Michael addition activated methylenes

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 ... 

Michael condensations are catalyzed by alkaU alkoxides, tertiary amines, and quaternary bases and salts. Active methylene compounds and aUphatic nitro compounds add to form P-substituted propionates. These addition reactions are frequendy reversible at high temperatures. Exceptions are the tertiary nitro adducts which are converted to olefins at elevated temperatures (24). 

Michael condensation is the addition of a compound with an active methylene group to an a, p-unsaturated keto-compound... 

The apparently loose structural requirements for antihista-iiiinic agents have already been alluded to. Thus, active compounds. ire obtained almost regardless of the nature of the atom that connects the side chain with the benzhydryl moiety. In fact, a methylene group, too, can also serve as the bridging group. Reaction of the aminoester, 95 (obtained by Michael addition of... 

The Knoevenagel reaction has many similarities to the Michael addition, in which a base is required to form a carbanion Ifom an activated methylene precursor which subsequently undergoes nucleophilic addition to an alkene containing a group such as an ester capable of stabilizing the resulting anion by delocalization. These reactions are widely used for... 

Examples of the Michael-type addition of carbanions, derived from activated methylene compounds, with electron-deficient alkenes under phase-transfer catalytic conditions have been reported [e.g. 1-17] (Table 6.16). Although the basic conditions are normally provided by sodium hydroxide or potassium carbonate, fluoride and cyanide salts have also been used [e.g. 1, 12-14]. Soliddiquid two-phase systems, with or without added organic solvent [e.g. 15-18] and polymer-supported catalysts [11] have been employed, as well as normal liquiddiquid conditions. The micellar ammonium catalysts have also been used, e.g. for the condensation of p-dicarbonyl compounds with but-3-en-2-one [19], and they are reported to be superior to tetra-n-butylammonium bromide at low base concentrations. 

Selected examples of the Michael-type addition of activated methylene compounds with electron-... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

Another interesting example of Ugi-Michael process is represented by the synthesis of pyridones 145 (Fig. 28), which originate from an intramolecular domino addition-elimination reaction of the active methylene group proceeding through intermediate 144 [120]. 

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

The enedione (283) is a useful starting material for a two-step synthesis of 2,3,4,5-tetrasubstituted furans which are not otherwise readily accessible (81JCS(P1)2398). Michael addition of an active methylene compound, e.g. (284), to the enedione (283) led to the two regioisomeric adducts (285) and (286) which could then be cyclized to furans (287) and (288) under mild conditions (Scheme 75). The formation of Michael adducts was successful with both j8-ketoesters (284) and cyclic 1,3-diones. Normal routes to furans require much more drastic conditions the Michael addition allowed the preparation of 1,4-diones particularly activated by the presence of an easily enolizable group. This is a useful synthetic pathway because alternative routes for the preparation of complex furans are not at present available. 

A unique utilization of an activated methylene group to form a thiophene derivative is represented in the cyclization in acidic xylene of (95), formed by Michael addition of 2-mercapto diethyl acetal, to cyclohexenone. Compound (96), produced as a crystalline solid in better than 80% yield, was readily converted to the corresponding thiophene (97) or benzothiophene (98) by oxidation. Oxidation of (96) with chloranil gave (97) in 63% yield (70JHC393). 

In the case of a ketone with two active methylene groups, such as dibenzylketone, the reaction can take two courses. The pyranone results from Michael addition to the alkyne followed by normal ring closure. The second product, a resorcinol, arises from either Michael condensation followed by an intramolecular Claisen condensation or the order of these two reactions may be reversed (60JCS5153). 

Michael acceptors which carry a good leaving group at the a-carbon atom or whose electron-withdrawing group itself can serve as the leaving group may be cyclopropanated by active methylene compounds under basic conditions via a prototropic shift subsequent to the Michael addition as outlined in equation 139. Thus, the basicity of the carbanions involved must be balanced to allow the requisite prototropic shift otherwise, the reaction will be very slow or will not work. 

The color developer is oxidized by the activated silver bromide produced in the third step of Figure 28-12 to a quinonimmonium salt, 23. This substance readily undergoes a Michael-type conjugate addition (Section 18-9D) with the anion, R2CH , of the active methylene compound to give an N -substituted 4-amino-AMV-diethylbenzenamine, 24. 

