Methylenecyclopropane as C1 synthetic units: [1+4] cycloaddition via a nickel catalyst

Article abstract of DOI:10.1039/c1cc13540f

Nickel-catalyzed reactions of methylenecyclopropanes and thioanhydrides afford sulfur-containing heterocyclic compounds via [1+4] cycloaddition. The reactions represent a new use for methylenecyclopropane as a possible one-carbon building block to replace

Full text of DOI:10.1039/c1cc13540f

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 9711–9713
www.rsc.org/chemcomm
COMMUNICATION
Methylenecyclopropane as C1 synthetic units: [1+4] cycloaddition via a
nickel catalystw
Tasuku Inami, Takuya Kurahashi* and Seijiro Matsubara*
Received 15th June 2011, Accepted 13th July 2011
DOI: 10.1039/c1cc13540f
Nickel-catalyzed reactions of methylenecyclopropanes and
thioanhydrides afford sulfur-containing heterocyclic compounds
via [1+4] cycloaddition. The reactions represent a new use for
methylenecyclopropane as a possible one-carbon building block
to replace carbon monoxide, isocyanides, and Fischer carbene
complexes.
In the presence of a transition metal catalyst, methylenecyclo-
propanes (MCPs) easily undergo a variety of reactions owing
to a potent thermodynamic driving force originating from the
relief of the cyclopropane ring strain.1,2 Among the reactions
Scheme 1 Reaction modes of methylenecyclopropane in cycloadditions
affording five-membered ring compounds.
of MCPs, a formal [3+2] cycloaddition, in which MCPs are
incorporated as three-carbon (C3) synthetic units, provides
various carbon–carbon unsaturated compounds as a reaction
partner instead of an alkyne.12 Thus, we examined decarbonyl-
ative addition of thiophthalic anhydrides to MCPs. We found
that the reaction afforded an unexpected type of cycloadduct,
thiophthalide, whose heterocyclic skeleton is found in materials
such as pharmaceutical drugs and fluorescent probes for optical
imaging.13 The reaction of thiophthalic anhydride 1a with MCP
2a in the presence of Ni(cod)2 (10 mol%), PPr3 (20 mol%),
and a Lewis acid (methylaluminium bis(2,6-di-tert-butyl-
4-methylphenoxide, MAD) in refluxing toluene (130 1C) for
9 h initially provided thiophthalide 3aa in 31% yield (Table 1,
entry 1). Further exploration of ligands revealed that the use
of PMe2Ph improved the yield of 3aa to 85% (entry 3). The
use of other ligands such as PMe3, PMePh2, PPh3, and PCy3
resulted in lower yields of 3aa (entries 2–6). We found that the use
of MAD as an additive is crucial for efficient transformation
(entries 7–9). In the absence of MAD, the reaction afforded
3aa in 11% yield (entry 10).
facile synthetic access to structurally diverse five-membered
carbo- and heterocyclic compounds. It has been a research
subject of great interest (Scheme 1).1,3,4 Furthermore, [2+3]
cycloaddition and [4+1] cycloaddition have also been developed
as alternative methods for assembling five-membered cyclic
compounds; MCPs can also contribute as two-carbon (C2) and
four-carbon (C4) synthetic units.5,6 Although MCPs have been
recognized as reactive building blocks for numerous transition
metal-catalyzed transformations, no example of the use of MCPs
as one-carbon (C1) synthetic units has appeared in the literature.
We have set out to further explore transition metal-catalyzed
cycloaddition of MCPs, motivated by their unique reactivity and
possible use as a C1 building block in [1+4] cycloaddition as a
surrogate for molecular compounds such as carbon monoxide,7
isocyanides,8 and Fischer carbene complexes.9,10 Here, we
report an unprecedented type of [1+4] cycloaddition of MCPs
and thiophthalic anhydrides to afford thiophthalides.
We recently demonstrated nickel-catalyzed decarbonylative
cycloaddition of alkynes with five-membered heterocyclic
compounds to give six-membered heterocyclic compounds.11
The reactions consist of a substitution reaction in which a
carbon monoxide is replaced by an alkyne acting as a C2
synthetic unit in a thiophthalic anhydride through catalysis.
Through continuous study, we became intrigued by the use of
The reaction of 2-naphthyl-substituted MCP 2a with 1a
also afforded cycloadduct 3ab in 82% isolated yield (Table 2).
The molecular structure of 3ab was unambiguously confirmed
by X-ray single-crystal analysis, which showed that the cyclo-
adduct is indeed a five-membered sulfur-containing hetero-
cycle and has a trans configuration of the double bond (see ESIw).
