Enamine-Michael/cyclization

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

An enamine intermediate has been proposed as being formed by hydride reduction of a transient iminium ion [14, 15]. The electrophilic capture of the enamine is possible by a Michael acceptor thus, reductive Michael cyclizations of enal enones such as 9 or 11 were described in many cases (intramolecular reactions) (Scheme 11.5) [16]. 

The possibility that the stereoselectivity arises from either a thermodynamic preference or a subsequent process (cyclization) is less likely with imines as conjugate addition leads to an N-protonated immonium ion, which should rapidly undergo proton transfer. The resulting neutral product should be substantially less likely to undergo reversal to starting material than the dipolar intermediate involved in enamine Michael additions. 

Application of solid-state chemistry for quantitative multistep cascades in a ball mill is also demonstrated by reaction of enamine ketone 291 with 1,2-dibenzoylethene 292 (Scheme 3.78). Pyrrole derivative 293 was obtained by Kaupp et al. in quantitative yield through four reaction steps (vinylogous Michael addition, imine/enamine rearrangement, cyclization, and elimination), without the use of add catalysts [18]. 

The products could be easily isolated by filtration, and recrystallizafion from elhanol led to the pure desired compounds. The authors suggested an iminium ion-catalyzed Knoevenagel condensation mechanism, followed by enamine-Michael addition and intramolecular cyclization. One year later, the same group reported the diammonium hydrogenphosphate-catalyzed synthesis of various pyrano-pyrimidinones by exchanging dimedone by barbituric and thiobarbituric add in aqueous ethanol at ambient temperature [13]. The desired compounds could be afforded in good yields. 

SCHEME 13.16 Piperidine-catalyzed Knoevenagel/enamine-Michael addition/cyclization sequence. 

An acid-catalyzed version of this reaction was published by Wang et al. in 2013 [50]. A substoichiometric amount of acetic acid in refluxing ethanol mediates the Knoevenagel/ enamine-Michael addition/cyclization sequence to provide the spirodihydropyridines in high yields. 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

SCHEME 13.34 Direct cyclization of Knoevenagel/enamine-Michael addition products to the corresponding pyridone derivatives 115, 118, and 122 [53-55],... 

Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

In an interesting example, two unsaturated aldehydes form each the corresponding enamine in the presence of a proUne-derived catalyst. A first iminium-enamine Michael addition is followed by a second addition onto the unsaturated ester function present in one of the initial reagents. Photoinduced electron transfer and debromination give a radical that adds onto methacrylic aldehyde and cyclize to a highly functionalized decaline 60 (see Scheme 8.27) [46]. 

The utilization of both enamine- and iminium-activation enables rapid access to complex structures from simple starting materials. The first examples were reported for the deployment of one catalyst in these transformations, list and coworkers described a highly selective reductive Michael cyclization (Scheme 4.27). In a first catalytic cycle a hydride transfer occurs yielding an enamine inter-... 

Scheme 2.7 Asymmetric reductive Michael cyclization and schematic representation of the tandem iminium-enamine catalysis mechanism...

Fluorme-containing Michael addition acceptors have been used as synthons, a portion of a molecule recognizably related to a simpler molecule, for the introduction of fluorine into the organic molecules Their reactions with enamines and ketones lead to a condensarion-cyclization process... 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

From a mechanistic standpoint, ammonia serves two functions 1) it behaves as a base to catalyze an aldol reaction between 2 equivalents of 31 to generate the corresponding enal 33, and 2) it is the source of nitrogen for the resultant pyridyl ring. This occurs through formation of enamine 34 with a third equivalent of 31. The Michael addition of 34 to 33 followed by cyclization gives rise to 32. 

The Michael reaction with enamines is exemplified in this procedure. In a second (spontaneous) step of the reaction, an aldol-type condensation occurs resulting in cyclization. Finally, the morpholine enamine of the product forms and is hydrolized by the addition of water to yield a mixture of octalones, which is separated by fractional crystallization. J -Octalone-2 can be reduced by lithium in anhydrous ammonia to the saturated tra/i5-2-decalone (Chapter 3, Section III). 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

All of these reactions proceed in a similar pathway which involves the Michael type additions of enamines to nitroalkenes or addition of nitroalkanes to imines and cyclization. This process has been achieved by solid-phase variation (Scheme 10.2).14... 

A convenient synthesis of thieno[3,2-6]pyridines using the enamine (299), prepared in high yield by the Michael addition of (293) to dimethyl acetylenedicarboxylate, has been described (equation 26) (78JCR(S)393). The cyclization to (300) is effected by sodium hydride in DMF. 

There are numerous studies on the synthesis of pyrrolizines from enam-ines. In these reactions, one of the step is the closure to a new hydrogenated pyrrole ring. In polar solvents, the reaction of enamines with dimethyl acetylenedicarboxylate follows two different pathways, the formation of cycloadducts (18) and Michael adducts (19) (81T3525). Subsequent studies of this reaction have demonstrated (by low-temperature NMR) that compounds of the type 20 are intermediates in this cyclization (83JA4775). On the basis of this information (83JA4775), the authors then studied this type of cyclization using dienamines (21). The reaction follows the scheme shown, with a [1,6] antarafacial hydrogen shift and the formation of a dipo-... 

A much more generally useful process was developed by Robinson to prepare cyclohexenones from ketones and methyl vinyl ketone or its derivatives. Again, because good compilations of the Robinson annulation exist,8 only a few examples are given here. The first step of this process, the Michael addition, is carried out by normal base catalysis, while the second step, the aldol condensation, is best accomplished by the use of a secondary amine to form the enamine of the acyclic ketone, which then cyclizes... 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

Any uncyclized diketone precursor to the octalone, formed by hydrolysis of the initial Michael alkylation product (129), may readily be cyclized by treatment with boiling ethanolic potassium hydroxide. The formation of dihydropyrans by cycloaddition of MVK to enamines at low temperature has been discussed in Section III.B. 

Treatment of enamines with a,/ -unsaturated esters yields Michael adducts 189, which undergo reductive cyclization with lithium aluminium hydride to tetrahydropyrans 190. Elimination of the secondary amine moiety then affords dihydropyrans 191 (equation 81)102. 

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. 

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