A combined DFT and NMR investigation of the zinc organometallic intermediate proposed in the syn-selective tandem chain extension-aldol reaction of β-keto esters

The tandem chain extension-aldol (TCA) reaction of β-keto esters provides an α-substituted γ-keto ester with an average syn:anti selectivity of 10:1. It is proposed that the reaction proceeds via a carbon-zinc bound organometallic intermediate potentially bearing mechanistic similarity to the Reformatsky reaction. Evidence, derived from control Reformatsky reactions and a study of the structure of the TCA intermediate utilizing DFT methods and NMR spectroscopy, suggests the γ-keto group of the TCA intermediate plays a significant role in diastereoselectivity observed in this reaction. Such coordination effects have design implications for future zinc mediated reactions.     

Mechanism of the transition-metal-catalyzed hydroarylation of bromo-alkynes revisited: hydrogen versus bromine migration

A comprehensive mechanistic study of the InCl(3)-, AuCl-, and PtCl(2)-catalyzed cycloisomerization of the 2-(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst-dependent selectivity of the reactions. The results revealed that the 6-endo-dig cyclization is the most favorable pathway in both InCl(3)- and AuCl-catalyzed reactions. When AuCl is used, the 9-bromophenanthrene product could be formed by consecutive 1,2-H/1,2-Br migrations from the Wheland-type intermediate of the 6-endo-dig cyclization. However, in the InCl(3)-catalyzed reactions, the chloride-assisted intermolecular H-migrations between two Wheland-type intermediates are more favorable. These Cl-assisted H-migrations would eventually lead to 10-bromophenanthrene through proto-demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl(2) catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl(2)-catalyzed alkyne-vinylidene rearrangement and the 5-exo-dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9- and 10-bromophenanthrene products, as a result of the Cl-assisted H-migrations after the cyclization of the Pt-vinylidene intermediate. Alternatively, the intermediate from the 5-exo-dig cyclization would be transformed into a relatively stable Pt-carbene intermediate irreversibly, which could give rise to the 9-alkylidene fluorene product through a 1,2-H shift with a 28.1 kcal mol(-1) activation barrier. These findings shed new light on the complex product mixtures of the PtCl(2)-catalyzed reaction.     

Adsorption and reaction of 1-epoxy-3-butene on Pt(111): implications for heterogeneous catalysis of unsaturated oxygenates

High-resolution electron energy loss spectroscopy (HREELS), temperature-programmed desorption (TPD), and density functional theory (DFT) calculations were used to study the adsorption and reaction of 1-epoxy-3-butene (EpB) on Pt(111). These investigations were conducted to help elucidate mechanisms for improving olefin hydrogenation selectivity in reactions of unsaturated oxygenates. EpB dosed to Pt(111) at 91 K adsorbs molecularly on the surface through the vinyl group with apparent rehybridization to a di-sigma-bound state. By 233 K, however, EpB undergoes epoxide ring opening to form an aldehyde intermediate, which further decomposes upon heating to yield gas phase products CO, H2, and propylene. Comparison of the HREELS and TPD data to experiments performed with 2-butenal (crotonaldehyde) shows that EpB and 2-butenal decompose through related pathways. However, the EpB-derived aldehyde intermediate clearly has a unique structure, features of which have been elucidated by DFT calculations. In conjunction with previous surface science studies of EpB chemistry, these results can help explain selectivity trends for reactions of EpB on Pt catalysts and bimetallic PtAg catalysts, with indications that the enhanced olefin hydrogenation selectivity of PtAg catalysts likely originates from a bifunctional effect.     

C-glycosylation reactions of sulfur-substituted glycosyl donors: evidence against the role of neighboring-group participation

Nucleophilic substitution reactions of C-4 sulfur-substituted tetrahydropyran acetals revealed that neighboring-group participation does not control product formation. Spectroscopic evidence for the formation of an intermediate sulfonium ion is provided, as are data from nucleophilic substitution reactions demonstrating that products are formed from oxocarbenium ion intermediates. The selectivity was not sensitive to solvent or to which Lewis acid was employed. The identity of the heteroatom at the C-4 position also did not significantly impact diastereoselectivity. Consequently, neighboring-group participation was not responsible for the formation of either the major or the minor products. These studies implicate a Curtin-Hammett kinetic scenario in which the formation of a low-energy intermediate does not necessitate its involvement in the product-forming pathway.     

