Regioselective Benzylation Research Articles

Regioselective benzylation of imidazo[1,5-a]pyridines and indoles via iodine catalyzed reaction using alcohols - An approach to crystal structure prediction, DFT studies and Hirshfeld surface analysis

Iodine catalysed, regioselective C-1 benzylation of imidazo[1,5-a] pyridines and C-3 benzylation of indoles with diphenylmethanol has been developed. This new protocol provides an efficient protocol in the synthesis of the benzylation methodology as it targets exclusively CH bonds, even in presence of reactive NH bonds and variety of benzyl substituted indoles and imidazo[1,5-a] pyridines are synthesized with broad range of functionalities leads to the elegant formation of new CC bond under metal free conditions. This report represents a mild protocol for the synthesis of tris(heteroaryl/aryl) methanes from solid bench stable diarylmethanols. The products formed are interesting for their potential biological applications. The crystal structure of the compound 3k was determined by single crystal X-ray diffraction studies. The compound crystallized in triclinic crystal system with P-1 space group. The molecular structure is stabilized by short intermolecular interactions and intramolecular CH⋯N hydrogen bond interactions. The crystal structure also exhibits intermolecular CH⋯π, CCl⋯π and π⋯π stacking interactions. The intermolecular interactions are quantified through Hirshfeld surface analysis using fingerprint plots. The surface properties were analysed using 3D Hirshfeld surfaces. Further, the density functional theory calculations were carried to calculate the electronic properties of the molecule. The HOMO-LUMO energy gap is found to be 4.0981 eV. Finally, the chemically active sites on the molecule are identified by analysing the molecular electrostatic potential map.

Improved Total Synthesis of 1,3,6-Trigalloyl-β-d-glucose from Glucose

AbstractA total synthesis of the naturally occurring 1,3,6-trigalloyl-β-d-glucose is reported. The highlights of the synthesis include a regioselective benzylation of levoglucosan, followed by a 1,6-ring opening via acetolysis. Galloyl substituents were introduced via esterification, and the mixture of anomers obtained could be fully converted into the targeted β-anomer via selective hydrazinolysis followed by activation of the anomeric position by a trichloroacetimidate of the 1′-anomeric hydroxyl group. 1,3,6-Trigalloyl-β-d-glucose and its synthetic α-anomer were obtained in an overall yield of 31% and 22%, respectively, from levoglucosan or in an overall yield of 37% of the β-isomer exclusively by recycling the α-isomer.

Post-synthetic benzylation of the mRNA 5' cap via enzymatic cascade reactions.

mRNAs are emerging modalities for vaccination and protein replacement therapy. Increasing the amount of protein produced by stabilizing the transcript or enhancing translation without eliciting a strong immune response are major steps towards overcoming the present limitations and improving their therapeutic potential. The 5' cap is a hallmark of mRNAs and non-natural modifications can alter the properties of the entire transcript selectively. Here, we developed a versatile enzymatic cascade for regioselective benzylation of various biomolecules and applied it for post-synthetic modification of mRNA at the 5' cap to demonstrate its potential. Starting from six synthetic methionine analogues bearing (hetero-)benzyl groups, S-adenosyl-l-methionine analogues are formed and utilized for N7G-cap modification of mRNAs. This post-synthetic enzymatic modification exclusively modifies mRNAs at the terminal N7G, producing mRNAs with functional 5' caps. It avoids the wrong orientation of the 5' cap-a problem in common co-transcriptional capping. In the case of the 4-chlorobenzyl group, protein production was increased to 139% during in vitro translation and to 128-150% in four different cell lines. This 5' cap modification did not activate cytosolic pathogen recognition receptors TLR3, TLR7 or TLR8 significantly more than control mRNAs, underlining its potential to contribute to the development of future mRNA therapeutics.

Regioselective Benzylation of Quinoxalin‐2(1H)‐ones with Methylarenes Under Transition‐Metal‐Free Conditions

AbstractA simple protocol of metal‐free C−H benzylation on the C3 position of quinoxalin‐2(1H)‐ones via the oxidation of Di‐tert‐butyl peroxide (DTBP) was developed. This environmentally friendly transformation showed high efficiency and well‐tolerated functionalization, providing the desired products in moderate to good yields. The radical mechanism was confirmed by control experiment as well.

Merging antimicrobial and visible emission properties within 1,3,4-trisubstituted-1,2,3-triazolium salts.

