Methyl a-acetamidoacrylate

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

Trifluoromethanesulfonyloxy Methyl a-acetamidoacrylate, PdlOAclj, n-Bu N, LiCl, feis-(diphenylphosphinoferrocene) 38 [8]... 

A mixture of 4-bromo-l-(4-methylphenylsulfonyl)indole (88 mg, 0.25 mmol), methyl a-acetamidoacrylate (91 mg, 0.64 mmol), PdCl2(PPh3)2 (16 mg, 0.023 mmol) and NaOAc (82 mg, 0.98 mmol) in EtjN (0.8 ml) and DMF (0.4 ml) was heated to 120°C in a sealed tube for 2 h. The tube was opened and the contents diluted with EtOAc and filtered through Celite. The EtOAc was washed successively with 10% HCl, sat. NaHC03 and brine and then dried (MgS04). The residue was purified by elution through silica gel with 10 1 benzene-EtOAc to give the product as a yellow solid (93 mg, 90%). 

Several optimization studies have been carried out under these phosphine-free conditions. The reaction of bromobenzene and styrene was studied using Pd(OAc)2 as the catalyst, and potassium phosphate and (V,(V-dimethylacetamide (DMA) were found to be the best base and solvent. Under these conditions, the Pd content can be reduced to as low as 0.025 mol %.142 The reaction of substituted bromobenzenes with methyl a-acetamidoacrylate has also been studied carefully, since the products are potential precursors of modified amino acids. Good results were obtained using either N, (V-diisopropylethylamine or NaOAc as the base. 

Reaction using ligand 4 b, substrate methyl-a-acetamidoacrylate ... 

Several diphosphine ligands have been applied and the corresponding complexes have been tested for the immobilization (Fig. 2.1.6.3). The activity of different free and immobilized complexes in the enantioselective hydrogenation of dimethyl itaconate and methyl a-acetamidoacrylate was investigated. In blank reactions over pure mesoporous materials no reaction took place. When rhodium supported on carriers was used as catalyst, no enantiomeric excess was observed. 

For the hydrogenation of methyl a-acetamidoacrylate, the best results were again obtained with the (S,S)-Me-Duphos ligand. The complex showed complete conversion with 94% or 93% ee in homogeneous and heterogeneous media, respectively. When methyl a-acetamidoacrylate was used as a probe molecule for enantioselective hydrogenations over RhDuphos immobilized on M41S-type materials, 99% ee and a TON of 2000 were obtained over RhDuphos/Al-MCM-41 (S/Rh = 2000 1), whereas RhDuphos/Al-MCM-48 resulted in 97% ee and a TON of 2900 (S/Rh = 3000 1). 

Bromo-l-(4-methylphcnylsulfonyl) Methyl a-acetamidoacrylate, Pd(PPh3)2Cl2, NaOAc, Et,N 90 [2]... 

Silica-supported Lewis acids are useful catalysts with microwave irradiation for conjugate additions. The silica-supported catalysts are obtained by treatment of silica with ZnCh [Si(Zn)], Et2AlCl [Si(Al)] or TiCl4 [Si(Ti)] [ 150-152], The Michael addition of methyl a-acetamidoacrylate (196) with indole (2) under Si(M) heterogeneous catalysis assisted by microwave irradiation afforded the alanine derivative 197 within 15 min and/or bis-indolyl 198, depending on the reaction conditions (Scheme 45) [153]. While the bis-indolyl product 198 is only formed when Si(Zn) was used as catalyst, the alanine derivative 197, as a single product is formed under thermal heating in a yield of 12%. The best yields were observed with Si(Al) (Table 5). The product 198 was obtained by elimination of acetamide followed by a-Michael addition between intermediate 199 with a second mole of indole. 

The Michael addition of methyl a-acetamidoacrylate (196) with pyrrole (1) under silica-supported Lewis acid (Si(M) Si(Zn), Si(Al) and Si(Ti)) assisted by microwave irradiation (MW) afforded the alanine derivatives 395 and 396 dependent on the reaction conditions (Scheme 81) [153]. Both MW and thermal activation for pyrrole gave only Michael product 396, whereas alanine derivatives 395, which are the a-Michael addition product, and 396 were observed with A1 and Ti-catalyst. This behavior shows that aluminium and titanium Lewis acids can form a new acceptor in an irreversible way. The Si(M) or p-TsOH catalyzed reactions of N-benzylpyrrolc 397 with the acrylate 196 under MW gave the product 398 as sole product. The reaction yield has been increased by using a catalytic amount of p-TsOH (Scheme 82). 

Most of the Pd-catalyzed syntheses are carried out in the presence of phosphine although there are exceptions when this is not necessary. One such example is the coupling of aryl triflate with methyl a-acetamidoacrylate catalyzed by a mixture containing Pd(OAc)2/dppf/nBu3N/LiF (Scheme 1-24) [184]. A mixture containing Pd(0Ac)2/NaHC03/nBu4NCl is also catalytically active in most cases. 

Rh-MeBPE(33)-Al-MCM-48 catalyst exhibited 95% ee for the hydrogenation of methyl a-acetamidoacrylate, while its homogeneous counterpart showed 90% ee. These chiral heterogeneous catalysts can be reused at least four times without any activity loss, with a TON in excess of than 4000. 

Table 7.2 Asymmetric hydrogenation of methyl a-acetamidoacrylate with Rh(l)-Et-DuPhos complex the effect of the miscibility of ionic liquid with an organic solvent on catalytic activity.

When the biphosphine is chiral, but posesses a symmetry axis, there are only two possible diastereomeric modes of binding in an enamide complex in which olefin and amide groups are coordinated to the metal. R - Phenylbis (diphenylphosphino) ethane complexes are disymmetric and consequently there are four possible enamide complexes - either face of the olefin may be cis or trans to PI. Complexation of methyl a-acetamidoacrylate gives only one of these but complexation of acetamidocinnamic acid or its esters leads to two diastereomeric complexes (21) (Figure 2). A combination of labelling experiments demonstrates that these are regioisomers (same olefin face coordinated to the metal) rather than stereoisomers. 

Different heterocycles, e.g. furan, pyrrole, N-ben2ylpyrrole, indole, and pyrazole react with methyl a-acetamidoacrylate to give a-amino acid precursors under irradiation with silica-supported Lewis acids as catalysts [135]. Inhomogeneous catalysis, long reaction times were required. The reaction of vmylpyrazoles with imines has also been realized [136]. 

Piersanti and coworkers explored the effectiveness of a range of Lewis acids in promoting alkylation of indole by methyl a-acetamidoacrylate. This led not only to successful p-addition but also to a-addition (amidoalkylation, see Sect. 7). Ethylaluminum dichloride (two equiv.) and ZrCLt were the most effective in giving the p-adduct, while several soft Lewis acids, of which Bi(OTf)3 was most practical, gave the a-adducts. 1-Methylindole and several C-5 analogs showed the same selectivity [292]. 

The addition of diazomethane to methyl a-acetamidoacrylate (99) followed by pyrolysis is the basis of a newly reported preparation of 1-aminocyclo-propanecarboxylic acid derivatives. Diazomethane adds to olefins (1(X)) and, when X or Y = acetyl, thermal isomerization to A -acetyl-A -pyrazolines occurs as well as other side-reactions and cyclopropane formation. Neither from these, nor by thermolysis of 3-acyl-3-alkoxycarbonyl-A -pyrazolines, were the yields of cyclopropanes good. From thermolysis of 4-vinyT3,3-di-(alkoxycarbonyl)pyrazolines, cyclopropanes were undetected. 

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