Indoles hydroarylation

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2.3-/)]indole 176 has been constructed by the intramolecular Heck reaction and hydroarylation[145]. The asymmetric cyclization of the enamide 174 using (S)-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the (5)-oxindole aldehyde 175 in 84% yield and 95% ee. and total synthesis of (—)-physostig-mine (176) has been achieved[146]. 

A highly regio- and stereo-selective Brpnsted acid-catalysed addition of aromatic heterocycles, such as pyrroles, furans, and indoles, to ynamides RC=CN(R)(EWG), catalysed by Tf2NH at —35 °C, has been developed as an equivalent of hydroarylation of ynamides.41... 

As shown in Table 2, reaction of heteroaromatic compounds with alkynoates occurs under very mild conditions [4, 6]. Heteroaromatic compounds such as pyrroles, furans, and indoles readily hydroarylate alkynoates at room temperature in the presence of a catalytic amount of Pd(OAc)2 in acetic acid or CH2C12, usually affording ds-heteroarylalkenes. This reaction provides a synthetic route to hetero-arylalkenes, especially ds-alkenes, from simple heteroaromatic compounds. 

Hydroarylation. Catalytic Ar—H bond activation is observed with a complexed Pd species and the delivery of the aryl group to alkenes shows some asymmetric induction. For heterocycles such as methylfuran, pyrroles, and indoles, Ar—H activation by Pd(OAc)2 is adequate in their addition to 2-alkynoic esters in a frans-fashion. ... 

The first carbon addition to allenes catalyzed by gold was described by Hashmi and was the addition of furans to allenones, a reaction that is discussed as a conjugate addition to carbonyls. Then the annulation of 2-allenyl indoles was described (equation 111)and an enantioselective version was later developed for terminal allenes. Then Nelson described the cyclization of an N-substituted pyrrol in the synthesis of (—)-Rhazinilam (equation 112). In that case, gold notably improved the yields and selectivities obtained with Pd(II) or Ag(l), and gave complete retention of the chiral information of the allene. The most recent report is on the hydroarylations of allenes with gold-covered substituted benzenes as substrates. ""... 

The intermolecular hydroarylation of indoles or pyrroles with alkynes in the presence of cationic gold(I) catalysts leads to 2 1-adducts With (Z)-2-en-4-yn-l-ols as an unsaturated reaction partner, indoles are converted into dihydrocyclohepta[ )] indoles in a one-pot reaction sequence that involves a gold-catalyzed intermolecular Friedel-Crafts alkylation followed by an intramolecular hydroarylation (Scheme 4-9). ... 

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. ... 

A TFA-promoted regioselective hydroarylation of 2,3-allenoates R C=C=C (R )C02Et with N-Ts- or A-Ac-indoles has been reported to occur at the electron-rich C=C bond, giving rise to 4-indolyl-4-arylbut-2-enoates. The E Z selectivity was found to be dependent on the reaction temperature and time. A mechanism involving the formation of ( )- and (Z)-allylic carbocations generated in situ on protonation of the allenoate with TEA, followed by Friedel-Crafts attack at the 3-position of the indoles, was proposed. ... 

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)). 

Ding and Yoshikai reported a unique cobalt-catalyzed intra-molecular olefin hydroarylation for the production of dihydropyrroloindoles and tetrahydropyri-doindoles. These compounds are important because they provide the scaffolding for a number of biologically relevant compounds including indole alkaloids such as strychnine, brucine, and vincamine. The process was shown to be switchable... 

As part of our investigation of the hydroarylation of alkynes (or alkenylation of arenes) catalyzed by electrophilic transition metal complexes, our group reported the intra- and intermolecular reaction of indoles with alkynes catalyzed by gold (see Ref. [118, 133] in Chap. 1). Thus, alkynyUndole III-l cycUzes readily in the presence of a cationic gold(I) complex to give azepino[4,5-h]indole derivative III-2, whereas the use of AuCls leads to indoloazocine III-3 by a S-endo-dig process, this cyclization mode has not been observed in other hydroarylation of alkynes (Scheme 4.7). Under certain forcing conditions, aUenes and tetracyclic compounds were also obtained (see Refs. [118, 133] in Chap. 1). 

Hydroarylation of Alkynes. Hydroarylation of propynoic acid derivatives with indoles was achieved via an intermolecu-lar Fe-catalyzed, Ag-mediated process, providing access to 3,3 -bis(indolyl)propanoic acid derivatives. A catalytic system of 5 mol % FeCls and 15 mol% AgOTf in AcOH at 40 °C for 36 h regioselectively produced ethyl 3,3-bis( l//-indol-3-yl)propanoate in 86% yield (eq 71). 

