Facile syntheses of histamine-and imidazole-4-propionic acid-derived room-temperature ionic liquids

Article abstract of DOI:10.1080/00397911.2011.555053

We report synthesis of histamine-and imidazole-4-propionic acid-based ionic liquids containing a variety of alkyl and aryl groups placed at the two different positions of the constituent imidazole ring in convenient steps in good yields.

Full text of DOI:10.1080/00397911.2011.555053

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Facile Syntheses of Histamine- and
Imidazole-4-propionic Acid–Derived
Room-Temperature Ionic Liquids
Ravi Kant Dubey a , Neeraj Kumar a & Rahul Jain b
a Department of Pharmaceutical Technology (Bulk Drugs) , National
Institute of Pharmaceutical Education and Research , Punjab , India
b Department of Medicinal Chemistry , National Institute of
Pharmaceutical Education and Research , Punjab , India
Accepted author version posted online: 19 Dec 2011.Published
online: 09 Apr 2012.
To cite this article: Ravi Kant Dubey , Neeraj Kumar & Rahul Jain (2012) Facile Syntheses of
Histamine- and Imidazole-4-propionic Acid–Derived Room-Temperature Ionic Liquids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:15, 2207-2216, DOI: 10.1080/00397911.2011.555053
To link to this article: http://dx.doi.org/10.1080/00397911.2011.555053
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Synthetic Communications1, 42: 2207–2216, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.555053
FACILE SYNTHESES OF HISTAMINE- AND IMIDAZOLE-
4-PROPIONIC ACID–DERIVED ROOM-TEMPERATURE
IONIC LIQUIDS
Ravi Kant Dubey,1 Neeraj Kumar,1 and Rahul Jain2
1Department of Pharmaceutical Technology (Bulk Drugs), National
Institute of Pharmaceutical Education and Research, Punjab, India
2Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, Punjab, India
GRAPHICAL ABSTRACT
Abstract We report synthesis of histamine- and imidazole-4-propionic acid–based ionic
liquids containing a variety of alkyl and aryl groups placed at the two different positions
of the constituent imidazole ring in convenient steps in good yields.
Keywords Histamine; imidazole-4-propionic acid; ionic liquids; synthesis
INTRODUCTION
Ionic liquids have attracted interest in recent years mainly as greener alterna-
tives to conventional organic solvents, with the aim of facilitating safe and ecofriendly
chemistry.[1] The room-temperature ionic liquids (RTILs) are commonly referred
Received December 28, 2010.
Address correspondence to Rahul Jain, Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India. E-mail:
rahuljain@niper.ac.in
2207

2208
R. K. DUBEY, N. KUMAR, AND R. JAIN
to as designer solvents as they can be tuned to specific applications.[2–5] The
imidazolium-based ionic liquids are the most used and best investigated class of ionic
liquids. Many literature reports have associated imidazolium ionic liquids with many
drawbacks such as incompatibility with basic conditions, hygroscopic nature, and active
participation in many chemical reactions.[6–10] In our previous attempts to impart better
physicochemical properties to imidazolium ionic liquids, we incorporated various bulky
groups in the imidazole ring and found quite stable ionic liquids. We observed that many
of these ionic liquids showed solid-like characteristics and melting points approaching
and even above 100 ꢀC.[11] This may be accounted as a consequence of the symmetric
nature of those ionic liquids. Furthermore, the alkylation at the C-2 position of the imi-
dazole ring with larger alkyl groups has been associated with increase in melting
point.[12] As most of functions of ionic liquids require them to be in a fluid state, we
developed some new RTILs using histamine and imidazole-4-propionic acid as precur-
sors. We have attempted the incorporation of some alkyl and aryl groups at the N-1 and
N-3 positions of the imidazole ring of these precursors. It is also important to mention
that presence of an amino or a carboxylic acid group in the side chain may lead to other
chemical use of these ionic liquids in addition to as a solvent in organic reactions.
RESULTS AND DISCUSSION
Four series in all, the first two containing histamine-derived ionic liquids and
the other two consisting of imidazole-4-propionic acid–derived ionic liquids, were
synthesized. The first series of ionic liquids, 3a–c, involves the introduction of ident-
ical alkyl groups at the N-1 and N-3 positions, whereas in ionic liquids 5a–c different
alkyl groups have been attached at the N-1 and N-3 (Scheme 1). Histamine ꢁ 2HCl (1)
upon reaction with di-tert-butyl dicarbonate in the presence of NaOH in a dioxane–
water mixture readily yielded N-a-Boc-histamine 2. The simultaneous alkylation and
quaternization at N1 and N3 of the imidazole ring in compounds 2 was carried out
by refluxing it with various alkyl halides in the presence of potassium carbonate to
obtain 1,3-dialkylimidazolium halides ionic liquids 3a–c.
