Enantioselective CuH-Catalyzed Hydroacylation Employing Unsaturated Carboxylic Acids as Aldehyde Surrogates

Article abstract of DOI:10.1021/jacs.7b04937

The direct asymmetric copper hydride (CuH)-catalyzed coupling of α,β-unsaturated carboxylic acids to aryl alkenes to access chiral α-aryl dialkyl ketones is reported. A variety of substrate substitution patterns, sensitive functional groups, and heterocycles are tolerated in this reaction, which significantly expands the range of accessible products compared with existing hydroacylation methodology. Although mechanistic studies are ongoing, we propose that CuH-catalyzed silylation of unsaturated acids occurs to access a uniquely effective acyl electrophilic coupling partner.

Full text of DOI:10.1021/jacs.7b04937

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Communication
Enantioselective CuH-Catalyzed Hydroacylation Employing
Unsaturated Carboxylic Acids as Aldehyde Surrogates
Yujing Zhou, Jeffrey S Bandar, and Stephen L. Buchwald
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Enantioselective CuH-Catalyzed Hydroacylation Employing
Unsaturated Carboxylic Acids as Aldehyde Surrogates
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Yujing Zhou, Jeffrey S. Bandar, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Supporting Information Placeholder
molecular hydroacylation have been reported using sub-
strates of broad value that feature a coordinating substituent
(e.g. salicylaldehydes, 2-(methylthio)benzaldehydes and α-
substituted acrylamides).9 Meanwhile, the branch-selective
addition of simple aliphatic aldehydes to styrenes provides
direct access to dialkyl ketones bearing an α-aryl stereocen-
ter, although only racemic methods for this transformation
have been reported (Scheme 1a).10 To avoid the problems
associated with aldehyde decarbonylation and stereocenter
epimerization, we reasoned that a complementary approach
toward hydroacylation could potentially provide rapid access
to enantioenriched tertiary α-aryl dialkyl ketones.
ABSTRACT: The direct asymmetric copper hydride (CuH)-
catalyzed coupling of α,β-unsaturated carboxylic acids to aryl
alkenes is reported to access chiral α-aryl dialkyl ketones. A
variety of substrate substitution patterns, sensitive functional
groups and heterocycles are tolerated in this reaction, which
significantly expands the range of accessible products com-
pared to existing hydroacylation methodology. Although
mechanistic studies are ongoing, we propose that CuH-
catalyzed silylation of unsaturated acids occurs to access a
uniquely effective acyl electrophilic coupling partner.
Scheme 1. Previous work in hydroacylation using (a) alde-
hydes, (b) aryl anhydrides, and (c, this work) α,β-
unsaturated carboxylic acids to access chiral α-aryl ketones.
Chiral α-aryl ketones represent an important functional
group due to their synthetic utility and common occurrence
in molecules of broad interest.1 While a number of catalytic
methods exist for preparing enantioenriched quaternary α-
aryl ketones2, catalytic assembly of acyclic tertiary variants
via C–C bond formation is made challenging by the acidic
nature of the stereocenter.3,4 This has recently been ad-
dressed via transition metal-catalyzed asymmetric coupling
reactions of α-bromo ketones to aryl organometallic rea-
gents5a,b, benzylic bromides to acyl chlorides5c, and benzylic
zinc reagents to thioesters5d; additionally, chiral Lewis acid-
catalyzed insertion of aryldiazoalkanes into aldehyde C–H
bonds has also been described.5e Despite this progress, com-
plementary catalytic methods for preparing chiral tertiary α-
aryl dialkyl ketones from abundant and stable functional
groups remain in high demand.
