Synthesis of pyrido[2,3-b]indoles and pyrimidoindoles via Pd-catalyzed amidation and cyclization

Biologically and pharmaceutically active core structures containing a new class of 4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto-enol tautomerism in 4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques. The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum yields.     

The Ritter reaction in the synthesis of ortho-fused nitrogen-containing heterocycles

The acid-catalysed condensation of a 1,4- and a 1,5-ditertiary diol with various arylated nitriles is shown to provide a simple and novel route to reduced benz[f]indoles, naphth[1,8a,8-fg]indoles, benzo[4,5]cyclohepta[1,2-b]pyrroles, and benzo[g]quinolines.     

Thermolysis of benzannulated enyne-carbodiimides. Application in the synthesis of pyrido[1',2':1,2]pyrimido[4,5-b]indoles and related heteroaromatic compounds

Several derivatives of the pyrido[1',2':1,2]pyrimido[4,5-b]indoles 4 and the pyrazino[1',2':1,2]pyrimido[4,5-b]indoles 14 were synthesized by treatment of the benzannulated enyne-isocyanates 8 with the iminophosphoranes 9 and 13, respectively, for the aza-Wittig reaction followed by thermolysis. The reaction presumably proceeds through an initial formation of the corresponding benzannulated enyne-carbodiimides, such as 10, followed by a formal intramolecular hetero Diels-Alder reaction. Surprisingly, when the iminophosphorane 17 was used for condensation with 8, the expected pyrimido[1',6':1,2]pyrimido[4,5-b]indoles 16 were not obtained. Instead, the isomeric pyrimido[6',1':2,3]pyrimido[4,5-b]indoles 21 were isolated. Presumably, an alternative reaction pathway involving an initial [2 + 2] cycloaddition reaction to form 19 followed by ring opening could lead to 20 and, after an intramolecular radical-radical coupling, 21. Treatment of the urea derivatives 24 with dibromotriphenylphosphorane also produced in situ the benzannulated enyne-carbodiimides 25, which on thermolysis gave the isoquinolino[2',1':1,2]pyrimido[4,5-b]indoles 26. Methylation of 4a, 14a, and 26a with methyl iodide occurred exclusively at the site of the indolo nitrogen. The planar geometry of those novel heteroaromatic compounds, resembling many DNA-binding agents, makes them potential candidates as DNA intercalators.     

The synthesis of novel heteroaryl-fused 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Effective inhibitors of HCV NS5B polymerase

Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused indole ring systems, including: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each molecular class are briefly presented.     

Direct synthesis of fused indoles by gold-catalyzed cascade cyclization of diynes

A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused indoles, such as aryl-annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole derivatives in good to excellent yields, through an intramolecular cascade 5-endo-dig hydroamination followed by a 6- or 7-endo-dig cycloisomerization, without producing theoretical byproduct. Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes and T. rubrum, demonstrating the practical application of the described cascade reaction for drug discovery.     

Visible‐Light Cascade Photooxygenation of Tetrahydrocarbazoles and Cyclohepta[b]indoles: Access to C,N‐Diacyliminium Ions

Tetrahydrocarbazoles and perhydrocyclohepta[b]indoles undergo a catalytic cascade singlet oxygenation in alkaline medium, which leads to chiral tricyclic perhydropyrido‐ and perhydroazepino[1,2‐a]indoles in a single operation. These photooxygenation products are new synthetic equivalents of uncommon C,N‐diacyliminium ions and can be functionalized with the aid of phosphoric acid organocatalysis.     

