Direct Aldol–Reduction Process using Difluoromethyl Aryl Ketones and Aryl Aldehydes in the Presence of Potassium tert‐Butoxide: One‐Pot Efficient Stereoselective Synthesis of Symmetrical and Unsymmetrical anti‐2,2‐Difluoropropane‐1,3‐diols

Abstract

Abstract:The potassium tert-butoxide.mediated deprotonation of two difluoromethyl aryl ketones in the presence of aryl aldehydes in anhydrous dimethylformamide (DMF), provides an efficient and stereoselective synthesis of anti-2,2-difluoropropane-1,3-diols. Both symmetrical and unsymmetrical diols could be prepared in moderate to good yields from readily available starting materials.Keywords: aldehydes; aldol reaction; diastereoselectivity; difluoromethyl ketones; diols; fluorine Organofluorine compounds have found broad applications in medicinal chemistry, [1] agrochemistry, [2] materials science, [3] and homogeneous catalysis. [4] In particular, compounds having a difluoromethylene moiety (CF 2 ) have been the focus of considerable research efforts because this group is recognized to be isosteric and isopolar with an ethereal oxygen atom. [5] Indeed, incorporation of CF 2 groups has been used with some success in the design and optimization of a number of drug candidates.[6] Since 1996 we have been involved in the development of a new methodology for introducing CF 2 and CF 3 moieties into organic molecules using the tetrakis(dimethylamino)ethylene (TDAE) reducing reagent. [7] In the course of this work, we also examined another option for introducing the CF 2 group involving the deprotonation of difluoromethyl ketones. However, when naphthyl-A C H T U N G T R E N N U N G amine-derived ketone 1 [8,9] was deprotonated at À20 8C by potassium tert-butoxide (1 equiv.) in anhydrous DMF in the presence of 2 equivalents of benzaldehyde 2, the reaction being allowed to warm up to room temperature over a period of 4 h, we were surprised to find that the reaction did not yield the expected carbinol 3 as in the analogous TDAE-mediated reaction, [9] but instead gave a mixture of fluorinated compounds (by fluorine NMR in CDCl 3 ) which included unreacted 1 (a doublet centred at d F = À123.80 ppm/CFCl 3 , J = 52.78 Hz) as a minor component along with major product 4, represented by the AB system centred at À119.15 ppm (Scheme 1).Silica gel chromatographic purification of the crude material provided the major product (75% yield) as an oil that was analyzed by