Bromo-substituted indoles

Kororamide A (141) was isolated from Australian bryozoan Amathia tortuosa by Carroll et al. (Figure 11) [68]. The structure was determined by extensive NMR spectroscopic techniques and it was assigned as 2,6,7-tri-bromo substituted indole ring coimected to a proline moiety through Z-enamide functionality. 

Methoxy-, methyl- and bromo-substituted indoles also participated readily in a tandem palladium/copper catalyzed C—H functionalization/ C—H insertion reaction with ethyl diazoacetate (147) and iodobenzene (146) (2015JAC4435). More significantly, the authors were able to illustrate that a copper catalyzed N—H insertion could also be performed in tandem with the C—H functionalization. In this case, 4-aminoindole (149) smoothly underwent coupling to give 150 in 79% yield. 

Rudisill and Stille developed a two-step procedure in which 2-bromo-or 2-trifluoromethanesulfonyloxyacetanilides were coupled with tri-n-butyl-stannylacetylenes in the presence of Pd(PPh3)4.[l], Cyclization was then effected with PdCl2(CH3CN)2. The conditions are compatible with a variety of carbocyclic substituents so the procedure can provide 2-substituted indoles with carbocyclic substituents. The reported yield ranges from 40% to 97% for the coupling and from 40% to 82% for cyclization. 

Substituted indoles can be prepared from o-bromo or o-iodoanilines by paHadium-cataly2ed cycli2ation of AJ-aHyl derivatives (31). 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

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). 

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). 

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. ... 

Direct 2-bromination of 3-substituted indoles can be carried out using N-bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodoindoles can be prepared very efficiently via a-lithiation (section 17.6.1) 2-haloindoles are also available from the reaction of oxindoles with phosphoryl halides. Bromination of methyl indole-3-carboxylate gives a mixture of 5- and 6-bromo derivatives. ... 

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