A convenient synthesis of pyrimidinone and pyrimidine containing bisheteroarenes and analogs

Abstract

The synthesis of pyrimidinone containing bisheteroarenes (3) and related analogs (9 and 10) by the reaction of active methylenes or substituted methyl acrylate with nitrogen containing precursors viz. amidines, or thiourea in water as well as other organic solvents was studied. Synthesized compounds have further been explored for the synthesis of diversified pyrimidines 4, 6–8, 11, 12 and 14 through a sequential approach.

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Introduction

Diversified naturally occurring pyrimidinones, pyrimidines and their structural implication on biological systems¹ has drawn attention of organic chemists towards further exploration of their chemistry. Among other nitrogen heterocycles, pyrimidinone and pyrimidines are the main constituents of many natural products such as farinamycin (i, isolated from Streptomyces griseus),^1a terremide-B (ii),^1b 4-thiouridine (iii, isolated from Escherichia coli),^1c lathyrine (iv, extracted from L. tingitanus), thiamine (v, vitamine B1, isolated from ricebran), varioline B (vi, isolated from a marine organism kirkpatrickia varialosa); Fig. 1.^1d

Fig. 1 Naturally occurring pyrimidinones and pyrimidines.

Further, these molecules form core structure of DNA and RNA (uracil, thymine, cytosine) and are building blocks for many biologically active compounds with established medicinal values.² Literature search indicated that compounds having pyrimidinone and pyrimidine nucleus possess broad range of biological activities.^1–7 Pyrimidinone is a basic nucleus of various clinically useful drugs such as allopurinol (i, free radical scavenger, antimetabolite enzyme inhibitor drug),³ raltegravir (ii, antiretroviral HIV drug),⁴ thiadiazolopyrimidinones (iii, anti-osteoporosis),⁵ temelastine (iv, antihistaminic drug),⁵ lamivudine (v, anti-AIDS drug) (Fig. 2).⁶

Similarly, pyrimidine is also an integral part in various important drugs such as mezilamine (vi, antipsychotic drug),⁶ pyrimethamine (vii, antimalarials drugs),¹ sulfadimidine (viii, sulfonamide antibacterial drug),⁶ epirazole (ix, anti-ulcer drug)⁶ and trimethoprim (x, bacteriostatic antibiotic drugs),^1,7 as well as other well known drugs (Fig. 2).^6,7

The importance of these molecules in drug development^1–7 inspired us to synthesize bisheteroarenes which possess a combo structure of pyrimidine and azaheterocycles in anticipation of their utility in synthesis of biologically active compounds.

Fig. 2 Pyrimidone and pyrimidine containing drug candidate.

Results and discussion

Chemistry

Water is a green solvent and received considerable attention in organic chemistry due to profound economic, environmental, safety and societal advantages over conventional reactions in organic solvents.⁸ Organic reactions performed in water have shown unique properties towards improved selectivity. Various reactions have been reported in aqueous medium with substantial rate acceleration, even water-insoluble substrates have been used in a suspension to yield products.⁸ Therefore water is a cheapest, non hazardous and universal solvent which needs continuous efforts to study various synthetic reactions in aqueous medium.

Use of sodium in absolute ethanol or methanol under extremely dry conditions is often required for synthesis of pyrimidinone (3).⁹ In our efforts to synthesize pyrimidinone under very simple reaction conditions, we studied synthesis of substituted pyrimidinones in aqueous medium. We first explored preparation of 6-methyl-2-phenylpyrimidin-4(3H)-one (3a) from benzimidamide (2a) with ethyl 3-oxobutanoate (1a). This reaction was previously reported in refluxing ethanol with 86–98% yields, as depicted in Table 1.^9a–d The typical reaction conditions involved refluxing of 2a with ethyl 3-oxobutanoate (1a) in presence of strong base such as sodium or EtONa in dry ethanol (Table 1).^9a–d In contrast, when a mixture of 1a and 2a was stirred in presence of KOH in water, it was completed within 48 h leading to the formation of 3a in 97% yield as shown in Table 1. Therefore, it was concluded that water could be a medium of choice over sodium in dry ethanol. This method offered easy purification of products as pure product precipitated on reaction completion which could be isolated by simple filtration.

Table 1 Reaction of benzimidamide (2a) with ethyl 3-oxobutanoate (1a)

Solvent	Base	Temp. (°C)	Time	Yield (%)
Ethanol	Na	Reflux	Overnight	86 (ref. 9a)
Ethanol	EtONa	Reflux	18 h	97 (ref. 9b)
Ethanol	Na	Reflux	18 h	98 (ref. 9c)
Ethanol	EtONa	Reflux	18 h	98 (ref. 9d)
H2O	KOH	rt	24 h	67
H2O	KOH	rt	48 h	97

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On the basis of above results, we performed various reactions of alkyl 3-oxobutanoate (1a and 1b) with benzimidamide (2a) isonicotinimidamide (2b), nicotinimidamide (2c), picolinimidamide (2d) and 1H-pyrazole-1-carboximidamide (2e) in aqueous medium which proceeded by the condensation and subsequently cyclization as shown in Scheme 1, Table 2.

Scheme 1 Synthesis of pyrimidinone containing bisheteroarenes (3) in water (Table 2).

Table 2 Mps and yields of bisheteroarenes (3) (Scheme 1)

Entry	Product	t ^a/h	Mp (°C)	Yield (%)
a Reaction time.
3a		48	220–221	97
3b		48	239–240	70
3c		96	213–214	68
3d		96	110–111	76
3e		24	175–176	80
3f		60	149–151	74
3g		24	65–66	76
3h		60	160–162	52

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To explore the immediate utility of synthesized pyrimidinone (3), we explored reaction of 6-methyl-2-phenylpyrimidin-4(3H)-one (3a) in POCl₃ at 140 °C for the formation of chlorinated pyrimidine (4) which was susceptible for substitution of chlorine by nucleophile such as ethyl thioglyconate etc.

