Simple and efficient synthesis of racemic substituted mandelic acid esters from nonactivated arenes and ethyl glyoxylate

Article abstract of DOI:10.1055/s-0028-1083154

Direct synthesis of racemic aromatic α-hydroxyacetic acid esters via Friedel-Crafts reaction of nonactivated, simple arenes with ethyl glyoxylate promoted by SnCl₄ or AlCl₃ is described. The use of SnCl₄ opens a fast access to various alkyl- and aryl-substituted mandelic acids esters at room temperature within two hours in good yield (>80%) and with high regioselectivity. The procedure was successfully employed also for the alkylation of compounds with condensed aromatic rings. Alternative hydroxyalkylations with AlCl₃ require longer reaction time and higher temperature to get a good yield.

Full text of DOI:10.1055/s-0028-1083154

PAPER
3237
Simple and Efficient Synthesis of Racemic Substituted Mandelic Acid Esters
from Nonactivated Arenes and Ethyl Glyoxylate
Synthesis
a
of Racemic
c
Substituted
e
Mandelic
k
A
cid Esters Kwiatkowski,a Jakub Majer,a Piotr Kwiatkowski,a Janusz Jurczak*a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
Department of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
Fax +48(22)6326681; E-mail: jurczak@icho.edu.pl
b
Received 24 March 2008; revised 19 June 2008
OH
Abstract: Direct synthesis of racemic aromatic a-hydroxyacetic
acid esters via Friedel–Crafts reaction of nonactivated, simple ar-
enes with ethyl glyoxylate promoted by SnCl4 or AlCl3 is described.
The use of SnCl4 opens a fast access to various alkyl- and aryl-sub-
stituted mandelic acids esters at room temperature within two hours
in good yield (>80%) and with high regioselectivity. The procedure
was successfully employed also for the alkylation of compounds
with condensed aromatic rings. Alternative hydroxyalkylations
with AlCl3 require longer reaction time and higher temperature to
get a good yield.
Lewis acid
CH2Cl2
CO2Et
CO2Et
R
+
R
O
R = alkyl, aryl
2
3a–n
1a–n
Scheme 1 Reaction of nonactivated arenes 1 with ethyl glyoxylate
(2)
(Scheme 1). This approach is especially attractive since
arenes are usually much more easily accessible than the
corresponding aromatic aldehydes. A similar methodolo-
gy was previously described for the two-step synthesis of
mandelates, employing the SnCl4-promoted reaction of
ethyl oxomalonate with arenes followed by decarboxyla-
tion;11d however, the yields were usually moderate. The
route to various mandelic acid derivatives, as presented
here, seems to be more economic, since this easy and ef-
ficient one-step synthesis is based on the use of less ex-
pensive and readily available ethyl glyoxylate.
Key words: arenes, Friedel–Crafts hydroxyalkylation, ethyl glyox-
ylate, a-hydroxy esters, Lewis acids, mandelic acids
Mandelic acid and its derivatives are an important class of
molecules used in medicine, for example, as antibacterial
and antiaging agents,1 and as intermediates for the synthe-
sis of target molecules (e.g., various pharmaceuticals).2
They are usually synthesized in the racemic form via the
reaction of aromatic aldehydes with hydrocyanic acid fol-
lowed by acidic hydrolysis.3 Optically pure aromatic a-
hydroxy acids are usually prepared by enzymatic resolu-
tions of racemates or in an enantioselective approach from
aldehydes using chiral catalyst.4 Another very attractive
method of their synthesis is based on the Friedel–Crafts
reaction5 of aromatic or heteroaromatic compounds with
1,2-dicarbonyl compounds, especially glyoxylates, pyru-
vates, and trifluoropyruvates. This approach is well
known both in racemic and asymmetric version;6 how-
ever, in most cases, it is limited to highly activated aromat-
ics, for example, phenols,7,8 anilines, and heteroaromatics
– pyrroles, indoles, and furans.9 In fact, the examples
showing the use of simple aromatic compounds without
highly activating groups are rare and outdated.10 Some
other examples of the Lewis acid promoted reactions of
alkyl substituted benzenes were reported for oxoma-
lonates.11 According to previous research, the use of the
Brønsted (mineral) acids in this reaction usually leads to
disubstituted products, diarylacetates.12
Our initial studies of the reaction of toluene (1a) with eth-
yl glyoxylate (2), in the presence of various common
Lewis acids (Scheme 2, Table 1) were conducted to select
the best promoter for the reaction.
