Mechanism for the reduction of ketones to the corresponding alcohols using supercritical 2-propanol

The mechanism for the reduction of ketones into the corresponding alcohols using supercritical 2-propanol under non-catalytic conditions was investigated. The studies of the kinetic-isotope effect and isotopic-labeling for the reduction of benzophenone and acetophenone were carried out using (CH₃)₂CD(OH), (CH₃)₂CH(OD), (CD₃)₂CH(OH), and (CD₃)₂CD(OD). It was clarified that the α- and hydroxyl hydrogens on 2-propanol, respectively, transfer to the carbonyl C and O in the rate-determining step. These isotope studies also suggested that this reaction proceeds via a six-membered cyclic transition state analogous to that of the Meerwein-Ponndorf-Verley reduction. The fact that Hammett's reaction constant for this reaction was low, i.e., ρ=0.33, and that the reduction of the prochiral ketones using optically active alcohols at supercritical or high temperature provided optically active products also supported the existence of a six-membered cyclic transition state.     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.     

Chiral diphenylselenophosphoramides: a new class of chiral ligands for the titanium(IV) alkoxide-promoted addition of diethylzinc to aldehydes

Chiral C₂-symmetric diphenylselenophosphoramides 1 and 2 were prepared from the reaction of diphenylselenophosphinic chloride with (1R,2R)-(−)-1,2-diaminocyclohexane and (1R,2R)-(+)-1,2-diphenylethylenediamine, respectively, in high yields. Another novel chiral ligand 3 was prepared from the reaction of diphenylselenophosphinic chloride with (R)-(+)-1,1′-binaphthyl-2,2′-diamine using butyllithium as the base. The ligands were used as catalytic chiral ligands in the titanium(IV) alkoxide-promoted enantioselective addition reaction of diethylzinc to aldehydes.     

Novel approach to 6-alkenyl-substituted pyridoxine derivatives based on the Heck reaction

A new synthetic approach to 6-alkenyl-substituted pyridoxine derivatives was developed based on the Heck reaction. The reaction, which was catalyzed using a mixture of Pd(OAc)₂, (o-Tol)₃P and Bu₃N as a base, led to seven new 6-alkenyl pyridoxine derivatives. When acrylic acid was used the products of decarboxylation and dimerization were formed.     

A direct synthetic route to B-trifluoroborazines

B-Tris(alkylamino)-N-trialkyl-borazines and B-tris(arylamino)-N-triaryl-borazines may be prepared almost quantitatively by employing the appropriate stoichiometry in the reaction between boron trichloride and an alkyl- or aryl-amine. The borazines so formed react with boron trifluoride or boron trifluoride etherate to give good yields of the B-trifluoro-N-trialkyl- and B-trifluoro-N-triaryl-borazines. Using this methods, (CH₃NBF)₃, (p-ClC₆H₄NBF)₃ and (C₆F₅NBF)₃ have been prepared. The analogous reaction using (C₆F₅)₃B as a route to B-tris(pentafluorophenyl)borazines was unsuccesful.     

Development of radical addition-cyclization-elimination reaction of oxime ether and its application to formal synthesis of (±)-martinelline

Radical addition-cyclization-elimination (RACE) reaction of oxime ether carrying unsaturated ester provides a novel method for the construction of pyrroloquinoline. Treatment of oxime ethers with Bu₃SnH and AIBN gave N-norpyrroloquinoline as a major product, which was also obtained by the radical reaction of the corresponding hydrazone and imine. The radical reaction of aldehyde and ketone carrying unsaturated ester proceeded stereoselectively to give cis-furoquinolines and cis-hydroxyesters. The RACE reactions by using each of Bu₃SnNMe₂, Bu₃SnD, and/or D₂O were also examined in order to propose a reaction pathway to N-norpyrroloquinoline. Furthermore, the synthetic utility of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of (±)-martinelline.     

