Simple procedure for preparation of α-fluoro esters by fluorination of ester enol silyl ethers with perchloryl fluoride

Article abstract of DOI:10.1016/S0022-1139(02)00185-9

Fluorination of ester enol silyl ethers in THF at room temperature using diluted perchloryl fluoride (FClO₃) in the presence of ca. 0.5M eq. of t-BuNH₂ as an additive produced the corresponding α-fluoro esters in over 80% yields.

Full text of DOI:10.1016/S0022-1139(02)00185-9

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Journal of Fluorine Chemistry 117 (2002) 173±176
Simple procedure for preparation of a-¯uoro esters by ¯uorination
of ester enol silyl ethers with perchloryl ¯uoride
Hidehito Fujisawa, Yoshio Takeuchi*
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 27 April 2002; received in revised form 11 June 2002; accepted 17 June 2002
Dedicated to Professor LevM. Yagupolskii on the occasion of his 80th birthday.
Abstract
Fluorination of ester enol silyl ethers in THF at room temperature using diluted perchloryl ¯uoride (FClO3) in the presence of ca. 0.5 M eq.
of t-BuNH2 as an additive produced the corresponding a-¯uoro esters in over 80% yields.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: a-Fluoro ester; Perchloryl ¯uoride; Ester enol silyl ether
1. Introduction
available, we employed a reliable and safe procedure, which
involves the slow generation of FClO3 [5] and entrainment
as a diluted gas in N2 [6]. A solution of the lithium enolate
of ester 1a in THF, formed by treatment with LDA by the
usual procedure, was subjected to slow introduction of
diluted FClO3 at À50 8C for 60 min. This produced the
a-¯uoro ester 2a in 56% yield. However, attempted applica-
tion of this procedure to the esters 1b and 1c gave the
corresponding a-¯uoro esters 2b and 2c only in trace yields.
Attempted ¯uorination of 1a with FP-T5001 [3] to produce
2a was unsuccessful (Scheme 1). These results can be
ascribed to the dif®culty in generating the stable carbanion
at the position a to the ester groups.
As a strategy to avoid this complication of lithium enolate
instability, we focused on ¯uorination of the corresponding
enol silyl ethers. Ester enol silyl ethers were prepared by
treatment of the esters with LDA and TMSCl, according to the
reported general procedure [7]. We ®rst attempted ¯uorina-
tion of silyl ether 3a with 15% F2/He under various conditions
[4]. Since the enol silyl ether was sensitive to acid and slowly
decomposed during reaction, some bases were used as addi-
tives. However, the results were unsatisfactory (Scheme 2).
We next attempted ¯uorination of 3a with diluted FClO3
generated by our procedure [6]. Temperature, additive, and
solvent were examined in order to optimize the reaction
conditions. We found that the presence of a base is important
to this reaction and the use of ca. 0.5 M eq. of amine as an
additive seemed to be generally effective (Table 1).
In the course of preparing a key intermediate for the
synthesis of ¯uorine-containing potential medicinals, we
encountered the need for a practical synthesis of a-¯uoro
esters. In contrast to the case of enolizable ketones, direct
¯uorination of esters has been problematic. Two groups
reported direct ¯uorination of a-substituted esters with
perchloryl ¯uoride (FClO3) to afford a-substituted a-¯uoro
esters [1]. However, there has been no successful report
describing the ¯uorination of a-unsubstituted esters. An
alternative route to a-¯uoro esters involves ¯uorination of
enol silyl ethers, derived from esters, with CF3OF [2], N-
¯uoropyridinium tri¯ate (FP-T5001) [3], or 5% F2/N2 [4].
However, all of these ¯uorinations require the use of sensi-
tive reagents and/or lack generality.
We report here a practical method for the general pre-
paration of a-¯uoro esters by ¯uorination of the correspond-
ing enol silyl ethers using diluted FClO3 in the presence of a
half molar equivalent of amine compound.
2. Results and discussion
We ®rst attempted direct ¯uorination of esters with FClO3,
following a procedure similar to the literature method [1].
Since this hazardous reagent is no longer commercially
* Corresponding author. Tel.: ‡81-76-434-7555; fax: ‡81-76-434-5053.
E-mail address: takeuchi@ms.toyama-mpu.ac.jp (Y. Takeuchi).
We then investigated the kinds of amine compounds most
suitable for this ¯uorination. The best result was obtained
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 8 5 - 9

