A novel general method for preparation of α-fluoro-α-arylcarboxylic acid. Direct fluorination of silyl ketene acetals with Selectfluor

Article abstract of DOI:10.1016/j.tetlet.2006.08.057

The reaction of an α-arylcarboxylic acid with TBSCl and LiHMDS in THF yielded bis-silyl ketene acetal, which was directly fluorinated with inexpensive Selectfluor to produce the corresponding α-fluoro-α-arylcarboxylic acid in high yield. Application of the methodology to the synthesis of α-fluorocarboxylic ester from the corresponding carboxylic ester is also described.

Full text of DOI:10.1016/j.tetlet.2006.08.057

Tetrahedron Letters 47 (2006) 7641–7644
A novel general method for preparation of
a-fluoro-a-arylcarboxylic acid. Direct fluorination
of silyl ketene acetals with Selectfluor
Ò
*
Fei Zhang and Jake Z. Song
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 14 October 2005; revised 16 August 2006; accepted 17 August 2006
Available online 7 September 2006
Abstract—The reaction of an a-arylcarboxylic acid with TBSCl and LiHMDS in THF yielded bis-silyl ketene acetal, which was
ꢀ
directly fluorinated with inexpensive Selectfluor to produce the corresponding a-fluoro-a-arylcarboxylic acid in high yield. Appli-
cation of the methodology to the synthesis of a-fluorocarboxylic ester from the corresponding carboxylic ester is also described.
ꢁ
2006 Published by Elsevier Ltd.
1. Introduction
fluorinating reagents and complicated side reactions
associated with fluorination.
1
0
The a-fluoro-a-arylcarboxylic acid structural motif is
the basis for a series of active pharmaceutical ingredi-
We now wish to report a practical method for accom-
plishing this transformation with high conversion and
minimal side reactions. As a general procedure, bis-
TBS ketene acetals can be conveniently prepared from
free a-arylcarboxylic acids by reacting with TBSCl/
LiHMDS and without purification, subsequent fluorina-
1
2
ents as well as agrochemicals and has been widely
employed as a building block in organic synthesis. Con-
ventionally, these targets were prepared from a-aryl-
carboxylic acids by fluorinating the corresponding
metal enolates of acid derivatives with N-fluoro-o-benz-
3
ꢀ
enesulfonimide or NFSI (N-fluorobenzenesulfon-
tion with Selectfluor in MeCN provides a-fluoro-a-
arylcarboxylic acids cleanly after an aqueous work-up.
4
imide, (PhSO ) N–F). Despite the reported efficiency
2
2
of those processes, the approaches were not practical
for large scale production because of the high costs of
those fluorinating reagents. Additionally, this method-
The synthesis of bis-silyl ketene acetals from free acids11
is usually achieved by deprotonating the free acids with
either n-alkyllithium or amide bases followed by silyl-
ation and the process has been generally believed to
proceed through the dianion intermediates. In the
application of this method to our synthesis, we observed
5
ology is only applicable to acid derivatives such as
ꢀ
6
esters. Because Selectfluor is an inexpensive fluorinat-
7
5
12
ing reagent readily available in bulk, the use of Select-
ꢀ
fluor as our choice of fluorinating reagent is highly
desirable. To date, the preparation of a-fluorocarbonyl
compounds by the reaction of Selectfluor with enol
8
that LiHMDS is the preferred base because n-BuLi or
ꢀ
13
n-HexLi sometimes caused decomposition. By adding
acetates or silyl enol ethers has been broadly present
in the literature. Furthermore, the use of silyl ketene
acetals as intermediates in the conversion of acids to
a-chloro or bromo acids has also become widely prac-
2.2 equiv of LiHMDS to the THF solution of a-aryl-
carboxylic acids and TBSCl at an ambient temperature,
good conversions (>95%) from acids to bis-TBS ketene
1
acetals were confirmed by H NMR (Scheme 1).
9
ticed. However, to the best of our knowledge, this
methodology has not been extended to the fluorination
reaction presumably because of the high reactivity of
Analogously, bis-TMS and TES silyl ketene acetals
could also be prepared efficiently with the same protocol
and excellent conversions were confirmed by NMR.
ꢀ
However, fluorination reaction between Selectfluor
and bis-TMS silyl ketene acetal derived from 2-fluoro-
phenylacetic acid gave the desired 2-fluoro-2-(2-fluoro-
phenyl)-acetic acid in only ꢀ70% conversion and
*
0
Corresponding author. Tel.: +1 732 594 9416; fax: +1 732 594
499; e-mail: fei_zhang@merck.com
1
040-4039/$ - see front matter ꢁ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.08.057

