New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Cyclization reactions of 3-hydrazino[1, 2, 4]triazino[5, 6-b]indole

The reaction of 3-hydrazino[1, 2, 4]triazino[5, 6-b]indole I with nitrous acid affords the azide III which could be cyclized with acetic anhydride to 10-acetyl-10H-tetrazolo[5′,1′:3, 4][1, 2, 4]triazino[5, 6-b]indole IIb . Cyclization reactions of I with acetic anhydride, ethyl chloroformate, carbon disulphide and aromatic aldehydes to the corresponding fused triazolo derivatives V–VIII are reported. On the other hand cyclization reactions of I with malononitrile, ethyl cyanoacetate, ethyl acetoacetate and acetylacetone to the corresponding condensed pyrazolino derivatives IX–XI are also reported. The reaction of I with α-dicarbonyl compounds to form mono and dihydrazones are reported. The structure of the compounds prepared and their cyclization mechanisms are reported.     

Pyrimidine derivatives and related compounds. A novel synthesis of pyrimidines,pyrazolo[4,3-d]pyrimidines and isoxazolo[4,3-d] pyrimidine

Benzoylacetonitrile (II) reacted with trichloroacetonitrile (III) to yield the β-amino-β-trichloromethylacrylonitrile IV. Compound IV reacted with hydrazine hydrate to yield 5-amino-4-cyano-3-phenylpyrazole (V) and with 2-aminopyridine to yield the aminopyridine derivative VIII (cf., Chart I). Compound IV reacted with III to yield 2,4-bis(trichloromethyl)-5-cyano-6-phenylpyrimidine (I) which could be converted into a variety of pyrazolo[4,3-d]pyrimidine derivatives by treatment with hydrazine hydrate under a variety of different experimental conditions (cf., Chart II).     

Synthesis of a novel series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives

A series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives has been synthesized as possible antileukemic agents by condensation of methyl 3-(ethoxymethylene)amino-2-benzothiophene carboxylate (II) with a variety of amines to afford the corresponding 3-aryl and 3-alkyl [I]benzothieno[3,2-d]pyrimidin-4(3H)-ones, Ill and IV, respectively. In addition, Mannich reactions of [I]benzothieno[3,2-d]pyrimidin-4(3H)-one (VIII) with formaldehyde and secondary amines gave the expected derivatives, IX. 3-Amino[I]benzothieno[3,2-d]-pyrimidin-4(3H)-one (VI) reacted with substituted aromatic aldehydes in the presence of boron trifluoride to yield the corresponding imines VII.     

Reactions with 5-aminopyrazoles. I. Synthesis of halogen-containing fused pyrazoles

5-Amino-3-phenylpyrazole (I) and 5-amino-4-bromo-3-phenylpyrazole (II) reacted with ethyl acetoacetate and acetylacetone to give various pyrazolo[1,5-a]pyrimidines IV-VI and with benzoins to give different fused pyrazoles, namely, imidazo[1,2-b]pyrazoles IX, pyrrolo[2,3-c]pyrazoles X and pyrazolo[4,3-b][1,4]oxazines XII. Diazotized II was coupled with active methylene-containing nitriles to afford pyrazolo[5,1-c]-as-triazines XIV.     

Action of 1,2-diamines and o-aminophenols on 1-alkyl-3-carboxyindole-2-acetic acid anhydrides. Preparation of new ring systems

1-Alkyl-3-carboxyindole-2-acetic acid anhydrides (I) react with ethylenediamine and with o-phenylenediamine to give directly 10-alkylimidazo[3,2:1′,2′]pyrido[4,5-b]indol-5(1H)-ones (II) and 5,6-dihydro-5-alkyl-13H-indolo[2′,3′:4,5]pyrido[1,2-a]benzimidazol-13-one (V), respectively. However, anhydrides I react with o-aminophenol and with o-aminothiophenol to give carboxyindole-acetanilide derivatives IX, which can be cyclised to indolo[2′,3′:4,5]pyrido[2,1-b]benzoxazolone and indolo[2′,3′:4,5]pyrido[2,1-b]benzthiazolone (XI). Some derivatives of II and V were prepared to help in elucidating the structures.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

