4H-Benzo[d][1,3]oxazin-4-ones and Dihydro Analogs from Substituted Anthranilic Acids and Orthoesters.
ABSTRACT: A one-pot route to 2-alkyl and 2-aryl-4H-benzo[d][1,3]oxazin-4-ones (also known as 4H-3,1-benzoxazin-4-ones) has been developed and studied. The method involves the reaction of aryl-substituted anthranilic acids with orthoesters in ethanol catalyzed by acetic acid. Additionally, we have also investigated the reaction under microwave conditions. Not all of the substrates were successful in yielding the target heterocycles as some of the reactions failed to undergo the final elimination. This process led to the isolation of (±)-2-alkyl/aryl-2-ethoxy-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-ones. The formation of the dihydro analogs correlated with the electron density on the aromatic ring: Electron-donating groups favored the 4H- benzo[d][1,3]oxazin-4-ones, while electron-withdrawing groups tended to favor the dihydro product. Substituting a pyridine ring for the benzene ring in the substrate acid suppressed the reaction.
Project description:The aminomethylation of hydroxylated isoflavones with 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol, and 5-amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-hydroalkyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-4-ones 4 and/or the tautomeric 7-hydroxy-8-(1,3-oxazepan-3-ylmethyl)-4H-chromen-4-ones 5. The ratio of these tautomers was dependent on solvent polarity, electronic effects of aryl substituents in the isoflavone and the structure of the amino alcohol. NMR studies confirmed the interconversion of tautomeric forms.
Project description:A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation-cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)6 and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is extended to include challenging ortho-bromophenols. Finally, to highlight the versatility of the developed method, Mo(CO)6 is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.
Project description:Glycoside hydrolases catalyze the selective hydrolysis of glycosidic bonds in oligosaccharides, polysaccharides, and their conjugates. ?-glucosidases occur in all domains of living organisms and constitute a major group among glycoside hydrolases. On the other hand, the benzoxazinoids occur in living systems and act as stable ?-glucosides, such as 2-(2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one)-?-D-gluco-pyranose, which hydrolyse to an aglycone DIMBOA. Here, we synthesized the library of novel 1,3-benzoxazine scaffold based aglycones by using 2-aminobenzyl alcohols and aldehydes from one-pot reaction in a chloroacetic acid catalytic system via aerobic oxidative synthesis. Among the synthesized benzoxazines, 4-(7-chloro-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-yl)phenol (compound 7) exhibit significant inhibition towards glucosidase compared to acarbose, with a IC50 value of 11.5 µM. Based upon results generated by in silico target prediction algorithms (Naïve Bayesian classifier), these aglycones potentially target the additional sodium/glucose cotransporter 1 (where a log likelihood score of 2.70 was observed). Furthermore, the in vitro glucosidase activity was correlated with the in silico docking results, with a high docking score for the aglycones towards the substrate binding site of glycosidase. Evidently, the in vitro and in vivo experiments clearly suggest an anti-hyperglycemic effect via glucose uptake inhibition by 4-(7-chloro-2,4-dihydro-1H-benzo[d][1,3]oxazin-2-yl)phenol in the starved rat model. These synthetic aglycones could constitute a novel pharmacological approach for the treatment, or re-enforcement of existing treatments, of type 2 diabetes and associated secondary complications.
Project description:Nine 3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones (17-25), some of which contain fluoro-substituents, have been regiospecifically prepared by reaction of 2,3-diaminopyridines with ethyl aroylacetates. In two cases, open intermediates have been isolated and these are related to the reaction pathway. The X-ray crystal structure of 1-methyl-4-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (23) has been solved (formula, C15H13N3O; crystal system, monoclinic; space group, C2/c). This is an asymmetric unit constituted by a single nonplanar molecule and its conformational enantiomer due to the presence of the seven-membered diazepin-2-one moiety, which introduces a certain degree of torsion in the adjacent pyridine ring. The 1H, 13C, 15N, and 19F NMR spectra were obtained and the chemical shifts, together with those of the previously published 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones (1-16), i.e., a total of 544 values, were successfully compared with the chemical shifts calculated at the gauge invariant atomic orbital (GIAO)/Becke, three-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level. The seven-membered ring inversion barrier in 5-benzyl-2-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (25) was determined and, in conjunction with the data from the literature, compared with the B3LYP/6-311++G(d,p) computed values. This allowed the determination of several structural effects. The rotation about the exocyclic N1-CR bond was also calculated and its dynamic properties were discussed.
