Cinchona trifluoromethylation

The most promising results are offered by trifluoromethyl aminoalcohols as chiral ligands (entry 10). Cinchona alkaloids in the presence of pyridine (entry 7) and cinchona-derived surfactants (entry 6), which provide an asymmetric micellar microenvironment in aqueous solvents, are also worthy of note. 

Significant progress in the substrate scope of the Pt-cinchona systems has been made in the last 5 years. Besides a-keto acids and esters, a-keto acetals, a-keto ethers, and some trifluoromethyl ketones have been shown to give high ee s. It is now possible to classify ketones concerning their suitability as substrates for the Pt-cinchona catalyst system, as depicted in Figure 18.6. Nevertheless, for the synthetic chemist, the substrate scope is still relatively narrow, and it is not expected that new important substrate classes will be found in the near future. However, the chemoselectivity of this system has not yet been exploited to its full value, and this might be a potential for future synthetically useful applications. 

Plaquevent and coworkers re-examined and sharply improved this method for a rapid access to enantioenriched P-trifluoromethyl-P-amino acid [47]. Nine cinchona-based catalysts were screened, and the best result was obtained using (DHQ)2PHAL 80. The reaction was performed starting with the p-nitrobenzyl enaminoester 81 at 80 °C and afforded the expected imine ester 82 in 90% isolated yield and 71% ee (Scheme 7.36). The authors put a special emphasis on the mechanistic aspect of the reaction using a deuterated substrate. According to the results, the deprotonation is both rate and asymmetric determining step. 

In 1994, the first enantioselective trifluoromethylation reaction was achieved with the Ruppert-Prakash reagent, TMSCF3, in the presence of the cinchona-based quaternary ammonium fluoride 140 [65]. The chiral induction can arise from the dual activation mode of the catalyst, that is, the fluoride anion acts as the nucleophilic activator of (TMS)CF3 and the chiral ammonium cation activates the carbonyl group of 141. However, the observed ee values of the obtained carbinols 142 do not exceed 51 % and decrease considerably when nonaromatic carbonyl compounds (15% ee for R1 = n-C7H15 R2 = H) are used, which implies that 7t-7t stacking interactions between the carbonyl compound and cinchoninium occur (Scheme 8.54). 

Recently, the groups of Mukaiyama [69] and Feng [70] independently demonstrated that aryl oxide anions such as phenoxide [69] or binaphthoxide [70] can be used instead of fluoride to activate (TMS)CF3 as a Lewis base. Several types of aromatic ketones and aldehydes were smoothly trifluoromethylated within a few hours in the presence of cinchona-based quaternary ammonium salts bearing an aryl oxide anion 148 or 149, affording the corresponding product in excellent yields and with moderate to high ee values (up to 87% ee) (Schemes 8.58 and 8.59). 

After this study, the employment of ammonium salts derived from Cinchona alkaloid catalysts, such as [4-(trifluoromethyl)benzyl]cinchoninium bromide (60), for the PTC conjugate addition of 2-afkyUndanones to methyl vinyl ketone was carried out in a two phase toluene/50% aqueous NaOH system yielding higher enantioselec-tivities (up to 80% ee) of the corresponding Michael adduct which is a key intermediate in drug synthesis (Scheme 2.33) [102]. 

A quaternary stereogenic carbon center was effectively cOTistructed by the y-selective conjugate addition of this class of nucleophile to highly electrophilic, P-trifluoromethyl nitroolefins using cinchona alkaloid-derived thiourea 19c as a... 

Aryl trifluoromethyl ketones have been alkynylated in high ee using readily available chiral cinchona alkaloids that afford either propargylic tertiary alcohol product... 

The catalytic enantio-selective addition of zinc alkynylides to various trifluo-romethyl ketones with selectivities that surpass 94% ee has been reported. By using 0 pseudoenantiomeric cinchona alkaloids as chiral ligands (e.g. 22), both enantiomers of the trifluoromethylated products were synthesized. The first experimental and computational evidence has been provided in support of alkynyl group transfer from an intermediate complex formed by transmetallation reaction between the alkynylide and the titanium catalyst. 

The aerobic epoxidation of j0-trifluoromethyl-, -disubstimted enones, catalysed by cinchona alkaloid (73), in methyl t-butyl ether under air in the presence of CS2CO3 and methylhydrazine affords enantiomerically enriched trifluoromethyl-substituted epoxides in excellent yields and up to 96-99% ee. 0-labeling experiments suggest a mechanism involving the activation of molecular oxygen." ... 

Non-fluoride initiators have been employed satisfactorily as well, including Lewis bases (amines, amine A-oxides, carbonates and phosphates," LiOAc," " f-BusF ), Lewis acids," A-heterocyclic carbenes, or even without initiator in DMSO as solvent. The addition of TMSCF3 to carbonyl compounds in the presence of a chiral initiator allows the enantioselective preparation of trifluoromethyl alcohols. For this purpose, quaternary ammonium fluorides derived from cinchona alkaloids (1) have been employed, affording moderate (up to 51% ee) " to high enantioselectivities (up to 92% ee). Also, the corresponding bromides were used in combination with an external fluoride source (KF or TMAF, up to 94% ee) or with disodium (R)-binaphtholate (up to 71% ee), or simply a cinchonidine-derived ammoniumphenoxide (up to 87% ee). Moreover, the use of a chiral TASF derivative (2) has also been reported (up to 52% ee). ... 

Alternatively, Shibata and coworkers first realized the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 69 in 2010 by developing a cinchona-alkaloid-catalyzed asymmetric conjugate addition/cyclization/dehydration cascade reaction with hydroxylamines 67 and enones 68 (Scheme 2.19). A wide range of substrates could be employed in this reaction to give the desired cyclized products with excellent enantioselectivities [33]. 

Functionalization of the cinchona structure with a thiourea at the C6 position of the quinolone ring was demonstrated shortly after development of the C9 derivatives [69]. The transformation of the C6 methoxy group into a thiourea bearing a 3,5-di(trifluoromethyl)phenyl group, without affecting the stereochemistry at C9, resulted in a highly effective organocatalyst for the asymmetric Henry reaction of nitromethane with aromatic aldehydes (Scheme 6.28). 

Cinchona alkaloids with a thiourea group have also been applied for the asymmetric preparation of amino acid derivatives. Recent examples include an asymmetric Mannich reaction leading to P-amino ester derivatives with a benzoxazole moiety [77] and the formation of P-amino esters with a benzothiazole group [78]. The latter reaction was catalyzed efficiently by a C9 thiourea derivative (26) with a 2,6-dichloro-4-(trifluoromethyl)phenyl group connected to the thiourea group as shown in Scheme 6.34. 

Cinchona-alkaloid-catalysed conjugate cyanation of enones has enabled the synthesis of trifluoromethyl-substituted diarylpyrroles with ee<96%P° Thiochro-manes have been formed by asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with a,/ -unsaturated A-acylpyrazoles. Asymmetric organocatalysed oxy-Michael addition to y-hydroxy a,/ -unsaturated thioesters on reaction with t-BuCHO has been used to form -hydroxy carbonyl compounds HOCH2C H(OH)CH2CO.SAr via cyclic hemiacetal intermediates. 

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