Indoles alkynylation

Some recent studies have underlined the effect that certain physical properties of the reaction medium have in governing the nature and yields of the products obtained when indole Grignard reagents react with alkyl or alkynyl halides. Such factors include the basicity and dielectric constant of the medium and its ability to solvate any of the reacting species. ... 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2-substituded indoles <06T5109>. 

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>. 

Cyclization of 2-(l-alkynyl)XV-alkylidene anilines is catalyzed by palladium to give indoles (Equation (114)).471 Two mechanisms are proposed the regioselective insersion of an H-Pd-OAc species to the alkyne moiety (formation of a vinylpalladium species) followed by (i) carbopalladation of the imine moiety and /3-hydride elimination or (ii) oxidative addition to the imino C-H bond and reductive coupling. 

Iwasawa and co-workers developed a facile method for the construction of polycyclic indole derivatives 190a and 190b by the tungsten(0)-catalyzed reaction of A-(2-(l-alkynyl)phenyl)imine 188 with the electron-rich alkenes 189a and 189b (Scheme 32).42b Photoirradiation of a mixture of imine 188 and ketene silyl acetal 189a with 10mol% of... 

The Sonogashira reaction frequently serves as a platform for the construction of indoles, and we will explore this application in Chapter 3, but it also is a valuable method for the preparation of alkynyl pyrroles. 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

The unique reactivity pattern of alkynyl iodonium salts discussed in Sections II,A.2 and II,D,la can also serve as two-carbon conjunctive reagents in the synthesis of pyrroles, dihydropyrroles, and indoles. Feldman et al. found that combination of alkyl or aralkyl tosylamide anions 101 with phenyl(propynyl)iodonium triflate (102) furnishes the corresponding dihydropyrroles 103 (95JOC7722) (Scheme 28). 

Alkynyl anilines are simple and convenient starting materials for the preparation of indoles. Unprotected, unfunctionalized 2-ethynyl aniline can be cycloisomerized to indole via molybdenum vinylidene-mediated catalysis [15]. Unlike (Et3N)Mo(CO)5,... 

The alkynyl ketone route to pyrimidines is now well established synthetically, and an example of its use in natural products chemistry is the synthesis of several meridianin analogs, including meridinian D 697 from the indole precursor 696 <2005AGE6951>. 

In certain cases copper catalyzed processes might also be used for the N-alkynylation of azoles. Methyl indole-3-carboxylate was coupled with 1-bromo-2-triisopropylsilyl-acetylene in the presence of a copper-phenantroline catalyst to give the desired 1-ethynylindole derivative in excellent yield (6.74.),105... 

A related synthesis of highly substituted furans was reported by Schmalz and Zhang from cyclopropyl alkynyl ketones. The reaction scope included a great variety of nucleophiles such as several alcohols, indole or even acetic acid [140]. 

Pyrrole and indole rings can also be constructed by intramolecular addition of nitrogen to a multiple bond activated by metal ion complexation. Thus, 1-aminomethyl-l-alkynyl carbinols (obtained by reduction of cyanohydrins of acetylenic ketones) are cyclized to pyrroles by palladium(II) salts. In this reaction the palladium(II)-complexed alkyne functions as the electrophile with aromatization involving elimination of palladium(II) and water (Scheme 42) (81TL4277). 

Catalytic reduction of the C-alkenyl and -alkynyl substituents over palladium or Raney nickel can be effected without concomitant hydrogenation of the heterocyclic system to give the corresponding alkyl-pyrroles and -indoles (72HC(25-2)65, B-77MI30504). 

Treatment of an isocycanobenzene derivative (186) bearing an alkenyl or alkynyl group at the o-position, with Bu3SnH/AIBN generates an indole derivative (187) as shown in eq. 3.72 [200-203]. 

We have reported on a tandem procedure for the synthesis of 3-allyl-N-(alkoxycarbonyl)indoles 115 via the reaction of 2-(alkynyl)phenylisocyanates 114 and allyl carbonates 5 in the presence of Pd(PPh3)4 (lmol%) and CuCl (4 mol%) bimetallic catalyst [80]. A proposed mechanism is shown in Scheme 35. Initially, the insertion of the isocyanates 114 into the complex 7, formed by the reaction of 5 with Pd(0), would form the 7r-allylpalladium intermediates 117. This intermediate, with Pd - N bonding, could be in equilibrium with the Pd - O bonded intermediates 118, which should more probably be represented as the bis-7r-allylpalladium analogue 119. Insertion of the alkyne then occurs to form the indoles 115 and the Pd(0) species is regenerated. It should be emphasized that no carboamination takes place at all in the absence of CuCl the product 116 was obtained. 

Likewise, the alkynyl 3-(2-iodophenyl) indole 191 is transformed under similar conditions into the 6,7-dihydro-5H-4b-aza-benzo[a]aceanthrylene 192 in good yield (Scheme 74). 

A further extension of this strategy has been employed as a route to carbazoles, as illustrated by the synthesis of the system 116 from the 2-nitrobiphenyl derivative 117 (Equation 30) <20040L533>. A substituted 2-nitrobiphenyl derivative has been cyclized to a carbazole using P(OEt)3 en route to the pyridocarbazole alkaloid ellipticine <2006HCA111>. It should also be mentioned that annulation of o-(alkynyl)nitrobenzene precursors with TBAF or pyridine gave access to indol-3-one-l-oxides (isatogens) <2003T2497>. 

A synthesis of [3]-fused furans involving a ring enlargement can be effected by the treatment of a-alkynyl-a-cyclopropylcycloalkanones with an electron-rich Au(l) catalyst in the presence of a suitable nucleophile (Equation 18) <2006AGE6704>. The nucleophiles that can be used include alcohols, phenols, carboxylic acids, indole, and 2-pyrrolidone. Open-chain ketones as well as other ring sizes react with comparable yields. Silver and lanthanide triflates are also effective catalysts for this transformation. 

Alkylation of arylhydroxylamines. The trimethylsilyl ether of phenylhydroxylam-ines undergo nucleophilic o- and p-alkylation with trialkylaluminums. Only N- lkylation occurs in the absence of the trimethylsilyl group. This reaction is particularly useful for preparation of o-alkynyl derivatives of aromatic amines, which provide a convenient access to indoles. 

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