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]. 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

The formal addition of a C-H bond at activated methylenes and methynes (pronucleophiles) to activated alkenes in the presence of a base is well known as the Michael reaction (Scheme 1, Type A) [1]. In modem organic syntheses, the use of transition metal (TM) catalysts enables the C-H addition of activated methylenes and methynes to activated alkenes perfectly under neutral conditions (Scheme 1, Type B) [2]. In general, the nonfunctionalized carbon-carbon multiple bonds (for example, EWG2 = H in Scheme 1) are unreactive toward carbon nucleophiles because of their electron rich Jt-orbitals. The pioneering efforts by various research groups resulted in the development of transition metal-catalyzed addition of a C-H bond at active alkanes to such unactivated C-C multiple bonds. This reaction consists of the formal addition of a C-H bond across the C-C multiple bonds and is called a hydrocarbonation reaction. As a milestone in this hydro-carbonation area, early in the 1970s, Takahashi et al. reported the Pd-catalyzed addition of the C-H bond of pronucleophiles to 1,3-dienes [3], The first Pd-catalyzed reaction of activated methylenes with unsubstituted allenes was apparently reported by Coulson [4]. The synthetic applications of this reaction were very limited. In the last decade, the Pd-catalyzed addition of C-H bonds to various unacti-... 

The prerequisite 1,5-dicarbonyl compounds and their equivalents can be formed in situ by a Michael addition of activated methylene groups onto O Ji-unsaturated systems <1996CHEC-II>. In this manner, 5-alkylidene-2-thioxo-dihydropyrimidincM,6(l //,5//)-dione 84 reacts with ethyl 3-oxobutanoate under microwave irradiation to from the intermediate 1,5-dicarbonyl compound 85, which spontaneously cyclize to afford the corresponding 4//-pyrans in high yield (Scheme 28) <2003SC3747>. 

In a one-pot three-component reaction, aromatic aldehydes, malononitrile and 1,3-dicarbonyl compounds react to form 2-amino-5-carboxy-4-aryl-47/-pyran-3-carbonitriles 87. The reaction proceeds by an initial Knoevenagel condensation of malononitrile with the aromatic aldehyde to afford the 2-benzylidenemalononitrile intermediate 88. Michael addition of the activated methylene group forms the 1,5-dicarbonyl equivalent 89, which upon ring closure affords 477-pyrans (Scheme 29) <2004SL871, 1999H(51)1101 >. 

Approaches of type (i) include the Michael type addition of ester activated methylene groups to a,( -unsaturated carbonyls with subsequent cyclization to afford 277-pyran-2-ones <1984CHEC, 1996CHEC-II>. In this manner, 3-acylamino-277-pyran-2-ones are prepared by the reaction of (3-ethoxyvinyl ketones or P-(dimethylamino)vinyl ketones with iV-acylglycines (Scheme 138) <2005S1269, 2004HAC85>. 

Both 1,3- and 1,4- bis[2-(2-arylethenesulfonyl)vinyl]benzenes, synthesized by a Knoevenagel reaction between the appropriate benzenedicarbaldehyde and 2-arylethenesulfonylacetic acid, behave as Michael acceptors and undergo double Michael addition reactions with activated methylene compounds. The products are phenylene-bis(tetrahy-drothiopyran 1,1-dioxides) 460 (Scheme 158) <2005JHC255>. 

A Michael addition consists of the addition of the enolate of an active-methylene compound, the anion of a nitroalkane, or a ketone enolate to an acceptor-substituted alkene. Such Michael additions can occur in the presence of catalytic amounts of hydroxide or alkoxide. The mechanism of the Michael addition is shown in Figure 13.67. The addition step of the reaction initially leads to the conjugate base of the reaction product. Protonation subsequently gives the product in its neutral and more stable form. The Michael addition is named after the American chemist Arthur Michael. 

Fig. 13.67. Mechanism of the base-catalyzed Michael addition of active-methylene compounds (top) and of ketones (bottom), respectively. Subst refers to a substituent, and EWG stands for electron-with-drawing group.

---