Cyclohexanone nitrostyrene

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

It was, however, found 22) that when the pyrrolidine enamine of cyclohexanone was allowed to react with an excess of -nitrostyrene, a bis adduct (46), made up of one molecule of the enamine and two molecules of olefin, was obtained in addition to the monoadduct. That the bis adduct is not derived from the monoadduct was shown by the latter s failure to react with (9-nitrostyrene. Therefore, this adduct must be formed by the addition of the olefin to the dipolar intermediate (47), as shown in the following scheme. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Scheme 6.180 Mechanistic proposal for the Michael reaction of cyclohexanone with tram-nitrostyrene catalyzed by 213.

The Michael reactions [149-152] between cyclohexanone and trons-nitroalkenes were also explored by Xiao and co-workers utilizing bifunctional pyrrolidine-thiourea 213 and the pyrrolidine-thioureas 214-217 (Figure 6.61) [344]. The model Michael reaction between cyclohexanone and trons-nitrostyrene identified water as the best solvent and 217 to be the most efficient catalysts concerning the activity and asymmetric induction (90% yield 96% ee dr 98 2 in 12 h at 35 °C) in the presence of benzoic acid (10mol%) as additive. The optimized catalytic system allowed the formation of a broad spectrum of Michael adducts such as 1-6 resulting from... 

Asymmetric Michael addition to to-nitrostyrenes,2 The enamine (2) formed from cyclohexanone and this prolinol derivative reacts with 2-aryl-1-nitroethylenes (3) to form, after acid hydrolysis of the primary adduct, essentially only one (4) of the four possible y-nitro ketones. 

Another concise route to 107 featured the facile construction of the cyclohexanone derivative 109 via the Michael addition of triply deprotonated methyl dioxohexanoate to the nitrostyrene (108 (Scheme 9) (115). Ketalization of 109 followed by hydrogenation of the nitro function and then cyclization of the resulting amino ester by thermolysis in refluxing xylene furnished the lactam 110, which was reduced LiAlH4 to the amine 111. All attempts to cyclize 111 via a Pictet-Spengler reaction led to complex mixtures of products. However, when the unstable enone 112, which was obtained by acid-catalyzed hydrolysis of 111,... 

Scheme 2.37 The (S)-proline-catalyzed addition of cyclohexanone to nitrostyrene 3.

Scheme 2.41 The addition of cyclohexanone to nitrostyrene, mediated by Cordova s catalyst.

Similar results were obtained with enamines of acyclic ketones such as desoxybenzoin. Nitrostyrene gave only the less substituted mono-alkylated enamine and hence the / -nitro-a-phenylethyl ketone on hydrolysis117. Surprisingly 2-nitropropene gives mainly the tetrasubstituted cyclohexanone enamine106. A hexahydrobenzo-l,2-oxazine-7V-oxide (55) was isolated at low temperatures (in 80% yield) which rearranged at room temperature to a mixture of alkylated enamine isomers107 (Scheme 39). 

Reaction of 3-substituted cyclohexanone enamines with / -nitrostyrene gives, on hydrolysis, a mixture of 6- and 2-alkylated ketones (59 and 57 ratio 4 1, respectively). Since the 6-alkylated ketone (59) is formed in much greater amount than enamine (58)... 

The reaction of chiral enamine 81 (X = CH2) with / -nitrostyrenes has also been investigated by Seebach and coworkers118". Only one of the four possible enantiomeric-ally pure diastereomers was formed and a-alkylated cyclohexanones were obtained in 90% or greater optical purity (Scheme 73). Their configuration was deduced as (l R, 2S) by chemical methods and X-ray analysis. 

