High-yielding cleavage of (aryloxy)acetates

Article abstract of DOI:10.1002/ejoc.200700769

A reliable and high-yielding one-pot sequence for the removal of O-carboxymethyl moieties from phenols is presented. When diethylphosphoryl azide is employed as the azide transfer reagent in the Curtius rearrangement and glycerol in the subsequent hydrolytic workup, the protocol can be reliably applied to a very broad scope of substrates. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700769

FULL PAPER
DOI: 10.1002/ejoc.200700769
High-Yielding Cleavage of (Aryloxy)acetates
Anke Spurg[a] and Siegfried R. Waldvogel*[a]
Keywords: Azides / Cleavage reactions / Carboxylic acids / Arenes / Rearrangement
A reliable and high-yielding one-pot sequence for the re- glycerol in the subsequent hydrolytic workup, the protocol
moval of O-carboxymethyl moieties from phenols is pre-
sented. When diethylphosphoryl azide is employed as the
azide transfer reagent in the Curtius rearrangement and
can be reliably applied to a very broad scope of substrates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
yield the carboxymethoxy substituent, which was sub-
sequently degraded in a Curtius rearrangement by em-
ploying diphenyl phosphoryl azide (DPPA) as the azide
transfer reagent.[15] This approach also gave access to labile
iodo-substituted phenols.
Introduction
(Aryloxy)acetates are a common motif in plant growth
modulators.[1–3] This particular class of compounds exhibits
an exceptional stability towards electrophilic conditions.
The strong electron-withdrawing effect of the carbonyl sys-
tem onto the methylene group makes it less susceptible to
heterolytic cleavage, as this would destabilize the resulting
cationic intermediate (Scheme 1). Consequently, most
transformations on the aryl moiety do not affect this par-
ticular side chain. Under electrophilic conditions, a meth-
oxy group on the arene moiety undergoes cleavage rather
than the acetate skeleton of 1.[4]
However, the yield for the individual cleavage sequence
did not exceed 60%. Therefore, multiple deprotection reac-
tions led to an unacceptable loss of material. Because the
saponification works almost quantitatively, the side reac-
tions occur in the subsequent steps. Initially, triaryl phos-
phates 2 were identified as byproducts by using spectromet-
ric and spectroscopic means.[14] However, the formation of
2 could not be avoided by employing smaller amounts of
DPPA. Furthermore, the purification of low molecular
weight phenols turned out to be tedious, as the DPPA rea-
gent liberates phenol upon workup. Therefore, we devel-
oped a significantly ameliorated cleavage sequence that
overcomes all these preparative hurdles. With the use of
DEPA (Figure 1) as the azide transfer reagent, only ethanol
was produced as a low-boiling byproduct. Addition of glyc-
erol during the workup converted intermediates like 2 into
the desired phenols and water-soluble cyclic phosphates.
Scheme 1. Electronic effects in (aryloxy)acetates.
The robust character of the phenoxy derivatives of this
class of compounds led to the development of some depro-
tection protocols involving harsh and prolonged reaction
conditions.[5] Other methods involve very high temperatures
(Ͼ270 °C),[6] gas-phase chemistry,[7] electrochemical[8] or
photochemical[9] procedures, or irradiation techniques.[10]
Because alkoxycarbonylmethoxy moieties turned out to be
beneficial for oxidative processes involving strong Lewis ac-
ids,[11,12] a mild and reliable method for its removal is de-
sired. This would allow exploitation of this particularly
stable and transformation-directing moiety[13] as a protect-
ing group for phenols. Initial studies led to a strategy for
the cleavage.[14] That protocol involved saponification to
Figure 1. Azide transfer reagents and byproduct 2.
Results and Discussion
The required substrates were prepared according to stan-
dard procedures starting from commercially available phe-
nols. Alkylation with ethyl bromoacetate and subsequent
saponification to 5 was performed in good-to-excellent
yields (Scheme 2). The Curtius degradation and workup
(Scheme 3) provided the alkyl-substituted phenols in excel-
[a] University of Bonn, Kekulé-Institute for Organic Chemistry
and Biochemistry,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax: +49-228-739608
E-mail: waldvogel@uni-bonn.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 337–342
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
337

A. Spurg, S. R. Waldvogel
FULL PAPER
lent yields (Table 1, Entries 2 and 3). Small derivatives like can be performed in the presence of additional functional
p-cresol are more volatile and more soluble in the aqueous groups in good yield. This makes it to an attractive and
media. Therefore, the yield is slightly lower (Table 1, En- practical transformation.
try 1). The same trend can be followed to phenol derivatives
involving arenes as substituents (Table 1, Entries 4 and 5).
