Boric acid in organic synthesis: scope and recent developments

In recent years boric acid [H 3 BO 3 ] has played an important role in organic synthesis. The present review summarizes the latest developments in boric acid catalyzed transformations especially esterification, transesterification, aza-Michael and thia-Michael addition, condensation, Friedel-Crafts reactions, Tishenko reactions, halogenations, ipso substitution, decarboxylation, protection and deprotection reactions, amidation and transamidation reactions, multicomponent reactions including synthesis of nitrogen and oxygen heterocycles. Boric acid has emerged as an efficient, mild, commercially available, inexpensive catalyst in the formation of various biologically important organic compounds reported during the last decade


Introduction
Over the past decade the chemistry of boric acid has undergone a rapid development.This growing interest is mainly due to its mild and highly selective properties, combined with its environmentally benign character and commercial availability.Boric acid is now routinely used in organic synthesis as effective acid catalysts for various selective transformations of simple and complex molecules.The purpose of the present review is to summarize the utility of boric acid with emphasis on recent synthetic applications.Literature coverage is through to the end of 2017.

General Informations and Structural Features of Boric Acid
Boric acid is a weak inorganic acid, and is also called boracic acid or orthoboric acid.It is a white crystalline solid having the following physical properties: Chemical formula : H 3 BO 3 or B(OH) 3  Molar mass: 61.83 g/mol Density 1.435 g/cm 3 Melting point: 170.9 o C (339.6 o F; 444.0 K) Boiling point : 300 o C (572 o F; 573 K) pK a : 9.24, 12.4, 13.3 Solubility : Soluble in water and in lower alcohols; moderately soluble in pyridine; very slightly soluble in acetone Figure 1A shows that the central boron atom is connected to three hydroxy (-OH) groups, which are capable of strong hydrogen bonding.Its solid crystalline structure consists of parallel layers of boric acid held together by hydrogen bonds (Figure 1B).It serves as a source of weak monobasic acid.It has been used in various acid catalyzed reactions.It is easy to handle, and safe to use, as a low concentration of boric acid does not pose any toxicity.It is also used as an antiseptic agent, in acne treatment, as preservative, insecticide, pH buffer, as swimming pool chemical and a precursor to many useful chemicals.

Esterification Reactions
Esterification is one of the oldest, most widely used and most important chemical transformations in organic synthesis, with wide applications in chemical industries, pharmaceuticals, foods, perfumes and cosmetics.These reactions are applied to natural products synthesis, in protection or kinetics resolution of carboxylic acids and in intramolecular reactions to prepare lactones.Esterification of carboxylic acids, hydroxy acids, sugar acids has been studied using boric acid.

Esterification of carboxylic acids
Aliphatic and aromatic carboxylic acids undergo direct esterification reactions with phenols catalyzed by a combination of boric acid and sulfuric acid.Neither boric acid nor sulfuric acid alone catalyzes the reaction.Thus, phenyl benzoate (3) was produced in nearly quantitative yield when water is removed by azeotropic distillation from refluxing toluene containing phenol, benzoic acid, and a catalytic amount of boric acid and sulfuric acid (Scheme 1).Scheme 1. Boric acid catalyzed esterification of carboxylic acid.

Esterification of α-hydroxy acids
Chemoselective esterification of α-hydroxy acids with boric acid was reported by Houston and co-workers. 2 When malic acid (4) (a dicarboxylic acid which contains a hydroxyl group that is in the α-position relative to one carboxylic acid and in the β-position relative to another) and methanol were allowed to react with boric acid overnight at room temperature, a high yield of monoester 5 was obtained (Scheme 2).The -CO 2 H group with respect to β-hydroxy group remained unchanged.The effect of α-OH group relative to carboxylate was discussed.A five-membered cyclic neutral ester 6 and an anionic species 7 (Figure 2) may be formed during the reaction, accelerating the esterification reactions.Scheme 2. Boric acid catalyzed methyl ester synthesis of α-hydroxy acid.
Figure 2. Compounds 6 and 7, possible intermediates in the esterification of an α-hydroxy acid.

Esterification of sugar acids
Esterification of sugar acids with methanol has been accomplished in the presence of boric acid.Thus when sialic acid (8) (a sugar acid) was treated with anhydrous methanol in presence of catalytic amount of boric acid under nitrogen atmosphere at 50 ⁰C, methyl ester 9 was formed in 90% yield (Scheme 3). 3 This reactions proceeded with high efficiency in certain sugar acid molecules but is highly substrate dependent.Glucuronic acid containing a β-hydroxycarboxylate motif, and the bacterial monosaccharide, 3-deoxy-D-manno-oct-2ulosonic acid (KDO) containing an α-hydroxycarboxylate motif failed to esterify under boric acid catalysis in methanol.

