Indoles intramolecular arylation

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

The copper(I) iodide promoted cyclization of 7V-(2-haloaryl)-substituted enaminones is a good method to yield indoles and carbazoles. This type of intramolecular arylation is a reasonable alternative to the route via benzyne (see Section A.l.f) (equation 106). The method could be extended to 7V-(2-haloaryl)alkyl-substituted enaminones which give the expected dihydroisoquinolines whereas a nucleophilic attack of the nitrogen instead of the /1-carbon give the undesired indoles159 (equation 107). 

Zhao and Larock have introduced a convenient method for the preparation of substituted dibenzofurans as well as carbazoles and indoles by palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. These reactions proceed by carbopalladation of the alkyne, heteroatom-directed migration of palladium from a vinyl to the adjacent aryl position, and ring closure via intramolecular arylation (Scheme 87) <2006JOC5340>. 

Intramolecular arylation reaction has been applied to the synthesis of indole and isoquinoline derivatives. For example, the 3-indolylacetic acid 190 has been synthesized as follows87 ... 

One of the latest additions to the impressive repertoire of indole alkaloid total syntheses using intramolecular Heck strategy is the total synthesis of hippadine (18a) [109]. As depicted in Scheme 43, an intramolecular aryl-Heck cyclization of substrate 241 under normal Heck conditions gave Ihe cyclized product 242, which was transformed into hippadine (18a) upon further manipulations. 

An extension of the palladium(0) catalyzed direct arylation reactions was reported by Lautens et al. in 2005. Based on the Catellani reaction [32], a direct intramolecular arylation of indole (C2) followed ort/m-alkylation, via a norbor-nene-mediated tandem aromatic alkylation/Heck reaction (Scheme 17) [33]. An analogous process was later developed for thiophenes and furans, allowing formation of a range of interesting hetero-aryl polycyclic products (Scheme 17) [34]. 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

Intramolecular arylation of 28 and 29 occurred at either C-2 or C-3 to give 30 and 31 when the C-3 or C-2 position is substituted [11], The alkenylpalladium intermediate 33, generated by the reaction of the bis-indole 32 with an alkyne as a relay, attacks the indole to give 34 [12],... 

The Pd-catalyzed intramolecular coupling of aryl halides or triflates with aromatic rings to give biaryl compounds offers useful synthetic methods. Intramolecular aryla-tion of benzene derivatives was reported first by Ames. Cyclization of 102, catalyzed by Pd(OAc)2 in the presence of DBU, is an example [23]. Pyrimido[4,5-fe]indole was prepared by intramolecular arylation of 4-anilino-5-iodopyrimidine 103 in 86 % yield in the presence of Pd(OAc>2, PPh3 and AcONa in DMF [24]. Cyclization of the monobrominated diarylpyrazole 104 afforded pyrazolo[l,5-/]phenanthridine in 65 % yield in the presence of phosphine-free Pd(OAc>2, Bu NBr, LiCl and K2CO3 in DMF at 110°C [25]. 

In intramolecular arylation of the indole 105, the C-2 arylation product of the pyrrole ring was obtained preferentially without attacking the benzene ring. On the other hand, when the C-2 position is bloeked, arylation of 106 oecurs in the benzene ring to give 107, showing that pyrrole is more reactive than benzene [26]. 

Intramolecular amination of A/, AT-dimethylhydrazone of o-chlorophenylacetal-dehyde (73) offers a facile synthetic method of indoles. 1-Aminoindole 75 was prepared by intramolecular arylation of 73. For this reaction, (ferrocenyl)amino-phosphine VIII-3 was a better ligand than P(f-Bu)3. Al,Al-dimethylhydrazones have no hydrogen to be displaced, and the arylation is explained by isomerization to the enamine form 74. Another possibility may be insertion of C=N bond to Ar-Pd bond, followed by dehydropalladation. Similarly, the quinoline 77 was obtained by intramolecular amination of 2,6-dichlorophenylpropionaldehyde N,N-dimethylhydrazone (76) [55]. 

The Cu( I)-catalyzed intramolecular arylation approach as an efficient route toward the construction of multisubstituted indole cores was first demonstrated by Cusack. 

Accordingly, employment of P-keto anilides 238 in an intramolecular arylation reaction, catalyzed by the Cu(I)-L-proline system, led to an efficient assembly of the target indole derivatives 239 (Scheme 9.85) [238,239]. The authors demonstrated that electronic effects of substituents on the aromatic ring have very little influence on this arylation reaction, as complete conversion was observed for substrates possessing both electron-donating and electron-withdrawing groups. 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

Palladium-catalyzed Arylation ofBenzothiophenes, Pyrroles, Indoles, and Furans. The combination of Pd(OAc)2 and P(t-Bu)3 is also effective for the intramolecular arylation of heterocyclic units. Notably, the high-yielding arylation of a benzoth-iophene unit to form a thienocarboline was reported (eq 28). ... 

Intramolecular construction of the key C—N bond has, as in the synthesis of indoles, proven to be a popular strategy in synthesizing benzimidazoles. Brain et al. adopted this approach and developed a synthesis of benzimidazoles via an intramolecular arylation of amidine substrates (Scheme 24.10, disconnection D-1) [54,55]. Thus, amidines such as 26 could be converted into the desired heterocycles under the action of a Pd2(dba)3/triphenylphosphine catalyst using low catalyst loadings and microwave irradiation (Scheme 24.11). 

Subsequently, the same group reported a more practical method for preparing indoles by using the azaallylic anion as a synthon (Scheme 8) [36]. They found that imines 25 could couple with o-dihalobenzenes 26 to produce intermediates 27, which underwent an intramolecular aryl amination to afford 1,2,3-trisubstituted indoles 28. Because the azaallylic anion could be prepared by a Pd-catalyzed reaction of alkenyl halides and primary amines, they were able to develop a domino three-component synthesis of indoles. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki-Heck ring closure <06JOC5340>. 

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