Nickel‐Catalyzed Regioselective Hydroalkylation and Hydroarylation of Alkenyl Boronic Esters

Metal hydride catalyzed hydrocarbonation reactions of alkenes are an efficient approach to construct new carbon–carbon bonds from readily available alkenes. However, the regioselectivity of hydrocarbonation remains challenging to be controlled. In nickel hydride (NiH) catalyzed hydrocarbonation, linear selectivity is most often obtained because of the relative stability of the linear Ni–alkyl intermediate over its branched counterpart. Herein, we show that the boronic pinacol ester (Bpin) group directs a Ni‐catalyzed hydrocarbonation to occur at its adjacent carbon center, resulting in formal branch selectivity. Both alkyl and aryl halides can be used as electrophiles in this hydrocarbonation, providing access to a wide range of secondary alkyl Bpin derivatives, which are valuable building blocks in synthetic chemistry. The utility of the method is demonstrated by the late‐stage functionalization of natural products and drug molecules, the synthesis of an anticancer agent, and iterative syntheses.     

Chemical and stereochemical behaviour of bifunctional enantiomeric silicon compounds : I. Study of α-naphthylferrocenyl-fluorosilane and -chlorofluorosilane

The synthesis of the first bifunctional enantiomeric silicon compounds is described. A high selectivity between the two functional groups is observed in substitution reactions with organolithium compounds and Grignard reagents, the more polarizable group being specifically replaced. The stereochemistry of the reactions has been determined by chemical correlations. The stability of the pentacoordinated intermediate (discussed in terms of apicophilicity of the various groups) does not suffice to explain the results. Inversion of the configuration comes from an axial attack of the reactant and retention of configuration is explained by an equatorial attack.     

Zirconium-catalyzed chemoselective methylalumination of ethers, amines, and sulfides bearing two terminal alkenyl groups

Chemoselectivity in the methylalumination reaction of unsymmetrical ethers, amines, and sulfides bearing two different terminal alkenyl groups, a 13-tetradecenyl group and an allyl, 4-pentenyl or 6-heptenyl group was examined. The methylalumination of the allyl derivatives proceeded with complete chemoselectivity to afford only the 13-tetradecenyl-monomethylated products. In the methylalumination reactions of the 4-pentenyl and the 6-heptenyl derivatives, in addition to the 13-tetradecenyl-monomethylated products, and dimethylated products were also obtained. However, as in the case of the allyl derivatives, monomethylation to the shorter 4-pentenyl or 6-heptenyl group was not observed, except in the case of 6-heptenyl 13-tetradecenyl amine. The unique selectivity was rationalized upon how readily the intramolecular ligand exchange reaction between intermediate zirconocenium-alkene and zirconocenium-heteroatom complexes could occur.     

Mechanism of the Transition‐Metal‐Catalyzed Hydroarylation of Bromo‐Alkynes Revisited: Hydrogen versus Bromine Migration

A comprehensive mechanistic study of the InCl₃‐, AuCl‐, and PtCl₂‐catalyzed cycloisomerization of the 2‐(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst‐dependent selectivity of the reactions. The results revealed that the 6‐endo‐dig cyclization is the most favorable pathway in both InCl₃‐ and AuCl‐catalyzed reactions. When AuCl is used, the 9‐bromophenanthrene product could be formed by consecutive 1,2‐H/1,2‐Br migrations from the Wheland‐type intermediate of the 6‐endo‐dig cyclization. However, in the InCl₃‐catalyzed reactions, the chloride‐assisted intermolecular H‐migrations between two Wheland‐type intermediates are more favorable. These Cl‐assisted H‐migrations would eventually lead to 10‐bromophenanthrene through proto‐demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl₂ catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl₂‐catalyzed alkyne–vinylidene rearrangement and the 5‐exo‐dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9‐ and 10‐bromophenanthrene products, as a result of the Cl‐assisted H‐migrations after the cyclization of the Pt–vinylidene intermediate. Alternatively, the intermediate from the 5‐exo‐dig cyclization would be transformed into a relatively stable Pt–carbene intermediate irreversibly, which could give rise to the 9‐alkylidene fluorene product through a 1,2‐H shift with a 28.1 kcal mol^?1 activation barrier. These findings shed new light on the complex product mixtures of the PtCl₂‐catalyzed reaction.     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

Pt/Al2O3 catalysts in the synthesis of nitrogen heterocycles. Catalytic synthesis of pyrazines

