Bobbitt's Salt-Mediated Oxidation of Alkynyl-ols and -diols to the Corresponding Aldehydes and Their Application in Tandem Reactions.

Propargyl alcohol derivatives were readily oxidized using Bobbitt's salt to yield the corresponding propynal products. 2-Butyn-1,4-diol may be selectively oxidized to provide either 4-hydroxy-2-butynal or acetylene dicarboxaldehyde, and the resulting stable dichloromethane solutions containing the chemically sensitive acetylene aldehydes were used directly in subsequent Wittig, Grignard, or Diels-Alder reactions. This method provides safe and efficient access to propynals and allows the preparation of polyfunctional acetylene compounds from readily accessible starting material without the use of protecting groups.

Unrecognized Intramolecular and Intermolecular Attractive Interactions between Fluorine-Containing Motifs and Ether, Carbonyl, and Amino Moieties.

In order to elucidate to what extent Coulombic and other interactions contribute to the origins of contrasteric phenomena, we have identified a significant, previously unrecognized interaction between fluorine-containing motifs and groups or molecules containing main-group heteroatoms. The axial conformers of both 2-methoxy- and 2-trifluoromethoxytetrahydropyrans preferentially adopt a rotameric arrangement in which the OCH3 and the OCF3 groups are gauche to the ring oxygen. Given that one would expect a repulsive Columbic interaction to exist between the electronegative fluorines of the CF3 group and the ring oxygen in this rotomeric orientation, this surprising result suggests that an attractive interaction exists between the CF3 group and the oxygen of the ring. The generality and origin of this interaction was examined using nonpolar CF4 to probe intermolecular interactions with systems such as dimethyl ether, trimethylamine, trimethylphosphine, and acetone. In each case there was an attractive interaction leading to formation of a complex. The attraction is not due to van der Waals forces. Rather, the fluorine lone pairs of the CF4 often act as an electron donor in these complexes leading to a transfer of charge between the reactants and formation of the complex. These previously unrecognized fluorine-heteroatom interactions likely play a significant role in the context of understanding the binding interactions of medicinally relevant molecules or pharmaceuticals possessing fluorine-containing pharmacophores with their targets.

The Anomeric Effect: It's Complicated.

The origin of the anomeric effect has been reexamined in a coordinated experimental and computational investigation. The results of these studies implicate a number of different, but correlated, interactions that in the aggregate are responsible for the anomeric effect. No single factor is uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. A CH···G nonbonded attraction between a polar axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle has been demonstrated experimentally. The hyperconjugation model involving electron transfer from a ring heteroatom to an excited state of an axial C-G bond was shown to be, at most, a minor contributor because of the very small changes in charge density at the ring heteroatom(s): the main charge transfer is from hydrogen to G in the H-C-G unit. This appears to result from lengthening the C-G bond to minimize repulsion with the ring atom lone pair(s) and the advantage of having a more positive hydrogen that leads to a stabilizing Coulombic interaction with the ring heteroatom(s). In short, the anomeric effect arises mainly from two separate CH···G nonbonded Coulombic attractions.

Experimental Demonstration of a Sizeable Nonclassical CH···G Hydrogen Bond in Cyclohexane Derivatives: Stabilization of an Axial Cyano Group.

Base-catalyzed equilibration of anancomeric cyanocyclohexanes demonstrates that replacement of cis-3,5-dimethyl holding groups with electron-withdrawing CF3 groups dramatically increases the proportion of the axial cyano isomer present at equilibrium. The CF3 groups exert an effect on the conformational energy of the cyano group worth about 0.6 kcal/mol. A nonclassical hydrogen bond between the axial CN group and the syn-axial hydrogens is a major contributor to the axial stability of the group.

Enhancement of the Oxidizing Power of an Oxoammonium Salt by Electronic Modification of a Distal Group.

The multigram preparation and characterization of a novel TEMPO-based oxoammonium salt, 2,2,6,6-tetramethyl-4-(2,2,2-trifluoroacetamido)-1-oxopiperidinium tetrafluoroborate (5), and its corresponding nitroxide (4) are reported. The solubility profile of 5 in solvents commonly used for alcohol oxidations differs substantially from that of Bobbitt's salt, 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (1). The rates of oxidation of a representative series of primary, secondary, and benzylic alcohols by 1 and 5 in acetonitrile solvent at room temperature have been determined, and oxoammonium salt 5 has been found to oxidize alcohols more rapidly than does 1. The rate of oxidation of meta- and para-substituted benzylic alcohols by either 1 or 5 displays a strong linear correlation to Hammett parameters (r > 0.99) with slopes (ρ) of -2.7 and -2.8, respectively, indicating that the rate-limiting step in the oxidations involves hydride abstraction from the carbinol carbon of the alcohol substrate.

Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane.

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

Regioselective Lithium-Iodine Exchange-Initiated Cleavage of 2-Iodomethyl-1,3-dioxanes: A Complex-Induced Proximity Effect.

