By intramolecular Michael additions

The intramolecular Michael-type addition of the nitrogen atom of piperidines to activated alkenes located at a C(2)-side chain is a quite common way of access to the quinolizidine system. Some examples are given below. 

---

The pyrimido[6,1 + [ 1,3]oxazines 298 and 300 were formed from the functionalized pyrimidines 297 and 299, respectively, by intramolecular Michael addition. m-Addition was predominant (Equations 29 and 30) <20050BC1964>. 

Some syntheses of decanones and octalones, angularly substituted by a CF3 group, have also been performed by means of radical cyclization or by intramolecular Michael addition. These precursors have allowed access to other steroid derivatives with a trifluoromethyl group in the 19 position (Figure 4.8). ... 

Several groups have prepared cyclopentane systems by intramolecular Michael addition.72 Reaction of the triester (292 Scheme 37) with phenyl vinyl ketone (293) and base produces the cyclopentane (295) in good yield via an intermolecular (giving 294) and subsequent intramolecular Michael addition.72 When the Michael acceptor is a cyclohexenone (Scheme 38), the c/s-fused hydrindanone is produced (298 or 297).72b 72f Spiro systems can also be formed by these reactions (300a,b equation 66) in which the Michael addition gives a spiro ring fusion. 

Condensation of fumaric acid chloride monoethyl ester 147 with aminoalcohol 146, followed by intramolecular Michael addition of the isolated amide 148, afforded the l,4-benzoxazepine-3-acetate 149. The thermodynamically favored 3,5-tram-isomers were obtained (Scheme 21) <2002BMC385, 2002BMC401, 2002JME4571>. 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Scheme 2.54 The domino 1,4-hydride addition followed by intramolecular Michael addition.

Substituted indolizines 18 are formed in Chichibabin reactions of l-[alkyl(aryl)carbonylmethyl]-2-alkylpyridinium halides 17 (Scheme 11) <1972AJC1003>. Various modifications of this method are used for the preparation of many other pyrrolo[l,2-< ]azines and pyrrolo[l,2- ]azoles. Indolizines can also be made by intramolecular Michael additions, e.g., by the cyclization of 2-acylpyridine 19 (Scheme 12). 

In a recent total synthesis of ( )-morphine, the key step was a cyclization step induced by intramolecular Michael addition on a vinylic sulfone followed by bromide displacement (Scheme 77). The entire... 

The cycHc urea moiety provides structural rigidity as well as hydrogen-bonding possibihties similar to those of the imidazoles described above. The corresponding 2-imidazolones have been prepared on a soHd phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate followed by intramolecular Michael addition [73]. However, due to the paucity of data presented on the characterized compounds and the brief experimental procedure, this synthesis is not discussed in detail. Access to cyclic ureas or thioureas has also been obtained by reaction with carbonyl- or thiocarbonyldiimidazole through a cyclo-release mechanism [74—76]. 1,3-Dihydroimidazolones have been obtained by treatment of ureido acetals with TFA and subsequent conversion in an intramolecular cyclization via an N-acyliminium ion [77]. 

Bicyclic products (50) and (51) have been obtained from the protected piperidinone (49) by intramolecular Michael addition (Scheme 31). ... 

Theonella sp. collected off Hachijo-jima Island [30]. Theonellamide F (35) is a bicyclic peptide containing twelve aminoacids. In this cyclic peptide a dehydroalanine residue is masked by intramolecular Michael addition, giving rise to the elaborate and unprecedented histidino-alanine bridge. Further separation of the antifungal fraction of the sponge extract afforded five related peptides, theonellamides A-E [31]. Theonellamide A... 

Goff and Zuckermann [51] reported the synthesis of 2-oxopiperazine 16 by intramolecular Michael addition on the solid phase. The coupling of resin-bound unsaturated dipeptoids with a variety of Fmoc-L-amino acids, N,N -diisopropylcarbodiimide (DIPCDI), and 1-hydroxybenzotriazole (HOBt) affords tripeptoids, which after treatment with 20% piperidine in DMF, were acylated with benzoyl chloride-EtaN in 1,2-dichloroethane. Following treatment with 95% TFA in H2O, a diastereomeric ratio of monoketopiperazines 16 was obtained (Fig. 8). Rather than benzoyl chloride, phenylisocyanate or bromoacetic acid and an amine could be used. 

