Syntheses and reactions of methyl [3-(4-phenyl-thiazol-2-yl)- thioureido] alkanoates and related compounds

Thiazole thioureas 4a-d and 6 bearing an amino acid ester residue were prepared by a one-pot sequential reaction of methyl thiocarbamate 2 with amino acid methyl ester hydrochlorides. Some chemoselective reactions of 4a,b with alkyl halides were studied .


Introduction
Acquired immune compromised deficiency syndrome (AIDS) is caused by HIV (a retrovirus) affecting 33 million people worldwide, mostly affecting women and children in Sub-Sahara Africa. 1 Three million people around the world die of AIDS each year and, so far, more than 25 million people have died of the disease.
Lately, multiple antiretroviral agents have been produced to block replication of the HIV-1 virus by blocking HIV reverse transcriptase 2 or by blocking HIV protease. 3Among the most important anti-retroviral agents recently introduced are the non-nucleoside reverse transcriptase inhibitors (NNRTI), such as nevirapine 4 and delavirdine 5 able to reduce RT inhibition to subnanomolar concentrations.
7][8][9] Uckun et al. 10 described the synthesis of a series of thiazole thioureas with alkyl, aryl, heteroaryl substituents as newly identified NNRTI of HIV, including mutant strains of HIV, and effective in the treatment of multi-drug resistant HIV infection.
We have recently reported a new and efficient synthesis of novel quinazoline thioureas bearing an amino acid ester residue based on domino reaction of N-(2-cyanophenyl)benzimidoyl isothioyanate with amino acid methyl ester hydrochlorides. 11

Results and Discussion
2][13][14] In this paper, we described the development of a new series of thiazole thioureas bearing amino acid esters which can be used as potent NNRTIs.
The required thiazole thioureas 4a-d and 6 were easily prepared starting from 4-phenylthiazol-2-ylamine (1) through methyl thiocarbamate 2 as a key intermediate in one-pot sequential reaction strategy (Scheme 1).First step; 4-phenyl-thiazol-2-ylamine (1) reacts with equimolar amount of carbon disulfide in basic media (KOH) using DMSO as solvent at 80 ºC for 2h.The reaction mixture was then cooled to 0 ºC and dimethyl sulfate was added simultaneously.The in situ generated methyl thiocarbamate 2 was extracted and used without further purification.
Compound 2 is an interesting reactive intermediate for the synthesis of a variety of heterocyclic compounds. 15This reactivity is due to leaving group ability of SMe group when reacting with nucleophiles.Thus, equimolar amount of amino acid ester hydrochloride 3 adds to in situ generated methyl thiocarbamate 2 in the presence of triethylamine in ethyl alcohol to afford methyl [3-(4-phenyl-thiazol-2-yl)-thioureido] alkanoate 4. Similarly, methyl paminobenzoate 5 adds to 2 to afford thiourea 6.
The syntheses of 4a-d and 6 reported herein have the advantage of one-pot synthesis in addition to operational simplicity and availability giving a series of very interesting compounds.

Scheme 1
The structure assignments of amino acid esters 4a-d and 6 are based on spectral and physicochemical analysis.All isolated products exhibited a rather interesting conformation as indicated from all 1 H NMR spectra, figure 2. Thus, the 1 H NMR spectrum of 4b showed three signals; a quartet, a triplet and a singlet at δ 4.12, 2.83 and 3.69 ppm consequent to two CH 2 groups of the β-alanine residue and OCH 3 group, respectively.
In addition the 1 H NMR spectrum of 4b gave two exchangeable singlets at δ 11.29 and 10.57ppm corresponding to two NH groups.This implies that N3-H group participate in a strong intramolecular hydrogen bond interaction with the thiazole nitrogen of the type N3-H•••N=C. 10,11,16][23] The intermolecular hydrogen bond could be distinguished by comparison of the 1 H NMR spectra with similar compound lacking the ester function group.1-Benzyl-3-(4-phenyl-thiazol-2yl)-thiourea 7 was similarly prepared by the reaction of benzyl amine with insitu generated methyl thiocarbamate 2, scheme 1.The   [24][25][26] induced by hydrogen bond interactions.Earlier we reported the chemoselective S-alkylation reaction in similar compounds afforded only a single compound preserving the intramolecular hydrogen bond. 11he 1 H NMR spectrum clearly deduced the alkylation site and the position of double bond.The 1 H NMR spectrum of 10b has shown a broad singlet at δ 10.68 attributed to N1H group partipating in an intermolecular hydrogen bond of the type N1-H•••O=C, [21][22][23]

General procedure for preparation of 4, 6 and 7
To a vigorously stirred solution of 4-phenyl-thiazol-2-ylamine (1) (0.9 g, 5.0 mmol) in dimethylsulfoxide (10 ml) at room temperature, carbon disulfide (0.4 ml, 6.5 mmol) and potassium hydroxide (0.31 g, 5.5 mmol) solution in 2 mL H 2 O were added dropwise simultaneously over 30 min, the mixture was then allowed to stir for 30 min in water bath at 80 ºC.The reaction mixture was cooled in an ice bath to 0 ºC and dimethyl sulfate (0.5 mL, 5.0 mmol) was added dropwise for 15 min under cooling.Stirring was continued for 3 h, the reaction mixture was poured into ice-water and then it was extracted with chloroform.The solvent was removed by distillation under reduced pressure.Thus, the obtained crude methyl thiocarbamate 2 dissolved in ethanol 30 mL cooled to 10 ºC and was treated with nucleophiles [amino acid methyl ester hydrochloride 3 (5.0mmol) and triethyl amine (0.7 mL, 5.0 mmol); methyl paminobenzoate 5 (0.75 g, 5.0 mmol) or benzyl amine (0.55 mL, 5.

figure 2 . 11 allyl
Scheme 2 1H NMR spectrum of 7 shows chemical shift at 11.49 ppm due to NH group participating in an intramolecular hydrogen bond; while gave chemical shift at 6.38 ppm due to N1H group.
Solvent were purified and dried in the usual way.The boiling range of the petroleum ether used was 40-60 o C. Thin layer chromatography (TLC): silica gel 60 F 254 plastic plates (E.Merck, layer thickness 0.2 mm) detected by UV absorption.
28emental analyses were performed on a Flash EA-1112 instrument at the Microanalytical laboratory, Faculty of Science, Suez Canal University, Ismailia, Egypt.Melting points were determined on a Buchi 510 melting-point apparatus and the values are uncorrected.NMR spectra measured with Bruker (200 MHz) and TMS (0.00 ppm) was used as internal standard.The starting compounds 1 was prepared according to described methods.28