A Straightforward Synthesis of 4,7-Disubstituted 1,4-Oxazepanes via a Bronsted Acid-Catalyzed Intramolecular Etherification Reaction

Author(s): Juan-Carlos Castillo, Jaime Portilla, Braulio Insuasty, Jairo Quiroga, Rodrigo Abonia*

Journal Name: Current Organic Synthesis

Volume 15 , Issue 3 , 2018

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Graphical Abstract:


Aim and Objective: Although many synthetic methods are known for seven-membered N,Oheterocycles, most of them focus on fused benzoxazepines. In fact, an exhaustive searching of the literature revealed that very few synthetic approaches for non-fused 1,4-oxazepanes have been reported. Thus, straightforward and efficient synthetic strategies for the construction of diversely substituted 1,4-oxazepanes would be a welcome access to a relatively underexplored chemical space. Two of these strategies were undertaken in this study.

Materials and Methods: One of our reactions proceeded by the treatment of ethanolamines with polyformaldehyde and N-vinylpyrrolidin-2-one in ACN as solvent at room temperature in order to obtain the title 1,4- oxazepane derivatives. Alternatively, through a careful temperature control, analog structures were selectively obtained from a H2SO4 catalyzed intramolecular etherification reaction of diversely substituted N-tethered bisalcohols in p-dioxane as solvent.

Results: Based on intramolecular etherifications, two strategies (i.e. a three-component Mannich-type approach and cyclization of N-tethered bis-alcohols), were implemented for the synthesis of novel and diversely 4,7- disubstituted 1,4-oxazepanes in moderate to good yields. Structures of the new obtained compounds were confirmed by 1- and 2D NMR techniques as well as MS spectra.

Conclusion: According to the results, the above intramolecular etherification reactions proceeded with the formation of benzylic carbocations as the key intermediates for the generation of the title compounds. Temperature and the nature of the R1 substituent in the N-tethered bis-alcohols were critical variables for the selective formation of the desired products from this kind of precursors.

Keywords: Etherification reactions, N-tethered bis-alcohols, Mannich-type reactions, three-component reactions, 1, 4-oxazepanes, intramolecular cyclization.

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Article Details

Year: 2018
Page: [370 - 379]
Pages: 10
DOI: 10.2174/1570179414666171011160917
Price: $65

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