Rhodium-catalyzed highly enantioselective direct intermolecular hydroacylation of 1,1-disubstituted alkenes with unfunctionalized aldehydes

Article abstract of DOI:10.1021/ja905908z

(Chemical Equation Presented) We have established that a cationic rhodium(I)/(R,R)-QuinoxP* complex catalyzes the highly enantioselective direct intermolecular hydroacylation of D-substituted acrylamides with unfunctionalized aliphatic aldehydes to yield the corresponding E-ketoamides in high yields with excellent ee values.

Full text of DOI:10.1021/ja905908z

Published on Web 08/17/2009
Rhodium-Catalyzed Highly Enantioselective Direct Intermolecular
Hydroacylation of 1,1-Disubstituted Alkenes with Unfunctionalized Aldehydes
Yu Shibata and Ken Tanaka*
Department of Applied Chemistry, Graduate School of Engineering, Tokyo UniVersity of Agriculture and
Technology, Koganei, Tokyo 184-8588, Japan
Received July 16, 2009; E-mail: tanaka-k@cc.tuat.ac.jp
Table 1. Screening of Chiral Bisphosphine Ligandsa
Transition metal catalyzed vinylic or aromatic sp2 C-H bond
alkylations with alkenes have been extensively studied, and a number
of efficient methods are available.1 However, the majority of enantio-
selective variants are intramolecular reactions (eq 1).2 Although a
number of efficient intermolecular sp2 C-H bond alkylations with
alkenes have been reported, the successful enantioselective reactions
using disubstituted alkenes have been limited to those with highly
reactive norbornenes (eq 2).3-6 Transition metal catalyzed hydro-
acylations of alkenes with aldehydes, which involve aldehyde sp2 C-H
bond activation as a key step, are also in the same situation. Although
large numbers of enantioselective intramolecular hydroacylations of
disubstituted alkenes have been reported,7 only two examples of
intermolecular variants have been succeeded to date.8,9 Bolm and
Stemmler demonstrated the first enantioselective intermolecular hy-
droacylation of disubstituted alkenes, while substrates were limited to
salicylaldehydes and norbornenes.8 Willis and co-workers recently
reported a notable success by using disubstituted allenes instead of
disubstituted alkenes.9 Although this report is the most successful
achievement in this area, substrates were still limited to ꢀ-S-aldehydes
and aryl-substituted allenes.9
entry
ligand
catalyst (%)
convn (%)
yield (%)
ee (%)
1
2
3
4
(R)-BINAP
(S,S)-DIOP
(S,S)-BDPP
(S,S)-Chiraphos
(R,R)-Me-BPE
(R,R)-Me-Duphos
(R,R)-QuinoxP*
(R,R)-QuinoxP*
10
10
10
10
10
10
10
5
58
44
1
89
6
92
90
>99
14
29
<1
<1
<1
66
74
87
35 (+)
22 (-)
-
-
-
88 (+)
99 (+)
98 (+)
5
6
7b
8b c
,
a [Rh(cod)2]BF4 (0.0050 mmol), ligand (0.0050 mmol), 1a (0.050
mmol), 2a (0.050 mmol), and (CH2Cl)2 (0.5 mL, 0.1 M) were used. The
active catalysts were generated in situ by hydrogenation.
b [Rh(nbd)2]BF4 was used. c Concentration of 2a: 0.5 M. 1a: 1.1 equiv.
is sharp contrast to previously reported enantioselective inter- and
intramolecular hydroacylations.7-9 Although the use of BINAP and
DIOP, possessing large bite angles, showed modest catalytic activity
for this reaction, both yields and ee values were low (entries 1 and 2).
Bisphosphine ligands, possessing smaller bite angles than BINAP and
DIOP, were then examined. However, almost no catalytic activities
were observed by using BDPP and Me-BPE (entries 3 and 5), and
rapid decarbonylation was observed by using Chiraphos (entry 4).
Pleasingly, monoaryl-bisphosphine ligands were found to be highly
effective (entries 6 and 7), and both high yield and ee value were
achieved by using QuinoxP*13 as a ligand (entry 7). Furthermore,
employing a high substrate concentration allowed reducing the catalyst
loading to 5 mol % (entry 8).
In the above two successful examples, functionalized aldehydes were
