In situ generation of vinyl allenes and its applications to one-pot assembly of cyclohexene, cyclooctadiene, 3,7-nonadienone, and bicyclo[6.4.0]dodecene derivatives with palladium-catalyzed multicomponent reactions

Article abstract of DOI:10.1021/ja054144v

A novel tandem Pd-catalyzed cross-coupling and [4 + 4] cycloaddition sequence allows the rapid synthesis of eight-membered carbocycles starting from α-bromovinyl arenes and propargyl bromides in one reaction vessel. It is noteworthy that four components a

Full text of DOI:10.1021/ja054144v

Published on Web 01/07/2006
In Situ Generation of Vinyl Allenes and Its Applications to
One-Pot Assembly of Cyclohexene, Cyclooctadiene,
3,7-Nonadienone, and Bicyclo[6.4.0]dodecene Derivatives with
Palladium-Catalyzed Multicomponent Reactions
Phil Ho Lee,*,† Kooyeon Lee,† and Youngjin Kang‡
Contribution from the Department of Chemistry, Kangwon National UniVersity,
Chunchon 200-701, Republic of Korea, and Department of Science Education,
Kangwon National UniVersity, Chunchon 200-701, Republic of Korea
Received July 11, 2005; E-mail: phlee@kangwon.ac.kr
Abstract: A novel tandem Pd-catalyzed cross-coupling and [4 + 4] cycloaddition sequence allows the
rapid synthesis of eight-membered carbocycles starting from R-bromovinyl arenes and propargyl bromides
in one reaction vessel. It is noteworthy that four components are assembled into one molecule via this
procedure. In contrast to R-bromovinyl arenes, R-bromovinyl alkanes afforded tandem cross-coupling and
homo [4 + 2] cycloaddition products. Subjecting an equimolar mixture of R-bromostyrene and 2-bromo-
1-octene to propargyl bromides furnished the tandem Pd-catalyzed cross-coupling and hetero [4 + 2]
cycloaddition product. Exposure of equimolar mixtures of R-bromovinyl arenes to allenylindium resulted in
tandem a Pd-catalyzed cross-coupling and hetero [4 + 4] cycloaddition products. Synthesis of vinylallene
from the reaction of vinyl triflate with allenylindium followed by Pd-catalyzed carbon monoxide insertion
reaction gave the corresponding 3,7-nonadienone product via tandem Pd-catalyzed cross-coupling and [4
+ 4 + 1] annulation. Tandem Pd-catalyzed cross-coupling, [4 + 4] cycloaddition, and [4 + 2] cycloaddition
provided the rapid synthesis of bicyclo[6.4.0]dodecene derivatives starting from R-bromovinyl arenes,
propargyl bromides, and dienophiles in one operation, in which five components were integrated into one
molecule.
Introduction
development of new multicomponent reactions that allow
assembly of polysubstituted carbocycles in a regioselective
Transition metal-catalyzed multicomponent reactions (MCR)
have attracted considerable attention due to the fact that complex
organic molecules and drugs can be easily prepared from simple
compounds in one reaction sequence.1 Although a range of
strategies involving the sequential generation of radical and
anionic species has been used for such transformations,2
relatively few transition metal-catalyzed MCRs have been
reported for the synthesis of complex cyclic compounds.3 Thus,
manner is in high demand. In particular, the construction of
eight-membered carbocycles via MCR remains a significant
synthetic challenge because they constitute common structural
cores of a large number of biologically important natural and
unnatural products.4,5
Recently, we discovered an efficient method for the synthesis
of substituted allenes, polyallenes, and unsymmetrical bis-
(allenes) from the reactions of a variety of electrophilic coupling
partners with allenylindiums generated in situ.6 Thus, R-bro-
mostyrene reacted with 1-bromo-2-butyne (2d) bearing a methyl
substituent at the γ-position to give 3-methyl-4-phenyl-1,2,4-
pentatriene (3) in 85% yield via cross-coupling reaction. trans-
4-Phenyl-1,2,4-hexatriene (5) was obtained in 92% yield from
cis-1-bromo-2-methyl-1-phenylethene (4) and propargyl bromide
(2a). However, treatment of R-bromostyrene with allenylindium
produced unexpectedly 3,4-dimethylene-1,6-diphenyl-1,5-cy-
clooctadiene (6b) in 94% yield (Scheme 1).
