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

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 H-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.

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

“…Working towards the synthesis of a library of novel 1,3-disubstituted indazole derivatives necessitated us to develop a regioselective method that would permit the installation of a wide variety of alkyl sidechains at the N -1 position of methyl ester 9 ( Table 1 ). Considering the reported influence of the reaction solvent and/or base on the regiochemical outcome of indazole N -alkylation [ 17 , 21 – 22 24 ], our initial efforts focused on examining the effect of varying these reaction parameters, using n -pentyl bromide as the prototypical N -alkylating reagent ( Table 1 ).…”

“…Furthermore, employing toluene or 1,4-dioxane as the reaction solvent failed to provide regioisomer 10 or 11 ( Table 1 , entries 13 and 14). The latter observation may be due to the restricted solubility of Cs 2 CO 3 in toluene and 1,4-dioxane [ 24 ] . Using K 2 CO 3 in MeCN, Longworth et al have obtained 10 with a similar degree of N -1 regioselectivity (ratio N -1: N -2 = 2.8:1) [ 26 ].…”

“…Apart from the 1 H -indazole scaffold [ 36 – 37 ], the steric influence of adjacent substituent(s) on N -alkylation regioselectivity has previously been described for other nitrogen-containing heterocycles, such as pyrazole [ 38 ], purine, and related 1,3-azoles [ 39 ]. Although the N -alkylation of indazole 12, using conditions A (NaH in THF), proceeded with poor regioselectivity (ratio N -1 ( 25 ): N -2 ( 26 ) = 1:1.3), Bookser et al have obtained a similar regioselective outcome using a combination of NaHMDS and MeI instead of NaH and n -pentyl bromide ( Table 2 , entry 1), respectively [ 24 ].…”

“…The latter observed preference for the formation of the corresponding N -1 regioisomer ( 33 , 35 , and 37 , respectively), under both conditions A and B, highlights the steric influence of the halogen C-3 substituent. Furthermore, Bookser et al have noted comparable regioselectivity with related C-3 bromo substituted N-containing heterocycles, under similar reaction conditions [ 24 ]. Marked N -1 regioselectivity was achieved with 3-nitro substituted indazole 19 , when using NaH in THF (conditions A) (ratio N -1 ( 39 ): N -2 ( 40 ) = 83:1) ( Table 2 , entry 8).…”

“…Bookser et al have investigated the N -alkylation of related bicyclic azolo-fused-ring heterocycles, including 1 H -indazole, employing NaHMDS in tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO), and observed solvent-dependent regioselectivity [ 24 ]. Mechanistic hypotheses, based on elegant experimentation, were proposed to underline the roles that tight and solvent-separated ion pairs played in the observed trend in regioselectivity [ 24 ].…”