Convenient synthesis of 4-trifluoromethyl-substituted imidazole derivatives

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines (2) with trifluoroacetic anhydride, react with ammonia to give 4-trifluoromethyl-3,4-dihydroimidazoles (3) in high yields. Dehydration of 3 gives 4-trifluoromethylimidazoles (4) in high yields. The novel ring transformation of 1 into 3 occurs via a regioselective attack of ammonia on the C-2 position of the ring.     

Convenient synthesis of 4-triflouromethylpyrazoles by cyclization of triflouroacetylated hydrazones

Several 4-trifluoromethyl-1-alkylpyrazoles were synthesized in good yields by trifluoroacetic anhydride-pyridine induced cyclization reaction of acylhydrazones prepared from aldehyde dialkylhydrazones and trifluoroacetic anhydride.     

Convenient synthesis of 5-trifluoroacetylated imidazoles by ring transformation of mesoionic 1,3-oxazolium-5-olates

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines (2) with trifluoroacetic anhydride, react with amidines to give 5-trifluoroacetylimidazoles (3) in moderate yield. The novel ring transformations of 1 into 3 occur via an initial attack of amidines on the C-2 position of the ring.     

New synthesis of 3-trifluoromethylpyrroles by condensation of mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates with phosphorus ylides

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), obtained from the reaction of N-acyl-N-alkylglycines with trifluoroacetic anhydride, react with phosphorus ylides to give β-trifluoromethylpyrroles (2) in good yields. The novel ring transformations of 1 into 2 occur via an initial attack of the ylide anions on the C-2 position of the ring.     

A diastereoselective synthesis of 4-azidotetrahydropyrans via the Prins-cyclization

A three component coupling of aldehydes, homoallylic alcohols and sodium azide is achieved in the presence of trifluoroacetic acid in dichloromethane to produce 4-azidotetrahydropyran derivatives in high yields with all cis-selectivity. The use of trifluoroacetic acid makes this procedure simple and cost-effective.     

Convenient synthesis of alpha-trifluoromethylated acyloins from alpha-hydroxy or alpha-amino acids

Alpha-trifluoromethylated acyloins (2 and 6) have been prepared from alpha-hydroxy acids (1), N-acylprolines (5) or N-acyl-N-alkyl alpha-amino acids (8) by novel transformation reactions with trifluoroacetic anhydride (TFAA) in the presence of pyridine. The former reaction of 1 could proceed through mesoionic 1,3-dioxolium-4-olates, whereas the latter two reactions of alpha-amino acids (5 and 8) could involve mesoionic 1,3-oxazolium-5-olates. The reaction of 1 with TFAA shows more potential for practical applications because of the ready availability of the starting materials and ease of manipulation.     

Parallel solid-phase synthesis of 2-arylamino-6H-pyrano[2,3-f]benzimidazole-6-ones

The parallel solid-phase synthesis of a hydrophilic psoralen analogue, 2-arylamino-6H-pyrano[2,3-f]benzimidazole-6-ones (2-arylaminoimidazocoumarins), has been developed. The resin-bound 7-fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid underwent aromatic substitution with primary amines, followed by reduction of the nitro group with tin(II) chloride. The cyclization of the o-dianilino intermediates was accomplished with aryl isothiocyanates in the presence of 1,3-diisopropylcarbodiimide (DIC). The final products were released from the resin with trifluoroacetic acid (TFA) and obtained in high purity and good isolated yield. The 2-arylaminoimidazocoumarins exhibit interesting spectral properties.     

The synthesis of 3,4,4a,9a-tetrahydro-2(1H)-carbazolones

Cyclization of 4-(1-methylindol-3-yl)-2-butanone and the corresponding 1-benzyl analog in trifluoroacetic acid furnishes 9-methyl- and 9-benzyl-3,4,4a,9a-tetrahydro-2(1H)-carbazolone, respectively. Under the same conditions, 4-(indol-3-yl)-2-butanone gives the dimer, 3-(3-oxo-butyl)-2-[3-(3-oxobutyl)-2-indolinyl] indole. When boron trifluoride etherate is used instead of trifluoroacetic acid, the desired 3,4,4a,9a-tetrahydro-2(1H)-carbazolone is obtained. The determination of the structure of the tetrahydrocarbazolones is described and the stereochemistry of the ring fusion is discussed.     

Three-component synthesis of 2-aryl-4-arylthio-tetrahydro-2H-pyrans via the Prins-cyclization

A three-component coupling of aldehyde, homoallylic alcohol and aryl thiol has been achieved in the presence of trifluoroacetic acid in dichloromethane at room temperature to produce 4-arylthiotetrahydropyrans in good yields with all cis-selectivity. This method is simple, selective and convenient for introducing a thiol group on a tetrahydropyran ring.     

合成α 酮酸的新方法

本文报道了一种新的简便的合成α-酮酸(4)的新方法. 用三氟乙酸酐在4-N,N-二甲基氨基吡啶催化下在二氯乙烷溶剂中和易于制得的2,3-二(三甲基硅氧基)羧酸三甲基硅酯(1)反应生成2,3-二(三氟乙酰羧酸三甲硅酯(2). 向反应混合物中加入吡啶生成2-三氟乙酰氧基-2-烯酸(3). 分别用氢氧化钾水溶液和盐酸处理3得产物4 .     

