Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.     

Synthesis of the polycyclic core of vincorine via cascade reactions

We developed a six-step synthesis of the polycyclic core of vincorine using two cascades of reactions. A cascade of Michael–Mannich reactions was employed for one-pot preparation of a polycyclic intermediate, which was transformed into the desired polycyclic pyrroloindoline ring system using a cascade of methanolysis-N-imine cyclization reactions.     

Synthesis of pyridine fused polycyclic amines using sequential ring-closing metathesis and radical cyclisation reactions

The syntheses of novel pyridine fused polycyclic bridgehead amines are described using sequential ring-closing metathesis (RCM) and 5-exo-trig intramolecular radical cyclisation reactions. Critical to the success of the two sequential steps were the RCM catalyst and/or the nature of the nitrogen atom.     

A cascade process toward the synthesis of fused polycyclic dihydropyridines

The synthesis of fused polycyclic dihydropyridines was achieved using a cascade process comprising a Suzuki coupling, a nucleophilic cyclization and a hydrogen migration. Several functional groups are tolerated in this reaction and the methodology could be applied with success to quinoline and isoquinoline derivatives.     

Synthesis of angularly fused cyclopentanoids and analogous tricycles via photoinduced ketyl radical/radical anion fragmentation-cyclization reactions

Angular fused tricycles were synthesized through intramolecular tandem fragmentation-cyclization reactions by photochemically induced electron transfer (PET) of tricyclic α-cyclopropyl ketones with an unsaturated side chain at the position γ to the carbonyl group. The reactions resulted in regioselective cleavage of a β-cyclopropyl bond with formation of angular fused tricyclic ring systems via ketyl radical/radical anions as reactive intermediates. In general, triethylamine (TEA) was used as a strong reducing reagent in acetonitrile. The preferred regioselectivity of the cyclization step (exo vs endo) depending on the substitution pattern at the quaternary carbon center (Cβ′) of the tricyclic α-cyclopropyl ketones was investigated. In addition, we also checked a two-step pathway for the synthesis of angular dioxa-triquinanes including photolysis of an allyloxy-substituted cyclopenta[c]furanone derivative and subsequent β-cleavage of the resulted dioxa-[4.5.5.5]fenestrane under reductive PET conditions.     

Synthetic applications in radical/radical cationic cascade reactions

Oxidative photoinduced electron transfer (PET) reactions have been performed with various cyclic cyclopropyl(vinyl) silyl ethers bearing an olefinic or acetylenic side chain. The reactions result in bi- to tetracyclic ring systems via a fragmentation-radical/radical cationic addition reaction pathway with well defined ring juncture. The mode of cyclisation (endo/exo) can be partially controlled by addition of nucleophiles due to the suppression of radical cationic reaction pathways. Quantum chemical calculation of the cyclisation transition states underline the experimentally found selectivities. Additional mechanistic studies concerning the saturation step reveal that the final radical is saturated mostly by the solvent and traces of water in the solvent.     

Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade cyclization

We report a 2-iodoxybenzoic acid (IBX)-mediated intarmolecular oxidative spiro-fused tandem cyclization reaction of tryptophan analogs bearing an N-arylamides side-chain to rapidly afford polycyclic spiroindolines featuring multiple stereocenters including a quaternary stereocenters under mild reaction conditions. Among them, a novelty azaphosphol idine-containing spiroindoline compound is synthesized for the first time. It may open the door to azaphos pholidine-containing spiroindoline compound of potential interest in synthetic and medicinal chemistry. A plausible mechanism is proposed.     

Lewis acid-mediated radical cyclization: stereocontrol in cascade radical addition-cyclization-trapping reactions

An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid-mediated cascade radical addition-cyclization-trapping reaction proceeded smoothly with good enantio- and diastereoselectivities, providing various chiral γ-lactams.     

Synthesis of heteroarenes using cascade radical cyclisation via iminyl radicals

Cascade radical cyclisation involving homolytic aromatic substitution has been used to synthesise new tetracycles. Treatment of vinyl iodide radical precursors with Me(3)Sn. radicals (from hexamethylditin) yielded intermediate vinyl radicals which undergo 5-exo cyclisation onto suitably placed nitrile groups to yield intermediate iminyl radicals. The iminyl radicals undergo aromatic homolytic substitution via 6-endo cyclisation (or 5-exo cyclisation followed by neophyl rearrangement) with loss of hydrogen (H.) in a H-abstraction step. We propose that this abstraction was facilitated by tert-butoxyl (t-BuO.) radicals from di-tert-butyl peroxide or methyl radicals, generated from breakdown of trimethylstannyl radicals (Me(3)Sn.). The biologically active alkaloids mappicine and luotonin A were synthesised using the new methodology. A novel radical conversion of nitriles to primary amides is proposed.     

