Malonic monoester

Attempted addition of malonate monoester 1017 to pyrrole led to the formation of ester 1018 in 65% yield, presumably through a sequence of events involving radical substitution followed by decarboxylation, as shown in Scheme 196 <2003TL6853>. 

Many modified Marckwald procedures are available to prepare structurally diverse imidazoles most of them are focused on the preparation of an oe-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) <2005TL7315>. 

Other halides may be used in place of the bromo ester. Reaction of a pro-pargyl halide, for example, with various carbonyl compound gives y,d-acetylenic alcohols of type (6) in good yield.223 Also the carbonyl component may be replaced by an orthoformic ester, which leads to a malonic monoester monoaldehyde acetal of type (7) in 44-58% yield.224... 

P-Keto esters. After conversion of potassium malonic monoesters to the Mg salts with MgCU-EtjN, the reaction with acid chlorides proceeds smoothly and safely. 

The reaction of 1-adamantane carboxylic acid proceeded smoothly at 80 °C, providing Boc-protected amine 92 in high yield, but the slow step of the process was addition of the ert-butoxy nucleophile (butoxide or butanol) to the isocyanate intermediate. Of numerous catalysts and conditions screened to accelerate that addition, zinc triflate in tetrahydrofuran solvent proved optimal, allowing the process to occur smoothly at 40 °C for a range of alkyl carboxylic acids. In some cases, such as the stereoretentive conversion of or-methyl-y -siloxy propionic acid 93 to Boc-protected chiral amine 94, inclusion of additional tert-butanol was required. Catalysis was proposed to occur via an isocyanate-derived, zinc-complexed carbamoyl bromide. The Lebel conditions were also applied to malonate monoesters as a route to cr-disubstituted-cr-amino acids. 

Meldrum s Acid. Meldmm s acid [2033-24-1] (3) is commercially used for the production of monoesters of malonic acid and beta-keto acids (17). The chemistry of Meldmm s acid is extensively reviewed in Reference 18. 

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Porcine liver esterase (PLE) gives excellent enantioselectivity with both dimethyl 3-methylglutarate [19013-37-7] (lb) and malonate (2b) diester. It is apparent from Table 1 that the enzyme s selectivity strongly depends on the size of the alkyl group in the 2-position. The hydrolysis of ethyl derivative (2c) gives the S-enantiomer with 75% ee whereas the hydrolysis of heptyl derivative (2d) results in the R-monoester with 90% ee. Chymotrypsin [9004-07-3] (CT) does not discriminate glutarates that have small substituents in the 3-position well. However, when hydroxyl is replaced by the much bulkier benzyl derivative (Ic), enantioselectivity improves significantly. 

In a similar way, carbocycles having a quaternary center could be obtained from acyclic unsaturated 1,3-dicarbonyl compounds [206]. Other combinations are the domino hydroformylation/Wittig olefmation/hydrogenation described by Breit and coworkers [207]. The same group also developed the useful domino hydroformyla-tion/Knoevenagel/hydrogenation/decarboxylation process (Scheme 6/2.14) [208] a typical example is the reaction of 6/2-66 in the presence of a monoester of malonic acid to give 6/2-67 in 41 % yield in a syn anti-ratio of 96 4. Compounds 6/2-68 and 6/2-69 can be assumed as intermediates. 

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). 

Another useful compound is the 1 2 telomer of malonate and butadiene, 137. The first example is the synthesis of pellitorine (138), a naturally occurring pesticide (126). The terminal double bond was hydrogenated selectively with RuCl2(PPh3)3 as a catalyst. Partial hydrolysis afforded the monoester, which was treated with PhSeSePh to displace one of the carboxyl group with phenylselenyl group. Oxidative removal of the phenylselenyl group afforded 2,4-decadienoate (139), which is converted to pellitorine (138) ... 

Ozonolysis of diketene affords formaldehyde [50-00-0] and the very un-stable malonic anhydride [15159-48-5] (114), which readily decomposes to C02 and ketene, but can be converted at low temperature to malonic acid monoesters or Meldrum s acid (115) (see Malonic acid AND DERIVATIVES). 

Meszaros et al.15 found that it melts at 99-100c,C. The structure was proved by UV, IR, and H NMR. The product isolated by Shur and Israelstam was probably the monoester (mp = 153-154CC) of the malonate (70 R = 6-Me), which is easily formed from the pyridopyrimidine (71 R = 6-Me) under the conditions applied to the polyphosphoric acid reaction mixture. 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

Diesters of -a I k an cd i car boxy I i c acids can be monosaponified by addition of one equivalent of hydroxide. Best results are obtained if conditions can be found under which the desired product precipitates from the reaction mixture. This is, for instance, observed for all the examples shown in Scheme 10.1. The products of monosaponification of malonic esters are significantly less electrophilic than the diesters, which leads to a highly selective reaction. This is, however, not so for the undecanoic diacid diester. With this compound precipitation of the monoester salt from the reaction mixture is presumably the main reason for the high yield obtained. 

The procedure described here for compound 1 is a scaleup of a published method.6 Phase-transfer catalysis7 and concentrated alkali are used to effect a one-pot conversion of diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of 1-cyanocyclopropanecar-boxylic acid (86%) by the use of ethyl cyanoacetate and 1-acetyl-cyclopropanecarboxylic acid (69%) by use of ethyl acetoacetate.6... 

For a new potential -3-receptor agonist a pig liver esterase-based enantioselec-tive synthesis was devised (Scheme 6.18). The substituted malonic acid diester was hydrolysed at pH 7.2 and yielded 86% of the (S)-monoester with an ee of 97% [62]. This reaction immediately demonstrates the great advantage of starting with a symmetric molecule. The enzyme very efficiently desymmetrizes the diester and excellent yields with high optical purities are obtained. No extra steps are necessary and no additional chemicals need to be added. 

Glycine is the only a amino acid without a chiral centre, but replacing one of the two protons on the central carbon with, say, deuterium creates one the CH2 carbon is prochiral. Similarly, converting malonate derivative into its monoester makes a chiral centre where there was none the central C is prochiral. 

Both the malonic ester synthesis and the acetoacetic ester synthesis arc relatively easy to carry out because they involve unusually acidic carbonyl compounds. As a result, relatively mild bases like sodium ethoxide in an alcohol solvent can be used to prepare the necessary enolate ions. Alternatively, it s also possible in many cases to alkylate the a position of monoketones, monoesters, and nitrile. . A strong, sterically hindered base such as LDA is needed, so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

The Doebner condensation uses malonic acid, malonic acid monoesters, or cyanoacetic acid instead of the coiTesponding dialkyl malonates. Usually the product stereoisomer with the carboxyl group trans to the larger substituent predominates. 

The required malonic acid monoesters are readily prepared by heating the strongly acidic isopropylidene malonate (Meldrum s acid, 7.3) in an alcohol. Acetone is liberated in the process. 

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