Ruppert’s reagent

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

A general method for the preparation of trifluoromethyl sulfides involves the utilization of trimethyl(trifluoromethyl)silane ("Ruppert s Reagent") in a reaction with disulfides 32. ... 

Trimethyltrifluoromethylsilane, which is now generally referred to as Ruppert s reagent [92], has been widely investigated [93-96] as an intermediate for transferring the trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of poly-fluoroalkyl Grignard or lithium derivatives. This approach also complements other methods for transfer of trifluoromethide ion. A variety of procedures have now been developed for the synthesis of this compound but the electrochemical procedure [93]... 

Examples of the application of Ruppert s reagent are shown in Figure 10.44, including the especially interesting diastereoselective procedures. 

Scheme 2.126 Preparation of trifluoromethyltrimethyl silane (MejSiCFj, Ruppert s Reagent). Ruppert s original method [2c] above) leads, after aqueous work-up, to the formation of stoichiometric amounts of the carcinogenic HMPA (OP(NMe2)3). In addition, ozone-depleting CFjBr is used as the starting material. A recent method beloiv), with potential for technical upscale, utilizes the inexpensive CHF, and depends on a catalytic cycle initiated by diphenyldisulfide [69].

Finally, no consideration of the chemistry of a-haloaUqtlsilanes would be complete without mention of Ruppert s reagent (58). In the presence of a source of fluoride (usually tetrabutylammonium fluoride), the reagent will deliver a trifluoromethyl group to carbonyl groups of aldehydes and ketones, esters,and a variety of other functional groups (Scheme 18). The exceptional versatility of the reagent is revealed in an excellent review from Prakash and Yudin.l ... 

The carbonyl group of oxazolidinones undergoes a clean addition of Ruppert s reagent (trifluoromethyl trimethylsilane). jhe reaction catalyzed by cesium fluoride is quantitative (Eq. 24). The cleavage of the TMS ether (see p. 148 for other silyl group removal) liberates a-amino trifluoromethyl ketones. 

Isomerizations. The isomerization of 1 to thiolactone 55 occurs in DMSO solution in the presence of NaH. It is reported that photolysis of 1 in methanol also affords 55. The reaction of 1 with (trifiuoromethyl)trimethylsilane (Ruppert s reagent) in THF in the presence of fluoride yields the trifluoromethylated thi-etane 56 (eq 23). A plausible mechanism of the transformation is a ring-opening/ring-closure process initiated by nucleophilic addition of trifluoromethanide to the carbonyl group of 1. 

Full details have been provided for the optimized preparation of (trifluo-romethyl)trimethylsilane (Ruppert s Reagent ). It acts as a nucleophilic trifluoromethide equivalent, normally under fluoride ion initiation, reacting readily with a variety of carbonyl electrophiles and related species . 

Li G, Chen Y, Missert JR, Rungta A, Dougherty TJ, Grossman ZD, Pandey RK (1999) Application of Ruppert s reagent in preparing novel perfluorinated porphyrins, chlorins and bacteriochlorins. J Chem Soc Perkin Trans 1 Org Bio-Org Chem 13 1785-1787... 

Nucleophilic Addition. The electrophilic nature of the a-position of this inner salt makes it prone to nucleophilic addition. Treatment with Ruppert s reagent (CFsSiMes) gives a 2-trifluoromethyl-dihydropyridine derivative in a 79% yield with complete regioselectivity (eq 6). This dihydropyridine intermediate can be subsequently oxidized to a 2-trifluoromethylated inner salt upon treatment with DDQ in a 60% yield. This overall process features a net 2-trifluoromethylation of the parent inner salt. 

Table 6.2 Trifluoromethylation of aldehydes with Ruppert s reagent — selected examples.

Figure 6.9 Experimental setup of the trifluor-omethylation reaction with Ruppert s reagent. Purification by various scavenger resins in flow PS-benzaldehyde (PS-CHO) for residual Ruppert s reagent, QuadraPure-SA (QP-SA ...

Although the reaction is usually conducted under homogeneous conditions, a chiral ammonium fluoride-catalyzed trifluoromethylation of carbonyl compounds should be described in this section. The catalytic asymmetric trifluoromethylation of an acetophenone derivative with Ruppert s reagent was investigated by a research group of Pfizer for process research and development of a substance-P (neuro-kini-1) receptor antagonist CJ-17,493 149 (Scheme 4.35). ° The commercially available alcohol 150 was acylated to... 

Qing reported a Cu-mediated trifluoromethylation of terminal allq nes using Ruppert s reagent as the CF3 source. Similar conditions were also used for the trifluoromethylation of heterocycles, such as oxadiazoles, benzimidazoles, benzoxazoles, benzothiazoles and indoles. Sodeoka reported trifluoromethylation of the indole C2 position using copper catalysis in conjunction with Togni s reagent. ... 

Interesting modes of reactivity for the installation of CF3 are also appearing, such as that reported by Kanai whereby the activation of pyridine AFoxides by boron Lewis acids renders them reactive to CF3 transfer from the silicate derived from Ruppert s reagent (Scheme 15.116). ... 

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