Palladium-Catalyzed Cross-Coupling of <i>N</i>-Sulfonylaziridines and Alkenylboronic Acids: Stereospecific Synthesis of Homoallylic Amines with Di- and Trisubstituted Alkenes

Teh, Wei Pin; Michael, Forrest E.

doi:10.1021/acs.orglett.7b00504

Cited by 24 publications

(9 citation statements)

References 22 publications

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“…Aziridines have been employed successfully as C(sp 3 ) electrophiles in a number of cross-coupling reactions. Work from our lab and those of Michael, Jamison, Takeda/Minakata, May, and Xiao have demonstrated that coupling reactions with aziridines can afford access to substituted ethylamines, important nitrogen-containing motifs in medicinal chemistry (Figure B) . Organometallic nucleophiles such as organozinc halides or organoboron reagents have been employed as coupling partners to form both C(sp 3 )–C(sp 2 ) and C(sp 3 )–C(sp 3 ) bonds (Figure B, top).…”

Section: Introductionmentioning

confidence: 97%

Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Dongbang

Doyle

2022

J. Am. Chem. Soc.

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Aziridines are readily available C(sp 3 ) precursors that afford valuable β-functionalized amines upon ring opening. In this article, we report a Ni/photoredox methodology for C(sp 3 )−C(sp 3 ) cross-coupling between aziridines and methyl/1°/2°aliphatic alcohols activated as benzaldehyde dialkyl acetals. Orthogonal activation modes of each alkyl coupling partner facilitate cross-selectivity in the C(sp 3 )−C(sp 3 ) bondforming reaction: the benzaldehyde dialkyl acetal is activated via hydrogen atom abstraction and β-scission via a bromine radical (generated in situ from single-electron oxidation of bromide), whereas the aziridine is activated at the Ni center via reduction. We demonstrate that an Ni(II) azametallacycle, conventionally proposed in aziridine cross-coupling, is not an intermediate in the productive cross-coupling. Rather, stoichiometric organometallic and linear free energy relationship studies indicate that aziridine activation proceeds via Ni(I) oxidative addition, a previously unexplored elementary step.

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Section: Introductionmentioning

confidence: 97%

Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Dongbang

Doyle

2022

J. Am. Chem. Soc.

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“…In particular Kauffmann and co-workers have prepared homoallylic amines by allylation of 2-azaallyl anions using allyl bromide as an electrophile 34 . Homoallylic amines are incredibly useful precursors for the synthesis of a vast number of biologically active molecules 11,[35][36][37][38][39][40][41][42][43][44][45][46][47][48] . Economical methods to prepare homoallylic amines remain in demand.…”

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confidence: 99%

Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms

et al. 2021

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Allylation of nucleophiles with highly reactive electrophiles like allyl halides can be conducted without metal catalysts. Less reactive electrophiles, such as allyl esters and carbonates, usually require a transition metal catalyst to facilitate the allylation. Herein, we report a unique transition-metal-free allylation strategy with allyl ether electrophiles. Reaction of a host of allyl ethers with 2-azaallyl anions delivers valuable homoallylic amine derivatives (up to 92%), which are significant in the pharmaceutical industry. Interestingly, no deprotonative isomerization or cyclization of the products were observed. The potential synthetic utility and ease of operation is demonstrated by a gram scale telescoped preparation of a homoallylic amine. In addition, mechanistic studies provide insight into these C(sp3)–C(sp3) bond-forming reactions.

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“…Similar reaction conditions are applicable to the C3-selective ring-opening alkenylation of 2-alkylaziridines, which enables the syntheses of homoallylic amines (Scheme 12). 39 It is noted that the coupled products serve as useful synthetic precursors for 2,5dialkylpyrrolidines through acid-mediated diastereoselective intramolecular hydroamination across the CC bonds.…”

Section: C3-selective Ring-opening Arylation and Alkenylation Of 2-al...mentioning

confidence: 99%

Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies

2020

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Metrics & MoreArticle Recommendations CONSPECTUS: Aziridines, i.e., the smallest saturated N-heterocycles, serve as useful building blocks in synthetic organic chemistry. Because of the release of the large ring strain energy accommodated in the small ring, (ca. 27 kcal/mol), aziridines undergo ring-opening reactions with a variety of nucleophiles. Therefore, among the synthetic reactions utilizing aziridines, regioselective ring-opening substitutions of aziridines with nucleophiles, such as heteroatomic nucleophiles (e.g., amines, alcohols, and thiols) and carbonaceous nucleophiles (e.g., carbanions, organometallic reagents, and electron-rich arenes), constitute a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. However, the regioselection in such traditional ring-opening substitutions of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging to achieve, especially in the case of Lewis acid-promoted variants. Therefore, the development of robust catalytic ring-opening functionalization methods that enable precise prediction of regioselectivity and stereochemistry is desirable. In this direction, our group focused on the highly regioselective and stereospecific nature of the stoichiometric oxidative addition elementary step of 2-substituted aziridines into Pd(0) complexes in an S N 2 fashion. In conjunction with the recent advancements in transition-metal-catalyzed cross-coupling reactions of alkyl pseudohalides containing a C(sp 3 )−Q (Q = O, N, S, etc.) bond, aziridines can be used as nonclassical alkyl pseudohalides in regioselective and stereospecific cross-couplings.In this Account, starting from the background of transition-metal-catalyzed ring-opening functionalization of aziridines, our contributions to the palladium-catalyzed regioselective and stereoinvertive cross-couplings of aziridines with organoboron reagents to form C(sp 3 )−C, C(sp 3 )−B, and C(sp 3 )−Si bonds have been compiled. The developed methods allow the syntheses of medicinally important amine compounds, e.g., enantioenriched β-phenethylamines, β-amino acids, and their boron and silyl surrogates, from readily available enantiopure aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst (i.e., Pd/NHC vs Pd/PR 3 systems). Computational studies rationalized the detailed mechanisms of the full catalytic cycle and the regioselectivity and stereospecificity of the reactions. The computational results suggested that the interactions operating between the Pd catalyst and aziridine substrate play important roles in determining the regioselection of the aziridine ring-opening event (i.e., oxidative addition). Also, the computational results rationalized the role of water molecules in promoting the transmetalation step through the formation of a Pd−hydroxide active intermediate. This Account evidences the benefits of synergistic collaborations between experimental and computational met...

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Palladium-Catalyzed Cross-Coupling of N-Sulfonylaziridines and Alkenylboronic Acids: Stereospecific Synthesis of Homoallylic Amines with Di- and Trisubstituted Alkenes

Cited by 24 publications

References 22 publications

Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms

Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies

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Palladium-Catalyzed Cross-Coupling of N-Sulfonylaziridines and Alkenylboronic Acids: Stereospecific Synthesis of Homoallylic Amines with Di- and Trisubstituted Alkenes

Cited by 24 publications

References 22 publications

Ni/Photoredox-Catalyzed C(sp3)–C(sp3) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Ni/Photoredox-Catalyzed C(sp3)–C(sp3) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Transition-metal-free allylation of 2-azaallyls with allyl ethers through polar and radical mechanisms

Palladium-Catalyzed Regioselective and Stereospecific Ring-Opening Cross-Coupling of Aziridines: Experimental and Computational Studies

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Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors

Ni/Photoredox-Catalyzed C(sp³)–C(sp³) Coupling between Aziridines and Acetals as Alcohol-Derived Alkyl Radical Precursors