Synthesis of 2,5-Bis(hetero)aryl 4′-Substituted 4,5′-Bisoxazoles via Copper(I)-Catalyzed Domino Reactions of Activated Methylene Isocyanides with 2‑Phenyl- and 2‑(2-Thienyl)-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-5(4<i>H</i>)‑ones

An efficient straightforward synthesis of 2,5,4′-trisubstituted 4,5′-bisoxazoles via copper­(I)-catalyzed domino reactions of 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)­methylene]-5-oxazolones with activated methylene isocyanides has been reported. The overall domino process comprised of formation of one C–C and two C–O bonds involves initial nucleophilic ring opening of oxazolones by cupriomethylene isocyanides followed by sequential construction of two oxazole rings in the presence of copper catalyst. The broad substrate scope and excellent functional group compatibility of the reaction has been demonstrated by employing a variety of heteroaryl- and aryl-substituted oxazolones and activated methylene isocyanides, yielding bisoxazoles with three potential points of diversity. A probable mechanism for this novel copper-catalyzed domino process has been proposed

Synthesis of Thieno-Fused Five- and Six-Membered Nitrogen and Oxygen Heterocycles via Intramolecular Heteroannulation of 4,5-Substituted 3‑Amino or 3‑Hydroxy 2‑Functionalized Thiophenes

Diverse general high-yield routes for novel thieno-fused five- and six-membered nitrogen and oxygen heterocycles such as thieno­[3,2-<i>b</i>]­pyrroles, thieno­[3,2-<i>b</i>]­furans, thieno­[3,2-<i>b</i>]­indoles, thieno­[3,2-<i>b</i>]­benzofurans, thieno­[3,2-<i>b</i>]­pyridine-5-ones, thieno­[3,2-<i>b</i>]­pyran-5-ones, thieno­[3,2-<i>b</i>]­isoquinolin-5-ones, thieno­[3,2-<i>b</i>]­chromen-5-ones, thieno­[3,2-<i>b</i>]­quinolin-9-ones, and thieno­[3,2-<i>b</i>]­chromen-9-ones have been developed via in situ or stepwise intramolecular heteroannulation of newly synthesized 4,5-substituted 3-amino- or 3-hydroxy 2-functionalized thiophenes. These substituted 3-amino/hydroxythiophenes were readily obtained in high yields from easily accessible precursors, in a sequential one-pot process, by treatment of a range of (het)­aryl/unsubstituted acetonitriles or acetates with (het)­aryl dithioesters in the presence of LDA, followed by in situ alkylation–intramolecular condensation of the resulting enethiolate salts with functionalized activated methylene halides. The functionalized activated methylene halides employed in these reactions for the synthesis of various thieno-fused heterocycles were cinnamyl bromide, 2-bromobenzyl chloride, bromocrotonate, 2-(bromomethyl)­benzoate, and 2-chlorophenacyl bromide. A few of the 4,5-substituted 3-amino/hydroxy-2-stryrylthiophenes (or 2-acrylates) displayed strong fluorescence, and their absorption/emission spectra have also been examined

Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α‑Oxoketene Dithioacetals and β‑(Methylthio)-β-(het)aryl-2-propenones

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)­aryl/(methylthio)­enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)­enones were converted to the corresponding α-bromo-β-(methylthio)­enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)­aryl/alkyl-4-(het)­aroyl-5-(methylthio)/(het)­aryloxazoles via concomitant formation of the C4–N and C5–O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)­arylenones were subjected to base induced conjugate addition–elimination with various primary amides to furnish β-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C–H functionalization/C–O bond formation, afforded the corresponding regioisomeric 2-(het)­aryl/alkyl-4-(methylthio)/(het)­aryl-5-(het)­aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-(<i>n</i>-butyl)­oxazoles from the corresponding 4- or 5-(methylthio)­oxazoles

Sequential One-Pot Synthesis of Tri- and Tetrasubstituted Thiophenes and Fluorescent Push–Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)­aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)­aryl active methylene ketones with (het)­aryl dithioesters followed by <i>S</i>-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of <i>S</i>-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push–pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent

One-Pot Synthesis of Functionalized Benzo[<i>b</i>]thiophenes and Their Hetero-Fused Analogues via Intramolecular Copper-Catalyzed S‑Arylation of In Situ Generated Enethiolates

An efficient one-pot synthesis of highly functionalized multisubstituted benzo­[<i>b</i>]­thiophenes and their hetero-fused analogues, such as thieno­[2,3-<i>b</i>]­thiophenes, indolo­[2,3-<i>b</i>]­thiophenes, and pyrazolo­[3,2-<i>c</i>]­thiophenes, has been reported. The overall strategy involves sequential base-mediated condensation of 2-bromohet­(aryl)­acetonitrile precursors with (het)­aryl/alkyl dithioesters or other thiocarbonyl species such as dimethyl trithiocarbonate, <i>S</i>-methyl xanthates, methyl <i>N</i>-imidazolyl dithioate, <i>N</i>-alkyl dithiocarbamate, and phenyl isothiocyanate, followed by intramolecular copper-catalyzed arylthiolation of in situ generated enethiolates, furnishing a broad range of 2-functionalized 3-cyanobenzo­[<i>b</i>]- and/hetero-fused thiophenes in high yields

One-Pot Synthesis of 2‑(Het)aryl/alkyl-3-cyanobenzofurans from 2‑(2-Bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles and Benzyl Carbamate

A one-pot synthesis of 2-(het)­aryl/alkyl-3-cyanobenzofurans has been reported. The overall sequence involves base-induced reaction of 2-(2-bromoaryl)-3-(het)­aryl-3-(methylthio)­acrylonitriles with benzyl carbamate, generating α-(het)­aroyl-α-(2-bromoaryl)­acetonitriles, which are in situ subjected to copper-catalyzed intramolecular <i>O</i>-arylation, furnishing the 2-(het)­aryl/alkyl-3-cyanobenzofurans in high yields. A probable mechanism for the base-induced cleavage of 2-(2-bromoaryl)-3-(het)­aryl-3-(methylthio)­acrylonitriles to α-(het)­aroyl-α-(2-bromoaryl)­acetonitriles in the presence of benzyl carbamate has been proposed

One-Pot Synthesis of 2‑(Het)aryl/alkyl-3-cyanobenzofurans from 2‑(2-Bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles and Benzyl Carbamate

A one-pot synthesis of 2-(het)­aryl/alkyl-3-cyanobenzofurans has been reported. The overall sequence involves base-induced reaction of 2-(2-bromoaryl)-3-(het)­aryl-3-(methylthio)­acrylonitriles with benzyl carbamate, generating α-(het)­aroyl-α-(2-bromoaryl)­acetonitriles, which are in situ subjected to copper-catalyzed intramolecular <i>O</i>-arylation, furnishing the 2-(het)­aryl/alkyl-3-cyanobenzofurans in high yields. A probable mechanism for the base-induced cleavage of 2-(2-bromoaryl)-3-(het)­aryl-3-(methylthio)­acrylonitriles to α-(het)­aroyl-α-(2-bromoaryl)­acetonitriles in the presence of benzyl carbamate has been proposed

Additional file 2: of Steroids in fluid and/or vasoactive infusion dependent pediatric shock: study protocol for a randomized controlled trial

Summary of mechanistic studies. This table summarizes the mechanistic studies that will be performed as part of the STRIPES pilot study, including the rationale, timing, and amount of blood sample required for each test. (PDF 202 kb