Pd-Catalyzed Cyclization of 1-Allyl-2-indolecarboxamides by Intramolecular Amidation of Unactivated Ethylenic Bond

Abstract

The intramolecular Pd(II)-mediated cyclization of 1-allyl-2-indolecarboxamides leads to pyrazino[1,2-a]indoles through the conversion of the olefinic C-H bond into a C-N bond by ­reaction with an amide group. When operating on the allylamide, a domino process was observed with a double C-H functionalization.

Key words

cyclizations - fused-ring systems - indoles - palladium - domino reactions

References and Notes

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16

Experimental Procedure.
A suspension of 2a (276 mg, 1.0 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), Na₂CO₃ (318 mg, 3.0 mmol), Bu₄NCl (278 mg, 1.0 mmol) and p-benzoquinone (108 mg, 1 mmol) in DMF (10 mL) was stirred for 24 h at 100 °C. The solution was washed with brine (25 mL) and extracted with Et₂O (2 × 25 mL). The organic layer was dried over Na₂SO₄ and taken to dryness under reduced pressure. The residue was chromatographed on a silica gel column with light PE-EtOAc 12:1 as eluent to give 3a.
Data for 3-Methyl-2-phenyl-2 H -pyrazino[1,2- a ]indol-1-one (3a).
Mp 249-250 °C (diisopropyl ether). IR (nujol): 1682 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.95 (3 H, s), 7.24 (1 H, s), 7.29-7.34 (3 H, m), 7.39-7.45 (2 H, m), 7.48-7.56 (3 H, m), 7.68 (1 H, d, J = 8.2 Hz), 7.85 (1 H, d, J = 8.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7 (q), 103.5 (d), 104.1 (d), 110.8 (d), 122.6 (d), 123.0 (s), 123.1 (d), 124.3 (d), 127.4 (s), 128.0 (s), 129.1 (d), 129.4 (d), 129.9 (d), 132.3 (s), 137.9 (s), 158.4 (s). MS: m/z = 274 [M⁺]. Anal. Calcd for C₁₈H₁₄N₂O: C, 78.81; H, 5.14; N, 10.21. Found: C, 78.97; H, 4.99; N, 10.32.

18

3-Methyl-2-(pyridin-2-yl)-3,4-dihydro-2 H -pyrazino[1,2- a ]indol-1-one (8).
Mp 198-199 °C (diisopropyl ether). IR (nujol): 1678 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.46 (3 H, d, J = 6.7 Hz), 4.32 (1 H, d, J = 12.0 Hz), 4.44 (1 H, dd, J = 4.0, 12.0 Hz), 5.43-5.51 (1 H, m), 7.13 (1 H, dd, J = 5.0, 7.0 Hz), 7.18-7.24 (1 H, m), 7.34-7.44 (2 H, m), 7.45 (1 H, s), 7.71-7.80 (2 H, m), 8.17 (1 H, d, J = 8.4 Hz), 8.47 (1 H, d, J = 4.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 19.3 (q), 46.4 (t), 51.5 (d), 107.9 (d), 110.1 (d), 120.1 (d), 120.7 (d), 121.2 (d), 123.2 (d), 125.3 (d), 128.0 (s), 129.2 (s), 137.3 (s), 137.7 (d), 148.1 (d), 152.9 (s), 159.7 (s). MS: m/z = 277 [M⁺]. Anal. Calcd for C₁₇H₁₅N₃O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.51; H, 5.27; N, 15.01.

20

2-Methyl-12,12a-dihydro-1 H -pyrrolo[1′,2′:4,5]pyr-azino[1,2- a ]indol-5-one (10).
Oil. IR (nujol): 1657 cm^-1. ¹H NMR (400 MHz, DMSO): δ = 1.83 (3 H, s), 2.59-2.69 (1 H, m), 2.78 (1 H, dd, J = 9.2, 15.9 Hz), 3.97 (1 H, dd, J = 12.1, 12.2 Hz), 4.52-4.65 (1 H, m), 4.92 (1 H, dd, J = 4.4, 12.1 Hz), 6.80 (1 H, s), 7.08 (1 H, s), 7.12 (1 H, dd, J = 7.7, 8.3 Hz), 7.31 (1 H, dd, J = 7.7, 8.0 Hz), 7.57 (1 H, d, J = 8.3 Hz), 7.67 (1 H, d, J = 8.0 Hz). ¹³C NMR (100 MHz, DMSO): δ = 14.4 (q), 38.8 (t), 45.9 (t), 57.5 (d), 106.6 (d), 109.9 (d), 116.6 (d), 121.1 (d), 122.6 (s), 123.2 (d), 125.0 (d), 128.0 (s), 129.6 (s), 136.8 (s), 169.7 (s). MS: m/z 238 [M⁺]. Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.79; H, 6.01; N, 11.92.