Synthesis, reactivity and applications of 1-fluoroalkyl carboxylates: novel synthetic substrates for esterases and lipases

Article abstract of DOI:10.1016/j.tet.2007.02.059

A series of 1-fluoroalkyl carboxylate derivatives was synthesised by reacting a carboxylic acid and a ketone or aldehyde with (diethylamino)sulfur trifluoride (DAST). The reactivity of these compounds towards the nucleophiles benzylamine and water was inv

Full text of DOI:10.1016/j.tet.2007.02.059

Tetrahedron 63 (2007) 3306–3311
Synthesis, reactivity and applications of 1-fluoroalkyl
carboxylates: novel synthetic substrates for esterases and lipases
*
Carl S. Rye, Jonathan B. Baell and Ian Street
The Walter and Eliza Hall Institute of Medical Research, Division of Structural Biology, 4 Research Avenue,
Bundoora, VIC 3086, Australia
Received 7 September 2006; revised 5 February 2007; accepted 15 February 2007
Available online 20 February 2007
Abstract—A series of 1-fluoroalkyl carboxylate derivatives was synthesised by reacting a carboxylic acid and a ketone or aldehyde with (di-
ethylamino)sulfur trifluoride (DAST). The reactivity of these compounds towards the nucleophiles benzylamine and water was investigated.
The hydrolysis of the 1-fluoroalkyl carboxylates by an esterase was observed, along with the concomitant release of the fluoride ion, dem-
onstrating the potential for a new esterase assay platform. Other applications may include a detectable in situ inhibitor synthesis protocol.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
by varying the nature of the ‘leaving group’ moiety of the 1-
fluoroalkyl carboxylate. It is envisioned that with a suitable
nucleophile and 1-fluoroalkyl carboxylate, the coupling re-
action would not occur unless the two components were
brought together in close proximity, such as in the active
site of an enzyme. Thus, one might imagine an easily detect-
able in situ inhibitor synthesis for a particular target using
a library of nucleophiles and 1-fluoroalkyl carboxylates.
Other groups have shown that potent ligands to particular
targets can be self-assembled in situ from weakly binding
fragments,1–4 allowing for the screening of smaller, frag-
ment libraries rather than larger, more complicated screen-
ing libraries. However, many of these techniques employ
reversible chemical reactions, and the detection of these cou-
pling events is not necessarily trivial, often involving labori-
ous HPLC and mass spectroscopy techniques.
1-Fluoroalkyl carboxylate derivatives are a class of esters for
which there is only a modest amount of literature informa-
tion, both with regard to their synthesis and their stability/
reactivity characteristics. An interesting attribute of these
1-fluoroalkyl carboxylates is that upon hydrolysis of the es-
ter, they release a fluoride ion. The liberation of this easily
detectable leaving group could then be utilised in a number
of chemical and biological applications. We have inves-
tigated a one step synthesis of a variety of 1-fluoroalkyl
carboxylate derivatives using the fluorinating agent (diethyl-
amino)sulfur trifluoride (DAST), their reactivity towards
nucleophiles and their application as novel substrates for
carboxylic acid esterases and lipases.
Our initial interest in 1-fluoroalkyl carboxylates stemmed
from the thought that the release of the fluoride ion resulting
from the reaction with a nucleophile could be an effective
way to monitor the progress of a coupling reaction between
two partners of suitable reactivity (Fig. 1). In addition to
altering nucleophiles, the coupling reaction may be tunable
A wide assortment of techniques exist to measure the fluo-
ride ion including a fluoride ion-selective electrode as well
as a number of chemical ‘sensor’ compounds that selectively
bind the fluoride ion to produce a change in fluorescence or
colour. The initial leaving group formed from the reaction of
a 1-fluoroalkyl carboxylate with a nucleophile is the highly
unstable a-fluoro alkoxide, which immediately decomposes
to produce a ketone or aldehyde and the fluoride ion.5 The
release of the fluoride ion from a similar system has been ob-
served with the hydrolysis of 5-fluoro glycosides by glycosi-
dases.6 As the glycosidic linkage is hydrolysed in this
reaction, a reactive fluorohydrin is generated at carbon 5
of the sugar (open-chain form), which rapidly eliminates
thefluorideion.Thedecompositionof1-fluoroalkylcarboxyl-
ates has been observed7,8 and utilised, for example, in the
conversion of enol acetates to ketones9 or a-fluoroketones.10
O
R2
R3
R2
R3
O
F -
+
+
R1
Nu
O
F
O
R1
Nu
Figure 1. Reaction of a 1-fluoroalkyl carboxylate with a nucleophile (Nu).