Scheme 1. Reagents and conditions: (i) Boc2O, NaOH, dioxane–water, 2 h, rt; (ii) RX, K2CO3, acetone,
reflux, 5–6 h; (iii) NaH, RX, DMF, ꢂ15 to ꢂ5ꢀC, 3 h; (iv) C4H9Br, 5–6 h, 80–90ꢀC.

SYNTHESIS OF IONIC LIQUIDS
2209
Scheme 2. Reagents and conditions: (i) CH3OH, HCL, 0ꢀC, 2 h; (ii) 10% Pd-C, H2, rt 24 h; (iii) RX,
K2CO3, acetone, reflux, 5–6 h; (iv) NaH, RX, DMF, ꢂ15 to ꢂ5ꢀC, 3 h; (v) C4H9Br, 5–6 h, 80–90ꢀC.
For synthesizing the second series of the ionic liquids 5a–c, the direct and
regiospecifc N-1 alkylation was achieved by the reaction of alkyl or aryl halides with
2 in the presence of sodium hydride as a base in dimethylformamide (DMF) at
ꢂ15 ꢀC to yield compounds 4a–c, using a method reported earlier.[13] The reaction
of 4a–c with neat 1-bromobutane provided ionic liquids 5a–c.
Urocanic acid ester methyl ester was required as the starting material for the
synthesis of imidazole-4-propanoic acid–derived ionic liquids (Scheme 2). Urocanic
acid (6) was converted to its methyl ester derivative 7 in the presence of methanol
and anhydrous HCl. The latter compound, 7, upon hydrogenation using Pd-C,
produced 8. The ionic liquids 9a–c were obtained by refluxing 8 in the presence of
a base with various alkyl halides. The alkylation reaction at the N-1 position of the
imidazole ring of 8 at low temperature using alkyl=aryl halides in the presence of a
base provided compounds 10a–c. The alkylated compounds 10a–c upon quaterniza-
tion using neat 1-bromobutane produced ionic liquids 11a–c.
In addition to these sets of ionic liquids, a C-2 alkylated imidazole-4-propionic
acid–derived ionic liquid was also prepared (Scheme 3). As mentioned earlier, substi-
tution at the C-2 position with a methyl group has not provided completely inert ionic
liquids, while substitution with bulkier alkyl groups led to solid-like characteristics in
the ionic liquids. Therefore, it was important and worthwhile to observe the effect of
the C-2 alkylation on the physical characteristics of a side chain containing an imidaz-
ole ring. Compound 10a, upon reaction with isobutyric acid in the presence of silver
nitrate and ammonium persulfate in 10% sulfuric acid, readily provided C-2 alkylated
compound 12, which upon reaction with n-butyl bromide yielded the RTIL 13.

2210
R. K. DUBEY, N. KUMAR, AND R. JAIN
Scheme 3. Reagents and conditions: (i) (CH3)2CHCOOH, AgNO3, 10% H2SO4, (NH4)2S2O8. 80ꢀC; (ii)
C4H8Br, 85ꢀC.
As previously discussed, sometimes ionic liquids participate in a variety of
chemical reactions. This may be attributed to the presence of some reactive function-
ality in the core of ionic liquids. Although the ionic liquids reported herein contain a
Boc group on the side-chain amino functionality of histamine and a methyl ester
group on the side chain of imidazole-4-propanoic acid, a convenient one-step depro-
tection would offer free amino- or carboxylic acid group–containing ionic liquids.
These ionic liquids with reactive free amino and carboxylic acid functionality may also
be useful in certain kind of ionic liquid–mediated reactions.
CONCLUSION
To summarize, we have successfully synthesized series of new histamine- and
imidazole-4-propionic acid–derived ionic liquids with a number of alkyl or aryl
groups placed at two different positions of the constituent imidazole ring. These ionic
liquids are expected to offer ideal physicochemical properties, including low hygro-
scopicity as compared to their unsubstituted counterparts and better stability. Owing
to their amino and carboxylic acid functionalities, these could provide some beneficial
results in certain kind of reactions. Our efforts in the direction of establishing utility
of the newly synthesized ionic liquid will be reported in due course.