7642
F. Zhang, J. Z. Song / Tetrahedron Letters 47 (2006) 7641–7644
OSiR'3
F
R' SiCl/ LiHMDS
SelectFluor
MeCN
3
Ar
COOH
Ar
Ar
COOH
OSiR'3
THF
R
R
R
~70% for R'=Me
85% for R'=Et
R = Me, H
Ar = Phenyl , heteroaromatics
R' = Me, Et, -Butyldimethyl
~
Conversion: >95%
t
Scheme 1. The synthesis and fluorination of bis-silyl ketene acetals.
approximately 30% 2-fluorophenylacetic acid was
detected by HPLC. Despite our efforts to exclude adven-
titious water in the reaction to achieve a higher conver-
sion, the reaction consistently stalled at 70% and no
further conversion was achieved even with the addi-
tional charge of Selectfluor . With bis-TES silyl ketene
acetal as the fluorination substrate, only a slightly
improved conversion was obtained.
(entry 11) and a-alkyl-a-aryl disubstituted substrate
(entry 9). The lower yields observed in entries 1 and 4
appear to be the result of the instability of the products.
To extend the application of this methodology, the reac-
tion was briefly expanded to alkylsilyl ketene acetal
other than bis-silyl ketene acetal (Scheme 3). The meth-
od proved to be applicable to both a-aryl and a-alkyl
substituted carboxylic esters. For example, starting from
methyl 2-fluorophenylacetate, the TBS silyl ketene ace-
tal could be conveniently prepared as a mixture of E
and Z isomers. The treatment of the mixture with Select-
ꢀ
Considering the fact that a commercially available
ꢀ
Selectfluor is usually contaminated with variable amount
À
of impurities such as F and inorganic acids, we
ꢀ
suspected that the bis-TMS silyl ketene acetal might
have already been hydrolyzed prior to the fluorina-
fluor in MeCN afforded methyl 2-fluoro-2-(2-fluoro-
phenyl)-acetate in a quantitative yield after aqueous
work-up and column chromatography.
ꢀ
tion reaction with Selectfluor . Based on our speculation,
the performance of the reaction would then depend
upon the relative stability of bis-silyl ketene acetals
towards possible impurities in commercially available
ꢀ
In conclusion, the reaction between Selectfluor and a
bis-TBS silyl ketene acetal provides a general method
for the preparation of a-fluoro-a-arylcarboxylic acid
from the corresponding a-arylcarboxylic acid. Addition-
ally, extension of the methodology to esters without
using the expensive NFSI will surely find its application
in the synthesis of a-fluoroacid derivatives widely
present in synthetic organic chemistry.
ꢀ
Selectfluor .
To further optimize the fluorination reaction, we chose
TBS as the more robust silyl masking group. Consistent
with our hypothesis, the fluorination reaction between
ꢀ
Selectfluor and bis-TBS silyl ketene acetals gave
>
95% conversion for all substrates screened, and hydro-
lysis back to a-arylcarboxylic acids was typically <4%
Scheme 2). In a further survey of a series of a-arylcarb-
(
2. General procedure for the conversion of a-arylcarb-
oxylic acids to a-fluoro-a-arylcarboxylic acids using
Selectfluor
oxylic acids using our protocol, it was apparent that the
complete conversion of free acids to bis-TBS silyl ketene
acetals needed to be secured before fluorination because
ꢀ
ꢀ
free acids are completely inert to Selectfluor .
Carboxylic acid (10 mmol) and TBSCl (23 mmol,
2
.3 equiv) were dissolved in 10 mL THF at room tem-
As a general procedure, bis-TBS silyl ketene acetals were
treated with Selectfluor in MeCN and instant fluorina-
perature before cooling to 0 ꢂC in an ice bath. LiHMDS
(22 mL, 1 M in THF, 2.2 equiv) was introduced drop-
wise into the solution maintaining the batch temperature
below 20 ꢂC. The resulting reddish solution was stirred
at ambient temperature for 2–16 h before concentrating
in vacuum to dryness. The residual oil was re-dissolved
into hexanes (LiCl quickly precipitated) and filtered
before LiCl was washed with a minimum amount of
hexanes (5–10 mL). The filtrates were collected and
concentrated in vacuum to dryness to leave bis-TBS
ꢀ
tions were observed with a slight exotherm. Typically
within 5 min, excellent conversions were achieved and
simple aqueous acid/base extraction produced the
1
4
desired a-fluoro-a-arylcarboxylic acids, which could
be obtained in an analytical pure form by silica gel
column chromatography. The chemistry works well for
a number of electron-rich and poor aromatic substrates
(
Table 1). The method is also applicable to hetero-
1
aromatic substrates that are sensitive to electrophiles
ketene acetal as a brown oil ( H NMR in C D : olefinic
6
6
Select-F
OTBS
R
F
Ar
COOH
Ar
COOH
Ar
OTBS
MeCN
R
(<4 A% by HPLC)
R
>95% conversion
R = Me or H
ꢀ
Scheme 2. Improved fluorination with Selectfluor using bis-TBS silyl ketene acetals.

