Protection of the Benzoxaborole Moiety: Synthesis and

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Protection of the Benzoxaborole Moiety: Synthesis and Functionalization of Zwitterionic Benzoxaborole Complexes James M. Gamrat, Giulia Mancini, Sarah J. Burke, Rebecca C. Colandrea, Nicholas R. Sadowski, Bryan C. Figula, and John W. Tomsho J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00677 • Publication Date (Web): 04 May 2018 Downloaded from http://pubs.acs.org on May 4, 2018

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The Journal of Organic Chemistry

Protection of the Benzoxaborole Moiety: Synthesis and Functionali‐ zation of Zwitterionic Benzoxaborole Complexes James M. Gamrat, Giulia Mancini, Sarah J. Burke†, Rebecca C. Colandrea, Nicholas R. Sadowski, Bryan C. Figula††, John W. Tomsho* Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, 19104, United States.

ABSTRACT: The synthesis and utility of three benzoxaborole protecting groups is reported. These protecting groups improve organic solubility and allow otherwise incompatible reactions (oxidations, substitutions, and mild reductions) to be achieved in the presence of the benzoxaborole moiety. 3-(N,N-dimethylamino)-1-propanol was determined to be useful in one-step sequences and is readily cleaved upon workup. Two other groups, N-methylsalicylidenimine and 2-[1-(methylimino)ethyl]phenol, are suitable for multi-step syntheses. Deprotection with mild aqueous acid allows for chromatography-free isolation of the benzoxaborole in high yields.

The incorporation of boronic acids and benzoxaboroles into pharmaceutical agents has been motivated by their interesting interactions with biological targets. This reactivity arises from an empty p-orbital on the boron atom, resulting in reversible binding to Lewis basic amino acids in enzyme active sites.1-3 Benzoxaboroles in particular have become increasingly relevant in drug design and in the pharmaceutical industry.4-5 These cyclic derivatives of phenyl boronic acid (Figure 1) contain a benzene-fused oxaborole ring which introduces ring strain about the boron center and enhances reactivity.1,4,6 Two benzoxaborole-containing drugs have recently been approved by the FDA: Kerydin® (tavaborole), an aminoacyl transfer ribonucleic acid (tRNA) synthetase inhibitor used for the treatment of onychomycosis (toenail fungus),7-8 and Eucrisa® (crisaborole), a PDE-4 enzyme inhibitor used for the treatment of atopic dermatitis (eczema).9-10 Benzoxaboroles also exhibit many other types of bioactivities4 including antibacterial,11-14 antiviral,15-16 and anti-malarial activities.17 Benzoxaboroles are generally considered more stable than their boronic acid counterparts, and there are numerous reports Figure 1. a) Phenylboronic acid, b) Benzoxaborole, c) tavaborole, and d) crisaborole.

of reactions that do not require protection.14, 17-19 Yet the possibility of side reactivity arising from a more reactive p-orbital about the boron center is concerning for reactions with nucleophiles and oxidizing agents. Also, lack of solubility in organic solvents arises as Lewis-basic substituents are introduced. In the case of boronic acids, these issues are addressed with a series of trivalent protecting groups such as MIDA boronates20, trifluoroborate salts21-22 as well as divalent pinacol esters (Bpin) and 1,8-diaminonaphthalene (Bdan) complexes.23 At this time, there has been only one benzoxaborole protecting group described in the literature: 1-dimethylamino-8-methylaminonaphthalene.24 Although stable to a variety of reaction conditions and column chromatography, this protecting group is not stable to oxidation, and its subsequent removal with re-isolation of the benzoxaborole was not described. Our synthetic efforts were hampered by an inability to reproduce a literature oxidation of a primary alcohol (4c, Scheme 1) with pyridinium chlorochromate (PCC) in the presence of the benzoxaborole.19 We observed extremely poor solubility of 4c and attempts at oxidation resulted in complex mixtures with very low yields of the desired aldehyde product. These solubility and reactivity issues could be a result of oligomer formation via condensation of the benzylic alcohol with the benzoxaborole (See MS data for 4c in experimental). Solubility was increased by making the methyl or ethyl esters of the benzoxaborole, but complex mixtures were still obtained under oxidative conditions. It became evident that these solubility and chemoselec-

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With complexes 5a-c in hand, the scope of reactions that can be performed with benzoxaboroles protected by 1 (Scheme 2) was examined. We were pleased to observe that the solubility of these protected complexes in common organic solvents increased significantly compared to their unprotected benzoxaborole counterparts. Encouraged by this discovery, 5b was subjected to diisobutylaluminum hydride (DIBAL-H) in DCM followed by aqueous workup, which resulted in clean formation of aldehyde 6 as the only product. While there was detectable product formation when unprotected, DIBAL-H caused partial decomposition of the benzoxaborole and the resulting complex product mixture required chromatographic purification. Inspired by this stability, we decided to pursue additional reactions that we struggled to achieve without protecting 4c. With 5c in hand, oxidation of the benzylic alcohol with manganese dioxide produced 6 in good yield after deprotection via extractive workup. An iodisation reaction with sodium iodide and trimethylsilyl chloride provided the benzylic iodide 7 after deprotection via workup in 72% yield without the need for chromatography. Finally, a Mitsunobu reaction was attempted using a polystyrene-supported triphenylphosphine in the presence of phthalimide allowing for the smooth conversion to benzylic phthalimide 8 in 64% yield. This reaction was also successfully performed with PPh3, but removal of the triphenylphosphine oxide byproduct hindered the isolation of 8. It is noted that these reactions were unsuccessful or very low yielding without the use of a protecting group. These examples therefore provide evidence that improving solubility and masking the p-orbital affects these compounds’ useful reactivity under certain conditions. Following the encouraging results observed when the boron center was transiently protected with 1, we next aimed to design more robust protecting groups that would be stable to column chromatography and across multiple synthetic steps. Using the backbone of 1 as a scaffold, it was hypothesized that incorporation of a phenolic alcohol would provide both an increase in complex rigidity and stability. After unsuccessfully

Scheme 1. Synthesis and deprotection conditions for 1.

tivity issues needed to be addressed by introduction of a benzoxaborole protecting group. Our aim was to design protecting groups that were a) inexpensive and commercially available or readily synthesized, b) could withstand mild oxidative conditions, and c) would improve the solubility of benzoxaboroles, especially ones containing Lewis-basic/polymerizing substituents. To address these issues and the dearth of available benzoxaborole protecting groups, bivalent molecules that would form stable ring complexes with boron via an ester linkage and dative coordination of a nitrogen were envisioned. This nitrogen coordination would mask boron’s p-orbital thereby decreasing side reactivity while also improving the solubility of these compounds in organic solvents. To this end, three benzoxaborole protecting groups were examined: 3-(N,N-dimethylamino)-1propanol 1, N-methylsalicylidenimine 2, and 2-[1-(methylimino)ethyl]phenol 3 (Figure 2). These protecting groups have exhibited outstanding stability to conditions that were completely unsuccessful or low yielding without a protecting group. Thus, these protecting groups will be very useful tools to the medicinal chemist pursuing target compounds containing a benzoxaborole. In the development of these protecting groups, compounds containing both an alcohol and amine which would form a stable, zwitterionic ring structure with the oxaborole were screened. Amino alcohol 1, which is commercially available and inexpensive, readily coordinated with benzoxaboroles in good yields upon stirring at room temperature in an ether/acetone mixture to form complexes 5a-c (Scheme 1). Letsinger et al.25-26 have reported complexes of borinic acids with 2-dimethylaminoethanol that form 5-membered ring complexes, so these were also investigated in this study with benzoxaboroles. While complexation was observed, the amine coordination did not go to completion as determined by 1H and 11B NMR and would therefore not be useful for this application. Instead, focus was shifted to the 6-membered ring complexes formed with 1. Unfortunately, rapid deprotection of complexes with 1 during aqueous workup was observed. It was hypothesized that this lability could be an asset if 1 was utilized for one-step sequences where the benzoxaborole is protected in situ without further purification, transformed, deprotected, and isolated during the reaction workup (Scheme 2).