Further, reaction of chlorinated pyrimidine (4) with ethyl thioglyconate and K₂CO₃ in refluxing ethanol yielded ethyl 2-(6-methyl-2-phenylpyrimidin-4-ylthio)acetate (5) and hydrolyzed product (6); Scheme 2 (Table 3). However, above reaction in NaH/THF produced regioselectively pyrimidine (5). In order to prepare hydrazone containing derivative as present in anti-tubercular drug isoniazide, pyrimidine (5) was converted into 2-(6-methyl-2-phenylpyrimidin-4-ylthio)acetohydrazide (7) in presence of hydrazine in ethanol at reflux temperature in anticipation of its anti-tubercular activity; Scheme 2.

Scheme 2 Pyrimidinone (3a) applied as precursor for the synthesis of pyrimidines (4, 5–7) (Table 3).

Table 3 Reaction optimization condition and yields of pyrimidines (5 & 6) (Scheme 2)

S. no.	Solvent	Base	Temp.	t/h	Yield of 5 (%)	Yield of 6 (%)
a 15% unreacted starting (4) recovered. b 20% unreacted starting (4) recovered.
1	EtOH	—	rt	10	—	—
2	EtOH	Et3N (2 eq.)	rt	10	—	—
3	EtOH	Et3N (2 eq.)	120	10	—	—
4	EtOH	K2CO3	120	60	41^a	38
5	THF	NaH	80	40	72^b	00

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The aza Michael type reaction of benzimidamide (2a) with methyl 2-cyano-3,3-bis(methylthio)acrylate (8) in aqueous medium formed pyrimidinone (9a) in 10% yield. However, when same reaction was performed in DMF or ethanol, the yield of product was 42–85% (Table 4). Thus, other pyrimidinone (9b and 9c) were prepared in DMF or ethanol as shown in Scheme 3 (Table 4).

Scheme 3 Synthesis of pyrimidinone containing bisheteroarenes (9), (Table 4).

Table 4 Reaction optimization condition, mp and yields of bisheteroarenes (9) (Scheme 3)

Com.	Product	Base	Solvent	T (°C)	t (h)	Mp	Yield (%)
9a		KOH	H2O	rt	48		10
		KOH	DMF	rt	48		42
		NaOH	DMF	rt	48		45
		Et3N	EtOH	140	30	333–334	85
9b		Et3N	EtOH	140	30	321–322	65
9c		NaOH	DMF	rt	72	240–241	91

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Toward the study for diversification of synthesized pyrimidinone (9), we further explored the reaction of pyrimidin-4(3H)-one (9) and hydrazine in refluxing ethanol which yielded 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (10) in 56% yield, while the reaction of pyrimidin-4(3H)-one (9) in POCl₃ at 140 °C yielded chlorinated pyrimidine (11). Compound 11 on reaction with ethyl thioglyconate (5) in presence of Et₃N in refluxing ethanol produced mono substituted product (12) instead of anticipated cyclic product (13). However, when the reaction of 11 and 5 was attempted in NaH/THF, compound 14 was obtained in 53% yield instead of target compound 13 (Scheme 4, Table 5).

Scheme 4 Pyrimidinone (9) applied as precursor for the synthesis of pyrimidine containing bisheteroarenes (10–12) (Table 5).

Table 5 Mps and yields of bisheteroarenes (10–13) (Scheme 4)

Entry	Product	t ^a	Mp	Yield (%)
a Reaction time. b Start to decompose. c 5% (13).
10		10 h	334–336^b	56
11a		20 h	166–167	76
11b		30 h	190–191	61
12a		7 h	157–158	51^c
12b		30 h	153–154	88
14		4 h	171–172	53

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After the synthetic study of pyrimidinone (3 and 9) by the reaction of amidine (2) with ethyl 3-oxobutanoate (1) and 4 respectively, we intended to synthesize new pyrimidinone analogs via multi component reaction. Initially, we attempted reaction of thiourea (15), methyl 2-cyanoacetate (16) and benzaldehyde (17) in ethanol at reflux temperature which produced 4-oxo-2-thioxo-6-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (18) in good yield. Further, reaction of pyrimidinone (18) with ethyl 2-bromoacetate (19) in presence of K₂CO₃ in DMF yielded mono and disubstiuted pyrimidine derivative 20 and 21. In anticipation to synthesize pyrimidinone (18) in aqueous medium, we further explored the reaction of thiourea (15), methyl 2-cyanoacetate (16), benzaldehyde (17) in presence of K₂CO₃ in water which gave a precipitate within a minute. For complete consumption of residual starting materials, the reaction mixture was further stirred for 5–15 minutes. The obtained precipitate was filtered as pure product which did not require any further purification or crystallization. The product was identified as (E)-methyl 2-cyano-3-(4-aryl) acrylate (22) instead of anticipated product pyrimidinone (18), Scheme 5 (Table 6).

Scheme 5 Synthesis of pyrimidinone (18) and (E)-methyl 2-cyano-3-(4-aryl)acrylate (22) applied as precursor for the synthesis of pyrimidine (20 and 21) (Table 6).

Table 6 Mps and yields of bisheteroarenes (18, 20–22) (Scheme 5)

Entry	Product	Temp.	t ^a	Mp	Yield (%)
a Reaction time.
18		Reflux	5 h	286–287	95
20		rt	5 h	94–95	21
21		rt	5 h	91–92	55
22a		rt	10 min	108–109	92
22b		rt	15 min	119–120	96
22c		rt	10 min	103–104	90
22d		rt	10 min	210–211	98
22e		rt	10 min	159–160	95

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Conclusion

In conclusion, a convenient synthesis of pyrimidinone containing bisheteroarenes and analogs by the reaction of nitrogen containing precursors viz. amidines, thiourea with active methylenes or acrylate in water as well as other organic solvents had been developed. These compounds were further explored the synthesis of diversified pyrimidines through sequential approach. The optimized reaction condition will be further explored for synthesis of various biological active compounds.

