Under the guidance of :Mrs. M.V. Kumudhavalli, M.Pharm., (Ph.D.) Assistant Professor DEPT. OF PHARMACEUTICAL CHEM.

Presented by:VISHWANATH DHRUWANSH B.PHARM

2011
VINAYAKA MISSIONS COLLEGE OF PHARMACY, SALEM, TAMILNADU

AIM AND OBJECTIVE

1, 3-Thiazolines (4, 5-dihydro-1, 3-thiazoles) and 5, 6-dihydro-4H-1, 3thiazines 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.
2

LITERATURE REVIEW
Notzel, 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 R1 S obtained. R1 S
Cl R1 CO2Me R2 NaHCO3, MeCN NH2 MeO2C S R2 R2 HN Cl MeO2C N

Figure: 1,3-thiazolines from 2-chloro-2-cyclopropylideneacetates Wipf, 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.
OH S H N Cbz N H O OMe
-H2O

S H N Cbz N O OMe

Figure: 1, 3-thiazines from -Hydroxy thioamide Seebacher warner, et al., 26 has reported New 1, 3-Thiazoles and 1,3-Thiazines from 1-Thiocarbamoylpyrazoles. New 1, 3thiazoles 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.
N N S Ar S R N
Thiazoline ( for n = 1)

NH2 Br(CH2)nCOOEt

N N

(CH2 )n O

N Ar S R N

Thiazine ( for n = 2)

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

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.
O

PPh3, Py, CCl4 CH3CN

Ph OH

+
HS NH2 Ph

Figure:1, 3-thiazolines from triisobutylalluminium with esters

Busacca, 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 onestep 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.
O S R R OEt N

i-Bu3Al, Toluene

+
HS NH2 .HCl

Figure: 1,3-thiazolines from carboxylic acid 4

Plan Of Work
1. 2. 3.

Exhaustive literature survey Synthesis of compounds Structure elucidation of synthesized compounds by following methods: 1H-NMR spectra studies Mass spectra studies
S C Br NH2 n=1 S R N R
2-substituted 5,6-dihydro-4H-thiazine

Scheme
R

H2 (CH2)n C

NH2

HBr

S N (CH ) 2 n n=2 S N

2-substituted 4.5-dihydro thiazole

Where, R= substitution

EXPERIMENTAL WORK
Proposed mechanism
Br .HBr H2N
H2N

Br

S
S C R NH2 Et3N R
S Et3N R NH2 C R NH2

NH2 H2N

H2N

Et NH3 Br S R N R H2N S

Et NH3 Br

R N

N H

R H2 N

HN

NH3

NH3

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

2-substituted-5, 6-dihydro-4H-1, 3-thiazines

General 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)

S

NH2

S Br NH2 HBr Et3N THF N

Thiobenzamide

Bromoethylamine salt

2-phenyl-4, 5-dihydro-1, 3-thiazoline

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

N NH2
Br NH2 HBr Et3N THF

S
thionicotinamide

S
2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazoline

Bromoethylamine salt

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

NH2 Br S
4-bromobenzothioamide Bromoethylamine salt Br NH2 HBr Et3N THF

S Br N
2-(4-bromophenyl)-4,5-dihydrothiazole

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

S NH2
Br Et3N NH2 HBr THF

S S
thiophene-3-carbothioamide

S N

Bromoethylamine salt

2-(3-thiophenyl)-4, 5-dihydro-1, 3-thiazoline

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

O2N NH2
Br NH2 HBr Et3N THF

S O2N N

S
3-nitrobenzothioamide Bromoethylamine salt 2-(3-nitrophenyl)-4, 5-dihydro-1, 3-thiazoline

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

NH2
Br NH2 HBr Et3N THF

S
thiobenzamide Bromopropylamine salt

S
2-phenyl-5, 6-dihydro-4H-1, 3-thiazine

Synthesis of 2-(4-Bromo Phenyl)-5, 6-Dihydro-4H-Thiazine (Compound: 7)

NH2 Br S
4-bromobenzothioamide Br NH2 HBr Et3N THF

S Br N
Bromopropylamine salt 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine

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

OH S

OH NH2
Br NH2 HBr Et3N THF

S
2-Hydroxy benzothioamide Bromopropylamine salt 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazine

10

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

NH2
Br NH2 HBr Et3N THF

S S

S S
Bromopropylamine salt thiophene-3-carbothioamide

N
2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine

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

O 2N NH2
Br NH2 HBr Et3N THF

O2N

S
3-nitrobenzothioamide Bromopropylamine salt 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazine

