Mono and difluorination of centers α to sulfonates and phosphonates using AcOF

Article abstract of DOI:10.1016/j.jfluchem.2013.01.003

Acetyl hypofluorite, made easily from diluted fluorine and AcONa is very efficient in fluorinating anionic centers. Compounds containing the moieties CH₂SO₂ or COCH₂PO react with bases to create the corresponding anions wh

Full text of DOI:10.1016/j.jfluchem.2013.01.003

Journal of Fluorine Chemistry 146 (2013) 66–69
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Mono and difluorination of centers
a to sulfonates and phosphonates using AcOF
*
Inna Vints, Julia Gatenyo, Shlomo Rozen
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel
A R T I C L E I N F O
A B S T R A C T
Article history:
Acetyl hypofluorite, made easily from diluted fluorine and AcONa is very efficient in fluorinating anionic
centers. Compounds containing the moieties –CH2SO2– or –COCH2PO– react with bases to create the
corresponding anions which can react with AcOF to produce derivatives containing either the –CHFSO2–
or –COCHFPO– groups. Larger excess of base and AcOF result in the difluoro compounds containing the –
CF2SO2– or –COCF2PO– sub-structures. The fluorinations proceed fast and smoothly and usually with
very good yield even when the base is dissolved in aqueous solution as is the case with K2CO3 or NaHCO3.
ß 2013 Elsevier B.V. All rights reserved.
Received 21 September 2012
Received in revised form 1 January 2013
Accepted 2 January 2013
Available online 11 January 2013
Keywords:
F2
AcOF
Fluorosulfonate
Difluorosulfonate
Fluoroketophosphonate
Difluoroketophosphonate
1. Introduction
as the family of a-fluoro carbonyls. Many materials of this type
have potentially interesting biological activities [13].
There is a growing interest in developing new methodologies
for the introduction of fluorine containing groups such as CF2 [1]
and CF2H [2], into organic compounds due to their usefulness in
material science, pharmaceuticals, and agrochemical industries
[3].
These compounds usually have unique physical, chemical, and
biological properties that are highly important in many fields
including drug development since introducing fluorine atom into a
bioactive molecule can significantly enhance its chance to become
a drug candidate and eventually a drug [4,5].
Mono- and di-fluoro(phenylsulfonyl)methane derivatives
could be useful for the synthesis of functionalized mono and
difluoromethylated compounds, which could undergo various
transformations such as Michael addition, nucleophilic fluoroalk-
ylation of epoxides and more [14]. Another advantage of these
derivatives is the fact that the phenylsulfonyl moiety can be easily
removed to produce fluoromethyl-substituted compounds [15].
Since many of the most important biochemicals are organopho-
sphates, found in DNA and RNA as well as in many cofactors that
are essential to life, the organophosphorus chemistry has been
The diflouoromethyl group can act, among other roles, as a
lipophilic isostere of the hydroxyl group as well as hydrogen donor
for hydrogen bonding [6]. This group has been also used in sugar
chemistry as well [7], and plays an important role in the field of
herbicides [8], liquid crystals [9], and is essential part of modern
anesthetics such as desflurane and isoflurane [10].
Monofluorinated compounds could be obtained either by direct
action of fluorine on a substrate [11], or by numerous nucleophilic
substitutions. Those analogs which happen to be biologically active
are very important class of drug candidates, and are considered to
be promising bioisosteres of the respective parent molecules
[7,12]. An important sub-group consists of compounds having
rapidly developing recently [16]. In particular,
a-mono-haloge-
nated and -dihalogenated phosphonates have been designed as
a,a
phosphate mimics used as metabolite probes, anticancer drugs,
antidiabetes, and enzyme inhibitors due to their structural and
electronic similarities to the parent phosphate groups [17].
Obviously
difluoromethyl phosphonates have also been synthesized [18].
