Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid towards salicylaldehyde-derived alkynes and allenes

The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3-methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give a new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Synthesis of furo[2,3-b]pyridin-4(7H)-ones and related quinolinone via Brønsted acid-promoted cyclisation of alkynes

N-Alkyl-4-alkoxy-3-alkynylpyridin-2(1H)-ones readily undergo acid-promoted 5-endo-heteroannulation to furopyridinium intermediates that are dealkylated in situ to provide the corresponding furo[2,3-b]pyridin-4(7H)-ones. The same strategy applies to the formation of furo[2,3-b]quinolin-4(9H)-ones. In the case of Me₃Si-substituted alkynes, hydration of the triple bond was observed.     

I2-catalyzed one-pot synthesis of benzofuro/thieno[2,3-b]pyrrole motifs

A novel I₂-catalyzed one-pot multicomponent protocol for the synthesis of a variety of elusive furo[2,3-b]pyrrole and thieno[2,3-b]pyrrole libraries has been established. To date, cyclization among alkanone, hydrazine and 2-bromobenzofuran or 2-bromobenzo[b]thiophene has not been explored in one-pot. Thus, the proposed single step protocol provides a versatile alternative to existing routes for accessing useful furo[2,3-b]pyrrole and thieno[2,3-b]pyrrole libraries.     

Synthesis of novel tricyclic isoindole derivatives

Novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles were prepared from the thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in acetic anhydride. The structure of 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindole 6a was determined by X-ray crystallography.     

Synthesis of 4-aza analog of ramelteon: a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative as melatonin receptor ligand

The 4-aza analog of ramelteon (−)-1, a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative, was synthesized via the intramolecular inverse electron demand Diels-Alder reaction followed by fluoride-induced desilylation-cyclization.     

Application of ortho-chloro-β-aroylthioamides in synthesis(II): an efficient one-pot, three-component synthesis of tricyclic thiochromeno[2,3-b]pyridine derivatives

Tricyclic thiochromeno[2,3-b]pyridine derivatives have been successfully synthesized in an unusual one-pot multicomponent cascade reaction from ortho-halo-β-aroylthioamides, Meldrum's acid, and aromatic aldehydes. The reaction presumably proceeds via Knoevenagel condensation-Michael addition-cyclocondensation-decarboxylation-rearrangement-intramolecular S_NAr reaction sequence. High bond forming efficiency of this reaction makes it attractive for the synthesis of thiochromeno[2,3-b]pyridine derivatives in a single step operation.     

Synthesis of substituted thiazolo[4,5-b]pyridines and other annulated heterocycles via SN2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions

A new combinatorial method for the preparation of substituted thiazolo[4,5-b]pyridines, which utilizes cyanoacetamide, heterocumulenes (isothiocyanates, carbon bisulfide), and ethyl-4-chloroacetoacetate in a new S_N2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions has been developed. The obtained thiazolo[4,5-b]pyridines were then used together with aldehydes and malononitrile in another Knoevenagel reaction→Michael reaction→hetero-Thorpe-Ziegler domino reaction for the synthesis of substituted 4,6-dihydro-5H-pyrano[2,3-d]thiazolo[4,5-b]pyridines.     

Synthese von Furo [2,3-b]chinolinen

A new route to furo[2,3-b]quinolines has been developed based on the use of N-arylaconamides as starting materials. These anilides when heated with polyphosphoric acid, readily underwent intramolecular cyclization to furnish the respective 1,2-dihydro-2-oxo-quinoline-3-acetic acids which were then transformed into the corresponding dihydrofuro[2,3-b]quinolines by literature procedures. Sequential treatment of the dihydro compound withNBS andDBU afforded the corresponding furo[2,3-b]quinoline. The NMR spectra of the furoquinolines are discussed.

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Mitt.: siehe Lit.     

Preparation of thieno[2,3-b]pyrroles starting from ketene-N,S-acetals

Thieno[2,3-b]pyrroles 4 can easily be synthesised in two different ways by using phenyl isothiocyanate and activated methylene compounds. The priority of the formation of the thiophene or pyrrole ring is investigated.     

