Preparation of 2,4-diarylquinolines and substituted dihydrobenz-[c]acridines by the condensation of certain c(α),o-dilithiooximes with 2-aminobenzophenones

C(α),O-Dilithiooximes were prepared in an excess of lithium diisopropylamide and condensed with several 2-aminobenzophenones, followed by acid hydrolysis of the oximes to the ketones, which then underwent cyclodehydration and linear dehydration to give substituted quinolines or dihydrobenz[c]acridines.     

The preparation of phenacylpyrazoles,acylpyrazoles, imidazolylisoxazoles and imidazolylpyrazoles from c(α)-dianions of oximes,phenylhydrazones and acylhydrazones

C(α),O-Dilithiooximes, C(α), N-dilithiophenylhydrazones, or C(α), N-dilithioacylhydrazones were prepared in an excess of lithium diisopropylamide (LDA) and condensed with a variety of esters followed by acid-cyclization to give substituted isoxazoles and pyrazoles.     

The preparation of 5-phenacylisoxazoles and 5-hydroxyphenyl-isoxazoles and -pyrazoles by the condensation of C(a)-dianions with ethyl benzoylacetate and methyl salicylate

C(α), O-Dilithiooximes and C(α), N-Dilithiophenylhydrazones were prepared in an excess of lithium diisopropylamide (LDA). The former was condensed with ethyl benzoylacetate and methyl salicylate, and the latter condensed with methyl salicylate. The resulting precyclization intermediates were then treated with aqueous acid, which was followed by cyclodehydration to give phenacylisoxazoles and hydroxyphenyl-isoxazoles and -pyrazoles.     

The preparation of N-(1H-pyrazol-3-yl)arylamides and 1H-pyrazol-3-amines from polylithiated C(α),N-thiosemicarbazones and C(α),N-semicarbazones

C(α),N-Thiosemicarbazones or C(α),N-semicarbazones were polylithiated with excess lithium diiso-propylamide, and the resulting cyclized intermediates were condensed with aromatic esters to afford N-(1H-pyrazol-3-yl)arylamides. The polylithiated intermediates were also quenched with aqueous acid to give 5-substituted, 1H-pyrazol-3-amines.     

The reactions of C(α), O-dilithiooximes,C(α), N-dilithiophenylhydrazones,and C(α), N,N-trilithiohydrazones with diethyl oxalate to give biisoxazoles,bipyrazoles, and pyridazones

Several C(α), O-dilithiooximes were condensed with diethyl oxalate and acid-cyclized to give biisoxazoles. Only dilithio p-fluoroacetophenone phenylhydrazone gave the bipyrazole when condensed with this diester. Other C(α), N-dilithiophenylhydrazones and several C(α), N,N-trilithio-hydrazones were condensed with diethyl oxalate and acid-cyclized to give the intramolecular 4-hydroxy-3-pyridazones. Several non-cyclized intermediates were isolated and a reaction mechanism is presented.     

A new synthesis of 2-pyrazolin-5-ones from the condensation of C(α),N-dilithiophenylhydrazones with diethyl carbonate

C(α),N-Dilithiophenylhydrazones were prepared from phenylhydrazones in an excess of lithium diisopropylamide and condensed with diethyl carbonate followed by an acid cyclization to give 2-pyrazolin-5-ones.     

Preparation of 1H‐pyrazole‐5‐carboxamides from dilithiated C(α), N‐phenylhydrazones and lithiated ethyl oxanilates or lithiated ethyl oxamate

Dilithiated C(α), N‐phenylhydrazones were prepared in excess lithium diisopropylamide and condensed with either ethyl oxanilate, ethyl 4′‐chlorooxanilate, or ethyl oxamate to give intermediates that were quenched and acid cyclized to substituted lH‐pyrazole‐5‐carboxamides.     

