Reaction of 6-aminouracils with aldehydes in water as both solvent and reactant under FeCl₃·6H₂O catalysis: towards 5-alkyl/arylidenebarbituric acids

Abstract

5-Alkyl/arylidenebarbituric acids were efficiently synthesized through an FeCl₃·6H₂O catalyzed domino reaction of 6-aminouracils, water and aldehydes with water serving a dual role as both solvent and reactant, under benign reaction conditions. A study on comparative substrate scope of 6-aminouracil versus barbituric acid showed similar efficacy towards 5-alkyl/arylidenebarbituric acids. The protocol is the first detailed report to prepare regioselectively 5-alkyl/arylidenebarbituric acids starting from 6-aminouracils, which is an alternative and competing strategy to hitherto all known reactions directly employing barbituric acids.

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Introduction

The synthesis of alkyl/arylidenebarbituric acids and their thio- analogs has received considerable attention for their potential pharmacological applications such as antioxidant¹ and anticancer² agents; inhibitors of methionine aminopeptidase-1 (MetAP-1),³ urease⁴ and mushroom tyrosinase;⁵ and against non-alcoholic fatty liver disease (NAFLD)⁶ (Fig. 1). Because of the presence of a strongly polarized exocyclic double bond, they are also versatile precursors of a wide variety of molecules through reactions with carbanions⁷ and typical Lewis bases such as alkoxides,⁸ amines,^8a,9 thiols,¹⁰ water¹¹ and hydrogensulfite ion.¹² Moreover, the easy reducibility of the double bond¹³ offers these compounds as suitable candidates in the synthesis of 5-monoalkylbarbiturates such as Uridine Phosphorylase (UrdPase) inhibiting 5-benzylbarbiturates,¹⁴ unsymmetrical disulfides¹⁵ and for the mild oxidation of alcohols.¹⁶ Also, 5-arylidenebarbituric acids and their thio- analogs are important building blocks for biologically active pyrazolo-[3,4-d]-pyrimidine derivatives¹⁷ and other fused-pyrimidines.¹⁸ Some 5-arylidenebarbituric acids have also been studied as non-linear optical materials and dyes,¹⁹ and in trapping radicals that they can be used as thermal stabilizers in rigid PVC.²⁰ They have also found applications in analytical studies.²¹

Fig. 1 Some biologically active 5-arylidenebarbituric acids.

The classical preparation of 5-arylidenebarbituric acids by Knoevenagel condensation of barbituric acids and aldehydes in either basic or acidic conditions using organic solvents²² resulted yields that were not quite satisfactory due to the formation of disubstituted products accompanying the desired products.^22e,f,23 Consequently, to achieve the mono condensation product, various methods have been put forward by employing different materials like aminosulfonic acid,²⁴ aluminas,²⁵ clays,²⁶ mixed solids,²⁷ hydrotropes,²⁸ NaOH/Flyash,²⁹ ionic liquids,³⁰ surfactants,³¹ TMSCl,³² Yb(OTf),³³ Nickel nanoparticles,³⁴ SiO₂·12WO₃·24H₂O³⁵ and gels³⁶ as catalysts. Efforts for catalyst-free procedures in a suitable solvent³⁷ and catalyst- and solvent-free³⁸ approaches have also been made. In a newer method, Lasri et al. have also shown that acyclic nitrones on reaction with barbituric acid get transformed to 5-arylidenebarbituric acids.³⁹ While these procedures are useful, many of them are also confronted with one or more limitations such as the use of toxic solvents, expensive catalysts, modest product yields, limited substrate scope and long reaction times. Therefore, the development of easy and modular synthetic strategy for this important class of compounds, especially under mild and environmentally benign reaction conditions, still represents a highly rewarding methodological challenge in the rapidly growing field of diversity-oriented synthesis.

Recently, in our FeCl₃·6H₂O catalyzed synthetic program towards 5-monalkylbarbiturates, we have demonstrated that the reaction proceeded through an in situ formed barbituric acid.⁴⁰ To the best of our knowledge, no detailed investigation has been made on 6-aminouracils as substrates for 5-alkyl/arylidenebarbituric acids. That, barbituric acids have been the only starting materials in all the established protocols except in a report by Daqing and co-workers which however the compounds were obtained as a mixture with bisuracils.⁴¹ This result prompted us to explore for a formal synthetic route towards 5-alky/arylidenebarbituric acids from 6-aminouracils, water and aldehydes. Thus, based on our previous findings, we have now developed a FeCl₃·6H₂O catalyzed pseudo three-component domino reaction of 6-aminouracils, water and aldehydes, where water serves as both solvent and reactant, leading efficiently to 5-alkyl/arylidenebarbituric acids, and the results are presented here in this paper (Scheme 1). This tandem reaction involves an initial FeCl₃·6H₂O and water assisted amine hydrolysis of 6-aminouracil to barbituric acid followed by Knoevenagel condensation with aldehydes.

