Benzoquinones reaction with indoles

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

Michael additions to quinones. In the presence of TrC104, enol silyl ethers undergo 1,4-addition to benzoquinone to give adducts that cyclize to benzofurans.1 A similar reaction with diimidoquinones produces indole derivatives. 

Hydroxyindoles may be accessed using the Nenitzescu reaction, as illustrated by preparation of the indole 381 from the enamine 382 and 1,4-benzoquinone (Equation 107) <1996JOC9055>. Additional applications of this strategy encompass syntheses of 1 -alkyl-5 -hydroxynaltrindole derivatives <2005JME635>, and lO-hydroxy-5,6-dihydroindolo[2,l- ]isoquinolines <2001JOC4457>. An alternative approach to 5-hydroxyindole derivatives involves Lewis acid-mediated reactions of benzoquinone monoimines with enol ethers <1997TL6135>. 

Air oxygen can also play the role of oxidant in the amination reactions. It is well known that 1,4-benzoquinone reacts with aliphatic amines in the presence of copper acetate to give 2,5-bis(dialkylamino)-l,4-benzoquinones in good yields [64]. The reaction mechanism involves nucleophilic 1,4-addition followed by oxidation of intermediate aminohydroquinones with air oxygen. The reactions of this type, which are also inherent to ort/io-quinones, have been reviewed earlier [65, 66]. It is interesting that amination is also possible in case of some heterocyclic phenols, which are first converted in situ into the corresponding ort/io-quinones. This approach has successfully been exploited to aminate ort/io-quinones generated from quinolines, indoles, acridines, isoquinolines, quinoxalines, benzofurans, and benzothiazoles (Scheme 15) (for review, see [65, 66]). 

In a series of papers, Kucklander has provided additional evidence for the Nenitzescu-Allen mechanism, in particular theD->-E- F- G transformation [18-20]. Eor example, isolated carbinolamine 35 gives byproducts 36-38 in addition to indole 39 (Scheme 7, equation 1) [18]. The formation of 36 presumably involves reaction of iminium ion 40 with acetate and rearrangement of 41 to 36 as shown (Scheme 7, eqnation 2) [20], Kucklander and Hiihnermann found that benzoquinone reacts with p-arylaminocrotonates in propionic acid to afford 6-hydroxyindoles 42 (10%-30%) (equation 3), along with the byproducts 5-acyloxy-4-hydroxyindoles (20%-35%) and arylaminobenzofurans (10%-15%) [21]. 

Reaction with 2-Aminoquinones. Acyl and carbox3miethyl radicals generated using Mn(OAc)3 react with 2-aminoquinones in a fashion similar to that of their naphthoquinone counterparts. In case of 2-arylainino-l,4-benzoquinones, sequential radical addition/cycUzation occurs to afford the corresponding acridine derivatives (eq 34). The yield is lowered in the presence of an electron-withdrawing group on the aniline. Benzo[/]-indole-4,9-diones and their derivatives can be obtained exclusively with... 

You and coworkers employed 4,7-dihydroindoles 79 instead of indoles 75 in the Friedel-Crafts reaction with nitroalkenes 77 (Scheme 11.22) [41]. Catalyst Ig with a 9-anthryl group displayed excellent performance. The notable point in this reaction is the use of the syringe pump technique to achieve high enantioselectivities and suppress the background reaction. Subsequent oxidation of Friedel-Crafts adducts 80 by p-benzoquinone afforded 2-substituted indole derivatives 81 in excellent yields without racemization. This approach and the simple asymmetric Friedel-Crafts reaction of indoles are complementary methods for obtaining the different substitution patterns of chiral indole derivatives. 

Oestreich and co-workers reported an enantioselective intramolecular Fujiwara-Moritani reaction of indole and pyrrole derivatives. Using a suitable oxidant e.g., PhCOg Bu, benzoquinone, O2), they evaluated a chiral bidentate pyridyl-oxazoline ligand (PyOx) developed by Stolz and a series of nicotine-oxazoline ligands (NicOx) with Pd(OAc)2 as a catalyst precursor (Scheme 7.25). Indoles and pyrroles underwent a 5-exo-trig cyclization, but the chemical yield and enantioselectivity were generally unsatisfactoiy. 

