Camphorpyrazolium-based chiral functional ionic liquids

Tetrahedron: Asymmetry 25 (2014) 1280–1285

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy

Camphorpyrazolium-based chiral functional ionic liquids Jesús Pastrán a, Giuseppe Agrifoglio a, Teresa González b, Alexander Briceño b, Romano Dorta a,⇑,  a b

Departamento de Química, Universidad Simón Bolívar, Caracas, Venezuela Centro de Química, Instituto Venezolano de Investigaciones Cientificas, Miranda, Venezuela

a r t i c l e

i n f o

Article history: Received 25 June 2014 Accepted 31 July 2014

a b s t r a c t The solvent-less quaternization of N-phenyl-camphorpyrazole 4 with BrC4H9, IC2H4OCH3, and IC2H4OC2H4OC4H9 afforded the corresponding chiral pyrazolium halides 5a, 6a, and 7a in excellent yields. The anions were modified either by trihalide formation with Br2 and I2, or by salt metathesis with LiNTf2 and NaCo(CO)4. All pyrazolium salts bearing the di-ether side chain 7a–d were liquids at room temperature, while the X-ray crystal structure of the bis(trifluoromethylsulfonyl)amide salt of the corresponding mono-ether analogue 6c (mp 97 °C) revealed intermolecular H-bonding interactions. Furthermore, an improved protocol for the well-known but notoriously low-yielding synthesis of (+)-hydroxymethylenecamphor 3 is disclosed. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Pyrazolium-based ionic liquids have been receiving relatively little attention compared to their imidazolium-based analogues, in spite of the fact that both cations are structural isomers and have comparable physical properties.1 Chiral ionic liquids have great potential for a wide range of applications including asymmetric synthesis, enantioselective separation processes, NMR shift reagents, and liquid crystals.2 Schulz et al. demonstrated an effective transfer of chirality through ion pairing in chiral ionic liquids.3 For the above reasons, inexpensive camphorpyrazolium-based chiral ionic liquids seemed to be worthwhile synthetic targets. Furthermore, the combination of the role of a chiral ionic liquid with a reactive moiety creates potentially very useful chiral functional ionic liquids. Herein we report on the synthesis of new camphorpyrazolium-based chiral ionic liquids, some of which are accompanied by functional trihalide and cobaltate anions. 2. Results and discussion Camphor is a readily available building block from the ‘chiral pool’ that can be easily transformed into the corresponding pyrazolium salts. The camphor motif and similar derivatives have previously been used in the anionic part of chiral ionic liquids,3,4

⇑ Corresponding author. E-mail address: [email protected] (R. Dorta). Current address: Department Chemie und Pharmazie, Anorganische und Allgemeine Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstr. 1, 91058 Erlangen, Germany.  

http://dx.doi.org/10.1016/j.tetasy.2014.07.014 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

while herein it is integrated in the cationic part. We first found it necessary to optimize the synthesis of the starting material (+)hydroxymethylenecamphor 3 (see Scheme 1), a molecule known since the days of Claisen5 and an important chiral building block. By using standard protocols, compound 3 could be reproducibly obtained in only 20–30% yields from camphor via the in situ formation of the Na+ or K+ enolate of camphor 1, followed by the addition of formates.6 Even following an improved protocol that requires excess KH as the endizing base and successive in situ addition of ethyl formate,7 we were unable to obtain significantly higher yields of 3. We repeatedly monitored the immediate evolution of a gas when ethyl formate was added to the alkali camphor enolate/KH mixture at room temperature. The formation of CO upon contact of formates and formamides with a base has been described,8 and in the case of the synthesis of 3 it appears to be a competing side reaction at room temperature (Eq. 1). The low yields obtained by using standard protocols are due to loss of the ethyl formate electrophile in the form of gaseous CO upon reaction with the enolate or excess enolizing base. It should be noted that an excess of KH in the reaction mixture shifts the equilibrium (1) even further by liberating H2. O H

OEt

+ :B

CO (g) + EtO - + HB+

ð1Þ

To avoid these problems, we reacted the isolated and analytically pure potassium enolate 19 (Scheme 1) with ethyl formate at low temperature and on a 50 g scale. This afforded salt 2, which was isolated and then titrated with HCl in aqueous solution. At equivalence point copious amounts of 3 precipitated, and excellent yields of sublimed, analytically pure material were obtained (ca. 80%, >30 g

1281

J. Pastrán et al. / Tetrahedron: Asymmetry 25 (2014) 1280–1285 O OK H OK 1

OEt O

THF -78°C - RT

HCl titration

O O

H2O

2

H

N

ref.10 N

Ph 4

3

Scheme 1.

scale). We are unaware of NMR data for this product, and our material exhibited a characteristic proton resonance of the hydroxymethylene C–H proton at 6.7 ppm in CDCl3 solution (pure Z isomer), while in CD3OD the main resonance was due to the E-isomer, which appeared at 7.3 ppm (E/Z  88:12). With readily accessible 3 in hand, the multi-gram synthesis of 4 was straightforward, and its X-ray crystal structure (Fig. 1) confirmed the previous structural assignment based on 1D H NMR data.10 The asymmetric unit of 4 contains two crystallographically independent molecules, each with identical chirality of the stereogenic atoms. Molecular parameters such as torsion angles in each molecule differ significantly [for A: 40.5(3)°; for B: 47.0(3)°].