Next we used two of the best performing Lewis acids in
the Friedel–Crafts hydroxyalkylation, focusing our atten-
tion on the simple mono- and disubstituted alkylated de-
rivatives of benzene, and subsequently extending our
study to tri- and tetrasubstituted arenes (Scheme 1,
Table 2). The positive results obtained in the reactions of
simple alkylbenzenes encouraged us to further extend our
study to the compounds having condensed aromatic rings
(Table 3).
Table 1 shows the results obtained for the model reaction
of toluene with ethyl glyoxylate, carried out in the pres-
ence of various Lewis acids as promoters (Scheme 2). The
experiments were carried out at room temperature for 2–3
hours, using anhydrous dichloromethane as a solvent. In
the case of AlCl3, we repeated the experiment at higher
temperature (reflux of CH2Cl2) and extend the reaction
time to 20 hours, since this classic promoter is relatively
less active than the rest of the tested Lewis acids (a very
low yield was obtained for the reaction at r.t. for 3 h; entry
4).
Here, we focus our attention on the neglected Friedel–
Crafts reactions of simple alkyl- and aryl-substituted ben-
zenes as well as polyaromatic systems with glyoxylates,
leading directly to various mandelate analogues
SYNTHESIS 2008, No. 20, pp 3237–3244
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083154; Art ID: P04308SS
© Georg Thieme Verlag Stuttgart · New York

3238
J. Kwiatkowski et al.
PAPER
OH
OEt
O
Lewis
acid
3a-para
OEt
O
CO2Et
+
+
(1 equiv)
OH
O
OEt
2
1a
O
3a-ortho
4a
Scheme 2 The model reaction of 1a and 2 studied to select a suitable Lewis acid
The highest yield and regioselectivity were observed in
the reaction promoted by SnCl4 (entry 1). AlCl3 was effec-
tive only at elevated temperature (entry 5); the yield
reached 88%, while the regioselectivity did not change
significantly, compared to the reaction carried out at room
temperature. Unfortunately, neither of the two promoters
was effective in the catalytic approach (10 mol% of Lewis
acid). Both TiCl4 and ZrCl4 performed well, but the ob-
tained regioselectivities and yields (especially for ZrCl4)
were worse than for SnCl4. We also investigated the pos-
sibility of using other Lewis and Brønsted acids:
BF3·OEt2, Yb(OTf)3 (20 mol%), MeSO3H, and CF3SO3H.
The reaction promoted by BF3·OEt2 proceeded very slow-
ly and led to a mixture of products. The use of MeSO3H
did not lead to the expected product (Scheme 2, 3a), while
in the case of CF3SO3H, the product 4a with two aryl
groups was obtained. Similarly, Yb(OTf)3, which had
been used successfully in the reactions of ethyl glyoxylate
with more active arenes,13 gave only traces of the desired
product 3a.
Table 1 Comparison of Common Lewis Acids in the Reaction of
Toluene (1a) with Ethyl Glyoxylate (2)a
Entry
Lewis acid (1 equiv)
Yield (%)b Regioselectivityc (%
of para-product)
1
SnCl4
TiCl4
89
96:4
85:15
87:13
87:13
90:10
–
2
77
3
ZrCl4
56
4
AlCl3
35
5d
6
AlCl3
88
Yb(OTf)3
trace
a Reaction conditions: ethyl glyoxylate (3 mmol), CH2Cl2 (4 mL), tol-
uene (2 mmol), and Lewis acid [1 equiv; 20 mol% for Yb(OTf)3] at
r.t.
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d The experiment was conducted in refluxing CH2Cl2 for 20 h.
Table 2 The Friedel–Crafts Alkylation of Substituted Benzenes 1 Promoted by Lewis Acida
ArH
Lewis acid
Product
Yield (%)b
Regioselectivityc
(% of para-product)
OH
89
96:4
CO2Et
SnCl4
AlCl3
84d
92:8d
1a
3a
88
90:10
OH
CO2Et
80
98:2
SnCl4
76d
98:2d
1b
1c
3b
3c
OH
CO2Et
SnCl4
AlCl3
84
73
100:0
100:0
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Substituted Mandelic Acid Esters
3239
Table 2 The Friedel–Crafts Alkylation of Substituted Benzenes 1 Promoted by Lewis Acida (continued)
ArH
Lewis acid
SnCl4
Product
Yield (%)b
Regioselectivityc
(% of para-product)
OH
CO2Et
80
56
100:0
100:0
1d
1e
3d
3e
3f
AlCl3
SnCl4
AlCl3
SnCl4
OH
86
e
CO2Et
–
73d
86
OH
92
98:2
CO2Et
89d
96:4d
1f
AlCl3
SnCl4
AlCl3
SnCl4
AlCl3
90
98:2
OH
OH
OH
89
96:4
CO2Et
CO2Et
CO2Et
88d
94:6d
1g
3g
3h
76
96:4
90
e
–
74d
1h
75
90
e
SnCl4
–
1i
1j
3i
3j
AlCl3
SnCl4
70
90
72
OH
CO2Et
99:1
95:5
f
AlCl3
a Reaction conditions: ethyl glyoxylate (3 mmol) in CH2Cl2 (4 mL), aromatic compound (2 mmol), and SnCl4 (1 equiv) at r.t. for 2–3 h or AlCl3
(1 equiv) at reflux for 20 h.
