Nickel-catalyzed ring-opening hydroacylation of methylenecyclopropanes: Synthesis of γ,δ-unsaturated ketones from aldehydes

Article abstract of DOI:10.1021/ja9046894

(Chemical Equation Presented) A nickel-catalyzed intermolecular hydroacylation of methylenecyclopropanes (MCPs) has been developed. The reaction proceeds with stereospecific cleavage of the proximal C-C bond of the cyclopropane ring to give γ,δ-unsaturate

Full text of DOI:10.1021/ja9046894

Published on Web 07/28/2009
Nickel-Catalyzed Ring-Opening Hydroacylation of Methylenecyclopropanes:
Synthesis of γ,δ-Unsaturated Ketones from Aldehydes
Hiroki Taniguchi, Toshimichi Ohmura,* and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Katsura, Kyoto 615-8510, Japan
Received June 9, 2009; E-mail: ohmura@sbchem.kyoto-u.ac.jp; suginome@sbchem.kyoto-u.ac.jp
Table 1. Optimization of Reaction Conditionsa
Transition-metal-catalyzed hydroacylation of unsaturated hydrocar-
bons has become increasingly important in recent organic synthesis
because of growing demands for efficient, atom-economical processes.1
Hydroacylation has allowed efficient construction of useful organic
structures via C-C bond formation at aldehyde C-H bonds: R,ꢀ-
unsaturated ketones from alkynes,2 ꢀ,γ-unsaturated ketones from 1,2-
and 1,3-dienes,3 and cyclopentanes by intramolecular reaction of
4-pentenal derivatives.4 To expand the scope of hydroacylation, it
would be highly desirable to exploit new reaction partners with efficient
catalyst systems that would produce ketones that are difficult to
synthesize by other methods.
entry
ligand (P/Ni)
yield (%)b
1
2
3
4
5
6
7
8
PPh3 (1:1)
31
60
46
46
PCyPh2 (1:1)
PCy2Ph (1:1)
PCy3 (1:1)
P(t-Bu)3 (1:1)
P(n-Bu)3 (1:1)
P(n-Bu)3 (2:1)
-
trace
90 (87)c
29
Methylenecyclopropanes (MCPs) are interesting candidates for
hydroacylation because of their unique, multifarious reactivities.5
However, no attempt at MCP hydroacylation has been reported,6 except
for rhodium-catalyzed intramolecular hydroacylation to form seven-
membered-ring γ,δ-unsaturated ketones.7 Herein, we describe the
nickel-catalyzed intermolecular hydroacylation of MCPs.8 We found
that the reaction proceeds via stereospecific opening of the cyclopro-
pane ring to give γ,δ-unsaturated ketones.
<3d
a 1a (0.20 mmol), 2a (0.30 mmol), Ni(cod)2 (10 µmol), and ligand
(0-20 µmol) were stirred in toluene (0.1 mL) for 16 h at 50 °C, unless
otherwise noted. b GC yield based on 1a. c Isolated yield when the
reaction was carried out for 4 h at 60 °C using 2a (0.40 mml). The
reaction gave the product with a cis/trans ratio of 97:3. d Complex
mixture.
We found the new hydroacylation in a reaction of benzaldehyde
(1a) with 7-methylenebicyclo[4.1.0]heptane (2a, 1.5 equiv) in toluene
at 50 °C in the presence of Ni(cod)2 (5 mol %) and PPh3 (5 mol %)
(Table 1, entry 1). The reaction gave cis-1-benzoyl-2-vinylcyclohexane
(3a) in 31% yield after 16 h, indicating that hydroacylation took place
via stereospecific cleavage of the proximal C-C bond of the MCP.
The major side reaction was oligomerization of 2a,9 whereas neither
decarbonylative products2a such as 1-phenyl-2-vinylcyclohexane nor
simple addition products that retained the cyclopropane ring8c were
formed under these conditions. The yield of 3a was improved to
46-60% using cyclohexyl-substituted phosphorus ligands (entries
2-4), while P(t-Bu)3 was ineffective for the reaction (entry 5). We
finally found that the hydroacylation was effectively catalyzed by a
nickel complex bearing less sterically demanding P(n-Bu)3, affording
3a in 90% yield (entry 6). It should be noted that the ratio of ligand
to nickel (P/Ni ) 1:1) is critical for the catalyst efficiency: slower
hydroacylation with faster oligomerization was encountered with a P/Ni
ratio of 2:1 (entry 7), while phosphine-free nickel gave a complex
mixture (entry 8). The hydroacylation proceeded smoothly at 60 °C
to give 3a in high yield, although a small amount of the trans isomer
was formed (cis/trans ) 97:3; entry 6).
Various aldehydes were subjected to the reaction with 2a in the
presence of Ni(cod)2 (5 mol %) with P(n-Bu)3 (5 mol %) (Table 2,
entries 1-11). Reaction of aryl aldehydes 1b-d took place at 60 °C
to give the corresponding ketones 3b-d in high yields (entries 1-3).
