Base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates to 4-alkylidene-2-oxazolidinones

The base catalyzed cyclization of N-aryl and N-alkyl-O-propargyl carbamates is studied in detail. The effect of various bases and solvents on the efficacy of this cyclization reaction is analyzed and a new base-solvent system (LiOH in DMF) for effective cyclization of these carbamates is reported. A number of differentially substituted O-propargyl carbamates were cyclized to the corresponding 2-oxazolidinones under these conditions. The reaction conditions reported here are mild and no side reactions were observed in any of the substrates studied. A propargyl carbonate group was unaffected during the course of the cyclization of the O-propargyl carbamate group. The propargyl carbamates were prepared from the corresponding alkyl or aryl amines and the corresponding propargyl chloroformate, resulting in oxazolidinones diversely substituted at the nitrogen atom. N-Aryl-O-propargyl carbamates cyclized readily to the corresponding oxazolidinones with LiOH in DMF, whereas N-alkyl-O-propargyl carbamates reacted slowly under the same conditions. O-Propargyl carbamates substituted at the 1-position tend to cyclize faster whereas those substituted at 3-position cyclize considerably slower than the unsubstituted carbamates.     

Regioselective synthesis of pyridoquinolones and pyridocoumarins via molecular iodine-mediated 6-endo-dig electrophilic cylization

Angular-pyridoquinolone and pyridocoumarin derivatives have been efficiently synthesized in 60-95% yields by molecular iodine-mediated cyclization of easily available starting materials, 6-(N-propargyl)amino quinolone and coumarin derivatives, in the presence of NaHCO₃. The reaction was carried out at room temperature.     

Transition metal-catalyzed pentannulation of propargyl acetates via styrylcarbene intermediates

The indene formation from phenyl-substituted sec- and tert-propargyl esters (terminal alkynes) was achieved by platinum or ruthenium catalysis via E-vinylcarbenoid intermediate. Considering the competitive reactions of pentannulation versus cyclopropanation, the equilibrium ratios of E and Z vinylcarbenoid intermediates from sec- and tert-propargyl esters are estimated at ca. 10:90 and 40:60, respectively. Two reaction pathways, Nazarov-type cyclization and/or metallacycle from styrylcarbenoid species, are proposed by considering ratios of products in the control experiment.     

Synthesis of novel 3-bromo-1,2-dihydroquinolines via palladium mediated intramolecular cyclization of N-tosyl-N-propargyl anilines

Facile synthesis of novel 3-bromo-1,2-dihydroquinolines by the intramolecular cyclization of N-tosyl-N-propargyl anilines catalyzed by Pd(OAc)₂ in conjunction with CuBr₂ and LiBr.     

Synthesis of crescent shaped heterocycle-fused aromatics via Garratt-Braverman cyclization and their DNA-binding studies

Three crescent shaped heterocycle-fused phenanthrene based systems 1–3 have been synthesized starting from benzene (or substituted benzene) 1,2-bis-propargyl alcohols. Bis-alkylation with propargylic bromides provided the key intermediate, the bis-propargyl bis-ethers. In spite of the possibility of many competing reactions, the latter underwent facile double Garratt-Braverman cyclization to provide compounds 1–3 in near quantitative yield, in a striking reaction involving the formation of four C–C bonds in a single step. Compounds 1–3 showed binding interaction with DNA, predominantly, via groove binding along with partial intercalation (combilexins). Molecular docking study supported the proposed binding modes.     

Silver-Free Au(I) Catalysis Enabled by Bifunctional Urea- and Squaramide-Phosphine Ligands via H-Bonding

A library of gold(I) chloride complexes with phosphine ligands incorporating pendant (thio)urea and squaramide H-bond donors was prepared with the aim of promoting chloride abstraction from Au(I) via H-bonding. In the absence of silver additives, complexes bearing squaramides and trifluoromethylated aromatic ureas displayed good catalytic activity in the cyclization of N-propargyl benzamides, as well as in a 1,6-enyne cycloisomerization, a tandem cyclization-indole addition reaction and the hydrohydrazination of phenylacetylene. Kinetic studies and DFT calculations indicate that the energetic span of the reaction is accounted by both the chloride abstraction step, facilitated by the bidentate H-bond donor via an associative mechanism, and the subsequent cyclization step.     

