Bicyclic carbopalladation reaction with two gem-reaction centers. Efficient construction of fused bicyclic skeletons

Full text of DOI:10.1021/jo981709f

9156
J . Org. Chem. 1998, 63, 9156-9157
Sch em e 1
Bicyclic Ca r bop a lla d a tion Rea ction w ith Tw o
gem -Rea ction Cen ter s. Efficien t Con str u ction
of F u sed Bicyclic Sk eleton s
Shengming Ma* and Bin Xu
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received August 24, 1998
Synthetic efficiency is one of the most pursued objectives
for chemists. Although bicyclic compounds are present in
many important compounds, such as synthetic intermedi-
ates, target molecules of biological interests, etc.,1,2 among
so many methodologies, one of the most commonly used
approaches is a “ring by ring” strategy with low to moderate
efficiency.3-7 We would like to propose here a new strategy
for the efficient synthesis of bicyclic compounds, in which
the two rings are expected to be formed in one step (Scheme
1). The advantage of this protocol is that the bicyclic
compounds with different ring sizes as well as functional
groups can be prepared from the corresponding precursors
in just “one shot”.
Cyclic carbopalladation reaction of unsaturated C-C
bonds has become one of the most powerful tools for the
synthesis of cyclic compounds via a C-C bond-formation
reaction,8 with overwhelming emerging of both new cycliza-
tion protocols and synthetic applications to complex target
molecules. We began our hypothesis with a well-designed
cyclic carbopalladation, i.e., bicyclic carbopalladation reac-
tion of the corresponding precursors with two carbon-
bromine bonds, in which the two bromine atoms are con-
nected to the same carbon atom (Scheme 2). One formidable
Sch em e 2
challenge in this bicyclization is R-dehalopalladation,9 from
which the formation of an sp2-carbon-centered carbene
intermediate would be expected. We report herein the
realization of our hypothesis. To our knowledge, this rep-
resents the first transitional metal-catalyzed bicyclic car-
bometalation reaction of gem-dibromides.10
We started our study with dibromide 111 (eq 1). After
(1) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Pavoac, F.; White,
C. T. In The Total Synthesis of Natural Products; Apsimon, J .; Ed.; J ohn
Wiley & Sons: New York, 1983; Vol. 5. Rigby, J . H. In Studies in Natural
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V.: Amsterdam, 1988; Vol. 12. Chang, C. W. J .; Scheuer, P. J . Top. Curr.
Chem. 1993, 167, 33. Fraga, B. M. Nat. Prod. Rep. 1998, 15, 73. Fraga, B.
M. Nat. Prod. Rep. 1995, 12, 303.
(2) For most recent studies, see: Evans, D. A.; Ripin, D. H. B.; J ohnson,
J . S.; Shaughnessy, E. A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2119.
Shimoma, F.; Kondo, H.; Yuuya, S.; Suzuki, T.; Hagiwara, H.; Ando, M. J .
Nat. Prod. 1998, 61, 22. Bassett, S.; Ovenden, S. P. B.; Gable, R. W.; Capon,
R. J . Aust. J . Chem. 1997, 50, 1137. Kawano, H.; Itoh, M.; Katoh, T.;
Terashima, S. Tetrahedron Lett. 1997, 38, 7769. Harmata, M.; Carter, K.
W. Tetrahedron Lett. 1997, 38, 7985. Marczak, S.; Michalak, K.; Urbanczyk-
Lipkowska, Z.; Wicha, J . J . Org. Chem. 1998, 63, 2218.
tedious attempts, finally we found that this reaction afforded
fused 6,6-bicyclic product 2 in 68% yield in xylene at 80-85
°C for 24 h under the catalysis of 10 mol % Pd(PPh3)4 and
n-Bu4NCl12 using K2CO3 as the base (conditions A). The
results in CH3CN, EtOH-DMF, and toluene were poor.