The CDC reaction between indoles and quinones or benzoquinone is possible with a catalytic amount of I2 under ultrasonic irradiation, giving (3-indolyl)quinones in 30-90% yields (Scheme 8.45). ... 

The best yields of 5-hydroxyindoles are obtained when equimolar amounts of the quinone and enamine are used. An excess of enamine gives rise to non-indolic products derived from reaction of two enamine units and one quinone unit or the product which results from the initial Michael addition of the enamine to the quinone. Use of excess quinone has been reported less frequently, but limited studies indicate no advantage. When 2,5-dichloro-l,4-benzoquinone (32) was treated with a 50% excess of ethyl 3-... 

Reactions of 2-(2-nitrovinyl)-l,4-benzoquinone with furans, indoles, and endocyclic enol ethers form angular, fused heterocyclic quinoid ring systems (see Eq. 8.13).23... 

Dimethyl 2-(17/-indol-2-yl)but-2-enedioate, easily available by reaction of 4,7-dihydroindole with dimethyl acet-ylenedicarboxylate followed by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), treated with PTAD provided compound 703, which was thermaly isomerized to 704 (Scheme 111) <2006JOC7793>. 

In addition to examining the vinylation of l-methyl-2-indolecarboxaldehyde with methyl acrylate (Pd(OAc>2/HOAc/AgOAc) to give methyl ( )-3-(2-formyl-l-methyl-3-indoiyl)-acrylate in 60% yield, Pindur found that similar reactions of methyl 3-(l-methyl-2-indolyl)-acrylate afford bis(carbomethoxy)carbazoles albeit in low yield [85]. Fujiwara discovered that the combination of catalytic Pd(OAc)2 with benzoquinone and t-butylhydroperoxide serves to couple indole with methyl acrylate to give methyl ( )-3-(3-indolyl)acrylate in 52% yield [86]. 

Bcnzofuran-4,7-dioncs have been synthesized regioselectively by [3 + 2] photoaddition of 2-hydroxy-1,4-benzoquinones with a range of alkenes (equation 185)664. The reaction occurs in 30-60% yield and is a useful method for the synthesis of the benzofuran ring system, which is important in natural products like acamelin665. Substituted naphthoquinones may also be used in this reaction666,667 and this has lead to a very simple two-step synthesis of maturinone. In a similar reaction, a [3 + 2] photoaddition reaction of 2-amino-1,4-naphthoquinones with electron-rich alkenes gave 13-82% yields of 2,3-dihydro-177-bcn/ /]indole-4,9-diones in a single-step process which involved photolysis followed by oxidation (equation 186)668,669. 

The reaction of 1,1-enediamines with 1,4-benzoquinone takes a different course132. Acyclic 1,1-enediamines 149 react with 1,4-benzoquinone in refluxing acetic acid to give after workup two products 150 and 151, resulting from dehydration and deamination, respectively (equation 57). Only benzofurans 152 (21-27%) are isolated in the case of enediamines 8 derived from 4-bromoacetophenone. Cyclic 1,1-enediamine 8 (n = 2, R = H) examined in the reaction leads exclusively to a low yield (9%) of the tricyclic indole 153. 

The reaction of 3-(2-bromoethyl)indole (284) with 2-chloropyridine gave indoloquinolizine 285, which was dehydrogenated with tetrachloro-o-benzoquinone to yield indoloquinolizinium salt 286 (62JA3393 68CPB549). 

Hegedus proposed that the mechanism of this transformation proceeds through a Wacker-type reaction mechanism that is promoted by Pd(II). As shown below, coordination of the olefin to Pd(II) results in precipitate 121, which upon treatment with Et,N undergoes intramolecular trany-aminopalladation to afford intermediate 122. As expected, the nitrogen atom attack occurs in a 5-exo-trig fashion to afford 123. [l-Hydride elimination of 123 gives rise to exocyclic olefin 124, which rearranges to indole 120. The final step of this mechanism leads to the formation of catalytically inactive Pd(0). However, addition of oxidants such as benzoquinone allows for catalytic turnover. 

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