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Article

Synthesis of Novel Multifunctional bora-Ibuprofen Derivatives

by
Randika T. Abeysinghe
,
Alexis C. Ravenscroft
,
Steven W. Knowlden
,
Novruz G. Akhmedov
,
Brian S. Dolinar
and
Brian V. Popp
*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
*
Author to whom correspondence should be addressed.
Inorganics 2023, 11(2), 70; https://doi.org/10.3390/inorganics11020070
Submission received: 29 December 2022 / Revised: 26 January 2023 / Accepted: 26 January 2023 / Published: 2 February 2023
(This article belongs to the Special Issue Synthesis and Innovative Biological Activity of Boron-Containing Compounds)
Browse Figures
Versions Notes

Abstract

:
A unique class of β-boron-functionalized non-steroidal anti-inflammatory compound (pinB-NSAID) was previously synthesized via copper-catalyzed 1,2-difunctionalization of the respective vinyl arene with CO2 and B2pin2 reagents. Here, pinacolylboron-functionalized ibuprofen (pinB-ibuprofen) was used as a model substrate to develop the conditions for pinacol deprotection and subsequent boron functionalization. Initial pinacol-boronic ester deprotection was achieved by transesterification with diethanolamine (DEA) from the boralactonate organic salt. The resulting DEA boronate adopts a spirocyclic boralactonate structure rather than a diazaborocane–DABO boronate structure. The subsequent acid-mediated hydrolysis of DEA and transesterification/transamination provided a diverse scope of new boron-containing ibuprofen derivatives.

1. Introduction

Boronic acid- and ester-containing molecules have garnered significant attention in synthetic and medicinal chemistry due to the unique chemical properties of the boron center [1]. Neutral, trivalent boron compounds feature an empty p-orbital that makes the compounds Lewis acidic, enabling reactions with nucleophiles/Lewis bases, such as organometallic reagents, alcohols/alkoxides, amines, hydroxy acids, halides, etc. [1]. This reactivity has made organoboron compounds important synthons in catalysis as starting materials and intermediates in transition-metal-catalyzed cross-coupling reactions (e.g., Suzuki–Miyaura [2] and Chan–Lam [3]) and C–X bond forming reactions [4]. Under physiological conditions, boronic-acid derivatives convert from a trivalent sp2 hybridized form to a tetravalent sp3 hybridized form upon capture by Lewis bases, enabling enzyme inhibition. In 2003, the United States Federal Drug Administration (FDA) approved the first boron-containing therapeutic agent, Bortezomib, that acts as a proteasome inhibitor to treat multiple myeloma and cell lymphoma [5]. In subsequent years, several other boron-containing drugs featuring either a boronic-acid bioisostere replacing a carboxylic acid/aldehyde (e.g., Bortezomib and Ixazomib) or an oxaborole motif (e.g., Tavaborole and Crisaborole) were approved by the FDA to treat various conditions (Figure 1a) [5,6,7].
The identification and preparation of new boron therapeutic agents, especially ones featuring unique pharmacologically important motifs, has been a highly active area of investigation [5,6,7,8,9,10,11,12,13]. In 2016, Popp and co-workers reported a redox neutral copper-catalyzed boracarboxylation method to add carboxylic acid and boron ester (pinacolylboron, (pinB)) groups to vinyl styrene regioselectively [14]. This unique catalytic entry point to the pharmacologically important α-aryl propionic acid pharmacophore allowed for the first synthesis of boron-containing non-steroidal anti-inflammatory drug (pinB-NSAID) congeners of ibuprofen and naproxen (Figure 1b). Subsequently, the synthesis of pinB-fenoprofen and pinB-flurbiprofen, using the same copper catalyst system with inclusion of triphenyl phosphine (PPh3) as a catalytic additive, was reported [15,16]. Herein, we report a mild, high-yielding method to remove pinacol from pinB-ibuprofen (1), allowing for structural and electronic diversification of the boron center through transesterification/transamination reactions and providing new opportunities for screening the medicinal potential of boron-containing NSAIDs [10,11].

