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

Abstract

The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding N-alkyl 1H- or 2H-indazole derivative, the efficient synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of N-1 regioselectivity.

Study of the Addition Mechanism of 1H-Indazole and Its 4-, 5-, 6-, and 7-Nitro Derivatives to Formaldehyde in Aqueous Hydrochloric Acid Solutions

“…The 13 C chemical shifts are very different in isomers 2 and 3 , a fact well known for other N -substituted indazoles. 47 , 48 The signal of C3, a singlet or a doublet with a small coupling constant, is also a useful probe to determine the position of the CH 2 OH group: 135 ppm ( 2 ) and 123 ppm ( 3 ) in average. The 15 N chemical shifts of N1 and N2 atoms are also very different for isomers 2 and 3 .…”

“Walking the nitrogen around the ring”: Chemical synthesis and spectroscopic characterization of novel 4‐, 5‐, 6‐, and 7‐azaindazole analogs of the synthetic cannabinoid receptor agonist MDMB‐PINACA

“…Preparation of the desired N ‐1‐ n ‐pentyl substituted pyrazolopyridines 47 – 50 was achieved via S N 2 alkylation of the C‐3 iodo intermediates 44 – 46 and commercially obtained 51 , using 1‐bromopentane, in the presence of cesium carbonate in N , N ‐dimethylformamide (DMF) (Table 1). 24 Although the N ‐alkylation of 44 – 46 and 51 also gave the corresponding N ‐2 substituted regioisomer ( 52 – 55 ), all 3‐iodo‐pyrazolopyridines ( 44 – 46 and 51 ) demonstrated a strong preference for the formation of the desired N ‐1 regioisomer (>threefold). Interestingly, no evidence for the presence of regioisomeric by‐products arising from the N ‐alkylation of the pyridyl N‐atom was observed.…”

“…It should be noted that apart from N ‐2 alkylated derivative 55 , the isolation of the minor N ‐2 regioisomers 52 – 54 generally required the use of PTLC, due to co‐elution with the corresponding major N ‐1 regioisomer when employing wet flash column chromatography. The regiochemical assignment of isomers 52 – 54 was confirmed through the use of 1 H‐ 13 C HMBC NMR, as described previously 24 …”

“…Following a modified procedure, 22 to a round bottom flask was added the appropriate 3‐iodo pyrazolopyridine (1 equiv.) and DMF (1 M, with respect to the appropriate aryl iodide).…”

“…Following our previous work, 25 we reasoned that 1). 24 Although the N-alkylation of such as CUMYL-CBMICA (56), AMB-FUBINACA (57), or MDMB-4en-PINACA (58) (Figure 5).…”