N

R

5b: R = C4H9; X = Br 7b: R = C2H4OC2H4OC4H9; X = I

N Ph

X2

no solvent

LiN(Tf)2 - LiX

R-X 4

X3

N

no solvent 125 °C

R

N Ph

X

H2O/AcMe CHCl3

5a: R = C4H9; X = Br 6a: R = C2H4OCH3; X = I 7a: R = C2H4OC2H4OC4H9; X = I

Na[Co(CO)4] - NaI

N

R

N Ph N(Tf)2 5c: R = C4H9 6c: R = C2H4OCH3 7c: R = C2H4OC2H4OC4H9

CH2Cl2

N

R

6d: R = C2H4OCH3 7d: R = C2H4OC2H4OC4H9

N Ph

[Co(CO)4]

Scheme 2.

Figure 1. View of the two independent molecules of 4 in the unit cell. H atoms are omitted. Selected bond lengths (Å) and angles (°) are: N1a–C12a 1.422(2), N1a–N2a 1.382(3), N2a–C2a 1.333(3), N1b–C12b 1.426(2), N1b–C1b 1.378(3), N2b–C2b 1.332(3), C12a–N1a–N2a 118.7(2), C1a–N1a–C12a 130.9(2), N2a–N1a–C1a 110.3(2), C12b–N1b–N2b 119.0(2), C12b–N1b–C1b 130.0(2), N2b–N1b–C1b 110.9(2).

Alkylation of 4 with a slight excess of butylbromide, methoxyethyliodide, and 1-butoxy-2-diethyl-ether-iodide afforded the camphorpyrazolium salts 5a, 6a, and 7a in fair to good yields (36–77%, see Scheme 2). These salts were then used as starting materials for anion exchange reactions as outlined in Scheme 2. The X-ray crystal structure of 6a along with a selection of structural parameters is presented in Figure 2. The torsion angle between the phenyl ring and the pyrazole ring is 74.2° (measured along N2–N1–C12–C13), and the structure shows disordered methoxy-ethyl side chains. No H-bridging interactions with the ether function or the anion are present. In an attempt to lower the melting points and viscosities of 5a, 6a, and 7a, we decided to introduce the bis(trifluoromethylsulfonyl)amide (NTf2) anion by metathetical exchange with LiN(Tf)2 in a water–acetone–CHCl3 mixture. Chiral ionic liquids 5c, 6c, and

7c were thus obtained in good to excellent yields (67–92%). Single crystals of 6c were grown by slow evaporation of an ethanol solution. A partial view of the crystal structure is depicted in Figure 3. The bis(trifluoromethanesulfonyl)amide anion was found to be disordered over two sets of positions. Self-assembly between the cations and anions is obtained from multiple supramolecular interactions, which showed five types of interactions. First, the hydrogen atoms of the phenyl ring of the chiral cation bridge the fluorine atoms of the anion. The CF3 groups also show F  H contacts with the bridge-head methyl groups of the camphor units. Thirdly, we observed O  H bridging between the sulfonyl group of the anion and the H-atom of the pyrazolium ring. Fourthly, the H-atom of one of the non-bridgehead methyl groups of the camphor unit bridges the O-atom of the ether side chain of a neighboring cation. Finally, the CF3 groups also show F  F interactions that are known to play a vital role in directing molecular assemblies.11 The cooperative effect of all of these H-bonding and F  F interactions may explain why, in this case, the NTf2 anion does not cause 6c to become a room temperature ionic liquid. It should be noted that the torsion angle between the phenyl and pyrazole rings in 6c is smaller than in 6a (66.9° vs 74.2°). Our interest in functional ionic liquids prompted us to synthesize the corresponding trihalide chiral ionic liquids 5b and 7b12 by reacting the bromide and iodide 5a and 7a with Br2 or I2, respectively. These reactions were high-yielding (91–93%) and tri-iodide 7b turned out to be a liquid at RT. The Co-containing chiral ionic liquids 6d and 7d were prepared by salt metathesis with Na[Co(CO)4] in CH2Cl2 in good isolated yields (87–88%) (Scheme 2).13 To the best of our knowledge, these are the first examples of transition metal based chiral ionic liquids. The results in Table 1 show that with the exception of 6a, all of the compounds may be classified as ionic liquids, even though only derivatives 7

1282

J. Pastrán et al. / Tetrahedron: Asymmetry 25 (2014) 1280–1285

Figure 2. View of the molecular structure of 6a in the crystal, with the ether side chain disordered over two sets of positions. Selected bond lengths (Å) and angles (°) are: N1– C1 1.337(6), N2–C8 1.329(8), N1–N2 1.371(6), N1–C12 1.445(7), N2–C18 1.481(7), C19A–O1A 1.51(2), O1A–C20 1.43(1), C19B–O1B 1.81(2), O1B–C20 1.38(2), C1–N1–N2 107.2(4), C1–N1–C12 128.9(4), N2–N1–C12 123.7(4), N1–C1–C7 109.5(4), C8–N2–N1 109.3(4), N2–C8–C7 108.9(5), C13–C12–N1 119.9(4), C17–C12–N1 118.4(4), N2–C18– C19A 113.0(7), C19A–O1A–C20 95.0(9), C19B–O1B–C20 108.0(1).

