P-Aminoketones

Conversely, activated methylene compounds undergo an addition reaction across the C=N bond of imines. For example, benzylic ketones react with benzylidene anilines to from P-aminoketones [35], whereas the analogous reaction of diphenyl-methylene-protected a-amino esters, and nitriles, produces a disastereomeric mixture of the A-protected a,p-diamino esters, and nitriles [36, 37]. 

The ring opening of 2-acylaziridines can be performed on the action of Sml2 in THF-MeOH mixture. The final product—A -tosyl-p-aminoketone—is formed in 95% yield (Molander and Stengel 1995 Scheme 7.46). 

This is a fairly general reaction, and requires an amine plus an aldehyde (usually, but not necessarily, formaldehyde) together with an enolizable ketone, which together generate a P-aminoketone via an iminium system. The Mannich reaction is surprisingly... 

After the initially performed aldol condensations and the process optimisation, the scope of the reaction was further extended to an enantiomeric Mannich reaction. The authors started from A-PMP-protected ot-imino ethyl glyoxylate and cyclohexanone in the presence of 5% catalyst loading. In 10 min at 60°C, the conversions were complete and the p-aminoketone was obtained in 91% yield and >95% ee after purification on column. 

A number of other simple cyclic amine targets with oxygen substitution have been prepared using a nitrone cycloaddition strategy to provide both the N- and O-functionalities. These include the pyrrolidines darlinine 193 and analogues (248), (+)-preussin (194) (249) and the piperidines (—)-allosedamine (195) (250), and the related structure 196 (251) as well as analogous p-aminoketones (Fig. 1.4) (252). 

Gadhwal, S., Baruah, M., Prajapati, D. and Sandhu, J.S., Microwave-assisted regioselective synthesis of p-aminoketones via the mannich reaction, Synlett, 2000, 3, 341—342. 

PCC is used to remove menthyl substituents working as chiral auxiliaries—from amines.306 The oxidation of menthylamines with PCC leads to P-aminoketones that, on treatment with base, suffer a retro-Michael reaction leading to free amines. 

Other carbon nucleophiles may also be employed in such a coupling reaction that provides (3-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the Ai-Boc p-lactam 96 to afford p-aminoketones 97 in 90-96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. 

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

Another group of applications consists of electrosynthesis of substances that can be otherwise synthesized only with difficulty. The chemical reduction of p-aminoketones is complicated by the elimination of these compounds. A polarographic two-electron wave in acidic solution, corresponding to the reduction of carbonyl grouping to p-aminoalcohol... 

Weigel, W., Schiller, S., and Henning, H.-G. (1997) Stereoselective photocycli-zation to 2-aminocyclopropanols by photolysis of p-aminoketones and oxidative ring opening to enaminones. Tetrahedron, 53 (23), 7855-7866. 

Asymmetric Mannich reactions.24 Our enolate alkylation methodology has been subsequently extended to include asymmetric Mannich reactions. The Mannich reaction can be viewed as an imino analogue of the aldol reaction and is a very common synthetic method for the preparation of P-aminoketones. 

Diastereoselective enolate amination as an approach to a-aminoke-tones.42 We have demonstrated that the Mannich reaction is successful for the highly stereoselective introduction of P-aminoketone moieties (vide supra, Asymmetric Mannich Reactions24). The diastereofacially selective electrophilic amination of enolates is attractive as a complementary approach to the asymmetric... 

The catalyst 17 was used also in Mannich condensations the reaction of a ketone with imines afforded P-aminoketones in good yield and high enantiomeric excess (ee) (Puglisi et al. 2002). Extension of the PEG-... 

Proline-promoted condensation to hydroxyacetone as the aldol donor gave access to synthetically relevant syft-I -hydroxy-P-aminoketones, that were obtained in moderate to good yields, and good to high dia-stereo- and enantioselectivities (equation b, Scheme 6). Exploiting its solubility properties, the PEG-Pro catalyst was easily recovered and recycled to promote all of the above-mentioned reactions that occurred in slowly diminishing yields but virtually unchanged enantioselectivities. 

The base-catalyzed deamination of p-aminoketone methiodides has been elaimed to follow an E2 mechanism involving the partial carbanionic character of the intermediate 24Q 809.810 whereas the deamination of the corresponding indole derivatives would occur... 

Other hydrogenolytic reactions, involving the R—CH2 bond between the substrate and the methylene group of the Mannich base, are carried out on the Mannich bases of succinimide, - on some thiazolidinc derivatives- - and on cyclic P-aminoketones. ... 

