Various condensation reagents and conditions used for the synthesis of carboxylic acid esters under the nearly equimolar carboxylic acids and alcohols (recent and selected examples).
In this chapter, recent advances in the synthesis of carboxylic acid esters are summarized based on the utilization of carboxylic acids as electrophiles or nucleophiles in reactions. Condensation reagents or catalysts connect the carboxylic acids with the alcohols to afford the corresponding esters, together with the formation of 1 equiv. of H2O, in which the carboxylic acids can be regarded as the electrophile. In contrast, the carboxylate ion intermediates derived from the carboxylic acids react with alkyl halides, carbocations, or their equivalents to produce the esters, in which the carboxylate ions from the carboxylic acids can be regarded as the nucleophile. This chapter mainly introduces the recent progress in this field of the formation of esters, based on the classification of the role of carboxylic acids in reactions.
- carboxylic acids
- condensation reagents
- reaction media
- reaction methods
- SN2 reactions
- transition metal catalysts
- addition reactions
In organic chemistry, the development of the efficient synthesis of carboxylic acid esters using carboxylic acids is still one of central research topics, because the organic material compounds, drug molecules, and natural products often contain ester unit as the functional group [1, 2, 3]. As for the view point of the synthesis of esters, the corresponding carboxylic acids are usually utilized as the key starting material and play an important role [1, 2, 3].
So far, many kinds of synthetic methods for the esters from carboxylic acids are well recognized and utilized, but a lot of researchers still have studied to investigate the new methods or aspects, because the synthesis of esters is also important from the point of view of green chemistry and industry. In this chapter, recent advances in the synthesis of carboxylic acid esters are described. The reactions are classified into two categories, i.e., the reactions utilizing carboxylic acids as (1) electrophiles and (2) nucleophiles, in which the reactions are conducted by using various chemical reagents and catalysts as well as by using interesting reaction media and methods. Although many papers have appeared in this filed, we herein have introduced important and selected examples because of the limitation of number of pages.
2. Synthesis of carboxylic acid esters using carboxylic acids as electrophiles
The typical and traditional method for the synthesis of carboxylic acid esters is the reaction of carboxylic acids with an excess amount of alcohols in the presence of a catalytic amount of H2SO4 by using Dean-Stark apparatus [1, 2, 3], in which H2SO4 catalyzes the addition of the alcohol to the carboxylic acid, and the H2O thus generated is removed by Dean-Stark apparatus (Scheme 1 (a)). This reaction is called as Fischer esterification. However, there are some drawbacks. The excess amount of alcohols is used. The Dean-Stark apparatus is usually necessary. In addition, the substrates bearing the functional group which reacts with the acid cannot be utilized in this reaction. The alternative and reliable method to be developed is the use of DCC in the presence of a catalytic amount of DMAP (Scheme 1 (b)) . DCC can serve as useful condensation reagents. The use of DCC as the condensation reagent realizes the decrease of the amount of alcohols. In addition, Mitsunobu reaction is also reliable method [5, 6, 7, 8].
Besides the use of DCC, other condensation reagents are also developed. 2-Halo-pyridinium salts called Mukaiyama condensation reagent serve as effective reagents . Mukaiyama et al. have extensively contributed this research area for the development of useful condensation reagents . In addition, BOP ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate)) [11, 12], CDI (carbonyldiimidazole) [13, 14], DMT-MM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride) [15, 16, 17], and so on [18, 19] are well established and used in the ester formation reactions.
As described above, many condensation reagents have been developed so far. However, there are still reports for this filed. Table 1 shows recent and selected reports of condensation reactions between carboxylic acids and alcohols using a stoichiometric amount of condensation reagents. Basically, the amount of alcohols is not excess (Table 1). For examples, polymer-bounded Ph3P (or Ph3P)/I2/microwave [20, 21, 22, 23] and Ph3P/I2/Zn(OTf)2 condition  have been reported, because the combination of PPh3 and I2 in the presence of the base has been well known so far [25, 26]. In addition, the use of Ph2PCl/I2/imidazole , Ph3PBr2 , POCl3/DMAP/Et3N , or PPh3/BnN3/microwave (Staudinger’s phosphazene)  systems was found to be effective for the esterification. The hypervalent iodine reagents could be utilized in coupling reactions [31, 32]. The combination of PPh3 and trichloroisocyanuric acid was also effective . These reactions are based on the activation of PPh3. The catalytic activation of PPh3 can be achieved by iron . Photo-irradiated procedure in the presence of PPh3 with a catalytic amount of flavin and azo compound under O2 was developed . XtalFluor-E and tropylium-based coupling reagents were found to be effective for the esterification [36, 37].