Despite the large electron-donating effect of alkoxy substit-
uents in the 4-position, these substrates are still compatible
and provide good-to-excellent results (Table 1, Entries 6
and 7).
Table 1. Yields for deblocking sequence.[16–37]
Scheme 2. Preparation of starting materials.
Scheme 3. Reliable deblocking sequence.
The slightly lower yield for the benzyloxy-substituted
system might be attributed to the sensitivity of this group
towards the acidic workup conditions. When even more
electron-rich substrates were converted, for example, deriva-
tives of sesamol, only moderate results were obtained.
Methylsulfanyl-substituted phenols also represent suitable
targets for the deblocking sequence (Table 1, Entry 8).
Halogen atoms in the substitution pattern do not interfere
with the transformations (Table 1, Entries 9–11). The yields
correspond to the stability of the individual phenol deriva-
tive. Organic azides like DPPA or DEPA are capable of 1,3-
dipolar cycloaddition.[38] However, treatment of 5l under
the given conditions did not result in the formation of het-
erocycles nor in the isomerization to styrene derivatives
(Table 1, Entry 12). Substrates containing carbonyl or car-
bonyl-analogous moieties can also be used under this pro-
tocol (Table 1, Entries 13–15). No significant side reactions
of the oxidation-prone and base-labile carbaldehyde moiety
were found. The better solubilities in water of resulting phe-
nols 3m–o Ϫ with additional polar groups Ϫ result in a
lower but still practical yield. Application of this one-pot
protocol to heterocyclic substrates involving benzothiazoles
or coumarins provided the deprotected hydroxy compounds
in moderate yields, which is also attributed to solubility in
water (Table 1, Entries 16 and 17). Multiple deprotection
reactions can be performed by this one-pot procedure for
lipophilic product 3r by using DPPA or DEPA (Table 1,
Entries 18–20). Apparently, multiple deprotection reactions
338
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 337–342

High-Yielding Cleavage of (Aryloxy)acetates
organic layer was washed with water (50 mL) and brine (50 mL),
dried with magnesium sulfate, and concentrated under reduced
pressure. Purification was performed by column chromatography.
Table 1. (continued)
General Procedure for Ethyl Phenoxyacetates: Phenol derivative 3
(46 mmol) and potassium carbonate (69 mmol, 1.5 equiv.) were
suspended in N,N-dimethylformamide (120 mL). After the addition
of ethyl bromoacetate (5.65 mL, 8.52 g, 51 mmol, 1.1 equiv.) the
reaction mixture was stirred for 18 h at ambient temperature. For
workup, H2O (300 mL) was added, and the aqueous layer was ex-
tracted with ethyl acetate (2ϫ200 mL). The combined organic
layer was washed with H2O (3ϫ100 mL) and brine (2ϫ50 mL),
dried with magnesium sulfate, and concentrated under reduced
pressure. Purification of ethyl phenoxyacetates 4 was performed by
crystallization (cyclohexane/ethyl acetate) or distillation. Analytical
data are only given if the compounds are new, differ significantly
from literature, or are less detailed.
Ethyl (2-Isopropyl-5-methylphenoxy)acetate (4b): 2-Isopropyl-5-
methylphenol (thymol) (3b; 6.00 g, 40.0 mmol), potassium carbon-
ate (8.29 g, 60.0 mmol), ethyl bromoacetate (4.87 mL, 7.35 g,
44.0 mmol). Ethyl (2-isopropyl-5-methylphenoxy)acetate (4b) was
obtained after distillation (95 °C; 2.7 ϫ102 mbar)[17] as a colorless
1
oil in 8.35 g (88%) yield. H NMR (400 MHz, CDCl3, 20 °C): δ =
1.23 [d, 3J = 6.9 Hz, 6 H, CH(CH3)2], 1.31 (t, 3J = 7.1 Hz, 3 H,
CH2CH3), 2.31 (s, 3 H, Ar-CH3), 3.38 [sept, 3J = 6.9 Hz, 1 H,
CH(CH3)2], 4.27 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 4.63 (s, 2 H,
3
OCH2CO), 6.58 (s, 1 H, Ar-H), 6.79 (d, J = 7.7 Hz, 1 H, Ar-H),
[a] (i) DEPA, Et3N, DMF, toluene 1 h, 25 °C then 3 h reflux; (ii)
KOH, H2O, 8 min, 25 °C; (iii) citric acid, H2O; (iv) KOH, H2O,
EtOH, glycerol 2 h reflux; (v) citric acid, H2O. [b] (i) DPPA, Et3N,
DMF, toluene, 1 h, 25 °C, then 3 h reflux, (ii) KOH, H2O, 8 min,
25 °C; (iii) citric acid, H2O.