Successful attempts to prepare fluoro(phenylsulfonyl)methane
and -fluoro- -ketophosphonates compounds by using Select-
a variety of successful inhibitors including a,a-
a
b
fluor or other NF reagents have been described [14a,19]. Some of
these fluorinating agents are commercially available and therefore
quite popular for laboratory work. Nevertheless, they are prepared
from elemental fluorine, are relatively weak electrophiles requir-
ing usually non hydrated anionic centers, quite expensive and
carry a large amine residue, which eventually is wasted. Acetyl
hypofluorite – AcOF is also prepared by F2 [20], but uses much
cheaper and more readily available starting material – sodium
acetate. Its reactions are usually very fast, a few minutes at room
fluorine atom
a to some oxygen containing functional group such
* Corresponding author. Tel.: +972 3 6408378; fax: +972 3 6409293.
E-mail address: rozens@post.tau.ac.il (S. Rozen).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.003

I. Vints et al. / Journal of Fluorine Chemistry 146 (2013) 66–69
67
Table 1
1: Base
Fluorination of (phenylsulfonyl)methane derivatives with AcOF. Ph ꢀ SO2 ꢀ CH2 ꢀ X1 ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ! Ph ꢀ SO2 ꢀ CHF ꢀ X2 or Ph ꢀ SO2 ꢀ CF2 ꢀ X3.
2: AcOF; Fewmin; R:T:
Entry
X
Base (eq.)
Solvent
AcOF (eq.)
Product
Yield (%)a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1e
COPh
COPh
COPh
COMe
COMe
NO2
K2CO3 (1)
MeOH/H2O
MeOH/H2O
t-BuOH
1
3
3
1
3
1
3
3
3
3
3
3
2a
3a
3a
2b
3b
2c
3c
2d
3d
2e
2e
3e
90
70
K2CO3 (4)
t-BuOK (3)
K2CO3 (1)
100
90
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
t-BuOH
K2CO3 (4)
90
NaHCO3 (0.5)
K2CO3 (1)
70
NO2
100
85
CN
t-BuOK (0.5)
K2CO3 (5)
CN
MeOH/H2O
MeOH/H2O
t-BuOH
75
SO2Ph
SO2Ph
SO2Ph
K2CO3 (1.5)
t-BuOK (0.7)
t-BuOK (7)
70
80
t-BuOH
90
a
Isolated yields.
temperature, and usually the yields are very good. These are some
of the reasons why at the time AcOF was the reagent which gave
the positron emitting tomography (PET) a new life by enabling
efficient synthesis of the [18]F fluorodeoxyglucose (18FDG) and is
still used for introducing the [18]F nuclide into organic molecules
when no alternative to electrophilic fluorination is available [21].
In the past we have used acetyl hypofluorite for quite a
few processes such as aromatic fluorinations [22], reactions
such as NaHCO3 is sufficient. Thus, treating nitromethyl phenyl
sulfone (1c) with 0.5 mol eq. of NaHCO3 followed by 1 mol eq. of
AcOF led to the formation of (fluoro(nitro)methylsulfonyl)benzene
(2c)[14a] in 70% yield. It was enough to use 1 mol eq. of the
stronger base K2CO3 followed by 3 mol eq. of AcOF to form
quantitatively the difluorinated product – (difluoro(nitro)methyl-
sulfonyl)benzene (3c).
Acidity of (phenylsulfonyl)acetonitrile (1d) is similar to 1a and
is lower than 1c. The best results in this case were obtained when
using 0.5 mol eq. of t-BuOK and 3 mol eq. of AcOF to form 2-fluoro-
2-(phenylsulfonyl)ethane nitrile (2d) [14a] in 85% yield. By adding
5 mol eq. of K2CO3 and 3 mol eq. of AcOF the difluorinated 2,2-
difluoro-2-(phenylsulfonyl)ethane nitrile (3d) was obtained in 75%
yield.
with enolates resulting in
and activation of the position of pyridine derivatives [24].
