Acyl iminium ion

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 stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

The use of allylsilane cyclization onto iminium or acyl iminium ions is well reported <1998T10309,1998SL921, 1998H(48)507, 1998EJ02461>. One example shows the iminium moiety generated by oxidation of a trimethylsilyl (TMS) group (Equation 45) <1998JOC841>. 

A mechanistic rational for the ionization of pyrrole-3-triflates 72 was proposed as shown below (Eq. 8). Heterolytic cleavage of the sulfonate ester bond, assisted by donation of the nitrogen lone pair, results in loss of the triflinate ion59 and gives rise to the C-acyl iminium ion intermediate 73. This process is further facilitated by the stabilizing effect of a... 

To provide further evidence for the intermediacy of cyclic C-acyl iminium ions of the type mentioned above, a preliminary experiment was conducted (Eq. 12). It seemed reasonable that the mixed aminal linkage... 

Evidence that this reduction proceeds mainly via an N-acyl iminium ion intermediate 120 was obtained by carrying out the triethylsilane reduction of 108 in deuterated trifluoroacetic acid (Scheme 49). As before, two C-4 epimeric protected kainoid analogues 121 and 122 were obtained, H NMR showing loss of the C-4 proton in both products accompanied by a simplification in the spin-spin coupling pattern of the C-5 protons.73 A close examination of the 2H NMR spectrum of each diastereoisomer did, however, reveal a trace of deuteration at C-5 indicating that a small percentage of the reduction also occurs via a benzylic carbocation intermediate 123 (Figure 12). 

Two other approaches using acyl iminium ion intermediates were developed by the Shono (Shono et al. 1987) and Skrinjar (Skrinjar et al. 1992) gronps in a synthesis of racemic and (+)-anatoxin-a,... 

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

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). 

N-Acylated iminium ions have gained increasing importance in the past few years. As the less electron-rich counterparts of the aforementioned softer iminium ions, they offer strongly enhanced reactivities towards nucleophiles, combined with the attractive possibility of introducing additional functionalities (e.g. the amide group) into the desired heterocycles. 

Research in the laboratory of R.L. Danheiser has shown that allenylsilanes can be reacted with electrophiles other than enones, such as aldehydes and A/-acyl iminium ions to generate oxygen and nitrogen heterocycles." Aldehydes can function as heteroallenophiles and the reaction of C3 substituted allenylsilane with the achiral cyclohexane carbaldehyde afforded predominantly c/s-substituted dihydrofurans. 

Wie in den Massenspektren freier Aminosauren und Aminosaure-ester wird auch bei den Acyl-Dcrivaten der einfachen aliphatischen Aminosauren aus dem Molekiil-Ion sehr leicht ein COOH- bzw. COOR-Radikal abgespalten und ein Acyl-iminium-Ion A gebildet. Aus dem Ion A der... 

Complex multi-ring heterocyclic molecules like 136 have been prepared in one pot and under mild conditions by combining a base-catalyzed intermolecular Michael addition reaction of an a,p-unsaturated carbonyl compound and a suitable p-ketoamide pronucleophile with an acid-catalyzed intramolecular N-acyl iminium ion cyclization of the resulting adduct (Scheme 3.40). 

Conversely, when the reaction was carried out by using Amberlyst A15 (200%) in the presence or absence of liquid BEMP (10%), the only observed reaction product was substituted pyrrole 135, which was isolated in 68% yield product 134 was not present at all in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10%) and Amberlyst A15 (200%), the sole reaction product was the desired tetracyclic product 136 -obtained in 83% yield as a 1 1 mixture of diastereoisomers. By using sub-stoichiometric quantities of PS-BEMP (10%) and Amberlyst A15 (50%), an 85% conversion into 136 after 5 days was produced. These results demonstrate that PS-BEMP and Amberlyst A15 can operate as mutually compatible strongly basic and strongly acidic reagents, respectively, in the same vessel to facilitate the Michael-initiated N-acyl iminium ion cyclization cascade. 

Table 3.12 Polycyclic products obtained by Michael-initiated A-acyl iminium ion cyclization cascade between p-ketoamides and a,p-unsaturated carbonyl compounds catalysed by PS-BEMP and Amberlyst A-15 mixture.

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. 

Catalysts (25) are the Lewis acid-Lewis base bifunctional catalysts in which Lewis acid-Al(III) moiety activates acyl iminium ion and the Lewis base (oxygen of phosphine oxide) does TMSCN, simultaneously (Scheme 5.7). Halogen atoms at the 6-position enhanced both yields and enantioselectivity in Reissert-type cyanation of the imino part of 26. However, the order for the activation is not parallel to the electronegativity of the halogen atoms and, moreover, the strong electron-withdrawing trifluoromethyl group provided unexpectedly the worst result for the activation [13]. It is not simple to explain this phenomenon only in terms of the increased Lewis acidity of the metal center. Trifluoromethylated BINOL-zirconium catalysts (28) for asymmetric hetero Diels-Alder reaction (Scheme 5.8) [14], trifluoromethylated arylphosphine-palladium catalyst (32) for asymmetric hydrosilylation (Scheme 5.9) [15], and fluorinated BINOL-zinc catalyst (35) for asymmetric phenylation (Scheme 5.10) [16] are known. 

Addition of Grignard reagents to five- and six-membered systems (11) and (12) also leads to V-acyl-iminium ion precursors. The products, being tertiary alcohols, are rather susceptible, however, to ringopening and dehydration, so that their isolation may be problematic. Nevertheless, this methodology has proven highly useful for the synthesis of the amphibian alkaloid histrionicotoxin. ... 

Flynn, G.A., Giroux, E.L. and Dage, R.C. (1987) An acyl-iminium ion cycUzation route to a novel conformationally restricted dipeptide mimic applications to angiotensin-converting enzyme inhibition. J. Am. Chem. Soc. 109 7914-7915. 

Very recently, Pilling et al. explored a new methodology using a combination of PS-BEMP (10%) and Amberlyst A15 (200%) to facilitate the Michael-initiated V-acyl iminium ion cyclization cascade starting from p-ketoamide substrates, thus providing a unique entry to a variety of complex heterocyclic molecules [40] (Scheme 6.8). 

Grieco - Cyclocondensatlon ofC-acyl iminium ions with cyciopentadiene [86TL1975]... 

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