Brønsted Acid-Catalyzed Direct Substitution of 2-Ethoxytetrahydrofuran with Trifluoroborate Salts

Metal-free transformations of organotrifluoroborates are advantageous since they avoid the use of frequently expensive and sensitive transition metals. Lewis acid-catalyzed reactions involving potassium trifluoroborate salts have emerged as an alternative to metal-catalyzed protocols. However, the drawbacks to these methods are that they rely on the generation of unstable boron dihalide species, thereby resulting in low functional group tolerance. Recently, we discovered that in the presence of a Brønsted acid, trifluoroborate salts react rapidly with in situ generated oxocarbenium ions. Here, we report Brønsted acid-catalyzed direct substitution of 2-ethoxytetrahydrofuran using potassium trifluoroborate salts. The reaction occurs when tetrafluoroboric acid is used as a catalyst to afford functionalized furans in moderate to excellent yields. A variety of alkenyland alkynyltrifluoroborate salts readily participate in this transformation.


Introduction
Ethers are an important functional group in organic chemistry as they are present in pharmaceutical agents and bioactive compounds [1].More specifically, dialkyl ethers such as tetrahydrofurans (THF) and tetrahydropyrans (THP), present as either sugar-derived units or simpler units, account for a large percentage of ethers in bioactive agents.Several methodologies have been developed for the construction of THP rings towards the synthesis of natural products [2].More recently, THF rings have been increasingly observed in the structures of new bioactive compounds, specifically macrolides, potentially due to their smaller molecular weight and less complex structures as compared to their THP counterparts [3].
Herein, we report a transition metal-free methodology for the synthesis of 2-akenyl and 2-alkynyl tetrahydrofurans.Direct substitution at the 2-position of 2-ethoxytetrahydrofuran occurs in the presence of a Brønsted acid catalyst.Recently, our group has discovered that Brønsted acid-catalyzed reactions of benzhydryl alcohols [4] and acetals/ketals [5] with organotrifluoroborates proceed with excellent functional group tolerance.Previously, organotrifluoroborate salts have been shown to act as shelf-stable equivalents of boronic acids [6].Trifluoroborates are attractive reagents due to their relative nontoxic nature and straightforward preparation [7][8][9][10].Recently, metal-free transformations involving organotrifluoroborates have emerged as an alternative to metal-catalyzed protocols [11].More specifically, their Lewis acid-catalyzed reactions with stabilized carbocations such as iminium [12] and oxocarbenium ions [13][14][15][16] have been explored.However, the drawbacks to these methods are that they rely on the generation of unstable boron dihalide species thereby resulting in low functional group tolerance.
As a result, our efforts were focused on the development of an operationally simple protocol for the direct substitution of 2-ethoxytetrahydrofuran at the 2-position.

Results and Discussion
Previously, we discovered that tetrafluoroboric acid (HBF 4 ) is an effective catalyst for the reactions of trifluoroborate salts [4,5].To investigate the efficiency of the HBF 4 as a Brønsted acid-catalyst towards the substitution of 2-ethoxytetrahydrofuran, we first looked at using unsubstituted potassium phenylacetylenetrifluoroborate salt (S1) as a model substrate (Table 1). to these methods are that they rely on the generation of unstable boron dihalide species thereby resulting in low functional group tolerance.The number of methodologies for the preparation of C-glycosides has increased tremendously over the past several decades due their presence in natural products and enzymatically stable analogs of pharmaceutical importance [17][18][19][20][21][22][23][24][25][26].In particular, the synthesis of 2-alkenyl and 2-alkynyl tetrahydrofuran products has been relatively well explored.Notably, the treatment of 2benzenesulphonyl cyclic ethers with organozinc reagents produced alkynylated products [27,28].Moreover, intermolecular substitution of halides and intramolecular rearrangements using alkynyl stannanes have been reported [29,30].Additionally, alkynylated furan derivatives were prepared using acetylenic triflones [31,32].Furthermore, 2-alkynyl oxacycles were synthesized using cyclic and acyclic carbonates in the presence of a palladium catalyst [33].More recently, boronic acid-catalyzed reaction for direct carbo-and heterocyclizations of free allylic alcohols has been developed [34].
As a result, our efforts were focused on the development of an operationally simple protocol for the direct substitution of 2-ethoxytetrahydrofuran at the 2-position.

