Chan, Chung Woo

Dominic Ng, Chun Ming

Ho, Joyce

Tin, Kam Chung

NOPR

Indian Journal of ChemistryVol.36B, March 1997, pp. 216-219Rapid CommunicationAn efficient synthesis of 1,2,4-oxa-thiazoles from N-acylthioureaderivativesChung Woo Chan*, Chun Ming Dominic Ng, Joyce Ho &Kam Chung TinDepartment of Biology and Chemistry, City University ofHong Kong, Tat Chee Ave, Kowloon, Hong KongReceived 4 November, 1996; accepted 26 February 19961,2,4-0xathiazoles have been synthesized from theirprecursors, the N-acylthioureas by oxidative cyclizationreaction. Ring structure and the charge distribution above thering have also been studied.The chemistry including synthesis of 1,2,4-oxathiazoles and elucidation of their structures havenot been studied well. On the contrary, ringcompounds with analogous structures have beenstudied in detail I, and some of them found topossess a certain degree of biological activities". Byreviewing the ring structure of 1,2,4-oxathiazoles,one may expect that these compounds should alsoexhibit a comparable degree of biological activitiesas other classes of heterocycles with similarstructures do. We therefore thought of interest todevelop a convenient and general synthetic route forthis class of compounds.Our preliminary results on the synthesis of 1,2.4-oxathiazoles by the oxidative cyclization ' of thecorresponding N-acylthiourea derivatives, asdepicted in Scheme I, are reported in this note.o SII IIRI-C-N-C-RlIH[0) o-s-- I".~RI~N RlScheme IThe required N-acylthiourea derivatives 1a-6awere prepared from the reaction of acid chlorideswith sodium thiocyanates and subsequent reactionwith appropriate 10 or 2° amine as depicted inScheme II. When alcohol such as ethanol was usedinstead of the amine, it gave the thiocarbamatescompoundstscheme Ilj.Hvdrogen peroxide andbromine were used as oxidants for the oxidativecyclization of N-acylthioureas under variousconditions. Bromine appeared to be more feasibleoIIRI-C-CIo SII IIRI-C-N-C-NJllR)IH+ NaSCNo SII IRI-C-N-C-OR)IH4.Compd RI R2la C6Hs H2a C~s H3a C~; CH3-ta C6H,Sa c.n, 1\-N 0L..J6a HScheme IIoxidant than hydrogen peroxide which has beenused as an oxidizing agent in the preparation of 3,5-disubstituted-l,2,4-oxathiazolines4 1,2,4-oxathiazoles lb-Sb were prepared by the bromineoxidation reaction of La-Sa. Hydrogen peroxidebrought about the replacement of sulphur atom onthiocarbonyl group of the N-acylthiourea derivative1a by an oxygen atom to form the N-acylureaderivative 1c. It also attacked the more nucleophiliccarbonyl centre of compound 6a which led todisintegration, thus preventing the formation of O-Sbond that was necessary for the ring formation inboth the cases (Figure 1).I. I,Figure 1RAPID COMMUNICATIONS 217o SII IIRI-C-N-C~XR2RJIHo-~ sP--_ .. '...*RI~NAX-R24bCompd RI xH NH NNC2H" or>.-N 0'LJScheme IIIBromine reaction allowed a smooth conversion ofla-Sa to the corresponding target ring moleculeslb-5b, but failed with that bearing the phenylformoyl group (6a) (cf Scheme III). The proposedmechanism for the oxidative cyclization reactioninvolves the initial abstraction of a hydride fromNH group, followed by attack of the oxygen atomof acyl group upon the less electronegative sulphuratom of the thiocarbonyl bond to form O-S bondwith the elimination of central NH proton (Figure-2).We found that when diethylamine, a moderateorganic base, was added to the reaction mixture, it?ffi~---...... R'-C-~-C-~2,..HaSlo S.II IIR'-C-~ -CC-~R2H H.6<-6-Br-BrFigure 2was possible to synthesize the 1,2,4-oxathiazolewith much greater ease. Addition of diethylaminefacilitates the removal of the