2. Results and Discussion

Numerous methods have been reported to hydrolyze/transesterify diols in organoboron esters [1]. We began evaluating classical methods to hydrolyze pinB-ibuprofen (1pin) that generally used reagents that were expected to be incompatible with the carboxylic acid functional group (Figure 2a). Not surprisingly, transborylation with boron trichloride [17,18] and reductive cleavage with lithium aluminum hydride [19,20] led to intractable product mixtures. Oxidative cleavage with sodium periodate [21] cleaved the sp3C–B bond to give the deborylation–hydroxylation product [14]. Hydrolysis with potassium hydrogen fluoride [22,23,24,25] led to the isolation of a difluoroboralactonate salt that has proven remarkably stable [14,26].
Boronic-ester hydrolysis via transesterification with an exogenous boronic acid has been achieved previously (Figure 2b). Biphasic transesterification with excess phenyl boronic acid and pinB-ibuprofen (1) led to difficulties in product isolation [27] while attempts to use solid-phase polystyrene-based boronic acid were also unsuccessful [28]. Klein and co-workers reported a monophasic transesterification method using excess methyl boronic acid, after which the resultant methyl pinacol ester was removed via evaporation at a slightly elevated temperature, 40 °C [29]. Again, inefficient transesterification was observed, leading to the problematic isolation of boron-containing products.
Deprotection of cyclic boronic esters has been achieved by transesterification with a variety of diethanolamine derivatives, providing sp3-hybridized zwitterionic diethanolamine boronate ester (dioxazaborocane, DABO boronate, [30,31], Figure 2c), after which mild acid hydrolysis of DEA from DABO boronate cleanly provided the boronic acid [32,33,34,35,36]. Santos and co-workers demonstrated the two-step method with 2°-alkylpinacolyl boronate-ester deprotection, yielding 2°-alkylboronic acids with a variety of functional groups (e.g., ester, cyano, amide) [35]. Gratifyingly, when 1pin was mixed with DEA in diethyl ether, a suspension formed, and after extended stirring, a small amount of fine, white precipitate appeared on the walls of the flask, albeit in amounts that prevented isolation. The white precipitate was presumed to be DABO-ibuprofen (1DABO).
Further experimental screening showed that after adding a slight excess of Hünig’s base to 1pin in diethyl ether, the initial suspension resolved to a clear solution over 30 min. NMR characterization of the pale-yellow oil remaining after the removal of solvent indicated the formation of a new, possibly tetravalent, boron species as indicated by an upfield shift in the 11B NMR resonance from 33.5 ppm (1pin) to 15.8 ppm (Figure 3a, left overlay), mirroring the 11B and 1H shifts observed in the IPr-copper(I) boralactonate complexes that we recently isolated and characterized [16]. Although a definitive X-ray structural characterization of the molecule has been elusive, we cautiously assign it as the [1pin][DIPEA-H] organic salt.
Redissolution of the salt in diethyl ether, and addition of excess DEA, led to the formation of significant amounts of an insoluble white precipitate. The precipitate was collected via simple filtration and found to be insoluble in most non-polar solvents, including CDCl3. NMR characterization in CD3OD revealed no pinacol resonances and characteristic DEA resonances in the 1H NMR spectrum, while a further upfield shift of the boron resonance to 9.34 ppm was observed in the 11B NMR spectrum (Figure 3a, right overlay). This shift was consistent with other previously characterized DABO boronate esters [35,37]; however, there was some ambiguity, since the shift could also be consistent with retention of the boralactonate structure (1DEA). All attempts to grow X-ray-quality crystals were unsuccessful, so we carried out extensive NMR characterization to elucidate the solution structure. Dynamical behavior on the NMR time-scale of 1DEA was not observed. Detailed analysis of the 1H NMR spectrum showed that the methylene 1H resonances of the α-aryl propionic ester AMX spin system were upfield shifted, consistent with the retention of the boralactonate ring [16], while the four magnetically inequivalent pairs of DEA protons were best described as an AA’XX’ spin system (Figure S4 (Supplementary Materials)), which is markedly different from the ABMX system observed for independently prepared DABO methyl boronate (Figure S5). The final structural confirmation was obtained by acquiring two-dimensional 1H-15N CIGAR-HMBC spectra [38] for the DEA boronate and DABO methyl boronate (Figure 3b and Figure S6). The heteronuclear inverse-correlation experiment was optimized to reveal vicinal (3J), and to a lesser extent geminal (2J) 1H-15N coupling. The DEA boronate CIGAR spectrum showed two- and three-bond correlations to the DEA AA’XX’ spin system (Figure 3b). In contrast, the DABO methyl boronate CIGAR spectrum showed three-bond correlations to the DEA AB spin system, as well as a three-bond correlation, across the 11B nucleus, to the methyl group. These NMR experiments collectively confirm that DEA boronate adopts the spirocyclic boralactonate structure (1DEA) rather than the DABO boronate structure (1DABO).
After further synthetic optimization, conditions were identified for the preparation of 1DEA by mixing 1pin, Hünig’s base, and excess DEA in Et2O, then heating the mixture in a sealed vial for 4 h (Scheme 1). Yields of up to 80% were achieved at a 0.1 mmol scale. Reactions at scales of up to 1 mmol required longer reaction times (8–12 h) and generally gave slightly lower yields (65–75%). The isolated compound was found to be reasonably air and moisture stable, with no significant decomposition observed over 2–3 months when stored in the solid state on the benchtop, in a clear glass vial. Further, the compound was observed to be stable with no apparent decomposition when dissolved in CD3OD for at least 4 weeks, as judged by the 1H and 11B NMR experiments.
From the outset, our objective was to identify a synthetic method that would first enable pinacol deprotection from pinB-NSAIDs and other boracarboxylated products, and then enable the addition of new diols, amino alcohols, diamines, etc., to the boron center for catalytic and medicinal chemistry substrate library generation. Given the instability of reported DABO boronates to aqueous acid (cf., [35]), we reasoned that a biphasic reaction mixture would allow for the initial generation of an aqueous-soluble boronic acid via DEA hydrolysis, followed by the formation of an organic, soluble, desired boronic ester via esterification with an exogenous diol. Indeed, we have preliminary evidence to support rapid hydrolysis of DEA from 1DEA in 0.1 M HCl; however, an unambiguous solution and solid-state characterization of the presumed ibuprofen-derived boronic acid has not yet been obtained and will be reported in due course elsewhere.
Using a biphasic reaction medium composed of the equivalent volumes of aqueous HCl and diethyl ether, we observed an excellent formal transesterification reactivity in 2 h at room temperature with a variety of diols (Scheme 2). Six-membered, 1,3-diol boronic-ester derivatives (1a–e) were prepared in yields between 78% and 83%. The preparation of 1a and 1e was performed at a 0.7 and 0.31 mmol scale, respectively, providing slightly reduced yields in both cases. A single crystal of 1e was obtained by the slow recrystallization from n-heptane at room temperature, revealing similar structural features to those reported previously for 1pin [15]. Five-membered, 1,2-diol boronic-ester derivatives (1f–i) were also synthesized in moderate to excellent yields, and no reduction in yield was observed when the reactions were scaled three-fold. In all cases, the mixtures of the diastereomers (i.e., benzylic α-aryl propionic acid racemate) were obtained and the attempts at selective recrystallization were not successful. Transamination with 1,8-diaminonaphthalene provided 1Bdan (1j) in a 68% yield. Diols with acid-sensitive groups such as ethers (e.g., 3-phenoxypropane-1,2-diol, 1k) and monosaccharides were not tolerated under the reaction conditions, producing intractable mixtures of product.

