Boron Chemistry: An Overview - ACS Symposium Series (ACS

Chapter 1

Boron Chemistry: An Overview

Downloaded by 5.62.159.48 on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch001

Heather DeFrancesco, Joshua Dudley, and Adiel Coca* Chemistry Department, Southern Connecticut State University, 501 Crescent St., New Haven, Connecticut 06515, United States *E-mail: [email protected]

Boron compounds have been used extensively in organic synthesis for more than sixty years. Some of the best known organic reactions such as hydroboration and the Suzuki–Miyaura coupling reaction involve organoboron derivatives. The study of compounds containing boronic acids for application in pharmaceuticals and materials science has grown tremendously over the last few decades. Several boron-containing protease inhibitors have been approved by the U.S. Food and Drug Administration recently. This chapter will introduce the reader to some of the basic properties and applications of boron compounds.

Introduction Boron (B) is a group 13 (IIIA) metalloid element. The chemical properties of boron are more similar to carbon and silicon than other group 13 elements, although boron is more electron deficient, as discussed below, than both carbon and silicon. Elemental boron was first isolated in 1808 independently by British chemist Sir Humphry Davy and by French chemists Joseph Louis Gay-Lussac and Louis Jaques Thénard (1, 2). The relative abundance of boron in the Earth’s crust is approximately 10 parts per million, making boron the second most abundant group 13 element after aluminum and 38th most abundant element overall (3). Important sources of boron are the minerals borax, Na2[B4O5(OH)4]·8H2O, and kernite, Na2[B4O6(OH)2]·3H2O (4). Large deposits of these minerals are found in Kern County, California and in parts of Turkey. Boron has three valence electrons and has a ground state electron configuration of 1s22s22p1. Boron typically forms trivalent neutral compounds © 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


such as boron trifluoride (BF3) in which the boron has six valence electrons. Thus, the boron atom is sp2 hybridized, has an empty p-orbital, and has a trigonal planar geometry. These types of compounds are electron-deficient due to the empty p-orbital on boron and are isoelectronic with carbocations. The Lewis acidity of trivalent boron compounds has been exploited in a number of reactions. Boron can also form negatively charged tetravalent compounds, which adopt a tetrahedral geometry. The carbon-boron bond (1.55-1.59 Å) in tricoordinated boron compounds is longer than a typical carbon-carbon bond (5). On the other hand, the boron-oxygen bond in trivalent organoboron compounds is relatively short and in the range of 1.31-1.38 Å compared to an ether C-O bond (1.43 Å). This bond shortening is a result of the partial double bond character in the B-O bond due to the lone pairs on oxygen interacting with the empty p-orbital on boron. The difference in electronegativity between boron (2.05) and carbon (2.55) explains the observed weak electron donation of boron functional groups. B-C π-conjugation due to the empty p-orbital on boron has been confirmed in aryl- and alkenylboron compounds. In these compounds, boron groups behave as weak electron withdrawing groups. This phenomenon is illustrated, for example, in the fact that the beta carbon of alkenylboronic acids and esters is typically deshielded slightly in 13C NMR spectra.

Figure 1. Structures of boromycin, aplasmomycin A, tartrolon B, and AI-2. 2 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Few boron-containing natural products have been isolated. These include the boric acid-based ionophoric macrodiolide antibiotics boromycin, borophycin, aplasmomycins A, B, and C, and tartrolons B, C, and E (Figure 1) (6–11). Boromycin was isolated in 1967 from Streptomyces antibioticus and it was the first natural product isolated containing boron. Exposure to boromycin causes the release of potassium ions in Gram-positive bacteria. It also has shown anti-HIV activity (12). Borophycin, the aplasmomycins and the tartrolons were isolated from marine bacteria. Another boron-containing natural product is autoinducer-2, AI-2 (13). The bacterial signaling molecule AI-2 has been reported to be involved in intercellular communication between bacteria through a process called quorum sensing. To date, no natural product having either a tricoordinated boronic acid or boronic ester group has been isolated. Organoboron compounds have found many uses over the last sixty years. These uses include being involved in several important reactions such as hydroboration and the Suzuki–Miyaura reaction, among others. In addition, organoboron compounds have found several applications in the pharmaceutical industry, as neutron capture therapy agents, and in materials science and molecular imaging. In this chapter, a very brief overview of organoboron compounds will be covered to introduce the reader to this highly impactful area of research. Other chapters in this book will cover in more detail recent advances in different aspects of boron chemistry. This chapter as well as the rest of the book is primarily concerned with small-molecule boron chemistry.

