VINAYAKA MISSIONS COLLEGE OF PHARMACY, SALEM, TAMILNADUUnder the guidance of :-Mrs. M.V. Kumudhavalli, M.Pharm., (Ph.D.) Assistant ProfessorDEPT. OF PHARMACEUTICAL CHEM.Presented by:-VISHWANATH DHRUWANSHB.PHARM

2011

1, 3-Thiazolines (4, 5-dihydro-1, 3-thiazoles) and 5, 6-dihydro-4H-1, 3-thiazines are valuable heterocyclic compounds and due to the diversity in their chemical properties finds wide application in medicine and in synthetic practice. In view of its synthetic importance many routes have been developed to gain access to 1, 3-thiazolines and 1, 3-thiazines. Several methods exist for the preparation of thiazolines and thiazines.Current methods of their synthesis rely on condensation of -amino thiols or -amino alcohols with nitriles, carboxylic acids and esters. In case of amino alcohols for introducing sulfur a sulfurating agent has to be used. However, difficult access to a large variety of -amnio thiols is a severe limitation of this method. The other exploitable synthetic procedures are cyclisation of N-(-hydroxy) thioamides and acylamino alcohols or thiols, thionation of oxazoline. Thiazolines and thiazines can also be accesses from thioamides via S-alkylation with amino alcohol followed by deaminative cyclisation. Despite these procedures, there continues to be a demand for improved methods for their preparation in terms of mild reaction conditions, cleaner reactions, and simple isolation of the product.

AIM AND OBJECTIVE2

LITERATURE REVIEWNotzel, M. W. et al., 24 5-Spirocyclopropyl thiazolines were prepared in two steps under basic conditions starting from thioamides and 2-chloro-2-cyclopropylideneacetates via nucleophilic attack of the sulfur atom to the Michael acceptor followed by intra molecular substitution. With R1 H, mixtures of two or three diastereomers were obtained.

Figure: 1,3-thiazolines from 2-chloro-2-cyclopropylideneacetatesWipf, P. et al., 25 has reported Synthesis of peptide thiazolines from -hydroxythio-amides. An investigation of racemization in cyclodehydration protocols. The formation of thiazolines from -hydroxythioamides under TsCl/Et3N, SOCl2, and Mitsunobu conditions leads to extensive epimerization at the C(2) exo methine position. In contrast, thiazolines of>94% diastereomeric purity are isolated when the Burgess cyclodehydration protocol is applied.

Figure: 1, 3-thiazines from -Hydroxy thioamideSeebacher warner, et al., 26 has reported New 1, 3-Thiazoles and 1,3-Thiazines from 1-Thiocarbamoylpyrazoles. New 1, 3-thiazoles and 1, 3-thiazines are prepared from 1-thiocarbamoyl-pyrazoles. The structures of the title compounds are established by a single crystal structure analysis. Furthermore, antiprotozoal activities of one compound have been determined.

Figure:1,3-thiazolines & 1,3-thiazines from Thiocarbamoylpyrazoles 3

*Vorbruggan, H. et al., has reported an efficient process for the synthesis of thiazolines. Benzoic acid and amino ethanethiol were reacted in the presence of PPh3, CCl4, and pyridine, affording in 45% yield.

Figure: 1,3-thiazolines from carboxylic acidBusacca, C. A. et al., has reported the condensation of aminoethanethiol hydro-chloride. HCl with aryl, heteroaryl, and alkyl esters in the presence of triisobutylaluminium (2.5 equiv), which activates the carbonyl group. This one-step procedure showed a wide tolerance to functional groups. The authors explained the lowest yield (21%) obtained with ethyl cinnamate by a competing Michael addition reaction. With 3-pyridyl ester isolation of a small amount (8%) of pyridyl amide disulde suggested initial attack of the carbonyl by the nitrogen nucleophile followed by attack of the sulfur nucleophile promoting cyclization to afford 3-pyridyl-4,5-dihydro-1,3-thiazoline.

Figure:1, 3-thiazolines from triisobutylalluminium with esters

Exhaustive literature surveySynthesis of compounds Structure elucidation of synthesized compounds by following methods:1H-NMR spectra studiesMass spectra studies

Plan Of WorkScheme

Proposed mechanism2-substituted-5, 6-dihydro-4H-1, 3-thiazines

2-substituted-4, 5-dihydro-1, 3-thiazolines

EXPERIMENTAL WORKGeneral Experimental Procedure: Bromoamine hydrobromide salt and thioamide was taken in THF. Triethyl amine was added to this mixture drop-wise with constant stirring. Temperature of the reaction mixture was maintained at 60-70 oC. When the addition of Et3N was over, contents were further heated at 70-80 oC till the reaction was complete, which was monitored by GC-MS and TLC. After the completion of the reaction contents were neutralized with saturated NaHCO3 sol. and extracted with ethyl acetate. Ethyl acetate layer was dried over Sod. Sulfate and solvent was removed under vacuum. Further chromatographic purification afforded the pure product.

