Showing papers on "Heck reaction published in 2022"

Aromatic π-Components for Enantioselective Heck Reactions and Heck/Anion-Capture Domino Sequences.

Abstract: ConspectusOlefin functionalization represents one of the most important synthetic transformations in organic synthesis. Over the past decades, palladium-catalyzed enantioselective Heck reactions, and Heck/anion-capture domino sequences through olefin carbopalladation followed by termination of the resulting alkyl-Pd species have been extensively developed. Extension of the coupling partners from classical olefins to other π-components would enable further advances and open new space in this field. Aromatics are important and easily available bulk chemicals. Dearomative transformation of endocyclic aromatic π-bonds via the Heck reaction pathway provides an efficient and straightforward route to structurally diverse alicyclic compounds. Nevertheless, major challenges for this transformation include aromaticity breaking and reactivity and selectivity issues.Recently, we have engaged in developing catalytic enantioselective dearomative Heck reactions and related domino reactions. A range of heteroarenes and naphthalenes have been employed as novel π-coupling partners in these reactions. Through dearomative migratory insertion of endocyclic aromatic C-C π-bonds followed by interception of the transient alkyl-Pd species, enantioselective Heck reactions, reductive Heck reactions, Heck/anion-capture difunctionalization reactions, and heteroarenyne cycloisomerization reactions have been established. Relying on β-H elimination of the alkyl-Pd intermediate, we realized enantioselective dearomative Heck reactions with a range of aromatic partners, including heterocyclic indoles, pyrroles, furans, benzofurans, and more challenging carbocyclic naphthalenes. In order to avoid the utilization of organohalide electrophiles, heteroarenyne cycloisomerization reaction was developed by merging intermolecular alkyne hydropalladation with intramolecular dearomative Heck reaction. Cycloisomerization of alkyne-tethered indoles delivered chiral indolines in excellent enantioselectivities with 100% atom economy. On the other hand, Heck/anion-capture domino sequences were established through nucleophilic trapping of the alkyl-Pd intermediate. When HCO2Na was employed as a capturing reagent, the enantioselective dearomative reductive Heck reaction of indoles was realized. By employing other nucleophiles, including alkynes, N-sulfonylhydrazones, and organoboron reagents, we developed a series of dearomative difunctionalization reactions. Two vicinal stereocenters with excellent enantio- and diastereoselectivities were constructed in the corresponding Heck/Sonogashira, Heck/vinylation, and Heck/borylation reactions. Moreover, dearomative 1,4-diarylation of naphthalenes was developed through Heck/Suzuki domino reactions, in which competitive C-H arylation and the direct Suzuki reaction were almost fully inhibited in the presence of a spiro-phosphoramidite ligand.In this Account, we provide a panoramic view of our results since 2015 on enantioselective Heck reactions and related domino sequences by extending the coupling partners from classical olefins to aromatic systems. Investigations outlined in this Account established straightforward and efficient access to a variety of structurally diverse chiral heteropolycyclic molecules starting from simple and planar aromatic compounds.

Palladium/Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2) –H alkylation reaction

