Iminium ions, electrophilicities

The iminium ion electrophile can also be prepared separately, as a crystalline solid known as Eschen-moser s salt (Me2N =CH21 ) and, with this, the reaction is normally carried ont in a non-polar solvent. Examples that illnstrate the variation in iminium ion structure that can be tolerated include the reaction of indole with quinolines, catalysed by indium(lll) chloride, with benzylidene derivatives of arylamines, catalysed by lanthanide triflates, with ethyl glyoxylate imines " (no catalyst required) and with dihydro-1,4-oxazin-2-ones. °" ... 

Reaction of phenylethyl amine with aldehyde or ketone forms intermediate imine, which under the acidic conditions is protonated to give the highly reactive iminium ion. Electrophilic substitution on the aromatic ring provides 1,2,3,4-tetrahydro isoquinoline after rapid loss of a proton and... 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

The tetrasubstituted isomer of the morpholine enamine of 2-methyl-cyclohexanone (20) because cf the diminished electronic overlap should be expected to exhibit lower degree of enamine-type reactivity toward electrophilic agents than the trisubstituted isomer. This was demonstrated to be the case when the treatment of the enamine with dilute acetic acid at room temperature resulted in the completely selective hydrolysis of the trisubstituted isomer within 5 min. The tetrasubstituted isomer was rather slow to react and was 96% hydrolyzed after 22 hr (77). The slowness might also be due to the intermediacy of quaternary iminium ion 23, which suffers from a severe. 4< strain 7,7a) between the equatorial C-2 methyl group and the methylene group adjacent to the nitrogen atom, 23 being formed by the stereoelectronically controlled axial protonation of 20. 

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. 

Under acidic conditions, imine 12 is protonated to give the iminium ion 13 which undergoes an electrophilic aromatic substitution reaction to form the new carbon-carbon bond. Rapid loss of a proton and concomitant re-aromatization gives the tetrahydroisoquinoline 14. 

The reductive couphng of imines can follow different pathways, depending on the nature of the one-electron reducing agent (cathode, metal, low-valent metal salt), the presence of a protic or electrophihc reagent, and the experimental conditions (Scheme 2). Starting from the imine 7, the one-electron reduction is facihtated by the preliminary formation of the iminiiim ion 8 by protonation or reaction with an electrophile, e.g., trimethylsilyl (TMS) chloride. Alternatively, the radical anion 9 is first formed by direct reduction of the imine 7, followed by protonation or reaction with the electrophile, so giving the same intermediate a-amino radical 10. The 1,2-diamine 11 can be formed from the radical 10 by dimerization (and subsequent removal of the electrophile) or addition to the iminium ion 8, followed by one-electron reduction of the so formed aminyl radical. In certain cases/conditions the radical 9 can be further reduced to the carbanion 12, which then attacks the... 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

The 2-azonia analog of the Cope rearrangement is estimated to be accelerated by 106, relative to the unsubstituted system.270 The product of the rearrangement is an isomeric iminium ion, which is a mild electrophile. In synthetic applications, the reaction is often designed to generate this electrophilic site in a position that can lead to a cyclization by reaction with a nucleophilic site. For example, the presence of a 4-hydroxy substituent generates an enol that can react with the iminiun ion intermediate to form a five-membered ring.271... 

Most reactions of alkenyl and allylic silanes require strong carbon electrophiles and Lewis acid catalysts are often involved. The most useful electrophiles from a synthetic standpoint are carbonyl compounds, iminium ions, and electrophilic alkenes. 

Iminium ions are reactive electrophiles toward both alkenyl and allylic silanes. Useful techniques for closing nitrogen-containing rings are based on in situ generation of iminium ions from amines and formaldehyde.121... 

