Use of fluoroform as a source of difluorocarbene in the synthesis of N-CF2H heterocycles and difluoromethoxypyridines

Article abstract of DOI:10.1016/j.jfluchem.2014.08.015

Fluoroform is used as a source of difluorocarbene to convert various N-, O-, and C-nucleophiles to their difluoromethylated derivatives. Imidazole, benzimidazole, benztriazole, hydroxypyridines, and their derivatives underwent reaction at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/acetonitrile) process to provide moderate to good yields of the respective products. Nitrophenols required addition of a co-solvent (methanol) to obtain good yields of products.

Full text of DOI:10.1016/j.jfluchem.2014.08.015

Journal of Fluorine Chemistry 168 (2014) 34–39
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Use of fluoroform as a source of difluorocarbene in the synthesis
of N-CF2H heterocycles and difluoromethoxypyridines
Charles S. Thomoson a, Linhua Wang b, William R. Dolbier a,
*
a Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, United States
b Syngenta, 410 Swing Road, Greensboro, NC 27409, United States
A R T I C L E I N F O
A B S T R A C T
Article history:
Fluoroform is used as a source of difluorocarbene to convert various N-, O-, and C-nucleophiles to their
difluoromethylated derivatives. Imidazole, benzimidazole, benztriazole, hydroxypyridines, and their
derivatives underwent reaction at moderate temperatures and atmospheric pressure, using potassium
hydroxide as base in a two-phase (water/acetonitrile) process to provide moderate to good yields of the
respective products. Nitrophenols required addition of a co-solvent (methanol) to obtain good yields of
products.
Received 30 July 2014
Received in revised form 16 August 2014
Accepted 22 August 2014
Available online 30 August 2014
Keywords:
ß 2014 Elsevier B.V. All rights reserved.
Fluoroform
Difluoromethylation
Difluorocarbene
Difluoromethoxy group
1. Introduction
basic conditions in the presence of a proton donor, with the best
early method using chlorodifluoromethane (F22) as the difluor-
Naturally occurring fluorinated molecules are rare, and therefore
virtually all fluorinated molecules are of synthetic origin. Interest in
the development of new methods for incorporating fluorine into
molecules is at an all-time high, because of the well-known effect
fluorine can have on a molecule’s physical, chemical, or biological
properties [1,2]. The difluoromethyl group holds particular interest
within pharmaceutical and agrochemical product development. The
introduction of a CF2H group can affect membrane permeability,
bioavailability, binding affinity, and lipophilicity [3]. Therefore, the
difluoromethyl moiety has, for example, been incorporated into
pharmaceuticals such as Pantoprazole [4], Sulfentrazone [5] and
Neuropeptide Y antagonist [6] (Fig. 1). Heterocycles such as
imidazoles, benzimidazoles, and pyridines, play important roles in
biological processes [7]. Likewise, many pharmaceuticals mimic the
biologically active natural products, which contain heterocycles
[7]. Therefore discovery of new methods for incorporation of the
CF2H group into such molecules is a worthy goal.
ocarbene precursor [8]. Because CHF2Cl is a recognized ozone-
depleter, this reaction has fallen out of favor. In recent reports,
Greaney and co-workers used sodium chlorodifluoroacetate to
difluoromethylate N-nucleophiles in DMF at 95 8C (Scheme 1) [9],
and Prakash and co-workers reported a one-step method of
difluoromethylating imidazoles and benzimidazoles under neutral
conditions in triglyme using TMSCF3 as the difluorocarbene source
(Scheme 1) [10]. Alternative, related methodologies involve the use
of sodium trifluoroacetate [11], methyl chlorodifluoroacetate [12],
chlorodifluoromethylphenyl sulfone [13], N-tosyl-S-difluoromethyl-
S-phenylsulfoximine [14], and TMSCF2Br [15,16].
In the last couple of years, fluoroform has received considerable
attention, with a number of important papers appearing from the
groups of Grushin, Parkash and Shibata reporting that one could
conveniently utilize fluoroform in a great variety of nucleophilic
trifluoromethylation reactions [17–20]. At about the same time
that these papers were appearing, we reported the use of
There are a number of methods for preparation of 1-difluor-
omethylimidazoles and benzimidazoles. Most of these methodolo-
gies involve the use of a difluorocarbene-generating reaction, under
fluoroform as a source of difluorocarbene for the efficient
preparation of aryl difluoromethyl ethers and thioethers from
their respective phenols and thiophenols (Scheme 2) [21]. This
reaction proceeds at atmospheric pressure, in a two-phase process,
using KOH as base, conditions that were reminiscent of the popular
earlier process that used CHF2Cl as the difluorocarbene source. An
advantage of this difluoromethylation reaction is the fact that aryl
*
Corresponding author. Tel.: +1 352 392 0591.
E-mail address: wrd@chem.ufl.edu (W.R. Dolbier).
http://dx.doi.org/10.1016/j.jfluchem.2014.08.015
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