Figure 3. The crystal structure of salt 6c showing the network of secondary interactions and the disordered N(Tf) 2 anions (two sets of positions). Distances of the highlighted intermolecular interactions in Å are: H9b  O3aiv 2.833, H11c  F6iv 2.612, F5aiv  F2iii 2.776, F5iv  F3aiii 2.872, H16a  F1iii 2.800, H15a  F3iii 2.666, H15a  F2aiii 2.816, H9aii  O1 2.932, H4bii  O4aiii 2.725, H1aii  O4iii 2.775, H1aii  O5aiii 2.470, H19aii  O5iii 2.848, F5iii  F3aii 2.872, F2ii  F5aiii 2.776, H20bii  O3aii 2.648, H19bii  O3aii 2.763, H9bi  O3aii 2.833, H9ai  O1ii 2.932, H11ci  F6ii 2.612 Å.

of the salts than the corresponding mono-ether chain of the same length 5c and 6c, while the di-ether chain grants the lowest melting points in a series (mp(6c) > mp(5c) > mp(7c)). This may be explained by the lower packing efficiency caused by the presence of the ether function and the lengthening of the side chains.14 Similarly, the melting point is decreased by substituting the halide anions with bis(trifluoromethylsulfonyl)amide and tri-halide anions.15

Table 1

Compound

R

X

Yield (%)

Mp (°C)

5a 5b 5c 6a 6c 6d 7a 7b 7c 7d

–C4H9 –C4H9 –C4H9 –C2H4OCH3 –C2H4OCH3 –C2H4OCH3 –C2H4OC2H4OC4H9 –C2H4OC2H4OC4H9 –C2H4OC2H4OC4H9 –C2H4OC2H4OC4H9

Br Br3 NTf2 I NTf2 Co(CO)4 I I3 NTf2 Co(CO)4

36 93 67 55 78 87 77 91 92 88

78–80 70–72 80–82 136–138 94–95 62–64 Liquid at Liquid at Liquid at Liquid at

rt rt rt rt

with the di-ether chain are liquid at room temperature. The butyl chain appears to be more efficient in lowering the melting point

3. Conclusion New chiral camphorpyrazolium ionic liquids have been synthesized based on an improved preparation of the starting material (+)-hydroxymethylenecamphor 3. Some of the new salts are liquid at RT, and low melting points were achieved by the use of trihalide and bis(trifluoromethylsulfonyl)amide anions, and by N-alkylation

J. Pastrán et al. / Tetrahedron: Asymmetry 25 (2014) 1280–1285

with long chain poly-ether function. Transition metal containing chiral ionic liquids were also synthesized by introducing a cobaltate anion. 4. Experimental 4.1. General All reactions with air-sensitive compounds were carried out under anaerobic and anhydrous conditions, using standard Schlenk and glove box techniques. THF and Et2O were distilled under dry nitrogen from purple Na/Ph2CO solutions; pentane, hexanes, and THF-d8 from Na2K alloy; CH2Cl2 and CD2Cl2 from CaH2. Acetone (Fluka p.a., new and sealed bottle) and CDCl3 were degassed with three freeze–pump–thaw cycles and then kept in a glove box (CDCl3 additionally over activated 4 Å molecular sieves). The organic halides were distilled from CaH2 before use. NMR spectra were recorded on a Jeol 400 MHz spectrometer. Melting points were measured in sealed capillary tubes and are uncorrected. Values of c are in g/100 mL. Elemental analyses were performed at IVIC and samples were handled in air (hygroscopic compounds are corrected for water content) with the exception of 1, which was sampled in an Ar-filled glovebox. Commercial camphor was dried as follows: a mixture of camphor (65 g), activated MS 3 Å (20 g), and dry acetone was stirred overnight. After separation of the MS and evaporation of the acetone, camphor was sublimed bulb-to-bulb (102 mbar, 140 °C, ice-cooled receiver bulb). Commercial KH in oil (25 g) was washed with hexanes (4  50 mL) and dried in vacuo. Ethyl formate was dried over CaH2, fractionally distilled, and kept over activated MS 4 Å. Compound 4 was prepared according to the literature.10 4.1.1. Potassium-camphorenolate 1 Camphor (38.3 g, 252 mmol) was added portionwise over 10 min to a stirred slurry of KH (11.0 g, 274 mmol) in THF (500 mL). Immediate gas evolution took place and the reaction was thermoneutral. The reaction mixture was stirred for 18 h turning very slightly yellowish. A small amount of a solid residue was separated by GF-4 filtration, and the resulting clear solution was evaporated and dried in high vacuum for 12 h to afford a snowwhite powder (51.3 g, 99%). Elemental analysis found: C 62.90, H 8.20. Calcd for C10H15KO0.2THF: C 63.36, H 8.17. 1H NMR (400 MHz, THF-d8) d = 0.70 (s, 3H), 0.78 (s, 3H), 0.90 (s, 3H), 0.97–1.08 (m, 2H), 1.30–1.40 (m, 1H), 1.86–1.93 (m, 1H), 1.95– 2.01 (m, 1H), 3.47–3.52 (m, 1H), the spectrum indicated the presence of 0.2 equiv of THF. 13C NMR (101 MHz, THF-D8) d = 11.81, 21.65, 21.82, 31.59, 33.11, 50.47, 52.94, 54.99, 83.72, 178.49. 4.1.2. (1R,4S)-3-(Hydroxymethylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 3 Ethyl formate (50.0 mL, 0.62 mol) was added dropwise over 10 min to a clear yellowish solution of 1 (50.0 g, 0.263 mol) in THF (800 mL) at 78 °C and the resulting clear mixture was stirred for 1 h at this temperature and then allowed to gradually warm to RT over 12 h. The onset of the reaction was observed between 30 and 25 °C, when large amounts of a white solid started precipitating. The mixture was then evaporated to dryness, and the pinkish white solid was mechanically crushed and dried in vacuo. The addition of water (600 mL) afforded a yellow solution and a white supernatant solid, which was filtered off (ca. 6 g of a wet solid smelling of camphor). The yellow solution was titrated against HCl 0.9 M with ca. 280 mL to induce a precipitation of pale yellow clumps. An additional 20 mL of HCl 0.9 M assured a pH  1–2, and the solid was separated by filtration, washed with copious amounts of water, dried in a desiccator (2d, do not high vacuum