*Synthesis of 2-Phenyl-4, 5-Dihydro-1, 3-Thiazoline (Compound: 1)

Synthesis of 2-(3-Pyridyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 2)

*Synthesis of 2-(4-Bromo Phenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 3)

Synthesis of 2-(3-Thiophenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 4)

*Synthesis of 2-(3-Nitrophenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 5) Synthesis of 2-Phenyl-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 6)

*Synthesis of 2-(4-Bromo Phenyl)-5, 6-Dihydro-4H-Thiazine (Compound: 7) Synthesis of 2-(2-Hydroxy Phenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 8)

*Synthesis of 2-(3-Thiophenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 9) Synthesis of 2-(3-Nitro Phenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 10)

2-Phenyl-4, 5-Dihydro-1, 3-Thiazoline (Compound: 1)

RESULT & DISCUSSIONFigure: Gas Chromatogram of 2-phenyl-4, 5-dihydro-1, 3-thiazoline

Figure: Mass spectra of 2-phenyl-4, 5-dihydro-1, 3-thiazoline

* Figure: 1H NMR of 2-phenyl-4, 5-dihydro-1, 3-thiazoline

The compound with oily nature have molecular formula C9H9NS was analyzed in Gas chromatogram shows single peak at 6.066 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 163 and fragmented peaks at 117 & 60, that confirm the molecular weight is 163 and fragmentation of struture.

Table: NMR Interpretation of 2-phenyl-4, 5-dihydro-1, 3- thiazoline

Observed Value ( ppm)Signal due to7.8-7.9(m,2H)7.3-7.4(m,3H)4.43-4.47,(t,2H)3.38-3.42(t,2H)

*2-(3-Pyridyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 2)

Figure:Gas Chromatogram of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazolineFigure:Mass spectra of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazoline

*Figure :1H NMR of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazolineTable NMR Interpretation of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazoline

The compound with melting point 111-113oC have molecular formula C8H8N2S was analyzed in Gas chromatography shows single peak at 8.566 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 164 and fragmented peaks at 136 & 60, that confirm the molecular weight 164 and fragmentation of struture.

Observed Value ( ppm)Signal due to9.04 (s,1H)8.68-8.69(d,1H)8.12-8.15(d,1H)7.28-7.39(m,1H)4.45-4.50(t,2H)3.44-3.48(t,2H)

*2-(4-Bromo Phenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 3)

Figure: Gas chromatogram of 2-(4-bromo phenyl)-4, 5-dihydro-1, 3-ThiazolineFigure:Mass spectra of 2-(4-bromo phenyl)-4, 5-dihydro-1, 3-thiazoline

*Figure: 1 H NMR of 2-(4-bromo phenyl)-4, 5-dihydro-1, 3-thiazolineTable: NMR Interpretation of 2-(p-bromo phenyl)-4, 5-dihydro-1,3-thiazolineThe compound with melting point 90-92oC have molecular formula C9H8BrNS was analyzed in Gas chromatography shows single peak at 12.56 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 242.9 and fragmented peaks at 194.9, 102, & 60, that confirm the molecular weight 242 and fragmentation of struture.

Observed Value ( ppm)Signal due to7.68-7.71, (d,2H)7.52-7.53(d,2H),4.42-4.46(t,2H),3.41-3.45(t,2H)

*2-(3-Thiophenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 4)

Figure: Gas chromatogram of 2-(3-thiophenyl)-4, 5-dihydro-1, 3-thiazolineFigure no.:Mass spectra of 2-(3-thiophenyl)-4,5-dihydro-1,3-thiazoline

* Figure: 1H NMR of 2-(3-thiophenyl)-4, 5-dihydro-1, 3-thiazolineTable : NMR Interpretation of 2-(3-thiophenyl)-4, 5-dihydro1-3-thiazolineThe compound with melting point 40-42 oC have molcular formula C7H7NS2 was analyzed in Gas chromatography shows single peak at 9.63 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 169 and fragmented peaks at 123, 110 & 60, that confirm the molecular weight 169 and fragmentation of struture.

