Michael addition mechanism

The maleimide group can undergo a variety of chemical reactions. The reactivity of the double bond is a consequence of the electron withdrawing nature of the two adjacent carbonyl groups which create a very electron-deficient double bond, and therefore is susceptible to homo- and copolymerizations. Such polymerizations may be induced by free radicals or anions. Nucleophiles such as primary and secondary amines, phenates, thiophenates, carboxylates, etc. may react via the classical Michael addition mechanism. The maleimide group furthermore is a very reactive dienophile and can therefore be employed in a variety of Diels Alder reactions. Bisdienes such as divinylbenzene, bis(vinylbenzyl) compounds, bis(propenylphenoxy) compounds and bis(benzocyclobutenes) are very attractive Diels Alder comonomers and therefore some are used as constituents for BMI resin formulations. An important chemical reaction of the maleimide group is the ENE reaction with allylphenyl compounds. The most attractive comonomer of this family is DABA particularly when tough bismaleimide resins are desired. 

The Michael addition mechanism, whereby sulfur nucleophiles react with organic molecules containing activated unsaturated bonds, is probably a major pathway for organosulfur formation in marine sediments. In reducing sediments, where environmental factors can result in incomplete oxidation of sulfide (e.g. intertidal sediments), bisulfide (HS ) as well as polysulfide ions (S 2 ) are probably the major sulnir nucleophiles. Kinetic studies of reactions of these nucleophiles with simple molecules containing activated unsaturated bonds (acrylic acid, acrylonitrile) indicate that polysulfide ions are more reactive than bisulfide. These results are in agreement with some previous studies (30) as well as frontier molecular orbital considerations. Studies on pH variation indicate that the speciation of reactants influences reaction rates. In seawater medium, which resembles pore water constitution, acrylic acid reacts with HS at a lower rate relative to acrylonitrile because of the reduced electrophilicity of the acrylate ion at seawater pH. 

Salinity exerts a positive influence on the rate of the addition reaction depending on the polarizability of the organic molecule. This effect is pronounced for unsaturated molecules containing a terminal carboxyl group. These results suggest that hypersaline palaeoenvironmental conditions would have favored organosulfur formation by the Michael addition mechanism. 

Further evidence for the addition of H2S to carbon-carbon double bonds very early in sediments, and further insights into reaction mechanisms, have been reported by Vairavamurthy and Mopper in 1987 and 1989 (109.110). They identified 3-mercaptopropionic acid (3-MPA) as a major thiol in anoxic intertidal marine sediment and demonstrated that the thiol formation could occur by the reaction of HS with acrylic acid in sediment water and seawater at ambient temperature The formation of 3-MPA was hypothesized to occur by a Michael addition mechanism whereby the nucleophile HS adds to the activated double bond in the a,/3-unsaturated carbonyl system ... 

The Timmis reaction makes use of the regioselective condensations of 6-amino-5-nitroso-pyrimidines with aldehydes, ketones, esters, and nitriles under base catalysis. An extension of this principle is seen in the condensation reaction of 6-amino-5-nitroso-(320) and 6-amino-5-phenylazo-1,3-dimethyluracils (321) with dimethyl alkenedicarboxylate and propiolamide, respectively, leading by a Michael addition mechanism to 6,7-bis(methoxycarbonyl)- (322) and 6-carbamoyl-l,3-dimethyllumazine (323) (Scheme 52) <82JHC949>. 

Figure 42 Michael addition mechanism (reaction a) and enamine mechanism (reaction b) of inactivation of GABA-AT by...

Iglesias, M Marinas. JM Sinisterra. JV. Barium hydroxide as catalyst in organic reactions. XVI. Contribution to the study of the Michael addition mechanism to chalcone in imerfacial solid-liquid conditions. Tetrahedron. 1987 43, 2335-2342. 

The previously accepted pathway consisted of P-H oxidative addition to Pt(0) to form 19 followed by coordination and insertion of the alkene in the Pt-P bond to form 20 and a final reductive elimination to furnish the product and regenerate the catalyst. Another possibility is the nucleophilic attack of phosphido complex 19 to the alkene ( Michael addition mechanism, as in anionic polymerisation) to generate the zwitterionic intermediate 21. This complex can yield the hydrophosphination product 11 via one of two complementary pathways. Carbanion attack at the cationic platinum hydride i.e. intramolecular hydrogen transfer) would yield the final phosphine complexed to Pt(0) that would be displaced by an equivalent of PHR R to furnish, after oxidative addition, starting complex 19. Alternatively, the anionic carbon atom in 21 could attack the platinum centre directly, forming the cyclic intermediate 22. From here Pt-P bond dissociation would generate 20, which would furnish the product after reductive elimination. 

The Michael addition mechanism offers an easy explanation for by-product formation if zwitterion 21 attacks a second molecule of alkene instead of the proton transfer in Scheme 6.10. In this case (Scheme 6.11), the newly generated zwitterion 21 can yield a by-product with two alkene fragments or attack another alkene to eventually produce by-products derived from the insertion of three or more alkenes (23). 

