Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 86, Issue 6, Pages 4671-4698Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.1c00086
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Funding
- Chulabhorn Research Institute (CRI)
- Chulabhorn Graduate Institute (CGI)
- Mahidol University
- Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education
- Thailand Research Fund (TRF) [RSA6180045]
- Royal Golden Jubilee (RGJ) scholarship program [PHD/0139/2560]
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The combination of catalytic aqueous hydrochloric acid and N-bromosuccinimide generated electrophilic bromine monochloride, facilitating the spiroannulation of 2-alkynolyl anilides to form gem-dibromospirocyclic benzo[d][1,3]oxazines in high yields. The resulted spirocyclic products contained benzo[d][1,3]oxazine, which serves as a useful pharmacophore and synthetic precursor. Additionally, base-promoted debrominative aromatization of these spirocycles led to the preparation of rare and synthetically useful 2-aryl-3-bromofurans.
The combination of catalytic aqueous hydrochloric acid (HCl) and N-bromosuccinimide (NBS) generated electrophilic bromine monochloride (BrCl), which readily induced spiroannulation of 2-alkynolyl anilides (n = 1-3) to form gem-dibromospirocyclic benzo[d][1,3]oxazines in up to 92% yield. The reaction occurred under mild and metal-free conditions using EtOAc as a green solvent. The resulted spirocyclic products contained benzo[d][1,3]oxazine, which was useful both as a pharmacophore and synthetic precursor. In addition, the current protocol allowed to effortlessly introduce the sp(3)-gem-dibromide carbon adjacent to the sterically demanding spiroketal center. These spiroheterocycles (n = 1) were shown to be synthetically versatile and conveniently maneuvered. Base-promoted debrominative aromatization of these spirocycles unmasked rare and synthetically useful 2-aryl-3-bromofurans in mostly excellent yields. These 3-bromofurans were well-suited substrates for intramolecular Ullmann C-N bond coupling to construct difficult-to-prepare 4H-furo[3,2-b]indoles. Additionally, the current protocol was flexible and adaptable to preparing the gem-dichloride variants.
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