Oxidative annulation of indoles

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

By using an olefin embedded into the parent molecule Stoltz developed the oxidative annulation of indoles. The optimal catalyst consisted of palladium acetate and ethyl nicotinate, and molecular oxygen was used as the oxidant in the process. The reaction proceeded equally well irrespective of the attachment point of the alkyl chain bearing the pendant olefin bond on the five membered ring, and the formation of five and six membered rings were both effective (6.95.),127... 

Figure 9.6 The palladium-catalysed oxidative annulation of indoles.

Ferreira, E.M. and Stoltz, B.M. (2003) Catalytic C-H bond functionalization with paUadium(II) aerobic oxidative annulations of indoles. J. Am. Chem. Soc., 125, 9578-9. 

Shortly afterwards, Stoltz et al. (5- and 6-exo-trig cyclizations) [129] and Beccalli et al. (6-exo-trig cyclization) [135] simultaneously reported palladium] I)-catalyzed oxidative annulations of indoles. The observation that an electronically modified pyridine ligand increases chemical yields emerged from the systematic survey by Stoltz et al. [vide supra) [129]. Under an atmosphere of dioxygen, a number of indoles cyclized in moderate to good yields (218 221 and 219 222 Scheme 7.53). As a quaternary carbon is formed upon cyclization of the C—Pd" onto C-1... 

Ferreira EM, Stoltz BM (2003) Catalytic C-H bond fimctimialization with palladium(II) aerobic oxidative annulation of indoles. J Am Chem Soc 125 9578-9579... 

Scheme 4. Annulation of indole and the stereochemistry of oxidative dihydrobenzofuran formation.

The choice of solvent also proved to be important in these indole annulations. In standard solvents and in the absence of catalyst, the annulated indole products were susceptible to oxidative decomposition. After a thorough analysis of solvent and catalyst effects, it was found that the products were stabilized in the presence of the Pd(OAc)2/ethyl nicotinate catalyst in a 4 1 mixture of tert-amyl alcohol/AcOH as the solvent. Since the oxidative decomposition of indoles is generally initiated by addition at C(3), it was hypothesized that the catalyst and/or AcOH can act as a competitive inhibitor. With this carefully optimized system, the oxidatively annulated indoles could be accessed in good to excellent yields. 

A wide variety of heterocycles can be readily prepared by the heteroannulation of alkynes. For example, the palladium-catalyzed annulation of internal alkynes by 2-iodoanilines provides easy access to 2,3-disubstituted indoles by a process that involves initial reduction of Pd(OAc)2 to Pd(0), oxidative addition of the aryl halide to Pd(0), c/s-addition of the arylpalladium... 

The double iron-mediated arylamine cyclization provides a highly convergent route to indolo[2,3-fc]carbazole (Scheme 16). Double electrophilic substitution of m-phenylenediamine 34 by reaction with the complex salt 6a affords the diiron complex 35, which on oxidative cyclization using iodine in pyridine leads to indolo[2,3-b]carbazole 36 [98].Thus,ithasbeen demonstrated that the bidirectional annulation of two indole rings can be applied to the synthesis of indolocarbazoles. 

In spite of its formal similarity to the above mentioned annulation processes, the reaction shown in 4.37. includes a unique migration step. Oxidative insertion of the palladium into the phenyl-iodine bond is followed by the migration of the palladium onto the more electron rich indole ring. The 2-indolylpalladium complex than carbopalladates the pendant alkync moiety and the process ends by the formal activation of a C-H bond of the phenyl substituent and subsequent reductive elimination, furnishing the pentacyclic product.48 The same strategy has been utilised in the preparation of the indoloindolone framework from /V-bcnzoyl-3-(o-iodophcnyl)-indolc in an oxidative addition - palladium migration - C-H activation sequence.49... 

While both 2- and 3-furylcarbene complexes 99 and 103 gave [fo -annulated benzofurans (100 and 104), only the 2-pyrrolyl carbene complex 105 afforded the aromatic indole skeleton (106). In contrast, annulation of the 2,5-dimethylated 3-pyrrolylcarbene complex 107 occurred at the 4-position to give isoindole quinone 108 after oxidative work-up [82g]. 

