Synthesis and application of azolium ionic liquid tagged TADDOL catalysts

Ionic liquid (IL) tagged organocatalysts based on TADDOL ( α , α,α ’, α ’-tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol) comprising various aryl substituents tethered with triazolium and imidazolium based ionic liquids are synthesised in good yields. Investigation of these IL-tagged catalysts on hydrogen-bonding catalyzed hetero-Diels-Alder (HDA) reactions between activated dienes (such as Rawal’s diene and Brassard’s diene) and benzaldehyde indicated their potential and limitations for applications in organocatalysis.

][8][9][10][11][12][13][14][15] Ionic liquid tagged catalysts can be tuned to attain a required physical property, such as solubility, or compatibility with the reaction medium and thermal stability. 1619]14 Accordingly, we envisaged that a properly functionalized ionic liquid tag can render TADDOLs novel properties and improve their usefulness as organocatalysts.Immobilizing TADDOL catalysts with ionic liquids has the potential to render the TADDOLs tuneable solubility for working under homogeneous conditions, without diminishing their catalytic activity or their amount of catalyst loading, unlike TADDOLs immobilized on solid supports.There have not been reports about investigations of the advantages of ionic liquid tags in immobilizing TADDOL catalysts.Here we report the results of our investigations on the use of 1,2,3-triazolium salts and imidazolium salts as suitable ionic liquid tags for TADDOLs (Figure 1, formula 2).
While imidazolium salts have been fully established as ionic liquids, 1,2,3-triazolium salts were unknown in this areas until recently.]13,9 They are easily accessible by Cu-catalyzed cycloaddition of azides and terminal alkynes (Meldal-Sharpless click reaction) 23 followed by N-alkylation of the resulting 1,2,3-triazole. 20,24Since functionality can be introduced virtually by all substituents found in the reactants this synthesis renders very versatile.In addition, the counterion can be easily changed for further tuning of the ionic liquid properties.

Result and Discussion
TADDOLs are often synthesized starting from dialkyl tartrate and a ketone or an aldehyde forming a 1,4-dioxolane with two ester functions, which are eventually transformed into diarylcarbinols by reaction with Grignard reagents. 2In principle, ionic liquid tags could be tethered either to the aryl groups of the carbinol substructures or to the substituents in position 2 of the dioxolane ring. 25We chose the latter possibility for its straightforwardness.In order to have much structural flexibility we established the TADDOL moiety at an early stage and various IL-tags were linked at a later stage by means of a propargyl group enabling Cu-catalyzed Meldal-Sharpless click reaction.Thus propargylated 3-hydroxybenzaldehyde 3 26,27 was condensed with dimethyl L-(+)-tartate 4 in the presence of trimethyl orthoformate and catalytic amounts of p-toluene sulfonic acid to furnish the intended dioxolane ring system 5 in good yield.Consecutively Grignard reaction (8 equivalents of Grignard reagent 6) was employed to introduce the necessary aromatic sub-units into the 3-propargyloxyisomer 5 smoothly to furnish the envisaged tetraaryl substituted products 7 (Scheme 1).The isomeric product of 5 which was obtained from 4-hydroxybenzaldehyde was found to be unstable and difficult to handle at the later stages of the synthesis.It furnished uncomfortably low yields in the consecutive steps.Seemingly, the electron donating property of the propargyloxy group at position 4 increased the ability to stabilize positive charges at the benzylidene position and thus renders the dioxolane ring more sensitive to ring opening under the influence of acids or Lewis acids, a phenomenon which was reported in the literature. 28ow the floor was laid for Cu (I)-catalyzed click reaction with azides.We chose butyl or benzyl azide 8 and used the well-established click reaction method utilizing Cu(II)-sulphate (25  mol%) in the presence of Na-ascorbate (20 mol%) in DMF:methanol (1:1) mixture.The 1,2,3triazoles 9 were obtained in excellent yields.The transformation into the corresponding 1,2,3triazolium iodides 10 was achieved in high yields by a straight forward alkylation using excess of methyl iodide (10 equivalents) in acetonitrile.Reactions attempted with other methylating agents such as methyl triflate (MeOTf) at room temperature and at -25 o C furnished very low yields.Nevertheless, exchange of iodide by other anions was possible by salt metathesis, such as with silver tetrafluoroborate leading to 1,2,3-triazolium tetrafluoroborates 11 in quantitative yields.
