Michael reaction activated methylenes

Aldol and Michael reactions. Active methylene compounds such as ethyl cyanoacetate and malonic esters react with aldehydes and electron-deficient alkenes in the aldol and Michael mode, respectively. 

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). 

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... 

The bispyrazolodihydropyran 435 was obtained directly as a rapidly formed insoluble by-product in the reaction of 3-methyl-l-phenylpyrazol-5-one 433 with activated nitriles 434 in the presence of catalytic piperidine (Equation 117) <2000MOL746, 2000JCCS937>. It is proposed that the reaction proceeds by loss of the active methylene moiety from the initial Michael adduct, allowing attack by a second molecule of pyrazol-5-one. 

The reactivity of phenylacetic esters with electron-deficient alkenes is generally fairly poor, even under phase-transfer catalytic conditions. The reaction with cinnamic esters is often accompanied by hydrolysis and the yield of the adduct with chalcone is generally <60% [10]. The activity of the methylene group towards alkylation has been enhanced by the initial complexation of the phenyl ring with chromium tricarbonyl (see Section 6.2), but this procedure has not been applied to the Michael reaction. 

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]. 

There are some examples of pyran synthesis by Method 2, which involves the reactions of unsaturated ketones with methylene-active nitriles. In a typical case of Method 2, the Michael reaction of a,j5-unsaturated carbonyl compounds 26 (77TL1835, 78JHC57,... 

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 activated Ba(OH)2 catalyst was successfully used for the Michael reactions of chalcone with active methylene compounds 290), as well as for the Michael reaction of other benzylidene derivatives of acetone, butanone, 3-methylbutanone, 4-methyl-2-pentanone, and 3,3-dimethylbutanone with ethyl acetoacetate and diethyl malonate. The reaction with diethyl malonate gave good yields of the Michael adduct (between 65 and 93%), whereas with ethyl acetoacetate various products were obtained, depending on temperature and amount of catalyst (Scheme 43) 291). Thus, by varying the reaction conditions, it was possible to obtain a single product with practically 100% selectivity, the yields being higher than those obtained with soluble catalysts, such as KOH, NaOH, or piperidine. 

When 6-aminopyrimidinone 460 (R = Me, X = O) was reacted with an equimolar amount of 3-dimethylaminopro-piophenone hydrochlorides 524 in boiling ethanol, it gave selectively the 7-arylpyrido[2,3- pyrimidines 525 in moderate to good yields. The Michael adducts 527 and the derived hemiacetals 528 were isolated in some cases. Similarly, reaction of 460 with 524 (X = OMe), in 2 1 molar ratio, led to 525 (X = OMe) in 60% yield, whereas, when the molar ratio was 1 1, the product 526 was formed via formation of the intermediate 529 that resulted from a second alkylation of the initial Michael adduct on the active methylene group (Equation 43) <2002T4873>. 

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. 

Several points arise from consideration of this mechanism (i) unlike alkylation of stabilized enolates, the Michael reaction regenerates a basic species and thus usually catalytic quantities of base can be utilized 7 7 12 (ii) the high acidity of the doubly activated methylene permits the use of weaker bases, e.g. simple amines (piperidine, triethylamine etc.) or hydroxides (Triton B, i.e. benzyltrimethylammoni-um hydroxide) (iii) it was recognized early that, when a full equivalent of base was used, the final more... 

Keywords active methylene compound, chalcone, Michael reaction, alumina, microwave irradiation... 

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-... 

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. 

Interestingly, the reaction of active methylene compounds having a nitrile group with a,/l-unsaturated carbonyl compounds give Michael adducts without contamination by the corresponding aldol products (Eq. 61) [89-92]. Murahashi and coworkers [89-91] proposed that the addition of the C-H bond to a low-valent ruthenium constitutes the initial step. Recently, Takaya and Murahashi [94] applied their aldol and Michael addition reactions to solid-phase synthesis using polymer-supported nitriles. 

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