Gem-difluoro

Methyliodobenzene difluoride cleaves aryl dithioketals. The reactions are conducted in dichloromethane solutions at 0 °C to give gem-difluoro compounds in 65-90% yields [4 (equation 6)... 

The gem-dichloro and gem-dibromo analogues (24e and 24f) are more potent inhibitors of HLE compared to PPE, whereas the gem-difluoro (3-lactam 24a is equally efficient against the two enzymes (Table 11.4).34... 

Quite recently, Troupel et al. have developed an effective synthesis of gem-difluoro-/ -oxonitriles using an electrogenerated base derived from phenyl bromide and a sacrificial magnesium anode together with a nickel cathode coated with a small deposit of cadmium as shown in Scheme 4.5 [34]. 

The carbonyl of aldehydes and ketones can be transformed into a gem-difluoro group. This transformation can be performed either directly with DAST or in an indirect manner by treating the corresponding thioacetal or hydrazone with an oxidant (NBS, dibromohydantoin, etc.) in the presence of a source of fluoride ions (e.g., HF-pyridin complex or TBABF prepared from TBAF and KHF2). ... 

Yoshigama and Fuchigami have also reported that several dithioacetals of aliphatic and alicyclic ketones can be converted to their gem difluoro-derivatives in a similar manner. However, they found that with diphenyl dithioacetals only one C - S bond is cleaved to give the monofluoro- compound... 

Many aldehydes and ketones have been converted to gem-difluoro compounds with sulfur tetrafluoride SF4,240 including quinones, which give 1,1,4,4-tetrafluorocyclohexadiene derivatives. With ketones, yields can be raised and the reaction temperature lowered, by the addition of anhydrous HF.241 Carboxylic acids, acyl chlorides, and amides react with SF4 to give 1,1,1-trifluorides. In these cases the first product is the acyl fluoride, which then undergoes the gem-difluorination reaction ... 

Ketones are less reactive than the aldehydes (see Section 8.4.2.). Ketones, e.g. 1 and 3, can be converted to the corresponding gem-difluoro compounds, e.g. 2 and 4, respectively, with (dia-lkylamino)trifluoro-A4-sulfanes at temperatures ranging from 20 to 80 C (see Table 4). 

Suprisingly, the treatment of furanones such as benzofuran-3(2//)-one (6) with DAST does not result in the formation of the desired gem-difluoro compound, but instead in the formation of the monofluorinated addition product 7 in good yield.52... 

Analogous reactions with perfluoro(isopropyl-l,3,5-triazine) and per-fluoro(diisopropyI-l,3,5-triazine) with CsF yielded adducts 116 and 117, respectively, which were detected by 19F-NMR. Use of potassium fluoride, either alone or associated with 18-crown-6, did not lead to the formation of the adducts. In contrast, from tris(perfluoroisopropyl)-l,3,5-triazine no adduct was detected. This is quite interesting because it would indicate the importance of the gem-difluoro substitution to stabilize the adduct,160 in analogy with the effect of gem-dimethoxy substitution.76... 

The chemical effect of a gem-difluoro group on cyclopropane is to facilitate the thermal cleavage of the distal ring bond. This is illustrated by the facile endojexo isomerization of tricyclic cTO-difluorocyclopropane 1, which occurs at 60 C.4... 

The increasing tendency toward thermal extrusion of CF2 with increasing number of fluorine substituents on the cyclopropane ring has been demonstrated in studies of 1,1-difluorocyclo-propane, 1,1,2-trifluorocyclopropane, 1,1.2,2-tetrafluorocyclopropane,19 and perfluorocyclo-propane.20 Studies of the thermolysis of 1,1,2,2-tetrafluorospiropentane 8 21 and 1,1.2,2-tetra-fluoro-3-methylenecyclopropane (25),22 however, demonstrated that the CF2-CF2 bond in a tetrafluorocyclopropane is substantially weakened. In the case of 25, rearrangement to 2-(di-fluoromethylene)-l,l-difluorocyclopropane (26) occurs irreversibly at 150°C at a rate that was calculated to be 7850 times faster than that of the gem-difluoro analog 21. 

Moreover, high levels of stereoselectivity were obtained for gem-difluoro-p-aminoesters and gem-difluoro-p-lactams using either (R)-phenylglycinol or (R)-methoxyphenylglycinol [143]. 

Scheme 55 Synthesis of gem-difluoro-P-aminoesters and gem-difluoro-P-lactams from ethyl bromodifluoroacetate...

The HF-SbF5 superacid finds numerous additional useful applications in other fluorination reactions. Ally lie amines are hydrofluorinated in HF-SbF5 (7 1) to give /3-fluoro-substituted products (—20°C, 24—85% yields).545 HF-SbF5 in combination with /V-bromosuccinimide transforms allylic amines and haloalkyl amines into gem-difluoro derivatives (0°C or 20°C, 43-70% yield).546... 

An excellent method for the preparation of gem-difluoro compounds from aldehydes and ketones consists of conversion of the carbonyl compound to the corresponding 1,3-dithiolane followed by treatment with two equivalents of l,3-dibromo-5,5-dimethylhydantoin (DBH) and pyridinium poly(hydrogen fluoride) (HF-pyridine) in methylene chloride. Attempted extension of this procedure to 7-methoxy-2,2-dimethyl-4-chromanone, however, gave only the dihydro- 1,4-dithiin derivative 1 in 78% yield. This transformation, which proceeded in excellent yield with a variety of 4-chromanones, was found to require only the DBH (i.e. fluoride ion played no role). 

Begue, J.-P. Bonnet-Delpon, D. Rock, M. H. The addition of N-lithiated amines to 1,1,1-tri-fluoromethylstyrene, a concise synthesis of 3-gem-difluoro-2-phenyl allylic amines. Synlett 1995, 659-660. 

The synthesis of gem-difluoro compounds 1 from aldehydes or ketones using sulfur tetrafluoride has already been discussed in Houbcn-Wcyl, Vol.5/3, p84 (see also VoI.ElOa, p336fi ). 

The reaction of aldehydes or ketones with organosulfur trifluorides yields gem-difluoro compounds... 

The reaction of hydrazones and their derivatives 1 with iodine monofluoride (IF), prepared from the elements, yields the corresponding gem-difluoro compounds 2 (Table 1). Unsubstituted hydrazones 1 (R = R = H) are usually the most suitable substrates for this transformation. 

Semicarbazones (Table 1, R = CONH2) also react with iodine monofluoride. The gem-difluoro compounds are generally obtained in lower yields than with unsubstituted hydrazones, but the corresponding aldehyde derivatives (entry 16) arc reactive in this case. Finally, in the reaction of tosylhydrazones, gew-difluorides are obtained in only low to moderate yields (entries 4 and 23). 

Other reagents, such as bromine monofluoride, generated in situ from A -bromosuccinimide and pyridinium poly(hydrogen fluoride) [NBS, (HF) /pyridine] or poly(4-vinylpyridinium) poly(hydrogen fluoride) [NBS, (HF) /PVP], and elemental fluorine, as well as electrochemical methods, have been described for the transformation of hydrazones into. gem-difluoro compounds. 

Yield of gem-difluoro compound in parentheses. Azine was obtained in 53% yield. 

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