Synthetic approaches to activated pyrrolo[3,2,1-hi]indoles: synthesis of 6,8-dimethoxy pyrrolo[3,2,1-hi]indole

6,8-Dimethoxypyrrolo[3,2,1-hi]indole 25 has been formed by the dehydrogenation of the related tetrahydro compound 23, which in turn was formed by reduction of the related isatin 22. Approaches to achieve the cyclisation of N-hydroxyethylindoles, N-dimethylacetamidoindoles, and C7-substituted chloroacetylindoles were unsuccessful.     

Some reactions of 6,8-dimethoxypyrrolo[3,2,1-hi]indoles

Two 6,8-dimethoxypyrrolo[3,2,1-hi]indole carboxylic esters were hydrolyzed and decarboxylated. In an investigation of their electrophilic substitutions, some pyrroloindoles were formylated using the Vilsmeier reagent, and acylated with oxalyl chloride followed by quenching with dimethylamine to give the glyoxylic amides. The electrophilic substitutions occur at the C2 or C4 position (α to the nitrogen atom) rather than the C1 or C5 position (β to the nitrogen atom). Four of the formyl and acyl products were reduced to the corresponding methanol derivatives. These compounds reacted on treatment with a range of acids, but pure products could not be separated from the complex mixtures.     

Synthesis of pyrrolo[3,2,1-hi]indazoles from indole-7-ketoximes

Treatment of the 2,4-dinitrophenyl ethers of some indole-7-ketoximes with base results in a cyclisation reaction to yield pyrrolo[3,2,1-hi]indazoles.     

Synthesis of indolo[2,3-c]quinolines from 3-arylindole-2-ketoximes

Treatment of the 2,4-dinitrophenyl ethers of some 3-arylindole-2-ketoximes with base results in a cyclisation reaction to yield indolo[2,3-c]quinolines.     

One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts alkylation/oxidative coupling reaction of indoles and salicylaldehydes

An I₂-mediated Friedel-Crafts alkylation/oxidative coupling reaction of indoles and salicylaldehydes was developed. With the developed protocol, a series of indolylchromeno[2,3-b]indoles were obtained in good yields (up to 88%) under mild reaction conditions. Two possible reaction mechanisms were tentatively brought forward to account for the formation of the products in light of some control experiments.     

Synthesis of a novel pyrrolo[1,2-c][1.3]benzodiazepine analogue of VPA-985

The seven-step synthesis of a novel structural isomer of VPA-985, N-[3-chloro-4-(5H-pyrrolo[1,2-c][1.3]benzodiazepin-6(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide, is described. (2-Aminophenyl)(1H-pyrrol-2-yl)methanone was converted with thiophosgene into (2-isothiocyanatophenyl)(1H-pyrrol-2-yl)methanone which was cyclised in the presence of base to 5-thioxo-5,6-dihydro-11H-pyrrolo[1,2-c][1.3]benzodiazepin-11-one. The latter underwent desulfurisation with Raney nickel followed by reduction with lithium aluminium hydride in the presence of aluminium trichloride and the resulting 6,11-dihydro-5H-pyrrolo[1,2-c][1.3]-benzodiazepine acylated with 2-chloro-4-nitrobenzoyl chloride to afford 6-(2-chloro-4-nitrobenzoyl)-6,11-dihydro-5H-pyrrolo[1,2-c][1.3]benzodiazepine. The nitro group in the latter compound was reduced with zinc and ammonium chloride to give the corresponding aniline derivative which was then acylated with 2-methyl-5-fluorobenzoyl chloride to provide the final product.     

Mechanisms of cyclisation of indolo oxime ethers. Part 2: Formation of ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indole-5-carboxylates

The cyclisation of a series of ethyl 3′-phenyl-4′,6′-dimethoxyindol-7′-yl-2-(hydroxyimino)acetates was investigated using ¹H NMR spectroscopy to determine the mechanism of formation of the corresponding ethyl 6,8-dimethoxypyrazolo[4,5,1-hi]indole-5-carboxylates. The electronic requirements of the reaction were determined and used, along with the effect of removing the ester functionality, to determine that the reaction proceeds through a concerted intramolecular substitution.     