The reactions of ethyl 3,4-dihydro-4-quinazolylacetate and its derivatives with cyclopentanone. An attempt at the synthesis of the 6,8-diazasteroid system VII

The reaction of ethyl 3,4-dihydro-4-quinazolylacetate ( 1a ) with cyclopentanone in the presence of trifluoroacetic acid gave mainly two decomposition products, carbostyril (VIII) and ethyl 2-aminocinnamate (IX). Two compounds which are suggested to have the 6,8-diazasteroid skeleton were also obtained in poor yield. Ethyl 3,4-dihydro-2-p-methoxyphenyl-4-quinazolylacetate (1b), however, gave 2-p-methoxyphenylquinazoline (XII) as a decomposition product and did not condense with cyclopentanone. Furthermore, two ethyl 3,4-dihydroquinazolylacetates substituted at the 2-position with cyclohexyl (1c) and methyl (1d) groups could not be converted to the expected diazasteroid system.     

Trifluoroacetic acid in the synthesis of thiolcarbamates and s-methyl alkanethioates

The major products of the reaction of 2-bromohexanoic acid with methyl thiocyanate in trifluoroacetic acid are S-methyl 2-bromohexanethioate (II) (55% yield), S-methyl 2,2,2-trifluoroethanethioate (IV) (31% yield), N-trifluoro-acetyltrifluoroacetamide (V) (11% yield), and N-trifluoroacetyl-S-methylthiol-carbamate (III) (29% yield). N-2-Bromohexanoyl-S-methylthiolcarbamate (I), N-2-bromohexanoyltrifluoroacetaraide (VI), 2-thiapropioamide(VII), and S-methyl hex-anethioate (VIII) are also formed in minor amounts.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 195–198, January, 1991.     

Tetrafluoroboric acid, a useful deprotecting reagent in peptide synthesis

We have found that tetrafluoroboric acid (HBF4) in trifluoroacetic acid (TFA) in the presence of thioanisole cleaves various protecting groups currently used in peptide synthesis. HBF4 in TFA cleaves an amino acid amide from 4-methylbenzhydrylamine resin more effectively than trifluoromethanesulfonic acid in TFA. Lamprey gonadotropin-releasing hormone (a 10-residue peptide amide) was synthesized using 1 M HBF4-thioanisole in TFA by both solution-phase and solid-phase methods.     

An unusual reaction of benzalaminoacetals in trifluoroacetic acid: facile synthesis of 2-benzylpyrazines

Benzalaminoacetals (1), upon refluxing with trifluoroacetic acid, lead to 2-benzylpyrazines, rather than the expected isoquinolines. This unusual reaction represents another useful way to prepare a variety of 2-benzylpyrazines from the corresponding benzaldehydes.     

Design and synthesis of a multi-detachable benzhydrylamine-resin for solid phase peptide synthesis

Peptides with C-terminal α-carboxamides were synthesized from a multi-detachable benzhydrylamine-resin containing a Boc-(4-acetoxy)benzhydryl-amine handle of unambiguous origin. The peptides bound to the new resin are stable to trifluoroacetic acid, but are cleavable by hydrogen fluoride, base and nucleophiles to give unprotected or protected peptide fragments.     

Solution-phase automated synthesis of tripeptide derivatives

An improved general method for automated synthesis of tripeptides was developed, in which methanesulfonic acid (MSA) was used in place of trifluoroacetic acid (TFA), thus making it possible to avoid, 1) corrosion of the apparatus by strong acid vapor, 2) formation of emulsions, and 3) use of the restricted solvent, dichloromethane. As an application of the automated synthesis apparatus, 216 fragment tripeptide derivatives were synthesized systematically using the MSA method, in excellent yield and with increased efficiency.     

Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of gem-bistrifluoroacetates and their reactions with fluoride nucleophiles

Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P₂O₅. Since gem-difluorides were derived from ketones, HF and P₂O₅, this constitutes a practical synthesis of gem-difluorides.     

A practical synthesis of N-tosylimines of arylaldehydes

Synthesis of N-tosylimines of arylaldehydes was carried out by the reaction of arylaldehydes and p-toluenesulfonamide in methylene chloride in the presence of trifluoroacetic anhydride as a dehydrating agent.     

A new method for the synthesis of 4H-1,3,4-thiadiazino[5,6-b]quinoxalines

The reaction of 6-chloro-2-[1-methyl-2-(Mmemylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 5 with acetic anhydride or trifluoroacetic anhydride resulted in dehydrative cyclization to give 2-(N-acetyl)-memylamino-8-chloro-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 6 or 8-chloro-2-(N-trifluoroacetyl)methylamino-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 9 , respectively. The oxidation of compound 6 or 9 with 2-fold molar amount of m-chloroperbenzoic acid afforded the 4H-1,3,4-thiadiazino-[5,6-b]quinoxaline 1,1-dioxide 8 or 13 , respectively. The acetyl group of compound 6 was hardly hydrolyzed, but the trifluoroacetyl group of compound 9 was easily hydrolyzed to change into 8-chloro-4-methyl-2-memylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 10 . The acylation of compound 10 with acetic anhydride, trifluoroacetic anhydride, phenyl isocyanate, and chloroacetyl chloride furnished the 2-(N-acetyl)methylamino 6 , 2-(N-trifluoroacetyl)methylamino 9 , 2-(1-methyl-3-phenylureido) 11 , and 2-(N-chloroacetyl)methylamino 12 derivatives, respectively.     

Experiments on the synthesis of carotenoid glycosides

Isozeaxanthin was treated with trifluoroacetic acid and tetra-O-benzoyl-1-thio-β-d-glucose to afford β,β-carotene-4,4′-bisthioglucoside isomers in good yields. The deprotected compounds are mimetics of naturally occurring thermoxanthins and can show favourable effects against oxidation stress.