Enamine reaction with enones

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 1.25), followed by a stereoselective hetero-Diels-Alder reaction with enone 77 to give aminal 82. The presence of sihca facilitates the hydrolysis step in the catalytic cycle. 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasub-stituted isomer of the enamine (equation 16)51. Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in the transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. 

It should be noted that in contrast to the reactions of ,/ -enones with sulfilimines (see Section 7.3.1.1.2.1.), in the case of the a,/S-unsaturated oxosteroids no enamine formation occurs. The amides 37 (R1 = R2 = OAc R3 = Ac) and 39, formed in the reactions of 35 with 21-ace-toxysteroids 34 (R1 = R2 = OAc) and 38, followed by acetylation, are not in accordance with the proposed mechanism for such reactions113. The formation of these amides is explained by the participation of the 21-acetoxy group in the transition state formation. 

The cyclization of the enamine onto the enone could be drawn as a Diels-Alder reaction with two heteroatoms (N and 0) instead of the ionic mechanism we have drawn. 

Sevin, A., Masure, D., Giessner-Prettre, C., Pfau, M. A theoretical investigation of enantioselectivity Michael reaction of secondary enamines with enones. Helv. Chim. Acta 1990, 73, 552-573. 

Bicych[4.n.l]enones. These substances (3) can be obtained by cyclodialkylation of pyrrolidine enamines of cycloalkanones (1) with l,4-dichloro-2-butene (2) in the presence of potassium iodide, DMF, and this hindered amine. Yields of (3) are about 40% when n = 2 and 3, but only about 10% when n = 5. The reaction with the enamine of 4-methylcyclohexanone is improved by addition of HMPT. 

It has to be pointed out that simple enolizable aldehydes and ketones, which are not acidic enough compounds to be directly used as pro-nucleophiles in this context, can nevertheless be employed as Michael donors in the reaction with enals or enones, which have been previously activated as the corresponding iminium ion, but their use requires prior activation via enamine activation. In these cases, it is usually proposed that the amine catalyst is involved in a dual activation profile interacting with both the Michael donor and the acceptor, although the enamine activation of the pro-nucleophile is mandatory for the reaction to occur, the activation of the acceptor being of less relevance in most cases. For these reasons, this chemistry has been covered in Chapter 2. 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

One of the first examples of an enamine-catalyzed cascade reaction for the synthesis of a complex alkaloid was reported by Itoh et al. (179). Reaction of the dihydrocarboline 194 with enone 195 in the presence of (5)-12 (7 days) gave the tetracycle 196 as a single diastereomer and in excellent enantiopurity (99%). This reaction can be described best as an enamine-catalyzed Mannich-Michael domino addition. Further manipulations then gave access to the indole alkaloid ent-dihydrocorynantheol (197) in an elegant and facile manner. As depicted in... 

Heterocyclic ketene aminals have been found to be good aza-ene compounds which can undergo hetero-ene reactions readily with activated carbonyl compounds and enones " to provide novel and efficient synthetic routes to y-lactam-fused diaza-heterocycles and fused di- and tri-heterocycles, respectively. Such aminals bearing a secondary enamine moiety have been found to undergo an efficient aza-ene reaction with 4-phenyl-l,2,4-triazoline-3,5-dione under very mild conditions. The regio- and diastero-selectivity of the ene reaction of 4-phenyl-l,2,4-triazoline-3,5-dione with chiral allylic alcohols and their derivatives have been studied, " while Singleton and Hang have proposed a new mechanism for the ene reactions of triazolinediones which involves an open biradical as the key intermediate. This biradical is assumed either to form the ene product or to form reversibly an intermediate aziridinium imide which would be a shunt off the main ene mechanistic pathway. 

Whereas a,P-unsaturated aldehydes and enones, nitroolefins, and imines have been used extensively in organocatalyzed enantioselective F-C reactions with various aromatic nucleophiles since 2001, the introduction of new classes of electrophiles in such transformations only started in the last four or five years. In 2007, two independent groups described how N-protected enamines could act as good substrates for preparing, in the presence of chiral phosphoric acids 26e and... 

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