Direct Mannich reaction

Terada et al. found the direct Mannich reaction between iV-Boc-protected aldi-mines 11 and acetyl acetone (12) to be catalyzed by different phosphoric acids 3 (Scheme 6). Varying the aromatic groups at the 3,3 -positions influenced the yields slightly (88-99%), but the enantioselectivities to a high degree (12-95% ee). 

Later in 2007, Gong utilized If and saturated derivative 2 in a direct Mannich reaction between in situ generated N-aryl imines and cyclic ketones as well aromatic ketones (Scheme 5.3) [10], It was found that electron poor anilines as coupling partners gave the highest enantioselectivities. The authors postulate that acid promoted enolization of the ketone forms the reactive enol which adds to the protonated aldimine. 

Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2 with a-imino ester 79 was achieved with high enantioselectivity by the utilization of N-spiro chiral quaternary ammonium bromide le as catalyst (Table 5.14) [42],... 

Direct Mannich reactions of cyclic 1,3-dicarbonyls with acyl imines, R1-CH=N-CO2R2, gives o -quaternary-carbon-bearing products (9 X = CH2, O Y = Me, OMe, OEt) with yieldIdelee up to 98/90/99%, using cinchona alkaloid catalysts 25 ... 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

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-... 

Enantioselective Direct Mannich Reaction Products with One Stereogenic Center... 

The phase-transfer-catalyzed direct Mannich reaction of 28 with a-imino ester 64 was achieved with high enantioselectivity by using 32e as catalyst (Scheme 4.23) [63]. This method enables the catalytic asymmetric synthesis of differentially protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the util-... 

Table 6.19 Chiral phosphoric acid-catalyzed direct Mannich reactions of aldimines.

General Procedure for Direct Mannich Reaction of Aldehydes and Preformed Imines [10] (p. 39)... 

Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vignola N, List B (2004) Catalytic asymmetric intramolecular alpha-alkylation of aldehydes. J Am Chem Soc 126 450-451... 

Brpnsted Acid Catalyzed Direct Mannich Reaction. 236... 

Although in many cases products 256 can be directly prepared by Mannich synthesis, the replacement reaction is particularly convenient (l)in the case of primary amines, as it yields a secondary amine derivative hardly obtainable through other synthetic routes, and (2) in the case of arylamincs, as it makes it possible to avoid engaging an activated, reactive, aryl group in the direct Mannich reaction. Moreover, the method is frequently adopted in the synthesis of polymeric substances (Chap. III). 

SCHEME 10.53 A syn approach between the si faces of the prochiral components of the sugar-directed Mannich reaction is preferred. 

Juhl, K., Gathergood, N., Jorgensen, K. A. Catalytic asymmetric direct Mannich reactions of carbonyl compounds with a-imino esters. Angew. Chem., tnt. Ed. Engt. 2001,40, 2995-2997. 

Scheme 11.22 Direct Mannich reaction with N-fert-butoxycarbonyl imines.

Figure 3.2 Assumed mechanism of enantioselective direct Mannich reaction catalyzed by chiral phosphoric acid.

Scheme 3.2 Enantioselective direct Mannich reaction of various imines.

Scheme 3.5 Three component direct Mannich reaction.

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

Terada and co-workers reported the direct Mannich reaction of 1,3-pentanedione with N-Boc-aldimines catalyzed by 21c, leading to (3-amino ketones with excellent enantioselectivities (Equation 10.36) [75]. 

Ishihara et al. used the chiral sulfonic acid 98 in the direct Mannich reaction of A-Cbz-protected phenylaldimines lOOa-d and acetylacetone (Scheme 5.42) [58]. 

The classic direct Mannich reaction discovered in 1912 [192a] is an aminoalkylation of carbonylic compounds involving ammonia (or a primary or secondary amine derivative), a non-enolizable aldehyde (usually formaldehyde) or a ketone, and an enolizable carbonyl compound, leading to P-aminocarbonyl derivatives [192b-e]. The indirect version of the Mannich reaction is the corresponding two-component reaction of a preformed iminium salt [193] and an enolizable carbonyl compound. 

---