Imidazolidinone-derived enamines

Lakhdar, S., Maji, B., Mayr, H. (2012). Imidazolidinone-Derived Enamines Nucleophiles with Low Reactivity. Angew. Chem. Int. Ed., 51(23), 5739-5742. 

Type B enamine catalysts have been developed more recently. They include the diarylprolinol ethers (developed by the Hayashi and Jprgensen groups, e.g. 47 and its derivatives) [71-75] as well as the MacMillan imidazolidinone catalysts (e.g. 46) [76-78]. They excel in reactions where hydrogen bonding assistance is either not required or is not essential, such as a-halogenation reactions as well as some conjugate addition reactions (Scheme 12). 

In each of the tandem iminium ion/enamine cascade processes described above, the enamine is trapped in an intramolecular fashion. The ability to perform the trapping seQuence in an intermolecular manner would allow for the one—pot introduction of three points of diversity. IVIacNlillan has realised this goal and described a series of secondary amine catalysed conjugate addition—enamine trapping sequences with oc P Unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give the products in near perfect enantiomeric excess (Scheme 47) [178]. 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

Planarization in the pyrrolidine enamines increases p-character in the lone pair and renders nitrogen a stronger donor. Enamines derived from imidazolidinones are 10 -1(P times less reactive than those based on the proline-derived Hayashi-Jprgensen catalyst. ... 

Scheme 18.7 Electrophilic addition of copper derivatives to enamine of imidazolidinone.

The conformational preferences of enamines derived from prolinol, diarylpro-lynols, prolinol ethers, diarylprolynol ethers, and chiral imidazolidinones have been... 

Dixon and co-workers [182] published an enantioselective aryloxylation of aldehydes using an inverse-electron-demand hetero-Diels-Alder reaction of in s/tM-generated enamines and o-quinones. After trying different proline-derived catalysts, imidazolidinone 120 gave the best enantioselectivities (Scheme 12.34). 

Organocatalysts To date, the main classes of organocatalysts that have been used are [42] imidazolidinone, diarylprolinol silyl ether, cinchona alkaloid, and phosphoric acid and thiourea derivatives. Essentially, two modes of activation can be considered the reversible formation of iminiums/enamines (covalent activation) with a,P-unsaturated aldehydes and ketones in the presence of primary or secondary chiral amines (Figure 35.1), and activation via hydrogen-bond formation (non-covalent activation) when chiral catalysts bearing hydrogen-bond donors are used (Figure 35.2). 

Nucleophilicity parameters N and % for electrophile-nucleophile combination based on the Mayr equation log k=+E) were reported for fluorides in protic solvents, enamines derived from imidazolidinones, trimethylsilyl enol ethers with perfluori-nated substituents at the a-carbon, O-methylated Breslow intermediates, anions of nucleobases and their subunits, enamides, symmetrical and unsymmetrical hydrazines, and heteroarylboron compounds. Of note, replacement of CH3 with CF3 and C6H5 with CgF5 in the trimethylsilyl enol ethers reduces the nucleophilicity by 8 and 4.5 orders of magnitude, respectively. Hydrazines have very similar nucle-ophilicities to alkyl amines in other words, there is no evidence of an a-effect. With NH2NMC2, there is a fast reversible reaction corresponding to addition of the tertiary amine, followed by a slow irreversible reaction for addition at the primary amine, with a 3000-fold difference in nucleophilicity between the two sites. ... 

---