Reactions of 1,5-π-cyclization of gem-difluoro-substituted azomethine ylides involving an aromatic ring

Reactions of N-(5-R-furan-2-ylmethylidene)anilines with difluorocarbene proceeds through intermediate azomethine ylides suffering 1,5-π-cyclization to yield 6,6-difluorocyclopropa[b]furo[2,3-c]pyrrole and/or 4,4,6,6-tetrafluorocyclopropa[b]furo[2,3-c]pyrrole. The heating of these compounds without solvent resulted in high yields of 2,5-disubstituted 7-fluoro-4,5-dihydrofuro[3,2-c]pyridin-4(5H)-ones.     

Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastereoselective cascade sequence

A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The viability of this approach was demonstrated by syntheses of a series of furo[2,3-b]chromene and pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids,hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.     

Efficient regioselective heterocyclisation leading to fluorescent fused pyrazine derivatives

The regioselective syntheses of substituted pyrrolo[2,3-b]quinoxaline, pyrido[2,3-b]pyrrolo[2,3-e]pyrazine, pyrido[2,3-b]pyrrolo[3,2-e]pyrazine and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine are reported. Differential reactivity between two amino groups in ortho-diaminopyridine can be exploited to obtain new regio-defined unsymmetrical pyridopyrrolopyrazine derivatives. Weak electron-donating methyl or moderately electron-withdrawing carboxylic groups attached to the aromatic ortho-diamines reduce the regioselectivity of obtaining unsymmetrical substituted pyrrolo[2,3-b]quinoxaline. The fluorescence properties of the resultant 1-alkyl pyridopyrrolopyrazine and substituted pyrrolo[2,3-b]quinoxaline derivatives are presented.     

One-pot synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives using Fischer carbene complex

A new route for the synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives have been explored through the coupling of carbene complexes with pyridine-bridged enynes. This reaction process, involving the annulation of both furan and benzene ring on to a pre-existing pyridine ring is highly efficient in the presence of triphenylphosphine as ligand additive.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Polycyclic N-heterocyclic compounds. Part 61: A novel Truce-Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines

The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, β-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce-Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields.     

Furopyridines. XVIII. Photocycloaddition of furo[2,3-c]pyridin-7(6H)-one with acrylonitrile

The photocycloaddition of furo[2,3-c]pyridin-7(6H)-one ( 1 ) and its N-mefhyl derivative ( 1-Me ) to acrylonitrile has been studied. The structures of the photoadducts isolated by colum chromatography were determined by the nuclear magnetic resonance spectroscopy and single crystal X-ray analysis. The cyclo-addition of 1 afforded an adduct 2 at the carbonyl oxygen and 8-cyano-8,9-dihydrofuro[d]azocin-7(6H)-one ( 3 ), and the addition of 1-Me the N-methyl derivative 3-Me of 3 , (9S*)-9-cyano-6-methyl-3a,7a-dihydro-3a,7a-ethanofuro[2,3-c]pyridin-7(6H)-one ( 4 ), (2S*, 2aR*, 7bR*)- ( 5 ) and (1R*, 2aS*, 7bS*)-2-cyano-3-methyl-4-oxo-1,2,2a,3,4,7b-hexahydrocyclobuta[e]furo[2,3-c]pyridine ( 6 ).     

Efficient palladium-mediated or base-induced 5-endo-dig cyclisation of C5-alkynylated pyrimidine derivatives: conventional and microwave-assisted synthesis of novel furo[2,3-d]pyrimidines

A series of the novel 5-alkynyl- and furo[2,3-d]pyrimidine derivatives in which the sugar moiety is replaced by a methoxymethyl (MOM) group is synthesised using the Sonogashira cross-coupling reaction under both conventional and microwave conditions, in good to excellent yields. The 5-endo-dig cyclisation of 5-alkynylpyrimidine derivatives promoted by a Pd-catalyst or base gives the corresponding furo[2,3-d]pyrimidines in good yields.