Cobalt-Catalyzed Enantioselective Vinylation of Activated Ketones and Imines

Article abstract of DOI:10.1021/jacs.6b02372

We present here an unprecedented cobalt-catalyzed enantioselective vinylation of α-ketoesters, isatins, and imines to deliver a range of synthetically useful allylic alcohols and amines in high enantiopurity. This method employs commercially available and easy to handle catalysts and reagents and exhibits a high degree of practicality. The efficiency, selectivity, and operational simplicity of this catalytic system coupled with the substrate generality render this method a valuable tool in organic synthesis.

Full text of DOI:10.1021/jacs.6b02372

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Article
Cobalt-Catalyzed Enantioselective Vinylation of Activated Ketones and Imines
Yuan Huang, Rui-Zhi Huang, and Yu Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02372 • Publication Date (Web): 03 May 2016
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Cobalt-Catalyzed Enantioselective Vinylation of Activated
Ketones and Imines
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Yuan Huang,§ Rui-Zhi Huang,§ and Yu Zhao
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543
ABSTRACT: We present here an unprecedented cobalt-catalyzed enantioselective vinylation of α-ketoesters, isatins and
imines to deliver a range of synthetically useful allylic alcohols and amines in high enantiopurity. This method employs
commercially available and easy-to-handle catalysts and reagents, and exhibits a high degree of practicality. The
efficiency, selectivity and operational simplicity of this catalytic system coupled with the substrate generality render this
method a valuable tool in organic synthesis.
INTRODUCTION
involves the tandem hydrometalation-transmetalation of
alkynes to afford the organozinc reagents and thus
necessitates the use of two stoichiometric metallic
reagents. The use of vinyl boron reagents that are more
readily available has also been actively investigated and
found much success especially in the asymmetric
vinylation of imines (Scheme 1b). In addition to examples
of organocatalytic asymmetric Petasis reaction,14 Rh-chiral
diene complexes have been almost exclusively used for
the metal-catalyzed systems.15 Another elegant approach
that circumvents the use of organometallic reagent is the
reductive coupling of alkynes (or conjugated enyne, etc)
with carbonyls and imines (Scheme 1c).16 The Rh/Ir-
catalyzed hydrogen-mediated coupling, especially, has
been applied to the vinylation of a range of carbonyls and
imines in excellent stereoselectivity. However, this
approach has been limited to the preparation of dienyl
allylic alcohols and certain tri- and tetra-substituted allyl
amines to date.
Allylic alcohols and amines are among the most
abundant and significant structural motifs in organic
synthesis. They are present in numerous biologically
active molecules and drugs (Figure 1); they can also
undergo various selective transformations with high
fidelity to afford a range of stereo-defined compounds of
value in chemistry and medicine.1 Consequently, the
construction of allylic alcohols and amines in
a
stereoselective fashion has been focal point in
a
methodology development for decades. The traditional
approaches that have proven to be highly successful
include kinetic resolution of allylic alcohols by the
Sharpless asymmetric epoxidation,2 enantioselective
reduction of enones3 as well as vinylation of carbonyls and
imines.4 Other approaches such as metal-catalyzed
rearrangement of allylic imidates,5 allylic oxidation or
amination,6 amination of allenes7 and organocatalytic
tandem reactions8 have also been documented in recent
years.
Despite the great advances in this important area of
research, a general, practical catalytic system that utilizes
readily available catalysts and reagents and works for the
asymmetric vinylation of a wide range of substrate types
still remains to be developed. The access to tertiary allylic
alcohols and amines with different substitution patterns,
in particular, is much less established.12,16e Also it is
noteworthy that precious metal catalysts (such as Rh, Ir,
etc) are utilized in most catalytic vinylation reactions. The
development of catalytic methods using the more
economical and abundant base metals will be highly
desired, which has served as a key impetus for the
promotion of sustainable chemical synthesis.17 Based on
the recent discovery of hydroallylation of alkenes made in
our laboratory,18 we became particularly interested in
cobalt catalysis for carbon-carbon bond forming
reactions.19,20 Herein we present our recent development
of an unprecedented cobalt-catalyzed highly efficient and
enantioselective vinylation of α-ketoesters, isatins and
Figure 1. Chiral Allylic Alcohols/Amines in Natural
Products
Out of the various strategies, the asymmetric vinylation
is arguably the most general one to access allylic alcohols
and amines of various substitution patterns, including
tertiary alcohols and amines (Scheme 1). The catalytic
asymmetric addition of preformed vinyl zinc reagents to
aldehydes,9,10 imines11 and even ketones12 has been well-
established and found wide use in total synthesis of
complex molecules (Scheme 1a).13 This approach, however,
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imines, using commercially available cobalt halides, chiral 10-12). The desired product 2a was not obtained at all in
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bisphosphine ligands and vinyl boronic acid reagents.
the absence of K2CO3, suggesting a base-facilitated
transmetalation of vinyl boronic acid with cobalt halide.
