6,6-Disubstituted furo[3,4-c]isoxazoles and 7,7-disubstituted pyrano-[3,4-c]isoxazoles from intramolecular cycloaddition reactions

The reaction of β-nitroenones with unsaturated alkoxides anions, followed by intramolecular 1,3-dipolar cycloaddition, afforded in good yields 6,6-disubstituted furo[3,4-c]isoxazoles and 7,7-disubstituted pyrano[3,4-c]isoxazoles.     

Synthesis of conformationally restricted nicotine analogues by intramolecular [3+2] cycloaddition

We describe the synthesis of a series of conformationally constrained nicotine analogues 2-5 from appropriate pyridine-containing enals, featuring an intramolecular azomethine ylide-alkene [3+2] cycloaddition. The objective of the current project is to develop new selective nAChRs-targeting ligands. Of the nicotine analogues that we have studied, the conformation-restricting ring B unit can be either a five-membered carbocycle, or a six-membered carbocycle or heterocycle. The present work constitutes a general method for rapid assembly of other related tricyclic nicotine analogues.     

Synthesis of 1-(hydroxyaryl)furo[3,4-c]pyridines from 1-amino(alkoxy)furo[3,4-c]pyridines and (poly)phenols

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Syntheses of furo[3,4-c]coumarins and related furyl coumarin derivatives via intramolecular Wittig reactions

A new and general strategy for highly functional furo[3,4-c]coumarins and related furyl coumarin derivatives has been developed, which is based on an extraordinarily facile intramolecular Wittig reaction, starting from α,β-unsaturated ketones, tributylphosphine, and acyl chlorides. The phosphorus ylides were proposed to be the key intermediates for constructing the crucial furan ring, leading to a wide variety of substituted furyl coumarins in one step.     

A New synthesis of 4,5,6,7-tetrahydrofuro[2,3-c]pyridines and furo[2,3-c]pyrrolidines

New syntheses of 4,5,6,7-tetrahydrofuro[2,3-c]pyridines and furo[2,3-c]pyrrolidine derivatives, starting from furan-3-carboxaldehyde, are reported.     

Synthesis and reactions of 2-and 4-substituted furo[3,2-c]pyridines

Substituted furopropenoic acids were prepared from appropriate aldehyde under the Doebner’s conditions. Obtained acids were converted to the corresponding azides, which were cyclized by heating in Dowtherm to furopyridones. These compounds were aromatized with phosphorus oxychloride to chloro derivatives of furo[3,2-c]pyridine (Va, Vb). Chloro derivative Vb was reduced with hydrazine hydrate to 2-(4-aminophenyl)furo[3,2-c]pyridine in ethanol and Pd/C as a catalyst. Chloro derivative Va was converted to 4-amino-2-(3-pyridyl)furo[3,2-c]pyridine under the same conditions. The chlorine atom in other chloro derivatives (VIIa, VIIb) was replaced by nucleophilic substitution with alkoxides (sodium ethoxide, propoxide, and isopropoxide) and the corresponding alkoxy derivatives were formed. By reaction of VII with cyclic secondary amines (morpholine, piperidine, and pyrrolidine) 4-substituted furopyridines were prepared.     

A sequential Pummerer-Diels-Alder route for the generation and trapping of furo[3,4-c]pyridines: synthesis of heterocyclic analogues of 1-arylnaphthalene lignans

The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an alpha-thiocarbocation, the interception of which by a neighboring keto functionality produces an alpha-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels-Alder cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and the entire sequence can be run in one pot. The facility of the sequential Pummerer-Diels-Alder reaction hinges on the experimental conditions, the best results being obtained with heptafluorobutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer-Diels-Alder reaction is further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration of the resulting hydoxylated isoquinoline derivative.     

