Indian Journal of Chemistry Vol. 42B. March 2003. pp. 616-620

Chemistry of benzocycloheptenones: Part I - Synthesis of 2,5-disubstituted 1,3,4-thiadiazoles/oxadiazoles as biologically active heterocycles

Venkateswarlu Peesapati* & Srikant Venkata Chitty

Industrial Chemistry Labs - Centre fo r Environment. J NT University . Mahaveer Marg. Hyderabad - 500 028 . Indi a

Received 19 November 2001; accepted (revised) 20 August 2002

A series of new I 0-methyl-2-(5-methyllphenyl-I .3.4-thiadiazol-2-ylmethyl) 3.5.6.7-tetrahydro-3H-benzo[6.7Jcyclo­hepta[ 1.2-c Jpyridazin-3-thiones 5, 8 and I 0-methyl-2-(5-methyllphenyl-I.3.4-oxadiazol-2-ylmethyl)-3.5.6.7-tetrahydro-3H­benzo[6.7] cyclohepta[ 1.2-c]pyridazi n-3-ones 6, 9 and other thiadi azole deri vatives 11 have been sy nthesized. All the com­pounds have been evaluated for their antimicrobial ac ti vity.

As part of our ongoing study in the design and syn­thesis of novel heterocyclic compounds, we have re­cently reported the synthesis of polyheterocyclic compounds. Further, our earlier work l

.3 showed that

significant antimicrobial activity in such polyhetero­cyclic compounds- have prompted us to synthesize some new oxadiazolo and thiadiazolo derivati ves to study their structure-activity relationship. Further­more, a number of 2,5-disubstituted 1 ,3,4-oxal thiadi­azoles have been reported to possess antibacterial, antiinflammatory, anticonvulsant, hypoglycemic and antituberclosis activit/·8. Led by these observations, the synthesis of some new biologically active 2,5-disubstituted 1,3,4-oxadiazoles/thiadiazoles 5, 6, 8, 9 and 11 were undertaken starting from 3H­benzo[6,7]cyclohepta [1 ,2-c] pyridazi n-3-one 1.

Ethyl 2-( 1 0-methyl-3-oxo-3,5,6,7 -tetrahydro-3H­benzo[6,7]cyclohepta[l ,2-c] pyridazin-2-yl)acetate 2, obtained by the condensation of 3,5,6,7-tetrahydro-3H-benzo [6,7]cyclohepta[ 1 ,2-c ]pyridazin-3-one 1 with ethyl bromoacetate in the presence of potassium carbonate, on reaction with hydrazine in ethanol, yielded the key intermediate 3 in good yield. The IR spectrum of 3 exhibited absorption bands in the re­gion 3100-3360 (-NH and -NH2) and 1666 cm-I (br, CO) functionality . The subsequent reaction of the tri­cyclic amine derivative 3 was converted into N-acetyl derivative 4 by treating with acetic anhydride in acetic acid. The physical data of compounds 2-11 are given in Table I and spectral data in Table II.

Reaction of 4 with phosphorus pentasulfide in xy­lene at reflux temperature afforded fused thiadiazolo compound 5 along with oxadiazolo derivative 6 as a minor product. On the other hand, reaction of 4 with

phosphorus oxychloride in refluxing acetonitrile led to exclusive oxadiazole 6 only . In IH NMR spectrum the N-CH2 protons of the thiadiazolo compound ap­peared at 8 6.35 whereas in oxadiazolo compound the N-CH2 protons appeared at 8 5.60. The formation of thialoxadiazole rings involves N-acetyl group was evident by the absence of absorption bands due to either of these groups in the IR spectrum of 5 and 6.

Similarly, the pyridazinyl-2-acetyl hydrazide de­rivative 3 was converted into 8 and 9 through the in­termediate 7 (see Scheme I). Here also, we have ob­served small amount of oxadiazole derivative as a minor product along with the major compound 8 when 7 wa treated with phosphorus pentasulfide in xylene. Similar phenomenon was observed by earlier workers9

. It has been observed that dehydrative ring closure of 4 and 7 is faster and gave better yields with thionyl chloride when compared wi th phosphorus oxychloride.