Results and Discussion
Previously, we discovered that tetrafluoroboric acid (HBF4) is an effective catalyst for the reactions of trifluoroborate salts [4,5].To investigate the efficiency of the HBF4 as a Brønsted acidcatalyst towards the substitution of 2-ethoxytetrahydrofuran, we first looked at using unsubstituted potassium phenylacetylenetrifluoroborate salt (S1) as a model substrate (Table 1).We found that the substitution was achieved with 75% yield of the desired product 1a when a slight excess of 1.1 equivalents of both the organotrifluoroborate (S1) and HBF4 acid catalyst were used (Table 1, entry 1).Attempts to use an alternative acid such as trifluoroacetic acid, which has a pKa similar to that of HBF4, only resulted in trace amounts of product formation (Table 1, entry 2).Our previous studies indicated that increasing the amounts of trifluoroborate salt and HBF4•OEt2 to 1.5 equivalents resulted in a higher yield for the alkynylation of ketals [5].We then looked to apply these reaction conditions to the direct functionalization of 2-ethoxytetrahydrofuran.To our delight, product 1a was obtained in an excellent 92% yield (  We found that the substitution was achieved with 75% yield of the desired product 1a when a slight excess of 1.1 equivalents of both the organotrifluoroborate (S1) and HBF 4 acid catalyst were used (Table 1, entry 1).Attempts to use an alternative acid such as trifluoroacetic acid, which has a pK a similar to that of HBF 4 , only resulted in trace amounts of product formation (Table 1, entry 2).Our previous studies indicated that increasing the amounts of trifluoroborate salt and HBF 4 ¨OEt 2 to 1.5 equivalents resulted in a higher yield for the alkynylation of ketals [5].We then looked to apply these reaction conditions to the direct functionalization of 2-ethoxytetrahydrofuran.To our delight, product 1a was obtained in an excellent 92% yield (Table 1, entry 3).Other reaction conditions, such as Catalysts 2016, 6, 94 3 of 8 reaction temperature and solvent, were not directly explored since both conditions were already extensively studied in our previously described set of novel Brønsted acid-catalyzed reactions [4,5].
With the developed reaction conditions in hand, the scope of potassium alkynyltrifluoroborate salts was explored (Figure 1).We found that neutral naphthylacetylenetrifluoroborate salt afforded product 1b in virtually quantitative yield.Electron-rich p-butyl and p-methoxy substituted derivatives of phenylacetylenetrifluoroborate salt produced the desired products 1c and 1d in 93% and 78% yields, respectively.Notably, a scaled-up reaction afforded 0.18 g of 1c in essentially identical yield to the small-scale synthesis.The developed reaction conditions were also tolerant to electron-deficient groups of phenylacetylenetrifluoroborate salts such as fluoro, dichloro and trifluoromethyl substituents.Substituted furans 1e-1g were obtained in good to excellent yields.In addition to phenylacetylenetrifluoroborates, hexynyltrifluoroborate salt reacted with 2-ethoxytetrahydrofuran to afford product 1h in 64% yield.
Catalysts 2016, 6, 94 3 of 8 as reaction temperature and solvent, were not directly explored since both conditions were already extensively studied in our previously described set of novel Brønsted acid-catalyzed reactions [4,5].
With the developed reaction conditions in hand, the scope of potassium alkynyltrifluoroborate salts was explored (Figure 1).We found that neutral naphthylacetylenetrifluoroborate salt afforded product 1b in virtually quantitative yield.Electron-rich p-butyl and p-methoxy substituted derivatives of phenylacetylenetrifluoroborate salt produced the desired products 1c and 1d in 93% and 78% yields, respectively.Notably, a scaled-up reaction afforded 0.18 g of 1c in essentially identical yield to the small-scale synthesis.The developed reaction conditions were also tolerant to electron-deficient groups of phenylacetylenetrifluoroborate salts such as fluoro, dichloro and trifluoromethyl substituents.Substituted furans 1e-1g were obtained in good to excellent yields.In addition to phenylacetylenetrifluoroborates, hexynyltrifluoroborate salt reacted with 2ethoxytetrahydrofuran to afford product 1h in 64% yield.We then discovered that potassium trans-styryltrifluoroborate salt and its derivatives reacted well under the developed reaction conditions to afford the alkenylated products in moderate to good yields (Figure 2).The reaction of unsubstituted potassium trans-styryltrifluoroborate salt with the starting material afforded product 2a in 74% yield.The effect of aromatic substituents was then explored.It was found that potassium 2-(3-fluorophenyl)vinyltrifluoroborate and potassium (E)trifluoro(4-(trifluoromethyl)styryl)borate reacted similarly to the unsubstituted transstyryltrifluoroborate salt and the desired products 2b and 2c were formed in 78% yield.In contrast, electron-rich trans-styryltrifluoroborate salt derivative containing a methyl group in the para-position resulted in a modest 54% yield of 2d.In addition, reaction of 2-ethoxytetrahydrofuran with potassium We then discovered that potassium trans-styryltrifluoroborate salt and its derivatives reacted well under the developed reaction conditions to afford the alkenylated products in moderate to good yields (Figure 2).The reaction of unsubstituted potassium trans-styryltrifluoroborate salt with the starting material afforded product 2a in 74% yield.The effect of aromatic substituents was then explored.It was found that potassium 2-(3-fluorophenyl)vinyltrifluoroborate and potassium (E)-trifluoro(4-(trifluoromethyl)styryl)borate reacted similarly to the unsubstituted trans-styryltrifluoroborate salt and the desired products 2b and 2c were formed in 78% yield.In contrast, electron-rich trans-styryltrifluoroborate salt derivative containing a methyl group in the para-position resulted in a modest 54% yield of 2d.In addition, reaction of 2-ethoxytetrahydrofuran with potassium (E)-4-phenylstyryltrifluoroborate salt afforded product 2e in 72% yield.Potassium trifluoro(1H-inden-2-yl)borate also participated in the reaction.Product 2f was obtained in 79% yield.Detailed experimental procedures and characterization can be found in the supporting information file.
(E)-4-phenylstyryltrifluoroborate salt afforded product 2e in 72% yield.Potassium trifluoro(1Hinden-2-yl)borate also participated in the reaction.Product 2f was obtained in 79% yield.Detailed experimental procedures and characterization can be found in the supporting information file.We propose that the protonation of 2-ethoxytetrahydrofuran leads to the elimination of ethanol (I) and the formation of 5-membered-ring oxocarbenium ion intermediate (II) (Scheme 1).The nucleophilic trifluoroborate salt then reacts at the 2-position generating the desired product (III).Furthermore, we propose that the ethanol produced from the generation of the oxocarbenium ion acts as a sequestering agent of the boron trifluoride byproduct.This in situ generation of ethanol is advantageous since previously, MacMillian and co-workers used hydrofluoric acid in order to sequester the boron trifluoride byproduct produced from the conjugate addition of organotrifluoroborates to activated enals [49].