7.12 (d, 3J = 7.7 Hz, 1 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 20 °C): δ = 14.1, 21.3, 22.7, 26.6, 61.1, 65.7, 112.4, 122.2,
126.2, 134.6, 136.2, 155.0, 169.2 ppm. MS (EI, 70 eV): m/z (%) =
236 (74) [M]+, 221 (100) [M – CH3]+, 149 (70) [M – C4H7O2]+, 147
(84) [M – CH3 – C3H4O2 – H]+. HRMS (EI): calcd. for C14H20O3
[M]+ 236.1412; found 236.1409.
Conclusions
Ethyl (3,5-Di-tert-butylphenoxy)acetate (4c): 3,5-Di-tert-butylphe-
nol (3c, 8.60 g, 41.7 mmol), potassium carbonate (8.60 g,
62.6 mmol), ethyl bromoacetate (5.10 mL, 7.70 g, 45.9 mmol).
Ethyl (3,5-di-tert-butylphenoxy)acetate (4c) was obtained after dis-
tillation (117 °C, 2.3ϫ10–2 mbar) as a colorless oil in 11.5 g (94%)
yield. 1H NMR (400 MHz, [D6]DMSO, 20 °C): δ = 1.19–1.23 (t, 3J
A reliable and high yielding deblocking sequence for
(aryloxy)acetates was established. The whole transforma-
tion sequence was performed in one pot. The Curtius de-
gradation can be performed in a practical manner when
diethylphosphoryl azide (DEPA) as the azide transfer rea-
gent and glycerol in the acidic hydrolytic workup are used.
The sequence is a valuable tool for a broad scope of sub-
strates and allows even multiple deprotections. As a potent
and easily applicable method for their cleavage is now estab-
lished, alkoxycarbonylmethoxy moieties can be considered
as protecting groups for aromatic and heteroaromatic hy-
droxy functions. This class of protecting groups is particu-
larly useful under strong electrophilic conditions.
3
= 7.1 Hz, 3 H, CH2CH3), 1.25 [s, 18 H, C(CH3)3], 4.15–4.20 (q, J
= 7.1 Hz, 2 H, CH2CH3), 4.74 (s, 2 H, OCH2CO), 6.70 (d, 4J =
1.6 Hz, 2 H, Ar-H), 7.00 (m, 1 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO, 20 °C): δ = 14.0, 31.0, 34.5, 60.4, 64.7,
108.7, 114.8, 151.6, 157.1, 168.9 ppm. MS (EI, 70 eV): m/z (%) =
292 (56) [M]+, 277 (100) [M – CH3]+, 219 (4) [M – CO2C2H5]+, 147
(7) [M – CH2CO2C2H5 – C4H9]+, 57 (7) [C4H9]+. HRMS (EI):
calcd. for C18H28O3 [M]+ 292.2038; found 292.2038. C18H28O3
(292.41): calcd. C 73.93, H 9.65; found C 73.52, H 9.57. GC: tR
=
11.07 min.
Ethyl (4-Tritylphenoxy)acetate (4e): 4-Tritylphenol (3e; 5.47 g,
16.3 mmol), potassium carbonate (3.40 g, 24.5 mmol), ethyl bro-
moacetate (2.00 mL, 3.00 g, 17.9 mmol). Ethyl (4-tritylphenoxy)-
acetate (4e) was obtained as a light brown solid in 6.00 g (93%)
Experimental Section
General Procedure for the Cleavage Sequence: (Aryloxy)acetic acid
(1.20 mmol) was dissolved in anhydrous toluene (5 mL) and anhy-
drous N,N-dimethylformamide (0.50 mL). After the addition of
NEt3 (1.01 equiv.) and diethylphosphoryl azide (DEPA; 1.1 equiv.),
the mixture was stirred for 30 min at ambient temperature and then
brought to reflux for 3 h. A potassium hydroxide solution (50 wt.-
1
3
yield. H NMR (300 MHz, CDCl3, 20 °C): δ = 1.26–1.31 (t, J =
3
7.1 Hz, 3 H, CH2CH3), 4.23–4.30 (q, J = 7.1 Hz, 2 H, CH2CH3),
4.59 (s, 2 H, OCH2CO), 6.67–6.79 (d, 3J = 9.0 Hz, 2 H, Ar-H),
3
7.10–7.12 (d, J = 9.0 Hz, 2 H, Ar-H), 7.17–7.26 (m, 15 H, Ar-H)
ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 14.2, 61.3, 64.3, 65.4,
% in H2O, 2 mL), ethanol (5 mL), and glycerol (2.5 mL) were then 113.5, 125.9, 127.4, 131.1, 132.2, 140.9, 146.1, 155.8, 169.0 ppm.