SYNTHESIS AND REACTIONS OF SOME NEW THIENO[2,3-b]-PYRIDINES AND THE ANTIMICROBIAL EFFECTS

Abstract

3,5-Dicyano-6-mercapto-4-phenylpyridin-2(1H)-one (1) was reacted with ethyl chloroacetate to give compound (II) which on reaction with hydrazine hydrate gave the corresponding hydrazide derivative (III). Acylation of (III) with acetic acid, phenylisocyanate, or phenylisothiocyanate gave different monoacyl derivatives (IV-VI). Condensation of III with aromatic aldehydes and acetylacetone gave compounds VII_a-c, VIII respectively. Compound I was reacted with chloroanilides, bromoacetone and phenacyl bromide to yield the IX-XI; these and compound II gave thieno[2,3-b]-pyridines (XU-XV) on treatment with sodium ethoxide solution. Reaction of XII with acetic anhydride gave the diacetyl derivative XVI. Hydrolysis of compound XII with sodium hydroxide gave the corresponding acid (XVII) which on treatment with acetic anhydride gave the oxazine derivative (XVIII). Reaction of oxazine compound XVIII with ammonium acetate and hydrazine hydrate gave pyrido[3′,2′:4,5] thieno[3,2-d]pyrimidin-4.7-dione derivative (XIX) and (XX) respectively. The N-amino derivative (XX) was reacted with 4-nitrobenzaldehyde to give the corresponding azomethine (XXI).

Significant in vitro gram-positive and gram negative antibacterial activities as well as anti-fungal effect were observed for some members of the series.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

Über in 6-Stellung basisch substituierte Morphanthridine. 8. Mitteilung über siebengliedrige Heterocyclen

Morphanthridines III with a basic substituent in position 6, which show neuroleptic activity, have been synthesised as follows: Chlorination of the lactams I with POCl₃ gave the iminochlorides II, which were converted by bases to the amidines III. The 11-oxo-morphanthridines VI and VII were synthesised using the same procedure, 2-(1-methylpiperazine-4-carbonyl)-2′-amino-benzophenone (XI) was obtained directly from the 6-chloro-11-oxo-morphanthridine (V) or by extended heating of VI with N-methylpiperazine. Reduction of the 11-oxo-compounds VI and VII with NaBH₄ gave the 11-hydroxy-compounds IX and X. 3-(2-aminophenyl)-phtalide (VIII) resulted from the acid hydrolysis of IX.     

On the mechanism and stereochemistry of the formation of β‐lactam derivatives of 2,4‐disubstituted‐2,3‐dihydro‐benzo[1,4]diazepines

2‐Chloro‐4‐phenyl‐2a‐(4′‐methoxyphenyl)‐3,5‐dihydroazatetracyclic [1,2‐d]benzo [ 1,4]diazepin‐1 ‐one ( III _a) and 2‐chloro‐4‐methyl‐2a‐(4′‐methoxyphenyl)‐3,5‐dihydroazatetracyclic[1,2‐d]‐benzo[1,4]diazepin‐1‐one ( III _b) were synthesized. 1‐Benzoyl‐2‐phenyl‐4‐(4′‐methoxyphenyl)[1,4]‐benzodiazepine ( II _a) was formed through benzoylation of starting material 2‐phenyl‐4‐(4′‐methoxyphenyl)‐[1,4]benzodiazepine ( I _a) with the inversion of seven‐member ring boat conformation. The thus formed β‐lactams should have four pairs of stereoisomers. However, only one pair of enantiomers (2S,2R,4R) and (2R,2aS,4S) was obtained. The mechanism and stereochemistry of the formation of these compounds were studied on the basis of nmr spectroscopy and further confirmed by X‐ray diffraction.     

