Synthesis of Pyrroles, Indoles, and Carbazoles Through Transition-Metal- Catalyzed CÀH Functionalization

FOCUS REVIEW

DOI: 10.1002/ajoc.201300016

Synthesis of Pyrroles, Indoles, and Carbazoles through Transition-Metal- Catalyzed CÀH Functionalization

Naohiko Yoshikai*[a] and Ye Wei[b]

Asian J. Org. Chem. 2013, 2, 466 – 478 466 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

Abstract: Pyrroles, indoles, and carbazoles are among the most important families of nitrogen- containing heterocycles that occur frequently in natural products, pharmaceuticals, agrochemi- cals, and other functional molecules. Consequently, improved syntheses of these compounds continue to interest synthetic chemists. This Focus Review describes recent advances in synthetic methods for producing these privileged heterocycles that feature transition-metal-catalyzed CÀH activation approaches. Because of the common five-membered pyrrole core, some of the CÀH activation approaches are applicable to two or more of the pyrrole, indole, and carbazole skele- tons. The reactions discussed here not only serve as atom- and step-economical alternatives to the existing synthetic methods, but also show the latest developments in organometallic chemistry and homogeneous catalysis.

Keywords: CÀH activation · heterocycles · homogeneous catalysis · palladium · rhodium

1. Introduction sequently, the development of synthetic methods for producing these privileged heterocyclic scaffolds has received Pyrrole and its benzo-fused analogues indole and carbazole considerable attention from synthetic chemists.[2,3] Whereas are extremely common structural units in biologically classical synthetic methods, such as the Paal–Knorr pyrrole active natural and unnatural compounds, as well as in dyes, synthesis and the Fischer indole synthesis, have been impor- pigments, and other functional materials (Scheme 1).[1] Con- tant methods for more than a hundred years, transition- metal-catalyzed reactions have emerged and evolved into practical alternatives over the past several decades. The preparation of a tryptamine-based gonadotropin-releasing hormone (GnRH) antagonist through Larock, Fischer, and Castro indole syntheses is an illustrative example that shows the practical utility of such well-established synthetic methods (Scheme 2).[4]

Scheme 1. Examples of biologically active and other functional molecules that contain pyrrole, indole, or carbazole moieties.

Scheme 2. Preparation of a tryptamine-based GnRH antagonist through [a] Prof. N. Yoshikai Larock, Fischer, and Castro indole syntheses. Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University A common problem in many of the existing synthetic Singapore 637371 (Singapore) methods is, however, the requirement for “prefunctional- Fax : (+65)6791-1961 ized” starting materials. For example, with respect to the E-mail: [email protected] above-mentioned indole syntheses, Fischer and Larock/ [b] Prof. Y. Wei College of Pharmacy Castro methods require carcinogenic aryl hydrazines and Third Military Medical University, (China) rather expensive 2-iodoaniline derivatives, respectively. Fur-

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thermore, the diversity of commercially available aryl hy- arylation,[7] however, was scarcely revisited for a long drazines and 2-haloanilines is relatively limited and much time.[8] In 2002, Bedford and Cazin reported a palladium- narrower than that of simple anilines. This limited availabil- catalyzed one-pot synthesis of N-alkylcarbazole from 2- ity poses a serious obstacle when one wishes to access a di- chloro-N-alkylaniline and aryl bromides by sequential verse array of indoles with various substituents on the ben- Buchwald-Hartwig amination and CÀH arylation zene ring. (Scheme 4).[9] Modification of the original catalytic system In the above context, over the last several years, remark- able progress has been made in the syntheses of pyrroles, indoles, and carbazoles through transition-metal-catalyzed CÀH bond functionalization, which is summarized in this Focus Review.[5] Herein, such emerging synthetic methods are classified based on the key bond disconnection (Scheme 3). Thus, transition metal-catalyzed CÀH activa-

Scheme 4. Carbazole synthesis through sequential CÀN cross-coupling/ intramolecular direct CÀH arylation.

