Polarity matching of radical trapping: high yielding 3-exo and 4-exo cyclizations

A catalyzed synthesis of cyclopropanes and cyclobutanes via radical chemistry is described. The method that generally proceeds in high yields uses epoxides as radical precursors and titanocene(III) complexes as the electron transfer catalysts (see scheme). The key to the success of the transformation is constituted by the chemoselectivity of radical reduction. Electrophilic enol radicals generated through cyclization are reduced rapidly whereas their precursors, nucleophilic alkyl radicals, remain unaffected.     

Titanocene catalyzed 4-exo cyclizations: mechanism, experiment, catalyst design

A method for the preparation of a variety of cyclobutanes via 4-exo cyclization of radicals is presented. Radical generation is carried out by electron transfer from titanocene(III) chlorides to epoxides. The reaction relies on the acceleration of the cyclization through the use of alpha,beta-unsaturated carbonyl compounds as radical traps and the thermodynamic stabilization of the cyclobutylcarbinyl radicals through conjugation. The mechanism of the transformation was investigated by a combined theoretical and experimental study. The computational results provide the crucial energetic and structural features of pertinent intermediates and transition structures. Moreover, the origins of the diastereoselectivity of the 4-exo cyclization are outlined for the first time. Catalysts for those cases where "Cp2TiCl" did not perform in a satisfactory manner have been devised. Through the introduction of tert-butyl or cyclo-hexyl substituted cyclopentadienyl ligands the longevity of the pivotal beta-titanoxy radicals is increased sufficiently enough to enable the slow but often surprisingly diastereoselective formation of the cyclobutylcarbinyl radical. The resulting transformation constitutes the first general approach to cyclobutanes using radical chemistry.     

Radical cyclizations in 1,4-dimethylpiperazine

N-Allylic or N-vinylic α,α,α-trichloroacetamides, upon heating in 1,4-dimethylpiperazine, undergo radical cyclization to give the corresponding γ-lactams.     

A combined theoretical and experimental study of efficient and fast titanocene-catalyzed 3-exo cyclizations

The mechanism of titanocene mediated 3-exo cyclizations was investigated by a combined theoretical and experimental study. A gradient corrected density functional theory (DFT) method has been scaled against titanocene dichloride, the parent butenyl radical, and in bond dissociation energy (BDE) calculations. The BP86 method using density fitting, and a basis set of triple-zeta quality emerged as a highly reliable tool for studying titanocene mediated radical reactions. The computational results revealed important kinetic and thermodynamic features of cyclopropane formation. Surprisingly, the beta-titanoxy radicals, the first intermediates of our investigations, were demonstrated to possess essentially the same thermodynamic stabilization as the corresponding alkyl radicals by comparison of the calculated BDEs. In contrast to suggestions for samarium mediated reactions, the cyclization was shown to be thermodynamically favorable in agreement with earlier kinetic studies. It was established that stereoselectivity of the cyclization is governed by the stability of the intermediates and thus the trans disubstituted products are formed preferentially. The observed ratios of products are in good to excellent agreement with the DFT results. By a combination of computational and experimental results, it was also shown that for the completion of the overall cyclopropane formation the efficiency of the trapping of the cyclopropylcarbinyl radicals is decisive.     

Proline-catalysed asymmetric ketol cyclizations: The template mechanism revisited

A modified template mechanism based on modelling studies of energy minimised complexes is presented for the asymmetric proline-catalysed cyclization of triketones1,2 and3 to the 2S,3S-ketols1a,2a and3a respectively. The template model involves a three-point contact as favoured in enzyme-substrate interactions. Our minimisation studies are in agreement with the divergent behaviour of the 6,5-, 6,6-and 6,7-bicyclic systems. They support the high 93.4%ee observed with the 6,5-bicyclic ketol and the lower 73%ee found with the 6,6-bicyclic ketol. The calculations also explain the lack of asymmetric induction with the 6,7-bicyclic system     

Cyanide-catalyzed cyclizations via aldimine coupling

Aldimine coupling (AIC) is the nitrogen analogue of the benzoin condensation and has been applied to dialdimines, providing the first examples of cyclizations effected by cyanide-catalyzed AIC. Sodium cyanide promoted the facile, intramolecular cyclization of several dialdimines in N,N-dimethylformamide, methanol, or methylene chloride/water (phase-transfer conditions) yielding a variety of six-membered heterocycles. Under aerobic conditions, an oxidative cyclization occurs to provide the diimine heterocycle. Oligomerization was observed with rigid dialdimines for which cyclization was precluded.     

Radical cyclizations terminated by ir-catalyzed hydrogen atom transfer

A system for coupling catalytic radical cyclization and Ir-catalyzed hydrogen atom transfer (HAT) is described. It is essential that the HAT catalyst activates H(2) quickly and is not a hydrogenation catalyst. Vaska's complex was found to fulfill both purposes efficiently.     

Radical and Heck cyclizations of diastereomeric o-haloanilide atropisomers

The outcomes of radical cyclizations and Heck reactions of N-(cyclohex-2-enyl)-N-(2-iodophenyl)acetamides depend critically on the configurations of the chiral axis and the stereocenter. In substrates without an ortho-methyl group, the diastereomeric precursors interconvert slowly at ambient temperatures. Cyclization of enriched mixtures of diastereomers provided similar yields of acetyl tetrahydrocarbazoles or dihydrocarbazoles, suggesting that interconversion of the radical or organometallic intermediates also occurs. Diastereomers of N-(cyclohex-2-enyl)-N-(2-iodo-4,6-dimethylphenyl)acetamides with an additional ortho-methyl group did not interconvert at ambient temperatures and were readily resolved. In radical cyclizations, syn diastereomers were prone to cyclize, while anti isomers were not. Strikingly, Heck reactions gave the opposite result; anti isomers were prone to cyclization and syn isomers were not. Heck reactions of allylic acetates occur with β-hydride elimination when acetate is trans to palladium and with β-acetoxy elimination when acetate is cis. This is surprising because prior studies have suggested that a trans relationship of palladium and acetoxy is essential for acetate elimination. Analyses of the results provide insights into mechanisms for radical cyclization and for insertion and elimination in the Heck reaction.     

