3-formyl indole derivatives

Scheme 13.8 Visible-light-induced synthesis of 3-formyl Indole derivatives.

Formylation of the V-allyl indole derivatives 311 (obtained by allylation of the indole 310) afforded l-allyl-7-formyl-indole 312. Subsequent condensation of 7-formyl indole derivatives 312 with ethyl acetate in presence of sodium ethoxide gave 313 (89S322). Reaction of 312 with N-methylhydroxylamine hydrochloride afforded the cycloadduct, tetracyclic... 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

In 1992, Molina et al. synthesized partial structures of lavendamycin using the aza-Wittig reaction as the main strategy (68) to form a /3-carboline at the 2-position of a quinoline (Scheme 23) (68). The reactions of the iminophosphorane 194, prepared from 3-formyl-l-methyl indole by treatment with ethyl azidoacetate and triphenylphosphine, with the 2-formyl-quinoline derivatives 195 in toluene at 160°C in a sealed tube gave the corresponding quinoline derivatives 196 and 197. Treatment of iminophosphorane 194 with pyruvaldehyde yielded the key j3-carboline intermediate 198, which was reacted alternatively with the 2-aminobenzaldehyde 199 and JV-(0-formylphenyl)triphenyliminophosphorane 200 to obtain the corresponding partial structures of lavendamycin, 201 and 202, respectively. 

Whereas 2-formylthiophene and 3-formyl indole react with diethyl azodicarboxylate to give products arising from radical reactions at their respective formyl groups, 2-formylfuran gives a product derived from an initial 4+2 cycloaddition (Scheme 8) <9719313>. 

The reaction of N-protected 3-formyl and 3-acetylindole with ra-chloroperoxybenzoic acid has been investigated. 1-Benzenesulfonyl-3-formyl and 1-acetyl-3-formyl indoles gave modest yields of 3-indolones via hydrolysis of unstable formate esters. Some of the corresponding 2-hydroxyindol-3-ones were also formed. The 3-acetoxy derivative of 1-benzenesulfonylindole is more stable and was isolated in 80% yield from the oxidation of 3-acetyl-l-benzenesulfonylindole. <94S411>... 

Chloroform added dropwise at room temp, to a stirred mixture of N-methyl-aniline, aq. 50%-NaOH, benzyltriethylammonium chloride, and, optionally, methylene chloride, and stirring continued 1-2 hrs. -> N-formyl-N-methylaniline. Y 76%. F. e. s. J. Grafe, I. Frohlidi, and M. Muhlstadt, Z. Chem. 14, 434 (1974) s. a. M. Makosza and A. Kacprowicz, Rocz. Chem. 49, 1627 (1975) (Eng) C. A. 84, 43265 N-alkylation with alkyl halides, ibid. 49, 1203 (Eng) C. A. 84, 30793 cf. R. Brehme, Synthesis 1976, 113 with tetrabutylammonium hydrogen sulfate as phase transfer catalyst, indole derivs., cf. A. Barco et al., Synthesis 1976, 124. 

Later on, the Marchetti group [40] suggested another indole synthesis starting with the hydroformylation of 2-(5-chloro-2-nitrostyryl)-l,3-dioxolane (Scheme 5.150). With a sufficiently long reaction time, the nitro group was reduced and the resulting amine reacted in an intermolecular maimer with the formyl group under water ehmination to afford the indole derivative. 

A general synthesis of tryptophan involves condensation of 3-formyl-indole with oxazolinones derived from N-acyl-glycine. Recently, Kirby and Varley 225) have used this method to synthesize tryptophan stereoselectively labelled with tritium and deuterium in the p-methylene group. The synthesis employed is depicted in the following scheme (21) to (24) and (25). The hydrogenation step leading to the racemate... 

Tritiated tryptophan has been prepared by catalytic dehalogenation of the 5-bromo-derivative by Birkofer and Hempel 44). Labelling with tritium at the a- 62) and P-carbon 318) of tryptophan has been reported. Kirby and Varley 225) prepared tryptophan stereoselectively labelled with tritium and deuterium at the p-methylene group by using labelled 3-formyl indole as a starting compound (see also Section II.2.). 

Aromatics containing electron releasing groups such as phenols, dim ethyl am in oben 2en e and indole are formylated by 2-ethoxy-l,3-dithiolane in the presence of boron trifluoroetherate, followed by hydrolysis (114). The preformed dithiolanium tetrafluoroborate also undergoes Friedel-Crafts reaction with aromatics such as dim ethyl am in oben 2en e and indole (115), and was used to generate dithiolanium derivatives (formyl precursors) from the enoltrimethylsilyl ether derivatives (116). 

The Reimer-Tiemann reaction has also been used to formylate 2,5-dimethylpyrrole and its iV-methyl derivative and indoles having methyl, methoxyl, and phenyl substituents. Significantly, 3-methylindole gave only 3-chloro-4-methylquinoline. ... 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Alkanoyl-heteroaromaten mit elektronenlieferndem Heterocyclus lassen sich mit Hydriden meist leicht zu Alkyl-heteroaromaten reduzieren. Die Methode wird haupt-sachlich in der Pyrrol- und Indol-Reihe angewendet. Formyl- und Acyl-pyrrole werden analog den entsprechenden Carbonsauren (s.S. 171) und Carbonsaure-estem (s.S. 220) mit Ausnahme der N-alkylierten Derivate bereits mit Lithiumalanat in die Alkyl-pyrrole uberfiihrt9,10 z.B. ... 

Addition of methyllithium to the lactone 1219, followed by reduction with sodium borohydride in refluxing ethanol, afforded, almost quantitatively, ellipticine (228). Reaction of the compound 1219 with the lithio derivative of formaldehyde diethylmercaptal, and reduction with sodium borohydride in refluxing ethanol, led to the mercaptal 1221. Cleavage of the mercaptal 1221 with bis(trifluoroacetoxy) iodobenzene [Phl(OCOCF3)2] in aqueous acetonitrile gave the 11-formyl derivative, which was reduced with sodium cyanoborohydride (NaBHsCN) to 12-hydroxyellipticine (232) (710,711) (Scheme 5.202). The same group also reported the synthesis of further pyiido[4,3-fc]carbazole derivatives by condensation of 2-substituted indoles with 3-acetylpyridine (712). 

Triethyl orthoformate is often used in reactions with enolates and carbanions to form diethyl acetals that on treatment with dilute acid give the corresponding formyl derivatives. However, when indole is heated at 160 C with triethyl orthoformate the locus of reaction is at N-1 rather than at C-3, and 1-(diethoxymethyl)indole is formed (Scheme 7.6). The A -substituent is easily removed by acidic hydrolysis to reform indole. 

If Trp residues are present in the molecule, it is advisable to protect the indole function in order to suppress possible side reactions. For this purpose usually the A "-formyl derivative is used which is removed by rapid base treatment without affecting the disulfide bonds already formed 118 ... 

---