Lithium-iodine exchange-initiated fragmentation of a series of 4-substituted 2-iodomethyl-1,3-dioxanes proceeds rapidly and regioselectively to afford enol ether alcohols by preferential cleavage of the less congested C(2)-O(1) bond. The results demonstrate that a complex-induced proximity effect (CIPE) is likely responsible for the selectivity of the cleavage.

Metal-Free Oxidation of Primary Amines to Nitriles through Coupled Catalytic Cycles.

Synergism among several intertwined catalytic cycles allows for selective, room temperature oxidation of primary amines to the corresponding nitriles in 85-98% isolated yield. This metal-free, scalable, operationally simple method employs a catalytic quantity of 4-acetamido-TEMPO (ACT; TEMPO=2,2,6,6-tetramethylpiperidine N-oxide) radical and the inexpensive, environmentally benign triple salt oxone as the terminal oxidant under mild conditions. Simple filtration of the reaction mixture through silica gel affords pure nitrile products.

The Role of CH···O Coulombic Interactions in Determining Rotameric Conformations of Phenyl Substituted 1,3-Dioxanes and Tetrahydropyrans.

The rotameric conformations of the phenyl ring in both the axial and the equatorial conformers of phenyl substituted 1,3-dioxanes and tetrahydropyrans are compared with those of the corresponding phenylcyclohexanes at the MP2/6-311+G* level. The compounds with an axial phenyl commonly adopt a conformation in which the plane of the aromatic ring is perpendicular to the benzylic C-H bond. However, axial 5-phenyl-1,3-dioxane adopts a "parallel" conformation that allows an ortho hydrogen to be proximate to the two ring oxygens, leading to attractive CH···O interactions. Stabilizing Coulombic interactions of this sort are found with many of the oxygen-containing six-membered rings that were investigated.

Effect of remote aryl substituents on the conformational equilibria of 2,2-diaryl-1,3-dioxanes: importance of electrostatic interactions.

The conformational preference of a variety of 2,2-diaryl-1,3-dioxanes bearing remote substituents on the phenyl rings has been studied via equilibration of configurationally isomeric 2,2-diaryl-cis-4,6-dimethyl-1,3-dioxane epimers, X-ray crystallography, (1)H NOESY analysis, and B3LYP/6-311+G* calculations. When the aryl ring bears a remote electron-withdrawing substituent, the isomer having both the higher dipole moment and the electron-withdrawing group in the equatorial phenyl ring and/or an electron-donating group in the axial ring has the lower energy. These results differ from the conclusions reported in a previous study of similar systems. The conformational energy differences of para-substituted 2,2-diaryl-1,3-dioxanes are linearly related to the Hammett σ values with a slope (ρ) of 0.6. In addition, there is a trend toward longer bond lengths between the C(2) ketal center and the aryl ring as the electron-withdrawing nature of the para-substituent is increased. Electrostatic interactions, rather than a hyperconjugative anomeric effect, appear to be responsible for the conformational behavior of such molecules.

Access to nitriles from aldehydes mediated by an oxoammonium salt.

A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl-imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.

Facile oxidation of primary amines to nitriles using an oxoammonium salt.

The oxidation of primary amines using a stoichiometric quantity of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH2Cl2-pyridine solvent at room temperature or at gentle reflux affords nitriles in good yield under mild conditions. The mechanism of the oxidation, which has been investigated computationally, involves a hydride transfer from the amine to the oxygen atom of 1 as the rate-limiting step.

Asymmetric intramolecular carbolithiation of achiral substrates: synthesis of enantioenriched (R)-(+)-cuparene and (R)-(+)-herbertene.

Concise syntheses of the sesquiterpenes (R)-(+)-cuparene and (R)-(+)-herbertene by asymmetric cyclization of achiral olefinic alkyllithium precursors in the presence of (-)-sparteine are reported. The quaternary stereogenic center in each product is set at the final step of the synthesis by enantioselective (er = 61:39) 5-exo ring closure.

Oxoammonium salt oxidations of alcohols in the presence of pyridine bases.

Oxoammonium salt oxidations (using 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) of alcohols containing a ß-oxygen atom in the presence of pyridine yield dimeric esters, while in the presence of 2,6-lutidine the product is a simple aldehyde. The formation of a betaine between pyridine and an aldehyde is presented to explain this disparity in reactivity. The betaine is oxidized by the oxoammonium salt to give an N-acylpyridinium ion that serves as an acylating agent for ester formation. Steric effects deter the formation of such a betaine with 2,6-disubstituted pyridines. A series of alcohols containing a ß-oxygen substituent were oxidized to aldehydes in the presence of 2,6-lutidine, and a short study of the relative reactivity of various alcohols is given. An overall mechanism for oxoammonium cation oxidations is suggested, premised on nucleophilic additions to the oxygen atom of the positively charged nitrogen-oxygen double bond. Possible mechanisms for both dimeric oxidations and simple oxidations are given.

Intramolecular carbolithiation cascades as a route to a highly strained carbocyclic framework: competition between 5-exo-trig ring closure and proton transfer.

