Dibutylamine (DBA): A highly efficient catalyst for the synthesis of pyrano[2,3-d]pyrimidine derivatives in aqueous media

Peer review under responsibility of Taibah University.

Abstract

Annulated pyrano[2,3-d]pyrimidine derivatives were synthesized via one-pot, three-component condensation reactions of various aromatic aldehydes, malononitrile and barbituric acid in aqueous ethanol using dibutylamine (DBA) as catalyst. The potential application of DBA in organic synthesis is increasing rapidly due to its reaction simplicity, minimal reaction time, high yields of the desired products (83–94%) and low cost chemicals. All of the synthesized pyrano[2,3-d]pyrimidine derivatives were characterized by IR, ¹H NMR, ¹³C NMR and mass spectra.

Keywords:

• Annulated pyrano[2,3-d]pyrimidines
• Barbituric acid
• Knoevenagel–Michael addition reaction
• Spectral analysis
• Aromatic aldehydes
• DBA catalyst

1 Introduction

Heterocyclic compounds have received considerable attention in recent years due to their variety of biological activities, especially as inhibitors of PDE5 extracted from human platelets [1], HIV-1 reverse transcriptase [2], human EPK2 [3] and cyclin-dependent kinase [4]. The study of aromatic six membered N-heterocyclic rings is of great importance in the pharmaceutical sector due to bio-isosteric factors, which are of theoretical and practical importance. Pyrimidine rings have significant pharmacological importance as an integral part of DNA and RNA in several biological processes [5–7]. Therefore, the chemotherapeutic efficacy of annulated pyrano[2,3-d]pyrimidines is related to their ability to inhibit enzyme action for DNA biosynthesis, such as dihydrofolate reductase (DHFR), thymidylate synthetase (TSase), thymidine phosphorylase (TPase) and reverse transcriptase (RTase). When pyrano[2,3-d]pyrimidine moieties are annulated into one molecule, the resultant derivative has enhanced pharmaceutical activity, such as, antitumor [8], antihypertensive [9], antibacterial [10] and antileishmanial activity [11]. Therefore, for the preparation of these complex molecules, large efforts have been made towards the synthetic manipulation of annulated uracils, which occupy a distinct and unique place in medicinal chemistry. Annulated pyrano[2,3-d]pyrimidine derivatives are unsaturated N-heterocyclics formed as a fusion of pyran and pyrimidine rings, consisting of one oxygen atom at 8 and two nitrogen atoms at the 1 and 3 positions. They are synthesized by various procedures based on multicomponent reactions, such as Knoevenagel condensation, Michael addition followed by cyclodehydration and finally heterocyclization.

Multicomponent reactions (MCRs) have gained significant interest from modern medicinal and combinatorial chemists [12,13] due to the powerful bond forming efficiency, diversity-oriented synthesis (DOS), simple reaction design, atom-economy, environmental concerns and the possibility to construct target compounds using several assorted elements in a single chemical procedure [14,15]. Pyrano[2,3-d]pyrimidine derivatives have been reported using different catalysts, such as Zn[(l)proline]₂ [16], [BMIm]BF₄ [17], N-methylmorpholine [18], DAHP [19], SBA-Pr-SO₃H [20], H₁₄[NaP₅W₃₀O₁₁₀] [21], 1,4-dioxane [22], l-proline [23] and [K Al(SO4)₂] [24]. Et₃N was used as a catalyst for the synthesis of pyrano[2,3-d]pyrimidine derivatives under microwave irradiation [25]. A catalyst-free procedure was also examined for the preparation of pyrano[2,3-d]pyrimidine derivatives [26]. In addition, ultrasonic irradiation [27] and ball-milling techniques [28] were used for the synthesis of pyrano[2,3-d]pyrimidine derivatives. The solvent and the inexpensive, mild and reusable catalyst for MCRs play an important role in the synthesis and its selectivity of targeted products. One of these catalysts is dibutylamine (DBA), which has received significant interest as a high reactive, eco-friendly, inexpensive, readily available and non-toxic catalyst to obtain corresponding products in excellent yields with high selectivity [29].

