Malonic olefination

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

Facile reaction of a carbon nucleophile with an olefinic bond of COD is the first example of carbon-carbon bond formation by means of Pd. COD forms a stable complex with PdCl2. When this complex 192 is treated with malonate or acetoacetate in ether under heterogeneous conditions at room temperature in the presence of Na2C03, a facile carbopalladation takes place to give the new complex 193, formed by the introduction of malonate to COD. The complex has TT-olefin and cr-Pd bonds. By the treatment of the new complex 193 with a base, the malonate carbanion attacks the cr-Pd—C bond, affording the bicy-clo[6.1,0]-nonane 194. The complex also reacts with another molecule of malonate which attacks the rr-olefin bond to give the bicyclo[3.3.0]octane 195 by a transannulation reaction[l2.191]. The formation of 194 involves the novel cyclopropanation reaction of alkenes by nucleophilic attack of two carbanions. 

An analogous sequence on acid, 29 (obtained by decarboxylative hydrolysis of the malonic ester), leads to carbromal (30). Dehy-drohalogenation of 30 by means of silver oxide affords the corresponding olefin, ectylurea (31), itself a sedative-hypnotic. 

The formation of the naphthalene (73) from the bis-ylide (72) and diethyl ketomalonate involves an unusual olefin synthesis on the carbonyl of an ester group. The methylene-pyrans (75) were formed when the diethyl malonates (74) were refluxed with j3-keto-ylides in xylene or decalin. Possible intermediates are the ketens (76) and the allenes (77). Addition of ylide to the allenes gives the betaines (78) which form methylene-pyrans either directly or via acetylenes as shown. 

We have chosen epoxy olefin 10 as substrate for our initial examinations for two reasons. Firstly, 10 is synthesized in a straightforward manner from al-lyl diethyl malonate by epoxidation and an Sn2 reaction with prenyl bromide. Secondly, it is known from the work of others [17-20] and ourselves [65, 66,73,74] that compounds similar to 10 cyclize to yield mainly the essential ds-fused radicals with selectivities of about 85 15 to 90 10. 

Electrochemical oxidations of anions lead to radicals that may add to the carbon-carbon double bonds. In this way, the oxidation of anions of dimethyl malonate or methyl acetylacetate in the presence of olefines gives di- or tetrahy-drofurans derivatives in moderate yields (Scheme 43) [60]. 

Co(CO)4] ) dehydrohalogenation [Eq. (15)] followed by addition of HCo(CO)4, or whether splitting out of HCo(CO)4 occurs from the alkyl-cobalt [Eq. (14)], which is the malonate precursor, followed by HCo(CO)4 addition in the opposite direction. In one case [Eq. (15)], olefin formation proceeds directly from the bromide and no reversibility of any steps is required, while according to Eq. (14) olefin formation proceeds from elimination of HCo(CO)4. 

A pentopyranoside-fused butenolide is the key intermediate for the synthesis of the natural micotoxin patulin [226, 227]. Its synthesis involves Wittig olefination of a 3,4-di-O-protected arabinopyran-2-uloside, followed by protecting group removal and dehydration (Scheme 47). In other research, the glucopyranosid-2-uloside 190 was converted into the butenolide derivative 191 by aldol condensation with diethyl malonate and transesterification [228]. The latter was shown to be prone to autoxi-dation, leading to 192. Subsequent Michael addition with hydroxide ion, followed by decarboxylation, furnishes C-branched-chain sugar 193. 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

An alternative complementary olefination procedure involving alkylidene malonates was also developed that produces (Z) olefins as major stereoisomers when the R substituent is aliphatic (equation 93)130. The stereoselectivity depends on the bimetallic compounds and may be improved by bulky ester substituents (such as menthyl groups)131. 

Olefins react with manganese(III) acetate to give 7-lactones.824 The mechanism is probably free-radical, involving addition of CH2COOH to the double bond. Lactone formation has also been accomplished by treatment of olefins with lead tetraacetate,825 with a-bromo carboxylic acids in the presence of benzoyl peroxide as catalyst,826 and with dialkyl malonates and iron(III) perchlorate Fe(C104)3-9H20.827 Olefins can also be converted to 7-lactones by indirect routes.828 OS VII, 400. 

Stereoselective allylic alkylations have been carried out with the aid of palladium catalysts. The 17-(Z)-ethylidene groups of steroids (obtained from the ketones by Wittig olefination) form n-allyl palladium complexes in the presence of copper(n) salts (B.M. Trost, 1974, 1976). Their alkylation with dimethyl malonate anions in the presence of 1,2-ethane-diylbis[diphenylphosphine] (— diphos) gives a reaction exclusively at the side chain and only the (20S) products. If one starts with the endocyclic 16,17 double bond and replaces an (S)-20-acetoxy group by using tetrakis(triphenylphospbine)palladium,the substitution occurs with complete retention of configuration, resulting from two complete inversions (B.M. Trost, 1976). 