Boron Compounds Organoboron compounds contain at least one carbon-to-boron bond and can be classified as boranes, borohydrides (which may or may not contain a carbon-to-boron bond), borinic acids, borinic esters, boronic acids, boronic (boronate) esters, boronamides, boryl anions, and borate anions, among others (Figure 2). It should be mentioned that the classification of boron compounds in the literature varies greatly. Boranes include trivalent boron compounds bearing any combination of organic groups and/or hydrogen atoms on boron. Thus, these can be further classified into boron hydrides (contain at least one hydrogen atom on boron) and triorganoboranes (contain three organic groups on boron). Borinic acids contain one hydroxyl group and two organic groups on boron. Borinic esters contain an alkoxy group instead of the hydroxyl group. Boronic acids and esters are perhaps the most studied and most synthetically useful organoboron compounds. These species contain two hydroxyl (boronic acids) or two alkoxy (boronic esters) groups along with one organic group. Boronamides contain two nitrogen atoms bonded to boron. Boryl anions can be formed from reduction of a boron halogen bond and are isoelectronic with N-heterocyclic carbenes (NHC). Borohydrides have a central negatively charged tetrahedral boron atom bearing at least one hydrogen atom. Borate anions describe tetrahedral boron anion salts such as boron oxyanions and organotrifluoroborates (RBF3-). There are other boron compounds that, although are not technically organoboron compounds, are utilized in synthesis as well. These compounds include borate (boric) esters and 3 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


boron trihalides (containing three halogens on boron). Borate esters are trivalent and contain three alkoxy groups on boron. Borate esters can be easily made from boric acid, B(OH)3. Boric acid is a fairly non-toxic compound that is the metabolic end-product of many organoboron compounds. In humans, boric acid has a lethal dose level similar to table salt. In plants, boric acid is an essential nutrient as boron helps bind polysaccharides in the cell wall and maintains plasma membranes and metabolic pathways (14). Below is a brief introduction to some important boranes, borohydrides, boronic acids, boronic esters, and borates in synthesis.

Figure 2. Select examples of boron compounds.

Boranes and Borohydrides Between 1912 and 1936, Alfred Stock discovered that boron forms a range of hydrides. Stock synthesized a series of boron hydrides whose structures could not be explained simply by using valence bond theory (15). Stock was able to successfully synthesize and characterize a series of boranes including B2H6, B4H10, B5H9, B5H11, B6H10, and B10H14. Boron hydrides contain multi-center bonding which allows for the formation of clusters, where the atoms form a cage-like structure. In the structure of these compounds, each boron forms a 2-center 2-electron bond with terminal hydrogen atoms, with the remaining hydrogen atoms forming 3-center 2-electron (2 electrons shared by three atoms) bonds that bridge two boron atoms (Figure 3). Boron hydrides generally form dimers unless restricted by sterics around boron. For example, borane (BH3) generally prefers to form the dimer diborane (B2H6), which allows the boron atoms to have a complete octet of valence shell electrons. Borane only exists as a monomer at high temperatures or when it forms a 1:1 adduct with Lewis basic solvents/ligands such as tetrahydrofuran, amines, and dimethylsulfide (Eq 1).

Figure 3. Structure of diborane.

4 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The structures of other important neutral boron hydrides are shown in Figure 4. Among these boranes are catecholborane and pinacolborane, which have been used to synthesize precursors for the Suzuki–Miyaura reaction. Sterically hindered boranes such as thexylborane, disiamylborane, and 9-borabicyclo[3.3.1]nonane (9-BBN-H) have been used for highly regioselective and stereoselective hydroborations (16, 17). Asymmetric hydroborations have also been accomplished with chiral boranes such as diisopinocampheyl borane (Ipc2BH) (18).

Figure 4. Structures of some boron hydrides.

