2-alkynylaniline derivatives

In contrast to the palladium-catalyzed reactions, little attention has been paid to other transition-metal catalysts. Recently some efficient reactions using copper(i or 11), gold(m), platinum(n), and tungsten(O) have been developed for the synthesis of nitrogen-heterocycles. The copper-catalyzed cyclizations of 2-alkynylaniline derivatives into... 

Other indoles that have been prepared using the Sonogashira coupling and cyclization sequence include 5,7-difluoroindole and 5,6,7-trifluoroindole [219], 4-, 5-, and 7-methoxyindoles and 5-, 6-, and 7-(triisopropylsilyl)oxyindoles [220], the 5,6-dichloroindole SB 242784, a compound in development for the treatment of osteoporosis [221], 5-azaindoles [222], 7-azaindoles [160], 2,2-biindolyls [223,176], 2-octylindole for use in a synthesis of carazostatin [224], chiral indole precursors for syntheses of carbazoquinocins A and D [225], a series of 5,7-disubstituted indoles [226], a pyrrolo[2,3-eJindole [226], an indolo[7,6-g]indole [227], pyrrolo[3,2,l-y]quinolines from 4-arylamino-8-iodoquinolines [228], optically active indol-2-ylarylcarbinols [229], 2-alkynylindoles [176], 7-substituted indoles via the lithiation of the intermediate 2-alkynylaniline derivative [230], and a variety of 2,5,6-trisubstituted indoles [231], This latter study employs tetrabutylammonium fluoride, instead of Cul or alkoxide, to effect the final cyclization of 215 to indoles 216 as summarized here. 

The cyclization of 2-alkynylaniline derivatives has become a general method for the assembly of 2-substituted indoles [2, 4]. While a range of other transition metals and Lewis acids can mediate similar intramolecular cyclizations, a useful feature of palladium catalysis is that it can also be employed to assemble the cyclization precursors. The latter is often accomplished by coupling more traditional palladium-catalyzed coupling chemistry with cyclization, and provides an avenue to readily expand the diversity of indole products available. As illustrated with the examples in Scheme 6.5, this can be done via the Sonogashira coupling of 2 with R-X [5], the Stille... 

Lu has demonstrated that this aryl halide-mediated cydization can be coupled with the generation of the alkynylaniline derivative via Sonogashira coupling, providing a multicomponent route to build up indoles from anilides, terminal alkynes and aryl halides (Scheme 6.15) [19]. Similar approaches have been applied to the construction of benzofurans [20] and substituted fiirans [21]. 

A variety of differently fused indoles 155 can be efficiently assembled via the W(0)-catalyzed cycloisomerization of o-alkynylaniline derivatives 154 under photoirradiation conditions. The proposed mechanistic rationale featured a 1,2 Stevens-type rearrangement in the metal-containing ammonium ylide 157, followed by a 1,2-alkyl... 

Scheme 8.86 Intermolecular carbometallation and subsequent cyclization of o-alkynylaniline derivatives [500].

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]. 

A popular route involving C-N bond formation is based on intramolecular annulation of 2-alkynylanilines, which are in turn readily available by, for instance, palladium-catalyzed coupling of the corresponding 2-iodoanilines, or triflates derived from 2-aminophenols, with suitable acetylenes. In a representative example, base-induced... 

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. 

CycUzations. In a catalytic process 2-aryl-3-alkenylindoles are generated from aldimines derived from o-alkynylanilines. Cyclization reactions of enynes and dienynes under reductive conditions (HCOOH)" or in the presence of aryl iodides to participate in a coupling process are useful. 

Indole derivatives. A method for hydrolysis of indole-3-acetonitriles is by exposing them to air in the presence of BU4NF. 2-Substituted indoles are conveniently prepared from 2-alkynylanilines in refluxing THF with BU4NF. ... 

Perez-Castells and coworkers devised a tandem enyne methathesis Diels-Alder reaction strategy for the assembly of polycyclic indole structures [109]. The enyne metathesis reaction using Grubbs s catalyst (311) with the 2-alkynylaniline 310 in the absence of a dienophile proceeded to form the mono- and bis-indole derivatives 313 and 314 (Scheme 66). Testing the hypothesis that a Diels-Alder cycloaddition with an activated diene might be faster than the undesired cross-metathesis reaction which led to the formation of 314, a one-pot reaction with maleic anhydride (312) as the dienophile was conducted. Disappointingly, the above reaction resulted in a... 

The oxidative dearomatization of para-substituted o-alkynylanilines 290 using (diacetoxyiodo)benzene affords 2-alkynyl cyclohexadienimines 291, which can act as active substrates for reaction with electron-rich styrenes 292 in the presence of metal salts the Bi(OTf)3-catalyzed reactions give 3,4-dihydro-cyclopenta[c,rf indoles 293 and the AgOTf-catalyzed reactions provide tricyclic pyrrole derivatives 294... 

Synthesis of indole derivatives from 2-alkynylanilines by means of gold catalysis 13IJC856. 

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)). 

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). 

Treatment of o-ethynylbenzamides with a catalytic amount of PhCH2PdCl(PPh3)2 in THF at reflux results in 6-endo-dig cycUzation to give isoquinolin-l-ones (Scheme 2 )P Intercepting the o--vinylpalladium(II) intermediate derived from lV-carbomethoxy-2-alkynylaniline shown in Scheme 22 by allyl chloride produces 2-alkyl-3-allylindolesP This result proves involvement of the rr-bonded palladium(II) species. 

Sakai and Konakahara et al. found that InBrs is effective in catalyzing the intramolecular cyclization of 2-alkynylanilines to form polysubstituted indoles [232] (Figure 8.109). Activation of the alkyne by InBrs, increasing the electrophilicity of the triple bond, is the role played by InBrs in this case. The authors also reported in the same paper the synthesis of idolyl amine derivatives by utilizing the indole generated in situ to add to imines in the presence of TMSCl with increased catalyst use. 

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