Regioconvergent Nucleophilic Substitutions with Morita–Baylis–Hillman Fluorides

Lithium iodide enables regioconvergent C–F bond functionalization of isomeric Morita–Baylis–Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon–carbon and carbon–heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.


■ INTRODUCTION
The general significance of fluorinated organic compounds in the life sciences has stimulated the introduction of many practical methods to make them. 1,2Organofluorines have become readily available starting materials that are rapidly growing in popularity among synthetic chemists.The usefulness of aryl fluorides in nucleophilic aromatic substitution and transition metal-catalyzed cross-coupling reactions is well documented.C sp2 −F functionalization is a frequently employed venue to form carbon−carbon or carbon−heteroatom bonds, while applications of aliphatic substrates are less explored.Activation of a C sp3 −F bond often requires strong Lewis acids and harsh conditions that may favor competing hydrodefluorination pathways and reduce functional group tolerance, although synthetically attractive protocols for carbon−carbon coupling, 3−8 carbon−heteroatom bond formation, 9−11 and halide exchange 12,13 are known. 14−21 We have become increasingly interested in the development of synthetic methodologies that provide unique access to multifunctional compounds and exploit new reactivity patterns, in particular when these complement the outcome of existing reactions.−31 By contrast, we envisioned that fluoride displacement might also be possible via attack at the vinylic carbon.Herein, we report that such a pathway by which the fluoride is replaced via formal S N 2′ reaction can indeed be realized through activation with inexpensive lithium iodide at room temperature (Scheme 1).This protocol affords unprecedented regioselectivity control with carbon, sulfur, and nitrogen nucleophiles producing a variety of compounds in high yields and with good to excellent E/Z ratios.Moreover, this method allows regioconvergent substitution with isomeric MBH fluorides, which is attributed to the formation of a common (Z)-2-(iodomethyl)cinnamate intermediate that is readily consumed in the presence of a nucleophile.
In accordance with previous literature reports, we observed that the MBH fluoride 1 undergoes nucleophilic substitution at the allylic carbon when treated with silyl enol ethers 2 and 3 in the presence of catalytic amounts of DABCO, 26−31 and we obtained 4 and 5 in 10% and 85% yields, respectively.The low yield of 4 was attributed to the low stability of silyl enol ether 2, which rapidly decomposed at room temperature.We discovered that employing enamines as nucleophiles switches the regioselectivity to the vinylic carbon resulting in S N 2′ fluoride displacement (Scheme 2).We were pleased to find that both 6 and 7 afforded 8 and 9 in 74−83% yield and E/Z ratios of 16:1 and 20:1, respectively.
When treating a 1:1 isomeric mixture of 10 and 11 with allylamine, 12, we observed that 10 reacts to the corresponding amine adduct 14 while 11 is not consumed.Further investigation revealed that the addition of LiI facilitates regioconvergent transformation of both 10 and 11 to a single iodide intermediate 13 which reacts quantitatively at room temperature with 12 to 14 exhibiting a high E/Z ratio of >20:1 (Scheme 3).We were able to isolate 13 to prove its central role in the regioconvergent defluorination pathway (see S1).However, we found that 10 can be directly transformed to 14 via S N 2′ fluoride displacement in the absence of LiI, but consumption of 11 was not observed unless it was converted in situ to intermediate 13 which undergoes S N 2 reaction with the amine nucleophile toward the same product.Alternatively, LiI can be replaced with TBAI, YI 3 , or YbI 3 , while TMSI proved less efficient, see SI.This generally points to negligible countercation effects at least when LiI, TBAI, etc., are used.According to Streitwieser, 32 nucleophilic substitutions at allylic substrates by anionic nucleophiles are generally of the S N 2 type, or when the S N 2′ reaction prevails due to steric hindrance it proceeds with anti stereochemistry.The former is observed with the primary fluoride 11, while 10 is sterically hindered and therefore undergoes anti-S N 2′ displacement.The diastereoselective conversion of 10 to the Z isomer of 13 is in agreement with an S N 2′ transition state having the phenyl and the ester groups in a coplanar trans conformation according to a study of the reaction between phosphorus nucleophiles and MBH acetates by Georgiadis et al. 33 This explains the regioconvergent generation of Z-13 from either allylic fluoride.Finally, S N 2 displacement of the iodide in Z-13 with 12 gives E-14 in high yield and in excellent diastereomeric excess.This method is highly advantageous as it allows the use of both MBH fluoride isomers which are typically obtained as a mixture from their corresponding alcohols and are difficult to separate by column chromatography.
Intrigued by the regioconvergence and high diastereoselectivity of this reaction, we began screening various conditions including base additives, stoichiometry of reactants, and solvents (see SI).We determined that optimal results are obtained with two equivalents of nucleophile, diisopropylethylamine, and LiI in dichloromethane at room temperature.It is noteworthy, however, that only slightly lower yields were obtained with one equivalent of lithium iodide, and the reaction was found to proceed with catalytic amounts, generating 14 in 52% yield as well as 25% of a dialkylation byproduct, see SI. Next, we evaluated the substrate scope under optimized conditions.As shown in Scheme 4, a diverse array of nucleophiles undergoes the desired regioconvergent allylic substitution with isomeric mixtures of MBH fluorides in high yields and good to excellent diastereoselectivity. MBH fluorides with different ester groups gave the corresponding products 14−17 in almost quantitative yields and 20:1 dr when treated with allylamine.Overall, amine nucleophiles are well tolerated and give yields ranging from 83% to 99%.The reaction with primary, secondary, and heterocyclic amines all afford the desired products 18 and 20−25 in >20:1 dr.A moderate decrease in dr (10:1) was observed when aniline was used in the synthesis of 19, while yields were not affected.Interestingly, thiols are also tolerated, and we obtained 26 in 99% yield and 10:1 dr.A noticeable drop in the diastereoselectivity was observed with carbon nucleophiles that can, however, be generated in situ with Hunig's base, thus eliminating the need to prepare enamines.The use of dimethyl malonate, 1-pyrrolidino-1-cyclohexene, and 2-carbethoxycyclopentanone afforded the desired products 27−29 with yields ranging from 81% to 95% and dr's between 4:1 and 10:1.The reaction outcome proved sensitive to the presence of electronwithdrawing and electron-donating groups in the phenyl ring of the MBH fluoride.The 4-cyanophenyl and 4-nitrophenyl derivatives quantitatively converted to the intermediate 13, but subsequent amination with 12 was not observed even after heating to 50 °C overnight.By contrast, overalkylation to the tertiary amine byproduct could not be controlled with the 3methoxyphenyl MBH fluoride despite the use of two equivalents of 12.
We discovered that HFIP-assisted palladium-catalyzed asymmetric alkylation is also possible and proceeds exclusively at the same carbon atom.Similar to our LiI protocol, we discovered that isomeric mixtures of MBH fluorides 10 and 11 react in a regioconvergent mechanism with the palladium catalyst following fluoride abstraction with HFIP.The comprehensive screening of palladium complexes and reaction conditions revealed that 29 can be obtained in 95% yield, 65% ee, and 10:1 diastereomeric ratio, Scheme 5 and SI.
In conclusion, we have introduced a practical method that allows smooth substitution at the vinylic carbon of MBH fluorides with excellent regioconvergence, yield, and E/Z The Journal of Organic Chemistry diastereoselectivity with carbon, sulfur, and nitrogen nucleophiles.The use of LiI increases the practicality of this chemistry by enabling regioconvergent substitution of isomeric fluoride mixtures via a common intermediate.This affords multifunctional MBH derivatives in 81−99% yields and high dr's in most cases.Asymmetric catalytic substitution at the vinylic carbon is also possible, albeit with only moderate enantioselectivity.This method complements previously reported regioselective substitutions of MBH fluorides with silylated pronucleophiles that react at the allylic carbon center.In addition, the necessity to separate E/Z isomers of the MBH fluoride starting materials is overcome with inexpensive lithium iodide which produces a common allylic iodide intermediate and thus significantly increases overall yields.
■ EXPERIMENTAL SECTION General Information.All chemicals and solvents were used as purchased without further purification.The MBH fluorides were synthesized following literature procedures. 22−24,26−29 NMR spectra were obtained at 400 MHz ( 1 H NMR) and 100 MHz ( 13 C NMR) in deuterated chloroform or methanol.Chemical shifts are reported in ppm relative to the solvent peak.Reaction products were purified by column chromatography on silica gel (particle size 40−63 μm) as described below.

