Titanocene-Catalyzed Alkylation of Aryl-Substituted Alkenes with Alkyl Halides

Terao, Jun; Watabe, Hiroyasu; Miyamoto, Masako; Kambe, Nobuaki

doi:10.1246/bcsj.76.2209

Cited by 47 publications

(7 citation statements)

References 21 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

2021

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“…In 2003, Kambe reported the titanocene-catalyzed Heck-type reaction of alkyl halides with vinyl arenes (Scheme 31). 67 The reaction proceeded efficiently at 0 °C for unactivated primary and secondary alkyl bromides and even chlorides (products 169a–e ), however, considerable amounts of by-products were observed in some cases. The Ti(III)-complex formed in situ from the Ti(IV)-catalyst and the Grignard reagent is believed to generate alkyl radicals, as well as to trap the benzylic radical intermediate towards an alkyl Ti(IV) species 170 , which upon β-H elimination delivers the Heck product 169 .…”

Section: Other Metals In Heck-type Reactionsmentioning

confidence: 99%

Transition-Metal-Catalyzed Alkyl Heck-Type Reactions

Kurandina¹,

Chuentragool²,

Gevorgyan

2019

Synthesis

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The Heck reaction is one of the most reliable and useful strategies for the construction of C–C bonds in organic synthesis. However, in contrast to the well-established aryl Heck reaction, the analogous reaction employing alkyl electrophiles is much less developed. Significant progress in this area was recently achieved by merging radical-mediated and transition-metal-catalyzed approaches. This review summarizes the advances in alkyl Heck-type reactions from its discovery early in the 1970s up until the end of 2018.1 Introduction2 Pd-Catalyzed Heck-Type Reactions2.1 Benzylic Electrophiles2.2 α-Carbonyl Alkyl Halides2.3 Fluoroalkyl Halides2.4 α-Functionalized Alkyl Halides2.5 Unactivated Alkyl Electrophiles3 Ni-Catalyzed Heck-Type Reactions3.1 Benzylic Electrophiles3.2 α-Carbonyl Alkyl Halides3.3 Unactivated Alkyl Halides4 Co-Catalyzed Heck-Type Reactions5 Cu-Catalyzed Heck-Type Reactions6 Other Metals in Heck-Type Reactions7 Conclusion

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“…While the use of aryl or vinyl electrophiles in these coupling reactions has been widely demonstrated, recent efforts have successfully extended the scope to include unactivated alkyl electrophiles . Owing to the general difficulty in activating alkyl electrophiles using transition metal catalysts, this has typically required either: 1) the use of alkyl iodides,, or 2) the use of strongly reducing conditions (e.g., alkylmetal reductants) –. Recent efforts in our group have led to the development of a general palladium‐catalyzed carbocyclization of unactivated primary and secondary alkyl bromides under mild conditions .…”

Section: Figurementioning

confidence: 99%

Nickel‐Catalyzed Mizoroki–Heck‐Type Reactions of Unactivated Alkyl Bromides

Kwiatkowski

Alexanian

2018

Angewandte Chemie

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The development of ag eneral, nickel-catalyzed alkyl-Mizoroki-Heck reaction of unactivated alkylbromides is described. The mild reaction proceeds efficiently using aw ide range of primary and secondary alkyl bromides,and examples of intermolecular cross-couplings are provided. Reaction alkene regioselectivity is significantly enhanced over prior carbocyclizations using palladium catalysis.Mechanistic investigations are consistent with ad irect carbocyclization in contrast to the auto-tandem atom-transfer cyclization and halide elimination previously observed with palladium catalysis.

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Titanocene-Catalyzed Alkylation of Aryl-Substituted Alkenes with Alkyl Halides

Cited by 47 publications

References 21 publications

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

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

Transition-Metal-Catalyzed Alkyl Heck-Type Reactions

Nickel‐Catalyzed Mizoroki–Heck‐Type Reactions of Unactivated Alkyl Bromides

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