Amines enantioselective Michael addition

Enantioselective Michael Additions. Amine 1 has also been used as an effective ligand for enantioselective Michael reactions of ketone lithium enolate donors with various benzylidene acceptors. As representative examples, the lithium enolates of aryl methyl ketones were reacted with dimethyl benzylidene-malonate in the presence of 1 (eq 9). The lithium enolate was generated from the corresponding ketone by treatment with hex-amethyldisilazide in the presence of lithium bromide in toluene. The resulting enolate was then exposed to 1 and allowed to stir for 30 min to form the desired ternary complex. After addition of the benzylidene acceptor, the desired products were isolated in acceptable yields and with high % ee. 

Figure 2.4 Other secondary amine catalysts employed in the enantioselective Michael addition of ketones to nitroalkenes.

Scheme 2.10 Enantioselective Michael addition of ketones to nitroalkenes catalyzed by primary amine-sulfonamide catalysts 27a-b and by 9-epi amino cinchona alkaloid 28a.

Figure 2.6 Some chiral pyrrolidine-based amines employed as catalysts in the enantioselective Michael addition of aldehydes to nitroalkenes.

Scheme 3.20 Enantioselective Michael addition of nitroalkanes to cyclic enones catalyzed by chiral secondary amines.

In 2003, Melchiorre and Jprgensen found modest enantioselectivities in the first catalytic version of the direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by the chiral amine (5)-2-[bis(3,5-dimethylphenyl)methyl] pyrrolidine (21) (Scheme 2.13) [34]. Further studies on the reaction carried out by different groups led to more efficient catalysts such as diphenylprolinol ethers 22a [35] and 22b [36] and imidazohdinone 23 [37] (Schane 2.13). The highest enantioselectivities reported to date (95-99% ee) have been obtained with catalyst 22b employing significantly lower catalyst loadings (1-5 mol%) than those reported with other organocatalysts (20-30 mol%)[36]. 

In 2003, Takemoto and coworkers published the enantioselective Michael addition of malonates to nitro-olefins catalysed by the first bifunctional thiourea 15, providing the corresponding products in high yields and enantioselectivities. The proposed mechanism involved a bifunctional transition state, where activation of the nitro-olefin is promoted by the thiourea group, while the activation of the malonate occurred by the tertiary amine (Scheme 19.18). ... 

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

Despite the fact that extensive studies have been conducted on secondary-amine-catalyzed Michael addition of unmodified a-monosubstituted aldehydes, there are few reports on the use of a,a-disubstimted aldehydes as nucleophiles, probably due to the high hinderance during the formation of enamine intermediates. By using (5)-l-(2-pyrrolidinylmethyl)pyrrolidme/TFA salt 19 as catalyst, Barbas and co-workers [13] reported the first application of a,a-disubstituted aldehydes in the enantiose-lective Michael reactions with nitroalkenes (Scheme 5.6). The corresponding Michael adducts bearing an all-carbon quaternary stereocenter were obtained in moderate diastereoselectivities and with moderate to good enantioselectivities (up to 91%). 

An enantioselective Michael addition of 3-aryloxindole to PhCH=CHS02Ph, catalysed by the quinine-derived amine-thiourea (205) as a multiple hydrogen-bonding donor, has been developed. The resulting adducts, containing a chiral quaternary carbon centre at the 3-position of the oxindole, were obtained with <98% eeP" An... 

A hydroamination/N-sulfonyliminium cyclization cascade was carried out enantioselectively with gold and BINOL-phosphoric acid catalysts to generate fused indole 188. The method can also be extended to furnish lactams with up to 93% ee (13OL4330). Polycyclic indoline 189 was prepared via an indium/TFA-catalyzed tandem cycloannulation of P-oxodithioesters with tryptamine in yields up to 92% (130L1974). Dixon and colleagues utilized an enantioselective Michael addition/iminium ion cyclization of trypt-amine-derived ureas in the synthesis of tetracyclic indole 190 (22 examples, up to 78% yield and 96% ee) (130L2946). 

The use of another cinchona alkaloid-derived primary amine in combination with TFA has allowed highly enantioselective Michael additions of... 

In 2002, Itoh and Kanemasa found that the combined use of both amine and chiral Lewis acid (R,R)-DBFOX-Ph complex of Ni(II) can be an active catalyst for enantioselective Michael addition of nitromethane or malononitrile to unsaturated carbonyl compounds [37a,b]. Recently, they have reported a new enol ketone synthesis through the reactions between cyclic 1,3-dicarbonyl donors and a,p-unsaturated carbonyl acceptors under the double catalytic activation conditions (10mol% each) of Ni(11)-perchlorate hexahydrate and (2,2,6,6-tetramethylpiperidine (TMP) (114))(Scheme 16.33) [38a,b]. Thus, 1,3-cyclohexanedione (112) is allowed to react with 4-bromo-l-crotonoyl-3,5-dimethylpyrazole (113), in THF at room temperature in the presence of both catalytic amounts to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahy-drobenzopyran-2(H),5-diones (115) in good yields along with high enantioselectivity up to 99% ee. 

Ma has reported a related organocatalytic route to chiral piperidines through an enantioselective Michael addition of aldehydes onto nitroalkenes, followed by intramolecular aminalization, catalyzed by the Hayashi-Jprgensen catalyst in the presence of benzoic acid [34],... 

Based on the enantioselective Michael addition/ISOC (intramolecular silyl nitronate olefin cycloaddition)/lragmentation sequence previously developed by the group of Rodriguez [33a], Shao and coworkers proposed an extrapolation for the construction of spirooxindoles catalyzed by a bifunctional tertiary amine-thiourea catalyst XV between 4-allyl-substituted oxindoles 63 and nitrostyrenes 64 (Scheme 10.21) [33b]. After the addition of TMSCl and EtgN at -30 C, the Michael adduct underwent an ISCX3 to afford the spiro oxime derivatives 65 in very good yields (85-85%), and excellent diastereo (up to >30 1) and enantioselectivities (94-99% ee) after the treatment with TBAF. 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

Bandini and Umani-Ronchi reported catalytic enantioselective Michael addition of indoles to a,P-unsaturated ketones (Scheme 6.95) [113]. In this reaction, the combined use of Al[(R,R)-salen]Cl complex (67a) and 2,6-lutidine is necessary to obtain Michael adducts in high enantiomeric excess. Among various amines, 2,6-lutidine... 

The high performance of 64 compared to Hantzsch ester 39 was demonstrated by Akiyama and coworkers in the asymmetric transfer hydrogenation of trifluor-omethylacetophenone derivatives (Scheme 11.17a) [31]. Benzothiazoline 64c afforded 68 in 89% yield with 96% ee. In contrast, a significant reduction of reactivity and enantioselectivity was observed when 39 was used (4% yield, 45% ee). Enders and coworkers also reported the superiority of benzothiazoline over Hantzsch ester in a symmetric synthesis of tetrahydroisoquinolines via the reductive amination/aza-Michael addition sequence (Scheme 11.17b) [32]. Benzothiazoline 64d had a beneficial effect on both chemical yield and selectivity (98% yield,... 

Mei RQ, Xu XY, Li YC, Fu JY, Huang (JC, Wang LX. Highly effective and enantioselective Michael addition of 4-hydroxy-coumarin to a, p-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011 52(14) 1566-1568. 

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