F. Zhang, J. Z. Song / Tetrahedron Letters 47 (2006) 7641–7644
7643
Table 1. Preparation of a-fluoro-a-arylcarboxylic acids from a-arylcarboxylic acids using Selectfluorꢀ
OTBS
OTBS
Select-F
R
F
TBSCl/ LiHMDS
THF
Ar
COOH
Ar
COOH
Ar
MeCN
R
R
Yields: 80% - 95%
Entry
R
Ar
Yield (%)
a
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
Me
H
H
p-Methoxyphenyl
o-Methoxyphenyl
m-Methoxyphenyl
p-Nitrophenyl
o-Nitrophenyl
m-Nitrophenyl
o-Fluorophenyl
Phenyl
<10
87
87
a
<10
80
88
95
92
91
88
93
Phenyl
o-Methylphenyl
2-Thiophenyl
1
1
0
1
a
Bis-TBS silyl ketene acetal formation was clean. However, a significant colour change and severe decomposition were observed during isolation and
purification by column chromatography.
F
F
LiHMDS / TBSCl
THF, -78 oC to r.t.
F
Selectfluor
MeCN
O
OMe
OTBS
COOMe
OMe
F
~
100% for two steps
Scheme 3. Extension of the methodology to the synthesis of methyl 2-fluoro-2-(2-fluorophenyl)-acetate.
proton at 5–6 ppm and >95% conversion from the
acid).
References and notes
1
2
. Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
chemistry; John Wiley and Sons: New York, 1991.
. Cartwright, D. Recent Developments in Fluorine-
Containing Agrochemicals. In Organofluorine Chemistry,
Principles and Commercial Applications; Banks, R. E.,
Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New
York, 1994.
. Davies, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631.
. Differding, E.; Ofner, H. Synlett 1991, 187, and references
cited herein.
ꢀ
Selectfluor
(13 mmol) was suspended in MeCN
(
40 mL) and the solution of crude bis-TBS ketene acetal
ꢀ
in 10 mL MeCN was introduced into the Selectfluor
1
5
solution dropwise maintaining T < 50 ꢂC (slight exo-
therm). The reaction was allowed to stand at ambient
temperature for 15 min before it was poured into an
3
4
1
N aqueous HCl (100 mL) and extracted with MTBE
(
3 · 50 mL). The organic layers were combined and ex-
tracted with 0.5 N aqueous NaOH (3 · 50 mL). The
residual silyl impurities were further removed by com-
bining the aqueous NaOH layers and re-extraction with
MTBE (3 · 50 mL). The organic layers were discarded
and an aqueous NaOH solution was acidified with 5 N
HCl until pH = 1.
5. NFSI is available from Aldrich only in 5 g packages for
ꢀ
ꢀ$3000/mol and Selectfluor is available from a number
of vendors, for example, Scott Medical, in bulk for only
ꢀ
$300/mol.
ꢀ
6
. Structure of Selectfluor :
Cl
+
The acidified aqueous solution was extracted with
N
-
MTBE (3 · 50 mL), dried with MgSO , filtered and con-
(BF4 )2
4
centrated in vacuum to leave an oil which usually exhib-
N
F
+
1
ited a clean H NMR spectrum. If desired, the analytical
samples can be obtained by silica gel chromatography
with 1.5% or 2% MeOH in CH Cl to give the corre-
sponding a-fluoro-a-arylcarboxylic acid as a crystalline
(a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lal, G. S.;
Sharif, I.; Syvret, R. G. J. Chem. Soc., Chem. Commun.
2
2
1
992, 595; (b) Banks, R. E. U.S. Patent 5,086,178,
material.
1
992.
ꢀ
7
. Another advantage that Selectfluor offers for fluorina-
tion reaction is the easy aqueous workup because of
water solubility of byproducts derived from Selectfluor .
Acknowledgements
ꢀ
8
9
. Lal, G. S. J. Org. Chem. 1993, 58, 2791.
. For asymmetric version, see: Angibaud, P.; Chaumette, J.
L.; Desmurs, J. R.; Duhamel, L.; Ple, G.; Valnot, J. Y.;
Duhamel, P. Tetrahedron: Asymmetry 1995, 6, 1919–
1932.
We are grateful to Thomas Novak and Monica Yang in
Analytical Research at Merck Research Laboratories
for their help in high resolution mass spectroscopy and
IR spectroscopy experiments.