Aza-Morita–Baylis–Hillman reaction with ion-supported Ph3P

Various N-tosyl arylimines reacted with methyl vinyl ketone and ethyl vinyl ketone in the presence of ion-supported Ph₃P A and B to give adducts, N-(2′-methylene-3′-oxo-1′-arylbutyl)-4-methylbenzenesulfonamides and N-(2′-methylene-3′-oxo-1′-arylpentyl)-4-methylbenzenesulfonamides, respectively, in good yields with high purity by simple diethyl ether extraction of the reaction mixture. Moreover, ion-supported Ph₃P A and B could be repeatedly used for the same reaction to provide the corresponding adducts while maintaining good yields with high purity.     

Phosphine-catalyzed enantioselective [3+2] annulations of 2,3-butadienoates with imines

The first systematic screening of chiral phosphines in the cycloaddition reaction between 2,3-butadienoates and arylimines has led to the identification of fairly efficient catalysts. 2-Aryl-3-pyrrolines have been obtained with enantiomeric excesses up to 64%. In one instance, the enantiomeric excess could be increased to 91% ee by combining the enantioselective cyclization reaction with a crystallization step.     

meso-Phbox-Pd(II) catalyzed tandem carbonylative cyclization of 1-ethynyl-1-propargyl acetate

Palladium(ii) catalyzed carbonylation of 1-ethynyl-1-propargyl acetate is described; in the absence of the bisoxazoline (box) ligand, the second triple bond did not react, affording cyclic orthoesters and . The use of meso-Phbox-Pd(ii) strikingly changed the course of the reaction, yielding bicyclic lactone by tandem carbonylative cyclization as a result of insertion of the second triple bond.     

Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via radical-mediated cascade cyclization

A two-step synthesis of rare 2-azabicyclo[2.2.2]octanes is described. N-propargyl amides obtained via Cu(I)-catalyzed three-component coupling, underwent radical-mediated cascade cyclization to afford 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes with arylidene functionality on the two-carbon bridge in 43–62% yields. Phenylidene and 1-naphtylidene derivatives were obtained exclusively as Z diastereomers, whereas electron rich groups in the arylidene substituent afforded product mixtures favoring the Z diastereomer by 2.3:1 M ratio.     

New synthetic approach to substituted isoindolo[2,1-a]quinoline carboxylic acids via intramolecular Diels-Alder reaction of 4-(N-furyl-2)-4-arylaminobutenes-1 with maleic anhydride

Acylation of substituted 4-(furyl-2)-4-arylaminobut-1-enes with maleic anhydride provided 2-allyl-6-carboxy-4-oxo-3-aza-10-oxatricyclo[5.2.1.0^1,5]dec-8-enes in high yield under mild reaction conditions. The Diels-Alder adducts are formed via an initial amide formation followed by a stereoselective intramolecular [4+2] exo-cycloaddition reaction. Treatment of the tricyclic compounds with phosphoric acid at high temperatures (70-120 °C) promoted cyclic ether opening, intramolecular cyclization and aromatization to give the corresponding tetracyclic compounds, 5,6,6a,11-tetrahydro-10-carboxyisoindolo[2,1-a]quinolines, in moderate yields. The influence of the acid and the reaction temperature on the cyclization reactions are also discussed.     

Iodine/CuI-mediated alkyne–carbonyl metathesis reaction: synthesis of 1-aryl-1,2-dihydrochromeno[2,3-b]azepine-3,6-dione

Iodine/cuprous iodide-mediated intramolecular alkyne–carbonyl metathesis reaction has been developed using 2-(N-aryl-N-propargyl)aminochromone-3-carbaldehyde as the substrate. It led to the synthesis of hitherto unreported chromeno[2,3-b]azepine-3,6-dione. The special features of this methodology are mild reaction conditions, 100% atom economy and use of inexpensive reagents. This is the first example of I₂/CuI-mediated alkyne–carbonyl metathesis reaction.     

Synthetic scope, computational chemistry and mechanism of a base induced 5-endo cyclization of benzyl alkynyl sulfides

We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring. Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the formation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium methoxide. Geometries were optimized with CAM-B3LYP/6-311+G(d,p) in acetonitrile with the CPCM solvent model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former. From benzyl(propa-1,2-dien-1-yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base that undergoes 5-endo-trig cyclization followed by a protonation step.     

