The Reactivity of Difluorocarbene with Hydroxylamines: Synthesis of Carbamoyl Fluorides

Abstract

Carbamoyl fluorides are formed in reactions of hydroxylamines with difluorocarbene generated from sodium bromodifluoroacetate as readily available andn on-toxic carbene precursor. The process showsahigh functional group tolerance, and the reactionp ath hasb een rationalized by computational calculations.[a] Reaction conditions:N ,N-dibenzylhydroxylamine (1a, 0.25 mmol) and BrCF 2 CO 2 Na (D,0.50 mmol) in DMF. [b] Addition of K 2 CO 3 (2 equiv.).Scheme 3. Formation of 9 from sodium bromodifluoroacetate (D)a nd N,N-dibenzylhydroxylamine( 1a)( relative free energies to D and 1a in kcal mol À1 ).

Facile Access to AgOCF3 and Its New Applications as a Reservoir for OCF2 for the Direct Synthesis of N−CF3, Aryl or Alkyl Carbamoyl Fluorides

“…Such compounds, in turn, have shown activities and applications as insecticides or esterase inhibitors, and serve as valuable intermediates in the synthesis of unsymmetrical, disubstituted carbonyl compounds. Although traditional synthetic approaches involve highly toxic and gaseous reagents, there have recently been elegant advances involving the direct conversion of amines with CO 2 and a deoxyfluorination reagent, or using difluorocarbenes . Pleasingly, the subjection of secondary amine 8 a to AgOCF 3 along with the base (DIPEA) at room temperature gave the corresponding carbamoyl fluorides within 2 h reaction time.…”

“…Althought raditional synthetic approaches involveh ighly toxic and gaseous reagents, [12] there have recently been elegant advances involving the direct conversion of amines with CO 2 and ad eoxyfluorination reagent, [13] or using difluorocarbenes. [14] Pleasingly,t he subjection of secondary amine 8a to AgOCF 3 along with the base (DIPEA) at room temperature gave the corresponding carbamoyl fluorides within 2h reaction time. We exploredanumber of examples, electron-rich, deficient and heterocyclic (8c)a mines as well as drug derivative 8g and the Boc-protected amine (8d), and all generated the corresponding carbamoyl fluorides in high yields (see Figure 3C)w ithouta ny formation of double addition products.…”

Modern synthesis of carbamoyl fluorides

“…The desired compounds are obtained in moderate to very good yields. 21 Herein, the key to success is the in situ formation of the difluorocarbene able to react with hydroxylamines. DFT calculations were performed in order to rationalize the reaction mechanism.…”

An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F‐Labeled α‐SCF3 Carbonyl Compounds

“…[1] As a singlet carbene [2] and the most stable dihalocarbene, [1d] difluorocarbene shows moderate electrophilicity due to both strong inductive effect and electron-donating resonance effect induced by fluorine. The understanding of its reactivity has led to a variety of novel organic transformations, [1] including difluoromethylation, [3] trifluoromethylation, [4] and [2+1] cycloaddition [3a] .…”

“…[1] As a singlet carbene [2] and the most stable dihalocarbene, [1d] difluorocarbene shows moderate electrophilicity due to both strong inductive effect and electron-donating resonance effect induced by fluorine. The understanding of its reactivity has led to a variety of novel organic transformations, [1] including difluoromethylation, [3] trifluoromethylation, [4] and [2+1] cycloaddition [3a] . We recently discovered a difluorocarbene-derived one-step [ 18 F]trifluoromethylthiolation protocol, [5] which is one of the first examples [5–6] for [ 18 F]trifluoromethylthiolation despite the fact that significant accomplishments have been made for non-radioactive trifluoromethylthiolation.…”