Synthesis of indole

Experiment. Benzene from Phenylhydrazine.—Allow 5 g. of phenylhydrazine, dissolved in a mixture of 5 c.c. of glacial acetic acid and 10 c.c. of water, to run slowly into an ordinary distilling flask in which a solution of 25 g. of copper sulphate in 75 c.c. of water is heated to the boiling point. A downward condenser is attached to the flask. A vigorous evolution of nitrogen takes place and the benzene at once begins to distil with the steam. Collect and purify (as described on p. 286). Yield 2-3 g. 

Like hydrazobenzene, phenylhydrazine decomposes when overheated one molecule hydrogenates a second. 

As in the case of hydrazobenzene, the decomposition is catalytically accelerated by finely divided platinum. 

Test the behaviour of phenylhydrazine towards Fehling s solution and towards ammoniacal silver solution. 

If sodium nitrite solution is run drop by drop into an aqueous solution of a phenylhydrazine salt the yellow, poisonous a-nitrosophenyl-hydrazine is formed it can be converted, with elimination of water, into phenyl azide. 

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There are a number of other sources of information available about the synthesis of indoles. The most comprehensive entree to the older literature is through Volume 25, Parts I-IIl, of The Chemistry of Heterocyclic Compounds, which were published between 1972 and 1979[23]. Work to the early 1980s is reviewed in Comprehensive Heterocyclic Chemistry[24 and a second edition is forthcoming[25]. Other reviews emphasizing recent developments are also availablc[26-28]. 

A two-step synthesis of indoles from o-nitrobenzaldehydes proceeds by condensation with nitromcthanc followed by reductive cyclization. Like the Leim-gruber Batcho method, the principal application of the reaction is to indoles with only carbocyclic substituents. The forniation of the o,p-dinitrostyrenes is usually done under classical Henry condensation conditions but KF/18-crown-6 in propanol was found to be an advantageous reaction medium for acetoxy-substituted compounds[1]. The o,p-dinitrostyrenes can also be obtained by nitration of p-nitrostyrenes[2]. 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

Phenylhydrazine has been used in the synthesis of indole derivatives. The hydrazones of aldehydes and ketones contain-... 

In 1971, Batcho and Leimgruber introduced a new method for the synthesis of indoles. For example, condensation of o-nitrotoluene (5) with N,N-dimethylformamide dimethyl acetal (6) (DMFDMA) was followed by reduction of the rrans-P-dimethylamino-2-nitrostyrene (7) which resulted to provide the indole (8). ... 

In 1974, Gassman et al. reported a general method for the synthesis of indoles. For example, aniline 5 was reacted sequentially with r-BuOCl, methylthio-2-propanone 6 and triethylamine to yield methylthioindole 7 in 69% yield. The Raney-nickel mediated desulfurization of 7 then provided 2-methylindole 8 in 79% yield. The scope and mechanism of the process were discussed in the same report by Gassman and coworkers as well. 

Anisole and mixtures of diethyl ether with aromatic hydrocarbons have both been widely employed as solvents for these reactions. Ethers other than diethyl ether and anisole have also been successfully used (cf. refs. 14-17). Hcxamethylphosphorotriamide has recently been used as a solvent for indole Grignard reactions. Young and Mizianty have recently described the use of an aromatic magnesium halide (phenylmagnesium bromide) for the synthesis of indole magnesium bromide. 

The combination of silyl enol ethers and fluoride ion provides more reactive anions to give alkylated nitre compounds in good yields after oxidation v/ith DDQ, as shovm in Eq. 9.22. This process provides a new method for synthesis of indoles and oxyindoles fsee Chapter 10, Symhesis of Hatarocydic Compoioids). 

The2-aminophenethyl alcohols resulting from condensation of orr/ici-nitrotoliienes are good precursors for preparation of indoles. Watanabe and co workers have developed ruthenium-catalyzed dehydrogenadveiV-heterocyclizadon for synthesis of indoles and other hereto cycles from 2-aminophenethyl alcohols or 2-nitrophenylethyl alcohols fEq. 10.52. The oxidadve cycli-zadon of 2-aminophenethyl alcohols are also catalyzed by Pd-based catalysts. ... 

The nonaromatic lactones from cis-13, and trcyclohexaneacetic acid14 were important intermediates in the synthesis of indole alkaloids. 

Fig. 26 Solid-phase synthesis of indol-2-ones by microwave-assisted radical cyclization. Reagents and conditions a NaH, DMF b BusSnH, AIBN, DMF, MW 170 °C, 45 min, sealed vessel c 10% TFA in CH2CI2. R = H, F, Me, OCF3 R = Phe, 3-OMe - Phe, 4-Me - Phe, 3,4-0CH20-Ph, (CH2)4, diMe R" = H, Me R " = H, Me...

Thus far, we have discovered and demonstrated a new and effident method for the synthesis of indoles from various carbonyl compounds. This, in conjunction with the use of alkyries in the palladium-catalyzed indolization, widens the spectrum of indoles that can be prepared by these means. The simple procedure, mild reaction conditions, and ready availability of the starting materials render these methods valuable additions to indole chemistry. We next extended this method to the synthesis of the indole core of a PGD2 receptor antagonist, laropiprant 3. 

Scheme 2.123. Synthesis of indols via a domino carbolithiation/addition/cyclization process.

In continuation of the aforementioned reaction, Hiroya and coworkers used cop-per(II) acetate for the synthesis of indoles 2-943 in reasonable yields from the corresponding ethynylanilines 2-941 by a domino intermolecular Michael addition/cop-per-assisted nucleophilic tosylate displacement reaction via 2-942 (Scheme 2.211) [482],... 

The sequence could even be prolonged by including a Pummerer reaction. Thus, treatment of 4-103 with trifluoroacetic acid (TFA) gave the furan 4-104, which underwent a cycloaddition to furnish 4-105 the erythryna skeleton 4-109 was obtained after subsequent addition of a Lewis acid such as BF3- Et20 (Scheme 4.23) [33]. It can be assumed that 4-106, 4-107 and 4-108 act as intermediates. In a more recent example, these authors also used the procedure for the synthesis of indole alkaloids of the Aspidosperma type [34]. 

Yamazaki, Kondo and coworkers [78] reported on a combination of a Heck reaction and an animation on solid phase for the synthesis of indole carboxylate 6/1-148, employing an acetylated immobilized enamide 6/1-145 and a bifunctionalized... 

Pal and coworkers described a Pd°-catalyzed water-based synthesis of indoles 6/1-224 using iodoanilines as 6/1-222 and alkynes 6/1-223 in up to 89% yield (Scheme 6/1.57) [112],... 

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