Pd-catalyzed formal Mizoroki–Heck coupling of unactivated alkyl chlorides

The use of alkyl chlorides in Pd-catalyzed Mizoroki–Heck coupling reactions remains an unsolved problem despite their significant potential for synthetic utility and applicability. The combination of the high thermodynamic barrier of alkyl chloride activation and kinetic propensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown to efficiently participate in Mizoroki–Heck cross-coupling reactions with excellent functional group compatibility under mild reaction conditions via photoinduced Pd catalysis. The reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds and iterative double Mizoroki–Heck annulations, affording high molecular complexity in a single step. Notably, studies on the kinetic isotope effects in combination with density functional theory (DFT)-computations completely exclude the involvement of a previously proposed β-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer process is the key catalytic turnover step. This distinctive single-electron transfer mediated reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-catalyzed Mizoroki–Heck cross-coupling with alkyl electrophiles, wherein the β-hydride elimination is involved in the formation of both the desired product and undesired by-products.

T he Mizoroki-Heck reaction, discovered in the early 1970s, represents the first methodology to forge C-C bonds via Pd catalysis, enabling highly efficient synthesis of multisubstituted olefin products 1,2 . Owing to its high versatility, the Mizoroki-Heck reaction has been extensively applied in the field of organic chemistry from academic research to industrial processes [3][4][5][6][7] . Similar to other Pd-catalyzed cross-coupling reactions, aryl halides or pseudohalides are mainly utilized as electrophiles in the Mizoroki-Heck reactions, owing to their superior reactivity and robustness in comparison with those of alkyl analogs. The utilization of alkyl electrophiles for the Mizoroki-Heck reaction is significantly more challenging compared with the aryl congeners (Fig. 1a). The rates of Pd oxidative addition to alkyl electrophiles are sluggish and the resulting alkylpalladium species are prone to undesired β-hydride eliminations 8 . Unlike other cross-coupling reactions, because the β-hydride elimination is the key catalyst turnover step in the Mizoroki-Heck reactions, simple suppression of the undesired β-hydride elimination via catalyst or ligand design can reduce catalytic efficiency. Therefore, the control of the productive yet detrimental β-hydride elimination pathways is a significant hurdle that must be overcome 9,10 .
Over the decades, significant progress has been made in the field of Pd-catalyzed alkyl Mizoroki-Heck reactions, notably in single-electron catalysis, which can prevent undesired βhydride eliminations through the formation of a Pd(I)/alkyl radical hybrid [11][12][13][14] . Thermal Pd-catalyzed alkyl Mizoroki-Heck reactions of primary and secondary alkyl bromides and iodides were developed by Fu 15 , Alexanian [16][17][18] , and Zhou 19 groups. More recently, photoirradiated Pd catalysis, which harnesses visible light energy to generate Pd(I)/alkyl radical hybrid species via the single-electron oxidative addition of Pd(0) to alkyl halides 20 , has been highlighted as a versatile activation strategy that enables various salient transformations under mild reaction conditions (Fig. 1b) 21,22 . Such transformations include desaturation 23 , reduction 24 , addition to (hetero)arenes 25 , carbonylation 26 , and 1,4-difunctionalization of conjugated dienes [27][28][29] . By applying this strategy, the Gevorgyan group reported the first visible light-induced Pd-catalyzed Mizoroki-Heck reaction of alkyl bromides and iodides 30 . Subsequently, the Fu group reported the first Pd-catalyzed Mizoroki-Heck coupling of tertiary alkyl bromides, which are highly susceptible to β-hydride elimination 9 , expanding the reactivity to silyl enol ethers and enamides 31 . Similar reactions have also been reported by using other alkyl electrophiles, including N-hydroxyphthalimide esters or tertiary alkyl iodides, by Fu 32 , and Glorius 33 , and Gevorgyan 34 groups. In particular, alkyl chlorides are the preferred substrates of choice over bromides and iodides for a number of reasons 35,36 . Most notably, the diversity and the abundant supply of naturally occurring and commercial chemicals [37][38][39] , high economic preference owing to their low costs 8 , diminished toxicity compared with other alkyl halides 40 , exceptional stability during multistep synthesis, and late-stage functionalization capability 41 make these compounds attractive synthetic building blocks. However, the stronger C-Cl bond strength, both homolytically and heterolytically, compared with C-Br and C-I bonds has limited the utilization of alkyl chlorides in transition metal catalysis 42,43 . This has resulted in difficulties in both transition metal-mediated oxidative additions and direct reductions via single-electron transfer (SET) 44 .