later allowed the synthesis of NÀH carbazoles from unprotected 2-chloroanilines in either a one-pot or stepwise Scheme 3. Possible disconnections of pyrrole, indole, and carbazole, and [10] the corresponding CÀH functionalization strategies. manner. Indole derivatives were also synthesized from 2- chloroanilines and bromoalkenes. tion has proven effective for forging CÀC bonds through dehydrohalogenation or dehydrogenation (disconnection a), Naohiko Yoshikai received his B.Sc. (2000), CÀC and CÀN bonds simultaneously through annulation M.Sc. (2002), and Ph.D. degrees (2005) with an alkyne (disconnections a and b), or CÀN bonds from the University of Tokyo under the through oxidative amination or (formal) nitrene insertion guidance of Professor Eiichi Nakamura. (disconnection b or c). Then he was appointed as an Assistant Pro- fessor of Chemistry at the same institute. In 2009, he moved to Singapore to join the Di- vision of Chemistry and Biological Chemis- 2.1. CÀH/CÀX Coupling try, School of Physical and Mathematical Sciences, at Nanyang Technological Univer- In the early 1980s, Ames and Opalko reported that diaryl sity as a Nanyang Assistant Professor/Sin- gapore National Research Foundation Re- ethers and diaryl amines with a 2-bromo or 2-iodo substitu- search Fellow. His research interests are fo- ent underwent palladium-catalyzed dehydrohalogenative cused on the development and mechanistic cyclization to afford dibenzofurans and carbazoles, respec- study of new transition-metal-catalyzed re- tively.[6] This seminal work on biaryl synthesis through CÀH actions and their synthetic applications.

Ye Wei was born in 1982 in China. He earned his B.Sc. degree in 2005 from Hua- qiao University and his Ph.D. degree in Abstract in Japanese: 2010 from Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, under the guidance of Prof. Weiping Su. After a two-year postdoctoral appontiment with Prof. Naohiko Yoshikai at Nanyang Technological University, he went back to China to join the College of Pharmacy at Third Military Medical Uni- versity as an Associate Professor. His cur- rent research interests are primarily focused on atom- and step-economic synthetic methods, with an emphasis on the transition-metal-mediated organic transformations and exploiting metal–organic cooperatively catalyzed reactions.

Asian J. Org. Chem. 2013, 2, 466 – 478468 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

In 2004, Fagnou and co-workers published the first major contribution of their group in the area of CÀH functionalization, that is, palladium-catalyzed intramolecular biaryl synthesis through direct arylation, which allowed efficient formation of six- and seven-membered rings.[11] The power of their PdÀPCy3 catalytic system was also demonstrated for the synthesis of carbazole derivatives.[12] For example, the carbazole natural product Mukonine was readily synthesized with the intramolecular CÀH arylation as the key Scheme 7. Preparation of N-sulfonylindole through addition of sulfonamides to bromoacetylenes with subsequent intramolecular CÀH alkeny- step (Scheme 5). lation. DMF =N,N-dimethylformamide.

2.2. CÀH/CÀH Coupling

Oxidative linkage of two CÀH bonds is one of the ideal strategies for CÀC bond formation.[15] This strategy be- comes particularly attractive if the process is catalytic and requires only a harmless and inexpensive oxidant. In 1975, kermark et al. found that a stoichiometric amount of Pd- ACHTUNGRE (OAc)2 effected cyclization of diarylamines to carbazoles (Scheme 8a).[16] Subsequent studies by the groups of ker- Scheme 5. Synthesis of Mukonine by using Fagnou and co-workers direct arylation protocol. Tf =trifluoromethanesulfonyl.

