylcopper III to an N-protected
R
Ph
Ph
H
R
O
2b
2c
R = Me, Me-BPE (L3)
R = Et, Et-BPE (L4)
R = i-Pr, i-Pr-BPE (L5)
R= Ph, Ph-BPE (L6)
Ar = 4-MeO-3,5-tBu2C6H2:
DTBM-SEGPHOS (L1)
Ar = Ph: SEGPHOS (L2)
While successful in the intramolecular case, the develop-
ment of an intermolecular transformation would require the
chemoselective hydrometalation of a styrene in the presence
of a suitably protected imine. The identification of reaction
conditions with the desired selectivity was expected to be
challenging, since several of the commonly used imine pro-
tecting groups are strongly electron-withdrawing, and hydro-
cupration of the imine was expected to be facile (Figure
(B)). Indeed, important work by Lipshutz showed that
phosphine-ligated copper hydride species can be highly effi-
cient catalysts for the enantioselective reduction of N-
phosphinoyl ketimines. The competitive hydrocupration of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
imine (IV) would provide a copper amide (V
), which is in
turn protonated by t-BuOH to furnish addition product VII
and release the copper tert-butoxide (VIII). Subsequent σ-
bond metathesis of VIII with a hydridic silane (IX) would
regenerate the copper hydride catalyst and complete the
1
17
1
6
catalytic cycle. The strategy described herein provides rapid
access to the enantioselective assembly of highly substituted
amines bearing adjacent stereocenters from easily available
olefin and imine building blocks. Furthermore, this mecha-
nistic framework does not require the use of exogenous acid-
ic or basic additives, thereby potentially allowing for sensitive
functional groups to be tolerated.
the imine component would lead to its unproductive reduc-
tion and result in diminished yields of the desired styrene-
derived adduct.
a
Table 2. Substrate Scope of Styrenes
R
2
R
2
P(O)Ph
2
5 mol % Cu(OAc)
6 mol % (S,S)-Ph-BPE
2
N
Ph
NHP(O)Ph2
R
1
+
(
MeO) MeSiH, t-BuOH
THF, RT, 12 h
2
R
1
Ph
H
Table 1. Copper-Catalyzed Asymmetric Addition of
Styrene-Derived Nucleophiles to Imines: Effect of Re-
styrene
imine
enantioenriched amine
a
Me
Ph
action Parameters
Me
Me
Ph
Ph
Me
NHP(O)Ph
2
P(O)Ph2
5 mol % Cu(OAc)2
NHP(O)Ph2
NHP(O)Ph
2
NHP(O)Ph2
H
N
Ph
Ph
F3C
6
mol % (S,S)-Ph-BPE
H
+
+
C(O)NEt2
Ph
Ph
H
(MeO)2MeSiH, t-BuOH
NHP(O)Ph2
Ph
3
5a
5b
THF, RT, 12 h
Ph
(2.0 equiv)
(1.0 equiv)
95% yield (3:1 dr)
99% ee (99% ee)
85% yield (2:1 dr)
98% ee (97% ee)
82% yield (2:1 dr)
99% ee (99% ee)
"
standard conditions"
1
2a
3
4
Me
Me
Me
Ph
Ph
Ph
NHP(O)Ph
2
entry
variation from the
standard conditions”
yield of 3
(dr)
ee of 3
yield
of 4
NHP(O)Ph
2
NHP(O)Ph2
“
t-BuO
CO
2
t-Bu
5c
5% yield (2:1 dr)
Cl
b
1
2
3
4
5
6
7
8
none
95% (3:1) 99% ee (99% ee)
1.5%
85%
65%
20%
35%
54%
31%
36%
<10%
5d
5e
7
79% yield (3:1 dr)
99% ee (99% ee)
90% yield (3:1 dr)
99% ee (99% ee)
9
9% ee (99% ee)
L1 instead of L6
L2 instead of L6
L3 instead of L6
L4 instead of L6
L5 instead of L6
no t-BuOH
9% (1:1)
<5%
95% ee (99% ee)
n.d.
Me
Me
Me
Me
Ph
Ph
Ph
NHP(O)Ph
2
NHP(O)Ph
2
c
<5%
n.d.
NHP(O)Ph
2
Me
N
Br
5% yield (2:1 dr)
5
f
5g
5h
56% (1:1)
46% (1:1)
41% (3:1)
86% ee (83% ee)
78% ee (70% ee)
99% ee (99% ee)
n.d.