(a) Typical approach to hydroacylation using aliphatic aldehydes
metal
catalyst
O
O
+
Me
Ar
R
H
R
Ar
racemic
(b) Our previous work using aryl anhydrides as aldehyde surrogates
O
OH
O
O
L*CuH
R3SiH
+
Me
Ar2
Me
or
Ar1
Ar1
Ar1
O
Ar1
Ar2
Ar2
hydroacylation and1,2-reduction
(c) α,β-Unsaturated acid electrophiles for hydroacylation (this work)
O
O
L*CuH
R2
+
R1
OH
Ar
R1
R2
R3SiH
Ar
hydroacylation and1,4-reduction
Hydroacylation, typically achieved by the addition of an
aldehyde C–H bond across an alkene π-bond, is a stream-
lined approach for the construction of ketones from readily
available functional groups.6 While numerous enantioselec-
tive intramolecular hydroacylation processes have been re-
ported, intermolecular variants remain less developed.7 The
primary challenge associated with this transformation is sup-
pressing aldehyde decarbonylation, which often occurs
readily for substrates without a coordinating substituent.8
Nonetheless, impressive examples of enantioselective inter-
As part of a broader program using chiral copper hydride
(CuH) species as catalysts for enantioselective hydrofunc-
tionalization reactions11, we sought to utilize acyl electro-
philes as surrogates for aldehydes in order to address limita-
tions of existing hydroacylation methodology. Inspired by
prior work by Miura12a and Krische12b, we recently reported a
CuH-catalyzed method for coupling styrenes to symmetrical
aryl anhydrides to afford chiral α-aryl ketones or, after con-
comitant 1,2-reduction, chiral alcohols (Scheme 1b).13 In
1
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a
1
yields determined by H NMR analysis of crude reaction
(S,S)-Ph-BPE 1,2-Bis((2S,5S)-2,5-
diphenylphospholano)ethane.
order to expand the synthetic utility of this hydroacylation
strategy, we recognized the need to develop an improved
method that avoids use of symmetrical anhydrides and, im-
portantly, employs aliphatic aldehyde surrogates. We herein
report the use of α,β-unsaturated carboxylic acids as direct
coupling partners in a CuH-catalyzed dual hydroacylation
and reduction process that provides access to highly enanti-
oenriched tertiary α-aryl dialkyl ketones (Scheme 1c).
1
2
3
4
5
6
7
8
mixture,
=
This finding prompted a structure-activity relationship
(SAR) study of the electrophilic acyl species (Scheme 2b).
First, no coupling was observed when butanoic acid (1d) or
its silyl ester 1e were used, clearly indicating the requirement
for α,β-unsaturation in this process. Crotonaldehyde (1f)
also provided no product, which suggests reduction of the
acid to an aldehyde does not occur prior to hydroacylation.
Additionally, other crotonoyl-based electrophiles, such as
crotonoyl chloride (1g) or alkyl crotonates (1h and 1i), pro-
vided no hydroacylation product. On the other hand, the use
of methyl(dimethoxy)silyl crotonate (1j) led to 20% yield of
ketone 3a in 80% ee, suggesting silylated crotonic acid may
be an active intermediate in the direct coupling of acids.
9
In CuH-catalyzed hydrofunctionalization reactions,
chemoselective hydrocupration of an olefin in the presence
of an electrophilic coupling partner is required in order to
obtain high product yields.14 This requisite is realized when
using aryl anhydride coupling partners (Scheme 1b); howev-
er, no hydroacylation of 4-fluorostyrene was seen when bu-
tyric anhydride, an aliphatic anhydride (1a), was subjected
to the previously reported reaction conditions (Scheme 2a).
Instead, only direct reduction of butyric anhydride to n-
butanol was observed. We hypothesized that reactions of α,β-
unsaturated anhydrides may display similar chemoselectivity
as with aryl anhydrides to allow for styrenyl hydroacylation,
and with concomitant 1,4-reduction of the unsaturated car-
bonyl, would produce chiral α-aryl dialkyl ketones. This hy-
pothesis was validated when crotonic anhydride (1b) was
subjected to the reaction conditions, which provided chiral
ketone 3a in 70% yield and 94% ee after treatment with
NH4F. In the course of searching for acyl electrophile alter-
natives to anhydrides, we discovered that α,β-unsaturated
carboxylic acids directly engage in this hydroacylation pro-
cess. Thus, the use of crotonic acid (1c) and 8 equiv of silane
provided ketone 3a in 85% yield and 88% ee.
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Based on the above observations and previous studies on
CuH chemistry, we are currently able to propose the reaction
pathway outlined in Scheme 3.15 First, carboxylic acid depro-
tonation and silylation is catalyzed by CuH in the presence
of a hydrosilane, generating activated acyl electrophile 4
(Step A).16 Additionally, enantioselective hydrocupration of
a styrene generates a chiral copper(I) benzylic intermediate
(5, Step B), which represents the active nucleophilic partner.
