Nickel-catalyzed [3+2+2] cycloadditions between alkynylidenecyclopropanes and activated alkenes

Article abstract of DOI:10.1002/anie.201004438

Now with nickel: [3C+2C+2C] cycloadditions involving non-activated alkylidenecyclopropanes provide a practical entry to a variety of interesting 6,7-fused bicyclic systems (see scheme; cod=1,5-cyclooctadiene). DFT calculations, combined with experimental

Full text of DOI:10.1002/anie.201004438

Communications
DOI: 10.1002/anie.201004438
Cycloaddition
Nickel-Catalyzed [3+2+2] Cycloadditions between
Alkynylidenecyclopropanes and Activated Alkenes**
Lucꢀa Saya, Gaurav Bhargava, Miguel A. Navarro, Moises Gulꢀas, Fernando Lꢁpez,*
Israel Fernꢂndez, Luis Castedo, and Josꢃ L. Mascareꢄas*
Dedicated to Professor Josꢃ Barluenga on the occasion of his 70th birthday
Owing to the simultaneous presence of a coordinating double
bond and a strained carbocycle, methylene- and alkylidene-
cyclopropanes (ACPs) undergo a number of interesting
metal-assisted transformations.[1] In this context, over the
last few years, we have developed a variety of [3+n]
palladium-catalyzed intramolecular cycloadditions of alkyli-
denecyclopropanes (such as 1), which provide practical
entries to a variety of interesting bicycles (2 and 3,
Scheme 1a).[2] Very recently, we also showed that the
introduction of an additional two-carbon partner into the
system makes it possible to accomplish intramolecular
[3+2+2] annulation reactions that lead to cycloheptane-
containing tricycles of type 4.[3] In related studies, Evans and
co-workers have elegantly demonstrated the possibility of
using rhodium catalysts to induce intermolecular [3+2+2]
processes (!3’, Scheme 1a).[4] All of these reactions take
ꢀ
place with cleavage of the distal bond of the ACP (C2 C3),
and most probably proceed through the formation of 2-
alkylidene metallacyclobutane intermediates of type A,
resulting from a distal insertion of the metal in the ACP
Scheme 1. a) Previously reported metal-catalyzed [3+2] [3+2+2] and
[4+3] cycloadditions involving ACP distal-bond cleavage, and b) our
nickel-catalyzed cycloaddition involving proximal-bond cleavage.
EWG=electron-withdrawing group.
(Scheme 1a).[4,2f]
On the other hand, it has been shown that nickel
complexes can promote alternative [3+2] and [3+2+2]
annulations of ACPs, which involve the cleavage of a
ꢀ
proximal bond of the cyclopropane (C1 C2/3), instead of
the distal one.[5] However, this chemistry is so far restricted to
the use of methylenecyclopropane,[6] cyclopropylidene ace-
tates,[7] or bicyclopropylidene,[8] as three-carbon (3C) part-
ners. As part of our ongoing research on the development of
metal-catalyzed cycloaddition reactions, we wondered about
the behavior of substrates like 1 in the presence of nickel
catalysts, envisaging that they could perform differently than
with palladium and rhodium complexes.
[*] L. Saya, Dr. G. Bhargava, M. A. Navarro, Dr. M. Gulꢀas,
Prof. Dr. L. Castedo, Prof. Dr. J. L. Mascareꢁas
Departamento de Quꢀmica Orgꢂnica,Centro Singular de Investiga-
ciꢃn en Quꢀmica Biolꢃgica y Materiales Moleculares y Unidad
Asociada al CSIC, Universidad de Santiago de Compostela
15782, Santiago de Compostela (Spain)
Fax: (+34)981595-012
E-mail: joseluis.mascarenas@usc.es
Dr. F. Lꢃpez
Instituto de Quꢀmica Orgꢂnica General (CSIC)
Juan de la Cierva 3, 28006, Madrid (Spain)
Herein, we report a new type of nickel-catalyzed cyclo-
addition of ACPs that provides products resulting from the
Dr. I. Fernꢂndez
ꢀ
formal cleavage of the cyclopropane proximal bond (C1 C2).
