Hypotensive activity.30 It is also an effective inhibitor of cutaneous plasma

Hypotensive activity.30 It is also an effective inhibitor of cutaneous plasma extravasation31 and a monoamine oxidase inhibitor.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptReacting o-fluorobenzoic acid with 4,5-dimethylbenzyne and unsymmetrical 3methoxybenzyne under our CsF/THF optimized conditions afforded the corresponding xanthones 28 and 29 in 47 and 71 yields, respectively (entries 8 and 9). The low yield in the former case may be attributed to the poor solubility (and hence isolation complications) of the desired product 28. The unsymmetrical benzyne precursor provided the product 29 as a single regioisomer.33 2.3. Synthesis of 4-Chromanones and Flavones The phenolate anion (see intermediate 10 in Scheme 2) formed in situ could also be potentially trapped with a Michael acceptor in an intramolecular fashion. This would open up a novel route to biologically interesting 4-chromanones, flavones, and chromones from readily available acrylic and propiolic acids.34 Indeed, in the reaction of methacrylic acid with benzyne under the optimized reaction conditions used in the synthesis of o-hydroxyaryl ketones, the 4-chromanone 30 was formed in a moderate 58 yield.Avapritinib Surprisingly, none of the dihydrocoumarin product that could result from the ring closure of an intermediate like 8 was detected, which suggests that the formation of the 4-membered ring intermediate is a more favorable pathway. None of the uncyclized hydroxyaryl ketone product was detected either, suggesting a very fast rate of cyclization for the final Michael addition reaction. Running the methacrylic acid reaction in the presence of various bases (e.g. Cs2CO3, Et3N, iPr2NEt, sym-collidine) failed to improve the yield of the reaction. Substituting the substrate with either the TES- or TBDMS-esters of methacrylic acid both afforded the desired product in lower yields. Running the reaction at decreased temperatures and/or switching the solvent to DME resulted in a lower yield of the desired product. After additional optimization, we have found that diluting the reaction mixture helps to improve the yield of the 4-chromanone 30 by 10 . Apparently, one of the side reactions involves an intermolecular process. One of the significant challenges observed in this transformation is the poor reactivity of the starting carboxylic acid. As a result, running the reaction with 1.5 equiv of the benzyne precursor does not lead to complete conversion of the starting carboxylic acid.35 Running the reaction with 2.0 equiv of the precursor 2 allows the carboxylic acid to react completely. However, it also results in increased amounts of overarylation products (e.g. an alcohol analogous to intermediate 5 in Scheme 2). Running the reaction under dilute conditions with 1.Zidebactam 75 equiv of the benzyne precursor provides an 80 yield of the desired product 30.PMID:24118276 Finally, adding the benzyne precursor and CsF in two separate portions allowed us to improve the yield up to 84 .36 The latter reaction conditions were applied to a number of other 2-alkenoic acids (Table 4). 3-Alkyl-substituted acrylic acids successfully provided the corresponding cyclohexylsubstituted and propyl-substituted 4-chromanones 31 and 32 in 85 and 82 yields, respectively (entries 2 and 3). The carboxylic acid with a nitrile substituent at the end of an alkyl chain provided the 4-chromanone 33 in a 71 yield (entry 4). 3,3-Dialkyl-substituted acrylic acids (3-methyl-2-butenoic acid and geranic acid) prov.