Larisa N. Kulikova

The first synthesis and X-ray crystal structure of tetrahydropyrrolo[2,3-d]azocines

Tetrahydropyrrolo[3,2-c]pyridines (THPP) upon the reaction with DMAD in acetonitrile or DMSO at rt underwent ring expansion, affording tetrahydropyrrolo[2,3-d]azocines; these latter compounds have not previously been reported in the literature. The crystal structure and conformation of these derivatives was established by X-ray crystallography.

Chapter 2 Synthesis of Heteroannulated Azocine Derivatives

Publisher Summary This chapter reviews that azocinoindoles have been investigated extensively due to the host of alkaloids with an azocinoindole fragment in their structure. The existence of six isomeric azocinoindoles, in which an azocine ring is annulated with a pyrrole fragment, is possible. This chapter explores that the first method for the preparation of tetrahydroazocino indoles was reported in 1966. In the succeeding years, this reaction came to be known as the witkop photocyclization. The main reasons for investigating the reactivity of azocinoindoles is connected with the synthesis of pentacyclic indole alkaloids of the Strychnos group. A different approach to the derivation of Strychnos-type pentacyclic alkaloids has been used. Photocyclization of N-chloroacetyl derivative 99 takes place in position 4 of the indole core to form 100.

Cleavage of some annulated tetrahydropyridines under the action of dimethyl acetylene dicarboxylate in protic solvents. New practical route to substituted pyrroles and indoles

Tetrahydropyrrolo[3,2-c]pyridines and tetrahydropyrido[4,3-b]indoles undergo piperidine ring opening under the action of dimethyl acetylene dicarboxylate in alcohols or in aqueous dioxane, providing β-(alk)oxy-substituted pyrroles (indoles) in moderate to high yields.

Investigation on the antiplatelet activity of pyrrolo[3,2‐c]pyridine‐containing compounds

A series of 4,5,6,7‐tetrahydro‐1H‐pyrrolo[3,2‐c]pyridines (THPPs), mostly C(2)‐substituted derivatives, and some 2, 3, 4, 5‐tetrahydro‐1H‐pyrido[4, 3‐b]indoles (THPIs) were synthesized and tested in‐vitro for their ability to inhibit aggregation of human platelet‐rich plasma (PRP) induced by adenosine 5′‐diphosphate (ADP) and adrenaline (epinephrine). 5‐Benzyl THPP (3), 2‐(benzylamino)methyl THPP (5f) and 2‐ethyl THPI (6) moderately and dose‐dependently inhibited platelet aggregation induced by adrenaline and, to a lesser extent, by ADP. These compounds inhibited the second phase of the PRP aggregation triggered by adrenaline, which largely depends upon thromboxane A2 production and ADP release. In the adrenaline‐stimulated aggregation, the THPI derivative 6 was found to be nearly equipotent with aspirin, their IC50 values (concentration effecting 50% inhibition of aggregation) being 90 and 60 μM, respectively. A relation between activity and calculated octanol‐water partition coefficient suggested that a log P value around 2.5 should be the optimal lipophilicity value for the activity of THPP‐containing compounds.

Transformations of tetrahydro-1,4-benzoxazepines and tetrahydro-1,4-benzothiazepines under the action of alkynes. First example of the synthesis of tetrahydro-1,4-benzothiazonine-6-carboxylate

It was shown that 2,3,4,5-tetrahydro-1,4-benzoxazepines were cleaved at the N–C(5) bond under the action of activated alkynes in methanol, forming o-(methoxyethyl)- and o-(methoxybenzyl)-phenyl(aminoethyl) ethers. The cleavage rate depended on the electronic effects of the substituents at the C-5 atom. Thiazepine ring expansion in tetrahydro-1,4-benzothiazepine was achieved for the first time via reaction with methyl propiolate to give a benzothiazonine.

The first synthesis of 6-(phenylethynyl)-substituted tetrahydroazocino[5,4-b]indoles

The reaction of 2-methyl-1-(phenylethynyl)-2,3,4,9-tetrahydro-1Н-β-carboline with activated alkynes in acetonitrile led to the formation of 1-vinyl-substituted β-carbolines and condensed azocines.

Transformations of tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-ones in the presence of alkynes bearing electron-withdrawing substituents

Tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines in the presence of activated alkynes were transformed into mixtures of pyrimido[5′,4′:4,5]thieno[3,2-d]azocines and spiro[pyridine-4,5′-thieno[2,3-d]pyrimidines].

Tandem cleavage of 2,3,5-trimethyl 7-trifluoroacetyl-1,2,3,4-tetrahydro-pyrrolo[1,2-c]pyrimidine by activated alkynes, caused by Michael addition of a tertiary nitrogen atom to a triple bond

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.

Synthesis of 4-amino-substituted tetrahydropyrimido[4,5-d]azocines

A method for the preparation of 4-amino-substituted tetrahydropyrimido[4,5-d]azocines containing an aromatic pyrimidine fragment has been developed. It was established that tetrahydropyrido[4,3-d]pyri-midines are cleaved by the action of activated alkynes with the formation of 6-vinylpyrimidines.

Synthesis of azecino[5,4-b]indoles and indolo[3,2-e][2]benzazonines via tandem transformation of hydrogenated indoloquinolizines and indolizines

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.