Ligand-controlled stereodivergent alkenylation of alkynes to access functionalized trans- and cis-1,3-dienes

Precise stereocontrol of functionalized alkenes represents a long-standing research topic in organic synthesis. Nevertheless, the development of a catalytic, easily tunable synthetic approach for the stereodivergent synthesis of both E-selective and even more challenging Z-selective highly substituted 1,3-dienes from common substrates remains underexploited. Here, we report a photoredox and nickel dual catalytic strategy for the stereodivergent sulfonylalkenylation of terminal alkynes with vinyl triflates and sodium sulfinates under mild conditions. With a judicious choice of simple nickel catalyst and ligand, this method enables efficient and divergent access to both Z- and E-sulfonyl-1,3-dienes from the same set of simple starting materials. This method features broad substrate scope, good functional compatibility, and excellent chemo-, regio-, and stereoselectivity. Experimental and DFT mechanistic studies offer insights into the observed divergent stereoselectivity controlled by ligands.

photocatalysts with different triplet state energies (Fig. 1a) 57 . Despite attractive, such a contra-thermodynamic alkene isomerization strategy relies on the structure of alkenes or photocatalysts. Thus, the development of photoredox/nickel dual-catalyzed divergent method with a complementary stereoselective tuning strategy to access more diverse types of alkenes, such as functionalized cis-and trans-1,3-dienes, under mild and operationally simple conditions would be of particular interest.
Here, we show a ligand-controlled stereodivergent alkenylfunctionalization of alkynes with vinyl triflates and sodium sulfinates via photoredox and nickel dual catalysis (Fig. 1b). This strategy furnishes a wide array of synthetically valuable cisand trans-sulfonyl-1,3dienes 58,59 in one pot from simple starting materials. Detailed mechanistic experiments and computational investigations offer insights into the origins of the observed stereoselectivity and the role of dynamic ligand exchange in the dual ligand system.

Reaction optimizations
Our investigations were started with phenylacetylene 1, vinyl triflate 2, and sodium p-tolylsulfinate 3 as model substrates (Table 1). After some experimentations, we found that in the presence of Ru(dtbbpy) 3 (PF 6 ) 2 as the photocatalyst, Ni(OAc) 2 •4H 2 O as the nickel catalyst, and 1,10phenanthroline (1,10-phen) as the ligand, irradiation of the reaction mixture in DMF with blue LEDs gave the sulfonylated diene product 4b in 45% yield with excellent regio-and anti-selectivity (entry 1). Pleasingly, employing terpyridine (tpy) as the ligand dramatically improved the yield of product 4b to 86% without observation of syn-selective isomer (entry 2). Further evaluation of nickel catalysts or pre-catalysts disclosed that Ni(OAc) 2 •4H 2 O was the optimal catalyst for this antiselective transformation (entries [3][4][5][6]. During this process, we noticed that the nature of nickel salts played an intriguing effect on the trans/ cis selectivity. Switching to phosphine-ligated nickel pre-catalysts resulted in the formation of a mixture of trans/cis isomers 4a and 4b in varied yields and Z/E ratios (entries 4-6). Interestingly, the use of NiCl 2 •dppf in the absence of terpyridine led to the exclusive formation of syn-selective product 4a, albeit in low yield (entry 7). The addition of 1,10-phen as an exogenous ligand turned out to be beneficial to the yield of 4b, together with the formation of isomer 4a (entry 8) 60 . Careful examination of the ratio of nickel and ligand revealed that the use of 20 mol% NiCl 2 •dppf with 10 mol% 1,10-phen furnished 4a in 80% yield with excellent cis/trans selectivity (entries [8][9][10][11]. Finally, control experiments disclosed that photocatalyst, nickel catalyst, and light were all essential for this stereodivergent reaction (entries 12-14) (see Supplementary Information for more optimization details).
To further demonstrate the synthetic applicability of this dualprotocol, late-stage modifications of complex molecules have been evaluated (Fig. 3a). Under the syn-selective conditions (entry 11, Table 1), the reaction of complex terminal alkynes or vinyl triflates, derived from estrone, indomethacin (anti-inflammatory), glucose, borneol, and amino acid, proceeded smoothly to afford the desired E-1,3-dienes with high yields and excellent stereoselectivity (55a-59a). Under the anti-selective condition (entry 2, Table 1), nevertheless, reactions with these complex substrates proceeded in comparable yields yet moderate stereoselectivity, probably due to the significant steric hindrance of these complex substrates (55b-59b). Moreover, the resulting sulfonyl 1,3-dienes are useful building blocks in organic synthesis (Fig. 3b). Hydrogenation of 4b in the presence of palladium on carbon (Pd/C) and H 2 gave alkyl sulfone 60 in 95% yield. Oxidation of 4b with m-CPBA or KMnO 4 yielded epoxide 61 and polyol 62, respectively. Furthermore, treatment of 4b with n-butyllithium, followed by the addition of MeI, afforded 68% yield of (Z)-tetra-substituted sulfonyl alkene 63, the stereoselective synthesis of which remains challenging. Cross-coupling of 4b with methylmagnesium bromide in the presence of catalytic Ni(acac) 2 furnished (E)-tri-substituted 1,3-dienes 64 in 78% yield and excellent stereoselectivity. Finally, cycloaddition reactions of 4a or 4b with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) 65 resulted in the formation of the two stereoisomers of products 66 and 66' in moderate yields.

