Tandem ionic liquid antimicrobial toxicity and asymmetric catalysis study: Carbonyl-ene reactions with trifluoropyruvate

Article abstract of DOI:10.1039/c3gc40875b

The asymmetric carbonyl-ene reaction of trifluoropyruvate with five alkenes catalysed by [Pd{(R)-BINAP}](SbF₆)₂ were carried out in good yields and enantioselectivities (up to 96% yield and 96% ee) in low antimicrobial toxicity C2-substituted imidazolium ionic liquids (ILs). Toxicity data was included in the selection criteria for reaction optimisation after a preliminary IL screen. The Pd(ii) catalyst immobilised in an IL was recycled and reused up to 7 times without decrease of either yield or ee. One IL prepared, which was determined to be of high antimicrobial toxicity was assigned a low priority for future applications.

Full text of DOI:10.1039/c3gc40875b

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Tandem ionic liquid antimicrobial toxicity and
asymmetric catalysis study: carbonyl-ene reactions
Cite this: DOI: 10.1039/c3gc40875b
with trifluoropyruvate†
Rohitkumar G. Gore,a Thi-Kim-Thu Truong,a Milan Pour,b Lauren Myles,c
Stephen J. Connon*c and Nicholas Gathergood*a
The asymmetric carbonyl-ene reaction of trifluoropyruvate with five alkenes catalysed by [Pd{(R)-BINAP}]-
(SbF6)2 were carried out in good yields and enantioselectivities (up to 96% yield and 96% ee) in low anti-
microbial toxicity C2-substituted imidazolium ionic liquids (ILs). Toxicity data was included in the selection
criteria for reaction optimisation after a preliminary IL screen. The Pd(II) catalyst immobilised in an IL was
recycled and reused up to 7 times without decrease of either yield or ee. One IL prepared, which was
determined to be of high antimicrobial toxicity was assigned a low priority for future applications.
Received 11th May 2013,
Accepted 9th July 2013
DOI: 10.1039/c3gc40875b
www.rsc.org/greenchem
and ethyl trifluoropyruvate catalysed by Lewis acid-platinum
Introduction
group metal complexes of the type [M{(R)-BINAP}]2+ (M = Pt,
The enantioselective carbonyl-ene reaction1 has gained much Pd, Ni).8k This study revealed subtle but significant differences
attention in the past two decades as an atom-economic, in the reactivity of these catalysts. For instance, the palladium-
reliable and convenient process for generating homoallylic based Lewis acid [Pd-{(R)-BINAP}]2+ catalyses the ene reaction
alcohols, which are important building blocks for the syn- between methylene cycloalkanes and ethyl trifluoropyruvate to
thesis of many natural products and pharmaceutical com- afford the expected α-hydroxy ester in good yield and excellent
pounds.2,3 The achievement of high enantioselectivity has diastereo- and enantioselectivity. In contrast, under the same
been reported, initially in 1988, when Yamamato presented conditions, the corresponding [M{(R)-BINAP}]2+ (M = Pt, Ni)
the first asymmetric carbonyl-ene reaction using modified Al- catalyses both the isomerisation of methylene cycloalkane and
BINAP complexes.4 Subsequently Mikami and other groups the ene reaction of the resulting mixture of methylene
developed Ti-BINOL catalysts,5 while Evans and co-workers cycloalkane and 1-methylcycloalkene at similar rates to afford
reported that both Cu-Box6 and Sc-PyBox7 were efficient cata- a range of α-hydroxy esters in high regioselectivity, good
lysts. Other metal complexes derived from Pd and Pt,8 Co,9 diastereoselectivity, and good to excellent enantioselectivity. In
Ni,10 Cr,11 In3 and several lanthanides12 have also been used addition, [Pt{(R)-BINAP}]2+ also catalyses post-reaction isomeri-
to catalyse this reaction. Mikami and co-workers obtained high sation of the ene product as well as consecutive ene reactions
enantioselectivities (between 84% and 98% ee) in the reactions to afford a double carbonyl-ene product.8k In another study by
of ethyl trifluoropyruvate and alkenes catalysed by a ‘naked’ this research group, with the same reaction model, it revealed
palladium(II) complex with the chiral atropos-SEGPHOS and an that platinum complexes of enantiopure conformationally
atropos-platinum complex with BIPHEP.8b,n–o Doherty et al. flexible tropos NUPHOS diphosphines either rival or outper-
reported a comparative study of the carbonyl-ene reaction form their atropisomeric enantiopure BINAP counterparts.8p
between a range of 1,1′-disubstituted or trisubstituted alkenes Recently, Luo and co-worker reported that the Pd(II)-BINA-
PHANE catalyst afforded both good yields and excellent enan-
tiomeric excess as high as 99.6% in the case of the carbonyl-
aSchool of Chemical Sciences and National Institute for Cellular Biotechnology,
ene reaction between ethyl trifluoropyruvate and alkenes.8m
Dublin City University, Glasnevin, Dublin 9, Ireland.
Chiral transition metal complexes in asymmetric catalysis
E-mail: Nick.Gathergood@dcu.ie; Fax: +35 317005503
bCentre for New Antivirals and Antineoplastics, Department of Inorganic and Organic
Chemistry, Charles University, Faculty of Pharmacy, Heyrovskeho 1203, CZ-500 03,
Hradec Kralove, Czech Republic
often (when well designed) promote the formation of products
with high enantioselectivity, however, many are expensive.
Therefore recycling of these catalysts has attracted great inter-
est in industrial applications.13 Immobilisation of chiral cata-
lysts with either solid supports or polymers is a representative
method to recover and reuse catalysts.13 However, often solid
cTrinity Biomedical Sciences Institute, School of Chemistry, University of Dublin,
Trinity College, Dublin 2, Ireland. E-mail: connons@tcd.ie; Fax: +35 316712826
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3gc40875b
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supported catalysts resulted in decreased enantioselectivity solvents, with for instance, benzene and dichloromethane
and/or activity.13d Recently, ionic liquids (ILs) have been rated Red.24 In addition, the environmental impact due to the
shown to extend catalyst lifetime in a variety of asymmetric cata- utilization of volatile solvents, during the IL synthesis and
lytic reactions14 such as dihydroxylation,14a–c Diels–Alder,14d product isolation, ideally should also be included in a life
allylic amination,14e Michael,14f fluorination,14f epoxidation,14g cycle assessment (LCA) of the catalyzed reaction under study.
hydrogenation,14h and aldol reactions.14i Facile product iso-
Our research effort is directed towards the development of
lation by either extraction with non-polar solvents or distilla- environmentally friendly ILs which can also offer performance
tion, if realised, can be a major advantage associated with advantages over established methods.25 As a part of our inter-
IL-based methods. However, the environmental impact due to est in performing asymmetric catalysis (e.g. Diels–Alder26 and
the utilization of these solvents should also be included in any hydrogenation27) in ILs, we present herein enantioselective
life cycle assessment (LCA). There can also be benefits from a carbonyl-ene reactions of ethyl trifluoropyruvate and alkenes
selectivity standpoint: For instance, in enantioselective carbo- catalysed by chiral Pd(II)-BINAP complexes carried out in IL
nyl-ene reactions between various alkenes and either ethyl- or solvent. While we design the ILs to have low antimicrobial toxi-
phenylglyoxal catalysed by chiral platinum complexes, the city, it is only by tandem toxicity screening to supplement the
product ee obtained in 1-ethyl-2-methylimidazolium bis(tri- catalysis studies that we can direct the research program
fluoromethylsulfonyl)amide is higher (up to 95%), or at least towards ‘greener’ ILs where possible. The Pd(II)-BINAP catalyst
comparable, to those obtained in dichloromethane.8j Recycling class was chosen for this carbonyl-ene reaction because it gives
of the IL phase, afforded after three runs, the same enantio- the expected α-hydroxy ester in good yield and excellent dia-
selectivity with decreased product yield. Recently, Luo and co- stereo- and enantioselectivity.8k In addition, when using Pd(II)-
workers reported that the chiral Lewis acidic palladium(II) cata- BINAP as the catalyst, enantioselectivities for carbonyl ene pro-
lyst incorporating (R)-BINAP is stable in 1-butyl-2,3-dimethyl- ducts typically are observed up to 90% ee. Thus, if our ILs have
imidazolium bis(trifluoromethylsulfonyl)amide and could be a synergistic effect on the enantioinduction conferred by the
recycled 21 times with retention of high enantioselectivity in catalyst, this can be evaluated. This cannot be determined if
each recycle.8l
using the Pd(II)-BINAPHANE catalyst which affords almost
Due to the wide range of applications and versatility, possi- enantiopure product when using CH2Cl2 as the solvent.8m Fur-
ble uses of ILs15 have triggered an issue of waste manage- thermore, to the best of our knowledge, the use of chiral Pd(II)-
ment. Hence it is important to study the environmental BINAP catalysed carbonyl-ene reactions of ethyl trifluoropyru-
impact of such ILs, especially with the potential for accidental vate and alkenes in ILs with recovery and reuse of the chiral
release into the natural environment. Due to their very low catalysts has not been previously reported. The performance of
vapour pressure, ILs have a low possibility of air pollution. these ILs in comparison with common organic solvents, and
However, ILs due to their ionic interactions, they are highly the recycling of the catalyst/IL media are investigated.