Abstract: •Highly enantioselective domino Heck/intramolecular C–H alkylation•Immediate access to synthetically valuable chiral 5,4- and 5,5-spirocycle derivatives•A position of the phenyl ring-dependent enantiodivergent synthesis•Better understanding of the overall reaction mechanism by experimental studies Although the past three decades have witnessed enormous advancement of domino Heck/C–H functionalizations, the highly chemo-, regio-, and enantio-selective palladium-catalyzed domino Heck/intramolecular C–H alkylation of unactivated alkenes reactions remained a challenge. Reported herein is a highly enantioselective domino Heck/intramolecular C–H alkylation of unactivated alkenes for efficient synthesis of various chiral strained 5,4- and 5,5-spirocycles bearing a challenging all-carbon quaternary stereocenter by using Xu-Phos. Our forays into the enantioselective palladium-catalyzed domino Heck/ C–H functionalization strategy could open up new avenues for the asymmetric construction of various spirocycles for bioactive compounds. This efficient protocol could also inspire the discovery of different catalytic systems and give new impetus to the design of other related processes. Over the past 30 years, Heck-type difunctionalization of unactivated alkenes involving C−H bond activation has emerged as a powerful strategy for the construction of synthetically valuable spirocycles; however, the development of asymmetric version has largely lagged behind. Herein, we demonstrate a robust Heck-type difunctionalization of a broad range of unactivated alkenes enabled by the first palladium/Xu-Phos-catalyzed tandem Heck/remote C–H bond alkylation. Moreover, both enantiomers of the product can be efficiently prepared using the same enantiomer of a chiral ligand via a position of the phenyl ring-dependent enantiodivergent synthesis. The salient features of this methodology include operational simplicity, high chemo- and enantio-selectivities, and broad substrate scope. In addition, we first revealed that the C(sp2)–H activation, alkene insertion, and C−I reductive elimination steps are reversible by experiments. Over the past 30 years, Heck-type difunctionalization of unactivated alkenes involving C−H bond activation has emerged as a powerful strategy for the construction of synthetically valuable spirocycles; however, the development of asymmetric version has largely lagged behind. Herein, we demonstrate a robust Heck-type difunctionalization of a broad range of unactivated alkenes enabled by the first palladium/Xu-Phos-catalyzed tandem Heck/remote C–H bond alkylation. Moreover, both enantiomers of the product can be efficiently prepared using the same enantiomer of a chiral ligand via a position of the phenyl ring-dependent enantiodivergent synthesis. The salient features of this methodology include operational simplicity, high chemo- and enantio-selectivities, and broad substrate scope. In addition, we first revealed that the C(sp2)–H activation, alkene insertion, and C−I reductive elimination steps are reversible by experiments. Chiral spirocycles are key structural skeletons found in a wide range of bioactive natural products,1Kita Y. Fujioka H. Enantioselective constructions of quaternary carbons and their application to the asymmetric total syntheses of fredericamycin A and discorhabdin A.Pure Appl. Chem. 2007; 79: 701-713Google Scholar, 2Posner G.H. Hamill T.G. An asymmetric total synthesis of fragrant spiro[4.5]decane sesquiterpene (-)-.beta.-vetivone via an enantiomerically pure vinylic sulfoxide.J. Org. 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The use of spirocyclic scaffolds in drug discovery.Bioorg. Med. Chem. Lett. 2014; 24: 3673-3682Google Scholar Although a plenty of methods have been developed for the preparation of spiro stereocenters,8Rios R. Enantioselective methodologies for the synthesis of spiro compounds.Chem. Soc. Rev. 2012; 41: 1060-1074Google Scholar, 9Ding A. Meazza M. Guo H. Yang J.W. Rios R. New development in the enantioselective synthesis of spiro compounds.Chem. Soc. Rev. 2018; 47: 5946-5996Google Scholar, 10Narayan R. Potowski M. Jia Z.-J. Antonchick A.P. Waldmann H. Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides for biology-oriented synthesis.Acc. Chem. Res. 2014; 47: 1296-1310Google Scholar, 11Tan B. Candeias N.R. Barbas 3rd, C.F. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst.Nat. Chem. 2011; 3: 473-477Google Scholar, 12Godfrey R.C. Green N.J. Nichol G.S. Lawrence A.L. 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Asymmetric electrophilic fluorination using an anionic chiral phase-transfer catalyst.Science. 2011; 334: 1681-1684Google Scholar most of them still need to elaborate a preconstructed monocycle.8Rios R. Enantioselective methodologies for the synthesis of spiro compounds.Chem. Soc. Rev. 2012; 41: 1060-1074Google Scholar,9Ding A. Meazza M. Guo H. Yang J.W. Rios R. New development in the enantioselective synthesis of spiro compounds.Chem. Soc. Rev. 2018; 47: 5946-5996Google Scholar Therefore, it is highly desirable to explore novel protocols for the construction of two cycles along with a quaternary stereocenter in one operation. Functionalizing C–H bonds selectively at various locations in molecules will ultimately afford synthetic chemists transformative tools to modify and construct molecular structures.18Chen X. Engle K.M. Wang D.-H. Yu J.-Q. Palladium(II)-catalyzed C–H activation/C−C cross-coupling reactions: versatility and practicality.Angew. Chem. Int. Ed. 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Res. 2012; 45: 864-873Google Scholar C–H bonds that are remote from functional groups are widespread, and distinguishing these C–H bonds bearing little difference in electronic property is a formidable challenge in C–H activation. To date, much pioneering work utilized the intrinsic steric or electronic properties of the arenes,24Cho J.-Y. Tse M.K. Holmes D. Maleczka Jr., R.E. Smith 3rd, M.R. Remarkably selective iridium catalysts for the elaboration of aromatic C–H bonds.Science. 2002; 295: 305-308Google Scholar, 25Cheng C. Hartwig J.F. Rhodium-catalyzed intermolecular C–H silylation of arenes with high steric regiocontrol.Science. 2014; 343: 853-857Google Scholar, 26Phipps R.J. Gaunt M.J. A meta-selective copper-catalyzed C–H bond arylation.Science. 2009; 323: 1593-1597Google Scholar, 27Duong H.A. Gilligan R.E. Cooke M.L. Phipps R.J. Gaunt M.J. Copper(II)-catalyzed meta-selective direct arylation of α-aryl carbonyl compounds.Angew. Chem. Int. Ed. Engl. 2011; 50: 463-466Google Scholar, 28Zhang Y.-H. Shi B.-F. Yu J.-Q. Pd(II)-catalyzed olefination of electron-deficient arenes using 2,6-dialkylpyridine ligands.J. Am. Chem. Soc. 2009; 131: 5072-5074Google Scholar or the type of “U”-shaped directing group (DG).29Leow D. Li G. Mei T.-S. Yu J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template.Nature. 2012; 486: 518-522Google Scholar,30Tang R.-Y. Li G. Yu J.-Q. Conformation-induced remote meta-C–H activation of amines.Nature. 2014; 507: 215-220Google Scholar Although a large number of brilliant achievements were made using DG, there exists a point to be noted that is the DG needs to be installed on the substrate and removed after the reaction. Instead of using a DG that is covalently bound to a substrate for site-selective C–H activation, an alternative approach is utilizing a transient DG can be generated in situ under the reaction conditions would open the door to new reactivities (Figures 1A and 1B ).31Ping Y. Li Y. Zhu J. Kong W. Construction of quaternary stereocenters by palladium-catalyzed carbopalladation-initiated cascade reactions.Angew. Chem. Int. Ed. Engl. 2019; 58: 1562-1573Google Scholar, 32Grigg R. Fretwell P. Meerholtz C. Sridharan V. Palladium catalysed synthesis of spiroindolines.Tetrahedron. 1994; 50: 359-370Google Scholar, 33Ruck R.T. Huffman M.A. Kim M.M. Shevlin M. Kandur W.V. Davies I.W. Palladium-catalyzed tandem Heck reaction/C-H functionalization--preparation of spiro-indane-oxindoles.Angew. Chem. Int. Ed. Engl. 2008; 47: 4711-4714Google Scholar, 34Satyanarayana G. Maichle-Mössmer C. Maier M.E. Formation of pentacyclic structures by a domino sequence on cyclic enamides.Chem. Commun. (Camb). 2009; 2009: 1571-1573Google Scholar, 35Piou T. Neuville L. Zhu J. Spirocyclization by palladium-catalyzed domino heck-direct C-H arylation reactions: synthesis of spirodihydroquinolin-2-ones.Org. Lett. 2012; 14: 3760-3763Google Scholar, 36Piou T. Neuville L. Zhu J. Activation of a C(sp3)-H bond by a transient σ-alkylpalladium(II) complex: synthesis of spirooxindoles through a palladium-catalyzed domino carbopalladation/C(sp3)-C(sp3) bond-forming process.Angew. Chem. Int. Ed. Engl. 2012; 51: 11561-11565Google Scholar, 37Franzoni I. Yoon H. García-López J.