The work described herein employs potassium hydroxide impregnated alumina (KOH-alumina) as a mild, efficient, and recyclable catalyst for a one-pot solvent-free and environmentally safer synthesis of 3,4,6-triarylpyridazines and some substituted pyridazines from active methylene carbonyl species, 1,2-dicarbonyls, and hydrazine hydrate by microwave (MW) irradiation. The method offers highly convergent, inexpensive, and functionality-tolerable procedure for rapid access to important pyridazine compounds in good yields.
Pyridazines have received considerable attention because of their important pharmacological and biological properties [
The synthesis of pyridazine frameworks has been achieved primarily by the addition of hydrazine or its derivative to an appropriate 1,4-diketones and 1,4-ketoacids [
To address the challenge of green synthesis, multicomponent reactions (MCRs) provide a solution since they are more efficient, cost effective, and less wasteful than traditional methods. Such synthetic approach, however, when teamed with microwave (MW) irradiation, facilitates the reaction better as MW gives very efficient thermal management and atom efficiency thus resulting in faster reaction with an increased product yield. In another development, in recent years, the use of inorganic solid supports as catalysts for the synthesis of various biologically active molecules has increased tremendously. Among these inorganic solid supports, potassium hydroxide coated with alumina (KOH-alumina) has been a versatile reagent for various reactions and transformations such as in transesterification and biodiesel production [
Therefore, based on our previous work on pyridazine synthesis [
One-pot synthesis of substituted pyridazines.
Initially, the three-component synthesis was optimized by irradiating a mixture of acetophenone (
Optimization of the reaction condition and the catalyst recyclability with compound
Entry | Reaction conditions | Time (min) | Yield (%)a |
---|---|---|---|
1 | KOH-alumina (5 mol%) | 3 | 57 |
2 | KOH-alumina (5 mol%) | 10 | 64 |
3 | KOH-alumina (10 mol%) | 2 | 60 |
4 | KOH-alumina (10 mol%) | 4 | 72 |
5 | KOH-alumina (10 mol%) | 6 | 89 |
6 | KOH-alumina (10 mol%) | 8 | 88 |
7 | KOH-alumina (recycled once) | 15 | 61 |
8 | KOH-alumina (recycled twice) | 18 | 30 |
9 | KOH-alumina (recycled three times) | 22 | 27 |
aIsolated yields.
Thus, the present method was employed for the synthesis of a series of 3,4,5-triarylpyridazines involving different aromatic ketones (
KOH-alumina (10 mol%) catalyzed solvent-free synthesis of substituted pyridazines under microwave (MW) irradiation.
Entry | Substrate | Substrate | Product | Time (min) | Yield (%)a | M.p. (°C)c |
---|---|---|---|---|---|---|
1 | R3 = C6H5 | R1 = R2 = C6H5 | 6 | 89 | 182–184[ | |
2 | R3 = 4-CH3C6H4 | R1 = R2 = C6H5 | 5 | 86 | 160–162[ | |
3 | R3 = 2-CH3OC6H4 | R1 = R2 = C6H5 | 10 | 76 | 137–139 | |
4 | R3 = 4-CH3OC6H4 | R1 = R2 = C6H5 | 8 | 85b | 164–166[ | |
5 | R3 = 4-BrC6H4 | R1 = R2 = C6H5 | 8 | 81 | 147–149[ | |
6 | R3 = 4-ClC6H4 | R1 = R2 = C6H5 | 6 | 76 | 179–181[ | |
7 | R3 = 4-NO2C6H4 | R1 = R2 = C6H5 | 6 | 73b | 164–166[ | |
8 | R3 = | R1 = R2 = C6H5 | 8 | 77b | 190–192[ |
aSolated yield. bPurified by column chromatography. cLiterature references.
Similarly, the scope of this methodology was extended to synthesize other substituted pyridazines involving different active methylene carbonyl compounds such as ethyl cyano acetate (
KOH-alumina (10 mol%) catalyzed solvent-free synthesis of substituted pyridazines under microwave (MW) irradiation.
Entry | Substrate | Substrate | Product | Time (min) | Yield (%)a | M.p. (°C)c |
---|---|---|---|---|---|---|
1 | R4 = CN, | R1 = R2 = C6H5 | 8 | 81 | 270–272[ | |
R5 = COOC2H5 ( | ||||||
2 | ( | R1 = R2 = H | 8 | 76b | 182–184[ | |
3 | ( | R1 = R2 = CH3 | 8 | 87 | 209–211[ | |
4 | R4 = R5 = COOC2H5 ( | R1 = R2 = C6H5 | 8 | 82 | 217–219[ | |
5 | R4 = COOC2H5, | R1 = R2 = C6H5 | 8 | 86 | 77–79[ | |
R5 = COCH3 ( | ||||||
6 | R4 = R5 = COCH3 ( | R1 = R2 = C6H5 | 8 | 79 | 132–134[ |
aIsolated yield. bPurified by column chromatography. cLiterature references.
One-pot synthesis of substituted pyridazines.
The reactions were clean and all the products were purified by simple work-up and crystallization except for products
From the mechanistic point of view, the formation of the triarlpyridazines
Plausible mechanism for the formation of substituted pyridazines.
In summary, we have established a mild and efficient method for the synthesis of highly functionalized substituted pyridazines and other substituted pyridazinones using KOH-alumina (10 mol%). More importantly, the methodology presented here offers milder, more efficient, and particularly an environmentally friendly approach towards the synthesis of pyridazines by the use of potassium hydroxide impregnated on alumina as a recyclable catalyst.
All the chemicals obtained commercially were directly used without further purification. KOH-alumina was prepared according to the procedure reported by Sukata [
A thoroughly mixed aromatic ketone (
A thoroughly mixed 1,2-dicarbonyl compound (
White solid; mp 182–184°C; 1H NMR (400 MHz, CDCl3):
Light yellow solid; mp 160–162°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 137–139°C; 1H NMR (400 MHz, CDCl3):
Yellow solid; mp 164–166°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 147–149°C; 1H NMR (400 MHz, CDCl3):
Light yellow solid; mp 179–181°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 164–166°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 190–192°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 270–272°C; 1H NMR (400 MHz, CDCl3 + DMSO-
White solid; mp 182–184°C; 1H NMR (400 MHz, CDCl3 + DMSO-
White solid; mp 209–211°C; 1H NMR (400 MHz, CDCl3 + DMSO-
White solid; mp 217–219°C; 1H NMR (400 MHz, CDCl3):
White solid; mp 77–79°C; 1H NMR (400 MHz, CDCl3 + DMSO-
White solid; mp 132–134°C; 1H NMR (400 MHz, CDCl3):
H. Mecadon thanks the University Grants Commission (UGC), India for the Financial Assistance under the RGNF scheme, and the SAIF, NEHU for the data analyses.