Indoles coupling with anilines

The Pd-catalyzed coupling of o-haloanilines and terminal alkynes tends to produce either the 2-(l-alkynyl)aniline or mixtures of the alkynylanilines and the corresponding indoles [17,18]. However, iV-benzyl-2-iodoaniline has recently been cross-coupled with terminal alkynes to afford the corresponding ben-zylindoles using a Pd zeolite catalyst (Eq. 14) [39]. One can also employ stoichiometric amounts of copper acetylides to effect this transformation [22-24]. 

There are no detailed reports on the mechanism of the Bateho-Leimgruber process, but it is proposed below. In the presence of the base, o-nitrotoluene is coupled with iV.A dimethylformamide dimethyl acetal [DMFDMA, Me2NCH(OMe)2] to offer the dimethylamino imine. Hydrogenation then reduces the nitro group to aniline. When workup with an acid, cyclization and re-aromatization then delivered the indole. 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

Previous chapters presented examples of Pd-catalyzed carbon-hydrogen activation as a route to indole ring formation, and several new examples are presented here. Lu and coworkers effected C-H activation of A-arylamides and subsequent coupling with alkynes to give 2,3-disubsti-mted indoles (Scheme 3, equation 1) [33]. Similar indoles were synthesized by Cabrera and colleagues from a Pd-catalyzed direct combination of anilines and a-diketones (equation 2) [34], With 2,3-hexanedione, only 2-n-Pr-3-methyhndole was obtained (95%), and 4-methoxyaniline afforded 2,3-diphenyl-5-methoxyindole in lower yield... 

As an alternative to the use of aniline derivatives in this chemistry, Lebel has recently reported that carboxylic acids can be coupled with sodium azide and alkynes to form indoles (Scheme 6.49) [66]. In this chemistry, a Curtius rearrangement first occurs to generate in situ an ortho-iodoaryUsocyanate, which in the presence of nucleophiles can convert to the NH unit required for palladium-catalyzed indole... 

PS-TsCl was used in the solid-phase synthesis of indoles. Loading of anilines 8 onto PS-TsCI was followed by Sonogashira coupling (eq 9). The coupled products cyclized under the reaction condihons to provide the corresponding indoles this cycliza-tion was promoted by the electron-withdrawing sulfonyl linker. Traceless cleavage of the sulfonyl linker with TBAF provided the indoles in 85-100% yield. 

Shi et al. reported a unique indole synthesis from simple anilines without the aid of any directing group on the nitrogen [34]. Thus, aniline itself (85) couples with dimethyl acetylenedicarboxylate (2b) in the presence of Pd(OAc)2 under O2 to produce indole 86 (Scheme 25.41). A reaction mechanism involving initial hydroam-ination/palladation or aminopalladation of 2b and subsequent cyclopalladation has been proposed. 

Using 2-(2-haloalkenyl)aryl halides 17 as coupling partners, the Willis group discovered an alternative route to indoles (Scheme 6) [33, 34]. Thus, Pd-catalyzed double amination of 17 with aniline delivered 1-phenyl indoles 18 in good yields. 

N-heterocycles like indole, substituted indoles, pyrazole, imidazole, benzamide, morpholine, benzimidazole, thiobenzamide, aniline, benzylaniline, octylaniline, heptylaniline, and cyclohexylaniline couple with aryl iodides and bromides in the... 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

Other derivatives of pyrrole that are of interest as coupling components are indole (12.39) and substituted indoles. Indole may be considered as a pyrrole with a benzo ring fused to it, or as a cyclized derivative of an 7V-monosubstituted aniline. For an aniline compound one expects either a C-coupling in the 5-position or an TV-cou-... 

Binks and Ridd164 have made a complete kinetic study of the reaction of indole with several diazotized amines (p-nitroaniline, p-chloroaniline, sulfanilic acid, and aniline). Only the reaction with p-nitrodiazonium salt exhibits a simple kinetic form (pseudo first-order reaction) in the other cases the kinetics appear to be due to the superposition of two reactions, a normal azo-coupling reaction and an autocatalytic side reaction that removes diazonium ions, but does not form azo compounds. 

The reaction of pentafluoroiodobenzene with aromatic compounds such as anilines, pyrroles, indoles, imidazoles, aromatic ethers and phenols leads to aryl—aryl coupling477. The reactions proceed via pentafluorophenyl radicals which are generated by photoin-duced electron transfer (PET) and loss of iodide ion. Coupling between the pentafluorophenyl radical and the radical cation of the donor gives biaryl cations (138,139) which lose a proton. The reaction is illustrated for N, A-dimethylaniline (equation 125). 

Finally, ortho- 2,2-dibromovinyl)-aniline or -acetanilide can successfully be applied in a sequential cyclizing amination-cross coupling reaction with diethyl phosphonate to furnish the indolyl phosphonic ester 136 or the N-acetyl 2-aryl indole 137 as recently shown by Bisseret and coworkers [ 105] (Scheme 50). This sequence can be also performed with corresponding phenol derivatives furnishing benzofurans. For the N-acetyl 2-aryl indole 137 it can be shown that the Suzuki coupling occurs prior to the intramolecular animation as a consequence of the gradual difference in reactivity between trans-and czs-carbon-bromine bonds. 

Similar tryptophan syntheses may also be performed starting from suitable triethylsilyl (TES)-substituted alkyne components, which gives indolic intermediates bearing the readily removable TES functionality at C-2 as illustrated by the sequence featuring coupling of the aniline 367 with the alkyne 368, and conversion of the resulting... 

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