Crystal structures of condensation products of 3,5-dibromosalicylic aldehyde with streptocide, norsulfazole, and ethazole

Crystal structures of 4-[(3,5-dibromo-2-hydroxy-benzylidene)-amino]-benzenesulfonamide (I), 4-[(3,5-dibromo-2-hydroxy-benzylidene)-amino]-N-thiazol-2-yl-benzenesulfonamide (II), and 4-[((3,5-dibromo-2-hydroxy-benzylidene)-amino]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-benzenesulfonamide (III) have been determined. The crystals of I are monoclinic, a = 8.645(2) Å, b = 12.622(3) Å, c = 14.414(3) Å; β = 104.31(3)°, space group P2₁/n, Z = 4, R = 0.0642. The crystals of II are also monoclinic, a = 10.313(2) Å, b = 11.288(2) Å, c = 15.766(3) Å; α = 99.37(3)°, space group P2₁/c, Z = 4, R = 0.0635. The crystals of III are triclinic, a = 10.567(2) Å, b = 10.849(2) Å, c = 18.432(4) Å; α = 75.97(3)°, β = 89.71(3)°, γ = 87.33(3)°, space group P-1, Z = 4, R = 0.0644. The asymmetric part of the unit cell of compounds I and II contains a single molecule of the Schiff’s base, while in III two independent azomethine molecules A and B. The studied compounds I–III adopt the E-configuration relatively to the double azomethine bond C=N. Owing to phenolic oxygen together with nitrogen and oxygen atoms of the sulfonamide group, compound I makes in a crystalline state a two-dimensional hydrogen bonded network parallel to the plane (1 0 1). Compound II forms centrosymmetric dimers in the crystals via N-H…N hydrogen bonds. These dimers, in their turn, are connected by hydrogen bonds O-H…O into infinite chains running along the double screw axis b. As in II, molecules and of compound III form centrosymmetric dimers through hydrogen bonding N-H…N. These dimers are linked into infinite chains running along the c axis by hydrogen bonds C-H…O. The π-π-stacking interaction of aromatic rings is observed in all the compounds studied.     

Conversion of some monocyclic β-lactams into novel di-β-lactams

Monocyclic β-lactams (V & XI) carrying a carboxy function have been used to annelate the Schiff bases (II & X) using POCl₃ in the presence of triethylamine to obtain the di-β-lactams (VI & XII). Alternately, (VI) could also be prepared by annelation of the Schiff base (IX) derived from the α-amino-β-lactam (VIII), with phenoxyacetyl chloride.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

Neurotrope und psychotrope Substanzen, 6. Mitt.: Synthese neuer Aminoderivate von 6,11-Dihydrodibenzo[b,e]thiepin

Zusammenfassung Ausgehend vom 6,11-Dihydrodibenzo[b,e]thiepin-11-on (II) wurde über den Alkohol III das Chlorid V gewonnen, das durch übliche Umsetzungen die Amine VI–VIII, das Phthalimidoderivat IX, das primäre Amin X und das Nitril XI lieferte. Bei der Reaktion mit 3-Dimethylaminopropylmagnesiumchlorid ergab es das antireserpin-wirksame 11-(3-Dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]thiepin (XII), das zum ebenfalls antireserpin-aktiven sekundären Amin XIV partiell demethyliert wurde.

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The preparation of 11-chloro-6,11-dihydrodibenzo[b,e]thiepine (V) from the ketone II via III is described. Usual transformations gave amines VI–VIII, the phthalimido derivative IX, the primary amine X, and the nitrile XI. Treatment of V with 3-dimethylaminopropylmagnesium chloride resulted in 11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]thiepine (XII), having antireserpine activity. Partial demethylation of XII gave the secondary amine XIV, which had the same type of pharmacodynamic activity.

     

Ein neuer zugang zu indeno[1,2-b]pyridinen

A new synthesis of 5H-indeno[1,2-6]pyridines [IV] starting from 4-cyanobutyrophenones [I] or their cyclization products, the 6-phenyl-3,4-dihydropyridin-2-ones [II], is reported. The condensation of I or II in polyphosphoric acid with aromatic or heteroaromatic aldehydes [III] yields 1,2,3,4-tetrahydro-5H-indeno[1,2-b]pyridin-2-ones [IV]. 2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines [X, XI] which were previously difficult to obtain can now be easily synthesized from compounds IV.     

