Three‐Component Radical Cross‐Coupling: Asymmetric Vicinal Sulfonyl‐Esterification of Alkenes Involving Sulfur Dioxide

A novel catalytic system for radical cross‐coupling reactions based on copper and chiral Pyridyl‐bis(imidazole) (PyBim) ligands is described. It overcomes the challenges of chemoselectivity and enantioselectivity, achieving a highly enantioselective vicinal sulfonyl‐esterification reaction of alkenes involving sulfur dioxide. This strategy involves the use of earth‐abundant metal catalyst, mild reaction conditions, a broad range of substrates (84 examples), high yields (up to 97% yield), and exceptional control over enantioselectivity. The reaction system is compatible with different types of radical precursors, including O‐acylhydroxylamines, cycloketone oxime esters, aryldiazonium salts, and drug molecules. Chiral ligand PyBim is identified as particularly effective in achieving the desired high enantioselectivity. Mechanistic studies reveal that copper/PyBim system plays a vital role in C─O coupling, employing an outer‐sphere model. In addition, the side arm effect of ligand is observed.

Chiral Pyridine-Bis(Oxazoline) (PyBox) ligands, despite their distinct advantages in various reactions, face significant challenges in the modification of the ligand skeleton and synthesis of the oxazoline moiety, which prolong and complicate the creation of ligand libraries. [9] As a result, the Cu/PyBim system has the potential to complement radical cross-coupling reactions, displaying distinct properties (Figure 1B).
Due to the high reactivity and short lifespan of radical intermediates compared to their ionic counterparts, there has been limited research on the copper-catalyzed radical asymmetric oxy-sulfonylation of alkenes.6a] This groundbreaking achievement was made possible through the use of a novel catalyst, a combination of copper(I) and cinchona alkaloid-derived sulfonamide ligand.Despite this significant breakthrough, the development of a universal strategy for the high enantioselective vicinal sulfonyl-esterification of alkenes still poses several challenges: [11] 1) In the multicomponent reaction, the radical precursor might couple with carboxylic acids directly; [5b,7e,12] 2) Sulfur dioxide's versatility as an amphoteric ligand presents challenges for transition metal-catalyzed asymmetric reactions involving its use; [11,13] 3) The mechanism for the asymmetric vicinal sulfonyl-esterification of alkenes is still not well understood (Figure 1C, bottom).
In this context, as part of our ongoing efforts on sulfur dioxide insertion reactions, we developed a general and efficient method to achieve asymmetric vicinal sulfonyl-esterification of alkenes utilizing Cu/PyBim system. [14]The method encompasses the use of an earth-abundant metal catalyst, along with mild reaction conditions, a wide range of substrates, and excellent control over enantioselectivity.Notably, this method can be applied to different types of radical precursors, including O-acylhydroxylamines, cycloketone oxime esters, aryldiazonium salts, and drug molecules.Mechanism studies revealed that asymmetric coupling of C─O bonds was successfully achieved within the rigid chiral space formed by the tridentate nonscorpionate ligand PyBim and copper salts, employing an outersphere model.

Results and Discussion
Initially, we probed the reaction conditions using carboxylic acid 1a and morpholino benzoate 2a as the reaction partners (Table 1).After screening various reaction parameters, the optimal conditions involve using Cu(MeCN) 4 PF 6 as the catalyst, L1 as the ligand, Na 2 CO 3 as the base, 4Å molecular sieve (MS) as the additive, SOgen as the SO 2 surrogate, and 2-Me-THF as the solvent.
Stirring the mixture at room temperature for 12 h under argon, the desired chiral sulfonyl lactone (3a) was obtained in 93% isolated yield and 96% ee (entry 1).Investigation of ligands, including PyBim (L1-L3), PyBox (L4-L5), and Box (L6-L8) (entries 1-8), revealed that PyBox ligand L4 demonstrated higher enantioselectivity compared to the Box ligand.Furthermore, PyBim was identified as the most effective ligand for achieving exceptional enantioselectivity.Different solvents were tested, and 2-Me-THF was identified as the best one (entries 9-12).4Å MS and Na 2 CO 3 were found not to be necessary for maintaining great enantioselectivity, but they were beneficial for improving the yield (entries 13 and 14).In terms of the base, K 2 CO 3 and Cs 2 CO 3 were not as effective as Na 2 CO 3 (entries 15 and 16).When using DABSO as the SO 2 surrogate, the product was obtained in a much lower yield with moderate ee, and no product was obtained using either Na 2 S 2 O 5 or K 2 S 2 O 5 (entries 17-19).These results clearly indicated that the use of SOgen was essential for the successful transformation.When morpholine-4-sulfonyl chloride was used as the source of the sulfonyl group, the desired product could be obtained in a low yield (entry 20).
