Palladium‐Catalyzed Atroposelective Suzuki–Miyaura Coupling to Construct Axially Chiral Tetra‐Substituted α‐Boryl Styrenes

Abstract Palladium‐catalyzed Suzuki–Miyaura (SM) coupling is a valuable method for forming C─C bonds, including those between aryl moieties. However, achieving atroposelective synthesis of axially chiral styrenes via SM coupling remains challenging. In this study, a palladium‐catalyzed atroposelective Suzuki–Miyaura coupling between gem‐diborylalkenes and aryl halides is presented. Using the monophosphine ligand Me‐BI‐DIME (L2), a range of axially chiral tetra‐substituted acyclic styrenes with high yields and excellent enantioselectivities are successfully synthesized. Control experiments reveal that the gem‐diboryl group significantly influences the product enantioselectivities and the coupling prefers to occur at sites with lower steric hindrance. Additionally, the alkenyl boronate group in the products proves versatile, allowing for various transformations while maintaining high optical purities.


Introduction
Atropisomerism, a type of stereoisomerism resulting from restricted rotation around a single bond, is widely found in natural products, bioactive molecules and chiral ligands. [1]In recent decades, tremendous effort has been devoted to the development of novel methods to construct axially chiral molecules, particularly C─C atropisomers. [2]While significant advancement has been achieved on atroposelective syntheses of axially chiral biaryl compounds, [3] constructing axially chiral tri-or tetra-substituted acyclic alkenes remains a challenging task (Scheme 1a). [4]To date, very few examples of atroposelective synthesis have been DOI: 10.1002/advs.202309706 reported for achieving tetrasubstituted acyclic styrenes, such as enantioselective bifunctionalization of internal alkynes, [5] functionalization of preformed tri-or tetra-substituted styrenes, [6] and C─H functionalization of the arene of tetrasubstituted styrenes [7] (Scheme 1b).Giving the increasing importance of axially chiral styrenes, further development of novel atroposelective synthetic methods is highly desirable.
Transition metal-catalyzed Suzuki-Miyaura (SM) coupling is a highly effective method for constructing C─C bonds.However, the construction of C─C atropisomers via Suzuki-Miyaura coupling has not been extensively explored in the synthetic community.In 2000, the Buchwald and Cammidge groups independently reported seminal work on atroposelective Suzuki coupling to synthesize axially chiral biaryl compounds. [8]With the rapid development of novel chiral ligands, [9] asymmetric Suzuki-Miyaura coupling to generate biaryl atropisomers has been intensively studied. [10]In contrast, atroposelective syntheses of axially chiral tri-and tetra-substituted acyclic olefins largely remain dormant (Scheme 2a).In 2022, Tan and co-workers reported a palladium-catalyzed atroposelective Suzuki-Miyaura coupling between aryl bromides and vinyl boronates. [11]With the assistance of a directing group, trisubstituted axially chiral acyclic olefins were obtained with excellent enantioselectivities and good Z-selectivities.However, attempts to construct tetra-substituted alkene analogues were unsuccessful (Scheme 2b, right).5b] gem-Diboryl alkenes are versatile building blocks that can be used to construct substituted alkenes via chemodivergent functionalization of the two boryl groups. [12]e were intrigued whether gem-diboryl alkenes could be utilized to synthesize axially chiral tetra-substituted -boryl styrenes (Scheme 2c).To achieve this goal, several challenges need to be addressed.First, the control of chemoselectivity is essential for this atroposelective Suzuki-Miyaura coupling.Second, further reactions with the coupling products need to be minimized.Lastly, it is not clear whether derivatization of the -boryl styrene products will retention the optical purities at the outset of our studies, although Song's work provides an encouraging example Scheme 1. Strategies for the atroposelective syntheses of unlocked tetra-substituted acyclic styrenes.
Given our ongoing interest in constructing of axially chiral molecules and enantioselective synthesis of alkenylboronates, [13] we report herein a palladium-catalyzed atroposelective Suzuki-Miyaura coupling between aryl halides and gem-diborylalkenes (Scheme 2c).With a monophosphine, Me-BI-DIME (L2), as the ligand, a series of axially chiral tetrasubstituted -boryl styrenes were synthesized in good yields with excellent enantioselectivities and E-selectivities.Notably, the reaction does not require any directing group.Moreover, the alkenyl boronate unit in the products can directly undergo various transformations, allowing for further functionalization of the coupling products.

