Iminium salts, from amines

Another classical approach is the Pictet-Spengler isoquinoline synthesis. 66c x is variation generates an iminium salt from an amine and an aldehyde (a Schiff base), which cyclizes with an aromatic ring to complete the reaction. A synthetic example is taken from Liang s synthesis of chrysotricine.1 2 xhg reaction of amine 279 with aldehyde 280, in the presence of trifluoroacetic acid, initially gave an iminium salt (281). Subsequent Friedel-Crafts cyclization of the iminium salt gave the isoquinoline product (282 in 70% yield). The amino groups of amino acid derivatives also serve as excellent partners in this reaction.1 3... 

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. 

For purposes of characterization of enamines the perchlorate salts are preferred, as they crystallize well, and the perchlorate anion has no tendency to add to the iminium cation. Other salts, including hexachlorostannates (13), hexachloroantimonates (13), chlorides, bromides, tetraphenylborates, and nitrates, have also been used. Recently a method for the preparation of iminium salts directly from aldehydes or ketones and the amine perchlorate has been reported (16). 

The close agreement of the three methods supports the contention that protonation at low temperatures first occurs at nitrogen and is followed by a proton shift to give the iminium salt (M). The rate of this rearrangement is dependent on temperature, the nature of the amine, and the nature of the carbonyl compound from which the enamine was made. Even with this complication the availability of iminium salts is not impaired since the protonation reaction is usually carried out at higher temperatures than —70°. Structurally complicated enamines such as trichlorovinyl amine can be readily protonated (17,18). 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

Spelling of amonium, imonium, and iminium indicates derivation from amine and imine onium salts. 

Iminium ions bearing an electron-withdrawing group bonded to the sp carbon of the iminium function are very reactive dienophiles. Thus, iminium ions 26 generated from phenylglyoxal (Scheme 6.15, R = Ph) or pyruvic aldehyde (R = Me) with methylamine hydrochloride, react with cyclopenta-diene in water at room temperature with good diastereoselectivity [25] (Scheme 6.15). If glyoxylic acid is used, the formation of iminium salt requires the free amine rather than the amine hydrochloride. 

This is the most common method for the preparation of enamines and usually takes place when an aldehyde or ketone containing an a hydrogen is treated with a secondary amine. The water is usually removed azeotropically or with a drying agent, but molecular sieves can also be used. Stable primary enamines have also been prepared.Enamino-ketones have been prepared from diketones and secondary amines using microwave irradiation on silica gel. ° Secondary amine perchlorates react with aldehydes and ketones to give iminium salts (2, p. 1178). Tertiary amines can only give salts (12). 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

Addition of Vinyl and Aryl Groups. The reaction of aromatic radicals, generated by decomposition of diazonium salts, with iminium salts in the presence of TiCE in aqueous media produces secondary amines (Eq. 11.53).91 The iminium salts are formed in situ from aromatic amines and aldehydes. 

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... 

The excellent reducing properties of potassium tetracarbonylhydrido-ferrate have been used to good effect in providing an efficient general piperidine synthesis from alkyl and aryl amines and glutaraldehyde210 (Scheme 138). The reaction probably proceeds via reduction of intermediate Schiff bases and cyclization via the iminium salt. 

In 1998, Page and coworkers reported a series of dihydroisoquinoline-related iminium salts which can be readily synthesized in three steps from a chiral amine (Scheme 14) [140-143], Among the catalysts tested for asymmetric epoxidation, iminium salts 74 were found to be efficient catalysts (Fig. 24, Table 7, entries 2, 4-6, 17-19). Iminium salts 74a can epoxidize 4-phenyl-1,2-dihydronaphthalene in up to 63% ee (Table 7, entry 17). 

The formation of NNN, NNK, and NNA from nicotine probably involved the intermediacy of cyclic iminium salts, as shown in Figure 5 (28). These salts can undergo hydrolysis to the free amines which are nitrosated, or at near neutral pH, can be directly nitrosated to give nitrosamines. The formation of nitrosamines from iminium salts under neutral conditions has been demonstrated in at least two studies and is of interest because iminium salts are known to be intermediates in the mammalian metabolism of nicotine (26,29,30,31). The possibility that tobacco bacteria could nitrosate nicotine via this pathway is currently under investigation. 

Tertiary amines are made from iminium salts by catalytic hydrogenation or by LiAlH4 reduction. The iminium salts are usually unstable, and so are reduced as they are formed by a reducing agent already in the reaction mixture. A mild reducing agent, e.g. sodium cyanoborohydride (NaBHsCN), can also be used. 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

Other alkylation reactions are observed in the condensation of cyclo-propanium ions (generated in situ) with ketones 89.92)> enamines6, nitroalkanes 93>, dimethylmalonate 92>, and phenol. 92> Thus, 7-hydroxy-7-pyrrolidinobicyclo[4.1.0]heptane (56) as well as the 7,7-dipyrrolidino derivative (54) react with acetone to give the amino ketone 113. 89> This reaction may be pictured as an addition of the enol form of the ketone to the reactive iminium salt formed from the carbinol amine. In like manner, phenol undergoes ortho substitution with the carbinol amine 114 formed from cyclopropanone and dimethyl amine. 

Here again, loss of Y = H would result in rearomatization and formation of 12, but in the case of Y = Me, this cannot occur. However, assistance by the amine nitrogen lone pair can aid the rearomatization process, producing the copper-bound phenol product and an imininm salt. Hydrolysis during the workup procedure could release the 2-meth-ylphenol product and result in a retro-Mannich reaction to give the observed secondary amine (PY2) and formaldehyde. A small amount (<10%) of N—Me—PY2 is often observed as a byproduct and its yield is at the expense of the PY2 and formaldehyde thus, it appears to be derived from direct reduction of the intermediate iminium salt [167],... 

This reaction allows the preparation of tertiary methylamines from secondary amines via treatment with formaldehyde in the presence of formic acid. The formate anion acts as hydride donor to reduce the imine or iminium salt, so that the overall process is a reductive amination. The formation of quaternary amines is not possible. 

Among the best enol equivalents for aldehydes are enamines.19 They are stable compounds, easily made from aldehydes 95 and secondary amines, reacting with electrophiles in the same way as enols 96 to give iminium salts 97, hydrolysed to substituted aldehydes 98. 

When cesium fluoride is used instead of zinc chloride, a diaminomethane derivative is obtained, whose formation is explained by the addition of the iminium salt to the secondary amine resulting from its hydrolysis.219... 

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). 

If a proton is added to enamine, diastereomers are possible products when an optically active secondary amine is used, assuming the iminium salt has been produced. To investigate this matter, the series of reactions shown in Figure 4 is performed. The salt is made from the acid using HC1, and D20 hydrolysis of the resultant salt is carried out. Since deuterium is not incorporated into the recovered a-phenylpropionaldehyde, chirality is believed to be induced before the hydrolysis (4). 

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