1283

dry to avoid product loss by sublimation!), and then sublimed in a Kugelrohr apparatus (100 °C, 5  102 mbar, bulbs cooled with dry ice) to afford 37.4 g (79%) of a soft white solid. Mp: 74–76 °C. Anal. Found: C 73.51, H 8.91. Calcd for C11H16O2: C 73.30, H 8.95. 1 [a]25 D = +76.5 (c 4.24, CHCl3). H NMR (400 MHz, CDCl3) d = 0.85 (s, 3H), 0.93 (s, 3H), 0.97 (s, 3H), 1.35–1.50 (m, 2H), 1.65–1.75 (m, 1H), 1.95–2.10 (m, 1H), 2.44 (d, J = 4 Hz, 1H), 6.78 (s, 1H), 7.0–9.0 (br, 1H). 13C NMR (101 MHz, CDCl3) d = 8.5, 18.7, 20.3, 27.7, 30.1, 46.6, 49.8, 58.5, 119.4, 151.7, 212.8. 4.1.3. General protocol for the preparation of pyrazolium salts Compound 4 and alkyl or alkoxy halides were mixed at room temperature in a 100 mL Schlenk tube. After the sample was cooled to 180 °C, the tube was evacuated and filled with N2. The reaction mixture was heated at 125 °C for 18 h. The residue was washed with diethyl ether and dried under vacuum for 4 h. Single crystals of 4 suitable for an X-ray diffraction study were obtained by slow evaporation of a saturated diethyl ether solution. 4.1.4. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-butyl-4,5,6,7-tetrahydro-4,7-methanoindazolium bromide 5a Compound 4 (1.00 g, 3.96 mmol) and bromobutane (5.80 g, 42.3 mmol). Recrystallization from acetone provided a hygroscopic white solid (548 mg, 36%). Anal. Calcd: C21H29BrN23H2O: C 56.88, H 7.96, N 6.32. Found: C 57.52, H 7.73, N 6.30. Mp 78–80 °C; 1 [a]25 D = +13.3 (c 2.70, C2H5OH). H NMR (CDCl3): d = 0.75 (t, 3H, J = 7.5 Hz, CH3), 0.77 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.13–1.23 (m, 2H, CH2), 1.38–1.46 (m, 2H, CH2), 1.55–1.62 (m, 2H, CH2), 1.82–1.89 (m, 1H, CH), 2.13–2.16 (m, 1H, CH), 3.08–3.09 (d, J = 3.6 Hz, 1H, CH), 4.21–4.28 (m, 1H, CH), 4.44– 4.51 (m, 1H, CH), 7.50–7.70 (m, 5H, aromatics), 8.72 (s, 1H, CH). 13 C{1H} NMR (CDCl3): d = 10.15, 13.45, 18.71, 19.36, 20.39, 26.63, 31.74, 33.25, 47.67, 50.01, 54.31, 63.22, 128.27, 128.46, 128.82, 130.48, 130.86, 131.08, 131.65, 132.87, 161.76. 4.1.5. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-methoxyethyl-4,5,6,7tetrahydro-4,7-methanoindazolium iodide 6a Compound 4 (300 mg, 1.19 mmol) and 1-methoxyethyl iodide (600 mg, 3.23 mmol). Recrystallization from acetone provided a hygroscopic white solid (285 mg, 55%). Anal. Calcd: C20H27IN2O: C 54.80, H 6.21, N 6.39. Found: C 54.61, H 6.29, N 6.34. Mp: 136– 1 138 °C. [a]25 D = +6.5 (c 3.10, C2H5OH). H NMR (CDCl3): d = 0.80 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.46–1.48 (m, 2H, CH2), 1.88–1.90 (m, 1H, CH), 2.16–2.18 (m, 1H, CH), 3.07–3.08 (d, J = 4.0 Hz, 1H, CH), 3.27 (s, 3H, CH3), 3.67–3.68 (m, 1H, CH), 3.74–3.76 (m, 1H, CH), 4.34–4.36 (m, 1H, CH), 4.59–4.60 (m, 1H, CH), 7.63–7.70 (m, 5H, aromatics), 8.55 (s, 1H, CH). 13C{1H} NMR (CDCl3): d = 10.06, 18.73, 20.38, 26.55, 33.19, 47.63, 49.76, 54.27, 59.09, 63.35, 70.41, 128.94, 129.01, 129.08, 130.34, 130.60, 130.83, 130.99, 132.87, 161.91. Single crystals suitable for an Xray analysis were obtained by slow diffusion of hexane into a CH2Cl2 solution of 6a. 4.1.6. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-(30 ,60 -dioxadecyl)-4,5, 6,7-tetrahydro-4,7-methanoindazolium iodide 7a Compound 4 (700 mg, 2.77 mmol) and 1-butoxy-2-diethylether iodide (827 mg, 3.04 mmol). Washing with Et2O (3  5 mL) gave an 1 orange syrup (1130 mg, 77%). [a]25 D = +5.7 (c 1.80, C2H5OH). H NMR (CDCl3): d = 0.77 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.89 (t, J = 7.5 Hz, 3H, CH3), 0.96 (s, 3H, CH3), 1.32–1.34 (m, 2H, CH2), 1.45– 1.55 (m, 4H, CH2), 1.90 (m, 1H, CH), 2.17 (m, 1H, CH), 3.06 (d, J = 4.0 Hz, 1H, CH), 3.40 (m, 2H, CH2), 3.48 (m, 2H, CH2), 3.55 (m, 2H, CH2), 3.80 (m, 1H, CH), 3.92 (m, 1H, CH), 4.31–4.36 (m, 1H, CH), 4.58–4.62 (m, 1H, CH), 7.60–7.73 (m, 5H, aromatic), 8.65 (s, 1H, CH). 13C{1H} NMR (CDCl3): d = 10.07, 14.02, 18.79, 19.38, 20.41, 26.64, 31.87, 33.23, 47.66, 49.75, 54.21, 63.29, 69.19,