In continuation of the current research from our laboratory to develop efficient multicomponent reactions (MCRs) for the preparation of pyrimidine-annulated bioactive molecules [30], we report here, the dibutylamine (DBA) catalyzed efficient, simple and fast synthesis of pyrano[2,3-d]pyrimidine derivatives via one-pot, three-component domino Knoevenagel–Michael addition reaction in aqueous media (Scheme 1).

Scheme 1 General synthesis of substituted pyrano[2,3-d]pyrimidines 4(a–j).

2 Experimental

2.1 Apparatus and analysis

All chemicals were obtained from Merck and S.D. Fine Chem. Co. and were used without further purification. Melting points were determined by the open capillary method and were uncorrected. IR spectra were recorded on a Perkin–Elmer 298 spectrophotometer using KBr pellets. ¹H and ¹³C NMR spectra were recorded using a Bruker instrument (¹H at 400 MHz and ¹³C at 100 MHz) in DMSO-d₆ solvent with tetramethylsilane as the internal standard. Chemical shifts are reported in ppm. Mass spectra were recorded on a Shimadzu GC-MS-QP-2010 model using the direct injection probe technique. Reactions were monitored by thin-layer chromatography on 0.2-mm precoated plates of silica gel G60 F254 (Merck).

2.2 General procedure for the synthesis of pyrano[2,3-d]pyrimidine derivatives 4(a–j)

Substituted aromatic aldehydes 1 (1 mmol), malononitrile 2 (1 mmol), barbituric acid 3 (1 mmol) and 20 mol% dibutylamine (DBA) were added to an RB flask with 16 ml aqueous media (1:1 ratio) and were stirred for 43–129 min at room temperature. The progress of the reaction was monitored by TLC. The solid product was filtered, washed with cold water and recrystallized from ethanol to obtain pure pyrano[2,3-d]pyrimidine derivatives with excellent yields (83–94%).

2.3 Spectral data for the synthesized pyrano[2,3-d]pyrimidine derivatives 4(a–j)

2.3.1 7-Amino-5-(4-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4a)

White powder, IR (KBr, ν cm⁻¹): 3411 (NH₂), 3209, 3163 (NH), 2989 (C–H), 2206 (C–N), 1732 (C=O), 1461 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 13.01 (s, 1H, NH), 8.93 (s, 1H, NH), 7.94 (d, J = 7.1 Hz, 2H, Ar-H), 7.47 (d, J = 7.1 Hz, 2H, Ar-H), 6.79 (s, 2H, NH₂), 4.96 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 176.47 (C=O), 170.60 (CNH₂), 153.93 (CONH), 151.36 (C=O), 150.32 (C-14), 147.44 (C-11), 128.99 (C-12), 123.19 (C-13), 120.41 (C–N), 104.46 (C-5), 75.53 (C-9), 70.70 (C-10) ppm; MS (m/z): 328.2 [M+H⁺].

2.3.2 7-Amino-5-(3-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4b)

White powder, IR (KBr ν cm⁻¹): 3314 (NH₂), 3301, 3247 (NH), 2942 (C–H), 2212 (C–N), 1605 (C=O), 1476 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 12.02 (s, 1H, NH), 10.21 (s, 1H, NH), 8.38 (s, 1H, Ar-H), 8.19 (d, J = 6.3 Hz, 2H, Ar-H), 6.82 (s, 2H, NH₂), 3.94 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 166.12 (C=O), 160.73 (CNH₂), 157.01 (CONH), 151.56 (C=O), 150.57 (C-14), 146.11 (C-11), 129.23 (C-12), 123.08 (C-13), 119.45 (C–N), 104.42 (C-5), 79.32 (C-9), 71.10 (C-10) ppm; MS (m/z): 328.2 [M+H⁺].