Scheme 2. Reactions of complexes protected by 1.

Figure 2. (1) 3-(N,N-dimethylamino)-1-propanol (2) N-methylsalicylidenimine (3) 2-[1-(methylimino)ethyl]-phenol.

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The Journal of Organic Chemistry Scheme 5. Reaction scope with 11a and 9c.

Scheme 3. Synthesis conditions for benzoxaborole protection with 2 and 3

evaluating some labile phenolic o-benzylamine protecting groups (see Supporting information, Figure S2), compounds 2 and 3 were found to have the desired properties for these synthetic studies. Similar compounds have been used for the synthesis of fluorescent boranil complexes,27 as fluorescent sensors for boronic acids,28-29 and to synthesize fluorescent borinate complexes,30 but have not been used for the purpose of protecting benzoxaboroles during chemical transformations. These protecting groups are readily synthesized from cheap, commercially available salicylaldehyde or 2’-hydroxyacetophenone in excellent yields via condensation with methylamine as described in the literature (See supporting information, Scheme S1).31-32 To synthesize protected benzoxaboroles 9a-d and 10a-d, compounds 2 and 3, respectively, were refluxed with the corresponding benzoxaborole in toluene under Dean-Stark conditions (Scheme 3). All of these protected complexes were stable to slightly acidic to basic aqueous conditions, thus they were stable to aqueous extraction and purification by column chromatography. It was observed that strong aqueous acids and bases resulted in deprotection. Next, the types of reactions that could be performed in presence of these protecting groups was examined (Schemes 4-5). Due to our struggles with 4c, we were particularly interested in oxidation reactions and other methods of functionalization of alcohols that were limited by extremely poor solubility and chemical incompatibility. As stated previously, attempts to oxidize 4c without protection were either unsuccessful or led to complex mixtures. However, protection of benzoxaborole 4c with 2 and 3 allowed for the successful oxidization of the primary alcohol to the aldehyde (9c and 10c) with Dess-Martin perioidinane (DMP) in higher yields than reported in the literature after chromatography with no side reactivity observed (Scheme 4). Oxidation with PCC was attempted, but the acidic nature of the reagent, even when absorbed onto neutral alumina or buffered with sodium acetate, led to deprotection. Successful

oxidization of 9c with Collins reagent in 58% yield, provides evidence that the complex can withstand some Cr (VI) reagents. Lower yields were obtained for the protection step and no significant advantage was observed when the protecting group contained a methyl substituent (3) so we pursued reactions with 2 for the remainder of the sequence. With reasonable quantities of aldehyde 11a, the stability of protecting group 2 to reducing conditions was examined (Scheme 5). This aldehyde was subjected to reductive amination in the presence of 4-chloroaniline and sodium triacetoxyborohydride to produce amine 12 in 73% yield after chromatography. We were pleased to observe selective reduction of the aniline imine, leaving the protecting group imine intact. We believe that the protecting group imine provides conjugation when in complex with the Lewis acidic boron giving it aromatic character and providing rigidity, which explains the fluorescence activity observed with these complexes (See supporting information, Figure S1). Lastly, an acetylation on the free amine of 12 with acetic anhydride successfully provided amide 13 in 51% yield after chromatography. We would like to note some other reactions that were successful and some that suffered from some limitations. Most interestingly, we attempted to oxidize aldehyde 11a to the carboxylic acid in the presence of potassium permanganate in acetone. The protecting group remained intact, but we observed oxidation of the benzoxaborole’s benzylic carbon to a carbonyl (Scheme 5, 14). This interesting reactivity further proves that benzoxaoboroles may suffer from some synthetic limitations in the presence of certain reagents. An Appel reaction to make a benzylic bromide was attempted with PPh3 and N-bromosuccinimide, which was successful as determined in the crude NMR. Unfortunately, chromatographic separation of the prod-

Scheme 4. Oxidation reactions with complexes protected by 2 and 3.



uct from the triphenylphosphine oxide byproduct was challenging and led to a 36% yield. Polystyrene-supported PPh3 could be an alternative to increase the yields for these reactions. Additionally, oxidation of 9c with 2-iodoxybenzoic acid (IBX) was successful. Finally, the optimal deprotection conditions necessary for complexes with 2 were determined. Since some aqueous acidic conditions led to deprotection of the complexes, 1M aqueous HCl in THF was used to promote deprotection (Scheme 6). The complexes smoothly deprotected under these conditions at room temperature in two to three hours and did not require column chromatography to re-isolate the free benzoxaborole. The presence of acid hydrolyses the free imine to the aldehyde, which can be removed via extraction with aqueous sodium bisulfite. This is advantageous since column chromatography with unprotected benzoxaboroles typically results in low recovered yields.

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or oven-dried glassware. 3-(N,N-dimethylamino)-1-propanol (1) was purchased from Fisher Scientific and used without further purification. Polystyrene-supported triphenylphosphine (PS-PPh3) was obtained from Biotage. All other commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Oakwood Chemicals, or Fisher Scientific and used without further purification. Dry tetrahydrofuran (THF) and dichloromethane (DCM) were obtained from a Pure Solv MD-5 Solvent Purification System. Dichloroethane (DCE) and acetonitrile (ACN) were dried over activated 4Å molecular sieves (Sigma-Aldrich) for 3 days prior to use.33 All other solvents were obtained from Sigma-Aldrich or Fisher Scientific and used without further purification. Concentration refers to solvent removal on a rotary evaporator followed by further evacuation with a two-stage mechanical pump. NMR spectra data were obtained on a Bucker Avance 400 MHz NMR spectrometer. Chemical shifts are reported in parts per million (ppm) against tetramethylsilane (TMS) standard or residual solvent signal. 11B Spectra are reported in ppm using BF3ꞏOEt2 as an external standard. 13C resonances next to boron are typically not observed due to quadrupolar relaxation. Mass spectra were obtained on a Thermo-Fisher Exactive Orbitrap Mass Spectrometer using Matrix-Assistant Inlet Ionization (MAII) as an ionization source (3-nitrobenzonitrile matrix).34-35 Chemical ionization (CI) was necessary for one compound. Thin layer chromatography was performed on Sorbtech Silica XG Aluminumbacked TLC plates. TLC plates were visualized under a UV lamp (short and long wave). Flash column chromatography was performed with Sorbtech silica (Porosity 60 Å, Particle size 4063 µm, 230 x 400 mesh). Columns that were run with triethylamine (TEA) were neutralized with 2-3 column volumes of stated mobile phase before loading sample. As a note, some protected complexes are very hygroscopic. Solids that have absorbed moisture from the air may be dissolved in a minimum volume of acetone, precipitated with hexane, and vacuum-dried to afford a dry solid.

