On the mechanism and kinetics of radical reactions of epoxyketones and epoxynitriles induced by titanocene chloride

The reactions of a series of epoxynitriles and epoxyketones induced by titanocene chloride have been studied. The kinetics of the decyanogenation of beta,gamma-epoxynitriles with Ti(III) corresponds to a radical reaction (k25 approximately 106 s-1), as demonstrated by competition experiments with H-transfer from 1,4-cyclohexadiene (1,4-CHD) or PhSH or conjugate addition to acrylonitrile. The 5-exo cyclization onto nitrile induced by Ti(III) is a radical reaction (k25 approximately 107 s-1) as seen in competition experiments with H-transfer from PhSH or the titanocene-water complex. The iminyl or alkoxyl radicals generated by 5-exo cyclization onto nitriles or ketones only undergo a reduction with Ti(III). This reaction overwhelms any alternative process, such as tandem cyclization onto alkenes or beta-scission. Iminyl radicals generated by 4-exo cyclizations onto nitriles undergo reduction with Ti(III) and beta-scission reaction in a ratio of 96:4 when the alpha-substituent is CN. Alkoxyl radicals from 4-exo cyclizations onto ketone carbonyls undergo reduction with Ti(III) and beta-scission in a ratio of 60:40 when the alpha-substituent is COOR. In nearly all the reactions studied, the role of Ti(III) is triple: a radical initiator (homolytic cleavage of oxirane), a Lewis acid (coordination to CN or C=O), and a terminator (reduction of iminyl or alkoxyl radicals).     

Alkanethioimidoyl radicals: evaluation of beta-scission rates and of cyclization onto S-alkenyl substituents

Thioimidoyl radicals were generated by addition of alkylsulfanyl radicals to alkyl isonitriles and were characterized by electron paramagnetic resonance (EPR) spectroscopy. The beta-scissions of their C.S-C bonds were studied by variable-temperature EPR spectroscopy and the fragmentation rate constants and activation energies were calculated. The scission rates depend on the stability of the released alkyl radicals but in any case, at room temperature, the processes were fast. Data collected on similar oxyimidoyls showed that their fragmentations are slightly slower compared to those of analogous thioimidoyls. The scission rates of selenoimidoyls could not be studied by EPR and were evaluated by theoretical calculations. EPR experiments also enabled both beta-scission and 5-exo ring closure rate constants of two S-but-3-enyl-substituted imidoyl radicals to be determined, showing that cyclization prevails only at low temperatures. Density functional theory (DFT) theoretical calculations predicted that the fragmentation process preferentially occurs from the s-cis rotamers (X-C bond) of the imidoyl radicals. Thio- and seleno-imidoyls (but not oxyimidoyls) prefer s-trans conformations so that their fragmentations involve prior rotation about the X-C bond.     

Controlling regioselectivity in cyclization of unsaturated amidyl radicals: 5-exo versus 6-endo

Intramolecular cyclization of an amidyl radical onto an olefin provides an appealing method for the synthesis of lactams and other nitrogen-containing heterocycles. Here we conducted the first, systematic theoretical study on the regioselectivity in the cyclization of various types of pent-4-enamidyl radicals that carried synthetically relevant substituents. It was found that the cyclization of most of the substituted pent-4-enamidyl radicals produced the 5-exo products (gamma-lactams) almost exclusively. Marcus theory analysis showed the involvement of both the thermodynamic (stabilization of the starting double bond or the resulting radical center) and intrinsic (mainly steric effects) contributions in determining the 5-exo selectivity. Nonetheless, in two types of systems we found that the delta-lactams became the favored products through the 6-endo cyclization. In one of the systems an aromatic substituent was placed at the C4-position, whereas in the other system an electron-rich aromatic ring was incorporated into the pent-4-enamidyl radical backbone at the C2- and C3-positions. This unprecedented 6-endo mode of amidyl radical cyclization provided an interesting route for the preparation of mono- and bicyclic delta-lactams (pyridinones).     

