One-Pot Synthesis of Spiro Pyrroloimidazoles and 2-Arylimidazoles from 1,2-Diaza-1,3-butadienes and Arylamidines

Abstract

1,2-Diaza-1,3-butadienes react as Michael acceptors with nitrogen 1,3-dinucleophiles, such as arylamidines, in a one-pot heterocyclization reaction. Depending on the nature of the acyl ­residue at the terminal carbon of the heterodiene system, spiro ­pyrroloimidazole derivatives or 2-arylimidazoles can be obtained.

Key words

1,2-diaza-1,3-butadienes - arylamidines - nucleophilic additions - cyclizations - spiro compounds

References and Notes

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7

Procedure for the Preparation of Spiro Pyrroloimidazole Derivatives 3a-i 1,2-Diaza-1,3-butadiene 1a-e (2 mmol), prepared and used as a EE/EZ-isomer mixture,^1b and DIPEA (2 mmol) were dissolved in THF (8 mL) under magnetic stirring. Then solid arylamidine 2a,b (1 mmol) was added and the reaction mixture was allowed to stand at r.t. until complete disappearance of 1a-e (0.25-1 h, monitored by silica gel TLC). The reaction mixture was then refluxed for the appropriate time (4-6 h). The solvent was removed under reduced pressure and the diastereomers of 3a-i were obtained by silica gel chromatographic separation (eluent: CH₂Cl₂-EtOAc mixtures).

8

Data for Methyl 7-[(Methoxycarbonyl)amino]-6-[2-(methoxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-2-phenyl-1,3,7-triazaspiro[4.4]nona-1,8-diene-9-carboxylate (3b)
5 R / S ,6 R / S-Isomer
White powder from EtOAc-n-pentane, mp 161-163 °C (dec.). IR (Nujol): 3465, 3303, 3244, 3192, 1735, 1721, 1707, 1673, 1648, 1608, 1543, 1515 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.06 (s, 3 H, CH₃), 2.10 (s, 3 H, CH₃), 3.46 (s, 3 H, OCH₃), 3.60 (s, 3 H, OCH₃), 3.69 (s, 3 H, OCH₃), 6.13 (s, 1 H, NH), 7.53 (t, J = 7.6 Hz, 2 H, Ar), 7.60 (t, J = 7.6 Hz, 1 H, Ar), 7.98 (d, J = 7.6 Hz, 2 H, Ar), 8.27 (s, 1 H, NH), 8.81 (s, 1 H, NH), 11.88 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.58, 16.47, 50.31, 52.34, 81.45, 88.87, 96.90, 126.86, 128.37, 128.78, 131.82, 156.29, 156.95, 158.41, 163.86, 184.58. MS: m/z (%) = 460 [M⁺] (4), 370 (100), 296 (22), 236 (42). Anal. Calcd for C₂₀H₂₄N₆O₇: C, 52.17; H, 5.25; N, 18.25. Found: C, 52.20; H, 5.22; N, 18.27.
5 R / S ,6 S / R -Isomer
Colorless crystals from THF-n-pentane, mp 152-154 °C (dec.). IR (Nujol): 3484, 3435, 3339, 3306, 1744, 1723, 1687, 1620, 1602, 1578, 1511 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.15 (s, 3 H, CH₃), 2.11 (s, 3 H, CH₃), 3.42 (s, 3 H, OCH₃), 3.60 (s, 3 H, OCH₃), 3.68 (s, 3 H, OCH₃), 5.90 (s, 1 H, NH), 7.56 (t, J = 7.6 Hz, 2 H, Ar), 7.62 (t, J = 7.6 Hz, 1 H, Ar), 7.90 (s, 1 H, NH), 8.04 (d, J = 7.6 Hz, 2 H, Ar), 8.64 (s, 1 H, NH), 11.65 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.86, 17.06, 50.31, 52.31, 52.46, 80.22, 85.91, 96.72, 127.37, 128.35, 128.75, 132.18, 156.46, 156.54, 161.88, 163.64, 164.18, 183.08. MS: m/z (%) = 460 [M⁺] (1), 370 (100), 296 (21), 236 (18). Anal. Calcd for C₂₀H₂₄N₆O₇: C, 52.17; H, 5.25; N, 18.25. Found: C, 52.16; H, 5.23; N, 18.26.

10

Data of B": ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.39 (s, 9 H, Ot-Bu), 1.94 (s, 3 H, CH₃), 6.86 (s, 1 H, NH), 7.54 (t, J = 7.6 Hz, 2 H, Ar), 7.61 (t, J = 7.6 Hz, 1 H, Ar), 7.95 (d, J = 7.6 Hz, 2 H, Ar), 9.64 (s, 1 H, NH), 11.41 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 11.99, 27.97, 79.19, 93.64, 127.09, 128.38, 128.76, 132.26, 151.66, 152.66, 160.86, 181.69. MS: m/z (%) = 317 [M⁺ + 1] (0.5), 260 (3), 216 (12), 202 (57), 104 (100).

11

Crystallographic data (excluding structure factors) for compound 3b and 4c have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 637246 and 637245. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

12

Procedure for the Preparation 2-Arylimidazole Derivatives 4a-e To a solution of 1,2-diaza-1,3-butadiene 1f-i (1 mmol) and DIEA (1.2 mmol) in THF (6 mL) solid arylamidine 2a,b (1 mmol) was added under magnetic stirring at r.t. After the disappearance of 1f-i (0.25-0.5 h) the reaction mixture was refluxed (4-6 h). Compound 4a was obtained by direct crystallization from the reaction medium and was filtered off with satisfactory purity whereas compounds 4b-e were obtained after chromatographic purification (elution: CH₂Cl₂-EtOAc mixtures).

13

Data for N , N -Diethyl-5-methyl-2-phenyl-1 H -imidazole-4-carboxamide (4c)
Colorless crystals from Et₂O, mp 187-190 °C. IR (Nujol): 3114, 1595,1566, 1538, 1494 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.14 (br s, 3 H, CH₃), 1.23 (br s, 3 H, CH₃), 2.40 (s, 3 H, CH₃), 3.37 (br s, 2 H, NCH₂), 3.77 (br s, 2 H, NCH₂), 7.34 (t, J = 7.6 Hz, 1 H, Ar), 7.45 (t, J = 7.6 Hz, 2 H, Ar), 7.90 (d, J = 7.6 Hz, 2 H, Ar), 12.59 (s, 1 H, NH). ¹³C NMR (100 MHz DMSO-d ₆): δ = 10.84, 12.97, 14.68, 39.66, 42.45, 124.59, 128.01, 128.70, 130.33, 132.54, 132.76, 142.21, 164.12. MS: m/z (%) = 257 [M⁺] (27), 185 (100), 158 (99). Anal. Calcd for C₁₅H₁₉N₃O: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.99; H, 7.47; N, 16.35.