Ligand-Metal Cooperation Enables C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

Gilbert, Michael M.; Trenerry, Michael; Longley, Victoria; Berry, John F.; Weix, Daniel J.

doi:10.33774/chemrxiv-2021-hjdbr

Cited by 3 publications

(4 citation statements)

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“…Sterically hindered zinc reagents, such as orthosubstituted arylzincs and 2°alkyl zinc reagents, coupled in low yields under these conditions. Comparison with related ringopening alkylations that proceed via nickeladihydropyran (Scheme 4C), reported after our initial disclosure of these results, 27,75,76 are informative on how mechanistic differences can lead to differences in reactivity and scope. Those reactions are able to couple alkyl bromides instead of alkylzinc reagents, but are limited to monofunctionalization (γ-functionalization) of aryl cyclopropyl ketones.…”

Section: Exclusion Of Mechanisms Involving Uncatalyzed Ring-opening H...mentioning

confidence: 98%

“…18,24 We show here a new, cooperative mechanism for cyclopropane C−C activation that includes aspects of both strategies: charge transfer from the terpyridine ligand to the substrate followed by concerted asynchronous ring-opening and Ni−C bond formation (Scheme 1C). 27,28 Because Me 3 Si + (TMS + ) activation of the carbonyl is required for this step, the resulting C−C activation/cross-coupling reactions result in regio-and stereospecific functionalization of both carbons (via cross-coupling and silyl enol ether formation) instead of monofunctionalization. By taking advantage of advances in cyclopropyl ketone synthesis, these new reactions allow for access to intermediates that are difficult to access using conventional conjugate addition reactions.…”

Section: ■ Introductionmentioning

confidence: 99%

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Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

et al. 2023

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Reactions that cleave C–C bonds and enable functionalization at both carbon sites are powerful strategic tools in synthetic chemistry. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of 3-carbon fragments, but general approaches to net C–C activation/difunctionalization are unknown. Herein, we demonstrate the cross-coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. A combination of experimental and theoretical studies rules out more established mechanisms and sheds light on how cooperation between the redox-active terpyridine (tpy) ligand and the nickel atom enables the C–C bond activation step. The reduced (tpy·–)NiI species activates the C–C bond via a concerted asynchronous ring-opening transition state. The resulting alkylnickel(II) intermediate can then be engaged by aryl, alkenyl, and alkylzinc reagents to furnish cross-coupled products. This allows quick access to products that are difficult to make by conjugate addition methods, such as β-allylated and β -benzylated enol ethers. The utility of this approach is demonstrated in the synthesis of a key (±)-taiwaniaquinol B intermediate and the total synthesis of prostaglandin D1.

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Section: Exclusion Of Mechanisms Involving Uncatalyzed Ring-opening H...mentioning

confidence: 98%

Section: ■ Introductionmentioning

confidence: 99%

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

et al. 2023

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“…However, stoichiometric formation of organometallic reagents (e.g., Mg, Li) imposes limitations on synthetic design, and the relatively harsh conditions, causing air sensitivity and low chemoselectivity, also do not meet the standard toward sustainability . For these reasons, catalytic carbonyl arylation has been widely explored, and elegant examples have been achieved using different transition metal catalysts, such as rhodium, − chromium, , cobalt, and nickel − (Figure A, up). Nevertheless, most transformations are still limited to aryl iodides or aryl boronic acids .…”

Section: Introductionmentioning

confidence: 99%

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis

et al. 2022

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The formation of carbon–carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy toleratesamong othersacidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

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“…These experiments are consistent with a mechanism involving free-radical intermediates, in analogy to prior studies on nickel-catalyzed processes with both alkyl halides or redox-active esters. , Similarly, ring opening was observed in couplings of cyclopropanecarboxaldehyde ( 13 ) leading to product 14 exclusively as the Z -isomer (Scheme C). In this case, we attribute ring-opening of the cyclopropane unit to a nickel-catalyzed process involving the intermediacy of 15 , potentially involving the initial oxidative addition of a low-valent nickel species to the aldehyde, promoted by Et 3 SiCl. , An experiment employing stoichiometric Ni(cod) 2 but lacking the zinc reductant resulted in the formation of product 3a in high yield, suggesting that key organonickel intermediates involved in product formation do not require reduction at the nickel center but rather that the zinc reductant is involved in catalyst regeneration (Scheme D).…”

mentioning

confidence: 95%

Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes

Xiao

Montgomery

2021

J. Am. Chem. Soc.

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The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.Cross-coupling reactions have revolutionized the landscape of carbon-carbon bond construction, with extensive application in the synthesis of natural products, pharmaceuticals, agrochemicals, and functionalized polymers. 1 Coupling of Grignard or organolithium reagents with carbonyl compounds remains among the most frequently used synthetic reactions (Figure 1A), 2 although limitations exist due to the instability, basicity, and lack of functional group compatibility of the requisite highly nucleophilic reagents. Barbier-type reactions 3 and Nozaki-Hiyama-Kishi (NHK) 4 couplings are attractive as they avoid the handling of air-and moisture-sensitive organometallic reagents, and have been employed in many complex settings, 5 although the reaction scope is often limited in cases where sp 3 alkyl fragments are added to aliphatic enolizable aldehydes.An attractive approach to deliver organohalide feedstocks to carbonyl compounds that obviates the need for preformed organometallic reagents are transition-metal-catalyzed reductive coupling reactions. 6 To date, the coupling of aldehydes with organohalides using a stoichiometric reducing agent can be catalyzed by Cr, 7 Rh, 8 Co, 9 and Ni, 10 but current systems are often restricted to aryl, allylic or propargylic halides and aromatic aldehydes. The catalytic transformation of aliphatic aldehydes with less-activated sp 3 counterparts remains a synthetic challenge. 7c-e,11 Aliphatic aldehydes often exhibit attenuated reactivity, and competing enolization reactions lead to side product formation. 10d Additionally, compared with sp 2 -hybridized halides, unactivated alkyl halides are less suitable coupling partners due to lower reactivity and undesirable side pathways such as homocoupling or competing b-H eliminations of reactive intermediates. 12 The wide availability of alkyl carboxylic acids makes this substrate class an attractive coupling partner for processes of this type. 13 In recent studies, Baran, Weix, and others have extensively explored the utility of redox-active esters (RAEs), as a carboxylic acid-derived radical precursors in a variety of carbon-carbon and carbon-heteroatom bon...

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Ligand-Metal Cooperation Enables C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

Cited by 3 publications

References 36 publications

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis

Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes

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