Polyesterification of monohydroxyethyl ester of dicarboxylic acids
Alemdar et al. 4 found that boric acid-pyridine mixture works as an mild catalyst for polyesterification of the monohydroxyethyl esters of succinic acid 10, maleic acid 11 and phthalic acid 12.The catalyst system was demonstrated to give colorless polyesters 13, 14, 15 of low molecular weights (M: 1650-1950) within 4 h at 130 o C (Scheme 4).

Transesterification Reactions
Transesterification of esters with alcohols have been reported using boric acid.Kondaiah and co-workers reported that boric acid acts as an environmentally benign catalyst for transesterification of ethyl acetoacetate (16) with a variety of alcohols including allylic alcohols, propargyl alcohols and sterically hindered primary and secondary alcohols in good to excellent yields.In a specific example, the transesterified β-ketoester 17 can be prepared from ethyl acetoacetate (16) and cyclohexanol using boric acid in refluxing xylene.(Scheme 5).

Aza-Michael Addition Reactions
Aza-Michael addition of aromatic amines to divinyl sulfone (18) and electron-deficient alkenes (20) has been accomplished in the presence of boric acid/glycerol in water under reflux to obtain the corresponding addition products in good to excellent yields without polymerization.The method can thus be used to produce Nsubstituted thiomorpholine- Scheme 7. Boric acid catalyzed aza-Michael addition of amine to α,β-unsaturated ester.

Thia-Michael Addition Reactions
Aliphatic and aromatic thiols undergo thia-Michael addition reactions to α,β-unsaturated nitriles, esters, ketones and aldehydes in presence of boric acid with very good yields in water at room temperature.

Condensation Reactions
Cross-aldol condensation of aldehydes with ketones is an important synthetic reaction for the synthesis of α,βunsaturated carbonyl compounds, which are known to show diverse biological activities. 9,10These α,βunsaturated carbonyl compounds are used as intermediates for the synthesis of various pharmaceuticals, agrochemicals and perfumes. 11,12Condensation of carbonyls with indoles give bis-(3-indolyl)methanes, and with pyrrole to give dipyrromethanes which show a wide variety of biological activities. 13It was found that boric acid effectively catalyzes the reactions.

Condensation of carbonyl compounds and active methylene compounds
Brun and his co-workers 14 showed that boric acid can act as an efficient Lewis acid catalyst for the cross-aldol condensation reactions of acetophenone derivatives/activated methylene compounds with aldehydes under microwave irradiation under solvent free conditions.Thus, when compounds 27 and 28 were mixed thoroughly with boric acid, and the mixture was subjected to microwave irradiation, the condensation product 29 was produced smoothly in very good yields (Scheme 9).
Offenhauer and Nelsen 15 have also cited boric acid to catalyze the aldol condensation of acetophenone and a variety of aliphatic and aromatic aldehydes and subsequent dehydration to form α,β-unsaturated ketones in high yields.Scheme 9. Cross-aldol condensation reaction catalyzed by boric acid.

Condensation of carbonyl compounds and indoles
Meshram and his group observed that boric acid can be used in the condensation of indoles with aromatic aldehydes (30) for the synthesis of diindolylmethanes (31).Thus, when boric acid was added to a stirred solution of indole and an aromatic aldehyde in water at room temperature, 31 was formed in high yield within 20-40 min.(Scheme 10). 16The same condensation reaction was reported by Yadav et al. 17 under solvent-free conditions.
Scheme 10.Boric acid promoted condensation reactions between indole and aldehydes.
Bisindolylmethanes and tetra-indolyl derivatives were synthesized by Kumar and his group by the condensation of indoles with mono-aldehydes 30 and di-aldehydes such as terephthalaldehyde, in a stirred mixture at room temperature using silica-supported boric acid to give bisindolylmethanes 31 and the tetraindole derivative 32 respectively (Scheme 11).

Condensation of carbonyl compounds and pyrrole
A simple and efficient methodology catalyzed by boric acid was demonstrated by Pratibha 19 for the synthesis of dipyrromethanes (33).Two equivalents of pyrrole and one equivalent of aldehyde gave 33 in good yield at room temperature when treated with boric acid in water (Scheme 12).The same condensation reaction was reported by Singhal et al. 20 , also in aqueous medium, using boric acid.