–
soluble in water16–18 (except in a few cases, e.g. NTf2– and PF6 )
which presents a viable route these ILs can be transported and
interact with the environment. Therefore, in order to evaluate
the biocompatibility of ILs (or ideally any chemical), toxicity,
eco-toxicity, biodegradation, bioaccumulation and persistence
Results and discussion
Synthesis of ILs
studies should be carried out. There is however, a counter In order to design ‘green’ ILs, factors such as toxicity, eco-
argument, that extensive assessment of the environmental toxicity and biodegradation have been considered.19–23,28 There
impact of every IL investigated as part of a new technology, are some commonly used cations such as imidazolium, pyridi-
would stifle the project progress towards meeting performance nium, phosphonium, and sulphonium ions. Among these
goals.19 A balance should be found, where limited assessment classes of ILs, imidazolium have been studied in the most
of the impact of the IL on the environment is performed.19,20 detail due in part to their facile preparation, low viscosity and
If, during this preliminary screen, the IL was determined to be low melting points.29 The Gathergood and Scammells groups
a high toxicity biocide, in our opinion it would be unwise to have previously described how the incorporation of oxygen-
continue optimising a methodology using this as the solvent. based functionality into the side-chain of imidazolium-derived
With this in mind, ILs can be categorised in the pattern of ILs such as esters20c,30 and ethers31 can reduce antimicrobial
‘Traffic Signal Lights’ as discussed at the BATIL (biodegradation toxicity. ILs with long hydrocarbon side chains have been
and toxicity of ionic liquids) meeting in DECHEMA, Frankfurt, reported to be very toxic to bacteria and fungi due to their lipo-
2009.19 As we start classifying ILs in three colours (Red, Yellow philicity.32 According to these guidelines above, achiral ILs
and Green), we can find that most ILs assessed by Stephens with ester and amide functionality in the side chains have
et al.19 are in the undesirable Red and Yellow regions, been selected as a target for this work.
although this information was solely based on toxicity data.19
Our objective was to design low antimicrobial toxicity ILs
For an IL to be classified more accurately by a ‘Traffic Signal and to use them in carbonyl-ene reactions as solvent. A series
Lights’ pattern, detailed information about the toxicity, bio- of achiral 1,2-dimethylimidazolium ILs were selected instead
degradation and synthesis21,22 are required.23 A similar classifi- of 1-methylimidazolium analogues, so as to block the free
cation system has been applied to commonly used organic acidic position at C2 and minimise any inhibiting effects on
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Fig. 1 ILs used as reaction solvents.
the carbonyl-ene reaction. Several amide side chain-based ILs temperature in most cases (except 3a) in yields ranging from
were synthesised along with analogues incorporating ester side 56–95%. The last step, anion metathesis, was performed on
chains, due to unknown stability of the more labile later class imidazolium bromide salts to obtain bistriflimide (NTf2), tetra-
of ILs under the target reaction conditions (Fig. 1).
fluoroborate (BF4), dicyanamide (N(CN)2), and octyl sulfate
Preparation of these ILs was carried out in three steps (OctOSO3) anion analogues. The yields for this last step were 1
(Scheme 1). The first step was preparation of alkylating 85%, 2 91%, 3 49%, 6 68%, 7 85%, 8 80%, 8b 94%, 8c 95%, 8d
reagents by treatment of bromoacetyl bromide with either alco- 79% and 9 quantitative (Scheme 1, also see Experimental
hols or amine, in presence of base.31 The methyl and ethyl bro- section). IL 433 (with an iso-butyl ester at the C2-position) and
moacetate were commercially available. Low temperature
−15 °C was used during the addition of bromoacetyl bromide.
Verifying by 1H-NMR spectroscopic analysis, the α-bromoesters
5
27 were prepared according to literature procedure (Fig. 1).
Enantioselective catalytic carbonyl-ene reactions in ILs
prepared were found to be of high purity. α-Bromoamides were With the goal of demonstrating environmentally friendly ILs are
prepared from decylamine, pyrrolidine, piperidine, morpho- compatible and beneficial in asymmetric reactions, we investi-
line, and bis(2-methoxyethyl)amine31 (Scheme 1).
gated their effect in the catalytic carbonyl-ene reaction of ethyl
The second step, i.e. alkylation of the heterocycle with trifluoropyruvate (11) and methylenecyclohexane (10) with the
α-bromoesters/amides, gave the IL bromide (e.g. 8a, Fig. 1) in situ prepared catalyst [Pd{(R)-BINAP}](SbF6)2 (Scheme 2).
salts. 1,2-Dimethylimidazole was added to a solution of This reaction proceeds effectively in dichloromethane (100%
α-bromoester/α-bromoamide in diethyl ether at room tempera- chemoselectivity, >99% conv., 93% ee).8k However, dichloro-
ture (RT) under inert atmosphere. Product precipitated from the methane is not a sustainable solvent because of its high
reaction mixture and was easily isolated, then dried in vacuo. vapour pressure and high toxicity.24 In this study, screening
The bromide salts (1a–9a) formed were solid at room for alternative solvents was thus examined as shown in
Scheme 1 Synthetic route to ILs with either an ester or an amide group in the side chain.
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Scheme 2 Enantioselective carbonyl-ene reactions catalysed by {[(R)-BINAP]Pd}(SbF6)2.
Table 1 Screening of solvent for the enantioselective carbonyl-ene reactiona of
11 with 10
obtained in the reactions using ILs containing an ester side
chain at C1 1–3 (76–78% yield, entries 5–7 vs. entry 1).
The effect of cation and counterion structure can also be
evaluated. Reactions in amide side chain-based ILs 5–8 gave
higher product yields than results in the ester side chain ILs
1–3, although the structure of cation for ILs 5–8 had no signifi-
cant impact on either yield or enantioselectivity. To investigate
the anion effect, ILs with commonly used anions, such as Br,
BF4, NTf2, OctOSO3 and N(CN)2 were studied. From the series
of 8–8d, only the NTf2 IL 8 gave a comparable result (89%
yield, 91% ee) to that obtained in dichloromethane (entry 11
vs. entry 1). No conversion was observed in the case of IL 8a,
8b, 8c with Br, N(CN)2 and OctOSO3 anions, respectively
(entries 13–15). This could be explained by either an exchange
of those anions with SbF6 which could result in catalyst de-
activation or due to the hydrophilic properties of 8a–c com-
pared to the hydrophobic NTf2 ILs 1–8. The use of IL 8d (with
the BF4 counterion), led to just 10% yield of racemic product
12 (entry 16). To study the effect of a long linear alkyl chain,
Entry
Solvent
Yieldb (%)
ee (%)
1
2
3
4
5
6
7
8
CH2Cl2
Et2O
PhMe
THF
1
2
3
4
5
6
7
8
8a
8b
8c
8d
9
93
68
84
0
76
78
77
89
89
85
87
89
0
90
98
96
ndc
85
90
89
91
92
89
90
91
nd
nd
nd
0
9
10
11
12
13
14
15
16
17
0
0
10
90
80
a Conditions: methylenecyclohexane (10) 0.25 mmol, ethyl
trifluoropyruvate (11) 0.375 mmol (1.5 equiv.), {[(R)-BINAP]Pd}(SbF6)2
0.0125 mmol (5 mol%), IL 0.25 mmol (1 equiv.) or
2 mL of the decyl amide IL 9 was screened. While the yield of 12 was
conventional solvent (entries 1–4), RT, 30 min. b Isolated yield after flash
the same as when the reaction carried out in ILs 4, 5 and 8, a
decrease in ee of 12 by 10% is observed in 9 (entry 17 vs.
entries 8, 9 and 12).
column chromatography. c nd: not determined.