Intramolecular Michael addition. Stork and co-workers have examined a route to c/s-hydrindanes by intramolecular Michael addition rather than vinylo-gous aldol condensation. Thus the 3,4-disubstituted cyclohexenone 1 undergoes Michael addition rather than aldol condensation when treated with K2CO3 at 20° (40 hours the reaction is hindered by the 8-methyl group). The method should be general. 

A general route to pyrroles has been developed using isocyanides with sodium hydride in the presence of Michael acceptors. The reagents tosylbenzyl isocyanide (TosBIC) and tosyl-methyl isocyanide (TosMIC) have been the preferred reagents in these transformations (eq 50). Pyrroles have also been prepared using sodium hydride in conjuction with -carbonyl-0-methyloximes via alkylation followed by intramolecular Michael addition. ... 

A sequence involving intermolecular Pd-catalyzed carbonylative amidation followed by intramolecular Michael addition has been employed for the construction of isoindolin-l-ones [97dj. For example, treatment of 147 with 4-methoxyaniline under standard conditions for Pd-catalyzed carbonylative coupling gave isoindolinone... 

The simplest p-alkylphenol is p-cresol (35), which has a methyl substituent. One of the first detailed studies of the HRP-catalyzed oxidation of p-cresol was reported in 1976 [51]. Recently, a detailed in situ NMR analysis revealed details of the coupling mechanism of the p-cresol polymerization. NMR and H- H gCOSY 2D NMR analysis suggested that ortho-ortho coupling (43) is the dominant coupling mechanism at the initial stage of the polymerization. The consumption of dimer accelerated only after the complete conversion of the monomer in the reaction mixture. After a reaction time of about 75 min, the formation of Pummerer s ketone (44) was observed. These ketonic species are formed from ortho-para-coupled dimers by intramolecular Michael addition. They are probably not able to participate in the further polymerization process and remain as side products (Scheme 9) [76]. Experiments with 4-propylphenol have revealed that the formation of Pummerer s ketone may be suppressed at lower temperatures [112]. 

We decided to evaluate our hypothesis with readily available substrates having a tethered enone to the starting aldehyde in order to maximize the chances of bond formation (Scheme 18) [141]. After screening for reactimi conditicms, we found that the use of 10 mol% of azolium salt 7 in the presence of DBU was the most efficient combination to promote the reaction and afford 3,4-dihydrocoumarins structures in high yield. The reaction was performed in acetonitrile at low cmicentration to prevent homo-aldol coupling. In this process, acylation of the alkoxide followed by intramolecular Michael addition was a plausible pathway, but it was ruled out after subjecting the acylated substrate to the reaction conditimis, which was found to be mneactive. 

Flavanones 25 are often synthesized by Claisen-Schmidt condensation followed by intramolecular Michael addition reaction of the corresponding chalcone derivative. Climent et al. reported a new environment-friendly method to prepare flavanones 25 by the reaction of 5-substituted-2-hydroxyacetophenones and benzaldehydes using hydro-talcites as basic catalysts (Scheme 16) [81]. Substitution over both aromatic rings influenced the reaction coxu-se leading to flavanones 25 in 7-45% of yields in only Ih of reaction time. 

Gofl996 Goff, D.A. and Zuckermann, R.N., The Synthesis of 2-Oxopiperazines by Intramolecular Michael Addition on Solid Support, Tetrahedron Lett., 37 (1996) 6247-6250. 

The first use of 5 was the addition to the aldehyde 4. The product 6 was ozonized, and the resulting aldehyde was earned on to the cc,P-uiisatuiated ester. Exposure of the hydroxy ester to benzaldehyde under basic conditions delivered, by intramolecular Michael addition, the... 

Guijar et al. converted a C-allyl glycoside to a CAA by hydroxylation of the double bond followed by Jones oxidation [38]. An acid ftmction was also introduced by reacting the free anomeric center with methyl(triphenylphosphor-anylidene) acetate in a Wittig reaction and followed by conversion to a C-glycoside by intramolecular Michael addition, cf. Scheme 5 for the preparation of 36 from 2,3 5,6-di-O-isopropylidene-D-mannofuranose (34) [6]. A disadvantage of this... 

---