Halo indoles

Halo-, and even more so, 2-halo-indoles are unstable and mnst be utilised as soon as they are prepared A -acyl- or A -sulfonyl-haloindoles are much more stable. A variety of methods are available for the p-halogenation of indoles bromine or iodine (the latter with potassium hydroxide) in dimethylformamide give very high yields pyridinium tribromide works efficiently iodination and chlorination tend to... 

Reaction of 3-substituted indoles with halogens can be more complex initial 3-halogenation occurs generating a 3-halo-3//-indole, ° but the actual products obtained then depend upon the reaction conditions, solvent etc. Thus, nucleophiles can add at C-2 in the intermediate 3-halo-3//-indoles when, after loss of hydrogen halide, a 2-substituted indole is obtained as final product, for example in aqueous solvents, water addition produces oxindoles (20.13.1) comparable methanol addition gives 2-methoxyindoles. 2-Bromination of 3-substituted indoles can be carried ont nsing A -bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodo-indoles can be prepared very efficiently via a-lithiation (20.5.1). 2-Halo-indoles are also available from the reaction of oxindoles with phosphoryl halides. Some 2,3-diiodo-indoles can be obtained by iodination of the indol-2-ylcarboxyfic acid. ... 

One of the most convenient iV-protecting gronps in indole a-lithiations is carbon dioxide becanse the iV-protecting gronp is installed in situ and, fnrther, falls off during normal work-up. This technique has been nsed to prepared 2-halo-indoles and to introdnce a variety of substitnents by reaction with appropriate electrophiles - aldehydes, ketones, chloroformates, etc. ... 

NBS reacts with the indole nucleus following the normal pattern of electrophilic substitution attack at the 3-position is favored. When this position is blocked substitution occurs at the 2-position. Indole and 3-alkylated indoles exposed to one mole of NBS under anhydrous conditions yield 3-bromoindole and 2-bromo-3-alkylindoles respectively 175,394). By contrast, halogenation in hydroxylic solvents often leads directly to oxindoles and both 2- and 3-halo-indoles readily form... 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

A pseudo 1,2 cycloaddition (actually a 1,3 cycloaddition, but may be considered a 1,2 type if a three-membered ring is considered analogous to an alkene) is observed when the pyrrolidine enamine of cyclohexanone is allowed to react with N-carbethoxyaziridine (129) to produce octahydro-indole 130 91). Octahydroindoles and pyrrolidines can also be produced through the intramolecular alkylation of the enamines of certain halo-ketourethanes 176a). 

The application of Heck cyclizations to the synthesis of indoles, indolines, and oxindoles was discovered independently by Mori-Ban s [296-298], and Heck s groups [299]. These investigators found that Pd can effect the cyclization of o-halo-lV-allylanilines to indoles under Heck conditions [300], The cyclization of o-halo-/V-allylanilines to indojes is a general and efficient methodology, especially with the Larock improvements where he cyclized o-halo-W-allylanilines and o-halo-N-acryloylanilides into indoles and oxindoles [301]. For example, the conversion of 279 to 280 can be performed at lower temperature, shorter reaction time, and with less catalyst to give 3-methylindole (280) in 97% yield. Larock s improved conditions, which have been widely adopted, are catalytic (2%) Pd(OAc)2, n-Bu4NCl, DMF, base (usually... 

Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole. 

Odle, R. Blevins, B. Ratcliff, M. Hegedus, L. S. Conversion of 2-Halo-V-allylanilines to Indoles via Palladium(O) Oxidative Addition-Insertion Reactions, J. Org. Chem. 1980,45, 2709-2710. 

The n.m.r. spectra of several 5,6-dihydroxyindoles (and their diacetyl derivatives) obtained by reduction of different non-halo-genated aminochromes were compared with those obtained from the appropriate 5,6-dihydroxy-(or 5,6-diacetoxy)-iodoindoles produced by reduction of the corresponding iodoaminochromes. The n.m.r. data clearly demonstrated the presence of a- and /3-protons in the indole nuclei (except in the case of the products derived from 2-methylnoradrenochrome and the corresponding iodoaminochrome,... 

Lithiation can also be induced in the conventional way from halo compounds, for example, the sodium salt of 5-bromoindole can be converted to the 5-lithio derivative by treatment with t-butyllithium, and in turn leads to various 5-substituted indoles (92H(34)1169). 

A recent procedure which utilizes the pivaloyl derivative of o-bromoaniline as one of the fragments is also a type llac approach. The compound is converted to its dilithio derivative at -78 °C. Reaction with a-halo ketones then affords indole hydrates by N-alkylation and reaction of the o-lithiated position with the carbonyl group dehydration subsequently yields indoles (equation 108) (81TL1475). The (V-trifluoroacetyl and N-t-butoxycarbonyl derivatives of o-bromoaniline exhibit similar reactivity. 

Direct alkylation of indoles under neutral conditions has been observed for especially reactive alkyl halides. 3-Methylbutenyl bromide gives the 3-substituted indole in acetic acid-sodium acetate at room temperature (equation 170) (69TL2485). At higher temperature in acidic solution, 1,2-dimethylindole undergoes bisallylation (equation 171) (67CJC2628). a-Halo ketones including bromoacetone, 3-bromo-2-butanone and 2-chlorocyclohexanone can alkylate 2-substituted indoles in aqueous acetic acid, but the acidic conditions used in these reactions would probably be destructive of indole itself (72JOC2010). 

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