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H. Fujisawa, Y. Takeuchi / Journal of Fluorine Chemistry 117 (2002) 173±176
Scheme 1. Fluorination of esters 1.
when enol silyl ether 3a in THF was subjected to our FClO3
¯uorination for 30 min at room temperature, with 0.5 M eq.
of t-BuNH2 as an additive, to give 2a in 83% yield. In the
case of ¯uorination of 3a with FP-T5001, an amine com-
pound seemed not to be important (Table 2).
In order to see the generality of this reaction, several ester
enol silyl ethers 3b±f were subjected to our ¯uorination using
0.5 M eq. of t-BuNH2 as an additive. The corresponding a-
¯uoro esters 2b±f were obtained in excellent yields (Table 3).
Scheme 2. Reaction of enol silyl ether 3a with 15% F2 in He.
Enol ethers derived from ketones are usually ¯uorinated
with FClO3 in basic conditions, such as in pyridine solvent, to
produce a-¯uoroketones [8]. In contrast, enol silyl ethers
derived from esters are rather unstable under basic conditions,
especially in the presence of moisture, and they, therefore,
Table 1
Reaction of enol silyl ether 3a with FClO3
Additive (eq.)
Solvent
Temperature
Time (min)
Yield (%)
±
CHCl3
THF
THF
THF
THF
THF
THF
THF
THF
THF
RT
RT
15
15
15
15
15
15
15
30
30
30
Trace
45
±
Et3N (0.1)
Et3N (0.5)
Et3N (1.0)
Na2CO3 (1.0)
Pyridine (1.0)
Et3N (0.5)
Et3N (0.5)
Et3N (0.5)
RT
22
RT
53
RT
RT
44
38
RT
38
RT
0 8C
À78 8C
67
56
73
Table 2
Reaction of 3a with FClO3 using 0.5 M eq. of amine compounds
Reagent
Additive (eq.)
Solvent
Temperature
Time (min)
Yield (%)
FClO3
(i-Pr)2NH (0.5)
(p-H2N-Ph±)2
PhNHMe (0.5)
PhCHMeNH2 (0.5)
PhCHMeNH2 (0.5)
t-BuNH2 (0.5)
±
THF
RT
30
30
63
21
45
80
71
83
59
50
FClO3
FClO3
THF
THF
RT
RT
30
FClO3
THF
RT
30
FClO3
THF
À78 8C
RT
RT
30
FClO3
FP-T5001
FP-T5001
THF
CH2Cl2
CH2Cl2
30
120
120
t-BuNH2 (0.5)
RT