Bioactive molecules displaying visible wavelength emission can be useful for bioimaging, chemosensing and photodynamic therapy applications. Reported herein are 1,3,4-trisubsituted-1,2,3-triazolium salts displaying both antimicrobial and visible emission properties. Using a click chemistry approach, 2-fluorenyl, 1-naphthyl, 2-naphthyl, 2-anthracenyl and 1-pyrenyl units were incorporated at the N1 position, imparting visible emission properties to their triazolium bromide salts with Stokes shifts greater than 100 nm relative to the emission of their triazole precursors. The increasing size of such hydrophobic aryl units impacts minimum inhibitory concentration (MIC) values against Gram-positive bacteria, Gram-negative bacteria and yeast, and can be counterbalanced by hydrophobic substituent variation at other positions of the molecule in order to preserve bioactivity. Among the series of compounds studied are analogs displaying blue, green and yellow colored emission and MIC values as low as 0.4 μM (Gram-positive bacteria), 8 μM (Gram-negative bacteria) and 2 μM (yeast). XRD analysis validates the regioselective benzylation at the N3 position of the 1,2,3-triazole ring and the ability of such compounds to associate through dimeric intermolecular π-stacking interactions.

One-pot synthesis of orthogonally protected sugars through sequential base-promoted/acid-catalyzed steps: A solvent-free approach with self-generation of a catalytic species

A varied set of solvent-free, one-pot synthetic sequences were developed to carry out the orthogonal protection of saccharide polyols. These sequences are composed of an initial regioselective benzylation, silylation or iodination (under mildly basic conditions), followed by an acid catalyzed protection of two further hydroxyl sites via the generation of a cyclic acetal. These processes allow recycling of the ammonium or pyridinium side products generated in the former step as effective catalytic species for the latter step.

Visible‐Light‐Promoted Copper‐Catalyzed Regioselective Benzylation of Pyridine N‐Oxides versus Thermal Acylation Reaction with Toluene Derivatives

Copper‐catalyzed visible light mediated direct C–H bond benzylation of pyridine N‐oxides with toluene derivatives was accomplished by recent developments in photochemical carbon–carbon bond formation through a photo‐induced bond‐dissociation strategy. This visible light driven protocol has been successfully applied to a broad scope of pyridine N‐oxides and toluene derivatives. Furthermore, preliminary research indicates that the acylation reaction can be carried out under thermal reaction conditions. This protocol provides easy access to 2‐benzyl and 2‐acyl pyridine N‐oxide derivatives in the presence of a copper catalyst.

Organotin-catalyzed regioselective benzylation of carbohydrate trans-diols

A convenient approach to regioselective benzylation of carbohydrate trans-diols was developed, where 0.1equiv. of Bu2SnCl2 and 0.1equiv. of TBABr were used as the catalysts and 2.0equiv. of BnCl was used as the benzylation reagent. In most cases, similar or better benzylation regioselectivities and isolated yields were obtained by using catalytic amounts of Bu2SnCl2, rather than stoichiometric amounts of organotin reagents required.

Solvent‐directed Regioselective Benzylation of Adenine: Characterization of N9‐benzyladenine and N3‐benzyladenine

The preferred sites for the benzylation of adenine under basic conditions were proven to be the N9 and N3 positions. Formation of the N9‐benzyladenine product is favored in polar aprotic solvents, such as DMSO, whereas the proportion of N3‐benzyladenine formed increases as the proportion of polar protic solvents, such as water, increases. X‐ray crystal structures were obtained for both N9‐benzyladenine and N3‐benzyladenine. 1H‐13C HMBC NMR spectroscopy revealed diagnostic correlations used to assign the 1H and 13C NMR chemical shifts confirming that the solution structures in three different solvents were the same as the isolated crystals. 13C NMR assignment for N9‐benzyladenine, N3‐benzyladenine, and N7‐benzyladenine was confirmed by computation using ADF.

Large scale synthesis and regioselective protection schemes of ethyl 2-azido-2-deoxy-1-thio-α-d-cellobioside for preparation of heparin thiodisaccharide building blocks

Crystalline acetylated ethyl 2-azido-2-deoxy-1-thio-α-d-cellobioside has been prepared on a multigram scale from cellobiose in an overall yield of 23% with no chromatography required and converted after deacetylation into the 4′,6′-O-benzylidene and 4′,6′-O-benzylidene-6-O-TBDMS protected derivatives. Applying a number of regioselective benzylation methods on these gave access to a variety of regioselectively protected derivatives, both mono-ols (2′- and 3-OH), diols (2′,6-, 2′,3-, and 3,6-di-OH), and triols (2′,3,6- and 2′,3′,3-tri-OH). A number of these derivatives were further processed by benzoylation followed by removal or opening of the benzylidene acetal and selective oxidation of the exposed primary alcohol to give heparin building block intermediates comprising a range of possible sulfation patterns.

ChemInform Abstract: Palladium‐Catalyzed Regioselective Benzylation—Annulation of Pyridine N‐Oxides with Toluene Derivatives via Multiple C—H Bond Activations: Benzylation versus Arylation.

AbstractConditions for the palladium‐catalyzed 2‐arylation vs.

Palladium-catalyzed regioselective benzylation-annulation of pyridine N-oxides with toluene derivatives via multiple C-H bond activations: benzylation versus arylation.

