Indole-2-carboxylic acid amides

Indole-3-carboxylic acid amides 23a [21, 22] and esters 23b [23] can be obtained by irradiation in dichloromethane (DCM) of the 3-diazo-4-oxo-3,4-dihydroquino-line 21 in the presence of alkylamines, dialkylamines, arylamines or alcohols (ZH in Scheme 12.7), through a Wolff-type rearrangement involving a carbenoid species leading to the ketene-like intermediate 22 (Scheme 12.7). 

In an extension of earlier work, Buigada et al. have also reported on the reaction of the cyclic phosphite (66) with dimethylacetylene dicarboxylate (58) in the presence of proton sources such as carboxylic acids, amide N-H bonds in succinimide or phthalimide and amine N-H bonds in p UTole or indole. With carboxylic acids (67) a mixture of the ylid (68) and the cyclic phosphorane (69) was obtained and in some instances (e.g. with 2,4,6- trimethylbenzoic and p-methoxybenzoic acids) the ylid and phosphorane were shown to be in equilibrium. With amides as the proton source, ylids were generally formed although with N-methylbenzamide (PhCONHMe)a signal attributed to (70) was observed at = - 52 p.p.m. which had disappeared by the end of the reaction through rearrangement to (71). With amines (e.g. pyrrole) the products were again a mixture of ylid (72) and phosphorane (73) and the entire set of results was rationalised in terms of HSAB theory and the symbiotic effect around phosphorus. 

Fluorinated indoles reveal very similar properties in comparison to their non-fluorinated analogues. However, it should be noted that the chemistry of monofluori-nated indoles (with fluorine atom attached to both 2 and 3 position) is scarcely studied. For example, 3-fluoroindole derivative 19a was debenzylated to give indole carboxylic acid ester 157 quantitatively the latter one was converted into amide 159 by hydrolysis followed by reaction with the corresponding amine in the presence of BOP reagent [9a]. Nitrogen atom in case of 3-fluorosubstituted indole derivatives has usual nucleophilicity and can participate in standard indole reactions, for example reaction with tosyl chloride provided V-sulfonylation product in 61 % yield [15]. 

Biochemical tests are usually performed after pure cultures have been obtained. The standard indole, methyl red, Voges-Proskauer, citrate, and litmus milk tests may be used to show important physiological characteristics. To study the functional diversity of bacteria, the utilization of carbohydrates, amines, amides, carboxylic acids, amino acids, polymers, and other carbon and nitrogen sources can be tested.28 Dilution-based most-probable number (MPN) techniques with phospholipid fatty acids as biomarkers have been employed for studying different bacterial species in lakes.40 The patterns of antibiotic resistance in bacteria isolated from natural waters have been useful for identifying sources of water pollution.34... 

The indole 22 was previously isolated from the sponge Dysidea etheria [110] and has now been obtained from the Antarctic ice bacterium ARK 13-2-437. The lipid phase of Hel45 delivered additionally N-(2-hydroxyethyl)-ll-octadecen-amide and the new natural products 17-methyl-16-octadecenoic acid [95] and indole-3-carboxylic acid thiomethyl ester (23). 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

Reaction of Jt-excessive heterocycles (e.g. thiophene, indole), enol ethers (e.g. dihydropyran) and enol acetates, and carboxylic acids with chlorosulfonyl isocyanate leads in generally excellent yields to A-chlorosulfonylamides. These intermediates are converted into the corresponding nitriles by heating in DMF, although the yields can be somewhat variable. A recent reinvestigation of the N-chlorosulfonylamide to nitrile conversion revealed that treatment of the amides with one equivalent of triethylamine led to formation of the nitriles in excellent yield. Clearly, the mechanisms of the DMF and the EtsN induced transformations are different. 

Mannich Reaction on a Resin-Bound Indole Scaffold (89) (Fig. 18).50 Commercially available indole 5- or 6-carboxylic acid supported on Rink amide resin is suspended in HOAc/l,4-dioxane (1 4). A secondary amine (1.5 equiv.) and formaldehyde (1.5 equiv.) are added. The suspension is shaken for 1.5 h at RT. The resin is then filtered, washed with appropriate solvents, and dried under vacuum to obtain (90). 

Enantioselective additions of a,f)-unsaturated 2-acyl imidazoles, catalyzed by bis(oxazolinyl)pyridine-scandium(III)triflate complex, were used for the asymmetric synthesis of 3-substituted indoles. The complex 114 was one of the most promising catalysts. The choice of acetonitrile as the solvent and the use of 4 A molecular sieves were also found to be advantageous. The 2-acyl imidazole residue in the alkylation products of u,(i-unsaturated 2-acyl imidazoles could be transformed into synthetically useful amides, esters, carboxylic acid, ketones, and aldehydes (Scheme 32) [105]. Moreover, the catalyst 114 produced both the intramolecular indole alkylation and the 2-substituted indoles in good yield and enantioselectivity (Scheme 33) [106]. The complex... 

Scheme IS. 3-Amides and 3-carboxylic acids as DMGs in DoM of indoles for the synthesis of 2,3-substituted indoles.

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