Michael addition Of anilines

Problem 20.37 Ouinoline is prepared by the Skraup reaction of aniline, glycerol and nitrobenzene. Suggest a mechanism involving Michael addition of aniline to an a,)3-unsaturated aldehyde, ring closure, and then dehydration and oxidation. 

Condensation reactions remain popular for the synthesis of quinolines <2006JOC6592>. Some modern variations on these classic reactions include an example of a solventless system, and the use of indium(m) chloride on silica gel under microwave conditions (Equation 160) <2003T813>. These fast, clean, high-yielding reactions gave aromatized products under indium(m) catalysis after a typical Michael addition of aniline to vinyl ketone. 

Protonation of glycerol 6.4 catalyses dehydration via secondary carbonium ion 6.5 to give enol 6.6. Acid catalysed elimination of a second water molecule affords acrolein 6.7. Thus glycerol acts essentially as a protected form of acrolein, slowly releasing this unstable a,p unsaturated aldehyde into the reaction medium. Better yields are realised with this approach than if acrolein itself is present from the start. The reaction proceeds with a Michael addition of aniline 6.3 to acrolein, producing saturated aldehyde 6.8 which cyclises via an aromatic substitution reaction to alcohol 6.9. Acid-catalysed dehydration to 6.10 then oxidation yields quinoline 6.1. Nitrobenzene can be used as a mild oxidant, as can iodine and ferric salts. 

A solventless synthesis of substituted quinolines occurs when anilines are reacted with alkyl vinyl ketones in the presence of indium(III) chloride on silica gel and with microwave radiation <03T813>. The mechanism proposed involves Michael addition of aniline to the vinyl ketone followed by cyclization and aromatization under the catalysis of InClj/SiOj. The reactions are fast, clean, and high-yielding. 

Scettri et al. reported the aza-Michael addition of aniline to chalcones under solvent-free conditions, promoted by cinchonine. The corresponding products were obtained in good yield but with poor ee (11-58%). The enantioselectivity was improved up to 99% by the addition of an achiral silicon-based Lewis acid catalyst such as trimethylsilyl iodide (TMSI). ... 

For the formation of 45, nitrobenzene would be reduced to aniline by CO/H2O (see Chapter 4.2.). By aldol condensation, an a,p-unsaturated aldehyde is formed. Michael addition of aniline to the unsaturated aldehyde followed by ring closure with dehydration would form 1,2-dihydroquinoline. Oxidation of this last product by nitrobenzene would yield 45. This sequence of reactions is similar to what proposed in Scheme 15. For the formation of 46, an intermediate nitrene was suggested (Scheme 16). Addition of the nitrene to the aldehyde would give an oxaziridine and, correspondingly, an isomeric nitrone. The nitrone would then be reduced by CO to the Schiff base and this, in turn, would be reduced to the amine. Final reaction with one more molecule of aldehyde would lead to 46. Some previously made comments on the formation of Schiff bases from nitroarenes and aldehydes vide supra and Chapter 4.5.) also apply to the first part of this scheme. 

Among the few examples of pure acidic activation in Michael addition to nitroalkenes, the recent works of Ooi and coworkers described the aza-Michael addition of aniline [50] by the charged chiral C2 symmetric phosphonium 50 (Scheme 34.16). Indeed, the acidic spirocycUc catalyst 50 was able to asymmetrically activate a Lewis base such as 2,4-dimethoxyaniline, to promote the addition to nitroolefins with excellent yields and selectivity. 

Amore et al. (2006) have established a very simple and rapid methodology for the synthesis of N-aryl functionalized P-amino ester by microwave promoted Michael addition of anilines to a, P-unsaturated esters. Hydrolysis of this ester may give H-functionalized P-amino acid, easily. 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Ni(II)(OAc)2bpy and Co(II)(OAc)2bpy catalyze the Michael addition of nitro-methane, malononitrile, and aniline to a,j8-unsaturated ketones, methyl acrylate, and acrylonitrile in DMF under neutral conditions [116]. FeCls 6H2O is a highly efficient catalyst of Michael reaction of 1,3-dicarbonyl compounds with a,/3-unsaturated ketones under mild and neutral conditions (Sch. 24) [117]. There is literature precedent for this reaction with dual catalysis Ni(II) immobilized on a clay support and FeCl3 to activate the enone [118]. The mechanism proposed for the single-center catalysis involves coordination of the enone to a diketonato complex [119]. The chemo-... 

