Nitroalkenes cyclohexanone reactions

The stereochemical outcome of the addition of lithium enolates of aldehydes and ketones to nitroalkenes is dependent upon the geometry of the nitroalkene and the enolate anion. The synjanti selectivity in the reaction of the lithium enolates of propanal, eyelopentanone and cyclohexanone with ( )- and (Z)-l-nitropropene has been reported1. 

The initial addition step is reversible allowing isomerization of the ( )- and (Z)-nitroalkenes and equilibration between the initially formed syn- and ann -imminium ion adducts. The spn-ad-duct is identical to that obtained from the lithium enolate of cyclohexanone and ( >(2-nitro-cthenyl)benzenc. The preference for the. yyu-adduct can be rationalized by inferring the transition state 1 which is similar to that proposed for the reaction of (-E)-nitroalkcnes with ( )-eno-lates11, l2. 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

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. 

Reaction of cyclohexanone imines with nitroalkenes provides a new synthetic method of tetrahydroindole derivatives (Eq. 10.9).11... 

Scheme 6.179 Product range of the 213-catalyzed Michael reaction of cyclohexanone with various nitroalkenes.

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... 

Cyclohexanones. The ability of tri-n-butyltin hydride to effect denitration (10, 413) permits use of a-nitroalkenes for construction of cyclohexanones by a Diels-Alder reaction. Only one regioisomer (as a mixture of stereoisomers) is formed in the example cited, owing to the reinforcing effect of the nitro group in control of the direction of Ihc cycloaddition.1 ... 

Reactions of the lithium etiolate of cyclohexanone with E-l-nitroalkenes in the presence of chiral lithium amides have been studied by Seebach and co workers [558], and good diastereo- and enantioselectivities are obtained in a few cases. The tin enolate of TV-propionoyloxazolidinone 6.83 undergoes diastereo- and enan-tioselective Michael reactions when coordinated to chiral amine 2.13 (R = NH-l-Np) [682] (Figure 7.59). Similar reactions show low enantiomeric excesses (5 70%) however, some Michael additions catalyzed by chiral catalysts have shown high selectivities ( 7.16). 

In this context, a wide variety of different chiral primary amines has been developed and tested in this reaction with different results (Scheme 2.8). The first example of a primary amine-catalyzed Michael reaction of ketones with nitroalkenes was reported by Cordova,who found that alanine-derived amide 20a was an excellent catalyst for this transformation. However, in this report, the reaction scope was also mainly focused on the use of cyclohexanone, with a single example of an acyclic enone (2-butanone) providing the Michael... 

Scheme 7.7 Enantioselective S3mthesis of cyclohexanones by Michael/Michael cascade reaction between enones and nitroalkenes.

In 2007 Sun and coworkers reported the use of the proline derived triamine 17 in the presence of weak acids as a highly stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroalkenes (Scheme 11.16). All selected aromatic nitroalkenes gave excellent yields and selectivities, with the exception of electron-deficient substrates (Ar = 4-CN-Ph, 4-N02-Ph), which also require much longer reaction times. 

Proline derivatives possess a prominent position among the aminocatalysts utilised for carbonyl activation. In combination with the readily tunable properties of the (thio)urea functionality for electrophile activation, the development of bifunctional chiral pyrrolidine-based (thio)ureas was a rational extension. In 2006, Tang and coworkers reported thiourea 55 that can catalyse the conjugate addition reaction between cyclohexanone and nitroalkenes (Scheme 19.63). In the presence of 20 mol% of chiral thiourea 55 and butyric acid as the cocatalyst, the q -products were delivered in high yields (up to 98%) and in excellent diastereo- (up to >99 1 dr) and enan-tioselectivities (up to 98% enantiomeric excess). In addition to aromatic nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long reaction time (6 days). 

Scheme 19.63 Secondary amine-thiourea for the a mmetric Michael reaction between cyclohexanone and nitroalkenes.

A series of pyrrolidine catalysts has been investigated for the asymmetric Michael addition of cyclohexanone to nitroalkenes, which is the classical model commonly used. When an aminal-pyrrolidine, developed by Alexakis et al. was employed as an organocatalyst for the conjugate addition of cyclohexanone to nitrostyrene, it led quantitatively to the Michael product with 84% de and 87% ee (Scheme 1.48). Better stereoselectivities for this reaction were... 

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