Finally, treatment of 3 with formic acid yielded 10 (see Scheme I) which on dehydrati ve ring-c losure by treatment with phosphorus pentasulfide in xylene afforded 10-methyl-2-( 1 ,3,4-thiadiazole-2-ylmethyl)-3,5,6,7 -tetralhydro-3H-benzo[6, 7]cyclohepta[ 1 ,2-c ]pyri ­dazine-3-thione 11. The structural assignments of all these compounds were based on their spectral data and elemental analysis.

Antibacterial activity

Compounds 2a, 4b, 7a-b and 11a-b showed mod­erate activity against gram-positive bacterium Staphy­lococcus aureus and gram-negative bacterium Kleb­siella using Cefotaxime as a reference compound .

PEESAPATI et at.: SYNTHESIS OFTHIADlAZOLE/OXADlAZOLE DERIVATIVES 617

6a-b +

la-b

5a-b

(';; oX

2a-b

t iii 0

6a-b

r NHNH2

xfj,N 0

\ h R ;:/ VIII

I RI ~

3a-b

o 0

~/

d3,N 0

R \ h ;:/ I ... vii

RI ~

rNHNH-~--o

d3,N 0

\ h R ;:/ I

RI ~

fNHNHJ-H

d3,N 0

\ h R ;:/

9a-b

a)R=CH3,RI=H

b) R= RI =CH3

7a-b

8a-b

RI ~ I lOa-b

Ila-b

i) BrCH2COOC2Hs, acetone, K2C03, ii) Anhyd. Hydrazine, EtOH, iii) Acetic acid / acetic anhydride, iv) P2SS, xylene, v) POCl), acetonitrile, vi) Benzoyl chloride, triethyl amine, DMF, vii) Thionyl chloride, viii) Formic acid.

Scheme I

Experimental Section Commercially available solvents were distilled by

recommended procedures prior to use. Melting points were determined using Gallenkamp apparatus and are uncorrected. IR spectra were recorded on a FT-IR 1605 Perkin Elmer, 'H NMR in CDCb / DMSO-d6 on a varian FT-80A spectrometer with TMS as internal standard and mass spectra on a VG-micromass 7070 H mass spectrometer.

Ethy I 2-(1 O-methyl-3-.oxo-3,5,6, 7 -tetrahydro-3H­benzo[6,7]cycIohepta[1,2-c] pyridazin-2-yl)acetate 2a. A mixture of 1a (2.0g, 8.84 mmole) , ethyl bro­moacetate (0.98 mL, 8.84 mmole) and anhyd . potas­si um carbonate (2.43g, l7 .68 mmole) in dry acetone (20 mL) was heated under reflux for 2 hr. The inor­ganic solids were filtered while hot and solvent was removed under reduced pressure. The resulting resi­due was triturated with water to remove potassium

618 INDIAN 1. CHEM., SEC S , MARCH 2003

Table I - Physical data of compounds 2-11

Compd Mol. m.p. Yield Found (Calcd) %

formula (0C) (%) C H N

2a C18H20N20 ) 11 8-20 87 69 .20 6.38 8.92 (69 .23 6.41 8.97)

2b C I9Hn N2O) 86-88 85 69.90 6.70 8.52 (69.93 6.74 8.58)

3a CI6HI SN40 2 198-200 88 64.40 6.00 18.75 (64.42 6.04 18.79)

3b C17H20N402 2 18-20 80 65 .35 6.35 17.90 (65.38 6.41 17.94)

4a ClsH20N40 ) 220-22 88 63.50 5.82 16.40 (63.52 5.88 16.47)

4b C1 9H22N40 ) 260-64 85 64.35 6.17 15.77 (64.40 6.21 15.8 1)

Sa CI8HI8N4S2 174-76 26 60.05 5.00 15.79 (61.01 5.08 15.81)

Sb CI9H20N4S2 154-56 30 61.90 5.40 15.1 8 (6 1.95 5.43 15.2 1)

