Strategies toward Dicarbofunctionalization of Unactivated Olefins by

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Strategies towards Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling Ramesh Giri, and Shekhar KC J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03128 • Publication Date (Web): 26 Feb 2018 Downloaded from http://pubs.acs.org on February 27, 2018

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The Journal of Organic Chemistry

Strategies towards Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling Ramesh Giri,* Shekhar KC Department of Chemistry and & Chemical Biology, The University of New Mexico, Albuquerque, New Mexico 87131, United States [email protected] Graphic Abstract:

Abstract: The use of combined Heck carbometalation and cross-coupling remains one of the most powerful ways for the difunctionalization of unactivated olefins with organometallic reagents and organohalides. This synopsis will provide an overview of this reaction developed in the last three and a half decades. Herein, both the three-component and the two-component cyclization/cross-coupling processes will be reviewed with focus on strategies utilized to overcome the complications of -hydride elimination from Heck C(sp3)-[M] intermediates, which usually functions as a major side reaction. INTRODUCTION Cross-coupling remains one of the most versatile synthetic methods for constructing a new carbon-carbon (C-C) bond.1,2 In this method, an organohalide is coupled with an organometallic reagent in the presence of a transition metal (TM) catalyst such as Pd to create a C-C bond (Scheme 1). An equally versatile method is the Heck reaction that functionalizes olefins with 1 ACS Paragon Plus Environment

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organohalides through the formation of a new C-C bond with the application of a TM-catalyst, typically Pd (Scheme 1).3 These two processes that won the Nobel prize in 2010 have relished a wide-ranging application in the synthesis and manufacturing of building blocks, bioactive molecules, natural products, drug targets, pharmaceuticals and materials.4 Integration of the cross-coupling and the Heck reaction into one synthetic platform could engender a novel and powerful synthetic method (Scheme 2), and find important applications in rapidly building molecular complexity from simple and readily available feedstock chemicals.5 Mechanistically, both processes share the first of the three elementary steps that complete their respective catalytic cycles wherein an organohalide undergoes oxidative addition (OA) to TMs in low oxidation states, generally Pd(0) or Ni(0) (represented as [M]), to generate R-MII-X.6 The second elementary step where the catalytic dichotomy begins and the third step that culminates their catalytic cycles remain unique to each reaction. The cross-coupling utilizes an organometallic reagent in the second step wherein the organic nucleophilic component is transmetalated to R-MII-X intermediates prior to the third reductive elimination step (RE) to form products. In the Heck reaction, the second step is marked by the migratory insertion (MI) of olefins into the R-MII-X bond with the generation of a new alkyltransition metal species, R’-MII-X, that eventually undergoes -hydride (-H) elimination to furnish products. The idea behind olefin dicarbofunctionalization by the joint Heck reaction/cross-coupling was to intercalate the Heck carbometalation step (MI) that generates R’-MII-X in between oxidative addition and transmetalation steps of the cross-coupling process (Scheme 3). This arrangement would create a new catalytic cycle consisting of four elementary steps – oxidative addition, carbometalation, transmetalation and reductive elimination – that can effectively difunctionalize olefins with two carbon-based entities. However, the new catalytic cycle is now prone to follow the third elementary step of the Heck reaction i.e. -H elimination, which functions as a major side reaction along with the direct cross-coupling (Scheme 3). This difficulty ingrained in the new catalytic cycle 2 ACS Paragon Plus Environment

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that requires the execution of the four elementary steps in the desired sequence of events makes the development of olefin dicarbofunctionalization by integrated Heck carbometalation/crosscoupling a fundamentally challenging process.

Scheme 1. Direct cross-coupling and Heck reaction

Scheme 2. Olefin dicarbofunctionalization

Scheme 3. Catalytic cycle and side reactions Despite fundamental complications, the concept of combining these two catalytic reactions in one synthetic platform was conceived and executed as early as 1982 by Chiusoli and Catellani when they dicarbofunctionalized norbornene with alkynes and aryl/vinyl bromides using Pd(PPh3)4 as a catalyst.7 In the last 35 years, several olefin dicarbofunctionalization reactions have been developed, which have utilized olefin substrates both as intermolecular reactants in a threecomponent process and as a tether to organohalides or organometallic reagents for a two3 ACS Paragon Plus Environment


