Iminium ethers nucleophilic additions

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

If the anodic oxidation of N-alkylanilines is performed in the presence of nucleophiles like enol ethers, nucleophilic substitution in the of-position to nitrogen by the enol ether can be observed in low yields. The electrophilic intermediate is the N-aryl iminium ion or the N-aryl imine after loss of two electrons and one or two protons. These intermediates add to the enol ether to give acetals (up to 26%) as addition products, or the first addition step is followed by an electrophilic aromatic substitution to form tetrahydroqui-nolines (13-39%) [47]. It should be noted at this point that better results for the nucleophilic a-substitution to nitrogen can be obtained with N,N-dialkylanilines (see next subsection). Optimum results, however, are obtained with N-acylated compounds via the intermediate N-acyl iminium ions (see Ref. 8). 

Two C-C Bond-Forming Events In 2008, Frechet and coworkers described an impressive asymmetric cascade reaction promoted by soluble star polymers with core-confined catalytic entities [10]. The encapsulation of catalysts into soluble star polymers allowed the use of incompatible catalysts and prevented undesired interactions between these catalytic systems. The organocascade corresponded to a nucleophilic addition of Af-methylindole to a,p-unsaturated aldehydes followed by a Michael addition of the adduct to methylvinylketone (MVK) in the presence of H-bonding additive (Scheme 12.5). Each catalyst - imidazolidinone 8 for the nucleophilic addition and diphenylprolinol methyl ether 9 for the Michael addition - or their combination cannot mediate both reaction steps. In particular, p-toluenesulfonic acid (p-TSA) diminished the ability of the chiral pyrrolidine 9 to effect enamine activation. Therefore, p-TSA and 9 were encapsulated in the core of star polymers, which cannot penetrate each other. Imidazolidone 8 was added to the acid star polymer and diffused to the core to form the salt, which allowed the iminium activation and catalyzed the first step. The second step was catalyzed by the pyrrolidine star polymer in presence of the H-bonding additive 10, which... 

It has been shown that in addition to iminium ether hydrolysis, other heteroatom and C-based nucleophiles may be incorporated into the lactam products. Through the addition of nucleophiles in a solution of DMF at ambient temperature, a range of lactams... 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Cdrdova has shown that using unprotected iV-hydroxycarbamates 71 as the nucleophile with diarylprohnol ether 30 as catalyst gave direct access to 5-hydrox-yisoxazolidines 72 (91-99% ee) which are convenient precursors to p-amino alcohols and p-amino acids (Scheme 31) [110], Interestingly, these reactions proceed efficiently (3-16 h) without the need for an additional co-acid unlike the majority of other iminium ion catalysed transformations, an unexpected result which highlights the need for further mechanistic understanding. 

However, formation of this bond through the conjugate addition of a soft sulfur nucleophile to a,P-unsaturated aldehydes is efficiently catalysed using iminium ion catalysis [116], Using diarylprolinol silyl ether 55 the addition of a series of sulfur based nucleophiles to a variety of a,P-unsaturated aldehydes was shown to be effective (73-87% yield 89-97% ee). The products were isolated as their p-hydroxy sulfide derivatives 73 after in situ reduction of the products (Scheme 33). 

Simultaneous publication of the iminium ion catalysed hydrophosphination of a,p-unsaturated aldehydes by Melchiorre and Cordova showed diarylprolinol silyl ether 55 was effective in the conjugate addition of diphenylphosphine 74 [117, 118], Direct transformation of the products allowed for one-pot methods for the preparation of P-phosphine alcohols 75 (72-85% yield 90-98% ee), P-phosphine oxide acids 76 (65% yield 92% ee) and 3-amino phosphines 77 (71% yield 87% ee) (Scheme 34). These reports represent the first examples of the addition of P-centred nucleophiles and the resulting highly functionalised products may well have further use in asymmetric catalysis. 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

The iminium salts of 2,3-dihydropyridines are far more stable than the free bases and have been used extensively in the synthesis of alkaloids. N-Benzyl iminium salt 26, formed from the Polonovski-Potier reaction of V-oxide 25, was transformed into enol ether 27, which is a synthon for the unstable AT-benzvl-l, 2-dihvdropyridine 28 (Scheme 5) <2004LOC168>. The same transformation on a similar iminium salt has been used in the formation of macrocyclic marine alkaloids <1995TL2059>. Carbon nucleophiles, such as the silylenol ethers of esters, have been shown to undergo 1,2-addition rather than 1,4-addition to 2,3-dihydropyridinium salts <1999T14995>. 

If the enol component is an aldehyde, none of these methods will do and enamines or silyl enol ethers are the best choice. Enamines are excellent nucleophilic components and the iminium ion that is formed in die conjugate addition can provide the electrophilic component in a cydization reaction. Acid-catalysed hydrolysis of the f) amino-ketone liberates the amine that was used to form... 

Most ir-nucleophiles employed in iminium ion cyclizations have a predetennined postcyclization destiny. For example, aromatic terminators will rearomatize, organosilanes will eliminate silicon through anticipated pathways and acetals and enol ethers will produce carbonyl compounds. However, the cyclizations of simple alkenes have supplied products that are the formal results of eliminations, additions and Wagner-Meerwein rearrangements. Almost exclusively Mannich-type cyclizations of unsaturated amines have been employed to prepare piperidines. 

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... 

Michael additions are among the most important organocatalytic transformations.The ability of prolinol silyl ethers to form enamines, diena-mines, trienamines or iminium ions makes them appealing in a number of chemical transformations based on addition of a nucleophile to an a,p-unsaturated carbonyl compound or other Michael acceptor. The first example of Michael addition catalysed by a prolinol silyl ether was published by Hayashi and coworkers. Aliphatic aldehydes added to a range of aryl-substituted nitroalkenes. Prolinol silyl ether Cla presumably formed chiral enamines with aldehydes. The F-anh-enamine was formed and it reacted with nitroalkene via an acyclic synclinal transition state, originally proposed... 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

In 2005, J0rgensen et al. extended the conjugate addition of sulfur nucleophiles to a,P-unsaturated aldehydes under iminium catalysis with trimethylsilyl ether 56 (10 mol%) as catalyst [385]. Very high enantioselectivities (89-97% ee) were reported for the addition of aliphatic thiols to different aromatic and aliphatic enals at low temperatures (-24°C) where the employment of an acid cocatalyst (PhCOjH, 10 mol%) was mandatory in order to improve the reaction rate. This methodology has been incorporated into domino reactions by the same group and others to successfully prepare optically active sulfur-containing heterocyclic compounds [385, 386],... 

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