Synthesis of Novel Multifunctional bora -Ibuprofen Derivatives

: 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 CO 2 and B 2 pin 2 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.


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 sp 2 hybridized form to a tetravalent sp 3 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 pinBflurbiprofen, using the same copper catalyst system with inclusion of triphenyl phosphine (PPh 3 ) 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].
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].
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.
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 sp 3 -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., es-ter, cyano, amide) [35].Gratifyingly, when 1 pin 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 (1 DABO ).Deprotection of cyclic boronic esters has been achieved by transes variety of diethanolamine derivatives, providing sp 3 -hybridized zwitte mine boronate ester (dioxazaborocane, DABO boronate, [30,31], Figur mild acid hydrolysis of DEA from DABO boronate cleanly provided the 36].Santos and co-workers demonstrated the two-step method with boronate-ester deprotection, yielding 2°-alkylboronic acids with a va groups (e.g., ester, cyano, amide) [35].Gratifyingly, when 1 pin was m diethyl ether, a suspension formed, and after extended stirring, a sma white precipitate appeared on the walls of the flask, albeit in amounts t lation.The white precipitate was presumed to be DABO-ibuprofen (1 DA  Further experimental screening showed that after adding a slight base to 1 pin in diethyl ether, the initial suspension resolved to a clea minutes.NMR characterization of the pale-yellow oil remaining after t vent indicated the formation of a new, possibly tetravalent, boron spec an upfield shift in the 11 B NMR resonance from 33.5 ppm (1 pin ) to 15.8 p overlay), mirroring the 11 B and 1 H shifts observed in the IPr-copper(I) b plexes that we recently isolated and characterized [16].Although a defi tural characterization of the molecule has been elusive, we cautious Redissolution of the salt in diethyl ether, and addition of excess D mation of significant amounts of an insoluble white precipitate.The p lected via simple filtration and found to be insoluble in most non-polar s Further experimental screening showed that after adding a slight excess of Hünig's base to 1 pin 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 11 B NMR resonance from 33.5 ppm (1 pin ) to 15.8 ppm (Figure 3a, left overlay), mirroring the 11 B and 1 H 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 [1 pin ][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 CDCl 3 .NMR characterization in CD 3 OD revealed no pinacol resonances and characteristic DEA resonances in the 1 H NMR spectrum, while a further upfield shift of the boron resonance to 9.34 ppm was observed in the 11 B 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 (1 DEA ).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 1 DEA was not observed.Detailed analysis of the 1 H NMR spectrum showed that the methylene 1 H 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 1 H- 15 N 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 ( 3 J), and to a lesser extent geminal ( 2 J) 1 H- 15 N 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 11 B nucleus, to the methyl group.These NMR experiments collectively confirm that DEA boronate adopts the spirocyclic boralactonate structure (1 DEA ) rather than the DABO boronate structure (1 DABO ).
DABO methyl boronate (Figure 3b and S6).The heteronuclear inverse-correlation experiment was optimized to reveal vicinal ( 3 J), and to a lesser extent geminal ( 2 J) 1 H- 15 N 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 threebond correlation, across the 11 B nucleus, to the methyl group.These NMR experiments collectively confirm that DEA boronate adopts the spirocyclic boralactonate structure (1 DEA ) rather than the DABO boronate structure (1 DABO ).After further synthetic optimization, conditions were identified for the preparation of 1 DEA by mixing 1 pin , Hünig's base, and excess DEA in Et2O, then heating the mixture in After further synthetic optimization, conditions were identified for the preparation of 1 DEA by mixing 1 pin , Hünig's base, and excess DEA in Et 2 O, 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 CD 3 OD for at least 4 weeks, as judged by the 1  From the outset, our objective was to identify a synthetic method enable pinacol deprotection from pinB-NSAIDs and other boracarbo and then enable the addition of new diols, amino alcohols, diamines, center for catalytic and medicinal chemistry substrate library generation bility of reported DABO boronates to aqueous acid (cf., [35]), we reason reaction mixture would allow for the initial generation of an aqueous-so via DEA hydrolysis, followed by the formation of an organic, soluble ester via esterification with an exogenous diol.Indeed, we have prelim support rapid hydrolysis of DEA from 1 DEA in 0.1 M HCl; however, an lution and solid-state characterization of the presumed ibuprofen-der has not yet been obtained and will be reported in due course elsewhere Using a biphasic reaction medium composed of the equivalent vo HCl and diethyl ether, we observed an excellent formal transesterificat hours at room temperature with a variety of diols (Scheme 2).Six-memb ronic-ester derivatives (1a-e) were prepared in yields between 78% and ration of 1a and 1e was performed at a 0.7 and 0.31 mmol scale, respec slightly reduced yields in both cases.A single crystal of 1e was obtaine crystallization from n-heptane at room temperature, revealing similar s to those reported previously for 1 pin [15].Five-membered, 1,2-diol bor tives (1f-i) were also synthesized in moderate to excellent yields, and no was observed when the reactions were scaled three-fold.In all cases, th diastereomers (i.e., benzylic α-aryl propionic acid racemate) were obt tempts at selective recrystallization were not successful.Transaminat minonaphthalene provided 1 Bdan (1j) in a 68% yield.Diols with acid-sens as ethers (e.g., 3-phenoxypropane-1,2-diol, 1k) and monosaccharides w under the reaction conditions, producing intractable mixtures of produ 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 1 DEA 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 1 pin [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 1 Bdan (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.

