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20 Three Carbon—Heteroatom Bonds: Acid Halides; Carboxylic Acids and Acid Salts; Esters, and Lactones; Peroxy Acids and R(CO)OX Compounds;R(CO)X, X = S, Se, Te

DOI: 10.1055/sos-SD-020-00001

Panek, J. S.Science of Synthesis, (2007201.

This volume covers the preparation of carboxylic acid derivatives, all of which have a carbon forming three formal bonds to heteroatoms, including acid halides, carboxylic acids, and carboxylic acid salts (Vol. 20a). Also covered are esters, lactones, peroxy acids, and R1(CO)OX compounds, as well as structural types of R1(CO)X (X=S, Se, Te) (Vol. 20b). ­Table 1 summarizes graphically the carboxylic acid derivatives covered in Volume 20.

Table 1 Classes of the Three CarbonHeteroatom Bond Containing Carboxylic Acid Derivatives Covered in Volume 20

Product Class Structural Formula(s) Section
acid halides R1C(O)X (X=halo) 20.1
carboxylic acids R1CO2H 20.2
alkanoic acids R1CO2H (R1=alkyl) 20.2.1
arenedicarboxylic acids Ar1(CO2H)2 20.2.2
butenedioic acids, acetylenedicarboxylic acid HO2CCR1=CR2CO2H, HO2CCCCO2H 20.2.3
alkanedioic acids HO2C(CR1R2)nCO2H 20.2.4
2-oxo- and 2-imino-substituted alkanoic acids R1C(=X)CO2H (X=O, N) 20.2.5
2,2-diheteroatom-substituted alkanoic acids R1CX(Y)CO2H 20.2.6
2-aminoalkanoic acids (α-amino acids) R1R2C(NH2)CO2H 20.2.7
2-heteroatom-substituted alkanoic acids R1CH(X)CO2H (X=halo, O, S, Se, Te) 20.2.8
alk-2-ynoic acids R1CCCO2H 20.2.9
arenecarboxylic acids Ar1CO2H 20.2.10
alk-2-enoic acids R1CH=CHCO2H 20.2.11
3-oxoalkanoic and 3,3-dioxyalkanoic acids R1C(O)CH2CO2H, R1C(OR2)2CH2CO2H 20.2.12
3-heteroatom-substituted alkanoic acids R1CHXCH2CO2H (X=halo, O, S, N, P) 20.2.13
carboxylic acid salts R1CO2M, R1CO2NR24, R1CO2PR24 20.3
carboxylic acid anhydrides (R1CO)2O 20.4
carboxylic acid esters R1CO2R2 20.5
alkyl alkanoates R1CO2R2 (R1=alkyl) 20.5.1
arenedicarboxylic acid esters Ar(CO2R1)2 20.5.2
butenedioic acid esters/butynedioic acid esters R1O2CCR2=CR3CO2R4, R1O2CCCCO2R2 20.5.3
alkanedioic acid esters R3O2C(CR1R2)nCO2R4 20.5.4
alkynyl alkanoates R1CO2CCR2 20.5.5
aryl alkanoates R1CO2Ar1 20.5.6
alkenyl alkanoates R1CO2CR2=CR3R4 20.5.7
2-oxo- and 2-imino-substituted alkanoic acid esters, and related compounds R1C(=X)CO2R2 20.5.8
2,2-diheteroatom-substituted alkanoic acid esters R1CX(Y)CO2R2 20.5.9
2-aminoalkanoic acid esters (α-amino acid esters) R1R2C(NH2)CO2R3 20.5.10
2-heteroatom-substituted alkanoic acid esters R1R2CXCO2R3 20.5.11
alk-2-ynoic acid esters R1CCCO2R2 20.5.12
arenecarboxylic acid esters Ar1CO2R1 20.5.13
alk-2-enoic acid esters R1CH=CHCO2R2 20.5.14
3-oxo- and 3,3-diheteroatom-substituted alkanoic acid esters R1C(O)CH2CO2R2, R1CX(Y)CH2CO2R2 20.5.15
3-heteroatom-substituted alkanoic acid esters R1CHXCH2CO2R2 (X=halo, O, S, N, P) 20.5.16
lactones 20.6
peroxy acids and derivatives R1CO2OR2 20.7
thiocarboxylic S-acids, selenocarboxylic Se-acids, ­tellurocarboxylic Te-acids, and derivatives R1C(O)X (X=S, Se, Te): R1C(O)XH, R1C(O)XM, R1C(O)XR2, R1C(O)XZ 20.8

