Imine compounds Michael additions

The 6-methoxymethylene penicillanic acid [93040-42-7] (31, R = CH OCH (2)-isomer, R" = R " = 3) designed to mimic the amino acrylate species found usiag clavulanic acid and sulbactam. Upon the reaction of this compound with the enzyme, the potential exists for further Michael addition to inactivate the enzyme. The compound is indeed a -lactamase inhibitor but no synergy data have been reported. The related imine stmcture... 

After reduction of the nitro function of the porphyrin, the porphyrinamine intermediate can be reacted with z./l-unsaturated carbonyl compounds to yield porphyrins with a fused pyridine ring, which is formed by Michael addition, imine formation and dehydrogenation. 

The Nef reaction can also be carried out with reducing agents. Aqueous titanium chloride reduces nitro compounds to imines, which are readily hydrolyzed to carbonyl compounds (Eq. 6.17).28 The Michael addition of nitroalkanes to enones followed by reaction with TiCl3 provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cw-jasmone is readily obtained,28 as shown in Eq. 6.18. 

A one pot samarium-catalyzed three-component reaction of aldehydes, amines, and nitroal-kanes leads to pyrroles. The reaction proceeds via imines, generated from the amine and carbonyl compound, followed by the Michael addition of the nitro compound (Eq. 10.10).12a In... 

Some chiral quaternary ammonium salts are also effective in Michael addition reactions. The Merck catalysts 7 (R=4-CF3, X=Br) and 9 (R=4-CF3, X=Br, 10,11-dihydro) were used tor the Michael additions of 59,61, and 64 to vinyl ketones to give the adducts 60,62, and 65 (isolated as 66), respectively,148,491 with excellent enantioselectivity, as shown in Scheme 19. The Michael addition of the O Donnell imine 23 to the a,(3-unsaturated carbonyl compounds also efficiently proceeded by use of the N-anthracenyl-methyl catalyst 12 (R=allyl, X=Br), giving the Michael adducts 67 (Scheme 20).1251... 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

A wide variety of structures have been found to act as sources of the electrophilic groups of suicide inhibitors (Figure 7.5). These structures will only give rise to an electrophilic group if the compound containing the structure can act as a substrate for the enzyme. They often take the form of a,p unsaturated carbonyl compounds and imines formed by the reverse of a Michael addition at the active site of the enzyme. 

The od.p unsaturated carbonyl compounds and imines formed in this manner react by a type of Michael addition with nucleophilic groups (Nu), such as the OH of serine residues, the SH of cysteine residues and the w-NH2 of lysine residues, frequently found at the active sites of enzymes. 

Protocol 6 involves heating Mannich compound 10 in DMSO, apparently causing elimination of dimethylamine and formation of enone 20 as a reactive intermediate. The corresponding enone has been synthesized in the 9-butyl series,6,22 but comparable yields are obtained in pyridine cyclization reactions involving either the preformed enone or the Mannich HQ salt.7 Prior to addition of 10, ketone 9 is heated with ammonium chloride in DMSO to promote the formation of imine 21. Isomerization of this imine to the enamine tautomer 22, Michael addition of this nucleophile to enone 20, and elimination of water account for the formation of product 11. Like many polycyclic terpyridyl analogues, this product is sparingly soluble in DMSO and is readily isolated by filtration of the reaction mixture. 

Lewis acid-catalyzed tandem Michael imino-aldol reactions enable the one-pot synthesis of 7-acyl-(5-lactams from a, j6-unsaturated thio-esters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbClj with Sn(OTf>3 (5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf)3, once again proved to be the Lewis acid of choice (Scheme 4, 15 16 = 81 19, 94%). 

Finally, a fascinating development in the field of lanthanum-BINOL complexes remains to be mentioned [25]. These compounds so far have proved to catalyze enantioselectively hydrophos-phonylations of imines [26], nitroaldol reactions [27], Michael additions [28] and cpoxidations of... 

The Michael addition /ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCOs to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respeetively. 

Enantioselective Copjugate Additions. The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,p-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine. Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2) ... 

Angelo, J. d.. Cave, C., Desmaele, D., Dumas, F. The asymmetric Michael addition reactions using chiral imines Application to the synthesis of compounds of biological interest. Trends in Organic Chemistry 993,4, 555-616. 

Allylic barium reagents prepared in this way can realize highly a-selective reactions with different electrophiles, e.g. cross-coupling reactions with allylic halides or allylic phosphates, additions to carbonyl compounds or imines, and ring opening of epoxides. A selective Michael addition reaction with an a,/ -unsaturated cy-cloalkanone can also be performed by use of an allylic barium reagent. 

Naturally occurring ketones and their readily prepared derivatives have also been used as chiral auxiliaries. Menthone ketals have been the subject of some study [373, 374], For example, enolates of compound 1.106, obtained from 8-phenylmenthone, are alkylated with a good stereoselectivity [375]. Cleavage of the chiral auxiliary is accomplished by hydrolysis. Enolates of tert-butylglycine camphor imine 1.107 are alkylated [154, 159] or suffer Michael additions [376] with a high stereoselectivity, and the auxiliary is cleaved by treatment of the prod-... 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

While base-catalyzed Michael additions of Schiff s bases of the type Me3CCH = NCH2C02Me are known to be catalyzed by NEt3 and DBU [129], the ratio of Michael adduct to cycloaddition product formed in the reaction depended on the presence of lithium ion [130]. By contrast, the pro-azaphosphatrane bases induce a clean Michael addition of the imine with various a, -unsaturated compounds in the absence of lithium ion [127]. 

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