Unlike boranes, which are strong Lewis acids, borohydrides are nucleophilic in nature. In 1940, Hermann Irving Schlesinger and Herbert Charles Brown reported the synthesis of lithium borohydride, the first alkali metal borohydride described (Figure 5) (19). Perhaps the most important borohydride is sodium borohydride, which has been used for numerous reductions of aldehydes, ketones, enones, acid chlorides, and other functional groups (20). Superhydride (lithium triethylborohydride) is even more reactive due to the electron-donating alkyl groups; it reduces numerous other functional groups (21, 22). Other important borohydrides include sodium cyanoborohydride and sodium triacetoxyborohydride, which have been used often in reductive aminations (23, 24). Sterically hindered tri-sec-butylborohydrides such as L-selectride (lithium tri-sec-butylborohydride) and K-selectride (potassium tri-sec-butylborohydride) have been used for asymmetric carbonyl reductions of hindered cyclic and bicyclic ketones (25).



Figure 5. Structures of some borohydrides. Triorganoboranes have served as useful alkylating agents. For example, these compounds have extensively been studied in the allylation of carbonyl groups with allylboranes such as triallylboron (Figure 6) (26). Many chiral triorganoboranes have been developed since the 1980s for asymmetric allylborations as well, such as the α-pinene derived B-allyldiisopinocamphenylborane (Ipc2Ballyl) (27). Most triorganoboranes are prone to air oxidation and are often oxidized to borinic acids. Many borinic acids are also fairly air sensitive and are oxidized to the more stable boronic acids. The oxidation of triorganoboranes and borinic acids is the result of the large difference between the B-C and B-O bond strengths. In fact, B-C bonds (323 kJ/mol) are weaker compared to C-C bonds (358 kJ/mol), whereas B-O bonds (519 kJ/mol) are much stronger than C-O bonds (384 kJ/mol) (28). The stronger B-O bonds are due to their partial double bond character as a result of the π-dative interaction between the lone pairs on oxygen and the empty p-orbital on boron.

Figure 6. Structures of some allylboranes. Boronic Acids and Boronic Esters Boronic acids and boronic (boronate) esters exemplified by phenylboronic acid and phenylboronic acid pinacol ester in Figure 7 are extremely useful functionalities in synthesis. As previously mentioned, they serve as precursors for the Suzuki–Miyaura reaction. In addition, boronic acids are very popular in medicinal chemistry as discussed later. Most boronic acids and boronic esters are fairly air stable and moderately stable to most reaction conditions (except those mentioned below). Aliphatic boronic acids and esters tend to oxidize more easily than aryl- and alkenyl boronic acids and esters. These compounds are also susceptible to deboronation with aqueous bases, aqueous acids, nucleophiles, 6 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


and oxidants due to the empty p-orbital on boron. Boronic acids with relatively small organic groups are very polar and water soluble. Thus, boronic acids often present problems in chromatographic separation and during extractions. Additionally, boronic acids that have been scrupulously dried are converted to boronic anhydrides (boroxines), which complicates characterization (Figure 8). Since boronic acids and boronic esters can be routinely interconverted, boronic esters are usually preferred as they are easier to purify and characterize. Acyclic boronic esters are susceptible to hydrolysis yielding boronic acids, whereas bulky cyclic boronic esters such as pinacol boronic esters are more robust. Boronic esters containing a trivalent ligand such as N-methyliminodiacetic acid (MIDA) that effectively rehybridizes the boron atom from sp2 to sp3 (thus removing the empty p-orbital through a dative bond) have been used to improve the stability towards air and other reaction conditions of the boron partner in the Suzuki–Miyaura reaction (29). Since MIDA boronate esters are easily cleaved under mildly basic conditions, they have been used as a boronic acid protecting group and have allowed for an iterative cross-coupling strategy to be developed (29).

Figure 7. Structures of some boronic acids and boronic esters.

Figure 8. General structure of a boroxine.

Unlike carboxylic acids, boronic acids do not behave as Brønsted acids, but are instead mild Lewis acids. Boronic acids and boronic esters are weaker Lewis acids than boranes due to the interaction in boronic acids and boronic esters between the lone pairs on the oxygen atoms with the empty p-orbital on boron. Boronic acids and boronic esters ionize water to form a borate anion and hydronium ion (Eq 2). Thus, the pKa of boronic acids and boronic esters in water is indirectly related to their Lewis acidity.



