Indian Journal of Chemistry Vol. 408, July 200 1 , pp. 584-586

Heterocyclic systems containing bridgehead nitrogen atom : Synthesis, stereo­chemistry and evaluation of biological activity of thiazolo [3 ,2-b ] -s-tetrazines and

trans-dihydropyrazolo[3' ,4' :4,5]thiazolo[3,2-b ]-s-tetrazines

Jag Mohan

Department of Chemistry. M.D. University, Rohtak- 12400 1 , India Received 14 Jllne 1 999; accepted (revised) 27 Jllne 2000

3.3-Diethy 1-2H,4H-thiazolo[3,2-b ] -s-tetrazin-6(7 H)-one 2, 3,3-diethyl -2HAH -6, 7 -dihydrothiazolo[3,2-b ]-s-tetrazine hydrobromide 4 and 6-aryl-3, 3-diethyl-2H, 4H-thiazolo[3,2.-b]-s-tetrazine hydrobromide 5 have been synthesised by the reaction of 6.6-diethyl- l , 2, 4, 5-tetrahydro-s-tetrazin-3-thione 1 with chloroacetic acid, 1 .2-dibromoethane and u­haloketones. respectively. 7-Arylidene-3,3-diethyl-2HAH-thiazolo[3.2-b]-s-tetrazin-6(7 H) -ones 3 have been prepared either by the condensation of 2 with aldehyde or in a single step by the reaction of I with ethyl chloroacetate and aldehydes in the presence of pyridine and piperidine. Condensation of 3 with 2,4-dinitrophenylhydrazine in the presence of anhydrous so­dium acetate furnishes 7,8-diaryl-2HAH-trans-8,8a-dihydropyrazolo[3'A':4,5]thiazol0 [3,2,-b]-s-tetrazines 6. The antibacte­rial and antifungal activity of some of the compounds have also been evaluated.

In continuation of our earlier work on the synthesis of biologically active condensed bridgehead nitrogen heterocyclic systems 1 -5 and in view of the reported antimicrobial activity of thiazolo-s-tetrazines6-7, the synthesis, stereochemistry and associated antimicro­bial activity of some interesting condensed bridge­head nitrogen heterocyclic systems derived from 6, 6-diethyl- I ,2,4,5-tetrahydro-s-tetrazine-3-thione 1 have been reported in this paper.

Compound 1 obtained by the reaction of 3-pentanone with thiocarbohydrazide following the method of Lamon8, on condensation with chloroacetic acid furnished in one step the cyclized product, 3,3-diethyl-2H, 4 H-thiazolo[3,2-b ]-s-tetrazin-6 (7 H)-one 2. 7-(p-Chlorobenzylidene)-3�3-diethyl-2H, 4H- thi­azolo[3 ,2-b ]-s-tetrazin-6 (7 H)-one 3 (Scheme J) has been prepared by the following two routes : (i), the thiazolidinone 2 was condensed with aldehydes, ( i i ) I was directly heated with ethyl chloroacetate and alde­hydes in the presence of pyridine and piperidine. Condensation of 3 (Ar=p-C 1 C6H4-) with 2,4-dinitrophenylhydrazine yielded in one step the cy­c1ized product, 3, 3-diethyl-8-(p-chlorophenyl)-7 -(2, 4- dinitrophenyl)-2H,4H-tralls-8,8a-dihydropyrazolo­[3',4' :4.5]thiazolo[3.2-b ]-s-tetrazine 6. The structure of 6 was supported by IR and IHNMR spectral data (vide Experimental). The appearance of two doublets (1= 1 .2 Hz) at 87.40 and 7 .90 for C-8a-H and C-8-H corroborated the cyclic structure and trails configura­tion9•

Similarly, 1 on condensation with 1 ,2-dibromoethane and a-haloketones furnished 3, 3-diethyl-2H, 4H-6, 7 -dihydrothiazolo[3,2-b ]-s-tetrazine hydrobromide 4 and 6-aryl-3, 3-diethyl-2H, 4H­thiazolo[3,2-b ]-s-tetrazine hydrobromides 5, respec­tively.

Antimicrobial activity

The compounds 2, 4, 5 (R=Br) and 6 were evalu­ated for their antimicrobial activity against the gram­positive Staphylococclls allreus and gram-negative Escherichia coli and Pseudomollas aerugillosa bacte­ria and fungus Calldida albicaJls by neat samples and serial plate dilution method to , The minimum inhibi­tory concentration (MIC) of the compound 4 against S. aureus and Calbicalls is 250,ug/mL. The com­pounds 5 (R=Br) and 6 were found to be active against S.aureus and C.albicalls when treated as neat samples, and may be used as a local applicant in the form of powder or ointment provided further studies indicate the absence of toxicity .

