Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes to alkynes

Article abstract of DOI:10.1021/ol1028628

Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes (MCPs) to arkylalkynes via proximal bond cleavage is reported. The reaction provides a facile route for the preparation of cyclopenta[a]indene derivatives.

Full text of DOI:10.1021/ol1028628

ORGANIC
LETTERS
2011
Vol. 13, No. 4
640–643
Ni-Catalyzed Intramolecular Cycloaddition
of Methylenecyclopropanes to Alkynes
Bangben Yao, Yong Li, Zunjun Liang, and Yuhong Zhang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
yhzhang@zju.edu.cn
Received November 30, 2010
ABSTRACT
Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes (MCPs) to arkylalkynes via proximal bond cleavage is reported. The
reaction provides a facile route for the preparation of cyclopenta[a]indene derivatives.
Transition-metal-catalyzed organic reactions involving
the activation of C-C σ bonds have recently aroused
considerable interest because of their great importance in
organic synthesis and as a fundamental challenge in organic
chemistry.1 Among the substrates utilized in C-C activation
reactions, methylenecyclopropanes (MCPs) occupy a privi-
leged position because of their ready accessibility and high
reactivity.2 In the past decades, numerous promising transi-
tion-metal systems for accessing complex polycyclic frame-
works by cycloaddition of MCPs have been reported.3 Two
typical oxidative cleavages in cycloaddition reactions of
MCPs have been observed: distal-bond (Scheme 1, I) and
proximal-bond cleavage.4-8 However, few examples of in-
tramolecular cycloaddition of MCPs via proximal-bond
cleavage are available.9 Herein, we report a unique Ni-
catalyzed intramolecular cycloaddition of MCPs with aryl-
alkynes via the cleavage of proximal bonds (Scheme 1, II).
For the first time, an aryl ring moiety was employed as the
linker of MCPs and alkynes, which led to the formation of
(4) Intermolecular [3 þ 2] cycloadditions of MCPs via distal bond
cleavage, see: (a) Binger, P.; Schuchardt, U. Chem. Ber. 1981, 114, 3313.
(b) Binger, P.; Doyle, M.; Benn, R. Chem. Ber. 1983, 116, 1. (c)
Nakamura, I.; Oh, B.-H.; Saito, S.; Yamamoto, Y. Angew. Chem., Int.
Ed. 2001, 40, 1298. (d) Oh, B.-H.; Nakamura, I.; Saito, S.; Yamamoto,
Y. Tetrahedron Lett. 2001, 42, 6203. (e) Siriwardana, A. I.; Nakamura,
I.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3202. (f) Thormeier, S.;
Carboni, B.; Kaufmann, D. E. J. Organomet. Chem. 2002, 657, 136.
(5) Intermolecular cycloadditions of MCPs via proximal bond cleavage:
(a) Noyori, R.; Odagi, T.; Takaya, H. J. Am. Chem. Soc. 1970, 92, 5780. (b)
Noroyi, R.; Kumagai, Y.; Umeda, I.; Takaya, H. J. Am. Chem. Soc. 1972,
94, 4018. (c) de Meijere, A.; Kurahashi, T. Angew. Chem., Int. Ed. 2005, 44,
7881. (d) Kawasaki, T.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2002, 67,
4911. (e) Murakami, M.; Ishida, N.; Miura, T. Chem. Commun. 2006,643. (f)
Binger, P.; Wedemann, P. Tetrahedron Lett. 1985, 26, 1045.
(6) Intermolecular [3 þ 2 þ 2] cycloadditions of MCPs via proximal
bond cleavage: (a) Saito, S.; Masuda, M.; Komagawa, S. J. Am. Chem.
Soc. 2004, 126, 10540. (b) Komagawa, S.; Saito, S. Angew. Chem., Int.
Ed. 2006, 45, 2446. (c) Saito, S.; Komagawa, S.; Azumaya, I.; Masuda,
M. J. Org. Chem. 2007, 72, 9114. (d) Yamasaki, R.; Terashima, N.;
Sotome, I.; Komagawa, S.; Saito, S. J. Org. Chem. 2010, 75, 480. (e)
Zhao, L.-G.; de Meijere, A. Adv. Synth. Catal. 2006, 348, 2484.
(1) For reviews, see: (a) Crabtree,R.H.Chem. Rev. 1985,85, 245. (b) van
der Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759. (c) Jun, C.-H.
Chem.Soc.Rev. 2004, 33, 610. (d) Horino, Y. Angew. Chem., Int. Ed. 2007,46,
2144. (e) Park, Y.-J.;Park, J.-W.; Jun, C.-H.Acc. Chem. Res. 2008, 41, 222. (f)
ꢀ
Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48, 2452. (g) Winter,
C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 2460.
(2) Selected reviews: (a) Henry, N. C.; Wong, M. Y.; Chun, W. T.;
Yu, C. Y. Chem. Rev. 1989, 89, 165. (b) Nakamura, E.; Yamago, S. Acc.
Chem. Res. 2002, 35, 867. (c) Brandi, A.; Cicchi, S.; Cordero, F. M.;
Goti, A. Chem. Rev. 2003, 103, 1213. (d) de Meijere, A.; Kozhushkov,
S. I.; Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89. (e) Shao, L.-X.;
Shi, M. Curr. Org. Chem. 2007, 11, 1135.
(3) (a) Trost, B. M. Angew. Chem., Int. Ed. 1986, 25, 1. (b) Binger, P.;
Buch,H.M.Top. Curr. Chem. 1987,135,77.(c)Lautens,M.;Klute,W.;Tam,
€
W. Chem, Rev. 1996, 96, 49. (d) Nakamura, I.; Yamamoto, Y. Adv. Synth.
Catal. 2002, 344, 111. (e) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev.
€
2007, 107, 3117. (f) Furstner, A.; Aıssa, C. J. Am. Chem. Soc. 2006, 128, 6306.
€
(g) Aıssa, C.; Furstner, A. J. Am. Chem. Soc. 2007, 129, 14836.
r
10.1021/ol1028628
Published on Web 01/18/2011
2011 American Chemical Society

