Free NH indoles

Heating of 3-acetylindole derivatives 537 with an alkene in toluene in the presence of 10 mol% of RuH2CO(PPh3)3 afforded only the product of the alkylation of the pyrrole ring 538 in good yield (Equation 129) <1997TL5737>. The free NH indole 537 (R = H) deactivated the catalyst. 

Although not a palladium-catalyzed reaction, the Ir(I)-catalyzed C-H borylation reaction developed independently by Smith and Malezcka [58] and Hartwig and Miyaura [59] deserves some mention in the context of indole and pyrrole functionalization. Based on the original studies, indoles and pyrroles can be borylated (and hence cross coupled under Suzuki conditions) to form either the C2 or C3 functionalised products (Scheme 35) [60, 61]. Free (NH)-indoles and pyrroles react exclusively at the C2, whereas /V-TIPS indole and pyrroles are borylated at the C3 positions. Interestingly, Smith, Maleczka and co-workers also demonstrated that when the C2 position of indole is blocked, then the borylation reaction takes place at the C7-position of the indole nucleus [62]. They propose that an A-chelation to Ir (or B) is responsible for the observed selectivity. 

Although much has been learnt about the reactivity and regioselectivity in direct functionalization of heteroarenes, the ability to manipulate and controllably switch the selectivity is extremely rare. In 2005, a method for direct and selective C2 or C3 elaboration of free-(NH) indoles using palladium-catalyzed C-H functionalization was developed by Gaunt and co-workers (Scheme 49) [43]. 

Wang X, Lane BS, Sames D (2005) Direct C-arylation of free (NH)-indoles and pyrroles catalyzed by Ar-Rh(III) complexes assembled in situ. J Am Chem Soc 127 4996—4997... 

Fujiwara and coworkers [23] recently described a single example of a catalytic inter-molecular oxidative coupling using the free NH indole nucleus. Under Pd(OAc)2 and a... 

In all of the aforementioned cases, the palladium(II)-catalysed indole alkenylation occurred preferentially at the 3-position of the indole moiety, which is consistent with the natural reactivity of indole towards electrophihc aromatic substitution reactions. More recently, a palladium(ll)-catalysed direct oxidative coupling of indole and alkenes was described by Gaunt and coworkers [28] that exploits a selective, solvent-controlled C—H functionalization of free NH indoles and leads to the substitution of the indole core at either the 2- or the 3-position. 

Selective arylation at the C-3 position of free NH-indoles occurs in the presence of Pd(OAc)2 and an ammonium chloride salt (eq 150). No ligand is requiredfor the transformation. A variety of aryl bromides can be employed as coupling partners limitations of the system include the use of indoles bearing strong electron-withdrawing substituents. The role of the ammonium salt is in preventing the formation of Pd black by stabilizing Pd clusters. ... 

Alternatively, very clean 3-substitution of NH indoles by aryl bromides can be achieved by use of phosphine-free conditions, but the reaction is inhibited by electron-withdrawing groups on the indole. Similar reactions using phosphines give 1- or 3-arylation depending on the phosphine. ... 

In 2005, Sames [50] developed a C-H arylation of N-alkyl indoles (indoles with a free NH can also be used) and pyrroles with aryl iodides using a rhodium catalyst. They demonstrated that CsOPiv activates the rhodium catalyst to form Rh(OPiv)2(Ph)L2 (L = P[p-(CF3)CgH4]j). In 2006, Sames [51] also developed a palladium NHC catalyst 53 for the C-H arylation of N-protected indoles, pyrroles, imidazoles, and imidazo[l,2-a]pyridines (Section 17.2.4.5) with aryl iodides. 

Two representatives of this class of compounds, one with a free NH— benzopyrano[2,3-b]indole(VIII)—and the other, an V-methyl derivative (IX) were prepared by the condensation of oxindoles with ethyl salicylate in the presence of sodium hydride, followed by ring closure with hydrochloric acid (Scheme 1) [6]. The products were identified by elemental analyses as well as by their spectra (u.v., i.r., n.m.r. and mass). Methylation of (VIII) also gave (IX) in 77 per cent yield. 

Potassium aryltrifluoroborate salts are excellent coupling partners for free or protected NH-indoles at the C-2 position the palladium- and copper-catalyzed transformation takes place under mild conditions, in air, at room temperature. Furthermore, conditions were developed for the coupling of indoles with aryl boronic acids, employing Pd(OAc)2 as the catalyst and a copper salt or O2 as the oxidant. ... 

The free NH group is of course required for the autoxidation described above, and photo-oxygenation [14] of the vinyl indoles (13) took the route shown. No products deriving from the addition of O2 to the 2,3-bond of the indole nucleus were observed, and the peroxide (14) apparently rearranges in protic solvents to the dioxetan (15). 

A plausible mechanism for the autooxidation is postulated based on the isolation of some intermediates. The reaction is thought to proceed through intermediates 176a-d followed by a novel type of autooxidation. The first step involves abstraction of the indole NH proton in 175 and subsequent O-methylation to form azaeno-late derivatives 176, which tautomerize to the enamines. The second step, autooxidation, is thought to be a free-radical process. 

Methyltryptamine hydrochloride (3-[2-aminoethyl] 5-methylindole hydrochloride) [1010-95-3] M 210.7, m 289-291°(dec), 290-292°, pKEst(i) "3 (protonation of ring NH), pKEst(2) 9.0 (CH2NH2), pKEst(3) 10.9 (acidic indole NH). Recrystd from H2O. The free base has m 93-95° (from C6H6-cyclohexane), and the picrate has m 243°(dec) (from EtOH). [Young J Chem Soc 3493 7958 Gaddum et al. Quart J Exp Physiol 40 49 7955 Rohm Hoppe Seyler s Z Physiol Chem 297 229 1954.]... 

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