Indoles from highly

For a general, simple high yield indole synthesis from anilines and methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508 (1973). For indoles from N-( /3 -hydroxy-ethyl aniline esters see BSC 2485(1973). For a 2-acyl-indoles in one step from orthoamino-ketones and alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-aminocarbonyls see JOC 38,3622-24(1972). Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het. Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972). 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

Ji N-Y, Li X-M, Ding L-P, Wang B-G (2007) Aristolane Sesquiterpenes and Highly Brominated Indoles from the Marine Red Alga Laurencia similis (Rhodomelaceae). Helv Chim Acta 90 385... 

Indole (2) undergoes electrophilic substitution preferentially at the b(C3)-position whereas pyrrole (1) reacts predominantly at the a(C2)-position [15]. The positional selectivity in these five-membered ring systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from 3 (for indole, 2) and a (for pyrrole, 1) are the more stabilized. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as Lewis acid catalysis, heating, or high pressure [15]. However, calculations of the frontier electron population for indole and pyrrole show that the HOMO of indole exhibits high electron density at the C3 while the HOMO of pyrrole is high at the C2 position [25-28] (Scheme 3). 

The abundance of indole derivatives in natural products results in continuous efforts in the development of flexible and especially regioselective approaches for this architecture [163]. A general approach to the synthesis of indoles from o-alkynylhaloarenes relying on the combination Pd(OAc)2/IPr HC1 has recently been reported [164], High yields after short reaction times were obtained in refluxing toluene (Scheme 18). 

The initial product 508 of AFC reactions of aromatic aldehydes, primary amines, and indoles is highly reactive and further addition of indoles gives undesired adduct 509 (Scheme 104) <2006OL4939>. In addition, aromatic aldehydes are themselves known to react with indoles directly to afford the undesired bisindolyl product 509. After screening catalysts (AcOH, TFA, Sc(DS)3, dodecylbenzenesulfonic acid, carboxylic acids from -C7Hi5 to -Ci3H27), it was revealed that decanoic acid ( -C9Hi9C02H) efficiently promoted the reaction without formation of product 509. 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

There are numerous reports of cyclizations to an aromatic ring that involve reactive centres generated photochemically. The elimination of nitrogen from N-phenyltriazolopyrimidines (168) gives an intermediate that leads on to pyrimidino[4,5 Z)]indoles in high yield. A similar reaction involving a more... 

A semi-systematic study of the hydrolysis of ethyl indole-2-carboxylate in aqueous media at high temperature indicated that decarboxylation of indole-2-carboxylic acid proceeded by an arenium ion mechanism and was inhibited by base. Because base facilitated hydrolysis of the ester, it was possible to obtain either the acid or indole from the ester merely by manipulating the number of equivalents of base present. 

Indoles were high (0.02-1.2), evidence that auto-catalysls occurred In distilled water. In aqueous CRM-1, Indoles underwent sensitized photolysis, possibly through a superoxide or singlet-oxygen Intermediate. The same photoproduct of 3-MI, o-(N-formyl)amlnoacetophenone, was found In both distilled water and In aqueous CRH-1. Carbazole underwent direct photolysis In both distilled water and aqueous CRM-1, Indicating that It has a different photolysis mechanism from that of Indoles In the two systems studied. 

Formal insertions into aromatic C-H bonds often proceed by another mechanism. This is also true in intramolecular cases, and the formation of carbazole from biphen-2-ylnitrene, a weU-studied example, probably occurs by an electrocycHc reaction followed by 1,5-hydrogen shift The high yielding synthesis of indoles from azidocinnamates proceeds similarly by cycHzation of a vinyl nitrene (Scheme 6.32). 

More recently, Dong s group developed a palladium-catalyzed synthesis of indoles from nitroalkenes [43]. This was the first report on transition metal-catalyzed transformation of conjugated nitroalkenes into indoles. Under mild reaction conditions (1 bar carbon monoxide, 110 °C), palladium catalyzes the reductive cyclization of nitroalkenes to form a putative nitrosoalkene intermediate, which then rearranges to provide 3-arylindoles in high yields (Table 9.5). Notably, this novel C-H bond amination takes advantage of carbon monoxide as an inexpensive stoichiometric reductant and produces carbon dioxide as the major byproduct. 

Indoles are highly nucleophilic aromatic compounds, activated by the nitrogen. NaOH Is a strong base, and CHCI3 possesses an acidic hydrogen, since the carbanlon Is stabllsed by electron withdrawal from the adjacent chlorine atoms. 

Ji NY, Li XM, Ding LP, Wang BG (2007) Aristolane sesquiterpenes and highly brominated indoles from the marine red alga Laurencia similis Rhodomelaceae). Helv Chim Acta 90 385-391... 

A more recent example sees the conversion of an aryl ether (9) to an Af-aryl-2-hydroxypropion-amide (10) in high overall yields from the starting materials, ultimately leading to a two-step Smiles-Sonogashira synthesis of indoles from 2,3-dihalophenols [5]. 

Singh, N., and Singh, K. N. (2012). Iodine-catalyzed highly efficient synthesis of 3-alkylated/3-alkenylated indoles from 1,3-dicarbonyl compounds. Synlett, 23, 2116-2120. 

A simple preparation of indoles from anilines is based on a specific o-alkylation of ar. amines with sulfides in the presence of an active chlorine source such as tert-hwtyl hypochlorite . A lactamol has been obtained by double ring closure of a diketone in one operation combining 4 simple steps, all of which occur stereospecifically in high yield in the same medium . Another multiple reaction is the stereospecific rearrangement of an epoxytetrahydrofuranolactone in the course of synthetic studies on tetrodotoxin. A new riboflavin synthesis via its 5-oxide has been reported . 

Another example, synthesis of indoles from anilines, fell somewhat in the middle. Search-time discovery of explicit schemes took 3.6 times longer than standard REACCS or prior registration. Searching for implicit schemes took over 11 times as long to complete, and returned only a few extra answers. The low number of additional implicit schemes could be explained by the high degree of historical interest in this reaction, and therefore the relatively large number of explicit schemes in the literature. 

Indoles from cinnolines. A mixture of 4-phenylcinnoline, amalgamated Zn-wool, acetic acid, and water refluxed 2 hrs. S-phenjdindole. Y 88%.—The reduction of high-melting cinnolines is facilitated by addition of dioxane. 3-Aryl-indoles which are difficult to prepare otherwise, can be obtained by this method. F. e. s. J. M. Bruce, Soc. 1959, 2366. 

An efficient methodology for the synthesis of 2-substituted indoles from N-acetyl O-iodoanilide using [Pd(ll)]/ NaY (obtained by calcination of [Pd(NH3)4]/NaY) was reported by Yum et al. [22]. It requires the use of cesium carbonate as base in the presence of stoichiometric amount of LiCl to achieve reasonably good conversion (Scheme 7). This methodology offers moderate to high isolated yields (40-80%) of product. 

Jones and coworkers described the formation of 7-methyl indoles from ruthenium-catalyzed C(sp )-H bond activation of 2,6-xylylisocyanide in 1986 (Eq. (7.1)) [6]. The catalytic reaction proceeded by using ruthenium(II) complex Ru(dmpe)2H2 or Ru(dmpe)2(2-naphthyl)H as catalyst (20mol%) in CgDg at high temperature (140°C). Further studies indicated that the substrate scope is restricted to 2,6-disubstituted (2,6-dimethyl, 2-ethyl-6-methyl, 2,6-diethyl) isocyanides, since less substituted isocyanides only produced stoichiometric indole N-H oxidative addition adducts with [Ru(dmpe)2]. 

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