In order to attain imidazolium-tagged TADDOL catalysts we started with 4-(imidazole-1-yl)butanone 12, which was reported as the Michael addition product of imidazole to methyl vinyl ketone in the presence of catalytic amounts of N-methylimidazole in DMSO (Scheme 2). 29nlike in the reported procedures we used triethylamine base.The consecutive use of trimethyl orthoformate procedure previously applied for the synthesis of the analogous1,3-dioxolane 6 did not provide the desired product for ketone 12.This is presumably due to the low reactivity of the aliphatic ketone 12 as compared to the aldehyde 6 under this reaction condition.The 1,3dioxolane 13 was prepared in good yield by reaction of 12 with dimethyl tartrate in the presence of the Lewis acid boron trifluoride etherate in ethyl acetate.The subsequent Grignard reaction with phenyl magnesium bromide (10 fold excess) provided the carbinol 14 in 58 % yield.N-Methylation with methyl iodide (5 equivalents) to imidazolium salt 15 and further salt metathesis to the tetrafluoroborate 16 with silver tetrafluoroborate took place in excellent yields.
With these IL-tagged TADDOLs in hand we approached their application as IL-tagged organocatalysts.We report here our first attempts to use them in hetero-Diels -Alder reactions (HDA reaction) as potential recyclable catalysts.The IL-tagged TADDOL catalysts (10, 11, 15 and 16) were first investigated in the hydrogen-bonding promoted HDA reaction of Brassard's diene 17 with benzaldehyde (Table 1).Initially, the reaction was carried out at room temperature using 2.5 -5.0 molar equivalent of freshly distilled benzaldehyde in the presence of 20 mol % of catalyst.The catalysts constitute ionic liquid subunits, which have limited solubility in non-polar solvents.However, they are completely soluble in excess of benzaldehyde, which serves as a solvent for the neat reactions.Under these conditions the intended cycloadducts 18 were obtained, however, as racemates with low to moderate yields (Table 1).The same reaction was reported by K. Ding et al, 30 for non-supported naphthyl TADDOLs affording 67 % yield and 83 % ee.A cycloaddition product was not reported when the TADDOL catalyst was missing.In our cases the best yield (58 %) was obtained with the naphthyl TADDOL 11c at room temperature.As shown with the catalyst 11d (entries 8-10, Table 1) lowering the reaction temperature resulted in diminished yields.This effect can also be attributed to the fact that the viscosity of the mixture increased which hampers miscibility of the reaction solution and causes crystallization of the catalyst.In order to alleviate this problem, additional solvents such as toluene, dichloromethane and carbon tetrachloride were used.Non-polar solvents such as toluene often being considered to increase selectivity, 31 furnished only trace amounts of the product in our case (not shown).This can be ascribed to the low solubility of the IL-tagged catalysts in nonpolar solvents.The more polar solvent dichloromethane and carbon tetrachloride did not improve the yield or enantioselectivity (entries 11, 12, Table 1).a isolated yields.