General Methods
All commercially available compounds were used as received, and were purchased from Oakwood Chemical, Alfa Aesar, or Fisher Chemical. 1 pin 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 1 H, 13 C, and 11 B 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 13 C), and internal (capillary) BF3•OEt2 (32.1 ppm).The 11 B 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).

General Procedure for Preparing the Spirocyclic Boralactonate Salt [1 pin ][DIPEA-H]
A 20 mL scintillation vial was charged with pinB-ibuprofen 1 pin (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 hour.The resulting solution was concentrated under a vacuum, providing a yellow oil.The oil was dissolved in CD3OD and analyzed by 1 H and 11 B NMR spectroscopy.The salt was used without further purification.

General Methods
All commercially available compounds were used as received, and were purchased from Oakwood Chemical, Alfa Aesar, or Fisher Chemical. 1 pin 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 1 H, 13 C, and 11 B 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 CDCl 3 ) or to residual proteo solvent (1.94 or 3.31 ppm for CD 3 CN and CD 3 OD, respectively), CD 3 CN or CD 3 OD (1.30 or 49.30 ppm for 13 C), and internal (capillary) BF 3 •OEt 2 (32.1 ppm).The 11 B 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).

General Procedure for Preparing the Spirocyclic Boralactonate Salt [1 pin ][DIPEA-H]
A 20 mL scintillation vial was charged with pinB-ibuprofen 1 pin (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 CD 3 OD and analyzed by 1 H and 11 B NMR spectroscopy.The salt was used without further purification.

General Procedure for the Synthesis of Diethanolamine Boronate Ibuprofen 1 DEA
A 20 mL scintillation vial was charged with pinB-ibuprofen 1 pin (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.

General Procedure for Preparing the bora-Ibuprofen Derivatives 1a-j
A 20 mL scintillation vial was charged with bora-ibuprofen diethanolamine adduct 1 DEA (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.

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 subse-

Scheme 2 .
Scheme 2. Scope of boron-containing ibuprofen derivatives.a Reactions performed on 0.1 mmol scale with respect to 1 DEA .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 .
Scheme 2. Scope of boron-containing ibuprofen derivatives.aq: Reactions performed on 0.1 mmol scale with respect to 1 DEA .All reported yields are isolated.b 0.7 mmol scale.c 0.31 mmol scale.d Intractable mixture observed after reaction work-up.