Indole-carboxaldehyde

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]. 

Better results have been obtained using the 3-(2-pyrrolidinylidene)indolenine intermediate 13.3A which can be prepared from indole-3-carboxaldehyde and pyrrolidine[16]. 

Etryptamine (23) is a tryptamine derivative which has been used as an antidepressant. Its synthesis involves the condensation of indole-3-carboxaldehyde (21) with the active methylene group of 1-nitropropane to form the inner nitronium salt of the substituted nitrovinyl indole (22). This then is readily reduced to etryptamine (23)... 

A mixture of 1.44 g. (0.0099 mole) of indole-3-carboxaldehyde,2 7.0 g. (0.053 mole) of diammonium hydrogen phosphate, 30 g. (30 ml., 0.34 mole) of 1-nitropropane, and 10 ml. of glacial acetic acid is refluxed for 12.5 hours. During the reflux period the pale-yellow mixture becomes dark red. The volatile reactants and solvent are removed under reduced pressure, and an excess of water is then added to the dark residue. After a short time, crude indole-3-carbonitrile precipitates rapidly. It is separated by filtration and dried under reduced pressure weight 1.20-1.34 g. (85-95%). Crystallization from acetone-hexane, with decoloriza-tion by activated carbon, yields 0.68-0.89 g. (48-63%) of fairly pure indole-3-carbonitrile, m.p. 179.5-182.5° (Note 1). 

Indole-3-carbonitrile has been prepared by the dehydration of indole-3-carboxaldehyde oxime,8 5 indole-3-glyoxalic acid oxime,58 or indole-3-carboxamide 8 by the action of cyanogen... 

Indole, 1-methyl-, 40, 68 Indole-3-acetic acid, 44, 64 Indoleacetonitrile, 44, 65 Indole-3-carbonitrile, 43, 58 Indole-3-carboxaldehyde, conversion to indole-3-carbonitrile, 43, 58 Indole-2-carboxylic acid, ethyl ESTER, 43, 40... 

In total, 185 substances were found in the wing-sac liquid of male S. bilineata from a Costa Rican population. For a more detailed analysis the relative peak area of thirteen focus compounds was compared (Table 14.1). Of these nine were male-specific substances (indole, indol-3-carboxaldehyde, indole-3-carboxylic acid, 2-aminoacetophenon, anthranilic acid, SHJOH-dipyrrolofl -aT -dJpyrazine-5,10-dione (pyrocoll), indolo[2,l-b]quinazoline-6,12-dione (tryptanthrin), 2,6,10-trimethyl-3-oxo-6,10-dodecadienolide, and a compound C15H24O2 of unknown structure), three were fatty acids (tetradecanoic acid, hexadecanoic acid, and octadecanoic acid), and one a steroid (cholesterol). On average, the cumulative peak area of these substances made up 62.5 20.7% of the whole chromatogram area. 

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. 

Fig. 9.9 Transformation of the phytoalexin brassinin (28) by (i) L. maculans virulent on canola to indole-3-carboxaldehyde (30) and (ii) L. maculans virulent on brown mustard to indolyl-3-methanamine (31)...

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

A solution of 4.35 g indole-3-carboxaldehyde in 17.2 mL nitroethane was treated with 0.77 g ammonium acetate and heated, with occasional swirling, on the steam bath for 2.5 h. The excess reagent was removed under vacuum and the resulting yellow solids washed with H20 and air dried. Trituration under 25 mL dry MeOH, filtration, and air-drying gave 5.22 g (86%) 1-(3-indolyl)-2-nitropropene-1 as a yellow powder with mp 190-192 °C. 

In a sequence that proceeds by tandem directed ortho metalation steps (Scheme 133) the N,N-diethyl isonicotinamide (447a) has been converted into the chemotherapeutic alkaloid ellipticine (589) (Scheme 182) (80JA1457). Thus, in a rapid, one-pot procedure, metalation of 447a followed by condensation with N-protected indole-3-carboxaldehyde derivatives leads to the intermediates 615 which, upon second metalation and aerial oxidation affords the quinones 616 in modest to good yields. Established steps were used to convert 616, R = CH2OMe into ellipticine (589), concluding a route which complements that based on the oxazolino DMG (Scheme 175). 

Indole-3-carboxaldehyde (1) T1(02CCF3)3 (2) CuBr2 4-Bromo 58 L10J... 

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). 

SYNTHESIS To a 50 °C warmed mixture of 60 mL glacial acetic acid and IS mL acetic anhydride, there was added 66 g crystalline ammonium acetate, and stirring continued until solution was complete (20 min). To this there was added a solution of 87 g indole 3-carboxaldehyde (see under a-MT for preparation) and 300 mL nitropropane in 360 mL acetic acid. The mixture was held at reflux temperature for... 

This was made basic with the addition of200 mL 5 N NaOH, which allowed the separation of a yellow solid. This was diluted by the addition of 200 mL hot H2O and, after cooling again, the product was removed by filtration and washed with cold H2O. This can be recrystallized from aqueous DMF to yield, after air drying, 24.5 g (84%) of indole-3-carboxaldehyde as faint orange needles. 

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>. 

When jV-protected indole-3-carboxaldehydes were allowed to react with tosylmethyl isocyanide, 3-(oxazol-5-yl)-indoles were obtained in satisfactory yields and applied to the synthesis of novel indole-based IMPDH inhibitors <02BMCL3305>. In the same context, a modified approach to 2-(JV-aryl)oxazoles employing an iminophosphorane/ isothiocyanate-mediated methodology and its application to the synthesis of the potent IMPDH inhibitor BMS-337197, was reported <020L2091>. 

The indole linker 1.11 (68), easily prepared from aminomethyl PS resin and N-carboxyalkylated indole-3-carboxaldehyde, was used to support amines and to transform them on SP, obtaining, by release with TFA-DCM 1/1 in 30 min, a variety of compounds, including amides, sulfonamides, guanidines, ureas, and carbamates. 

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