51698-53-4

Upstream product

• 93-17-4 3,4-dimethoxyphenylacetonitrile 
• 74-88-4 methyl iodide 
• 6380-23-0 3,4-dimethoxystyrene 
• 7677-24-9 trimethylsilyl cyanide 
• 74-83-9 methyl bromide 
• 1131-62-0 1-(3,4-dimethoxyphenyl)ethanone 
• 67-56-1 methanol 
• 77-78-1 dimethyl sulfate 
• 574010-95-0 N’-(1-(3,4-dimethoxyphenyl)ethylidene)-4-methylbenzenesulfonohydrazide 
• 333-20-0 potassium thioacyanate 
• 5653-65-6 1-(3,4-dimethoxyphenyl)ethanol 
• 7306-46-9 4-chloromethyl-1,2-dimethoxy-benzene 
• 120-14-9 3,4-dimethoxy-benzaldehyde 

Downstream Products

• 82418-24-4 2-(3,4-Dimethoxyphenyl)-4-(1-imidazolyl)-2,3-dimethyl-3-butennitril 
• 97259-44-4 3.4-Dimethoxy-α.α-bis-<3.4.5-trimethoxy-benzyl>-phenylacetonitril 
• 94961-16-7 α-Methyl-α-(3,4-dimethoxy-phenyl)-β-(3,4,5-trimethoxy-phenyl)-propionitril 
• 23023-16-7 2‐(3,4‐dimethoxyphenyl)‐2‐methylpropionitrile 
• 40181-00-8 2-(3,4-di-methoxyphenyl)propionaldehyde 
• 252212-84-3 2-(3,4-dimethoxyphenyl)-1-(isopropylamino)propane 
• 252212-81-0 2-(3,4-dihydroxyphenyl)-1-(isopropylamino)propane 
• 499993-06-5 3-benzyl-1-ethylsulfanyl-7,8-dimethoxy-5-methyl-1,3-dihydrobenzo[d]azepin-2-one 
• 499993-28-1 (Z)-N-benzyl-N-[2-(3,4-dimethoxyphenyl)prop-1-enyl]-2-ethylsulfanylacetamide 
• 499993-27-0 (E)-N-benzyl-N-[2-(3,4-dimethoxyphenyl)prop-1-enyl]-2-ethylsulfanylacetamide 
• 499993-04-3 (E)-N-benzyl-N-[2-(3,4-dimethoxyphenyl)prop-1-enyl]-2-ethylsulfinylacetamide 
• 499993-03-2 (E)-N-benzyl-N-[2-(3,4-dimethoxyphenyl)prop-1-enyl]-2-ethylsulfinylacetamide 
• 96577-68-3 α-Methyl-α-(3,4-dimethoxy-phenyl)-β-(3,4,5-trimethoxy-phenyl)-propionsaeureamid 
• 96867-54-8 β-Methyl-β-<3.4-dimethoxy-phenyl>-γ-<3.4.5-trimethoxy-phenyl>-propylamin 

Relevant academic research and scientific papers

Enantioselective Nickel-Catalyzed Hydrocyanation using Chiral Phosphine-Phosphite Ligands: Recent Improvements and Insights

The asymmetric hydrocyanation of vinylarenes was investigated using hydrogen cyanide (HCN) in the presence of 5 mol% of a catalyst prepared from a phenol-derived chiral phosphine-phosphite ligand and bis(cyclooctadiene)nickel [Ni(cod)2]. The reactions were performed in tetrahydrofuran (THF) at room temperature to give exclusively the branched nitriles with superior enantioselectivities of 88-99% ee for vinylarenes and 74-94% ee for vinylheteroarenes, respectively. Using styrene as a model substrate it was shown that the catalyst loading could be decreased to 0.42 mol% without any loss of selectivity (88% ee). The structure of the pre-catalyst, i.e., a tetrahedral Ni(0)(P,P-chelate)(cod) complex, was proven by X-ray and NMR analysis. Additional insight into the reaction course was gained by monitoring the hydrocyanation of styrene-d8 by means of 2D NMR spectroscopy.

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.

