Indoles, palladium-catalyzed aryl amination

Scheme 54 Indole synthesis via palladium-catalyzed aryl amination...

The first reports of palladium-catalyzed arylation (equation 39) of azoles occurred with catalysts bearing DPPF as the ligand125. These reactions of indole, pyrrole and carbazole with activated aryl halides were carried out at 80-100°C. The reactions of indole and pyrrole with unactivated aryl halides such as bromobenzene, 4-bromo-r -butylbenzene and 3-bromoanisole occurred in high yields. However, the conditions of these reactions were more severe than those typically necessary to conduct palladium-catalyzed coupling of aryl halides with amines (equation 40). 

Continuing their investigation of tandem cascade reactions toward indole synthesis, Barluenga et al. reported a process combining palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation (Scheme 24.1, disconnection D-7) [51]. The process is outlined in Scheme 24.9 initial palladium-catalyzed aza-enolate arylation generates intermediate imine 23 and then palladium-catalyzed intramolecular amination, presumably via intermediate enamine 24, results in the product indole in excellent 86% yield. An XPhos-derived catalyst facilitated both steps of the cascade, and a wide range of imines could be incorporated. 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

The 2,3-substituted indols are formed via a palladium-catalyzed coupling reaction of aryl halide, o-alkenylphenyl isocyanide, and amine (Equation (122)).481 Oxidative addition of an aryl halide, insertion of both the isonitrile and alkene moieties of o-alkenylphenyl isocyanide, and 1,3-hydrogen migration may form a 7r-allylpalladium species, which is then attacked by an amine to afford an indol. 

Indoles, pyrroles and carbazoles themselves are suitable substrates for palladium-catalyzed amination. An initial study of this reaction using DPPF-ligated palladium as catalyst showed that these reactions occurred readily with electron-poor aryl halides. With unactivated aryl bromides, the reaction with pyrrole or indole resulted in good yield, but reaction times were long and the temperature was 120 °C. Thus, an improved catalyst system was necessary for reactions to occur in a more general fashion and with temperature- or base-sensitive substrates. 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

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. 

Aryl halides which are rather inert in usual organic reactions can undergo reactions by means of palladium catalysts. Thus, styrene and stilbene derivatives are obtained by reaction of olefins with aryl bromides at 125 °C using Pd(0Ac)2 (1 mol%) and tri-(o-tolyl)phosphine (2 mol%)83. The palladium-catalyzed vinylic substitution reaction is applicable to a variety of heterocyclic bromides including pyridine, thiophene, indole, furan, quinoline and isoquinoline84. Thus, reaction of 3-bromopyri-dine with l-(3-butenyl)phthalimide at 100 °C gives l-[4-(3 -pyridyl)-3-butenyl]-phthalimide (yield of mixed amine 57%, selectivity 68%) at 100 °C. This phthalimide is subsequently converted to nornicotine (188) (Scheme 59). The reaction of acrylic... 

Recently, Buchwald and Hartwig have developed the palladium-catalyzed coupling reaction of aryl halides with amines (Scheme 165), and they have extended this reaction to the intramolecular version to give a variety of the aza-heterocyclic compounds 547 (Scheme 166).231 This methodology has provided a wide variety of alkaloids, such as indoles,232 inda-zoles,233 benzimidazoles,234 benazepines,235 phena-zines,236 carbapenems,237 the mitomycin ring system,238 a-carbolines,239 and polyheterocycles.240 Pharmacologically active natural products, such as (—)-asperlicin (550) (Scheme 167),241 dehydrobufotenine (553) (Scheme 168),242 and makaluvamine C... 

The aromatic ring version of the Mori-Ban-Heck indole synthesis can be called an aryl-Heck reaction. This palladium-catalyzed cyclization of o-halo diaryl amines has seen many applications in carbazole and carboline synthesis. 

The first Pd-catalyzed intramolecular amination of an aryl halide was reported by Boger in 1984. This transformation was stoichiometric in palladium and generated the indole core of lavendamycin. ... 

The Hartwig-Buchwald arylation of amines can also be favorably combined with the Heck reaction [383, 384]. For example, the intramolecular palladium-catalyzed N-arylation of immobilized dehydro(halophenyl)alaninate was found to proceed smoothly to form indolecarboxylates. The method was successfully combined with the Heck reaction to constitute a one-pot indole synthesis in the form of a palladium-catalyzed cascade C,N-arylation reaction (Scheme 8.58) [383, 384]. 

The author next examined construction of polycyclic indoles by palladium-catalyzed C-H arylation using 2-(aminomethyl)indole 7x, which was prepared from ethynylaniline la and amine 3h (Table 5, entry 11). By treatment with 20 mol.% of Pd(OAc)2 and 40 mol.% of PPha, dihydrobenzazepine-fused indole 10 was efficiently obtained in 80% yield over 2 steps (Scheme 3). One-pot three-component indole formation/Pd-catalyzed C-H arylation also provided polycyclic indole 10 in 84% yield from la. 

Cenini, S. Bettettini, E. Fedele, M. Tollari, S. (1996) Intramolecular amination catalyzed by ruthenium and palladium synthesis of 2-acyl indoles and 2-aryl quinolines by carbon-ylation of 2-nitrochalcones, J. Mol Catal A-Chem., Ill, 37-41. 

All substrates mentioned in the previous chapter easily undergo palladium-catalyzed aminocarbonylation also. It should be mentioned that even allylic carbonates instead of halides could be converted into carboxamides by this method, as it vas demonstrated during the total synthesis of antillatoxin [94]. The use of aryl chlorides is somewhat restricted owing to the low reactivity ofthese type of substrates in oxidative addition to palladium(O), as well as the competitive amination observed, for example, in the reaction of 1-chloroisoquinoline [95]. Functionalization of a great number of pharmaceutically important skeletons, for example, steroids [96-99], tropenes [100], benzodiazepines [101], indoles [102], benzo[c[quinolizine derivatives [103], and quinolones [104], have been carried out. 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

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