Chemistry
Malonic ester synthesis
Malonic ester synthesis is a chemical reaction that involves the conversion of a malonic ester to a substituted acetic acid. The reaction involves the use of a strong base to deprotonate the malonic ester, followed by the addition of an alkyl halide to form a new carbon-carbon bond. The resulting product can be further modified to produce a variety of organic compounds.
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6 Key excerpts on "Malonic ester synthesis"
eBook - ePub- (Author)
- 2014(Publication Date)
- Wiley-VCH(Publisher)
Malonic Acid and Derivatives Harald Strittmatter, Lonza Ltd., Visp, Switzerland Stefan Hildbrand, Lonza Ltd., Basel, Switzerland Peter Pollak, Lonza Ltd., Basel, Switzerland1. Introduction
Three-carbon 1,3-dicarboxylic acid derivatives (malonic acid, malonates, cyanoacetic acid, cyanoacetates, and malononitrile) are widely used in industry for the manufacture of pharmaceuticals, agrochemicals, vitamins, dyes, adhesives, and fragrances. The common feature of malonic acid and its derivatives is the high reactivity of the central methylene group. Due to the increasingly electron-withdrawing character of the substituents, the acidity of the hydrogen atoms in the 2-position increases in the order malonates < cyanoacetates < malononitrile. Therefore, all these compounds undergo reactions typical of 1,3-dicarbonyl compounds. For example they are easily alkylated or arylated, undergo aldol and Knoevenagel condensations, and they can be used for the synthesis of pyrimidines and other nitrogen heterocycles.Malonic acid and derivatives are basically all produced by reaction of a two-carbon building block with a one-carbon unit (Fig. 1 ). Thus, cyanoacetates are prepared from sodium chloroacetate and sodium cyanide, followed by acidification and subsequent esterification. Malonates are produced either by a cobalt-catalyzed alkoxycarbonylation of chloroacetates with carbon monoxide in the presence of alcohol, or by hydrolysis of cyanoacetic acid followed by esterification. For the production of malononitrile, the continuous high-temperature reaction of cyanogen chloride and acetonitrile has almost totally replaced the former synthesis, based on dehydration of cyanoacetamide (1 ).Figure 1. Synthetic routes for malonates, cyanoacetates, and malononitrile2. Malonic Acid
Physical Properties. Important physical properties of malonic acid (propanedioic acid, methanedicarboxylic acid) are listed in Table 1 . Its pK a
eBook - PDF- Ramesh Chandra, Snigdha Singh, Aarushi Singh(Authors)
- 2019(Publication Date)
- Arcler Press(Publisher)
In organic chemistry, drug molecules, the organic material compounds, and natural products often have ester unit as the functional group, so the production of the efficient synthesis of carboxylic acid esters by the use of carboxylic acids is still one of the central research topics (Mitsunobu & Yamada, 1967; Li & Corey, 2007). As for the viewpoint, the corresponding carboxylic acids are typically applied as the crucial initiating material and play a significant role in the synthesis of esters (Neises & Steglich, 1978). So far, numerous types of approaches for the synthesis of esters from carboxylic acids are well known and applied, but a lot of researchers still have investigated the new approaches or aspects, from the point of view of green chemistry and industry the synthesis of esters also plays an important role. Novel developments in the formation of carboxylic acid esters are explained. The reactions are divided into two divisions, i.e., the reactions in the carboxylic acids are used as (1) nucleophiles and (2) electrophiles, in which many chemical reagents and catalysts as well as stimulating reaction media and methods are used for conducting the reactions. While many papers have come into being in this filed, we herein have presented key and particular examples (Mitsunobu & Yamada, 1967). 4.2. SYNTHESIS OF CARBOXYLIC ACID ESTERS US-ING CARBOXYLIC ACIDS AS ELECTROPHILES The reaction of carboxylic acids with an additional amount of alcohols in the existence of a catalytic amount of H 2 SO 4 by using Dean-Stark apparatus, Recent Advances in the Synthesis of Carboxylic Acid Esters 137 in which H 2 SO 4 catalyzes the adding of the alcohol to the carboxylic acid, and the H 2 O thus produced is eliminated by Dean-Stark apparatus, is the characteristic and outdated method for the production of carboxylic acid esters (Figure 4.1 (a)). This reaction is known as Fischer esterification. Though, there are some downsides.
