3172
N. Arai et al.
LETTER
Then, K2CO3 (138.2 mg, 1 mmol), which was dried under vacuum
at 140 °C for 2 h, Pd(OAc)2 (5.6 mg, 0.025 mmol), and PPh3 (13.1
mg, 0.05 mmol) were added to the mixture and stirring at 140 °C
was continued for 27 h. After the reaction is complete, isolation and
purification procedures were carried out in a similar manner to the
above-mentioned palladium-catalyzed reactions.
pared by the reaction of imidazole with sodium hydride in
situ, with 2-iodobenzyl bromide followed by the addition
of the palladium catalyst and potassium carbonate afford-
ed 2a in 55% yield after stirring for 48 hours at 140 °C.
The reaction with 2-bromobenzyl bromide also afforded
2a although the yield was slightly lower (44%). In addi-
tion, the reaction with pyrrole to form 2b proceeded in
48% yield in a similar one-pot protocol (Scheme 2).
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research (No. 16550092) by Japan Society for the Promotion of
Science.
In summary, palladium-catalyzed CH arylation of imida-
zole derivative was performed in the intramolecular ver-
sion, which was a facile preparation protocol for the fused
heteroaromatic compounds. The reaction was found to
proceed under mild conditions compared with the corre-
sponding intermolecular CH arylation. The method would
be applicable for several other ring systems and heteroat-
om species.
References and Notes
(1) Comprehensive Heterocyclic Chemistry, Vol. 1–8;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996.
(2) (a) Delest, B.; Tisserand, J.-Y.; Robert, J. M.; Nourrisson,
M.-R.; Pinson, P.; Duflos, M.; Baut, G. L.; Renard, P.;
Pfeiffer, B. Tetrahedron 2004, 60, 6079. (b) Kuroda, T.;
Suzuki, F. Tetrahedron Lett. 1991, 32, 6915.
1-(2-Iodobenzyl)-1H-imidazole (1a)
To a 25-mL two-necked flask equipped with a magnetic stirring bar
were added NaH (48.0 mg, 2 mmol) and 3 mL of THF under an ar-
gon atmosphere. Imidazole (68.1 mg, 1 mmol) was then added. Af-
ter the evolution of hydrogen stopped, 2-iodobenzyl bromide (296.9
mg, 1 mmol) was added and stirring was continued at r.t. for 1 h.
The mixture was poured into a mixture of 20 mL of H2O and 20 mL
of Et2O and the two phases were separated. The aqueous layer was
extracted with Et2O twice and the combined organic layer was dried
over anhyd Na2SO4. Concentration of the solvent under reduced
pressure left a crude oil, which was purified by column chromatog-
raphy on silica gel using hexane–EtOAc = 1:1 as an eluent to afford
(3) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317.
(4) See also: (a) Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka,
T. Angew. Chem. Int. Ed. 2005, 44, 5103. (b) Campeau, L.-
C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186. (c) Parisien, M.; Valette, D.; Fagnou, K. J.
Org. Chem. 2005, 70, 7578. (d) Campo, M. A.; Huang, Q.;
Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003,
125, 11506. (e) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J.
Org. Chem. 1997, 62, 2. (f) Lablanc, M.; Fagnou, K. Org.
Lett. 2005, 7, 2849. (g) Lafrance, M.; Blaquière, N.;
Fagnou, K. Chem. Commun. 2004, 2874. (h) Bressy, C.;
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127,
13148.
(5) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
(b) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,
211.
(6) (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie,
M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem.
Soc. 2003, 125, 1700. (b) Masui, K.; Mori, A.; Takamura,
K.; Okano, K.; Kinoshita, M.; Ikeda, T. Org. Lett. 2004, 6,
2011. (c) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui,
K.; Mori, A. Org. Lett. 2005, 7, 5083.
(7) (a) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159. (b) David, E.;
Perrin, J.; Pellet-Rostaing, S.; Chabert, J. F.; Lemaire, M. J.