substituents were found to be compatible with this transformation (3e-3j).Next, we examined various electrophilic amines 2, and observed that the optimal reaction conditions could accommodate a derivative containing a seven-membered ring (3k).Additionally, different acyclic substrates provided the desired products with good yields and excellent enantioselectivities (3l-3p).Notably, several commercially available blockbuster drugs underwent the reaction successfully (3q-3u).This strategy enabled the modification of antidepressants such as Nortriptyline, Maprotiline, Duloxetine, and Paroxetine, as well as the anti-Alzheimer's drug Donepezil.
Subsequently we proceeded to investigate the asymmetric vicinal sulfonyl-esterification of alkenes using alternative radical species (Scheme 1, bottom).Encouragingly, we observed that cycloketone oxime esters 4 and carboxylic acid 1 were also compatible with the current reaction system, albeit with slightly modified conditions.We then focused on examining the impact of substituents on reactant 1 on the reaction outcome.Electronneutral substitutions on substrates led to the formation of desired products (5a-5d) with excellent enantioselectivities (up to 99% ee).Monosubstituted 4-phenylpenta-4-enoic acids, with methyl or tert-butyl at para, meta and ortho positions, yielded products (5e-5 g) with moderate to good yields, indicating that steric bulk influenced the reaction efficiency.Furthermore, electronwithdrawing substituents such as m-OMe group and halogens were well-tolerated (5h-5k).Notably, the gem-dimethyl carboxylic acid was compatible with the reaction conditions, affording the product (5l) with excellent yield but slightly decreased enantioselectivity.In addition, the substrate containing an alkyne moiety underwent 1,2-addition to yield the five-membered ring product (5m).Subsequent evaluation of two other cycloketone oxime esters revealed their effectiveness in the transformation, yielding products 5n and 5o with excellent enantioselectivities.
Encouraged by these promising results, we sought to expand the scope of radical species to the aryl radicals for the asymmetric vicinal sulfonyl-esterification of alkenes.To our satisfaction, the reaction between aryldiazonium salts 6 and carboxylic acid 1 proceeded smoothly, yielding the desired products (Scheme 2).The catalytic system displayed excellent functional group tolerance, as carboxylic acids with various substitutions all performed well, providing the corresponding products (7a-7k) in good to excellent yields and high enantioselectivities. [16] Substrates containing thiofuran or gem-dimethyl groups showed a slight decrease in chiral selectivity, resulting in products (7l and 7m) with 81% and 82% ee, respectively.Notably, reactant 1 lacking styrene moiety could be tolerated under the standard reaction conditions, resulting in products with high enantioselectivity (7n and 7o), albeit with diminished yields.We examined the utilization of internal olefin as a substrate under standard conditions.Although the yield was relatively low, we were able to obtain product 7p with a 95% ee and a 4:1 dr.Furthermore, we also investigated the reactivity of non-activated olefins as substrates under standard conditions, which resulted in a lower yield and moderate enantioselectivity in the formation of product 7q.
Furthermore, we investigated arange of substituted aryldiazonium salts in the transformation (Scheme 2), and the optimized conditions proved to be applicable to biphenyl and naphthoyl diazonium salts as well (7r and 7s).Importantly, substrates containing terminal alkynes were amenable to the reaction and afforded the desired products (7t) in moderate yield but exceptional enantioselectivity.Aryldiazonium salts substituted with electrondonating groups, such as methyl (7u), tert-butyl (7v), 4-methoxy (7w), and phenoxy (7x), were also suitable reactants.In addition, halide-substituted aryldiazonium salts were well-tolerated (7y-7aa), opening up possibilities for further conversions through cross-coupling reactions.Substrates with electron-deficient substituents, such as meta-methylthio (7ab), meta-methoxy (7ac), benzoyl (7ad), formyl (7ae), and ester (7af) groups, also underwent the transformation efficiently.Furthermore, substrates with strongly electron-withdrawing trifluoromethyl and nitro groups (7ag-7ah) were both compatible with this strategy.Finally, a heteroaromatic diazonium salt proved to be an effective radical precursor, providing the corresponding products (7ai) in an acceptable yield and high enantioselectivity.Of particular interest, even a substrate derived from l-menthol demonstrated good reactivity under the current conditions (7aj), albeit with a slightly lower enantiomeric excess.
