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. 2022 Oct 5;144(39):17815-17823.
doi: 10.1021/jacs.2c02817. Epub 2022 Sep 22.

Copper-Catalyzed Coupling of Alkyl Vicinal Bis(boronic Esters) to an Array of Electrophiles

Ningxin Xu  1 , Ziyin Kong  1 , Johnny Z Wang  1 , Gabriel J Lovinger  1 , James P Morken  1
Affiliations

Copper-Catalyzed Coupling of Alkyl Vicinal Bis(boronic Esters) to an Array of Electrophiles

Ningxin Xu et al. J Am Chem Soc. .

Abstract

A neighboring boronate group in the substrate provides a dramatic rate acceleration in transmetalation to copper and thereby enables organoboronic esters to participate in unprecedented site-selective cross-couplings. This cross-coupling operates under practical experimental conditions and allows for coupling between vicinal bis(boronic esters) and allyl, alkynyl, and propargyl electrophiles as well as a simple proton. Because the reactive substrates are vicinal bis(boronic esters), the cross-coupling described herein provides an expedient new method for the construction of boron-containing reaction products from alkenes. Mechanistic experiments suggest that chelated cyclic ate complexes may play a role in the transmetalation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.. Scope of the Cu-catalyzed cross-coupling of vicinal bis(boronates) and organic electrophiles.
Yields are of isolated material after purification by column chromatography. Enantiomer ratio (er) determined by chiral HPLC or SFC analysis. The oxidation step was omitted for compounds 21, 29, and 30. A loading of 30 mol% CuCN was employed for section k.
Figure 2.
Figure 2.. Mechanistic aspects of the Cu-catalyzed coupling reaction.
a. A general catalytic cycle of reaction of vicinal bis(boronates). b. Stoichiometric reaction of substrates with CuOtBu shows a rate enhancement for reaction of bis(boronates) versus monoboronates. c. Reaction of labeled substrate indicates the coupling proceeds with retention of configuration at carbon. d. Inhibition of the coupling by 12-crown-4 suggests that lithium ion is required for the reaction. e. Substrate activation does not occur when the adjacent boronate is a less Lewis acidic diazaborole. f.-h. Treatment of organoboronic esters with potassium methoxide relative to boron suggests the intermediacy of internally chelated borates. i.-k. GIAO-DFT-based chemical shift calculations are consistent with the assignment of cyclic chelated ate complexes. Methods/basis sets are for calculation of isotropic shielding constants; geometry optimizations were by B3LYP(D3)/6–311G(d), B3LYP/cc-pVDZ, or M06–2x/6–31+G(dp). See Supporting Information for details.
Figure 3.
Figure 3.. DFT Calculations.
a. Ground state and transition state structures for the reaction of methoxide-activated EtB(pin) B3LYP-D3/Def2SVP//B3LYP-D3/6–311++G** with PCM (THF) solvent model. b. Calculated barrier for transmetalation of methoxide-activated EtB(pin). c. Ground state and transition state structures for the reaction of methoxide-activated vicinal diboronate 5. d. Calculated barrier for transmetalation of methoxide-activated vicinal diboronate 5.
Figure 4.
Figure 4.. Application of the Cu-catalyzed coupling reaction to targets of interest.
(a) Preparative scale tandem diboration/copper-catalyzed coupling. (b) Synthesis of (R)-arundic acid by diboration, coupling, hydrogenation, homologation and oxidation. (b) Construction of 1,4 dioxygenated motifs by two sequential diboration/coupling tandem reactions. (c) Construction of a precursor to anquicyclinones by alkyne coupling.
Scheme 1.
Scheme 1.. Issues in Diboration of Alkenes and Subsequent Coupling
See this image and copyright information in PMC

References

    1. Zhang JS; Liu L; Chen T; Han LB Transition-Metal-Catalyzed Three-Component Difunctionalizations of Alkenes. Chemistry–An Asian Journal 2018, 13, 2277–2291. - PubMed
    2. Derosa J; Apolinar O; Kang T; Tran VT; Engle KM Recent Developments in Nickel-Catalyzed Intermolecular Dicarbofunctionalization of Alkenes. Chem. Sci. 2020, 11, 4287–4296. - PMC - PubMed