EXPERIMENTAL
Compounds were routinely checked for their purity on precoated silica gel G254
thin-layer chromatography (TLC) plates (Merck), and the spots were visualized
under ultraviolet (UV) spectrophotometry and then by exposing them to iodine
vapors. Column chromatographic purification was carried out on Merck silica gel
(100–200 mesh). Melting points were recorded on a capillary melting-point apparatus
as well as differential scanning calorimetry (DSC). NMR spectra were recorded on a
300-MHz Bruker FT-NMR (Advance DPX 300) spectrometer using tetramethylsi-
lane (TMS) as internal standard, and the chemical shifts are reported in d units. Mass
spectra were recorded by (HRMS; high-resolution mass spectrometry Finnigan Mat
LCQ spectrometer, Xcaliber software) (APCI=ESI) and on matrix-assisted laser
desorption=ionization (MALDI).
Synthesis of 2
To a solution of histamine ꢁ 2HCl (2.7 mmol) in dioxane–water (2:1, 15 mL),
4 N NaOH was added to adjust the pH to 12. After the addition of di-tert-butyl

SYNTHESIS OF IONIC LIQUIDS
2211
dicarbonate (6.8 mmol), the reaction was stirred overnight. The reaction mixture
was extracted with CH2Cl2 (4 ꢃ 20 mL). The solvent was removed under reduced
pressure, and column chromatography over silica gel (100–200 mesh) afforded 2.
This compound was obtained as a colorless solid. Yield: 85%; 1H NMR
(CD3OD): d 2.77 (t, 2H, CH2, J ¼ 6.8 Hz), 3.36 (t, 2H, CH2, J ¼ 6.4 Hz), 1.43 (s, 9H,
3 ꢃ CH3), 6.7 (s, 1H, 5-Ar-H), 7.5 (s, 1H, 2-Ar-H), 5.21 (bs, 1H, NH), 9.4 (bs, 1H,
NH); MS (MALDI): m=z 212 (M þ 1). Anal. calcd. for C10H17N3O2: C, 56.85; H,
8.11; N, 19.89. Found: C, 56.63; H, 8.57; N, 20.13.
Synthesis of 7
A solution of urocanic acid (14.5 mmol) in methanol (10 mL) was chilled at 0 ꢀC,
and through this solution dry HCl gas was passed. The reaction was continued for 2 h,
and the mixture was worked up by the solvent evaporation to afford the product 7.
This compound was obtained as a colorless solid. Yield: 87%; 1H NMR
(CD3OD): d 3.81 (s, 3H, OCH3), 6.58 (d, 1H, CH, J ¼ 16.4 Hz), 7.58 (d, 1H, CH,
J ¼ 16.4 Hz), 7.90 (s, 1H, 5-Ar-H), 9.03 (s, 1H, 2-Ar-H); MS (APCI): m=z 153
(M þ 1). Anal. calcd. for C7H9N2O2Cl: C, 44.58; H, 4.81; N, 14.85. Found: C,
44.39; H, 4.66; N, 15.02.
Synthesis of 8
To a solution of urocanic acid methyl ester (0.5 g, 2.65 mmol) in methanol was
added 10% Pd-C (25 mg), and a hydrogen balloon was attached to the round-
bottomed flask. The mixture was hydrogenated for 24 h at ambient temperature
and then filtered using celite. The filtrate was evaporated under reduced pressure to
afford the desired product 8.
This compound was obtained as a colorless solid. Yield: 96%; 1H NMR
(CD3OD): d 2.74 (t, 2H, CH2, J ¼ 7.2 Hz), 3.01 (t, 2H, CH2, J ¼ 7.2 Hz), 3.69 (s,
3H, OCH3), 7.32 (s, 1H, 5-Ar-H), 8.75 (s, 1H, 2-Ar-H); MS (APCI): m=z 155
(M þ 1). Anal. calcd. for C7H10N2O2: C, 54.54; H, 6.54; N, 18.17. Found: C, 54.28;
H, 6.29; N, 17.95.
Synthesis of 3a–c and 9a–c
General procedure. tert-Butyl-2-(1H-imidazol-4-yl)ethylcarbamate (2, 0.48
mmol) or imidazole-4-propionic acid methyl ester (8, 0.48 mmol) was stirred with alkyl
halide (1.44 mmol) in the presence of potassium carbonate (0.95 mmol) in acetone
(5 mL) at 60–70 ꢀC for 5–6 h. The solvent was removed under reduced pressure and
column chromatography over silica gel (100:200 mesh) gave products 3a–c or 9a–c.
