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The thermolysis reactions of benzoazacyclodecatrienes under microwave irradiation conditions in toluene at 150 °C afforded complex azabenzo[a]cyclopropa[cd]azulene and (epiminomethano)cyclopenta[a]indene frameworks. Cyclopropanes were established as intermediates of the ultimate thermolysis products.

We report an efficient domino reaction for synthesizing new pyrrolo[2,1-a]isoquinolines from 1-aryl-3,4-dihydroisoquinolines and vinyl ethynyl ketones. We also address the chemical selectivity of vinyl ethynyl ketones; i.e., adduct formation by the double or triple bond. The reaction outcome depends on the solvent, temperature, microwave irradiation, and catalyst. Donor substituents in the initial isoquinolines provide a regioselective addition to double or triple bonds.

Thieno[2,3-c]pyrrolines bearing a branched substituent at the nitrogen atom reacted with dehydrobenzene, furnishing thienylaziridines. N-Benzyl-substituted thienopyrroline under the reaction conditions gave a Stevens rearrangement product, 6-benzyl-5-phenylthieno[2,3-c]-pyrroline.

1,2,3,4-Tetrahydroisoquinolines bearing phenacyl group at the nitrogen atom in their reaction with benzyne in acetonitrile undergo ring expansion to give 1H-3-benzazepines.

Cyanomethyl-substituted tetrahydroisoquinolines and tetrahydrothieno[3,2-c]pyridines were synthesized by multicomponent reaction of the dihydro analogues of aforesaid systems with benzyne and acetonitrile. The products obtained relate to alkaloids of isoquinoline family of 1,2,3,4-tetrahydro level.

Three-component reactions of tetrahydropyrrolo[1,2-a][1,4]benzodiazepines with methyl propiolate or acetylacetylene and СН, NH, SH, and ОН acids were studied in various solvents. The reaction direction is assumed to depend on the nucleophilicity of anion, formed through deprotonation of acid by the anionic center of initial Michael-type zwitterion.

1-Aryl-substituted tetrahydrothieno[3,2-с]pyridines easily undergo domino reactions with activated alkynes, giving good yields of the corresponding tetrahydrothieno[2,3-d]azocines. The reactions of 1-methyl-substituted tetrahydrothieno[3,2-с]pyridine were more complicated.

It has been established that the reaction of pyrrolo[1,2-a][1,4]benzodiazepines with activated alkynes gives pyrrolo[1,2-a][1,6]benzodiazonines as the products of diazepine ring expansion. In the case of pyrrolo[1,2-a][1,4]benzodiazepine, substituted with formyl group at the pyrrole ring, both expansion and cleavage of the diazepine fragment can occur.

A study was carried out on the domino transformations of tetrahydrobenzofuro[2,3-c]pyridines and tetrahydrobenzofuro[3,2-c]pyridines by the action of activated alkynes in methanol and acetonitrile. This reaction is a new method for the synthesis of spiro[benzofuropyridines] showing acetylcholinesterase inhibition activity.

Triazolo[1′,5′:1,2]pyrimido[4,5-d]azocines were synthesized by the tandem expansion of the tetrahydropyridine ring in tetrahydropyridotriazolopyrimidines by the action of activated alkynes. Under these conditions, triazolopyridopyrimidines benzylated at the nitrogen atom of the pyrimidine moiety undergo the Hofmann cleavage of the tetrahydropyridine ring to form 5-vinyltriazolo[1,5-a]pyrimidines.

The reactions of partially hydrogenated indole-fused quinolizines and indolizines with activated alkynes in methanol, acetonitrile, and dichloromethane were studied. The reactions were shown to be accompanied by the cleavage of the bridging C-N bond. Azecino[5,4-b]-indole and indolo[3,2-e][2]benzazonine derivatives were synthesized.

It has been found that 2,3,3-trimethyl-1-phenyl- and 1,2-dimethyl-3-spirocyclohexyltetrahydro-isoquinolines react with activated alkynes in methanol with cleavage of the tetrahydropyridine ring to give methoxybenzyl- and methoxyethylbenzenes, and in boiling acetonitrile form N-butenoyl derivatives from N-methylspirocylohexyltetrahydroisoquinoline by its reaction with acetylacetylene.

