C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Synthesis of Condensed Pyrroloindolesa
In summary, we have developed a highly efficient Pd-catalyzed
cyclization of N-(2-halobenzyl)-substituted pyrroles or phenyl variants
to afford condensed hetero- or carbocycles, respectively, via tandem
activation of benzyl halide and aromatic C-H bond. Further investiga-
tions are in progress to elucidate mechanistic details.
Acknowledgment. This research was supported by the EEWS
program of KAIST and KRF (Grant KRF-2006-312-C00587).
Supporting Information Available: Data and copies of 1H and 13
C
NMR spectra of new compounds. This material is available free of
References
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a Conditions: substrate (0.2 mmol), Pd(OAc)2 (5 mol %), ligand 3 (10
mol %), Et3N (2 equiv) in benzene (0.3 mL) at 100 °C for indicated time.
b Isolated yield. c Pd(OAc)2 (10 mol %) and 3 (20 mol %) at 120 °C.
At present, we argue that since the reaction is facilitated by electron-
withdrawing substituents, the plausible Friedel-Crafts path is not
operative although the measured low KIE values do not clearly endorse
a ruling out of this route.13e This reasoning, and in light of the recent
similar observations by others,16 led us to propose that the ring closure
proceeds via a base-assisted deprotonative metalation pathway with
the dependence on acidity of the C-H bond being cleaved.17
The Pd-catalyzed cyclization protocol was successfully applied to
a broad range of N-(2-chlorobenzyl)pyrroles to furnish pyrroloindoles
(Table 2). The substrates were readily prepared either by N-arylation
of aryl halides with pyrroles or by the Paal-Knorr reaction of anilines
with 2,5-dimethoxytetrahydrofuran.8 In general, the Pd-catalyzed
cyclization reactions proceeded with excellent efficiency irrespective
of substrate types, although sterically congested substrates demanded
higher temperatures with larger catalyst loadings (entries 2 and 4).
A labile chloro group on substrates was well-tolerated under the
conditions giving chloropyrroloindoles in excellent yields which
could be further manipulated by arylation under the subsequent
Suzuki reaction conditions in one-pot (entries 5-6).8 Cyclization
of N-(2-chloromethyl)naphthyl pyrrole and a derivative of 4H-
indole-4-one provided tetracyclic compounds with high efficiency
(entries 7-8). Interestingly, the reaction of substrates bearing
electron-deficient groups on the pyrrole was also highly efficient
to give products which are difficult to obtain using the conventional
Friedel-Crafts approach (entries 9-10).4
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Chang, S. J. Am. Chem. Soc. 2008, 130, 7824. (d) Cho, S. H.; Hwang,
S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(8) See the Supporting Information for details.
(9) Lie´gault, B.; Renaud, J.-L.; Bruneau, C. Chem. Soc. ReV. 2008, 37, 290.
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Century; Wiley: New York, 2004.
(11) In these cases, an acetyl-substituted side product, 2-biphenylmethyl acetate,
was obtained up to 10% in addition to the desired compound.
(12) (a) Jones, W. D. Acc. Chem. Res. 2003, 36, 140. (b) Tunge, J. A.; Foresee,
L. N. Organometallics 2005, 24, 6440. (c) Campeau, L.-C.; Parisien, M.;
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Soc. 2008, 130, 5636.
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J. Am. Chem. Soc. 2007, 129, 7742.
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The cyclization protocol was briefly examined to extend for the
synthesis of 9H-fluorene by employing 2-phenylbenzyl bromide (eq
3).18 The desired condensed carbocycle was obtained albeit with
modest yield under unoptimized conditions.
(18) Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2006, 128, 1434.
JA806897H
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