Synthesis of 8,9‐dialkoxybenzodiazepines and 7,8‐dialkoxyisoquinolines

o‐Aroylarylacetone type 1,5‐diketone derivatives (5, 6) were synthesised from arylacetones (1) protected as 1,3‐dioxolanes (4) through directed ortho lithiation followed by acylation with aroyl chlorides. 8,9‐Dialkoxy‐2,3‐benzodiazepines 9 were obtained by cyclisation of diketones 6 with hydrazine. The reaction of diketones 6 with ammonia gave 7,8‐dialkoxyisoquinolines 11. Reaction of ketals 5 with hydrazine hydrochloride and hydroxylamine hydrochloride afforded N‐amino‐7,8‐dialkoxyisoquinolinium chlorides (10) and 7,8‐dialkoxyisoquinolinium oxides (12), respectively.     

On the behavior of α-brominated dimethyl o-benzenediacetate toward nitrogen nucleophiles. Part II. Reaction of dimethyl α-bromo-o-benzenediacetate with hydrazines

Dimethyl α-bromo-o-benzenediacetate ( 1 ) condensed with hydrazine and acetylhydrazine to give respectively 1-carbomethoxy-2-amino-1,4-dihydro-3-(2H)isoquinolinone (2) and its N-acetyl derivative ( 9 ). Replacement of the bromine atom of 1 with the N-1-methylhydrazino ( 3 ) and the N-1-phenylhydrazino ( 5 ) groups occurred by allowing 1 to react respectively with methylhydrazine and phenylhydrazine. In the latter case alkylation by 1 at the N-2 also occurred which led to the formation of the 2-phenylaminoisoquinolinone ( 8 ). Derivatives 3 and 5 smoothly cyclized to the 1-earbomethoxy-5(H)-1,2,3,4-tetrahydro-2,3-benzodiazepin-4-ones 4 and 6 . A series of derivatives of 2 were also pharmacologically tested as antiinflammatory and CNS depressant agents.     

4‐Toluenesulfonamide as a Building Block for Synthesis of Novel Triazepines,Pyrimidines, and Azoles

N‐{(E)‐(dimethylamino)methylidenearbamothioyl}‐4‐toluenesulfonamide ( 2 ) was obtained by reaction of N‐carbamothioyl‐4‐toluenesulfonamide ( 1 ) with dimethylformamide dimethylacetal or alternatively by the reaction of 1‐(dimethylamino)methylidenethiourea with tosyl chloride. Compound 2 was reacted with substituted anilines to yield anilinomethylidine derivatives 3a , 3b , 3c , 3d , 3e , 3f , 3g . Treatment of 3a , 3b , 3c , 3d , 3e , 3f , 3g with phenacyl bromide gave triazepines 4a , 4b , 4c , 4d , 4e , 4f , 4g and imidazoles 5a , 5b , 5c , 5d , 5e , 5f , 5g . Esterification of compound 3e afforded ester derivative 6 , which was subjected to react with hydrazine to yield hydrazide derivative 7 . Oxadiazole 8 was obtained by reaction of 7 with CS₂/KOH. Compound 3e was treated with o‐aminophenol or o‐aminothiophenol to give benzazoles 9a , 9b . N‐(Diaminomethylidene)‐4‐toluenesulfonamide ( 10 ) reacted with enaminones to yield pyrimidines 11 , 12 , 13 , respectively. The structures of the compounds were elucidated by elemental and spectral analyses. Some selected compounds were screened for their in vitro antifungal activity. In general, the newly synthesized compounds showed good antifungal activity.     

SOME CHLOROHYDROXYBENZENESULFONYL DERIVATIVES

Abstract

2,4-; 2,6-; 2,3-; 3,4-; 2,5-; and 3,5-dichlorophenols by reaction with chlorosulfonic acid were converted to the following substituted benzenesulfonyl chlorides: 3,5-dichloro-2-hydroxy-; 3,5-dichloro-4-hydroxy-; 2,3-dichloro-4-hydroxy-; 4,5-dichloro-2-hydroxy-; 2,5-dichloro-4-hydroxy-; and 2,6-dichloro-4-hydroxy-respectively. In addition o-chlorophenol gave 5-chloro-4-hydroxybenzene-1,3-bis-sulfonyl chloride. The various sulfonyl chlorides have been condensed with nucleophilic reagents, e.g. ammonia, amines, hydrazine, phenylhydrazine, N, N-dimethylhydrazine, and sodium azide. 3,5-Dichloro-2-hydroxybenzenesulfonyl azide has been reacted with norbornene, triphenylphosphine, dimethylsulfoxide, and cyclohexene. 3,5-Dichloro-2-hydroxybenzenesulfonyl chloride with phenylisocyanate gave the 2-(N-phenyl-carbamoyloxy) derivative which on heating gave a heterocyclic compound. The chlorohydroxybenzenesulfonyl derivatives are of interest as potential herbicides and their ir and nmr spectral characteristics are briefly discussed.     