The product subclasses dealing with alkanoic acids (Section 20.2.1) and alkyl alkanoates (Section 20.5.1) are further subdivided according to how the product is obtained from its precursor (Sections and, respectively). These sections cover general methods that are sometimes also applicable to subsequent special classes of carboxylic acids or esters covered in Volume 20.

Each section contains a brief introduction to the specific class and discussion of the most useful and reliable methods for the preparation of each functional group, including background, safety, representative examples, and general experimental procedures. Some sections are further divided into variations according to transformations from different reagents.

This introduction will outline the individual product classes together with highlighted synthetic methods.

Section 20.1 pertains to the preparation and chemistry of acid halides. Acid halides are used widely as acylating agents for nucleophilic species in organic synthesis. Among them, acid iodides are some of the best acylating agents because of the iodide's competency as a leaving group. Acid halides are also moderate to powerful electrophiles and participate in highly efficient additionelimination reactions through a tetrahedral transition state. These reactions proceed even with relatively weak nucleophiles. The most common method for the synthesis of acid halides is halogenation of carboxylic acids. Synthesis from acid chlorides is another frequently used method (Scheme 1).[‌1‌‌3‌]

Scheme 1 Synthesis of Acid Halides from Acid Chlorides[‌1‌‌3‌]

Carboxylic acids, characterized by the presence of a carboxy group (written as CO2H), are widespread in nature and are typically weak acids. Ester hydrolysis is one of the most fundamental approaches to carboxylic acid synthesis. Many of the chemical reactions used for their preparation are oxidations, as the carbon atom of the carboxy group has a high oxidation state. Other common synthetic procedures involve hydrolysis of nitriles and carboxylation of organometallic intermediates.

Arenedicarboxylic acids (Section 20.2.2) are versatile monomers and components for high-performance polymers and liquid-crystalline compounds. The easiest way to obtain arenedicarboxylic acids is by the hydrolysis of arenedicarboxylic acid esters. Other reactions, such as replacement of hydrogens and halo groups with carboxylic acid (Scheme 2),[‌4‌] as well as other functional-group transformations and metal-catalyzed carboxylation reactions, have also contributed largely to the synthesis of arenedicarboxylic acids.

Scheme 2 Palladium-Catalyzed Carbonylation of 2,5-Dibromobicyclo[4.2.0]octa-1,3,5-triene[‌4‌]

Section 20.2.3 covers butenedioic acids and acetylenedicarboxylic acid (butynedioic acid), which are frequently used in a variety of organic reactions, such as DielsAlder reactions, conjugate additions, and hydrogenations. The synthesis of these substrates includes oxidations of furfural, furan, or crotonaldehyde using vanadium(V) oxide, rearrangements from acetoacetic acid esters, aldol condensation (Scheme 3),[‌5‌] carboxylation of organometallic species, elimination protocols, and other oxidative methods.

Scheme 3 Synthesis of a Butenedioic Acid through Aldol Condensation[‌5‌]

Alkanedioic acids (Section 20.2.4) are most commonly synthesized by oxidative protocols, e.g. from lactones, nitroalkanes, cyclobutanones, halocyclobutenes, or dihalocyclobutanones (Scheme 4).[‌6‌] The protocol in Scheme 4 is stereospecific with regard to the substituents of the starting dichlorocyclobutanones (and the alkenes from which they are prepared by cycloaddition). Other synthetic methods to alkanedioic acids are oxidative couplings of carboxylate dianions, anhydride cleavage, and allylic alkylation.

