Bicyclic Adducts Research Articles

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams.

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study.

An experimental and theoretical investigation on the iridium-catalyzed hydroacylation of C1-substituted oxabenzonorbornadienes with salicylaldehyde is reported. Utilizing commercially available [Ir(COD)Cl]2 in the presence of 5 M KOH in dioxane at 65 °C, provided a variety of hydroacylated bicyclic adducts in up to a 95% yield with complete stereo- and regioselectivity. The mechanism and origins of selectivity in the iridium-catalyzed hydroacylation reaction has been examined at the M06/Def2TZVP level of theory. The catalytic cycle consists of three key steps including oxidative addition into the aldehyde C–H bond, insertion of the olefin into the iridium hydride, and C–C bond-forming reductive elimination. Computational results indicate the origin of regioselectivity is involved in the reductive elimination step.

Oxygen-Tethered 1,6-Enynes and [4.1.0]-Bicyclic Ether Skeletons as Hedonic Materials for the Fragrance Industry

AbstractThe synthesis of original structures for the fragrance industry bearing bicyclic scaffolds is described. To the best of our knowledge, these structures are not found in the fragrance industry, neither from natural nor synthetic pathways. NHC–gold-type catalysts showed excellent activities leading to light bicyclic enol ethers. Several bicyclic adducts were prepared in good to excellent yields (18–99%). Evaluation of NHC–Au complexes allowed to reach a TOF of 300 h–1. The evaluation for the organoleptic properties of [4.1.0]-bicyclic ethers were compared with the unprecedented properties of the 1,6-enyne precursors. Evaluations of starting materials showed a great interest in these structures with various olfactory facets. In this study, we depicted the similarity and differences between starting ethers and their cycloisomerized bicyclic counterparts.

Indium-Catalyzed Cycloisomerization of 1,6-Cyclohexenylalkynes

Efficient four- and five-step routes to access functionalized bicyclo[3.2.1]oct-2-ene and bicyclo[3.3.1]nonadiene via indium-mediated cycloisomerization of 1,6-enynes has been developed. This atom-economical catalytic process was optimized and relied on the efficiency of InCl3 leading to the preparation of functionalized bicyclic adducts in up to 99% isolated yield. The cyclization occurred on two different processes (5-exo versus 6-endo pathway) and were influenced by the substitution of the alkynyl moiety. The exo process was favored for non-substituted alkynes whereas the endo pathway was generally observed for substituted alkynes. Then, the presence of electron-withdrawing groups on the aryl substituted alkyne increased the ratio of the exo isomer. DFT calculations were performed on stability of intermediates and corroborated the intervention of InCl3.

Gold-Catalyzed Cycloisomerization of 1,6-Cyclohexenylalkyne: An Efficient Entry to Bicyclo[3.2.1]oct-2-ene and Bicyclo[3.3.1]nonadiene.

An efficient and mild synthetic route for the preparation of functionalized bicyclo[3.2.1]oct-2-ene and bicyclo[3.3.1]nonadiene via gold-mediated cycloisomerization of 1,6-enynes has been developed. This atom-economical catalytic process was optimized and relied on the efficiency of IPrAuNTf2 allowing the formation of functionalized bicyclic adducts in 55-91% isolated yields (18 products). The reliable access to bicyclic derivatives was demonstrated on a 3 g scale with a low catalyst loading. The process occurred on a 5-exo versus 6-endo pathway depending on the substitution of the alkynyl moiety. Density functional theory (DFT) calculations were performed on the stability of intermediates, and this study corroborated the endo/exo ratio and the mechanistic pathway with key intermediates. Reduction of the ester moiety and hydrogenation of the exo-methylene double bond of the bicyclo[3.2.1]oct-2-ene adduct illustrated the potential postfunctionalization of bicyclic derivatives.

Gold-Catalyzed Diastereoselective Formal Intermolecular [4 + 2 + 1] Cycloaddition of 1,3-Dien-8-yne with Diazo Ester.

The first example of gold-catalyzed formal intermolecular [4 + 2 + 1] cycloaddition was developed using 1,3-dien-8-yne as C4 and C2 units and diazo ester as the C1 unit, which provides expedient access to a series of structurally complicated [5.3.0] bicyclic adducts in moderate yields with moderate to high diastereoselectivities. The key route involved a cascade process of dienyne cycloisomerization, cyclopropyl gold carbene's trapping, and subsequent divinyl cyclopropane (DVCP) Cope rearrangement.

An Electrophilic Ruthenium Complex that Enables the Cycloisomerization of 1,6‐Enynes to Access Azabicyclo[4.1.0]heptenes

AbstractCycloisomerization of 1,6‐enynes to access azabicyclo[4.1.0]heptenes was achieved in the presence of commercially available [RuCl2(CO)3]2 after a comprehensive study on the electronic properties of ruthenium complexes. A series of 1,6‐enynes bearing an internal/terminal alkyne motif proved to be good candidates for substrates, giving their corresponding bicyclo[4.1.0]heptenes in good to excellent yields. Substitution patterns on either alkyne or alkene have no significant influence on the yields of bicyclic adducts.

