Fluorinated dienophiles

This section deals with fluorinated dienes and fluorinated dienophiles in which the fluorine atom(s) are attached directly to the double bond(s). The reason for highlighting work in this area is to show how there is a significant need for new methodology indeed, the formation of cyclic mono- or di-fluorocompounds remains the one significant area where building block chemistry is weak. 

Fluorinated dienophiles. Although ethylene reacts with butadiene to give a 99 98% yield of a Diels-Alder adduct [63], tetrafluoroethylene and 1,1-dichloro-2,2-difluoroethylene prefer to react with 1,3-butadiene via a [2+2] pathway to form almost exclusively cyclobutane adducts [61, 64] (equation 61). This obvious difference in the behavior of hydrocarbon ethylenes and fluorocarbon ethylenes is believed to result not from a lack of reactivity of the latter species toward [2+4] cycloadditions but rather from the fact that the rate of nonconcerted cyclobutane formation is greatly enhanced [65]... 

The behavior of strained,/Zuorimiret/ methylenecyelopropanes depends upon the position and level of fluorination [34], l-(Difluoromethylene)cyclopropane is much like tetrafluoroethylene in its preference for [2+2] cycloaddition (equation 37), but Its 2,2-difluoro isomer favors [4+2] cycloadditions (equation 38). Perfluoromethylenecyclopropane is an exceptionally reactive dienophile but does not undergo [2+2] cycloadditions, possibly because of stenc reasons [34, 45] Cycloadditions involving most possible combinations of simple fluoroalkenes and alkenes or alkynes have been tried [85], but kinetic activation enthalpies (A/f j for only the dimerizations of tetrafluoroethylene (22 6-23 5 kcal/mol), chlorotri-fluoroethylene (23 6 kcal/mol), and perfluoropropene (31.6 kcal/mol) and the cycloaddition between chlorotnfluoroethylene and perfluoropropene (25.5 kcal/mol) have been determined accurately [97, 98] Some cycloadditions involving more functionalized alkenes are listed in Table 5 [99. 100, 101, 102, 103]... 

For dienophiles with vinylic fluorine, such as perfluoropropene, the [2+4] reactivity is diminished so that [2-1-2] cycloaddition dominates [71] (equation 64). 

Similarly, partially fluorinated and perfluorinated methylenecyclopropanes [57, 52], cyclopropenes [55, 84, 55], cyclobutenes [75, 56], and bicychc alkenes [57, 55, 59, 90] apparently denve dienophilic reactivity from relief of their ground-state strain during reaction Thus 2,2-difluoromethylenecyclopropane and perfluoromethylenecyclopropane undergo exclusive [244] cycloadditions [57, 52] (equations 72 and 73), whereas (difluoromethylene)cyclopropane undergoes only [24-2] cycloadditions [57]... 

Fluorinated cyclopropenes have long been known to be reactive dienophiles [9], and the past 20 years have provided us with a few more nonexceptional examples [S3, 84, S5]. 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104], In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(tntIuoromethyl)benzyne were shown to react in moderate yields with A7-(trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

Fluorine-substituted heterodienes are particularly prone to inverse electron demand Diels-Alder reactions with electron-rich dienophiles, as can be seen from the examples in equations 94-97 [113, 114, 115, 116, 117]... 

Aromatic fluoro-compounds have been prepared by thermal cycloaddition of fluorinated 1,3-butadienes 10-12 (Figure 2.1) with several dienophiles. Fluorophenols were obtained by cycloaddition of diene 10 with quinones [11]... 

The Diels-Alder reactions of dienes 11 and 12 with many dienophiles allowed other fluorinated aromatics to be synthesized [12,13]. For example, diene 11 reacted with dimethylacetylenedicarboxylate and ethylpropiolate (Scheme 2.8) to give trifluoromethyl diethylphthalate and trifluoromethylethylbenzoate, and diene 12 with/ -benzoquinone affords 5-fluoronaphthoquinone (Equation 2.5). 

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

Fluorinated cyclopentadienes would be ideal components for cycloaddition reactions leading to fluorinated carbocycles. However, there are few reports of such species. Treatment of the thallium(I) salt of cyclopentadiene with Select-fluor led to the formation of fluorocyclopentadiene (Eq. 118), which reacted with dienophiles to afford cycloadducts in the syn orientation [317]. 

This effect cannot be explained by simply considering differences in frontier orbital energies. A useful monofluorinated dienophile has been prepared [364] using metallated difluoroenol carbamate chemistry (Eq. 143) cycloaddition occurred smoothly with a range of dienes, and desulfination could be achieved under mild conditions without loss of the fluorine atom. Wakselman and co-workers [365] synthesised a rare competent difluorinated dienophile. Lewis acid catalysed Diels-Alder reaction with furan afforded an acceptable yield of (unfortunately) unstable cycloadduct which decomposed to a phenolic product via a dehydrofluorination reaction, circumscribing its utility (Eq. 144). 

Fluorinated dienes have been described, though again, the incidence is rare. Treatment of an a,/ -unsaturated-a-fluoroaldehyde with chlorotrimethyl silane afforded [369] the l-trimethylsilyloxy-2-fluorobutadiene which underwent [4 + 2] cycloadditions with dienophiles, though more slowly than its non-fluori-nated counterpart, and with lower regioselectivity (Eq. 148). 

Substituting vinylic hydrogen in a,P-unsaturated carbonyl compounds with vinylic fluorine does not affect their dienophilic character negatively Indeed, 3,3-difluoroacrylic acid is more reactive toward furan than its nonfluonnated counterpart [95] (equation 81) Consistent with this observation is the fact that tetrafluorobenzoquinone forms only a bis-Diels-Alder adduct in 68% yield in its reaction with cyclopentadiene at room temperature [96, 97 ... 

Fluorinated thioketones <1965JOC1390> and perhalogenoalkylthioacetyl fluorides <1992CB1889> are reactive dienophiles and rapidly add across the 9,10-bond of anthracene to form the isothiochroman nucleus 494 (Equation 170). Similar products result from the treatment of the sulfenyl chloride 495 with triethylamine when a thioaldehyde is generated (Scheme 182) <1991J(P1)3225>. 

Krishnaiah, A. and Narsaiah, B. 2002. Studies on inverse electron demand hetero Diels-Alder reaction of perfluoroalkyl 2(1H) pyridones with different dienophiles under microwave irradiation. Journal of Fluorine Chemistry, 113 133-37. 

Dienes are deactivated by the presence of electron-withdrawing substituents. Thus, fluorinated dienes arc generally less reactive than their nonfluorinated counterparts. Monofluorinated dienes, for example, 2-fluoro-l-(trimethylsiloxy)-1.3-dienes, undergo [4-f-2]-cyeloaddition reactions with a large variety of dienophiles (see Table 10). 

In this section we will consider [4 + 2] cycloaddition reactions in which the fluoroalkene acts as the dienophile. For related reactions involving fluorinated dienes, see Section IIG. 

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