Departamento de Quꢀmica Orgꢂnica, Universidad Complutense,
Facultad de Ciencias Quꢀmicas
28040 Madrid (Spain)
In particular, we demonstrate that ACPs of type 1, when
treated with [Ni(cod)2] (cod = 1,5-cyclooctadiene) and an
electron-deficient alkene, participate in a novel [3C+2C+2C]
cycloaddition reaction to give 6,7-fused bicyclic systems of
type 5 (Scheme 1b). In addition, we present DFT calculations
which, combined with experimental data, suggest that the
catalytic cycle involves the initial formation of 1-alkylidene-
nickelacyclobutane intermediates like B.
[**] This work was supported by the Spanish MEC [SAF2007-61015,
Consolider-Ingenio 2010 (CSD2007-00006)], the CSIC, the Xunta de
Galicia (GRC2010/12, INCITE09 209 122 PR, and PGIDIT06P-
XIB209126PR). We thank the Xunta de Galicia for an Isabel Barreto
contract to L.S. and an Anxeles Alvariꢁo contract to M.G. I.F. is a
Ramon y Cajal fellow. We thank Johnson–Matthey for a gift of
metals.
Initial assays were carried out with ACP 1a. As shown in
Table 1, this compound remained unchanged in the presence
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004438.
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Table 1: Preliminary assays of nickel-catalyzed cycloadditions of 1a.
Table 2: Nickel-catalyzed [3+2+2] cycloadditions of 1a and alkenes.
Entry[a] MVK
[equiv]
[Ni] (mol%)
Solvent
T
5aa/
Yield[c]
Entry[a]
Alkene
5/6 (ratio)[b]
5aa/6aa
Yield[c]
80
[8C] 6aa[b]
1
2
(71:29)
(76:24)
(80:20)
1
2
3
4
5
6
7
8
9
10
0
0
2
2
2
10
10
10
10
10
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2] (10)
[Ni(cod)2]/
toluene RT
toluene 90
toluene RT
toluene 40
toluene 90
toluene 40
DMF 40
dioxane 40
THF
toluene 40
–
–
0[d]
0[d]
40[e]
50[f]
58[g]
80
49
73
75
0
5ab/6ab
5ac/6ac
70
74:26
64:36
72:28
71:29
67:33
67:33
65:35
–
3
51
4
5
6
5ad/6ad
(83:17)
40[d]
–
–
–
–
–
40
–
[a] Conditions: 1a (0.2m in toluene), 10 mol% [Ni(cod)2], 10 equiv of
alkene unless otherwise noted, for 3 h. [b] Based on the 1H NMR
spectrum of the crude reaction mixture. [c] Combined yield of 5a and 6a
after full conversion. [d] 1.2 equiv of the alkene was employed.
PPh3(10)
[a] Conditions: 1a (0.2m in toluene), 10 mol% [Ni(cod)2], MVK (0–
10 equiv) for 3–12 h. [b] Based on the H NMR spectrum of the crude
1
reaction mixture. [c] Combined yield of 5aa and 6aa after full conversion,
unless otherwise noted. [d] Compound 1a was recovered after 12 h.
[e] 88% conversion. [f] 66% conversion. [g] 65% conversion. DMF=
N,N-dimethylformamide, THF=tetrahydrofuran.
and efficiency of the cycloaddition, we evaluated the reac-
tivity of derivative 1b, which features an electron-withdraw-
ing ester substituent on the alkyne. The formation of [3+2+2]
adducts of type 5 was now found to be clearly favored, and the
competitive [3+2] cycloadducts (6) were not detected
(Table 3, entries 1–4). However, the transformations suffered
from moderate conversion,[12] probably because of catalyst
inhibition by the product.[13] In any case, when phenyl vinyl
sulfone was used as an intermolecular two carbon (2C)
partner, the [3+2+2] cycloadduct could be obtained in up to
68% yield (Table 3, entry 4).
In search of a compromise to favor the [3+2+2] annealing
process while avoiding the potential deactivation of the
catalyst, we analyzed the performance of enynes equipped
with other activating substituents on the alkyne group.
Remarkably, substrate 1c, which bears a CH2OAc substitu-
ent, provided full conversion using 10 mol% of catalyst, and
gave higher [3+2+2]/[3+2] ratios (80:20) than those obtained
from the cycloaddition of the nonactivated analogue 1a
(71:29; Table 3, entry 5 vs. Table 1, entry 6).