A further extension of this strategy has been employed as a route to carbazoles, as illustrated by the synthesis of the system 116 from the 2-nitrobiphenyl derivative 117 (Equation 30) <20040L533>. A substituted 2-nitrobiphenyl derivative has been cyclized to a carbazole using P(OEt)3 en route to the pyridocarbazole alkaloid ellipticine <2006HCA111>. It should also be mentioned that annulation of o-(alkynyl)nitrobenzene precursors with TBAF or pyridine gave access to indol-3-one-l-oxides (isatogens) <2003T2497>. 

Substituted indoles are of biological interest and are not readily synthesized by conventional methods of indole chemistry. Annulation of a nuclear methyl and an a-ethoxyimine (or an imidate) under basic conditions is a promising procedure. The pyridine oxide ester (87.1) may be converted in high yields into two kinds of pyrrole carboxylic ester the potassium salt of the imidate, on heating in DMF, gives the 3-(2-oxocarboxylate) whereas dilute mineral acid leads to the 2-carboxylate ester. 

Dieck reported preparation of the tetrahydrocarbazole 337 by heteroannulation of o-iodoaniline with 1,3-cyclohexadiene [137], As a recent example, heteroannulation of the o-iodoaniline derivative 338 with the conjugate dienyl sulfone 339 afforded the vinylogous 2-sulfonylindoline 340, which was converted to the indole derivative 341 by oxidative dehydrogenation [138]. Pd-catalyzed annulation of 1,3-dienes by o-iodoacetoxycoumain 342 offers a synthetic method for dihydro-furocoumarins. The dihydrofurocoumarin 343 was obtained by the reaction of 342 with 1-phenylbutadiene in 80% yield. After optimization, the uses of Pd(OAc)2,... 

The Larock method for annulation between vicinal iodo-arylamines and 1,2-dienes in the preparation of indoles can be adapted for preparation of azaindoles using corresponding azine substrates. Thus, substituted-3//-pyrrolo[2,3-fc]pyridin-3-ones can be prepared from 2-amino-3-iodopyridine derivatives by a palladium carboannulation process with al-lenic compounds (Scheme 104). The bicychc products, the methylene derivatives 308, and the alkylidenes 309 can be oxidatively cleaved with ketone formation. The reaction may proceed by formation of a pyridinylpaUadium complex followed by the rr-allyl complexa-tion of aUenic derivatives 310. Since the polar substituents on terminal carbons of the 7r-allyl system influence the regiochemistry of the reactions, nucleophilic attack of the nitrogen atom on the most electron-deficient carbon atom of the rr-allyl system affords either of the... 

Under rhodium-catalyzed conditions, hydrazine 137 undergoes oxidative annulation with alkyne 135 to furnish 1,2,3-tri-substituted indole 138 in moderate to excellent yield. The 1-aminoindole products can be substituted at C2 and C3 with aryl, heteroaryl, alkyl, and alkynyl groups (free hydroxyls and alkyl chlorides are also tolerated). 1,3-Dinitrobenzene acts as the stoichiometric oxidant and this is believed to be the first report of its use as such in a transition metal-catalyzed C-H activation (140L6176). 

The scope and mechanism of palladium-catalyzed annulation of internal alkynes to give 2,3-disubstituted indoles, the effect of substituents on the aniline nitrogen or on the alkynes, as well as the effect of the salts such as LiCl or n-BuaNCl were studied by Larock and coworkers (1998 JOC7652). The mechanism they propose for indole synthesis proceeds as follows (a) reduction of the Pd(OAc)2 to Pd(0) (b) coordination of the chloride to form a chloride-Ugated zerovalent palladium species (c) oxidative addition of the aryl iodide to Pd(0) (d) coordination of the alkyne to the... 

The aerobic dehydrogenative annulation of 2-aryl-substituted pyrroles and indoles for a variety of alkynes, using the system ruthenium(Il) catalyst with oxidant Cu(0Ac)2.H20, was then reported. The reaction was now performed under ambient air as the ideal sacrificial oxidant, thus only 10 mol% of Cu (0Ac)2.H20 could be used for efficient transformations of indoles [(Eq. 89)] [178]. This method could also be applied to synthesize pyrrolo[2,l-a]isoquinolines from 2-arylpyrroles with dialkyl-, diaryl-, or alkylarylacetylenes with an excellent regioselectivity. The competition experiments showed that an electron-deficient alkyne favours this reaction and that the more acidic C-H bond activation is favoured [(Eq. 89)] [178]. 

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