added, and the reaction mixture was heated at reflux for 2 h. For
workup, the reaction mixture was brought to pH = 5 by the ad-
dition of a saturated citric acid solution. Subsequently, the aqueous
layer was extracted with ethyl acetate (3ϫ50 mL). The combined
MS (EI, 70 eV): m/z (%) = 422 (36) [M]+, 345 (100) [M – C6H5]+,
234 (8) [M – OCH2CO2C2H5 – C6H5 + H]+, 165 (12) [C(C6H5)2]+.
HRMS (EI): calcd. for C29H26O3 [M]+ 422.1882; found 422.1880.
GC: tR = 20.44 min.
Eur. J. Org. Chem. 2008, 337–342
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
339

A. Spurg, S. R. Waldvogel
OCH3]+, 137 (4) [M
–
FULL PAPER
Ethyl 2-(4-Methylsulfanylphenoxy)acetate (4h): 4-(Methylsulfanyl)-
phenol (3h, 5.19 g, 37.0 mmol), potassium carbonate (7.66 g,
55.5 mmol), ethyl bromoacetate (4.50 mL, 6.80 g, 40.7 mmol).
(6) [M
–
CH2CO2C2H5
–
CH3
–
CH2CO2C2H5 – 2 CH3 – OCH3]+. HRMS (EI): calcd. for
C14H18O6 [M]+ 282.1103; found 282.1105. C14H18O6 (282.3): calcd.
C 59.57, H 6.43; found C 59.59, H 6.38. GC: tR = 12.71 min.
Product 4h was obtained as
a colorless oil (b.p. 133 °C,
4.2ϫ10–2 mbar)[26] in 7.65 g (91%) yield. 1H NMR (400 MHz,
4-Ethoxycarbonylmethoxy-3-methoxybenzonitrile (4o): 4-Hydroxy-
3-methoxybenzonitrile (3o; 4.66 g 31.3 mmol), potassium carbon-
ate (6.48 g, 47.0 mmol), ethyl bromoacetate (3.80 mL, 5.74 g,
34.4 mmol). 4-Ethoxycarbonylmethoxy-3-methoxybenzonitrile (4o)
3
CDCl3, 20 °C): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.44 (s, 3
3
H, SCH3), 4.24–4.29 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.59 (s, 2 H,
3
3
OCH2CO), 6.84–6.87 (d, J = 8.9 Hz, 2 H, Ar-H), 7.24–7.26 (d, J
= 8.9 Hz, 2 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3, 20 °C):
δ = 14.1, 17.5, 61.3, 65.5, 115.3, 129.6, 130.1, 156.2, 168.7 ppm.
MS (EI, 70 eV): m/z (%) = 226 (100) [M]+, 211 (2) [M – CH3]+,
198 (4) [M – C2H6 + H]+, 153 (12) [M – CO2C2H5]+, 139 (92) [M –
CH2CO2C2H5]+, 125 (16) [M – CH2CO2C2H5 – CH3 + H]+, 108
(6) [M – OCH2CO2C2H5 – CH3]+, 77 [C6H5]+, 73 (5) [CO2C2H5]+.
HRMS (EI): calcd. for C11H14O3S [M]+ 226.0664; found 226.0667.
C11H14O3S (226.3): calcd. C 58.38, H 6.24; found C 58.30, H 6.19.
GC: tR = 10.10 min.
