Iminium activation catalytic cycle

Fig. 2 Catalytic cycles for the iminium ion activated Diels-Alder and conjugate addition reactions...

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

One of the most compelling features of iminium ion catalysis is the proposed mechanistic rationale for the transformations, which leads to highly predictable reaction outcomes. Despite impressive advances and the plethora of reactions reported efforts to provide a detailed mechanistic understanding of the catalytic cycle are limited. The reported work has focussed on the Diels-Alder cycloaddition and has provided useful indicators that could be used in design of more active catalysts. 

This reaction is believed to proceed via nucleophilic combination of in situ generated Cu-acetylide and iminium ion. Mechanistic studies indicate a strong positive non-linear effect based on which a catalytic cycle is proposed that involves a dimeric Cu/quinap complex as the active catalytic species. 

The catalytic cycles are, however, different in the reaction sequence for formation of the enamines which are key intermediates in these aldol reactions. With the type I aldolase a primary amino function of the enzyme is used for direct formation of a neutral imine (Ha) whereas starting from L-proline enamine synthesis proceeds via a positive iminium system (lib) (Scheme 6.23). In this respect, investigations by List et al. on the dependence of the catalytic potential on the type of amino acid are of particular interest. In these studies it has been shown that for catalytic activity the presence of a pyrrolidine ring (in L-proline (S)-37) and the carboxylic acid group is required [69]. 

This proline-catalysed aldol proceeds via initial formation of an enamine with the donor component. This enamine then reacts with the re-face of the acceptor through a closed-transition state, as depicted in Figure 7.4, to give the anti-product as the major diastereomer. The proline also activates the acceptor by hydrogen bonding within this ensemble and thus plays a bifunctional role in the reaction. The resulting iminium ion is then hydrolysed to close the catalytic cycle. 

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... 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

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. 

The cyclobutane intermediate is not an irreversible sink for the catalyst, but remains reversibly linked to the catalytic cycle. In this mechanistic scenario, the enantioselectivity of the reaction does not depend on the difference of the activation energies for the electrophilic attack on the two diastereotopic faces of the enamine intermediate and is controlled, according to the Curtin—Hammett principle, by the relative stability and reactivity of the diastereomeric intermediates (cyclobutane and enamine of the Michael adduct) downstream in the catalytic cycle [58, 60]. A very recent detailed mechanistic study of another reaction catalyzed by diarylproUnol sdyl ethers, the a-chlorination of aldehydes by iV-chlorosuccinimide, also suggests that the stereochemical outcome of this process is not determined by the transition state of the electrophilic attack to the enamine, but instead is correlated with the relative stability and reactivity of the diastereomeric 1,2-addition products from the resulting iminium intermediate [60]. 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

In the hypothesized catalytic cycle, in the presence of catalyst and the co-catalyst acetic acid, the enamide 1 is tautomerized to the corresponding imine, which is activated by the acid via an iminium intermediate. In the following step, only chiral phosphoric acid is active enough to catalyze the hydrogenation of the imine, while the acetic acid role is probably only to help keep a sufficient concentration of iminium intermediate present since it was used in such small quantities (Figure 15.7). 

The detailed mechanistic explanation pictures the initial weak interaction among the bifunctional thiourea catalyst 158, the malonic ester 157 as nucleophile, and the nitroalkane 140 as electrophile that should promote the first chemo- and stereoselective Michael addition. The resulting adduct A would be poised to participate directly in the second catalytic cycle by acting as donor in a regioselective ititro-Michael reaction with the a,p-unsaturated aldehyde 95, here activated as iminium ion by the secondary amine catalyst (5)-76. The new inteimediate B, with its aldehyde and malonate moiety suitably spatial disposed, would undergo a base-promoted aldol cychzation to efficiently generate the planned cyclohexanol 159 in moderate yield (up to 87%) and marvelous enantioselectivity (up to >99% ee). 

The observed excellent stereoselectivities (dr=91 9 to >95 5, 94 to >99% ee) could be ascribed to the steric hindrance created by the employed catalyst in each step of the catalytic cycle reported below (Scheme 2.56). Once the chiral amine (S)-70 activates the acrolein 131 as electrophile by generating the vinylogous iminium ion A, the indole 171 performs an intermolecular Friedel-Crafts-type reaction. The resulting enamine B acts as nucleophile in the Michael addition of the nitroalkene 140 leading to the iminium ion D, which upon hydrolysis liberates the catalyst and yields the intermediate aldehyde 173. The latter compound enters in the second cycle by reacting with the iminium ion A, previously formed by the free catalyst. The subsequent intramolecular enamine-mediated aldol reaction of E completes the ring closure generating the intermediate F, which after dehydration and hydrolysis is transformed in the desired indole 172. 

The role of the imidazolidinone catalyst 100 employed is depicted in Scheme 6.13. In the proposed cycle, the nucleophile (Nu) is added over the first formed a,p-unsaturated iminium ion 102. After a fast hydrolysis, adduct 104 and catalyst 100 are released. The adduct 104 would then enter in the second catalytic cycle to form the active enamine 105, which could trap the electrophile (E) present in the reaction in a highly diastereoselective addition. 

Thus, the reaction would start by the condensation between the aldehyde and the thiourea to give an imine I (Scheme 9.11, A), which would be promoted by Brpnsted acid. The catalyst could be involved in the activation of such imine (B) for the subsequent attack of the p-ketoester (C), through formation of a chiral iminium species II, to undergo an enantioselective Mannich reaction, as suggested by DFT calculations. The ensuing cyclization reaction (D) and dehydration (E) afiford the desired chiral Biginelli products and released the chiral phosphoric acid catalyst restarting the catalytic cycle. 

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brpnsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see [45-58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brpnsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester lb giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see [59-61]). 

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