1284

J. Pastrán et al. / Tetrahedron: Asymmetry 25 (2014) 1280–1285

69.84, 70.49, 71.14, 128.89, 129.23, 129.46, 130.20, 130.48, 131.09, 132.79, 161.71. 4.1.7. General protocol for the preparation of trihalide ionic liquids Either Br2 or I2 was slowly added to a stirred CH2Cl2 solution of the corresponding (+)-camphorpyrazolium bromide or iodide, respectively, at ca. 15 °C. After stirring overnight the volatiles were evaporated, and the product was washed with hexanes and dried in vacuo for 8 h. 4.1.8. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-butyl-4,5,6,7-tetrahydro-4,7-methanoindazolium tribromide 5b Br2 (450 mg, 2.81 mmol) and 5a (1.01 g, 2.59 mmol). Orange solid (1.322 g, 93%). Anal. Calcd: C21H29Br3N2: C 45.93, H 5.32, N 5.10. Found: C 45.99, H 5.48, N 5.03. Mp: 70–72 °C. 1 [a]25 D = +7.9 (c 5.40, C2H5OH). H NMR (CDCl3): d = 0.82 (s, 3H, CH3), 0.84 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.97 (s, 3H, CH3), 1.23–1.28 (m, 2H, CH2), 1.44–1.55 (m, 2H, CH2), 1.69–1.75 (m, 2H, CH2), 1.92–1.97 (m, 1H, CH), 2.17–2.20 (m, 1H, CH), 3.15 (d, J = 3.67 Hz, 1H, CH), 4.08–4.18 (m, 2H, CH2), 7.57–7.77 (m, 5H, CH-aromatics), 8.01 (s, 1H, CH-pyrazolium). 13C{1H} NMR (CDCl3): d = 10.17, 13.50, 18.79, 19.66, 20.53, 26.75, 31.49, 33.33, 47.75, 50.21, 54.53, 63.51, 128.54, 129.21, 130.31, 130.82, 131.08, 133.12, 162.34. 4.1.9. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-(30 ,60 -dioxadecyl)-4,5, 6,7-tetrahydro-4,7-methanoindazolium triiodide 7b I2 (152 mg, 0.599 mmol) and 7a (313 mg, 0.599 mmol). Dark brown hygroscopic syrup (426 mg, 91%) Anal. Calcd: C25H37I3N2O2 2H2O: C, 36.87; H, 5.07; N, 3.44. Found: C, 36.87; H, 4.59; N, 3.42. 1 [a]25 D = +3.5 (c 1.30, C2H5OH). H NMR (CDCl3): d = 0.82 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.35–1.37 (m, 2H, CH2), 1.49–1.56 (m, 4H, 2CH2), 1.97–2.00 (m, 1H, CH), 2.21– 2.24 (m, 1H, CH), 3.16–3.17 (d, J = 3.6 Hz, 1H, CH), 3.43–3.62 (m, 6H, CH2), 3.70–3.90 (m, 2H, CH2), 4.27–4.33 (m, 2H, CH2), 7.64– 7.75 (m, 5H), 8.16 (s, 1H). 13C{1H} NMR (CDCl3): d = 10.18 ppm, 14.14, 18.86, 19.45, 20.67, 26.83, 31.94, 33.44, 47.74, 50.07, 54.52, 63.60, 68.61, 69.95, 70.78, 71.27, 129.03, 129.26, 129.37, 130.52, 130.80, 130.99, 131.08, 131.29, 133.24, 162.52. 4.1.10. General preparation of bis(trifluoromethylsulfonyl)amide ionic liquids A solution of LiN(Tf)2 in water (5 mL) was slowly added to the pyrazolium halides in a water–acetone mixture (1:1) under magnetic stirring for 2 h to afford a white solid or colorless oil. The product was extracted in CHCl3 (3  5 mL), dried over MgSO4, filtered, evaporated to dryness, and left in a vacuo for 8 h. 4.1.11. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-butyl-4,5,6,7-tetrahydro-4,7-methanoindazolium bis(trifluoromethylsulfonyl)amide 5c LiN(Tf)2 (121 mg, 0.421 mmol) and 5a (154 mg, 0.393 mmol). White solid (154 mg, 67%). Anal. Calcd: C23H29F6N3O4S2: C 46.85, H 4.96, N 7.13, S 10.88. Found: C 47.25, H 5.07, N 7.18, S 11.04. 1 Mp: 80–82 °C. [a]25 H NMR (CDCl3): D = +8.4 (c 1.06, C2H5OH). d = 0.79 (s, 6H, 2CH3), 0.82 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.13– 1.23 (m, 2H, CH2), 1.33–1.43 (m, 2H, CH2), 1.58–1.66 (m, 2H, CH2), 1.90–1.95 (m, 1H, CH), 2.15–2.21 (m, 1H, CH), 3.07–3.08 (d, J = 4.0 Hz 1H, CH), 3.99–4.08 (m, 2H, CH2), 7.47–7.75 (m, 5H), 7.86 (s, 1H). 13C{1H} NMR (CDCl3): d = 10.01, 13.18, 18.67, 19.37, 20.15, 26.46, 31.29, 33.02, 47.60, 49.67, 54.45, 63.39, 115.17, 118.36, 121.57, 124.76, 128.08, 128.18, 129.24, 129.89, 130.67, 130.87, 130.93, 133.08, 162.31.

