Carbazoles palladium -catalyzed oxidative

A molybdenum-mediated oxidative coupling of aniline 1 with cyclohexene 2a provides carbazole 3. Alternatively, the same overall transformation of aniline 1 to carbazole 3 is achieved by iron-mediated oxidative coupling with cyclo-hexa-1,3-diene 2b or by palladium-catalyzed oxidative coupling with arenes 2c. The use of appropriately substituted anilines and unsaturated six-membered hydrocarbons opens up the way to highly convergent organometallic syntheses of carbazole alkaloids. 

C-H activation can be used to generate carbazoles from N-aryl anilines by palladium catalyzed oxidative coupling (Scheme 3) [12]. Although this is a powerful method, it is ultimately limited by the fact that more heavily substituted N-aryl anilines may not couple selectively, leading to the formation of more than one product. 

Scheme 3. Formation of carbazoles via palladium catalyzed oxidative coupling.

In conclusion, the fantastically diverse chemistry of indole has been significantly enriched by palladium-catalyzed reactions. The accessibility of all of the possible halogenated indoles and several indolyl triflates has resulted in a wealth of synthetic applications as witnessed by the length of this chapter. In addition to the standard Pd-catalyzed reactions such as Negishi, Suzuki, Heck, Stille and Sonogashira, which have had great success in indole chemistry, oxidative coupling and cyclization are powerful routes to a variety of carbazoles, carbolines, indolocarbazoles, and other fused indoles. 

Addition of the arylamines 117 to 2-methoxy-3-methyl-l,4-benzoquinone 118 affords regioselectively the 5-arylamino-2-methoxy-3-methyl-l,4-benzo-quinones 119 (Scheme 37). Palladium(II)-catalyzed oxidative cyclization leads to the carbazole-l,4-quinones 28 [135,136],previously obtained by the iron-mediated approach (cf. Scheme 14). Regioselective addition of methyllithium to the quinones 28 provides carbazomycin G 29a and carbazomycin H 29b [96,135]. Reduction of 29a with lithium aluminum hydride followed by elimination of water on workup generates carbazomycin B 23a [135]. Addition of heptylmag-... 

Akermark et al. reported the palladium(II)-mediated intramolecular oxidative cyclization of diphenylamines 567 to carbazoles 568 (355). Many substituents are tolerated in this oxidative cyclization, which represents the best procedure for the cyclization of the diphenylamines to carbazole derivatives. However, stoichiometric amounts of palladium(II) acetate are required for the cyclization of diphenylamines containing electron-releasing or moderately electron-attracting substituents. For the cyclization of diphenylamines containing electron-attracting substituents an over-stoichiometric amount of palladium(II) acetate is required. Moreover, the cyclization is catalyzed by TFA or methanesulfonic acid (355). We demonstrated that this reaction becomes catalytic with palladium through a reoxidation of palladium(O) to palladium(II) using cupric acetate (10,544—547). Since then, several alternative palladium-catalyzed carbazole constructions have been reported (548-556) (Scheme 5.23). 

One year later, we extended the aforementioned palladium(II)-catalyzed approach to a series of 6-oxygenated carbazole alkaloids, glycozoline (86), glycozolinine (glycozolinol) (91), glycomaurrol (92), micromeline (100), and methyl 6-methoxycarbazole-3-carboxylate (104) (547). The palladium(0)-catalyzed coupling of 4-bromoanisole (670) and p-toluidine (1028), followed by palladium(II)-catalyzed oxidative cyclization, afforded directly glycozoline (86). 

Carbazole-l,4-quinones, the key intermediates of this approach, can be even more effidently prepared by the palladium(II)-catalyzed oxidative cydization (see below. Scheme 15.17). In a screening for anti-TB active carbazoles, 3-methoxy-2-methyl-carbazole-l,4-quinone showed significant inhibition of Mycobacterium tuberculosis strain H37RV, with an MIC90 value 2.2 p.g/mL (9 p,M) [40]. Thus, carbazoles may be developed as anti-TB drug candidates by structural modifications. 

Scheme 15.16 Palladium(ll)-catalyzed oxidative cyclization to 4-methoxy-2-methyl-5H-benzo[fo]carbazole-6,l 1-dione.

The carbazoquinodns are carbazole-3,4-quinone alkaloids and have been isolated from Streptomyces violaceus 2942-SVS3 [61]. They are strong antioxidative agents and thus represent potential drugs for the treatment of diseases initiated by oxygen-derived free radicals. We have developed an effident synthesis of carbazoquinodn C using palladium(II)-catalyzed oxidative cydization as the key step (Scheme 15.17, Table 15.2) [62]. 

