How to Reach Stereogenic Trifluoromethylated Carbon? En Route to the “Grail” of the Asymmetric Trifluoromethylation Reaction

Abstract

The importance of trifluoromethylated molecules has undergone regular growth during the last years, and asymmetric molecules with the CF3 group borne by a chiral carbon have become more popular. However, methods used to achieve such molecules are still limited. The building block strategy has been the method most employed these last years and stereocontrolled trifluoromethylation reactions have begun to emerge as potential valuable alternatives. Trifluoromethylation of chiral molecules, by using diastereoselective induction, seems promising and already gives good results in certain cases. However, although actively studied to this day, the enantioselective trifluoromethylation of prochiral compounds is still not very efficient even if some interesting results have been already described. Nevertheless, such reactions still present a challenge in terms of efficiency. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis of trifluoromethyl alcohols from tert-butoxy-β-(trifluoromethyl)styrenes and trifluoromethylbenzyl ketones under the conditions of the Leuckart–Wallach reaction

“…For example enantiopure trifluoromethyl alcohols are versatile intermediates for the synthesis of antiferroelectric liquid crystalline molecules [20,21] and recently trifluoromethylated GABA [22] and mevalonate analogues [23] were prepared. Similar trifluoromethyl alcohols were previously prepared by nucleophilic trifluoromethylation of the corresponding aldehydes using Rupert's reagent [24][25][26] or analogues [27,28]. However, most variations of the Rupert-Prakash reaction have a common drawback: frequently low yields were obtained with enolizable carbonyl compounds [29].…”

Regioselective 1,4-trifluoromethylation of α,β-unsaturated ketones via a S-(trifluoromethyl)diphenylsulfonium salts/copper system

“…One of the challenges in synthetic organic chemistry is the nucleophilic 1,4-addition of the trifluoromethyl (CF 3 ) group into electron-deficient internal alkenes as represented by the Michael addition reaction, even in a racemic, non-stereoselective fashion [1–5]. The nucleophilic trifluoromethylation to conjugated alkenes essentially occurs solely via a 1,2-addition [1–11], not a 1,4-addition (Scheme 1), with the exception of non-general examples of 1,4-additive trifluoromethylation of (trifluoromethyl)trimethylsilane (Me 3 SiCF 3 , Ruppert–Prakash reagent) to very specific substrates such as trans -1-benzoyl-2-(dimethylamino)ethylene [12], 2-polyfluoroalkylchromones [13–14], isoxazoles with a nitro group at the 4-position [15], and Morita–Baylis–Hillman adducts (via S N 2’ [16] or successive S N 2’/S N 2’ mode [17]).…”

Palladium‐Catalyzed Suzuki–Miyaura Cross‐Coupling of Secondary α‐(Trifluoromethyl)benzyl Tosylates

“…[1] In this context, the ability to generate stereogenic centers with at rifluoromethyl substituent in as elective fashion is an important goal. [2] Them ajority of existing methods are based around the addition of the Ruppert-Prakash reagent to aldehydes and imines. [3] An alternative approach has been the desymmetrization of prochiral trifluoromethylated building blocks, [4] an advantage of this method being that the construction of aC (sp 3 )ÀCF 3 bond, which is often an on-trivial undertaking,c an be avoided.…”

“…Fors ubstrate (À)-1a (> 99:1 e.r. ), with 20 mol %NaBAr F 4 ,the loading of Pd(dba) 2 and XPhos could be decreased to 0.2 mol %and 0.4 mol %, respectively,togive 2a in 92 %yield and 96:4 e.r. Using ahigher catalyst loading of Pd(dba) 2 (1.5 mol %) and XPhos (3 mol %), 2a was obtained in 90 %y ield but in 86:14 e.r.,s uggesting that the loss in stereochemical integrity may be due to isomerization of the initially formed Pd II intermediate by aPd 0 species.…”