N-aryl carbazoles

A rather unusual procedure has been published for the palladium- and copper-catalyzed synthesis of triarylamines, using an alkaline water-ethanol emulsion stabilized by cetyltrimethylammonium bromide [41]. Anyway, this method overcomes the problem in the synthesis of N-aryl carbazoles (Eq. 14), which are not accessible by the method developed by Hartwig and Buchwald [42],... 

Optically pure N-aryl carbazole 364 with a planar chirality was transformed into 365 presenting axial and planar chirality by a totally diastereoselective migration of the tricarbonyl chromium. Interestingly, the enantiomeric excess in 365 was high at the beginning of the transfer and decreased after 2 h in refluxing toluene. A slow racemization stemmed from a slippage of the tricarbonyl chromium from one phenyl of the carbazole to the other. 

Studer et al. developed an aryne-based approach to carbazoles. Sdyltriflate 254 was exposed to a source of fluoride to generate benzyne in the presence of nitrosoarene 255, cyclization to carbazole 256 occurred. Depending on the reaction conditions, either N-H or N-aryl carbazoles could be selectively formed (13AG(I)2968). 

S. Riedmuller, B.J. Nachtsheim, Palladium-catalyzed synthesis of N-arylated carbazoles using anilines and cyclic diaryHodonium salts, Beil-stein J. Org. Chem. 9 (2013) 1202-1209. 

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 double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

Although the preparation has been repeated, there have been no other reports of the type of reaction, (described in 1923) in which carbazole in the presence of excess potassium hydroxide and nitrobenzene at only 50°C gave a good yield of 9-(4-nitrophenyl)-carbazole, presumably via an adduct such as 43 subsequently oxidized by excess nitrobenzene and/or air. More recent examples of N-arylation of carbazoles have involved copper catalysis in reaction of aryl halides with carbazoles. Thus, copper bronze and potassium carbonate heated with the carbazole and the appropriate aromatic halide have produced 9-(4-methoxyphenyl)- and 9-(2-tolyl)carbazoles 9-(4-phenylphenyl)carbazole, l,4-di(carbazol-9-yl)benzene, 4,4 -di(carbazol-9-yl)biphenyl, and 9-(2-pyridyl)- and 9-(2-quinolyl)carbazoles 9-[2-(2-phenylphenyl)phenyl]- and 9-[2-(4-methylphenyl)phenyl] carbazoles 9-(3-bromo-6-nitrophenyl)-, 9-[3-(carbazol-9-yl]-, 9-(2-nitrophenyl)-, 9-(4-methyl-2-nitrophenyl)-, 9-(4-methoxycarbonyl)-l-nitro-, and l-nitro-9-(4-tolyl)carbazoles 9-(2-methoxycarbonylphenyl)carbazole 9-[2- 2-... 

R = H or Me) is formally a carbazole N-arylation. The ring closure was effected by diazotization and heating. Minor products in these processes were the dibenz [4,5 6,7]azepino[l,2,3-jfc]carbazoles... 

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. 

The dehydrohalogenation approach outlined in Scheme 1 reduces problems of selectivity in the synthesis of carbazoles. The method can be improved further by producing the N-aryl-2-haloaniline starting materials in the same pot as the subsequent carbazole product. This is achieved by Buchwald-Hartwig amination of 2-chloroanilines with aryl bromides [13], An illustrative example of this one-pot procedure is shown in Scheme 4. 

Sterically hindered alkylmonophosphines provided improved catalyst systems (Table 5) [163]. In this case, reactions occurred within 8 h at 100 °C for both activated and deactivated aryl bromides and with electron-poor or electron-neutral aryl chlorides. Reactions of ortho-substituted aryl halides were unusual, providing a mixture of 1- and 3-substituted indoles, but these aryl halides were suitable substrates when the 3-position of the indole was also substituted. The origin of this C- vs. N-arylation is unknown. The Tosoh group has also used this catalyst system for the arylation of the parent pyrrole, indole, and carbazole. They observed that Rb2C03 was a particularly effective base [187]. 

As an excellent complement to the Pd-catalyzed methodology that has been utilized in a number of applications, in general experimentally simple and inexpensive catalyst system for the N-arylation of a wide variety of azoles (pyrrole, indoles, 7-azaindole, carbazole) has been developed (Equation 37) <2001JA7727>. In particular, it was shown that the combination of air stable Cul and racemic ( )-l,2-cyclohexanediamine 186a in the presence of K3PO4 is an extremely efficient and general catalyst system for the N-arylation of a number of azoles. Competitive C-arylation under these conditions is not observed. 

Due to resonance stabilization and their higher nucleophilicity, heteroatoms stabilize the growing carbenium ions better than alkyl and aryl groups do N-vinyl carbazole is more reactive than vinyl ethers because of nitrogen s higher nucleophilicity. However, the reactivity of the growing carbenium ions follows the opposite order shown above, with the most stable... 

From a retrosynfhetic viewpoint, N-aryl-l,2-diimine Ni precatalysts are synthesized by (i) reaction of 1,2 diimines with nickel halides from (ii) 1,2-diimine ligands which in turn are obtained by (iii) condensing 1,2-dicarbonyl substrates with two equivalents of primary aromatic amines, usually under acidic conditions [11]. In analogy, the synthesis of N-hetaryl 1,2 diimine catalysts starts from the corresponding substituted N-heterocyclic primary amines as the amine building blocks. The synthesis of three types of such heterocycles, N-amino-pyrroles, -indoles and -carbazoles, and their corresponding diimine derivatives is presented in the following sections. 