† Department of Chemistry, Kangwon National University.
‡ Department of Science Education, Kangwon National University.
(1) (a) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV.
2005, 105, 1001. (b) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc.
ReV. 2004, 33, 302. (c) Tsuji, J. Transition Metal Reagents and Catalysts:
InnoVations in Organic Synthesis; Wiley: New York, 2002. (d) Ikeda, S.-
I. J. Synth. Org. Chem. Jpn. 2001, 59, 960. (e) Tietze, L. F.; Haunert, F.
Stimulating Concepts in Chemistry; Vogtle, F., Stoddart, J. F., Shibasaki,
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33, 511. (h) Hegedus, L. S. Transition Metals in the Synthesis of Complex
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1996, 96, 365. (j) Tietze, L. F. Chem. ReV. 1996, 96, 115. (k) Bunce, R.
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9
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J. AM. CHEM. SOC. 2006, 128, 1139-1146
1139

A R T I C L E S
Scheme 1
Lee et al.
Scheme 2
Stimulated by these results, we reported the highly efficient
synthesis of bicyclo[6.4.0]dodecene derivatives by tandem five-
component reactions of two molecules of R-bromostyrene, two
molecules of propargyl bromide, and a dienophile.7 As part of
a project aimed at finding new MCRs that would be useful in
organic synthesis, we report herein in full the novel intermo-
lecular tandem Pd-catalyzed cross-coupling reactions, Pd-
catalyzed [4 + 4] cycloaddition reactions, and [4 + 2]
cycloaddition reactions and Pd-catalyzed cross-coupling reac-
tions followed by [4 + 4 + 1] annulation or [4 + 2]
cycloaddition reactions to give cyclooctadiene, bicyclo[6.4.0]-
dodecene, 3,7-nonadiene, and cyclohexene derivatives in one-
pot multicomponent assembly (Scheme 2).
stirred at 50 °C for 2 h. In the 1H NMR spectrum of the crude
product mixture, 3,4-dimethylene-1,6-diphenyl-1,5-cycloocta-
diene (6b) was observed as the major compound, indicative of
a tandem Pd-catalyzed cross-coupling-Pd-catalyzed [4 + 4]
cycloaddition taking place, yielding 6b in 94% isolated yield.
Reaction of the enol triflate of 3-bromoacetophenone with
allenylindium produced 4-(3-bromophenyl)-1,2,4-pentatriene
(10) in 70% yield (DMF, 50 °C, 1 h) via Pd-catalyzed cross-
coupling. Prolonged reaction time (2 h) gave 6m in 79% yield
(Scheme 3).5n,9 This result implies that 6m is produced via Pd-
catalyzed [4 + 4] cycloaddition reaction of 10.
For the vinyl bromides as electrophilic coupling partners,
electronic variation on the aromatic substituents did not diminish
the efficiency and selectivity (entries 8-19, Table 1). It is
noteworthy that protection of hydroxyl and amino groups on
substrates is not necessary, as demonstrated by the reaction of
3-hydroxy-R-bromostyrene (entry 11) and 3-amino-R-bromosty-
rene (entries 12 and 13). The reaction worked equally well with
R-bromovinyl arenes having halides such as Cl and Br (entries
14 and 17). 4-Bromo-R-bromostyrene selectively afforded the
desired cyclooctadiene 6p in 84% yield under the present
conditions (entry 17). This result implies that vinyl bromide is
more reactive than aryl bromide in coupling reactions with
allenylindium. 2-Deutero-1-bromo-1-phenylethene (cis:trans )
1:1.7) gave cyclooctadiene 6c in 87% yield in which deuterium
was inserted at the 7- and/or 8-positions (Scheme 4).
Results and Discussions
Pd-Catalyzed Cross-Coupling Reactions and Pd-Catalyzed
[4 + 4] Cycloadditions. Four-component assembly by Pd-
catalyzed cross-coupling and Pd-catalyzed [4 + 4] cycloaddition
was first examined by using R-bromostyrene and propargyl
bromide. The organoindium reagent obtained from 1 equiv of
indium and 1.5 equiv of propargyl bromide was added to a
solution of 1 equiv of R-bromostyrene in the presence of 4 mol
% of Pd(PPh3)4 and 3 equiv of LiCl,6,8 and the solution was
(5) For [2 + 2 + 2 + 2] cycloaddition, see: (a) Salem, B.; Suffert, J. Angew.