-A. Poblador-Bahamonde A.I. Lautens M. Exploring the mechanism of the Pd-catalyzed spirocyclization reaction: a combined DFT and experimental study.Chem. Sci. 2018; 9: 1496-1509Google Scholar, 38Pérez-Gómez M. Navarro L. Saura-Llamas I. Bautista D. Lautens M. García-López J.-A. Synthesis and reactivity of model intermediates proposed for the Pd-catalyzed remote C−H functionalization of N-(2-Haloaryl)acrylamides.Organometallics. 2017; 36: 4465-4476Google Scholar, 39Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.Nat. Chem. 2017; 9: 361-368Google Scholar, 40Ye F. Ge Y. Spannenberg A. Neumann H. Beller M. The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles.Nat. Commun. 2020; 11: 5383Google Scholar As a pioneering study, Grigg et al. successfully implemented this strategy in the Pd-catalyzed remote-C–H functionalization of the heteroaromatic tethered alkene moiety through carbopalladation of alkenes to form neopentyl-type σ-alkylpalladium intermediate as the DG.32Grigg R. Fretwell P. Meerholtz C. Sridharan V. Palladium catalysed synthesis of spiroindolines.Tetrahedron. 1994; 50: 359-370Google Scholar This marks that the direct and selective functionalization of remote C–H alkylation of arenes has been successfully applied to the construction of spirocycles. Using the same concept, Ruck et al. accomplished the expansion of the C(sp2)–H scope to an unactivated aryl C–H bond.33Ruck R.T. Huffman M.A. Kim M.M. Shevlin M. Kandur W.V. Davies I.W. Palladium-catalyzed tandem Heck reaction/C-H functionalization--preparation of spiro-indane-oxindoles.Angew. Chem. Int. Ed. Engl. 2008; 47: 4711-4714Google Scholar Subsequently, Zhu et al. demonstrated that the σ-alkylpalladium intermediate can activate the C(sp3)–H bond, thereby leading to the 5,6-spiroheterocycles.36Piou T. Neuville L. Zhu J. Activation of a C(sp3)-H bond by a transient σ-alkylpalladium(II) complex: synthesis of spirooxindoles through a palladium-catalyzed domino carbopalladation/C(sp3)-C(sp3) bond-forming process.Angew. Chem. Int. Ed. Engl. 2012; 51: 11561-11565Google Scholar Notably, continued interest in this reaction has recently culminated with the highly strained spiro-fused benzocyclobutene derivatives by Lautens.39Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.Nat. Chem. 2017; 9: 361-368Google Scholar Very recently, Beller’s group combined selective nucleophilic substitution (SN2′), Pd-catalyzed Heck, and C–H activation reaction in a cascade manner, affording the highly strained racemic 5,4-spiroheterocycles in good-to-high yields.40Ye F. Ge Y. Spannenberg A. Neumann H. Beller M. The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles.Nat. Commun. 2020; 11: 5383Google Scholar In the classic domino Heck/intramolecular C–H alkylation reaction, the carbopalladation step is an enantiodetermining step, but this step is reversible.31Ping Y. Li Y. Zhu J. Kong W. Construction of quaternary stereocenters by palladium-catalyzed carbopalladation-initiated cascade reactions.Angew. Chem. Int. Ed. Engl. 2019; 58: 1562-1573Google Scholar,33Ruck R.T. Huffman M.A. Kim M.M. Shevlin M. Kandur W.V. Davies I.W. Palladium-catalyzed tandem Heck reaction/C-H functionalization--preparation of spiro-indane-oxindoles.Angew. Chem. Int. Ed. Engl. 2008; 47: 4711-4714Google Scholar Nowadays, much progress has been made in racemic domino Heck/intramolecular C–H alkylation reaction to construct complex molecular architectures. However, because of no conclusive evidence, there remain some unresolved issues relating to the mechanism of this kind of reaction, such as: (1) whether the carbopalladation step is reversible, (2) whether the C(sp2)–H activation step is reversible, and (3) whether the C–I reductive elimination is reversible. Moreover, the development of an enantioselective version remains extremely challenging because of the following issues: (1) presence of various competitive side reactions, such as reductive Heck reaction, carboiodination reaction, and 1,4-Pd migration/C(sp2)–H functionalization41Huang Q. Fazio A. Dai G. Campo M.A. Larock R.C. Pd-catalyzed alkyl to aryl migration and cyclization: an efficient synthesis of fused polycycles via multiple C-H activation.J. Am. Chem. Soc. 2004; 126: 7460-7461Google Scholar, 42Sickert M. Weinstabl H. Peters B. Hou X. Lautens M. Intermolecular domino reaction of two aryl iodides involving two C-H functionalizations.Angew. Chem. Int. Ed. Engl. 2014; 53: 5147-5151Google Scholar, 43Bunescu A. Piou T. Wang Q. Zhu J. Pd-catalyzed dehydrogenative aryl–aryl bond formation via double C(sp2)– H bond activation efficient synthesis of [3,4]-fused oxindoles.Org. Lett. 2015; 17: 334-337Google Scholar; (2) when having two different ortho-position C–H of aromatic ring, how to control the site-selectivity; and (3) the high temperature was required in previous work,39Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.Nat. Chem. 2017; 9: 361-368Google Scholar,40Ye F. Ge Y. Spannenberg A. Neumann H. Beller M. The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles.Nat. Commun. 2020; 11: 5383Google Scholar which easily lead to the ring-opening byproduct (Figure 1A). Inspired by the good performance of Xu-Phos in asymmetric Heck and related cascade reactions,44Zhang Z.-M. Xu B. Qian Y. Wu L. Wu Y. Zhou L. Liu Y. Zhang J. Palladium-catalyzed enantioselective reductive heck reactions: convenient access to 3,3-Disubstituted 2,3-dihydrobenzofuran.Angew. Chem. Int. Ed. Engl. 2018; 57: 10373-10377Google Scholar, 45Zhang Z.-M. Xu B. Wu L. Wu Y. Qian Y. Zhou L. Liu Y. Zhang J. Enantioselective dicarbofunctionalization of unactivated alkenes by palladium-catalyzed tandem heck/Suzuki coupling reaction.Angew. Chem. Int. Ed. Engl. 2019; 58: 14653-14659Google Scholar, 46Zhang Z.-M. Xu B. Wu L. Zhou L. Ji D. Liu Y. Li Z. Zhang J. Palladium/XuPhos-catalyzed enantioselective carboiodination of olefin-tethered aryl iodides.J. Am. Chem. Soc. 2019; 141: 8110-8115Google Scholar, 47Zhou L. Li S. Xu B. Ji D. Wu L. Liu Y. Zhang Z.-M. Zhang J. Enantioselective difunctionalization of alkenes by a palladium-catalyzed heck/Sonogashira sequence.Angew. Chem. Int. Ed. Engl. 2020; 59: 2769-2775Google Scholar, 48Whyte A. Bajohr J. Arora R. Torelli A. Lautens M. Sequential Pd0 and PdII-catalyzed cyclizations: enantioselective heck and nucleopalladation reactions.Angew. Chem. Int. Ed. 2021; 60: 20231-20236Google Scholar, 49Jones D.J. Lautens M. McGlacken G.P. The emergence of Pd-mediated reversible oxidative addition in cross coupling, carbohalogenation and carbonylation reactions.Nat. Catal. 2019; 2: 843-851Google Scholar, 50Marchese A.D. Larin E.M. Mirabi B. Lautens M. Metal-catalyzed approaches toward the oxindole core.Acc. Chem. Res. 2020; 53: 1605-1619Google Scholar, 51Newman S.G. Lautens M. Palladium-catalyzed carboiodination of alkenes: carbon-carbon bond formation with retention of reactive functionality.J. Am. Chem. Soc. 2011; 133: 1778-1780Google Scholar, 52Yoon H. Marchese A.D. Lautens M. Carboiodination catalyzed by nickel.J. Am. Chem. Soc. 2018; 140: 10950-10954Google Scholar, 53Liu H. Li C. Qiu D. Tong X. Palladium-catalyzed cycloisomerizations of (Z)-1-iodo-1,6-dienes: iodine atom transfer and mechanistic insight to alkyl iodide reductive elimination.J. Am. Chem. Soc. 2011; 133: 6187-6193Google Scholar we became very interested in addressing this long-standing unsolved asymmetric tandem Heck reaction/C–H alkylation, which, if successful, would provide an immediate access to synthetically valuable optically active 5,4- and 5,5-spirocycle derivatives.54Carreira E.M. Fessard T.C. Four-membered ring-containing spirocycles: synthetic strategies and opportunities.Chem. Rev. 2014; 114: 8257-8322Google Scholar Herein, we present a robust palladium/Xu-Phos catalyst system for asymmetric tandem Heck reaction/C–H alkylation using a palladacycle intermediate (Figure 1C). Synthesis of both enantiomers of the product can be accomplished depending on the site of the substituent on the aromatic or heteroaromatic ring (Figure 1D). Moreover, this reaction exhibits a broad scope of the unactivated aryl tethered alkene moiety while under operationally simple and mild reaction conditions. We began our investigation by revisiting our previously developed catalytic system for enantioselective cascade Heck-type reactions of alkene-tethered aryl iodides.44Zhang Z.-M. Xu B. Qian Y. Wu L. Wu Y. Zhou L. Liu Y. Zhang J. Palladium-catalyzed enantioselective reductive heck reactions: convenient access to 3,3-Disubstituted 2,3-dihydrobenzofuran.Angew. Chem. Int. Ed. Engl. 2018; 57: 10373-10377Google Scholar, 45Zhang Z.-M. Xu B. Wu L. Wu Y. Qian Y. Zhou L. Liu Y. Zhang J. Enantioselective dicarbofunctionalization of unactivated alkenes by palladium-catalyzed tandem heck/Suzuki coupling reaction.Angew. Chem. Int. Ed. Engl. 2019; 58: 14653-14659Google Scholar, 46Zhang Z.