Cyclic Amidine Research Articles

P19-52 In silico and in vitro genotoxicity evaluation of vildagliptin impurities: vildagliptin cyclic amidine, vildagliptin diketopiperazine and vildagliptine amide

P19-52 In silico and in vitro genotoxicity evaluation of vildagliptin impurities: vildagliptin cyclic amidine, vildagliptin diketopiperazine and vildagliptine amide

Total Syntheses of Streptamidine and Klebsazolicin Using Biomimetic On‐Resin Ring‐Closing Amidine Formation

AbstractDiketopiperazine (DKP) derived cyclic amidine structures widely exist in peptide natural products according to the genome mining result. The largely unknown bioactivity and mode of action are partially caused by the poor availability of the compounds via microbiological and chemical approaches. To tackle this challenge, in this work, we have developed the on‐resin ring‐closing amidine formation strategy to synthesize peptides containing N‐terminal DKP derived cyclic amidine structure, in which the 6‐exo‐trig cyclization mediated by HgCl2 activation of thioamides was the key step. Leveraging from this new strategy, we finished the total syntheses of streptamidine and klebsazolicin. Meanwhile, eleven klebsazolicin analogues were synthesized for its structure–activity relationship study.

Total Syntheses of Streptamidine and Klebsazolicin Using Biomimetic On-Resin Ring-Closing Amidine Formation.

Diketopiperazine (DKP) derived cyclic amidine structures widely exist in peptide natural products according to the genome mining result. The largely unknown bioactivity and mode of action are partially caused by the poor availability of the compounds via microbiological and chemical approaches. To tackle this challenge, in this work, we have developed the on-resin ring-closing amidine formation strategy to synthesize peptides containing N-terminal DKP derived cyclic amidine structure, in which the 6-exo-trig cyclization mediated by HgCl2 activation of thioamides was the key step. Leveraging from this new strategy, we finished the total syntheses of streptamidine and klebsazolicin. Meanwhile, eleven klebsazolicin analogues were synthesized for its structure-activity relationship study.

Sulfonamido, amido heterocyclic adducts of tetrazole derivatives as BACE1 inhibitors: in silico exploration.

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime.

Importance of hydrogen bonding in base-catalyzed transesterification reactions with vicinal diols

The transesterification reaction kinetics of 2-(benzoyloxy)ethyl benzoate with various alcohols (ethylene glycol, 1,3-propanediol, 1-butanol, propylene glycol and 1,2-butylene glycol) using various cyclic amidine catalysts were investigated. For transesterification with excess glycol (glycolysis), the rate was nearly zero order in diester and glycol concentration, which is substantially different from classical transesterification kinetics with mono-alcohols. The measured kinetic parameters during glycolysis are consistent with a reaction path that is kinetically limited by the decomposition of the reaction intermediate formed from the alkoxide and diester. The DFT-calculated reaction energy and activation barrier for decomposition of this intermediate reveal a critical role of intramolecular hydrogen-bond stabilization made possible by the vicinal –OH of the glycol that effectively increases the concentration of the intermediate during reaction resulting in acceleration of the overall transesterification rate. These findings indicate the nature of both the alcohol solvent and the catalyst influence transesterification rate, and results suggest they are also important in the deconstruction of carbonyl-containing condensation polymers.

Synthesis, structures, and properties of manganese(i) complexes featuring tridentate amidine-toting protic amine ligands

Cationic Mn(CO)3 complexes having a protic amine ligand with cyclic amidine side arms were prepared and their catalytic properties of transfer hydrogenation of acetophenone and electrochemical reduction of CO2 were compared.

