Trisubstituted acrylic acids

TABLE 6-1. Asymmetric Hydrogenation of Trisubstituted Acrylic Acids Catalyzed by Chiral Ferrocenylphosphine-Rhodium Complexes... 

Only limited successful examples of asymmetric hydrogenation of acrylic acids derivatives have included the use of chiral Rh complexes (Scheme 1.17). The diamino phosphine (28) utilizes selective ligation of the amino unit to a Rh center and also exerts electrostatic interaction with a substrate. Its Rh complex catalyzes enantioselective hydrogenation of 2-methylcinnamic acid in 92% optical yield [116], Certain cationic Rh complexes can attain highly enantioselective hydrogenation of trisubstituted acrylic acids [ 1171. 2-(6 -Methoxynaphth-2 -yl)acrylic acid is hydrogenated by an (.S ..S )-BIPNOR- Rh complex in methanol at 4 atm to give (.S)-naproxen with 98% ee but only in 30% yield [26]. 

Asymmetric Hydrogenations. Catalytic asymmetric hydrogenations of p-disubstituted-a-phenylacrylic acids have been achieved using the Rh complex of (4) (eq 9). Asymmetric hydrogenation of unsymmetrically substituted trisubstituted acrylic acids leads to the formation of two stereocenters in high ee. The variation of the terminal dialkylamino substituents has little effect on enantioselectivity. A study of a Ru° complex of (1) was reported as a model for understanding the stereoselective transition state of asymmetric hydrogenations. ... 

The reaction of nitrone 101 with such olefins 5 as propylene, n-hexene, allyl alcohol, styrene, acrylic acid, methyl acrylate, acrylonitrile, and butadiene are all regiospecific to give S-substituted isoxazolidines of type l.77 The reaction with olefins 6 seems to be regio- and stereo-specific thus, nitrone 101 and methyl methacrylate give cycloadduct lilt as the sole product.77 Similarly, 101 and 1 -methyl-1-phenylethylene gives adduct Hit.77 In the reactions with olefins 7 or 8, the stereospecificity is more evident.77,78 The isoxazolidine obtained is always one of the two possible epimers. The reaction of nitrone 101 with trisubstituted olefins is highly stereoselective.64 Some results are summarized in Table III. 

Trisubstituted acrylic acids, such as alkene (2.52), where the carboxylic acid is believed to bind to the amino groups of the ligand (2.54), also undergo enantioselective rhodium-catalysed hydrogenation. a-Methyldimamic acid is reduced with 99% ee using the rhodium catalyst prepared from a 2 1 mixture of PipPhos (2.16c) andtriphenylphosphine. ... 

More highly functionalized products can be obtained, often in better yield, by the ene reaction of a-substituted acrylate esters. EtAlCb is a more effective catalyst than AlCb for these reactions because it is a Brpnsted base as well as a Lewis acid. The EtAlCb catdyzed reactions of methyl a-bromo- and a-chloro-acrylate with trans-1,2-disubstituted and trisubstituted alkenes are both regio- and stereo-specific. - The major product (13a 85-95%) is formed via transition state (12a) in which the methoxycar-bonyl group is endo. The stereochemistry of the major adduct was established by the stereospecific conversion of (13a) to both diastereomers of ( )-2-amino-4-methyl-5-hexenoic acid and confirmed by X-ray crystallographic analysis in a related system. ... 

Subsequently, MBH adducts were successfully utilized as novel stereodefined electrophiles in the Friedel-Crafts reaction with benzene in the presence of a Lewis acid " and sulfuric acid, leading to the stereoselective synthesis of (Z)- and ( )-functionalized trisubstituted alkenes. Notably, MBH adducts obtained from acrylonitrile provide high (Z)-stereoselectivities, while adducts derived from methyl acrylate and aromatic aldehydes give high ( )-stereo-selectivities. When the MBH adducts drived from methyl acrylate and aliphatic aldehydes were involved in the Friedel-Crafts reaction, no significant stereoselectivity was observed (Scheme 3.29). 

Darses and co-workers have published a series of papers on the synthesis of stereo-defined trisubstituted alkenes by the coupling of readily available unreactive MBH adducts with either organoboronic acids or potassium tri-fluoro(organo)borates in the presence of a rhodium complex via a reaction pathway involving a 1,4-addition/p-hydroxy elimination mechanism. Compared with the aforementioned Pd-catalyzed cross-coupling reaction, this reaction does not need the activation of the hydroxyl group with acetate or carbonate therefore it is more desirable, particularly in terms of atom economy. For the MBH adducts derived from methyl acrylates, the initial reported catalyst, [ Rh-(cod)Cl 2], was active at 50 °C for boronic acids and at 70 °C... 

Mizoroki-Heck couplings of bromo- and chloroarenes were successfully achieved by using the electron-rich benzimidazolylidene palladium complex 2 (Figure 15.1), generated in situ in tetrabutylammonium bromide as solvent [29]. The coupling of 4-chloroacetophenone with butyl acrylate in the presence of 1 mol% 2 yields 93% 4-acetyl-(El-cinnamic ester in 6 h reaction time. Butyl acrylate was also coupled with 2 equiv of bromobenzene leading to the trisubstituted olefin 3,3-diphenylpropenoic acid butyl ester in 91% yield. 

The authors found that the addition of TMEDA before oxidation was necessary to increase both reproducibility and yields of this sequential process, presumably due to the inhibition of the oxidative dimerization [98], a side reaction known in the chemistry of organocopper compounds. Alkynes with electron-withdrawing groups directly bound to the sp carbon were also employed in the stereoselective carbocupration [99]. For example, the carbocupration of alkynoates 341 promoted by Lewis acids, such as trimethylsilyl triflate, leads to the isomeric TMS-allenoate compounds, which on hydrolysis or a Mukaiyama-type aldol reaction produce the corresponding di- and trisubstituted acrylates 342 (Scheme 10.116) [100]. 

Note that a three-component version working in water and at room temperature has been reported [76]. It involves an arylboronic acid, an unactivated alkyne and methyl acrylate and is catalyzed by Rh(OH)(COD)2 (4 mol%). It afford 3,4,4 -trisubstituted dienic esters in good yields and full stereoselectivity. 

The coupling of 3-tert-butyl [1 - " C]malonate (393) with the /3-amino acid derivative 395 to give amide 396 was developed as an alternative route to the 1,4 addition of 395 to the corresponding [l- " C]acrylate 394, which might have failed due to radiation-induced polymerization. Subsequent treatment with 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadi-phosphetane-2,4-disulfide (Lawesson s reagent) followed by Raney nickel-mediated desulfurization of the thioamide function formed converted 396 into the target /3-amino acid ester 397. Intramolecular ester condensation upon treatment of 397 with sodium methoxide and concluding saponification and decarboxylation of the f-butyl ester function afforded the trisubstituted 4-[2- " C]piperidone derivative 398. 

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