An unprecedented intramolecular to intermolecular mechanistic switch in 1,1-diaminoazines leading to differential product formation during the I2-induced tandem oxidative transformation (original) (raw)
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Tetrahedron, 2017
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The [3+2] cycloaddition (32CA) reactions involving 6-butoxy-5,6-dihydro-4H-1,2-oxazine 2oxide and dimethyl maleate are examined in this study. Molecular electron density theory (MEDT) is applied at the M06-2X/6-311G(d,p) level, coupled with the D3 dispersion correction. The nitrone species are identified as zwitterionic entities through an analysis of the electron localization function (ELF). Conceptual DFT indices are utilized to classify dimethyl maleate as the electrophilic component and the nitrone as the nucleophilic counterpart. The [3+2] cycloaddition processes are predominantly governed by kinetic control, as indicated by activation free energies of-23.64 and-11.42 kcal.mol−1 for the exo and endo pathways, respectively, aligning with experimental findings. The formation of a pseudoradical center initiates at carbon atoms C3 and C4. A subsequent docking analysis is conducted on cycloadducts 3 and 4 in relation to the main protease of SARS-CoV2 (6LU7), alongside the co-crystal ligand. The results of this analysis reveal that cycloadducts 3 exhibit higher binding energy, while cycloadducts 4 display lower binding energy compared to the co-crystal ligand.
Synthesis, quantum chemical studies, molecular docking, molecular dynamics simulation and ADMET studies on 2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-1, 4,5-triphenyl-1H-imidazole derivatives, 2023
A novel 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4,5-triphenyl-1H-imidazole (DDTI) molecule was synthesised and characterised by FT-IR and NMR (1 H and 13 C) spectral techniques. The molecular structure was optimised using the density functional theory (DFT) method with B3LYP/6-311 G (d, p) basis set. Natural bonding orbital (NBO) analysis was used to determine the electron densities of donor (i) and acceptor (j) bonds as well as the hyperconjugative interaction energy (E (2)). In highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) calculations, the smaller energy gap value was discovered. Molecular electrostatic potential has been analysed. The Mulliken atomic charges of the carbon, nitrogen and oxygen atoms were calculated at the same level of theory. The dipole moment, polarizability and first-order hyperpolarizability demonstrate the good nonlinear optical (NLO) feature of the title molecule. Molecular docking studies are implemented to analyse the binding energy of the DDTI compound against standard drugs such as the crystal structure of ADP ribose phosphatase of NSP3 from SARS-CoV-2 in complex with MES, SARS-CoV-2 main protease with an unliganded active site (2019-nCoV, corona virus disease 2019, COVID-19) and the crystal structure of COVID-19 main protease in complex with an inhibitor N3 found to be considered having better antiviral agent. Molecular dynamics simulation was performed for COVID-19 main protease (Mpro: 6WCF/6Y84/6LU7) to understand the elements governing the inhibitory effect and the stability of interactions under dynamic conditions. Virtual ADMET studies were carried out as well and a relationship between biological, electronic and physicochemical qualifications of the target compound was determined. Toxicity prediction by computational technique for the title compound was also carried out.
Tetrahedron, 1990
The aza-Wittig reaction of iminophosphorane 2 derived from 1 -aminoS-phenyl-2-thioxo-4-imidazolidinone 1 with heterocumulenes leads to fused imidazoles. Iminophosphorane 2 reacts under mild conditions with isothiocyanates to form imidazo [l,5-dj-[1,3,4]thiadiazines3 which undergo S-methylation to give imidazo [l,5-crJ[l,3,4]thiadiazinium salts 4. lminophosphorane 2 also reacts with isocyanates under mild conditions to give imidazo [l,5-4[1,3,4]oxadiazines 5. The N-aminoheterocycle 1 by the action of diary1 carbodiimides undergoes ring-closure/ring-opening reaction to give the corresponding [1,2,4]triazoles7, which by sequential treatment with trimethyloxonium tetrafluoroborate and triethylamine/methanoI are converted into the oxygen analog 9. The crystal structure of the hydrated salt 4a has been solved by X-Ray diffraction methods. The two independent cations form dimers that pack in chains along the haxis through hydrogen interactions, in such a way that all anions and solvent molecules (H,O and 2 HCCI, in the asymmetric unit) are located in the unit cell into two channels which are described.
Scientia Pharmaceutica
According to our quantum and chemical calculations 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylic acid imidazolide is theoretically almost as reactive as its 2-carbonyl analog, and it forms the corresponding N-pyridyl-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides with many aminopyridines. However, in practice, the sulfo group introduces significant changes at times and prevents the acylation of sterically hindered amines. One of these products was 2-amino-6-methylpyridine. Thus, it has been concluded that aminopyridines interact with imidazolide in aromatic form where the target for the initial electrophilic attack is the ring nitrogen. To confirm the structure of all substances synthesized, 1H-NMR spectroscopy and X-ray diffraction analysis were used. From X-ray diffraction data it follows that in the crystalline phase the carbonyl and sulfo group may occupy different positions with respect to the plane of the benzothiazine bicycle: this position may be unilatera...