Addition of chalcogenolate anions to terminal alkynes using microwave and solvent-free conditions: easy access to bis-organochalcogen alkenes

We present here the reaction of diphenyl dichalcogenides (Se and Te) with propargyl alcohols using alumina supported sodium borohydride under solvent-free conditions. This efficient and improved method is general and furnishes the corresponding vinyl chalcogenide preferentially with a Z configuration. We also observed that when the same protocol was applied to phenyl acetylene, the (E)-bis-organochalcogen alkenes were obtained in good yields and high selectivity. The use of MW irradiation facilitates the procedure and accelerates the reaction.     

Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond

Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6′-dimers, 3,6-dimethoxylcatechol β,β′ dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (−) pinoresinol. Structure–function relationship analysis allowed four basic rules to be defined: meta-excluded, C–C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (−) pinoresinols (but no (−) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.     

Polymer-supported N-benzyl- and N-benzhydryl-2-nitrobenzenesulfonamides as alternative to aldehyde linkers

Polymer-supported N-benzyl- and N-benzhydryl-2-nitrobenzenesulfonamides 1 were N-alkylated using three different routes: via Fukuyama reaction with alcohols, by N-alkylation with electrophiles, and by Michael addition reaction with α,β-unsaturated carbonyl compounds. The N-alkylated products were obtained in excellent purity and high yield. The 2-nitrobenzenesulfonyl (Nos) group was then cleaved to yield polymer-supported N-alkylated benzylamines and benzhydrylamines. N-alkylation of polymer-supported 2-nitrobenzenesulfonamide linkers 1 described herein represents an alternative route to reductive amination of aldehyde linkers.     

A simple route to side-chain fluorinated β-lactams from ring-fluorinated aziridines

β-Lactams bearing a Ph₂CF substituent at the C(4)-atom were synthesized from N-alkyl-2-fluoro-3,3-diphenylaziridines. The transformation was realized using SbF₃-mediated isomerization of the monofluoroaziridines to fluorinated aldimines, followed by Staudinger reaction with ketenes. It was shown that this reaction sequence can be performed as a one-pot procedure.     

Palladium-mediated fragmentation reactions of meta photocycloadducts to afford arylated or oxidatively cyclised products

Whilst seeking to improve the yield of a Heck-style arylation/fragmentation reaction using a silyloxy substituted meta photocycloadduct, an alternative reaction pathway was discovered that led to the formation of the unique oxidatively cyclised compound 8. This tricyclic ether is believed to form as the result of the meta photocycloadduct structure fragmenting to give a π-allyl palladium species and then subsequently being displaced by a neighbouring hydroxyl group. An attempt to develop an enantioselective version of this reaction via the desymmetrisation of a meso π-allyl palladium intermediate was made using the meta photocycloadduct derived from anisole and Z-but-2-ene-1,4-diol, however no enantioenrichment of the products could be detected.     

Tandem palladium-catalyzed borylation and Suzuki coupling (BSC) to thienocarbazole precursors

Substituted 2-methyl-2′-nitro diaryl compounds in the benzo[b]thiophene series were prepared by palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction in good to high yields. The borylation reaction was performed on methylated 6-bromobenzo[b]thiophenes using pinacolborane and was followed by in situ Suzuki coupling with substituted (CF₃, OMe) 2-bromonitrobenzenes. The compounds obtained were cyclized to the corresponding ring A substituted thienocarbazoles which can have biological activity or/and be used as biomarkers due to their fluorescence properties and possible DNA intercalation.     

The intramolecular tandem Michael/Mannich-type reaction of α,β-unsaturated carbonyl compounds with acyliminium ions provides access to chiral indolizidines

The intramolecular tandem Michael/Mannich-type (Michael addition/halo-Mannich-type) reaction using TiCl₄/n-Bu₄NI system between the α,β-unsaturated carbonyl compounds possessing an Evans oxazolidinone as a chiral auxiliary and N-acyliminium ion intermediates is described. The reaction was promoted in a mixed solvent of AcOEt–CH₂Cl₂ to afford indolizidine compounds with three stereogenic centers.     