Polymethyl derivatives of furo[3,4-c]pyran4-one,furo[3,4-c] pyridin-4-one and pyrrolo[3,4-c]pyran-4-one

The: title compounds were prepared from Michael adducts, obtained from acetoacetic esters and trans-3-hexene-2,5-dione, and from the corresponding dehydration products, by direct cyclization to oxygen rings or by reaction with ammonia (or methylamine) to give nitrogen rings.     

Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.     

Syntheses of substituted and fused furo[3,2-c]pyridines

Department of Organic Chemistry, Slovak Technical University, 812 37 Bratislava, Slovak Republic. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1390–1392, October, 1995. Original article submitted August 24, 1995.     

Cu(I) substitutions. furo[3,2-b] pyridines,furo[3,2-c] pyridines and 1h-thieno[3,4-b] 2-pyran-l-ones from cuprous acetylides

The reaction of cuprous acetylides with aryl halides bearing a nucleophilic ortho substituent provides a versatile route to heterocyclic substances. The present work portrays the ease with which polyheterosystems can be constructed with this reaction. The synthesis of 2-substituted 7-iodofuro[3,2-c]pyridines, 2-substituted furo[3,2-b]pyridines, and 3-substituted lH-thieno-[3,4-b]-2-pyran-l-ones (thiaisocoumarins) is described. The latter two ring systems have not been previously reported.     

A novel preparation of thiazolo[5,4-c]pyridines and the synthesis of some imidazo[4,5-c]pyridines and oxazolo[4,5-c]pyridines

Diethoxymethyl acetate was used to cyclize o-disubstituted aminopyridines to oxazolo[4,5-c]pyridines and imidazo[4,5-c]pyridines. All the possible imidazole-methylated imidazo[4,5-c]pyridines were prepared. A novel synthesis of 2-substituted thiazolo[5,4-c]pyridines and 4-amino-3-pyridinethiol was discovered.     

Recyclization of perhydrooxazolo[5,4-c]pyridines to 5,6,7,8-tetrahydrooxazolo[3,4-c]pyrimidines

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 855–856, June, 1991.     

Synthesis of 3-amino derivatives of benzo[b]furo[2,3-c]pyridines

The reaction of 1,7-dimethyl-3(2H)-benzo[b]furo[2,3-c]pyridone with phosphoric acid amides gave 1,7-dimethyl-3-dimethylamino (morpholino)benzo[b]furo[2,3-c]pyridines. A method for the synthesis of 3-amino derivatives of 4-nitrobenzo[b]furo[2,3-c]pyridines, which consists in heating 1,7-dimethyl-4-nitro-3(2H)-benzo[b]furo[2,3-c]pyridone with hexamethyldisilazane and secondary or primary amines in pyridine, was developed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1552–1555, November, 1991.     

Synthesis and structure of 3-oxopyrano[3,4-c]pyridines

Acylation of the enamine of 2,2-dimethyltetrahydropyran-4-one with acid chlorides produced -acylpyran-4-ones which give 3-oxopyrano[3,4-c]pyridines when treated with cyanoacetamide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1137–1142, August, 1989.     

Facile synthesis of benzo[4,5]furo[3,2-c]pyridines via palladium-catalyzed intramolecular Heck reaction

The heating of 4-chloropyridine with 2-bromophenol in either neat or DME as solvent gives rise to 2-bromophenoxy pyridines, which were treated with Pd(OAc)₂ and various ligands to afford functionalized benzo[4,5]furo[3,2-c]pyridines.     

Electrophilic substitution in benzo[b]furo[2,3-c]pyridines: nitration,acylation

It has been shown that the nitration and acylation of substituted benzo[b]furo[2,3-c]pyridines proceeds exclusively at position 6 of the benzene ring. If position 6 is blocked by a substitutnt, the product of monosubstitution at the C₍₈₎ atom is formed. The molecules that were investigated have been calculated in the MNDO approximation.L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Tar Chemistry, National Academy of Sciences of Ukraine, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 694–699, May, 1995. Original article submitted March 22, 1995.