Alkylidenemalonate addition

Knef and coworkers have fouad that 2-lithio-2-sulfoaylpropane and 2-lithio-2-nitropropane behave differenlly in the addition to dimethyl alkylidenemalonate. Thus, 2-Lithio-2-snlfonyl-propane reacts with it iiimost exclusively on the CSii-face and leads to the ruin -addnct, whereas 2-lithio-2-nitropropane reacts under similar reaction conditions, exclusively on the Wfi -face, providing the iy)i-prodnct fEq. 4.134. ... 

Various methylenetetrahydrofurans were accessible by a combination of a Zn-promoted Michael addition and a cyclization using alkylidenemalonates and pro-pargyl alcohol as substrates, as reported by Nakamura and coworkers [108]. Tetrasubstituted pyridines of type 2-189 have been obtained through a solvent-free InCl3-promoted domino process of 2-187 and 2-188 (Scheme 2.44) [109]. 

The 1,4-addition of sp3-geminated organodimetal compounds, prepared by the Gaude-mar/Normant coupling reaction, to alkylidenemalonate gives Z-alkene selectively through elimination of the malonate moiety (equation 33)56,57. 

The addition of Grignard reagents to 1,1-doubly activated alkenes, e.g. alkylidenemalonates (105),68 84a d alkylidenecyanoacetates (106),84e-f alkylideneisocyanatoacetates (107),alkylidenephos-phonoacetates (108),848 isopropylidenemethylenemalonates (109)84iaddition mode exclusively (Schemes 34 and 35). Similarly, as shown in Scheme 36, Mukaiyama reports that the addition of Grignard reagents to chiral oxazepines (110) and (111) affords an enantiose-lective synthesis of -substituted carboxylic acids.85... 

The addition of allylic (or benzylic) zinc halides to alkylidenemalonates (105),lo2s-c alkylidene-cyanoacetates (106),l02d e alkylidenephosphonoacetates (108),84,1 alkylidene barbiturates102f and their ary-lidene analogs occurs exclusively in a 1,4-addition mode. However, the addition of allylic zinc halides to alkylidenemalonates (105) is temperature dependent at low temperatures (-15 C), the homoallylic ma-lonate (128) is obtained, while at higher temperatures (68 C) the isomeric 2-cyclopentenedicarboxylate esters (129) are obtained by a zinc halide promoted electrocyclic closure of the intermediate ester (127 Scheme 48).102 ... 

Michael reactions of chiral lithioenamines of p-oxo esters with dimethyl alkylidenemalonates were studied.173-176 Especially the a-alkyl-substituted compounds (161) and (163), derived from L-valine t-butyl ester, afford, after hydrolysis, the adducts (162) and (164), respectively, diastereoselectively and with high ee (Scheme 57).175 In the presence of TMS-C1, even weaker acceptors like acrylates or MVK were shown to react.176 A somewhat related diastereoselective 1,4-addition, followed by a Pictet-Spen-gler-type cyclization, allows the preparation of compound (165 Scheme 58),177 a central intermediate for the synthesis of several alkaloids.177-178... 

Bernadi and Scolastico, and later Evans in a more effective manner, indicated that the enantioselective addition reaction using silyl enol ethers can be catalyzed by Lewis acidic copper(II) cation complexes derived from bisoxazolines [38-40]. In the presence of the copper complex (S,S)-14 (10 mol %), silyl enol ethers derived from thioesters add to alkylidenemalonates or 2-alkenoyloxazo-lidone in high ees (Scheme 12). Bernadi, Scolastico, and Seebach employed a titanium complex derived from TADDOL for the addition of silyl enol ethers to nitroalkenes or 2-cyclopentenone [41-43], although these are stoichiometric reactions. 

Tandem intramolecular 1,3-dipolar cycloadditions and cycloreversion, phosphinimine alkylidenemalonate cyclization, and retro-malonate additions have been reviewed.52 The origins of the stereoselection in the 1,3-dipolar cycloadditions to chiral alkenes53 and the 3 + 2-cycloadditions of fullerene, Cea, have been reviewed.54 The selectivity of the double 3 + 2-cycloaddition of tethered double vinyl carbene species in die presence of C6o varies witii the nature of the tether.55... 