Effects of alpha-Alkoxy Substitution and Conformational Constraints on 6-exo Radical Cyclizations of Hydrazones via Reversible Thiyl and Stannyl Additions

Access to multifunctional hydrazones of relevance to dysiherbaine synthesis studies is described. Subsequent radical cyclizations of multifunctional hydrazones via a Si- and C-linked tethering strategy are shown to function effectively in 6-exo fashion. Conformational constraints are proposed to play a key role in suppressing unproductive premature reduction pathways. The stereochemical outcomes suggest that minimizing the dipole repulsion between neighboring CN and C-O bonds favors a C_α-C(N) dihedral angle placing the CN bond axial within a chairlike transition state, in contrast to the usual Beckwith-Houk model.     

Facile synthesis of N-substituted-4-cyano-4-phenylpiperidines via phase-transfer catalysis

Phenylacetonitrile can be condensed with N-substituted-bis(2-chloroethyl)amines in aqueous sodium hydroxide solution to produce N-substituted-4-cyano-4-phenylpiperidines. Hexadecyltributylphosphonium bromide is an effective catalyst for this phase-transfer reaction.     

Asymmetric cyclizations via a sequential Michael addition/Conia-ene reaction by combining multifunctional quaternary phosphonium salt and silver catalysis

A one-pot asymmetric Michael addition/Conia-ene reaction sequence, catalyzed by combination of a dipeptide-derived multifunctional quaternary phosphonium salt and Ag₂CO₃ has been developed, which provides a series of synthetically important chiral methylenecyclopentane derivatives in moderate to excellent yields (up to 97%) and enantioselectivities (up to 93%).     

N-Acyliminium cyclizations via reversible 2-aza-cope rearrangements

The existence of a reversible 2-aza-Cope rearrangement in cyclizations of N-acyliminium ions derived from 1′- and 2′-vinyl-N-(3′-butenyl)-5-hydroxy-2-pyrrolidinones is established.     

Synthesis of 4'-Spironucleoside via Radical Translocation Cyclization Reaction

A novel synthetic strategy for the construction of 4＇-spironucleosides via cascade radical translocation cyclization of N-allyl-N-（2＇-bromophenyl） amide moiety of 5＇-carboxylic nucleosides and the N-propynyl analogues is described. The conformationally restricted nucleosides herein synthesized are of potentially biological interests.     

Preparation of aza-polycyclic aromatic compounds via superelectrophilic cyclizations

Alkenyl-substituted N-heterocycles react in superacidic CF3SO3H (triflic acid) to produce dicationic intermediates. These superelectrophiles undergo cyclizations to give varied aza-polycyclic aromatic compounds in generally good yields (27-99%, 16 examples). Theoretical calculations indicate a preference for charge-separated dicationic intermediates.     

Synthesis of polyhydroxylated xanthones via acyl radical cyclizations

2-Formylphenoxy quinones can be converted into xanthones via an acyl radical intermediate with NBS and AIBN.     

Radical 4‐exo Cyclizations via Template Catalysis

The mechanism of catalytic 4‐exo cyclizations without gem‐dialkyl substitution was investigated by a comparison of cyclic voltammetry, EPR, and computational studies with previously published synthetic results. The most active catalyst is a super‐unsaturated 13‐electron titanocene(III) complex that is formed by supramolecular activation through hydrogen bonding. The template catalyst binds radicals via a two‐point binding that is mandatory for the success of the 4‐exo cyclization. The computational investigations revealed that formation of the observed trans‐cyclobutane product is not possible from the most stable substrate radical. Instead, the most stable product is formed with the lowest energy of activation from a disfavored substrate in a Curtin–Hammett related scenario.     

Magnetic nanowires via template electrodeposition

The magnetic NiFe_x nanowires were prepared via template-guided electrodeposition. Anodized nanoporous aluminum was used as a template. The pore density and dimensions of alumina templates can be controlled by anodization conditions. Magnetic nanorods (or nanowires) with various aspect ratios were prepared by controlling the electrodeposition time. SEM and TEM micrographs revealed the wire and rod shape morphologies with 50 nm in diameter and 1.5 ~ 10 μm in length. Elemental analysis and ESCA studies suggested that NiFe₃ magnetic alloy was formed. The X-ray diffraction pattern indicates that all the nanowires are stabilized in a BCC structure with a [1 1 0] texture oriented along the long axis of the nanowires. The magnetic measurement showed no hysteresis loops for the whole aspect ratios of the nanowires. Nevertheless, the magnetization is more temperature sensitive for nanowires with lower aspect ratio. This is caused by the fact that the easy magnetization axis is always parallel to the long axis of the nanowires.     

Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl-2-hydroxymethylperhydro-1,3-benzoxazine derivatives

Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.     

Metal complex catalysis on a double stranded DNA template

The reaction of ester hydrolysis catalysed by a DNA duplex in a sequence specific fashion has been developed, which is the fastest and most high yielding in comparison with the known reactions of this type.