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. 2022 Sep 21;7(39):35269-35279.
doi: 10.1021/acsomega.2c04653. eCollection 2022 Oct 4.

Synthesis of 7-Aminocoumarins from 7-Hydroxycoumarins via Amide Smiles Rearrangement

Daniel S Lippe  1 , Omar Elghawy  1 , Adam M Zucker  1 , Evan S K Yanagawa  1 , Erin Mathews  1 , Yusef G Ahmed  1 , Paige N D'Elia  1 , Sabrina Bimson  1 , Ryan R Walvoord  1
Affiliations

Synthesis of 7-Aminocoumarins from 7-Hydroxycoumarins via Amide Smiles Rearrangement

Daniel S Lippe et al. ACS Omega. .

Abstract

N-Substituted 7-aminocoumarins can be synthesized from readily available 7-hydroxycoumarins via alkylation with α-bromoacetamides and subsequent tandem O → N Smiles rearrangement-amide hydrolysis. The key rearrangement sequence proceeds under mild conditions to provide convenient access to various N-alkyl and N-aryl products in moderate to high yields. The process is operationally simple, inexpensive, transition-metal-free, and can be telescoped into a one-pot process.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Methods for synthesizing 7-aminocoumarins: (a) Pechmann condensation of aminophenols, (b) Buchwald–Hartwig cross-coupling of sulfonylated hydroxycoumarins, and (c) amination of coumarin ethers via Smiles rearrangement–hydrolysis.
Scheme 1
Scheme 1. Synthesis of Acetamide-Linked Coumarin Substrates
Scheme 2
Scheme 2. Substrate Scope of Amines and 7-Hydroxycoumarins in the Tandem Rearrangement–Hydrolysis Reaction
Reactions were performed on a 0.31 mmol scale. Yields refer to isolated yields following column chromatography. bReaction was performed under standard conditions, followed by HCl, EtOH, 90 °C for 5 h. cReaction was performed at 100 °C for 30 h.
Scheme 3
Scheme 3. One-Pot Alkylation–Rearrangement–Hydrolysis Sequence
Figure 2
Figure 2
Mechanistic studies: (a) treatment of tertiary amide 4oa with standard reaction conditions, (b) stepwise analysis of the rearrangement–hydrolysis sequence of 4da via NMR monitoring, and (c) formation of the unhydrolyzed intermediate when applying standard reaction conditions to primary amide 4na.
Scheme 4
Scheme 4. Proposed Mechanism
See this image and copyright information in PMC

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