Regarding the use of alkyl chlorides for Mizoroki-Heck reactions, to overcome the aforementioned challenges, early first-row transition metal catalysts such as a titanocene 45 or a Co 46,47 catalyst accompanied by over-stoichiometric Grignard reagents as a reductant were developed with limited applicability. Otherwise, activated alkyl chlorides such as benzyl chlorides 48 or α-acyl chlorides 49 were required with Ni or Pd catalytic systems. Regarding unactivated alkyl chlorides, thermal Pd-catalyzed conditions reported by the Fu group were applicable but limited to intramolecular annulations with only four examples that proceed under the assistance of the Thorpe-Ingold effect 15 . The Zhou group reported a protocol for alkyl iodides amenable to primary alkyl chlorides using an in situ Finkelstein reaction with LiI to generate alkyl iodides under harsh reaction conditions at 110°C 19 . Despite the recent advances, photoexcited Pd catalysis has failed to activate of unactivated alkyl chlorides with no reported example of utilizing alkyl chloride to achieve a C-C bond formation. Therefore, a general and effective method to activate alkyl chlorides for Mizoroki-Heck coupling is a longstanding challenge in Pd-catalyzed cross-coupling chemistry.
Herein, highly efficient Mizoroki-Heck reactions of various unactivated primary, secondary, and even tertiary alkyl chlorides are achieved under mild reaction conditions via visible lightmediated Pd catalysis (Fig. 1c). The reaction exhibits excellent functional group tolerance with wide synthetic applicability, including late-stage transformations of bioactive scaffolds and annulative double Mizoroki-Heck reactions, directly furnishing complex structures. From judiciously designed kinetic experiments and computational studies, the catalytic turnover is shown to occur through an oxidative mass transfer assisted by a chlorine atom, not the previously conjectured β-hydride elimination. This contradicts with the fundamental principle of excited Pd catalysis as the stabilization of alkylpalladium(II) species prevents βhydride elimination via Pd(I)/alkyl radical hybrid formation. The SET-mediated mechanism provides a rationale for the photoinduced Pd catalysis to overcome the mechanistic dichotomy of two-electron-based Pd-catalyzed alkyl Mizoroki-Heck coupling, where β-hydride elimination is an essential elementary step for product formation and catalytic turnover, but also an undesired side-reaction which must be prevented.
Taking advantage of the high efficiency, exceptional functional group tolerance, mild reaction conditions, and operative simplicity of the developed reaction, the synthetic applicability of the alkyl chloride Mizoroki-Heck reaction was investigated (Table 4). First, the conditions were applied to complex bioactive molecules for bioconjugation and late-stage functionalization. To offer the highest practicality, the bioactive scaffold-derived compartment was used as the limiting reagent. Complex steroid carbon skeletons residing in either the olefin (vinylated estrone, 70%, 24a) or alkyl chloride (cholesteryl chloride, 80%, 3ac) reacted smoothly to furnish the desired products. It should be noted that a mixture of diastereomers was obtained due to the intermediary radical species, even though a single diastereomer was used. Terpenoid-derived menthyl chloride also showed good reactivity (68%, 3ad). Other bioactive molecules and drug derivatives, including those of δ-tocopherol (66%, 25a), gemfibrozil (75%, 3ae), naproxen (70%, 3af), and vanillin (95%, 26a) showed good to excellent yields. To our delight, even a biotin derivative afforded styrylated biotin in a high yield, providing opportunities for bioconjugation (81%, 3ag).
