Carbazoles iron-mediated synthesis

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]. 

Despite many applications of the iron-mediated synthesis of carbazoles, this method offers limited access to 2-oxygenated tricyclic carbazoles due to the moderate yield... 

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). 

Electrophilic substitution of the appropriately functionalized arylamine and subsequent iron-mediated oxidative cyclization with aromatization generates the carbazole skeleton. Annulation of the furan ring by treatment with catalytic amounts of amberlyst 15 affords furostifoline directly. Comparison of the six total syntheses reported so far for furostifoline demonstrates the superiority of the iron-mediated synthesis (Table 1 in ref. [43a]). Starting from the 2-methoxy-substituted tricarbonyliron-coordinated cyclohexadienylium salt this sequence has been applied to the synthesis of furoclausine-A (Scheme 15.12) [45]. 

Scheme 15 Iron-mediated synthesis of 2,7-dioxygenated carbazole alkaloids...

The iron-mediated synthesis of 2-oxygenated carbazoles is limited. On the other hand, a molybdenum-mediated approach works as a complementary route (Scheme 23.24) [31]. Similar to iron-coordinated cation 55, molybdenum-coordinated cations 61 react with electron-rich anilines 62 to give (if-cyclohexenyl)molybdenum complex 63. Then the oxidative cyclization of 63 followed by the subsequent aromatiza-tion and demetallation using activated manganese dioxide afforded the corresponding... 

Moreover, following the same synthetic approach, an efficient iron-mediated synthesis of pyrano[3,2-a]carbazole alkaloids has been reported. The first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine, as well as the first asymmetric synthesis of (-)-tra j-dihydroxygirinimbine (Scheme 4-130), have been accomplished using this strategy. ... 

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 carbazole construction using iron-mediated arylamine cydization for the C-N bond formation was applied to the synthesis of 4-deoxycarbazomycin B [84]. The synthesis of this model compound demonstrates also the course of the two key steps which are involved in the iron-mediated carbazole synthesis (Scheme 10). 

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 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. 

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). 

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). 

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). 

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... 

In addition to the aforementioned syntheses of various carbazole-l,4-quinone alkaloids, many formal syntheses for this class of carbazole alkaloids were also reported. These syntheses involve the oxidation of the appropriate 1- or 4-oxygenated-3-methylcarbazoles using Fremy s salt (potassium nitrosodisulfonate), or PCC (pyridinium chlorochromate), or Phl(OCCXI F3)2 [bis(trifluoroacetoxy)iodo]-benzene. Our iron-mediated formal synthesis of murrayaquinone A (107) was achieved starting from murrayafoline A (7) (see Scheme 5.34). Cleavage of the methyl ether in murrayafoline A (7) and subsequent oxidation of the resulting intermediate hydroxycarbazole with Fremy s salt provided murrayaquinone A (107) (574,632) (Scheme 5.113). 

Our total synthesis of carbazoquinocin C (274) based on the iron-mediated construction of the carbazole framework as a key step uses the fully functionalized arylamine 921 and cyclohexadiene (597) as precursors (640) (Scheme 5.119). 

A common precursor, the 6-bromocarbazole derivative 927, required for the total synthesis of the carbazole-3,4-quinone alkaloids (+ )-carquinostatin A K )-278] (641) and (+ )-lavanduquinocin [( )-280] (642), was prepared by iron-mediated one-pot C-C and C-N bond formation. Recently, the same methodology was adopted for the first enantioselective total synthesis of carquinostatin A (278) (643) and lavandu-quinocin (280) (644). 

Six years after the original isolation, we reported the first total synthesis of furostifoline (224) (688). This synthesis is based on an iron-mediated construction of the carbazole nucleus using 1,3-cyclohexadiene (597) and the 4-amino-7-methylbenzofuran (1103) as precursors (Scheme 5.177). 

Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron... 

A broad structural variety of carbazole alkaloids vdth useful biological activities has been isolated from different natural sources. The pharmacological potential of this class of natural products led to the development of diverse methods for the synthesis of carbazoies [29,30]. We elaborated an efficient iron-mediated construction of the carbazole framework by consecutive C-C and C-N bond formation. This method provides highly convergent routes to carbazoies as demonstrated first for 4-deoxycarbazomycin B (Scheme 15.8) [31]. 

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>. 

In 1989 we reported an iron-mediated route for the construction of the tricyclic carbazole skeleton [72, 73]. This convergent method was applied to the total synthesis of the naturally occurring alkaloid carbazomycin A [72]. Key steps of our iron-mediated approach are the consecutive C C bond formation and oxidative cyclization (formation of the C N bond) between an electrophilic tricarbonyl(ri -cyclohexadienyhum)iron complex salt 30 and an arylamine 31 (Scheme 10). Subsequent oxidation and demetalation provides the aromatized carbazole 32. 

Scheme 10 General principle of the iron-mediated carbazole synthesis...

The iron-mediated arylamine cyclization (mode A in Scheme 12) proceeds via the steps cyclodehydrogenation, aromatization, and concomitant demetalation, and can be achieved with various oxidizing agents (e.g., very active manganese dioxide [92, 93], iodine in pyridine [94—96], and ferroceifium hexafluorophosphate [92,97, 98]). Applications of this procedure to the total symthesis of carbazole alkaloids include for example hyellazole [97] and carazostatin [98] for reviews, see [18-20, 83]. More recent applications of this route to natural product synthesis are described in Sect. 3.1.1. 

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