One-pot Mannich reaction

In addition to the ionic liquid-mediated procedure in solution (see Scheme 6.112), Leadbeater and coworkers also presented a solid-phase protocol for a one-pot Mannich reaction employing the above mentioned chlorotrityl linker [67]. In this approach, p-chlorobenzaldehyde and phenylacetylene were condensed with readily prepared immobilized piperazines (Scheme 7.56). 

Scheme 7.56 One-pot Mannich reaction utilizing polymer-supported piperazine.

Under the reaction conditions used in the one-pot Mannich reaction described above, L-proline (S)-27 was clearly found to be the preferred organocatalyst. As is apparent from Scheme 5.14, the best yield (90%) and enantioselectivity (93% ee) were obtained by use of this organocatalyst [23]. The suitability of all other organo-catalysts used in this one-pot reaction, using 3-methylbutanal as aldehyde, was poor. Remarkably lower yields and poor enantioselectivity were obtained when the thiazolidine catalyst (S)-31 and other pyrrolidine-based organocatalysts were used. 

Zheng X, Qian YB, Wang Y (2010) 2-Pytrotidinecarboxyhc add ionic liquid as a highly efficient organocatalyst for the asymmetric one-pot Mannich reaction. Eur J Org Chem 515-522... 

Synthesis of faceted Cu nanoparticles and their use as catalysts in C-N coupling reactions (including the three-component, one-pot Mannich reaction) with high selectivity for the desired products was recently reported by Wang et al. [263]. 

TABLE 11.1 Synthesis of spiroheterocycles via the one-pot Mannich reaction of ketone, amine, and formaldehyde... 

In our discussion, many calixarens have been mentioned in number of chemical reactions as catalyst, however out of these, quaternary ammonium-terminated calixarenes calix[4]arene 4 and calix[6]arene 2 catalysts were used in one-pot Mannich reaction of benzaldehyde, acetophenone and aniline in aqueous media to produce p-aminocarbonyl compounds (see Fig. 27.7) [19]. These calix[n]arene catalysts emphasized not only the high catalytic activity but also have an outstanding reusability with high yield, at low loading amoxmt. Advantages of that were, short reaction times, high yields, and easy work-up that make them great candidate for Mannich-type reactions (see Table 27.5). 

In 2013, Mamoka and coworkers published a one-pot cross double Mannich reaction of acetaldehyde catalyzed by a binaphthyl-based aminosulfonamide [4]. The functionalized diamines were obtained as a single stereoisomer in moderate yields (45-57%) with excellent enantioselectivity (99%). The procedure was also extended to other electrophiles such as nitrosobenzene. Two examples of a one-pot Mannich reaction-aminoxylation were described, and the yn-p-amino-a-hydroxyaldehydes were obtained with excellent stereoselectivity (dr > 20 1, ee 99%). These reactions were performed by using a large excess of acetaldehyde to produce the single Mannich adduct, and the excess amount of acetaldehyde was removed by evaporation before the addition of the second electrophile. This operational procedure lowers the synthetic appeal of this strategy, and, as a result, it is in the limit of the field of MBFTs. 

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

Scheme 2.18 One-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions.

Cordova, A., Barbas, C. E. Direct organocatalytic asymmetric Mannich-type reactions in aqueous media one-pot Mannich-allylation reactions. Tetrahedron Lett. 2003,44,1923-1926. 

Several procedures for a one-pot Mannich-type reaction in water to give (3-amino carbonyl compounds catalyzed by either Lewis acid or Bronsted acid with or without addition of surfactants have been developed. The reactions are high yielding however, the diastereoselectivities are moderate. The HBF4-catalyzed reaction between aldimines and ketene silyl acetals in a water/SDS mixture provides high stereoselectivity with very good yields (Scheme 5.19). 

Gong K, Dong F, Wang HL, Liu ZL (2007) Basic functionalized ionic liquid catalyzed one-pot Mannich-type reaction three component synthesis of P-amino carbonyl compounds. Monatsh fur Chemie 138 1195-1198... 

Both 208 and 209 [l,4,2]-benzoxazaphosphinanes are accessible by a one-pot Mannich-type reaction, with slow addition of -propyl- or... 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Keywords Indoles, aldehydes, secondary amines, L-Proline, solvent-free, room temperature, one-pot multicomponent reaction, Mannich-type reaction, 3-amino alkylated indoles... 

Loh and coworkers reported a one-pot Mannich-type reaction between aldehydes, aromatic amines, and silyl enol ethers in water in the presence of 20 mol% indium trichloride, giving the corresponding j8-aminoketones in 30-94% yields. - The use of glyoxylic acid monohydrate directly afforded the -amino adds. However, reactions using prochiral silyl enol ethers gave very low diastereoselectivities, the syn product being the major isomer. The catalyst could be recovered after completion of the reaction and reused for another reaction without any significant drop in activity. 

Loh, T.-R and Wei, L. L., Novel one-pot Mannich-type reaction in water indium trichloride-catalyzed condensation of aldehydes, amines and silyl enol ethers for the synthesis of amino ketones and esters. Tetrahedron Lett., 1998, 39,323-326. 

Dondoni, A., Massi, A., Sabbatini, S. (2005). Multiple component approaches to C-glycosyl p-amino acids by complementary one-pot Mannich-type and Reformatsky-type reactions. Chemistry - A European Journal, 11,7110-7125. 

In 2010, Monge et al. reported a one-pot tandem reaction by combining bifunctional thiourea and Au complex [77], affording dihydropynole derivatives in moderate yields and high enantioselectivities. The reaction was based on a bifunctional thiourea-catalyzed Mannich-type reaction and a subsequent Au-catalyzed alkyne hydroamination and isomerization of propargylated malononitrile and N-Boc-protected imines (Scheme 9.72). Notably, acidic additive proved cracial to prevent deactivation of the gold catalyst and enhance the reactivity and selectivity. 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

Cordova has also shown hydrogen peroxide to be an effective oxidant in the epoxidation of a,P-unsatnrated aldehydes using diarylprolinol ether 30 as the catalyst (Fig. 9) [146, 147], Within these reports it was also shown that the resulting epoxy aldehydes could be used directly in either Wittig or Mannich reactions, providing synthetically useful one-pot protocols to prepare densely functionalised building blocks for further elaboration. 

---