Amino- -unsaturated ketones

In confirmation of this expectation, Cromwell et al [6, 35] have found carbonyl shifts of the order of 20—80 cm in /3-amino-unsaturated ketones, although a-amino a/3-unsaturated ketones are normal. They find, however, that there is still a considerable frequency shift in fully substituted amines, although it is not so great as that occurring with materials which can form hydrogen bonds. They conclude that in these substituted amines a resonance is occurring... 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

A related ring closure is also successful in the thiazole series. Treatment of a /3-amino-a,/3-unsaturated ketone with thiocyanogen gave the intermediate thiocyano compound (323) which underwent ring closure to the 2-iminothiazoline derivative (324) (83MI40300). Related reactions are described in Chapter 4.19, and for those involving potassium selenocyanate see Chapter 4.20. 

The Nenitzescu reaction generally occurs under relatively mild reaction conditions. Moreover mono-, di-, and tri-substituted quinones react with equal facility. Many enamines including p-aminoacrylonitriles, p-aminoacrylamides, and p-amino-a,p-unsaturated ketones react with quinones to form indole nuclei as well. The mild reaction conditions and the availability of the starting material render it attractive even in those instances where the yield of the product is low. ... 

The amine-catalyzed Diels-Alder dimerization reaction of a, 3-unsaturated ketones in water was developed by Barbas et al. to form cyclohexanone derivatives (Eq. 12.12). They believe that the reaction proceeds via the in situ formation of 2-amino-1,3-butadiene and iminium-activated enone, as the diene and dienophile, respectively. 

Amino alcohols (33) were transformed to ketones on copper.360 361 The transformation involves the dehydrogenation of the hydroxyl group, the elimination of dimethylamine, and the hydrogenation of the unsaturated ketone (Scheme 4.111). 

The Michael addition of nitro compounds to a,P-unsaturated ketones or esters followed by reduction of the nitro to amino group is useful for the preparation of various heterocycles. This is presented in Chapter 10 (Synthesis of Heterocycles). 

Method B The protected amino ester (10 mmol) and a,P-unsaturated ketone (10 mmol) are stirred with K,CO, (0.28 g) and TEBA-C1 (0.23 g, 1 mmol) at room temperature until the mixture solidifies. The mixture is allowed to stand for 10 h, and H20 (100 ml) is then added. The precipitated pyrrolidine is collected, washed with H20, and recrystallized from MeOH. 

Polyamino acids are easy to prepare by nucleophUe-initiated polymerisation of amino acid JV-carboxyanhydrides. Polymers such as poly-(L)-leucine act as robust catalysts for the epoxi-dation of a wide range of electron-poor alkenes, such as y-substituted a,Ji-unsaturated ketones. The optically active epoxides so formed may be transformed into heterocyclic compounds, polyhydroxylated materials and biologically active compounds such as dUtiazem and taxol side chain. 

For example, the formation of mixtures of 4,5- and 4,7-dihydroisomers 45 and 46 was observed by Werman and Hartman [79] in the reaction of 3-amino-l,2,4-triazole with two equivalents of methylarylketone in the presence of ZnCl2 as a catalyst (Scheme 20). The ratios between two position isomers were from 50 50 to 74 26. However, Desenko et al. [80] established that treatment of the same starting compounds under acidic catalysis (acetic or mineral acids) yielded only 4,5-dihy-droderivatives 46 and heterocycles 47 [81]. In the latter case, the third component of the multicomponent condensation was the solvent - DMF. It is worth noting that heterocychc compounds 46 were also the products of the reaction between 3-amino-1,2,4-triazole with a,p-unsaturated ketones 48 (Scheme 20). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Lauret, C. and Roberts, S.M. Asymmetric Epoxidation of a, -Unsaturated Ketones Catalyzed by Poly(amino acids). Aldrichimica Acta 2002, 35(2), 47-51. 

Vicinal effects can also play a part in the course of the reaction utilizing Oppenauer conditions. 1,3-Diols or / -amino alcohols may not react, presumably on account of formation of an aluminum complex.5 5 46b> If oxidation were to take place it would probably be followed by dehydration to give an unsaturated ketone. Retro-aldol cleavage has been found to occur with a 17,21-dihydroxy steroid.32 The 11 -hydroxyl group which is generally inert to Oppenauer oxidation will react if a hydroxyl group is present on the... 

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