7644
F. Zhang, J. Z. Song / Tetrahedron Letters 47 (2006) 7641–7644
À1
1
0. Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
737–1755, and literature cited herein.
1. (a) Demnitz, F. W. J. Tetrahedron Lett. 1989, 30, 6109–
126.8, 126.7, 89.9, 87.9. IR (KBr, cm ) 2925.3 (br),
1
1697.7, 1231.5, 1047.3; HRMS (MÀ1) calculated:
1
1
153.0352, observed: 153.0350. Entry 11: Yield 93%;
H
6112; (b) Ainsworth, C.; Kuo, Y.-N. J. Organomet. Chem.
NMR (CDCl
3
, 400 MHz): d (ppm) 8.1 (br, 1H), 7.5 (s,
1
972, 46, 73; (c) Brun, E. M.; Casades, I.; Gil, S.; Mestres,
1H), 7.39–7.40 (m, 1H), 7.20–7.21 (m, 1H), 5.99 (d,
1
9
R.; Parra, M. Tetrahedron Lett. 1998, 39, 5443–5446.
2. (a) Mekelburger, H. B.; Wilcox, C. S. Formation of
Enolates. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; pp
J = 47.8 Hz, 1H); F NMR (CDCl
3
, 376 MHz): d (ppm)
1
3
1
À177.53; C NMR (CDCl , 100 MHz): d (ppm) 173.9,
3
173.6, 133.9, 133.7, 127.1, 125.59, 125.56, 125.3, 125.2,
À1
86.0, 84.2. IR (KBr, cm ) 2987.9 (br), 1696.4, 1231.5,
9
9–131; (b) Thomson, C. M. Dianion Chemistry in Organic
11 50 84 3. 9. 95 1; 7 H. RMS (MÀ1) calculated: 158.9916, observed:
Synthesis; CRC Press: Boca Raton, FL, 1994, pp 88–129.
1
3. For example: Treatment of 2-fluorophenylacetic acid in
15. Selectfluor has a reasonable solubility in MeCN at room
temperature, but was not sufficiently soluble to form a
homogeneous solution under the reaction condition and
concentration. Furthermore, the ‘reverse addition’ proce-
dure was adopted because it was more convenient to
transfer ketene acetal solution into Selectfluor/MeCN
suspension via a syringe pump while the temperature was
maintained. No difluorination was observed because the
product was totally inert to Selectfluor.
2
THF with 2 equiv of n-BuLi followed by D O quench did
not give the recovered starting material in its full integrity
and severe decomposition was detected by NMR.
1
1
4. Some representative spectral data: Entry 8: Yield 92%; H
NMR (CDCl
3
, 400 MHz): d (ppm) 7.43–7.50 (m, 5H), 5.90
1
9
(
br, 1H), 5.83 (d, J = 47.5 Hz, 1H); F NMR (CDCl3,
1
3
3
76 MHz): d (ppm) À181.2; C NMR (CDCl
3
, 100 MHz):
d (ppm) 174.1, 173.8, 133.6, 133.4, 130.00, 129.98, 129.0,