Scheme 4 Alkanedioic Acids from Dichlorocyclobutanones[‌6‌]

Section 20.2.5 introduces α-heteroatom-substituted carboxylic acids of the type R1C(=X)CO2H. They are found in essential biochemical systems and therefore play a central role in major metabolic pathways, and also are important synthetic intermediates toward biologically active compounds. Hydrolysis of the corresponding esters is the most common method for the synthesis of this product subclass (Scheme 5). Hydrolysis of other compounds, such as nitriles, can also be used for the synthesis. Other valuable methods include oxidation, FriedelCrafts acylation, and aldol condensation of pyruvic acid with benzaldehydes.

Scheme 5 2-Oxo- and 2-(Oxyimino)alkanoic Acids by Hydrolysis of Esters

The chemistry of 2,2-diheteroatom-substituted alkanoic acids is covered in Section 20.2.6. The conditions for synthesis of these compounds are typically very harsh, often involving high acidity, high refluxing temperatures, or strongly oxidizing conditions. The synthesis can be achieved by the following methods: hydrolysis of 2,2-diheteroatom-substituted esters or amides, hydrolysis of thiazoles or α,α-dihalo acid halides, oxidation of α-hydroxycarboxylic acids, 2,2-diheteroatom-substituted aldehydes, or 2,2-dihaloalkan-1-ols, oxidative cleavage of an alkynol, addition to various substrates, [3,3]-sigmatropic rearrangement of allyl trihaloacetates (Scheme 6),[‌7‌,‌8‌] or nucleophilic substitution at the α-carbon of 2,2-diheteroatom-substituted acetic acids.

Scheme 6 2,2-Dihalopent-4-enoic Acids by Claisen-Type Rearrangements[‌7‌,‌8‌]

The synthesis of α-amino acids is covered in Section 20.2.7. They are among the most common motifs in nature and show a wide range of biological, chemical, and material properties. Numerous nonnatural α-amino acids have been synthesized as probes of protein structure, as catalysts, and as pharmaceutical and agricultural agents from the study of the 20 proteogenic amino acids. There are many methods for the preparation of α-amino acids, and the most reliable and experimentally well-described syntheses of 2-aminoalkanoic acids and 2-alkyl-2-aminoalkanoic acids are discussed in detail. The challenge for the diastereoselective synthesis of 2-alkyl-2-aminoalkanoic acids lies in the construction of a fully-substituted carbon center. One of the most extensively used methods for the preparation of 2-alkyl-2-aminoalkanoic acids is alkylation of a chiral α-amino acid enolate equivalent (Scheme 7).[‌9‌,‌10‌]

Scheme 7 Synthesis of 2-Alkyl-2-aminoalkanoic Acids by Alkylation of Oxazinones[‌9‌,‌10‌]

Section 20.2.8 discusses methods for the synthesis of 2-heteroatom-substituted alkanoic acids with an emphasis on methods for their enantioselective synthesis. This subclass of compounds is widely used in total synthesis and medicinal chemistry. Deaminative substitution of optically enriched amino acids is a frequently used method for the synthesis of chiral alkanoic acids (Scheme 8).[‌11‌,‌12‌] This reaction occurs with net retention of configuration.

Scheme 8 Synthesis of 2-Hydroxyalkanoic Acids from Amino Acids[‌11‌,‌12‌]

Alk-2-ynoic acids (Section 20.2.9) serve as important building blocks in various fields, including total synthesis of biologically active compounds and other complex molecules. In addition, they are valuable substrates for exploring a wide range of reactions, such as cycloadditions and reactions with nucleophiles, as their reactivity is enhanced by the electron-withdrawing carboxy group. The most widely reported synthesis of alk-2-ynoic acids involves the addition of metalated alk-1-ynes to solid or gaseous carbon dioxide (Scheme 9).

