Nitrostyrenes malonates

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acety-lacetone) to trans-(H)-nitrostyrene, catalyzed by the bifunctional thiourea catalyst as shown in Scheme 3.6 [32]. The analogous Michael addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [33]. Himo et al. performed a density functional study on the related cinchona-thiourea catalyzed Henry-reaction between nitromethane and benzaldehyde [34]. 

Takemoto[131] first bifunctional thiourea catalyst asym. addition of malonates to nitrostyrenes (up to 99% yl. 94% ee)... 

The Takemoto group synthesized a series ofdiaminocyclohexane-based thiourea derivatives (e.g., 12, 40, 57, and 58) for catalysis of the Michael addition [149-152] ofmalonates to trons-j3-nitrostyrenes (Figure 6.18) [129, 207]. In the model, Michael addition of diethyl malonate to trons-]3-nitrostyrene at room temperature and in toluene as the solvent tertiary amine-functionalized thiourea 12 (10mol% loading) was identified to be the most efficient catalyst in terms of catalytic activity (86%... 

Figure 6.18 Chiral amine 56 and thiourea derivatives (10mol% loading) screened in the asymmetric Michael addition of diethyl malonate to trcms-P-nitrostyrene in toluene.

Scheme 6.56 Typical products of the asymmetric Michael addition of dialkyl malonates to frans-P-nitrostyrenes in the presence of 12.

Scheme 6.61 Mechanistic proposals of the 12-catalyzed asymmetric Michael addition of diethyl malonate to trans-P-nitrostyrene proposed by the Takemoto group (A, B, and C) and initial enolate complex (D) with the ammonium group as additional hydrogen-bond donor initiating an alternative mechanism suggested by Sods, Ptipai, and coworkers.

Dixon et al. screened cinchonine-derived thioureas 117-120 for their performance in the dimethyl malonate Michael addition to tra s-(5-nitrostyrene in dichlo-romethane at room temperature and at -20°C [274]. As shown in Figure 6.38, all candidates revealed comparable activity, but monodentate hydrogen-bond donor 118 exhibited very low asymmetric induction producing the desired Michael... 

Figure 6.38 Cinchonine-derived thioureas (10mol% loading) screened in the Michael reaction of dimethyl malonate to trans- 3-nitrostyrene.

Scheme 6.113 Product range for the 117-catalyzed Michael reaction of dimethyl malonate to various tram-P-nitrostyrenes.

Figure 6.40 (Thio)urea catalysts derived from dihydroquinine and dihydroquinidine screening results obtained from the asymmetric Michael addition of dimethyl malonate to frans-p-nitrostyrene.

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Slotta and Heller (109, 110) prepared their starting material, viz., trimethoxyphenylpropionic acid by condensation of the substituted benzaldehyde with malonic acid and reduction of the resulting cinnamic acid. Mescaline was then obtained by Hofmann degradation of the trimethoxyphenlypropionamide. Kindler and Peschke (103) synthesized very pure, crystallized mescaline by condensation of 3 4 5-trimethoxy-benzaldehyde with potassium cyanide, acetylation, and catalytic reduction to the amine. Slotta and Szyska (111, 112) improved Spath s first synthesis, obtaining mescaline directly by the electrolytic reduction of w-nitrotrimethoxystyrene. Hahn and Wassmuth (113, 114) started from elemicine and first prepared trimethoxyphenylacetaldehyde by ozonization. The oxime was then reduced to mescaline. Kindler (115) and Kindler and Peschke (38, 103) improved the catalytic reduction of w-nitrostyrenes to the corresponding phenethylamines. Hahn and Rumpf (116) described the preparation of mescaline by reduction of w-nitrotrimethoxystyrene with Adam s catalyst. A review has been published by Jensch (117). 

Figure 4.4 The two proposed models explaining the 68a-catalyzed Michael reaction of malonates with nitrostyrenes.

Scheme 4.7 Influence of cinchona catalysts structure on the yield and enantioselec-tivity of the Michael reaction of dimethyl malonate with nitrostyrene.

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

Some interesting applications of the conjugate addition of malonates to nitroolefins are the stereoselective synthesis of the antispastic agent (/ )-Baclofen [238b], and the antidepressant drug (/ )-rolipram, the latter obtained via highly stereoselective conjugate addition of a malonic acid half-thioester to a nitrostyrene derivative catalyzed by urea 154 [242],... 

Hayashi et al. [39] described, in 2007, a new tandem Michael-Henry reaction that gives rise to chiral cyclohexanes (463) with total control of four stereocenters. The reaction between 2,5-dihydroxy-3,4-dihydrofuran (60) and a different set of nitro-styrenes (28) was efficiently catalyzed by the diphenylprolinol derivative VII, rendering the chiral cyclohexanes (61) in high yields and enantioselectivities (Scheme 10.19). In 2009, Cordova and co-workers [40] reported a similar reaction using alkylidene malonates instead of nitrostyrenes, obtaining the corresponding cyclohexanes with good yields and stereoselectivities. 

Two new series of bifunctional hydrogen-bond-donor asymmetric organocatalysts have been described, based on 2-aminoquinazol-4-(l//)-one (111a) or 3-amino-benzothiadiazine-1,1-dioxide (111b) skeletons. Both types catalyse Michael additions (e.g. nitrostyrene and diethyl malonate), hydrazinations of the a-carbon of ketones and /3-ketoesters, and isomerizations of alkyne esters to aUene esters (mainly... 

The catalytic performance of the lithium salt of (5)- or (f )-3,3 -bis[bis-(phenyl) hydroxymethyl]-2,2 -dihydroxy-dinaphthalene-l,l (4, BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Using nitrostyrene and cyclohex-2-enone as Michael acceptors efficient asymmetric C-C and C-N bond formations with up to 95% ee at room temperature were observed. A transition-state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular stmcture of the acetone solvate of BIMBOL. 

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