Mechanistic studies
To gain insights into the potential mechanism, we have performed some preliminary mechanistic experiments (Fig. 4). On the one hand, we conducted a number of experiments regarding the photocatalytic part. Stern-Volmer fluorescence quenching studies indicated that the photoexcited *Ru(dtbbpy) 3 2+ was quenched by TsNa, other than alkyne 1 or vinyl triflate 2 (Fig. 4a). Light on/off experiments under both antiand syn-selective conditions were performed, which showed that the desired couplings ceased in the dark (See Supplementary Figure 6-7); additionally, quantum yields (ϕ) of both antiand syn-selective reactions were determined to be less than 1 (See Supplementary  Information) 61 . These results ruled out the possibility of a radical chain pathway in this photochemical process. Furthermore, time-course studies of template reactions (phenylacetylene 1, vinyl triflate 2, and TsNa 3) showed that anti/syn-selectivity of products 4a and 4b remained steady under the conditions shown in entries 2 or 11 (Fig. 4b).
On the other hand, we detected a small amount of side product E-51 with careful monitoring of this reaction, implying that this reaction could proceed via sulfonyl addition followed by alkenylation (Fig. 4c).
Then, radical inhibition and probe reactions were performed (Figs. 4d-4e). The addition of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the standard systems (entries 1 and 11, Table 1) completely shut down the desired reactions, while the addition of 1,1-diphenylethylene gave the desired products 4a/4b in slightly decreased yields, together with a  small amount of alkyl sulfone adduct 68 (Fig. 4d). Reaction of vinyl triflate 2 and TsNa with 1,5-diene 69, instead of alkyne 1, gave a small amount of tosylation/cyclization product 70 and tosylation/cyclization/alkenylation product 70' under the syn-selective condition; interestingly, the parallel reaction under the anti-selective condition resulted in the formation of 9% yield of 70, together with 71% yield of 70' (Fig. 4e). These results implied that different reaction pathways could be involved in synand anti-selective systems. Additionally, control reactions with stoichiometric Ni(cod) 2 and dppf in the absence of 1,10-phen gave good yields of product 4a (Z/E > 99:1), in contrast to the results with catalytic Ni(cod) 2 /dppf (entry 7, Table 1), suggesting the importance of a synergistic effect with the two ligands (Fig. 4e) 62 . Furthermore, the reaction of alkyne 1, alkenyl boronic acid 71, and TsCl with catalytic NiCl 2 (py) 4 /tpy or NiCl 2 •dppf/phen gave a small amount of anti-selective diene 4b under thermal conditions 35 , demonstrating the intriguing role of light irradiation in this stereodivergent alkenylation and further highlighting the synthetic advantage of this photochemical dual-protocol. Next, we performed density functional theory (DFT) calculations to gain a deeper understanding of the mechanism and catalytic cycle, particularly to rationalize the stereoselectivity controlled by the different ligands (Computational details are given in the supporting information) (Fig. 5). We chose 51a/b as the model substrate with terpyridine and dppf/phenanthroline as the model ligands for the anti/syn selective conditions, respectively (Table 1, entries 3 and 11). In Fig. 5a, the Ni-catalytic cycle with terpyridine as the ligand begins with the Ni I -SO 2 Me intermediate N1 57 . First, phenylacetylene 1 coordinates to the intermediate N1 and produces N2, followed by the rearrangement of the SO 2 Me moiety from a Ni-S to Ni-O bonding mode with an energy barrier of 11.9 kcal/mol (N2-3TS). Two intermediates are formed in which the sulfonyl group is in a suitable orientation to either attack the terminal (N3) or internal (N3') carbon of the alkyne. The sulfonyl group then migrates to the terminal carbon of the alkyne via a five-membered ring transition state (N3-4ZTS) with an energy barrier of 18.4 kcal/mol. In contrast, the migratory insertion into the internal carbon is disfavored by 3.0 kcal/mol (N3'-4'TS), which is consistent with the observed regioselectivity of this reaction. In the intermediate N4Z, the phenyl and sulfonyl moieties are anti-oriented after migratory insertion. Thus, it can either undergo direct S N -Ar type of oxidative addition of vinyl triflate 2 via  transition state N4-5ZTS, with an energy barrier of 31.6 kcal/mol, resulting in the syn-selective product 51b, or undergo anti/syn isomerization followed by oxidative addition. The C-C bond rotates during the anti/syn isomerization with an activation energy of 25.1 kcal/mol, leading to the intermediate N4E. The S N -Ar-type oxidative addition of vinyl triflate to N4E has an energy barrier of only 18.6 kcal/mol (N4-5ETS), which lies 8.7 kcal/mol below the transition state N4-5ZTS. The proximity of the sulfonyl and OTf groups in the transition state N4-5ZTS may account for the high oxidative addition energy barrier. A comparison of the two oxidative addition routes implies that the formation of anti-selective product E is preferred since the transition state N4Z-ETS is favored by 6.5 kcal/mol over N4-5ZTS, which explains the anti-stereoselectivity when terpyridine was used as the ligand. After the reductive elimination, the crosscoupling product is formed, together with the generation of the Ni I intermediate N6. The reduction of N6 to Ni 0 intermediate N8 by the Ru-photocatalyst is calculated to be thermodynamically disfavored (+2.2 kcal/mol, see Supplementary Figure 19). In contrast, the radical addition of sulfonyl radical to N6 is barrierless, with an energy gain of 28.1 kcal/mol 63,64 . The generated Ni II intermediate N7 can then be reduced by the Ru-photocatalyst and start the next catalytic cycle.