Other recent repiorts of the automated synthesis of SP libraries of discretes include those of Wilson et al. (166), who prepared a library of more than 1000 aminohydantoins from a-hydrazino amino acids, amines, and aldehydes Perumattam et al. (167), who reported a 200-member library based on an anhydride template using anhydrides, primary amines, and a-amino acids Smith et al. (168), who described the synthesis of a library of more than 1000 piperazinediones from a-amino acids Crawshaw et al. (169), who presented a >200-member Ubrary of cyclohexanones from maleimides, nitrostyrenes, and aminobutadienes Shao et al. (170), who described a 96-member library of quina-zolinediones from anhydrides and amines Lebl et al. (21), presenting a 30,816-member... 

Table 7.14 Asymmetric Michael addition of cyclohexanone to P-nitrostyrene using ionic liquid-supported chiral pyrrolidines as a catalyst.

The preference for attack at the Cg-position can clearly be attributed to developing gauche butane interactions with the R-substituent for axial attack at C2, thus necessitating equatorial attack at Cj with consequent increase in the activation energy owing to developing non-bonded twist interactions in 60 (Scheme 41). In contrast to j9-nitrostyrene, 1-nitropropene undergoes both axial and equatorial attack on both 3- and 4-substituted cyclohexanone enamines, except for reaction at C2 of the 3-substituted enamine where only equatorial attack occurs . 

P,P] Risaliti and co-workers in 1966 reported the stereoselective additions of enamines derived from cyclohexanone and morpholine, piperidine, and pyrrolidine to / -nitrostyrene (Eq. [1], Scheme 15) (34). The less-substituted enamines of the general structure 15.1 were isolated prior to hydrolysis. The location of the double bond of 15.1 was established by H-NMR spectroscopy and by addition to diethyl azodicarboxylate. The... 

Addition of Nitrostyrenes to Substituted Cyclohexanone Morpholine Enamines (Eq. [1], Scheme 19)... 

Reactions of the enamine derived from cyclohexanone and prolinol methyl ether with /(-nitrostyrenes have been described by Seebach and co-workers (Scheme 20, Table 6) (33,44). This procedure uniformly provides the syn diastereomer as the exclusive detectable product. With the exception of the 2-bromo-/ -nitrostyrene in entry 4, enantiomeric excesses of > 92% are observed. 

Addition of the Proline Methyl Ether Enamine of Cyclohexanone (20.1) to Nitrostyrenes (Scheme 20). 

P, P] Seebach and Brock reported the dichlorodiisopropoxytitanium-mediated addition of the trimethylsilyl enol ether of cyclohexanone to /3-nitrostyrenes (83). The initial products generated are nitronic esters 39.1-39.3. Separation followed by fluoride-induced desilylation of these intermediates yields the corresponding syn and anti nitroketones. The results of this study are summarized in Scheme 39 and Table 12. Anti isomers are obtained in moderate diastereomeric excess. Moreover, the method is complementary to the additions of similar substrates by way of their lithium enolates (2) or enamines (vide supra), which provide the syn diastereomers. Further reactions of the intermediate nitronic esters were briefly explored. For example, addition of aldehydes and activated olefins provides stereoselectively the products from nitroaldol and [3 + 2] cycloadditions. 

Figure 2.5 Proposed models for Michael reaction between cyclohexanone and nitrostyrenes catalyzed by pyrrolidine-diamines 14a-c in the presence of a Bronsted acid co-catalyst.

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Chen et al, designed and synthesised a series of chiral pyrrolidinyl-sulfamide derivatives, identifying 3j as an efficient bifunctional organocatalyst for the direct Michael addition of cyclohexanone to a wide range of nitrostyrenes. The desired Michael adducts were obtained in high chemical... 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

L-proline as catalyst [ 109]. Further studies on the reaction were carried out by Alexakis et al. using the hydrochloride salt of lV-isopropyl-2,2 -bipyrrolidine (30, Hg. 2.4) as catalyst in CHCI3 as solvent. In this study the highest enantioselectivity (81%) was obtained for the addition of cyclohexanone to nitrostyrene also with a very high diaste-reoselectivity (syn/anli 94/6) [50]. As in the case of the conjugate addition of aldehydes, the observed syn selectivity was in accordance with the Seebach-GoUnski model [70]. 

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