Fused benzodiazepines were found to react with activated alkynes to effect either vinylation of unsubstituted nitrogen atom or dealkylation of nitrogen and its further vinylation. For benzodiazepinones bearing lactam fragment, the reactions with alkynes proceed by several pathways: formation of vinyl-substituted benzodiazepines, the Stevens rearangement products, and expansion of the diazepine ring: benzodiazonine and diazecine.

It has been shown that, on interacting 2-ethyl-3,3,5,5-tetramethyl- and 2-ethyl-1,3,3,5,5-pentamethyl-1,2,4,5-tetrahydro-3H-benz-2-azepines with ethyl propiolate in methanol, fission of the azepine ring occurs at the C(1)-N(2) bond involving a molecule of solvent. The indicated azepines do not react with acetylenedicarboxylic acid ester under these conditions.

A reaction of 10-R-substituted tetrahydrobenzo[b][1,6]naphthyridines (R = CN, CONH2, Me) with dimethyl acetylenedicarboxylate, methyl and ethyl propiolates, and acetylacetylene has been studied. It was found that 1-acryloyl-10-cyanotetrahydrobenzo[b][1,6]naphthyridines are the major products of the reaction of alkyl propiolates with 10-cyano-substituted naphthyridines, whereas the reaction with 10-carbamoyl-substituted naphthyridines gives a mixture of 1-acryloyl-substituted naphthyridines and hexahydrobenzo[b]pyrido[3,4,5-d,e][1,6]naphthyridines. The latter are the only products in the reaction of 10-carbamoyl-substituted naphthyridines with acetylacetylene.

Tetrahydroisoquinolines underwent tandem piperidine ring enlargement in the presence of activated alkynes in acetonitrile or methanol, producing tetrahydrobenzo[d]azocines in high yields. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A reaction of substituted hexahydroazepino[4,3-b]-and-[3,4-b]indoles with activated alkynes was studied. A one-step method for the synthesis of isomeric hexahydroazonino[5,6-b]indoles different by positions of the double bond in the azonine ring was developed.

The interaction of 7-trifluoroacetyltetrahydropyrrolo[1,2-c]pyrimidine with acetylenedicarboxylic ester (DMAD) and ethyl propiolate in acetonitrile and alcohols has been studied. It was established that DMAD splits pyrrolopyrimidine at the aminal fragment in acetonitrile and methanol with the formation of 1-H-and 2-(N-dimethoxycarbonylvinyl-N-methyl)aminoethyl-1-methoxymethyl-3-methyl-5-trifluoroacetylpyrroles. In acetonitrile ethyl propiolate splits pyrrolopyrimidine both at the aminal fragment and at the C(3)-N(2) bond (Hofmann reaction), but in ethanol only at the C(3)-N(2) bond with the formation of 2-propenylpyrroles.

The transformations of tetrahydrothieno[3,2-c]-and tetrahydrobenzothieno[2,3-c]pyridines in the reactions with acetylenedicarboxylic ester, alkyl propiolates, and acetylacetylene in alcohols were studied. Tetrahydrobenzothieno[3,2-d]azocines and 2-methoxyethyl-3-vinyl-aminoethylbenzothiophenes were synthesized.

The transformations of 1-substituted tetrahydro-β-carbolines by the action of activated alkynes were studied. The action of dimethyl acetylenedicarboxylate in methanol gives products of the opening of the tetrahydropyridine fragment, namely, 2-methoxyalkylindoles. The action of ethyl propiolate in ethanol and of tosylacetylene in methanol gives mixtures of azocino[5,4-b]indoles and 2-alkoxyindoles. The action of ethyl propiolate in acetonitrile gives azocinoindoles.

