Iminium salts, addition ketones

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. 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

The reaction from an enamine is initiated by the addition of a trace of a strong acid, e.g. /7-toluenesulfonic acid (TsOH, 4-methylbenzene-sulfonic acid), to the ketone and pyrrolidine in a solvent such as toluene. When the mixture is at reflux in a Dean-Stark apparatus, water is liberated and is removed through azeotropic distillation, leaving the enamine in the reaction vessel. After a follow-up reaction between the enamine and a suitable electrophile, an iminium salt is produced that liberates both the a-substituted ketone and pyrrolidine when it is treated with aqueous acid (Scheme 6.20). 

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. 

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. 

The reaction was shown to be triggered by protonation of the ketone and reduction to 139. Cyclisation of the carbon centred radical to the pyridinium ring next produced radical cation 140. Addition of a second electron then gave enamine 141, which underwent reversible protonation to iminium salt 138. Further cathodic reduction completes the sequence (Scheme 38). Interestingly, such cyclisations appear to be reversible as the product mixtures attained better reflect a reaction under thermodynamic control than one under kinetic control <03EJO2919>. 

Resolving Agent. Scalemic CSA has been used to resolve amines by forming diastereomeric salts which can be separated by fractional crystallization (eq 11). In this instance, after obtaining the desired crystalline diastereomeric salt, the undesired diastereomer was completely transformed into the desired one by a resolution-racemization procedure (eq 12). Additionally, racemic ketones can be resolved by forming enantiomeric iminium salts (eq 13). Two different procedures have been devised depending on the ease of enamine formation. 

Preformed iminium salts have been used extensively in organic synthesis. The facility of the condensation is a function of iminium salt substitution. Treatment of formaldehyde-derived methyl(methylene)ammonium halides (or trifluoroacetates) (46) with Grignard and lithium reagents results in the high yield formation of dimethylaminomethyl-containing compounds (47). Subsequent oxidation or alkylation of these products has been employed to generate terminal alkenes (48 Scheme 7). As expected, addition yields are modest for the mote-hindered iminium salts derived frrom other aldehydes and are somewhat lower for those derived from cyclic ketones. ... 

A later report of the total synthesis of ( -methylpallidinine (106) involved construction of the morphinan nucleus by addition of diazomethane to an iminium salt. The requisite iminium salt 104 was synthesized from the ketone 103 as shown in Scheme 20. When the iminium salt 104 was treated with diazomethane, the morphinan 105 was directly formed in 30% yield along with the aziridinium ion. In Evans s morphine synthesis, a morphinan product was produced directly in 30% yield from reaction of diazomethane... 

In analogy to the synthesis of iminium salts (Section 4.2.2.1.), acyiiminium ions (60) can be obtained from carbonyl precursors (1), such as ketones or aldehydes, and carboxylic acid amides (62 Scheme 30). In addition, other amides can be used, such as p-toluenesulfonamides, which lead to the corresponding N-tosylated iminium salts. ... 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

The anions (67c)-((i7e) are prepared by the low temperature transmetallation reactions of n-butylli-thium with the corresponding allylic tin or lead compounds. The addition of (67d) to aldehydes and ketones proceeds with C—C bond formation at either terminus. Dialkyl ketones give the a-products, while benzaldehydes and benzophenone afford the y-products. Aliphatic aldehydes, acetophenone and substituted acetophenones give both types of products. The anion (67e) is not stable in solution even at -95 °C and cannot be preformed prior to its reaction with the desired substrate (67e) may be generated by Li-Br exchange between n-butyllithium and 3,3-difluoro-3-bromopropene at -95 C. ) en this preparation is performed in the presence of chlorosilanes, aldehydes, ketones, and esters, the a-products are obtained, often in good yields (Scheme 46). Reactions of (67c) with TMS-Cl and benzaldehyde afford y-adducts, whereas those with methyl iodide, acetophenone and pentanal produce a-adducts predomi-nantly. ° Anions (67a) and (67b) give a-alkylation products wiA aliphatic halides and TMS-Cl, but afford y-adducts with iminium salts. ... 

Reactions of free ketones with imines are far more restricted than those with preformed iminium salts. Examples of ketone-imine condensations are included in several reviews - and are limited to the use of arylimines, mainly benzylideneaniline. Blatt and Gross have noted that the reproducibility of uncatalyzed additions of ketones to Schiff bases is poor but can be improved by the addition of small amounts of hydrochloric acid. The highest yields of 3-amino ketones are obtained using 10 mol % of concentrated hydrochloric acid and 95% ethanol as solvent, and by performing the reaction at room temperature. The reaction, however, is of limited applicability, as it is restricted to methyl ketones and cycloalkanones. Deamination leading to unsaturated ketones is a major side reaction. In addition to hydrochloric acid, boron trifluoride etherate has been used as a catalyst in reactions of aromatic imines with methyl ketones, cyclic ketones and an epoxy ketone. ... 

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