Indole Cyclization Research Articles

ChemInform Abstract: Total Synthesis of (.+‐.)‐Deethylibophyllidine: Studies of a Fischer Indolization Route and a Successful Approach via a Pummerer Rearrangement/Thionium Ion‐Mediated Indole Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total Synthesis of (+/-)-Deethylibophyllidine: Studies of a Fischer Indolization Route and a Successful Approach via a Pummerer Rearrangement/Thionium Ion-Mediated Indole Cyclization.

The total synthesis of (+/-)-deethylibophyllidine is described, proceeding in eight steps from 4-(methoxyphenyl)ethylamine in 5% overall yield (Scheme 6). In terms of sequential annulation, the strategy involves the following operations: E --> DE --> ABDE --> ABCDE (Scheme 1). The key steps in the synthesis are the stereoselective formation of octahydroindol-6-ones by acid treatment of dihydroanisole derivatives, the regioselective Fischer indolization to obtain octahydropyrrolo[3,2-c]carbazoles, and the tandem process consisting of Pummerer rearrangement upon a beta-amino sulfoxide and thionium ion cyclization upon a beta-indole position of a 2,3-disubstituted indole to generate the quaternary spiro center. Attempts to effect the construction of the pentacyclic framework by means of Fischer indolization of the octahydropyrrolo[3,2,1-hi]indol-6-one resulted in failure (Scheme 2).

Synthesis and biological evaluation of novel 2,6-diaminobenz[cd]indole inhibitors of thymidylate synthase using the protein structure as a guide.

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.

ChemInform Abstract: Oxidative Radical Cyclization of (ω‐Iodoalkyl)indoles and Pyrroles. Synthesis of (‐)‐Monomorine and Three Diastereomeres.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Preparation of Alkyl-Substituted Indoles in the Benzene Portion. Part 10. Synthesis of 4- and/or 5-Alkylated 1,6,7,8-Tetrahydrocyclopent(g)indoles, Model Compounds for Herbindole and Trikentrin Syntheses.

Synthetic pathways leading to model compounds 25, 27, 33, 20d, 32b, 37, and 42 for the marine alkaloids, herbindoles and trikentrins (1b-i), are presented. p-Toluenesulfonic acid-mediated indole cyclization reactions, 19→20 and 38→39, assisted with thiols such as benzylthiol or thiophenol, are key steps for preparation of the compounds having the 1, 6, 7, 8-tetrahydrocyclopent[g]indole structure. Novel reactions of the phenylsulfone group in 20c and 20e with allyltrimethylsilane in the presence of dichloroethylaluminum as well as with trimethylaluminum, are explained in terms of participation of an intermediary reactive species 29.

Preparation of Alkyl-Substituted Indoles in the Benzene Portion. Part 11. Total Synthesis of (6R,8S)-Herbindole A, (6R,8S)-Herbindole B, (6R,8S)-Herbindole C, (6R,8S)-cis-Trikentrin A, (6R,8S)-cis-Trikentrin B, (6R,8R)-trans-Trikentrin B, and (6R,8R)-iso-trans-Trikentrin B. Determination of the Absolute Structures of Natural Herbindoles and Trikentrins.

The key intermediate, (3R, 5S)-3, 5-dimethyl-1-cyclopentenylmethanol (13) for chiral syntheses of herbindoles and trikentrins, was prepared from the known Dields-Alder adduct 12. Employing pertinent methodologies developed in the previous model study (preceding paper), the title herbindoles 31, 34, and 38 as well as trikentrins 4, 6, 41, and 47 having (6R, 8S)- or (6R, 8R)-absolute configuration of the dimethyl groups on the 1, 6, 7, 8-tetrahydrocyclopent[g]indole moiety were synthesized starting from 13 by way of precursor compounds 24b, 27a, and 27b for the crucial indole cyclization reaction. The following results were also obtained. (i) The proposed chemical structures of three herbindoles were confirmed. (ii) The absolute structures of herbindole A and trans-trikentrin B were established to be 1 and 7 by directly comparing optical properties between synthetic materials and the natural products. (iii) The absolute structures of herbindole B (2) and herbindole C (3) were assumed by analogy with 1. (iv) The absolute structures of cis-trikentrin B (6) and iso-trans-trikentrin B (8) were estimated by a circular dichroism (CD) analysis study. (v) Our previous proposal for the absolute configuration of cis-trikentrin A (4) was further confirmed.

Synthesis of some 5H,12H‐[1]benzoxepino[4,3‐b]indol‐6‐ones. A new heterocyclic ring system

AbstractThe synthesis of the title compounds 5H,12H‐[1]benzoxepino[4,3‐b]indol‐6‐ones 10 was effected by the Fischer indole cyclization of some 2,3‐dihydro‐4‐phenylhydrazono[1]benzoxepin‐5‐ones 9, obtained from the 3,4‐dihydro‐4‐hydroxymethylene[1]benzoxepin‐5(2H)‐ones 7 by the Japp‐Klingemann reaction. The structure of these new heterocyclic compounds was supported by ir, 1H nmr and ms spectral data.