The 1,2,3-triazolium and imidazolium tagged organocatalysts were further tested in HDA reaction of Rawal's diene 19 with benzaldehyde (Table 2).The reactions were carried out with 5-10 molar equivalent of benzaldehyde in the presence of 20 mol % of catalyst.At 0 °C and in the case of 10d, 11b and 13 even at -24 °C the intended cycloaddition adducts 20 were obtained in a non-enantioselective fashion in low yields.It turned out that phenyl substituted triazoliumtagged TADDOLs are less effective than 1-naphthyl-substituted TADDOLs (Table 2, compare enties 1, 2 and 3 or entries 3 and 5).Catalysts 11b and 15 even failed to give a product at -24 °C (entries 5 and 12).A more systematic variation of conditions was performed with catalyst 11d.Here, low enantioselectivities (maximum 26 % ee) were observed when the catalyst 11d (20 mol%) was used in the reactions conducted at -24 and -78 o C (entries 7 -8).Lowering the catalyst loading to 10 mol% resulted in a decrease in yield while the enantioselectivity was not affected (Table 2, entries 7 and 9) Since unlike Brassard´s diene Rawal's diene is reactive enough to undergo HDA reaction with benzaldehyde without the aid of any catalysts at room temperature the uncatalyzed cycloaddition is likely to run as background reaction thus giving low enantioselectivities or even racemic products. 32 The fact that 1-naphthyl-substituted TADDOLs perform better than phenyl-substituted ones in terms of enantioselectivity was well documented in the literature for untagged TADDOL catalysts. 30This improved efficiency is attributed to the better steric shielding ability of the naphthyl group and the stronger π-π donor-acceptor interaction (π-stacking) between the naphthyl substituents and the aldehyde.
When the IL-tagged TADDOLs were applied to the cycloaddition with Rawal´s diene an increase in the viscosity of the reaction medium and crystallization of the catalyst was observed with decreasing temperature as in the case of Brassard´s diene (v.s.).To circumvent this obstacle small amounts of toluene were added.However, this did not improve the solubility of the catalyst at lower temperatures. .When CH2Cl2 (entry 10, Table 2) and CCl4 (entry 11, Table 2) were used as solvents no enantioselectivities were observed and the yields were lower.Attempts to improve the selectivity by increasing the amount of IL-tagged organocatalyst at various temperatures had shown incomplete dissolution of the catalyst in the reaction mixture.Consequently, the investigations were made at a catalyst concentration of 20 % or less.

Conclusions
In summary, ionic liquid tagged TADDOLs are reported for the first time.1,2,3-Triazolium or imidazolium units were used as ionic liquid tags.The former were obtained via Meldal-Sharpless "click"-reaction of propargyloxy-substituted TADDOLs and N-methylation of the resulting 1,2,3-triazoles eventually followed by salt metathesis with silver tetrafluoroborate.The imidazolium moiety was introduced by the Michael-addition of imidazole to methyl vinyl ketone and building up the dioxolane ring with dimethyl tartrate followed by Grignard reaction and Nmethylation.Both synthetic routes are straight forward and allow the preparation of the ILtagged TADDOLs in good yields.The IL-tagged TADDOLs were applied to hetero-Diels Alder reactions between Brassard´s diene or Rawals´s diene and benzaldehyde.In the former case only racemic cycloaddition products were obtained while in latter case modest enantioselectivities were observed.

Experimental Section
General. 1 H-NMR and 13 C-NMR solution spectra were recorded at 300 MHz and 75 MHz, respectively; with a Bruker AC 300 in CDCl3 as the solvent in 5 mm NMR tubes with TMS as internal standard.The assignment of 13 C signals is based on APT measurements.HRMS was obtained with a Waters UPLC, LCT Premier XE instrument.Determination of enantioselectivities was achieved using chiral columns (Daicel Chemical Industries LTD), mobile phase: n-hexane : i-propanol (98:20 -80:20), flow rate: 0.5-1.0mL / min.The optical rotations were measured on a Perkin Elmer-241 polarimeter.The measurements were made at a wavelength of 589 nm using 100 x 3.5 mm cuvette.

3-Propargyloxybenzaldehyde (3).
