A Facile Microwave-Assisted Synthesis of Some Fused Pyrimidine Derivatives

INTRODUCTION

Pyrimidines and fused pyrimidines compounds, are a big family of the heterocyclic compounds, which have been focus of great interest because of their wide range of biological and pharmacological activities as antibacterial and antifungal activities^(1-4)_, anticancer^(5-8), anti-inflammatory⁽⁹⁾ and  many thieno[2,3-d] pyrimidine derivatives have been proved to use in case of Alzheimer and Parkinson disease⁽¹⁰⁾.

Microwave irradiation has attracted attention of organic synthesis due to the reduction in reaction times, good yields and cleaner reaction than conventional procedure^(11-16). There are several examples describing the advantage of using microwave irradiation for synthesis the thieno [2,3-d]pyridine-4(3H)ones  for example ,  Hesse  reported the synthesis of thieno[2,3-d]pyrimidin-4(3H)-ones under microwave irradiation in good yield⁽¹⁷⁾.

It seemed most interesting to extend the scope of synthesize of pyrimidine derivatives having active moieties under microwave irradiation with the aim  to evaluate    their biological activity as antibacterial or antifungal agents.

EXPERIMENTAL

Melting point are uncorrected . Microwave reaction were performed on a microwave oven start SYNTH-Milestone-open vessel. IR spectra were recorded in potassium bromide on Perkin-Elmer 380 and 387 spectrometer. ¹H-NMR spectra were run on a JEOL-JNMGX-300 and Junm Ex-400 in DMSO-d₆ or CDCl₃  using TMS as internal standard and chemical shift were expressed as part of million, ppm ( values) against TMS and internal references. Electron impact (E1) MS spectra were obtained with aid of a ShimaDZU Gemsqp 5050. A spectrometers at 70 ev. Elemental analysis were recorded on a Heruss CHN analyser.

General procedure for synthesis of 5,6-disubtituted thieno[2,3-d]pyrimidin-4(3H)-ones (4_a-c)

A mixture of 1_a,b ( 1 mmol) and formamide ( 5-6 mmol)  in  ( 1 mmol) acetic acid, was irradiation in the microwave oven  for10 min. at (300 W)  130^oC. The reaction mixture was cooled and poured into iced-cold water, filtered, washed and recrystallized from ethanol.

5,6-Dimethyl -3H-thieno[2,3-d]pyrimidin-4-one (4_a): M.p. 180-183^oC; IR(cm^-1): 3320, 1670; ¹H-NMR(DMSO-d₆)

1.7(s, 3H, CH₃), 2.0(s, 3H, CH₃), 7.80 (1H, s, pyrimidine -H), 10.00 (br. s, 1H, NH); MS: m/z (%), 180[M⁺] (95) (C8H8N2OS);CHN anal. calcd %: C:53.33; H: 4.44; N:15.55; Found: C: 53.45; H: 4.30; N:15.56.

5,6,7,8-Tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4one(4_b)

M.p. 257-259^oC, IR(cm^-1): br. 3400, 1670; ¹H-NMR (DMSO-d₆): 1.8-1.87 (m, 4H, CH₂ at C-6 and C-7), 2.65-2.70 (m, 2H, CH₂ at C-5); 2.80-2.89 (m, 2H, CH₂ at C-8), 7.80 (s, 1H, pyrimidine -H), 10.90 (br. s, 1H, NH); MS: m/z (%) 206 [M⁺](90) (C10H10N2OS); CHN Anal. Calcd . %  : C, 58.25; H,4.85; N, 13.59 Found: C, 58.30; H, 4.83; N, 13.60.

3,5,6,7,8,9-Hexahydrocyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (4_c)

M.p.: 212-215^oC; IR (cm^-1): br 3410, 1710; ¹H-NMR(DMSO-d₆): 1.56-1.58 (m, 4H, 2CH₂ at C-6 d C-7); 1.83-189 (m, 2H, CH₂ at C-8), 2.70-283 (m, 2H, CH₂ at C-5),  2.96-3.0 (m, 2H, CH₂ at C-9), 8.01 (s, 1H, pyrimidine -H) 12.5( br. s, 1H, NH); MS: m/z (%) 220[M⁺] (100) (C₁₁H₁₂N₂OS); CHN . Anal. Calcd. %:  C:60.00; H:5.45, N: 12.72; Found: C: 60.10, H: 5.47; N: 12.70.