6a CI8HI8N40 2 138-40 25 67.01 5.52 17.30 (67 .08 5.59 17.39)

6b CI9H20N402 158-61 28 67 .8 1 5.92 16.60 (67.85 5.95 16.66)

7a C23 Hn N4O) 110-12 63 68.60 5.44 13.90 (68.65 5.47 13.93)

7b C24H24N40 ) 158-61 65 69 .20 5.70 13.43 (69.23 5.76 13.46)

8a C2)H20N4S2 172 decompd. 35 66.30 4.75 13.40 (66.34 4.80 13.46)

8b C24Hn N4S2 180-82 30 66.95 5.05 13.00 (66.97 5.11 13.02)

9a C2)H20N40 2 58-60 30 71.85 5.15 14.55 (71.87 5.20 14.58)

9b C24HnN402 82-84 28 72.30 5.50 13.95 (72.36 5.52 14.07;

lOa C 17HI8N4O) 167-70 66 62.50 5.47 17.15 (62.57 5.52 17.17)

lOb ClsH20N40 ) 218-20 65 63 .50 5.80 16.40 (63.52 5.88 16.47)

11a C17HI6N4S1 158-6 1 23 59.95 4.68 16.45 (60.00 4.70 16.47)

lIb CI8HI8N4S2 172-74 25 59.95 5.05 15.75 (61.01 5.08 15.8 1)

T able II - Spectral data of compounds 2 - 11

Compd IR (KBr) IHNMR Mass (cm-I) (8 ppm) (M+)

2a 1740 (CO), 1.20-1.39 (3 H, t,-OCH2CH) , 2.05-2 .20 (2H, m, 6-CH2), 2.35 (3H, s, IO-CH), 2.35-2 .50 (2H, t, 1665 (C=O) 5-CH2), 2.55-2.70 (2H, t, 7-CH2), 4.20-4.32 (2H, q, -OCH2), 4.90 (2H, s, N-CH2), 6.75-7.30 (3H,

m, aromatic) and 7.35 (lH, s, 4-CH).

2b 1738 (CO), 1.20-1.40 (3H, t, -OCH2CH) , 2.10-2.25 (2H, m, 6-CH2}, 2.40 (6H, s, 9, IO-CH), 2.40-2.50 (2B, 1676 (CO) t, 5-CH2), 2.55-2.70 (2H, t, 7-CH2), 4.20-4.30 (2H, q, -OCH2), 4.90 (2H, s, N-CH2), 6.70 and 7.00

(2H, s, aromatic) and 7.50 (\ H, S, 4-CH).

-(Contd)

PEESAPATI et aL.: SYNTHESIS OF THIADlAZOLE/OXADIAZOLE DERIVATIVES 619

T able II - Spectral data of compounds 2 - ll-(Contd)

Compd IR (KB r) IHNMR Mass (em-I) (8 ppm) (M+)

3a 3100-3300 2.05 -2.20 (2H, m, 6-CH2) , 2.40 (3H, s, 10-CH3), 2.30-2.50 (2H, t, 5-CH2), 2.55-2.70 (2H, t, 7-(-NH & -NH2), CH2), 4.10 (2H, brs, NH2), 4.80 (2H, s, N-CH2), 6.75-7 .20 (3 H, m, aromatic), 7.60 (lH, s, 4-CH) 1686 (CON H), and 9.10 ( I H, brs, NH).

1655 (CO)

3b 3100-3360 2.00-2.20 (2 H, m, 6-CH2), 2.30 (6H, s, 9,1 0-CH3), 2.35-2.50 (2H, t, 5-CH2), 2.50-2 .65 (2H, t, 7-(-NH & -NH2), CH2), 4.10 (2H, brs, NH2), 4.75 (2H, s, N-CH2) , 6.70 & 7.00 (2H, s, aromatic), 7.90 (I H, s, 4-CH) 1666 (br, CO) and 9.25 (I H, brs, NH).

