Synthetic antibacterials. VIII. 7-(1′-alkylhydrazino)-1,8-naphthyridines and related compounds

Synthesis and in vitro antibacterial activity of 7-(1′-alkylhydrazino)-1,8-naphthyridines related to nalidixic acid were investigated. Namely, treatment of 7-alkylamino-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids 1a-d with sodium nitrite in the presence of hydrochloric acid gave the 1-ethyl-1,4-dihydro-7-(N-nitrosoalkylamino)-4-oxo-1,8-naphthyridine-3-carboxylic acids 2a-d , which upon reacting with zinc dust in acetic acid gave the 7-(1′-alkylhydrazino)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids 3a-d. The compound 3a was alternately obtained by the reaction of 7-chloro-1-ethyl-1,4-dihydro-4-oxo-1,8-naphth-yridine-3-carboxylic acid ( 4 ) with methylhydrazine. The reaction of 7-chloro-4-hydroxy-1,8-naphthyridine-3-carboxylic acid ( 5 ) with methylhydrazine gave the 4-hydroxy-7-(1′-methylhydrazino)-4-oxo-1,8-naphthyridine-3-carboxylic acid ( 6 ), which upon treatment with alkyl halides afforded the 1-alkyl-1,4-dihydro-7-(1′-methyl-hydrazino)-4-oxo-1,8-naphthyridines 3a and 3e-g. The reaction of the appropriate 3 with ketones gave the corresponding 7-(1′-methylalkylidenehydrazino)-1,8-naphthyridines 7a-c and 8a-b. Among the compounds prepared, certain 3 and 7 exhibited good activity against Gram-negative bacteria.     

Comparison of the electrophilic and free-radical addition of halogens with hexafluoro-1,3-butadiene and 1,3-butadiene

Ionic and photochemical reaction of chlorine (Cl₂), bromine (Br₂) and iodine monochloride (ICl) to hexafluoro-1,3-butadiene (1) and 1,3-butadiene (2) were carried out under conditions that would provide product distributions under controlled ionic or free-radical conditions. Product distributions for ionic reaction of Cl₂ and Br₂ with 1 are similar and suggest a weakly-bridged halonium ion species. Theoretical calculations support weakly-bridged chloronium and bromonium ions for both dienes 1 and 2. There are more of the 1,4-dihalo-2-butene products from ionic halogenation of 1 than 2 which correlates with the greater charge density on carbon-4 of halonium ions from 1. Ionic and free-radical reactions of ICl with 1 give 8 and 2% of 3-chloro-4-iodohexafluoro-1-butene and 4-chloro-3-iodohexafluoro-1-butene, respectively. The minor cis-1,4-dihalo-2-butene products from 1 and 2 are reported when formed.     

Quantitative estimation of trans-1,4 and cis-1,4 isomers in polychloroprene by high-resolution NMR

In the ¹H-NMR spectrum of polychloroprene dissolved in C₆D₆, the ?CH proton signal was separated into two triplet peaks. These triplet signals were assigned to the ?CH proton in the trans-1,4 and cis-1,4 isomers by measurement of ¹H-NMR spectra of 3-chloro-1-butene and a mixture of trans- and cis-2-chloro-2-butene as model compounds for the 1,2, trans-1,4 and cis-1,4 isomers. In ¹H-NMR spectra (220 Mcps) of polychloroprene dissolved in C₆D₆, two triplet signals were separated completely from which the relative concentrations of trans-1,4 and cis-1,4 isomers could be obtained quantitatively.     

