Addition of active methylene compounds

The palladium(O)-catalyzed reaction of 1,3-dienes with active methylene compounds to give 1,4-addition of a hydrogen atom and a stabilized carbanion is complicated by the formation of 2 1 telomerization products [27]. It was found by Hata et al. [21a] that bidentate phosphines such as l,2-(diphenylphosphino)ethane favor formation of the 1 1 adduct. More recent studies by Jolly have shown that the use of more a-donating bidentate phosphines on palladium gave a high selectivity for 1 1 adducts [23]. For example, 1,3-butadiene reacted with 11 to give the 1,4-addition product 12 in 82% yield, along with 18% of the 1,2-addition product 13 (Eq. (7)). 

In a related study, Trost and Zhi [24] showed that the use of dppp(l,3-(diphenylphosphino)propane) as a ligand on palladium also led to a high selectivity for 1,4-addition of active methylene compounds to 1,3-dienes. For example, 2,3-dimethylbuta- 1,3-diene gave an excellent yield with a number of active methylene compounds [Eq.(9)]. Interestingly, the reaction temperature is of importance for the 1,4-selectivity. Thus, in the reaction of (PhS02)CH2 with isoprene employing the Pd(0)-dppp system, the ratio between the desired 1,4-addition product and the telomerization product was 73 27 at 70 °C but increased to 95 5 at 100 °C. Also, cyclic dienes gave an excellent yield of the 1,4-addition products [Eq.(10)]. 

Palladium-catalyzed addition of phenylsulfinic acid to butadiene and isoprene gave mainly 1,2-addition products. From butadiene, a 4 1 ratio of 1,2- to 1,4-addition product was obtained in high yield [Eq.(ll)] [27]. It was later shown that the 1,2-addition product is the kinetic product and that prolonged reaction time increased the amount of 1,4-addition product [27b]. 

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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 ... 

Quinone monoacetals such as 2-methoxyben2oquinonemonoacetal [64701-03-7] (66) show regiospeciftc addition of active methylene compounds (66), yielding 83% (67) and 63% (68) on reactions with ethyl malonate. 

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

Addition of Active Methylenes In the previous decade Cinellu et al. studied certain 1,3-dicarbonyl gold complexes and some applications in organic synthesis were subsequently proposed [78]. Intermolecular addition of activated methylene compounds to alkenes was developed by using AuCl3/AgOTf [79]. 

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.

Moreno-Manas et al. [98] reported on a similar effect of triphenylphosphine for the Michael addition of active methylene compounds to n-acceptor olefins such as methyl vinyl ketone, acrylonitrile, and 2-vinylpyridine and dialkyl azodi-carboxylates. They compared the reactivity of RuH2(PPh3)4, RuCl2(PPh3)3, and PPh3 and concluded that for /5-diketones, ketoesters, and ketoamides, triphenylphosphine released from the ruthenium complexes contributes totally or partially to the catalysis. 

Recently, a Russian group100-102 has developed a synthesis of primary 1,1-en-ediamines 82 from the addition of active methylene compounds to cyanamides 81 (equation 27). 

The RuH2(PPh3)4-catalyzed addition of active methylene compounds can also be applied to conjugate additions to a,/3-unsaturated carbonyl compounds (Michael additions). In 1989, Murahashi reported the first example of the transition metal-catalyzed Michael addition of active methylene compounds [74]. One of the notable advances of this catalytic reaction is that the addition of C-H bonds to a,/3-unsaturat-ed carbonyl compounds give Michael adducts without contamination by the corresponding aldol products (Eq. 9.56) [74]. Recently, Murahashi applied their aldol and Michael addition reactions to a solid-phase synthesis using polymer-supported nitriles (Scheme 9.12) [76]. In this case, four component reactions took place with high diastereoselectivity. 