4a 3100-3260 1.95 (3H , s, COCH3), 2.00-2 .10 (2H, m, 6-CH2), 2.35 (3H, s, 10-CH3), 2.40-2.45 (2H, t, 5-CH2),

(NH), 1660 (CO), 2.50-2 .60 (2 H, t, 7-CH2), 4.80 (2H, s, N-CH2), 6.75-7.30 (3 H, m, aromatic), 7.35 (lH, s, 4-CH) 1674 (CON H) and 10.00 ( I H, s, NH).

4b 3100-3260 (NH), 1.90 (3H, s, COCH3), 2.00-2 .10 (2H, m, 6-CH2), 2.25 (6H, s, 9,10-CH3), 2.30- 2.45 (2H, t, 5-1674 (CON H), CH2), 2.50-2.60 (2 H, t, 7-CH2), 4.85 (2 H, s, N-CH2), 6.65 & 6.90 (2H, s, aromatic), 7.50 (I H, s,

1650 (CO) 4-CH) and 9.80-10.00 (I H, brs, NHNH).

Sa 1149 (C=S) 2. 10-2.25 (2H, m, 6-CH2 ), 2.40 (3H, s, I 0-CH3), 2.30-2.50 (2H, t, 5-CH2 ) , 2.50-2.70 (2H, t, 7- 354 CH2), 2.80 (3H, S, CH3), 6.30 (2H, s, N-CH2), 7.05-7.45 (3H, m, aromatic) and 7.65 (I H, s, 4-CH).

5b 1135 (C=S) 2.10-2.25 (2H, m, 6-CH2), 2.30 (6H, s, 9,1 0-CH3), 2.35-2.50 (2H, t, 5-CH2), 2.50-2.65 (2H, t, 7- 368 CH2), 2.75 (3H, s, CH3), 6.30 (2H, s, N-CH2), 6.95 & 7.30 (2H, s, aromatic) and 7.60 ( IH, s, 4-CH).

6a 1665 (CO) 2.00-2.10 (2H, m, 6-CH2), 2.35 (3H, s, IO-CH3), 2.40-2.45 (2H, t, 5-CH2), 2.55-2.65 (2H, t, 7- 322 CH2), 2.55 (3H, s, CH3), 5.00 (2H, s, N-CH2) , 6.80-7 .30 (3H, m, aromatic) and 7.35 ( IH, s, 4-CH).

6b 1665 (CO) 2.05-2.20 (2H , m, 6-CH2), 2.30 (6H, s, 9,IO-CH3), 2.35- 2.50 (2H, t, 5-CH2), 2.50- 2.65 (2H, t, 336 7-CH2), 2.55 (3 H, s, CH3), 5.55 (2 H, s, N-CH2) , 6.75 & 6.95 (2H, s, aromatic) and 7.25 ( I H, s, 4-CH).

7a 3140-33 10 (N H), 2.00-2.10 (2H, m, 6-CH2), 2.25 (3H, s, 1 0-CH3), 2.15- 2.25 (2 H, t, 5-CH2), 2.30- 2.35 (2H, t, 7-1680 (CONH), CH2), 5.00 (2H, s, N-CH2), 7.00 - 8.05 (9H, m, aromatic & 4-CH) and 10.15 (2 H, brs, NHNH).

1648 (CO)

7b 3130-3330 (N H), 2.00-2. 10 (2H, m, 6-CH 2), 2.20 (6H, s, 9,IO-CH3), 2.30-2.40 (2H , t, 5-CH2), 2.40-2.50 (2H, t, 7-1683 (CONH), CH2), 4.90 (2H, s, N-CH2), 6.70-7.90 (8 H, m, aromatic & 4-CH) and 10.20 (2H, brs, NHNH).

1652 (CO)

8a 1152 (C=S) 2. 10-2.25 (2H, m, 6-CH2), 2.40 (3H, s, 10-CH3), 2.35-2.50 (2H, t, 5-CH2), 2.55-2.70 (2H, t, 7- 416 CH2) , 6.38 ( I H, s, N-CH2) and 7.10-8.00 (9H, m, aromatic & 4-CH ).

