An improved solvent-free synthesis of flunixin and 2-(arylamino) nicotinic acid derivatives using boric acid as catalyst

Table 1 Optimization of the reaction conditions for the synthesis of (3a)

Entry	Ratio of 1/2	Catalyst	Catalyst loading (mole %)	Solvent	Temp (°C)	Time (h)	Yield^c (%)
1	2:1	–	–	H₂O	Reflux	24	–
2	2:1	–	–	–	100	10	35
3	2:1	K₂CO₃	15	–	100	24	Trace
4	2:1	NEt₃	15	–	100	24	–
5	2:1	K₂CO₃	15	H₂O	Reflux	24	Trace
6	2:1	NEt₃	15	H₂O	Reflux	24	–
7	2:1	Fe₃O₄	15	H₂O	Reflux	24	–
8	2:1	DABCO^a	15	H₂O	Reflux	24	Trace
9	2:1	PTSA	15	H₂O	Reflux	24	65
10	2:1	H₃BO₃	15	H₂O	Reflux	24	60
11	2:1	H₃BO₃	15	EtOH	Reflux	24	40
12	2:1	H₃BO₃	15	n-Hexanol	Reflux	24	62
13	2:1	H₃BO₃	15	PEG-400^b	Reflux	24	30
14	2:1	H₃BO₃	15	DMF	Reflux	24	45
15	2:1	H₃BO₃	15	Xylene	Reflux	24	Trace
14	2:1	H₃BO₃	15	Toluene	Reflux	24	50
17	2:1	H₃BO₃	15	–	100	10	68
18	2:1	H₃BO₃	30	–	100	10	82
19	2:1	H₃BO₃	48	–	100	10	84
20	2:1	H₃BO₃	30	–	80	12	45
21	2:1	H ₃ BO ₃	30	–	120	10	90
22	2:1	H₃BO₃	30	–	150	10	90
23	2:1	PTSA	30	–	120	9	90
24	1:1	H₃BO₃	30	–	120	20	60

Reaction conditions: 2-methyl-3-trifluoromethylanilin (2 mmol), 2-chloronicotinic acid (1 mmol)
The optimum reaction conditions are in italics
^a1,4-diazabicyclo[2.2.2]octane
^bPolyethylene glycol
^cThe yields refer to the isolated product

ISSN: 2661-801X