Ring transformations of heterocyclic compounds. XX Benzo‐fused spiro[cyclohexadiene‐dihydroindoles] by ring transformation of pyrylium salts with anhydrobases of benzo[e]‐ and benzo[g]indolium salts

The diastereoselective synthesis of 6‐aroyl‐3,5‐diarylspiro[cyclohexa‐2,4‐diene‐1,2′2′,3′‐dihydro‐1′H‐benzo[e]indoles] 6 and ‐benzo[g]indoles] 7 from 2,4,6‐triarylpyrylium perchlorates 1 and in situ generated 2‐methylene‐2,3‐dihydro‐1H‐benzo[e]indoles 3 or ‐benzo[g]indoles 5 (anhydrobases of the corresponding 2‐methyl‐1H‐benzo[e]indolium perchlorates 2 and 2‐methyl‐3H‐benzo[g]indolium perchlorates 4 , respectively) in the presence of triethylamine/acetic acid in ethanol by a 2,5‐[C₄+C₂] pyrylium ring transformation is reported. Spectroscopic data of the transformation products and their mode of formation are discussed.     

Synthesis of 1H-[1,2]diazepino[4,5-b]indole derivatives

A synthesis of four 1H-[1,2]diazepino[4,5-b]indole derivatives and some preliminary information about their biological activity are presented. The starting materials were 2-ethoxycarbonylindoles and 2-ethoxy-carbonyl-3-formylindoles, la, b and 2a, b, respectively. 2-Ethoxycarbonyls la, b reacted with 1-dimethylamino-2-nitroethylene and -2-ethoxycarbonyl-3-formylindoles 2a, b in the presence of nitroalkanes (nitromethane or nitroethane) giving 3-(2-nitrovinyl)indoles 3a, b. Reduction of 3a, b yielded β-(2-oxoalkyl)indoles 4. On reaction with an excess of hydrazine hydrate, compounds 4 gave satisfactory yields of 5-oxo-1H-[1,2]diazepino[4,5-b]indoles 5.     

One‐Pot Sequential Propargylation/Cycloisomerization: A Facile [4+2]‐Benzannulation Approach to Carbazoles

A novel one‐pot [4+2]‐benzannulation approach to substituted carbazoles is accomplished by acid‐catalyzed C3‐propargylation of 2‐alkenyl/aryl indoles with 1‐aryl propargylic alcohols, followed by cycloisomerization. A variety of 2‐alkenylated indoles and 2‐aryl/heteroaryl indoles successfully participated in this tandem reaction with 1‐aryl/heteroaryl propargylic alcohols to provide diversely substituted and annulated carbazoles, as well as an aza[5]helicene.     

Carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions in water for the synthesis of 3-substituted indoles

[reaction: see text] The carboxylic acid catalyzed three-component aza-Friedel-Crafts reactions of aldehydes, primary amines, and indoles in water have been developed. The aza-Friedel-Crafts products could be easily transformed to various 3-substituted indoles including biologically active compounds. This system offers a novel efficient method for the synthesis of 3-substituted indoles.     

Chemoselective functionalization of α-carbolines at the C-2, C-3, C-4, and C-6 positions using Suzuki-Miyaura reactions

The synthesis of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles (α-carbolines) by palladium-catalyzed cross-coupling reactions from the corresponding halopyrido[2,3-b]indoles is described. A sequential and a one-pot chemoselective double Suzuki-Miyaura coupling route is presented for the synthesis of symmetrically and unsymmetrically disubstituted pyrido[2,3-b]indoles.     

Synthesis of pyrido[1,2-a]indole malonates and amines through aryne annulation

Pyrido[1,2-a]indoles are known as medicinally and pharmaceutically important compounds, but there is a lack of efficient methods for their synthesis. We report a convenient and efficient route to these privileged structures starting from easily accessible 2-substituted pyridines and aryne precursors. A small library of compounds has been synthesized utilizing the developed method, affording variously substituted pyrido[1,2-a]indoles in moderate to good yields.     

Azacarbazoles

Alkylation of 5H-pyridazino [4, 5-b] indole with halogen compounds or dimethyl sulfate in the presence of alkaline reagents gives 2-alkyl-2H-pyridazino [4, 5-b] indoles. Reduction of the methiodide or chlorobenzylate of 5H-pyridazino [4, 5-b] indole also gives 2-alkyl derivatives. LiAlH₄ reduction of 3-alkyl-3H-pyridazino [4, 5-b] indolones-4 gives 3-alkyl-3H-pyridazino [4, 5-b] indoles.For Part I see [1]. The main results of the research were reported at the Conference on Heterocyclic Rings in Organic Synthesis, Kiev, June 1964.     

