Clean synthesis of (S)-(-)-5,7-disubstitute–2-(4-chlorophenyl-3-methylbutanimine)-2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives in water

1 INTRODUCTION
2H-1, 2, 4-thiadiazolo [2, 3-a] pyrimidine derivatives are a novel group of synthetic herbicidal agents ^[1-3], which are active against the weeds of Digitaria sanguinalis (L) Scop, and Chenopodium. In general, these compounds behave in a manner similar to that of sulfonylurea herbicides, inhibiting the synthesis of acetolactate, which has become a very attractive target for herbicides ^[4-7]. Moreover, because of 2H-1, 2, 4-thiadiazolo [2, 3-a] pyrimidine derivatives containing an inherently weak N-S bond which benefits plant’s absorption and metabolism, it’s selective activities are superior to the sulfonylurea ^[8]. (S)-(-)-2-(4-chlorophenyl)-3-methylbutyric acid compounds have also attracted the attention of many investigators due to insecticidal, antibacterial, pesticidal activities and promoting effect on plant growth ^[9-11].In recent years, organic reactions in water have been the object of growing efforts since water is cheap, safe and a clean solvent ^[12-13]. In fact, organic solvent removal is of paramount importance to minimize economic cost and environmental impact of chemical processes. A survey of literature shows that many organic reactions have recently been accelerated by PTC and that hydrogen peroxide, which is the most environmentally, and economically attractive oxidant, in place of bromine, is to generate the cyclization in water. In view of these observations, series of new compounds (S)-(-)-5,7-disubstitute-2-(4-chlorophenyl-3-methylbutanimine)-2H-1,2,4-thiadiazolo[2,3-a] pyrimidine derivatives were synthesized using TBAB as solid-liquid phase transfer catalyst under water and hydrogen peroxide as oxidant. All of them are new compounds and their structures have been exactly determined by IR, ¹H NMR and elemental analysis. In this study, we used a modificatory method to prepare higher purity (S)-(-)-5,7- disubstitute-2-(4-chlorophenyl-3-methylbutanimine)-2H-1,2,4-thiadiazolo [2,3-a] pyrimidine derivatives, and under water the intermediate (S)-(-)-N-[3-methyl-2-(4-chlorophenyl)-butyryl]-N′-(2-pyrimidinyl)thioureas undergoes a fast reaction with an added hydrogen peroxide using TBAB as liquid-liquid phase transfer catalyst to give the corresponding (S)-(-)-5,7-disubstitute-2-(4-chlorophenyl-3-methylbutanimi)-2H-1,2,4-thiadiazolo[2,3-a] pyrimidine derivatives in good yield. This modificatory method shortened the reaction time from 5-6 h to 1-2 h and yielded 2H-1, 2, 4-thiadiazolo [2, 3-a] pyrimidine derivatives quantitatively compared with conventional method, In summary, hydrogen peroxide as oxidant and the use of catalytic amounts of PTC, generated products of (S)-(-)-5,7-disubstitute-2-(4-chlorophenyl-3-methylbutanimine)-2H-1,2,4-thiadiazolo[2,3-a] pyrimidine derivatives. The new method is efficient and environmentally friendly since no organic solvent is required through the whole procedure and pure products can be isolated.
   The title compounds were synthesized by the method in Scheme 1.