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d Reaction carried out under solvent-free conditions: ethyl glyoxylate (4 mmol) in aromatic compound (4 mL) and of SnCl4 (1 equiv) at r.t. for
0.5 h.
e Only one product of monosubstitution is possible.
f The experiment was conducted at r.t.
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

3240
J. Kwiatkowski et al.
PAPER
Table 3 The Friedel–Crafts Alkylation of Compounds with Condensed Aromatic Ringsa
ArH
Lewis acid
SnCl4
Product
Yield (%)b
OH
91
CO2Et
(a:b = 3:1)c
1k
3k
76
d
AlCl3
(a:b = 1:1)c
OH
OH
SnCl4
62 (one product)
CO2Et
1l
3l
CO2Et
54
SnCl4
AlCl3
78 (one product)f
1m
3m
75 (one product)f
90 (one product)e
OH
CO2Et
SnCl4
1n
3n
a Reaction conditions: ethyl glyoxylate (3 mmol), CH2Cl2 (4 mL), aromatic compound (2 mmol), and SnCl4 (1 equiv) at r.t. for 2–3 h or AlCl3
(1 equiv) at reflux for 20 h.
b Isolated yield.
c Determined by 1H NMR spectroscopy.
d The experiment was conducted in refluxing CH2Cl2 for 20 h.
e The substitution position was not confirmed, but a monosubstituted product was obtained.
f The reaction was carried out in Et2O (r.t.) over 5 h (SnCl4) or 20 h (AlCl3).
The Alkylation of Simple Arenes Promoted by SnCl4
or AlCl3
with good to very good yields of 86–92%. Additionally,
we investigated the possibility of carrying out the SnCl4-
promoted reactions under the solvent-free conditions us-
For the Friedel–Crafts alkylation reactions of monosubsti- ing liquid aromatic compounds in an amount larger than
tuted benzenes, the product of para-substitution dominat- stoichiometric. In most cases, the drop in yields and regio-
ed over the product of ortho-substitution. The SnCl4- selectivities is less than 6% compared to the reactions
promoted reactions were carried out at room temperature performed in the presence of CH2Cl2 (except for p-xylene
for two hours, while cheaper and less toxic AlCl3 require and mesitylene, where the yield decreased by 15–17%).
higher temperature and longer reaction time. The results
With respect to the AlCl3-promoted reactions of mono-
of the reactions of various alkylbenzenes with ethyl gly-
substituted benzenes, the yields obtained are more depen-
oxylate promoted either by SnCl4 or by AlCl3 are shown
dent on the nature of the substituent (e.g., 88% of 3a for
PhCH3, 73% of 3c for t-BuPh, and 56% of 3d for biphe-
nyl, respectively). The correlation of regioselectivity is re-
versed: only one product is obtained for t-BuPh and
in the Table 2. Reactions of monosubstituted arenes
(products: 3a–d), promoted by SnCl4 perform very well in
the terms of yield (80–89%) and regioselectivity (>95% of
para-product) obtained. A similarly high efficacy was ob-
biphenyl, while the ratio of the para-substitution product
served in the reactions of disubstituted arenes 1e–g as well
to the ortho-substitution product is 9:1 for toluene. For the
as mesitylene (1h), durene (1i), and fluorene (1j). The re-
alkylation of disubstituted benzenes, that is, xylenes 1f
and 1g and fluorine (1j), the regioselectivities were found
gioselectivities obtained were excellent: 96–99%, along
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Substituted Mandelic Acid Esters
3241
ried out on commercial plates coated with 0.25 mm of Merck Kie-
selgel 60. Preparative flash silica chromatography was performed
using Merck Kieselgel 60 (230–400 mesh).
to be equally high as in case of the monosubstituted arenes
(95–98%). The reaction yields for disubstituted benzenes
1e–g, j as well as for mesitylene (1h) and durene (1i) were
also very good (70–90%).