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H. Fujisawa, Y. Takeuchi/ Journal of Fluorine Chemistry 117 (2002) 173±176
175
Table 3
Fluorination of enol silyl ethers 3b±f
Silyl ether
R1
R2
H
R3
Et
Reagent
Solvent
Time (min)
Product
Yield (%)
3b
PhCH2
FClO3
FP-T5001
THF
CH2Cl2
30
120
2b
83
13
3c
n-C5H11
H
Et
FClO3
FP-T5001
THF
30
2c
88
13
CH2Cl2
120
3d
3e
3f
Et
H
H
CH2Ph
Bu
FClO3
FClO3
FClO3
THF
THF
THF
30
30
20
2d
2e
2f
92
100
92
Me
±(CH2)5±
Me
slowly decompose into the original esters in the presence of
excess of amine compound. However, reaction with FClO3
in the presence of even small amount of moisture seems to
make the medium acidic and this also leads to decomposition
of the silyl ethers. Because of this, we feel an important factor
necessary to carry out this delicate ¯uorination effectively is
the careful control of the nature of the medium to avoid
decomposition of the rather unstable ester enol ethers during
reaction. However, additional study may be necessary to clear
the role of amine compound in this ¯uorination.
into a 20 ml two-necked ¯ask equipped with stirrer and
re¯ux condenser and was heated in an oil bath. The bath
temperature was raised gradually and was ®nally kept
around 90 8C. After about 10 min, FClO3 started to be
evolved [5]. The freshly generated FClO3 was entrained
as a diluted gas in nitrogen [6] and introduced into a
solution of aqueous 10% sodium hydroxide containing
5% sodium thiosulfate. The scrubbed gases were passed
over solid sodium ¯uoride and then solid calcium chloride
[5].
The diluted FClO3 gas thus prepared was introduced
into a solution of ester enol silyl ether 3 (0.2 mmol) and
t-BuNH2 (0.1 mmol) in dry THF (0.5 ml) at room tem-
perature for 20±30 min. The resulting mixture was con-
centrated to give an oil, dissolved in CHCl3 and ®ltered
through silica gel to remove polar substances. Removal of
solvent gave a-¯uoro ester 2 contaminated with a small
amount of starting material 1. Yields were calculated
3. Conclusion
In contrast to a-chlorination or a-bromination of esters,
practical procedures for a-¯uorination of esters have been
problematic. With this in mind, we have developed a simple
procedure for this purpose using FClO3 ¯uorination of ester
enol silyl ethers in the presence of suitable amount of a base.
1
based on H NMR.
4.2. Ethyl 2-fluoro-2-phenylacetate (2a) [2]
4. Experimental
Yield: 83%; colorless oil; IR (neat) 1735 (C=O) cmÀ1; 1H
NMR d (ppm) 1.26 (t, J ˆ 7:3 Hz, 3H), 4.25 (m, 2H), 5.77
(d, J ˆ 47:8 Hz, 1H), 7.39±7.46 (m, 5H); 19F NMR d (ppm)
IR spectra were obtained on a Perkin-Elmer 1600 (ET-IR)
spectrophotometer. 1H and 19F NMR spectra were obtained
with a JEOL GX-270 (270.05 MHz for 1H and 254.19 MHz
for 19F) spectrometer in CDCl3 with Me4Si or CFCl3 as an
internal reference. Mass spectra were measured on a JEOL
JMS-GCmate. High-resolution mass spectra were obtained
using a JEOL JMS-AX 505 HAD. Commercially available
FP-T5001 was used [3]. Enol silyl ethers were prepared
according to the reported procedure [7]. Silica gel (Fuji
Silysia BW-200) was used for column chromatography.
‡
À180.37 (d, J ˆ 47:3 Hz, 1F); MS m/z 182 (M ), 163
‡
‡
‡
(M À F), 109 (M À COOEt), 90 (M À COOEt À F);
‡
HRMS m/z calcd. for C10H11FO2 (M ): 182.0743, found:
182.0744.
4.3. Ethyl 2-fluoro-3-phenylpropanoate (2b) [9]
Yield: 83%; colorless oil; IR (neat) 1734 (C=O) cmÀ1
;
1H NMR d (ppm) 1.11 (t, J ˆ 7:2 Hz, 3H), 2.93±3.19 (m,
2H), 4.08 (q, J ˆ 7:2 Hz, 2H), 4.95 (ddd, J ˆ 48:9, 7.4,
4.5 Hz, 1H), 7.06±7.21 (m, 5H); 19F NMR d (ppm)
4.1. General procedure for preparation of a-fluoro
esters by FClO3 fluorination of the corresponding
ester enol silyl ethers
‡
À190.30 (dt, J ˆ 49:2, 24.2 Hz, 1F); MS m/z 196 (M ),
‡
‡
‡
177 (M À F), 122 (M À COOEt), 103 (M À COOEt
‡
A mixture of potassium perchlorate (0.5 g, 3.6 mmol)
in ¯uorosulfonic acid (2 ml, 34.8 mmol) was charged
ÀF); HRMS m/z calcd. for C11H13FO2 (M ): 196.0900,
found: 196.0909.

