Fluoroalkyl

Unlike the 3-position, the 5-position is very susceptible to nucleophilic substitutions and additions. Thus, a series of publications report that 5-fluoroalkyl-l,2,4-oxadiazoles 94 undergo reaction with hydrazine or hydroxylamine to furnish 3-fluoroalkyl-l,2,4-triazoles 95 (X = NH) and 3-fluoroalkyl-1,2,4-oxadiazoles 95 (X = 0), a reaction that proceeds via addition of the nitrogen nucleophile to the 5-position (Scheme 9) <2005JOC3288, 2004EJ0974, 2003JOC605>. 

The range of imines that are suitable for reaction has been extended to include the fluoro-substituted aldimines 317 <2002JCM131> and N-unsubstituted imines 319 <1999AXC2158, 2002PJC1137, 2003TL2015>, thus allowing access to 5-fluoroalkyl-4,5-dihydro-l,2,4-oxadiazoles 318 and 4-unsubstituted 4,5-dihydro-l,2,4-oxadiazoles 320 as shown in Equations (60) and (61), respectively. 

Numerous S -fluoroaryl or S -fluoroalkyl derivatives of cysteine have been described. Thus, fluorination of S -benzyl cysteine has been performed with XeFa- The photochemical trifluoromethylation of cysteine, or of its disulfide, affords optically pure S -trifluoromethyl cysteine. Some electrophilic halogenated compounds (such as trifluorochloroethylene) are able to achieve the 5-fluoroalkylation of cysteine. 

S -Mono-, di-, and trifluoro derivatives of methionine and 5-fluoroalkyl derivatives of cysteine are accessible through fluorination. Thus, fluorination of methionine sulfoxide with xenon fluoride, or more easily using DAST, provided 5-monofluor-omethionine. Photochemical trifluoromethylation of homocysteine leads to 5-trifluoromethionine. These S -fluoroalkyl compounds are also available through fluoroalkylation of homocysteine. Thus, the addition of difluorocarbene (formed from Freon 11 (CHF2CI)) affords S -difluoromethionine. ... 

The presence of a 3-fluoroalkyl group did not prevent 4-bromination, but extended reaction times were necessary to obtain high yields (80-94%). Under similar conditions l-substituted-5-fluoroalkyl- and -3,5-... 

Thus, in the presence of Rh2(OAc)4, ethyl-2-diazofluoroacetoacetate, obtained by the reaction of ethylfluoroalkylacetoacetate with perfluoroalkane-sulfonylazide, reacts with nitriles giving 5-fluoroalkyl-substituted 1,3-oxazoles (00JFC(103)139) (Scheme 56). 

When treated with hydroxylamine, /1-aminovinylketones 75 give 5-amino-5-fluoroalkyl-2-isoxazoline 76, while /1-aminovinylketones 77 yield 3-hydroxy-5-fluoroalkyl-A2-isoxazoline 78 treatment of 77 with hydrazine hydrate and phenylhydrazine leads to pyrazole and mixture pyrazole and 5-hydroxy-A2-pyrazoline corresponding (96IZV1306) (Scheme 78). 

Fluoro-5-(fluoroalkyl) derivatives 160 are synthesized from the corresponding ketene dithioacetals 161 (Scheme 35) [85,86]. The 4,5-bis(methoxy-... 

In many cases, mixtures of the 3- and 5-fluoroalkyl regioisomers were obtained. However, when reactions were performed in neutral alcoholic media, 5-fluoroalkyl-5-hydroxypyrazoline intermediates 94 were isolated instead of the dehydrated final products 96 (entries 1, 6,7, 9 Table 1) [48]. This observation conld be explained on the basis of the influence of the fluoroalkyl group adjacent to the hydroxyl gronp that stabilizes the hydroxypyrazoline 94, preventing the dehydration process (via a). In addition, the dehydration involves a cationic intermediate, whose formation could explain why, when R is an electron-withdrawing group, the dehydration does not occur or occurs with difficulty. In contrast, in an acidic medium, 94 was not observed, probably because the dehydration follows a different mechanism (via b). In acidic EtOH solution (H2SO4 catalyst), at room temperature or at reflux, the... 

Shavnya A, Sakya SM, Munich ML, Rast B, DeMello KL, Jaynes BH (2005) Efficient fluoride-mediated synthesis of 5-alkyl amino- euid ether-substituted pyrazoles. Tetrahedron Lett 46 6887-6891. For the regioselective synthesis of 1-alkyl-5-fluoroalkyl-3-hydroxypyrazoles, see Hamper BC, Kurtzweil ML, Beck JP (1992) Cyclocondensation of alkylhydrazines and p-substituted acetylenic esters Synthesis of 3-hydroxypyrazoles. J Org Chem 57 5680-5686... 

To account for formation of the desired 5-fluoroalkyl oxazoles, the more nucleophilic fluoroalkylated carbonyl group should participate in cyclizatiou rather than the ester group. The mechanism of this reaction is ontlined below. As a key intermediate rhodium carbenoid is formed [34]. 

A number of 5-fluoroalkylated IH-1,2,3-triazoles 54 was synthesized in good yield by the 1(X) % regioselective 1,3-dipolar cycloaddition of (Z)-ethyl-3-fluoroalkyl-3-pyrrolidino-acrylates with aryl or benzyl azides [57]. 

Peng W, Zhu S (2003) Efficient synthesis of 5-fluoroalkylated IH-1,2,3-triazoles and application of the bromodifluoromethylated triazole to the synthesis of novel bicychc gem-difluorinated lH-pyrano[3,4-d][l,2,3]-tiiazol-4-one compounds. Tetrahedron 59 4395-4404... 

Pryadeina MV, Burgart YV, Saloutin VI, Kodess MI, Ulomskii EN, Rusinov VL (2004) Synthesis of 7-alkyl(aryl)-6-aIkoxycarbonyl-5-fluoroalkyl-l, 2,4-tri(tetr)azolo[ 1,5-a]pyrimi-dines. Russ J Org Chem 40 902-907... 

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