Cycloaddition of 1a with aryl-substituted MCPs possessing an
electron-donating and an electron-withdrawing group also
afforded correspondingly substituted cycloadducts in high yields
(3ac, 87%; 3ad, 86%). Although MCPs such as 2-octyl-1-
methylenecyclopropane and benzylidene cyclopropane failed
to participate in the reaction, 2-methyl-2-phenyl-1-methylene-
cyclopropane reacted with 1a to give 3ae in 60% isolated yield.
Department of Material Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan.
E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp,
matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13540f
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9711–9713 9711

View Online
Table 1 Nickel-catalyzed [1+4] cycloadditiona
These results suggested that an aryl substituent on the cyclo-
propane ring of MCPs is crucial for the transformation.
Cycloaddition of MCP 2a with 2,3-naphthalenedicarboxylic
thioanhydride gave 3ba in 75% yield, whereas the reaction
with 1,2-naphthalenedicarboxylic thioanhydride furnished
3ca, consisting of regioisomers in a 1/1 ratio, in 44% yield.
Thiophthalic anhydrides having various substituents were also
examined in reaction with MCP 2a. Thus, we found that a
methyl substituent has little effect on the regioselectivity
regardless of its substitution position (3da and 3ea), whereas
4-methoxy and 4-fluoro substituents significantly affected the
regioselectivity. Cycloadducts 3fa and 3ga were isolated as sole
products in 44% and 68% yields, respectively. The observed
regioselectivity is ascribed to preferential oxidative addition to
nickel(0) of the more electron-deficient carbonyl moiety.
To gain further insight into the cycloaddition reaction
mechanism, we performed additional experiments. We first
examined the reaction of 1a with MCP 2a–13C, the exomethylene
carbon of which was 13C enriched (Scheme 2). The results of
13C NMR spectroscopy of the cycloadduct 3aa–13C revealed
that an exomethylene of MCP 2a was converted to a methyl
group of 3aa during the reaction. We next examined the
reaction of 1a with partially deuterated MCP 2a–D or 2a–D0
(Scheme 3). The reaction of 1a with 2a–D afforded 3aa–D,
whereas that with 2a–D0 gave 3aa–D0, suggesting that one of
the methylene protons on the cyclopropane ring of MCP 2a
was rearranged to contribute to the methyl group of cycloadduct
3aa through the nickel-catalyzed transformation.
Entry
Ligand
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
PPr3
PMe3
PMe2Ph
PMePh2
PPh3
MAD
MAD
MAD
MAD
MAD
MAD
ZnCl2
AlMe3
B(C6F5)3
—
31
55
85
74
32
10
13
51
64
11
PCy3
PMe2Ph
PMe2Ph
PMe2Ph
PMe2Ph
a
All reactions were performed using Ni(cod)2 (10 mol%), ligand
(20 mol%), 1a (0.4 mmol), and 2a (0.2 mmol) at 130 1C for 9 h.
Isolated yields based on 2a.
b
Table 2 Nickel-catalyzed cycloaddition of 1 with 2
On the basis of these observations, we propose the following
reaction mechanism for the present [1+4] cycloaddition
(Scheme 4). Oxidative addition of 1a to nickel(0) and subsequent
decarbonylation afford nickelacycle 4. MCP 2a is then inserted
into the thio–nickel bond to give intermediate 5. With its
cyclopropane unit, the carbon–nickel bond undergoes facile
cyclopropylmethyl–homoallyl metal-type rearrangement to
furnish nickelacycle 6. After b-hydride elimination and insertion
of the newly formed hydride–nickel bond to the carbon–carbon
double bond, 6 furnishes thermally more stable six-membered
Productsa
Scheme 2 Cycloaddition of 1a with 13C-enriched MCP 2a.
a
b
Isolated yields given. Ratio of regioisomers.
