Reaction with malonate anion

In a second synthesis of labeled phenylalanine Battersby et al. (305, 306) used the pro-R specific enzyme horse liver alcohol dehydrogenase to reduce [ HJbenzaldehyde 306, Ha = H. The (lS)-[l- H,]benzyl alcohol 307 obtained was converted via tosylation and reaction with malonate anion to the acid 308 (Scheme 81), which, on bromination and ammonolysis, gave (2RS, 3R)-[3- Hi]phenylalanine 297, He = H. Ife and Haslam (309) used the more direct replacement of the tosylates of the alcohol 307 with acetamidomalonic ester in a similar synthesis of (3R)- and (3S)-[3- Hi]pheny-lalanines. Fermenting yeast replaced liver alcohol dehydrogenase in a further synthesis (310). 

Selectivity for one functional group in preference to another can be used to good advantage in reactions with malonate anions. One example is the reaction of diethyl 2-phenyl diethyl malonate and 2-chloroacetonitrile under basic conditions to give 4.53.29 In this case, the malonate anion displaced chlorine rather than reacting with... 

Barbee TR, Guy H, Heeg MJ, Albizati KF. Functional group hybrids. Reactivity of a -nucleofuge a,(3-unsaturated ketones. 2. Reactions with malonate anion. Concerning the mechanism of the Favorskii rearrangement. J. Org. Chem. 1991 56 6773-6781. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

Certain pyrones react with active hydrogen compounds in a quite different way they display their alkenic character by participating in Michael reactions, thus coumarin itself gives 316 with malonate anion, and coumarins 317 react with arylboronic acids catalyzed by rhodium giving 318 in greater than 99% ee <2005OL2285>. 

Trapping experiments with malonate anions in the controlled/living polymerization of vinyl ethers initiated by mixtures of hydrogen iodide (HI) and Lewis acids revealed that the total concentration of the growing species (the sum of dormant and active) stays nearly constant and equal to that of the introduced initiator when monomer is present in the reaction mixture. However, after complete monomer consumption, the concentration of the growing species decays relatively rapidly [251,252]. 

Methanolysis of (108a) furnishes the thioxosulfonamide (145) as yellow crystals in quantitative yield (Scheme 53) <78AG(E)195>. n-Butyllithium and phenyllithium are commonly used as nucleophiles and attack the sulfur atom, but the lithium salts of isocyanides attack mainly the carbon atoms of the ring. Attack on the sulfur atom of the thiiranimine (108c) is observed in the reactions with the anion of diethyl malonate, a phosphorus ylide, /V-methylindole and enamines or ynamines (Scheme 54) <80JOC4366>. 

Sharpless and Kim reported a one-pot synthesis of cyclic sulfates 96 from 1,2-diols via catalytic oxidation with ruthenium chloride51. The cyclic sulfates 96 thus formed on treatment with nucleophiles give /2-sulfates 97, which in turn are hydrolyzed to the / -hydroxy compounds 98 (equation 54). Hence the cyclic sulfates 96 are synthetically equivalent to epoxides. The results of ring opening of cyclic sulfates 96 are shown in Table 4. When the reaction of 99 with malonate anion is carried out in DME, the /2-sulfate moiety serves as a leaving group to give cyclopropane 100 (equation 55)51. 

Both cyclic and acyclic mei o-aziridines with an A-3,5-dinitrobenzoyl activating group undergo a ring-opening reaction when treated with malonate anions, in the presence of a catalyst formed from La-(0-/-Pr)3, Yb(OTf)3, and a Schiff base. A 63-99% yield of the trans-product is obtained, with 97 > 99.5% ee. 

Transition metal-benzyl complexes also react readily with nucleophiles, but the origin of this enhanced reactivity results from effects other than the typical rapid rate of nucleophilic attack at an electrophilic benzyUc carbon. As shown in Equation 11.17, benzyl groups can be bound in an fashion, much like an aUyl group. As presented later in this chapter, cationic iq -allyl complexes react with a variety of nucleophiles. iq -Benzyl groups are common in the chemistry of palladium(II), - and these ti -benzyl and phen-ethyl complexes react with a variety of nucleophiles. For example, these complexes react with malonate anions, and they have been shown to react with amines " during some recently developed hydroamination processes. These reactions occur with predominant inversion of configuration. ... 

While geranyl acetate 169 reacts with malonate anions as well as with its sulfonyl analog to give, in both cases, the linear products, neryl acetate 171 undergoes primary attack only with the sulfonyl compound and gives rise to the branched reaction product with the malonate anion [78]. 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

The intramolecular carbopalladation (or insertion) of the triple bond in dimethyl 4-pentynylmalonate (215) with Pd—H species and malonate anion as shown by 216 proceeds in the presence of f-BuOK and 18-crown ether, affording the methylenecyclopentane derivatives 217 and 218, the amounts of which depend on the reaction conditions. The Pd—H species may be formed... 

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Ligand 92 was readily prepared by reaction of (+)-pinocarvone with 1-phenacylpyridinium iodide. The authors similarly prepared corresponding 5,6-dihydro-1,10-phenanthrolines derived from (+)-pinocarvone and a tetrahydroquinolone (structure 93, [127]) and obtained up to 81% in the palladium-catalyzed test reaction. Chelucci et al. [ 128] reported the synthesis of chiral Ci-symmetric 1,10-phenanthrolines incorporated in asteroid backbone. Structure 94 derived from 5o -cholestan-4-one in Scheme 51, allowed very high yield and up to 96% ee using BSA and tetrabutylammonium fluoride to generate the malonate anion. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

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. 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

Rainier devised a variant of the 5-exo-dig radical cyclization of 2-alkynylisocyanides 122 wherein thiols were utilized to both initiate the radical cascade as well as act as nucleophiles in the reaction with the indolenine intermediate 123 yielding the indoles 124 . When R = TMS, elimination of the C-10 thioether can be effected in a gramine-like fashion so as to add nucleophiles (e.g., malonate anion) in the presence of Bu3P allowing for the preparation of more highly functionalized indoles. 

This reaction was easily performed with malonic ester derivatives using approaches described above for nitro carbanions. It should be noted that the anion of malonic ester can be prepared not only by the reactions of bases with malonates but also by desilylation of silyl ketene acetal (449) with fluoride anion. 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

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