General Synthetic Methods
All reactions were set up in two-dram glass vials at room temperature under air.Unless otherwise noted, all reagents were obtained from Sigma-Aldrich (Oakville, ON, Canada or Milwaukee, WI, USA) and used without further purification.Potassium trifluoroborate salts were synthesized according to published procedures [4,5,16,50,51].Reaction progress was monitored via thin layer chromatography (TLC) on silica gel (60 Å) with visualization using ultraviolet light (254 nm) and by staining with phosphomolybdic acid (PMA).NMR characterization data was collected at We propose that the of 2-ethoxytetrahydrofuran leads to the elimination of ethanol (I) and the formation of 5-membered-ring oxocarbenium ion intermediate (II) (Scheme 1).The nucleophilic trifluoroborate salt then reacts at the 2-position generating the desired product (III).Furthermore, we propose that the ethanol produced from the generation of the oxocarbenium ion acts as a sequestering agent of the boron trifluoride byproduct.This in situ generation of ethanol is advantageous since previously, MacMillian and co-workers used hydrofluoric acid in order to sequester the boron trifluoride byproduct produced from the conjugate addition of organotrifluoroborates to activated enals [49].
(E)-4-phenylstyryltrifluoroborate salt afforded product 2e in 72% yield.Potassium trifluoro(1Hinden-2-yl)borate also participated in the reaction.Product 2f was obtained in 79% yield.Detailed experimental procedures and characterization can be found in the supporting information file.We propose that the protonation of 2-ethoxytetrahydrofuran leads to the elimination of ethanol (I) and the formation of 5-membered-ring oxocarbenium ion intermediate (II) (Scheme 1).The nucleophilic trifluoroborate salt then reacts at the 2-position generating the desired product (III).Furthermore, we propose that the ethanol produced from the generation of the oxocarbenium ion acts as a sequestering agent of the boron trifluoride byproduct.This in situ generation of ethanol is advantageous since previously, MacMillian and co-workers used hydrofluoric acid in order to sequester the boron trifluoride byproduct produced from the conjugate addition of organotrifluoroborates to activated enals [49].

General Synthetic Methods
All reactions were set up in two-dram glass vials at room temperature under air.Unless otherwise noted, all reagents were obtained from Sigma-Aldrich (Oakville, ON, Canada or Milwaukee, WI, USA) and used without further purification.Potassium trifluoroborate salts were synthesized according to published procedures [4,5,16,50,51].Reaction progress was monitored via thin layer chromatography (TLC) on silica gel (60 Å) with visualization using ultraviolet light (254 nm) and by staining with phosphomolybdic acid (PMA).NMR characterization data was collected at Scheme 1. Proposed mechanistic pathway for the preparation of 2-alkenyl and 2-alkynyl tetrahydrofurans.

