Cooperative triple catalysis enables regioirregular formal Mizoroki–Heck reactions

The Mizoroki–Heck reaction between alkenes and aryl halides represents one of the most important methods for C−C bond formation in synthetic chemistry. Governed by their electronic and steric nature, alkenes are generally arylated with high regioselectivity, which conversely hampers diversity, in particular, if the regioirregular isomer is targeted. Usually, electron-poor alkenes selectively afford the corresponding β-coupled products, and achieving the opposite regioselectivity to obtain their α-arylated congeners is highly challenging. It would be desirable to access the irregular α-regioisomer by simple variation of the reaction conditions, keeping the standard substrates, thereby significantly enlarging the product space. Herein, we describe an intermolecular α-arylation of electron-poor alkenes through cooperative nickel, photoredox and sulfinate catalysis. This triple catalysis system operates under mild conditions and features excellent functional group tolerance. The orchestration of radical, transition metal and ionic bond-forming and -cleaving reactions in a single process is highly challenging, but certainly opens valuable doors in terms of reactivity. Moreover, the intermolecular α-arylation, α-alkenylation and α-alkynylation of styrenes could also be achieved through a one-pot process. The Mizoroki–Heck reaction forms C−C bonds between aryl halides and alkenes. For electron-deficient alkenes, β-coupled products are typically formed and synthesizing α-arylated products is challenging. Now, a triple catalysis system (nickel, photoredox catalysis and sulfinate) enables regioirregular formal Mizoroki–Heck reactions for electron-deficient alkenes and styrenes to give α-arylated alkenes.

D eveloping selective and sustainable synthetic methodologies is of great importance in modern organic synthesis [1][2][3] . Along these lines, transition metal catalysis has played a key role, as recognized by the awarding of the Nobel prize for various reactions [4][5][6][7] . For example, the palladium-catalysed Mizoroki-Heck coupling reaction, enabling the arylation of alkenes using aryl (pseudo)halides, represents one of the most versatile and popular tools for the preparation of pharmaceuticals, agrochemicals and advanced materials [8][9][10] . As the organopalladium insertion step is controlled by the electronic and steric nature of the alkene coupling partner, alkenes bearing electron-donating groups (EDG), such as vinyl ethers and enamides, normally give 1,1-disubstituted alkenes by highly selective α-coupling (Fig. 1a) [11][12][13] . Electron-neutral alkenes, such as aliphatic alkenes, often afford a mixture of regioisomers with low selectivity, typically favouring the linear regioisomer 14 .
Considering the intrinsic regioselectivity of Mizoroki-Heck couplings, it would be highly desirable to access the irregular regioisomer of the omnipresent Mizoroki-Heck reaction, ideally by simple variation of the reaction conditions, keeping the standard substrates, thereby significantly enlarging the product space. Indeed, by manipulating the transition metal catalyst, ligand and/or aryl pseudohalide substrate, good αand β-regioselectivities can be achieved for both electron-rich and aliphatic alkenes [15][16][17][18][19][20][21][22][23] . However, electronpoor alkenes, such as acrylates and styrenes, which are probably the most widely used starting alkenes in the Mizoroki-Heck coupling reaction, usually furnish the corresponding β-coupling products highly selectively and, due to the dominating electronic factors, achieving the opposite regioselective insertion to obtain the corresponding α-arylation products is highly challenging 24,25 .
Despite significant achievements in this area, no general solution for the α-selective coupling of acrylates has been offered to date. To our knowledge, only two examples based on Pd catalysis have been reported to realize regioirregular Mizoroki-Heck reactions. In 2011, Göttker-Schnetmann and co-workers disclosed an interesting α-phenylation of methyl acrylate using a rather complex organopalladium species as a stoichiometric reagent (Fig. 1b) 26 .
Very recently, Leyva-Pérez and co-workers found that a designed palladium cluster enables the selective intramolecular α-arylation of electron-deficient alkenes, directly providing valuable unsaturated lactones (Fig. 1c) 27 . However, the use of complex palladium catalysts, high temperatures, a large excess of the alkene coupling partner and/or restriction to the intramolecular variant largely limit the broad application of these elegant processes. Therefore, a general catalytic method for the regioselective intermolecular α-arylation of acrylates or derivatives thereof with commercially available aryl halides is still highly demanded.
Our reaction design to achieve this challenging goal is illustrated in Fig. 1e. An excited photoredox catalyst should first oxidize an arenesulfinate salt by single-electron transfer (SET) to afford an arylsulfonyl radical. Regioselective radical addition of the sulfonyl radical to an electron-deficient alkene 1 will then generate the adduct radical A [66][67][68][69] . On the other hand, oxidative addition of Ni(0) to an aromatic bromide 2 leads to an Ar-Ni-Br complex [70][71][72][73] . Trapping of radical A by the Ar-Ni-Br species will provide the corresponding Ar-Ni(III)-alkyl intermediate, and subsequent reductive elimination will deliver the intermediate D along with a Ni(I) complex [74][75][76][77] . Alternatively, the Ni(0) complex might react with radical A prior to oxidative addition to the aryl bromide, that is, in reverse order (not shown in Fig. 1e). SET reduction of the Ni(I) species by the initially reduced photoredox catalyst (PC n−1 complex) will lead to the Ni(0) species and restore the initial PC oxidation state, thereby closing both the PC and Ni catalysis cycles. Finally, base-mediated elimination of the aromatic sulfinate should afford the targeted α-arylated alkene E, closing the sulfinate catalysis cycle. Notably, such α-arylated electron-deficient alkenes are prevalent in natural products and also appear as useful intermediates in organic synthesis, rendering our suggested sequence highly valuable with many potential applications 78 .