Subsequently, the reaction with a dual ligand system (dppf and phenanthroline) was explored, and the catalytic cycle is depicted in Fig. 5b. Based on a recent report 62 , we proposed that the dynamic ligand exchanges on Ni intermediates promote different steps in the syn-selective catalytic cycle. The phosphine ligand dppf facilitates the Ni I reduction and Ni 0 oxidative addition steps, while the phenanthroline ligand facilitates the radical addition step. The binding of vinyl triflate 2 to dppf-Ni 0 forms the intermediate P1, which undergoes S N -Ar-type oxidative addition to afford the Ni II cation P2 with an energy barrier of only 7.9 kcal/mol 65,66 . Next, the sulfonyl radical R1 can either add to P2 via the transition state P2-5TS with a 16.2 kcal/mol barrier, leading to P5, or add to the alkyne, forming the vinyl radical R2, with a barrier of 13.8 kcal/mol. The radical addition to an alkyne is kinetically and thermodynamically favored. The Ni II cation P2 then undergoes ligand exchange with phenanthroline to afford Ni II intermediate Phen1. The vinyl radical R2 undergoes radical addition with two distinct orientations to the Ni II cation Phen1, resulting in an anti-or synselective Ni III intermediate (Phen2E or Phen2Z). The transition state of the syn-selective radical addition is 14.1 kcal/mol (Phen1-2ZTS), favored by 7.3 kcal/mol over the anti-selective radical addition (Phen1-2ETS), which may be due to the coordination of the oxygen atom from the sulfonyl group to the Ni II metal center. Also, the syn-selective Ni III intermediate Phen2Z is more stable than the anti-selective Ni III intermediate Phen2E (15.9 kcal/mol difference in energy). With a barrier of only 3.5 kcal/mol, the reductive elimination of Phen2Z is rapid, yielding the syn-selective product. The resulting Ni I cation Phen3 again undergoes ligand exchange with dppf to afford the dppf-Ni I intermediate P4. In contrast to the tpy-Ni I intermediate N6, the intermediate P4 can easily be reduced by the Ru-photocatalyst, leading to    (Fig. 5c). Given that 32% syn-selective product was obtained when only dppf was used as the ligand (see Table 1, entry 7), the synselective catalytic cycle with only dppf as the ligand was also explored (see Supplementary Figure 15 for the energy profile). The stereoselectivity can also be explained by the 19.1 kcal/mol energy difference between the anti/syn radical addition step (P2-3ZTS vs. P2-3ETS). Alternatively, another catalytic pathway involving the migratory insertion of alkyne to dppf-ligated vinyl-Ni species was investigated, in which the regio-and stereoselectivity can also be explained (See Supplementary Figure 16 for the energy profile). However, this pathway was not chosen as the main catalytic pathway due to the observed hydrosulfonylation by-product 51 (Fig. 4c), which cannot be generated by this pathway.
Based on these experimental and computational results, we propose a plausible reaction pathway as depicted in Fig. 6. Upon light excitation, photoexcited *Ru(dtbbpy) 3 2+ (E 1/2 *ox = +0.81 V vs. SCE) 67,68 interacts with RSO 2 Na (TsNa, E red = + 0.45 V versus SCE in CH 3 CN) 69 to release sulfonyl radical and the reducing Ru(I). In the case of terpyridine as ligand, the sulfonyl radical is trapped by Ni(I) I to give RSO 2 -Ni(II) II 57 , which is then single-electron reduced by Ru(I) to generate RSO 2 -Ni(I) II. Migratory insertion of II into alkyne III regioselectively delivers cis-alkenylNi(I) species IV, followed by isomerization, to afford the trans-alkenylNi(I) V. S N -Ar type oxidative addition of V with vinyl triflate affords trans-Ni(III) VI, followed by reductive elimination, to furnish anti-addition dienes. In the case of NiCl 2 •dppf/phen, which is more electron-rich and less sterically hindered compared to NiCl 2 (py) 4 /tpy, dppf-ligated Ni(I) VII is more prone to a SET reduction by Ru(I) to generate Ni(0) species, followed by binding and facile S N -Ar type oxidative addition with vinyl triflate to form dppf-ligated alkenylNi(II) IX. Then, IX undergoes ligand exchange with 1,10-phen to form phen-ligated alkenylNi(II) X. At the same time, the sulfonyl radical adds to alkyne to form vinyl radical XI, which is subsequently captured by phen-ligated alkenylNi(II) X to generate the more stable cis-Ni(III) species XII. Reductive elimination of Ni(III) XII furnishes syn-selective product as well as Ni(I) I, the latter of which undergoes ligand exchange with dppf to yield (dppf) Ni(I) VII. Finally, Ru(I) (Ru(dtbbpy) 3 + , E 1/2 II/I = −1.45 V vs SCE) 67 is feasible to reduce (dppf)Ni(I) VII or (terpy)Ni(II) II [E 1/2 (Ni II /Ni 0 ) = −1.2 V versus SCE in DMF] 70 to regenerate the ground state Ru(dtbbpy) 3 2+ and close the two catalytic cycles.
In summary, we have developed a dual photoredox and nickel catalyzed stereodivergent three-component alkenyl-functionalization of alkynes with vinyl triflates and sodium sulfinates under mild and operationally simple conditions. Such a photochemical dual strategy enables divergent and straightforward access to synand anti-selective sulfonyl-1,3-dienes by a simple choice of nickel catalyst and ligand without the reliance on the structures of photocatalyst and alkene products. This method demonstrates broad substrate scope and excellent chemo-, regio-, and stereo-selectivity, with potential applications in late-stage functionalizations. A series of mechanistic experiments, including Stern-Volmer fluorescence quenching studies, light on/off experiments, determination of quantum yields, radical probe reactions, and time course studies, as well as detailed computational investigations, offer insights into the origins of the observed stereoselectivity controlled by simple ligands.

