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Title of Thesis
SYNTHESIS, STRUCTURE AND BIOACTIVITY OF SOME THIAZAHETEROCYCLES

Author(s)
SADAF SAEED
Institute/University/Department Details
Department of Chemistry/ Quaid-i-Azam University, Islamabad
Session
2008
Subject
Organic Chemistry
Number of Pages
281
Keywords (Extracted from title, table of contents and abstract of thesis)
thiazaheterocycles, oxathiazepine, eudistomins, oximes, oxadiazin

Abstract
The work described in this thesis consists of synthesis. structure and bioactivity of some new heterocyclic compounds. The compounds included in this thesis are seven membered ring compounds, which contain heteroatoms nitrogen, oxygen and sulphur. Few six membered ring compounds were also synthesized which contain nitrogen and oxygen atoms.

The seven membered compounds include different 3-substituted phenyl- 5,6-dihydro-7 H-1,4,2- oxathiazepin-7-one (78-97), 4,I,3-benzoxathiazepin-5-one (123-137), pyrido[2,3e][I,4,2]oxathiazepin-5-one (161-173), 5,6-dihydro-7H-1,,4,2-oxathiazepin-7-one(188-192), 6-[(acetyloxy)amino]-3-(4-substitutedphenyl)-5,5-dimethyl-5,6-dihydro-7 H-1,4,2 oxathiazepin-7-one (197-198). These compounds were prepared by treating hydroximinoyl chlorides with different mercapto acids. These acids included 3-mercaptopropanoic acid, 2mercaptosalicylic acid. 2-mercaptonicotinic acid. cysteine and penicilamine. The first step in the synthesis of these compounds was the formation of oximes by treating aldehydes with hydroxylamine hydrochloride. The variety of aldehydes was selected for this work with aromatic and heteroaromatic nuclei. The second step was the conversion of these oximes to the hydroximinoyl chlorides. This step was carried out by treating oximes with different chlorinating agents, NCS and BTMAICI4. These hydroximinoyl chlorides in the next step were treated with different mercapto acids to give oxime acids. The reaction was carried out in the presence of base, triethyl amine. The last step was cyclization and carried out by adding DCC as cyclizing agent to the reaction mixture.

The chemical reactivity of these compounds was investigated by carrying out different reactions. Thus oxathiazepines were treated with phosphorus pentasulphide, primary and secondary amines, LiAlH4 and alcohol to get thiones. amides, alcohols and esters respectively. It was found that the same ring cleaved product was obtained under both acidic and basic conditions. Ring also cleaved in case of reaction with amine, alcohol and LiAlH4.

The synthesis of another class of six membered ring compounds i.e. 1,2,4-oxadiazin-5-one and 6,6-dimethyl-1,2,4-oxadiazin-5-one (217-221) was also carried out by treating amidoximes with chloroacetyl chloride and 2-bromo-2-methylpropanoyl bromide. The amidoximes were prepared by treating hydroximinoyl chloride with different primary and secondary amines which include benzylamine, 2-aminopyridine, 2-chloroaminobenzene, 1-naphthylamine, 4-aminopyridine, cyclopropylamine, dibenzylamine and diisopropylamine. 7,7-dimethyl-3,5-disubstituteddihydro-1H-[1 ,3]thiazolo[3,4-c][1,3]oxazol-l-one(199-201) were also synthesized by the reaction of aldehydes with Penicillamine. The compounds thus formed were characterized by different spectroscopic techniques like UV, IR, 1H, 13C NMR, COSY, HMQC, DNMR and mass spectral analysis. NOE experiments were performed to confirm the stereochemistry of the hydroximinoyl chlorides, oxime acids and amidoximes. These compounds were found to have Z- configuration. Elemental analysis and X-ray crystal analysis was also carried out in many cases.

The synthesized compounds after characterization were subjected to biological activity testing; antibacterial, antifungal, antioxidant and antidiabetic activities. Some of the compounds were found to exhibit excellent antibacterial and antifungal activity. The oxime acids proved to be good antioxidants while a few oxathiazepines have also shown good antidiabetic activity.