Project description:The KOH-promoted chemodivergent benzannulation of ortho-fluorobenzamides with 2-propyn-1-ol can afford either 1,4-benzoxazepin-5(4H)-ones or 1,3-benzoxazin-4(4H)-ones in good yields with high selectivity, depending greatly upon the use of solvents. In the case of using DMSO, the intermolecular benzannulation produced seven-membered benzo-fused heterocycles of 1,4-benzoxazepin-5(4H)-ones, whereas in MeCN, the six-membered benzo-fused heterocycles of 1,3-benzoxazin-4(4H)-ones were formed. The KOH-promoted benzannulation proceeded most probably through the C-F nucleophilic substitution of ortho-fluorobenzamides with 2-propyn-1-ol to give the intermediate of ortho-[(2-propynyl)oxy]benzamide, which underwent the intramolecular hydroamidation in a different manner to afford either seven- or six-membered benzo-fused heterocycles.
Project description:Three ring-substituted 3-aryl analogs of 2-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one, namely 3-(4-meth-oxy-phen-yl)-2-phenyl-4H-1,3-benzo-thia-zin-4-one, C21H17NO2S, (I), 2-phenyl-3-[4-(tri-fluoro-meth-yl)phen-yl]-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one toluene hemisolvate, C21H14F3NOS·0.5C7H8, (II), and 3-(3-bromo-phen-yl)-2-phenyl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one toluene hemisolvate, C20H14BrNOS·0.5C7H8, (III), were synthesized and their crystal structures determined. The hemisolvates differ in that in (II), the asymmetric unit comprises two molecules of the benzo-thia-zinone compound and a toluene solvent mol-ecule, whereas in (III), the unit comprises one benzo-thia-zinone mol-ecule and a half-occupancy toluene solvent mol-ecule. All crystals are of racemic mixtures of the chiral 2-C atom of the thia-zine moiety, which in all structures has a screw-boat puckering, with the puckering amplitude values within the range 0.575-0.603?Å. In all three structures, the benzene plane of the benzo-thia-zine system makes a dihedral angle in the range 78.60?(5) to 98.40?(5)° with the unsubstituted benzene plane and in the range 70.50?(1) to 121.00?(5)° with the substituted benzene plane. The CF3 substituent group in one of the mol-ecules of (II) shows positional disorder, with an occupancy ratio of 0.57?(3):0.43?(3). In the crystals of (I) and (II), weak inter-molecular C-H?O inter-actions are present, giving in (I), mol-ecules arranged in a plane parallel to (010), and in (II), chains along a. In addition, all three structures show weak C-H?? inter-actions involving various aromatic rings.
Project description:There has been a significant interest in organoboron compounds such as arylboronic acids, arylboronate esters and potassium aryltrifluoroborate salts because they are versatile coupling partners in metal-catalysed cross-coupling reactions. On the other hand, their nitrogen analogues, namely, 1,3,2-benzodiazaborole-type compounds have been studied extensively for their intriguing absorption and fluorescence characteristics. Here we describe the first palladium-catalysed Suzuki-Miyaura cross-coupling reaction of easily accessible and ultra-stabilised 2-aryl-1,3-dihydro-1H-benzo[d]1,3,2-diazaborole derivatives with various aryl bromides. Aryl bromides bearing electron-withdrawing, electron-neutral and electron-donating substituents are reacted under the catalytic system furnishing unsymmetrical biaryl products in isolated yields of up to 96% in only 10 minutes.
