6-Arylindoles, synthesis

Arylbismuth 671, 673 Arylboronic acid 671, 673 Arylbutenes, formation of 613 Aryl-2-cyclohexenones 653 Aryl ethers—see also AUyl aryl ethers. Diaryl ethers. Phenyl ethers, Propargyl aryl ethers formation from calixarenes 1387 Aryl haUdes, as phenol precursors 396, 397 Ai-Arylhydroxylamines, isomerization of 801-805 oxidation of 419 3-Arylindoles, synthesis of 1236 Aryl ketones, oxidation of 424, 425 Aryloxylium cations 179 Asatone, synthesis of 1178, 1179 Ash, from incineration of municipal waste, phenoUc compounds in 938 Aspersitin, synthesis of 1327, 1328 Aspirin 10, 11... 

A-tosylhydrazones (equation 2) [52]. The reaction can also be executed in one pot from arylhalide, aldehyde, and tosyl hydrazine. A novel 2-arylindole synthesis that was discovered by Rashinkar entails the Pd-catalyzed reaction of o-nitrobenzyl cyanides with arylboronic acids (equation 3) [53]. Tobisu and Chatani accomplished the direct Pd-catalyzed alkynylation of anihdes leading to indoles (equation 4) [54], Lee and colleagues induced nitriles into becoming indole-3-carboxylates through the Blaise reaction (equation 5) [55]. 

This method has been applied to a large-scale preparation of 6-bromoindole, which reacts with various arylboronic acids via the Suzuki reaction to afford 6-arylindoles (Eq. 10.50).64 6-Bromo-5-methoxyindole for use in the synthesis of marine bromoindole65 and 5-amino-7-ethoxycarbonylindole for use in synthesis of l//-pyrrolo[3,2-g]quinazoline ring system (Eq. 10.51)66 have been prepared from the appropriate o-nitrotoluene. 

Recently, synthesis of the 4-arylindole portion of the antitumor agent diazonamide has been achieved starling from 3-bromo-2-methylnitrobenzene via Suzuki coupling and the Batcho reaction.67b... 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Another Suzuki coupling reaction was described by Zhang et al., to produce arylindoles 116a and b, using solid-phase synthesis [76]. The synthesis was achieved by palladium-mediated coupling/intramolecular indole cycli-zation of resin-bound 2-trimethylsilylindole 117, Scheme 29. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

The Buchwald-Hartwig aryl animation methodology cited above in this section was engaged by Hartwig and others to synthesize AT-arylindoles 377 [469]. Carbazole can be N-arylated under these same conditions with p-cyanobromobenzene (97% yield). Aryl chlorides also function in this reaction. The power of this animation method is seen by the facile synthesis of tris-carbazole 378 [469c]. 

The synthesis of A-arylindoles from A,A-diaryl-A -trifluoroacetyl enehydrazines, a process analogous to the Fischer indole synthesis, has been studied in various solvents, including water, and in solvent-free conditions. Solvent polarity, or presence, appears to have had little influence on the reaction course. The A-TFA group has been found to be necessary for efficient reaction, with less electron-withdrawing substituents giving slower reactions, and triflyl diverting the reaction course after the... 

The vinyl triflate of Kornfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(A-rerr-butoxycarbonyl-A-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [257], A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [258], Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in Chapter 10 (pyrazines) [259], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 240 with arenes [260]. Subsequent desulfurization and hydrolysis furnishes 2-arytmethylindoles 241. Bis-indole 242 was also prepared in this study. Aryl iodides couple with indole under basic conditions to afford 2-arylindoles [261]. 

Brown, J.A., Synthesis of 7V-arylindole-2-carboxylates via an intramolecular palladium-catalyzed annulation of didehydrophenylalanine derivatives. Tetrahedron Lett., 41, 1623, 2000. 

Organometallic cross-coupling reactions provide a regiocontrolled method for the introduction of substituents to the indole ring. Palladium-catalzyed cross-coupling of 2-indolyldimethylsilanols have been utilized in the synthesis of 2-arylindoles <04OL3649>. For example, treatment of indole-2-silanol 206 and aryl iodides 207 with a palladium catalyst, copper iodide, and sodium f-butoxide provided 2-arylindoles 208. 

S. Patel, L. Malkowitz, J. Di Salvo, S.G. Pacholok, K. Cheng, Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives discovery of potent ligands for a variety of G-protein coupled receptors, Bioorg. Med. 

The coupling of arylzinc halides with alkyl (E)-2,3-dibromoalkenoates occurs at C-3. 3-Arylindoles are obtained from 3-indolylzinc halides with haloarenes." A synthesis of 1,4-disubstituted butadienes starts from the hydrozirconation of ethynyl phenyl selenide. After Pd(0)-catalyzed coupling with alkenyl bromides, the seleno group is replaced via Grignard reaction in the presence of (Ph3P)2NiCl2. 

The aryl amination protocol described previously was found to be incompatible with the formation of N-aryl heterocycles such as N-arylindoles. The electron richness of heteroaromatic substrates limits the applicability of N-arylation of indoles to more reactive aryl iodides and bromides. However, good results were obtained in coupling a number of aryl bromides and indole derivatives employing a Pd(OAc)2/SIPr HCl/NaOH catalytic system. This protocol additionally overcomes a common problem in indole synthesis, namely the formation of C-arylation side products (Scheme 23). 

Mino et al. recently reported the synthesis of optically pure phosphine ligands 348 and 349 based on atropisomeric N-arylindoles and demonstrated their potency as ligands for palladium-catalyzed asymmetric allylic alkylation (up to 99% ee) (10TA711). 

The reaction of 7 -unsubstituted anilines with phenacyl halides is a useful way to make 2-arylindoles <7 JCS(C)2606>. This reaction is known as the Bischler indole synthesis. The reaction is typically carried out by heating a phenacyl halide with an excess of an anUinium salt. The reaction is believed to involve imine formation followed by protropic shifts and cyclization at the less hindered aldiminium carbon (Scheme 36) <80AJC343>. 

Very few examples of C2-lithiation reactions involving V-aryUndoles are known [258]. In the search for new indolyl phosphine ligands (e.g., 72) for palladium-catalyzed amination reactions, mono-lithiation and di-lithiation reactions involving V-arylindoles have been used (Scheme 15). Beller reported the synthesis of indolyl ligand 72a using a mono-lithiation of V-phenylindole (71a) [277], whereas Nifant ev used a dilithiation of 71b under much colder conditions to give bis (phosphine)indole 72b [278]. 

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