Scheme 3 Cycloaddition of 1a with deuterated MCP 2a.
c
9712 Chem. Commun., 2011, 47, 9711–9713
This journal is The Royal Society of Chemistry 2011

View Online
58, 502; (e) A. de Meijere, S. I. Kozhushkov, T. Spath, M. von
¨
Seebach, S. Lohr, H. Nuske, T. Pohlmann, M. Es-Sayed and
¨
S. Brase, Pure Appl. Chem., 2000, 72, 1745.
¨
¨
3 For pioneering studies of [3+2] cycloaddition with MCPs, see:
(a) R. Noyori, T. Odagi and H. Takaya, J. Am. Chem. Soc., 1970,
92, 5780; (b) R. Noyori, Y. Kumagai, I. Umeda and H. Takaya,
J. Am. Chem. Soc., 1972, 94, 4018; (c) P. Binger, Angew. Chem.,
Int. Ed. Engl., 1972, 11, 433; (d) P. Binger and U. Schuchardt,
Angew. Chem., Int. Ed. Engl., 1977, 16, 249; (e) P. Binger and
U. Schuchardt, Chem. Ber., 1981, 114, 3313.
4 For examples of [3+2] cycloaddition in the absence of a transition
metal catalyst, see: (a) S. Yamago, S. Ejiri, M. Nakamura and
E. Nakamura, J. Am. Chem. Soc., 1993, 115, 5344; (b) S. Ejiri,
S. Yamago and E. Nakamura, J. Am. Chem. Soc., 1992, 114, 8707;
(c) E. Nakamura, S. Yamago, S. Ejiri, A. E. Dorigo and
K. Morokuma, J. Am. Chem. Soc., 1991, 113, 3183; (d) S. Yamago
and E. Nakamura, J. Am. Chem. Soc., 1989, 111, 7285.
5 R. Noyori, T. Ishigami, N. Hayashi and H. Takaya, J. Am. Chem.
Soc., 1973, 95, 1674.
6 (a) T. Kurahashi, Y.-T. Wu, K. Meindl, S. Ruhl and A. de Meijere,
¨
Synlett, 2005, 805; (b) M. Shi, L.-P. Liu and J. Tang, Org. Lett.,
2006, 8, 4043.
Scheme 4 A plausible reaction mechanism.
7 (a) B. E. Eaton and B. Rollman, J. Am. Chem. Soc., 1992,
114, 6245; (b) M. Murakami, K. Itami and Y. Ito, J. Am. Chem.
Soc., 1997, 119, 2950; (c) M. Oshita, K. Yamashita, M. Tobisu and
N. Chatani, J. Am. Chem. Soc., 2005, 127, 761; (d) M. Murakami,
K. Itami and Y. Ito, Organometallics, 1999, 18, 1326; (e) M. S. Sigman
and B. E. Eaton, J. Am. Chem. Soc., 1996, 118, 11788;
(f) M. Murakami, K. Itami and Y. Ito, Angew. Chem., Int. Ed. Engl.,
1995, 34, 2691; (g) L. S. Liebeskind and R. Chidambaram, J. Am.
Chem. Soc., 1987, 109, 5025; (h) M. Murakami, K. Itami and Y. Ito,
J. Am. Chem. Soc., 1999, 121, 4130.
8 (a) Y. Ito, H. Kato and T. Saegusa, J. Org. Chem., 1982, 47, 741;
(b) N. Chatani, M. Oshita, M. Tobisu, Y. Ishii and S. Murai,
J. Am. Chem. Soc., 2003, 125, 7812; (c) S. Park, R. Shintani and
T. Hayashi, Chem. Lett., 2009, 204; (d) P. Fontaine, G. Masson
and J. Zhu, Org. Lett., 2009, 11, 1555.
nickelacycle 7, followed by reductive elimination to afford 3aa.
Notably, the quaternary carbon from MCP is incorporated into
the newly formed five-membered ring by replacing a carbon
monoxide of 1a as a consequence of the process. The effects
of MAD as the Lewis acid are not yet clear; however, we
assumed that MAD might promote thio-nickelation of MCP
by coordinating to the carbonyl oxygen of nickelacycle 4.
In conclusion, we have developed a new type of cyclo-
addition of MCPs with thiophthalic anhydrides and a nickel
catalyst in which a carbon monoxide is replaced with a quaternary
carbon from MCP to give highly substituted thiophthalides.
These are useful synthetic precursors for preparation of sulfur-
containing five-membered heterocyclic compounds. These results
highlight the potential of MCPs as C1 synthetic units in a
cyclic compound. The use of MCPs as C1 synthetic units offers
an advantage in introducing a quaternary carbon directly into
a ring system, which allows MCPs to behave as if they were
carbene species. Detailed studies that aim to elucidate the
reaction mechanism, and efforts to expand the scope of the use
of MCPs as C1 synthetic units, are underway.
