COMMUNICATIONS DOI: 10.1002/adsc.201000548
Direct Aldol–Reduction Process using Difluoromethyl Aryl Ketones and Aryl Aldehydes in the Presence of Potassium tertButoxide: One-Pot Efficient Stereoselective Synthesis of Symmetrical and Unsymmetrical anti-2,2-Difluoropropane-1,3-diols Wei Xu,a Maurice Mdebielle,b,* Marie-Hlne Bellance,b and William R. Dolbier Jr.a a b
University of Florida, Department of Chemistry, Gainesville, FL 32611, USA Universit de Lyon & Universit Claude Bernard Lyon 1 (UCBL), Institut de Chimie et Biochimie Molculaires et Supramolculaires (ICBMS), Equipe “Synthse de Molcules d’IntrÞt Thrapeutique (SMITH)”, Btiment Curien, 43 boulevard du 11 Novembre, 69622 Villeurbanne, France Phone: (+ 33)-(0)4-7243-1989; e-mail:
[email protected]
Received: July 13, 2010; Revised: September 8, 2010; Published online: October 26, 2010 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 (CF2) 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 CF2 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 CF2 and CF3 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 CF2 group involving the deprotonation of difluoromethyl ketones. However, when naphthylACHTUNGREamine-derived ketone 1[8,9] was deprotonated at 20 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 Adv. Synth. Catal. 2010, 352, 2787 – 2790
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 CDCl3) which included unreacted 1 (a doublet centred at dF = 123.80 ppm/CFCl3, J = 52.78 Hz) as a minor component along with major product 4, represented by the AB system centred at 119.15 ppm (Scheme 1). Silica gel chromatographic purification of the crude material provided the major product (75% yield) as an oil that was analyzed by 19F NMR in CDCl3 (partly soluble): AB system [dF = 117.42 ppm (1 F, dd, J = 262.7 and 17.2 Hz), 119.45 ppm (1 F, ddd, J = 262.7, 18.4 and 4.6 Hz)] along with a small triplet centred at dF = 118.4 ppm (2 F, t, J = 10.31 Hz) (98.2/1.5 ratio of
Scheme 1. Deprotonation reaction of difluoromethyl aryl ketone 1 in DMF in the presence of tert-butoxide and benzACHTUNGREaldehyde 2.
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Scheme 2. Deprotonation reaction of difluoromethyl ketone 5 in DMF in the presence of tert-butoxide and aldehydes 2, 6–10.
aryl ketones. Diols 11–13 were completely soluble in CDCl3, acetone-d6 and DMSO-d6, and a single multiplet was uniformly observed in their 19F NMR spectra in all three solvents. However for diols 14–16 less soluble in CDCl3 the same behaviour noticed for diol 4 was also observed. Nevertheless all of the diols prepared by our method exhibited only a multiplet in acetone-d6, which is typical for previously prepared anti-isomers.[10–13] The reaction is moreover highly diastereoselective (de > 96), since only a single isomer is observed by 19F NMR, in contrast to the results of Prakash et al.[11] The reaction mechanism, not yet fully understood, may follow an aldol–Tischenko pathway with spontaneous in situ base-catalyzed hydrolysis of the ester since none of this intermediate was isolated after work-up. The stereochemistry in favour of the anti-diols may be explained by the equatorial positions of all aryl groups in the transition state (Scheme 3). Another good indication for such a pathway is that benzoic acid derivatives are obtained
Scheme 3. Proposed reaction mechanism for the diastereoselective synthesis of the anti-2,2-difluoro-1,3-diols.
