Michael addition Of enamines

The Michael addition of enamines to nitroalkenes proceeds with high Yyn selectivity. The Yyn selectivity is explained by an acyclic synclinal model, in which there is some favorable interaction between the nitro group and the nitrogen lone pair of the enamine group CEq. 4.67i. Both Z- and E-nitrostyrenes afford the same product in over 90% diastereoselecdvity. 

Another pyrrole synthesis based on intramolecular substitution of the nitro group by amino function is presented in Eq. 10.7, in which the Michael addition of enamines to nitroalkenes is used.9... 

In related asymmetric Michael-additions of enamine (206) and 2-aryl- 1-nitro-ethylenes, only one of the four possible enantiomerically pure diastereomers was formed 204). Hydrolysis of the crude primary products furnished a-alkylated cyclohexanones of > 90 % enantiomeric excess 204). 

The Michael addition of enamines to a,p-unsaturated ketones may be coupled with intramolecular aldol condensations to produce cyclic ketones. This sequence of reactions is an alternative approach to traditional Robinson annulations (Scheme 3.22). 

The enantioselective Michael addition of enamines derived from / -tetralone and proline methyl ether to nitrostyrenes has been described by Blarer and Seebach (33,45). Enamines of /1-tetralone have two potential sites of nucleophilicity, C-l and C-3 in 21.1 and 21.2(Scheme 21). For the substrates studied, attack occurs preferentially at C-3. The results of this study are summarized in Table 7 and Scheme 21. 

Reactions of enamine derivatives of auxiliary 1.64 [162, 252, 262] are often disappointing, except when R = CH20SiMe3 [162], However, the alkylation of enamines derived from 1.65 (R = Me) gives satisfactory results [253, 275], as do the Michael additions of enamines of bicyclic pyrrolidine 1.68 [294],... 

Scheme 4.17 Enantioselective Michael addition of enamines to nitroalkenes.

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

Seebach D, Golinski J, Synthesis of open-chain 2,3-disubstituted 4-nitroketones by diastereoselective Michael-addition of ( )-enamines to ( )-nitroolefins. A topological rule for G—G-bond forming processes between prochiral centres. Preliminary commimication. Helv. Chim. Acta 1981 64(5) 1413-1423. 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

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). 

The best yields of 5-hydroxyindoles are obtained when equimolar amounts of the quinone and enamine are used. An excess of enamine gives rise to non-indolic products derived from reaction of two enamine units and one quinone unit or the product which results from the initial Michael addition of the enamine to the quinone. Use of excess quinone has been reported less frequently, but limited studies indicate no advantage. When 2,5-dichloro-l,4-benzoquinone (32) was treated with a 50% excess of ethyl 3-... 

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. 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

Michael addition of the enamine to the 1,3-enyne double bond (intermediate 151) and subsequent intramolecular attack of the triple bond by the amino group (intermediate 152) with the r XH elimination (formation of 2,6-isomer 148). 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an cr,/3-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C—C bond made in the Michael addition step is the one between the a- carbon of the ketone donor and the /3 carbon of the unsaturated acceptor. 

Two closely related methods for the diastereoselective preparation of <5-oxo esters have been developed. The first method uses the chelated lithio enamine 2. These Michael donors are readily available from the tert-butyl ester of L-valine and jS-oxo esters. The Michael addition of this lithio enamine 2 to 2-(arylmethylene)propanedioates, followed by hydrolytic removal of the auxiliary, provides d-oxo esters with contiguous quaternary and tertiary carbon centers with high diastereoselectivity59 60. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

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... 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Figure 6.27 Representative (R,R)-l,2-diaminocyclohexane-derived thiourea derivatives incorporating a phthalimide (Phthal) and tetraphenylphthalimide (TPhP) moiety catalyst screening was performed in the Michael addition of acetophenone-derived morpholine enamine to trans-()-nitrostyrene in toluene as the solvent.

Scheme 6.94 Typical products obtained from the 86-catalyzed Michael addition of aryl methyl-ketone-derived morpholine enamines to various aromatic nitroalkenes and subsequent acidic hydrolysis.

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

Figure 6.32 Proposed intermediates in the 100-catalyzed Michael addition of ketones to nitroalkenes favored Z-enamine (A) and disfavored E-enamine (B).

A number of conformationally restricted fluorinated inhibitors have been synthesized and evaluated. These smdies show that (1) subtle conformational differences of the substrates affect the inhibition (potency, reversible or irreversible character) (Figure 7.50), (2) a third inhibition process involving an aromatization mechanism could take place (Figure 7.51). When the Michael addition and enamine pathways lead to a covalently modified active site residue, the aromatization pathway produces a modified coenzyme able to produce a tight binding complex with the enzyme, responsible for the inhibition (Figure 7.51). ... 

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. 

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