Malonates, addition with

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

Knoevenagel condensation of malonic acid with heptaldehyde [111-71-7] followed by ring closure, gives the fragrance y-nonanoic lactone [104-61-0] (6) (14). Beside organic synthesis, malonic acid can also be used as electrolyte additive for anodization of aluminum [7429-90-5] (15), or as additive in adhesive compositions (16). 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

This work was repeated by several groups7 11 in the reaction of sodium dimethyl-malonate with methyl sorbate, Farmer and Metha9 observed small amounts of the 1,4-adduct besides the 1,6-addition product. Difficulties in conducting the transformations and analyzing the products are evident from reports on malonate additions to ethyl muconate12-14 depending on the reaction conditions, the expected 1,4-adduct (equation 4) or isomerization products formed by double bond displacement were isolated. Nucleophilic 1,4- and 1,6-addition reactions to 2,4-pentadienenitrile were also reported15-17. 

A potential industrial route to potassium dinitromethane (18) involves treatment of methyl malonate (107) with red fuming nitric acid to give methyl Q ,Q -dinitroacetate (108), followed by hydrolysis-decarboxylation with aqueous potassium hydroxide. Dinitromethane is a precursor to 2,2-dinitroethanol and 2,2-dinitro-1,3-propanediol, both of which are useful in addition and esterification reactions for the production of energetic oligomers and plasticizers. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Barbas developed this procedure further by introducing an asymmetric three-component Michael reaction that should be applicable to many other conjugate addition reactions. He used a Wittig olefmation to prepare, in situ, an a,P-unsatu-rated ketone that subsequently underwent a conjugate addition with malonates (Scheme 21) [94]. The rate of the conjugate addition process was observed to be considerably faster than the analogous reaction reported by Jprgensen which was attributed to the presence of triphenylphosphine oxide within the reaction mixture. 

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. 

Substituted cyclopropyl rings conjugated with a triple bond system have recently received attention as C5 building blocks. The procedure described here is a modification of the decarboxylation-elimination reaction for the preparation of a.3 acetylenic acids from enol sulfonates of acyl malonates. Addition of aqueous alkali to the enol sulfonate of diethyl cyclopropyl carbonyl malonate gives cycl opropyl propiol ic acid, but the yield is 1 ow. 

Mettler and colleagues reported an alternative synthesis of malonate 16 in the same paper (Griffiths et al., 1991) in which they condensed cyclohexanone with ethyl cyano-acetate instead of diethyl malonate in the Knoevenagel reaction to give ethyl cyano(cyclohexylidene)-acetate (18). In the presence of a catalytic amount of sodium cyanide, the Michael addition of HCN to cyanoacetate 18 proceeded in good yield at room temperature to generate the dicyanoester 19. Intermediate 19 was selectively converted to malonate 16 with pressurized HCI treatment in ethanol (Scheme 16.4). 

As is to be expected, an alkynic ketone undergoes a Michael addition with a carbanion, leading eventually to a pyranone (50JA1022). Using malonic esters, a 3-alkoxycarbonyl derivative results, which is hydrolyzed to the 2-oxopyran-3-carboxylic acid under alkaline conditions, but to the pyranone by sulfuric acid. Rapid ester exchange is observed with the initial products, the alcohol used as solvent determining the nature of the alkyl group in the 3-carboxylic esters (Scheme 90). 

In contrast to the malonate additions to methylenecycloalkane-derived ir-allyl complexes, where substantial endocyclic addition has been observed with the cyclohexyl analog, essentially exclusive exocy-clic addition occurs for both the five- and six-membered ring cases with PhS02Na (equations 282 and 283)219... 

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 ftdlerene, Cgo, have been reviewed.54 The selectivity of the double 3 + 2-cycloaddition of tethered double vinyl carbene species in the presence of C6o varies with the nature of the tether.55... 

The first asymmetric iron-catalyzed conjugate addition was reported in 1977. Benzylidene malonate 56 with an ephedrine moiety as chiral auxiliary was converted with Grignard reagents such as nBuMgBr in the presence of catalytic amounts of various metal salts. The optically active phenylpropionic acid 57 was obtained with... 

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. 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

The point of addition of the radical to a phenylated compound can be reversed when another ester group is introduced into the substrate molecule. Thus, benzal diethyl malonate reacts with formamide under ultraviolet irradiation in the presence of benzophenone to give derivatives of l-phenyl-l,2,2-tricarboxyethane [61),... 

Alkyhdene malonate substitute complex (89) undergoes diastereoselective Michael-type additions with a number of nucleophiles including organolithiums, Grignards see Grignard Reagents), aUyl tributylstaimane, and ketene silyl... 

In octanoic acid solvent, alkyl substitution of malonic acids causes a small decrease in AG and thus an increase in rate as seen from Table 47. This is in contrast to the alkyl substituent effect in water (Table 46). The enthalpy of activation is clearly more favorable for decarboxylation of alkyl malonic acids than malonic acid in octanoic acid. Both Ai/ and AG are less favorable for decarboxylation of malonic acid in octanoic acid compared to water. This is expected on the basis of either the concerted (2) or the zwitterion mechanism (3) and (4). Association of the carboxyl groups of malonic acid with the octanoic acid solvent would thwart the attainment of the concerted transition state. Also generation of the zwitterion would be suppressed in octanoic acid. It is clear that additional work is required... 

Although it probably did not involve a Heck reaction per se, Balme and co-workers employed an interesting tandem reaction in their construction of A 2) capnellene (147) (Scheme 6-26) [54J. Presumably vinyl iodide 144 undergoes initial oxidative addition with the palladium(O) catalyst to furnish a cr-alkenylpalladium(n) intermediate that is complexed to the pendant alkene. Intramolecular addition of the soft malonate nucleophile to this complex, from the opposite face, followed by reductive elimination, then provides tricycle... 

The use of a stabilized carbanion as external nucleophile in the arylation or vinylation of conjugated dienes leads to a 1,4-addition of carbon atoms. This was first demonstrated by Dieck and co-workers [38] in 1983, who showed that l-bromo-2-methylpropene and sodium dimethyl malonate reacted with isoprene in the presence of a palladium catalyst to give 20 in moderate yield [Eq.(21)]. 

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