Nucleophilic trifluoromethylation of some polycyclic ketones #

Ruppert’s reagent (CF 3 -SiMe 3 ) was used in the reaction with derivatives of pentacyclo-[5.4.0.0 2,6 .0 3,10 .0 5,9 ]undecane-8,11-dione (‘cage’ dione) in the presence of dry CsF to yield trifluoromethyl O -silylated products. Subsequent acidic hydrolysis gave the corresponding hydroxy derivatives. In the case of the ‘cage’ dione the transannular cyclization leading to oxahexacyclic ( O -bridged) product was observed.


Introduction
The chemistry of fluorinated compounds has been extensively explored in recent decades.It is well established that introduction of the trifluoromethyl group into a known substance results in significant changes in the chemical, physical and biological properties. 1 Direct trifluoromethylation of aromatic compounds is mostly based on the reactions of in situ generated •CF 3 radical. 2The non-direct trifluoromethylation with SF 4 used as a source of fluorine atoms has been developed by Dmowski. 3 On the other hand, there are known methods that explore an ionic CF 3 -moiety, e.g. the sulfonium salt of type 1 is an efficient source of the trifluoromethyl cation (Scheme 1). 4 In recent times, nucleophilic trifluoromethylation has been widely explored for introduction of the CF 3 -group using carbonyl substrates such as aldehydes, ketones or esters 5 and trimethyl(trifluoromethyl)silane (3) known as the Ruppert's reagent. 6For the first time presented at 14 th European Symposium on Fluorine Chemistry, Poznań, Poland, July 11-16, 2004, Book of Abstracts, A-P-75, 164.In the original protocol, tetrabutylammonium fluoride (TBAF) was used as a catalyst in the reaction of 3 with carbonyl compounds yielding the corresponding trifluoromethylated alcohols via O-silylated derivatives. 7At present, cesium fluoride seems to be a catalyst of choice.5a However recently, an efficient application of the new catalysts in nucleophilic trifluoromethylation was described. 8he relatively easily available polycyclic 'cage' ketones 6 and 9 can be used as building blocks for the preparation of more complex systems, including hosts in supramolecular chemistry. 9Adamantanone (2), which belongs to the polycyclic 'cage' structures, reacts easily with 3 yielding trimethylsilyl derivative 4 which after acidic hydrolysis can be easily converted to 2-(trifluoromethyl)adamantan-2-ol (5) (Scheme 2). 10 O

Issue in
In the case of the dione 9 reactions with primary amines, are reported to yield the corresponding monoimine derivatives which upon treatment with reducing agents (NaBH 4 , LiAlH 4 ) undergo a transannular cyclization via formation of the O-bridge. 11Reactivities of 6 and 9 have been studied in our group for some years and their ability to undergo transannular cyclization was observed in reactions with diverse O-and S-nucleophiles. 12The aim of the present study was to examine their reactions with Ruppert's reagent 3 and to elaborate a straightforward protocol for preparation of trifluoromethylated polycyclic alcohols.

Results and Discussion
The experiment with 3 and 6 was performed in dry 1,2-dimetoxyethane (DME) in the presence of catalytic amount of cesium fluoride (dried at 200-300 o C).The expected O-silylated product 7 was smoothly obtained and subsequent hydrolysis followed by crystallization from hexane led to a colorless solid identified as alcohol 8 (Scheme 3).

