Indian Journal of Chemistry Vol. 40B, February 200 I, pp. 124-1 28

Synthesis of new 4-thiazolidinones bearing potentially active heteryl moities

v S Ingle, A R Sawale, R 0 Ingle & R A Mane* Department of Chemistry. Dr Babasaheb Ambcdkar Marathwada University, AUl'angabad 431 004, India

Received 14 December 1998; accepted (revised) 26 July 2000

2-Acyl-3-methyl-7 -substituted-I ,4-benzothiazines IA and 5-acyl-l-aryl-2-mercapto-4-methy limidazoles 1 B have been converted to their respective hyd razones 2A and 2B by refluxing thcm with hydrazine hydrate in digol. The hydrazino derivatives on condensation with aryl isothiocyanates give asymmetric thioureas 3A and 3B. The thioureas when refluxed with monochloroacetic acid in glacial acetic acid using anhydrous sodium acetate as catalyst yield the title products, 2-[(-3'­methyl-4H-7'-substituted- 1 ,4-bcnzothi azi n-2' -yl)-methy l-ketoiminyl]imino-3-aryl-4-thiazolidinones 4A and 2-[( I '-subst ituted pheny 1-2' -mercapto-4' -methy Ii midazol-5' -yl )-met yl-ketoi mi ny I] i mi no-3-substituted pheny 1-4-thiazol idi nones 4B. Some of the newly synthes ised compounds have been screened against Altemaria brassicae. Cloeosporill1l1 alllpelop/ragulll and Fusarium oxysporiulll and the results are presented.

4-Thiazolidinones have been synthesised for wide range of industrial , pharmaceutical and biological purposes I. Literature reveals that 4-thiazolidinones having heteryl mOieties and imidazoles are biologically significant molecules2

-s. Synthesis of 1,4-

benzothiazines has retained its significance and is gaining the attention of the chemists due to their wide spectrum of biological activities9

. In view of these findings and in continuation of our earlier work IOG

.b

,

we report herein the synthesis of some new benzothiazenyl-4-thiazolidinones and imidazolyl-4-thiazolidinones wh ich are expected to possess potent pharmacological activities.

Results and Discussion

In the present work 2-acyl-3-methyl-I,4-benzothiazines lA and 5-acyl-I-aryl-2-mercapto-4-methylimidazoles IB were converted to their respective hydrazones 2A and 2B. 2-Acetyl-3-methyl­substituted-I,4-benzothiazines were prepared by condensing I-acetyl-l-chloroacetone and 2-amino­benzene thioles at room temperature in alcoholic sod ium hydroxide. The hydrazones were then condensed with aryl isothiocyanates to give respective asymmetric thiocarbamides 3A and 3B. The thio­carbamides 3A were condensed with monochloro­acetic acid in the presence of anhydrous sodium acetate in refluxing acetic acid to furnish the thiazolidinones. There was possibility of formation of two products 4a and 4a'. TLC study indicated the presence of only one product. The authenticity of the product was further confirmed by the chemical method IUa-b. The formation of product 4A, 2-[(-3'-

methyl-4H-7'-substi tuted-1 ,4-benzothiazin-2'-yl)-methyl­ketoiminyl]imino-3-ary l-4-thiazolidinones is con fi rmed as follows.

The product 4A-a obtained by cyclocondensation of thiocarbamide, 3A-a (where R = R' = H) and chloroacetic acid, was hydrolysed with alcoholic hydrochloric acid, a solid N-phenylthiazolidione (m.p. 200°C), a known compound lOa formed was filtered. The filtrate on basification gave 2-hydrazinoacetyl-3-methyl-4H-l ,4-benzothiazine, 2A-a (R = H).

If the product form ed is 4A', its hydrolysis under the simi lar condition would give aniline as one of the products. These compounds were not formed in the reaction. This rules out the possibility of fo rmation of 4A'.

Similarly, the hydrolysis of the product obtained by cyclocondensation of 3B-a (R = R' = H) was carried out whereby N-phenylthiazolidione was formed. This confirms the structure of the condensed products as 4B, 2-[(l'-substituted phenyl-2'-mercapto-4'-methyl­i midazol-5'- y l)-methy I ketoi min y I] i mi no-3-substi tu ted phenyl-4-thiazolidinones since in the hydrolysis there was no formation of ani lines as one of the products, this rules out the possibility of formation of compound 4B'.

The structure of the compounds 4A and 4B were further supported on the basis of mechanism of cyclocondensation of thiocarbamides, 3A and 3B separately with chloroacetic acid. The NH attached to azo nitrogen is more acidic than NH attached to aromatic ring and hence supports the formation of 4A and 4B.

