Regio- and Stereoselective One-Pot Synthesis of Unknown Oxazoline-Fused Pyridazines by ‘Michael Addition-Pyridazine Cyclization-Oxazoline Cyclization’ Cascade Reactions of 4-Chloro-1,2-diaza-1,3-butadienes with 3-Dimethylaminopropenoates

Abstract

A one-pot, three-step regio- and stereoselective synthesis of unknown functionalized oxazoline-fused pyridazines is reported. The approach involves base-assisted ‘Michael addition-pyridazine cyclization-oxazoline cyclization’ cascade reactions of 4-chloro-1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates.

1,2-diaza-1,3-butadienes - 3-dimethylaminopropenoates - Michael additions - cyclizations - oxazoline-fused pyr­idazines

References and Notes

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9

General Procedure for the Synthesis of II and 3a-k 4-Chloro-1,2-diaza-1,3-butadiene 1a-g and 3-dimethyl-aminopropenoate 2a-d were synthesized by known procedures and were isolated as an E/Z isomeric mixture^5,7e and Z-isomer,⁸ respectively. To a CHCl₃ solution (5 mL) of 4-chloro-1,2-diaza-1,3-butadiene 1a-g (1 mmol) was added 3-dimethylaminopropenoate 2a-d (2 mmol) and DIPEA (1 mmol) and the reaction mixture was refluxed for the appropriate time (see Table [1] ). In order to obtain the intermediate II the reaction between 1a and 2a was heated to reflux for 5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluent cyclohexane-EtOAc mixtures).

10

Data for Methyl (3a S *,4 R *,7a S* )-5-(Aminocarbonyl)-4-(dimethylamino)-7-methyl-2-phenyl-3a,4,5,7a-tetra-hydropyridazino[4,5- d ][1,3]oxazole-3a-carboxylate (3a)
Colorless crystals from cyclohexane-EtOAc, mp 187-191 °C (dec.). IR (mull): ν_max = 3403, 3304, 3252, 3159, 1740, 1703, 1681, 1634, 1591 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.11 [s, 9 H, CH₃ and N(CH₃)₂], 3.73 (s, 3 H, OCH₃), 5.70 (s, 1 H, CH), 5.72 (s, 1 H, CH), 6.61 (br s, 2 H, CONH₂, D₂O exch.), 7.49 (t, 2 H, J = 8.0 Hz, Ar), 7.61 (t, 1 H, J = 8.0 Hz, Ar), 7.85 (d, 2 H, J = 8.0 Hz, Ar). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.70 (q), 42.42 (q), 52.54 (q), 67.20 (d), 71.00 (d), 77.15 (s), 125.45 (s), 128.26 (d), 128.86 (d), 132.76 (d), 142.72 (s), 156.68 (s), 164.05 (s), 168.93 (s). MS: m/z (%) = 359 [M⁺] (13), 316 (16), 257 (49), 211 (29), 168 (42), 149 (56), 125 (53), 111 (100). Anal. Calcd for C₁₇H₂₁N₅O₄: C, 56.82; H, 5.89; N, 19.49. Found: C, 56.97; H, 5.68; N, 19.62.

11

Crystallographic data for compound 3a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 657267. 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 Clerici F. Gelmi ML. Gambini A. J. Org. Chem.  1999,  64:  5764 

13

Data for Methyl (3 R *,4 R *,5 R* )-2-(Aminocarbonyl)-4-(benzoylamino)-5-chloro-3-(dimethylamino)-6-methyl-2,3,4,5-tetrahydro-4-pyridazinecarboxylate (II)
White powder from Et₂O, mp 133-134 °C (dec.). IR (mull): ν_max = 3465, 3342, 3280, 3205, 1735, 1698, 1658, 1581 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.21 (s, 3 H, CH₃), 2.49 [br s, 6 H, N(CH₃)₂], 3.73 (s, 3 H, OCH₃), 4.94 (br s, 1 H, CONH₂, D₂O exch.), 5.25 (s, 1 H, CH), 5.34 (s, 1 H, CH), 6.47 (br s, 1 H, CONH₂), 7.40-7.52 (m, 2 H, Ar), 7.53-7.60 (m, 1 H, Ar), 7.80-7.88 (m, 3 H, Ar and NH, D₂O exch.). ¹³C NMR (100 MHz, CDCl₃): δ = 22.26 (q), 43.96 (q), 49.88 (d), 53.97 (q), 59.88 (s), 69.34 (d), 127.80 (d), 129.22 (d), 132.70 (d), 133.38 (s), 144.61 (s), 157.23 (s), 167.60 (s), 170.58 (s). MS: m/z (%) = 360 [M⁺ - HCl] (65), 317 (100), 257 (10), 214 (14), 196 (23), 187 (30), 111 (69). Anal. Calcd for C₁₇H₂₂N₅O₄Cl: C, 51.58; H, 5.60; N, 17.69. Found: C, 51.72; H, 5.81; N, 17.48.