Pyrrolo[2,1-c][1,4]benzoxazepines. 2. Synthesis of 5-phenyl derivatives

A series of 5-phenylpyrrolo[2,1-c][1,4]benzoxazepines with basic substituents at the 11-position has been synthesized utilizing a nucleophilic aromatic fluoride displacement-cyclization. Piperidinyl derivatives were prepared by Vilsmeier formylation of the key 1-[(2-fluorophenyl)phenylmethyl]pyrrole ( 4 ) followed by addition of a piperidinyl Grignard reagent and cyclization of the resulting carbinol. A (dimethylamino)methyl derivative was prepared via an analogous cyclization of α-(dimethylamino)methyl-1-[(2-fluorophenyl)phenyl-methyl]-1H-pyrrole-2-methanol ( 10 ), obtained by the Hoeben-Hoesch acylation of 4 with chloroacetonitrile, addition of dimethylamine to the resulting α-chloroketone 8 , and reduction of the α-(dimethylamino)ketone 9 with sodium borohydride to give 10 .     

Synthesis of new carbamate derivatives of indole and their modification

Oximation of indoles having a methoxycarbonylamino group on C⁵ and an acyl group on C³ with hydroxylamine hydrochloride in the presence of pyridine gave the corresponding oximes. The reduction of the 3-C=O group with sodium tetrahydridoborate in the presence of sodium hydroxide was accompanied by removal of the methoxycarbonyl group at the pyrrole nitrogen atom with formation of racemic alcohols. 1,4-Addition of 1-(pyridin-3-yl)butane-1,3-dione to dimethyl 1,4-benzoquinone diimine N,N′-dicarboxylate in dioxane in the presence of sodium methoxide, followed by heating in boiling 22% hydrochloric acid, afforded methyl 2-methyl-5-(methoxycarbonylamino)-3-(pyridin-3-ylcarbonyl)-1H-indole-1-carboxylate. 3-(Dimethylamino)-1-(4-methyl-1,2,5-oxadiazol-3-yl)prop-2-en-1-one reacted with N,N′-bis(methoxycarbonyl)- and N,N′-bis(phenylsulfonyl)-1,4-benzoquinone diimines in methylene chloride and acetic acid, respectively, in the presence of BF₃ · Et₂O to produce indoles having a 1,2,5-oxadiazolylcarbonyl group on C₃.     

Polycondensed heterocycles. II. A new preparative route to 11-Oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine

6-Methylthio-10-oxo-5H,10H-pyrrolo[1,2-b]isoquinoline 11 was isolated in an attempted synthesis of 11-oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 1 from 1-(2-methylthiobenzyl)pyrrole-2-carboxylic acid chloride 9 , obtained using as starting material o-methylthiobenzyl bromide 3 and passing through 1-(2-methylthiobenzyl)pyrrole-2-carbonitrile 5 , by cyclization with aluminum chloride. However the successful demethylation with sodium in dimethylacetamide of 1-(2-methylthiobenzyl)pyrrole-2-carboxyamide 12 , formed by hydrolysis of nitrile 5 , allowed us to prepare by another way the corresponding thiol 13 and consequently the 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 14 , which when subjected to intramolecular ring closure by CDI in place of DCC gave 1 in higher yield, 69% instead of 43%. Finally, the direct cyanation of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 16 , prepared utilizing the 1-(2-mercaptobenzyl)pyrrole 15 obtained by demethylation of the corresponding thioanisol 4 which was carried out as above, afforded the unexpected 1-(2-ethylthio-benzyl)pyrrole-2-carbonitrile 17 .     

Quinazolines and 1,4-benzodiazepines. XCIV. Pyrazino[1,2-a][1,4]benzodiazepines

A series of pyrazino[1,2-a][1,4]benzodiazepines were prepared by acylating the primary amino group of an α-amino-1,4-benzodiazepine-2-ylideneacetic acid ester ( 1 ) with α-chloroacyl chlorides followed by cyclo-dehydrohalogenation with triethylamine in dimethylformamide. Some pharmacological data for CNS-activity are discussed.     

Synthesis of 3-(2-Aminoethyl)pyrrole Derivatives

3-(2-Di-n-propylaminoethyl)pyrrole (1a) was prepared in good yield by reduction of pyrrole-3-(N,N-di-n-propylglyoxamide) (9) with lithium aluminum hydride. 3-(2-Di-n-propylaminoethyl)-5-acetylpyrrole (1b) was prepared by first acetylation of 1-p-toluenesulfonyl-3-(2-di-n-propylaminoethyl)pyrrole (6) followed by hydrolysis of the p-toluenesulfonyl substituent. The starting material 6 was prepared by homologation of 1-(p-toluenesulfonyl)pyrrole-3-carboxaldehyde (3) to the corresponding acetaldehyde followed by reductive amination of the latter.     

Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide

The synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide ( 5 ), a novel sulfur-containing tetracyclic benzodiazepine, is reported starting from pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-diox-ide ( 6 ) by cycloaddition of tosylmethyl isocyanide to the azomethine double bond. Pyrrolobenzothiadiazepine 6 was obtained by iron powder/acetic acid reduction of 1-(2-nitrobenzenefulfonyl)pyrrole-2-carboxaldehyde ( 7 ) and subsequent ring closure of intermediate aminoaldehyde or by cyclization of 1-(2-formamidobenzene-sulfonyl)pyrrole ( 8 ) with phosphorus oxychloride via a Bischler-Napieralski reaction. Formylation of 1-(2-ami-nobenzenesulfonyl)pyrrole with acetic-formic anhydride gave 8. The structure of 5 was confirmed by oxidation with activated manganese dioxide of dihydro derivative 9 , obtained through cyclization of 11-amino-methyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide ( 10 ) with triethyl orthoformate. The last compound was prepared alternatively by catalytic reduction of nitro derivative 11 , obtained by addition of nitromethane to pyrrolobenzothiadiazepine 6 , or by lithium aluminum hydride/sulfuric acid reduction of amide 13 , synthesized starting from ethyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-carboxyl-ate 5,5-dioxide.     

The synthesis of sterically demanding amino acid-derived cyclic phosphonamides

The preparation and utilization of C(2)-symmetric 1,4-diamines in the synthesis of amino acid-derived cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods: (i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/hydrolysis sequence. The pseudo C(2)-symmetric cyclic phosphonamides 1-3 are prepared by condensation of the C(2)-symmetric 1,4-diamines to P(III) centers, followed by oxidation.     

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 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine

We have synthesized 5H-imidazo[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine 1 in five steps from 1-(2-amino-methylphenyl) pyrrole 4 . Amidino derivatives 11-12 have also been prepared.     

Synthesis of meso‐Pyrrole‐Substituted 22‐Oxacorroles by a “3+2” Approach

Unsymmetrical 22‐oxacorrole containing two aryl groups and one pyrrole group at the meso position was synthesized by condensing one equivalent of 16‐oxatripyrrane with one equivalent of meso aryl dipyromethane under mild acid‐catalyzed conditions followed by oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ). This [3+2] condensation approach was expected to yield meso‐free 25‐oxasmaragdyrin but unexpectedly afforded unsymmetrical meso‐pyrrole‐substituted 22‐oxacorrole. We demonstrated the versatility of the reaction by synthesizing four new meso‐pyrrole‐substituted 22‐oxacorroles. The reactivity of α‐position of meso‐pyrrole was tested by carrying out various functionalization reactions such as bromination, formylation, and nitration and obtained the functionalized meso‐pyrrole‐substituted 22‐oxacorroles in decent yields. The X‐ray structure obtained for one of the functionalized meso‐pyrrole substituted 22‐oxacorrole revealed that the macrocycle was nearly planar and the meso‐pyrrole was in the perpendicular orientation with respect to the macrocyclic plane. The meso‐pyrrole‐substituted 22‐oxacorroles absorb strongly in 400–700 nm region with one strong Soret band and four weak Q bands. The 22‐oxacorroles are strongly fluorescent and showed emission maxima at ≈650 nm with decent quantum yields and singlet‐state lifetimes. The 22‐oxacorroles are redox‐active and exhibited three irreversible oxidations and one or two reversible reduction(s). A preliminary biological study indicated that meso‐pyrrole corroles are biocompatible.     

Preparation and reactions of some 1,2,3,4-Tetrahydro-2,3-disubstituted 7(or 8)hydroxy-1,4-dioxopyrazino[1,2-a] indoles

1,2,3,4-Tetrahydro-2,3-disubstituted 7(or 8) hydroxy-1,4-dioxopyrazino[1,2-a]indoles have been prepared by the condensation of 6(or 5)benzyloxyindole-2-carbonyl chloride with d1-N- alkylamino acid ethyl esters in the presence of triethyl amine followed by the hydrogenolysis over palladium-carbon. Methylation and alkaline hydrolysis of 1,2,3,4-tetrahydro-2-benzy1-1,4-dioxopyrazino[1,2-a]indole are discussed.     

A Convenient and Efficient Route to 1,4-Bis（heteroaryl）-buta-1,3-diene and 4-Heteroarylbut-1-en-3-yne from 1,4-Dichlorobut-2-yne

A convenient and practical route to functionalized conjugated 1,3-enynes and 1,3-dienes is described. 1,4-Bis（heteroaryl）- 1,3-diene and 1-heteroarylbut- 1-en-3-yne derivatives were prepared from 1,4-dichloro-2-butyne and corresponding N-heteroarenes such as imidazole, pyrrole, pyrazole and indole derivatives in the presence of bases in good to high yields.     

