Background Art In the past two decades, organofluorine compounds have attracted much attention due to their unique properties and unusual reactivities. Among them, trifluoromethyl group (CF3) containing compounds are of particular importance for different applications in the materials field, as well as in the pharmaceutical and agrochemical industries. Although many trifluoromethylation methods are known, such as organometallic, nucleophilic, electrophilic and radical trifluoromethylations, fluoride induced nucleophilic trifluoromethylation with (trifluoromethyl) trimethylsilane (TMS-CF3) previously developed by the present inventors is considered a straightforward, convenient and versatile method.

See, Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393 ; Prakash, G. K. S.; Yudin, A. K. Chenu. Rev. 1997, 97, 757, the content of which is incorporated herein by reference thereto. TMS-CF3 was commonly prepared from ozone- depleting trifluoromethyl halides, but recently, a non-Freon based preparation has been reported. See Prakash, G. K. S.; Hu, J.; Olah, G. A., J Org. Chez. 2003, 68, 4457, incorporated herein by reference thereto.

Since the 1990s, there has been increasing research interest in trifluoromethylation using trifluoromethane (CF3H) as a trifluoromethylating precursor. CF3H has low toxicity and is not ozone-depleting. It is a side-product of the multi-step industrial synthesis of Teflon. @ The efficient production of CF3H has been disclosed via fluorination of methane with hydrogen fluoride and chlorine (Webster J. L.; Lerou, J. J. US Patent 5,446, 218,1995).

For example, Shono and co-workers used electrochemically reduced 2-pyrrolidone base to deprotonate CF3H to generate the trifluoromethyl anion equivalent that reacts with aldehydes and ketones (Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem.

1991, 56, 2). Troupel et al. also reported that cathodic reduction of iodobenzene generates a strong base, which deprotonates CF3H, inducing its addition to aldehydes (Barhdadi, R.; Troupel, M.; Perichon, J. Chenu. Comma. 1998, 1251). Thereafter, two research groups

carried out extensive studies on the nucleophilic trifluoromethylation using CF3H as a precursor. Normant and co-workers have demonstrated the trifluoromethylation of aldehydes by CF3H/potassium dimsylate in DMF (Folleas, B.; Marek, I. ; Normant, J. -F. ; Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973; Folleas, B.; Marek, I. ; Normant, J. -F. ; Saint-Jalmes, L. Tetrahedron 2000, 56, 275). They suggested that the CFs'/DMF adduct was the key intermediate in the trifluoromethyl transfer process.

Additionally, Roques, Langlois and co-workers reported the nucleophilic trifluoromethylation of carbonyl compounds and disulfide with CF3H and different bases in DMF. See, (a) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771. (b) Large, S.; Roques, N. ; Langlois, B. R X Org Chem. 2000, 65, 8848. (c) Roques, N.; Russell, J.; Langlois, B.; Saint-Jalmes, L.; Large, S. PCTInt. Appl. 1998, WO 9822435. (d) Roques, N.; Mispelaere, C. Tetrahedron Lett 1999, 40, 6411, each of which are incorporated herein by reference.

CF3-/N-formylmorpholine adduct was also developed as a stable reagent for the trifluoromethylation of non-enolizable carbonyl compounds (Billard, T. B.; Langlois, B. R Org. Lett. 2000,2, 2101). Under similar consideration, piperazino hemiaminal oftrifluoro- acetaldehyde was also used as a trifluoromethylating agent (Billard, T. ; Langlois, B. R. ; Blond, G. Eur. J Org. Chez1. 2001,1467 ; Billard, T.; Langlois, B. R. J. Org. Chez. 2002, 67, 997; Langlois, B. R. ; Billard, T. Synthesis 2003,185).

Trifluoromethyl iodide (CF3I) has also been successfully used as a nucleophilic trifluoromethylating agent under the activation of electron-donating tetrakis- (dimethylamino) ethylene (TDAE) (Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. Jr. Org. Lett. 2001,3, 4271). Motherwell et al. reported the nucleophilic trifluoromethylation using trifluoromethyl-acetophenone-N, N-dimethyl-trime-thylsilylamine adduct (Motherwell, W. B.; Storey, L. J. Synlett 2002,646). Langlois et al. also have reported nucleophilic trifluoromethylations of non-enolizable carbonyl compounds using trifluoroacetic acid derivatives, trifluoromethanesulfinic acid derivatives and trifluoroacetophenone ( (a) Langlois, B. R.; Billard, T. Synthesis 2003,185. (b) Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B. R. Stilett 2003,230. (c) Inschauspe, D.; Sortais, J. -P. ; Billard, T.; Langlois, B. R. Synlett 2003, 233. (d) Jablonski, L.; Billard, T.; Langlois, B. R.

Tetrahedron Lett. 2003, 44, 1055). More recently, a nucleophilic trifluoromethylation method using trifluoroactetamides from amino alcohols was reported (Joubert, J.; Roussel, S.; Christophe, C.; Billard, T.; Langlois, B. R. ; Vidal, T. Ange. Chem. Int. Ed. 2003, 42, 3133). Thus, there is a need to develop a convenient and non-ozone depleting reagent for the nucleophilic trifluoromethylation.

Nucleophilic displacement of the trifluoromethyl group has been reported for trifluoromethyl aryl sulfones with sodium methoxide (Shein, S. M.; Krasnopol'skaya, M. I. ; B oiko, V. N., Zh. Obshei Khi1. 1966, 36, 2141). A similar reaction between trifluoromethyl aryl sulfone and Grignard reagents has been reported for the preparation of sulfones (Steensma, R. W.; Galabi, S.; Tagat, J. R.; McCombie, S. W., Tetrahedron Lett.

2001, 42, 2281). More recently, Cheburkov et al. reported that perfluoroalkyl sulfones react with metal hydroxides in water or alcohol solution and with ammonia to form fluorinated sulfonic acid derivatives (Barrera, M. D.; Cheburkov, Y.; Lamanna, W. M. J. Fluorine Chez. 2002, 117, 13).

A reductive trifluoromethylation using trifluoromethyl sulfides, sulfoxides and sulfones as trifluoromethyl (CF3) group precursors has previously been reported (Prakash, G. K. S.; Hu, J.; Olah, G. A., J. Org Chem. 2003, 68, 4457). Under reductive conditions when magnesium metal was used, however, the reaction only worked with chlorosilanes as electrophiles, while attempts to react with carbonyl compounds failed.

All of these methods of trifluoromethylation or difluoromethylation have drawbacks.