In 2007, Ackermann and Althammer reported an alternative strategy for one-pot carbazole synthesis through sequential CÀN and CÀC bond formations (Scheme 6). Thus,

ACHTUNGRE Scheme 8. (a) Pd(OAc)2-mediated cyclization of diarylamine to give car- ACHTUNGRE ACHTUNGRE bazole. (b) Pd(OAc)2-catalyzed, Cu(OAc)2-mediated cyclization of aryla- minoquinone to carbazolequinone, and carbazole alkaloids synthesized Scheme 6. Carbazole/indole synthesis from anilines and dihalogenated through kermark–Knçlker cyclization. arenes/olefins.

mark and Knçlker significantly improved the reaction and a variety of carbazole derivatives, including the natural demonstrated its utility in the synthesis of naturally occur- product Murrayafoline A, were assembled from simple ani- ring carbazole alkaloids.[17] Most importantly, the reaction ACHTUNGRE line derivatives and o-dihalogenated arenes with the aid of was made catalytic in Pd(OAc)2 by using an oxidant such as [13] ACHTUNGRE aPdÀPCy3 catalyst. The reaction also allowed the synthe- Cu(OAc)2 or molecular oxygen (Scheme 8b). On the other sis of an annulated indole from cyclic 1,2-dibromoalkenes. hand, the acidic reaction medium (acetic acid) and harsh Urabe and co-workers developed the nucleophilic addi- reaction conditions often caused undesirable side reactions tion of sulfonamides to bromoalkynes to afford olefins with and, thus, limited the substrate scope. Notable modifica- sulfonamide and bromo groups and cis stereochemistry.[14] tions have been made, including the one-pot N-arylation/ With an aryl group on the nitrogen atom, the adduct was oxidative coupling protocol by Fujii and co-workers,[18] the suitable for palladium-catalyzed intramolecular CÀH/CÀBr use of pivalic acid as a superior solvent by Fagnou et al.,[19] coupling to furnish an N-sulfonylindole (Scheme 7). and the use of Pt/C instead of a palladium catalyst in hydrothermal water by Yamamoto and Matsubara.[20]

Asian J. Org. Chem. 2013, 2, 466 – 478469 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

ACHTUNGRE In 2008, Glorius and co-workers brought about a signifi- dium(II) with the aid of Cu(OAc)2. Based on the results of cant breakthrough in the scope of the oxidative palladium mechanistic studies, which included a large H/D kinetic iso- catalysis by introducing a new substrate class and modified tope effect (KIE), the intramolecular CÀH activation step reaction conditions. They showed that N-aryl enamines, was proposed to involve s-bond metathesis or base-assisted which can be readily prepared from anilines and b-dicar- deprotonation[23] rather than electrophilic palladation. bonyl compounds, are efficiently cyclized into indoles in the Glorius and co-workers’ discovery of the enamine cycli- ACHTUNGRE presence of catalytic Pd(OAc)2 and a stoichiometric zation was followed by the development of several alterna- ACHTUNGRE amount of Cu(OAc)2 with K2CO3 and DMF as the base and tive reaction systems for the same type of transformation. the solvent, respectively (Scheme 9).[21] A variety of indole Cacchi and co-workers developed a copper-based system derivatives with electron-withdrawing substituents on the with air as an oxidant (Scheme 11a).[24] Zhao and co-work- C3 position were synthesized and the reaction tolerated a remarkably broad range of functional groups.

Scheme 9. Palladium(II)-catalyzed, copper(II)-mediated cyclization of N-arylenamines to give indoles. EWG = electron-withdrawing group; Piv =pivaloyl. Scheme 11. Several reaction systems for oxidative cyclization of N-aryl enamines to give indoles. DCE =1,2-dichloroethane.

The follow-up study by the same group led to an improved catalytic system with K3PO4 instead of K2CO3, ers reported a metal-free reaction system with iodobenzene which proved effective on a preparatively useful scale.[22] diacatate as a stoichiometric oxidant (Scheme 11b).[25, 26] The reaction was proposed to begin with electrophilic palla- Liang and co-workers reported a catalytic system compris- ACHTUNGRE dation of the enamine and subsequent deprotonation, ing FeCl3 as a catalyst and Cu(OAc)2·CuCl2 as an oxidant which led to a vinylpalladium(II) species (Scheme 10). This (Scheme 11c).[27] species then undergoes intramolecular aromatic CÀH acti- Building on the chemistry pioneered by kermark, vation, and a subsequent reductive elimination affords the Knçlker, and Glorius, in 2012 we disclosed a palladium-cat- product and palladium(0), which is then reoxidized to palla- alyzed aerobic oxidative cyclization reaction of N-aryl imines to indoles (Scheme 12).[28, 29] A variety of N-aryl imines derived from anilines and ketones, including aceto- phenones, 2-arylacetophenones, and aliphatic methyl ketones, for example, cyclopropyl methyl ketone, were effi-

Scheme 10. Proposed mechanism for palladium(II)-catalyzed indole for- Scheme 12. Palladium(II)-catalyzed aerobic cyclization of N-aryl imines mation from an enamine. to give indoles.

