Michael 3,4-Addition

The extension of this aqueous Michael reaction to acrolein was performed by Deslongchamps. One application was the total synthesis of 13-a -methyl-14a -hydroxys-teroid. 

A hydrophobic polymer-supported scandium(III) catalyst was also successfully used in the Michael reaction of unsaturated ketones with silyl enol ethers. Recently, an amphiphilic resin-supported rhodium/phosphine complex was used as catalyst in the 1,4-addition of various boronic acids to enones in water at 25°C. High yields were obtained and the catalyst was easily separated and subjected to a second and third round of reactions with no decrease in activity.  

The application of this procedure to the condensation of a-nitroalkanones with a-alkyl-q ,j8-imsaturated aldehydes afforded, in a one-pot synthesis, functionalized, bridged, and bicyclic lactones containing 10-, 11-, 13-, and 15-membered rings. Recently, Ballini et al. showed that the Michael addition of primary aliphatic nitro compounds to a,p -unsaturated enones performed in aqueous media provided the one-pot synthesis of 1,4-diketones, 1,4-diols, S-nitroalkanols, or hydroxytetrahydrofurans by appropriate choice of reaction conditions.  

The beneficial effect of water-soluble calixarenes as phase-transfer catalysts was noticed in the Michael addition of activated methyl and methylene compounds to a,/ -unsaturated ketones and nitriles in aqueous NaOH solution at room temperature.  

It is to be noted that Michael additions of dicarbonyl compounds and nitroalkanes to 2-cyclohexen-l-one occurred in water without phase transfer agents by careful control of the pH of the solution.  

The asymmetric Michael addition of active methylene or methine compounds to electron-deficient olefins, particularly o,[l-unsaturated carbonyl compounds, represents a fundamental - yet useful - approach to construct functionalized carbon frameworks [36]. 

Maruoka and coworkers developed the diastereo- and enantioselective conjugate addition of nitroalkanes to alkylidenemalonates under mild phase-transfer conditions 

Entry Nitroalkane (R1) Malonate (R2, R3) Reaction time (h) Yield (%) anti/syn ratio ee (%) 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the 

Asymmetric conjugate addition of a-substituted-oc-cyanoacetates 77 to acetylenic esters under phase-transfer conditions is somewhat of a challenge, because of the difficulty encountered in controlling the stereochemistry of the product. In addition, despite numerous examples of the conjugate additions to alkenoic esters, no successful asymmetric conjugate additions to acetylenic esters have been reported to date. In this context, Maruoka and coworkers recently developed a new morpholine-derived phase-transfer catalyst (S)-76 and applied it to the asymmetric conjugate additions of a-alkyl-a-cyanoacetates 77 to acetylenic esters, as indicated in Table 5.11 [40], In this asymmetric transformation, an all-carbon quaternary stereocenter can be constructed with a high enantiomeric purity. 

Lewis acid-catalyzed Michael addition of silyl enol ether to a,P-unsaturated system. 

Mukaiyama reagent such as 2-chloro-l-methyl-pyridinium iodide for esterification or amide formation. 

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.  

Mukaiyama, T. Usui, M. Shimada, E. Saigo, K. Chem. Lett. 1975, 1045. 

Kobayashi, S. Soai, K. Ikeda, S. Mukaiyama, T. Chem. Lett. 1977, 635. 

The addition reaction of enethiolates towards Michael acceptors has been investigated (for reviews, see [120, 362]). It was established that lithium dithioester enethiolates undergo regioselective 1,4-addition with a wide 

To a solution of LDA (40mmol) in THF (200ml) cooled at -45°C, methyl dithioacctate (3.92 ml, 40 mmol) was added dropwise. The yellow colour rapidly disappeared. The mixture was stirred for 5 min. 2-Cyclohexenone (3.92 ml. 40 mmol) was then added dropwise. A yellow colour appeared. The resulting mixture was stirred for IS min. An aqueous solution of ammonium chloride was added and the mixture partitioned between ether and brine. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Methyl (cyclohexanonc-3-yl)dithioacetate (3) (6.75 g, 33.4 mmol, 83%) was isolated by flash chromatography on silica gel using cyclohexane/ethyl acetate (9 1) as the eluent. 

With reactive Michael partners the reaction had to be run at lower temperatures (-98°C for methyl vinyl ketone for a 30% yield), and with less reactive ones the temperature had to be raised for the addition to occur (- 1()°C for 3-methylcyclohexenone for a 52% yield). 

Some potentialities of the 8-ketodithioesters are illustrated by the easy conversions of the dithioester group in ester and amide functions [332). The overall sequences arc indirect 1,4-addition on 2-cyclohexenone of, respectively, an ester enolate for (4) or an amide enolate for (5). 

The stereochemical aspects of the Michael addition of lithium dithioester enethiolates in the challenging acyclic series have been examined [362]. A stereospecific addition of a ds-enethiolate to an ( )-enone furnishes the anti isomer (6). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 172, Springer-Verlag Berlin Heidelberg 2009 

Fluorous Mukaiyama reagent 1 equiv DMAP, 3 equiv EtaN 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 184, Springer International Publishing Switzerland 2014 

Example 5, Enantio selective Mukaiyama-Michael reaction  

Pyridinium halide reagent for esterifieation or formatioa General scheme  

Draw a Lewis structure for cyclohexenone that involves charge separation for the most polar bond. Then, draw a Lewis structure that will delocalize one or both charges. Next, examine the actual geometry of cyclohexenone. Are the bond distances consistent with the Lewis structure shown above, or have they altered in accord with your alternative (charge separated) Lewis structure (Structures for cyclohexene and cyclohexanone are available for reference.) 