Table 1 The Substituents of Target Compounds 9a-9i

2 RESULTS AND DISCUSSION
(S)-(-)-2-(4-chlorophenyl)-3-methylbutyric acid was separated from its antipode using (S)-(-)-a–methyl benzyl amine as chiral separation. The intermediate (S)-(-)N-[3-methyl-2-(4-chlorophenyl)butyryl]-N'-(2-pyrimidinyl) thioureas (8) were synthesized by the reaction of (S)-(-)2-(4-chlorophenyl)-3-methylbutyl acyl chloride and 4,6-disubstituted-pyrimidine-2-yl-thiourea. Series of compounds (S)-(-) (9) were obtained by oxidizing cyclization of corresponding compounds (S)-(-) (8), using TBAB as PTC catalyst and hydrogen peroxide as oxidant in water.
    4, 6-Disubstituted-2-amino-pyrimidine was partially soluble in water. Using HCl as acid (6 molar equiv.) allowed the 4, 6-disubstitute-2-amino-pyrimidine to sufficiently soluble in water. Potassium thiocyanide was added to the reaction, the mixture stirred at 90 - 100 ℃ for several hours, (7) was obtained after the reaction mixture was left to cool. (8) were synthesized after acyl chloride was added to a solution of the (7) in 10 % NaOH solution and prolonged for 1 ~ 2 h.. In some reports, (9) have been prepared oxidizing cyclization (8), bromine as oxidant in chloroform.. In order to achieve an even more efficient and environmentally friendly process, we planned to develop an advanced procedure enabling the synthesis of 5, 7- disubstitute-2H-1, 2, 4-thiadiazolo [2, 3-a] pyrimidine by oxidizing cyclization without bromine, possibly without use of any organic solvent throughout the whole process .Oxidizing cyclization of (8) in water at 0 - 2 ℃ with H₂O₂ (1.5 - 2.0 molar equiv.) and the mixture continued to stirred at ambient for 1 ~ 2 h to ensure complete conversion to (9) , as the result of this, 40 ~ 60 % only of Oxidizing cyclization (9) was obtain. By using of PTC catalyst to the procedure; the yield of (9) was further improved. The best result of the process as obtained by using 1.5 % TBAF (Tetrabutyl ammonium fluoride) only, to generate 90 - 95 % overall yield of (9). Although good yield of Oxidizing cyclization was obtained, TBAF is a quite expensive compound. In order to develop a practical and economical procedure, using of TBAB in place of TBAF, 75 - 80 % of (9) was isolated. In summary, oxidant of hydrogen peroxide in place of bromine and the use of catalytic amounts of TBAB, generated products of 5,7- disubstituted-acyl-2H-1, 2, 4-thiadiazolo[2,3-a]pyrimidine. The new method is atomically efficient and environmentally friendly since no organic solvent is required through the whole procedure and pure products can be isolated.
    All the structures of the newly synthesized compounds (9) were elucidated and confirmed by elemental analyses (Table 2), ¹H NMR (Table 3) and optical rotatios data (Table 4). The IR (KBr) spectrum displayed absorptions at about 1690 cm^-1, 1600 cm^-1 and 1370 cm^-1, which are assigned for C=O, C=N and CH(CH₃)₂ functions respectively. The ¹H NMR (DMSO-d₆) spectrum revealed signals at about δ 0.80 (d, 3H, CH(CH₃)₂), d 1.00 (d, 3H, CH(CH₃)₂), d 2.10 - 2.30 (m, 1H, CH(CH₃)₂), δ 3.80 ~ 4.00 (m, 1H, CHCH(CH₃)₂), d 7.20 - 7.40 (m, 4H, Ph-H) and about d 6.50 (s, 1H, Py-H). The optical rotatios dates showed these compounds is (S)-(-). Based on the foregoing spectral data, the target compounds were assigned the structure (9).