Table 1. Optimization of Reaction Condition Studies a
Scheme 1
entry
catalyst
ligand
solvent
THF
yieldb (%)
1
2
Rh(PPh3)3Cl
Pd(PPh3)4
Ni(COD)2
0 c
38 d
64
0
PPh3
PPh3
PPh3
PPh3
PPh3
xylene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
4
NiCl2 2H2O
3
5
NiCl2(PPh3)2
NiCl2(PCy3)2
0
6
0
7
NiBr2(diglyme) PPh3
0
8
Ni(acac)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
PPh3
0
9
P(Bu-n)3 DMSO
51
58
62
59
0
valuable 5,5-fused polycyclic systems. The transformation
provides a facile accessment for cyclopenta[a]indene
derivatives.10
10
11
12
13
14
15
16
17
18
19
dppe
dppp
dppb
PPh3
DMSO
DMSO
DMSO
The viability of the approach was tested on substrate 3a,
which is easily assembled by Sonogashira coupling of 2-bro-
mobenzaldehyde with phenyl acetylene and a subsequent
Wittig reaction (see the Supporting Information). As shown
in Table 1, rhodium catalyst, which was utilized in the cycliza-
tion of MCPs,3f failed to promote the attempted cycloaddi-
tion reaction (Table 1, entry 1). Treatment of 3a in xylene
with 10 mol % of Pd(PPh3)4 and 20 mol % of PPh3 at 140 °C
for 48 h provided the desired cycloadduct 4a, albeit in rather
low yield (Table 1, entry 2). To our delight, the use of nickel
catalyst considerably increased the efficiency of the reaction
to give 4a in 64% yield in DMSO at 120 °C for 12 h (Table 1,
DMSO
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
DMSO
0
PPh3
PPh3
PPh3
PPh3
PPh3
DMF
40
trace
trace
trace
71 e
dioxane
toluene
CH3CN
xylene/DMSO
a Reaction conditions: 3a (0.3 mmol), Ni catalyst (0.015 mmol),
ligand (0.06 mmol), solvent (5 mL), 120 °C, N2, 12 h. b Isolated yields.
c Rh(PPh3)3Cl (0.015 mmol), AgSbF6 (0.0225 mmol), THF (5 mL).
d Pd(PPh3)4 (0.03 mmol), 140 °C, 48 h. e Xylene/DMSO = 0.5:4.5 mL.
phosphine ligands was crucial to the reaction (Table 1, entries
9-12). Both alkyl- and arylphosphines showed effects on the
transformation (Table 1, entries 3 and 9). Bidentate phos-
phine ligands, such as dppe, dppp, and dppb, improved the
cyclization process as well (Table 1, entries 10-12). No reac-
tion took place without catalyst or ligand (Table 1, entries 13
and 14). We screened different solvents, and the most suitable
media for this cyclization transformation is the combination
of DMSO and xylene (Table 1, entries 15-19). Thus, the
reaction efficiently proceeded when 5 mol % of Ni(COD)2
and 20 mol % of PPh3 were used in the combination of
DMSO and xylene at 120 °C for 12 h.
With the optimal reaction conditions in hand, we next
studied the scope and generality of the reaction (Table 2).
A variety of arylalkynes could be used in the cyclization
reaction. For example, para-substituted ethynylarenes
provided the corresponding cyclopenta[a]indene products
in moderate yields (Table 2, entries 2 and 3). It is important
to note that the chloride group tolerated in the reaction
thus made it possible for further assembly through the
cross-coupling reactions (Table 2, entry 4). Ethynylarenes
with an ortho substitutent delivered the corresponding
product 4e in lower yield (Table 2, entry 5), illustrating
that the steric hindrance played the role to the reaction.
Meta-substituted ethynylarenes such as 3f and 3g were
more efficient compared with their para or ortho ana-
loguesand affordedslightlyhigheryields (Table 2, entries 6
entry 2). Other nickel species, such as NiCl2 2H2O, NiCl2-
3
(PPh3)2, NiCl2(PCy3)2, NiBr2(diglyme), and Ni(acac)2, were
completely ineffective (Table1, entries 4-8). The use of
(7) Intramolecular cycloadditions of MCPs via distal bond cleavage: (a)
Yamago, S.; Nakamura, E. J. Chem. Soc., Chem. Commun. 1988, 1112. (b)
Lewis, R. T.; Motherwell, W. B.; Shipman, M. J. Chem. Soc., Chem.
€
Commun. 1988, 948. (c) Stolle, A.; Becker, H.; Salaun, J.; de Meijere, A.
Tetrahedron Lett. 1994, 35, 3517. (d) Corlay, H.; Lewis, R. T.; Motherwell,
€
€
W. B.; Shipman, M. Tetrahedron 1995, 51, 3303. (e) Brase, S.; Schomenauer,
S.; McGaffin, G.; Stolle, A.; de Meijere, A. Chem.;Eur. J. 1996, 2, 545. (f)
Corlay, H.; Motherwell, W. B.; Pennell, A. M. K.; Shipman, M.; Slawin,
A. M. Z.; Williams, D. J. Tetrahedron 1996, 52, 4883. (g) Lautens, M.; Ren,
Y.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994, 116, 8821. (h) Lautens, M.;
Ren, Y. J. Am. Chem. Soc. 1996, 118, 9597. (i) Lautens, M.; Ren, Y. J. Am.
Chem. Soc. 1996, 118, 10668. (j) Corlay, H.; Fouquet, E.; Magnier, E.;
Motherwell, W. B. Chem. Commun. 1999, 183.
(8) Recent works of intramolecular cycloadditions of MCPs via
distal bond cleavage: (a) Delgado, A.; Rodrıguez, J. R.; Castedo, L.;
~
Mascarenas, J. L. J. Am. Chem. Soc. 2003, 125, 9282. (b) Evans, P. A.;
ꢀ
Inglesby, P. A. J. Am. Chem. Soc. 2008, 130, 12838. (c) Duran, J.; Gulıas,
~
M.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2005, 7, 5693. (d) Trillo, B.;
~
Gulıas, M.; Castedo, L.; Mascarenas, J. L. Adv. Synth. Catal. 2006, 348,
~
2381. (e) Gulıas, M.; Garcıa, R.; Delgado, A.; Castedo, L.; Mascarenas,
ꢀ
ꢀ
J. L. J. Am. Chem. Soc. 2006, 128, 384. (f) Gulıas, M.; Duran, J.; Lopez,
~
F.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc. 2007, 129, 11026.
ꢀ
(g) Bhargava, G.; Trillo, B.; Araya, M.; Lopez, F.; Castedo, L.;
~
ꢀ
Mascarenas, J. L. Chem. Commun. 2010, 46, 270. (h) Lopez, F.; Delgado,
~
A.; Rodrıguez, J. R.; Castedo, L.; Mascarenas, J. L. J. Am. Chem. Soc.
2004, 126, 10262.
(9) Bapuji, S. A.; Motherwell, W. B.; Shipman, M. Tetrahedron Lett.
1989, 30, 7107.
(10) (a) Baker, Wilson; Glockling, F.; McOmie, J. F. W. J. Chem.
Soc. 1951, 3357. (b) Oh, D.-C.; Williams, P. G.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Org. Lett. 2006, 8, 1021.
Org. Lett., Vol. 13, No. 4, 2011
641