NH proton and thusmakes the cyclization step proceed easier. Anotheradvantage of the base-catalysed cyclization reactionis that it avoided the clumsy separation processwhich was usually required after the addition ofbromine. This is because during the reaction thebase is converted to its salt, the diethylammoniumbromide, which is readily soluble in water but notin the organic solvent, and hence the final productcan be obtained by simple extraction with anorganic solvent.The structures of the ring productswere determined from their lH NMR and IRspectra. All the 1,2,4-oxathiazoles synthesized wereobtained in their salt forms. Their solubilityproperties were quite similar except for compound5b that was soluble in water. Their melting pointswere higher than the corresponding N-acylthioureaor thio-carbamate derivatives. This 'can beattributed to the attractive force between theopposite charges in the products. There are twotautomeric forms in which the ring can exist (Figure3), the positive charge can be located either in theendo or exocyclic position. So far there has been noevident to conclude as to which of the two forms ismore stable.<ll e0-5 Br(~R'/"'::N X-R2IHFigure 3In conclusion, the use of bromine as an oxidizingagent allowed us to achieve a great success in thesynthesis of the 1,2,4-oxathiazolium compoundswith reasonable yields. We are still investigating onthe synthesis of 1,2,4-oxathiazoline compoundsespecially those which are more soluble in water byplacing different substituents in ring .Experimental SectionlH NMR spectra were recorded in CDCI3 or inacetone-a, on a Hitachi R-1200 instrument. CHNanalyses were performed on a Leco CHN-9000instrument. IR spectra were recorded on a BomemMB-120 Fourier-Transform infra-red spectrometer.218 INDIAN J. CHEM. SEe B, MARCH 1997Synthesis of the thiourea derivatives la-3a,5a-6a and thiocarbamate derivative 4a. Generalprocedure. A solution of sodium thiocyanate(4.05g, 50mmoles) in acetone (50mL) was slowlyadded dropwise at O°C to an acid chloride(50mmoles) in acetone (20mL) with continuousstirring. The mixture was filtered using Celite onfilter paper. The filtrate was slowly added at roomtemperature to an amine or alcohol (50nU110Ies) inacetone (20mL) with continuous stirring.Thereafter, two-third of the solvent was distilledunder vacuum. The concentrate was left overnightin a fridge. Crystals formed were collected anddried in vacuum.N-Benzoylphenylthiourea 1a. Yield 87%, m.p.131-32° ; IH NMR (CDCh, 20°C): 8 7.59 (rn, 10H,CJ-Is), 9.24 (br, IH, NH), 12.53 (br, IH, NH); IR(nujol rnull): 3281, 1669, 1606, 1581 cm'. Anal.Calcd for CIJ-i12N20S: C, 65.50; H, 4.70; N;10.95.Found: C, 65.50; H, 4.65; N, 10.95%.N-Benzoyl-( 3-nitro)phenylthiourea 2a. Yield79%, m.p. 175-76°; IH NMR (CDCb, 20°C): 87.24-7.91 (m, 9H, CJ-Is), 9.04 (br, IH, NH), 12.51(br, IH, NH); IR (nujol mull): 3267, 3150, 1653,1582, 1541, 1533, 1509, 1321 ern". Anal. Calcdfor CIJlIIN303S: C, 55.80; H, 3.70; N, 13.95.Found: C, 55.75; H, 3.50: N, 13.75%.N-Benzoylmethylphenylthiourea 3a. Yield71%, m.p. 139-40°; IH NMR (CDCb, 20°C): 83.75 (s, 3H, CH3), 7.25-7.59 (m, 10H, CJ-Is), 8.61(br, IH, NH); IR (nujol mull): 3375, 3215, 3190,1698, 1600(m), 1585, 1515(m) cm'. Anal. Calcdfor CIsHI4N20S: C, 66.65; H, 5.20; N, 10.35.Found: C, 66.33; H, 5.12; N, 10.30%.N-Benzoylethylthiocarbamate 4a. Yield 75%,oily liquid at room temperature; IH NMR (CDCI3,20°C): 8 1.3-1.5 (t, 3H, CH3), 4.4-4.8 (q, 2H, CHz),7.3-8.4 (m, 5H, CJ-Is), 9.6 (br, IH, NH); IR (nujolmull): 3270,1972,1695,1507,1276,1194 cm'.Anal. calcd for ClOHIIN02S: C, 57.40; H, 5.30;N,6.70. Found: C, 