Reaction of Active Methylene Compounds

The C-H bond cleavage of active methylene compounds with a transition metal catalyst is another method for the functionalization of these C-H bonds. To date, several reactions have been developed. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers. One of the most attractive research subjects is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. The mthenium-catalyzed reaction active methylene compounds with carbonyl compounds involving aldehyde, ketones, and a,y3-unsatu-rated ketones and esters is described in this section. 

Murahashi reported the first example of transition metal-catalyzed addition of activated nitriles to aldehydes and ketones, giving a,/3-unsaturated nitriles (Eq. 9.55) 

This reaction does not require a base, and proceeds under neutral reaction conditions. Later, the analogous Knoevenagel reaction of aldehydes with cyanoacetate using RuH2(PPh3)4 was reported by Lin in 1993 [75]. 

For aldol and Michael reaction of nitriles, cyclopentadienyl ruthenium enolate complexes shows catalytic activity. The reaction of 2-methylphenylacetonitrile with ethyl acrylate gave the corresponding Michael addition product in 99% yield (Eq. 9.58) [79] 

Murahashi and Naota studied the reaction mechanism of cyclopentadienyl ruthenium enolate complex-catalyzed aldol and Michael addition reactions [80-82]. This mechanistic study revealed that the cone angle of the tertiary phosphine ligands largely affects the stability of C- and N-bound complexes [80, 82], Thus, ligation of bulky phosphine ligand would favor the N -bound complexes [80] 

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Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

Thiophenes can be synthesized from a sequence involving the reaction of activated methylene compounds with carbon disulfide in base. The resulting disulfide salts, without isolation, are reacted with phenacyl bromide to afford highly substituted thiophenes, 78. Compound 78 reacts with ethyl cyanoacetate, malononitrile, or acrylonitrile to afford thieno[3,2-/ ]pyridine derivatives <1995CCC1578>. 

Diazo compounds have previously been prepared by a variety of methods. Some of these methods Include hydrazone oxidations, the reaction of diazomethane with acid chlorides,4 the reaction of activated methylene compounds with tosyl azide, decomposition of N-nitroso compounds, ... 

C. Reaction of Active Methylene Compounds with Dithiole... 

Fig. 13.52. Mechanism of the Knoevenagel reaction of active-methylene compounds -H indicates the migration of a proton.

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. 

The use of C-H bonds is obviously one of the simplest and most straightforward methods in organic synthesis. From the synthetic point of view, the alkylation, alkenylation, arylation, and silylation of C-H bonds are regarded as practical tools since these reactions exhibit high selectivity, high efficiency, and are widely applicable, all of which are essential for practical organic synthesis. The hydroacylation of olefins provides unsymmetrical ketones, which are highly versatile synthetic intermediates. Transition-metal-catalyzed aldol and Michael addition reactions of active methylene compounds are now widely used for enantioselective and di-astereoselective C-C bond formation reactions under neutral conditions. 

The addition of a base to an acetylenic ester or ketone provides another method of preparation of enaminones594,595. A convenient one-pot synthesis of enaminones from trimethylsilylethynyl ketones and amines was described596. The reaction of activated methylene compounds, such as cycloalkanones, MeCOPh and PhCH2COOMe, with amide acetals gave high yields of enaminones597 (equation 39). 

Hashida et al. also found a good linear relationship for the azo coupling rates of 11 P-dicarbonyl compounds and the pK values of these C-acids. However, two dicarbonyl compounds with a trifluoromethyl group attached to one of the carbonyl functions were exceptions. Furthermore, no relationship between log k and pK could be observed for azo coupling reactions of active methylene compounds other than p-dicarbonyls. 

In the reactions of 1,1-dihalides, tin salts of 1,1-dimercaptoalkenes give somewhat better yields (only an 18% yield of 564 is obtained with the disodium salt). The reaction of active methylene compounds with carbon disulfide is a common method for obtaining 1,1-dimercaptoalkene derivatives, as exemplified in the synthesis of 565. The reaction of dimercaptoalkene salts with phosgene yields 2-keto-4-methylene-l,3-dithietanes. 

Carboxylation reaction of active methylene compounds with lanthanoid system was first attained by using a lanthanoid complex obtained from the reaction between lanthanum isopropoxide (LalO Prlj) and 2 equiv of phenyl isocyanate (Ph-N=C=0). Under CO2 at atmospheric pressure, phenylacetonitrile, an active methylene compound (equimolar with respect to LalCyPrlj), was effectively... 

