Organic synthesis reactions involving inorganic substances such as potassium carbonate or potassium phosphate

Organic synthesis reactions involving inorganic substances such as potassium carbonate or potassium phosphate often do not use ethyl acetate or isopropyl acetate as solvents. Ketones, acetonitrile and amide solvents are commonly used. If toluene, ethyl acetate, etc. are used as solvents, a phase transfer catalyst is often required.

What if a phase transfer catalyst is not added? The following two cases illustrate special treatment during special periods. If the stability of ethyl acetate is not very satisfactory, isopropyl acetate can be used.

Case 1

Condensation reaction of sulfonamide and carboxyl groups under CDI conditions

• Based on CDI, the solvent and base were optimized. The classical DBU conditions did not react well, but the inorganic base gave good results.
• Among them, potassium phosphate with weaker alkalinity has the best effect, and finally the potassium phosphate/isopropyl acetate conditions were confirmed.
• For CDI reactions, ethyl acetate is often used as the solvent, but organic bases are generally used. The data in the table below are better with inorganic bases. The results of ethyl acetate and isopropyl acetate are similar, and the latter is selected from the perspective of stability

References

Org. Processing Res. Dev. 2019, 23, 1829 − 1840

Case 2

SN2 reaction selectivity of imidazole

• Compound 7 and Compound 8 prepare Compound 9

• 1.0eq. LiHMDS was initially used as a base with poor positional selectivity 85/15 (entry 1)
• Comparing a series of organic and inorganic bases, the data show that inorganic bases have better position selectivity than organic bases. Among them, the reaction of potassium phosphate and potassium carbonate has better conversion and position selectivity.
• Using THF as a solvent, potassium phosphate as a base has good positional selectivity, but poor optical selectivity (entry 7)
• Using potassium carbonate as a base, the effects of different solvents on optical selectivity were compared, among which ethyl acetate (entry 18) with relatively small polarity was very effective, with a position selectivity of 96/4 and an optical selectivity of 97/3.

Zoom in on the data as shown below:

• Ethyl acetate, potassium carbonate system, size 5.6kg, yield 98%, optical selectivity 97/3

• Further enlargement, using potassium phosphate instead of potassium carbonate, or ethyl acetate as solvent, better optical selectivity, 98/2. Size 20kg, lower yield.

References

Org. Process Res. Dev. 2012, 16, 1635 − 1645