Scheme 1 Domino synthesis of 5-monoalkylbarbiturates.

The reaction has proved to be operationally simple with mild conditions and affords high yields. The use of versatile FeCl₃·6H₂O (ref. 42) and water provides cost effectiveness and environmental benignity, while the further role of water as both solvent and reactant describes wider scope of the relatively unexplored aqueous media domino-reactions⁴³ which is a current focal point in promoting greener synthesis. It can also be noted that while the general reactions of 6-aminouracils with aldehydes gave bisuracils,^41,44 this reaction, under the optimized conditions, furnished exclusively 5-alkyl/arylidenebarbituric acids as the end products. Thus, this protocol also shows a new reactivity of 6-aminouracils as valuable substrates for 5-alkyl/arylidenebarbituric acids. In addition, a detailed comparative study of 6-aminouracils versus barbituric acids as substrates for these compounds under the same reaction conditions is also presented.

Results and discussion

Initially, we found that the reaction of 6-aminouracil (1a, 1 mmol), water (2, 10 mL) and benzaldehyde (3a, 1 mmol) in the presence of FeCl₃·6H₂O (10 mol%) under refluxing condition for 60 minutes gave 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione (4aa) in 70% yield, whose structure was further authenticated through literature data (Table 1, entry 1).^38d In subsequent optimization of the reaction under aqueous medium, 15 mol% of FeCl₃·6H₂O was found optimal as the catalyst load which furnished 4aa with a maximum yield of 85%, since further increase in catalyst load did not raise the product yield (Table 1, entries 2–4). To acquire the best effect of the reaction, a number of potential Lewis acids as catalysts and various solvents were tried. Interestingly, the reaction was found most effective only in water and FeCl₃·6H₂O. Also all the screened catalysts such as NiCl₂, 6H₂O, CoCl₂·6H₂O, Cu(OAc)₂ and CuCl₂·2H₂O failed to deliver the desired product, except with p-toluenesulphonic acid monohydrate (p-TsOH·H₂O) which however, yielded 4aa only in trace amount (Table 1,entries 5–9). On the other hand, even FeCl₃·6H₂O catalyzed reactions in polar solvents such as EtOH, DMSO, CH₃CN and non-polar solvent like toluene or reactions carried out under solvent-free conditions were also found ineffective (Table 1, entries 10–14). In one case, the reaction when carried out in CH₃COOH : water (1 : 1) alone proceeded however it only gave a mixture of 4aa and 5, as compared to when FeCl₃·6H₂O was employed (Table 1, entry 15). Also, in another attempt to succeed the reaction at room temperature by stirring a mixture of 1a, 2 and 3a for 10 hours in the presence of FeCl₃·6H₂O, bisuracil 5 was isolated along with unreacted 3a (Table 1, entry 16). On the contrary, when this same reaction was performed under refluxing conditions, only 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione (4aa) was obtained (Scheme 2). All these observations, therefore, led to an inference that FeCl₃·6H₂O and water were specific and vital for the synthesis of 5-alkyl/arylidenebarbituric acids through this protocol.

Table 1 Optimization of the reaction under varying conditions^a

Entry	Catalyst (mol%)	Solvent^b	Temp (°C)	Time (min)	Yield^c (%)
a Reaction scale: 1a (1 mmol), 2 (10 mL) and 3a (1 mmol).b 10 mL.c Isolated yield.d RT ≈ 24 °C.
1	FeCl3·6H2O (10)	H2O	Reflux	60	70
2	FeCl3·6H2O (15)	H2O	Reflux	35	85
3	FeCl3·6H2O (20)	H2O	Reflux	35	85
4	FeCl3·6H2O (25)	H2O	Reflux	35	85
5	NiCl2·6H2O (15)	H2O	Reflux	35	0
6	CoCl2·6H2O (15)	H2O	Reflux	35	0
7	Cu(OAc)2 (15)	H2O	Reflux	35	0
8	CuCl2·2H2O (15)	H2O	Reflux	35	0
9	p-TsOH.H2O (15)	H2O	Reflux	35	Trace
10	FeCl3·6H2O (15)	EtOH	Reflux	35	0
11	FeCl3·6H2O (15)	DMSO	Reflux	35	0
12	FeCl3·6H2O (15)	CH3CN	Reflux	35	0
13	FeCl3·6H2O (15)	Toluene	Reflux	35	0
14	FeCl3·6H2O (15)	—	Heat	35	0
15	—	AcOH : H2O (1 : 1)	Reflux	35	20%
16	FeCl3·6H2O (15)	H2O	RT^d	600	0

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Scheme 2 Reaction study for 5-alkyl/arylidenebarbituric acids.