Experimental Section

TLC was run on silica gel-G plates using acetone­benzene ( l :3) as irrigant. Melting points are uncor­rected. IR (KBr, Vmax in cm- I) and IHNMR spectra (8, ppm down field from TMS) were recorded on Hitachi 2 1 5 and Beckman IR-20 and Varian VXR-200 MHz and Perkin-Elmer (P-32) spectrometers, respectively. All compounds gave satisfactory C, H, N, S elemental analysis.

JAG MOHAN: HETEROCYCLIC SYSTEMS CONTAINING BRIDGEHEAD NITROGEN ATOM 585

2 �4 H N 3 N H , � 5� H B r

1�5 S 7 e

4

5

( i v ) �

\. ,{\

a • R = Br

b , R = C6H5 c , R = C l d , R = H

HXH I . ,

H N t : H

y 5

5

0 ) )

vi

2�" H N 3 H I 1 5

l y�::t S 7 8

1...

1 ( ii l

2� H 3 NH 1 I ' 5 N�

N 0

'--1 � 7 C HAr 3

0 ) C l C H2 COOH , N.OAc , ( i i ) A r C HO , N.OAc

( i ii) C I C � C OO E t , Py r id i ne , A r C HO , piperldln� ,

<iv ) B r C H2 C H2 B r ; ( v ) R C O C H2 X }V I ) 2 , 4 - 0initro -

phenyl h y d r a z i ne .

Scheme I

6, 6,-Diethyl-l, 2, 4, 5-tetrahydro-s-tetrazine-3-thione 1. It was prepared by the treatment of 3-pentanone with thiocarbohydrazide according to the method of Lamon8, yield 65%, m.p. 1 20°; IR: 1 1 20 (C=S), 1 525 (C-N stretching), 3240, 3472 (N-H stretching).

3,3-Diethyl-2H, 4H-thiazolo[3,2-b]-s-tetrazin-6(7H)-one 2. A mixture of 1 ( 1 .74g, O.Olmole), chlo­roacetic acid (0.94g, 0. 1 mole) and anhydrous sodium acetate ( 1 .64g, 0.02mole) in absolute ethanol (30 mL) was refluxed on a steam-bath for 5 hr. The reaction mixture was concentrated, cooled and poured into cold water. The light brown solid, thus separated, was filtered, washed wel1 with water and crystal1ized from rectified spirit as colourless cystals, mp >250°, yield 1 .8g (84%); IR: 1 535 (C-N stretching), 1 620 (C=N), 1 725 (C=O), 3240, 3330 (N-H stretching).

7-(p-Chlorobenzylidene)-3,3-diethyl-2H,4H-thia­zolo[3, 2-b ]-s-tetrazin-6 (7 H)-one (3, Ar=p-CI

C6H4-). A mixture of 1 ( 1 .74g, 0.0 1 mole), ethyl chlo­roacetate ( 1 .22g, 0.0 1 mole), pyridine (0.90 mL) and anhydrous ethanol (30mL) was refluxed on a steam­bath for 4 hr. p-Chlorobenzaldhyde ( l AO g, 0.0 1 mole) and piperidine (0.70 mole) were then added and the reaction mixture was refluxed further for 4 hr and cooled. The yel10w solid, thus separated, was filtered, washed with water and crystal1ized from glacial acetic acid to give yel10w granular crystals, mp 1 64°, yield 2.8g (83%); IR: 830 (p-substituted phenyl ring), 1 520 (C-N stretching), 1 600, 1 6 10 (C=C and C=N), 3340 (N-H stretching).

8-(p-ChlorophenyI)-7 -(2,4-dinitrophenyl)-3,3-di­ethyl-2H, 4H-trans-8, 8a-dihydropyrazolo[3' ,4' :4, 5]thiazolo[3,2-b ]-s-tctrazine 6. A mixture of 3 ( 1 . 1 g, 0.003 mole), 2,4-dini trophenylhydrazine (0.56 g, 0.003 mole) and anhydrous sodium acetate (OA9g, 0.006 mole) in gl. acetic acid (20mL) was heated un­der reflux on a heating mantle for 6 hr, cooled and

586 INDIAN J CHEM, SEC B, JULY 2001

poured into water. The solid, thus separated, was fil­tered, washed with water and crystallized from gl. acetic acid as orange flakes, mp >230, yield 1 .2g (70%); IR: 830, 840, 875 ( l , 2,4-trisubstituted ben­zene ring and p-substituted phenyl ring), 1 525 (C-N stretching); 1 6 10, 1 620 (C=C and C=N), 3320 (N-H stretching), IHNMR (DMSO-d6): 1 .20 (6H,t, J=7Hz, 2x-CH2-CH3), 1 .90 (4H, g, J=7Hz, 2x-CH2-CH3), 2.54(2H, br.s, 2 x NH, exchangeable with 020), 7. 1 6 ( 1H, d , J= 1 .2Hz, C-8a-H), 7.0-9.0 (7H, m, Ar-H), 8 . 10( 1 H,d, J= 1 .2Hz, C-8-H).

