Indoles Michael addition

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). 

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-... 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

A remarkably simple fused indole devoid of the traditional side chains is described as an antidepressant agent. Michael addition of the anion from indole ester 119 to acrylonitrile affords the cyanide 120. Selective... 

In continuation of the aforementioned reaction, Hiroya and coworkers used cop-per(II) acetate for the synthesis of indoles 2-943 in reasonable yields from the corresponding ethynylanilines 2-941 by a domino intermolecular Michael addition/cop-per-assisted nucleophilic tosylate displacement reaction via 2-942 (Scheme 2.211) [482],... 

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

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. 

Mahboobi et al. described a novel synthesis of staurosporinone (293) (791). The intermolecular Michael addition of l-(indol-3-yl)-2-nitroethene (1472) to methyl indol-3-ylacetate (1313) provided with high diastereoselectivity methyl 2,3-bis(indol-3-yl)-4-nitrobutanoate (1473). Catalytic hydrogenation and lactamization afforded 2,3-bis(indol-3-yl)-y-butyrolactam (1474) in 87% yield. Oxidative cyclization of the ds-lactam 1474 with DDQ in the presence of catalytic amounts of p-TsOH led to staurosporinone (293) (791) (Scheme 5.249). 

In terms of Michael additions at the indole C-3-position, montmorillonite KIO has been shown to be effective in promoting the conjugate addition of indoles to a,p-unsaturated carbonyl compounds <99MC929>. In what is also a Michael process, microwave irradiation has been shown to be effective in promoting the trimolecular condensation of substituted indoles 111 with... 

A fused tricyclic ring system based on an indole provides yet another NSAID. Michael addition of the anion from diethyl methylmalonate to cyclohexanone followed by acid hydrolysis of the product gives cyclohexanone (21-3), which incorporates the characteristic profen 2-substituted carboxylic side chain. Sequential reaction with para-chlorophenylhydrazine and a strong acid gives the fused indole... 

Compounds derived from indole have been extensively investigated as potential psychoactive dmgs. The construction of a tricyclic indole derivative starts by benzyltrimethylammonium hydroxide catalyzed Michael addition of 2-carbethoxy-indole (70-1) to acrylonitrile to give the adduct (70-2). In one of several alternatives... 

In contrast to the reactivity of the nitroethylenes, acrylonitrile generally reacts with indoles to form the l-(2-cyanoethyl) derivatives (B-70MI30500,79MI30501), whereas Michael addition at the 3-position requires the catalytic effect of copper(II) salts. The addition-elimination reaction of pyrroles and indoles with l,l-dicyano-2-ethoxyethylene proceeds in low yield (<30%) to give the dicyanovinyl derivatives, which can be converted by standard procedures into the formyl compounds (81H(16)1499). Tetracyanoethylene forms charge transfer complexes with indoles, which collapse to the Michael adduct anions and subsequently eliminate a cyanide ion with the formation of the tricyanovinylindole (B-70MI30500). 

Analogous [ 4 + 2] cycloaddition reactions of DMAD with indoles would disrupt the aromatic character of the fused benzene ring. It is not unexpected, therefore, that indole reacts with two molecules of DMAD to give the dihydrocarbazole derivative (234), via an initial Michael addition reaction, followed by cycloaddition of DMAD to the vinylindole. Aromatization of the 1 2 adduct (234) normally yields the carbazoletetracarboxylic ester... 

Michael addition reaction at the 5-position <8lUP30500). The dihydroindoles are readily dehydrogenated with DDQ to give the indoles, but the 4,5,6,7-tetrahydroindoles have resisted all attempts to convert them into the fully aromatic systems (81JOC4515, cf. 81ACS(B)77>. 

N-Methyl- and N-phenyl-2-vinylpyrroles 20a,b react with DMAD at reflux temperature in chloroform to give, in moderate yields, the dihydroindoles 22 via a 1,3-H shift from the Diels-Alder intermediate 21 (55-75%) (80JOC4515). These adducts were readily converted into the corresponding indoles 23 with Dichlorodicyanoquinone (DDQ). 2-Vinyl-pyrrole failed to give [4 + 2]-cycloadducts with acetylenic esters (80JOC4515). Spectroscopic analysis of the product mixtures indicated the presence of polymeric compounds resulting from Michael addition reactions. 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

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