Tnfluoromethyl substituted

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... 

Hexafluoroacetone azine accepts nucleophiles (ROH, RSH, R NH) in positions 1 and 2 to yield hydrazones [27] Phosphites give open-chain products via a skeletal rearrangement [22] Radical addition reactions are also reported [22] Treatment of tnfluoropyruvates with tosylhydrazine and phosphorus oxychlo-ride-pyndme yields tnfluoromethyl-substituted diazo compounds [24] (equation 3)... 

From semiamidals, the correspondmg tnfluoromethyl substituted N-acyl mines [25, 28], 1,3-diambutadienes [27], N-sulfonyl mines [5, 29], N sulfinyl mines [30], and N-phosphoryl mines [31] can be obtamed in high yields on reaction with powerful dehydratmg realms like POC -pyndine or tnfluoroacetic anhydnde-pyndme [2, 5]... 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

Bis(tnfluoromethyl -substituted phosphoranes are obtained on reaction of bis(tnfluoromethyl)-substituted heterodienes and P(ni) species [74J, 742 143] In the case of sulfur- and selemum-contaimng phosphoranes, the corresponding heterodienes are generated in situ from heterocyclic precursors [137] (equation 32)... 

Bis(tnfluoromethyl)-subsntuted hetero-1,3-dienes and acetylenes react to give open-chain tnfluoromethyl-substituted N-propargylic amides, 4//-1.3 oxazines, and 2-oxazohnes [42,144] The formation of 2-oxazolmes is an example of pathway 2 (equabon 25), where only one carbon atom of the acetylene moiety IS incorporated into the new nng system The selectivity of this reaction can be controlled efficiently in favor of the five-membered nng system by altering the reaction conditions In the presence of 4-dimethylaminopyndine, the five-mem-... 

Bis(tnfluoromethyl)-substituted nitrile ylides undergo dimerization reactions in the absence of trapping reagents [143, 168, 170] (equation 38)... 

Likewise, trifluoromethyl-substituted nitrile imines [172] and nitnle oxides [173,174, 7 75] have been used to synthesize tnfluoromethyl substituted five-membered ring systems of the pyrazole, isomzole, isoxazohne, and 1,2,4-oxadiazole... 

Trifluoromethyl-substitutedazimines are surprisingly stable compounds. They are accessible by 1,3-dipole metathesis from tnfluoromethyl-substituted azomethine imines and certain nitroso compounds [187, 188] On photolysis, an electrocyclic ring closure first gives the triaziridines, which are stable at room temperature. On heating above 80-100 C, a valence tautomenzation takes place and azimines are formed [189] (equation 43). 

Bis(tnfluoromethyl) substituted heterodienes, being the most reactive hetero-dienes known to date, must be regarded as having unique synthetic potential... 

From the synthetic viewpoint, a particularly interesting trifluoroacetylation reaction of simple vinyl ethers was reported first by Hojo et al in 1976 [73] The scope and limitation of this particular reaction were elaborated intensively, the reaction proved to be of general applicability with practically no restrictions on substituents of the vinyl ether moiety 9] (equation 34) This general validity is particularly beneficial because a trifluoroacetylated vinyl ether is the synthetic equivalent of a specifically protected tnfluoromethyl-substituted 1,3-dicarbonyl compound 19], thus the reaction provides access to a broad spectrum of variously substituted synthetic building blocks with selective reactivities on each carbon acceptor (a) and donor (d) center (equation 35) Obviously, such building blocks can react as heterodiene systems m cycloaddition reactions [< 74] or can be treated with a wide variety ot 1,2 or 1 3-dinucleophihc species to give any desired tnfluoromethyl-substituted carbocychc or heterocyclic system [8 75] Treatment of simple vinyl ethers with an excess of trifluoroacetic anhydride at elevated temperature leads to doubly acylated products [76] Comparable acylation reactions occur with vinyl thioethers [73], and the mesoiomc l,3-oxathiol-4-ones show, at least in a formal sense, similar behavior [77] (equation 36)... 

The use of tnfluoromethyl-substituted a-pyrones in Diels-Alder reactions with all types of dienophiles provides an interesting route to trifluoromethyl-benzenes [118] (equation 98)... 

Highly reactive dipolar bis(tnfluoromethyl)-substituted heterodienes are excellent traps for one-skeleton-atom species , even when these are shortlived The hetero-1,3-dienes add electron rich and electron poor carbenes (724,125,126,127,128 129,130], carbene complexes [131], carbene analogues [SnCl2, Sn(C[Pg.856]

A wide variety of a-tnfluoromethyl ab-ammo acids ate readily available from the reaction of 5-fluoro-4-tnfluoromethyl-l,3 azoles with allyhc alcohols [755, 759] a-Tnfluoromethyl-substituted a-amino acids show antibacterial and antihy pertensive activity Some are highly specific enzyme inhibitors (suicide inhibitors) and may be important as bioregulators [740] Furthermore, they are interesting candidates for peptide modification... 

Tnfluoromethyl-substituted nitrones have been prepared [184, 185, 186] and used for [3+2] cycloaddition reactions [755, 186] (equation 42). 

The reaction of tnfluoropyruvates or their acyl iimnes with carbon nucleophiles offers a convenient route to a-tnfluoromethyl substituted a-hydroxy or a-amino acids Reduction of the keto or immo function yields 3,3,3-tnfluorolac-tates or 3,3,3-tnfluoroalanine esters [32],... 

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