The Baylis-Hillman Bromides as Versatile Synthons: A Facile One-Pot Synthesis of Indolizine and Benzofused Indolizine Frameworks

Abstract

A facile one-pot synthesis of indolizine, benzofused indolizines {pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]isoquinoline} derivatives from the Baylis-Hillman (B-H) bromides, via an interesting strategy involving 1,5-cyclization of nitrogen ylides has been described.

Baylis-Hillman bromides - 1,5-cyclization strategy - indolizines - benzofused indolizines - quinoline - isoquinoline

References and Notes

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<A NAME="RD35708ST-11">11</A>

1-Aza-8-cyano-7-phenylbicyclo[4.3.0]nona-2,4,6,8-tetraene (2a) - Representative Procedure
To 2-(bromomethyl)-3-phenylprop-2-enenitrile [¹0] (1 mmol, 0.222 g) pyridine (3 mL) was added and stirred for 15 min (formation of pyridinium salt was observed as shown by TLC) at r.t. The reaction mixture was diluted with DMF (3 mL) and K₂CO₃ (5 mmol, 0.690 g) was added. The reaction mixture was then heated at 80 ˚C for 3 h and was allowed to cool to r.t. Saturated aq NaCl soln (5 mL) was added and extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layer was dried over anhyd Na₂SO₄. Solvent was evaporated, and the residue, thus obtained, was purified by column chromatography (SiO₂, 5% EtOAc in hexanes) to furnish the pure compound 2a as a colorless solid. Yield 52% (0.114 g); mp 128-130 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 6.60-6.70 (m, 1 H), 6.77-6.86 (m, 1 H), 7.32-7.40 (m, 1 H), 7.46-7.53 (m, 2 H), 7.56-7.68 (m, 3 H), 7.74 (s, 1 H), 7.88 (d, 1 H, J = 7.2 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 96.94, 113.60, 116.22, 117.46, 118.16, 118.92, 120.05, 125.31, 127.15, 128.67, 129.00, 129.68, 132.56. IR (KBr): ν = 2222 cm^-¹. LC-MS: m/z = 219 [M + H]⁺. Anal. Calcd for C₁₅H₁₀N₂: C, 82.55; H, 4.62; N, 12.84. Found: C, 82.51; H, 4.65; N, 12.70.

<A NAME="RD35708ST-12">12</A>

Detailed X-ray crystallographic data are available from the CCDC, 12 Union road, Cambridge CB2 1EZ, UK; for compounds 2a (CCDC # 693505), 3a (CCDC # 693506), 4a (CCDC # 693507).

<A NAME="RD35708ST-13">13</A>

1-Aza-12-cyano-11-phenyltricyclo[8.3.0.0 ^²,7 ]trideca-2,4,-6,8,10,12-hexaene (3a) - Representative Procedure
To a stirred solution of 2-(bromomethyl)-3-phenylprop-2-enenitrile (1 mmol, 0.222 g) in DMF (3 mL) was added quinoline (2 mmol, 0.258 g) at r.t. After stirring for 1 h (salt formation was observed as evidenced by TLC), K₂CO₃ (5 mmol, 0.690 g) was added and heated for 5 h at 80 ˚C. The reaction mixture was allowed to cool to r.t. and diluted with sat. aq NaCl soln (5 mL) and extracted with CH₂Cl₂ (5 × 10 mL). The combined organic layers were dried over anhyd Na₂SO₄. Solvent was evaporated, and the residue, thus obtained, was purified by column chromatography (SiO₂, 8% EtOAc in hexanes) to furnish the pure compound 3a as a colorless solid. Yield 45% (0.120 g); mp 160-162 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, 1 H, J = 9.6 Hz), 7.34-7.68 (m, 9 H), 7.85 (d, 1 H, J = 8.4 Hz), 8.26 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 96.68, 114.43, 116.19, 117.35, 118.04, 120.39, 122.03, 124.52, 125.64, 127.50, 128.10, 128.84, 128.92, 129.00, 129.05, 132.28, 132.38.
IR (KBr): ν = 2226 cm^-¹. LC-MS: m/z = 269 [M + H]⁺. Anal. Calcd for C₁₉H₁₂N_2: C, 85.05; H, 4.51; N, 10.44. Found: C, 85.11; H, 4.54; N, 10.57.

<A NAME="RD35708ST-14">14</A>

The single crystal X-ray structure revealed the presence of two molecules in the asymmetric unit. For clarity we have shown one molecule in the ORTEP diagram.