Chem., Int. Ed. 2004, 43, 2826. (b) Boussie, T. R.; Streitwieser, A. J. Org.
Chem. 1993, 58, 2377. (c) Walther, D.; Braun, D.; Schulz, W.; Rosenthal,
U. Z. Anorg. Allg. Chem. 1989, 577, 270. (d) Lawrie, C. J.; Gable, K. P.;
Carpenter, B. K. Organometallics 1989, 8, 2274. (e) Colborn, R. E.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 5470. For [4 + 2 + 2]
cycloaddition, see: (f) Baik, M.-H.; Baum, E. W.; Burland, M. C.; Evans,
P. A. J. Am. Chem. Soc. 2005, 127, 1602. (g) Evans, P. A.; Baum, E. W.
J. Am. Chem. Soc. 2004, 126, 11150. (h) Varela, J. A.; Castedo, L.; Saa,
C. Org. Lett. 2003, 5, 2841. (i) Evans, P. A.; Robinson, J. E.; Baum, E.
W.; Fazal, A. N. J. Am. Chem. Soc. 2002, 124, 8782. (j) Gilbertson, S. R.;
DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784. (k) Chen, Y.; Snyder, J.
K. J. Org. Chem. 1998, 63, 2060. (l) Lautens, M.; Tam, W.; Lautens, J.
C.; Edwards, L. G.; Crudden, C. M.; Smith, A. C. J. Am. Chem. Soc. 1995,
117, 6863 and references therein. For [5 + 2 + 1] cycloaddition, see: (m)
Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem.
Soc. 2002, 124, 2876. For [4 + 4] cycloaddition, see: (n) Murakami, M.;
Itami, K.; Ito, Y. Synlett 1999, 951. (o) Wender, P. A.; Nuss, J. M.; Smith,
D. B.; Suarez-Sobrino, A.; Vagberg, J.; Decosta, D.; Bordner, J. J. Org.
Chem. 1997, 62, 4908 and references therein. (p) Itoh, K.; Masuda, K.;
Fukahori, T.; Nakano, K.; Aoki, K.; Nagashima, H. Organometallics 1994,
13, 1020. (q) Schneider, R.; Siegel, H.; Hopf, H. Liebigs Ann. Chem. 1981,
1812. For [6 + 2] cycloaddition, see: (r) Wender, P. A.; Correa, A. G.;
Sato, Y.; Sun, R. J. J. Am. Chem. Soc. 2000, 122, 7815 and references
therein. (s) Rigby, J. H. Tetrahedron 1999, 55, 4521. (t) Chafee, K.; Huo,
P.; Sheridan, J. B.; Barbieri, A.; Aistars, A.; Lalancette, R. A.; Ostrander,
R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1995, 117, 1900.
Reaction of R-bromostyrene with 3-bromo-1-butyne and
indium provided the product 6d in 90% yield consisting of three
stereoisomers (1.3:1.0:1.3) with respect to the orientation of the
two methyl groups of the exocyclic double bonds (entry 5).
Vinyl triflates can also be used in tandem cross-coupling/
cycloaddition catalyzed by Pd(0) (entries 7 and 16). For
propargyl halides as nucleophilic cross-coupling partners, the
(6) Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901.
(7) Lee, P. H.; Lee, K. Angew. Chem., Int. Ed. 2005, 44, 3253.
(8) (a) Lee, P. H.; Seomoon, D.; Lee, K. Org. Lett. 2005, 7, 343. (b) Lee, P.
H.; Seomoon, D.; Lee, K.; Kim, S.; Kim, H.; Shim, E.; Lee, M.; Lee, S.;
Kim, M.; Sridhar, M. AdV. Synth. Catal. 2004, 346, 1641. (c) Lee, K.;
Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (d) Lee, P. H.; Sung,
S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201.
(9) Although reaction of the enol triflate of 3-bromoacetophenone with
allenylindium produced 6m in 79% yield (DMF, 50 °C, 2 h) via
Pd-catalyzed cross-coupling reaction and [4 + 4] cycloaddition, 4-(3-
bromophenyl)-1,2,4-pentatriene (10) via Pd-catalyzed cross-coupling reac-
tion was obtained in 70% yield using DMF at 50 °C for 1 h. The fact that
6m is not formed in any amount under these conditions is a confusing
observation.
