Liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives from poly(ethylene glycol) supported 2-bromo-2-methylpropanoate

Article abstract of DOI:10.1002/jccs.200700082

An efficient liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives with good yields and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG-bound 2-bromo-2-methylpropanoate with phenoxides in the presence of a catalytic amount of NBu₄I and KI, and subsequent cleavage from the PEG.

Full text of DOI:10.1002/jccs.200700082

Journal of the Chinese Chemical Society, 2007, 54, 575-578
575
Communication
Liquid-Phase Synthesis of 2-Methyl-2-aryloxypropanoic Acid Derivatives
from Poly(ethylene glycol) Supported 2-Bromo-2-methylpropanoate
Bin Huang (
Qiu-Ying Wang (
), Pei-Gang Huang (
), Lei Guo (
), Shou-Ri Sheng* (
) and Shao-Hua Jiang (
),
)
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, P. R. China
An efficient liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives with good yields
and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG-bound
2-bromo-2-methylpropanoate with phenoxides in the presence of a catalytic amount of NBu4I and KI, and
subsequent cleavage from the PEG.
Keywords: Liquid-phase synthesis; PEG-Bound 2-bromo-2-methylpropanoate; 2-Methyl-2-aryl-
oxypropanoic acid derivatives; Alkylation; PPAR agonist.
The polymer-supported liquid-phase organic synthe-
sis (LPOS) of small organic molecules has been a subject of
intense research activity recently.1 It profits from both the
advantageous features of homogeneous solution chemistry
(high reactivity, lack of diffusion phenomena and ease of
analysis without following the cleavage-and-check tech-
nique) and of solid-phase methods (use of excess reagents
and easy isolation and purification of products). Among the
various soluble polymers, polyethylene glycol (PEG) is the
most useful and promising polymer, which is soluble in
many solvents, such as CH2Cl2, CHCl3, THF, CH3OH or
H2O at room temperature and can be precipitated from a so-
lution by addition of diethyl ether, tert-butyl methyl ether,
propan-2-ol or hexane.2 Furthermore, the PEG-bound in-
termediate products can be adequately characterized by
TLC analysis, 1H NMR or IR spectroscopy.
ever, these methods involved difficulties such as laborious
manipulation, low overall yields and safety issues. To our
knowledge, a liquid-phase synthesis of 2-methyl-2-aryl-
oxypropanoic acids using PEG as the support has not yet
been reported. Herein we wish to report a novel liquid-
phase synthesis of this derivatives using PEG as soluble
support (Scheme I).
As shown in Scheme I, esterification of commercially
available difunctional PEG (MW = 4,000) with 2-bromo-
2-methylpropanoic acid in the presence of dicyclohexyl-
carbodiimide (DCC) and 4-dimethylaminopyridine (DMAP)
in anhydrous CH2Cl2 at room temperature for 24 h readily
In the last decade, many organization and pharmaceu-
tical companies have carried out extensive research and de-
velopment on the PPAR agonists,3 major therapeutic candi-
dates for the treatment of human metabolic diseases. An
important functionality common to many of the PPAR
agonists and earlier pharmaceuticals developed to treat
dislipidemia such as Clofibrate4 and Fenofibrate,5 is the
2-methylpropanoic moiety (Fig. 1). There are a limited
number of methods for the preparation of 2-methyl-2-aryl-
oxypropanoic acid derivatives in the literature.4b,5,6 The
alkylation reaction of phenols with ethyl 2-bromo-2-meth-
ylpropanoate (and other esters) and the Bargellini reaction
using materials of 1,1,1-trichloro-2-propanol and phenols
are two common procedures among those methods. How-
Fig. 1. 2-Methyl-2-aryloxypropanoic acid derivatives.
Scheme I

