Evidence that protons can be the active catalysts in Lewis acid mediated hetero-Michael addition reactions

The mechanism of Lewis acid catalysed hetero‐Michael addition reactions of weakly basic nucleophiles to α,β‐unsaturated ketones was investigated. Protons, rather than metal ions, were identified as the active catalysts. Other mechanisms have been ruled out by analyses of side products and of stoichiometric enone–catalyst mixtures and by the use of radical inhibitors. No evidence for the involvement of π‐olefin–metal complexes or for carbonyl–metal‐ion interactions was obtained. The reactions did not proceed in the presence of the non‐coordinating base 2,6‐di‐tert‐butylpyridine. An excellent correlation of catalytic activities with cation hydrolysis constants was obtained. Different reactivities of mono‐ and dicarbonyl substrates have been rationalised. A ¹H NMR probe for the assessment of proton generation was established and Lewis acids have been classified according to their propensity to hydrolyse in organic solvents. Brønsted acid‐catalysed conjugate addition reactions of nitrogen, oxygen, sulfur and carbon nucleophiles are developed and implications for asymmetric Lewis acid catalysis are discussed.     

Highly stereoselective ring-opening addition of terminal acetylenes to bicyclic olefins catalyzed by nickel complexes

[reaction: see text] Treatment of 7-oxa- and 7-azabenzonorbornadienes with terminal acetylenes in the presence of Ni(dppe)Cl2, ZnCl2, and Zn powder in toluene at 90 degrees C afforded the corresponding cis-2-alkynyl-1,2-dihydronaphthalene derivatives in moderate to excellent yields with remarkably high stereoselectivity.     

Highly stereoselective synthesis of vicinal diols by stannous chloride-mediated addition of hydroxyallylic stannanes to aldehydes

A new protocol for the synthesis of vicinal diols was accomplished by the reaction of unprotected α-hydroxymethylmetals, as hydroxymethyl anion equivalents, with aldehydes. The treatment of hydroxyallylic stannanes, which were prepared from α,β-unsaturated aldehydes and Bu₃SnLi in situ, with various aldehydes gave but-3-en-1,2-diols in the presence of SnCl₂. The stereochemistry of the diol and olefin moieties demonstrated syn- and E-selectivities, respectively. We propose the following reaction mechanism; transmetalation of a hydroxyallylic stannane with SnCl₂ gives a rearranged allylic tin(II) species that undergoes aldehyde addition via a cyclic transition state. The strict interaction between the unprotected hydroxy moiety and the tin(II) center accounts for the selectivity.     

Pmo analysis of cycloadditions- II. The transition state of the addition of formonitrile oxide to acetylene

Perturbation calculations on the transition state of the reaction of formonitrile oxide (fulminic acid) with acetylene are reported. The energy partitioning in covalent and non-covalent contributions reveals that the type II behavior of formonitrile oxide which is expected according to the classification scheme of cycloadditions is observed only if distortions of the molecules as in the ab-initio calculated transition state structure are taken into account. The results support unequal bond formation with a preference for the CC bond.     

Highly enantioselective vinylogous addition of 2-trimethylsilyloxyfuran to aldehydes promoted by the SiCl4/chiral Lewis base system

This paper reports the regio-, diastereo- and highly enantioselective vinylogous aldol reaction of 2-trimethylsilyloxyfuran (TMSOF) promoted by the SiCl₄/Lewis base catalytic system. Several electron-pair donors proved to be effective as SiCl₄ activators versus the TMSOF γ-selective addition to aldehydes giving rise to different diastereoisomeric ratios, while Denmark’s chiral bis-phosphoramide (R,R)-7 gave the highest enantioselectivity for both the anti- and syn-diastereoisomers. Furthermore, by using ambident electrophiles such as α,β-unsaturated aldehydes, the SiCl₄/Lewis base-promoted process leads exclusively to the 1,2-addition products.     

Phosphonyl radical addition to enol ethers. The stereoselective synthesis of cyclic ethers

Addition of diethyl phosphite or diethyl thiophosphite to enol ethers, in the presence of a radical initiator, results in the regioselective synthesis of organophosphonate or phosphonothioate derivatives, respectively, under mild conditions. This method can be applied to the stereoselective formation of substituted tetrahydrofurans and tetrahydropyrans, on cyclisation of vinyl ethers bearing unsaturated side chains.     

