Michael addition of indoles

Michael Additions of Indoles to Conjugate Systems by Various Acid Catalysts... 

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... 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

Michael Additions of Indoles Under Basic and Neutral Conditions... 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

N-Michael addition of indole to achiral Ni(II) complex 278 led to the synthesis of racemic ct-amino acid 280 [202], The first of the two-step reactions is... 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

The indole and pyrrole rings are incorporated into many biologically active molecules. Therefore, the functionalization of indole and pyrrole cores via Michael-type additions has been discussed. This chapter especially focuses on studies of the last 10 years on catalyst systems, enantioselective synthesis and the design of natural products or biological active molecules as related to Michael additions of indole and pyrrole. 

Rasappan R, Hager M et al (2006) Highly enantioselective michael additions of indole to benzylidene malonate using simple bis(oxazoline) ligands importance of metal/ligand ratio. Org Lett 8 6099-6102... 

The Pd-catalyzed Michael addition of indoles to enones occurs readily in ionic liquids,... 

The same 43/water biphasic system efficiently works for the Michael addition of indoles to a,P-unsaturated enones, the Mannich reaction in its one-pot three-component version, the allyl stannylation of carbonyl compounds and the asymmetric hydroxymethylation of silylenolethers. The last reaction (Figure 45) is carried out in the presence of the chiral bipyridine 45. ... 

SCHEME 11.31. Aza-Michael addition of indoles catalyzed by chiral phosphoric acids. 

MacMillan and co-workers [45] reported an organocatalytic Michael addition in their total synthesis of flustramine B (120) in 2004 (Scheme 17.20). Organocatalytic Michael addition of indole 116 to acrolein 118 using imidazolidinone catalyst 117... 

Quite recently, Gu and coworkers reported the use of gluconic acid aqueous solutions ( GAAS ) as medium for Michael addition of indoles to ot,p-unsaturated ketones (Scheme 10). Compared with other traditional aqueous or organic solvents, gluconic acid has been found to greatly promote the reaction rate of Michael addition, as shown in... 

Scheme 10 Michael addition of indole on cyclopent-2-enone.

Table 7 Comparison of gluconic acid aqueous solutions ("GAAS") with other solvents for the Michael addition of indole on cyclopent-2-enone. ...

Scheme 1.32 A -Triflylphosphoramide-catalysed Michael additions of indoles to a,P-unsaturated a-keto esters.

Scheme 19.29 Asymmetric Michael additions of indoles to a,p-unsaturated ketones catalysed by Al(salen).

Umani-Ronchi s group described the asymmetric Michael addition of indoles to simple a,p-unsaturated ketones catalysed by (R,R)-Al(salen) 3 with 2,6-lutidine, furnishing the corresponding p-indolyl ketones in 35-96% yields and 49-89% enantiomeric excess (Scheme 19.29). ... 

Type of reaction C-C Ixuid formation Reaction conditions Water, room temperature Synthetic strategy Michael addition of indoles Catalyst Glucosyl tolylsidfonyl hydrazine (1)... 

Wu, P., Wan, Y., and (2ai, J. (2008). Carbohydrate-based tolylsulfonyl hydrazines Efficient catalysts for Michael addition of indoles to electron-deficient olefins in water. Synlett, 1193-1198. 

Firouzabadi, H., Iranpoor, N. and Nowrouzi, E, The facile and efficient Michael addition of indoles and pyrrole to a,/ -unsaturated electron-deficient compounds catalyzed by aluminium dodecyl sulfate trihydrate [A1(Ds)3] 3H2 0 in water, Chem. Commun., 2005, 789-791. 

Recently, Firouzabadi and Iranpoor reported that aluminum dodecylsulfate trihydrate [A1(DS)3 3H20] prepared by addition of hydrated aluminum nitrate or aluminum chloride to an aqueous solution of sodium dodecylsulfate effectively catalyzes Michael addition of indoles to a, p-unsaturate ketones in water (Scheme 6.85)... 

Bandini and Umani-Ronchi reported catalytic enantioselective Michael addition of indoles to a,P-unsaturated ketones (Scheme 6.95) [113]. In this reaction, the combined use of Al[(R,R)-salen]Cl complex (67a) and 2,6-lutidine is necessary to obtain Michael adducts in high enantiomeric excess. Among various amines, 2,6-lutidine... 

Several groups had worked on the Friedel-Crafts type Michael addition of indoles to a,P-unsaturated compounds catalyzed by In(III) salts. Yadav et al. 

In 2009, Cai et al. reported a cascade olefin cross-metathesis/intramolecular Friedel-Crafts alkylation for the construction of polycyclic indoles 133 (Scheme 5.89) [90], A Ru complex (134)/chiral Brpnsted acid [(S)-135] binary system was used in this relay catalysis. Recently, the same group reported an enantioselective intramolecular aza-Michael addition of indoles using a similar binary catalyst system (Scheme 5.90) [91]. 

While investigating the Michael addition of indoles onto activated 1,1-cyclopropanediesters, Kerr and coworkers inadvertently discovered the [3+2] annulation of alkylin-doles with cyclopropanes affording a new tricyclic indole... 

Applications of tryptophan synthetase Tryptophan synthetase (EC 4.2.1.20) is a pyridoxal phosphate-dependent enzyme that, in the cell, catalyzes the a,/3-elimination of water from serine to form a pyridoxyl-bound a-aminoacrylate, which undergoes Michael addition of indole to form the named amino acid. This type of reaction has been used to prepare (5)-tryptophan isotopomers with a variety of labeling patterns by use of different labeled indoles and (5)-serines in yields of up to 98% based on indole and 92% based on (5)-serine. 

---