At this point the use of different vinyl boron reagents
including styrenyl pinacol boronic esters and
trifluoroborate potassium salt was examined again. In
contract to the use of boronic acids, these reagents led to
no product formation.
Scheme 1. Strategies for Enantioselective Vinylation
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Table 1. Optimization of Vinylation of α-Ketoesters
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entry
metal
FeBr2
NiBr2
CuCl
Co(OAc)2
CoI2
ligand
DPPP
2a yield (%)a
2a erb
1
2
<2
<2
<2
<2
90
<2
60
50
60
54
30
<2
/
DPPP
/
3
DPPP
/
4
5
DPPP
/
/
DPPP
6
7
CoI2
(R)-BINAP
(R)-(S)-Josiphos
(R,R’,S,S’)-DuanPhos
(S,S)-BDPP
(S,S)-BDPP
(S,S)-BDPP
(S,S)-BDPP
/
CoI2
50:50
11:89
96:4
94.5:5.5
94:8
/
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12
CoI2
CoI2
CoBr2
CoCl2
CoF2
aIsolated yields. bDetermined by chiral HPLC analysis.
RESULTS AND DISCUSSION
Enantioselective vinylation of α-ketoesters. We
initiated our studies by exploring the reaction with α-
ketoesters, as asymmetric vinylation of this class of
substrate has not been thoroughly explored before,16e
despite the great utility of the resulting tertiary allylic α-
hydroxy esters (Table 1). Emphasis was also put on the use
of readily available vinylating agents for practical
considerations. After numerous trials, vinyl boronic acids
proved to be the most promising and the most convenient
choice, as many of them are commercially available and
can be used as received. Out of the various catalysts
examined initially (entries 1-5), the vinylated product 2a
was obtained only with CoI2-bis phosphine complex in
excellent yield (entry 5). Various chiral bis-phosphine
ligands were then screened, the identity of which was
found to have a profound effect on the efficiency of the
vinylation. While BINAP shut down the vinylation (entry
6), the reactions using Josiphos or Duanphos proceeded
in good yield, albeit with only low or moderate
enantioselectivity (entries 7-8). To our delight, excellent
enantioselectivity of 96:4 er was obtained for 2a by using
BDPP as the ligand (entry 9). Other cobalt salts were also
screened, which unfortunately led to no further
improvement on reactivity or enantioselectivity (entries
The scope of this catalytic system turned out to be
broad (Scheme 2). Under the optimal conditions using
catalytic CoI2 and BDPP, various styrenyl boronic acids
bearing electron-poor or electron-rich substituents on the
arene as well as alkyl-substituted vinyl boronic acids
underwent reaction with 1a smoothly to yield 2a-2d in
uniformly high enantioselectivity. The catalytic activity of
this system, however, needs further improvement. In
some cases the use of higher catalyst loading was
necessary to product the allylic alcohols in good yield
(e.g., 2d). The use of vinyl boronic acids bearing α-
substituent failed to yield the product, while the use of β-
disubstituted vinylating reagent led to the formation of
product in low yield but excellent enantioselectivity (98:2
er for 2e). For the scope of the substrate, α-Ketoesters
bearing other alkyl substituent also worked similarly well
(2e). Just as a test, glyoxylate also worked under these
conditions to yield secondary alcohols (such as 2g) in
good yield but slightly reduced er. We were also intrigued
to prepare bis-allylic alcohols by the vinylation of α,β-
unsaturated α-ketoesters. However, a decrease in the
selectivity was observed for 2h (92:8 er).21 Fortunately,
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in good yield, which would be difficult to access using
DuanPhos was identified to be the optimal choice for this
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series of substrates, which yielded 2h in a higher er of
95.5:4.5 (the opposite enantiomer was prepared).
other method. The alkene moiety in 2a could also be
functionalized in different ways. For example, epoxidation
of the alkene using m-CPBA produced the corresponding
The new set of conditions worked uniformly well for the
preparation of a range of bis-allylic α-hydroxy esters.
Different vinylating reagents including 2-methyl-vinyl
boronic acid underwent reactions with the same level of
enantioselectivity to yield 2h-2j. Various substituents at
the aryl unit in the substrates could be well-tolerated to
yield 2k-2q with high enantioselectivity as well.
Heterocycle- and diene-containing substrates also worked
out smoothly (2r-2s). The relative and absolute
configuration of ent-2i was unambiguously assigned by
single crystal x-ray analysis. The configurations of the
other products were assigned by analogy.