In the view point of green chemistry, the use of a catalytic amount of reagents is one of the attractive approaches, in which the ratio between carboxylic acids and alcohols is approximately equal. In 2000, Yamamoto et al. reported that 0.1 to 1.0 mol% hafnium (IV) salts in toluene at reflux condition catalyzed the condensation reaction of equimolar amount of carboxylic acids and alcohols (Table 2, entry 1) [38, 39, 40, 41, 42, 43, 44, 45, 46, 47]. Since then, various types of catalysts have been found for the effective esterification reactions. Selected examples are summarized in Table 2. Diphenylammonium triflate (entry 2) , fluoroalkyldistannoxane (entry 3) , HClO4-SiO2 (entry 4) [50, 51, 52], Ti4+-mont (mont = montmorillonite, entry 5) , bulky diarylammonium arenesulfonates (entry 6) [54, 55, 56, 57, 58], Zn(ClO4)2-6H2O (entry 7) , pentafluorophenylammonium triflate (entry 8) , TsOH or CSA (entry 9) , phosohorofluoridic acid (entry 10) ,
Another approach for the esterification of carboxylic acids with alcohols (2 equiv.) was developed by Kobayashi and coworkers [69, 70, 71], in which
The use of resin was also reported by Uozumi et al., who designed and synthesized the porous phenolsulfonic acid formaldehyde resin (PAFR) from 4-hydroxybenzenesulfonic acid and formaldehyde (5 equiv.) in H2O (Scheme 3). The solid resin was allowed to react with RCOOH and R’OH to give the corresponding esters in good yields [72, 73]. The merit of the resin is that it can be recovered by the simple filtration and reused without the significant loss of the catalytic activity. Other type of solid catalysts bearing SO3H unit are also reported. For examples, polystyrene-supported sulfonic acid catalyst , SBA-15-functionalized propylsulfonic acid catalyst ,
As for the promising reaction tool for the esterification, the use of the flow chemistry has emerged. For example, Uozumi et al. applied the PAFR to the flow method [72, 73]. Fukuyama et al. demonstrated Fisher esterification by the flow system, in which silica bearing terminal -SO3H group was used [79, 80].
3. Synthesis of carboxylic acid esters using carboxylic acids as nucleophiles
3.1. Nucleophilic reactions of carboxylate ion intermediates
3.1.1. The use of bases and ionic liquids
Because the acidity of carboxylic acids is relatively high, it is easy to generate and accumulate the carboxylate ion intermediates by the deprotonation of carboxylic acids. SN2 reaction of carboxylate ions with alkyl halides is one of the most popular approaches, when carboxylate ions can be used as the nucleophiles. It was found that CsF or KF is the effective base toward carboxylic acids by Clark and Miller . Since then, various reactions have been reported in these fields. Recent examples of this chemistry utilize the combination of bases (such as Huning’s base, Et3N and KF) and various ionic liquids (such as imidazolium salts and phosphonium salts), summarized in Figure 1 [82, 83, 84, 85, 86, 87, 88, 89, 90]. The countercations of carboxylate ions are bulky cations such as imidazolium salts and phosphonium salts, which seem to increase the reactivity of the carboxylate ions toward electrophiles.