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Direct Aldol–Reduction Process using Difluoromethyl Aryl Ketones and Aryl Aldehydes
after acidification of the aqueous phase and extraction. In conclusion, a new, highly efficient, one-pot diastereoselective synthesis of symmetrical and unsymmetrical anti-2,2-difluoropropane-1,3-diols has been discovered, using difluoromethyl aryl ketones as readily available starting materials. This methodology offers an advantage over the previously reported “difluoromethylene dianion equivalent” methods, since it allows the direct one-pot synthesis of unsymmetrical diols. None of the yields have been optimized. Work is in progress to elucidate the mechanism of the reaction and to further exemplify the application of the method to a series of difluoromethyl aryl (heterocyclic) ketones in the presence of aryl, and heteroaryl aldehydes. Preliminary results indicate that enolizable aldehydes such as n-C8H17CHO are not appropriate electrophiles in analogous reactions with ketone 5, and difluoromethyl ketones R1CH2COCF2H (R1 = alkyl, aryl) maybe not viable substrates due to competitive deprotonation of the CH2 moiety. The reaction may be thus limited to the use of aryl and heteroaryl aldehydes and difluoromethyl aryl(heterocyclic) ketones ArACHTUNGRE(Het)COCF2H.
Experimental Section General Procedure for the Synthesis of the 2,2Difluoropropane-1,3-diols Under nitrogen, in a flame-dried, 50-mL, three-necked flask were placed the difluoromethyl aryl ketone 1 or 5 (1 mmol) and the corresponding aldehyde (2 mmol), followed by 5 mL of anhydrous DMF with stirring. The solution was then cooled to 30 8C and t-BuOK (1 mL from a 1 M THF solution, 1 mmol) was added dropwise. The resultant mixture, initially colourless or yellowish, turned quickly to orange-red, and was further stirred at 30 8C for 2 h and finally warmed-up to room temperature for 2 h. The reaction mixture was then quenched with water (10 mL) and extracted with dichloromethane (3 10 mL); the combined organic extracts were washed with brine (3 10 mL) and dried over Na2SO4. Filtration and evaporation of the solvent left a residue that was purified by flash column chromatography (silica gel, EtOAc/petroleum ether) to give the pure product. 1-(4-Dimethylamino)naphthalen-1-yl)-2,2-difluoro-3phenylpropane-1,3-diol (4): For anti-isomer: 1H NMR (300 MHz, CDCl3): d = 2.83 (s, 6 H, NMe2), 5.21 (dd, 1 H, J = 17.89, 4.53 Hz, CHOH), 5.92 (dd, 1 H, J = 18.45, 3.39 Hz, CHOH), 7.04 (1 H, d, J = 7.92 Hz, ArH), 7.31–7.48 (m, 7 H, ArH), 7.74 (d, 1 H, J = 7.92 Hz, ArH), 7.82 (d, 1 H, J = 8.10 Hz, ArH), 8.23 (d, 1 H, J = 7.92 Hz, ArH); 19F NMR (281 MHz, CFCl3/CDCl3): d = 117.42 (dd, 1 F, J = 262.7, 17.2 Hz), 119.45 (ddd, 1 F, J = 262.7, 18.35, 4.60 Hz). For syn-isomer: 19F NMR (281 MHz, CFCl3/CDCl3): d = 118.35 (t, 2 F, J = 10.31 Hz); MS (CI): m/z (%) = 358 (M+, 68), 340 (M+ H2O, 100), 234 (8), 107 (4). HR-MS (CI): m/z = 358.1618 [M + H+], calcd. for C21H22F2NO2 : 358.1611. Adv. Synth. Catal. 2010, 352, 2787 – 2790