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epoxide
5
in
a
good 80% yield and perfect
diastereoselectivity (>20:1 dr) without any erosion of the
enantioselectivity (96:4 er).
Scheme 3. Derivatization of α-Ketoesters
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Scheme 2. Scope of Vinylation of α-Ketoestersa
Enantioselective vinylation of oxindoles. With the
simple and highly efficient procedure in hand, we became
insterested in applying this cobalt-catalyzed system to the
enantioselective vinylation of isatins, since chiral 3-
alkenyl-3-hydroxy oxindoles represent the core structure
of a large number of biologically active entities.22
A
number of successful methods have been reported for the
addition of aryl boronic acid to isatins catalyzed by Rh, Pd,
Ru and Ir complexes.23, 24 The extension to asymmetric
vinylation, however, was only disclosed by Hayashi and
co-workers as part of their Rh-catalyzed additions of
phenyl/alkenyl boronic acids to PMB-protected isatins.23a
The addition of 2-phenyl vinyl boronic acid to
unprotected isatin was chosen for the reaction condition
optimization. The combination of DuanPhos and CoBr2
was identified as the best choice in term of reactivity and
enantioselectivity. Under the optimal conditions, tertiary
allylic alcohol 7a was obtained in 80% yield with an
excellent 96.5:3.5 er (Scheme 4). The efficiency and
enantioselectivity of this system turned to be very robust
for this class of substrate. Firstly, different isatin
substrates bearing methyl-, benzyl-, PMB-substituents on
the nitrogen underwent reaction with 2-phenyl
vinylboronic acid with similar efficiency and selectivity
(7a-7d). Further experiments then focused on the use of
unprotected isatins. The vinylatin of various substituted
isatins led to the vinylation products 7e-7k in uniformly
high selectivity. The absolute configuration of 7j was
assigned by comparing the optical rotation to the
previous report.23a A variety of vinyl boronic acids bearing
electron-neutral, electron-withdraw and electron-
donating substituents on the aryl structure are well
tolerated to produce 7l-7n in good to excellent er. It is
also noteworthy that 1-propenyl boronic acid proved to be
effective in the addition to isatin similar to α-ketoester to
produce 70 in 95:5 er. The use of β-disubstituted vinyl
boronic acid also led to the formation of 7p in good yield
and excellent ee, although the use of BDPP as the ligand
proved to be beneficial than Duanphos (only 64:36 er was
aSee SI for the detailed procedure. b20 mol% catalyst was used to produce the
product in reasonable yield.
This series of enantioenriched vinylation products are
synthetically versatile and representative derivatizations
of them are shown in Scheme 3. Hydrolysis of the ester
moiety in 2a produced the allylic α-hydroxy acid 3 in 78%
yield with 98:2 er (after recrystallization). The relative
and absolute configuration of 3 was also assigned by
single crystal x-ray analysis. Alternatively, reduction of
the ester using LAH produced the primary-tertiary diol 4
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obtained in this case). With 7o in hand, an efficient moderate after screening different types of chiral
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procedure was worked out to yield 10, an analogue of the
anti-inflammatory agent Convolutamydine A.25 The
protection of the alcohol in 7o was found to be necessary
for the key Wacker oxidation step, in which one single
regio-isomer was obtained to yield the methyl ketone 9
exclusively. Steric effect likely plays an important role in
determining the regioselectivity for the oxidation of
internal alkene in 8.
phosphine ligands (entries 5-8). The best result (60%,
86:14 er) was obtained by the use of BDPP, which was,
however, still far from satisfactory.
As these studies pointed out, a more reactive imine
substrate that is on the other side more stable at higher
temperature should be adopted. Inspired by the previous
report on Rh-catalyzed vinylation,15a we examined the
vinylation of cyclic imine 12a. To our delight, the desired
product 14a could be obtained in a higher yield of 78%
(entry 9). Through the screening of various chiral
bisphosphine ligands, DuanPhos proved to be the optimal
to yield 14a in 68% yield with a high er of 96.5:3.5 (entry
11). Further fine-tuning of the reaction parameters showed
that the use of CoBr2 was superior, producing 14a as
essentially a single enantiomer in 75% yield (entry 12).
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Scheme 4. Enantioselective Vinylation of Oxindolesa
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Table 2. Test of Imines for Asymmetric Vinylation
entry
imine
11a
ligand
DPPP
13/14a yield (%)a
13/14a erb
1
2
<2
<2
<2
<2
60
18
/
11b
11c
DPPP
/
3
DPPP
/
/
4
11d
11e
DPPP
5
DPPP
/
6
11e
(R)-(S)-Josiphos
(R,R’,S,S’)-DuanPhos
(S,S)-BDPP
DPPP
68:32
72:28
86:14
/
7
11e
25
60
78
60
68
8
11e
9
12a
12a
12a
12a
10
11
12c
(S,S)-BDPP
(R,R’,S,S’)-DuanPhos
(R,R’,S,S’)-DuanPhos
85:15
96.5:3.5
>99.5:0.5
75
c
aIsolated yields. bDetermined by chiral HPLC analysis. CoBr2 was used and
the reaction time was 24 h.