2-(Chloromethyl)-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3Н)-ones reacted with acetylenedicarboxylate ester, methyl propiolate or acetylacetylene, forming mixtures of 2-(chloromethyl)-5,6,7,10-tetrahydropyrimido[5',4':4,5]thieno[3,2-d]azocin-4(3Н)-ones and 2'-chloromethyl-6'-methylidene-2,3-dihydro-1Н-spiro[pyrido[4,5']thieno[2,3-d]pyrimidin]-4'(3'H)-ones in various ratios. Analogous products were also obtained in the reaction of 2-(methoxymethyl) derivative with methyl propiolate, while using 2-[(morpholin-4-yl)-methyl] derivative in a similar reaction led to the formation of a more complex product mixture.

2-Alkyl or 2-aryl-substituted 4-hydroxymethylisoindolines smoothly undergo intramolecular recyclization through reaction with arynes to give isobenzofurans with good yields.

The reaction of 10-carboxamido tetrahydrobenzo[b][1,6]naphthyridines 1-3 with activated terminal alkynes in DMF/methanol resulted with the formation of hexahydrobenzo[b]pyrido[3,4,5-de]-1,6-naph-thyridines 7-10- representatives of a new heterocyclic system.

The regioselectivity of the reaction of 10-substituted benzonaphthyridines with dehydrobenzene strongly depends on the electronic effects of the C-10 substituent furnishing predominantly Stevens rearrangement [cf.

Reaction of pyrrolobenzodiazepines (I) with activated alkynes gives pyrrolo[1,2-a][1,6]benzodiazonines as products of a diazepine ring expansion.

Reaction of 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline with activated alkynes affords stable tetrahydropyrrolo[2,1- a ]isoquinolin-4-ium ylides. Further reactions of ylide 2 gives access to substituted dihydropyrrolo[2,1- a ]isoquinolines in good yields.

Heating 1-vinyl-4,5,6,7-tetrahydro-5-methyl-4,6-ethanopyrrolo(3,2-c)pyridine (1) in the presence of acetic or trifluoroacetic anhydride resulted in bicyclic saturated fragment cleavage, affording cyclohepteno(b)pyrroles 2a,b in low yields. In the case of trifluoroacetic anhydride, the major product of the reaction, -trifluoroacetylsubstituted tetrahydropyrrolo(3,2-c)pyridine 3 was isolated in 34% yield.

2-Alkyl or 2-benzyl-substituted 4-hydroxymethyl(formyl)isoindoles readily react with electron-deficient alkynes undergoing intramolecular cyclization to produce 1-aminomethyl-substituted isobenzofurans in good yields.

1,2,3,4-Tetrahydro-2,4,5-trimethylpyrrolo[1,2-c]pyrimidine and its 7-formyl derivative when treated with nitric acid are converted to substituted tetrahydropyrrolo-[1,2-c]pyrimidine-7-carboxylic acid. Conversion occurs through opening of the aminal moiety and formylation of the second molecule of tetrahydropyrrolo[1,2-c]pyrimidine by formaldehyde formed to the 7-formyl-substituted derivative.

Reaction of readily available tetrahydropyridotriazolopyrimidines (III) with activated alkynes in refluxing MeOH affords the title triazolopyrimidoazocines (V) via a tandem expansion of the tetrahydropyridine ring.

A variety of tetrahydrobenzoxazepines and related-thiazepines (X) are synthesized and subjected to reactions with activated alkynes in MeOH while the benzoxazepines suffer a ring cleavage at the N—C(5) bond [ (XII)], benzothiazepine (Xd) undergoes an unprecedented thiazepine ring expansion furnishing a benzothiazonine (XIV).