Encouraged by the results, the optimized conditions were used for series of reactions of benzaldehydes with 6-aminouracil (1a) and the target compounds were obtained in high to excellent yields. The presence of electron releasing or withdrawing groups in the benzene ring of various benzaldehydes did not have significant influence upon the reactions and their corresponding 5-arylidenebarbiturates (4aa–ah) were thus conveniently prepared (Table 2). The synthesis was also extended to polyaromatic hydrocarbons and α,β-unsaturated aldehydes such as 9-anthracenaldehyde and cinnamaldehyde where their corresponding products 4ai and 4aj respectively were also obtained. Reactions with heterocyclic aldehydes such as thiophene-2-carboxaldehyde and indole-3-carboxaldehye were also found effective and gave their resultant 4ak and 4al in 81% and 83% respectively. Aliphatic aldehydes such as butyraldehyde and valeraldehyde also underwent condensation smoothly to give their respective products 4am and 4an in good yields (Table 2).

Table 2 Scope of the domino synthesis of 5-alkyl/arylidenebarbituric acids from 6-aminouracil, water and aldehydes^a

a All reactions were carried out using 1 mmol each of 1 and 3, and 10 mL of 2.b Isolated yield.

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The scope of the synthesis was further expanded towards 1-methyl-6-aminouracil (1b) and 1,3-dimethyl-6-aminouracil (1c) under the same reaction conditions and the results are shown in Table 3. Both the uracils also underwent reactions well with various aldehydes and their corresponding 5-alkyl/arylidenebarbituric acids were successfully prepared. However, it was observed that reactions involving 1b and 1c were found relatively slower and sluggish than when 1a was used, with 1c as the slowest. This may be attributed to the effect of the electron releasing methyl group/s present in 1b and 1c, which retarded the rate of amine hydrolysis to form barbituric acid. Thus a reactivity aptitude of 6-aminuracil > 1-methyl-6-aminouracil > 1,3-dimethyl-6-aminouracil was observed during the study. Moreover, the products obtained from reactions involving 1-methyl-6-aminouracil were as E- and Z- isomeric mixture as revealed by their ¹H- and ¹³C-NMR spectra.

Table 3 Scope of substituted 6-aminouracils towards 5-alkyl/arylidenebarbituric acids^a

a All reactions were carried out with 1 (1 mmol), 2 (10 mL) and 3 (1 mmol).b Isolated yield.c Combined diastereomeric yield.

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Next, we turned our attention towards investigating a comparative substrate prospect of 6-aminouracils (1) versus barbituric acids (6) towards 5-alkyl/arylidenebarbituric acids (4) under the same reaction conditions. Thus, a series of reactions of barbituric acids and various aldehydes was performed and the comparative results are shown in Table 4. Interestingly, both the reactions showed similar competency for 5-alkyl/arylidenebarbituric acids offering similar yields without significant differences in reaction times. Thus, this observation revealed that 6-aminouracils could be proficient substrates, competent with barbiturates, for the synthesis of 5-alkyl/arylidenebarbituric acids through this method.

Table 4 Comparative substrate scope of 6-aminouracils versus barbituric acid towards 5-alkyl/arylidenebarbituric acids^a

Entry	Product (4)	Time (min)		Yield^b (%)
		1	6	1	6
a Reactions were carried out using 1 mmol each of 1 and 3, and 10 mL of 2.b Isolated yield.c Combined diastereomeric yield.
1	4aa	35	30	85	87
2	4ac	40	35	81	85
3	4ad	20	20	95	95
4	4ae	20	20	96	97
5	4af	30	25	90	90
6	4ag	40	36	87	88
7	4aj	40	35	91	91
8	4al	40	35	83	85
9	4an	50	40	73	75
10	4bb	40	35	88^c	88^c
11	4ca	40	35	85	86
12	4cb	45	40	85	86
13	4cc	50	45	78	79
14	4cd	60	50	71	74

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All the products were purified by recrystallization and characterized through their ¹H-¹³C-NMR, Mass, IR spectral data and elemental analyses. Known compounds were further authenticated with literature reports.

To rationalize the reaction mechanism, 6-aminouracil (1a) was refluxed in the presence of FeCl₃·6H₂O and water. The reaction completed swiftly and subsequent isolation yielded barbituric acid (Scheme 3).⁴⁵ This result was indicative that the reaction proceeded via barbituric acid. Moreover, when uncatalyzed and catalyzed condensation of barbituric acid (6a) and benzaldehyde in water was compared, it was found that the latter process in the presence of FeCl₃·6H₂O was more efficient and completed faster. This also suggested for the catalytic role of FeCl₃·6H₂O in the Knoevenagel condensation too. Thus, based upon literature reports^40,41,46 and our results a possible mechanism is outlined in Scheme 4. The coordination of FeCl₃ with 6-aminouracil facilitated an amine hydrolysis to form barbituric acid via apparent intermediates 7 to 9. Meanwhile the aldehyde also apparently gets activated by FeCl₃ to form 11, which on subsequent interaction with the FeCl₃ activated complex 10 of the then formed barbituric acid (6a) prodeeded the Knoevenagel condensation to furnish the final product 4.

