Indoles arylations

The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

Taber and Tian have employed the Neber protocol to prepare a-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-... 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Aryl indole as a G-protein-coupled receptor (GPCR) privileged scaffold. The indole ring is a premier example of a privileged scaffold. The heterocycle is present in a profusion of medicinally important natural products and pharmaceutical substances, and it is associated with an extraordinary manifold of biological... 

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. 

Stereoselective chromium tricarbonyl migration was achieved in the sterically hindered A -aryl indole chromium complex 178b by refluxing in toluene (Equation 34) <20060L1097>. 

Arylated indoles are important intermediates for the synthesis of various agonists... 

Dinnell, K., Chicchi, G. G., Dhar, M. J. et al. 2-Aryl indole NKj receptor antagonists optimisation of the 2-aryl ring and the indole nitrogen substituent. Bioorg. Med. Chem. Lett. 2001,11,1237-1240. 

DaSilva, C.A., Pai, L.Y. et al. (2007) Estrogen receptor ligands. Part 16 2-aryl indoles as highly subtype selective ligands for ERa. Bioorganic el Medicinal Chemistry Letters, 17, 2322-2328. 

Aryl-Indoles Scientists at Merck described 2-aryl-indoles as ERa-selective SERMs [137]. HTS uncovered indole 101, which showed reasonable receptor affinity but very high ERa selectivity. However, 101 expressed agonism in an immature rat... 

A related example from He and co-workers demonstrated that phosphinous ligands on Pd(0) are also able affect an indole arylation reaction. A small selection of C3 arylated indoles can be realized using this method. Of particular note is the C3 selectivity observed in this reaction, when compared to the work of Sames who observed C2 selectivity (Scheme 15). 

Alkylation of 2-alkyl- and 2-aryl-indoles can be achieved by trifluoracetic-acid-catalysed condensation with either aromatic aldehydes or aliphatic ketones in the presence of the triethylsilane, which reduces the intermediate 3-aIkylidene-3//-indolium cations. ... 

Direct cyclisation of ortfto-alkynyl-anilines can be effected simply by treatment with tetra-n-bntylam-monium fluoride, potassium f-butoxide or potassium hydride, or simply with gold(III) chloride. Treatment of l-(2-arylethynyl)-2-nitroarenes with indium and aqneons hydrogen iodide prodnces 2-aryl-indoles, the reagent combination both reduces the nitro to amine and then the acid activates the alkyne for the ring closure. Copper(II) salts or diethylzinc in refluxing toluene can be ntihsed with IV-sulfonyl-ort/fo-alkynyl-anilines. 

Fig. 15.4-5 Examples of CPCR active the library against several CPCRs led to the compounds based on the 2-aryl-indoles discovery of NPYs, NKi, chemokine privileged scaffold identified from a focused CCR3/CCR5, serotonin 5-HT2a/5-HT6. and combinatorial library at Merck. Screening of SST4 receptor antagonists [91].

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

Twenty years later, Sames revisited and expanded this challenging chemistry by developing a Pd-catalyzed regioselective C2-arylation of N-alkyl and N-aryl indoles (Scheme 3,04OL2897). This methodology ben-... 

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