Total Synthesis of (+)‐Cinereain and (−)‐Janoxepin through a Fragment Coupling/Retro‐Claisen Rearrangement Cascade

AbstractTotal syntheses of (+)‐cinereain and (−)‐janoxepin, two fungal cyclotripeptides featuring a complex heterocyclic core and interesting phytotoxic and antimalarial activities, have been achieved in a convergent manner. A key step in this synthesis is a one‐pot cascade initiated by the cyclocondensation of two fragments—a hindered 2‐vinylcyclopropane‐1‐acyl fluoride and an electron‐deficient cyclic amidine—to release a reactive spiro[2‐vinylcyclopropane‐1,5′‐pyrimidine‐4′,6′‐dione]. This intermediate underwent a spontaneous retro‐Claisen rearrangement that was rationalized by DFT calculations. The cascade directly afforded a 2,5‐dihydrooxepin‐fused heterotricyclic product, and the challenging oxepin ring was finally forged by the palladium‐catalyzed β‐hydride elimination of an allylic fluoride intermediate.

Degradation of mirubactin to multiple siderophores with varying Fe(III) chelation properties.

Three siderophores mirubactins B-D (4-6) were identified as the degradation products of previously isolated mirubactin (1). Their structures were revealed by HR-ESI-MS/MS, NMR analyses, and density functional calculations, among which 4 contains an unusual cyclic amidine functionality. Cyclic voltammetry showed that 5 and 6 have reduced iron complexing capacity. Mirubactin (1) and Fe(III) could also form a stable complex, which may be an ingenious approach to compete for iron acquisition by the producing organisms.

Hydrazone‐Based Ligand with Pyrrolidine Donor and Its Molybdenum(VI) Complex: Synthesis, Structure, and Reactivity

AbstractThe Schiff‐base condensation of salicylaldehyde and 4‐aminobutanehydrazide hydrochloride leads to the hydrazone‐based ligand H2salhyab containing an amino side chain. The reaction of H2salhyab ⋅ HCl with bis(acetylacetonato)dioxidomolybdenum leads to the formation of [MoO2(salhycab)(MeOH)] (H2salhycab=2‐((pyrrolidine‐2‐ylidenehydrazineylidene)methyl)phenol), whereby the amino side chain reacted with the hydrazide carbonyl group to form a cyclic amidine with a pyrrolidine ring leading a new type of tridentate hydrazone ligand with [NNO] donor set. X‐ray crystallography revealed the additional coordination of a methanol molecule at the molybdenum(VI) center which leads to the formation of hydrogen‐bonded dimers of the neutral complex in the crystal structure. The complex [MoO2(salhycab)(MeOH)] was found to be an efficient catalyst for the peroxidic oxidation of phenyl methyl sulfide.

Utilization of Borane-Catalyzed Hydrosilylation as a Dearomatizing Tool: Six-Membered Cyclic Amidine Synthesis from Isoquinolines and Pyridines

AbstractIn this study, a convenient strategy to synthesize six-membered­ cyclic amidines from isoquinolines and pyridines has been developed. Borane-catalyzed hydrosilylation of each N-heteroarene was utilized as a dearomatizing tool. Substrate scope is broad with respect to both isoquinolines and pyridines, with various reaction pathways depending on the substitution pattern of the N-heteroarenes. The reaction mechanism and reactivity of each class of N-heteroarenes has been discussed. The resulting six-membered (Z)-sulfonyl amidine products are rarely reported and are mostly unprecedented. The scalability of this method and versatility of the cyclic amidine products are also presented.

Photolysis Mechanism of Quaternary Amidinium Salts

AbstractPhotoinduced polymerization reactions are an energy‐saving and environmentally friendly technology used in applications such as curing and coating. Photo initiators are one of the key materials which generate active species by photoirradiation. Many types of radical and cationic photo initiators (photoacid generators) have been developed. However, anionic photo initiators (photobase generators), which are more advantageous in terms of corrosion and lack of deactivation, remain under development. Cyclic amidine compounds, such as DBU® (1,8‐Diazabicyclo[5.4.0]undec‐7‐ene) and DBN (1,5‐Diazabicyclo[4.3.0]non‐5‐ene), are strong organic bases, widely used as catalysts in organic, polymerization, and crosslinking reactions. Developing a photobase initiator that can generate such a strong base is important, because there are few photobase generators with strong basicity and high reactivity for practical applications. In this study, we investigated the elementary mechanism of photolysis of quaternary amidinium borate salts by transient absorption measurements. We confirm that photoinduced electron transfer is a key step in the photo decomposition of quaternary amidinium borate salts and that the position of the sensitizing chromophore in the molecules significantly affects the decomposition efficiency.

