Ketones, addition derivatives cyclic

Arai and co-workers have used chiral ammonium salts 89 and 90 (Scheme 1.25) derived from cinchona alkaloids as phase-transfer catalysts for asymmetric Dar-zens reactions (Table 1.12). They obtained moderate enantioselectivities for the addition of cyclic 92 (Entries 4—6) [43] and acyclic 91 (Entries 1-3) chloroketones [44] to a range of alkyl and aromatic aldehydes [45] and also obtained moderate selectivities on treatment of chlorosulfone 93 with aromatic aldehydes (Entries 7-9) [46, 47]. Treatment of chlorosulfone 93 with ketones resulted in low enantioselectivities. 

Similar reactions have been carried out on acetylene. Aldehydes add to alkynes in the presence of a rhodium catalyst to give conjugated ketones. In a cyclic version of the addition of aldehydes, 4-pentenal was converted to cyclopen-tanone with a rhodium-complex catalyst. In the presence of a palladium catalyst, a tosylamide group added to an alkene unit to generate A-tosylpyrrolidine derivatives. ... 

Since the initial studies, the substrate scope has expanded to include heteroatom-substituted ketones [208-216], cyclic ketones [217] and aldehydes [211, 218-226] as donors, and formaldehyde-derived imines [218, 227-232] as well as glyoxylate-derived imines [96, 220, 233-237] as acceptors. In addition, several alternative catalysts to proline have been pursued [238-242]. 

Enamines derived from a secondary amine and aldehydes or ketones, linear and cyclic, have also been shown to react with equal facility (Scheme 47).so 33,37,38,206,2io—213 ]n azj(je addition to enamines formed in situ... 

The conjugate addition of cyclic or acyclic a-substituted ft-keto esters to cy,/3-unsaturated ketones can be achieved with good diastereo- and enantio-selectivity (<98% ee) by using derivatives of Cinchona alkaloids, such as (104), a chiral organo-catalysts.155... 

Pyrrolidine-based diamine (136) and triamine derivatives that incorporate the secondary diamine motif have been developed as additional organocatalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to... 

Scheme 2.50 Michael addition of cyclic ketones to the chalcone derivative 49, catalyzed by 38.

Cyclic ketone with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Mannich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enoUtes such as that derived from ethyl acetoacetate. This starting material wias prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

V,7V-Dialkyl derivatives of 1 have been successfully applied to the asymmetric addition of dialkylzinc reagents to aldehydes, giving products of moderate enantiomeric excess.In addition, ruthenium(II) complexes of 1 have been demonstrated to be excellent catalysts for the control of the enantioselective transfer hydrogenation of ketones to alcohols at catalyst loadings as low as 1 mol The ruthenium/1 complex has been applied to a range of ketone substrates, including cyclic enones and a-amino and alkoxy substituted derivatives. 

In contrast to the -enolates derived from cyclic ketones, addition of propiophenone trichlorosilyl enolate (Z)-21 to aldehydes requires longer reaction times and higher loadings of catalyst. Although the yields of the aldol products remain high, both the diastereo- and enantioselectivities are attenuated as compared to their E counterparts (eq 9, Table 8). 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

In 2013 Chen et al. reported the direct organocatalytic Michael addition of cyclic ketones to l,l-bis(phenylsulfonyl)ethylene using the camphor-derived pyrrolidine 25." The desired Michael adducts were obtained in high chemical yields and very good stereoselectivities (Scheme 11.21). 

In 2011, the group of Chen reported the application of proline-based reduced dipeptides in the asymmetric Michael addition of cyclic ketones to tra s-p-nitrostyrenes. Comparative studies revealed that the presence of the carbonyl moiety at the N-terminal L-proline unit results in a lower enantioselectivity compared to the corresponding amine analogues. Thus, a series of reduced dipeptides was tested on the above-mentioned Michael addition unveiling reduced dipeptide 17, derived from L-proline and L-phenylalanine, as the optimal catalyst generating the desired products in... 

A bifunctional iminiumyhydrogen-bonding catalysis has been very recently employed for the first enantioselective organocatalytic conjugate addition of a phosphorous nucleophile (diarylphosphane oxides) to a,ji-unsaturated ketones [370]. The process, which allows efficient additions to cyclic and linear enones as well as the generation of quaternary stereocenters, is catalyzed by quinine-derived thiourea... 

Moving to the use of 9-deo3gr-9-amino-epi Cinchona-, in 2007, shortly after the disclosure of their usefulness in conjugate additions, summarised in Section 14.2, Liu and coworkers demonstrated that these primaiy amines are also efficient in catalytic asymmetric 1,2-additions proceeding through enamine intermediates. The authors reported a highly enantioselective aldol addition of cyclic ketones to aromatic aldehydes catalysed by a primary amine derived from cinchonine (CNA) and proceeding in the absence of... 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

Scheme 1.21 Michael additions of cyclic ketones to vinyl sulfone catalysed by cinchona alkaloid-derived primary amine.

The Michael addition of cyclic ketones to l,3-diene-l,l-dicarboxylates ArCH= CHCH=CH(C02R)2> catalysed by the proline-derived salt (252), has been reported to proceed in a 1,4- (rather than 1,6-) manner with 45-80% ee and <83 17 drP More successful was the proline thioether (253), which under solvent-free conditions was able to catalyse the 1,4-addition of ketones R CH2COR to monohaloalkenes ArCH=C(X)CH=CHN02 with up to >99% ee and >99 1 dr ... 

Quintard and Alexakis examined the catalysis of the addition of cyclic ketones to (Z)-l,2-bis(sulfone)vinylene 78 with their aminal secondary amine catalysts and obtained moderate enantioselectivities (64-73% ee) [75] while Lu s group used the more reactive and less sterically sensitive primary amines. The latter group [76] had shown that the primary amine derived from cinchonidine (94) was very efficient in this reaction with six-membered cyclic ketones 95 or prochiral ketones 96 (Scheme 34.34). Unprecedented enantioselectivity was obtained with this catalytic system on combining catalyst 94 and benzoic acid as additive under mild conditions while in the case of prochiral ketones 95 moderate diastereoselectivity was observed. 

Aryl ketones can be aminated also using as catalyst the amine 27 derived from cinchona alkaloids (20 mol%) [35]. For this reaction, the addition ofp-toluenesulfonic acid (40 mol%), and 4 A molecular sieves was compulsory in order to achieve good enantioselectivities. Under similar conditions, aryl ketones, such as propiophe-nones, butyrophenones, heteroaryl ketones or even cyclic 1-tetralone, and diethyl azodicarboxylate (18a) in isopropanol as solvent, yielded at 40°C the aminated product in good results (39-77%, 88-97% ee). 

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