INTRODUCTION

Microwave Induced Organic Reaction Enhancement (MORE) Chemistry¹ is gaining importance as a simple, non-conventional technique for organic synthesis. Important features of MORE technique are requirement of simple, inexpensive instrument, rapid synthesis of organic compounds, easy access to very high temperatures in sealed containers, good control over the energy input in a reaction and eco-friendly technology. It can be termed as “e-chemistry” because it is easy, effective, economic and eco-friendly.²

MORE chemistry is just more than a decade concept used by many biochemists and chemists for hydrolytic reaction and organic synthesis. It is gaining popularity as a non-classical approach due to its utility in highly accelerated synthesis of divergent types of organic molecules. Traditionally, commercial microwave ovens are used as a convenient source of energy in chemical laboratories for efficient heating o water, for moisture analysis and wet ashing procedures of biological and geological materials. Their computerized versions are commercially available for acid digestion of ores and minerals in explosion proof vessels and for rapid determination of thermodynamic functions of chemical reactions.

Application of microwave technology to catalytic hydrogenations of alkenes, hydro cracking of bitumen obtained from tar/sand, degradation of polychlorinated hydrocarbons, waste material management, polymer and ceramic technology are well known. Short ‘response time’ and highly accelerated reaction rate are the main advantages of MORE chemistry.³

MORE chemistry offers a simple, non-conventional technique for the synthesis of a large variety of compounds having medicinal, pharmaceutical and commercial importance. Highly accelerated rate of reaction is the main advantage, which enables the chemists to carry out the synthesis in much lesser time with reasonably good yields. For eg: esterification of benzoic acid with methanol proceeds one hundred times faster in microwave oven in sealed vessel than the conventional method. It provides a rapid and relatively inexpensive access to very high temperatures and pressure in sealed containers like Teflon bomb. Recent simplifications of this technique have increased safety profile and practical utility of microwave ovens for their use in the organic laboratories without any modification. Furthermore, there is no need for sealed vessels, reflux condensers, stirrers water separators etc. The currently available classical methods require much more elaborate apparatus, longer heating times, large volumes of organic solvents and it allow virtually no control over energy inputs.^4,5

The solvents used for organic synthesis conventionally, are of major concern as environment pollutants, many among which are proved carcinogenic, mutagenic and allergens. An eco-friendly method of organic synthesis is an important, distinct and salient feature of MORE chemistry. It does not require use of solvent (dry media synthesis) or requires very little solvent as energy transfer medium. Thus it offers a clean eco-friendly method.⁶

Pyrimidine, being an integral part of DNA and RNA, imparts diverse pharmacological properties such as effective bactericide and fungicide.^7,8 Certain pyrimidine derivatives are also known to possess antimalarial,⁹ antifilarial,¹⁰ antibacterial, antifungal,^11-12 anticonvulsant¹³ and antihistamine¹⁴ activity. Fused pyrimidine derivatives have attracted attention of numerous researchers over many years, due to their important biological activities. Preclinical data from literature survey indicated that the heterocycles in association with the pyrimidine has shown good antimicrobial,^15-17 antioxidant,¹⁷ antitumour,¹⁸ analgesic, and anti-inflammatory^19,20 activities. In particular, heterocycle fused pyrimidine derivatives were found as potent antimicrobial agent.^21-26

Motivated by the above mentioned findings to discover improved and efficient method for the synthesis of our earlier reported products,^27,28 we have synthesized some new pyrimidines by microwave assisted method. All the newly synthesized compounds were characterized by spectroscopic techniques and selected compounds were evaluated for their in vitro antifungal activity to find out Minimum Inhibitory Concentration.

EXPERIMENTAL:

Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. Melting points were determined by Micro control based melting point instrument and are uncorrected. All reactions were monitored by thin-layer chromatography on 0.25 mm silica gel (60GF-254) plates, using ethyl acetate: butanol: chloroform in the ratio of [1:2:1] as mobile phase and visualized with UV light. Column chromatography was performed on silica gel (200-300 mesh). Infra red (IR) spectra was recorded by using KBr pellet on a Thermo Nicolate IR-400 FTIR spectrophotometer, ¹H NMR spectra was recorded on Bruker Avance-400F spectrometer (400 MHz) using tetramethylsilane as internal standard (chemical shift in δ ppm) and LC-MS with Waters Micromass Q-Tof Micro.