RuO4-mediated oxidation of N-benzylated tertiary amines. 3. Behavior of 1,4-dibenzylpiperazine and its oxygenated derivatives

1,4-Dibenzylpiperazine (1),-2-piperazinone (7),-2,6-piperazinedione (9), and 1-benzoyl-4-benzylpiperazine (30) were oxidized by RuO₄ (generated in situ) by attack at their endocyclic and exocyclic (i.e., benzylic) aminic N-α-C-H bonds to afford various oxygenated derivatives, including acyclic diformamides, benzaldehyde, and benzoic acid. The reaction outcome was complicated by (i) the hydrolysis of diformamides, occurred during the work-up, and (ii) the reaction of benzaldehyde with the hydrolysis-derived amines giving imidazolidines and/or Schiff bases. Benzoic acid resulted from benzaldehyde only. Compounds 7, 30, and 1-benzylpiperazine, but not 9, were transiently formed during the oxidation of 1. In the same reaction conditions, 1,4-dibenzyl-2,3-(or 2,5)-piperazinedione, 1,4-dibenzyl-2,3,6-piperazinetrione, 4-benzyol-1-benzyl-2-piperazinone, and 1,4-dibenzoylpiperazine were inert. The proposed oxidation mechanism involves the formation of endocyclic and exocyclic iminium cations, as well as of cyclic enamines. The latter intermediates probably result by base-induced deprotonation of the iminium cations, provided an N ⁺−β-proton is available. In the case of 1, the cations were trapped with NaCN as the corresponding α-aminonitriles. The statistically corrected regioselectivity (endocyclic/exocyclic) of the RuO₄-induced oxidation reaction of 1, 7, and 30 was 1.2–1.3.     

New hypoxia-selective cytotoxines derived from quinoxaline 1,4-dioxides

A new series of quinoxaline 1,4-dioxides, structurally related to the benzotriazine tirapazamine 1 have been prepared starting from 5,6-dichlorobenzofuroxane 2 . The Beirut reaction between 2 and alkyl or aryl thiopropanones afforded the 2-methyl-3-alkyl(aryl)thioquinoxaline 1,4-dioxides 3a-3e . Selective oxidation of 3 with m-chloroperbenzoic acid yielded the sulphinyl 4a-4c and sulphonyl 5a-5b derivatives. Replacement of the sulphonyl group of 5a by chlorine or bromine gave 6 or 7 , while nucleophilic displacement by 3-(N,N-dimethylamino)propylamine afforded 8 . A dimer 9 was prepared from 5a and hydrazine hydrate. The methylthio group of 3a was replaced by using formamidine acetate giving the amino compound 10 . Bromination of the methyl group of 3b afforded 11 , which reacted with 2-aminoethanol giving 12 . Compounds were tested as cytotoxic agents both in oxic and in hypoxic cells.     

Synthesis of 4H-1,4-benzothiazine 1-oxide and 1,1-dioxide. Analogs of quinolone antibacterial agents

4-Cyclopropyl-5,7-difluoro-6-(4-methyl-1-piperazinyl)-4H-1,4-benzothiazine-2-carboxylic acid 1-oxide (2c) and 4-cyclopropyl-5,7-difluoro-6-(4-methyl-1-piperazinyl)-4H-1,4-benzothiazine-2-carboxylic acid 1,1-dioxide (2d) were prepared and assayed for antibacterial activity and inhibition of DNA gyrase.     

Electrochemical oxidation of 2,4,5-triaryl-substituted pyrroles. II. Oxidative dimerization of 4,5-diphenyl-2-mesitylylpyrrole

2,4,5-Triaryl-substituted pyrroles lead, upon chemical or electrochemical oxidation, to an intermediate β-β'-dimer, which, in the course of the reaction, undergoes further oxidation to a tetracyclic derivative. To improve the selectivity towards the uncyclized dimer the oxidation of a triarylpyrrole in which the ortho positions of the phenyl group in position 2 are hindered by the presence of methyl groups was attempted. The cyclization was hindered, but an α-β'-dimer was obtained as the major product. An unexspected isomeric α-β'-dimer, in which the mesitylyl group is shifted into the β position of the pyrrole ring which undergoes the oxidation, was obtained in minor amounts. Electroanalytical data indicate that the process goes through the formation of a monomeric radical cation, followed by a slow chemical reaction.     