9
79% yield (10:1 dr)
77% ee (61% ee)
77% yield (2:1 dr)
98% ee (98% ee)
9
9% ee (99% ee)
Me
Ph
MeO
Ph
NHP(O)Ph
2
d
NHP(O)Ph
2
2b instead of 2a
2c instead of 2a
5%
N
3
F C
Ts
e
5i
7% yield (4:1 dr)
99% ee (99% ee)
5j
9
6%
n.d.
7
56% yield (1:1 dr)
97% ee (96% ee)
X-ray of 5f
(minor diastereomer)
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), Cu(OAc)
MeSiH (5 equiv), THF (0.5 M), rt, 12 h.
NMR spectroscopic analysis using 1,3,5-
2
(5 mol %), L (6
mol %), t-BuOH (2 equiv), (MeO)
Yields were determined by
2
a
1
Yields are of isolated product as a mixture of two diastereomers on a 0.5 mmol
H
scale. The relative and absolute stereochemistry of both diastereomers were
determined by X-ray crystallography or further derivatization of the product, see
SI for details. The ee of the minor diastereomer is shown in parentheses.
trimethoxybenzene as the internal standard. Enantiomeric excess values were
b
determined by chiral HPLC analysis. The ee of the minor diastereomer is
c
d
e
shown in parentheses. 30% conv. of 2a. 41% conv. of 2b. 12% conv. of 2c.
Following a survey of imine protecting groups and reaction
conditions, N-phosphinoylimines were identified as suitable
substrates for the desired asymmetric addition reaction.
Phosphinoylimines could be conveniently prepared from the
parent carbonyl compounds and the deprotection of the re-
2
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
sulting N-phosphinoylamines could be effected under acidic
We next set out to investigate the substrate scope of this
reaction (Table 2). A number of styrenes with various elec-
tronic properties (5a 5f) could be successfully converted
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
conditions (see Supporting Information). The copper cata-
lyst based on Ph-BPE (L6) was found to be highly effective
for the asymmetric nucleophilic addition, providing the cou-
–
into the corresponding amine product with excellent levels of
enantioselectivity and moderate levels of diastereoselectivity.
Chlorinated (5e) and brominated (5f) styrenes were tolerat-
ed, thus opening up possibilities for further derivatization
using cross-coupling technologies. Interestingly, the use of an
ortho-substituted styrene furnished the coupled product
with good diastereocontrol (5g), although slight decrease of
enantioselectivity was also observed. Furthermore, nitrogen
pled product
3
in excellent yield with outstanding enantio-
control (Table 1, entry 1). The effectiveness of this ligand is
consistent with the ligand effects observed in our previously
reported indoline synthesis, for which Ph-BPE was also
found to be the optimal ligand.1 In contrast, the use of other
ligands led to the formation of a significant amount of reduc-
2a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tion product
droamination, based on DTBM-SEGPHOS (L1), provided
only 9% product and 85% reduced amine . In addition,
4
. For example, our optimal catalyst for hy-
1
0
heterocycles (5h and 5i) and a β–substituted styrene (5j
)
3
4
were also suitable for this asymmetric addition. The lower
yield of 5j is presumably due to the slower hydrocupration of
these β–substituted styrenes.
bulky phenyl substituents on the phospholane moiety of the
BPE ligand proved essential not only for achieving high levels
of enantioselectivity but also for enabling the desired
chemoselectivity (entries 4–6). Omitting tert-butanol result-
ed in a dramatic loss in yield (entry 7). We reasoned that the
We next examined the scope of the imine coupling partner
Table 3). Our protocol was found to readily accommodate a
(
variety of electron-rich (6a and 6b) and electron-poor (6c
and 6d) imines. Furthermore, a broad spectrum of imines
bearing a pendant heterocycle, including an indole (6e), a
thiophene (6f), a pyridine (6g), an azaindole (6h) and a thi-
azole (6i), could be effectively transformed into the corre-
sponding amine products in a highly enantioselective fash-
ion. These results are notable, because heterocycles are prev-
alent structural elements in pharmaceuticals and the metal-
catalyzed enantioselective transformation of these substrates
is generally challenging. Additionally, an α,β-unsaturated
imine also underwent the current nucleophilic addition with
protonation of copper amide
ure 1) with t-BuOH bypassed the slow transmetalation of
with a hydrosilane and thus greatly facilitated the catalyst
(
V L*Cu-N(P(O)Ph2)R*, Fig-
V
1
2a,18
turnover.
The choice of the N-protecting group of the
imine was crucial for the successful implementation of this
transformation, with sulfonyl, aryl, and alkyl protecting
groups providing much lower yields (entries 8 and 9, see
Supporting Information for full details).
