Carbazoles oxidative cyclization

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Akermark first reported the efficient oxidative coupling of diphenyl amines to carbazoles 37 with Pd(OAc)2 in refluxing acetic acid [45]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO2), and 20 years later Akermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 38 to carbazole-l,4-quinones 39 [46]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6,11-quinones (e.g., 40). 

Hill described the Pd(OAc)2-oxidative cyclization of bisindolylmaleimides (e.g., 49) to indolo[2,3-a]pyrrolo[3,4-c]carbazoles (e.g., 50) [69], which is the core ring system in numerous natural products, many of which have potent protein kinase activity [70]. Other workers employed this Pd-induced reaction to prepare additional examples of this ring system [71, 72]. Ohkubo found that PdClj/DMF was necessary to prevent acid-induced decomposition of benzene-ring substituted benzyloxy analogues of 49, and the yields of cyclized products under these conditions are 85-100% [71]. 

An oxidative cyclization leads to the C-N bond formation and furnishes the carbazole nucleus. The three modes of the iron-mediated carbazole synthesis differ in the procedures which are used for the oxidative cyclization [77,78]. 

The reaction of the complex salt 6a with the arylamine 12 affords by regio-selective electrophilic substitution the iron complex 13 [88] (Scheme 11). The oxidative cyclization of complex 13 with very active manganese dioxide provides directly mukonine 14, which by ester cleavage was converted to mukoeic acid 15 [89]. Further applications of the iron-mediated construction of the carbazole framework to the synthesis of 1-oxygenated carbazole alkaloids include murrayanine, koenoline, and murrayafoline A [89]. 

The iron-mediated synthesis of 2-oxygenated carbazole alkaloids is limited and provides only a moderate yield (11%) for the oxidative cyclization to 2-methoxy-3-methylcarbazole using iodine in pyridine as the reagent [90]. Ferricenium hexafluorophosphate is the superior reagent for the iron-mediated arylamine cyclization leading to 3-oxygenated carbazoles (Scheme 12). Electrophilic substitution of the arylamines 16 with the complex salt 6a leads to the iron complexes 17. Oxidative cyclization of the complexes 17 with an excess of ferricenium hexafluorophosphate in the presence of sodium carbonate affords... 

The total synthesis of the carbazomycins emphasizes the utility of the iron-mediated synthesis for the construction of highly substituted carbazole derivatives. The reaction of the complex salts 6a and 6b with the arylamine 20 leads to the iron complexes 21, which prior to oxidative cyclization have to be protected by chemoselective 0-acetylation to 22 (Scheme 13). Oxidation with very active manganese dioxide followed by ester cleavage provides carbazomycin B 23a [93] and carbazomycin C 23b [94]. The regioselectivity of the cyclization of complex 22b to a 6-methoxycarbazole is rationalized by previous results from deuterium labeling studies [87] and the regiodirecting effect of the 2-methoxy substituent of the intermediate tricarbonyliron-coordinated cyclo-hexadienylium ion [79c, 79d]. Starting from the appropriate arylamine, the same sequence of reactions has been applied to the total synthesis of carbazomycin E (carbazomycinal) [95]. 

The carbazole-1,4-quinol alkaloids are also accessible by the iron-mediated arylamine cyclization (Scheme 14). Electrophilic substitution reaction of the arylamine 24 with the complex salts 6a and 6b affords the iron complexes 25. Protection to the acetates 26 and oxidative cyclization with very active manganese dioxide leads to the carbazoles 27, which are oxidized to the carbazole-... 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

The double iron-mediated arylamine cyclization provides a highly convergent route to indolo[2,3-fc]carbazole (Scheme 16). Double electrophilic substitution of m-phenylenediamine 34 by reaction with the complex salt 6a affords the diiron complex 35, which on oxidative cyclization using iodine in pyridine leads to indolo[2,3-b]carbazole 36 [98].Thus,ithasbeen demonstrated that the bidirectional annulation of two indole rings can be applied to the synthesis of indolocarbazoles. 

