An Efficient Method for the Hydrolysis of Potassium Organotrifluoroborates Promoted by Montmorillonite K10

An efficient and non-expensive method for conversion of diverse potassium organotrifluoroborates to their corresponding boronic acids promoted by montmorillonite K10 using water as the reaction solvent is described. Further interconversion of potassium organotrifluoroborates to their corresponding boronic esters, via boronic acid intermediates was also successfully accomplished. The products were obtained in good yields, being the rate of hydrolysis influenced by the type of substituent present in the boronic acid.


Introduction
Transition metal-catalyzed cross-coupling reaction between electrophilic reagents and organometallic compounds are currently the most used method for the formation of new C-C bonds. 1 Although a wide variety of organometallic reagents can be used, all with their advantages and limitations, the Suzuki reaction has become the most used due to the mild conditions required to be performed, relative stability and low toxicity of boronic acids. 2 Boronic acids are the most common partner in Suzuki cross-coupling reactions due to the high Lewis acidity of boron atom, since this is the critical factor of the transmetalation step in the mechanism.In addition, these compounds have also been used as drug delivery agents, 3 sensors, 4 as well as biological inhibitors. 5Moreover, the recent interest in small molecules containing boronic acids, in special after the Food and Drug Administration (FDA) approval of the drug Velcade, makes boronic acids compounds of great interest.These reagents, however, have some limitations: many are difficult to purify, and are in equilibrium with anhydrides (boroximes), which makes determination of the stoichiometry of the reaction also difficult.As a consequence, they are generally used in excess. 6Some of these problems can be solved by the use of boronic esters, which exist only in the monomeric form. 7However, the low atom economy and the high cost of pinacol make the use of these reagents unattractive. 8n the other hand, transmetalation is sometimes not desired and the maintenance of the boron atom to be used for further reactions, preferably in an orthogonal manner, is a subject of great interest. 9Within this context, some boron protecting groups such as N-methyliminodiacetyl [B(mida)] 10 and 1,8-naphthalenediamine [B(dan)] 11 were developed, however, despite easy removal under mild conditions, the insertion of these groups requires longer reaction times and high temperatures.
Potassium organotrifluoroborates emerged as an alternative to [B(mida)] and [B(dan)] as a protecting group for boronic acids 12 specially due to their stability and crystallinity.Moreover, organotrifluoroborates are the most atom-efficient boronic acid surrogates available. 13In addition, some methods are available to hydrolyze these reagents back into the corresponding boronic acids or boronates. 14Indeed, it is also known that the hydrolysis of potassium organotrifluoroborates is very dependent on the organic moiety. 15dditionally to these characteristics, the reactivity differences between organotrifluoroborates and boranes in some dibora intermediates 16 can be explored in the crosscoupling reactions in a highly chemoselective fashion, leaving the trifluoroborate moiety intact for subsequent transformations.
Within this context, this work describes an efficient method for conversion of potassium organotrifluoroborates into the corresponding boronic acids or esters using montmorillonite K10 under green conditions.

Experimental
All reagents and solvents used (purchased from Aldrich Chemical Co.) were previously purified and dried in agreement with the literature, 17 and used as received.Reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel 60 plates (F254) using UV light, vanillin and p-anisaldehyde as visualizing agents. 1 H and 13 C nuclear magnetic resonance (NMR) data were recorded in CDCl 3 or dimethylsulfoxide-d 6 (DMSO-d 6 ).The chemical shifts are reported as delta (d) units in parts per million (ppm) relative to the solvent residual peak as the internal reference. 11B (128 MHz) NMR spectra and 19 F (376 MHz) were calibrated using BF 3 •Et 2 O (0.0 ppm) as external reference in the case of 11 B NMR and chemical shifts were referenced to external CF 3 CO 2 H (0.0 ppm) in the case of 19 F NMR. Coupling constants (J) for all spectra are reported in hertz (Hz).
General procedure for the hydrolysis of potassium organotrifluoroborates (2a-2o) In a flask containing the appropriate potassium organotrifluoroborate (0.5 mmol) in distilled water (1 mL) was added montmorillonite K10 (150% m/m).The mixture was stirred for the time indicated in Scheme 1 at room temperature.After this period, the mixture was extracted with EtOAc (3 × 10 mL) and the organic phase was washed with water (2 × 15 mL).The organic phase was dried over anhydrous MgSO 4 , filtered and the solvent was removed in vacuo to yield the corresponding boronic acids 2a-o.Scheme 1. Hydrolysis of different potassium organotrifluoroborates to the corresponding boronic acids using montmorillonite K10.