2H‑1,2,3‑Benzothiadiazine 1,1-dioxides are a class of compounds of pharmacological interest. After earlier studies carried out at our laboratory on various transformations (alkylation, acylation, reduction) at the hetero ring, the present manuscript focuses on the transformation of substituents at the aromatic carbocycle, including nucleophilic substitution of chlorine atoms and demethylation of the methoxy group with amines. The new methods described here allow the introduction of versatile functional groups on the aromatic ring, making these compounds useful building blocks for organic and medicinal chemistry applications.
HERON rearrangement of N,N?-diacyl-N,N?-dialkoxyhydrazines ? a theoretical and experimental study
Tetrahedron, 1999
Ab initio calculations at the B3LYP/6-31G* level on N-methoxy-N-dimethylaminoformamide and its rearrangement to methyl formate and 1,l-dimethyldiazene through the HERON reaction, have been carried out in conjunction with an experimental study of the HERON reactions of N,N'-diacyl-N,N'-dialkoxyhydrazines. Substituent effects are in accord with the theoretical properties of the transition state and point to an anomericaily driven process in which donor groups on the anomeric nitrogen and withdrawing groups on the migrating alkoxy oxygen facilitate the rearrangement process.
Herein we report the diastereoselective synthesis of a 3-amino-1,2,4-oxadiazine (AOXD) scaffold. The presence of a NO bond in the ring prevents the planar geometry of the aromatic system and induces a strong decrease in the basicity of the guanidine moiety. While DIBAL-H appeared to be the most efficient reducing agent because it exhibited high diastereoselectivity, we observed various behaviors of the Mitsunobu reaction on the resulting β-aminoalcohol, leading to either inversion or retention of configuration depending on the steric hindrance in the vicinitude of the hydroxy group. The physicochemical properties (pKa, and log D) and hepatic stability of several AOXD derivatives were experimentally determined and found that the AOXD scaffold possesses promising properties for drug development. Moreover, we synthesized alchornedine, the only natural product with the AOXD scaffold. Based on a comparison of the analytical data, we found that the reported structure of alchornedine was incorrect and hypothesized a new one. were screened for the diastereoselective synthesis of chiral AOXDs and the relationship between chirality and NMR characteristics was highlighted. As a novel scaffold, the physicochemical properties of AOXD were also investigated. Finally, alchornedine was synthesized, and its spectra and analytical data were compared with those of the isolated compound previously reported. 14 RESULTS AND DISCUSSION As an initial experiment, achiral N-Boc-glycine was used as the starting material for exploring the synthesis of racemic AOXD (Scheme 1). N-Boc-glycine reacted with N, N'-carbonyl diimidazole (CDI) and N,O-dimethylhydroxylamine to form the corresponding Weinreb amide (2) in 99% yield. 18 The nucleophilic addition between 2 and 3,4-dichloro-phenyl magnesium bromide furnished ketone 3 in 86% yield, which was directly reduced by NaBH4, to yield alcohol 4 in 99% yield. As a key step in AOXD synthesis, the Mitsunobu reaction between alcohol 4 and N-hydroxyphthalimide (NHPI) was conducted to form the CON bond, affording the key intermediate, 5, in 94% yield. Then, phthaloyl and Boc protections were successively removed by hydrazine hydrate and HCl treatments, affording 6 and 7 in 94% and 96% yield, respectively. Finally, the cyclization reaction of 7 was carried out with BrCN, to afford racemic AOXD 8 and its 4-cyanated side product 9 in 81% and 17% yield, respectively (see SI section I). The presence of such a side product indicated that the nitrogen atom at position 4 (-HN-CH2-) in 8 is more nucleophilic toward BrCN than those at positions 3 and 2, respectively. X-ray crystallography confirmed the AOXD structure of 8 (Scheme 1), with a C=N double bond located between N 2 and C 3 , rather than C 3 and N 4 , likely because of the stabilization of p-π conjugation between the oxygen atom and the C=N double bond. Meanwhile, the bivalent character of the oxygen atom induced the expected non-planar geometry of AOXD, in which C 6 is located far out of the plane constituted by the N 2 =C 3-N 4 moiety. Moreover, the N 2-O 1 and N 4-C 5 bonds are unparallel because of the different bond angles between N 2-O 1-C 6 and N 4-C 5-C 6. Despite the absence of any functional groups at C 5 of AOXD, or on ortho position of the phenyl ring, the oxadiazine ring in 8 is perpendicular to the phenyl ring, which allows the hydrogen atom C 6 H to be in the same axis as the aromatic ring (for more details of crystallographic data and structure refinement parameters, see SI). Scheme 1. Synthesis of racemic AOXD 8. X-ray crystallographic structure. Thermal ellipsoids are shown at the 50% probability level.
Tetrahedron Letters, 2019
An interesting protocol for the synthesis of benzothiadiazine 1,1-dioxides through iodinecatalyzed one-pot dehomologative oxidation of styrenes and readily available 2aminobenzenesulfonamide has been developed. Diverse benzothiadiazine 1,1-dioxides were prepared using I2 as a catalyst, TBHP as an oxidant and Na2CO3 as a base. This reliable, metal and ligand free conversion involves dehomologation of styrene to aromatic aldehyde which on subsequent cyclisation affords benzothiadiazine 1,1-dioxides in good yield.