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1140 J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006

In Situ Generation of Vinyl Allenes
A R T I C L E S
Scheme 3
Table 1. Tandem Cross-Coupling-[4 + 4] Cycloadditiona
Scheme 4
entry
R1
R2
R3
X1
X2
compd
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
TMS
Ph
Ph
Ph
Ph
H
H
H
H
Me
Me
Me
H
H
Me
H
H
Me
H
H
Me
H
H
H
H
H
Br
Br
Br
OTf
Br
Br
OTf
Br
Br
Br
Br
Br
Br
Br
OTf
OTf
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Br
Br
Cl
Br
Br
Cl
Br
Br
Cl
Br
Br
Cl
6a
6b
6c
6b
6d
6e
6e
6f
6g
6h
6i
6j
6k
6l
71
94
87c
71
H
90d
91e
72e
87
Ph
Ph
Me
Me
H
H
Me
H
H
Me
H
H
Me
H
4-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
3-HO-C6H4
3-H2N-C6H4
3-H2N-C6H4
2-Cl-C6H4
3-Br-C6H4
3-Br-C6H4
4-Br-C6H4
4-F3C-C6H4
4-F3C-C6H4
Scheme 5
87
79e
81
71
63e
83
6m
6n
6p
6q
6r
79
65e
84
H
Me
H
Me
91
71e
a Reaction performed in the presence of 4 mol % of Pd(Ph3P)4, 1 equiv
of In, and 1.5 equiv of propargyl halide in DMF for 2 h at 50 °C. b Isolated
yields. c 87% d-incoporated 2-deutero-1-bromo-1-phenylethene (cis:trans )
1:1.7) was used. d The product consisted of three stereoisomers (1.3:1.0:
1.3) with respect to the orientation of the two methyl groups of the exocyclic
double bonds. e 2 equiv of In, 3 equiv of 3-chloro-3-methyl-1-butyne, and
5 equiv of LiBr were used.
we tried to prepare cyclooctadiene from R-bromostyrene under
the Murakami conditions in one-pot operation, vinylallenes were
produced exclusively in 86% yield and no [4 + 4] cycloaddition
product of the vinylallene was formed. (1-Phenylvinyl)tributyltin
was prepared in 90% yield from Grignard reagent obtained from
R-bromostyrene and Mg with tributyltin chloride. Treatment of
(1-phenylvinyl)tributyltin with propargyl bromide in the pres-
ence of Pd(0) catalyst gave vinylallene in 89% yield, and the
longer reaction time (24 h) resulted in decomposition of
vinylallene.10
presence of two methyl substituents at the R-position exhibited
little effect on both the reaction rate and product yield. In the
case of 3-chloro-3-methyl-1-butyne, products 6e,h,k,n,r having
four methyl groups on terminal olefins were obtained in 63-
91% yields under the optimum conditions (entries 6, 7, 10, 13,
16, and 19). (R-Bromovinyl)trimethylsilane reacted with pro-
pargyl bromide and indium to produce 6a in 71% yield (entry
1). However, R-bromovinyl phenyl sulfone, R-bromovinyl
phenyl sulfide, and R-bromovinyl benzoate failed to deliver the
desired compounds due to their thermal instability.
Pd-Catalyzed Cross-Coupling and Homo [4 + 2], Hetero
[4 + 2], or Hetero [4 + 4] Cycloaddition Reactions. To
demonstrate the efficiency and scope of the present method,
we applied this MCR to 2-halo-1-alkenes. Although R-halovinyl
arenes produced 3,4-dimethylene-1,6-diphenyl-1,5-cycloocta-
diene derivatives in good to excellent yields via tandem cross-
coupling and [4 + 4] cycloaddition reactions catalyzed by Pd(0),
treatment of 2-halo-1-alkenes with propargyl bromide and
indium under the optimized conditions afforded cyclohexene
derivatives via the tandem cross-coupling and [4 + 2] cycload-
dition sequence. Reaction of 2-bromo-1-octene or 2-iodo-1-
octene with the allenylindium reagent gave rise to 1,4-dihexyl-
3-methylene-4-propadienyl-1-cyclohexene (11) in 71% and 43%
yields, respectively (Scheme 6).5n
Pd-catalyzed [4 + 4] cycloaddition reactions using the
vinylallene as a starting material were recently reported.5n In
the reported reaction, the vinylallene was obtained from (1-
phenylvinyl)magnesium bromide and propargyl bromide in the
presence of Pd(0) catalyst.10 However, in situ preparation of
vinylallenes using inversion of the charge polarization of the
reaction components (R-bromostyrene and propargyl bromide)
was applied using the present method (Scheme 5). Although
(10) Murakami, M.; Thami, K.; Ito, Y. Organometallics 1999, 18, 1326.
