Iminium salts nucleophilic addition

The formation of 88 is postulated to be occurring by the nucleophilic attack of a hydride ion (47), abstracted from the secondary amine, on the a-carbon atom of the iminium salt (89). The resulting carbonium ion (90) then loses a proton to give the imine (91), which could not be separated because of its instability (4H). In the case of 2-methyIhexamethylenimine, however, the corresponding dehydro compound /l -2-methylazacyclo-heptene (92) was isolated. The hydride addition to the iminium ion occurs from the less hindered exo side. 

In most reviews of enamine chemistry the reactions of iminium salts are scattered throughout the review and are consequently not covered in a comprehensive manner. This chapter will be an attempt to look at reactions that, at one stage or another, proceed by nucleophilic addition to the iminium intermediate. The subject of enamines has been reviewed 1-4) and certain aspects of iminium salt chemistry such as reduction of aromatic quaternary salts have been treated in detail (5). Consequently, the reduction of aromatic quaternary salts with complex hydrides will be presented here only briefly. Although the literature (especially 1950-1967) has been checked with care, the author can make no claim to completeness. The... 

Another class of nucleophilic addition to iminium salts can be found in the addition of diazoalkanes. These are of great interest since they were known to add and then reaet further to form three-membered rings as in the case of C=S, C=0, and C=C functions 103). Leonard and Jann 104-106) found that treatment of iminium perchlorates with diazomethane and other diazoalkanes yielded aziridinium salts. Treatment of an iminium salt such as N-cyclohexylidinepyrrolidinium perchlorate (66) with diazomethane yielded a new product whose structure was established by spectral and chemical means to be 5-azoniadispiro[4.0.5.1]dodecane perchlorate (67). The UV spectrum was devoid of any absorption above... 

As a result, one might expect that there is only a slight difference between the iminium salts and the parent ketone (4-rm-butylcyclohcxanone) concerning the stereochemical course of the addition reaction and. actually, this assumption proves to be true. In each case the diastereomer resulting from the less hindered equatorial attack of the nucleophile clearly predominates10. 

Petasis reported an efficient addition of vinyl boronic acid to iminium salts.92 While no reaction was observed when acetonitrile was used as solvent, the reaction went smoothly in water to give allyl amines (Eq. 11.54). The reaction of the boron reagent with iminium ions generated from glyoxylic acid and amines affords novel a-amino acids (Eq. 11.55). Carboalumination of alkynes in the presence of catalytic Cp2ZrCl2 and H2O affords vinylalane intermediates, which serve as nucleophiles in the subsequent addition to enantiomerically enriched... 

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... 

For a review of nucleophilic addition to iminium salts, see Paukstelis Cook, in Cook, Ref. 45. pp, 275-356. See Cho Chun J. Chem. Soc., Perkin Trans. 1 1990, 3200 Chan Osborn J. Am. Chem. Soc. 1990,112, 9400, and references cited in these papers. 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

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 classical Mannich aminomethylation is one of the most important ionic carbon-carbon bond forming reactions in organic chemistry [35]. However, only substituents with electron-withdrawing groups are suitable for the ionic addition. Electron-donating groups directly bonded to the carbon-centered radical favor nucleophilic radical addition to methylene-iminium salts. Thus, the radical-type Mannich reaction provides products which are complementary to those obtained with the classical ionic reaction. 

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>. 

It might appear that the simplest possible type of system to which ALPH might apply is a system with one lone pair only, and which does not involve a proton transfer. Reactions of a-substituted amines, or their microscopic reverse, nucleophilic additions to iminium ions, thus suggest themselves as suitable testbeds for ALPH, but the information on such systems is sparse. Stevens (1984) has studied the addition of carbon nucleophiles to tetra-hydropyridinium salts from the standpoint of utility in organic synthesis, and found a preference for axial attack, in accord with ALPH (Scheme 4). 

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