-M. Xu B. Wu L. Zhou L. Ji D. Liu Y. Li Z. Zhang J. Palladium/XuPhos-catalyzed enantioselective carboiodination of olefin-tethered aryl iodides.J. Am. Chem. Soc. 2019; 141: 8110-8115Google Scholar, 47Zhou L. Li S. Xu B. Ji D. Wu L. Liu Y. Zhang Z.-M. Zhang J. Enantioselective difunctionalization of alkenes by a palladium-catalyzed heck/Sonogashira sequence.Angew. Chem. Int. Ed. Engl. 2020; 59: 2769-2775Google Scholar, 48Whyte A. Bajohr J. Arora R. Torelli A. Lautens M. Sequential Pd0 and PdII-catalyzed cyclizations: enantioselective heck and nucleopalladation reactions.Angew. Chem. Int. Ed. 2021; 60: 20231-20236Google Scholar With the ortho-iodophenol-derived allyl ether 1a as the model substrate, we conducted a preliminary study in isopropyl ether (120°C) for 24 h with Pd2(dba)3⋅CHCl3 as the precatalyst, N-Me-Xu-Phos (N-Me-Xu3) as the chiral ligand, and Cs2CO3 as the base (Figure 2). Our initial efforts resulted in poor yield of the desired product 4a with a moderate enantiomeric ratio (e.r.) (67% conversion, 22% yield with 88:12 e.r.) together with a series of byproducts 2, 3, and 5 (Figure 2, entry 1), indicating that the synthesis of the highly strained chiral 5,4-spirocycles is indeed very challenging. Subsequently, further evaluation of the reaction conditions revealed that all of bases, additives, Pd salts, and temperature were the key factors to obtain a robust reaction. Several points are noteworthy: (1) this reaction is very sensitive to the bases (Figure 2, entries 2–6). For example, when PMP was chosen as the base, the byproduct 2 was given as the main product via carboiodination of alkene (Figure 2, entry 3). Nevertheless, changing to CsOAc, a 1,4-Pd shift of palladacycle followed by ortho-C–H activation led to the fused polycycle 6 (Figure 2, entry 4). (2) In Lauten’s work, 1a quickly converts to the target compound 4a in good yield by using the racemic ligand (PtBu3) at 100°C for 1 h (Figure 2, entry 9).39Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.Nat. Chem. 2017; 9: 361-368Google Scholar By a huge margin, the rate of reaction is greatly reduced under current conditions without PtBu3 (Figure 2, entry 8). Even extending to 72 h and warming up to 110°C, the desired product 4a was obtained in only 48% yield (63% conversion). Indeed, adding the racemic ligand was beneficial to the conversion of the reaction (Figure 2, entries 2 versus 3, and 7 versus 8). However, such a strong racemic background reaction poses a great challenge to the high enantioselectivity. (3) The potassium bases are beneficial to the enantioselectivity (Figure 2, entries 5, 6 versus 2). (4) Reducing the temperature to 110°C could inhibit the formation of the ring-opening byproduct 5 (Figure 2, entries 1–6 versus 7, 8). After an extensive evaluation of the reaction conditions, the current conditions were not satisfactory (Figure 2, entry 7). Not only the desired product 4a was provided with 92.5:7.5 e.r. but also the conditions have poor universality (more detail see the supplemental information; Tables S1–S7; Figure S1). Then, we focused our attention on screening of chiral ligands (Figures S2–S4). First, various commercially available chiral ligands such as biphosphines (L1–L7), monophosphine (L8), phosphoramidite (L9), ferrocene-derived P,N-ligands (L10–L11), and bis(oxazoline) (L12) were tested occasionally together with the byproduct 7. The biphosphine ligands (L1-L4, L6, and L7) and ferrocene-derived P,N-ligands (L10–L11) failed to give the desired product 4a. Both a bulky biarylphosphine (L5) and monophosphine (L8) gave 4a in good yield without any enantioselectivity. Only the phosphoramidite (L9) delivered 4a but with low enantioselectivity. Subsequently, we examined the performance of a Sadphos kit (including Ming-Phos,55Zhang Z.-M. Chen P. Li W. Niu Y. Zhao X.-L. Zhang J. A new type of chiral sulfinamide monophosphine ligands: stereodivergent synthesis and application in enantioselective gold(I)-catalyzed cycloaddition reactions.Angew. Chem. Int. Ed. 2014; 53: 4350-4354Google Scholar Xu-Phos,44Zhang Z.-M. Xu B. Qian Y. Wu L. Wu Y. Zhou L. Liu Y. Zhang J. Palladium-catalyzed enantioselective reductive heck reactions: convenient access to 3,3-Disubstituted 2,3-dihydrobenzofuran.Angew. Chem. Int. Ed. Engl. 2018; 57: 10373-10377Google Scholar, 45Zhang Z.-M. Xu B. Wu L. Wu Y. Qian Y. Zhou L. Liu Y. Zhang J. Enantioselective dicarbofunctionalization of unactivated alkenes by palladium-catalyzed tandem heck/Suzuki coupling reaction.Angew. Chem. Int. Ed. Engl. 2019; 58: 14653-14659Google Scholar, 46Zhang Z.-M. Xu B. Wu L. Zhou L. Ji D. Liu Y. Li Z. Zhang J. Palladium/XuPhos-catalyzed enantioselective carboiodination of olefin-tethered aryl iodides.J. Am. Chem. Soc. 2019; 141: 8110-8115Google Scholar, 47Zhou L. Li S. Xu B. Ji D. Wu L. Liu Y. Zhang Z.-M. Zhang J. Enantioselective difunctionalization of alkenes by a palladium-catalyzed heck/Sonogashira sequence.Angew. Chem. Int. Ed. Engl. 2020; 59: 2769-2775Google Scholar, 48Whyte A. Bajohr J. Arora R. Torelli A. Lautens M. Sequential Pd0 and PdII-catalyzed cyclizations: enantioselective heck and nucleopalladation reactions.Angew. Chem. Int. Ed. 2021; 60: 20231-20236Google Scholar Xiang-Phos,56Wang L. Zhang K. Wang Y. Li W. Chen M. Zhang J. Enantioselective synthesis of isoxazolines enabled by palladium-catalyzed carboetherification of alkenyl oximes.Angew. Chem. Int. Ed. Engl. 2020; 59: 4421-4427Google Scholar PC-Phos,57Wang Y. Zhang P. Di X. Dai Q. Zhang Z.-M. Zhang J. Gold-catalyzed asymmetric intramolecular cyclization of N-allenamides for the synthesis of chiral tetrahydrocarbolines.Angew. Chem. Int. Ed. Engl. 2017; 56: 15905-15909Google Scholar Xiao-Phos,58Dai Q. Li W. Li Z. Zhang J. P-chiral phosphines enabled by palladium/Xiao-phos-catalyzed asymmetric P−C cross-coupling of secondary phosphine oxides and aryl bromides.J. Am. Chem. Soc. 2019; 141: 20556-20564Google Scholar Wei-Phos,59Zhou W. Su X. Tao M. Zhu C. Zhao Q. Zhang J. Chiral sulfinamide bisphosphine catalysts: design, synthesis, and application in highly enantioselective intermolecular cross-Rauhut-Currier reactions.Angew. Chem. Int. Ed. Engl. 2015; 54: 14853-14857Google Scholar TY-Phos60Lin T.-Y. Pan Z. Tu Y. Zhu S. Wu H.-H. Liu Y. Li Z. Zhang J. Design and synthesis of TY-phos and application in palladium-catalyzed enantioselective fluoroarylation of gem-difluoroalkenes.Angew. Chem. Int. Ed. Engl. 2020; 59: 22957-22962Google Scholar etc.). The dicyclohexyl phosphine ligands (Xu-Phos) remained the most effective for enantioselective induction. Inspired by these results, other Xu-Phos, such as N-Me-Xu4 (Figure 2, entry 11) and N-CD3-Xu4 (Figure 2, entry 10), were then examined under previous reaction conditions, of which the better results could be obtained by using the newly indentified N-CD3-Xu4 as the chiral ligand. To the best of our knowledge, the introduction of deuterium atom in the chiral ligand to increase the enantioselectivity is rarely reported. With the optimal reaction conditions established, we next examined the generality of this enantioselective tandem Heck reaction/C–H alkylation. First, the effect of allyl substituents was examined, and the results are shown in Figure 3. A broad series of allyl substituted aryl iodides 1 including monosubstituted phenyl rings with electron-donating or electron-withdrawing groups at different positions (ortho, meta, or para), a disubstituted phenyl ring, worked smoothly to afford 4a–4l in 65%–96% yields with 91:9–96.5:3.5 ers. The absolute configuration of the product was confirmed by the X-ray diffraction analysis of 4b. In addition, highly strained 5,4-spiro-fused 2,3-dihydrobenzofurans 4m–4n that contain medicinally relevant heterocycles, such as 9,9-dimethyl-9H-fluorene and 9-phenyl-9H-carbazol-1-yl, were isolated in 70%–71% yields with 95:5–96:4 ers. The effect of substituents on the benzene ring of the 2- iodophenoxy moiety was then investigated under the optimal reaction conditions. The desired products 4o–4ad were also obtained in 44%–86% yields with 92.5:7.5–97:3 ers for the reactions with substrates bearing monosubstituted phenyl rings with either the electron-rich or electron-deficient group at C4 or C5, a disubstituted phenyl ring, and a naphthalene ring. When using N-Me-Xu4 as a chiral ligand, except in one particular case (4e), no better enantioselectivities were given. It is general phenomenon that the introduction of deuterium atom is beneficial to increase the enantioselectivity. To gain deep insight into the reaction mechanism, several control experiments were carried out (Figure 4). Although a series of byproducts had been inhibited under the standard conditions, a key mechanistic question is whether the intermediate σ-alkyl palladium or palladacycle could be trapped by the