This reaction is highly stereoselective, usually to a larger extent than the corresponding reduction. The following are the main conclusions on the stereochemistry of organometal addition to a-asymmetric P-aminoketones that can be drawn from the great wealth of results reported in the literature "- ... 

Homocyclic derivatives can also be obtained (Fig. 130) by amino group replacement of the Mannich base by nucleophilic reagents, such as mono- and dialkyl ketones. " The same p-aminoketone may behave as a nucleophilic reagent in self-condensation reactions. Arylketobases (335, Ar in the place of RCHi, path a) have also been studied. ... 

Fig. 134. Synthesis of pyran derivatives from P-aminoketones (bold lines represent the original skeleton of the Mannich ba.se).

Halt enation— The introduction of halogens into Mannich bases is usually carried out according to the well-known synthetic methods of organic chemistry (Table 30). In particular, the replacement of hydrogen atoms in the a or a position of P-aminoketones is performed with the aim of controlling the regioselcctivity of the reaction" ... 

By contrast, irradiation in benzene of P-aminoketones having a secondary amino group produces photopinacolizatiorf with formation of the diols 372. 

P-Aminoketones 511 are employed mostly as pharmaceuticals, many of them currently in use. Investigations of their properties are of continuing interest in several branches of medicinal chemistry (Fig. 76, Chap. Moreover, these compounds are precursors of a substantial group of derivatives equally important in pharmacology, namely, the y-aminoalcohols 512, which arc readily prepared by hydrogenation or addition of organometal to the carbonyl group. - ... 

Polymerization of epoxy monomers, requiring probably the simultaneous participation of the phenolic hydroxy group, and the production of polyurethanes are the main applications of the abovementioned catalysts. In particular, their role in the trimerization of the i.scx yanate group " appears quite relevant and several investigations of the synthesis of epoxy resins-- " - and polyurethanes- arc reported. A different type of catalyst is constituted by acetophenone-derived p-aminoketones employed with photocurable resins. -- ... 

Pharmaceuticals made from Mannich bases are reported in Table 43, where almost the whole range of the different classes is represented. C-Mannich bases, in particular cyclic and acyclic P-aminoketones, predominate, although N-Mannich bases, especially amide derivatives, are also well represented. 

The optically active p-aminoketones reported in Table 13 may be involved in rac-... 

Removal of the amine moiety in piperazine derivatives in acidic medium " is thought to occur from the enolic form of the ammonium salt, at least at very low pH values. However,. step b has not been interpreted entirely from the mechanistic point of view, as far as the participation of ammonium/enolate structures is concerned. Several cyclic transition states have been envisaged, some of which involve the presence of a hydroxy group or the enolic form of the P-aminoketone. In particular, the participation of OH groups belonging to other molecules, such as carboxyacids present in the reaction medium, cannot be excluded. " By contrast, a nucleophilic attack by an acid anion on the carbonyl C atom has been claimed to be the rate-determining step for deamination in the reaction between p-aminoketones and triethyl phosphite in dimethylformamide. ... 

Deamination has also been recognized as the rate-determining step in some replacement reactions carried out on phenolic and indolic Mannich ba-ses. - In phenolic derivatives, in particular (Fig. 88), a pre-equilibrium takes place similar to that described above for p-aminoketones, and is followed by the elimination of amine via an E cB-type mechanism. ... 

As with C-alkylation, the mechanism of amino group replacement can follow the elimination/addition or the nucleophilic replacement path. Both mechanisms are indeed mentioned in the literature and are cxrcasionally claimed to occur concurrently. The elimination/addition path is suggested in the reaction of p-aminoketones with uracils, and a four-centered transition state is proposed for the. same reaction with indole Mannich bases. ... 

Fig. 113. The carbonyl group reduction of a-chiral P-aminoketones (only one enantiomer of the racemic pair is represented).

Heterocyclic compounds originated by the involvement of the amine moiety of the base (group B) can be prepared from several different classes of Mannich derivatives P-aminoketones in particular, are largely employed. Thus, 4-hydroxypipcridines 322 are obtained from bis-ketones 321 (Fig. 124), prepared by Mannich synthesis with primary alkylaminc. Both the mechanism and the stereochemistry - of the reaction have been investigated it has been demonstrated that cyclization proceeds -stereo.specif-ically, and the resulting product has the configuration depicted in 322. 

I. Absoiute configuration of some a-mcthyl-p-aminoketones. Tetrahedron, 25, 4147, 1969. 

Fig. 166. Intermediate steps in the alkaloid synthesis afToiding P-aminoketone structmes (bold lines).

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