In a continuation of work on the synthesis of eightand nine-membered nitrogen-containing heterocycles [1-3] and on the use of the Ugi reaction in the synthesis of benzodiazepine derivatives [4], we decided to develop a new isocyanide multicomponent reaction (MCR) using the reaction which we have discovered for the tandem expansion of heteroannelated tetrahydropyridines and azepines under the influence of activated alkynes. The experimental data we obtained earlier allowed us to suggest with certainty that propiolic acid, in contrast to its esters did not give products of the ring expansion with heteroannelated tetrahydropyridines. We have proposed that if propiolic acid was used as the carboxylic component in the Passerini reaction [5] then the oxoethylpropiolate A formed in situ, being an activated alkyne, might react with heteroannelated tetrahydropyridines introduced in this reaction as a fourth component. As a model experiment, we studied a MCR with tetrahydrothienopyridine 1 [6], butyraldehyde (2), propiolic acid (3), and isonitrile 4. The reaction was carried out at a temperature of -5 to 0°C in an atmosphere of argon. As a result the required thienoazocine 5 was isolated from the reaction mixture in a yield of 32%. Thus, we have found the first example of a multicomponent reaction for the expansion of a tetrahydropyridine ring. Despite the small yield of the required azocine, this reaction may serve as an effective method for the synthesis of difficult to obtain derivatives of medium nitrogen heterocycles. H and C NMR spectra were recorded with a Bruker WP-400 spectrometer (400 and 100 MHz respectively) in CDCl3 solution with TMS as internal standard. The assignment of the signals in the H NMR spectra was based on the data from the H-H COSY experiment. IR spectra of nujol mulls were recorded on an Infralum FT-801 Fourier spectrometer. The LC/MS spectra were obtained with a system which included an Agilent 1100 series liquid chromatograph and an Agilent Technologies LC/MSD VL mass spectrometer (electrospray injection, APCI), ELSD Sedex 75 detector. Butyraldehyde (2), propiolic acid (3), and the isonitrile 4 were commercial products. The aldehyde 2 was distilled at normal pressure under argon before use in the reaction, the other reagents were used without additional purification.

Reaction of N-ethylpyrazinocarbazole (IIIa) with acetylene derivatives (IV) in MeCN affords the title diazocinocarbazoles (V), which are representatives of a previously unknown heterocyclic system.

Reaction of tetrahydropyridopyrimidinones with activated alkynes in MeOH affords pyrimidoazocine and/or products of the pyridine ring opening, i.e.

N-Alkyl substituted tetrahydropyrrolo[3,2-c]pyridines have been obtained by alkylation of 4,5,6,7-tetrahydro-4,-5, 7-trimethylpyrrolo[3,2-c]pyridine and its 2-formyl derivative chloroalkyldimethylamines, acrylonitrile, methyl acetylenedicarboxylate and dichloroethane. 2-Formyl substituted tetrahydropyrrolo[3,2-c]pyridine has been reduced with sodium borohydride and condensed with monoethanolamine and hydroxylamine. The stereochemistry of the products has been studied by 1H NMR spectroscopy.

It has previously been shown that 5-o-chlorobenzyltetrahydrothieno[3,2-c]pyridines react with alkynes only in alcohols to form the products of cleavage of the tetrahydropyridine ring and involving molecules of the solvent and the products of debenzylation (N-vinyltetrahydrothienopyridines) [1]. 2-Trifluoroacetamidotetrahydrothieno[2,3-c]pyridines react readily with alkynes both in methanol and in acetonitrile to give a high yield of tetrahydrothieno[3,2-d]azocines [2]. 2-Acetamido-substituted thienopyridines react with alkynes in acetonitrile at 20oC to give modest yields (30-59%) of the thienoazocines. There occur in methanol simul-taneous processes of expansion and cleavage of the tetrahydropyridine fragment to form a mixture of the acetamido-substituted tetrahydrothieno[3,2-d]azocines and 2-acetamido-3-ethoxycarbonyl-4-(N-vinyl-N-R)aminoethyl-5-methoxymethylthiophenes [2]. Continuing our study of the dependence of the transformation of tetrahydrothienopyridines with activated alkynes we have shown, for the first time, that the tetrahydrobenzothieno[2,3-c]pyridines 1, 2 react with acetylene dicarboxylic ester (ADCE) in acetonitrile to form the spiro[benzothiophene-3,4'-pyridines] 3, 4 in 20-35% yields.

It has been shown that the most efficient catalysts for the synthesis of 4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine from 1,2,5-trimethylpyridin-4-one and acetylene under Trofimov conditions are rubidium and potassium hydroxides. Use of Triton B or a mixture of trimethylbenzylammonium chloride with rubidium hydroxide as catalyst gives O-alkylated oxime. Their configurations and conformations were established through separation of the individual isomers of 1-vinyl-4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines. Acetyl nitrate nitration of the cis isomer of this compound gave the 2- and 3-nitro derivatives. Similar nitration of 4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine gave the 2-nitro-7-hydroxy derivative.