Experimental section

General

The reagents and solvents used in this study were of analytical grade and used without further purification. All the reactions were monitored on Merck aluminum thin layer chromatography (TLC, UV_254nm) plates. Column chromatography was carried out on silica gel (60–120 mesh). The melting points were determined on Buchi melting point M560 apparatus in open capillaries and are uncorrected. Commercial reagents were used without purification.¹H (300 MHz) and ¹³C NMR (75 MHz) spectra were recorded on a Bruker WM-300 using CDCl₃ and DMSO-d₆ as the solvent. Chemical shift are reported in parts per million shift (δ-value) based on the middle peak of the solvent (CDCl₃/DMSO-d₆) as the internal standard. Signal patterns are indicated as s-singlet; bs-broad singlet; d-doublet; dd-double doublet; t-triplet; m-multiplet; brm-broad multiplet. Coupling constants (J) are given in Hertz. Infrared (IR) spectra were recorded on a Perkin-Elmer AX-1 spectrophotometer in KBr disc and reported in wave number (cm⁻¹). ESI mass spectra were recorded on Shimadzu LC-MS after dissolving the compounds in acetonitrile and methanol.

General procedure for the synthesis of 6-alkyl-2-heteroaryl/phenylpyrimidin-4(3H)-one (3)

A mixture of amidine (2, 4 mmol) and potassium hydroxide (4.1 mmol) in water (10 mL) was stirred for 5 minutes at room temperature and subsequently ethyl 3-oxoalkanoate (1, 4.1 mmol) were added to this solution. Th content was stirred for 24–96 h (Table 1) at room temperature. After completion of the reaction, the aqueous phase was neutralized with N/10 HCl. The precipitate obtained was filtered (or extract with excess ethyl acetate, in case precipitate did not formed) and recrystallized with methanol as pure bisheteroarene (3).

6-Methyl-2-phenylpyrimidin-4(3H)-one (3a). White solid; R_f: 0.26 (30% ethyl acetate–hexane); IR (KBr, ν_max/cm⁻¹): 1667 (C=O), 3449 (NH); UV(CH₃OH, λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 238 nm (1300), 285 nm (700); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.24 (s, 3H, CH₃), 6.18 (s, 1H, CH), 7.45–7.57 (m, 3H, Ar-H), 8.04–8.07 (m, 2H, Ar-H), 8.25 (s, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 24.2 (CH₃), 110.7 (CH), 128.5 (2 × Ar-H), 129.4 (2 × Ar-H), 132.3 (Ar-H), 133.5, 157.8, 164.7, 165.2 (C=O); MS (C₁₁H₁₀N₂O): 185 [M − H]⁺, 187 [M + H]⁺, 209 [ M + Na]⁺.

6-Methyl-2-(pyridin-4-yl)pyrimidin-4(3H)-one (3b). White solid; R_f: 0.41 (dichloromethane); IR (KBr, ν_max/cm⁻¹): 1685 (C=O), 3432 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.28 (s, 3H, CH₃), 6.34 (s, 1H, CH), 7.99 (d, J = 4.8 Hz, 2H, Ar-H), 8.69 (d, J = 4.8 Hz, 2H, Ar-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 24.1 (CH₃), 110.9 (CH), 122.4 (2 × Ar-H), 141.8, 151.0 (2 × Ar-H), 156.4, 162.5, 166.1 (C=O); MS (C₁₀H₉N₃O): 188.2 [M + H]⁺.

6-methyl-2-(pyridin-3-yl)pyrimidin-4(3H)-one (3c). White solid; R_f: 0.22 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1684 (C=O), 3434 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.15 (s, 3H, CH₃), 6.14 (s, 1H, CH), 7.37–7.41 (m, 1H, Ar-H), 8.13 (s, 1H, NH), 8.26–8.29 (m, 1H, Ar-H), 8.55–8.57 (m, 1H, Ar-H), 9.08 (s, 1H, Ar-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 24.20 (CH₃), 110.4 (CH), 124.4 (Ar-H), 130.2, 136.2 (Ar-H), 149.5 (Ar-H), 152.5 (Ar-H), 153.0, 157.2, 165.7 (C=O); MS (C₁₀H₉N₃O): 188 [M + H]⁺.

6-Methyl-2-(pyridin-2-yl)pyrimidin-4(3H)-one (3d). White solid; R_f: 0.31 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1686 (C=O), 3435 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.13 (s, 3H, CH₃), 6.09 (s, 1H, CH), 7.46–7.50 (m, 1H, Ar-H), 7.84–7.90 (m, 1H, Ar-H), 8.12–8.15 (m, 2H, Ar-H & NH), 8.57 (d, J = 3.9 Hz, 1H, Ar-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 23.7 (CH₃), 113.0 (CH), 123.2 (Ar-H), 127.5, 138.8 (Ar-H), 149.2 (Ar-H), 150.0 (Ar-H), 154.9, 163.3 (C=O), 164.0; MS (C₁₀H₉N₃O): 188 [M + H]⁺.

6-Ethyl-2-(pyridin-4-yl)pyrimidin-4(3H)-one (3e). White solid; R_f: 0.30 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1656 (C=O), 3434 (NH); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.32 (t, J = 7.5 Hz, 3H, CH₃), 2.69 (q, J = 7.5 Hz, 2H, CH₂), 6.42 (s, 1H, CH), 7.27 (s, 1H, NH), 8.17 (d, J = 4.8 Hz, 2H, Ar-H), 8.82 (d, J = 4.8 Hz, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 12.4 (CH₃), 31.1 (CH₂), 111.2 (CH), 121.8 (2 × Ar-H), 139.9, 151.1 (2 × Ar-H), 154.6, 166.1 (C=O), 171.8; MS (C₁₁H₁₁N₃O): 202.2 [M + H]⁺.