The reaction ultimately produces silyl enol ether 6, which is
observed in high yield as judged by 1H NMR spectroscopy of
the crude reaction mixture and allows access to chiral ketone
3 upon treatment with NH4F.17 At this time, the mechanism
by which chiral benzyl copper 5 and the silylated acid 4 cou-
ple (Step C), and if other reaction intermediates are in-
volved, is unknown and is the subject of ongoing investiga-
tions.18,19
Scheme 2. (a) Discovery and (b) SAR of CuH-catalyzed
tandem hydroacylation and 1,4-reduction with unsaturated
acyl electrophiles.a
Scheme 3. Currently proposed pathway for hydroacylation.
O
O
Cu(OAc)2 (4 mol%)
(S,S)-Ph-BPE (4.4 mol%)
O
O
4
L*CuH
Me
+
Me
R
X
Ar
[Si]–H
Step A
O[Si]
Ar
R
OH
R
O[Si]
Me
Me(OMe)2SiH (4 equiv)
THF, rt, 24 h
(NH4F workup)
Me
1, acyl
electrophile
(1.5 equiv)
2, Ar =
4-FC6H4
R
3a
Step C
6
L*CuH
L*Cu
Ar
F
Step B
5
Ar
a) Initial discovery of asymmetric hydroacylation using enoic acids
Step A: acid silylation (activation) Step B: enantioselective hydrocupration
hydroacylation and 1,4-reduction (mechanistic studies ongoing)
O
O
O
O
O
Step C:
Me
O
Me Me
O
Me Me
OH
The current scope of accessible chiral α-aryl ketones
through the CuH-catalyzed coupling of α,β-unsaturated ac-
ids to aryl alkenes is shown in Table 1.20a First, the vinyl
arene scope was explored using simple unsaturated carbox-
ylic acid coupling partners (Table 1a). Electron deficient and
electron rich, as well as ortho-substituted styrenes, provide
chiral ketones in excellent yield and enantioselectivity (3a-
c). A variety of alkenes containing coordinating atoms or
consisting of heterocycles, such as a piperizine, pyrimidine,
pyrazole, pyridine, benzofuran and carbazole, engage in this
hydroacylation process delivering ketones in high enantiopu-
rity (3d-i). In contrast to our previous hydroacylation meth-
od utilizing aryl anhydride reagents, we found that β-
1a
1b
1c
85% yield, 88% ee
0% yield
70% yield, 94% ee
b) Structure-activity relationship study of acyl electrophiles
O
O
O
Me
Me
OH
Me
Me
OSiMe(OMe)2
Me
H
1d
1e
1f
0% yield
0% yield
0% yield
O
O
O
OR
Me
OSiMe(OMe)2
1j
20% yield, 80% ee
Cl
1g
R = Me, 1h R = tBu, 1i
0% yield 0% yield
0% yield
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a All yields represent average isolated yields of two runs, per-
substituted styrenes couple to unsaturated acids in both high
1
2
3
4
5
6
7
8
yield and enantioselectivity (Table 1b).20b β-substituted sty-
renes containing functional groups that could potentially be
reduced by reactive CuH intermediates, such as a t-butyl
ester (3j) and methyl ester (3k), are well tolerated, as is a
PMB-protected alcohol (3l). Carboxylic acid substrates con-
taining ethers (3m and 3n), a thioether (3o) and potentially-
reducible functional groups, such as a nitro group (3p) and a
cis-alkene (3q), couple to styrenes in excellent yield and ste-
reoselectivity (Table 1c).
formed with 1 mmol of alkene.
The substrates shown in Table 1 demonstrate that β-alkyl-
and symmetrical β,β-dialkyl-substituted unsaturated carbox-
ylic acids are competent hydroacylation coupling partners
for a variety of styrene types.20c α-Alkyl substituted unsatu-
rated acids, such as tiglic or angelic acid, do not engage in
hydroacylation under the current reaction conditions. Simi-
larly, acrylic acid, an unsubstituted unsaturated carboxylic
acid that would provide access to ethyl ketones, does not
participate in this transformation (Scheme 4a). To address
this limitation, we found that β-ethoxyacrylic acid (9) acts as
an acrylic acid surrogate to deliver chiral ethyl ketones in
good yield and enantiopurity (Scheme 4b). This approach,
which we propose proceeds via a 1,4-reduction/β-ethoxy
elimination pathway, is general as shown for ortho-
substituted substrate 10a and β-substituted styrene-derived
ketone 10b.