Using Et3N, Ag2CO3 (in CH3CN), or K2CO3 (without n-Bu4-
NCl) as the base, the reactions were low-yielding and not
1
clean. The H NMR data are as follows: 5.23 (s, 2 H), 5.04
(s, 2 H), 3.70 (s, 12 H), 2.82 (s, 4 H), 2.63 (s, 4 H) ppm. The
1
simplicity of the H NMR data led us to doubt the structure
of this cyclized product, since the six sp2-carbon atoms will
not be on the same plane. This would, in principle, make
the cyclic protons chemical environmentally unequal, thus
complicating the splitting patterns. We determined the
structure of the cyclization product as 2 unambiguously by
X-ray study.13 R-Debromopalladation was not observed
under the current reaction conditions.9
(3) For Pd-catalyzed syntheses of bicycles from monocycles, see: Trost,
B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1977, 99, 3867. Lu, X.; Ma, S.;
J i, J .; Zhu, G.; J iang, H. Pure Appl. Chem. 1994, 66, 1501. Ma, S.; Negishi,
E. J . Am. Chem. Soc. 1995, 117, 6345.
(4) For radical-initiated syntheses of bicycles from monocycles, see: J olly,
R. S.; Livinghouse, T. J . Am. Chem. Soc. 1988, 110, 7536. Hayes, T. K.;
Villani, R.; Weinreb, S. M. J . Am. Chem. Soc. 1988, 110, 5533.
(5) For some miscellaneous examples, see: Corey, E. J .; Nicolaou, K. C.;
Melvin, L. S., J r. J . Am. Chem. Soc. 1975, 97, 654. Corey, E. J .; Mitra, R.
B.; Uda, H. J . Am. Chem. Soc. 1964, 86, 485. Corey, E. J .; Wess, G.; Xiang,
Y. B.; Singh, A. K. J . Am. Chem. Soc. 1987, 109, 4717.
(6) For Pauson-Khand-type formations of metal-containing bicyclic
intermediates followed by CO insertion to afford bicyclic compounds, see:
(a) Co: Reviews: Schore, N. E. Org. React. 1991, 40, 1. Shore, N. E. In
Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol. 12, p 703. (b) Zr:
Negishi, E.; Holmes, S. J .; Tour, J . M.; Miller, J . A.; Cederbaum, F. E.;
Swanson, D. R.; Takahashi, T. J . Am. Chem. Soc. 1989, 111, 3336. (c) Ti:
Grossman, R. B.; Buchwald, S. L. J . Org. Chem. 1992, 57, 5803.
(7) For some most recent studies on methodologies for the synthesis of
bicyclic compounds, see: (a) Wender, P. A.; Husfeld, C. O.; Langkopf, E.;
Love, J . A. J . Am. Chem. Soc. 1998, 120, 1940. (b) Chatani, N.; Morimoto,
T.; Fukumoto, Y.; Murai, S. J . Am. Chem. Soc. 1998, 120, 5335.
(8) Ma, S. Youji Huaxue 1991, 11, 561. (b) de Meijere, A.; Meyer, F. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (c) Negishi, E.; Coperet, C.;
Ma, S.; Liou, S.; Liu, F. Chem. Rev. 1996, 96, 365.
(9) For the formation of alkylidenecarbenes from 1,1-dibromoalk-1-enes
via R-dehalometalation reactions, see: (a) Kunishima, M.; Hioki, K.; Ohara,
T.; Tani, S. J . Chem. Soc., Chem. Commun. 1992, 219. (b) Kunishima, M.;
Hioki, K.; Tani, S.; Kato, A. Tetrahedron Lett. 1994, 35, 7253. (c) Harada,
T.; Hara, D.; Hattori, K.; Oku, A. Tetrahedron Lett. 1988, 29, 3821.
(10) For monocyclic carbopalladation of gem-dibromides, see: Nuss, J .