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1141

A R T I C L E S
Lee et al.
Scheme 6. Tandem Cross-Coupling-Homo [4 + 2] Cycloaddition
from 2-Halo-1-alkenes
Scheme 7. Tandem Cross-Coupling-Homo or Hetero [4 + 2]
Cycloaddition and Cross-Coupling-Hetero [4 + 4] Cycloaddition
Figure 1. Molecular structure of 9i along with the atom-numbering
schemes. Displacement ellipsoids are drawn at the 50% probability level.
Selected bond lengths (Å) and angles (deg): C1-C2 1.478(2), C2-C3
1.346(2), C3-C4 1.516(2), C4-C5 1.520(2), C1-C8 1.351(2), C1-C12
1.521(2), C10-C11 1.524(2), C11-C12 1.532(2); C1-C2-C3 134.29-
(14), C1-C12-C11, 111.06(13), C2-C3-C4 127.84(14), C3-C4-C5
116.39(13), C8-C1-C2 128.16, C8-C1-C12 116.45(14).
bromide under the optimum conditions produced tandem cross-
coupling-homo [4 + 4] cycloaddition products 6b and cross-
coupling-homo [4 + 2] cycloaddition products 11 in 31% and
28% yield, respectively, and tandem cross-coupling-hetero [4
+ 2] cycloaddition product 12 in 12% yield. Subjecting a
mixture of 4-(trifluoromethyl)-R-bromostyrene and 4-(methoxy-
phenyl)-R-bromostyrene to 1.5 equiv of propargyl bromide and
1 equiv of indium gave the tandem cross-coupling-hetero [4
+ 4] cycloaddition product 13 in 39% yield and cross-coupling-
homo [4 + 4] cycloaddition products 6g,q in 12% and 18%
yield, respectively (Scheme 7).
We also examined the tandem Pd-catalyzed cross-coupling/
cycloaddition sequence with the mixture of a R-bromovinyl
arene and 2-halo-1-alkenes. Reaction of equimolar mixture of
R-bromostyrene and 2-bromo-1-octene with 2 equiv of propargyl
After the Pd-catalyzed cross-coupling of the enol triflate of
3-bromoacetophenone with allenylindium, exposure of the crude
Scheme 8
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1142 J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006

In Situ Generation of Vinyl Allenes
A R T I C L E S
Scheme 9. Tandem Cross-Coupling-Homo [4 + 4]
Cycloaddition-[4 + 2] Cycloaddition
(Scheme 9). The structure of 9a was determined by spectros-
copy. In addition, the compound 9i as a representative was
characterized structurally using X-ray crystallography (Figure
1).12
This transformation shows that five-components were as-
sembled via intermolecular tandem cross-coupling-[4 + 4] and
[4 + 2] cycloaddition (Scheme 10).
We next focused on the scope and functional group tolerance
of the above MCR reaction. The results of several five-
component MCRs are summarized in Table 2. With a variety
of dienophiles (8a-d and 8f-l), intermediate 6b gave rise to
bicyclo[6.4.0]dodecene derivatives in good yields (entries
1-11). Similarly, R-bromostyrene reacted with maleimide (8j)
to produce 9g in 79% yield (entry 7). For a vast number of
R-bromovinyl arenes as organic electrophiles, the presence of
various substituents such as 4-methoxy, 2-chloro, 3-bromo, and
4-trifluoromethyl on the aromatic ring did not affect the
efficiency of the tandem reactions (entries 12 and 13 and 16-
18). The reaction performed equally well with R-bromovinyl
arenes having unprotected hydroxyl and amino groups (entries
14 and 15). Treatment of 4-trifluoromethyl-R-bromostyrene (1i)
with 2 equiv of propargyl bromide and indium followed by 1
equiv of naphthoquinone (8e) afforded 9s in 64% yield (entry
18). Reaction of 1d with allenylindium followed by glyoxylic
acid ethyl ester produced 9n in 69% yield (entry 14). The enol
triflate of 3-bromoacetophenone underwent the tandem reaction
to afford 9r in 66% yield under the present conditions (entry
17).
