Superacid catalyzed hydroxyalkylation of aromatics with ethyl trifluoropyruvate: A new synthetic route to Mosher's acid analogs

Article abstract of DOI:10.1055/s-2003-37517

A new superacid catalyzed Friedel-Crafts hydroxyalkylation of aromatics with ethyl trifluoropyruvate is described. The trifluoromethanesulfonic acid or gallium(III) trifluoromethane-sulfonate catalyzed reactions give α-hydroxy α-trifluoromethyl phenyl acetic acid ethyl ester and its derivatives (analogs of Mosher's acid) in good yields for both highly activated heteroaromatics and substituted benzenes.

Full text of DOI:10.1055/s-2003-37517

LETTER
527
Superacid Catalyzed Hydroxyalkylation of Aromatics with Ethyl Trifluoro-
pyruvate: A New Synthetic Route to Mosher’s Acid Analogs
S
uperacid Catalyze
.
d
H
ydroxya
K
lkylation of Arom
.
atics Surya Prakash,* Ping Yan, Béla Török, George A. Olah*
Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, University Park, Los Angeles,
CA 90089-1661, USA.
Fax +1(213)7406270; E-mail: gprakash@usc.edu
Received 20 January 2003
Abstract: A new superacid catalyzed Friedel–Crafts hydroxy-
alkylation of aromatics with ethyl trifluoropyruvate is described.
The trifluoromethanesulfonic acid or gallium(III) trifluoromethane-
sulfonate catalyzed reactions give α-hydroxy α-trifluoromethyl
phenyl acetic acid ethyl ester and its derivatives (analogs of
Mosher’s acid) in good yields for both highly activated hetero-
aromatics and substituted benzenes.
OMe
C
OH
F3C
C
O
Key words: Friedel–Crafts hydroxyalkylation, α-trifluoromethyl
alcohol, gallium triflate, trifluoromethanesulfonic acid, Mosher’s
acid
(R)-MTPA
Figure 1
Herein, we report a new superacid catalyzed synthetic
route for the preparation of a wide range of Mosher’s acid
derivatives with substitution on the phenyl ring, which are
not easily obtained by the original synthetic methodology
employing phenyl trifluoromethyl ketones.5 The modifi-
cation on the aromatic component of the reagent can elec-
tronically tune the reactivity and also influence the extent
of deshielding and thus the chemical shift differences of
the derivatized diastereotopic groups. The Friedel–Crafts
hydroxyalkylation with trifluoromethyl ketones was only
reported for highly activated aromatic compounds.7 Re-
cently, the reactions in water of ethyl glyoxylate with het-
eroaromatic compounds and another enantioselective
approach using Cu(OTf)2-bisoxazoline complexes were
also published.8 However, these methodologies are only
practical in the cases of electron-rich aromatic compounds
of very high activity. A Lewis acid catalyzed synthesis of
α-trifluoromethyl amines from arenes and α-trifluoroace-
taldehyde hemiaminal was also reported very recently.9 In
our present approach, with the application of the super-
acidic trifluoromethanesulfonic acid, the use of a wide
range of aromatics including even deactivated benzene
derivatives is possible. Our method is based on the
Friedel–Crafts hydroxyalkylation of substituted aromatics
with ethyl 3,3,3-trifluoropyruvate 1, which gives the
racemic Mosher’s acid precursor, ethyl α-hydroxy α-
trifluoromethyl phenyl acetate and its derivatives 2
(Scheme 1). After the final resolution, both (R)- and (S)-
isomers can be obtained.
Organofluorine compounds have gained increased atten-
tion due to their unique physical and biological properties
induced by the fluorine atom.1 In pharmaceutical industry,
several novel fluorine-containing drugs have been devel-
oped, including anti-inflammatory agents, anticancer and
antiviral agents, etc.2 A wide range of new applications
with organofluorine compounds have also been intro-
duced in material science, from biocompatible polymers
to novel liquid crystals.1a,b Among the fluorine-containing
functional groups, trifluoromethyl group is unique due to
its strong electron-withdrawing nature. In the recent de-
cades numerous methodologies were developed for the in-
troduction of CF3 group either from CF3-containing
starting materials or by selective fluorination.1,3 Due to the
increased medicinal interest, the synthesis of biologically
active CF3-substituted compounds, such as alcohols,
amines and amino acids is becoming very important and
is in great demand.1,2,4 One of the most well-known CF3
compounds, the Mosher’s acid (MTPA) (Figure 1) and its
derivatives are widely used to determine the enantiomeric
excess (ee) of chiral compounds through derivatization.5
Mosher’s acid is stable towards racemization and can in-
duce reasonable differences in 19F NMR chemical shift of
its diastereotopic derivatives. In addition, 1H NMR results
can also be used for verification of 19F NMR based ee cal-
culations. However, certain limitations of the reagent,
such as overlapping signals of some diastereotopic groups
from the MTPA derivatives and also very sluggish reac-
tion of bulky substrates, should be taken into account. To
address these disadvantages, some variations of Mosher’s
acid were reported6 and suited only to specific demands.