Notably, when 1,5-dichloropentane (2ah) was subjected to the reaction conditions with 2 equiv of 1a, an iterative double Mizoroki-Heck coupling proceeded smoothly to furnish an exo-(arylmethylene)cyclohexane framework (60%, 3ah) without the aid of the Thorpe-Ingold effect. In addition to simple 1,5dichloropentane, oxygen containing 1,5-dichloride smoothly furnished the tetrahydropyran structure (70%, 3ai). Similarly, a tert-butoxycarbonyl protected amine (86%, 3aj) or an aniline (75%, 3ak) analog could also be incorporated, resulting in 4functionalized piperidine derivatives, which are key moieties in a variety of drugs including cyproheptadine and its analogs. With chlorambucil methyl ester 2al, an N-arylpiperidine was prepared in a single step (76%, 3al). However, the use of other olefin substrates except 1a led to incomplete conversions leading to a mixture of the mono-Mizoroki-Heck product and the cyclized product. To the best of our knowledge, this type of one-step β,βdifunctionalization of styrenes has not been previously reported, which could provide a direct entry to six-membered cyclic compounds with an exocyclic double bond.
Mechanistic investigations. To examine the reaction mechanism, it was first attempted to confirm that the reaction indeed proceeds through a radical pathway involving a Pd(I)/alkyl radical hybrid, as previously reported 20,21,31 . First, when a control experiment with a radical scavenger was performed, complete shutdown of reactivity was observed with the addition of 1 equiv of (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) to the standard reaction conditions (Fig. 2a). Moreover, the addition of radical clock substrate 2am furnished the ring-opening product 3an exclusively and no direct Mizoroki-Heck product 3am was detected, indicative of cyclopropylmethyl radical generation (Fig. 2b). Stern-Volmer quenching experiments with 2a also revealed that photoinduced activation of alkyl chlorides through the excited Pd (0) catalyst was feasible, providing further evidence for a singleelectron reduction event (Supplementary Fig. 3). Thorough kinetic studies using both 1a-d 2 and 2n-d 1 revealed that the initial reduction of the alkyl chloride is the rate-limiting step, as the kinetic isotope effects (KIEs) arising from both the α and βposition of the styrene were 1.0, whereas that from the alkyl chloride was 1.6, indicating a secondary deuterium effect (Supplementary Figs. 4-6, Fig. 2c).
Next, the more controversial step of the reaction mechanism, the product forming catalyst turnover step, was examined (Fig. 2d). After generation of the alkyl radical, it undergoes facile insertion to the olefin substrate, generating a radical adduct, I- rad. However, the subsequent formation of the olefin product and concomitant regeneration of a Pd(0) species may occur via a few possible mechanisms (III). First, the Pd(II) species II formed after radical ligation may undergo direct β-hydride elimination to furnish the product (Fig. 2d, upper pathway), as previously proposed by the Fu group 9 . Another reaction mechanism involving SET or mass transfer from the Pd(I) species to provide either I-cat or I-Cl, followed by base-assisted elimination is equally plausible (Fig. 2d, lower pathway) 25,50 .
The Fu group proposed that the β-hydride elimination pathway was operative in the photoirradiated Pd-catalyzed Mizoroki-Heck coupling of alkyl bromides 9 . However, we questioned its operation in the developed reaction because the photoirradiated Pd catalytic system inherently prevents the occurrence of β-hydride elimination 20 . Indeed, time-dependent density functional theory computations on the Pd-alkyl species (as in II) showed clear excitation into the Pd-alkyl antibonding orbitals in the blue light energy region ( Supplementary Fig. 11). Moreover, contrasting observations regarding the substrate electronics were reported, where electron-poor styrenes failed to furnish the Mizoroki-Heck products under the reaction conditions herein, whereas they smoothly proceeded with alkyl bromides in dual phosphine-based photoinduced Pd catalytic systems 9,[32][33][34] . This indicates that an oxidative process may be involved in the reaction because the reactivity trend is counterintuitive as radical addition to electron-poor olefins should be more facile. This substrate-dependent reactivity was further studied in a quantitative manner via density functional theory (DFT) computation of the oxidation potentials of various I-rad species to I-cat (Fig. 3a). A decreasing trend in yields was observed as the oxidation potential of I-rad increased. Notably, a clear cutoff potential region was identified between    R = F and R = CF 3 , as commonly expected for an oxidative transformation 51,52 . The results suggest that an