Nickel-catalyzed regio- and enantio-selective Markovnikov hydromonofluoroalkylation of 1,3-dienes

A highly enantio- and regio-selective Markovnikov hydromonofluoro(methyl)alkylation of 1,3-dienes was developed using redox-neutral nickel catalysis. It provided a facile strategy to construct diverse monofluoromethyl- or monofluoroalkyl-containing chiral allylic molecules. Notably, this represents the first catalytic asymmetric Markovnikov hydrofluoroalkylation of olefins. The practicability of this methodology is further highlighted by its broad substrate scope, mild base-free conditions, excellent enantio- and regio-selectivity, and diversified product elaborations to access useful fluorinated building blocks.


Introduction
The selective introduction of a uorine or uoroalkyl moiety into molecules oen results in improved physical, chemical, and biological properties. 1 In particular, the installation of a monouoromethyl (CH 2 F) group as a bioisostere of various functional groups, such as methyl and hydroxymethyl, has been established as a robust and routine tactic in pharmaceutical chemistry and agrochemistry to tune the properties of bioactive compounds, including bioavailability and metabolic stability. 2 Typical drugs or inhibitors featuring a CH 2 F unit are shown in Scheme 1a. 3 However, despite the signicant progress made in selective uoroalkylation, 4 the efficient incorporation of a CH 2 F group in a highly enantioselective manner remains challenging and very much in demand. 5 While the hydrouoroalkylation of alkenes is a powerful strategy to introduce a uoroalkyl group selectively, 6 the catalytic enantioselective incorporation of a monouoroalkyl group is unexplored. Notably, most known alkene hydrouoroalkylations are based on radical processes, affording linear adducts with anti-Markovnikov regioselectivity. 6,7 It is considered both interesting and urgent to develop the Markovnikov hydro-uoroalkylation of olens. This not only offers the potential to develop catalytic enantioselective versions, but would afford branched adducts with a chemical space shape distinct from linear products, which are interesting targets for drug discovery because of the intimate relationship between the shape and their properties of organic molecules (Scheme 1b). 8 Following our interest in selective uoroalkylation, 9 we recently developed the Scheme 1 Regioselective hydrofluoroalkylation of alkenes.
Transition-metal-catalyzed regio-and enantio-selective hydrofunctionalization of 1,3-dienes 1 offers an efficient and atomeconomical method to access chiral functionalized allylic compounds from readily available starting materials. 10 Over the past few years, various highly enantioselective protocols have been used: hydroamination, 11 hydroalkylation, 12 hydroarylation, 13 and hydrosulfonylation, 14 among others. 15 Despite the advances made, these reactions mainly rely on using chiral precious metal Pd and Rh catalysts. Since the landmark work of the Zhou group in 2018, 12c the use of earth-abundant and low-cost chiral Ni catalysts for developing the asymmetric hydrofunctionalization of acyclic 1,3-dienes has gained increasing attention. 12c,e,f,13b,c Despite ongoing achievements, the catalytic enantio-and regio-selective Markovnikov hydromonouoromethylation of 1,3-dienes to construct functionalized chiral allylic compounds with a CH 2 F at the stereocenter is unexplored.
Inspired by these elegant advances, we speculated that the implementation of catalytic asymmetric 1,3-dienes hydro-monouoromethylation would provide a new direction for enantioselective monouoromethylation and constitutes a new branch for the hydrofunctionalizations of 1,3-dienes. To reach this goal, the quest for a suitable monouoromethyl reagent would be the key to success. Among various monouoromethyl agents, uorobis(phenyl-sulfonyl)methane (FBSM) 16a,b 2a proves to be a robust one in developing catalytic enantioselective monouoromethylation reactions, 5,16 since the landmark work of Shibata. 16a On this basis, we determined to use FBSM 2a as a latent monouoromethyl agent to explore the asymmetric Markovnikov hydromonouoromethylation of 1,3-dienes 1 under the action of chiral nickel catalysis.
Encouraged by these results, we then tested the performance of chiral bisoxazoline ligands and P,N-based PHOX (entries 3-6), and found that the use of (S,Sp)-Ph-Phosferrox L6a could improve the ee of product 3a to 68% (entry 6). Interestingly, base DIPEA proved to be unnecessary in the current reaction. A comparable result was obtained in the absence of DIPEA (entries 6 vs. 7). The focus of further optimization was on chiral ferrocene-based chiral ligands, but there was no improvement in the ee values (entry 8, see the ESI † for details). Subsequently, we turned our attention to exploring P-chiral phosphine ligands because they usually exhibit distinct chirality-inducing ability. 17 To our delight, P-chiral (S,S)-QuinoxP* 18 L8, never before used in hydrofunctionalizations of 1,3-dienes, proved to be efficient; it afforded 3a in 95% NMR yield with 96% ee within 16 h (entry 10). An examination of the solvent effect revealed that EtOH was still the best solvent (entries 10 vs. 11-15), although the use of THF also afforded the desired product 3a in 99% NMR yield, but with a slightly lower ee (entry 12). Moreover, the use of a 5 mol% Ni catalyst afforded the product 3a in 86% isolated yield with 96% ee, albeit within 72 h (entry 16).