employed to stabilize the key acylrhodium intermediates with aldehyde
chelation control, which suppresses competitive rhodium-catalyzed
reductive decarbonylation.10,11 Our research group recently developed
a cationic rhodium(I)/dppb complex-catalyzed direct intermolecular
hydroacylation of N,N-dialkylacrylamides with unfunctionalized al-
dehydes presumably through the stabilization of acylrhodium inter-
mediates with alkene chelation to rhodium instead of aldehyde
chelation.12 Here, we achieved highly enantioselective direct inter-
molecular hydroacylation of 1,1-disubstituted alkenes with unfunc-
tionalized aldehydes by using a cationic rhodium(I)/QuinoxP* complex
as a catalyst.
A series of aldehydes 1a-h and acrylamides 2a-d was subjected
to the above optimal reaction conditions as shown in Table 2. N,N-
Diphenyl- (2a), N-methyl-N-phenyl- (2b), and N,N-dibenzylmeth-
acrylamides (2c) reacted with 1a to yield the corresponding γ-keto-
amides in high yields with excellent ee values (entries 1-3). Not only
methacrylamides 2a-c but also 2-phenylacrylamide 2d could be
employed (entry 4). With respect to aldehydes, a variety of primary
and secondary unfunctionalized aliphatic aldehydes 1b-f reacted with
We first screened chiral bisphosphine ligands in the reaction of
hydrocinnamaldehyde (1a) and N,N-diphenylmethacrylamide (2a) as
shown in Table 1. The study revealed that not only enantioselectivity
but also product yields were highly dependent on the ligands, which
9
12552 J. AM. CHEM. SOC. 2009, 131, 12552–12553
10.1021/ja905908z CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Rhodium-Catalyzed Enantioselective Hydroacylation of
Acrylamides 2a-d with Aliphatic Aldehydes 1a-ha
Scheme 1
entry
1
R1
2
R2
R3, R4
yield (%)b
ee (%)
1
2
1a Ph(CH2)2
1a Ph(CH2)2
1a Ph(CH2)2
1a Ph(CH2)2
1b n-Pr
1c n-C7H15
1d i-Bu
2a Me Ph2
2b Me Me, Ph
2c Me Bn2
87
74
73
78
79
75
74
80
81
76
73
0
98 (+)
96 (+)
97 (+)
99 (+)
98 (+)
98 (+)
98 (R, +)
97 (+)
98 (+)
98 (+)
97 (+)
-
3c
4c
5d
6
2d Ph
Ph2
2a Me Ph2
2a Me Ph2
2a Me Ph2
7d
8c d
1d i-Bu
1e c-C5H9
2d Ph
Ph2
,
tionalized aldehydes. Future work will focus on establishment of the
enantio- and diastereoselective hydroacylation of trisubstituted alkenes
with aldehydes.
9d
2a Me Ph2
2a Me Ph2
10
11c
12
13
1f
1f
Cy
Cy
2d Ph
2a Me Ph2
1h BnO(CH2)3 2a Me Ph2
Ph2
Acknowledgment. This work was supported partly by Grants-
in-Aid for Scientific Research (Nos. 19028015, 20675002, and 21•906)
from MEXT, Japan. We thank Umicore for generous support in
supplying rhodium complexes.
1g t-Bu
74
98 (+)
a [Rh(nbd)2]BF4 (0.025 mmol), (R,R)-QuinoxP* (0.025 mmol),
1
(0.550 mmol), 2 (0.500 mmol), and (CH2Cl)2 (1.0 mL) were used. The
active catalysts were generated in situ by hydrogenation. b Yield based
on 2. c Catalyst: 10 mol %. d 2 equiv of 1 was used due to its volatility.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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A possible mechanism for highly selective production of (R)-3da
is shown in Scheme 1. The formation of intermediate A might be more
favorable than that of intermediate B due to the steric interaction
between the amide moiety of 2a and the tert-butyl group of (R,R)-
QuinoxP* in intermediate B. We believed that strong bidentate
coordination of substituted acrylamides to the cationic rhodium might
stabilize the acylrhodium intermediate and construct the rigid chiral
environment.
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In conclusion, we have established that a cationic rhodium(I)/
QuinoxP* complex catalyzes the highly enantioselective direct inter-
molecular hydroacylation of 1,1-disubstituted alkenes with unfunc-
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