6-Ethyl-2-(pyridin-3-yl)pyrimidin-4(3H)-one (3f). White solid; R_f: 0.40 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1689 (C=O), 3430 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 1.16 (t, J = 7.5 Hz, 3H, CH₃), 2.51 (q, J = 7.5 Hz, 2H, CH₂), 6.20 (s, 1H, CH), 7.47–7.51 (m, 1H, Ar-H), 8.40–8.43 (m, 1H, Ar-H), 8.65–8.67 (m, 1H, Ar-H), 8.82 (s, 1H), 9.18 (s, 1H, Ar-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 13.1 (CH₃), 30.6 (CH₂), 108.8 (CH), 124.3 (Ar-H), 131.1, 136.1 (Ar-H), 149.6 (Ar-H), 152.2 (Ar-H), 158.0, 167.3 (C=O), 170.2; MS (C₁₁H₁₁N₃O): 202.2 [M + H]⁺.

6-Ethyl-2-(pyridin-2-yl)pyrimidin-4(3H)-one (3g). White solid; R_f: 0.75 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1692 (C=O), 3448 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 1.26 (t, J = 7.8 Hz, 3H, CH₃), 2.60 (q, J = 7.8 Hz, 2H, CH₂), 6.28 (s, 1H, CH), 7.43 (t, J = 7.2 Hz, 1H, Ar-H), 7.85 (t, J = 7.5 Hz, 1H, Ar-H), 8.41 (d, J = 7.8 Hz, 1H, Ar-H), 8.60 (s, 1H), 10.95 (bs, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 12.5 (CH₃), 31.0 (CH₂), 112.2 (CH), 122.5 (Ar-H), 126.8 (Ar-H), 137.9 (Ar-H), 148.3, 149.2, (Ar-H), 153.3, 162.5 (C=O), 170.5; MS (C₁₁H₁₁N₃O): 202.2 [M + H]⁺.

6-Methyl-2-(1H-pyrazol-1-yl)pyrimidin-4(3H)-one (3h). White solid; R_f: 0.60 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1670 (C=O), 3480 (NH); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 258 nm (900), 287 nm (475), 310 (300); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.29 (s, 3H, CH₃), 6.30 (s, 1H, CH), 6.54 (t, J = 1.5 Hz, 1H, pyrazol-H), 7.81 (s, 1H, pyrazol-H), 8.50 (s, 1H, pyrazol-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 23.8 (CH₃), 106.4 (CH), 109.4 (pyrazol-H), 110.4, 129.9 (pyrazol-H), 143.9 (pyrazol-H), 152.7, 168.9 (C=O); MS (C₈H₈N₄O): 175 [M − H]⁺, 199 [M + Na]⁺.

General procedure for the synthesis of 4-chloro-6-methyl-2-phenylpyrimidine (4)

Bisheteroarene (3a, 10 mmol) in POCl₃ (10 mL) was refluxed at 140 °C for 15 h. After completion, the reaction mixture was cooled and poured onto crushed ice with vigorous stirring and the precipitate obtained was filtered, washed with water and dried. Residue was recrystallized with hexane. white crystalline solid; R_f: 0.50 (5% ethyl acetate–hexane); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 258 nm (2000); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 2.56 (s, 3H, CH₃), 7.08 (s, 1H, CH), 7.48 (m, 3H, Ar-H), 8.44 (m, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 24.4 (CH₃), 118.7 (CH), 128.9 (4 × Ar-H), 131.6 (Ar-H), 136.8, 161.7, 165.4, 169.3; MS (C₁₁H₉ClN₂): 242 [M + K − H]⁺.

Synthesis of ethyl 2-(6-methyl-2-phenylpyrimidin-4-ylthio)-acetate (5) & 2-(6-methyl-2-phenylpyrimidin-4-ylthio)acetic acid (6)

Method A. A mixture of pyrimidine (4, 3 mmol), ethyl thioglycolate (3.5 mmol) and K₂CO₃ (3.5 mmol) in ethanol (50 mL) was refluxed at 120 °C for 60 h After completion of the reaction, ethanol was removed under reduced pressure and residue was poured on cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered, washed with water and finally purified by silica gel column chromatography using 1% methanol in chloroform which gave 5 as major product and 6 as miner product.

Method B. A mixture of pyrimidine (4, 3 mmol), ethyl thioglycolate (3.5 mmol) and NaH (3.5 mmol) in THF (50 mL) was refluxed at 80 °C for 40 h After completion of the reaction, THF was removed under reduced pressure and residue was poured on cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered, washed with water and finally purified by a silica gel column chromatography using 1% methanol in chloroform.

2-(6-Methyl-2-phenylpyrimidin-4-ylthio)acetate (5). Crystalline white solid; Mp: 50–51 °C; R_f: 0.22 (4% ethyl acetate–hexane); IR (KBr, ν_max/cm⁻¹): 1738 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.24 (t, J = 7.2 Hz, 3H, CH₃), 2.44 (s, 3H, CH₃), 4.01 (s, 2H, SCH₂), 4.19 (q, J = 7.2 Hz, 2H, OCH₂) 6.94 (s, 1H, CH), 7.44 (t, J = 0.5 Hz, 3H, Ar-H), 8.42 (d, J = 0.5 Hz, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 14.5 (CH₃), 24.3 (CH₃), 32.2 (SCH₂), 62.1 (OCH₂), 116.1 (CH), 128.7 (Ar-H), 128.9 (Ar-H), 129.0 (Ar-H), 129.6 (Ar-H), 131.1 (Ar-H), 137.8, 163.7, 165.5, 167.7 (C–S), 169.5 (C=O); MS (C₁₅H₁₆N₂O₂S): 289.2 [M + H]⁺.