inclusion of phenyl, cyclohexenyl, cyclopropyl or methylboronic acid, phenylacetylene, sodium formate, and ethyl 3-phenylpropiolate. To probe this question, several competing reactions were performed (Figure 4A). Note that no desired product 4a was detected with using phenyl, cyclohexenyl-boronic acid, or phenylacetylene as the second substrates. These results supported that the C(sp3)–C(sp) and C(sp3)–C(sp2) cross-coupling of the domino Heck/Suzuki or Sonogashira reaction is more favored than this present domino Heck/remote C–H alkylation reaction. However, the C(sp3)–C(sp3) cross-coupling is obviously unfavored. Subsequently, adding sodium formate or ethyl 3-phenylpropiolate to the reaction mixture, roughly the same amount of the reductive Heck product 3 or alkyne insertion61Yoon H. Rölz M. Landau F. Lautens M. Palladium-catalyzed spirocyclization through C-H activation and regioselective alkyne insertion.Angew. Chem. Int. Ed. Engl. 2017; 56: 10920-10923Google Scholar product 9 with the spirocycle 4a was furnished. All these results further confirmed that the realization of domino Heck/remote C–H alkylation reaction is extremely challenging,31Ping Y. Li Y. Zhu J. Kong W. Construction of quaternary stereocenters by palladium-catalyzed carbopalladation-initiated cascade reactions.Angew. Chem. Int. Ed. Engl. 2019; 58: 1562-1573Google Scholar,39Ye J. Shi Z. Sperger T. Yasukawa Y. Kingston C. Schoenebeck F. Lautens M. Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.Nat. Chem. 2017; 9: 361-368Google Scholar,40Ye F. Ge Y. Spannenberg A. Neumann H. Beller M. The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles.Nat. Commun. 2020; 11: 5383Google Scholar especially in an enantioselective manner. It is worth noting that ers of 3, 8, 9, 12, and 13 are different, which might result from the transmetalation step taking place before the alkene insertion or the different extent of reversibility in the alkene insertion. Experiments with D2O instead of H2O were conducted under the optimal conditions by using 1a and 1g as the substrates (Figure 4B), respectively. In total, 75% D-labeled 4a was obtained in 85% yield with 94:6 er. Nevertheless, ortho-methyl aryl group–derived 1g could not afford D-labeled 4g. Deuterium (D)-labeling experiments confirmed our assumption that the step of C–H bond activation is reversible. Moreover, the five-membered palladacycle of C(sp2)–H bond activation was favored comparing with the less-strained six-membered palladacycle of C(sp3)–H bond activation under the reaction conditions.35Piou T. Neuville L. Zhu J. Spirocyclization by palladium-catalyzed domino heck-direct C-H arylation reactions: synthesis of spirodihydroquinolin-2-ones.Org. Lett. 2012; 14: 3760-3763Google Scholar Nonlinear effect studies on the enantiomeric composition of the chiral ligand N-CD3-Xu4 and product 4a (Figure 4C) and initial rate experiments62Cook A.K. Sanford M.S. Mechanism of the palladium-catalyzed Arene C−H acetoxylation: a comparison of catalysts and ligand effects.J. Am. Chem. Soc. 2015; 137: 3109-3118Google Scholar, 63Burés J. A simple graphical method to determine the order in catalyst.Angew. Chem. Int. Ed. Engl. 2016; 55: 2028-2031Google Scholar, 64Xu S. Zhang Z.-M. Xu B. Liu B. Liu Y. Zhang J. Enantioselective regiodivergent synthesis of chiral pyrrolidines with two quaternary stereocenters via ligand-controlled copper(I)-catalyzed asymmetric 1,3-dipolar cycloadditions.J. Am. Chem. Soc. 2018; 140: 2272-2283Google Scholar (Figure 4D) indicated that there is a clear first-order dependence on the catalyst. These results are consistent with an active catalyst/ligand being of a monomeric nature and the reaction possessing a first-order dependence on catalyst. When carboiodination compound 2ae (5-exo) was subjected to the catalysis of Pd(dba)2/QPhos or Pd2(dba)3·CHCl3/N-Me-Xu3, 6-endo-products 16a and 16a′ could be obtained, which indicates that the alkene insertion and carboiodination steps are reversible. Subsequently, we examined the progress of the reaction as a function of time and temperature with ortho-iodophenol–derived allyl ether 1ae as the model substrate (Figure 4F). At 100 °C, the reaction proceeded smoothly and gave the 5-exo-product 2ae with 93% ee and 95:5 rr. With the increase of reaction time, the ratios of 5-exo-product and 6-endo-product, and ee value hardly changes. However, the proportion of 6-endo-product increased notably with increasing temperature (120°C and 150°C). Meanwhile, the ee value of 5-exo-product decreased obviously. Based on the results of the above experiment and previous works, a reasonable pathway for this palladium-catalyzed Heck/intramolecular C–H alkylation reaction is shown in Figure 5. First, the arylpalladium species I was generated by oxidative addition of 1 or 14 with Pd(0) complex, then followed by an intramolecular 5-exo-Heck-type or 6-endo-Heck-type reactions form chiral σ-alkylpalladium species II or II′. Next, aryl (Ar2) C–H bond activation using the σ-alkylpalladium intermediate II deprotonation gave a spiropalladacycle III, which produces the corresponding product 4 or 15 and regenerates the Pd(0) catalyst to the next catalyzed cycle from reductive elimination. Nevertheless, σ-alkylpalladium species II through C–I elimination also produced iodide 2. The β-H elimination of 6-endo-cyclization σ-alkylpalladium species II’ could deliver the endo-products 16a and 16a′. In this study, it is worth noting that C(sp2)–H activation, carbopalladation, and C–I reductive elimination steps are reversible. Encouraged by these excellent results, we applied this method to the construction of the optically active 5,5-spirocycles. Both enantiomers of a chiral molecule are often required in organic synthesis, biological chemistry, and the medicinal and pharmaceutical industries. Generally, the synthesis of the enantiomer of a chiral molecule could be obtained by using the enantiomer of chiral ligands. Herein, we envisaged that the synthesis of a pair of enantiomers might be achieved by changing the position of the aromatic or heteroatomic aromatic rings (Figure 6). Using various aryl iodides 14 bearing electron-donating/withdrawing groups at the para- and meta-positions of phenyl rings, both (R)- and (S)-enantiomers of the spiro-indane-dihydrobenzofuran products 15a–15f were obtained in high yields (80%–99% for the (R)-enantiomers and 82%–98% for the (S)-enantiomers) with excellent enantioselectivity (95:5–97:3 ers for the (R)-enantiomers and 95:5–97.5:2.5 ers for the (S)-enantiomers) under the standard condition, respectively. With the linkers at C2 or C3 of heteroatomic aromatic rings, such as thiophene, benzothiophene, and furan, the corresponding 5,5-spirocycle products 15g–15n were also obtained with good results (93%–99% yields with 95:5–98.5:1.5 ers for the (R)-enantiomers and 94%–>99% yields with 95:5–98.5:1.5 ers for the (S)-enantiomers). Then, we further extended the scope of alkene-tethered aryl iodides 14 (Figure 7). In more than 40 examples, the desired products 15o–15bc were synthesized exclusively in good yields with excellent enantioselectivities (up to 98.5:1.5 er). Substrates bearing monosubstituted phenyl rings with electron-donating or electron-withdrawing groups at different positions (ortho or para), a disubstituted phenyl ring, a trisubstituted phenyl ring, a naphthalene, a pyrene, and medicinally relevant heterocycles (dibenzo[b,d]thiophene, benzofuran, thiophene, and indole) could be well tolerated. Notably, the present asymmetric catalytic system is applicable to tert-butyl carbamate (BocN) as a tether, delivering the indolines 15al–15am in good yields and with good ee values. In summary, we have developed the first highly enantioselective palladium-catalyzed domino Heck/intramolecular C–H alkylation of alkenes with excellent chemo- and regio-selectivities. The method not only constructs various chiral 5,4- and 5,5-spirocycles including one challenging all-carbon quaternary stereocenter but also exhibits superior catalytic properties of Xu-Phos, which open up new avenues for the asymmetric domino Heck/intramolecular C–H activation reaction. Moreover, this work also provides an alternative solution that a position of the phenyl ring-dependent enantiodivergent synthesis enables the synthesis of both enantiomers of the product using the same enantiomer of a chiral catalyst. Moreover, this protocol works with a wide range of substrates and tolerates a series of functional groups under operationally simple and mild reaction conditions. In addition, the reversibility of the C(sp2)–H activation, alkene insertion, and C−I reductive elimination steps was revealed by experiment. Further direction will focus on the development of asymmetric functionalization of palladacycles and will be reported in the due course.