General Synthetic Methods
All reactions were set up in two-dram glass vials at room temperature under air.Unless otherwise noted, all reagents were obtained from Sigma-Aldrich (Oakville, ON, Canada or Milwaukee, WI, USA) and used without further purification.Potassium trifluoroborate salts were synthesized according to published procedures [4,5,16,50,51].Reaction progress was monitored via thin layer chromatography (TLC) on silica gel (60 Å) with visualization using ultraviolet light (254 nm) and by staining with phosphomolybdic acid (PMA).NMR characterization data was collected at 25 ˝C on an Oxford AS400 NMR as solutions in deuterated solvents (CDCl 3 and DMSO-d 6 were obtained from Cambridge Isotope Laboratories, Inc., Andover, MA, USA). 1 H and 19 F-NMR spectra were collected at 400 and 376 MHz, respectively, while 13 C { 1 H} and 11 B NMR spectra were collected at 100 and 128 MHz, respectively.Chemical shifts are expressed in ppm values.NMR spectra were processed with ACD/NMR Processor Academic Edition software (Version 12.01, Advanced Chemistry Development, Inc.).FT-IR spectra were recorded on a Bruker ALPHA-P spectrometer using a platinum ATR with a diamond ATR crystal.Spectra are reported in terms of frequency of absorption (cm ´1) and only partial data is provided.

General Procedure for the Synthesis of Alkynyl Potassium Organotrifluoroborate Salts
Potassium alkynyltrifluoroborate salts were prepared according to known procedures [4,5,16,51].To a solution of the indicated terminal alkyne (1.0 equiv.) in dry THF at ´70 ˝C under argon atmosphere was added n-BuLi (1.0 equiv.)dropwise, and the solution was stirred for 1 h at this temperature.Trimethylborate (1.5 equiv.) was added dropwise at ´60 ˝C.The solution was stirred at this temperature for 2 h.A saturated aqueous solution of KHF 2 (6.0 equiv.) was added at ´20 ˝C.The mixture was allowed to stir for 1 h at ´20 ˝C and for 1 h at room temperature.The solvent was removed under reduced pressure, and the resulting solid was placed under vacuum overnight to remove any remaining water.The solid was washed several times with hot acetone (4 ˆ10 mL), which was collected and concentrated to a volume of ~10 mL.The product was precipitated with diethyl ether (30 mL) and cooled to 4 ˝C to complete precipitation.The crystalline trifluoroborate salt was collected by gravity filtration.

General Procedure for the Synthesis of Alkenyl Potassium Organotrifluoroborate Salts
Potassium alkenyltrifluoroborate salts were prepared according to a procedure modified from Molander and coworkers [50].To a solution of the indicated boronic acid (1.0 equiv.) in Et 2 O (6 mL) was added KHF 2 (2.8 equiv.),followed by H 2 O (2.7 mL) over a period of 30 min.After stirring at rt for 3 h, the solvent was removed under reduced pressure, and the resulting solid was placed under vacuum overnight to remove any remaining water.The solid was washed several times with hot acetone (4 ˆ10 mL), which was collected and concentrated to a volume of ~10 mL.The product was precipitated with diethyl ether (30 mL) and cooled to 4 ˝C to complete precipitation.The crystalline trifluoroborate salt was collected by gravity filtration.

General Procedure for the Synthesis of Tetrahydrofurans
In a two-dram vial containing a stir bar, the indicated potassium trifluoroborate salt (1.5 equiv.) was added at room temperature followed by the addition of anhydrous acetonitrile (C = 0.1 M). 2-ethoxytetrahydrofuran (1.0 equiv.) was then added to the solution, and the solution was stirred at ´10 ˝C for 5 min.HBF 4 ¨OEt 2 (1.5 equiv.) was added to the stirring solution at ´10 ˝C.The solution was stirred at this temperature for 15 min.The reaction was quenched with water and extracted with 20 mL of ethyl acetate.The organic layer was washed with water (3 ˆ15 mL) followed by brine (1 ˆ10 mL).The organic layer was dried with MgSO 4 and concentrated.The crude product was purified by flash chromatography and concentrated.In the cases where a CH 3 CN/hexanes extraction was required, the product was solubilized in 5 mL of acetonitrile and 1 mL of hexanes was added forming a bi-layer.The two layers were thoroughly mixed and cooled to 0 ˝C in an ice bath to promote separation.The bottom acetonitrile layer was then removed and the extraction was performed again on the same hexanes layer.The acetonitrile extractions were then concentrated to afford the product.

Conclusions
In summary, a novel methodology for the alkenyl-and alkynylation of tetrahydrofuran has been developed.The reaction occurs rapidly between 2-ethoxytetrahydrofuran and a variety of alkenyl-and alkynyltrifluoroborate salts to yield the desired products in moderate to excellent yields.The reaction proceeds under mild Brønsted acid-catalyzed conditions within fifteen minutes.Further investigation into the scope of this reaction and its application towards bioactive compounds is currently ongoing.

Table 1 .
Optimization of conditions for the synthesis of tetrahydrofuran 1a.