Indoles from 2-alkynylanilines

Newer conditions to constract indoles from the Sonogashira 2-alkynylanilines are an electrochanical cyclization that avoids the use of metal catalysts aud add or base [31] and the employment of a recyclable sihca-snpported palladinm catalyst [32]. In both cases the yields of indoles are exceUent. Sanz reported a clever synthesis of 4-haloindoles, which can be further functionalized, from 2,3-dihalophenols via a Smiles rearrangement and... 

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]. 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

The combination of Pd-catalyzed coupling of terminal acetylenes with o-alkynylanilines or o-alkynylnitrobenzenes followed by base or Cul cyclization to an indole has been used in many situations with great success. Arcadi employed this methodology to prepare a series of 2-vinyl-, 2-aryl-, and 2-heteroarylindoles from 2-aminophenylacetylene and a subsequent elaboration of the acetylenic terminus. A final Pd-catalyzed cyclization completes the scheme [218]. 

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. 

Palladium-catalyzed intramolecular cyclization of the imine 84, which is available from the corresponding o-alkyny-laniline and thiophene-2-carboxaldehyde, affords the indole 85 (Scheme 55). Several other related indoles have been prepared in this manner by varying the aldehyde or 0-alkynylaniline components <2000JA5662, CHEC-III (3.03.3)288>. 

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. ... 

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

Scheme 3 Copper-Mediated Indole Syntheses from 2-Alkynylanilines - 2...

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... 

Yamamoto was first to report that orfho-alkynylanilines, which are fully substituted at the N-site, could undergo a transition metal-catalyzed cycloisomerization reaction to give indoles via a formal 1,3-migration of a suitable migrating group from the... 

A formal [3 + 2] cydoaddition route leading to the preparation of di- and tri-substituted indoles 264 from ortho-haloanilines 261 and copper(I) acetylides 262 was introduced by Castro (Scheme 9.92) [75, 76, 111], simultaneously with the mentioned earlier coupling-cyclization reaction en route to benzofurans 57 (Scheme 9.21). It is believed that this stoichiometric in copper cascade reaction proceeded with the generation of an intermediary ortho-alkynylaniline 263 [77]. Attempts to turn this reaction into a more practical catalytic process, using basic conditions to generate Cu(I)-acetylide from a terminal alkyne in the presence of Cul, provided poor yields of the respective indoles 264. 

Treatment of alkynylaniline 116 with a copper catalyst and aqueous tert-butylhydroperoxide (TBHP) initiated C—C bond formation via nucleophilic attack of the nitrogen followed by C—O bond formation from TBHP as the oxidant, which finally formed indole 117. A number of substituted aryl groups and anilines are tolerated and the product indoles are furnished in very good yields (13OL1802). 

Four years later, within a more in-depth study on the Rh-catalyzed synthesis of indoles starting from o-alkynylanilines, the same group successfully extended this approach to the preparation of benzofurans starting from o-alkynylphenols [29]. 

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