4.1.12. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-methoxyethyl-4,5, 6,7-tetrahydro-4,7-methanoindazolium bis(trifluoromethylsulfonyl)amide 6c LiN(Tf)2 (161 mg, 0.561 mmol) and 6a (219 mg, 0.497 mmol). White solid (227 mg, 78%). Anal. Calcd: C22H27F6N3O5S2: C 44.67, H 4.60, N 7.10. Found: C 44.77, H 4.72, N 7.12. Mp: 94–95 °C. 1 [a]25 D = +4.3 (c 1.03, C2H5OH). H NMR (CDCl3): d = 0.79 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.36–1.40 (m, 2H, CH2), 1.90–1.92 (m, 1H, CH), 2.16–2.20 (m, 1H, CH), 3.07–3.08 (d, J = 3.68 Hz, 1H, CH), 3.26 (s, 3H, CH3), 3.54–3.58 (m, 2H, CH2), 4.14– 4.21 (m, 2H, CH2), 7.48–7.71 (m, 5H), 7.89 (s, 1H). 13C{1H} NMR (CDCl3): d = 9.97, 18.66, 20.11, 26.47, 32.98, 47.56, 49.21, 54.41, 58.94, 63.37, 69.69, 115.14, 118.34, 121.54, 124.74, 128.33, 128.76, 129.34, 130.26, 130.52, 130.73, 133.02, 162.41, 177.05. 4.1.13. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-(30 ,60 -dioxadecyl)-4, 5,6,7-tetrahydro-4,7-methanoindazolium bis(trifluoromethylsulfonyl) amide 7c LiN(Tf)2 (1.728 g, 6.019 mmol) and 7a (3158 mg, 5.998 mmol). Orange oil (3.76 g, 92%). Anal. Calcd for: C27H37F6N3O6S2: C 47.85, H 5.50, N 6.20, S 9.46. Found: C 47.81, H 5.39, N 6.35, S 9.37. 1 [a]25 D = +2.1 (c 2.27, C2H5OH). H NMR (CDCl3): d = 0.78 (s, 3H, CH3), 0.82 (s, 3H, CH3), 0.88–0.91 (t, J = 7.2 Hz, 3H, CH3), 0.97 (s, 3H, CH3), 1.33–1.38 (m, 4H, 2CH2), 1.52–1.54 (m, 2H, CH2), 1.90– 1.93 (m, 1H, CH), 2.15–2.20 (m, 1H, CH), 3.06–3.07 (d, J = 4.0 Hz, 1H, CH), 3.39–3.43 (t, J = 6.8 Hz, 4H, 2CH2), 3.49–3.80 (m, 4H, 2CH2), 4.16–4.22 (m, 2H, CH2), 7.58–7.71 (m, 5H), 8.02 (s, 1H). 13 C{1H} NMR (CDCl3): d = 9.95, 13.95, 18.68, 19.34, 20.15, 26.51, 31.85, 32.99, 47.59, 49.23, 54.34, 63.31, 68.37, 69.79, 70.44, 71.13, 115.21, 118.34, 121.54, 123.89, 128.48, 129.03, 129.28, 130.18, 130.29, 130.41, 130.63, 130.81, 132.97, 162.21. 4.1.14. General protocol for the preparation of tetracarbonylcobaltate ionic liquids A solution of Na[Co(CO)4] in CH2Cl2 was added slowly to the pyrazolium salts in dichloromethane under stirring for 18 h to afford a yellow solution. The solvent was then evaporated and the residue was dried in vacuo. The crude product was redissolved in fresh CH2Cl2, the salts filtered off, and the solution evaporated to dryness. The resulting solid was washed with pentane and dried in vacuo. 4.1.15. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-methoxyethyl-4,5,6, 7-tetrahydro-4,7-methanoindazolium tetracarbonylcobaltate 6d Na[Co(CO)4] (221 mg, 1.14 mmol) and 6a (500 mg, 1.14 mmol). White hygroscopic solid (474 mg, 84%). Anal. Calcd for C24H27CoN2 O53/2H2O: C 56.58, H 5.94, N 5.50. Found: C 56.26, H 6.03, N 6.10. 1 Mp: 62–64 °C; [a]20 D = +27.0 (c 0.18, C2H5OH). IR (KBr): 1888 cm [[Co(CO)4]]. 1H NMR (THF-d8): d = 0.83 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.99 (s, 3H, CH3), 1.39–1.41 (m, 1H, CH), 1.53–1.56 (m, 1H, CH), 1.94–1.98 (m, 1H, CH), 2.18–2.22 (m, 1H, CH), 3.11–3.12 (d, 1H, CH), 3.27 (s, 3H, CH3), 3.60–3.70 (m, 2H, CH2) 4.26–4.40 (m, 2H, CH2), 7.70–7.77 (m, 5H), 8.28 (s, 1H). 13C{1H} NMR (THF-d8): d = 9.34, 17.94, 19.58, 26.45, 32.68, 47.60, 49.29, 54.15, 58.12, 63.11, 69.69, 128.98, 129.19, 130.22, 130.37, 130.63, 131.17, 132.62, 161.78. 4.1.16. (4S,7R)-7,8,8-Trimethyl-1-phenyl-2-(30 ,60 -dioxadecyl)-4, 5,6,7-tetrahydro-4,7-methanoindazolium tetracarbonylcobaltate 7d Na[Co(CO)4] (527 mg, 2.72 mmol) and 7a (1417 mg, 2.70 mmol). Green oil (1.467 g, 96%). Anal. Calcd for C29H37CoN2O6 H2O: C 59.38, H 6.70, N 4.78. Found: C 59.16, H 6.80, N 5.17. 1 [a]25 [Co(CO)4]. 1H D = +14.0 (c 0.18, C2H5OH). IR (KBr): 1889 cm NMR (CD2Cl2): d = 0.79 (s, 3H, CH3), 0.82 (s, 3H, CH3), 0.88–0.94