First of all, trifluoromethane is a low-boiling gas (b. p.-84 °C) and its handling as a reagent in the laboratory is not convenient. Second, none of these trifluoromethylations work well with enolizable carbonyl compounds. Thus, there remains a need for a convenient and efficient method for the nucleophilic trifluoromethylation.

Furthermore, due to the unique properties of fluorine atom, more and more organofluorine compounds have been found to have certain biological effects that mimic or block other compounds or that provide polar or lipophilic effects. For instance, C-F bond is known to mimic a C-H bond because of its similar bond length, and difluoromethylene group is known to be isosteric and isopolar to an ethereal oxygen (Yudin, A. K.; Prakash, G.

K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J. A7n. Chem. Soc. 1997, 119, 1572- 1581; and the references therein). Thus, the synthesis of fluorine-containing analogs of bioactive natural products are of great interest for their potential applications in pharmaceutical industry. Since anti-1, 3-diol functionality is a fundamental unit in many naturally occurring compounds, its stereoselective preparation is always attractive to synthetic organic chemists. anti-2, 2-Difluoropropan-1, 3-diols 3 are a group of interesting compounds, however, not much is known about their synthesis. Currently, the only reported method to synthesize these compounds is via the diasteroselective Meerwein- Pondorff-Verley reduction of aa-difluoro-p-hydroxy ketones (Kuroboshi, M.; Ishihara, T.

Bull. Chem. Soc. Jpn. 1990, 63, 1185-1190). The disadvantage of this approach is the

requirement of preparation of a, a-difluoro-p-hydroxy ketones as the precursors. In 1997, the preparation of difluorobis (trimethylsilyl) methane (TMSCF2TMS) as a potential difluoromethylene dianion ("-CF2-") equivalent was reported (Yudin, A. K.; Prakash, G. K.

S. ; Deffieux, D.; Bradley, M.; Bau, R ; Olah, G. A. J. Am. Chent. Soc. 1997, 119, 1572- 1581), but TMSCF2TMS was found only to couple with one molecule of aldehyde such as benzaldehyde to give 2, 2-difluoro-1-phenylethanol (after acidic hydrolysis). Thus, there remains a need to develop a synthetic methodology for difluoromethylenation to introduce difluoromethylene dianion species ("-CF2-") to prepare 2, 2-difluoropropan-1, 3-diols directly from the carbonyl compounds.

Summary of the Invention With these considerations in mind, a long sought after, yet simple and efficient method for the nucleophilic trifluoromethylation and difluoromethylenation of fluoromethylatable substrates has been developed. In addition, a convenient method of preparing 2,2-difluoropropan-diols directly from carbonyl compounds has also been developed.

One aspect of the invention provides a convenient method for preparing trifluoromethylated substrates by reacting a substrate, a trifluoromethylating agent, and an alkoxide or a hydroxide base, under reaction conditions sufficient to trifluoromethylate the substrate. The reaction conditions include a temperature between about-25°C to about 55°C, and for a time of between 30 minutes to 20 hours, and preferably include a temperature of between-30°C to about room temperature.

In accordance with the method of the invention, the trifluoromethylating agent includes but is not limited to trifluoromethyl phenyl sulfone, trifluoromethyl phenyl sulfoxide, and methyl trifluoromethyl sulfone. The alkoxide or hydroxide base includes but is not limited to potassium tert-butoxide, sodium methoxide, and potassium hydroxide.

In a preferred embodiment of the invention, the alkoxide or hydroxide base is added to a mixture including the substrate and the trifluoromethylating agent. The reaction mixture is stirred at a first temperature, and is then warmed to a second temperature. Preferably, the mixture is warmed for about 2 hours.

Another aspect of the invention provides a method for preparing a difluoromethylenated substrate by reacting a substrate with a difluoromethylenating agent and an alkoxide or hydroxide base under conditions sufficient to difluoromethylenate the substrate. In accordance with the invention, the difluoromethylating agent includes but is

not limited to difluoromethyl phenyl sulfone or difluoromethyl sulfoxide. The alkoxide or hydroxide base includes but is not limited to potassium tert-butoxide, sodium methoxide, and potassium hydroxide.

Preferably, the trifluoromethylation and the difluoromethylenation reactions take place in the presence of a solvent, for example, DMF or DMSO.

In accordance with the invention, a 2, 2-difluoro-propan-1, 3-diol may be prepared by these methods. A difluorodisulfide having the general formula RSCF2SR, wherein R is an aryl or an alkyl group may also be prepared in this manner.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and are intended to provide further explanation of the invention claimed.

Brief Description of the Figures The accompanying figures, which are incorporated herein and constitute part of this specification, are included to illustrate and provide a further understanding of the apparatus and system of the invention. Together with the description, the figures serve to explain the principles of the invention. In these figures: Figure 1 is an illustration of certain reaction schemes that generate CF3 species; Figure 2 is an illustration of certain reaction schemes that generate CF2 species; Figure 3 is an illustration of a certain reaction scheme in which an alkoxide or hydroxide base attacks a trifluoromethylating agent to generate the trifluoromethyl anion ; Figure 4 is an illustration of a disulfide base undergoing trifluoromethylation; Figure 5 illustrates a difluoromethylenation of a substrate generating mono- substituted and di-substituted products; Figure 6 is an illustration of a certain reaction scheme in which benzaldehyde reacts with trimethyl phenyl sulfone and tBuOK ; Figure 7 illustrates the synthesis of a symmetrical anti-diol product; and Figure 8 illustrates the synthesis of a non-symmetric anti-diol product.

Detailed Description of the Preferred Embodiments The purpose and advantages of the present invention will be set forth in and will become apparent from the description that follows, as well as will be learned by practice of the invention. Additional advantages of the invention will be realized and attained by the reactions particularly pointed out in the written description and claims hereof, as well as

from the appended figures. To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and described herein, the invention includes a convenient method of fluoromethylation of a fluoromethylatable substrate or compound.

The invention also includes a convenient method of fluoromethylenation of a fluoromethylenatable substrate or compound. In particular, trifluoromethylation or difluoromethylenation are exemplified.

