3- Bromoindole, reaction with indole

Pyridinium bromide perbromide efficiently brominates pyrroles already substituted by electron-withdrawing substituents and also gives a high yield of 3-bromoindole in its reaction with indole. In conjunction with sulfuryl chloride, it has been used in the synthesis of 3-bromo-2-chloro-, 2-bromo-3-chloro- and 2,3-dibromo-indole (81SC253). 3-Methylindole reacts with A-bromosuccinimide in acetic acid to give the 2-bromo derivative which reacts further with an excess of A-bromosuccinimide to yield 2,6-dibromo-3-methylindole (B-70MI30500, 72HC(25-2)127) whilst in aqueous or alcoholic media, 3-bromo-3-methylox-indole is produced (cf. Scheme 15). All of these reactions proceed via the 3-bromo-3A-indolium cation, but the course of the reaction depends not only upon the orientation or... 

Early syntheses of haloindoles involved direct reactions of indoles with chlorine, bromine, or iodine. In some cases, this approach was reasonably successful, but the instability of the resulting 3-haloindoles made product isolation and further chemistry difficult. For example, although attempted preparations of 3-chloro-, 3-bromo-, and 3-iodoindole were described in the early 1900 s [2], only recently have practical syntheses of these compounds and their N-protected derivatives become available. For example, 3-bromoindole (2) can be prepared in... 

Both inter- and intramolecular Heck reactions of indoles have been pursued and these will be considered in turn. Appropriately, Heck and co-workers were the first to use Pd-catalyzed vinyl substitution reactions with haloindoles [239]. Thus, l-acetyl-3-bromoindole (217) gave a 50% yield of 3-indolylacrylate 218. A similar reaction with 5-bromoindole yielded ( )-methyl 3-(5-indolyl)acrylate (53% yield), but 3-bromoindole gave no identifiable product. 

A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03M13519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier-Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium... 

Lithio compounds can also be obtained by exchange reactions with halo compounds, for example, the sodium salt of S-bromoindole can be converted to the S-lithio derivative by treatment with /-butyllithium, and this in turn allows synthesis of various S-substituted indoles. 

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for l-methyl-2-bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1-methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively. 

Condensation of 1 with 5-bromoindole 573 (R = Br) in the presence of hydrochloric acid gave indolyl dibenzazepinone 575 (72CR(C)965 73CR(C)117). The reaction involved the trimerization of 573 to give 574, which upon reaction with dimedone gave 575. Similarly 575 (R = H) was obtained when 1 was reacted with indole 573 (R = H) in the presence of 47% HBr (03IJC(B)2573). 

A detailed study of the Suzuki reaction of benzene-ring substituted bromoindoles was published <04JOC6812>. The highest yields were obtained with indole substrates containing a tosyl nitrogen protecting group. Palladium-catalyzed carbonylation reactions of unprotected bromoindoles allowed for the synthesis of indolecarboxamides. For example, treatment of 5-... 

Except for 3-bromoindole, it is necessary to proceed via the indoline, because treatment of indole with 1,1-dimethyIpropargyl chloride (31) in the presence of base leads to product mixtures resulting from reaction of in situ formed dimethyl-vinylidene carbene. Sheu and co-workers isolated the three products 32, 33 and 34 on reaction of indole-3-carbaldehyde (30) (Scheme 7) [53]. In the main reaction, indole C3 attacks at dimethylvinylidene carbene forming a vinyl anion, which is protonated to give the 3-allenylindolenine. Hydroxide then attacks the carbal-dehyde moiety with loss of formic acid and formation of a 3-allenylindole. Addition of a second equivalent of indole-3-carbaldehyde (30) affords 32 and 33. 

Formal A -trifluoromethylation of indole was performed in several steps, starting from indoline. At first step 3-cyanoindoline was treated with NaH, followed by CS2 and then Mel to form thioderivative 64. The latter was treated with tetrabutylam-monium dihydrogen trifluoride, followed by NBS, to give A -CFs-indoline 65. Aromatization of 65 was carried out by reaction with NBS in CCI4 at reflux, leading to A -trifluoromethyl-3-bromoindole 66 [31]. 

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