Scheme 6. Deprotection conditions for complexes protected by 2.

These reported studies demonstrate that protection of the benzoxaborole moiety is necessary in certain circumstances, including for reactions that require incompatible reagents and to increase the solubility of certain benzoxaboroles. This is especially evident in the case of 4c, which is not readily soluble in most common organic solvents, including DMF and DMSO. Also, its chemical incompatibility with oxidizing agents proves problematic since these are important synthetic transformations. This work has shown that protection of benzoxaboroles with 1 can be useful in one-step sequences with in situ protection and subsequent deprotection during aqueous workup. Protection with 1 improved chemoselectivity by masking boron’s p-orbital, thereby increasing yields and completely eliminating the formation of complex reaction mixtures. Protection of benzoxaboroles with 2 and 3 have proven useful in multi-step synthetic sequences. These complexes exhibit excellent stability to a) oxidation, b) reduction, and c) substitution conditions. When unprotected, the benzoxaboroles were unreactive or produced complex product mixtures. We have also successfully performed common purification techniques (i.e. extraction and chromatography) with the added benefit of increased solubility in organic solvents. In summary, these protecting groups will increase the types of chemical transformations that can be achieved in the presence of the benzoxaborole moiety.

N-methylsalicylidenimine (2). Modified from the literature.31 Salicylaldehyde (6 mL, 6.9 g, 56 mmol) was dissolved in absolute EtOH (150 mL) in a round-bottom flask. To the mixture was added a solution of MeNH2 (33 wt % in EtOH, 14 mL, 112 mmol) and the reaction immediately became a bright yellow color. The yellow mixture was stirred at rt for 8 h and solvent was removed to afford a yellow oil 2 (7.6 g, quant.) that was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 13.4 (br s, 1H), 8.34 (s, 1H), 7.29 (t, 1H, J=7.7), 7.24 (d, 1H, J=7.5), 6.94 (d, 1H, J=8.4), 6.86 (t, 1H, J=7.4), 3.48 (s, 3H). Spectra match those in the literature.31 2-[1-(methylimino)ethyl]phenol (3). Modified from the literature.32 2’-hydroxyacetophenone (5 mL, 5.65 g, 41.5 mmol) was added to a round-bottom flask and dissolved in absolute EtOH (120 mL). A solution of MeNH2 (33 wt % in EtOH, 16 mL, 128 mmol) was added and the mixture was heated to 50 °C for 5 h. The reaction was cooled to rt and stirred overnight. The solvent was removed to afford a yellow solid 3 (6.2 g, quant.), which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.49 (dd, 1H, J=1.6, 8.0), 7.29 (ddd, 1H, J=1.6, 7.0, 7.8), 6.92 (dd, 1H, J=1.2, 8.4), 6.75 (ddd, 1H, J= J=1.2, 7.0, 8.0), 3.34 (s, 3H), 2.34 (s, 3H). Spectra match those in the literature.32

Experimental Section General Procedures Protection reactions were performed under an ambient atmosphere unless otherwise specified. Moisture and/or air-sensitive reactions were performed under an argon atmosphere in flame-


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Synthesis of 3-cyanobenzoxaborole (4b) 4-methyl-3-bromobenzonitrile (S1). Synthesized from p-tolunitrile by the literature procedure.36 3-bromo-4-hydroxmethylbenzonitrile (S2). An argonflushed round-bottom flask was charged with S1 (9.9 g, 51 mmol), N-bromosuccinimide (13.6 g, 76.5 mmol), benzoyl peroxide (61 mg, 0.25 mmol), and CCl4 (250 mL). The mixture was brought to reflux for 6 h and then filtered upon completion with CCl4 (2 x 20 mL). The resulting crude oil was suspended in dioxane:water (1:1, 300 mL), sodium carbonate (5 g) was added, and the mixture was brought to reflux overnight. The product mixture was extracted against EtOAc (3 x 75 mL) and concentrated to solid 4, which was used in the next reaction without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 1H), 7.66 (q, 2H), 4.80 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 145.1, 135.4, 131.2, 128.4, 121.8, 117.2, 112.6, 64.2. Spectra match those in the literature.37 3-bromo-4-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl] benzonitrile (S3). To a round-bottom flask containing crude S2 was added dry DCM (120 mL). This was stirred, then p-toluenesulfonic acid (1.30 g, 6.8 mmol, 13 mol% from S1) was added quickly followed by 3,4-Dihydro-2H-pyran (6.5 mL, 76.6 mmol, 1.5 eq from S1) at rt. The resulting solution was stirred overnight. The reaction was quenched with saturated NaHCO3 (150 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 150 mL) and combined organics were washed with water and brine. The organics were concentrated and subjected to flash chromatography (SiO2, Gradient 20:1 Hexanes:EtOAc-4:1 Hexanes:EtOAc) to afford S3 (4.94 g, 32% from S1) as a clear liquid. 1H NMR (CDCl3, 400 MHz) δ 7.67 (d, 1H, J=8), 7.61 (d, 1H, J=8), 4.85 (d, 1H, J=15), 4.78 (m, 1H), 4.57 (d, 1H, J=15), 3.86 (s, 1H), 3.56 (m, 1H), 1.5-1.8 (m, 7H). HRMS (MAII) m/z: calc. for C13H15BNO2 [M+H]+ 296.0281, found 296.0255. 3-cyanobenzoxaborole (4b). To a flame-dried round-bottom flask was added S3 (4.94 g, 16.6 mmol) and THF (60 mL). The flask was cooled to -78 ̊C and n-BuLi solution (2.5 M in hexanes, 7.3 mL, 18.3 mmol) was added dropwise via syringe over 15 min. After the addition, the mixture was stirred at -78 ̊C for 30 min. B(OiPr)3 (4.0 mL, 17.3 mmol) was added via syringe at -78 ̊C and the reaction was warmed to rt to stir for 3 h. Then, the reaction was cooled to 0 ̊C, quenched with water (20 mL), diluted with EtOAc, and extracted (3 x 75 mL). The combined organics were dried over Na2SO4 and concentrated to a crude residue. Without purification, the residue was dissolved in MeOH (75 mL) and p-TSA (1.5 g, 8.3 mmol) was added. The mixture was stirred overnight at rt and then concentrated to an oil. The residue was quickly dissolved in EtOAc and extracted with 1M hydroxide (2 x 30 mL). The aqueous layer was acidified with c. HCl and back extracted with EtOAc (3 x 75 mL). The combined organics were dried and concentrated to produce a yellow solid S3 (873 mg, 33%), which was analytically pure and did not require further purification. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 7.92 (d, 2H, J=8), 7.64 (d, 1H, J=8), 5.07 (s, 2H). 11B NMR (DMSO-d6, 128 MHz) δ 32.3. Spectra match those in the literature.37