A study was carried out on the use of Pt/Al₂O₂ catalysts in the synthesis of pyrazines via the dehydrogenation of piperazines, dehydrodeamination of diamines, and dehydrocyclocondensation of N-hydroxyalkyldiamines. In contrast to the current hypothesis of the intermediate formation of piperazine in the latter two reactions, evidence was found that these reactions proceed through initial dehydrogenation and the dehydrogenated intermediate then undergoes cyclization. Polyalkylpyrazines, formed by the alkylotion of the pyrazine ring by hydrogenolysis products, are the major side-products in all the reactions studied. Pyrazines may be obtained in high yield and satisfactory selectivity by selecting suitable modifiers, which enhance the dehydrogenation activity of the catalyst and suppress the hydrogenolysis of the C-N bond.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1516–1525, November, 1993.     

Enantioselective cyanosilylation of ketones catalyzed by a chiral oxazaborolidinium ion

The chiral oxazaborolidinium salt 1 (X = TfO) is an excellent catalyst for the cyanosilylation of methyl ketones promoted by trimethylsilyl cyanide and diphenylmethyl phosphine oxide as co-reactants (to generate Ph(2)MePOTMS(N=C:) as a reactive intermediate). The face selectivity of this reaction parallels that previously observed for the corresponding reaction of aldehydes. A unifying and rational mechanistic explanation is provided for these enantioselective reactions. Evidence is presented to support the importance of alpha-C-H...O hydrogen bonding, pi,pi-interaction of the complexed ketonic carbonyl with the mexyl group of 1, and an early transition state for high enantioselectivity. The cyanosilylation reaction described herein provides access to many useful chiral compounds.     

Remote control of diastereoselectivity in intramolecular reactions of chiral allylsilanes

During investigations of cyclization reactions between chiral allylsilanes and N-acyliminium ions, it was discovered that a suitably positioned benzyloxy group on the allylsilane component caused a reversal in the diastereoselectivity of these reactions relative to that normally observed with alkyl-substituted allylsilanes. This effect was subsequently observed in two other reaction types. Investigations into this effect led to the proposal of product formation through thermodynamic control facilitated by neighboring group interactions with a transient cationic species. This hypothesis was experimentally supported by the isolation of an intermediate in the proposed mechanistic pathway.     

Use of a membrane reactor to improve selectivity to intermediate products in consecutive catalytic reactions

Through modeling it has been shown that a concentric-tube catalytic membrane reactor can be used to increase the selectivity for the intermediate products of a consecutive reaction scheme. The reactants are fed to the tube-side of the reactor where the catalyst is also located. The wall of the tube is permeable, allowing the intermediate products to pass through to the annular space instead of undergoing further reaction. The annular space is swept by an inert gas flow and contains no catalyst. Both permselective and non-permselective membranes have been considered in both co-current and counter-current flow regimes. In contrast to most catalytic membrane reactor applications where reactions are reversible and thermodynamically limited, in the present study the reactions considered are irreversible and are under kinetic control.     

Kinetic study of the phenolysis of O-methyl and O-phenyl O-2,4-dinitrophenyl thiocarbonates and O-ethyl 2,4-dinitrophenyl dithiocarbonate

The reactions of a series of phenols with O-methyl O-2,4-dinitrophenyl thiocarbonate (MDNPTOC), O-phenyl O-2,4-dinitrophenyl thiocarbonate (PDNPTOC), and O-ethyl 2,4-dinitrophenyl dithiocarbonate (EDNPDTC) are studied kinetically in water, at 25.0 degrees C and an ionic strength of 0.2 M (KCl). All reactions show pseudo-first-order kinetics under an excess of phenol over the substrate, and are first order in phenoxide anion. The reactions of EDNPDTC show a linear Br?nsted-type plot of slope beta = 0.67, suggesting a concerted mechanism. On the other hand, the phenolyses of MDNPTOC and PDNPTOC exhibit linear Br?nsted-type plots of slopes beta = 0.27 and 0.28, respectively, consistent with stepwise mechanisms where the formation of an anionic tetrahedral intermediate (T(-)) is rate determining. By comparison of the kinetics and mechanisms of the reactions under investigation with similar reactions, the following conclusions arise: (i). Substitution of S(-) by O(-) in the intermediate T(-) destabilizes this species. (ii). The change of DNPO in T(-) to DNPS also destabilizes this intermediate. (iii). Substitution of MeO by PhO as the nonleaving group of the substrate does not affect the kinetics, probably by a compensation of electronic and steric effects. (iv). The change of an amino group in a tetrahedral intermediate to a phenoxy group destabilizes the intermediate.     

