Quinoline coupling with indole

The metal- and solvent-free CDC coupling of quinolines 106 with indoles and pyrroles proceeds smoothly in the presence of stoichiometric amounts of HCl (Scheme 8.54). The reaction mechanism involves the nucleophilic attack of indole on the quinolinium ion (108) followed by the oxidation of the coupling product hy 108 to give coupling products 107. 

Adapting Gribble s method for synthesizing indol-3-yl triflate [37], Mdrour et al converted 2-formyl- l-(phenylsulfonyl)- l//-indole (31) to indol-2-yl triflate 32 in two steps. 32 was subsequently coupled with benzofuryl-2-boronic acid to furnish 2-benzofurylindole 33 [38, 39]. In another case, 2-bromoacetaniline was coupled with 2-formyl-3-furylboronic acid 35 [40]. The resulting Suzuki coupling adduct underwent a spontaneous cyclization, forming tricyclic furo[2,3-c]quinoline 36. 

Several aryl bromides were coupled with the vinylogous amide below in moderate to excellent yields by Edmonson et al., Eq. (154) [126]. The Merck investigators also reported that this C-N bond forming reaction could be exploited to prepare quinoline and indole derivatives. 

Utilized Pd(OAc)2 and SPhos 24 as the catalyst system to effectively catalyze Suzuki-Miyaura cross-couplings with only 1.1 equiv. of trifluoroborates [84e]. More recently, Molander and coworkers have developed a general cross-coupling system to many classes of heteroaromatic trifluoroborates employing Pd(OAc)2 and RuPhos 23 [84j]. Furan 135, thiophene 132, pyrrole 126, pyrazole 130, isoxazole 131, pyridine 127, pyrimidine 133, indole 129, benzothiophene 136, benzofuran 135, quinoline 128, and isoquinoUne could all be cross-coupled with only 1.04 equiv. of trifluoroborate salts, affording the corresponding cross-coupled products in good yield (Scheme 2.25). 

Scheme 8.54 Metal- and solvent-free, auto-oxidative coupling of quinolines with indoles and pyrroles.

NHC (IMS HCl) as the ligand or even under ligand-free conditions. Copper salts were applied in these transformations as well. In 2003, a nickel-catalyzed system was also developed. With Ni(0) generated in situ as the catalyst and 2,2 -hipyridine or N,A/ -his(2,6-diisopropylphenyl)dihy-droimidazol-2-ylidene (SIPr) as the ligand, the intramolecular coupling of aiyl chlorides with amines was achieved with NaOfBu as the base. Indoles, quinolines, benzazepines, benzoxazines, and benzoxazepines were produced in good yields from the corresponding substrates. 

Amides can also be obtained by AICI3 catalyzed ester amine exchange which proceeds primarily without racemization of chiral centers (eq 24). The reaction of phenols with /3-keto esters is known as the Pechmann condensation (eq 25). Aryl amines are used in the Riehm quinoline synthesis (eq 26) Aromatic systems may be coupled via the Scholl reaction (eq 27) and indole derivatives are prepared in the Stolle synthesis (eq 28). In the Zincke-Suhl reaction, phenols are converted to dienones (eq 29). 3 ... 

The C-2 selective oxidative C-H coupling of unactivated pyridines with heterocycles was achieved in the presence of Pd(OAc)2, phenanthroline as the ligand, a silver oxidant, and pivalic acid (eq 145). Moderate to good yields were obtained when heteroarenes, such as thiophenes, indoles, furans, indazoles, or xanthines, were coupled to p3uidine (or p3razine, quinoline, pyrimidine). Virtually no homo-coupling or other regioselective (C-3 or C-4) products were observed in the reaction. 

With the preliminary results in hand, it was crucial that the C2 group on the indole could be readily removed. The C2 carboxylic acid derivatives of coupling products were initially employed toward this endeavor (Scheme 4). There are relatively few decarboxylation methods on indole acids reported in the literature, most of which utilize harsh reaction conditions. Nevertheless, Jagan tested several of the reported methods, including the use of copper chromite in quinoline at 215 °C, copper(I)oxide in DMA at 200 °C, and substoichiometric amounts of indole acid copper salts at 200 Much to his dismay, most of these reactions led to decomposition. Moreover, adjusting temperature or switching to microwave heating failed to provide the desired decarboxylation. 

Sakai N, Annaka K, Konakahara T (2004) Palladium-catalyzed coupling reaction of terminal alkynes with aryl iodides in the presence of indium tribromide and its application to a one-pot synthesis of 2-phenylindole. Org Lett 6 1527-1530. doi 10.1021/ol036499u Sakai N, Annaka K, Eujita A, Sato A, Konakahara T (2008) InBr 3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group. J Org Chem 73 4160-4165. doi 10.1021/jo800464u... 

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