4-Chloro-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-d] pyrimidine (7): Conventional method

A mixture of 4_b (5 mmol) and phosphorus oxychloride (15 ml) was heated under reflux for 20 h. After completion of reaction, The excess phosphorus oxychloride was removed by distillation under reduced pressure ,the residue left was titrated with sodium bicarbonate solution (10%); the solid separated was filtered, dried and recrystallized from toluene.

Microwave method

A mixture of 4_b(5 mmol)  and phosphorus oxychloride (15 ml) was irradiated in microwave oven at( 60 W) 120^oC for 15 min.. After completion of reaction, The workup was carried out as described for conventional method. M.p: 93-96^oC ; IR (cm^-1): 1620, 1580; ¹H-NMR(DMSO-d₆): 1.90-1.94, (m, 4H, 2CH₂, at C6 & C7), 2.90-2.94 (m, 2H, CH₂ , C-5), 3.00-3.40 (m, 2H, CH₂ at C-8), 8.72 (d, 1H pyrimidine -H); MS: m/z (%) 224[M⁺] (56%) ( C₁₀H₉³⁵Cl N₂S), 226[M+2] (30)( C₁₀ H₉³⁷ClN₂S);CHN: Anal. Calcd.: C: 53. 57: H: 4.01; N: 12.50.Found C: 53.21, H: 4.20, N: 12.49.

General procedure for synthesis of  4-N-(aryl)- 5,6,7,8-tetrahydrobenzo [4,5]thieno[2,3-d]pyrimidines (8):

conventional method:

A solution of compound 7 (10 mmol) and aryl amine (2.0 mmol) in 2-propanol (30 mL) was stirred under reflux for  12h., the solvent was removed under reduced pressure and the solid product was filtered dried and washed several times with petroleum ether.

Microwave Method

A mixture of compound 7 (1.0 mmol) and aryl amine (2.0 mmol) in 2-propanol (10 mL) was stirred for 5 min., then the mixture was irradiated in the microwave oven at (60W) 100^oC for 20 min. The workup was carried out as described for conventional method.

4-N-(4-methylphenyl)-5,6,7,8-tetrahydro[4,5]thieno[2,3-d]    pyrimidine   (8_a)

M.p . ^oC : 235-237^oC; IR (cm^-1): br. 3410; 1620; ¹H-NMR(DMSO-d₆): 1.85-1.98 (m, 4H, CH₂ at C-6, C-7) 2.28(s, 3H, CH₃), 2.34-2.64 (m, 2H, CH₂ at C-5) 2.9-3.04 (m, 2H, CH₂ at C-8), 7.1-7.80 (m,4H,Ar-H) , 7.95-8.1, ( br.s, 1H, NH), 8.22 (s, 1H, pyrimidin-H). MS: m/z (%) 295[M⁺] (95%).( C₁₇H₁₇N₃S); CHN: Anal. Calcd      .:C:69.15.H: 5.76; N: 14.23. Found: C: 69.30, H: 5.31; N: 14.34.

4-N-(3-Trifluoromethylphenyl)-5,6,7,8- tetrahydrobenzo[4,5]thieno [2,3-d] pyrimidine (8_b)

M.p^oC. 224-225 ^oC; IR (cm^-1): br. 3390, 1610; ¹H-NMR (DMSO-d₆): 1.80-1.87(m, 4H, 2CH₂ at C-6 d C-7), 2.40-2.60(m, 2H, CH₂ at C-5), 2.93-3.00 (m, 2H, CH_2, at C-8), 7.31  -7.80 (m, 4H, Ar-H), 8.10(s, 1H, pyrimidin-H) ,8.7-8.9 (br. s, 1H, NH); MS: m/z (%) 349(100) ( C₁₇H14F₃N₃S); CHN : Anal. Calcd. (%) C: 58.45; H: 4.01; N: 12.03; Found: C, 58.36; H: 4.36; N: 12.98.

4-N-(2,5-Dimethylphenyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] pyrimidine(8_c)

M.p^oC. 213-215^oC; IR (cm^-1): br. 3140, 1610; ¹H-NMR (DMSO-d₆): 1.80-1.87 (m, 4H, 2CH₂ at C-6d C-7), 2.31(s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.44 (m, 2H, CH₂ at C-5), 2.94-2.97 (m, 2H, CH₂ at C-8), 7.16-7.80 (m, 3H, Ar-H), 8.18 (s, 1H, pyrimidine -H) ,8.41( br. s, 1H, NH); MS: m/z (%); 309 (60%). C₁₈H₁₉N₃S; CHN :Anal. Calcd. (%): C, 69.90, H: 6.14, N: 13.59; Found: C: 69.93; H 69.92.

