Ruthenium-catalyzed enyne cycloisomerizations. Effect of allylic silyl ether on regioselectivity

The ruthenium-catalyzed cycloisomerization of 1,6- and 1,7-enynes substituted in the terminal allylic position with a tert-butyldimethylsilyl ether group emerges as an effective reaction to form unprecedented five- or six-membered rings possessing a geometrically defined enol silane. Straightforward synthetic access to a variety of achiral 1,6- and 1,7-enynes, as well as chiral ones, is presented. Ruthenium catalysts effect efficiently such single-step cycloisomerization at room temperature in acetone under neutral conditions. The cycloisomerization functions with (E) or (Z) 1,2-disubstituted alkenes. Parameters influencing the enol silane geometry are discussed. The level of selectivity depends on the alkyne substitution, the geometry of the double bond, and the nature of the catalyst. Furthermore, examples of stereoinduction are shown and lead to highly substituted carbo- and heterocycles with excellent diastereocontrol.     

Cobalt-phosphite-catalyzed asymmetric Pauson-Khand reaction

A complex formed from dicobalt octacarbonyl and a chiral aryl bisphosphite served as a catalyst for the intramolecular asymmetric Pauson-Khand reaction. Bicyclic cyclopentenones were obtained in up to 75% enantiomeric excess. For a terminal 1,6-enyne, the incremental enantiomeric excess was found to increase from 4 to 26% over the course of the reaction. The scope of this process was examined for a variety of 1,6- and 1,7-enynes, and a moderate degree of enantioselectivity was maintained only in the case of aryl-substituted 1,6-enynes.     

Carbohydrate carbocyclization by a zinc-mediated tandem reaction and ring-closing enyne metathesis

Methyl 5-deoxy-5-iodo-pentofuranosides are reductively ring-opened and propargylated in a tandem fashion in the presence of zinc. The 1,7-enynes thus obtained are subjected to ring-closing enyne metathesis with catalyst B to produce functionalized 1-vinyl cyclohexenes. By adding BnNH(2) to the tandem reaction, an amino group can be introduced in the 1,7-enyne products. Addition of 2-TMS-ethynylcerium(III) chloride after the reductive ring-opening produces the corresponding 1,6-enynes. Further annulation of the product 1,3-dienes can be achieved through a Diels-Alder reaction with good control of stereochemistry. These procedures constitute efficient methods for rapid carbocyclization and annulation of carbohydrates to produce a variety of functionalized five- and six-membered ring systems.     

Mild and efficient molybdenum-mediated Pauson-Khand-type reaction

[reaction: see text] The molybdenum-mediated Pauson-Khand reaction promoted by Mo(CO)3(DMF)3 takes place under very mild conditions in the absence of any promoter. High yields in Pauson-Khand adducts are obtained in the cyclization of a wide variety of functionalized 1,6- and 1,7-enynes. Enynes bearing electron withdrawing groups at the alkene terminus are particularly good substrates.     

Selective ruthenium-catalyzed transformations of enynes with diazoalkanes into alkenylbicyclo[3.1.0]hexanes

Reaction of a variety of CCH bond-containing 1,6-enynes with N2CHSiMe3 in the presence of RuCl(COD)Cp* as catalyst precursor leads, at room temperature, to the general formation of alkenylbicyclo[3.1.0]hexanes with high Z-stereoselectivity of the alkenyl group and cis arrangement of the alkenyl group and an initial double-bond substituent, for an E-configuration of this double bond. The stereochemistry is established by determining the X-ray structures of three bicyclic products. The same reaction with 1,6-enynes bearing an R substituent on the C1 carbon of the triple bond results in either cyclopropanation of the double bond with bulky R groups (SiMe3, Ph) or formation of alkylidene-alkenyl five-membered heterocycles, resulting from a beta elimination process, with less bulky R groups (R = Me, CH2CH=CH2). The reaction can be applied to in situ desilylation in methanol and direct formation of vinylbicyclo[3.1.0]hexanes and to the formation of some alkenylbicyclo[4.1.0]heptanes from 1,7-enynes. The catalytic formation of alkenylbicyclo[3.1.0]hexanes also takes place with enynes and N2CHCO2Et or N2CHPh. The reaction can be understood to proceed by an initial [2+2] addition of the Ru=CHSiMe3 bond with the enyne CCH bond, successively leading to an alkenylruthenium-carbene and a key alkenyl bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis, into bicyclo[3.1.0]hexanes. Density functional theory calculations performed starting from the model system Ru(HCCH)(CH2=CH2)Cl(C5H5) show that the transformation into a ruthenacyclobutane intermediate occurs with a temporary eta3-coordination of the cyclopentadienyl ligand. This step is followed by coordination of the alkenyl group, which leads to a mixed alkyl-allyl ligand. Because of the non-equivalence of the terminal allylic carbon atoms, their coupling favors cyclopropanation rather than the expected metathesis process. A direct comparison of the energy profiles with respect to those involving the Grubbs catalyst is presented, showing that cyclopropanation is favored with respect to enyne metathesis.     