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component cyclization/cross-coupling reaction. In this synopsis, we will look at the developments in these two areas through the lens of strategies utilized to overcome the complications of -H elimination

from

C(sp3)-[M]

intermediates,

and

mainly

focus

our

discussion

on

dicarbofunctionalization of unactivated olefins by combined Heck carbometalation and crosscoupling. THREE-COMPONENT OLEFIN DICARBOFUNCTIONALIZATION Development of three-component dicarbofunctionalization of unactivated olefins remains very challenging due to the intermolecular nature of the reactants. In the last three and a half decades, three different strategies have been exploited in order to overcome the complications of H elimination and/or direct cross-coupling that function as major side reactions – 1) use of geometrically constrained olefin substrates, 2) use of heteroatom-bearing olefins as substrates to stabilize alkyl-metal species as transient metallacycles, and 3) use of dienes or styrenes as substrates to stabilize alkyl-metal species as -allyl-[M] or -benzyl-[M] intermediates. The strategy of using geometrically constrained olefins remained popular in the early stages of reaction developments. Norbornene and norbornadiene were the most widely utilized geometrically constrained olefins to execute dicarbofunctionalization by cross-coupling with organometallic reagents after the report by Kosugi, Migita and coworkers8 in 1987 for the arylvinylation of norbornene with bromobenzene and tributylvinyltin by using Pd(PPh3)4 as a catalyst (Scheme 4).7,9 These bicyclic molecules suppress -H elimination from the Heck C(sp3)-[M] intermediates by geometrically restricting bond rotations that prevent the C(sp3)-[M] species from attaining syn-coplanarity with a -hydrogen required for -H elimination. The versatility of the Pdcatalyzed dicarbofunctionalization reactions on bicyclic molecules were also extensively demonstrated by independent examples from Catellani,10 Kang11 and Goodson12 who utilized

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organotin and organoboron reagents along with aryldiazonium salts, and aryl and vinyl halides as carbon sources.

Scheme 4. Dicarbofunctionalization of norbornene Recently, we implemented a strategy of using removable coordinating groups to intercept and stabilize the Heck C(sp3)–[M] species generated in situ during reaction via the formation of transient metallacycles (Scheme 5).13 This approach is based on the idea that -H elimination from C(sp3)-metallacycles generally proceeds much slower than from acyclic C(sp3)-[M] species because of restricted bond rotations imposed by the cyclic structures.14 In a related Pd-catalyzed two-component reaction that oxidatively homodiarylated olefins with ArB(OH)2, Larhed and coworkers also invoked similar intramolecular coordination by Me2N- group as a stabilizer of C(sp3)-[Pd]X species.15 The idea of forming C(sp3)-metallacycles in situ is also widely utilized in directed C(sp3)-C-H bond activation reactions as a way to prevent -H elimination from substrates containing -H’s.16 In coordination-assisted olefin difunctionalization, we also envisioned that the substrates could function as bidentate ligands due to the presence of the heteroatom and the olefin, which could intercept the initial oxidative addition intermediates, R-[M]-X, as species 1 (Scheme 5).13 This bidentate coordination could then enable the Heck carbometalation of R-[M]X upon the coordinated olefins to proceed much faster than the direct cross-coupling between organohalides and organometallic reagents that usually operates as a serious side reaction. Based on this concept, we recently disclosed a Ni(cod)2-catalyzed diarylation of 2vinylbenzaldehyde (Scheme 6) and 2-vinylaniline (Scheme 7)

derivatives with various aryl

halides/triflates and arylzinc reagents to furnish diarylated products in good to excellent yields.13 5 ACS Paragon Plus Environment


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In this process, we converted 2-vinylbenzaldehyde and 2-vinylaniline derivatives to their corresponding imines by reacting them with aniline and benzaldehyde, respectively, in order to utilize them as easily removable coordinating groups. The reaction proceeded with a complete regioselectivity wherein the aryl groups from aryl halides were added to the terminal carbon and the aryl groups from arylzinc reagents were attached to the internal carbon of the vinyl group. As expected, control experiments with parent 2-vinylbenzaldehyde showed that the aldehyde substrate did not form any diarylated product and remained unreacted. These control experiments indicated that the imine group was indeed critical for the transformation to proceed via the formation of five- and six-membered transient metallacycles to stabilize the Heck C(sp3)-[Ni]X intermediates, and promote the subsequent transmetalation and reductive elimination steps (Scheme 8). The imines could also be readily hydrolyzed with dilute HCl during workup without requiring a separate step for their removal after the diarylation reaction was complete to furnish 2-(1,2-diarylethyl)benzaldehyde derivatives.