General procedure for synthesis of 3,5,6-trisubtituted-1H-2-thioxo thieno[2,3,-d] pyrimidin-4-ones(11)

A mixture of 1_b ( 1 mmol) and the appropriate isothiocyanate (1.1 mmol) in (10 ml) acetic acid, the mixture was irradiated in microwave oven at (300 W)120^oC for 20 min. The cold reaction was poured onto crushed ice, the solid obtained was filtered, washed with water, dried and recrystallized from ethanol.

3-Allyl-2-thioxo-2,3,5,6,7,8-hexahydro-1H-benzo[4,5]thieno[2,3-d] pyrimidin-4-one(11_a)

M.p.: 234-237^oC, IR (cm^-1) 3330, 1710, 1210; ¹H-NMR (DMSO-d₆): 1.68-1.73, (m, 4H, 2CH₂ at C-6 d C-7), 2.30-2.50(m, 2H, CH₂ at C-5), 2.89-2.90(m, 2H, CH₂ at C-8); 4.35-4.50(br. m, 2H, NCH₂), 5.41-5.60 (m, 2H, =CH₂); 5.89-6.30 (m, 1H, HC=), 11.9(s, 1H, NH); MS: m/z (%); 278(100) ( C₁₃H₁₄N₂OS_{2 )}; CHN: Anal. Calcd.: C, 56.11; H: 5.03; N: 10.07; Found: C: 56.60; H: 4.34; N: 9.85.

3-(Phenyl)-2-thioxo-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno[2,3-d] pyrimidin-4-one(11_b)

M.p.:261-263^oC;IR(cm^-1):3400,1700,1200;¹H-NMR(CDCl₃): 1.80-1.84 (m, 4H, 2CH₂ at C-6 d  C-7), 2.58-2.61 (m, 2H, CH₂ at C-5), 2.85-2.90 (m, 2H, CH at C-8), 7.30-7.60 (m, 5H, Ar-H), 11.5(br.s, 1H, NH) MS: m/z (%) 314[M⁺](100) C₁₆H₁₄N₂OS₂; CHN :Anal. Calcd, C: 61.14; H: 4.45; N: 8.91, Found: C: 61.20; H:4.53; N: 8.90.

3-(4-Chlorophenyl)-2-thioxo-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno [2,3-d]pyrimidine-4-one (11_c)

M.p.: 289-291^oC, IR (cm^-1) 3200, 1700, 1220; ¹H-NMR(CDCl₃): 1.70-1.76 (m, 4H, CH₂ at C₆  & C₇) 2.60-2.64 (m, 2H, CH₂ at C-5); 2.71-2.74 (m, 2H, CH₂ at C₈), 7.30-7.50 (m, 4H,  Ar -H); 8.5(br.s, 1H, NH); MS: m/z (%) 348[M⁺] (90) C₁₆H₁₃Cl³⁵N₂OS, 350[M+2] (25)( C₁₆H₁₃Cl³⁷N₂OS₂); CHN: Anal. Calcd (%): C, 55.09; H,3.73; N, 8.03; Found: C, 55.30; H, 3.76; N, 8.09.

General procedure for synthesis of : 3-Substituted-2-hydrazino-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones.(12).

A mixture of compound 11_b (1.0 mmol), and hydrazine hydrate (99%)(2.0 mmol) in ethanol (15 ml) was submitted to microwave irradiation for 5 min. at( 60W) 100^oC. After cooling the reaction mixture poured into ice cooled water and stirred for 10 min the solid product was filtered, dried and recrystallized from ethanol.

3-Allyl-2-hydrazino-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d] pyrimidin-4-one(12_a)

M.p.196-199^oC; IR (cm^-1): 3390, 3310,, 1610, 1580, ¹H-NMR: 1.70-1.73 (m, 4H, 2CH₂ at C-6 & C-7); 2.61-2.68(m, 2H,, CH₂ at C-5); 2.80-2.82(m, 2H, CH₂ at C-8), 4.01-4.30 (br. s, 2H, NH₂), 4.50-4.56(m, 2H, NCH₂), 4.96(d d, 1H, J =10.5 Hz, =CH₂), 5.12, (dd, 1H, J= 17.5 Hz, =CH₂), 5.80-5.84(m, 1H, CH=); 8.5 (br. s, 1H, NH). MS: m/z(%) 276 [M⁺] (90%),( C₁₃H₁₆N₄OS); CHN Anal. Calcd.%: C, 56.52; H, 5. 79; N, 20.28; Found :C,56.56; H, 5.83; N,20.24.