Next, we turned our attention to evaluating the range of substrates that could be utilized for the synthesis of six-membered lactones from aryldiazonium salts 6 and 5-hexenoic acid 8 in the presence of a copper catalyst.As shown in Figure 2, a strong side arm effect was observed in this reaction, highlighting the essential role of Pybim's side arms in promoting high levels of enantioselectivity. [17]In the presence of a hydrogen side arm, PyBim yielded only trace amount of six-membered lactone 9a.When the side arm was ethyl or benzyl, 9a with low enantioselectivity was obtained.Intriguingly, upon employing benzoyl or benzylcarbonyl as the side arm, a substantial enhancement in enantioselectivity of 9a was observed.Overall, the results indicated that the enantioselectivity of the reaction progressively improved with the enhanced electron-withdrawing effect of the PyBim ligand's side arm.Based on the aforementioned experiments and literature reports, [9,10] it was observed that PyBim had the capability to modulate the enantioselectivity of a reaction by manipulating the electronic effect of the ligand through modification of the side arm.As shown in Scheme 3, a wide range of substitutions on the aromatic rings of reactants 6 and 8 were compatible with the established reaction, leading to the formation of products 9a-9i in moderate to high yields and high enantioselectivities.We attempted to synthesize the seven-membered ring product 11a.Unfortunately, only trace amounts of the desired product were obtained.
To demonstrate the practicality of our strategy for the asymmetric vicinal sulfonyl-esterification of alkenes, we conducted several synthetic applications (Scheme 4).Using this method, we successfully achieved the sulfonyl modification of the natural product (R)-Bovinianin A in a single step (12a-12c). [18]igure 2. Influence of side arm on the asymmetric synthesis of six-membered lactones.
Furthermore, the chiral sulfonyl lactones produced through this process could be readily converted into other valuable compounds with different functional groups.For instance, treatment of 5a with nickel-mediated reduction yielded Boc-protected amine 13 in 83% yield with 99% ee.The reaction of 7a with Lawesson reagent furnished the thiolated product 14 with enantioselective preservation.Additionally, the carbonyl group of 7a could be selectively reduced to form hemiacetal 15, which could then be further reduced to produce compound 16.Likewise, compound 7t underwent a copper-catalyzed click reaction, leading to the formation of triazole compound 17.
In order to gain a better understanding of the mechanism, a series of experiments were conducted to gain a comprehen-sive understanding of the mechanism (Figure 3).First, when 3.0 equiv.TEMPO was added under the standard conditions, the desired product 3a was not detected, but the TEMPOadduct 18 was observed (Figure 3A).Second, the addition of 3.0 equiv.1,1-diphenylethylene did not lead to the formation of the desired product 3a.Instead, compounds 19 and 20, derived from nitrogen radicals and sulfonyl radicals, were detected (Figure 3B).These results strongly suggested a radical process in the reaction.Additionally, we observed a linear correlation between the enantiopurity of product 7a and the enantiopurity of ligand L1, indicating that a single chiral ligand and a copper complex were involved in the enantiocontrol step (Figure 3C). [19]heme 3. Substrate scope.a) SOgen (0.41 mmol), 1-methyl-4-vinylbenzene (0.40 mmol), aryldiazonium salt 6 (0.4 mmol, 2 equiv), Cu(MeCN) 4 PF 6 (0.01 mmol, 5 mol %), L12 (0.012 mmol, 6 mol %), 2,6-di-tert-ButylPyridine (0.4 mmol, 2 equiv), CH 2 Cl 2 (2.0 mL) were used.To get more information of the mechanism, we conducted density functional theory (DFT) calculations (for more details, refer to the Supporting Information)(Figure 3D). [20]The catalyst Cu(MeCN) 4 PF 6 undergoes ligand exchange with L1 to form the Cu I MeCN-L1 complex (Int0).The deprotonation of carboxylic acid (1a) complexed with Int0 yields the Cu I -L1-enoic acid (Int1), leading to a decrease in Gibbs energy by 16.5 kcal mol −1 .Int1, along with the p-methylphenyl diazonium compound, produce Cu II -L1-enoic acid (Int2) and an aryl radical through single electron transfer (SET), resulting in a decrease in the Gibbs energy by 19.4 kcal mol −1 .Subsequently, the aryl radical captures sulfur dioxide to form a sulfonyl radical with a barrierless process.Although aryl radicals are theoretically capable of directly adding to alkenes, DFT calculations carried out by the Lei group reveal the presence of an energy barrier hindering this addition