Keywords

SiO₂.TTC, 3,4-Dihydropyrimidin-2(1H)-ones, Urea/thiourea.

Introduction

Dihydropyrimidone and their derivatives have been useful for natural, synthetic, pharmacological, therapeutic and bioorganic chemistry mainly due to their wide range of biological activities and its applications [1-7]. Research in multicomponent reactions (MCRs) is an encoring and hot topic in organic chemistry, as there advantages in preparations of heterocyclic compounds and in drugs discovery procedures [8]. These organic compounds show different activities as calcium channel blocks, antihypertensive agents, alpha antagonists of neuropeptids etc. Various synthetic methods have been reported by different pharmacists such as acids [9-13], microwave variants [14-27], Mn(OAc)2 [28-32] LiBr [33,34], ammonium salt [35], on reagents like CAN and clay [36]. But most of the methods have limitations in terms of yields, catalyst loading, stability, long reaction time etc. causing disposal. In continuation of our research on the introduction of more efficient solid supportive catalyst in organic synthesis.

Materials and Methods

All the chemicals and solvents were purchased from Merckand Sigma Aldrich. All reagents are received which are purified by distillation and recrystallization. The reaction was monitored by TLC.

The spot were detected either under UV light or by placing in an iodine chamber. Melting points were determined in pen capillaries methods.

General procedure for synthesis of 3,4-Dihydropyrimidin-2(1H)-ones/thiones

Aromatic aldehyde (1 mmol), ethylacetoacetate (1 mmol), urea/thiourea (1 mmol) and SiO₂.TTC (10%) were stirred in round bottom flask for 5-30 min with solvent Chloroform (1 ml) at room temperature. The development of reaction was monitored by thin-layer chromatography. The completion of reaction confirmed with TLC. After drying it was purified by recrystallization from hot alcohol and further purification by column chromatography. The product obtained after the usual workup were characterised using spectroscopic techniques Scheme 1.

Scheme 1: Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones/thiones

Results and Discussion

The optimum condition for the synthesis of 3,4-Dihydropyrimidon-2(1H)-ones or thiones derivatives were established by considering a reaction between aldehyde, ethylacetoacetate, urea or thiourea with SiO₂.TTC (Silica supported titanium trichloride) using chloroform as a solvent. The product obtained was confirmed by melting points and spectral data.

The effectiveness of solid supportive catalyst SiO₂.TCC was determined with respect to its leading amounts. There was no improvement in yield with increasing amount from 0.10 mmol of catalyst (Table 1, Entry 3).

Thus, the most appropriate amount for anhydrous SiO₂.TTC as a catalyst was found to be 0.1 mmol as per results summarized in Table 1.

Table 1: Investigation of catalytic effects for synthesis of 3,4-Dihydropyrimidine -2(1H) ones/thiones.

As summarized in Table 2, aromatic/aliphatic aldehydes with electron-donating or electron withdrawing groups, ethylacetoacetate and urea/thiourea in presence of SiO₂.TTC were reacted, resulting in corresponding 3,4-dihydropyrimidin-2(1H)-ones/thiones in good to excellent yields.

Entry	Aldehydea	X	Productb	Time (Min)	Yieldc (%)
1		O		05	92
2		S		30	90
3		O		05	91
4		S		25	89
5		O		25	90
6		S		25	88
7		O		05	95
8		S		25	84
9		S		25	92
10		O		25	90
11		O		25	89
12		O		50	80
13		O		50	84
14		O		15	92
15		S		25	90
16		O		15	90
17		S		25	88

Table 2: Synthesis of diydrohyropyrimidones catalysed by SiO₂.TTC.

Three components reacted smoothly in presence of solid supportive SiO₂.TTC with CHCl₃ gave good yields of corresponding products (Table 2). SiO₂.TTC was proved to be an efficient catalyst under mild conditions. Various aromatic aldehydes containing either electron donating or withdrawing substituents at different position reacted well under present reaction condition (Table 2) proving the wide scope and generality of the protocol. The nature and substitution pattern of different substituents affected the course of reaction in terms of time and yields. These aromatic aldehyde having electron withdrawing groups gave excellent yields, in short reaction time (Table 2, Entry 7) but those with electron donating substitution gave comparatively low yields with slow reaction rate (Table 2, Entry 3,14,16). Further aldehydes with o-substituents were found to be less reactive (Table 2, Entry 5,6) aliphatic aldehydes were less reactive even at more time (Table 2, Entry 12,13). The products obtained from thiourea gives moderate yields (Table 2, Entry 2,4,6,8,9,15,17). This proved wide scopes and generality of the present protocol. The categorization date of various 1H, NMR, IR achieved for various compounds are given in Table 2.

Characterization

(i) 4-(4-Chlorophenyl) 3,4-dihydro-6-phenylpyrimidin-2(1H)-one (Table 2, Entry 3): Melting point 266°C;

¹HNMR (400 MHz, DMSO); δ =8.65 (s, 1H, NH), 8.08 (s, 1H, NH), 7.53 7.33 m, (m, 9H, Ar H), 5.45(d, J 2.8 Hz, 1H, CH), 5.18 (d, 1H, J 2.8 Hz, CH)

IR (KBr) cm^-1 3232, 2936, 1685, 1573 and 1465

(ii) 3,4-Dihydro-4-(4-hydroxyphenyl)-6-phenylpyrimidin- 2(1H)-one (Table 2, Entry 9): Melting point 256°C

¹HNMR (400 MHz, DMSO) δ=9.20 (s, 1H, NH), 8.14 7.53 (m, 9H, Ar H), 7.35 7.31 (s, 1H, NH), 7.28 (d, J 8.8 Hz, 1H, CH), 5.56 (s, 1H, OH) 5.15 (d, 1H, J 8.8 Hz, CH);

IR (KBr) cm^-1 3386, 2922, 1626, 1519 and 1445

(iii) 3,4-Dihydro-4-(4-methoxyphenyl)-6-phenylpyrimidin-2(1H)-one (Table 2, Entry 16):

¹HNMR (400 MHz, DMSO) δ=12.06 (s, 1H, NH), 9.35 (s, 1H, NH), 8.38 7.22 (m, 9H, Ar H), 6.95 (d, J 8.7 Hz, 1H, CH), 5.47 (d, 1H, J 8.7 Hz, CH), 3.75 (s, 3H, OCH₃);

IR (KBr) cm^-1 3382, 2936, 1614, 1522, 1418

Conclusion

In this research paper, we successfully developed a simple and highly efficient one pot synthesis of 3,4-Dihydropyrimidin- 2(1H)-ones or thiones derivatives from easily available starting materials using SiO₂.TTC. We developed multi components reaction of ethyl acetoacetate, aromatic aldehydes, and urea/thiourea using SiO₂.TTC catalyst. This protocol is attractive in terms economy, short reaction times, simple easy workup make this procedure a useful addition to modern synthetic methods are few of the advantages of this procedure.

Acknowledgement

The authors acknowledge the kind support to this work by Principal Dr. S.T. Gadade C.K.Thakhur A.C.S. College, New Panvel, Raigad, Maharaahtra, India.

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