Scheme 9 Synthesis of Alk-2-ynoic Acids by Carboxylation of Alk-1-ynylmetal Reagents with Carbon Dioxide

Methods for the synthesis of aromatic carboxylic acids (Section 20.2.10) are generally similar to those of aliphatic acids (e.g., oxidation, hydrolysis). However, arenes are more susceptible to oxidation than alkenes. Unwanted reactions of the aromatic group may occur under strongly oxidizing conditions. One of the simplest methods for synthesis of aromatic carboxylic acids involves addition of a nucleophilic aryl organometallic species to carbon dioxide (Scheme 10).[‌13‌,‌14‌] The organometallic compounds most often used are lithium or magnesium aryl carbanions.

Scheme 10 Synthesis of Arenecarboxylic Acids by Carboxylation of Arylmetal Species[‌13‌,‌14‌]

The synthesis of alk-2-enoic acids is covered in Section 20.2.11. This product subclass is ubiquitous in many classes of natural products and the most common method for the synthesis of the unsaturated acid functionality is hydrolysis of a corresponding ester. Other important and powerful methods for the direct synthesis include carboxylation of alkenyl organometallics, elimination reactions, carbonyl alkenations (Scheme 11),[‌15‌,‌16‌] reduction of alk-1-ynoic acids, cycloaddition of alkynoic acids, palladium-catalyzed cross coupling to β-halogen-substituted alk-2-enoic acids, Heck reaction, and alkene metathesis.

Scheme 11 Synthesis of Alk-2-enoic Acids by Carbonyl Alkenations[‌15‌,‌16‌]

Section 20.2.12 discusses the chemistry of 3-oxoalkanoic and 3,3-dioxyalkanoic acids. They are valuable intermediates in total synthesis as well as convenient precursors of ketones and β-oxo esters. The two main synthetic methods employ the acidic or basic hydrolysis of β-oxo esters, which are described in Section 20.5.15. Other important methods are acylation of bis(trimethylsilyl) malonate, acylation of trimethylsilyl acetates (Scheme 12),[‌17‌] carboxylation of methyl ketones, electrocarboxylation of chloroacetone, electrocarboxylation of vinyl trifluoromethanesulfonates, hydration of alk-2-ynoic acids, and hydroxyacylation and oxidation of alkenes.

Scheme 12 Synthesis of 3-Oxoalkanoic Acids by Acylation of Trimethylsilyl Acetate[‌17‌]

The synthesis of β-heteroatom-substituted alkanoic acids is outlined in Section 20.2.13. Common synthetic methods are ring opening of cyclic precursors (Scheme 13),[‌18‌] addition to α,β-unsaturated compounds, or oxidations of a range of substrates, including haloalkanoic acids, hydroxy- and sulfanylalkanoic acids and derivatives, and amino- and phosphonoalkanoic acids and derivatives.

Scheme 13 β-Heteroatom-Substituted Alkanoic Acids by Ring Opening of Oxiranes[‌18‌]

Section 20.3 covers the chemistry of carboxylic acid salts. They are reactive intermediates and isolable species in organic synthesis and medicinal chemistry. They often have better stability, crystallinity, and water solubility than the corresponding carboxylic acids. These properties make them valuable to the synthetic purification and administration of orally bioavailable medicines (e.g., penicillin antibiotics, Scheme 14).

Scheme 14 Penicillin Antibiotics as Carboxylic Acid Salts

Carboxylic acid salts are commonly prepared by the reaction of an appropriate base with the corresponding carboxylic acids (Scheme 15).

Scheme 15 Preparation of Common Carboxylic Acid Salts

Synthetic methods toward carboxylic acid anhydrides (Section 20.4) are generally through the activation of the carboxylic acids followed by attack of a second carboxylate unit to produce the anhydrides. The most common method for the synthesis of anhydrides is the removal of one molecule of water (dehydration) from the carboxylic acids (Scheme 16).[‌19‌]

Scheme 16 Anhydride Synthesis from Carboxylic Acids[‌19‌]

Carboxylic acid esters are covered in Section 20.5. They are one of the most important classes of organic compounds. The most general preparation of esters is performed by the reaction of a carboxylic acid and an alcohol, conventionally under acid catalysis (Scheme 17). Other important methods for the synthesis of alkyl alkanoates, including alcoholysis, oxidation of acetals, ozonolysis of alkenes, BaeyerVilliger oxidation of ketones, Favorskii rearrangement, Wolff rearrangement, and so on, are depicted with specific examples in Section 20.5.1

