Michael reaction with indole

A new iodine-catalysed, remarkably simple Michael reaction of indoles with enones, e.g. PhCH=CHCOR, has been developed.183 The Sml3-catalysed reaction of indoles with electron-deficient alkenes (e.g. enones) afforded the corresponding Michael adducts in high yields. As in the previous case, the substitution on the indole nucleus occurred exclusively at the 3-position and A-alkylation products have not been observed.184... 

The high diastereoselective synthesis of multifunctionalized 3,4-dihydro-coumarins bearing a quaternary stereocenter was developed through tandem Michael additions of indole and its derivatives (1-methyl, 2-methyl, 4-methoxy, 5-methoxy, 5-bromo, 6-benzyloxy) to 3-nitrocoumarines (3-nitro-chromen-2-one, 6- and 7-methyl-3-nitro-chromen-2-one) followed by methyl vinyl ketone in a one-pot step. For the tandem Michael additions, after the first Michael reaction of indole (2) with 3-nitrocoumarine (51) catalyzed... 

Recently, the use of 3-(2/-nitrovinyl)indole (227) as a Michael acceptor with indoles as nucleophile have been reported [174,177]. Michael reaction of 227 with eight 3-unsubstituted indoles (2, 14, 19, 228-235) on TLC-grade... 

Very simple and efficient Michael reaction of indoles 449 with cyclic and acyclic unsaturated ketones has been accomplished in the presence of only 1 mol% of iodine as catalyst at room temperature under solvent-free conditions (Equation 106) <2005TL2479>. 

Michael reaction Catalyzed by HfCU, indoles and pyrroles undergo Michael reactions with enones at C-3, and C-2/C-5, respectively. The reaction of pyrazole and imidazole takes place at an N-atom. 

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

In an outstanding study, calix[6]arene sulfonic acids (Calix[6]arene 3a-3d) were employed as efficient surfactant-type acid catalysts for Michael reactions of indoles with a,p-unsaturated ketones in water [24]. It was pointed out that calix[6] arene sulfonic acids were efficient inverse phase-transfer catalysts, and performed a significant catalytic activity in water (see Fig. 27.10). This remarkable activity in... 

Fig. 27.10 Michael reaction of indole with chalcone in the presence of calix[6]arene sulfonic acids...

Michael-type Reactions. The Michael reaction of indoles with a series of electron-deficient olefins, like a , -unsaturated ketones and -nitrostyrene, is catalyzed by Y(OTf)3 to give the corresponding 3-substituted indoles in high yield (eq 5). In this case, Y(OTf)3 was found to be the superior catalyst compared to BiCl3, SbCls, ZnCl2, LaCls, AICI3, and La(OTf)3. 

The [3+2] cycloaddition reaction with indoles developed by Kerr and co workers led to the belief that cyclopropanes had a very similar reactivity to a,p-unsaturated carbonyl moieties in their ability to react with nucleophiles in a homo-Michael type addition. Hence, the use of substituted cyclopropanes as precursors for cycloaddition reactions has become very popular due to their ability to undergo ring-opening while in the presence of a Lewis acid. 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

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. 

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

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... 

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... 

D-Camphorsulfonic acid (d-CSA) was identified as catalyst for the enantioselec-tive Michael-type Friedel-Crafts reactions of indoles with aromatic enones ArCH= CHCOAr to afford the corresponding /i-indolyl ketones in excellent yields and moderate enantioselectivities. A surprising synergistic effect was discovered between [Bmim] Br and d-CSA, which may originate from the catalytic Lewis acid activation of the Brpnsted acid.162... 

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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