FeCl₃·6H₂O catalyzed aqueous media domino synthesis of 5-monoalkylbarbiturates: water as both reactant and solvent

Abstract

A novel, simple and straightforward route to 5-monoalkylbarbiturates by FeCl₃·6H₂O catalyzed domino reactions of 6-aminouracils, water and α,β-unsaturated ketones, where water plays a key dual role as both reactant and solvent, is described. Significantly, all the reactions efficiently furnished exclusively 5-monoalkylbarbiturates and not pyrido[2,3-d]pyrimidines as generally produced from the reactions of 6-aminouracils and α,β-unsaturated carbonyls.

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Introduction

In recent years, the development of greener synthetic methods has been highly prioritized in view of the adverse implications of various chemical processes. Especially, taking into account the undesirable impacts of organic solvents, efforts to accomplish efficient organic synthesis in aqueous medium present a focal point of research in current synthetic chemistry. Water is not only the most abundant and non-toxic solvent, it also enables novel reactivity and accelerates reaction by the hydrophobic and ‘on water’ effects.¹ Meanwhile, multi-component reactions (MCRs)² and auto-tandem catalysis³ have become powerful strategies towards convergent synthesis for the facts that the former allows flexible, convergent, pot, atom and step economic synthesis while the latter provides maximum catalyst utilization efficiency by catalyzing two or more mechanistically different organic transformations. However, the development of multi-component reactions in aqueous environments is a recent endeavour that has received relatively little attention and consequently requires greater emphasis.^1a,g,4

In these developments, iron catalysts have emerged as a center of renewed interest both in homogeneous and heterogeneous catalysis. Well known for their wide range of tolerance, iron catalysts are diversely applied in addition, substitution, cycloaddition and polymerization reactions to name a few.⁵ In particular, FeCl₃·6H₂O has received tremendous applications in organic syntheses whose applicability has been further advantaged by its cost effectiveness, ease of handling and environmental benignity.^5,6 Thus, iron catalyzed organic transformations are highly applicable approaches in organic syntheses.

5-Alkylbarbiturates are an intriguing and re-emerging privileged class of compounds in medicinal chemistry which have broad range of activities such as anticonvulsant,⁷ sedative,⁸ immunomodulating and antitumor properties;⁹ whilst a number of them also have found wide applications in the manufacture of dyes,¹⁰ non linear optical study¹¹ and in supramolecular chemistry.¹² Further synthetic interest on 5-alkylbarbiturates has been elevated with the development of highly potent antibacterial PNU-286607(-)-1 (ref. 13) and inhibitors of matrix metalloproteinase (MMP)¹⁴ and mutant SOD1-dependent protein aggregation.¹⁵ Classically, 5-alkylbarbiturates can be synthesized by condensation of alkylated malonic esters and urea in the presence of sodium alkoxide.¹⁶ However, the yields of this reaction are often modest due to the presence of side reactions such as hydrolysis of the malonate, decarbethoxylation, transesterification, and urea degradation. Moreover, the need for dry solvents and high temperature in addition to the requirement of inert atmosphere and metallic sodium limits the use of this classical method in the perspective of combinatorial purposes and diversity-oriented synthetic programs. Alternatively, 5-alkylation of unsubstituted barbituric acid could be a strategy towards 5-alkylbarbiturates.¹⁷ But, in particular, direct construction of 5-monoalkylbarbiturates by alkylation of barbituric acid derivatives still remains a difficult and an inspiring task.

A common challenge en route to 5-monoalkylbarbiturates is the specific 5-monoalkylation of barbituric acid derivatives. For decades, there was no simple procedure for this strategy until, lately, Jursic and co-workers developed an effective reductive alkylation procedure in the presence of platinum and palladium catalysts.¹⁸ More recently, Löfberg and group have described Ir(III) catalyzed reaction of barbituric acid and alcohols as an alternative route to 5-monoalkylbarbiturates.¹⁹ Another method for 5-monoalkylbarbiturates via ring opening of spiro[2.5]barbiturates was also described by Singh and Paul.²⁰ Although these protocols are useful, the use of expensive catalysts and complex reaction conditions rather limits their applicability. The only multi-component strategy showing a prospect towards 5-monoalkylbarbiturates was developed recently by Volonterio and Zanda.²¹ On the other hand, the highly viable route to 5-monoalkylbarbiturates by Michael addition of barbituric acid to α,β-unsaturated carbonyls has been highly underrepresented since the first report given by Zalukaev and Trostyanetskaya²² and the compounds were characterized only on the basis of IR spectral data. And, to the best of our knowledge on literature survey, there is only another report describing Michael addition of barbituric acid to α,β-unsaturated carbonyls.²³

Therefore, in view of the need to design effective synthetic route for 5-monoalkylbarbiturates, and in conjunction with our continued pursuit on environment friendly synthetic developments,²⁴ we report herein the application of FeCl₃·6H₂O catalyzed domino reactions of 6-aminouracils, water and α,β-unsaturated ketones as a straightforward route to 5-monoalkylbarbiturates, where water significantly serves as both reactant and solvent (Scheme 1). This tandem reaction involves an initial FeCl₃·6H₂O and water mediated amine hydrolysis of the 6-aminouracil to barbituric acid followed by Michael type addition to α,β-unsaturated ketones. To the best of our knowledge, 6-aminouracils have not been explored for direct synthesis of 5-monoalkylbarbiturates. And at this point it can be noted that the general reactivity of 6-aminouracils with α,β-unsaturated carbonyls gives pyrido[2,3-d]pyrimidines,²⁵ whereas this new found reaction produced solely 5-monoalkylbarbiturates as the final products. Thus, a new reactivity role of 6-aminouracils as valuable substrates towards 5-monoalkylbarbiturates is also discovered.

Scheme 1 Domino synthesis of 5-monoalkylbarbiturates.

Results and discussion

Initially we refluxed 6-aminouracil (1a, 1 mmol), water (2, 10 mL) and benzylideneacetone (3a, 1 mmol) in the presence of FeCl₃·6H₂O (10 mol%) for sixty minutes (Table 1, entry 1). To our delight, the reaction gave 5-(3-oxo-1-phenylbutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4aa) in 80% yield. Much to our satisfaction, the reaction was then set for optimization as shown in Table 1. Fortunately, optimization of the FeCl₃·6H₂O catalyst was arrived at 15 mol% which afforded the highest yield of 4aa in 92% yield (Table 1, entry 2). Further, to get the best effect of the reaction, some potential Lewis acid catalysts and a number of solvents were screened (Table 1, entries 5–12). Interestingly, the reaction was found to work only with water and FeCl₃·6H₂O. Even solvents such as EtOH and DMSO or reactions performed under solventless condition failed to furnish the desired product (Table 1, entries 8–13). In an attempt to succeed the reaction at room temperature (≈24 °C), the process was not satisfactory and gave 4aa only in 10% yield, even after stirring for 24 hours (Table 1, entry 14) (Scheme 2). In another process, simultaneous mixing of 6-aminouracil (1a), benzaldehyde (6) and acetone (7) in the presence of FeCl₃·6H₂O and water did not yield the desired 5-monoalkylbarbiturate, and only barbituric acid (5) and benzylidenebarbituric acid (8) were isolated (Scheme 2). We observed that, although barbituric acid was formed in the process, the rate of formation of 8 greatly exceeded the rate of generation of benzylideneacetone (3a). Nevertheless, these results indicated that FeCl₃·6H₂O and water were specifically essential to obtain 5-monoalkylbarbiturates through this protocol.

