Functionalized carbazoles, synthesis

The application of indolo-2,3-quinodimethanes and their cyclic analogs in the synthesis of carbazole alkaloids has attracted wide interest since they could undergo Diels-Alder reactions with a wide variety of dienophiles to afford functionalized carbazole derivatives. This represents the shortest and most elegant method for the preparation of selectively functionalized carbazole derivatives (514). 

The electrocyclic reaction of divinylindoles to functionalized carbazole derivatives has emerged as an efficient method for the synthesis of a diverse range of carbazole derivatives. This reaction has been achieved at high temperatures in the presence of palladium on charcoal or DDQ. The palladium catalyst or DDQ act as dehydrogenating agent (534,535) (Scheme 5.19). 

An efficient synthesis of functionalized carbazoles was developed by the palladium-catalyzed annulation of a variety of internal alkynes. This reaction involves arylpalladation of the alkyne, followed by intramolecular Heck olefination, and double bond isomerization. The iodoindole 588 reacts with the alkyne 589 in the presence of a catalytic amount of palladium(O) to give substituted carbazoles 590. In this reaction two new C-C bonds are formed in a single step. Higher reaction temperatures were necessary due to the low reactivity of the iodoindole (566) (Scheme 5.29). 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

The first efficient synthetic strategy for 2,7-functionalized carbazoles was reported by Smith and Brown in 1951 [21,22], The crucial step in this synthesis is the formation of the azide compound generally starting from an... 

Ackermann employed a different reaction order to meld 1,2-dihaloaryls together with anilines to access a series of carbazoles, including murrayafoline A (Scheme 2, equations 1 and 2) [23]. Jean and colleagues reported a tandem Suzuki/aryl-Heck protocol to prepare functionalized carbazoles and glycosinine (equation 3) [24]. Larock and Liu synthesized a series of carbazoles and the alkaloid muko-nine via an aryl-Heck reaction, which featured an aryne mediated preparation of the requisite diaryl amines [25]. Willis and coworkers reported an indole synthesis involving Heck arylation followed by double bond isomerization (equation 4) [26]. Urabe and colleagues described a similar aryl-Heck indolization from p-bromo-Al-aryl enamines giving 2-alkylindoles [27]. 

Hartwig and Tan reported a simple indole synthesis from an oxime acetate involving C-H functionalization (Scheme 3, equation 1) [22]. Buchwald described an excellent versatile carbazole synthesis that also involved C-H activation (equation 2) [23], as did Youn [24], Antonchick [25], Gault [26], and Shi [27], who synthesized 4-deoxy-carbazomycin B (equation 3). 

The gold-catalysed intramolecular amination of allylic alcohols with alkylamines has provided substituted pyrrolidine and piperidine derivatives with excellent yields and selectivities (up to 99% yield and 96% ee)." The reaction mechanism was found to be consistent with the net syn addition of the amine relative to the departing hydroxyl group (Scheme 6). The synthesis of functionalized carbazoles through gold-catalysed deacylative cycloisomerization of 3-acylindole/ynes has been reported. ... 

The intramolecular trapping of benzyne intermediates with tethered nucleophiles is a powerful strategy for the synthesis of benzo-fused heterocycles. In this field, 7-functionalized benzoxazoles 59 and benzothiazoles 60 have been prepared by anionic cyclization of the corresponding lithiated benzyne (thio)amides and (thio)carbamates, which were generated from 3-haloaniline derivatives (Scheme 12.34) [55]. Related to this, substituted indolines 61 have also been accessed by benzyne-mediated cyclization-functionalization from Boc-protected (2-bromo-4-methoxy)phenetylamines using Mg(TMP)2 2LiCl as a base. This methodology has also been applied to the preparation of functionalized carbazoles (Scheme 12.34) [56]. 

In 2005, Tsang et al. reported the new methodology for carbazole synthesis. The key feature of this methodology is the combination of a C—H bond functionalization and an intramolecular N-arylation (intramolecular C—H bond amination) starting from N-substituted-2-arylanilines. In the presence of a catalytic amount of... 

Other nitrogen-containing functional groups also work as a nitrogen source in the intramolecular C—H bond amination for carbazole synthesis. Smitrovich and... 

Applying these methodologies monomers such as isobutylene, vinyl ethers, styrene and styrenic derivatives, oxazolines, N-vinyl carbazole, etc. can be efficiently polymerized leading to well-defined structures. Compared to anionic polymerization cationic polymerization requires less demanding experimental conditions and can be applied at room temperature or higher in many cases, and a wide variety of monomers with pendant functional groups can be used. Despite the recent developments in cationic polymerization the method cannot be used with the same success for the synthesis of well-defined complex copolymeric architectures. 

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]. 

A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). 

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). 

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... 

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). 

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... 

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]. 

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