Oundation” We would like to thank Ms. Inge Eisensee for data extraction. Dr. Jawaheer is supported by a Career Development Award (K01AR053496) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
Aryne insertions into C-N,1,2 C-C,3 C-Si,4 C-Sn,5 and C-Hal6 bonds and the C=O bond of aldehydes7 have been well documented in the literature. The formal insertion of a benzyne ring into the C-O bond of a carboxylic acid would provide a powerful synthetic transformation to access a range of biologically important molecules. In our previous work, we have reported that the reaction of arenecarboxylic acids with arynes in MeCN provides the corresponding aryl esters in excellent yields, i.e. the product is formed by formal benzyne insertion into the O-H bond of the starting material (Scheme 1).8 Following up on this chemistry, we found and reported in an earlier communication reaction conditions,2013 Elsevier Ltd. All rights reserved. Correspondence to: Richard C. Larock, [email protected]. Supplementary data Supplementary data related to this article can be found online at DOI. Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form.Ibezapolstat Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Ampicillin sodium Dubrovskiy and LarockPagewhich allow one to obtain good to excellent yields of the corresponding C-O insertion products.PMID:24278086 9 Later, Ma and coworkers reported an interesting cascade sequence that starts from 2,3-allenoic acids and affords chromones in good to excellent yields using KF/18crown-6 in THF.10 The present manuscript provides a complete account of the scope and limitations of the synthesis of o-hydroxyaryl ketones starting from carboxylic acids, as well as its applications to the synthesis of xanthones, 4-chromanones and flavones.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript2. Results and Discussion2.1. Synthesis of o-Hydroxyaryl Ketones We allowed a simple aliphatic carboxylic acid (butyric acid, 1) to react with the Kobayashi benzyne precursor o-(trimethylsilyl)phenyl triflate11 (2) in the presence of CsF in acetonitrile (Table 1). At both room temperature and at 65 , as expected,8 the O-arylation product, ester 4, was predominately formed (entries 1 and 2). To avoid the formation of the latter product, we switched to a far less acidic solvent, THF. To our delight, together with the monoarylation product 4, the o-hydroxyaryl ketone 3 was formed in a 26 yield (entry 3). A closer examination of the reaction mixture revealed that additional products inseparable by chromatography, namely tertiary alcohol 5 and xanthene 6, both bis-aryne insertion products, are produced (Scheme 2). Based on our findings, we propose the following mechanism for the formation of products 3-6. The aryl anion intermediate 8, formed after nucleophilic attack of the carboxylate group of the carboxylic acid on the highly electrophilic benzyne (7) generated in situ, undergoes a formal anionic Fries rearrangement to the phenoxide 10 by a four-membered ring intermediate 9.12 This results in formation of the desired o-hydroxyaryl ketone 3 after pro.