Org. Chem. 2005, 70, 3569. (c) Glover, B.; Harvey, K. A.;
Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003,
5, 301. (d) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003,
125, 5274. (e) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003,
125, 10580. (f) Sezen, B.; Sames, D. Org. Lett. 2003, 5,
3607. (g) Rieth, R. D.; Mankad, N. P.; Calimano, E.;
Sadighi, J. P. Org. Lett. 2004, 6, 3981. (h) Okazawa, T.;
Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002,
124, 5286. (i) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura,
M.; Nomura, M. Tetrahedron 2003, 59, 5685. (j) Kalyani,
D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (k) For a review: Zificsak, C. A.;
Hlasta, D. J. Tetrahedron 2004, 60, 8991.
1
236.7 mg of 1a as a colorless oil (88%). H NMR (300 MHz,
CDCl3): d = 5.10 (2 H, s), 6.81 (1 H, d, J = 7.5 Hz), 6.88 (1 H, s),
6.97 (1 H, dd, J = 7.8, 7.8 Hz), 7.06 (1 H, s), 7.26 (1 H, dd, J = 7.5
Hz), 7.54 (1 H, s), 7.82 (1 H, d, J = 7.8 Hz). 13C NMR (75 MHz,
CDCl3): d = 55.6, 98.3, 119.6, 128.8, 129.1, 129.9, 130.2, 137.9,
138.8, 140.0. IR (KBr): 3109, 1508, 1238, 1074, 1014, 868, 748,
735, 663 cm–1. HRMS: m/z calcd for 283.9810; found: 283.9826.
5H-Imidazo[5,1-a]isoindole (2a)
To a 25-mL Schlenk tube equipped with a magnetic stirring bar was
added K2CO3 (138.2 mg, 1 mmol). The Schlenk tube was heated at
140 °C for 2 h under vacuum and the atmosphere was replaced with
argon. Then, 1a (142.1 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol), PPh3(13.1 mg, 0.05 mmol), and 3 mL of DMSO were added
and the resulting mixture was heated at 100 °C for 22 h. After cool-
ing to r.t. the mixture was diluted with 20 mL of EtOAc and passed
through a Celite® pad. The cake was washed with 10 mL of EtOAc.
To the filtrate was added 20 mL of H2O. The mixture was vigorous-
ly shaken and the two phases were separated. The organic layer was
washed twice with H2O and dried over anhyd Na2SO4. Removal of
the solvent under reduced pressure left a crude solid, which was pu-
rified by chromatography on silica gel using hexane–EtOAc = 1:3
as eluent to afford 61.1 mg of 2a. 1H NMR (300 MHz, CDCl3): d =
5.00 (2 H, s), 7.18 (1 H, s), 7.24 (1 H, dd, J = 7.5, 7.5 Hz), 7.37 (1
H, dd, J = 8.1, 8.1 Hz), 7.39 (1 H, d, J = 7.5 Hz), 7.55 (1 H, d,
J = 7.2 Hz), 7.72 (1 H, s,). 13C NMR (CDCl3): d = 48.8, 118.6,
120.3, 123.9, 126.6, 128.6, 130.7, 132.5, 138.9, 140.6. IR (KBr):
3103, 1618, 1485, 1454, 1437, 1084, 929, 758, 652 cm–1. HRMS:
m/z calcd for 156.0687; found: 156.0676.
One-Pot Synthesis of 2a with 1a and Imidazole Sodium Salt
To a 25-mL Schlenk tube equipped with a magnetic stirring bar
were added NaH (12.0 mg, 0.5 mmol), imidazole (34.0 mg, 0.5
mmol) and 3 mL of DMSO. The mixture was stirred for 2 h at r.t. to
form the sodium salt. Then, 2-iodobenzyl bromide (148.5 mg, 0.5
mmol) was added and stirring was continued for further 3 h at r.t.
(8) (a) Allin, S. M.; Bowman, W. R.; Elsegood, M. R. J.;
McKee, V.; Karim, R.; Rahman, S. S. Tetrahedron 2005, 61,
2689. (b) Byun, Y. S.; Jung, C. H.; Park, Y. T. J. Heterocycl.
Chem. 1995, 32, 1835.
(9) The ratio of 3 and 4 was consistent with the Miura’s results
(see ref. 5a).
Synlett 2006, No. 18, 3170–3172 © Thieme Stuttgart · New York