Michael cyclization reaction mechanism

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Here catalysis involves the formation of a ruthenium vinylidene, an anti-Markovnikov addition of water (368), and cyclization of an acylmetal species onto the alkene. Although cyclization may occur via hydroacylation (Scheme 52, path A) (460-462) or the Michael addition reaction (Scheme 52, path B) (463,464), the requirement for an electron-withdrawing substiment on the alkene and the absence of aldehyde formation suggest path B to be the more likely mechanism (465,466). Trost discovered that the use of the cationic mthenium catalyst CpRu(MeCN)3+PFg is tolerant of 1,2-di-and trisubstimted alkenes and promotes cyclization of 1,6- and 1,7-enynes to five- and six-membered ring products (467). In a number of examples, the mthenium reaction is complementary to the Pd-catalyzed cyclization described above, selectively forming the 1,4-diene over the traditional 1,... 

Unfettered by the bounds of common Michael acceptors with electron-withdrawing groups, the Glorius group have impressively demonstrated the Stetter reaction of aldehydes with tethered unactivated 1,1-disubstituted alkenes. The cyclization reaction generally proceeds smoothly to afford cyclic ketones with quaternary stereocenters in excellent yields with high enantioselectivity. Based on detailed DFT calculations, they proposed a concerted mechanism for this reaction the proton migration and C—C bond formation between the Breslow enolate and the alkene occur simultaneously (Scheme 7.23). 

A plausible reaction mechanism is illustrated in Scheme 5.50. Initially, Knoevenagel condensation between an aryl aldehyde and malononitrile, under basic conditions, gives Michael acceptor 69, which reacts with intermediate 156 via intermolecular Stetter reaction, leading to adduct 70. Then, upon effect of the base, an intramolecular cyclization occurs to give friran 68. 

Although, at this point, the mechanism of this reaction is not clear, the authors proposed a reasonable mechanism as shown in Scheme 11.6. The formation of cyclohexa-1, 3-dienes was explained as follows firsL the Knoevenagel condensation of aryl aldehyde 53 with malononitrile 54 gives malononitrile 58. Next, the Michael addition reaction of 55 with malononitrile 58 affords intermediate 59, followed by the intramolecular cyclization to render intermediate 60. 

It should be pointed out that the formation of spiro-quinoxaline derivative 134 could be due to the Michael addition of hydrazine to the partially positive C(3) atom of the quinoxalin-2(l//)-one 50 in the first stage of the reaction mechanism with the formation of intermediate A capable reversible tautomerization to intermediate B. Then cyclization involves the nucleophilic attack of the amino group on the carbonyl group of the 3-arylacylidene fragment of quinoxalin-2(l//)-one (Scheme 6.53). 

Feng et al. [104] developed an efficient method combining the advantages of ultrasonication with microwave radiation for the synthesis of polysubstituted pyridines (137) (Scheme 35). The reaction was carried out via a K2CO3-promoted tandem addition/cyclization/hydrogen shift process. The proposed reaction mechanism consists of a Michael addition. 

C) is necessary for the photochemical reaction to compete with thermal Michael addition. The mechanism of the reaction is presumed to involve ET-sensitized addition to yield P-aminoesters, followed by thermal cyclization to yield the lactams. The use of acrylonitrile in place of methyl acrylate affords more complex product mixtures, resulting from trapping of the intermediate radical adducts by acrylonitrile. 

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). 

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. 

This reaction achieves an umpolung cyclization in vhich a terminal alkyne is hydrated and undergoes an intramolecular Michael addition according to the mechanism depicted in Scheme 6.34. 

The chemistry used to prepare the antischistosomal hydroxyquinolines provided the initial entry to this series. Thus, addition-elimination of aminopicoline (38-1) to EMME (38-2) gives the corresponding enamino ester (38-3). Thermal cyclization of that intermediate leads to the hydroxyquinoline (38-4). Reaction of the ambident anion from that compound leads to alkylation via the keto tautomer and thus the formation of the Al-alkylated derivative (38-5). Saponification of the ester then gives nalidixic acid (38-6) [44]. It has incidentally been shown that the presence of the strong Michael acceptor function in this series plays a little role in the mechanism of action in these compounds. 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

In an examination of the mechanism of the solvolysis of the tricyclic alcohol (627) which led to the successful synthesis of seychellene (628), Frater has shown that the minor product is the tricyclic olefin (629) which is formed by the process depicted in Scheme 79. An alternative synthesis of seychellene (628) and patchouli alcohol (635) depends upon the construction of the key tricyclic ketol (631) by an intramolecular Michael reaction followed by an aldol cyclization of (630) (Scheme 80). The minor ketol (632) can be converted into epi-sey-... 

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