Phenylboronic acid (2a)
Yield: 59 mg (97%) as a white solid; mp > 200 o C;  4 (s).This is in agreement with data previously reported. 14neral procedure for the synthesis of boronic esters from potassium organotrifluoroborates (3a-3m) In a flask containing the appropriate boronic acid 1a-m (0.25 mmol) in tetrahydrofuran (THF; 3 mL) was added montmorillonite K10 (150% m/m) followed by pinacol (30 mg, 0.25 mmol).The mixture was stirred for 15 min to homogenize the contents, and powdered 4 Å molecular sieves (150% m/m) were added.The mixture was then stirred at room temperature for the time indicated in Scheme 2. After this period, the mixture was extracted with EtOAc (3 × 10 mL) and the organic phase was washed with water (2 × 15 mL).The organic phase was dried over anhydrous MgSO 4 , filtered and the solvent was removed in vacuo.

Results and Discussion
For preliminary optimization of the reaction conditions, a solution of potassium aryltrifluoroborate 1a (1 mmol) in H 2 O was treated with different clays at room temperature.The results are depicted in Table 1.
From Table 1, it can be seen that when montmorillonites were used, the conversion of 1a to the corresponding boronic acid 2a was quantitative (Table 1, entries 2 and 3).However, no product was observed when only H 2 O was used after 90 min, indicating that the presence of additives is essential for the progress of the reaction.This result is probably due to the acidic character of the montmorillonites used and, mainly, due to the presence of the silicon atom in their structures. 31Since silicon presents a strong interaction with fluorine atom, this would favor the cleavage of the B-F bond in the tetrahedral structure of compound 1a, leading to the formation of the intermediate phenyldifluoroborane, which immediately undergoes a nucleophilic attack from water.Lennox and Lloyd-Jones 32 detailed the mechanism of hydrolysis as an equilibrium between the boronic acid and the organotrifluoroborate driven toward boronic acid due to the abstraction of fluoride, which can be promoted by a base and/or glassware.The differences in reaction times using the montmorillonite KSF or K10 can be explained by their surface areas.For montmorillonite clays the surface area of K10 has a higher value (about 220-270 m 2 g -1 ) when compared to KSF (20-40 m 2 g -1 ). 31 After that, the amount of montmorillonite K10 to promote the reaction was investigated.The amount of clay was changed from 200 to 25% m/m.It was observed that the conversion of 1a to 2a did not change considerably when the amount of the catalyst varied from 200 to 50% m/m (Table 1, entries 4-6), however, when the amount of the catalyst was decreased to 25% m/m, a lower conversion was observed (Table 1, entry 7).Despite having similar conversions, the increase in the amount of the clay led to a considerable decrease in reaction time.
Finally, the most suitable solvent for the hydrolysis of 1a was investigated.As potassium aryltrifluoroborates are salts, it was expected that water would be the most appropriate solvent to perform the reaction.Accordingly, better results were achieved using water as the solvent, leading to the desired product quantitatively after 30 min reaction at room temperature (Table 2, entry 1).Although, when the same reaction was performed under reflux, a decrease in the conversion was observed (Table 2, entry 2).The use of a less polar solvent, such as THF, provided the corresponding boronic acid 2a also in good conversions (Table 2, entry 3).However, when dichloromethane was used, only 8% conversion was observed (Table 2, entry 4).Finally, when more polar solvents, such as methanol or acetonitrile were used in the reaction, lower conversions were observed (Table 2, entries 5-6).
The optimized reaction conditions, namely 1a (0.5 mmol), montmorillonite K10 (150% m/m) in H 2 O (1.0 mL) at 25 o C, were then applied for the hydrolysis of several potassium aryltrifluoroborates containing a wide range of functional groups and the results are shown in Scheme 1. From the results shown in Scheme 1, electron-donating or electron-withdrawing groups, as well as their position on the aromatic ring, have a dramatic influence on the product yield and reaction time.This fact is in accordance with previous work described by Perrin and co-workers 15 where the rate of organotrifluoroborate solvolysis is governed by substituent groups. 32For example, when potassium 2-, 3-or 4-methoxyphenyltrifluoroborates were used, the corresponding products 2b-d were obtained in good yields and in different reaction times, being the 4-derivative obtained in higher yield and shorter reaction time.Potassium aryltrifluoroborates containing hydroxyl or amino groups were also efficiently hydrolyzed.This is an interesting result as it was previously described that the hydrolysis of 2e using lithium hydroxide resulted in decomposition of the starting material to a dark polymeric mixture. 33When potassium organotrifluoroborates containing halogens were used, the corresponding products 2g and 2h were also obtained in good yields.