Synthesis of 3-hydroxymethylbenzoxaborole (4c) 2-bromo-terephthalic acid (S4). Was prepared via literature procedures and all spectra match those reported.38 2-bromo-1,4-bis(hydroxymethyl)benzene (S5). A flamedried round-bottom flask was charged with S4 (5.5 g, 22.4 mmol) and fitted with a pressure-equalizing addition funnel. The solid was dissolved in THF (100 mL) and cooled to 0 °C. BH3ꞏTHF (1M in THF, 50 mL, 50 mmol) was added dropwise from the addition funnel to the reaction mixture over 45 min. This mixture was stirred at 0 °C for 1 h, warmed to rt, and stirred for 3 h. The reaction was quenched slowly with the addition of MeOH (50 mL) and the mixture was concentrated. The solid residue was dissolved in EtOAc and water (40 mL) and transferred to a separatory funnel. The aqueous layer was extracted with EtOAc (3 x 75 mL), combined organics were washed with brine, dried over Na2SO4 and concentrated to afford a white solid S5 (3.89 g, 80%) which needed no further purification. 1H NMR (DMSO-d6, 400 MHz) δ 7.49 (m, 2H), 7.29 (d, 1H, J=7.8), 5.39 (t, 1H), 5.28 (t, 1H), 4.48 (t, 4H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ 143.3, 139.1, 129.7, 127.9, 125.5, 120.8, 62.4, 61.8. Spectra match those in the literature.19 Alcohol protection with Dihydropyran (S6). Modified from the literature.19 To a round-bottom flask containing S5 (3.89 g, 17.9 mmol) was added dry DCM (100 mL) and the solid was suspended by stirring. Then, p-toluenesulfonic acid (390 mg, 2.05 mmol) was added quickly followed by DHP (4.2 mL, 49.5 mmol) at rt. The mixture became homogeneous upon vigorous stirring and the resulting solution was stirred overnight. The reaction was quenched with saturated NaHCO3 (30 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 75 mL) and combined organics were washing with water and brine. The organics were concentrated and the residue was subject to flash chromatography (SiO2, 9:1 Hexanes:EtOAc) to afford a clear oil 5 (5.22 g, 75%). 1H NMR (CDCl3, 400 MHz) 7.56 (s, 1H), 7.46 (d, 2H, J=7.8), 7.28 (d, 2H, J=11.7), 4.69-4.82 (overlapping d and t, 4H), 4.47 and 4.58 (2x d, 1H each), 3.88 (m, 2H), 3.54 (m, 2H), 1.62-.187 (m, 12H). 13C{1H} NMR (CDCl3, 100 MHz) δ 139.3, 136.9, 131.6, 129.0, 126.6, 98.3, 97.7, 62.17, 62.14, 30.5, 30.4, 25.44, 25.42, 19.3, 19.2. Spectra match those in the literature.19 Synthesis of 5-hydroxymethylbenzoxaborole (4c). Modified from the literature.19 To a flame-dried round-bottom flask was added S6 (5.2 g, 13.5 mmol) and THF (50 mL). The flask was cooled to -78 ̊C and n-BuLi solution (2.5 M in hexanes, 5.6 mL, 14 mmol) was added dropwise via syringe over 30 min. After the addition, the mixture was stirred at -78 ̊ C for 30 min. B(OiPr)3 (3.2 mL, 15.1 mmol) was added via syringe at -78 ̊C and the reaction was warmed to rt to stir for 3 h. Then, the reaction was cooled to 0 ̊C, quenched with saturated NH4Cl (40 mL), and diluted with water/EtOAc. The aqueous layer was extracted with EtOAc (3 x 50 mL) and combined organics were washed with brine, dried over Na2SO4, and concentrated. The crude residue was dissolved in MeOH (100 mL) and p-TSA (1.39 g, 7.30 mmol) was added. The mixture was stirred for 5 h at rt and then concentrated to an oil. The residue was quickly dissolved in EtOAc and extracted (3 x 50 mL) against water (~40 mL). Combined organics were washed with brine and dried over Na2SO4. Solvent removal produced an off-white solid, which was suspended in hexanes, filtered, and washed with diethyl ether (3 x 20 mL) to produce a white solid 4c (1.7



g, 77%). The compound was analytically pure and did not require further purification. 1H NMR (MeOD, 400 MHz) δ 7.38 (s, 1H), 7.40 (d, 1H, J=7.8), 7.34 (d, 1H, J=7.8), 4.95 (s, 2H), 4.52 (s, 2H). 11B NMR (MeOD, 128 MHz) δ 32.0. Spectra match those in the literature.19

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Protection of benzoxaborole with salicimine (9a). A roundbottom flask was charged with a stir bar, 4a (153 mg, 1.14 mmol), and a solution of 2 (196 mg, 1.45 mmol) in toluene (8 mL). The flask was fitted with a Dean-Stark trap and the suspension was brought to reflux for 5 h. The reaction was then cooled to rt, concentrated, and the resulting residue was subjected to flash chromatography (SiO2, EtOAc w/ 0.5% TEA) to afford 9a (235 mg, 82%). White solid; mp 158-160ºC; 1H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.49 (t, 1H, J=7.6), 7.37 (d, 1H, J=7), 7.30 (m, 2H), 7.21 (m, 2H), 7.02 (d, 1H, J=8.4), 6.88 (t, 1H, J=7.5), 5.20 (d, 1H, J=13.8), 5.04 (d, 1H, J=13.8), 3.18 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 162.4, 160.2, 148.9, 137.4, 130.8, 128.5, 127.7, 126.5, 120.6, 119.8, 118.8, 115.5, 72.3, 42.8, 11B NMR (CDCl3, 128 MHz) δ 8.9. HRMS (MAII) m/z: calc. for C15H15BNO2 [M+H]+ 252.1190, found 252.1181.

3-Nitrobenzoxaborole (4d) was prepared as per the literature and all spectra match those reported.18 Protection of benzoxaborole with N,N-dimethylaminopropanol (5a). To an open round-bottom flask was added 4a (200 mg, 1.49 mmol), anhydrous Na2SO4 (1.68 g, 11.8 mmol), and ether:acetone (1:1 mixture, 6 mL). The mixture was stirred vigorously and 1 (177 µL, 1.50 mmol) was added at rt. Stirring continued for 5.5 h at rt, then the mixture was diluted with EtOAc (~5 mL) and filtered. The filter cake was washed with EtOAc (3 x 8 mL) and the filtrate was concentrated to afford 5a (230 mg, 98%). The compound was analytically pure and did not require further purification. Hygroscopic white solid; 1H NMR (CDCl3, 400 MHz) δ 7.52 (br d, 1H, J=6.4), 7.16 (br m, 3H), 5.04 (s, 2H), 4.05 (br t, 2H, J=5.5), 3.15 (br s, 2H), 2.44 (s, 6H), 1.92 (br t, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 150.0, 129.6, 127.4, 125.9, 120.6, 71.9, 60.1, 58.3, 45.4, 24.1. 11 B NMR (CDCl3, 128 MHz) δ 10.3. HRMS (MAII) m/z: calc. for C12H19BNO2 [M+H]+ 220.1503, found 220.1514.

Protection of 6-cyanobenzoxaborole with salicimine (9b). A round-bottom flask was charged with a stir bar, 4b (165 mg, 1.04 mmol), and a solution of 2 (196 mg, 1.45 mmol) in toluene (15 mL). The flask was fitted with a Dean-Stark trap and the mixture was brought to reflux for 5 h. The reaction was then cooled to rt, concentrated to a minimum amount of toluene (12 mL), and precipitated with hexane. After cooling to promote further precipitation, the solid was filtered and washed with cold hexane (3 x 5 mL) to afford 9b (221 mg, 77%). The compound was analytically pure and did not require further purification. Pale yellow solid; mp 197-201ºC; 1H NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.66 (s, 1H), 7.56 (t, 1H, J=7.9), 7.35 (d, 1H, J=7.6), 7.31 (d, 1H, J=7.8), 7.01 (d, 1H, J=8.4), 6.93 (t, 1H, J=7.4), 5.22 (d, 1H, J=15.2), 5.06 (d, 1H, J=15.2), 3.18 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ 163.1, 159.7, 154.1, 138.0, 132.8, 131.6, 131.0, 121.5, 120.0, 119.6, 119.3, 115.3, 110.3, 72.1, 42.7. 11B NMR (CDCl3, 128 MHz) δ 8.4. HRMS (MAII) m/z: calc. for C16H14BN2O2 [M+H]+ 277.1143, found 277.1135.

