Optimisation of reaction conditions for the asymmetric Biginelli reaction of 4-nitrobenzaldehyde, thiourea, and ethyl acetoacetate^a.

Entry	Catalyst loading [mol%]	Solvent	Conversionb [%]	ee [%]
1	10	Toluene	99	92
2	10	CPME	99 (98) d	92
3	10	NBP	NR	—
4	10	GVL	NR	—
5	10	2-MeTHF	40	—
6c	10	scCO2	NR	—
7	10	Neat	91	46

^aReaction conditions: 3a (0.03 mmol), thiourea (1.2 equiv.), ethyl acetoacetate (3 equiv.), (S)-3,3′-bis(triphenylsilyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate, solvent (0.1 M), 60 hours at 50 °C.

^bConversion was determined by LC-MS analysis of the reaction mixture; entries were performed in duplicate.

^cReaction conditions: stirred for 60 hours under 80 bars of CO₂ at 50 °C.

^dIsolated yield.