Indole-fused products

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Thermolysis of 2-azido cinnamates containing oriho-vinyl, -styryl, -allyl, and cycloalkenyl substituents led generally to mixtures of products, including isoquinolines, azepines, indoles, fused aziridines and cyclopropanes, arising from the decomposition of the intermediate dihydrotri-azole cycloadducts or azirines89. 

Under the influence of UV light, 7V-methylindoles add dimethyl acetylenedicarboxylate, generating cyclobuteno-fused products,and even simple aUcenes add in an apparent 2 -t 2 fashion to A-acyl-indoles, but the mechanism probably involves radical intermediates Other photochemical additions to form N-benzoyl-indolines fused to four-membered rings include addition to the carbonyl group in benzophenone and the double bond in methyl acrylate "... 

Finally, fused indole natural products that have been synthesized include thienodolin (thieno[2,3-f) indole) <04EJO258 and rutaecarpine (indoloquinazoline) <04TL997>. And lastly, in addition to previously mentioned examples, carbazole natural products that have been prepared include hyellazole <04TL5411>, carbazomycin B <04T1513>, and carbazoquinocin C <04OL329>. 

Bennasar extended his research on 2- and 3-indolylacyl radicals to intramolecular cyclizations to yield 2,3-fused indoles [112], Under nomeductive conditions (n-Bu6Sn2, hv), radical 201 underwent a cascade addition-oxidative cyclization sequence with a number of alkene acceptors including dimethyl fumarate (45%), methyl 1-cyclohexenecarboxylate (53%), methyl crotonate (71%), vinyl sulfone (22%), and the a,p-unsaturated lactam ester, 2-oxo-5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid dibenzyl ester (41%) to form cyclopenta[h]indol-3-ones 202. Reaction of 201 with acrylonitrile and methyl acrylate, however, generated cyclo-hepta[h]indoles, the products of bis-addition-cyclization sequences. 

In 2012, Melchiorre et al. reported a novel stereoselective access to chiral frans-fused tetracyclic indole-based products having four stereogenic centres on the basis of a multicatalytic tandem Diels-Alder-benzoin reaction involving JV-Boc protected 3-(2-methyl-indol-3-yl)acrylaldehyde derivative and fra s-l,2-dibenzoylethylene derivative as substrates." As shown in Scheme 2.32, the process was successively induced by chiral diphenylproli-nol trimethylsilyl ether in the presence of bullgr 2,4,6-trimethylbenzoic acid (TMBA) as co-catalyst for the Diels-Alder reaction (trienamine catalysis), and an AT-heterocyclic carbene for the following cross-benzoin condensation... 

Pyrolysis of Meldrum s acid derivatives with a suitably placed hydroxyl group can lead to the formation of ring-fused pyranones, as illustrated by the reactions of 356 (2010S1361) and 358 (20100BC4383) to give the indole- and pyrrohzinone-fused products 357 and 359, respectively (Scheme 70). 

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline IV-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

Another compound 9 with three heterocyclic rings linearly fused (5 5 5) with two heteroatoms has been prepared from 1,1 -carbonyl diindole 297 <2001T5199>. Palladium-mediated coupling of the 2- and 2 -positions of 297 afforded the 1,1 -carbonyl-2,2 -biindolyl 9. 1,1 -Carbonyl diindole 297 was in turn obtained in 41% yield from 1,1 -carbonyldiimidazole 296 by reaction with indole in DMSO at 125 °C. The palladium-catalyzed coupling step afforded the desired product 9 in low yield and required a stoichiometric amount of palladium acetate. Therefore, it was felt prohibitively expensive. Addition of various co-oxidants (Ac20, Mn02, and Cu(OAc)2, etc) to make the reaction catalytic in palladium did not result in any improvement of the yield of 18 (Scheme 53). 

Enamides 163 undergo photochemical conrotatory six-electron electrocyclic reactions to yield the dihydro intermediate 164, which in turn yields the fraws-fused cyclic product 165 (equation 105) by a (l,5)-suprafacial hydrogen shift. Several natural product syntheses like that of benzylisoquinoline and indole type alkaloids can be achieved by this type of photocyclization (equations 106163, 107164, 108165 and 109166). 

Two types of benzothiazepines with fused indole rings 301 and 302 (Figure 4) have been reported as products of a Fischer indole type synthesis (1993EJM659). 

Tryptophane was found by Hopkins and Cole to have the empirical formula CnHijN Oz and to yield large amounts of indole and skatole when heated, and when subjected to putrefaction by bacteria the above-mentioned four products resulted. As under anaerobic conditions a large yield of skatoleacetic acid was obtained, and as skatole was the principal product when it was fused with potash, Hopkins and Cole regarded their substance as skatoleaminoacetic acid rather than the isomeric indoleaminopropionic acid. 

The furo[3,4-3]indoles undergo cycloaddition reactions with NPMI, maleic anhydride, and DMAD in the presence of -TsOH to give the fused carbazoles 125-129, products of the subsequent in situ ring-opening of the oxobridge of the intermediary cycloadducts (Scheme 12) <1996JOC6166>. 

Fused 2-substituted thiazoles are most conveniently synthesized by condensing an a-haloketone with a thiono-amide. Thiazolo[5,4- ]indoles 118 were prepared via the Gunch reaction using bromindoxyl 117 and primary thionoamides of phenylacetic acid, phenylpropionic acid, and cyanoacetic acid affording the products as either... 

The side chain on the fused five-membered ring can, interestingly, form part of a piperidine or piperazine ring. The scheme for preparing the first of these takes advantage of the reactivity of the indole 3 position. The relatively weak base, sodium hydroxide, thus catalyzes the addition of bromoindole (16-1) to the carbonyl group in 4-iV-methylpiperidone (16-2) to afford carbinol (16-3). This product dehydrates in the presence of acid catalytic reduction of the thus-produced olefin then affords the... 

A fused tricyclic ring system based on an indole provides yet another NSAID. Michael addition of the anion from diethyl methylmalonate to cyclohexanone followed by acid hydrolysis of the product gives cyclohexanone (21-3), which incorporates the characteristic profen 2-substituted carboxylic side chain. Sequential reaction with para-chlorophenylhydrazine and a strong acid gives the fused indole... 

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