3-(4-Chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydro-3H-benzo[4,5]-thieno[2,3-d]pyrimidin-4-one(12_b)

M.p.204-206^oC; IR(cm^-1), 3410 (br.),1610, 1580 ; ¹H-NMR (DMSO-d₆): 1.74-1.80(m, 4H, 2CH₂ at C-6 d C-7); 2.63-2.70( m, 2H, CH₂ at C-5), 2.80-2.83 (m, 2H, CH₂ at C-8), 4.3 (br. s, 2H, NH₂), 7.4-7.9 (m, 4H, Ar-H), 8.01 (br. s, 1H, NH); MS: m/z(%) 346 [M⁺] (90) (C₁₆ H₁₅ ³⁵Cl N₄OS), 348[ M+2] (25) (C₁₆H₁₅³⁷ClH₄OS); CHN : Anal. Calcd:  C,55.49; H, 4.33; N , 16.18 ; Found: C, 55.45; H: 4.30; N: 16.14.

4-Allyl-6,7,8,9-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,2,4]triazolo [3,4,-b]pyrimidin-5-one (13_a)

A mixture of compound 12_a(1.0 mmol) and formic acid (10 ml) was submitted to microwave irradiation for 10 min. at (60 W)80⁰C after cooling the reaction mixture was poured into ice-cooled water, the formed solid was collected by filtration washed several time with ethanol, dried and recrystallized from ethanol.: M.p. 213-215^oC, IR (cm^-1), 1680, 1610, ¹H-NMR (CDCl₃): 1.80-1.86 (m, 4H, 2CH₂ at C₇ and C-8), 2.60-2.78( m, CH₂ at C-6), 3.00-3.42 (m, 2H, CH₂ at C-9); 4.50-4.56(m, 2H, NCH₂), 4.96(dd, 1H, J =10.5 Hz, =CH₂), 5.12, (dd, 1H, J= 17.5 Hz, =CH₂), 5.80-5.84(m, 1H, C-H=); 8.5 (br. s, 1H, NH). 9.30 (s, 1H, triazolo -H); MS, m/z = 286 (90) (C₁₄H₁₄N₄OS); CHN : Anal. Calcd :C, 58.74 ;H, 4.89; N: 19.58. Found: C: 58.79; H: 4.80; N; 19.55.

General procedure for synthesis of: 4-Substituted-1-methyl-6,7,8,9-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,2,4]triazolo[3,4-b] Pyrimidine 5-ones(13_b,c).

A mixture of  compound 12_a,b  (1.0 mmol) and acetic acid (10 ml) was submitted to microwave irradiation for 10 min  at ( 60W )80^oC. After cooling the reaction mixture was poured into ice-cooled water. The solid product was collected by filtration washed several time with ethanol, dried and recrystallized from ethanol.

4-Allyl-1-methyl-6,7,8,9-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,2,4] triazolo [3,4-b] pyrimidin-5-one (13_b).

M.p.: 228-230^oC; IR (cm^-1):1700, 1610; ¹H-NMR (DMSO-d₆): 1.78-1.89 (m, 4H, 2CH₂ at C-7& C-8), 2.6 (m, 2H, CH₂ at C-6) ,2.76  (s, 3H, CH₃),2.96-3.2 (m, 2H at C-9); 4.57-4.70 (m, 2H, N-CH₂), 5.10 (dd, 1H, J=  19.8, CH₂₌), 5.40 (dd, H, J = 17.5, CH₂₌‘) 6.03(m, 1H, HC=); MS: m/z [M⁺] 300 (100); C₁₅H₁₆N₄OS. CHN : Anal. Calcd: C,60.00; H, 5.33; N, 18.66, Found: C,60.50; H, 5.40; N,18.65.