To test the validity of this mechanism, it was reasoned that a weak add (t-BuOH or water) should quench the zwitterion 21 and suppress or at least decrease the formation of by-products. This is indeed the case, although the addition of more alkene increases the quantity of by-products, even in the presence of t-BuOH. It should be noted that the presence of these protic additives is not innocent, since it also increases the reaction rates and affects the enantioselectivity. For example adding 20 equivalents of t-BuOH to the reaction of PH(Is)Me with tert-butyl acrylate halves the time for the completion of the reaction (from 5 to 2 days) and doubles the enantiomeric excess from 28% to 56%. The latter enantioselectivity is the best obtained to date with the systems discussed in this section. More evidence for the Michael addition mechanism came from trapping intermediate 21 with electrophiles other than a proton. Scheme 6.12 shows that performing the hydrophosphination reaction in the presence of benzaldehyde produced some of the three-component coupling product 25. 

Figure 14.6 Michael addition mechanism between ethyl acetoacetate and methyl acrylate. Modified from Mather, B.D., Viswanathan, K., Miller, K.M., Long, T.E., 2006. Michael addition reactions in macromolecular design for emerging technologies. Prog. Polym. Sci. 31, 487—531 with permission from Elsevier.

The reaction of 3-acetyl-2H-l-benzopyran-2-ones with malononitrile affords dicya-nomethylene derivative (213), which dimerizes via a Michael addition mechanism to generate (214) the subsequent cascade eventually produces (215). ... 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

The mechanism of both syntheses has been studied in detail, and well summarized (44,45). Interesting questions remain for example, in neither of these sequences is it certain whether the carbonyl compound or its Schiff base is undergoing Michael addition. 

Fig. 5. Curing mechanism of a maleimide resin via Michael addition.

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

There is no published mechanistic study on the Auwers flavone synthesis. The mechanism may involve the nucleophilic addition of oxonium 7, derived from 1, with hydroxide to give 8. Base-promoted ring opening of 8 could provide the putative intermediate 9, which then could undergo an intramolecular Michael addition to form 10. Expulsion of bromide ion from 10 would then give flavonol 2. 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

The intramolecnlar Michael addition is used as a key step for synthesis of epibaddine fScheme4 36 Epibaddine is an analgesic, operating by a nonopioid mechanism, it is severiil hundred dmes more potent than morphine... 

The powerful nucleophilicity of enaimnes illows the dclthcion of rutro ilkenes to take place without the presence of Lewis acids The isolanon of secondary products, which can be explained by an initial Michael addition, suggests the participation of zwitlerionic intermediates m the mechanism of the reaction fEq 8 97i... 

Thomsen Click Organic Process to view an animation showing the mechanism of the Michael addition reaction. 

Fermenting baker s yeast also catalyzes the 1,4-addition of a formal trifluoroethanol-d1-synthon to a,/i-unsaturated aldehydes, to give optically active l,l,l-trifluoro-2-hydroxy-5-alka-nones52. Presumably, the mechanism involves oxidation of the alcohol to the corresponding aldehyde followed by an umpolung step with thiamine pyrophosphate and Michael addition to the a,/i-unsaturated aldehyde. For example, l,l,l-trifluoro-2-hydroxy-5-hexanone (yield 26%, ee 93%) is thus obtained from trifluoroethanol and l-bnten-3-one. 

Three possible mechanisms may be envisioned for this reaction. The first two i.e. 1) Michael addition of R M to the acetylenic sulfone followed by a-elimination of LiOjSPh to yield a vinyl carbene which undergoes a 1,2 aryl shift and 2) carbometallation of the acetylenic sulfone by R M followed by a straightforward -elimination, where discarded by the authors. The third mechanism in which the organometallic reagent acts as an electron donor and the central intermediates is the radical anion ... 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

As indicated, many of the more highly fimctionalized building blocks did not result in 2-pyridones. However, a thorough structure elucidation of by-products and intermediates was used to propose a mechanism for the formation of the 2-pyridone core based on a Michael addition followed by a Dimroth-type rearrangement (Fig. 3). 

The HX compounds are electrophilic reagents, and many polyhalo and polycyano alkenes, (e.g., Cl2C=CHCl) do not react with them at all in the absence of free-radical conditions. When such reactions do occur, however, they take place by a nucleophilic addition mechanism, (i.e., initial attack is by X ). This type of mechanism also occurs with Michael-type substrates C=C—Z, where the orientation is always such that the halogen goes to the carbon that does not bear the Z, so the product is of the form X—C—CH—Z, even in the presence of free-radical initiators. Hydrogen iodide adds 1,4 to conjugated dienes in the gas phase by a pericyclic mechanism ... 

Lipase from C.antarctica also catalyzes carbon-carbon bond formation through aldol condensation of hexanal. The reaction is believed to proceed according to the same mechanism as the Michael additions [113]. Lipase from Pseudomonas sp. 

Adiponitrile is produced at over 1 million tpa and, being used in the manufacture of hexamethylene diamine and (to a small extent) adipic acid, it is by far the highest-volume organic material that is produced electro-chemically. The mechanism (Scheme 7.13) involves electrolytic reduction of acrylonitrile followed by protonation, further reduction, Michael addition and a final protonation step. 

Fig. 32 Proposed cooperative bimetallic intramolecular mechanism for the enantioselective Michael addition of a-cyanoesters 57 to vinylketones...

In a related example, reaction of N-hydroxy-N-methylthiophene-2-carboximidamide 56 with DMAD gave a double Michael addition product 57, which when heated at reflux in xylenes, afforded hydroxypyrimidinone 60 in 57% overall yield (Scheme 6.21) [9f]. The mechanism invoked was opening of the oxa-diazole 57 to 58, followed by a [3,3]-Claisen-type rearrangement to 59, which, after tautomerization and cyclization, afforded 60. 

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