IBX in aqueous medium: a green protocol for the Biginelli reaction

Abstract

Iodoxy benzoic acid (IBX) used as an effective catalyst for the synthesis 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) via the Biginelli reaction in water. The immobilized catalyst could be easily recovered by simple filtration and recycled without significant decrease of the catalytic activity.

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Introduction

Multicomponent reactions (MCR) have been gaining notable attention and interest since their discovery¹ for their outstanding capacity to form numerous new bonds from a variety of starting materials in one pot, in a single operation.² Owing to their bond forming efficiency, multicomponent reactions are the preferred approach in the drug discovery process.^3,4 When compared with traditional approaches multicomponent reactions present several advantages in terms of synthesis procedure, work-up, product yield, cost involvement, time requirement, labour expenditure and waste production. Nowadays efforts are being made to discover and design novel multicomponent reactions using three to four components to produce valuable heterocyclic scaffolds which have extensive and diverse applications in different areas of applied chemistry.⁵

Dihydropyrimidinones (DHPMs) and their derivatives, outcomes of the Biginelli reaction,¹ fall under the major class of heterocycles that possess a broad range of important biological and pharmacological activities. They have been observed to act as calcium channel blockers, antihypertensive agents, antagonists, and neuropeptide Y (NPY) antagonists,^6–8 besides this many of the derivatives have antifungal, antiviral, anticancer, antibacterial, antitumor and anti-inflammatory activities.^9,10Alkaloidse.g. Batzalladine found in marine sources containing a dihydropyrimidinone core, exhibit significant HIVgp-120-CD4 inhibitor activity.¹¹ Therefore the synthesis of these privileged scaffolds by using convenient, green chemistry procedure is of prime concern.

The most straightforward synthesis of this heterocyclic system involves a three-component coupling of aromatic aldehyde, urea or thiourea and β-keto esters. Remarkable modifications in the synthetic protocol were also carried out to produce DHMPs in good yields. Most of these procedures made use of diverse catalysts like heteropolyacids,¹² CuCl₂·H₂O,¹³L-proline,¹⁴praseodymium methanesulfonate,¹⁵chloroacetic acid,¹⁶H₂SO₄,¹⁷ BF₃·EtOH–CuCl,¹⁸ LaCl₃·7H₂O with catalytic concentrated HCl,¹⁹ CeCl₃·7H₂O,²⁰InCl₃,²¹BiCl₃,²²Cu(OTf)₂,²³ TMSCl,²⁴LiClO₄,²⁵LiBr,²⁶InBr₃,²⁷phenyl pyruvic acid,²⁸ FeCl₃·6H₂O–HCl,²⁹TMSI³⁰ and CdCl₂³¹. Very recently it has also been shown that DHPMs can be synthesized by using thiamine hydrochloride under ultrasound conditions.³² Hitherto, all these methodologies come up with drawbacks such as prolonged reaction time, tedious catalyst preparation and work-up, formation of inevitable side or sticky products, and exhaustive usage of energy sources and solvents which result in a lower yield of the desired product. So, considering all these facts and with an emphasis on human health and environmental protection, the development of an eco-friendly and environment friendly reagent system is highly desirable.

The novel reagents which could provide chemoselectivity with efficiency are being constantly sought for contemporary organic synthesis. In this regard the hypervalent iodine reagent IBX is amply demonstrated in organic synthesis owing to its mild, highly specific and eco-friendly nature.^33–36 To date reported data about IBX reveals that it is used in alcohol oxidation,³⁷ conversion of primary alcohols/aldehydes to carboxylic acids,³⁸oxidation of 1,2 amino alcohols to 1,2-diols without oxidative cleavage of the C–C bond³⁹ and in the conversion of 1,4-diols to γ-lactols.⁴⁰ With the background of global warming, disposal of organic solvent is a major problem. The idea of replacing them with water has gained interest in last few years due to its non-toxic and non-flammable properties. Besides, the physical and chemical properties of water encourage good reactivity and selectivity in reactions in comparison to organic solvents.⁴¹

In the context of our ongoing research project on the development of green methodologies for the synthesis of heterocyclic compounds of biological importance and the use of heterogeneous catalysts in organic reactions,⁴² here we would like to report our investigation concerning the IBX-mediated synthesis of 3,4-dihydropyrimidine-2-(1H)-ones in water (Scheme 1).