Table 1 Optimization of the reaction under different 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	80
2	FeCl3·6H2O (15)	H2O	Reflux	45	92
3	FeCl3·6H2O (20)	H2O	Reflux	45	92
4	FeCl3·6H2O (25)	H2O	Reflux	45	92
5	CuCl2·2H2O (15)	H2O	Reflux	60	0
6	NiCl2·6H2O (15)	H2O	Reflux	60	0
7	CoCl2·6H2O (15)	H2O	Reflux	60	0
8	FeCl3·6H2O (15)	EtOH	Reflux	60	0
9	FeCl3·6H2O (15)	CH3CN	Reflux	60	0
10	FeCl3·6H2O (15)	CHCl3	Reflux	60	0
11	FeCl3·6H2O (15)	Toluene	Reflux	60	0
12	FeCl3·6H2O (15)	DMSO	Reflux	60	0
13	FeCl3·6H2O (15)	—	Heat	50	0
14	FeCl3·6H2O (15)	H2O	RT^d	1440	10

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Scheme 2 Reaction study towards 5-monoalkylbarbiturates.

Next, a comparative study on the substrate prospect of 6-aminouracil (1a) versus barbituric acid (5) towards 5-monoalkylbarbiturates was investigated by executing some parallel reactions with selected arylideneacetones (3) under the same reaction conditions (Table 2). Interestingly, both the reactions showed almost equal competency for 5-monoalkylbarbiturates yielding similar yields without significant differences in reaction times. Thus, this observation described that 6-aminouracil could be an equally competent and alternative substrate towards 5-monalkylbarbiturates.

Table 2 Comparative substrate prospect of 6-aminouracil (1a) versus barbituric acid (5) towards 5-monoalkylbarbiturates (4)^a

Entry	R^3	Product	Time (min)		Yield^b (%)
			1a	5	1a	5
a All reactions were carried out using 1 mmol each of 1a/5, 3 and 10 mL of 2.b Isolated yield.
1	C6H5	4aa	45	40	92	92
2	3-OCH3C6H4	4ad	50	45	85	85
3	4-ClC6H4	4ae	45	41	92	93
4	4-NO2C6H4	4af	45	40	89	89
5	2-Thiophenyl	4am	50	45	81	82

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Subsequently, under the optimized conditions, we then explored the scope of the reaction. As shown in Table 3, a wide array of 5-monoalkylbarbiturates was prepared from the reaction of 6-aminouracil (1a), water (2) and various α,β-unsaturated ketones (3). It was found that, the presence of electron withdrawing or donating groups in the ortho, meta- or para- positions of the benzene ring of various arylideneacetones (3a–f) or chalcones (3g–k) had no significant impact on the reaction and they were conveniently transformed to their corresponding 5-monoalkylbarbiturates (Table 3, entries 1–11; 76–92%). To our delight, heterylideneacetones (3l and 3m) and heterylideneacetophenones (3n and 3o) also participated well in the reaction and provided their corresponding products in good to high yields (Table 3, entries 12–15; 76–81%). Other substituted alken-2-ones (3p–r) also responded moderately to the reaction and their resultant 5-monoalkylbarbiturates were successfully obtained although the reactions were slightly sluggish (Table 3, entries 16–18; 71–74%).

Table 3 FeCl₃·6H₂O catalyzed aqueous media domino synthesis of 5-monoalkylbarbiturates^a

Entry	3			Time (min)	Product	Yield^b (%)
	R^3	R^4
a Reaction scale: 1a (1 mmol), 2 (10 mL) and 3 (1 mmol).b Isolated yield.c Purified by column chromatography.
1	C6H5	CH3	3a	45	4aa	92
2	2-ClC6H4	CH3	3b	45	4ab	88
3	3-ClC6H4	CH3	3c	50	4ac	85
4	3-OCH3C6H4	CH3	3d	50	4ad	85
5	4-ClC6H4	CH3	3e	45	4ae	92
6	4-NO2C6H4	CH3	3f	45	4af	89
7	C6H5	C6H5	3g	45	4ag	87
8	2-ClC6H4	C6H5	3h	45	4ah	90
9	3-OCH3C6H4	C6H5	3i	50	4ai	83
10	4-ClC6H4	C6H5	3j	45	4aj	90
11	3,5-(OCH3)2C6H3	C6H5	3k	50	4ak	76
12	2-Furyl	CH3	3l	45	4al	78
13	2-Thiophenyl	CH3	3m	50	4am	81
14	2-Furyl	C6H5	3n	60	4an^c	76
15	2-Thiophenyl	C6H5	3o	50	4ao	80
16	Ethyl	CH3	3p	50	4ap^c	71
17	Butyl	CH3	3q	50	4aq^c	73
18	Butyl	C6H5	3r	50	4ar^c	74

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The scope of the reaction was also extended towards 1-methyl-6-aminouracil (1b) and 1,3-dimethyl-6-aminouracil (1c) under the same conditions and the results are shown in Table 4. Gratifyingly, all reactions of 1b or 1c with various α,β-unsaturated ketones (3) and water (2) proceeded successfully without much complexity and furnished their 5-monoalkylbarbiturates (68–91%). However, in the case of 1,3-dimethyl-6-aminouracil (1c), conversions were found to be relatively slower than when 6-aminouracil (1a) or 1-methyl-6-aminouracil (1b) was employed. This may be due to the presence of electron releasing methyl group/s which impeded hydrolysis of the amine to form barbituric acid. And, unlike those reactions with 6-aminouracil (1a), most of the reactions involving 1-methyl-6-aminouracil (1b) and 1,3-dimethyl-6-aminouracil (1c) were slightly sluggish. Thus, a reactivity aptitude: 6-aminouracil (1a) > 1-methyl-6-aminouracil (1b) > 1,3-dimethyl-6-aminouracil (1c) was observed in this study. Furthermore, the 5-monoalkylbarbiturates (4bi–4bl) obtained from reactions involving 1-methyl-6-aminouracil (1b) showed their existence as diastereoisomers as revealed by ¹H and ¹³C NMR spectra. Meanwhile, to further supplement the structural characterization, a single crystal X-ray diffraction study was probed upon 4bb whose X-ray structure is depicted in Fig. 1.