Facile and rapid immobilization of copper(II) bis(oxazoline) catalysts on silica: application to Diels-Alder reactions, recycling, and unexpected effects on enantioselectivity

Two chiral copper(II) bis(oxazoline) complexes have been immobilized on silica via electrostatic interactions using a remarkably straightforward procedure. The immobilized catalysts were tested in a standard Diels-Alder reaction and gave surprising results. Where the immobilized Cu((S,S)-phenyl-box)(OTf)₂ catalyst was used, the predominant enantiomer formed was the opposite of that produced using the same catalyst in a homogeneous reaction. This is a startling result given that the only difference is the electrostatic immobilization of the catalyst on amorphous silica. The activity of the catalyst in a hetero Diels-Alder reaction was also tested. This catalyst was also recycled, successfully maintaining a similar activity to the homogeneous analogue through a number of cycles.     

An improved approach to determining the yield of derivatization reaction and its application to the investigation of the silylation of some anabolic steroids

An approach to determining the yield of derivatization reaction is based on a comparison of chromatographic peak areas of the derivative and native (underivatizied) compound. In contrast to the previous publication [J. Anal. Chem., 2011, vol. 66, no. 12, pp. 1186–1189], ratio of the sensitivity coefficients of the derivative and native forms of the analyte was calculated using only experimental data obtained upon varying the derivatization conditions (solution containing equal amounts of underivatized compound and a respective derivative was analyzed previously). The approach was used to investigate the influence of the reaction time and the type of an external action on the yield of the derivatization (silylation) reaction for some anabolic steroids (methyltestosterone, methandienone, oxandrolone and oral-turinabol) containing a hindered tertiary hydroxyl group at C17. The amounts of the derivatized steroids were equal to about 20–60 ng (depending on the component). Steroids were derivatized with a mixture of pyridine and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% trimethylchlorosilane. The derivatization reaction was carried out for 15, 30 or 45 min under conventional heating, sonication at room temperature, and sonication at elevated temperature.     

Enantioselective Organocatalyzed Michael Addition of Isobutyraldehyde to Maleimides in Aqueous Media

Thiourea was introduced into (R,R)-1,2-diphenylethylenediamine as an organocatalyst to promote the reaction between isobutyraldehydes and maleimides. Enantioselective Michael addition reaction was carried out as an eco-friendly method using water as the solvent. As a result of the reaction between isobutyraldehyde and maleimide, ≥97% yield and 99% enantioselectivity were obtained at a low catalyst loading of 0.01 mol%. The solvent effect can be explained by theoretical calculations that indicate the participation of a transition state, in which the CF₃ substituent of the catalyst is a hydrogen bond activated by the surrounding water molecules. This discovery enabled the use of low catalyst loading in the organic reactions of chiral substances for pharmaceutical applications. Furthermore, a solvent effect for Michael reaction of the organocatalysts was proposed, and the organic reaction mechanisms were determined through quantum calculations.     

Palladium(II)/2,2′-bipyridine-catalyzed addition of arylboronic acids to N-tosyl-arylaldimines

A Pd(II)/NO₂-bpy-catalyzed addition of the arylboronic acids to N-tosylaldimines to yield diarylmethylamines with moderate to excellent yield was developed. The use of bipyridines as the ligands is crucial in this reaction. The asymmetric version of the reaction also showed that a moderate high yield and ee value can be obtained using the pymox ligands.     