More recently, an environmentally benign method using air as oxidant has been developed for the oxidative cyclization of arylamine-substituted tricarbonyl-iron-cyclohexadiene complexes to carbazoles (Scheme 19). Reaction of methyl 4-aminosalicylate 45 with the complex salt 6a affords the iron complex 46, which on oxidation in acidic medium by air provides the tricarbonyliron-complexed 4a,9a-dihydrocarbazole 47. Aromatization with concomitant demetalation by treatment of the crude product with p-chloranil leads to mukonidine 48 [88]. The spectral data of this compound are in agreement with those reported by Wu[22j. 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

The molybdenum-mediated arylamine cyclization was also applied to the total synthesis of pyrano[3,2-a]carbazole alkaloids (Scheme 26). Reaction of the 5-aminochromene 71 with the complex salt 62 affords the complex 72, which on oxidative cyclization provides girinimbine 73, a key compound for the transformation into further pyrano[3,2-a] carbazole alkaloids. Oxidation of 73 with DDQ leads to murrayacine 74, while epoxidation of 73 using meta-chloro-perbenzoic acid (MCPBA) followed by hydrolysis provides dihydroxygirinim-bine75 [113]. 

The oxidative cyclization of Ar,Ar-diarylamines to carbazoles has been achieved by thermal or photolytic induction [7, 75]. However, the yields for this transformation are mostly moderate. Better results are obtained by the palladium(II)-mediated oxidative cyclization of Ar,Ar-diarylamines (Scheme 27). Oxidative cyclization by heating of the Ar,Ar-diarylamines 76 in the presence of a stoichiometric amount of palladium(II) acetate in acetic acid under reflux provides the corresponding 3-substituted carbazoles 77 in 70-80% yield [118]. The cou-... 

The palladium(II)-mediated oxidative cyclization of Ar,AT-diarylamines is useful for convergent total syntheses of a range of structurally different carbazole alkaloids. Goldberg coupling of 2,3-dimethoxyacetanilide 80 and 2-bromo-5-methylanisole 81 and subsequent alkaline hydrolysis affords the diarylamine 82... 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

The palladium(II)-mediated oxidative cyclization is also applied to the synthesis of carbazole-l,4-quinone alkaloids. The required arylamino-l,4-benzo-quinones are readily prepared by arylamine addition to the 1,4-benzoquinone and in situ reoxidation of the resulting hydroquinone [131]. 

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). 

Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(ri -cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C-C and C-N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). 

Over the past 15 years, we developed three procedures for the iron-mediated carbazole synthesis, which differ in the mode of oxidative cyclization arylamine cyclization, quinone imine cyclization, and oxidative cyclization by air (8,10,557,558). The one-pot transformation of the arylamine-substituted tricarbonyl(ri -cyclohexadiene) iron complexes 571 to the 9H-carbazoles 573 proceeds via a sequence of cyclization, aromatization, and demetalation. This iron-mediated arylamine cyclization has been widely applied to the total synthesis of a broad range of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated carbazole alkaloids (Scheme 5.24). 

The two key steps for the construction of the carbazole framework by the iron-mediated approach are, first, C-C bond formation by electrophilic aromatic substitution of the arylamine with the tricarbonyliron-complexed cyclohexadienyl cation and, second, C-N bond formation and aromatization by an oxidative cyclization. Application of this methodology provides murrayanine (9) and koenoline (8) in three steps and 15%, and in four steps and 14% overall yield, respectively, starting from the commercial nitroaryl derivative 601 (573,574) (Scheme 5.33). 

Electrophilic aromatic substitution of 3-methoxy-4-methylaniline (655) using the 2-methoxy-substituted iron complex salt 665, followed by oxidative cyclization with concomitant aromatization of the resulting iron complex salt 666, affords 2,7-dimethoxy-3-methylcarbazole (667). Oxidation of the carbazole 667 with DDQ... 

Electrophilic aromatic substitution of the arylamine 780a using the iron-complex salt 602 afforded the iron-complex 785. Oxidative cyclization of complex 785 in toluene at room temperature with very active manganese dioxide afforded carbazomycin A (260) in 25% yield, along with the tricarbonyliron-complexed 4b,8a-dihydro-3H-carbazol-3-one (786) (17% yield). The quinone imine 786 was also converted to carbazomycin A (260) by a sequence of demetalation and O-methylation (Scheme 5.86). The synthesis via the iron-mediated arylamine cyclization provides carbazomycin A (260) in two steps and 21% overall yield based on 602 (607-609) (Scheme 5.86). 

