Nickel-catalyzed ring-opening alkylative coupling of enone with methylenecyclopropane in the presence of triethylborane

Article abstract of DOI:10.1021/ol303548x

Nickel-catalyzed alkylative coupling of an enone or enal with methylenecyclopropane in the presence of triethylborane was achieved via stereospecific proximal C-C bond cleavage of methylenecyclopropane. With the use of methylenecyclopropane possessing an

Full text of DOI:10.1021/ol303548x

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1182–1185
Nickel-Catalyzed Ring-Opening Alkylative
Coupling of Enone with
Methylenecyclopropane in the Presence
of Triethylborane
Kenichi Ogata,* Daisuke Shimada, Shouichi Furuya, and Shin-ichi Fukuzawa
Department of Applied Chemistry, Institute of Science and Enginnering,
Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
kogata@kc.chuo-u.ac.jp; orgsynth@kc.chuo-u.ac.jp
Received December 27, 2012
ABSTRACT
Nickel-catalyzed alkylative coupling of an enone or enal with methylenecyclopropane in the presence of triethylborane was achieved via
stereospecific proximal CÀC bond cleavage of methylenecyclopropane. With the use of methylenecyclopropane possessing an acyclic alkyl
substituent, this reaction was also accompanied by the β-hydrogen elimination.
The nickel-catalyzed reductive and alkylative coupling
reaction of a carbonyl compound with a CÀC unsaturated
compound is an effective means of synthesizing new un-
saturated compounds via CÀC bond formation. Although
alkynes are used as the CÀC unsaturated compounds1 in
the majority of earlier studies, reactions involving alkene
compounds such as R-olefins,2 1,3-dienes,3 allenes,4 and
norbornenes5 have also been reported. Within this class of
reactions, our research group has recently reported the
unique reductive coupling reaction of methylenecyclopro-
pane with aldehydes involving ring-opening or retention of
the three-membered ring in the presence of a reducing
agent using the nickel(0) catalyst system.6 The ring-opening
coupling reaction of methylenecyclopropane with an
aldehyde using silane as the reducing agent proceeded in
the presence of the Ni(cod)2/N-heterocyclic carbene cata-
lyst to generate a silylated allylic alcohol.6a In contrast, in
the presence of the Ni(cod)2/PCy3 catalyst, the ring-retaining
reaction of methylenecyclopropane with the aldehyde
proceeded using triethylborane as a reductant.6b
(1) (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119,
9065. (b) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121,
6098. (c) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122,
6950. (d) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221.
(e) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003,
125, 3442. (f) Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem.
Soc. 2004, 126, 3698. (g) Herath, A.; Montgomery, J. J. Am. Chem. Soc.
2006, 128, 14030. (h) Sa-ei, K.; Montgomery, J. Org. Lett. 2006, 8, 4441.
(i) Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem.
Soc. 2007, 129, 9568. (j) Baxer, R. D.; Montgomery, J. J. Am. Chem. Soc.
2008, 130, 9662. (k) Saito, N.; Katayama, T.; Sato, Y. Org. Lett. 2008,
10, 3829. (l) Malik, H. A.; Chaulagain, M. R.; Montgomery, J. Org. Lett.
2009, 11, 5734. (m) Malik, H. A.; Sormunen, G. J.; Montgomery, J.
J. Am. Chem. Soc. 2010, 132, 6304.
In certain instances, the aldehyde has been replaced by
R,β-unsaturated carbonyl compounds (as a reaction part-
ner for the CÀC unsaturated compound), where a unit
of the CÀC double bond participates in the coupling
reaction.7 Montgomery et al. reported the nickel-catalyzed
(2) (a) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 14194.
(b) Ho, C.-Y.; Jamison, T. F. Angew. Chem., Int. Ed. 2007, 46, 782. (c)
Yang, Y.; Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L-.X.; Zhou,
Q.-L. J. Am. Chem. Soc. 2007, 129, 2248.
(3) (a) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. J. Am.
Chem. Soc. 2006, 128, 8559. (b) Sawaki, R.; Sato, Y.; Mori, M. Org. Lett.
2004, 6, 1131. (c) Sato, Y.; Hinata, Y.; Seki, R.; Oonishi, Y.; Saito, N.
Org. Lett. 2007, 9, 5597.
(4) Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 7320.
(5) (a) Ogata, K.; Atsuumi, Y.; Fukuzawa, S.-i. Angew. Chem., Int.
Ed. 2011, 50, 5896. (b) Ogata, K.; Toh, A.; Shimada, D.; Fukuzawa, S.-i.
Chem. Lett. 2012, 41, 157.
(6) (a) Ogata, K.; Atsuumi, Y.; Fukuzawa, S.-i. Org. Lett. 2010, 12,
4536. (b) Ogata, K.; Shimada, D.; Fukuzawa, S.-i. Chem.;Eur. J. 2012,
18, 6142.
(7) (a) Herath, A.; Thompson, B. B.; Montgomery, J. J. Am. Chem.
Soc. 2007, 129, 8712. (b) Li, W.; Herath, A.; Montgomery, J. J. Am.
Chem. Soc. 2009, 131, 17024. (c) Herath, A.; Montgomery, J. J. Am.
Chem. Soc. 2006, 128, 14030. (d) Li, W.; Chen, N.; Montogomery, J.
Angew. Chem., Int. Ed. 2010, 49, 8712.
r
10.1021/ol303548x
Published on Web 03/01/2013
2013 American Chemical Society