Although the slow reaction of benzaldehydes having 4-dimethylamino,
4-methoxycarbonyl, and 2-methyl groups resulted in the major
formation of oligomers of 2a at 60 °C, ketones 3e-g were obtained
in high yield when the reactions were carried out at 80 °C (entries
4-6). The nickel catalyst was also effective for the reactions with
2-furfural (1h) and 2-thiophenecarboxaldehyde (1i), giving the corre-
sponding ketones 3h and 3i in high yields (entries 7 and 8). The
hydroacylation was also applicable to aliphatic aldehydes 1j and 1k,
although a higher reaction temperature (80-100 °C) was required
(entries 9 and 10). However, the reaction of pivalaldehyde (1l) suffered
from sluggish hydroacylation with major formation of the dimer of
2a (entry 11). Although the reactions of 2a generally gave the
corresponding cis ketones stereospecifically (cis/trans > 99:1), a small
amount of the trans isomers were formed in the reactions with some
aldehydes having electron-deficient or sterically demanding aryl groups
(entries 1, 2, 5, and 6).10
Various MCPs were then reacted with aldehyde 1a (Table 2, entries
12-18). Diastereomeric cis-2b and trans-2b reacted with 1a in a highly
stereospecific manner, giving (S*,S*)-4 and (S*,R*)-4, respectively,
with high diastereomeric purities (entries 12 and 13). Reaction of 2c
bearing silyloxy groups took place slowly at 80 °C to give 5 in good
yield (entry 14). Sterically hindered 2d also underwent reaction with
1a to give highly methylated ketone 6 in 83% yield (entry 15).
Reactions of MCPs 2e-g, which have two nonequivalent C-C bonds
to be cleaved, proceeded with selective cleavage of the less hindered
C-C bond to give ketones 7-9 in good yields (entry 16-18).11
Reaction of 2-vinylbenzaldehyde (1m) with trans-2b gave ketone
10 (42%) with the unexpected cyclopropane-retaining adduct 11 in
34% yield (eq 1):
This result suggests a mechanism involving a cyclopropylmethylnickel
9
11298 J. AM. CHEM. SOC. 2009, 131, 11298–11299
10.1021/ja9046894 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Nickel-Catalyzed Reaction of Aldehyde 1 with MCP 2a
which gives ketones 3-10 via reductive elimination.12 Cyclopropane
11 may be formed via direct reductive elimination from B, probably
because intramolecular coordination of the vinyl group in the aldehyde
partially suppresses the ꢀ-carbon elimination.
Scheme 1. Possible Mechanism
In conclusion, we have established an efficient method for
conversion of aldehydes to γ,δ-unsaturated ketones via nickel-
catalyzed ring-opening hydroacylation of MCPs. The reaction is
applicable to a wide array of aldehydes and proceeds with high
stereospecificity and regioselectivity for the cleavage of the
cyclopropane ring.
Acknowledgment. H.T. acknowledges JSPS for fellowship
support.
Supporting Information Available: Experimental details and
product characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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(9) GC/MS analysis indicated the formation of the dimer of 2a as a major
byproduct. For the structure of the dimer, see the Supporting Information.
(10) Isomerization of initially formed cis-3g to the trans isomer was observed
in the reaction of 1g with 2a under these conditions.
a 1 (0.20 mmol), 2 (0.40 mmol), Ni(cod)2 (10 µmol), and P(n-Bu)3
(10 µmol) were stirred in toluene (0.1 mL) at 60 °C, unless otherwise
noted. b Isolated yield based on 1. c cis/trans ) 98:2. d cis/trans ) 98:2.
e At 80 °C. f cis/trans ) 91:9. g cis/trans ) 58:42. h At 100 °C. i 2b (cis/
trans ) 92:8) was used. j dr ) 94:6. k 2c (0.30 mmol) was used. l Yield
of major isomer.
(11) Substituted MCPs such as benzylidenecyclopropane and (3-phenylpropyl-
idene)cyclopropane did not give clean reactions. See the Supporting
Information.
intermediate B, as shown in Scheme 1. Oxidative addition of the C-H
bond of the formyl group in 1 followed by coordination of 2 gives
complex A, which affords acyl(cyclopropylmethyl)nickel complex B
by insertion of the CdC bond into the Ni-H bond. Intermediate B
undergoes ꢀ-carbon elimination to form acyl(homoallyl)nickel C,
(12) Reaction of naphthaldehyde-a-d1 with 2a gave deuterated 3b having a
1-deuterioethenyl group (99% D). For details, see the Supporting Information.
JA9046894
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