Convenient Preparation of Primary Amides via Activation of Carboxylic Acids with Ethyl Chloroformate and Triethylamine under Mild Conditions

Noguchi, Takuya; Sato, Masahiro; Yokoo, Yuki; Jung, Seunghee; Imai, Nobuyuki

doi:10.1246/cl.130096

Cited by 16 publications

(5 citation statements)

References 7 publications

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“…We attributed those difficulties to the evaporation of NH 3 from the available commercial solution. Seeking alternative and more convenient NH 3 sources that might be suitable for the present protocol of activation of the CO 2 H group, and keeping in mind to avoid the use of liquid ammonia, we found the use of NH 4 Cl solution as an advantageous option . The replacement of the NH 3 solution in THF for an aqueous solution of NH 4 Cl afforded racemic BRV in 58% overall yield from 4 (Scheme A).…”

Section: Resultsmentioning

confidence: 99%

“…Seeking alternative and more convenient NH 3 sources that might be suitable for the present protocol of activation of the CO 2 H group, and keeping in mind to avoid the use of liquid ammonia, we found the use of NH 4 Cl solution as an advantageous option. 17 The replacement of the NH 3 solution in THF for an aqueous solution of NH 4 Cl afforded racemic BRV in 58% overall yield from 4 (Scheme 6A). The use of 4 as the limiting reagent of this transformation was also tested using 3.0 equiv of the bromoacid 8; however, this condition provided BRV in only 30% yield.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

Franco,

Silva,

Rosa

et al. 2023

ACS Omega

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An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to improve the efficiency and allow an easy scale-up of the enantioselective photochemical reaction step. The intermediate obtained from the photochemical step was converted into BRV by two different pathways, followed by one alkylation and amidation, thus giving the desired active pharmaceutical ingredients (API) in 44% overall yield, 9:1 diastereoisomeric ratio (dr) and >99:1 enantiomeric ratio (er).

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

Franco,

Silva,

Rosa

et al. 2023

ACS Omega

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“…General procedure for the synthesis of primary amides ( 5 a and 5 d ). A similar protocol to that described by Imai and coworkers is followed: [23] To a solution of the triazine (0.27 mmol) in THF (3 mL) and triethylamine (0.81 mmol, 3 equiv. ), ethyl chloroformate (0.38 mmol, 1.4 equiv.)…”

Section: Methodsmentioning

confidence: 99%

Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

García-Lacuna

Baumann

2023

Adv Synth Catal

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Benzyne and related arynes are classical high‐energy species with a rich history of widespread applications in synthesis. However, despite several synthetic routes being available to generate arynes and their precursors, none represents an ideal entry to benzyne chemistry in view of safety, scalability, and sustainability. Here we report a new photochemical flow process allowing for the generation of benzyne precursors in high yields, and throughput, with easy isolation of multigram quantities of products. This process leverages a catalyst‐free photochemical rearrangement via a photoexcited nitro arene which involves a cyclic hydroxylamine intermediate that has been fully characterized. The resulting precursors were converted to benzynes via a second photochemical flow process generating heterocyclic targets upon trapping with azide and sydnone partners. Remarkably, when reacting the benzyne precursors with secondary amines, a wide range of aryl triazines is obtained in good yields via a third photo‐flow transformation. This represents a modular approach to synthesize these species, that avoids the use of potentially explosive diazonium salts. Ultimately, three photochemical flow processes using a single high‐power LED light source (365 nm, adjustable in‐put power) are presented with manifest benefits compared to batch processing. Moreover, the functionalization of a pendent carboxyl group to form sets of biologically relevant aryl triazine‐based amides highlights further applications of these unique and industrially relevant triazine entities.

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“…There has been only one previous report involving direct conversion of carboxylic acids into primary amides at room temperature using aqueous ammonium hydroxide that employed ethyl chloroformate. 16 After these promising results for primary amide synthesis, we attempted a Tf 2 O mediated one-pot conversion of carboxylic acids through to nitriles via the primary amides. This was based on the fact that Tf 2 O had been previously reported to promote conversion of primary amides into nitriles in the presence of an organic base.…”

Section: Paper Syn Openmentioning

confidence: 99%

“…This led to the conclusion that Tf 2 O is a unique reagent for promoting amide into nitrile conversion in good yield. Even ethyl chloroformate (ClCOOEt), which has been previously found to be a good reagent to promote acid into primary amide conversion, 16 did not work for amide into nitrile conversion under the given conditions (entries 8 and 9). Furthermore, Tf 2 O also demonstrated a wide substrate scope along with high level of chemoselectivity for amide into nitrile conversions, as demonstrated in Scheme 3.…”

Section: Paper Syn Openmentioning

confidence: 99%

Triflic Anhydride Promoted Synthesis of Primary Amides and their Conversion into Nitriles

Rana

Tiwari

Thakur

et al. 2018

SynOpen

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A facile, two-pot conversion of carboxylic acids into the corresponding nitriles has been developed using triflic anhydride as a promoter and aqueous NH4OH as a source of nitrogen. The methodology involves synthesis of primary amides from carboxylic acids as the key first step using triflic anhydride and aqueous NH4OH as a source of nitrogen. Triflic anhydride is also found to be an excellent reagent for conversion of primary amides into nitriles, affording high yields with considerable chemoselectivity and functional group tolerance. In spite of the mild reaction conditions and broad substrate scope for the two-step conversions, all attempts for one-pot domino conversion of acids into nitriles exhibited limited success because of poor yields.

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Convenient Preparation of Primary Amides via Activation of Carboxylic Acids with Ethyl Chloroformate and Triethylamine under Mild Conditions

Abstract: Primary amides were easily prepared in 22–99% yields from the corresponding carboxylic acids 1 or 5 with NH4Cl via activation with ClCO2Et and Et3N. The enantiomers of the corresponding primary amides of Cbz-, Boc-, or Fmoc-α-amino acids can be separated by using a chiral column.

Cited by 16 publications

References 7 publications

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions

Modular Photochemical Flow Synthesis of Structurally Diverse Benzyne and Triazine Precursors

Triflic Anhydride Promoted Synthesis of Primary Amides and their Conversion into Nitriles

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