Keywords: Fluoroalkyl carboxylate; Enzyme catalysis; Esterase; Assay;
DAST.
* Corresponding author. Tel.: +61 3 9345 2101; fax: +61 3 9345 2211;
e-mail: rye@wehi.edu.au
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.059

C. S. Rye et al. / Tetrahedron 63 (2007) 3306–3311
3307
Another application of 1-fluoroalkyl carboxylates lies in a
novel assay platform for carboxylic acid esterase or lipase
activity. Using a 1-fluoroalkyl carboxylate as a synthetic
substrate, the progress of the enzyme reaction could be mon-
itored through the release of the fluoride ion. We have found
that the 1-fluoroalkyl carboxylates are easily synthesised in
one step from the acid precursors, and the properties of the
‘leaving group’ moiety can be tailored for a specific esterase
with respect to size, hydrophobicity and functional groups.
We have shown that the 1-fluoroalkyl carboxylates described
in this paper are hydrolysed by an esterase, resulting in the
release of the fluoride ion (vide infra).
We determined that the reaction to give compound 8 was
very insensitive to changes in reaction conditions. The use
of dry DCM (distilled over CaH2) or ‘wet’ DCM from a re-
agent bottle made no difference to the isolated yield. React-
ing DAST and water in DCM to produce HF prior to adding
cyclopentanone, benzoic acid and additional DAST had very
little effect on the yield. Reaction times of 20 min and 24 h
showed no difference to the yield or purity of the product,
nor did reactions conducted at 0 ꢀC, or with a slow addition
of DAST (over 1 h), or with a large excess of DAST
(8 equiv).
Not all desired 1-fluoroalkyl carboxylates could be synthes-
ised, and some were too unstable to be isolated. Reactions
with 1,1-dichloroacetone or hexachloroacetone and benzoic
acid did not produce any desired products. The 1-fluoroalkyl
carboxylate formed from the reaction of acetaldehyde and
2. Results and discussion
2.1. Synthesis
1
benzoic acid was isolated, but was unstable; its H NMR
There are several ways to synthesise 1-fluoroalkyl carboxy-
lates, however, many are specific to the particular type of
product (e.g., difluoromethyl esters), require more than
one synthetic step, or produce the 1-fluoroalkyl carboxylate
as a minor by-product.5,9,11–16 The synthesis of the 1-fluo-
roalkyl carboxylates reported herein was accomplished
using the fluorinating agent (diethylamino)sulfur trifluoride
(DAST), based on a paper which reported the synthesis of
compound 9.17 The 1-fluoroalkyl carboxylates were synthes-
ised in moderate to good yields by reacting the appropriate
acid and ketone or aldehyde with DAST, using dichloro-
methane (DCM) to solubilise the starting materials if neces-
sary (Fig. 2). The presence of fluorine in the products was
spectrum showed evidence of decomposition into benzoic
acid and acetaldehyde after a short period of time. Similarly,
the reaction product formed from butyric acid and acetone
was isolated, but decomposed upon standing overnight at
room temperature. Reactions with benzoic acid and either
2-cyclopenten-1-one, 2-cyclohexen-1-one, trans-4-phenyl-
3-buten-2-one, or 2-furaldehyde appeared to produce the
desired 1-fluoroalkyl carboxylate products by TLC, how-
ever, no product was isolated from purification attempts
of the crude reaction mixtures by either silica gel or neutral
alumina column chromatography.