Effective 1,5-, 1,6- and 1,7-remote stereocontrol in reactions of alkoxy- and hydroxy-substituted allylstannanes with aldehydes

Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively with tin(iv) halides to generate allyltin trihalides which react with aldehydes to give (Z)-alk-3-enols with useful levels of 1,5-, 1,6- and 1,7-stereocontrol. Alk-2-enylstannanes with a stereogenic centre bearing a hydroxy or alkoxy group at the 4-, 5- or 6-position, react with overall (Z)-1,5-, 1,6- and 1,7-syn-stereoselectivity with respect to the hydroxy and alkoxy substituents. The analogous reactions of alkoxy- and -hydroxyalk-2-enylstannanes with a methyl bearing stereogenic centre at the 4- or 5-position react with overall (Z)-1,5- and 1,6-anti-stereoselectivity with respect to the hydroxy and methyl substituents.     

Ruthenium-catalysed synthesis of fluorinated bicyclic amino esters through tandem carbene addition/cyclopropanation of enynes

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF(3))(CO(2)R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp*=C(5)Me(5) , PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N(2)CHSiMe(3), whereas N(2)CHCO(2)Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions.     

Mesomorphic behaviour in bent-shaped molecules with side wings at different positions of a central naphthalene core

Six bent-shaped molecules were prepared with central bent cores based on 2,7-, 1,7-, 1,6-, 1,3-, 1,2- and 2,3-dihydroxynaphthalene groups with side wings containing a Schiff's base moiety and dodecyloxy tail, N(2,7), N(1,7), N(1,6), N(1,3), N(1,2) and N(2,3). All of the compounds form fluid smectic mesophases and their mesomorphic behaviour and properties are discussed in terms of their molecular structure. The compounds are categorized into two groups; in one of them, N(2,7), N(1,6) and N(1,3), the bent cores have a bent angle of 120° between the side wings, whereas in the other, N(1,7), N(1,2) and N(2,3), the bent angle is 60°. The typical banana molecule, N(2,7), in the first group, forms a chiral blue phase that shows two distinguishable domains with opposite optical rotations and circular dichroism. Under an electric field, the chiral blue phase is transformed to strongly birefringent B2 phase which possesses a basically homochiral SmC_AP_A structure. N(1,3) also forms a chiral blue phase, but, in contrast, N(1,6), where the side wings are asymmetrically substituted, forms a typical antiferroelectric B2 phase with the racemic SmC_SP_A structure. N(1,2) and N(2,3) of the other group assume a U-like shape to form a conventional SmA phase. Of interest is the fact that N(1,7) forms a chiral blue phase irrespective of having a small bent angle of 60°. This indicates that the distance between side wings as well as the bent angle plays an important role for the formation of banana-shaped smectic phases.     

Direct Evidence of Significantly Different Chemical Behavior and Excited‐State Dynamics of 1,7‐ and 1,6‐Regioisomers of Pyrrolidinyl‐Substituted Perylene Diimide

Novel bay‐functionalized perylene diimides with additional substitution sites close to the perylene core have been prepared by the reaction between 1,7(6)‐dibromoperylene diimide 6 (dibromo‐PDI) and 2‐(benzyloxymethyl)pyrrolidine 5 . Distinct differences in the chemical behaviors of the 1,7‐ and 1,6‐regioisomers have been discerned. While the 1,6‐dibromo‐PDI produced the corresponding 1,6‐bis‐substituted derivative more efficiently, the 1,7‐dibromo‐PDI underwent predominant mono‐debromination, yielding a mono‐substituted PDI along with a small amount of the corresponding 1,7‐bis‐substituted compound. By varying the reaction conditions, a controlled stepwise bis‐substitution of the bromo substituents was also achieved, allowing the direct synthesis of asymmetrical 1,6‐ and 1,7‐PDIs. The compounds were isolated as individual regioisomers. Fullerene (C₆₀) was then covalently linked at the bay region of the newly prepared PDIs. In this way, two separate sets of perylene diimide–fullerene dyads, namely single‐bridged (SB‐1,7‐PDI‐C₆₀ and SB‐1,6‐PDI‐C₆₀) and double‐bridged (DB‐1,7‐PDI‐C₆₀ and DB‐1,6‐PDI‐C₆₀), were synthesized. The fullerene was intentionally attached at the bay region of the PDI to achieve close proximity of the two chromophores and to ensure an efficient photoinduced electron transfer. A detailed study of the photodynamics has revealed that photoinduced electron transfer from the perylene diimide chromophore to the fullerene occurs in all four dyads in polar benzonitrile, and also occurs in the single‐bridged dyads in nonpolar toluene. The process was found to be substantially faster and more efficient in the dyads containing the 1,7‐regioisomer, both for the singly‐ and double‐bridged molecules. In the case of the single‐bridged dyads, SB‐1,7‐PDI‐C₆₀ and SB‐1,6‐PDI‐C₆₀, different relaxation pathways of their charge‐separated states have been discovered. To the best of our knowledge, this is the first observation of photoinduced electron transfer in PDI‐C₆₀ dyads in a nonpolar medium.     