2-(6-Methyl-2-phenylpyrimidin-4-ylthio)acetic acid (6). Crystalline white solid; Mp: 127–128 °C; R_f: 0.30 (dichloromethane); UV(CH₃OH, λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 258 nm (900), 220 nm (1400), 298 (1600); IR (KBr, ν_max/cm⁻¹): 1727 (C=O), 3447 (OH); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 2.30 (s, 3H, CH₃), 3.95 (s, 2H, SCH₂), 6.59 (s, 1H, CH), 7.41 (m, 3H, Ar-H), 8.31 (m, 2H, Ar-H), 9.31 (bs, 1H, OH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 24.3 (CH₃), 32.6 (SCH₂), 116.3 (CH), 128.7 (2 × Ar-H), 128.9 (2 × Ar-H), 131.4 (Ar-H), 137.1, 164.1, 166.2, 167.8 (C–S), 173.2 (C=O); MS (C₁₃H₁₂N₂O₂S): 259 [M − H]⁺, 259 [M − 2Na]⁺.

Synthesis of 2-(6-methyl-2-phenylpyrimidin-4-ylthio)aceto-hydrazide (7)

Pyrimidine (5, 1.0 mmol) and hydrazine hydrate (1 mL) in ethanol (40 mL) were refluxed with vigorous stirring for 10 h. After the completion of reaction, reaction mixture was left for overnight. Precipitate was formed which was filtered and recrystallized with dichloromethane. R_f: 0.13 (4% chloroform); IR (KBr, ν_max/cm⁻¹): 1661 (C=O), 3288 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.41 (s, 3H, CH₃), 4.02 (s, 2H, SCH₂), 7.22 (s, 1H, CH), 7.48–7.50 (m, 3H, Ar-H), 8.31-8.34 (m, 2H, Ar-H), 9.46 (bs, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 24.2 (CH₃), 31.7 (SCH₂), 116.4 (CH), 128.7 (2 × Ar-H), 129.5 (2 × Ar-H), 131.8 (Ar-H), 137.5, 163.2, 166.4, 168.1 (C–S), 169.2 (C=O); MS (C₁₃H₁₄N₄OS): 275.2 [M + H]⁺, 325.2 [M + K]⁺.

Synthesis of 1,6-dihydro-4-(methylthio)-6-oxo-2-heteroaryl/phenylpyrimidine-5-carbonitrile (9)

A mixture of amidine (2, 2.0 mmol) and methyl 2-cyano-3,3-dimethylthioacrylate (8, 2.0 mmol) in DMF (10 mL) or EtOH (20 mL) in the presence of powdered KOH or NaOH (2.1 mmol) or Et₃N (3 mmol) was stirred at room temperature or reflux as shown in Table 3. The reaction was monitored using TLC. After consumption of 8, the residue was poured onto crushed ice with vigorous stirring. The aqueous suspension was neutralized with N/10 HCl (if required). The precipitate obtained was filtered, washed with water and dried. Further washing with cold methanol yielded 9 as white solid.

1,6-Dihydro-4-(methylthio)-6-oxo-2-phenylpyrimidine-5-carbonitrile (9a). White solid; R_f: 0.41 (50% ethyl acetate–hexane); IR (KBr, ν_max/cm⁻¹): 1665 (C=O), 2223 (CN), 3440 (NH); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 238 nm (1200), 285 nm (700); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.49 (s, 3H, SCH₃), 7.34 (t, J = 3.0 Hz, 3H, Ar-H), 8.21 (t, J = 3.0 Hz, 2H, Ar-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 12.6 (SCH₃), 89.8, 119.3 (CN), 128.9 (2 × Ar-H), 129.0 (Ar-H), 131.2 (2 × Ar-H), 139.0, 163.8, 171.5, 172.0; MS (C₁₂H₉N₃OS): 242 [M − H]⁺, 244 [M + H]⁺, 282[M + K]⁺.

1,6-Dihydro-4-(methylthio)-6-oxo-2-(pyridin-4-yl) pyrimidine-5-carbonitrile (9b). White solid; R_f: 0.10 (ethyl acetate); IR (KBr, ν_max/cm⁻¹): 1664 (C=O), 2212 (CN), 3441 (NH); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.48 (s, 3H, SCH₃), 8.09 (t, J = 4.5 Hz, 3H, Ar-H), 8.84 (t, J = 4.5 Hz, 2H, Ar-H); MS (C₁₁H₈N₄OS): 245.2 [M + H]⁺.

1,6-Dihydro-4-(methylthio)-6-oxo-2-(1H-pyrazol-1-yl) pyrimidine-5-carbonitrile (9c). White solid; R_f: 0.75 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1687 (C=O), 2211 (CN), 3480 (NH); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 258 nm (900), 287 nm (400), 310 nm (350); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.65 (s, 3H, SCH₃), 6.68 (d, J = 1.2 Hz, 1H, pyrazol-H), 7.98 (bs, 1H, pyrazol-H), 8.68 (d, J = 1.2 Hz, 1H, pyrazol-H); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 13.8 (SCH₃), 90.3, 111.5 (pyrazol-H), 115.1 (CN), 131.6 (pyrazol-H), 146.1 (pyrazol-H), 150.4, 163.3 (C=O), 176.8; MS (C₉H₇N₅OS): 232 [M − H]⁺, 234 [M + H]⁺, 256 [M + Na]⁺.