Isomeric [with respect to the fusion of the piperidine and pyrrolidine rings, as well as with respect to the mutual orientation of the substituents attached to the C(2) and C(3a) carbon atoms] 3a, 7-dimethyl-4,6-diphenyl2-ethynyl-7a-hydroxyperhydropyrrolo[3,2-c]pyridines were isolated for the first time in the reaction of 3,5-dimethyl-2,6-diphenyl-4-piperidinone oxime with acetylene under the conditions of the Trofimov reaction under pressure. It was established that, in solutions, the isomers of this compound with an axial-equatorial fusion of the rings exist in the form of ring—chain tautomers.

It has been shown that the most efficient catalysts for the synthesis of 4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine from 1,2,5-trimethylpyridin-4-one and acetylene under Trofimov conditions are rubidium and potassium hydroxides. Use of Triton B or a mixture of trimethylbenzylammonium chloride with rubidium hydroxide as catalyst gives O-alkylated oxime. Their configurations and conformations were established through separation of the individual isomers of 1-vinyl-4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines. Acetyl nitrate nitration of the cis isomer of this compound gave the 2- and 3-nitro derivatives. Similar nitration of 4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine gave the 2-nitro-7-hydroxy derivative.

The transformations of 1-substituted tetrahydro-β-carbolines by the action of activated alkynes were studied. The action of dimethyl acetylenedicarboxylate in methanol gives products of the opening of the tetrahydropyridine fragment, namely, 2-methoxyalkylindoles. The action of ethyl propiolate in ethanol and of tosylacetylene in methanol gives mixtures of azocino[5,4-b]indoles and 2-alkoxyindoles. The action of ethyl propiolate in acetonitrile gives azocinoindoles.

2-Trifluoroacetyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines reacted with ethyl propynoate in acetonitrile and methanol to give ethyl 2-trifluoroaceyl-4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocine-5-carboxylates. The reactions of 2-trifluoroacetyl-1-vinyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines with ethyl propynoate in alcohols were accompanied by cleavage of the tetrahydropyridine fragment with formation of alkyl 3-{benzyl[2-(3-alkoxy-5-trifluoroacetyl-1-vinyl-1H-pyrrol-2-yl)ethyl]amino}acrylates.

The reactions of NH- and N-vinyl-4,5,7-trimethyl-4,5,6,7-tetrahydropyrrolo-[3,2-c]pyridines and their 2-substituted derivatives with acetic and trifluoroacetic anhydrides have been studied. Trifluoroacetylation of tetrahydropyrrolo-[3,2-c]pyridines occurs at the α-position of the pyrrole ring, whereas cleavage of the tetrahydropyridine ring with formation of 3-vinylpyrroles occurs with acetic anhydride. 2-Acetyl-4,5,7-trimethyl-1-vinyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine was synthesized by the Vilsmeier-Haack reaction.

2-([2,2]-5-Paracyclophanyl)pyrrole has been synthesized and nitration and formylation of it have been effected. The 1-β-cyanoethyl derivative and 2-formyl-5-paracyclophanyl-3H-pyrrolizine have been obtained from 5-formyl-2-([2,2]-5-paracyclophanyl)pyrrole by the action of acrylonitrile and acrolein respectively under Michael reaction conditions.

Hydrogenated γ-carbolines underwent tandem piperidine ring cleavage on treatment with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate (EP) in the presence of alcohols, producing 3-alkoxymethyl-substituted indoles in high yields. These compounds were cyclized to tetrahydroazocino[4,5-b]indoles in the presence of AlCl3. Hydrogenated β-carbolines produced tetrahydroazocino[5,4-b]indoles directly upon treatment with EP in ethanol. The resulting azocinoindole derivatives were subjected to a preliminary evaluation of their in vitro acetylcholinesterase (AChE) inhibitory activities. Most of them were found to inhibit AChE with IC50 values in the micromolar range, compound 17 being the most potent (IC50 = 8.7 μM). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)