Regioselective intramolecular oxidation of phenols and anisoles by dioxiranes generated in situ

A novel method for regioselective oxidation of phenols and anisoles has been developed in which dioxiranes, generated in situ from ketones and Oxone, oxidize phenol derivatives in an intramolecular fashion. A series of ketones with electron-withdrawing groups, such as CF(3), COOMe, and CH(2)Cl, were attached to phenols, anisoles, or aryl rings via a C(2) or C(3) methylene linker. In a homogeneous solvent system of CH(3)CN and H(2)O, oxidation of phenol derivatives 1-10 afforded spiro 2-hydroxydienones in 24-55% yields regardless of the presence of other substituents (ortho Me, meta Me or Br) on the aryl ring and the length of the linker. Experimental evidences were provided to support the mechanism that involves a regioselective pi bond epoxidation of aryl rings followed by epoxide rearrangement and hemiketal formation.     

Selective oxidation of unactivated C-H bonds by supramolecular control

Efficient methods for dioxirane-based selective C-H bond oxidation by supramolecular control in H(2)O have been developed. With β-cyclodextrin as the supramolecular host, site-selective oxidation of the terminal over the internal tertiary C-H bond of 3,7-dimethyloctyl esters 3a-c was achieved. In addition, β-cyclodextrin selectively enhanced the C-H bond oxidation of cumene in a mixture of cumene and ethyl benzene in H(2)O. Through (1)H NMR studies, the selectivity in C-H bond oxidation could be attributed to the inclusion complex formation between β-cyclodextrin and the substrates.     

Substituent effects on regioselective intramolecular oxidation of unactivated C-H bonds: stereoselective synthesis of substituted tetrahydropyrans

Our previously reported intramolecular delta-selective C-H bond oxidation by dioxiranes, generated in situ from activated ketones, offers a novel approach to the synthesis of tetrahydropyrans. To synthesize substituted tetrahydropyrans in a stereoselective manner, we examined the effects of alkyl, nitrogen, and oxygen substituents at the alpha-, beta-, and gamma-sites of ketones on the stereoselectivities of intramolecular C-H bond oxidation reactions. Ketones 1-4 with a methyl group at the alpha-, beta-, or gamma-site showed the diastereoselectivities that agreed with the trans/cis ratio predicted by considering steric interactions in the transition states. Furthermore, ketones 5 and 6 carrying a bulky phthalimido group at the alpha- and the beta-sites, respectively, exhibited excellent stereoselectivity, each affording only one diastereomer. However, ketones 9 and 10 bearing beta-oxygen substituents gave reversed stereoselectivity as compared to those with beta-alkyl or nitrogen substituents, possibly because of the hydrogen bonding interaction in the transition state. For ketones 12 and 13, both bearing methyl and silyloxy groups, the hydrogen bonding interaction was probably more important than the steric effect on the diastereoselectivity of intramolecular oxidation of C-H bonds.     

Iterative multifunctionalization of unactivated C-H bonds in piperidines by way of intramolecular Rh(II)-catalyzed aminations

Efficient stereocontrolled synthesis of di-, tri-, tetra-, and pentasubstituted piperidines from simple 2-sulfamoyloxymethyl piperidine derivatives has been performed by way of intramolecular Rh-catalyzed amination of saturated C-H bonds. In this process, the sulfamoyloxymethyl arm was directly or indirectly involved in the functionalization of every saturated methylene group of the piperidine ring at C-3, C-4, C-5, and C-6. Direct application to the total synthesis of iminosugars and related compounds demonstrated the synthetic potential of this strategy.     

Palladium-catalyzed oxygenation of unactivated sp3 C-H bonds

This communication describes a new palladium-catalyzed method for the oxygenation of unactivated sp3 C-H bonds. A wide variety of alkane substrates containing readily available oxime and/or pyridine directing groups are oxidized with extremely high levels of chemo-, regio-, and in some cases diastereoselectivity. The substrate scope of these reactions is discussed, and the high selectivities are rationalized on the basis of the requirements of putative palladium alkyl intermediates.     

Novel pathways for oxygen insertion into unactivated C-H bonds by dioxiranes. Transition structures for stepwise routes via radical pairs and comparison with the concerted pathway

