Optimized Synthesis of 7-Azaindazole by a Diels–Alder Cascade and Associated Process Safety

Abstract

Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron demand [4ps+2ps] reactions with alkynes, they could be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-aza-indazole by a one-pot Diels-Alder cascade that starts from a pyrimidine substituted in the 2-position by an (alkynyl)hydrazone. The safety of the process and the environmental impact were thoroughly evaluated. Eventually, a selection of crosscoupling reactions of 17 was studied and allowed the introduction of carbon-and nitrogen-based nucleophiles at the C5-position in good to excellent yields.

Regio‐ and Stereoselective Hydroelementation of SF5‐Alkynes and Further Functionalizations.

“…After a short optimization, we found that the combination of NaH in DMSO was compatible with a wide variety of nucleophiles, securing a good solubility of the system, a full conversion and still a perfect regio‐ and stereoselectivity. Several nitrogen‐containing heteroaromatic compounds can easily be introduced on SF 5 ‐alkynes such as indole ( 3 ab ), benzotriazole ( 3 ad ), tetrazole ( 3 ae ), carbazole ( 3 af ), 6‐ or 7‐aza‐indazoles ( 3 ag‐h , 3 dh ) [23] with yields ranging from 43 to 73 %. In addition, the 2‐SF 5 ‐indole [21] is also a competent nucleophile in these conditions and provide compound 3 ac in 50 % yield bearing two SF 5 motifs.…”

Synthesis and Physicochemical Properties of 2-SF5-(Aza)Indoles, a New Family of SF5 Heterocycles

“…We started with differential scanning calorimetry (DSC) − analysis to gain information about the thermal tolerance threshold of our process and the thermal stability of 2-SF 5 -indoles (Figure A) . Both 2-SF 5 -indole 5a and 8 induce a strong release of energy (exothermic) when the threshold of thermal stability is reached, with enthalpies of −1180 kJ/kg with an onset above 165 °C for 5a and −1324 kJ/kg starting above 310 °C for 8 .…”

Divergent Synthesis of 6- or 7-Aza-Indazoles via Intramolecular Diels–Alder Cascade of Pyrazines

“…We then turned our attention to the reactivity of compound 7 in Diels–Alder cascades (Scheme ). Based on our previous activation strategy for pyrimidines, , we anticipated that acylation of the N7-atom from the hydrazone function with trifluoracetic anhydride should trigger a conformational switch of the side chain, bringing the 2-azadiene (the C2C5 moiety of the pyrazine ring) in close proximity to the alkynyl dienophile, thus favoring the initial [4 + 2] cycloaddition. Indeed, upon treatment of 7a by trifluoroacetic anhydride and 3-pentanone (acting as a trap for the HCN liberated during the retro-[4 + 2] step, leading to the corresponding cyanohydrin) , in THF at 60 °C for 4 h, 6-aza-indazole 8a and 7-aza-indazole 9a were produced in a 78:22 ratio (after aqueous hydrolysis).…”

“…Inspired by our recent investigations on the Diels–Alder cascade of pyrimidines, − we report herein the straightforward synthesis of 6-aza-indazoles 8 or 7-aza-indazoles 9 as the major to exclusive cycloadducts via an intramolecular Diels–Alder cascade of pyrazine 7 (Scheme C). Compared to the current state-of-the-art, this reaction sequence is characterized by mild reaction conditions and a predictable selectivity depending on the nature of the pyrazine’s substitution.…”