2.3.3 7-Amino-5-(2-nitrophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4c)

White powder, IR (KBr ν cm⁻¹): 3302 (NH₂), 3331, 3142 (NH), 2938 (C–H), 2172 (C–N), 1645 (C=O), 1527 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.12 (s, 1H, NH), 10.79 (s, 1H, NH), 7.69–7.63 (m, 3H, Ar-H), 6.82 (s, 2H, NH₂), 3.94 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 179.44 (C=O), 170.14 (CNH₂), 159.59 (CONH), 156.79 (C=O), 149.87 (C-14), 134.52 (C-11), 132.12 (C-12), 130.05 (C-13), 127.31 (C–N), 91.81 (C-5), 84.24 (C-9), 57.01 (C-10) ppm; MS (m/z): 350.02 [M+Na⁺].

2.3.4 7-Amino-5-(4-hydroxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4d)

Yellow powder, IR (KBr, ν cm⁻¹): 3457 (OH), 3260 (NH₂), 3131, 3088 (NH), 2293 (C–H), 2242 (C–N), 1729 (C=O), 1678 (C=O), 1555 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.87 (s, 1H, NH), 10.79 (s, 1H, NH), 6.98 (d, J = 7.5 Hz, 2H, Ar-H), 6.82 (s, 2H, NH₂), 6.61 (d, J = 7.6 Hz, 2H, Ar-H), 6.05 (s, 1H, OH), 4.31 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 168.93 (C=O), 157.19 (C-14), 155.61 (CNH₂), 153.38 (CONH), 152.72 (C=O), 129.32–129.20 (C-12 & C-16), 118.20 (C–N), 115.16 (C-13), 97.22 (C-5), 58.65 (C-9), 54.87 (C-10) ppm; MS (m/z): 298.06 [M+H⁺].

2.3.5 7-Amino-5-(3-hydroxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4e)

Yellow powder, IR (KBr, ν cm⁻¹): 3439 (OH), 3337 (NH₂), 3193, 3028 (NH), 2206 (C–H), 2131 (C–N), 1677 (C=O), 1625 (C=O), 14,741 (C=C); ¹H NMR (400 MHz, DMSO-d₆): δ = 12.04 (s, 1H, NH), 10.62 (s, 1H, NH), 6.97–6.83 (m, 3H, Ar-H), 6.61 (s, 2H, NH₂), 6.09 (s, 1H, OH), 3.94 (s, 1H, CH); ¹³C NMR (100 MHz, DMSO-d₆): δ = 179.43 (C=O), 170.23 (C-14), 159.49 (CNH₂), 157.19 (CONH), 155.08 (C=O), 129.31 (C-16), 129.20 (C–N), 115.15 (C-13), 93.41 (C-5), 84.21 (C-9), 52.03 (C-10); MS (m/z): 299.02 [M+H⁺].

2.3.6 7-Amino-5-(4-bromophenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4f)

White powder, IR (KBr, ν cm⁻¹): 3370 (NH₂), 3340, 3189 (NH), 3080 (C–H), 2220 (C–N), 1684 (C=O), 1567 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 14.10 (s, 1H, NH), 13.01 (s, 1H, NH), 7.75 (d, J = 7.1 Hz, 2H, Ar-H), 7.33 (d, J = 7.1 Hz, 2H, Ar-H), 6.82 (s, 2H, NH₂), 3.90 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 173.47 (C=O), 160.34 (CNH₂), 153.89 (CONH), 145.91 (C=O), 138.53 (C-11), 131.97 (C-13 & C-15), 129.69 (C-12 & C-16), 124.03 (C-14), 121.28 (C–N), 105.25 (C-5), 69.60 (C-9), 50.10 (C-10) ppm; MS (m/z): 384.12 [M+Na⁺].