Reactions of Acid Chlorides/Ketenes with 2‐Substituted 4,5‐Dihydro‐4,4‐dimethyl‐1,3‐thiazoles: Formation of Penam Derivatives

Addition reactions of acid chlorides with various 2‐substituted 4,5‐dihydro‐4,4‐dimethyl‐5‐(methylsulfanyl)‐1,3‐thiazoles under basic conditions were studied. Two kinds of products were obtained from these additions, β‐lactams and non‐β‐lactam adducts. When the reaction was carried out with 4,5‐dihydro‐1,3‐thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2+2] cycloaddition and led to the correspoding β‐lactam. On the other hand, acid chlorides and 4,5‐dihydro‐1,3‐thiazoles bearing an α‐H‐atom at the C(2)‐substituent underwent C(α)‐ and/or N‐addition reactions and furnished non‐β‐lactam adducts, i.e., C(α)‐ and/or N‐acylated 1,3‐thiazolidines. The attempted transformations of sulfonyl esters of exo‐6‐hydroxy penams to endo‐6‐azido penams failed, although they were successful with mono‐β‐lactams under the same conditions.     

Synthesis, Reactions, and Anti-arrhythmic activity of Substituted Heterocyclic Systems Using 5-Chloroanisic Acid as Starting Material

Summary. A series of substituted heterocyclic systems were prepared from N1-[4-(4-fluorocinnamoyl)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Treating of the cinnamoyl derivative with hydrazine hydrate in dioxane afforded a pyrazoline, which was reacted with morpholine and paraformaldehyde to give the N-substituted pyrazoline. Acylation of pyrazoline with acetyl chloride in dioxane afforded the N-acetyl analogue. Also, the cinamoyl derivative was reacted with methylhydrazine, phenylhydrazine, or ethyl cyanoacetate to yield the corresponding N-methyl-, N-phenylpyrazoline, pyrane, and pyridone derivatives. Condensation of the cinnamoyl derivative with cyanothioacetamide gave the pyridinethione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. Also, it was reacted with malononitrile or ethyl acetoacetae to give the cyano amino analougues and ethyl carboxylate, which was reacted with methylhydrazine to give the (indazolyl)phenyl derivative. On the other hand, reaction of cinnamoyl derivative with acetyl acetone afforded the cyclohexenyl derivative, which was reacted with hydrazine hydrate to give the [methylindazolyl]phenyl derivative. Condensation of the cinnamoyl derivative with guanidine hydrochloride or thiourea afforded the aminopyrimidine derivative and thioxopyrimidine. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis of substituted dihydroisocarbostyrils from 5-hydroxyamides obtained from dilithio-N-substituted o-toluamides

δ-Hydroxyamides, prepared by condensation of ketones or aldehydes at the 2-methyl group of Nsubstituted o-toluamides by means of n-butyllithium, were cyclodehydrated with sulfuric acid to form 2,3-disubstituted and 2,3,3-trisubstituted 3,4-dihydroisocarbostyriIs. Also, δ-hydroxyamides obtained from condensation of ketones at the 2-benzyl group of N-methyl-o-benzylbenzamide, were cyclodehydrated to give 2,3,3,4-tetrasubstituted 3,4-dihydroisocarbo-styrils. All of the products appeared to be new. This new method, which involves an unusual acid catalyzed cyclodehydration, is convenient and apparently quite general.     

A new preparation of substituted 4H-1-benzothiopyran-4-ones from c(α)N-benzoylhydrazones or c(α)N-carboalkoxyhydrazones and methyl thiosalicylate

C(α)N-Benzoylhydrazones or C(α),N-carboalkoxyhydrazones were dilithiated with excess lithium diisopropylamide, and the dianion-type intermediates were condensed with lithiated methyl thiosalicylate, followed by cyclization/hydrolysis to substituted 4H-1-benzothiopyran-4-ones (thioflavones/thiochromones).     

An improved synthesis of 3,5-disubstituted isoxazoles and pyrazoles from C(α),O-dilithiooximes and C(α),N-dilithiophenylhydrazones

C(α),O-Dilithiooximes and C(α),N-dilithiophenylhydrazones were prepared using an excess of lithium diisopropylamide (1:3). Condensation with esters followed by acid cyclization gave isoxazoles and pyrazoles.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

Two‐Step Synthetic Route to 10‐Substituted Isoalloxazines

10‐Substituted isoalloxazines were synthesized in two steps starting from 1,2‐phenylenediamine. Monoalkylation of the diamine resulted in 2‐amino‐N‐alkylanilines, which were subsequently condensed with alloxan in boric acid and acetic acid to give 10‐substituted isoalloxazines.     

