Nitrones trifluoromethyl

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

Nitrones are among the most highly studied and useful reagents for the synthesis of five-membered-nng heterocycles. The first fluonnated nitrone, N-methyl-C-(trifluoromethyl)nitrone, was prepared recently and used to introduce Irifluoromethyl groups into such heterocycles... 

Trifluoromethyl-substituted nitrones have been prepared [184, 185, 186] and used for [3+2] cycloaddition reactions [iS5, 186] (equation 42). 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Nucleophilic Perfluoroalkylation of Nitrones The reaction of a,N-diaryl nitrones with (trifluoromethyl)trimethylsilane (TMSCF3) gives O-trimethylsilyl ethers of a-(trifluoromethyl)-hydroxylamines. This reaction is initiated by potassium ten -butoxide. Removal of the trimethylsilyl group on acid treatment leads to a-(trifluoromethyl)hydroxylamines, whereas catalytic hydrogenation gives a-(trifluoromethyl)amines (Scheme 2.194). 

Nitrones with alkyl groups bound directly to the 1,3-dipolar moiety fail to react with TMSCF3, but trifluoromethylation of 3,y-unsaturated nitrones such as u-styryl-/V-phenyl nitrone gives the products of trifluoromethylation (Scheme 2.196) (681, 682). 

As mentioned above (303) (Scheme 3.90, Eq. 1), bis-trifluoromethyl thioketene has the deoxygenating ability toward alkyl nitronates, which is also based on cycloaddition to the C=S bond. 

Eq. 45) while a more recent publication described diastereoselective reactions of two trifluoromethyl silyl nitronates [145]. 

Trifluoral was also converted to a C-(trifluoromethyl)nitrone [163] which underwent regio- and stereo-selective cycloaddition with alkenes, affording potentially useful aminoalcohols after N-0 bond cleavage (Eq. 52)... 

Chiral crotonates derived from S-citronellol, l-(—)-menthol, and 5-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active trifluoromethylated a, /i-unsaturated aryl sulfones (43) with nitrones yield the corresponding isoxazolidines (44) and (45) with high regio- and... 

Trifluoromethyl Imines, Oximes, Hydrazones, Imidoyl Chlorides, Nitrones, Diazo and Diazirine Compounds... 

Trifluoromethyl-substituted nitrones have been prepared [78JFC-(12)153 88JFC(39)39, 88MI2 89JHC381] and used as building blocks for five-membered ring synthesis (Scheme 66). 

Nitrone 1 reacts with the parent 3,3,3-trifluoropropenc and with various 3,3,3-trifluoro-propenes which arc substituted in the 1-position with another electron-withdrawing group (ester, nitro or sulfone). Regioselectivity depends on the LUMO coefficient of C2 which is larger for sulfones and nitro compounds. However, with 3,3,3-trifluoropropene the predominant formation of the 5-(trifluoromethyl)isoxazolidine is not explained by orbital coefficients, but by stcric hindrance. 

With 1,1-disubstituted trifiuoromelhylated alkenes, such as -(trifluoromethyl)styrene, cy-doaddilion with nitrone 1 is regioselective, and a 50 50 mixture of the a. s/trani -isomers is obtained, as observed in Dicls-Alder cycloaddition reactions (see Section 2.1.1.6.2.1.1.). When the reaction is performed solvent-free under microwave irradiation, instead of under thermal conditions (boiling toluene), the yield is improved from 65% to 98% and the reaction time decreases from 48 hours to 4 minutes, however, stereoselectivity is not improved. ... 

Trifluoromethyl-substituted alkynes can also react with nitrones, leading to rearranged cycloadducts. The cycloaddition of ethyl 4,4,4-trifluorobut-2-ynoate and hexafluorobut-2-yne " with C,A -diphenyl nitrone is a route to trifluoromethyl-substituted indoles. 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.nitrile imines, " " nitronates," and munchones." Depending on reaction conditions, cycloadditions may occur via a two-step process. 

Ar-Methyl-C-(trifluoromethyl) nitrone (1) is generated by dehydration of the corresponding hydrate and, with various alkenes, provides isoxazolidines regioseleclively. Endo approach is favored, regardless of the nature of the alkene substituent."6... 

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