4-(4-Chlorophenyl)-1-methyl-6,7,8,9-tetrahydro-4H-benzo[4,5] thieno[2,3-d][1,2,4] triazolo[3, 4,-b] pyrimidin-5 -one (13_c)

M.p.: 300<, IR (cm^-1): 1680, 1610; ¹H-NMR (DMSO-d₆): 1.80-1.86 (m, 4H, 2CH₂ at C-7 d C-8) 2.5 -268(m, 2H, CH₂ at C-6); 2.73 (s, 3H, CH₃),  3.00-3.20 (m, 2H, CH₂ at C-9) 7.30-7.70 (m, 4H, Ar-H); MS: m/z(%) 370 [M⁺] (100) (C₁₈H₁₅³⁵ClN₄OS; 372[M+2] (40)(C₁₈H₁₅³⁷ClN₄OS); CHN: Anal. Calcd. C: 58.29; H: 4.04; N: 15.11. Found :C, 58.62; H, 4.09; N, 15.12.

General procedure for synthesis of: 4-Substituted-1-mercapto-6,7,8,9-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,2,4]triazolo[3,4-b]pyrimidin-5-ones (14_a,b).

A mixture of 12_a,b    (1.0 mmol) and carbon disulphide (10 mL) in pyridine (10 mL) was stirred for 10 min.,  then  submitted to microwave irradiation for  10 min at (60 W) 40^oC. The mixture was evaporated under reduced pressure and the residue was treated with ethanol. The formed solid was filtered and washed several times with water, dried, and recrystallized from ethanol.

4-Allyl-1-mercapto-6,7,8,9- tetrahydrobenzo[b] thieno[2,3-d][1,2,4] triazolo[3,4-b] pyrimidin 5(4H) one (14_a)

M.p. : 246-248 ^oC, IR (Cm^-1): 3200, 1680, 1210; ¹H-NMR (CDCl₃-d₆) 1.78-1.81(m, 4H, CH₂ at C-7 d C-8), 2.65-2.71 (m, 2H, CH₂ at C-6); 2.95-3.00 (m, 2H, CH₂ at C-9); 4.48-4.60 (m, 2H, N-CH₂), 5.00 (dd, 1H, J= 9.8 Hz, =CH₂); 5.27 (dd, 1H, J= 16.8 Hz, =CH₂) 5.86-5.91 (m, 1H, HC=); 10.6 (br. s, 1H, SH); MS: m/z(%) ,[M⁺] 318 (100) (C₁₄H₁₄N₄OS₂₎; CHN: Anal. Cacld. (%): C, 52.83; H , 4.40; N, 17.61. Found C: 52.89; H: 4.48; N: 17.69.

4-(Chlorophenyl)-1-mercapto-6,7,8,9-tetrahydrobenzo[b]thieno[2,3-b] [1,2,4] triazolo[3,4-b] pyrimidin-5 (4H)-one (14_b)

M.p.: 260-263 ^oC, IR (cm^-1): 3300, 1600, 1610, 1200; ¹H-NMR (CDCl₃-d₃): 1.80-1.84 (m, 4H, 2CH₂ at C-7 d C-8); 2.50-2.62 (m, 2H, CH₂ at C-6); 2.95-3.2(m, 2H, CH₂ at C-9), 7.1-7.80 (m, 4H, Ar-H), 11.5 (br. s, 1H, SH); MS: m/z(%) ,[M⁺] 388 (90) (C₁₇H₁₃³⁵ClN₄OS₂), 390[M+2] (25) (C₁₇H₁₃³⁷ClN₄OS₂); CHN Anal. Calcd. (%) : C, 52.50; H , 3.34; N, 14.41. Found: C, 52.59; H, 3.40; N, 14.40.

Results and Discussion

The starting materials, namely 2-amino-3-(carboxyamide or carboxylic acid)-4,5-disubtituted thiophene 1_a,b were prepared according to the corresponding literature methods^(18,19).

The reaction of 1_a,b and formamide under a microwave irradiation with reactants ratio of 1:2 at 1:5-6 in the presence of one equivalent of acetic acid at (300 W) for 10 min 130^oC yielded thienopyrimidinone derivatives 4_a-c (Scheme 1, Table 1).

