Base-promoted cyclocondensation of symmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1) with guanidine hydrochloride has been found to generate E-2-amino-4-aryl-6-(2-arylethenyl)pyrimidines (3) in good yield, the structures of which have been established from analytical and spectral data. The corresponding unsymmetrical analogues (2), however, were found to produce a mixture of two isomeric products non-regioselectively.

Keywords: (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones, guanidine hydrochloride, sodium hydroxide, e-2-amino-4-aryl-6-(2-arylethenyl)pyrimidines

A considerable attention has been focused on synthesis of various substituted pyrimidines due to their interesting biological activities.^1–3 Aminopyrimidines constitute one of the important classes of pyrimidines. The pharmaceutical importance of these compounds lies on the fact that they can be effectively used as analgesics, anti-inflammatory, anticonvulsant, insecticidal, herbicidal, antitubercular, anticancer and antidiabetic agents.^4–6 Also, the pyrimidine and aminopyrimidine structures are frequently-occurring motifs in commercially available drugs such as anti-atherosclerotic aronixil,⁷ anti-anxiolytic buspirone,⁸ and other medicinally relevant compounds.^9,10 Symmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1) and their unsymmetrical analogues (2), which could be constructed easily, also possess structural features similar to α,α'-bis(arylmethylene)cycloalkanones previously utilized by us for studying their reaction with thiourea and guanidine hydrochloride.^11,12 It is evident from the literature that the reaction of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1 and 2) with guanidine has not been studied so far, although there are reports of cyclocondensation of varieties of α,β-unsaturated ketones with guanidine.^13,14 In this paper, we report a facile synthesis of E-2-amino-4-aryl-6-(2-arylethenyl) pyrimidines by base-promoted cyclocondensation of various (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with guanidine hydrochloride.

Reagents were purchased (Spectrochem or SRL) and used without further purification. Melting points were determined on a Köfler block and are uncorrected. ¹H and ¹³C NMR spectra were obtained in CDCl₃ on Bruker AV-300 (300MHz and 75MHz, respectively) spectrometer using TMS as an internal standard. Analytical samples were dried in vacuo at room temperature. The carbon, hydrogen and nitrogen percentages in the synthesized products were analyzed by using two Perkin-Elmer 2400 series II C, H, N analyzers. HRMS were recorded on a Waters Xevo G2QT mass spectrometer. Thin layer chromatography was carried out on silica gel G.

Synthesis of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1 and 2)

The symmetrical compounds (1) were prepared by base-catalyzed condensation of benzalde-hydes and acetone in 2:1 mole ratio (Scheme 1).¹⁵ The unsymmetrical compounds (2) were obtained by two successive condensation steps–(E)-4-phenylbut-3-en-2-one was first prepared by a known method and then subjected to base-catalyzed condensation with benzaldehydes (Scheme 2).¹⁵ They were characterized from their spectral data.

Scheme 1 Synthesis of symmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones.

Scheme 2 Synthesis of unsymmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones.

General procedure for base-promoted reaction of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1 and 2) with guanidine hydrochloride

A mixture of 1 or 2 (1mmol), guanidine hydrochloride (1mmol), sodium hydroxide (5mmol) and ethanol (20ml) was refluxed for 2h. The mixture was poured into ice cold water after completion of the reaction. The solid thus obtained was filtered off, washed with water until it was free from alkali. The crude product was extracted with chloroform and dried over anhydrous sodium sulphate. The concentrate of the chloroform extract was chromatographed over silica gel using petroleum ether-ethyl acetate (4:1) as eluent. Spectral data of the synthesized compounds were as follows:

E-2-Amino-4-phenyl-6-(2-phenylethenyl)-pyrimidine (3a): Yield: 65%, m.p. 128-130°C; IR: ν_max 3320 and 3198 (NH₂), 3005, 1632, 1575, 1350, 1160, 821cm^-1. ¹H NMR (300MHz, CDCl₃): δ20 (2H, br. s, NH₂), 7.02 (1H, d, J=16.2Hz, C=C-H), 7.12 (1H, s, H-5 of pyrimidine moiety), 7.31-7.42 (3H, m, Ar-H), 7.49 (3H, br. s, Ar-H), 7.60 (2H, d, J=6.9Hz, Ar-H), 7.83 (1H, d, J=16.1Hz, H- C=C), 8.03 (2H, br. s, Ar-H). ¹³C NMR (75MHz, CDCl₃): δ106.14, 126.05, 127.13 (2 carbons), 127.62 (2 carbons), 128.79 (2 carbons), 128.84 (2 carbons), 129.22, 130.66, 135.89, 136.62, 137.28, 162.92, 163.68, 166.24. HRMS for C₁₈H₁₆N₃ (M+H)⁺: Calcd. 273.1344, Found. 274.1338. Anal. Calcd. for C₁₈H₁₅N₃: C, 79.10; H, 5.53; N, 15.37%. Found C, 79.01; H, 5.69; N, 15.18%.

E-2-Amino-4-(p-methylphenyl)-6-(2-p-methyl-phenylethenyl)pyrimidine (3b): Yield: 61%, m.p. 142-143°C; IR: ν_max 3343 and 3200 (NH₂), 2922, 1638, 1570, 1364, 1180, 1116, 818cm^–1. ¹H NMR (300 MHz, CDCl₃): δ38 (3H, s. Ar-CH₃₎, 2.42 (3H, s, Ar-CH₃), 5.11 (2H, br. s, NH₂), 6.95 (1H, d, J=15.9Hz, C=C-H), 7.08 (1H, s, H-5 of pyrimidine moiety), 7.20 (2H, d, J=8.1Hz, Ar-H), 7.29 (2H, d, J=8.1Hz, Ar-H), 7.49 (2H, d, J=7.8Hz, Ar-H), 7.79 (1H, d, J=15.9, H-C=C), 7.93 (2H, d, J=7.8Hz, Ar-H). HRMS for C₂₀H₂₀N₃ (M+H)⁺: Calcd. 302.1657, Found. 302.1678. Anal. Calcd. for C₂₀H₁₉N₃: C, 79.70; H, 6.35; N, 13.94%. Found C, 79.51; H, 6.50; N, 13.66%.

E-2-Amino-4-(p-chlorophenyl)-6-(2-p-chloro-phenylethenyl)pyrimidine (3c): Yield: 75%, m.p. 212-214°C; IR: ν_max 3349 and 3205 (NH₂), 2923, 1651, 1560, 1359, 1196, 826cm^–1. ¹H NMR (300MHz, CDCl₃): δ10 (2H, br. s, NH₂), 6.97 (1H, d, J=15.9Hz, C=C-H), 7.05 (1H, s, H-5 of pyrimidine moiety), 7.37 (2H, d, J=8.4Hz, Ar-H), 7.46 (2H, d, J=8.4Hz, Ar-H), 7.52 (2H, d, J=8.7Hz, Ar-H), 7.77 (1H, d, J=15.9Hz, H-C=C), 7.98 (2H, d, J=8.4Hz, Ar-H). Anal. Calcd. for C₁₈H₁₃N₃Cl₂: C, 63.17; H, 3.83; N, 12.28%. Found C, 63.01; H, 3.60; N, 12.51%.

E-2-Amino-4-(p-methoxyphenyl)-6-(2-p-methoxyphenylethenyl)pyrimidine (3d): Yield: 58%, m.p. 152-153°C; IR: ν_max 3330 and 3189 (NH₂), 2932, 1651, 1636, 1605, 1512, 1252, 1173, 828cm^–1. ¹H NMR (300 MHz, CDCl₃): δ85 (3H, s. Ar-OCH₃), 3.88 (3H, s, Ar-OCH₃), 5.07 (2H, br. s, NH₂), 6.87 (1H, d, J=16.0Hz, C=C-H), 6.93 (2H, d, J=8.7Hz, Ar-H), 6.99 (2H, d, J=9.0Hz, Ar-H), 7.04 (1H, s, H-5 of pyrimidine moiety), 7.54 (2H, d, J=8.7Hz, Ar-H), 7.77 (1H, d, J=15.9Hz, H-C=C), 8.01 (2H, d, J=8.7Hz, Ar-H). Anal. Calcd. for C₂₀H₁₉N₃O₂: C, 72.05; H, 5.74; N, 12.60%. Found C, 71.92; H, 5.59; N, 12.42%.