Protection of 6-cyanobenzoxaborole with N,N-dimethylaminopropanol (5b). To an open round-bottom flask was added 4b (161 mg, 1.01 mmol), anhydrous Na2SO4 (1.20 g, 8.47 mmol), and ether:acetone (1:1 mixture, 10 mL). The mixture was stirred vigorously and 1 (120 µL, 1.02 mmol) was added at rt. Stirring continued for 5.5 h at rt, then the mixture was diluted with EtOAc (~5 mL) and filtered. The filter cake was washed with EtOAc (3 x 8 mL) and the filtrate was concentrated to afford 5 (223 mg, 90%). The compound was analytically pure and did not require further purification. Hygroscopic, pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.79 (s, 1H), 7.52 (d, 1H, J=7.8), 7.25 (d, 1H, J=8.4), 5.04 (s, 2H), 3.99 (br s, 2H), 3.15 (br s, 2H), 2.42 (br s, 6H), 1.93 (br s, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 155.4, 133.6, 131.46, 121.5, 120.1, 109.8, 71.8, 60.0, 58.4, 45.4, 23.9. 11B NMR (CDCl3, 128 MHz) δ 9.8. HRMS (MAII) m/z: calc. for C13H18BN2O2 [M+H]+ 245.1456, found 245.1447.

Protection of 6-hydroxymethylbenzoxaborole with salicimine (9c). A round-bottom flask was charged with a stir bar, 4c (415 mg, 2.53 mmol), and a solution of 2 (400 mg, 2.96 mmol) in toluene (10 mL). The flask was fitted with a Dean-Stark trap and the suspension was brought to reflux for 5 h. The reaction was then cooled to rt and hexane (30 mL) was added. The resulting precipitate was filtered, washed with cold hexanes (3 x ~10 mL), and dried in vacuo to afford 9c (711 mg, 87%). The compound was analytically pure and did not require further purification. White, fluffy solid; mp 179-183ºC; 1H NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.49 (t, 1H, J=7.8), 7.36 (s, 1H), 7.31 (d, 2H, J=8.2), 7.29 (d, 1H, J=9), 7.20 (d, 1H, J=7.6), 7.00 (d, 1H, J=8.4), 6.88 (t, 1H, J=7.5), 5.18 (d, 1H, J=13.9), 5.03 (d, 1H, J=13.8), 4.64 (s, 2H), 3.17 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 162.5, 160.0, 148.6, 139.1, 137.5, 130.9, 127.2, 127.1, 120.7, 119.7, 118.9, 115.4, 72.1, 65.8, 42.8. 11B NMR (CDCl3, 128 MHz) δ 8.8. HRMS (MAII) m/z: calc. for C16H17BNO3 [M+H]+ 282.1296, found 282.1288.

Protection of 6-hydroxymethylbenzoxaborole with N,N-dimethylaminopropanol (5c). To an open round-bottom flask was added 4c (200 mg, 1.22 mmol), anhydrous Na2SO4 (1.3 g, 9.15 mmol), and ether:acetone (1:1 mixture, 10 mL). The mixture was stirred vigorously and 1 (144 µL, 1.22 mmol) was added at rt. Stirring continued for 5.5 h at rt, then the mixture was diluted with EtOAc (~5 mL) and filtered. The filter cake was washed with EtOAc (3 x 8 mL) and the filtrate was concentrated to afford 5c (301 mg, 98%. The compound was analytically pure and did not require further purification. Hygroscopic white solid; 1H NMR (CDCl3, 400 MHz) δ 7.51 (br s, 1H), 7.25 (br s, 1H), 7.13 (d, 1H, J=7.6), 5.00 (s, 2H), 4.66 (br s, 2H), 3.99 (br t, 2H, J=4.8), 3.09 (br s, 2H), 2.41 (s, 6H), 1.88 (br t, 2H, J=5.2). 13C{1H} NMR (CDCl3, 100 MHz) δ 149.8, 138.6, 128.6, 127.0, 120.6, 71.6, 65.7, 60.2, 58.3, 45.4, 24.3. 11 B NMR (CDCl3, 128 MHz) δ 10.2. HRMS (MAII) m/z: calc. for C13H21BNO3 [M+H]+ 250.1609, found 250.1611.

Protection of 6-nitrobenzoxaborole with salicimine (9d). A round-bottom flask was charged with a stir bar, 4d (207 mg, 1.18 mmol), and a solution of 2 (233 mg, 1.73 mmol) in toluene (15 mL). The flask was fitted with a Dean-Stark trap and the solution was brought to reflux overnight. The reaction was then


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cooled to rt, concentrated to an oil, and precipitated with hexanes. The mixture was concentrated again and the solid was subject to column chromatography (SiO2, 4:1 EtOAc:hexanes with 1% triethylamine) to afford 9d (298 mg, 85%). Pale yellow solid; mp 175-178ºC; 1H NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 8.19 (s, 1H), 8.15 (d, 1H, J=8.2), 7.54 (t, 1H, J=7.8), 7.35 (t, 2H, J=6.9), 7.00 (d, 1H, J=8.4), 6.93 (t, 1H, J=7.6), 5.24 (d, 1H, J=15.5), 5.09 (d, 1H, J=15.5), 3.19 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 163.3, 159.7, 156.2, 147.6, 138.1, 131.1, 123.8, 123.5, 121.4, 119.6, 119.4, 71.9, 42.7. 11B NMR (CDCl3, 128 MHz) δ 8.4. HRMS (MAII) m/z: calc. for C15H14BN2O4 [M+H]+ 297.1041, found 297.1058.

NMR (CDCl3, 400 MHz) δ 7.58 (d, 1H, J=8.1), 7.46 (t, 1H, J=7.7), 7.31 (s, 2H), 7.27 (d, 1H, J=7.8), 7.21 (d, 1H, J=7.6), 7.02 (d, 1H, J=8.3), 6.88 (t, 1H, J=7.7), 5.18 (d, 1H, J=13.9), 5.03 (d, 1H, J=13.9), 4.63 (s, 2H), 3.08 (s, 3H), 2.57 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ 170.2, 159.2, 148.6, 138.9, 136.3, 127.9, 127.2, 127.0, 120.8, 120.6, 118.6, 117.2, 71.8, 65.9, 37.0, 16.3. 11B NMR (CDCl3, 128 MHz) δ 8.7. HRMS (MAII) m/z: calc. for C17H19BNO3 [M+H]+ 296.1453, found 296.1446. Protection of 6-nitrobenzoxaborole with 2-[1-(methylimino)ethyl]phenol (10d). A round-bottom flask was charged with a stir bar, 4d (184 mg, 1.23 mmol), 3 (203 mg, 1.12 mmol), and toluene (25 mL). The flask was fitted with a Dean-Stark trap and the mixture was brought to reflux for 5 h. The reaction was then cooled to rt, concentrated to a minimum amount of toluene (1-2 mL), and hexane (30 mL) was added. The resulting precipitate was filtered, washed with cold hexanes (3 x ~10 mL), and dried in vacuo to afford 10d (288 mg, 83%). The compound was analytically pure and did not require further purification. Yellow solid; mp 249-251ºC; 1H NMR (CDCl3, 400 MHz) δ 8.14 (2 x s, 2H), 7.62 (d, 1H, J=8.0), 7.49 (t, 1H, J=7.8), 7.33 (d, 1H, J=8.2), 7.01 (d, 1H, J=8.4), 6.93 (t, 1H, J=7.6), 5.24 (d, 1H, J=15.5), 5.10 (d, 1H, J=15.5), 3.09 (s, 3H), 2.62 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 158.7, 156.1, 136.9, 128.1, 123.7, 123.3, 121.4, 120.4, 119.1, 71.6, 36.9, 16.4. 11 B NMR (CDCl3, 128 MHz) δ 8.2. HRMS (MAII) m/z: calc. for C16H16BN2O4 [M+H]+ 311.1198, found 311.1190.