Asian J. Org. Chem. 2013, 2, 466 – 478470 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

ciently converted into indole products in the presence of 2.3. CÀH/NÀH/Alkyne Annulation ACHTUNGRE catalytic Pd(OAc)2 and molecular oxygen (1 atm.) with

Bu4NBr and dimethyl sulfoxide (DMSO) as the crucial ad- Annulation of o-haloaniline derivatives and alkynes, known ditive and solvent, respectively, under mild conditions. as the Larock indole synthesis, offers a highly reliable The catalytic cycle shown in Scheme 13 was proposed. method for the synthesis of indoles that is compatible with Palladation of the N-aryl enamine generated through tauto- various functional groups. On the other hand, this method merization of the imine and subsequent elimination of suffers from the high cost and limited availability of o-haloanilines. In this context, the rhodium(III)-catalyzedACHTUNGRE oxidative annulation reaction disclosed by Fagnou and co-workers in 2008, is a highly attractive alternative (Scheme 15).[33, 34] Thus, a cationic rhodium(III)ACHTUNGRE catalyst,

Scheme 13. Proposed mechanism for palladium(II)-catalyzed indole for- ACHTUNGRE mation from N-aryl imines. Scheme 15. Rhodium(III)-catalyzed, copper(II)-mediated oxidative annulation of acetanilides and alkynes to give indoles. Am=amyl.

HOAc gives an a-palladated imine.[30] This intermediate undergoes intramolecular aromatic CÀH activation then re- which is generated from [Cp*RhCl2]2 and AgSbF6, in com- ductive elimination to afford the 3H-indole and palladi- bination with a stoichiometric copper(II) oxidant, allowed um(0). The former quickly tautomerizes to the indole prod- direct coupling of N-acetyl anilines and internal alkynes to uct and the latter is oxidized to palladium(II) by molecular form a variety of N-acetyl indoles. oxygen and HOAc. The mechanism of the intramolecular A subsequent investigation by the same group led to CÀH activation step appears similar to that involved in a significant improvement of the catalytic system. With Glorius and co-workers enamine cyclization because the a preformed cationic rhodium(III)ACHTUNGRE complex ACHTUNGRE ACHTUNGRE ACHTUNGRE H/D KIE is similar in magnitude. [Cp*Rh(MeCN)3][SbF6]2 as a catalyst, the reaction was As a major limitation of the imine cyclization reaction, made much milder and catalytic in copper(II) with molecu- imines with b-hydrogen atoms underwent dehydrogenation lar oxygen (1 atm.) as a terminal oxidant.[35] The improved rather than oxidative cyclization, presumably through rapid catalytic system enabled a concise synthesis of Paullone b-hydride elimination of the putative a-palladated imine (Scheme 16a) and extended the scope of the reaction to the (Scheme 14). This reactivity could be used for the prepara- synthesis of pyrroles from enamides and alkynes tion of arylamines from amines and cyclohexanones (Scheme 16b). The regioselectivity of the reaction with un- through dehydrogenative aromatization of the imine inter- symmetrical alkynes was primarily governed by electronic mediates.[31,32] effects, and moderately affected by steric factors. Extensive mechanistic studies led to the proposal of the catalytic cycle outlined in Scheme 17, which involves depro- tonative ortho-rhodation assisted by the amide-oxygen atom, insertion of the alkyne into the RhÀaryl bond then deprotonation to form a six-membered rhodacycle, and CÀN reductive elimination to generate the indole product and a rhodium(I) species that is oxidized to rhodium(III)ACHTUNGRE Scheme 14. Dehydrogenative aromatization of an N-aryl imine derived ACHTUNGRE from tetralone. with the aid of Cu(OAc)2/O2. Whereas the ortho-rhodation step is intrinsically reversible, its reversibility in the annulation reaction depends on the rate of the subsequent alkyne insertion step. Therefore, it is reversible and irreversible with the original and the improved catalytic systems, respectively. The importance of precoordination of the alkyne