576 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Huang et al.
gave rise to the corresponding PEG bound 2-bromo-2-
methylpropanoate 2. The conversion of terminal hydroxyl
groups on PEG was determined by 1H NMR analysis to be
quantitative. The loaded resin 2 showed complete disap-
pearance of the hydroxyl OH stretch and the appearance of
a C=O stretch at 1735 cm-1. With the resin 2 in hand, the
preparation of phenolic ethers resin 4, the key for the suc-
cess of this protocol was investigated. Conversion of resin
2 into resin 4 under standard conditions (phenol, NaH,
THF, rt) was first attempted; the conversion yield after 2
days was calculated to be 56% from the 1H NMR spectrum,
but the reaction never reached completion even by warm-
ing up to 50 °C for 2 days. To our delight, when a catalytic
amount of NBu4I/KI in DMF was added to the mixture, the
reaction went to almost completion over 12 h and gave a
high yield of the corresponding PEG-bound resin 4. Fol-
lowed by hydrolysis of resin 4 using sodium hydroxide
aqueous solution and subsequently acidified with hydro-
chloric acid solution, 2-methyl-2-aryloxypropanoic acids 5
was obtained in good yields (81-91%) with excellent purity
(> 90% by HPLC analysis) of the crude products, and the
results are summarized in Table 1. It should be noted, in
some cases, a trace amount of the PEG residue might con-
taminate the final products 5. But this problem could be
easily solved by passing the crude product through a pad of
silica gel column (acetone-methanol as the eluent, 1:1).
On the other hand, resin 4 cleaved with another method
was further investigated as shown in Scheme II. For exam-
ple, treatment of the resin 4b with 0.1 N EtONa in ethanol
at room temperature for 8 h afforded Clofibrate 6b in 90%
yield and 95% HPLC purity.7 This methodology also could
be used for preparation of the other corresponding esters.
In summary, we have developed a novel liquid-phase
methodology for the synthesis of 2-methyl-2-aryloxypro-
panoic acid derivatives on soluble PEG support with satis-
factory yields and high purity. The mild reaction conditions
ensure the applicability of this procedure to combinatorial
chemistry library synthesis.
EXPERIMENTAL SECTION
Melting points were determined on an X4 melting
point apparatus and are uncorrected; 1H NMR spectra were
recorded on a Bruker Avance 400 MHz spectrometer; IR
spectra were determined on a Perkin-Elmer SP One FT-IR
spectrophotometer; Microanalyses were performed with a
PE 2400 elemental analyzer. All the chemicals were used
without further purification.
General procedure for preparation of PEG-bound
2-bromo-2-methylpropanoate 2
To a stirred solution of PEG (5.0 g, 2.5 mmol) in di-
chloromethane (20 mL) were added 2-bromo-2-methyl-
propanoic acid (1.67 g, 10 mol), DCC (2.06 g, 10 mol) and
DMAP (0.305 g, 2.5 mol). After the mixture was stirred at
Table 1. Synthesis of 2-methyl-2-aryloxypropanoic acids
Entry
Phenol (3)
C6H5OH (3a)
Product
Yield (%)a
Purity (%)b
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
86
91
84
90
83
84
81
90
94
97
94
95
95
95
93
95
p-ClC6H4OH (3b)
o-ClC6H4OH (3c)
p-BrC6H4OH (3b)
p-MeOC6H4OH (3d)
p-MeC6H4OH (3d)
p-F3CC6H4OH (3e)
p-(4-ClC6H4CO)C6H4OH (3f)
5g
5h
a Isolated yield based on loading of original HO-PEG-OH.
b Purity determined by HPLC analysis of the crude products before purification.
Scheme II

