Michael addition, intramolecular

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6 ... 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

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. 

Macrolactone synthesis 6,51, 71, 72, 94, 124,131,163,187,195 McMurry coupling 43 Medium ring synthesis 43,45,75, 77 Metathesis, Alkene (see Grubbs) Metathesis, Alkyne (see alkyne metathesis) Michael addition Intramolecular 166,166, 167,201 Intermolecular 57,84, 153, 166,204... 

Tandem intramolecular Michael addition - intramolecular alkylation can lead to cyclopropanes. Matthew J. Gaunt of the University of Cambridge has shown (Angew. Chem. Int. Ed. 2004,43, 2681) that this intramolecular Michael addition also responds to organocatalysis. In this case, the catalyst, a quinine-derived amine, covalently binds to the substrate, then is released at the end of the reaction. 

Quinoline, Isoquinoline, and their Benzo- and Hydro-derivatives. - Relatively few syntheses of quinolines are based on 2,3-disubstituted pyridines a recent addition to their number is illustrated in Scheme 33. The essential steps are Michael addition, intramolecular acylation, and aromatization via loss of toluene-p-sulphenic acid. ... 

Compound (120) was prepared from 8,10-dihydrosweroside aglucone (32), which could be alkylated in aprotic solvent in the presence of a strong base to (33). However, under the same conditions, but in the absence of the alkylating agent, a sequence of four base-catalyzed reactions (dimerization by a vinylogous Michael addition, intramolecular aldolization, lactonization and cyclization by hetero Michael addition) gave the final product (120). Detailed analysis of its formation would exceed the frame of this paper [result to be published]. 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

In 2013, Enders and co-workers reported a kinetically controlled asymmetric organocatalytic Michael addition/intramolecular Henry domino reaction, providing a facile access to enantioenriched cis-nitroindanol products 164 in excellent yields (61->99%) with up to 97% ee and 17 1 dr (Scheme 6.77). ... 

A solid-supported carbonate reagent was used to initiate the formation of 2H-l,4-benzoxazin-2-ones 303 from P-nitroacrylate 301 and 2-aminophenol 302 (Scheme 7.72) [154]. This hetero-Michael addition/intramolecular transesteri-fication/elimination of HN03/[l,3]-proton shift domino reaction proceeded in moderate to excellent yields. In another study, a series of various functionalized pyrrolo[l,2-r]pyrazines 305 were made synthetically available through the reaction of vinyl azides 304 and lH-2-pyrrolecarbaldehyde (Scheme 7.73). The deprotonated pyrrole initially reacts in a Michael manner with the vinyl azides, with nitrogen as... 

Scheme 7.73 Michael addition intramolecular condensation reaction.

A soln. of 2-carbomethoxy-2-cyclohexenone in chloroform added during 25 min to a mixture of startg. p-ketoester and 0.47 eqs. CS2CO3 in the same solvent at room temp., 2.5 h later CS2CO3 removed, and the crude product refluxed with / -TsOH in benzene product. Y 70% (99.5% cis-cis isomer). Solvent effects and reaction mechanisms s. P. Deslongchamps, J.-F. Lavallee, Tetrahedron Letters 29, 5117-8 (1988) 14a-hydroxysteroids by sequential Michael addition-intramolecular aldol condensation s. ibid. 6033-6. 

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[l)]thiophene-4,6-dicarbonitriles was synthesized by a one-pot domino reaction of 5-aryldihydro-3(2H)-thiophenes, malonitrile, and aromatic aldehydes in the presence of morpholine (13BMCL2101). A mechanism was proposed that involves a sequence of Knovenagel condensation, Michael addition, intramolecular Thorpe-Ziegler cyclization, tautomerization, and elimination. The compounds were evaluated for their AChE (acetylcholinase) activity. The 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[l)] thiophene-4,6-dicarbonitrile was found to be the most potent with IC50 4.16 xmol/L. 

The tandem Michael addition-intramolecular Wittig reaction of the five-membered cyclic phosphonium ylide (174), generated from the phosphonium salt (173), with Q, /3-unsaturated thioester (175) afforded a diastereoisomeric mixture of cycloheptene derivatives (176a,b), in which the cw-diastereoisomer (176a) prevailed (Scheme 27). The reaction can be rationalized as proceeding via a rigid phosphabicyclic intermediate... 

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