1
was obtained as a colorless solid in 6.24 g (85%) yield. H NMR
(300 MHz, CDCl3, 20 °C): δ = 1.27 (t, 3J = 7.1 Hz, 3 H, CH2CH3),
3.91 (s, 3 H, OCH3), 4.23–4.31 (q, 3J = 7.1 Hz, 2 H, CH2CH3),
4.74 (s, 2 H, OCH2CO), 6.80–6.83 (d, 3J = 8.4 Hz, 1 H, Ar-H),
4
3
7.12–7.13 (d, J = 1.8 Hz, 1 H, Ar-H), 7.23–7.26 (dd, J = 8.4 Hz,
4J = 1.8 Hz, 1 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3, 20 °C):
δ = 14.1, 56.2, 61.7, 65.9, 105.4, 113.4, 114.8, 118.9, 126.0, 149.6,
151.0, 167.9 ppm. MS (EI, 70 eV): m/z (%) = 235 (100) [M]+, 162
(40) [M – CO2C2H5]+, 147 (34) [M – CO2C2H5 – CH3]+, 134 (5)
[M – CH2CO2C2H5 – CH3 + H]+, 117 (11) [M – OCH2CO2C2H5 –
CH3]+, 102 (8) [C7H4N]+, [C6H5]+. HRMS (EI): calcd. for
C12H13NO4 [M]+ 235.0845; found 235.0848. GC: tR = 11.30 min.
Ethyl (4-Chloro-2-isopropyl-5-methylphenoxy)acetate (4i): 4-Chlo-
rothymol (3i; 3.50 g, 19.0 mmol), 3.93 g (28.5 mmol) potassium car-
bonate, 2.31 mL (3.48 g, 20.9 mmol) ethyl bromoacetate. Ethyl (4-
chloro-2-isopropyl-5-methylphenoxy)acetate (4i) was obtained as
colorless oil in 4.60 g (90%) yield. 1H NMR (400 MHz, [D6]-
5-Ethoxycarbonylmethoxy-2-methylbenzothiazole (4p): 5-Hydroxy-
2-methylbenzothiazole (3p; 3.00 g, 18.2 mmol), potassium carbon-
ate (3.77 g, 27.3 mmol), ethyl bromoacetate (2.20 mL, 3.34 g,
20.0 mmol). Product 4p was obtained after distillation
(2.1ϫ10–1 mbar, 127 °C) as a colorless oil in 2.88 g (63%) yield.
M.p. 43 °C. 1H NMR (400 MHz, [D6]DMSO, 20 °C): δ = 1.20–
1.23 (t, 3J = 7.1 Hz, 3 H, CH2CH3), 2.76 (s, 3 H, CCH3), 4.15–4.20
(q, 3J = 7.1 Hz, 2 H, CH2CH3), 4.86 (s, 2 H, OCH2CO), 7.04–7.07
(dd, 3J = 8.8 Hz, 4J = 2.5 Hz, 1 H, Ar-H), 7.42–7.43 (d, 4J = 2.5 Hz,
1 H, Ar-H), 7.88–7.91 (d, 3J = 8.8 Hz, 1 H, Ar-H) ppm. 13C NMR
(100 MHz, [D6]DMSO, 20 °C): δ = 13.9, 19.7, 60.6, 65.0, 106.0,
114.3, 122.3, 127.5, 154.0, 156.6, 168.3, 168.6 ppm. MS (EI, 70 eV):
m/z (%) = 251 (100) [M]+, 178 (40) [M – CO2C2H5]+, 164 (26) [M –
3
DMSO, 20 °C): δ = 1.15 [d, J = 6.9 Hz, 6 H, CH(CH3)2], 1.20 (t,
3J = 7.1 Hz, 3 H, CH2CH3), 2.25 (s, 3 H, Ar-CH3), 3.25 [sept, J
3
= 6.9 Hz, 1 H, CH(CH3)2], 4.16 (q, 3J = 7.1 Hz, 2 H, CH2CH3),
4.79 (s, 2 H, OCH2CO), 6.88 (s, 1 H, Ar-H), 7.15 (s, 1 H, Ar-H)
ppm. 13C NMR (100 MHz, [D6]DMSO, 20 °C): δ = 13.9, 19.3,
22.1, 26.2, 60.5, 65.0, 114.4, 125.0, 126.0, 133.2, 136,0, 153.4,
162.1 ppm. MS (EI, 70 eV): m/z (%) = 270 (76) [M]+, 255 (46) [M –
CH3]+, 183 (100) [M – C4H7O2]+, 181 (80) [M – CH3 – C3H4O2 –
H]+, 169 (36) [M – CH3 – C4H6O2]+. HRMS (EI): calcd. for
C14H19ClO3 [M]+ 270.1023; found 270.1023. GC: tR = 10.9 min.
Ethyl (3-Iodophenoxy)acetate (4k): 3-Iodophenol (3k; 3.00 g,
13.6 mmol), potassium carbonate (2.80 g, 20.4 mmol), ethyl bro-
moacetate (1.70 mL, 2.51 g, 15.0 mmol). Ethyl (3-iodophenoxy)-
acetate (4k) was obtained as a colorless solid in 3.37 g (90%) yield.
