Studies on the chemistry of thienoanellated O,N- and S,N-containing heterocycles. 3. Synthesis of tricyclic thieno[2,3-b][1,4]thiazines via nucleophilic substitution of activated precursors

Starting from thieno[2,3][1,4-b]thiazine 1 new synthetic pathways to the tricyclic compounds 5, 12, 13, 14, 20 and the tetracyclic ring system 19 are described. Under mild reaction conditions some intermediates can be isolated. Reaction of 8 with several amines leads to the amidines 15–18 .     

Studies on the chemistry of 1,4-oxazines. 18. Synthesis of tricyclic 1,4-benzoxazines via nucleophilic substitution of activated precursors

Starting from activated benzoxazines 1 and 2 new synthetic pathways to the tricyclic compounds 4, 9, 12 and 16 are described. Reaction of the hydrazides 17a,b with thionylchloride leads to the novel thiatriazolo-benzoxazines 18a,b .     

The Synthesis of pyrimido[4,5-b][1,4]diazocines and pyrido[2,3-b][1,4]diazoeines

The reaction conditions for the preparation of 7H,8H-1,3-dimethyl-2,4,6,9-tetraoxopyrimidino[4,5-b][1,4]-diazocine ( 9 ), 1,3-dimethy 1–2,4,6,11-tetraoxobenzo[f]pyrimidino[4,5-b][1,4]diazocine ( 10 ), 7H,8H-1,3-dimethyl-2,4,6,10-tetraoxopyrimidino[4,5-b][1,4]diazonine ( 16 ), and 7H,8H-6,9-dioxopyridino[2,3-b][1,4]diazocine ( 19 ) were determined. The mechanism of the formation of these compounds was established. The scope of these reactions was found to be general for eight and nine ring formation from 2,3-diamino-N-heterocycles.     

Short Synthesis of Enantiopure Thieno[2,3‐f]triazolo[1,5‐a][1,4]diazepines and Thieno[2,3‐f][1,4]diazepin‐5‐ones

Starting from 2‐carboxy‐3‐thenylazide 1 and enantiopure amines 2 as the chiral building blocks, we developed a two‐step synthesis of the title compounds involving an intramolecular azide cycloaddition as the key step.     

Tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepine and -cyclopenta[e]pyrido[2,3-b][1,4]diazepine derivatives

In pursuing the study on compounds obtained by condensation of N-monoalkylated aromatic and hetero-aromatic diamines with α- and β-ketoesters, 7,8,9,10-tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepin-6(5H)-ones 4a, 4b and 5,7,8,10-tetrahydrocyclopenta[e]pyrido[2,3,-b][l,4]diazepin-9H)-ones 5a, 5b were prepared starting from 2,3-diaminopyridine or 2,3-diamino-5-chloropyridine and ethyl 2-oxo-cyclopentanecarboxylate. Compounds 4a,b and 5a,b suffer thermally induced ring contraction to the imidazolone derivatives 8a,b and 7a,b respectively and are unsuitable for preparing diazepinone derivatives. Thus the methylated diazepinones 15, 17 and 18 , stable on heating, were prepared. Compound 17 was transformed into the clozapine analogue 22 , through the diazepinthione 20 and its S-methyl derivative 21 .     

Synthesis of thieno[2,3‐b][1,5]benzoxazepine derivatives

A new series of 4‐(4‐methylpiperazin‐1‐yl)thieno[2,3‐b][1,5]benzoxazepines 1a‐k has been synthesized from 4‐bromo‐2‐methylthiophene 6 or ethyl 2‐amino‐4,5‐dimethyl‐3‐thiophencarboxylate 10 . Preparation of the key intermediate thieno[2,3‐b][1,5]benzoxazepine‐4(5H)‐ones 4a‐i, 4k were carried out by treatment of 2‐bromo‐N‐(2‐hydroxyphenyl)‐3‐thiophencarboxamides 5a‐i, 5k with potassium carbonate in DMSO. Compounds 1 are thienoanalogues of loxapine, a potent antipsychotic drug. Of these compounds, the neu‐roleptic activity of 2‐methyl‐4‐(4‐methylpiperazin‐l‐yl)thieno[2,3‐b][1,5]benzoxazepine 1a (R¹, R³=H, R²=CH₃) demonstrated potent antipsychotic activity.     

Synthesis of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines

A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former step, the bulkiness of both starting nitropyridones and C2 reagents is found to be essential for avoiding N-alkylation, which undergoes O-alkylation efficiently. The subsequent reductive cyclization affords pyridoxazines with carbon substituents at both the 2- and the 6-positions that have not been available.     

Derivatives of pyrido[2,3‐b][1,4]diazepine and of the dipyrido[1,2‐a:2′,3′‐b]imidazole heterocyclic system

With a continuing interest in heteropolycyclic systems which may show biological activities, we studied the reaction of 3‐amino‐2‐(methylamino)pyridine with diethyl 1,3‐acetonedicarboxylate in order to develop pyridodiazepinone derivatives. From the reaction mixture, we separated dipyrido[1,2‐a:2′,3′‐d]imidazole derivatives ( 3 and 4 ) besides two isomeric pyrido[2,3‐b][1,4]diazepine derivatives ( 5 and 6 ) in which the complex structural differentiation was achieved through nmr experiments and chemical evidence. Several attempts to elaborate isomers 5 and 6 have not yet given significant results.     

