Dialkylaminodifluorosulfinium Salts: XtalFluor-E and XtalFluor-M

Introduction

Fluorination is an important reaction in medicinal chemistry.[1] Fluorinated analogues of biomolecules frequently show increased biological power, lipidic permeability and metabolic stability. Diethylaminosulfur trifluoride (DAST) has been widely used for directly replacing a hydroxyl group by fluorine under very mild conditions.[2] [3] Nevertheless, the corrosive properties of DAST make it unsuitable for high-scale usage.

In this context, commercially available aminodifluorosulfinium salts,[4] such as XtalFluor-E (1) or XtalFluor-M (2), are efficient alternatives. These fluorinating agents are crystalline, more selective and significantly more stable[5] than Deoxo-Fluor or DAST and do not react violently with water.[6]

Reaction of DAST with tetrafluroboric acid provides, by elimination of HF, diethylaminodifluorosulfinium tetrafluoroborate 1 in excellent yield (Scheme [1]).[5]

Scheme 1

Abstracts

(A) Failure of Hydrocinnamyl Alcohol with XtalFluor-M: The reaction of hydrocinnamyl alcohol with 2 or 1 in acetonitrile provided an intractable mixture. For this reaction to proceed, the addition of exogenous sources of fluoride, such as Et3N·3HF or Et3N·2HF, was necessary.[5]
(B) Halogenation of Alcohols with XtalFluor Reagents: Reaction of primary, secondary and tertiary alcohols with 1 using Et3N·3HF as a promoter gave the fluorinated nucleophilic substitution products. The addition order was a key parameter in this reaction. To obtain good selectivity and stereochemical integrity, 1,8-diazabicycloundec-7-ene (DBU) had to be used together with the fluorination agents.[5] A mixture of fluorinated bridged biphenyl systems has been obtained from 3-hydroxyspirodienones by means of a XtalFluor-E-promoted rearrangement. When compound 2 was used instead of compound 1, substrate decomposition was observed.[6] Chlorination, bromination and iodination reaction of primary alcohols in good yield has been described using a combination of tetraethylammonium halide and XtalFluor-E.[7]
(C) Geminal Difluorination of Carbonyl Groups: L´Heureux et al. have reported the geminal difluorination of carbonyl groups of aldehydes and ketones. They demonstrated that compound 1 alone was incapable of performing such transformations.[5] [8] To obtain geminal difluorinated products, it was necessary to use a promoter and increase the temperature (e.g., CH2Cl2 or 1,2-dichloroethane at reflux).
(D) Fluorination Processes on Carbohydrate Derivatives: Fuchs and co-workers have recently reported the preparation of a fluorodisaccharide in excellent yield without side products using XtalFluor-E, thus eliminating the need for purification.[9] The effective preparation of glycosyl fluorides from thio-, seleno-, telluro- and glycosyl sulfoxides has been performed in 30 minutes by Williams and co-workers with evidence that fluoride is delivered by the tetrafluoroborate counterion [10]
(E) Enantioselective Ring Expansion of Prolinols: Direct ring expansion of N-alkyl prolinols to produce the corresponding 3-azidopiperidines in good and excellent regio-, diastereo- and enantioselectivity was achieved by using XtalFluor-E. Formation of an aziridinium intermediate which reacts with a nucleophile such as tetrabutylammonium azide (Bu4NN3) is proposed.[11]
(F) Cyclodehydration Agents: Paquin and co-workers have recently reported[12] the use of 1 as a practical cyclodehydration agent to obtain 1,3,4-oxadiazoles among other nitrogen-containing heterocycles.[13] The addition of acetic acid improved the yield and selectivity of the oxadiazole formation.
(G) Activating Agents for Carboxylic Acids: Compound 1 has proved to be an efficient coupling agent for the synthesis of amides by activation of the carboxylic acid.[14] Moreover, this reaction is carried out with primary and secondary amines in good yield without epimerization or racemization.

• References

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