Enantioselective vinylation of Imines. Owing to the
ubiquitous existence of chiral allylic amine in biologically
and pharmacologically active molecules, we were
intrigued to find out whether our cobalt system could be
applied to the asymmetric vinylation of imines as well. As
the varied protecting groups on nitrogen are known to
result in drastically different reactivity of imines, we
initiated our studies by exploring various imine
substrates. As summarized in Table 2, our study initiated
with the vinylation of acyclic imines 11a-11e using 2-
phenyl-vinylboronic acid in the presence of CoI2 and
DPPP. While these imines have proven to be effective
substrates for Rh- or Pd-catalyzed arylation reaction, the
cobalt-bisphosphine system failed to promote an efficient
vinylation for 11a-11d (entries 1-4). In addition, imines 11a,
11b, 11d underwent significant decomposition. While
appreciable conversion was observed with 11e in the
presence of DPPP, the enantioselectivity of 13e was only
With the optimal reaction condition in hand, a variety
of highly substituted benzoxathiazine-2,2-dioxides 12
were examined (scheme 5). Imines containing a range of
arene substituents (including chloro, bromo, methyl and
methoxy) at various positions underwent reaction
smoothly, providing vinylation products 14a-14e in good
yield with uniformly excellent enantioselectivity
(>99.5:0.5 er). Various vinyl boronic acids containing aryl
and alkyl substituents on the alkene were also well-
tolerated to provide 14f-14m in good yields and again
nearly perfect enantioselectivities (>99.5:0.5 er). Single x-
ray analysis of 14k further supported the assignment of
the absolute configuration of the products. For this
catalytic system, not only the level of enantioselectivity
compares favorably with previous report on the vinylation
of this type of substrates, but the use of commercially
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Experimental procedures, characterization data for all the
available cobalt salt, ligand and reagents also renders this
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products and computational details. This material is
available free of charge via the Internet at
http://pubs.acs.org.
method a much more economical and convenient choice
to access these valuable allylic amines in an enantiopure
form.
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The corresponding ketoimine substrates bearing a
methyl or ester substituent (11f and 11g, Table 2) were also
examined under the optimal conditions. Unfortunately,
no reactivity was observed, which clearly points to the
limitation of the catalytic activity of this cobalt-catalyzed
system. Efforts to identify more reactive base-metal
catalyzed enantioselective vinylation that hopefully
maintains the level of practicality of this system are
ongoing in our laboratory.
AUTHOR INFORMATION
Corresponding Author
zhaoyu@nus.edu.sg
Author Contributions
§These authors contributed equally.
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Notes
Scheme 5. Enantioselective Vinylation of Imine
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for the generous financial support from
Singapore National Research Foundation (R-143-000-477-281
and R-143-000-606-281) and the Ministry of Education
(MOE) of Singapore (R-143-000-613-112).
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CONCLUSIONS
We have demonstrated, for the first time, a cobalt-
catalyzed enantioselective vinylation of α-ketoesters,
isatins and imines, which greatly expands the scope of
cobalt catalysis in asymmetric synthesis. This
transformation utilizes a convenient procedure using
commercially available catalysts and reagents, and
delivers tertiary allylic alcohols and cyclic allylic amines
in excellent enantioselectivity. The high efficiency,
selectivity
and
operational
simplicity
of
this
transformation, coupled with the wide range of
electrophiles are expected to render this method a
valuable tool in asymmetric synthesis.
ASSOCIATED CONTENT
Supporting Information
(10) For selected examples of asymmetric vinylation of
aldehydes using alkenyl silanes or boranes, see: (a) Tomita, D.;
Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
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4138−4139. (b) Aikawa, K.; Hioki, Y. Mikami, K. J. Am. Chem. Soc.
(18) Huang, Y.; Ma, C.; Lee, Y. X.; Huang, R.-Z.; Zhao, Y.
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2009, 131, 13922−13923. (c) Shono, T.; Harada, T. Org. Lett. 2010,
13, 5270−5273.
(11) For selected examples, see: (a) Wang, S.; Seto, C. T. Org.
Lett. 2006, 8, 3979−3982. (b) Trost, B. M.; Hung, C. I.; Koester, D.
C.; Miller, Y. Org. Lett. 2015, 17, 3778−3781.
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(24) Our group has previously reported an alternative kinetic
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