Molecular yardsticks. Rigid probes to define the spatial dimensions of the benzodiazepine receptor binding site.

A series of rigid planar azadiindoles (8a, 8b, and 8d), benzannelated pyridodiindoles (11a, 11b, and 11d), and indolopyridoimidazoles (11c, 20, and 24) were synthesized from 4-oxo-1,2,3,4-tetrahydro-beta-carboline 5 via the Fischer indole cyclization with the appropriate arylhydrazines. These analogues were employed as probes ("molecular yardsticks") to define the spatial dimensions of the lipophilic regions of the benzodiazepine receptor (BzR) binding cleft. Benzannelated indoles 11a-d and indolopyridoimidazoles 20 and 24 were important in establishing an area of negative interaction (S1, see Figure 6, part b) in the binding cleft common to the interactions of both inverse agonists and agonists. Data from this chemical and computer-assisted analysis of the pharmacophore (see Figure 6) indicates that inverse agonists and agonists bind to the same binding region, but the pharmacophoric descriptors required for the two activities are different, in keeping with previous studies with these planar ligands. However, the hydrogen bond donating site H1 and the lipophilic region L1 in the receptor binding site are common interactions experienced by both series of ligands. The low affinities of both indolo[3,2-c]carbazole (3a) and indolo[3,2-b]isoquinoline (3b) for the BzR are consonant with the requirements of a hydrogen bond acceptor interaction at donor site H1 and a hydrogen bond donor interaction at acceptor site A2 for potent inverse agonist activity in the beta-carboline series. The hydrochloride salts of 1-aza- 8a (IC50 10.6 nM), 2-aza- 8b (IC50 51.5 nM), and 4-azadiindole 8d (IC50 11.2 nM) were found to be much more soluble in water than the corresponding salt of the parent diindole 2. Moreover, aza analogues 8a and 8b were shown to be partial inverse agonists with proconvulsant potencies comparable to that of the parent diindole 2.

Total synthesis of (+)-Herbindole A, (+)-herbindole B, and (+)-herbindole C. Determination of the absolute configuration of the natural herbindoles

(6R, 8S)-(+)-Herbindole A ( 3a), 8 ( 3b), and C ( 3c) were synthesized from the chirality-definite Diels-Alder adduct 7 using an acid-induced indole cyclization reaction of 4 to 5, as well as novel reactions of the PhSO 2 group of 24 with Mg in MeOH, Me 3Al, and a combination of allyltrimethylsilane and EtAlCl 2. The absolute structure of natural herbindole A was determined to be 1a, and those of natural herbindoles B and C were assumed to be 1b and 1c.

Synthesis of teleocidins A, B and their congeners. Part 1. An efficient synthesis method of N-(7-Alkyl-4-indolyl)- N-methyl-L-valine esters, essential intermediates for teleocidin synthesis

Details of the synthesis method of N-[7-(3,7-dimethyl-1,6-octadien-3-yl)-4-indolyl]-N-methyl-L-valine esters 19 and 20, essential precursors for the tumor promoters lyngbyatoxin A (= teleocidin A-1) ( 2) and teleocidin A-2 ( 3) are presented. Key reaction steps are i) introduction of the linalyl side chain into 12 to form 18 and ii) successive indole cyclization of 21 by way of thioamide derivatives 22.

The second generation synthesis of a tumor promoter pendolmycin

Total synthesis of a tumor promoter pendolmycin ( 1) was accomplished in the stereospecific manner using a d-serine derivative 7 and an l-valine derivative 16 as chiral sources. Methyl 2-(bromomethyl)benzoate was used for the critical step of the indole cyclization 25 → 26 and 28.

The fischer indole synthesis of 8-methyl-5-substituted-1-oxo-β-carbolines: A remarkable high yield of a [1,2]-methyl migration.

A very unusual high yield of rearranged products ( via methyl migration) has been obtained in the Fischer indole cyclization of the 3-(2,5-dimethyl phenylhydrazone) of 2,3-piperidine dione ( 6b). When a less activated aromatic ring is present in the phenylhydrazone 6, such a behaviour is not observed and cyclization occurs essentially without rearrangement.

ChemInform Abstract: Syntheses of (.+‐.)‐ and (‐)‐cis‐Trikentrin A, (.+‐.)‐ and (‐)‐trans‐Trikentrin A, (.+‐.)‐cis‐Trikentrin B, (.+‐.)‐trans‐Trikentrin B, and (.+‐.)‐iso‐trans‐Trikentrin B.