Unsurprisingly, the FBSM adduct 3a could efficiently undergo a reductive desulfonylation to access chiral a-mono-uoromethyl (CH 2 F) allylic compound 4a with 96% ee under the action of Mg/MeOH 19 (Scheme 2A). This result stimulated us to explore the assembly of deuterated monouoromethyl (CD 2 F)containing chiral allylic molecules, given that the incorporation of a deuterium atom in the bioactive molecules is emerging as a promising tactic to modulate the bioactivity or pharmacological properties in drug discovery programs since the rst deuterated drug, Austedo, was approved by FDA in 2017. 20a However, while the development of efficient approaches for preparing deuterated compounds is of current interest, the selective introduction of a CD 2 F group into the stereogenic center is still a challenging task and remains unexplored. 21 To our delight, chiral deuterated allylic product D-4a featuring a CD 2 F group at the stereocenter, difficult to access by other methods, could be obtained smoothly by using CD 3 OD as the solvent in the desulfonylation step. Furthermore, a tandem Ni-catalyzed asymmetric hydro-monouoro bis(phenylsulfonyl)methylation/reductive desulfonylation sequence was developed for the direct access of a-CH 2 F and a-CD 2 F substituted chiral allylic compounds 4 and D-4 (Scheme 2B). Both aryl-and alkyl-substituted 1,3-dienes were suitable partners for this tandem sequence, as exemplied by the preparation of 4a-4d and D-4a-4d with excellent ee values. It is worth mentioning that the facile synthesis of chiral allylic compounds bearing a CD 2 F-substituted stereocenter justied the use of FBSM as the monouoromethylation reagent and further highlighted the value of our method.
The excellent regio-and enantio-selectivity of the above hydromonouoromethylation inspired us to explore the realization of enantioselective hydromonouoroalkylation with diethyl uoromalonate 4p,16d 5 because of its ability to simultaneously incorporate a uorine atom and two convertible ester groups, 22 which allows the construction of functionalized chiral mono-uorinated molecules with high structural complexity. Aer optimization of the reaction conditions (see the ESI † for details), the combination of Ni(COD) 2 and (S,S)-QuinoxP* L8 still proved to be an optimal catalytic system. 23 As illustrated in Scheme 3, the substrate scope was examined by running the reaction in EtOH at 50°C using 5 mol% of Ni(COD) 2 -ligated (S,S)-QuinoxP* as the catalyst. Both (hetero)aromatic and aliphatic 1,3-dienes were suitable substrates, affording the 4,3-Markovnikov adducts 6 with excellent regio-and enantio-selectivity. Regardless of the nature and position of the substituent on the phenyl ring of aryl 1,3dienes, all reacted well with 5 to afford the products 6a-6u in 68-99% yields with 93-99% ee. The XRD analysis of 6t conrmed its absolute conguration to be (S), and that of other products was assigned by analogy. Various functional groups, such as ester (6e), nitrile (6f), ketone (6g), aldehyde (6h), amine (6m), and nonconjugated alkene (6n), on the aryl ring of aromatic 1,3-dienes were well-tolerated under this hydromonouoroalkylation as well. Heteroaromatic 2-furyl-and 2-thienyl-substituted 1,3-dienes, as well as conjugated triene, also afforded the adducts 6v-6x in 93-98% yields and 91-98% ee. Moreover, linear and branched alkyl-substituted 1,3-dienes were tolerated, affording 4,3-Markovnikov adducts 6y-6ab in 79-97% yields and 90-97% ee, with high to excellent regioselectivity, albeit with the generation of a small amount of 4,1-addition isomer in these cases. 13c The use of a 10 mol% Ni catalyst was required to ensure excellent yields in the case of heteroaryl and alkyl 1,3-dienes. The protocol was also applied to the late-stage hydromonouoroalkylation of (S)-Scheme 3 Scope of enantioselective hydromonofluoroalkylation of 1,3-dienes 1 with diethyl fluoromalonate 5. Conditions: 1 (0.375 mmol), 2 (0.25 mmol), Ni(COD) 2 (5 mol%), and L8 (5.5 mol%) at 50°C in EtOH (1.5 mL), unless otherwise noted. Yields of isolated products were reported and ee was determined by chiral HPLC analysis. a Using Ni(COD) 2 (10 mol%) and L8 (11 mol%). b At 70°C. c At 50-70°C. d At 60°C. e At 80°C. f At 75°C. The rr indicates the regioselectivity ratio of 4,3-Markovnikov isomer with another isomer, which was determined by 1 H NMR analysis. The ee value of 6z and 6aa was determined by their derivatives; see the ESI † for details. The dr value of 6ac and 6ad was determined by 19 F NMR analysis.