Synthesis of Bicyclic Adduct through Regioselective Baeyer-Villager oxidation

Baeyer-Villager oxidation reaction has become accepted as a right approach in the ring expansions for the preparation of both bicyclic and tricyclic lacotnes; however, successful application of the regioselective Bayer-Villager oxidation protocol to the synthesis of particularly congested scaffolds remains distinctly tricky. Herein the Baeyer–Villiger oxidation of Bicyclo[3.2.0]hept-3-ene-6-one is studied with oxygen insertion leading to the functionalized oxabicyclic adduct with complete regioselectivity.

Modular Access to N-Substituted cis 5-Amino-3-hydroxypiperidines.

A sequence of oxidative cleavage/reductive amination/reductive cleavage enables the preparation of N-substituted cis 5-amino-3-hydroxypiperidines from a readily available bicyclic adduct. This new route provides straightforward and versatile access to drug-relevant scaffolds or fragments.

Silver-Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines.

A synthetic method to prepare partially hydrogenated isoquinolines efficiently from silver-mediated [3,3]-sigmatropic rearrangement/Diels-Alder reaction of 1,9-dien-4-yne esters is described. The reactions were shown to be robust with a wide variety of substitution patterns tolerated to provide the corresponding nitrogen-containing heterocyclic products in good to excellent yields. This includes examples containing a bridgehead sp3 quaternary carbon center as well as the cycloisomerization of one substrate to give the corresponding bicyclic adduct in excellent yield at the gram scale.

Simultaneous Upgrading of Furanics and Phenolics through Hydroxyalkylation/Aldol Condensation Reactions.

The simultaneous conversion of cyclopentanone and m-cresol has been investigated on a series of solid-acid catalysts. Both compounds are representative of biomass-derived streams. Cyclopentanone can be readily obtained from sugar-derived furfurals through Piancatelli rearrangement under reducing conditions. Cresol represents a family of phenolic compounds, typically obtained from the depolymerization of lignin. In the first biomass conversion strategy proposed here, furfural is converted in high yields and selectivity to cyclopentanone (CPO) over metal catalysts such as Pd-Fe/SiO2 at 600 psi (∼4.14 MPa) H2 and 150 °C. Subsequently, CPO and cresol are further converted through acid-catalyzed hydroxyalkylation. This C-C coupling reaction may be used to generate products in the molecular weight range that is appropriate for transportation fuels. As molecules beyond this range may be undesirable for fuel production, a catalyst with a suitable porous structure may be advantageous for controlling the product distribution in the desirable range. If Amberlyst resins were used as a catalyst, C12 -C24 products were obtained whereas when zeolites with smaller pore sizes were used, they selectively produced C10 products. Alternatively, CPO can undergo the acid-catalyzed self-aldol condensation to form C10 bicyclic adducts. As an illustration of the potential for practical implementation of this strategy for biofuel production, the long-chain oxygenates obtained from hydroxyalkylation/aldol condensation were successfully upgraded through hydrodeoxygenation to a mixture of linear alkanes and saturated cyclic hydrocarbons, which in practice would be direct drop-in components for transportation fuels. Aqueous acidic environments, which are typically encountered during the liquid-phase upgrading of bio-oils, would inhibit the efficiency of base-catalyzed processes. Therefore, the proposed acid-catalyzed upgrading strategy is advantageous for biomass conversion in terms of process simplicity.

Ruthenium/Iridium-Catalyzed C-2 Activation of Indoles with Bicyclic Olefins: An Easy Access to Functionalized Heterocyclic Motifs

Selective C-2 functionalization of N-protected and free indoles is reported. The ruthenium-catalyzed C-2 activation of indoles provided an easy access to cyclopentenylated indoles. Hydroheteroarylated bicyclic motifs were synthesized via iridium-catalyzed C-2 activation of NH indoles. The methodology was extended to different bicyclic adducts such as diaza- or urea-derived bicyclic olefins.

A new approach on diminutive effects for non-covalent interactions: fused bicyclic hydrogen-bonded complexes of hypohalous acids with fluoromethanol

ABSTRACTThe computational study of dimer and trimer complexes of fluoromethanol (CH2FOH) with one or two molecules of hypohalous acids (HOX; X = F, Cl or Br) was carried out at the MP2/aug-cc-pVDZ computational level. Also to show the reliability of these results, the binding distance and interaction energy have been compared with large basis set aug-cc-pVTZ level for some systems. The 1:1 ratio gives two different hexagonal and heptagonal ring complexes and the 1:2 ratio of CH2FOH/HOX leads to fused bicyclic hydrogen-bonded trimer adducts constructed from hexagonal and heptagonal rings. The results show diminutive effects in the range of 0.36–0.78 kcal/mol for the trimer bicyclic systems. Redshifts with bond elongations were observed for H–O and C–F bonds, while blueshifts along with bond contractions were seen for the C–H and the X–O bonds. The CH2FOH/HOX complexes were analysed using the Quantum Theory of Atoms in Molecules (QTAIM) and natural bond orbital methodologies.