Table 1. Effect of Phosphine Ligandsa
Table 2. Nickel-Catalyzed Reductive Coupling between 1aÀk
and 2a in the Presence of Triethylboranea
entry
phosphine
PPh3
yieldb (%)
1
84 (81)c
2d
3e
4f
5
PPh3
35
0
PPh3
PPh3
0
P(p-CF3C6H4)3
P(p-MeOC6H4)3
PEt3
PnBu3
79
78
65
56
65
6
7
8
9
PCy3
a Reaction conditions: Ni(cod)2 (0.10 mmol), 1a (2.0 mmol), 2a
(1.0 mmol), MeOH (2.0 mmol), THF (3 mL), and BEt3 (1.0 M hexane
solution, 2 mL, 2.0 mmol) were employed. b GC yield. c Isolated yield.
d Reaction was conducted in the absence of MeOH. e ZnEt2 was used
instead of BEt3. f Et3SiH was used instead of BEt3.
reductive coupling reaction of an enone with an alkyne in
the presence of triethylborane, leading to γ,δ-unsaturated
carbonyl compounds.7a,b The replacement of the enone
with an enal, also reported by Montgomery et al., favored
the reductive cyclization reaction.7c Concerning the reac-
tion of enone with alkene compound in the presence of
borane or silane, successful example using allene as alkene
molecule have been reported by Montgomery et al.7d
However, the coupling partner for the reductive or alkyl-
ative coupling reaction of R,β-unsaturated ketones with
alkene compounds has scarcely been studied.8
In this paper, we demonstrate the first example of an
alkylative coupling reaction of anR,β-unsaturated carbon-
yl compound with methylenecyclopropane via stereospe-
cific cleavage of the three-membered ring in the presence of
triethylborane and a nickel catalyst.
First, various phosphine ligand of the nickel catalyst
were screened in alkylative coupling reaction between
methyl vinyl ketone 1a and methylenecyclopropane 2a
in the presence of triethylborane and MeOH, as shown
in Table 1. Using Ni(cod)2/PPh3 catalyst, the alkylative
coupling reaction proceeded smoothly at room tempera-
ture via stereospecific cleavage of the proximal CÀC bond
of 2a to give 3aa in high yield (entry 1).9 However, con-
ducting the reaction in the absence of MeOH resulted in a
lower yield of 3aa (entry 2).10 The use of diethyl zinc or
(8) Nickel-catalyzed direct conjugate addition of alkene compound
and enone has been reported: (a) Ho, C.-Y.; Ohmiya, H.; Jamison, T. F.
Angew. Chem., Int. Ed. 2008, 47, 1893. (b) Ogoshi, S.; Haba, T.; Ohashi,
M. J. Am. Chem. Soc. 2009, 131, 10350.
(9) The selective formation of 3 and its syn structure was determined by
X-ray analysis. Compound 3ka was converted to the corresponding car-
boxylic acid 5ka in 85% yield by Pinnick oxidation using NaClO2,NaH2PO4,
and 2-methyl-2-butene, and the crystal structure of the product 5ka was
obtained. See the Supporting Information. CCDC no. 915409.
(10) MeOH probably acts as an activation reagent of triethylborane
in the reaction pathway. See ref 7.
a Reaction conditions: Ni(cod)2 (0.10 mmol), 1 (2.0 mmol), 2a
(1.0 mmol), MeOH (2.0 mmol), THF (3 mL), and BEt3 (1.0 M hexane
solution, 2 mL, 2.0 mmol) were employed. b Isolated yield. c Diaste-
reomeric ratio.
Org. Lett., Vol. 15, No. 6, 2013
1183