Scheme 17 Brønsted Acid Catalyzed Esterification

The synthesis of arenedicarboxylic acid esters is covered in Section 20.5.2. There are two common methods for the easy access to this class of compounds: direct esterification of arenedicarboxylic acid esters using various reagents and the DielsAlder reaction of precursor dicarboxylic acid esters and dienes followed by aromatization (Scheme 18).[‌20‌]

Scheme 18 Synthesis of Arenedicarboxylic Acid Esters by DielsAlder Reaction[‌20‌]

The synthesis of butenedioic and acetylenedicarboxylic (butynedioic) acid esters is covered in detail in Section 20.5.3. There are many different methods leading to this subclass, generally including the following types: anhydride cleavage, organometallic-catalyzed carbenoid dimerization, phosphorus-based alkenations, 1,4-additions of alcohols, elimination protocols, semihydrogenation of the corresponding acetylenedicarboxylate, and other methods. One of the classical approaches is the elimination of an activated leaving group from a succinic acid ester derivative (Scheme 19).[‌21‌]

Scheme 19 Synthesis of a Butenedioic Acid Ester by Elimination[‌21‌]

Section 20.5.4 covers the synthesis of alkanedioic acid esters. The simplest and most common approaches to succinate esters are esterification of succinic acid and reduction of butenedioates. Asymmetric alkylations using N-acyloxazolidinones (Evans' asymmetric alkylation) is perhaps the most general and widely used method for the synthesis of enantiomerically pure α-alkylsuccinates (Scheme 20).[‌22‌]

Scheme 20 Synthesis of α-Alkylsuccinates by Asymmetric Alkylation[‌22‌]

For asymmetric synthesis of amino- or hydroxy-substituted succinates, a common strategy is aldol condensation of ester enolate derivatives to α-imino or α-oxo esters using either a chiral auxiliary or chiral Lewis acids (Scheme 21).[‌23‌] Other methods and examples presented in this section include alkene dimerization, rearrangements, carbonylation of alkenes catalyzed by transition metals, conjugate addition, Stobbe condensations, and stereoselective sigmatropic rearrangements.

Scheme 21 Synthesis by Aldol Condensation[‌23‌]

The synthesis of alkynyl alkanoates is described in Section 20.5.5. There are three general pathways to alkynyl esters; these are shown in Scheme 22. The most straightforward pathway is esterification of a carboxylic acid derivative with an ynolate. Another widely used method is the SN2 reaction of a carboxylate anion nucleophile with a suitable alkynyl electrophile, such as an alkynyliodonium salt. Lastly, iodobenzene dicarboxylates react with acetylide anions to afford alkynyl alkanoates.

Scheme 22 Common Strategies for the Synthesis of Alkynyl Alkanoates

Aryl alkanoates (Section 20.5.6) are both important core strutures of many biologically active natural products and important intermediates in organic synthesis. The most straightforward route is O-acylation of phenols (Scheme 23, route a). Acyl halides are the most commonly used acylating agents. A more widely used strategy is the activation and direct oxidation of arene CH bonds (Scheme 23, route b), since arenes are more widely available than the corresponding phenols. Displacement of diazonium groups by nucleophiles (the Sandmeyer reaction) is another useful method for the synthesis of aryl alkanoates.

Scheme 23 Synthesis of Aryl Alkanoates by Activation and Oxidation of Arenes

Alkenyl alkanoates (Section 20.5.7) can be regarded as masked enols (Scheme 24), which makes them very useful in a number of synthesis activities. For example, alkenyl alkanoates participate in many reactions including alkene addition reactions (Scheme 24), cycloadditions, aldol reactions, and acylation reactions.

Scheme 24 Alkenyl Alkanoates as Masked Enol Equivalents

Methods for the synthesis of alkenyl alkanoates include enolate O-acylation, O-acylation of alkynolate-derived enolates, catalyzed alkyne alkoxycarbonylation, alkenylmercury and alkenyl halide coupling with metal acetate salts, Fischer carbene coupling with acid chlorides, elimination, and Wittig-type alkenation reactions.