Synthesis,characterization, and antitumour studies of some curcuminoid analogues and their aluminum complexes

Aluminum(III) complexes of three curcuminoid analogues [1,7-diphenyl-1,6-heptadiene-3,5-dione, HL¹; 1,7-bis(2-hydroxyphenyl)-1,6-heptadiene-3,5-dione, HL²; and 1,7-bis(4-ethoxyphenyl)-1,6-heptadiene-3,5-dione, HL³] of [AlL₃] stoichiometry were synthesized and characterized by UV, IR, ¹H NMR, and mass spectral data. The compounds were investigated for cytotoxic and antitumor activities. The aluminum chelates are remarkably active compared to free curcuminoid analogues. The aluminum complex of HL² with hydroxyl in the phenyl ring was most active towards Ehrlich ascites carcinoma cells (concentration needed for 50% inhibition of 5?μg/mL) and cultured L929 cells (1?μg/mL produced 60?+?3% cell death). Increase in lifespan and reduction of solid tumor volume in mice were also largest for the aluminum complex of HL². The study reveals that the antitumor activities of curcuminoids are more enhanced by complexation with aluminum than with transition metal ions.     

Rhodium-catalyzed reductive cyclization of 1,6-diynes and 1,6-enynes mediated by hydrogen: catalytic C-C bond formation via capture of hydrogenation intermediates

Catalytic hydrogenation of carbon-, nitrogen- and oxygen-tethered 1,6-diynes 1a-9a and 1,6-enynes 10a-18a using cationic Rh(I) precatalysts at ambient temperature and pressure enables reductive carbocyclization to afford 1,2-dialkylidene cyclopentanes 1b-9b and monoalkylidene cyclopentanes 10b-18b, respectively, in good to excellent yields and as single alkene stereoisomers. Notably, the 1,3-diene and alkene containing cyclization products 1b-9b and 10b-18b are not subject to over-reduction under the conditions of catalytic hydrogenation in which they are formed. Reductive cyclization 1,6-diyne 1a and 1,6-enyne 10a performed under an atmosphere of D(2) provides the carbocyclization products deuterio-1b and deuterio-10b, respectively, which incorporate two deuterium atoms. The collective data are consistent with a catalytic mechanism involving heterolytic activation of elemental hydrogen (H(2) + Rh(+)X(-) --> Rh-H + HX) followed by Rh(I)-mediated oxidative cyclization of the 1,6-diyne or 1,6-enyne substrates to afford (hydrido)Rh(III)-based metallocyclopentadiene and metallocyclopentene intermediates, respectively. These transformations represent the first examples of metal-catalyzed reductive carbocyclization mediated by hydrogen.     

Mechanistic dichotomy in CpRu(CH(3)CN)(3)PF(6) catalyzed enyne cycloisomerizations

Enynes are easily accessible building blocks as a result of the rich chemistry of alkynes and thus represent attractive substrates for ring formation. A ruthenium catalyst for cycloisomerization effects such reaction of 1,6- and 1,7-enynes typically at room temperature in acetone or DMF under neutral conditions. The reaction is effective for forming five- and six-membered rings of widely divergent structure. The alkyne may bear both election-donating and election-withdrawing substituents. The alkene may be di- or trisubstituted. Introduction of a quaternary center at the propargylic position of an ynoate, however, completely changes the nature of the reaction. In the case of a 1,6-enynoate, a seven-membered ring forms in excellent yield under equally mild conditions. Evidence is presented to indicate a complete change in mechanism. In the former case, the reaction involves the intermediacy of a ruthenacyclopentene. In the latter case, a C-H insertion to form a pi-allylruthenium intermediate is proposed and supported by deuterium-labeling studies. A rationale is presented for the structural dependence of the mechanism.     