LPOS of 2-Methyl-2-aryloxypropanoic Acids
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 577
r.t. for 24 h, the precipitate was removed by filtration and
the polymer was precipitated by addition of diethyl ether
(200 mL) to the filtrate. For completion of the precipita-
tion, the suspension was left at 0 °C for another 30 min. The
white precipitate was collected and washed several times
with diethyl ether, and then dried in vacuo to afford the
PEG bound ester 2 as a white power: 1H NMR (CDCl3) d
1.94 (s, 3H), 3.65-3.75 (m, PEG CH2), 4.33 (t, J = 4.98 Hz,
2H, PEG-OCH2CH2OCO); IR (KBr) n 2887, 1735, 1646,
1567, 1467, 1360, 1280, 1242, 1147, 1116, 1062, 964, 842
cm-1.
°C); 1H NMR (400 MHz, DMSO-d6) d 13.15 (s, 1H), 7.32
(d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 1.51 (s, 6H);
13C NMR (100 MHz, DMSO-d6) d 175.5, 154.9, 129.6,
126.0, 120.9, 79.4, 25.5; IR (KBr) n 3010, 2910, 1700,
1600, 1489, 1379, 1295, 1240, 1150, 1080, 975, 930, 824,
756, 690 cm-1; Anal. Calcd for C10H11ClO3: C, 55.96; H,
5.17. Found: C, 56.01; H, 5.20.
2-(2-Chlorophenoxy)-2-methylpropanoic acid (5c)
1
Colorless solid; mp 75-76 °C (Lit.6 mp 72 °C); H
NMR (400 MHz, CDCl3) d 13.18 (s, 1H), 7.41 (dd, J = 7.5,
1.6 Hz, 1H), 7.20 (ddd, J = 8.0, 7.5, 1.2 Hz, 1H), 7.05 (dd, J
= 8.5, 1.2 Hz, 1H), 7.02 (ddd, J = 8.5, 8.0, 1.6 Hz, 1H), 1.63
(s, 6H); 13C NMR (100 MHz, CDCl3) d 178.8, 150.6, 130.6,
127.8, 127.5, 124.5, 121.7, 81.4, 25.2; IR (film) n 3000,
2908, 1699, 1600, 1490, 1376, 1296, 1243, 1152, 1079,
975, 928, 776, 689 cm-1; Anal. Calcd for C10H11ClO3: C,
55.96; H, 5.17. Found: C, 56.02; H, 5.23.
General procedure for preparation of 2-methyl-2-
aryloxypropanoic acids 5
To a solution of phenol (3) (8 mmol) in anhydrous
THF (10 mL) and DMF (3 mL) was added NaH (60% dis-
persion in mineral oil, 320 mg, 8.0 mmol) under nitrogen
atmosphere at r.t. After stirring at 50 °C for 30 min, the
mixture was cooled to r.t. and the PEG-bound ester 2 (1.0
mmol), n-Bu4NI (0.1 mmol), KI (1.5 mmol) was added.
The mixture was stirred at 50 °C for 12 h. After accom-
plishment of the reaction, the reaction mixture was cooled
and the diethyl ether (60 mL) was added to allow the pre-
cipitation of PEG-bound product 4, which was collected by
filtration and washed with diethyl ether three times. The
obtained product 4 was dissolved in 2 mL of 0.5 N NaOH
aqueous solution and stirred for 12 h at room temperature.
Then the solution was acidified to PH 2-3 using 2 N HCl
and the final crude product was precipitated. After filtra-
tion, the collected solids were redissolved in a small amount
of methanol/acetone (1/1) mixed solvent, and the solution
was allowed to pass through a pad of silica gel column us-
ing acetone-methanol (1:1) as the eluent. The combined fil-
trate was evaporated under reduced pressure to give the
products 5a-5h.
2-(4-Bromophenoxy)-2-methylpropanoic acid (5d)
Colorless solid; mp 132-133 °C (Lit.6 mp 135 °C); 1H
NMR (400 MHz, DMSO-d6) d 13.15 (s, 1H), 7.41 (d, J =
8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 1.55 (s, 6H); 13C
NMR (100 MHz, DMSO-d6) d 175.2, 154.6, 129.3, 125.8,
120.2, 79.2, 25.4; IR (KBr) n 3010, 2910, 1701, 1601,
1490, 1382, 1295, 1242, 1152, 1079, 978, 933, 825, 760,
691 cm-1; Anal. Calcd for C10H11BrO3: C, 46.36; H, 4.28.
Found: C, 46.43; H, 4.36.
2-(4-Methoxyphenoxy)-2-methylpropanoic acid (5e)
Beige solid; mp 58-59 °C (Lit.4a mp 57 °C); 1H NMR
(400 MHz, CDCl3) d 13.15 (s, 1H), 6.94 (d, J = 8.9 Hz, 2H),
6.83 (d, J = 8.9 Hz, 2H), 3.77 (s, 3H), 1.53 (s, 6H); 13C
NMR (100 MHz, DMSO-d6) d 175.7, 155.3, 149.6, 121.6,
114.9, 79.4, 55.8, 25.6; IR (KBr) n 3006, 2908, 1698, 1600,
1490, 1378, 1294, 1240, 1150, 1080, 980, 935, 822, 760
cm-1; Anal. Calcd for C11H14O4: C, 62.85; H, 6.71. Found:
C, 62.78; H, 6.69.
2-Phenoxy-2-methylpropanoic acid (5a)
Colorless solid; mp 45-46 °C (Lit.5a mp 46-48 °C); 1H
NMR (CDCl3) d 13.12 (s, 1H), 7.31-7.26 (m, 3H), 6.96-
6.93 (m, 2H), 1.60 (s, 6H); 13C NMR (100 MHz, CDCl3) d
179.0, 154.5, 129.3, 123.1, 120.4, 79.4, 25.1; IR (KBr) n
3010, 2907, 1698, 1597, 1489, 1381, 1294, 1240, 1151,
1081, 976, 930, 754, 690 cm-1; Anal. Calcd for C10H12O3:
C, 66.65; H, 6.71. Found: C, 66.71; H, 6.78.
2-(4-Methylphenoxy)-2-methylpropanoic acid (5f)
Colorless solid; mp 65-67 °C; 1H NMR (400 MHz,
CDCl3) d 13.13 (s, 1H), 6.92 (d, J = 8.5 Hz, 2H), 6.81 (d, J =
8.5 Hz, 2H), 2.35 (s, 3H), 1.53 (s, 6H); 13C NMR (100 MHz,
DMSO-d6) d 175.5, 155.1, 149.5, 121.2, 114.4, 79.2, 25.5,
20.5; IR (KBr) n 3000, 2908, 1698, 1495, 1376, 1295,
1242, 1151, 1082, 981, 936, 824, 760 cm-1; Anal. Calcd for
C11H14O3: C, 68.02; H, 7.27. Found: C, 68.12; H, 7.36.
2-(4-Chlorophenoxy)-2-methylpropanoic acid (5b)
Colorless solid; mp 120-121 °C (Lit.8 mp 120-122

