2-Aryl indoles

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. 

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... 

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].

An interesting selectivity was uncovered in the direct cross-dehydrogenative coupUng between N-protected indoles and arenes (Scheme 11.40) [151]. Thus, whereas 2-arylated indoles 67a were preferentially obtained from N-acetyhndole in the presence of Cu(OAc)2, the reaction of N-pivalolyUndole with AgOAc led to 67b, with excellent selectivities. The reason for this C-2/C-3 selectivity is most likely due to the formation of higher-order palladium clusters or paUadium/copper clusters under the different reaction conditions. A related reaction between aryl-boronic acids and arenes or heteroarenes also proceeds under oxidative conditions with Pd(OAc)2 as catalyst [76]. A catalytic cycle initiated by an electrophihc attack of Pd(II) on the arene, followed by transmetallation with the aryl boronic acid and reductive elimination, was suggested. In this transformation, Cu(OAc)2 as stoichiometric oxidant could be replaced by O2, and for indoles, arylation at C-2 was observed. 

Nagano and Li reported an intramolecular C-C bond-forming CDC reaction for the synthesis of indole derivatives (Scheme 8.28). Cyclization of aniline derivatives (72) effectively proceeds in the presence of a catalytic amount of tetrabutylammonium iodide and 2.5 equiv. of TBHP to afford a variety of 3-acyl-2-aryl indoles (73). The catalytic formation of iodine (I2) by TBHP seems to be essential for the reaction to occur. 

Scheme 3 Synthesis of 2-aryl indoles, 2-vinylic indoles and 2-alkynyl indoles via Pd-catalyzed intramolecular N-arylation...

---