9
10
11
12
13
14
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60
Table 1. Ketone substrate scope for the direct coupling of aryl
alkenes to α,β-unsaturated carboxylic acids.a
R1
7
Ar
R3
R3
O
Cu(OAc)2 (4 mol%)
(S,S)-Ph-BPE (4.4 mol%)
+
R2
R1
O
Me(OMe)2SiH (8 equiv)
THF, 30 °C, 24 h
(NH4F workup)
Ar
R2
OH
3
8 (1.5 equiv)
a) vinyl arene scope
Scheme 4. The use of (a) acrylic acid and (b) β-
O
O
O
ethoxyacrylic acid to access chiral ethyl ketones.a
Me
Me
Me
OMe
Me
3a
i-Pr
Me
3c
a) No coupling observed using acrylic acid electrophile
3b
77% yield
84% yield
91% ee
86% yield
91% ee
O
Cu(OAc)2 (4 mol%)
(S,S)-Ph-BPE (4.4 mol%)
O
93% ee
OMe
Me
Me
F
+
OH
acrylic acid
Ar
O
O
O
Me(OMe)2SiH (8 equiv)
THF, 30 °C, 24 h
Ar
no product
Me
Me
Me
Me
i-Pr
i-Pr
(NH4F workup)
b) Utilizing β-ethoxyacrylic acid to access chiral ethyl ketones
3d
3e
78% yield
85% ee
3f
N
O
N
N N
conditions
as above
72% yield
97% ee
58% yield
91% ee
O
O
N
N
N
+
Me
R
R
EtO
OH
Ar
Ar
9 (1.5 equiv)
F
7
10
Boc
O
O
O
O
Me
Me
OMe
Me
OPiv
Me
Me
N
Me
10a
66% yield
95% ee
10b
Me
Me
i-Pr
60% yield
95% ee
3g
83% yield
95% ee
3i
3h
83% yield
88% ee
72% yield
93% ee
Ph
O
N
OMe
Et
b) β-substituted styrene scope
a
Yields represent average isolated yields of two runs, per-
O
Me
Me
O
3k
CO2Me 82% yield
99% ee
formed with 1 mmol of alkene.
OPiv
Me
3j
Me
Me
Ph
Ph
To demonstrate the scalability of this methodology, a 10
mmol scale reaction using just 1 mol% catalyst loading is
shown in Eq 1 to provide 1.5 g of chiral ketone 3a with 92%
ee. Given the ready accessibility of α,β-unsaturated acids and
aryl alkenes, this method represents a highly practical ap-
proach to chiral α-aryl dialkyl ketones containing a range of
functional groups and substitution patterns.21 Furthermore,
by utilizing in situ activated acyl electrophiles as surrogates
for aldehydes, this work addresses current substrate limita-
tions of existing hydroacylation methodogy. The mechanism
of this unprecedented coupling reaction is currently under
investigation, as are additional CuH-catalyzed transfor-
mations involving unsaturated carboxylic acid substrates.
O
3l
83% yield
97% ee
OPMB
80% yield
97% ee
Ph
c) carboxylic acid scope
O
O
O
O
BnO
3m
Me
N
Me
Me
MeS
3n
3o
62% yield
92% ee
80% yield
94% ee
89% yield
97% ee
N
N
OMe
Me
F
O
O
O2N
Me
Me
N
Me
Me
3p
3q
61% yield
89% ee
76% yield
96% ee
OMe
O
3
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Chem. Rev. 2015, 115, 3468. (c) Willis, M. C. Chem. Rev. 2010, 110, 725.
(d) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222.
(7) Selected examples of enantioselective intramolecular alkene hy-
droacylation: (a) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.;
Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821. (b) Kundu, K.;
McCullagh, J. V.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2005, 127, 16042.
(c) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 6932. (d) Janssen-Müller, D.; Schedler, M.; Fleige, M.; Daniliuc, C.
G.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 12492. (e) Yang, J.; Yoshi-
kai, N. J. Am. Chem. Soc. 2014, 136, 16748. (f) Yang, G.; Rérat, A.; Lim, Y.
J.; Gosmini, C.; Yoshikai, N. Angew. Chem., Int. Ed. 2017, 56, 2449. (g) Du,
X.-W.; Ghosh, A.; Stanley, L. M. Org. Lett. 2014, 16, 4036. (h) Rastelli, E.
J.; Truong, N. T.; Coltart, D. M. Org. Lett. 2016, 18, 5588. (i) Hoffman, T.
J.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 10670.
