3-Hydroxy-4-oxo-3,4-dihydro-5-azabenzo-1,2,3-triazene

The known but long-neglected compound HODhat was shown to be in certain situations a useful peptide coupling additive. Uronium and phosphonium salts with HODhat built into the system were also useful stand-alone coupling reagents. Comparisons with related additives and coupling reagents showed that the new systems were sometimes more and sometimes less effective than previously described systems in the case of stepwise and segment couplings. Applications to assembly of the model decapeptide ACP showed that HDATU was far more effective than HDTU and more effective than HATU under some conditions.     

Microwave-assisted one-pot regioselective synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines

A protocol for regioselective one-pot synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has been developed. Starting from commercially available 2-aminophenols, a base-mediated regioselective O-alkylation took place with 2-bromoalkanoates to give the acyclic intermediates, which underwent spontaneously an intramolecular amidation reaction to furnish 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines in 44-82% yields. For the acyclic intermediate possessing an electron-withdrawing group, microwave heating was necessary for the annulation reaction.     

4-Halogeno-3-oxides and sulfides of the 3,4-dihydro-2h-1,2,3-diazaphosphole system

4-Bromodiazaphosphole-3-oxides or sulfides can be obtained by reaction of the corresponding unsubstituted derivative with appropriate reagents. PTAB was demonstrated to be very regio- and stereoselective, allowing bromination exclusively at the 4-position of the ring with prevalent or exclusive formation of one of the two possible isomers. However, when regioselectivity is not required, cheaper and more available bromine or NBS can be used conveniently. 4-Chlorodiazaphosphole-3-oxides can be obtained by reaction of the corresponding unsubstituted derivative with NCS. 4-Bromodiazaphosphole-3-oxides undergo stereoselective methanolysis as well as parent unsubstituted oxides.     

Synthesis of alkyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates as peptidomimetic building blocks

A general synthesis of new alkyl 4-alkyl-2-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate peptidomimetic building blocks from the corresponding alkyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylates through carbanion oxidation is described.     

Synthesis of substituted 4-(3-alkyl-1,2,4-oxadiazol-5-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines and 4-(1H-benzimidazol-2-ylmethyl)-3,4-dihydro-2H-1,4-benzoxazines

Substituted 2H-1,4-benzoxazines were synthesized from substituted 2-amino phenols and 1,2-dibromoethane using K₂CO₃ in good to excellent yields. The cyclized products were further reacted with alkyl bromides to obtain the desired N-substituted 3,4-dihydro-2H-1,4-benzoxazines.     

Synthesis and Reactivity of Substituted N-Hydroxy-1,4-dihydro-1,4-azaphosphorins

Abstract

The synthesis of substituted N-hydroxy-1,4-dihydro-1,4-azaphosphorins 4 has been carried out by adding the di (trimethylsilyl)peroxide 3 to the anion 2 generated from the addition of n-butyllithium to compound 1.     

Reactivity of 2-ethoxy-5-alkyl-3,4-dihydro-2H-pyrans towards aluminum alkyls : a facile synthesis of cyclobutylmethanols

2-Ethoxy-5-alkyl-3,4-dihydro-2H-pyrans react with Albuⁱ₃ and through a regioselective hydride addition provide substituted cyclobutylmethanols in very good yields.     

Study on conformation interconversion of 3-alkyl-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines from dynamic NMR experiments and ab initio density functional calculations

Variable-temperature NMR experiments and ab initio density functional calculations were carried out to investigate the conformation interconversion of novel chiral 3-alkyl-3,4-dihydro-2H-benzo[1,4]oxazine derivatives. With CDCl3 as the solvent, the coalescence temperatures of H2, H3, H11, and H19 of product 1 are about 289, 304, 292, and 316 K, with the corresponding activation free energies at 58.0 +/- 6.7, 60.9 +/- 7.1, 58.3 +/- 6.8, and 59.6 +/- 6.9 kJ.mol(-1), respectively. When dimethyl sulfoxide (DMSO-d6) was used as the solvent, 1H and 13C NMR signals were completely assigned at 375 K. The effects of solvent and temperature were investigated through a polarizable continuum model. At each theoretical level (MP2 or B3LYP), the changing tendencies of the calculated activation free energies and interconversion rates agree well with those of the NMR results. In addition, the interconversion rate at each specified temperature was calculated to be about 1.5 times faster in DMSO-d6 than in CDCl3. Accordingly, we failed to observe the coalescence phenomena of H3 and H19 in DMSO-d6 by NMR measurements from 296 to 375 K. The substitution effect at the R1-R5 positions was considered using density functional calculations, with the activation barriers decreasing as follows: product 6 > 3 > 1 > 7 > 2. This sequence is consistent with that of the reaction heats, except for product 7, implying that the interconversion processes may be thermodynamically controlled. Surprisingly, the substituted groups near the acetyl group in product 2 and 7 do not elevate the activation barrier but, instead, lower it somewhat, with the possible reasons for this provided in the paper.     