Synthesis of a New Series of Imidazo[1,5-d]pyrido[2,3-b][1,4]thiazines as Potential Ligands for the GABA Receptor Complex

Summary.  Starting from 2-chloro-3-nitropyridine, 1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to give the intermediate 1H-pyrido[2,3-b][1,4]thiazin-2-ylphosphate derivative, which in turn afforded the 1,2,4-oxadiazolylimidazo[1,5-d]pyrido[2,3-b]pyrazine derivatives. The title compounds are potential ligands for the γ-aminobutyric acid A/benzodiazepine receptor complex. Corresponding author. E-mail: thomas.erker@univie.ac.at Received February 22, 2002. Accepted March 6, 2002     

Synthesis of [1,4]benzodioxino[2,3‐c and 2,3‐d]pyridazinones

Reaction of chloropyridazin‐3‐one 1, 5 and 10 with catechol in the presence of potassium carbonate gave the corresponding [1,4]benzodioxino[2,3‐e and/or 2,3‐d]pyridazinones 2, 7, 8 and 11 .     

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3‐d]pyrimidine antifolates

The effect of conformational restriction of the C9‐N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6(5H,8H)‐one ( 4 ), 1,3‐diamino‐8‐(3′,4′,5′‐trimethoxybenzyl)‐9‐hydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidin‐6‐(8H)‐one ( 5 ) and 1,3‐diamino‐(8H)‐(3′,4′,5′‐trimethoxybenzyl)‐7,9‐dihydro‐pyrrolo[3,4‐c]pyrido[2,3‐d]pyrimidine ( 7 ) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclo‐condensation of the β‐keto ester 17 with 2,4,6‐triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.     

Synthesis of 1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine

The synthesis of 7,8‐dihydro‐5(6H)‐quinolinone ( 3 ) from commercially available 3‐amino‐2‐cyclohexen‐1‐one ( 1 ) and 3‐(dimethylamino)acrolein ( 4 ) in 23% yield avoids the preparation of propynal ( 2 ). Conversion of 5‐(4‐methylphenylsulfonyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]azepine ( 12 ) to 6‐(4‐methylphenylsulfonyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 24 ) is described. Removal of the N‐(4‐methylphenylsulfonyl) group with 40% sulfuric acid in acetic acid gave the tricyclic azepine 26. Application of a similar series of reactions to 5‐(4‐nitrobenzoyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]‐azepine ( 13 ) afforded 6‐(4‐nitrobenzoyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 25 ).     

2,4-Diaryl-2,3-dihydrobenzo[b][1,4]thiazepines

2,4-Diaryl-2,3-dihydrobenzo[b][1,4]thiazepines are obtained in a single stage from chalcones and ortho-aminothiophenol in the presence of triethylamine. The nature of the electronic transitions in their UV absorption spectra is discussed with the use of quantum-chemical methods. It was shown that the seven-membered ring does not invert in the range of temperatures between –80 and +140 °C and is in the boat form. The main initial event in the fragmentation of the molecules of the obtained compounds under electron impact is the formation of benzothiazole-containing radicalions. In an acidic medium 2,4-diphenyl-2,3-dihydrobenzo[b][1,4]thiazepine is hydrolyzed to 3-(2-aminophenylthio)-1,3-diphenyl-1-propanone, and in its reaction with 2,4-dinitrophenylhydrazine chalcone hydrazone and o-aminothiophenol are formed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1638–1642, December, 1983.     

Synthesis and biological evaluation of benzo[7,8]chromeno[5,6‐b][1,4]oxazin‐3‐ones

The O‐methylmonoximes 2,3 of stenocarpoquinone‐A and β‐lapachone reacted with methyl phenylacetate to give 1,4‐benzoxazine derivatives 8a, 8b and oxazole 11a. Compound 8a was transformed to compounds 13_I , 13_II , 14. Treatment of compound 14 with osmium tetroxide afforded compounds 15 , 16 and esterification of the latter gave the bis‐ and mono‐ esters 17_I , 17_II , 18. All products are strongly fluorescent. Compounds 8a,b , 11a , 13–18 (azabenzo analogues of khellactones) were tested for their ability to interact with DPPH, to compete with dimethylsulfoxide for hydroxyl radicals, to inhibit soybean lipoxygenase and trypsin activities in vitro. Compounds 16 and 17_II were found to compete significantly with dimethylsulfoxide for hydroxyl radicals, whereas compounds 8a , 11a , 14 and 17_I were found to inhibit strongly soybean lipoxygenase.     

Synthesis of New Pyrimido[5′,4′:5,6][1,4]thiazino[2,3‐b]quinoxaline Derivatives in One Step

As a continuation of our search for new heterocyclic compounds, the synthesis of pyrimido[5′,4′:5,6][1,4]thiazino[2,3‐b]quinoxaline ring system is described. A series of new derivatives of this heterocyclic system ( 3a–d ) have been synthesized through the one‐pot heterocyclization of the appropriate 5‐amino6‐methylpyrimidine‐4‐thiols and 2,3‐dichloroquinoxaline in the presence of K₂CO₃ in dimethylformamide under reflux. N‐alkylation of the synthesized compounds with alkyl halides in KOH/dimethylformamide also gave the desired new derivatives of N‐alkylated pyrimido[5′,4′:5,6][1,4]thiazino[2,3‐b]quinoxalines ( 4a–h ). All the synthesized products were characterized and confirmed by their spectroscopic and microanalytical data.     

A one-pot synthesis of pyrido[2,3-b][1,4]oxazin-2-ones

Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.     

Synthesis of novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines via Bischler-Napieralski-type reactions

[reaction: see text] Novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines were readily prepared from 5-amino-4,6-bis(arylthio)pyrimidines and carboxylic acids via Bischler-Napieralski-type reactions. The 6-aryl sulfide group of the resulting pyrimido[4,5-b][1,4]benzothiazepines could be selectively oxidized to its corresponding sulfoxide, which underwent facile substitution reactions when treated with nucleophiles such as an amine. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.