Mixture of compounds 4a and 5a: IR: ν_max 3341, 3210, 3051, 2986, 1632, 1580, 1363, 1170, 828cm^–1. ¹H NMR (300MHz, CDCl₃): δ38 (approx. 1.2H, s, Ar-CH₃ of one component), 2.42 (approx. 1.8H, s, Ar-CH₃ of the other component), 5.29 (2H, br. s, NH₂ of both the components), 7.03-8.04 (approx. 12H, m, aromatic and olefinic protons). HRMS for C₁₉H₁₈N₃ (M+H)⁺: Calcd. 288.1501, Found. 288.1514.

Mixture of compounds 4b and 5b: IR: ν_max 3350, 3200, 3041, 2950, 1645, 1612, 1542, 1175, 830cm^–1. ¹H NMR (300MHz, CDCl₃): δ82 (approx. 1.5H, s, Ar-OCH₃ of one component), 3.85 (approx. 1.5H, s, Ar-OCH₃ of the other component), 5.09 (2H, br. s, NH₂ of both the components), 6.86-8.04 (approx. 12H, m, aromatic and olefinic protons).

Mixture of compounds 4c and 5c: IR: ν_max 3368, 3198, 2956, 1623, 1600, 1576, 1185, 991, 832cm^–1. ¹H NMR (300MHz, CDCl₃): δ00-5.10 (2H, m, NH₂ of both the components), 6.01 (approx. 0.8H, s, –OCH₂O- of one component), 6.04 (approx. 1.2H, s, –OCH₂O- of the other component), 6.65-8.02 (approx. 11H, m, aromatic and olefinic protons).

Symmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1a-d) were chosen first for carrying out the targeted reaction. When each of these (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones (1mol) was treated with guanidine hydrochloride (1mol or 2mol) in 10% ethanolic sodium hydroxide. Under refluxing condition. The reaction proceeded smoothly and was found to be complete within 2h. Product isolation from the reaction mixture with each of 1a-d through work up in the usual way (vide Experimental) followed by purification by column chromatograpy over silica gel furnished a single product in good yield (Scheme 3) (Table 1). Analytical and spectral data of the products definitely showed that only 1:1 cyclocondensation took place resulting in the formation of the hitherto unknown compounds E-2-amino-4-aryl-6-(2-arylethenyl) pyrimidines (3). The reaction of the unsymmetrical compounds 2a-c with guanidine hydrochloride was then studied by using the similar reaction conditions (Scheme 4).

Scheme 3 Reaction of symmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with guanidine.

Scheme 4 Reaction of unsymmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with guanidine.

In case of the unsymmetrical starting materials 2a-c, the reaction was not at all regioselective, and it was evident from the ¹H NMR spectral features of the resulting materials obtained after passing the concentrate of the reaction mixtures through chromatography columns in the usual way that a mixture of two isomeric products 4 and 5 in the approximate ratio 3:2 to 1:1 (Table 2) was formed in these cases. These two isomeric compounds could not be separated by exhaustive column chromatograpy over silica gel as well as over neutral alumina. Attempted separation by preparative chromatograpy over silica gel as well as neutral alumina also did not meet with success.

In conclusion, we have developed a simple and convenient method for synthesis of E-2-amino-4-aryl-6-(2-arylethenyl)pyrimidines, a group of hitherto unknown 2-aminopyrimidines, by base-promoted condensation of (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with guanidine hydrochloride. However, involvement of several unsymmetrical (1E,4E)-1,5-diarylpenta-1,4-dien-3-ones in this process with a view to increasing the structural variation of such products was not successful as no regioselectivity was observed in these cases.

Financial assistance from the UGC-CAS and DST-PURSE programme, Department of Chemistry, is gratefully acknowledged. The authors also acknowledge the DST-FIST programme of Department of Chemistry, Jadavpur University, for providing the NMR spectral data. N. S. and C. G. are thankful to the UGC, New Delhi for their Research Fellowships.

The author declares no conflict of interest.

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