Synthesis of pyrrolo[3,2-b]benzofurans and pyrrolo[3,2-b]naphthofurans via addition of a silyloxypyrrole to activated quinones

The uncatalyzed reaction of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 with 1,4-quinones bearing an electron withdrawing group at C-2 has been studied. Use of 1,4-quinones 4, 5 bearing an ester group at C-2 provided an efficient synthesis of the respective pyrrolidinobenzofuran adduct 9 or pyrrolidinonaphthofuran adduct 10 whereas use of 1,4-quinones 6, 7 and 8 bearing an acetyl group at C-2 afforded silyloxypyrroles 11, 12 and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of Eu(fod)₃ to the reaction of 2-acetyl-1,4-naphthoquinone 7 and 3-acetyl-5-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 provided a method for obtaining the pyrrolidinonaphthofuran adducts 14 and 15 together with silyloxypyrroles 12 and 13. Oxidative rearrangement of pyrrolidinonaphthofuran adduct 15 to pyrrolidino pyranonaphthoquinone 16 using ceric ammonium nitrate in acetonitrile provided a novel approach for the synthesis of an aza-analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Stereoselective intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes: synthesis of novel annelated pyrrolo[1,2-a]indoles

Novel classes of pyrano-1,3-dioxane-, pyranopyrimidine- and pyranopyrazole-fused pyrrolo[1,2-a]indoles are synthesised via stereoselective intramolecular 1-oxa-1,3-butadiene hetero Diels-Alder reactions.     

Tandem synthesis of functionalized tetrahydro-4aH-benzo[c]isoquino[1,2-t]pyrrolo[1,2-a][1,6]naphthyridines

An effective route to fused hexacyclic derivatives of isoquinoline is described via tandem reaction of isoquinoline, dialkyl acetylenedicarboxylates, and 3-chloropentane-2,4-dione or alkyl 3-chloroacetoacetates.     

Thermal ring contraction of dibenz[b,f]azepin-5-yl radicals: new routes to pyrrolo[3,2,1-jk]carbazoles

Flash vacuum pyrolysis (FVP) of N-allyl- or N-benzyldibenz[b,f]azepine at temperatures from 750 to 950 degrees C gives pyrrolo[3,2,1-jk]carbazole as the major product. The mechanism of the ring contraction involves dibenzazepin-1-yl radical formation, followed by transannular attack and formation of a 2-(indol-1-yl)phenyl radical which cyclizes. The mechanism is supported by independent generation of 2-(indol-1-yl)phenyl radicals by two different methods, and the use of 1-(2-nitrophenyl)indole as a radical generator gives an optimized synthetic route to pyrrolo[3,2,1-jk]carbazole (54% overall yield in two steps from indole). The first substituted pyrrolo[3,2,1-jk]carbazoles have been synthesized by FVP methods and also by reactions of the parent compound with electrophiles, leading to a range of 4-substituted pyrrolocarbazoles.     

Synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles by Curtius reaction in Morita-Baylis-Hillman derivatives

Synthesis of substituted pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles from the Morita-Baylis-Hillman derivatives of acrylates via saponification followed by Curtius reaction is described.     

Divergent synthesis of isoindolo[2,1-a]indole and indolo[1,2-a]indole through copper-catalysed C- and N-arylations

A simple and efficient synthetic route to both isoindolo[2,1-a]indole and its structural isomer indolo[1,2-a]indole skeletons is presented. The key steps of the strategy are based on copper-catalysed C_aryl-C and C_aryl-N bond formation reactions, respectively. Moreover, we report the first copper-mediated intramolecular C-H functionalisation of an indole.     

One-pot construction of isoindolo[2,1-a]quinoline system

Polycyclic compounds bearing isoindolo[2,1-a]quinoline system were easily prepared stereo- and regioselectively, and in one-pot, in a tandem fashion containing Povarov’s multicomponent and condensation reactions. Involving a stepwise route for the aza Diels-Alder reaction within the synthesis was suggested.     

DDQ induced oxidative cyclisations of 1,2-dihydronaptho[2,1-b]furans

The DDQ mediated oxidative cyclisation reactions of a series of dihydronaptho[2,1-b]furans were examined. In the presence of an acid catalyst, the reaction yielded polycyclic ethers and lactones in good to excellent yields.     

Synthesis of pyridino[3′,2′:4,5]pyrrolo[3,2-g]pyrrolo[3,4-e]indolizin-1,3-dione and pyrrolo[3,2-c]pyrazole skeletons

A three step synthesis of an isogranulatimide analogue, in which the imidazole moiety is replaced by a pyrrole unit and the indole heterocycle is replaced by a 7-azaindole moiety is described. Moreover, a novel synthetic pathway to the pyrrolo[3,2-c]pyrazole skeleton is reported.     

A new synthetic method for the 2H-[1,2,3]thiadiazolo[5,4-b]indoles

The systematic study of oxidative cyclization of 3-hydrazono-1,3-dihydroindole-2-thiones has been carried out and a series of new 2H-[1,2,3]thiadiazolo[5,4-b]indoles has been prepared. The elaborated reaction represents an efficient method for the synthesis of fused 1,2,3-thiadiazoles.     

Photochemical synthesis of benz[h]isoquinolines

The synthesis of benz[h]isoquinolines has been achieved using a highly convergent photochemical method. The approach presented provides ready access to biologically active compounds and building blocks not readily available through other methods.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.