In 2007, Fujii, Ohno and their coworkers developed an efficient one-pot Buch-wald-Hartwig /V-arylation and oxidative coupling reaction to synthesize carbazoles (Scheme 27) [95]. Typically, Pd-catalyzed N-arylation of anilines with aryl triflates was conducted in toluene under the standard conditions. After completion of the N-ary I at ion as determined by TLC, acetic acid was added and an oxygen balloon was connected to the reaction flask (oxygen conditions) or it was subjected to air by an open system (air conditions). The protocol afforded various types of functionalized carbazoles in good to excellent yields (46->99%). 

Differential scanning calorimetry was used by Murrill and co-workers (43-45) to elucidate solid - solid phase transitions in a large number of organic compounds. First-order transitions were reported for tetrahedral compounds of the type CR1R2R2R4, where R is methyl, methylol, amino, nitro, and carboxy, as well as for octahedral-type compounds. This technique was also used to detect phase transitions in alkali metal stearates (46), some dibenzazepines, carbazoles, and phenothiazines (16), and the half esters of O-phthalic acid (31). The solid-state decomposition kinetics and activation parameters of N-aryl-N -tosyl-oxydt-imide N-oxides were determined using DSC by Dorko et al. (49). 

A construction of the carbazole framework involving copper(ll)-catalyzed aryla-mine arylation and palladium(ll)-mediated oxidative cyclization has been reported by Menendez et al. (Scheme 41) [190, 191]. The diarylamines 95 were obtained by copper(ll) acetate-catalyzed N-arylation of arylamines 31 with phe-nyllead triacetate (183) using Barton s conditions [192]. Subsequent oxidative cyclization using palladium(ll) acetate under microwave irradiation afforded the carbazoles 32. This procedure was applied to the synthesis of murrayafoline A (188) [190]. 

Scheme 41 Synthesis of carbazoles 32 by Cu(ll)-catalyzed N-arylation of the arylamines 31 and subsequent oxidative cyclization of the diarylamines 95...

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. 

Further applications of the double N-arylation to the synthesis of carbazoles include the natural products ellipticine [207] and mukonine (201) [208], and various non-natural ll-phenylbenzofuro[3,2-6]carbazoles [209]. 

Kamishawa et al. studied the migration of a tricarbonyl chromium from a N-aryl group to a carbazole. The migration is controlled by the dioxolane group. 

Azoles such as pyrrole (57), carbazole (58), and indole can be N-arylated in the presence of DPPF [48]. Various N-arylated indoles were prepared conveniently by N-arylation of indole with aryl iodides, bromides, chlorides, and triflates. Suitable ligands are selected from bulky biphenyl- or binaphthyl-based phosphines IV-12, rV-14, and VI-3 depending on the kinds of aryl halides used [49],... 

In this domino process, benzylamine was reacted with 2-halobenzamides through UUman-type coupling to yield the N-arylated intermediate 144 (Scheme 9.26). Then, a copper-catalyzed aerobic oxidation of 144 afforded the intermediate 145, which underwent an intramolecular nucleophilic addition of the amide to provide 146. Under the used reaction conditions, the intermediate 146 was oxidized to provide the desired products 147 in excellent yield. This protocol was also utilized by Fu et al. [80] by employing easily available a-amino adds instead of benzylamines to synthesize similar analogs. Very recently, the same method was applied for the synthesis of pyrimido[4,5-b]carbazoles by Nagarajan et al. [81]. 

Consecutive palladiumotalyzed carbon-nitrogen bond forming reactions can also be employed to access aromatic heterocycles. Nozaki has demonstrated this approach in the double N-arylation of 20 as a route to efficiently generate carbazoles (Scheme 6.40) [52]. This reaction can proceed with a range of alkyl and aryl amines, replacement of the aryl halides with sulfonates, and can even be performed consecutively to construct extended heteroacenes. 

In 1980s, Boger et al. reported pioneering work on carbazole synthesis by using palladium-mediated intramolecular N-arylation. The reaction of 4-(2-bromophenyl)pyridin-3-ylamines 6 in the presence of stoichiometric palladium complex gave P-carboline 7 (Scheme 23.3) [6]. This synthetic strategy was applied to the syntheses of other carbazole derivatives, 8 and 9, which were the synthetic intermediates for neuropeptide Y Y1 antagonists and clausenamine A, respectively (Scheme 23.3) [7]. 

Metal-catalyzed N-arylation of amines with haloarenes (Buchwald-Hartwig coupling) has been developed since the 1990s and provided more efficient access to carbazoles. Nozaki et al. reported the palladium-catalyzed double N-arylation of primary amines with 2,2 -dihalobiphenyls [8], A variety of dihalobiphenyls 10 and anilines 11 with electron-donating or electron-withdrawing substituent(s) are applicable to give multisubstituted carbazoles 12 in moderate to high yields (Scheme 23.4). 

Double N-arylation can also be conducted by using copper catalysts. In 2007, Martin, Li, and co-workers independently reported pyrrole synthesis via copper-catalyzed C—N bond formation between l,4-dihalo-l,3-dienes and amines [13]. They applied this methodology to carbazole synthesis (Scheme 23.9). In general, diiodobiaryl gave better results than dibromobiaryls. As a nitrogen source, carbamates and amides were investigated in their reports. 

---