Asian J. Org. Chem. 2013, 2, 466 – 478471 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

Scheme 18. Regiocontrolled synthesis of dialkylpyrroles from enynes.

regiochemistry of the final dialkylindole/pyrrole products can be secured by the regioselective annulation of enynes, in which CÀN bond formation takes place at the carbon atom that is proximal to the alkenyl group. Glorius and co-workers discovered a different type of rhodium(III)-catalyzedACHTUNGRE oxidative annulation reaction to produce pyrroles (Scheme 19).[37] Enamides with methyl

Scheme 16. Improved rhodium(III)ACHTUNGRE catalytic system for a) concise synthesis of Paullone and b) annulation of enamides and alkynes to give pyrroles. Boc=tert-butyloxycarbonyl; TBS =tert-butyldimethylsilyl.

Scheme 19. Rhodium(III)-catalyzedACHTUNGRE annulation of enamines and alkynes involving allylic C(spACHTUNGRE 3)ÀH activation.

and ester groups at the a and b positions, respectively, underwent annulation with an alkyne at the NÀH and methyl CÀH bonds, presumably through C(spACHTUNGRE 3)ÀH bond activation. Interestingly, when the b substituent R1 was H, the rhodium catalyst appeared to reversibly activate the b-CÀH position, but no pyrrole product arising from such a process was ob- tained. Since a study by Ackermann et al. in 2011,[38] rutheniu- m(II) catalysts have proven to serve as inexpensive alternatives to rhodium(III)ACHTUNGRE catalysts in a series of oxidative CÀH functionalization reactions. They developed an annulation reaction of N-pyrimidylindoles with alkynes to form indole ACHTUNGRE ACHTUNGRE products with a [RuCl2(p-cymene)]2 catalyst and Cu(OAc)2 as the oxidant (Scheme 20a).[39] The pyrimidyl group on the indole product was readily removed by using NaOEt. They Scheme 17. Proposed catalytic cycle for rhodium(III)-catalyzedACHTUNGRE annulation of N-acetyl anilines and alkynes. further demonstrated the feasibility of the ruthenium-catalyzed annulation reaction for the synthesis of pyrroles from enamines and alkynes (Scheme 20b).[40] to the rhodium(III)ACHTUNGRE catalyst was also indicated but is not Whereas the above annulative indole syntheses require shown in Scheme 17. anilines with directing groups on the nitrogen atom, Jiao A significant limitation of the annulation reaction was and co-workers achieved oxidative annulation by using un- poor regioselectivity with unsymmetrical dialkylalkynes. protected anilines. Thus, simple anilines underwent oxida- Fagnou and co-workers solved this problem by combining tive coupling with dimethyl acetylenedicarboxylate ACHTUNGRE oxidative annulation of enynes and hydrogenation of the (DMAD) in the presence of catalytic Pd(OAc)2 and molec- resulting indole/pyrrole products (Scheme 18).[36] Thus, the ular oxygen (1 atm., Scheme 21a).[41] Although the scope of

Asian J. Org. Chem. 2013, 2, 466 – 478472 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

Scheme 22. Palladium(II)-catalyzed, copper(II)-mediated oxidative annulation of anilines and diarylalkynes to give a) indoles or b) pyrroles.

