Michael addition, with enamines

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). 

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. 

Scheme 27 Asymmetric enamine-catalyzed Michael additions with aldehyde donors...

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). ... 

Recently Martin and Narayanan [104] reported that the a-aminonitrile 2(JV,iV-diethylamino)-2-phenylacetonitrile undergoes a Michael addition with acrylonitrile in the absence of solvent but in the presence of benzyltrimethyl-ammonium hydroxide. The residue, obtained by ether extraction, is rapidly dehydrocyanated during distillation to give the enamine 4-(jV,jV-diethyl-amino)-4-phenyl-3-butenenitrile in 58 % yield (Eq. 44). Whether this reaction... 

Quaternary stereocenters can be obtained with high selectivity with ot-amino acid amides as chiral auxiliaries, which were first converted with P-oxo esters to give enamines such as compounds 58. According to a combinatorial strategy, various enamino esters 58 were screened in Michael additions with MVK (41a) and several metal salts as catalysts. With FeCl3, however, the maximum stereoselectivity achieved was only 77% ee (with enamine 58a derived from L-isoleucine dimethylamide). Cu(0Ac)2H20 turned out be the optimal catalyst for this transformation. With L-valine diethylamide as chiral auxiliary in compound 58b, reaction proceeds with 86% yield and 98% ee after aqueous workup [79]. Importantly, this valuable method for the construction of quaternary stereocenters [80] under ambient conditions seems to be generally applicable to a number of Michael donors [81]. In all cases, the auxiliary can be quantitatively recovered after workup. 

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 enamine 103 of our familiar unsymmetrical ketone 23 gives a clean Michael addition with methyl acrylate on the less substituted side to give the ketoester xyn-104 as the only product providing that the reaction is carried out in MeOH.38... 

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. 

The first synthesis of polyzonimine (119) was a synthesis of the racemate carried out by Smolanoff and co-workers in 1975 at the time of its isolation and structure elucidation (111). Oxidation of 3,3-dimethylcyclohexene (368) with meto-perchlorobenzoic acid followed by treatment of the epoxide with lithium bromide and HMPA in refluxing benzene gave the carboxal-dehyde 369. The morpholino enamine 370 was then subjected to Michael addition with nitro-ethylene, generated from 2-acetoxy-nitroethane, to afford a nitro aldehyde 37L Ketalization and reduction with Raney nickel then afforded ( )-119 in overall yield for the five steps of 22% (Scheme 45) (111). 

The 1,4-dihydropyridine 148 (as well as the 3,4-dihydropyridine 147 which is retrosynthetically equivalent) can be linked with the retrosynthetic process a. As a double enamine, it could be derived from the enaminone 149 (via h), which in turn should be accessible (via i) from the 1,5-dicarbonyl system 150 and NH3 by cyclocondensation. The systems 149 and 150 are retroanalytically interlinked, not only by dehydrogenation of 145 and 146 respectively, but also by a retro-MiCHAEL addition involving enamines or enolates with a, p-unsaturated carbonyl systems as starting materials for the synthesis of 1,4-dihydropyridines. 

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]. 

Wang and coworkers achieved p-functionalisation of simple aldehydes. This concept was realised by oxidation of an enamine formed from the catalyst and aldehydes with suitable oxidant, such as IBX. The thus-formed unsaturated iminium ion underwent a Michael addition with various nucleophiles. Similarly, Hayashi s laboratory described oxidation of enamines with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) and then Michael addition using nitromethane as nucleophile. ... 

The mechanism proposed by the authors is depicted in this scheme. A first equivalent of a,fS-unsaturated aldehyde was activated as its corresponding iminium ion by chiral diphenylprolinol trimethylsilyl ether and then underwent the first nitromethane Michael addition to afford a nitroalkane enamine intermediate. Subsequent hydrolysis generated a nitroaldehyde intermediate and the catalyst, which could promote a second Michael addition with a second equivalent of iminium, furnishing an enamine intermediate. This enamine reacted via an intramolecular aldol cyclization to give a novel iminium intermediate. After hydrolysis, the catalyst was regenerated, and the intermediate alcohol could be dehydrated to afford the final products. 

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. 

Each of the respective research groups effected the transformation of the endocyclic enamine 62 to ( )-mesembrine by means of a Michael addition with methyl vinyl ketone (Scheme 16). The yields for this reaction reported... 

In this process - which is complementary to the classical Hantzsch synthesis - primarily a,P-unsaturated imines 174 are likely to be formed, which undergo Michael addition with the P-ketoester ( 175) followed by cyclizing enamine formation establishing the C-2/C-3 bond of the 1,4-dihydropyridine 173. 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

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... 

A reaction related to the Michael addition reactions of enamines to unsaturated esters, which leads to S-ketoesters, is the reaction with 1-carb-ethoxy-l-cyanocyclopropane (318). This gives access to ketones substituted with the next higher homologous acid chain. 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

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. 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

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). 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

---