Next, attention was turned to electron-poor aryltrifluoroborates, which as expected, required a longer time for complete deprotection.As an example, potassium organotrifluoroborate containing an aldehyde 2i was obtained in moderate yield after 24 h.The same behavior was observed for compound 2l, obtained in 90% after 24 h.
Sterically-hindered potassium aryltrifluoroborates provided the corresponding arylboronic acids 2j and 2k in good yields and short reaction time.The use of potassium heteroaryltrifluoroborates led to the corresponding boronic acids 2m and 2n in excellent yields.
Finally, the hydrolysis of non-aromatic trifluoroborates was examined, and the conditions developed were proven to be effective, giving 2o in good yield after 1 h.However, the reaction was not efficient for the allenyl derivative, where 2p was not obtained and only a complex mixture of compounds was observed.
In addition, the use of montmorillonite K10 was applied in the synthesis of some boronic esters 3, which present higher stability comparing with boronic acids 2.
In a first attempt, the same reaction conditions for the hydrolysis of potassium organotrifluoroborates were used, however, equimolar amounts of pinacol were added to the reaction.The reaction was monitored by 11 B NMR and after 1 h, a mixture of the desired compound 3a, boronic acid 2a and the starting material was observed.When the reaction was carried out employing a longer reaction time, the same result was observed (Table 3, entries 1 and 2).This result indicates that the presence of water in the reaction might be a problem for the formation of 3a and, in an attempt to improve the conversion to 3a, different solvents were screened (Table 3).
Low conversions were observed when ethyl acetate, N,N-dimethylformamide or dioxane were used in the reaction (Table 3, entries 3-5).The use of acetonitrile also gave the product in lower conversions (Table 3, entry 6).From the different solvents employed to promote the reaction, the best result was observed when THF was used, where 3a was obtained in 70% conversion determined by 11 B NMR after 1 h (Table 3, entry 7).It is interesting to note that the conversion was maintained even after 3 h of reaction.Of note, the addition of 4 Å molecular sieves to the reaction medium led to the total consumption of pinacol after 3 h and 3a was obtained as the sole product in a 100% conversion (Table 3, entry 8).The robustness of the developed method was tested by applying the reaction conditions for the synthesis of other different boronic esters.The results are summarized in Scheme 2.
From Scheme 2, it can be seen that the presence of electron-donating or electron-withdrawing groups did not significantly interfere with the reaction.However, the reaction time presented variation depending on the substrate structure.For example, boronic ester 3a was obtained in 97% yield after 3 h, and the reaction for o-disubstituted pinacol ester 3c required 6 h to be completed.
The synthesis of non-aromatic pinacol esters was also examined, and 3k was obtained in good yield after 5 h.When potassium allenyl trifluoroborate was used, the corresponding boronic ester 3l was obtained in 60% yield after 5 h.Finally, the use of catechol led to the corresponding boronic ester 3m in good yield after 4 h, indicating that the method could be applied to other diols.
The recoverability and recyclability of the montmorillonite K10 was also evaluated after successive reactions using potassium phenyltrifluoroborate 1a.In the first cycles, the observed conversions to 2a were equivalent and a longer reaction time was required for the reaction completion.However, after the third cycle the observed conversions were lower.The results are summarized in Table 4.

Conclusions
In summary, an efficient and non-expensive method for conversion of diverse potassium organotrifluoroborates to their corresponding boronic acids promoted by montmorillonite K10 using water as the reaction solvent was described.Further interconversion of potassium organotrifluoroborates to their corresponding boronic esters, via boronic acid intermediates, was also successfully accomplished.The method is simple, fast and general, allowing further applications in the synthesis of more complex compounds.
reactions were performed using 1a (0.5 mmol) in water (1.0 mL) and montmorillonite K10 (150% m/m) at 25 o C for the time indicated.At the end of the reaction, the supernatant was decanted and the remaining solid washed with water (2 × 1.0 mL); b the conversion was determined by11 B NMR based on 2a.

Table 1 .
Influence of different amount of montmorillonite K10 in the hydrolysis of 1a at 25 o C a 11the conversion was determined by11B NMR based on 2a.

Table 2 .
Influence of different solvents on the hydrolysis of 1a at 25 o C c the reaction was conducted under reflux.THF: tetrahydrofuran.

Table 3 .
Influence of different solvents on the synthesis of 3a at 25 o C o C for 3 h.DMF: N,N-dimethylformamide; THF: tetrahydrofuran.

Table 4 .
Recyclability of montmorillonite K10 after successive reactions a