Question

List and justify an alternative method to synthesize your target molecule that might increase the overall efficiency of your synthesis (like higher yields of the desired target and reduction of the side products formed). The reaction is about the carboxylic acid react with primary amine to get amide product by using EDCl and Catalyst of DMAP and DMF.

Answer 1

Well, EDCI is also a good coupling reagent, can result in a good yield of product amide (also depends on the substrates i.e acid and amine which are used as starting materials).

though, instead of  EDCI coupling condition, you can perform the two-step protocol in which you can first convert the acid into acyl chloride then treat the resulted acyl chloride with the primary amine in the presence of the equivalent amount of base (usually triethylamine). This condition usually gives the product yields above 80% with no byproducts.

SOCI, DMF HNR - EIN R'AN R1OH RICI OR Oxalyl chloride, cat. DMF, CH2Cl2 0 °C, 1-4 h

The second alternative one-step protocol for this is the carrying out reaction using the T₃P as the coupling reagent. the biproduct of this rection is water-soluble and can be easily removed by aqueous workup, Also, this rection usually gives high yields of amide products when primary amines are used as the coupling partner. The reaction mechanism is given below.

+ HN2 TSP. Et N i RILNR2 + prior + H2N^R? T;P. EIN * CH2Cl R1-OH Lojo Water soluble byproduct easily removed by aqueous work up. NET Rio 08-06 ROTO 0.-250 ТАР HNR2