Preparation of Indoles

The intramolecular cyclization of substituted 2-alkenylanilines (57) catalyzed by PdCl2 affords a novel route directly to 1,2,3-trialklylindoles (58), which can be further methylated to Fischer s base salts. The cyclization reaction is complex, and the reaction mixture contains much of the corresponding quinoline compound (59). The composition of the crude product and its yield depend strongly upon the nature of the substituents. The yields of pure indoles are moderate.63 

An unusual indole synthesis consists of reaction between a 1-methyl-3-nitropyridinium salt (60) and the -me thy limine of a dialkyl ketone (61). 

A mixture of three products is obtained, in which the 7-methylated indole (62, R7 = Me) predominates (when methyl ethyl ketone is the ketone used), and predominates greatly when a substituent is present at position 4.64 The reaction mechanism is extremely complex, and the 7-methyl group is claimed to arise from the ethyl group of the ketimine. The synthesis is general, but gives a mixture of polyalkylated indoles in poor yield. Instead of a preformed alkylimine, a simple mixture of a dialkyl ketone and a primary alkylamine can be used. The N atom of the indole is provided by the alkylamine the N atom of the pyridinium salt is eliminated, along with the nitro group.65 67 

Another novel indole synthesis consists of the addition of a nitrile oxide to 1-carbethoxy-2-(or 3-)allylpyrrole, reduction of the resulting isoxazoline (63) to a (3-hydroxyketone, and regiospecific cyclization using zinc or magnesium triflate to a 4-(or 7)-substituted indole (64).68 The overall yields are excellent. 

Yet another novel indole synthesis involves a Diels-Alder addition of a dienophile to a 2- (or 3-) (2-nitrovinyl)pyrrole to give in 46-50% yield indoles (65) in which the dienophile moiety appears in the 4,5- or 6,7-positions, respectively. 69 

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The material in the succeeding chapters describes both the synthesis of the indole ring and means of substituent modification which are especially important in indole chemistry. The first seven chapters describe the preparation of indoles from benzenoid precursors. Chapter 8 describes preparation of indoles from pyrroles by annelation reactions. These syntheses can be categorized by using the concept of bond disconnection to specify the bond(s) formed in the synthesis. The categories are indicated by the number and identity of the bond(s) formed. This classification is given in Scheme 1.1. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Preparation of indole-2-carboxylate esters by the Hemetsberger method... 

A solution of trifluoroacetic acid in toluene was found to be advantageous for cydization of pyruvate hydrazoncs having nitro substituents[4]. p-Toluene-sulfonic acid or Amberlyst-15 in toluene has also been found to give excellent results in preparation of indole-2-carboxylale esters from pyruvate hydra-zoiies[5,6J. Acidic zeolite catalysts have been used with xylene as a solvent to convert phenylhydraziiies and ketones to indoles both in one-flask procedures and in a flow-through reactor[7]. 

Over 100 years after the initial discovery, the Fischer indole synthesis remains the most commonly employed method for the preparation of indoles. ... 

The Gassman process has also been applied to the preparation of indoles which are devoid of a substituent at the 2 position. For example, indolization of aniline 5 with methylthioacetaldehyde 25 or methylthioacetaldehyde dimethyl acetal 26 furnished indole 27 however, a higher yield was obtained when the acetal 26 was employed. ... 

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. ... 

A catch and release synthesis of tetrazoles and cyclic amidines has been reported making use of solid-supported oximes [94]. When bound sulpho-nyloximes, obtained by reacting polymer supported sulfonyl chloride with oximes, were reacted with nucleophiles, tetrazoles or cychc amidines were obtained (Scheme 19). Alternatively, the use of TMS-CN affords imino nitriles, which have been used as intermediates for the preparation of indoles, 1,2,3,4-tetrahydropyridines, quinoxalines and benzimidazoles. 

Tin-mediated-radical cyclization of isonitriles provides a useful strategy for the preparation of indoles (Fukuyama reaction).90 This radical cyclization is used for synthesis of 6-hydroxy-indole-3-acetic acid, which is the aromatic subunit of Nephilatoxin. The requisite isonitriles are prepared from nitroarenes via amines (Eq. 10.66).91... 

Siu J, Baxendale IR, Ley SV (2004) Microwave assisted Leimgruber-Batcho reaction for the preparation of indoles, azaindoles and pyrroylquinolines. Org Biomol Chem 160... 

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

Alkynyl anilines are simple and convenient starting materials for the preparation of indoles. Unprotected, unfunctionalized 2-ethynyl aniline can be cycloisomerized to indole via molybdenum vinylidene-mediated catalysis [15]. Unlike (Et3N)Mo(CO)5,... 

Similar to A-allvlanilincs. their ease of formation makes N-acryloylanilines also an attractive starting material for the preparation of indole derivatives. Acrylates having an cr-substituent give rise to chiral oxindole derivatives, both a common building block of natural products and a frequently employed synthon en route to them.18 By using a chiral palladium-BINAP catalyst Overmann was able to achieve high enantioselectivity in the transformation shown in 3.14.19... 

The most common application of the intramolecular addition of amines onto carbon-carbon triple bonds is the preparation of indoles from o-ethynyl-anilines. The reaction might be carried out in a myriad of ways, of which we only show some typical examples. 

Unlike in the case of the preparation of indoles and benzofuranes, the synthesis of benzothiophenes from o-ethynyl-thiophenols is not known. A close analogy was reported by Larock, where phenylacetylene was coupled with 2-iodothioanisole. Ring closure of the formed o-ethynyl-sulfide was initiated by the addition of different electrophiles. The reaction led to the formation of the benzothiophene core bearing the electrophile in the... 

The usual approach to the preparation of indoles and carbazoles with alkyl substituents on the carbocyclic ring has been to use an aromatic starting material having an appropriate substituent. By applying a satisfactory ring closure method, the alkyl derivatives are then... 

Figure 15.3. Strategies for the preparation of indoles on insoluble supports. Y protective group.

Several new variations of methods for preparation of indoles by Pd-mediated cyclization were reported. Vinylene carbonate was found to be a satisfactory C2-C3 precursor for synthesis of N-acylindolin-2-ols and A-acylindoles from o-iodoacetanilides under Heck conditions. <95H(41)1627>... 

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