M.p. 42–43 °C. 1H NMR (300 MHz, CDCl3, 20 °C): δ = 1.28–1.33
(t, 3J = 7.1 Hz, 3 H, CH2CH3), 4.24–4.31 (q, 3J = 7.1 Hz, 2 H,
CH2CO2C2H5]+, 148 (32) [M
–
OCH2CO2C2H5]+, 136 (5)
[C7H4OS]+, 107 [C6H3S]+. HRMS (EI): calcd. for C12H13NO3S
[M]+ 251.0616; found 251.0620. C12H13NO3S (251.3): calcd. C
57.35, H 5.21, N 5.57; found C 57.32, H 5.01, N 5.53. GC: tR
=
12.23 min.
3
4
CH2CH3), 4.59 (s, 2 H, OCH2CO), 6.86–6.89 (dd, J = 8.3 Hz, J
Ethyl (2Ј-Ethoxycarbonylmethoxy-3,5,3Ј,5Ј-tetramethylbiphenyl-2-
yloxy)acetate (4r): 3,3Ј,5,5Ј-Tetramethylbiphenyl-2,2Ј-diol (3r;
3.61 g, 14.9 mmol), potassium carbonate (6.20 g, 44.7 mmol), ethyl
bromoacetate (3.60 mL, 5.47 g, 32.8 mmol). Ethyl (2Ј-ethoxycar-
bonylmethoxy-3,5,3Ј,5Ј-tetramethylbiphenyl-2-yloxy)acetate (4r)
was obtained as a colorless solid in 4.78 g (77%) yield. M.p. 38–
39 °C. 1H NMR (400 MHz, CDCl3, 20 °C): δ = 1.20 (t, J = 7.1 Hz,
6 H, CH2CH3), 2.27 (s, 6 H, Ar-CH3), 2.33 (s, 6 H, Ar-CH3), 4.11
(q, J = 7.1 Hz, 4 H, CH2CH3), 4.15 (s, 4 H, OCH2CO), 6.96–6.97
(s, 2 H, Ar-H), 6.97 (s, 2 H, Ar-H) ppm. 13C NMR (100 MHz,
CDCl3, 20 °C): δ = 14.0, 16.5, 20.6, 60.8, 69.5, 129.6, 130.8, 130.9,
131.3, 133.3, 152.4, 169.1 ppm. MS (EI, 70 eV): m/z (%) = 414 (100)
[M]+, 341 (6) [M – C3H5O2]+, 267 (8) [M – C6H11O4]+, 253 (36)
[M – C7H13O4]+. HRMS (EI): calcd. for C24H30O6 [M]+ 414.2042;
found 414.2044. C24H30O6 (414.20): calcd. C 69.54, H 7.30; found
C 69.27, H 7.39. GC: tR = 15.5 min.
= 2.5 Hz, 1 H, Ar-H), 6.98–7.03 (m, 3J = 8.3 Hz, 1 H, Ar-H), 7.26–
4
3
7.27 (d, J = 2.5 Hz, 1 H, Ar-H), 7.32–7.35 (d, J = 7.7 Hz, 1 H,
Ar-H) ppm. 13C NMR (75 MHz, CDCl3, 20 °C): δ = 14.1, 61.5,
65.4, 94.2, 114.2, 124.0, 130.8, 130.9, 158.3, 168.4 ppm. MS (EI,
70 eV): m/z (%) = 306 (100) [M]+, 233 (40) [M – CO2C2H5]+, 220
(4) [M – CH2CO2C2H5 + H]+, 203 (26) [M – OCH2CO2C2H5]+,
106 (10) [M – CO2C2H5 – I]+, 92 (5) [M – CH2CO2C2H5 – I]+, 76
(13) [M – OCH2CO2C2H5 – I]+. HRMS (EI): calcd. for C10H11O3I
[M]+ 305.9753; found 305.9756. C10H11IO3 (306.1): calcd. C 39.24,
H 3.62; found C 39.10, H 3.32. GC: tR = 10.24 min.