2.2. Reactivity
1
confirmed by characteristic couplings in both the H and
13C NMR spectra, in addition to 19F NMR spectra.
The progress of the reactions between a series of 1-fluo-
roalkyl carboxylates and either benzylamine or water was
monitored by quantifying the amount of product formed
over time by the HPLC analysis of reaction mixtures. The
presence of the fluoride ion in the reaction mixtures was
confirmed by using the compound 1-[9,10-dioxo-1-(3-
phenyl-thioureido)-9,10-dihydro-anthracen-2-yl]-3-phenyl-
thiourea,18 a selective fluoride ion sensor; an increase in
absorbance at 561 nm characteristic of its complexation
with the fluoride ion was observed. In addition, the ketone
or aldehyde reaction products were often observed in the
HPLC analysis of the reaction mixtures. The amide products
N-benzylpropionamide and N-benzylphenylacetamide from
the reaction of benzylamine with compounds 1 and 4,
respectively, were isolated and purified by silica gel chroma-
tography for production of the HPLC standard curves; the
1H NMR spectra agreed with published data.19
R2 R3
O
O
O
Et2N SF3
DCM
+
R1
OH
R2
R3
R1
O
F
Figure 2. General scheme for the synthesis of 1-fluoroalkyl carboxylates.
The precise reaction mechanism for the formation of the 1-
fluoroalkyl carboxylates remains to be elucidated. Contrary
to one report,17 no reaction was observed between benzoyl
fluoride and acetone (with or without DAST), or between
1,1-difluorocyclohexane and benzoic acid. Thus one may
postulate that the intermediate formed from the initial attack
of the carboxylic acid with DAST reacts with the ketone or
aldehyde, or perhaps with the a-fluoro alcohol generated
from the reaction of the ketone or aldehyde with trace
amounts of HF in the reaction mixture (Fig. 3).
O
F
F
F
O
HF
+
+
S
R1
Et2N SF2
OH
+
R1
O
NEt2
O
F
OH
H
HF
R2
H
R2
O
F
F
O
O
F
OH
H
H
F
HF
+
S
+
S
+
R2
O
NEt2
O
F
NEt2
R2
R1
R1
Figure 3. Possible reaction mechanism for the formation of 1-fluoroalkyl carboxylates.

3308
C. S. Rye et al. / Tetrahedron 63 (2007) 3306–3311
The initial rates for the reactions of various 1-fluoroalkyl
carboxylates with benzylamine or water to form the corre-
sponding amides or carboxylic acids are presented in Table
1. As reference points, the reactions with phenyl benzoate
(7) and methyl benzoate (12) were also monitored; note
that no reaction was observed with methyl benzoate under
the conditions employed. The alkyl 1-fluoroalkyl carboxyl-
ates (1 and 4) were more susceptible towards nucleophilic at-
tack than were their aryl counterparts (3 and 8) presumably
due to the more bulky and conjugated aryl carbonyl group
hindering nucleophilic attack. A good comparison can be
made between the alkyl compound 4 and the aryl compound
8 having the same fluorocyclopentyl moiety; in the reaction
with benzylamine, compound 4 reacted 25-fold faster than
compound 8.
to ensure a reaction rate fast enough to be reasonably mon-
itored. Unfortunately, the reactions of the most unreactive
compounds (8–12) with water were still too slow to be mea-
sured accurately. An overall reactivity range of 300-fold was
observed for the reaction of benzylamine with the 1-fluo-
roalkyl carboxylates used in this study. This reactivity range
could conceivably be expanded upon by further experimenta-
tion with other candidate molecules (different nucleophiles
and fluoroalkyl‘leaving groups’), allowing for the fine tuning
of the coupling reaction to suit a particular application.
