A Versatile One-Pot Procedure for the Synthesis of 5-Aryl-6H-1,3,4-thiadiazine-2-amines from Aromatic Ketones

Abstract

6H-1,3,4-Thiadiazines are a promising class of non-aromatic heterocycles for the agricultural and pharmaceutical industry. Although known for a long time, they have not received widespread attention, in part due to their cumbersome synthesis. The novel route described herein for the direct transformation of aromatic alkyl ketones into 5-aryl-6H-1,3,4-thiadiazine-2-amines provides moderate to excellent yields while employing readily available reagents under mild reaction conditions.

Key words

cyclization - heterocycles - carbazones - chemoselectivity - one-pot procedure

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• 16 General Procedure for the Preparation of 5-Aryl-6H-1,3,4-thiadiazine-2-amines – Exemplified for Table 1, Entry 5 To a solution of TsOH·H₂O (5 mmol) and NBS (0.5 mmol) in MeCN (25 mL) was added 4-methoxyacetophenone (0.5 mmol), and the mixture was heated to reflux. After 2 h, the solution was cooled to 0 °C, 4 Å MS; 5 min later TSC (0.55 mmol) was added, and the resulting suspension was stirred for 1 h. KOH (4.5 mmol) was added, and the suspension was heated to reflux once again. After 30 min, the mixture was allowed to cool to room temperature. The reaction mixture was filtered, and the solid residue was washed with MeOH. The solvents were evaporated in vacuo, and the residue was purified by flash chromatography on silica (CH₂Cl₂–MeOH–NH₃, 10:1:0.1% v/v) to yield 5-(4-methoxyphenyl)-6H-1,3,4-thiadiazine-2-amine as a brown, crystalline solid (0.069g, 72% yield). Flash chromatography should be carried out as quickly as possible to minimize product decomposition on silica. 5-(4-Methoxyphenyl)-6H-1,3,4-thiadiazine-2-amine (Table 1, Entry 5) Yield: 0.067 g (61%); brown, crystalline solid. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.86–7.82 [m, 2 H, (CH)₂,_arom], 7.02–6.97 [m, 2 H, (CH)₂,_arom], 6.92 (br s, 1 H, NH), 3.83 (s, 3H , OCH₃), 3.64 (s, 2 H, CH₂S). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.7 [C(=NNR)(CH₂)Ph], 153.2 (COCH₃), 147.6 [C(=NNR)(NH₂)S], 128.1 (C₂,_arom-ortho), 127.4 (C_arom-thiadiazidinyl), 114.1 (C₂,_arom-meta), 55.3 (CH₂).
• 17 When the synthesis of 5-phenyl-6H-1,3,4-thiadiazine-2-amine was repeated on a scale of 2.0 g (16.7 mmol), flash chromatography yielded a brown oil rather than a yellow solid. Although LC–MS showed a high degree of purity, the product was further purified as follows: The oil was taken up in a small amount of MeOH, the solution was warmed to reflux, and the same volume of Et₂O was added slowly. Whilst continuing to heat, more Et₂O was added dropwise until precipitation occurred. The yellow crystals were filtered off, the volume of the residual oil was reduced in vacuo, and the crystallization procedure was repeated twice more to yield 5-phenyl-6H-1,3,4-thiadiazine-2-amine as a yellow-brown, crystalline solid (1.56 g, 49% yield).