Dienamine Activation

Positively activated olefins have also been condensed with dienamines derived from aldehydes 321,330,347,348) and ketones. Of special interest is the formation of bridged systems from homoannular dienes (229-231) which has been applied to the isoquinuclidine system of the iboga alkaloids (137-140,349). 

The first asymmetric isomerization of an allylamine was achieved with the optically active cobalt catalysts as mentioned above. The isomerization of 1 with Co(acac)2/(+)-DIOP/ Bu2AlH catalyst gave (3/ )-3 with 32% ee (39% chemical yield) accompanied by a considerable amount of undesired dienamine 4. Although with the same catalyst system, a higher enantioselectivity (57% ee) and chemical yield (60%) were obtained by using the secondary allylamine 5 as the... 

The acid-catalysed cyclization of the dienamines (150) prepared from citral (152) and a range of secondary amines has been studied acid treatment of citral-pyrrolidine enamines (151) gave exclusively a-cyclocitral in 41% yield. When enamines derived from optically active (—)-pyrro idines were used, optically active... 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

Effects of additives in the isomerization of substrate 45 by catalyst 17 were studied under the conditions of [S]=0.24 mol L [S] [C] =100 at 60 °C in THE The results are briefly summarized in Table 1, and are important both for mechanistic studies and improvements of the catalyst activity. Simple tertiary amines retard the reaction drastically, which suggests the coordination order of amines to Rh-BINAP species to be proportional with the order of basicity of simple tertiary amines, allylamines and enamines. Without the presence of simple tertiary amines, this phenomenon enables the fast replacement of the enamine formed from the catalyst by a substrate molecule that permits a smooth catalytic cycle. The presence of chelate diolefins like COD also disturbs the catalytic cycle. An over-isomerized by product, dienamine 44, acts as a strong catalyst poison. 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzo-furazan oxide (171) with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Earlier developments to 1981 were surveyed by Porter <84CHEC-I(3)157>, and later progress has been reviewed by Haddadin and Issidorides <93H(35)1503> who first demonstrated this reaction. Dienamines and azadienes (172) also react with benzofurazan oxide to yield... 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

The first formed chroman-2-ols were, after work-up, oxidised with PCC to naturally widespread 3,4-dihydrocoumarins, in high yield, diastereo- and enantioselectivity. Recently, a powerful Michael/Michael cascade reaction catalysed by prolinol lb via dienamine activation of a, 3-unsaturated aldehydes combined with ethyleneindolinones has been reported. Complex 3,3 -spirooxindoles fused with a cyclobutane bearing four stereogenic centres were obtained in good yield and high diastereo- and enantioselectivity (Scheme 7.18). Surprisingly, catalyst 10 proved to be less active and... 

Addition of benzoic acid enhanced the reactivity of the catalyst in the Michael addition of aldehydes. Therefore, less reactive trisubstituted nitroalkenes could also be used. Acetic acid as acidic additive also helped in the addition of unsaturated aldehydes to nitroalkenes (Scheme 8.3). This reaction proceeds via dienamine activation of unsaturated aldehydes. 

Aleman, Fraile and coworkers described 1,3-dipolar cycloadditions of unsaturated aldehydes and cyclic azomethine imines (Scheme 8.36). The reaction proceeds either via iminium or dienamine activation of the corresponding aldehyde, giving chiral tetrahydroisoquinoline derivatives. Interestingly, it can be controlled either by the structure of the dipole or by additives such as tetrabutylammonium bromide. This transformation was investigated also by Du, Wang and coworkers. ... 

Later, Melchiorre and coworkers accomplished a challenging direct vinylogous aldol reaction of 3-methyl-2-(yclohexen-l-one with a-keto esters utilising a bifunctional primary amine-thiourea. Catalyst 48 based on the (l/ ,2/ )Kiiphenylethylene-l,2-diamine backbone combined with benzoic acid as cocatalyst promoted the reaction by means of a concomitant activation of both reacting partners (see TS in Scheme 19.55), the ketone via dienamine catalysis and the ester via hydrogen-bonding interactions (Scheme 19.55). 

One year later, Vicario and coworkers developed an unprecedented [2-1-2] cycloaddition reaction of a,p-unsaturated aldehydes with a-hydro gr-methylnitroalkenes (Scheme 19.58). The addition of the achiral thiourea 8 proved to be essential for achieving high levels of efficiency and enantio-control, since it served to activate the electrophile through hydrogenbonding interactions, while prolinol ether 51 served to activate the nucleophile by means of dienamine catalysis. The [2 + 2] cycloaddition... 

The clue to the rationalization of these results came from theoretical calculations at the DPT level of theory. These calculations showed that the two most stable dienamine conformers were the E-s-trans-2>E and the E-s-trans-3Z, which differed in energy by 1.4kcal/mol. Assuming that these two isomers were readily interconvertible by reprotonation to the iminium ion followed by deprotonation, the experimentally observed diastereomer mixture could be explained. However, the calculations showed that the "y-amination of these two intermediates was endothermic. On the other hand, the less stable s-cis conformers were predicted to react in an exothermic fashion with diethyl azodicarboxylate via a Diels-Alder cycloaddition. The reaction of the E-s-cis-3E conformer was the more exothermic one, and it showed an activation energy lower than that of the E-s-cis-3Z conformer by 6.5 kcal/mol. Hydrolysis of this adduct would then lead to the observed "y-amination product, with (R) configuration (Scheme 2.18). 

In 2009, Christmann and co-workers [111] disclosed a Ranhut-Currier-type intramolecular Michael reaction via dienamine activation for the construction of iridoid framework. Catalyzed by J0rgensen-Hayashi catalyst 7, the reaction proceeded well to afford the cyclopentene derivatives including (+)-rotundial in moderate to good yields with good enantioselectivities (Scheme 5.53). 

S.4.4.5. -Substituted Cyclohexenone Derivatives. Inspired with the dien-amine catalysis developed by Jprgensen and co-workers [138], Melchiorre and coworkers [139] found that the chiral primary amine salts 142 could selectively activate the 7-position of ummodified cyclic a,(3-unsaturated ketones through dienamine catalysis (Scheme 5.70). The direct vinylogous Michael addition of p-substituted... 

SCHEME 6.8. In situ dienamine activation of a,p-unsaturated ketones by secondary amine... 

SCHEME 6.9. Intramolecular Diels-Alder reactions through in situ dienamine activation of 2-enals. 

The use of an amine catalyst for the activation of an a,(3-unsaturated carbonyl group as a nucleophile represents a very useful extension of the concept of enamine activation. By transmission of the nucleophilic properties of an enamine to an adjacent olefin (vinylogy), the dienamine can be considered to be a compound bearing two nucleophilic sites (the a- and the y-position) and furthermore it can react as an electron-rich diene in [4 + 2] cycloadditions. This concept was introduced in 2006 by Jorgensen et al. who successfully applied it for the stereoselective y-amination of a,(3-unsaturated carbonyl compounds (166) (Scheme 43). 

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