Lewis acids catalyze the addition of allylboronates to aldehydes by electrophilic activation of the dioxaborolane in a closed transition structure

This study addressed the mechanism of the recently reported Lewis acid-catalyzed manifold for additions of allylboronates to aldehydes. A series of control experiments using various reagents and conditions, and kinetic studies by low-temperature NMR spectroscopy, were performed to investigate the origin of the activation provided by the best catalyst, Sc(OTf)3. The results obtained are strongly supportive of a mechanism involving electrophilic boron activation by coordination of the metal ion to one of the boronate oxygens in a closed bimolecular transition state.     

A highly stereoselective synthesis of optically active trisubstituted 1,2-ethylenediamines: the first example of grignard addition to N-diphenylphosphinoyl ketimines derived from amino acids

The efficient synthesis of optically active trisubstituted 1,2-ethylenediamines is described. Addition of aryl and/or alkyl Grignard reagents to alpha-amino N-diphenylphosphinoyl ketimines derived from alpha-amino acids was demonstrated to afford the desired trisubstituted 1,2-ethylenediamines in good yields and with high diastereoselectivities. Subsequent removal of the diphenyphosphinoyl group from the adduct was smoothly accomplished in reasonable yield without racemization under newly developed reductive conditions.     

Mechanistic impact of water addition to SmI2: consequences in the ground and transition state

The mechanistic impact of water addition to SmI2 on the ground state and rate-limiting transition state structures in the reduction of benzyl bromide was determined using UV-vis spectroscopy, cyclic voltammetry, vapor pressure osmommetry, and stopped-flow spectrophotometric studies. The results obtained from these studies show that, upon addition of water, SmI2 in THF (or DME) becomes partially water-solvated by displacing metal-coordinated solvent. Further addition of water displaces remaining bound solvent and induces a monomer-dimer equilibrium of the SmI2-water complex. Concomitant with this process, a thermodynamically more powerful reductant is created. Rate studies on the reduction of benzyl bromide by SmI2-water are consistent with reaction occurring through a dimeric transition state with the assembly of the activated complex requiring an equivalent of water at low concentrations but not at higher concentrations. The mechanistic complexity of the SmI2-water system shows that simple empirical models describing the role of water in SmI2-mediated reductions are likely to contain a high degree of uncertainty.     

Highly stereoselective chemoenzymatic synthesis of the 3H-isobenzofuran skeleton. Access to enantiopure 3-methylphthalides

A straightforward synthesis of (S)-3-methylphthalides has been developed, with the key asymmetric step being the bioreduction of 2-acetylbenzonitriles. Enzymatic processes have been found to be highly dependent on the pH value, with acidic conditions being required to avoid undesired side reactions. Baker's yeast was found to be the best biocatalyst acting in a highly stereoselective fashion. The simple treatment of the reaction crudes with aqueous HCl has provided access to enantiopure (S)-3-methylphthalides in moderate to excellent yields.     

Oxidative addition of water to novel Ir(I) complexes stabilized by dimethyl sulfoxide ligands.

The oxidative addition of water to novel Ir(I) DMSO complexes is described. IrCl(DMSO)3 (1) is synthesized in 90% yield when treating a toluene slurry of [Ir2Cl2(COE)4] (COE = cyclooctene) with excess DMSO. Its dimer, [Ir2Cl2(DMSO)4] (2) is obtained in 95% yield starting from 1. The cationic complex [Ir(DMSO)4]PF6 (6) is prepared in situ from [Ir(COE)2(O=CMe2)2]PF6 (5). These complexes add water at room temperature, giving rise to the oxidative addition products syn-[(DMSO)2HIr(mu-OH)2(mu-Cl)IrH(DMSO)2] [IrCl2(DMSO)2] (3) and anti-[(DMSO)2(DMSO)HIr(mu-OH)2IrH(DMSO)2(DMSO)](PF6)2 (7), respectively. Reductive elimination in pyridine leads to quantitative isolation of mixed Ir(I) DMSO-pyridine complexes IrCl(py)(DMSO)2 (4) and [Ir(py)2(DMSO)2]PF6 (8), respectively. Compounds 1, 3, and 7 have been characterized by X-ray crystallography. 3 and 7 show dimeric structures with the hydroxo ligands bridging the iridium atoms and in 7 both O- and S-bonded DMSO ligands are present.     

