Debenzylation Reaction Research Articles

Star-shaped dendritic molecules based on carboxylated carbazole and pyrrole as peripheral oxidizable units

The synthesis and spectroscopic characterization of three tricarboxylated pyrrole (Pyr)- and carbazole (Cbz)-containing star-shaped dendritic molecules 1– 3 have been described here. Clauson–Kaas, amide coupling and debenzylation reactions have been used as key chemical tools. Electropolymerization of these oxidizable molecules has been investigated. The carboxylated Cbz-based molecules upon oxidative electropolymerization produced stable electroactive polyCOOH polyCbz films.

Intramolecular N to N acyl migration in conformationally mobile 1′-acyl-1-benzyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinoline] systems promoted by debenzylation conditions (HCOONH4/Pd/C)

Abstract We report an efficient and useful synthesis of new attractive spiropiperdine scaffolds 4 based on an intramolecular acyl transfer process in 1′-acyl-1-benzyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinolines] 3 using simple and mild debenzylation reaction conditions (HCOONH4/Pd/C). The compounds 3 were prepared by acylating 1-benzyl-4′-methyl-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-quinolines] 2 that are easily available from 1-benzyl-4-piperidone 1. The intramolecular character of this process was proven primarily through a crossover experiment technique. Through an examination of all spectroscopic information (1H, 13C NMR, VT-1H NMR, and 2D NMR) it was possible to correctly predict amide configurations and piperidine ring conformations of starting and final spiropiperidine compounds.

Synthesis and α-glucosidase inhibitory, DPPH scavenging activity of substituted 2-oxo-2H-chromen-7-yl-dihydrogen phosphate derivatives

Series of phosphorylated coumarin derivatives (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j) were synthesized by Pechmann condensation, phosphorylation, and debenzylation reactions in very good yields. Thus, synthesized compounds (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j) were evaluated for their α-glucosidase and 1,1-diphenyl-2-picrylhydrazyl scavenging activities; few compounds showed moderate to good activity. J. Heterocyclic Chem., 00, 00 (2011).

Hydrogenolysis of N-protected aminooxetanes over palladium: An efficient method for a one-step ring opening and debenzylation reaction

An efficient method for the palladium mediated hydrogenation of an optically active, N-protected aminooxetane derivative has been developed. Using appropriate solvents, in a one-step reaction, a chiral 1,4-aminoalcohol derivative [(2 S,3 R)-4-amino-3-benzoyloxy-2-benzylbutan-1-ol] was formed over a Pd/C catalyst, during hydrogenolytic ring opening and debenzylation reactions.

Unprecedented Hexa- and Undecanuclear Frameworks of Two New Tin(IV) Oxo Clusters Resulting from Partial Debenzylation Reactions

A new and facile synthetic route to the known neutral cluster ((PhCH2)2SnO)6[((PhCH2)2SnOH)2- (CO3)]2 (2) as well as its reactivity toward trifluoromethanesulfonic acid (HO3SCF3, TfOH) are reported. The solid-state structure of the new solvate 2·6C7H8 has been determined by single-crystal X-ray diffraction. The core of 2 can be described as a pair of coplanar pentanuclear [(PhCH2)2SnO]5 ladders bridged at their ends by two carbonate groups. Successive additions of TfOH to a suspension of 2 in CD3CN were monitored by 119Sn{1H} NMR spectroscopy showing the transformation of the fingerprint of 2 (δ = −244, −246, −306 ppm), via new upfield signals, to a final broad resonance located at δ = −474 ppm. Thereafter, two unprecedented ionic monobenzyltin(IV) oxo clusters, 3 and 4, resulting from a debenzylation reaction and exhibiting unusual hexa- and undecanuclear frameworks, respectively, have been isolated as single crystals.

