Indole with methyl vinyl ketone

Annelation of steroidal dienamines with substituted phenacyl bromides (7 examples) or with benzenediazonium salts (11 examples) has been shown to lead to the corresponding furano- and indolo-steroids.89 Thus the A3,5-dienamine derived from A4-androstene-3,17-dione reacted with p-bromophenacyl bromide to yield the A5-androstano[3,4-h]furan (199) in 26% yield, and reaction of the same A3,5-dienamine with benzenediazonium fluoroborate at -45 °C led to formation of the hydrazone (200) which underwent Fischer-indole cyclization on treatment with phosphorus oxychloride to produce the A4-androstano[6,7-6]indole (201). The A3,5-dienamine derived from 17/3-acetoxyandrost-4-en-3-one has been converted into the benz[4,5,6]-steroid (202 R1 = Me, R2 = H) by reaction with methyl vinyl ketone and into the analogous benzsteroid (202 R1 = H, R2 = Me) on treatment with crotonal-dehyde.90 A route to the condensed pyrroline ring system (203) has been devised... 

Reactions with otP-Unsaturated Ketones, Nitriles and Nitro-Compomds Such reactions are usually effected using acid (see below), or one of a number of mild Lewis acids, such as scandium iodide (with microwave heating), indium bromide " or hafnium triflate, and can be looked on as an extension of the reactions discussed in 20.1.1.6. In the simplest situation, indole reacts with methyl vinyl ketone in a conjugate fashion in acetic acid/acetic anhydride. ... 

Michael addition reactions between Af-methylindole (108) and hexenal (107), and the resulting adduct 110 with methyl vinyl ketone (MVK, 109). The addition of a H bonding catalyst 116 to activate the MVK improved the yield of final indole products 111, from 33% to 89%, while the enantiomeric excess remained unchanged (>99%). 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

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... 

Solid sodium sulphonate species 41 (Figure 43) impregnated with [dbim][SbF6] (25% wt) is itself capable to catalyse the 1,4-addition of several indole derivatives to methyl vinyl ketone (MVK) and other Michael acceptors in water (Figure 46)7 ... 

Indole-3-carboxylate esters and 3-acetylindoles can be prepared by palladium-catalyzed cycli-zation of enamines (14). These can be prepared from the corresponding anilines by condensation with j8-dicarbonyl compounds or by palladium-catalyzed substitution reactions with ethyl acrylate or methyl vinyl ketone <86BCJ927, 90S215>. Overall yields for the two-step process are 60-80% (Scheme 33). 

The conjugate addition of indoles to electrophilic alkenes has been known for many years with early examples including methyl vinyl ketone [203] and nitroethylene [204]. A range of new catalysts have been explored. These include a variety of protic and Lewis acids. There has also been exploration of various supported catalysts. Both protic and Lewis acids have also been used in conjunction with ionic liquids, usually imidazolium salts. Many of these studies have been carried out with 1,3-diarylpropen-1-ones as the reactants, but some also include enones such as methyl vinyl ketone and cyclic enones. Chiral catalysts can give enantio-selective additions. Much of the work with chiral catalysts has been summarized by Bandini, MeUoni, Tommasi and Umani-Ronchi [205]. For the most part, the successful reactions have used either enones or nitroalkenes. There are few reports, for example, of addition to acrylate esters. 

Addition by the Heterocycle. Under Heck conditions, 3-phenyM-vinyltbiophenes 86 were formed from 3-iodo-4-phenylthiophene and ethyl vinyl ketone, methyl acrylate, and m-nitrostyrene (Scheme 37) 4-Iodo-3-trimethylsilylfuran under similar Heck conditions with alkenes reacted in two regioselecUve manners. Alkenes with electron- withdrawing groups, such as methyl vinyl ketone and ethyl acrylate, gave exclusively tron -substituted alkenes 87. AEyl alcohol, styrene, and 4-methylstyrene gave a,a-disubstituted products 88.t" l-(Phenylsulfonyl)indol-3-yl trifluoromethanesulfonate under Heck conditions provides 3-vinylindoles 89. " An excellent yield was reported for the reaction between the triflated deaza nucleoside 90 and ethyl acrylate. ... 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

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