Difluoroacetaldehyde N‐Triftosylhydrazone (DFHZ‐Tfs) as a Bench‐Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

Abstract

Despite the growing importance of volatile functionalized diazoalkanes in organic synthesis, their safe generation and utilization remain a formidable challenge because of their difficult handling along with storage and security issues. In this study, we developed a bench‐stable difluoroacetaldehyde N‐triftosylhydrazone (DFHZ‐Tfs) as an operationally safe diazo surrogate that can release in situ two low‐molecular‐weight diazoalkanes, diazoacetaldehyde (CHOCHN2) or difluorodiazoethane (CF2HCHN2), in a controlled fashion under specific conditions. DFHZ‐Tfs has been successfully employed in the Fe‐catalyzed cyclopropanation and Doyle–Kirmse reactions, thus highlighting the synthetic utility of DFHZ‐Tfs in the efficient construction of molecule frameworks containing CHO or CF2H groups. Moreover, the reaction mechanism for the generation of CHOCHN2 from CF2HCHN2 was elucidated by density functional theory (DFT) calculations.

Carbodefluorination via a carbene-initiated rearrangement strategy

“…In addition to indole-3-carbinols, indole-2-carbinols could also be employed without difficulty in this transformation, affording the corresponding products featuring an enamine motif (34)(35)(36)(37)(38), which are difficult to access with conventional methods 56,57 . Regarding the scope of N-triftosylhydrazones, an array of substrates reacted smoothly with indole-3carbinol, affording the corresponding products (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56) in high yield. Functional groups such as methyl (39,40), tert-butyl (41), methoxy (42,53), trifluoromethoxy (43), phenyl (44), halogen (45-48, 51, 52), trifluoromethyl (49), and vinyl (50) were well tolerated.…”

“…1c, up). Through the formation of N-sulfonylhydrazones, fluoroalkyl ketones have recently become versatile coupling partners, especially as a source of fluoroalkyl carbene in a range of C-C bond-forming reactions [39][40][41][42][43][44][45][46][47] . We envisaged that an intramolecular rearrangement strategy could provide an advantageous route for the efficient carbodefluorination of trifluoromethyl ketones, i.e., the formation of an oxonium ylide intermediate by nucleophilic addition of β,γ-unsaturated alcohols to a fluoroalkyl metal carbene might enable a sequential C-F bond cleavage / C-C bond formation through the Claisen rearrangement of an in situ generated difluorovinyl ether intermediate (Fig.…”

Difluorodiazoethane as a masked acetylene equivalent in formal [3 + 2] cycloadditions with ketones to access 2,3-functionalized furans

“…Therefore, the preparation of structurally diverse 2,3-functionalized furans is highly desirable. In this context, leveraging on our ongoing interest in the synthesis and reaction of fluoroalkyl N-sulfonylhydrazones, 7,11 herein we describe an unprecedented reactivity mode of CF 2 HCHN 2 as acetylene equivalent in the [3 + 2] cycloaddition of difluoroacetaldehyde N-tosylhydrazone (DFHZ-Ts) with enolates of β-ketones under mild conditions (Fig. 1c).…”

“…Nevertheless, its safe generation and utilization remain challenging 3,5e,i,j until we developed difluoroacetaldehyde N-triftosylhydrazones (DFHZ-Tfs) as an operationally safe and bench-stable diazo precursor for the in situ formation of CF 2 HCHN 2 under basic conditions. 7 Notably, we achieved a base-mediated defluorination of CF 2 HCHN 2 into diazoacetaldehyde (CHOCHN 2 ) under aqueous conditions (Fig. 1B, top).…”