A combination of 2,3 sigmatropic rearrangement (Pummerer-type reaction) followed by an electrophilic aromatic substitution of the intermediate sulfenium ion, the formation of an iminium ion and, finally, a second electrophilic aromatic substitution, was used by Daich and coworkers for the synthesis of iso-indolo-isoquinolinones as 4-314 (Scheme 4.68) [106]. Thus, reaction of the two diastereo-meric sulfoxides 4-313, easily obtainable from 4-312 by a Grignard reaction and oxidation, led to 4-314 as a single product after crystallization in 42% yield. 

Another method of activation we considered was the use of a secondary amine to generate a more electrophilic iminium species, examples of which have been used in vinylsilane-terminated cyclization reactions, particularly by Overman and co-workers [Eq. (4.8)] [51]. In our case, the unsaturated iminium ion would be activated for... 

Alternatively, the ring C/D enlargement-contraction to form the spiroin-dolenine moiety could take place via an electrophilic attack on bisindolenamine 323 to afford the iminium ion 324 or its equivalent carbinolamine 325. Ring closure to hydroxyaziridinium ion 326, followed by C—C fragmentation could... 

Carbinolamines are chemically unstable and, in the case of tertiary amines, dissociate to generate the secondary amine and aldehydes as products or eliminate water to generate the iminium ion. The iminium ion, if formed, can reversibly add water to reform the carbinolamine or add other nucleophiles if present. If the nucleophile happens to be within the same molecule and five or six atoms removed from the electrophilic carbon of the iminium ion, cyclization can occur and form a stable 5- or 6-membered ring system. For example, the 4-imidazolidinone is a major metabolite of lidocaine, which is formed in vivo or can be formed upon isolation of the A -deethyl metabolite of lidocaine if a trace of acetaldehyde happens to be present in the solvent used for extraction (116,118) (Fig. 4.52). 

Now the stereochemistry. Assume the thermodynamically more stable iminium ion forms (Me groups cis). The Cope rearrangement occurs from a chair conformation. This puts the Ph, H2, and HI 1 all pointing up both before and after the rearrangement. Assuming the Mannich reaction occurs without a change in conformation (a reasonable assumption, considering the proximity of the nucleophilic and electrophilic centers), the Ph, H2, and HI 1 should all be cis in the product. 

In Section 10.6 we shall meet the Mannich reaction, where an imine or iminium ion acts as an electrophile for nucleophiles of the enolate anion type. 

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. 

An example of the 7d-type cyclization is that of iminium salt 38b obtained by decarbonylation of a-(ferf-amino) acid 38a. Attack of the nucleophilic malonate on the newly formed electrophilic carbon of the iminium ion gives dicarboxylate 39a (79JOC4173). 

The most usefid electrophiles from a synthetic standpoint are carbonyl compounds, iminium ions, and electrophilic alkenes. 

Section C of Scheme 9.4 give some other examples of cyclization involving iminium ions as electrophiles in reactions with unsaturated silanes. 

Hydrogen bonding to substrates such as carbonyl compounds, imines, etc., results in electrophilic activation toward nucleophilic attack (Scheme 3.1). Thus, hydrogen bonding represents a third mode of electrophihc activation, besides substrate coordination to, for example, a metal-based Lewis acid or iminium ion formation (Scheme 3.1). Typical hydrogen bond donors such as (thio)ureas are therefore often referred to as pseudo-Lewis-acids. ... 

Rate constants have been determined for the reaction of four iminium ions (Me2S=CH2, Pri,N=CH2. Ph(Me)N=CH2, and Mc2N=CHC1) with a range of nucleophiles.44 The results allow calculation of electrophilicity parameters for these ions, helping to predict whether a particular aminomethylation reaction is likely to work. 

In the presence of the TiCLt catalyst, 6-amino-substituted allylsilanes readily react with isobutyraldehyde to yield piperidine derivatives 88 (equation 60)128. Presumably, an iminium ion intermediate is formed and the Boc group is replaced under the reaction conditions. It is noteworthy that the regioselectivity is different when acid chloride in used as the electrophile (cf Section II.B.5). 

---