A convenient synthesis of 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-, 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo-, and 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines

The reactions of 1-alkylamino-1-alkylthio-3-phenylpropene-3-thiones 3 with thiophosgene and phosgene in toluene, followed by treatment of the reaction mixture with triethylamine gave 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo- 4 , 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-4H-1,3-thiazines 5 , respectively in good to excellent yields. Similarly treatment of compounds 3 with N-arylimidoyl dichloride in benzene at room temperature gave 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines 6 in excellent yields. The reactions of compounds 3 with oxalyl chloride in toluene gave also 5 in good yields.     

Synthesis and anticonvulsant activity of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones

Previously we reported the potent anticonvulsant activity of 3-dimethylamino-3,4-dihydro-2(1H)-quinazolinone. In this report, a series of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones was synthesized in three steps from isatoic anhydrides or an anthranilic acid. Structure/activity investigations revealed optimal activity for the 3-isopropyl and 3-cyciohexyl analogs. These compounds were effective against seizures induced by maximal electroshock.     

1,2- vs 1,4-Addition of acylbenzotriazoles to alpha,beta-unsaturated aldehydes and ketones. A novel route to 3-alkyl-4,6-diaryl-3,4-dihydropyran-2-ones

Lithiation of aliphatic 1-acylbenzotriazoles with subsequent reaction with alpha,beta-unsaturated ketones and aldehydes affords either 3,4,6-trisubstituted 3,4-dihydropyran-2-ones or 1,3-dienes depending on the carbonyl reagent used. Substituent effects on product yield and isomer ratio are discussed.     

Chloro- and dichloro-3-alkyl-1,2,3-benzotriazin-4(3H)ones

Several chloro- and dichloro-3-alkyl-1,2,3-benzotriazin-4(3H)ones have been prepared by diazotization of methyl anthranilates. A brief study was made of factors affecting the formation of 3-allyl-1,2,3-benzotriazin-4(3H)one from methyl anthranilate. Good nmr evidence was obtained to substantiate the previously proposed methyl 2-(3-allyltriazeno)benzoate (VIc) intermediate.     

A nitrogen-15 NMR study of hydrogen bonding in 1-alkyl-4-imino-1,4-dihydro-3-quinolinecarboxylic acids and related compounds

The title compounds contain groups (amine, amide, imine, carboxylic acid) that are capable of forming intramolecular hydrogen bonds involving a six-membered ring. In compounds where the two interacting functional groups are imine and carboxylic acid, the imine is protonated to give a zwitterion; where the two groups are imine and amide, the amide remains intact and forms a hydrogen bond to the imine nitrogen. The former is confirmed by the iminium 15N signal, which shows the coupling of 1J(15N,1H) -85 to -86.8 Hz and 3J(1H,1H) 3.7-4.2 Hz between the iminium proton and the methine proton of a cyclopropyl substituent on the iminium nitrogen. Hydrogen bonding of the amide is confirmed by its high 1H chemical shift and by coupling of the amide hydrogen to (amide) nitrogen [(1J(15N,1H) -84.7 to -90.7 Hz)] and to ortho carbons of a phenyl substituent. Data obtained from N,N-dimethylanthranilic acid show 15N-1H coupling of (-)8.2 Hz at 223 K (increasing to (-)5.3 Hz at 243 K) consistent with the presence of a N... H-O hydrogen bond.     

Grignard-type reactions with transition metals: alkylation of carbon compounds in protic solvents

Allylic halides react with reduced cobalt or nickel halides and with carbonyl compounds according to a pattern analogous to that of a Grignard reaction but with the difference that protic solvents can be used.     

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.     

Studies on the chemistry of 1,4-oxazines,XV: Synthesis of ethyl 3,4-dihydro-4-tosyl-2H-1,4-benzoxazine-3-carboxylate

A four step synthesis of ethyl 3,4-dihydro-4-tosyl-2H-1,4-benzoxazine-3-carboxylate (4) from the acetal5 is described.

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Studien zur Chemie der 1,4-Oxazine, 15. Mitt.: Synthese des 3,4-Dihydro-4-tosyl-2H-1,4-benzoxazin-3-carbonsäureethylesters (Kurze Mitteilung)

Zusammenfassung Eine Synthese des 3,4-Dihydro-4-tosyl-2H-1,4-benzoxazin-3-carbon-säureethylesters (4) über vier Stufen wird, ausgehend vom Acetal5, beschrieben.