Protection of benzoxaborole with 2-[1-(methylimino)ethyl]phenol (10a). A round-bottom flask was charged with a stir bar, 4a (910 mg, 6.81 mmol), 3 (1.22 g, 8.17 mmol) and toluene (10 mL). The flask was fitted with a DeanStark trap and the suspension was brought to reflux for 5 h. The reaction was then cooled to rt, concentrated to a minimum amount of toluene (1-2 mL), and hexane (30 mL) was added. The resulting precipitate was filtered, washed with cold hexanes (3 x ~10 mL), and dried in vacuo to afford 10a (1.0 g, 55%). The compound was analytically pure and did not require further purification. Off-white solid; mp 159-161ºC; 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, 1H, J=8), 7.45 (t, 1H, J=7.9), 7.30 (m, 2H), 7.19 (m, 2H), 7.03 (d, 1H, J=8.3), 6.88 (t, 1H, J=7.6), 5.20 (d, 1H, J=13.8), 5.04 (d, 1H, J=13.8), 3.09 (s, 3H), 2.57 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ 170.0, 159.3, 148.8, 136.2, 128.3, 127.9, 127.6, 126.4, 120.6, 118.5, 117.3, 72.0, 37.0, 16.3. 11 B NMR (CDCl3, 128 MHz) δ 8.7. HRMS (MAII) m/z: calc. for C16H17BNO2 [M+H]+ 266.1347, found 266.1371.

DIBAL-H reduction of nitrile (6). To a round-bottom flask containing 5b (212 mg, 0.865 mmol) was added DCM (7 mL) and the solution was cooled to -78 ºC. DIBAL-H (1M in Hexane, 1.3 mL, 1.3 mmol) was added dropwise via syringe over 15 min. After addition, the reaction was stirred for 30 min at 78 ºC and then warmed to rt over 8 h. The reaction was quenched with EtOAc (12 mL) and 1M HCl (8 mL), which also promoted deprotection. The mixture was transferred to a separatory funnel with additional EtOAc (~15 mL) and water (5 mL). The mixture was extracted and the aqueous layer was treated with additional EtOAc (2 x 15 mL). The combined organics were washed with brine, dried over Na2SO4, and filtered. Concentration afforded 6 (111 mg, 79%) which was analytically pure and did not require further purification. Off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 10.06 (s, 1H), 9.45 (s, 1H, B-OH), 8.27 (s, 1H), 8.00 (d, 1H, J=7.8), 7.63 (d, 1H, J=7.8), 5.08 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ 193.6, 160.7, 135.8, 132.8, 132.0, 122.8, 70.5. 11B NMR (DMSO-d6, 128 MHz) δ 31.6. HRMS (MAII) m/z: calc. for C8H8BO3 [M+H]+ 163.0561, found 163.0568. All spectra match those reported.19

Protection of 6-cyanobenzoxaborole with 2-[1-(methylimino)ethyl]phenol (10b). A round-bottom flask was charged with a stir bar, 4b (150 mg, 0.940 mmol), 3 (196 mg, 1.32 mmol), and toluene (10 mL). The flask was fitted with a Dean-Stark trap and the suspension was brought to reflux for 5 h. The reaction was then cooled to rt, concentrated to a minimum amount of toluene (1-2 mL), and hexane (30 mL) was added. The resulting precipitate was filtered, washed with cold hexanes (3 x ~10 mL), and dried in vacuo to afford 10b (100 mg, 36%). The compound was analytically pure and did not require further purification. Yellow solid; mp 235-239ºC; 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, 1H, J=8.1), 7.58 (s, 1H), 7.54 (d, 1H, J=7.8), 7.49 (t, 1H, J=7.8), 7.29 (d, 1H, J=7.8), 7.01 (d, 1H, J=8.3), 6.93 (t, 1H, J=7.7), 5.21 (d, 1H, J=15.1), 5.07 (d, 1H, J=15.1), 3.07 (s, 3H), 2.60 (s, 3H), 13C{1H} NMR (CDCl3, 100 MHz) δ 171.0, 158.8, 154.0, 136.8, 132.7, 131.4, 128.1, 121.5, 120.5, 120.1, 119.1, 117.1, 110.2, 71.8, 36.9, 16.4, 11 B NMR (CDCl3, 128 MHz) δ 8.3. HRMS (MAII) m/z: calc. for C17H16BN2O2 [M+H]+ 291.1299, found 291.1325.

Oxidation of alcohol with MnO2 (6). In a round-bottom flask, 5c (211 mg, 0.850 mmol) was dissolved in dry DCM (6 mL) and MnO2 (1.2 g, 13.8 mmol) was added at rt. The mixture was stirred for 32 h at rt, filtered over celite, and the filter cake was washed with EtOAc (3 x 15 mL). The filtrate was transferred to a separatory funnel and washed with 1M HCl (~20 mL) to promote deprotection. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 6 (99 mg, 72%) which did not require further purification. Off-white solid. Characterization exactly matches the previous procedure for 6.

Protection of 6-hydroxymethylbenzoxaborole with 2-[1(methylimino)ethyl]phenol (10c). A round-bottom flask was charged with a stir bar, 4c (403 mg, 2.45 mmol), 3 (435 mg, 2.91 mmol), and toluene (10 mL). The flask was fitted with a Dean-Stark trap and the suspension was brought to reflux for 5 h. The reaction was then cooled to rt and hexane (30 mL) was added. The resulting precipitate was filtered, washed with cold hexanes (3 x ~10 mL), and dried in vacuo to afford 10c (723 mg, 87%). The compound was analytically pure and did not require further purification. White, fluffy solid; mp 178-181ºC; 1H



Synthesis of 6-iodomethylbenzoxaborole (7). To a dry roundbottom flask with a stir bar was added 5c (245 mg, 0.983 mmol) and NaI (460 mg, 3.06 mmol). Chlorotrimethylsilane (375 µL, 2.95 mmol) was added dropwise over 5 min at 0 °C, allowed to stir at 0°C for 5 min, and warmed to rt for 3 h. The mixture was concentrated, dissolved in ether (25 mL) and 1M HCl (~10 mL), and transferred to a separatory funnel. The aqueous layer was extracted once more with ether (25 mL) and combined organics were washed once with with sat’d NaHSO3 and once with sat’d brine. The organic layer was dried over Na2SO4, filtered, concentrated, and dried in vacuo to afford 7 (181 mg, 72%) which did not require further purification. White solid; mp 147-151ºC; 1 H NMR (CDCl3, 400 MHz) δ 7.75 (s, 1H), 7.51 (d, 1H, J=7.8), 7.29 (d, 1H, J=7.9), 5.06 (s, 2H), 4.52 (s, 2H). 13C{1H} NMR (CDCl3, 100 MHz) δ 153.5, 138.5, 131.7, 130.5, 121.6, 71.2, 5.4. 11B NMR (CDCl3, 128 MHz) δ 32.2. HRMS (MAII) m/z: calc. for C8H8BO2 [M-I]+ 147.0612, found 147.0623.