Aktivierte Chinone: O- versus C-Addition von Phenolen; eine neue,regiospezifische Synthese von Xanthonen,Thioxanthonen und N-Methyl-9-acridonen

Activated quinones: O- versus C-addition of phenols. New regiospecific syntheses of xanthones, thioxanthones and N-methyl-9-acridones The acid catalyzed reaction of phenols with activated quinones, e.g. 2-methoxycarbonyl-1, 4-benzoquinone or 2-acetyl-1, 4-benzoquinone, leads to substituted biphenylderivatives (C, C-addition) as has been previously described [1]. O, C-Addition of phenols has now been achieved by using 2-methoxypyridin or 4-dimethyl-aminopyridin [4] as basic catalysts. The resulting substituted diphenylethers can serve as convenient starting materials for regiospecific syntheses of substituted xanthones, especially for 1, 4-dimethoxyxanthones. Arylthiols and N-methyl-N-arylamines also react readily with activated quinones to give substituted di-aryl-thioethers and N-methyl-N, N-diarylamines respectively; both types of compounds are convenient materials for regiospecific syntheses of substituted thioxanthones and N-methyl-9-acridones.     

The preparation of N-carboalkoxypyrazoles and N-phenylpyrazoles from C(α)-dianions of carboalkoxyhydrazones and phenylhydrazones

The 1,4-dianions of C(α),N-carboalkoxyhydrazones and C(α),N-phenylhydrazones were prepared in an excess of lithium diisopropylamide (LDA). These dilithiated intermediates resulted from metalation of substituted hydrazones of several all-aliphatic cyclic ketones, aliphatic-aromatic cyclic ketones phenylacetaldehyde, and several substituted propiophenones or acetophenones. The esters utilized for Claisen-type condensations of these dianion intermediates included methyl salicylate, methyl p-hydroxybenzoate, methyl nicotinate and related materials. The condensations were followed by acid-cyclizations to give a variety of N-phenylpyrazoles and N-carboalkoxypyrazoles, most of which are new.     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

Summary. A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis of aryl 3-(2-imidazolyl)propyl ketones

The approach to the title compounds was via lithiation-substitution of N-methyl or N-(triphenylmethyl)-imidazole by some iodo ketals. 4-Chloro-4′-halobutyrophenones (halo = F, Cl, Br) were converted by sodium iodide to the corresponding aliphatic iodides which were subsequently ketalized with ethylene glycol to provide the corresponding iodo ketals. Lithiation of either 1-methyl- or 1-(triphenylmethyl)imid-azole with N-butyllithium generated the corresponding 2-lithioimidazoles, in situ, which were then reacted with these iodo ketals to form the corresponding C-2 substituted imidazoles. Dilute aqueous acid hydrolysis released the ketone from the ketal. For N-triphenylmethyl protected imidazoles, the triphenylmethyl group was also hydrolyzed to give triphenylmethanol and 3-(2-imidazolyl)propyl 4-haloaryl ketones. These N-unsubstituted imidazolyl ketones can be alkylated independently with triphenylmethyl chloride to form the corresponding N-triphenylmethyl imidazole derivatives.     

Synthesis of Furo[2,3‐d]pyridazin‐4(5H)‐one and Its N(5)‐Substituted Derivatives

We report the efficient preparation of furo[2,3‐d]pyridazin‐4(5H)‐one and its N‐substituted derivatives starting from methyl 2‐methylfuran‐3‐carboxylate. The Me group was converted to the aldehyde group, which was then condensed with hydrazine derivatives. Then, the ester functionalities were hydrolyzed to the corresponding acids, followed by treatment with SOCl₂ to give N‐substituted furopyridazinone derivatives.