Ethyl glyoxylate (commercially available in 1:1 toluene solution)
was separated from toluene through distillation in vacuo (36–40 °C/
10 mmHg). Then the distillation was repeated in order to obtain
pure substance with no traces of toluene.
The Alkylation of Compounds with Condensed Aro-
matic Rings Promoted by SnCl4 or AlCl3
The substitution position in fluorene was determined employing ad-
vanced NMR techniques: COSY and NOE experiments. In the 1H
NOE experiment, the activation of the C-1 carbon protons (3.87
ppm) resulted in obtaining a signal (singlet) from the C-10 hydro-
gen atom (7.59 ppm).
The reactions of polycyclic aromatic hydrocarbons with
ethyl glyoxylate (Table 3) were carried out employing the
same method as the reactions of simple arenes.
SnCl4-Promoted Friedel–Crafts Alkylation of Arenes 1 with
Ethyl Glyoxylate (2) in CH2Cl2 or Et2O; General Procedure
To a stirred solution of ethyl glyoxylate (2; 0.306 g, 3.0 mmol) in
CH2Cl2 (4 mL) or Et2O (4 mL, used in the alkylation of anthracene)
was added the appropriate aromatic compound 1a–n (2.0 mmol).
Then, SnCl4 (0.625 g, 2.4 mmol) was slowly added (portionwise) at
r.t. and the stirring was continued for 2 h. After that time, aq 2 M
HCl (5 mL) was added to the vigorously stirred reaction mixture.
After ca. 10 min, the organic layer was separated and the aqueous
layer was extracted with Et2O (2 × 10 mL). The organic layers were
then combined and quenched with aq sat. NaHCO3 (15 mL). After
separating the organic layer, the aqueous layer was extracted with
Et2O (15 mL). The separated organic layers were combined, dried
(MgSO4), concentrated in vacuo, and subjected to flash chromatog-
raphy using hexane–EtOAc (9:1) as an eluent.
The yields obtained in the reactions promoted by SnCl4
were very good for naphthalene (91%, 3k) and chrysene
(90%, 3n), while the yield was lower for a-methylnaph-
thalene (62%, 3l). With respect to anthracene, the relative-
ly low yield (54%, 3m) was attributable to partial
decomposition of the product. In view of that, we found
that the reaction carried out in another solvent, Et2O, pro-
ceeded slower (completion time: 5 h), but the amount of
decomposition products dramatically decreased, resulting
in an increase of the reaction yield to 78%. Only one re-
gioisomer was obtained in all SnCl4-promoted reactions,
except for naphthalene (75% of the a-substitution prod-
uct, 3k). Using the other Lewis acid, AlCl3, we obtained a
1:1 mixture of kinetic and thermodynamic products for
naphthalene, and a mixture of few products for anthracene
(probably due to subsequent decomposition of the prod-
uct). Once again, however, the use of Et2O as a solvent
gave exclusively the desired product in 75% yield (the re-
action was carried out at r.t. for 20 h).
Solvent-Free SnCl4-Promoted Friedel–Crafts Alkylation of
Arenes 1 with Ethyl Glyoxylate (2); General Procedure
Ethyl glyoxylate (2; 0.408 g, 4.0 mmol) was added to the stirred ap-
propriate aromatic compound 1a–n (4 mL). Then SnCl4 (1.146 g,
4.4 mmol) was slowly added (portionwise) at r.t. and the stirring
was continued for 0.5 h. Et2O (5 mL) was added to the stirred sus-
pension, followed by aq 2 M HCl (10 mL). After ca. 10 min, the or-
ganic layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 × 15 mL). The organic layers were then combined and
quenched with aq sat. NaHCO3 (15 mL). After separation of the or-
ganic layer, the aqueous layer was extracted with CH2Cl2 (15 mL).
The separated organic layers were combined, dried (MgSO4), con-
centrated in vacuo, and subjected to flash chromatography using
hexane–EtOAc (9:1) as an eluent.
