Retro-Michael-addition

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

In the synthesis of N heterocycles, this technique also overcomes competitive retro Michael addition that lowers the yield of 1,4-adduct in the Michael addition of amines to nitro olefins. Thus, a toluene solution of nitro olefin 159 was treated with allylamine 160, EtgN, and TMSCI under nitrogen at ambient tern-... 

The reaction starts with the formation of a mixed anhydride and an acetate on treatment with an excess of acetic anhydride at 80 °C. There follows a Dieckmann condensation to give 2-590 and an intramolecular rearrangement/Michael addi-hon/retro Michael addition to afford the desired tetracyclic compound 2-592 via 2-591 in an overall yield of remarkable 92%. 

A retro-Michael addition process leading to an aminomethyl-dihydrodipyridopyra-zine analogue was described by Guillaumet and coworkers in the context of prepar-... 

The recognition of consonant bifunctional relationships in the target molecule allows their disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition [equivalent, according to Corey s formalisation, to the application of the corresponding transforms (= operators) to the appropriate retrons]. 

Bifunctional systems In the case of bifunctional systems (or molecules) only two alternatives are possible the bifunctional relationships are either "consonant" or "dissonant" (apart from molecules or systems with functional groups of type A to which we have referred to as "assonant"). In the first case, the synthetic problem will have been solved, in principle, in applying the "heuristic principle" HP-2 that is to say, the molecule will be disconnected according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-Michael addition, proceeding if necessary by a prior adjustment of the heteroatom oxidation level (FGI). 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

Several studies have shown that the amide bonds that comprise the PAM AM dendrimer backbone are relatively unstable and begin decomposing at temperatures as low as 75 °C [45,50,52,56-58]. The low onset temperature of dendrimer decomposition is not surprising given that PAMAM den-drimers can undergo retro-Michael addition reactions at temperatures above 100 °C [16]. Far more forcing conditions are required to fully activate the catalysts, which suggests that the dendrimer decomposes into various surface species that continue to poison the nanoparticle surfaces. 

The condensation of aminobenzotriazoles with DMAD gave (Z)-conjugate addition adducts which underwent ring closure in boiling Dowtherm to give triazolo[4,5-/]quinolinones (100) (Equation (57)) <93H(36)259>. The quinolinone form of the product (100) is supported by 13C NMR spectroscopic evidence. It was found that ring closure to the tricycle fails in the absence of an N-methyl substituent retro-Michael addition takes place instead. 

The retro-Michael addition is shown in Scheme 2.40. The standard components are generated, with the enolate acting as an equivalent to a carbanion and an a,/S-unsaturated carbonyl compound as an equivalent to the cationic counterpart. 

Retro-Diels-Alder cycloaddition Retro-Michael addition Retro [2 + 2] cycloaddition... 

Compound 568 is transformed into 569 by heating in DMF, evidently via ring opening (retro-Michael addition) and subsequent oxidative cyclization <1998HCA718>. 

An alternative process can be imagined where the Michael addition is the product-determining step (Case B, Scheme 7). In this circumstance, collapse of the dipolar intermediate is more rapid than retro-Michael addition and thus a kinetically controlled process is responsible for determining the relative configuration of the stereogenic centers that result from the conjugate addition.1... 

Not reported retro-Michael addition occurred during recrystallization. 

As in the uncatalyzed reactions with enamines (vide supra), there is potentially more than one point where stereochemical differentiation can occur (Scheme 59). Selectivity can occur if the initial addition of the enol ether to the Lewis acid complex of the a,/J-unsaturated acceptor (step A) is the product-determining step. Reversion of the initial adduct 59.1 to the neutral starting acceptor and the silyl enol ether is possible, at least in some cases. If the Michael-retro-Michael manifold is rapid, then selectivity in the product generation would be determined by the relative rates of the decomposition of the diastereomers of the dipolar intermediate (59.1). For example, preferential loss of the silyl cation (or rm-butyl cation for tert-butyl esters step B) from one of the isomers could lead to selectivity in product construction. Alternatively, intramolecular transfer of the silyl cation from the donor to the acceptor (step D) could be preferred for one of the diastereomeric intermediates. If the Michael-retro-Michael addition pathway is rapid and an alternative mechanism (silyl transfer) is product-determining, then the stereochemistry of the adducts formed should show little dependence on the configuration of the starting materials employed, as is observed. 

The standard Ireland conditions for the ester enolate rearrangement (lithium diisopropylamine, tetrahydrofuran) give a retro-Michael addition product in this ease. However, silyl ketene acetal 15 is successfully obtained by the silyl triflate/triethylamine protocol539 for the preparation of ketene acetals which proceeds via a silyladon and then deprotonation mechanism560-563. 

Another aspect to Rogers s work on the synthesis of unsymmetrical hydroxylamines (Section 4.2.5.1) is that the elimination step is base catalyzed (occurring at room temperature).16 Salts of amine oxides derived from P-aminopropionic esters 45 or nitriles 46 undergo the reaction, which involves a retro-Michael addition, facilitated by the formal positive charge on nitrogen. 

The 1,4-dihydropyridine 148 (as well as the 3,4-dihydropyridine 147 which is retrosynthetically equivalent) can be linked with the retrosynthetic process a. As a double enamine, it could be derived from the enaminone 149 (via h), which in turn should be accessible (via i) from the 1,5-dicarbonyl system 150 and NH3 by cyclocondensation. The systems 149 and 150 are retroanalytically interlinked, not only by dehydrogenation of 145 and 146 respectively, but also by a retro-MiCHAEL addition involving enamines or enolates with a, p-unsaturated carbonyl systems as starting materials for the synthesis of 1,4-dihydropyridines. 

Tetrahydrodiazepin-5-ones, when heated with HCl, are transformed by retro-Michael addition and recondensation into alkenylpyrazoles (Scheme 7) <84H(22)2265>. 

Nal chiral amines such as DBU, ° (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, C2-symmetric (2S,55)-2,5-diphenylpyrrolidine, (-)-quinine, and proline polymer catalysts such as antibody 38C2" and polymer-anchored chiral catalysts and solid base catalysts such as MgO and Mg-Al-O-r-Bu hydrotalcite. Furthermore, the solvent-free Michael addition has been established by application of CeCb 7H20-NaI as catalyst or microwave irradiation of reactants on BiCb or Cdh, EuCb, CeCb 5H20, and alumina surfaces. It is interesting that the thermal treatment or microwave irradiation of 1,5-ketodiesters or 1,5-diketones in DMSO in the presence of NaX (X = Cl, Br, I) results in the retro-Michael addition. ... 

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