2.3. Hydrolysis by esterase
The release of the fluoride ion when hydrolysed may allow
the 1-fluoroalkyl carboxylates to be used as a novel assay
platform for a variety of esterases and lipases. The back-
ground hydrolysis rate with water is sufficiently slow as
not to compete and interfere with the enzymatic hydrolysis.
A selection of the 1-fluoroalkyl carboxylates (4, 8, 9 and 11)
All reactions were significantly faster with benzylamine
compared with water. As a consequence, 20 equiv of water
were used compared with 3 equiv of benzylamine in order
Table 1. Initial reaction rates
Compound
Benzylamine nucleophile
Water nucleophile
Initial ratea
Relative Ratec
Initial rateb
Relative ratec
(ꢁ10ꢂ2 mM/min)
(ꢁ10ꢂ3 mM/min)
O
O
F
1
2
3
4
5
18.4
39.0
14.4
12.7
7.7
3.0
1.5
1.8
9.9
5.0
5.9
O
Ph
F
6.8
6.0
3.6
3.1
Ph
Ph
O
O
F
Ph
O
Ph
O
F
n.d.d
Ph
Ph
O
O
F
6.5
0.99
0.38
0.30
3.3
1.3
1.0
O
F
O
6
7
2.0
4.3
1.0
Ph
O
Ph
O
0.47
Ph
Ph
O
O
F
8
0.14
0.08
0.07
0.06
0.29
0.17
0.15
0.13
N/Ae
N/Ae
N/Ae
N/Ae
Ph
O
O
F
9
Ph
O
O
F
10
11
Ph
O
O
F
Ph
O
O
12
No product detected
No product detected
Ph
O
a
[Compound] was 97 mM in CH3CN, 3 equiv of benzylamine, 50 ꢀC.
b
c
d
e
[Compound] was 94 mM in CH3CN, 20 equiv of water, 2 equiv Et3N, 50 ꢀC.
Relative to phenyl benzoate (7) as 1.0.
Not determined.
Reaction was too slow to be measured accurately.

C. S. Rye et al. / Tetrahedron 63 (2007) 3306–3311
3309
O
O
A
+
EtOH
O
OH
EtOH
EtOH
t = 458 min
88 %
t = 236 min
75 %
t = 111 min
50 %
t = 47 min
28 %
0 %
t = 0 min
ppm
4.0
O
3.5
3.0
2.5
2.0
1.5
1.0
O
F
B
O
O
OH
HF
+
+
9
9
HF
42 %
t = 470 min
32 %
t = 247 min
23 %
t = 124 min
13 %
t = 60 min
0 %
t = 0 min
-95
-100
-105
-110
-115
-120
ppm
Figure 4. NMR spectra showing the hydrolysis of ethyl butyrate (A, 1H NMR) and compound 9 (B, 19F NMR) by an esterase from porcine liver. Reaction time is
given on the left and % conversion on the right. Reaction conditions: [substrate]¼7.4 mM; buffer¼7.6 mM sodium phosphate in D2O, pD¼8.0, 24% acetone;
2 units of enzyme, room temperature. 19F spectra are 1H-decoupled.
were found to be degraded by an esterase from porcine liver
(EC 3.1.1.1, Sigma E-3019). The remaining compounds
were not tested. The hydrolysis catalysed by the esterase re-
sulted in the release of the fluoride ion as evidenced by its
characteristic 19F NMR peak at ꢂ122.4 ppm; tetrabutylam-
monium fluoride gives a signal at ꢂ122.4 ppm (relative to
CCl3F). No measurable hydrolysis occurred in the absence
of enzyme over a 24 h period. The poor aqueous solubility
of the 1-fluoroalkyl carboxylates prevented complete char-
acterisation of all of the esterase-catalysed hydrolysis reac-
1
tions; however, H and 19F NMR experiments performed
on ‘cloudy’ mixtures in D2O buffer containing up to 30%
deuterated acetone confirmed the activity of this esterase
on all of the 1-fluoroalkyl carboxylates investigated. It is
conceivable that water soluble 1-fluoroalkyl carboxylates
could be synthesised to be used in an assay platform.

