Anhydride, trifluoroacetic reaction with amines

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Alnl-salen complex (salen = N,N -bis(salicyhdene)-ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6, which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [5]. 

Trifluoromethyl derivatives of thiochromone are also available from thiosalicylic acid by conversion to alkyl 2-mercaptophenyl ketones followed by a Baker-Venkataraman reaction with trifluoroacetic anhydride in triethyl-amine (Scheme 205) <2005PS(180)1315>. 

Methyleneimmonium salts 31 are conveniently prepared from mcihylene-bis-amines, formaldehyde-N,0-acetals, or methylene halogenides. Electrochemical reactions on various alkylamines have also been used to generate methyleneimmonium salts, and trimethylamine N-oxide 34 (Fig. 20) is reported as a source of the corresponding methyleneimmonium salt by reaction with trifluoroacetic anhydride. ... 

Iminium ion cycUzations such as the Pictet-Spengler reaction have been widely used in alkaloid chemistry to create a carbon-carbon bond between the carbon a to the basic nitrogen and an aromatic ring. The requisite iminium ions in these reactions are often readily available via the modified Polonov-ski reaction. Although two steps, IV-oxide formation and reaction with trifluoroacetic anhydride, are involved, this approach is often preferable to the reaction of a tertiary amine with mercury(II) acetate, in which it is necessary to destroy the amine-mercury complex at the end of the reaction. In this way the secoheteroyohimbinoidiV-oxide (34) was cyclized selectively to uammigine (35 equation 12). Using mercuiy(II) acetate a nearly equal mixture of (35) and its C-3 P-H epimer tetrahydroalstonine is obtained. 

In a variation of the known conversion of phthalideisoquinolines into rhoeadines, the -lactone 1 derived from jS-hydrastine was converted to its iV-oxide. The secondary amine 2 was obtained from the iV-oxide by reaction with trifluoroacetic anhydride, in a modified Polonovski reaction. The papaverrubine 3 was then generated from the amine 2 as shown below ... 

Another example is provided by the application of the modified Polonovski reaction to A3-piperideines. Treatment of amine oxides (141) with trifluoroacetic anhydride results in the formation of iminium ion (142). These compounds can behave as useful synthetic intermediates, reacting with a number of nucleophiles such as cyanide ion (80JA1064). 

The latter, on reaction with methylamine yielded via the P-epoxide 373, the trans-a aminoalcohol 374, which was N-acylated to the amide 375. Acid-catalysed dehydration of the tertiary alcohol 375, led to the olefin 375, from which the key radical precursor, the chlorothioether377 was secured in quantitative yield by reaction with N-chlorosuccinimide. In keeping with the earlier results recorded for structurally related compounds, 377 on heating in the presence of ruthenium dichloride and triphenylphosphine also underwent a 5-exo radical addition to generate the cyclohexyl radical 378 which recaptured the chlorine atom to furnish the a-chloro-c/5-hydroindolone 379. Oxidation of thioether 379 gave the corresponding sulfoxide 380, which on successive treatment with trifluoroacetic anhydride and aqueous bicarbonate led to the chloro-a-ketoamide 381. The olefin 382 resulting from base induced dehydrochlorination of 381, was reduced to the hydroxy-amine 383, which was obtained as the sole diastereoisomer... 

The pyridinium perchlorate (212), which is the precursor of the mesoionic oxazolone (213), is formed by the action of acetic anhydride and perchloric acid on l,2-dihydro-2-oxopyridin-l-acetic acid. The mesoion (213) is chemically unstable and is generated in solution for its reactions by treatment with a tertiary amine. Compound (213) is easily substituted at C-3, and with trifluoroacetic anhydride forms the stable 3-trifluoroacetyl mesoion (70JCS(C)1485). 

The Beckmann rearrangement also allowed the preparation of cyclopropyl-amines 183-189 yy accessible in 68-77 % yield from the reaction of the oxime (76) with tosyl chloride in dioxane or with trifluoroacetic anhydride in dimethoxy-ethane (equation 13). Bicyclic- and tricyclic aminocyclopropanes (79 and 81) could be obtained from ketones (78 and 80) and hydroxylaminic reagents (equations 14 and 15). Further examples are reported in Refs 188a-j. 