The generality of the α-arylation reaction was further evaluated by exploring the scope with respect to the alkene acceptor ( Table 3). The ester substituent of the acrylate could be readily varied, as documented by the successful direct synthesis of the α-arylated acrylates 53-59 (66-76%). However, crotonates reacted with lower efficiency, likely due to steric effects (60). The α-arylation reaction also proceeded with acrylonitrile, vinylphosphonate and an acrylamide as acceptors, albeit in lower yields (61)(62)(63). Unfortunately, other electron-deficient alkenes, such as phenyl vinyl sulfone, methyl vinyl ketone, 2-cyclopenten-1-one and 2(5H)-furanone, failed to afford the corresponding α-arylation products (Supporting Information). In the reaction with the vinyl ketone, we observed only the radical addition of the sulfonyl radical to the vinyl ketone (Giese reaction product). With regard to unactivated alkenes such as 1-hexene, neither radical addition nor difunctionalization products were detected. Next, we probed a range of more complex aryl bromides and acrylates to demonstrate the suitability of the method for late-stage functionalization. Substrates derived from d-allofuranose, vanillin, tocopherol and cholesterol all reacted smoothly to provide the desired products in good yields (64)(65)(66)(67).
We continued our studies by exploring the intermolecular α-arylation of styrenes to access 1,1-diarylalkenes (Table 4). These investigations were conducted with 4-bromobenzophenone as the coupling partner. We found that the reaction with para-trifluoromethylstyrene did not proceed under the conditions optimized for acrylate arylation. The problematic step was the base-mediated elimination of sulfinate, due to the lower acidity of the α-proton in the intermediate aryl sulfone. Careful experimentation identified DBU as the ideal base for this elimination. However, DBU was not compatible with the first two steps of the cascade reaction (1,2-difunctionalization). This revised protocol was employed for the arylation of all the systems in this study. Therefore, a one-pot protocol was developed with DBU treatment after the initial cooperative photoredox/Ni-catalysed 1,2-difunctionalization, and the targeted 68 was isolated in 66% yield. The p-MeO 2 C-substituted congener reacted with similar efficiency (69). Styrene acceptors bearing halogen atoms at different positions of the arene moiety  c If the photoredox catalyst, nickel catalyst, ligand, sulfinate, irradiation or base was omitted, the reaction did not proceed. ND, not detected.
could also be transformed to afford the corresponding products 70-74 in yields of 51-74%. For more electron-rich styrenes containing p-methoxy and benzofuran entities, the α-arylation proceeded with lower yields (75 and 76). Moreover, a benzylic ester as side chain was also tolerated (77), and alkenes derived from important drugs such as fenofibrate and oestrone could be selectively arylated  at the α-position (78 and 79). It is important to note that by applying this second strategy, the cascade reaction can be stopped at the 1,2-difunctionalization stage by just leaving out the final DBU treatment to obtain arylsulfones of type D (see Fig. 1e and the mechanistic studies below). Along with aryl bromides, we were delighted to discover that bromoalkynes as well as (E)-bromoalkenes are also eligible electrophiles for this transformation, with these substrates furnishing a variety of interesting 1,3-enynes and 1,3-dienes (80)(81)(82)(83)(84).
The practicality and synthetic potential of the α-arylation of acrylates were then explored (Fig. 2). The robustness was documented by repeating four reactions on a larger scale, with comparable yields being obtained in all cases (18 (51%), 3 (73%), 13 (72%) and 20 (51%)). The synthetic value of this methodology was further highlighted by synthesizing some medicinally interesting compounds through chemical modification of the α-arylated acrylates.
For example, the tert-butyl ester moiety in 18 can be cleaved to provide the corresponding acrylic acid 85 in near quantitative yield. The known asymmetric hydrogenation of this acid would directly lead to flurbiprofen, which is an important anti-pain and anti-inflammatory agent (Fig. 2a) 79 . Nucleophilic addition of pyrrole to the double bond of 18 furnished the ester 86, which is a key intermediate in the preparation of an ipalbidine variant 80 . Base-promoted [4 + 2] annulation of 18 with malononitrile delivered the polysubstituted pyridinone 87 in 54% yield, which can be used for the preparation of an epidermal growth factor inhibitor derivative 81 . Moreover, the polysubstituted 4,5-dihydroisoxazole 88 was obtained in 75% yield by [3 + 2] annulation of 3 with 1-nitropropane (Fig. 2b) 82 . The tilidine variant 89, a derivative of a synthetic opioid painkiller, was easily accessed by [4 + 2] annulation of an enamine with 3 (ref. 83 ). Iodine-catalysed cyclopropanation of 13 with a diazo ester afforded  the corresponding cyclopropane 90 in a very high yield (Fig. 2c) 84 , and intermolecular hydroamination with benzylamine gave the β-amino acid ester 91 in 83% yield. In addition, an intermediate (92) in the preparation of an (S)-equol derivative was successfully prepared by Pd-catalysed arylation of 20 with an arenediazonium salt. Subsequent hydrolysis, asymmetric hydrogenation and deprotection, as described previously, would then lead to the (S)-equol derivative (Fig. 2d) 85 .