Scheme 10. Assembly of 5 Components via Tandem
Cross-Coupling-[4 + 4] Cycloaddition-[4 + 2] Cycloaddition
Unfortunately, the desired bicyclo[6.4.0]dodecene derivatives
from (R-bromovinyl)trimethylsilane and propargyl bromide or
4-methoxy-R-bromostyrene and 3-chloro-3-methyl-1-butyne
under the present conditions were not obtained, due to the
instability of 6a under the conditions of the [4 + 2] cycload-
dition reaction and the development of severe nonbonded
interactions in the case of 6h.
Although a variety of dienophiles could be used in MCRs,
the following dienophiles did not partake in tandem [4 + 2]
cycloadditions:
product to carbon monoxide atmosphere under balloon pressure
resulted in 3,7-nonadienone 14a in 45% yield, which was
produced via a tandem Pd-catalyzed five-component reaction
by cross-coupling and [4 + 4 + 1] annulation (Scheme 8).11
Treatment of enol triflates with indium reagents in situ generated
from 3-chloro-3-methyl-1-butyne and indium followed by
carbon monoxide afforded 14b,c in 66% and 51% yields,
respectively, in one-pot.
Pd-Catalyzed Cross-Coupling Reactions: [4 + 4] and [4
+ 2] Cycloadditions. Because 6b was a 1,3-diene, we
investigated the following tandem [4 + 2] cycloaddition of crude
1,3-diene 6b. Thus, 6b was treated with 1.5 equiv of tetra-
cyanoethylene (70 °C, benzene, 18 h) to afford 9a in 84% yield
Mechanistic Insights. Although the mechanism to describe
the formation of the six-, eight-, and nine-membered rings has
not been established, a possible reaction pathway is described
in Scheme 11. Oxidative addition of a Pd(0) catalyst to the vinyl
bromide, subsequent transmetalation with organoindium re-
(12) SHELXTL NT Crystal Structure Analysis Package, version 5.14; Bruker
(11) Murakami, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. 1998, 37, 3418.
AXS, Analytical X-ray System: Madison, WI, 1999.
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Table 2. Tandem Cross-Coupling-[4 + 4] Cycloaddition and [4 + 2] Cycloadditiona
a Cross-coupling and [4 + 4] cycloaddition: in THF (2 mL), 1 (0.5 mmol), 2 (0.75 mmol), and indium (0.5 mmol) were reacted in the presence of 4 mol
% Pd(PPh3)4 and LiCl (1.5 mmol) under N2 at 50 °C for 2 h. [4 + 2] cycloaddition: crude 6 was reacted with 8 (0.38 mmol) in benzene (2 mL) at 70 °C
for 18 h. b [4 + 2] cycloaddition proceeded in benzene at 80 °C for 2 h. c 2.5 equiv of methyl vinyl ketone was used. d Dimethyl fumarate was used.
e Dimethyl maleate was used. Isomeric ratio of product: 1:1.2 ) cis:trans. f Enol triflate of 3-bromoacetophenone was used as starting material.
agent13 in situ generated from propargyl bromide and indium,
and reductive elimination affords the vinylallene 7. Insertion
of Pd(0) to the vinylallene produces a five-membered pallada-
cycle 16, which subsequently reacts with another molecule of
7 at the internal double bond of the allene. The C-C bond
formed from connection of the 1-position of the allenes gives
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In Situ Generation of Vinyl Allenes
A R T I C L E S
Scheme 11
a bis(π-allyl)palladium intermediate 18. If R is an aromatic
group, the σ-bis(alkenyl)palladium intermediate 17, which is
one of resonance contributors of 18, would be more significant
as it is stabilized by the extended conjugation from the aromatic
R substituent to the endocyclic C-C double bond. Subsequent
reductive elimination of 17 would then give eight-membered
carbocycle 6. Finally, [4 + 2] cycloaddition of the 1,3-diene 6
with a variety of dienophiles produces the observed bicyclo-
[6.4.0]dodecene derivatives 9. Alternatively, insertion of carbon
monoxide to σ-bis(alkenyl)palladium intermediate 17 followed
by reductive elimination affords a nine-membered ring 14.