Electron withdrawing groups on the organic group of boronic acids and boronic esters increases their Lewis acidity (lower pKa), whereas sterically hindered groups (such as ortho substituents in phenylboronic acids) decreases their Lewis acidity. The pKa value for boronic acids range from approximately 4.0 to 10.5 (Figure 9) (5). Boronic esters typically have lower pKa values than their corresponding boronic acids by about 2-4 units (30).

Figure 9. Representative boronic acids with corresponding pKa’s. Borates Boron has a high affinity for oxygen, leading to the formation of borates, which are boron-containing oxyanions. Other borates include trifluoroborates. Trifluoroborates have been successfully used as boronic acid protecting groups, similarly to MIDA boronate esters, due to the tetracoordinated boron in these compounds (Figure 10). They also have been employed in a number of reactions including the Suzuki–Miyaura reaction. Trifluoroborates can be hydrolyzed efficiently with silica gel and water (31). One major issue with them is their insolubility in apolar solvents. However, trifluoroborates are often purified in these solvents through crystallization.

Figure 10. Structure of a trifluoroborate.

Reactions In this section, a very short overview of some of the reactions that involve boron compounds will be discussed as it is impossible to do justice to all of the important research that has been done involving the synthesis of or the use of 8 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


boron compounds. More details can be found in other chapters of this book or in the references below. Edward Franlkand is credited with the first reported synthesis of an organoboron compound more than 150 years ago as he synthesized triethylborane (BEt3) by reacting triethylborate (B(OEt)3) with an excess of diethylzinc, Et2Zn (Scheme 1) (32). The resulting air-sensitive triethylborane (BEt3) was then carefully air oxidized to diethyl ethylboronic ester, EtB(OEt)2, which was then hydrolyzed to ethylboronic acid, EtB(OH)2. Other "hard" organometallic reagents such as organolithium or Grignard reagents also have been used to synthesize boronic acids and boronic esters from borate esters at low temperatures (Scheme 1) (33). This method is limited in scope due to the intolerance by the organometallic reagents for several functional groups.

Scheme 1. Reactions of organometallic reagents with borate esters.

The convenient reduction of aldehydes, ketones, and acid chlorides to alcohols with sodium borohydride (NaBH4) was described in 1949 (Eq 3) (20). Although NaBH4 is easier to handle than lithium aluminum hydride (LiAlH4), it typically doesn’t reduce carboxylic acids, amides or other functional groups that are susceptible to LiAlH4 reduction. The related reagent lithium borohydride (LiBH4) has been reported to be more reactive than NaBH4 as it reduces esters to alcohols more readily (34). This difference in reactivity is due to the better carbonyl activation by the tighter binding to the oxygen with the smaller lithium cation. Choosing the appropriate solvent can also increase the reactivity of the borohydride reagents significantly. Generally, protic solvents such as methanol increase the reactivity of borohydride reagents by forming alkoxyborohydrides, which are more reactive than both NaBH4 and LiBH4. As a result, NaBH4 in methanol reduces most esters (albeit slowly) to primary alcohols and primary amides are converted to amines with LiBH4 in a methanol/THF mixture (35, 36). In the presence of Lewis acidic lanthanide chlorides such as cerium chloride, NaBH4 in methanol will reduce α,β-unsaturated ketones to allylic alcohols with only very small amounts of the saturated alcohol (Eq 4) (37). This reaction is often referred to as the Luche reduction. Trialkylborohydrides such as Superhydride (LiEt3BH) are even stronger reducing agents due to the electron donating alkyl groups. These can reduce sterically hindered ketones, alkyl halides, sulfonate esters, epoxides, tertiary amides, among other functional groups (21, 22). Sterically hindered borohydrides such as L-selectride, Li(sec-Bu)3BH, can introduce steric control in the reduction of ketones such as 2-methylcyclohexanone and camphor (25). Reductive amination of ketones 9 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


and aldehydes in a one-pot reaction has been carried out with the use of sodium cyanoborohydride, Na(CN)BH3, at a pH of 6-8 in methanol (Eq 5) (23). Sodium triacetoxyborohydride, NaBH(OAc)3, has been reported as a more selective alternative to sodium cyanoborohydride for direct reductive aminations of ketones and aldehydes (24). This reagent also avoids the production of toxic byproducts such as HCN and NaCN.

