Nitroalkanes Michael-type addition

All of these reactions proceed in a similar pathway which involves the Michael type additions of enamines to nitroalkenes or addition of nitroalkanes to imines and cyclization. This process has been achieved by solid-phase variation (Scheme 10.2).14... 

Nitroalkanes react with Jt-deficient alkenes, for example, p-nitro ketones are produced from a,P-unsaturated ketones [41], whereas allylic nitro compounds have been prepared via the Michael-type addition of nitroalkanes with electron-deficient alkynes (Table 6.19). The reaction in either dimethylsulphoxide [42] or dimethyl-formamide [43] is catalysed by potassium fluoride in the presence of benzyltriethyl-ammonium chloride the reaction with dimethyl acetylenedicarboxylate is only successful in dimethylsulphoxide [42], Primary nitroalkanes produce double Michael adducts [42,44], A-Protected a-aminoacetonitriles react with alkynes under catalysed solidiliquid conditions to produce the Michael adducts [45] which, upon treatment with aqueous copper(Il) sulphate, are converted into a,p-unsaturated ketones. 

Selected examples of the Michael-type addition of secondary nitroalkanes with electron-deficient alkynes... 

Wang and co-workers [57,58] reported several Michael-type enantioselective additions with nitro-olefins. Under neat conditions, 1,3-dinitro compounds were generated in the 74 addition of nitroalkanes 75 to various P-substituted nitro-olefins (Scheme 15). Other Michael-type involving nitro-olefins reactions were illustrated using triazole donors 77 to offer good yields and high enantioselectivities (Scheme 16). 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

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 Michael addition of nih oalkanes to alkenes substituted with two elecbon-withdrawing groups at the a- and 3-positions provides a new method for the preparation of functionalized alkenes. Although reactions are not new, Ballini and coworkers have used this sbategy in the synthesis of polyfunctionalized unsaturated carbonyl derivatives by Michael addition of nih oalkanes to enediones as shown in Eqs. 7.124-7.126. Success of this type of reaction depends on the base and solvent. They have found that DBU in acetonihile is the method of choice for this puipose. This base-solvent system has been used widely in Michael additions of nitroalkanes to elechon-deficient alkenes (see Section 4.3, which discusses the Michael addition). ... 

In 2008, Ye and coworkers also developed a new type of multifunctional cinch-onidine-based catalyst, such as 119 having an additional primary amine moiety, for the Michael addition of nitroalkane to cydic enones [32], In the presence of an acid cocatalyst, the primary amine moiety of 119 can act as a Lewis base to activate the Michael acceptor via iminium formation. The catalysts 119a and 119b (5 mol%) provided quite excellent enantioselectivity (up to 98% ee) for the Michael addition of nitroalkanes to cyclohexenone (Scheme 9.40). The observed retardation of the reaction rate and the opposite sense of enantioselectivity obtained with the catalyst 119b indicated the importance of the configuration of the cydohexane... 

The Michael addition reaction is commonly recognized as one of the most important carbon-carbon bond-forming reactions in organic synthesis, and major efforts have been made to develop efficient catalytic systems for this type of transformation. In particular, the Michael addition of a carbon nucleophile to nitroalkenes is a useful synthetic method for the preparation of nitroalkanes [76], which are versatile synthetic intermediates owing to the various possible easy transformations of the nitro group into other useful functional groups, such as amino groups and nitrile oxides. 

Alumina supported KF has been introduced by Ando etal.[42] and Clark etal.[43] as a basic catalyst for many types of the reactions such as o-methylation of phenol, crown ether synthesis, Michael addition of various nitroalkanes to unsaturated carbonyl compounds etc. 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

Kitazume and coworkers used microreactors with microchaimels 100 pm wide and 40 pm deep for the synthesis of a series of organofluorine compounds [19,20]. The silylation of4,4,4-trifluorobutan-2-one and the Mukaiyama-type aldol reaction of the resulting enol silyl ether with acetals gave good yields of the desired products [20]. They also described nitro-aldol reactions of 2,2-difluoro-l-ethoxyethanol and Michael additions of nitroalkanes to ethyl 4,4,4-trifluorocrotonate and ethyl 4,4-difluorocrotonate [19,20]. Reactions were carried out at room temperature, and... 

Zhao and co workers [54] developed simply primary-secondary diamine catalysts derived from primary amino acids. This type of catalysts such as 105 was found to catalyze the asymmetric Michael addition of malonates to acyclic a,p-unsaturated ketones with good activity and excellent enantioselectivity (Scheme 5.27). Liang and coworkers designed a new primary amine catalyst combining two privileged skeletons, cinchona and cylohexanediamine [55], The obtained optimal catalysts 107 and 110 were applicable to the Michael additions reactions of malonate or nitroalkanes to a,p-unsaturated ketones. The reactions worked well with both cyclic and acyclic enones (Scheme 5.28). 

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