Nitroalkenes malonates

The intramolecular variant of the nickel-catalyzed alkylative coupling is especially robust and has been extensively developed for the cycUzation of alkynes tethered to a variety of a,P-unsaturated systems in the presence of organozinc and organozirconium reducing agents (Scheme 8.2) [22]. Alkylative cycUzations were effective for both terminal and internal alkynes with high levels of chemo-and stereo-selectivity. The scope and tolerance of the electron-deficient alkene component was broad as enones, alkylidene malonates, nitroalkenes, and unsaturated imides were all tolerated (Scheme 8.3) [23]. 

In 2(X)9, Xu et al. group reported a cascade Michael/Michael/aldol reaction by the combination of secondary amines and bifimctional quinine-derived thioureas, giving rise to polysubstituted cyclohexanes with multiple chiral centers and substituted patterns from readily available malonates, nitroalkenes, and enals with satisfactory yield and high enantioselectivities (Schane 9.34) [31]. Initially, a bifunctional base/... 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Scheme 6.120 Michael adducts prepared from the 122-catalyzed asymmetric addition of dimethyl malonate to trans-P-nitroalkenes.

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)-(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, /3-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202... 

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. 

Evidently, although the system tolerates both aromatic and aliphatic aldehydes, the introduction of an electron-withdrawing substituent on the aromatic substrate results in a decreased yield. To gain information about the mechanism of the overall tandem reaction, kinetic studies were carried out to identify the rate-determining step. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde, nitromethane and dimethyl malonate revealed that the reaction is first order in nickel catalyst, indicating that the Michael addition of dimethyl malonate to the nitroalkene is the ratedetermining step. 

The bifunctional thiourea catalyst 16 was developed by Takemoto and co-workers in 2003 [61, 62], The Michael reaction of diethyl malonate with nitroalkenes proceeded with excellent enantioselectivities (Equation 10.31). 

On the other hand, imidazolidines 53a and 53c have also been successfully employed in this reaction, showing a similar behavior to that observed in the same reaction with malonate nucleophiles and with 53c appearing as the most efficient catalyst (Scheme 3.21). ° The use of differently substituted nitroalkenes was also evaluated but diastereoselectivities still remained rather low, obtaining... 

Scheme 4.5 68a-catalyzed enantioselective Michael addition of malonates to nitroalkenes and application to the total synthesis of (R)-(-)-baclofen. 

Therefore, under the optimized conditions, 9-ep -dihydroquinine-derived thiourea 71a performed very well in the Michael reaction of diethyl malonate with nitroalkenes, furnishing the final compounds with enantioselectivities around 90% ee (Scheme 4.8). Remarkably, this catalyst also seemed to tolerate the use of (3-alkyl substituted nitroalkenes as substrates, furnishing the expected final compounds with only a small decrease in enantioselectivity, although only a few examples were studied in that case. In an independent work, 9-e i-cinchonine-derived thiourea 72b was also reported to be a very efficient catalyst for this reaction, obtaining the final Michael adducts in... 

Scheme 4.9 Enantioselective Michael addition of malonates to nitroalkenes catalyzed by thiourea compounds.

Scheme 4.11 Enantioselective Michael addition of malonic acid half-thioesters to nitroalkenes catalyzed by 70b.

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