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176
H. Fujisawa, Y. Takeuchi / Journal of Fluorine Chemistry 117 (2002) 173±176
‡
4.4. Ethyl 2-fluoroheptanoate (2c)
NMR d (ppm) À165.50 (brs, 1F); MS m/z 160 (M ), 141
‡
‡
‡
(M À F), 101 (M À COOMe), 82 (M À COOMe À F);
Yield: 88%; colorless oil; IR (neat) 1739 (C=O) cmÀ1; 1H
NMR d (ppm) 1.27±1.52 (m, 12H), 1.79±1.96 (m, 2H), 4.26
(q, J ˆ 7:1 Hz, 2H), 4.89 (ddd, J ˆ 48:9, 5.9, 5.9 Hz, 1H);
19F NMR d (ppm) À192.48 (dt, J ˆ 49:9, 25.0 Hz, 1F); MS
HRMS m/z calcd. for C8H13FO2 (M ): 160.0900, found:
160.0901.
‡
‡
‡
‡
m/z 176 (M ), 103 (M À COOEt), 84 (M À COOEt À F);
References
‡
HRMS m/z calcd. for C9H17FO2 (M ): 176.1213, found:
176.1211.
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4279;
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Commun. (1976) 468.
Yield: 92%; colorless oil; IR (neat) 1737 (C=O) cmÀ1; 1H
NMR d (ppm) 0.98 (t, J ˆ 7:4 Hz, 3H), 1.67±1.99 (m, 2H),
4.87 (ddd, J ˆ 49:0, 6.8, 6.8 Hz, 1H), 5.20 (s, 2H), 7.34 (brs,
5H); 19F NMR d (ppm) À193.99 (dt, J ˆ 48:8, 24.8 Hz, 1F);
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4845.
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‡
‡
MS m/z 196 (M ), 177 (M À F); HRMS m/z calcd. for
‡
C11H13FO2 (M ): 196.0900, found: 196.0897.
4.6. Butyl 2-fluoropropanoate (2e)
Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 52 (1987)
5061;
Yield: 100%; colorless oil; IR (neat) 1740 (C=O) cmÀ1
;
1H NMR d (ppm) 0.87 (t, J ˆ 7:3 Hz, 3H), 1.26±1.69 (m,
7H), 4.13 (t, J ˆ 6:3 Hz, 2H), 4.93 (dq, J ˆ 48:5, 6.9 Hz,
1H); 19F NMR d (ppm) À184.86 (dq, J ˆ 48:0, 24.0 Hz,
Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 53 (1988)
4160.
[7] C. Ainsworth, F. Chen, Y.-N. Kuo, J. Organomet. Chem. 46 (1972)
59;
‡
‡
1F); MS m/z 148 (M ), 129 (M À F); HRMS m/z calcd. for
J.K. Rasmussen, A. Hassner, J. Org. Chem. 39 (1974) 2558;
N.L. Holy, Y.F. Wang, J. Am. Chem. Soc. 99 (1977) 944;
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5259.
‡
C7H13FO2 (M ): 148.0900, found: 148.0898.
4.7. Methyl 1-fluorocyclohexanecarboxylate (2f) [10]
[9] A. Thenappan, D.J. Burton, J. Org. Chem. 55 (1990) 2311.
[10] A.O. Amanetoullah, M.M. Chaabouni, A. Baklouti, Synth. Commun.
26 (6) (1996) 1155.
Yield: 92%; colorless oil; IR (neat) 1739 (C=O) cmÀ1
1H NMR d (ppm) 1.64±1.96 (m, 10H), 3.78 (s, 3H); 19F
;