From Olefination to Alkylation: In-Situ Halogenation of Julia− Kocienski Intermediates Leading to Formal Nucleophilic Iodo- and Bromodifluoromethylation of Carbonyl Compounds

Iodo- and bromodifluoromethylated compounds are important synthetic intermediates and halogenbond acceptors. However, direct introduction of −CF2I and −CF2Br groups through nucleophilic addition is particularly challenging because of the high tendency of decomposition of CF2Br− and CF2I− to difluorocarbene. In this work, we have developed a formal nucleophilic iodo- and bromodifluoromethylation for carbonyl compounds. The key strategy of the method is the halogenation of in situ-generated sulfinate intermediates from the Julia−Kocienski reaction to change the reaction pathway from the traditional olefination to alkylation. Interesting halogen−π interactions between the halocarbon and aromatic donors were observed in the crystal structures of the products. The method could also be extended to the introduction of other fluorinated groups, such as −CFClBr, −CFClI, −CFBr2, and −CFMeI, which opens up new avenues for the synthesis of a wide range of useful fluorinated products.

Yanchuan Zhao，Bing Gao，Jinbo Hu

Selective introduction of fluorinated moieties into organic molecules can often impart beneficial properties, and therefore, fluorinated compounds have found wide applications as pharmaceuticals and materials. Among them, iodo- and bromodifluoromethylated compounds are of vital importance because they are valuable synthetic intermediates for many other biologically important compounds containing difluoromethylene (which is known to be isosteric and isopolar to an ethereal oxygen) as well as candidates for investigating halogen bonding.Despite these important applications, their preparation still largely relies on multistep modifications of CF2I- and CF2Br-containing substances, such as XCF2COOEt (X = Br, I),which seriously decreases the synthetic efficiency and diversity. On the other hand, nucleophilic fluoroalkylation has proved to be an efficient and reliable route to fluorinated compounds, as exemplified by the remarkable success of nucleophilic trifluoromethylation of diverse bioactive molecules with the Ruppert−Prakash reagent (Me3SiCF3). Thus, it is very appealing to develop the analogous nucleophilic iodo- and bromodifluoromethylation methods. However, the introduction of −CF2I and −CF2Br groups through nucleophilic addition is particularly challenging, mainly because of the much faster decomposition of CF2Br− and CF2I − to difluorocarbene (CF2:) than that of CF3 −. As a result, direct nucleophilic iodo- and bromodifluoromethylations of carbonyl compounds, such as simple aldehydes and ketones, have not been achieved to date, and indeed, an efficient preparation of gem-difluorinated cyclopropenes using Me3SiCF2Br as a difluorocarbene precursor was recently disclosed by us.One alternative strategy for constructing −CF2I and −CF2Br groups is to halogenate a difluoromethylene-containing sulfinate (−CF2SO2M, M = metal). Typically, these fluoroalkyl sulfinates are generated through sulfinatodehalogenation reactions. Therefore, the method is limited to the transformation between different perfluoroalkyl halides via the sulfinate intermediates. A more appealing access to sulfinates is through Smiles rearrangement in the Julia−Kocienski reaction between heteroaryl sulfones and carbonyl compounds; however, the sulfinate intermediates in this case are generally labile species that spontaneously decompose to the corresponding alkenes . Despite the availability monitored or isolated. In 2010, during our investigation of difluoroolefination with difluoromethyl 2-pyridyl sulfone , we found that the difluorinated sulfinate intermediate could be both characterized by 19F NMR spectroscopy and trapped with CH3I to afford the corresponding sulfone at low temperature. We therefore surmised that the classical Julia−Kocienski olefination reaction could probably be transformed into formal nucleophilic iodo- and bromodifluoromethylation reactions if we could succeed in halogenating the in situ-generated sulfinate intermediates .

we have reported the unprecedented iodo- and bromodifluoromethylation reactions of carbonyl compounds through a new synthetic strategy, namely, halogenation of the in situ-generated sulfinate intermediates in the Julia−Kocienski reaction to change the reaction pathway from olefination to alkylation. A wide range of aldehydes and ketones were subjected to the present method to give the corresponding iodo- and bromodifluoromethylated products in high yields. Halogen−π interactions between the halocarbon and aromatic donors were observed in the crystal structures of the products. The method could also be extended to the introduction of other fluorinated groups, such as −CFClBr, −CFClI, −CFBr2, and −CFMeI, which opens up a new avenue for the synthesis of a wide range of useful fluorinated compounds. The “hijacking” of the sulfinate intermediates in the Julia−Kocienski reaction for other synthetic applications has been largely ignored in the past, and our work adds new possibilities for further elaboration of this classical reaction.