Debenzylation Reaction Research Articles

Synthesis of Pd/Carbon Hollow Spheres by the Microwave Discharge Method for Catalytic Debenzylation.

Pd/C catalysts have been widely applied in the debenzylation process due to their excellent ability of hydrogenolysis. However, they have been suffering from the problems of agglomeration and loss of active components, which lead to decreased and unstable activity. Thus, it is still a challenge to achieve Pd/C catalysts with high activity and stability. Herein, we propose a strategy for preparing Pd/C catalysts on porous carbon hollow spheres by a microwave discharge method. Due to the high-temperature property and reducibility of microwave discharge, Pd precursors can be rapidly reduced, resulting in well-dispersed Pd nanoparticles with a small size on the carbon carrier. Besides, the matched mesopores in the carbon hollow spheres can anchor Pd nanoparticles and effectively reduce the agglomeration and loss of Pd nanoparticles during the catalytic reaction. As a result, the as-prepared Pd/mesoporous carbon hollow spheres exhibit high and stable activity in the debenzylation reaction.

Aminodiphosphine substituted 2Fe2Se complex as new precursor to single and double butterfly Fe/Se models related to FeFe hydrogenase models

A convenient way to synthesize the aminediphosphine (PNP) substituted Fe/Se models with [Fe2(µ-Se2)(CO)4(μ-PNP)] as a new precursor was described. Firstly, treatment of [Fe2(µ-SeR)2(CO)6] (R = C6H5 and CH2C6H5) with (Ph2P)2NBui in refluxing xylene gave [Fe2(μ-SeR)2(CO)4(μ-Ph2P)2NBui] (R = C6H51 and CH2C6H52). Further debenzylation reaction was found in complex 2 after long-time heating, and precursor complex [Fe2(μ-Se2)(CO)4(μ-Ph2P)2NBui] (3) was isolated with satisfactory yield. GC–MS analysis showed that the reaction involved the formation of (C6H5CH2)2. Further, the “open” single butterfly complex 2 and “closed” butterfly complex [Fe2(µ-pdSe)(CO)4(μ-Ph2P)2NBui] (pdSe = Se(CH2)3Se) (4) were conveniently prepared via a new synthetic route involving the reaction of 3 with 2 equiv of Et3BHLi, followed by treatment of the resulting [Fe2(μ-SeLi)2(CO)4(μ-Ph2P)2NBui] with BzBr (Bz = CH2C6H5) and Br(CH2)3Br, respectively. On the other hand, to obtain a double butterfly complex [{Fe2(μ-SeEt)(CO)4(μ-Ph2P)2NBui}2(μ-Se2)] (5), the first Fe4Se4 carbonyl model containing two PNP substituents, successive reactions were performed, including treating precursor complex 3 with EtMgBr, protonation with CF3CO2H (TFA), and air-direct oxidation. All the complexes were well characterized by various spectral techniques and particularly by X-ray crystallography. Moreover, a comparison of the electrochemical and electrocatalytic properties of single and double clusters 4 and 5 is also presented.

Structural Effects of Microcrystalline Cellulose-Derived Carbon Supports on Catalytic Performance of the Pd(OH)2/C Catalysts for the Hydrogenolytic Debenzylation of Hexanitrohexaazaisowurtzitane Derivatives

In order to reduce the noble metal palladium dosage in the preparation of CL-20 so as to reduce its production cost, several carbon supports were prepared successfully using the hydrothermal carbonization method in the absence or presence of urea using microcrystalline cellulose (MC) as the carbon source, and the corresponding Pd(OH)2/C catalysts were fabricated using the deposition–precipitation method, which showed high activity in the debenzylation reaction of hexabenzylhexaazaisowurtzitane (HBIW) and tetraacetyldibenzylhexaazaisowurtzitane (TADB). It was found that all the catalysts showed a high efficiency in the debenzylation of HBIW, indicating that the structure of the used carbon supports had a limited impact on the catalyst performance in this reaction. On the contrary, the activities of the catalysts in the debenzylation of TADB were quite different. The results of the nitrogen sorption isotherm measurement (BET), scanning electron microscope (SEM), scanning transmission electron microscopy (STEM), powder X-ray diffraction (XRD), element analysis and temperature programmed desorption (TPD), as well as X-ray photoelectron spectra (XPS) characterizations of the supports and catalysts, showed that the relatively high activity of Pd/HTC in the debenzylation of TADB was related to the high Pd dispersion and novel mesoporous structure, while the further higher activity and stability of Pd/HTC-N1:1 in the same reaction were related with its high Pd dispersion, high total oxidized Pd species, and high surface pyridinic N contents as well as the eggshell distribution of Pd species on the support.

