Michael reactions intramolecular additions

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. 

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. 

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. 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

With an excess of a highly nucleophilic Michael donor (phenylsulfanate, piperidine, dimeth-ylamine), the addition products can further undergo substitution of the chlorine. In an intramolecular version of this conversion, cyclic skeletons 18 were prepared in a single step engaging a Michael addition-substitution reaction sequence. In a few cases attack at the ester carbonyl functionality of 17 led to lactams 19. ... 

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. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

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... 

In 2011, the Fukuyama group reported the first total synthesis of (-)-conophylline, whose structure consists of two pentacyclic aspidosperma skeletons (Scheme 13.5) [6]. The two aspidosperma skeletons were both constructed through a similar intramolecular Michael addition/Mannich reaction cascade stfategy, which could produce three new rings and three new stereogenic centers with complete stereoselectivity in just one step. 

Many important intramolecular reactions, such as aldol reaction, Michael addition, transannular reaction, and a-alkylation reaction, could be reaUzed via enamine catalysis. 

The Smith group, in 2011, developed a highly diastereo- and enanhoselective intramolecular Michael addition/lactonization reaction. The authors applied a chiral tetramisole (74) to catalyze the cyclization of multifunctional substrates 75 or 77, affording fused indanes 76 or dihydrobenzofuran carboxylates 78, respectively, in good yields and with excellent ees (Scheme 36.20) [26]. 

Scheme 36.20 Organocatalytic intramolecular Michael addition/lactonization reaction.

Intramolecular Michael Addition 5-exo-tet favored Organic Reactions 1995, 47, 315-552... 

---