On the basis of the results in Table 1 and antimicrobial toxi-
city data (vide infra) the ester IL 4 was selected for further reac-
tion optimisation, and substrate scope studies. The amide-
based IL 5 was also included for comparison in stability/
recycling studies.
Table 1. The reaction was conducted with 11 (1.5 equiv.), in
the presence of IL (1.0 equiv.), and catalyst [Pd{(R)-BINAP}]-
(SbF6)2 (5 mol%) at RT for 30 min.
As illustrated in Table 1, reaction in diethyl ether and
toluene resulted in good enantioselectivity (96–98% ee) and
lower yield (68% and 84% respectively) in comparison to reac-
tion in dichloromethane (entries 1 vs. 2 and 3). Our results in
Catalyst optimisation study
dichloromethane are in good agreement with those obtained Optimisation of reaction conditions was carried out, and the
by Doherty et al.8b under identical reaction conditions (100% results shown in Table 2. The first parameter investigated was
conv., 93% ee). Tetrahydrofuran solvent gave 0% conversion the amount of IL, as a reduction in the quantity required
(entry 4) which may be explained by competitive complexation would lead to a significant benefit in the overall ‘greenness’ of
to the catalyst system. The use of IL 1 gave 12 in only 76% the reaction. We were pleased to find that decreasing the
yield and 85% ee (entry 5), while the use of ILs 2 and 3 as the amount of IL from 1 equiv. to 0.5 equiv. (Table 2 entry 1 vs. 2)
solvent afforded the product 12 with similar enantioselectivity lead to an increase in the yield from 89% to 96%, while retain-
(89–90% ee, entries 6 and 7) to that obtained in dichloro- ing high enantioselectivity (91% ee). However, 1.5 equiv. of
methane (entry 1), although the yield decreased dramatically ethyl trifluoropyruvate (11) was required for a high yield, with
(77–78%). The results of carbonyl-ene reaction in ILs 4 and 5 yields of only 78% and 68% attained when 1 equiv. present
(89% yield, 91–92% ee, entries 8 and 9) were comparable with (entries 3 and 4). Decreasing the catalyst loading from 5 mol%
that in dichloromethane.
to 2 mol%, gave a slight (6%) decrease in yield, however a
The use of ILs 6 and 7 resulted in similar levels of product further dramatic 39% decrease in yield was observed at 10 mol%
enantiomeric excess (89–90% ee) to reactions performed in catalyst loading (entry 2 vs. entries 5 and 6). The enantio-
dichloromethane, although the yield decreased slightly selectivity did not significantly change throughout this catalyst
(85–87%, entries 10 and 11). The results of carbonyl-ene reac- loading study (87–91% ee). At 10 mol% catalyst loading (entry
tion in ILs 8 (89% yield, 91% ee, entry 12) were comparable 6), the reaction mixture was very viscous, and efficient stirring
with those in dichloromethane. Thus, lower yields were a problem, which we attribute to the low yield. Adjusting the
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Table 2 Condition optimisation for the enantioselective carbonyl-ene reaction of 11 with 10 in IL 4 catalysed by {[(R)-BINAP]Pd}(SbF6)2
Entry
10 (equiv.)
11 (equiv.)
Catalyst (equiv.)
IL 4 (equiv.)
Temperature (°C)
Time (min)
Yielda (%)
ee (%)
1
2
3
4
5
6
7
8
1
1
1
1.5
1
1
1
1
1
1.5
1.5
1
0.05
0.05
0.05
0.05
0.02
0.10
0.05
0.05
0.05
0.05
0.05
1
25
25
25
25
25
25
40
0
30
30
30
30
30
30
30
30
60
120
15
89
96
78
68
90
51
92
93
88
93
90
91
91
89
91
87
88
87
90
87
87
88
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
10
11
25
25
25
1
1
a Isolated yield.
Table 3 Substrate scope for the enantioselective carbonyl-ene reactiona of 11
to alkenes 10–10d in IL 4 catalysed by {[(R)-BINAP]Pd}(SbF6)2
reaction temperature (40 °C or 0 °C, entries 7 and 8) and reac-
tion time (15, 60 or 120 min, entries 9–11) did not lead to an
increase in either the yield or ee.33 The optimal conditions in
Table 2 are given in entry 2, and were selected for use in the
substrate scope study.
Entry Alkene
1
Product
Yieldb (%)
96
ee (%)
91c
Substrate scope
96c
The scope of the carbonyl-ene reaction was next studied under
the optimised reaction conditions described in Table 2, entry 2
(1 equiv. alkene, 1.5 equiv. of 11, 0.5 equiv. of IL 4, 5 mol%
catalyst, 25 °C, 30 min). A range of aliphatic, aromatic and
cycloalkene substrates were screened in the reaction with ethyl
trifluoropyruvate (11) (Table 3).
2
3
82
80 (12b/12b′ = 1.8)d 94c
Excellent isolated yield and good enantiomeric excess were
observed for the product in the reaction involving methylene
cyclohexane (10) (96% yield, 91% ee, entry 1). Good isolated
yield and excellent enantiomeric excess for the product were
observed when using methylene cyclopentane (10a) as the
substrate in the carbonyl ene reaction (82% yield, 96% ee,
entry 2).
In reactions involving 2,3-dimethyl-1-butene 10b, two pro-
ducts (12b and 12b′) were observed with 80% combined yield
(ratio 12b/12b′ = 1.8) and 94% ee for both compounds
(Table 3, entry 3). This mixture of products can be explained
by the reported possible catalytic mechanism due to the avail-
ability of two different C–H bonds alpha to the carbon–carbon
double bond.8m Furthermore, both 2,3-dimethyl-1-butene
(10b) and ethyl trifluoropyruvate (11) are small compounds
which can easily access the Pd-catalyst to allow 10b to
approach the coordinated ethyl trifluoropyruvate 11 in two
different ways.8m Alkene 10c gave product 12c in 81% yield and
96% ee. With α-methylstyrene (10d), moderate yield and
enantioselectivity were observed (71% yield, 75% ee, entry 5,
94c
4
5
81
71
96c
75e
a Conditions: alkene 0.25 mmol (1 equiv.), ethyl trifluoropyruvate (11)
0.375 mmol (1.5 equiv.), catalyst {[(R)-BINAP]Pd}(SbF6)2 0.0125 mmol
(5 mol%), IL 4 0.125 mmol (0.5 equiv.), 25 °C, 30 min. b Isolated yield.
c Determined by chiral GC. d Ratio of products was determined by
1H- and 19F-NMR spectroscopic analysis. e Determined by chiral HPLC.
Table 3). The results in Table 3 also show that the enantio- or 2,3-dimethyl-1-butene (10b) (80% yield, 94% ee, entry 3 vs.
selectivities obtained using aliphatic alkenes (10–10c) were 87% yield, 95% ee in CH2Cl2) in IL 4 were similar.8k
higher than associated with the conjugated aromatic substrate
10d (91–96% >75% ee).