Synthesis of antimicrobial agents. II. Syntheses and antibacterial activities of optically active 7-(3-hydroxypyrrolidin-1-yl)quinolones

Two optically active isomers of 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxypyrrolidin-1-yl)-4-oxoquinoline-3-carboxylic acid ( 10 ) were prepared. One of the isomer, 7-[(3S)-hydroxypyrrolidin-1-yl] derivative 8 , was about 4 times more potent in vitro than the other, 7-[(3R)-hydroxypyrrolidin-1-yl] derivative 4 , and approximately two times more active than the racemate, 7-[(3RS)-hydroxypyrrolidine-1-yl] derivative 10. Optical active 8 was the most active in in vivo, followed by 10 , and 4 was the least active compound. But, they were more potent than CI-934 12 and norfloxacin. From the results, (3S)-hydroxypyrrolidinyl group was found to be one of the beneficial group for PCA-anti-bacterial agent.     

Mercuric ion-catalyzed hydration of derivatives of 1,4-dichloro-2-butyne. Hydration of 1-aryloxy-4-arylthio-2-butynes, 1,4-bis(arylthio)-2-butynes,and 1,4-bis(arylsulfonyl)-1-butynes

The mercuric ion-catalyzed hydration of 1,4-bis(arylthio)-2-butynes and 1-aryloxy-4-arylthio-2-butynes was studied. The 1,4-bis(arylsulfonyl)-2-butynes afforded 1,4-bis(arylsulfonyl)-2-butanones (7). The 1,4-bis(arylthio)-2-butynes afforded a variety of products in acetic acid among which were: 1,4-bis(arylthiomethyl)vinyl acetate ( 18 ); 1,4-bis(arylthio)-2-butanone ( 15 ); 1-(arylthio)-3-buten-2-one ( 16 ); and 1-(arylthio)-4-acetoxy-2-butanone ( 17 ). Ketone 15 eliminates arylthiol in an acidic medium yielding 16 which undergoes Michael addition of solvent to give 17. Treatment of 7 with base in the presence of a nucleophile (ArSH) analogously leads to elimination of arylsulfinic acid, followed by Michael addition of arylthiol. Hydration of 5 in methanol cleanly gave 1-(arylthio)-4-methoxy-2-butanones ( 19 ). In contrast, 1-aryloxy-4-arylthio-24)utynes afforded chromenes ( 8 ) by intramolecular cyclization. No thiochromenes were formed in any of the examples investigated.     

Synthesis and carbon-13 NMR study of 2-benzyl, 2-methyl, 2-aryloctahydropyrrolo [3,4-c] pyrroles and the 1,2,3,5-tetrahydropyrrolo [3,4-c] pyrrole ring system

2-Benzyl, 2-phenyl, 2- (3-methoxyphenyl) and 2-(3-trifluoromethylphenyl) octahydropyrrolo[3,4-c]pyrrole ( 9a, 9b, 9c , and 9d , respectively) were prepared in five steps from 1-benzylpyrrole-3,4-dicarboxylic acid ( 2 ). 2-Methyloctahydropyrrolo [3,4-c]pyrrole ( 9′a ) was prepared analogously in six steps from 1-methylpyrrole-3,4-dicarboxylic acid ( 3 ). Diborane reduction of 1-benzyl-N-methyl-1H-pyrrole-3,4-dicarboximide ( 7′a ) and 1, N-dibenzyl-1H-pyrrole-3,4-dicarboximide ( 7a ) gave 5-benzyl-2-methyl and 2, 5-dibenzyl-1,2,3,5-tetrahydropyrrolo [3,4-c]pyrrole ( 19 ′ and 19 , respectively); the first reported members of the 1,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole ring system. A detailed study of the carbon-13 nmr shifts permitted a complete assignment for all compounds. Mono and disubstituted products produce a systematic effect on the shifts for the bicyclic ring systems which can be readily interpreted in terms of substituent chemical shifts. The effect of protonation at nitrogen is also shown to produce a series of well defined chemical shifts for the octahydropyrrolo [3,4-c] pyrrole ring system.     

Preparation of pyrrole and pyrrolidine derivatives of pyrimidine. 1‐(2‐pyrimidinyl)pyrrole ‐ an inhibitor of X. phaseoli and X. malvacearum

Pyrrole and pyrrolidine derivatives of pyrimidine were prepared in which the nitrogen atom of the pyrrole or pyrrolidine ring is bonded directly to the 2‐ or 4‐carbon atom of the pyrimidine ring. Pyrrole derivatives were prepared by the dry distillation of an intimate mixture of an aminopyrimidine with mucic acid and by the reaction of a chloropyrimidine with potassium pyrrole. Pyrrolidine derivatives were prepared by the reaction of a chloropyrimidine with pyrrolidine and, in a single instance, by the catalytic hydrogenation of a pyrimidinylpyrrole. At a concentration of 200 mcg/mL, 1‐(2‐pyrimidinyl)pyrrole inhibited two plant pathogenic bacteria — Xanthomanus phaseoli (pathogenic on the bean plant) and Xanthomanus malvacearum (pathogenic on the cotton plant).