Synthesis of 3-amino-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (10)

A mixture of pyrimidinone (9, 2 mmol) and hydrazine hydrate (2.5 mmol) in methanol (50 mL) was refluxed (Table 4). After completion of the reaction, methanol was removed under reduced pressure and residue was poured in cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered, washed with water and finally purified by washing with ether. Cream coloured solid; R_f: 0.57 (EtOAc); IR (KBr, ν_max/cm⁻¹): 1645 (C=O), 3268, 3419 (NH); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 198 nm (2900), 237 nm (1900); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 5.50 (bs, 2H, NH₂), 7.46–7.54 (m, 3H, Ar-H), 7.99 (d, J = 7.2 Hz, 2H, Ar-H), 11.71 (bs, 1H, NH); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 92.0, 128.5 (2 × Ar-H), 129.5 (2 × Ar-H), 132.3 (Ar-H), 133.4, 151.0, 155.1, 155.9, 160.6 (C=O); MS (C₁₁H₉N₅O): 226 [M − H]⁺, 250[ M + Na]⁺.

Synthesis of 4-chloro-6-(methylthio)-2-heteroaryl/phenyl pyrimidine-5-carbonitrile (11)

Pyrimidinone (9, 4 mmol) in POCl₃ (5 mL) was refluxed at 140 °C (Table 4). After completion, the reaction mixture was cooled and poured onto crushed ice with vigorous stirring. The precipitate obtained was filtered, washed with water and dried and purified by a silica gel column chromatography using solvent ethyl acetate in hexane.

4-Chloro-6-(methylthio)-2-phenylpyrimidine-5-carbonitrile (11a). White crystalline solid; R_f: 0.65 (5% ethyl acetate–hexane); IR (KBr, ν_max/cm⁻¹): 2219 (CN); UV(CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 278 nm (1150); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 2.77 (s, 3H, SCH₃), 7.47–7.60 (m, 3H, Ar-H), 8.44 (m, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 13.8 (SCH₃), 103.5, 112.9, 129.2 (2 × Ar-H), 129.9 (2 × Ar-H), 133.5 (Ar-H), 135.1, 162.2, 164.4, 176.0; MS (C₁₂H₈ClN₃S): 242 [M + Na–4H]⁺, 260 [M − H]⁺.

4-Chloro-6-(methylthio)-2-(1H-pyrazol-1-yl)pyrimidine-5-carbonitrile (11b). White crystalline solid; R_f: 0.50 (dichloromethane); IR (KBr, ν_max/cm⁻¹): 2224 (CN); UV (CH₃OH), λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 272 nm (1220); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 2.79 (s, 3H, SCH₃), 6.57 (q, J = 1.50 Hz, 1H, pyrazol-H), 7.91 (d, J = 0.60 Hz, 1H, pyrazol-H), 8.55 (d, J = 2.70 Hz, 1H, pyrazol-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 14.0 (SCH₃), 102.7, 110.8 (pyrazol-H), 112.3, 130.8 (pyrazol-H), 146.3 (pyrazol-H), 154.0, 163.8, 178.6; MS (C₉H₆ClN₅S): 252 [M + H]⁺.

Synthesis of ethyl 2-(5-cyano-6-(methylthio)-2-phenyl pyrimidin-4-ylthio)acetate (12a)

Pyrimidine (11a, 1 mmol), ethyl thioglycolate (1.5 mmol) and Et₃N (1.5 mmol) in ethanol (20 mL) were refluxed at 120 °C. After completion of the reaction, ethanol was removed under reduced pressure and residue was poured in cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered and purified by a silica gel column chromatography using ethyl acetate (0.5–1.0%) in hexane. White solid, R_f: 0.48 (10% EtOAc in hexane); IR (KBr, ν_max/cm⁻¹): 2211 (CN), 1736 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.26 (t, J = 7.2 Hz, 3H, CH₃), 2.74 (s, 3H, SCH₃), 4.06 (s, 2H, SCH₂), 4.19 (q, J = 7.2 Hz, 2H, OCH₂), 7.46–7.57 (m, 3H, Ar-H), 8.43 (t, J = 0.50 Hz, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 13.3 (SCH₃), 14.5 (CH₃), 32.7 (SCH₂), 62.5 (OCH₂), 100.2, 113.4 (CN), 129.0 (2 × Ar-H), 129.7 (2 × Ar-H), 132.8 (Ar-H), 136.2, 162.5, 168.5 (C=O), 170.9, 173.5; MS (C₁₆H₁₅N₃O₂S₂): 344[M − H]⁺, 346 [M + H]⁺.

Ethyl 5-amino-4-(methylthio)-2-(1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine-6-carboxylate (12b)

Pyrimidine (11b, 2 mmol), ethyl thioglycolate (2.4 mmol) and Et₃N (2.5 mmol) in ethanol (50 mL) were refluxed for 30 h at 120 °C. After completion of the reaction, cool the reaction mixture. Precipitate was formed which was filtered and recrystallized in methanol. White solid, R_f: 0.26 (CHCl₃); λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 202 (600), 269 (1900); IR (KBr, ν_max/cm⁻¹): 2215 (CN), 1737 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.27 (t, J = 7.2 Hz, 3H, CH₃), 2.77 (s, 3H, SCH₃), 4.07 (s, 2H, CH₂), 4.19 (q, J = 7.2 Hz, 2H, OCH₂), 6.57 (dd, J = 1.5 & 1.2 Hz, 1H, pyrazole-H), 7.87 (d, J = 0.9 Hz, 1H, pyrazole-H), 8.59 (d, J = 0.9 Hz, 1H, pyrazole-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 12.1 (SCH₃), 13.1 (CH₃), 31.6 (SCH₂), 61.1 (OCH₂), 97.4, 108.9 (Ar-H), 111.6 (CN), 129.5 (Ar-H), 144.2 (Ar-H), 151.6, 166.9 (C=O), 171.8, 174.7; MS (C₁₃H₁₃N₅O₂S₂): 358 [M + Na]⁺.