Synthesis, Structure and Molecular Recognition of Functionalised Tetraoxacalix[2]arene[2]triazines

Functionalised dialkoxy-substituted tetraoxacalix[2]arene[2]triazine macrocycles 6 have been readily synthesised by the fragment coupling approach using methyl 3,5-dihydroxy-4-alkoxybenzoates and cyanuric chloride as the starting materials under very mild conditions. AlCl(3)-mediated deallylation and debenzylation reactions afforded the lower-rim dihydroxy-substituted tetraoxacalix[2]arene[2]triazine derivatives 11 and 13 in good yields. Although dialkoxy-substituted tetraoxacalix[2]arene[2]triazine macrocycles are fluxional in solution on the NMR spectroscopy timescale, they adopt a symmetric or slightly distorted 1,3-alternate conformation with the bridging oxygen atoms conjugated with the triazine rings. The dihydroxylated tetraoxacalix[2]arene[2]triazine 13 b, which gives a mixture of monomer and dimer in solution according to a diffusion NMR spectroscopy study, adopts a 1,3-alternate conformation and forms a cyclic tetrameric assembly in the solid state due to the formation of intermolecular hydrogen-bonding networks. This dihydroxylated macrocyclic host molecule, a hydrogen-bond donor macrocycle with a V-shaped cleft, interacts with 2,2'-bipyridine, 4,4'-bipyridine and 1,10-phenanthroline guests. Although in solution they form the corresponding 1:1 complexes with binding constants ranging from 37.7 to 213 M(-1), 2:2 host-guest complexes were observed in the crystalline state. Hydrogen-bonding interactions, along with other non-covalent interactions, such as lone-pair-electron-pi and C-H...pi interactions, were found to be the driving force for the formation of host-guest complexes.

Preparation of Supported Pd Catalysts: From the Pd Precursor Solution to the Deposited Pd2+ Phase

The preparation by the deposition-precipitation method (using Na(2)PdCl(4) as a palladium precursor and Na(2)CO(3) as a basic agent) of Pd catalysts supported on gamma-Al(2)O(3) and on two different types of active carbons has been followed by several techniques (UV-vis, EXAFS, XRPD, and TPR). This work consists of four successive parts: the investigation of (i) the palladium precursor liquid solution (in the absence of substrate), (ii) the solid precipitated phase (in the absence of substrate), (iii) the precipitated Pd(2+)-phase on the supports as a function of Pd loading from 0.5 to 5.0 wt % (i.e., the final catalyst for debenzylation reactions), and (iv) the Pd(0)-phase formed upon reduction in H(2) atmosphere at 393 K. A time/pH-dependent UV-vis experiment indicates that Pd(2+) is present in the mother solution mainly as PdCl(2)(H(2)O)(2)] and [PdCl(H(2)O)(3)](+). Upon progressive addition of NaOH (3.0 < pH < approximately 3.8), the concentration of the two complexes is almost constant and then they rapidly disappear because of the precipitation of an amorphous aggregation of Pd(2+)-polynuclearhydroxo complexes. This phase represents a model material for the active supported phase. Thermal treatments at increasing temperature of this phase cause progressive water loss and resulted in a progressive increase in crystallinity typical of a defective PdO-like phase. The EXAFS spectrum of the final catalysts has been found to be intermediate between that of the unsupported amorphous Pd(2+)-polynuclearhydroxo complexes and that of the PdO-like phase. Independent of the support, EXAFS was not able to evidence any fraction of reduced metallic Pd, meaning that all Pd is in the 2+ oxidation state within the sensitivity of the technique (a few percent). Analogously, independent of the support, XRPD was not able to detect the presence of any crystalline supported phase. The Pd local environment of the as-precipitated samples changes slightly as a function of Pd loading from 0.5 to 2.0 wt %: at higher loadings, no further modification has been observed. After reduction in an H(2) atmosphere, two trends have been observed: (i) the dispersion of Pd nanoparticles tends to decrease with increasing Pd concentration, less significantly on Al(2)O(3)-supported samples and more significantly on carbon-supported ones and (ii) the dispersion depends on the carrier following the sequence Al(2)O(3) >> Cp > Cw according to the increasing palladium-support interaction strength.

