Indole-3-carboxaldehydes, reactions

Reaction of the TMS-nitro compound 1496 and the indole carboxaldehyde 1497 with a catalytic amount of TBAF led to the desired alcohol 1498, which, on further treatment with TFAA, followed by elimination of the corresponding trifluoroacetate with DBU, afforded the frans-stilbene 1499. Reductive cyclization of 1499 under Cadogan-Sundberg conditions afforded the bisindole 1500. Finally, condensation of 1500 with (dimethylamino)acetaldehyde diethyl acetal led to tjipanazole D (359) in 71% yield (796) (Scheme 5.255). 

The image-forming reaction is based on the fixation of HBr and on further condensation with indole-carboxaldehyde as shown in the scheme. 

A further example for a metal-initiated reaction sequence providing an indole-inspired NP-based complex scaffold was reported by Van der Eycken and coworkers [7]. In this case, a Ugi reaction provided the desired substrate for the sequence of cyclization reactions initiated by the activation of the acetylene with a gold catalyst. The Ugi four-component reaction employed the indole-carboxaldehyde 12, the nitrile 13, amine 14, and carboxyhc acid 15 and led to the formation of the intermediate 16. In the presence of a gold(I) catalyst, instead of the expected indoloazepinone that could be formed via an endo-dig cyclization, a tetracyclic spiroindoline 17 was formed diastereoselectively (Scheme 13.3). 

Tryptophans can also be prepared by reduction of a,(3-dehydrotryptophans. These can be obtained by a classical azlactone type synthesis from derivatives of indole-3-carboxaldehyde. These reactions usually rquire an iV-EW substituent and the yields are modest[15]. 

A versatile and regioselective synthesis of benzo[b]furans, naphthalenes, indoles and benzothiophenes was achieved by reaction of o-alkynylarene and heteroarene carboxaldehyde derivatives in the presence of iodonium ions. The reaction mechanism was also discussed <06CEJ5790>. 

Kraus found that a Pd-catalyzed cyclization is superior to those involving tin-initiated radical cyclizations in the construction of pyrrolo[l,2-a]indoles such as 260 [273]. The bromide corresponding to 259 cyclizes in 48% yield, and lV-(2-bromo-l-cyclohexenecarbonyl)indole-3-carboxaldehyde cyclizes in 60% yield. In contrast, the corresponding radical reactions afford these products in 35-53% yields. Substrate 261 failed to cyclize under these Heck conditions. 

SYNTHESIS To a solution of 1.21 g 5-methoxyindole-3-carboxaldehyde in 15 mL nitroethane there was added 0.3 g anhydrous ammonium acetate, and the mixture was held at steam-bath temperature. Periodic assay by TLC showed the reaction to be complete in 1.5 h. The volatiles were removed under vacuum, and the residue (1.58 g of rusty red crystals) was recrystallized from 15 mL boiling isopropanol. After filtration and air-drying, there was obtained 1.24 g (82%) of 5-methoxy-3-(2-nitropropenyl)indole as dull gold crystals with a melting point of 178-179 °C. The literature value is 182-184 °C. 

Recently, Indian workers (61) reported that 2-naphthylmethylene triphenylarsorane reacted with substituted benzaldehydes to give the corresponding epoxides exclusively, whereas l-bromo-2-naphthylmethylene triphenylarsorane reacted with substituted benzaldehydes to give only olefins. In no case were both olefin and epoxide isolated and in all cases only fram-epoxides or trans-olefins were detected. It has also been reported that reaction of indole-3-carboxaldehyde with semistabilized ar-sonium ylides followed only the trans -carbonyl olefination (91). 

Other substrates suitable for intramolecular reactions were prepared by alkylation of indole-3-carboxaldehyde with 5-chloropentyne followed by a Wittig reaction. The indole-3-acrylate 319 was heated at 300°C and then dehydrogenated to the pyridocarbazole 320 (87JOC4661). A similar cyclization of the indole-3-acrylate 321 afforded the pentacyclic compound 322 (89H1871). 

Indole-3-carboxaldehydes gave the corresponding cyanohydrin silyl ethers 137 upon heating with trimethylsilyl cyanide in acetonitrile or DME. After subsequent oxidation with DDQ, good yields of the carbonyl nitriles 138 were obtained, also providing a mild new route for the parent system 138 (R1 = R2 = H). Further elaboration provided the imidates 139, which participated in a reaction with tryptophan esters to give moderate yields of the marine alkaloids rhopaladins A-D <02T2813>. 

In general, the side chain derivatives of azaindoles undergo reactions analogous to those with indoles. The azagramines and 3-carboxaldehydes are the most useful, leading to many other azalogs of indole derivatives of biological importance. Unfortunately, most of the reactions and compounds involve the more accessible 7-azaindoles, so few comparisons in reactivity differences can be made. 

TMG (1) catalyses one-pot simultaneous reaction of indole-3-carboxaldehyde, a dialkyl- or diphenyl phosphite, and a primary amine to give the corresponding a-aminophosphonates in good yield (60-85%) (Scheme 4.10) [30], It is known as Kabachnik-Fields reaction. 

An annulation of indole-2-carboxaldehyde to 3-carboethoxy-P -carboline was accomplished by using reductive amination to install a side chain with a -acetal functionality. Cyclization occurred on reaction with TiCl,. <94T6299> Methyl 4-methyl-p -carboline-3-carboxylate was prepared by a similar protocol. 

Regioselective thallation (see Section 2.03.4.2) can be used to introduce halogen at C4 or C7 of the indole ring. For example, 5,7 and 6,7-dibromoindole-3-carboxaldehyde can be converted to the corresponding 4-bromo derivative by reaction with T1(02CCF3)3 and CuBrj <89H(29)1663>. 

Indole-5-boronic add has also been used successfully in Suzuki coupling <92H(34)1395). Organothallium derivatives have also been used in Suzuki coupling reactions. The 4-substituted thallation intermediate from indole-3-carboxaldehyde can be coupled with both aryl and vinyl-boronic acids (Equation (122)) <86CPB397i>. 

The kinds of catalysts that have been used for these reactions are similar to those for Z i5-(3-indolyl)methanes [194-201]. In one study, I2 was found generally superior to Lewis acids [202]. This same study found evidence of redistribution in the case of unsymmetrical fr T-indolylmethanes. Specifically, reaction of indole-3-carboxaldehyde with 1-methylindole gave only the frw-(l-methyl-3-indolyl) methane and gave indole as a by-product, suggesting thermodynamic control and enhanced stability of the 1-substituted trimer. 

YamadaF, Fukui Y, Shinmyo D, Somei M (1993) Introduction of nucleophiles or ethyl group to the indole nucleus through nucleophilic substitution and/or radical reactions of 1-methox-yindole-3- and -2-carboxaldehyde. Heterocycles 35 99-104... 

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