2.3.7 7-Amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4 g)

Yellow powder, IR (KBr, ν cm⁻¹): 3371 (NH₂), 3301, 3212 (NH), 3114 (C–H), 2129 (C–N), 1694 (C=O), 1572 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.98 (s, 1H, NH), 10.80 (s, 1H, NH), 7.31 (t, J = 7.3 Hz, 2H, Ar-H), 7.14–7.06 (m, 3H, Ar-H), 6.82 (s, 2H, NH₂), 4.29 (s, 1H, CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 160.39 (C=O), 155.61 (CNH₂), 153.91 (CONH), 151.36 (C=O), 145.92 (C-11), 128.68 (C-12), 128.49 (C-13), 127.61 (C-14), 118.21 (C–N), 93.41 (C-5), 58.66 (C-9), 50.89 (C-10) ppm; MS (m/z): 283.08 [M+H⁺].

2.3.8 7-Amino-5-(4-methoxyphenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d] pyrimidine-6-carbonitrile (4 h)

Dark yellow powder, IR (KBr, ν cm⁻¹): 3317 (NH₂), 3282, 3145 (NH), 3063 (C–H), 2215(C–N), 1743 (C=O), 1668 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.98 (s, 1H, NH), 10.80 (s, 1H, NH), 7.14 (d, J = 7.5 Hz, 2H, Ar-H), 6.86–6.82 (m, 4H, Ar-H & NH₂), 4.16 (s, 1H, CH), 3.81 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 161.99 (C=O), 159.11 (C-14), 155.61 (CNH₂), 151.97 (CONH), 151.36 (C=O), 130.34 (C-11), 129.50 (C-12), 123.56 (C–N), 113.14 (C-13), 93.41 (C-5), 58.66 (C-9), 57.46 (CH₃), 53.46 (C-10) ppm; MS (m/z): 313.01 [M+H⁺].

2.3.9 7-Amino-5-(2-methoxyphenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d] pyrimidine-6-carbonitrile (4i)

Yellow powder, IR (KBr, ν cm⁻¹): 3419 (NH₂), 3202, 3137 (NH), 3016 (C–H), 2272(C–N), 1765 (C=O), 1609 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.93 (s, 1H, NH), 10.71 (s, 1H, NH), 7.44 (d, J = 4.6 Hz, 1H, Ar-H), 7.14–7.7.11 (m, 4H, Ar-H & NH₂), 4.16 (s, 1H, CH), 3.73 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 169.87 (C=O), 161.02 (C-14), 158.21 (CNH₂), 152.46 (CONH), 151.82 (C=O), 131.15 (C-11), 129.09 (C-12), 124.02 (C–N), 113.18 (C-13), 94.39 (C-5), 58.93 (C-9), 57.41 (CH₃), 53.57 (C-10) ppm; MS (m/z): 313.05 [M+H⁺].

2.3.10 7-Amino-5-(3,4-dimethoxyphenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (4j)

Yellow powder, IR (KBr, ν cm⁻¹): 3194 (NH₂), 3103, 2223 (NH), 1734 (C–H), 2609 (C–N), 1662 (C=O), 1262 (C=C). ¹H NMR (400 MHz, DMSO-d₆): δ = 10.98 (s, 1H, NH), 10.80 (s, 1H, NH), 6.83–6.80 (m, 5H, Ar-H & NH₂), 4.29 (s, 1H, CH), 3.83 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ = 164.65 (C=O), 155.61 (CNH₂), 153.94 (CONH), 151.97 (C=O), 149.25 (C-14), 148.54 (C-13), 131.34 (C-11), 126.92 (C-16), 119.53 (C–N), 116.52 (C-12), 114.27 (C-15), 93.40 (C-5), 58.66 (C-9), 57.91 (CH₃), 56.78 (CH₃), 51.23 (C-10) ppm; MS (m/z): 343 [M+H⁺].