Diisobutylaluminium Hydride (DIBAL‐H) Promoted Secondary Rim Regioselective Demethylations of Permethylated β‐Cyclodextrin: A Mechanistic Proposal

AbstractDiisobutylaluminium hydride (DIBAL‐H) promotes secondary rim regioselective bis‐de‐O‐methylation at the 2A‐ and 3B‐positions of permethylated β‐cyclodextrin. This result contrasts with the selective bis‐de‐O‐benzylation of perbenzylated cyclodextrins in which regioselective deprotection occurs at the primary rim. To gain an insight into the mechanism of this remarkable contrasting behavior, the two corresponding permethylated cyclodextrins with an alcohol function at either the 2‐ or 3‐position were synthesized. The cyclodextrin with the alcohol at the 3‐position reacts withDIBAL‐H to afford the 2A,3B‐diol whereas the cyclodextrin with the alcohol at the 2‐position is unreactive. This observation allows us to propose a mechanism for the demethylation reaction that involves for each demethylation step two molecules of aluminium reagent, in accord with the previous hypothesis on the debenzylation reaction. The second demethylation step appears to be faster than the first, the coordination of aluminium now being an intramolecular process.

Chemical Clockwise Tridifferentiation of α‐ and β‐Cyclodextrins: Bascule‐Bridge or Deoxy‐Sugars Strategies

The selective and efficient functionalisation of large concave molecules is a chemical challenge opening the door to various applications, such as artificial enzymes. We propose here a method, based on deprotection of benzylated cyclodextrins, to selectively access a variety of complex structures with two or three new different functionalities on the primary platform. Our strategy is based on a mechanistic hypothesis involving the approach of an aluminium reagent between the primary oxygen atom and the endocyclic one of the same sugar unit. Due to its cyclic directionality, a change in steric hindrance on a given position of the cyclodextrin has a different effect on the clockwise or the counterclockwise directions. This concept is illustrated and exploited in two complementary ways: deoxygenation of the primary position of two diametrically opposed sugars induces a debenzylation reaction on the neighbouring clockwise sugars of alpha- and beta-cyclodextrins. Reversible capping, or bascule-bridging, of the same pair of sugars has the same effect on the debenzylation of alpha-cyclodextrin, but induces an important change of the geometry of beta-cyclodextrin, hence allowing the selective access to yet another functionalisation pattern. A combined use of deoxygenation and bascule-bridging allows the access to an alpha-cyclodextrin with its three pairs of primary functions differentiated and ready for further modifications. Bascule-bridge or deoxy-sugars are two complementary means to operate steric decompression and induce selective reactions to efficiently access a number of new patterns of functionalities on concave molecules.

Solid-Supported Acids for Debenzylation of Aryl Benzyl Ethers

Solid-supported acids have been investigated for aromatic debenzylation reactions. Stoichiometric amounts of solid-supported acids in refluxing toluene with or without 4 equiv of methanol effectively provided the desired aromatic debenzylation products of various systems in moderate to excellent yields (up to 98%).

Control of catalytic debenzylation and dehalogenation reactions during liquid-phase reduction by H 2

