Green Synthesis of Novel Heterocycles Carrying Triazole Derivatives of Dihydropyrimidine.

 

Dawle J. K. ¹*, Mathapati S. R.², Bondge A. S.³, Momin K. I.⁴

¹Research Laboratory of Pure  and Applied Chemistry, Maharashtra Mahavidyalaya, Nilanga.

²Asst. Prof. Department of Chemistry, Shri Madhavrao Patil Mahavidyalaya, Murum.

³Asst. Prof. Department of Chemistry, Shivneri Mahavidyalaya, Shirur Anatpal.

⁴Asst. Prof. Department of Chemistry, Rajarshri Shahu, Mahavidyalaya, Latur.

ABSTRACT:

The novel heterocycles, Ethyl -6- methyl- 2- oxo- 4- (2- phenyl -1,2,3-triazol-4-yl) - 3,4 dihydropyrimidine-5- carboxylate (4) have been synthesized from 1,3-dicarbonyl compounds, appropriate aldehyde and urea or thiourea under green method. 6– Methyl – 4 –(2- phenyl -1,2,3-triazol-4-yl) –5-(5-substituted phenyl -1, 3, 4–oxadiazol -2- yl) -3, 4-dihydropyrimidine-2(1H)-one (6 a-g) have been synthesized from comp. (4) using hydrazine hydrate, substituted benzoic acid, phosphorous oxychloride by microwave irradiation reported in literature. Above synthesized heterocycles 6 a-g irradiated under microwave with hydrazine hydrate to get amino triazole derivatives of dihydropyrimidine 7 a-g.

 

The structures of newly synthesized compounds have been confirmed by IR and ¹H NMR spectra.

 

 

INTRODUCTION:

Compounds carrying the dihydropyrimidines ring have been reported to demonstrate a wide range of pharmacological activities^1-3 which include antibacterial, antifungal, antitubercular, anticonvulsant, analgesic⁴, antihistaminic, and antihypertensive activity⁵. Pyrimidines are considered to be important not only because they are integral part of genetic material viz. DNA and RNA as nucleotide and nucleoside but they are also important in numerous biological activities such as bactericidal, fungicidal, insecticidal etc. Biodynamic property of pyrimidine ring system prompted us to account for their pharmacological properties, especially as antibacterial agents⁶ which are our part of further study.

 

In recent years the remarkable efficiency of compounds having 1,2,3-triazole and 1,3,4 -triazole nucleus have been demonstrated including antibacterial⁷, antifungal⁸, antiviral⁹, antimicrobial activities¹⁰. 1,2,3-triazole related compounds have attracted much attention due to their inspirable role in medicine, agriculture and industry.

 

The literature survey reveals that all these three moities -dihydropyrimidines, and triazole have varied activities. In present work, syntheses of the compounds having these three biologically active rings is carried out by green methods^11a,b which overhead on conventional methods^12a-c and confirmed further by their spectral analysis

 

RESULT AND DISCUSSION:

The reaction between 2-phenyl-1,2,3-triazole-4-carbaldehyde 1, urea or thiourea 2 and ethylacetoacetate 3 in acidic medium in the presence of CuCl₂.2H₂O catalyst followed by green method  resulted in formation of Ethyl -6- methyl- 2- oxo- 4- (2- phenyl -1,2,3-triazol-4-yl) - 3,4-dihydropyrimidine-5- carboxylate 4, which on reaction with hydrazine hydrate gave 6- methyl- 2- oxo- 4- (2- phenyl -1,2,3-triazol-4-yl)-3,4-dihydropyrimidine-5-carbohydrazide 5. The reaction of this comp. 5 with different substituted aromatic acids in presence of phosphorus oxychloride under microwave irradiation gave 6–Methyl–4–(2- phenyl -1,2,3-triazol-4-yl)–5-(5-substituted phenyl-1,3,4–oxadiazol-2-yl) -3,4-dihydropyrimidine-2(1H)-one (6a-g). Amino-1,3,4- triazole  derivatives 7a-g can be obtained from 6a-g by reacting with hydazine hydrated under MWI.