Deactivation and Regeneration of Palladium Catalysts for Hydrogenation Debenzylation of 2,4,6,8,10,12-Hexabenzyl-2,4,6,8,10,12-Hexaazaisowurtzitane (HBIW)

2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW, also known as CL-20) is an important energetic compound. As one of the representatives of the third generation of energetic materials, it has an excellent performance, providing broad application prospects for the development of new weapons and equipment. The synthesis of CL-20 is usually obtained from 2,4,6,8,10,12-hexabenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (HBIW) through two catalytic hydrogenolysis and debenzylation reactions, followed by nitration. The most critical step is the hydrogenolysis debenzyl-acetylation process of HBIW because this process requires a large amount of expensive palladium-based catalyst, and the catalyst is completely deactivated after one use. In response to this problem, there is no suitable solution at present, resulting in the high cost of the entire synthesis process. Therefore, reducing the production cost of CL-20 by increasing the catalyst stability is one of the current research priorities. By using AAS, XRD, XPS, TEM, BET, TG and other characterization techniques, the reasons for catalyst deactivation were explored. Studies have shown that the main reason for catalyst deactivation is that a large number of blockages accumulate in the pores of the catalyst after the reaction, which greatly weakens the transfer of the reactant HBIW, intermediate substances, and product 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADBIW) in the catalyst pores, and the blockage may block the active site of the catalyst. A regeneration treatment method for catalyst deactivation was developed. This method uses chloroform and glacial acetic acid as reagents, which, when combined with stirring and ultrasonic operation, finally restores the activity of the Pd(OH)2/C catalyst. The BET and TG parameters of the regenerated catalyst indicate that catalyst textural and structural properties have greatly recovered, indicating that this treatment method can remove the blockages in the catalyst pores.

Practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin

A practical and efficient total synthetic route of the resveratrol dimer (±)-ε-viniferin (2) with benzyl as protecting group for phenols was achieved with high overall yield. The synthetic approach involved a palladium-catalyzed direct arylation, triethylsilane-mediated reduction of benzofuran, and selective debenzylation reaction. Selective debenzylation in the presence of reducible and acid-sensitive groups catalyzed using Pd/C and 1,4-cyclohexadiene was implemented to complete the total synthesis.

Solvent-controlled synthesis of bulky and polar-bulky galactonoamidines

The goal of this study was the design and synthesis of bulky and polar-bulky galactonoamidines that have a potential to interact with both catalytic amino acids in the active site of human α-galactosidase. While a library of more than 25 compounds was previously synthesized following established protocols, the coupling of the selected amines with activated perbenzylated galactothionolactam yielded only small amounts for some of the perbenzylated targets. A computational approach disclosed relative energy differences of selected adducts and suggested a solvent change that then allowed a successful synthesis of the precursor compounds in 20–75%. Subsequent attempts to globally deprotect perbenzylated galactonoamidines by Pd catalyzed hydrogenation resulted in unwanted Pd coordination, incomplete debenzylation reactions, partial compound hydrolysis, and even complete decomposition. A lengthy protocol was elaborated to purify the targeted carbohydrate derivatives after modified debenzylation conditions.

Synthesis of endo-fused 5-unsubstituted Hexahydro-2H-pyrano[3,2-c]quinolinesvia Sequential Sc(OTf)3-catalyzed Cationic Imino-Diels-Alder Reaction/N-debenzylation using N-benzylanilines, 3,4-dihydro-2H-pyran and Paraformaldehyde under MW Irradiation.