It has been well known so far that F− source such as KF and CsF can serve as good base toward carboxylic acids, described above . Because of this reason, Bu4NF is also the attractive reagent for the deprotonation of carboxylic acid. In 2001, Maruoka et al. reported in situ generation of Bu4NF from the combination of a catalytic amount of Bu4NHSO4 (5 mol%) and KF-H2O (5 equiv.), which takes the proton of carboxylic acids to generate reactive carboxylate ion intermediates, whose countercation is presumably bulky Bu4N+ (Scheme 4(a)) . In addition, Matsumoto et al. also reported the reactions of carboxylic acids with a stoichiometric amount of Bu4NF cleanly generated and accumulated reactive carboxylate ion intermediates, which reacted with various alkyl halides to give the corresponding esters in moderate to good yields (Scheme 4 (b)) .
The use of good affinity of F− and metals such as Si and Sn was also developed in order to generate and accumulate highly reactive carboxylate ion intermediates. For example, the reaction of silyl-protected carboxylic acids with Ph3CF in the presence of a small amount of SiF4 produced the corresponding esters, in which SiF4 might activate both silyl-protected carboxylic acids (substrates) and Ph3C-F to generate carboxylate ions and Ph3C+, respectively (Scheme 5(a), Noyori et al.) . The combination of silyl-protected carboxylic acids and Bu4NF was also reported by Maruoka et al. (Scheme 5 (b)) . Nozaki et al. reported the use of Sn in 1992. The intermediate bearing COO-Sn bond reacted with alkyl halides in the presence of CsF, as shown in Scheme 5 (c) .
3.1.2. The use of electrochemical reduction methods
Electrochemistry is a clean technique, and basically the electron serves as the reagent instead of chemical reagents [96, 97, 98, 99]. Therefore, electrochemistry in organic synthesis does not generate the waste derived from reagents, and is recognized as one of the powerful tools for green chemistry. The pioneering work for the esterification of carboxylic acids and alkyl halides using electrochemistry was developed by Nonaka et al. (Scheme 6) [100, 101]. The solution containing carboxylic acids underwent electrochemical reduction to generate highly reactive carboxylate ions, which reacted with alkyl halides to produce the corresponding esters. Matsumoto et al. investigated the detailed reaction condition, the scope and limitations, and the mechanism of the electroreductive esterification reaction (Scheme 6) .
The use of electro-generated base (EGB)  is also effective to generate reactive carboxylate ion intermediates, developed by Shono et al. (Scheme 7) . 2-Pyrrolidone was electrochemically reduced and 2-pyrrolidone anion was generated and accumulated as the base in the solution phase, which reacted with carboxylic acids to generate carboxylate ions bearing the quaternary ammonium cation. The reaction was applicable to the formation of macrolides.
3.1.3. The use of electrophile equivalents
Some substrates were found to be effective as the electrophile equivalents, when carboxylic acids served as the nucleophile (Figure 2). For example, One of the interesting examples is the use of 2-benzyloxy-1-methylpyridinium triflate reported by Dudley (Figure 2(a)) . The benzyl cation was gradually generated, which was allowed to react with carboxylic acids. The in situ version was also established by Albiniak et al. . Cu-mediated coupling reactions using aryl trialkoxysilanes  or arylboronic acids  were developed by Cheng et al. (Figure 2(b)). Diaryliodonium salts were found to be good electrophiles for the esterification (Figure 2(c)) . Meier et al. reported the use of diphenyl carbonate as the electrophile to produce phenyl esters (Figure 2(d)) [109, 110]. Kunishima et al. found that 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT) serves as the benzyl cation equivalent via SN2 mechanism in the presence of a catalytic amount of TfOH at room temperature (Figure 2(e)) . The reaction at high temperature also proceeded without TfOH. Thus,
Recently, dimethyl sulfoxide (DMSO) was utilized for the source of CH3- unit in the reaction with carboxylic acids to give the methyl esters shown in Scheme 8. The generation of methyl radical was indicated .
In situ generation of benzyl bromide from toluene derivatives by using NaBrO3/NaHSO3, followed by the nucleophilic reactions of the carboxylic acids could be achieved by Khan et al. (Scheme 9) . Although aliphatic carboxylic acids were not suitable, the aromatic carboxylic acids can be converted to the corresponding esters.
