Cobalt-catalyzed enantioselective intramolecular hydroacylation of ketones and olefins

Article abstract of DOI:10.1021/ja509919x

Cobalt-chiral diphoshine catalytic systems promote intramolecular hydroacylation reactions of 2-acylbenzaldehydes and 2-alkenylbenzaldehydes to afford phthalide and indanone derivatives, respectively, in moderate to good yields with high enantioselectivities. The ketone hydroacylation did not exhibit a significant H/D kinetic isotope effect (KIE) with respect to the aldehyde C-H bond, indicating that C-H activation would not be involved in the rate-limiting step.

Full text of DOI:10.1021/ja509919x

Communication
pubs.acs.org/JACS
Cobalt-Catalyzed Enantioselective Intramolecular Hydroacylation of
Ketones and Olefins
Junfeng Yang and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
Scheme 1. Enantioselective Intramolecular Hydroacylation of
Ketone and Olefin
ABSTRACT: Cobalt−chiral diphoshine catalytic systems
promote intramolecular hydroacylation reactions of 2-
acylbenzaldehydes and 2-alkenylbenzaldehydes to afford
phthalide and indanone derivatives, respectively, in
moderate to good yields with high enantioselectivities.
The ketone hydroacylation did not exhibit a significant H/
D kinetic isotope effect (KIE) with respect to the aldehyde
C−H bond, indicating that C−H activation would not be
involved in the rate-limiting step.
he catalytic addition of an aldehyde C−H bond across an
Tunsaturated bond, hydroacylation, represents an atom-
efficient synthetic approach to carbonyl compounds.1 Such
transformations have been achieved in both inter- and
intramolecular settings, conventionally and most extensively
using rhodium catalysts.2 Given the parallelism between the
reactivities of cobalt and rhodium in various catalytic trans-
formations including C−H functionalizations,3,4 the use of more
abundant cobalt as alternative catalysts for hydroacylation is a
logical idea. Nevertheless, such examples have been rare. In the
late 1990s, Brookhart demonstrated intermolecular hydro-
acylation of vinylsilane using a Cp*Co(I)−bisolefin catalyst.5
Very recently, Dong developed the intermolecular hydro-
acylation of 1,3-dienes using a cobalt−diphosphine catalyst,
which was proposed to involve, unlike typical rhodium-catalyzed
hydroacylations, aldehyde/diene oxidative cyclization as a key
step.6 Besides these intermolecular examples, cobalt-catalyzed
intramolecular hydroacylation has been documented for only a
few substrates such as 2-vinylbenzaldehyde5a and 4-pentenal.7
We report here that cobalt−chiral diphosphine catalysts8,9
promote intramolecular hydroacylation reactions of 2-acylben-
zaldehyde and 2-alkenylbenzaldehyde derivatives to afford
enantioenriched phthalides and indanones (Scheme 1a),
respectively, thus serving as viable alternatives to previously
developed chiral rhodium catalysts (Scheme 1b,c).10−13
and enantioselectivity of the reaction to the ligand structure (see
the Supporting Information (SI) for full details). Only a few
diphosphines promoted the desired cyclization to a reasonable
extent (entries 2−4), among which (R,R)-Ph-BPE exhibited a
high enantioselectivity of 95% ee (entry 2). With many other
diphosphines, the product 2a was formed only in low yields or
not at all (entries 5−8), although the conversion of 1a was
generally high (up to 90%). In such cases, except for the
recovered 1a, only a trace amount of 3-hydroxyindan-1-one, a
byproduct arising from intramolecular aldol reaction of 1a, was
observed by GC analysis (no decarbonylation product was
detected). Thus, we speculate that intermolecular aldol
condensation of 1a took place to produce oligomeric products.