Substituent cross-interaction effects on the electronic character of the C=N bridging group in substituted benzylidene anilines--models for molecular cores of mesogenic compounds. A 13C NMR study and comparison with theoretical results

13C NMR chemical shifts delta(C)(C=N) were measured in CDCl3 for a wide set of mesogenic molecule model compounds, viz. the substituted benzylidene anilines p-X-C6H4CH=NC6H4-p-Y (X = NO2, CN, CF3, F, Cl, H, Me, MeO, or NMe2; Y = NO2, CN, F, Cl, H, Me, MeO, or NMe2). The substituent dependence of delta(C)(C=N) was used as a tool to study electronic substituent effects on the azomethine unit. The benzylidene substituents X have a reverse effect on delta(C)(C=N): electron-withdrawing substituents cause shielding, while electron-donating ones behave oppositely, the inductive effects clearly predominating over the resonance effects. In contrast, the aniline substituents Y exert normal effects: electron-withdrawing substituents cause deshielding, while electron-donating ones cause shielding of the C=N carbon, the strengths of the inductive and resonance effects being closely similar. Additionally, the presence of a specific cross-interaction between X and Y could be verified. The electronic effects of the neighboring aromatic ring substituents systematically modify the sensitivity of the C=N group to the electronic effects of the benzylidene or aniline ring substituents. Electron-withdrawing substituents on the aniline ring decrease the sensitivity of delta(C)(C=N) to the substitution on the benzylidine ring, while electron-donating substituents have the opposite effect. In contrast, electron-withdrawing substituents on the benzylidene ring increase the sensitivity of delta(C)(C=N) to the substituent on the aniline ring, while electron-donating substituents act in the opposite way. These results can be rationalized in terms of the substituent-sensitive balance of the electron delocalization (mesomeric effects). The present NMR characteristics are discussed as regards the computational literature data. Valuable information has been obtained on the effects of the substituents on the molecular core of the mesogenic model compounds.     

Generation of alpha-phosphonovinyl radicals and development of a new route to highly functionalized vinylphosphonates and vinylphosphonate-incorporated carbocyclic or heterocyclic compounds via a radical trapping sequence

The first direct generation of synthetically useful alpha-phosphonovinyl radicals was achieved by treatment of alpha-phosphonovinyl halides with a tributyltin radical. The alpha-phosphonovinyl radicals 2a-d were trapped with electron-rich olefins and an electron-deficient olefin to produce alpha-functionalized vinylphosphonates 3a-f in 16-55% yields. The alpha-phosphonovinyl radicals 7e-g containing the YCH2CH=CH2 (Y = O, CH2, S) substituent at the beta-position afforded mixtures of 5-exo and 6-endo cyclization products, 5e-g and 6e-g, in good yields. The 5-exo/6-endo product ratios increase in the following order of the beta-substituent: OCH2CH=CH2 > CH2CH2CH=CH2 > SCH2CH=CH2. The effects of the beta-substituents upon the cyclization reaction were discussed. Radical cyclization of alpha-phosphonovinyl radicals bearing functional groups such as geranyloxy, geranylthio, and (2-cyclohexen-1-yl)thio groups at the beta-position afforded 5-exo, 5-exo and 6-endo, and cis-fused-5,6-ring cyclization products incorporating an alpha,beta-unsaturated phosphonate unit within the ring, respectively, in good yields. The alpha-phosphonovinyl radical 20 underwent tandem radical cyclization-radical cyclization to produce a mixture of two isomeric bicyclo[4.3.0]nonenes including a vinylphosphonate moiety in high yield.     

Direct synthesis of previously inaccessible bridgehead azabicyclics by intramolecular cyclization of alpha-sulfonamido and alpha-sulfonimido radicals

Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are described. Both approaches capitalize on the electrophilicity of alpha-sulfonyl radicals and their propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and 6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction center is a carbon-carbon triple bond, the first cyclization gives rise to vinyl radicals that hold sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads importantly to the introduction of a styrene functionality sufficiently activated to allow a second ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been elucidated by X-ray crystallographic methods. Despite key differences from the norm in the alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit good hydrolytic stability. For 13, generation of the alpha-sulfonamide carbanion is possible and regiospecific oxidation with chromyl acetate has been achieved.     

Cyclizations of N-stannylaminyl radicals onto nitriles

[reaction: see text] Stannylaminyl radicals derived from radical reactions of Bu(3)SnH with azidoalkylmalononitriles exhibit highly efficient 5- and 6-exo cyclization onto either nitrile group to give aminoiminyl radicals that in turn are reduced to amidines or undergo successive 5-exo cyclization onto an internal alkene.     

