Solution phase parallel synthesis of 4-aminophenyl ethers using a carboxyl-functionalized ionic liquid as support

Article abstract of DOI:10.1007/s00706-005-0361-4

A small sortiment of 4-aminophenyl ether derivatives was constructed with good yields and purities via Williamson reaction using the carboxyl- functionalized ionic liquid [cmmim][BF₄] as soluble support. The recovered ionic liquid could be reused for several times with similar capacity. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-005-0361-4

Monatshefte f€ur Chemie 136, 1751–1755 (2005)
DOI 10.1007/s00706-005-0361-4
Solution Phase Parallel Synthesis
of 4-Aminophenyl Ethers Using
a Carboxyl-Functionalized Ionic
Liquid as Support
ꢀ
Yanqing Peng, Fengping Yi, Gonghua Song , and Ying Zhang
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides & Pharmaceuticals,
East China University of Science and Technology, Shanghai 200237, China
Received January 24, 2005; accepted (revised) March 1, 2005
Published online September 7, 2005 # Springer-Verlag 2005
Summary. A small sortiment of 4-aminophenyl ether derivatives was constructed with good yields
and purities via Williamson reaction using the carboxyl-functionalized ionic liquid [cmmim][BF4] as
soluble support. The recovered ionic liquid could be reused for several times with similar capacity.
Keywords. Parallel synthesis; Functional ionic liquid; Supports; 4-Aminophenyl ethers; Combina-
torial chemistry.
Introduction
Combinatorial chemistry is now widely used to generate vast sortiments of mole-
cules for the discovery of new drugs and materials. It generates large numbers of
compounds rapidly in parallel fashion, rather than by sequential reiteration of
individual syntheses [1]. Solid-phase organic synthesis (SPOS) plays an important
role in combinatorial chemistry. Although the insoluble resin offers the advantage
of easy purification by filtration, it is often a liability at the reaction stage because
of the heterogeneous nature of SPOS [2].
In response to these limitations, several strategies have been developed. Soluble
polymer supports (e.g. PEG) offer certain advantages over insoluble polymers in
terms of ease of analysis and monitoring and, most importantly, the establishment
of homogeneous conditions [3]. In addition, owing to the homogeneity of liquid-
phase reactions, the reaction conditions can be readily shifted from solution-phase
systems without large changes, and the amount of the excess reagents is less than
that in solid-phase reactions. More recently, functionalized ionic liquids have been
ꢀ
Corresponding author. E-mail: ghsong@ecust.edu.cn

1752
Y. Peng et al.
Scheme 1
reported as soluble supports in solution-phase parallel synthesis [4]. Functionalized
ionic liquids, instead of resin beads, are employed as the supports to facilitate the
separation process. Functionalized ionic liquids are immiscible with weakly polar
solvents (e.g. hexane, cyclohexane, benzene, toluene, or diethyl ether) but miscible
with many polar solvents (e.g. water, methanol, ethanol, or acetonitrile). This can
be used to separate excess reagents and by-products from the supported products.
Moreover, the use of functionalized ionic liquids as soluble supports also has other
advantages, such as higher loading capacity and ease in reaction monitoring.
In connection with our research program on solution-phase synthesis and func-
tionalized ionic liquids, we report herein the synthesis of a carboxyl-functionalized
ionic liquid and its application as soluble support in parallel synthesis of 4-ami-
nophenyl ethers (Scheme 1). This strategy has advantages including ready product
isolation and reusability of the ionic liquid support. To the best of our knowledge, it
is the first report on the use of a carboxyl-functionalized ionic liquid as soluble
support in solution phase parallel synthesis.
Results and Discussions
Our starting point was to prepare the carboxyl-functionalized ionic liquid,
1-carboxymethyl-3-methylimidazolium tetrafluoroborate (2, [cmmim][BF4]), from
the commercially available N-methylimidazole (1). Thus, 1 was reacted with an
equimolar amount of chloroacetic acid yielding the corresponding imidazolium
cation. The solid [cmmim][Cl] was treated through standard anion metathesis,
affording [cmmim][BF4] 2 in high yield (93%).
To further evaluate its efficiency in parallel synthesis, 2 was utilized in the
construction of a small sortiment of amino ethers. Subsequent transformation of
2 into 3 was performed in one-pot fashion. Thus 2 reacted with an excess thionyl
chloride in acetonitrile to yield an acyl chloride-type ionic liquid. This was fol-
lowed by treatment with 2 equiv. of 4-aminophenol without purification of the
intermediate. The isolation procedure for the IL-supported substrate 3 involved