Heterogeneous catalysis, which is being used more frequently in the fine chemicals industry, does not always provide the desired selectivity because various functional groups become labile to reduction by hydrogen on a noble metal under similar reaction conditions. To study the selectivity of debenzylation versus dechlorination in an aromatic compound, the kinetics of the reduction of 4-chloro-N,N-dibenzylaniline on supported Pd catalysts in a buffered solvent under hydrogen reduction conditions were investigated. The turnover frequency on a Pd/C catalyst was 2–40 times higher than that on Pd dispersed on SiO 2, TiO 2, and Al 2O 3. The effects of hydrogen pressure, organic substrate concentration, temperature, solvent, and catalyst support on the selectivity were not great at a pH of 5.4, whereas the effect of acid or base modifiers was very significant. Only dechlorination reactions occurred under basic conditions, and the use of an acid confirmed a preferential promotion of debenzylation reactions; consequently, as the pH decreased from 12 to 0.1, the selectivity for dechlorination decreased from essentially 100% to almost 0. Using a triethylamine/acetic acid buffer system to control pH, it was determined that the inflection point in selectivity corresponds to a pH value equal to the p K a of the benzyl-protected amine (4.5 in this case). Consequently, one important finding is that the dechlorination reaction can occur at high rates even under acidic conditions, as long as the pH of the reaction mixture is greater than the p K a of the protected amine. Furthermore, generation of an acidic product like HCl during a dechlorination reaction can decrease the system pH and markedly alter selectivity unless a buffer is present. For reactions carried out at a pH of 5.4, the initial rate of organic substrate consumption was modeled by a classical Langmuir–Hinshelwood sequence, with the assumption of two types of active sites, one site to adsorb H atoms and the other to adsorb the organic substrate, yielding a slightly better fit to the data. The Weisz–Prater criterion was applied to verify the absence of mass transfer effects.

Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK1 Receptor Antagonist Aprepitant

An efficient and highly stereoselective one-pot Grignard addition/hydrogenation procedure is a key step in the synthesis of the NK1 receptor antagonist aprepitant. The critical influence of pH on the nature and stability of the intermediate Grignard adducts, along with their reactivity in the hydrogenation reaction, is described. The observation of a defluorinated impurity under hydrogen-starved conditions led to mechanistic studies that revealed unusual kinetics in the hydrogenation reaction. Detailed analysis of the kinetic profiles under hydrogen-starved conditions indicated the two steps of the reaction, debenzylation of the Grignard adducts and reduction of the incipient imine, occurred in near perfect stepwise fashion wherein the debenzylation reaction was essentially complete before any imine reduction took place. Under hydrogen-saturated conditions the inhibition of the imine reduction was less complete, but the partial buildup of reactive imine intermediate led to a dramatic spike in reaction rat...

Artificial Glycosyl Phosphorylases

alpha- and beta-Cyclodextrin 6(A),6(D)-diacids (1 and 2), beta-cyclodextrin-6-monoacid (14), beta-cyclodextrin 6(A),6(D)-di-O-sulfate (16) and beta-cyclodextrin-6-heptasulfate (19) were synthesised. Acids 1, 2 and 14 were made from perbenzylated alpha- or beta-cyclodextrin, by diisobutylaluminum hydride (DIBAL)-promoted debenzylation, oxidation and deprotection. Addition of molecular sieves was found to improve the debenzylation reaction. Sulfates 16 and 19 were made by sulfation of the appropriately partially protected derivatives and deprotection. Catalysis of 4-nitrophenyl glycoside cleavage by these cyclodextrin derivatives was studied. Compounds 1, 2 and 16 were found to catalyse the reaction, with the catalysis following Michaelis-Menten kinetics and depending first order on the phosphate concentration. In a phosphate buffer (0.5 M, 59 degrees C, pH 8.0), K(M) varied from 2-10 mM and the k(cat)/k(uncat) ratio from 80-1000 depending on the stereochemistry of the substrate and the catalyst, with 2 being the best catalyst and with the sulfated 16 also displaying catalytic ability. The monoacid 14 and the heptasulfate 19 were not catalytic.

Selective removal of a benzyl protecting group in the presence of an aryl chloride under gaseous and transfer hydrogenolysis conditions

Selective removal of a benzyl protecting group in the presence of an aryl chloride using Pd/C under gaseous and transfer hydrogenolysis conditions is described. The addition of chloride salts to the debenzylation reaction provides excellent selectivity.