Mechanistic studies. To support the mechanistic proposal depicted in Fig. 1e, additional experiments were conducted. First, the addition of 2 equiv. (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) fully suppressed the model reaction (Fig. 3a). The radical nature of this transformation was further supported by the radical probe experiment performed with alkene 93 as the acceptor to furnish the ring-opened product 94 in 87% yield (Fig. 3b). Stern-Volmer fluorescence quenching experiments revealed that only 4-F-C 6 H 4 SO 2 Na quenched the excited state of Ru*(II), in accordance with our proposed mechanism (Supplementary Section 7.5). In addition, we found that stoichiometric reaction of the presynthesized Ar-Ni II -Br complex 86 ( Supplementary Information 7.3) with 1a afforded the desired product 3 in 41% yield. When a catalytic amount (10 mol%) of the nickel complex was used, the product 3 was formed in 35% yield. These results indicate that this Ni(II) complex might be a competent intermediate in the transformation (Fig. 3c,d). The absence of a hydrosulfonylation product in the reaction of tert-butyl acrylate with 4-F-C 6 H 4 SO 2 Na showed that ionic conjugate addition did not occur (Fig. 3e). As described above, in the absence of B 2 pin 2 , the desired product 3 was also formed in the model reaction, albeit in a low yield (26%, Table 1, entry 1). This result shows that the cascade reaction can also proceed without the formation of any potential boron-based intermediate. To further  Thus, 4-NC-C 6 H 4 Bpin did not participate, which indicates that the aryl bromide and B 2 pin 2 do not react to provide the corresponding arylboronic acid pinacol ester (Fig. 3f).  In addition, we also conducted the reaction between ethyl acrylate and an aryl bromide in the presence of 1 equiv. PhSO 2 Na in the absence of base, which afforded the three-component coupling product 95 in 55% yield (Fig. 3g). To explore the sulfinate elimination step, intermediate 95 was then treated with B 2 pin 2 (1 equiv.), but the desired product 96 was not detected, whereas a 49% yield of 96 could be obtained on addition of Na 3 PO 4 (1 equiv.). Interestingly, the combined action of B 2 pin 2 and Na 3 PO 4 (1 equiv.  The radical nature of this reaction is supported by obtaining the ring-opened product 94 in 87% yield. c, α-Arylation using a stoichiometric amount of a preformed Ar-Ni II -Br complex. d, α-Arylation using a preformed Ar-Ni II -Br complex as catalyst. e, Attempted ionic addition of the 4-F-PhSO 2 Na to acceptor 1a. f, Competition experiment performed with an aryl bromide and an arylboronic ester as potential aryl donors. g, Three-component coupling and subsequent sulfinate elimination shows that the combination of B 2 pin 2 and Na 3 PO 4 enhances the sulfinate elimination efficiency. h,i, 11 B NMR spectroscopy was used to evaluate the interactions between B 2 pin 2 and individual reactants (h) and between B 2 pin 2 , Na 3 PO 4 and individual reactants (i).  (Fig. 3h). In contrast, after the addition of 1 equiv. Na 3 PO 4 to B 2 pin 2 , a small new peak appeared upfield (21.68 ppm), implying the formation of a boronate complex with the phosphate in which B 2 pin 2 acts as a Lewis acid. Subsequent addition of 1a or 2a to the mixture of B 2 pin 2 and Na 3 PO 4 did not alter the intensity of the upfield small peak (Fig. 3i)

Conclusions
In summary, we have developed a robust method for the intermolecular regioirregular formal Mizoroki-Heck reaction of electron-deficient alkenes and styrenes with readily available aryl bromides. The cascade reaction proceeds by triple catalysis involving nickel catalysis, photoredox catalysis and sulfinate catalysis, with all three catalysis cycles interwoven. A variety of value-added α-arylated alkenes, 1,3-enynes and 1,3-dienes have been successfully constructed in good yield and with excellent regioselectivity. Mechanistic studies show that these transformations proceed through a radical addition/metal-radical coupling/ionic elimination cascade. We believe that this method offers a solution to a longstanding synthetic challenge, namely the intermolecular α-arylation of electron-poor alkenes, and should therefore find many applications. Future advances in selective functionalization based on this triple catalysis strategy are foreseen.

Data availability
The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information.