Upon further screening of cobalt precatalysts and reductants,
we identified the combination of CoBr2 (10 mol %), (R,R)-Ph-
BPE (10 mol %), and indium powder (20 mol %) as the optimum
catalytic system, which afforded 2a in 92% yield with 95% ee
(entry 11). The use of other reductants such as manganese and
zinc powders did not affect the enantioselectivity but led to lower
yields (entries 9 and 10). The catalyst loading could be reduced
to 2.5 mol % without a decrease in the yield and
The present study commenced with a search for achiral
cobalt(I) catalysts generated from cobalt(II) precatalysts and
reductants6,9,14 that can promote intramolecular hydroacylation
of 2-acetylbenzaldehyde (1a). With a couple of trials, we found
that the desired cyclization proceeded in the presence of CoCl2
(10 mol %), dppe (10 mol %), and manganese powder (3 equiv)
in acetonitrile at 80 °C, affording the phthalide product 2a in 95%
yield (Table 1, entry 1). With this initial finding, we attempted
enantioselective cyclization of 1a using a variety of chiral
diphosphines, which revealed the high sensitivity of the efficiency
Received: September 25, 2014
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja509919x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Table 1. Screening of Reaction Conditions for Intramolecular
Ketone Hydroacylation
Scheme 2. Enantioselective Intramolecular Hydroacylation of
Various 2-Acylbenzaldehydes
a
a
b
c
entry
ligand
reductant
yield (%)
ee (%)
1
2
3
4
5
6
7
8
dppe
Mn (3 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (1 equiv)
Mn (20 mol %)
Zn (20 mol %)
In (20 mol %)
In (20 mol %)
95
70
37
73
4
−
(R,R)-Ph-BPE
95
85
79
ND
ND
ND
−
95
95
95
95
(R,R,S,S)-Duanphos
(R,R)-Tol-DIPAMP
(R,R)-DIPAMP
(R,R)-Me-DuPhos
(R,R)-BDPP
12
15
0
(S,S)-Chiraphos
(R,R)-Ph-BPE
d
9
59
82
92
d
10
(R,R)-Ph-BPE
d
11
(R,R)-Ph-BPE
de
,
12
(R,R)-Ph-BPE
95
a
b
The reaction was performed on a 0.1 mmol scale. Determined by
c
GC. Determined by chiral HPLC analysis. ND = not determined. The
absolute stereochemistry was assigned by comparison of the optical
d
rotation with the literature data (see the SI). CoBr2 was used instead
e
of CoCl2. 2.5 mol % each of CoBr2 and ligand was used.
a
The reaction was performed on a 0.3 mmol scale. Isolated yields are
shown. The ee’s were determined by chiral HPLC analysis.
enantioselectivity (entry 12). Note that the reaction was also
found to proceed at room temperature at a slower rate.
predominant decarbonylation to afford propiophenone as the
major product.
With the Co−Ph−BPE catalytic system in hand, we explored
the scope of the enantioselective intramolecular hydroacylation
using various 2-acylbenzaldehyde derivatives (Scheme 2). 2-
Acetylbenzaldehydes substituted at the 4- or 5-position
participated in the reaction to afford the corresponding
phthalides 2b−2g in moderate to good yields with enantiose-
lectivities of 90% ee or greater. Chloro, bromo, and ester
substituents were tolerated (see 2e−2g). The reaction was found
to be sensitive to steric influence and strong electronic
perturbation on the benzene ring. Thus, the presence of a
substituent at the 3- or 6-position in the substrates 1r and 1s shut
down the desired hydroacylation reaction. The reaction of 2-
acetylbenzaldehyde bearing a 4-diethylamino group 1t resulted
in almost complete recovery of the starting material.15
Acyl groups other than the acetyl group also served as internal
acceptors for the enantioselective hydroacylation. Ethyl and
isopropyl ketone substrates smoothly participated in the reaction
to afford the corresponding products 2h and 2i in good yields
with high enantioselectivities. Diaryl ketone substrates were also
amenable to the cyclization reaction, where the enantioselectivity
was affected by both the electronic and steric properties of the
aroyl group (see 2j−2q). Compared to the case of the parent
benzoyl substrate (2j; 91% ee), the enantioselectivity was
apparently enhanced with a 4-methoxybenzoyl group (2k; 98%
ee) and lowered with 4-chloro-, 3-methoxy-, 2-methoxy-, and 2-
methylbenzoyl groups (2m, 2o−2q; 82−88% ee). A substrate
with a longer tether, 1u, did not afford the expected 7-membered
lactone,12b,c while an aliphatic substrate 1v underwent
With the successful demonstration of the cobalt-catalyzed
enantioselective intramolecular hydroacylation of 2-acylbenzal-
dehydes, we next turned our attention to the reaction of an
analogous olefinic substrate. As we did for the substrate 1a, we
initially identified the combination of CoCl2 (10 mol %), dppp
(10 mol %), and zinc powder (1 equiv) as an effective achiral
catalytic system for the cyclization of 2-(1-phenylvinyl)benz-
aldehyde (3a) to indanone 4a in acetonitrile at 80 °C (Table 2,
entry 1). Upon subsequent screening of chiral ligands, (R,R)-
BDPP was found to promote the reaction with comparable
efficiency with an enantioselectivity of 93% ee (entry 2). Other
chiral diphosphines exhibited only modest enantioselectivities
(ca. 30−50% ee; entries 3−7) or afforded no desired product
(see the SI). GC analysis of such unsuccessful cases indicated the
formation of a mixture of products arising from decarbonylation
or reduction of the CO or CC bond. The reaction with
(R,R)-BDPP proceeded smoothly at room temperature using a
lower amount (50 mol %) of zinc powder (entry 8).