In the case of either methylene cyclopentane (10a) (82%
yield, 96% ee, entry 2 vs. 100% conv., 96% ee in CH2Cl2),8k or
In comparison with the reaction in CH2Cl2, the result α-methylstyrene (71% yield, 75% ee vs. >99% conversion, 78%
obtained on reaction with either methylene cyclohexane (10) ee) the enantiomeric excess of the products are similar to
(96% yield, 91% ee, entry 1 vs. 96% yield, 93% ee in CH2Cl2),8k when the reaction is performed in either CH2Cl2 or IL 4,
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Table 4 Enantioselective carbonyl-ene reactiona of 11 to 10 in either recycled
catalyst/IL 4 or 5
Table 5 Antifungal toxicity screening of ILs (MIC IC80 or IC50)
IL (μM)
Reaction in ester side
chain IL 4
Reaction in amide side
chain IL 5
2–7,
8a–d
Strain
Time (h)
1
8
9
Cycle
Yieldb (%)
eec (%)
Yieldb (%)
eec (%)
Candida albicans ATCC 44859a 24 h
1000 >2000 >2000
>1000 >2000 >2000
1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
>1000 >2000 >2000
250
250
250
250
62.5
125
31.25
31.25
15.62
31.25
15.62
31.25
62.5
48 h
Candida albicans ATCC 90028a 24 h
48 h
1
2
3
4
5
6
7
8
96
92
90
92
92
90
92
77
91
91
92
93
93
92
91
84
90
88
84
75
69
—
—
—
93
92
89
86
73
—
—
—
Candida parapsilosis ATCC
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
72 h
120 h
22019a
Candida krusei ATCC 6258a
Candida krusei E28a
Candida tropicalis 156a
Candida glabrata 20/Ia
a Conditions: methylenecyclohexane (10) 0.25 mmol (1 equiv.), ethyl
trifluoropyruvate (11) 0.375 mmol (1.5 equiv.), catalyst {[(R)-BINAP]Pd}-
(SbF6)2 0.0125 mmol (5 mol%) for the first cycle, IL 0.125 mmol
125
(0.5 equiv.) for the first cycle, RT, 30 min. b Isolated yield. c Determined Candida lusitaniae 2446/Ia
250
250
250
500
250
500
by chiral GC.
Trichosporon beigelii 1188a
Aspergillus fumigatus 231b
however, comparison of the isolated yield is not possible, as
only conversion (albeit >99%) was reported.
The recyclability of catalyst [Pd{(R)-BINAP}](SbF6)2/IL media
was also evaluated (Table 4). After 30 min the reaction mixture
Absidia corymbifera 272b
>1000 >2000 >2000 >1000
>1000 >2000 >2000 >1000
>1000 >2000 >2000
>1000 >2000 >2000
Trichophyton mentagrophytes
250
250
445b
was extracted into diethyl ether (2 mL × 3), and the product 12
isolated by column chromatography. The ether-immiscible
phase, including the IL and catalyst was dried under vacuum
to remove residual solvent. Then, to this recycled IL immobi-
lised catalyst was added new substrates and the reaction
repeated. Using this procedure, the IL 4 and immobilised cata-
lyst could be recycled and reused 7 times, maintaining both
similar activity and enantioselectivity. From cycle 8 onwards, a
slight drop in yield and enantiomeric excess was observed.
Due to the susceptibility of ester groups to undergo hydro-
lysis, we were pleased that IL 4 performed effectively over 7
cycles. Our expectation was that the amide IL 5 would give
superior recycling performance, due to the susceptibility of the
ester bond to hydrolysis, however, this was not the case. On
cycle 4 in amide IL 5, the yield had dropped to 75%, and by
cycle 5 the enantioselectivity decreased to 73% ee (Table 4).
a MIC = IC80 b MIC = IC50
. .
Table 6 Antibacterial toxicity screening of ILs (MIC IC95
IL (μM)
)
2–7,
8a–d
Strain
Time (h)
1
8
9
Staphylococcus aureus
ATCC 6538
Staphylococcus aureus
HK 5996/08
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
24 h
48 h
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
>1000 >2000 >1000
62.5
62.5
125
125
250
250
Staphylococcus
epidermidis HK 6966/08
Enterococcus sp.
HK 14365/08
Escherichia coli
ATCC 8739
Klebsiella pneumonia
HK 11750/08
Klebsiella pneumonia
ESBL HK 14368/08
Pseudomonas aeruginosa 24 h
ATCC 9027 48 h
62.5
125
250
250
250
250
250
250
1000
Antifungal and antibacterial toxicity
The NTf2 based ILs 1–9 performed well as the solvent in the
enantioselective catalytic carbonyl-ene reactions of ethyl tri-
fluoropyruvate (11) and alkenes, in several examples leading to
results comparable to those obtained in CH2Cl2. Our research
philosophy is to provide antimicrobial toxicity data for ILs we
>1000 >2000 >1000 >1000
prepare, thus antifungal and antibacterial properties were in media), irrespective of the incorporation of either ester or
studied concurrently for all ILs (Tables 5 and 6). ILs are not amide side chains. Due to the low solubility of ILs 1, 8 and 9
omitted from the toxicity screening due to poor performance the maximum concentration achieved was only 1000 μM in the
(8a–d) in the carbonyl ene reactions studied, as 1–7, 8–8d and media for antibacterial toxicity screening and 1000 μM for
9 may find use in other applications. With toxicity data avail- 1 and 9 in the media for antifungal toxicity screening.
able, a decision can be made on whether they can be rec-
The long alkyl (i.e. decyl) amide side chain in IL 9 was
ommended for further study or not. The antifungal toxicity demonstrated to be the structural feature leading to the high
results (Table 5) and antibacterial toxicity results (Table 6) toxicity of 9 in most of the fungi and bacterial strains,
reveal that all ILs (except 9), did not exhibit high toxicity in the especially with IC80 values of 15.6 μM to Candida krusei E28
test system up to 2000 μM concentration (or the solubility limit and Candida tropicalis 156 and IC95 values of 62.5 μM to
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Staphylococcus aureus and Enterococcus sp. IL 1 has inhibited 1–8d are classed ‘Yellow’ under the ‘Traffic Signal Light’ categ-
both Candida albicans strains at 1000 μM concentration after orisation and warrant further toxicity, eco-toxicity and bio-
24 h, which was eventually suppressed over the period of 48 h, degradation evaluation and hold promise for consideration in
and may be due to hydrolysis of the ester. In summary, the IL based technologies.
antimicrobial toxicity data supported the further study of ILs 4
and 5 (combined with Table 1 results) in the catalyst optimi-
sation screening investigation and support the assignment of
low priority to IL 9 for future applications.
Experimental section
General information
The NMR spectra were recorded in CDCl3. 1H-NMR spectra
were recorded at 400 MHz. The chemical shifts (δ) are reported
Conclusions
in part per million, relative to TMS as internal standard.
A series of imidazolium-based ILs substituted at the C2-posi- J values are given in hertz. 13C NMR spectra were recorded at
tion of the heterocycle and incorporating either ester or amide 100 MHz. TLC experiments were carried out in 0.2 mm thick
groups have been synthesised. Tandem assessment of their silica gel plates (GF254) and visualization was accomplished
performance in the enantioselective catalytic carbonyl-ene by UV light or phosphomolybdic acid solution. The columns
reactions of ethyl trifluoropyruvate (11) and methylenecyclo- were hand-packed with silica l60 (200–300 mesh). All reagents
hexane (10) with the in situ prepared catalyst [Pd{(R)-BINAP}]- and solvents were purchased from commercial sources (Acros,
(SbF6)2 and antimicrobial toxicity have been studied. By Aldrich) and were used without further purification. α-Bromo-
including toxicity data of ILs as a parameter in the selection esters/amides were prepared according to literature methods.
criteria for reaction optimisation, ILs with undesirable high Compounds 4 and 5 were prepared according to literature.27,34
toxicity (antimicrobial screened herein) can be avoided. We
1H-Imidazolium-1,2-dimethyl-3-(2-ethoxy-2-oxoethyl)-1-methyl
determined that the n-decylamide derivative 9, was the only IL bis(trifluoromethanesulfonimide) (1). A round bottom flask
in the study of high antimicrobial toxicity (IC80 values of was charged with ethyl bromoacetate (1.00 g, 5.90 mmol) and
15.6 μM to Candida krusei E28 and Candida tropicalis 156 and diethyl ether (20 mL) under nitrogen. To this solution was
IC95 values of 62.5 μM to Staphylococcus aureus and Entero- added 1,2-dimethylimidazole (0.575 g, 5.90 mmol). The reac-
coccus sp.) Although this gave the carbonyl ene product in tion mixture was stirred vigorously for 24 h. The product preci-
yields similar to those obtained in CH2Cl2 solvent, the enantio- pitated as a white solid. The product was then washed with
selectivity was ca. 10% lower. Therefore there was no clear diethyl ether (10 × 10 mL), then solvent was removed on the
reason to continue with this IL in the current study. All the rotary evaporator. Product 1H-imidazolium,1,2-dimethyl-3-
other ILs prepared were demonstrated to be of acceptable low (2-ethoxy-2-oxoethyl)-1-methyl-, bromide (1a) was dried in vacuo
antimicrobial toxicity, based on the scope (20 strains) of the for 72 h to give a white solid at RT in 95% yield (1.50 g,
screen. Ester- and amide-based ILs (4 and 5 respectively) were 5.60 mmol). Melting point: 130–131 °C. 1H-NMR (400 MHz,
selected for further reaction optimisation and recycling studies CDCl3): 7.93 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 5.49 (s,
based on the initial results of the asymmetric carbonyl-ene 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 2.75 (s, 3H), 1.31 (t,
reaction screen.