578 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Huang et al.
2-(4-Trifluoromethylphenoxy)-2-methylpropanoic acid
(5g)
REFERENCES
Colorless solid; mp 103-104 °C; 1H NMR (400 MHz,
DMSO-d6) d 13.25 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 6.92 (d,
J = 8.8 Hz, 2H), 1.56 (s, 6H); 13C NMR (100 MHz, DMSO-
d6) d 175.0, 159.1, 127.5, 122.1, 118.5, 79.4, 25.6; IR (KBr)
n 3000, 2905, 1701, 1497, 1379, 1300, 1245, 1152, 1084,
982, 938, 826, 763 cm-1; Anal. Calcd for C11H11FO4: C,
53.23; H, 4.47. Found: C, 53.19; H, 4.53.
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2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic
acid (5h)
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Colorless solid; mp 179-180 °C (Lit.5a mp 185 °C);1H
NMR (400 MHz, DMSO-d6) d 13.21 (s, 1H), 7.76 (d, J =
8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.4 Hz,
2H), 6.92 (d, J = 8.4 Hz, 2H), 1.71 (s, 6H); 13C NMR (100
MHz, DMSO-d6) d 193.8, 175.0, 160.1, 137.7, 136.8,
132.4, 131.8, 130.0, 129.2, 117.6, 79.4, 25.5; IR (KBr) n
3000, 2910, 1700, 1665, 1600, 1500, 1378, 1297, 1245,
1154, 1090, 985, 940, 832, 765 cm-1; Anal. Calcd for
C17H15ClO4: C, 64.06; H, 4.74. Found: C, 64.10; H, 4.50.
6. Gilman, H.; Wilder, G. J. Am. Chem. Soc. 1955, 77, 6644.
7. A mixture of resin 4b and 0.1 N EtONa in EtOH (8 mL) was
stirred at r.t. for 8 h. Then Et2O (40 mL) was added. The re-
sulting precipitate was filtered and washed with Et2O. The
combined filtrates were washed with H2O, dried over Na2SO4
and evaporated under reduced pressure to give ethyl 2-(4-
chlorophenoxy)-2-methylpropanoate (Clofibrate) (6b). Col-
orless oil; 1H NMR d = 7.28 (d, J = 8.6 Hz, 2H), 6.84 (d, J =
8.6 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 1.56 (s, 6H), 1.25 (t, J =
7.1 Hz, 3H); IR (film) n 3010, 2920, 1720, 1600, 1501, 1379,
1328, 1240, 1186, 1055, 976, 928, 825, 760, 691 cm-1.
8. Catalog handbook of fine chemicals, Aldrich Chemical Co.
2003-2004.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from
the National Natural Science Foundation of China (No.
20562005) and the NSF of Jiangxi Province (No. 0620021).
Received July 27, 2006.