Enamine activation catalytic cycle

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. 

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

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]. 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

The aldehyde formed in the first cycle reacts with an amine (E) yielding an enamine. This coordinates to the rhodium dihydrido species (G) of the second catalytic cycle. The insertion of the enamine in the rhodium hydrogen bond (H) is the next step before the hydrogenated molecule is cleaved (J) and the active rhodium complex is restored by adding a hydrogen molecule (F). 

The most commonly used type of catalyst is a relatively small, bifunctional molecule that contains both a Lewis base and a Bronsted acid center, the catalytic properties being based on the activation of both the donor and the acceptor of the substrates. The majority of organocatalysts are chiral amines, e.g. amino acids or peptides. The acceleration of the reaction is either based on a charge-activated reaction (formation of an imminium ion 4), or involves the generalized enamine catalytic cycle (formation of an enamine 5). In an imminium ion, the electrophilicity compared to a keton or an oxo-Michael system is increased. If the imminium ion is deprotonated to form an enamine species, the nucleophilicity of the a-carbon is increased by the electron-donating properties of the nitrogen. ... 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

Effects of additives in the isomerization of substrate 45 by catalyst 17 were studied under the conditions of [S]=0.24 mol L [S] [C] =100 at 60 °C in THE The results are briefly summarized in Table 1, and are important both for mechanistic studies and improvements of the catalyst activity. Simple tertiary amines retard the reaction drastically, which suggests the coordination order of amines to Rh-BINAP species to be proportional with the order of basicity of simple tertiary amines, allylamines and enamines. Without the presence of simple tertiary amines, this phenomenon enables the fast replacement of the enamine formed from the catalyst by a substrate molecule that permits a smooth catalytic cycle. The presence of chelate diolefins like COD also disturbs the catalytic cycle. An over-isomerized by product, dienamine 44, acts as a strong catalyst poison. 

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. 

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. 

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. 

Based on previonsly reported mechanistic considerations concerning the aminocatalytic field [50], the anthors proposed the catalytic cycle depicted in Scheme 9.13 to explain the stereoseleclion found in the final products 37. In this proposal, the enamine intermediate II is the active species responsible of the enantioselectivity of this process. 

---