Table 1: Microwave experimental condition for the synthesis of compound 4

 

Compound No.	R1	R2	X	Substrate ratio	Temp. (0C)	Power in put (W)	Yield (%)	M.p. (0C)	Lit..m.p21 (0C)
1a	CH3	CH3	NH2	1:6	130	300	85	180-183
1b	(CH2)4		NH2	1:5	130	300	86	257-259	255-275
1c	(CH2)5		NH2	1:5	130	300	81	210-211	209-211
1a	CH3	CH3	OH	1:6	130	300	79	180-183	—
1b	(CH2)4		OH	1:5	130	300	83	257-259	255-275
1c	(CH2)5		OH	1:5	130	300	81	210-211	209-211

 

The next step we converted  3H-thieno[2,3-d]pyrimidin-4-one 4_b in to 4-chlorothieno[2,3-d]pyrimidine derivatives 7 by the action of phosphorous  oxychloride using both classical and microwave   reaction^{(11,12,20-22)}; the latter method afforded higher yields of the required products in shorter time.(Scheme 3, Table 2)

Table 2: Experimental conditions used for the microwave assisted  and classical methods  synthesis of compounds 7 & 8.

Compound. No.	Ar	Microwave methoda		Classical Methodb		M.p. (0C)	Lit..m.p21 (0C)
		Reaction time (min.)	Yield %	Reaction time (h.)	Yield %
7a	—	15	75	20	48	93-95	90-92
8a	4-CH3-C6H4	20	85	12	13	235-237	—
8b	3-CF3C6H4	20	76	12	12	224-225	224-226
8c	2,5-CH3C6H4	20	84	12	15	213-215	—

 

a; Reaction conditions: 2-PrOH, reflux under MW irradiation (60 W)

b: Reaction conditions: 2-PrOH, reflux temperature.

Substitution with an aromatic amine was performed on chloro derivatives  under classical and microwave irradiation to produce the anilino derivatives8_a-c. (Scheme 3, Table 2) .The structure of synthesized compounds were assigned on the basis of its spectral data and elemental analysis.

 

Scheme 1: Synthetic route of Compounds 4.  Click here to View Scheme

 

The reaction mechanism may proceed via an o-amidine intermediated 3  as  illustrated in (Scheme 2)¹¹:

Scheme 2 Click here to View Scheme

 

 

Scheme 3: Synthetic route of compounds 7 &8 Click here to View Scheme

 

Next attention was focused on the prep. In the  classical synthesis of this compounds, a mixture of starting material  reacted  with alkyl or aryl thio isocyanates in  ethanol. This method provided  low to moderate yield and long reaction time⁽²²⁾. We have recently synthesis the target compounds 11_a-c using microwave irradiation in acetic acid (Scheme 4, Table 3).

Table 3: Microwave experimental conditions for the synthesis of compounds  11-14

Comp. No.	R	Temp. (oC)	Power in put (W)	Time (min.)	Yield (%)	M.P. (oC)	Lit.m.p21 (oC)
11a	CH2CH=CH2	120	300	20	85	234-235	——
11b	C6H5	120	300	20	87	261-263	259-261
11c	4-ClC6H4	120	300	20	85	289-291	289-290
12a	CH2CH=CH2	100	60	5	80	196-198	——
12b	4-ClC6H4	100	60	5	86	204-206	204-204
13a	CH2CH=CH2	80	60	10	87	213-215	——
13b	CH2CH=CH2	80	60	10	83	228-230	——
13c	4-ClC6H4	80	60	10	85	>300	300
14a	CH2CH=CH2	40	60	10	83	246-248	——
14b	4-ClC6H4	40	60	10	87	260-263	——

The MW method requires higher yields, short reaction time, and eco friendly. Reaction of 11_a-cwith hydrazine hydrate under microwave irradiation at 60 W(100^oC) for 5 min., afforded 2-hydrazino derivatives 12_a,b.(Scheme 4, Table 3). 

Cyclization of compound 12_a,b by aliphatic carboxylic acid, namely Formic or acetic acid under MW irradiation for 10 min at (60W) 80^oC gave the triazolo derivatives 13_aand  13_b,crespectively (Scheme 4,Table 3).

 

Scheme 4: Synthetic route of compounds 11-14 Click here to View Scheme

 

Finally, treatment of 12_a,b with carbon disulphide under microwave irradiation for 10 min. yielded  mercaptotriazolo derivatives 14_a,b(Scheme 4, Table 3).

The structure of compounds 11-14 were confirmed from their spectral data and elemental analysis.

ANTIMICROBIAL ACTIVITY:

The antimicrobial activity of the compounds considered was tested on the following organisms:

1. Candida albicans ATCC No. 10231.
2. Staphylocoecus Aureus ATCC No. 6538.
3. Eschierichia Coli ATCC No. 8739.
4. Proteus mirabilis ATCC No. 29906.