 

 

Scheme I

 

The structures of the newly synthesized compounds 7a-g were established on the basis of spectral data. The synthetic route followed for obtaining the title compounds is outlined in Scheme I. The physical characterizations of 7a-g   given in Table I.

 

EXPERIMENTAL:

All the chemicals were obtained from commercial suppliers and used after further purification. All the melting points were determined in open capillary tubes and areuncorrected. The IR spectra (ὑ in cm^-1) were recorded on a perkin-Elmer spectrophotometer in KBr pellets. ¹HMR spectra were recorded on Varian Gemini (200 MHz) spectrometer using DMSO-d6 as solvent and TMS as an internal standard. All chemical shifts values are reported in δ scale downfield from TMS. Homogeneity of the compound was checked by TLC on silica gel plates.

 

General procedure for the synthesis of 4-(2-phenyl- 1,2,3-triazol-4-yl)-3,4-dihydropyrimidine-2-one. (4):

A mixture of aromatic aldehyde i.e. 2-phenyl-1,2,3-triazole-4-carbaldehyde ﴾0.01M﴿ and ethylacetoacetate ﴾0.01M﴿ and urea (0.02M),CuCl₂.2H₂O (0.005M), 5- 4 drops of concentrated hydrochloric acid was grinded together for 5-10 min. using mortar and pistle of appropriate size.  The initial syrup is formed within 5-25 min.. The solid was kept overnight then washed with cold water and purified by the recrystallisation from ethanol. Completion of reaction is checked from TLC. The obtained product was identified from comparing product obtained by conventional method and their melting point, spectral data.  m.p.- 176-177^oC and yield =  92 %

 

IR (KBr) ν in cm^-1: 3296 (-NH amide), 3179 (-CH triazole), 3079 (-CH aromatic),2984 (-CH aliphatic), 1679 (-CO ester), 1632 (-CO amide), 1600 (aromatic ring),

1370 (-OEt ester), 1270, 996 (triazole ring).

 

¹HNMR (δ in ppm) :  10.32 (bs 1H, NH), 9.55 (bs,1H, NH), 7.63 (s, 3H, Tr-H), 7.32-8.02 (m, 5H, Ph) 5.72 (s, 1H, CH), 4.18 (q, J=7.2 Hz, 2H, OCH₂), 2.38 (s, 3H, CH₃), 1.25 (t, J=7.2 Hz, 3H, CH₃-CH₂O),

 

General procedure for the synthesis of 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidine-5- carbohydrazide (5):

To a hot solution of 4 (0.01M) in ethanol (15ml) was added hydrazine hydrate (0.99%, 0.01M) placed in microwave oven and irradiated for 4-6 min. Completion of reaction is checked from TLC and the product thus separated was filtered and purified by recrystallization from ethanol, crystalline solid obtained. The product was identified from IR spectra. m.p. = 190-192^oC, yield = 86%

 

IR (KBr) ν in cm^-1: 3314 cm (-NH amide), (Two bands  bet’n) 3043-3271 (-NH2),

 3179 (-CH triazole), 3085 (-CH aromatic), 2972 (-CH aliphatic), 1650 (-CO amide), 1610 (aromatic ring), 1270, 996 (triazole ring), 1086 (-N-N).

 

General procedure for the synthesis of 6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-(5-substituted phenyl-1,3,4–oxadiazol-2-yl)-3,4-dihydropyrimidine-2(1H)-one. (6a-g)

The mixture of 4-(2-phenyl-1,2,3-triazol-4-yl)-3,4-dihydropyrimidine-5- carbohydrazide 5 (0.02M), substituted aromatic acid Ar a-g (0.03M) and phosphorus-oxychloride (1ml) was ground to get homogeneous mixture and then heated in a beaker under microwave irradiation at 160W for 5-15 min. completion of reaction was monitored by TLC. The contents were cooled to room temp. and added to excess ice cold water. The solid product separated was collected by filtration and further purified by recrystllization from ethanol-DMF mixture (2:1).

 

Spectral details for few compounds from 6a-g are given below:

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-(5-phenyl-1,3,4–oxadiazol-2-yl)-3,4-dihydropyrimidine-2(1H)-one 6a.