Project description:7-Benzyl-3-tert-butyl-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C22H25N3O, (I), and 3-tert-butyl-7-(4-methylbenzyl)-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C23H27N3O, (II), are isomorphous in the space group P2(1), and molecules are linked into chains by C-H...O hydrogen bonds. In each of 3-tert-butyl-7-(4-methoxybenzyl)-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C23H27N3O2, (III), which has cell dimensions rather similar to those of (I) and (II), also in P2(1), and 3-tert-butyl-1-phenyl-7-[4-(trifluoromethyl)benzyl]-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C23H24F3N3O, (IV), there are no direction-specific interactions between the molecules. In 3-tert-butyl-7-(4-nitrobenzyl)-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C22H24N4O3, (V), a combination of C-H...O and C-H...N hydrogen bonds links the molecules into complex sheets. There are no direction-specific interactions between the molecules of 3-tert-butyl-7-(2,3-dimethoxybenzyl)-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C24H29N3O3, (VI), but a three-dimensional framework is formed in 3-tert-butyl-7-(3,4-methylenedioxybenzyl)-1-phenyl-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C23H25N3O3, (VII), by a combination of C-H...O, C-H...N and C-H...pi(arene) hydrogen bonds, while a combination of C-H...O and C-H...pi(arene) hydrogen bonds links the molecules of 3-tert-butyl-1-phenyl-7-(3,4,5-trimethoxybenzyl)-6,7-dihydro-1H,4H-pyrazolo[3,4-d][1,3]oxazine, C25H31N3O4, (VIII), into complex sheets. In each compound, the oxazine ring adopts a half-chair conformation, while the orientations of the pendent phenyl and tert-butyl substituents relative to the pyrazolo[3,4-d]oxazine unit are all very similar.
Project description:An efficient and diastereoselective (CDC)-Rh-catalyzed hydroalkylation of dienes with 1,3-oxazol-5(4H)-ones is reported. Aryl and alkyl substituted dienes are converted to ?,?-substituted oxazolones (24 examples) by the formation of N-substituted quaternary carbon stereogenic centers in good yields (up to 96%) and with high diastereoselectivity (>20?:?1 dr). The reaction is tolerant of a range of dienes and oxazolones bearing various functional groups. Utility of the oxazolone products is illustrated through hydrolysis to form ?,?-substituted ?-amino acid analogues and stereoselective epoxidation of the resultant alkene to create four contiguous stereocenters.
Project description:The syntheses and crystal structures of 2,3-bis-[3-(tri-fluoro-meth-yl)phen-yl]-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-m-CF3; C22H13F6NOS) (1) and 2,3-bis-(4-methyl-phen-yl)-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-p-CH3; C22H19NOS) (2) are reported. Each structure is racemic: the asymmetric unit of 2 consists of two mol-ecules. In both 1 and 2, the six-membered 1,3-thia-zine ring is close to an envelope conformation with the chiral C atom forming the flap. In 1, the 2-aryl group is pseudo-equatorial, while in 2 it is pseudo-axial. In 1, the pendant aryl rings form a V shape with an inter-centroid distance of 3.938?(3)?Å and an acute dihedral angle of 48.3?(2)° between them. Both CF3 groups are disordered over two orientations in 0.687?(19):0.313?(19) and 0.667?(16):0.33?(16) ratios. In each of the independent mol-ecules of 2, the aryl rings are almost orthogonal to each other [dihedral angles = 85.50?(12) and 86.07?(11)°]. In both structures, the chiral C atom and the O atoms participate in C-H?O-type hydrogen bonding between symmetry-related mol-ecules of 1 or the independent enanti-omers in 2, forming chains along the c-axis direction in 1 and the b-axis direction in 2. Additionally, in 1, ?-? contacts of both face-to-face and edge-to-face type, as well as ?-H?O and ?-H?F inter-actions are observed. In 2, a racemic mixture of mol-ecules forms layers in the ac plane linked by weak ?-? and C-H?? inter-actions.