Table 3. Substrate Scope of Iminesa
1
9
Me
excellent enantiocontrol (6j). Moreover, substantially less
5
mol % Cu(OAc)
2
P(O)Ph
2
N
6 mol % (S,S)-Ph-BPE
R
1
+
reactive ketimines (6k 6m) also represented suitable sub-
–
(MeO) MeSiH, t-BuOH
THF, RT, 12 h
2
R
1
R
2
R
2
NHP(O)Ph
2
strates, further highlighting the generality of the current en-
antioselective addition process. Finally, the absolute stereo-
chemistry at the benzylic position is found to be opposite to
styrene
Me
imine
enantioenriched amine
NMe
2
OMe
CF
3
Me
Me
that of the previously reported hydrofunctionalizations using
NHP(O)Ph
2
NHP(O)Ph
2
NHP(O)Ph
2
11a, 12a, 12c
the same ligand.
Combined with results of our com-
6
a
6b
6c
9
9
2% yield (4:1 dr)
5% ee (99% ee)
95% yield (6:1 dr)
99% ee (99% ee)
80% yield (3:1 dr)
99% ee
putational studies on the hydrocupration step, this observa-
tion suggests that the C–C bond formation (III + V → V,
Br
I
CN
Me
S
Me
Figure 1) is a stereoinvertive process (See Supporting Infor-
mation for details).
Me
N
Me
NHP(O)Ph
2
NHP(O)Ph
2
This copper-catalyzed enantioselective imine addition was
scalable and required very low catalyst loadings. For example,
we were able to couple 3-chlorostyrene (
7) to imine 2a on a
NHP(O)Ph
2
6
d
6e
6f
8
9
1% yield (3:1 dr)
7% ee (88% ee)
86% yield (6:1 dr)
98% ee (96% ee)
89% yield (3:1 dr)
99% ee (99% ee)
OMe
N
N
gram scale using only 0.5 mol % catalyst (Figure 2, eq 1).
Me
Me
Me
NMe
4a
N
NHP(O)Ph
2
Furthermore, the chiral sulfinimines developed by Ellman
N
Bn
S
2
NHP(O)Ph2
could be used in lieu of N-phosphinoylimines, delivering
NHP(O)Ph
2
enantiomerically enriched amine
9
with excellent diastere-
ocontrol (eq 2). The relative and absolute configuration of
were ascertained by X-ray crystallographic analysis.
6
g
6h
6i
75% yield (4:1 dr)
7% ee (99% ee)
87% yield (5:1 dr)
99% ee (99% ee)
95% yield (4:1 dr)
98% ee (97% ee)
2
0
9
9
Ph
Me
Me
Me
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Me NHP(O)Ph
2
Me NHP(O)Ph
2
Ph NHP(O)Ph
2
NHP(O)Ph
2
6
j
6k
6l
6m
75% yield
80% ee
8
9
6% yield (2:1 dr)
9% ee (99% ee)
72% yield (2:1 dr)
92% ee (88% ee)
31% yield
90% ee
a
Yields are of isolated product on a 0.5 mmol scale, see SI for details.
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Me
P(O)Ph
H
2
0.5 mol % Cu(OAc)2
0.75 mol % Ph-BPE
centers with excellent enantiocontrol. Utilizing a diverse
range of other (poly)unsaturated hydrocarbons as latent nu-
N
Ph
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(eq 1)
(
MeO)2MeSiH, t-BuOH
THF, RT, 24 h
Ph
NHP(O)Ph
2
Cl
cleophiles in the asymmetric addition to imines is currently
underway and will be reported in due course.
•
one gram scale
Cl
7
2a
5e
8
3% yield, 2.5:1 d.r.
99% ee (99% ee)
Me
Ph
ASSOCIATED CONTENT
5
mol % Cu(OAc)2
6 mol % Ph-BPE
(eq 2)
Ph
(MeO) MeSiH, t-BuOH
MTBE, RT, 24 h
2
Supporting Information. Experimental procedures and charac-
terization data. This materials is available free of charge via the
Internet at http://pubs.acs.org.