In order to find the best conditions, the reaction of 1 with
toluene was studied with a wide range of Lewis and Brøn-
sted acid catalysts. As shown in Table 1, trifluoro-
methanesulfonic acid10 (TfOH) (entry 1) gave the best
yield even at room temperature. The solid gallium
trifluoromethanesulfonate11 [Ga(OTf)3] (entry 6) also
gave good yield at elevated temperature. It is noteworthy
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0527,0531,ftx,en;S03503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

528
G. K. S. Prakash et al.
LETTER
MeO
F3C
Ar
C
(R)
O
HO
COOH
Ar
COOEt
1. O-methylation
CF3SO3H or
Ga(OTf)3
+
Ar-H
C
C
COOEt
F3C
+
2. hydrolysis
3. resolution
F3C
MeO
F3C
Ar
1
2
(S)
C
COOH
Scheme 1
that 1 can undergo competitive self-condensation under and fluorobenzene, 50% Ga(OTf)3 at 90 °C gave products
acidic conditions, so it is essential that an appropriate cat- in traces together with byproducts from 1.
alyst must promote the Friedel–Crafts hydroxyalkylation
much faster than the side reaction in order to obtain 2 in
Based on results in Table 1, the superacidic trifluoro-
methanesulfonic acid10 was used to address the low reac-
good yield. In the case of other catalysts, significant
tivity of chloro- and fluorobenzenes. The results are
amounts of byproducts from 1 were observed.
tabulated in Table 3. As shown, a series of substituted
Accordingly, Ga(OTf)3 and TfOH were selected for fur- benzenes readily reacted with 1 at room temperature to
ther applications. Wide variety of aromatics and hetero- give expected products in moderate to good yields.
aromatics reacted with ethyl trifluoropyruvate under
Ga(OTf)3 catalysis. The results are shown in Table 2.
In spite of the strong acidity of TfOH, no hydrolysis on the
methoxy group of anisole (entry 3) and the loss of t-butyl
For highly activated heteroaromatics (Table 2. entries group of t-butylbenzene (entry 6) were observed during
1–6), 10 mol% Ga(OTf)3 gave excellent yields of the the reaction. The reaction led to selective formation of
hydroxy trifluoromethyl aromatic acetic esters 2 at room para-products. In the case of chloro- and fluorobenzene,
temperature. Reactions are usually completed within 1–2 1 to 2 equivalents of TfOH are required to achieve good
h. In the case of highly activated pyrrole (entries 3 and 4), yields while raising temperature had no significant effect.
the reactant ratios are of great importance; even disubsti- This could be explained by the superelectrophilic12 activa-
tuted product (entry 4) can form selectively. N-methylpyr- tion of ethyl trifluoropyruvate under superacidic condi-
role (entry 5), however, only gave mono-alkylated tions (Scheme 2).
product under similar reaction conditions. In the case of
carbocyclic aromatics (entries 7–10), reactions were very
Bearing two C=O groups, 1 can be protonated twice to
form the dicationic species 3, which is significantly more
slow at room temperature, but raising temperature to 90
reactive than the monocation. Increasing TfOH amount
°C gave satisfactory yields. Unfortunately, as activities of
increases the bulk acidity of the medium and thus its abil-
aromatic compounds further decrease, e.g. chlorobenzene
ity to stabilize the dicationic intermediate. As a result, the
superelectrophilic dication can react with the deactivated
chloro- and fluorobenzene smoothly. However, nitroben-
Table 1 Effect of Catalysts in the Reaction of Toluene with Ethyl
zene did not react under severe reaction conditions (10
equiv CF3SO3H). It is known13 that diphenylated product
can be obtained from benzene and ethyl pyruvate in 100
equiv of triflic acid. Similarly we also observed small
amount of diarylated product in the case of anisole (entry
3).