8b 1150 (C=S) 2.10-2.25 (2H, m. 6-CH2) , 2.35 (6H, S, 9, 10-CH3), 2.42-2.55 (2H, t, 5-CH2), 2.55-2.70 (2 H, t, 7- 430 CHz), 6.40 (2H, S, N-CH2), and 7.00-8. 10 (8H, m, aromatic & 4-CH).

9a 1652 (CO) 2.10-2.25 (2H, m, 6-CH2), 2.40 (3H, S, 10-CH3), 2.45-2.55 (2H, t, 5-CH2), 2.60-2.75 (2H, t, 7- 384 CHz), 5.70 (I H, s, N-CHz) and 6.85-8.10 (9H, m, aromatic & 4-CH).

9b 1650 (CO) 2.00-2.15 (2H, m, 6-CH2) , 2.20 (6H, S. 9.IO-CH3)' 2.35-2.45 (2H, t, 5-CH2), 2.50-2.60 (2H, t, 7- 398 CH2), 5.60 (2H, s, N-CH2) and 6.75-8.00 (8H, m, aromatic & 4-CH).

lOa 3130-3300 (NH), 2.00-2 .15 (2H, m, 6-CH2), 2.35 (3H, m, 10-CH3), 2.40-2.45 (2H, t, 5-CH2) , 2.50-2 .60 (2H, t, 7-1710 (CO), CH2), 4.80 (2H, s, N-CH2), 6.75-7.30 (3H, m, aromatic), 7.35 (I H, s, 4-CH) and 9.00 ( I H, s,

1685 (CONH), CHO). 1662 (CO)

lOb 3100-3230 (N H), 2.00-2.10 (2H, m, 6-CH2), 2.30 (6H, s, 9,IO-CH3), 2.35- 2.45 (2H, t, 5-CH2), 2.50-2.60 (2H, t, 7-1683 (CON H), CH2) , 4.85 (2H, s, N-CH2), 6.65 & 6.90 (2H, s, aromatic), 7.50 (IH, s, 4-CH) & 9.00 (lH, S,

17 18 (CO), CHO). 1655 (CO)

lla 1145 (C=S) 2.10-2.20 (2H, m, 6-CH2), 2.40 (3 H, S, 10-CH3), 2.35-2.45 (2H, t, 5-CH2) , 2.50-2.65 (2 H, t, 7- 340 CH2), 6.40 (2H. s, N-CH2), 7.10-7.35 (3H, m, aromatic), 7.65 ( I H, S, 4-CH) and 9.00 ( I H, s, N=CH).

lIb 1150 (C=S) 2.10-2.25 (2H, m, 6-CH 2) , 2.30 (6H ,~, 9,10-CH3), 2.40-2.50 (2H, t, 5-CH2), 2.50-2.65 (2H, t, 7- 354 CH2), 6.40 (2H, s, N-CH2), 7.00 & 7.35 (2H, s, aromatic), 7.65 ( IH, s, 4-CH) and 9.10 (lH, s, N=CH) .

620 INDIAN J. CHEM ., SEC B, MARCH 2003

carbonate, solid separated out was filtered, washed with water, dried and recrystallized from ethanol to furnish 2a (2.4g).

2-(10-Methyl-3-oxo-3,s,6,7-tetrahydro-3H-benzo­[6, 7]cyclohepta[ 1 ,2-e ]py ridazin -2-yl)ethanohydra­zide 3a. To a solution of 2a (2.20 g, 7.05 mmole) in ethanol (20 mL), anhyd . hydrazine (2 .25 mL, 71.45 mmole) was added slowly and the mixture was stiLTed at room temperature for 1 hr. The solvent was re­moved under reduced pressure and triturated with wa­ter to give solid which was recrystallized from ethanol to afford 3a (1.85g).

