Conjugate addition of enamines

The 1,4-conjugate addition of enamines to the 4-phosphorylated 1,2-dia-zabuta-1,3-diene (184) provides a route to substituted 1-aminopyrroles (185) which can be further converted into 1-aminopyrroles (186) by basic hydrolysis (Scheme 26). Moderate to good yields of 2,6-diphosphonylated-l,2-dihyd-ropyridines (187) have been obtained in a one-pot reaction from either 1,4-dihydropyridines or pyridinium salts (Scheme 27). ... 

For a comprehensive coverage of conjugate addition reactions, see ref. [147]. For a comprehensive review of the stereochemical aspects of base-promoted Michael reaction, see ref. [148] for a similarly comprehensive review of acid-catalyzed Michael reactions and conjugate additions of enamines, see ref. [149]. 

There is appreciable interest in naphtho[2,3-c]pyran-5,10-diones because of their biological activity. A one-pot synthesis of the system involves the conjugate addition of enamines to 2-(l-hydroxyalkyl)-1,4-benzoquinones and the subsequent cyclisation (Scheme 24). The amine function may be lost or retained. Several natural products have been synthesised using this protocol <01JCS(P1)2977>. 

Conjugate additions of enamines to ot,p-unsaturated carbonyl or nitro compounds belong to the most commonly applied and useful organocatalytic C-C bondforming reactions (JS5,143-150). As already mentioned above, enamine-catalyzed conjugate additions are often used in combination with a-heterofunctionalizations. These combined examples will be described in more detail in Sect. 2.6. 

Conjugate addition of enamine to nitroalkene by means of (8) was reported by Dixon et al (Scheme 2.33) [84]. 

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

Alternatively, the enamine portion may be located in the Aralkyl chain. For instance, piperidines bearing a 7-chloro substituent yielded quinolizidines 263 through a conjugate addition of the nitrogen atom to acetylenic sulfones followed by an intramolecular alkylation (Scheme 55) <2000JOC4543>. Other cyclizations that are summarized below used as starting materials piperidine derivatives obtained by similar conjugate additions to vinyl sulfones (see Section 12.01.9.3.6). 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

Nitroalkenes can serve as the two-carbon fragment of a [3 + 2] cyclization involving enamines as nucleophiles (equation 86) (81LA1534). This reaction is presumably initiated by a conjugate addition of the enamine to the nitroalkene (equation 87). The most attractive formulation of the cyclization is via an intramolecular nucleophilic addition to the aci-form of the nitronate anion. This provides a reduced nitrogen substituent which could be eliminated to complete aromatization. This procedure has provided quite satisfactory yields over a range of structural types. 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

So if we want to make 9 we have a choice between adding an enolate equivalent of the aldehyde 7 to an unsaturated ester 8 or an enolate equivalent of the ester 11 to an unsaturated aldehyde 10. We prefer the first 9a as the unsaturated ester 8 is more likely to do conjugate addition. An enamine would be a good choice for 7. 

MacMillan s organocatalyst, 56a, which was used typically for electrophilic activation, was seen also to be efficient in promoting conjugate addition via enamine formation (Scheme 2.52) [42]. The proof of the enamine pathway was furnished by extended NMR studies. Gellman and colleagues noted an interesting dependence of selectivity on the catalyst structure improved conversion and ee-value can occur with the spirocyclopentane derivative 56b, and by the addition of a catechol derivative as acid additive (Scheme 2.52). The cyclohexane-derived catalyst 56c was unreactive, however. 

The best alternatives to enamines for conjugate addition of aldehyde, ketone, and acid derivative enols are silyl enol ethers, Their formation and some uses were discussed in Chapters 21 and 26-28, but these stable neutral nueleophiles also react very well with Michael acceptors either spontaneously or with Lewis acid catalysis at low temperature,... 

The mechanism of this cyclization involves a conjugate addition of the enamine (100) to the nitroallyl ester (101) to give 102, which on elimination produced 103. The immonium salt 103 undergoes proton transfer to give enamino nitro olefin 104, which cyclizes to an enamine (107) via 105 and 106. Hydrolysis of 107 produces the ketone (108). Depending on the reaction conditions and the structure of the enamine and nitroolefin components employed, intermediates can be isolated (equation 19). 

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). 

Conjugated 2-alkoxy-6-amino-l-metalla-l,3,5-hexatrienes of type M= C(OR) — C=C—C=C(NR2) are most easily accessible by addition of enamines to alkoxy(l-alkynyl)carbene complexes in a broad array of different substituents. Due to the highly unsaturated character of such compounds a variety of transformations into organic products can be anticipated. Since... 

If you want to do a conjugate addition of a carbonyl compound without having a second anion-stabilizing group, you need some stable and relatively unreactive enol equivalent. In Chapters 27 and 28 you saw how enamines are useful in alkylation reactions. These neutral species are also perfect for conjugate addition as they are soft nucleophiles but are more reactive than ends and can be prepared quantitatively in advance. The reactivity of enamines is such that heating the reactants together, sometimes neat, is all that is required. Protic or Lewis acid catalysis can also be used to catalyse the reaction at lower temperature. 

The conjugate addition of a carbon nucleophile to an a,/3-unsaturated acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /8-diketones) and unhindered or, -unsaturated acceptors. Enamines, prepared by reaction of a ketone with a disubstituted amine, are also good Michael donors. 

Clean conjugate addition of appropriate nucleophiles to allenic sulfoxides has been used to produce allylic sulfoxide systems. Homer has described the formation of functionalized allylic alcohols when adding nucleophiles like amines, alcohols or thiols to allenic sulfoxides in excess. If the addition is performed with equimolar amounts at lower temperature, so that the 2,3-sigmatropic rearrangement is avoided, the intermediate addition products (enamines or enol ethers) can be hydrolyzed to the synthetically valuable 3-keto sulfoxides (Scheme 20). ... 

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