Aza-Indolyls

Besides indoles 42 this novel reaction can be extended to 7-aza indoles 43 and substituted pyrroles 44 giving rise to the formation of 3-indolyl alkynones 37, 3-(7-aza indolyl) alkynones 45, and 2-pyrrolyl alkynones 46 (Scheme 28). 

With this versatile alkynone synthesis in hand, the application to the pyrimidine synthesis was tested as well. As previously shown, 4-(indol-3-yl)- and4-(7-aza-indol-3-yl)-2-amino pyrimidines 36, which are structurally related to the marine natural products class of meridianins, have displayed a considerable potential as kinase inhibitors [143]. Therefore, upon reacting indolyl (37, X = CH) and 7-aza-indolyl (45, X = N) substituted alkynones or the pyirolyl ynones 46 with an excess of guanidinium hydrochloride and potassium carbonate in 2-methoxy ethanol at 120°C for 12-24 h the heteroaryl substituted 2-amino pyrimidines 47, 48, and 49 were obtained in good to excellent yields (Scheme 29). 

Another total synthesis used the rich chemistry of iminophosphoranes (95AHC159). The /3-(3-indolyl)vinyl iminophosphorane 354 underwent an aza-Wittig/electrocyclic ring closure reaction to give the carboline 355 which was hydrolyzed with lithium hydroxide (Scheme 106). A selective reduction, deprotection, decarboxylation and diazotation followed by ring closure gave Fascaplysine (353) (94TL8851). 

The transition metal-catalyzed domino reactions will undoubtedly have a splendid future which is underlined by the increasing number of publications in this area Steglich et al. presented an approach to arcyriacyanin A via a domino Heck reaction between a bromo(indolyl)maleiimide and 4-bromoindole.1811 The synthesis of 33 -bifurans by Ling et al. was achieved using a novel palladium-catalyzed domino dimerization and subsequent cyclization of acetylenic ketones.1821 Other applications of a combination of Heck reactions for domino processes are the syntheses of aza-heterocydes developed by our group.1831... 

Robison, and Robison were the first to prepare 7-azagramine (3-dimethylaminoniethyl-7-azaindole), finding the following procedure to give optimum yields. The azaindole, 10% excess dimethyl-amine hydrochloride, and one molar equivalent of paraformaldehyde are refluxed together in w-butanol for 30 minutes, followed by evaporation under reduced pressure. The residue is extracted with dilute acid, from which the base is precipitated with sodium carbonate. This procedure has been used with only minor variations on a variety of 7-azaindoles. Williamson obtained 7-azagramine in 99% yield on a 0.2-mole scale, compared to 81%. Other 7-azagramines prepared similarly are l-phenyl-4-methyl (72%), ° l-butyl-4-methyl (64%), 6-chloro-4-methyl (60%), 4-methyl (28%), 2-methyl, and 5-methyl (60%). In the case of the last two 4-methyl compounds, it was found that the best yields were obtained with use of a 3 1 molar ratio of dimethylamine hydrochloride and only a 15-minute reflux period. With the 6-chloro-4-methyl isomer, some (6%) of the bis-(7-aza-3-indolyl)methylene by-product was formed. 

Several (7-aza-3-indolyl)acetonitriles were prepared by various methods including treatment of the azaindole in DMF with sodium hydride followed by chloroacetonitrile. Also, 4-, 5-, 6-, and 7-azaindoles gave the corresponding 2- and 3-indolyl-j3-propionitriles when heated with acrylonitrile. 

As mentioned above, (7-aza-3-indolyl)acetonitrile (129) was reduced catalytically to give 7-azatr3rptamine (131). Other 7-azatryptamines prepared similarly are 1-methyl, 1-benzyl, 2-methyl, and l-(2-aminoethyl). This patent also describes several other 1-, 2-, and 3-(aminoalkyl) derivatives of the four azaindole isomers. The several 4-, 5-, 6-, and 7-azaindolylalkanonitriles were also treated with hydrolylamine to give amidoximes and with hydrogen chloride in chloroform, followed by ammonia to give amidines. ... 

Enantioselective phase-transfer catalysis has also been successfiilly applied to intramolecular aza-Michael reactions, as elegantly exemplified by Bandini and Umani-Ronchi in the reaction of amide tethered indolyl a,p-unsaturated esters to yield 3,4-dihydropyrazino[l,2-a]-indol-l(2/i)-ones [109]. With the general assumption that the annulation reaction proceeds to give products with (5) configuration, a proposal for the transition state of the enantioselective step of the reaction was made by the same group two years later [110]. In this transition step a favorable ir-stacking interaction between the indole and the benzyl-CF3 groups was postulated (Scheme 11.30). 

Later, You et al. investigated relay catalysis consisting of a combination of the same ruthenium catalyst and a closely related chiral BINOL-derived phosphoric acid. As shown in Scheme 7.42, the use of this catalyst system in an asymmetric domino intramolecular Friedel-Crafts-type-aza-Michael reaction allowed a range of chiral fused indoles to be achieved in high yields and moderate to high enantioselectivities from the corresponding enones and indolyl olefins. 

As shown in Scheme 10.29, You and coworkers [50] disclosed the enantioselective aza-Friedel-Crafts reaction of indoles 145 with A-sulfonyl aldimines 146 by a (5)-BINOL-derived phosphoric acid 147. Their reactions in toluene completed within several hours for most of the substrates, providing a series of 3-indolyl methanamine derivatives 148 with up to >99% ee and the opposite absolute configuration from the previously described method. Unfortunately, when... 

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