Much research interest in the synthesis of carbazoles is directed at the preparation of natural products. The total syntheses of murrayafoline A 153 and murrayanine have been reported <04S2499>. The key step included a regioselective cycloaddition between oxazolidinone 150 and acrolein which led to benzoxazol-2-one 151 after DDQ oxidation. Ring opening of the oxazol-2-one ring of 151 followed by methylation provided A-phenylaniline 152. A palladium-catalyzed intramolecular cyclization of the latter then produced the natural product 153. Finally, venerable iron-mediated chemistry has been utilized in the total synthesis of furoclausine A 154 <04SL528> and 6-chlorohyellazole 155 <04SL2705>. 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

The palladium(II)-catalyzed oxidative cyclization has been applied to the total synthesis of a broad range of naturally occurring carbazole alkaloids. Earlier examples have been presented in our previous review in this series [19]. Herein, we describe recent progress in this area from our laboratories and other research groups. 

Scheme 25 Redox cascade of the palladium(II)-catalyzed oxidative cyclization of diarylamines 95 to carbazoles 32...

Our palladium-catalyzed approach for the construction of the carbazole framework led to the 6-oxygenated tricyclic carbazole alkaloids glycozoline (128), methyl 6-methoxycarbazole-3-carboxylate (133), glycomaurrol (135) and micromeline (130), as well as to the furo[2,3-c]carbazole alkaloid eustifoline-D (132) (Scheme 29) [149]. Palladium-catalyzed coupling of p-bromoanisole (125) and p-toluidine (126) as the first step led almost quantitatively to the diarylamine 127. Oxidative cyclization of intermediate 127 using 0.1 equiv. of palladium(ll) acetate in the presence of an excess of copper(ll) acetate provided glycozoline... 

In contrast to the synthetic approaches described in Sects. 3.2.1 and 3.2.2, the N-arylation and C-C coupling steps can also be reversed. Suzuki-Miyaura coupling of N-substituted 2-haloarylamines 189 with arylboronic acids 190 provides N-substituted 2-aminobiaryls 191 (Scheme 43). A palladium(II)-catalyzed oxidative cyclization of the latter forms the tricyclic carbazole framework. Different from the first reaction step in Scheme 24, this is an oxidative C-N coupling which requires N-H and C-H activation, whereas the C-C bond is formed in a crosscoupling process. 

Back utilized an interesting variant of the Heck reaction involving the palladium-catalyzed heteroannulation of o-iodoanilines 102 with dienyl sulfoncs 103 to afford 2-sulfonylindolines 104 <01JOC8599>. These indolines could be oxidized to the corresponding indoles with DDQ, whereupon D-A reaction of the resulting 2-vinylindoles with dienophiles led to a convenient route to carbazoles. 

Indeed, a variety of heterocyclic compounds, such as thiophenes, dithiophenes, pyrroles, indoles, or carbazoles can be involved as carbon-centered nucleophiles in these reactions to modify the pyrimidine ring (Scheme 31) [120-122]. For instance, it has been shown that 5-bromopyrimidine reacts with dithiophene into the corresponding 5-substituted pyrimidine due to palladium-catalyzed aryl-aryl C-C cross-coupling reaction. On the other hand, 5-bromo-4-dithiophenyl-substituted pyrimidine was prepared from the same starting material through the SH (addition-oxidation) reaction catalyzed by a Lewis acid in the presence of potassium... 

Kong, A., Han, X. and Lu, X. (2006) Highly efficient constmction of benzene ring in carbazoles by palladium-catalyzed endo-mode oxidative cyclization of 3-(3 -alkenyl)indoles. Org. Lett., 8, 1339-A2. 

In a multitude of publications, Knolker and coworkers have parlayed the twin Pd-catalyzed oxidative cyclizations to give carbazoles or carbazole-l,4-quinones into an impressive collection of natural-product syntheses [8-12] some recent examples are illustrated in Scheme 2 and include syntheses of glycozoline (equation 1) [13], isokoeniginequi-none A (equation 2) [14], and mukonine (equation 3) [15]. Knolker and colleagues were able to isolate and crystallize the palladium complex 2 from the Pd-catalyzed reaction of diaryl amine 1 to give four isomeric carbazoles, from which an x-ray crystal structure was obtained [16]. 

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