Scheme 1 Synthesis of 3,4-dihydropyrimidine-2-(1H)-one.

Results and discussion

The development of the IBX-mediated Biginelli reaction commenced with the screening of a variety of catalysts. To investigate the need for a catalyst in the synthesis of 3,4-dihydropyrimidine-2-(1H)-one we had run two sets of reactions, (1) a control reaction—where we reacted benzaldehyde, ethylactoacetate and urea in water in absence of any catalyst, (2) a test reaction—in this set we reacted the previously mentioned substrates in the presence of various catalystsviz. UHP, TBHS, β-CD, CuCl, CAS, iodine, DABCO and IBX. This set was used for the purpose of screening of most efficient catalyst by observing the influence of the catalyst on the reaction parameters. After the completion of reactions we observed that the control reaction yielded 20% of the product after 45 h at 100 °C and the effects of the catalysts on the reaction parameters are summarized in Table 1.

Table 1 Preparation of 3,4-dihydropyrimidine-2(1H)-one using various catalysts^a

Entry	Catalyst	Temp. (°C)	Time (h)	Yield^b
a Reaction condition: benzaldehyde (1 mmol), ethylacetoacetate (1 mmol), urea (1.2 mmol), catalyst (5 mol%), solvent: water (5 mL), time: 2.5 h, temp.: 60–100 °C. b Isolated yield.
1	None	100	45	20
2	UHP	80	6	76
3	TBHS	100	6	65
4	β-CD	100	6	69
5	CuCl	100	6	79
6	CAS	100	7	71
7	Iodine	80	4	81
8	DABCO	80	3.5	80
9	IBX	60	2.5	90

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The observations reveal that IBX offers the best results owing to its ability to activate the carbonyl group of aldehydes and ketones which speeds up the iminium formation and subsequently nucleophilic addition of the enolised β-keto ester. The same reaction was carried out separately in the presence of IBA and 2-iodobenzoic acid, and it was observed that the reaction needed more time for completion and produced a low yield, presumably due to their low reactivity.⁴³

Further to probe the effect of solvents, reactions were carried out in the presence of IBX as the catalyst, using various solvents and keeping the reaction time constant while the control reaction was set in a solvent free system. The success of the reaction was judged on the criteria of the product yield and reaction temperature (Table 2). Water accelerates the rate of reaction owing to its polar and protic nature.

Table 2 Effect of solvent on the synthesis of 3,4-dihydropyrimidine-2(1H)-ones^a

Entry	Solvent	Temp. (°C)	Yield^b (%)
a Reaction condition: benzaldehyde (1 mmol), ethylacetoacetate (1 mmol), urea (1.2 mmol) IBX (5 mol%), solvent: 5 mL, time: 2.5 h, temp.: 60 °C. b Isolated yield.
1	Water	60	90
2	Methanol	50	78
3	Ethanol	60	72
4	Chloroform	55	63
5	Dichloromethane	35	59
6	DMF	120	63
7	Acetonitrile	75	47
8	THF	55	78
9	DMSO	120	67
10	Solvent free	100	20

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According to the results in Table 1 and 2, the most efficient reaction system is IBX in water. With respect to the appealing results obtained from the catalyst and solvent screening, we framed the general protocol for the synthesis of 3,4-dihydropyrimidine-2(1H)-one by treating several aromatic aldehydes and β-keto esters with urea or thiourea using IBX in water (Table 3). The reaction conditions were compatible with various functional groups, ranging from the electron-withdrawing cyano and nitro groups to the halides. Indeed, it has been observed that the oxidation prone groups (–OH, –OMe) are tolerated in this reaction. In general the yields are high, regardless of the structural variations. Upon completion of reaction, IBX has been recovered along with some amount of IBA, the reduced analog of IBX. This IBA then on its oxidation collectively contributes to overall recovery of IBX. Thus about 60% of IBX was recovered and reused without loss of its activity for next few reaction cycles.