Methylindole furnished monohydroarylated products, demonstrating decreased reactivity with substitution at the 2-position of the indole (eq 72). It is notable that extended reaction times provided access to only double hydroarylated products. 

Methy lindole failed to produce hydroarylated products, illustrating only the 3-position of the indole is activated for hydroarylation under the reaction conditions. 

The title compound is proposed to react with FeCls to form a highly reactive cationic Fe(OTf)3 complex. Interactions between the propynoic substrate and Fe(OTf)3 generate a highly electrophilic complex, which readily undergoes electrophilic aromatic substitution, followed by protonation. The electron-rich nature of the thusly-fonned indolyl acrylate encourages an additional hydroarylation reaction to generate the bis(indol-3-yl) products. 

With the modified carboxylate-Ru(II) catalyst Ru(02CMes)2(/ -cymene), the hydroarylation of non-unactivated and unstrained alkenes was strongly improved in toluene, even in H2O. Various unactivated alkenes including ether, ketone, hydroxyl, ester, and fluorine functionalized alkenes led to monoalkylated products in moderate to high yields [(Eq. 41)] [125]. This alkylation method could also be applied directly to heterocycles such as indole and thiophene derivatives and proceeded in site-selective manner. 

Indole derivatives tethered by alkenyl or allenyl groups undergo efficient intramolecular hydroarylation. Treatment of 2-(4-pentenyl)indoles with a catalytic platinum/chiral phosphine complex induced intramolecular hydroarylation to give tetrahydrocarbazole in 93% yield with 90% ee (Scheme 18.14) [13], The similar intramolecular asymmetric hydroarylation was applied to indoles having internal olefins by use of a highly strained planar chiral platinacycle (Scheme 18.15) [14],... 

A catalytic 1 1 mixture of Au[P(/-Bu)2(o-biphenyl)]Cl and AgOTf promoted the room-temperature intramolecular exo hydroarylation of 2-allenyl indoles to give tetrahydrocarbazoles (Scheme 18.16) [15], For example, treatment of 2-(4,5-hexadienyl)indole with the Au-catalyst mixture gave tetrahydrocarbazole in greater than 99% yield. 

This intramolecular hydroarylation was applied to the synthesis of a chiral cyclic product. Treatment of 2-allenyl indole with a catalytic 1 2 mixture of [(S)-P-P]Au2Cl2 [(S)-P-P = (S)-3,5-fBu-4-MeOMeOBIPHEP] and AgBp4 in toluene at -10 °C for 17 h gave tetrahydrocarbazole in 88% yield with 92% ee (Scheme 18.17) [16],... 

Intramolecular hydroarylation of alkenes through direct aromatic C—H activation was applied to the asymmetric synthesis of the potent protein kinase C inhibitor tricyclic indole (Scheme 18.54) [44]. 

A gold(I)-catalyzed hydroarylation of an allene with indole was developed by Toste and Zeldin (Scheme 12.25) [30]. This reaction could be applied toward the total synthesis of flinderoles B 54 and flinderoles C 55, members of a new class of antimalarial bisindole alkaloids isolated from plants of the Flindersia genus. The key intermediate pyrrolidine 53 in the total synthesis of flinderoles B and C could be efficiently constructed as a single diastereomer via Au-catalyzed intramolecular hydroarylation of a pendant allene 52, which was prepared from commercially available tryptophol 51. 

By combining an initial gold-catalyzed hydroaminative indole formation with repetitive hydroarylations, Hirano et al. [48] reported the gold-catalyzed direct construction of highly fused carbazoles by multiple cyclization. Scheme 4.28 shows one example of this chemistry, and the overall yield of this pentacyclization is excellent, highlighting the efficiency of gold catalysis. 

In 2008, Chen et al. developed a Ru-catalyzed cascade process combining a CM and an intramolecular hydroarylation (Scheme 5.3) [10]. The approach could transfer co-indol-2-yl alkenes and ot,P-unsaturated compounds into polycyclic indole derivatives 6 in a single step. The combination of two mechanistically distinct transformations relying on a single Grubbs second-generation catalyst 3 (3mol%) makes this reaction remarkably useful. 

Scheme 8.5 Cobalt-catalysed intramolecular olefin hydroarylation on indole derivatives.

Although less studied than O- and N-nueleophiles, other nueleophilic partners possessing H-X bonds can participate in gold-eatalyzed hydrofunctionalization reactions. Hence, the intermoleeular hydroarylation ie. C(sp2)-H bond addition] of allenes with indoles was reported in the presence of [(IPr) AuCl]. Using the same catalyst, Che and co-workers investigated an interesting cascade terminated by an alkyne hydroarylation step. The intramolecular allene hydroarylation with indoles was also described by Alcaide and Almendros. ... 

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