Excellent yields and enantioselectivities (up to 96% yield 123.00, 122.41, 62.89, 50.01, 36.10, 14.10, 11.26. ES-MS (+ve)
J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3): 166.28, 145.62,
+
and 94% ee) were obtained using IL 4 as the solvent. During m/z: Found [M
the optimisation study, reducing the volume of IL by 50%, 183.1128. flask was charged with 1H-imidazolium,1,2-
−
Br–]+ 183.1127, C9H13N2O2 requires
A
lead to an increase of yield if 1.5 equiv. of ethyl trifluoropyru- dimethyl-3-(2-butoxy-2-oxoethyl)-1-methyl-, bromide (1.00 g,
vate was used. These results were either superior or compar- 0.38 mmol) and distilled water (5 mL). LiNTf2 (1.09 g,
able to those associated with conventional volatile solvents 0.38 mmol) in distilled water (5 mL) was added in one portion
(e.g. CH2Cl2). Substrate scope studies revealed identical enantio- and the suspension was stirred vigorously for 4 h at RT. The
selectivity when using methylenecyclopentane in either IL 4 or aqueous layer was removed and IL washed with water (3 ×
CH2Cl2.8k Furthermore, the IL 4 immobilised catalyst [Pd{(R)- 10 mL). Water was removed on the rotary evaporator and the
BINAP}](SbF6)2 reaction medium was recycled and reused up product dried in vacuo for 72 h to give the title compound 1 as
to 7 times without loss of activity. Overall, several ILs were a colourless liquid at RT in 85% yield (1.51 g, 0.326 mmol).
found to be a good solvent as a replacement for harmful VOCs 1H-NMR (400 MHz, CDCl3): 7.27 (d, J = 2.4 Hz, 1H), 7.23 (d, J =
(dichloromethane) and to be an efficient trap for the chiral Pd 2.0 Hz, 1H), 4.95 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H),
catalyst used in these carbonyl-ene reactions of ethyl trifluoro- 2.59 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz,
pyruvate. However, the environmental impact due to the utili- CDCl3): 165.73, 145.55, 122.42, 122.30, 119.72 (q, J = 320 Hz,
zation of volatile solvents, during the IL synthesis and product 2 CF3), 63.21, 49.34, 35.58, 13.91, 9.90. ES-MS (+ve) m/z: Found
– +
isolation, ideally should also be included in a LCA of the cata- [M − NTf2 ] 183.1130, C11H19N2O2+ requires 183.1128.
lyzed reaction under study. The n-decylamide based IL 9 was
1H-Imidazolium,1,2-dimethyl-3-(2-butoxy-2-oxoethyl)-1-methyl-,
determined to be of high antimicrobial toxicity ‘Red’, and is NTf2 (2). A flask was charged with butyl bromoacetate (8.17 g,
given a low priority for future applications. Conversely, ILs 41.9 mmol) and diethyl ether (150 mL) under nitrogen. To this
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solution was added 1,2-dimethylimidazole (4.02 g, was dried in vacuo for 72 h to give the title compound 3 as a col-
41.9 mmol). The reaction mixture was stirred vigorously for ourless liquid at RT in 49% yield (1.605 g, 3.16 mmol). 1H-NMR
24 h. The product precipitated as a white solid, and washed (400 MHz, CDCl3): 7.19 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.4 Hz,
with diethyl ether (10 × 100 mL). The solvent was removed on 1H), 4.88 (s, 2H), 4.31–4.27 (m, 2H), 3.75 (s, 3H), 3.60–3.58 (m,
the rotary evaporator, and the product was dried in vacuo for 2H), 3.46 (q, J = 7.2 Hz, 2H), 2.49 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).
72
h
to give 1H-imidazolium,1,2-dimethyl-3-(2-butoxy-2- 13C-NMR (100 MHz, CDCl3): 165.76, 145.56, 122.39, 122.30,
oxoethyl)-1-methyl-bromide (2a) as a white solid at RT in 71% 119.72 (q, J = 320 Hz, 2 CF3), 67.62, 66.66, 65.90, 49.20, 35.53,
1
– +
yield (8.66 g, 29.75 mmol). Melting point: 75–76 °C. H-NMR 15.03, 9.78. ES-MS (+ve) m/z: Found [M − NTf2 ] 227.1392,
(400 MHz, CDCl3): 7.91 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, C11H19N2O3+ requires 227.13902.
1H), 5.47 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 3.97 (s, 3H), 2.74 (s,
1H-Imidazolium,1,2-dimethyl-3-[2-[bis(2-methoxyethyl)amino]-
3H), 1.69–1.60 (m, 2H), 1.41–1.31 (m, 2H), 0.92 (t, J = 7.6 Hz, 2-oxoethyl]-, NTf2 (6). A RB flask was charged with 2-bromo-
3H). 13C-NMR (100 MHz, CDCl3): 166.33, 145.60, 122.97, N,N-bis(2-methoxyethyl)-acetamide (1.00 g, 3.93 mmol) and
122.44, 66.68, 49.98, 36.09, 30.35, 18.96, 13.65, 11.26. ES-MS diethyl ether (25 mL) under nitrogen. To this solution was
(+ve) m/z: Found [M − Br–]+ 211.1453, C11H19N2O2 requires added 1,2-dimethylimidazole (3.78 g, 3.93 mmol). The reaction
+
211.1441. A RB flask was charged with 1H-imidazolium,1,2- mixture was stirred vigorously for 24 h. The product precipi-
dimethyl-3-(2-butoxy-2-oxoethyl)-1-methyl-bromide (2a) (3.00 g, tated as a white solid and was washed with diethyl ether (10 ×
10.3 mmol) and distilled water (15 mL). Lithium bis(trifluoro- 25 mL). The solvent was removed on the rotary evaporator and
methanesulfonimide) (2.96 g, 10.3 mmol) in distilled water the product was dried in vacuo for 72 h to give 1H-imidazo-
(10 mL) was added in one portion and the suspension was lium-1,2-dimethyl-3-[2-[bis(2-methoxyethyl)amino]-2-oxoethyl]-
stirred vigorously for 4 h at RT. The aqueous layer was bromide (6a) as a white solid at RT in 85% yield (1.17 g,
removed and IL washed with water (3 × 40 mL). Water was 3.34 mmol). Melting point: 119–120 °C. 1H-NMR (400 MHz,
removed on the rotary evaporator and the product was dried in CDCl3): 7.56 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 5.70 (s,
vacuo for 72 h to give the title compound 2 as a colourless 2H), 3.93 (s, 3H), 3.74 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 4.8 Hz,
liquid at RT in 91% yield (4.61 g, 9.39 mmol). 1H-NMR 2H), 3.53 (t, J = 4.8 Hz, 2H), 3.49 (t, J = 4.8 Hz, 2H), 3.36 (s,
(400 MHz, CDCl3): 7.19 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 3H), 3.31 (s, 3H), 2.64 (s, 3H). 13C-NMR (100 MHz, CDCl3):
1H), 4.85 (s, 2H), 4.14 (t, J = 6.6 Hz, 2H), 3.75 (s, 3H), 2.48 (s, 165.47, 145.69, 122.90, 121.96, 70.46, 69.97, 59.18, 58.89,
3H), 1.63–1.55 (m, 2H), 1.36–1.26 (m, 2H), 0.87 (t, J = 7.2 Hz, 50.70, 48.55, 46.55, 35.93, 10.68. ES-MS (+ve) m/z: Found
+
3H). 13C-NMR (100 MHz, CDCl3): 165.79, 145.48, 122.40, [M − Br–]+ 270.1816, C13H24N3O3 requires 270.1812. A RB
122.35, 119.72 (q, J = 320 Hz, 2 CF3), 66.95, 49.22, 35.53, 30.25, flask was charged with 1H-imidazolium,1,2-dimethyl-3-[2-
– +
18.89, 13.56, 9.81. ES-MS (+ve) m/z: Found [M − NTf2 ]
[bis(2-methoxyethyl)amino]-2-oxoethyl]bromide (6a) (1.00 g,
2.85 mmol) and distilled water (4 mL). Lithium bis(trifluoro-
211.1449, C11H19N2O2+ requires 211.1441.