Acetal-vinyl sulfide cyclization on sugar substrates: effect of structure and substituent

A range of 2-deoxyfuranoside and -pyranoside derivatives were fashioned into derivatives that carry a vinyl or propenyl side chain. Extension of the alkene by a Suzuki cross-coupling reaction with 1-bromo-1-(phenylthio)ethene gave thioenol ethers as the cyclization substrates. The treatment of these substrates with BF(3).Et(2)O in tert-butylmethyl ether below 0 degrees C induced cyclization to optically active bicyclic ethers. If the cyclizations are carried out in toluene as the solvent, the isomerization of the terminal thioenol ether to the inner thioenol ether can take place prior to the cyclization. The cyclization reactions can be impeded by steric and electronic factors. The opening of the bicyclic ethers could be illustrated with the base-induced conversion of the ketone 53 to the cyclooctenone 54.     

Poly(aryl ether phenylquinoxalines) via anionic ring opening polymerization of macrocycles

A cyclic poly(aryl ether phenylquinoxaline) was prepared via the self-polymerization of 1 in an N-methyl-2-pyrrolidone (NMP) solution containing base using a pseudo-high dilution polymerization condition. The macrocycle formation of 1 was carried out in the presence of potassium carbonate in a NMP/toluene solvent mixture at a solids content of 1%. The water generated by phenoxide formation was removed as an azeotrope with toluene 170 °C. A concentrated solution of the macrocycle was added to the reaction mixture over an 8 hour period. The reaction was allowed to proceed for an additional 24h to ensure quantitative reaction. A number of characterization techniques were used to study the cyclization of 1 including GPC, HPLC, H NMR and matrix-assisted laser desorption ionization (MALDI) mass spectroscopy. The MALDI-TOF mass spectrum of the cyclization of 1 clearly showed that a mixture of macrocycles is obtained, with the expected distribution of molecular weights. Facile ring opening polymerization of the cyclic poly(aryl ether phenylquinoxaline) oligomers was accomplished with a nucleophilic initiator. High polymer was obtained for each polymerization temperature (η = 0.4–0.5 dl/g in NMP), however, prolonged reaction time resulted in significant gel formation. The Tg's were high and commensurate with the high molecular weight linear analog (250 °C).     

Total synthesis of 7-desmethoxyfusarentin and its methyl ether

A concise total synthesis of 7-desmethoxyfusarentin and its methyl ether has been accomplished involving a sequence of reactions such as Prins cyclization, ring opening of tetrahydropyran ring and Alder-Rickerts reaction as key steps. This is the first report on the construction of anti-1,3-diol unit of 7-desmethoxyfusarentin by means of Prins cyclization.     

2-Alkylindoles via palladium-catalyzed reductive cyclization of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates

The reaction of ethyl 3-(o-trifluoroacetamidophenyl)-1-propargyl carbonates with formate anions in the presence of Pd(PPh₃)₄ affords 2-alkylindoles in good to excellent yields.     

Selective formation of dihydropyran derivatives by a tandem domino ring-closing metathesis/cross-metathesis

A ring-closing metathesis (RCM)/cross-metathesis (CM) domino reaction has been applied to esters and unsymmetrical ether prepared from 1,5-hexadien-3-ol. For the first time, dihydropyran derivatives have been obtained via a regioselective cyclization. This reaction was performed in high yield and E stereoselectivity.     

Total synthesis of (+)-eupomatilone 2 via asymmetric [2,3]-Wittig rearrangement of highly oxygenated biphenylmethyl ethers

We have achieved the total synthesis of (±)- and (+)-eupomatilone 2 isolated from the Australian shrub Eupomatia bennettii. The key reaction was an asymmetric [2,3]-Wittig rearrangement employing a bis(oxazoline) chiral ligand. Although the highly oxygenated biphenylmethyl ether exhibited considerably lowered enantioselectivity as compared with the non-substituted biphenylmethyl ether, the selectivity was improved to 89% ee by using n-BuLi and ether as the base and the co-solvent, respectively.     

Alkyl radical cyclization to vinylogous carbonates for the stereoselective synthesis of unsymmetrical dioxa-cage compounds: effect of conformation on the rate of cyclization versus reduction

An efficient strategy for the stereoselective construction of unsymmetrical dioxa-cage compounds containing ether linkages employing a 6-exo-trig alkyl radical cyclization to vinylogous carbonates is developed. The radical precursors are prepared from the diols obtained from the Diels-Alder adducts via iodoetherification followed by addition of the alcohol to the ethyl propiolate. The geometrical constrains play important role in deciding the outcome of the reaction as cyclization versus simple reduction. Formation of the mono-oxa-cage compounds via a 5-exo-trig intramolecular alkyl radical cyclization to olefin is also described. The dioxa-cages could also be assembled employing a tandem oxymercuration reduction-radical cyclization to vinylogous carbonates protocol with equal efficiency and with reduced number of steps.