2-Oxo- and 2-imino-substituted alkanoic acid esters, and related esters with a C=X bond at the α-carbon (Section 20.5.8), are important intermediates in biological pathways. They find use in the syntheses of numerous natural products, β-amino-α-oxo acids, fluorinated amino acids, and a range of heterocycles. One of the most widely applied procedures for the synthesis of this subclass is oxidation of various precursors including α-hydroxy esters and α-diazo esters, as well as 3-oxo-2-(triphenylphosphoranylidene)propanoates (Scheme 25). Other methods involve esterification, hydrolysis, alcoholysis, and rearrangements, and these are also presented in this section.

Scheme 25 Synthesis of 2-Oxoalkanoic Acid Esters by Oxidation

2,2-Diheteroatom-substituted alkanoic acid esters (Section 20.5.9) are versatile intermediates in natural product synthesis. A classical method to prepare this product subclass is esterification of the corresponding acids, because this method is generally reliable and high yielding, requires only simple reaction techniques, and has a variety of available reaction conditions. Acetal formation is a long-developed method, as it is commonly used as a protective protocol for ketones. Other synthetic methods include alcoholysis, oxidative cleavage of an alkene, nucleophilic attack at an α-carbon, radical reactions, and rearrangements.

Section 20.5.10 covers the chemistry and synthesis of α-amino acid esters. They have similar functions and applications to the corresponding α-amino acids, and they can also be divided into three types according their structures: α,β-didehydroamino acid esters, 2-aminoalkanoic acid esters and 2-alkyl-2-aminoalkanoic acid esters. Many of the methods described for the synthesis of α-amino acids in Section 20.2.7 are also applicable to α-amino acid esters; as such this section is written as a complement to the carboxylic acid section described earlier. One of the examples using Schmidt rearrangement of β-oxo esters is depicted in Scheme 26.[‌24‌]

Scheme 26 Synthesis of α-Amido Esters by Schmidt Rearrangement[‌24‌]

2-Heteroatom-substituted alkanoates find their principal use in organic synthesis and medicinal chemistry. The preparation of this subclass of compounds is discussed in Section 20.5.11, with an emphasis on their enantioselective synthesis. The heteroatoms covered in this section are halogen, oxygen (hydroxy, alkoxy, and epoxide), sulfur, selenium, and tellurium. General methods for enantioselective synthesis are asymmetric catalysis, use of a transient chiral auxiliary, and kinetic resolution. One such example is shown below in Scheme 27.[‌25‌] In addition, methods that are applied in industry are highlighted in this section.

Scheme 27 Catalytic Asymmetric Hetero-DielsAlder Reactions of 2-Oxoalkanoates[‌25‌]

Alk-2-ynoic acid esters (Section 20.5.12), like alk-2-ynoic acids, are valuable candidates to explore a large number of reactions, due to their improved reactivity as a result of the electron-withdrawing group. They are also the most common precursors for the preparation of alk-2-enoic acid esters by partial reduction or nucleophilic addition to the triple bond. Typically, the most straightforward method is esterification of alk-2-ynoic acids, usually in the presence of catalysts. One of the best and most widely used methods is carboxylation of terminal alkynes (Scheme 28), since they are generally either commercially available or can be easily accessed through well-established procedures.

Scheme 28 Synthesis by Carboxylation of Terminal Alkynes

Section 20.5.13 is focused on the synthesis of arenecarboxylic acid esters. The general methods can be divided into two major reaction types: the arenecarbon bond formation and the construction of the aromatic ring. The aromatic-ring construction can be achieved by anionic methods, by radical cyclizations of β-oxo esters, by cycloadditions, by electrocyclization and elimination, through oxidative rearrangement of hydrazone derivatives, or lithiation and alkylation of benzoate esters. The most straightforward strategy is utilizing a FriedelCrafts acylation approach (Scheme 29).[‌26‌] Other methods for the synthesis of arenecarboxylic acid esters through arenecarbon bond formation include oxidation of benzylic ethers, radical benzyloxylation, metalation, or carbonylation of various substrates.