Friedel-Crafts Reactions
Friedel-Crafts reactions of aromatic and heteroaromatic compounds are one of the fundamental reactions for forming carbon-carbon bonds. 21Friedel-Crafts alkylation and acylation reactions have been studied using boric acid as an acid catalyst.

Acylation reactions
A series of N-acylsulfoximines 37 were synthesized from sulfoximines (e.g.36) with carboxylic acid by acylation reactions using boric acid in toluene under reflux conditions (Scheme 14). 23Boric acid forms an active acylating agent with the carboxylic acid, which reacts with 36 to produce acylation products 37 in 40-80% yields.

Tishchenko Reactions
It has been found that boric acid is an effective catalyst for the dismutation of certain aldehydes to the corresponding esters via a Tischenko-type reaction.When paraformaldehyde was heated with a catalytic quantity of boric acid in cyclohexane in an autoclave at 250 ⁰C for 5 h, a 77% yield of methyl formate (38)

Bromination Reactions
A green protocol for the synthesis of bromo-organic compounds using boric acid as a recyclable catalyst with very high selectivity was reported by Nath and Chaudhury (Scheme 16). 25 Substituted phenols, anilines, ARKAT USA, Inc styrene, aromatic ketones, dibenzylideneacetone, and imidazole compounds undergo bromination reactions with KBr in water in the presence of 30% H 2 O 2 and a very small amount of H 2 SO 4 and 5 mol% boric acid.Since neither elemental bromine nor volatile organic solvents were used the authors claim it to be a non-toxic synthesis.4,4'-dimethoxy-2'-hydroxychalcone 39 is selectively brominated at the olefinic double bond by this process.The brominated product 40 is an important precursor in flavonoid synthesis.

Ipso Substitution Reactions
Ipso substitution reactions of arylboronic acid has been studied using boric acid as catalyst.Gogoi et al. 26 have reported a simple and facile one-pot synthetic method of ipso hydroxylation of arylboronic acids 40 to the corresponding phenols 41 using boric acid as a green catalyst and aqueous hydrogen peroxide as an oxidizing agent in ethanol at room temperature (Scheme 17).

Protection and Deprotection Reactions
Protection and deprotection reactions are very important and widely used strategy for organic synthesis.
Reactions involving selective protection of functional groups such as alcohols, phenols, thiols and amines and their deprotections are common tools in the multi-step synthesis of complex natural products. 28,29Boric acid has been used as a green, selective and recyclable catalyst for protection of such functional groups by silylation and acetylation reactions and deprotection of trimethylsilyl ethers to their parent alcohols and phenols.

Protection of alcohols, phenols, thiols and amines
Rastomi and his co-workers reported that hydroxyl, thiol and amine groups can be protected by trimethysilylation process using catalytic amount of boric acid.Thus, when compound 44 was treated with hexamethyldisilazane (HMDS) in presence of boric acid in acetonitrile at room temperature, the corresponding silylated product 45 was obtained in 85% yield (Scheme 19). 30In case of thiols and amines, the reactions produced the corresponding silylation products in good yields under similar reaction conditions.

Deprotection of alcohols and phenols
The importance of the deprotection of trimethylsilyl ethers to their corresponding functional groups in multistep organic synthesis can not be overstated.Boric acid has been shown to catalyze such reactions efficiently to give good yields of the deprotected products.Trimethylsilyl ether of the type 50 was selectively deprotected to the corresponding phenol 51 using boric acid as catalyst in water at room temperature in 90% yield (scheme 21). 30

Amidation Reactions
The thermal condensation of carboxylic acids and amines in presence or absence of catalysts / reagents are known as amidation reactions.Many synthetic methods have been developed in the past, for the synthesis of amides, which are important building blocks in a large number of natural products and active pharmaceuticals. 31,32The classical amidation reactions which is carried out in absence of catalysts or reagents has traditionally been viewed as an unviable approach.The presumed formation of ammonium carboxylate salts, and extremely harsh conditions are required for the reactions to occur.Although there are several reports in the literature for amide formation, boric acid is found to be a suitable catalyst among them.Pingwah Tang reported in 2005, boric acid catalyzed direct amidation reaction of carboxylic acids and amines under anhydrous reaction conditions (Scheme 22). 33 Bisamides are important building blocks of many biologically active and pharmaceutical compounds, several synthetic methods for preparing these compounds have been developed in the past.A convenient preparation of symmetrical α-bisamides 62 has been described from the condensation of aromatic aldehydes 60 and amides 61 in presence of boric acid as catalyst under thermal and neat microwave irradiation conditions in moderate to good yields (Scheme 25). 36