1
2
3
4
5
6
7
8
O
Me
OH
(1.5 equiv)
Cu(OAc)2 (1 mol%)
(S,S)-Ph-BPE (1.1 mol%)
Me
Me
3a
1.5 g
76% yield
92% ee
(1)
+
Me(OMe)2SiH (8 equiv)
THF, 30 °C, 48 h
(NH4F workup)
F
F
2, 10 mmol
ASSOCIATED CONTENT
9
Supporting Information. The Supporting Information is avail-
able free of charge on the ACS Publications website.
Experimental procedures and characterization data for all com-
pounds (PDF).
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
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(8) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202.
(9) (a) Phan, D. H. T.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc.
2010, 132, 16254. (b) Coulter, M. M.; Fou, K. G. M.; Galligan, B.; Dong,
V. M. J. Am. Chem. Soc. 2010, 132, 16330. (c) Osborne, J. D.; Randell-Sly,
H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008,
130, 17232. (d) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552.
(e) For a review on additional examples of Rh-catalyzed asymmetric hy-
droacylation: Murphy, S. K.; Dong, V. M. Chem. Commun. 2014, 50,
13645. (f) Liu, F.; Bugaut, X.; Schedler, M. Frohlich, R.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 12626.
(10) (a) Murphy, S. K.; Bruch, A.; Dong, V. M. Angew. Chem., Int. Ed.
2014, 53, 2455. (b) Murphy, S. K.; Bruch, A.; Dong, V. M. Chem. Sci. 2015,
6, 174. (c) Xiao, L.-J.; Fu, X.-N.; Zhou, M.-J.; Xie, J.-H.; Wang, L.-X.; Xu,
X.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2016, 138, 2957. (d) Kim, J.; Yi, C. S.
ACS Catal. 2016, 6, 3336. (e) Schedler, M.; Wang, D.-S.; Glorius, F. Angew.
Chem., Int. Ed. 2013, 52, 2585.
(11) For reviews and selected examples, see: (a) Pirnot, M. T.; Wang,
Y.-M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55, 48. (b) Mohr, J.;
Oestreich, M. Angew. Chem., Int. Ed. 2016, 55, 12148. (c) Nguyen, K. D.;
Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J. Science 2016,
354, 300. (d) Gribble, M. W. Jr.; Pirnot, M. T.; Bandar, J. S.; Liu, R. Y.;
Buchwald, S. L. J. Am. Chem. Soc. 2017, 139, 2192. (e) Friis, S. D.; Pirnot,
M. T.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 8372. (f) Yang, Y.; Shi,
S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Science 2015, 349, 62.
(12) (a) Kokubo, K.; Miura, M.; Nomura, M. Organometallics 1995, 14,
4521. (b) Hong, Y.-T.; Barchuk, A.; Krische, M. J. Angew. Chem., Int. Ed.
2006, 45, 6885.
(13) Bandar, J. S.; Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138,
5821.
(14) For selected discussions on the chemoselectivity required in other
CuH-catalyzed hydrofunctionalization reactions see: (a) Niu, D.; Buch-
wald, S. L. J. Am. Chem. Soc. 2015, 137, 9716. (b) Yang, Y.; Perry, I. B.; Lu,
G.; Liu, P.; Buchwald, S. L. Science 2016, 353, 144. (c) Yang, Y.; Perry, I. B.;
Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 9787.
(15) (a) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108,
2916. (b) Bandar, J. S.; Pirnot, M. T.; Buchwald, S. L. J. Am. Chem. Soc.
2015, 137, 14812. (c) Issenhuth, J.-T.; Notter, F.-P.; Dagorne, S.; Dedieu,
A.; Bellemin-Laponnaz, S. Eur. J. Inorg. Chem. 2010, 2010, 529. (d) To-
bisch, S. Chem. Eur. J. 2016, 22, 8290. (e) Dang, L.; Zhao, H.; Lin, Z.;
Marder, T. B. Organometallics 2007, 26, 2824.
AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Research reported in this publication was supported by the Na-
tional Institutes of Health (GM46059). We also thank the NIH
for a supplemental grant for the purchase of supercritical fluid
chromatography equipment (GM058160-17S1) and a postdoc-
toral fellowship for J. S. B. (GM112197). The content is solely
the responsibility of the authors and does not necessarily repre-
sent the official views of the National Institutes of Health. We
thank Dr. Michael Pirnot for advice on this manuscript.