Comparison of the kinetics and thermodynamics for methyl radical addition to C=C, C=O, and C=S double bonds

The barriers, enthalpies, and rate constants for the addition of methyl radical to the double bonds of a selection of alkene, carbonyl, and thiocarbonyl species (CH(2)=Z, CH(3)CH=Z, and (CH(3))(2)C=Z, where Z = CH(2), O, or S) and for the reverse beta-scission reactions have been investigated using high-level ab inito calculations. The results are rationalized with the aid of the curve-crossing model. The addition reactions proceed via early transition structures in all cases. The barriers for addition of methyl radical to C=C bonds are largely determined by the reaction exothermicities. Addition to the unsubstituted carbon center of C=C double bonds is favored over addition to the substituted carbon center, both kinetically (lower barriers) and thermodynamically (greater exothermicities). The barriers for addition to C=O bonds are influenced by both the reaction exothermicity and the singlet-triplet gap of the substrate. Addition to the carbon center is favored over addition to the oxygen, also both thermodynamically and kinetically. For the thiocarbonyl systems, addition to the carbon center is thermodynamically favored over addition to sulfur. However, in this case, the reaction is contrathermodynamic, addition to the sulfur center having a lower barrier due to spin density considerations. Entropic differences among corresponding addition and beta-scission reactions are relatively minor, and the differences in reaction rates are thus dominated by differences in the respective reaction barriers.     

Preparation of polycyclic systems by sequential 5-exo-digonal radical cyclization, 1,5-hydrogen transfer from silicon, and 5-endo-trigonal cyclization

Radicals of type 1 undergo 5-exo diagonal cyclization, and the resulting vinyl radical abstracts hydrogen from silicon to afford a silicon-centered radical. This radical closes in a 5-endo trigonal manner to generate radicals of type 4, which are reduced (4 --> 5) by stannane, except when the starting acetylene carries a terminal trimethylstannyl group. In this case, radicals 4 expel trimethylstannyl radical to afford vinyl silanes 6. The stereochemical outcome of the radical cascade 1 --> 5 is controlled by the stereochemistry of the oxygen-bearing carbon in 1 (see starred atom). The sequence can be initiated by carbon-, alpha-substituted carbon-, oxyacyl-, and carbamoyl radicals and generates a silicon-containing ring fused onto a carbocycle or heterocycle. Numerous examples are described, as well as a number of transformations of the final cyclization products, especially their response to n-Bu(4)NF and to BF(3).OEt(2), reagents that cleave the newly formed carbon-silicon bond.     

Neutralization-Reionization of alkenylammonium cations: An experimental and ab initio study of intramolecular N-H … C=C interactions in cations and hypervalent ammonium radicals

A series of isomeric hexenylammonium and hexenyldimethylammonium cations were neutralized by collisional electron transfer in the gas phase in an attempt to generate hypervalent ammonium radicals. The radicals dissociated completely on the 4.8–5.4 µs time scale. Radicals in which the hexene double bond was in the 3-, 4-, and 5-positions dissociated by competitive N-H and N=C bond cleavages. Allylic 2-hexen-1-ylammonium and 2-hexen-1-yldimethylammonium radicals underwent predominant cleavages of allylic N-C bonds. Deuterium labeling experiments revealed no intramolecular hydrogen transfer from the hypervalent ammonium group to the hexene double bond. Ab initio and density functional theory calculations showed that alkenylammonium and alkenylmethyloxonium ions preferred hydrogen bonded structures in the gas phase. The stabilization through intramolecular H bonding in 3-buten-1-ylammonium and 3-buten-1-yl methyloxonium ions was calculated by B3LYP/6-311G(2d,p) at 26 and 18 kJ mol^?1, respectively. No intramolecular hydrogen bonding was found for the allylammonium ion. The hypervalent 3-buten-1-yl-methyloxonium radical was calculated to be unbound and predicted to dissociate exothermically by O-H bond cleavage. This dissociation may provide kinetic energy for the hydrogen atom to overcome a small energy barrier for exothermic addition to the double bond. The 3-butten-1-ylammonium and allylammonium radicals were found to be bound and preferred gauche conformations without intramolecular hydrogen bonding. Vertical neutralization of alkenylammonium ions was accompanied by small Franck-Condon effects. The failure to detect stable or metastable hypervalent alkenylammonium radicals was ascribed to the low activation barriers to exothermic dissociations by N-H and N-C bond cleavages.     

Alkenylthioimidoyl radicals: competition between beta-scission and cyclization to dihydrothiophen-2-ylidene-amines

[reaction: see text] But-3-enylthioimidoyl radicals were shown by EPR spectroscopy and end product analysis to ring-close predominantly in the 5-exo mode with a rate constant of 2.4 x 10(4) s(-)(1) at 300 K to afford substituted dihydrothiophenylmethyl radicals. This ring closure was in competition with dissociation to but-3-enyl radicals and an isothiocyanate. The dissociation predominated at temperatures above ca. 300 K.     

