432
J . Org. Chem. 1998, 63, 432-433
Sch em e 1
Gen er a tion a n d Cycliza tion of a
Ben zyn e-Teth er ed Alk yllith iu m : P r ep a r a tion
of 4-Su bstitu ted In d a n s
William F. Bailey* and Sarah C. Longstaff
Department of Chemistry, The University of Connecticut,
Storrs, Connecticut 06269-4060
Received November 11, 1997
The intramolecular addition of an organolithium to a
tethered benzyne intermediate, illustrated below, offers a
conceptually simple route to functionalized benzo-fused
carbocycles. Although intermolecular addition of an orga-
nolithium to a benzyne is a well characterized process,1 and
while intramolecular trapping of benzyne intermediates by
tethered heteroatomic nucleophiles or a stabilized carban-
ions, first demonstrated by Bunnett2 and Huisgen,3 has been
widely used for the construction of a variety of systems,4 the
possibility of effecting carbon-carbon bond formation by
cyclization of a benzyne-tethered organolithium appears not
to have been explored. In light of the facile 5-exo-dig
cyclization of simple acetylenic alkyllithiums,5 we were
prompted to investigate the 5-exo cyclization of a benzyne-
tethered alkyllithium. Herein we report that this methodol-
ogy may be used to advantage for the preparation of
4-substituted indans via cyclization of the benzyne-tethered
propyllithium generated from readily available 2-fluoro-1-
(3-iodopropyl)benzene (1). The novel five-step, one-pot
synthetic sequence, summarized in Scheme 1, delivers
isomerically pure indans in 60-70% yield.
Sch em e 2
loss of LiF to deliver the 1,2-dehydrobenzene intermediate.1
The first of these steps, the exchange reaction, was easily
accomplished following our general protocol.6 Thus, treat-
ment of an approximately 0.1 M solution of 1 in dry
n-pentane-diethyl ether (4:1 by vol) at -78 °C with 2.2
molar equiv of tert-butyllithium (t-BuLi) cleanly generates
the corresponding alkyllithium 2 as demonstrated by the fact
that quench of such a reaction mixture with MeOH at -78
°C affords 2-fluoro-1-propylbenzene in essentially quantita-
tive yield.8 Ortho lithiation of 2 to produce the dilithio
precursor of the benzyne intermediate proved more prob-
lematic.
The preparation of 2-fluoro-1-(3-iodopropyl)benzene (1)
was accomplished in straightforward fashion using classical
chemistry as illustrated in Scheme 2. At the inception of
this study it was realized that conversion of 1 to a benzyne-
tethered propyllithium would involve three discrete steps,
each of which finds ample literature precedent: (i) lithium-
iodine exchange to give 3-(2-fluorophenyl)propyllithium (2);6
regioselective abstraction of the proton ortho to the fluorine
substituent7 in 2 to generate a dilithio species, and (iii) rapid
(1) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967. (b) Wakefield, B. J . The Chemistry of Organolithium
Compounds; Pergamon: New York, 1974.
(2) (a) Bunnett, J . F.; Hrutfiord, B. F. J . Am. Chem. Soc. 1961, 83, 1691.
(b) Bunnett, J . F.; Kato, T.; Flynn, R. R.; Skorcz, J . A. J . Org. Chem. 1963,
28, 1.
(3) (a) Huisgen, R.; Ko¨nig, H.; Lepley, A. R. Chem. Ber. 1960, 93, 1496.
(b) Huisgen, R.; Sauer, J . Angew. Chem. 1960, 72, 91.
(4) (a) Kessar, S. V. Acc. Chem. Res. 1978, 11, 283, and references therein.
(b) Clark, R. D.; Caroon, J . M. J . Org. Chem. 1982, 47, 2804. (c) Pansegrau,
P. D.; Rieker, W. F.; Meyers, A. I. J . Am. Chem. Soc. 1988, 110, 7178. (d)
Biehl, E. D.; Khanapure, S. P. Acc. Chem. Res. 1989, 22, 275. (e) Iwao, M.
J . Org. Chem. 1990, 55, 3622. (f) Sielecki, T. M.; Meyers, A. I. J . Org. Chem.
1992, 57, 3673. (g) Stanetty, P.; Krumpak, B. J . Org. Chem. 1996, 61, 5130.
(5) (a) Bailey, W. F.; Ovaska, T. V.; Leipert, T. K. Tetrahedron Lett. 1989,
30, 3901. (b) Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990, 31, 627.
(c) Wu, G.; Cederbaum, F. E.; Negishi, E. Tetrahedron Lett. 1990, 31, 493.
(d) Bailey, W. F.; Ovaska, T. V. Chem. Lett. 1993, 819. (e) Bailey, W. F.;
Ovaska, T. V. J . Am. Chem. Soc. 1993, 115, 3080. (f) Bailey, W. F.; Wachter-
J urcsak, N. M.; Pineau, M. R.; Ovaska, T. V.; Warren, R. R.; Lewis, C. E.
J . Org. Chem. 1996, 61, 8216.
Although fluorobenzene may be regioselectively lithiated
at the ortho position by treatment with an alkyllithium,7
the fact that 2 is itself an alkyllithium presents an obvious
dilemma; the molecule is capable of acting as the base for
the ortho-lithiation. As illustrated below, such self-lithiation
by intermolecular proton transfer between two molecules of
2, which occurs when a solution of 2 is warmed, potentially
halves the yield of the benzyne intermediate. Fortunately,
this difficulty may be circumvented by judicious choice of
(6) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404.
(7) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 1. (b)
Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Wittig, G.; Pieper, G.; Fuhrmann,
G. Chem. Ber. 1940, 73, 1193. (d) Gilman, H.; Soddy, T. S. J . Org. Chem.
1957, 22, 1715.
(8) It might be noted that the second equivalent of t-BuLi used for the
exchange is not available for ortho-lithiation of 2 since it is rapidly consumed
by reaction with the cogenerated t-BuI to give isobutane, isobutylene, and
lithium iodide.6
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