Scheme 5. Coordination-assisted olefin dicarbofunctionalization

Scheme 6. Imine-assisted diarylation of 2-vinylbenzaldehydes


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Scheme 7. Imine-assisted diarylation of 2-vinylanilines

Scheme 8. Proposed catalytic cycle for imine-assisted olefin diarylation We further expanded the scope of the Ni-catalyzed coordination-assisted olefin diarylation by cross-coupling to pyridylvinylsilanes (Scheme 9).17 The pyridylsilyl moiety was utilized as a heteroatom coordinating group to intercept and stabilize the Heck C(sp3)-[Ni]X species as transient metallacycles. In this reaction, the pyridylvinylsilanes were reacted with aryl halides and arylzinc reagents to generate 1,2-diarylethylsilane derivatives, which are generally difficult to synthesize otherwise. The 1,2-diarylethylsilanes can also be readily converted by oxidation with H2O2/KF to variously substituted 1,2-diarylethanols.

Scheme 9. Pyridylsilyl-assisted diarylation of vinylsilanes 7 ACS Paragon Plus Environment


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Zhang and coworkers also invoked the coordination effect of an amide oxygen in a Ni-catalyzed tandem difluoroalkylation-arylation of vinyl groups in enamides with -bromodifluorocarbonyl compounds and arylboronic acids (Scheme 10).18 In this reaction, the amide oxygen would coordinate to the Ni-catalyst in order to intercept the alkyl radicals  to nitrogen generated after the addition of difluoroalkyl radicals to the N-vinyl group as C(sp3)-metallacycles (3). The formation of five-membered metallacycle on a carbon  to nitrogen remains critical for this reaction as similar reactions where heteroarenes containing N-allyl groups are used as substrates, the purported six-membered metallacycles undergo -H elimination/[Ni]-H reinsertion to form five-membered metallacycles as recently reported by Zhao and coworkers (Scheme 11).19 As a result, the reaction affords 1,3-diarylated products with aryl iodides and arylboronic acids. However, the reaction was also shown to be organohalide-dependent to furnish 1,3- versus 1,2addition products. A similar coordination approach for Ni-catalyzed difunctionalization was also used recently by Engle and coworkers by employing the Daugulis auxiliary (8-aminoquinoline)20 as a coordinating group for olefin bearing carboxamides (Scheme 12).21 In this reaction, olefintethered 8-aminoquinolinylamides were arylalkylated with aryl iodides and dialkylzinc reagents.

Scheme 10. Difluoroalkyl-arylation of enamides


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Scheme 11. 1,2-, 2,1- and 1,3-dicarbofunctionalization

Scheme 12. Aryl-alkylation of olefins in 8-aminoquinolinamides Another alternative approach to overcome the complications of -H elimination from the Heck C(sp3)-[M] intermediates is to stabilize them in situ as -allyl-[M] species. In this process, conjugated dienes are usually used as substrates rather than isolated olefins wherein the additional olefin of the diene forms a -allyl-[M] complex with the C(sp3)-[M] species generated after the Heck carbometalation process. For example, Oshima and coworkers showed in 2003 that a dpph/CoCl2 catalyst could catalyze the dicarbofunctionalization of conjugated dienes with Me3SiCH2MgCl and alkyl halides (Scheme 13).22 In this reaction, -H elimination was suppressed by the interception of C(sp3)-[Co] species as -allyl-[Co] intermediates (Scheme 14). The reaction is also facilitated by the ability of the Co-catalyst to generate alkyl radicals that readily add to olefins. A similar reaction with a dppf/NiCl2 was later developed by Kambe and coworkers for 1,4difunctionalization of conjugated dienes with alkyl halides and PhMgBr or PhZnCl (Scheme 15).23



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Scheme 13. 1,2-Dicarbofunctionalization of 1,3-dienes