The oxygen insertion into C-H bonds (of methane, isobutane, and acetone) by dioxiranes (parent dioxirane and dimethyldioxirane) to give alcohols was studied with the DFT theory, using both restricted and unrestricted B3LYP methods, and 6-31G(d) and 6-311+G(d,p) basis sets to evaluate the feasibility of stepwise mechanisms and their competition with the concerted counterpart. Confirming previous results by other authors, we have located, with the RB3LYP method, concerted TSs in which the oxygen bound to be inserted interacts very strongly with the hydrogen atom and very weakly with the carbon atom of the C-H bond. These TSs nicely explain all the experimental observations (e.g., configuration retention at the chiral centers), but all of them exhibit an RHF --> UHF wave function instability that preclude considering them as genuine transition structures. We also were able to characterize, with UB3LYP methods, two alternative two-step processes that can lead to final products (alcohol + carbonyl compound) via singlet radical pair intermediates. For the first step of both processes we located genuine diradicaloid TSs, namely, TSs rad,coll and TSs rad,perp, that have stable wave functions. In TSs rad,coll the alkane C-H bond tends to be collinear with the breaking O(1)- - -O(2) bond while in TSs rad,perp the alkane C-H bond is almost perpendicular to the O(1)- - -O(2) bond. The first step, of both processes, can represent an example of a "molecule induced homolysis" reaction: collision between alkane and dioxirane brings about the homolytic cleavage of the dioxirane O-O bond and the hydrogen abstraction follows afterward to produce the diradicaloid TS that then falls down to a singlet radical pair. This hypothesis was fully confirmed by IRC analysis in the case of TSs rad,coll. The possible pathways that lead from the intermediate radical pair to final products are discussed as well as the hypothesis that the radical collinear TSs may collapse directly to products in a "one-step nonconcerted" process. However, diradical mechanisms cannot explain the experimental data as satisfactorily as the concerted pathway does. As for computational predictions about competition of diradical vs concerted mechanisms, they strongly depend (i) on the alkane C-H type, (ii) on whether gas phase or solution is considered, and (iii) on the basis set used for calculations. In short, the concerted TS benefits, with respect to the corresponding diradicaloid TSs, of alkyl substitution at the C-H center, solvation effects, and basis set extension. Actually, in the case of DMD reactions with methane and acetone, the diradicaloid TSs are always (both in gas phase and in solution and with both the basis sets used) strongly favored over their concerted counterpart. In the case of DMD reaction with isobutane tertiary C-H bond the large favor for the diradicaloid TSs over the concerted TS, predicted in gas phase by the B3LYP/6-31G(d) method, progressively decreases as a result of basis set extension and introduction of solvent effects: the higher theory level [B3LYP/6-311+G(d,p)] suggests that in acetone solution TS conc has almost the same energy as TS rad,perp while TS rad,coll resides only 2 kcal/mol higher.     

Direct arylation of unactivated aromatic C-H bonds catalyzed by a stable organic radical

A stable zwitterionic radical can catalyze direct arylation of unactivated aromatic C-H bonds via a chain homolytic aromatic substitution mechanism in the presence of potassium tert-butoxide.     

Oxaziridine-mediated catalytic hydroxylation of unactivated 3 degrees C-H bonds using hydrogen peroxide

The design, structural characterization, and evaluation of a unique class of 1,2,3-benzoxathiazine-based oxaziridines as potent O-atom transfer agents for catalytic C-H hydroxylation and alkene epoxidation are described. Turnover of this reaction is made possible by employing a diaryl diselenide cocatalyst and urea.H2O2 as the terminal oxidant. Oxidation of saturated hydrocarbons is strongly biased toward 3 degrees C-H bonds even in systems possessing a significantly greater number of methylene groups. In addition, the benzoxathiazine catalyst is effective for epoxidation of terminal and electron-deficient olefins. Collectively, these findings represent an important first step toward the advancement of general methodology for selective C-H oxidation.     

Asymmetric epoxidation of cinnamic acid derivatives by in situ generated dioxiranes of chloroacetones: scope and limitations

Efficient epoxidation of chiral cinnamic acid derivatives has been achieved by in situ generated dioxiranes of chloroacetones with moderate to good diastereoselectivity (dr up to 90:10) in high yields. Reactivity of cinnamic acid derivatives containing different chiral auxiliaries versus chloroacetones–monochloroacetone 3 (MCA), 1,1-dichloroacetone 4 (DCA) and 1,1,1-trichloroacetone 5 (TCA) and Oxone? loading was studied. Both Oxone? loading and reaction time reduce with an increase of chlorine atoms in the acetone. The use of 1.1 equiv of TCA was found to be effective for the epoxidation of cinnamate substrates and enhances the reaction up to 4–10-fold compared to acetone and that also decreases the Oxone? loading. This method provided methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (?)-2, a key intermediate for the synthesis of diltiazem hydrochloride, with >99% of enantiomeric purity.     

Aerobic intramolecular aminothiocyanation of unactivated alkenes promoted by in situ generated iodine thiocyanate

Aerobic intramolecular aminothiocyanation of unactivated alkenes has been developed by in situ generated iodine thiocyanate under open-flask conditions. This protocol provides a concise and efficient method for synthesizing SCN-containing pyrrolidine, piperidine and indoline derivatives with isolated yields of up to 87%. Furthermore, mixing iodine and sodium thiocyanate with oxygen afforded iodine thiocyanate (ISCN) and dithiocyanatoiodate [I(SCN)₂]^- which were testified by liquid chromatography mass spectrometry. A mechanistic investigation indicates that iodonium ion and sulfonium ion intermediates might be involved in this transformation.     

