Secondary amine catalysis

For reactions which usually involve enol or enolate intermediates, enamine formation has been postulated for primary and secondary amine catalysis in order to explain abnormally high catalytic effects and abnormal rate laws. Shilov, Yashinov and coworkers (for the last paper of the series, see Volkova... 

Diarylprolinol silyl ether catalyst was able to promote enantioselective allqrlations of a,p-unsaturated aldehydes with stabilised carbcations as electrophiles. Dienamine intermediates were trapped by the electrophile in two positions. The y-disubstituted aldehydes were not good substrates for y-substitution. However, linear unbranched and p-substituted a,p-unsaturated aldehydes preferred y-substitution. ot-Substituted aldehydes were unreactive under secondary amine catalysis (Scheme 8.45). 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Access to Five and Six-Membered Rings via Secondary Amine Catalysis... 

Scheme 1.19 Intramolecular Michael addition using secondary amine catalysis... 

Saicic and co-workers [29] have also asymmetrically synthesized a five-manbered ring using secondary amine catalysis. In this example, however, the alkylation was achieved via use of a 7t-allylpaUadium complex as the electrophile (Scheme 1.24) [30]. However, it should be noted that the asymmetric induction comes from the palladium ligand as opposed to the use of a chiral secondary amine (which failed to give either any reaction or impart any enantioselectivity) [31]. 

The use of secondary amine catalysis in combination with radical chemistry was first introduced by MacMillan in 2007 in a process he termed as organo-SOMO catalysis [32]. hi this system, the enamine that is generated in the condensation of a chiral secondary amine and a carbonyl, is oxidized via a single electron process. This generates a three-7i-electron radical cation with a singly occupied molecular orbital (SOMO) which can react asymmetrically in a variety of different processes (Scheme 1.25). 

SCHEME 6.10. In situ trienamine activation of 2-enals by secondary amine catalysis. 

Aziridinations of a,P-unsaturated ketones triggered by chiral primary amine salts via iminium catalysis were reported soon after (Scheme 1.71) [113]. The reduced steric constraint of primary amines offers the unique possibility of catalyzing processes between sterically demanding parmers, overcoming the inherent difficulty of chiral secondary amine catalysis. The reaction affords valuable N-Cbz- as well as N-Boc-protected aziridines 167 with almost complete diastereocontrol and very high enantioselectivity (up to 99% ee). 

SCHEME 948 Cascade reaction combining Rh and secondary amine catalysis. 

---