Secondary iminium activation

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. 

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

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... 

As mentioned, the applications of chiral secondary amines in domino processes have been numerous, mainly because of the dual mechanism of activation allowing easy incorporation of other reactions [7, 8]. The first of these processes involves an iminium-enarnine (Scheme 7.1a), and the second an enamine-iminium activation (Scheme 7.1b), both of which can be in operation in domino reactions involving Michael reactions. These modes of action rely on the lower energy lowest unoccupied molecular orbital (LUMO) for the iminium ion and a rise in the highest occupied molecular orbital (HOMO) energy for enamine activation, which are discussed in further detail in Chapter 10 of this book [9, 10]. In the... 

In this example, the iminium activation mode is assumed trough reaction with secondary amines for the initial Michael addition. The domino reaction is concluded with a hemiaminalization process to the tetrahydropyridin-2-ol 260. 

Recently, Lattanzi, Peluso, and co-workers [84] have found that experimental and computational results on the diphenylprolinol-catalyzed Michael addition of malo-nodinitrile to tra .y-chalcones are consistent with a bifimctional noncovalent mode of activation of the reactive partners, provided by the secondary amine and hydroxyl hydrogen bonding, and not with an iminium activation. 

Because azlactone enolates can be generated under very mild conditions, these species were applied to chiral secondary amine f-16-catalyzed conjugate addition to enals, which proceeded via iminium activation (Scheme 23) [40]. Variable... 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

An enantioselective domino oxa-Michael Hemy reaction of substituted salicylaldehydes with nitroalkenes, proceeding through aromatic iminium activation has been developed by Xu et al. by using a chiral secondary amine organocatalyst and salicylic acid as a co-catalyst. This novel domino reaction served as an efficient method for the preparation of chiral 3-nitro-2/f-chromenes with moderate to good enantioseleetivities of up to 92% ee (Scheme 1.78). 

The majority of the organocatalysts that are commonly employed are chiral Lewis or Brpnsted bases, and the catalytic potential of base functionalities has been referred to in previous chapters to some extent already. As discussed before, the use of chiral primary or secondary amines for enamine or iminium activation belongs to the most important applications of asymmetric organocatalysts nowadays. In addition, also the interplay between an acidic (thio)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such bifunctional thiourea-containing acid-base catalysts, chiral catalysts containing a (Lewis or... 

Figure 33.2 Mechanism of iminium activation with secondary amines.

It is observed that 1,5-hydride transfer can be accelerated by iminium activation. Therefore, it is speculated that cinnamaldehyde derivatives 194 represent ideal acceptors that are susceptible to activation by secondary amine catalysts capable of forming an iminium ion (Scheme 1.85) [132], The resulting iminium ion activation is expected to increase hydride transfer to alkene. The subsequent ring-closure reaction mediated by enamine catalysis furnishes ring-fused tetrahydroquinoline derivatives in moderate yields and high levels of enantioselectivity. 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Another method of activation we considered was the use of a secondary amine to generate a more electrophilic iminium species, examples of which have been used in vinylsilane-terminated cyclization reactions, particularly by Overman and co-workers [Eq. (4.8)] [51]. In our case, the unsaturated iminium ion would be activated for... 

Based on the observation that the majority of secondary amines shown to be effective in iminium ion catalysed transformations were cyclic five-membered nitrogen containing heterocycles, it was postulated that a highly nucleophilic nitrogen was central to catalytic activity [44]. This proposal was reinforced by the discovery that secondary amines with a-heteroatoms (a-effect nucleophiles) provided an effective platform for the acceleration of iminium ion catalysed... 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

The majority of transformations reported within the literature using the concept of LUMO energy lowering iminium ion activation have nsed secondary amines as the catalyst. Under the aqueous acidic reaction conditions inherent to this mode of activation it is also possible to nse primary amines as efficient catalysts where the active species is the protonated imine 141 (Fig. 13). Althongh this is a somewhat less explored avenne of research, initial results suggest it will become an equally fruitful area with broad application. 

Oxidation of the salt (125) with active manganese dioxide gives a high yield of thiophene-2-carbaldehyde (67G397). Amines, both primary and secondary, readily cleave the ring with expulsion of hydrogen sulfide and generation of the iminium species (128) in up to 90%... 

Ring-constrained analogues 37 of the anti-inflammatory drug, diclofenac, have been prepared by acid-catalyzed condensation of aldehydes (or ethylene ketals of ketones) with 36 (Equation 4) <1998MI201>. This reaction presumably proceeds via intramolecular nucleophilic attack by the carboxylic acid group on an iminium ion intermediate from condensation of the secondary amine. Interestingly, the compounds 37 showed comparable activities to diclofenac in the formalin-induced rat paw edema test. 

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