Enamine Catalysis Cyclization

In addition to the enamine-enamine and enamine-iminium catalytic sequences, it was found that the resulting intermediate 6 can also initiate cyclization reactions in the subsequent step via a substrate-control mode. 

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Dihydroquinolines are obtained via Cu- or Ag-cata-lyzed A -coupling/cyclization when using 2-alkynylbenz-aldehydes, amines, and ketones, which combines metal and enamine catalysis, as demonstrated by Wu et al. [119]. 2-Alkynylbenzaldehyde derivatives have also been used as the additional nucleophile carrier in the silver-catalyzed synthesis of naphthyridines and thienopyridines recently reported by Verma et al. [120], A variety of naphthyridines and thienopyridines were prepared via dual activation using L-proline as the organocatalyst, whereas for other... 

Michael addition via iminium catalysis and subsequent intramolecular Mannich cyclization via enamine catalysis allows the formation of carbocycles with high efficiencies (Scheme 7.27) [44]. 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode, although an iminium mode might be involved in the following steps. In this regard, several catalytic cascade sequences, including enamine-enamine, enamine-iminium, and enamine cyclization, are discussed here. 

Design of Enamine-Enamine Cascades Three possible active sites (e.g., carbonyl group, nucleophilic a- and Y-positions) of enamine catalysis product 4 or 6 (Figure 1.1) can be further functionalized via a second enamine process in a cascade manner. Taking advantage of the electrophilic carbonyl in 4 and 6, intermolecular enamine-enamine (Scheme 1.3a) and enamine-enamine cyclization (Scheme 1.3b) cascades could be possible. In addition, the a-position of the same (Scheme 1.3c) or different (Scheme 1.3d, e.g., Robinson annulation) carbonyl group can be subjected to a second enamine process. 

Design of Enomine-Cyclization Cascade Reactions The nucleophilic Y in intermediate 6 can react with other electrophiles intermolecularly (Scheme 1.34a) or intramolecularly (Scheme 1.34b) as well as with the iminium ion. Moreover, the carbonyl group of 6 can also undergo intramolecular aldol reaction with nucleophilic X (Scheme 1.34c). These nucleophilic addition reactions after enamine catalysis induce cyclization reactions to produce versatile five- or six-membered ring structures. 

Scheme 2.7 Asymmetric reductive Michael cyclization and schematic representation of the tandem iminium-enamine catalysis mechanism...

Melchiorre and co-workers reported the first asymmetric aziridination of a,p-unsaturated ketones using the primary amine-amino acid salt 91 (Scheme 5.39) [68]. The reaction occurred via first nucleophilic addition of A-centered nucleophile (iminium catalysis) followed by intramolecular cyclization (enamine catalysis). Essential factors for the success of the current reaction included the proper selection of nitrogen nucleophile and the addition of solid NaHCO. Under the optimized conditions, a range of cyclic or acyclic enones can be incorporated in the protocol to afford either A-CBz or A-Boc aziridines with excellent diastereo- and enantioste-reocontrol (Scheme 5.39). 

A much more generally useful process was developed by Robinson to prepare cyclohexenones from ketones and methyl vinyl ketone or its derivatives. Again, because good compilations of the Robinson annulation exist,8 only a few examples are given here. The first step of this process, the Michael addition, is carried out by normal base catalysis, while the second step, the aldol condensation, is best accomplished by the use of a secondary amine to form the enamine of the acyclic ketone, which then cyclizes... 

All of these processes are of limited synthetic utility because of the requirement of the use of stoi chiometric amounts of palladium complexes. However, by judicious choice of reactants and condition the above-mentioned impediments to catalysis can be overcome. For example, an efficient palladium(II) catalyzed cyclization of o-allyl- and o-vinyl-anilines to indoles has been developed (equation 14).28 Be cause arylamines are -106 less basic than aliphatic amines, and because the cyclized product in thi system gave an enamine (indole) stabilized by aromatization, the problems of catalyst poisoning by sub strate or product were circumvented, and catalysis was successfully achieved. The system was quit tolerant of a variety of functional groups and was used to prepare indoloquinones in excellent yieli... 

Few examples of ene-yne cycloisomerization reactions are seen in the literature. The first results for ene-yne cycloisomerizations were with systems bearing an heteroatom (amine or oxygen) next to the alkene counterpart (forming an enamine or an enol ether). Indeed, Dake s group reported the cyclization of enesulfonamides on alkynes (69-70, Scheme 5.30) under catalysis by platinum and silver salts.85 Catalysis using AgOTf (1 1 mol%) was particularly efficient with systems such as 69 (Scheme 5.30)... 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Chiral secondary amines have proven to be amongst the most dynamic and efficient of asymmetric catalysts. There are essentially two modes of activation by secondary amines whereby a nucleophilic enamine or an electrophilic imininm ion is generated. Figure 1.4 shows a generic scheme of these two modes of activation and how they would be used in asymmetric organocatalytic cyclizations. A third mode of catalysis, named Organo-SOMO catalysis is discussed in Sect 1.5.1.5. 

An intramolecular application of this type of catalysis was included in his first publication on this process, whereby the SOMO activated enamine cyclized onto an unactivated alkene using catalyst 103 (Scheme 1.26). 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

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