Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4- d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

Brett C Bookser; Michael I Weinhouse; Aaron C Burns; Andrew N Valiere; Lino J Valdez; Pawel Stanczak; Jim Na; Arnold L Rheingold; Curtis E Moore; Brian Dyck

doi:10.1021/acs.joc.8b00540

Solvent-Controlled, Site-Selective N-Alkylation Reactions of Azolo-Fused Ring Heterocycles at N1-, N2-, and N3-Positions, Including Pyrazolo[3,4- d]pyrimidines, Purines, [1,2,3]Triazolo[4,5]pyridines, and Related Deaza-Compounds

J Org Chem. 2018 Jun 15;83(12):6334-6353. doi: 10.1021/acs.joc.8b00540. Epub 2018 Jun 6.

Authors

Brett C Bookser, Michael I Weinhouse, Aaron C Burns, Andrew N Valiere, Lino J Valdez, Pawel Stanczak, Jim Na, Arnold L Rheingold¹, Curtis E Moore¹, Brian Dyck

Affiliation

¹ Department of Chemistry, Crystallography Laboratory , University of California, San Diego , Urey Hall 5128, mail code 0358, 9500 Gilman Drive , La Jolla , California 92093-0358 , United States.

PMID: 29790748
DOI: 10.1021/acs.joc.8b00540

Abstract

Alkylation of 4-methoxy-1 H-pyrazolo[3,4- d]pyrimidine (1b) with iodomethane in THF using NaHMDS as base selectively provided N2-methyl product 4-methoxy-2-methyl-2 H-pyrazolo[3,4- d]pyrimidine (3b) in an 8/1 ratio over N1-methyl product (2b). Interestingly, conducting the reaction in DMSO reversed selectivity to provide a 4/1 ratio of N1/N2 methylated products. Crystal structures of product 3b with N1 and N7 coordinated to sodium indicated a potential role for the latter reinforcing the N2-selectivity. Limits of selectivity were tested with 26 heterocycles which revealed that N7 was a controlling element directing alkylations to favor N2 for pyrazolo- and N3 for imidazo- and triazolo-fused ring heterocycles when conducted in THF. Use of ¹H-detected pulsed field gradient-stimulated echo (PFG-STE) NMR defined the molecular weights of ionic reactive complexes. This data and DFT charge distribution calculations suggest close ion pairs (CIPs) or tight ion pairs (TIPs) control alkylation selectivity in THF and solvent-separated ion pairs (SIPs) are the reactive species in DMSO.