Nitroalkenes Michael-type reactions with

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

The nitroalkene intermediate can either form the dinitro product or go through a Michael-type addition with the encapsulated PEI. Eurthermore, because capsules swollen in methanol retain their catalytic activity when placed in toluene, the reaction can be run in a mixture of two different solvents. This allows both the encapsulated PEI and the nickel catalyst to operate in their respective ideal solvents, namely methanol and toluene. To demonstrate the scope of this one-pot process, the reaction was performed with dimethyl malonate (138) and various aromatic and aliphatic aldehydes. Table 3.13 shows the results. 

The most recent entry to bicyclic P-lactam compounds through this approach, has been introduced by Barrett and his coworkers [120] by using an intramolecular Michael type reaction of a Af-silyl p-lactam to a nitroalkene induced by fluoride ion (Scheme 45). Namely, the known P-lactam 299 [32a] readily prepared from CSI addition to 1,5-hexadiene, was protected by using TBDMSCI and DIPEA to produce the p-lactam 300. Subsequent ozonolysis, gave the aldehyde 301. Henry reaction of the aldehyde 301 with (phenylthio)-nitromethane furnished, after dehydration of the resulting nitroaldol, the nitroalkene 302 which smoothly cyclized to the carbapenam 303 in the presence of... 

There is also a modified version of Takemoto s catalyst, which incorporates a benzimidazole heterocycle as the H-bonding donor site in place of the thiourea moiety." This catalyst 82 has been tested with success in several Michael-type reactions of 1,3-dicarbonyl compounds to nitroalkenes, in particular focused on the use of malonates as donors (Scheme 4.20), providing the corresponding adducts in excellent yields and enantioselectivities. p-Ketoesters have also been tested, although in this case the performance of the catalyst was found to be highly dependent on the structure of the p-ketoester employed. It has also to be pointed out that the reaction required the incorporation of a Bronsted acid cocatalyst such as TFA for achieving the best enantioselectivity, although the presence of this co-catalyst did not have any influence in the catalytic activity. 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

Chen and co-workers presented, in 2007, a Michael-type Friedel-Crafts reaction of 2-naphthols and trans-P-nitroalkenes utilizing the bifunctional activating mode of cinchonine-derived catalyst 117 [277]. The nitroalkene was activated and steri-cally orientated by double hydrogen bonding, while the tertiary amino group interacts with the naphthol hydroxy group to activate the naphthol for the nucleophilic P-attack at the Michael acceptor nitroalkene (Scheme 6.117). 

It is a common point of view that the Barton-Zard reaction is a favorable one for the pyrrole synthesis. It is based on interaction of conjugated nitroalkenes with isocyanoacetates in the presence of a base [6, 74-76] and, basically, involves three steps (Scheme 43) the Michael-type addition of isocyanide carbanion to the C=C double bond of nitroalkene, cyclization of the resulting anion to give pyrroline derivative, and elimination of the nitrite anion followed by aromatization. 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

The combination of an imine derived from the reaction of acrolein organocatalyst 1 with simple indoles 84 and nitroalkenes 85 affords the 3-(cyclohexenylmethyl)-indoles 86 (Scheme 7.16) [59]. In this reaction, the indole 84 initiates the Friedel-Crafts-type reaction followed by a Michael reaction with nitroalkenes 85 to the intermediate 87. From this process, a hydrolysis takes place and the resulting compound enters another catalytic cycle involving a Michael/aldol condensation reaction similar to those reported previously. 

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

Lithium A number of Michael-type additions of organolithiums have been described. This is also the case of the reaction of aryllithiums with nitroalkene (389). Deprotonation of the benzylic fluoride (455) with LDA, directed by the neighbouring sulfoxide group, generated the benzyllithium intermediate (456), which underwent addition to the Michael acceptor R CH=CHY (Y = CO2BU, S02Ph R = Ar, alkyl, alkenyl) in a diastereoselective manner controlled by the chiral sulfur to afford the 5yn-configured product (457) with <99 1 dr ... 

One-pot system starting from parent ketones, sec-Buhi, Bu3SnBr, and Michael acceptor is accomplished for various types of substrates.233 The reaction of tin enolates with nitroalkenes is effectively catalyzed by Bu4NBr to give 7-nitroketones. The catalyzed reaction provides higher yield and selectivity as compared with the uncatalyzed... 

In parallel, Xu and coworkers discovered that in the presence of similar I L-tagged pyrrolidines 84c,d the reaction proceeded nearly as efficiently in the [bmimJIPFs] medium, so there is no need to dehver the acid co-catalyst (TFA) to the system because this role is obviously played by the IL fragment [96]. Catalysts 84a,b were recovered from the reactant medium by precipitation with ether, while the 84c,d/ IL systems were reused after product extraction without further purification. Four reaction cycles of catalysts 84 did not reduce reaction diastereo- and enantioselec-tivities however, the recovered catalysts gradually became less active with each cycle. Surfactant-type IL-supported asymmetric organocatalyst 84e synthesized by Luo and Cheng and coworkers in 2006 catalyzed Michael addition to nitroalkenes with high stereoselectivities in water without any additives [97]. 

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