Excited-State Palladium-Catalyzed Radical Migratory Mizoroki-Heck Reaction Enables C2-Alkenylation of Carbohydrates.

Abstract: Excited-state palladium catalysis has emerged as a promising strategy for developing novel and valuable reactions. Herein, we report the first excited-state Pd-catalyzed 1,2-radical migratory Mizoroki-Heck reaction that enables C2-alkenylation of carbohydrates using readily available 1-bromosugars and alkenes. The reaction tolerates a wide variety of functional groups and complex molecular architectures, including derivatives of natural products and marketed drugs. Preliminary mechanistic studies and DFT calculations suggest the involvement of visible-light-induced photoexcitation of Pd species, 1,2-spin-centered-shift (SCS) process, and Heck-type cross-coupling reaction. The reaction expands the reactivity profile of excited-state Pd catalysis and provides a streamlined protocol for the preparation of a wide variety of C2-alkenylated carbohydrate mimetics to aid the discovery and development of new therapeutics, agrochemicals, and materials.

Radical Aza-Heck Cyclization of Imidates via Energy Transfer, Electron Transfer, and Cobalt Catalysis.

Abstract: A radical aza-Heck cyclization has been developed to afford functionally rich products with four contiguous C-heteroatom bonds. This multi-catalytic strategy provides rapid syntheses of dense, medicinally relevant motifs by enabling the conversion of alcohol-derived imidates to heteroatom-rich fragments containing vinyl oxazolines/oxazoles, allyl amines, β-amino alcohols/halides, and combinations thereof. Mechanistic insights of this process show how three distinct photocatalytic cycles cooperate to enable: (1) imidate radical generation by energy transfer, (2) dehydrogenation by Co catalysis, and (3) catalyst turnover by electron transfer.

