Room temperature indole arylation

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

Scheme 17 Room temperature C2-arylation of indoles with Ar2lBF4. IMes = l,3-bis(2,4,6-...

Scheme 20 Proposed mechanism of Pd-catalyzed room temperature C2-arylation of indole.

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

The conditions developed by Chan and Lam <1998TL2933, 1998TL2941> can also be applied to pyrroles and indoles for N-arylation with arylboronic acids in the presence of cupric acetate and either triethylamine or pyridine at room temperature <1999T12757>. The use of microwave heating makes Ullman N-arylations of pyrroles and indoles a practical proposition <2003TL4217>. 

General Procedure for the N-Arylation of Indoles (Excerpted with permission from [119]. 2000 American Chemical Society) A Schlenk tube was charged with sodium ferf-butoxide (1.4 mmol), Pd2(dba)3 (0.005 mmol), and 4 (0.015 mmol). The Schlenk tube was fitted with a septum and attached to a Schlenk line. After the air atmosphere was replaced with argon, toluene (2 ml), aryl bromide (1.0 mmol), and the indole (1.2 mmol) were added. After the septum was replaced with a teflon valve, the reaction was sealed and heated to 80- 100°C with stirring until starting material was consumed as judged by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (20 ml), filtered, and concentrated. The crude reaction mixture was then purified by flash chromatography on silica gel. 

In these heterocyclization reactions, palladium can be used to introduce the alkene group as well as catalyze the cyclization. Reacting 2-hromoaniline with 1-alkenes and Li2PdCLi at room temperature leads to the vinylamtne. Upon heating this product with a Pd reagent at 100 °C, an intramolecular Heck arylation follows to give the indole (equation 95). 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

Larrosa reported the direct C2-arylation of indoles with aryl iodides at room temperature (Scheme 24) [46]. The mild conditions allow a broad range of functionalities on both coupling partners and the method is particularly advantageous due to the large pool of commercially available aryl iodides. 

Arylamines and diaryl ethers. Polyhaloarenes have been employed in A-arylation. By using certain carbene ligands, rapid reaction with chloroarenes at room temperature has been demonstrated. The (dba)2Pd-t-BujP system has a wide scope of arylation including that of indole and carbamates." (Formation of Al-dimethylaminoindole from 2-chlorophenylacetaldehyde MA-dimethylbydrazone is novel." ) A more complicated ligand for arylation of amines by aryl chlorides is 1."... 

In 2008, Lebrasseur and Larrosa reported a room temperature C-H arylation of indoles that allows the use of iodoarenes as the coupling partners (Scheme 19, 08JA2926). This methodology provides C2-arylated... 

Scheme 19 Pd-catalyzed direct C2 indole arylation with Arl at room temperature.

Recently, Zhang and coworkers reported a direct palladium-catalyzed C-2 arylation of indoles with potassium aryltrifluoroborate salts [204]. Remarkably, the direct arylation took place at room temperature when acetic acid was used as the solvent. 

Indole and its derivatives undergo smooth thiocyanation with ammonium thiocyanate in the presence of a mixture of Al203-MeS03H (AMA) under mild conditions without the use of any organic solvents to afford aryl thiocyanates in excellent yields and with high selectivity at room temperature (Hosseini-Sarvari and Tavakolian 2008) (Scheme 2.5). 

Maulide et al. developed a unified method for the direct transfer of ylides and the metal-free arylation of carbonyl compounds. This was applied in the synthesis of pyrrole 76 from 75 upon treatment with Martin s sulfurane in toluene at room temperature. The dearomatization of both indole and pyrrole could be effected with a variety of electron-donating or -withdrawing groups in good to excellent yields (13JA7312). 

Borylated pyrrole 88 was prepared by Oestreich by treatment of the corresponding pyrrole with pinacolborane and a ruthenium(II) thiolate complex. The direct synthesis of 88 promises to find wide utility in medicinal chemistry and was applied to a variety of substituted indoles (13JA10978). N-Methylpyrrole was directly arylated at room temperature by photoredox catalysis with diaryliodonium salts to furnish 89 in 84% yield (13SL507). 

Quesnel and Arndtsen reported a palladium-catalyzed carbonylation approach to the synthesis of acid chlorides. As an extension of this methodology, it was found that indoles, carbazoles, and anilines could be N-carbonylated at room temperature from simple aryl iodides and carbon monoxide in good yields (229- 230) (13JA16841). 

Fu et al. developed a room temperature, photoinduced, copper-catalyzed C—N Ullmarm coupling of electrophiles with nitrogen heterocycles (229- 231).The scope of allowed electrophiles is quite broad aryl halides, including hindered and deactivated examples, alkenyl halides, and alkynyl bromides are all tolerated. Indoles, benzimidazoles, and imidazoles can all undergo C-N coupling (13JA13107). 

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