Acetaldehydes Mannich reactions

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

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). 

The Mannich reaction of a ketone, an amine, and an aldehyde is one of the few three-component reactions in organic chemistry. Cyclohexanone, for example, reacts with dimethyJamine and acetaldehyde to yield an amino ketone ... 

Xiao, H.-M., Ling, Y., Zhai, Y.-F., Li, Y.-M. Theoretical studies on the mechanism of Mannich reaction involving iminium salt as potential Mannich reagent. Use of acetaldehyde as pseudo-acid component. Chemical Research in Chinese Universities 1997,13, 324-329. 

The loss of acetaldehyde from voacristine (143) when it was heated in acetic acid may well proceed by way of (144), produced by a reverse Mannich reaction cf. Scheme 28) note that (144) is an intermediate of the type necessary for the conversion of an iboga type into (132) by an ionic route. 4,20-Dehydro voacangine (145) was also produced in this reaction. 

To facilitate the use of p-amino-aldehydes or -alcohols, obtained through asymmetric Mannich reactions, List et al. provided a procedure to use N-Boc-protected, preformed imines (21, 22) (Scheme 5.13a). While this method requires the formation of the imines, it provides products that can be deprotected under mild conditions, as compared to the widely used and robust PMB-protection in these reactions. Even acetaldehyde is applicable as aldehyde source (Scheme 5.13b). The p-amino-aldehydes (23, 24) obtained from this transformation are extremely valuable building blocks in organic synthesis, making this discovery one of the most useful applications of proline catalysis to date. 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

One year later, the List group reported Mannich reactions involving the use of acetaldehyde 2r as the Mannich donor, which due to its reactive nature, is a very difficult substrate. Albeit not in high yields, they showed that under carefully controlled conditions such Mannich reactions could proceed in excellent selectivity, even in case of the aliphatic Boc-protected imines 23i and j (Scheme 5.15) [22],... 

Scheme 5.15 Mannich reactions involving acetaldehyde as the substrate...

Synthetically useful N-Boc-protected imines are also applicable to the amine-catalysed Mannich reaction. In 2008 List and coworkers reported the proline-catalysed asymmetric Mannich reaction of highly reactive acetaldehyde with N-Boc-protected imines (Scheme 17.9). With 20 mol% of l-proline the Mannich adducts were obtained with excellent enantioselectivity, albeit in low to moderate yields. On the other hand, the reaction using 2 mol% of (S)-3 gave the desired Mannich adducts in good yield with virtually perfect enantioselectivity. In the reaction catalysed by (S)-3, side reactions were completely suppressed and no byproducts were formed consequently, the turnover number of this reaction was significantly improved. 

N-Boc-protected imines were also applicable to the diastereo- and enan-tioselective Mannich reaction of aliphatic aldehydes other than acetaldehyde. The highly q n-selective asymmetric Mannich reaction catalysed by L-proline was reported by List and coworkers in 2007. In contrast, (5)-3 promoted the antz-selective asymmetric Mannich reaction between aliphatic aldehydes and iV-Boc-protected imines and the catalyst loading could be reduced to 1 mol% without loss of stereoselectivity. By using N-Cbz-protected aminoacetaldehyde instead of simple aliphatic aldehydes, both syn- and antz-vicinal diamines were synthesised by simply changing the catalyst through the above-mentioned amine-catalysed Mannich reactions, respectively. ... 

Utilization of acetaldehyde in the Mannich reaction with benzylisoquino-lines leads to 8-methyltetrahydroprotoberberines. Condensation of the resolved enantiomers of ( )-tetrahydropapaverine with acetaldehyde gave rise to (+)-coralydine and (4-)-0-methylcorytenchirine, as well as to the corresponding antipodes... 

Scheme 3.1 L-Proline-catalysed Mannich reactions of acetaldehyde with A -Boc imines.

On the other hand, diaryl prolinol silyl ethers have been applied as orga-nocatalysts for the asymmetric Mannich reaction of acetaldehyde with N-benzoyl-, iV-Boc- and iV-Ts-imines in the presence of para-aiirobtnzoic acid in THF. The generated (3-amino aldehyde products were isolated in good to high yields and excellent enantioselectivities (95-98% ee) after conversion into the corresponding alcohols by reduction with L1A1H4 (Scheme 3.10). 

Scheme 3.10 Mannich reactions of acetaldehyde catalysed by diaryl prolinol sUyl ether.

In 2009, List and coworkers reported a highly diastereo and enantioselective proline-catalyzed double Mannich reaction of acetaldehyde with A-Boc imines [3], The treatment of 1 equiv of acetaldehyde with 3 equiv of A-Boc imine derived from benzaldehyde in the presence of 20 mol% of L-Pro produced the double Mannich adduct 2 in quantitative yield and with exceptionally high diastereo and enantiose-lectivities (dr > 99 1, ee > 99%) (Scheme 12.2). The reaction was performed with a variety of A-Boc imines, namely aromatic and heteroaromatic substituted imines, and furnished the products in excellent yields (76-99%) and with similar stereoselectivities (dr > 99 1, ee > 99%). Even the unstable isovaleraldehyde-derived A-Boc imine gave the double Mannich adduct stereoselectively, albeit with a moderate yield (30%). 

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