Trifluoropyruvate
Entry Catalyst
Temp
(°C)
Time
(h)
Yielda
(%)
1
2
3
4
5
6
7
8
CF3SO3H
H2SO4
20
20
20
90
90
90
90
20
5
48
48
48
48
48
48
24
84
30
0
In conclusion, a new superacid catalyzed method has been
developed for the synthesis of a series of ethyl α-hydroxy
α-trifluoromethyl phenyl acetate derivatives (2). Trifluo-
romethanesulfonic acid and Ga(OTf)3 were found to be
efficient and selective catalysts for this reaction even in
the case of deactivated halobenzenes with TfOH. As the
products can be easily transformed into analogs of the
well known Mosher’s acids, the presently developed
method may broaden their applications and use.
CF3COOH
Nafion-H
Montmorillonite K-10
Ga(OTf)3
Cu(OTf)2
AlCl3
54
3
73
0
8
a Isolated yields.
Synlett 2003, No. 4, 527–531 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Superacid Catalyzed Hydroxyalkylation of Aromatics
529
Table 2 Ga(OTf)3 Catalyzed Hydroxyalkylation of Aromatics with Ethyl 3,3,3-Trifluoropyruvate
Entry ArH
1
Temp. (°C)
20
Time (h)
2
Products
Yielda (%)
98
Regioselectivity (%)
100
F3C
OH
COOEt
N
H
N
H
2
3
20
2
99
100
F3C
OH
COOEt
N
N
20
20
1
2
95
76
100
100
CF3
OH
COOEt
N
H
N
H
in excess
4
CF3
F3C
OH
COOEt
HO
EtOOC
N
H
N
H
2 equiv. of pyruvate
5
6
7
20
20
90
2
2
40
95
59
100
100
100
CF3
OH
COOEt
N
N
CF3
OH
O
O
F3C
COOEt
24
OH
COOEt
8
9
90
90
18
6
73
97
94
92
CH3
F3C
OH
COOEt
H3C
OCH3
F3C
OH
COOEt
H3CO
CH3
10
90
24
84
100
CH3
CF3
OH
H3C
COOEt
CH3
a Isolated yield.
General Procedures: 0.5 mmol aromatic compound and 0.5 mmol
ethyl trifluoropyruvate were added to a dry pressure tube containing
1.5 mL suitable solvent (CH2Cl2 or ClCH2CH2Cl) under inert
atmosphere. Subsequently, the required amount of acid catalyst
(usually 10–20 mol%) was added to the mixture followed by heat-
ing to the corresponding temperature. Reaction was followed by
19F NMR until completion. The reaction mixture was poured into
5 mL of water and extracted with CH2Cl2. After evaporation of sol-
vents, the residue was purified by flash chromatography to give the
final product.14
References
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, New York, 2000. (b) Banks,
R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry:
Principle and Commercial Applications; Plenum Press: New
York, 1994. (c) Liebman, J. F.; Greenberg, A.; Dolbier, W.
R. Jr. Fluorine-Containing Molecules, Structure, Reactivity,
Synthesis and Applications; VCH Publishers: Weinheim,
1988.
Synlett 2003, No. 4, 527–531 ISSN 0936-5214 © Thieme Stuttgart · New York

530
G. K. S. Prakash et al.
LETTER
Table 3 CF3SO3H Catalyzed Hydroxyalkylation of Aromatics with Ethyl 3,3,3-Trifluoropyruvate
Entry
1
Substrate
Temp. (°C)
20
Time (h)
20
Product
F3C
Yielda (%)
46
Regioselectivityb (%)
–
OH
COOEt
5
5
CH3
F3C
OH
COOEt
2
3
20
20
84
85
86
96
H3C
OCH3n
F3C
OH
COOEt
H3CO
CH3
5
CH3
CF3
OH
COOEt
4
20
83
–
H3C
CH3
CH3
CF3
OH
COOEt
CH3
F3C
CH3
5
6
20
20
8
5
50
86
–
H3C
H3C
CH3
H3C
CH3
CH3
OH
88
COOEt
H3C
H3C
CH3
F
F3C
OH
COOEt
7
8
20
20
20
20
72
60
88
86
F
Cl
F3C
OH
COOEt
Cl
a Isolated yield.
b Regioselectivity of isomer shown.
+OH
+OH
OEt
OEt
C
C
C
O
F3C
C
F3C
O
+OH
H+
H+
OEt
C
C
O
F3C
OH
OH
+C
OEt
+C
OEt
1
C+
C
O
F3C
F3C
OH
3
Scheme 2
Synlett 2003, No. 4, 527–531 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Superacid Catalyzed Hydroxyalkylation of Aromatics
531
(2) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M.
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Elsevier: Amsterdam, 1993.
(b) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical
Frontiers of Fluorine Chemistry; ACS Symposium Series:
Washington D. C., 1996. (c) Kukhar, V. P.; Soloshonok, V.