2.4. Oxidative CÀH Amination

Scheme 20. Rhodium(II)-catalyzed annulation of a) N-pyrimidylindoles and alkynes for indole synthesis and b) enamines and alkynes for pyrrole In 2005, Buchwald and co-workers reported the first exam- synthesis. ple of carbazole synthesis through oxidative aromatic CÀH [43] ACHTUNGRE bond amination. In the presence of a Pd(OAc)2 catalyst, ACHTUNGRE Cu(OAc)2, and molecular oxygen (1 atm.), 2-acetoaminobi- phenyl derivatives efficiently cyclized to afford N-acetyl ACHTUNGRE carbazoles (Scheme 23). The loading of Cu(OAc)2 could be

Scheme 23. Palladium(II)-catalyzed, copper(II)-mediated cyclization of 2-acetaminobiphenyls to give N-acetylcarbazoles.

reduced to a catalytic amount. This oxidative amination re- Scheme 21. Palladium(II)-catalyzed oxidative annulation of unprotected action in combination with the Suzuki–Miyaura coupling anilines and reactive alkynes/benzynes. N,N,-dimethylacetamide (DMA). opened a convenient route to carbazoles starting from 2- haloacetanilides and arylboronic acids. Shortly after this report, Matsubara and co-workers reported NÀH carbazole the alkyne was largely limited to DMAD and its analogues, synthesis from 2-aminobiphenyls with a Pt/C catalyst under the catalytic system allowed some intriguing transforma- hydrothermal conditions.[20] tions, such as formation of carbazole from o-silylphenyl tri- The follow-up studies of Buchwald and co-workers im- flate (Scheme 21b) and formation of a tricyclic indole de- proved the catalytic system, expanded the substrate scope, rivative from tetrahydroquinoline (Scheme 21c). The reac- and demonstrated the utility of the reaction in the synthesis tion was thought to involve initial formation of an enamine of carbazole alkaloids, such as Mukonidine.[44] Notably, the ACHTUNGRE intermediate then sequential palladation/reductive elimina- reaction did not require Cu(OAc)2 when DMSO was used tion processes as proposed for Glorius and co-workers en- as the solvent instead of toluene. Although the reaction amine cyclization (Scheme 10). However, a small intramo- was initially considered to involve intramolecular aromatic lecular KIE suggested that the aromatic CÀH activation oc- CÀH palladation of an amidopalladium(II) species, such curred through electrophilic palladation. a mechanism was not consistent with the substituent effects. Wang and co-workers recently developed an oxidative Alternatively, a mechanism involving Heck-like or Wacker- annulation reaction of simple anilines with diarylalkynes by like amidopalladation was suggested (Scheme 24). ACHTUNGRE using PdCl2 and Cu(OAc)2 as a catalyst and an oxidant, re- In 2008, Gaunt and co-workers reported that the same spectively, to afford 2,3-diarylindoles (Scheme 22a).[42] With type of carbazole-forming reaction could be achieved with modifications of the reaction conditions, the same starting 2-aminobiphenyls that contain N-alkyl, benzyl, and allyl ACHTUNGRE materials afforded pentaarylpyrroles (Scheme 22b). The groups in the presence of catalytic Pd(OAc)2 and ACHTUNGRE [45] proposed mechanisms for these reactions involve aminopal- PhI(OAc)2 (Scheme 25). Remarkably, the reaction took ladation of diarylalkyne as a common initial step. place at room temperature and tolerated various functional

Asian J. Org. Chem. 2013, 2, 466 – 478473 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

Note that oxidative palladium catalysis also allowed cyclization of 2-hydroxybiphenyls to dibenzofurans with the ap- propriate choice of ligand, oxidant, and other conditions.[46, 47] 2-(N-sulfonylamino)biaryls and 1,1-diaryl-2-(N-sulfonylamino)ethenes were used as precursors for N-sulfonylcarba- zoles and N-sulfonylindoles through palladium-catalyzed oxidative CÀH amination by Youn et al. and Inamoto/Doi et al., respectively (Scheme 27).[48,49] The palladium(II)/

Scheme 24. Suggested mechanism for palladium(II)-catalyzed aminative cyclization.

