Stereodivergent Palladium-Catalyzed C–F Bond Functionalization of gem-Difluoroalkenes

We herein describe a stereodivergent C–F bond functionalization of gem-difluoroalkenes. Using trisubstituted β,β-difluoroacrylates, both E and Z monofluoroalkene products can be obtained with excellent diastereoselectivities. The design of two different reaction manifolds, i.e., Pd(II)- versus Pd(0)-catalyzed cross-coupling of boronic acids, is the key to stereocontrol.

gem-Difluoroalkenes are privileged motifs in biological and synthetic applications. 1The two strong electron-withdrawing F atoms through the σ-bond can activate the alkene for nucleophilic attack.This fundamental property allows the gem-difluoroalkenes to serve as precursors for a broad spectrum of organic transformations.One of the most important synthetic applications of gem-difluoroalkenes in recent years is the selective transition metal-catalyzed C−F bond functionalization 2 for the synthesis of monofluoroalkenes.Monofluoroalkenes are of particular importance in medicinal chemistry because of their potential to act as amide bond isosteres and enol mimics. 3Thus, the utility of monofluoroalkenes can be found in pharmaceutical development, materials science, and organic synthesis.
In general, the carbon−fluorine bond transformation is considered much more difficult than C−I, C−Br, and C−Cl bonds because of the enormous bond dissociation energy (∼120 kcal/mol) of C−F bonds. 4However, in the presence of transition metal catalysts [M] (M = Cu, 5 Ni, 6 Rh, 7 Co, 8 Mn, 9 Ru, 10 Pd, 11 and Fe 12 ), gem-difluoroalkenes can undergo selective functionalization of a single C−F bond.The key step in these reactions is the β-fluoride elimination of the βfluoroalkylmetal intermediate (Scheme 1a).1a The formation of a strong M−F bond is the thermodynamic driving force for this process.The diastereoselectivity usually favors the Zmonofluoroalkene product.
Currently, transition-metal-catalyzed C−F bond functionalization of gem-difluoroalkenes has the following limitations.For trisubstituted gem-difluoroalkenes, such as β,β-difluorostyrene derivatives used by others, 5−12 the stereoselectivity favors the Z product on the basis of steric bias (Scheme 1b).For tetrasubstituted gem-difluoroalkenes, such as β,β-difluoroacrylate derivatives used by us, the stereoselectivity favors the E product based on chelation control by the directing group (Scheme 1c). 13Despite the vast literature in the field, 1−3 there is a lack of a general stereodivergent strategy of C−F bond functionalization to access both (Z)-and (E)-monofluoroalkenes from the same gem-difluoroalkene.
Stereoselective synthesis of multisubstituted alkenes has been a long-standing challenge in organic synthesis. 14A stereodivergent catalytic protocol to synthesize both Z and E isomers from one set of substrates offers a highly attractive solution.For instance, catalytic semihydrogenation of alkynes can lead to Z or E alkenes; 15a,b however, such a method is not practical and applicable to the preparation of monofluoroalkenes with higher substitution patterns.15c To the best of our knowledge, only Ito and co-workers have reported an indirect Cu(I)-catalyzed stereodivergent hydrodefluorination of gem-difluoroalkenes to synthesize disubstituted (Z)-and (E)-terminal monofluoroalkenes (Scheme 1d).5d The Z product was obtained via a borylation/deborylation sequence using B 2 pin 2 , and the E product was obtained using hydrosilane.The steric and electronic repulsions were claimed to be key factors in controlling the selectivity of Z and E products, respectively.
In order to develop a widely applicable stereodivergent C−F bond functionalization, the mode of stereocontrol must be expanded beyond steric/electronic repulsions.We envisioned a catalyst-controlled reaction motif by employing a trisubstituted gem-difluoroalkene 1 that contains a directing group (DG), which can potentially take on two different reaction pathways (a and b) depending on the catalytic system, to provide functionalized (E)-or (Z)-monofluoroalkene 2 (Scheme 2).In To test our hypothesis, we identified trisubstituted gemdifluoroalkene 1a, which contains an ester group, as a potential directing group, as a candidate for the stereodivergent C−F bond functionalization (Table 1).Compound 1a is a type of β,β-difluoroacrylate that can be prepared from the corresponding α-diazo ester precursor. 16Toste et al. reported a redoxneutral Pd(II)-catalyzed coupling of β,β-difluorostyrenes with boronic acids to synthesize monofluorostilbenes. 11 When 1a was subjected to the standard conditions, the monofluoroalkene product 2a was detected in 52% yield (Z/E > 99:1), along with 30% difluoro side product (i.e., conjugate addition product) (entry 1). 17We were delighted to see the "nondirected" pathway b (cf.Scheme 2) could provide the Z product in excellent diastereoselectivity.The goal was, therefore, to increase the yield of 2a while decreasing the side product formation by varying the Pd catalysts and ligands. 18mong the Pd(II) catalysts screened, only Pd(OAc) 2 gave comparable reactivity as Pd(TFA) 2 (entries 2−6).2,2′-Bipyridine ligand L1 gave a similar yield as dtbbpy (entry 7), and other bipyridine ligands L2 and L3 were also compared (entries 8 and 9).1,10-Phenanthroline ligand L4 and its analogues L5 and L6 were screened (entries 10−12).We found that using ligand L6 produced the least amount of difluoro side product (entry 12).Increasing the temperature from 50 to 65 °C gave a better yield (entry 13), and 1.0 equiv of boronic acid was effective (entry 14).Finally, we identified the combination of Pd(OAc) 2 /L6 as the optimal catalytic system for this reaction (entry 15).Other parameters, including solvents, reagents, and stoichiometry were screened with no further improvement. 18nder the Pd(II)-catalyzed conditions, various monofluoroalkenes (Z)-2 could be obtained from gem-difluoroalkenes 1 in excellent diastereoselectivities (dr > 99:1) (Scheme 3).Arylboronic acids containing different substituents were tolerated to afford products 2a−g in moderate yields.Reaction at the 1.0 mmol scale was also demonstrated (2a).Substituent group (R) of the ester moiety could also be varied, including different benzylic (2h−i), alkyl (2j), and aromatic (2k−l) groups.In all cases, only the Z products were formed.
Next, we investigated the scope of the "directed" pathway a (cf.Scheme 2) using Pd(0) catalyst and the same gemdifluoroalkenes 1 (Scheme 4).Previous work 13c has shown that Ph(PPh 3 ) 4 -catalyzed Suzuki−Miyaura cross-coupling of tetrasubstituted β,β-difluoroacrylates is highly diastereoselective.To our delight, by applying catalytic Ph(PPh trisubstituted 1a at 90 °C, 18 product 3a could be obtained in 27:1 dr (crude ratio) favoring the E diastereomer.The reaction was also performed at a 1.0 mmol scale with similar results.Various arylboronic acids were employed to generate monofluoroalkenes 3b−l.The reaction tolerated substituents at ortho, meta, and para positions of the benzene ring.Electronrich (3c) and electron-poor (3f) groups were compatible, although the latter gave a lower dr.Other functional groups, including chloro (3i), ester (3j), ketone (3k), and aldehyde (3l), were also tolerated.The diastereoselectivities were generally very high (>20:1 dr).Other boronic acids, such as naphthyl (3m), and heteroaryl ones, such as 3-thienyl (3n) and 3-furyl (3o), provided the products in excellent drs.The ester substituent group of 1 could be varied to include different alkyl (3p), benzyl (3q,r), and aryl (3s) groups with good diastereoselectivities.The structure of 3 and (E)-alkene geometry were unambiguously confirmed by X-ray crystallography through compound 3q.Some of the substrates required a lower temperature (80 °C) to ensure high diastereoselectivities.Upon isolation, all products were obtained as a single E diastereomer.
Further experiments were conducted to gain insights into the reaction mechanisms (Scheme 5).In the Pd-free reaction using a Grignard reagent, both Z and E products were obtained in poor selectivity via addition−elimination (Scheme 5a).Thus, the excellent diastereoselectivities in products (Z)-2 and (E)-3 (cf.Schemes 3 and 4) should be controlled by the Pd catalysts through "nondirected" and "directed" pathways, respectively (cf.Scheme 2).Intriguingly, subjecting β,βdifluoroacrylamide 4 to the standard Pd(II)-catalyzed conditions gave no desired product (Scheme 5b).However, under Pd(0)-catalyzed conditions, the monofluoroacrylamide product (E)-5 was obtained in excellent dr (>99:1).The amide functionality could also serve as an effective directing group in this reaction.Following the previous protocol, 13a we were able to obtain and characterize the trisubstituted monofluorovinyl Pd(II) complex Int-1 as a single diastereomer (Scheme 5c).Reacting Int-1 with boronic acid gave the desired product (E)-3a in good yield and diastereoselectivity, thus proving the intermediacy of the analogous monofluorovinyl Pd(II) complex in the "directed" pathway (cf.Scheme 2, intermediate A).
In conclusion, we have developed a novel stereodivergent C−F bond functionalization of trisubstituted gem-difluoroalkenes 1.Using the same substrate, both Z-and Emonofluoroalkene products could be obtained with excellent diastereoselectivities.The stereocontrol relies on two different reaction pathways involving Pd(II)-versus Pd(0)-catalyzed cross-coupling of arylboronic acids.Other types of C−C and C-heteroatom bond formation via the stereodivergent reaction design are currently under investigation in our laboratory.

Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
path a (directed pathway), 1 undergoes a chelation-assisted C−F bond oxidative addition with a metal catalyst [M 0 ] resulting in intermediate A. Transmetalation of A with an organometallic reagent R-Y at the [M II ] center leads to intermediate B. Final reductive elimination affords product (E)-2 and regenerates catalyst [M 0 ].In path b (nondirected pathway), 1 undergoes migratory insertion with an organometallic species [M II -R] resulting in intermediate C. Steric effect favors conformation D where syn-β-fluoride elimination takes place to afford the product (Z)-2 and regenerates the [M II ] catalyst.

Table 1 .
3 ) 4 to Effects of Pd(II) Catalysts and Ligands for the Stereoselective C−F Bond Functionalization of 1a to (Z)-2a.a a Unless specified otherwise, reactions were carried out using 1a (0.1 mmol), PhB(OH) 2 (0.2 mmol), [Pd II ] (10 mol %), and ligand (11 mol %) at 50 °C under argon.b Yield and diastereomeric ratio (dr) were determined by 19 F NMR analysis using benzotrifluoride as the internal standard.c Detected 30% of the difluoro side product by 19 F NMR. d Only trace difluoro side product was detected by 19 F NMR. e L6 (10 mol %) at 65 °C.f Reacted with 1.0 equiv of PhB(OH) 2 .