In 1956, H. C. Brown discovered that sodium borohydride and aluminum chloride convert olefins at elevated temperatures to trialkylboranes, which could subsequently be oxidized to alcohols with a sodium hydroxide and hydrogen peroxide treatment (38). A year later, Brown found a more convenient procedure utilizing diborane in ether solvents that converts olefins into organoboranes (or the corresponding alcohol if oxidized) at room temperature (39). Borane-methyl sulfide provides the added advantage that it is exceptionally stable at 0 ºC and can even be stored at room temperature, unlike BH3-THF which must be stored at 0 ºC (40). Alkene hydroboration reactions generally give syn addition where both the BH2 group and hydrogen atom add to the alkene from the same face of the double bond (Eq 6) (41). When the hydroboration is performed with unsymmetrical alkenes, the reaction affords the anti-Markovnikov product as the boron generally adds to the less substituted carbon of the alkene. Alkynes also participate in this reaction. For example, boranes such as catecholborane add to alkynes to afford (E)-alkenylboronic esters, which are valuable intermediates in synthesis as described later (Eq 7) (42). For his contribution to boron chemistry, Brown shared the 1979 Nobel prize in chemistry.



The transfer of an allyl group from triallylboron to aldehydes and ketones via an allylic rearrangement was reported in 1964 (Eq 8) (26). Many allylboranes, allylboronic esters, and allylboronamides participate in this reaction. Allylboration involves a six-membered chair-like transition state and the reaction can be performed at temperatures as low as -100 °C. In addition, asymmetric versions of this reaction also have been developed using various chiral allylboron reagents such as B-allyldiisopinocampheylborane (Ipc2Ballyl) (27).

The cross-Aldol reaction between a ketone enolate and an aldehyde electrophile produces complex product mixtures due to equilibrating enolate anions. One elegant and practical solution to this problem was provided by Teruaki Mukaiyama. Mukaiyama showed that vinyloxyboranes reacted competently in the cross-aldol reaction without formation of products derived from enolate equilibration (Scheme 2) (43). Vinyloxyboranes are formed from ketones and dialkylboron halides or triflates. Over the years, diastereoselective and enantioselective versions of this transformation have been developed.

Scheme 2. Cross-Aldol using Boron Enolates. In 1979, Akira Suzuki reported the palladium-catalyzed cross-coupling of 1-alkenylboranes to 1-alkenyl, 1-alkynyl, and aryl halides (Eq 9) (44, 45). This reaction, which is now known as the Suzuki-Miyaura cross-coupling, has been developed extensively and now allows for the coupling of a very broad range of organic fragments. In additon, the Suzuki-Miyaura cross-coupling is able to tolerate a broad scope of functional groups. Regio- and stereoselectivity is highly controllable in the Suzuki-Miyaura cross-coupling. It has been used in numerous syntheses of natural products and pharmaceuticals. Thus, it is one of the most important reactions in chemistry. It has also spurred great interest in the development of methods that provide access to boronic acids and boronic 11 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


esters. In order to facilitate the transmetalation step in the Suzuki-Miyaura cross-coupling, the reaction is carried out under basic conditions which converts the boronic acid or boronic ester into a borate anion. The basic conditions of the Suzuki-Miyaura cross-coupling occasionally lead to protodeboronation. Performing the Suzuki-Miyaura cross-coupling in an atmosphere of carbon monoxide affords ketones (Eq 10) (46). This variant is often referred to as the carbonylative Suzuki-Miyaura cross-coupling. Suzuki shared the Nobel prize in chemistry in 2010 for these discoveries.

The Miyaura borylation, which was described by Norio Miyaura in 1995, allows for the synthesis of boronic esters (Eq 11) (47). In this reaction, palladium catalyzes the borylation of alkenyl and aryl halides with alkoxydiboron compounds such as bis(pinacolato)diboron.

Arylboronic acids also can be coupled at room temperature with N-H and O-H containing compounds such as phenols, amines, anilines, amides, imides, ureas, carbamates, sulfonamides, and various heterocycles (Eq 12) (48, 49). The reaction is promoted by Cu(OAc)2 and a tertiary amine base. The Chan-Lam coupling was quickly employed to synthesize thyroxine (Scheme 3) (50).



Scheme 3. Synthesis of thyroxine utilizing the Chan-Lam coupling.

