Reaction of Hexachloroacetone with Activated Acetylenes in the Presence of N-Heterocycles. Synthesis of Trichloromethylated Bridgehead N-Heterocycles

Abstract

Pyridine reacts smoothly with hexachloroacetone (HCA) in the presence of dialkyl acetylenedicarboxylates or dibenzoylacetylene to produce indolizines. Under similar conditions, isoquinoline led to oxazino[2,3-a]isoquinolines and/or pyrrolo[2,1-a]isoquinolines. Dimethyl 3,3-bis(trichloromethyl)-3H,4aH-[1,3]oxazino[2,3-a]quinoline-1,2-dicarboxylate or dimethyl 1-methyl-7-(2,2,2-tri­chloroacetyl)-1H-pyrrolo[1,2-a]imidazole-5,6-dicarboxylate was obtained from the reaction of quinoline or N-methylimidazole with dimethyl acetylenedicarboxylate in the presence of HCA.

three-component reaction - indolizine - bridgehead N-heterocycles - activated acetylenes - hexachloroacetone

References and Notes

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10

Dimethyl 1-(2,2,2-Trichloroacetyl)-2,3-indolizine-dicarboxylate ( 3a): To a stirred solution of DMAD (0.28 g 2 mmol) and HCA (0.52 g, 2 mmol) in CH₂Cl₂ (10 mL) was added pyridine (0.16 g, 2 mmol) at r.t. The reaction mixture was then stirred for 24 h. The solvent was removed under reduced pressure and the viscous residue was purified by preparative TLC on silica gel (Merck 230-400 mesh, hexane-EtOAc) to give 3a. Yield: 0.62 g (82%); colorless crystals; mp 173-176 °C (dec.). IR (KBr): 1730, 1697, 1651 (3 × C=O), 1218 cm^-1. ¹H NMR: δ = 3.93, 4.02 (s, 2 × MeO), 7.14 (t, ³ J = 7 Hz, CH), 7.50 (t, ³ J = 9 Hz, CH), 8.42 (d, ³ J = 9 Hz, CH), 9.67 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 52.3, 53.0 (2 × MeO), 96.3 (CCl₃), 105.0, 114.2 (2 × C), 115.7, 121.9, 127.8, 128.6 (4 × CH), 134.3, 136.1 (2 × C), 160.2, 165.9, 176.0 (3 × C=O). MS: m/z (%) = 378 (M⁺·, 2), 231 (10), 261 (20), 260 (100), 143 (28), 115 (20). Anal. Calcd for C₁₄H₁₀ Cl₃NO₅ (378.6): C, 44.42; H, 2.66; N, 3.70. Found: C, 44.28; H, 2.72; N, 3.74. Similarly, the following compounds were prepared. All compounds gave satisfactory analytical and spectroscopic data. Compound 3b: Yield: 0.65 g (80%); white powder; mp 112-114 °C (dec.). IR (KBr): 1726, 1697, 1647 (3 × C=O), 1209 cm^-1. ¹H NMR: δ = 1.43 (t, ³ J = 7 Hz, CH₃), 1.48 (t, ³ J = 7 Hz, CH₃), 4.44 (q, ³ J = 7 Hz, CH₂O), 4.54 (q, ³ J = 7 Hz, CH₂O), 7.17 (t, ³ J = 7 Hz, CH), 7.54 (t, ³ J = 9 Hz, CH), 8.46 (d, ³ J = 9 Hz, CH), 9.74 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 14.4, 14.5 (2 × CH₃), 61.8, 62.5 (2 × MeO), 96.7 (CCl₃), 105.3, 114.6 (2 × C), 116.0, 122.3, 128.2, 129.0 (4 × CH), 135.0, 136.4 (2 ×C), 160.3, 165.9, 176.1 (3 × C=O). Compound 3c: Yield: 0.62 g (79%); yellow powder; mp 233-235 °C (dec.). IR (KBr): 1730, 1694, 1649 (3 × C=O), 1216 cm^-1. ¹H NMR: δ = 2.55 (s, CH₃), 3.96, 4.06 (s, 2 × MeO), 7.01 (dd, ³ J = 7 Hz, ⁴ J = 1 Hz, CH), 8.24 (s, CH), 9.57 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 22.4 (CH₃), 52.7, 53.4 (2 × MeO), 96.4 (CCl₃), 105.3, 114.1 (2 × C), 118.1, 121.2, 128.3 (3 × CH), 134.7 (C), 136.4, 140.2 (2 × C), 160.6, 166.5, 177.0 (3 × C=O). MS: m/z (%) = 392 (M⁺·, 5), 278 (20), 274 (100), 244 (10), 157 (57), 103 (30), 77 (37), 57 (28), 84 (70), 59 (18). Anal. Calcd for C₁₅H₁₂Cl₃NO₅ (392.6): C, 45.89; H, 3.08; N, 3.57. Found: C, 45.82; H, 3.10; N, 3.61. Compound 3d: Yield: 0.63 g (78%); yellow powder; mp 125-127 °C. IR (KBr): 1730, 1697, 1651 (3 × C=O), 1218 cm^-1. ¹H NMR: δ = 1.38 (t, ³ J = 7 Hz, CH₃), 2.85 (q, ³ J = 7 Hz, CH₂), 3.96, 4.06 (s, 2 × MeO), 7.01 (dd, ³ J = 7 Hz, ⁴ J = 1 Hz, CH), 8.28 (s, CH), 9.58 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 14.3 (CH₂), 29.1 (CH₃), 52.7, 53.4 (2 × MeO), 96.9 (CCl₃), 104.4, 114.1 (2 × C), 117.7, 119.8, 128.4 (3 × CH), 137.2 (C), 137.2, 145.9 (2 × C), 160.6, 166.5, 176.2 (3 × C=O). MS: m/z (%) = 407 (M⁺· + 1, 40), 406 (M⁺·, 20), 348 (38), 289 (85), 288 (100), 171 (62), 117 (62), 115 (62), 84 (70), 59 (58). Anal. Calcd for C₁₆H₁₄Cl₃NO₅ (406.64): C, 47.26; H, 3.47; N, 3.44. Found: C, 47.32; H, 3.43; N, 3.48. Compound 3e: Yield: 0.70 g (75%); dark yellow oil. IR (KBr): 1730, 1697, 1651 (3 × C=O), 1218 cm^-1. ¹H NMR: δ = 7.12 (t, ³ J = 8 Hz, 2 × CH), 7.23-7.36 (m, 5 × CH), 7.44 (d, ³ J = 7 Hz, 2 × CH), 7.45 (d, ³ J = 7 Hz, 2 × CH), 7.51 (t, ³ J = 7 Hz, CH), 8.40 (d, ³ J = 9 Hz, CH), 9.60 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 96.3 (CCl₃), 108.6 (C), 116.3, 121.5 (2 × CH), 126.1 (C), 128.3, 128.6 (4 × CH), 128.7 (CH), 129.1 (2 × CH), 129.2 (CH), 129.5 (2 × CH), 130.6 (C), 132.7, 133.4 (2 × CH), 138.2, 139.6, 140.3 (3 × C), 180.0, 187.9, 192.2 (3 × C=O). Compound 9: Yield 0.79 g (74%); yellow crystals; mp 178-179 °C (dec.). IR (KBr): 1733, 1706 (2 × C=O), 1274, 1225 cm^-1. ¹H NMR: δ = 3.79, 3.93 (s, 2 × CH₃), 5.87 (d, ³ J = 8 Hz, CH), 6.31 (d, ³ J = 8 Hz, CH), 6.70 (s, CH), 7.15 (t, ³ J = 7 Hz, CH), 7.32 (t, ³ J = 7 Hz, CH), 7.38 (d, ³ J = 7 Hz, CH), 7.77 (d, ³ J = 7 Hz, CH). ¹³C NMR: δ = 52.5, 53.5 (2 × MeO), 74.1, 79.9 (2 × CCl₃), 87.7, 104.6 (2 × C), 105.9, 111.3, 123.8 (3 × CH), 125.1 (C), 125.5, 127.6, 128.4 (3 × CH), 129.6 (C), 130.1 (CH), 143.8 (C), 162.7, 164.6 (2 × C=O). MS: m/z (%) = 537 (M⁺· + 1, 5), 536 (M⁺·, 70), 463 (100), 130 (86), 91 (100). Anal. Calcd for C₁₈H₁₃Cl₆NO₅ (536.0): C, 40.33; H, 2.44; N, 2.61. Found: C, 40.39; H, 2.43; N, 2.64. Compound 10a: Yield: 0.18 g (18%); yellow powder; mp 125-128 °C (dec.). IR (KBr): 1733 (sh), 1692, 1243, 1194 cm^-1. ¹H NMR: δ = 3.90, 3.91 (s, 2 × MeO), 7.29 (d, ³ J = 7 Hz, CH), 7.65 (d, ³ J = 7 Hz, CH), 7.67 (d, ³ J = 7 Hz, CH), 7.75 (dd, ³ J = 6 Hz, ³ J = 6 Hz, CH), 9.37 (d, ³ J = 7 Hz, CH), 9.47 (dd, ³ J = 6 Hz, ³ J = 6 Hz, CH). ¹³C NMR: δ = 51.9, 52.3 (2 × MeO), 95.7 (CCl₃), 109.7, 114.7 (2 × C), 116.5, 123.7 (2 × CH), 124.2 (C), 127.1, 127.2 (2 × CH), 127.8 (C), 128.3, 129.6 (2 × CH), 129.8, 134.0 (2 × C), 160.0, 164.1, 184.3 (3 × C=O). Compound 10b: Yield: 0.78 g (75%); orange powder; mp 217-219 °C (dec.). IR (KBr): 1715, 1629 (2 × C=O), 1227 cm^-1. ¹H NMR: δ = 7.11 (t, ³ J = 8 Hz, 2 × CH), 7.14 (t, ³ J = 8 Hz, 2 × CH), 7.22 (d, ³ J = 7 Hz, 3 × CH), 7.30 (d, ³ J = 7 Hz, 2 × CH), 7.34 (t, ³ J = 7 Hz, 2 × CH), 7.61 (m, 2 × CH), 7.76 (d, ³ J = 7 Hz, CH), 8.23 (d, ³ J = 8 Hz, CH), 8.85 (d, ³ J = 8 Hz, CH). ¹³C NMR: δ = 96.5 (CCl₃), 110.1 (C), 116.3, 123.2 (2 × CH), 123.7, 124.1 (2 × C), 124.6, 127.6 (2 × CH), 128.2 (2 × CH), 128.3 (2 × CH), 128.6 (CH), 128.9 (2 × CH), 129.1 (2 × CH), 129.3 (CH), 129.4 (C), 131.7, 131.9 (2 × C), 132.5, 132.8 (2 × CH), 139.5, 140.3 (2 × C), 186.6, 187.8, 191.9 (3 × C=O). MS: m/z (%) = 520 (M⁺·, 2), 279 (10), 149 (48), 105 (100), 77 (72), 58 (40). Anal. Calcd for C₂₈H₁₆Cl₃NO₃ (520.79): C, 64.58; H, 3.10; N, 2.69. Found: C, 64.63; H, 3.08; N, 2.72. Compound 13: Yield: 0.80 g (75%); yellow powder; mp 159-161 °C (dec.). IR (KBr): 1733, 1706 (2 × C=O), 1274, 1225 cm^-1. ¹H NMR: δ = 3.80, 3.89 (s, 2 × CH₃), 6.02 (d, ³ J = 4 Hz, CH), 6.15 (dd, ³ J = 10 Hz, ³ J = 4 Hz, CH), 6.70 (d, ³ J = 8 Hz, CH), 6.70 (d, ³ J = 10 Hz, CH), 7.06 (t, ³ J = 5 Hz, CH), 7.19 (t, ³ J = 8 Hz, CH), 7.38 (d, ³ J = 8, CH). ¹³C NMR: δ = 52.7, 53.4 (2 × MeO), 74.3, 81.8 (2 × CCl₃), 88.5 (C), 114.4 (CH), 116.3 (C), 117.2 (CH), 120.1 (C), 121.2, 123.2, 128.8, 129.3, 129.7 (5 × CH), 134.4, 149.4 (2 × C), 163.6, 164.2 (2 × C=O). Compound 14: Yield: 0.30 g (40%); yellow oil. IR (KBr): 1736 (sh), 1716, 1706 (sh, 3 × C=O), 1570, 1224 cm^-1. ¹H NMR: δ = 3.88, 3.89, 3.90 (s, 3 × CH₃), 6.88 (d, ³ J = 2 Hz, CH), 7.73 (d, ³ J = 2 Hz, CH). ¹³C NMR: δ = 36.4 (NCH₃), 52.0, 52.7 (2 × MeO), 93.2 (CCl₃), 108.7 (CH), 109.7, 122.7 (2 × C), 124.8 (CH), 126.1 (C), 140.6 (C), 160.4, 164.9, 178.9 (3 × C=O).

11a Skatteböl L. Jones ERH. Whiting MC. Org. Synth., Coll. Vol. 4   Wiley; New York: 1963.  p.792 

11b Bowden K. Heilborn IM. Jones ERH. Weedon BCL. J. Chem. Soc.  1946,  39 

12a HCA was introduced as a source of positive chlorine, see: Laskovics FM. Schulman EM. Tetrahedron Lett.  1977,  18:  759 

HCA was introduced as a source of dichlorocarbene, see:

12b Grant FW. Cassie WB. J. Org. Chem.  1960,  25:  1443 

12c Grant FW. Cassie WB. J. Org. Chem.  1960,  25:  2263 

12d HCA has been used for the preparation of amides, see: Panetta CA. Casanova TG. J. Org. Chem.  1970,  35:  2423 

12e HCA has also been used for the preparation of alkyl trichloroacetates, see: Freedlander RS. Bryson TA. Dunlap RB. Schulman EM. Lewis CA. J. Org. Chem.  1981,  46:  3519