3310
C. S. Rye et al. / Tetrahedron 63 (2007) 3306–3311
Compound 9 was soluble in reasonable amounts in aqueous
solutions containing about 24% acetone, and its rate of hy-
drolysis by the porcine liver esterase was compared to that
of ethyl butyrate, a standard commonly used to quantify
the enzyme activity. Under the conditions used the turnover
of compound 9 by the esterase was approximately half as fast
as for ethyl butyrate. Figure 4 shows the NMR spectra for the
hydrolysis of ethyl butyrate (1H) and compound 9 (19F) by
the esterase over time. Enzyme and substrate specificity
was demonstrated by the fact that no fluoride ion release
was observed after 24 h using an esterase from Mucor miehei
with compound 9 under the same conditions used for the
porcine liver esterase, while ethyl butyrate was readily hy-
drolysed by the same enzyme.
ketone or aldehyde (3 equiv) in dichloromethane (DCM)
(only enough to ensure a homogeneous solution) as the flask
was cooled in an ice bath (note: pre-cooling of the reaction
mixture often resulted in the starting materials precipitat-
ing). Where applicable, the ketone or aldehyde was used
as the solvent of the reaction, with no DCM added. The re-
action mixture was allowed to warm to ambient temperature
upon completion of the DAST addition, and was stirred for
2–4 h. The reaction mixture was then diluted with DCM
and poured into a mixture of saturated NaHCO3(aq) and ice.
The organic layer was washed once more with NaHCO3(aq),
and the combined aqueous layers were extracted with DCM
(1ꢁ). The combined organic layers were dried over MgSO4
and concentrated. The crude material was purified by col-
umn chromatography (conditions given for each compound
below).
3. Conclusion
4.3.1. Fluoro(phenyl)methyl propionate, 1. Purified using
PE/toluene 3:1; very pale yellow oil; H NMR (300 MHz,
1
The reaction of DAST with carboxylic acids and ketones or
aldehydes provides a fast, one step method to produce
a range of 1-fluoroalkyl carboxylates. The reactivity of the
1-fluoroalkyl carboxylates towards nucleophiles can be ad-
justed by the choice of fluoroalkyl ‘leaving group’, and the
release of the fluoride ion provides a way to monitor the
reaction. 1-Fluoroalkyl carboxylates may find application
as easily prepared synthetic substrates for the assay of carb-
oxylic acid esterase or lipase activity, and as alternative
screening fragments to those used currently in click chemis-
try and dynamic combinatorial chemistry.
CDCl3) d 7.52–7.45 (2H, m, Ar), 7.44–7.39 (3H, m, Ar),
7.21 (1H, d, JCF 55.2 Hz, CHF), 2.47 (2H, q, J 7.5 Hz,
CH2), 1.20 (3H, t, J 7.5 Hz, CH3); 13C NMR (75 MHz,
CDCl3) d 172.45 (C]O), 134.74 (d, JCF 23.0 Hz, C–
CHF), 130.12 (d, JCF 1.8 Hz, CH), 128.58 (CH), 126.61
(d, JCF 5.5 Hz, CH), 101.41 (d, JCF 220.6 Hz, CHF), 27.49
(CH2), 8.62 (CH3).