4-[2-(tert-Butoxycarbonylamino)ethyl]-1,3-dimethyl-1H-imidazol-3-ium
iodide (Entry 3a). This compound was obtained as a reddish brown liquid. Yield:
1
87%; H NMR (CDCl3): d 1.43 (s, 9H, 3 ꢃ CH3), 3.96 (s, 3H, N-CH3), 3.99 (s, 3H,
N-CH3), 2.92 (t, 2H, CH2, J ¼ 6.4 Hz), 3.44 (t, 2H, CH2, J ¼ 6.4 Hz), 5.3 (bs, 1H,
N-H), 7.2 (s, 1H, 5-Ar-H), 9.7 (s, 1H, 2-Ar-H); MS (MALDI): m=z 240 (Mþ 1ꢂHI).
Anal. calcd. for C12H22N3O2I: C, 39.25; H, 6.04; N, 11.44. Found: C, 39.70; H,
5.77; N, 11.24.

2212
R. K. DUBEY, N. KUMAR, AND R. JAIN
4-[2-(tert-Butoxycarbonylamino)ethyl]-1,3-diethyl-1H-imidazol-3-ium
iodide (Entry 3b). This compound was obtained as a colorless viscous liquid.
1
Yield: 47%; H NMR (CDCl3): d 1.43 (s, 9H, 3 ꢃ CH3), 1.61 (m, 6H, 2 ꢃ CH3),
4.28–4.36 (m, 4H, 2 ꢃ N-CH2), 2.94 (t, 2H, CH2, J ¼ 6.4 Hz), 3.49 (t, 2H, CH2,
J ¼ 6.4 Hz), 5.3 (bs, 1H, NH), 7.4 (s, 1H, 5-Ar-H), 9.8 (s, 1H, 2-Ar-H); MS
(MALDI); m=z 268.7 (M þ 1ꢂHI). Anal. calcd. for C14H26N3O2I: C, 42.54; H,
6.63; N, 10.63. Found: C, 42.87; H, 6.88; N, 10.29.
4-[2-(tert-Butoxycarbonylamino)ethyl]-1,3-dibenzyl-1H-imidazol-3-ium
bromide (Entry 3c). This compound was obtained as a colorless viscous liquid.
1
Yield: 38%; H NMR (CDCl3): d 1.39 (s, 9H, 3 ꢃ CH3), 5.46 (s, 2H, N-CH2), 5.53
(s, 2H, N-CH2), 2.75 (t, 2H, CH2, J ¼ 6.4 Hz), 3.29 (t, 2H, CH2, J ¼ 6.4 Hz), 6.76
(bs, 1H, NH), 7.27–7.46 (m, 10 ꢃ Ar-H),7.18 (s, 1H, 5-Ar-H), 10.31 (s, 1H,
2-Ar-H); MS (MALDI): m=z 392.8(M þ 1ꢂHBr). Anal. calcd. for C24H30N3O2Br:
C, 61.02; H, 6.40; N, 8.89. Found: C, 60.78; H, 6.81; N, 8.59.
4-(3-Methoxy-3-oxopropyl)-1,3-dimethyl-1H-imidazol-3-ium iodide (entry
9a). This compound was obtained as a colorless liquid. Yield 76%; 1H NMR
(CDCl3): d 3.96 (s, 3H, N-CH3), 4.00 (s, 3H, N-CH3), 2.76 (t, 2H, CH2, J ¼ 4.8 Hz),
2.97 (t, 2H, CH2, J ¼ 4.8 Hz), 3.67 (s, 3H, OCH3), 7.11 (s, 1H, 5-Ar-H), 9.73 (s, 1H,
2-Ar-H); MS (APCI): m=z 183 (M þ 1ꢂHI). Anal. calcd. for C9H15N2O2I: C, 34.85;
H, 4.88; N, 9.03. Found: C, 35.05; H, 4.66; N, 8.82.