J. Pastrán et al. / Tetrahedron: Asymmetry 25 (2014) 1280–1285

(m, 3H, CH3), 0.97 (s, 3H, CH3), 1.30–1.40 (m, 4H, 2CH2), 1.52 (m, 2H, CH2), 1.94–1.99 (m, 1H, CH), 2.22 (s, 1H, CH), 3.11 (s, 1H, CH), 3.40–3.64 (m, 8H, 4CH2), 4.07 (s, 2H, CH2), 7.40–7.75 (m, 5H), 7.94 (s, 1H). 13C{1H} NMR (CD2Cl2): d = 9.81, 13.83, 18.50, 19.45, 20.64, 27.33, 31.97, 33.64, 48.00, 49.23, 54.20, 63.57, 68.91, 70.01, 70.92, 71.13, 129.44, 129.61, 130.54, 130.61, 130.69, 130.91, 133.21, 162.69. 4.1.17. Crystal structure determinations Intensity data were recorded at room temperature on a Rigaku AFC-7S diffractometer equipped with a Mercury CCD detector using monochromated Mo(Ka) radiation (k = 0.71070 Å). Experimental details on unit cell and intensity measurements can be found in the CIF file deposited at the Cambridge Crystallographic Data Centre with the CCDC numbers 1007388 for 4, 1007390 for 6a, and 1007389 for 6c. An empirical absorption correction (multi-scan) was applied to all the data using the CrystalClear crystallographic software package.16 The structures were solved by direct methods and refined by full-matrix least-squares on F2. The H-atoms on C were placed in calculated positions using a riding atom model with fixed C–H distances [0.93 Å for C(sp2, CH), 0.96 Å for C(sp3, CH3), and 0.97 Å for C(sp3, CH2)]. All the H atoms were refined with isotropic displacement parameters set to 1.2  Ueq for C(sp2) and 1.5 for C(sp3) of the attached atom. In the structure 6a, the methoxy-ethyl chain was found disordered over two sets of positions. Likewise, in the structure of 6c, the bis(trifluoromethanesulfonyl)amide anion was found disordered over two sets of positions. All the refinement calculations were made using SHELXTL-NT.17 Acknowledgments

2.

3. 4.

5. 6. 7. 8. 9.

10. 11. 12.

13.

14. 15.

This work was supported by DID-USB and FONACIT (Projects S1-2001000851 and LAB-97000821). We thank Ms. Noelani Cigüela for technical assistance (NMR laboratory, USB). 16.

