Direct Access to Variously Substituted 2-Imino-4-thiazolines

Abstract

1,2-Diaza-1,3-dienes readily react as Michael acceptors with thiocyanic acid generated in situ from potassium thiocyanate. The acidic medium of the reaction promotes the intramolecular ring closure of the α-thiocyanato hydrazones allowing access to novel 2-imino-4-thiazolines functionalized at positions 3, 4, and 5 in a one-pot, high-yielding process.

1,2-diaza-1,3-dienes - thiocyanation - Michael addition - ring closure - 2-imino-4-thiazoline - heterocycles

References and Notes

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<A NAME="RD08010ST-13">13</A>

Typical One-Pot Procedure for the Preparation of 2-Imino-4-thiazoline Derivatives 4a-k
The requisite 1,2-diaza-1,3-butadiene 1a-k (1 mmol), prepared and used as an E,E/E,Z isomer mixture,^¹c was added to a solution of KSCN (106.7 mg, 1.1 mmol) in glacial AcOH (2 mL) under magnetic stirring. The consumption of 1a-k was rapid and TLC analysis indicated the presence one major product. The reaction mixture was allowed to stand at r.t. overnight to allow complete conversion of the Michael adduct into the corresponding 2-imino-4-thiazoline derivative. AcOH was removed in vacuo, the residue was dissolved in H₂O, and the solution neutralized with sat. Na₂CO₃. Compounds 4a-c,e,g-i were obtained by extraction of the aqueous phase with Et₂O. The dried organic layers were filtered and evaporated, and the crude compounds were isolated as powders or foams and purified by recrystallization or by flash chromatography on silica. Compounds 4d,f,j,k, precipitated from the aqueous medium after addition of sat. Na₂CO₃ and were isolated by filtration and recrystallized from an appropriate solvent mixture

<A NAME="RD08010ST-14">14</A>

Data for tert -Butyl-2-[3-(dimethylamino)-1-methyl-3-oxo-2-thiocyanatopropylidene]hydrazinecarboxylate (3j)
White powder from EtOAc-cyclohexane; mp 139-140 ˚C (dec.). IR (KBr): 3467, 3331, 2153, 1746, 1650, 1503 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.45 (s, 9 H, Ot-Bu), 1.86 (s, 3 H, CH₃), 2.86 and 2.97 [2 s, 6 H, N(CH₃)₂], 5.79 (s, 1 H, CH), 10.00 (s, 1 H, NH). ^¹³C NMR (100 MHz DMSO-d ₆): δ = 12.3 (q), 28.0 (q), 35.9 (q), 37.1 (q), 61.0 (d), 79.8 (s), 112.4 (s), 144.9 (s), 152.6 (s), 164.7 (s). ESI-MS: m/z calcd for C₁₂H₂₀N₄O₃S: 300.4; found: 301 [M + 1].

<A NAME="RD08010ST-15">15</A>

Data for tert -Butyl {5-[(Dimethylamino)carbonyl]-2-imino-4-methyl-1,3-thiazol-3 (2 H )-yl}carbamate (4j)
White powder from EtOAc-cyclohexane; mp 159-160 ˚C (dec.). IR (KBr): 3318, 3255, 3203, 1736, 1631, 1606 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.38 and 1.43 (2 s, 9 H, Ot-Bu), 1.89 (s, 3 H, CH₃), 2.93 [s, 6 H, N(CH₃)₂], 8.18 (br s, 1 H, NH), 9.64 (br s, 1 H, NH). ^¹³C NMR (100 MHz DMSO-d ₆): δ = 12.7 (q), 27.6 and 27.8 (2 q), 36.6 (q), 40.1 (q), 80.5 (s), 98.5 (s), 136.9 (s), 154.6 (s), 157.9 (s), 162.8 (s). ESI-MS: m/z calcd for C₁₂H₂₀N₄O₃S: 300.4; found: 301 [M + 1].