Acetamidoacrylates

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. 

Methyl o(-acetamidoacrylate, Pd/C (I) Methyl o<-( -butoxycarbonylamino)acrvlate. Pd(PPh3)2Cl2... 

Use of Qi-acetamidoacrylate esters in the Heck reaction allows for the introduction of a dehydroalanine side-chain. The dehydrotryptophans can be reduced catalytically, and this reduction can be done enantioselectively[17]. 

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%). 

Another important example of an enantioselective reaction mediated by a chiral catalyst is the hydrogenation of 3-substituted 2-acetamidoacrylic acid derivatives. 

Scheme 2.12. Enantioselective Reduction of 2-Acetamidoacrylic Acids by Chiral Phosphine Complexes of Rhodium...

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

Scheme 8.3 Hydrogenations of substituted acetamidoacrylates with thioether-phos-phinite ligands.

On the other hand, Bolm et al. have reported, more recently, the use of BINOL-derived A -phosphino sulfoximines as ligands in the rhodium-catalysed hydrogenation of dimethyl itaconate and a-acetamidoacrylates, achieving excellent enantioselectivities of up to 99% ee (Scheme 8.12). In the main... 

Scheme 8.22 Hydrogenation of acetamidoacrylic acid with iridium complexes containing dithioether ligands.

Fig. 5.1. Mechanism of ruthenium catalyzed enantioselective hydrogenation of a-acetamidoacrylate esters. Reproduced from J. Am. Chem. Soc124, 6649 (2002), by permission of the American Chemical Society.

Many other catalysts and ligands have been examined for the enantioselective reduction of a-acetamidoacrylates and related substrates. Phosphoramidites derived from BINOL and the cyclic amines piperidine and morpholine give excellent results.35... 

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. 

It should be noted, however, that despite many examples of the acceleration of Diels-Alder reactions by the use of aqueous media, Elguero59 reported that the Diels-Alder reaction between cyclopentadi-ene and methyl (and benzyl) 2-acetamidoacrylates proceeded better in toluene than in water both in yield and in exo/endo selectivity. Additionally, ultrasonic irradiation did not improve the yield. 

Complex 7-AI2O3/PTA/ (/< ./< )-(Mc-DuPHOS)Rh(COD) 1 (1) was prepared and tested in the hydrogenation of the prochiral substrate methyl-2-acetamidoacrylate (MAA). After full conversion, the products were separated from the catalyst and analyzed for Rh and W content and product selectivity. The catalyst was re-used three times. Analytical results show no rhodium leaching is observed. Complex 1 maintains its activity and selectivity in each successive run. The first three runs show tungsten (W) leaching but after that no more W is detectable. The leached W comes from the excess of PTA on alumina. The selectivity of both tethered and non-tethered forms gave the product in 94% ee. 

Diels-Alder reaction of methyl 2-acetamidoacrylate with cyclopentadiene in the presence of Si02-Al and Si02-Tl catalysts [53], Rate enhancement was not expressed quantitatively. Reaction conditions a stirred multi-mode tank microreactor, no solvent. 

The rhodium complexes with hydroxyphospholane ligand 125663 or 126660 catalyze the asymmetric hydrogenation of a-acetamidoacrylates with ee values in excess of 98%. System 125 is also very effective in the asymmetric hydrogenation of P-acetamidoacrylates (up to 99.6% ee).664 The planar-chiral heterocyclic ligand 127 complexed with rhodium(I) catalyzes the hydrogenation of a-acetamidoacrylates in excellent yields and ee values from 79-96% under mild conditions.665... 

Other systems that prove successful in the highly enantioselective hydrogenation of a-acetamidoacrylates include the spirophosphinites 128 (94.2-97.2% ee)666 and the Josiphos ligands 129 with rhodium(I) (84-96% ee). Excellent... 

Enamides, in addition to the acrylates shown above, are also asymmetrically hydrogenated with many of the same systems that prove useful for the acetamidoacrylate reductions. The Rh(I)/BICP (2(/J)-2/(i)-bis(dipenylphosphino)-1(R),] (R)-dicyclopenlane) 132 and Rh(I)/DuPHOS systems work well (>90% ee) for the asymmetric hydrogenation of /3-acctamidovinyl methoxymethyl ethers... 

Using unmodified Ru-BINAP and Rh-Et-DUPHOS catalysts Jacobs et al. performed hydrogenation reactions of dimethylitaconate (DMI) and methyl-2-acetamidoacrylate (MAA), respectively. [11,47] The continuous hydrogenation reaction was performed in a 100 mL stirred autoclave containing an MPF-60 membrane at the bottom, which also acts as a dead-end membrane reactor. The hydrogenation reactions will be discussed in paragraph 4.6.1. 

A very interesting development is the incorporation of an achiral di-phosphinerhodium(I) moiety at a specific site in the protein avidin (268). The protein binds biotin, which was first converted to the cationic rhodium complex shown in 42. a-Acetamidoacrylic acid was converted to N-acetylalanine with 40% ee in aqueous solution at pH 7 (0°C, 1.5 atm H2). 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

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