Diastereodivergent nucleophile-nucleophile alkene chlorofluorination

Abstract

The selective hetero-dihalogenation of alkenes provides useful building blocks for a broad range of chemical applications. Unlike homo-dihalogenation, selective hetero-dihalogenation reactions, especially fluorohalogenation, are underdeveloped. Current approaches combine an electrophilic halogen source with a nucleophilic halogen source, which necessarily leads to anti-addition, and regioselectivity has only been achieved using highly activated alkenes. Here we describe an alternative, nucleophile-nucleophile approach that adds chloride and fluoride ions over unactivated alkenes in a highly regio-, chemo- and diastereoselective manner. A curious switch in the reaction mechanism was discovered, which triggers a complete reversal of the diastereoselectivity to promote either anti- or syn-addition. The conditions are demonstrated on an array of pharmaceutically relevant compounds, and detailed mechanistic studies reveal the selectivity and the switch between the syn- and anti-diastereomers are based on different active iodanes and which of the two halides adds first.

Fig. 1. Approaches to alkene dihalogenation and the challenges in selective hetero-dihalogenation.

a, The classical E–Nu approach for homo- and hetero-dihalogenation. b, The alternative Nu–Nu approach, reported for homo-dihalogenation. c, Nu–Nu syn-dichlorination from Denmark. d, Nu–Nu syn-difluorination from Yoneda, Jacobsen, Gilmour and Lennox^–. e, The selectivity challenge with hetero-dihalogenation using the Nu–Nu approach. f, Regio, chemo- and diastereo (syn and anti)-selective chlorofluorination of unactivated alkenes. Previously reported methods for this transformation use the E–Nu approach to this reaction, give only anti-addition and have limited scope.

Fig. 2. Reaction optimization.

For full details, see Supplementary Tables 1–5. a, Challenges with Nu−Nu chlorofluorination to control chemo-, regio- and diastereoselectivity. Reaction of model compound 1a to products 1b–i (n/o, not observed) using the ‘ex-cell’ electrochemical approach. b, Chemoselectivity with different chloride sources. c, Temperature dependence on regioselectivity for anti-addition. d, Diastereoselectivity switch with changing nHF:amine ratio. e, A summary of the diastereoselectivity switch. IF₂ generation: p-iodotoluene in 5.6HF:amine and DCM (13 mA, 2.2 F, divided cell, Pt||Pt). Anti conditions: alkene (0.6 mmol), IF₂ (1 equiv.) solution in 5.6HF:amine, NEt₄Cl (1 equiv., 0.2 equiv. h⁻¹), DCM, −46 °C, 16 h; syn conditions: alkene (0.6 mmol), IF₂ (1 equiv.) solution in 5.6HF:amine adjusted to 7HF:amine, NEt₄Cl (1 equiv., 0.2 equiv. h⁻¹), DCM, −46 °C, 16 h.

Fig. 3. Mechanistic studies for syn- and anti-addition, addressing the active iodane and transition state.

a, DFT calculations modelled at −46 °C of iodine(III)–π complex formation, showing IFCl is the most reactive. Level of theory: M06-2X/6-31 + G(d)/LANL2DZ(I) + SMD(CH₂Cl₂)//M06-2X/def2-TZVP + SMD(CH₂Cl₂). b, Reactivity studies using preformed samples of IF₂ and ICl₂ to establish the active iodane under each set of conditions. Anti-addition to 1b is not observed with ICl₂ alone but is with 50:50 IF₂:ICl₂, providing evidence for IFCl to be the active iodane for anti-addition. Syn-addition to 1d does not predominate in the presence of ICl₂ and only forms with IF₂, providing evidence for IF₂ to be the active iodane for syn-addition. c, Natural Bond Orbital (NBO) calculations (DFT) of iodine(III)–π complex to establish regioselectivity of nucleophile attack. d, Consideration of which halide attacks first. For syn-addition, fluoride attacks first and for anti-addition, chloride attacks first. e–g, Anti-addition mechanisms discounted due to unfavourable transition state energies. The energies refer to the following starting materials: 40a in e, cis-but-2-ene in f, 40a in g. h, DFT calculations for the proposed mechanism for anti-addition, which shows a favourable transition state energy for a 1,2-chloride shift.

Fig. 4. Mechanistic studies that focus on characterizing the differences between 5.6HF:amine and 7.0HF:amine and the diastereodivergence trigger.

a, Analysis of the physical characteristics of each medium, which do not show a substantial difference between them. b, Assessment of the difference in nucleophilicity of fluoride in 5.6HF:amine and 7.0HF:amine by measuring the kinetics of the fluorination of p-nitrobenzyl bromide in each medium. The lines through plotted data are modelled second order fits. c, Assessment of the difference in nucleophilicity of chloride in 5.6HF:amine and 7.0HF:amine by measuring the kinetics of a chlorination reaction in each medium, which shows a lower nucleophilicity in 7.0HF:amine. The lines through plotted data are modelled second order fits. d, A diastereoselectivity switch can be achieved by controlling the concentration of chloride. e, A summary of the diastereodivergent Nu–Nu alkene chlorofluorination mechanisms. The bifurcation of mechanisms is dependent on the concentration and the relative nucleophilic activity of chloride and fluoride ions, which in turn dictates the structure and reactivity of the iodane, which halide adds first to the alkene, and the mechanism of iodane displacement.