4.3.2. 1-Fluoro-2-phenylethyl benzoate, 2. Purified using
PE/Et2O 20:1; pale yellow oil; 1H NMR (300 MHz,
CD3CN) d 8.03 (2H, ddd, J 8.4, 1.3, 1.3 Hz, Arortho), 7.67
(1H, tt, J 7.5, 1.3 Hz, Arpara), 7.52 (2H, ddd, J 8.4, 7.5,
1.3 Hz, Armeta), 7.40–7.23 (5H, m, Ar), 6.70 (1H, dt, JHF
55.8, JHH 5.0 Hz, CHF), 3.29 (2H, dd, JHF 17.2, JHH
5.0 Hz, CH2); 13C NMR (75 MHz, CD3CN) d 165.19
(C]O), 135.02 (CH), 134.93 (d, JCF 5.5 Hz, C), 130.90,
130.63, 129.74 (3CH), 129.74 (C), 129.43, 128.08 (2CH),
104.49 (d, JCF 223.4 Hz, CHF), 40.16 (d, JCF 23.0 Hz,
CH2); 19F NMR (282 MHz, CDCl3) d ꢂ127.49 (ddd,
J 55.8, 17.2, 16.3 Hz); IR (neat) 3064, 3033, 1736, 1260,
4. Experimental
4.1. HPLC analysis of reactions
Aliquots of the reaction mixtures were diluted with CH3CN
(2–20-fold), which were then injected (5 mL) into the HPLC.
The column used was a Phenomenex Luna 3u C18(2) 100A,
50ꢁ3.00 mm, 3 mm particle size. A linear gradient over
6 min from 20% CH3CN in water to 100% CH3CN was
used. All solvents also contained 0.1% formic acid. The
area under the corresponding product peak was measured
and the concentration of product was calculated from a
standard curve. Reaction rates were calculated based on
the initial linear portion of the concentration versus time
graphs.
998 cmꢂ1
.
4.3.3. Fluoro(phenyl)methyl benzoate, 3. Purified using
PE/toluene 2:1; very pale yellow oil; H NMR (300 MHz,
1
CDCl3) d 8.12 (2H, dd, J 8.4, 1.6 Hz, Arortho), 7.64–7.54
(3H, m, Ar), 7.50–7.43 (5H, m, Ar), 7.45 (1H, d, JHF
55.2 Hz, CHF); 13C NMR (75 MHz, CDCl3) d 164.53
(C]O), 134.81 (d, JCF 23.0 Hz, C–CHF), 133.94 (CH),
130.20 (d, JCF 1.8 Hz, CH), 130.16 (CH), 128.97 (C),
128.67, 128.57 (2CH), 126.15 (d, JCF 5.5 Hz, CH), 102.02
(d, JCF 222.4 Hz, CHF); 19F NMR (282 MHz, CDCl3)
d ꢂ122.30 (d, J 55.2 Hz); IR (neat) 3067, 3039, 1737,
4.2. General methods
All reagents were obtained from commercial suppliers and
were used without further purification. Column chromato-
graphy was performed with silica gel (230–400 mesh).
TLC was performed on Merck pre-coated 60 F254 silica
plates. CH2Cl2 was distilled over CaH2. The abbreviation
1257, 983, 708 cmꢂ1
.
4.3.4. 1-Fluorocyclopentyl 2-phenylacetate, 4. Purified
using PE/toluene 1:1/1:2; pale yellow oil; 1H NMR
(300 MHz, CDCl3) d 7.35–7.23 (5H, m, Ar), 3.62 (2H, s,
CH2), 2.40–2.20 (2H, m), 2.10–1.90 (2H, m), 1.80–1.60
(4H, m); 13C NMR (75 MHz, CDCl3) d 169.01 (C]O),
133.39 (C), 129.20, 128.55, 127.14 (3CH), 123.31 (d, JCF
235.3 Hz, CF), 41.62 (Ar–CH2), 36.82 (d, JCF 24.8 Hz,
CH2), 22.92 (CH2); 19F NMR (282 MHz, CDCl3)
d ꢂ99.74 (m); IR (neat) 3064, 3031, 2966, 2880, 1757,
1
‘PE’ refers to petroleum ether (bp 40–60 ꢀC). H and 13C
NMR spectra are referenced to TMS. 19F NMR spectra are
referenced to CCl3F.
4.3. General procedure
(Diethylamino)sulfur trifluoride (DAST) (2 equiv) was
added dropwise to a solution of the acid (1 equiv), and the
1340, 1126, 978, 771, 690 cmꢂ1
.

