1-(2'-Anilinyl)prop-2-yn-1-ol rearrangement for oxindole synthesis.

A synthetic method that relies on NIS (N-iodosuccinimide)-mediated cycloisomerization reactions of 1-(2'-anilinyl)prop-2-yn-1-ols to gem-3-(diiodomethyl)indolin-2-ones and 2-(iodomethylene)indolin-3-ones has been developed. The reactions were shown to be chemoselective, with secondary and tertiary alcoholic substrates exclusively giving the 3- and 2-oxindole products, respectively. In the case of the latter, the transformation features an unprecedented double 1,2-OH and 1,2-alkyl migration relay. Density functional theory (DFT) calculations based on proposed iodoaminocyclization species provide insight into this unique divergence in product selectivity.

Study of substrate dependence on the chemoselectivity of the gold-catalysed cycloisomerisation of aryl substituted 1,7-enynes.

The effects of starting material substitution patterns on reaction selectivity for the gold(I)-catalysed cycloisomerisations of aryl substituted 1,7-enynes were investigated. The results indicated the chemoselectivity of the reaction to be highly substrate and catalyst dependent. Either the piperidine or the tetrahydro-1H-azepine product was obtained in moderate to excellent yields depending on the steric and/or electronic nature of the substrate and the gold(I) catalyst. Overall, six-membered nitrogen ring formation was found to be favoured in reactions with 1,7-enyne derivatives containing a disubstituted alkene moiety or not bearing a sterically bulky substituent or a gold(I) catalyst with a pendant sterically unencumbered phosphine ligand. Formation of the seven-membered nitrogen heterocycle was observed in reactions where the substrate contained a tetrasubstituted alkene unit or a sterically demanding substituent.

Silver acetate catalyzed hydroamination of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols to (Z)-2-methylene-1-sulfonylindolin-3-ols.

A method to prepare (Z)-2-methylene-1-sulfonylindolin-3-ols efficiently that relies on silver acetate catalyzed hydroamination of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols is reported. The reactions proceed rapidly at room temperature with catalyst loadings as low as 1 mol % under conditions that did not require the exclusion of air or moisture. The utility of this N-heterocyclic ring-forming strategy as a synthetic tool that makes use of unsaturated alcohols was exemplified by the conversion of the (Z)-2-methylene-1-sulfonylindolin-3-ol to examples of other members of the indole family of compounds.

Brønsted acid-catalyzed cycloisomerization of but-2-yne-1,4-diols with or without 1,3-dicarbonyl compounds to tri- and tetrasubstituted furans.

A Brønsted acid-catalyzed method to prepare tri- and tetrasubstituted furans efficiently from cycloisomerization of but-2-yne-1,4-diols with or without 1,3-dicarbonyl compounds is described. By taking advantage of the orthogonal modes of reactivity of the alcoholic substrate through slight modification of the reaction conditions, a divergence in product selectivity was observed. At room temperature, p-TsOH·H(2)O-mediated tandem alkylation/cycloisomerization of the propargylic 1,4-diol with the ß-dicarbonyl compound was found to selectively occur to provide the tetrasubstituted furan product. On the other hand, increasing the reaction temperature to 80 °C was discovered to result in preferential p-TsOH·H(2)O-catalyzed dehydrative rearrangement of the unsaturated alcohol and formation of the 2,3,5-trisubstituted furan adduct.

Gold-catalyzed cycloisomerization of 1,7-diyne benzoates to indeno[1,2-c]azepines and azabicyclo[4.2.0]octa-1(8),5-dines.

A synthetic method that relies on Au(I)-catalyzed cycloisomerization reactions of 1,7-diyne benzoates to prepare indeno[1,2-c]azepines and azabicyclo[4.2.0]octa-1(8),5-dines is described.

Silver triflate catalyzed tandem heterocyclization/alkynylation of 1-((2-tosylamino)aryl)but-2-yne-1,4-diols to 2-alkynyl indoles.

Don't cross me! 2-Alkynyl indoles were prepared efficiently by the AgOTf-catalyzed tandem heterocyclization/alkynylation of 1-(2-tosylamino)aryl)but-2-yne-1,4-diols under mild conditions (see scheme). The attractiveness of this approach lies in the fact that both the indole ring and alkyne side chain of the N-heterocycle are sequentially formed from low cost, readily available, and ecologically benign starting materials. It also provides the first route to this synthetically valuable class of compounds that is not based on a cross-coupling strategy.