Table 2. Physical Constants of Compounds 9a-9i

Table 3. ¹H NMR data of Compounds 9a-9i ^*

Table 4 Optical rotatios data of Compounds 9a-9i

3 EXPERIMENTAL SECTION
All starting materials are commercial products of chemical or analytic grade purity. Sulfuric chloride was distillated before use and potassium thiocyanate was baked before use. 4,6-disubstitute-2-amino-pyrimidine (6) was prepared by the literature method. 8a~8i were obtained by the literature method. The melting points were determined on an XT4A micro digital melting point apparatus and are uncorrected. The isolated compounds (9) were characterized by elemental microanalyses. The C, H and N analyses were repeated twice. The result of elemental analyses is listed in Table 2. IR spectra were obtained on a Nicolet5DX FT-IR spectrophotometer in the region 4000-400cm^-1 KBr discs. ¹H NMR spectra were recorded on a Bruker Av 400 MHz spectrometer with CDCl₃ or d₆-DMSO as the solvent. Chemical shift values are reported in ppm (d) relative to TMS as internal standard. Optical rotatios were measured on a Perin –Elmer 241 Polarimeter in a dm cell, and concentrations are given in g/100 ml. Thin layer chromatography (TLC) analyses were carried out on 5×20 cm plates coated with silica gel GF₂₅₄ type 60 (50-250 mesh) using a ethyl acetate-petroleum ether mixture (1:2) as solvent.
3.1 Preparation and separation of the diastereomer N- (1-phenylethyl)-2-(4-chlorophenyl) -3-methylbutyramide(3)
To a solution of (±) 2-(4-chlorophenyl)-3-methylbutric acid (42.5 g, 0.2 mol) in THF(300 ml)was added dropwise triethylamine (21.3 g, 0.21 mol) and ClCO₂Et (22.8 g, 0.21 mol) at 0 ℃ over a period of 20 min. Then (S)-(-)-a-methylbenzylamine (25.4 g, 0.21 mol) was added and the reaction was stirred for 3 h at 0 ℃. After filtration, concentration and recrystallization from MeOH/H₂O (1:1), 23.3 g (33 %) of 3a were obtained 3b was obtained from the filtrate of the crystallization of 3a, thus the filtrate was evaporated to dryness and the residue recrystallized from toluene/heptane (3:1) to afford 20.5 g (29.3 %).
3.2 Preparation of (-)-2-(4-chlorophenyl)-3-methylbutric acid (4)
The hydrolysis of 3a (21.25 g, 0.1 mol)with 450 ml of HCl (6 mol?dm^-3) under reflux for 17 h led to 8.3 g (75 %) of pure 4 ([a]²⁵_D = -57.2, CHCl₃, c=1.37, e.e.99 %) after recrystallization from petroleum ether.
3.3 Preparation of (S)-(-)-2-(4-chlorophenyl)-3-methylbutyl acyl chloride (5)
To thionyl chloride (6 ml, 0.04 mol) in dry toluene was added 4 (2.11 g, 0.01 mol) and the resulting solution was refluxed for 2 h. Excessive thionyl chloride was removed under reduced pressure; the left liquid must not be purified and can be used for the further reaction.
3.4 General procedures for the preparation of the target compounds 9a-9i were as follows
4,6-disubstituted-2-amino-pyrimidine (0.01 mol) was dissolved in 10 ml HCl (6 mol/l), potassium sulfocyanide (0.01 mol, 0.97 g) was added and the mixture was stirred at 90 ~ 100 ℃ for 6 h, then the reaction mixture was left to cool. The solid precipitation (7) was collected. Through the dropping funnel, (S)-(-)2-(4-chlorophenyl)-3-methylbutyl acyl chloride (5) was added to a solution of the (7) in 10 % NaOH. The mixture was allowed to 40 ~ 50 ℃ and stirred at this temperature until the reaction finished (controlled by TLC). The solution was then cooled in an ice-bath. The precipitate (8), which formed by cooling was collected. A mixture of compounds (8) and equimolar H₂O₂ in water was stirred at 0 ~ 2 ℃ using of TBAB catalyst to the mixture and the mixture continued to stirred at ambient for 1 h to ensure complete conversion to generate (9), recrystallized from DMF-EtOH-H₂O to yield compound (9). Yield, m.p., elemental analysis, ¹H NMR and Optical rotatios date of the compounds 9 are given in Table 2, 3 and 4.

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水相中绿色合成（S）-（-）-5，7-二取代-2-（4-氯苯-3-甲基丁酰胺）-2H-1，2，4-噻二唑[2，3-α]－嘧啶衍生物
张斯勇  赵卿飞
（上海师范大学化学系，上海市，200234，中国）
摘要 以（S）－（－）－α－甲基苯甲胺为手性拆分剂，分离出纯光学活性（S）－（－）－2－（4－氯苯）－3－甲基丁酸，然后在水溶液中，以双氧水为氧化剂，四丁基溴化胺做为相转移催化剂，合成了一系列的新的（S）－（－）－5，7－二取代－2－（4－氯苯－3－甲基丁酰胺）－2H－1，2，4－噻二唑[2,3－α]嘧啶衍生物，通过红外，氢核磁，元素分析确定化合物结构。此方法与传统的方法比较具有反应时间短，产率高，环境友好等特点。
关键词 绿色合成，四丁基溴化胺，嘧啶衍生物