Hexahydro-2H-pyrano[3,2-c]quinolines are known to have antibacterial, antifungal, and antitumor properties. Great efforts have been made to develop new synthetic methods that lead to the synthesis of valuable libraries. Extensive methodologies, low yields, excessive amounts of catalyst and expensive reactants are some of the limitations of current methodologies. Developing a useful and efficient method to construct diversely substituted hexahydro-2Hpyrano[ 3,2-c]quinolines into good to excellent yields through a cationic imino-Diels-Alder/N-debenzylation methodology. The cationic imino-Diels-Alder/N-debenzylation methodology was used for the preparation of substituted hexahydro-2H-pyrano[3,2-c]quinolines. It involves the use of Sc(OTf)3 for activation of cationic imino- Diels-Alder cycloaddition reaction of N-benzylanilines, 3,4-dihydro-2H-pyran and paraformaldehyde in MeCN; and microwave irradiation to shorten reaction time to afford new 6-benzyl-hexahydro-2H-pyrano[3,2- c]quinolines whose catalytic transfer debenzylation reactions with HCO2NH4 in the presence of Pd/C (10%) and methanol give the new 5-unsubstituted pyrano[3,2-c]quinolines in excellent yields. We found that optimal conditions for the preparation of hexahydro-2H-pyrano[3,2-c]quinolines were Sc(OTf)3 0.5 % and acetonitrile at 160°C for 15 min; and using paraformaldehyde obtained the 6-benzylhexahydro- 2H-pyrano [3,2-c]quinolines with excellent yields, while the N-debenzylation process using ammonium formate in the presence of Pd/C and methanol resulted in the synthesis of hexahydro-2H-pyrano [3,2-c] quinolines with quantitative yields (95-98%). We describe an efficient method to synthesize hexahydro-2H-pyrano[3,2-c]quinolines via the cationic imino-Diels-Alder/N-debenzylation methodology using Sc(OTf)3 0.5 % as Lewis Acid catalyst. Excellent yields of the products, use of MW irradiation, short times of reactions, and an efficient and highly diversified method are some of the main advantages of this new protocol.

Effects of Surface Oxygen-Containing Groups of the Flowerlike Carbon Nanosheets on Palladium Dispersion, Catalytic Activity and Stability in Hydrogenolytic Debenzylation of Tetraacetyldibenzylhexaazaisowurtzitane

The influence of the surface chemical properties of the carbon support on the Pd dispersion, activity and stability of Pd(OH)2/C catalyst for the hydrogenolytic debenzylation of tetraacetyldibenzylhexaazaisowurtzitane (TADB) was studied in detail. The flowerlike nanosheet carbon material (NSC) was chosen as the pristine support, meanwhile chemical oxidation with nitric acid and physical calcination at 600 °C treatments were used to modify its surface properties, which were denoted as NSCox-2 (treated with 20 wt% HNO3) and NSC-600, respectively. The three carbon supports and the corresponding catalysts of Pd/NSC, Pd/NSC-600, and Pd/NSCox-2 were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), nitrogen sorption isotherm measurement (BET), powder X-ray diffraction (XRD), Raman spectra, X-ray photoelectron spectra (XPS), temperature-programmed desorption (TPD), temperature-programmed reduction (H2-TPR), thermogravimetric analysis (TG), and element analysis. The debenzylation activities of Pd/NSC, Pd/NSC-600, and Pd/NSCox-2, as well as the three catalysts after pre-reduction treatment were also evaluated. It was found that the activity and stability of the Pd(OH)2/C catalysts in the debenzylation reaction highly depended on the content of surface oxygen-containing groups of the carbon support.

Ultrasmall Pd Nanoparticles Supported on TiO2 for Catalytic Debenzylation via Hydrogenative C–N Bond Cleavage

Heterogeneous Pd has been developed as a well-known catalyst for debenzylation reactions via hydrogenative C–N bond cleavage. However, the extensive applications are still limited owing to a high l...

Synthesis and Pharmacological Effects of Diosgenin-Betulinic Acid Conjugates.

The target diosgenin–betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 µM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.