HN
t-Bu
1
+
Ph
S
9
O
S
O
8
4% yield
d.r. = 18:1:0.2:0.7
N
t-Bu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
AUTHOR INFORMATION
8
[X-ray]
Corresponding Author
Figure 2. Gram-Scale Synthesis with Low Catalyst Loadings
and the Use of Chiral Sulfinimines
*
sbuchwal@mit.edu
To gain further insight into the unique chemoselectivity
during the hydrocupration event, we studied the rates of the
CuH-catalyzed reduction of imine 2a with different support-
ing ligands by monitoring the reaction progress using calori-
metric analysis established by Blackmond (Figure 3(A)).21
Our kinetic data suggested that the undesired imine reduc-
tion with Ph-BPE is considerably slower than that using
DTBM-SEGPHOS and SEGPHOS. Furthermore, we per-
formed density-functional theory (DFT) calculations for the
styrene hydrocupration with the same set of CuH catalysts
ACKNOWLEDGMENT
Financial support was provided by the National Institutes of
Health (GM46059) and the MIT Undergraduate Research Op-
portunity Program (I.B.P). We acknowledge Dr. Gang Lu and
Prof. Peng Liu (University of Pittsburgh) for helpful discussion
on the computational study. We thank Dr. Yiming Wang (MIT)
for his advice on this manuscript and Dr. Peter Müller (MIT)
for X-ray crystallographic analysis. Calculations were performed
at the Extreme Science and Engineering Discovery Environ-
ment (XSEDE) supported by the NSF.
2
2
(Figure 3(B)). Our computational investigations revealed
that while the activation barrier for styrene hydrocupration
using Ph-BPE is comparable to that for DTBM-SEGPHOS,
REFERENCES
(
1) Chiral Amine Synthesis; Nugent, T.C. Ed.; Wiley-VCH: Weiheim,
2
this Ph-BPE-based hydrocupration is ca. 1.8 ×10 times faster
2010.
(
2) For recent reviews: (a) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev.
than that using SEGPHOS. Taken together, these findings
provide evidence for the unusual ability of the Ph-BPE-based
CuH catalyst to suppress the undesired imine reduction
while simultaneously facilitating the hydrocupration of weak-
ly polarized styrene substrates.
2011, 111, 1713. (b) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(3) Hydrolases in Organic Synthesis; Bornscheuer, U. T.; Kazlauskas, R.
J. Ed.; Wiley-VCH: Weinheim, 2006.
(4) For a review on the use of tert-butylsulfinamides: (a) Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600. For reviews on
catalytic asymmetric addition reactions to imines: (b) Kobayashi, S.; Mori,
Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. (c) Kobayashi,
S.; Ishitani, Chem. Rev. 1999, 99, 1069.
(5) Selected reviews: (a) H.-Y. Jang, M. J. Krische, Acc. Chem. Res.
2004, 37, 653. (b) E. Skucas, M.-Y. Ngai, V. Komanduri, M. J. Krische,
Acc. Chem. Res. 2007, 40, 1394.
(6) Selected recent examples: (a) Liang, T.; Zhang, W.; Krische, M. J. J.
Am. Chem. Soc. 2015, 137, 16024. (b) Zbieg, J. R.; Yamaguchi, E.; McIn-
turff, E. L.; Krische, M. J. Science 2012, 336, 324.
(A)
0.07!
DTBM-SEGPHOS!
SEGPHOS!
Ph-BPE!
0
.06!
0
0
.05!
.04!
2
mol % Cu(OAc)2
P(O)Ph2
NHP(O)Ph2
H
N
3 mol % L*
(MeO)2MeSiH, t-BuOH
THF, 25.0 °C
Ph
H
Ph
H
0.03!
2
a
4
0
0
.02!
.01!
(
7) (a) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem.
Soc. 2005, 127, 11269. (b) Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 7242. For a Ni-catalyzed asymmetric reductive
coupling of alkynes and imines: (c) Zhou, C.-Y.; Zhu, S.-F.; Wang, L.-X.;
Zhou, Q.-L. J. Am. Chem. Soc. 2010, 132, 10955. For non-
enantioselective examples: (d) Chen, T.-Y.; Tsutsumi, R.; Montgomery, T.
P.; Volchkov, I. Krische, M. J. J. Am. Chem. Soc. 2015, 137, 1798. (e) Oda,
S.; Franke, J.; Krische, M. J. Chem. Sci. 2016, 7, 136.
(8) For a non-enantioselective example of reductive coupling between
electron-deficient vinylazaarenes and imines: Komanduri, V.; Grant, C. D.;
Krische, M. J. J. Am. Chem. Soc. 2008, 130, 12592.
0
!
0
!
10!
20!
30!
40!
50!
60!
70!
80!
90!
100!
time (min)!
(B)
L*
ΔG‡
Ph
‡
P
DTBM-SEGPHOS (L1) 15.3
P
CuL*
Cu
H
SEGPHOS (L2)
Ph-BPE (L6)
18.1
15.1
+
H
H
Ph
Me
Ph
H
L*Cu
H
ΔG‡ is shown in kcal/mol.