3,3-Diethyl-2H ,4H -6, 7 -dihydrothiazolo[3,2-b[ -s­tetrazine hydrobromide 4. A mixture of 1 ( 1 .74g, 0.0 1 mole) and 1 ,2-dibromoethane ( 1 .88g, 0.0 1 mole) in anhydrous ethanol (30mL) was heated under reflux for 5 hr, concentrated and cooled. The colourless solid, thus separated, was filtered, washed with water and crystallised from ethanol as colourless crystals, mp 166°, yield 1 .7g (6 1 %); IR : 1 525 (C-N stretch­ing), 1 600 (C=N), 3 1 40 and 3260 (N-H stretching); I HNMR (DMSO-d6): 1 .0 (6H,t, J=7Hz, 2x-CH2-CH3, 1 .72 (4H, g, J=7Hz, 2xCHrCH), 2.32(2H, t, SCH2), 2.68(2H, t, NCH2), 5.20(2H, brs, 2 x NH, exchange­able with 020).

6- (p-Bromophenyl)-3,3-diethyl-2H,4H-thiazolo­[3,2-b ]-s-tetrazine hydro- bromide Sa. A mixture of 1 ( l .74g, 0.0 1 mole) and p-bromophenacyl bromide (2.78g, 0.0 1 mole) in benzene (30mL) was refluxed for 3 hr. The hydrobromide, thus separated, was fil­tered, washed with water and crystallized from a mixture of ethyl acetate-methanol (3 : 1 ) as light brown crystals, mp 1 84°, yield 2.8g (65%); IR : 835 ( l ,4-disubstituted benezene ring), 1 520 (C-N stretching), 1 600, 1 6 10 (C=C and C=N), 3040 (aromatic C-H stretching), 3260 (N-H stretching); IH NMR(CDCI3+ TFA): 1 .23(6H,t, J=7Hz, 2x-CH2-CHJ) 2.60 (4H, g, J=7Hz 2xCHrCH3, 3 .60 (2H, br.s, 2xNH, exchangeable with 020), 6.8 ( l H, s, C-7-H), 7.45(2H,d, 9Hz, H-3' and H-5'), 7 .73(2H, d, 9Hz, H-2' and H-6').

Other thiazolo[3,2-b ]-s-tetrazines 5b-d were pre-

pared similarly. 5b(R=Cl): obtained from 1 and p-ClC6H4COCH2Br, mp 1 75°, yield 57%; IR:830( l ,4-disubstituted benzene ring), 1 535 (C-N stretching), 1 600, 1 6 1 5 (C=C and C=N), 3030 (aro­matic C-H stretching), 3230, 3240 (N-H stretching).

5c (R=C6H5) : obtained from 1 and p­C6H5C6H4COCH2Br, mp 1 88°, yield 56%; IR:700, 745, 835 (mono and 1 ,4-disubstituted benzene rings), 1 525 (C-N stretching), 1 600, 1 620 (C=C and C=N), 3040 (aromatic C-H stretching); 3200, 3230 (N-H stretching).

5d (R=H): obtained from 1 and C6H5COCH2Cl, mp 162°, yield 48%; IR: 690, 740 (monosubstituted ben­zene ring), 1 5 1 5 (C-N stretching), 1 600, 1 6 10 (C=C and C=N), 3020(aromatic C-H stretching), 3230, 3240(N-H stretching).

Acknowledgement

The author is thankful to Hiratake Jun, Institute of Chemical Research, Kyoto University, Japan for ele­mental analysis, IR, IHNMR and mass spectra, to Dr 0 R Arora, Department of Microbiology, Medical College, Rohtak for biological screening and to the Head, Chemistry Department, M.D. University, Rohtak for providing laboratory facilities.

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Chem Abstr, 83, 1975, 10079. 7 Hoehn M M & William R H. Ger offen 2, 0 19, 838, 1971;

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(Himalaya Publishing House, Bombay, India). 1992. 62. 10 Nakahara H, Ishikawa T. Sarai Y, Kondo T & Mitsuhashi S,

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