Scheme 3 Barbituric acid from 6-aminouracil.

Scheme 4 Possible reaction mechanism.

Conclusions

In conclusion, we have demonstrated an efficient and operationally simple method for the synthesis of 5-alkyl/arylidenebarbituric acids under environmentally benign conditions, through a FeCl₃·6H₂O catalyzed domino reaction of 6-aminouracils, water and aldehydes, with water as both solvent and reactant. A comparative substrate study of 6-aminouracils versus barbituric acids towards 5-alkyl/arylidenebarbituric acids has also been detailed which showed similar efficacy. To the best of our knowledge, while barbituric acid has served as the only starting material for 5-alkyl/arylidenebarbituric acids till date, this work presents as the first detailed report demonstrating that 6-aminouracils can now also be alternative and equally competent substrates for the same compounds. Furthermore, the dual role of water as both solvent and reactant in this method significantly exemplifies for wider scope of aqueous media domino reactions in the light of promoting greener synthesis. Moreover, this report also highlights the hitherto unreported FeCl₃·6H₂O catalyzed aqueous media condensation of barbituric acid and aldehydes. On the whole, this procedure is highly applicable for 5-alkyl/arylidenebarbituric acids as provided by the versatility of the catalyst, operational simplicity, competency of 6-aminouracils and excellent yields of the reaction vis a vis to all methods involving only barbituric acids.

Experimental section

All reagents were obtained commercially and were used without further purification. IR spectra were recorded on a SHIMADZU infrared spectrometer as KBr pellets with absorption in cm⁻¹. ¹H- and ¹³C- NMR data were recorded either on 300 or 600 MHz BRUKER or JEOL 400 MHz NMR spectrometer at ≈ 25 °C using DMSO-d₆ or CDCl₃ as the solvent and resonances (δ) are expressed in ppm relative to tetramethylsilane (TMS). Data reported are as follows: Chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, ‡ = double signal), coupling constant (Hz) and integration. Mass spectral data were taken on WATERS ZQ 4000 analyzer equipped with ESI source. Melting points were taken through open capillary tube method and were uncorrected. Elemental analysis was done on Perkin–Elmer Series II Analyzer 2400. Thin layer chromatography (TLC) was performed using Merck precoated silica gel or silica gel G and the components were visualized under UV or iodine chamber.

General procedure for the synthesis of 5-alkyl/arylidenebarbituric acids from 6-aminouracils, water and aldehydes

6-Aminouracil (1 mmol), aldehyde (1 mmol) and FeCl₃·6H₂O (15 mol%) were added to hot or boiling water (10 mL) and the mixture was refluxed for appropriate time. On completion of the reaction, as indicated by TLC, the mixture was allowed to cool and was extracted with EtOAc (10 mL × 4). Upon drying with anhydrous Na₂SO₄ and subsequent evaporation of the solvent under reduced pressure, the crude product was obtained which was purified further by recrystallization from ethanol.

General procedure for the synthesis of 5-alkyl/arylidenebarbituric acids from barbituric acids and aldehydes

A mixture of 1 mmol each of barbituric acid and aldehyde was refluxed in water in the presence of FeCl₃·6H₂O (15 mol%) for an appropriate time. On completion of the reaction, as indicated by TLC, the reaction mass was cooled and extracted with EtOAc (10 mL × 4). The organic extract was dried over anhydrous Na₂SO₄ and the solvent evaporated under reduced pressure to afford the product which was purified further by recrystallization from ethanol.

Procedure for the synthesis of barbituric acid from 6-aminouracil

6-Aminouracil (1 mmol) was refluxed in water (10 mL) in the presence of FeCl₃·6H₂O (15 mol%) for 5 minutes. The reaction was cooled and then extracted with EtOAc (10 mL × 4). The organic layer was dried with anhydrous Na₂SO4 and the solvent removed under reduced pressure to give white solid which was recrystallized from water and ethanol (9 : 1). The physical and chemical properties were found identical with the literature data.⁴⁵

Acknowledgements

H. M. and S. J. K. thank the DST-INSPIRE, Govt. of India, for the financial assistance. The authors also thank SAIF-NEHU, IIT-Guwahati and GU for sample analyses.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Compound characterization data, copies of ¹H- and ¹³C-NMR spectra of all compounds. See DOI: 10.1039/c4ra03413a

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