Cyclic amidine hydroiodide for the synthesis of cyclic carbonates and cyclic dithiocarbonates from carbon dioxide or carbon disulfide under mild conditions

Hydroiodides of amidines can catalyze the reaction of carbon dioxide and epoxides under mild conditions such as ordinary pressure and ambient temperature, and the corresponding five-membered cyclic carbonates were obtained in high yields. The reaction of epoxide with carbon disulfide was also examined under the same conditions. Detailed investigation showed that the catalytic activity was highly affected by the counter anions of the amidine salts; the iodides were effective catalysts for both of the reaction of epoxide with carbon dioxide and carbon disulfide, whereas the bromide, chloride and fluoride counterparts exhibited almost no catalysis.

Polymer with Zwitterionic Structure in Main Chain via Polyaddition of Bifunctional Cyclic Amidine and Diisothiocyanate

A polymer containing a zwitterionic form in the main chain was synthesized by the polyaddition of a bifunctional cyclic amidine with diisothiocyanate. The ion conductivity of a composite film consisting of the polymer and lithium chloride was evaluated by AC impedance measurements, demonstrating its potential applicability as an ion-conductive material.

Synthesis and decrosslinking of networked polymers having zwitterion structure consisted by cyclic amidine and isothiocyanate

ABSTRACTWe have already found that the polymers, which are obtained by the polymerization of 4‐vinylphenyl isothoiocyanate after the zwitterion formation with cyclic amidines, are networked through the ionic interaction among the zwitterions becoming insoluble to various solvents. We report here on the results of the reaction of nucleophilic reagents such as amines and alcohols with the zwitterionic adduct to investigate about the decrosslinking through the resolution of ionic interactions. In the model reactions of amines and alcohols with the zwitterion compounds, which were consisted of the phenyl isothiocyanate and cyclic amidines, the reaction of nucleophilic reagents and zwitterionic adducts having methyl group at the 2‐position of the amidine proceed quantitatively. Based on the model reaction, such nucleophilic addition was applicable to decrosslinking reaction of the networked polymers containing the zwitterion structure in the side‐chain. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 2131–2137

N-Heterocyclic Olefin Catalysis for the Ring Opening of Cyclic Amidine Compounds: A Pathway to the Synthesis of ε-Caprolactam- and γ-Lactam-Derived Amines.

For the first time, 1,2-dimethyl-3-ethylimidazolium iodide (1a) catalyzes the ring opening of the bicyclic amidine system of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) on reaction with aldehydes. The mechanism here proposed involves an N-heterocyclic olefin (NHO) catalytic species that acts as a nucleophile to promote the cyclic amidine ring opening. The resulting ε-caprolactam- and γ-lactam-derived imines were obtained in moderate to excellent yields (28-99%) and reduced to the corresponding amines by sodium borohydride. Confirmation of the imine product was achieved via single-crystal X-ray diffraction studies.

Synergistic CO2 Mediation and Photocatalysis for α-Alkylation of Primary Aliphatic Amines

Recent work published by Rovis, Schoenebeck, and co-workers in Nature Chemistry describes a synergistic CO2 mediation and photocatalysis strategy for challenging α-alkylation of primary aliphatic amines by using quinuclidine as a hydrogen atom transfer (HAT) catalyst for γ-lactam synthesis. Electrostatic attraction between the in-situ-generated carbamate and quinuclidinium radical cation is critical for the selectivity.

