A clean procedure for the synthesis of 1,4-dihydropyridines via Hantzsch reaction in water

Figures & data

Figure 1.  A clean procedure for Hantzsch reaction in the sealed system.

Table 1. Effect of different reaction system on one-pot catalyst-free Hantzsch reaction.

Entry	Reaction system	Time (h)	Temperature (°C)	Yield (%)^a
1	Open	3.5	55–60	76
2	Open	2.0	70–75	82
3	Sealed with air	1.0	70–75	96
4	Sealed with CO2	1.0	70–75	91
5	Sealed with N2	1.0	70–75	96
6	Sealed with steam	1.0	70–75	96
^aIsolated yield.

Table 2. Effect of different solvents on one-pot catalyst-free Hantzsch reaction.^a

Entry	Solvents	Time (h)	Temperature (°C)	Yield (%)
1	Toluene	6.0	70–75	56
2	Dichloromethane	6.0	Reflux	33
3	C2H5OH	2.5	Reflux	70
4	C2H5OH/H2O	2.0	70–75	81
5	CH3OH	2.5	Reflux	71
6	CH3OH/H2O	2.0	Reflux	74
7	H2O	2.0 (1.0^b)	70–75	82 (96^b)
8	None	2.0	70–75	72
^aReaction conditions: n (aldehyde):n (β-keto esters):n (ammonium carbonate) = 1:2:1, open system.
^bSealed vessel.

Figure 2.  Recycling of filtrate in clean Hantzsch reaction.

Table 3. Effect of reaction temperature on Hantzsch reaction.

Entry	Reaction system	Temperature (°C)	Time (h)	Yield (%)^a
1	Opening	40–45	5.0	35
2	Sealed	40–45	5.0	35
3	Opening	55–60	3.5	76
4	Sealed	55–60	3.0	81
5	Opening	70–75	2.0	82
6	Sealed	70–75	1.0	96
	Opening	85–90	1.5	81
7	Sealed	85–90	1.0	96
^aIsolated yield.

Table 4. Effect of different ammonium salts on Hantzsch reaction.

Entry	Ammonium salts	Time (h)	Temperature (°C)	Yield (%)^a
1	NH4Cl	5.0	75–80	46
2	(NH4)2HSO4	5.0	75–80	42
3	NH4NO3	5.0	75–80	56
4	NH4HCO3	1.5	70–75	90
5	HCO2NH4	1.5	75–80	92
6	CH3COONH4	1.5	75–80	94
7	NH2CO2NH4	1.0	70–75	92
8	(NH4)2CO3	1.0	70–75	96
^aIsolated yield.

Table 5. Catalyst- and organic solvents-free synthesis of 1,4-dihydropyridines.

Entry	R1	R2	Compound	Time (h)	Yield (%)^a
1	4-OCH3C6H4	OEt	4a	1.0	96
2	4-CH3C6H4	OEt	4b	1.0	92
3	C6H5	OEt	4c	1.0	96
4	4-ClC6H4	OEt	4d	1.0	95
5	3-ClC6H4	OEt	4e	1.0	91
6	4-OHC6H4	OEt	4f	1.0	95
7	4-NO2C6H4	OEt	4g	1.0	96
8	3-NO2C6H4	OEt	4h	1.0	93
9	2-NO2C6H4	OEt	4i	1.5	93
10	C6H5	OMe	4j	1.0	95
11	4-CH3C6H4	OMe	4k	1.0	94
12	3-NO2C6H4	OMe	4l	1.0	95
13	n-propyl	OEt	4m	1.5	86
14	iso-propyl	OEt	4n	1.5	87
15	2-furyl	OEt	4o	1.0	93
^aIsolated yield.

short-legendScheme 1. Synthesis of 1,4-dihydropyridines via Hantzsch reaction in water.