Scheme 14. Proposed catalytic cycle for 1,2-dicarbofunctionalization of conjugated dienes

Scheme 15. 1,4-Difunctionalization of conjugated dienes The strategy of stabilizing Heck C(sp3)-[M] species as -allyl-[M] intermediates has also remained highly successful with Pd-catalysts. For example, Sigman and coworkers have recently utilized this approach for both 1,2-24 and 1,4-dicarbofunctionalization25 of conjugated dienes (Schemes 16 and 17). These reactions generally work when vinyl triflates or ArN2BF4 are used in combination with arylboronic acids as coupling partners. These reactions have also been 10 ACS Paragon Plus Environment

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proposed to proceed with the formation of -allyl-[Pd]X intermediates (Scheme 18). In those cases where isolated olefins were utilized as substrates, the Heck C(sp3)-[Pd]X intermediates usually underwent -H elimination but the reaction generally furnished 1,1-difunctionalized products (Scheme 19)24a,26 after the re-insertion of [Pd]-H’s into Heck products.27 Styrene derivatives are also known to follow a trend similar to those of the conjugated dienes wherein the Heck C(sp3)[M]X species are stabilized as -benzyl-[M] intermediates. In this respect, Song and coworkers demonstrated that Pd2(dba)3 could catalyze the 1,2-addition of vinyl triflates and arylboronic acids to styrene derivatives (Scheme 20).28

Scheme 16. 1,2-Vinyl-arylation of conjugated dienes

Scheme 17. 1,4-Vinyl-arylation of conjugated dienes



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Scheme 18. Proposed catalytic cycle for 1,2-vinyl-arylation of conjugated dienes

Scheme 19. 1,1-Vinyl-arylation of unactivated olefins

Scheme 20. 1,2-Alkenyl-arylation of styrene OLEFIN DICARBOFUNCTIONALIZATION BY CYCLIZATION/CROSS-COUPLING


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Cyclization/cross-coupling of tethered olefins with organohalides and organometallic reagents remains one of the most widely investigated olefin dicarbofunctionalization reactions. While these types of reactions are favored by the intramolecular process, the side reactions by -H elimination and direct cross-coupling still pose serious challenges for their development and scope. Over the years, five different approaches have been utilized in order to suppress -H elimination from the Heck C(sp3)-[M] intermediates during cyclization/cross-coupling – 1) use of CO to generate acylmetal species, 2) use of olefin substrates lacking in -H’s, 3) use of geometrically constrained olefin substrates, 4) use of heteroatom-bearing olefins as substrates to stabilize alkyl-metal species as transient metallacycles, and 5) use of first row late transition metals. The use of CO to generate acyl-metal species in order to suppress -H elimination has generally been applied for cyclization/esterification reactions wherein alcohols are typically used as nucleophiles.29 However, these types of reactions fall beyond the scope of this synopsis and will not be discussed. Suzuki and Miyaura demonstrated that the concept of using CO to prevent H elimination could be extended to a Pd-catalyzed carbonylative cyclization/cross-coupling of olefin-tethered alkyl halides with 9-alkyl-9-borabicyclo[3.3.1]nonane (9-alkyl-9-BBN) (Scheme 21).30 The reaction was conducted in the presence of light, which facilitated the formation of alkyl radicals and their facile addition to the tethered olefins to generate cyclized alkyl radicals (Scheme 22). These radicals were proposed to recombine with PdX to form C(sp3)-[Pd]X intermediates, which were then intercepted by CO to generate acyl-[Pd]X species to prevent -H elimination.



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Scheme 21. Carbonylative cyclization/cross-coupling

Scheme 22. Proposed catalytic cycle for carbonylative cyclization/cross-coupling An alternative and the most widely utilized strategy for cyclization/cross-coupling is the use of tethered 2,2-disubstituted terminal olefins. These olefins undergo Heck carbometalation and generate C(sp3)-[M] species lacking in -H’s. For example, Grigg and coworkers disclosed in 1997 a Pd/PPh3-catalyzed cyclization/cross-coupling of allyl ethers and amides tethered to aryl iodides with aryl- and vinylboronic acids to furnish five-membered heterocycles (Scheme 23).31 Grigg and coworkers further expanded the scope of this reaction to Stille couplings by using vinyl-, alkynyland heteroaryltin reagents (Scheme 24).32 This latter protocol could also be applied to the cyclization/cross-coupling of N-allyl-2-iodoaniline and O-allyl-2-iodophenol derivatives with complex vinyltin reagents derived from sugars, aminoacids, nucleotides and purines.33 While cyclization/cross-couplings generally furnish five-membered cyclic molecules, Wilson recently demonstrated that a Pd(0)/P(t-Bu)3-catalyst could also enable the formation of six-membered rings when 2,2-disubstituted terminal olefins tethered to 2-bromoanilines were utilized as substrates (Scheme 25).34