3. Materials and Methods

3.1. General Methods

All commercially available compounds were used as received, and were purchased from Oakwood Chemical, Alfa Aesar, or Fisher Chemical. 1pin was prepared according to the literature precedent [39]. The DABO methyl boronate was prepared based on the literature precedent and matched the previous spectroscopic characterization [35,40]. The 1H, 13C, and 11B NMR spectra were recorded on JEOL 400 MHz and Varian INOVA 600 MHz NMR spectrometers, and all deuterated solvents were purchased from Cambridge Isotope Laboratories, Inc. Chemical shifts (δ) were given in parts per million and referenced relative to tetramethylsilane (0.0 ppm for CDCl3) or to residual proteo solvent (1.94 or 3.31 ppm for CD3CN and CD3OD, respectively), CD3CN or CD3OD (1.30 or 49.30 ppm for 13C), and internal (capillary) BF3·OEt2 (32.1 ppm). The 11B NMR spectra were recorded using quartz NMR tubes purchased from Wilmad. High-resolution mass spectra were recorded on a Thermo Fisher Scientific Q-Exactive Mass Spectrometer with samples dissolved in methanol (Fisher Optima grade).

3.2. General Procedure for Preparing the Spirocyclic Boralactonate Salt [1pin][DIPEA-H]

A 20 mL scintillation vial was charged with pinB-ibuprofen 1pin (1 equiv, 0.1 mmol, 33.1 mg) and N,N-diisopropylethylamine (1.1 equiv, 0.11 mmol, 19 µL). Diethyl ether (2 mL) was added to the vial, and the resulting suspension was stirred at an ambient temperature for 1 h. The resulting solution was concentrated under a vacuum, providing a yellow oil. The oil was dissolved in CD3OD and analyzed by 1H and 11B NMR spectroscopy. The salt was used without further purification.
1H NMR (400 MHz, CD3OD) δ 7.18–7.11 (m, 2H), 7.08–7.00 (m, 2H), 3.85–3.59 (m, 1H), 3.58–3.50 (m, 2H), 3.04 (d, J 7.4, 2H), 2.43 (d, J 7.2, 2H), 1.83 (hept, J 6.8, 1H), 1.45 (s, 2H), 1.28 (m, 20H), 1.22–1.07 (m, 1H), 0.89 (d, J 6.6, 6H), 0.75–0.62 (m, 1H). 11B NMR (128 MHz, CD3OD) δ 15.8.

3.3. General Procedure for the Synthesis of Diethanolamine Boronate Ibuprofen 1DEA

A 20 mL scintillation vial was charged with pinB-ibuprofen 1pin (1 equiv, 0.1 mmol, 33.1 mg), N,N-diisopropylethylamine (1.1 equiv, 0.11 mmol, 19 μL), and diethanolamine (3 equiv, 0.3 mmol, 31.5 mg). Diethyl ether (2 mL) was added to the vial, which was sealed with a Teflon cap, and the resulting suspension was stirred at 50 °C for 4 h. After 4 h, a fine, white powder was vacuum filtered, washed with excess diethyl ether to remove the impurities, and further dried in vacuo to provide the diethanolamine boronate ibuprofen diethanolamine adduct.
1DEA: White solid, 80% yield (25.6 mg). 1H NMR (600 MHz, CD3OD) δ 7.15–7.11 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 3.81–3.76 (m, 4H), 3.65 (t, J = 9.5 Hz, 1H), 3.13 (t, J = 5.3 Hz, 4H), 2.42 (d, J = 7.2 Hz, 2H), 1.82 (hept, J = 6.7 Hz, 1H), 1.13 (dd, J = 13.7, 10.0 Hz, 1H), 0.88 (d, J = 6.7 Hz, 6H), 0.69 (dd, J = 13.7, 8.9 Hz, 1H). 13C NMR (101 MHz, CD3OD) δ 186.7, 142.9, 140.2, 130.0, 128.9, 57.7, 51.8, 50.3, 46.1, 31.5, 22.7. 11B NMR (128 MHz, CD3OD) δ 9.4. HRMS (ESI) m/z 320.2021 [C17H26BNO4− (M+H)− requires 320.2028].