Ethyl 4-((ethoxycarbonyl)(mercapto)methylene)-7-amino-3,4-dihydro-2-phenylthieno[3,2-d]pyrimidine-6-carboxylate (14)

Pyrimidine (11a, 1 mmol), ethyl thioglycolate (2.1 mmol) and NaH (4 mmol) in dry THF (20 mL) were refluxed at 70–80 °C. After completion of the reaction, THF was removed under reduced pressure and residue was poured on cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered and purified by a silica gel column chromatography using ethyl acetate (1.0%) in hexane. Yellowish green solid, green fluorescence in long range UV, R_f: 0.55 (10% EtOAc in hexane); λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 203 (850), 272 (400), 357 (100); IR (KBr, ν_max/cm⁻¹): 3495 (NH), 3376 (NH), 1674 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.38 (t, J = 7.2 Hz, 3H, CH₃), 1.53 (t, J = 6.9 Hz, 3H, CH₃), 1.66 (s, 1H, SH), 4.34 (q, J = 7.2 Hz, 2H, OCH₂), 4.74 (q, J = 6.9 Hz, 2H, OCH₂), 6.43 (bs, 2H, NH₂), 7.45–7.47 (m, 3H, Ar-H), 8.44.8.47 (m, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 14.8 (CH₃), 14.9 (CH₃), 60.7 (OCH₂), 63.5 (OCH₂), 94.8, 109.8, 128.8 (2 × Ar-H), 129.0, (2 × Ar-H), 131.4 (Ar-H), 137.4, 147.6, 163.0, 165.3, 165.5, 169.6; MS (C₁₉H₁₉N₃O₄S₂): 455 [M + K − H]⁺.

4-oxo-2-Thioxo-6-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (18)

Benzaldehyde (17, 5 mmol), methyl cyanoacetate (16, 5 mmol), thiourea (15, 5 mmol) and K₂CO₃ (5 mmol) in ethanol (25 mL) were refluxed at 120 °C. After completion of the reaction, ethanol was removed under reduced pressure and residue was poured on cold water with stirring. The aqueous phase was neutralized with N/10 HCl (if required). The crude product obtained was filtered and recrystallized with methanol. Yellow solid, R_f: 0.09 (dichloromethane); λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 220 (1300), 298 (1700); IR (KBr, ν_max/cm⁻¹): 3472 (NH), 3361 (NH), 2208 (CN), 1632 (C=O); ¹H NMR (DMSO-d₆, 300 MHz, δ ppm): 2.50 (s, 3H, CH₃), 7.31 (d, J = 7.8 Hz, 2H, Ar-H), 7.92 (d, J = 7.8 Hz, 2H, Ar-H), 12.99 (bh, 2H, NH); ¹³C NMR (DMSO-d₆, 75 MHz, δ ppm): 22.1 (CH₃), 103.4, 117.1 (CN), 130.7 (2 × Ar-H), 131.5 (2 × Ar-H), 144.8, 154.9, 162.2, 164.2, 177.5; MS (C₁₂H₉N₃OS): 242 [M − H]⁺.

Synthesis of ethyl 2-(5-cyano-2-thioxo-6-p-tolyl-1,2-dihydro pyrimidin-4-yloxy)acetate (20) and ethyl 2-(5-cyano-2-(2-ethoxy-2-oxoethylthio)-6-p-tolylpyrimidin-4-yloxy)acetate (21)

In a 100 mL R.B. flask, 4-oxo-2-thioxo-6-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (18, 2 mmol) was dissolved in dimethylformamide (DMF, 15 mL) at 80 °C. After stirring for five minutes, anhydrous K₂CO₃ (2.1 mmol) and ethyl 2-bromoacetate (19, 2.0 mmol) were added in reaction mixture. The reaction mixture was stirred for 9 h. The reaction mixture was poured on cold water with vigorous stirring and neutralized it with acetic acid. The precipitate was filtered and dried. The crude was purified by column chromatography using silica gel (100–200 mesh) which yielded compound 20 (2.0% EtOAc in hexane) and 21 (2.5% EtOAc in hexane).

Ethyl 2-(5-cyano-2-thioxo-6-p-tolyl-1,2-dihydropyrimidin-4-yloxy)acetate (20). White solid; R_f: 0.50 (20% EtOAc in hexane); IR (KBr, ν_max/cm⁻¹): 2222 (CN), 1754 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.32 (t, J = 7.2 Hz, 3H, CH₃), 2.46 (s, 3H, CH₃), 4.27 (q, J = 7.2 Hz, 2H, OCH₂), 4.76 (s, 2H, OCH₂), 7.32 (d, J = 8.1 Hz, 2H, Ar-H), 7.92 (d, J = 8.4 Hz, 2H, Ar-H), 8.29 (s, 1H, NH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 14.4 (CH₃), 22.2 (CH₃), 62.1 (OCH₂), 62.4 (OCH₂), 100.9, 115.7 (CN), 129.1, 130.5 (2 × Ar-H), 131.8 (2 × Ar-H), 145.5, 156.5 (2 × Ar), 162.7, 167.2; MS (C₁₆H₁₅N₃O₃S): 330 [M + H]⁺.

Ethyl 2-(5-cyano-2-(2-ethoxy-2-oxoethylthio)-6-p-tolyl pyrimidin-4-yloxy)acetate (21). White solid; R_f: 0.36 (20% EtOAc in hexane); IR (KBr, ν_max/cm⁻¹): 2225 (CN), 1749 & 1546 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 1.24 (t, J = 7.2 Hz, 3H, CH₃), 1.30 (t, J = 7.2 Hz, 3H, CH₃), 2.42 (s, 3H, CH₃), 3.96 (s, 2H, CH₂), 4.19 (q, J = 7.2 Hz, 2H, OCH₂), 4.27 (q, J = 7.2 Hz, 2H, SCH₂), 5.01 (s, 2H, OCH₂), 7.29 (d, J = 8.1 Hz, 2H, Ar-H), 7.94 (d, J = 8.4 Hz, 2H, Ar-H); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 14.4 (CH₃), 14.5 (CH₃), 21.9 (CH₃) 34.2 (SCH₃), 62.1 (OCH₂), 62.3 (OCH₂), 64.2 (OCH₂), 88.3, 114.7 (CN), 129.5 (2 × Ar-H), 129.8 (2 × Ar-H), 132.3 (Ar-H), 143.2, 167.3, 168.9, 169.2, 169.5, 173.4; MS (C₂₀H₂₁N₃O₅S): 416.2 [M + H]⁺, 438.3 [M + Na]⁺, 454.1 [M + K]⁺.