3,3Ј-Dimethoxy-4-ethoxycarbonylmethoxyacetophenone (4n): 3,5-
Dimethoxy-4-hydroxyacetophenone (3n; 4.81 g, 24.5 mmol), potas-
sium carbonate (5.10 g, 13.8 mmol), ethyl bromoacetate (3.00 mL,
4.51 g, 27.0 mmol). 3,3Ј-Dimethoxy-4-ethoxycarbonylmethoxyace-
tophenone (4n) was obtained as a light yellow solid in 6.22 g (90%)
yield. 1H NMR (400 MHz, [D6]DMSO, 20 °C): δ = 1.18–1.21 (t, 3J
4,4Ј-Bis(ethoxycarbonylmethoxy)benzophenone (4t): 2,6-Dihydroxy-
= 7.1 Hz, 3 H, CH2CH3), 2.56 (s, 3 H, COCH3), 3.82 (s, 6 H, benzophenone (3t; 6.24 g, 29.1 mmol), potassium carbonate
OCH3), 4.11–4.16 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 4.63 (s, 2 H,
(12.10 g, 87.3 mmol), ethyl bromoacetate (7.10 mL, 10.70 g,
OCH2CO), 7.23 (s, 2 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]-
64.0 mmol). 4,4Ј-Bis(Ethoxycarbonylmethoxy)benzophenone (4t)
1
DMSO, 20 °C): δ = 14.1, 26.7, 56.2, 60.5, 68.8, 106.0, 132.1, 140.0, was obtained as a colorless solid in 11.24 g (99%) yield. H NMR
3
151.9, 168.7, 197.0 ppm. MS (EI, 70 eV): m/z (%) = 282 (100)
(400 MHz, [D6]DMSO, 20 °C): δ = 1.20–1.24 (t, J = 7.1 Hz, 6 H,
[M]+, 267 (26) [M – CH3]+, 209 (16) [M – CO2C2H5]+, 195 [M –
CH2CH3), 4.16–4.21 (q, J = 7.1 Hz, 4 H, CH2CH3), 4.90 (s, 4 H,
3
3
3
CH2CO2C2H5]+,167 (7) [M – CH2CO2C2H5 – 2 CH3 + 2 H]+, 149 OCH2CO), 7.06–7.09 (d, J = 8.9 Hz, 4 H, Ar-H), 7.69–7.71 (d, J
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High-Yielding Cleavage of (Aryloxy)acetates
= 8.9 Hz, 4 H, Ar-H) ppm. 13C NMR (100 MHz, [D6]DMSO, ethoxycarbonylmethoxy-3,5,3Ј,5Ј-tetramethylbiphenyl-2-yloxy)-
20 °C): δ = 14.0, 60,7, 64.6, 114.3, 130.5, 131.7, 160.8, 168.3,
193.0 ppm. MS (EI, 70 eV): m/z (%) = 386 (100) [M]+, 313 (13)
[M – CO2C2H5]+, 271 (4) [M – CH2CO2C2H5 – C2H5 + H]+, 207
ethyl acetate (4r; 4.78 g 11.5 mmol). (2Ј-Carboxymethoxy-3,5,3Ј,5Ј-
tetramethylbiphenyl-2-yloxy)acetic acid (5r) was obtained as a col-
orless solid in 3.29 g (80%) yield. 1H NMR (400 MHz, [D6]DMSO,
(54) [M – C6H4OCH2CO2C2H5]+, 196 (12) [M – OCH2CO2C2H5 – 20 °C): δ = 2.23 (s, 6 H, Ar-CH3), 2.25 (s, 6 H, Ar-CH3), 4.04 (s, 4
CH2CO2C2H5]+, 179 (6) [C6H4OCH2CO2C2H5]+, 121 (4) [CO-
H, OCH2CO), 6.89 (s, 2 H, Ar-H), 7.00 (s, 2 H, Ar-H), 12.62 (s, 2
C6H4OH]+. HRMS (EI): calcd. for C21H22O7 [M]+ 386.1366; found
H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO, 20 °C): δ = 16.7,
386.1368. C21H22O7 (386.4): calcd. C 65.28, H 5.74; found C 65.19, 20.7, 69.2, 129.8, 130.9, 131.1, 131.5, 132.8, 152.3, 170.4 ppm. MS
H 5.83. GC: tR = 19.15 min.
(EI, 70 eV): m/z (%) = 358 (100) [M]+, 300 (24) [M – CH2CO2H +
H]+, 253 [M – CH2CO2H – CO2H – H]+, 237 (34) [M – 2 CO2H –
2 CH3 – H]+, 223 (24) [M – CH2CO2H – CO2H – 2 CH3 – H]+,
209 (10) [M – CH2CO2H – CO2H – 3 CH3]+. HRMS (EI): calcd.
for C20H22O6 [M]+ 358.1416; found 358.1418.