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Scheme 23. Cyclization/cross-coupling of 2,2-disubstituted olefins with organoboron reagents

Scheme 24. Cyclization/cross-coupling of 2,2-disubstituted olefins with organotin reagents

Scheme 25. Cyclization/cross-coupling of 2,2-disubstituted olefins to form six-membered heterocycles Cyclization/cross-coupling of tethered olefins that would generate Heck C(sp3)-[M] species bearing -H’s is also possible without having to conduct the reactions under CO atmosphere. However, these reactions generally work with olefins contained in geometrically constrained molecules. For example, Grigg and coworkers showed in a pioneering work in 1988 that a Pd/PPh3-catalyst could catalyze the dicarbofunctionalizaton of olefins in bicyclic molecules



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containing 2-iodobenzamides tethers by cyclization followed by the interception of the resultant C(sp3) -[Pd]X species with vinyl- and heteroaryltin reagents (Scheme 26).35

Scheme 26. Cyclization/cross-coupling of bicyclic molecules A few literature reports have also shown that a coordinating group present in olefin-containing molecules could assist in stabilizing Heck C(sp3)-[M] species bearing -H’s. These coordinating groups usually convert the Heck C(sp3)-[M] species into bicyclic C(sp3)-metallacycles, which slow down the process of -H elimination. The coordination-assisted stabilization of Heck C(sp3)-[M] species was first reported by Delgado and coworkers in 1994 for a stoichiometric Ni-mediated cyclization/carbonylation and cyclization/cyanation of vinyl bromides containing tethered olefins based on stereoselectivity studies and control experiments with substrates lacking appropriately located heteroatoms.36 Later, Ahn, Kim and coworkers also disclosed a similar coordination effect in a Pd-catalyzed cyclization/cross-coupling of tethered olefins in N-allyl-N-(2-bromoallyl)-4toluenesulfonamide with arylboronic acids (Scheme 27).37 In this reaction, the authors explained the success of the reaction by invoking the stabilization of cyclized C(sp3)-[Pd]X intermediates with the coordination of sulfonyl oxygen, which was believed to prevent the resultant C(sp3)metallacycle 4 from undergoing -H elimination. The authors further demonstrated that the reaction condition was also applicable to furnish five- and six-membered carbocycles and fivemembered O-heterocycles.38 However, these reactions also produced direct cross-coupling and the Heck products depending upon the nature of organoboronic acids. Therefore, there is no clear


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indication whether there is any involvement of heteroatoms for coordination assistance to stabilize the Heck C(sp3)-[Pd]X species containing -H’s that are generated as intermediates during these reactions.

Scheme 27. Cyclization/cross-coupling assisted by sulfonamide coordination We have recently shown that the use of enolates as nucleophiles instead of organometallic reagents would enable dicarbofunctionalization of unactivated olefins with aryl halides where no special consideration in substrate design is required. In this reaction, we demonstrated that Pd(dba)2 could catalyze regioselective 1,2-dicarbofunctionalization of unactivated olefins in Nallylarylacetamide derivatives bearing acidic -protons (DMSO pKa ~27) with aryl iodides (Scheme 28).39 The reaction afforded a variety of 1,3,4-trisubstituted pyrrolidinone derivatives from simple and readily available arylacetamide derivatives. The reaction condition was also applicable for the post-synthetic modifications of commercially available non-steroidal antiinflammatory drugs (NSAID), such as tolmetin and indomethacin, where the arylacetic acid side chain was decorated by installing a variety of 4-benzylpyrrolidinone scaffolds. Mechanistic studies revealed that the reaction proceeded by initial Heck reaction after -H elimination from the C(sp3)[Pd]X intermediates followed by interception of the Heck product by the intramolecular enolate (Scheme 29). This mechanistic disclosure not only showed the facile nature of -H elimination from C(sp3)-[Pd]X species that generally functioned as a serious side reaction but also the possibility under favorable conditions to exploit the process of -H elimination in a constructive manner to regioselectively dicarbofunctionalize unactivated olefins. A similar Pd-catalyzed 17 ACS Paragon Plus Environment


