Nitroolefins conjugate addition with

The use of strongly stabilized nucleophiles, for example, of [(EtO)2P(0)CHX] Li+ 58a-d, where X is a powerful EWG group, such as Me02C, CN, S02Me, or P(O) (OEt)2, in the conjugated addition with a-nitroolefins gives rise to more complex processes (201b) (Scheme 3.58). 

Alexakis et al. showed that under optimized experimental conditions, the enantioselectivity of the Cu-catalyzed conjugate addition of dialkylzinc to cyclic nitroolefin was improved to 95% with both (A,A)-55 and (R,S,S)-29.79,79a Biphenol-based phosphoramidite ligand (S,S)-55 also provided acyclic nitroalkenes adducts with 95-96% ee.42... 

Since the trapping of the lactam enolate with electrophiles should not be limited to nitroolefins, extension to conjugate additions to alkenylsulfones, the ring opening of N-tosylaziridines, alkylation with functionalized halides, and silylation with chlorotrimethylsilane were explored. 

Conjugate addition of indole to nitroolefins was carried out by thermal heating in a sealed tube or by addition of indolyl magnesium iodide or microwave irradiation. The results indicated that the microwave technique is most efficient with respect to time and yield (Scheme 26) [97]. 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Seebach studied the conjugate addition reaction of nitroolefin 10 with butyllith-ium in the presence of the multidentate ligand 11 (accessible from tartaric acid), which yielded the adduct 12 in up to 58% ee (Scheme 4) [18]. 

High enantioselectivites in the aza-Michael reaction have been achieved using alternate organocatalysts, and the addition of benzotriazole to nitroolefins occurs with up to 94% ee using bifimctional catalysts such as (11.64). Guerin and Miller have developed an alternate approach to the enantioselective introduction of triazoles based on the asymmetric conjugate addition of azide followed by a 1,3-dipolar cycloaddition of the product with an alkyne. In this approach, the addition of hydrazoic acid to Michael acceptors such as (11.133) proceeds with good ee in the presence of the dipeptide (11.134). ... 

On the other hand, chiral primary amine-thiourea catalysts 85 and 90 developed by Tsogoeva [125] and Jacobsen [130], respectively, show an opposite sense of relative stereoinduction in the conjugate addition of acyclic ketones to nitroolefins (see Scheme 2.41 for 90). These anti selective catalysts stand in contrast to the usually obtained results which lead to selective formation of the i yn-conflgured diastereoiso-mers. The unexpected situation suggests participation of a Z-enamine intermediate. Moreover, with respect to the electrophile activation by the urea-type catalysts, it is also demonstrated that only one oxygen of the nitro group is bound to the thiourea moiety in an out-of-plane arrangement [125,130]. 

The asymmetric conjugate addition of activated methylenes is one of the most studied organocatalytic reactions. A wide variety of Michael acceptors such as enals, enones, a,P-unsaturated nitriles, nitroolefins, a,(i-unsaturated imides, and vinyl sulfones have been successfully employed as elechophiles with high degree of stereocontrol. 

A similar scenario has been demonstrated by Najera et al. to support the bifunc-tional Br0nsted acid-base organocatalytic character and the origin of the observed enantioselectivity achieved by protonated 2-aminobenzimidazol-derived catalyst 163 in the conjugate addition of malonates and 1,3-diketones to nitroolefins [251]. DFT calculations have shown that the lowest energy transition state corresponds to the addition of the malonate or diketone to the electrophile with activation of the nucleophile by formation of two hydrogen bonds with the amino-benzimidazole moiety and activation of the nitroolefin better achieved by the protonated tertiary amine (C, Fig. 2.19). 

On the other hand, more recent studies on the conjugate addition of azide to nitroolefins catalyzed by Cinchona alkaloids have led to the synthesis of optically active P-azido nitro compounds in high yields but with low enantioselectiv-ity [344]. 

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