Regioselective synthesis of spirocyclic pyrrolines via a palladium-catalyzed Narasaka–Heck/C–H activation/[4 + 2] annulation cascade reaction

Abstract: A novel palladium-catalyzed spirocyclization through sequential Narasaka–Heck cyclization, C–H activation and [4 + 2] annulation has been developed. In this reaction, cheap and readily available 2-chlorobenzoic acid or ethyl phenylpropiolate was employed as the C2 insertion unit to react with γ,δ-unsaturated oxime ester. The key step in this transformation is the regioselective insertion of the C2 synthon into the spiro-palladacycle intermediate that is formed by the δ-C–H activation process, thereby efficiently assembling a series of spirocyclic pyrrolines with high regiocontrol. Furthermore, density functional theory (DFT) calculations and control experiments were performed to gain some insights into the reaction mechanism.

Palladium-Catalyzed Tandem Heck/Carbonylation/Aminocarbonylation En Route to Chiral Het-erocyclic α-Ketoamides

Abstract: An unprecedented tandem carbonylation/aminocarbonylation triggered by palladium-catalyzed enantioselective Heck-type exocyclopalladation delivering chiral heterocyclic α-ketoamides has been developed. The uncommon double CO insertion into the σ-alkylpalladium intermediate takes place selectively under...

Dendritic structured palladium complexes: magnetically retrievable, highly efficient heterogeneous nanocatalyst for Suzuki and Heck cross-coupling reactions

Abstract: The recyclable nanomagnetic Pd-complex PAMAM G0-Pd@γ-Fe2O3 is reported for catalytic C–C cross-coupling reactions of challenging substrates. Mainly, a great variety of aryl chlorides can be used as substrates for Suzuki–Miyaura and Mizoroki–Heck reactions under mild reaction conditions (60–90 °C) and low catalyst loading (<1 mol% Pd) in aqueous media. The presence of numerous polar groups in the polymer matrix increases the solubility of the catalyst in water, thus facilitating its operation in aqueous environments. The immobilization of the catalyst on the surface of a magnetic platform allows its effective recovery and reuse without significant loss of catalytic activity for at least six cycles with total leaching of <1% palladium metal, meeting the requirements for acceptable metal residues in the pharmaceutical industry.

Palladium-Catalyzed Cascade Heck-type Thiocarbonylation for the Synthesis of Functionalized Thioesters

Abstract: A palladium-catalyzed cascade Heck-type cyclization and carbonylation reaction has been developed for the synthesis of functionalized thioesters. With arylsulfonyl chlorides as odorless and readily available sulfur source, a variety of...