A fluoromethylatable substrate or compound is one that is capable of being fluoromethylated by a fluoromethylating agent. A"fluoromethylating agent"as the term is used herein refers to an agent capable of generating a fluoromethylating species that is capable of forming a bond with the fluoromethylatable substrate, according to the present process, while a fluoromethylenatable substrate or compound is one that is capable of being fluoromethylenated by a fluoromethylenating agent. The term"fluoromethylenating agent" as the term is used herein refers to an agent capable of generating a fluoromethylating species that is capable of forming two bonds with at least one fluoromethylenatable substrate, according to the present process. Suitable substrates or compounds include carbonyl compounds, disulfides and other electrophiles which undergo alkoxide or hydroxide induced nucleophilic fluoromethylation or fluoromethylenation.

With reference to Figure 1, a general reaction scheme that generates the CF3 species is illustrated. As shown, a nucleophilic base, such as but not limited to an alkoxide or hydroxide, is utilized in the reaction and the carbon-sulfur bond of the trifluoromethylating agent, trifluoromethyl phenyl sulfone 1a or trifluoromethyl phenyl sulfoxide lb, is cleaved to give a trifluoromethyl anion (CF3-) species. The trifluoromethyl anion undergoes addition to a substrate compound such as a carbonyl compound for trifluoromethylation of the substrate compound. Thus, a convenient and efficient trifluoromethylation process is provided. The driving force of this substitution is the formation of strong a S-O bond (348 - 551 kJ/mol) and the high polarity of the C-S bond of the trifluoromethylating agent, i. e., trifluoromethyl phenyl sulfone la or trifluoromethyl phenyl sulfoxide Ib. Notably, the generation of pseudohalide CF3'species is somewhat similar to the reaction between benzenesulfonyl halides with alkoxides.

In another aspect of the invention, a substrate compound undergoes difluoromethylenation. In this aspect of the invention, the difluoromethylenating agent includes difluoromethyl phenyl sulfoxide, which acts as a"-CF2-"synthon. Based on the previous mechanistic scheme to generate the CF3 species as illustrated in Figure 1, a similar

type of S-C bond cleavage occurs with difluoromethyl phenyl sulfone lc (PhSO2CP2H), as shown in Figure 2.

The CFzH hydrogen of difluoromethyl phenyl sulfone I c is rather acidic, and a common base such as sodium methoxide or even aqueous sodium hydroxide can deprotonate it in an equilibrium mode to generate PhSO2CF2-anion 4 as reported by Hine, J.; Porter, J. J. J. Am. Cheni. Soc. 1960, 82, 6178-6181; Stahly, P. J. Fluorine Chem. 1989, 43, 53-66. Moreover, in 1989, Stahly had shown that the in situ generated anion 4 can react with aldehydes to give difluoromethylated carbinols in aqueous NaOH media in the presence of a phase-transfer agent (Stahly, P. J. Fluorine Chenu. 1989, 43, 53-66). But Stahly did not report any S-C bond cleavage under the aqueous NaOH condition (at room temperature for 4 h). Obviously, aqueous NaOH is not nucleophilic enough to activate the S-C bond scission. Thus, indicative of these reports is that with the hydroxide or alkoxide base, the deprotonation on difluoromethyl sulfone 1 c is much faster than the S-C bond cleavage. Advantageously, utilization of the alkoxide such as tBuOK working both as a base and a nucleophile, the sulfone 1 c reacts stepwise with two electrophiles to give new difluoromethylene-containing products, as illustrated in Figure 2. Thus, difluoromethyl phenyl sulfone lc acts as a selective difluoromethylene dianion ("-CF2-") species.

Advantageously, both phenyl trifluoromethyl sulfone 1 a and trifluoromethyl sulfoxide lb are commercially available (b. p. 203 °C/760 mmHg for la, b. p. 85-87°C/10 mmHg for lb). Alternatively, both phenyl trifluoromethyl sulfone la and trifluoromethyl sulfoxide 1b and can also be conveniently prepared from trifluoromethane in high yields, as known in the art. Difluoromethyl phenyl sulfone lc can also be readily prepared from chlorodifluoromethane, as known in the art. As these components of the present method are readily available or easily prepared, the present method of the invention provides a convenient route for efficient nucleophilic trifluoromethylation and difluoromethylenation of substrates.

Referring to Figure 3, an alkoxide base, such as but not limited to potassium tert- butoxide (BuOK), is used as a nucleophile to attack the sulfur center of phenyl trifluoromethyl sulfone la and generates the trifluoromethyl anion. In one preferred embodiment, a DMF solution of tBuOK (two molar equivalents) is slowly added into an equimolar mixture of phenyl trifluoromethyl sulfone la and benzaldehyde in DMF at-50°C.

The reaction mixture is stirred at-50°C for about 1 h, and then is warmed to room temperature over a period of about 2 h. The product is l-phenyl-2-trifluoromethylethanol and is produced in about 71 % yield.

Advantageously, only traces of benzoic acid and benzyl alcohol are detected by NMR in the reaction. Thus, the implication is that in the present invention at low temperature, the Cannizzaro reaction rate is much slower than the tert-butoxide induced trifluoromethylation process. Table 1 below shows the optimal reaction conditions. For example, as shown in Table 1, entry b, when excess benzaldehyde is introduced, the yield of the product 5 can be improved based on the amount of phenyl trifluoromethyl sulfone 1 a used.

Shono and co-workers found that when they used CF3H/tBuOK/DMF to react with benzaldehyde at-50°C, benzyl alcohol and benzoic acid were formed by the competing Cannizzaro reaction (Shono, T.; Ishifume, M.; Okada, T.; Kashimura, S. J Org Chem.

1991, 56, 2). As mentioned above, the product of the present method is substantially free of benzyl alcohol and benzoic acid. Although Russell and Roques repeated the Shono reaction using excess CF3H (9.5 eq. ) and tBuOK (2.2 eq. ) at-50°C, and 67 % yield of trifluoromethylated product 5 was formed and no benzyl alcohol was detected (Russell, J.; Roques, N. Tez7flahedron 1998, 54, 13771), they reported that the high reaction temperature with excess base could lead to Cannizzaro reaction and jeopardize the nucleophilic trifluoromethylation.

TABLE 1 Trifluoromethylation of Benzaldehyde by PhS02CF3 Induced by Alkoxide or Hydroxide. benzaldehyde sulfone 1a alkoxide solvent temperature time yield (9, %) a 1 eq. 1 eq. t-BuOK (2 eq.) DMF-50 °C 1 h 71 b 3 eq. 1 eq. t-BuOK (2 eq.) DMF-30 °C~r. t. 30 min 91 c 1 eq. 2 eq. t-BuOK (2 eq.) DMF -50 °C#r. t. 3 h 84 d 3 eq. 1 eq. MeONa (3 eq. ) DMF-30 °C~r. t. 3 h 30 e 3 eq. 1 eq. KOH (8 eq.) DMF r. t. 20 h 45 f 3 eq. 1 eq. t-BuOK (2 eq. ) DMSO r. t.. 1 h 76 yields were determined by 19F NMR based on the amount of 1a used.