Using a one-pot process of oxidative cyclization in air, the arylamine 780a was transformed to the tricarbonyl(ri -4b,8a-dihydro-9H-carbazole)iron complex 792. Finally, demetalation of 792 and subsequent aromatization gave carbazomycin A (260). This synthesis provided carbazomycin A (260) in three steps and 65% overall yield based on 602 (previous route four steps and 35% yield based on 602) (610) (Scheme 5.88). 

The construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (614). Reaction of the iron complex salt 602 with the fully functionalized arylamine 814 in air provided the tricarbonyliron-coordinated 4b,8a-dihydrocarbazole complex 819 via sequential C-C and C-N bond formation. This one-pot annulation is the result of an electrophilic aromatic substitution and a subsequent iron-mediated oxidative cyclization by air as the oxidizing agent. The aromatization with concomitant demetalation of complex 819 using NBS under basic reaction conditions, led to the carbazole. Using the same reagent under acidic reaction conditions the carbazole was... 

Construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (641,642). The reaction of the (R)-arylamine 928 with the iron complex salt 602 in air provided by concomitant oxidative cyclization the tricarbonyliron-complexed 4b,8a-dihydro-9H-carbazole (931). Demetalation of the complex 931, followed by aromatization and regioselective electrophilic bromination, afforded the 6-bromocarbazole 927, which represents a crucial precursor for the synthesis of the 6-substituted carbazole... 

The intramolecular oxidative cyclization of the anilinobenzoquinone 940 with a catalytic amount of palladium(II) acetate in the presence of copper(II) acetate in air afforded the carbazole-l,4-quinone 941 in almost quantitative yield. The regioselective introduction of the heptyl side chain at C-1 of the carbazole-l,4-quinone 941 was achieved by a 1,2-addition of the corresponding Grignard reagent to give the carbazole-l,4-quinol 942 in 55% yield. However, 1,4-addition at C-3 and 1,2-addition at C-4 led to the regioisomeric products 943 and 944 as well. Finally, under acidic reaction conditions, the carbazole-l,4-quinol 942 was smoothly transformed to... 

Our palladium(II)-catalyzed approach for the carbazomycins G (269) and H (270) requires the carbazole-l,4-quinones 941 and 981 as precursors (compare the iron-mediated synthesis, see Scheme 5.137). These intermediates should result from oxidative cyclization of the arylamino-l,4-benzoquinones, which in turn are prepared from the arylamines 839 and 984 and 2-methoxy-3-methyl-l,4-benzoqui-none (939) (652) (Scheme 5.138). 

One of the carbazole-l,4-quinones, 3-methoxy-2-methylcarbazole-l,4-quinone (941), required for the total synthesis of carbazomycin G (269), was already used as a key intermediate for the total synthesis of carbazoquinocin C, and was obtained by the addition of aniline (839) to 2-methoxy-3-methyl-l,4-benzoquinone (939), followed by oxidative cyclization with catalytic amounts of palladium(II) acetate (545,645) (see Schemes 5.124 and 5.125). Similarly, in a two-pot operation, 4-meth-oxyaniline (984) was transformed to 3,6-dimethoxy-2-methylcarbazole-l,4-quinone... 

The relay compound 1025 required for the synthesis of all of these 7-oxygenated carbazole alkaloids was obtained starting from commercially available 4-bromo-toluene (1023) and m-anisidine (840) in two steps and 72% overall yield. Buchwald-Hartwig amination of 4-bromotoluene (1023) with m-anisidine (840) furnished quantitatively the corresponding diarylamine 1024. Oxidative cyclization of 1024 using catalytic amounts of palladium(ll) acetate afforded 3-methyl-7-methoxycarbazole (1025). Oxidation of 1025 with DDQ led to clauszoline-K (98), which, on cleavage of the methyl ether using boron tribromide, afforded 3-formyl-7-hydroxycarbazole (99) (546) (Scheme 5.149). 

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). 

Generally high yields of substituted carbazoles can be obtained by oxidative cyclization of diphenylamines using Pd(OAc)2 to effect cyclization (equation 59) (75JOC1365). This method has been used, for example, to close the carbazole ring in the synthesis of the anti-tumor alkaloid ellipticine (equation 60) (80TL3319). 

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