During this optimization and subsequent studies, we noted a
significant difference between the ketone hydroacylation and the
olefin hydroacylation in terms of the appearance of the reaction
mixture. In the ketone hydroacylation, a dark brown solution
formed immediately upon the addition of MeCN to a
heterogeneous mixture of cobalt(II) salt, Ph-BPE, and metal
reductant, without a sign of the characteristic blue color of
Co(II). On the other hand, the color of the olefin hydroacylation
solution was initially light green, which only gradually turned
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Table 2. Screening of Reaction Conditions for Intramolecular
Olefin Hydroacylation
Scheme 3. Intramolecular Hydroacylation of 2-
a
a
Alkenylbenzaldehydes
b
c
entry
ligand
reductant
yield (%)
ee (%)
1
2
3
4
5
6
7
dppp
Zn (1 equiv)
Zn (1 equiv)
Zn (1 equiv)
Zn (1 equiv)
Zn (1 equiv)
Zn (1 equiv)
Zn (1 equiv)
Zn (50 mol %)
Mn (1 equiv)
In (1 equiv)
79
78
87
17
50
15
22
99
0
−
(R,R)-BDPP
93
53
52
51
42
31
97
−
(R,R)-DIOP
(R)-SEGPHOS
(R,R,S,S)-Duanphos
(R,R)-Me-BPE
(R)-Prophos
a
The reaction was performed on a 0.3 mmol scale. Isolated yields are
d
8
(R,R)-BDPP
b
shown. The ee’s were determined by chiral HPLC analysis. The
d
9
(R,R)-BDPP
reaction was performed at 80 °C. c 1H NMR yield. Ee value was not
d
10
(R,R)-BDPP
0
b
−
determined.
a
The reaction was performed on a 0.1 mmol scale. Determined by
GC. Determined by chiral HPLC analysis. The absolute stereo-
chemistry was assigned by comparison of the optical rotation with the
c
Scheme 4. Deuterium-Labeling Experiments
d
literature data (see the SI). The reaction was performed at room
temperature.
dark brown over several hours. Furthermore, manganese and
indium powders did not promote the reaction at all, where the
color remained green (entries 9 and 10). These observations
suggest that the reduction of the Co(II)−BDPP precatalyst is
much slower than that of the Co(II)−Ph−BPE precatalyst,
occurring along with the reaction progress.
The present olefin hydroacylation turned out rather sensitive
to substituents on the olefinic and aromatic moieties, thus
offering a narrower scope compared with that of the ketone
hydroacylation (Scheme 3). While the substrates bearing 1-
phenylvinyl or 1-methylvinyl groups underwent the cyclization
reaction with excellent enantioselectivities (see 4a and 4b), a
significant decrease in the enantioselectivity (81% ee) was
observed with the one bearing a 1-ethylvinyl group (see 4c). The
reaction of the substrate bearing a 1-(4-fluorophenyl)vinyl group
proceeded at an elevated temperature of 80 °C (see 4d), while
the one bearing a 1-(4-methoxyphenyl)vinyl group reacted
sluggishly even at this temperature (see 4e). In contrast to the
ketone hydroacylation (see 2b in Scheme 2), a methoxy group on
the para position of the formyl group completely shut down the
reaction (see 3g). Note that linear substrates such as 4-pentenal
(3h) and 4-phenyl-4-pentenal (3i) failed to participate in the
reaction.