Estimation on the intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies in glycine and alanine peptides

Computation of accurate intramolecular hydrogen-bonding energies for peptides is of great importance in understanding the conformational stabilities of peptides and developing a more accurate force field for proteins. We have proposed a method to determine the intramolecular seven-membered ring N-H...O=C hydrogen-bonding energies in glycine and alanine peptides. In this article, the method is further applied to evaluate the intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies in peptides. The optimal structures of the intramolecular 10-membered ring N-H...O=C hydrogen bonds in glycine and alanine tripetide molecules are obtained at the MP2 level with 6-31G(d), 6-31G(d,p), and 6-31+G(d,p) basis sets. The intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies are then evaluated based on our method at the MP2/6-311++G(3df,2p) level with basis set superposition error correction. The intramolecular 10-membered ring N-H...O=C hydrogen-bonding energies are calculated to be in the range of -6.84 to -7.66, -4.44 to -4.98, and -6.95 to -7.88 kcal/mol. The method is also applied to estimate the individual intermolecular hydrogen-bonding energies in the dimers of amino-acetaldehyde, 2-amino-acetamide, formamide, and oxalamide, each dimer having two identical intermolecular hydrogen bonds. According to our method, the individual intermolecular hydrogen-bonding energies in the four dimers are calculated to be -1.77, -1.67, -6.35, and -4.82 kcal/mol at the MP2/6-311++G(d,p) level, which are in good agreement with the values of -1.84, -1.72, -6.23, and -4.93 kcal/mol predicted by the supermolecular method.     

Reducing ability of supramolecular C60 dianion toward C=O, C=C and N-N bonds

Different from C60 dianion which readily reacts with electrophiles, supramolecular C60 dianion (2) generated from gamma-cyclodextrin-bicapped C60 (1) and NaBH4 (or diborate) in DMSO-H2O (9:1, v/v) is able to reduce N-N+, C=C-EWG and C=O bonds to provide the respective dihydro derivatives; 1-mediated reduction of acetophenone with NaBH4 in the presence of (Me2N)2CH2 and EtONa gives turn over frequency (TOF)/h of 400.     

Solid-state photochemical [2+2] cycloaddition in a hydrogen-bonded metal complex containing several parallel and crisscross C=C bonds

One-dimensional hydrogen-bonded complex [Zn(bpe)(2)(H(2)O)(4)](NO(3))(2).8/3 H(2)O.2/3 bpe (1, bpe=4,4'-bipyridylethylene) containing coordination complex cations [Zn(bpe)(2)(H(2)O)(4)](2+) with parallel and crisscross double bonds undergoes photochemical [2+2] cycloaddition in the solid state and produces tetrakis(4-pyridyl)cyclobutane (tpcb) in up to 100 % yield with rctt-tpcb (2a) as major and rtct-tpcb (2b) as minor product. The bpe ligands with crisscross conformation of C=C bonds appear to undergo pedal-like motion prior to photodimerization. Grinding single crystals to powder accelerates the pedal motion of crisscrossed olefins in the bpe ligands to parallel alignment and provides the rctt-cyclobutane stereoisomer 2a quantitatively. In addition, 100 % photodimerization of ground 1 indicates that the free bpe ligands, which are remote from each other in a pool of water, and NO(3)(-) ions moved toward each other to give a mixture of rctt- and rtct-tpcb isomers.     

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.     

Shape of 4S- and 4R-hydroxyproline in gas phase

The alpha-amino acids 4(S)-hydroxyproline and 4(R)-hydroxyproline have been studied under isolation conditions in gas phase using laser-ablation molecular-beam Fourier transform microwave spectroscopy. Two conformers of each molecule have been detected in the jet-cooled rotational spectrum. The most stable conformer in both molecules exhibits an intramolecular N...H-O hydrogen bond (configuration 1) between the hydrogen atom of the carboxylic group and the nitrogen atom. The second conformer is characterized by an intramolecular N-H...O=C hydrogen bond (configuration 2). The conformers of 4(R)-hydroxyproline adopt a C(gamma)-exo puckering, while those of 4(S)-hydroxyproline present a C(gamma)-endo ring conformation. These ring conformations, which show the same propensity observed in collagen-like peptides, are stabilized by additional intramolecular hydrogen bonds involving the 4-hydroxyl group, with the exception of the most stable form of 4(S)-hydroxyproline for which a n-pi interaction between the oxygen atom of the 4-hydroxyl group and the carboxyl group carbon seems to be established. A gauche effect could be also contributing to stabilize the observed conformers.     