Abstract Synthesis of the titled indole alkaloids from a marine source was accomplished according to the general scheme in Chart 1. The key steps were preparation of suitably substituted β-hydroxyl carbonyl compounds ( 8b ) from 7b , and the subsequent indole cyclization reaction of 8b to form 9b .

Synthetic approach to pentaleno[2,1-b:5,4-b']diindoles

A combination of the Weiss reaction and the Fischer indole cyclization was employed to prepare the hexahydro-5,11-dihydropentaleno[2,1-b:5,4-b'] diindoles. These diindole perhydropentalenes were converted into a variety of 6,12-disubstituted derivatives; numerous attempts were made to convert these intermediates into bis(indolo-substituted) pentalenes

Syntheses of (±)- and (-)-cis-trikentrin A, (±)- and (-)-trans-trikentrin A, (±)-cis-trikentrin B, (±)-trans-trikentrin B, and (±)-iso-trans-trikentrin B

Synthesis of the titled indole alkaloids from a marine source was accomplished according to the general scheme in Chart 1. The key steps were preparation of suitably substituted β-hydroxyl carbonyl compounds ( 8b) from 7b, and the subsequent indole cyclization reaction of 8b to form 9b.

ChemInform Abstract: Polyaza‐Cavity Shaped Molecules. Part 14. Anellated 2‐(2′‐Pyridyl)indoles, 2,2′‐Biindoles, and Related Systems.

AbstractFischer indole cyclization of the phenylhydrazones (III), derived from the ketones (I), forms the pyridylindoles (IV).

Synthesis of 7,8,9,10‐tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3‐c]quinolines

AbstractA series of structurally novel 7,8,9,10‐tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3‐c,]quinolines, 4a‐c, were synthesized via a facile Fischer indole cyclization from the appropriately substituted hydrazinoquinolines 2a‐c. Acetamides 4a,c were hydrolyzed to 5a,b and further converted to tertiary amines 6a‐c. Potent antihypertensive activity has been observed with a number of the title compounds as well as the intermediate 3a.

Steroidal lactam quinoxalines, lactam indoles, and lactam thiazoles

Steroidal lactams have been reported to possess unusual anticancer activity ( I , 2). On the other hand, steroidal quinoxaline, indole, and thiazole derivatives present biological action (3). I t was of interest to combine these three heterocyclic nuclei to the steroid lactam and to study their biological activity. Extension of Fisher indole cyclization to ketolactam steroids with phenylhydrazine yielded the corresponding indole derivatives of A and D ring, respectively (4-6). By condensation of 16a-bromo-3-aza-A -homo-4aandrosten-4,17-dione ( I I) and 2a-bromo-13a-amino-13,17seco-5a-androstan-l7-oic-13,17-lactam-3-one ( IIa) (7) and the o -phenylenediamine by refluxing xylene according to a similar procedure (8), quinoxalines (I1 I ) and ( I I Ia) were obtained.

Microenvironmental Kinetic Effects within a Lyotropic Smectic Biophase Model: Conformational Restrictions in Fischer Indole Cyclization

The microenvironmental orientation effects, arising from an ordered solvent structure, were studied in a model liquid crystalline biophase for the cyclization of a series of 2‐substituted cyclohexanone phenylhydrazones. The magnitude of such solvent‐induced intramolecular conformationsl constraints was determined from a comparison of the kinetics of the Fischer indole rearrangement in a lyotropic smectic liquid crystal versus those in an isotropic liquid of similar chemical composition but lacking the structured nature of the mesophase. Solutions consisting of 50% (w/w) polyoxyethylene 6 tridecyl ether or 44% (w/v) polyethylene glycol in aqueous buffers comprised the smectic or isotropic media, respectively. The apparent dissociation constants of the conjugate acids of the phenylhydrazones were determined kinetically, as were their partition coefficients between lipid and polar isotropic phases approximating the compositions of the smectic lamellae. Intrinsic first‐order rate constants, corrected for partitioning within the lamellar mesophase, were used to compute the enthalpies and entropies of activation. The somewhat slower intrinsic rates of cyclization and the accompanying less negative entropies of activation generally observed in the liquid crystalline medium, as opposed to the isotropic system, are attributed to the orienting effects of the lamellar lyotropic mesophase.

Fischer indole cyclization of several ortho-substituted phenylhydrazones

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFischer indole cyclization of several ortho-substituted phenylhydrazonesWalter F. Gannon, Joseph D. Benigni, Donald E. Dickson, and Ralph L. MinnisCite this: J. Org. Chem. 1969, 34, 10, 3002–3006Publication Date (Print):October 1, 1969Publication History Published online1 May 2002Published inissue 1 October 1969https://doi.org/10.1021/jo01262a045RIGHTS & PERMISSIONSArticle Views264Altmetric-Citations13LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (653 KB) Get e-Alerts Get e-Alerts