Replacing the acetyl residue in 1c with a tert-butyl-
dimethylsilyl group (1d) led to improved selectivity without
eroding the catalyst efficiency. Indeed, the cycloaddition
between 1d and methyl vinyl ketone at 408C, in the presence
of [Ni(cod)2] (10 mol%), exclusively gave the desired
[3+2+2] cycloaddition product 5da, which was isolated in
an excellent 89% yield (Table 3, entry 6). The cycloaddition
of 1d was also carried out with other alkenes, including ethyl
acrylate, acrolein, and phenyl vinyl sulfone. In all of these
cases, the reaction was complete after 12 hours and the
[3+2+2] cycloadducts were obtained in good to excellent
yields (Table 3, entries 7–9).[14] Importantly, the presence of a
germinal diester in the connecting chain of 1d is not
mandatory, as the cycloaddition of the ether (1e) or N-tosyl
derivatives (1 f) led to comparable yields and also complete
selectivities in favor of the desired [3+2+2] adducts (Table 3,
entries 10–13).
of [Ni(cod)2] (10 mol%), even when heated in toluene at
908C (Table 1, entries 1 and 2). However, 1a did react at
room temperature with the same nickel complex when it was
treated with 2 equivalents of methyl vinyl ketone (MVK),
thereby providing a 74:26 mixture of the [3+2+2] and [3+2]
cycloadducts 5aa and 6aa, which were isolated in a 40%
combined yield (Table 1, entry 3). Raising the temperature to
408C, or even to 908C, led only to a marginal increase in the
efficiency of the process (Table 1, entries 4 and 5). Con-
versely, increasing the amount of methyl vinyl ketone up to
10 equivalents allowed for full conversions after 3 hours at
408C, and cycloadducts 5aa and 6aa were isolated in a good
80% combined yield (ratio 71:29; Table 1, entry 6).[9,10] The
reaction could also be performed in other solvents, such as
N,N-dimethylformamide, dioxane, or tetrahydrofuran; how-
ever, the products were obtained in somewhat lower yields
and selectivities (Table 1, entries 7–9). Interestingly, the
addition of an external ligand, such as PPh3, completely
inhibited the cycloaddition (Table 1, entry 10), whereas other
sources of nickel(0), such as [NiCl2(PPh3)2]/Et2Zn or Ni-
(acac)2/Et2Zn proved to be ineffective.[10]
The electronic and structural requirements of the alkene
component were studied next (Table 2). Gratifyingly, cyclo-
addition reactions of 1a with ethyl acrylate, acrolein, or
phenyl vinyl sulfone were also efficient, thus providing the
desired [3+2+2] adducts 5ab–5ad with moderate selectivities
and good overall yields (Table 2, entries 1–4). The presence of
the electron-withdrawing group on the alkene seems to be
mandatory, as the reactions with nonactivated alkenes, such as
styrene or methyl-5-hexenoate, led to recovery of 1a (Table 2,
entries 5 and 6).[11]
Envisaging that the electronic properties of the alkyne
could play an important role in determining the selectivity
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Table 3: Ni-catalyzed [3+2+2] cycloadditions of 1b–g and alkenes.
boring positions, which confirms
that both the [3+2+2] and [3+2]
cycloaddition reactions took place
by cleavage of a proximal bond of
the cyclopropane ring.
It was also interesting to find
that the presence of the alkyne unit
tethered to the ACP was not only
essential for the [3+2+2] process
but also for the [3+2] cycloaddition.
Indeed, ACP 1h, which lacked an
alkyne moiety, failed to give any
cycloaddition product, and only
starting material was recovered
even after several hours at high
temperature or using higher
amounts of alkene (Scheme 3). Per-
forming this reaction in the pres-
ence of different amounts of an
external alkyne, such as 2-hexyne,
did not bring any difference, thus
confirming that the tethered alkyne
is critical for both annulation pro-
cesses.