9 (a) M. A. Sierra, B. Soderberg, P. A. Lander and L. S. Hegedus,
Organometallics, 1993, 12, 3769; (b) J. Barluenga, M. Toma
A. Ballesteros, J. Santamarıa and A. Suarez-Sobrino, J. Org.
Chem., 1997, 62, 9229; (c) J. Barluenga, H. Fanlo, S. Lopez and
J. Florez, Angew. Chem., Int. Ed., 2007, 46, 4136; (d) F. Aznar,
M. Fananas-Mastral, J. Alonso and F. J. Fananas, Chem.–Eur. J.,
2008, 14, 325; (e) J. Barluenga, S. Lopez and J. Florez, Angew.
Chem., Int. Ed., 2003, 42, 231.
´
s,
´
´
´
´
´
´
´
´
10 (a) M. W. Giese and W. H. Moser, Org. Lett., 2008, 10, 4215;
(b) J. H. Rigby and Z. Wang, Org. Lett., 2003, 5, 263; (c) J. H. Rigby
and W. Dong, Org. Lett., 2000, 2, 1673; (d) J. D. Colomvakos, I. Egle,
J. Ma, D. L. Pole, T. T. Tidwell and J. Warkentin, J. Org. Chem.,
1996, 61, 9552; (e) W. H. Moser, L. A. Feltes, L. Sun, M. W. Giese
and R. W. Rarrell, J. Org. Chem., 2006, 71, 6542; (f) C. Spino,
This work was supported by Grants-in-Aid from the
Ministry of Education, Culture, Sports, Science, and Technology,
Japan. T.K. also acknowledges the support from Asahi Glass
Foundation, Kansai Research Foundation, and Toyota Physical
and Chemical Research Institute.
H. Rezaei, K. Dupont-Gaudet and F. Belanger, J. Am. Chem. Soc.,
´
2004, 126, 9926; (g) A. Mizuno, H. Kurosawa and N. Iwasawa,
Angew. Chem., Int. Ed., 2009, 48, 8318; (h) L.-Q. Lu, J.-J. Zhang,
F. Li, Y. Cheng, J. An, J.-R. Chen and W.-J. Xiao, Angew. Chem.,
Int. Ed., 2010, 49, 4495.
11 (a) Y. Kajita, T. Kurahashi and S. Matsubara, J. Am. Chem. Soc.,
2008, 130, 6058; (b) Y. Kajita, T. Kurahashi and S. Matsubara,
J. Am. Chem. Soc., 2008, 130, 17226; (c) T. Inami, Y. Baba,
T. Kurahashi and S. Matsubara, Org. Lett., 2011, 13, 1912.
12 (a) K. Fujiwara, T. Kurahashi and S. Masubara, Org. Lett., 2010,
12, 4548; (b) K. Fujiwara, T. Kurahashi and S. Masubara, Chem.
Lett., 2010, 39, 322; (c) Y. Ochi, T. Kurahashi and S. Matsubara,
Org. Lett., 2011, 13, 1374.
Notes and references
1 For recent reviews, see: (a) M. Lautens, W. Klute and W. Tam,
Chem. Rev., 1996, 96, 49; (b) A. Brandi, S. Cicchi, F. M. Cordero
and A. Goti, Chem. Rev., 2003, 103, 1213; (c) I. Nakamura and
Y. Yamamoto, Adv. Synth. Catal., 2002, 344, 111; (d) E. Nakamura
and S. Yamago, Acc. Chem. Res., 2002, 35, 867.
13 (a) S. Kenmoku, Y. Urano, H. Kojima and T. Nagano, J. Am.
Chem. Soc., 2007, 129, 7313; (b) S. Marui, T. Yamamoto, K. Sudo,
H. Akimoto and S. Kishimoto, Chem. Pharm. Bull., 1995, 43, 588;
(c) E. K. Molzen, J. Perregaard and E. Meier, J. Med. Chem., 1995,
38, 2009; (d) M. Romero, P. Renard, D. H. Caignard, G. Atassi,
X. Solans, P. Constans, C. Bailly and M. D. Pujol, J. Med. Chem.,
2007, 50, 294.
2 Variants of MCP, such as trimethylenemethane (TMM) and
bicyclopropylidene (BCP), were also developed and have been
widely employed as cycloaddends.(a) B. M. Trost and D. M. T.
Chan, J. Am. Chem. Soc., 1979, 101, 6429; (b) B. M. Trost, Angew.
Chem., Int. Ed. Engl., 1986, 25, 1; (c) P. Le Perchec and
J.-M. Conia, Tetrahedron Lett., 1970, 38, 1587; (d) A. de Meijere,
¨
S. I. Kozhushkov, T. Spath and N. S. Zefirov, J. Org. Chem., 1993,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9711–9713 9713