Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents

Hirbawi, Nadia; Lin, Patricia C.; Jarvo, Elizabeth R.

doi:10.1021/acs.joc.2c01590

Cited by 4 publications

(4 citation statements)

References 76 publications

(124 reference statements)

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“…This mechanistic understanding is useful in development of a stereospecific synthesis of alkyl iodides. 21 Furthermore, the overall stereoablative reaction at the secondary center is not due to epimerization reactions of the alkyl iodide but instead due to subsequent nickel-catalyzed steps.…”

Section: Resultsmentioning

confidence: 99%

“…Both experimental and computational results demonstrate that conversion of the alkyl mesylates to the alkyl iodides occurs via a single invertive S N 2 displacement reaction. This mechanistic understanding is useful in development of a stereospecific synthesis of alkyl iodides . Furthermore, the overall stereoablative reaction at the secondary center is not due to epimerization reactions of the alkyl iodide but instead due to subsequent nickel-catalyzed steps.…”

Section: Resultsmentioning

confidence: 99%

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A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

et al. 2023

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Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

et al. 2023

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“…This involves combining an electrophile and a nucleophile in the presence of a metal catalyst, constituting a typical cross-coupling reaction . The conventional nucleophilic components are organometallic reagents derived from elements like magnesium, boron, silicon, tin, and zinc . On the other hand, the electrophiles are typically organic halides, sulfonates, and triflates .…”

Section: Introductionmentioning

confidence: 99%

Silver-Promoted Rapid Synthesis of 3-Arylindan-1-ones: Microwave-Assisted Reductive Coupling of N-Tosylhydrazone and Boronic Acids

Tamizharasan,

Santhoshkumar,

Devarajan

et al. 2024

J. Org. Chem.

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An efficient and straightforward one-pot tandem synthesis of 3-arylindan-1-ones was consummated through silver nitrate-promoted C−C coupling of simple indane-1,3-dione with arylboronic acid via 1,3-indanedione monotosylhydrazone under microwave conditions. The resulting series of 3-arylindan-1-ones exhibited impressive yields, surpassing those achievable with traditional methods and requiring a shorter time frame. This innovative approach significantly accelerated the synthesis of biologically active compounds such as (+)-indatraline (Lu 19-005) and several other industrially relevant substances.

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“…To better understand and further develop this reactivity manifold, we have examined the mechanism of the reaction . We determined that, in addition to serving as the terminal reductant, the Grignard reagent serves as a source of nucleophilic iodide and transforms dimesylate 47 to diiodide 48 in situ in a stereospecific S N 2 step . Subsequent XAT of the secondary alkyl iodide generates an alkyl radical ( 49 ) that rapidly epimerizes. , Based on radical clock experiments, this radical is consumed at a rate competitive to 5-exo-trig cyclization.…”

Section: Introductionmentioning

confidence: 99%

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

Herbert,

Jarvo

2023

Acc. Chem. Res.

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Conspectus Nickel-catalyzed reactions of alkyl alcohol derivatives leverage the high prevalence of hydroxyl groups in natural products, medicinal agents, and synthetic intermediates to provide access to C(sp3)-rich frameworks. This Account describes our laboratory’s development of stereospecific and stereoconvergent C–C bond forming reactions employing C(sp3)–O and C(sp3)–N electrophiles. In the context of development of new transformations, we also define fundamental characteristics of the nickel catalysts. Part I details the nickel-catalyzed cross-coupling reactions developed by our group which hinges on stereospecific formation of stable π-benzyl intermediates. Acyclic and cyclic ethers, esters, carbamates, lactones, and sulfonamides undergo Kumada-, Suzuki-, and Negishi-type coupling reactions to produce enantioenriched products with high fidelity of stereochemical information. We describe extension to include ring-opening reactions of saturated heterocycles to afford acyclic 1,3-fragments in high diastereomeric ratios. We also describe our advances in stereospecific nickel-catalyzed cross-electrophile coupling reactions. Tethered C–O and C–X electrophiles proved fruitful for construction of a variety of carbocyclic frameworks. We report an intramolecular cross-electrophile coupling of benzylic pivalates with aryl bromides for the synthesis of indanes and tetralins. We found that 4-halotetrahydropyrans and 4-halopiperidines readily undergo stereospecific ring contraction to afford substituted cyclopropanes. Mechanistic investigations are consistent with closed-shell intermediates, a Ni(0)/Ni(II) cycle, and an intramolecular SN2-type reaction of a key organonickel intermediate to form the cyclopropane. Building toward more complex cascade reactions, we have demonstrated that 2-alkynyl piperidines incorporate MeMgI in a dicarbofunctionalization of the alkyne to afford highly substituted vinyl cyclopropanes. In Part II we present our development of stereoconvergent reactions of alkyl alcohol derivatives. In order to expand the utility of the intramolecular XEC reaction, we sought to employ unactivated alkyl electrophiles. Specifically, alkyl dimesylates engage in intramolecular XEC reactions to form alkyl cyclopropanes. In contrast to our previous work, these reactions proceed through open-shell intermediates and favor stereoconvergent formation of the trans-cyclopropane. Enantioselective aldol reactions can be employed in syntheses of 1,3-diols which furnish enantioenriched cyclopropanes in high ee. Experimental and computational evidence reveals that MeMgI mediates formation of alkyl iodides in situ. The coupling reaction initiates with halogen atom abstraction at the secondary alkyl iodide. The alkyl Ni(II) complex then proceeds through a stereospecific SN2-type ring closure to form cyclopropane. In an effort to increase functional group compatibility in the synthesis of cyclopropanes from alkyl dimesylates we developed a zinc-mediated reaction of 1,3-dimesylates prepared from medicinal analogues. In cha...

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Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents

Cited by 4 publications

References 76 publications

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes

Silver-Promoted Rapid Synthesis of 3-Arylindan-1-ones: Microwave-Assisted Reductive Coupling of N-Tosylhydrazone and Boronic Acids

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

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