Stereoselective C-glycosylation reactions of pyranoses: the conformational preference and reactions of the mannosyl cation

A systematic study of C-glycosylations of acetals related to mannose and other pyranoses was conducted. The C-5 alkoxyalkyl group provides only a modest influence on stereoselectivity. On the other hand, studies of pentopyranoses bearing alkoxy groups at C-2, C-3, and C-4 showed that the alkoxy groups exerted powerful influences on selectivity. In the case of mannose, the high alpha selectivity observed with C-mannosylation was reversed to high beta selectivity if the C-5 alkoxyalkyl group were removed. An analysis of the conformational preferences of the intermediate oxocarbenium ions, including the mannosyl cation, as well as consideration of steric effects that develop in the transition states for nucleophilic attack provide explanations for these phenomena.     

The role of steric and electronic interactions in the stereocontrol of the asymmetric 1,3-dipolar reactions of 5-ethoxy-3-p-(S)-tolylsulfinylfuran-2(5H)-ones with diazoalkanes: theoretical calculations and experimental evidences

The addition of diazomethane and diazoethane to (5S,SS)- and (5R,SS)-5-ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones (1a and 1b) and their 4-methylderivatives (2a and 2b) proceeded in almost quantitative yields and complete regioselectivity. The observed pi-facial selectivity is determined by the configurations at both C-5 and the sulfinyl group, the later being the most important. The syn adducts were almost exclusively obtained from 1a and 2a in apolar solvents but the pi-facial selectivity was strongly decreased in more polar solvents. On the other hand, the major adducts from 1b and 2b were the anti ones and such predominance was slightly increased with solvent polarity. The exo-selectivity was complete in all the cases except for the anti approach to compounds 2a (in polar solvents) and 2b. The role of the sulfinyl group in this behavior was inferred by comparison of these results with those obtained in reactions of diazoalkanes with 5-methoxyfuran-2(5H)-one (3). Steric interactions seem to be the main ones responsible for the observed exo selectivity of reactions with diazoethane, but electronic factors, which can be modulated by the solvent, are also significant in the pi-facial selectivity control. DFT computational methods are able to correctly predict the reactivity, regioselectivity, and pi-facial selectivity exhibited by 5-alkoxyfuranones as well as their changes with the solvent polarity. A C-H.O hydrogen bond, involving the oxygen atom of the 5-alkoxy group at dipolarophiles and the endo-hydrogen atom at dipoles, seems to play a key role in the electronic interactions influencing the stereochemical course of these reactions.     

Executing and rationalizing the synthesis of a difluorinated analogue of a ring-expanded calystegine B2

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.     

Mechanistic investigations of the ethylene tetramerisation reaction

The unprecedented selective tetramerisation of ethylene to 1-octene was recently reported. In the present study various mechanistic aspects of this novel transformation were investigated. The unusually high 1-octene selectivity in chromium-catalyzed ethylene tetramerisation reactions is caused by the unique extended metallacyclic mechanism in operation. Both 1-octene and higher 1-alkenes are formed by further ethylene insertion into a metallacycloheptane intermediate, whereas 1-hexene is formed by elimination from this species as in other reported trimerisation reactions. This is supported by deuterium labeling studies, analysis of the molar distribution of 1-alkene products, and identification of secondary co-oligomerization reaction products. In addition, the formation of two C6 cyclic products, methylenecyclopentane and methylcyclopentane, is discussed, and a bimetallic disproportionation mechanism to account for the available data is proposed.     

Oxidative Interception of the Hydroamination Pathway: A Gold‐Catalyzed Diamination of Alkenes

A complimentary diamination of alkenes by using homogeneous gold catalysts is described. The reaction is one of very few examples of homogeneous gold oxidation catalysis and proceeds with high selectivity under mild conditions. Individual steps of the suggested catalytic cycle were investigated on isolated model gold complexes, and new pathways for gold‐catalyzed amination reactions were established. The key step is an intramolecular alkyl–nitrogen bond formation from a gold(III) intermediate. This process validates the concept of reductive elimination from high oxidation catalyst states for this type of C? N bond forming reactions.