Synthesis of nucleoside analogs of 1,4-oxathiane, 1,4-dithiane,and 1,4-dioxane

The two regioisomers 6-chloro-9-(1, 4-oxathian-3-yl)-9H-purine ( 5 ) and 6-chloro-9-(1,4-oxathian-2-yl)-9H-purine ( 6 ) were obtained when 3-acetoxy-1,4-oxathiane ( 3 ) was subjected to the acid-catalyzed fusion procedure; compound 3 was prepared by a Pummerer reaction with 1,4-oxathiane 4-oxide ( 2 ). The nucleoside analog 6 could he converted into the adenine derivative 7 and 9-(1,4-oxathian-2-yl)-9H-purine-6(1H)thione ( 8 ). The following nucleoside analogs have also been synthesized: 6-chloro-9-(1,4-dithian-2-yl)-9H-purine ( 13 ), 9-(1,4-dithian-2-yl)adenine ( 14 ), 9-(1,4-dithian-2-yl)-9H-purine-6(1H)thione ( 15 ), and 6-chloro-9-(1,4-dioxan-2-yl)-9H-purine ( 18 ).     

Thermal chemistry of C4 hydrocarbons on Pt(111): Mechanism for double-bond isomerization

The thermal chemistry of a number of C4 hydrocarbons (1,3-butadiene, 1-bromo-3-butene, 1-bromo-2-butene, trans-2-butene, cis-2-butene, 1-butene, 2-iodobutane, 1-iodobutane, and butane) was investigated on clean and hydrogen- and deuterium-predosed Pt(111) single-crystal surfaces by temperature-programmed desorption and reflection-absorption infrared spectroscopy. A combination of rapid beta-hydride eliminations from alkyls to olefins and the reverse insertions of those olefins into metal-hydrogen bonds explains the hydrogenation, dehydrogenation, and H-D exchange products that desorb from the surface. A preference for hydrogenation at the end carbons and dehydrogenation from the inner carbons also explains the extent of the isotope exchange and the preferential isomerization of 1-butene to 2-butene observed on this Pt(111) surface. The reactions of more dehydrogenated C4 species is also discussed.     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

Novel synthesis of substituted N-(3-aryl-1,8-naphthyridin-2-yl) and N,N′-bis(3-aryl-1,8-naphthyridin-2-yl)benzene-1,4-diamines and 2-(4-((3-aryl-1,8-naphthyridin-2-yl)amino)phenyl)isoindoline-1,3-diones and their biological evaluation

A straightforward and highly efficient series of new substituted 3-aryl-1,8-naphthyridine derivatives 3a–e, 4a–e, and 6a–e were synthesized. Condensation dissimilar quantities of 2-chloro-3-aryl-1,8-naphthyridine 1a–e with benzene-1,4-diamine 2 and sodium ethoxide refluxing in ethanol solvent yielded the compounds 3a–e and 4a–e. The 2-(4-((3-aryl-1,8-naphthyridin-2-yl)amino)phenyl)isoindoline-1,3-diones 6a–e were obtained by treatment of compounds 3a–e with phthalic anhydride 5 in refluxing N,N-dimethylformamide is described. All synthesized compounds evaluated for their antimicrobial activity. The structures of the compounds have been proven on the established of spectral (IR, ¹H NMR, and ¹³C NMR) data and elemental analyses. The reaction will be characterized by good efficacy, easy workup, simple purification of the products, and availability of catalyst.     

Neighboring olefinic double-bond participation in gas phase pyrolysis of some alkenyl chlorides

4-Chloro-1-butene, 5-chloro-1-pentene, and 6-chloro-1-hexene have been shown to decompose, in a static system, mainly to hydrogen chloride and the corresponding alkadienes. In packed and unpacked clean Pyrex vessels the reactions were significantly heterogeneous. However, in a vessel seasoned with allyl bromide these reactions were homogeneous, unimolecular, and follow a first-order law. The working temperature range was 389.6–480.0°C and with a pressure range of 53–221 Torr. The rate constants for the homogeneous reactions were expressed by the following Arrhenius equations: 4-chloro-1-butene: logk(sec^?1) = (13.79 ± 0.17) – (223.8 ± 2.1)kJ/mole/2.303RT; 5-chloro-1-pentene: logk(sec^?1) = (14.25 ± 1.20) – (238.4 ± 12.7)kJ/mole/2.303RT; and 6-chloro-1-hexene: logk(sec^?1) = (12.38 ± 0.22) – (209.6 ± 2.9)kJ/mole/2.303RT. The olefinic double bond has been found to participate in the rate of dehydrohalogenation of 4-chloro-1-butene. The insulation of the CH₂?CH in chlorobutene by one or two methylene chains to the reaction center does not indicate neighboring group participation. The three-membered conformation is the most favored structure for anchimeric assistance of the double bond in gas phase pyrolysis of alkenyl chlorides. The heterolytic nature of these eliminations is also supported by the present work.     

