Al₂O₃/MeSO₃H: A Novel and Recyclable Catalyst for One-Pot Synthesis of 3,4-Dihydropyrimidinones or Their Sulfur Derivatives in Biginelli Condensation

Figures & data

Scheme 1 Four of these related heterocyclic compounds 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) that have pharmacological properties are illustrated above.

Scheme 2 One-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and thiones using Al₂O₃/CH₃SO₃H (AMA).

Table 1. Reaction of benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), and urea (1.2 mmol) under various reaction conditions

Entry	Conditions	Catalyst ^a	Time (h)	Yield (%) ^b
1	CH2Cl2/Refluxed	AMA	10	45
2	CH3CN/60 °C	AMA	10	90
3	THF/60 °C	AMA	10	70
4	Toluene/60 °C	AMA	10	75
5	DMF/60 °C	AMA	10	80
6	C2H5OH/60 °C	AMA	1	98, 97, 96, 95, 95 ^c
7	C2H5OH/rt	AMA	3	53
8	C2 H5 OH/Refluxed	None	24	25
9	C2H5OH/60 °C	Al2O3	10	0

Table 2. Synthesis of dihydropyrimidin-ones and -thiones (DHPMs) by the condensation of aldehydes, β-dicarbonyls, and urea or thiourea catalyzed by Al₂O₃/CH₃SO₃H (AMA) as a recyclable catalyst in ethanol

							Mp (°C)
Entry	DHPM ^a	R^1	R^2/R^3	X	Yield (%) ^b	Time (min)	Found	Reported
1	8a	C6H5 (5a)	Me/OEt (7a)	O	98	25	204–206	202–204^[ ^37 ^]
2	8b	4-O2N-C6H4 (5b)	Me/OEt (7a)	O	91	35	209–211	208–211^[ ^37 ^]
3	8c	4-Cl-C6H4 (5c)	Me/OEt (7a)	O	95	30	212–214	213–215^[ ^37 ^]
4	8d	4-CH3O-C6H4 (5d)	Me/OEt (7a)	O	96	35	203–205	201–203^[ ^37 ^]
5	8e	3-Cl-C6H4 (5e)	Me/OEt (7a)	O	90	40	190–192	190–193^[ ^38 ^]
6	8f	3-O2N-C6H4 (5f)	Me/OEt (7a)	O	92	35	227–229	226–227^[ ^37 ^]
7	8g	2-Cl-C6H4 (5g)	Me/OEt (7a)	O	88	60	216–217	215–218^[ ^9 ^]
8	8h		Me/OEt (7a)	O	95	25	209–210	209–210^[ ^39 ^]
9	8i	4-CH3-C6H4 (5i)	Me/OEt (7a)	O	96	20	169–171	169–171^[ ^11 ^]
10	8j	2,4-CH3O-C6H3 (5j)	Me/OEt (7a)	O	95	35	157–159	158–160^[ ^40 ^]
11	8k	4-CN-C6H4 (5k)	Me/OEt (7a)	O	85	60	219–221	219–222^[ ^38 ^]
12	8l	2,6-Cl-C6H3 (5l)	Me/OEt (7a)	O	88	100	280–283	—
13	8m	4-iPr-C6H4 (5m)	Me/OEt (7a)	O	90	20	140–142	—
14	8n	4-CH3-C6H4 (5i)	Me/Me (7b)	O	93	40	204–206	—
15	8o	3-Cl-C6H4 (5e)	Me/Me (7b)	O	86	55	280–281	284–285^[ ^41 ^]
16	8p	C6H5 (5a)	Me/Me (7b)	O	89	30	229–230	233–236^[ ^16 ^]
17	8q	4-CH3-C6H4 (5i)	ClCH2//OEt (7c)	O	90	110	164–166	—
18	8r	3-O2N-C6H4 (5f)	ClCH2//OEt (7b)	O	87	130	162–164	—
19	8s	C6H5 (5a)	ClCH2//OEt (7b)	O	84	90	174–176	—
20	8t		Me/OEt (7a)	O	91	50	196–198	—
21	8u	C6H5 (5a)	Me/Me (7c)	S	89	180	183(dec)	185(dec)^[ ^42 ^]
22	8v	C6H5 (5a)	Me/OEt (7a)	S	85	130	209–211	208–210^[ ^9 ^]
23	8w	3-NO2-C6H4 (5f)	Me/OEt (7a)	S	88	150	206–208	—
24	8x	3-OH-C6H4 (5o)	Me/OEt (7a)	S	87	52	183–184	184–186^[ ^43 ^]
25	8y	3-OH-C6H4 (5o)	Me/OEt (7a)	O	94	100	163–165	163–166^[ ^9 ^]
26	8z	n-C5H11 (5p)	Me/OEt (7a)	O	85	120	151–154	—
27	8a′	n-C4H9 (5q)	Me/OEt (7a)	S	83	180	138–140	—
28	8b′	C6H5 (5a)	Me/OCCH2Ph (7d)	S	89	165	157–159	—
29	8a	C6H5 (5a)	Me/OEt (7a)	O	98 ^c	25	204–206	202–204^[ ^37 ^]

Scheme 3 Suggested Biginelli reaction mechanism.

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