We present here a general method for introducing one or
a-fluoro carbonyl derivatives [23],
a
two fluorine atoms
by using AcOF.
a – to a sulfonate or a phosphonate moiety
Successful mono fluorination was also achieved with
bis(phenylsulfonyl)methane (1e) by using 1.5 mol eq. of
K2CO3 followed by 3 mol eq. of AcOF. The product formed in
70% yield was identified as 1-fluoro-1,1-bis(phenylsulfonyl)-
methane (2e) [25]. The yield could be increased to 80% when
t-BuOK was used as the base. When large excess of t-BuOK
(7 mol eq.) was employed the difluorinated product 1,1-
difluoro-1,1-bis(phenylsulfonyl)methane (3e) [26] was obtained
in 90% yield. The results and conditions are summarized in
Table 1.
2. Results and discussion
A series of
a
-mono- and
a,a-difluoro-sulfones, and a-mono-,
and -difluoro-b
a
,
a
-ketophosphonates, were synthesized in good
yields via electrophilic fluorination using AcOF. Unlike most other
electrophilic processes the present reaction offers the option of
using aqueous solutions whenever appropriate without affecting
the final outcome.
Thus, an aqueous methanol solution of 1-phenyl-2-(phenyl-
sulfonyl)ethanone (1a) containing 0.7 mol eq. K2CO3 was treated
with 1 mol eq. of AcOF to give 2-fluoro-1-phenyl-2-(phenylsul-
fonyl)ethanone (2a) [25] in 90% yield. To obtain the difluoro
derivative the concentration of the basic aqueous solution was
increased to 4 mol eq. and an excess of AcOF was used. The 2,2-
difluoro-1-phenyl-2-(phenylsulfonyl)ethanone (3a) [25] was
formed in 70% yield. If the yield of 3a is important the aqueous
conditions have to be abandoned and t-BuOK in t-BuOH has to
be used. Such change brings the yield of 3a to practically 100%.
Similarly, when phenylsulfonylacetone (1b) was treated with
1 mol eq. of K2CO3 followed by 1 mol eq. of AcOF, 1-fluoro-1-
(phenylsulfonyl)propan-2-one (2b) [14a] was generated in 90%
yield. Using 4-fold excess of K2CO3 led to the difluorinated product
– 1,1-difluoro-1-(phenylsulfonyl)propane-2-one (3b) [25] in 90%
yield.
With
b-ketophosphonates, K2CO3 was not strong enough base
to deprotonate the substrate so we had to replace it with t-BuOK to
generate the desired products. Thus, when diethyl 2-oxo-2-
phenylethylphosphonate (4a) was treated with 0.5 mol eq. of t-
BuOK and 1 mol eq. of AcOF, 5a [19] was produced in 65% yield.
Reacting 4a and dimethyl 2-oxopropylphosphonate (4b) with
3 mol eq. of t-BuOK followed by excess of AcOF produced the
difluorinated products 6a [19] and 6b [27] in quantitative yields
(Table 2).
In conclusion, it has been shown that among its many versatile
reactions AcOF can be also useful as a fluorinating agent not only
a
to carbonyls, but also to other electron withdrawing groups.
a
Whenever an anion can be formed, even in aqueous solutions, the
reaction proceeds well and usually with very good yields. Since the
reactions with the acetyl hypofluorite are very fast the reaction is
also very suitable for PET studies.
Since protons alpha to nitro compounds have higher acidity
than those neighboring the carbonyl moiety, using weaker base
Table 2
1: Base
Fluorination of
b
-ketophosphonates with AcOF. R ꢀ CO ꢀ CH2 ꢀ PO ðXÞ2 ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ! R ꢀ CO ꢀ CHF ꢀ PO ðXÞ2 or R ꢀ CO ꢀ CF2 ꢀ PO ðXÞ2
.
6
4
5
2: AcOF; Few min; R:T:
Entry
R
X
Base (eq.)
Solvent
AcOF (eq.)
Product
Yield (%)a
4a
4a
4b
Ph
Ph
Me
OEt
t-BuOK (0.5)
t-BuOK (3)
t-BuOK (3)
t-BuOH
t-BuOH
t-BuOH
1
5a
6a
6b
65
100
100
OEt
3.5
3
OMe
a
Isolated yields.

68
I. Vints et al. / Journal of Fluorine Chemistry 146 (2013) 66–69
3. Experimental
described above, using 1 mol eq. of K2CO3 and 1 eq. of the AcOF
solution. A colorless liquid (0.43 g, 90% yield) was obtained.