Additive-Free Nickel-Catalyzed Debenzylation Reactions via Hydrogenative C–O and C–N Bond Cleavage

C–O and C–N cleavage reactions play a fundamental role in synthetic chemistry and biomass valorization. Many efforts have been done in the past in order to develop efficient catalysts able to mediate these transformations. However, still some drawbacks are present: necessity for additives and occurrence of side reactions. Here, an array of Ni-based catalysts derived from the thermal decomposition of a Ni(II)/phenanthroline complex onto different supports was prepared. Ni–N–C@Al2O3-1000 material (pyrolyzed at 1000 °C) was the most efficient catalyst for both O- and N-debenzylation of various substrates (>20 examples) using dihydrogen as reductant. Advantageously, this process is water tolerant, proceeds free of any additive, and does not show overhydrogenation of the arene ring. The structure, morphology, and chemical composition of Ni–N–C@Al2O3-1000 have been elucidated. It is constituted by variously sized Al2O3-supported Ni(0)/NiOx nanoparticles (NPs) embedded by layers of nitrogen-doped carbon.

Nickel‐Catalyzed Annulation of o‐Haloarylamidines with Aryl Acetylenes: Synthesis of Isoquinolone and 1‐Aminoisoquinoline Derivatives

AbstractAn efficient method for the synthesis of substituted 1(2H)‐isoquinolone derivatives via nickel‐catalyzed annulation of substituted 2‐halobenzamidines with aryl alkynes in the presence of water is described. Benzo[4,5]imidazo[2,1‐a]isoquinolines were formed as the dominated products when dry dimethyl sulfoxide was used as the solvent. Furthermore, when benzyl substituted amidines were used as the substrates, debenzylation reaction occured to provide various 1‐aminoisoquinoline products.magnified image

Cathodic Behaviour of Dicationic Imidazolium Bromides: The Role of the Spacer

AbstractThe cathodic reduction of dicationic imidazolium bromides, whose spacer is either an aliphatic chain or a xylyl group, leads to the formation of the corresponding N‐heterocyclic carbenes (NHCs), which were isolated as the corresponding thiones, after reaction with elemental sulfur. The behaviour of the dications was compared with the corresponding monocations. The behaviour of dicarbenes depends on the nature of the spacer. This study evidenced that dicarbenes deriving from xylyl dications are less stable than the corresponding aliphatic ones (giving lower yields in thiones), due to a debenzylation reaction. On the other hand, the yields in thiones starting from aliphatic dications are higher than the corresponding monocations, suggesting a cooperative reduction at the electrode of the two imidazolium moieties. The cathodic process was confirmed using the co‐electrogenerated hydrogen to reduce 2,2,2‐trifluoroacetophenone to the corresponding alcohol.

A Novel and Efficient Route for Synthesis of Taladegib

Taladegib (LY-2940680), a small molecule Hedgehog signalling pathway inhibitor, was obtained from N-benzyl-4-piperidone via Borch reductive amination, acylation with 4-fluoro-2-(trifluoromethyl)benzoyl chloride, debenzylation, substitution with 1,4-dichlorophthalazine and Suzuki cross-coupling reaction with 1-methyl-1H-pyrazole-5-boronic acid. The advantages of this synthesis route were the elimination of Boc protection and deprotection and the inexpensive starting materials. Furthermore, the debenzylation reaction was achieved with simplified operational procedure using ammonium formate as hydrogen source that provided high reaction yield. This synthetic procedure was suitable for large-scale production of the compound for biological evaluation and further study.

Study of Deactivation of Pd(OH)2/C Catalyst in Reductive Debenzylation of Hexabenzylhexaazaisowurtzitane

AbstractThe conversion of hexabenzylhexaazaisowurtzitane (HBIW) to 2,6,8,12‐tetraacetyl‐4,10‐dibenzyl‐2,4,6,8,10,12‐hexaazaisowurtzitane (TADB) is the major challenge in the production of hexanitrohexaazaisowurtzitane (HNIW) which only proceeds over supported palladium catalyst in a reductive debenzylation reaction. The catalyst is quickly deactivated during the debenzylation reaction. In this study, the change in Pd content in the catalyst during the reaction was measured. It was demonstrated that a portion of the palladium particles in the catalyst was leached during the reaction. The H2 chemisorption isotherm on the catalyst at 303 K showed that the volume of chemisorbed H2 on spent catalyst was significantly less than that on fresh catalyst. The N2 physisorption isotherm on the catalyst at 77 K revealed that the surface area of spent catalyst was less than that of fresh catalyst. Moreover, the FESEM‐EDS and TEM images and also wide‐angle XRD patterns demonstrated that the mean sizes of palladium crystallites and particles in spent catalyst were larger than those in the fresh catalyst. These results demonstrated that the leaching of palladium particles and the aggregation of palladium particles in catalyst play active roles in the deactivation of catalyst in the debenzylation of HBIW.

