A Mechanistic Investigation of the N-Hydroxyphthalimide Catalyzed Benzylic Oxidation Mediated by Sodium Chlorite.

A detailed investigation into the mechanistic course of N-hydroxyphthalimide catalyzed oxidation of benzylic centers using sodium chlorite as the stoichiometric oxidant is reported. Through a combination of experimental, spectroscopic, and computational techniques, the transformation is interrogated, providing improved reaction conditions and an enhanced understanding of the mechanism. Performing the transformation in the presence of acetic acid or a pH 4.5 buffer leads to extended reaction times but improves the catalyst lifetime, leading to the complete consumption of the starting material. Chlorine dioxide is identified as the active oxidant that is able to oxidize the N-hydroxyphthalimide anion to the phthalimide-N-oxyl radical, the proposed catalytically active species, which is able to abstract a hydrogen atom from the substrate. A second molecule of chlorine dioxide reacts with the resultant radical and, after loss of hypochlorous acid, leads to the observed product. Through a broad variety of techniques including UV/vis, EPR and Raman spectroscopy, isotopic labeling, and the use of radical traps, evidence for the mechanism is presented that is supported through electronic structural calculations.

Peracid Oxidation of Unactivated sp3 C-H Bonds: An Important Solvent Effect.

The peracid oxidation of hydrocarbons in chlorinated solvents is a low yielding and poorly selective process. Through a combination of DFT calculations, spectroscopic studies, and kinetic measurement it is shown that the origin of this is electronic in nature and can be influenced through the addition of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). Performing the reaction of a cycloalkane with mCPBA in a fluorinated alcohol solvent such as nonafluoro-tert-butanol (NFTB) or hexafluoroisopropanol (HFIP), which act as strong HBD and poor HBA, leads to significantly higher yields and selectivities being observed for the alcohol product. Application of the optimised reaction conditions allows for the selective oxidation of both cyclic and linear alkane substrates delivering the corresponding alcohol in up to 86 % yield. The transformation shows selectivity for tertiary centres over secondary centres and the oxidation of secondary centres is strongly influenced by stereoelectronic effects. Primary centres are not oxidised by this method. A simple computational model developed to understand this transformation provides a powerful tool to reliably predict the influence of substitution and functionality on reaction outcome.

Organocatalytic Michael addition-lactonisation of carboxylic acids using α,ß-unsaturated trichloromethyl ketones as α,ß-unsaturated ester equivalents.

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,ß-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.

α-Ketophosphonates as ester surrogates: isothiourea-catalyzed asymmetric diester and lactone synthesis.

Isothiourea HBTM-2.1 catalyzes the asymmetric Michael addition/lactonization of aryl- and alkenylacetic acids using α-keto-ß,γ-unsaturated phosphonates as α,ß-unsaturated ester surrogates, giving access to a diverse range of stereodefined lactones or enantioenriched functionalized diesters upon ring-opening.

Isothiourea-catalyzed asymmetric synthesis of ß-lactams and ß-amino esters from arylacetic acid derivatives and N-sulfonylaldimines.

The isothiourea HBTM-2.1 (5 mol %) catalyzes the asymmetric formal [2 + 2] cycloaddition of both arylacetic acids (following activation with tosyl chloride) and preformed 2-arylacetic anhydrides with N-sulfonylaldimines, generating stereodefined 2,3-diaryl-ß-amino esters (after ring-opening) and 3,4-diaryl-anti-ß-lactams, respectively, with high diastereocontrol (up to >95:5 dr) and good to excellent enantiocontrol. Deprotection of the N-tosyl substituent within the ß-lactam framework was possible without racemization by treatment with SmI2.

Expedient synthesis of 17α,21-dihydroxy-9ß,11ß-epoxy-16α-methylpregna-1,4-diene-3,20-dione 21-acetate from prednisolone utilising a novel Mattox rearrangement.

A six step transformation of prednisolone to 17α,21-dihydroxy-9ß,11ß-epoxy-16α-amethylpregna-1,4-diene-3,20-dione 21-acetate has been achieved in 13% unoptimised yield. Novel conditions for effecting a Mattox rearrangement and double dehydration of prednisolone were identified. Enhanced knowledge on the oxidation of silyl Δ(19,20)-enol ethers and structural factors that impact the success of the oxidation are also presented.

Isotopic labeling for determination of enantiomeric purity by 2H NMR spectroscopy.

The use of 2H NMR spectroscopy as a tool for the analysis of enantiomeric purity is reported. Enantiopure isotopically chiral substrates bearing a monodeuterated methylene unit were prepared; introduction of an additional asymmetric center leads to diastereomers which can be distinguished by 2H NMR on a standard spectrometer. The assays allow for simple semiquantitative analysis of asymmetric transformations.

Isopinocampheylborane derivatives with >99% ee via the DMAP complex.

The complex 8 of isopinocampheylborane and p-(dimethylamino)pyridine (DMAP) can be obtained with >99% ee starting from alpha-pinene with 80-90% ee by hydroboration using DMAP.BH3 (5) activated by 5% iodine, or by the conventional hydroboration of alpha-pinene, followed by addition of DMAP. Purification of the air-stable 8 is readily accomplished by crystallization from methanol. Conversion of 8 into the trifluoroborate adduct 1 using KHF2 occurs without erosion of ee. Generation of the derived 2 in situ with TMSCl as the fluorophile also occurs with little, if any, loss of ee, as evidenced by the preparation of the salicaldimine complex 11 and the derived amino alcohol 12 with 94% ee overall.

Intramolecular hydroboration of unsaturated phosphine boranes.

Homoallylic phosphine boranes undergo intramolecular hydroboration upon activation by triflic acid. The reaction occurs via an intermediate B-trifluorosulfonyloxyborane complex such as 15, followed by S(N)1-like or S(N)2-like displacement of the triflate leaving group, apparently leading to the formation of a four-center transition state. In the case of trisubstituted double bonds, as in the substrates 29 and 32, ionic hydrogenation of the alkene competes with internal hydroboration.

A mechanistic alternative for the intramolecular hydroboration of homoallylic amine and phosphine borane complexes.

Intramolecular hydroboration is demonstrated starting from homoallylic amine boranes upon activation by iodine. The process involves a B-iodoborane complex as the intermediate and may occur via internal displacement of iodide by the alkene to generate a cationic borane-alkene pi-complex on the way to hydroboration products. The reaction can be carried out using a catalytic amount of iodine.