Trifluoroacetylation of aromatics

CoCl2 CATALYZED TRIFLUOROACETYLATION OF AROMATICS USING TRIFLUOROACETIC ANHYDRIDE... 

Fifty years ago, Simons et al. synthesized trifluoroacetophenone for the first time (eqn. 1, refs. 1,2). Since then, the trifluoroacetylation of aromatic compounds has continuously attracted the interest of chemists (refs. 3-16). Indeed, the classic Friedel-Crafts reaction (refs. 1,2) requires sub-stoichiometric quantities of aluminium chloride and trifluoroacetylchloride whose boiling point, - 27 °C, makes it difficult to use. Moreover, some F/Cl exchange between trifluoro-acetophenone... 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

Takeuchi and co-workers showed that the ratio of N- to C-substitution on the apparent intermediate 75a by a series of aromatics in arene/TFA mixtures was sensitive to the structure of the precursor to 75a (phenyl azide, N-phenylhydroxylamine or O-trifluoroacetyl-N-phenylhydroxylamine) even though the decomposition rates of these precursors were unaffected by the identity of the arene. This result is consistent with the characterization of 75a from N3 and Br trapping studies as a short-lived intermediate that will usually react through ion pair or preassociation processes that may be leaving-group dependent. ... 

Aromatic acyloxylation can be achieved via the decomposition of diacyl peroxides in the presence of aromatic substrates. By careful choice of reaction conditions, either acyloxylation or trifluoromethylation of the ring system can be achieved, using trifluoroacetyl peroxide generated in situ from trifluoroacetic anhydride and sodium percarbonate (Figure 3.117).492... 

Sawada H, Nakayama M, Yoshida M, Yoshida T, Kamigata N (1990) Trifluoromethylation of aromatic compounds with bis(trifluoroacetyl) peroxide. J Fluor Chem 46 423-431... 

Although generation and reactions of 1,1,1-trifluorobiacetyl was reported as early as in 1957, the compound was not isolated in this work [637], Trifluoromelhyl-substituted derivatives 1071 were obtained via trifluoroacetylation of hydrazones 1070 [638, 639], acylation of (trifluoroacetimidoyl)lithium derivatives 1075 [640], or condensation of trifluoroacetimidoyl chlorides 1077 with aromatic aldehydes in presence of sodium hydride [641] (Scheme 230). These methodologies were also used for the synthesis of trifluoromethyl glyoxal equivalents 1064 [640,642]. 

By use of TV-(trifluoroacetyl)- or TV-(trichloroacetyl)-imidazoleare obtained symmetric aliphatic and aromatic anhydrides even from carboxylic acids that do not form insoluble salts in benzene, ether, or THF (Table 13—1). In this case the acid is treated with the imidazolide in a 2 1 molar ratio, and an insoluble imidazolium trifluoro- or tri-chloroacetate is formed. 

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

Nitric acid-trifluoroacetic anhydride mixtures are used extensively for nitrolysis and N-nitration reactions (see Chapters 5 and 6). The same is not true for aromatic nitrations. This reagent contains trifluoroacetyl nitrate, which can ionize to nitronium and trifluoroacetate ions in the presence of strong acid. 

This reagent tends to give high ortho para ratios for some nitrations.2 Another convenient procedure involves reaction of the aromatic compound in chloroform or dichloromethane with a nitrate salt and trifluoroacetic anhydride.3 Presumably, trifluoroacetyl nitrate is generated under these conditions. 

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