Iminium activation reactions

Nucleophile-specific parameters N and % of enamides have allowed their rates of reaction with various electrophiles to be predicted and thereby reveal the stepwise nature of iminium-activated reactions of electrophilic a,)0-unsaturated aldehydes with enamides and the inadvisability of using strong acid co-catalysts. ... 

The amine-catalyzed Diels-Alder dimerization reaction of a, 3-unsaturated ketones in water was developed by Barbas et al. to form cyclohexanone derivatives (Eq. 12.12). They believe that the reaction proceeds via the in situ formation of 2-amino-1,3-butadiene and iminium-activated enone, as the diene and dienophile, respectively. 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

In line with the mechanistic rationale of LUMO-lowering iminium activation, MacMillan hypothesized that intermediate 2, generated from the secondary amine 1 and an a,/f-un saturated aldehyde, could be activated towards cydoaddi-tion with an appropriate diene (Scheme 3.1). The Diels-Alder reaction would form iminium ion cydoadduct 5 that, in the presence of water, would hydrolyze to yield the enantioenriched product 6 and regenerate the chiral imidazolidinone catalyst 1. 

A limitation of MacMillan s approach towards iminium-activated Diels-Alder reactions has been the use of a-substituted a,/ -unsaturated aldehydes as dieno-philes. Recently, Ishihara and Nakano [31] succeeded in partially overcoming this problem by identifying a novel primary amine organocatalyst for this type of... 

Enantioselective Conjugate Addition Reactions via Iminium Activation... 

The catalytic cycle operating for a generic Michael-type reaction of a nucleophile (Nu-H) to an a, 3-unsaturated aldehyde or ketone proceeding via iminium activation has been indicated in Scheme 3.1. As it can be seen in this proposed mechanism, all the steps involving iminium formation and hydrolysis are supposed to be in dynamic equilibrium, therefore concluding that the conjugate... 

Figure 3.1 Factors to be considered when designing a chiral secondary amine catalyst to be used in Michael reactions under iminium activation.

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

Oxindoles are a particular class of cyclic amides which are acidic enough to play the role of pro-nucleophiles in conjugate additions under iminium activation. In particular, the reaction between 3-alkyl substituted oxindoles and ot,p-unsaturated aldehydes leading to the formation of a quaternary stereocenter at the heterocyclic unit has been studied by several authors (Scheme 3.12). The use of 0-trialkylsilyldiarylprolinols like 31a as catalysts led... 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

Once in the modern organocatalysis era and with the mechanistic rationale for the iminium activation concept in hand, many different and more efficient methodologies have been developed for this particular reaction. For example, and still focused on the use of secondary amines as catalysts, imidazolidine 53a and proline-tetrazole 2a catalysts have been developed for the conjugate addition of malonates to acyclic enones (Scheme 3.17). For the 53a-catalyzed reaction, this proceeded well in terms of yields and enantioselectivities for a wide range of differently substituted arylideneacetones and for cyclohexenone but yields tend to decrease when more bulky substituents were placed around the carbonyl moiety. Importantly, the enantioselectivity of the reaction was very dependent upon the nature of the malonate reagent, observing that dibenzyl malonate and diethylmalonate furnished the best results. The most... 

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