Maruoka and coworkers developed the diastereo- and enantioselective conjugate addition of nitroalkanes to alkylidenemalonates under mild phase-transfer conditions... 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

Michael-adducts obtained by Barbas et al. (ref. 43) from the addition of acetone to alkylidenemalonates... 

Conjugate addition of RMnCl to alkylidenemalonic esters proceeds in generally good yields (80-87%, equation I), which are generally higher than those obtained by use of RLi or RMgCl. A new synthesis of citronellol (1) is based on this reaction.3... 

Alkylidenemalonate 59 was a substrate in the Taddol-based phosphoramidite 61-mediated addition of diethyl zinc to afford the ethyl adduct 60 in 73% ee [39]. The unsaturated imine 62 was a substrate in an amidephosphine 64 copper-catalyzed ethylation to afford 63 in moderate ee after hydrolysis (Scheme 7) [40]. 

The addition of copper salts was found to favor the conjugate addition of (Irignard reagents to alkylidenemalonic esters,9 and Mimeh-1 Vterson subsequently found that the addition of 1 mole % of eopper(l) chloride was generally useful for promoting the... 

Iron catalysts are very effective for the substitution of acyl chlorides [Eq. (198) 439.440] and thiol esters [Eq. (199) 376] with Grignard reagents to yield ketones. 1.4-Addition of Grignard reagents to an alkylidenemalonate derivative, as shown in Eq. (158) [182,183] was also promoted with an iron catalyst, but the degree of the asymmetric induction was inferior to that of the reaction catalyzed by nickel. 

The Lewis acid-promoted reactions of acrylates and propiolates with allylsilanes usually afford [2-1-2] adducts as described in the next section [470-473]. The corresponding [3-1-2] adducts are obtained as minor products although there are a few exceptions. The ratio of the two kinds of cycloadduct depends on the reaction temperature [470] - the proportion of [3-1-2] adducts increases with increasing temperature. The product ratio from cycloaddition to alkylidenemalonates and their derivatives is markedly temperature-dependent (Scheme 10.170) [474, 475]. Cyclobutanes are major products at low temperature, and [3-1-2] cycloaddition proceeds predominantly at higher temperature. In addition, the [2-1-2] cycloadducts are smoothly isomerized to the [3-1-2] adducts in the presence of a Lewis acid. This behavior clearly shows that [3-1-2] cycloaddition is thermodynamically favored. 

P-Hydroxylamino esters. Alkylidenemalonic esters undergo Michael addition with the bissilylated hydroxylamine, while the corresponding acrylic esters react very sluggishly. The addition is subject to 1,2-asymmetric induction by an allylic substituent. 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

In the report by Rovis, triazolium salt 120d derived from phenylalanine was identified as the best eatalyst for the conjugate addition of glyoxylamides with a variety of p-substituted alkylidenemalonates (Scheme 6.12). Moderate to... 

Addition of Grignard reagents to alkylidenemalonic esters s. 9, 770 of acetylenic Grignard reagents cf. M. Julia and G. Descoins, Bl. 7964, 2541... 

By far, the most often used nucleophiles are malonates, which can be deproto-nated by the aUcoxide formed in the reaction of allyl carbonates or by an added base such as NaH. This standard nucleophile has been applied in all types of aUylations, and many applications are also reported in this monograph. The nucleophihc species can also be generated by 1,4-addition, for example, of alkoxides, generated from carbonates, onto alkylidenemalonates both inter- and intramolecularly [92]. The substitution products can be subjected to a thermal desalkoxycarboxylation or, after hydrolysis, decarboxylation, giving rise to carboxylic esters or acids [93]. Therefore, in combination with this decomposition, malonates can also be used as surrogates for ester enolates [94], which generally cannot be used as nucleophiles in allylations. 

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