In summary, we have found an easy and general proce-
dure for the efficient synthesis of mandelic acid deriva-
tives, employing the SnCl4- or AlCl3-promoted Friedel–
Crafts alkylation of simple arenes without highly activat-
ing substituents. Products of SnCl4-promoted alkylation
of arenes were obtained in very good yields exceeding
80% as well as with excellent regioselectivities exceeding
95% (the reaction clearly proceeded at ambient tempera-
ture over a short period of time). Furthermore, the SnCl4-
promoted reaction of liquid alkylbenzenes could be car-
ried out without the need of using additional solvent. The
promoter was effective also in the reactions of polycyclic
aromatic hydrocarbons. This significantly broadens the
scope of the potential products. Despite the need to in-
crease the reaction time and temperature, the classic
Friedel–Crafts reaction using AlCl3 performs very well
also in the alkylation of simple arenes, affording the prod-
ucts in good yields (≥70%) and high regioselectivities
(≥90%).
AlCl3-Promoted Friedel–Crafts Alkylation of Arenes 1 with
Ethyl Glyoxylate (2) in CH2Cl2 or Et2O; General Procedure
To a stirred solution of ethyl glyoxylate (2; 0.460 g, 4.5 mmol) in
CH2Cl2 (3 mL) or Et2O (3 mL, used in the alkylation of anthracene)
was added AlCl3 (0.600 g, 4.5 mmol) at r.t. and the stirring was con-
tinued for ca. 10 min. After the AlCl3 had dissolved, the appropriate
aromatic compound 1a–n (3.0 mmol) was added and the stirring
was continued for 20 h under reflux (50 °C, oil bath). Aq 2 M HCl
(5 mL) was slowly added to the stirred suspension cooled to r.t. Af-
ter ca. 10 min, the organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). The organic layers were
combined and quenched with aq sat NaHCO3 (15 mL) After sepa-
rating the organic layer, the aqueous layer was extracted with
CH2Cl2 (15 mL). The separated organic layers were combined,
dried (MgSO4), concentrated in vacuo, and subjected to flash chro-
matography using hexane–EtOAc (9:1) as an eluent.
The NMR spectra were recorded in CDCl3 using a Varian Gemini
400 MHz or 200 MHz spectrometer while the NOE and COSY ex-
periments were performed on a Bruker 500 MHz spectrometer.
Chemical shifts of 1H NMR and 13C NMR are reported as d values
relative to TMS (0.00) and CDCl3 (77.0), respectively. The high-
resolution mass spectra (HRMS) were recorded on a Mariner PE
Biosystems unit using the ESI technique. The IR spectra were taken
on an FT-IR PerkinElmer Spectrum 2000. Analytical TLC was car-
Ethyl Hydroxy(4-methylphenyl)acetate (3a)14
Yield: 345 mg (89%); mp 70–71 °C (Lit.15 mp 72 °C).
IR (KBr): 3463, 2995, 2978, 2953, 2900, 1726, 1611, 1514, 1309,
1224, 1183, 1081, 1018, 834, 763 cm–1.
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

3242
J. Kwiatkowski et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 7.31–7.30 (m, 2 H), 7.18–7.17 (m,
2 H), 5.12 (d, J = 5.6 Hz, 1 H), 4.30–4.12 (m, 2 H), 3.44 (d, J = 5.6
Hz, 1 H), 2.35 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 Hz, CDCl3): d = 173.8, 138.2, 135.5, 129.2, 126.4,
72.7, 62.1, 21.1, 14.0.
IR (KBr): 3474, 2981, 2926, 1735, 1615, 1503, 1446, 1219, 1194,
1120, 1074, 1022, 818 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.18–7.16 (m, 1 H), 7.01–6.99 (m,
2 H), 5.31 (s, 1 H), 4.30–4.11 (m, 2 H), 3.31 (s, 1 H), 2.39 (s, 3 H),
2.30 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H).
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.95; H,
7.12.
13C NMR (100 MHz, CDCl3): d = 174.3, 138.1, 136.2, 133.8, 131.5,
126.9, 126.7, 70.2, 62.0, 21.0, 19.1, 14.0.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.25; H,
7.78.
Ethyl Hydroxy(4-isopropylphenyl)acetate (3b)16
Yield: 355 mg (80%); mp 37–39 °C (Lit.17 mp 39–41 °C).
IR (KBr): 3483, 2962, 2934, 2872, 1733, 1513, 1465, 1258, 1213,
1191, 1083, 1019, 832 cm–1.
Ethyl (3,4-Dimethylphenyl)(hydroxy)acetate (3g)
Yield: 370 mg (89%); oil.
1H NMR (400 MHz, CDCl3): d = 7.35–7.31 (m, 2 H), 7.23–7.20 (m,
2 H), 5.12 (s, 1 H), 4.31–4.12 (m, 2 H), 3.40 (s, 1 H), 2.95–2.85 (m,
1 H), 1.24 (d, J = 6.8 Hz, 6 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.8, 149.1, 135.8, 126.6, 126.5,
72.7, 62.1, 33.8, 23.88, 23.86 14.0.