Acetyl Bromide-Alcohols as Convenient Reaction Systems for: a) Removal of N-tert-Boc, N-Cbz And N-Ac Protective Groups, b) Esterifications and Transesterifications, c) Debenzylation of Aryl-O-Benzyl Ethers

Hydrogen bromide generated in situ by the addition of acetyl bromide to alcohols is a useful reagent for esterifications and transesterifications; N-tert-Boc, N-Cbz, and N-Ac deprotections; and debenzylation reactions.

Antitumour imidazotetrazines. Part 33. New syntheses of the antitumour drug temozolomide using ‘masked’ methyl isocyanates

Ethyl 8-carbamoyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazin-3-ylacetate 6a can be prepared by treating 5-diazoimidazole-4-carboxamide 3 with ethyl isocyanatoacetate or by diazotisation of N-(5-amino-4-carbamoylimidazol-1-ylcarbonyl)glycine ethyl ester 5. Barton radical decarboxylation of the tetrazin-3-ylacetic acid 6b affords temozolomide 1(26%) whereas deprotection of the 3-trimethylsilylmethyl-imidazotetrazine 6g with TBAF in acetonitrile–acetic acid yields 1 in 78% yield. 3-Benzylimidazotetrazinones 10a–c are stable to hydrogenolytic or oxidative debenzylation reactions.

Synthesis of pyrido[1,2-c][1,3]benzoxazines based on 1-benzyl-3-hydroxy-3-methyl-6-(2-benzyloxyphenyl)-4-piperidones

The stereomeric 1-benzyl-3-hydroxy-3-methyl-6e-(2-bemyloxyphenyl)-4-piperidones on debenzylation and subsequent reaction with formaldehyde are converted into cis- and trans-1,3,4-10b-tetrahydro-3-hydroxy-3-methyl-2-oxopyrido-[1,2-c][1,3]benzoxazines.

Bis(benzyl)polyamine analogs as novel substrates for polyamine oxidase.

N,N'-Bis(benzyl)polyamine analogs were found to be substrates for highly purified polyamine oxidase. Metabolism of these analogs was apparently dependent on molecular O2 and resulted in the formation of benzaldehyde, H2O2, and a polyamine analog with free terminal amines. The debenzylation reaction was optimal between pH 9 and 10, identical to the pH optimum for polyamine oxidase activity when N1-acetylspermine was used as the substrate. On a molecular sieve column the debenzylating activity co-eluted with N1-acetylspermine oxidizing activity, at an apparent molecular mass of approximately 65 kDa. The purified enzyme also appeared to have a molecular mass of approximately 65 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Debenzylation of the bis(benzyl)polyamines was competitively inhibited by N1-acetylspermine and N1-acetylspermidine. The specific irreversible inhibitor of polyamine oxidase, N1,N4-bis(buta-2,3-dienyl)butanediamine also inhibited the debenzylation, whereas inhibitors of diamine and monoamine oxidases did not. The evolution of benzaldehyde from bis(benzyl)polyamine analogs by polyamine oxidase allowed the development of a simple rapid spectrophotometric assay for use in the measurement of polyamine oxidase activity in partially purified tissue or cell extracts. Further, metabolism of a bis(benzyl)polyamine analog by polyamine oxidase was found to be an important element in the growth inhibitory properties of the compound in a mouse model of malaria.

Oxidative debenzylation of 4-methoxy-α-methylbenzyl esters

4-Methoxy-α-methylbenzyl alcohol was introduced as a new protecting group for carboxylic acids. 4-Methoxy-α-methyl benzyl esters obtained from the coupling of 4-methoxy-α-methylbenzyl alcohol and corresponding acids, were hydrolyzed in good yield by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). This process is compatible with several functional groups which are vulnerable to the reductive debenzylation reaction.

ChemInform Abstract: An Efficient Synthesis of Partially Protected α‐D‐Ribofuranosides from D‐Ribose by Way of a Unique Selective Debenzylation Reaction.

ChemInform Abstract: An Efficient Synthesis of Partially Protected α‐D‐Ribofuranosides from D‐Ribose by Way of a Unique Selective Debenzylation Reaction.