General Procedure for Aryloxy Acids
Method A: Ethyl (aryloxy)acetate 4 (35 mmol) was dissolved in
tetrahydrofuran (40 mL) and sodium hydroxide solution (20 wt.-%
in H2O, 20 mL). The mixture was brought to reflux for 3 h. For
workup, the reaction mixture was adjusted to pH = 1 by the ad-
dition of hydrochloric acid. Subsequently, the aqueous layer was
extracted with ethyl acetate (3ϫ100 mL). The combined organic
layer was washed with brine (2ϫ75 mL), dried with magnesium
sulfate, and concentrated under reduced pressure. Purification was
performed by crystallization (ethanol/H2O, 9:1).
4,4Ј-Bis(carboxymethoxy)benzophenone (5t): Prepared according to
general procedure A by using: 4,4Ј-bis(ethoxycarbonylmethoxy)-
benzophenone (4t; 10.64 g, 26.6 mmol). 4,4Ј-Bis(carboxymethoxy)-
benzophenone (5t) was obtained as a light yellow solid in 7.13 g
1
(76%) yield. H NMR (400 MHz, [D6]DMSO, 20 °C): δ = 4.80 (s,
3
2 H, OCH2CO), 7.05–7.07 (d, J = 8.8 Hz, 2 H, Ar-H), 7.69–7.71
3
(d, J = 8.8 Hz, 2 H, Ar-H), 13.10 (s, 1 H, OH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 20 °C): δ = 64.5, 114.3, 130.4, 131.7, 161.0,
169.8, 193.1 ppm. MS (EI, 70 eV): m/z (%) = 330 (82) [M]+, 285
(4) [M – CO2H]+, 271 (8) [M – CH2CO2H]+, 243 (4) [M – 2 CO2H
+ 3H]+, 179 (100) [M – 2 OCH2CO2H – H]+, 121 (12) [CO-
C6H4OH]+, 92 (4) [C6H4O]+. HRMS (EI): calcd. for C17H14O7
[M]+ 330.0740; found 330.0745. C17H14O7 (330.3): calcd. C 61.82,
H 4.27; found C 61.68, H 4.48.
Method B: Ethyl (aryloxy)acetate 4 (18 mmol) and lithium hydrox-
ide monohydrate (36 mmol, 2 equiv.) were dissolved in tetra-
hydrofuran (30 mL). The mixture was stirred at ambient tempera-
ture for 1 d. For workup, the reaction mixture was adjusted to pH
= 1 by the addition of hydrochloric acid. Subsequently, the aqueous
layer was extracted with ethyl acetate (3ϫ100 mL). The combined
organic layer was washed with brine (2ϫ75 mL), dried with mag-
nesium sulfate, and concentrated under reduced pressure. Purifica-
tion was performed by crystallization (ethanol/H2O, 9:1).
Supporting Information (see footnote on the first page of this arti-
1
cle): General remarks and H and 13C NMR spectra.
3,3Ј-Dimethoxy-4-carboxymethoxyacetophenone (5n): Prepared ac-
cording to general procedure B by using: 3,3Ј-dimethoxy-4-ethoxy-
carbonylmethoxyacetophenone (4n; 3.25 g, 11.5 mmol), lithium hy-
droxide monohydrate (0.97 g, 23.0 mmol). 3,3Ј-Dimethoxy-4-car-
boxymethoxyacetophenone (5n) was obtained as a light brown so-
lid in 2.79 g (96%) yield. 1H NMR (400 MHz, [D6]DMSO, 20 °C):
δ = 2.57 (s, 3 H, CH3CO), 3.84 (s, 6 H, OCH3), 4.56 (s, 2 H,
OCH2CO), 7.24 (s, 2 H, Ar-H), 12.94 (s, 1 H, OH) ppm. 13C NMR
(100 MHz, [D6]DMSO, 20 °C): δ = 26.5, 56.1, 68.4, 105.9, 131.9,
140.0, 151.8, 169.9, 196.7 ppm. MS (EI, 70 eV): m/z (%) = 254 (100)
[M]+, 239 (26) [M – CH3]+, 195 (72) [M – CH2CO2H]+, 181 (15)
[M – CH3 – CH2CO2H + H]+, 152 (4) [M – 3 CH3 – CH2CO2H
+ 2 H]+. HRMS (EI): calcd. for C12H14O6 [M]+ 254.0790; found
254.0794. C12H14O6 (254.2): calcd. C 56.69, H 5.55; found C 56.63,
H 5.39.
Acknowledgments
The studies were supported by the University of Bonn. A. S. is
grateful for a fellowship by the Theodor-Laymann-Foundation
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Received: August 18, 2007
Published Online: November 7, 2007
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Eur. J. Org. Chem. 2008, 337–342