On the behavior of α-brominated dimethyl o-benzenediacetate toward nitrogen nucleophiles . Part I. Reaction of dimethyl α,α'-dibromo o-benzenediacetate with hydrazines

Meso- ( 1a ) and racemic dimethyl α,α'-dibromo o-benzenediacetate ( 1b ) when condensed with hydrazine and methylhydrazine furnished respectively 1,3-dicarbomethoxyisoindole ( 5a ) and its N-methyl derivative ( 5b ). Reaction of phenylhydrazine with 1a led to the N-phenylisoindole ( 5c ) and to the N-anilino isoindoline ( 6 ) as the cis isomer; conversely, 1b was transformed into a mixture of the 2-phenyl-1,2,3,4-tetrahydrophthalazine ( 7 ), the trans isomer of ( 6 ), the N-anilinoisoindole ( 5d ) and dimethyl α-(N'-phenylhydrazino)-o-benzenediacetate ( 8 ). Compounds 1a and 1b were also condensed with acetylhydrazine to give a mixture of the N-acetylaminoisoindoline ( 12 ) and of the 2-acetyl-1,2,3,4-tetrahydrophthalazine ( 13 ).     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles containing a sterically hindered 4-hydroxy-3,5-di(tert-butyl)phenyl group

A series of 2,5-disubstituted 1,3,4-oxadiazoles containing one or two 4-hydroxydi(tert-butyl)phenyl groups has been synthesized. These sterically hindered compounds were prepared by condensation of acids containing the indicated fragment and their derivatives with hydrazine dihydrochloride, hydrazides, and hydrochlorides of iminoesters of acids, by the reaction of 4-hydroxy-3,5-di(tert-butyl)thiphenol with 2-chloromethylsubstituted 1,3,4-oxadiazoles in the presence of KOH, and by cyclodehydration of N-acyl-N-[4-hydroxy-3,5-di(tertbutyl)benzoyl]hydrazones under action of POCl₃.I. M. Gubkin State Oil and Gas Academy, Moscow 117917. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 822–828, June, 1997.     

Synthetic Studies on the Synthesis of Some New Fused Heterocyclic Compounds Derived from 3,5‐Pyrazolidinedione

Condensation of 1‐phenylpyrazolidine‐3,5‐dione 1 with 3‐formylchromone afforded 4‐(chromenylmethylene)pyrazolidinedione 2 , which was reacted with hydrazine or hydroxylamine in different molar ratios and conditions to give the corresponding pyrazole and isoxazole derivatives 3 ‐ 8 , respectively. Compound 2 was subject to react with ammonia, N,S‐ or S,S‐acetals, mercaptoacetic acid, cyanoacetamide or cyanothioacetamide to give the corresponding pyridine, dithiine, thiazine and thiophene, 9 ‐ 14 , respectively. The reaction of compound 2 with thiourea, guanidine, cystamine, o‐aminothiophenol, ethylenediamine, o‐phenelenediamine or barbituric acid afforded the corresponding thiazine, pyrimidine, thiazepine, diazepine, and pyran derivatives 17 ‐ 23 , respectively. The study of the reaction of compound 2 with nucleophiles via chromene ring opening was investigated.     

Synthesis of 3-aminopyrazolo[3,4-d]pyrimidine derivatives using N-bis(methylthio)methylene-p-toluenesulfonamide

N-Bis(methylthio)methylene-p-toluenesulfonamide ( 1 ) reacted with active methylene compounds such as malononitrile ( 2a ) and, cyanoacetamide ( 2b ) to give the corresponding 3-methylthio-3-p-toluenesulfonylami-nopropenenitrile derivatives 3a,b which were found to be convenient starting materials for the synthesis of 3,5-diaminopyrazole derivatives. Reaction of 3a and 3b with hydrazines gave the corresponding 3,5-diaminopyrazoles 4a-e , key intermediates for the synthesis of 3-aminopyrazolo[3,4-d]pyrimidine derivatives 5a-d .     