A. Fluorine-Containing Amino Acids, Synthesis and
Properties; Wiley: New York, 1995.
3,3,3-Trifluoro-2-hydroxy-2-(4-methylphenyl)-propion-
ic acid ethyl ester:
1H NMR (250 MHz, CDCl3): δ 1.37 (t, J = 7.2 Hz, 3 H), 2.36
(s, 3 H), 4.30 (s, -OH), 4.31–4.52 (m, 2 H), 7.21 (d, J = 8.5
Hz, 2 H), 7.67 (d, 2 H). 19F NMR (470 MHz, CDCl3): δ
–76.98. 13C NMR (125 MHz, CDCl3): δ 169.1, 139.6, 130.0,
129.1, 126.7, 123.1 (q, J = 285.5 Hz), 77.7 (q, J = 30.2 Hz),
64.3, 21.1, 13.9.
(3) (a) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(b) Prakash, G. K. S.; Yudin, K. A. Chem. Rev. 1997, 97,
757. (c) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem.
2001, 112, 123; and references cited therein.
(4) (a) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem.
2001, 66, 2572. (b) Prakash, G. K. S.; Mandal, M.; Olah, G.
A. Angew. Chem. Int. Ed. 2001, 40, 589. (c) Bravo, P.;
Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett.
1998, 39, 7771. (d) Xu, Y.; Dolbier, W. R. Jr. Tetrahedron
Lett. 1998, 39, 9151.
3,3,3-Trifluoro-2-hydroxy-2-(4-methoxyphenyl)-prop-
ionic acid ethyl ester:
1H NMR (360 MHz, CDCl3): δ 1.38 (t, 3 H, J = 7.3 Hz), 3.82
(s, 3 H), 4.29 (s, -OH), 4.33–4.52 (m, 2 H), 6.93 (d, 1 H,
J = 9.0 Hz), 7.71 (d, 1 H). 19F NMR (338 MHz, CDCl3): δ
–77.22 (s). 13C NMR (90 MHz CDCl3): δ 169.1, 160.5,
128.2, 124.8, 122.4 (q, J = 285.8 Hz), 113.8, 77.5 (q, J = 30.5
Hz), 64.3, 55.3, 13.9.
3,3,3-Trifluoro-2-hydroxy-2-(4-t-butylphenyl)-propionic
acid ethyl ester:
(5) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543. (b) Goldberg, Y.; Alper, H. J. Org. Chem.
1992, 57, 3731.
(6) (a) Streinz, L.; Svatos, A.; Vrkoc, J.; Meinwald, J. J. Chem.
Soc., Perkin Trans. 1 1994, 3509. (b) Takahashi, T.;
Fukushima, A.; Tanaka, Y.; Segawa, M.; Hori, H.; Takeuchi,
Y.; Burchardt, A.; Haufe, G. Chirality 2000, 12, 458; and
references cited therein.
1H NMR (360 MHz, CDCl3): δ 1.32 (s, 9 H), 1.38 (t, J = 7.0
Hz, 3 H), 4.30 (s, 1 H), 4.31–4.51 (m, 2 H), 7.42 (m, 2 H),
7.70 (d, 2 H, J = 8.3 Hz). 19F NMR (338 MHz, CDCl3): δ
–76.93 (s). 13C NMR (90 MHz, CDCl3): δ 169.2, 152.7,
130.0, 126.6, 125.5, 123.2 (q, J = 285.6 Hz), 77.8 (q, J = 30.9
Hz), 64.4, 34.7, 31.3, 14.0.
3,3,3-Trifluoro-2-hydroxy-2-(4-fluorophenyl)-propionic
acid ethyl ester:
(7) (a) Dyachenko, V. I.; Kolomiets, A. F.; Fokin, A. V. J. Org.
Chem. USSR (Engl. Transl.) 1992, 28, 1345.
1H NMR (360 MHz, CDCl3): δ 1.38 (t, J = 7.5 Hz, 3 H), 4.39
(s, 1 H), 4.34–4.53 (m, 2 H), 7.09 (m, 2 H), 7.80 (m, 2 H).
19F NMR (338 MHz, CDCl3): δ –77.20 (s), –112.66 (q,
J = 9.1 Hz). 13C NMR (90 MHz, CDCl3): δ 168.75, 163.5 (d,
J = 248.8 Hz), 128.9 (dd, J = 8.6 Hz, 2.7 Hz), 128.6 (d,
J = 3.3 Hz), 122.9 (q, J = 285.7 Hz), 115.4 (d, J = 22.8 Hz),
77.4 (q, J = 30.5 Hz), 64.6, 13.8.