It should be noted that nonmetallic redox reactions also experience the sonication influence. The preparation of y-lactons from olefines upon manganese triacetate oxidation is an example. The reaction with monomethyl malonate in acetic acid, which does not occur at 0-10°C, proceeds smoothly when sonication is applied (Allegretti et al. 1993). From cyclohexene, only the cis ring fusion in the bicyclic lactone is observed the product is formed at 80% yield for 15 min at 10°C. The overall scheme of the reaction, without the detailed mechanism is shown in Scheme 8-18. 

A Cr(VI)-catalyst complex has been proposed as the reactive oxidizing species in the oxidation of frans-stibene with chromic acid, catalysed separately by 1,10-phenanthroline (PHEN), oxalic acid, and picolinic acid (PA). The oxidation process is believed to involve a nucleophilic attack of the olefinic bond on the Cr(VI)-catalyst complex to generate a ternary complex.31 PA- and PHEN-catalysed chromic acid oxidation of primary alcohols also is proposed to proceed through a similar ternary complex. Methanol- reacted nearly six times slower than methanol, supporting a hydride transfer mechanism in this oxidation.32 Kinetics of chromic acid oxidation of dimethyl and diethyl malonates, in the presence and absence of oxalic acid, have been obtained and the activation parameters have been calculated.33 Reactivity in the chromic acid oxidation of three alicyclic ketoximes has been rationalized on the basis of I-strain. Kinetic and activation parameters have been determined and a mechanism... 

Whereas it has been demonstrated that both malonate ions and thiolate ions can catalyze the free radical chain addition reaction of perfluoroalkyl iodides to olefins [289,290], under appropriate conditions one can obtain products deriving from substitution in such processes. Following early work carried out photo-lytically in liquid ammonia, recent reports have indicated that good yields of substitution products can be obtained in polar solvents at room temperature, without irradiation [291-296]. 

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. 

Addition of dimethylsulfonium methylide (122) to various Michael acceptors (121), followed by alkylation, has been reported to produce functionalized 1-substituted alkenes (124), arising via the unprecedented elimination (123), rather than the usual cyclopropanation products. In silyl substituted substrates, where a facile Peterson-type olefination is possible from the adduct, elimination took place instead. Aryl-substituted Michael acceptors (121 R1 = Ar) underwent a similar olefination to give 1-substituted styrene derivatives with moderate yields along with a side product, which arose by nucleophilic demethylation from the adduct of dimethylsulfonium methylide and arylidene malonates. Hammett studies revealed that selectivity for olefination versus demethylation increases as the aryl substituent becomes more electron deficient.164... 

In addition to the cathodic hydrodimerization of activated olefins and the Kolbe reaction, the anodic dimerization of CH-acidic compounds is another possibility for the electrochemical C—C coupling. Monsanto 281 > has used the anodic dimerization of malonates in a laboratory synthesis of intermediates for useful sequestrants and detergency builders. 

The observed stoichiometrically imbalanced polymerization behavior is rationalized by involvement of olefin-Pd(O) complex 14, which leads to cascade bidirectional allylation. Thus, after the first allylation of 13, 14 selectively forms the allylpalladium(II) complex at the other allylic terminal. Therefore, the polymer end groups are always the malonic ester moiety even in the presence of excess 13, which would not terminate the polycondensation by the attack on both polymer end groups. This behavior is dependent on the ligand of the Pd(0) catalyst bis(diphenylphosphino)butane (dppb) is indispensable, and use of PPh3 results in low molecular weight polymer as expected by Carothers and Flory s basic principle [1-3]. 

Dibutyl telluride 59 reacts with iodomethyl triphenylphosphonium iodide to give triphenylmethylidene phosphor-ane, which reacts with aldehydes leading to the methylenation products in good yields.119 The same reagent 59 also assists the reaction of dibromomalonates 60 with aldehydes and activated olefins affording alkylidene malonates 61 and cyclopropanes 62 derivatives, respectively (Scheme 30). 

The synthesis of 6a-methyldigitoxigenin acetate (394) has been reported according to Scheme 19.198 Pregn-4-en-21-ol-3,20-dione was converted into its 6a-methyl derivative (387) using a previously described five-step reaction sequence biological hydroxylation furnished the 14a,12-diol (388) and reduction of the derived 21-acetate gave the 5/3-dihydro-steroid (389). Dehydration furnished the A14-olefin (390) which was converted into the 21-mesylate and thence into the lactone (391) by reaction with the monoethyl ester of malonic acid. The crude lactone was decarbox-ylated, reduced to the 3/3-alcohol (392), and converted into the bromohydrin (393) via its 3/3-acetate and thence by debromination into 6a-methyldigitoxigen 3-acetate... 

On the basis of this palladium-mediated Michael addition cyclization process, a novel two-step synthetic entry into functionalized furan derivatives 67 has also been devised (Scheme 28). Substitution of benzylidene (or alkyli-dene) malonates for their ethoxymethylene analog (65) as activating olefins gave rise to the formation of the corresponding 2-ethoxy-4-arylidene tetrahy-drofurans 66. An in situ addition of potassium ferf-buloxidc induced a decar-boxylative elimination reaction which was followed by an isomerization of the exocyclic double bond. The entire process successively involved a conjugate addition, a palladium-catalyzed cyclization-coupling reaction, a base-induced eliminative decarboxylation, and finally, a double bond isomerization [73]. 

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