Scheme 29 FriedelCrafts Approach to an Arenecarboxylic Acid Ester[‌26‌]

Alk-2-enoic acid esters (Section 20.5.14) can often be found in natural products and medicinal agents. They are also important synthetic intermediates in organic synthesis. The α,β-unsaturated ester functionality can undergo reactions such as conjugate additions and cycloadditions, in which the ester group can be further modified building in additional complexity. There are four major methods for the synthesis of this class of compounds: alkoxycarbonylation of alkenyl organometallics, elimination reactions, aldol-type condensation, and, lastly, Wittig reaction (and related alkenylations), which is one of the most reliable methods for the introduction of the α,β-unsaturated ester functionality (Scheme 30).[‌27‌,‌28‌]

Scheme 30 Alk-2-enoic Acid Esters from Wittig and Peterson Reactions[‌27‌,‌28‌]

3-Oxoalkanoic acid esters (Section 20.5.15), also referred to as β-oxo esters or β-keto esters, are valuable intermediates in a large pool of molecular synthesis. Literature reports regarding the synthesis of this subclass are numerous. Among them, the most direct method is oxidation of 3-hydroxyalkanoic acid esters. In addition, acylation of 3-oxoalkanoic acid esters is a very efficient and amenable strategy for large-scale syntheses (Scheme 31).[‌29‌]

Scheme 31 Acylation of Methyl Acetoacetate with Acid Chlorides[‌29‌]

Section 20.5.16 outlines the synthesis of β-heteroatom-substituted alkanoic acid esters. Most of the general synthetic methods for the synthesis of β-heteroatom-substituted alkanoic acids are also applicable to the corresponding esters. For instance, addition to α,β-unsaturated esters, cycloaddition reactions, and ring opening of cyclic precursors are typical examples.

Lactones (Section 20.6) are frequently found in chemistry and nature, and many of them are important synthetic intermediates and building blocks because of their bifunctionality. In addition, chiral lactones are potential templates for the diastereoselective construction of additional stereocenters. General strategies for the synthesis of lactones are shown in Scheme 32. The most obvious synthetic pathway for the synthesis of lactones is to construct the two CO bonds directly (routes a and b). The lactone ring can also be obtained from an ester precursor by a CC bond formation reaction (route c), such as intramolecular WittigHorner reaction, alkylation, cross coupling, cycloaddition, or ring-closing metathesis. In addition, lactones may be prepared from other cyclic compounds such as ketones or cyclic anhydrides (route d).

Scheme 32 General Strategies for the Synthesis of Lactones

Organic peroxides (Section 20.7) are widely used in research laboratories because of their exceptional reactivity and utility as oxidizing agents. Because of the weak peroxide bond, peroxides are exceptionally prone to violent decomposition, which can be initiated by heat, mechanical shock, or friction, especially in the presence of certain catalysts and promoters. As a class, they are among the most hazardous substances handled in the laboratories. The synthesis of peroxy acids and derivatives frequently begins with hydrogen peroxide (Scheme 33).[‌30‌] They are also widely used as a source of free radicals to initiate a number of addition and polymerization reactions. The chemistry and synthesis of O-acylhydroxylamine and related sulfur, selenium, and tellurium compounds, acyl hypohalites, and peroxy acid esters are also discussed in this section.

Scheme 33 Preparation of Phthaloyl Peroxide[‌30‌]

Section 20.8 reviews the synthesis of thiocarboxylic S-acids and their derivatives. There are a large number of methods leading to thiocarboxylic S-acids and related compounds. One example for the direct synthesis of thioesters from carboxylic acids and thiols is described in Scheme 34.[‌31‌] Selenocarboxylic Se-acids, tellurocarboxylic Te-acids, and related compounds are also discussed briefly at the end of the section. The chemistry and synthesis of each product subclass is discussed separately.

Scheme 34 Synthesis of Thiocarboxylic S-Acid Esters from Carboxylic Acids and Thiols[‌31‌]