The preparation of fairly strained carbocyclic ring systems by intramolecular 5-exo-trig ring closure has been well documented, and the absence of proton transfers that would compromise such cyclizations is a hallmark of this chemistry. In an effort to explore the limitations of this approach to more highly strained systems, the preparation of a stellane (tricyclo[3.3.0.0(3,7)]octane) framework by an intramolecular carbolithiation cascade involving three coupled 5-exo-trig cyclizations of the vinyllithium derived from 2-bromo-4-vinyl-1,6-heptadiene by lithium-bromine exchange was investigated. The cascade does not afford the stellane; rather, the cascade is terminated after two cyclizations by a proton transfer that occurs by an intermolecular process catalyzed by trace amounts of endo-5-methyl-2-methylenebicyclo[2.2.1]heptane present in reaction mixtures as a consequence of inadvertent quenching of an intermediate alkyllithium during prolonged reaction times at room temperature.

Intramolecular carbolithiation as a route to a sterically congested cyclopentene: synthesis of the longtailed mealybug pheromone.

A concise preparation of the pheromone secreted by the female longtailed mealybug [viz., 2-(1,5,5-trimethylcyclopent-2-en-1-yl)ethyl acetate] (1) is described. The key step in the synthesis of 1 involves 5-exo-trig ring closure of the vinyllithium derived from (Z)-1-iodo-4,4,5-trimethyl-1,5-hexadiene by lithium-iodine exchange.

Computational study of the enantioselective deprotonation of a cyclopropanecarboxamide with an alkyllithium in the presence of sparteine.

The enantioselective deprotonation of N,N-diisopropy-1-methylcyclopropanecarboxamide (2) with i-PrLi-(-)-sparteine has been studied at theoretical levels up through B3LYP/6-311+G*. Thirty-six conformationally flexible intermediate complexes involving i-PrLi-(-)-sparteine and 2 were located via geometry optimizations The lowest energy complex would lead to abstraction of the pro-S hydrogen from 2, and several higher energy complexes would lead to loss of the pro-R hydrogen. The lowest energy complex was found to have the lowest activation energy leading to loss of the pro-S hydrogen of 2 as observed experimentally. The results demonstrate that the conformations of the N,N-diisopropyl groups in the amide moiety of 2 have a large effect on the enantioselectivity of the lithiation.

Contrasting reactions of ketones and thioketones with alkyllithiums: a coordinated experimental and computational investigation.

The reaction of ketones with organolithium reagents generally proceeds by addition of the organometallic to the electrophilic carbon of the C═O group to give the lithium salt of a tertiary alcohol. The seemingly analogous reaction of thioketones with organolithiums is a fundamentally different process: such reactions typically afford a variety of products, and addition of the organolithium to carbon of the C═S group to give a thiol is a relatively unimportant component. Reactions of the stable thioketone, adamantantanethione (1), with several alkyllithiums (MeLi, n-BuLi and t-BuLi) in a variety of solvents have been studied in the first comprehensive investigation of the reactions of organolithiums with a representative alkyl-substituted thione. Reactions of 1 with n-BuLi or t-BuLi afforded 2-adamantanethiol (2) as the major product. In an effort to explain the marked difference in behavior of ketones and thioketones in reactions with organolithiums, transition states for both the addition and reduction reactions have been located at the B3LYP/6-311+G* level using acetone and thioacetone as model substrates. The transition states for the addition of dimeric MeLi to the C═O and C═S carbons of acetone and thioacetone were significantly different as a result of the small bond angles preferred by divalent sulfur, and this accounts for the much slower addition to a C═S carbon vis-à-vis a C═O group. Transition states for reduction of acetone and thioacetone by EtLi were similar, but the greater exothermicity of the reduction of the thioketone results in an earlier transition state and lower activation energy for this process than that for the reduction of a ketone. The possible role of radical-mediated processes in this chemistry is also discussed.

Selective oxoammonium salt oxidations of alcohols to aldehydes and aldehydes to carboxylic acids.

The oxidation of alcohols to aldehydes using stoichiometric 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH(2)Cl(2) at room temperature is a highly selective process favoring reaction at the carbinol center best able to accommodate a positive charge. The oxidation of aldehydes to carboxylic acids by 1 in wet acetonitrile is also selective; the rate of the process correlates with the concentration of aldehyde hydrate. A convenient and high yield method for oxidation of alcohols directly to carboxylic acids has been developed.

Computational study of the properties and reactions of small molecules containing O, S, and Se.

The reactions and properties of a series of chalcogen-containing compounds (CH(3))(2)X and (CH(3))(2)C═X, where X = O, S, and Se, were studied computationally at the CBS-QB3 level to examine the differences among these molecules. The reactions and properties investigated include the double bond dissociation energy, the ionization potential, the interaction energies with a series of acids including a proton, CH(3)(+), Li(+), MeLi, and MeOH, and the enolization energies of the (CH(3))(2)C═X species. The effect of substituting the O of acetamide with S or Se also was studied. The changes that result from these reactions were examined via changes in structure and changes in charge distribution using the Hirshfeld charges.