Tricyclic indoles

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

Kraus has reported the synthesis of a tricyclic indole related to the pyrroloiitdnoquinone marine naniral products fScheme 10 9, in which an intramolecnlar S jAr and the reducdve cyclizadon of anitro aldehyde are involved as key steps Related target compounds have been prepared by Jonle and coworkers via a sirrular strategy... 

The method that has been most utilized for the preparation of aromatic carbazoles from noncarbazole precursors is the dehydrogenation of a tricyclic indole, usually a 1,2,3,4-tetrahydrocarbazole. The synthesis of the latter s is outside the scope of this article. The next most used precursors are biphenyls with an ortho nitrogen substituent, and the next, diphenylamines the synthesis of these precursors is also not dealt with in detail here. Finally, a variety of approaches utilizing precursor indoles have been described some of these have been used only once, whereas others have been used often enough that they can be described as general. 

Compounds derived from indole have been extensively investigated as potential psychoactive dmgs. The construction of a tricyclic indole derivative starts by benzyltrimethylammonium hydroxide catalyzed Michael addition of 2-carbethoxy-indole (70-1) to acrylonitrile to give the adduct (70-2). In one of several alternatives... 

Easy Construction of a Tricyclic Indole Related to the Mitomycins... 

As part of a programme of studies on the synthesis of mitomycins, the dione 1 was treated with sodium hydride in dry THF at room temperature. This gave an epimeric mixture of carbinolamines which was highly acid sensitive and which, on treatment with glacial acetic acid at room temperature for 5 minutes, underwent dehydration to the tricyclic indole derivative 2. 

Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2//-pyrroles with moderate to good yields.68 The Pt(II)-or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3-dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4C104-Taniaphos with nearly complete exo- selectivity and enantioselec-tivities up to 85% ee.10 The 3 + 2-cycloaddition of benzol/>]thiophene 1,1-dioxide... 

A series of tricyclic indole alkaloids (physostigmine alkaloids) has been obtained from the cheilostome bryozoan Flustrafoliacea (90). In addition, flustramide B (83) and flustrarine B (84) were isolated from this bryozoan (91). Flustrarine B (84) was prepared from previously known fiustramine B (85) (92) via oxidation with hydrogen peroxide. Five fiustramine derivatives, dihydroflustramine C (86) and its N-oxide (87), fiustramine D (88) and its N-oxide (89), and isoflustramine D (90), were isolated from the methylene chloride fraction of the aqueous methanol extract of a Canadian F. foliacea, and these alkaloids were found to be responsible for the antimicrobial activity of the extract (93). Oxidation of dihydroflustramine C (86) and fiustramine D (88) with m-chloroperbenzoic acid afforded the corresponding A-oxides (87 and 88, respectively). 

In many instances, however, solvolysis of a halocyclopropane is deliberately accomplished in order to install an essential vinyl halide or hindered olefin. In 2000, Murphy and coworkers performed a silver ion-mediated ring expansion of gem-dibromocyclopropane 18 in wet acetone to afford the allylic alcohol 19 in 82% yield (Scheme 4.5).16 Under these conditions the desired cyclononene product was obtained as an inseparable mixture of E- and Z-isomers (7 93). Interestingly, two sets of peaks observed in the1H NMR spectrum indicated that the Z-isomer existed as two separate conformers at room temperature. This intermediate was subsequently used in Murphy s approach to the radical-based preparation of tricyclic indoles. 

The reaction of 1,1-enediamines with 1,4-benzoquinone takes a different course132. Acyclic 1,1-enediamines 149 react with 1,4-benzoquinone in refluxing acetic acid to give after workup two products 150 and 151, resulting from dehydration and deamination, respectively (equation 57). Only benzofurans 152 (21-27%) are isolated in the case of enediamines 8 derived from 4-bromoacetophenone. Cyclic 1,1-enediamine 8 (n = 2, R = H) examined in the reaction leads exclusively to a low yield (9%) of the tricyclic indole 153. 

Palladium-catalyzed cyclization-carboalkoxylation of alkenyl indoles tolerated substitution along the alkenyl chain and at the internal and tfr-terminal olefinic position. In addition to 2-(4-alkenyl)indoles, 2-(3-alkenyl)-, 2-(5-hexenyl)-, 3-(3-butenyl)-, and 3-(4-pentenyl)indoles also underwent efficient palladium-catalyzed cyclization-carboalkoxylation to form the corresponding tricyclic indole derivatives in moderate to good yield with excellent regioselectivity. By employing this procedure, efficient palladium-catalyzed cyclization-carboalkoxylation of 2-(4-pentenyl)indole with ethanol, 1-octanol, 2-propanol, and cyclohexanol was achieved. 