11

RESULT & DISCUSSION

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

Figure: 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

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

Observed Value ( ppm) 7.8-7.9 7.3-7.4 4.43-4.47, 3.38-3.42 Signal due to (m,2H) (m,3H) (t,2H) (t,2H)

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.
13

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

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

Figure:Mass spectra of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazoline 14

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

Table NMR Interpretation of 2-(3-pyridyl)-4, 5-dihydro-1, 3-thiazoline Signal due to Observed Value ( ppm) 9.04 8.68-8.69 8.12-8.15 7.28-7.39 4.45-4.50 3.44-3.48 (s,1H) (d,1H) (d,1H) (m,1H) (t,2H) (t,2H)

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 15 the molecular weight 164 and fragmentation of struture.

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-Thiazoline

Figure:Mass spectra of 2-(4-bromo phenyl)-4, 5-dihydro-1, 3-thiazoline 16

Figure:

1H

NMR of 2-(4-bromo phenyl)-4, 5-dihydro-1, 3-thiazoline Signal due to (d,2H) (d,2H), (t,2H), (t,2H)

Table: NMR Interpretation of 2-(p-bromo phenyl)-4, 5-dihydro-1,3-thiazoline

Observed Value ( ppm) 7.68-7.71, 7.52-7.53 4.42-4.46 3.41-3.45

The 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.
17

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

Figure: Gas chromatogram of 2-(3-thiophenyl)-4, 5-dihydro-1, 3-thiazoline

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

18

Figure: 1H NMR of 2-(3-thiophenyl)-4, 5-dihydro-1, 3-thiazoline Table : NMR Interpretation of 2-(3-thiophenyl)-4, 5-dihydro1-3-thiazoline Observed Value ( ppm) 7.41-7.45 7.05-7.07 4.37-4.41 3.42-3.46 Signal due to (m,2H), (m,1H) (t,2H) (t,2H)

The 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.
19

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 20

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

Table : NMR Interpretation of 2-(3-Nitrophenyl)-4, 5-dihydro thiazoline

Observed Value ( ppm) 8.676 8.32-8.30 8.16-8.14 7.62-7.58 4.53-4.49 3.52-3-48 Signal due to (s,1H) (d,1H) (d,1H) (t,2H) (t,2H) (t,2H)

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.
21

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

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

Figure: : Mass spectra of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazine 22

Figure: 1H NMR of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazine Table: NMR Interpretation of 2-phenyl-5, 6-dihydro-4H-1, 3-thiazine Signal due to Observed Value ( ppm) 7.78-7.75 (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)

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.
23

2-(4-Bromo Phenyl)-5, 6-Dihydro-4H-Thiazine (Compound: 7)

Figure: Gas Chromatogram of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine

Figure: Mass spectra of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine 24

Figure: 1H NMR of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine Table : NMR Interpretation of 2-(4-Bromo phenyl)-5,6-dihydro-4H-thiazine Observed Value ( ppm) 7.68-7.71 7.52-7.60 4.42-4.6 3.41-3.52 1.92-1.98 Signal due to (m,2H) (m,3H) (t,2H) (t,2H) (m,2H)

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.
25

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

26

Figure: 1H NMR of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazine Table: NMR Interpretation of 2-(2-Hydroxy phenyl)-5, 6-dihydro-4H-1, 3-thiazine Signal due to Observed Value ( ppm) 12.65 (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)

The 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.
27

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 28

Figure : 1H NMR of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine Table : NMR Interpretation of 2-(3-thiophenyl)-5, 6-dihydro-4H-1, 3-thiazine Observed Value ( ppm) 7.45-7.44 7.35-7.34 7.02-7.00 3.87-3.85 1.15-3.12 1.95-1.89 Signal due to (d,2H) (t,2H) (q,2H) (t,2H) (t,2H) (m,2H)

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 29 fragmentation of struture.

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 30

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

Table : NMR Interpretation of 2-(3-nitro phenyl)-5, 6-dihydro-4H-1, 3-thiazine Observed Value ( ppm) 8.65-8.64 8.27-8.25 8.11.8.09 7.57-7.53 3.97-3.94 3.22.-3.19 1.98-1.92 Signal due to (t,1H) (q,1H) (d,1H) (t,1H) (t,2H) (t,2H) (m,2H)

The 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 31 struture.

Summary & Conclusion