4-(3-Methoxy-3-oxopropyl)-1,3-diethyl-1H-imidazol-3-ium iodide (Entry
1
9b). This compound was obtained as a reddish brown liquid. Yield 78%; H NMR
(CDCl3): d 1.26 (m, 6H, 2 ꢃ CH3), 4.49 (s, 4H, 2 ꢃ N-CH2), 2.77 (t, 2H, CH2,
J ¼ 6.9 Hz), 3.08 (t, 2H, CH2, J ¼ 6.7 Hz), 3.73 (s, 3H, OCH3), 7.0 (s, 1H, 5-Ar-H),
8.41 (s, 1H, 2-Ar-H); MS (APCI): m=z 211 (M þ 1-HI). Anal. calcd. for
C11H19N2O2I: C, 39.07; H, 5.66; N, 8.28. Found: C, 39.35; H, 5.87; N, 8.37.
4-(3-Methoxy-3-oxopropyl)-1,3-dibenzyl-1H-imidazol-3-ium
bromide
1
(Entry 9c). This compound was obtained as a light brown liquid. Yield 89%; H
NMR (CDCl3): d 1.26 (s, 6H, 2 ꢃ CH3), 5.56 (s, 4H, 2 ꢃ N-CH2), 2.45 (t, 2H,
CH2, J ¼ 6.9 Hz), 2.77 (t, 2H, CH2, J ¼ 6.4 Hz), 3.63 (s, 3H, OCH3), 7.27–7.47 (m,
10 ꢃ Ar-H), 6.8 (s, 1H, 5-Ar-H), 10.95 (s, 1H, 2-Ar-H); MS (APCI): m=z 335
(M þ 1ꢂHBr). Anal. calcd. for C21H23N2O2Br: C, 60.73; H, 5.58; N, 6.74. Found:
C, 60.56; H, 5.82; N, 6.91.
Synthesis of 4a–c and 10a–c
General procedure. Sodium hydride (60% suspension, 3.2 mmol) was placed
in a two-necked flask, and tert-butyl-2-(1H-imidazol-4-yl)ethyl carbamate (2,
1.5 mmol) or imidazole-4-propionic acid methyl ester (8, 1.5 mmol) in DMF (15 mL)
was added under nitrogen atmosphere at ꢂ15 ꢀC. The reaction mixture was stirred
for another 1 h at ꢂ15 ꢀC, and then alkyl halide (0.54 mmol) was added. The tempera-
ture of the reaction was raised to ꢂ5 ꢀC, and the reaction mixture was stirred for
another 3 h under N2. After completion, the reaction was quenched with methanol
(5 mL), and the solvent was evaporated to give the crude product, which was purified
using silica-gel (100–200 mesh) column chromatography to obtain 4a–c or 10a–c.

SYNTHESIS OF IONIC LIQUIDS
2213
tert-Butyl-2-(1-methyl-1H-imidazol-4-yl)ethyl carbamate (Entry 4a).
1
This compound was obtained as a colorless viscous liquid. Yield: 55%; H NMR
(CDCl3): d 1.43 (s, 9H, 3 ꢃ CH3), 2.91 (s, 3H, N-CH3), 3.14 (t, 2H, CH2, J ¼ 7.2 Hz),
3.49 (t, 2H, CH2, J ¼ 6.972 Hz), 5.21 (bs, 1H, NH), 6.67 (s, 1H, 5-Ar-H), 7.39 (s, 1H,
2-Ar-H); MS (MALDI): m=z 226 (M þ 1). Anal. calcd. for C11H19N3O2: C, 58.64; H,
8.50; N, 18.65. Found: C, 58.25; H, 8.76; N, 18.88.
tert-Butyl-2-(1-ethyl-1H-imidazol-4-yl)ethyl carbamate (Entry 4b). This
1
compound was obtained as a colorless liquid. Yield 52%; H NMR (CDCl3): d
1.41 (t, 3H, CH3, J ¼ 7.5 Hz), 1.43 (s, 9H, 3 ꢃ CH3), 2.72 (t, 2H, CH2, J ¼ 6.56 Hz),
3.40 (t, 2H, CH2, J ¼ 6.16 Hz), 3.92 (q, 2H, N-CH2, J ¼ 7.56 Hz), 5.21 (bs, 1H, NH),
6.70 (s, 1H, 5-Ar-H), 7.39 (s, 1H, 2-Ar-H); MS (MALDI): m=z 240 (M þ 1). Anal.
calcd. for C12H21N3O2: C, 60.23; H, 8.84; N, 17.56. Found: C, 60.65; H, 8.58; N,
17.60.
tert-Butyl-2-(1-benzyl-1H-imidazol-4-yl)ethyl carbamate (Entry 4c).
