Michael addition/cyclocondensation

The Cl sequence introduced in Chap. 2.2 represents a mild and catalytic access to chalcones. l,3-Diarylprop-2-en-l-ones are bifunctional electrophilic Michael-systems and per se important three-carbon building blocks in synthetic heterocyclic chemistry [33]. Among many classes of five-, six-, and seven-membered heterocycles the underlying principle is always the Michael-addition-cyclocondensation sequence of chalcones and bifunctional nucleophiles [176-181, 222-229]. Furthermore, chalcones can also participate in cycloadditions, as dienophiles and dipolar-ophiles and furnish in the case of 1,3-dipolar cycloadditions with diazo alkanes pyrazolines [230, 231], with azides triazolines [232], with nitrones isoxazolidines [233] with azomethinylides pyrrolidines [234], or with nitriloxides isoxazolines [235]. Therefore, the mild, catalytic access to chalcones by the CIR excellently sets the stage for the development of consecutive MCRs based upon cyclocondensation strategies. 

Recently, Muller and co-workers [145] have reported a series of 3,5-disubstituted and 1,3,5-trisubstituted pyrazoles 104 and 105 by reacting an acyl chloride, a terminal alkyne and a hydrazine via a consecutive one-pot three-component Sonogashira coupling/Michael addition/cyclocondensation sequence under microwave irradiation. The desired products were obtained in good to excellent yields. These obtained pyrazoles are highly fluorescent, both in solution and in the solid state (Scheme 81). 

A novel one-pot approach for the synthesis of 2,4-disubstituted 3//-benzo[h] [1, 5]diazepines 115 has been disclosed by Muller and co-workers [163]. The compounds were obtained in good yields by the reaction of an acyl chloride, a terminal alkyne and a benzene-1,2-diamine via a consecutive one-pot, three-component Sonogashira coupling/Michael addition/cyclocondensation sequence, under micro-wave irradiation (Scheme 89). 

The biselectrophilic reactivity motif of alkynones is also present in 3-substituted alkyl propiolates 2. Utilizing the previously described Michael addition/cyclocondensation approach with various binucleophiles allows the introduction of oxo/hydroxyl substituents to the heterocycle. An example of the concept is the copper(I)-catalyzed carboxylation of terminal alkynes, which allows the convenient synthesis of 3-substituted alkyl propiolates 2 a by trapping the intermediary carboxylate with methyl iodide. This one-pot procedure can be expanded to a three-component process by adding binucleophiles such as amidines 36 and hydrazines 20 to furnish the corresponding 2,6-disubstituted pyrimidin-4(3fl)-ones 54 and 1,5-disubsti-tuted 3-hydroxypyrazoles 55 in a one-pot fashion. The incorporation of nontoxic, abundant and economical carbon dioxide provides an environmentally benign access to interesting heterocyclic structures (Scheme 33) (2014ASC(356)3135). 

An acid-catalyzed Michael addition-cyclocondensation reaction of alk5mones with thiophenol has been utilized to have quick access to a range of 2,4-disubstituted benzothiazepines 95 (Scheme 16) wherein the beneficial role of MW... 

SCHEME 16 Tandem Michael addition-cyclocondensation leading to benzothiazepines. MW, microwave. 

The reaction of carbanions derived from tetrahydrothiopyran-4-one and its benzologue with the pyran-2-one 500 (X = COzMe, Y = MeS) affords isothiochromans and 67/-dibenzo[AY]thiopyrans, respectively, through a carbanion-mediated annulation sequence outlined in Scheme 185. In the latter case, the actual product depends on the amount of base used with an excess, Michael addition of hydroxide ion is preferred to a cyclocondensation and results in the displacement of MeS and formation of a hydroxy-substituted dibenzo[AY]thiopyran <2001JOC5333, 2002J(P1)1426>. 

MUller reports a four component, one-pot synthesis of pyridines <02TL6907>. For example, aryl halide 15 and propargylic alcohol 16 were combined in the presence of copper and palladium to afford enone 17. The addition of cyclic enamine 18 led to Michael addition and the subsequent cyclocondensation was achieved by adding ammonium chloride and acetic acid (19—>20). Other multicomponent approaches to substituted pyridines have been reports by Litvinov <02RCBIE362>, Elkholy <02SC3493> and Veronese <02T9709>. 

Bismuth(m) nitrate catalyzes Michael addition of a,/Yunsaturated ketones with amines, thiols, and carbamates, although the promoting role of Bi(N03)3 is not fully understood (Equation (91)).100 The Biginelli cyclocondensation of a mixture of (3-keto esters, aldehydes, and urea is mediated by BiCl3, affording 3,4-dihydropyrimidin-2(lH)-ones (Equation (92)).149 Bi(OCOCF3)3 is an efficient catalyst for the regio- and chemoselective synthesis of /3-enaminones in water.150... 

The enaminedione may be heterocyclic and its intramolecular condensation via Michael addition of an indole moiety is possible, as shown in a new, easy and simple route to the olivacine-type alkaloid ring system by cyclocondensing a substituted indolylethyl-aminomethylenepiperidine-2,4-dione, followed by elimination of ethanea-mine moietyr89 (equation 214). 