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cyclization/cross-coupling of olefins tethered to dicarbonyl compounds bearing acidic -protons (DMSO pKa ~13) with aryl halides was also disclosed by Balme and coworkers in 1987 that furnished cyclopentyl rings (Scheme 30).40 However, the reaction was proposed to proceed via Lewis acid activation of olefins by ArPdX followed by intramolecular attack by the tethered enolate upon the coordinated olefins (Scheme 31).41 These examples clearly demonstrate the mechanistic subtleties associated with the nature of enolate nucleophiles used in these types of olefin dicarbofunctionalization reactions. In some cases, the dependence of the reaction upon the nature of enolate nucleophiles is also reflected by the formation of the Heck products as a major byproduct along with the expected dicarbofunctionalized products.42 Balme and coworkers further expanded the scope of this reaction to form cyclohexyl rings 42a and bicyclic molecules,42b and to synthesize monounsaturated sesquiterpene, (±)-Δ9(12)-capnellene.43 More recently, Waser and coworkers also disclosed a similar cyclization/cross-coupling of olefins tethered to dicarbonyl compounds with bromoalkynylsilane.44

Scheme 28. Tandem Heck reaction/enolate cyclization of N-allylarylacetamides


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Scheme 29. Proposed catalytic cycle for the tandem Heck reaction/enolate cyclization of Nallylarylacetamides

Scheme 30. Cyclization/cross-coupling olefins tethered to dicarbonyl compounds

Scheme 31. Proposed catalytic cycle for the cyclization/cross-coupling olefins tethered to dicarbonyl compounds The use of first row late TMs such as Fe, Co, Ni and Cu has remained very successful in the cyclization/cross-coupling of tethered olefins that would generate Heck C(sp3)-[M] intermediates 19 ACS Paragon Plus Environment


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containing -H’s. Reactions with these catalysts do not require special considerations in substrate designs and reaction conditions and, therefore, display a wide substrate scope and versatility. The C(sp3)-[M] intermediates of these catalysts are believed to have a higher barrier for -H elimination and a lower barrier for reductive elimination compared to the corresponding C(sp3)[Pd]X species.6b In addition, the cyclization/cross-coupling reactions are also facilitated by the ability of these TMs to reduce organohalides by a single electron transfer (SET)2 process to generate carbon-centered radicals, which are known to undergo facile addition to unactivated olefins. In this respect, Oshima and coworkers45 disclosed in 2001 a (dppe)CoCl2-catalyzed cyclization/cross-coupling of olefin-tethered alkyl halides with aryl Grignard reagents where C(sp3)-[Co] species bearing -H’s were generated as reaction intermediates (Scheme 32).46 Mechanistic studies indicated that the reaction would proceed via the formation of alkyl radicals followed by their addition to olefins and radical recombination with the Co-catalyst to generate C(sp3)-[Co] species prior to reductive elimination (Scheme 33). Recently, a FeCl2-catalyzed variant of this reaction was also reported by Kang and coworkers.47 Similar radical cyclization/cross-coupling reactions are also known to be promoted by Ni-catalysts. For example, Cárdenas and coworkers disclosed in 2007 that a Ni/pybox system could catalyze the cyclization/cross-coupling of olefin-tethered alkyl iodides with alkylzinc reagents (Scheme 34).48 The radical nature of the reaction was proposed based on ring opening of cyclopropylmethyl iodide and interception of alkyl radicals by TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) under the reaction condition. A later report by the authors also showed that a Ni/TMEDA (N,N,N′,N′tetramethylethylenediamine) could catalyze a similar cyclization/cross-coupling reaction with alkyl Grignard reagents.49


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Scheme 32. Cyclization/arylation with aryl Grignard reagents

Scheme 33. Proposed catalytic cycle for the cyclization/arylation with aryl Grignard reagents