Effective immobilisation of lipase to enhance esterification potential and reusability

A commercial lipase, “Lipolase T100”, was immobilised onto silica by means of physical adsorption. The silica-bound lipase was subsequently exposed to 1 vol. % glutaraldehyde (pentane-1,5-dial). The silica was loaded repeatedly with the Lipolase T100 in 0.05 M Tris buffer (pH 8.5) until saturation was achieved. During the 1st, 2nd, 3rd, 4th, and 5th cycles of loading of silica with the enzyme, the protein-binding on the silica achieved 51.73 %, 48.27 %, 26.92 %, 10.73 %, and 4.29 %, respectively. The synthesis of methyl salicylate (methyl 2-hydroxybenzoate) and linalyl ferulate (3,7-dimethylocta-1,6-dien-3-yl 4-hydroxy-3-methoxycinnamate) carried out at 45°C under shaking with mole ratios of 200 mM of acid and 500 mM alcohol in DMSO using 15 mg mL^?1 of hyper-activated biocatalyst resulted in yield(s) of 77.2 % of methyl salicylate and 65.3 % of linalyl ferulate in the presence of molecular sieves. The hyper-activated biocatalyst was more efficient than the previously reported silica-bound lipase with minimum leaching of the enzyme from the reaction mixture. The K _m and V _max of the free (0.142 mM and 38.31 μmol min^?1 mL^?1, respectively) and silica-bound lipase (0.043 mM and 26.32 μmol min^?1 mg^?1, respectively) were determined for the hydrolysis of p-NPP. During repeated esterification studies using silica-bound lipase, yields of 50.1 % of methyl salicylate after the 5th cycle, and 53.9 % of linalyl ferulate after the 7th cycle of esterification were recorded. In the presence of molecular sieves (30 mg mL^?1) in the reaction mixture, the maximum syntheses of methyl salicylate (77.2 %) and linalyl ferulate (65.3 %) were also observed. In a volumetric batch scale-up, when the reaction volume was increased to 50 mL, 44.9 % and 31.4 % yields of methyl salicylate and linalyl ferulate, respectively, were achieved.     

Enantioenriched 1-aryl-2-fluoroethylamines. Efficient lipase-catalysed resolution and limitations to the Mitsunobu inversion protocol

Both enantiomers of eight 1-aryl-2-fluoroethylamines have been synthesised starting with 1-aryl-2-fluoroethanones. Kinetic resolution of the amines using lipase B from Candida antarctica with ethyl methoxyacetate as the acyl donor gave the (R)-amines in 96-99% ee and the (S)-methoxyacetamides in >99.5% ee. The resolution was robust with respect to variation in reaction temperature, acyl donor concentration, water activity and substrate structure. Nine other lipase preparations failed to catalyse the reaction or gave a low enantioselectivity. Secondly, a Mitsunobu inversion protocol starting with enantioenriched 1-aryl-2-fluoroethanols using phthalimide as nucleophile was employed in the synthesis of the (S)-1-aryl-2-fluoroethylamines. Both the inversion efficiency and yield depended on the aromatic substituents. For six of the substrates, clean inversion of the stereochemistry was observed. However, racemisation and low yields were the result when electron-donating substituents were present at the aromatic ring. When substituted with a cyano or a nitro group, an unexpected fluorine elimination occurred, limiting the yield for these transformations. The absolute configuration of the 1-aryl-2-fluoroethylamines was determined using circular dichroism.     

tert-Butylnitrite as a convenient and easy-removable oxidant for the conversion of benzylic alcohols to ketones and aldehydes

The oxidation of primary and secondary benzylic alcohols was achieved by using tert-butyl nitrite (t-BuONO) as a stoichiometric oxidant. Various substrates were effectively converted into the corresponding ketones or aldehydes in good to excellent yields. The reaction presumably proceeded by a nitrosyl exchange and a subsequent thermal decomposition of benzylic nitrites. This process would realize an oxidation of alcohols with oxygen in theory by combining with a reproduction of alkyl nitrites from NO and alcohols under an O₂ atmosphere. In addition, almost pure oxidized products were readily obtained by simple evaporation of the reaction mixtures since t-BuONO produced only volatile side products.