Ethyl 2‐(tert‐Butoxycarbonyloxyimino)‐2‐cyanoacetate (Boc‐Oxyma): An Efficient Reagent for the Racemization Free Synthesis of Ureas, Carbamates and Thiocarbamates via Lossen Rearrangement

Abstract

Boc-Oxyma (Ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate) has been reported previously as an efficient coupling reagent for the synthesis of amides, peptides, esters, thioesters and hydroxamic acids. It is known for its excellent racemization suppression capability, and also as an environment friendly reagent as it generates only Oxyma as solid byproduct that can be recovered easily and recycled for the synthesis of the same reagent. In this update, we report a simple, efficient, environment friendly, chemoselective and racemization free method for the synthesis of ureas, carbamates and thiocarbamates from hydroxamic acids via Lossen rearrangement by using Boc-Oxyma. We have achieved racemization free di-and tripeptidyl ureas with very good yield by using this protocol. A rigorous mechanistic investigation is also incorporated.

Supporting-Electrolyte-Free Anodic Oxidation of Oxamic Acids into Isocyanates: An Expedient Way to Access Ureas, Carbamates, and Thiocarbamates

“…For instance, the use of an alkaline solution of bromine in the Hofmann rearrangement and the formation of potentially explosive azides in the Curtius rearrangement limit their use for large-scale synthesis . As an alternative, the Lossen rearrangement provides access to isocyanates under relatively mild conditions but still requires the synthesis of a potentially unstable hydroxamic acid. , Some recent developments using dehydrating agents, such as carbonyldiimidazole (CDI), and activating reagents, such as dimethyl carbonate (DMC), have received particular attention (Figure ). Additional developments, such as amine carboxylation using CO 2 as the carbon source, − reductive carboxylation of nitroaromatics, and carbamate metathesis, have emerged. − However, these methods still suffer from the limited availability and stability of the commercial starting materials, metal catalysts, and toxic gas reagents, which could be disfavored by industries.…”

Benign synthesis of unsymmetrical arylurea derivatives using 3-substituted dioxazolones as isocyanate surrogates

“…Importantly, this conventional synthesis is found to be inefficient toward the preparation of unsymmetrical substituted ureas regarding the formation of symmetrical urea side products (1,12). To overcome these limitations, practical and greener routes for the synthesis of unsymmetrical N, N'-substituted ureas have been explored focusing on the in situ generations of isocyanate intermediates from various precursors such as carboxylic acid/acid chloride (via Curtius rearrangement) (13)(14)(15)(16)(17), amide (via Hofmann rearrangement) (18,19), hydroxamic acid (via Lossen rearrangement) (20)(21)(22)(23)(24)(25), formamide (26), carbamic acid (27,28), carbamate (29)(30)(31)(32)(33), N-carbamoylimidazolide (34,35), acetoacetanilide (36,37), and isocyanide (38)(39)(40) (Scheme 2(b)). These synthetic methodologies work efficiently for the synthesis of unsymmetrical monoaryl substituted ureas.…”

Visible-Light-Enabled Construction of Thiocarbamates from Isocyanides, Thiols, and Water at Room Temperature

“…As an important class of organosulfur compounds, thiocarbamates are ubiquitously found in various pharmaceutical molecules that possess a broad spectrum of biological properties such as antiviral, fungicidal, bactericidal, anesthetic, herbicidal, and pesticidal activities. Owing to their important biological activity and pharmacological value, thiocarbamates have attracted much attention from chemists in both academic and industrial communities. − Generally, thiocarbamates are prepared by the reaction of carbamoyl chlorides with thiols in the presence of base (Scheme a), the reaction of alkyl chlorothioformate (RSCOCl) with amines (Scheme a), the nucleophilic addition of thiols to isocyanates, and the reactions of amines, thiols with phosgene derived carbonyldiimidazoles, and di- tert -butyl dicarbonate . Alternative methods for construction of thiocarbamates through direct carbonylation of amines with carbon monoxide (CO) and RSSR or S 8 /RX have also been developed (Scheme b) .…”

“…For example, Lee developed a one-pot synthesis of thiocarbamates from CBZ­(Boc)-protected amines and thiophenols . Mandal and co-workers described Boc-Oxyma mediated synthesis of thiocarbamates from hydroxamic acids via Lossen rearrangement . Tang presented the thiocarbamation of imidazopyridines with carbamoyl chloride and elemental sulfur leading to imidazopyridines-thiocarbamates .…”