IR (KBr): 3475, 2980, 2939, 1734, 1503, 1453, 1258, 1237, 1197,
1091, 1022, 807, 737 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.17 (s, 1 H), 7.14–7.10 (m, 2 H),
5.08 (s, 1 H), 4.31–4.11 (m, 2 H), 3.38 (s, 1 H), 2.26 (s, 3 H), 2.25
(s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H).
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.22; H,
8.15.
13C NMR (100 MHz, CDCl3): d = 173.9, 136.8, 135.9, 129.8, 127.7,
124.0, 72.8, 62.1, 19.7, 19.5, 14.0.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.18; H,
7.70.
Ethyl 4-tert-Butylphenyl(hydroxy)acetate (3c)
Yield: 396 mg (84%); oil.
IR (KBr): 3475, 2964, 2906, 2870, 1733, 1513, 1464, 1268, 1199,
1183, 1084, 1018 cm–1.
Ethyl Hydroxy(mesityl)acetate (3h)
Yield: 400 mg (90%); mp 51–52 °C (Lit.18 mp 54 °C).
1H NMR (400 MHz, CDCl3): d = 7.40–7.32 (m, 4 H), 5.13 (s, 1 H),
4.32–4.12 (m, 2 H), 3.43 (s, 1 H) 1.31 (s, 9 H), 1.24 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): d = 173.7, 151.3, 135.4, 126.2, 125.5,
72.7, 62.1, 34.5, 31.3, 14.0.
IR (KBr): 3427, 2961, 2923, 1739, 1608, 1486, 1463, 1213, 1078,
1013, 856 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.84 (s, 2 H), 5.52 (s, 1 H), 4.32–
4.15 (m, 2 H), 3.25 (s, 1 H), 2.33 (s, 6 H), 2.26 (s, 3 H), 1.22 (t,
J = 7.2 Hz, 3 H).
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.04; H,
8.45.
13C NMR (100 MHz, CDCl3): d = 174.9, 137.8, 137.1, 131.4, 129.8,
69.1, 62.2, 20.9, 19.9, 14.1.
Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.30; H,
8.24.
Ethyl Biphenyl-4-yl(hydroxy)acetate (3d)
Yield: 410 mg (80%); mp 109–111 °C.
IR (KBr): 3440, 3063, 3036, 2981, 2912, 1735, 1489, 1477, 1199,
1184, 1074, 1024, 837, 755, 733, 686 cm–1.
Ethyl Hydroxy(2,3,5,6-tetramethylphenyl)acetate (3i)
Yield: 425 mg (90%); mp 110–111 °C.
1H NMR (400 MHz, CDCl3): d = 7.60–7.57 (m, 4 H), 7.50–7.48 (m,
2 H), 7.45–7.41 (m, 2 H), 7.37–7.32 (m, 1 H), 5.21 (d, J = 5.6 Hz, 1
H), 4.33–4.15 (m, 2 H), 3.52 (d, J = 5.6 Hz, 1 H), 1.25 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): d = 173.6, 141.3, 140.6, 137.4, 128.8,
127.4, 127.3, 127.1, 126.9, 72.6, 62.3, 14.0.
IR (KBr): 3396, 2982, 2962, 2917, 2864, 1750, 1474, 1232, 1097,
1061, 1008, 869 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.95 (s, 1 H), 5.63 (s, 1 H), 4.33–
4.17 (m, 2 H), 3.16 (s, 1 H), 2.22 (s, 12 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 175.4, 134.3, 134.2, 133.3, 132.1,
69.6, 62.1, 20.5, 15.6, 14.1.
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.99; H,
6.24.
Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.16; H,
8.54.
Ethyl (2,5-Dimethylphenyl)(hydroxy)acetate (3e)
Yield: 358 mg (86%); oil.
Ethyl 9H-Fluoren-2-yl(hydroxy)acetate (3j)
Yield: 482 mg (90%); mp 128–129 °C.
IR (KBr): 3474, 2981, 2926, 1732, 1504, 1446, 1254, 1217, 1119,
1072, 1022, 812 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.11 (s, 1 H), 7.07–7.01 (m, 2 H),
5.32 (s, 1 H), 4.32–4.12 (m, 2 H), 3.41 (s, 1 H), 2.38 (s, 3 H), 2.30
(s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 136.4, 135.7, 133.1, 130.6,
129.1, 127.3, 70.3, 62.1, 20.9, 18.8, 14.0.