A solution of 3-hydroxybenzaldehyde (3.66 g, 30 mmol) in DMF (50 mL) was placed in a two necked flask fitted with an efficient reflux condenser.Na2CO3 (12.45 g, 90 mmol) was added.The reaction mixture was heated to 55 -60 o C for half an hour and was cooled to room temperature.Then propargyl bromide 80% in toluene (4.05 mL, 36 mmol) was added.The reaction mixture was stirred at the same temperature while its progress was being followed by TLC.After completion (about 4 h) the mixture was poured into ice water (100 mL) with stirring.The resulting solution was extracted with Et2O (100 mL) three times.The combined organic extracts were washed with additional cold water (100 mL) two times and dried with MgSO4.The organic solvent was removed under reduced pressure to furnish the title product as a yellowish liquid.Yield 92%. 1 H NMR (300 MHz CDCl3):  ppm = 10.0 (s, 1H), 7.68 -7.37 (m, 3 H), 7.32 -7.16 (m, 1 H), 4.74 (d, J = 2.41, 2 H), 2.57 (t, J = 2.39, 2.39 Hz, 1 H). 13   (5).A solution of 3-propargyloxybenzaldehyde 3 ( 4.3 g, 26.9 mmol) in dry benzene (30 mL) at 0 o C was kept in a distillation set up under a steady flow of argon.(Caution: benzene is a carcinogenic substance).p-TsOH catalyst (172 mg, 1 mmol) was added followed by trimethyl orthoformate (TMOF) (4 mL, 30 mmol).The mixture was stirred at the same temperature for half an hour and L-(+)-dimethyl tartrate 4 (5.3 g, 30 mmol) was added.Then, it was heated gently to 60 o C, at which point an azeotropic distillate started.N.B.The temperature of the heating oil bath was kept between 75 -85 o C until the benzene/methanol azeotrope boiling at about 57 o C has ceased to distil off.The heating was continued until the temperature of the distillate increases to 80 o C.After the completion of the reaction was confirmed by TLC the remaining benzene was distilled off under reduced pressure within a well ventilated fume hood.The resulting oil was diluted with CH2Cl2, neutralized by Et3N and washed with distilled water (100 mL) and brine (100 mL) to furnish the title product (6) as a pale yellow oil.Yield 84%. 1   Grignard reagent was prepared from magnesium turnings (2.0 g, 83 mmol) in dry THF (80 mL) with a slow addition of bromobenzene (12.56 g, 80 mmol) in a three neck round-bottom flask fitted with a efficient condenser which has been oven dried and flushed with argon.The reaction mixture was set to reflux by itself with a controlled addition of the bromobenzene.After the complete consumption of the Mg tunings refluxing was continued for additional one hour using a water-bath.After this time the mixture was allowed to cool to room temperature and was further cooled to -15 o C. To it was added 2-(3-(prop-2-ynyloxy)phenyl)-1,3-dioxolane-4,5-dicarboxylate dimethyl ester 6 (3.2 g, 10 mmol) in dry THF (30 mL) while keeping the temperature below -10 o C.After complete addition of 6 the reaction flask was allowed to warm to room temperature and was left to stir overnight.The resulting solution was diluted by Et2O (200 mL) and quenched by concentrated NH4Cl 100 mL at 0 o C. The ether phase was separated and dried with MgSO4, the solvent was removed under vacuum to give a yellow solid, which was purified by silica gel column chromatography using cyclohexane: ethyl acetate (7.5:2.5) to furnish pure product as yellowish oil.Yield 63%. 1   ,5-diyl) bis(diphenylmethanol) 7a (1 g, 1,76 mmol) was dissolved in DMF : MeOH, 1:1 (20 mL).Butyl azide (174 mg, 1.76 mmol) and CuSO4 (71 mg, 0.44 mmol) was added followed by sodium ascorbate (70 mg, 0.35 mmol) with vigorous stirring.The mixture was left to stir for three days.The resulting solution was diluted with CH2Cl2 (200 mL) and was washed several times with ice cold water.The organic phase was separated and dried with MgSO4 and the solvent was removed under vacuum to give a yellow solid, which was purified by column chromatography using cyclohexane: ethyl acetate (7.5 : 2.5) to furnish the title product 9a.Yield 82%. 