Benzaldehyde Mannich reaction

Diethyl dl-1 -aminobenzylphosphonate has been prepared by a Mannich reaction of diethyl phosphite, benzaldehyde, and ammonia, resolved as its D-mandelate salt, and hydrolysed to give (+)-l-aminobenzylphosphonic acid.27 While the tetraethyl-diamide (33) reacts with benzaldehyde to give the expected phosphonic diamide (34), the corresponding tetramethyl-diamide reacts, with migration of the dimethyl-amino-group, to give (35).28... 

Keywords /i-naplithol, benzaldehyde, piperidine, Mannich reaction, acidic alumina, aminoalkylation, microwave irradiation... 

Instead of following the procedure described in Scheme 35, 1,4-benzothiazepine 206 can also be formed by the Mannich reaction of 2-benzoylmethylthio-4,5-dimethoxybenzoylamine hydrochloride 209 with benzaldehyde in the presence of NaOH in methanol. A good yield is observed for the diastereoisomers 92a and 92b in a ratio of 6 5 (Scheme 36) <1995TL753>. 

S)-Proline also catalyzed Mannich reactions in a three-component (donor aldehyde, 4-methoxyaniline, arylaldehyde) protocol - that is, without preformation of imine (Table 2.14) [71b, 82]. (For experimental details see Chapter 14.2.2). This three-component format also afforded the syn-Mannich products in good yields with high diastereoselectivity and enantioselectivities when slow addition of donor aldehyde and/or formation of the imine prior to addition of donor aldehyde was used at a lower reaction temperature, such —20 °C. Reactivity of benzaldehyde and of N-PMP-imine of benzaldehyde as acceptors was compared in the... 

A novel Mannich reaction between A -alkoxycarbonylpyrroles 739, formaldehyde, and primary amine hydrochlorides catalyzed by Y(OTf)3 gave a monoaminoalkylation product 741 some times in good yield (14-81%) in aqueous media (Scheme 146) <2001TL461>. When formaldehyde was replaced by acetaldehyde or benzaldehyde, no reaction occurred. There was no formation of the 2,7-diazabicyclo[2.2.1]hept-5-ene 740 (through the aza-Diels-Alder reaction of an N-protected pyrrole with an aldehyde and amine salts by catalysis with triflate). 

Isopelletierine (23) undergoes a Mannich reaction with both m-methoxy- and m-hydroxy-benzaldehyde, to give respectively a mixture of the cis (24 R = Me) and trans (25 R = Me) quinolizidines, and exclusively the tran -quinolizidine (25 R = H). The ratio of stereoisomers in the former reaction varies widely with solvent used. ... 

For the Mannich reaction, a screw-capped fritted glass reaction vessel was charged with the resin (0.3 g, 0.75 mmol g ), Cu Cl (45 mg, 0.45 mmol), and benzaldehyde (0.16 mL, 1.57 mmol). After shaking for 0.5 h, phenyl-acetylene (0.173 niL, 1.57 mmol) was added to the mixture, and the reaction vessel was heated at 85 °C with shaking for 3 h. The resin was filtered hot and washed thoroughly with dioxane (once), DMF (three times), 20% aqueous AcOH (once), DMF (once), 7 m NH4OH (once), DMF (once), MeOH (three times), THF (three times), and CH2CI2 (three times). 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

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]. 

In 2004, Hayashi and coworkers found trans-4-TBSO-(5)-proline 29 to be more active than the parent proline organocatalyst for the asymmetric a-aminojylation of enolisable aldehydes 8 (R = H) or cyclic ketones 11 (X=-CH2-, -C(Me)2-, -S-) with nitrosobenzene to prepare optically pure (>99% ee) hydrojylamine derivatives 12 or 13 in 50-76% yield (Scheme 10.2). Compound 29 (30 mol%) also efficiently catalysed the a-aminojylation/intramolecular Michael cascade reaction of cyclohexenones 34 with nitrosobenzene to afford bicyclic compounds 35 with veiy high enantioselectivity (Scheme 10.7). Furthermore, in the presence of organocatalyst 29, three-component Mannich reactions of acetone 8 (R = Me, R = H) with benzaldehyde derivatives 9 (R = Ar) and 4-metho3yaniline produced the corresponding enantiomers (90-98% ee) of p-amino ketones 16 in mild experimental conditions (—20 °C) (Scheme 10.3). 

The q n-adduct 18 has been obtained by the direct asymmetric three-component Mannich reaction using ketones such as cyclohexanone, with benzaldehyde derivatives and p-anisidine in the presence of L-alanine or OTBDPS-L-serine (Scheme 12.6). ... 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

In the early 1900s, the distinguished Italian chemist Mario Betti demonstrated that 2-naphthol (1) can be a good carbon nucleophile toward imine 3, produced from benzaldehyde and aniline. Although the Betti reaction is mechanistically related to the Mannich reaction, Betti s work preceded the development of this more widely known reaction. ... 

A process that has been popularized and utilized extensively by Overman and coworkers involves a tandem 2-aza-Cope rearrangement followed by trapping of the resultant isomer by a Mannich reaction. First demonstrated in 1979, this has become a powerful methodology that has found substantial utility in alkaloid synthesis. " The reaction between 215 and benzaldehyde results in formation of iminium ion 217, which undergoes the 2-azonia-Cope rearrangement to give iminium ion 218. Trapping of 218 by the enol functionality results in pyrrolidine 219. 

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. 

Finn and Petasis have independently shown that salicylaldehyde is a suitable aldehyde for the Petasis borono-Mannich reaction, with alkenyl, aryl and heteroaryl-boronic acids (Equation 6) [30, 31]. The reaction works best for aliphatic secondary amines, as in the formation of 41 primary amines give modest yields of adducts 41. Benzaldehydes lacking ortho hydroxyl functionality do not react, with even ortho methoxy functionality being unsuitable, which is consistent with a tethering mechanism via putative intermediate 9 (Figure 7.3). Petasis and Boral reported that reactions occurred at room temperature over 24-36 h, using EtOH, MeOH or acetonitrile. 

On the other hand, a direct asymmetric Mannich reaction was reported, in 2009, by Rutjes et al. in the course of developing a synthesis of the bioactive quinolizidine alkaloid lasubine II. Therefore, the key step of this synthesis was the L-proline-catalysed Mannich reaction between acetone, para-mtm-benzaldehyde and veratryl aldehyde, providing the expected Mannich adduct in moderate yield and almost complete enantioselectivity (Scheme 3.5). This chiral p-amino ketone was further converted into the desired (-F )-lasubine II. 

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