A palladium-catalyzed cross-dehydrogenative coupling (CDC) reaction of pyridine N-oxides with toluenes has been developed that operates under mild conditions. 2-Benzylpyridines can be obtained directly by this method via a CDC reaction between unactivated toluenes and pyridine N-oxides. In addition, azafluorene N-oxides, of value for future medicinal chemistry applications, can be obtained successfully by this procedure via four tandem C-H bond activations.

ChemInform Abstract: Regioselective Benzylation of Diols and Polyols by Catalytic Amounts of an Organotin Reagent.

AbstractThe methodology fails with substrates lacking a cis‐vicinal diol moiety due to formation of regioisomeric benzylation products.

Direct Synthesis of Polybenzylated Glutamic Acid Monoesters: Disambiguation of N,N-Dibenzylglutamic Acid α- and γ-Benzyl Esters

In this study, we explored the regioselective benzylation of l -glutamic acid under substoichiometric amounts of the alkylating agent. Our results demonstrate unambiguously that N,N-dibenzylglutamic acid γ-benzyl ester was not obtained by direct benzylation of l -glutamic acid as reported by other authors. Instead, under such reaction conditions N,N-dibenzylglutamic acid α-benzyl ester was obtained.

Regioselective Benzylation of 2-Deoxy-2-Aminosugars Using Crown Ethers: Application to a Shortened Synthesis of Hyaluronic Acid Oligomers.

The combination of benzyl bromide, sodium hydroxide and 15-crown-5 in tetrahydrofuran is shown to be an efficient method for installing benzyl groups at both the 4- and 6-positions regioselectively directly from peracetylated N-trichloroacetyl-protected glucosamine and galactosamine. Application of this benzylation strategy proved to significantly shorten the synthetic route to hyaluronic acid tetra- and hexamers.

ChemInform Abstract: Tin‐Mediated Regioselective Benzylation and Allylation of Polyols: Applicability of a Catalytic Approach under Solvent‐Free Conditions.

The first catalytic version of the stannylene-mediated benzylation and allylation of polyols is reported. The methodology is based on a simple solvent-free protocol that significantly advances, in terms of both experimental ease and synthetic scope, the applicability of tin-promoted selective protections. The described approach is indeed endowed with a very large number of advantages over routine protocols: use of a low catalytic loading of cheap Bu2SnO, a single-step process with avoided use of solvents, a minimally demanding experimental procedure with reactions performed under air, reduced reaction times, a much simpler work up, a wide target scope, and yields that, in many cases, compare favorably to routine protocols. In addition, the catalytic solvent-free approach extends the scope of stannylene chemistry to unprecedented applications to reducing sugars and in the synthesis of highly benzylated building blocks otherwise accessed through much more demanding procedures. From a conceptual point of vie...

Regioselective Benzylation of Diols and Polyols by Catalytic Amounts of an Organotin Reagent

AbstractAn efficient one‐pot method for the selective benzylation of diols and polyols using 0.1 equiv. of organotin reagents and tetrabutylammonium bromide as catalyst has been developed. The diols and polyols containing a cis‐vicinal diol were regioselectively benzylated in 70–94% isolated yields. A catalytic reaction mechanism was also proposed.magnified image

Tin-Mediated Regioselective Benzylation and Allylation of Polyols: Applicability of a Catalytic Approach Under Solvent-Free Conditions

The first catalytic version of the stannylene-mediated benzylation and allylation of polyols is reported. The methodology is based on a simple solvent-free protocol that significantly advances, in terms of both experimental ease and synthetic scope, the applicability of tin-promoted selective protections. The described approach is indeed endowed with a very large number of advantages over routine protocols: use of a low catalytic loading of cheap Bu2SnO, a single-step process with avoided use of solvents, a minimally demanding experimental procedure with reactions performed under air, reduced reaction times, a much simpler work up, a wide target scope, and yields that, in many cases, compare favorably to routine protocols. In addition, the catalytic solvent-free approach extends the scope of stannylene chemistry to unprecedented applications to reducing sugars and in the synthesis of highly benzylated building blocks otherwise accessed through much more demanding procedures. From a conceptual point of view, the described results indicate that solvent-free conditions can assist the development of catalytic approaches otherwise ineffective in solution.

ChemInform Abstract: A Practical Approach to Regioselective O‐Benzylation of Primary Positions of Polyols.

AbstractTwo sequential additions of Bn‐Br and DIPEA in the presence of substoichiometric Bu4NI are optimal for the efficient regioselective benzylation of a variety of carbohydrate‐derived polyols at a primary ‐OH group.

ChemInform Abstract: Microwave‐Assisted Regioselective Benzylation: An Access to Glycal Derivatives with a Free Hydroxyl Group at C4.

AbstractD‐Glucal, D‐galactal (I), and their 6‐O‐protected derivatives, e.g. (IV), are benzylated in a two‐step sequence.