Ni(ClO4)(2)-catalysed regio- and diastereoselective [3+2] cycloaddition of indoles and aryl oxiranyl-dicarboxylates/diketones: a facile access to furo[3,4-b]indoles

Ni(ClO(4))(2)·6H(2)O-catalysed regioselective and diastereoselective [3+2]-annulations of aryl oxiranyl-dicarboxylates and indoles via selective C-C bond cleavage of oxirane were revealed. The cycloadditions proceed smoothly with high regio- and diastereoselectivity under mild conditions leading to 1H-furo[3,4-b]indoles in good to excellent yields.     

Synthesis of substituted 3-amino-4-cyano-1-oxo-1,2,5,10-tetrahydroazepino [3,4-b]indoles

The preparation of 3-amino- and 3-dialkylamino-4-cyanoazepino[3,4-fc]indoles bearing substituents on the aromatic nucleus and N¹⁰ is outlined. Starting from suitable substituted ethyl 3-formylindole-2-carboxy-latcs 2 , condensation with malononitrile ( 3 ) and subsequent sodium borohydride-reduction yielded ethyl 3-(2,2-dicyanoethyl)indole-2-carboxylates 5 and 19 , respectively, which were cyclized in boiling alkoxides to 3-alkoxy-4-cyanoazepino[3,4-b]indoles 10,11,20 and 21 . This sequence constitutes a novel and flexible route to functional azepino[3,4-b>]indoles. The aminolysis of 10,11,20 and 21 with different amines and ammonia yielded the title compounds which were screened for their possible biological activity.     

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.     

Preparation of peri-annulated indoles from polynitro compounds

A novel peri-annulated heterocyclic system of 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indole was prepared starting from TNT via 4,6-dinitro-1-tosylindoline as a key intermediate. Base-induced CC bond shift in 1,2-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles affords isomeric 2,11-dihydrobenz[6,7]oxepino[4,3,2-cd]indoles.     

Regioselective unusual formation of spirocyclic 4-{2'-benzo(2',3'-dihydro)furo}- 9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole by 4-exo-trig aryl radical cyclization and rearrangement

4-(2'-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished exclusively the 4-{2'-benzo(2',3'-dihydro)furo}-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles in excellent yield (75-80%) via 4-exo-trig cyclization, opening of the oxetene ring, and 5-endo-trig cyclization.     

Palladium-catalyzed annulative allylic alkylation for regioselective construction of indole-fused medium-sized cyclic ethers

A new palladium-catalyzed annulative allylic alkylation (AAA) reaction of 2-(indol-2-yl)phenols with dual allylic electrophiles such as isobutylene dicarbonate and butene dicarbonate is described, leading to the regioselective synthesis of tetracyclic medium-sized cyclic ethers possessing a bridged aryl-indole scaffold, namely, benzo[2,3]oxocino[4,5-b]indoles and benzo[2,3]oxepino[4,5-b]indoles, in good to excellent yields. This protocol demonstrates a broad substrate scope, good compatibility with substituents and high regioselectivity, providing a catalytic and flexible method for creating bridged aryl-indole skeletons.     

A simple synthesis of 4‐chloro‐5‐hydroxy‐1H‐benzo[g]indoles

The reaction of methyl 2‐(3‐chloro‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)propenoate ( 2a ) with primary amines gave 4‐chloro‐5‐hydroxy‐3‐methoxycarbonyl‐1H‐benzo[g]indoles 5a‐f as major compounds and 3‐methoxycarbonyl‐4,9‐dioxo‐2,3,4,9‐tetrahydro‐1H‐benzo[f]indoles 6a‐d as minor ones. Whereas the reaction of 3‐(3‐chloro‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐3‐buten‐2‐one ( 2b ) with primary amines afforded the corresponding 1H‐benzo[g]indoles 5g‐i as major products and 3‐acetyl‐4,9‐dihydro‐4,9‐dioxo‐1H‐benzo[f]indoles 7g, h as minor products.