Entry[a]
1
X
R
Alkene
5/6[b]
100:0
100:0
5, yield [%][c]
5ba
44[d]
1
2
1b
1b
C(CO2Et)2
C(CO2Et)2
CO2Et[h]
CO2Et[h]
5bb
5bc
50[e]
24[f]
3
1b
C(CO2Et)2
CO2Et[h]
100:0
4
5
1b
1c
C(CO2Et)2
C(CO2Et)2
CO2Et[h]
100:0
80:20
5bd
5ca
68[g]
72
CH2OAc[h]
6
7
1d
1d
C(CO2Et)2
C(CO2Et)2
CH2OTBS
CH2OTBS
100:0
100:0
5da
5db
89
84
8
1d
1d
1e
C(CO2Et)2
C(CO2Et)2
O
CH2OTBS
CH2OTBS
CH2OTBS
100:0
100:0
100:0
5dc
5dd
5ea
45
72
71
9
10
11
12
1 f
1 f
NTs
NTs
CH2OTBS
CH2OTBS
100:0
100:0
5 fa
5 fb
69
62
In order to obtain more mech-
anistic information, we performed
preliminary DFT calculations using
=
substrate 1a’ and Ni(CH2 CH2)2 as
13
14
1 f
NTs
NTs
CH2OTBS
Me
100:0
80:20
5 fd
5ga
96
91
model reactants.[16] The computa-
tional data indicated that the reac-
tion starts with a proximal insertion
of the nickel complex into the
cyclopropane ring. This insertion
might lead to two different isomers
1g
[a] Conditions: 1a (0.2m in toluene), 10 mol% [Ni(cod)2], 10 equiv of alkene, 12 h at 408C, unless
otherwise noted. [b] Based on the 1H NMR spectrum of the crude reaction mixture. [c] Yield of pure 5.
Full conversion unless otherwise noted. [d] 69% conversion. [e] 66% conversion. [f] 25% conversion.
[g] 71% conversion. [h] Reaction carried out at 908C. Ac=acetyl, TBS=tert-butyldimethylsilyl.
The reaction of the N-tosyl derivative 1g provided the
corresponding cycloadducts in a 91% combined yield, and in
an 80:20 ratio, analogous to the outcome with 1a. Cyclo-
adduct 5ga as well as the homologous 5 fa were characterized
by X-ray crystallographic analysis, after recrystallization from
a mixture of diethyl ether/hexanes (Figure 1).[15]
In order to gain an insight into the reaction mechanism,
we performed a control experiment using tetradeuterated 1c
([D4]1c; Scheme 2). Analysis of the products revealed the
incorporation of the deuterated methylene groups in neigh-
Scheme 2. Nickel-catalyzed cycloaddition of [D4]1c.
Scheme 3. Control reaction with alkylidenecyclopropane 1h.
Z-i and E-i, the E isomer being 3.2 kcalmolꢀ1 more stable
(Scheme 4). However, intramolecular coordination of the
alkyne to the nickel is only possible in the Z isomer (Z-i), thus
leading to intermediates iia or iib.[17] Whilst a migratory
Figure 1. X-ray diffraction of cycloadducts 5 fa and 5ga (hydrogen
atoms in 5 fa are omitted for clarity).
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=
Scheme 4. Calculated reaction profile (B3LYP/def2-SVP level) for the reaction between 1’ and [Ni(CH2 CH2)2]. Free energies (DG298) are given in
kcalmolꢀ1
.
insertion into the alkyne from iia into iiia has a rather high
activation barrier, the same process from the coordinatively
saturated intermediate iib is much easier (energy barrier of
10.2 kcalmolꢀ1).
Intermediate iiib might evolve by different pathways. Of
all the possibilities studied,[10] the favored pathway consists of
an initial coordination of the methyl vinyl ketone to the nickel
provided cycloadducts arising from the distal opening of the
cyclopropane, the current method provides complementary,
synthetically useful 6,7-fused bicyclic systems, resulting from
cleavage of the proximal bond of the ring. According to DFT
calculations, the reaction involves the formation of a nickel-
acyclobutane species (like iib) as the key intermediate.
ꢀ
Received: July 20, 2010
Published online: November 17, 2010
center, followed by insertion into the Csp2 Ni bond to provide
intermediate iv (overall energy barrier of 26.2 kcalmolꢀ1).
This transformation is kinetically favored over other alter-
native reaction pathways[10] owing to the stabilizing coordi-
nation of the carbonyl group of the ketone to the nickel
moiety in the saddle point TS3 (and in intermediate iv). An
alternative process, which would also eventually afford
products of type 5, could involve the insertion of the methyl
Keywords: cycloaddition · cyclopropanes · insertion · nickel ·
.
transition metals
[1] a) M. Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107,
3117; b) A. Brandi, S. Cicchi, F. M. Cordero, A. Goti, Chem. Rev.
2003, 103, 1213 – 1269; c) M. Murakami, N. Ishida, T. Miura,
Chem. Commun. 2006, 643 – 645; d) R. Castro-Rodrigo, M. A.