Asymmetric epoxidation of cinnamic acid derivatives using dioxiranes generated in situ from dehydrocholic acid

The asymmetric epoxidation of different cinnamic acid derivatives in water–NaHCO₃ has been achieved using dehydrocholic acid as the optically active ketone and Oxone® as the oxygen source (with product e.e. values of up to 75%).     

An unexpected oxidation of unactivated methylene C-H using DIB/TBHP protocol

An in situ generated hypervalent iodine species, bis(tert-butylperoxy)iodobenzene, was used as a peroxy radical source for the oxidation of unreactive, remote, and isolated alkyl (cyclic or aliphatic) esters and amides to the corresponding keto compounds under very mild conditions.     

Intermolecular amidation of unactivated sp2 and sp2 C-H bonds via palladium-catalyzed cascade C-H activation/nitrene insertion

This communication describes the Pd(OAc)2-catalyzed intermolecular amidation reactions of unactivated sp2 and sp3 C-H bonds using primary amides and potassium persulfate. The substrates containing a pendent oxime or pyridine group were amidated with excellent chemo- and regioselectivities. It is noteworthy that reactive C-X bonds were well-tolerated and a variety of primary amides can be effective nucleophiles for the Pd-catalyzed C-H amidation reactions. For the reaction of unactivated sp3 C-H bonds, beta-amidation of 1 degrees sp3 C-H bonds versus 2 degrees C-H bonds is preferred. The catalytic reaction is initiated by chelation-assisted cyclopalladation involving C-H bond activation. Preliminary mechanistic study suggested that the persulfate oxidation of primary amides should generate reactive nitrene species, which then reacted with the cyclopalladated complex.     

The C-H...O and C-H...N intramolecular hydrogen bonds in betainealdehydes of azoles containing the pyridinium cation

The comparison of the values of the chemical shifts of the pyridinium protons in the ylides of -dicarbonyl compounds and in betainealdehydes of thiazole and imidazole established the presence of the intramolecular C-H...O and C-H...N hydrogen bond between the -protons of the pyridinium and the oxygen atoms of the formyl group and the nitrogen of the amide fragment in the anionoid part of the betaine. The conclusion was confirmed by the varying influence of the effects of protonation on the character of the deshielding of the - and -protons.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 626–628, May, 1989.     

Inter- and intramolecular activation of aromatic C-H bonds by diphosphine and hydrido-bridged dinuclear iridium complexes

Reactions of [(Cp*Ir)2(mu-dmpm)(mu-H)2]2+ (1) with NaOtBu in aromatic solvent at room temperature give [(Cp*Ir)(H)(mu-dmpm)(mu-H)(Cp*Ir)(Ar)]+ [Ar = Ph (3), p-Tol (4a), m-Tol (4b), 2-furanyl (5a), 3-furanyl (5b)] via intermolecular aromatic C-H activation. Treatment of [(Cp*Ir)2(mu-dppm)(mu-H)2]2+ (2) with base (Et2NH) results in intramolecular C-H activation of the phenyl group in the dppm ligand to give [(Cp*Ir)(H){mu-PPh(C6H4)CH2PPh2}(mu-H)(Cp*Ir)]+ (6). The structures of 3, 5a, and 6 have been determined by X-ray diffraction methods.     

Investigation and mechanistic study into intramolecular hydroalkoxylation of unactivated alkenols catalyzed by cationic lanthanide complexes

Cationic lanthanide complexes of the type [Ln(CH₃CN)₉]³⁺[(AlCl₄)₃]^3–·CH₃CN (Ln = Pr, Nd, Sm, Gd, Er, Yb, Y) served as effective catalysts for the intramolecular hydroalkoxylation/cyclization of unactivated alkenols to yield the cyclic ethers with Markovnikov regioselectivity under mild conditions. Novel cationic complexes, [AlCl(CH₃CN)₅]²⁺[(AlCl₄)₂]^2–·CH₃CN and [Nd(CH₃CN)₉]³⁺[(FeCl₄)₃]^3–·CH₃CN, were synthesized and evaluated for the intramolecular hydroalkoxylation/cyclization of unactivated alkenols for comparison. The active sequence of [Nd(CH₃CN)₉]³⁺[(FeCl₄)₃]^3–·CH₃CN < [AlCl(CH₃CN)₅]²⁺[(AlCl₄)₂]^2–·CH₃CN < [Nd(CH₃CN)₉]³⁺[(AlCl₄)₃]^3–·CH₃CN observed indicated that both the cation and anion have great influence on the activity. Comparative study on the activity of AlCl₃ and its cationic complex [AlCl(CH₃CN)₅]²⁺[(AlCl₄)₂]^2–·CH₃CN revealed the formation of the cationic Al center enhanced the activity greatly. The ¹H NMR studies indicated the activation of hydroxyl and olefin by the cationic Ln³⁺ center were involved in the reaction pathways.