Synthesis of polymers having zwitterionic structure via the radical polymerization of 4‐vinylphenyl isothiocyanate/cyclic amidine adduct

ABSTRACTPolymers having a zwitterionic pendant group have found a wide range of applications such as fungicides, fire‐retardants, lubricating oil additives, emulsifiers, cryoprotectants, and electronic materials. Their properties depend not only on the polymer main chains but also on the zwitterionic structures. In this article, the synthesis of novel polymers having zwitterionic structures is described. A zwitterionic monomer (4‐vinylphenyl isothiocyanate [VPI]‐1,2‐dimetyl‐1,4,5,6,‐tetrahydropirimidine [DMTHP]) was synthesized by the reaction of VPI and a cyclic amidine DMTHP. A radical polymerization of VPI‐DMTHP was carried out using 2,2′‐azobis(2,4‐dimethyl‐4‐methoxy)valeronitrile (V‐70) as an initiator to give poly(VPI‐DMTHP). The obtained poly(VPI‐DMTHP) was not soluble in any of the investigated organic solvents, probably because it had a networked structure resulting from the ionic interactions. Copolymers of VPI‐DMTHP and other vinyl monomers such as styrene, methyl methacrylate, t‐butyl methacrylate, and N‐vinylpyrrolidone were synthesized. The obtained copolymers were also insoluble in all of the examined common organic solvents even when the VPI‐DMTHP content was low (5 mol %), indicating the existence of strong ionic interactions in the zwitterionic moieties. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 2303–2309

Water-soluble NNN-pincer complexes of cobalt, nickel and palladium: Solid-state structures and catalytic activity

Neutral NNN-pincer ligand 1 based on a pyridyl core and cyclic amidine pendant arms was synthesized via a straightforward condensation reaction. Its square-planar palladium acetate complex 2 was prepared in methanol and featured a cyclic, hexameric solid-state structure assembled through moderately strong N⋯H⋯O hydrogen bonds involving the ligand backbone and the non-coordinated acetate group. The octahedral, diamagnetic Co(III) complex 3 was prepared via in-situ air oxidation of its Co(II) analog. Its solid-state structure confirmed the oxidation state of the metal and revealed the presence of weak bridging and terminal NH⋯Cl hydrogen bonds. Paramagnetic nickel complex 4 was prepared in a similar fashion to 1 and was postulated to have a covalent attachment of the acetate moieties to the metal. Derivatives 2 and 3 had excellent water solubility and stability while 4 was sparingly soluble in water. Cyclic voltammetry revealed electrochemically reversible electron transfer steps corresponding to the Co(II)/Co(III) and Ni(II)/Ni(III) redox couples at −0.31V and 1.04V versus SHE, respectively. Complex 4 displayed catalytic competency towards the thiolation of iodobenzene with dimethyldisulfide and zinc in DMF. In water, 4 was able to catalyze the Negishi cross-coupling of iodobenzene.

Design and synthesis of some tricyclic pyrimidines and triazines via cycloaddition and intermolecular cyclization of cyclic amidine

The cyclic amidine 3 was used as a precursor in this research, which was synthesized by chlorination of compound 1, followed by ring closure with hydrazine hydrate. Cyclization of amidine compound 3 with acetylacetone, ethyl cyanoacetate, chalcone analogue 6 and benzylidenemalononitrile (8) tolerated the expected tricyclic pyrimidines 4, 5, 7 and 9, respectively. Reaction of 3 with ammonium thiocyanate followed by cyclization of the product 10 with DMF, ethyl chloroformate and chloroacetyl chloride afforded triazine derivatives 11–13, respectively. Nucleophilic substitution of the later compound with EtONa gave ethyl methyl ether derivative 14. The benzamide derivative 15 was obtained by reaction of 3 with benzoylisothiocyanate or benzoylation of compound 10 with benzoyl chloride. Finely, heterocylization of 15 in the presence of Et3N gave the triazine derivative 16. 6-(4-Chlorophenyl)-4-(4-isopropylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (3) was used as the starting material for the synthesis of pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine and pyrido[2′,3′:3,4]pyrazolo[1,5-a][1,3,5]triazine derivatives via cycloaddition and intermolecular cyclization reactions.

N-(Hetero)aryl-2-imidazolines: an emerging privileged motif for contemporary drug design

The diverse biological activities of compounds containing N-(hetero)aryl-2-imidazoline moiety and methods to construct them are comprehensively reviewed for the first time. This intriguing non-flat, cyclic amidine motif clearly represents an emerging privileged structure.