Table 4 Substituted 6-aminouracils towards 5-monoalkylbarbiturates^a

Entry	1b/1c R^1	3			Time (min)	Product	Yield^b (%)
		R^3	R^4
a All reactions were carried out using 1 (1 mmol), 2 (10 mL) and 3 (1 mmol).b Isolated yield.c Purified by column chromatography.d Combined diastereomeric yield.
1	CH3	C6H5	CH3	3a	90	4ba^c	83
2	CH3	2-ClC6H4	CH3	3b	120	4bb	87
3	CH3	3-ClC6H4	CH3	3c	120	4bc^c	78
4	CH3	3-OCH3C6H4	CH3	3d	120	4bd^c	85
5	CH3	3-NO2C6H4	CH3	3s	120	4be^c	84
6	CH3	4-BrC6H4	CH3	3t	90	4bf^c	87
7	CH3	4-OHC6H4	CH3	3u	120	4bg	68
8	CH3	4-NO2C6H4	CH3	3f	105	4bh^c	84
9	H	2-ClC6H4	CH3	3b	60	4bi^c^,^d	88
10	H	2-FC6H4	C6H5	3v	60	4bj^c^,^d	85
11	H	3-ClC6H4	CH3	3c	60	4bk^c^,^d	88
12	H	4-BrC6H4	CH3	3w	50	4bl^c^,^d	91

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Fig. 1 X-ray crystal structure of 4bb.²⁶

To probe the reaction mechanism, 6-aminouracil (1a) was refluxed alone in water in the presence of FeCl₃·6H₂O. The reaction completed swiftly within minutes and yielded barbituric acid (Scheme 3). Furthermore, when barbituric acid and benzylideneacetone were refluxed without any catalyst for 45 minutes, the product 4aa was resulted but only in 20% yield, which was indicative that FeCl₃·6H₂O also has catalytic role in the addition step. Thus, based upon literature reports^6b,c,e,20,27 and our results, a possible mechanism is proposed in Scheme 4. The coordination of 6-aminouracil with FeCl₃ facilitated amine hydrolysis by water and generated barbituric acid (5) via 9 and 10. The in situ formed barbituric acid further underwent complexation with FeCl₃ to give intermediate 11 while, apparently, α,β-unsaturated ketone (3) also gets activated with FeCl₃ to 12. Subsequent addition of the activated complex 11 to 12 followed by protonation finally led to the formation of 5-monoalkylbarbiturate 4.

Scheme 3 Barbituric acid from 6-aminouracil.

Scheme 4 Proposed reaction mechanism.

Conclusions

In summary we have developed, for the first time, a simple, general and environment friendly protocol for synthesis of 5-monoalkybarbiturates directly through FeCl₃·6H₂O catalyzed domino reaction of 6-aminouracils, water and α,β-unsaturated ketones. Significantly, this study has also demonstrated the key role of water as both reactant and solvent in achieving the synthesis, which further exemplifies for wider applications of aqueous media organic synthesis. Moreover, while barbituric acid has served as common substrate for 5-monalkylbarbiturates thus far, our study has now demonstrated that 6-aminouracils can be also alternative and equally competent reactants towards obtaining the same compounds. Therefore, provided by the versatility of the catalyst, wide substrate scope and mild reaction conditions, the protocol is highly facile which remarkably expands the procedural scopes for the synthesis of a huge library of important 5-monoalkylbarbiturates, suitable as well for combinatorial synthetic study.

Experimental section

All reagents were purchased from commercial suppliers and were used without further purification. The α,β-unsaturated ketones were prepared according to literature procedure.²⁸ IR spectra were recorded on a SHIMADZU infrared spectrometer as KBr pellets with absorption in cm⁻¹. ¹H and ¹³C NMR spectra were recorded in CDCl₃ or DMSO-d₆ or MeOH-d₄ on 300 MHz Bruker NMR spectrometer at ≈25 °C and resonances (δ) are given in ppm relative to tetramethylsilane. Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, ^‡ = double signal), coupling constants (Hz) and integration. LCMS were obtained on Waters ZQ 4000 and equipped with ESI source. Melting points were determined using Veego VMP-D and not corrected. The X-ray crystal structure determination was done on a Bruker, SMART APEX II CCD system. Elemental analysis was done on Perkin Elmer Series II Analyzer 2400. Column chromatography was performed on silica gel (200–300 mesh) using ethyl acetate : hexane (6 : 4) as the eluent. Thin Layer Chromatography (TLC) was performed using Merck pre-coated silica gel or silica gel G and the components were visualized under a UV or an iodine chamber.

General procedure for the synthesis of 5-monoalkylbarbiturates (4aa–ar and 4ba–bl) from 6-aminouracils, water and α,β-unsaturated ketones

A mixture of 6-aminouracil (1a/1b/1c, 1 mmol), α,β-unsaturated ketone (3, 1 mmol) in water (2, 10 mL) was refluxed in the presence of FeCl₃·6H₂O (15 mol%) as catalyst for appropriate time (Tables 3 and 4). On completion of the reaction, as indicated by TLC, the crude reaction mass was cooled and was extracted with ethyl acetate (10 mL × 4). After drying with anhydrous Na₂SO₄ and evaporation under reduced pressure, the crude product was purified suitably either by recrystallization from DCM : ethanol (6 : 4) solvent mixture or ethanol or column chromatography on silica gel using ethyl acetate : hexane (6 : 4) as the eluent to afford 5-monoalkylbarbiturates.

General procedure for the synthesis of 5-monoalkylbarbiturates from barbituric acid and α,β-unsaturated ketones (Table 2)

A mixture of barbituric acid (5, 1 mmol) and α,β-unsaturated ketone (3, 1 mmol) was refluxed in the presence of FeCl₃·6H₂O (15 mol%) in water (10 mL) for appropriate time. On completion of the reactions, as indicated by TLC, the reaction mass was cooled and extracted with ethyl acetate (10 mL × 4) and dried over anhydrous Na₂SO₄. After concentrated under reduced pressure, the obtained crude solids were further purified by recrystallization from DCM : ethanol (6 : 4) solvent mixture to afford the 5-monoalkylbarbiturates.

Procedure for the synthesis of barbituric acid from 6-aminouracil

6-Aminouracil (1a, 1 mmol) was refluxed in water (2, 10 mL) in the presence of FeCl₃·6H₂O (15 mol%) for 5 minutes. On completion of the reaction, as indicated by TLC, the reaction mass was cooled and extracted with ethyl acetate (10 mL × 4). The organic extract was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The obtained solid product was purified by recrystallization from ethanol : water (1 : 9). The physical and chemical properties are identical to that reported in the literature.²⁹

5-(3-Oxo-1-phenylbutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4aa)³⁰

Yield 0.252 g (92%). White solid, mp 152–154 °C (from EtOH/DCM). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 2.08 (s, 3H), 3.05–3.14 (m, 1H), 3.31–3.40 (m, 1H), 3.65 (d, 1H, J = 3.9 Hz), 3.88–3.95 (m, 1H), 7.04–7.13 (m, 2H), 7.18–7.27 (m, 3H), 11.03 (s, 1H), 11.09 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 30.7, 41.8, 45.6, 52.2, 127.8, 128.1, 128.8, 139.7, 150.9, 170.2, 170.7, 207.4; IR (KBr) (ν_max/cm⁻¹) 3392, 2923, 1729, 1704, 1681, 1664; MS (ESI): m/z calcd for C₁₄H₁₄N₂O₄: 274.10; found 275.10 [M + H]⁺, 297.00 [M + Na]⁺; anal. calcd for C₁₄H₁₄N₂O₄: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.44; H, 5.26; N, 10.08%.