In addition to tBuOK being used as a nucleophilic base, other agents can be used such as sodium methoxide (CH3ONa) and potassium hydroxide (KOH). (Table 1, entries d and e).

Preferably, the nucleophilic base is potassium tert-butoxide. As can be seen from Table 1, sodium methoxide and potassium hydroxide had lower yields. Without being held to any theory, it is postulated that there are several possible reasons for the lower yields. First,

both sodium methoxide and KOH can not readily dissolve in DMF, which can affect the reaction rate. Second, unlike potassium tert-butoxide, sodium methoxide may react with benzaldehyde via a Meerwein-Pondorff-Verley type reduction pathway. Third, KOH has lower nucleophilicity than tBuOK, so the reaction rate can be slow. Here Cannizzaro reaction may still happen as a competing side-reaction, but it should not be a dominating factor to affect the yield since excess benzaldehyde is present.

Preferably, reaction takes place in a solvent. For purpose of illustration and not limitation the solvent can be DMF. As the CFa'/DMF adduct is not a necessary intermediate for this new type of nucleophilic trifluoromethylation, other solvents can be used such as (DMSO) dimethyl sulfoxide, as shown in Table 1, entry f. From a mechanistic point of view, however, it can be reasonably postulated that the intermediate species 2 shown in FIG.

1 is formed and could act as a trifluoromethylating agent.

As lower yields of product, after hydrolysis, is obtained when catalytic amounts of tBuOK is used, excess amounts of tBuOK (2 eq. ) is preferred to achieve high yields in the trifluoromethylation reactions of the invention. Although catalytic amounts of tBuOK have lower product yield, the introduction of additional tBuOK increases product yield.

Advantageously, tBuOK reacts with water readily and it may be partially hydrolyzed during storage and handling. Moreover, excess tBuOK removes the moisture from the solvent and reagents. More importantly, excess tBuOK in the reaction mixture eliminates the possibility of hydrolysis of CF3-to form CF3H. It is known that CF3H can be deprotonated by tBuOK and undergo trifluoromethylation of carbonyl compounds, thus, the present methodology allows the preparation of trifluoromethylated products in high yields in the case of non-enolizable aldehydes, as illustrated in Table 2, entries 1-5.

Advantageously, non-enolizable ketones can also be easily trifluoromethylated using the present invention, as illustrated in Table 2, entries 7-12. Since there is no Cannizarro reaction between ketones and tBuOK, these reactions can be carried out even at higher temperatures, such as 25°C. Due to lower reactivity of ketones compared with aldehydes, the ketone reactions take a little bit longer time (2-3 h) to complete. However, with enolizable aldehydes and ketones, only low yield (10-30 %) of trifluoromethylated products were observed, because of the competing and facile aldol reactions.

It is noteworthy that phenyl trifluoromethyl sulfoxide lb worked equally well as la, the similar trifluoromethylations were observed with aldehyde and ketone (Table 2, entries 6 and 13).

TABLE 2 Reaction of Trifluoromethyl Phenyl Sulfone (1a) or Sulfoxide (1b) (2 equiv) with Non-enolizable Carbonyl Compounds (1 equiv) and tBuOK (2.5 equiv) in DMF at-50°C to Room Temperature. carbonyl trifluoromethylating a o gF NMR entry compound agent product yield (%) (ppm) b O OH 1 I % H 1a I CF3 77-78. 5 (d) U OU OH w w H 2 H la CF3 62-78. 4 (d) O OH 3 eH la CF3 83-78. 9 (d) Eut/ O Et/OH 4 H la CF3 76-78. 7 (d) Oh// Ph 0 OH 5 H 1a >4CF3 79C-72. 3 (d) 0 OH 6 ¢<H 1b CF3 68-78. 5 (d) 0 HO CF3 7 la 86-74. 5 i/// O HO CF3 8 Cl I la 74-75. 1 o O HO CF3 9 la 83-74. 7 OzN// O on HO CF3 10 la 85-74. 4 Me Meo-y ? HOCHA 11 Me0 I/I/1a I//73-75. 0 Met n OH 12 g 1a vCF3 82-76. 1 HO CF3 9 HOCFg 13 <1 1 b < 83-74. 5

isolated yields. bUse CFCI3 as internal reference. cDetermined by 19F NMR using PhOCF3 as internal standard.

Advantageously, the by-product of one of the preferred reactions is tert-butyl benzenesulfonate, which can be readily hydrolyzed into t-butyl alcohol and benzenesulfonic

acid derivatives. Thus, aqueous washing can easily remove most of the by-products and simplify the purification process.

With reference to Figure 4, and as mentioned above, the substrate compound can be a disulfide. Disulfide substrates can easily be trifluoromethylated with the present invention.

As shown in FIG. 3, PhSOsCFs (1 eq. ) and tBuOK (2 eq. ) reacted with diphenyl disulfide (1.2 eq. ) at-30°C to room temperature in 30 minutes to give quantitative conversion (87 % isolated) of trifluoromethyl phenyl sulfide 10 (19F NMR : -43.3 ppm). This reaction was even more facile than that of carbonyl compounds.

The trifluoromethyl phenyl sulfone/tBuOK trifluoromethylation method can also be applied to other systems. For instance, methyl benzoate can be trifluoromethylated to generate 2,2, 2-trifluoroacetophenone in 30 % yield at about-50°C to about-20°C. CF3Cu can be in situ generated with trifluoromethyl phenyl sulfone/tBuOK and copper iodide (CuI), and then further react with iodobenzene at 80°C for 20 h to give a, a, a- trifluorotoluene in 26 % yield.

Other types of sulfones, such as methyl trifluoromethyl sulfone (ld) can be used as the trifluoromethylating agent. When diphenyl disulfide was used as the model substrate, however, the reaction only gave minimal yield of product 7 (-2 %). This is probably due to the facile deprotonation of the methyl group by tBuOK, leading to other products.

In another aspect of the invention, a method for preparing difluoromethylenated substrates is provided. In this aspect of the invention, a substrate is reacted with a difluoromethylenating agent and an alkoxide or an hydroxide base. The difluoromethylenating agent includes but is not limited to difluoromethyl phenyl sulfone or difluoromethyl phenyl sulfoxide. In particular and as shown in Table 3, and Figure 5, a PhSO2CF2H/tBuOK system is reacted with diphenyl disulfide (PhSSPh), as an electrophile.