1H-Imidazolium,1,2-dimethyl-3-[2-(2-ethoxyethoxy)-2-oxoethyl]- methanesulfonimide) (0.819 g, 2.85 mmol) in distilled water
1-methyl-, NTf2 (3). A RB flask was charged with 2-ethoxyethyl (4 mL) was added in one portion and the suspension was
bromoacetate (3.51 g, 16.58 mmol) and diethyl ether (75 mL) stirred vigorously for 4 h at RT. The top aqueous layer was
under nitrogen. To this solution was added 1,2-dimethylimida- removed and the IL washed with water (3 × 4 mL) and residual
zole (1.75 g, 18.24 mmol). The reaction mixture was stirred vigo- water was removed on the rotary evaporator. The product was
rously for 24 h and the product separated as a brown liquid dried in vacuo for 72 h to give the title compound 6 as a colour-
phase. The product was then washed with diethyl ether (10 × less liquid at RT in 68% yield (1.07 g, 1.94 mmol). 1H-NMR
100 mL), solvent removed on the rotary evaporator and (400 MHz, CDCl3): 7.17 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 2.0 Hz,
dried in vacuo for 72 h to give 1H-imidazolium,1,2-dimethyl-3- 1H), 5.26 (s, 2H), 3.81 (s, 3H), 3.65 (dd, J = 4.8, 4.4 Hz, 2H),
[2-(2-ethoxyethoxy)-2-oxoethyl]-1-methyl-bromide (3a) as a brown 3.59–3.56 (m, 4H), 3.53–3.50 (m, 2H), 3.40 (s, 3H), 3.34 (s, 3H),
liquid at RT in 61% yield (3.11 g, 10.13 mmol). 1H-NMR 2.52 (s, 3H). 13C-NMR (100 MHz, CDCl3): 165.17, 145.74,
(400 MHz, CDCl3): 7.81 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 122.68, 121.65, 119.76 (q, J = 320 Hz, 2 CF3), 70.52, 69.68,
1H), 5.42 (s, 2H), 4.31–4.27 (m, 2H), 3.90 (s, 3H), 3.62–3.59 (m, 59.10, 58.88, 50.14, 48.31, 46.39, 35.38, 9.69. ES-MS (+ve) m/z:
– +
2H), 3.47 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). Found [M − NTf2 ] 270.1823, C12H20N3O+ requires 270.1812.
13C-NMR (100 MHz, CDCl3): 166.38, 145.70, 122.95, 122.48,
1H-Imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-morpholinyl)ethyl]-,
67.77, 66.67, 65.62, 49.94, 36.09, 15.12, 11.16. ES-MS (+ve) m/z: NTf2 (7). A RB flask was charged with N-(bromoacetyl)morpho-
+
Found [M − Br–]+ 227.1397, C11H19N2O3 requires 227.1390. line (1.00 g, 4.80 mmol) and diethyl ether (25 mL) under nitro-
A RB flask was charged with 1H-imidazolium,1,2-dimethyl-3- gen. To this solution was added 1,2-dimethylimidazole
[2-(2-ethoxyethoxy)-2-oxoethyl]-1-methyl-bromide (3a) (2.00 g, (0.466 g, 4.80 mmol). The reaction mixture was stirred vigor-
6.5 mmol) and distilled water (9 mL). Lithium bis(trifluoro- ously for 24 h. The product precipitated as a white solid, then
methanesulfonimide) (1.87 g, 6.5 mmol) in distilled water washed with diethyl ether (10 × 25 mL). The solvent was
(9 mL) was added in one portion and the suspension removed on the rotary evaporator and the product was dried in
was stirred vigorously for 4 h at RT. The aqueous layer was vacuo for 72 h to give 1H-imidazolium,1,2-dimethyl-3-[2-oxo-2-
removed, the IL washed with water (3 × 40 mL). The excess (1-morpholinyl)ethyl]bromide (7a) as a white solid at RT in
water was removed on the rotary evaporator and the product 77% yield (1.12 g, 3.68 mmol). Melting point: 199–200 °C.
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1H-NMR (400 MHz, CDCl3): 7.67 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2 CF3), 50.04, 45.95, 43.67, 35.39, 26.07, 25.35, 24.09, 9.96.
– +
2.4 Hz, 1H), 5.85 (s, 2H), 3.83 (s, 3H), 3.79 (dd, J = 5.2, 4.4 Hz, ES-MS (+ve) m/z: Found [M − NTf2 ] 222.1609, C12H20N3O+
2H), 3.68 (dd, J = 5.2, 4.4 Hz, 2H), 3.65 (dd, J = 5.2, 4.4 Hz, 2H), requires 222.1601.
3.52 (dd, J = 5.2, 4.4 Hz, 2H), 2.68 (s, 3H). 13C-NMR (100 MHz,
1H-Imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-,
CDCl3): 163.12, 146.25, 123.22, 121.51, 66.75, 66.44, 51.04, N(CN)2 (8b). A flask was charged with 1H-imidazolium,1,2-
45.59, 42.64, 35.78, 11.17. ES-MS (+ve) m/z: Found [M − Br–]+ dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-, bromide (8a) (1.00 g,
+
224.1395, C11H18N3O2 requires 224.1393. A RB flask was 3.30 mmol) and acetone (5 mL) under a nitrogen atmosphere.
charged with 1H-imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-mor- Sodium dicyanamide (0.442 g, 4.96 mmol) was added in one
pholinyl)ethyl]bromide (7a) (1.10 g, 3.62 mmol) and distilled portion and the suspension was stirred vigorously for 4 days at
water (4 mL). Lithium bis(trifluoromethane) sulfonamide RT. The fine white precipitate was filtered quickly in air and
(1.04 g, 3.62 mmol) in distilled water (4 mL) was added in one washed with dry acetonitrile (2 × 4 mL). The filtrate and wash-
portion and the suspension was stirred vigorously for 4 h at ings were combined and solvent removed by rotary evapor-
RT. The top aqueous layer was removed; the IL washed with ation, then dried in vacuo for 2 days to give the title compound
water (3 × 4 mL) and residual water was removed on the rotary 8b as a white solid at RT in 99% yield (0.950 g, 3.20 mmol).
evaporator. The product was dried in vacuo for 72 h to give the Melting point: 84–85 °C. 1H-NMR (600 MHz, CD3CN): 7.34 (d, J
title compound 7 as a colourless liquid at RT in 85% yield = 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 5.14 (s, 2H), 3.77 (s, 3H),
(1.56 g, 3.09 mmol). 1H-NMR (400 MHz, CDCl3): 7.23 (d, J = 2.0 3.51 (t, J = 5.4 Hz, 2H), 3.43 (t, J = 6.0 Hz, 2H), 2.46 (s, 3H),
Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 5.11 (s, 2H), 3.82 (s, 3H), 3.77 1.69–1.67 (m, 4H), 1.56–1.54 (m, 2H). 13C-NMR (150 MHz,
(dd, J = 5.2, 4.4 Hz, 2H), 3.72 (dd, J = 5.2, 4.4 Hz, 2H), 3.60 (dd, CD3CN): 163.48, 147.84, 123.90, 123.45, 121.20, 47.16, 44.63,
J = 5.2, 4.4 Hz, 2H), 3.54 (dd, J = 5.2, 4.4 Hz, 2H), 2.53 (s, 3H). 36.62, 27.38, 26.79, 25.49, 10.98. ES-MS (+ve) m/z: Found
– +
13C-NMR (100 MHz, CDCl3): 162.51, 145.96, 122.76, 121.74, [M − N(CN)2 ] 222.1616, C12H20N3O+ requires 222.1601.