The synthesis of benzofuroquinolines. I. Some benzofuro[2,3-b]quinoline and benzofuro[3,2-c]quinoline derivatives

Benzofuro[2,3-b]quinoline ( Ia ) and its 11-methyl derivative ( Ib ) were synthesized by demethylcyclization of 3-(o-methoxyphenyl)-1,2-dihydroquinolin-2-ones (VIa,b). Benzofuro[2,3-b]quinoline-11-carboxylic acid (Id) was synthesized by chlorination followed by the action of potassium hydroxide of a lactone (IX) prepared by demethyl-cyclization of 3-(o-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (VIII). Isomeric benzofuro[3,2-c]quinoline (Ha) and its 6-methyl derivative (IIb) were synthesized by demethyl-cyclization of 3-(o-methoxyphenyl)-1,4-dihydroquinolin-4-ones (XIa,b). Both the methyl derivatives (Ib and IIb) were converted to the carboxylic acids (Id and IId) through condensation with benzaldehyde followed by oxidation. The benzofuroquinolines (Ia,b,d and IIa,b) thus obtained were oxidized to the corresponding N-oxides (IIIa,b,d and IVa,b).     

Synthesis of heterocyclic compounds from 2-phenyl-1,2,3-triazole-4-formylhydrazine

2-Phenyl-1, 2, 3-triazole-4-formylhydrazine (2) was prepared by hydrazinolysis of the corresponding ester 1. Reaction of 2 with CS₂/KOH gave the oxadiazole derivatives (3) which via Mannich reaction with different dialkyl amines furnished 3-N, N-dialkyl derivatives (4a–c). Also, condensation of 2 with appropriate aromatic acid in POCI₃ yielded oxadiazole derivatives (5a–c), or with aldehydes and ketones afforded hydrazones (6a–c). Cyclization of (6a–c) with acetic anhydride gave the desired dihydroxadiazole derivatives (7a–c). On the other hand, reaction of dithiocarbazate (8) with hydrazine hydrate gave the corresponding triazole derivative (9) which on treatment with carboxylic acids in refluxing POCI₃ yielded s-triazole [3, 4–b]-1, 3, 4-thiadiazole derivatives (10a–b). The structures of all the above compounds were confirmed by means of IR, ¹H NMR, MS and elemental analysis.     

Synthesis of 1,3,5-Trisubstituted 1H-1,2,4-Triazoles Containing Hetaryl Fragments

N¹-Phenyl- and N¹-(3,5-dichloro-2-pyridyl)amidrazones have been synthesized by the reaction of imino esters of heterocyclic acids with phenyl- or (3,5-dichloro-2-pyridyl)hydrazine. Acylation of the products with acid chlorides leads to 1-phenyl- and 1-(3,5-dichloro-2-pyridyl)-3-hetaryl-5-R²-1H-1,2,4-triazoles. Compounds of this type are also formed by the condensation of N-acylimino esters of heterocyclic acids with phenyl- or (3,5-dichloro-2-pyridyl)hydrazine.     

Facile Synthesis of Alkyl and Aryl Substituted Dibenzo[b,g][1,8]naphthyridin-5-ones

The reaction of 2,4-dichloroquinolines with o-aminoacetophenone and o-aminobenzophenone under neat conditions yielded 2′-acetyl and 2′-benzoyl substituted-4-chloro-2-(N-phenylamino)quinolines, respectively, which on treatment with sodium methoxide afforded the 2′-substituted-4-methoxy-2-(N-phenylamino)quinolines. These potential intermediates, on polyphosphoric acid–catalyzed cyclization at two different temperatures, gave the respective 6-methyl and 6-phenyl substituted dibenzo[b,g][1,8]naphthyridin-5-ones. These temperature differences for the formation of the final products were due to the in situ formation of the respective 2′-substituted-2-(N-phenylamino)quinolin-4-ones from the chloro and methoxy intermediates. The naphthyridin-5-ones were subjected to N-methylation, where the methyl group in the 1-position was found to hinder the reaction sterically, consequently increasing the reaction time to more than that of the other derivatives.     

Synthesis and anticonvulsant activity of some novel 3-aminoquinazolines

A number of novel 3-aminoquinazolines were obtained via two synthetic pathways. In the first method o-aminobenzoylhydrazines were prepared either by reacting an isatoic anhydride and a hydrazine or by reacting o-nitrobenzoic acid with a hydrazine, followed by catalytic reduction. Subsequent cyclization with an appropriate orthoester provided 3-aminoquinazolines and 2-methyl-3-aminoquinazolines. The second pathway involved condensation of o-aminoacetophenone with a hydrazine to form hydrazones which were reduced to aminohydrazines and cyclized as above to yield 4-methyl-3-aminoquinazolines and 2,4-dimethyl-3-aminoquinazolines. The title compounds were evaluated in mice in MES and sc Met seizure models for anticonvulsant activity, and in the rotorod test for neurotoxicity. They were generally toxic. However, 4-methyl-3-(N-piperidino)-3,4-dihydroquinazoline hydrochloride exhibited activity comparable to that of methaqualone.     