As shown in Figure 5 and Table 3, entries b and g, with the different reactant ratio, both mono-substitution product 12 and double-substitution product 13 can be obtained at room temperature in high selectivity. Thus, the reactivities of deprotonation and S-C bond cleavage are different and these two steps can be controlled selectively, as illustrated in Figure 5. Excess tBuOK facilitates the completion of S-C bond cleavage process, which is similar to the above-mentioned trifluoromethyl sulfone system. Furthermore, the formation and consumption of PhSCF2H 14 with time (Table 1, entries e and f) indicated that there is an equilibrium between anionic species 16 and 14 under the protonation/deprotonation with tBuOH/tBuOK. TABLE 3 Difluoromethylenation of PhSSPh with 1c. DMF O Ph-S-CF2H + tBuOK + PhSSPh Ph-S-CFzSPh + PhSCF2SPh + PhSCF2H 0 RT 0 1c 11 12 13 14 Reactant ratio Product yield'I Entry Reaction 1c tBuOK 11 time 12 13 14 a 1 eq. 1. 0 eq. 1. 0eq. 30 min 76 % 0 % 5 % b 1 eq. 1. 5 eq. 1. 0 eq. 50 min Bj 3 % 6 % c 1 eq. 2. 5eq. 2. 0eq. 14h 64% 22% 14% d 1 eq. 3. 0eq. 2. 0eq. 4h 41 % 44% 14% e 1 eq. 3. 5eq. 2. 0eq. 4h 0% 84% 16% f 1 eq. 3. 5eq. 2. 0eq. 15h 0% 97% 3% g 1 eq. 4. 0eq. 2. 0eq. 4h o% 0% [a] The yields were determined by 19F NMR with PhOCF3 as the internal standard.

Referring to Figure 6, benzaldehyde is reacted with difluoromethyl phenyl sulfone/tBuOK in DMF. Similar to the reaction with diphenyl disulfide, PhSO2CF2H (1.0 <BR> <BR> eq.)/tBuOK (3.0 eq. ) reacts with benzaldehyde (2.0 eq. ) at-50°C ~ RT for 90 minutes to generate mono-substituted product 17 (41% 19F NMR yield) as earlier shown by Stahly in the aqueous NaOH medium, and di-substituted product 18 (58 % 19F NMR yield, antilsyn = 98: 1). When difluoromethyl phenyl sulfone (1.0 eq.)/tBuOK (4.0 eq. ) reacted with 3.0 eq. of PhCHO at-50°C to RT for 8 h, under the activation of'BuOK, the in situ formed alkoxide 17b undergoes S-C bond fission to generate a dianionic intermediate 19, which can further react with another molecule of benzaldehyde to form di-substituted anti-diol product 18a in excellent yield (92 % 19F NMR yield, 82 % isolated) and high diastereoselectivity (antilsyn = 97: 3, de = 94 %). The observed high diastereoselectivity can be interpreted by the charge-charge repulsion effect during the second addition, as shown in Figure 7. To our knowledge, this may be the first example in which high diastereoselectivity has been achieved in a reaction where a dianionic species reacts with another neutral electrophile involving an intramolecular charge-charge repulsion effect

(during the product formation) rather than the traditional steric control (based on the Cram's rule).

Table 4, below, demonstrates the application of this methodology to synthesize various 2, 2-difluoropropan-1, 3-diols with high stereoselectivity from non-enolizable aldehydes. The yield of diols is a little bit lower for electron-rich aldehydes (entries d and g), probably due to the relative instability of the corresponding dianion intermediate.

TABLE 4 Preparation of 2, 2-difluoropropan-1, 3-diols from aldehydes (3 equiv. ) and difluoromethyl phenyl sulfone 1c (1 equiv. ) with ZBuOK (4 equiv. ) in DMF at-50 °C to room temperature. Entry Substrates Products Yield (%) anti-isyn-de (%) ratio OH OH a 82 97 : 3 94 z oH OH OH OU b ci F2-*, a 78 94 : 6 88 CI z Gi OH OH c Br c 70 96 : 4 92 OH Oh OH OH OH OH O 0 d MeO c 52 94 : 6 88 H MeO OMe OH OH 0 e G /Fz I//69 97 : 3 94 H OH OH SH 75 96 : 4 92 H Ph Ph Oh oh Oh oh g WH/63 93 : 7 86 9 isolated yields. banti-lsyn-ratio were determined bu 19F NMR.

With reference to Figure 8, in addition to the symmetric anti-2, 2-difluoropropan-1, 3- diols, this new methodology can also be used to synthesize non-symmetric amati-2, 2-

difluoropropan-1, 3-diols. Difluoro (phenylsulfonyl) methyl substituted alcohol 17a can be easily obtained and isolated through Stahly's approach in high yield. The activation of 17a with tBuOK generates the dianion intermediate 19, which further reacts withp- chlorobenzaldehyde to give non-symmetric anti-2, 2-difluoropropan-1, 3-diol 21 (after hydrolysis) with high diastereoselectivity.

The present invention will be further understood by the examples set forth below, which are provided for purpose of illustration and not limitation.

Examples General: Unless otherwise mentioned, all other chemicals were purchased from commercial sources. Potassium tert-butoxide (95 %) was used as received. DMF was distilled over calcium hydride, and stored over activated molecular sieve. Phenyl trifluoromethyl sulfone (la) or trifluoromethyl phenyl sulfoxide (lb) was prepared by the oxidation of phenyl trifluoromethyl sulfide with hydrogen peroxide or mCPBA.

Difluoromethyl phenyl sulfone (lc) was prepared using known procedures from chlorodifluoromethane and sodium thiophenoxide. Methyl trifluoromethyl sulfone (ld) was prepared using known procedures using methyl lithium and triflic anhydride. Most of the trifluorinated products are known, and their characterization results are consistent with the reported data.

