Indoles coupling with acrylates

Zembower and co-workers explored the double Heek reaetion in one-pot and completed the synthesis of DG-041 1, EPj receptor antagonist [18]. A practically reliable catalytic system Pd(OAc)2/(o-tolyl)3 afifeeted both the transformations, intramolecular Heck reaction of bromo intermediate 38 to form indole ring, as well as intermolecular Heck coupling of resulting indole intermediate with acrylic acid 39 to give 40, en route to 41 (Seheme 9.10). 

The reaction of //-protected dehydroalanine methyl esters (e.g. 56, 59) with other indoles 58 can also be effected to give the corresponding dehydrotryptophans 60, invariably as the Z-isomers [81]. Murakami, Yokoyama and co-workers also studied oxidative couplings of acrylates, acrylonitrile, and enones with 2-carboethoxyindole, 1-benzylindole, and l-benzyl-2-carboethoxyindole and PdCfe and CuCk or Cu(OAc) 2 to give C-3 substitution in 50-84% yields [82, 83]. 

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 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. 

Palladium(II)-mediated oxidative coupling reactions involving the indole nucleus have been studied extensively in the literature. Fujiwara et al. [8b] reported that the reaction of A-acetylindole (8) with methyl acrylate (4b) gives (ii)-methyl 3-(l-acetyl-l//-indol-2-yl)acrylate (9, 4%) and ( )-methyl 3-(l-acetyl-l//-indol-3-yl)acrylate (10, 20%), along with A-acetyl-2,3-bis(methoxycarbonyl)carbazole (12,9%) which was believed to be generated by an electrocyclization and subsequent dehydrogenation of a 2,3-dialkenylated indole intermediate (11, Scheme 9.1). 

Itahara et al. [9] found that A-2,6-dichlorobenzoylindole (13) was oxidatively coupled with methyl acrylate (4b) in the presence of stoichiometric Pd(OAc)2 in acetic acid, affording the 3-alkenylated product 14 in 25% yield. Similarly, A-tosylindole (15) reacted with ethyl acrylate (4c) to generate the 3-alkenylated indole 16 in 48% yield (Scheme 9.2) [10]. Unlike what Fujiwara et al. [8b] had observed in the reaction with A-acetylindole (8) and methyl acrylate (4b), both cases did not produce any 2-alkenylated indoles, presumably due to the steric hindrance of the relatively bulky 2,6-dichlorobenzoyl and tosyl groups. 

Heteroaromatic compounds show similar behavior to benzene derivatives. Furan, pyrrole, thiophene, benzofuran, indole, benzothiophene, and their related compounds undergo CDC reactions with alkenes. In the case of furan, the coupling reactions with acrylates, acrylonitrile, styrenes, and... 

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]. 

Metal enolate complexes have also been used to catalyze the allylation of carbonyl compounds ° °, addition of aldehydes to l,3-dienes ° and alkynes as well as the addition of alkenes to alkynes " and indoles ". In the latter study, 5 mol% of Pd(acac)2 (29) and 10 mol% of PPhs were found to be an effective catalyst system for the coupling of Ai-methylindole (93) with a variety of 2-acetoxymethyl-substituted electron-deficient alkenes, including methyl 2-(acetoxymethyl)acrylate (94) (equation 26). Substituted indoles (95) constitute an important class of biologically active natural products and synthetic routes to these valuable compounds have therefore attracted considerable attention. 

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