In order to gain mechanistic insight into the present
intramolecular hydroacylation reactions, we performed experi-
ments using substrates bearing a deuterated formyl group (1a-d
and 3b-d; Schemes 4 and S1). The reaction of a mixture of 1a-d
and 1b under the Co−Ph−BPE catalysis cleanly produced a
mixture of deuterated phthalide 2a-d and nondeuterated
phthalide 2b without any H/D crossover, demonstrating the
intramolecularity of the hydroacylation process and excluding a
Tishchenko-type mechanism involving a free cobalt hydride
species (Scheme 4a).16 Comparison of initial rates of individual
reactions of 1a and 1a-d at 25 °C (up to ca. 25% conversion) gave
a kinetic isotope effect (KIE) of 1.1 0.1, suggesting that the C−
H activation is not involved in the rate-limiting step (Scheme
4b). We surmise that reductive elimination rather than ketone
insertion is the rate-limiting step, because the latter step would
also exhibit a certain (if not substantial) magnitude of KIE (see
the SI for further discussion).12b On the other hand, the reaction
of 3b-d gave highly fluctuating yields even with the same batch of
substrate and catalyst (Scheme S1). We speculate that the
fluctuation comes from the slow and heterogeneous nature of the
precatalyst reduction (vide infra), the efficiency of which would
be susceptible to subtle changes of the reaction conditions. The
search for a protocol suitable for kinetic analysis is currently
underway.17
In summary, we have demonstrated that cobalt−chiral
diphosphine catalytic systems are capable of promoting the
C
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Journal of the American Chemical Society
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(6) Chen, Q.-A.; Kim, D. K.; Dong, V. M. J. Am. Chem. Soc. 2014, 136,
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(7) Vinogradov, M. G.; Tuzikov, A. B.; Nikishin, G. I.; Shelimov, B. N.;
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Kou, K. G. M.; Dong, V. M. Chem. Sci. 2011, 2, 407. (b) Shen, Z.;
Dornan, P. K.; Khan, H. A.; Woo, T. K.; Dong, V. M. J. Am. Chem. Soc.
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enantioselective intramolecular hydroacylation of ketones and
olefins. While these reactions appear to involve, as in the case of
rhodium-catalyzed hydroacylations, catalytic cycles consisting of
C−H oxidative addition, insertion of the CX bond into the
Co−H bond, and C−X reductive elimination, the relative rates of
the elementary steps deserve further investigation. Efforts to
expand the scope of cobalt-catalyzed hydroacylation of
unsaturated bonds are also underway.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and compound character-
ization. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
nyoshikai@ntu.edu.sg
■
Notes
The authors declare no competing financial interest.
(13) For other examples of enantioselective Rh-catalyzed hydro-
acylation of CC bonds, see refs 2b, 2j, 2k, and the following: (a) Phan,
D. H.; Kou, K. G. M.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 16354.
(b) Coulter, M. M.; Kou, K. G. M.; Galligan, B.; Dong, V. M. J. Am.
Chem. Soc. 2010, 132, 16330. (c) Shibata, Y.; Tanaka, K. J. Am. Chem.
Soc. 2009, 131, 12552. (d) Coulter, M. M.; Dornan, P. K.; Dong, V. M. J.
Am. Chem. Soc. 2009, 131, 6932. (e) Osborne, J. D.; Randell-Sly, H. E.;
Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130,
17232. (f) Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.;
Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821. (g) Taura, Y.;
Tanaka, M.; Wu, X.-M.; Funakoshi, K.; Sakai, K. Tetrahedron 1991, 47,
4879.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Iwao Ojima on the occasion of
his 70th birthday. This work was supported by the National
Research Foundation Singapore (NRF-RF-2009-05), Nanyang
Technological University, and JST, CREST.
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