5-(1-(2-Chlorophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ab)

Yield, 0.271 g (88%). White solid, mp 102–104 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.10 (s, 3H), 2.90–2.94 (m, 1H), 3.24–3.33 (m, 1H), 3.84 (d, 1H, J = 3.3 Hz), 4.68 (m, 1H), 7.08–7.39 (m, 4H), 9.46 (s, 1H), 9.58 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 30.0, 36.6, 44.5, 50.8, 127.4, 128.7, 128.9, 129.9, 133.6, 137.9, 150.5, 168.8, 169.0, 208.8; IR (KBr) (ν_max/cm⁻¹) 3410, 3011, 2924, 1719, 1701, 1687, 1659, 1551; MS (ESI): m/z calcd for C₁₄H₁₃ClN₂O₄: 308.06; found 308.92 [M + H]⁺, 331.04 [M + Na]⁺; anal. calcd for C₁₄H₁₃ClN₂O₄: C, 54.47; H, 4.24; N, 9.07. Found: C, 54.69; H, 4.09; N, 9.19%.

5-(1-(3-Chlorophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ac)

Yield, 0.262 g (85%). White solid, mp 103–105 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.18 (s, 3H), 2.90–2.98 (m, 1H), 3.51–3.61 (m, 1H), 3.89 (d, 1H, J = 3.3 Hz), 4.09–4.16 (m, 1H), 7.09–7.27 (m, 4H), 9.10 (s, 1H), 9.16 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 30.3, 40.8, 45.1, 51.3, 126.3, 128.1, 130.2, 134.6, 141.2, 149.8, 168.8, 208.2; IR (KBr) (ν_max/cm⁻¹) 3232, 3109, 2924, 1728, 1701, 1693, 1647, 1554; MS (ESI): m/z calcd for C₁₄H₁₃ClN₂O₄: 308.06; found 308.92 [M + H]⁺, 331.01 [M + Na]⁺; anal. calcd for C₁₄H₁₃ClN₂O₄: C, 54.47; H, 4.24; N, 9.07. Found: C, 54.71; H, 4.06; N, 9.25%.

5-(1-(3-Methoxyphenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ad)

Yield, 0.258 g (85%). White solid, mp 141–143 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.15 (s, 3H), 2.90–2.97 (m, 1H), 3.45–3.55 (m, 1H), 3.68 (s, 3H), 3.81 (d, 1H, J = 3.9 Hz), 4.03–4.12 (m, 1H), 6.69–6.78 (m, 3H), 7.10–7.15 (m, 1H), 9.39 (s, 1H), 9.47 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 30.2, 41.8, 45.2, 51.4, 55.1, 113.1, 113.8, 120.1, 129.9, 140.1, 150.2, 159.5, 169.4, 169.6, 208.3; IR (KBr) (ν_max/cm⁻¹) 3437, 3082, 2924, 1723, 1708, 1684, 1668, 1546; MS (ESI): m/z calcd for C₁₅H₁₆N₂O₅: 304.11; found 304.79 [M + H]⁺, 323.76 [M + H₂O]⁺; anal. calcd for C₁₅H₁₆N₂O₅: C, 59.21; H, 5.30; N, 9.21. Found: C, 59.35; H, 5.45; N, 9.05%.

5-(1-(4-Chlorophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ae)

Yield, 0.284 g (92%). White solid, mp 247–249 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.15 (s, 3H), 2.91–2.97 (m, 1H), 3.48–3.57 (m, 1H), 3.86 (d, 1H, J = 3.0 Hz), 4.10–4.12 (m, 1H), 7.09 (d, 2H, J = 8.4 Hz), 7.18 (d, 2H, J = 8.4 Hz), 9.67 (s, 1H), 9.71 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 30.3, 40.7, 45.2, 51.3, 129.0, 129.4, 133.6, 137.4, 150.4, 169.3, 169.5, 208.4; IR (KBr) (ν_max/cm⁻¹) 3347, 3011, 2924, 1721, 1703, 1681, 1661, 1557; MS (ESI): m/z calcd for C₁₄H₁₃ClN₂O₄: 308.06; found 309.10 [M + H]⁺, 331.01 [M + Na]⁺; anal. calcd for C₁₄H₁₃ClN₂O₄: C, 54.47; H, 4.24; N, 9.07. Found: C, 54.70; H, 4.07; N, 9.21%.

5-(1-(4-Nitrophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4af)

Yield, 0.284 g (89%). White solid, mp 214–216 °C (from EtOH/DCM). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 2.02 (s, 3H), 3.03–3.12 (m, 1H), 3.73–3.77 (m, 1H), 3.84 (d, 1H, J = 3.6 Hz), 4.08–4.11 (m, 1H), 7.37–7.48 (m, 2H), 8.09–8.20 (m, 2H), 11.24 (s, 1H), 11.30 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 24.4, 42.4, 49.4, 70.6, 117.1, 123.5, 124.3, 139.3, 143.5, 164.4, 166.0, 200.4; IR (KBr) (ν_max/cm⁻¹) 3437, 3078, 2924, 1710, 1703, 1682, 1658, 1558; MS (ESI): m/z calcd for C₁₄H₁₃N₃O₆: 319.08; found 319.92 [M + H]⁺, 342.01 [M + Na]⁺; anal. calcd for C₁₄H₁₃N₃O₆: C, 52.67; H, 4.10; N, 13.16. Found: C, 52.83; H, 3.95; N, 13.29%.

5-(3-Oxo-1,3-diphenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ag)²³

Yield, 0.292 g (87%). White solid, mp 176–178 °C (from EtOH/DCM). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 3.58–3.66 (m, 1H), 3.79 (d, 1H, J = 3.6 Hz), 4.00–4.09 (m, 1H), 4.13–4.19 (m, 1H), 7.23 (d, 2H, J = 9.0 Hz), 7.28–7.31 (m, 3H), 7.53 (t, 2H, J = 7.3 Hz), 7.65 (t, 1H, J = 6.9 Hz), 7.98 (d, 2H, J = 7.5 Hz), 11.06 (s, 1H), 11.11 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 45.8, 46.8, 56.9, 132.6, 133.0, 133.1, 133.6, 134.0, 138.6, 141.8, 144.7, 155.7, 175.1, 175.5, 203.5; IR (KBr) (ν_max/cm⁻¹) 3424, 3017, 2923, 1721, 1705, 1682, 1662, 1561; MS (ESI): m/z calcd for C₁₉H₁₆N₂O₄: 336.11; found 337.01 [M + H]⁺, 359.01 [M + Na]⁺; anal. calcd for C₁₉H₁₆N₂O₄: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.71; H, 4.67; N, 8.49%.