 

IR ν in cm^-1: 3335 (-NH), 3190 (-CH Triazole), 3080 (Ar-CH), 2995 (alipha. –CH), 1663(-CO amide), 1618 (C=N), 1065 (N-N), 1012 (C-O-C),1138,960 (triazole ring).

 

¹HNMR (δ in ppm) :  10.35 (bs 1H, NH), 9.56 (bs,1H, NH), 7.64 (s, 3H, Tr-H),

7.34-8.18 (m, 10 H,C-H aromatic), 5.74 (s, 1H, CH), , 2.38 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[5-(4-Cl-phenyl)-1,3,4–oxadiazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 6b.

 

IR ν in cm^-1: 3343 (-NH), 3120 (-CH Triazole), 3078 (Ar-CH), 2990 (alipha. –CH),

 1665 (-CO amide), 1685 (C=N), 1033 (C-O-C), 1140,965 (triazole ring).

 

¹HNMR (δ in ppm) :  10.38 (bs 1H, NH), 9.56 (bs,1H, NH), 7.65 (s, 3H, Tr-H),

 7.45-8.43 (m,9H, Ar-H), 5.78 (s, 1H, CH), , 2.42 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[5-(4-OMe-phenyl)-1,3,4–oxadiazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 6d.

 

IR ν in cm^-1: 3343 (-NH), 3118 (-CH Triazole), 2937 (Ar-CH), 2976 (alipha. –CH),

1663 (-CO amide), 1783 (C=N), 1052 (C-O-C), 1142,964 (triazole ring).

 

¹HNMR (δ in ppm) :  10.31 (bs 1H, NH), 9.55 (bs,1H, NH), 7.64 (s, 3H, Tr-H),

 7.32-8.20 (m,9H, Ar-H), 5.67 (s, 1H, CH), , 2.32 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[5-(3-NO2-phenyl)-1,3,4–oxadiazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 6g.

IR ν in cm^-1: 3323 (-NH), 3142 (-CH Triazole), 3069 (Ar-CH), 2982 (alipha. –CH),

1666 (-CO amide), 1699 (C=N), 1045 (C-O-C), 1142,965 (triazole ring).

 

¹HNMR (δ in ppm):  10.37 (bs 1H, NH), 9.57 (bs, 1H, NH), 7.68 (s, 3H, Tr-H),

7.45-8.48 (m,9H, Ar-H), 5.76 (s, 1H, CH), 2.45 (s, 3H, CH₃).

 

General procedure for the synthesis of 6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-(1-N-amino-5-substituted

phenyl-1,3,4–triazole-2-yl)-3,4-dihydropyrimidine-

2(1H)-one. (7a-g)

The mixture of 6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-(5-substituted phenyl-1,3,4–oxadiazol-2-yl)-3,4-dihydropyrimidine-2(1H)-one (6a-g) (0.1 mol) and hydrazine hydrate (0.4 mol) and ethanol (40 ml) was taken RBF placed in microwave oven and irradiated for 5-8 min. After completion of reaction (monitored by TLC), mixture was cooled and the resulting solid was filtered, dried and recrystallized from ethanol to yield compound 7a-g. The melting point and yields are summarized in Table I Spectral details for few compounds from 7a-g are given below:

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-(1-N-amino-5-phenyl-1,3,4–triazol-2-yl)-3,4-dihydropyrimidine-2(1H)-one 7a.

 

IR ν in cm^-1: 3338 (-NH), 3213 (-NH), 3175 (-CH Triazole), 3086 (Ar-CH), 2990 (alipha. –CH), 1665 (-CO amide), 1623 (C=N), 1070 (N-N), 1140,963 (triazole ring).

 

¹HNMR (δ in ppm) :  10.37 (bs 1H, NH), 9.57 (bs,1H, NH), 4.13 (s, 2H,NH₂), 7.66 (s, 3H, Tr-H),7.61-8.37 (m, 10 H,C-H aromatic), 5.70 (s, 1H, CH), , 2.40 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[1-N-amino -5-(4-Cl-phenyl)-1,3,4–triazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 7b.