Scheme 34. Cyclization/alkylation with alkylzinc reagents Cyclization/cross-coupling reactions are generally performed with unactivated olefins tethered to alkyl and aryl halides. However, a few examples of similar reactions where olefins are tethered to organometallic reagents are also emerging. In this respect, we recently reported a Cu-catalyzed cyclization/cross-coupling of aryl and heteroaryl iodides with alkyl and arylzinc reagents generated in situ from the reaction of alkyl and aryl halides with Zn (Scheme 35).50 This method



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allowed us to readily access a wide range of complex cyclopentyl, pyrrolidinyl, furanyl, indanyl, indolinyl and dihydrofuranyl scaffolds.

Mechanistic studies with radical probes and

diastereoselectivity studies indicated that the alkylzinc reagents derived from alkyl halides underwent cyclization during organozinc preparation. In contrast, olefin-tethered arylzinc reagents could be readily prepared without much cyclization during organozinc preparation, which subsequently underwent radical cyclization and cross-coupling in the presence of a Cu-catalyst.

Scheme 35. Cyclization/cross-coupling of olefin-tethered alkyl and arylzinc reagents Brown and You also demonstrated that a CuBr/dppbz-Me catalyst could catalyze the cyclization/cross-coupling of olefins tethered to aryl-9-BBN reagents with aryl iodides (Scheme 36).51 In contrast to the mechanism of cyclization/arylation with olefin-tethered arylzinc reagents, this reaction proceeded with migratory insertion of olefins for cyclization followed by reaction with aryl iodides to furnish the desired products. The reaction could be rendered enantioselective with the use of CuBr/BenzP* as a chiral catalyst.52 Fu and Cong also disclosed that a Ni/diamine* catalyst could catalyze enantioselective cyclization/alkylation of olefins tethered to aryl-9-BBN with primary and secondary alkyl halides (Scheme 37).53 In this reaction, the cyclization/crosscoupling with a racemic secondary alkyl bromide also proceeded stereoconvergently in which the absolute stereochemistry of the second chiral center was controlled by the same catalyst.


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Scheme 36. Cyclization/arylation of olefin-tethered aryl-9-BBN

Scheme 37. Cyclization/alkylation of olefin-tethered aryl-9-BBN SUMMARY In conclusion, a significant progress has been made over three and a half decades in the use of the combined Heck carbometalation and cross-coupling to difunctionalize unactivated olefins with organohalides and organometallic reagents. While several strategies have been exploited since its discovery in early eighties, the more recent developments by the use of heteroatoms for coordination assistance and the first row late TMs have expanded the scope of this type of transformation to a wide range of simple molecules that generate Heck C(sp3)-[M] intermediates bearing -H’s, the most difficult class of substrates for olefin dicarbofunctionalization. These strategies have been very successful in executing dicarbofunctionalization reactions by both the three-component and the two-component cyclization/cross-coupling processes. AUTHOR INFORMATION Corresponding author *Email: [email protected]



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ORCID Ramesh Giri: 0000-0002-8993-9131 Notes: The authors declare no competing financial interests. Biographies

Ramesh Giri completed M.Sc. in Chemistry with distinction from Tribhuvan University, Nepal in 2000. He then joined the University of Cambridge, UK as a Shell Centenary Scholar where he earned M.Phil. in 2003 with Prof. J. B. Spencer. After receiving his Ph.D. in Chemistry from The Scripps Research Institute in 2009 with Prof. Jin-Quan Yu and completing postdoctoral studies with Prof. John F. Hartwig at UC Berkeley/UIUC, he joined the faculty of the Department of Chemistry & Chemical Biology at the University of New Mexico in 2012 as an Assistant Professor. His research group is interested in developing organic transformations with transition metals and investigating their mechanisms.

Shekhar KC received a master’s degree in Chemistry from Tribhuvan University in 2009. After teaching undergraduate students at St. Xavier College in Nepal, he came to the University of New Mexico in 2014 to pursue PhD in Chemistry. In 2015, he joined the Giri research group where he is conducting research on olefin difunctionalization.


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ACKNOWLEDGEMENT We thank the University of New Mexico (UNM) and the National Science Foundation (NSF CHE1554299) for financial support.

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