methyl substituents in the 2-position also participated
in this reaction to afford the product 3ha in 88% yield
(entry 7). The reaction using the cyclic enone 1i proceeded
to give the corresponding product 3ia, albeit in moderate
yield (entry 8). The alkylative coupling reaction also pro-
ceeded upon replacement of the enone with an enal (entries 9
and 10).
Table 3. Nickel-Catalyzed Reductive Coupling between 1a and
2aÀf in the Presence of Triethylboranea
After screening the enones, the scope of the reaction was
further examined with various methylenecyclopropane
partners (Table 3). Seven- and six-membered bicyclic
methylenecyclopropanes also afforded the corresponding
products 3ab and 3ac in high yields (entries 1 and 2).
Cyclooctene-fused methylenecyclopropane 2d also partici-
pated in the reaction to give the product 3ad bearing a double
bond in the cyclic structure (entry 3). Methylenecyclopro-
panes bearing cis-alkyl silyl ether provided the corresponding
products 3ae in good yield (entry 4). The reaction of methy-
lenecyclopropane 2f bearing cyclohexyl group proceeded
with the selective cleavage of the less hindered proximal
CÀC bond to give the product 3af (entry 5).
As shown in Scheme 1, in the case of the reaction with
n-propyl-substituted methylenecyclopropane 2g, the pro-
duct 4ag, which involves sp3 CÀH bond cleavage of the
propyl chain, was formed in addition to the product 3ag.
The product 4ag was obtained only as the E-type stereo-
product on the CÀC double bond, which was generated
during the coupling reaction.
Scheme 1
a Reaction conditions: Ni(cod)2 (0.10 mmol), 1a (2.0 mmol), 2
(1.0 mmol), MeOH (2.0 mmol), THF (3 mL), and BEt3 (1.0 M hexane
solution, 2 mL, 2.0 mmol) were employed. b Isolated yield. c Diaste-
reomeric ratio.
triethylsilane instead of triethylborane inhibited the pro-
duction of 2aa (entries 3 and 4). The reaction also pro-
ceeded effectively in the presence of p-substituted aryl
phosphines such as P(p-CF3C6H4)3 and P(p-MeOC6H4)3
(entries 5 and 6). The reaction using trialkylphosphines
such as PEt3, PnBu3, and PCy3 resulted in lower yields than
that obtained using PPh3 (entries 7À9). From the result of
screening of phosphine ligands, the highest yield of the
ring-opening alkylativecoupling product2aa was achieved
using the PPh3 ligand in the presence of BEt3 and MeOH.
Using the optimized catalytic system, the scope of the
nickel-catalyzed alkylative coupling reaction was exam-
ined using various types of enones or enals as shown in
Table 2. Enones bearing phenyl- or para-substituted aryl
groups such as electron-donating (methyl and methoxy) or
electron-withdrawing (chloro) substituents also afforded
product 3 in good to high yields (entries 2À5). The use of
enones bearing alkyl substituents (such as methyl and
n-hexyl groups) in the 1-position yielded the corresponding
alkylative coupling products (entries 5 and 6). Enones with
To obtain insight into the reaction mechanism, further
reactions were carried out using methanol-d1. The Ni(cod)2/
PPh3-catalyzed reaction between 1a and 2a in the presence
of triethylborane and methanol-d1 afforded compound
3aa-D (97% deuterium incorporation) (Scheme 2).
Deuterium is incorporated solely into the R-position of
Scheme 2
1184
Org. Lett., Vol. 15, No. 6, 2013

