Regioselective Suzuki Cross-Coupling Reactions at the 2-Position of Di- and Tribrominated Pyrroles

Abstract

The 2,3,4-tribromopyrrole 4 and the 2,3-dibromopyrrole 10 were shown to undergo regioselective Suzuki cross-coupling ­reactions at the 2-position. After optimization best yields in the ­reaction with 4-tert-butylphenyl boronic acid (5a) were 68% and 86%. Other boronic acids 5 were employed in the reaction with pyrrole 4 and gave the monosubstitution products 6 in 33-52% yield. A subsequent cross-coupling at positions C-3 and C-4 could be achieved on 3,4-dibromopyrrole 6a (84% yield).

Key words

catalysis - cross-coupling - heterocycles - palladium - pyrroles - regioselectivity

References

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16

Typical Procedure.
A Schlenk flask was charged with tribromopyrrole 4 (188 mg, 0.5 mmol), boronic acid 5a (107 mg, 0.6 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol) and Cs₂CO₃ (198 mg, 0.6 mmol). The flask was evacuated and flushed with argon (five cycles). Mesitylene (5 mL), EtOH (1 mL) and H₂O (1 mL) were added. The flask was once again purged with argon. The reaction mixture was heated to 150 °C and stirred for 20 h. Then, H₂O (4 mL) was added and the aqueous layer was extracted with toluene (3 × 5 mL). The combined organic layers were washed with H₂O (25 mL) and brine (25 mL) and dried over Na₂SO₄. After filtration and removal of the solvents the crude product was purified by flash chromatograpy (silica, pentane-Et₂O, 3:1) to give pyrrole 6a (142 mg, 0.33 mmol, 66%) as a white solid; mp 162-164 °C. ¹H NMR (360 MHz, CDCl₃): δ = 1.36 (s, 9 H), 1.38 (t, ³ J = 7.2 Hz, 3 H), 4.34 (q, ³ J = 7.2 Hz, 2 H), 7.49 (d, ³ J = 8.4 Hz, 2 H), 7.62 (d, ³ J = 8.4 Hz, 2 H), 9.55 (br s, 1 H) ppm. ¹³C NMR (90.6 MHz, CDCl₃): δ = 14.5, 31.4, 35.0, 61.4, 101.1, 108.0, 120.3, 126.0, 127.3, 127.3, 134.0, 152.5, 160.0 ppm. Anal. Calcd for C₁₇H₁₉Br₂NO₂ (429.15): C, 47.58; H, 4.46; N, 3.26. Found: C, 47.37; H, 4.42; N, 3.09.