Tuning Redox States of Phenalenyl-Based Molecules by Consecutive Reduction toward Transition Metal-Free Heck-Type C–C Cross-Coupling

Abstract: Phenalenyl-based molecules can switch their redox states on successive addition of electrons from a cation to a radical to an anion. Utilizing this phenomenal ability, we have designed the first example where all three redox states have been utilized to design a Heck-type coupling reaction. In this work, we have developed a protocol where a phenalenyl moiety tunes its redox states and acts as a catalyst in Matsuda–Heck-type and Mizoroki–Heck-type coupling reactions. A wide range of substrate scopes was successfully achieved in both processes under ambient reaction conditions. Moreover, the characterization of active catalysts for both Heck-type couplings was accomplished with the help of different spectroscopic techniques. The control experiments unveiled that these catalytic processes follow a radical mechanism, and several key radical intermediates have been arrested and characterized. It was realized that the catalytic reactions are selective toward the use of mono- and doubly reduced phenalenyl species. This study implies that tuning the energy of the frontier orbital (singly occupied molecular orbital (SOMO) or highest occupied molecular orbital (HOMO)) of the reduced phenalenyl moiety plays a key role in accomplishing these reactions.

One-Pot Dual Catalysis of a Photoactive Coordination Polymer and Palladium Acetate for the Highly Efficient Cross-Coupling Reaction via Interfacial Electron Transfer.

Abstract: We report herein an exploration of the straightforward one-pot dual-catalysis strategy, i.e., direct combination of a photoactive coordination polymer (CP) with another metal catalyst, for carrying out the desirable photoinduced organic transformation. The strategy overcomes the necessity of the presynthesis of the metal/CP composite that has been demonstrated to be invalid in our case. A new two-dimensional CP showing the desirable properties of wide-range visible-light absorption and efficient photoinduced charge generation was synthesized via a solvothermal reaction. The synthesized CP was successfully applied to the photocatalytic C-C cross-coupling reaction via the one-pot dual-catalysis method, in combination with the simple and ligand-free palladium salt of Pd(OAc)2 as a metal catalyst. The reaction features a short reaction time, mild reaction conditions, good recyclability, and a high yield of Heck products from a broad variety of substrates. A comparative experiment showed the presynthesized Pd/CP composite was invalid for the reaction, demonstrating the significance of the one-pot dual-catalysis strategy. Mechanistic studies suggest the one-pot reaction depends on the synergy between the photocatalysis of a synthesized CP to generate reactive aryl radicals and Pd catalysis to generate target products, in which the interfacial electron transfer has been demonstrated to be vital for producing the transient and catalytically active Pd(0) species near the surface of the CP. The study shows the direct combination of a CP photocatalyst and a metal catalyst is a highly feasible method for the photochemical reaction and enhances the prospects of application of photoactive CPs.

Palladium-Catalyzed Heck Cyclization/Allylation with Homoallyl Alcohols via Retro-Allylation

Abstract: A palladium-catalyzed reaction of aryl iodide-tethered alkenes with homoallyl alcohol is reported, providing a convenient and efficient approach to C(sp3)-allylation product. The cascade process involves intramolecular Heck/retro-allylation. This new approach...

Selective hydrogenation catalyst made via heat-processing of biogenic Pd nanoparticles and novel ‘green’ catalyst for Heck coupling using waste sulfidogenic bacteria

Abstract: A heterogeneous Pd catalyst, biologically-mineralized palladium nanoparticles (bio-Pd), was synthesized using sulfidogenic bacteria which reduced soluble Pd(II) to catalytically-active Pd-nanoparticles (NPs). Heat treatment (processing) of bio-Pd (5 or 20 wt% on the cells) made by Desulfovibrio desulfuricans evolved supported Pd-catalyst comprising Pd-NPs held on large spherical hollow structures. The rate of hydrogenation of 2-butyne-1,4-diol was ~5-fold slower than for a commercial catalyst (~twice that of native bio-Pd), but with high selectivity to the alkene, fulfilling a key industrial criterion. In the Heck reaction, while bio-Pd showed a comparable reaction rate in ethyl cinnamate synthesis to that achieved by commercial Pd/C, heat-treated bio-Pd had negligible activity. D. desulfuricans bio-Pd was replaced by bio-Pd made using a consortium of waste acidophilic sulfidogenic bacteria (CAS) supplied from an unrelated primary remediation process. This gave comparable activity to commercial 5 wt% Pd/C in ethyl cinnamate synthesis, signposting an economic, scalable route to catalyst manufacture.

Precise electrical gating of the single-molecule Mizoroki-Heck reaction

Abstract: Abstract Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. These results extend the tuning scope of chemical reactions from the macroscopic view to the single-molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena.

Precise electrical gating of the single-molecule Mizoroki-Heck reaction

Abstract: Abstract Precise tuning of chemical reactions with predictable and controllable manners, an ultimate goal chemists desire to achieve, is valuable in the scientific community. This tunability is necessary to understand and regulate chemical transformations at both macroscopic and single-molecule levels to meet demands in potential application scenarios. Herein, we realise accurate tuning of a single-molecule Mizoroki-Heck reaction via applying gate voltages as well as complete deciphering of its detailed intrinsic mechanism by employing an in-situ electrical single-molecule detection, which possesses the capability of single-event tracking. The Mizoroki-Heck reaction can be regulated in different dimensions with a constant catalyst molecule, including the molecular orbital gating of Pd(0) catalyst, the on/off switching of the Mizoroki-Heck reaction, the promotion of its turnover frequency, and the regulation of each elementary reaction within the Mizoroki-Heck catalytic cycle. These results extend the tuning scope of chemical reactions from the macroscopic view to the single-molecule approach, inspiring new insights into designing different strategies or devices to unveil reaction mechanisms and discover novel phenomena.

Development of a C-C Bond Cleavage/Vinylation/Mizoroki-Heck Cascade Reaction: Application to the Total Synthesis of 14- and 15-Hydroxypatchoulol.

Abstract: A C-C bond cleavage/vinylation/Mizoroki-Heck cascade reaction has been developed to provide access to densely functionalized bicyclo[2.2.2]octane frameworks. The sequence proceeds through the coupling of dihydroxylated pinene derivatives, prepared from carvone, with gem-dichloroalkenes. The method was applied to 12-step total syntheses of both 14- and 15-hydroxypatchoulol, which provided unambiguous support for the structure of the natural products and corrects a misassignment in the isolation report.