Synthetic utility
To further highlight the practicality of the reaction, a gram-scale synthesis of product 6a and its synthetic elaborations toward structurally diversied uorine-containing molecules was conducted. As shown in Scheme 4, starting from 1a (7.5 mmol) and 5 (5 mmol), 1.47 g of 6a could be readily generated in 95% yield and with 97% ee under the standard conditions. The two ester groups of 6a could be selectively hydrolyzed to uorinated carboxylic acid or dicarboxylic acid, as demonstrated by the synthesis of 7 (94% yield and 12 : 1 dr) via a porcine liver esterase (PLE) enabled hydrolytic desymmetrization, and 8 (99% yield) via NaOH-mediated hydrolysis. The treatment of 6a with m-CPBA led to the epoxidation of the alkenyl and afforded chiral uorinated epoxide 9 in 73% yield, albeit with modest dr. Compound 6a could also be selectively reduced with LiAl(O t Bu) 3 or NaBH 4 , affording a uorinated hydroxy ester 10 in 67% yield with 1.4 : 1 dr and 96% ee, or a uorinated diol 11 in 83% yield with 97% ee, respectively.

Conclusions
In summary, we have developed a highly enantioselective Markovnikov regioselective hydromonouoroalkyl(methyl)ation of 1,3-dienes by using chiral Ni catalysis, allowing access to various functionalized chiral allylic compounds bearing a CH 2 F, CD 2 F or monouoroalkyl group at the stereocenter. Remarkably, such a methodology provides a new direction for enantioselective monouoroalkyl(methyl)ation, and it constitutes a new branch of asymmetric 1,3-diene hydrofunctionalizations. Moreover, this Scheme 4 Synthetic utility. represents the rst enantio-and regio-selective Markovnikov hydrouoroalkylation of olens. The salient features include broad substrate scope for both aromatic and aliphatic 1,3-dienes, excellent enantio-and regio-selectivity, good functional group tolerance, mild base-free conditions, and diverse product transformations. Further studies in our laboratory will focus on elucidating the reaction mechanism 25 and developing other asymmetric Markovnikov regioselective hydrouoroalkylation reactions.

Data availability
All of the experimental data have been included in the ESI. † Crystallographic data can be obtained from the CCDC (2130032 and 2130034).

Conflicts of interest
There are no conicts to declare.