Enamines with iminium ions

The reaction of enamines with iminium ions provides access to substituted j3 amino aldehydes and ketones (Scheme 61). In a similar manner the Mannich reaction gives access to oc,) -unsaturated aldehydes or -amino ketones (Scheme 62). Enamines undergo the Vilsmeier reaction to give a-formyl ketones Solvolysis of the Vilsmeier salt with aqueous or alcoholic sodium hydrogen sulphide produces an enamino thioaldehyde. The use of A-dichloromethylene-A,A -dimethylammonium chloride gives tertiary /5-ketoamides (Scheme 63). Iminoalkylation of enamines with nitrilium salts provides access to enamino ketones and j3-diketones (Scheme 64). 

Here is an example, which picks up where we left off a catalytic enantioselective conjugate addition. As you know from Chapter 11, aldehydes and ketones react with secondary amines to form enamines, via iminium ions. But this unsaturated aldehyde can t form an enamine because the iminium ion that is generated by condensation with the cyclic secondary amine... 

Enders also developed, a so-called branehed domino reaetion. In this case a nitroalkene was combined with two equivalents of an aldehyde, catalyst and an oxidant. The most effective oxidation agent IBX oxidised enamine to iminium ion, which served as an acceptor in the last part of the cascade. In this way, cyclohexene derivatives were assembled in good yield and with high diastereomeric and enantiomeric purities (Scheme 8.19). 

The reason the ehemical community overlooked organocatalysis is complex and difficult to state. This burgeoning field is associated with many transient chemical characteristics that include the modes of catalysis (enamine and iminium ion catalysis)/ atypical reactivity and various transformations. 

Notably, stereochemical outcomes of both reaction sequences depicted in Scheme 4.42 and Scheme 4.43 were in accordance with other aminocatalytic reactions catalyzed by 165 where electrophilic or nucleophilic reagent approaches the corresponding enamine or iminium ion intermediates from the side opposite to the bulky substituent present on the C-2 carbon atom of the catalysts 165 [75]. 

Diamination was first reported in 2007 by Jprgensen and coworkers with a combination of enamine and iminium-ion activation modes catalyzed by the diaryl prolinol silyl ether 3 (10 mol%) [18]. The sequential addition of succinimide as the nucleophile and diethyl azodicarboxylate as the electrophile afforded the syn-diaminated products 32 and 33 in promising overall yield (40%) with high levels of stereoselectivities (dr up to 8/2, ee 99%) (Scheme 12.14). 

The ability of the diarylprolinol catalysts to participate in both enamine- and iminium-ion achvations makes them ideal for the sequential addition of nucleophiles and electrophiles through cascade catalysis (Scheme 2.8). Conjugate addition of a nucleophile to the iminium ion forms a transient enamine intermediate 3, which can effectively react with an electrophile in the a-position, forming an a,P-disubstituted adduct. This process commonly proceeds to afford the products in good yields and with high enantio- and diastereoselectivities. If the nucleophile and electrophile are part of the same molecule, cyclic products are obtained. The cascade concept has been widely explored and some illustrative examples are given below [13, 17]. 

Figure 6.14 Simplified scheme for enamine and iminium ion catalysis with C9 amino cinchona alkaloid derivatives.

In terms of enamine and iminium ion catalysis, an intramolecular cascade conjugate addition/Mannich reaction was shown to be effectively catalyzed by 36 [108]. The reaction involves the construction of a tetracycUc structure from the indoyl methyl enone shown in Scheme 6.53. The highest enantioselectivities were obtained with addition of nitrobenzoic acid and with ethyl acetate as the solvent... 

Discussions hitherto have been on the energetic details of various modes of substrate activation leading to vital intermediates such as enamines and iminium ions. Once such reactive species are generated, the next important event in the reaction sequence is the new bond formation. The following section provides highlights of the bond-forming process, with particular emphasis on stereoselectivity issues. 

Cascade reactions triggered by the combination of chiral amines and achiral Brpnsted acid were well documented on the basis of enamine and iminium ion formation, while examples with the combination of a chiral amine catalyst and a chiral Brpnsted acid were rare, hi 2(X)7, Zhou and List reported an elegant cascade intramolecular aldol-reduction process to prepare chiral 3-substituted cyclohexyl-amines by combining achiral enamine catalysis and chiral phosphoric acid catalysis [38]. Unusually, achiral aryl primary amine was exploited as an amino catalyst to generate a transient enamine intermediate to facilitate an intramolecular aldolization-dehydration process, while chiral phosphoric acid was harnessed to accelerate the following conjugate reduction-reductive amination cascade. Starting from readily available 2,6-diketones and aryl amines, pharmaceutically relevant 3-substituted cyclohexyamine derivatives were readily produced in satisfactory yield and excellent enantioselectivity (Scheme 9.42). 

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. 

The reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

Azides have been shown to react with itniniutn salts to give addition products. The same product is obtained if the iminium salt is treated with azide ion or if the enamine is treated with hydrazoic acid 14). The yields of the products were all very high (85-95 %). The interest in this reaction centers on the fact that the azides react with isonitriles to give substituted tetrazoles (83) 44). 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

Mechanism of enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate has no hydrogen attached to N and so must lose H+ from the carbon two atoms away. 

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