Practical preparation of challenging amides from non-nucleophilic amines and esters under flow conditions

Vrijdag, Johannes; Delgado, Francisco; Alonso, Nerea; Borggraeve, Wim M. De; Pérez-Macías, Natalia; Alcázar, Jesús

doi:10.1039/c4cc07129h

Cited by 46 publications

(28 citation statements)

References 21 publications

(2 reference statements)

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“…A particularly important conversion is the transformation of esters into amides34, which are key components of peptides and proteins, as well as privileged molecules in medicinal chemistry5, as exemplified in some top-selling drugs such as Harvoni, Januiva, Glivec and Symbicort6. Direct amidation of esters with amines typically requires stoichiometric amounts of promoters or metal mediators78910 (Fig. 1a).…”

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confidence: 99%

Direct amidation of esters with nitroarenes

2017

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Esters are one of the most common functional groups in natural and synthetic products, and the one-step conversion of the ester group into other functional groups is an attractive strategy in organic synthesis. Direct amidation of esters is particularly appealing due to the omnipresence of the amide moiety in biomolecules, fine chemicals, and drug candidates. However, efficient methods for direct amidation of unactivated esters are still lacking. Here we report nickel-catalysed reductive coupling of unactivated esters with nitroarenes to furnish in one step a wide range of amides bearing functional groups relevant to the development of drugs and agrochemicals. The method has been used to expedite the syntheses of bio-active molecules and natural products, as well as their post-synthetic modifications. Preliminary mechanistic study indicates a reaction pathway distinct from conventional amidation methods using anilines as nitrogen sources. The work provides a novel and efficient method for amide synthesis.

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confidence: 99%

Direct amidation of esters with nitroarenes

2017

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“…2-Methyl-substituted oxazole ester 14 was prepared by a convenient one-pot procedure based on the work of Benoit and co-workers. [19] Unfortunately, in this investigation, the latter protocol could not be used to couple esters 14 and 18 with amines due to dominant side reactions resulting from the acidic nature of the 5-oxazole proton. [18] Extension of the latter method allows the incorporation of a wide variety of aromatic and conjugated aldehydes into 2,4-disubstituted oxazoles that are otherwise not readily accessible or require a multistep synthesis.…”

Section: Resultsmentioning

confidence: 94%

“…Previously, we developed a base-mediated protocol to prepare challenging amides from non-nucleophilic amines and esters under flow conditions. [19] Unfortunately, in this investigation, the latter protocol could not be used to couple esters 14 and 18 with amines due to dominant side reactions resulting from the acidic nature of the 5-oxazole proton. [20] With the oxazole building blocks and derived acyl chlorides 16 and 20 in hand, we turned our attention to the synthesis of tertiary pyridinamide cyclisation precursors 23a-f, 26a,b, 29a,b, 32a,b (Schemes 3 and 4).…”

Section: Resultsmentioning

confidence: 99%

Towards New Tricyclic Motifs: Intramolecular C–H Arylation as the Key Step in a Formal [3+3] Cyclocondensation Strategy

2017

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Tricyclic scaffolds structurally related to the well‐known benzodiazepine class of drugs show diverse biological activities strikingly different from those of their benzodiazepine counterparts. Interested by this scaffold‐hopping perspective, we previously developed a continuous‐flow method for the conversion of benzodiazepinediones into oxazoloquinolinones. Attempted extension of this synthetic route to the corresponding oxazolonaphthyridinone scaffolds met with limited success, however. This encouraged us to develop a different approach to pyridine‐based tricyclic motifs. In line with our interest in scaffold hopping, in this paper we describe a general, convergent [3+3] cyclocondensation approach to [1,3]oxazolo[4,5‐c]‐1‐naphthyridin‐4(5H)‐ones. The key synthetic steps in this approach are: (1) the construction of an amide linkage connecting two peripheral heterocycles; and (2) a palladium‐catalysed intramolecular C–H arylation to complete the tricyclic scaffold.

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“…Thea nalogous base-promoted amidation [17] was also feasible using either LiOMe or NaOMe as base in aM eOH/ PhCH 3 mixed solvent system. Theoptimized flow process led to both shorter residence time and milder temperature compared to the acid-mediated method (Scheme 6).…”

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confidence: 99%

7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

et al. 2018

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Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapyf or the treatment of HIV,has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir,D TG was produced in 4.5 hi n sequential flowoperations from commercially available materials.Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of afunctionalized pyridone,and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

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Practical preparation of challenging amides from non-nucleophilic amines and esters under flow conditions

Cited by 46 publications

References 21 publications

Direct amidation of esters with nitroarenes

Direct amidation of esters with nitroarenes

Towards New Tricyclic Motifs: Intramolecular C–H Arylation as the Key Step in a Formal [3+3] Cyclocondensation Strategy

7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

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