Malonic alkylidene-, esters

Good yields of 1,4-addition products have also been obtained with alkylidene malonate esters which generally react with organomanganese reagents in the absence of copper salts9 (see Table IV). 

A series of alkenes 20, derived from amino acids, react with the dienol 21a to give adducts 22. Formation of the additional lactone and lactam rings occurs prior to isolation of the product. A complete facial selectivity, but only moderate (22a) to low (22b and 22c) yields are obtained9. To prevent lactone ring formation several protected derivatives of dienol 21 were reacted with alkylidene malonic ester 20a. Only diene 21g reacts in an acceptable yield and selectivity10. 

Among other types of electrophilic compounds that give alkylation of indoles are alkylidene malonate esters. Jorgensen and coworkers observed 50-70% ee using a Cu(BOX) catalyst [262]. 

The unsaturated side chain may be introduced by dimethylvinyl-Grignard addition on alkylidene malonic ester containing one leaving group 25 [38], thus allowing the formation of a transition state similar to the aforementioned ylid reactions, which collapses to give the 3-membered ring 26 (Reaction scheme 15). 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

Both butenolides 50 and 51, one tethered to an a, -unsaturated ester, the other to an unsaturated nitrile, failed to undergo cyclization. Instead, the C=C 7i-bond of the butenolide was reduced, leading cleanly and efficiently to saturation of that bond, and to compounds 54 and 55, respectively. In contrast, the corresponding alkylidene malonate 52, as well as the alkylidene malononitrile 53, both cyclize to afford a mixture of the cis-anti-cis and cis-syn-cis linearly fused lactones 56 and 57. 

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. 

Reactions which may at first glance appear to involve ylides may not in fact do so. For example, a bromomalonic ester reacted with a variety of aldehydes in the presence of tributylarsine to form alkylidene- or arylidene-malonic esters, but no base was required and it was suggested that reaction proceeded not via an ylide but via an arsonium salt formed by extraction of a bromonium ion from the malonic ester The malonate anion... 

In contrast to allyl halides substituted with one ASG, the cyclopropanation reaction proceeds relatively smoothly when a second ASG is present. Generally, the best results are obtained with sodium borohydride, sodium cyanide, potassium cyanide, and the sodium salts of alcohols or thiols as the nucleophilic species (Table 22, entries 3-26). Even spiroalkanes can be synthesized with the nucleophiles described above (Table 23). Examples illustrating this route are the conversion of a tetracyclic enamino ester with potassium cyanide to the corresponding electrophilic cyclopropane 2, and the facile one-pot synthesis of 1,1 -bis(hydroxymethyl)cyclo-propanes 3 by reduction of halogenated alkylidene malonates with lithium aluminium hydride. ... 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Addition of vinyl esters occurs still more readily. 2-(Acyloxy)propionitriles are obtained in more than 80% yield. Also, hydrogen cyanide can be added to esters of, / -unsaturated acids,116,117 e.g., ethyl crotonate and alkylidene-malonate) ... 

In 1974,Mukaiyama and co-workers reported the first examples of Lewis acid-catalyzed Michael reactions between silyl enolates and a,p-unsaturated carbonyl compounds [33]. Evans and co-workers developed a catalytic asymmetric Michael reaction of silyl enol ethers of thiol esters to alkylidene malonates. For example, the reaction of alkylidene malonate 23 with 2.2 equiv of silyl enol ether 22 was carried out in the presence of 10 mol % of catalyst 25 and 2 equiv of hexa-fluoro-2-propanol (HFIP) in PhMe/CH2Cl2 (3 1) at -78 °C to give the expected adduct 24 in 93% ee (Scheme 5) [34]. Borane complex-catalyzed asymmetric Michael addition has also been reported [35]. 

Excellent selectivities were observed in Lewis acid-promoted Diels-Alder reactions of chiral alkylidene malonates (D), fumarates (C) and allenic esters (G) with cyclopentadiene (see, column 3 in die table below). 

Amri and co-workers have described a one-pot synthesis of 4-alkylidene-2-cyclohexen-l-ones 56 in 47-71% yields via a tandem three-step 5n2 substitu-tion ieacetylation-cyclization series of reactions in the presence of anhydrous K2CO3 in absolute ethanol under reflux, using MBH acetates 54 as starting materials (Scheme 4.19). Subsequently, decarboxylation products 57, prepared from the reaction of MBH acetates and p-diketone or malonate esters, were reported to be treated with LHMDS (THF, 0 °C to room temp.) by Kim and co-workers, " affording 4-arylidenecyclohexane-l,3-dione derivatives 58 in 47 83% yields (Scheme 4.20). Similarly, when aza-MBH adducts 59a-c were... 

The synthesis of functionalized tetrahydro-1,2-oxazines 76 from nitroolefins 75 and nitrosoarenes has been studied by Zhong and coworkers. This enantio and diastereoselective organocatalytic process takes place via a domino sequence comprising an initial proline-catalyzed enantioselective aminoxylation of the starting material taking place by addition of the enamine onto the 0=N nitroso bond, followed by a final aza-Michael addition (Scheme 3.20) [57]. The same group has reported a very similar reaction starting from 2-alkylidene derivatives of malonic ester [58]. 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

PhSSPh with retention/ or photochemically/ Methyl phenyl N-methyl-sulphoximide gives adducts with ketones after conversion into its carban-ion, from which either tertiary alcohols are obtained by Al-Hg reduction under neutral conditions, or alkenes by reduction in aqueous acid, thus providing an alternative to the Wittig methylenation reaction/ Oxosul-phonium ylides formed by N-dimethylation followed by carbanion formation with NaH are useful as alkylidene-transfer reagents/ Uses of sulphoximides in heterocyclic synthesis have been reported methyl phenyl sulphoximide reacts through N with ethoxymethylene malonate esters. ... 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

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