10-Ethyl-10// indole, preparation

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20"C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

Synthetic approaches toward mitomycin analogs have prompted the preparations of many benzopyrrolizines.46 49 One involved base-catalyzed 1,4-addition of ethyl indole-2-carboxylates (67) to an acrylic ester, followed by... 

The Vilsmeier reaction is a very efficient method for the preparation of 3-formyl-indoles/° and for other 3-acyl-indoles using tertiary amides of other acids in place of dimethylformamide. Even indoles carrying an electron-withdrawing group at the 2-position, for example ethyl indole-2-carboxylate, undergo smooth Vilsmeier 3-formylation. ... 

Heterocyclic compounds have a wide range of applications and are also extensively distributed in nature. These compounds are also important intermediates in organic synthesis. Several examples involving modification of selectivity in the preparation and reactivity of heterocyclic compounds have been reported. The degradation of ethyl indole-2-carboxylate (44) with 0.2 m NaOH has been reported by Strauss [20]. This reaction leads to the formation of indole (46) if the power input enables a temperature of 255 °C to be achieved or to indol-2-carboxylic acid (45) if the temperature is limited to 200 °C (Scheme 5.14). 

One of the first applications of palladium to indole synthesis was due to Hegedus [12-17], who adapted the known Pd-mediated amination of alkenes [18] to the intramoleclar amination of o-vinyl- or o-allylanilines (Scheme 1, equations 1 and 2). This Wacker-like process involves Pd(II) and can be stoichiometric or catalytic. For an excellent review of the Hegedus indole synthesis, see Johnston [19]. Although it is rarely referred to as such, the Hegedus reaction has found several applications and extensions in indole synthesis (equations 3-5) [20, 21, 23]. The preparation of ethyl indole-2-carboxylates (equation 4) [21] has been improved by McNulty and Keskar [22], and Danheiser synthesized 6- -butyl-l,2-dimethyl-4-hydroxyindole via a... 

N-[2-( 1 -Methoxyindol-3-yl)ethyl]-1 -methoxyindole-3-acetamide (43a), its AT-methyl analog (43b), and Ar-[2-(l-methoxyindol-3-yl)ethyl]indole-3-acet-amide (51) are prepared by the following route (Scheme 8) [23]. 

Anomalous Fischer cyclizations are observed with certain c-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which w ould be formed by (ip50-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacelate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

A 20% excess of ethylmagnesium bromide was prepared from magnesium (6.5 g) in ether (80 ml) by adding ethyl bromide (30 g) in ether (30 ml). Indole (25.8 g) in benzene (50 ml) was then added slowly with stirring and stirring was continued for 20 min after addition was complete. A solution of allyl bromide (29.2 g) in benzene (20 ml) was then added slowly. The mixture was stirred overnight and then diluted with ether and the product isolated and purified by distillation (22.7 g, 70% yield). 

In an attempt to prepare ethyl 3-indolylacetate (225) by the action of ethyl chloroacetate on indole magnesium iodide, only unidentified oily products were obtained under a variety of different experimental conditions. However, when indole magnesium iodide was treated with ethyl -chloropropionate in other, a product, identified as 3-[)3-(l-indolyl)propionyl]indole (226) by its behavior on alkaline hydrolysis and by the number of active hydrogen atoms it contained, was obtained. ... 

Majima et al. prepared ethyl y-(3-indolyl)-y-oxobut3rrate (250) in a similar manner by the condensation of the indole Grignard reagent with -ethoxycarboiiylpropionyl chloride.Methyl y-(3-indolyl)-y-oxobutyrate (251) has been obtained by the action of mcthoxycarbonylpropionyl chloride on indole magnesium iodide in ether. Ballantine et al. prepared methyl y-(5-methoxy-3-... 

That alkylation of the anhydro-bases takes place at the indole nitrogen atom in the jS-carboline series was established conclusively by the identity of the product (429), prepared by treatment of pyr-N-ethyl-jS-carboline anhydro-base (428) with ethyl iodide, with 2,9-diethyl-jS-carbolinium iodide (429) obtained from the reaction of imi-A-ethyl-jS-carboline (430) with ethyl iodide (see Section IV, A, 2). 

A similar synthesis starting with l-(2-nitrobenzyl)pyrrol-2-aldehyde used ethanol-ethyl acetate as solvent (62). Indoles are prepared in excellent yield by hydrogenation of o-nitrobenzyl ketones over Pd-on-C (i). Azaindoles are correspondingly prepared from nitropyridines (97). 

Aroylation of 3-arylhydrazonoisatin with aroyl chlorides gave 1043, which cyclized with ammonium acetate to give [1,2,4]triazino[5,6-A>]indole 1044 (92MI1). Derivatives of 1045 were prepared (92MI1). Cyclocondensation of 5-ethyl-3-hydrazino-5/f[l,2,4]triazino[5,6-b]indole 165 with succinic anhydride in acetic acid gave pyridazinedione derivative 1046 (90MI7) (Scheme 197). 

Heating pyridine-2,3-dicarboxylic acid anhydride with l-ethyl-2-methylindole has been claimed to yield solely the pyridine-2-carboxylic acid, albeit in low yield. This then clearly reacts with Af,A/-diethyl-3-toluidine in acetic anhydride to give the 7-azaphthalide. This is surprising in view of a later report70 in which a one-pot process has been described. Heating pyridine-2,3-dicarboxylic anhydride, prepared in situ, with the indole and subsequent reaction with 3-/V,/V-diethylamino-phenetol under identical conditions to those used in Scheme 8 (but without intermediate isolations) produced a 20 1 mixture of the 4- and 7-azaisomers 16 and 17. It appears that in the previous report the major intermediate isomer, the pyridine-3-carboxylic acid, has not been isolated. 

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