The neighboring group effect that boron provides has been exploited to displace halogens from α-haloalkylboronic esters. Nucleophiles such as organometallic reagents add first to boron to form a tetravalent boron anion which rearranges to quickly displace the halogen on the adjacent carbon atom (51). A similar 1,2-migration is observed when dichloromethyl lithium is added to alkylboronic esters whereby the alkyl group migrates to displace one of the chlorine atoms from the dichloromethyl group (Scheme 4) (52). The remaining chlorine atom in the resulting α-haloalkylboronic esters has been displaced by various nucleophiles including organometallic reagents, amines, alkoxides, and thiolates utilizing this neighboring group effect. Donald Matteson has developed this chemistry to perform homologations of boronic esters. Asymmetric versions of this reaction have been reported using chiral boronic esters (substrate control) or chiral carbanions (reagent control) (53, 54). This reaction is essential for the asymmetric syntheses of various chiral α-aminoboronic acid-based enzyme inhibitors, which are discussed below.

Scheme 4. Homologation of alkylboronic esters.



Alkenylboronic acids were found to add to the adduct of a secondary amine and paraformaldehyde at room temperature to produce (E)-allylamines (Scheme 5) (55). The Petasis borono-Mannich reaction has been extended to include arylboronic acids as well. Stereoselective syntheses of α-amino acids using this method have been disclosed (56).

Scheme 5. Petasis borono-Mannich reaction. The Lewis acidity of trivalent boron compounds has been utilized for many years to catalyze a wide range of organic reactions. Boron trihalides such as boron tribromide (BBr3), boron trichloride (BCl3), and boron trifluoride (BF3) have been used as Lewis acids regularly in synthesis. Among these three, boron tribromide is the strongest Lewis acid, whereas boron trifluoride is the weakest. This difference in Lewis acidity is a result of stronger π-bonding between fluorine and boron due to better orbital overlap since boron and fluorine are on the same row of the periodic table. The lone pairs on chlorine and bromine overlap poorly with the empty porbital on boron, which makes the p-orbital on boron more available as a Lews acidic site. Both BCl3 and BBr3 are capable of dealkylating alkyl ethers (Eq 13) (57). Over the last few decades, many examples of chiral boron catalysts have been described. For example, Elias James Corey developed a triflic acid activated chiral oxazaborolidine catalyst for asymmetric Diels-Alder reactions (Eq 14) (58).



Robust tetrahedral boron compounds, which are readily made from boronic acids, have been described. For example, boronic acids can be converted to potassium organotrifluoroborate salts when treated with aqueous potassium hydrogenfluoride (potassium bifluoride), KHF2 (Eq 15) (59). Similarly, MIDA boronic esters can be prepared by reacting boronic acids with N-methyliminodiacetic acid (Eq 16) (29). Both potassium organotrifluoroborate salts and MIDA boronic esters serve as protecting groups for boronic acids as well as starting materials in reactions such as the Suzuki-Miyaura cross-coupling.



Characterization Boron has two stable isotopes, 10B and 11B, as well as 14 other known radioactive isotopes (60). Both stable boron nuclei are active in nuclear magnetic resonance (NMR) spectroscopy. 11B NMR spectroscopy is routinely used for the characterization of boron-containing compounds and it is preferred for NMR studies for several reasons. Boron-10 has a 19.6 percent natural abundance and has a nuclear spin (I) of 3, whereas boron-11 has an 80.4 percent natural abundance and has a nuclear spin of 3/2. Boron-11 also has a higher magnetic receptivity and wider chemical shift range. However, small coupling constants in 11B NMR spectra, i.e., less than10 Hz, are difficult to measure. The signal from boron trifluoride diethyl etherate, BF3·O(C2H5)2, is typically used as the external reference. The chemical shift value for trivalent boron compounds ranges from approximately -10 to +100 ppm in 11B NMR spectra whereas tetravalent boron compounds typically have chemical shift values between +10 to -130 ppm. For example, the 11B resonance for boronic acids and boronic esters is typically between 25 to 35 ppm and trialkylboranes are generally around 75 to 95 ppm. The quadrupolar relaxation mechanism of 11B nuclei often leads to broadening of the 13C NMR signal of carbon atoms directly attached to boron. Thus, quaternary carbons with attached boryl groups are often not detected in 13C NMR spectra. Boronic acids, boronic esters, borinic acids, and borinic esters show a very strong B-O IR stretching frequency around 1350 to 1310 cm-1 (61). Similarly, the B-N bond of boronamides shows a strong band between 1378 and 1332 cm-1. Boronic acids and borinic acids will also have a strong broad hydrogen bonded OH frequency around 3300 to 3200 cm-1. The B-Cl stretching frequency of trivalent boron chloride compounds is around 910 to 890 cm-1 whereas the B-F stretching frequency in trifluoroborates has been reported to vary from 1227 to 951 cm-1 (59). Borane hydrides have a B-H stretching mode near 2630 to 2350 cm-1. The isotopic pattern due to the ratio of 10B and 11B (~1:4) is well observed in mass spectrometry for boron compounds.