General Procedure of the Regioconvergent Substitution of MBH Fluorides with C-, N-, and S-Nucleophiles.
A vial was charged with LiI (0.2 mmol), MBH fluoride (0.1 mmol), nucleophile (0.2 mmol), diisopropylethylamine (0.2 mmol), and anhydrous dichloromethane (0.5 mL).The mixture was stirred at room temperature under N 2 atmosphere for 24 h.The residue of the crude reaction mixture was directly dry loaded onto silica gel and purified by flash chromatography using hexanes−ethyl acetate mixtures as mobile phase as described below.
General Procedure of the Regioconvergent Substitution of MBH Fluorides with Enamines.A vial was charged with the MBH fluoride (0.1 mmol), enamine (0.1 mmol), and THF (0.5 mL) under nitrogen.The reaction was stirred at room temperature for 18 h.The mixture was quenched with saturated ammonium chloride and extracted with CH 2 Cl 2 , followed by purification of the residue by flash chromatography as described below.
General Procedure of the Regioconvergent Substitution of MBH Fluorides with Silyl Enol Ethers.A vial was charged with the silyl enol ether (0.1 mmol), DABCO (0.01 mmol), MBH fluoride The Journal of Organic Chemistry (0.1 mmol), and anhydrous CH 2 Cl 2 (0.5 mL) under nitrogen.The reaction was stirred for 18 h.The mixture was quenched with saturated ammonium chloride and extracted with CH 2 Cl 2 , followed by purification of the residue by flash chromatography as described below.

Scheme 2 .
Scheme 2. Fluoride Substitution at the Allylic Carbon in the MBH Fluoride 1 with Silyl Enol Ethers versus S N 2′ Displacement by the Corresponding Enamines

Scheme 4 .
Scheme 4. Scope of the Regioconvergent Allylic Substitution Reaction a