via the oxa-π-allyl intermediate C to produce the nickelÀ
ethyl intermediate E. The borane enolate of E reacts with
methanol to give the intermediate F. Finally, reductive
elimination from F affords the stereodefined product 3.
When di-n-propyl-substituted methylenecyclopropane
2g was used (Scheme 2), product 4ag was also produced.
The formation of 4ag probably resulted from β-hydrogen
elimination from intermediate E through the formation of
intermediate G, involving π-coordination of the E-alkene
unit, given that the interaction of nickel metal with the
β-hydrogen of flexible n-alkyl groups is more probable
than the interaction with cycloalkyl groups.
Scheme 3
In summary, we have demonstrated the first examples of
the alkylative coupling reaction between enones (enals),
methylenecyclopropane, and triethylborane leading to
γ,δ-unsaturated carbonyl compounds via cleavage of the
proximal CÀC bond of methylenecyclopropane.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovation Areas Molec-
ular Activation Directed toward Straightforward Syn-
thesis from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We are grateful to Prof.
Makoto Yamashita (Chuo University) for assistance with
X-ray analyses.
Supporting Information Available. Standard experi-
mental procedure, characterization data for new com-
pounds, and ORTEP drawing. This material is available
free of charge via the Internet at http://pubs.acs.org.
this product. It is thus deduced that the proton incorporated
into the R-position of product 3 is derived from MeOH.11
A possible pathway for the coupling reaction is shown in
Scheme 3. First, the nickelacyclopentane intermediate A,
involving coordination ofthe borane moiety tothe carbon-
yl carbon, is formed by the reaction of a nickel phosphine
complex with enone 1 and methylenecyclopropane 2 and
borane.12,13 Next, the intermediate A undergoes β-carbon
elimination to generate intermediate B.14 Intermediate B
then undergoes transmetalation of the ethyl group from
the borane moiety to the nickel metal (intermediate D)
(12) The report for the formation of Et2BOMe and EtB(OMe)2
from BEt3 in the presence of MeOH: Chem, K.-M.; Gunderson, K. G.;
Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Chem. Lett.
1987, 1923In nickel-catalyzed reductive coupling reaction, it is also reported
that these alkoxy borane species act as reducing agents; see ref 7.
(13) In the reductive coupling reaction in the presence of borane
compound, borane coordination probably accelerates the oxidative
cyclization of alkyne and aldehyde; see: McCarren, P. R.; Liu, P.;
Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc.
2009, 131, 6654.
(14) In nickel-catalyzed dimerization of methylenecyclopropane,
cyclopropropenylÀbutenyl rearrangement was proposed. See: Binger,
P.; Doyle, M. J.; Benn, R. Chem. Ber. 1983, 116, 1.
(11) In the case of reaction between 1a and 2a in the presence of
triethylborane and MeOH, followed by quench with D2O, deuterium
was not incorporated into product and 3aa was obtained 74% isolated
yield.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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