Applications of Organoboron Compounds Many boron compounds have found applications in medicinal chemistry and materials science. For example, α-aminoboronic acids are capable of forming dative bonds with nucleophilic amino acid residues such as serine and threonine, which are found in the active site of proteases. These dative bonds, which are reversible, are stronger than non-bonding intermolecular interactions. The best known example is the anticancer drug bortezomib (marketed as Velcade), which was approved by the Food and Drug Administration (FDA) in 2003 for the treatment of relapsed or refractory multiple myeloma (Figure 11). Multiple myeloma is a cancer of plasma cells. Bortezomib has the distinction of being the first approved proteasome inhibitor as well as the first approved boronic acid-based drug on the market. The dipeptidyl boronic acid binds reversibly with the chymotrypsin-like (CT-L) subunit of the proteasome through its boronic acid group (62). The proteasome is responsible for the degradation of misfolded proteins and ubiquitylated proteins. Proteasome inhibition leads to the 16 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


accumulation of pro-apoptotic proteins (proteins that regulate the cell suicide process) in tumorigenic cells but not normal tissue. In 2006, bortezomib was also approved by the FDA for the treatment of mantle cell lymphoma.

Figure 11. Structures of bortezomib, ixazomib, and delanzomib.

The second generation proteasome inhibitor ixazomib (marketed as Ninlaro) has improved characteristics compared to bortezomib. For example, it has a shorter half-life and wider distribution in blood compared to bortezomib. It inhibits the CT-L subunit as well as the trypsin-like (T-L) and caspase-like (C-L) subunits of the proteasome. Ixazomib is typically administered orally as a citrate boronic ester prodrug which hydrolysis in the plasma to the active boronic acid form shown in Figure 11. Ixazomib was approved by the FDA in late 2015 as the first oral proteasome inhibitor for the treatment of multiple myeloma. It is used in combination with lenalidomide and dexamethasone. Another related boronic acid-based proteasome inhibitor is delanzomib, which reversibly inhibits CT-L and C-L. Delanzomib is also administered orally and in combination with lenalidomide and dexamethasone. It is currently in clinical studies. The boron atom in bortezomib interacts with the hydroxyl group in a nucleophilic terminal threonine residue whereas several intermolecular interactions hold this small molecule in the active site of the CT-L subunit of the proteasome (Figure 12). The tetrahedral borate anion is a transition state analogue that resembles the tetrahedral intermediate of amidolysis which is formed when proteases hydrolyze peptides. Tavaborole (marketed under Kerydin) is an oxaborole topical antifungal, which was approved in 2014 by the FDA for the treatment of onychomycosis (Figure 13). Onychomycosis is a fungal infection of the toenail. Tavaborole interferes with fungal protein synthesis through the inhibition of cytoplasmic leucyl-tRNA synthetase (63). The related crisaborole is currently in clinical trials for the treatment of psoriasis and eczema (Figure 13). Crisaborole inhibits phosphodiesterase-4 (PDE-4), which reduces the release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) (64). 17 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 12. Key interaction of bortezomib with a terminal threonine residue in the CT-L subunit of the proteasome (other interactions not shown).

Figure 13. Structures of tavaborole and crisaborole.

Compared to arylboronic acids, oxaboroles are more electrophilic due to the ring strain caused by the short B-O bond within the ring. This ring strain is released when the boron is hydroxylated to form a tetrahedral borate anion. Tavaborole, for example, reacts with the cis diol of the ribose unit in the terminal adenosine of leucyl-tRNA, which renders the cytoplasmic leucyl-tRNA synthetase enzyme inactive (Eq 17) (65).