Reaction Development
We initiated our studies with 1-iodo-2-methoxynaphthalene (1a) and gem-diborylalkene 2a as the model substrates to establish an effective catalytic system.The representative results are summarized in Table 1.First, a variety of bases were examined in the presence of 10 mol % Pd(OAc) 2 , 15 mol % BINAP (L1) and a mixed solvent system (toluene-H 2 O) at 30 °C for 48 h (Table 1, entries 1-4).It was found that the choice of base significantly influenced the conversion of the starting materials and the yield of 3a.
Next, various substituents at the -position of -halogenated naphthalene 1 were tested with Me-BI-DIME (L2) as the ligand (Table 2).In general, -halogenated naphthalene containing an alkoxyl group at the -position performed well in the atroposelective coupling reactions.The size of the alkyl group (R 1 ) has a substantial effect on the enantioselectivity of the reaction.Coupling products 3a-f were obtained in 71-90% yields with 84-94% ee, with isopropyl being the optimal group.The reaction of aryl bromide 1e' provided 3e in 90% yield with 92% ee.Product 3g, containing an isopropylthio group at the C2-position, was obtained in 76% yield with 84% ee, but the enantioselectivities of products 3h and 3i decreased significantly.In addition, no reaction occurred when a dimethylamine or N-protected amine group was introduced to the C2-position.The reaction could be easily scaled up to 1 mmol without any loss of the efficiency, yielding 3e in 88% yield with 94% ee.a) Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.12 mmol, 1.2 equiv), [Pd]   (10 mol %), L (15 mol %) and base (3.0 equiv in 0.2 mL H 2 O) in 1.0 mL toluene at 30 °C under argon atmosphere for 48 h.Yields were determined by 1 H NMR with 1,3,5-trimethoxybenzene as the internal standard.The enantiomeric excesses were determined by HPLC; b) THF was used; c) PhCF 3 was used; d) The reaction was stirred at 20 °C for 72 h and isolated yield was listed.

Substrate Scope
With the optimized conditions established, we next examined the scope of this atroposelective synthesis of tetra-substituted styrenes.Table 3 summarizes our findings.The reaction proved tolerant to naphthyl iodides 1 containing either electron-donating or electron-withdrawing groups at the C4-, C5-or C6-position of the naphthyl group, giving 4a-g in 59-91% yields with 91-96% ee.This atroposelective cross-coupling was also applicable to substituted 5-iodoquinoline, affording product 4h in 80% yield with 93% ee.Then various gem-diboryl alkenes were investigated.Subsequent investigation of various gem-diboryl alkenes revealed excellent discrimination of the two geminal boryl groups for 2-aryl-2-alkyl gem-diborylalkenes, providing 4i-p in 69-90% yields with 91-97% ee.Notably, the formation of the corresponding diastereomer, generated from the coupling with the boryl group cis to the aryl group, was not observed.Next, the reactions with various symmetrical gem-diboryl alkenes were examined.(Diborylmethylene)cyclohexane reacted smoothly with several O-substituted naphthyl iodides, providing 4q-u in 64-89% yields with 88-97% ee.
absolute configuration of 4j was determined to be R by X-ray diffraction.We also explored the product diversity of this atroposelective cross-coupling with aryl bromides.A variety of aryl bromides and gem-diborylalkenes reacted to give 5a-k in 65-95% yields with 88-93% ee.Notably, the reaction tolerated aryl chloride, delivering 5l in 94% yield with 94% ee.Iodinated tetrahydronaphthalene participated in the reaction to form product 5m in 63% yield with 85% ee.For the substrate with a formyl group at the ortho-position, product 5n was isolated in 78% yield with 60% ee.