Download Full Thesis
3439.36 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
323.2 KB
2 1 Introduction 1
260.98 KB
  1.1 Oxathiazepine 1
  1.2 Structure And Theoretical Studies 1
  1.3 Isolation Of Oxathiazepine 1
  1.4 Isolation Structure And Biological Evaluation Of Cysteine Derived Eudistomins 4
  1.5 Stereochemistry Of Eudistomins 4
  1.6 Synthetic Approaches 5
  1.7 Structure Activity Relationship ( Sar ) In Eudistomins 12
  1.8 Plan Of Work 14
  1.9 References 28
3 2 Results And Discussion 31
1642.11 KB
  2.1 Oximes 31
  2.2 Hydroximinoyl Chlorides 39
  2.3 Attempted Synthesis Of 3-{[(Z)-( Hydroxyimino )( Pyridin-4 yl)Methyl] Thio } Propanoic Acid 57
  2.4 Synthesis Of.3-Substituted Phenyl- 5 ,6 -Dihydro-7h- 1,4,2- Oxathiazepin-7-One (78- 96) 69
  2.5 Synthesis Of 2-{[ Hydroxyimino )Methyl ] Thio }Benzoic Acids (108-122) 90
  2.6 Synthesis Of Differently Substituted 4 ,1,3 - Benzoxathiazepinones (123-137) 107
  2.7 Synthesis Of Differently Substituted 2-{[( Hydroxyimino )Methyl ] Thio }Nicotinic Acid (148-160) 126
  2.8 Synthesis Of Differently Substituted Pyrido [ 2,3-E][1,4,2]Oxathiazepin-5-One (161 -173) 137
  2.9 Synthesis Of Differently Substituted 3-{[( Hydroxyimino )Methyl ] Thio } Propanoic Acid (183-187) 152
  2.10 Synthesis Of Differently Substituted 5 ,6 -Dihydro-7h-L,4,2-Oxathiazepin-7-One(188-192) 157
  2.11 Synthesis Of 2-[( Acetyloxy )Amino ]-3-{[(Z)-(4-Substitutedphenyl)( Hydroxyimino )Methyl] Thio }-3-Methylbutanoic Acid (195-196) 161
  2.12 Synthesis Of 6 -[( Acetyloxy )Amino]-3-(4-Substitutedphenyl)-5,5-Dimethyl-5,6-Dihydro-7h-
  2.13 Synthesis Of Penicillamine Derivatives 165
  2.14 Synthesis Of Oxadiazin 167
  2.15 References 174
4 3 Biological Studies 175
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  3.1 Antimicrobial Activity Of Oximes 175
  3.2 Antifungal Activity Testing By Poison Plate Method 193
  3.3 Antioxidant Activity 207
  3.4 Antidiabetic Activity 211
  3.5 Conclusions 213
  3.6 References 214
5 4 Experimental 215
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  4.1 Synthesis Of Oximes 216
  4.2 Synthesis Of Hydroximinoyl Chloride 222
  4.3 Synthesis Of 3-{[(Z)-( Hydroxyimino )Methyl ] Thio } Propanoic Acids 228
  4.4 Preparation Of Differently Substituted 1 ,4,2 - Oxathiazepinones 235
  4.5 Synthesis Of Differently Substituted 2-{[( Hydroxyimino )Methyl ] Thio }Benzoic Acid 244
  4.6 Synthesis Of Differently Substituted 4 ,1,3 - Benzoxathiazepinones 249
  4.7 Preparation Of Differently Substituted 2-{[( Hydroxyimino )Methyl ] Thio }Nicotinic Acid 258
  4.8 Synthesis Of Differently Substituted 1 ,4,2 -Oxathiazepin-5-One 262
  4.9 Preparation Of Differently Substituted 3-{[( Hydroxyimino )Methyl ] Thio } Propanoic Acid Containing Cysteine Derivative 270
  4.10 Preparation Of Differently Substituted 5 ,6 -Dihydro-7 H-L,4,2-Oxathiazepin-7-One 271
  4.11 Preparation Of 2- [( Acetyloxy )Amino ]-3-Mercapto-3-Methylbutanoic Acid(194) 273
  4.12 Preparation Of 2-[( Acetyloxy )Amino ]-3-{[(Z)-(4- Substitutedpheny1)( Hydroxyimino )Methyl] Thio }3-Methylbutanoic Acid 273
  4.13 Preparation Of 6-[( Acetyloxy )Amino ]-3-(4-Substitutedphenyl)-5,5-Dimethyl-5,6 -Dihydro-7 H- 4.14 Synthesis Of Penicillamine Derivatives 275
  4.15 Synthesis Of Carboxamidoximes 276
  4.16 Synthesis Of Oxadiazin 279
  4.17 References 281