3.4. General Procedure for Preparing the bora-Ibuprofen Derivatives 1a–j

A 20 mL scintillation vial was charged with bora-ibuprofen diethanolamine adduct 1DEA (1 equiv, 0.1 mmol, 31.9 mg) and diol/diamine (1.1 equiv, 0.11 mmol). Diethyl ether (2 mL) and 0.1 M HCl (2 mL) were added to the vial, and the resulting suspension was stirred at ambient temperature for 2 h. The biphasic solution was added to a 15 mL separatory funnel, and then extracted with diethyl ether (3 × 4 mL). The combined organic extracts were washed with saturated sodium chloride (4 mL) and dried with sodium sulfate. The organic solvent was removed under a reduced pressure to obtain the desired product. The compound was further dried in vacuo and, if necessary, purified by recrystallization from n-heptane at room temperature.
1a: White solid, 82% yield (23.8 mg). 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 7.7 Hz, 2H), 7.06 (d, J = 7.7 Hz, 2H), 3.95–3.86 (m, 4H), 3.76 (dd, J = 10.1, 6.0 Hz, 1H), 2.42 (d, J = 7.2 Hz, 2H), 1.88–1.77 (m, 2H), 1.49 (dd, J = 16.0, 10.2 Hz, 1H), 1.16–1.09 (m, 1H), 0.87 (dd, J = 6.6, 1.0 Hz, 7H). 13C NMR (101 MHz, CDCl3) δ 180.1, 140.4, 138.1, 129.3, 127.5, 77.3, 77.2, 77.0, 76.7, 61.7, 46.3, 45.1, 30.2, 27.2, 22.4. 11B NMR (128 MHz, CDCl3) δ 31.7. HRMS (ESI) m/z 289.1622 [C16H23BO4− (M-H)− requires 289.1617].
1b: White solid, 81% yield (24.5 mg). 1H NMR (600 MHz, CDCl3) δ 7.24–7.18 (m, 2H), 7.09–7.04 (m, 2H), 3.88 (dddd, J = 11.0, 6.5, 4.4, 2.1 Hz, 2H), 3.77 (dd, J = 10.0, 6.2 Hz, 1H), 3.47 (dt, J = 11.0, 9.4 Hz, 2H), 2.43 (d, J = 7.2 Hz, 2H), 2.03–1.94 (m, 1H), 1.83 (hept, J = 6.7 Hz, 1H), 1.50 (dd, J = 15.9, 10.0 Hz, 1H), 1.18–1.09 (m, 1H), 0.88 (dd, J = 6.6, 1.0 Hz, 6H), 0.80 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 207.2, 181.1, 140.4, 138.1, 129.2, 127.6, 127.5, 83.4, 77.4, 77.2, 77.0, 76.7, 67.6, 46.4, 45.1, 31.2, 30.9, 30.2, 29.7, 24.6, 24.5, 22.4, 19.5, 12.6. 11B NMR (128 MHz, CDCl3) δ 28.7. HRMS (ESI) m/z 303.1777 [C17H25BO4− (M-H)− requires 303.1773].
1c: White solid, 85% yield (27.1 mg). 1H NMR (400 MHz, CDCl3) δ 7.22–7.18 (m, 2H), 7.08–7.03 (m, 2H), 3.79 (dd, J = 9.6, 6.6 Hz, 1H), 3.52 (s, 4H), 2.42 (s, 2H), 1.82 (hept, J = 6.7 Hz, 1H), 1.52 (dd, J = 16.0, 9.6 Hz, 1H), 1.19 (dd, J = 16.0, 6.7 Hz, 1H), 0.87 (d, J = 6.6 Hz, 6H), 0.83 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 179.5, 140.4, 138.0, 129.2, 127.5, 77.3, 77.0, 76.7, 72.0, 46.2, 45.0, 31.6, 30.1, 22.4, 22.3, 21.7. 11B NMR (128 MHz, CDCl3) δ 30.2. HRMS (ESI) m/z 341.1895 [C18H27BO4+Na (M+Na)+ requires 341.1985].
