Mannich allylation

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

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. 

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

The Mannich reaction must be used to make (43). Allylic bromide (45) can be made from alcohol (46) by the strategy shown,... 

It has also been shown that dimethylsilyl enolates can be activated by diisopropylamine and water and exhibit a high reactivity toward iV-tosyl imines to give Mannich-type reaction products in the absence of a Fewis acid or a Bronsted acid.51 For example, the reaction of [(1-cyclohexen-l-yl)oxy]dimethylsilane with 4-methyl-A -(phenylmethylene)benzene sulfonamide gave re/-4-methyl-N- (f )-[(15)-(2-oxocyclohexyl)phenyl-methyl] benzenesulfonamide (anti-isomer) in 91% yield stereoselectively (99 1 anti syn) (Eq. 11.30). On the other hand, Fi and co-workers reported a ruthenium-catalyzed tandem olefin migration/aldol and Mannich-type reactions by reacting allyl alcohol and imine in protic solvents.52... 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

In asymmetric reactions, chiral phosphine ligands such as BINAP derivatives are used as effective chiral ligands in silver complexes. In particular, an Agr-BINAP complex activates aldehydes and imines effectively and asymmetric allylations,220-222 aldol reactions 223 and Mannich-type reactions224 proceed in high yield with high selectivity (Scheme 51). 

Recently, ruthenium-catalyzed tandem olefin migration/aldol-type or Mannich-type reactions have been developed with aldehydes or imines and allylic alcohols (Scheme 74). 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Rearrangement of allylic acetals. 3-Acetylpyrrolidines can be obtained in good yield by an acid-catalyzed rearrangement of 5-methyl-5-vinyloxazolidines. The rearrangement involves an aza-Cope rearrangement followed by Mannich cycli-zation (equation I).1... 

Furthermore, the use of a Lewis acid promoter leads to increased stereoselectivities (Table 19, entry C)252,254. Compared to the aprotic reaction, where allyl silane was used instead of allyl bromide and indium chloride, an almost complete reversal of the diastereos-electivity was found. It was demonstrated recently that the Lewis acid catalysed allylation reaction can be carried out efficiently without any organic solvent in saturated ammonium chloride solution255. Finally, Lewis acid catalysed Mannich reactions can be carried out conveniently in mixtures of organic solvents and water. However, the exact role of the Lewis acid catalyst has not been clarified (Table 19, entry D)253. The same reaction can be carried out in pure water with catalysis by indium trichloride256. 

Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction. 

Organoaluminum-promoted Beckmann rearrangement/methylation of cyclohexanone oxime mesylate, followed by allylation of ketimine 40a and Mannich cyclization of the intermediate iminium-allylsilane, provides piperidine 40b possessing cxo-unsaturation (08BKC1669). 

In parallel to the bismuth(III)-catalyzed three-component allylation reaction, we have reported the corresponding three-component bismuth(III)-catalyzed Mannich-type reaction. A major merit of the three-component reaction is indeed that many unique structures can be afforded rapidly when three or more reactants are combined in a single step to afford new compounds. The development of an efficient bismuth-catalyzed Mannich-type three-component reaction that combines an aldehyde, an amine, and a silyl enolate to give compounds with a (3-amino carbonyl core... 

Albert S.C. Chun of the Hong Kong Polytechnic University reports (J. Org. Chem. 68 1589, 2003) two important transformations. The three-component (Mannich) condensation of 10 with 11 and 12 proceeds with high diastereoselectivity, to give the amino alcohol 13. Hydroboration of the alkyne 14 followed by transmetalation of the intermediate vinyl borane gives a zinc species, which under catalysis by the easily-prepared 3-naphthol 13 adds to aromatic and branched aldehydes with high . The product allylic alcohols are useful intermediates for organic synthesis. 

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

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