Pheromones of insects and their analogs

Dodec-8Z-en-1-ol (VIII) and tetradec-8Z-en-1-ol (IX) and the corresponding acetates (X and IX) — components of the sex pheromones of many species of Lepidoptera — have been synthesized from cyclooctene (I) in three stages. The ozonolysis of (I) (–70°C, CH₂Cl₂-MeOH, NaHCO₃; –20°C, Ac₂O/Et₃N) led to methyl 8-oxooctanoate (II). The DNPH of (II), (III), mp 59–61°C. The coupling of (II) with n-C₃H₁₇ CH=PPh₃ (IV) or with n-C₅H₁₁ CH=PPh₃ (V) (–70°C, 2 h; 25°C, 15 h, Ar) gave the methyl esters of dodec-8Z-enoic (VI) and tetradec-8Z-enoic (VII) acids, respectively. The reduction of (VI) and (VII) [(i-Bu)₂AlH, 0°C, 2 h; 25°C, 15 h] gave the corresponding alcohols (VIII) and (IX) by the acetylation (Ac₂O-Py, 25°C, 24 h) of which, (X) and (XI), were obtained. The yields (%): (II) 80, (VI) 45, (VII) 60, (VIII) 95, (IX) 90, (X) 75, (XI) 74. The IR and PMR spectra of compounds (II) and (VI–XI) are given.Institute of Chemistry, Bashkir Scientific Center, Urals Branch, Academy of Sciences of the USSR, Ufa. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 276–279, March–April, 1989.     

Dibenzo[b,f]oxepin‐10(11H)‐one and dibenzo[b,f]thiepin‐10(11H)‐one as useful synthons in the synthesis of various dibenzo[e,h]azulenes

The present review focuses on dibenzo[b,f]oxepin‐10(11H)‐one ( I , X = O) and dibenzo[b,f]thiepin‐10(11H)‐one ( I , X = S) as common synthons in the efficient synthesis of various dibenzoxepino[4,5‐ and dibenzothiepino[4,5]‐fused five‐membered heterocycles: [2,3] fused thiophene ( II ), [3,4] fused thiophene ( III ), furan ( IV ), pyrrole ( V ), imidazole ( VI ), pyrazole ( VII ), oxazole ( VIII ), and thiazole ( IX ). The potential of I to be converted into reactive intermediates that readily undergo heteroaromatic annulation reactions by cyclocondensation with proper binucleophiles allows formation of a range of enumerated functionalized dibenzo[e,h]azulene [4] structures ( II , III , IV , V , VI , VII , VIII , IX ). Dibenzo[e,h]azulenes as heterotetracyclic scaffold can be exploited in further modifications to obtain compounds with altered physicochemical and biological profile. J. Heterocyclic Chem., (2012).     

Reaction of 2-carboxy-1-methylindole-3-acetic acid anhydride with amines and with S-methylisothiosemicarbazide

2-Carboxy-1-alkylindole-3-acetic acid anhydrides (I) condensed with S-methylisothiosemicarbazide in DMF to form 5,11-dihydro-6-methyl-2-methylthioindolo[3′,2′:4,5]pyrido[1,2-b]-s-triazol-5-one (II). Compound II underwent ring opening on refluxing with sodium hydroxide solution to give IV. The anhydride I reacted with primary amines in benzene to give 2-carboxy-1-alkylindole-3-acetanilide derivatives (VI) which yielded l-methylindole-3-acetic acid by decarboxylation followed by hydrolysis. Compound II oxidised to the diketo compound X which could be prepared by the hydrolysis of the azomethine derivative IX with acetic acid-hydrochloric acid mixture. Compound II reacted with benzyl chloride to yield the dibenzyl derivative XII, condensed with p-chlorobenzaldehyde to form the 11-p-chlorobenzylidene derivative XI and coupled with arenediazonium salt to give the 11-arylhydrazone derivatives XIII.