Scheme 27. Palladium(II)-catalyzed oxidative CÀH amination with an aminotosyl group to give carbazoles and indoles. Ts=p-toluenesulfonyl.

oxone system of Youn et al. was proposed to involve a palladium(II)/palladium(IV) catalytic cycle, whereas the palladium(II)/copper(II) system of Inamoto/Doi et al. appears mechanistically more related to the Buchwald system (see above). More recently, Chang and co-workers devised copper- based and metal-free systems for carbazole synthesis Scheme 25. Palladium(II)-catalyzed cyclization of 2-alkylaminobiphenyls to give N-alkylcarbazoles by using an iodine(III)ACHTUNGRE oxidant. through intramolecular oxidative CÀH amination of 2-sul- fonylaminobiphenyl and related substrates under mild conditions (Scheme 28).[50] Whereas the copper-based system groups on the aryl groups of the starting material. Amino- biphenyls with a protected glycosyl group on the nitrogen atom also underwent the reaction. The stoichiometric reaction of 2-(N-benzyl)aminobiphen- ACHTUNGRE yl with Pd(OAc)2 affords a trinuclear palladium complex that features two six-membered palladacycle moieties and four bridging acetate ligands (Scheme 26). The reaction is believed to go through oxidation of such a pallada(II)cycle Scheme 28. Cyclization of 2-sulfonylaminobiphenyls to give N-sulfonyl- with the hypervalent iodine oxidant to give a palladium(IV) carbazoles by using copper-catalyzed or metal-free systems. intermediate, and a CÀN reductive elimination follows.

ACHTUNGRE ACHTUNGRE consisted of Cu(OTf)2 and PhI(OAc)2 as the catalyst and oxidant, respectively, the use of a stronger oxidant, phenyl ACHTUNGRE iodonium bis(trifluoroacetate), PhI(OTFA)2, allowed metal-free cyclization. Mechanistic experiments suggested that the reaction involves a radical intermediate, and that the copper(II) catalyst activates the hypervalent iodine re- agent. Whereas the above examples used a free NÀH bond and Scheme 26. Stoichiometric cyclopalladation of 2-benzylaminobiphenyl to an external oxidant for CÀH amination, Tan and Hartwig give a trinuclear palladium(II) complex introduced a conceptually different strategy for indole syn-

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2.5. CÀH Amination through (Formal) Nitrene Insertion

Intramolecular CÀH amination through thermal decompo- sition of azide precursors is one of classical methods for the synthesis of indoles and carbazoles. This method, however, suffers from harsh conditions and limited scope. This (formal) nitrene insertion chemistry has received renewed attention in recent years.[54] In 2006, Taber and Tian demonstrated the utility of thermal rearrangement of 2H-azirines, which can be readily prepared by a Neber reaction of oximes derived from a-arylketones (Scheme 31a).[55] Short- Scheme 29. Palladium(0)-catalyzed cyclization of O-acetyloximes to give indoles. dba=dibenyzlidineacetone.

thesis, where an oxime NÀO bond serves as an “internal oxidant” for CÀH amination (Scheme 29).[51,52] Thus, O-acetyl oximes derived from 1,1-diarylacetone derivatives and a few other ketones cyclized into indole products in the ACHTUNGRE presence of Pd(dba)2 catalyst and Cs2CO3. The reaction was proposed to proceed through a catalytic cycle consisting of four elementary steps, that is, oxidative addition of the oxime NÀO bond to palladium(0) to form an iminylpalladium(II) species,[53] tautomerization to a palla- Scheme 31. Thermal and rhodium(II)-catalyzed rearrangement of 2H- dium(II) enamide, intramolecular CÀH palladation, and azirines to give indoles. CÀN reductive elimination (Scheme 30). The viability of

ly after this report, Narasaka and co-workers reported that the same cyclization reaction was efficiently catalyzed by a rhodium(II) catalyst, presumably through a rhodium-nitrenoid species (Scheme 31b).[56] In 2007 and 2008, Driver and co-workers reported rhodium(II)-catalyzed denitrogenative CÀH amination reactions for the synthesis of indoles from a-azidocinnamates and 2-azidostyrenes, respectively (Scheme 32a and b).[57–59] These reactions serve as complementary methods for the preparation of 2-substituted indoles, wherein the substituents at the C2 position are the ester and aryl/alkyl substituents from the former and the latter reactions, respectively. The same amination strategy was also applicable to carbazole synthesis from 2-azidobiphenyl derivatives.[60] Further-

