Iminium salts preformed

With an unsymmetrical ketone as CH-acidic substrate, two regioisomeric products can be formed. A regioselective reaction may in such cases be achieved by employing a preformed iminium salt instead of formaldehyde and ammonia. An iminium salt reagent—the Eschenmoser salt—has also found application in Mannich reactions. ... 

The addition of electron-rich enamines2-5 to preformed imines and imine derivatives so far has scarcely been investigated6 -15 compared to the addition of enolatcs (see Section 1.4.3., refs 16 and 17 and literature cited therein). Most of the known examples refer to iminium salts because they are more reactive than the corresponding iinines due to their highly polarized C-N double bond (see Section 1.4.1.6., ref 16 and literature cited therein). 

Similarly, in 5.0m LP-DE, preformed TFA-iminium salt 37 gave a 1 1 mixture of 34 and 35. In contrast, heating 37 in water alone gave the cycloadduct 36 in 55% yield. 

Primary amino methylene substituents were introduced by a sequence of cya-nodehalogenation and subsequent reduction of the resulting nitrile with borane dimethyl sulfide. To incorporate tertiary aminomethylene substituents into the 2-pyri-done framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. 

Although the use of cyclic enals improved the overall product distribution by suppressing the 1,4-addition pathway,33 34 a general solution remained elusive. To solve the competing reaction pathway problem or to improve the pathway that would ultimately lead to the 2H-pyran 33 involved extensive experimental modifications. Our solution eventually involved the utilization of preformed a,P-unsaturated iminium salts instead of generating them in situ.35-38... 

The usage of a,P-unsaturated iminium salts clearly represents a general and efficient solution leading to 2//-pyranyl products exclusively via the C-1,2-addition pathway. The reaction of the pyrone 22 led to the pyran product 23 in a much-improved yield relative to Moreno-Manas s study, and also gave previously unknown products 30b and 30c under these reaction conditions [Scheme 5]. The significance of using preformed a,P-unsaturated iminium salts to control regioselectivity of this formal cycloaddition reaction was recently validated in an account reported by Cravotto.39... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

A second route involves preforming first the allylic halide addition to form the iminium salt arising from the alkylation on the highly nucleophic sulfur atom. Subsequent treatment with triethylamine provided the S-allyl thioimidoester which was usually not observed but underwent a deprotonation and a fast [3,3] sigmatropic transposition to give the a-allyl thioamide. With pyroglutamate derivatives no diastereoselectivity was found. An analogous sequence [197] was used with a thioacyl proline derivative, with some stereoselectivity. 

The above additions to activated imines presumably involve iminium salt/complex intermediates. Addition to preformed iminium salts can also be effective, as in the examples given here. 

Reduction of Preformed Imines and Iminium Salts of Ammonia, Primary and Secondary Amirtes... 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

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. ... 

Preformed Iminium Salts Iminium Salts Generated In Situ... 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

The mechanism of the Petasis boronic acid-Mannich reaction is not fully understood. In the first step of the reaction, upon mixing the carbonyl and the amine components, three possible products can form iminium salt A, diamine B, and a-hydroxy amine C. It was shown that preformed iminium salts do not react with boronic acids. This observation suggests that the reaction does not go through intermediate A. Both intermediate B and C can promote the formation of the product. Most likely, the reaction proceeds through intermediate C, where the hydroxyl group attacks the electrophilic boron leading to an ate -complex. Subsequent vinyl transfer provides the allylic amine along with the boronic acid sideproduct. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of /3-amino ketones. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have been developed [18]. These materials however, are often hy-... 

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. ... 

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