Aniline derivatives, Mannich reactions

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. 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

Proline and its derivatives also catalyze the classical asymmetric Mannich reaction between aqueous formaldehyde, anilines, and ketones. This was the first successful direct catalytic a-hydroxymethylation of ketones, and the corresponding a-aminomethyl ketones were isolated in excellent yields with up to >99 % ee (Scheme 4) [34]. 

Pyridylethyl derivatives of 2 are formed by reaction of a- or y-vinyl-pyridine with 2.107 Treatment of 1 or 2, as well as the 5-arylidene derivatives, with acrylonitrile in the presence of pyridine results in formation of 84 by cyanoethylation on the ring nitrogen (Scheme 2) however, cyanoethyla-tion of 5-aryl-2-iminothiazolidinones involves the exocyclic nitrogen.108 Aminoalkylation (Mannich reaction) of 2 or 2-aryl-4-thiazolidinones with formaldehyde and amines in warm alcoholic solvents affords the desired 3-alkylated product 85 (Scheme 2),109,110 whereas 3-aryl-2-iminothiazoli-dinones react with substituted anilines and aliphatic amines and formaldehyde to give the 2-arylaminomethyl derivatives 86 [Eq. (25)].111... 

List " suggested that the proline-catalyzed Mannich reaction proceeds in close analogy to the proline-catalyzed aldol reaction. As detailed in Scheme 6.10, the ketone and proline combine to form an enamine. The aldehyde reacts with a primary amine (usually an aniline derivative) giving an imine. The enamine and imine then combine to produce, after hydrolysis, the Mannich product. 

Propose an explanation for the better performance of ortho thiomethyl para methoxy aniline derived imines in the silver phosphine catalyzed vinylogous Mannich reactions of silyloxy furans with aliphatic imines according to Snapper and Hoveyda in contrast to the standard ortho methoxy aniline derived imines (Table 5.2). 

The Mannich reaction involves the condensation of an aldehyde or ketone with an iminium salt usually derived from formaldehyde or other aldehyde and an amine. An example is the use of four acidic ionic liquids in the reaction of benzaldehyde, aniline and acetophenone to give a /S-amino ketone as in Scheme 5.2-114 [259]. 

Acyclic chiral a-amino acids or derivatives are also effleient eatalysts for the asymmetric two- or three-components Mannich reaction. Protected or free 2-hydroxyketones reacted with 16 in the presence of L-tiyptophan, O-protected-L-threonine or L-serine and generally led to the a ft-adduct 17, explained by the formation of a (Z)-enamine stabilised by an intramolecular hydrogen bond (Scheme 12.5). Threonine surfactant 14 was equally effective for the three-component reaction with hydro gracetone, benzalde-hyde derivatives and anilines. ... 

Yao et al. [92] reported one-pot synthesis of flavanone 64 via Mannich type reaction catalyzed by molecular iodine. A simple workup and the high compatibihty of functional groups made this an attractive synthetic approach to access flavanone derivatives (Scheme 10.46). The three-component Mannich reaction of aldehyde, amine, and enolizable ketone to obtain the P-aminocaibottyl compounds has been known, bnt when the Mannich reaction of benzaldehyde, aniline, and 2-hydroxyacetophenone had been explored in the presence of iodine, no trace of p-aminocaiboi l compound is observed and flavanone was formed as the sole product in moderate yield. 

A general bismuth-triflate-catalyzed direct-type Mannich reaction of cyclohexanone with imines derived from various benzaldehydes and anilines was reported. P-Aminocarbonyl compounds are obtained efficiently in the presence of 5 mol%... 

Considering the water tolerance of lanthanide Lewis acids, a logical extension of the above-mentioned three-component coupling reaction is the reaction in aqueous media. Kobayashi et al. reported Mannich-type reaction of aldehydes, aniline derivative, and methyl enol ethers with 10mol% of Yb(OTf)3 in THF/H2O solvent system (Table 13.4) [8]. Applicability of commercially available aqueous formaldehyde and chloroacetaldehyde solution is of particular importance from the synthetic point of view (entries 1-3). A wide variety of aldehydes were transformed... 

The successful use of the silver complex formed from an iso-leucine-derived phosphine (L2 in Scheme 11.4) as catalyst for the multicomponent Mannich reaction of silyl enol ethers 10 with in situ formed aliphatic imines allowed its application in the enantioselective synthesis of the alkaloid sedamine (56% yield, 98% ee) [17]. Also cyclic and acyclic alkenyl trichloroacetates (10, Z = EtOCO) can be used in the reaction with ethyl glyoxylate and diverse aniline derivatives 11 catalyzed by... 

The ion pair [emim][Pro] efficiently catalyzed multicomponent reactions of carbonyl compounds. In the presence of this catalyst a three-component Mannich reaction of ketones with aniline derivatives and aromatic aldehydes in moist DM SO or DMF was highly regio-, stereo-, and enantioselective to give sy dipolar aprotic solvents, did not, however, allow post-reaction IL recovery. 

Several examples of Bi(OTf)3-catalyzed Mannich-type reactions with various silyl enol ethers are summarized in Table 12. Silyl enol ethers derived from aromatic and aliphatic ketones were reacted with an equimolar mixture of aldehyde and aniline (Scheme 10). The corresponding (3-amino ketones 27 were obtained in good yields (Table 12, entries 1M-) from aromatic-derived silyl enol ethers, except for the more hindered isobutyrophenone derivative. Silyl enol ethers derived from cyclopentanone or cyclohexanone afforded the (3-amino ketones in good yields (Table 12, entries 5 and 6). 

The quinone methide (11) derived from flavan by a retro-Diels-Alder reaction gives only a 4% yield of acridine when heated with aniline. However, the other products include the diphenylmethane (12) and the Mannich base (13) both of which yield the tricyclic compound upon pyrolysis (J.L. Asherson. 0. Bilgic and D.W. Young, J. chem. Soc. Perkin I, 1980, 522). 

Synthetically important chiral 1-monosubstituted 1,3-diamines (145) are synthesized in Mannich-t)fpe reactions of enecarbamates (140) with aromatic and aliphatic hemiaminal ethers (141) in the presence of phosphoric acid 95a. This process involves the highly reactive Mannich-t)fpe product (144), which is entrapped by a methanol molecule generated during the formation of the imine (143) derived from the hemiaminal ether (141) (Scheme 28.15) [72]. Similarly, diastereo- and enantio-enriched anti-l,2-disubstituted 1,3-diamines are prepared by the Mannich-type reaction of aldehydes, anilines, and enecarbamates in the presence of chiral phosphoric acid [73]. 

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