Palladation of indoles

Besides the synthetic route depicted in 5.5. the seven membered central heterocyclic ring of iboga alkaloids was also accessed by the palladium mediated closure of the indole derivative bearing a pendant double bond shown in 5.21. The reaction is believed to be initiated by the palladation of indole in the 2-position followed by insertion of the double bond. Since fi-hydride elimination from the formed intermediate is blocked by the conformational rigidity of the system, the reaction stops at this stage and the addition of a reducing agent is required to remove the palladium and obtain the product.21... 

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. 

Several examples of the cyclization of indole derivatives with alkenic side chains in the 3-position have been reported.6 In these examples, palladium chloride in combination with silver tetrafluoroborate is the cyclizing agent. The palladium tetrafluoroborate, presumably formed, should be a very reactive palladating species and probably is the reason why these reactions proceed at room temperature, although the mechanism is not yet completely clear. These reactions were worked up reductively (by addition of sodium borohydride) in order to reduce the expected alkenic product or any relatively stable organopalladium complexes that may have been formed (equation 4).6... 

Oxidative cross-coupling with alkenes is possible with Pd(OAc)2 [109], The reaction proceeds by the palladation of benzene to form phenylpalladium acetate (164), followed by alkene insertion and elimination of /1-hydrogen. Heteroaromatics such as furan and thiophene react more easily than benzene [109]. Stilbene (177) is formed by the reaction of benzene and styrene. The complex skeleton of paraberquamide 179 was obtained in 80% yield by the Pd(II)-promoted coupling of the indole ring with the double bond in 178, followed by reduction of the intermediate with NaBELt [110]. 

Using this concept the Sanford group found that direct C2-arylation of indoles and pyrroles could be effected under remarkably mild conditions with aryl iodo-nium salts and palladium(II) catalysts (Scheme 19) [42], The high C2 selectivity of the functionalization is attributed to a mechanism involving initial palladation at C3 followed by fast palladium migration to C2 under acidic conditions as initially proposed by Gaunt [43] and Sames [29], The reaction also works well for simple pyrroles, again with C2 selectivity. 

Transition metal catalysed prenylation. There is a new one-step N-tert-prenylation of indole developed by Baran and co-workers [42] which still outcom-petes the chemoenzymatic approach (Scheme 5). Isobutene (21) as prenyl source is reacted with side-chain Fmoc-protected tryptophan methyl ester 20 in the presence of catalytic amounts of Pd(OAc)2 and superstoichiometric amounts of Ag(I) trifluoroacetate and Cu(II) acetate. The protocol also requires the presence of oxygen. After about 1 day at 35°C, the N-tert-prenylated indole is obtained in a yield of about 60%. The mechanism has not been elucidated, but may involve a 7i-allyl-Pd(II) complex which is coordinated by the indole nitrogen or by C3. In the latter case, a Pd-Claisen rearrangement of a 3-palladated indole would follow. Ag (I) functions as reoxidant of Pd(0). 

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... 

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]. 

In 2002, Baran and Corey [44] described the total synthesis of (+)-austamide and its naturally occurring relatives (+)-deoxyisoaustamide and (-l-)-hydratoaustamide (Scheme 9.15). The efficient synthesis of these compounds featured a palladium(II)-mediated cyclization to form an eight-membered ring as the key step. Indole 102 was treated with stoichiometric palladium acetate in a 1 1 1 mixture of acetic acid, water and tetrahydrofuran (THP) to produce dihydroindoloazocine 103 in 29% yield. A unique mechanism, illustrated in Scheme 9.15, was proposed for this transformation. After palladation of the indole at C(2), 7-exo cyclization provides intermediate 108, which forms cationic intermediate 109 upon acid-mediated heterolysis. This intermediate undergoes a deprotonation and subsequent migration of the indolyl species to afford product 103. A possible alternative mechanism... 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

Capita, E., Brown, J.M. and Ricci, A. (2005) Directed palladation fine tuning permits the catalytic 2-alkenylation of indoles. Chem. Commun., 1854-6. 

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. 

Also in 2010, DeBoef and Gorelsky reported a combination of experimental and computational work to elucidate the mechanism of C2-oxidative cross-coupling of indoles with benzene previously reported by DeBoef in 2008 [50]. The results of their work led to the conclusion that both C-H bond cleavage events proceeded via a single unifying mechanism—a concerted metallation-deprotonation process (Scheme 9). Furthermore, their experiments lead them to the conclusion that the palladation at indole takes place directly at the C2-position without C3-palladation and subsequent C3/C2-palladium migration as previously reported [27, 35] and described herein (vide supra). 

Very recently, diaryliodine(III) reagents have been used in palladium(II) catalysed arylation where the involvement of Pd(IV) intermediates is implicated, e.g. ort/zo-arylation proceeding via ortAo-palladation, " and 2-arylation of indoles proceeding via direct palladation," followed by oxidation to form 11 and 12 respectively, and reductive elimination (Scheme 13). 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

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