'H,"C and"F NMR spectra were recorded on superconducting NMR spectrometers at either 500 or 360 MHz. 1H NMR chemical shifts were determined relative to internal (CH3) 4Si (TMS) at 8 0.0 or to the signal of a residual protonated solvent: CDC13 8 7. 26. 13C NMR chemical shifts were determined relative to internal TMS at 8 0.0 or to the 13C signal of solvent: CDC13 6 77.0. 19F NMR chemical shifts were determined relative to internal CFCl3 at 8 0.0. The 19F NMR yields were determined by the integration of the corresponding product peaks with respect to PhOCF3 internal standard. The structures and ratios of anti-and syn-isomers of diols (3) were determined by 19F NMR (with the splitting patterns and the coupling constants) of the reaction products before isolation. Silica gel column chromatography was used to isolate the products using 60-200 mesh silica gel (from J. T. Baker). Mass spectra were recorded on GC-MS spectrometer with a mass selective detector at 70 eV. HRMS data were recorded on a VG 7070 high-resolution mass spectrometer.

Example 1: Preparation of 4-Methyl-a-phenyl-a- (trifluoromethyl) benzenemethanol Into a dry Schlenk flask under an argon atmosphere, was added 7 mL DMF solution of phenyl trifluoromethyl sulfone (la, 420 mg, 2 mmol) and 4-methylbenzophenone (196 mg, 1 mmol) at-50°C, was added 3 mL DMF solution of tBuOK (280 mg, 2.5 mmol). The reaction flask was then sealed and the reaction mixture was then stirred from-50°C for Ih, followed by stirring at-50°C to room temperature overnight. The reaction mixture was quenched with 10 mL of ice water, and extracted with ether (20 ml x 3). The combined ether phase was washed with saturated NH4CI aqueous solution, followed by washing with water. After drying over MgSO¢, the ether solvent was removed under vacuum. The crude product was further purified by column chromatography (hexanes/ether = 9/1) to give 225 mg of product, 4-methyl-a-phenyl-a- (trifluoromethyl) benzenemethanol as a colorless oily liquid, yield 85 %. 1H NMR (CDC13) : 6 2.36 (s, 3H); 2.89 (s, 1H) ; 7.17-7. 51 (m, 9H). 19F NMR (CDC13) : 5-74. 4. MS: 266 (M+).

Example 2: Preparation of 1-Phenyl-2, 2, 2-trifluoroethanol The reaction condition is similar as described in Example 1 except that benzaldehyde was used as the substrate. Product 1-Phenyl-2, 2,2-trifluoroethanol was isolated as a yellow oily liquid, 77 % yield. 1H NMR (CDC13) : 5 2.86 (s, 1H) ; 5. 01 (q, 3JH-F = 6.3 Hz, 1H); 7.43 (m, 2H); 7.48 (m, 3H). I9F (CDCl3) : # - 78. 5 (d, 3JH-F = 6.2 Hz). MS: 176 (M+).

Example 3: Preparation of 1-(2'-Naphthyl)-2, 2, 2-trifluoroethanol The reaction condition is similar as described in Example 1, except that 2- naphthaldehyde was used as the substrate. Product 1-(2'-naphthyl)-2, 2, 2-trifluoroethanol was isolated as a yellow solid, 62 % yield. 1H NMR (CDC13) : 8 2.76 (b, 1H) ; 5.19 (q, 3JH-F = 6. 7 Hz, 1H) ; 7.51-7. 96 (m, 7H). 19F (CDC13) : 8-78. 4 (d, 3JH-F = 6.7 Hz). MS: 226 (M+) Example 4: Preparation of 4'-Ethyl-phenyl-2, 2, 2-trifluoroethanol The reaction condition is similar as described in Example 1, except that 4- ethylbenzaldehyde was used as the substrate. Product 4'-ethyl-phenyl-2,2, 2-trifluoroethanol was isolated as a oily liquid, 83 % yield. 1H NMR (CDC13) : 8 1.25 (t, 3H) ; 2.60 (b, 1H) ; 2.67 (q, 2H); 4.99 (m, 1H) ; 7.25 (d, 2H); 7.38 (d, 2H). 19F NMR (CDCl3) : 8-78. 9 (d, 3JH-F = 7. 7 Hz). 13C NMR (CDC13) : # 15.4 ; 28.6 ; 72.6 (q, J = 31.9 Hz); 124.3 (q, J = 282.5 Hz); 127.4 ; 128.1 ; 131.2 ; 145.8. MS: 204 (M+).

Example 5: Preparation of 4'-Biphenyl-2, 2,2-trifluoroethanol The reaction condition is similar as described in Example 1, except that 4- phenylbenzaldehyde was used as the substrate. Product 4'-biphenyl-2,2, 2-trifluoroethanol was isolated as a white solid, 76 % yield. 1H NMR (CDCl3) : 8 2.87 (b, 1H) ; 5.07 (m, 1H); 7.40-7. 65 (m, 9 H). 19F NMR (CDC13) : 6-78. 7 (d, J = 7.6 Hz). 13C NMR (CDC13) : # 72.6 (q, J = 31.6 Hz) ; 124.3 (q, J=281. 8Hz) ; 127. 1 ; 127.3 ; 127.7 ; 127.8 ; 128.8 ; 132.8 ; 140.3 ; 142.5. MS: 252 (M+).

Example 6: Preparation of a-Phenyl-a- (trifluoromethyl) benzenemethanol The reaction condition is similar as described in Example 1, except that benzophenone was used as the substrate. Product a-phenyl-a- (trifluoromethyl) benzenemethanol was isolated as a oily liquid, 86 % yield.'H NMR (CDC13) : # 3.01 (b, 1H) ; 7. 35-7.38 (m, 6H); 7.49-7. 52 (m, 4H). 19F NMR (CDC13) : 8-74. 5. MS: 252 (M+). For the same reaction, trifluoromethyl phenyl sulfoxide (PhSOCF3) can also be used as the replacement of PhSOzCPs, the yield of the product α-Phenyl-α-(trifluoromethyl)benzenemethanol was 83 %.

Example 7: Preparation of 4, 4'-Dichloro-a-phenyl-a- (trifluoromethyl) benzenemethanol The reaction condition is similar as described in Example 1, except that 4,4'- dichlorobenzophenone was used as the substrate. Product 4,4'-dichloro-a-phenyl-a- (trifluoromethyl) benzenemethanol was isolated as a pale yellow oily liquid, 74 % yield. 1H NMR (CDC13) : 8 2.95 (s, 1H) ; 7.34 (d, 4H) ; 7.40 (d, 4H). 19F NMR (CDC13) : 6-75. 1. MS: 320 (M+).

