Azepino indole

The interesting alkaloids malassezindole A 82 and B 83 from the human pathogenic yeast Malassezia jurfur have been shown to contain an azepino indole skeleton <05HCA1472>. 

The azepino-indole (600 E = COjMe) is produced by thermolysis of methyl 2-azidodiphenylmethane4 -carboxylate, N3C6H4CH2C6H4C02Me. Treatment of the pyrrolo-azepine (601) with benzoylmethylenetriphenyl-phosphorane, PhCOCH=PPh3, yields the bridged compound (602) by successive Michael addition and intramolecular Wittig reaction The imidazo-azepine (604) is formed from (603) by ring-expansion with diazomethane.Addition of dimethyl acetylenedicarboxylate to the cyclo-... 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

Sauleau, P., Martin, M.-T., Tran Huu Dau, M.-E., Youssef, D.T.A., and Bourguet-Kondradd, M.-L. (2006) Hyertiazepine, an azepino-indole-type alkaloid from the Red sea marine sponge Hyrtios erectus. J. Nat. Prod., 69, 1676-1679. 

The corresponding 8/7-azepino[l,2-a]indol-8-one (18) with hydrogen bromide yields the deep-blue, fully conj ugated 8-hydroxyazepino[l, 2- ]indolinium bromide (19) which with Meerwein s reagent yields 8-ethoxyazepinof 1,2-a]indolinium tetrafluoroborate (20).218... 

Thermolysis of the vinyl azide 26 in xylene yields ethyl 8-(mcthoxymcthyl)-l,8-dihydro-benz[2,3]azepino[4,5- >]indole-2-carboxylate (27) by attack of the vinyl nitrene at the 2-phenyl group.83... 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

The results of the methanolic solvolysis study shown in Fig. 7.15 reveals that nucleophilic attack on the cyclopropyl quinone methide by methanol affords the pyrido[1,2-a]indole (73 ppm) and azepino[l,2-a]indole (29ppm) trapping products. Initially, nucleophilic attack on the cyclopropane ring affords the hydroquinone derivatives (see Scheme 7.17) that oxidizes to the quinones upon aerobic workup. 

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

FIGURE 7.16 Trapping of the phosphate of 5 -dGMP by the pyrido [1,2-a] indole quinone methide. The 13C-NMR shows most trapping with ring retention, labeled pyrido, with trace amounts of ring expansion, labeled azepino. ... 

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

A concise method for the synthesis of the 5-substituted azepino[3,4-b]indol-l-ones 37 (eg. R = Bn, R1 = Ph) has been described, based on the Pd-mediated cross coupling reactions of azepino[3,4-b]indol-5-yl trifluoromethanesulfonates eg. 36. These latter compounds were accessed in turn from the corresponding azepino[3,4-i>]indole-l,5-dione <00T4491>. 

Lithiation of a seven-membered azaheterocycle has also been observed with an azepino[5,4,3-cindole derivative (87JOC3319). Mono-... 

A vinylogous indole derivative like 264 reacts with DMAD to give a phenanthridone derivative (267) (Scheme 42). An interesting case of the reaction of an enamine system is observed in the case of the 2H-pyrrolizine (268), which gives a mixture of the azepino[2,l,7-crflpyrrolizine derivative (271) and the 1 1 adduct (275) (Scheme 43) 164,165 reaction of 3-ethoxycarbonylmethylene-3 -pyrrolizine, on the other hand, yields a pyrrolo[2,l,5-croom temperature, the primary adduct (278) is isolated and undergoes thermal cyclization to 281 (Scheme 44). ... 

The intermolecular 1,5-dipolar cycloaddition of tungsten-containing vinylazome-thine ylides with ketene acetals produced azepino[l,2-a]indole derivatives in good... 

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

Indole-fused, or indole-benzo-fused azepinone derivatives have attracted synthetic attention and examples include the preparation of 85 in 84% yield from 84 by intramolecular Heck coupling [01SL848], as well as the preparation of paullone 87 (a CDK inhibitor) by cyclisation of 86 under basic conditions borylation/Suzuki coupling technology was used to access 86 [02JOC1199]. Acid-catalysed cyclisation with polyphosphoric acid was used to prepare the racemic reduced azepino[4,5-6]indoles 92a,b from the precursors 91, which were obtained in turn from CDl-mediated coupling of 88 and 89, followed by reduction of the amide with lithium aluminium hydride [01H1455]. 

PPA/phosphorus pentoxide (P2OS) cyclization of indole 414 provides azepino[3,4-7]indole-l,5-dione 415 in 86% yield as a precursor for azepino[3,4-7]indol-5-yl trifluoromethanesulfonate, the key intermediate in design of 5-substituted azepino[3,4-3]indol-l-ones (Equation 99) <2000T4491>. 

The amine-forming pathway is not the most favoured one. In the case of aliphatic azides, primary zimines are very minor products -. In aromatic azides, where rearrangement is impossible, amine formation is more frequently encountered, sometimes in nearly quantitative yields. The reaction course can be solvent dependent, thus pyrolysis of o-azidodiphenylmethane (SI) in decalin, which is a good hydrogen donor, yielded the abstraction product, o-aminodiphenyl-methane (32), while pyrolysis in 1,2,3-trichlorobenzene yielded exclusively azepino [2,l-a]-ll/f-indole (310) . Some cases of intra-... 

In one case a similar reaction of an aryl azide has been observed. The thermal decomposition of o-azidodiphenylmethane (309) yielded (66%) azepino[2,l-a]-//-indole (310) . 

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