2,2-Difluoro-1,3-diphenylpropane-1,3-diol (11):[10,11] For anti-isomer: 1H NMR (300 MHz, CDCl3): d = 3.11 (brs, 2 H, OH), 5.07 (t, 2H J = 11.2 Hz, CHOH), 7.39–7.49 (m, 10 H, ArH); 19F NMR (281 MHz, CFCl3/CDCl3): d = 119.23 (t, 2 F, J = 11.4 Hz). 2,2-Difluoro-1-phenyl-3-p-tolylpropane-1,3-diol (12): For anti-isomer: 1H NMR (300 MHz, acetone-d6): d = 2.32 (s, 3 H, Me), 5.31–5.38 (m, 4 H, -OH and CHOH), 7.17–7.19 (m, 2 H, ArH), 7.34 (m, 5 H, ArH), 7.43–7.54 (m, 2 H, ArH); 19 F NMR (281 MHz, CFCl3/acetone-d6): d = 122.26 (m, 2 F); 13C NMR (75 MHz, CDCl3): d = 21.4, 73.8 (m), 119.3 (t, J = 251.7 Hz), 127.9, 128.0, 128.5, 129.0, 129.3, 133.2, 136.3, 138.9; HR-MS (ESI): m/z = 296.1453 [M + NH4+], calcd. for C16H20F2O2 : 296.1457; elemental analysis calcd. for C16H16F2O2 : C 69.05, H 5.79; found: C 69.32, H 5.91. 2,2-Difluoro-1-(4-methoxyphenyl)-3-phenylpropane-1,3diol (13): For anti-isomer: 1H NMR (300 MHz, acetone-d6): d = 3.73 (s, 3 H, -OMe), 5.13–5.26 (m, 2 H, CHOH), 6.84– 6.87 (m, 2 H, ArH), 7.27–7.45 (m, 7 H, ArH); 19F NMR (281 MHz, CFCl3/acetone-d6): d = 122.47 (m, 2 F); 13 C NMR (75 MHz, CDCl3): d = 55.5, 73.2 (m), 113, 119.6 (t, J = 251.7 Hz), 128.1, 128.4, 128.9, 129.0, 129.4, 136.5, 159.9; HR-MS (ESI): m/z = 312.1406 [M + NH4+], calcd. for C16H20F2O3 : 312.1406; elemental analysis calcd. for C16H16F2O3 : C 65.30, H 5.48; found: C 65.50, H 5.81. 1-(4-Chlorophenyl)-2,2-Difluoro-3-phenylpropane-1,3diol (14):[11] Forn anti-isomer: 1H NMR (300 MHz, acetoned6): d = 5.23–5.34 (m, 2 H, CHOH), 7.12–7.53 (m, 7 H, ArH), 7.99–8.02 (m, 2 H, ArH); 19F NMR (281 MHz, CFCl3/acetone-d6): d = 122.58 (m, 2 F); 13C NMR (75 MHz, acetoned6): d = 70.8 (m), 120.9 (t, J = 251.1 Hz), 127.9, 128.4, 128.1, 129.7, 130.1, 131.5, 133.4, 138.7; HR-MS (ESI): m/z = 312.0910 [M + NH4+], calcd. for C15H17ClF2NO2 : 312.0916; elemental analysis calcd. for C15H13ClF2O2 : C 60.31, H 4.39; found: C 60.50, H 4.81. 1-(4-Bromophenyl)-2,2-Difluoro-3-phenylpropane-1,3diol (15): For anti-isomer: 1H NMR (300 MHz, acetone-d6): d = 5.23–5.31 (m, 2 H, CHOH), 7.20–7.96 (m, 9 H, ArH); 19 F NMR (281 MHz, CFCl3/acetone-d6): d = 122.64 (m, 2 F); 13C NMR (75 MHz, acetone-d6): d = 71.2 (m), 121.0 (t, J = 252.2 Hz), 128.0, 128.1, 128.5, 130.5, 131.0, 131.6, 131.9, 138.3; HR-MS (ESI): m/z = 360.0405 [M + NH4+], calcd. for C16H17BrF2NO2 : 360.0335; elemental analysis calcd. for C15H13BrF2O2 : C 52.50, H 3.82; found: C 52.30, H 3.81. 2,2-Difluoro-1-(4-nitrophenyl)-3-phenylpropane-1,3-diol (16): For anti-isomer: 1H NMR (300 MHz, acetone-d6): d = 3.71 (brs, 1 H, OH), 4.15 (brs, 1 H, OH), 5.17 (t, 1 H, J = 18.8 Hz, CHOH), 5.18 (t, 1 H, J = 17.9 Hz, CHOH), 7.37– 7.74 (m, 5 H, ArH), 7.61–7.65 (m, 2 H, ArH), 8.16–8.19 (m, 2 H, ArH); 19F NMR (281 MHz, CFCl3/acetone-d6): d = 122.2 (m, 2 F).
Acknowledgements Support of our work by the Centre National de la Recherche Scientifique (CNRS), Universit Claude Bernard Lyon 1 (UCBL), and in part National Science Foundation (NSF) is gratefully acknowledged.
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