Alkenes trifluoromethylation

Egami H, Shimizu R, Kawamura S, Sodeoka M (2013) Alkene trifluoromethylation coupled with C-C bond formation construction of trifluoromethylated carbocycles and heterocycles. Angew Chem Int Ed 52 4000-4003... 

Methylarsine, trifluoromethylarsine, and bis(trifluoromethyl)arsine [371-74-4] C2HAsF, are gases at room temperature all other primary and secondary arsines are liquids or solids. These compounds are extremely sensitive to oxygen, and ia some cases are spontaneously inflammable ia air (45). They readily undergo addition reactions with alkenes (51), alkynes (52), aldehydes (qv) (53), ketones (qv) (54), isocyanates (55), and a2o compounds (56). They also react with diborane (43) and a variety of other Lewis acids. Alkyl haUdes react with primary and secondary arsiaes to yield quaternary arsenic compounds (57). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Diene moieties, reactive in [2 + 4] additions, can be formed from benzazetines by ring opening to azaxylylenes (Section 5.09.4.2.3). 3,4-Bis(trifluoromethyl)-l,2-dithietene is in equilibrium with hexafluorobutane-2,3-dithione, which adds alkenes to form 2,3-bis-(trifluoromethyl)-l,4-dithiins (Scheme 17 Section 5.15.2.4.6). Systems with more than two conjugated double bonds can react by [6ir + 2ir] processes, which in azepines can compete with the [47t + 27t] reaction (Scheme 18 Section 5.16.3.8.1). Oxepins prefer to react as 47t components, through their oxanorcaradiene isomer, in which the 47r-system is nearly planar (Section 5.17.2.2.5). Thiepins behave similarly (Section 5.17.2.4.4). Nonaromatic heteronins also react in orbital symmetry-controlled [4 + 2] and [8 + 2] cycloadditions (Scheme 19 Section 5.20.3.2.2). 

Although one trifluoromethyl group activates an alkene as a dienophile, two or more can actually inhibit dienophilic reactivity, as evidenced by the fact that... 

Syntheses of fluoro-substituted pyrazoles continue to be of interest. Both 3- and 5-fluoropyrazoles (44 and 45, respectively) can be prepared from 43 <96JOC2763>. Treatment of 43 with hydrazine followed by N-alkylation provides 44, whereas reactions with monosubstituted hydrazines afford 45. The 4-(trifluoromcthyl)pyrazoles 47 are obtained from J-trifluoromethyl vinamidinium salt 46 <96TL1829>. The 5-trifluoromethyl-3-carboethoxypyrazoles 49 are obtained from the 1,3-dipolar cycloadditions of trifluoromethyl alkenes 48 with ethyl diazoacetate <96T4383>. 

The most common situation where this effect is seen is in a comparison of E- and Z- isomers of trifluoromethyl- or difluoromethyl-substituted alkenes, but as the naphthalene examples indicate, the effect is not unique to that situation. 

Trifluoromethyl groups that are bound to sp2 carbons of alkenes, arenes, or heterocyclic compounds are slightly deshielded compared to the saturated counterparts, but the influence is relatively small (Scheme 5.32). 

Raasch, and Schaumann and co-workers, have studied the reactions of bis (trifluoromethyl)thioketene (83 R1 = CF3) with alkenes, with thioketones, and with carbodiimides or Schiff-base imines. The products were, respectively, thietans, 1,3-dithietans (84 R1 = CF3), and 1,3-thiazetidines (85 R1 = CF3) (from the carbodiimide).114,115 With phenyl azide the 1,2,3,4-thiatriazoline (86 R = CF3) is formed subsequent pyrolysis yields2,l-benzisothiazole.114... 

Absolute rates for the addition of the methyl radical and the trifluoromethyl radical to dienes and a number of smaller alkenes have been collected by Tedder (Table l)3. Comparison of the rate data for the apolai4 methyl radical and the electrophilic trifluoromethyl radical clearly show the electron-rich nature of butadiene in comparison to ethylene or propene. This is also borne out by several studies, in which relative rates have been determined for the reaction of small alkyl radicals with alkenes. An extensive list of relative rates for the reaction of the trifluoromethyl radical has been measured by Pearson and Szwarc5,6. Relative rates have been obtained in these studies by competition with hydrogen... 

TABLE 1. Absolute rate constants for the addition of methyl and trifluoromethyl radicals to simple alkenes at 164 °C3... 

TABLE 2. Relative rate constants for the addition of the trifluoromethyl radical and the diethyl a-benzylmalonyl radical to simple alkenes and dienes... 

Another convenient entry to fused cyclobutene-1,2-diesters was via site selective modification of the norbomene rt-bond in Smith s fe-alkene 49, e.g. treatment with 3,6-di(2 -pyridyl)-s-tetrazine 51 followed by DDQ oxidation afforded the cyclobutene-derivative 53 <97AA119>, while direct coupling with 3,5-f> (trifluoromethyl)-l,3,4-oxadiazo]e 54 furnished the tas(cyclobutene-l,2-diester) 55 (Scheme 6) <97SL196>. 

Both these parameters reflect a moderate stability for BrN3 in methanol. This feature made it impossible to apply the azide clock method to determine the lifetime of the ionic intermediates arising from deactivated alkenes (for example, / ,p -bis(trifluoromethyl)stilbenes). Nevertheless, for a couple of p-methoxy substituted stilbenes and unsubstituted stilbenes the selectivity ratios reported in Table II have been found. (IT)... 

Bis [(trifluoromethyl)thio] acetaldehyde (83a) has been prepared from an enam-ine precursor (84), although refluxing in aqueous ethanolic HCl is required to effect this reaction.The aldehyde is less stable than its enol tautomer (83b), and many reactions typical of aldehydes fail. For example, addition of aqueous silver nitrate immediately yields the silver salt of (83b), rather than giving precipitation of (elemental) silver. The (trifluoromethyl)thio substituent has pseudohalogenic character and, together with the hydroxy group, stabilizes the alkene tautomer in the manner of a push-pull alkene. The enol-aldehyde equilibrium mixture in acetonitrile shows an apparent of 2.6 when titrated with aqueous hydroxide. 

Halogen atoms. The introduction of side-chains on 9-trifluoromethyl-paullone 409 can be accomplished applying a Stille coupling (Scheme 86, Section 5.2.1.1 (2005EJM655)). Similarly, a Heck reaction of iodo 409 with terminal alkenes under standard conditions affords 2-substituted paullones 413 exclusively as E-isomers. The reaction of terminal alkynes with 409 in the presence of cuprous iodide and a palladium catalyst in triethylamine furnishes the 2-alkynyl-paullones 412 (2000BMCL567). 

Difluorophosphoryl(trifluoromethyl) peroxide, 16 135, 136 reactions of, 16 136 Difluoropolysulfanes, 16 302, 325-327 NMR of, 16 325, 326 separation of, 16 327 Difluorosilylene, 29 15-36 alternate layer reactions, 29 26-27 in nuclear recoil systems, 29 22 polymerization, 29 15 reaction mechanisms with alkenes and alkynes, 29 17-19 under co-condensation conditions, 29 28-32, 34-35... 

TABLE 4. B3LYP/6-31G(d) activation barriers (AE, kcal mol ) for the epoxidation of a series of alkenes with dimethyldioxirane (DMDO) and methyl(trifluoromethyl)dioxirane (TFDO). The barriers in parentheses are at the B3LYP/6-31- -G(d,p) level of theory. Other computational approaches are indicated by footnotes. The barriers have been computed with respect to isolated reactants... 

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