Solution Phase Parallel Synthesis
1753
Table 1. Synthesis of 4-aminophenyl ethers 5 using 2 as soluble ionic liquid support
Product
RX
Yield=%a
Purity=%
5a
5b
5c
5d
5e
2,4-(Cl)2–C6H3CH2Cl
C6H5CH2Br
79
80
75
77
78
98
99
99
96
98
2,4-(NO2)2–C6H3Cl
C6H5COCH2Br
CH3CH2CH2CH2Br
a
All yields are based on IL-bound aminophenol 3
neutralization, evaporation, and a simple extraction of the excess reagent with ethyl
acetate to afford the immobilized 4-aminophenol in 96% yield.
The step next was the formation of products grafted on ionic liquid 4a–4e via
Williamson ether synthesis. IL-supported aminophenol 3 was reacted with a 1.5-
fold excess of various halides in 95% ethanol in the presence of NaOH. HPLC
analysis was used to follow the course of these transformations. After the reaction
was complete, the product remained covalently bound to the support, and purifica-
tion could be accomplished through simple procedure. In all cases, as expected, no
excess reagent and by-products were observed by HPLC analysis.
Following solvent washes, immobilized products 4a–4e were subjected to
cleavage with concentrated HCl in ethanol to provide the desired compounds in
75–80% overall yield based on the loading of 3 (Table 1). Each crude product was
1
then characterized by GC-MS and H NMR and gave 96–99% purity without
chromatographic purification.
Finally, for economical and environmental reasons, the regeneration and reuse
of 2 was examined by performing the synthesis of 5b. After the cleavage proce-
dure, the residue after extraction was treated with acetone and concentrated HCl.
The precipitates thus formed were filtered off and the filtrate was concentrated to
give regenerated 2. The recovered 2 was then dried for a short time under vacuum
to remove traces of water and then recycled. The IL-bound aminophenol 3 was
synthesized in the same way using recovered functionalized ionic liquid and was
employed in the next run. Thus 2 could be reused for five times without evident
loss in efficiency. The recovery of ionic liquid was >95% in each run.
In conclusion, we have developed a novel and efficient liquid-phase method
for the parallel synthesis of 4-aminophenyl ether derivatives via Williamson reac-
tions using the carboxyl-functionalized ionic liquid 2 as soluble support. The
procedure afforded the desired products in good yields and high purities. Further-
more, the recovered ionic liquid could be reused for several times without loss of
efficiency.
Experimental
Reagents (A. R. Grade) were purchased and used without further purification.1H NMR spectra were
recorded on a Bruker AM 500 (500 MHz) spectrometer with TMS as internal standard. The mass
spectra were recorded on a Micromass LCT KC317 spectrometer (ESI). Melting points were deter-
€
mined on a BUCHI B-540 apparatus. All final products 5a–5e are known compounds; their physical
and spectroscopic data were compared with those reported in Refs. [5–9] and found to be identical.