Kinetics, products, and stereochemistry of the reaction of chlorine atoms with cis- and trans-2-butene in 10-700 Torr of N2 or N2/O2 diluent at 297 K

The reactions of Cl atoms with cis- and trans-2-butene have been studied using FTIR and GC analyses. The rate constant of the reaction was measured using the relative rate technique. Rate constants for the cis and trans isomers are indistinguishable over the pressure range 10-900 Torr of N2 or air and agree well with previous measurements at 760 Torr. Product yields for the reaction of cis-2-butene with Cl in N2 at 700 Torr are meso-2,3-dichlorobutane (47%), DL-2,3-dichlorobutane (18%), 3-chloro-1-butene (13%), cis-1-chloro-2-butene (13%), trans-1-chloro-2-butene (2%), and trans-2-butene (8%). The yields of these products depend on the total pressure. For trans-2-butene, the product yields are as follows: meso-2,3-dichlorobutane (48%), dl-2,3-dichlorobutane (17%), 3-chloro-1-butene (12%), cis-1-chloro-2-butene (2%), trans-1-chloro-2-butene (16%), and cis-2-butene (2%). The products are formed via addition, addition-elimination from a chemically activated adduct, and abstraction reactions. These reactions form (1) the stabilized 3-chloro-2-butyl radical, (2) the chemically activated 3-chloro-2-butyl radical, and (3) the methylallyl radical. These radicals subsequently react with Cl2 to form the products via a proposed chemical mechanism, which is discussed herein. This is the first detailed study of stereochemical effects on the products of a gas-phase Cl+olefin reaction. FTIR spectra (0.25 cm(-1) resolution) of meso- and DL-2,3-dichlorobutane are presented. The relative rate technique was used (at 900 Torr and 297 K) to measure: k(Cl + 3-chloro-1-butene) = (2.1 +/- 0.4) x 10(-10), k(Cl + 1-chloro-2-butene) = (2.2 +/- 0.4) x 10(-10), and k(Cl + 2,3-dichlorobutane) = (1.1 +/- 0.2) x 10(-11) cm3 molecule(-1) s(-1).     

Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

1,2- and 1,4-Diacetoxylation of 1,3-butadiene via 2,5-dihydrothiophene 1,1-dioxide as a probable intermediate

Sulphur dioxide has been found to promote a novel liquid-phase oxidation of 1,3-butadiene in acetic anhydride with oxygen gas and catalytic amounts of concentrated protic acids (e.g. hydrobromic acid). 1,2-Diacetoxy-3-butene and 1,4-diacetoxy-2-butene together with small amounts of 1-hydroxy-2-acetoxy-3-butene and 1-hydroxy-4-acetoxy-2-butene are formed in the reaction.     

Cyclization reactions of 2-(2-chloro-4-nitrophenylsulfonyl)-1-(2-thienyl)ethanone

A new sulfonyl group-containing heterocyclic compound 2-(2-chloro-4-nitrophenylsulfonyl)-1-(2-thienyl)ethanone 2 was prepared from the corresponding sulfide 2-(2-chloro-4-nitrophenylthio)-1-(2-thienyl)ethanone 1 . Two different cyclization reactions of the compound 2 were discussed. In contrast to the tandem alkylation-cyclization process [1], another cyclic procedure was described. In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene as a base and dimethylformamide as a solvent, compound 2 was treated with ethyl acrylate or methyl methacrylate at 50–55° to give the 1,4-benzoxathiin 4,4-dioxide 5 or 6 respectively via a tandem Michael conjugate addition-cyclization process.     