Table 3 Aqueous phase synthesis of 3,4-dihydropyrimidine-2(1H)-ones^ab

Entry	Compound	R	R1	X	Time (h)	% Yield
a All products were well characterized using ^1H NMR, and IR spectra. b Yields refer to isolated pure products.
1	4a		CH3	O	1.5	90
2	4b		CH3	S	2.5	92
3	4c		C2H5	O	3.0	87
4	4d		CH3	O	3.0	83
5	4e		CH3	O	3.0	82
6	4f		CH3	S	2.5	72
7	4g		C2H5	O	3.0	85
8	4h		C2H5	S	3.5	71
9	4i		CH3	O	3.5	82
10	4j		C2H5	S	3.0	86
11	4k		C2H5	O	2.0	90
12	4l		C2H5	S	2.0	93
13	4m		C2H5	O	2.5	90
14	4n		CH3	S	3.5	88
15	4o		C2H5	O	3.0	77
16	4p		C2H5	S	3.0	80
17	4q		C2H5	O	2.5	72
18	4r		C2H5	S	3.0	86
19	4s		C2H5	O	2.5	79
20	4t		C2H5	S	3.0	82

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Experimental

General procedures

All commercial reagents were used as received without purification and all solvents were reagent grade. The reaction was monitored by TLC using 0.25 mm E-Merck silica gel 60 F₂₅₄ precoated plates, which were visualized with UV light. Melting points were taken in open capillaries on a Veego apparatus and are uncorrected. Infrared spectra were recorded on a Simadzu spectrophotometer in a KBr disc, and the absorption bands are expressed in cm⁻¹. ¹H NMR spectra were recorded on a Varian AS 400 MHz spectrometer in DMSO-d₆, chemical shifts (δ) are in parts per million (ppm) relative to TMS.

General procedure

A mixture of benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol) and a urea (1.2 mmol) in water (5 mL) was stirred at 60 °C in the presence of a catalytic amount of IBX (5 mol%). The progress of the reaction was monitored by TLC. After completion of the reaction IBX was recovered by filtration. The product was extracted with diethyl ether (2 × 5 mL) and the combined organic layer was washed with brine (2 × 5 mL), dried over MgSO₄ and evaporated under reduced pressure. The crude product obtained was purified by column chromatography and further recrystallized from ethanol to obtain the pure product.

Physical and spectral data of the products

Ethyl-4-(4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4c). ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 1.13 (t, 3H), 2.24 (s, 3H), 3.98 (q, 2H), 5.04 (s, 1H), 5.69 (s, 1H), 7.03 (d, 2H, J = 7.5 Hz), 7.66 (d, 2H, J = 7.5 Hz), 8.12 (s, 1H) 9.36 (s, 1H); IR (KBr): 3292, 3196, 1724, 1620, 1468 cm⁻¹.

Ethyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g). ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 1.10 (t, 3H), 2.23 (s, 3H) 3.71 (s, 3H), 3.98 (q, 2H), 5.08 (s, 1H), 6.88 (d, 2H, J = 7.2 Hz), 7.15 (d, 2H, J = 7.2 Hz), 7.68 (s, 1H), 9.15 (s, 1H); IR (KBr): 3292, 3196, 1724, 1620, 1468 cm⁻¹.

Ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4m). ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm): 1.09 (t, 3H), 2.24 (s, 3H), 3.98 (q, 2H), 5.13 (s, 1H), 7.22–7.32 (m, 5H), 7.72 (s, 1H), 9.19 (s, 1H); IR (KBr): 3292, 3196, 1724, 1620, 1468 cm⁻¹.

Conclusion

In summary, we have developed an expedient, elegant and clean protocol for the synthesis of 3,4-dihydropyrimidine-2(1H)-ones (DHPMs) from aldehyde, urea/thiourea and β-keto esters. The remarkable features of this procedure are atom efficiency, high conversions, operational simplicity and ready availability of reagents at low cost. We anticipate that the recyclability of the catalyst and use of aqueous reaction medium will make this protocol more appealing and commercially viable.

Acknowledgements

We are thankful to Dr S.T. Gadade, Principal, C. K. Thakur College, for his generous support.

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