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. 2017 Sep 22;3(9):e1701028.
doi: 10.1126/sciadv.1701028. eCollection 2017 Sep.

Borate esters: Simple catalysts for the sustainable synthesis of complex amides

Marco T Sabatini  1 , Lee T Boulton  2 , Tom D Sheppard  1
Affiliations

Borate esters: Simple catalysts for the sustainable synthesis of complex amides

Marco T Sabatini et al. Sci Adv. .

Abstract

Chemical reactions for the formation of amide bonds are among the most commonly used transformations in organic chemistry, yet they are often highly inefficient. A novel protocol for amidation using a simple borate ester catalyst is reported. The process presents significant improvements over other catalytic amidation methods in terms of efficiency and safety, with an unprecedented substrate scope including functionalized heterocycles and even unprotected amino acids. The method was used to access a wide range of functionalized amide derivatives, including pharmaceutically relevant targets, important synthetic intermediates, a catalyst, and a natural product.

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Figures

Fig. 1
Fig. 1. Approaches to amide bond formation.
(A) Conventional methods for amidation proceeding via an activated carboxylic acid. (B) Recent catalytic amidations using group IV metal or boronic acid catalysts. THF, tetrahydrofuran. (C) Borate ester–catalyzed amide bond formation. TAME, tert-amyl methyl ether; PhMe, toluene.
Fig. 2
Fig. 2. Towards a borate-catalyzed amide coupling.
(A) Proposed catalytic cycle for amidation. (B) Catalyst selection. (C) Time course of borate amidation with different boron catalysts.
Fig. 3
Fig. 3. Scope of borate-catalyzed amide bond formation.
(A) Secondary amides. (B) Tertiary amides. (C) Challenging amides. (D) Amino acid amides. mol %, mole percent; Boc, tert-butoxycarbonyl. Reactions run according to general procedure A for 24 hours unless stated otherwise. *Amide synthesized using 20 mole percent (mol %) B(OCH2CF3)3. †Reaction performed in PhMe instead of TAME. ‡Amide synthesized using 1 mol % B(OCH2CF3)3. §Amide synthesized using 5 mol % B(OCH2CF3)3.
Fig. 4
Fig. 4. Chemoselective amide bond formation from amino acids.
(A) Chemoselective amino acid couplings. (B) Sequential amidation/condensation to form imidazolidinones. dr, diastereomeric ratio. Reactions run according to general procedures B and C for 24 hours unless stated otherwise. *Using 30 mol % B(OCH2CF3)3. †Using 2 equiv. of amine. ‡Using 1.2 equiv. of benzylamine.
Fig. 5
Fig. 5. Application to the synthesis of APIs.
Reactions run according to general procedures A or B for 24 hours unless stated otherwise. *Using 1.5 equiv. of homopiperazine. †Using 2 equiv. of H-Gly-OttBu. ‡Using 1.0 equiv. of B(OCH2CF3)3.
Fig. 6
Fig. 6. Environmental metrics for catalytic amidation reactions.
(A) PMI calculations for a selection of catalytic amide bond formation processes. MIBA, 5-methoxy-2-iodophenylboronic acid. (B) Improved PMIs of large-scale borate-catalyzed amidation procedures.
Fig. 7
Fig. 7. Mechanism of the amidation reaction.
(A) Proposed mechanism. (B) Low reactivity of a trifluoroethyl ester acylating agent. Sol, solvent.
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