The Michael addition-elimination of ylides to alpha,beta-unsaturated imines. Highly stereoselective synthesis of vinylcyclopropanecarbaldehydes and vinylcyclopropylaziridines

The Michael addition-elimination of ylide to alpha,beta-unsaturated imines leads to a highly diastereoselective and enantioselective synthesis of vinylcyclopropanecarbaldehydes in good to high yields for the first time. A sequential cyclopropanation-aziridination protocol for the preparation of cyclopropylaziridines is also developed with good diastereoselectivity in good to high yields.     

Ab initio molecular orbital calculations on the transition state for the addition of a methyl radical to vinyl monomers

Ab initio molecular orbital calculations have been performed on the transition state for the addition of methyl radical to twelve vinyl monomers using the SV 3–21G basis set. A linear relationship has been found between the calculated energies of activation and previously calculated energies of reaction. This supports the assumption of an Evans-Polanyi type rule in previous work which attempted to correlate reactivity with calculated energies of reaction. The activation energies obtained for methyl addition to butadiene and styrene were calculated to be negative. This is caused by errors introduced by a number of sources, viz. basis set superposition error, spin contamination and zero point energy. These errors are discussed. Previous authors have reported reasonable agreement between calculated activation energies at SV3–21G and experimental values for methyl addition to ethylene, this work suggests that this agreement was coincidental and results from the fortuitous cancellation of errors. The nature of the transition state for these radical addition reactions is discussed and the limitations of the SV3–21G basis set are highlighted. The theoretical prediction of activation energies for radical addition reactions would require much larger calculations, beyond the computational means of most research laboratories.     

A highly stereoselective approach to the synthesis of functionalized pyran derivatives by Lewis acid assisted ketal reduction and allylation

Reduction of bicyclic ketal 1 gave functionalized pyran derivatives 7a or 7b in a highly stereoselective manner, depending upon the reduction conditions utilized. For example, treatment of ketal 1 with TiCl4/Et3SiH produced exclusively diol 7b with the 2,5-syn relationship in good yield. Alternatively, reduction of ketal 1 by DIBALH gave 2,5-anti-diol 7a stereoselectively. Alane reductions of ketal 1 were highly stereoselective also; however, the syn/anti selectivity observed was strongly dependent on the ratio of reagents employed for in situ generation of the alane. Lewis acid catalyzed allylation of ketal 1 gave pyran 10 in a stereospecific alkylation reaction.     

The N-hydroxymethyl group for stereoselective conjugate addition: application to the synthesis of (-)-statine

[reaction: see text] Efficient synthesis of enantiomerically pure (-)-statine was achieved with the stereoselective intramolecular conjugate addition of the hydroxyl group tethered to the amino group of a configurationally stable N-Boc-L-leucinal derivative.     

The fluoride ion-induced intramolecular conjugate addition of propargylsilanes to dihydropyridones. A novel method for the stereoselective construction of azabicyclic ring systems

The fluoride ion-induced intramolecular conjugate addition of propargylsilanes to dihydropyridones is reported. Our results revealed that tetrabutylammonium triphenyldifluorosilicate (TBAT), an air-stable, non-hygroscopic fluoride ion source, catalyzes cyclocondensation to provide the corresponding 1-vinylidene indolizidines in a high yield as single isomers, while Lewis acid catalysts were ineffective. The scope of this method was further investigated in the reactions leading to compounds with larger ring size. In these cases dihydropyridones with the propargylsilane located in the side-chain underwent cyclization to give 9-vinylidene quinolizidines with significantly lower yields.     

The transition state in the reduction of ketone by lithium tri-t-butoxyaluminohydride. A kinetic isotope effect study.

Analysis of experimental and calculated kinetic isotope effects in the title reaction (LiAl(OBu^t)₃H and LiAl(OBu^t)₃D) leads to the conclusion that the transition state occurs close to the mid-point of the reaction coordinate.     

Silylketenes under Kulinkovich conditions: alkene/ketene exchange versus nucleophilic addition. Application to the stereoselective preparation of vinylcyclopropanols

Silylketenes react under Kulinkovich conditions through two competitive pathways: alkene/ketene exchange versus nucleophilic addition. In both cases, the organotitanium intermediate reacts with an aldehyde to yield an adduct which can undergo an elimination to yield a vinylcyclopropanol or an α,β-unsaturated carbonyl compound.