Methods
General procedure for the cis-selective alkenylation To a flame-dried 8 mL reaction vial equipped with a magnetic stir bar was charged with Ru(dtbbpy) 3 (PF 6 ) 2 (1 mol %), NiCl 2 •dppf (20 mol %), 1,10-phenanthrane (10 mol %), sulfinate (1.5 equiv.), and DMF [0.04 M]. The reaction mixture was degassed by nitrogen sparging for 30 min, followed by the addition of vinyl triflate (0.10 mmol) and alkyne (1.5 equiv). The reaction mixture was irradiated with blue LEDs for 6 h (around 35°C, with a cooling fan placed on the top of the vial). The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried with MgSO 4 , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, petroleum ether/ ethyl acetate) to afford the products.

General procedures for the trans-selective alkenylation
To a flame-dried 8 mL reaction vial equipped with a magnetic stir bar was charged with Ru(dtbbpy) 3 (PF 6 ) 2 (1 mol %), Ni(OAc) 2 • 4H 2 O (10 mol %), terpyridine (10 mol %), sulfinate (1.5 equiv.) and DMF [0.04 M]. The reaction mixture was degassed by nitrogen sparging for 30 min, followed by the addition of vinyl triflate (0.10 mmol) and alkyne (1.5 equiv.). Then the reaction mixture was irradiated with blue LEDs for 6 h (around 35°C). The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried with MgSO 4 , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, petroleum ether/ ethyl acetate) to afford the products.

Data availability
The data supporting the findings of this study are available within the paper and its Supplementary Information. Supplementary Data file 1 contains the cartesian coordinates of the calculated structures. The crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2117868 and 2117869. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/ structures/.