The mechanism of reactions of organopalladium salts with vinylcyclopropanes

Cyclopropylmercuric chloride, lithium chloropalladite and methyl acrylate react at 0–25°C to give an 81% yield of methyl sorbate. A π-allylic palladium intermediate is proposed since vinylcyclopropane, carbomethoxymercuric acetate, and lithium chloropalladate give the same product. The corresponding reactions with styrene and cyclopropylmercuric chloride or vinylcyclopropane and phenylmercuric chloride also give the same, isolable π-allylic palladium complex. Deuterium labeling experiments support the occurrence of a common intermediate in the two reactions. 1,1-Dicarboethoxy-2-vinylcyclopropane reacts similarly with “phenylpalladium chloride” but the π-allylic product has the palladium attached at the benzyl carbon rather than the next carbon away. The reaction with “phenylpalladium acetate” in place of the chloride yields only dienes. Studies with the deuterated vinylcyclopropane diester suggest that the mode of elimination from the initial palladium adduct is strongly influenced by the anion present. The reaction of “cyclopropylpalladium chloride” with alkenes appears to be a general method for preparing, selectively, internal π-allylic palladium complexes.     

Asymmetric cyclopropane synthesis via phosphine oxide mediated cascade reactions

A silyloxy-THF has been converted into a cyclopropane containing three stereocentres as mixture of diastereoisomers. The mechanism of the reaction has been established and the source of stereochemical leakage proposed. An alternative stereospecific cascade reaction has been discovered.     

Enantioselective synthesis of fused dihydropyranones via squaramide-catalyzed Michael addition/lactonization cascade reaction

A highly enantioselective (49–99% ee) Michael addition/lactonization cascade process has been developed to construct 3,4-dihydropyran-2-one in the presence of a bifunctional squaramide. Various α,β-unsaturated N-acyl heterocycles were well tolerated and afforded 3,4-dihydropyran-2-ones in moderate to excellent isolated yields (50–99%). Both cyclic and acyclic β-diketones functioned as appropriate donors. The resulting 3,4-dihydropyran-2-ones could be readily converted into oxadecalinones.     

Synthesis and radical ring-opening polymerization of vinylcyclopropanes bearing vinylsilane groups

Synthesis and radical polymerization of novel vinylcyclopropanes; 1-carboethoxy-2-trimethylsilyl-2-vinylcyclopropane ( 1a ) and 1-carboethoxy-2-(1-trimethylsilyl)-vinylcyclopropane ( 1b ), were examined. 1a and 1b were prepared by the coupling reaction of 2-trimethylsilylbutadiene with ethyl diazoacetate, which was prepared from glycine ethyl ester hydrochloride. The radical polymerization of 1a and 1b was carried out at 60°C in bulk for 40 h in the presence of 2,2′-azobis(isobutyronitrile) (5 mol % vs. monomer). Poly( 1 ) consisted of a 1,5-ring-opened unit. Desilylation reaction of poly( 1 ) proceeded quantitatively in aqueous hydrochloric acid. © 1998 John Wiley & Sons, Inc. J. Polym. Sci. A Polym. Chem. 36: 2037–2042, 1998     

Synthesis of polycyclic fused benzimidazole derivatives

Am easy method for the synthesis of tetraeyclie systems containing an imidazole and an iso-thiazole or an imidazole and a thiazine ring, by reacting 2H-1,3-benzothiazine-2-thion-4(3H)one with aromatic primary diarnines is reported. The structures were assigned based upon mass spectra and modes of cleavage of the compounds. The most important fragments are described.     

Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization

[reaction: see text] Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.     

Stereoselective synthesis of tetracyclic indolines via gold-catalyzed cascade cyclization reactions

A reliable synthetic route to fused polycyclic indolines is documented by the development of a stereoselective gold catalyzed cascade cyclization of indole propargylic alcohols.     

Rapid access to polycyclic indolines related to the stephacidin alkaloids using a radical cascade

A new and very rapid access to indoline intermediates useful for the synthesis of alkaloids related to the stephacidins has been established using a radical cascade process initiated from a sulphur-substituted diketopiperazine.     

Palladium-catalyzed cascade reactions of coumarins with alkynes: synthesis of highly substituted cyclopentadiene fused chromones

The coupling of coumarins with alkynes is described, which proceeds through a palladium-catalyzed cascade sequence. This process provides a new route to the synthesis of highly substituted cyclopentadiene fused chromones.