1d: White solid, 78% yield (27.1 mg). 1H NMR (600 MHz, CDCl3) δ 7.23–7.19 (m, 2H), 7.08–7.03 (m, 2H), 3.78 (dd, J = 9.5, 6.7 Hz, 1H), 3.59 (ddd, J = 11.1, 4.4, 1.5 Hz, 2H), 3.51 (ddd, J = 11.3, 7.6, 1.5 Hz, 2H), 2.42 (d, J = 7.1 Hz, 2H), 1.82 (dp, J = 13.5, 6.8 Hz, 1H), 1.51 (dd, J = 16.0, 9.5 Hz, 1H), 1.20 (tdd, J = 11.0, 8.4, 5.4 Hz, 3H), 1.16–1.10 (m, 2H), 0.88 (d, J = 6.6 Hz, 7H), 0.85 (t, J = 7.1 Hz, 4H), 0.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 180.9, 140.5, 138.1, 129.3, 129.3, 127.6, 77.4, 77.1, 76.8, 70.9, 70.9, 46.4, 45.2, 37.1, 34.3, 30.2, 22.5, 18.9, 16.4, 14.9. 11B NMR (128 MHz, CDCl3) δ 28.3. HRMS (ESI) m/z 345.2244 [C20H31BO4− (M-H)− requires 345.2243].
1e: White solid, 79% yield (32.7 mg). 1H NMR (600 MHz, CDCl3) δ 7.25 (s, 1H), 7.13 (2 H, d, J 8.0), 7.06 (2 H, d, J 8.0), 4.84 (2 H, dd, J 13.2, 2.9), 4.31 (2 H, t, J 12.3), 3.76 (1 H, dd, J 10.5, 6.0), 2.42 (2 H, d, J 7.2), 1.82 (1 H, hept, J 6.7), 1.48 (1 H, dd, J 16.1, 10.4), 1.17 (1 H, dd, J 16.1, 6.0), 0.88 (6 H, d, J 6.6). 13C NMR (101 MHz, CDCl3) δ 180.6, 140.9, 137.4, 129.8, 129.5, 128.1, 127.5, 127.3, 83.4, 67.0, 46.3, 45.1, 30.2, 22.5, 19.0. 11B NMR (128 MHz, CDCl3) δ 33.4. HRMS (ESI) m/z 412.0571 [C16H21BBrNO6− (M-H)− requires 412.0573]. Melting point: 141–148   ℃ .
1f: White solid, 70% yield (20.4 mg). 1H NMR (400 MHz, CDCl3) 7.19 (2 H, d, J 7.9), 7.05 (2 H, dd, J 7.8, 5.2), 4.19 (1 H, t, J 8.3), 3.82 (1 H, dt, J 9.0, 6.8), 3.63 (1 H, q, J 7.5), 2.41 (2 H, dd, J 7.2, 2.9), 1.82 (1 H, dp, J 12.9, 6.3), 1.56 (1 H, ddd, J 32.5, 16.0, 9.4), 1.28 (1 H, dd, J 16.0, 7.6), 1.20 (2 H, t, J 6.6), 1.11 (4 H, d, J 5.0), 0.86 (6 H, dd, J 6.7, 4.4). 13C NMR (101 MHz, CDCl3) δ 179.6, 140.6, 137.5, 129.3, 129.2, 127.5, 127.4, 83.3, 73.2, 72.1, 46.3, 45.0, 30.1, 30.1, 24.6, 24.5, 22.4, 22.3, 22.3, 21.5, −0.04. 11B NMR (128 MHz, CDCl3) δ 34.6. HRMS (ESI) m/z 289.1620 [C16H23BO4− (M-H)− requires 289.1617].