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Collins Reagent oxidation of salicylimine-protected alcohol (11a). To a dry round-bottom flask containing a stir bar and dry DCM (5 mL) was added pyridine (340 µL, 4.20 mmol). The flask was flushed with argon, cooled to 0 ºC, and CrO3 (219 mg, 2.19 mmol) was added in one portion. The mixture was allowed to stir for 45 min at 0 ºC after which 9c (100 mg, 0.37 mmol) was added in one portion. The mixture was stirred at 0ºC for 1 h, filtered over silica, and washed acetone (5 x 5 mL). The filtrate was concentrated and the resulting brown solid was subjected to column chromatography (SiO2, EtOAc with 1.5% triethylamine) to afford 11a (60 mg, 58%) as a hygroscopic yellow solid. Characterization exactly matches the previous procedure for 11a. Dess-Martin Oxidation of -protected alcohol (11b). Synthesized by the same procedure as 11a from 10c (300 mg, 1.01 mmol), Dess-Martin perioidinane (519 mg, 1.21 mmol), anhydrous NaHCO3 (254 mg, 3.03 mmol) in dry DCM (10 mL) and dry THF (4 mL) to produce 11b (148 mg, 50%), which was purified by column chromatography (SiO2, EtOAc with 1.5% triethylamine). Hygroscopic yellow solid; 1H NMR (CDCl3, 400 MHz) δ 9.96 (s, 1H), 7.83 (s, 1H), 7.79 (d, 1H, J=7.7), 7.60 (d, 1H, J=8.1), 7.46 (t, 1H, J=7.7), 7.36 (d, 1H, J=7.8), 7.01 (d, 1H, J=8.3), 6.89 (t, 1H, J=7.7), 5.25 (d, 1H, J=15.3), 5.09 (d, 1H, J=15.3), 3.07 (s, 3H), 2.59 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 193.0, 170.8, 159.0, 156.3, 136.6, 135.5, 130.3, 129.9, 128.1, 121.3, 120.5, 118.9, 117.0, 71.9, 36.9, 16.3. 11B NMR (CDCl3, 128 MHz) δ 8.5. HRMS (MAII) m/z: calc. for C17H17BNO3 [M+H]+ 294.1296, found 294.1274.

Mitsunobu reaction (8). To a round-bottom flask containing 5c (165 mg, 0.662 mmol) was added PS-PPh3 (2.32 mmol/g loading, 730 mg, 1.69 mmol) and phthalimide (150 mg, 1.02 mmol). THF (6 mL) was added, cooled to 0 ºC, and DIAD (195 µL, 1.02 mmol) was added dropwise over 15 min. The reaction was stirred for an additional 15 min at 0 ºC and warmed to rt for 24 h. The mixture was filtered, resin washed with EtOAc (3 x 10 mL), and the filtrate was washed with 1M HCl (5 mL) in a separatory funnel to promote deprotection. The organic phase was absorbed onto silica and subjected to flash chromatography (SiO2, 20:1 DCM:Acetone→1:1 DCM:acetone) to afford 8 (124 mg, 64%). White solid; mp 152-155ºC; 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 2H), 7.80 (s, 1H), 7.70 (m, 2H), 7.57 (dd, 1H, J=1.6, 7.8), 7.30 (d, 1H, J=7.8), 5.06 (s, 2H), 4.91 (s, 2H). 13 C{1H} NMR (CDCl3, 100 MHz) δ 168.0, 153.5, 135.3, 134.0, 132.0, 131.5, 130.4, 128.4, 123.3, 121.4, 71.0, 41.5. 11B NMR (CDCl3, 128 MHz) δ 32.7. HRMS (CI, Negative mode) m/z: calc. for C16H1210BNO4 [M]- 292.0895 (Monoisotope), found 292.0881.

Reductive amination (12). In a round-bottom flask, 11a (103 mg, 0.369 mmol) was dissolved in dry DCE (4 mL). 4-chloroaniline (50 mg, 0.392 mmol) and AcOH (20 µL, 0.349 mmol) were added and the mixture was stirred at rt for 8 h. After this time, sodium triacetoxyborohydride (130 mg, 0.613 mmol) was added and stirred at rt for 16 h. The mixture was concentrated to a residue that was absorbed onto silica and subjected to flash chromatography (SiO2, 20:1 DCM:acetone with 1% triethylamine) to afford 12 (105 mg, 73%). Yellow solid; mp 153-156 º C; 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.50 (t, 1H, J=7.8), 7.35 (s, 1H), 7.30 (t, 2H, J=7.8), 7.20 (d, 1H, J=7.6), 7.08 (d, 2H, J=8.6), 7.02 (d, 1H, J=8.4), 6.89 (t, 1H, J=7.5), 6.55 (d, 2H, J=8.6), 5.20 (d, 1H, J=13.8), 5.03 (d, 1H, J=13.8), 4.24 (s, 2H), 3.98 (br s, 1H), 3.17 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 162.5, 160.0, 148.4, 146.8, 137.5, 136.7, 130.9, 128.9, 127.8, 127.5, 121.7, 120.9, 119.7, 118.9, 115.4, 113.8, 72.1, 48.7, 42.9. 11B NMR (CDCl3, 128 MHz) δ 8.8. HRMS (MAII) m/z: calc. for C22H21BClN2O2 [M+H]+ 391.1379, found 391.1385, m/z: calc. for C16H15BNO2 [M-N(4ClPh)]+ 264.1190, found 264.1193.

Dess-Martin Oxidation of salicylimine-protected alcohol (11a). A round-bottom flask containing a stir bar was charged with Dess-Martin perioidinane (550 mg, 1.29 mmol), anhydrous NaHCO3 (259 mg, 3.08 mmol), and 9c (305 mg, 1.08 mmol). Dry DCM (10 mL) and dry THF (4 mL) were added to the round-bottom flask at rt and the mixture was stirred at rt for 4 h. The reaction was quenched with sat’d Na2S2O3 (6 mL), stirred for 5 min, and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with DCM (2 x 15 mL). Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was subject to column chromatography (SiO2, EtOAc with 1.5% triethylamine) to afford 11a (247 mg, 82%). Hygroscopic yellow solid; 1H NMR (CDCl3, 400 MHz) δ 9.98 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.81 (d, 1H, J=7.7), 7.52 (t, 1H, J=7.8), 7.37 (d, 1H, J=8), 7.34 (d, 1H, J 7.01 (d, 1H, J=8.4), 6.92 (t, 1H, J=7.6), 5.25 (d, 1H, J=15.3), 5.09 (d, 1H, J=15.3), 3.19 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 163.0, 159.9, 156.3, 137.9, 135.5, 131.0, 130.4, 130.1, 121.3, 119.6, 119.2, 115.3, 72.1, 42.7. 11B NMR (CDCl3, 128 MHz) δ 8.6. HRMS (MAII) m/z: calc. for C16H15BNO3 [M+H]+ 280.1140, found 280.1133.