Comparative in vitro Cytotoxic Studies of Novel 8-(4'/2'-Methoxy/Unsubstituted phenylcarbamoyl)bicyclo[3.3.1]nonane Derivatives on Ehrlich Ascites Carcinoma Cell Line.

Novel bicyclo[3.3.1]nonane derivatives were synthesized by an efficient methodology from acetoacetanilide, 2-methoxy and 4-methoxyacetoacetanilides, 1,3,5-trinitrobenzene and triethylamine. The structures of the compounds were characterized by UV/Visible, FTIR, (1)H NMR and 2D-correlation spectroscopy analysis. The in vitro cytotoxic studies were performed using Ehrlich Ascites Carcinoma cell line by Trypan blue dye exclusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay. The IC50 values of the 8-(4'-/2'-methoxy/unsubstituted phenylcarbamoyl)bicyclo[3.3.1]nonanes were found to be 110.65 μg/ml, 148.23 μg/ml and 151.71 μg/ml, respectively. Thus (4-methoxyphenylcarbomyl)bicyclo[3.3.1]nonane was more potent compared to other two bicyclic adducts.

Aza and oxo Diels–Alder reactions using cis-cyclohexadienediols of microbial origin: chemoenzymatic preparation of synthetically valuable heterocyclic scaffolds

Aza and oxo Diels–Alder reactions using enantiopure cis-cyclohexadienediols were studied. These dienediols were obtained from the biotransformation of monosubstituted arenes using bacterial dioxygenases (toluene and benzoate dioxygenases). Ethyl glyoxylate and its N-tosyl imine were used as dienophiles to afford the corresponding hetero Diels–Alder bicyclic adducts with excellent regio- and stereoselectivities. Quantum chemical calculations at the B3LYP/6-31+G(d,p) level of theory were performed to rationalize the observed selectivities especially the stereochemical aspects of the cycloadditions. The synthetic importance of these adducts is highlighted for the preparation of enantiopure 2,2,3,4,5,6-hexasubstituted piperidine and tetrahydropyran from toluene.

Diels–Alder reactions of five-membered heterocycles containing one heteroatom

Diels–Alder reactions of five-membered heterocycles containing one heteroatom with an N-arylmaleimide were studied. Cycloaddition of 2,5-dimethylfuran (4) with 2-(4-methylphenyl)maleimide (3) in toluene at 60°C gave bicyclic adduct 5. Cycloadditions of 3 with 2,5-dimethylthiophene (11) and 1,2,5-trimethylpyrrole (14) were also studied. Interestingly, the bicyclic compound 5 cleanly rearranged, with loss of water, when treated with p-toluenesulfonic acid in toluene at 80°C to give 4,7-dimethyl-2-p-tolylisoindoline-1,3-dione (6).

The reaction of dithioerythritol and dithiothreitol with As(III), Sb(III), and Bi(III) compounds

Arsenic trichloride and As2O3 reacted in methanol with dithioerythritol (DTE) and dithiothreitol (DTT) giving the known bicyclic adducts DTE-As and DTT-As, while Sb2O3 (in DMSO) and Bi2O3 (in MeOH) did not react. The oligo- or polymeric phenylarsine oxide reacted with DTE/DTT giving the cyclic adduct DTE-AsPh, while the structure of the DTT-AsPh is not certain. Under a 1:1 stoichiometry, antimony(III) and bismuth(III) chlorides as well as bismuth(III) nitrate pentahydrate afforded the respective monomeric, cyclic adducts with DTE/DTT in methanol, but in acetonitrile were also spectroscopically detected NH4 + and acetamide (AcNH2) occluded in the adducts. The 1H and 13C NMR spectra of Sb(III) and Bi(III) complexes showed broad to very broad signals. The exchange reaction between complexed DTE/DTT and 2,3-dithio-1-propanol (British Anti-Lewisite) was also studied. .

ChemInform Abstract: A Facile Synthesis of β‐Amino Carbonyl Compounds Through an Aza‐Michael Addition Reaction under Solvent‐Free Conditions.

AbstractPrimary and secondary aliphatic amines react at room temperature with oxanorbornene (I) to yield bicyclic adducts (III) whereas anilines produce significant amounts of (Z)‐β‐enamine esters (VI) as side products.

Silver‐Promoted Benzannulations of Siloxyalkynes with Pyridinium and Isoquinolinium Salts

We describe the development of efficient benzannulations of siloxy alkynes with pyridinium and isoquinolinium salts. Such reactions are successfully promoted by a stoichiometric amount of silver(I) benzolate under mild reaction conditions. This process proceeds via a formal inverse-electron demand Diels-Alder reaction, followed by fragmentation of the initially produced bicyclic adducts to deliver a range of synthetically useful phenols and naphthols.

ChemInform Abstract: Phosphonated Bicycles Bearing a N‐N Junction.

AbstractDiels—Alder reactions between the diene (I) and dienophiles (II) and (IV) give access to phosphonated bicyclic adducts bearing a N—N junction.