reaction. [21]herefore, in the presence of sulfur dioxide, the aryl radicals exhibit high chemical selectivity for capturing sulfur dioxide, rather than undergoing addition reactions with alkenes.This is consistent with the fact that by-products of uncaptured SO 2 were not detected in the experiment.The sulfonyl radical addition to the C═C bond of the Cu II -L1-enoic acid (Int2) via the TS2 transition state, forming a new divalent copper complex (Int3) with the spinpolarized singlet state.The Int3 with the triplet state T 1 was also evaluated, whose energy was higher than that of Int3 with the spin-polarized singlet state.The process releases an energy of 7.8 kcal mol −1 , which is consistent with the documented high propensity of radicals towards unsaturated bonds. [22]After the radical addition, Int3 approaches the carbon radical with the Cucoordinated oxygen and passes through the TS3 transition state to form the new divalent copper complex Int4.TS3 undergoes distinct reactions to produce diastereoisomers Int4-R and Int4-S via TS3-R and TS3-S, respectively.In this process, an intramolecular radical attack occurs onto the carboxylate oxygen atom, creating a chiral carbon atom according to the face of the approaching planar phenyl radical center.Subsequently, Int4-R and Int4-S release different enantiomers.Computational results suggest that TS3-R is favored by 4.7 kcal mol −1 , indicating a strong preference for the formation of the R-product.
To provide a more comprehensive explanation of the enantioselective nature of the reaction, we conducted an analysis of the interactions between the ligand and the substrate at the transition states TS3-R and TS3-S (Figure 4A).The comparative analysis of non-covalent interactions in the two transition states reveals that TS3-R possesses more favorable non-covalent interactions.The - interactions between the Ts group and the aromatic group on the substrate are stronger in TS3-R compared to TS3-S.Furthermore, TS3-R demonstrates C-H- interactions between the aromatic group on the substrate and the hydrogen on the imidazole of the ligand, while these interactions are absent in TS3-S.Moreover, TS3-S exhibits a stronger H-H repulsion between the substrate and the ligand.We measured the non-bonding interaction distances and found that the distance between the Ts group and the aromatic group on the substrate was 0.347 Å longer in TS3-S compared to TS3-R.Additionally, the distance between the hydrogen on the ligand's imidazole and the phenyl group on the substrate was 2.569 Å, indicating the potential formation of a C-H- interaction.Therefore, TS3-R is considered more stable.Combining experimental results and literature reports, [6a] we propose a potential mechanism for the reaction as illustrated in Figure 4B.First, a strong chelating Cu I -PyBim species II is generated and then combines with reactant 1a in the presence of a base, resulting in the formation of [PyBim/Cu I O 2 CR] species III.Then, species III undergoes a SET process with aryldiazonium salt 6a, leading to the formation of [PyBim/Cu II O 2 CR] species IV and p-methylphenyl radical V. Next, the p-methylphenyl radical V captures SO 2 to generate a sulfonyl radical VI, which subsequently adds to species IV, resulting in the formation of an alkyl radical VII.Then, an intramolecular radical substitution occurs, generating Cu II complex VIII.The dissociation of species VIII leads to the formation of product 7a and Cu I -PyBim IX.Finally, Cu I -PyBim IX combines with substrate 1a in the presence of a base to generate complex III for the next catalytic cycle.Intermediates IV, VIII and IX have been identified in the experiments by HRMS (for more details, refer to the Supporting Information).

Conclusion
In summary, we have developed a novel Cu/PyBim catalytic system and applied it to the asymmetric vicinal sulfonylesterification of alkenes involving sulfur dioxide.The reaction is conducted under mild conditions and demonstrates good substrate tolerance, providing satisfactory product yields with excellent enantiocontrol.Notably, this catalytic system is applicable to different types of radical precursors, including Oacylhydroxylamines, cycloketone oxime esters, aryldiazonium salts, and drug molecules.In the reaction, SOgen acts as a surrogate for sulfur dioxide and plays a crucial role.Mechanism studies and DFT calculation revealed that asymmetric coupling of C─O bonds was successfully achieved within the rigid chiral space formed by the tridentate non-scorpionate ligand PyBim and copper salts, employing an outer-sphere model.

Table 1 .
Optimizations of reaction conditions.