57.55; H, 5.25; N, 6.55%.Benzamidothiomorpholinoate 5a. Yield 86%,m.p. 140-42°; IH NMR (CDCh, 20°C): 8 3.6-3.8(m, 8H, CH2), 7.4-8.0 (m, 5H, CJ-Is), 8.6 (br, IH,NH); IR (nujol mull): 1680, 1597, 1516, 1233,1188, 1088 cm'.N-(Phenylformaoyl)phenylthiourea 6a. Yield91%, m.p. 158-60°; IH NMR (CDCh, 20°C): 6 7.2-7.7 (m, 10H, CJ-Is) , 8.8 (br, IH, NH), 11.1 (br,IH, NH); IR (nujol mull): 3150, 1727, 1594, 1223,1136 cm'.Synthesis of 1,2,4-oxathiazolium bromides 1b-5b.General procedure. A solution of bromine (2.16 g,13.5nunoles) in chloroform (20mL) was addeddropwise at O°C to the thiourea- or thiocarbamatederivative (l3.5nU110Ies) in chloroform (50mL) withcontinuous stirring. The mixture was left to stand atroom temperature for 112hr and the solvent distilledoff under vacuum. The product was recrystallizedfrom chloroform. The crystals or powder formedwere collected and dried under vacuum.3-Anilino-5-phenyl-1,2,4-oxathiazoliumbromide lb. Yield 78%, m.p. 201-2°; IH NMR(CDCh, 20°C): 8 7.2-8.5 (m, 10H, PhH); IR (nujolmull): 3345, 1618, 1530, 1282 cm,l. Anal. Calcdfor C1JlIIN20SBr: C, 50.15; H, 3.30; N, 8.35.Found: C, 50.20; H, 3.20; N, 8.45%.3-( 3-Nitroanilino )-5-phenyl-l, 2, 4-oxathiazo-lium bromide 2b. Yield 43%, m.p. 225-27°; IHNMR (CDCh, 20°C): 8 12.3-13.5 (b, PhH); IR(nujol mull): 3415, 1728(w), 1616, 1429, 1492(s),1315, 1242(m) ern". Anal. Calcd forCIJ-ilON303SBr: C, 44.30; H, 2.65; N, 11.05.Found: C, 44.75; H, 2.60; N, 10.80%.3-( N-Methyl-N-phenylamino. )-S-phenyl-1,2,4-oxathioazolium bromide 3b. Yield 75%, m.p. 167-68.5°; IH NMR (CDCh, 20°C): 8 4.0 (s, 3H, CH3),7.41-8.42 (rn, 10H, PhH); IR (nujol mull): 3100,3000, 1697, 1599, 1579(m), 1543 em". Anal.Calcd for ClsHJ3N20SBr: C, 35.40; H, 2.55; N,5.50. Found: C, 34.85; H, 2.55; N, 5.50%.3-E thoxy-5-p heny 1-1,2 ,4-oxathiazoli urnbromide 4b. Yield 68%, oily liquid; IH NMR(CDCh, 20°C): 8 1.1-1.4 (t, 3H, CH3), 3.9-4.5 (q,2H, CH2), 7.1-8.4 (m, 5H, PhH); IR (nujol mull):RAPID COMMUNICATIONS 2193251, 1762, 1676, 1462, 1265, 1206 cm'. Anal.Calcd for CIOHION02SBr: C, 41.70; H, 3.50; N,4.85. Found: C, 41.40; H, 3.55; N, 4.90%.3-Morpholino- 5 -phenyl- 1,2, 4-oxathiazoliumbromide 5b. Yield 86%, oily liquid; IH NMR(CDCh, 20°C): s 3.6 (s, 8H, CH2), 7.4 (s, 5H,PhH); IR (nujol mull): 2968, 2856, 1626, 1538,1440, 1271, 1118 cm'.AcknowledgmentThis research was supported by the CityUniversity of Hong Kong .. We grateful Mr C PBenz Chan and Mr H Y John Lai for their help inour research.References(a) Tsuge 0, Urano S & Oe K, J Org Chern, 45, 1980,5130.(b) Newton, C G & Ollis W D, J Chen! Soc Perkin Trans-I, 1984, 75.(c) Kurzer F, J Chern Soc Perkin Trans-I, 1985, 311.(d) Howe R & Shelton B R, J Org Chern, 46, 1981, 771.(e) Goerdeler.T & Lobach W, Chem Ber, 112, 1979m 517.(f) Vivona N, Cusmano G & Macaluso G, J Chem SocPerkin Trans-I, 1977,1616.(g) Shibuya & Nakanishi H, Bull Chem Soc Japan, 60,1987,2686.(h) Clapp L B, Ad" Heterocycl Chem, 20,1976,65.(i) Hetzheim A & Meckel K, Adv Heterocycl Cliem, 7,1%6, lX3.2 Gilchrist T L, In: Heterocyclic chemistry 2nd edn(Longman Group) 1992, p.322.3 (a) Muler P, In: The chemistry of functional groups.Suppl. E, Part I, edited by S Patai (Wiley, Chichester)1980, p. 469.(b) Katritzky Alan RL Advanced HeterocyclicChemistry.i st edn (Pergamon Press, New York) 1985,pAI8.4 Brown B T & Harris R L N, Pestic Sci., 4, 1973,215.

An efficient synthesis of 1,2,4-oxathiazoles from N-acylthiourea derivatives

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An efficient synthesis of 1,2,4-oxathiazoles from N-acylthiourea derivatives

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