Synthesis of 3-Halo-7-azaindoles through a 5-endo-dig Electrophilic Cyclization Reaction

Abstract

Biologically useful 7-azaindoles were synthesized by electrophilic cyclization of 3-alkynyl-N,N-dimethylpyridine-2-amines with molecular iodine. By this simple atom-economical approach under ambient reaction conditions, a library of interesting 3-iodo-7-azaindoles were synthesized in high yields. To synthesize the corresponding 3-bromo- and 3-chloro-7-azaindoles, an environmentally benign copper-mediated cyclization was employed, with inexpensive, nontoxic, and noncorrosive sodium chloride and sodium bromide as the sources of chlorine and bromine, respectively.

Key words

electrophilic cyclization - iodocyclization - bromocyclization - chlorocyclization - azaindoles

• References and Notes

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• 25 Halocyclization Reaction; General Procedures Method A. To a 6-dram vial containing the starting alkyne (0.3 mmol) was added CH₂Cl₂ (4.0 mL). I₂ (2.0 equiv) was then added, and the mixture was stirred at r.t. for 24 h. The reaction mixture was finally purified by column chromatography (silica gel, hexanes–EtOAc). Method B. To a 6-dram vial containing the starting alkyne (0.3 mmol) was added 95% EtOH (4.0 mL). The appropriate sodium halide (5.0 equiv) and CuSO₄·5 H₂O (5.0 equiv) were added, and the mixture was stirred at r.t. for 48 h. The mixture was finally purified by column chromatography (silica gel, hexanes–EtOAc). 3-Iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (20a) Yellow-brown solid; yield: 93 mg (93%); mp 86–89 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.80 (s, 3 H), 7.17 (dd, J = 7.6, 4.4 Hz, 1 H), 7.48–7.54 (m, 5 H), 7.76 (dd, J = 8.0, 1.2 Hz, 1 H), 8.37 (dd, J = 4.4, 1.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 30.56, 56.49, 116.93, 123.69, 128.55, 128.70, 128.97, 129.16, 129.26, 130.69, 131.16, 142.16, 143.98, 148.73. Other characterization data agreed with the previously reported values (See ref. 26).
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