Kinetic results implicating a polar radical reaction pathway in the rearrangement catalyzed by alpha-methyleneglutarate mutase

alpha-Methyleneglutarate mutase (MGM) catalyzes the rearrangement of 2-methyleneglutarate to 3-methylitaconate (2-methylene-3-methylsuccinate). A putative mechanism for the MGM-catalyzed reaction involves 3-exo cyclization of the 2-methyleneglutaric acid-4-yl radical to a cyclopropylcarbinyl radical intermediate that ring opens to the 3-hydroxycarbonyl-2-methylenebutanoic acid-4-yl radical (3-methylitaconic acid radical). Model reactions for this mechanism were studied by laser flash photolysis kinetic methods. alpha-Ester radicals were produced by 266 nm photolysis of alpha-phenylselenyl ester derivatives. Rate constants for cyclizations of the (Z)-1-ethoxycarbonyl-4-(2,2-diphenylcyclopropyl)-3-buten-1-yl radical ((Z)-8a) and (E)- and (Z)-1,3-di(ethoxycarbonyl)-4-(2,2-diphenylcyclopropyl)-3-buten-1-yl radicals ((E)- and (Z)-8b) were determined. The ester group in (Z)-8a accelerates the 3-exo cyclization in comparison to the parent radical lacking an ester group by a factor of 3, an effect ascribed to a polarized transition state. The ester groups at C3 in radicals 8b slow the 3-exo cyclization reaction by a factor of 50. The rate constant for cyclization of the 2-methyleneglutaric acid-4-yl radical is estimated to be k approximately 2000 s(-1) at ambient temperature. When coupled with the estimated partitioning of the intermediate cyclopropylcarbinyl radical, the overall rate constant for the conversion is estimated to be k approximately equal to 1 x 10(-3) s(-1), which is much too small for any radical reaction and several orders of magnitude too small for kinetic competence for the MGM-catalyzed process. The possibility that the radical reaction in nature involves an unusual mechanism in which polar effects are important is discussed.     

Transfer hydrogenation of activated C=C bonds catalyzed by ruthenium amido complexes: reaction scope, limitation, and enantioselectivity

[reaction: see text] It was found that the chemoselectivity could be completely switched from C=O to C=C bonds in the transfer hydrogenation of activated alpha,beta-unsaturated ketones catalyzed by diamine-ruthenium complex. Moreover, this addition via metal hydride had been applied to the reduction of various activated olefins. The electron-withdrawing ability of functional groups substituted on C=C bonds at the alpha- or beta-position had strong influence on the reactivity. In addition, a wide variety of chiral diamine-Ru(II)-(arene) systems was investigated to explore the asymmetric transfer hydrogenation of prochiral alpha,alpha-dicyanoolefins. Two parameters had been systematically studied, (i) the structure of the N-sulfonylated chiral diamine ligands, in which several chiral diamines substituted on the benzene ring of DPEN were first reported, and (ii) the structure of the metal precursors, and high enantioselectivitiy (up to 89% ee) at the beta-carbon was obtained.     

5-Exo versus 6-endo cyclization of primary aminyl radicals: an experimental and theoretical investigation

The cyclization of neutral primary pent-4-enylaminyl radicals was investigated experimentally and theoretically. Unlike the corresponding secondary aminyl radicals, primary pent-4-enylaminyl radicals underwent efficient cyclization to afford the pyrrolidine and/or piperidine products in good to high yields. While the simple pent-4-enylaminyl radical gave predominately the 5-exo cyclization product, 4-chloropent-4-enylaminyl radicals led to the formation of the corresponding 6-endo cyclization products in excellent regioselectivity. Theoretical calculations revealed that the 5-exo cyclization rate of primary aminyl radicals is about 3-4 orders of magnitude higher than that of secondary aminyl radicals.     

Synthesis and Crystal Structure of 2-Chloromethyl-1H-benzimidazole Nitrate, [ClCH_2(C_7H_6N_2)]NO_3

1 INTRODUCTION Benzimidazole is an interesting heterocyclic compound because it is found in various naturally occurring drugs, such as omeprazole, astemizole and emedastine difumarate[1]. The efficacy of sub- stituted benzimidazoles in the treatment of parasitic infections is well known[2～4]. Substituted benzimid- azole moieties are established pharmacophores in parasitic chemotherapy. Bis(2-benzimidazole) and some substituted bis(benzimidazol-2-yl)alkanes have attracted much interest …