1
This compound was obtained as a colorless liquid. Yield 69%; H NMR (CDCl3):
d 1.43 (s, 9H, 3 ꢃ CH3), 2.73 (t, 2H, CH2, J ¼ 6.52 Hz), 3.40 (t, 2H, CH2, J ¼ 6.16 Hz),
5.05 (s, 2H, N-CH2), 5.11 (bs, 1H, NH), 7.30 (m, 5H, 5 ꢃ Ar-H), 6.68 (s, 1H,
5-Ar-H), 7.46 (s, 1H, 2-Ar-H); MS (MALDI): m=z 244 (M þ 1). Anal. Calcd. for
C17H23N3O2: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.55; H, 7.28; N, 13.79.
Methyl-3-(1-methyl-1H-imidazol-4-yl)propanoate (Entry 10a). This com-
pound was obtained as a reddish brown viscous liquid. Yield 45%; 1H NMR
(CDCl3): d 2.67 (t, 2H, CH2, J ¼ 7.2 Hz), 2.88 (t, 2H, CH2, J ¼ 7.2 Hz), 3.62 (s,
3H, OCH3), 3.67 (s, 3H, N-CH3), 6.66 (s, 1H, 5-Ar-H), 7.45 (s, 1H, 2-Ar-H); MS
(MALDI): m=z 169 (M þ 1). Anal. calcd. for C8H12N2O2: C, 57.13; H, 7.19; N,
16.66. Found: C, 56.86; H, 6.93; N, 16.83.
Methyl-3-(1-ethyl-1H-imidazol-4-yl)propanoate (Entry 10b). This com-
1
pound was obtained as a pale brown viscous liquid. Yield 50%; H NMR (CDCl3):
d 1.41 (t, 3H, CH3, J ¼ 7.57 Hz), 2.66 (t, 2H, CH2, J ¼ 7.2 Hz), 2.88 (t, 2H, CH2,
J ¼ 7.2 Hz), 3.66 (s, 3H, OCH3), 3.90 (q, 2H, N-CH2, J ¼ 7.57 Hz), 6.69 (s, 1H,
5-Ar-H), 7.45 (s, 1H, 2-Ar-H); MS (MALDI): m=z 182 (M þ 1). Anal. calcd. for
C9H14N2O2: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.51; H, 7.39; N, 15.71.
Methyl-3-(1-benzyl-1H-imidazol-4-yl)propanoate (Entry 10c). This com-
1
pound was obtained as a pale brown viscous liquid. Yield 48%; H NMR (CDCl3):
d 2.65 (t, 2H, CH2, J ¼ 7.2 Hz), 2.88 (t, 2H, CH2, J ¼ 7.2 Hz), 3.64 (s, 3H, OCH3),
5.03 (s, 2H, N-CH2), 7.3–7.4 (m, 5 ꢃ Ar-H), 6.64 (s, 1H, 5-Ar-H), 7.44 (s, 1H,
2-Ar-H); MS (MALDI): m=z 244 (M þ 1). Anal. calcd. for C14H16N2O2: C, 68.83;
H, 6.60; N, 11.47. Found: C, 68.77; H, 6.26; N, 11.72.
Synthesis of 5a–c and 11a–c
General procedure. Bromobutane (3 mmol) was added to the N-1 alkylated
compounds 4a–c or 10a–c (1 mmol), and the reaction mixture was stirred for 5–6 h at
85–90ꢀC. The solvent was removed under reduced pressure, and column chromato-
graphy over silica gel (100–200 mesh) provided the quaternized compounds.

2214
R. K. DUBEY, N. KUMAR, AND R. JAIN
4-[2-(tert-Butoxycarbonylamino)ethyl]-3-butyl-1-methyl-1H-imidazol-3-
ium bromide (Entry 5a). This compound was obtained as a reddish brown viscous
1
liquid. Yield 89%; H NMR (CDCl3): d 0.96 (t, 3H, CH3, J ¼ 5.56 Hz), 1.43 (s, 9H,
3 ꢃ CH3), 1.43 (m, 2H, CH2), 1.86 (m, 2H, CH2), 2.87 (t, 2H, N-CH2, J ¼ 8.56 Hz),
4.03 (s, 3H, N-CH3), 3.46 (t, 2H, CH2, J ¼ 6.2 Hz), 4.2 (t, 2H, CH2, J ¼ 6.8 Hz), 5.5
(bs, 1H, NH), 7.27 (s, 1H, 5-Ar-H), 10.11 (s, 1H, 2-Ar-H); MS (APCI): m=z 282
(M þ 1-HBr). Anal. calcd. for C15H28N3O2Br: C, 49.73; H, 7.79; N, 11.60. Found:
C, 49.57; H, 7.96; N, 11.30.
