Trifluoromethylations heterocycles

Hojo et al. [218,308,309] described the trifluoroacetylation of alkenes activated by heteroatom donors such as vinyl ethers and ketene acetals (Eq. 116) the reaction occurs under mild conditions and can be used to prepare bis(trifluoro-acetyl) products from highly activated derivatives [310]. The main use of the products appears to be in the synthesis of trifluoromethyl heterocycles both... 

An example of each of these trifluoromethyl heterocycles is provided in Scheme 5.70. 

TRIFLUOROMETHYLATED HETEROCYCLES FROM p-TRIFLUORO-ACETYLATED LACTAMS AND BENZOLACTAMS... 

Trifluoromethylation reactions of heteroaromatic compounds represent a majority of reported nucleophihc perfluoroalkylations. For example, trifluoromethylation of halogenated quinolines, isoquinolines, or pyridines carried out under pressure using CF3X/CU powder system (X = 1 or Br) in DMF or (Me0)3P=0 solvent affords the corresponding trifluoromethylated heterocycles in 22-60% yield (Fig. 7.21). ... 

Figure 7.24 Preparation of trifluoromethylated heterocycles using CF3Si(CH3)3/CuI/KF system.

The aromatization of dihydro heterocycles was carried out using cerium ammonium nitrate (CAN) at ambient temperature and results in trifluoromethylated heterocycles in 18-68% yield (Fig. 7.32). While trifluoromethylation of 3-picoline is regioselective giving 5-methyl isomer in 41 % yield, the reaction of other 3-substituted pyridines leads to the mixture of — 3 and — 5 regioisomers. 

The presence of halogen X (X = F, Cl, Br, or 1) in the molecule of trifluoromethylated heterocycle opens an additional possibility for further regioselective transformations. Functiolization of these materials can be achieved using metal-halogen exchange (for X = Cl, Br, or 1) followed by the reaction of lithiated intermediate with different electrophiles." ... 

Muzalevskiy VM, Nenajdenko VG, Shastin AV, Balenkova ES, Haufe G (2009) a-Trifluoromethyl- P-aryl enamines in the s5mthesis of trifluoromethylated heterocycles by the Fischer and the Pictet-Spengjer reactions. Tetrahedron 65 7553-7561... 

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]. 

Yamanaka H, Takekawa T, Morita K, Ishihara T, Gupton J (1998) Preparation of novel p-trifluoromethyl vinamidium seilt and its synthetic application to trifluoromethylated heterocycles. Tetrahedron Lett 37 1829-1832... 

Hanamoto T, Hakoshima Y, Egashira M (2004) Ttibutyl(3,3,3-trifluoro-l-propynyl)stannane as an efficient reagent for the preparation of veuious trifluoromethylated heterocyclic compounds. Tetrahedron Lett 45 7573-7576... 

Honey MA, Pasceri R, Lewis W, Moody CJ (2012) Diverse trifluoromethyl heterocycles from a single precursor. J Oig Chem 77 1396-1405... 

Chloromethyl derivative 63, a useful precursor for other trifluoromethylated heterocycles [34] can be obtained by reaction of 61 with chloroacetylchloride followed by cyclization of the resulting diacylhydrazide with phosphorus oxychloride 62 (Scheme 19) [35],... 

Jones BG, Branch SK, Thompson AS, Brian GJ, Branch SK, Thompson AS, ThreadgiU MD (1996) Synthesis of a series of trifluoromethylazoles and determination of pK, of acidic and basic trifluoromethyl heterocycles by I9F NMR spectroscopy. J Chem Soc... 

Boivin J, El Kaim L, Zard SZ (1995) Trifluoromethyl ketones from carboxyUc adds. Part II. A versatile access to trifluoromethylated heterocycles. Tetrahedron 51 2585-2592... 

Zhu S, Song L, Jin G, Dai B, Hao J (2009) Recent progress on the synthesis of trifluoromethylated heterocyclic compounds based on ethyl 4,4,4-trifluoroacetoacetate and its derivatives. CurrOig Chem 13 1015-1027... 

Bouillon J-P, Ates C, Janousek Z, Viehe HG (1993) Trifluoromethylated heterocycles from P-trifluoroacetyl-lactams and -benzolactams. Tetrahedron Lett 34 5075-5078... 

Bonacorso HG, Martins MAP, Bittencourt ST, Lourega RV, Zanatta N (1999) Trifluoroacetylation of unsymmetrical ketone acetals. A convenient route to obtain alkyl side chain trifluoromethylated heterocycles. J Ruor Chem 99 177-182... 

Jeon SL, Kim JK, Son JB, Kim BT, Jeong IH (2007) One pot synthesis of novel a, P-dichloro-P-trifluoromethylated enones and their application to the synthesis of trifluoromethylated heterocycles. J Fluor Chem 128 153-157... 

InouyeY, Yokozawa T, Ishikawa N (1985) 2-Hydryl-2-(F-methyl)-F-propanoyl fluoride as a useful building block for the synthesis of trifluoromethylated heterocyclic compounds. Synthesis of l,3-dimethyl-2,3-dihydro-5-(F-methyl)-6-fluoro-2-thioxo-4(lH)-pyrimidinone and l,3-dimethyl-5-(F-methyl)-6-fluoro-2,4(lH, 3H)-pyrimidinedione. J Fluor Chem 27 379-384... 

Kubota T, Yamamoto K, Tanaka T (1983) Bis(l-trifluoromethyl-2,2,2-trifluoroethoxy)triphe-nylphosphorane. A new route to trifluoromethylated heterocycles. Chem Lett 167-168... 

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