Structure and Biocatalytic Scope of Coclaurine N-Methyltransferase

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)-reticulene at which point the pathway diverges. Coclaurine N-methyltransferase (CNMT) is a key enzyme in the pathway to (S)-reticulene, installing the N-methyl substituent that is essential for the bioactivity of many BIAs. In this paper, we describe the first crystal structure of CNMT which, along with mutagenesis studies, defines the enzymes active site architecture. The specificity of CNMT was also explored with a range of natural and synthetic substrates as well as co-factor analogues. Knowledge from this study could be used to generate improved CNMT variants required to produce BIAs or synthetic derivatives.

Ex situ generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: Evidence for a transmetallation step between two oxidative addition Pd-complexes

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of ex situ generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of LnPd(0) into HCN and an aryl bromide followed by a transmetallation step to LnPd(Ar)(CN) and LnPd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and LnPd(0).

Facile Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols Enabled by Metal-Ligand Cooperation

A facile ruthenium(II)-catalyzed α-alkylation of arylmethyl nitriles using alcohols is reported. The ruthenium pincer catalyst serves as an efficient catalyst for this atom-economical transformation that undergoes alkylation via borrowing hydrogen pathways, producing water as the only byproduct. Arylmethyl nitriles containing different substituents can be effectively alkylated using diverse primary alcohols. Notably, using ethanol and methanol as alkylating reagents, challenging ethylation and methylation of arylmethyl nitriles were performed. Secondary alcohols do not undergo alkylation reactions. Thus, phenylacetonitrile was chemoselectively alkylated using primary alcohols in the presence of secondary alcohols. Diols provided a mixture of products. When deuterium-labeled alcohol was used, the expected deuterium transposition occurred, providing both α-alkylation and α-deuteration of arylmethyl nitriles. Consumption of nitrile was monitored by GC, which indicated the involvement of first-order kinetics. Plausible mechanistic pathways are suggested on the basis of experimental evidence. The ruthenium catalyst reacts with base and generates an unsaturated intermediate, which further reacts with both nitriles and alcohols. While nitrile is transformed to enamine via [2 + 2] cycloaddition, alcohol is oxidized to aldehyde. The metal bound enamine adduct reacts with aldehyde via Michael addition, resulting in an ene-imine adduct, which perhaps undergoes direct hydrogenation by a Ru dihydride intermediate, produced from alcohol oxidation. However, in situ monitoring of the reaction mixture confirmed the presence of unsaturated vinyl nitrile in the reaction mixture in minor amounts (10%), indicating the possible dissociation of ene-imine adduct during the catalysis, which may further be hydrogenated to provide the α-alkylated nitriles. Overall, the efficient α-alkylation of nitriles using alcohols can be attributed to the amine-amide metal-ligand cooperation that is operative in the ruthenium pincer catalyst, which enables all of the catalytic intermediates to remain in the +2 oxidation state throughout the catalytic cycle.

Copper-Catalyzed Cyanation of N-Tosylhydrazones with Thiocyanate Salt as the "cN" Source

A novel protocol for the synthesis of α-aryl nitriles has been successfully achieved via a copper-catalyzed cyanation of N-tosylhydrazones employing thiocyanate as the source of cyanide. The features of this method include a convenient operation, readily available substrates, low-toxicity thiocyanate salts, and a broad substrate scope.

Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c

New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.

Enantioselective nickel-catalyzed hydrocyanation of vinylarenes using chiral phosphine-phosphite ligands and TMS-CN as a source of HCN

Anti-headache chemistry: In the presence of a tailored modular P,P ligand the nickel-catalyzed addition of HCN, generated in situ from TMS-CN, to styrene derivatives proceeds with an unprecedented level of stereocontrol (up to 97 % ee) to give 2-aryl-acetonitriles, for example, the depicted precursor of Ibuprofen. Copyright

Catalytic asymmetric protonation of silyl ketene imines

An efficient catalytic and highly enantioselective protonation of silyl ketene imines is described. The reaction is catalyzed by the chiral phosphoric acids TRIP or STRIP in the presence of a stoichiometric amount of methanol as the proton source and silyl acceptor. A variety of substituted racemic silyl ketene imines have been transformed into highly enantioenriched nitriles.

Facile preparation of α-aryl nitriles by direct cyanation of alcohols with TMSCN under the catalysis of InX3

(Chemical Equation Presented) A convenient and efficient synthesis of α-aryl nitrites was developed by direct cyanation of alcohols with TMSCN under the catalysis of Lewis acid. Using 5-10 mol % of InBr3 as the catalyst, a variety of benzylic alcohols can be converted to the corresponding nitriles in 5-30 min with yields of 46-99%.