M.; Levine, B. H.; Rennels, R. A.; Heravi, M. M. Tetrahedron Lett. 1991,
32, 5243. Nuss, J . M.; Rennels, R. A.; Levine, B. H. J . Am. Chem. Soc. 1993,
115, 6991. Torii, S.; Okumoto, H.; Tadokoro, T.; Nishimura, A.; Rashid, M.
A. Tetrahedron Lett. 1993, 34, 2139.
(11) All the starting compounds were synthesized by the sequential
alkylation of dimethyl malonate with 1,1,3-tribromo-2-(bromomethyl)-
propene and the corresponding alkenyl bromides or the reaction of allyl
alcohol with 1,1,3-tribromo-2-(bromomethyl)propene in the presence of NaH
in THF.
10.1021/jo981709f CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/21/1998

Communications
J . Org. Chem., Vol. 63, No. 25, 1998 9157
Sch em e 3
Under similar conditions, bicyclic ether 6 with one oxygen
atom on each ring could be prepared in 83% yield (eq 2).
Although seven-membered ring formation via cyclic Heck
reaction is not so well-documented,14 7,7-bicyclic compound
15
8 was prepared in 38% yield using Ag2CO3 instead of K2-
CO3 as the base (eq 3). The reaction under conditions A
afforded 8 together with its CdC bond isomer(s).
Sch em e 4
According to the strategy described in this paper, if two
CdC double bonds are fixed with different side chains, the
corresponding bicyclic compounds could be synthesized in
one shot. Two such examples for the formations of 6,7-
bicyclic compounds 10 and 12 are listed in eqs 4 and 5.
Under the catalysis of Pd(PPh3)4 and using CH3CN as the
solvent/Et3N as the base, the monocyclization reaction of 1
to afford monocyclic product 3 was observed cleanly; even
with longer reaction times the further cyclization of 3 was
not observed. However, 3 cyclized to form 2 under conditions
A in 92% NMR yield, indicating that 3 might be one of the
reaction intermediates in the bicyclization shown in eq 1
(Scheme 3, for plausible mechanisms of this reaction, see
Scheme 4).
In conclusion, we have developed the first bicyclic carbo-
palladation reaction, which was proven to be highly efficient
for the construction of bicyclic compounds; R-dehalopalla-
dation was not observed. The scope and cyclization patterns
of these reactions are being investigated in our laboratory.
(12) For phase transfer-catalyzed intermolecular Heck reactions in DMF,
see: J effery, T. J . Chem. Soc., Chem. Commun. 1984, 1287. J effery, T.
Tetrahedron Lett. 1985, 26, 2667. J effery, T. Synthesis 1987, 70.
(13) Cr ysta l d a ta for 2: C20H24O8, M ) 392.40, monoclinic, C2/c #15),
colorless, a ) 14.448(3) Å, b ) 11.673(5) Å, c ) 12.885(4) Å, 111.32(2) Å, Z
) 4, µ(Mo KR) ) 1.00 cm-1, Dcalc ) 1.287 g/cm3, F(000) ) 832.00, 2439 unique
reflections were measured to 2θmax ) 55.0 °C, 1491 reflections with I > 3.00σ-
(I) were used in the refinement, R ) 0.056.
(14) For the formation of seven-membered rings via an exo-mode cyclic
carbopalladation reaction of benzylic halides, see: Wu, G.; Lamaty, F.;
Negishi, E. J . Org. Chem. 1989, 54, 2507. (b) For the formation of seven-
membered rings via an exo-mode cyclic carbopalladation reaction of aryl
halides and an endo-mode cyclic carbopalladation of alkenyl halides, see:
Negishi, E.; Ma, S.; Sugihara, T.; Noda, Y. J . Org. Chem. 1997, 62, 1922.
(15) Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem. 1987, 52,
4130.
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, Laboratory of Organometallic
Chemistry, Chinese Academy of Sciences, and Shanghai
Institute of Organic Chemistry for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental section,
X-ray data of compound 2 and the 1H NMR spectra of the
compounds 2, 3, 6, 8, 10, and 12 (17 pages).
J O981709F