 

IR ν in cm^-1: 3348 (-NH), 3160 (-NH), 3133 (-CH Triazole), 3082 (Ar-CH), 2987 (alipha. –CH),

 1669 (-CO amide), 1689 (C=N), 1142,968 (triazole ring).

 

¹HNMR (δ in ppm) :  10.40 (bs 1H, NH), 9.55 (bs,1H, NH), 3.83 (s,2H,-NH₂), 7.68 (s, 3H, Tr-H), 7.72-8.53 (m,9H, Ar-H), 5.78 (s, 1H, CH), 2.45 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[1-N-amino -5-(4-Br-phenyl)-1,3,4–triazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 7c.

 

IR ν in cm^-1: 3342 (-NH), 3157 (-NH), 3130 (-CH Triazole), 3080 (Ar-CH), 2983 (alipha. –CH),

 1666 (-CO amide), 1686 (C=N), 1140,966 (triazole ring).

 

¹HNMR (δ in ppm) :  10.38 (bs 1H, NH), 9.51 (bs,1H, NH), 3.80 (s,2H,-NH₂), 7.62 (s, 3H, Tr-H), 7.68-8.50 (m,9H, Ar-H), 5.73 (s, 1H, CH),  2.42 (s, 3H, CH₃).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[1-N-amino-5-(4-OMe-phenyl)-1,3,4–triazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 7d.

 

IR ν in cm^-1: 3350 (-NH), 3253 (-NH₂), 3123 (-CH Triazole), 29433 (Ar-CH), 2971 (alipha. –CH), 1667 (-CO amide), 1789 (C=N), 1145,968 (triazole ring).

¹HNMR (δ in ppm) :  10.38 (bs 1H, NH), 9.58 (bs,1H, NH), 3.89 ( s, 2H,NH₂), 7.62 (s, 3H, Tr-H), 7.64-8.36 (m,9H, Ar-H), 5.62 (s, 1H, CH), , 2.36 (s, 3H, CH₃), 3.84 (s, 3H, -OMe).

 

6–Methyl–4–(2-phenyl-1,2,3-triazol-4-yl)–5-[1-N-amino -5-(3-NO₂-phenyl)-1,3,4–triazol-2-yl]-3,4-dihydropyrimidine-2(1H)-one 7g.

 

IR ν in cm^-1: 3335 (-NH), 3203 (-NH), 3148 (-CH Triazole), 3073 (Ar-CH), 2979 (alipha. –CH),

1672 (-CO amide), 1702 (C=N), 1145,968 (triazole ring).

 

¹HNMR (δ in ppm):  10.40 (bs 1H, NH), 9.59 (bs, 1H, NH), 3.80 (s,2H, -NH₂), 7.72 (s, 3H, Tr-H),7.56-8.69 (m,9H, Ar-H), 5.73 (s, 1H, CH), 2.48 (s, 3H, CH₃).

 

TABLE- I

Sr.No.	Ar	Molecular Formula	% Yield	m.p. in oC
7a	Ph	C21H19N9O	90	186-188
7b	4-Cl-Ph	C21H18N9OCl	81	202-203
7c	4-Br-Ph	C21H18N9OBr	86	212-214
7d	4-OMe-Ph	C22H21N9O2	85	250-252
7e	4-Me-Ph	C22H21N9O	84	255-257
7f	2-Cl-Ph	C21H18N9OCl	80	228-230
7g	3-NO2-Ph	C21H18N10O3	88	177-180

 

CONCLUSION:

The heterocyclic moieties of Dihydropyrimidines, amino-1,3,4-triazole and Triazole, even though have many biological activities but their synthesis involve non-green approach along with some hazardous outputs. In the present work, we have tried to synthesise heterocyclic compounds carrying such biological activities and minimize these along with minimal time consumption by the use of green methods like grinding and microwave irradiation.    

 

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Maharashtra Mahavidyalaya, Nilanga and Shri Madhavrao Patil Mahavidyalaya, Murum for providing the facilities and also thankful to IICT Hyderabad and NCL Pune for proving spectral data. 

 

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Received on 22.04.2012        Modified on 18.05.2012

Accepted on 24.05.2012        © AJRC All right reserved