C—H functionalization of indoles

C-H Functionalization of Indoles. The enantioselective C-H functionahzation of indoles with ethyl a-alkyl-a-diazoesters has been delineated in presence of Rh2(5-NTTL)4, furnishing a-alkyl-substituted 3-indolylacetates in high yields and with excellent enantioselectivities (82-96% yields, 79-99% ee) (eq 6). 4 While the scope of the reaction accommodates a wide array of substrates, exceptionally high performance is achieved with diazoesters with longer chain alkyl groups than an a-methyl substituent when N-aryl or A(-alkyl indole derivatives with small 2-substituents are used. 

Figure 16.1 Two distinct modes of C-H functionalization in the synthesis of indoie aikaioids indoie substitution and indoie synthesis, (a) C-H functionalization of indoles and (b) formation of indoles by C-H functionalization.

In all of the aforementioned cases, the palladium(II)-catalysed indole alkenylation occurred preferentially at the 3-position of the indole moiety, which is consistent with the natural reactivity of indole towards electrophihc aromatic substitution reactions. More recently, a palladium(ll)-catalysed direct oxidative coupling of indole and alkenes was described by Gaunt and coworkers [28] that exploits a selective, solvent-controlled C—H functionalization of free NH indoles and leads to the substitution of the indole core at either the 2- or the 3-position. 

Instead of the carbonylation of 2-nitrostyrenes, Ragaini and colleagues found that indoles can be prepared from the reaction of nitroarenes with alkynes [42]. By palladium-phenanthroline complexes, 3-arylindoles were efficiently produced from nitroarenes, arylalkynes and CO by an ortho-C-H functionalization of the nitroarene ring (Scheme 9.4). Both electron-withdrawing and electron-donating substituents are tolerated on the nitroarene, except for bromide and activated chloride. Nitroarenes bearing electron-withdrawing substituents react faster, but... 

Photoredox catalysis was utilized by Rueping et al. to effect the intramolecular C—H functionalization of tertiary amine 114. When conducted in the presence of oxygen, indole 115 was isolated as the major product in good yields. Depending on the substrate and reaction conditions, tetrahy-droquinohne derivatives or substituted anilines could also be obtained (13JA1823). 

Evano and colleagues disclosed a modular indole synthesis via the intramolecular carbocupration of N-aryl-ynamides (124 125) (130L3122).A series of indole derivatives was prepared by Jiao via the palladium-catalyzed aerobic oxidative intramolecular hydroamination and C-H functionalization of N-alkynylanilines (13T4408). Suh reported a microwave-assisted synthesis of 3-functionalized indoles via an intramolecular arene-alkene coupling of o-iodoanilino enamines (13T7211). 

In contrast to the alkynylation of acidic C-H bonds which can also be achieved using alkynyliodonium salts, the direct C-H functionalization of aromatic compounds or olefins has never been realized with this class of reagents so far. However, after several unsuccessful attempts using palladium or copper catalysts and alkynyliodonium salts for the alkynylation of heterocycles, Waser and Brand reported in 2009 the first efficient alkynylation of indoles using TIPS-EBX 52 and AuCl as catalyst (Scheme 18) [117]. With indole, selective C3-aIkynylation was obtained. The reaction was tolerant to many functional groups such as bromides, acids, or alcohols. The method was already used in the synthesis of starting materials for Friedel-Crafts reactions of aminocyclopropanes [118] and for hydroamidation to access indole c -enamides [119]. In 2010, Nevado and de Haro demonstrated that alkynylation was also possible using directly terminal propiolic ester derivatives and (diacetoxyiodo)benzene as co-oxidant [120]. 

Scheme 9.8 C-H functionalization of the indole at position C(3) catalyzed by Rh2(S-NTTL)4 (36).

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

Pd-Catalyzed C-H Bond Functionalization of Indoles and Pyrroles in Complex... 

In the context of this review, the indole motif, in particular, has attracted a great deal of attention in the development of C-H functionalization processes. Some of the earliest studies were reported in 1989 by Ohta, who investigated palladium-catalyzed coupling of 2-chloro-3,6-dialkyl pyrazines with protected indoles [22], Despite requiring highly elevated temperatures they were able to affect selective C2 or C3 heteroarylation of the indole core in moderate yields. Use of 1-tosyl-indole led, predominantly, to 3-heteroaryl indoles whilst 1-alkyl analogues were shown to undergo substitution at C2 (Scheme 10). 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

In 2003, Beccalli et al. reported an intramolecular variant, allowing chemoselective cyclization of indole carboxamide derivatives into (3-carbolinones (path A) or pyrazino[l,2-a]indoles (path B) (Scheme 40) [68]. The chemoselectivity of the cyclization could be controlled by the reaction conditions. PdCl2(MeCN)2 and benzoquinone in DMF/THF made possible C-H functionalization at the C3 position of indole, whilst Pd(OAc)2 in Na2CC>3 and -Bu4XC1 in DMF resulted in intramolecular amination of the double bond (N-H functionalization). 

Although much has been learnt about the reactivity and regioselectivity in direct functionalization of heteroarenes, the ability to manipulate and controllably switch the selectivity is extremely rare. In 2005, a method for direct and selective C2 or C3 elaboration of free-(NH) indoles using palladium-catalyzed C-H functionalization was developed by Gaunt and co-workers (Scheme 49) [43]. 

The following section looks at how palladium-catalyzed C-H functionalization has been successfully applied in synthetic strategies enabling rapid and elegant routes to complex natural products containing the indole and pyrrole nucleus. There are a number of metal-mediated examples where stoichiometric quantities of transition metals are employed to affect the desired transformation however, there are very few cases of catalytic functionalization with in the context of complex molecule synthesis. 

Not long before, the Hashimoto group reported another successful case of asymmetric C—H bond functionalization of indoles (Scheme 1.20)." In the presence of a different diazo ester 59 and catalytic amount of Rh2(i -PTTEA)4... 

Synthesis of pyrroles, indoles, and carbazoles through transition-metal-catalyzed C—H functionalization 13AJ0466. 

New strategies for the synthesis of N-alkylated indoles 12KGS415. Oxindole as starting material in organic synthesis 13ARK(1)470. Palladium-catalyzed dual C—H or N—H functionalization of unfunctionalized indole derivatives with alkenes and arenes 12BJO 1730. 

Grimster, N.P., Gauntlett, C., Godfrey, C.R.A. and Gaunt, M.J. (2005) Palladium-catalyzed inter-molecular alkenylation of indoles by solvent-controlled regioselective C—H functionalization. 

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