1 H NMR (300 MHz CDCl3):  = 7.73 -7.13 (m, 22 H), 7.03 -6.76 ( m, 3 H), 5.37 (d, J = 4.97 Hz, 1 H), 5.24 (s, 1 H), 5.20 (d, J = 4.96 Hz, 1 H), 5.09 (d, J = 2.69 Hz, 2 H), 4.33 (t, J = 7.23, 7.23 Hz, 2 H), 1.96 -1.82 (m, 2 H), 1.38 (dd, J = 14.77, 7.33 Hz, 2 H), 0.99 (t, J = 7.38, 7.38 Hz, 3 H). 13         ((4R,5R)-4-((3-(4,5bis(hydroxydiphenylmethyl)-1,3-dioxolan-2-yl)phenoxy)methyl)-1-butyl-3-methyl-1H-1,2,3triazol-3-ium iodide 10a (809 mg, 1 mmol) was dissolved in CH3CN (2 mL).To it was added AgBF4 (195 mg, 1.0 mmol).The mixture was stirred at room temperature for 1 hour.The AgI precipitate was filtered and volatiles were removed from the resulting liquid to furnish as a yellowish viscous liquid product.Yield 98%. 1 ).and to it was added AgBF4 (195 mg, 1.0 mmol).The reaction mixture was stirred at room temperature for 1 hour.The AgI precipitate was filtered and volatiles were removed from the resulting liquid to furnish the product as a brownish viscous liquid.Yield 99%. 1

4-(Imidazol-1-yl)butan-2-one (12)
. 29 To a stirred solution of imidazole (1.36 g, 20.0 mmol) in dry DMSO (20 mL) was added catalytic amount methylimidazole (82 mg, 1.0 mmol) and the mixture was cooled to 0 o C. To it was added methyl vinyl ketone (1.68 g, 24.0 mmol) and was allowed to warm to room temperature and heated up to 85 °C.When TLC indicated the complete consumption of the starting materials (about three hours) the reaction was made to cool to room temperature.It was diluted with distilled water (50 mL) and was extracted with ethyl acetate (50 mL) three times.The organic layer was separated and washed with additional water (50 mL).The organic phase was then dried with anhydrous sodium sulphate and volatiles were removed under reduced pressure to furnish the desired product as clear yellow oil.Yield 69 %. 1 H NMR (300 MHz CDCl3):  ppm = 7.40 (s, 1 H), 6.92 (s, 1 H), 6.87 (s, 1 H), 4.22 -4.05 (m, 2 H), 2.84 (m, 2 H), 2.06 (s, 3 H). 13 (920 mg, 6.75 mmol) were dissolved in ethyl acetate (25 mL).The reaction flask was placed in an ice bath to keep the temperature below 20 °C during the reaction.To the mixture was added BF3:OEt2 (3.6 mL, 13.5 mmol) dropwise.The reaction mixture was left to stir overnight.The resulting solution was poured into saturated sodium bicarbonate solution (50 mL) and was extracted with EtOAc (50 mL) three times.The organic layers were combined and washed with distilled water (50 mL) three times and dried over magnesium sulphate.Removal of volatiles under vacuum furnished the desired product as viscous liquid.Yield 78%. 1 30 The TADDOL catalyst 11d (97 mg, 0.1 mmol) was placed in a small reaction vial.The air was evacuated at 10 mbar and was flushed with argon three times.A freshly distilled benzaldehyde (256 mg, 2.5 mmol) was then injected and the contents were cooled to -24 o C. Brassard's diene 17 (102 mg, 0.5 mmol) was added and the mixture was stirred at -24 o C. At the completion of the reaction MeOH (0.5 mL) was added and stirred for 30 min at the same temperature.Volatiles were solvent was evaporated and the remainder was extracted with Et2O (3 mL) 3 times.The Et2O phase was removed to furnish the title product after column chromatography (Cyclohexane: Ethyl acetate, 2 : 1).Yield 49%. 1

Table 1 .
Selected examples of HDA reaction between Brassard's diene 17 and benzaldehyde