IR (KBr): 3463, 2979, 2942, 2912, 1731, 1476, 1191, 1081, 1023,
762, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.78–7.74 (m, 2 H), 7.59 (s, 1 H),
7.53 (d, J = 7.3 Hz, 1 H), 7.42–7.28 (m, 3 H), 5.22 (s, 1 H), 4.32–
4.13 (m, 2 H), 3.88 (s, 2 H), 3.56 (s, 1 H), 1.22 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.8, 143.6, 143.4, 142.0, 141.1,
136.9, 126.9, 126.8, 125.4, 125.0, 123.1, 120.0, 119.9, 73.1, 62.2,
36.8, 14.0.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.03; H,
7.68.
Anal. Calcd for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.00; H,
6.12.
Ethyl (2,4-Dimethylphenyl)(hydroxy)acetate (3f)
Yield: 383 mg (92%); oil.
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Substituted Mandelic Acid Esters
3243
Ethyl Hydroxy(naphthalen-1-yl)acetate (3k)19
Yield: 419 mg (91%); oil.
References
(1) Kang, S.-U.; Worthy, K. M.; Bindu, L. K.; Zhang, M.; Yang,
D.; Fisher, R. J.; Burke, T. R. Jr. J. Med. Chem. 2005, 48,
5369.
(2) (a) Mandelic acid derivatives as intermediates for
preparation of 2,3-dihydrobenzofuran-2-ones – anti-
inflammatory agents: 6-Acyl derivatives of
IR (KBr): 3463, 3052, 2982, 1732, 1599, 1511, 1368, 1214, 1096,
1020, 800, 791, 777 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 8,3 Hz, 1 H), 7.90–
7.83 (m, 2 H), 7.56–7.43 (m, 4 H), 5.79 (s, 1 H), 4.30–4.10 (m, 2 H),
3.60 (s, 1 H), 1.14 (t, J = 7.2 Hz, 1 H).
aminopenicillanic acid: Fulenmeier, A.; Quitt, P.; Volgler,
K.; Lanz, P. US Patent 3957758, 1976; Chem. Abstr. 1976,
85, 123909r. (b) Farge, D.; Moutonnier, C.; Messer, M. N.
Rhone-Poulenc S. A., South African Patent 7003341, 1970;
Chem. Abstr. 1971, 75, 63596. (c) Ihara Chemical Ind. Co.,
Japan Kokai Tokkyo Koho 8275948, 1982; Chem. Abstr.
1982, 97, 162591.
13C NMR (100 MHz, CDCl3): d = 174.2, 134.1, 134.0, 131.0, 129.3,
128.7, 126.5, 125.8, 125.7, 125.2, 123.7, 71.4, 62.3, 13.9.
Anal. Calcd for C14H14O3: C, 73.03; H, 6.13. Found: C, 73.03; H,
6.22.
Ethyl Hydroxy(4-methyl-naphthalen-1-yl)acetate (3l)
Yield: 303 mg (62%); oil.
(3) Poechlauer, P.; Skranc, W.; Wubbolts, M. Asymmetric
Catalysis on Industrial Scale, In The Large-Scale
Biocatalytic Synthesis of Enantiopure Cyanohydrins;
Blaster, H.-U.; Schmidt, E., Eds.; Wiley-VCH: Weinheim,
2004, 149–164.
(4) Coppola, G. M.; Schuster, H. F. a-Hydroxy Acids in
Enantioselective Syntheses; Wiley-VCH: Weinheim, 1997,
137–165.
(5) Friedel–Crafts and Related Reactions, Vol. 1–4; Olah,
G. A., Ed.; Wiley-Interscience: New York, 1963–1965.
(6) For reviews on enantioselective Friedel–Crafts reaction,
see: (a) Jørgensen, K. A. Synthesis 2003, 1117. (b) Bandini,
M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem. Int. Ed.
2004, 43, 550.
(7) Diastereoselective reactions of phenols: (a) Bigi, F.;
Casnati, G.; Sartori, C.; Dalprato, R.; Bortolini, R.
Tetrahedron: Asymmetry 1990, 1, 861. (b) Bigi, F.; Bocelli,
G.; Maggi, R.; Sartori, G. J. Org. Chem. 1999, 64, 5004.