The biological activity was planned according to the cup-plate method adopted with some modify ⁽²³⁾_. 

What man No. 2 filter paper disk (6.5 cm) was impregnated with 200 mg of the compound. The disk was placed on the surface of the cold solid medium petridishes vaccinated with considered organisms and then incubated at 5^oC for 1h. to permit good diffusion and then transferred to an incubated at 28^oC for 24 h.

A summary of the biological activity results is shown in Table 4.

Table 4: Antimicrobial activity of the compounds against bacteria and fungi.

 

Test	Compounds
Organism	5	7	8 b	11a	12b	13a	13b	14a
1	+	+	–	+	–	–	+	–
2	+	++	+	–	–	–	+	+
3	+	+	–	–	–	–	+	+
4	–	–	–	+	+	–	–	–

 

The sensitivity of microorganisms to the compound is identified in the following manner:

+++ = highly sensitive (inhibition zone 1.2-1.5 mm)

++ = fairly sensitive (inhibition zone 1.2-0.9 mm)

+  = Slightly sensitive (inhibition zone 0.9-0.6 mm)

–         = not sensitive.

References

1. Litvinov V. P.; Russian Chemical Bulletin, 53(3) , 487(2004).
2. Alagarsmy V., Murugarathan G. Venkateshperumal R., Biol. Pharm. Bull, 26, 1711(2003).
3. Keshav C. P., International Journal of Chem. Tech. research; 5(1), 141(2013).
4. Wang Y. D., Johnson  S., Power A., Ginnis  MC.; Miranda M. and Robindrah S. k., Bioorg. Med. Chem. Lett. , 15, 2763(2005).
5. Baselga  J., Averbuch, S. D., Drugs, 60, 33(2000).
6. Nargues  S., Soliman R., El-Tombary A. A., El-Hawash S. A., Shaaban  O. G.; Medical Chem. Research,  22(7), 3289 (2013)
7. L. Dang, H. Gui, Q. Zhan, Y. Hu, S. Gni ,Wuhan University J. of Natural Science, 17(21)77( 2012).
8. Elazab A.A, Al-Omar M. A., Abdel-Aziz A. A. M., Abdel-Aziz  N. I., El-Sayed  M. A., Aleisa A. M., Sayed-Ahmed M. , Abdel-Hamide S. G., Eur. J.Med. Chem., 45, 4188 (2010).
9. Vena K., Sharvan L. N., Shachindra L. N.,. Narendrath Chandra J. N.,  and Nurgund L. V.; Der pharma Chemica, 4(2), 581(2012).
10. Chaykovsky M., Lin M., Rosowsky A. and Modest E.; J. Med. Chem., 16 , 188(1977).
11. Fenj L., Yiqing F., Quingging M., Wenchua L., Zhiming L., Quanrui W., Fenggang T., Arkiovoc (i), 40 ( 2007)
12. Besson, T. and Chosson, E.; Comb. Chemis. High Throughput Screen. ,10, 1903(2007).
13. Akhil A. N., Ashish p., Rajesh  K. S., Kishore R. D.  , Pathi  L. G; Pharmagene, 1, 1(2013).
14. Sarika M., Neelam S., Madhuri V., Jitendra V., Pinki B. P. , Suresh C. A.; Bull. Korean Chem. Soc.; 28(12), 2338(2007).
15. Mizuno T., Iwai, T. , Ishino Y., Tetrahydron Lett.,45, 7073(2004).
16. Alexandre, F. R., Berecobar, A., Besson, T.; Tetrahydron Lett., 43, 3911(2002).
17. Hesse S. Perspicace E. , Kirch G., Tetrahydron Lett., 48, , 5261(2007).
18. Sabins R. W.; Rangnekar, D. W.; Sonawane N. D., J. Heterocyclic Chem. 36, 333(1999).
19. Gewald  K. and Schinike E. Chem. Ber.; 99,94(1966).
20. Liu G., Song B., Yang S., Yue W. Hu D. , Jin L and Lu  S., Molecules ,11, 272(2006).
21. El-Baih F. E., Al-Blowy H. A. S. , Al-Hazimi M., Molecules, 11, 498(2006).
22. El-Hiti G. A., Hussain A., Hegazy A. S. , Alotaibi M. H., J. of Sulfur Chemistry 32(4), 361(2011).
23. Abau-Zeid A. A. and Shehata Y. M., Indian J. Pharmacy, 31, 72 (1969).

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