Katayama, S., Watanabe, T., Yamauchi, M. Convenient synthesis of stable sulfur ylides by reaction of active methylene compounds with Corey-Kim reagent. Chem. Pharm. Bull. 1990, 38, 3314-3316. 

Regitz, M. Reaction of active methylene compounds with azides. I. New synthesis of a-diazo-P-dicarbonyl compounds from... 

Lee, J. C., Yuk, J. Y. An improved and efficient method for diazo transfer reaction of active methylene compounds. Synth. Common. 1995, 25, 1511-1515. 

The Michael-type addition reaction of a carbonucleophile with an activated olefin constitutes one of the most versatile methodologies for carbon-carbon bond formation [1]. Because of the usefulness of the reaction as well as the product, many approaches to the asymmetric Michael-type addition reactions have been reported, especially using chirally modified olefins [2-8]. However, the approach directed towards the enantioselective Michael-type addition reaction is a developing area. In this Chapter, the recent progress of the enantioselective Michael-type addition reaction of active methylene compounds and also organometallic reagents with achiral activated olefins under the control of an external chiral ligand or chiral catalysts will be summarized [9]. 

The recent progress in the Michael addition reaction of active methylene compounds with a, -unsaturated carbonyl compounds has been characterized by the... 

The reaction of active methylene compounds in the presence of base with thiiranes is well known however, yields tend to be diminished by intervening polymerization under the conditions that have... 

Mannich reaction. Reaction of active methylene compounds with formaldehyde and ammonia or primary or secondary amines to give (i-aminocar-bonyl compounds. 

The allylation of active methylene compounds with allyl alcohols or their derivatives, called the Tsuji-Trost reaction, is a widely used process in academia as well as in industry. Ranu et al. have reported that the reaction of active methylene compounds with allyl acetate catalyzed by palladium(O) nanoparticles (Scheme 5.22) led to mono-allylation in water, whereas the reaction in THF provided the bis-allylated product. This is a remarkable example of controlling the direction of a reaction by water. 

A similar dramatic influence of ionic liquid was also reported by Ranu s group in the Michael reaction of active methylene compounds with methyl vinyl ketone and methyl acrylate in the presence of an ionic liquid, 1-butyl-3-methylimidazolium hydroxide ([bmImjOH). Interestingly, open-chain 1,3-dicarbonyl compounds reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products (Scheme 5.55). 

Sakamoto, M., Fukuda, Y, Kamiyama, T., and Kawasaki, T., Studies on conjugated nitriles. Part 7. Lewis acid-promoted reaction of active methylene compounds with diethyl phosphorocyanidate. Preparation of a,P-unsaturated a-aminophosphonates, Chem. Pharm. Bull., 42, 1919, 1994. 

The products of aldol/dehydration reactions of active methylene compounds with unsaturated aldehydes undergo in situ hetero-IMDA reaction. Reaction of 2-phenyl-5-methyl-2.4-di-hydro-3//-pyrazol-3-one with 2-(3-methyl-2-butenyloxy)benzaldehyde in acetonitrile containing catalytic 1,2-ethanediammonium diacetate gave the products of a highly stereoselective IMDA reaction82. 

In a complementary process, the reaction of active methylene compounds, and derivatives such as the enamine shown, with ditosylated 1,3-dithiols, derived from the reaction of 1,3-dibromo-propane with potassium thiotosylate, can provide unusually substituted 1,3-dithianes (Equation... 

Aminomethylenation reactions of active methylene compounds with 1,3,5-triazine have also been described by Kreutzberger et al. <85AP(318)89, 85AP(3l8)82l>. A second equivalent of the active methylene compound can react as the third component to give ==CH—linked heterocycles, e.g. (61) from initial product (60) (Scheme 10) <86AP(319)18). 

The most important general methods for enaminone preparation are (i) direct condensations of ammonia or amines with 1,3-diketones or 3-ketoesters, (ii) nucleophilic reactions of lactams or related compounds with vinylogous acid chlorides, (iii) transformations catalyzed by organopalla-dium complexes, and (iv) the reactions of active methylene compounds with formamide acetals. This last method (iv) has been reviewed in detail... 

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