Cyclohexenes carbaldehyde

Acetophenone-sensitized photolysis of l-methyl-3-phenyl-2-cyclohexene-carbaldehyde oxime acetate (56) A solution of 56 (298 mg, 1.16 mmol)... 

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 fact that the residues R -R3 of the precursors A, B and C can be broadly varied demonstrates the high flexibility of our approach. R1 of component A can bear simple to demanding residues as well as valuable functional groups (Scheme 17). R2 is limited to aromatic and heteroaromatic substituents, due to the lower reactivity of the aliphatic ni-troalkenes. The residue R3 of component C allows the broadest diversity. Aliphatic as well as aromatic moieties are tolerated. Furthermore, acrolein (R3 = H) can be used, affording trisubstituted cyclohexene carbaldehydes. The best yields were obtained with aromatic substituents R2 and R3 (38%-60%). The replacement of R3 by aliphatic residues led to lower yields (25% and 29%), whereas sterically demanding aldehydes A had less influence on the yield. In contrast, the variation of the residues had only a small impact on the diastereoselectivity (68 32-... 

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). 

Dimethyl-3-cyclohexen-1 -carbaldehyde 2,4-Dimethyl-3-cyclohexene carbaldehyde 2,4-Dimethylcyclohex-3-ene-1 -carbaldehyde. See... 

The use of this catalyst allowed the same authors to elaborate an asymmetric domino Michael-Michael-aldol reaction, involving two aldehydes and a nitroalkene on the basis of an enamine-iminium-enamine activation. The corresponding cyclohexene-carbaldehydes were isolated with virtually complete diastereo- and enantioselectivities, as shown in Scheme 1.63. 

The partially positively charged carbon of the dienophile will bond preferentially to the partially negatively charged carbon of the diene. Therefore, 2-methoxy-3-cyclohexene-carbaldehyde will be the major product. 

Scheme 17.11 Proposed catalytic cycle for the diphenylprolinol trimethylsilyl ether catalyzed triple cascade reaction for the generation of tetrasubstituted cyclohexene carbaldehyde. Reproduced from Reference [45] with permission from the Royal Society of Chemistry.

The asynunetric organocatalytic triple cascade reaction for the synthesis of telrasu-bstituted cyclohexene carbaldehydes developed by Enders et al. (Scheme 1.30) [40] is a milestone of organocatalytic cascade reactions. This three-component domino reaction proceeds by way of a catalyzed Michael-Michael-aldol condensation sequence affording products in good to moderate yields (25 to 58%). Notably, four stereogenic centers are formed with high diastereoselectivity and complete enantioselectivity. 

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