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. 2020 Feb 5;142(5):2429-2437.
doi: 10.1021/jacs.9b11944. Epub 2020 Jan 24.

Ketone Synthesis from Benzyldiboronates and Esters: Leveraging α-Boryl Carbanions for Carbon-Carbon Bond Formation

Boran Lee  1 , Paul J Chirik  1
Affiliations

Ketone Synthesis from Benzyldiboronates and Esters: Leveraging α-Boryl Carbanions for Carbon-Carbon Bond Formation

Boran Lee et al. J Am Chem Soc. .

Abstract

An alkoxide-promoted method for the synthesis of ketones from readily available esters and benzyldiboronates is described. The synthetic method is compatible with a host of sterically differentiated alkyl groups, alkenes, acidic protons α to carbonyl groups, tertiary amides, and aryl rings having common organic functional groups. With esters bearing α-stereocenters, high enantiomeric excess was maintained during ketone formation, establishing minimal competing racemization by deprotonation. Monitoring the reaction between benzyldiboronate and LiOtBu in THF at 23 °C allowed for the identification of products arising from deborylation to form an α-boryl carbanion, deprotonation, and alkoxide addition to form an "-ate" complex. Addition of 4-trifluoromethylbenzoate to this mixture established the α-boryl carbanion as the intermediate responsible for C-C bond formation and ultimately ketone synthesis. Elucidation of the role of this intermediate leveraged additional bond-forming chemistry and enabled the one-pot synthesis of ketones with α-halogen atoms and quaternary centers with four-different carbon substituents.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
In situ monitoring of the treatment of benzyldiboronate 1 with LiOtBu in THF-d8 by 1H and 11B NMR spectroscopies.
Figure 2.
Figure 2.
(A) Reactions between activated benzyldiboronates and an ester and (B) 1H NMR spectrum of each reaction.
Scheme 1.
Scheme 1.
Activation of gem-Diboronates.
Scheme 2.
Scheme 2.
Conversion of 1,1-Diboronate Esters into Functionalized Ketones.
Scheme 3.
Scheme 3.. Scope of Carbonyl Coupling Partners.
Isolated yields are reported. Conditions: 1 (1 equiv.), LiOtBu (1.5 equiv.), carbonyl derivatives (1 equiv.), THF (0.05M with respect to 1), 23 °C, 3 h. bOnly protodeboronated product 5 was observed in the NMR spectrum of the unpurified product.
Scheme 4.
Scheme 4.
Possible Mechanisms for C–C Bond Formation.
Scheme 5.
Scheme 5.. Generation of α-Boryl Carbanion 8 and the Subsequent Coupling Reaction.
Isolated yields are given. Conditions: 5 (1 equiv.), LiTMP (1 equiv.), THF (0.05 M with respect to 1), 0 °C, 30 min, then methyl butyrate (1 equiv.), rt, 3 h. See Table 1 for the reaction from 1.
Scheme 6.
Scheme 6.. One-Pot Synthesis of Highly Substituted Ketones from Benzyldiboronates.
Isolated yields are given. See SI for experimental details. aLiOtBu (1 equiv.) b13a (1 equiv.) at 0 °C, then 23 °C, 10 h. c13b (2 equiv. 80 wt.% in toluene) at 23 °C then 45 °C, 2 h. d13c (1.2 equiv.), 23 °C, 18 h. e13e (1.5 equiv.), 23 °C, 1 h. f13d (1.2 equiv.), 23 °C, 1 h. g13d (2.5 equiv.), 23 °C, 1 h. h13e (1.2 equiv.), 23 °C, 1 h. i13f (1.5 equiv.) at 23 °C, then 45 °C, 10 h.
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