Gram-Scale Preparation of Acyl Fluorides and Their Reactions with Hindered Nucleophiles

Abstract

A series of acyl fluorides was synthesized at 100 mmol scale using phase transfer catalyzed halogen exchange between acyl chlorides and aqueous bifluoride solution. The convenient procedure consists of vigorous stirring of the biphasic mixture at rt, followed by extraction and distillation. Isolated acyl fluorides (usually 7 g to 20 g) display excellent purity, and can be transformed into sterically hindered amides and esters, when treated with lithium amide bases and alkoxides under mild conditions.

Synthetic Advantages of Defluorinative C−F Bond Functionalization

“…The small size of fluorine enables acylation of hindered nucleophiles, especially anionic O ‐ and N ‐species as illustrated in Scheme 12a. Bulky lithium amides react with acyl fluorides to generate sterically‐hindered amides; in contrast, acyl chlorides exhibit lower yields and undergo aromatic metalation side reactions, as reported by the Barbasiewicz Group [59] . Similarly, acyl fluorides are often uniquely effective for challenging O ‐acylation reactions with complex alkoxides, a feature frequently exploited in natural product synthesis as exemplified by Fürstner and co‐workers’ synthesis of aspercyclides ( 63 ) [60] .…”

“…Bulky lithium amides react with acyl fluorides to generate sterically-hindered amides; in contrast, acyl chlorides exhibit lower yields and undergo aromatic metalation side reactions, as reported by the Barbasiewicz Group. [59] Similarly, acyl fluorides are often uniquely effective for challenging O-acylation reactions with complex alkoxides, a feature frequently exploited in natural product synthesis as exemplified by Fürstner and co-workers' synthesis of aspercyclides (63). [60] It should also be noted that acyl fluorides typically undergo selective O-acylation of enolates over competing C-acylation.…”

Copper-catalyzed synthesis of primary amides through reductive N–O cleavage of dioxazolones

“…6–8 Several conventional strategies for the preparation of primary amides rely on the use of readily available carboxylic acid sources, ammonia treatment, activating agents such as thionyl chloride and oxalyl chloride, peptide-coupling agents, and phosphine-fluoride reagent system (Scheme 1A). 9–15 Moreover, catalytic hydration of organic nitriles has been explored to avoid undesired hydrolysis to carboxylic acids using transition metal catalysts such as cobalt, ruthenium, palladium, rhodium, and platinum. 16–18 However, these approaches are challenging because of their low functional group tolerance under harsh reaction conditions and reduced sustainability, which can produce toxic chemicals that may negatively impact environmental systems.…”

Are β-Lactones Involved in Carbon-Based Olefination Reactions?

“…Inspired by reactivity of sulfonate precursors used in the Hawkins olefination, 4b we chose derivatives of nonanoic, isobutyric, phenylacetic, and malonic acids, as examples of nonstabilized, semistabilized, and stabilized enolate precursors. For esterifications of acid chlorides, 24 we used fluorinated alcohols: 2,2,2-trifluoroethanol (TFE; p K a = 12.4), 1,1,1,3,3,3-hexafluoroisopropanol (HFIP; p K a = 9.3), and perfluoro- tert -butanol (PFTB; p K a = 5.4). 25 These alcohols were expected to form activated esters (more electrophilic than esters of simple alkanols), 4a combining stability of the enolates with reactivity in acyl substitution reactions.…”