Realizing the Trifunctional Potential of Alkyl 4-Chloro-2-diazo-3-oxobutanoates: Convenient Assembly of 6,7-Dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thiazine Core

Abstract

The first example of exploiting the trifunctional character of alkyl 4-chloro-2-diazo-3-oxobutanoates in the reactions with vicinal N,S-bis-nucleophiles leading to the formation of bicyclic 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]thiazines is presented. The key to the successful realization of the atom-economical synthetic strategy is the initial S N 2 event, which facilitates the subsequent domino 1,2,3-triazole formation via the Wolff reaction. Equally important is the choice of sodium acetate as the base: acetic acid formed in the course of the initial nucleophilic substitution acts as an efficient catalyst for the Wolff reaction, which suppresses the competing, unwanted fragmentation path (observed when other bases are used).

Diazocarbonyl and Related Compounds in the Synthesis of Azoles

“…Combining the halo, keto, and diazo functions in α -diazo- β -keto- γ -haloesters 356 has a potential for constructing fused triazole systems. This potential was realized in a recent work by Krasavin and co-workers who reacted these diazo compounds with aminothiols 357 ( Scheme 88 ) [ 174 ]. Initially, halogen is substituted by a more nucleophilic thiol group so that the subsequent imine formation becomes an intramolecular reaction and requires rather mild conditions to proceed.…”

Continued Exploration of Trifunctional Alkyl 4-Chloro-2-diazo-3-oxobutanoates: Streamlined Entry into [1,2,3]Triazolo[5,1-c][1,4]benzoxazines and [1,2,3]Triazolo[5,1-c][1,4]benzoxazepines

“…tert-Butyl carbamate, 19 2-(2-nitrovinyl)phenol, 20 ethyl 4-chloro-2-diazo-3-oxobutanoate (1a), and methyl 4-chloro-2-diazo-3-oxopentanoate (1b) 5 were prepared according to literature procedures. Data for the obtained compounds were in accordance with the literature data.…”

“…the formation of bicyclic 6,7-dihydro-4H- [1,2,3]triazolo [5,1-c] [1,4]thiazines 2. 5 These reactions proceeded in good to excellent (67-96%) yields and no fragmentation of -oxo--diazocetate moiety (known to be triggered by nucleophilic primary amines 6 ) was observed. Encouraged by this initial success, we were keen to extend this methodology to other bis-nucleophilic partners such as phenols bearing an amino functionality (in a protected form to ensure the selectivity of the initital SN2 event 7 ) attached to the o-position of the phenyl ring either directly or via a 1-2 carbon linker.…”

“…o-Aminophenols (and other phenols investigated in this work) could not be directly used in the reactions with 1a,b because, under basic conditions (required to activate the phenolic substrates), the -dicarbonyl diazo reagents undergo deacetylative fragmentation, as was observed previously. 5 o-Aminophenol and its p-substituted derivatives were Boc-protected by using a literature procedure, 8 and the resulting products 4a-e were obtained in excellent yields. Doubly protected product 4f was synthesized from 2,4-diaminophenol dihydrochloride by using sodium bicarbonate as a base.…”