Scheme 30. Proposed catalytic cycle for palladium(0)-catalyzed indole more, ZnI2 alone was shown to efficiently catalyze denitro- synthesis by oxime NÀO bond cleavage. genative cyclization of dienyl azides to pyrroles (Scheme 32c).[61] The rhodium(II)-catalyzed reactions most likely involve the first step was confirmed by a stoichiometric experiment rhodium-nitrenoid species as reactive intermediates, which with O-pentafluorobenzoyloxime as a substrate, which al- should form through denitrogenation of the starting materi- lowed the first isolation of a product of NÀO oxidative ad- als. Whereas the CÀH amination could a priori take place dition with palladium(0) (see inset in Scheme 30). This iso- in a concerted or a stepwise manner, pieces of experimental lated complex afforded the indole product upon heating evidence point to the latter pathway, in which electrophilic with Cs2CO3. attack of the nitrogen atom is followed by CÀH bond cleavage.[62] Notable among these pieces of evidence are the ab- sence of an H/D KIE in intramolecular competition between CÀH and CÀD cleavage (Scheme 33a) and the formation of 2,3-diphenylindole from 2-azidostyrene having b,b-diphenyl groups, which can be rationalized by a 1,2-

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Scheme 34. Rhodium(II)-catalyzed synthesis of 2,3-disubstituted indoles by migration of aryl or alkyl groups.

Scheme 35. Rhodium(II)-catalyzed indole synthesis from aryl azides involving migration of electron-withdrawing groups. esp =a,a,a,a-tetra- methyl-1,3- benzenedipropanoate.

Scheme 32. a) and b) Rhodium(II)-catalyzed indole synthesis from alkenyl- and aryl azides and c) Zinc(II)-catalyzed pyrrole synthesis from cant migration occurs with less electron-withdrawing dienyl azides. MS=molecular sieves. groups, such as esters and amides. Transition-metal-catalyzed reduction of a nitro group with carbon monoxide is an alternative method to generate a nitrene species.[65] This chemistry was successfully imple- mented for the synthesis of carbazoles and indoles through reductive CÀH amination. Thus, Smitrovich and Davies as well as Hsieh and Dong achieved conversion of 2-nitrobiar- yls and 1,1-diaryl-2-nitroethenes into carbazoles and 3-aryl indoles, respectively, by using a catalytic system consisting ACHTUNGRE [66, 67] of Pd(OAc)2 and 1,10-phenanthroline (Scheme 36).

Scheme 33. a) Intramolecular competition of aromatic CÀH/CÀD cleavage and b) formation of 2,3-diphenylindole through 1,2-phenyl shift. phenyl shift of the electrophilic amination intermediate (Scheme 33b). Driver and co-workers further extended the latter obser- vation to achieve the synthesis of 2,3-disubstituted indoles from a series of b,b-disubstituted 2-azidostyrenes (Scheme 34).[63] Most notably, with aryl and alkyl substituents on the b position, the aryl group preferentially underwent 1,2-migration with high selectivity (>95:5). Mechanis- Scheme 36. Synthesis of carbazoles and indoles through palladium-catalyzed reduction of nitro groups with carbon monoxide. tic studies, including Hammett analysis of the intramolecular competition of the migration of different aryl groups, suggested the formation of a phenonium ion intermediate. 2.6. Miscellaneous Another notable finding in the rhodium-catalyzed cyclization of 2-azidostyrene derivatives is 1,2-migration of an Takemoto and co-workers recently developed a palladium- electron-withdrawing group on the b position catalyzed reaction between aryl isocyanides that have (Scheme 35).[64] This phenomenon occurs with nitro, ketone, ortho-methyl groups and aryl halides, which affords 2-aryl and sulfonyl groups with high selectivity, whereas no signifi- indole derivatives (Scheme 37).[68] The reaction is thought

Asian J. Org. Chem. 2013, 2, 466 – 478476 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org Naohiko Yoshikai and Ye Wei.

Acknowledgements

This work was supported by the National Research Foundation, Singa- pore (NRF-RF-2009-05) and Nanyang Technological University.

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