C. S. Rye et al. / Tetrahedron 63 (2007) 3306–3311
3311
4.3.5. (E)-1-Fluorobut-2-enyl benzoate, 5. Purified using
PE/toluene 2:1; very pale yellow oil; H NMR (300 MHz,
4.3.10. 2-Fluorobutan-2-yl benzoate, 11. Purified using
PE/toluene 2:1; pale yellow oil; 1H NMR (300 MHz,
CDCl3) d 8.02 (2H, ddd, J 8.4, 1.3, 1.3 Hz, Arortho), 7.56
(1H, tt, J 7.5, 1.3 Hz, Arpara), 7.43 (2H, ddd, J 8.4, 7.5,
1.3 Hz, Armeta), 2.19 (2H, dq, JHH 7.5, JHF 2.9 Hz, CH2),
1.86 (3H, d, JHF¼19.3 Hz, CF–CH3), 1.03 (3H, t, J 7.5 Hz,
CH2–CH3); 13C NMR (75 MHz, CDCl3) d 163.60 (d, JCF
3.7 Hz, C]O), 133.17 (CH), 130.29 (C), 129.66, 128.34
(2CH), 117.28 (d, JCF 225.2 Hz, CF), 31.98 (d, JCF
24.8 Hz), 23.02 (d, JCF 25.7 Hz), 7.22 (d, JCF 4.6 Hz); 19F
NMR (282 MHz, CDCl3) d ꢂ104.77 (m); IR (neat) 3064,
1
CDCl3) d 8.08 (2H, ddd, J 8.4, 1.4, 1.4 Hz, Arortho), 7.59
(1H, tt, J 7.3, 1.4 Hz, Arpara), 7.45 (2H, ddd, J 8.4, 7.3,
1.4 Hz, Armeta), 6.83 (1H, m, JHF 55.0 Hz, OCHF), 6.14
(1H, dddq, J 15.7, 6.7, 3.9, 0.9 Hz, CHCH3), 5.77 (1H,
dddq, J 15.7, 7.8, 6.2, 1.7 Hz, CHF–CH]), 1.81 (3H,
dddd, J 6.7, 4.5, 1.7, 0.4 Hz, CH3); 13C NMR (75 MHz,
CDCl3) d 164.39 (C]O), 134.26 (d, JCF 10.3 Hz, ]CH),
133.72, 130.01 (2CH), 128.93 (C), 128.47 (CH), 124.52
(d, JCF 24.1 Hz, ]CH), 102.38 (d, JCF 216.1 Hz, CH),
17.54 (CH3); 19F NMR (282 MHz, CDCl3) d ꢂ121.36 (m);
IR (neat) 3064, 2974, 2921, 1736, 1678, 1247, 958,
2981, 2946, 2887, 1735, 1268, 1090, 888, 706 cmꢂ1
.
708 cmꢂ1
.
Supplementary data
4.3.6. 2-Fluoro-4-phenylbut-3-yn-2-yl benzoate, 6. Puri-
fied using PE/toluene 2:1; pale yellow oil; 1H NMR
(300 MHz, CDCl3) d 8.07 (2H, dd, J 8.4, 1.4 Hz, Ar), 7.59
(1H, tt, J 7.5, 1.4 Hz, Ar), 7.51–7.42 (4H, m, Ar), 7.36–
7.26 (3H, m, Ar), 2.13 (3H, d, JHF 17.8 Hz, CH3); 13C
NMR (75 MHz, CDCl3) d 162.78 (C]O), 133.57, 132.06,
129.98, 129.45, 129.36, 128.46, 128.28, 120.94, 103.96 (d,
JCF 217.8 Hz, CF), 86.72 (d, JCF 7.4 Hz, ^C–Ph), 83.39
(d, JCF 39.5 Hz, C^C–Ph), 28.08 (d, JCF 27.6 Hz, CH3);
19F NMR (282 MHz, CDCl3) d ꢂ89.59 (q, J 17.8 Hz); IR
1H and 13C NMR spectra of compounds 1–6 and 8–11 are
available as supplementary data. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2007.02.059.
