A New, Mild, and Efficient Synthesis of 2,2-Difluoro-3-hydroxyacids through a Selective Haloform Reaction

Abstract

[reaction: see text] Long-chain 2,2-difluoro-3-hydroxyacids have been synthesized in a new, straightforward manner by treatment of 4-hydroxy-1,1,1,3,3-pentafluoroalkyl ketones, easily obtained by reaction of pentafluoroenolate 2 with aldehydes and ketones, with base under mild conditions. The reaction sequence is marked by the selective cleavage of the CO-CF3 bond, as well as the absence of products arising from the alternative CO-CF2R bond cleavage. The process represents a convenient approach for the synthesis of 2,2-difluoro-3-hydroxyacids, as it is short, provides good to excellent yields under mild conditions, and uses hexafluoro-2-propanol, a very cheap reagent, as the fluorine source.

Catalytic Enantioselective Difluoroalkylation of Aldehydes

“…Importantly, this method tolerates the presence of amines, ketones, esters and other functional groups ( Table 1, entries 10-12 and 15), and the reaction with sterically hindered aldehydes gave 19 and 20 with 79-85 % yield and 84-87 % ee (Table 1, entries 13 and 14). Finally, the copper-catalyzed aldol reaction between the 2-naphthylsubstituted geminal diol and various aldehydes, including enolizable substrates such as cyclohexanecarboxaldehyde and 3-phenylpropionaldehyde, gave 24-28 in up to 94 % yield and 88 % ee (Table 1, entries [18][19][20][21][22].…”

“…[20] For example, the reduction of 8 with DIBAL produces anti-29 in high yields and with excellent diastereoselectivity (Scheme 3). [21] Oxidation of 25 with m-CPBA to the corresponding 2-naphthoate 30 and basic hydrolysis gave 2,2difluoro-3-hydroxy acid 31 in 85 % yield and 86 % ee. Alternatively, we realized that the Baeyer-Villiger oxidation followed by mild hydrolysis affords the first asymmetric route to 2,2-difluoro-3-hydroxy carboxylic acids, which are crucial precursors of several enzyme inhibitors and other biologically active compounds.…”

Katalytische enantioselektive Difluoralkylierung von Aldehyden

“…Mit dem neuen Liganden L14 waren wir daher in der Lage, die Katalysatorbeladung auf 5 Mol-% zu reduzieren, und wir erhielten das Aldolprodukt 2 und die analogen Verbindungen 8-10 in bis zu 98 % Ausbeute und 92 % ee, wenn mit 1.2 ¾quivalenten Benzaldehyd bei 10 8C gearbeitet wurde (Tabelle 1, Nr. [18][19][20][21][22] Die hier beschriebene Aldolreaktion ermçglicht einen einzigartigen Zugang zu wichtigen chiralen Bausteinen, einschließlich 2,2-Difluor-1,3-propanolen. [19] Im Anschluss testeten wir eine Reihe von Aldehyden, um den Anwendungsbereich der Reaktion zu bestimmen.…”

“…Im Allgemeinen wurden hohe Ausbeuten und Enantiomerenüberschüsse mit elektronreichen und elektronenarmen Substraten erhalten (Tabelle 1, Nr. [21] Die Oxidation von 25 mit m-CPBA zum entsprechenden 2-Naphthoat 30 und alkalische Hydrolyse ergab 2,2-Difluor-3-hydroxycarbonsäure 31 in 85 % Ausbeute und 86 % ee. Von Bedeutung ist, dass unsere Methode die Gegenwart von Aminen, Ketonen, Estern und anderen Funktionsgruppen toleriert (Nr.…”

Novel synthesis of primary arylamides from aryl methyl ketone oxidations using iodine in aqueous ammonia

“…8 These precedents motivated us to explore alternative routes to prepare amides from less expensive materials using mild conditions. In connection with other synthetic studies, we were attracted by the reports of Fang [9][10] and Talukdar 11 about the transformation of aldehydes to nitriles and amides, and we decided to apply these reactions in addition with other previous haloform reaction reports [12][13][14][15][16] to the synthesis of primary amides from methyl ketones. This report describes our successful endeavors in this area.…”