119.71 (q, J = 319 Hz, 2 CF3), 66.43, 66.25, 49.75, 45.09, 42.65,
1H-Imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-,
35.42, 9.92. ES-MS (+ve) m/z: Found [M − NTf2 ] 224.1389, octylsulfate (8c). A flask was charged with 1H-imidazo-
C12H20N3O+ requires 224.1393.
lium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-, bromide (8a)
– +
1H-Imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-, (1.00 g, 3.3 mmol) and distilled water (10 mL). Sodium octyl-
NTf2 (8). A RB flask was charged with 2-bromo-1-(piperidin-1- sulfate (0.768 g, 3.30 mmol) in distilled water (5 mL) was
yl)ethanone (4.61 g, 48.0 mmol) and diethyl ether (400 mL) added in one portion and the suspension was stirred vigor-
under nitrogen. To this solution was added 1,2-dimethylimida- ously for 24 h at RT. The water was removed on the rotary evap-
zole (9.00 g, 43.6 mmol). The reaction mixture was stirred vig- orator and residue was dissolved in chloroform (10 mL) and
orously for 24 h. The product precipitated as a white solid, washed with water. Organic layer was dried over anhydrous
then washed with diethyl ether (10 × 100 mL). The solvent was magnesium sulphate, filtered and solvent removed by rotary
removed on the rotary evaporator and the product was dried in evaporation. The product was dried in vacuo for 72 h to give
vacuo for 72 h to give 1H-imidazolium,1,2-dimethyl-3-[2-oxo-2- the title compound 8c as a white wax at RT in 79% yield
(1-piperidinyl)ethyl]-, bromide (8a) as a white solid at RT in (1.12 g, 2.60 mmol). Melting point: 40–42 °C 1H-NMR
56% yield (7.36 g, 24.45 mmol). Melting point: 123–124 °C. (600 MHz, CDCl3): 7.39 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 2.4 Hz,
1H-NMR (400 MHz, CD3CN): 7.45 (d, J = 2.0 Hz, 1H), 7.36 (d, 1H), 5.34 (s, 2H), 3.91 (t, J = 6.0 Hz, 2H), 3.77 (s, 3H), 3.46 (t, J
J = 2.4 Hz, 1H), 5.26 (s, 2H), 3.79 (s, 3H), 3.51 (t, J = 5.6 Hz, 2H), = 6.0 Hz, 4H), 2.52 (s, 3H), 2.44 (s, 3H), 1.64–1.50 (m, 8H),
3.45 (t, J = 5.2 Hz, 2H), 2.49 (s, 3H), 1.70–1.67 (m, 4H), 1.29–1.20 (m, 10H). 13C-NMR (150 MHz, CDCl3): 162.65,
1.56–1.55 (br m, 2H). 13C-NMR (100 MHz, CD3CN): 163.76, 146.02, 123.03, 121.65, 68.03, 50.28, 46.14, 43.58, 35.46, 31.84,
147.67, 123.75, 123.24, 51.14, 47.01, 44.42, 36.46, 27.23, 26.63, 29.49, 29.38, 29.28, 26.17, 25.89, 25.40, 24.20, 22.67, 14.13,
– +
25.32, 10.90. ES-MS (+ve) m/z: Found [M − Br–]+ 222.1610, 10.40. ES-MS (+ve) m/z: Found [M − OctOSO3 ] 222.1602,
C12H20N3O+ requires 222.1601. A RB flask was charged with C12H20N3O+ requires 222.1601.
1H-imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-
1H-Imidazolium,1,2-dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-,
bromide (8a) (0.700 g, 2.30 mmol) and distilled water BF4 (8d). A flask was charged with 1H-imidazolium,1,2-
(4 mL). Lithium bis(trifluoromethanesulfonimide) (0.665 g, dimethyl-3-[2-oxo-2-(1-piperidinyl)ethyl]-, bromide (8a) (1.00 g,
2.30 mmol) in distilled water (4 mL) was added in one portion 3.30 mmol) and acetone (10 mL) under a nitrogen atmosphere.
and the suspension was stirred vigorously for 4 h at RT. The Sodium tetrafluoroborate (0.472 g, 4.30 mmol) was added in
top aqueous layer was removed and the IL washed with water one portion and the suspension was stirred vigorously for 4
(3 × 40 mL). Residual water was removed on the rotary evapor- days at RT. The fine white precipitate was filtered quickly in air
ator and the product was dried in vacuo for 72 h to give the and washed with dry acetone (2 × 4 mL). The filtrate and wash-
title compound 8 as a colourless liquid at RT in 80% yield ings were combined and solvent removed by rotary evapor-
(0.93 g, 1.85 mmol). 1H-NMR (600 MHz, CDCl3): 7.10 (d, J = ation, then dried in vacuo for 2 days to give the title compound
2.4 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 4.98 (s, 2H), 3.72 (s, 3H), 8d as a white solid in 100% yield (1.02 g, 3.30 mmol). Melting
3.47 (t, J = 6.0 Hz, 2H), 3.37 (t, J = 5.4 Hz, 2H), 2.44 (s, 3H), point: 119–120 °C. 1H-NMR (600 MHz, CDCl3): 7.26 (d, J =
1.61–1.58 (m, 4H), 1.52–1.50 (br m, 2H). 13C-NMR (150 MHz, 1.8 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 5.15 (s, 2H), 3.79 (s, 3H),
CDCl3): 161.79, 145.93, 122.96, 122.75, 119.76 (q, J = 319.5 Hz, 3.53 (t, J = 5.4 Hz, 2H), 3.48 (t, J = 6.0 Hz, 2H), 2.51 (s, 3H),
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1.70–1.69 (m, 4H), 1.60–1.58 (m, 2H). 13C-NMR (150 MHz, loaded onto a silica gel column and eluted with hexane–ethyl
CDCl3): 162.39, 146.00, 122.59, 121.75, 49.60, 45.90, 43.53, acetate (5/1) to give ene product as a colourless oil. The iso-
1
35.19, 25.96, 25.37, 24.16, 9.74. ES-MS (+ve) m/z: Found [M − lated material was characterised by H-NMR (CDCl3, 400 MHz)
– +
BF4 ] 222.1597, C12H20N3O+ requires 222.1601.
and 13C-NMR (CDCl3, 100 MHz). The enantiomeric excess was
1H-Imidazolium,1,2-dimethyl-3-[2-(decylamino)-2-oxoethyl]-, determined by GC or HPLC with a chiral column and optical
NTf2 (9). A RB flask was charged with 2-bromo-N-decyl-aceta- rotation measured.
mide (3.00 g, 10.78 mmol) and diethyl ether (50 mL) under
nitrogen. To this solution was added 1,2-dimethylimidazole
(1.04 g, 10.78 mmol). The reaction mixture was stirred vigor-
Recycle procedure
ously for 24 h. The product precipitated as a white solid, then Following extraction of the products from the IL, the IL (con-
washed with diethyl ether (10 × 50 mL). The solvent was taining the catalyst) was dried under vacuum to remove the
removed on the rotary evaporator and the product was dried in residual. Fresh substrates were then added to the system and
vacuo for 72 h to give 1H-imidazolium,1,2-dimethyl-3-[2-(decyl- the reactions recommenced as described.
amino)-2-oxoethyl]bromide (9a) as a white solid at RT in 67%
(S)-Ethyl 2-(cyclohexenylmethyl)-3,3,3-trifluoro-2-hydroxypro-
yield (2.70 g, 7.21 mmol). Melting point: 95–96 °C. 1H-NMR panoate (12). The H NMR and 13C NMR of the product were
(400 MHz, CDCl3): 8.68 (dd, J = 5.6, 5.2 Hz, 1H), 7.62 (d, J = 2.4 consistent with the reported data.8b [α]D20 = −22.5 (c 1.0,
Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 5.23 (s, 2H), 3.84 (s, 3H), 3.15 CH2Cl2), 91% ee in agreement with literature.8b The enantio-
(t, J = 6.0 Hz, 2H), 2.75 (s, 3H), 1.55–1.47 (m, 2H), 1.23–1.17 meric excess was determined by chiral GC (column, CP-cyclo-
(m, 14H), 0.80 (t, J = 6.8 Hz, 3H). 13C-NMR (100 MHz, CDCl3): dextrin-beta-2,3,6-M-19, i.d. 0.25 mm × 25 m, VARIANT; carrier
164.31, 145.40, 122.76, 121.92, 51.06, 40.05, 35.89, 31.90, gas, helium 1 mL min−1; column, 120 °C; injection temp,
29.59, 29.57, 29.32, 29.26, 29.14, 27.07, 22.69, 14.14, 11.08. 150 °C, detector: 230 °C), (R)-enantiomer rt1: 11.04 min
ES-MS (+ve) m/z: Found [M − Br–]+ 294.2542, C17H32N3O+ (minor), (S)-enantiomer rt2: 11.40 min (major).