References and notes
(neat) 3064, 3006, 2253, 2227, 1739, 1264, 898, 711 cmꢂ1
;
1. Rideout, D. Science 1986, 233, 561–563.
2. Nguyen, R.; Huc, I. Angew. Chem., Int. Ed. 2001, 40, 1774–
1776.
HRMS (ESI): M+Na+, found 291.0795. C17H13O2FNa
requires 291.0797.
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4.3.7. 1-Fluorocyclopentyl benzoate, 8. Purified using PE/
toluene 1.3:1; pale yellow oil; 1H NMR (300 MHz, CDCl3)
d 8.03 (2H, ddd, J 8.5, 1.4, 1.4 Hz, Arortho), 7.56 (1H, tt,
J 7.4, 1.4 Hz, Arpara), 7.43 (2H, ddd, J 8.5, 7.4, 1.4 Hz,
Armeta), 2.54–2.35 (2H, m), 2.28–2.10 (2H, m), 1.86–1.70
(4H, m); 13C NMR (75 MHz, CDCl3) d 163.98 (C]O),
133.30 (CH), 129.97 (C), 129.80, 128.36 (2CH), 123.56
(d, JCF 236.2 Hz, CF), 37.04 (d, JCF 25.7 Hz, CH2), 23.10
(CH2); 19F NMR (282 MHz, CDCl3) d ꢂ99.36 (m); IR
(neat) 3064, 2973, 2946, 2877, 1732, 1275, 1173, 1100,
715 cmꢂ1
.
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Perkin Trans. 1 1988, 1149–1153.
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4.3.8. 2-Fluoropropan-2-yl benzoate, 9.17 Purified using
PE/toluene 6:5; very pale yellow oil; H NMR (300 MHz,
1
CDCl3) d 8.02 (2H, ddd, J 8.5, 1.4, 1.4 Hz, Arortho), 7.56
(1H, tt, J 7.4, 1.4 Hz, Arpara), 7.43 (2H, ddd, J 8.4, 7.4,
1.4 Hz, Armeta), 1.87 (6H, d, JHF 19.2 Hz, 2CH3); 13C
NMR (75 MHz, CDCl3) d 163.64 (d, JCF 3.7 Hz, C]O),
133.16 (CH), 130.29 (C), 129.65, 128.29 (2CH), 115.57
(d, JCF 221.5 Hz, CF), 25.37 (d, JCF 26.6 Hz); 19F NMR
(282 MHz, CDCl3) d ꢂ95.76 (sep, J 19.2 Hz); IR (neat)
3065, 3000, 2948, 1736, 1278, 1154, 1089, 870, 706 cmꢂ1
.
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4.3.9. 1-Fluorocyclohexyl benzoate, 10. Purified using PE/
toluene 1.3:1; pale yellow oil; 1H NMR (300 MHz, CDCl3)
d 8.02 (2H, ddd, J 8.5, 1.4, 1.4 Hz, Arortho), 7.56 (1H, tt,
J 7.4, 1.4 Hz, Arpara), 7.43 (2H, ddd, J 8.5, 7.4, 1.4 Hz,
Armeta), 2.35–2.06 (4H, m), 1.80–1.40 (6H, m); 13C NMR
(75 MHz, CDCl3) d 163.58 (C]O), 133.15 (CH), 130.45
(C), 129.69, 128.32 (2CH), 115.83 (d, JCF 232.6 Hz, CF),
34.17 (d, JCF 23.0 Hz, CH2), 24.59 (CH2), 22.87 (d, JCF
4.6 Hz, CH2); IR (neat) 3063, 2940, 2866, 1734, 1238,
1064, 933, 706 cmꢂ1; HRMS (ESI): M+Na+, found
245.0954. C13H15O2FNa requires 245.0954.
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