Iminium ions intramolecular reactions

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

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... 

It is assumed that the mechanism proceeds via activation of the imine by the ruthenium catalyst (structure 169), followed by reaction with ethyl diazoacetate to generate a metal-bound ylide intermediate. Intramolecular ruthenium- assisted attack of the carbanion 170 onto the iminium ion provides the corresponding aziridine with moderate to high // selectivity. Imines bearing electron-donating groups (R2) showed significant rate enhancement. 

Hine has demonstrated that simple amino acids, such as glycine and p-alanine, are not capable of intramolecular deprotonation in the reaction with isobutyraldehyde-2-d (Scheme 8) [62], Apparently, the carboxylate moiety in the iminium ion intermediate 29 is a relatively weak base and, as such, external bases, present in the buffer used (e.g. acetate ions), are largely responsible for the formation of the enamine intermediate 30. 

The dual nature of enamine-iminium pairs allows unique possibilities for domino processes. Reactions of enamines with electrophiles afford electrophilic iminium ions that are ready to react with another (internal or external) nucleophile. Conversely, reactions of unsaturated imininm ions with nucleophiles afford enamines. Examples of intramolecular enamtne-catalyzed domino processes are depicted in Scheme 35. In all of these reactions, both enamine and iminium mediated steps can be distinguished. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

Fustero has devised an intramolecular version of the iminium ion catalysed conjugate addition of nitrogen in the preparation of a series of simple pyrrolidine and piperidine derivatives [115]. The reactions proceed in chloroform to give the target heterocycles in good yield and excellent levels of stereocontrol (Scheme 32). 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

The reaction of iminium ions with dihydropyridines is a method, suggested from biosynthetic studies, for the formation of carbon-carbon bonds to these six-membered heterocycles. The 1,4-dihydropyridine (8), a presumed intermediate from the reaction of ammonia with glutaraldehyde, reacts with the cyclic iminium ion (159) to give, after oxidation, nicotine (160) (72CC1091). Another example of this reaction has provided a total synthesis of olivacine (163). The 1,2-dihydropyridine ring system in (161), generated from its chromium tricarbonyl complex, was observed to undergo an intramolecular cyclization... 

A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

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. 

An enamine intermediate has been proposed as being formed by hydride reduction of a transient iminium ion [14, 15]. The electrophilic capture of the enamine is possible by a Michael acceptor thus, reductive Michael cyclizations of enal enones such as 9 or 11 were described in many cases (intramolecular reactions) (Scheme 11.5) [16]. 

Electrophilic substitutions of alkenyl-, aryl-, and alkynylsilanes with heteroatom-stabilized cationic carbon species generated by the action of a Lewis or Brpnsted acid (acyl cation, oxocarbenium ion, etc.) provide powerful methods for carbon-carbon bond formation. Particularly, intramolecular reactions of alkenylsilanes with oxocarbenium and iminium ions are very valuable for stereoselective construction of cyclic ether and amine units.21-23 For example, the BFj OEt -promoted reaction of (E)- and (Z)-alkenylsilanes bearing an acetal moiety in the alkenyl ligand gives 2,6-disubstituted dihydropyrans in a stereospecific manner (Scheme l).23 Arylsilanes also can be utilized for a similar cyclization.24... 

The in situ release of a reactive iminium ion by cycloreversion of an azanor-bornene [211, 212] and a subsequent intramolecular aza Diels-Alder reaction... 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

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