Transamidation Reactions
Nguyen and his co-workers reported a novel method of transamidation of carboxamide 63 with amines 64 using boric acid.The scope of the methodology has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliphatic, cyclic and acyclic, primary and secondary amines.Thus, when a mixture of 63 and 64 were heated with a catalytic amount of boric acid and water for a specified time, the transamidation products 65 were obtained in 42-90% yields (Scheme 26). 37 Scheme 26.Boric acid catalyzed transamidation of carboxamides and amines.

Multicomponent Reactions
Multicomponent reactions (MCRs) have recently gained much practical importance due to their speed, diversity and efficiency. 38,39MCRs are useful for the expedient creation of chemical libraries of drug-like compounds and optimization in drug discovery programmes. 40

Ugi Three-component reaction
Kumar et al. reported an efficient one-pot Ugi three-component synthesis of 2-arylamino-2-phenylacetamide (66) from aldehydes, amines and isocyanides in water at room temperature using boric acid as catalysts (Scheme 27). 41Aromatic aldehydes containing either electron-donating or -withdrawing groups underwent the conversion smoothly.Several functional groups such as halogen (Cl, Br), NO 2 , ester and ether moieties were found to be stable under the reaction conditions.= tBuNC, cHeNC Scheme 27.Boric acid catalyzed Ugi-three component reactions.

Mannich reactions
β-Aminocarbonyl compounds (67, 68) were synthesized in a one-pot three component Mannich reaction of aromatic aldehydes, aromatic amines and cyclic ketones at ambient temperature catalyzed by boric acid and glycerol in water in good yields (Scheme 28). 42Syn diastereoselectivity was observed in major reactions.Boric acid and glycerol form a boron chelate complex (BCC) in water to release hydrogen ion and thus to increase the acidity of the medium which increased both the yield and diastereoselectivity of the Mannich reactions.

Biginelli reactions
Boric acid has also been used for Biginelli reactions, consisting of β-dicarbonyl compounds with dialdehydes and urea or thiourea to afford bis-dihydropyrimidinone derivatives 72 in presence of glacial acetic acid (Scheme 29). 43Tu et al. 44 have also synthesized dihydropyrimidinone derivatives using boric acid as catalyst in a classical Biginelli reaction of aromatic aldehydes, 1,3-dicarbonyl compounds and urea in glacial acetic acid in excellent yields (86-97%).

Synthesis of β-acetamido ketones
A series of β-acetamidoketones 75 were synthesized from aromatic aldehydes 73, acetophenones 74 and acetonitrile by a one-pot three component reaction using boric acid as a solid heterogeneous catalyst at room temperature.Karimi-Jaberi and Mohammadi (Scheme 30) stated that boric acid was been used as a solid acid catalyst for the preparation of β-acetamido ketones for the first time. 45