Discussion
To investigate the role of gem-diboryl group in this atroposelective Suzuki-Miyaura coupling, control experiments were performed.
For alkenylboronate 6a and 6b, inferior results were observed under the standard conditions, giving coupling products 7a in 50% yield with 80% ee and 7b in 31% yield with 34% ee (Scheme 3a).Extending the reaction time to 120 h, slightly improved the yields of 7a and 7b.These results suggest that the gem-diboryl group played a vital role in both the yields and the enantioselectivities of the reaction.Additionally, to investigate the origin of the chemoselectivity of this cross-coupling, gem-diboryl alkene substrates 6c and 6d were tested.Under the standard conditions, the corresponding product 7c was obtained in 62% yield with 97% ee and > 20:1 E-selectivity, while only a trace amount of 7d was detected.These results indicated that the steric bulk of the alkyl and aryl substituents of diborylalkenes has a substantial effect on the chemoselectivity of the reaction, and the coupling prefers to occur at the boryl group syn to the smaller group.To assess the configuration stability of the products, thermal racemization experiments were conducted with compound 4j.After treating 4j in isopropanol at 80 °C for 4.5 h, the enantiomeric excess of 4j decreased to 76% (Scheme 3b).Accordingly, the half-life of racemization for compound 4j at 80 °C is 19.3 h.The rotation barrier of 4j was determined to be 29.36 kcal mol −1 , which is classified into class II atropisomers (atropisomers possess a barrier to rotation, ΔG rot , between 20 and 30 kcal mol −1 ). [14]The synthetic utility of the atroposelective coupling is summarized in Scheme 3c.Treating 4j with NBS at −30 °C introduced a bromo group to the C6position selectively, and product 8 was obtained in 68% yield with 97% ee. [15]The bromo group of 8 could serve as a handle for further transformations.Trifluoroborate salt 9 was prepared in 85% yield from vinyl pinacol boronic ester 4u. [16]Borinic acid 10 was isolated in 58% yield after treating 3e with aryl lithium.Moreover, tetra-substituted styrene 4j participated in the Suzuki-Miyaura coupling with para-substituted phenyl iodides, [17] giving 11a-c in 55-65% yields with excellent retention of enantiopurities (92-96% ee).Alkenyl boronate 3e underwent homologation with in situ generated chloromethyl lithium, delivering allylic alcohol 12 in 85% yield with 94% ee after oxidation. [18]Allyl diphenylphosphinite 13 was obtained smoothly from 12 in 83% yield with 94% ee.As an example of axial to point chirality transfer, oxidation of the alkenyl boronate unit of 4j gave ketone 14 in 83% yield with 92% ee.It is worth noting that no erosion of the enantiopurity of recovered 14 was observed after treating 14 with NaO t Bu in i PrOH at room temperature overnight.The observed conservation of enantioselectivity is likely due to the low acidity of the H atom  to the carbonyl group induced by the stereoelectronic effect. [19]
chiral tetra-substituted acyclic styrenes were synthesized in good yields with excellent enantioselectivities and chemoselectivities.The alkenyl boronate group of the axially chiral styrenes can directly undergo various transformations with excellent enantioretention.

Experimental Section
General Procedure for the Palladium-Catalyzed Suzuki-Miyaura Coupling: An oven-dried 10 mL Schlenk tube was charged with Pd(dba) 2 (5.8 mg, 0.01 mmol, 10 mol %), L2 (5.2 mg, 0.015 mmol, 15 mol %) and toluene (0.3 mL) under argon atmosphere.The reaction mixture was stirred at Scheme 3. Further studies of the products.room temperature for 30 minutes.Then 1 (0.1 mmol, 1.0 equiv), 2 (0.12 mmol, 1.2 equiv), t BuONa (0.3 mmol, 3.0 equiv in 0.2 mL water) and toluene (0.7 mL) was added under argon atmosphere.The reaction mixture was stirred at 20 °C (water bath) for 72 h.The reaction mixture was diluted with ethyl acetate (10.0 mL) and filtered through a plug of Celite.The filtrate was washed with water and brine, dried over anhydrous 2 SO , and concentrated under vacuum to give yellow residue, which was purified by flash chromatography on silica gel with PE/EA to afford product.The ee value was determined by chiral phase HPLC (please see the Supporting Information for more details).
[CCDC 2293683 contains the supplementary crystallographic data for this paper.These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif .]

Table 1 .
Optimization of the reaction conditions.

Table 2 .
Evaluation of the -substituent of -halogenated naphthalene.