INGLE et al.: SYNTHESIS OF NEW 4-THIAZOLIDINONES

H

~/~IlCH:l R;g'sll~-CH:l

~-NH-n-NH-©-RI 3A S

!CI.CHr COOH AcONa I AcOH. reftuxed

Wrere R = H. CH3. CI R = H. CH3. OCH3. CI

Scheme I

NCS

j ~/BOH H3~~

H3C,JlNJ.

~ II~SH R-,Q; NH1--NH-N lQ 38 R

! CI.C~-COOH. . AcONa I AcOli

reftuxed

Wrere R = H. CH:l . OCH3. CI R = H. CH3. OCH3. CI

125

126 INDIAN J CHEM .. SEC B, FEBRUARY 200 1

The reaction pathways are depicted in Scheme I. The spectral data of the represented compounds of each series are incorporated in experimental section. Physical constant and elemental analysis of the products have been listed in Tables I and II.

Microbial Screening The microbial activity of the newly synthesized

compounds 4A and 4B was determined by filter paper disc method I I against Gloeosporium a1l1pelopIJagu/Il Pass, Fusarium oxysporum and Alterllaria brassicae at 100 and 250 ppm concentrations. Some of the compounds have shown better inhibitory property. 1,4-Benzothiazinyl thiazolidinones (4A, listed in Table II) with halogen and methoxy moieties have displayed better inhibition against Gloeosporium and FlIsarilllll at 250 ppm. It was observed that imidazolyl 4-thiazolidinones (4B, listed in Table III) with chloro and methoxy moieties are found to be stimulatory against Altemaria brassicae and neutral towards the other test organisms.

Experimental Section The melting points are uncorrected. IR spectra

were recorded on J ASCO spectrophotometer using KBr pellets; IHNMR spectra in CDCI) on a sophisticated multinuclear Ff·-NMR spectrophoto­meter model Ac-300 F (Brucker) 300 MHz using TMS as an internal standard (chemical shifts in 8, ppm) and mass spectra on a VG.70-70 H spectrometer at 70 eV.

Preparation of 2-acetyl-3-methyl-7 -substituted-4H-l,4-benzothiazines lA. A mixture of 2-aminobenzene thiols (0.01 mole) , aqueous sodium hydroxide (5 mL, 2N) and ethanol (20 mL) was taken in iodine flask. I-Acetyl-l-chloroacetone (0.01 mole) was then added dropwise to the iodine flask, kept at 10°C with constant stirring. After complete addition, stirring was further continued for 10 min. The reaction content was then filtered, washed with water and the crude product obtained was crystall ized from ethanol to give lA. lA-a; IR (KBr) : 720 (C-S-C), 1620 (C=O) and 3310 cm' l (NH); IH NMR (CDCI)): 2.28 (s, 3H, CH)), 2.4 (s, 3H, COCH) , 6.5-7.5 (m, 4H, Ar-H) and 8.8 (s, 1 H, NH); MS : mlz (0/0) 205 (M+, 64), 163 (62.6), 162 (100), 130 (21), 118 (16.5), 77 (8.9) and 43 (19.5).

Table I - Physical data of compounds lA, 2A, 18 and 28

SI R lA 2A 18 28 No mp Yield N (%) mp Yield N (%) mp Yield N (0/0 ) mp Yield N (0/0 )

°C (0/0 ) Found (Caled) °C (0/0) Found (Caled) °C (%) Found (Caled) °C (%) Found (Calcd)

a H 198 83 6.54 (6.83) 148 72 12.66 ( 12.78) 152 83 12.06 (11.98) 209 62 22.76 (22.54) b CH) 186 78 6.42 (6.40) 157 78 11.94 (12.01) 178 78 10.50 (10.44) 190 50 21.53 (20.84) c CI 192 62 5.57 (5.85) 165 74 10.98 (11.04) 155 80 11.38 (11.26) 223 55 19.96 (19.81) d OCH) 178 80 10.68 (10.57) 240 65 20.28 (20.54)

All the compounds were crystallized from ethanol. Lowering in m p by 20-30°C has been observed when mixed melting points were determined

Table II - Physical data of compounds 3A and 4A

SI R R' 3A 4A No mp Yi eld N (%) mp Yield N (%)

°C (%) Found (Caled) °C (%) Found (Caled)

a H H 174 72 15 .32 (15.81) 158 68 13.99 (14.21) b H CI 179 68 14.19 (14.4 1) 154 72 12.97 (13.06) c H Br 163 70 12.71 (12.93) 148 75 11.69 (11.83) d H CH) 158 63 15.Q2 (15.21) 137 72 13.65 (13.72) e H CH.1 162 69 14.32 (14.58) 152 70 13.09 (13.20) r OCH) H 161 74 15 .00 (15.21) 134 72 13.58 (13 .72) g CH) CI 171 72 13.73 (13.91) 145 68 13.03 (13.25) h CH) Br 183 72 15.31 (12.52) 138 70 11.22 (11.49)