Esteruelas, S. Fuertes, A. M. Lꢀpez, F. Lꢀpez, J. L. Mascareꢁas,
S. Mozo, E. Oꢁate, L. Saya, L. Villarino, J. Am. Chem. Soc. 2009,
131, 15572 – 15573; e) R. Castro-Rodrigo, M. A. Esteruelas,
A. M. Lꢀpez, F. Lꢀpez, J. L. Mascareꢁas, M. Olivꢂn, E. Oꢁate,
L. Saya, L. Villarino, J. Am. Chem. Soc. 2010, 132, 454 – 455.
[2] a) A. Delgado, J. R. Rodrꢃguez, L. Castedo, J. L. Mascareꢁas, J.
Am. Chem. Soc. 2003, 125, 9282 – 9283; b) J. Durꢂn, M. Gulꢃas, L.
Castedo, J. L. Mascareꢁas, Org. Lett. 2005, 7, 5693 – 5696; c) M.
Gulꢃas, R. Garcꢃa, A. Delgado, L. Castedo, J. L. Mascareꢁas, J.
ꢀ
vinyl ketone into the Csp3 Ni bond of iiib. However, the
corresponding transition state for this process turned out to
be 12.2 kcalmolꢀ1 higher in energy, making that pathway very
unlikely.[10,18,19] Intermediate iv produces the final adduct
after a reductive elimination step, with an energy barrier of
21.9 kcalmolꢀ1.[20]
In conclusion, we have developed the first nickel-cata-
lyzed [3C+2C+2C] cycloaddition involving nonactivated
ACPs. Contrary to previous palladium- and rhodium-cata-
lyzed cycloadditions of alkynylidenecyclopropanes,[2–4] which
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Communications
Am. Chem. Soc. 2006, 128, 384 – 385; d) B. Trillo, M. Gulꢃas, F.
[12] Slow addition (5 h) of the reactants (1b and MVK) to a solution
of [Ni(cod)2] (20 mol%) did not improve the conversion.
[13] Performing the cycloaddition between 1b and MVK (10 equiv)
in the presence of 20 mol% of cycloadduct 5ba afforded 30%
conversion. Increasing the amount of 5ba to up to 90% led to an
even lower conversion (18%). Comparison of these results with
those of Table 3 (entry 1) suggests that the cycloadduct 5ba
inhibits the cycloaddition, probably by coordinating to the nickel
catalyst.
[14] Substrates with terminal alkyne groups led to recovery of the
majority of the starting material.
[15] CCDC 791310 (5ga) and 782973 (5 fa) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Lꢀpez, L. Castedo, J. L. Mascareꢁas, Adv. Synth. Catal. 2006,
348, 2381 – 2384; e) M. Gulꢃas, J. Durꢂn, F. Lꢀpez, L. Castedo,
J. L. Mascareꢁas, J. Am. Chem. Soc. 2007, 129, 11026 – 11027;
f) R. Garcꢃa-Fandiꢁo, M. Gulꢃas, L. Castedo, J. R. Granja, J. L.
Mascareꢁas, D. J. Cꢂrdenas, Chem. Eur. J. 2008, 14, 272—281;
For
a ruthenium-catalyzed example, see: g) F. Lꢀpez, A.
Delgado, J. R. Rodrꢃguez, L. Castedo, J. L. Mascareꢁas, J. Am.
Chem. Soc. 2004, 126, 10262 – 10263.
[3] G. Bhargava, B. Trillo, M. Araya, F. Lꢀpez, L. Castedo, J. L.
Mascareꢁas, Chem. Commun. 2010, 46, 270 – 272.
[4] P. A. Evans, P. A. Inglesby, J. Am. Chem. Soc. 2008, 130, 12838 –
12839.
[5] For a review, see: P. Binger, H. M. Buch, Top. Curr. Chem. 1987,
135, 77 – 151.
[6] Alkylidenecyclopropanes usually participate in nickel-catalyzed
intermolecular [3+2] cycloadditions by cleavage of the distal
carbon bond of the cyclopropane ring. However, the cyclo-
additions between methylenecyclopropane and certain activated
alkenes, in the presence of “naked” nickel catalysts, provide
adducts arising from the cleavage of the proximal bond. For
examples, see: a) R. Noyori, T. Odagi, H. Takaya, J. Am. Chem.