Chemistry

Synthesis of 4-(substituted)-6-oxo-2-sulfanyl-1,6-dihydropyrimidine-5-carbonitrile (1)

To a mixture of the selected aryl aldehyde (50 mmol) and thiourea in absolute ethanol (15 ml), ethyl cyanoacetate (5.7 g, 50 mmol) and potassium carbonate (6.9 g, 50 mmol) were added. The reaction mixture was subjected for microwave irradiation until completion of the reaction at 160 watts. Then it was neutralized with glacial acetic acid. The separated solid product was filtered, dried and crystallized from suitable solvents.

4-(3-Hydroxyphenyl)-6-oxo-2-sulfanyl-1,6-dihydropyrimidine-5-carbonitrile(1a)

Reaction time: 4 min; Rf value: 0.53; Yield: 72%; M.p. 229 ^oC; IR, cm^–1: 3464 (OH), 3326 (NH), 3005 (Ar-CH), 2939 (Aliphatic CH), 2216 (C≡N), 1635 (C=O), 1509 (C=N), 1481 (C=C); ¹H NMR (DMSO-d₆) δ: 4.38 (s, 1H, NH), 6.82-7.24 (m, 4H, Ar-H), 9.57 (s, 1H, SH), 11.52 (s, 1H, OH); MS, m/z: 246.0 (M+1), 247.0 (M+2).

4-(4-Hydroxyphenyl)-6-oxo-2-sulfanyl-1,6-dihydropyrimidine-5-carbonitrile (1b)

Reaction time: 5 min; Rf value: 0.48; Yield: 77%; M.p. >250 ^oC; IR, cm^–1: 3598 (OH), 3316 (NH), 3083 (Ar-CH), 2836 (Aliphatic CH), 2214 (C≡N), 1716 (C=O), 1635 (C=N), 1509 (C=C); ¹H NMR (DMSO-d₆) δ: 4.82 (s, 1H, NH), 6.74 (d, 2H, Ar-H), 7.32 (d, 2H, Ar-H), 9.46 (s, 1H, SH), 11.58 (s, 1H, OH); MS, m/z: 246.0 (M+1).

4-(3-Nitrophenyl)-6-oxo-2-sulfanyl-1,6-dihydropyrimidine-5-carbonitrile (1c)

Reaction time: 4 min; Rf value: 0.58; Yield: 81%; M.p. 288 ^oC; IR, cm^–1: 3431 (NH), 3037 (Ar-CH), 2936 (Aliphatic CH), 2216 (C≡N), 1636 (C=O), 1523 (C=N), 1523 (C=C), 1352 (C-NO₂); ¹H NMR (DMSO-d₆) δ: 4.28 (s, 1H, NH), 7.75-8.54 (m, 4H, Ar-H), 11.73 (s, 1H, SH); MS, m/z: 273.1 (M-1).

4-(4-Nitrophenyl)-6-oxo-2-sulfanyl-1,6-dihydropyrimidine-5-carbonitrile (1d)

Reaction time: 5 min; Rf value: 0.55; Yield: 67%; M.p. 168 ^oC; IR, cm^–1: 3400 (NH), 2953 (Ar-CH), 2856 (Aliphatic CH), 2222 (C≡N), 1704 (C=O), 1602 (C=N), 1513 (C=C), 1348 (C-NO₂); ¹H NMR (DMSO-d₆) δ: 4.93 (s, 1H, NH), 7.95 (d, 2H, Ar-H), 8.30 (d, 2H, Ar-H), 11.73 (s, 1H, SH); MS, m/z: 272.9 (M-1).