Figure 3. Mechanistic Insight into the Unusual Chemoselec-
tivity of Hydrocupration
(9) For reviews on CuH catalysis: (a) Deutsch, C.; Krause, N.; Lipshutz,
B. H. Chem. Rev. 2008, 108, 2916. (b) Rendler, S.; Oestreich, M. Angew.
Chem. Int. Ed. 2007, 46, 498.
In summary, we have developed a mild and general copper-
catalyzed process for the enantioselective addition of sty-
rene-derived nucleophiles to imines. This process tolerates a
broad range of functionalized and heterocyclic substrates,
providing rapid access to amines bearing vicinal stereogenic
(10) For a review: Wang, Y.-M.; Pirnot, M. T. Angew. Chem. Int. Ed.
2
015, 55, 48.
11) (a) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem. Int.
Ed. 2013, 52, 10830. (b) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Org.
(
4
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
Lett. 2014, 16, 1498. (c) Nishikawa, D.; Hirano, K.; Miura, M. J. Am.
Chem. Soc. 2015, 137, 15620.
12) (a) Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 4666.
b) Wang, Y.-M.; Bruno, N. C.; Placeres, Á, L.; Zhu, S.; Buchwald, S. L. J.
Am. Chem. Soc. 2015, 137, 10524. (c) Wang, Y.-M.; Buchwald, S. L. J.
Am. Chem. Soc. 2016, 138, 5024. (d) Bandar, J. S.; Ascic, E.; Buchwald, S.
L. J. Am. Chem. Soc. 2016, 138, 5821. (e) Yang, Y.; Perry, I. B.; Lu, G.; Liu,
P.; Buchwald, S. L. Science 2016, 353, 144.
(13) For related CuH-catalyzed C–C bond formation involving vinyl- or
allylcopper intermediates: (c) Uehling, M. R.; Suess, A. M.; Lalic, G. J. Am.
Chem. Soc. 2015, 137, 1424. (d) Suess, A. M.; Uehling, M. R.; Kaminsky,
W.; Lalic, G. J. Am. Chem. Soc. 2015, 137, 7747. (e) Iwasaki, T.; Shimizu,
R.; Imanishi, R.; Kuniyasu, H.; Kambe, N. Angew. Chem. Int. Ed. 2015,
examples of copper-catalyzed enantioselective addition to imines using
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
preformed organometallic reagents: (a) R. Wada, T. Shibuguchi, S.
Makino, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128,
7687. (b) Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2011, 133, 3332. (c) Vieira, E. M.; Haeffner, F.; Snapper, M. L.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2012, 51, 6618.
(17) Lipshutz, B. H.; Shimizu, H. Angew. Chem. Int. Ed. 2004, 43,
2228.
(18) For the use of t-BuOH in CuH-catalyzed reactions: (a) Chen, J.-X.;
Daeuble, J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789. (b) Hughes, G.;
Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253. (c)
Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126,
8352. (d) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5821.
(19) The use of aliphatic aldimines provided low yield.
(20) The use of (R,R)-Ph-BPE instead of (S,S)-Ph-BPE afforded the
amine product in 80% yield and 1:1 dr.
(
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
4, 9347.
14) (a) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.; Shibasaki,
(
M. J. Am. Chem. Soc. 2008, 130, 16146. (b) Choi, B.; Saxena, A.; Smith, J.
J.; Churchill, G. H.; Lam, H. W. Synlett 2015, 26, 350.
(15) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem. Int. Ed. 2009, 48,
(21) Blackmond, D. G. Angew. Chem. Int. Ed. 2005, 44, 4302.
(22) Calculations were performed at the M06/SDD(Cu)-6-
311+G(d,p)/SMD(THF) level of theory with geometries optimized at the
B3LYP/SDD(Cu)-6-31G(d) level. See Supporting Information for details.
6
062.
16) For recent reviews on copper-catalyzed asymmetric nucleophilic
addition to imines: (a) M. Shibasaki, M. Kanai, Chem. Rev. 2008,108,
853. (b) Yamada, K.; Tomioka, K. Chem. Rev. 2008,108, 2874. Selected
(
2
P(O)Ph2
R1
N
CuL*
R1
L*CuH cat.
R1
R2
R3
R3
R2 NHP(O)Ph2
enantioenriched,
catalytically generated
organocopper
styrene
enantioenriched amine
5
ACS Paragon Plus Environment