Selective introduction of difluoromethyl group (CF₂H) into organic molecules is of great importance due to its ability to contribute special biological properties to those molecules. CF₂H functionality has been known to be isosteric and isopolar to hydroxyl (OH) group and behaves as a hydrogen donor through hydrogen bonding.^1-5 Moreover, CF₂H group has similar high lipophilicity as the trifluoromethyl group, which is useful in applications where a more lipophilic hydrogen bond donor other than OH is required.³ As a result, CF₂H group has been frequently incorporated into various biologically active compounds (such as enzyme inhibitors,⁶ sugars,⁷ pesticides,⁸ and herbicides⁹) and materials (such as liquid crystals¹⁰ and fluoropolymers¹¹). Many CF₂H-containing compounds have also been used as anesthetics, including well-known desflurane and isoflurane.¹²

Several methods have been developed for the preparation of CF₂H-containing compounds, including the deoxofluorination of aldehydes using SF₄, DAST, or SeF₄,¹³ nucleophilic fluorination of gem-bistriflates using TBAF,¹⁴ fluorination of 1,2- or 1,3-dithianes using BrF₃ and other in situ-generated halogen fluorides,^5,15 addition of CF₂Br₂ into double bonds,¹⁶ S_RN1 reaction between a nucleophile and CF₂HCl,¹⁷ and hydrogenation of terminal 1,1-difluoroalkenes.¹⁸ Nucleophilic introduction of a CF₂H building block into carbonyl compounds has been reported, using (difluoromethyl)dimethylphenylsilane,¹⁹ (chlorodifluoromethyl)trimethylsilane,³ or difluoromethyl phenyl sulfone²⁰ as the CF₂H precursor. Previously, we have reported the preparation of difluoromethylsilanes via the magnesium metal-mediated reductive difluoromethylation of chlorotrialkylsilanes using difluoromethyl phenyl sulfone.²¹ Herein, we would like to disclose a simple and efficient new method for the preparation of difluoromethyl compounds from readily available primary alkyl halides using difluoromethyl phenyl sulfone²² (1) as a CF₂H precursor.

The nucleophilic substitution reactions between difluoromethyl anion ("CF₂H^-", commonly generated in situ) and simple alkyl halides are generally difficult due to the unmatched hard-softness.²³ Recently, we have succeeded in the S_N2 reactions between (benzenesulfonyl)difluoromethyl anion (generated in situ from 1 and a base) and primary alkyl halides (preferably iodides) (see Scheme 1), which enabled us to synthesize 1,1-difluoroalkenes from primary alkyl halides in substitution-elimination mode.²⁴ As shown in Table 1, a variety of alkyl-substituted gem-difluoromethyl phenyl sulfones 3 were prepared in good yields using difluoromethyl sulfone 1 (1 equiv), primary alkyl iodides or bromides (4 equiv), and t-BuOK (2 equiv) at -50 C for about 1 h.²⁴

Scheme 1. Nucleophilic Substitution Reactions of 1 with 2

It is worthwhile to mention that the similar nucleophilic substitution reaction between the in situ-generated (benzenesulfonyl)difluoromethyl anion (from 1 and t-BuOK) and other electrophiles worked equally well. When excess elemental iodine was used as the electrophile, PhSO₂CF₂I (4) was produced in 92% yield (Scheme 2). Interestingly, when n-perfluorohexyl iodide was applied instead of I₂, the same product 4 was produced in 39% yield. Difluoromethyl phenyl sulfoxide, PhSOCF₂H, also reacts with n-butyl iodide in the presence of t-BuOK, to give 1,1-difluoropentyl phenyl sulfoxide (5) in 54% yield.

Scheme 2. Nucleophilic Substitution Reaction of 1 with I2

Reductive desulfonylation is widely used in the organic synthesis in order to remove the arenesulfonyl groups after the desired transformations.²⁵ After the desulfonylation, the arenesulfonyl groups are commonly replaced by a hydrogen atom. Reductive desulfonylations of gem-difluorinated sulfones are scarce. (Benzenesulfonyl)difluoromethyl carbinols have been reductively desulfonylated into difluoromethyl carbinols in low yields, using sodium metal in ethanol.^20a Similar poor yields were obtained when we tried a Na/MeOH system as a desulfonylating agent for the alkylated difluoromethyl sulfones 3. It soon became apparent that under the reaction conditions, the in situ-generated strong base MeONa will further complicate the reaction and thus decrease the desulfonylation efficiency. Inspired by the early report that the clean desulfonylation reaction can be obtained by applying a buffering agent to control the pH,²⁶ we added sodium monohydrogenphosphate (Na₂HPO₄) in our desulfonylation reactions in order to selectively produce difluoromethylated products (see Scheme 3). Sodium/mercury amalgam (5 wt % Na in Hg) was used, and the reactions were carried out at - 20 to 0 C for 0.5-1 h. Various difluoromethyl compounds 6 were obtained from the corresponding alkylated difluoromethyl sulfones 3 in excellent yields (see Table 2).²⁷ The reactions were highly selective, which simplified the final purification processes.

Scheme 3. Preparation of Difluoromethyl Compounds from 3

In conclusion, the substitution of the halogen atom of a primary alkyl halide (preferably alkyl iodide) by a CF₂H group has been achieved, using a nucleophilic substitution-reductive desulfonylation strategy. Difluoromethyl phenyl sulfone (1) acts as a difluoromethyl anion ("CF₂H^-") equivalent. This new synthetic methodology possesses many advantages, including convenience, cost, and efficiency, and promises to be a highly useful synthetic tool for many other potential applications.

Acknowledgment

Support of our work in part by the Loker Hydrocarbon Research Institute is gratefully acknowledged.