Example 8: Preparation of 4-Nitro-a-phenyl-a- (trifluoromethyl) benzenemethanol The reaction condition is similar as described in Example 1, except that 4- nitrobenzophenone was used as the substrate. Product 4-nitro-a-phenyl-a- (trifluoromethyl) benzenemethanol was isolated as a pale yellow oily liquid, 83 % yield. 1H NMR (CDC13) : 8 3.15 (s, 1H); 7.37-8. 23 (m, 9 H). 19F NMR (CDCl3) : 8-74. 7. MS: 297 (M+).

Example 9: Preparation of methoxy-a-phenyl-a- (trifluoromethyl) benzenemethanol The reaction condition is similar as described in Example 1, except that 4- methoxybenzophenone was used as the substrate. Product 4-methoxy-a-phenyl-a- (trifluoromethyl) benzenemethanol was isolated as a oily liquid, 73% yield. 1H NMR (CDCl3) : # 2.80 (s, 1H) ; 3.81 (s, 3H); 6.87-7. 49 (m, 9 H). 19F NMR (CDCl3) : 8-75. 0.

MS: 281 (M+-1).

Example 10: Preparation of 2- (Trifluoromethyl)-2-adamantanol The reaction condition is similar as described in Example 1, except that 2- adamantaldehyde was used as the substrate. Product 2- (trifluoromethyl)-2-adamantanol was isolated as a white solid (sublimed), 82 % yield. 1H NMR (CDC13) : 6 1.56-2. 27 (m, 15H).

19F (CDCl3) : 8-76. 1. MS: 220 (M+).

Example 11: Preparation of phenyl trifluoromethyl sulfide The reaction condition is similar as described in Example 1, except that PhSSPh was used as the substrate. phenyl trifluoromethyl sulfide, 87 % yield, colorless liquid. 1H NMR (CDC13) : 8 7.43 (t, J = 7. 5 Hz, 2H); 7.50 (t, J = 7.5 Hz, 1H) ; 8.67 (d, J = 7.5 Hz, 2 H). 19F (CDCl3) : 8-43. 2.

Example 12: Preparation of 2, 2-difluoro-1, 3-diphenyl-1, 3-propanediol The reaction was carried out in a Schlenk flask under an argon atmosphere. Into 5 mL DMF solution of difluoromethyl phenyl sulfone (1c, 480 mg, 2.5 mmol) and benzaldehyde (800 mg, 7.5 mmol) at-50°C, was added 5 mL DMF solution of tBuOK (1.12 g, 10 mmol).

The reaction flask was then sealed and the reaction mixture was then stirred from-50°C for lh, followed by stirring at-50°C to room temperature overnight. The reaction mixture was quenched with 20 mL of ice water, and extracted with ether (20 mL x 3). The combined ether phase was washed with saturated NH4C1 aqueous solution, followed by washing with water. After drying over MgS04, the ether solvent was removed under vacuum. The crude product was further purified by silica gel column (first hexanes/ethyl acetate (v/v = 9: 1); then hexanes/ethyl acetate (v/v = 1: 1) ) to give 541 mg 2, 2-Difluoro-1, 3-diphenyl-1, 3- propanediol as white crystalline solid, yield 82 %, anti-/syn-ratio = 97/3 determined by 19F NMR. For anti-isomer : 1H NMR (actone-d6): 8 5.27 (m, 4H); 7.28-7. 50 (m, 10 H). 13C NMR (acetone-d6): 6 72.3 (t, J = 28. 8 Hz); 121.6 (t, J = 252.6 Hz); 128.5 ; 128.7 ; 129.0 ; 138. 9. 19F NMR (acetone-d6): 8-120. 9 (pseudo t, J = 11 Hz, 2F). For syn-isomer: 19F (acetone-d6) : 8-120. 1 (dm, J= 249.7 Hz);-125. 0 (dt, J= 249.8 Hz, 15.5 Hz). HRMS (DCI/NH3) y calc'd for C15H18F2NO2 (M + NI-14) 282.1305, found 282.1304.

Example 13 : Preparation of 2,2-difluoro-1, 3-bis (4'-chloro-phenyl)-1, 3-propanediol The reaction condition is similar as described in Example 12, except that 4- chlorobenzaldehyde was used as the substrate. Product 2, 2-difluoro-1, 3-bis (4'-chloro- phenyl)-1, 3-propanediol was obtained as a pale yellow solid, 78 % yield. For anti-isomer: 1H NMR (CDC13) : 6 3.08 (d, J = 4.9 Hz, 2H) ; 5.06 (td, J = 11.3 Hz, 4.9 Hz, 2H); 7.37 (m, 8H). 13C NMR (CDC13) : 6 73.00 (t, J = 29.2 Hz); 118.75 (t, J = 251.6 Hz); 128.59 ; 129.06 ;

134.29 ; 134. 87. 19F NMR (CDC13) : 5-119. 222 (pseudo t, J = 10.7 Hz). For syn-isomer: 19F NMR (CDC13) : 6-119. 35 (dt, J = 256.5 Hz, 9.1 Hz);-127. 67 (dt, J = 256.5 Hz, 15.2 Hz).

HRMS (EI) : m/z calc'd for C15H12Cl2F2O2 (M+) 332.0182, found 332.0176.

Example 14: Preparation of 2,2-difluoro-1, 3-bis (4'-bromo-phenyl) -1, 3-propanediol The reaction condition is similar as described in Example 12, except that 4- bromobenzaldehyde was used as the substrate. Product 2, 2-difluoro-1, 3-bis (4'-bromo- phenyl) -1,3-propanediol was obtained as a pale yellow solid, 70 % yield. For anti-isomer: 1H NMR (CDC13) : # 3.20 (b, 2H); 5.02 (t, J = 11.2 Hz, 2H); 7.30 (d, J = 8.0 Hz, 4H); 7.51 (d, J = 8.0 Hz, 4 H). 13C NMR (CDCl3) : b 73.05 (t, J = 28.8 Hz); 118.67 (t, J = 252.6 Hz); 123.09 ; 129.36 ; 131.53 ; 134. 84. 19F NMR (CDC13) : #-119. 14 (pseudo t, J = 10.7 Hz). For syn-isomer : 19F NMR (CDCl3) : 6-118. 96 (dt, J = 254.8 Hz, 9.2 Hz);-127. 48 (dt, J = 254.8 Hz, 15.3 Hz). For anti-isomer: 19F NMR (CDC13) : 8-119. 1 (dt, J = 254.8 Hz, 9.2 Hz);-127. 5 (dt, J = 254.8 Hz, 15.2 Hz). HRMS (EI) : ? calc'd for C15Hl2Br2F202 (M+) 421. 9152, found 421. 9156.