The use of a-cyanoamines in place of their less stable iminium ion precursors often results in high product yields in the Pictet-Spengler and other ring closure reactions. Thus, the Polonovski-derived a-cyanoamine (39a) cyclized to (40) in 84% yield, whereas reaction of the tertiary amine (39b) with mercury(n) acetate was unsuccessful (equation 13). The conversion of unstable S,6-dihydropyridinium salts (41), obtained by reaction of tetrahydropyridine IV-oxides with trifluoroacetic anhydride, into the stable, synthetically versatile tetrahydropyridine-2-carbonitiile (42) is another area in which use of this methodology has met with particular success (equation 14). ... 

Enamines can be obtained as the products of the Polonovski reaction of amine oxides and, in particular, by reaction of piperidine A -oxides with acetic anhydride. This is primarily due to the fact that when acetate is the counterion the intermediate iminium ions are labile and readily tautomerize. The formation of enamines during the Polonovski reaction is also favored by the presence of a base. In fact, enamines are often obtained in high yield from the reaction of an IV-oxide with trifluoroacetic anhydride in the presence of triethylamine or pyridine. Conversion of intermediate iminium ions, generated under modi-fred Polonovski conditions, to enamine products can also occur during hydrolytic work-up. 

Vinyl sulfides are prepared from sulfoxides under a variety of conditions. These include reaction with acetic anhydride at reflux, with trifluoroacetic anhydride in the presence of an amine base and with acetic anhydride in the presence of an acid catalyst. In fact, precautions must be taken in certain Pum-merer reactions discussed in the preceding sections to avoid competing vinyl sulfide formation. 

Cave, A., Kan-Fan, C., Potier, P., Le Men, J. Modification of the Polonovski reaction. Reaction of trifluoroacetic anhydride with an amine oxide. Tetrahedron 1967, 23, 4681-4689. 

A simple modification of this technique has dramatic effects on the stability of the protecting group. If trifluoroacetyl is used rather than acetyl, the trifluoroacetamide (N-COCF3, N-TFA) is generated. Trifluoro-acetyl is usually attached by reaction of the amine with trifluoroacetic anhydride [(CF3C0)20] in the presence of triethylamine or pyridine, This group retains its stability to acid but is more sensitive to base (pH 1-... 

Starting material for the synthesis of varenicline is o-bromofluorobenzene, which reacts (via benzyne) with cyclopentadiene in a Diels-Alder reaction. Oxidative ring-opening and reductive amination provides a N-benzylbenz-azepine derivative. After N-protection with trifluoroacetic anhydride, nitration with a mixture of nitric andtrifluoromethanesulfonic acids, reduction, and condensation with glyoxal, hydrolysis of the trifluoroacetamide as a final step provides the active compound in good overall yield. [568, 569]... 

A modified Polonovski reaction is another efficient method for iV-demethyla-tion. The amine iV-oxide is treated with trifluoroacetic anhydride instead of the more usual acetic anhydride, and the resulting immonium salt is then hydrolyzed. ... 

The reaction of mercaptomethyleniminium salts 141 with trifluoroacetic anhydride in the presence of triethylamine yielded substituted 2-aminothiophenes, including 3-trifluoromethyl heterocycle 143. The starting mercaptomethyleniminium salts were prepared by S-alkylation of thioacetamides. When triethylamine was not used in the reaction, it was possible to isolate the intermediate ketene-S,N-aminals 142 and cyclize them under basic conditions [79]. 

Dehydration of pyronecarboxamide 22 with trifluoroacetic anhydride in the presence of pyridine leads to the formation of 2-cyano-6-(trifluoromethyl)-4-py-rone (40) in 61 % yield. The reactions of this cyanopyrone with A(-nucleophiles can proceed with or without substitution of the cyano group to give a wide range of novel trifluoromethylated compounds. Thus, cyanopyrone 40 easily reacted with aliphatic and aromatic amines in EtOH at -20 °C and o-phenylenediamine in... 

In principle, addition of a nucleophile to the C=N bond of the diazine ring can be accompanied by elimination of fluoroalkyl substituent. Two-step version of this reaction was used in the synthesis of alkaloid rutaecarpine (1210). In particular, reaction of anhydride 1206 with trifluoroacetic anhydride and then - with Irypt-amine led to the formation of quinazoline 1208, which was transformed to 1210 with elimination of trifluoromethane upon acid-catalyzed cycUzation, followed by alkaline hydrolysis (Scheme 260) [744]. 

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