1754
Y. Peng et al.
1-Carboxymethyl-3-methylimidazolium tetrafluoroborate (2, C6H9N2O2BF4)
A mixture of 9.45g of chloroacetic acid (100mmol) and 8.20 g of N-methylimidazole (100 mmol) was
heated at 70ꢁC for 8 h (monitored by TLC). After washing with 3ꢂ20 cm3 of ethyl ether, the resulting
white solid was then added to 10.98g NaBF4 (100mmol) and 100cm3 of acetonitrile. The suspension
was stirred rapidly and refluxed for 12h. After filtration and evaporation, 21.18 g 2 were obtained as
1
a yellowish liquid (93%). H NMR (500MHz, D2O): ꢀ ¼ 3.81 (s, CH3), 4.98 (s, CH2), 7.35–7.36
(d, J ¼ 5.2 Hz, H-4, H-5), 8.58 (s, H-2) ppm; FT-IR (KBr): ꢁꢀ¼ 3118, 3088, 3037, 2688, 1732, 1580,
1394, 1090 cmꢃ1
.
1-[(4-Hydroxylphenylcarbamoyl)methyl]-3-methylimidazolium tetrafluoroborate
(3, C12H14N3O2BF4)
To a stirred mixture of 4.56 g 2 (20 mmol) and 25cm3 of anhydrous acetonitrile at 0ꢁC was added
4.76g SOCl2 (40 mmol). The reaction mixture was heated to reflux until the starting material was
completely consumed as judged by TLC (3h). Excess SOCl2 and solvent were removed on a rotary
evaporator, and the residue was diluted with 10cm3 of anhydrous acetonitrile. The resulting solution
was dropped into a mixture of 4.36 g of 4-aminophenol (40 mmol) in 20 cm3 of anhydrous acetonitrile.
After refluxing for 2 h, 3 g of powdered anhydrous Na2CO3 were added with stirring until no gas was
released. The slurry was filtered and the filtrate was concentrated in vacuo. The residue was then
washed with 4ꢂ15cm3 of ethyl acetate. Further treatment in vacuo gave 5.87g 3 as a white solid
1
(92%, 98% purity). H NMR (500 MHz, D2O): ꢀ ¼ 3.92 (s, CH3), 5.18 (s, CH2), 6.87–7.29 (dd,
J ¼ 8.7, 8.7 Hz, C6H4), 7.48–7.49 (d, J ¼ 5.9 Hz, CH¼CH), 8.81 (s, CH¼N) ppm; FT-IR (KBr):
ꢁꢀ¼ 3311, 3162, 3118, 1684, 1602, 1561, 1506, 1443, 1302, 1231, 1064 cmꢃ1; MS (ESI): m=z
(%) ¼ 231.9 (100, [M]þ).
General Procedure for the Preparation of IL-bound Products (4a–e)
To a solution of 0.96 g 3 (3.0mmol) and 4.5mmol of halide in 10 cm3 of ethanol were added 0.12g
NaOH (3.0mmol). The mixture was then refluxed for 3 h. After filtration and evaporation, the residue
was washed with 4ꢂ15 cm3 CH2Cl2 to give 4a–4e.
1-{[4-(2,4-Dichlorobenzyloxy)phenylcarbamoyl]methyl}-3-methylimidazolium
tetrafluoroborate (4a, C19H18N3O2Cl2BF4)
1H NMR (500MHz, D2O): ꢀ ¼ 3.91 (s, CH3), 5.10 (s, CH2), 5.16 (s, OCH2), 7.01–7.02 (d, J ¼ 8.9 Hz,
CH¼CH), 7.46–7.51 (m, C6H3), 7.59–7.73 (m, C6H4), 9.08 (s, CH¼N), 10.39 (s, NH) ppm; FT-IR
(KBr): ꢁꢀ¼ 3192, 3184, 3122, 1695, 1608, 1556, 1511, 1461, 1415, 1396, 1300, 1238, 1185, 1106,
1064 cmꢃ1; MS (ESI): m=z (%) ¼ 390.1 (100, [M]þ).
General Procedure for Product Cleavage
To a solution of 4a–4e in 10 cm3 of ethanol was added 2 cm3 conc. HCl. The mixture was then refluxed
for 2 h. Upon completion, ethanol was removed by rotary evaporation and the residue was neutralized
with sat. aqu. NaOH. The aqueous phase was extracted with 2ꢂ10cm3 CHCl3, and the organic layer
was dried (Na2SO4), filtered, and concentrated under vacuum to afford 5a–5e.
4-(2,4-Dichlorbenzyloxy)anilin (5a, C13H11NOCl2)
1
Mp 69–70ꢁC (Ref. [5] 70–71ꢁC); H NMR (500MHz, CDCl3): ꢀ ¼ 5.04 (s, CH2), 6.64–6.82 (m,
C6H4), 7.25–7.40 (m, C6H5), 7.49 (s, NH2) ppm; MS (EI): m=z (%) ¼ 267 ([M]þ), 159, 108 (100),
80, 53.
4-(Benzyloxy)aniline (5b, C13H13NO)
1
Mp 54–55ꢁC (Ref. [6] 55–56ꢁC); H NMR (500 MHz, CDCl3): ꢀ ¼ 4.99 (s, CH2), 6.64–6.83 (dd,
J ¼ 8.7, 8.7 Hz, C6H4), 7.26 (s, NH2), 7.29–7.43 (m, C6H5) ppm; MS (EI): m=z (%) ¼ 199 ([M]þ), 108
(100), 91, 80, 65, 53.

Solution Phase Parallel Synthesis
1755
4-(2,4-Dinitrophenoxy)aniline (5c, C12H9N3O5)
1
Mp 140–141ꢁC (Ref. [7] 143–144ꢁC); H NMR (500MHz, CDCl3): ꢀ ¼ 3.77 (s, NH2), 6.74–6.95
(m, C6H4), 7.01–8.82 (m, C6H3) ppm; MS (EI): m=z (%) ¼ 275 ([M]þ), 182, 154, 108 (100), 93, 80,
65, 53.
2-(4-Aminophenoxy)-1-phenylethanone (5d, C14H13NO2)
1
Mp 97–98ꢁC (Ref. [8] 95ꢁC); H NMR (500MHz, CDCl3): ꢀ ¼ 5.19 (s, CH2), 6.62–6.82 (m, C6H4),
7.27 (s, NH2), 7.47–8.01 (m, C6H5) ppm; MS (EI): m=z (%) ¼ 227 ([M]þ), 108 (100), 92, 77, 65.
4-(Butoxy)aniline (5e, C10H15NO)
1
Mp 164–165ꢁC (Ref. [9] 168ꢁC); H NMR (500MHz, CDCl3): ꢀ ¼ 0.95–0.97 (t, J ¼ 7.4 Hz, CH3),
1.43–1.76 (m, CH2CH2), 3.88–3.90 (t, J ¼ 6.6 Hz, OCH2), 6.62–6.86 (m, C6H4), 7.26 (s, NH2) ppm;
MS (EI): m=z (%) ¼ 165 ([M]þ), 108 (100), 80, 65, 53.
Acknowledgments
Financial support for this work from the National Key Project for Basic Research (2003 CB 114402,
The Ministry of Science and Technology of China), Shanghai Commission of Science and Technology,
and the Shanghai Educational Commission are gratefully acknowledged.
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