1,1-Difluoro-1-(phenylsulfonyl)propan-2-one (3b) [25] was
prepared from phenylsulfonylacetone (1b) (0.20 g, 1.0 mmol) as
described above, using 4 mol eq. of K2CO3 and 3 mol eq. of the
AcOF solution. A colorless liquid (0.21 g, 90% yield) was obtained.
(Fluoro(nitro)methylsulfonyl)benzene (2c) [14] was prepared
from nitro methyl phenyl sulfone (1c) (0.10 g, 0.47 mmol) as
described above, using 0.5 mol eq. of NaHCO3 and 1 mol eq. of the
AcOF solution. A colorless liquid (0.07 g, 70% yield) was obtained.
(Difluoro(nitro)methylsulfonyl)benzene (3c) was prepared
from nitro methyl phenyl sulfone (1c) (0.63 g, 3.13 mmol) as
described above, using 1 mol eq. of K2CO3 and 3 mol eq. of the
AcOF solution. A colorless liquid (0.74 g, 100% yield) was obtained:
1H NMR spectra were recorded using a 400 MHz spectrometer
with CDCl3 as a solvent and Me4Si as an internal standard. The 19
F
NMR spectra were measured at 188.1 and 376.8 MHz with CFCl3,
serving as an internal standard. The proton broadband decoupled
13C NMR spectra were recorded at either 50.2 MHz or at
100.5 MHz. Here too, CDCl3 served as a solvent and Me4Si as an
internal standard. Known compounds described in this paper, have
the same spectral properties and mps (for the solids) as the ones
reported in the literature.
3.1. General fluorination procedure
1H NMR:
m). 13C NMR:
19F NMR:
d
7.71–7.75 (2H, m), 7.90–7.94 (1H, m), 8.03–8.05 (2H,
137.6, 131.3, 130.4, 130.3, 118.8 (t, JC–F = 332.5 Hz).
ꢀ92.0 (s). Anal. calculated for C7H5F2NO4S: C, 35.45; H,
Fluorine is a strong oxidant and corrosive material. In organic
chemistry, it is mostly used after dilution with nitrogen or helium.
Such dilution can be achieved by using either an appropriate
copper or monel vacuum line constructed in a well-ventilated area
or simply purchasing prediluted fluorine. A detailed description of
a simple setup had appeared in the past [28]. The reactions
themselves can be carried out in regular glassware. If elementary
precautions are taken, work with F2 is simple and we have had no
bad experience working with it.
d
d
2.12; F, 16.02. Found: C, 35.55; H, 1.93; F, 15.56.
2-Fluoro-2-(phenylsulfonyl)ethane nitrile (2d) [14] was
prepared from (phenylsulfonyl)acetonitrile (1d) (0.56 g,
3.08 mmol) as described above, using 0.5 mol eq. of t-BuOK and
3 mol eq. of the AcOF solution. A colorless liquid (0.52 g, 85% yield)
was obtained.
2,2-Difluoro-2-(phenylsulfonyl)ethane nitrile (3d) was pre-
pared from (phenylsulfonyl)acetonitrile (1d) (0.76 g, 4.22 mmol)
as described above, using 5 mol eq. of K2CO3 and 3 mol eq. of the
AcOF solution. A colorless liquid (0.69 g, 75% yield) was obtained:
3.2. Preparation of AcOF and its reaction with
and (phenylsulfonyl)methane derivatives
b-ketophosphonates
1H NMR:
J = 8.0 Hz). 13C NMR:
F = 287.4 Hz). 19F NMR:
C8H5F2NO2S: C, 44.24; H, 2.32; S, 14.76; N, 6.45; F, 17.49. Found:
C, 43.87; H, 2.24; S, 14.11; N, 6.17; F, 17.61.
1-Fluoro-1,1-bis(phenylsulfonyl)methane (2e) [25] was pre-
pared from bis(phenylsulfonyl)methane (1e) (0.36 g, 1.2 mmol) as
described above, using 0.7 mol eq. of t-BuOK and 3 eq. of the AcOF
solution. A white solid, mp 109 8C, (0.31 g, 80% yield) was obtained.