REFERENCES
(1) E. J. Corey and L. Kürti, Enantioselective Chemical Synthesis: Methods,
Logic and Practice; Direct Book Publishing: Dallas, 2010.
(2) For general approaches toward quaternary α-aryl ketones, see refer-
ence 1. For reviews on and selected examples of catalytic asymmetric syn-
thesis of quaternary α-aryl ketones: (a) Bellina, F.; Rossi, R. Chem. Rev.
2010, 110, 1082. (b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int.
Ed. 2010, 49, 676. (c) Bella, M.; Gasperi, T. Synthesis 2009, 10, 1583. (d)
Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 1261. (e) Lia, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
195. (f) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed.
2002, 41, 3492. (g) Kano, T.; Hayashi, Y.; Maruoka, K. J. Am. Chem. Soc.
2013, 135, 7134. (h) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128,
16050.
(3) Bordwell, F. G.; Harrelson, J. A., Jr. Can. J. Chem. 1990, 68, 1714.
(4) For reviews and selected examples of asymmetric protonation reac-
tions to access chiral α-aryl ketones, see: (a) Oudeyer, S.; Briere, J.-F.;
Levacher, V. Eur. J. Org. Chem. 2014, 6103. (b) Mohr, J. T.; Hong, A. Y.;
Stoltz, B. M. Nat. Chem. 2009, 1, 359. (c) Cheon, C. H.; Kanno, O.; Toste,
F. D. J. Am. Chem. Soc. 2011, 133, 13248. (d) Cheon, C. H.; Yamamoto, H.
J. Am. Chem. Soc. 2008, 130, 9246. (e) Yanagisawa, A.; Touge, T.; Arai, T.
Angew. Chem., Int. Ed. 2005, 44, 1546.
(5) (a) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int. Ed.
2009, 48, 154. (b) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264. (c)
Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013,
135, 7442. (d) Oost, R.; Misale, A.; Maulide, N. Angew. Chem., Int. Ed.
2016, 55, 4587. (e) Kang, B. C.; Nam, D. G.; Hwang, G.-S.; Ryu, D. H. Org.
Lett. 2015, 17, 4810.
(6) For selected reviews on transition-metal catalyzed hydroacylation,
see: (a) Ghosh, A.; Johnson, K. F.; Vickerman, K. L.; Walker, J. A., Jr.;
Stanley, L. M. Org. Chem. Front. 2016, 3, 639. (b) Yang, L.; Huang, H.
(16) Hydrogen evolution (bubbling) is observed when a solution of
LCuH is added to a reaction vial containing unsaturated carboxylic acid
and alkene (see Supporting Information).
(17) Upon prolonged reaction time or at higher reaction temperatures,
no further reduction of 6 is observed.
(18) It is possible that reduction of an α,β-unsaturated carbonyl inter-
mediate occurs either before or after hydroacylation occurs.
(19) When the commercially available Ph2SiD2 was used as the silane,
1H NMR analysis of semi-purified product showed deuterium incorporated
into the ketone product at positions derived from styrene hydrocupration
and 1,4-reduction of crotonic acid, indicating the dual role of the CuH
catalyst. We thank a reviewer for suggesting this experiment.
(20) (a) We found that for 1 mmol scale reactions heating the reaction
solution to 30 °C is optimal for achieving high yield and selectivity. (b) β,β-
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Disubstituted styrenes do not engage in hydroacylation under the current
reaction conditions. (c) β-Aryl unsaturated acids (e.g. cinnamic acid) do
(21) (a) Hayama, N.; Azuma, T.; Kobayashi, Y.; Takemoto, Y. Chem.
Pharm. Bull. 2016, 64, 704. (b) Gooßen, L. J.; Rodríguez, N.; Gooßen, K.
1
2
not engage in hydroacylation under the current reaction conditions.
Angew.
Chem.,
Int.
Ed.
2008,
47,
3100.
3
4
5
6
7
8
9
10
11
12
13
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15
16
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1
2
3
4
O
O
L*CuH (cat)
+
Ar
OH
R3SiH
Ar
(NH4F workup)
carboxylic acid
aryl alkene
chiral ketone
5
O
6
7
O
O
BnO
Me
i-Pr
OPMB
Me
i-Pr
8
9
63% yield
N
58% yield
91% ee
80% yield
97% ee
N
N N
92% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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48
49
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52
53
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58
59
60
Ar
NR2
6
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