oxidation-based mechanism is likely operative in the product formation pathway. Next, in order to independently investigate the catalyst turnover step, a number of kinetic studies using deuterated substrates were performed to observe and compare the KIE values in the proposed scenarios (Fig. 3b). As the identified rate-determining step, initial reduction of the alkyl chloride (Fig. 2b), is located prior to the elementary steps of interest, competitionbased kinetic experiments and DFT computations were carefully designed to unambiguously determine the KIEs of each step 53 . First, an intramolecular competition experiment, analogous to that reported by the Fu group 9 , was conducted using 1a-β-d 1 (Supplementary Fig. 7, Fig. 3b, first line). A KIE value of 1.2 was

Pd(I)Cl
Ar R

Pd(II)Cl E-H elimination
Ar R

Pd(0)
Ar    Table 2). Overall, these kinetic experiments, along with literature and computational data, strongly oppose the β-hydride elimination mechanism in the reaction, implying that an oxidative mechanism is more plausible. Notably, a benzyl chloride intermediate is smoothly converted to the desired elimination product under our standard reaction conditions, which is in clear contrast to previous reports of Pd-catalyzed Mizoroki-Heck reactions where the addition of halide transfer intermediates to the standard reaction conditions led to catalytic cycle poisoning 9 or only low elimination yields 19 ( Supplementary  Fig. 9). Moreover, considering that the observed KIE values from the two experiments in Fig. 3b Supplementary Fig. 10), further indicating that the direct oxidation pathway from I-rad to I-cat is unlikely. Moreover, when tert-butyl N-(acyloxy)phthalimide, a competent electrophile in the previously reported dual phosphine-based photoexcited Pd-catalyzed Heck reaction 32 , was employed, the reactivity was largely diminished (13% yield) under the standard conditions as a phthalimide group transfer is implausible. The reactivity was moderately recovered (22% yield) with the addition of lithium chloride, indirectly suggesting the role of chloride in the reaction mechanism (Supplementary Table 1). An analogous reaction mechanism has been recently reported in the identical Pd system to perform alkylation of unactivated arenes, which involves a bromine atom transfer as the key turnover process 59 . Unfortunately, even after numerous attempts, capturing the chlorine atom transfer transition state through DFT modeling was unsuccessful.
Combining the above mechanistic investigations, a plausible catalytic cycle was proposed (Fig. 4). After alkyl chloride reduction from the excited Pd(0) species to yield alkyl radicals, this radical is selectively inserted to the β-position of the styrene, yielding a Pd(I)/benzylic radical hybrid species. As β-hydride elimination is significantly prevented by irradiation, singleelectron oxidation mediated by a chlorine atom occurs to furnish a benzyl chloride species, regenerating the Pd(0) catalyst. A baseassisted elimination then produces the Mizoroki-Heck coupling product. However, we cannot fully exclude the possibilities of the engagement of photoexcited Pd species or higher order Pd species in direct single-electron oxidation events.
In conclusion, a general intermolecular Pd-catalyzed Mizoroki-Heck coupling of alkyl chlorides enabled by photoexcited Pd catalysis was reported. The developed reaction conditions are applicable to a wide range of styrenes and other activated olefins as well as diverse primary, secondary, and even tertiary alkyl chlorides. The synthetic utility of this reaction was demonstrated via late-stage functionalization of bioactive molecules and pharmaceutical scaffolds in the context of both olefins and alkyl chlorides. Notably, an iterative double Mizoroki-Heck coupling of 1,5-dichlorides was possible under identical reaction conditions, yielding a series of complex structures in a single step. Concrete mechanistic studies using experimental and computational methods revealed that an oxidative pathway is operative rather than the previously reported β-hydride elimination, rationally overcoming the mechanistic challenge of two-electron-based Pd-catalyzed alkyl Mizoroki-Heck coupling. We anticipate that this study will provide mechanistic insights to utilize photoinduced Pd catalysis to achieve traditionally unreachable transformations and expand the synthetic utility of the widespread Mizoroki-Heck reaction.

Data availability
Detailed experimental procedures, computational details, and all characterization data for new compounds are available from the Supplementary Information. Cartesian  Fig. 4 Proposed reaction mechanism. Reaction mechanism involving chlorine atom transfer as the key turnover step. ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21270-9