4-[2-(tert-Butoxycarbonylamino)ethyl]-3-butyl-1-ethyl-1H-imidazol-3-ium
bromide (Entry 5b). This compound was obtained as a colorless viscous liquid.
Yield 98%; 1H NMR (CDCl3): d 0.97 (t, 3H, CH3, J ¼ 5.2 Hz), 1.43 (s, 9H, 3 ꢃ CH3),
1.43 (m, 2H, CH2), 1.58 (t, 3H, CH3, J ¼ 7.32 Hz), 1.86 (m, 2H, CH2), 2.88 (t, 2H,
CH2, J ¼ 5.92 Hz), 3.49 (t, 2H, CH2, J ¼ 6.32 Hz), 4.23 (t, 2H, N-CH2, J ¼ 6.8 Hz),
4.35 (t, 2H, N-CH2, J ¼ 7.36 Hz), 5.47 (bs, 1H, NH), 7.41 (s, 1H, 5-Ar-H), 10.23
(s, 1H, 2-Ar-H); MS (MALDI): m=z 296.7 (M þ 1ꢂHBr). Anal. calcd. for
C16H30N3O2Br: C, 51.06; H, 8.03; N, 11.17. Found: C, 51.33; H, 7.71; N, 11.08.
4-[2-(tert-Butoxycarbonylamino)ethyl]-3-butyl-1-benzyl-1H-imidazol-3-
ium bromide (Entry 5c). This compound was obtained as a colorless viscous
1
liquid. Yield 99%; H NMR (CDCl3): d 0.96 (t, 3H, CH3, J ¼ 7.32 Hz), 1.27 (t, 2H,
N-CH2, J ¼ 8.16 Hz), 1.42 (m, 2H, CH2), 1.86 (m, 2H, CH2), 5.52 (s, 2H, N-CH2),
7.38 (m, 5 ꢃ Ar-H), 2.84 (t, 2H, CH2, J ¼ 6.44 Hz), 3.40 (t, 2H, CH2, J ¼ 6.36 Hz),
7.2 (s, 1H, 5-Ar-H), 10.27 (s, 1H, 2-Ar-H); MS (APCI): m=z 357 (M þ 1-HBr).
Anal. calcd. for C21H32N3O2Br: C, 57.57; H, 7.36; N, 9.58. Found: C, 57.19; H,
7.71; N, 9.23.
3-Butyl-4-(3-methoxy-3-oxopropyl)-1-methyl-1H-imidazol-3-ium bromide
(Entry 11a). This compound was obtained as a pale brown viscous liquid. Yield
1
59%; H NMR (CDCl3): d 0.92 (t, 3H, CH3, J ¼ 7.2 Hz), 1.35 (m, 2H, CH2), 1.82
(m, 2H, CH2), 2.71 (t, 2H, CH2, J ¼ 4.8 Hz), 2.93 (t, 2H, CH2, J ¼ 5.2 Hz), 3.65 (s,
3H, OCH3), 4.02 (s, 3H, N-CH3), 4.20 (t, 2H, N-CH2, J ¼ 5.2 Hz), 7.26 (s, 1H,
5-Ar-H), 10.18 (s, 1H, 2-Ar-H); MS (MALDI): m=z 225 (M þ 1ꢂHBr). Anal. calcd.
for C12H21N2O2Br: C, 47.22; H, 6.94; N, 9.18. Found: C, 47.66; H, 7.32; N, 9.37.
3-Butyl-4-(3-methoxy-3-oxopropyl)-1-ethyl-1H-imidazol-3-ium bromide
(Entry 11b). This compound was obtained as a pale brown viscous liquid. Yield
1
96%; H NMR (CDCl3): d 0.97 (t, 3H, CH3, J ¼ 7.2 Hz), 1.26 (m, 2H, CH2), 1.87
(m, 2H, CH2), 4.28 (t, 2H, N-CH2, J ¼ 7.6 Hz), 4.36 (t, 2H, N-CH2, J ¼ 3.6 Hz),
1.86 (t, 3H, CH3, J ¼ 3.6 Hz), 2.75 (t, 2H, CH2, J ¼ 7.2 Hz), 2.95 (t, 2H, CH2,
J ¼ 7.0 Hz), 3.71 (s, 3H, OCH3), 7.16 (s, 1H, 5-Ar-H), 10.54 (s, 1H, 2-Ar-H); MS
(APCI): m=z 239 (M þ 1ꢂHBr). Anal. calcd. for C13H23N2O2Br: C, 48.91; H,
7.26; N, 8.78. Found: C, 49.23; H, 6.97; N, 8.89.