A new synthesis of 3-alkoxyindoles, for example compound 535, has been elaborated involving a Stille-coupling and a reductive annulation as outlined in Scheme 72 <2006T10829>. It has also been shown that related methodology may be useful for preparation of tetrahydrocarbazoles and related tricyclic indole systems <2007T1183>. 

Reductive intramolecular cyclizations constitute a powerful tool for the synthesis of various indoles. The tricyclic indole derivative 118, a key intermediate in a previous synthesis of the alkaloid r//-physostigmine, was prepared by reductive cyclization of the precursor 119, for which an interesting synthetic route was developed <03JOC6133>. 

A number of variations of a tricyclic indole structure were prepared. Compound (8) was comparable in activity to imipramine in reversing ptosis and anticholinergic activity. Compound (9), which has the terminal N-benzyl function, was active in reversing reserpine ptosis and showed no anticholinergic and antihistaminic activity. Compound (10) was significant in that it demonstrated the importance of the location of the side chain, this form being inactive. 11... 

Related Pd-cyclizations have been applied to the synthesis of 3-carboethoxy-2-trifluoromethylindoles [329], 2-carbobenzyloxy-4-hydroxymethyl-3-methylindoles, a unit that is present in the antibiotic nosiheptide, from a 2-(2-iodoanilino) unsaturated ester [330], 2- and 3-indolecarboxylates on solid phase [331], stephacidin A [332], an indolylquinoline KDR kinase inhibitor [333], tricyclic indoles from (2-iodophenyl)alkyl allenes [334], and 3-cyanoindoles [335], A nice vaiiation utilizes the in situ synthesis of 2-iodoanilino enamines and subsequent cyclization as shown for the preparation of indoles 322 [336],... 

Scheme 12 shows the synthesis of isobatzellines A and B, having a sulfur function, by Alvarez and Joule et al. in 1999. After iV-l-methylation of the tricyclic indole 40, the crucial electrophilic substitution by dimethyl disulfide afforded 41. The hydrolysis of 41 followed by CAN oxidation, then replacement of the 7-methoxy group with an amino group, gave isobatzeUine B. By a similar procedure, they also synthesized isobatzelUne A [64]. 

In the 1980s Muratake and Natsume (202) in a number of reports presented a new, interesting approach to the synthesis of substituted indole derivatives that focused on their use as intermediates in the preparation of a variety of clavine alkaloids and mycotoxins. The method elaborated by the authors consisted of constructing the specifically substituted benzene portion of the indole nucleus, with 1-methoxycarbonylpyrrole being the starting material. The functionalized 4-alkylindole thus obtained was transformed to a tricyclic indole derivative which appeared to be a common intermediate for the synthesis of several ergot alkaloids, as exemplified by the synthesis of ( )-dihydrosetoclavine (203-205) (Scheme 42). Recently, the application of this method was extended by the authors (206) to the syntheses of a series of marine alkaloids, the hapalindoles. Most of these alkaloids have a tetracyclic framework made up of 3,4-substituted tryptamine and two isoprene units. 

An interesting intramolecular cycloaddition reaction of indoles with azides has also been reported. Heating solutions of l-(D-azidoalkylindoles 199, which bear an electron-attracting substituent (e.g., CHO, COMe, C02Me, CN) at C-3, has led to the formation of tricyclic indoles 201 as products [87] (Scheme 55). The authors suggest that after the initial 1,3-dipolar cycloaddition, the intermediate triazoline 200 loses nitrogen (perhaps via an aziridine intermediate) to produce the tricyclic products 201. 

Cationic 2-azadienes have also proven to be good diene partners in IDA cycloaddition reactions [17], As an example, the reaction of A-tosyl indole (14) with the A-alkenyl iminium species 13 (generated in situ from the corresponding A -alkoxymethyl enamine derivative 12), followed by deprotonation, produced the tricyclic indole product 15 with excellent stereochemical control (Scheme 5). The choice of tosyl group for indole protection proved crucial, as A-tosyl indole (14) is electron-rich enough to effect the [4-t-2] cycloaddition reaction but lacks the nucleophilicity to add to the resulting cycloadduct intermediate [18]. 

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