Example 15: Preparation of 2,2-difluoro-1, 3-bis (4'-methoxy-phenyl)-1, 3-propanediol The reaction condition is similar as described in Example 12, except that 4- methoxybenzaldehyde was used as the substrate. Product 2, 2-Difluoro-1, 3-bis (4'-methoxy- phenyl) -1,3-propanediol was obtained as a pale yellow sticky liquid, 52 % yield. For anti- isomer : 1H NMR (CDC13) : # 3. 78 (s, 6H) ; 3.81 (b, 2H); 4.94 (t, J = 11.8 Hz, 2H); 6.86 (d, J = 8.5 Hz, 4 H); 7.30 (d, J = 8.4 Hz, 4H). 19F NMR (CDC13) : 6-119. 6 (pseudo t, J = 13.1 Hz). 13C NMR (CDC13) : 8 55. 2; 73.1 (t, J = 28. 8 Hz) ; 113.62 ; 119.3 (t, J = 251. 3 Hz) ; 128.3 ; 129.0 ; 159.7. For Syn-isomer: 19F NMR (CDC13) : 8-119. 4 (dt, J = 253.5 Hz, 9.2 Hz);-128. 1 (dt, J = 253.3 Hz, 15.1 Hz). HRMS (EI) : m/z calc'd for C15Hl2Br2F202 (M+) 421. 9152, found 421. 9156.

Example 16: Preparation of 2,2-difluoro-1, 3-bis (2'-naphthyl)-1, 3-propanediol The reaction condition is similar as described in Example 12, except that 2- naphthaldehyde was used as the substrate. Product 2, 2-Difluoro-1, 3-bis (2'-naphthyl)-1, 3- propanediol was obtained as a pale yellow solid, 69 % yield. For anti-isomer : 1H NMR (CDC13) : 8 3.33 (b, 2H); 5.25 (t, J = 11.3 Hz, 2H) ; 7. 50-7. 91 (m, 10 H). 13C NMR (CDC13) : 6 74.09 (t, J = 28.9 Hz); 119.46 (t, J = 251.7 Hz); 125.08 ; 126.30 ; 126.48 ; 127.34 ; 127.68 ; 128.10 ; 128.17 ; 132.97 ; 133. 51. 19F NMR (CDC13) : 8-118. 35 (pseudo t, J = 11.3 Hz). For syn-isomer: 19F NMR (CDC13) : 8-117. 7 (dm, J = 250 Hz);-127. o (dt, J= 251 Hz, 15 Hz).

HRMS (EI) : niez calc'd for C23H18F202 (M+) 364.1275, found 364.1277.

Example 17: Preparation of 2, 2-difluoro-1,3-bis (4'-biphenyl) -1,3-propanediol The reaction condition is similar as described in Example 12, except that 4- phenylaldehyde used as the substrate. Product 2, 2-Difluoro-1, 3-bis (4'-biphenl)-1, 3- propanediol was obtained as a pale yellow solid, 75 % yield. For anti-isomer : 1H NMR : 6 3. 48 (b, 2H); 5.17 (t, J = 11.2 Hz, 2 H) ; 7. 36-7. 60 (m, 18 H). 13C NMR (CDC13) : 8 73.54 (t, J = 28.9 Hz); 119.32 (t, J = 252.1 Hz); 127.06 ; 127.23 ; 127.67 ; 128.19 ; 130.01 ; 135.04 ; 140.53 ; 141. 71. 19F NMR (CDC13) : 5-119. 04 (pseudo t, J = 11.2 Hz). For syn-isomer: 19F NMR (CDCl3) : 5-119. 3 (dm, J = 251 Hz);-127. 1 (dt, J= 251 Hz, 15.1 Hz). HRMS (EI) : m/z calc'd for C27H22F202 (M+) 416.1588, found 416.1570.

Example 18: Preparation of 2, 2-difluoro-1, 3-bis (2'-furanyl)-1, 3-propanediol The reaction condition is similar as described in Example 12, except that 2-furanyl aldehyde phenylaldehyde used as the substrate. Product 2, 2-diy oro-1, 3-bis (2'-furanyl)-l, 3- propanediol was obtained as a viscous liquid, 63 % yield. For anti-isomer : 1H NMR (CDC13) : 6 3.50 (b, 2H); 5.17 (t, J = 11.0 Hz, 2H) ; 6.39 (m, 2H); 6.45 (mb, 2H); 7.43 (m, 2H). 13C NMR (CDC13) : 6 67.38 (t, J = 29.1 Hz); 109.80 ; 110.60 ; 18.84 (t, J = 253.4 Hz); 143.13 ; 149.02. 19F NMR (CDC13) : 8-120. 95 (pseudo t, J = 11.0 Hz). For syn-isomer : 19F NMR (CDC13) : 8-120. 5 (dm, J= 253 Hz);-125. 3 (dt, J = 253 Hz, 14 Hz). HRMS (EI) : m/z calc'd for C11HloF204 (M+) 244.0547, found 244.0550.

Example 19: Preparation of 2, 2-difluoro-1-phenyl-3- (4'-chlorophenyl)-1, 3-propanediol Into the mixture of PhSO2CF2CH (OH) Ph (120 mg, 0.4 mmol) and 4- chlorobenzaldehyde (113 mg, 0.8 mmol) in DMF (3 mL) at-50°C, was added t-BuOK (90 mg, 0.8 mmol) in 2 mL DMF. The reaction mixture was stirred at-50°C to RT overnight.

The reaction was then quenched with cold NaCl aqueous solution, followed by extraction with Et2O (20 mL x 3). After drying over MgS04 and solvent removal, the product 2,2- Difluoro-l-pehneyl-3- (4'-chlorophenyl)-1, 3-propanediol was obtained by chromatography as a white solid, 76 % yield. For anti-isomer : 1H NMR (CDC13) : 8 3.22 (m, 2H); 5.04 (td, J = 11.0 Hz, 2H); 7. 36 (m, 9H). 13C NMR (CDC13) : # 72.9 (t, J = 29 Hz); 73.8 (t, J = 29 Hz); 118.7 (t, J = 259 Hz); 127.6 ; 128.6 ; 129.0 ; 134.3 ; 134.8. 19F NMR (CDC13) : 8-118. 2- 120. 1 (m).

It will be apparent to those skilled in the art that various modifications and variations can be made in the method and system of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention include modifications and variations that are within the scope of the appended claims and their equivalents.