Indole arylation

A related example from He and co-workers demonstrated that phosphinous ligands on Pd(0) are also able affect an indole arylation reaction. A small selection of C3 arylated indoles can be realized using this method. Of particular note is the C3 selectivity observed in this reaction, when compared to the work of Sames who observed C2 selectivity (Scheme 15). 

Scheme 19 Pd-catalyzed direct C2 indole arylation with Arl at room temperature.

Azaindoles bear an obvious resemblance to indoles, sharing the indene framework, but with one extra nitrogen. Therefore, Huestis and Fagnou turned to published methods for direct C2 indole arylation in order to develop a C2 arylation of azaindoles (09OL1357). 

Scheme 37 Rhodium-catalyzed free indole arylation (coe = cis-cydooctene).

Dominguez and co-workers have employed a Cu-catalyzed intramolecular indole arylation in their route to isoindolo[2,l-fl]indoles (09TL2129). The reaction proceeds via initial N-benzylation, after which the resulting N-(2-halobenzyl)indole undergoes an intramolecular Cu-cat-alyzed C2-arylation to give isoindolo[2,l-fl]indole (Scheme 42). This multistep procedure requires very high temperatures (180°C), and its scope and generality were not explored. 

Our initial work in the oxidative aryiation of heteroarenes was an example of the discovery of new chemical territory. However, we sought to not just discover this new reactivity, but to understand it. Consequently, both experimental and computational studies were performed to elucidate the mechanism of the oxidative indole arylations. Both sets of data indicate a concerted metalation-deprotonation mechanism (CMD) for the palladation of both the... 

Carbamates possess a more electron-rich nitrogen than amides or sulfonamides, and the intermolecular reaction of t-butylcarbamate with aryl halides to form t-Boc-protected anilines has been realized (Eq. 30). As one might expect from the increased rates for amine and indole arylation using the Pd(dba)2/P(t-Bu)3 catalyst, it is this system that allows for the arylation of i-butylcarbamate. Reaction of other carbamates, such as methyl or benzyl carbamate and oxazolinone, occurred in lower yield. However, reaction of t-butyl carbamate with bromoarenes occurred at 100 °C in yields ranging from 62% to 86% with electron-rich, electron-neutral, and sterically hindered or unhindered bromoarenes. Reactions of chloroarenes were again slower, but did occur at 130 °C to give Boc-protected aniline in 59% yield for reaction of chlorotoluene. 

An interesting selectivity was uncovered in the direct cross-dehydrogenative coupUng between N-protected indoles and arenes (Scheme 11.40) [151]. Thus, whereas 2-arylated indoles 67a were preferentially obtained from N-acetyhndole in the presence of Cu(OAc)2, the reaction of N-pivalolyUndole with AgOAc led to 67b, with excellent selectivities. The reason for this C-2/C-3 selectivity is most likely due to the formation of higher-order palladium clusters or paUadium/copper clusters under the different reaction conditions. A related reaction between aryl-boronic acids and arenes or heteroarenes also proceeds under oxidative conditions with Pd(OAc)2 as catalyst [76]. A catalytic cycle initiated by an electrophihc attack of Pd(II) on the arene, followed by transmetallation with the aryl boronic acid and reductive elimination, was suggested. In this transformation, Cu(OAc)2 as stoichiometric oxidant could be replaced by O2, and for indoles, arylation at C-2 was observed. 

A number of other research groups utilized aryl halides in their indole arylation methodologies including Beilina et al. who arylated indole at the C2 position under... 

SCHEME 10.33 Fagnou s intermolecular oxidative indole arylation. 

Further studies have come from the DeBoef group on oxidant-controlled regioselectivity, in which both benzofuran and indole arylations were examined in different solvent parameters. They surmised that solvent had little overall effect on regioselectivity compared to oxidant choice, and both DeBoef and Fagnou reasoned that site selectivity is most likely due to the formation of polymetallic clusters during catalysis. " ... 

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