Synthesis of 2-(3-Nitrophenyl)-4,6-dioxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-3-carbonitrile (2)

A mixture of 1 (0.01 mol), anthranilic acid (0.01 mol) and sodium ethoxide (0.01 mol) in ethanol was subjected for microwave irradiation for 4 min at 160 watts. The reaction mixture was cooled and then poured on ice cold water and acidified with hydrochloric acid. The produced solid was filtered off, dried and recrystalized from DMF/Water to give compound 2.

Reaction time: 4 min; Rf value: 0.72; Yield: 79%; M.p. 206 ^oC; IR, cm^–1: 3374 (NH), 3075 (Ar-CH), 2888 (Aliphatic CH), 2241 (C≡N), 1701 (C=O), 1552 (C=N), 1529 (C=C), 1352 (C-NO₂), 1228 (C-N-c); ¹H NMR (DMSO-d₆) δ: 7.85-8.56 (m, 8H, Ar-H), 13.23 (s, 1H, NH); MS, m/z: 360.2 (M+1).

7-(3-Nitrophenyl)-3,5-dioxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carbonitrile (3)

A mixture of 1 (0.01 mol), chloroacetic acid (0.01 mol), and fused sodiuim acetate in acetic acid (10 ml) was subjected for microwave irradiation for 4 min at 160 watts. The reaction mixture was then diluted with water, shaken well, and allowed to stand for 6 h. The residue was triturate with ethanol; solid product was filtered off and recrystallized from ethanol/water (1:1) to give 3.

Reaction time: 4 min; Rf value: 0.66; Yield: 75%; M.p. >250 ^oC; IR, cm^–1: 3087 (Ar-CH), 2907 (Aliphatic CH), 2221 (C≡N), 1689 (C=O), 1528 (C=N), 1481 (C=C), 1348 (C-NO₂), 1207 (C-N-c), 1098 (C-S-c); ¹H NMR (DMSO-d₆) δ: 3.94 (s, 2H, CH₂), 7.26-8.35 (m, 4H, Ar-H); MS, m/z: 315.2 (M+1).

Synthesis of 4-(substituted)-1-methyl-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4a-d)

Compounds 4a-d were synthesized according to reported method.²⁷

Synthesis of 2-hydrazinyl-4-(substituted)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (5a-d)

A mixture of compound 4a-d (10 mmols) and hydrazine hydrate (0.96 g, 30 mmols) in absolute alcohol (10 mL) was subjected for microwave irradiation until completion of reaction at 160 watts. The reaction mixture was poured into crushed ice, product was isolated and crystallized using suitable solvents.

2-Hydrazinyl-4-(3-hydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (5a)

Reaction time: 3 min; Rf value: 0.57; Yield: 83%; M.p. >250 ^oC; IR, cm^–1: 3339 (OH), 3299 (NH-NH₂), 2932 (Ar-CH), 2932 (Aliphatic CH), 2207 (C≡N), 1653 (C=O), 1526 (C=N), 1526 (C=C); ¹H NMR (DMSO-d₆) δ: 3.19 (s, 3H, N-CH₃), 4.68 (s, 1H, NH), 6.89-7.49 (m, 4H, Ar-H), 8.58 (s, 1H, OH), 9.17 (s, 2H, NH₂); MS, m/z: 258.1 (M+1).

2-Hydrazinyl-4-(4-hydroxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (5b)

Reaction time: 4 min; Rf value: 0.53; Yield: 78%; M.p. >250 ^oC; IR, cm^–1: 3471 (OH), 3326 (NH-NH₂), 2915 (Ar-CH), 2835 (Aliphatic CH), 2209 (C≡N), 1577 (C=O), 1518 (C=N), 1518 (C=C); ¹H NMR (DMSO-d₆) δ: 3.16 (s, 3H, N-CH₃), 4.77 (s, 1H, NH), 6.80 (d, 2H, Ar-H), 7.85 (d, 2H, Ar-H), 9.14 (s, 2H, NH₂), 9.97 (s, 1H, OH); MS, m/z: 258.1 (M+1), 259.1 (M+2).