Ruthenium dihydride complexes as enyne metathesis catalysts

Ruthenium–catalyzed enyne metathesis is a reliable and efficient method for the formation of 1,3-dienes, a common structural motif in synthetic organic chemistry. The development of new transition-metal complexes competent to catalyze enyne metathesis reactions remains an important research area. This report describes the use of ruthenium (IV) dihydride complexes with the general structure RuH₂Cl₂(PR₃)₂ as new catalysts for enyne metathesis. These ruthenium (IV) dihydrides have been largely unexplored as catalysts in metathesis-based transformations. The reactivity of these complexes with 1,6 and 1,7-enynes was investigated. The observed reaction products are consistent with the metathesis activity occurring through a ruthenium vinylidene intermediate.     

1,6‐ and 1,7‐Regioisomers of Dicyano‐Substituted Perylene Bisimides: Synthesis,Optical and Electrochemical Properties

In this study, 1,6‐ ad 1,7‐regioisomers of dicyano‐substituted perylene bisimides (1,6‐ C and 1,7‐ C ) were synthesized and successfully isolated from their regioisomeric mixture using conventional methods of separation, and subsequently characterized by 400 MHz ¹H NMR spectroscopy. This is the first time that the 1,6‐dicyanoperylene bisimide 1,6‐ C has been obtained in pure form. Moreover, the optical and electrochemical properties of 1,6‐ C and 1,7‐ C were found to be virtually the same. Time‐dependent density functional theory calculations performed on both dyes are reported in order to rationalize their electronic structures and optical properties.     

Rhodium-catalyzed silylcarbocyclization (SiCaC) and carbonylative silylcarbocyclization (CO-SiCaC) reactions of enynes

The reaction of a 1,6-enyne with a hydrosilane catalyzed by Rh(acac)(CO)(2), Rh(4)(CO)(12), or Rh(2)Co(2)(CO)(12) under ambient CO atmosphere or N(2) gives 2-methyl-1-silylmethylidene-2-cyclopentane or its heteroatom congener in excellent yield through silylcarbocycization (SiCaC) process. The same reaction, but in the presence of a phosphite such as P(OEt)(3) and P(OPh)(3) under 20 atm of CO, affords the corresponding 2-formylmethyl-1-silylmethylidene-2-cyclopentane or its heteroatom congener with excellent selectivity through carbonylative silylcarbocycization (CO-SiCaC) process. The SiCaC reaction has also been applied to a 1,6-enyne bearing a cyclohexenyl group as the alkene moiety and a 1,7-enyne system. The functionalized five- and six-membered ring systems obtained by these novel cyclization reactions serve as useful and versatile intermediates for the syntheses of natural and unnatural heterocyclic and carbocyclic compounds. Possible mechanisms for the SiCaC and CO-SiCaC reactions as well as unique features of these processes are discussed.     

Gold(I)-catalyzed cyclizations of 1,6-enynes: alkoxycyclizations and exo/endo skeletal rearrangements

Gold(I) complexes are the most active catalysts for alkoxy- or hydroxycyclization and for skeletal rearrangement reactions of 1,6-enynes. Intramolecular alkoxycyclizations also proceed efficiently in the presence of gold(I) catalysts. The first examples of the skeletal rearrangement of enynes by the endocyclic cyclization pathway are also documented. Iron(III) is also able to catalyze exo and endo skeletal rearrangements of 1,6-enynes, although the scope of this transformation is more limited. The gold(I)-catalyzed endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII, HgII, or RhI catalysts.     

Syntheses of 8-quinolinolatocobalt(III) complexes containing cyclen based auxiliary ligands as models for hypoxia-activated prodrugs