Table 2. Scope of the Substratesa
Figure 1. ORTEP drawing of compound 4i.
substrate derived from 2-bromopyridine-3-carbaldehyde
also tolerated and provided the cyclization product 4j in
53% yield, which provided an alternative route for fused
heterocyclic molecules (Table 2, entry 10). Alkyl alkynes
did not participate in this cyclization reaction. The struc-
ture of the product was further confirmed by X-ray single-
crystal diffraction of 4i (Figure 1).
Encouraged by the successful cyclization of monosub-
stituted methylenecyclopropane, we next extended our
reaction to disubstituted MCPs at the cyclopropyl alkene
carbon. To our delight, the disubstituted MCPs also parti-
cipated in the cyclization under the reaction conditions. In
these cases, however, COD presented better effect than
that of phosphine ligands. As can be seen from Table 3, both
methyl and aryl substituents of substrates 5 participated
in the reaction in xylene when the ligand was changed to
Table 3. Substrates with Substitution at the Exocyclic Methy-
lene Carbona
a Reaction conditions: 3 (0.3 mmol), Ni(COD)2 (0.05 equiv), PPh3
(0.2 equiv), xylene/DMSO = 0.5:4.5 mL, 120 °C, N2, 12 h. b Isolated yields.
and 7). The substrates formed from both electron-donat-
ing and electro-withdrawing substituted 2-bromobenzal-
dehyde performed well under the cycloaddition reactions
(Table 2, entries 8 and 9). Gratifyingly, the use of pyridine
a Reaction conditions: 5 (0.3 mmol), Ni(COD)2 (0.015 mmol), COD
(0.06 mmol), xylene (5.0 mL), 120 °C, N2, 12 h.
642
Org. Lett., Vol. 13, No. 4, 2011