Synthesis of some new azole,pyrimidine, pyran,and benzo/naphtho[b]furan derivatives incorporating thiazolo[3,2‐a]benzimidazole moiety

Reaction of E‐3‐(N,N‐dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 1 ) with some N‐nucleophiles, such as anilines 2a , 2b , 2c , 4‐amino‐N‐pyridin‐2‐yl‐benzenesulfonamide ( 4a ), 4‐amino‐N‐pyrimidin‐2‐yl‐benzenesulfonamide ( 4b ), hydrazine, hydroxylamine, thiourea, and guanidine afforded the corresponding arylaminoprop‐2‐en‐1‐one derivatives 3a , 3b , 3c , 5a , 5b , the pyrazole, isoxazole, pyrimidinethione and aminopyrimidine derivatives 7a , 7b , 9a , and 9b , respectively. The utility of compound 1 , as a versatile building block, for the synthesis of the pyranone 13 , benzo[b]furan 17a , and naphtho[1,2‐b]furan 17b was also explored via its reaction with 2‐benzamidoacetic acid ( 10 ), 1,4‐benzoquinone ( 14a ), and 1,4‐naphthoquinone ( 14b ), respectively. J. Heterocyclic Chem., (2011).     

Synthesis of Some Novel N-Substituted Phthalazinone and Pyridopyridazinone Derivatives

Phthalazinone and pyridopyridazinone derivatives 3, 5, and 9 were prepared via reaction ofappropriate lactams 2 and 8 with 2-bromoethylphthalimide, N-tosylaziridine, and N,O-ditosyl derivatives of N-methylethanolamine in a two-step process in the presence of MeONa/MeOH or NaH/dimethylformamide (DMF). Starting compounds 2 and 8 were obtained by reaction of hydrazine hydrate with isoindolinones 1 or azaisoindolinones 6. Selected N-(2-phthalimidoethyl)-phthalazinones were converted into corresponding 2-[2-(methylamino) ethyl]- derivatives in satisfactory yields by treatment with hydrazine.     

Benzofuran systems. Regioselective bromination and some other reactions of 1-(3-benzofuranyl)-2-phenylethanones

1-[3-(2-Alkylbenzofuranyl)]-2-(3,5-dibromo-4-hydroxyphenyl)ethanones 5a,b and 1-[3-(2-alkylbenzofuranyl)-2-(3-bromo-4-methoxyphenyl)ethanones 3a,b were readily prepared by selective bromination of hydroxy 1a,b and methoxy 1c,d ethanones, respectively. A successful method of O-alkylamination of 5a with N-(2-chloroethyl)-N,N-diethylammonium chloride to 6a by a two-phase reaction under phase transfer conditions has been applied. Lithium aluminium hydride reduction of the carbonyl group of 1b to carbinol 4b was carried out in good yields.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 8. Aminomethylation of 3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates as a method for the synthesis of new functionally substituted 3,7-diazabicyclo[3.3.1]nonane derivatives

Aminomethylation of 3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates upon treatment with primary amines and excess formaldehyde leads to 3,7-diazabicyclo[3.3.1]nonane derivatives. N-Methylmorpholinium 4-(2-chlorophenyl)-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate was obtained by the reaction of (E)-3-(2-chlorophenyl)-2-cyanoprop-2-enethioamide with 1-cyanoacetyl-3,5-dimethylpyrazole and N-methylmorpholine in acetone in quantitative yield. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2397–2400, December, 2007.     

Synthesis of pyrazolo[3,4-d]pyrimidine derivatives using ketene dithioacetals

The cyclization of 5-amino-3-methylthiopyrazole-4-carbonitriles or 4-carboxamides 3a-j , which were prepared by the reaction of ketene dithioacetals 1a,b [1a : bis(methylthiomethylenemalononitrile; 1b : bis(methylthio)methylenecyanoacetamide] with hydrazines (hydrazine hydrate, phenylhydrazine, p-chlorophenylhydrazine, p-nitrophenylhydrazine), with formamide or carbon disulfide proceeded to give the corresponding 4-amino- or 4-hydroxy-3-methylthiopyrazolo[3,4-d]pyrimidines 6a-h in good yields. 3-Aminopyrazolo[3,4-d]pyrimidine derivatives 6i-1 were also obtained by the application of the cyclization reaction of 3,5-diaminopyrazoles with formamide.     

Reactions of 4-Hydroxy-5-methyl(phenyl)-2-styryl-6H-1,3-oxazin-6-ones with Nucleophiles

4-Hydroxy-5-methyl(phenyl)-2-styryl-6H-1,3-oxazin-6-ones react with hydrazine and phenylhydrazine to give the corresponding 3,5-substituted triazoles. Treatment of the title compounds with ethanol and methanol leads to formation of N-cinnamoylmalonamates. The structure of the products was confirmed by the IR and ¹H and ¹³C NMR spectra.