10-M ethy 1-2-( 5-methy 1-1 ,3,4- thiadiazol-2-y Ime­thyl)-3,s,6,7 -tetrahydro-3H -beilZo [6,7]cyclohepta­[I,2-e]pyridazin-3-thione Sa. A mi xture of 3a (0.3g, I mmole) in 1 mL of acetic acid was added 0.1 mL of acetic anhydride. The addition was exothermic and after a few minutes a white solid was appeared. The mixture was refluxed for 1.5 hr and the solution was diluted while hot with 15 mL of water. The solid was filtered, dried and recrystallized from ethanol to af­fo rd 4a (0.3g). To a suspension of the above interme­di ate 4a (0.15g, 0.44 mmole) in xylene (5 mL) was added phosphorus pentasulfide (0.055g, 0.25 mrnole) and the mixture was refluxed for I hr. The solvent was removed under reduced pressure and poured into water. After usual work-up, the res idue was purified by preparative TLC (ethyl acetate-pet. ether 2:8) and recrystallized from benzene to afford Sa (0.04g).

IO-Methyl-2-(5-methyl-I,3,4-oxadiazol-2-ylme­thyl)-3,s,6,7 -tetrahydro-3H -benzo [6,7]cyclohepta­[1,2-e]pyridazin-3-one 6a. A mixture of 4a (0.15g, 0.44 mmole) in acetonitrile (5 mL) was added phos­phorus oxychloride (0.04 mL, 0.42 mmole). The mix ­ture was refluxed overnight. After the usual work-up, the resulting residue was purified by preparative TLC on a silica gel (methanol-chloroform 1 :9) and recrys­tallized from benzene-chloroform to afford 6a (0.035g).

10-Methyl-2-(s-phenyl-I,3,4-thiadiazol-2-ylme­thyl)-3,s,6,7 -tetrahydro-3H -benzo [6, 7]cyclohepta­[1,2-e]pyridazin-3-thione 8a. A mixture of 3a (0.3 g, 1 mrnole) , triethylamine (0.15 mL, 1.10 mmole) in 5 mL of N.N-dimethylformamide was treated dropwise with a solution of benzoyl chloride (0. 12 mL, 1.10 mmole) in 2 mL of N.N-dimethylformamide.The mix­ture was stirred at room temperature for 1 hr and neu­tralized with IN HC!. The solid obtained was filtered, washed with water and dried, and recrystallized from methanol to give 7a (0.25g). To a suspension of the

above intermediate 7a (0.14g, 0.34 mmole), in xylene (5 mL) phosphorus pentasulfide (0.044g, 0.2 mmole) was added. The mixture was refluxed for 1.5 hr. After usual work-up, the resulting gummy product was pu­rified by preparative TLC (benzene-ethyl acetate 9: 1) to give 8a (0.05g) .

10-Methyl-2-(s-phenyl-I,3,4-oxadiazol-2-ylmeth­yl)-3,s,6,7 -tetrahydro-3H -benzo[ 6, 7] cyclohepta­[I,2-e ]pyridazin-3-one 9a. A mixture of 7a (0.2g, 0.49 mmole ) in 4 mL of thionyl chloride was re­fluxed for 6 hr. The reaction mixture was cooled, poured into water, neutralized with sodium carbonate and extracted with chloroform. After the usual work­up, the residue was purified by preparati ve TLC (ben­zene - ethyl acetate, 8:2) and recrystallized from ben­zene to afford 9a (0.055g).

IO-Methyl-2-(I,3,4-thiadiazol-2-ylmethyl)-3,s,6,7-tetrahydro-3H -benzo[ 6, 7]cyclohepta[I,2-c ] pyridazin-3-thione lla. A mixture of 2a (0.35 g, 1.17 mmole) in formic acid 2 mL was refluxed for I hr. The solu­tion was then diluted with water (20 mL), the solid separated out was filtered and recrystalli zed from methanol to afford lOa (0.25 g). To a solution lOa (0. 15 g, 0.46 mmole) in xylene (7 mL) phosphorus pentasulfide (0.059g, 0.27 mrnole) was added and refluxed for 1 hr. After the usual work-up, the residue was purified by preparative TLC (ethyl acetate - pet. ether 8:2) and recrystallized from benzene to afford lla (0.035g).

Acknowledgement

One of the authors (SVC) is thankful to the CSIR, New Delhi for the award of a senior research fellowship.

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