Synthesis of (E)-methyl 2-cyano-3-phenylacrylate (22)

Benzaldehyde (17, 5 mmol), methyl cyanoacetate (16, 3 mmol), thiourea (15, 3 mmol, in presence or in absent) and K₂CO₃ (3 mmol) in water (15 mL) were sake at room temperature 5 to 15 min. The aqueous phase was neutralized with N/10 HCl (if required). The precipitate was filtered as pure product.

(E)-Methyl 2-cyano-3-p-tolylacrylate (22a). White solid; R_f: 0.53 (20% EtOAc in hexane); λ_max/nm⁻¹ (ε/dm⁻³ mol⁻¹ cm⁻¹): 204 (1000), 228 (800), 315 (1800); IR (KBr, ν_max/cm⁻¹): 2222 (CN), 1728 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 2.41 (s, 3H, CH₃), 3.91 (s, 3H, OCH₃), 7.27 (d, J = 8.1 Hz, 2H, Ar-H), 7.89 (d, J = 8.4 Hz, 2H, Ar-H), 8.20 (s, 1H, =CH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 22.2 (CH₃), 53.6 (OCH₃), 101.5 (=C), 116.1 (CN), 129.2, 130.4 (2 × Ar-H), 131.6 (2 × Ar-H), 145.1, 155.6 (=CH), 163.6 (C=O); MS (C₁₂H₁₁NO₂): 224 [M + Na]⁺.

(E)-Methyl 2-cyano-3-(3,4,5-trimethoxyphenyl)acrylate (22b). Yellow solid; R_f: 0.75 (50% EtOAc in hexane); IR (KBr, ν_max/cm⁻¹): 2219 (CN), 1733 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 3.26 (s, 6H, 2 × OCH₃), 3.91 (s, 3H, OCH₃), 3.92 (s, 3H, OCH₃), 7.34 (s, 2H, Ar-H), 8.19 (s, 1H, =CH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 52.3 (OCH₃), 55.2 (2 × OCH₃), 59.9 (OCH₃), 99.7 (=C), 107.8 (2 × Ar-H), 114.9 (CN), 125.5, 141.7, 152.2 (2C), 154.1 (=CH), 162.0 (C=O); MS (C₁₄H₁₅NO₅): 278.2 (M + H)⁺, 300.2 [M + Na]⁺.

(E)-Methyl 2-cyano-3-(4-methoxyphenyl)acrylate (22c). White solid; R_f: 0.37 (20% EtOAc in hexane); IR (KBr, ν_max/cm⁻¹): 2221 (CN), 1727 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 3.87 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 6.97 (d, J = 9.0 Hz, 2H, Ar-H), 7.97 (d, J = 9.0 Hz, 2H, Ar-H), 8.15 (s, 1H, =CH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 53.5 (OCH₃), 56.0 (OCH₃), 99.3 (=C), 115.2 (2 × Ar-H), 116.5 (CN), 124.7, 134.0 (2 × Ar-H), 154.9 (=CH), 164.0 (C=O), 164.2; MS (C₁₂H₁₁NO₃): 218.2 [M + H]⁺, 240.1 [M + Na]⁺, 256.2 [M + K]⁺.

(E)-Methyl 2-cyano-3-(4-hydroxyphenyl)acrylate (22d). Yellow solid; R_f: 0.77 (Dichloromethane); IR (KBr, ν_max/cm⁻¹): 2220 (CN), 1727 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 3.49 (h, 1H, OH), 3.89 (s, 3H, OCH₃), 6.94 (d, J = 9.0 Hz, 2H, Ar-H), 7.90 (d, J = 9.0 Hz, 2H, Ar-H), 8.14 (s, 1H, =CH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 52.2 (OCH₃), 96.3 (=C), 115.6 (CN), 115.8 (2 × Ar-H), 122.0, 133.2 (2 × Ar-H), 154.2 (=CH), 162.3 (C=O), 162.9; MS (C₁₁H₉NO₃): 203 [M + H]⁺.

(E)-Methyl 2-cyano-3-(4-hydroxy-3-methoxyphenyl) acrylate (22e). Yellow solid; R_f: 0.27 (Dichloromethane); IR (KBr, ν_max/cm⁻¹): 2220 (CN), 1727 (C=O); ¹H NMR (CDCl₃, 300 MHz, δ ppm): 3.80 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 4.62 (h, 1H, OH), 6.87 (d, J = 8.4 Hz, 1H, Ar-H), 7.27 (d, J = 8.4 Hz, 1H, Ar-H), 7.68 (s, 1H, Ar-H), 8.02 (s, 1H, =CH); ¹³C NMR (CDCl₃, 75 MHz, δ ppm): 53.4 (OCH₃), 56.3 (OCH₃), 97.9 (=C), 112.4 (Ar-H), 116.0 (Ar-H), 116.9 (CN), 123.9, 129.0 (Ar-H), 148.1, 152.7, 155.6 (=CH), 164.1 (C=O); MS (C₁₂H₁₁NO₄): 233 [M + H]⁺.

Acknowledgements

This work supported by DST, New Delhi, India for financial support as DST fast track young scientist fellowship [no SR/FT/CS-20/2011] to H.K.M. Authors are thankful to Director, CSIR-CIMAP for his kind support.

Notes and references

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