eBook - PDFScience of Synthesis: Houben-Weyl Methods of Molecular Transformations Vol. 20b
Three Carbon-Heteroatom Bonds: Esters, and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X=S, Se, Te
- James Panek(Author)
- 2014(Publication Date)
- Thieme Chemistry(Publisher)
Attempts to lower the molar ratio to 1:1 result in lower yields due to the formation of significant amounts of the homo-Claisen condensation products of ethyl stearate. It is also important to use the same alcoholic moiety in both ester components to prevent transesterification under the reaction conditions. Diethyl Hexadecylmalonate (46); Typical Procedure: [34] To a soln of NaOEt (1 mol) and diethyl oxalate (2; 2 mol) in EtOH (300 mL) was added ethyl stearate (1 mol) and the mixture was heated at 60 8C while the EtOH was continually re- moved by distillation. When no further EtOH was produced, the mixture was vacuum dis- tilled (15 Torr) to remove excess 2 (76–82 8C). To the remaining residue was added AcOH (66 g, 1 mol) and H 2 O (1 L). The mixture was heated with stirring at 50–60 8C for 15 min and then cooled to rt. The residue was taken up in Et 2 O (300 mL) and washed with NaHCO 3 and H 2 O. The Et 2 O layer was concentrated under reduced pressure to afford the crude a- [ethoxy(oxo)acetyl] ester. The crude a-[ethoxy(oxo)acetyl] ester was thermally decarbonylated by heating the mixture to 160 8C under reduced pressure to afford the crude malonate. Purification by vacuum distillation afforded pure 46; yield: 90%; bp 196–199 8C/2 Torr. 20.5.4.1.10 Method 10: Malonate Esters by Arylation of Malonate Derivatives 20.5.4.1.10.1 Variation 1: Via Electrophilic Aromatic Substitution A conceptually attractive approach to the synthesis of arylmalonates would involve the direct arylation of malonate carbanions. However, this is generally unattainable due to the lack of electrophilic arylating agents for these systems. An alternative approach to this bond construction involves the use of a malonium carbocation equivalent, which could participate in regioselective Friedel–Crafts-type alkylations of a wide range of aro- matic nucleophiles. One procedure that exemplifies this approach utilizes diethyl oxo- malonate (48) as the malonium ion equivalent (Scheme 26).
- Paulo Costa, Ronaldo Pilli, Sergio Pinheiro, Peter Bakuzis(Authors)
- 2022(Publication Date)
- Royal Society of Chemistry(Publisher)
Hydrolysis, followed by decarboxylation, produces the corresponding α-alkylated acetic acid (from malonates) or ketones. - Cinnamates and other α,β-unsaturated systems can be prepared by the Perkin or the Knoevenagel reactions. - Claisen condensations form β-keto esters and are involved in fatty acid biosynthesis. Under physiological conditions, the enolate is formed from the decarboxylation of malonyl CoA, which reacts with a thioester to form a β-ketothioester within the enzyme active site. - Alkylation of chiral N -acyl oxazolidinones derived from Evans' chiral auxiliary is a practical and powerful approach to prepare enantiomerically enriched α-alkylated carboxylic acids and derivatives. - The aldol reaction of lithium enolates derived from amides, esters, or thioesters generally does not provide high diastereomeric control. (Z)-Boron enolates generally provide syn aldol products with good stereocontrol and (E)-boron enolates afford the anti aldol product. - Silylketene acetals and silyl enol ethers may react with aldehydes under asymmetric catalysis by chiral Lewis acids to provide aldol products in high enantiomeric ratio (Mukaiyama reaction).
