Benzyl malonic acid

Fig. 4 Formation of the imprinting complex between benzyl-malonic acid (37) and the amino...

We also studied the pyridoxal-dependent decarboxylation of an aminomalonic acid, a process providing an a-amino acid as the product. Our interest was to induce stereoselectivity in the process. Therefore, we synthesized catalysts 42 and 43, which rigidly held chirally mounted groups [42]. With the basic 42 we obtained 42% ee favoring l-phenylalanine in the decarboxylation of 2-amino-2-benzyl-malonic acid, while with non-basic 43 the ee was too low to detect. We proposed that the basic side chain delivered a proton to the decarboxylation intermediate in a stereoselective fashion. 

Better results were obtained for the catalysis of the dehydrofluorination of 4-fluoro-4-(4-nitrophenyl)butanone by Shea et al. [94] and Mosbach et al [147]. Shea used benzyl-malonic acid as the template to position two polymerizable amines in a definite arrangement in the cavity. After removal of the template, dehydrofluorination was enhanced by this catalyst by a factor of 8.6. 

Benzoic acid — Thio-benzoic acid — Sulpho-benzoic acid — Phthalic acid—Ethyl-potassium phthalate—Phenyl-acetic acid—Cinnamic acid—Benzyl-malonic acid.56-58... 

Benzyl-malonic Acid.—When this acid in the form of its ethyl-potassium salt was submitted to electrolysis by Brown and Walker it showed a behavior materially different from that of malonic acid. The solution became dark-colored and contained no new compound. If oxidation occurred it was a complete oxidation into carbon dioxide and carbon monoxide, such as has been observed in the case of the unsaturated acids. 

The second procedure of this type was first described by Yamada et They used the diamidine of malonic acid (175) or cyanace-tamide (176) to prepare l-benzyl-5-amino-u-triazole-4-carboxamide... 

The preparation of malonic acid monoesters has been demonstrated using the microbial nitrilase activity of Corynebacterium nitrilophilus ATCC 21 419, Gordona terrae MA-1, or Rhodococcus rhodochrous ATCC 33 025 to hydrolyze methyl cyanoacetate, ethyl cyanoace-tate, M-propyl cyanoacetate, isopropyl cyanoacetate, M-butyl cyanoacetate, tertbutyl cyanoacetate, 2-ethylhexyl cyanoacetate, allyl cyanoacetate, and benzyl cyanoacetate [96]. By maintaining the concentration of nitrile in a reaction mixture at <5 wt%, significant inactivation of the nitrilase activity was avoided for example, a total of 25 g of M-propyl cyanoacetate was added in sequential 5g portions to a lOOmL suspension of Rhodococcus rhodochrous ATCC 33 025 cells (OD630 = 5.6) in 50 mM phosphate buffer (pH 7.0) over 30h at 25 °C to produce mono-M-propyl malonate in 100% yield (Figure 8.17). 

Copper complexes of substituted malonic acids had no influence on the acute toxicity towards adult zebra fish [227], possibly due to stronger chelating groups at the gill epithelia. In contrast, hatching of zebra fish, which is already very sensitive to Cu2+ alone, was delayed in the presence of hydrophobic ra-hexade-cyl malonate, and was not influenced by the less hydrophobic benzyl malonate [227], Overall, it appeared that the toxicity of free Cu2+ and the Cu-hexadecyl malonate complex was additive [227],... 

The variety of educts and products of the higher MCRs is illustrated here. Product 72 (Scheme 1.18) is formed from the five functional groups of lysine, benzaldehyde, and tert-butylisocyanide. The synthesis of 73 is achieved with hydrazine, furanaldehyde, malonic acid, and the isocyano methylester of acetic acid, compound 74 results from the reaction of benzylamine, 5-methyl-2-furanaldehyde, maleic acid mono-ethylester, and benzylisocyanide. ° Zhu et al. prepared a variety of related products, such as, 75, from (9-amino-methyl cinnamate, heptanal, and a-isocyano a-benzyl acetamides. 

On their side, Yin and Linker [216] made use of a 2-C-branched hexopyranoside, the synthesis of which was achieved by addition of dimethyl malonate to tri-O-benzyl-D-glucal (TUPAC name 3,4,6-tri-0-benzyl-l,5-anhydro-2-deoxy-D-araZtino-hex-l-enitol, Scheme 45) [217], Thus, saponification of the 2-C-[bis(meth-oxycarbonyl)]methyl derivative 184 to the corresponding malonic acid 185 was followed by heating in refluxing toluene. This led to decarboxylation and lactoniza-tion giving 186. The method was optimized and applied to the synthesis of pentoses and disaccharides. 

Benzo[6]thiophene aldehydes have been condensed with a variety of active methylene compounds, including cyclic511, 644 and open-chain645-647 ketones, aliphatic aldehydes,90 benzyl cyanides,93-436 malononitrile,487 rhodanine,144,648 hippuric acid,477 barbituric acid,487 diethyl malonate,487 and malonic acid (Section VI,M). Aliphatic nitro compounds condense smoothly with most benzo[6]-thiophene aldehydes03,141,337,343, 556,640,650 (except 5-hydroxy- and... 

The benzylic free radical produced by the addition of the carbamoyl radical to the ethyl cinnamate molecule is more stable than the alternative radical alpha to the ester group. With such an orientation of addition to the a,p-unsaturated ester, this reaction should lead to derivatives of malonic acid. However, it has been found that the intermediate radical, being a stable benzylic free radical, fails to perform the subsequent abstraction of a hydrogen atom from formamide, and thus no chain-transfer step takes place. Instead of performing this step it favours the combination with a semi-pinacol radical, which is present in solution, to yield the hydroxy ester which subsequently lactonizes to give the major product of the reaction (67). 

