2-Alkynylanilines, hydroamination

Guan (1,3-disubstituted indoles) [48], Rueping (photoredox catalysis) [49], and Jiao (/V-alkynylaniline hydroamination) [50]. Before Glorius, Lee and colleagues employed Pd-catalyzed oxidative cyclization in a synthesis of duocarmy-cin SA analogues [51]. Some additional examples of this oxidative cyclization to give indoles are in later chapters. 

Later, Arcadi showed that /J-keto-imines react with alkynes intramolecularly to give pyrroles. The intermolecular animation with aniliaes was later developed by Hayashi and Tanaka using a cationic Au(I) catalyst to form imines (equation 27). More recently, Arcadi etal. developed an intramolecular version for the cyclization of o-alkynylanilines to form indoles (equation 28) and Li reported a double intra- and intermolecular hydroamination to obtain A-vinylindoles. " O-Substituted hydroxylamines can also undergo this type of transformation to dihydroisoxazole derivatives. " " Tandem sequences that involve a first alkyne-hydroamination step with anilines have been recently developed " " and are similar to the previonsly discnssed additions with phenols that access isoflavone skeletons. 

A-vinylindoles took place. Moreover, the gold-catalyzed cyclization of 2-alkynylanilines can be combined with a gold-catalyzed Michael addition to enones, which afforded 3-alkylated indoles with good yield. Gold-catalyzed hydroamination/hydroarylation cascades of polyenyne-substituted anilines leading to condensed aromatics have been described recently. ... 

The direct Au-catalyzed synthesis of 2-arylindoles from aryl alkynes and o-iodoanilines was reported by Wang (eqnation 3) [17]. The An-catalyzed double hydroamination of o-alkynylanilines and terminal alkynes was fonnd by Li to give A-vinylindoles [18], Patil used a Au-catalyzed one-pot reaction between o-alkynylanilines and alkynols to give various 3-substituted indoles [19]. Zhang fonnd that both A-arylhydroxylamines [20] and... 

Utimoto has also shown that simple gold(III) salts catalyze the intramolecular hydroamination of alkynes with arylamines [4]. For example, treatment of 2-(3,3-dimethyl-l.butynyl)aniline with a catalytic amount of sodium tetrachloroaurate in refluxing TH F for 30 min led to isolation of 2-f-butylindole in 90% yield (Eq. (11.3)). Marinelli has modified and expanded the scope of Utimoto s procedure through employment of ethanol, ethanol/water [5], or ionic liquids 6] solvents. As an example of this modified protocol, treatment of 2-alkynylaniline 2 with a catalytic amount of NaAuCU dihydrate in ethanol at room temperature for 6h led to isolation of 2-(4-chlorophenyl)indole 3 in 92% yield (Eq. (11.4)). A similar hydroamination protocol employing AUCI3 as a catalyst has been recently reported by Majumdar [7]. 

Che has reported the tandem hydroamination/hydroarylation of aromatic amines wirh terminal alkynes to form dihydroquinolines in which 1 equiv of aniline combines with 2 equiv of alkyne [23]. For example, reaction of 3-methoxyanilme with pheny-lacetylene (5 equiv) and a catalytic 1 1 mixture of the gold(I) N-heterocydic carbene complex (IPr)AuCl (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) and AgOTf at 150 °C under microwave irradiation led to isolation of dihydroquinoline 21 in 82 % yield (Eq. (11.15)). Alternatively, reaction of o-acetylaniline with pheny-lacetylene catalyzed by a mixture of (IPr)AuCl and AgOTf at 150 °C led to isolation of the quinoline derivative 22 in 93% yield via incorporation of a single equivalent of alkyne (Eq. (11.16)). Arcadi has reported the gold(IlI)-catalyzed hydroamination/ hydroarylation of 2-alkynylanilines with a,p-enones to form C3-alkyl indoles [24]. As an example of this transformation, treatment of 2-(phenylethynyl)aniline with 4-phenyl-3-buten-2-one and a catalytic amount of sodium tetrachloroaurate dihydrate in ethanol at 30°C formed 1,2,3-trisubstituted indole 23 in 88% yield (Eq. (11.17)). 

Indole is one of the most important heterocyclic scaffolds for drug discovery. Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329, 330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331, 332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334, 335] (Scheme 15.104). Alternatively, o-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198, 200, 336-340]. These approaches have been thoroughly reviewed [10]. 

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). 

Zhang Y, Donahue IP, Li C-J (2007) Gold(in)-catalyzed double hydroamination of o-alkynylaniline with terminal aUcynes leading to A-vinylindoles. Org Lett 9(4) 627-630. doi 10.1021/ol062918m... 

When one of the N—H bonds of primary amines is used for arene formation, the other N—H bond can serve as another reaction site for further elaboration. For example, IV-unsubstituted 2-alkynylaniline derivatives 309 undergo a copper-catalyzed direct C—H/N—H coupling with azoles 310 followed by cycloisomerization to form A -azoylindoles 311 in good yields (Scheme 19.83) [153]. Oxadiazoles, benzoxa-zoles, and benzothiazoles can be used as the azole 310 for the reaction. Double hydroamination reaction of the anilines of type 309 with terminal alkynes leading to A -vinylindoles was reported by Zhang et al. [154]. 

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