3.2. The use of the functionalization of C-–H bonds
Recently, the esterification of carboxylic acids and suitable substrates via the functionalization of C-H bond has been extensively studied. For example, Zhang et al. found that the reaction of carboxylic acids and toluene in the presence Pd(OAc)2 (10 mol%), CF3SO3H (10 mol%) and
3.3. The use of metal catalysts
The addition of carboxylic acids onto C-C multiple bonds proceeds with high atom efficiency to afford the corresponding enol or alkyl esters. Hg salts have been used as the catalysts for these reactions for a long time; however, the use of these toxic salts should be avoided from the view point of green chemistry. Ruthenium complexes have been paid much attention for the alternative catalyst for the addition of carboxylic acids onto C-C multiple bonds. These ruthenium-catalyzed addition reactions of carboxylic acids to alkynes and several catalytic formation of alkyl esters by the addition of carboxylic acids to alkenes are summarized in this section.
3.3.1. The addition of carboxylic acids onto alkynes
The addition reaction of carboxylic acids onto alkynes with ruthenium catalysts through the Markovnikov’s rule was well investigated by Mitsudo and Dixneuf, independently [126, 127, 128]. In 1987, Mitsudo and coworkers reported that the reaction of carboxylic acids including
On the other hand, Dixneuf and coworkers developed the simpler catalytic system for the Markovnikov addition. Thus, (
The reaction mechanisms for both regioselective additions were proposed by Dixneuf et al. (Scheme 14), and the formation of vinylidene complex is crucial for the
Two simple catalytic systems, in which the regioselectivity is easily controlled by the use of the same or similar catalyst, have been reported [133, 134]. Goossen et al. found that the reaction of carboxylic acids and alkenes with RuCl2(
The stereoselective formation of
Two examples for the regio- and
3.3.2. The addition of carboxylic acids onto alkenes
In 2004, Oe et al. reported the first transition metal-catalyzed addition of carboxylic acids onto alkenes. Thus, the reaction of benzoic acids with norbornene was carried out in the presence of [Cp*RuCl2]2/AgOTf/Dppb catalyst in toluene at 85 °C to obtain the corresponding norbornyl benzoates in good to high yields (Scheme 20) . After that, several metal catalysts for the addition of carboxylic acids to alkenes have been reported and are summarized in Table 3.
Norbornene is a generally good substrate due to the strain of the C–C double bond, therefore the reported catalyst afforded the corresponding esters in high yields (Table 3) [142, 143, 144, 145]. In 2005, He et al. reported the Au catalyst, where the four alkenes including unstrained 1-octene were transformed into the corresponding esters in 75–95% yields (entry 1) . Hii et al. showed the catalytic activity of Cu(OTf)2, though only norbornene was used as an alkene substrate (entry 2) . In these cases, the addition of phenols onto alkenes was also catalyzed under the similar reaction conditions. With only norbornene, In(OTf)3 was also found as a good catalyst under the solvent-free reaction condition (entry 3) . An ubiquitous iron catalysis has been reported by Sakakura et al., where the unstable ester such as acrylates can be synthesized under the solvent-free reaction conditions (entry 4) . Modified ruthenium(II) catalysis including xantphos ligand improved the scope of substrates of alkenes compared to that with ruthenium(III) catalyst to afford the corresponding esters in up to 99% yield by Oe et al. (entry 5) .
Hartwig and He found that TfOH itself showed the catalytic activity for the present addition reactions (Scheme 21) [147, 148]. Interestingly, the relatively large amount of catalyst and/or higher reaction temperature decreased the chemical yield of the product. It might be due to the polymerization of substrates of alkenes. Accompanied with the importance of triflate in the metal-catalyzed reaction described above, these metal catalysts might act as a TfOH source.
Recently, an organocatalytic addition under the LED light irradiation conditions have been reported by Nicewicz et al. (Scheme 22) . The reaction of carboxylic acids and internal and/or cyclic alkenes proceeds nicely under mild conditions to afford the corresponding esters in up to 99% yield regio-selectively.
In this chapter, the recent progress of the esterification reactions using carboxylic acids as the starting material was overviewed, together with some basic and pioneering works. Various reagents, catalysts, synthetic media, and methods have been developed so far, and the quality of this field seems to be obviously increased. Because the topic of the efficient synthesis of esters is still an important task, it is expected that more innovative approach is discovered in near future.