3 Results and discussion

Herein, we report the synthesis of pyrano[2,3-d]pyrimidinones (4a–j) through domino Knoevenagel–Michael condensation pathways (Table 1). In the initial studies, hydroxybenzaldehyde 1 (1.0 mmol), malononitrile 2 (1.0 mmol) and barbituric acid 3 (1.0 mmol) were refluxed in aqueous ethanol using different catalysts for the synthesis of model product 4d. We found the base catalysts, such as N-methylimidazole, triethylamine, piperidine, morpholine and dibutylamine (Table 2), were equally competent in furnishing the desired model product 4d in good yields. Among these basic catalysts, 20 mol% of dibutylamine (DBA) gave the best result in terms of time of completion, and the product yield was 94%. In the absence of catalyst, the reaction was completed under reflux conditions after 189 min, and the yield of product was 37% (Table 2). Therefore, dibutylamine (DBA) catalyst is superior to all of the other tested catalysts.

Table 1 Synthesis of pyrano[2,3-d]pyrimidine derivatives 4(a–j).

Aldehyde	Product	Time (min)	Yield (%)^a	M.P. (°C)
				Found	Reported
		103	83	235–236	238–239 [26]
		110	86	239–241	262–263 [31]
		101	84	231–234	257–258 [28]
		53	94	158–160	163–167 [30]
		67	91	169–171	170–174 [30]
		72	89	228–232	235–236 [20]
		58	94	236–238	224–225 [31]
		67	91	289–293	290–293[30]
		59	87	301–303	230 [16]
		78	93	312–314	303–306 [30]

a Isolated yields.

Table 2 Effect of catalysts for the synthesis of model product 4d using aqueous ethanol.^a

Entry	Catalyst	Catalyst (mol%)	Time (min)	Yield (%)^b
1	N-methylamidazole	20 mol	114	79
2	Triethylamine	20 mol	83	90
3	Piperidine	20 mol	110	71
4	Morpholine	20 mol	140	68
5	Dibutylamine	5 mol	105	74
6	Dibutylamine	10 mol	68	86
7	Dibutylamine	15 mol	53	87
8	Dibutylamine	20 mol	53	94
9	Catalyst free	–	189	37

a Reaction conditions: hydroxybenzaldehyde (1 mmol), malononitrile (mmol), barbituric acid (1 mmol), DBA (20 mol%), aqueous ethanol, stirring/reflux, r.t.

b Isolated yields.

Further, we focused on the systematic evaluation of different solvents, such as ethanol:H₂O, DMF, CH₂Cl₂ and 1,4-dioxane (Table 3, entry 1–6), for the model reaction 4 using hydroxybenzaldehyde 1 (1.0 mmol), malononitrile 2 (1.0 mmol) and barbituric acid 3 (1.0 mmol) as reactants in presence of 20 mol% dibutylamine (DBA) catalyst (Scheme 2). The results indicated that the solvent has a significant effect on the product yield and reaction time. The best conversion was observed when the reaction proceeded in ethanol:H₂O (Table 3, entry 1). The use of aqueous ethanol as solvent in the reaction medium exhibits remarkable benefits, such as environmentally safe, devoid of carcinogenic effects, comparatively cheaper to operate and simple work up. Table 4 shows the comparative results of the different catalysts with the catalytic activity of DBU for the synthesis of pyrano[2,3-d]pyrimidine derivatives.

Table 3 Optimization of different solvents for the model reaction.^a

Entry	Solvent	Time (min)	Yield (%)^b
1	EtOH–H2O	53	94
3	DMF	59	61
4	CH2Cl2	103	58
5	1,4-Dioxane	72	63
6	Solvent less	192	57

a Reaction conditions: hydroxybenzaldehyde, malononitrile, barbituric acid (each 1 mol), DBA (20 mol%), aqueous ethanol, strring/reflux, r.t.

b Yields based on isolated yields.

Table 4 DBA comparison with different catalysts for the synthesis of pyrano[2,3-d]pyrimidine derivatives.

