Michael/enamine formation

Scheme 7.37 Enantioselective synthesis of 1,4-dihydropyridines by one-pot Michael/ enamine formation/intramolecular condensation reaction.

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Activation of Michael Acceptors by Iminium Ion Formation, Activation of Carbonyl Donors by Enamine Formation... 

The MacMillan catalysts (42, 45), the Jorgensen catalyst (51), and proline itself can promote Michael additions by iminium ion formation with the acceptor enal or enone (A, Scheme 4.22). Secondary amines can also activate a carbonyl donor by enamine formation (Scheme 4.22, B) [36, 37]. 

C-Nucleophiles have recently been added asymmetrically to azodicarboxylates as Michael-acceptors, resulting in a-amination of the nucleophilic component. Examples of this type of reaction, which is based on activation of the aldehyde or ketone component by enamine formation, are summarized in Scheme 4.27. Please note that this type of reaction is covered in more detail in chapter 7 of this book. 

Proline was among the first compounds to be tested in asymmetric conjugated reactions, both as a chiral ligand [8] and also as an organic catalyst [3]. The earliest asymmetric intermolecular Michael-type addition, in which proline catalyzed the reaction (arguably via enamine formation) was reported by Barbas and colleagues [9, 10] and by List and co-workers [11]. The reaction, which proceeded in high chemical yield (85-97%) and diastereoselectivity, albeit afforded near-racemic products in dimethyl sulfoxide (DMSO) [11] (Scheme 2.37). The enantio-selectivity of the addition was later ameliorated by Enders, who demonstrated that a small amount of methanol rather than DMSO was beneficial to the enantiose-lectivity of the addition reaction [12]. 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

Vinylindole 68 was deprotected and the crude product, after purification, was reacted with a large excess of butyric aldehyde in MeCN in the presence of molecular sieves to give 13a and 13b and l,3-ethyl-2,3,4,5-tetrahydro-2-methyl-l,5-methano-l,3-diazocino[l,8- ]indole-6-nitrile 12a and 12b as a mixture of diastereomers (1 2 a-CN, /3-CN) (Equation 5). The formation of these products can be rationalized in terms of a domino process consisting of enamine formation, Michael addition, and Mannich reaction. When TFA was added directly to the reaction mixture, only 13a and 13b were obtained since 12a and 12b in acidic medium rearrange to 13a and 13b (see Section 14.05.2.4 (Equation 3) <1995S592>. 

The diketo-aldehyde 37 has four electrophilic carbon atoms (A-D) and three positions for enolisation (1-3). Cyclisation could occur in twelve different ways. Three can be regioselectively realised by different conditions.6 With morpholine catalysis, the aldehyde forms an enamine which does a Michael addition on the enone (B) to give 39. Enamine formation with PhNHMe also gives the aldehyde enamine, but this time it does an aldol condensation with the simple ketone (D) to give 38. 

The 3-component condensation for synthesis of 3-acy 1-4-ary 1-1,4-dihydropyridines from amines, (3-dicarbonyl compounds and enals proceeds from enamine formation, Michael reaction and cyclodehydration is amenable to asymmetric induction, such as using ent-octahydro-lB. ... 

Activation for the Michael reaction could be by C02Et group or enamine formation. Ring expansion of (16) to <14> is unambiguous as only the more substituted side chain migrates, as in the Baeyer-Villiger reaction (Chapter... 

An alternative and useful method for intramolecular conjugate addition when the Michael donor is a ketone is the formation of an enamine and its reaction with a Michael acceptor. This can be advantageous as enamine formation occurs under reversible conditions to allow the formation of the product of greatest thermodynamic stability. Treatment of the ketone 40 with pyrrolidine and acetic acid leads to the bicyclic product 41, formed by reaction of only one of the two possible regio-isomeric enamines (1.51). Such reactions can be carried out with less than one equivalent of the secondary amine and have recently been termed organo-catalysis (as opposed to Lewis acid catalysis with a metal salt). The use of chiral secondary amines can promote asymmetric induction (see Section 1.1.4). 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

Azasteroids. 2-Methylcyclopentane-l,3-dione, Hidrite (desiccant), and 1 mole p-methoxyphenol added successively to a 50%-mineral oil dispersion of NaH in dioxane, stirred and refluxed under Ng while l-(j -dimethylaminoethyl)-3,4-dihydro-6-methoxyisoquinoline is added dropwise during 0.5 hr., stirring and refluxing continued 1.5 hrs. ( )-3-methoxy-8-azaestra-l,3,5(10),9(ll),14-pentane-17-one. Y 55-60%. — p-Methoxyphenol, chosen because its acidity lies between that of the startg. dione and the product, is added in order to protonate the intermediate anion, thus favor enamine formation and prevent retro-Michael-type scission. F. e. and procedure s. R. Clarkson, Soc. 1965, 4900. 

The process of enamine formation/aldol condensation/Michael addition/6-exo-trig cychzation/elimination cychzation was used to prepare thienothiopyrans. As... 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

The simple chiral secondary amine (S)-70 activates the linear aldehyde 139 by enamine formation, which selectively attacks the nitroalkenes 140 in a Michael-type reaction without any interference by the a,p-unsaturated aldehyde 95. Indeed, the latter prefers to be activated as iminium ion by the catalyst (5)-70 and to undergo the subsequent conjugate addition to form the Michael adduct B (Scheme 2.41). 

The imidazolidinone-catalysed intramolecular asymmeflic Michael addition has been studied by DFT. The mechanism is identified as enamine formation followed 0 by Michael addition (which is stereochemistry determining), followed by enol-keto tautomerization and hydrolysis. 

The ring-closing Michael addition of the enone-aldehyde 0=CH(CH2)4CH= CHCOMe, catalysed by imidazolidinone (251), has been shown by DFT calculations to proceed via the initial enamine formation from the aldehyde group, which then undergoes Michael addition to the enone moiety. ... 

In this process - which is complementary to the classical Hantzsch synthesis - primarily a,P-unsaturated imines 174 are likely to be formed, which undergo Michael addition with the P-ketoester ( 175) followed by cyclizing enamine formation establishing the C-2/C-3 bond of the 1,4-dihydropyridine 173. 

A potentially more simple procedure is the Reformatsky condensation of the bromoester (47) with ketones a-methylenebutyrolactones are produced, in one step, in fair to good yield. An efficient three-step synthesis consisting of ketone enamine formation, Michael addition to ethyl / -nitro-acrylate, and borohydride reduction has been reported the last process affords a mixture of the cw-butyrolactone and the /ra j-hydroxyester as shown in Scheme 14. 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

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