Regiospecific N9 alkylation of 6-(heteroaryl)purines: shielding of N7 by a proximal heteroaryl C-H1.
Purine alkylations have been plagued with formation of mixtures of N9 (usually desired), N7, and other regioisomers. We have developed methods for synthesis of 6-(azolyl)purine derivatives whose X-ray crystal structures show essentially coplanar conformations of the linked azole-purine rings. Such ring orientations position the C-H of the azole above N7 of the purine, which results in protection of N7 from alkylating agents. Treatment of 6-(2-butylimidazol-1-yl)-2-chloropurine (9) with sodium hydride in DMF followed by addition of ethyl iodide resulted in exclusive formation of 6-(2-butylimidazol-1-yl)-2-chloro-9-ethylpurine (10), whereas identical treatment of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (11) produced a regioisomeric mixture 12/13 (N9/N7, approximately 5:1). The linked imidazole and purine rings are coplanar in 9 (the butyl side chain is extended away from the purine ring and C-H is over N7) but are rotated approximately 57 degrees in 11, and the more bulky azole substituent in 11 did not prevent formation of the minor N7 regioisomer 13. Access to various regioisomerically pure 9-alkylpurines is now readily available.
Zhong
Minghong
M
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Robins
Morris J
MJ
D000478:Alkylation; D007093:Imidazoles / Q000138:chemical synthesis*; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
C522028:6-(2-butylimidazol-1-yl)-2-chloro-9-ethylpurine; D007093:Imidazoles; D011687:Purines