This reaction constitutes a special type of process in which a hydrogen atom and a nucleophile are added across the diene with fonnation of a carbon-hydrogen bond in the 1-position and a carbon-Nu bond in the 4-position. Some examples of such reactions are hydrosilylation [12-18], hydrostannation [19,20] amination [21,22], and addition of active methylene compounds [21 a,23,24], These reactions are initiated by an oxidative addition of H-Nu to the palladium(0) catalyst, which produces a palladium hydride species 1 where the nucleophile is coordinated to the metal (Scheme 8-1). The mechanism commonly accepted for these reactions involves insertion of the double bond into the palladium-hydride bond (hydride addition to the diene), which gives a (jr-allyl)palladium intermediate. Now depending on the nature of the nucleophile (Nu) the attack on the jr-allyl complex may occur either by external trans-aVtBck (path A) or via a cw-migration from palladium to carbon (path B). 

Addition of active methylene compounds to butadiene has been catalyzed by complexes of the nickel triad. A catalyst mixture of Ni(acac)2, PPr(OR )2, and borohydride was effective for the addition of R1R2CH2 (Ri = Ph, R2 = COCH3 Ri = Ph, R2 = CN Ri = Ra = COgEt Ri = COCH3, Rg = COgEt) to butadiene 26). Both Pd(0) and Pd(II) complexes are effective as catalysts for the addition of active methylene compounds such as 2,4-pentanedione and ethyl acetoacetate to butadiene 177, 269). Several products were obtained from these reactions since both the 1 1 and 1 2 addition occurred. 

The addition of active methylene compounds of C-5 of 6-methyl-3-phe-nyl- 1,2,4-triazine demonstrates a wider applicability of the reactions with carbanionic reagents for the synthesis of 5-substituted triazines (Scheme 13) (87CPB1378). 

Addition of Active Methylene Compounds to Unsaturated Functions 72... 

Ranu BC, Baneijee S (2005) Ionic liquid as catalyst and reaction medium. The dramatic influence of a task-specific ionic liquid, bmim][OH], in Michael addition of active methylene compounds to conjugated ketones, carboxylic esters, and nitriles. J Oig Lett 7 3049-3052... 

The addition of active methylene compounds to 2,3-dihydrofuran was promoted by catalytic amounts of AuCl3-AgOTf, providing 2-substituted THF derivatives, as depicted in the scheme below <05OL673>. 2-Lithiated dihydrofurans were shown to lead to heterospiro cycloalkanones <05H(66)57>. 

Depending on the catalyst, either subst. quinolizidines or 4-ketoquino-lizidines may be obtained by reductive cyclization of pyridine derivatives, prepared by Michael addition of active methylene compounds to 2-vinylpyridine. E A mixture of diethyl / -(2-pyridyl)ethylmalonate, Raney-Ni, and ethanol heated 1 hr. at 145° under a H2-pressure of 200 atm. —> 3-earbethoxy-4-ketoquinolizidine. Y 97%. (V. Boekelheide and S. Rotehild, Am. Soc. 71, 879 (1949).)... 

Pyranones can also be prepared from the Michael addition of active methylene compounds to the appropriate enaminones. Additions of methylene nitriles to the enaminones 364 and 366 under strongly basic conditions followed by acidification give the 2-pyranones 365 and 367, respectively. Scheme 103 (81S225 85JHC713). Additions of ethyl acetoacetate to enaminones are also reported to afford 2-pyranones (91CPB1655). 

Furthermore, this catalyst promotes asymmetric Mannich reactions [31] and Michael addition of active methylene compounds to a,p-unsaturated imides [32]. 

Inokuma, T, Hoashi, Y. and Takemoto, Y. (2006) Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to a,P-unsaturated imides Dual activation of imide by intra- and intermolecular hydrogen bonding. Journal of the American Chemical Society, 128, 9413-9419. 

In general, the addition of active methylene compounds to the double bond of a, P-unsaturated esters, ketones etc., in the presence of particularly the basic catalysts is termed as... 

The branched-3-C-methyl derivative 32 was formed stereoselectivity and in high yield when dimethylcopper lithium in the presence of TmsCl added 1,4-fashion to the corresponding 2,3-unsaturated lactone. Several similar examples were also described including addition of active methylene compounds e.g. diethyl malonate under basic conditions). ... 

Yao, X. and Li, C.-J. 2004. Highly efficient addition of activated methylene compounds to alkenes catalyzed by gold and silver. J. Am. Chem. Soc. 126 6884-6885. 

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