3-Butyl-4-(3-methoxy-3-oxopropyl)-1-benzyl-1H-imidazol-3-ium bromide
(Entry 11c). This compound was obtained as a pale brown viscous liquid. Yield 99%;
1H NMR (CDCl3): d 0.96 (t, 3H, CH3, J ¼ 5.2 Hz), 1.41 (m, 2H, CH2), 1.87 (m, 2H,
CH2), 4.2 (t, 2H, N-CH2, J ¼ 7.2 Hz), 5.59 (s, 2H, N-CH2), 7.38 (m, 5 ꢃ Ar-H), 2.7
(t, 2H, CH2, J ¼ 7.2 Hz), 2.91 (t, 2H, CH2, J ¼ 7.2 Hz), 3.65 (s, 3H, OCH3), 7.1

SYNTHESIS OF IONIC LIQUIDS
2215
(s, 1H, 5-Ar-H), 10.61 (s, 1H, 2-Ar-H); MS (MALDI): m=z 301.7 (M þ 1ꢂHBr). Anal.
calcd. for C13H23N2O2Br: C, 56.70; H, 6.61; N, 7.35. Found: C, 49.23; H, 6.97; N, 8.89.
Synthesis of 12
A solution of methyl-3-(1-methyl-1H-imidazol-4-yl)propanoate (10a, 1 mmol)
was added to a mixture of silver nitrate (0.6 mmol) and isobutyric acid (3.0 mmol)
in 10% H2SO4 (10 mL), and the reaction mixture was heated at 80 ꢀC. A freshly
prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added
dropwise over 15 min. The heating source was then removed, and the reaction pro-
ceeded with the evolution of carbon dioxide. After 15 min, the reaction mixture was
poured onto ice, made alkaline by adding 30% NH4OH solution and extracted with
EtOAc (4 ꢃ 50 mL). The combined extracts were washed with brine (2 ꢃ 10 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure to afford an
oil, which upon column chromatography over silica gel (100–200 mesh) afforded 12.
1
This compound was obtained as a dark brown liquid. Yield 96%; H NMR
(CDCl3): d 1.18 (d, 3H, CH3, J ¼ 4.56 Hz), 1.20 (d, 3H, CH3, J ¼ 4.64 Hz), 2.98 (m,
H, CH), 2.68 (t, 2H, CH2, J ¼ 4.24 Hz), 2.87 (t, 2H, CH2, J ¼ 3.84 Hz), 3.58 (s, 3H,
OCH3), 3.68 (s, 3H, N-CH3), 6.69 (s, 1H, 5-Ar-H); MS (APCI): m=z 211 (M þ 1).
Anal. calcd. for C11H18N2O2: C, 62.99; H, 8.55; N, 13.52. Found: C, 62.58; H,
8.68; N, 13.89.
Synthesis of 13
Bromobutane (3 mmol) was added to methyl-3-(2-isopropyl-1-methyl-1H-
imidazol-4-yl)propanoate (12, 1 mmol), and the reaction was stirred for 5 h at 85 ꢀC.
The column chromatography over silica gel (100–200 mesh) provided the quaternized
compound 13.
1
This compound was obtained as a brown viscous liquid. Yield 98%; H NMR
(CDCl3): d 0.97 (t, 3H, CH3, J ¼ 7.4 Hz), 1.21 (d, 3H, CH3, J ¼ 9.8 Hz), 1.23 (d, 3H,
CH3, J ¼ 9.8 Hz), 1.56 (t, 2H, N-CH2, J ¼ 8.16 Hz), 1.42 (m, 2H, CH2), 1.88 (m, 2H,
CH2), 2.68 (t, 2H, CH2, J ¼ 4.24 Hz), 2.87 (t, 2H, CH2, J ¼ 3.84 Hz), 3.73 (s, 3H,
OCH3), 4.06 (s, 3H, N-CH3), 4.25 (m, H, CH), 7.0 (s, 1H, 5-Ar-H); MS (APCI);
m=z 267 (M þ 1ꢂHBr). Anal. calcd. for C15H27N2O2Br: C, 51.88; H, 7.84; N, 8.07.
Found: C, 52.02; H, 8.18; N, 7.89.
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