5-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ah)²³

Yield, 0.333 g (90%). White solid, mp 196–198 °C (from EtOH/DCM). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 3.55–3.64 (m, 1H), 3.73–3.82 (m, 1H), 3.88 (d, 1H, J = 3.6 Hz), 4.65–4.71 (m, 1H), 7.21–7.29 (m, 2H), 7.40 (d, 2H, J = 7.2 Hz), 7.48–7.53 (m, 2H), 7.63 (t, 1H, J = 7.2 Hz), 7.93 (d, 2H, J = 7.2 Hz), 11.10 (s, 1H), 11.13 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 30.3, 41.2, 45.1, 120.2, 121.3, 122.0, 122.8, 123.5, 127.1, 127.6, 130.4, 132.7, 144.8, 145.9, 161.9, 192.9; IR (KBr) (ν_max/cm⁻¹) 3411, 3071, 2923, 1720, 1709, 1688, 1664, 1552; MS (ESI): m/z calcd for C₁₉H₁₅ClN₂O₄: 370.07; found 371.00 [M + H]⁺, 393.10 [M + Na]⁺; anal. calcd for C₁₉H₁₅ClN₂O₄: C, 61.55; H, 4.08; N, 7.56. Found: C, 61.64; H, 3.93; N, 7.67%.

5-(1-(3-Methoxyphenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ai)

Yield, 0.304 g (83%). White solid, mp 167–169 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 3.44–3.52 (m, 1H), 3.71 (s, 3H), 3.97 (d, 1H, J = 3.6 Hz), 4.09–4.18 (m, 1H), 4.34–4.37 (m, 1H), 6.75–6.84 (m, 3H), 7.14–7.20 (m, 1H), 7.37–7.57 (m, 3H), 7.94–7.99 (m, 2H), 8.88 (s, 1H), 8.94 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 40.5, 42.2, 51.6, 55.2, 113.1, 114.0, 120.2, 128.1, 128.6, 130.0, 133.4, 136.5, 140.5, 149.5, 159.6, 168.9, 169.0, 198.7; IR (KBr) (ν_max/cm⁻¹) 3391, 3019, 2924, 1719, 1702, 1682, 1660, 1559; MS (ESI): m/z calcd for C₂₀H₁₈N₂O₅: 366.12; found 367.10 [M + H]⁺, 389.00 [M + Na]⁺; anal. calcd for C₂₀H₁₈N₂O₅: C, 65.57; H, 4.95; N, 7.65. Found: C, 65.69; H, 5.12; N, 7.53%.

5-(1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4aj)

Yield, 0.333 g (90%). White solid, mp 175–177 °C (from EtOH/DCM). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 3.47–3.55 (m, 1H), 4.01 (d, 1H, J = 3.6 Hz), 4.10–4.19 (m, 1H), 4.39–4.45 (m, 1H), 7.23–7.30 (m, 4H), 7.45–7.50 (m, 2H), 7.57–7.62 (m, 1H), 7.97 (d, 2H, J = 8.1 Hz), 8.21 (s, 1H), 8.25 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 40.5, 41.2, 51.6, 128.1, 128.7, 129.2, 129.4, 133.6, 134.0, 137.7, 148.4, 152.4, 153.7, 168.1, 203.6; IR (KBr) (ν_max/cm⁻¹) 3380, 3067, 2924, 1719, 1705, 1687, 1661, 1552; MS (ESI): m/z calcd for C₁₉H₁₅ClN₂O₄: 370.07; found 370.93 [M + H]⁺, 393.00 [M + Na]⁺; anal. calcd for C₁₉H₁₅ClN₂O₄: C, 61.55; H, 4.08; N, 7.56. Found: C, 61.69; H, 3.95; N, 7.68%.

5-(1-(3,5-Dimethoxyphenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ak)

Yield, 0.301 g (76%). White solid, mp 206–208 °C (from EtOH). ¹H NMR (300 MHz, methanol-d₄): δ_H (ppm) 3.56–3.69 (m, 1H), 3.74 (s, 6H), 3.82 (m, 1H), 4.05–4.12 (m, 1H), 4.23–4.26 (m, 1H), 6.38 (s, 1H), 6.71 (s, 2H), 7.51–7.54 (m, 2H), 7.60–7.63 (m, 1H), 8.03–8.05 (m, 2H); ¹³C NMR (75 MHz, methanol-d₄): δ_C (ppm) 34.2, 36.9, 48.0, 92.9, 99.3, 121.2, 122.1, 126.7, 130.8, 134.5, 154.4, 161.5, 206.5; IR (KBr) (ν_max/cm⁻¹) 3384, 3066, 2924, 1714, 1701, 1686, 1656, 1542; MS (ESI): m/z calcd for C₂₁H₂₀N₂O₆: 396.13; found 397.21 [M + H]⁺, 419.14 [M + Na]⁺; anal. calcd for C₂₁H₂₀N₂O₆: C, 63.63; H, 5.09; N, 7.07. Found: C, 63.77; H, 5.26; N, 6.92%.

5-(1-(Furan-2-yl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4al)³¹

Yield, 0.206 g (78%). Yellow solid, mp 186–188 °C (from EtOH/DCM). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 2.12 (s, 3H), 3.13–3.25 (m, 2H), 3.71 (m, 1H), 4.01–4.06 (m, 1H), 6.03 (m, 1H), 6.30 (m, 1H), 7.46 (m, 1H), 11.09 (s, 1H), 11.20 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 24.1, 28.4, 37.9, 44.0, 100.3, 104.5, 136.1, 144.7, 147.6, 163.3, 163.8, 200.6; IR (KBr) (ν_max/cm⁻¹) 3205, 3001, 2916, 1720, 1705, 1690, 1655, 1522; MS (ESI): m/z calcd for C₁₂H₁₂N₂O₅: 264.07; found 264.90 [M + H]⁺, 286.90 [M + Na]⁺; anal. calcd for C₁₂H₁₂N₂O₅: C, 54.55; H, 4.58; N, 10.60. Found: C, 54.44; H, 4.70; N, 10.75%.

5-(3-Oxo-1-(thiophen-2-yl)butyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4am)

Yield, 0.227 g (81%). Yellow solid, mp 77–79 °C (from EtOH). ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 2.11 (s, 3H), 3.15–3.24 (m, 1H), 3.32–3.35 (m, 1H), 3.77 (d, 1H, J = 3.0 Hz), 4.24–4.30 (m, 1H), 6.76–6.77 (m, 1H), 6.90–6.93 (m, 1H), 7.35–7.37 (m, 1H), 11.18 (s, 1H), 11.22 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 29.0, 34.9, 45.5, 50.8, 123.4, 124.1, 125.6, 140.9, 149.4, 168.3, 168.8, 205.4; IR (KBr) (ν_max/cm⁻¹) 3310, 3012, 2919, 1716, 1702, 1677, 1658, 1551; MS (ESI): m/z calcd for C₁₂H₁₂N₂O₄S: 280.05; found 281.00 [M + H]⁺, 303.00 [M + Na]⁺; anal. calcd for C₁₂H₁₂N₂O₄S: C, 51.42; H, 4.32; N, 9.99. Found: C, 51.31; H, 4.47; N, 9.91%.