Gold-catalyzed cycloisomerizations of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols to 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols.

A method to prepare 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols by gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols with N-iodosuccinimide (NIS) is reported. The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in good to excellent yields (70-99%). The mechanism is suggested to involve activation of the alkyne moiety of the substrate by the gold(I) catalyst. This triggers intramolecular addition of the tethered aniline moiety to give a vinyl gold intermediate, which undergoes iododeauration with NIS to give the (E)-2-(iodomethylene)indolin-3-ol adduct. Subsequent 1,3-allylic alcohol isomerization (1,3-AAI) followed by formylation of this vinyl iodide intermediate then gives the 1H-indole-2-carbaldehyde.

Cyclopropyl carbinol rearrangement for benzo-fused nitrogen ring synthesis.

A synthetic method that relies on gold-catalysed cyclopropyl carbinol rearrangement of 2-tosylaminophenyl cyclopropylmethanols to prepare 2,3-dihydro-1H-benzo[b]azepines and 2-vinylindolines efficiently is reported. The reactions were shown to be chemoselective, with secondary and tertiary alcohol substrates exclusively providing benzo-fused five- and seven-membered ring products, respectively. The ring-forming process was also found to proceed in moderate to excellent yields under mild conditions only in the presence of the gold and silver catalyst combination. The mechanism is thought to involve activation of the alcohol by the (p-CF(3)C(6)H(4))(3)PAuCl/AgOTf (Tf = triflate) catalyst, resulting in ionization of the starting material. The tertiary carbocationic intermediate generated in situ in this manner then triggers ring-opening of the cyclopropane moiety and trapping by the tethered aniline group to give the 2,3-dihydro-1H-benzo[b]azepine. Cyclopropane ring fragmentation of the secondary carbocationic analogue, on the other hand, results in diene formation followed by subsequent intramolecular hydroamination to afford the 2-vinylindoline.

Rapid access to halohydrofurans via Brønsted acid-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with water and electrophilic halides.

A one-pot, two-step method to prepare 3-halohydrofurans efficiently by TfOH-catalyzed hydroxylation/halocyclization of cyclopropyl methanols with H(2)O and N-halosuccinimide (NXS, X=1, Br, Cl) or Selectfluor is described. The reactions proceed rapidly under mild and operationally straightforward conditions with a catalyst loading as low as 1 mol % and afford the 3-halohydrofuran products in moderate to excellent yields and, in most cases, with preferential cis diastereoselectivity. The method was shown to be applicable to cyclopropyl methanols containing electron-withdrawing, electron-donating, and sterically demanding functional groups and electrophilic halide sources. The mechanism is suggested to involve protonation of the alcohol substrate by the Brønsted acid catalyst and ionization of the starting material. This results in ring-opening of the cyclopropane moiety and in situ formation of a homoallylic alcohol intermediate, which undergoes subsequent intramolecular halocyclization on treating with the electrophilic halide source to give the halohydrofuran. The observed cis product selectivity is thought to be determined by the reaction proceeding through an in situ generated unsaturated alcohol intermediate that contains a (Z)-alkene moiety under the kinetically controlled conditions.

Gold-catalyzed intramolecular allylic amination of 2-tosylaminophenylprop-1-en-3-ols. A concise synthesis of (+/-)-angustureine.

An efficient synthetic route to 1,2-dihydroquinolines that relies on AuCl(3)/AgSbF(6)-catalyzed intramolecular allylic amination of 2-tosylaminophenylprop-1-en-3-ols is described herein. Uniquely, the reactions were found to only proceed rapidly at room temperature in the presence of the gold and silver catalyst combination and produce the 1,2-dihydroquinoline products in yields of 40-91%. The method was shown to be applicable to a broad range of 2-tosylaminophenylprop-1-en-3-ols containing electron-withdrawing, electron-donating, and sterically demanding substrate combinations. The mechanism is suggested to involve activation of the alcohol substrate by the AuCl(3)/AgSbF(6) catalyst. This is followed by ionization of the starting material, which causes intramolecular nucleophilic addition of the sulfonamide unit to the allylic cation moiety and construction of the 1,2-dihydroquinoline. The utility of this N-heterocyclic ring forming strategy as a synthetic tool that makes use of alcohols as pro-electrophiles was exemplified by its application to the synthesis of the bioactive tetrahydroquinoline alkaloid (+/-)-angustureine.