A series of tetrasubstituted thiazole derivatives 28 has been prepared via a multi-component tandem protocol <07T10054>. Reaction of bis(aroylmethyl)sulfides 23 with aryl aldehydes and ammonium acetate in 1 2 1 ratio under solvent-free microwave irradiation affords 28 in good yields. This reaction presumably starts with Knoevenagel condensation of sulfide with 2 equiv. of aryl aldehydes to give 24. Michael addition with ammonia and concomitant cyclocondensation lead to 26. Base-catalyzed ring opening of 26 to 27 and ring... 

Reactive three-carbon building blocks such as alkynones [32] and 1,3-diaryl pro-penones (chalcones) (for a review on the chemistry of 1,3-diaryl propenones, see e.g. [33]) which can react with bifunctional nucleophiles in a sequence of Michael addition and cyclocondensation open a facile access to five-, six-, and seven-membered heterocycles (Scheme 1). As a consequence, this general strategy has found broad application. However, standard syntheses of alkynones [34] and chalcones [33] are often harsh and require either strongly basic or strongly Lewis or Brpnsted acidic conditions. Therefore, the application in one-pot methodology, where delicately balanced reaction conditions are a prerequisite, is largely excluded. 

Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation Sequences Concluded by Michael Addition in Basic Media... 

Alkynones are potent Michael acceptors in heterocyclic chemistry and many five-, six-, and seven-membered heterocycles can be synthesized from reactive, bifunctional three-carbon building blocks such as alkynones by classical heterocyclic chemistry [32]. Taking into account the mild, catalytic access to alkynones the coupling-addition-cyclocondensation sequence for multicomponent approaches to five-, six-, and seven-ring heterocycles lies at hand (Scheme 19). 

Syntheses of 1,5-benzothiazepines can be achieved through various routes starting from 2-aminothiophenol and 1,3-drfunctional three-carbon budding blocks [184, 185]. Among them, a,(3-unsaturated carbonyl compounds such as enones [186-188] and ynones [189-192] are suited best for Michael addition and subsequent cyclocondensation. 

After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, ortho-ammo thiophenols 52 and acetic acid are added and reacted in the same reaction vessel under dielectric heating for 30 min at 60°C to furnish 2,4-disubstituted benzo[h][l, 5] thiazepines 53 via a coupling-addition-cyclocondensation sequence (Scheme 31) [193]. In the concluding heterocyclization step, dielectric heating is clearly superior over conductive heating. Although the Michael addition and cyclocondensation are essentially completed after 10 min at 60°C in the microwave cavity for electronically diverse substitution a reaction time of 30 min at 60°C has proven to be optimal. In contrast to 2,4-disubstituted benzo[h][l,4]diazepines 51 (vide supra), benzo[h] [1, 5]thiazepines 53 are essentially nonfluorescent. 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

Michael addition of 1 to dimethyl acetylene dicarboxylate in the presence of sodium methoxide, potassium fluoride, or aluminum trioxide gave 435 (R = Me) via an intermolecular cyclocondensation (89MI87). Regioselective cycloaddition of propargylic alcohol and dimedone in the presence of thiolate-bridged diruthenium complex afforded the tetrahydrobenzo[fr]pyran 451 (04JOC3408). 

Michael additions between the thioamido ester (200) and alkyl-3-methyl-2-oxobut-3-enoates (201) in the presence of an acid gives the thiazines (202) (Equation (24)) <88SC1043>, and in yet another variation on this theme ethyl propiolate (203) and 7V-phenylthiourea can be cyclocondensed to yield... 

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. 

Formation of the 1,4-dihydropyridines 165 occurs by two routes. In the first, NH3 and the P-dicarbonyl compound combine to give a P-enaminone 168, whereas the aldehyde and dicarbonyl compound interact to produce an a,p-unsaturated ketone 167 as the result of a Knoevenagel condensation 167 and 168 now undergo a Michael addition to give 5-aminopent-4-enones 169, followed by cyclocondensation. Alternatively, the two molecules of the P-dicarbonyl compound may interact with the aldehyde by Knoevenagel condensation followed by Michael addition to the 1,5-dicarbonyl system 170, which undergoes cyclocondensation with NH3. 

Michael addition, and cyclocondensation of acid chlorides 4, terminal alkynes 5, and 2-aminothiophenols 52 (Scheme 32) (2010MDV(14)443). 

Perumal has described a four-component sequential protocol that allows the synthesis in good yields of antitubercular 2-aryl-5-methyl-2,3-dihydro-l/f-3-pyrazolones 18 from atylhydrazines, methyl acetoacetate, aromatic aldehydes and 5-naphthol in the presence of / -TSA in water under reflux conditions [13], The reaction proceeds by an initial acid-catalyzed cyclocondensation of the hydrazine and dicarbonyl components to give pyrazolinone 19. A parallel acid-catalyzed condensation between p-naphthol and the aromatic aldehyde affords the intermediate quinone methide 20, and Michael addition of the enol form of 19 onto the exocyclic double bond of 20 furnishes the final product (Scheme 1.9). 

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