1
requires 294.2545. A RB flask was charged with 1H-imida-
(S)-Ethyl 2-(cyclopentenylmethyl)-3,3,3-trifluoro-2-hydro-
zolium,1,2-dimethyl-3-[2-(decylamino)-2-oxoethyl]bromide xypropanoate (12a). The H NMR and 13C NMR of the product
(0.600 g, 1.60 mmol) and distilled water (4 mL). Lithium bis- were consistent with the reported data.8k [α]D20 = −25.0 (c 1.0,
(trifluoromethanesulfonimide) (0.460 g, 1.60 mmol) in dis- CH2Cl2), 96% ee in agreement with literature.8b The enantio-
tilled water (4 mL) was added in one portion and the suspen- meric excess was determined by chiral GC (column, CP-cyclo-
sion was stirred vigorously for 4 h at RT. The top aqueous layer dextrin-beta-2,3,6-M-19, i.d. 0.25 mm × 25 m, VARIANT; carrier
was removed and the IL washed with water (3 × 4 mL) and gas, helium 1 mL min−1; column, 110 °C; injection temp,
residual water was removed on the rotary evaporator. The 150 °C, detector: 230 °C), (R)-enantiomer rt1: 7.26 min (minor),
product was dried in vacuo for 72 h to give the title compound (S)-enantiomer rt2: 7.50 min (major).
1
9 as a colourless liquid at RT in 94% yield (0.867 g,
Ethyl 2-hydroxy-5-methyl-4-methylene-2-(trifluoromethyl)-
1.51 mmol). 1H-NMR (400 MHz, CDCl3): 7.17 (d, J = 2.4 Hz, hexanoate (12b) and ethyl 2-hydroxy-4,5-dimethyl-2-(trifluoro-
1H), 7.08 (d, J = 2.0 Hz, 1H), 6.85 (t, J = 5.6 Hz, 1H), 4.77 (s, methyl)-4-hexenoate (12b′). The H NMR and 13C NMR of the
1
2H), 3.73 (s, 3H), 3.18–3.12 (m, 2H), 2.52 (s, 3H), 1.48–1.40 (m, product were consistent with the reported data.8m The enantio-
2H), 1.19–1.18 (br m, 14H), 0.80 (t, J = 7.8 Hz, 3H). 13C-NMR meric excess was determined by chiral GC (column, CP-cyclo-
(100 MHz, CDCl3): 163.75, 145.53, 122.42, 121.92, 119.78 (q, J = dextrin-beta-2,3,6-M-19, i.d. 0.25 mm × 25 m, VARIANT; carrier
319 Hz, 2 CF3), 50.42, 40.21, 35.43, 31.89, 29.55, 29.50, 29.31, gas, helium 1 mL min−1; column, 70 °C; injection temp,
29.21, 29.03, 26.83, 22.69, 14.13, 9.94. ES-MS (+ve) m/z: Found 150 °C, detector: 230 °C), 12b rt1: 23.63 min (minor), rt2:
– +
[M − NTf2 ] 294.2531, C12H20N3O+ requires 294.2545.
24.22 min (major), 12b′ rt1: 36.83 min (minor), rt2: 39.05 min
(major). Diastereomers could not be separated by column
chromatography. Absolute stereochemistry determined based
on comparison with Tan et al. reaction conditions in
General procedure of enantioselective catalytic carbonyl-ene
reactions in IL
To a solution of (R)-BINAP–PdCl2 (10 mg, 0.0125 mmol) in dichloromethane.8m
CH2Cl2 (2.0 mL) was added silver hexafluoroantimonate
(S)-Ethyl 2-hydroxy-5,5-dimethyl-4-methylene-2-(trifluoro-
AgSbF6 (9.4 mg, 0.0275 mmol) under argon atmosphere. After methyl)-hexanoate (12c). The 1H NMR and 13C NMR of the
the mixture was stirred at room temperature for 30 min, the product were consistent with the reported data.8m The enantio-
in situ activated catalyst solution in dichloromethane was trans- meric excess was determined by chiral GC (column, CP-cyclo-
ferred through a small filter into small flask which was already dextrin-beta-2,3,6-M-19, i.d. 0.25 mm × 25 m, VARIANT; carrier
charged with IL (0.5 or 1 mmol). After removing the dichloro- gas, helium 1 mL min−1; column, 100 °C; injection temp,
methane under vacuum, ethyl trifluoropyruvate 11 (50 µL, 150 °C, detector: 230 °C), (R)-enantiomer rt1: 8.48 min (minor),
0.375 mmol) and methylenecyclohexane (30 µL, 0.25 mmol) (S)-enantiomer rt2: 8.77 min (major).
were added to the mixture. The reaction mixture was stirred at
room temperature for 30 minutes.
(S)-Ethyl 2-hydroxy-4-phenyl-2-(trifluoromethyl)pent-4-enoate
(12d). The 1H NMR and 13C NMR of the product were con-
Then the reaction mixture was extracted with diethyl ether sistent with the reported data.8m The enantiomeric excess
(2 mL × 3). Removal of the ether gave a residue which was was determined by HPLC with a Chiralpak AS column (1%
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2-propanol in hexane, flow 0.5 mL min−1, (R)-enantiomer rt1:
9.37 min (minor), (S)-enantiomer rt2: 10.16 min (major).
Dimethyl sulfoxide (100%) served as a diluent for all com-
pounds; the final concentration did not exceed 2%. Mueller-
Hinton agar (MH, HiMedia, Čadersky-Envitek, Czech Republic)
buffered to pH 7.4 ( 0.2) was used as the test medium. The
wells of the microdilution tray contained 200 µL of the
Mueller-Hinton medium with 2-fold serial dilutions of the
compounds (2000 to 0.488 µmol L−1) and 10 µL of inoculum
suspension. Inoculum in MH medium was prepared to give a
final concentration of 0.5 McFarland scale (1.5 × 108 cfu mL−1).
The trays were incubated at 37 °C and MICs were read
visually after 24 h and 48 h. The MICs were defined as 95%
inhibition of the growth of control. MICs were determined
twice and in duplicate. The deviations from the usually
obtained values were no higher than the nearest concentration
value up and down the dilution scale.
Antifungal activity – experimental method
In vitro antifungal activities of the compounds were evaluated
on a panel of four ATCC strains (Candida albicans ATCC 44859,
Candida albicans ATCC 90028, Candida parapsilosis ATCC
22019, Candida krusei ATCC 6258) and eight clinical isolates of
yeasts (Candida krusei E28, Candida tropicalis 156, Candida
glabrata 20/I, Candida lusitaniae 2446/I, Trichosporon asahii
1188) and filamentous fungi (Aspergillus fumigatus 231, Absidia
corymbifera 272, Trichophyton mentagrophytes 445) from the col-
lection of fungal strains deposited at the Department of Bio-
logical and Medical Sciences, Faculty of Pharmacy, Charles
University, Hradec Králové, Czech Republic. Three ATCC
strains were used as the quality control strains. All the isolates
were maintained on Sabouraud dextrose agar prior to being
tested.
Acknowledgements
Minimum inhibitory concentrations (MICs) were deter- The authors thank the EPA in Ireland for funding this work.
mined by modified CLSI standard of microdilution format of The antibacterial and antifungal screening was supported by
the M27-A3 and M38-A2 documents.35,36 Dimethyl sulfoxide the Czech Science Foundation (project No. P207/10/2048).
(100%) served as a diluent for all compounds; the final con-
centration did not exceed 2%. RPMI 1640 (Sevapharma,
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