References 1. (a) Mamantov, G.; Caja, J.; Dunstan, T. D. J. US Pat. US 5,552,241 A, 1996.; (b) Deetlefs, M.; Seddon, K. R. Green Chem. 2003, 5, 181; (c) Abu-Lebdeh, Y.; Alarco, P.; Armand, M. Angew. Chem. Int. Ed. 2003, 42, 4499; (d) Cheng, J.; Li, Z.; Haught,

17.

1285

M.; Tang, Y. Chem. Commun. 2006, 4617; (e) Abu-Lebdeh, Y.; Abouimrane, A.; Alarco, P.-J.; Armand, M. J. Power Sources 2006, 154, 255; (f) Wasserscheid, P. US Pat. US 7,252,791 B2, 2007. For reviews, see (a) Baudequin, C.; Badoux, J.; Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2003, 14, 3081; (b) Baudequin, C.; Brégeon, D.; Levillain, J.; Guillen, F.; Gaumont, A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2005, 16, 3921; (c) Ohno, H.; Fukumoto, K. Acc. Chem. Res. 2007, 40, 1122; (d) Payagala, T.; Armstrong, D. W. Chirality 2012, 24, 17; For recent examples, see (e) Truong, T.-K.-T.; Vo-Thanh, G. Tetrahedron 2010, 66, 5277; (i) Hu, W.; Zhang, L.; Cao, H.; Song, L.; Zhao, H.; Yang, Z.; Cheng, Z.; Yang, H.; Guo, L. Phys. Chem. Chem. Phys. 2010, 12, 2632. Schulz, P. S.; Müller, N.; Bösmann, A.; Wasserscheid, P. Angew. Chem. Int. Ed. 2006, 46, 1293. (a) Ishida, Y.; Miyauchi, H.; Saigo, K. Chem. Commun. 2002, 2240; (b) Machado, M. Y.; Dorta, R. Synthesis 2005, 15, 2473; (c) Nobuoka, K.; Kitaoka, S.; Kunimitsu, K.; Iio, M.; Harran, T.; Wakisaka, A.; Ishikawa, Y. J. Org. Chem. 2005, 70, 10106; (d) Winkel, A.; Wilhelm, R. Eur. J. Org. Chem. 2010, 5817. Bishop, A. W.; Claisen, L.; Sinclair, W. Justus Liebigs Ann. Chem. 1894, 281, 314. (a) Lintvedt, R. L.; Fatta, A. M. Inorg. Chem. 1968, 7, 2489; (b) Brunner, H.; Scheck, T. Chem. Ber. 1991, 125, 701. LeCloux, D. D.; Tokar, C. J.; Osawa, M.; Houser, R. P.; Keyes, M. C.; Tolman, W. B. Organometallics 1994, 13, 2855. Powers, J. C.; Seidner, R.; Parsons, T. G.; Berwin, H. J. Org. Chem. 1966, 31, 2623. The use of less than 10 mol % excess of the rather expensive KH to prepare enolate 1 is noteworthy (for example the procedure in Ref. 7 uses a fivefold excess). Nagai, S.; Oda, N.; Ito, I.; Kudo, Y. Chem. Pharm. Bull. 1979, 27, 1771. Nayak, S. K.; Reddy, M. K.; Row, T. N. G.; Chopra, D. Cryst. Growth Des. 2011, 11, 1578. Compounds that contain the tri-iodide anion are widely known to exhibit antimicrobial and antibacterial activities. See for example: (a) He, S.; Wang, B.; Chen, H.; Tang, C.; Feng, Y. Appl. Mater. Interfaces 2012, 4, 2116–2123; (b) Shelanski, H. A. US Pat. US2,739,922. Transition metal containing functional ionic liquids form potentially useful catalytic biphasic media. For rare examples of room temperature ionic liquids containing transition metals, see: (a) Brown, R. J. C.; Dyson, P. J.; Ellis, D. J.; Welton, T. Chem. Commun. 2001, 1862–1863; (b) Noguera, G.; Mostany, J.; Agrifoglio, G.; Dorta, R. Adv. Synth. Catal. 2005, 347, 231; (c) Deng, F.; Hu, B.; Sun, W.; Chen, J.; Xia, C. Dalton Trans. 2007, 4262–4267. Henderson, W. A.; Young, V. G., Jr.; Fox, D. M.; De Long, H. C.; Trulove, P. C. Chem. Commun. 2006, 3708. Trihalides are known to lower the melting points of imidazolium and pyridinium salts: (a) Bortolini, O.; Bottai, M.; Chiappe, C.; Conte, V.; Pieraccini, D. Green Chem. 2002, 4, 621; (b) Chiappe, C.; Leandro, E.; Pieraccini, D. Chem. Commun. 2004, 2536; (c) Bao, W.; Wang, Z. Green Chem. 2006, 8, 1028; (d) Salazar, J.; Dorta, R. Synlett 2004, 1318. CRYSTALCLEAR, Software Users Guide, Version 1.3.6; Rigaku/MSC: The Woodlands, TX, USA, 2000. Bruker SHELXTL-NT. Version 5.1; Bruker AXS: Madison, Wisconsin, USA, 1998.