1g: White solid, 75% yield (24.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 4.64–4.52 (m, 1H), 4.27–4.18 (m, 1H), 4.01 (ddd, J = 9.2, 7.5, 5.7 Hz, 1H), 3.85 (dd, J = 9.6, 6.6 Hz, 1H), 3.55–3.38 (m, 2H), 2.44 (d, J = 7.2 Hz, 2H), 1.84 (dp, J = 13.5, 6.8 Hz, 1H), 1.64 (ddd, J = 16.2, 9.8, 2.3 Hz, 1H), 1.39–1.23 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 180.4, 141.0, 137.5, 129.6, 127.6, 127.6, 68.7, 46.5, 46.5, 46.2, 45.2, 30.3, 22.6, 15.3. 11B NMR (128 MHz, CDCl3) δ 33.0. HRMS (ESI) m/z 323.1230 [C16H22BClO− (M-H)− requires 323.1227].
1h: White solid, 93% yield (39.8 mg). 1H NMR (400 MHz, CDCl3) 7.30 (8 H, tdd, J 9.1, 4.8, 2.2), 7.24–7.05 (7 H, m), 5.07 (2 H, s), 4.11–3.97 (1 H, m), 2.50 (2 H, dd, J 7.2, 3.0), 2.00–1.76 (2 H, m), 1.61 (1 H, ddd, J 15.9, 14.2, 7.5), 1.01–0.87 (6 H, m).13C NMR (101 MHz, CDCl3) δ 179.6, 140.8, 140.3, 137.5, 129.4, 128.7, 128.2, 128.1, 127.9, 127.7, 127.6, 126.9, 125.8, 125.7, 86.5, 79.1, 46.5, 45.1, 30.2, 22.4. 11B NMR (128 MHz, CDCl3) δ 33.7. HRMS (ESI) m/z 427.2084 [C27H29BO4− (M-H)− requires 427.2086]. Melting point: 149–152 °C.
1i: White solid, 78% yield (22.5 mg). 1H NMR (600 MHz, CDCl3) δ 7.24–7.20 (m, 2H), 7.10–7.05 (m, 2H), 4.31–4.25 (m, 2H), 3.86 (dd, J = 9.2, 7.3 Hz, 1H), 2.43 (d, J = 7.1 Hz, 2H), 1.83 (dp, J = 13.5, 6.7 Hz, 1H), 1.68 (ddd, J = 13.8, 9.2, 4.5 Hz, 2H), 1.61 (dd, J = 16.1, 9.2 Hz, 1H), 1.52 (s, 2H), 1.41–1.32 (m, 3H), 1.29–1.19 (m, 2H), 0.90–0.86 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 180.3, 140.7, 137.5, 129.3, 127.5, 77.3, 77.2, 77.0, 76.7, 75.2, 46.4, 45.0, 30.2, 28.3, 22.4, 19.0. 11B NMR (128 MHz, CDCl3) δ 33.4. HRMS (ESI) m/z 329.1936 [C19H27BO4— (M-H)− requires 329.1930]. Melting point: 136–140 °C.
1j: Orange oil, 68% yield (25.4 mg). 1H NMR (400 MHz, CDCl3) 7.28–7.24 (2 H, m), 7.22–7.18 (1 H, m), 7.17–7.09 (3 H, m), 7.03 (2 H, dd, J 8.3, 7.2), 6.96 (2 H, d, J 8.2), 6.47 (1 H, dd, J 7.2, 1.1), 6.14 (2 H, d, J 7.2), 5.47 (2 H, s), 3.76 (1 H, t, J 7.9), 2.45 (2 H, d, J 7.2), 1.83 (1 H, dq, J 13.4, 6.7), 1.59 (1 H, dd, J 15.3, 7.5), 1.48–1.40 (1 H, m), 0.89 (7 H, d, J 6.6). 13C NMR (101 MHz, CDCl3) δ 179.7, 141.4, 140.9, 140.3, 137.1, 136.3, 134.7, 129.8, 129.2, 128.4, 127.6, 127.6, 127.1, 119.7, 117.6, 117.3, 113.1, 106.1, 105.8, 64.7, 47.2, 45.1, 32.0, 30.3, 29.0, 22.8, 22.5, 14.3. 11B NMR (128 MHz, CDCl3) δ 31.6. HRMS (ESI) m/z 371.1939 [C23H25BN2O2− (M-H)− requires 371.1936].