Synthesis of 1,8-, 1,6- and 3,6-dichloro-9H-thioxanthen-9-ones

Cyclization of 2-chloro-6-[(3-chlorophenyl)thio]benzoic acid ( 2 ) gave a mixture of 1,8-, 3 , and 1,6-dichloro-9H-thioxanthen-9-ones 4 . The mixture was converted to 1,8-diamino- 7 , and 1-amino-6-chloro-9H-thioxanthen-9-ones 8 , from which 3 and 4 were prepared separately, respectively. From a mixture of 4 and 3,6-dichloro-9H-thioxanthen-9-one ( 11 ) obtained by cyclizing 4-chloro-2-[(3-chlorophenyl)thio]benzoic acid ( 10 ) was separated 11 by conversion of 4 to 8 .     

Hydrophobic vitamin B12. Part 19: electroorganic reaction of DDT mediated by hydrophobic vitamin B12

The controlled-potential electrolysis of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) was carried out at -1.4 V vs. Ag-AgCl in the presence of a hydrophobic vitamin B12, heptamethyl cobyrinate perchlorate. DDT was dechlorinated to form 1,1-bis(4-chlorophenyl)-2,2-dichloroethane (DDD), 1,1-bis(4-chlorophenyl)-2,2-dichloroethylene (DDE), 1-chloro-2,2-bis(4-chlorophenyl)ethylene (DDMU) and 1,1,4,4-tetrakis(4-chlorophenyl)-2,3-dichloro-2-butene (TTDB)(E/Z), and quantitative recovery of the catalyst after the electrolysis was confirmed by electronic spectroscopy. A photo-sensitive intermediate having a cobalt-carbon bond formed during the electrolysis was characterized by electronic spectroscopy. A mechanism for the formation of various dechlorinated products was investigated by using deuterium solvents and various spectroscopic measurements such as UV-VIS and the EPR spin-trapping technique.     

1,4-Benzodiazepines III . Cyclization paths of hexaminium salts of 2-chioroacetamido-5-ehlorobenzophenone and its N-methyl derivative

This study reports the isolation and characterization of hexaminium salts of 2-chloroacetamido-5-chlorobenzophenone (I) and of 2-(N-methyl)chloroacetamido-5-chlorobenzophenone (II). The 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (VI) and 7-chloro-1,3-dihydro-1-meth-yI-5-phenyl-2H-1,4-benzodiazepin-2-one (VII), respectively are of pharmacodynamic importance. Based on chromatographic separation of some intermediates, and on spectrophotometric monitoring of cyclizations I → VI and II → VII, respectively, two different pathways for these reactions have been proposed. Since the slowest step in the reaction sequence II → VII follows the quasi first order rate law, intramolecular nucleophilic attack of the benzophenone carbonyl group on the hexamine moiety proved to be decisive for the cyclization (scheme II). However, cyclization I → VI seems to incorporate quite different solvolytic pathways in addition to one corresponding to the sequence II → VII. Isolated 4-imidazolidinone intermediates N,N' -methylene-bis[3-{2 -benzoyl-4-chIoro)phenyI]-4-imidazolidinone(III), and 3-(2 -benzoyl-4′-chlorophenyI)-4-imidazolidinone hydrochloride (IV) recyclize into the 1,4-benzodiazepine VI. The optimal reaction conditions have been found to be between pH 6-7.     

Evidence for π-allylic nickel complexes as intermediates in the reactions of nickelocene with allylic chlorides

Reactions of trans-1-chloro-2-butene and of 3-chloro-1-butene with nickelocene give mixtures of (1-methyl-2-propenyl)-, (trans-2-butenyl)-, and (cis-2-butenyl)-cyclopentadienes. The reaction between π-crotyl-π-cyclopentadienylnickel and 5-chlorocyclopentadiene yields identical products. In the presence of tetrahcloromethane, 5-(trichloromethyl)cyclopentadiene is formed. Mechanisms involving oxidative addition and π-allylic nickel complexes are discussed.     

