Gem-Difluorination

Hypervalent iodobenzene chlorofluo-rides, a useful fluorinating reagent, has been used for indirect anodic gem-difluorination [38, 39]. 

S. Debarge, S. Thibaudeau, B. Violeau, A. Martin-Mingot, M.P. Jouannetaud, J.C. Jacquesy, A. Cousson, Rearrangement or gem-difluorination of quinine and 9-epiquinine and their acetates in superacid. Tetrahedron 61 (2005) 2065-2073. 

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 ... 

F-Teda BF4 (6) has also been used for the gem-difluorination of active methylene compounds, / -oxo esters and amides.102 The reaction times can be significantly reduced by carrying out the two fluorination steps sequentially and, importantly, with the sodium enolate of the monofluoro intermediate for the second step. 

A systematic study of the reaction of different glycos-2- and 3-uloses with (diethylamino)sulfur trifluoride (DAST) was performed480 for the preparation of gem-difluorides. gem-Difluorination of glycos-2-uloses may take place effectively, but only if the neighboring groups have the same configuration, as shown in the following examples. 

A. El-Laghdach, R. Echarri, M. I. Matheu, M. I. Barena, and S. Castillon, gem-Difluorination versus 1,2 migration and fragmentation in the reaction of 2- and 3- uloses with DAST. Influence of stereochemistry at the anomeric carbon atom, J. Org. Chem., 56 (1991) 4556 1559. 

An electrochemical methodology using an in situ prepared difluoride from p-iodoanisol is an alternative approach for indirect anodic gem-difluorination of dithioacetals [52],... 

Furthermore, the hexafluoropropene iethylamine reagent is also employed for the gem-difluorination of 1,3-dithiolanes. Formation of a-fluoro sulfides and of vinyl fluorides (see Section 1.1.7.1.) is observed. 

Chlorodifluoromethylated derivatives represent good substrates for the preparation of gem-difluorinated heterocycles by means of electrochemical... 

In contrast, anodic oxidation of hydrazones in the presence of fluoride ions provides mainly monofluorinated products, and gem-difluorinated products are formed in low yields [90]. 

Figure 12.2 Effect of the gem-difluorinated analogue of MS-073 on the proliferation of multidrug resistant CHRC5 Chinese hamster cells in the presence of doxorubicin (1 pg/mL).

At more positive potentials, another fluorination step occurs and allows also the formation of gem-difluorinated compounds in high yields. 

Scheme 2.203 Example of the synthesis of gem-difluorinated carbohydrate analogs via a Reformatsky reaction with ethyl bromodifluoroacetate [41c].

Some typical reactions of 1,1 -difluoroethene with nucleophiles are summarized in Scheme 2.18. Alkoxides [3], trialkylsilyl anion [4], ester enolates [5], and diphenylphosphinyl anion [6] attack the gem-difluorinated carbon of 5. However, it is noteworthy that nucleophilic substitution and proton abstraction are in some cases competitive, and thus s -butyl lithium abstracts the (3 -vinylic proton predominantly to generate vinyllithium. The lithium species can be trapped with an aldehyde, providing difluoroallyl alcohol, which is then hydrolyzed to a, (3-unsaturated carboxylic ester (11) [ 7 ] (Scheme 2.19). Some synthetically useful examples are shown in Schemes 2.20 and 2.21. Tetrathiafulvalene derivative (14) is prepared from difluorinated derivative (13) [8]. An elegant intramolecular version was demonstrated by Ichikawa, which provided a range of cyclized compounds (17), including dihydrofurans, thiophenes, pyrroles, and cyclopentenes, and also corresponding benzo derivatives (20) [2]. 

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