(Difluoromethyl)trimethylsilane

In 1990, Broicher et al. first synthesized difluoromethyltrimethylsilane using trimethylchlorosilane and bromochlorodifluoromethane in the presence of hexaethylphosphoric triamine, and then used tri-n-butyltin hydrogen reduction to generate (difluoromethyl)trimethylsilane (Figure (1) below). In 2003, Prakash et al. reacted difluoromethylphenyl sulfone with magnesium shavings and trimethylchlorosilane to generate (difluoromethyl)trimethylsilane (Figure (2) below). In 2011, Tyutyunov et al., while studying the reaction of TMSCF3 with sodium borohydride in hopes of preparing NaBH3CF3, unexpectedly discovered that the reaction could undergo reductive defluorination to generate (difluoromethyl)trimethylsilane (Figure (3) below). Currently, considering the availability of raw materials and the scalability of the reaction, the commercial preparation of (difluoromethyl)trimethylsilane reagents mainly adopts the third method mentioned above (Figure (3) below).

A direct nucleophilic difluoromethylation reagent. The nucleophilic activation of the silicon center with Lewis base initiators allows transfer of the difluoromethyl moiety to electrophiles such as aldehydes, ketones, and aldimines. The copper-mediated difluoromethylation of halides using TMSCF2H tolerates amine, ether, amide, ester, aromatic bromide, and protected alcohol functionalities in aryl iodides and occurs in high yield and stereoselectivity with vinyl iodides.

(Difluoromethyl)trimethylsilane, can be used for difluoromethylation of carbonyl compounds. Difluromethylated compounds are very useful in materials science and medicinal and agricultural chemistry.

(1) Direct bromination to prepare TMSCF2Br.

(2) Difluoromethylation of aldehydes and ketones.

(3) Difluoromethylation of aldimines.

(4) Difluoromethylation of aryl and vinyl iodides.

[1] MIKHAIL D. KOSOBOKOV. Difluoro(trimethylsilyl)acetonitrile: Synthesis and Fluoroalkylation Reactions[J]. The Journal of Organic Chemistry, 2012, 77 13: 5850-5855. DOI:10.1021/jo301094b.
[2] YANCHUAN ZHAO. Efficient and Direct Nucleophilic Difluoromethylation of Carbonyl Compounds and Imines with Me3SiCF2H at Ambient or Low Temperature[J]. Organic Letters, 2011, 13 19: 5342-5345. DOI:10.1021/ol202208b.
[3] PATRICK S. FIER  John F H. Copper-Mediated Difluoromethylation of Aryl and Vinyl Iodides[J]. Journal of the American Chemical Society, 2012, 134 12: 5524-5527. DOI:10.1021/ja301013h.