Indole derivatives 3- halogenation

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

FADH2 halogenases such as tryptophan 7-halogenase have been shown to catalyze regioselective halogenation of a wide range of indole derivatives and aromatic heterocycles, where a cofactor regeneration system has recently been developed to use only a catalytic amount of cofactors (Scheme 7.13) [52, 53]. 

Halogen-metal exchange has also been used to produce 7-substituted indole derivatives, (Scheme 29) with the potassium salt of 7-bromoindole... 

Chloroindole has been prepared from indole and sulfuryl chloride (66JOC2627) and 3-bromo- and 3-iodo-indole have been obtained by direct halogenation in DMF (82S1096). 2-Methylindole reacts with sodium hypochlorite in carbon tetrachloride to give a 2 1 mixture of 1,3- and 3,3- dichloro derivatives (81JOC2054). 3-Substituted indoles are halogenated to yield 3-haloindolenium ions which react in a variety of ways, as illustrated by the reaction of 3-methylindole with NBS in aqueous acetic acid (Scheme 12). 

Bromo- and -iodoindoles, and the similarly reactive 2- and 3-triflates, " undergo palladium-catalysed couplings as normal aryl halides. Since 2- and 3-haloindoles are unstable it is expedient to employ their A -acyl derivatives. Halogen and triflate on the benzene ring of indoles take part unexceptionally in coupling reactions. 

This reaction was first reported by Mori and Ban in 1976. It is a synthesis of indole derivatives by an intramolecular Heck Reaction of o-halo-fV-aUylanilines catalyzed by a low-valent metal complex and is known as the Mori-Ban indole synthesis. In this reaction, the low-valent metal can be nickel or palladium, but the ortho halogen must be bromine or iodine. Often the o-iodo-fV-allylaniline is more reactive than corresponding o-bromo substrate. In addition, it has been found that the catalyst can be deactivated under the reaction conditions, thus aperiodic provision of fresh catalyst normally gives higher overall yields than that using the same total amount of catalyst at once. ... 

Some indole derivatives also show promising antimicrobial activity. Five out of 24 bisindo-lyhnethane Schtff base derivatives S3mthesized were found to specifically inhibit Salmonella tjfphi, S. paratyphi A and S. paratyphi B, even if the inhibition was moderate at best, when nitro or halogen substituents were introduced [43]. 

Halogen-containing compounds are not only produced by man, but also by Nature [1740-1742], A brominated indole derivative - Tyrian purple dye - was isolated from the mollusc Murex brandaris by the Phoenicians. Since that time, more than 1,000 halogenated natural products of various structural types have been isolated from sources such as bacteria, fungi, algae, higher plants, marine molluscs, insects, and mammals [1743], Whereas fluorinated and iodinated species are rather rare, chloro and bromo derivatives are found more often. The former are predominantly... 

The halogen-substituted indoles are key intermediates for some biologically active compound synthesis via Suzuki-Miyaura cross-coupling reactions. Furthermore, indoles also could be obtained from a, -ynones and primary amines directly by a sequential process and a wide variety of indole derivatives could be synthesized easily [44] (Scheme 8.18). 

Similar halogenations have been done on 2-lithio-l-phenylsulfonylindole[2], 2-Lithio-l-phenylsulfonylindole is readily converted to the 2-(trimethylsilyl) derivative[2,3]. 2-Trialkylstannylindoles can also be prepared via 2-lithio-indoles[4,5], 2-Sulfonamido groups can be introduced by reaction of a 2-lithioindole with sulfur dioxide, followed by conversion of the sulfinic acid group to the sulfonyl chloride with A-chlorosuccinimide[6]. 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Novel l//-imidazo[l,2-a]indole-3-carboxylates 47 were prepared <96SC745>. Thermolyses of halogenated 4,5-dicyanoimidazole derivatives 48 (X = H, Y = F, Cl X = 1, Y = Cl, Br, I) at 100-290 °C led to formation of perhaps the ultimate fused-ring imidazole, hexacaib(Hiitrilelris(iinidazo)triazene (HTT) <96JOC6666>. 

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