Indoles electrophilic palladation

Heteroaromatics have high reactivity toward electrophilic palladation and show good regioselectivity. Reactions with pyrrole,thiophene, furan, and indole have been reported (equation 3). The use of stoichiometric copper(II) ion gives a process catalytic in Pd. 

The electron-rich nature of heterocycles such as indoles, furans and thiophenes allows a different type of Heck reaction to be carried out. In this oxidative modification, the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. 

The electron-rich nature of heterocycles such as indoles, furans, and thiophenes allows a different type of Heck reaction to be carried out. " In this oxidative modification the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. This process is not catalytic in the standard way, but can be made so by the addition of a reoxidant selective for Pd(0) note, that the catalytic Pd(0) could not effect the first (electrophilic) ring palladation. " ... 

Even indoles bearing acyl or phenylsulfonyl substituents on nitrogen, are easily palladated at moderate temperatures, substitution occuring at C-3, or at the 2-position if C-3 is occupied. The metallated products are seldom isolated but allowed to react with acrylates, other alkenes (Heck reaction), or carbon monoxide in situ. Although electrophilic palladation normally requires one equivalent of palladium(II), the incorporation of reoxidants selective for Pd(0), such as t-butyl perbenzoate or copper(II) compounds, allows catalytic conversions to be carried out. ... 

Heck reaction conditions have been applied to introduction of the dehydroalanine side-chain on to indoles. Under catalytic conditions, 4-bromo-l-tosylindole is converted to the 4-isomer of dehydrotryptophan in 90% yield. However, with a stoichiometric amount of PdClj in acetic acid the 3 position was substituted, albeit in only 17% yield. A much better yield of the 3-substitution product was obtained by changing from acetyl to an N-ethoxycarbonyl protecting group in the dehydroalanine. <94CPB832> Both of these reactions presumably involve indolylpalladium species. Under the Heck conditions the 4-indolylpalladium(II) species is formed by oxidative addition. With the stoichiometric amount of PdClj, the dominant reaction is electrophilic palladation at the 3-position. 

Vinylation can be carried out directly at the 3-position on indoles without a halogen or sulfonate substituent <84H(22)1493>. This reaction presumably involves an electrophilic palladation at C3 followed by a Heck reaction (Equation (116)). These reactions can also be carried out in the presence of a cooxidant such as Cu(OAc)2 or AgOAc which serves to reoxidize palladium. Similar reactions have been carried out on 1-benzenesulfonylindole <84S236> and 1-acylindoles <83JCS(Pl)l36l>. 

Reaction of the imine 50, derived from o-iodoaniline and benzaldehyde, with diphenylacetylene afforded a mixture of the quinoline 53 and the isoindolo[2.1-ajindole 56. Formation of the quinoline can be understood by insertion of the C=N bond in 51, which is regarded as 6-endo cyclization of the intermediate 51 to generate 52, followed by -H elimination to yield the quinoline 53. On the other hand, the isoindolo[2.1-a]indole 56 is formed by 5-exo cyclization of 51 to produce 54. The final step is the electrophilic palladation of the a-palladium intermediate 54 to the adjacent aromatic ring to give 55, and reductive elimination gives rise to 56 [18]. The isoindolo[2.1-a]indole 59 was obtained in high yield from alkylarylacetylene 58 and the imine 50 [19]. 

Indoles as an important class of heterocycles were studied in carbonylations as well. In 2011, Lei s team developed an interesting procedure for the carbonylative transformation of indoles to the corresponding esters [48]. High regioselectivity was obtained and an electrophilic palladation mechanism was proposed. More recently. Lei s group developed some novel methodologies for the carbonylation of indoles [49-51]. Amides, a-ketoamides, esters, and alkynones were produced in good yields with I2 as an oxidant (Scheme 6.15). 

The direct palladium-catalyzed C3-alkynylation of free indoles with bromoacety-lenes was first described by Gu and Wang in 2009. The C2-selective alkynylation of indole proved to be especially challenging, and this was not realized until Waser et al. described a mild protocol using TIPS-protected hypervalent iodine reagent 101 and a palladium(II) catalyst (Scheme 10.34). Under optimized conditions, a variety of 7V-alkylated indoles 100 could undergo the alkynylation reaction via a palladium(II)/palladium(IV) mechanism to afford products 102-106 in moderate to good yields. It is unknown whether the C2-palladated intermediate is formed as result of a CMD mechanism, or via a pathway of electrophilic palladation at C3 followed by metal migration to C2. 

The use of acids as solvents is known to enhance the elec-trophilicity of cationic Pd and favor electrophilic palladation. Other solvents, such as AcOH, toluene, DMF, DMSO, and PEG 400, produced substandard yields, even when PivOH was added in substoichiometric quantities. Notably, unprotected 3-indolylaryl ketones could be cyclized, despite the tendency for indoles to dimerize under acidic conditions. Chloro substituents could also be incorporated however, longer reaction times were required (60-72 h) to afford good yields (38 6%). The Bn-protected indole could be cyclized, albeit in diminished conversions (54%). Electron-withdrawing substituents performed infe-riorly compared with electron-donating groups. 

In the first step, it was proposed that the highly electrophilic Pdn(TFA)2 catalyst affected selective electrophilic C-H bond activation exclusively on the electron rich indole. This generated an indole-Pd(II) complex I, which was able to selectively activate the benzene via a transfer-palladation pathway, which is controlled by C-H acidity. Reductive elimination afforded biaryl C-C bond formation and released Pd(0) which required oxidation to regenerate the active Pd(II) catalyst. 

Based on this observation the authors proposed that both C2- and C3-arylation pathways proceed via electrophilic addition of Pd(II) at the more electron-rich C3 position. This C3-palladated indole may then either undergo deprotonation and reductive elimination to give the 3-arylindole, or experience a C3 to C2 Pd migration, which then would lead to the C2-... 

After realizing that our hypotheses about oxidative cross-coupling reactions were not as unique as assumed, we quickly turned our attentirai to intermolecular oxidative amination reactions. In the carbazole example, regioselectivity was coti-trolled by the presence of a Lewis base that was attached near the C—H bmid that would be cleaved, resulting in a metallacyle intermediate. For die development of an intramolecular reaction, we chose to take advantage of the selectivity that is often observed in the selective metalation of electron-rich heteroarenes. At the time, the palladation of indoles was presumed to operate by an electrophilic aromatic substitution mechanism. (This has since been demonstrated to be incorrect, vide infra.) We hypothesized that regioselective palladation of an indole substrate could be followed by a subsequent C—N bond reductive elimination. At the time, the exact mechanism by which the intermediate containing Pd—C and Pd—N bonds could be formed was not clear, nor was the order of the two metalation steps, but the overall process seemed plausible. 

Reaction of the cyclometallated derivative of phenyl-2-pyridylketone 73 leads to indenol-chelated, palladium-containing derivatives 74. Here, incorporating an electrophilic (CO) function in the starting palladacycle signifies that, following alkyne insertion in the Pd-C bond, an intramolecular attack of the vinyl palladated unit on the metal-bound, activated CO function occurs. This is in sharp contrast to the reaction described in Scheme 9 whereby incorporating a nucleophilic, masked, secondary amine function leads to indole derivatives 40 and to the azepinium synthesis from the metallated benzylpyridine complex 34. Therefore, these reactions are rather sensitive to the nature of other potentially reactive functions within the metallacyclic framework. 

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