The inhibition of PDE-4 is also a target to treat type 2 diabetes since PDE4 degrades incretin hormones such as glucagon-like peptide 1 (GLP-1). This hormone degradation results in increased levels of GLP-1, which inhibits glucagon release and increases the release of insulin from the pancreas. Thus, serum sugar levels decrease. Dipeptide boronic acids such as talabostat (Figure 14) are not only capable of inhibiting PDE-4 but also other related enzymes such as PDE-2, PDE-8, PDE-9, and FAP (fibroblast activation protein). The inhibition of FAP by talabostat was investigated in clinical trials for the treatment of colorectal cancer (65). 18 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 14. Structure of talabostat. Boron neutron capture therapy (BNCT) has been used to treat brain and neck tumors. The therapeutic potential of BNCT has been recognized since 1936 (66). In BNCT, a compound such as p-borono-L-phenylalanine and sodium borocaptate (Na2B12H11SH) containing the non-radioactive isotope 10B is delivered to a tumor to release α-particles (4He nucleus) after being irradiated with thermal neutrons (Figure 15). The capture of the neutrons by 10B nuclei causes fission reactions that release α-particles and lead to the death of cancer cells. Since the depth penetration of α-particles is only limited to about one cell, the damage to nearby healthy cells is limited in BNCT.

Figure 15. Structures of p-borono-L-phenylalanine and sodium borocaptate. As discussed above for tavaborole, boronic acids are capable of reversibly binding cis-1,2- or cis-1,3-diols. This characteristic has been utilized in the development of potential sensors for saccharides such as glucose. Reliable measuring of blood glucose levels is critically important for patients with diabetes. Although many sensors utilizing biological recognition elements have been developed for sensing saccharides, synthetic chemosensors have the potential to be more stable and less expensive (30). Since boronic esters have a slightly lower pKa than boronic acids, the binding of a diol to a boronic acid will typically lead to slight favoring of the anionic borate anion over the neutral boronic esters. This increase in ionization can be measured through differences in either solubility or fluorescence intensity, among other characteristics. The incorporation of multiple 19 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


boronic acid groups has led to increased binding affinity for saccharides. Selection of an appropriate spacer helps with selectivity between different saccharides. For example, Drueckhammer developed a diboronic acid sensor that has a 400-fold greater affinity for glucose compared to fructose (Eq 18) (67).

Similar strategies have been used for the separation and immobilization of glycoproteins such as antibodies (68). Immobilized boronic acids have been developed that bind diols on the carbohydrate chains of various antibodies. This immobilization strategy has many potential uses, such as the detection of antigens. Soluble electrochemical sensing redox probes such as ferrocenylboronic acid-based systems have been employed to directly measure changes in electrochemical response as they bind a ligand such as a diol from a sugar or glycoprotein (Figure 16) (69). Similarly, probes bearing a boronic acid have been used to monitor catechol-based biomolecules such as dopamine as well as hard anions such as fluoride. The applications of boronic acid-based polymers has recently been reviewed (70).

Figure 16. Structure of ferrocenylboronic acid redox probe.

Conclusion Although the first organoborane compound was synthesized more than 150 years ago, it was almost another century before boron reagents first saw significant application in synthesis. Beginning in the 1940s, the potential of borohydride and borane reagents in synthesis was first recognized. However, it was not until the discovery of the Suzuki-Miyaura coupling reaction in the late 1970s that this area of chemistry really took off. Since then, many new reactions and advances have been reported; too numerous to mention here. The reader will find more recent advances and details in the remaining chapters of this book. The discovery that boronic acids can inhibit proteases has led to the approval of boronic acid-centered pharmaceuticals for the treatment of several diseases. Three boronic acid-based drugs (bortezomib, ixazomib, and tavaborole) have been approved for human use since 2003 with many more in the pipeline. Furthermore, boronic acid-based 20 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

materials are currently being studied as potential probes for important biological molecules such as saccharides, glycoproteins, and catecholamines as well as hard anions such as fluoride. These developments will no doubt spur further research in the area of organoboron chemistry in the upcoming years and many new exciting discoveries in their applications (including in synthesis) will be made as a result.

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