New ligands H(2)L2-H(2)L6 comprise the cyclen macrocycle which is N,N'-dialkylated at the 1,7-nitrogen atoms by three- and four-carbon alkyl chains bearing terminal sulfonic (C(3) H(2)L2), phosphonic (C(3) H(2)L3, C(4) H(2)L4) or carboxylic acid (C(3) H(2)L5, C(4) H(2)L6) groups, and HL7 is N-monoalkylated by a four-carbon sulfonic acid group. The ligands were prepared by alkylation of a bridged bisaminal intermediate. The syntheses of cobalt(III) complexes containing a tetradentate cyclen, N,N'-1,7-Me(2)cyclen, cyclam or L2-L7 ligand together with the bidentate 8-quinolinato (8QO(-)) ligand, of interest as it is a model for a more potent cytotoxic analogue, were investigated. Coordination of ligands (L) cyclen, N,N'-1,7-Me(2)cyclen or cyclam to cobalt(III) was achieved using Na(3)[Co(NO(6))] to form [Co(L)(NO(2))(2)](+). HOTf (trifluoromethansulfonic acid) was used to prepare the triflato complexes [Co(L)(OTf)(2)](+), followed by substitution of the labile triflato ligands to yield [Co(L)(8QO)](ClO(4))(2) isolated as the perchlorate salts. One further example containing cyclam and the 5-hydroxymethyl-8-quinolinato ligand was also prepared by this method. Complexes containing the pendant arm ligands L2-L6 were prepared from the cobalt precursor trans-[Co(py)(4)Cl(2)](+). Reaction of this complex with H(2)L2·4HCl and 8QOH produced [Co(L2)(8QO)] in one step and contains two deprotonated sulfonato pendant arms. The reaction of H(2)L3·4HBr with [Co(py)(4)Cl(2)](+) gave [Co(L3)]Cl in which L3 acts as a hexadenate ligand with the three-carbon phosphonato side chains coordinated to cobalt. H(2)L5·4HCl bearing three-carbon carboxylic acid pendant arms gave a similar result. The four-carbon ligands were coordinated to cobalt by reaction of [Co(py)(4)Cl(2)](+) with H(2)L4·4HBr or H(2)L6·4HCl to give [Co(HL4)Cl(2)] or [Co(H(2)L6)Cl(2)]Cl, which in turn with 8QOH gave the 8QO(-) complexes [Co(L4)(8QO)] bearing anionic phosphate pendant arms or [Co(H(2)L6)(8QO)]Cl(2) containing neutral carboxylic acid side chains. The reaction of Na(3)[Co(CO(3))(3)] with the mono-N-alkylated ligand HL7·4HCl and then HOTf gave [Co(L7)(CO(3))] and then in turn [Co(L7)(OTf)(2)]. The carbonato complex [Co(L7)(CO(3))] with [8QO](2)[SO(4)] produced [Co(L7)(CO(3))]. All complexes containing L7 bear an anionic sulfonato group on the side chain. The synthesis and characterisation of the six new ligands based on N-alkylated cylen ligand and the cobalt complexes outlined above are described, along with cyclic voltammograms of the 8QO(-) complexes and the molecular structures determined by X-ray crystallography of [Co(cyclen)(H(2)O)(2)](OTf)(3) (formed by aquation of the triflato complex), [Co(cyclen)(8QO)](ClO(4))(2), Co(L2)(8QO)·2H(2)O, Co(L4)(8QO)·6H(2)O and [Co(H(2)L6)Cl(2)]Cl·H(2)O. These demonstrate the coordination of the cyclen ligand in the folded anti-O,syn-N configuration with the N-alkylated nitrogens occupying apical positions.     

Metal-free visible-light-induced oxidative cyclization reaction of 1,6-enynes and arylsulfinic acids leading to sulfonylated benzofurans

A new and convenient visible-light-induced method has been developed for the synthesis of sulfonylated benzofurans via oxidative cyclization reaction of 1,6-enynes and arylsulfinic acids.This reaction was carried out under metal-free and mild conditions,in which the C-S,C-C and C=O bonds could be sequentially formed in one pot operation.     

Dicobalt octacarbonyl-catalyzed tandem cycloaddition reaction between diyne and diene under CO

Treatment of 1,7-diphenyl-1,6-heptadiyne and a symmetric butadiene such as 2,3-dimethyl-1,3-butadiene and 1,3-cyclohexadiene with Co(2)(CO)(8) (5 mol%) in CH(2)Cl(2) at 110 degrees C under 30 atm CO for 18 h afforded a 5.5.6 tricyclic enone in high yields. For unsymmetrical dienes such as 2-methyl-1,3-butadiene, 2-methyl-1, 3-pentadiene, and 3-methyl-1,3-pentadiene, two separable regioisomers were obtained. The catalytic reactions described are experimentally quite simple and provide a very useful synthetic procedure for the syntheses of [5.5.6] tricyclic enones.     

Zinc(II)-catalyzed redox cross-dehydrogenative coupling of propargylic amines and terminal alkynes for synthesis of N-tethered 1,6-enynes

The zinc(II)-catalyzed redox cross-dehydrogenative coupling (CDC) of propargylic amines and terminal alkynes proceeds to afford N-tethered 1,6-enynes. In the current CDC reaction, a C(sp)-C(sp(3)) bond is formed between the carbon adjacent to the nitrogen atom in the propargylic amine and the terminal carbon of the alkyne with reduction of the C-C triple bond of the propargylic amine, which acts as an internal oxidant.