CH) CH) 146 68 14.58 (14.65) 128 72 13.62 (13.77) j CH) OCH) 187 65 13.93 (14.07) 136 70 12.65 (12.78) k CI H 103 77 17. 19 (17.44) 143 68 12.93 (13.06) I CI CI 110 72 15.61 (15.75) 151 72 11.99 (12.09) III CI Br 105 68 13.89 (14.00) 127 70 10.95 (11.03) n CI CH) 102 72 16.63 (16.71) 146 72 12.49 (12.65) 0 CI OCH) 98 70 15.78 (15.95) 154 65 11.97 (12.21)

All compounds were crystalli sed from ag. AcOH

INGLE et af.: SYNTHESIS OF NEW 4-THIAZOLIDINONES 127

Table III - Physical data of compounds 38 and 48

SI R R' 38 48 No mp Yield N (%) mp Yield N (%)

°C (%) Found (Caled) °C (%) Found (Calcd)

a H H 100 6S IS.20 ( IS.37) 140 SO 16.20 (16.70) b H CI 177 60 16.00 (16.72) 20S 60 IS.20 ( IS .43) c H Br d H CH, 19S SO 17.S0 (17.72) IS7 SS 16.00( 16. 16) e H OCH) 20S 67 17.39 ( 17.03) 216 62 IS.30 (IS.S9) f CH) H 20S 6S 17.30 ( 17.72) 213 S2 16. 10 (16.16) g CH, CI 201 6S IS .20 ( IS .74) 232 63 14.20 (14.S6) h CH) Br

CH, CH3 2 16 SS 17.23 (17.11) 190 6S IS .23 ( IS .73) j CH) OCH3 172 70 17.2 1 (16.47) 200 60 IS .00 (1S.1 S) k CI H 13S 72 16. 10 (16.S4) ISO 60 IS .2 1 ( IS.43) I CI CI 192 64 IS.O I (1S.0S) 240 6S 14. 10 (14.32) m CI Br n CI CH3 20S 60 16.00 (16.29) 230 SS 14.S0 ( 14.97) 0 CI OCH) 170 6S IS .SO ( IS .71) 203 63 14.20 ( 14.47)

All the compounds of the series 38 were crystallized from ethanol, and 48 were crystall ized from ag. AcOH.

Synthesis of 2-hydrazinoacetyl-3-methyl-7-substituted-4H-I ,4-benzothiazines 2A. A mixture of IA (0.0 1 mole) and hydrazine hydrate (0.02 mole) was refluxed in digol ( 15 mL) for 3 hr. Reaction mixture was then cooled and poured on crushed ice. The solid obtained was filtered, washed with water and crystallized from ethanol to give 2A . 2A-a; IR (KBr): 750 (C-C), 1620 (C = N), 3 180 (N H 2) and 3280 (N H) cm- I; IH NMR (C OCI) : 2. 15 (s, 6H, 2 x CH), 5.15 (s, 2H, NH 2), 6.4-7.0 (m, 4 H, Ar-H), 9.6 (s, I H, NH) and 12.6 (s, I H, NH).

Synthesis of N 1-(4'-substituted phenyl)-N3-[3'­methyl-7'-substituted-4H -1, 4-benzothiazin-2'-yl)­methyl-ketoimino]thiocarbamides 3A. A mixture of 2A (0.0 I mole) and isothiocyanates (0.0 I mole) was refluxed in dioxane for 3 hI'. It was then concentrated and cooled. Solid obtained was filtered, washed with a little alcohol and crystalli zed from aqueous acetic acid to give 3A. 3A-B; IR (KBr): 728 (C-S-C), 1245 (C=S), 1610 (C=N), 3270 and 3350

S

(-NH-~-NH-) cm-I; IH NMR (COCl): 2. 15 (s, 6H,

2 X CHJ groups), 6.5-7.5 (m, 8H, Ar-H), 9.45 (s, I H, S

NH), 10.9 and 11.1 (s, br, 2H, NH1-NH).

Synthesis of 2-[(3'-methyl-7'-substituted-4' H-1,4-benzothiazin -2' -yl) -methy lketoiminy I] imi no-3-(4"-substituted phenyl)-4-thiazolidinones 4A. A mixture of 3A (0.0 1 mole), monochloroacetic acid (0.0 I mole) and anhydrous sodium acetate (0.0 I mole) in glacial acetic acid (25 mL) was refluxed for

4 hr. The reaction mixture was then cooled and poured on crushed ice. The solid fo rmed was filtered , washed with water and crystallized from aqueous acetic acid to give 4A. 4A-b; IR (KBr) : 724 (C-S-C), 1634 (C=N), 1694 (tertiary amide) and 32 15 (NH) cm- I; IH NMR (COCI): 2.05 (s, 3H, 'CH), 2. 15 (s, 3H, bCH), 4.4 (s, 2H, methylene protons), 6.4-7 .4 (m, 8H, Ar-H) and 9.4 (s, I H, NH) .

