Friedel Michael addition reactions

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Figure 1 A decision tree for classifying Friedel-Crafts, free radical, and Michael addition reactions sharing the reaction center shown in Figure 2...

We will show here the classification procedure with a specific dataset [28]. A reaction center, the addition of a C-H bond to a C=C double bond, was chosen that comprised a variety of different reaction types such as Michael additions, Friedel-Crafts alkylation of aromatic compounds by alkenes, or photochemical reactions. We wanted to see whether these different reaction types can be discerned by this... 

The elfectiveness of imidazolidinone of type 11 was confirmed by successful application to a broad range of chemical transformations, including cycloadditions, conjugate additions, Friedel-Crafts alkylations, Mukaiyama-Michael additions, hydrogenations, cyclopropanations, and epoxidations. A summary of these enantio-selective iminium catalyzed processes is provided by reaction subclass. 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

The analogy between imines and carbonyls was introduced earlier, and just as 1,3-dike-tonate complexes undergo electrophilic substitution reactions at the 2-position, so do their nitrogen analogues. Reactions of this type are commonly observed in macrocyclic ligands, and many examples are known. Electrophilic reactions ranging from nitration and Friedel-Crafts acylation to Michael addition have been described. Reactions of 1,3-diimi-nes and of 3-iminoketones are well known. The reactions are useful for the synthesis of derivatised macrocyclic complexes, as in the preparation of the nickel(n) complex of a nitro-substituted ligand depicted in Fig. 5-12. 

Bicyclic 3a//-cyclopentene[8 annulcnc-l,4-(5//,9a//)-dioncs undergo three types of acid-induced transannular reactions (1) Michael addition (5-exo-trig or 6-exo-trig) leading to the tetracyclic diones, (2) 3 + 2-cycloaddition followed by a novel sequential skeletal rearrangement to 2-naphthalenone derivatives, (3) ipso-Friedel-Crafts alkylation accompanied by the rearomatization and the loss of water (Scheme 25). The factors that control the reaction mode of these transannular cyclizations are discussed... 

The synthesis of the optically active chroman 489 can be achieved by use of a catalytic asymmetric tandem oxa-Michael addition Friedel-Crafts alkylation sequence between 3-methoxyphenol and (/. (-methyl 2-oxo-4-phenylbut-3-enoate. The chiral C2-symmetric box managanese(n)- complex 490 exerts excellent stereocontrol upon the reaction (Equation 200) <20030BC1953>, whereas only moderate enantioselectivity is observed in the presence of a chiral C2-symmetric 2,2 -bipyridyl copper(n)- complex (42% = ee) <20050L901>. 

A Lewis-acid-promoted cyclization of ethene tricarboxylate derivatived aromatic compounds 1162 provides a route to isochroman-3-ones 1163 via a Friedel-Crafts intramolecular Michael addition protocol. The substrate must possess two ///f to-positioncd electron donating groups in order for the reaction to proceed (Equation 452) <20040BC3134>. 

Roelfes s supramolecular assembly is one of the most efficient enan-tioselective catalysts for aqueous Michael additions. The DNA template approach has also been used for enantioselective Friedel-Crafts reactions in water, with outstanding results in terms of conversion and enantioselectivities (110). All these results confirm the impressive potential of DNA-based enantioselective catalysis. 

The tricyclic precursor 87b was easily obtained from 87a in two steps in an overall 90% yield. The condensation of 87b and 88b via a Friedel-Crafts reaction, followed by an intramolecular Michael addition and oxidation, led to a one-pot formation of the intermediate pentacyclic product 89 in ca. 30% yield. The conversion of 89 into 83 was accomplished by standard procedures of oxidation and demethylation. 

The electrophilicity index also accounts for the electrophilic activation/deactivation effects promoted by EW and electron-releasing substituents even beyond the case of cycloaddition processes. These effects are assessed as responses at the active site of the molecules. The empirical Hammett-like relationships found between the global and local electrophilicity indexes and the reaction rate coefficients correctly account for the substrate selectivity in Friedel-Crafts reactions, the reactivity of carbenium ions, the hydrolysis of esters, the reactivity at the carbon-carbon double bonds in conjugated Michael additions, the philicity pattern of carbenes and the superelectrophilicity of nitronium, oxonium and carboxonium ions. This last application is a very promising area of application. The enhanced electrophilicity pattern in these series results from... 

Microencapsulated Sc(OTf)3 has shown considerable promise for both batch and flow reactions in those procedures in which the reaction was recirculated through columns containing the reagent. This reagent was found to be more reactive than the monomeric Lewis acid. One example is the TMS-mediated Michael reaction shown in Figure 3.25. Microencapsulated Sc(OTf)3 was also found to be useful for Mannich reactions, Michael additions, and Friedel-Crafts—like acylations [51]. 

Oxoalkylbismuthonium salts react with a sodium salt of dibenzoylmethane to alkylate the active methylene carbon [304]. Treatment of a mixture of Ph3BiF2 and allyltrimethylsilane with lii, -O Hl, in the presence of excess electron-rich arenes yields allylated arenes via the Friedel-Crafts reaction (Scheme 14.149) [305]. The action of tBuOK on a mixture of alkenylbismuthonium salt and styrenes gives al-kylidenecyclopropanes in high yield (Scheme 14.150) [306]. Michael addition of sodium p-toluenesulfinate to a 1-hexynylbismuthonium salt results in the formation of 3-methyl-l-tosylcyclopentene [307]. 

To date, no known bisindole alkaloid has been shown to be only an artefact. In addition, no experimental evidence exists which undermines the assumption that bisindole alkaloids are actually formed from the completed monomeric partners. Support for this idea is derived from the kind of reactions apparently necessary to effect such dimerisations which are known biogenetic processes amine-aldehyde condensations, Mannich reactions, Michael additions, Friedel-Craft type condensations, Diels-Alder type processes, radical coupling etc. The observation that the skeletal distribution amongst monomeric alkaloids is reflected throughout the dimeric series lends further support. 

Synthesis by Other Cyclizations. The epimeric amines (49) have been made by means of a novel S 2 reaction of the corresponding 2-bromo-6-amino-cyclohexanone derivative. Double Michael addition of (+)-a-methylbenzyl-amine to cyclo-octa-2,7-dienone derivatives forms the basis of a synthesis of the enantiomeric forms of adaline (50). Intramolecular Friedel-Crafts alkylation has been used in the synthesis of derivatives of the 2,6-methanobenz-azepine, 2,6-methano-3-benzazocine, 2,6-methano-3-benzazonine, and... 

---