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.

Figures & data

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

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.

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.

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).

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