(b) Dyachenko, V. I.; Kolomiets, A. F.; Fokin, A. V. Izv.
Akad. Nauk, Ser. Khim. 1995, 3, 528. (c) Golubev, A. S.;
Kolomiets, A. F.; Fokin, A. V. Bull. Acad. Sci. USSR Div.
Chem. Sci.(Engl.Transl.) 1989, 38, 2180.
(8) (a) Zhuang, W.; Jorgensen, K. A. Chem. Commun. 2002,
1336. (b) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009.
(9) Gong, Y.; Kato, K. J. Fluorine Chem. 2002, 1-5, 5735.
(10) (a) Hazeldine, R. N.; Kidd, J. M. J. Chem. Soc. 1954, 4228.
(b) Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids;
Wiley Interscience: New York, 1985. (c) Yato, M.;
Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691.
(d) Sato, Y.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem.
Soc. 1995, 117, 3037.
3,3,3-Trifluoro-2-hydroxy-2-(4-chlorophenyl)-propionic
acid ethyl ester:
1H NMR (360 MHz, CDCl3): δ 1.38 (t, 3 H, J = 7.5 Hz), 4.38
(s, 1 H), 4.30–4.52 (m, 2 H), 7.39 (d, 2 H, J = 8.6 Hz), 7.75
(d, 2 H). 19F NMR (338 MHz, CDCl3): δ –77.09 (s). 13
C
NMR (90 MHz, CDCl3): δ 168.7, 136.0, 131.4, 128.7, 128.5,
122.9 (q, J = 285.9 Hz), 77.5 (q, J = 30.6 Hz), 64.8, 13.9.
3,3,3-Trifluoro-2-hydroxy-2-(2,5-dimethylphenyl)-pro-
pionic acid ethyl ester:
(11) Boumizane, K.; Herzog-Cance, M. H.; Jones, D. J.; Pascal,
J. L.; Potier, J.; Roziere, J. Polyhedron 1991, 10, 2757.
(12) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767.
(13) Yamazaki, T.; Saito, S.; Ohwada, T.; Shudo, K. Tetrahedron
Lett. 1995, 36, 5749.
1H NMR (360 MHz, CDCl3): δ 1.38 (t, 3 H, J = 7.3 Hz), 3.82
(s, 3 H), 4.29 (s, 1 H), 4.33–4.52 (m, 2 H), 6.93 (d, 1 H,
J = 9.0 Hz), 7.71 (d, 1 H). 19F NMR (338 MHz, CDCl3): δ
–73.65 (s). 13C NMR (90 MHz, CDCl3): δ 169.9, 135.2,
134.5, 132.5, 131.3, 129.9, 128.0 (q, J = 3.8 Hz), 123.5 (q,
J = 288.1 Hz), 79.6 (q, J = 28.8 Hz), 64.1, 21.2, 20.0, 13.8.
3,3,3-Trifluoro-2-hydroxy-2-(2,4,6-trimethylphenyl)-
propionic acid ethyl ester:
(14) New compounds were characterized by NMR (1H, 19F, 13C)
spectroscopy using Bruker AM-360 spectrometer. The
spectra were recorded in CDCl3 using TMS and CCl3F as
internal standards.
1H NMR (360 MHz, CDCl3): δ 1.26 (t, J = 7.0 Hz, 3 H), 2.18
(s, 3 H), 2.35(s, 6 H), 3.23 (s, -OH), 4.17–4.33 (m, 2 H), 6.80
2,5-Di(α-carboethoxy-a-hydroxytrifluoroethyl)-pyrrole:
1H NMR (360 MHz, CDCl3): δ 1.39 (t, J = 7.3 Hz, 6 H),
4.34–4.53 (m, 6 H), 6.44 (s, 1 H), 6.45 (s, 1 H), 9.18 (br s).
19F NMR (338 MHz, CDCl3): δ –78.92 (s). 13C NMR (90
MHz, CDCl3): δ 167.7, 122.4 (q, J = 285.5 Hz), 123.0,
122.9, 75.0 (q, J = 32.3 Hz), 64.8, 13.8.
(s, 2 H). 19F NMR (338 MHz, CDCl3): δ –76.17 (s). 13
C
NMR (90 MHz, CDCl3): δ 168.5, 137.6, 137.5, 131.2, 126.8,
123.0 (q, J = 284.8 Hz), 80.3 (q, J = 30.2 Hz), 61.7, 21.6,
21.5, 19.4, 12.6.
Synlett 2003, No. 4, 527–531 ISSN 0936-5214 © Thieme Stuttgart · New York