Display and describe the lowest-unoccupied molecular orbital (LUMO) for cyclohexenone. This is the orbital into which the nucleophile s pair of electrons will go. Does it anticipate both carbonyl and Michael products of nucleophilic addition Explain. A clearer picture is provided by a LUMO map for cyclohexenone. This gives the value of the LUMO on the accessible surface of the molecule, i.e., on the molecule s electron density surface. Does it anticipate both of the observed products If so, which should be the dominant Explain your choice. 

LUMO for cyclohexenone reveals the likely sites of nucleophilic attack. 

LUMO map for cyclohexenone shows (in blue) where the LUMO is most heavily concentrated. 

Hypervalent molecules incorporate elements with more than a normal complement of eight valence electrons (an octet). 

EWG electron-withdrawing group, such as ketone, ester, aldehyde, nitrile, sulfone, nitro group etc. 

Asymmetric Organocatalysis. Albrecht Berkessel and Harald Groger Copyright 2005 WILEY-VCH Veriag GmbH Co. KGaA, Weinheim ISBN 3-527-30517-3 

Nu is transported into the organic phase by a chiral phase-transfer catalyst, again resulting in a chiral ion pair from which asymmetric / -addition may proceed. 

Section 4.1.2 covers N- and O-nucleophiles and Section 4.1.3 covers S- and Se-nucleophiles. 

Using different thiols following adducts were obtained  

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Chemists usually learn about reactions according to fiinctional groups for example, How can I make an aldehyde and what reactions are known for aldehydes " This is clearly not a very good starting point for classifying reactions. The poor state of affairs in the definition of reaction types is further quite vividly illustrated by the fact that many chemical reactions are identified by being named after their inventor Diels-Alder reaction, Michael addition, Lobry-de Bruyn-van Ekenstein rear-... 

We will show here the classification procedure with a specific dataset [28]. A reaction center, the addition of a C-H bond to a C=C double bond, was chosen that comprised a variety of different reaction types such as Michael additions, Friedel-Crafts alkylation of aromatic compounds by alkenes, or photochemical reactions. We wanted to see whether these different reaction types can be discerned by this... 

The target compound is searched for a rctron. A retron is the structural subunit required to be present in the target in order to apply a transform. In Figure 10,3-30 the rctron of a Michael addition is a sequence of five carbon atoms with two carbonyl functions in the 1,5-position. For a Michael addition transform to be applied, it has to be present,... 

Figure 10.3-30. The retrosynthetic point of view the transform of a Michael addition. The structure fragment with a gray background is the retron of the Michael addition transforin.

Figure 10.1-32. Reaction center and reaction substructure the parts of the structures with a darker gray background are the reaction center, and those with a lighter gray background are the reaction substructures which must be present to achieve the reaction In the forward direction (in this case, Michael addition).

The Michael Addition Reaction consists in the addition of the sodio-derivative of ethyl acetoacetate, ethyl malonate or ethyl cyanoacetate to an olefine group... 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

Intramolecular Michael Addition 5-exo-tet favored Organic Reactions 1995, 47, 315-552... 

Stabilizing the resulting enolate of the Michael Addition product can shift the equilibrium as in the case of the vinyl silane shown below... 

A similar approach is followed in a recent study of the Lewis-acid catalysis of a Michael addition in acetonitrile. See Fukuzumi, S. Okamoto, T. Yasui, K Suenobu, T. Itoh, S. Otera, J. Chem. Lett. 1997, 667. 

Synthesis All by standard steps. Though the Michael addition on A could in the ciy occur at either double bond, the unsubstituted position out of the ring is much more reactive than the disubstituted position in the ring and only the wanted reaction occurs. Bull. Soc. Chim. France. 1955, 8. 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Torgov introduced an important variation of the Michael addition allylic alcohols are used as vinylogous a -synthons and 1,3-dioxo compounds as d -reagents (S.N. Ananchenko, 1962, 1963 H. Smith, 1964 C. Rufer) 1967). Mild reaction conditions have been successful in the addition of ],3-dioxo compounds to vinyl ketones. Potassium fluoride can act as weakly basic, non-nudeophilic catalyst in such Michael additions under essentially non-acidic and non-basic conditions (Y. Kitabara, 1964). 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

Dramatic rate accelerations of [4 + 2]cycloadditions were observed in an inert, extremely polar solvent, namely in5 M solutions oflithium perchlorate in diethyl ether(s 532 g LiC104 per litre ). Diels-Alder additions requiring several days, 10—20 kbar of pressure, and/ or elevated temperatures in apolar solvents are achieved in high yields in some hours at ambient pressure and temperature in this solvent (P.A. Grieco, 1990). Also several other reactions, e.g, allylic rearrangements and Michael additions, can be drastically accelerated by this magic solvent. The diastereoselectivities of the reactions in apolar solvents and in LiClO EtjO are often different or even complementary and become thus steerable. 

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

The Pd enolates also undergo intramolecular Michael addition when an enone of suitable size is present in the allyl d-keto ester 744[465]. The main product is the saturated ketone 745, hut the unsaturated ketone 746 and ally-lated product 747 are also obtained as byproducts. The Pd-catalyzed Michael... 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

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