2-Hydrazinyl-1-methyl-4-(3-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (5c)

Reaction time: 3 min; Rf value: 0.60; Yield: 82%; M.p. 247 ^oC; IR, cm^–1: 3312 (NH-NH₂), 2907 (Ar-CH), 2907 (Aliphatic CH), 2223 (C≡N), 1664 (C=O), 1609 (C=N), 1539 (C=C), 1280 (C-NO₂); ¹H NMR (DMSO-d₆) δ: 43.19 (s, 3H, N-CH₃), 7.78-8.36 (m, 4H, Ar-H), 8.72 (s, 1H, NH), 9.25 (s, 1H, NH); MS, m/z: 287.0 (M+1), 288.1 (M+2).

2-Hydrazinyl-1-methyl-4-(4-nitrophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (5d)

Reaction time: 3 min; Rf value: 0.58; Yield: 88%; M.p. 197 ^oC; IR, cm^–1: 3301 (NH-NH₂), 3015 (Ar-CH), 2935 (Aliphatic CH), 2200 (C≡N), 1599 (C=O), 1524 (C=N), 1524 (C=C), 1347 (C-NO₂); ¹H NMR (DMSO-d₆) δ: 3.17 (s, 3H, N-CH₃), 8.11 (d, 2H, Ar-H), 8.32 (d, 2H, Ar-H), 9.18 (s, 2H, NH₂), 10.02 (s, 1H, NH); MS, m/z: 287.1 (M+1), 288.1 (M+2).

Antifungal activity (Minimum inhibitory concentration) by serial dilution method

The minimum inhibitory concentration of the compounds was determined in Sabourauds dextrose broth (SDB) for fungi by the serial dilution method.^29–31 Fungal spores from 24 h to 7 days old Sabourauds agar slant cultures were suspended in SDB. The compounds (1–5) were screened for their antifungal activities in triplicate sets at different concentrations (1000, 500, 250 and 200 µg/mL). The compounds which were found to be active in primary screening were further diluted to obtain 100, 50, and 25 µg/mL concentrations. The tubes were incubated in BOD incubators at 28 ± 1 ^oC. The minimum inhibitory concentration (MIC) was recorded by visual observation after 72-96 h of incubation. The lowest concentration, which show no growth after spot subculture was considered as MIC for each compound. The highest dilution showing at least 99% inhibition was taken as minimum inhibitory concentration (MIC). Amphotericin B was used as standards for fungal study.

RESULTS AND DISCUSSION

Chemistry

In the present work, Compound 1 was synthesized by microwave irradiation of reaction mixture containing substituted aldehyde, thiourea, ethylcyanoacetate and potassium carbonate in minimum quantity of alcohol (Scheme 1). Compounds 4a-d were synthesized according to reported method. Microwave irradiation of 1 and anthranilic acid in minimum quantity of ethanol in the presence of sodium ethoxide yielded, 2-(3-Nitrophenyl)-4,6-dioxo-6,11-dihydro-4H-pyrimido[2,1-b]quinazoline-3-carbonitrile (2). Additionally, microwave irradiation of 1 with chloro acetic acid in acetic acid in the presence of sodium acetate yielded, 7-(3-Nitrophenyl)-3,5-dioxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carbonitrile (3) (Scheme 2). Nucleophilic substitution by hydrazine of the compounds 4a-d were carried out by Microwave irradiation with hydrazine hydrate to yield 2-hydrazinyl-4-(substituted)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile in minimum quantity of alcohol (5a-d) (Scheme 3). All the compounds synthesized by microwave irradiation have taken very short time to synthesis along with higher yield than conventional reflux technique. Additionally, it is also found that quantity of solvent utilized for microwave technique is very less (Table 1).