In their experiments, the reductive elimination of inter-
mediate B is difficult to give 6,5-fused bicyclic systems
(Scheme 2). On the basis of previous studies5,6,11 and our
experimental results, a plausible mechanism of the reaction
is proposed as shown in Scheme 2. Oxidative addition of
nickel(0) to the proximal C-C σ bond of cyclopropyl
alkene leads to the nickelacyclobutane species A. The
subsequent intramolecular addition of intermediates A
into C-C triple bond generates the six-membered nickel
cycle B, which undergoes the reductive elimination to
liberate the cyclopenta[a]indenes with the regenerate of
the Ni(0). According to previous DFT caculations and
experimental data for the reactions of alkylidenecyclopro-
panes, the reductive elimination of intermediate B is not
easy.11 In our system, the formation of larger conjugation
system might make the reductive elimination of intermedi-
ate B easier.
Scheme 2. Plausible Mechanism
In summary, we have developed a new nickel-catalyzed
intramolecularcycloaddition of MCPs witharylalkynes by
the cleavage of proximal C-C bond. Both monosubsti-
tuted and disubstituted MCPs underwent the reaction
smoothly. The procedure provided a general and efficient
method for the synthesis of cyclopenta[a]indenes.
1,5-cyclooctadiene (COD). Diarylidenecyclopropanes were
even more reactive to afford the corresponding cycload-
ducts in higher yields regardless of the electronic properties
of substituent on the aromatic rings.
Acknowledgment. Funding from Natural Science Foun-
dation of China (Nos. 21072169 and 20872126) and Fun-
damental Research Funds for the Central Universities
(2010QNA3011) is acknowledged.
In search of a possible [3 þ 2 þ 2] annulation process, we
performedthe reaction of3awithvarious activated alkenes
such as ethyl acrylate, acrolein, and styrene. However, the
desired [3 þ 2 þ 2] cycloadducts were not detected. During
~
our preparation of this manuscript, Mascarenas and
co-workers described an elegant example of [3 þ 2 þ 2]
Supporting Information Available. Experimental pro-
cedure, X-ray data for 4i (CIF), and spectroscopic data
(1H NMR, 13C NMR, and HRMS) for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
cycloaddition involving MCP proximal bond cleavage.11
ꢀ
(11) Saya, L.; Bhargava, G.; Vavarro, M. A.; Gulıas, M.; Lopez, F.;
ꢀ
~
Fernandez, I.; Castedo, L.; Mascarenas, J. L. Angew. Chem., Int. Ed.
2010, 49, 9886.
Org. Lett., Vol. 13, No. 4, 2011
643