Entry	Catalyst	Solvent	Condition	Time	Yield	Lit. Ref.
1	Zn[(l)proline]2	EtOH	Reflux	30 min–12 h	80–92	[16]
2	[BMIm]BF4	[BMIm]BF4	90 °C	3–5 h	82–95	[17]
3	N-methylmorpholine	[bmim][PF6]	70 °C	15 min	85–89	[18]
4	DAHP	EtOH	r.t.	2 h	71–81	[19]
5	SBA-Pr-SO3H	Solvent free	140 °C	5–45 min	91	[20]
6	H14[NaP5W30O110]	EtOH	Reflux	30–60 min	85–90	[21]
7	1,4-Dioxane	H2O	Reflux	1–2 min	60–70	[22]
8	l-Proline	Aq. EtOH	Reflux	30–120	68–85	[23]
9	[K Al(SO4)2]	H2O	80 °C	30–45 min	81–88	[24]
10	Et3N	DMF	MW	10–12 min	65–70	[25]
11	DBA	Aq. EtOH	Reflux	43–129 min	83–94	Present work

Scheme 2 Synthesis of model product 4d using different catalysts in aqueous ethanol.

The structural assignment of model product 4d was confirmed by IR, ¹HNMR, ¹³CNMR and mass spectrometric analysis. The IR spectra exhibited sharp absorption bands at 3457, 3260, 3131–3088, 2293, 1729, 1678 and 1555 cm⁻¹, which are attributed to OH, NH₂, NH, C–H, C–N, C=O and C=C stretching vibrations, respectively. The ¹H NMR spectrum of compound 4d had peaks at δ 10.87 (s, 1H, NH), δ 10.79 (s, 1H, NH), δ 6.98 (d, J = 7.5 Hz, 2H, Ar-H), δ 6.82 (s, 2H, NH₂), δ 6.61 (d, J = 7.6 Hz, 2H, Ar-H), δ 6.05 (s, 1H, OH) and δ 4.31 (s, 1H, CH) ppm (Fig. 1). In the ¹³CNMR spectrum of the compound 4d, 12 significant signals were recorded at 168.93, 157.19, 155.61, 153.38, 152.72, 129.32–129.20, 118.20, 115.16, 97.22, 58.65 and 54.87 ppm (Fig. 2). The molecular ion peak was observed in agreement with the molecular weight of the compound. The results indicated that a series of substituted aromatic aldehydes were successfully employed to prepare the corresponding product in excellent yields (83–94%) and there is no major effect on the yield of product by electron donating/withdrawing substituents.

Fig. 1 ¹H NMR spectra of 7-amino-5-(4-hydroxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitril (4d).

Fig. 2 ¹³C NMR spectra of 7-amino-5-(4-hydroxyphenyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]pyrimidine-6-carbonitril (4d).

Dibutylamine (DBA) is an amine that is basic in character, so it facilitates proton removal from active methylene compounds, thereby increasing the reaction rate yields of the desired products. Mechanistically, DBA is an effective catalyst for the formation of the higher reactive iminium group, which is utilized to facilitate the Knoevenagel condensation of malononitrile with aromatic aldehydes by loss of a water molecule, followed by Michael addition of barbituric acid on an electron deficient C-atom and an intra-molecular heterocyclization that leads to the formation of the pyrano[2,3-d]pyrimidine derivatives. A plausible mechanism for the synthesis of pyrano[2,3-d]pyrimidines is shown in Scheme 3.

Scheme 3 Plausible mechanism for the synthesis of pyrano[2,3-d]pyrimidines.

4 Conclusion

In conclusion, we have synthesized pyrano[2,3-d]pyrimidine derivatives via a one-pot, three-component domino Knoevenagel–Michael addition reaction using dibutylamine (DBA) as a new efficient catalyst in aqueous media. The synthetic method is simple because no special apparatus is required, and the compound formed is filtered and purified by simple crystallization. This synthesis is also advantageous in terms of atom economy and is devoid of any hazardous chemicals.

Acknowledgements

We are grateful to the Indian Institute of Integrative Medicine, Jammu & Kashmir, India for providing spectral data, and the Head of the Department of Chemistry, Prof. J.S. Meshram Nagpur University, for allowing synthetic work in the organic research laboratory.

Notes

Peer review under responsibility of Taibah University.

Appendix A

Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jtusci.2015.03.004.