Difluorobis(phenylsulfonyl)methane (3e) [26] was prepared
from bis(phenylsulfonyl)methane (1e) (0.27 g, 0.93 mmol) as de-
scribed above, using 7 mol eq. of t-BuOK and 3 mol eq. of the AcOF
solution. A white solid, mp 119 8C, (0.28 g, 90% yield) was obtained.
Diethyl 1-fluoro-2-oxo-2-phenylethylphosphonate (5a) [19]
was prepared from diethyl 2-oxo-2-phenylethylphosphonate (4a)
(0.45 g, 1.8 mmol) as described above, using 0.5 mol eq. of t-BuOK
and 1 mol eq. of the AcOF solution. A colorless liquid (0.32 g, 65%
yield) was obtained.
Diethyl 1,1-difluoro-2-oxo-2-phenylethylphosphonate (6a)
[19] was prepared from diethyl 2-oxo-2-phenylethylphosphonate
(4a) (0.36 g, 1.4 mmol) as described above, using 3.5 mol eq. of t-
BuOK and 3 mol eq. of the AcOF solution. A colorless liquid (0.41 g,
100% yield) was obtained.
Dimethyl 1,1-difluoro-2-oxopropylphosphonate (6b) [27]
was prepared from dimethyl 2-oxopropylphosphonate (4b)
(1.14 g, 6.9 mmol) as described above, using 3 mol eq. of t-BuOK
and 3 mol eq. of the AcOF solution. A colorless liquid (1.39 g, 100%
yield) was obtained.
d
7.73 (2H, t, J = 8.0 Hz), 7.91 (1H, t, J = 7.5 Hz), 8.06 (2H, d,
137.5, 131.6, 130.3, 129.8, 108.6 (t, JC–
A mixture of 10–15% F2 in N2 was bubbled into a cold (ꢀ30 8C)
suspension of 2 g of AcONaꢁAcOH dispersed in 100 mL of CH3CN
and 10 mL of AcOH all placed in a standard glass vessel. The
solvated salt could be made by leaving anhydrous AcONa over
AcOH in a closed desiccator for at least 24 h. It is quite important to
have a good stirring since the reaction is between the gas phase and
a solid one. The amount of the AcOF thus obtained could be easily
determined by reacting aliquots of the reaction mixture with
aqueous KI solution and titrating the liberated iodine. Typical
concentration are around 0.25 M.
d
d
ꢀ98.1 (s). Anal. calculated for
The substrates were first treated with
a base at room
temperature, and after 0.5 h AcOF was added in one portion.
When deprotonation could be achieved with K2CO3 or NaHCO3
water/methanol mixture was used as a solvent. When conditions
were modified to accommodate t-BuOK for a base, the solvent of
choice was t-butanol. The reactions were carried out on scales of 1–
10 mmol using 1–3 fold excess of AcOF. They were usually
monitored by TLC or NMR and in most cases were completed
within a few minutes. The reaction was terminated by pouring it
into NaHCO3 solution followed by water until neutral. In the case of
mono fluorination just water was added, drying the organic layer
over MgSO4 and evaporation of the solvent. The crude product was
purified by vacuum flash chromatography (Merck silica gel 60H)
with petroleum ether/dichloromethane serving as eluent. Most of
the products are known and referenced. Their physical properties
matched the ones appearing in the literature. All new compounds
were fully characterized.
2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethanone (2a) [25]
was prepared from 2-(phenylsulfonyl)acetophenone (1a) (0.53 g,
2.0 mmol) as described above, using 1 mol eq. of K2CO3 and
1 mol eq. of AcOF solution. A white solid, mp 95 8C, (0.50 g, 90%
yield) was obtained.
2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethanone (3a) [25]
was prepared from 2-(phenylsulfonyl)acetophenone (1a) (0.56 g,
2.2 mmol) as described above, using 3 mol eq. of t-BuOK and 3 eq.
of the AcOF solution. A white solid, mp 80 8C, (0.64 g, 100% yield)
was obtained.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
01.003.
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