Diazepines II. A new synthesis of 4h-pyrrolo[ 1,2-α] -[1,41] benzodiazepine

A convenient synthesis of a 4H-pyrroIo[1,2-α][1,4 ]benzodiazepine is described. 2,5-Di-methoxy-2-melhyl-5-phthalimidomethyltetrahydrofuran ( 3 ) was prepared starting from 2-methyl-5-phthalimidomelhylfuran ( 1 ). The condensation of 2-amino-5-chlorobenzophcnone with 3 to give 5-chloro-2-(2-methyl-5-phthalimidomethylpyrro]-1-yl)benzophenone ( 4 ), the treatment of which with hydrazine hydrate afforded 8-chloro-1-methyl-4H-pyrrolo[1,2-α] [1,4]benzodiazepine ( 5 ).     

Synthesis of substituted pyrimido[4,5‐b] and [5,4‐c]‐[1,8]naphthyridines

Ethyl 1‐ethyl‐7‐methyl‐4‐oxo‐1,4‐dihydro[1,8]naphthyridine‐3‐carboxylate ( 1 ), precursor of nalidixic acid, has been converted in two steps through ([1,8]naphthyridin‐3‐yl)carbonylguanidine derivatives into substituted pyrimido[4,5‐b] and [5,4‐c][1,8]naphthyridines.     

Efficient Procedures for 1-Bromo-1,3-Butadiene and 2-Bromo-1,3-Butadiene

Mixtures of Z- and E-1-bromo-1,3-butadiene in which the E- or Z- isomer predominates have been obtained in good yields by treating a mixture of Z- and E- 1,4-dibromo-2-butene (90% Z-isomer) or pure E-1,4-dibromo-2-butene, respectively, with powdered potassium hydroxide in high-boiling petroleum. 2-Bromo-1,3-butadiene was obtained in high yields by stirring a mixture of vinylacetylene, concentrated aqueous hydrogen bromide and copper(I) bromide.     

Reactions of some arenes and pyrazoles in MeCN under conditions of undivided-cell electrolysis

As exemplified for the first time by pyrazole and its 4-nitro and 3,5-dimethyl derivatives, N-arylation of pyrazoles can be performed under conditions of undivided-cell amperostatic electrolysis (Pt electrodes, MeCN) of systems containing the pyrazolate anion and (or) pyrazole, arene (benzene, 1,4-dimethoxybenzene, or xylene), and a supporting electrolyte. In the case of electrolysis involving 1,4-dimethoxybenzene as arene, N-arylation followed simultaneously three routes to form an ortho-substitution product (1,4-dimethoxy-2-(pyrazol-1-yl)benzene), an ipso-substitution product (4-methoxy-1-(pyrazol-1-yl)benzene), and an ipso-bisaddition product (1,4-dimethoxy-1,4-di(pyrazol-1-yl)cyclohexa-2,5-diene) in a total current yield of up to 50%. The acid-base properties of the pyrazoles under study affect the ratio of the N-arylation products and govern the required composition of the starting reaction mixture. In the case of a stronger base, such as 3,5-dimethylpyrazole, N-arylation with 1,4-dimethoxybenzene occurred even in the pyrazole—arene—tetraalkylammonium perchlorate system, whereas N-arylation of 4-nitropyrazole (a weaker base) proceeded only in the presence of the pyrazolate anion or another base, viz., sym-collidine. Oxidation of arene to the radical cation is the key anodic reaction. Not only the pyrazolate anion, but also highly basic pyrazole or a solvate complex of weakly basic pyrazole with collidine can serve as a nucleophilic partner in subsequent transformations of these radical cations.