Directed Lithiation of Protected 4-Chloropyrrolopyrimidine: Addition to Aldehydes and Ketones Aided by Bis(2-dimethylaminoethyl)ether

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route to new building blocks for medicinal chemistry. It was found that bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. Deuterium oxide quench experiments showed that this additive offered both a higher degree of lithiation and increased stability of the lithiated intermediate. The substrate scope of the protocol was investigated with 16 aldehydes and ketones, revealing the method to be excellently suited for reaction with aldehydes, cyclohexanone derivatives and 2,2,2-trifluoroacetophenone, while being less efficient for acetophenones. Yields in the range of 46-93% were obtained.

Automated summary

Lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine was investigated as a route to new building blocks for medicinal chemistry. The use of bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. The protocol showed good compatibility with aldehydes, cyclohexanone derivatives, and 2,2,2-trifluoroacetophenone, but was less efficient for acetophenones, with yields ranging from 46-93%.