Observed Value ( ppm)Signal due to7.41-7.45(m,2H),7.05-7.07(m,1H)4.37-4.41(t,2H)3.42-3.46(t,2H)

*2-(3-Nitrophenyl)-4, 5-Dihydro-1, 3-Thiazoline (Compound: 5) Figure: Gas chromatogram of 2-(3-Nitro phenyl)-4, 5-dihydro-1, 3- thiazoline Figure :Mass spectra of 2-(3-Nitro phenyl)-4, 5-dihydro-1, 3-thiazoline

*Figure: 1H NMR of 2-(3-Nitro phenyl)-4, 5-dihydro-1, 3-thiazolineTable : NMR Interpretation of 2-(3-Nitrophenyl)-4, 5-dihydro thiazoline

The compound with melting point 48-50 oC have molecular formula C9H8N2O2S was analyzed in Gas chromatography, shows single peak at 10.57 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 208 and fragmented peaks at 162 & 60, that confirm the molecular weight 208 and fragmentation of struture.

Observed Value ( ppm)Signal due to8.676 (s,1H)8.32-8.30(d,1H)8.16-8.14(d,1H)7.62-7.58(t,2H)4.53-4.49(t,2H)3.52-3-48(t,2H)

*2-Phenyl-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 6)

Figure: Gas Chromatogram of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazineFigure: : Mass spectra of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazine

*Figure: 1H NMR of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazineTable: NMR Interpretation of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazine

The compound with melting point 44-46 oC have molecular formula C10H11NS was analyzed in Gas chromatography, shows single peak at 8.66 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 177.1 and fragmented peaks at 130.1 & 74, that confirm the molecular weight 177 and fragmentation of struture.

Observed Value ( ppm)Signal due to7.78-7.75 (m,2H)7.42-7.39(m,3H)3.92-3-89(t,2H)3.16-3.13(t,2H)1.93-1.88(m,2H)

*2-(4-Bromo Phenyl)-5, 6-Dihydro-4H-Thiazine (Compound: 7) Figure: Gas Chromatogram of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazineFigure: Mass spectra of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine

*Figure: 1H NMR of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine

The compound with melting point 77-79 oC have molecular formula C10H10BrNS was analyzed in Gas chromatography, shows single peak at 12.56 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 256 and fragmented peaks at 182.2 & 74, that confirm the molecular weight 256 and fragmentation of struture. Table : NMR Interpretation of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine

Observed Value ( ppm)Signal due to7.68-7.71 (m,2H)7.52-7.60(m,3H)4.42-4.6(t,2H)3.41-3.52(t,2H)1.92-1.98(m,2H)

*2-(2-Hydroxy Phenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 8) Figure: Gas Chromatogram of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazine Figure:Mass spectra of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazine

* Figure: 1H NMR of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazineTable: NMR Interpretation of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazineThe compound with oily nature have molecular formula C10H11NOS was analyzed in Gas chromatography, shows single peak at 7.466 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 193 and fragmented peaks at 119 & 74, that confirm the molecular weight 193 and fragmentation of struture.

Observed Value ( ppm)Signal due to12.65 (s,1H)7.43(s,1H)7.42-7.31(m,1H)7.00-6.89(q,1H)6.87-6.85(m,1H)4.49-4.45(t,2H)3.38-3.34(t,2H)1.93-1.89(m,1H)

*Synthesis of 2-(3-Thiophenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 9)

Figure: Gas Chromatogram of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine

Figure: Mass spectra of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine

* Figure : 1H NMR of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazineTable : NMR Interpretation of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine

The compound with melting point 45-47 oC have molecular formula C8H9NS2 was analyzed in Gas chromatography, shows single peak at 8.9 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 183 and fragmented peaks at 127 & 74, that confirm the molecular weight 183 and fragmentation of struture.

Observed Value ( ppm)Signal due to7.45-7.44 (d,2H)7.35-7.34(t,2H)7.02-7.00(q,2H)3.87-3.85(t,2H)1.15-3.12(t,2H)1.95-1.89(m,2H)

*2-(3-Nitro Phenyl)-5, 6-Dihydro-4H-1, 3-Thiazine (Compound: 10) Figure: Gas Chromatogram of 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazine

Figure: Mass spectra of 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazine

*Figure:1H NMR of 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazineThe compound with melting point 86-88 oC have molecular formula C10H10N2O2S was analyzed in Gas chromatography, shows single peak at 12.02 min. That confirm the purity of the compound and the mass spectra was given moleclar ion (M+) peak at 222.1 and fragmented peaks at 175 & 74, that confirm the molecular weight 222 and fragmentation of struture. Table : NMR Interpretation of 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazine

Observed Value ( ppm)Signal due to8.65-8.64 (t,1H)8.27-8.25(q,1H)8.11.8.09(d,1H)7.57-7.53(t,1H)3.97-3.94(t,2H)3.22.-3.19(t,2H)1.98-1.92(m,2H)

Summary & Conclusion

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