Scheme 3
The reaction occurs stereoselectively and the trifluoromethyl anion approaches the carbonyl group from the exo-face exclusively.As a result, the final product 8 contained the hydroxy group placed at the endo position as evidenced by the X-ray study. 13he reaction of 3 with 9 was carried out under analogous conditions.Depending on the molar ratio of substrates dione 9 was expected to react either with one or two equivalents of CF 3 -SiMe 3 yielding mono-or bis-trifluoromethylated alcohols 10 or 11, respectively.The first attempted reaction of 9 with an equimolar amount of 3 was expected to yield the hydroxyketone 10 (Scheme 4).
After addition of CF 3 -SiMe 3 an exothermic reaction started and after 1.5 h the conversion was complete.The initially formed trimethylsilyl derivative was hydrolyzed without isolation and crude product was purified by crystallization from hexane to give colorless crystals with a narrow melting point.The second experiment with two equivalents of CF 3 -SiMe 3 should have led to 11, but unexpectedly the isolated product was identical with the substance obtained in the first entry; this result was confirmed by the absence of mixed melting point depression and by comparison of spectroscopic data.The IR-spectrum did not show the absorption band of the C=O group suggesting that a transannular process took place.In the 13 C-NMR spectra the characteristic signals appeared at 89.3 (q, 2 J C-F = 34 Hz) and 120.0 (s, O-C-O) ppm, respectively.The MS-CI exhibited a molecular peak at m/z 262 [M+1+NH 3 ] + .Finally, the structure of trifluoromethylated hemiacetal 13 was unambiguously confirmed by the X-ray single crystal diffraction analysis (Fig. 1). Figure 1.ORTEP-plots for compounds 13 and 21. 13 Noteworthy, the transannular cyclization under trifluoromethylation conditions was previously reported for the reaction of a 1,5-dione (i.e.bicyclo[3.3.1]nonane-2,6-dione) but in this case the successful formation of the product of bis-trifluoromethylation was reported. 14ccording to an other report the reaction of 1,4-dione (i.e.hexane-2,5-dione) with one or two equivalents of 3 did not afford the product of transannular cyclization. 15Recently, we have found that 9 easily reacts at low temperatures with amines as a nucleophilic agent and the formation of transannular cyclization products was established, 16

Scheme 5
The formation of 13 strongly supports the mechanistic pathway of the CF 3 -group addition to the carbonyl group formulated by Prakash et al. 17 The first step of the reaction is the replacement of the CF 3 -group by the fluorine anion and trifluoromethide anion (F 3 C¯) attacks the carbonyl group to form the salt of type 14.Apparently, the following transannular cyclization leading to 15 is faster than the addition of another molecule of 3 leading to the intermediate 17 which could give hydroxyketone 10.In the next step, reaction with another molecule of 3 generates a transient species 16 bearing pentacoordinated silicon atom.This intermediete rapidly transfers F 3 C-group to the next molecule of 9 and the formation of the O-silylated acetal 12 is observed (Scheme 5).
examine the limitation of transannular cyclization in this less strained structure.The distance between the two carbonyl groups, as evidenced by the X-ray study, is larger in comparison with 'cage' dione 9. 19,21b The product isolated after reaction with 3 and subsequent hydrolysis exhibited no C=O absorption, indicating the formation of hemiacetal 19; additional spectroscopic data are comparable with those registered for compound 12.In another experiment the imine 20 prepared in the reaction of aniline with 9, 20 was treated with 3 and in this case the formation of silylated ether 21 was observed.The transannular process has not been observed and even with an excess of 3 the C=N-group did not react.The X-ray analysis 13 showed that the CF 3 -group is placed at exo-position (Fig. 1).

Scheme 7
In summary, the synthesis of new derivatives of trifluoromethylated polycyclic compounds 8, 13 and 19 using Ruppert's reagent was presented.Transannular cyclization led to hemiacetals 13 and 19, but it was not observed in the reaction with monoimine 20.In all cases the trifluoromethylation process proceeded stereoselectively and the trifluoromethyl group is placed at the exo position, exclusively.

Experimental Section
General Procedures.Melting points were determined in a capillary by using a MelTemp 2 apparatus and are uncorrected.IR spectra were obtained using a NEXUS FT-IR apparatus.MS spectra were obtained using a Varian MAT-112S spectrometer, which was operated in the CI mode. 1 H-, 13 C-and 19 F-NMR spectra were recorded with a Bruker 300 MHz in CDCl 3 using TMS (δ = 0 ppm) or CFCl 3 , respectively, as an internal standards.Elemental analysis and HRMS (Finnigan MAT95) data were obtained at Polish Academy of Sciences.