Tertiary Alkylative Suzuki–Miyaura Couplings

Sheppard, Tom D.; Nishikata, Takashi; Tsuchiya, Naoki

doi:10.1055/a-1732-4597

Cited by 5 publications

(4 citation statements)

References 33 publications

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“…A Suzuki cross-coupling-type modification of ABB would be intriguing, being one of the most important processes in the production of pharmaceuticals, and to our knowledge is not yet reported. Nonetheless, one challenge to overcome is the disinclination of tertiary electrophiles, in our case, the ABB, toward Suzuki cross-coupling, which to date remained restricted with only a few successful reports . Inspired by the works of Fu , and Baran, and with our continuing interest in nickel catalysis, we report a nickel-catalyzed Suzuki Csp 2 –Csp 3 cross-coupling of ABBs with aryl and alkenyl boronic acids.…”

Section: Introductionmentioning

confidence: 99%

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Hsu,

Lin,

Hou

et al. 2023

J. Am. Chem. Soc.

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Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1azabicyclo[1.1.0]butane (ABB) can be harnessed for nickelcatalyzed Suzuki Csp 2 −Csp 3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr 2 ). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

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Section: Introductionmentioning

confidence: 99%

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Hsu,

Lin,

Hou

et al. 2023

J. Am. Chem. Soc.

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“…Modern pharmacophore designs are testing the limits of known chemistry such that newly emerging radical crosscoupling techniques are seeing increasing attention in drug discovery. [1] For example, the coupling of complex sp 3 hybridized tertiary carbons to (hetero)arenes to generate quaternary centers was rarely, if ever, employed a decade ago (Figure 1A). [2] In this context, canonical 2e À -crosscoupling techniques such as Suzuki-Miyaura [3] and Kumada [4][5] reactions suffer from low yields and/or poor chemoselectivity in addition to arduous preparation of organometallic reagents making them unreliable for modern medicinal chemistry campaigns.…”

Section: Introductionmentioning

confidence: 99%

“…[1] For example, the coupling of complex sp 3 hybridized tertiary carbons to (hetero)arenes to generate quaternary centers was rarely, if ever, employed a decade ago (Figure 1A). [2] In this context, canonical 2e À -crosscoupling techniques such as Suzuki-Miyaura [3] and Kumada [4][5] reactions suffer from low yields and/or poor chemoselectivity in addition to arduous preparation of organometallic reagents making them unreliable for modern medicinal chemistry campaigns. [6][7] Cross-electrophile type couplings are known in such contexts and due to their radical nature are amongst the most useful for this purpose.…”

Section: Introductionmentioning

confidence: 99%

Nickel‐Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers**

Laudadio,

Neigenfind,

Péter

et al. 2024

Angew Chem Int Ed

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There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)‐complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine‐stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross‐coupling, which is mediated by Ni(I) species via a Ni(I)‐Ni(II)‐Ni(III)‐Ni(I) catalytic cycle.

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“…However, the focus has predominantly been on primary and secondary carbon coupling partners. Integrating tertiary carbon coupling partners, such as tertiary alkyl halides, to form tetra-substituted carbon centers, presents significant challenges due to steric congestion. − The limited accessibility and apparent instability of tertiary halides − or tertiary metal reagents , further emphasize the need for new methodologies that allow C–Si cross-coupling using readily available tertiary C(sp 3 ) surrogates.…”

mentioning

confidence: 99%

From Quaternary Carbon to Tertiary C(sp³)–Si and C(sp³)–Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis

Chen,

Zheng,

Huang

et al. 2024

J. Am. Chem. Soc.

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Transition-metal-catalyzed C–Si/Ge cross-coupling offers promising avenues for the synthesis of organosilanes/organogermanes, yet it is fraught with long-standing challenges. A Ni/Ti-catalyzed strategy is reported here, allowing the use of disubstituted malononitriles as tertiary C(sp3) coupling partners to couple with chlorosilanes and chlorogermanes, respectively. This method enables the catalytic cleavage of the C(sp3)–CN bond of the quaternary carbon followed by the formation of C(sp3)–Si/C(sp3)–Ge bonds from ubiquitously available starting materials. The efficiency and generality are showcased by a broad scope for both of the coupling partners, therefore holding the potential to synthesize structurally diverse quaternary organosilanes and organogermanes that were difficult to access previously.

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Tertiary Alkylative Suzuki–Miyaura Couplings

Cited by 5 publications

References 33 publications

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Nickel‐Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers**

From Quaternary Carbon to Tertiary C(sp³)–Si and C(sp³)–Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis

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Tertiary Alkylative Suzuki–Miyaura Couplings

Cited by 5 publications

References 33 publications

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Nickel‐Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers**

From Quaternary Carbon to Tertiary C(sp3)–Si and C(sp3)–Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis

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Product

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From Quaternary Carbon to Tertiary C(sp³)–Si and C(sp³)–Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis