Polysubstituted indoles

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

In terms of methodologies for the preparation of A-arylindoles 140, Buchwald reported improved conditions for the palladium-catalyzed coupling of aryl chlorides, bromides, iodides and triflates 138 with a variety of 2-, 7- and polysubstituted indoles 139 utilizing novel electron-rich biaryl(dialkyl)phosphine ligands in combination with Pd2(dba)3 <00OL1403>. Alternatively, Watanabe reports similar A-arylations of pyrrole, indole and carbazoles with aryl bromides and chlorides using Pd(OAc)2/P(f-Bu)3 in xylene at 120°C <00TL481>. 

Scheme 26 Synthesis of polysubstituted indoles 37 and 38, precursors of dictyoden-...

A recent procedure describes a one-pot, two-step mutlicomponent reaction of bromoani-lines 13, aldehydes 14, acids 15 and isocyanides 16 yielding polysubstituted indoles 18 [34]. It is based on a Ugi four-component reaction yielding the precursor 17 for the in situ performed classical intramolecular Mizoroki-Heck reaction, thereby providing a facile access to highly substituted dihydro-indoles, l//-indoles and l//-indole-2-carboxyhc... 

Using a [3H-2] annulation of 2-(benzotiiazol-l-ylmethyl) pyrroles with enones and enals, Katritzky and colleagues fashioned a novel synthesis of polysubstituted indoles (Scheme 6, equations 1 and 2) [36, 37]. The requisite pyrroles were fashioned in three steps from propargylbenzo-ttiazole as shown. In a modified C-3 benzotriazole-mediated reaction, Katritzky and coworkers developed a different... 

One of the most common examples of this approach involves the coupling of aryl or vinyl halides with palladium-catalyzed cydization. This chemistry typically employs palladium(O) catalysts, which are postulated to undergo an initial oxidative addition of aryl or vinyl halides to form a palladium(II) complex to mediate cydization. This is followed by reductive elimination of the heterocyde-aryl or heterocyde-vinyl bond. This approach has been employed to construct a range of polysubstituted indoles. For example, Cacchi has shown that the Pd(PPh3)4 catalyzed coupling of trifluoroace-tanilides with aryl halides or vinyl halides/triflates proceeds to substituted indoles in good yield (Scheme 6.14) [18]. 

Keywords 2-Ethynylanilines, sulfonyl azide, nitroolefins, CuBr, 1,4-dioxane, room temperature, one-pot three-compOTient reaction, polysubstituted indoles... 

To a stirred mixture of p-toluenesulfonyl azide (3 0.30 mmol, 1.2 equiv), nitroolefin (2, 0.25 mmol, 1.0 equiv), and CuBr (0.025 mmol, 10 mol %) in anhydrous 1,4-dioxane (0.5 mL) was added a solution of 2-ethynylaniline (1 0.25 mmol, 1.0 equiv) in 1,4-dioxane (0.5 mL) at room temperature under nitrogen atmosphere. Triethylamine (104 pL, 0.75 mmol, 3.0 equiv) was tehn slowly added by syringe. The whole mixture was thereafter stirred vigorously until completion of the reaction (monitored by TLC, 3-5 h). Upon completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (3.0 mL) the mixture was stirred for additional 10 min and extracted with ethyl acetate (3 x 3.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using flash column chromatography (EtOAc/ -hexane, 1 3) to obtain polysubstituted indoles 4. All the products were characterized by their spectral studies. 

Chen, Z., Zheng, D., and Wu, J. (2011). A facile route to polysubstituted indoles via three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin. Org. Lett., 13, 848-851. 

Sakai N, Annaka K, Konakahara T (2004) Palladium-catalyzed coupling reaction of terminal alkynes with aryl iodides in the presence of indium tribromide and its application to a one-pot synthesis of 2-phenylindole. Org Lett 6 1527-1530. doi 10.1021/ol036499u Sakai N, Annaka K, Eujita A, Sato A, Konakahara T (2008) InBr 3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group. J Org Chem 73 4160-4165. doi 10.1021/jo800464u... 

Three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin also could lead to polysubstituted indole derivatives in moderate to good yields with CuBr catalyst. The reaction conditions are extremely mild and various polysubstituted indoles were obtained successfully. Initially, a triazole intermediate was formed from alkyne and sulfonyl azide in the presence of CuBr and triethy-lamine. It could convert into reactive ketenimine by the ring-opening rearrangement. Subsequently intramolecular nucleophilic addition, intermolecular Michael addition, and tautomerization could lead to the desired polysubstituted indoles [49] (Scheme 8.20). 

Scheme 8.20 Polysubstituted indole derivatives synthesis via three-component reaction of 2-ethynylaniline, sulfonyl azide, and nitroolefin.

Sakai and Konakahara et al. found that InBrs is effective in catalyzing the intramolecular cyclization of 2-alkynylanilines to form polysubstituted indoles [232] (Figure 8.109). Activation of the alkyne by InBrs, increasing the electrophilicity of the triple bond, is the role played by InBrs in this case. The authors also reported in the same paper the synthesis of idolyl amine derivatives by utilizing the indole generated in situ to add to imines in the presence of TMSCl with increased catalyst use. 

A palladium-catalyzed domino sequence for the synthesis of polysubstituted indol-izinones 229 from tertiary propargylic alcohols 228 and aryl iodides was developed by Kim and Kim [86] (Scheme 6.63). The authors reasoned that arylpaUadium species formed in situ by oxidative addition of Pd(0) to aryl haUde could coordinate with the triple bond and activate it. Then, nucleophilic attack of the neighboring pyridine group to the alkyne moiety would generate the indolizinium salt intermediate 231, followed by reductive elimination to furnish intermediate 232. Finally, 1,2-migradon would afford the desired indolizinones. 

Scheme 8 Synthesis of polysubstituted indoles via Pd-catalyzed intermolecular C-C bond formation and subsequent intramolecular N-arylation...

Echinulin, a polysubstituted piperazine-indole structure, an Aspergillus sp metabolite [1859-87-61],... 

Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equation 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 2]-cycloadducts, followed by retro-Diels-Alder reaction or rearrangement under thermodynamic control which leads diastereo-selectively to aminocyclopentenes. The reaction is called [3 + 2]-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration325 (equation 243). 

Ji and co-workers [73] have reported a new series of polysubstituted (3 -indolyl) benzo[/i]quinoline 78, synthesized via a one-pot MCR of an aldehyde, 3-cyano-acetyl indole, and naphthylamine under microwave irradiations in good yields (Scheme 59). 

Cryptoechinulin A (also C, G), polysubstituted piperazine-indole structures, Aspergillus sps metabolites [55179-54-9, 57944-03-3, 68836-03-3]. 

A range of pyridine-type hydroxyl heterocycles are brominated effectively with NBS/PPhs while NBS is used as a synthesis of pyridines.Polysubstituted pyrroles,4 furans, 4 pyrrolidin-2-ones,4 thiophenes, and 3,4-disubstituted indoles have also been prepared using NBS as a key reagent. 3-Methyl indole derivatives of general structure 12 are brominated in the methyl group to 13 with NBS under radical conditions. Under ionic conditions bromination occurs at the 2-position of the indole structure (12) to give products with general stracture 14 (eq 38). ... 

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