Soc. 1970, 92, 5780 – 5781; b) R. Noyori, Y. Kumagai, I. Umeda,
H. Takaya, J. Am. Chem. Soc. 1972, 94, 4018 – 4020; c) P. Binger,
Angew. Chem. Int. Ed. Eng. 1972, 11, 309 – 310; d) P. Binger,
Synthesis 1973, 427 – 428; e) P. Binger, J. Mcmeekin, Angew.
Chem. 1973, 85, 1053 – 1054; Angew. Chem. Int. Ed. Engl. 1973,
12, 995 – 996; f) P. Binger, E. Sternberg, U. Wittig, Chem. Ber.
1987, 120, 1933 – 1938; g) R. Noyori, M. Yamakawa, Tetrahedron
Lett. 1978, 19, 4823 – 4826; h) P. Binger, A. Brinkmann, W. J.
Richter, Tetrahedron Lett. 1983, 24, 3599 – 3602; i) P. Binger, P.
Wedemann, Tetrahedron Lett. 1983, 24, 5847 – 5850; j) P. Binger,
P. Wedemann, Tetrahedron Lett. 1985, 26, 1045 – 1048; k) T.
Kawasaki, S. Saito, Y. Yamamoto, J. Org. Chem. 2002, 67, 4911 –
4915.
[16] All the calculations were carried out at the B3LYP/def2-SVP
level using the Gaussian 03 rev. D.01 suite of programs. For
computational details, see the Supporting Information.
[17] Nickelacylobutane E-i could be involved in the formation of the
[3+2] cycloaddition products of type 6, as the alkene moiety of
these cycloadducts exhibits E stereochemistry. However, the
requirements of the intramolecularly linked alkyne (Scheme 3)
suggests that alternative mechanisms, probably involving
alkyne-stabilized nickelacyclopentenes, might be operating.[7] It
is possible that the higher selectivity observed for 1d in
comparison to 1c (Table 2, entries 5 and 6) might be related to
a greater difficulty in producing such intermediates owing to
steric reasons.
[18] Despite extensive investigation, a transition state corresponding
to a reductive elimination from iiia or iiib, to afford an
intramolecular [3+2] cycloadduct, could not be located compu-
tationally. This result is in agreement with experimental results,
as these types of 6,5-bicyclic systems were never detected.
[7] Saito and co-workers have developed a series of nickel-catalyzed
intermolecular [3+2+2] cycloadditions involving proximal-bond
cleavage of the cyclopropane ring. However, these methods are
limited to the use of alkynes as two-carbon components and
cyclopropylideneacetates as three-carbon partners, as the pres-
ence of the ester group on the ACP is mandatory for the
cycloaddition. For examples, see: a) S. Saito, M. Masuda, S.
Komagawa, J. Am. Chem. Soc. 2004, 126, 10540 – 10541; b) S.
Komagawa, S. Saito, Angew. Chem. 2006, 118, 2506 – 2509;
Angew. Chem. Int. Ed. 2006, 45, 2446 – 2449; c) S. Saito, S.
Komagawa, I. Azumaya, M. Masuda, J. Org. Chem. 2007, 72,
9114 – 9120; d) R. Yamasaki, N. Terashima, I. Sotome, S.
Komagawa, S. Saito, J. Org. Chem. 2010, 75, 480 – 483, and
references therein.
[8] For a nickel-catalyzed [3+2+2] cycloaddition using bicyclopro-
pylidene (3C) involving a proximal-bond cleavage, see: L. Zhao,
A. de Meijere, Adv. Synth. Catal. 2006, 348, 2484 – 2492.
[9] Increasing the temperature (up to 908C), modifying the
concentration of 1a, or increasing the number of equivalents
of methyl vinyl ketone did not provide any substantial improve-
ment in the yield or selectivity.
[19] DFT calculations on a substrate bearing an ester group instead
of the methyl group at the alkyne moiety revealed lower energy
barriers for the migratory-insertion steps eventually leading to
the [3+2+2] adducts. This result is consistent with the higher
[3+2+2]/[3+2] selectivity observed experimentally for this type
of precursor (1b).
[20] Regioisomers of type 9 were never observed. In agreement with
this results, DFT calculations showed that the corresponding
pathway leading to these products is more energetic than that
affording 5.
[10] For further details, see the Supporting Information.
[11] Similarly, alkenes with substituents at their b position, such as
ethyl 2-butenoate, failed to participate in the cycloaddition
reaction.
9890 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9886 –9890