Prekinamycin (35), like kinamycins A-F, was isolated from Streptomyces murayamaensis. Carbazole 33, a regioisomer of 7-deoxyprekinamycin (34), was synthesized in only four steps utilizing Pd(OAc), promoted oxidative cyclization as the pivotal step [27]. Similar to Furukawa s approach, the anilino-l,4-naphthoquinone 32 was obtained via Michael addition of the corresponding 2-methoxy-4-methyl-aniline to 1,4-naphthoquinone. Oxidative cyclization proceeded in 84% yield. 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

Michael addition of the aromatic amines to the vinyl ketones followed by subsequent cyclization and aromatization under catalysis by silica gel impregnated with indium(III)chloride has been successfully achieved under MWI to give the corresponding quinolines. Conventional heating produced polymerization of the vinyl ketones that drastically reduced the yield (00TL531). Thus, quinolines 273 were prepared in 55-87% yields by reacting anilines 271 with alkyl vinyl ketones 272 by irradiation in an MW oven for 5-12min (Scheme 57). 

Preparation of quinoxyfen is described in EP 326 330 [63]. Synthesis of 4,5,7-trichloroquinoline (24) follows known synthetic procedures. Addition of aniline 20 to the Michael acceptor 21 is followed by cyclization of 22 to a 4-... 

Michael addition of thiols and anilines to m-difluoroenals RCF2CH=CHCH=0, catalysed by (256b), has been reported to give the / -adducts with <98% ee the CFjR group strongly activates the substrate 0... 

X. Huang, T. Zhang, Cascade nucleophilic addition-cyclic Michael addition of arynes and phenols/anilines bearing ortho a,p-unsaturated groups fecile synthesis of 9-functionalized xanthenes/acridines, J. Org. Chem. 75 (2010) 506-509. 

Other nucleophiles add to conjugated systems to give Michael-type products. Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU (p. 488). Amines add to conjugated esters in the presence of InCla, La(OTf)3, or YTb(OTf)3 at 3kbar, for example, to give P-amino esters. This reaction can be initiated photochemically. An intramolecular addition of an amine unit to a conjugated ketone in the presence of a palladium catalyst, or... 

Diastereoselective domino Michael addition/Friedel-Crafts/SN-type cyclizations which allow the synthesis of bridged tetrahydroquinolines such as 2-405 have been observed by Yadav and coworkers when a mixture of anilines 2-403 and 6-hydroxy-a, 3-unsaturated aldehydes 2-404 were treated with catalytic amounts of Bi(OTf)3 or InClj in MeCN at 80 °C (Scheme 2.96) [222],... 

The Bunce group disclosed a straightforward domino process for the construction of aryl-fused nitrogen heterocycles by employing a combination of a reduction and a Michael addition [20]. The transformation involves an initial Fe-mediated reduction of nitroarenes 7-38, furnishing an aniline which undergoes a subsequent... 

The quinoline-based tyrosine kinase inhibitor pelitinib (31-11) incorporates a Michael acceptor function in the side chain that can form a covalent bond with a nucleophile on the target enzyme. Such an interaction would result in the irreversible inhibition of the target kinase. Reaction of aniline (31-1) with DMF acetal leads to the addition of a carbon atom to aniline nitrogen in the form of an amidine (31-2). This intermediate is next reacted with nitric in acetic acid to form the nitrated... 

In the course of mechanistic studies it was established that aniline does not react with the cyclopropenones (153 and 154) even under reflux conditions. It was therefore assumed that the formation of (158) involves initial nucleophilic attack by the aminopyridine ring nitrogen on the electrophilic cyclopropenone ring. In this way 155 is formed, which is then transformed via the reactive intermediates (156, 157, and/or 161) to the prodticts. Kascheres et al. noted that the formation of 157 is formally a stereospecific trans addition of the 2-aminopyridines to the double bond of the cyclopropenone (153). Such sterospecificity has been observed in kinetically controlled Michael additions. 

The Michael-type addition of an aniline to an unsaturated ester, generated in situ, provided an example of a type a ring closure in which the electrophilic center is sp2-hybridized <2004BML4147>. This reaction represents a synthetically useful procedure to access tetrahydro-1,4-benzodiazepines. 

Intermolecular Michael addition, including alkylation of heterocyclic aromatics and aniline... 

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