Imidazolidinone enamines

At present, one of the most successful catalysts for enamine activation has been proline (2). Proline is a cheap, widely and commercially available amino acid that can be found in both enantiomeric forms and, as such, represents a remarkable synthetic alternative to many established asymmetric catalysts. Given such attractive features, it has become the catalyst of choice for many enamine-catalyzed processes. However, various more recent studies have demonstrated that proline is not a universal catalyst for transformations that involve the a-functionalization of ketone or aldehyde carbonyls. Indeed, these studies have demonstrated that the iminium catalysts developed by MacMillan (imidazolidinones) and Jprgensen (pyrrolidines) are also highly effective for enamine activation with respect to... 

Michael additions using proline (2) as the organocatalyst have proven disappointing in terms of enantiocontrol, ° ° ° stimulating the search for a more selective enamine catalyst system. In this context, imidazolidinones (initially... 

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). 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

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]. 

Enantioselective Michael additions of aldehydes to enones using imidazolidinones as organocatalysts show evidence of enamine intermediates.217 Several co-catalysts -mainly phenols - raise the yield and/or ee. 

Direct enantioselective catalytic a-fluorination of aldehydes has been carried out using jV-fluorobenzenesulfonimide [F-N-(02SPh)2] and a chiral secondary amine (an imidazolidinone) to provide enamine organocatalysis.295... 

An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone-hydrogen bond donor pair affords Michael addition products in <90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172... 

Peelen TJ, Chi Y, Gellman SH (2005) Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones cocatalyst effects and evidence for an enamine intermediate. J Am Chem Soc 127 11598— 11599... 

Alkylation of aldehydes with enol silyl ethers is accomplished on oxidation of the latter species with CAN. By forming chiral enamines from the aldehydes and the imidazolidinone 20 in situ the reaction furnishes optically active products. ... 

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. ... 

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

Scheme 7.2 MacMillan et al. introducing imidazolidinone catalysts and the merged iminium—enamine process.

Figure 18.3 Nucleophilicity of enamines obtained from imidazolidinone catatysts...

In a similar approach, MacMillan reported an operationally simple procedure for the enantiocontrolled C-F bond formation. The enantiose-lective a-fluorination of aldehydes was based on the use of imidazolidinone I as the active catalyst. MacMillan proposed the use of M-fluorobenzene-sulfonimide 3 (NFSI) as a fluorinating agent (Seheme 18.5 B). A similar mechanism has been proposed for both ehlorination and fluorination with the MaeMillan eatalyst, in which the imidazolindinone enamine reacts with the halogen source, although this mechanism has not been proven... 

MacMillan has reported examples of synergistic catalysis in which copper salts are used. Although these results were driven by ad hoc hypotheses, most of these transformations are related to a Cu(i)/Cu(m) catalytic cycle. In any case, the superior performances offered by copper(i) salts, compared to strong Lewis acids tested in the processes, is an indication that the Lewis acidity of the metal salt is not playing a decisive role in these transformations. The complexation of the enamine 7i-system with Cu(iii)-R is expected to lead to rjl-iminium organocopper species that, upon reductive elimination, will form a carbon-carbon bond and liberate the active Cu(i) catalyst. Hydrolysis of the resulting iminium will also release the imidazolidinone catalyst to complete the organocatalytic cycle as shown in Scheme 18.7. 

Scheme 18.6 Stereoselective reaction by combination of iminium and enamine catalysis with imidazolidinones.

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

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