Double indolization

By analogy with (37) <84KGS1219> and (38) <83KGS1086>, the )S-positions in dihydrobenzo[2,l-b 3,4-Z> ]dipyrrole (39) are the sites where electrophilic substitutions occur. The benzodipyrrole (39) afforded, upon treatment with dimethylamine hydrochloride and formaldehyde in methanol followed by addition of alkali, the Mannich bis-base (293) (Equation (2)). Benzodipyrrole (39) has been claimed to behave towards electrophilic reagents as a double indole rather than an a,a -bipyrryl <87CC1176>. 

Two indoles were coupled in a synthesis of N-methylarcyriacyanin A 3.12, a slime mould alkaloid (Scheme 3.16). The same natural product could also be synthesized in a shorter sequence using a double indole coupling, although in modest yield (Scheme 3.17). 

In order to rationalize the mechanism of this reaction, firstly a CDC reaction involves the furane derivative, then a radical intermediate 30-A is produced and its addition to the first equiv. of indole leads to a radical species 30-B. A second SET process gives the substituted furane 30-C. Then, the double indolation can be explained by a Friedel-Crafts type allgrlation catalyzed by iron, which plays the role of a Lewis acid (Scheme 4.30). 

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through 3if-indoleninm intermediates. 

In the case of vinylfurans and vinylpyrroles there is the possibility of cycloaddition involving either the cyclic diene system or the diene system including the double bond. 2-Vinylfuran reacts in high yield with maleic anhydride in ether at room temperature to form the adduct involving the exocyclic double bond. Similarly, 2- and 3-vinylpyrroles react with 7T-electron-deficient alkenes and alkynes under relatively mild conditions to give the corresponding tetrahydro- and dihydro-indoles (Scheme 51) (80JOC4515). 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

EtOH). No methoxyl is present. It forms a series of crystalline double chlorides with cadmium, zinc or copper, does not give the thalleioquin reaction, and solutions of its sulphate are not fluorescent. It is diacidie and forms two series of salts of which the nitrate, B. HNOj, crystallises in minute prisms, m.p. 196°, insoluble in water. Cinchonamine hydrochloride, B. HCl, laminae or B. HCl. HjO, cubical crystals, has been suggested for use in the estimation of nitrates. When warmed with strong nitric acid the alkaloid furnishes dinitrocinchonamine. It gives an amorphous, monoacetyl derivative, and forms a methiodide, m.p. 208 , which with silver oxide yields an amorphous methylcinchonamine. Raymond-Hamet found that cinchonamine ves typical indole colour reactions and is probably an indole alkaloid. This seems to have been... 

Read ions of Heterocyclic Enamines with a,p-Unsaturated Compounds Enamines react readily with compounds containing a double bone activated by electronegative groups. Addition of acrolein to 1-methyl-2 ethylidenepyrrolidine, followed by dehydrogenation, leads to 1,7-dimethyl indole (133) (Scheme 9) (215). 

Finally, the Hammett equation has been applied in a few instances to heterocycles of the indole-benzofuran type. The double p method of Eq. (3) was first designed for this type of system and was here applied. When this approach was originally proposed, the only truly hetero-cychc system to which it was apphed was the substituted phthahds 14, and pertinent data on the hydrolysis of these compounds are included in Table IX. 

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

The application of double Fischer indolization has been demonstrated to provide larger amounts of the indolocarbazole 4 from the treatment of the hisphenylhydra-zone 151 with aqueous sulfuric acid (63JCS2504). A considerably more efficient protocol has been devised by Robinson, who obtained 4 in 35% yield on treatment of 1,4-cyclohexanedione bisphenylhydrazone (151) in a mixture of acetic acid and sulfuric acid (63JCS3097). In spite of many recent developments, this is still the method of choice for the preparation of the parent system 4 as the starting materials are cheap and readily available. Cyclization of 151 in ethanol-water containing... 

Just as there are heterocyclic analogs of benzene, there are also many heterocyclic analogs of naphthalene. Among the most common are quinoline, iso-quinoline, indole, and purine. Quinoline, isoquinoline, and purine all contain pyridine-like nitrogens that are part of a double bond and contribute one electron to the aromatic it system. Indole and purine both contain pyrrole-like nitrogens that contribute two - r electrons. 

Tetrahydrocarbazoles have been prepared in one-flask syntheses from indoles, ketones and maleic anhydride, with acid catalysis. The reactions involve a condensation of the indole 121 with the ketone or aldehyde, followed by in situ trapping of the vinylindole 122 with maleic anhydride to afford tetrahydrocarbazoles 123 after double bond isomerization <96T4555>. 

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

Chlorogenic acid forms a 1 1 complex with caffeine, which can be crystallized from aqueous alcohol and yields very little free caffeine on extraction with chloroform. Other compounds with which caffeine will complex in this way include isoeugenol, coumarin, indole-acetic acid, and anthocyanidin. The basis for this selection was the requirement for a substituted aromatic ring and a conjugated double bond in forming such a complex. This kind of complex does modify the physiological effects of caffeine.14 Complex formation will also increase the apparent aqueous solubility of caffeine in the presence of alkali benzoates, cinnamates, citrates, and salicylates.9... 

Imines derived from o-iodoaniline and arenecarboxaldehydes react with internal arylalkynes and catalytic Pd(0) to afford isoindolo[2,l-a]indoles by a process that involves alkyne insertion, addition across the C=N double bond and substitution of the aromatic ring (Scheme 11).12 This process exhibits very... 

In a more recent contribution, O Shea and coworkers described a related process leading to substituted indoles 2-544 and 2-545 by an intermolecular addition of alkyllithium to a styrene double bond and reaction of the formed intermediate 2-543 with an appropriate electrophile (Scheme 2.123) [285]. Using DMF, C-2 unsub-... 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

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