Novel Synthesis of Functionalized Indolizine Derivatives from Huisgen’s Zwitterions and 1-Methylimidazole/Dichloroketene Adduct

Dedicated to Professor Kazem Saidi, on the occasion of his 65^th birthday

Abstract

The reactive zwitterionic intermediates, generated from addition of pyridine derivatives to dialkyl acetylenedicarboxylates, react with 1-methylimidazole/dichloroketene adduct to afford functionalized dialkyl 1-(2,2-dichloroacetyl)indolizine-2,3-dicarboxylates in moderate yields.

Key words

indolizine - acetylenic ester - dichloroacetyl chloride - 1-methylimidazole - N-heterocycle

• References and Notes

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• 13 General Procedure for Preparation of Compounds 4, 7 and 8: To a stirred mixture of 1-methylimidazole (0.08 g, 1 mmol) and dichloroacetyl chloride (0.15 g, 1 mmol) in THF (2 mL) was added a solution of the N-heterocycle (1 mmol) in THF (2 mL). Then, a solution of dialkyl acetylene-dicarboxylate (1 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred for 12 h. The solvent was removed under reduced pressure and the residue was purified by silica gel (Merck 230–240 mesh) column chromatography using a hexane–EtOAc (5:1) mixture as eluent. Selected Spectroscopic Data Compound 5a: pale yellow crystals; yield: 0.36 g (56%); mp 114–116 °C. IR (KBr): 1715, 1700 (C=O), 1493 (C=C), 1254, 1210 (CO), 754 (CCl) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.93 (s, 3 H, MeO), 4.02 (s, 3 H, MeO), 6.73 (s, 1 H, CH), 7.16 (t, ³ J = 6.9 Hz, 1 H, CH), 7.53 (t, ³ J = 8.7 Hz, 1 H, CH), 8.57 (d, ³ J = 9.1 Hz, 1 H, CH), 9.53 (d, ³ J = 7.1 Hz, 1 H, CH). ¹³C NMR (125 MHz, CDCl₃): δ = 52.3 (MeO), 53.3 (MeO), 68.7 (CH), 106.3 (C), 113.9 (C), 116.8 (CH), 120.9 (CH), 128.3 (CH), 129.0 (C), 129.3 (CH), 139.3 (C), 160.2 (C=O), 166.7 (C=O), 180.1 (C=O). EI–MS: m/z (%) = 343 (10) [M⁺], 312 (5), 280 (10), 260 (100), 230 (14), 202 (7), 172 (5), 143 (20), 130 (7), 115 (14), 89 (8), 78 (9). Anal. Calcd for C₁₄H₁₁Cl₂NO₅ (343): C, 48.86; H, 3.22; N, 4.07. Found: C, 48.6; H, 3.3; N, 4.2. Compound 5b: pale yellow crystals; yield: 0.44 g (62%); mp 102–104 °C. IR (KBr): 1721, 1700 (C=O), 1495, 1430 (C=C), 1221, 1151 (CO), 756 (CCl) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.40 (t, ³ J = 7.2 Hz, 3 H, Me), 1.44 (t, ³ J = 7.2 Hz, 3 H, Me), 4.42 (q, ³ J = 7.2 Hz, 2 H, CH₂), 4.51 (q, ³ J = 7.2 Hz, 2 H, CH₂), 6.73 (s, 1 H, CH), 7.17 (t, ³ J = 6.0 Hz, 1 H, CH), 7.55 (t, ³ J = 7.9 Hz, 1 H, CH), 8.61 (d, ³ J = 9.1 Hz, 1 H, CH), 9.60 (d, ³ J = 7.1 Hz, 1 H, CH). ¹³C NMR (125 MHz, CDCl₃): δ = 13.9 (Me), 14.2 (Me), 61.4 (CH₂), 62.7 (CH₂), 68.4 (CH), 106.3 (C), 114.0 (C), 116.7 (CH), 120.9 (CH), 128.4 (CH), 128.6 (C), 129.2 (CH), 139.3 (C), 159.9 (C=O), 166.2 (C=O), 180.2 (C=O). EI–MS: m/z (%) = 371 (14) [M⁺], 326 (10), 288 (24), 271 (30), 225 (15), 214 (18), 170 (12), 143 (9), 91 (100), 78 (10), 55 (27). Anal. Calcd for C₁₆H₁₅Cl₂NO₅ (371): C, 51.63; H, 4.06; N, 3.76. Found: C, 51.9; H, 4.2; N, 3.9. X-ray Crystal Structure Determination of 5b: Structure determination and refinement data: formula, C₁₆H₁₅Cl₂NO₅; M_r 372.19; triclinic, space group P-1, a = 8.778(2), b = 10.099(1), c = 10.193(1) Å, α = 85.86(1)°, β = 72.21(1)°, γ = 82.35(1)°; Z = 2, V = 852.3(2) ų, D _calc = 1.450 Mg/m³; MoK_α radiation (0.71073 Å); T = 293(2) K. 3586 reflections collected on a Bruker P4 diffractometer, 2964 unique (R _int = 0.0229). All heavy atoms have been located by difference Fourier maps and refined anisotropically. All hydrogen atoms except those of the methylene groups and the aromatic ring, have been placed on calculated positions and refined by using the riding model. The remaining hydrogens have been located by difference Fourier maps. Final indices for 1692 reflections with I >2σ(Ι): R ₁ = 0.0615, wR ₂ = 0.1561, GOF = 1.054. The crystallographic data of 5b have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 874939. Copies of the data can be obtained, free of charge, via the internet (http://www.ccdc.cam.ac.uk/data_request/cif), e-mail ([e-mail]), or fax: [[phone]].
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