Formation of nitrogen heterocycles
Nitrogen heterocycles form the backbone of a host of biologically active molecules.Benzimidazole 46 and benzodiazepine 47 systems are known to be important constituents of many pharmaceutical and agrochemical products.Fused pyrimidines have been used for vasorelaxant activity. 48Quinazolinone derivatives are interesting chemotherapeutic having anticancer and anti-HIV properties. 49Imidazole 50 and pyridine 51 systems are one of the most important sub-structures found in a large number of natural products and pharmacologically active compounds.These important nitrogeneous heterocycles have efficiently been synthesized using as heterogeneous solid acid catalyst boric acid.16.5.1 Synthesis of benzimidazoles.A series of substituted benzimidazoles 76 were synthesized by Rajala and Patil from the reactions between aromatic aldehydes and o-phenylenediamine using boric acid as a acid catalyst in water (Scheme 31). 52The catalyst was found to be most effective for the synthesis of quinolines in terms of reaction times, yields and cost consideration, over the other heterogeneous solid acid catalysts like KHSO 4 , ionic liquids and Cu(OTf) 2. The same condensation reaction was reported by Heravi and Ashori using boric acid in water at room temperature. 53 rt, 25-80 min 65-92% + Scheme 31.Boric acid catalyzed synthesis of benzimidazoles in aqueous medium.
Maras and Kočevar reported a cyclocondensation reaction between substituted o-phenylenediamine 77 and carboxylic acids 78 to prepare a series of 2-substituted benzimidazoles 79 using boric acid as catalyst in toluene under reflux conditions (Scheme 32). 546.5.2Synthesis of benzodiazepines.Zhou and co-workers have reported that boric acid acts as an excellent catalyst for the synthesis of benzodiazepine derivatives 80, a class of bicyclic nitrogeneous heterocyclic compounds.When o-phenylenediamine and a enolizable ketones were refluxed in n-hexane in presence of boric acid for a specified time, 80 was furnished in excellent yields (Scheme 33). 55Aromatic and aliphatic ketones underwent the conversion with same efficiency.
The same cyclocondensation reaction was reported by Gholap and Tambe using boric acid as a green acid catalyst in water at room temperature. 56The reaction was proposed to proceed via the Knoevenagel condensation of an aldehyde and malononitrile, followed by the Michael addition of second molecule of malononitrile onto the Knoevenagel product.This then reacts with thiophenol and undergoes air oxidation to afford 87.Karimi-Jaberi and Ghasemi designed the synthesis of imidazo[1,2-a]pyridine derivatives (88) from the onepot three-component condensation reaction of aromatic aldehydes, 2-aminopyridines and cyclohexylisocyanide using boric acid catalyst under solvent-free conditions (Scheme 39).

Formation of oxygen heterocycles
Oxygen heterocycles also represent a very important class of biologically active compounds.Xanthenes show antiviral and antibacterial activities, 63 and benzopyrans form the backbone of many natural products and are also present in the recently discovered HIV inhibitory class of benzotripyrans. 64These oxygen heterocycles may be synthesized by using boric acid as catalysts.16.6.1Synthesis of dibenzoxanthenes.Karimi-Jaberi and Keshavarzi developed a simple and reliable method for the direct construction of biologically active 14-substituted-14H-dibenzo[a,j]xanthenes (89) in high yield from a one-pot condensation of β-naphthol with aldehydes in presence of boric acid under solvent-free conditions (Scheme 40). 65The mechanism of this reaction includes the initial generation of the carbocation, followed by the formation of aryl or alkyl methanebisnaphthols, which then undergo dehydration to give the final products.16.6.2Synthesis of benzopyrano-benzopyrans. Ganguly and his group found that boric acid can be utilized as a acid catalyst for the synthesis of 7-arylbenzopyrano[4,3-b]benzopyran-6,8-diones (90) by the three component reaction of 4-hydroxycoumarin, an aromatic aldehyde, and 5,5-dimethylcyclohexane-1,3-dione (dimedone) under aqueous micellar conditions (Scheme 41). 66Good to excellent yields, high selectivity, and green features including avoidance of organic solvent in the reactions and in the isolation stage and the use of a nontoxic water-compatible Lewis acid catalyst are key attractive features of the protocol.A plausible mechanism for the formation of compound 91 was also investigated.The mechanism highlights the formation and role of H 3 O + and the possible involvement of the oxime intermediate, B. Knovenagel condensation between the intermediate B and aromatic aldehyde followed by a intramolecular cyclization leads to the product.Therefore the formation of the title compound via the intramolecular cyclilization intermediacy of Knoevenagel adduct D of the performed oxime of ethyl acetate followed by ring closure in the presence of boric acid.Karimi-Jaberi and his co-worker 69 developed another boric acid catalyzed protocol for the synthesis of αaminonitriles (93) in a one-pot three-component condensation reaction of aldehyde, aromatic amine and trimethylsilyl cyanide at room temperature under stirring condition (Scheme 45).

Conclusions
This review gives an overview of active current interests in the synthetic applications of boric acid as catalyst.This growing interest of boric acid is mainly due to its very useful acidic properties, combined with its benign

Figure 1 .
Figure 1.Structure of boric acid (A), parallel layers in solid state (B) and view of crystalline state (C).

Scheme 28 .
Scheme 28.Mannich reactions of aromatic aldehydes, aromatic amines and cycloalkanones catalyzed by boric acid and glycerol in water.
Substituted pyrimidines 87, were also synthesized by using boric acid.Shinde et al. reported a condensation reactions of an aldehyde, malononitrile and thiophenol using boric acid and CTAB in water under conventional and ultrasound methods (Scheme 38).