5-(1-(Furan-2-yl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4an)³¹

Yield, 0.247 g (76%). Brown gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 3.50–3.55 (m, 1H), 3.97–4.13 (m, 2H). 4.51 (m, 1H), 6.09–6.18 (m, 2H), 6.93–7.51 (m, 4H), 7.94–7.96 (m, 2H), 9.39 (s, 1H), 9.53 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 35.6, 39.1, 49.8, 107.1, 110.5, 128.1, 128.6, 133.4, 136.3, 142.2, 150.3, 152.5, 168.7, 169.1, 198.1; IR (KBr) (ν_max/cm⁻¹) 3410, 3078, 2921, 1721, 1709, 1688, 1654, 1556; MS (ESI): m/z calcd for C₁₇H₁₄N₂O₅: 326.09; found 326.91 [M + H]⁺, 348.90 [M + Na]⁺; anal. calcd for C₁₇H₁₄N₂O₅: C, 62.57; H, 4.32; N, 8.59. Found: C, 62.71; H, 4.42; N, 8.44%.

5-(3-Oxo-3-phenyl-1-(thiophen-2-yl)propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ao)

Yield, 0.273 g (80%). Brown solid, mp > 300 °C (from EtOH); ¹H NMR (300 MHz, DMSO-d₆): δ_H (ppm) 3.68–3.76 (m, 1H), 3.91 (m, 1H), 3.97–4.05 (m, 1H), 4.50 (m, 1H), 6.84–6.91 (m, 2H), 7.33–7.35 (m, 1H), 7.53–7.64 (m, 3H), 7.95–7.97 (m, 2H), 11.16 (s, 1H), 11.22 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): δ_C (ppm) 35.9, 41.8, 51.4, 124.3, 125.0, 126.3, 127.4, 128.3, 132.9, 136.0, 141.8, 150.0, 169.1, 169.4, 197.4; IR (KBr) (ν_max/cm⁻¹) 3380, 3078, 2919, 1718, 1702, 1689, 1657, 1547; MS (ESI): m/z calcd for C₁₇H₁₄N₂O₄S: 342.07; found 343.11 [M + H]⁺, 365.09 [M + Na]⁺; anal. calcd for C₁₇H₁₄N₂O₄S: C, 59.64; H, 4.12; N, 8.18. Found: C, 59.77; H, 3.98; N, 8.30%.

5-(5-Oxohexan-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ap)

Yield, 0.160 g (71%). Red gummy solid (after column chromatography). ¹H NMR (300 MHz, methanol-d₄): δ_H (ppm) 0.83–0.96 (m, 3H), 1.55–1.60 (m, 2H), 2.16 (s, 3H), 2.51–2.59 (m, 1H), 2.71–2.77 (m, 2H), 3.59 (m, 1H), 11.03 (s, 2H); ¹³C NMR (75 MHz, methanol-d₄): δ_C (ppm) 13.5, 22.7, 26.5, 30.8, 37.8, 84.1, 145.3, 161.7, 203.5; IR (KBr) (ν_max/cm⁻¹) 3391, 2924, 1719, 1702, 1682, 1655; MS (ESI): m/z calcd for C₁₀H₁₄N₂O₄: 226.10; found 226.23 [M]⁺, 249.01 [M + Na]⁺; anal. calcd for C₁₀H₁₄N₂O₄: C, 53.09; H, 6.24; N, 12.38. Found: C, 52.97; H, 6.11; N, 12.51%.

5-(2-Oxooctan-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4aq)

Yield, 0.185 g (73%). Red gummy solid (after column chromatography). ¹H NMR (300 MHz, methanol-d₄): δ_H (ppm) 0.91 (m, 3H), 1.31–1.59 (m, 6H), 2.16 (s, 3H), 2.68–2.72 (m, 1H), 2.86–2.91 (m, 2H), 3.59–3.65 (m, 1H), 10.94 (s, 2H); ¹³C NMR (75 MHz, methanol-d₄): δ_C (ppm) 6.8, 22.6, 22.7, 24.7, 29.0, 32.1, 38.1, 84.5, 150.2, 161.7, 164.2, 203.4; IR (KBr) (ν_max/cm⁻¹) 3127, 2923, 1721, 1708, 1682, 1670; MS (ESI): m/z calcd for C₁₂H₁₈N₂O₄: 254.13; found 255.10 [M + H]⁺, 277.01 [M + Na]⁺; anal. calcd for C₁₂H₁₈N₂O₄: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.81; H, 7.00; N, 10.89%.

5-(1-Oxo-1-phenylheptan-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ar)

Yield, 0.234 g (74%). Red gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 0.90 (m, 3H), 1.13–1.15 (m, 2H), 1.26–1.46 (m, 4H), 3.18–3.25 (m, 1H), 3.39 (m, 1H), 3.42–3.54 (m, 1H), 3.75 (m, 1H), 7.46–7.49 (m, 2H), 7.58 (m, 1H), 7.94 (d, 2H, J = 7.5 Hz), 8.25 (s, 1H), 8.29 (s, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 7.5, 23.3, 25.6, 33.1, 42.1, 85.0, 121.7, 122.3, 127.0, 143.1, 162.3, 162.5, 162.8, 193.7; IR (KBr) (ν_max/cm⁻¹) 3210, 3052, 2923, 1722, 1709, 1687, 1661, 1558; MS (ESI): m/z calcd for C₁₇H₂₀N₂O₄: 316.14; found 316.96 [M + H]⁺, 339.10 [M + Na]⁺; anal. calcd for C₁₇H₂₀N₂O₄: C, 64.54; H, 6.37; N, 8.86. Found: C, 64.68; H, 6.27; N, 9.05%.

1,3-Dimethyl-5-(3-oxo-1-phenylbutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4ba)³⁰

Yield, 0.251 g (83%). Yellow gummmy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.18 (s, 3H), 2.89–2.91 (m, 1H), 2.96 (s, 3H), 3.10 (s, 3H), 3.42–3.51 (m, 1H), 3.84 (d, 1H, J = 4.2 Hz), 4.02–4.09 (m, 1H), 6.94–6.97 (m, 2H), 7.19–7.22 (m, 3H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 27.8, 27.9, 30.3, 44.0, 44.7, 52.5, 127.1, 128.3, 128.4, 137.5, 150.8, 167.5, 168.2, 206.4; IR (KBr) (ν_max/cm⁻¹) 3072, 2924, 1710, 1701, 1688, 1658, 1553; MS (ESI): m/z calcd for C₁₆H₁₈N₂O₄: 302.13; found 303.12 [M + H]⁺, 325.00 [M + Na]⁺; anal. calcd for C₁₆H₁₈N₂O₄: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.72; H, 5.86; N, 9.38%.