4. Conclusions

In this work, we have outlined a methodology to achieve pinacol deprotection from pinB-ibuprofen via transesterification with DEA. The characterization of the DEA adduct unexpectedly did not adopt the DABO boronate structure, but rather the DEA boralactonate zwitterionic structure. The DEA adduct is bench stable and amenable to subsequent synthetic elaboration via DEA hydrolysis under acidic aqueous biphasic-conditions, likely forming ibuprofen boronic-acid species, which can be functionalized via esterification/amination by the addition of diol or diamine to the biphasic reaction. Boron-containing ibuprofen derivatives with 1,2-diol and 1,3-diol motifs and 1,2-diaminonaphthalene were synthesized in moderate to excellent yields. This work paves the way for broader library syntheses to commence, with the aim of utilizing these organoboron carboxylic acids in catalysis and medicinal chemistry. Given the importance of NSAIDs in pain management and other disease pathways [41,42,43] and recognizing their well-known side effects [44,45,46], boron-containing NSAIDs may reveal new therapeutic opportunities [10,11].

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/inorganics11020070/s1, Figures S1–S40: NMR spectra; Table S1: Selected crystallographic and refinement parameters.

Author Contributions

Conceptualization, R.T.A.; methodology, R.T.A. and S.W.K.; formal analysis (spectroscopy and diffractometry), R.T.A., A.C.R., N.G.A. and B.S.D.; writing–original draft, R.T.A.; writing–review and editing, B.V.P.; supervision, B.V.P.; project administration, B.V.P.; funding acquisition, B.V.P. All authors have read the manuscript and agreed to the published version of the manuscript.

Funding

This research was funded by the National Science Foundation CAREER (CHE-1752986) and MRI (CHE-1228336) programs and the West Virginia University Don and Linda Brodie Resource Fund for Innovation.