eBook - PDF- Michael Bryant Smith(Author)
- 2013(Publication Date)
- CRC Press(Publisher)
75 4 Enolate Anion and Related Reactions An important general strategy for the preparation of amino acids involves generating a carbanion from an acid derivative and subsequent reaction with another suitably functionalized derivative. This reaction may be the conjugate addition discussed in Chapter 3, Section 3.2.2, but alkylation or acyl addition reactions may also be used. When appropriate functionality is present, these reactions constitute a useful route to non-α -amino acids. 4.1 ACID, ESTER, AND MALONATE ENOLATE ANION REACTIONS The reaction of an ester bearing an α -hydrogen atom with a nonnucleophilic base such as lithium diisopropylamide (LDA) generates the corresponding enolate anion. 1 Modern techniques allow generation of both mono- and dianions of carboxylic acids. Such enolate anions undergo C-alkylation and C-condensation reactions. An example of an ester enolate alkylation reaction first treated methyl 2-methyl-propanoate with lithium diisopropylamide to generate the enolate anion, and then with 4-bromobutanenitrile to give 1 . 2 Catalytic hydrogenation of the cyano group gave methyl 6-amino-2,2-dimethylhexanoate ( 2 ). In this case, the nitrile was the amine surrogate and the ester was the acid precursor. CO 2 Me N NH 2 CO 2 Me CO 2 Me Br 1. LDA, THF –78°C 2. –70°C 0°C H 2 , Ni (R) EtOH, 100°C 90 atm, 1 h 1 2 69% 37% C N C The enolate alkylation reaction that generated 1 used cyano as a nitrogen sur-rogate (see Chapter 1, Section 1.1.3). Other nitrogen surrogates may also be used in enolate alkylation reactions. An example is the reaction of the sodium enolate of diethyl 2-methyl malonate with phthalimide derivative 3 . This displacement reaction was followed by removal of the phthalimidoyl group, hydrolysis of the ester moieties, and decarboxylation to give 2-methyl-6-aminohexanoic acid ( 4 ). 3 Phthalimide 1 was prepared by reaction of 1,4-dibromobutane with potassium phthalimide. 3 The length 1 See Smith, M.B. Organic Synthesis , 3rd ed.
- Jean-Marc Campagne, Timothy J. Donohoe, Xuefeng Jiang, Ming Wang(Authors)
- 2024(Publication Date)
- Thieme Chemistry(Publisher)
261 20.5.1.2.9 Synthesis of Esters from Carboxylic Acids and Derivatives (Update 2024) R. M. de Figueiredo General Introduction The preparation of esters from carboxylic acids (and derivatives) was first described in Sci- ence of Synthesis in 2007 (Section 20.5.1.2) [1] and updated in 2011 (Section 20.5.1.2.8). [2] This is a second update that presents relevant methods either not covered in the previous chapters or developed since then. It will describe the synthesis of esters from carboxylic acids and alcohols, alkyl halides (and surrogates), alkenes, and allenes. Moreover, ester formation through C(sp 3 )-H functionalization and from carboxylic acid derivatives (e.g., N-acyloxazolidinones and amides) will also be reported. 20.5.1.2.9.1 Synthesis from Carboxylic Acids and Alcohols Several methods on this topic were previously discussed and can be found in Section 20.5.1.2 (2007) and Section 20.5.1.2.8 (2011). 20.5.1.2.9.1.1 Method 1: Synthesis through the Formation of Activated Esters The combination of carboxylic acids and alcohols is probably the most common and well- known way to reach esters. To allow the coupling reaction under mild conditions (room temperature and in the absence of strong acids), an additional step for the activation of the carboxylic acid group with an activating agent is required to improve the electrophi- licity of the carbonyl function toward the nucleophilic addition of the alcohol partner. A wide range of methods have been described so far, and they generally require an excess of the alcohol partner and a stoichiometric amount of the activating agent (Scheme 1). 1,1¢-Carbonyldiimidazole (1) was among the first activating agents used (Scheme 1). [3,4] A variant of the procedure is the application of imidazole carbamates such as meth- yl 1H-imidazole-1-carboxylate (7), which are more direct reagents for chemoselective es- terification of carboxylic acids.
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