5-(1-(2-Chlorophenyl)-3-oxobutyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4bb)

Yield, 0.292 g (87%). White solid, mp 93–95 °C (from EtOH/DCM).¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.13 (s, 3H), 2.89–2.97 (m, 1H), 3.10 (s, 6H), 3.29–3.38 (m, 1H), 3.75 (d, 1H, J = 4.5 Hz), 4.59–4.65 (m, 1H), 7.11–7.29 (m, 4H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.2, 28.4, 30.0, 38.7, 45.5, 52.6, 126.9, 128.2, 128.7, 129.7, 133.8, 136.5, 151.8, 167.4, 167.5, 206.1; IR (KBr) (ν_max/cm⁻¹) 3090, 2919, 1718, 1706, 1688, 1659, 1554; MS (ESI): m/z calcd for C₁₆H₁₇ClN₂O₄: 336.09; found 337.01 [M + H]⁺, 359.00 [M + Na]⁺. Anal. calcd for C₁₆H₁₇ClN₂O₄: C, 57.06; H, 5.09; N, 8.32. Found: C, 57. 18; H, 4.95; N, 8.47%.

5-(1-(3-Chlorophenyl)-3-oxobutyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4bc)

Yield, 0.263 g (78%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.20 (s, 3H), 2.90–3.00 (m, 1H), 3.03 (s, 3H), 3.12 (s, 3H), 3.42–3.51 (m, 1H), 3.84 (d, 1H, J = 3.9 Hz), 4.04–4.10 (m, 1H), 6.89 (d, 1H, J = 6.9 Hz), 7.01 (s, 1H), 7.14–7.26 (m, 2H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.0, 28.1, 30.3, 43.2, 44.7, 52.3, 125.5, 127.4, 128.4, 129.9, 134.6, 140.0, 150.7, 167.4, 167.9, 206.1; IR (KBr) (ν_max/cm⁻¹) 3055, 2924, 1727, 1710, 1687, 1660, 1552; MS (ESI): m/z calcd for C₁₆H₁₇ClN₂O₄: 336.09; found 337.01[M + H]⁺, 359.01 [M + Na]⁺. Anal. calcd for C₁₆H₁₇ClN₂O₄: C, 57.06; H, 5.09: N, 8.32. Found: C, 56.93; H, 4.96; N, 8.45%.

5-(1-(3-Methoxyphenyl)-3-oxobutyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4bd)

Yield, 0.282 g (85%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.17 (s, 3H), 2.87–2.95 (m, 1H), 2.96 (s, 3H), 3.06 (s, 3H), 3.08–3.47 (m, 1H), 3.69 (s, 3H), 3.81 (d, 1H, J = 3.9 Hz), 4.01–4.02 (m, 1H), 6.50–6.53 (m, 2H), 6.72–6.74 (m, 1H), 7.09–7.14 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 27.8, 27.9, 30.2, 43.8, 44.7, 52.3, 55.0, 113.0, 113.2, 119.2, 129.5, 139.1, 150.8, 159.5, 167.5, 168.1, 206.3; IR (KBr) (ν_max/cm⁻¹) 3067, 2923, 1719, 1707, 1680, 1651, 1561; MS (ESI): m/z calcd for C₁₇H₂₀N₂O₅: 332.14; found 333.15 [M + H]⁺; anal. calcd for C₁₇H₂₀N₂O₅: C, 61.44; H, 6.07; N, 8.43. Found: C, 61.59; H, 6.19; N, 8.27%.

1,3-Dimethyl-5-(1-(3-nitrophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4be)

Yield, 0.291 g (84%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.18 (s, 3H), 2.83–2.91 (m, 1H), 3.02 (s, 3H), 3.11 (s, 3H), 3.48–3.57 (m, 1H), 3.89 (d, 1H, J = 3.9 Hz), 4.20–4.27 (m, 1H), 7.43–7.51 (m, 2H), 7.92 (s, 1H), 8.05–8.07 (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.1, 28.2, 30.1, 42.2, 44.8, 52.0, 122.0, 122.9, 129.6, 134.1, 140.8, 148.1, 150.6, 167.1, 167.4, 206.0; IR (KBr) (ν_max/cm⁻¹) 3086, 2924, 1711, 1701, 1688, 1657, 1531; MS (ESI): m/z calcd for C₁₆H₁₇N₃O₆: 347.11; found 348.34 [M + H]⁺, 370.15 [M + Na]⁺; anal. calcd for C₁₆H₁₇N₃O₆: C, 55.33; H, 4.93; N, 12.10. Found: C, 55.17; H, 5.06; N, 11.98%.

5-(1-(4-Bromophenyl)-3-oxobutyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4bf)

Yield, 0.331 g (87%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.18 (s, 3H), 2.88–2.96 (m, 1H), 3.04 (s, 3H), 3.12 (s, 3H), 3.42–3.52 (m, 1H), 3.85 (d, 1H, J = 3.9 Hz), 4.05–4.11 (m, 1H), 6.89 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.1, 28.2, 30.4, 42.8, 45.1, 52.2, 122.2, 129.1, 131.8, 137.3, 150.8, 167.5, 167.9, 206.3; IR (KBr) (ν_max/cm⁻¹) 3029, 2924, 1718, 1710, 1693, 1674, 1516; MS (ESI): m/z calcd for C₁₆H₁₇BrN₂O₄: 380.04; found 381.12 [M + H]⁺, 403.00 [M + Na]⁺; anal. calcd for C₁₆H₁₇BrN₂O₄: C, 50.41; H, 4.49; N, 7.35. Found: C, 50.34; H, 4.61; N, 7.21%.

5-(1-(4-Hydroxyphenyl)-3-oxobutyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4bg)

Yield, 0.216 g (68%). White solid, mp 173–175 °C (from EtOH). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.04 (s, 3H), 2.88–2.93 (m, 1H), 3.02 (s, 3H), 3.10 (s, 3H), 3.38–3.47 (m, 1H), 3.83 (d, 1H, J = 3.9 Hz), 4.02–4.03 (m, 1H), 6.45 (s, 1H), 6.67 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.1 Hz); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.0, 28.1, 30.5, 43.6, 45.2, 52.9, 115.6, 128.4, 128.9, 151.0, 156.0, 167.7, 168.6, 207.3; IR (KBr) (ν_max/cm⁻¹) 3433, 3012, 2927, 1710, 1700, 1678, 1671, 1554; MS (ESI): m/z calcd for C₁₆H₁₈N₂O₅: 318.12; found 318.97 [M + H]⁺, 341.00 [M + H]⁺; anal. calcd for C₁₆H₁₈N₂O₅: C, 60.37; H, 5.70; N, 8.80. Found: C, 60.21; H, 5.85; N, 8.97%.