Data Availability Statement

X-ray crystallography data can be found through the CCDC (2225404, 1e). All other data can be found in the Supplementary Materials.

Acknowledgments

B.V.P. is grateful for the insightful discussions and numerous helpful suggestions provided by participants at the 2022 17th Boron in the Americas (BORAM) Chemistry Meeting held at Virginia Tech and hosted by Webster Santos. A.C.R. thanks the following programs at West Virginia University for research training opportunities: 2020–2021 Research Apprenticeship Program, the 2021 Summer Undergraduate Research Experience Program, and the Honors EXCEL Thesis Program.

Conflicts of Interest

The authors declare no conflict of interest.

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Inorganics 11 00070 g001 550
Figure 1. (a) United States Federal Drug Administration-approved boron-containing therapeutic drugs. (b) Boron-containing α-aryl propionic acid derivatives (pinB-NSAIDs) prepared via copper(I) catalysis.
Figure 1. (a) United States Federal Drug Administration-approved boron-containing therapeutic drugs. (b) Boron-containing α-aryl propionic acid derivatives (pinB-NSAIDs) prepared via copper(I) catalysis.
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Figure 2. Pinacolylboronic-ester deprotection methods.
Figure 2. Pinacolylboronic-ester deprotection methods.
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Figure 3. (a) Stepwise preparation of diethanolamine boronate ibuprofen (DEAB-ibuprofen, 1DEA) via boralactonate organic salt [1pin][DIPEA-H] as illustrated by 11B NMR spectra in CDCl3 (1pin) and CD3OD ([1pin][DIPEA-H] and 1DEA). (b) Two-dimensional 1H-15N CIGAR-HMBC NMR spectrum of 1DEA in CD3OD.
Figure 3. (a) Stepwise preparation of diethanolamine boronate ibuprofen (DEAB-ibuprofen, 1DEA) via boralactonate organic salt [1pin][DIPEA-H] as illustrated by 11B NMR spectra in CDCl3 (1pin) and CD3OD ([1pin][DIPEA-H] and 1DEA). (b) Two-dimensional 1H-15N CIGAR-HMBC NMR spectrum of 1DEA in CD3OD.
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Scheme 1. Synthesis of DEA boralactonate 1DEA.
Scheme 1. Synthesis of DEA boralactonate 1DEA.
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Inorganics 11 00070 sch002 550
Scheme 2. Scope of boron-containing ibuprofen derivatives. aq: Reactions performed on 0.1 mmol scale with respect to 1DEA. All reported yields are isolated. b 0.7 mmol scale. c 0.31 mmol scale. d Intractable mixture observed after reaction work-up.
Scheme 2. Scope of boron-containing ibuprofen derivatives. aq: Reactions performed on 0.1 mmol scale with respect to 1DEA. All reported yields are isolated. b 0.7 mmol scale. c 0.31 mmol scale. d Intractable mixture observed after reaction work-up.
Inorganics 11 00070 sch002
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Abeysinghe, R.T.; Ravenscroft, A.C.; Knowlden, S.W.; Akhmedov, N.G.; Dolinar, B.S.; Popp, B.V. Synthesis of Novel Multifunctional bora-Ibuprofen Derivatives. Inorganics 2023, 11, 70. https://doi.org/10.3390/inorganics11020070

AMA Style

Abeysinghe RT, Ravenscroft AC, Knowlden SW, Akhmedov NG, Dolinar BS, Popp BV. Synthesis of Novel Multifunctional bora-Ibuprofen Derivatives. Inorganics. 2023; 11(2):70. https://doi.org/10.3390/inorganics11020070

Chicago/Turabian Style

Abeysinghe, Randika T., Alexis C. Ravenscroft, Steven W. Knowlden, Novruz G. Akhmedov, Brian S. Dolinar, and Brian V. Popp. 2023. "Synthesis of Novel Multifunctional bora-Ibuprofen Derivatives" Inorganics 11, no. 2: 70. https://doi.org/10.3390/inorganics11020070

APA Style

Abeysinghe, R. T., Ravenscroft, A. C., Knowlden, S. W., Akhmedov, N. G., Dolinar, B. S., & Popp, B. V. (2023). Synthesis of Novel Multifunctional bora-Ibuprofen Derivatives. Inorganics, 11(2), 70. https://doi.org/10.3390/inorganics11020070

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