In sharp contrast with substrates in which R is an aromatic
ring, if R is an alkyl group, six-membered carbocycles were
produced selectively. In this case, the σ-bis(alkenyl)palladium
intermediate 17 is expected to be a minor contributor due to
the lack of stabilization by conjugation, and reductive elimina-
tion of the other contributor 19 produces six-membered ring
preferentially.
Scheme 12
observed. Exclusive formation of 6 from Pd-catalyzed [4 + 4]
cycloaddition of vinylallene by head to head connection might
be due to an attractive secondary orbital interaction between
the π system of C4-C5 of the five-membered palladacycle 16
and that of the double bond at C4-C5 of the vinylallene (Scheme
12).
In case of Scheme 7, the rate of formation of 6b is higher
than that of 11 and 12, which could be confirmed by both GC
and TLC. Therefore, 1b is consumed more rapidly than
2-bromo-1-octene under the optimum conditions. Although 12
might be more stabilized due to the increased congujation, 11
(28%) might be produced to a larger extent than 12 (12%) due
to lack of R-bromostyrene (1b).
Conclusions
In conclusion, this study has led to the development of a novel
tandem Pd-catalyzed cross-coupling/[4 + 4] cycloaddition
reaction that allows the rapid synthesis of eight-membered
carbocycles starting from R-bromovinyl arenes and propargyl
bromides in one reaction vessel. It is noteworthy that four
No eight-membered product 21 obtained from [4 + 4]
cycloaddition reactions by head to tail connection was ever
(13) Miao, W.; Chung, L. W.; Wu, Y.-D.; Chan, T, H. J. Am. Chem. Soc. 2004,
126, 13326.
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A R T I C L E S
Lee et al.
components are assembled into one product via this procedure.
In contrast to R-bromovinyl arenes, treatment of 2-halo-1-
alkenes and propargyl bromides under the optimum conditions
afforded tandem cross-coupling and homo [4 + 2] cycloaddition
products. Subjecting mixtures of R-bromostyrene and 2-bromo-
1-octene to propargyl bromides furnished tandem Pd-catalyzed
cross-coupling reaction-hetero [4 + 2] cycloaddition products.
Exposure of equimolar mixtures of a series of R-bromovinyl
arenes to in situ generated allenylindium reagents resulted in
tandem Pd-catalyzed cross-coupling and hetero [4 + 4] cy-
cloaddition product together with tandem Pd-catalyzed cross-
coupling/[4 + 4] cycloaddition products. After formation of
vinylallene from the reaction of a vinyl triflate with an
allenylindium reagent, exposure to carbon monoxide gave the
3,7-nonadienone product. Also, tandem Pd-catalyzed cross-
coupling/[4 + 4] cycloaddition and [4 + 2] cycloaddition led
to the rapid assembly of bicyclo[6.4.0]dodecane derivatives
starting from R-bromovinyl arenes, propargyl bromides, and
dienophiles. In addition, the present process is one of the
comparatively few examples in which a Pd(0) complex is
simultaneously involved in two catalytic cycles.14 The present
method provides highly efficient syntheses of eight-membered
carbocycles, bicyclo[6.4.0]dodecenes, 3,7-nonadienones, and
cyclohexene derivatives in good to excellent yields in one-pot
operation and therefore complements existing synthetic methods.
Acknowledgment. This work was supported by the CMDS
at KAIST and Grant No. R02-2003-000-10023-0 (C00044) of
the Basic Research Program of the KOSEF. We thank Professor
Thomas S. Livinghouse and Dr. Magdalena A. Stan of Montana
State University for proofreading this manuscript.
Supporting Information Available: Experimental procedures
and characterization of products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA054144V
(14) (a) Ho, T.-L. Tactics of Organic Synthesis; Wiley-Interscience: New York,
1994; p 79. (b) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience:
New York, 1992.
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