1,3-Dimethyl-5-(1-(4-nitrophenyl)-3-oxobutyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4bh)

Yield, 0.292 g (84%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.19 (s, 3H), 2.83–3.00 (m, 1H), 3.08 (s, 3H), 3.15 (s, 3H), 3.50–3.59 (m, 1H), 3.91 (d, 1H, J = 3.3 Hz), 4.27–4.29 (m, 1H), 7.27 (d, 2H, J = 8.4 Hz), 8.08 (d, 2H, J = 8.4 Hz); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.2, 28.3, 30.2, 42.1, 44.9, 51.9, 123.7, 128.7, 146.4, 147.3, 150.6, 167.1, 167.3, 206.1; IR (KBr) (ν_max/cm⁻¹) 3124, 2924, 1710, 1701, 1689, 1652, 1523; MS (ESI): m/z calcd for C₁₆H₁₇N₃O₆: 347.11; found 348.24 [M + H]⁺, 370.01 [M + Na]⁺; anal. calcd for C₁₆H₁₇N₃O₆: C, 55.33; H, 4.93; N, 12.10. Found: C, 55.19; H, 4.81; N, 12.27%.

5-(1-(2-Chlorophenyl)-3-oxobutyl)-1-methylpyrimidine-2,4,6(1H,3H,5H)-trione (4bi)

Yield, 0.284 g (88%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.12/2.13 (s^‡, 3H), 2.88–2.96 (m, 1H), 3.15/3.21 (s^‡, 3H), 3.27–3.31/3.33–3.38 (m^‡, 1H), 3.77/3.85 (d^‡, 1H, J = 4.2 Hz), 4.67–4.68 (m, 1H), 7.14–7.32 (m, 4H), 9.38/9.39 (s^‡, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 27.5/27.6, 29.9, 37.5/37.6, 38.9, 44.9, 126.8/126.9, 127.0/127.1, 128.3/128.4, 129.8/129.9, 133.6/133.7, 137.0/137.3, 150.4, 167.7, 168.1/168.2, 207.0/207.1; IR (KBr) (ν_max/cm⁻¹) 3356, 3095, 2924, 1712, 1701, 1681, 1654, 1585; MS (ESI): m/z calcd for C₁₅H₁₅ClN₂O₄: 322.07; found 323.09 [M + H]⁺, 345.01 [M + Na]⁺; anal. calcd for C₁₅H₁₅ClN₂O₄: C, 55.82; H, 4.68; N, 8.68. Found: C, 56.07; H, 4.50; N, 8.56%.

5-(1-(2-Fluorophenyl)-3-oxo-3-phenylpropyl)-1-methylpyrimidine-2,4,6(1H,3H,5H)-trione (4bj)

Yield, 0.328 g (85%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 3.04/3.13 (s^‡, 3H), 3.47–3.49/3.53–3.55 (m^‡, 1H), 3.95–3.97 (m, 1H), 3.99–4.03/4.05–4.09 (m^‡, 1H), 4.61–4.62 (m, 1H), 6.98–7.08 (m, 2H), 7.20–7.26 (m, 2H), 7.41–7.55 (m, 3H), 7.94–7.97 (m, 2H), 9.04/9.14 (s^‡, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 27.5, 37.3/37.5, 39.8/39.9, 51.9/52.0, 115.6/115.7, 115.9/116.0, 124.5, 125.6/125.8, 128.0, 128.6, 129.5/129.6, 129.7/129.8, 133.4, 136.4, 150.3/150.4, 167.8/168.0, 168.3/168.6, 197.7/197.8; IR (KBr) (ν_max/cm⁻¹) 3321, 3092, 2923, 1721, 1709, 1684, 1657, 1552; MS (ESI): m/z calcd for C₂₀H₁₇FN₂O₄: 368.12; found 369.13 [M + H]⁺; anal. calcd for C₂₀H₁₇FN₂O₄: C, 65.21; H, 4.65; N, 7.60. Found: C, 65.35; H, 4.51; N, 7.76%.

5-(1-(3-Chlorophenyl)-3-oxobutyl)-1-methylpyrimidine-2,4,6(1H,3H,5H)trione (4bk)

Yield, 0.284 g (88%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.20/2.21 (s^‡, 3H), 2.92–3.00 (m, 1H), 3.04/3.13 (s^‡, 3H), 3.50–3.59 (m, 1H), 3.88–3.92 (m^‡, 1H), 4.08–4.16 (m, 1H), 7.01–7.29 (m, 4H), 9.16/9.24 (s^‡, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 27.3/27.4, 30.2, 42.0/42.1, 44.7/44.9, 51.7/51.8, 125.8/126.0, 127.7/127.8, 128.24, 130.0, 134.5, 140.5, 150.0/150.1, 167.7/168.0, 168.3/168.6, 206.9; IR (KBr) (ν_max/cm⁻¹) 3341, 3088, 2924, 1719, 1710, 1689, 1660, 1552; MS (ESI): m/z calcd for C₁₅H₁₅ClN₂O₄: 322.07; found 323.15 [M + H]⁺, 345.10 [M + Na]⁺; anal. calcd for C₁₅H₁₅ClN₂O₄: 55.82; H, 4.68; N, 8.68. Found: C, 55.95; H, 4.51; N, 8.74%.

5-(1-(4-Bromophenyl)-3-oxobutyl)-1-methylpyrimidine-2,4,6(1H,3H,5H)-trione (4bl)

Yield, 0.334 g (91%). Yellow gummy solid (after column chromatography). ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 2.17/2.18 (s^‡, 3H), 2.88–2.96 (m, 1H), 3.03/3.12 (s^‡, 3H), 3.47–3.52/3.53–3.58 (m^‡, 1H), 3.87–3.91 (m^‡, 1H), 4.07–4.14 (m, 1H), 6.96–7.02 (m^‡, 2H), 7.36–7.43 (m^‡, 2H), 9.11/9.15 (s^‡, 1H); ¹³C NMR (75 MHz, CDCl₃): δ_C (ppm) 28.6, 30.4, 41.8/41.9, 45.0/45.1, 51.7/51.8, 122.1, 129.5, 132.0, 137.5, 150.1/150.2, 167.9/168.2, 168.4/168.7, 207.2; IR (KBr) (ν_max/cm⁻¹): 3323, 3097, 2924, 1719, 1702, 1689, 1658, 1551; MS (ESI): m/z calcd for C₁₅H₁₅BrN₂O₄: 366.02; found 367.01 [M + H]⁺, 389.00 [M + Na]⁺; anal. calcd for C₁₅H₁₅BrN₂O₄: C, 49.06; H, 4.12; N, 7.63. Found: C, 48.91; H, 3.98; N, 7.78%.

Acknowledgements

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

Notes and references

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26. ESI.†.
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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H- and ¹³C-NMR spectra of all compounds. CCDC 959094. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra00093e

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