Regiocontrolled Synthesis of 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazines

Abstract

Synthetic access to 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazines has been achieved in 3–4 steps from commercially available pyrazoles. Optimization of a protected hydroxyethyl group on N1 enabled the regiocontrolled construction of pyrazole-5-aldehydes in high yields; subsequent deprotection and reduction generated fused heterocyclic scaffolds bearing multiple substitution patterns. Moreover, the intermediate pyrazole lactols were shown to be versatile synthetic building blocks.

Glycerol‐1,2‐carbonate: A mild reagent for the N‐glycerylation of pyrazolecarboxylates

“…Cvetovich et al performed the cyclization of dimethyl 1‐(2‐hydroxyethyl)‐1 H ‐pyrazole‐3,5‐dicarboxylate with DBU in THF leading to methyl 4‐oxo‐6,7‐dihydro‐4 H ‐pyrazolo[5,1‐ c ][1,4]oxazine‐2‐carboxylate [28], and Guirado et al synthesized 3‐aryl‐5‐dichloromethyl‐1‐(2‐hydroxyethyl)‐2‐pyrazolines from dichlorovinylacetophenones and 2‐hydroxyethylhydrazine and treated the obtained pyrazolines with aqueous sodium hydroxide [29]. Furthermore, the synthesis of 6,7‐dihydro‐4 H ‐pyrazolo[5,1‐ c ][1,4]oxazines was developed from commercially available NH‐pyrazole starting with alkylation and formylation to obtain 1‐{2‐[( tert ‐butyldimethylsilyl)oxy]ethyl}‐1 H ‐pyrazole‐5‐carbaldehydes followed by one‐pot deprotection and reduction [30], while Xia et al obtained 3‐phenyl‐6,7‐dihydro‐4 H ‐pyrazolo[5,1‐ c ][1,4]oxazines through the two‐step synthesis of morpholine‐derived hydrazone intermediate formation and oxidation [31].…”

“…[29]. Furthermore, the synthesis of 6,7-dihydro-4H-pyrazolo[5,1-c] [1,4]oxazines was developed from commercially available NH-pyrazole starting with alkylation and formylation to obtain 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1H-pyrazole-5-carbaldehydes followed by one-pot deprotection and reduction [30], while Xia et al obtained 3-phenyl-6,7-dihydro-4H-pyrazolo [5,1-c] [1,4]oxazines through the two-step synthesis of morpholine-derived hydrazone intermediate formation and oxidation [31].…”

Route Design to Manufacture: Synthesis of the Heterocyclic Fragment of AZD5718 Using a Non-cryogenic Lithiation-Alkoxycarbonylation Reaction

“…Due to the symmetry of the 4-nitropyrazole, this alkylation reaction was void of regioselective problems. There are numerous methods for the site-selective metalation of nonsymmetrical pyrazoles followed by trapping with electrophiles to introduce the ester or amide functionality in the literature. − Methods to incorporate an ester functionality on the pyrazole ring were explored prior to the planned global reduction-cyclization. Treatment of pyrazole 18 with lithium diisopropylamide (LDA) in THF followed by quenching with ethyl chloroformate gave the product pyrazole 19a .…”