    1. Catalytic enantioselective alkene diboration: Morgan JB; Miller SP; Morken JP Rhodium-Catalyzed Enantioselective Diboration of Simple Alkenes. J. Am. Chem. Soc. 2003, 125, 8702–8703.Trudeau S; Morgan JB; Shrestha M; Morken JP Rh-Catalyzed Enantioselective Diboration of Simple Alkenes: Reaction Development and Substrate Scope. J. Org. Chem. 2005, 70, 9538–9544.Kliman LT; Mlynarski SN; Morken JP Pt-Catalyzed Enantioselective Diboration of Terminal Alkenes with B2pin2. J. Am. Chem. Soc. 2009, 131, 13210–13211.Coombs JR; Haeffner F; Kliman LT; Morken JP Scope and Mechanism of the Pt-Catalyzed Enantioselective Diboration of Monosubstituted Alkenes. J. Am. Chem. Soc. 2013, 135, 11222–11231.Toribatake K; Nishiyama H Asymmetric Diboration of Terminal Alkenes with a Rhodium Catalyst and Subsequent Oxidation: Enantioselective Synthesis of Optically Active 1,2–Diols. Angew. Chem. Int. Ed. 2013, 52, 11011–11015.Fang L; Yan L; Haeffner.; Morken, J. P. Carbohydrate-Catalyzed Enantioselective Alkene Diboration: Enhanced Reactivity of 1,2-Bonded Diboron Complexes. J. Am. Chem. Soc. 2016, 138, 25082511.Yan L; Meng Y; Haeffner F; Leon RM; Crockett MP; Morken JP Carbohydrate/DBU Cocatalyzed Alkene Diboration: Mechanistic Insight Provides Enhance Catalytic Efficiency and Substrate Scope. J. Am. Chem. Soc. 2018, 140, 3663–3673.

    1. For alternate catalytic enantioselective routes to vicinal diboronates, see: Lee Y; Jang H; Hoveyda AH Vicinal diboronates in high enantiomeric purity through tandem site-selective NHC–Cucatalyzed boron–copper additions to terminal alkynes. J. Am. Chem. Soc. 2009, 131, 18234–18235.Radomkit S; Liu Z; Closs A; Mikus MS; Hoveyda AH Practical, efficient, and broadly applicable synthesis of readily differentiable vicinal diboronate compounds by catalytic three-component reactions. Tetrahedron 2017, 73, 5011–5017.Morken JB; Morken JP Catalytic Enantioselective Hydrogenation of Vinyl Bis(boronates). J. Am. Chem. Soc. 2004, 126, 15338–15339.

    1. Miller SP; Morgan JB; Nepveux FJ; Morken JP Catalytic Asymmetric Carbohydroxylation of Alkenes by a Tandem Diboration/Suzuki Cross-Coupling/Oxidation Reaction. Org. Lett. 2004, 6, 131–133. - PubMed
    2. Mlynarski SN; Schuster CH; Morken JP Asymmetric Synthesis from Terminal Alkenes by Cascades of Diboration and Cross-Coupling. Nature 2014, 505, 386–390. - PMC - PubMed
    3. Willems S; Toupalas G; Reisenbauer JC; Morandi B A Site-Selective and Stereospecific Cascade Suzuki–Miyaura Annulation of Alkyl 1,2-Bis-Boronic Esters and 2,2′-Dihalo-1,1′-biaryls. Chem. Commun. 2021, 57, 3909–3912. - PubMed
    1. Fawcett A; Nitsch D; Ali M; Bateman JM; Myers EL; Aggarwal VK; Regio-and Stereoselective Homologation of 1, 2-Bis (Boronic Esters): Stereocontrolled Synthesis of 1, 3-Diols and Sch 725674. Angew. Chem. Int. Ed. 2016, 128, 14883–14887. - PMC - PubMed
    2. Fawcett A; Murtaza A; Gregson CH; Aggarwal VK Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines. J. Am. Chem. Soc. 2018, 141, 4573–4578. - PubMed

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