Acetylation of amine (13). To a dry round-bottom flask was added 12 (47 mg, 0.120 mmol) and DCM (3 mL). TEA (35 µL, 0.251 mmol) and acetic anhydride (40 µL, 0.420 mmol) were added via microsyringe under argon and stirred at rt for 5 h. After this time, the mixture was concentrated and the crude residue was subjected to flash chromatography (EtOAc w/ 2% TEA→ 3:1 EtOAc:acetone) to afford 13 (26 mg, 51%). Hygroscopic white solid; 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.48 (t, 1H, J=7.8), 7.29 (d, 1H, J=7.0), 7.24 (d, 2H, J=8.5), 7.09 (m, 3H), 6.99 (d, 1H, J=8.4), 6.87 (m, 3H), 5.14 (d, 1H, J=13.9), 5.05 (d, 1H, J=14.1), 4.99 (d, 1H, J=13.9), 6.63 (d, 1H,


Page 9 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


J=14), 3.09 (s, 3H), 1.84 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ 169.9, 162.5, 160.0, 141.3, 137.5, 134.9, 133.5, 130.9, 129.8, 129.5, 129.2, 128.6, 120.7, 119.7, 118.9, 115.5, 72.1, 52.7, 42.7, 22.8. 11B NMR (CDCl3, 128 MHz) δ 8.8. HRMS (MAII) m/z: calc. for C24H23BClN2O3 [M+H]+ 433.1485, found 433.1493.

separatory funnel containing water (~5 mL) and extracted. The aqueous layer was extracted further with EtOAc (2 x 10 mL) and the combined organics were washed with sat’d sodium bisulfite (2 x 10 mL) and brine. After drying over Na2SO4, the organic phase was concentrated to afford 4b (55 mg, 88%). Offwhite solid; 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (s, 1H), 7.10 (s, 1H), 7.06 (d, 1H), 6.80 (d, 1H), 4.24 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ 159.1, 135.0, 134.4, 123.3, 119.6, 110.4, 70.6. 11B NMR (DMSO-d6, 128 MHz) δ 31.5. All spectra match those reported.37

Oxidation of aldehyde with KMnO4 (14). To a round-bottom flask containing a solution of 11a (75 mg, 0.268 mmol) in acetone (3 mL) was added solid KMnO4 (130 mg, 0.822 mmol) in one portion at rt. The mixture was stirred for 3 h. The crude reaction mixture was diluted with EtOAc (~20 mL) and extracting against sat’d NaHSO3 (~10 mL) and 1M HCl (~15 mL). The aqueous phase was extracted again with EtOAc (~15 mL), combined organics dried over Na2SO4, filtered, and concentrated. The resulting residue was resuspended in EtOAc:Acetone (1:1), decanted, and concentrated to afford 14 (41 mg, 50%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.01 (br s, 1H), 9.07 (s, 1H), 8.07 (d, 2H, J=15.7), 7.80 (s, 1H), 7.68 (d, 1H, J=15.3), 7.02 (d, 2H, J=15.3), 3.09 (s, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ 170.5, 168.3, 158.3, 140.2, 138.6, 133.6, 133.6, 133.0, 125.4, 120.8, 119.3, 118.7, 116.2, 115.5, 42.3, 11B NMR (DMSO-d6, 128 MHz) δ 5.3. HRMS (MAII) m/z: calc. for C16H13BNO5 [M+H]+ 310.0881, found 310.0860.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Synthetic schemes for protecting groups and benzoxaboroles, Fluorescence measurements, and NMR spectra (file type, i.e., PDF)

AUTHOR INFORMATION Corresponding Author * Email: [email protected]

ORCID John W. Tomsho: 0000-0001-9972-8728 James M. Gamrat: 0000-0003-3863-3340 Giulia Mancini: 0000-0001-7898-6867 Present Addresses

Bromination via Appel Reaction (15). To a dry round-bottom flask was added 9c (111 mg, 0.394 mmol), PPh3 (141 mg, 0.537 mmol), and N-bromosuccinimide (107 mg, 0.601 mmol). DCM (5 mL) was added to dissolve at 0ºC and stirred for 1 h. The mixture was warmed to rt for 2 h and then concentrated to a solid residue. 1H NMR showed complete conversion to the benzylic bromide. The residue was subjected to flash chromatography (SiO2, DCM:ACN 9:1) to afford pure 15 (49 mg, 36%). Hygroscopic white solid. 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.50 (t, 1H, J=7.8), 7.38 (s, 1H), 7.33 (d, 2H, J=7.7), 7.20 (d, 1H, J=7.8), 7.01 (d, 1H, J=8.4), 6.89 (t, 1H, J=7.5), 5.17 (d, 1H, J=14.2), 5.03 (d, 1H, J=14.2), 4.51 (s, 2H), 3.18 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ 162.7, 159.9, 149.4, 137.6, 135.9, 130.9, 129.3, 129.0, 121.0, 119.7, 119.0, 115.4, 72.0, 42.9, 34.8. 11B NMR (CDCl3, 128 MHz) δ 8.7. HRMS (MAII) m/z: calc. for C16H15BNO2 [M-Br]+ 264.1190, found 264.1179.

†S.J.B. is currently located at

Science Department, Neumann University, One Neumann Drive, Aston, PA, 19014, United States ††B.C.F. is currently located at

Department of Chemistry, Georgetown University, Box 571227-1227, Washington, D.C. 20057, United States Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript.

Deprotection to isolate benzoxaborole (4a). To a round-bottom flask containing a solution of 9a (150 mg, 0.60 mmol) in THF (2 mL) was added 1M HCl (4 mL) at rt. The mixture was stirred for 2 h at rt, after which the mixture was diluted with EtOAc (~10 mL). The mixture was transferred to a separatory funnel containing water (~5 mL) and extracted. The aqueous layer was extracted further with EtOAc (2 x 10 mL) and the combined organics were washed with sat’d sodium bisulfite (2 x 10 mL) and brine. After drying over Na2SO4, the organic phase was concentrated to afford 4a (80 mg, quant.). White solid; 1H NMR (CDCl3, 400 MHz) δ 7.74 (d, 1H), 7.39 (t, 1H), 7.35 (t, 1H), 5.18 (s, 1H), 5.12 (s, 2H). 11B NMR (128 MHz, CDCl3) δ 32.6.

ACKNOWLEDGMENT The authors would like to thank the University of the Sciences for financial support of this work. We thank Timothy Wade of Drexel University as well as Veronica Smith and Dr. Charles McEwan of the University of the Sciences for HRMS analysis. We would also like to thank Timothy Enright and Dr. Walter Dorfner of the University of the Sciences for their helpful discussions.

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Deprotection to isolate 3-cyanobenzoxaborole (4b). To a round-bottom flask containing a solution of 9b (150 mg, 0.60 mmol) in THF (5 mL) was added 1M HCl (2.6 mL) at rt. The mixture was stirred for 2 h at rt, after which the mixture was diluted with EtOAc (~10 mL). The mixture was transferred to a



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Protection of the Benzoxaborole Moiety: Synthesis and

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