Aldehydes electrophilic amination

The reaction of 2-chloro-4,5-dihydroimidazole 347 with hydroxylamine-O-sulfonic acid gives 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 348, which reacts with aldehydes and cyclic ketones to give the imidazo[l,2-f] fused 4,5-dihydro-l,2,4-oxadiazoles 350 (Scheme 58). Mechanistically, the reaction may be explained by the reaction of an imidazoline NH with the carbonyl followed by intramolecular electrophilic amination of the anionic oxygen present in the resultant intermediate 349 and elimination of the sulfate group <2003JOC4791>. 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

We have an aldehyde, an amine, and a ketone. As in part (b), the amine reacts first to give an imine, and this behaves as a carbonyl analogue, which in the Mannich reaction is then the electrophile for an enolate anion equivalent. How can we remember the sequence of events The most common mistake is to react the aldehyde and ketone via an aldol reaction, but this then leads to an alcohol and one is faced with a substitution reaction to incorporate the amine. It is the mild acidic conditions that help us to avoid wrong... 

In addition to alkylation with alkyl halides, electrophilic amination has been achieved with di-(/< /r-butyl) azodi-carboxylate <2004HCA1016>, and reactions with aldehydes have generated alcohol derivatives <1999JOC8668, 2003TL671>. Dialkylation at the 5-position has also been achieved <1998TA3881>. 

A substantial acceleration of the Baylis-Hillman reaction has been observed when the reaction was conducted in water [19, 20]. Several different amine catalysts were tested by Aggarwal and coworkers, and as with reactions conducted in the absence of solvent, 3-hydroxyquinudidine was found to be the optimum catalyst in terms of rate [19]. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration. 

Azo-ene reactions. The ene reaction provides a powerful method for C-C bond formation with concomitant activation of an allylic C-H bond. A variety of functionalized carbon skeletons can be constructed due to the range of enophiles which can be used. For example, carbonyl compounds give homoallylic alcohols and imino derivatives of aldehydes afford homoallylic amines. The azo-ene reaction offers a method for effecting allylic amination by treatment of an alkene with an azo-diester to afford a diacyl hydrazine which upon N-N cleavage furnishes a carbamate. Subsequent hydrolysis of the carbamate provides an allylic amine. Use of chiral diazenedicarboxylates provides a method for effecting stereoselective electrophilic amination. 

Electrophilic aminations with 0-substituted hydroxylamines H2NOAr and H2NOCOAr (Ar = mesityl or dinitromesityl) have been reviewed . Numerous heterocycles have been transformed by the mesityl derivative 79 into the salts 80 and tatiary amines into 81. The action of 0-(2,4-dinitrophenyl)hydroxylamine 82 [Ar = 2,4-(02N)2C6H3] on aldehydes RCHO (R = CsHis, Ph, 4-MeOC6H4 and 4-O2NC6H4) results in oximes, which form nitriles under basic conditions . 

Finally, there is also a relevant example of an intermolecular conjugate Friedel-Crafts/electrophilic amination cascade developed very recently by Melchiorre in which 2-methyl-IH-indole reacted with a variety of a,p-unsatu-rated aldehydes and dialkyl azodicarboxylates in the presence of a primary amine catalyst, leading to the formation of a family of products containing two contiguous stereocenters, one of them a quaternary one (Scheme 7.43). This reaction started with the conjugate addition of 2-methyl-lH-indole to the enal... 

Scheme 7.43 Cascade conjugate Friedel-Crafts/electrophilic amination using a,P-disubstituted aldehydes.

Although detailed mechanistic studies on the Betti reaction have not been carried out, it is widely assumed the reaction follows a similar course to the Mannich reaction. This principally involves the condensation of the aldehyde and amine constituents to form the active iminium electrophile 7. 2-Naphthol (1) functions as a nucleophile, giving the intermediate represented by the resonance structures 8 and 9, which subsequently loses a proton to yield the product. It is easy to appreciate from this mechanism why acid catalysis may facilitate the reaction, and indeed increased rates have been observed using such catalysis. ... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

In 2011, Moreau, Greek and coworkers reported a multicatalytic process [6] merging two consecutive enamine catalytic cycles based on a Michael addition/a-amination cascade reaction [7]. The Michael addition of aldehydes to p-nitrostyrene followed by the electrophilic amination were catalyzed, respectively, by the diphenylprolinol silylether 5 and the 9-amino-(9-deoxy)-cpf-cinchonine 6 (Scheme 12.4), both previously described by Hayashi and coworkers [8] and Melchiorre and coworkers [9]. One interesting feature of this reaction is that diphenylprolinol silylether 5 can specifically catalyze the Michael addition, while 9-amino-(9-deoxy)-ep/-cinchonine 6 is required to promote the electrophilic amination. The Michael addition of propionaldehyde to p-nitrostyrene was achieved by using only 5 mol% of catalyst 5 in chloroform at 0 C. After completion of the reaction, dibenzyl azodicarboxylate (DEAD, 1.5 equiv), trifluoroacetic acid (15 mol%) and the second catalyst 6 (5 mol%) were added. The expected product 7 was obtained as a single diastereomer in good yield (80%) and with excellent enantioselectivity (ee 96%). Various nitroalkenes bearing electron-rich and electron-deficient aryl... 

Silylated cyanhydrins are themselves useful reagents which can undergo deprotonation to provide acyl anion equivalents. Electrophilic amination of these anions provides, after hydrolysis, amides, in a reaction that corresponds to an overall specific oxidation of aldehydes to amides. ... 

Many structures included an aromatic subunit. At the time, synthetic aromatic chemistry was at its height and electrophilic aromatic substitution reactions (SE-reac-tions) such as Friedel-Crafts alkylations [37] and acylations [38], nitrations [39] and diazotisations [40] were effectively used. Vorlander and others centred most procedures for the elongation of rod-like structures on carbonyl-reactions. It must be noted, however, that the scope of most of these reactions had not been realized until the late 1940s. Typical preparations of imines/anils (azines) [41] via aldehyde/ketone-amine/ aniline (hydrazine) condensations have remained standard synthetic methods of today [42] (Scheme 3). 

It is possible to use the enhanced electrophilicity in condensation reactions with aldehydes in the presence of amines to form imidazoles [77] (equation 16). 

The reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1 ... 

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