(8) (a) Nagata, W.; Okada, K.; Aoki, T. Synth. Commun. 1979,
9, 365. (b) Si, Y.-G.; Chen, J.; Li, F.; Li, J.-H.; Qin, Y.-J.;
Jiang, B. Adv. Synth. Catal. 2006, 348, 898 (also the Friedel–
Crafts reaction of phenolate used in the total synthesis of the
pesticide cycloprothrin).
IR (KBr): 3463, 3073, 2981, 2939, 2904, 1734, 1598, 1516, 1443,
1214, 1085, 1024, 824, 760 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.20–8.15 (m, 1 H), 8.05–8.01 (m,
1 H), 7.56–7.51 (m, 2 H), 7.38 (d, J = 7.2 Hz, 1 H), 7.30–7.27 (m, 1
H), 5.76 (s, 1 H), 4.30–4.10 (m, 2 H), 3.51 (s, 1 H), 2.68 (s, 3 H),
1.14 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 135.7, 133.1, 132.4, 131.1,
126.1, 126.0, 125.7, 125.5, 124.8, 124.2, 71.5, 62.2, 19.6, 14.0.
Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.93; H,
6.77.
Ethyl 1,4-Dihydroanthracen-9-yl(hydroxy)acetate20
Yield: 437 mg (78%); mp 104–105 °C (Lit.21 mp 107 °C).
IR (KBr): 3464, 3054, 2993, 2905, 1716, 1524, 1474, 1221, 1093,
1013, 889, 729 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.48 (s, 1 H), 8.33–8.31 (m, 2 H),
8.03–8.00 (m, 2 H), 7.54–7.44 (m, 4 H), 6.57 (s, 1 H), 4.21–4.08 (m,
2 H), 3.66 (s, 1 H), 0.99 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 175.3, 131.5, 130.4, 129.3, 129.2,
128.4, 126.6, 124.9, 123.7, 68.1, 62.3, 13.9.
(9) (a) Shue, Y.-K.; Carrera, G. M.; Hutchins, C. W.; Garvey,
D. S.; Nadzan, A. M. J. Org. Chem. 1991, 56, 2936.
(b) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am.
Chem. Soc. 2000, 122, 12517. (c) Zhang, W.; Wang, P. G.
J. Org. Chem. 2000, 65, 4732. (d) Zhuang, W.; Gathergood,
N.; Hazell, R.; Jørgensen, K. A. J. Org. Chem. 2001, 66,
1009. (e) Zhuang, W.; Jørgensen, K. A. Chem. Commun.
2002, 1336. (f) Prakash, G. K.; Yan, P.; Török, B.; Olah,
G. A. Synlett 2003, 527. (g) Ding, R.; Zhang, H. B.; Chen,
Y. J.; Liu, L.; Wang, D.; Jun, L. i. C. Synlett 2004, 555.
(h) Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004,
69, 146. (i) Kwiatkowski, P.; Majer, J.; Chaładaj, W.;
Jurczak, J. Org. Lett. 2006, 8, 5045. (j) Zhu, C.; Yuan, C.;
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Anal. Calcd for C18H16O3: C, 77.12; H, 5.75. Found: C, 76.94; H,
5.61.
Ethyl Chrysen-6-yl(hydroxy)acetate (3n)
Yield: 594 mg (90%); mp 145–146 °C.
IR (KBr): 3529, 3081, 2994, 2857, 1722, 1513, 1477, 1244, 1077,
1019, 821, 762 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.82–8.74 (m, 3 H), 8.67 (d,
J = 9.0 Hz, 1 H), 8.31–8.29 (m, 1 H), 8.01–7.96 (m, 2 H), 7.23–7.60
(m, 4 H), 5.96 (d, J = 4.3 Hz, 1 H), 4.31–4.14 (m, 2 H), 3.77 (d,
J = 4.3 Hz, 1 H), 1.12 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 132.8, 132.1, 131.2, 130.4,
129.8, 128.7, 128.6, 128.1, 127.3, 126.8, 126.64, 126.61, 126.5,
124.5, 123.7, 123.0, 121.8, 120.9, 72.4, 62.4, 14.0.
Anal. Calcd for C22H20O3: C, 79.98; H, 5.49. Found: C, 79.38; H,
5.54.
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Weinstock, H. H. J. Am. Chem. Soc. 1939, 61, 412.
Acknowledgment
Financial support from the Ministry of Science and Higher Educa-
tion (Grant PBZ-KBN-126/T09/06) and from the Foundation for
Polish Science (individually for P.K.) is gratefully acknowledged.
Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York

3244
J. Kwiatkowski et al.
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Synthesis 2008, No. 20, 3237–3244 © Thieme Stuttgart · New York