Site-selective hexa-hetero-functionalization of α-cyclodextrin an archetypical C₆-symmetric concave cycle.

Access to Cn (n>4) symmetric cyclic concave molecules with a different function on each of their n subunits is an unmet challenge. The reason lies in the lack of a post-functionalization method whose site selectivity is sufficiently understood, predictable and modulable to access most functionalization patterns. Here we disclose a new site-directing rule for a debenzylation reaction on cyclodextrins that solves this problem and allows the unprecedented access to penta- and ultimately hexa-differentiations of such C6 concave cycles. This achievement opens the access to objects with very high-density information.

Site-Selective Heterofunctionalization of Cyclodextrins: Discovery, Development, and Use in Catalysis

To fulfill the promise offered by concave molecules such as cyclodextrins, there is a desperate need for efficient methods for multiple heterofunctionalization. We have developed several strategies for preparing heterofunctionalized cyclodextrins based on a newly discovered regioselective debenzylation reaction of sugars and an understanding of its mechanism. Bascule bridging and tandem azide reduction–deprotection are two complementary ways of attaining an unprecedented degree of complexity of functionalization of the primary rim of cyclodextrins, permitting access to a diverse library of functionalized cyclodextrins. The resulting complex structures have a number of applications in a wide range of areas. We have explored some of these, such as asymmetric catalysis using regioisomers to induce enantioselectivity or very high turnover numbers, but it is our firm belief that this methodology opens many other possibilities.

Practical Synthesis of Polysubstituted Imidazoles via Iodine‐ Catalyzed Aerobic Oxidative Cyclization of Aryl Ketones and Benzylamines

AbstractA practical synthetic method for polysubstituted imidazoles via iodine‐catalyzed aerobic oxidative cyclization of aryl ketones and benzylamines has been developed. It was found to tolerate a broad range of substrates to prepare polysubstituted imidazole derivatives in a one‐pot manner, and thus importantly allowed product diversity for imidazole chemistry. Additionally, the resultant 1,2,4‐trisubstituted imidazoles could be conveniently transformed to functionalized 1,2,4,5‐tetrasubstituted imidazoles via electrophilic substitution or direct CH functionalization, or 2,4‐diaryl‐1H‐imidazoles by debenzylation reaction, which further indicates potential applications of this method in synthetic and pharmaceutical chemistry.

An “Against the Rules” Double Bank Shot with Diisobutylaluminum Hydride To Allow Triple Functionalization of α‐Cyclodextrin

Frustration leads to overreaction: when diametrically opposed regioselective debenzylation is frustrated, an unexpected double debenzylation reaction affords original tetrafunctionalized cyclodextrins in a controlled and efficient manner. A rationale of the reaction is proposed based on a kinetic study.

Towards hybrid carbazole/pyrrole-based carboxylated monomers: chemical synthesis, characterisation and electro-oxidation properties

Six novel hybrid carbazole (Cbz)–pyrrole (Pyr)-based carboxylated monomers were synthesised and unambiguously characterised using common spectroscopic tools. Clauson-Kaas, amide coupling, LAH (lithium aluminium hydride)-mediated reduction, esterification and debenzylation reactions were used as key chemical reactions towards their multi-step synthesis. The electro-oxidation features of all these six hybrid Cbz/Pyr-monomers were investigated for the electro-deposition of corresponding polyCOOH conducting coatings. Quite interestingly, and due to the fact that such electro-oxidisable monomers contain both types of oxidisable heterocycles, that is, Pyr and Cbz species, it was found that the successful electro-polymerisation of these hybrid Cbz/Pyr-monomers was highly dependent on the relative number of Cbz versus Pyr unit(s) present in corresponding monomers. Indeed, a successful electro-deposition of the corresponding conducting polymeric films onto a working Pt electrode was observed only for hybrid monomers characterised by a Cbz/Pyr unit(s) ratio greater than or equal to 1. This result has been validated by systematically tuning the number of oxidisable Cbz and Pyr unit(s) present in monomers through proper chemical design and monomer multi-step synthesis. In that case, cyclic voltammogram analyses readily confirmed the exclusive electro-deposition of conductingpolyCbz-films.