Mannich reactions selectivity

S. K. Bur, S. F. Martin, Vinylogous Mannich Reactions Selectivity and Synthetic Utility, Tetrahedron 2001, 57, 3221-3242. 

Vinylogous Mannich Reactions. Selectivity and Synthetic Utility," Bur, S.K. Martin. S.F. Tetrahedron, 2001, 57, 3221. 

Another type of preformed reagent (15) has been used to carry out diastereo-selective Mannich reactions. The lithium salts (14) are treated with TiCl4 to give 15,... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Isayama described the coupling reaction of N-methylimine 157 and ethyl crotonate catalyzed by Co(acac)2 and mediated by PhSiH3 to produce Mannich product 158 in 82% with syn-selectivity (Scheme 41) [71]. The (i-laclam 159 was readily synthesized by heating 158. In 2002, Matsuda et al. reported cationic Rh complex [Rh(COD) P(OPh)3 2]OTf (1 mol%) as an active catalyst for the reductive Mannich reaction [72]. N-Tosylaldiminc 160 was coupled with methyl acrylate and Et2MeSiH (200 mol%) at 45 °C to give the b-amino ester 161 in 96% with moderate anti-selectivity 68%. 

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

In a related publication, Kobayashi and his team reported on Zr-catalyzed asymmetric Mannich reactions that utilize the more electron-rich oxygenated ketene acetals shown in Scheme 6.28 [93], A noteworthy aspect of this study was that the levels of syn/anti diaste-reocontrol proved to be dependent on the nature of the alkoxide substituent whereas the (3-TBS acetals predominantly afforded the syn isomer, the OBn derivatives afforded a larger amount of the anti isomer. As before, the presence of an additive, this time 1,2-dimeth-ylimidazole (DMI), proved to be important with regard to the level of Ti-facial selectivity. The phenol activating group can be removed by the same procedure as reported previously, with essentially identical degrees of efficiency (see Scheme 6.27). 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

The scope of the enamine-catalyzed Mannich reaction can be considerably expanded by the use of preformed imines. These two-component Mannich reactions can be either syn selective [91, 94, 136, 220, 222, 230-233, 245, 248-258] (proline or its simple derivatives as catalysts) or anti selective [220, 259-268]... 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

Mannich reactions give rise to (i-amino carbonyl compounds which are amenable to further synthetic manipulations. Numerous stereoselective variants have been achieved by means of different types of catalysts including both metal complexes and organic molecules. In 2004, the groups of Akiyama and Terada independently selected this transformation as a model reaction for the introduction of a novel chiral motif to asymmetric catalysis [14, 15]. 

When performing a Mannich reaction in its initial three-component design, the selectivity is sometimes difficult to obtain due to the competition with the side processes, primarily the auto-aldol condensation [52, 80], A common solution for this problem is the pre-formation of an imine or the enolate, or both and thus the sequential (indirect) performance of the reaction (Scheme 35) [52],... 

Cordova A (2004) The direct catalytic asymmetric cross-Mannich reaction a highly enantio-selective route to 3-amino alcohols and alpha-amino acid derivatives. Chem Eur J 10 (8) 1987-1997... 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

The N-sulfinyl (thio)ureas are modular and easily accessible in one step by condensing tert-butanesulfinamide with the appropriate isocyanate or isothiocyanate. Figure 6.64 shows a representative selection of the prepared N-sulfinyl (thio)ureas evaluated for their catalytic activity in the aza-Henry (nitro-Mannich) reaction of N-Boc-protected benzaldimine and nitroethane producing adduct 1. 

In a closely related example, a Mannich reaction of the somewhat more complex phenol (20-1) with formaldehyde and fert-butylamine gives the aminomethylated product (20-2). Hydrolysis of the acetamide protecting group then affords the corresponding aniline (20-3). Alkylation with the quinoline (17-6) in this case also proceeds on aniline nitrogen. The selectivity over the more basic secondary side nitrogen can probably be ascribed to steric hindrance about the latter. There is thus obtained tebuquine (20-4) [22]. 

Exercise 17-21 a. A useful modification of aldol addition to methanal, known as the Mannich reaction, uses a secondary amine (usually as its hydrochloride salt) to selectively introduce one carbon atom at the alpha position of an aldehyde or ketone. The actual product is the salt of an amino ketone. For example,... 

The vinylogous Mannich reaction of triisopyloxyfurans with aldimines prepared from aldehydes and 2-aminophenol proceeded with moderate selectivity in the presence of a catalytic amount of a Ti(IV)-BINOL complex [22]. 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

A number of MCRs having enolate-derived nucleophilic components were subsequently discovered (Scheme 7.3), including the Hantzsch dihydropyridine synthesis [13], the Biginelli reaction [14, 15] and the Mannich reaction [16-20], An added complication in many of these MCRs is the potential irreversible addition of the nucleophile to the carbonyl component, leading to carbonyl addition products. Such MCRs, however, become feasible by the appropriate selection of components that do not favor such alternative transformations. For example, the use of formaldehyde is more effective in the Mannich reaction, because its greater reactivity towards the amine prevents its undesired reaction with the enolate component. 

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-... 

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