Table 1. Comparison of reaction time and yield by conventional and Microwave Technique

Compound Code	Reaction Time		% Yield
Compound Code	^aConv. (h)	^bMW (Min)	^aConv.	^bMW
1a	8	4	58	72
1b	10	5	62	77
1c	7	4	67	81
1d	11	5	54	67
2	8	4	58	79
3	9	4	49	75
5a	6	3	74	83
5b	6	4	66	78
5c	5	3	69	82
5d	6	3	71	88

a = Conventional, reported in earlier researches, b = Microwave

Table 2. Antifungal activities of compounds

Compounds	Minimum Inhibitory Concentration (µg/mL)
Compounds	*C. albicans*	*A. niger*
2	250	250
3	250	500
5a	500	750
5b	500	750
5c	250	500
5d	500	500
Amphotericin-B	100	50

Spectral Elucidation

All the pyrimidine derivatives were synthesized and confirmed by physical data, IR, ¹H NMR and Mass spectral data. All the compounds have shown C≡N peak in the range of 2241–2200 cm^-1, C=O peak in the range of 1701–1577 cm^-1, C=N peak in the range of 1609–1518 cm^-1 and C=C peak in the range of 1539–1481 cm^-1 in IR. The phenolic derivatives, 5a and 5b have shown the OH peak at 3339 and 3471 cm^-1, respectively. The nitro derivatives have shown C-NO₂ peak in the range of 1352–1280 cm^-1. The compound 1 showed peak in the range of 3431-3316 cm^-1 for the N-H stretch in IR. The compound 3 does not shown for the NH stretch in IR, which is absent in 2a-d compounds. The compounds 2 has shown C-S-C peak. Compounds, 5a-d have shown peak in the range of 3471–3301 cm^-1for NHNH₂.

All the compounds have shown peaks for Ar-H in the range of δ 6.80–8.56 in ¹H NMR. ¹H NMR of 1 has shown NH and SH peaks. The phenolic derivatives have shown singlet at δ 8.58 to δ 11.58 for Ar-OH in ¹H NMR. Additionally, ¹H NMR of 2 and 3 is lacking for SH peak and having NH peak. The 5a-d derivatives have shown peak for NH and NH₂ in ¹H NMR. All the synthesized derivatives have shown M+1 peak in mass spectra except 1c and 1d, which showed M-1 peak. The IR, ¹H NMR and Mass spectral data supported the structure of various synthesized compounds.

Antimicrobial activity

The newly synthesized compounds were screened for their antifungal activity against fungi (Candida albicans and Aspergillus niger). The results of preliminary antifungal testing of the compounds were reported as MIC (Table 2). The results of preliminary antifungal testing revealed that compounds 2 and 3 are showing good activity against both species of fungi. Compounds 2 exhibited potent activity against both the species. Polar substitution like hydrazine may reduce the antifungal activity.

CONCLUSION:

In conclusion, we have described simple and more efficient microwave assisted protocol for the synthesis of pyrimidine derivatives (1, 2, 3 and 5) with good yields. All the derivatives synthesized by microwave irradiation used less quantity of solvent. In comparison to conventional methods microwave heating offered advantages such as reduced reaction time, better yields, selectivity and reproducibility. Selected synthesized compounds (2, 3 and 5) have been investigated for their in vitro antifungal activities to find out MIC. In the newly synthesized compounds, it is clear that the highest antifungal activity was observed in compounds 2 and 3. Polar substitution like hydrazine may reduce the antifungal activity. To summarize with, we found that the novel class of pyrimidines have emerged as a valuable lead. Few of synthesized compounds might be useful as antifungal agents in future. These new pyrimidine derivatives have proved to be promising candidates for further efficacy evaluation.

CONFLICT OF INTEREST:

None.

ACKNOWLEDGMENT:

The authors are thankful to administration of Sri Adichunchanagiri College of Pharmacy, B. G. Nagara for providing laboratory facilities. Authors are also grateful to IISC, Bangalore, India and Panjab University, Chandigarh for providing spectral analysis data. Additionally, CM Bhalgat is thankful to ICMR for providing Fellowship.

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Received on 12.11.2014 Modified on 01.12.2014

Asian J. Research Chem 8(1): January 2015; Page 01-06

DOI: 10.5958/0974-4150.2015.00001.2