Synthesis of 5-acetyl-2-mercapto-4-methyl-I­arylimidazoles lB. Aniline (0.1 mole) was dissolved in dry acetonitrile (25 mL) in iodine flask. I-acetyl- I­chloroacetone (0.011 mole) was then added dropwise at 10°C with constant stirring to the iodine flask. After complete addit ion, stirring was continued for 1 hr. The reaction mixture was kept at room temperature for fu rther 12 hI'. Acetonitrile was removed under vacu um. The cx-aminoketone left over as semi solid mass was then allowed to react with potassium thiocyanate (0.0 I mole) in glacial acetic acid (15 mL) at reflux temperature for 30 min . It was then cooled and poured on crushed ice. The solid was isolated by filtration and crystallized from ethanol to give lB. IB-b; IR: 1500 (C=C), 1614 (C-N-C), 1743 (C=O) and 2480 (-S H weak) cm-I; IH NMR (COCl) : 2. 15 (s, 3H, CH), 2.4 (s, 3H, "CH3), 2.6 (s, 3H, bCH3),

7.0-7.6 (m, 4H, Ar-H) and 9.8 (s, weak, 1 H, SH); MS: mlz (%) 246 (M+' unstable), 138 ( 100), 108 (32.83), 92 (40.29), 65 (76. 11 ), 63 (8.95) and 43 (22.38).

Synthesis of 5-hydrazinoacetyl-2-mercapto-4-methyI-I-arylimidazoles 2B. A mixture of IB (0.01 mole) and hydrazine hydrate (0_02 mole) was refluxed

128 INDIAN J CHEM ., SEC B, FEBRUARY 2001

in digol (30 mL) for 4 hr. Reaction mixture was cooled, and poured on crushed ice. The solid obtained was filtered, washed with water and then crystallized from ethanol to give 2B. 2B-a ; JR (KBr): 1580 (C=C), 1600 (C=N), 2460 (S-H), 2890 (C-H stretch aliphatic) , 3030 (C-H aromatic) and 3100-3190 (NH) cn,- I; I H NMR (COCl): 1.30 (s, 6H, 2 x CH) groups), 4.75 (s, 2H, NHz conjugated), 6.20-7.75 (01, 5H, Ar-H) and 9.6 (s, weak, 1 H, SH).

Synthesis of N l_phenyl_N3 -[2'-mercapto-4'-methyl­l'-phenyl-imidazol-S'-yl)-methylketoimino ]thiocarba­mides 3B. A mixture of 2B (0.01 mole) and phenyl isothiocyanate (0.0 1 mole) was refluxed in alcohol (30 mL) for 5 hr. It was then concentrated and cooled. Solid obtained was filtered, washed with alcohol and crystalli zed from alcohol to give 3B. 3B-a; IR (KBr): 1250 (C=S stretch) , 1400-1590 (C=C and C=N), 2450 (SH stretch), 2830-2890 (C-H, aliphatic), 3050 (C-H aromatic) and 3210 (N-H) em-I; IH NMR (COCl) : 1.4 (s, 6H, 2 x CH3 groups), 7.0-7.5 (m, lOH, Ar-H),

S

8.9 (s, br, 2H, NH-~-NH) and 10.1 (s, weak, IH , S- H).

Synthesis of 2-[(1'-phenyl-2'-mercapto-4'-methyl­imidazol-S'-yl)-methylketoiminyl]imino-3-phenyl-4-thiazolidinones 4B. A mixture of 3B (0.01 mole), monochloroacetic acid (0.01 mole) and anhydrous sodium acetate (0.01 mole) in glacial acetic acid (25 mL) was refluxed for 5 hr. The reaction mixture was then cooled and poured on crushed ice. The solid formed was filtered , washed with water and

crystallized from aqueous acetic acid to give 4B. 4B­a; IR (KBr): 1450-1740 (C=C, C==N, and tertiary amide), 2470 (SH), 29 10-3020 (C-H ali phatic and aromatic) em- I; IH NMR (COCl): 1.75 (s, 3H, aCH) , 2.1 (s, 3H, bCH) , 4.06 (s, 2H, methylene protons), 7.0-7.46 (01, 10H, Ar-H) and 10.05 (s , weak, lH, SH).

Acknowledgement The authors are thankful to Dr Sudha Shrivastav,

TIFR, Mumbai and Dr M Vairamani, IICT, Hyderabad for spectral assistance. The au thors are grateful to Chairman, UGC, Delhi for the financial support.

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