Synthesis of Trifluoromethyl Heterocycles

The pyranobenzopyran 1 is readily available and has proved to be a useful starting material for the preparation of a number of 3-substituted chromones. Thus, reaction of 1 with a large excess of an enolisable ketone RCOCH3 in the presence of aqueous acid resulted in smooth conversion into the chromones 2. 

Give a mechanism for this transformation, and outline a simple synthesis of 1. 

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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... 

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... 

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... 

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

Methods for synthesis of a,(3-unsaturated trifluoromethyl ketones and their use in the synthesis of trifluoromethyl-substituted heterocycles 99UK483. 

The higher homologue of fluoral, pentafluoropropionaldehyde, prepared by reduction of ethyl pentafluoropropionate, is a precursor of diethyl tetrafluoroketene dithioacetal, which is a versatile building block for the synthesis of trifluoromethyl-substimted functional compounds, such as trifluoromethyl lactones, lactams, and heterocyclics, as exemplified in the Figure 2.53. ... 

Shaaban MR (2008) Microwave-assisted synthesis of fused heterocycles incorporating trifluoromethyl moiety. J Fluorine Chem 129 1156-1161... 

Reaction of trifluoromethyl vinyl ketones with magnesium/MesSiCl leads to a di-fluoro analog of Danishefsky s diene (24) [34] (Scheme 2.200) which is a useful building block for synthesis of fluorinated heterocycles [35],... 

Burger, K. Hennig, L. Fuchs, A. Greif, D. Spengler, J. Albericio, F. Domino reactions with fluorinated five-memhered heterocycles synthesis of trifluoromethyl substituted hutenohdes and y-ketoacids. Monatsh. Chem. 2005,136, 1763-1779. 

Andrew RJ, MeUor JM (2000) Synthesis of (trifluoromethyl)pynoles and related heterocycles from 4-ethoxy-l,l,l-trifluorobut-3-en-2-one. Tetrahedron 56 7267-7272... 

Methods for the synthesis of trifluoromethyl-substituted furans and benzofurans can be divided into several groups direct trifluoromethylation of heterocycle, transformation of functional groups of hetarene into trifluoromethyl substituent, Diels-Alder/retro-Diels-Alder sequence, and various methods for the furan ring formation from precursors bearing trifluoromethyl moiety. 

Linderman RJ, KiroUos KS (1989) An efficient method for the synthesis of trifluoromethyl substituted heterocycles. Tetrahedron Lett 30 2049-2052... 

Rodinovskaya LA, Shestopalov AM, Gromova AV, Shestopalov AA (2008) One-Pot synthesis of diverse 4-Di(tri)fluoromethyl-3-cyanopyridine-2(lH)-thiones and their utilities in the cascade synthesis of annulated heterocycles. J Comb Chem 10(2) 313-322 Suzuki H, Sakai N, Jwahara R, Fujiwa T, Satoh M, Kakehi A, Konakahara T (2007) Novel synthesis of 7-fluoro-8-(trifluoromethyl)-lH-l,6-naphthyridin-4-one derivatives intermo-lecular cyclization of an N-silyl-l-azaallyl anion with perfluoroalkene and subsequent intramolecular skeletal transformation of the resulting pentasubstituted pyridines. J Org Chem 72(15) 5878-5881... 

Abstract The synthesis, reactivity and applications of flnorinated a- and y-pyrones, chromones and coumarins are reviewed. The literature data clearly indicate that these heterocycles are very attractive building blocks for the synthesis of various heterocyclic compounds containing the R group. This chapter reviews the significant advances in this area, highlighting new and interesting trifluoromethylated derivatives and their novel transformations. The bibliography includes 204 references. 

Takahashi M, AMyama K, Sirzuki T, Inoue H (2(X)8) Synthesis of trifluoromethyl-1,2,4-triazine- and trifluoromethylpyrimidine-fused uracils. J Heterocycl Chem 45 601-605... 

Cushman M, Patel H, McKenzie A (1988) Synthesis of trifluoromethylated pyrazine-containing nitrogen heterocycles from trifluoropyruvaldehyde and ortho-diamines scope and regiochemistry. J Org Chem 53 5088-5092... 

Since heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, Shibata ct al. have developed a novel enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 46 on the basis of a domino oxa-Michael-intramolecular hemi-aminahzation-dehydration reaction of hydroxylamine with a range of ( )-trifluoromethylated enone derivatives 47 [81]. This process, which employed N-3,5-bis(trifluoromethyl)benzyl-quinidinium bromide 48 as a chiral phase-transfer catalyst combined with CsOH as a base provided a series of trifluoromethyl-substituted 2-isoxazolines 46 in high yields and enantioselectivities of up to 94% ee (Scheme 37.8). 

Matteis VD, von Delft FL, Jakobi H, Lindell S, Tiebes J, Rutjes FPJT. RCM-mediated synthesis of trifluoromethyl-containing nitrogen heterocycles. J. Org. Chem. 2006 71 7527-7532. 

Heteroaromatic esters such as 493 and amides are produced by the carbo-nylation of heterocyclic bromides[347,348]. Even dichloropyrazine (494) and chloropyridine are carbonylated under somewhat severe conditions (120 C, 40 atm)[349]. The carbonylation of trifluoroacetimidoyl iodide (495) proceeds under mild conditions, and can be used for the synthesis of the trifluoromethyl-glycine derivatives 496 and 497(350]. 

Nitrones are among the most highly studied and useful reagents for the synthesis of five-membered-nng heterocycles. The first fluonnated nitrone, N-methyl-C-(trifluoromethyl)nitrone, was prepared recently and used to introduce Irifluoromethyl groups into such heterocycles... 

The synthesis of photochromic 6n conjugate systems having a bis(2,3 -benzothienyl) unit 75 was described (04CC1010) (Scheme 23). These systems have unusual structures, in which the fluorine atom, the methyl group, or the trifluoromethyl group rather than the heterocycle is located in a vicinal position adjacent to the benzothienyl substituent in the per-fluorocyclopentene moiety. 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Transformation of a readily available heterocycle into a less readily available heterocycle is a time-honoured and valuable strategy in synthesis. In a recent example, a versatile and high yielding synthesis of trifluoromethylpyrroles was described, starting from trifluoromethyloxazolones. Typically, 2-trifluoromethyl-4-phenyl-5(2//) °xazolone was mixed with a-chloroacrylonitrile in methylene chloride at room temperature, triethylamine was added, and the mixture stirred. Standard work-up gave 3-cyano-2-phenyl-5-trifluoromethylpyrrole in 70% yield. 

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