A simple synthesis of 2-methyl-2-trifluoromethylchroman-4-ones is possible upon heating iV-benzyl-2-trifluoro-methyl-477-chromen-4-imines 1115 in the presence of malonic acid. The reaction proceeds through ring opening and recyclization of the intermediate 1116 (Scheme 277) <2002S2341>. 

Figure 13.39 shows that malonic ester syntheses can also lead to acetic acid derivatives with a heteroatom in the a-position. The benzylation of (acetamido)malonic acid diethyl ester... 

The data for this solvent were not used to calculate the parameters in Table 54. Similarly the data for decarboxylation of oxanilic acid in anisole were not used for the AH -AS correlation. With the reported AH value of 32.6 kcal.mole , the entropy of activation is calculated to be 3.59 0.03 eu compared to the reported value of 11.1 eu. In the decarboxylation of malonic acid, the data obtained with pyridine and ) -mercaptopropionic acid solvents deviated considerably from the plots and were not included in the correlation. The data for malonic acid decarboxylation appeared to be best correlated by two lines. One line was described by the following solvents acids, phenols, nitro-aromatics, benzaldehyde, and the melt the other line involved amines, alcohols, dimethylsulfoxide and triethyl phosphate. The latter line was not as well defined as the former. However, it was our intention to correlate as many solvents as possible with a minimum number of lines. The data for decarboxylation of malonic acid in water and in benzyl alcohol fell between these two lines and were not included in either correlation. The data for decarboxylation of benzylmalonic acid also appeared to be best correlated with two lines. One line was defined by the cresols, acids and the melt, while the other line was defined by the amines. Decarboxylation of cinnamalmalonic acid was correlated by two lines as indicated in Table 54. Similarly j8-resorcylic acid was correlated by two lines. The separation of data into parallel lines is presumably due to multiple solvation mechanisms . In support of this interpretation it is seen that when two lines are observed, acids fall into one line and amines into the other. It is not unexpected that the solvation mechanisms for these two classes of solvents would differ. It is interesting to note that all of the nitrogen containing acids are correlated reasonably well with one line for both basic and acidic solvents. Also the AHq values fall in a rather narrow range for all of the acids. From the values of p in Table 54, there appears to be little correlation between this parameter and the melting point of the acids, contrary to prior reports " ... 

The hydrogenolysis of benzyl esters provides a means for the selective eonversion of the ester to the acid under mild conditions. Substituted dibenzyl malonates are easily converted to the substituted malonic acids by hydrogenolysis in neutral medium thus avoiding the acyl cleavage or decarboxylation which can result from base or acid catalyzed ester hydrolysis (Eqns. 20.26-27).5 . 58 Monobenzylmalonates are selectively debenzylated and decarboxylated to give the substituted acetic esters. 

Dibenzyl malonate, CH,(C02CH2C6H5)2. Mol. wt. 284.30, b.p. 188°/0.2 min. Preparation in 5% yield by refluxing malonic acid, benzyl alcohol, and a trace of sulfuric acid in toluene under a constant water separator (method A ). The ester is sensitive to heat and should be distilled rapidly through a short-path system. ... 

Condensations. Conjugated thioesters are made from aldehydes and monothioesters of malonic acid at room temperature using Yb(OTf)3 as catalyst. Arylacetaldehydes afford thioesters containing a benzylic double bond. ... 

Heating a SchifFs base with diethyl malonate for 0.5 h in the presence of catalytic amounts of piperidine (or acetic acid, hydrochloric acid, or ammonium chloride) in closed ampoules affords the diethyl [(arylamino)benzyl]malonate in 50% yield.242... 

C]benzyl alcohol [7- " C]benzyl chloride [l- Clphenyl acetic acid ethyl ester [2- " C]phenyl malonic acid diethyl ester... 

In the electrolysis of cyan-acetic ester the formation of dicyan-succinic ester could not be observed likewise a union of the anions of benzyl-malonic ester, acetyl-malonic ester, and acetyl-dicarboxylic ester did not take place. Electrolysis of acid amides in the... 

Ester enolates undergo alkylation reactions. When ethyl 3-methylpentanoate (110) reacts with sodium ethoxide in ethanol and then with bromoethane, the product is 111. Alkylation of malonate derivatives leads to an interesting sequence of reactions that are useful in synthesis. The reaction of diethyl malonate (90) and NaOEt in ethanol, followed by reaction with benzyl bromide, gives 112. In a second reaction, 112 reacts with NaOEt in ethanol and then with iodomethane to give 113. Saponification of 113 (see Chapter 20, Section 20.2) gives the dicarboxylic acid, 114, and heating leads to decarboxylation (Section 22.8) and formation of acid 115. This overall sequence converted malonic acid via the diester to a substituted carboxylic acid, and it is known as the malonic ester synthesis. 

Consider two examples—a decarboxylation and an Sn2 reaction. The primary kinetic isotope effects (PKIE, ku ku for C relative to the natural abundance C, which is mostly C) at the methylene and carboxyl carbons in the decarboxylation of malonic acid are 1.076 and 1.065, respectively (Eq. 8.19). The values are very close. Indicating that a bond to each of these carbons breaks in the rate-determining step. The isotope effect (Icjs/in the displacement of chloride from benzyl chloride by cyanide is 1.0057, indicating that the bond to chlorine breaks in the rate-determining step (Eq. 8.20). 

---