C.S. Thomoson et al. / Journal of Fluorine Chemistry 168 (2014) 34–39
35
Scheme 3. Difluoromethylation results for imidazoles and benzimidazoles.
Fig. 1. Pharmaceuticals containing the CF2H moiety.
unstable at room temperature. Benzimidazoles gave generally
better yields. Due to lack of symmetry, difluoromethyl products
(1f, 1g), substituted at the 5-position, were a 1:1 mixture of
regioisomers that could not be separated. Benzotriazole provided a
good yield of product 1h, which contained only a minor amount of
its 2-substituted regioisomer, whereas 3-chloroindazole gave a
high yield of its regioisomeric 1- and 2-substituted products in a
2:1 ratio. Pure benztriazole product, 1h, could be isolated by
simple recrystallization from hexanes, but 1i-a and 1i-b could not
be readily separated by either recrystallization or column
chromatography.
2.2. Nitrophenol substrates
Scheme 1. Greaney’s and Prakash’s processes.
Since the addition of a co-solvent improved the solubility of
2-nitroimidazole, a variety of co-solvents were screened with
4-nitrophenols. The addition of methanol (ꢀ10% by volume)
improved the solubility of 4-nitrophenols the most and under
these conditions 1-(difluoromethoxy)-4-nitrobenzene (2a) could
be prepared in 83% yield, which compares with the 20% yield that
was obtained without cosolvent (Scheme 4). Therefore, these
conditions, using methanol as cosolvent, were used to examine
other nitrophenols (Table 2). When solubility issues did not
continue to be an issue, the yields of difluoromethoxy, nitro
benzenes were generally very good. In the cases of 2b and 2d,
solubility issues unfortunately remained.
difluoromethyl ethers and thioethers could be obtained at room
temperature, with a commercially available and inexpensive
source of difluorocarbene.
However, there were limitations to this process, as noted in
the initial publication. The reaction did not perform well when
3-hydroxypyridine or nitrophenols were used as substrates.
Therefore, we would like to report a modification of this
methodology that now allows inclusion of these more difficult
substrates, as well as an extension of the work to include
N-difluoromethylation of heterocycles and limited use with
carbon nucleophiles.
2.3. Pyridone/hydroxypyridine substrates
2. Results and discussion
As previously mentioned, under standard conditions, 3-hydro-
xypyridine was somewhat unreactive (Scheme 5). Under these
initial conditions, many byproducts were observed on 19F NMR.
Although not certain, a doublet that was observed at À98 ppm
might correspond to the product of difluoromethylation of the
nitrogen on the pyridine ring to form a pyridinium salt. In an
attempt to increase yields and limit byproduct production, a
variety of substrates were tested with substituents at the 2-, 5-,
and 6-positions (Table 3). Best yields were obtained with
hydroxypyridines bearing halogen substituents (3b–3g). 2-Meth-
yl-3-hydroxypyridine and 5-methyl-2-hydroxypyridine were less
reactive and produced yields comparable to 3-hydroxypyridine. No
reaction was observed with 2-nitro-3-hydroxypyridine, probably
due to poor solubility under these conditions. The addition of
methanol unfortunately did not affect the reactivity or solubility of
this substrate.
2.1. Imidazole, benzimidazole, benztriazole and indazole substrates
When the standard conditions of method B from our previous
work (using acetonitrile as solvent) were used with imidazole as
substrate, the expected N-CF2H product, 1-difluoromethyl-1H-
imidazole (1a) was obtained in a moderate, 50% yield (Scheme 3).
Thus, we explored the reactivity of a variety of substituted
imidazole and benzimidazole compounds under these conditions.
Overall, the behavior of substituted imidazoles in this reaction
proved satisfactory, with moderate to good yields being obtained
(Table 1).
2-Nitroimidazole was insoluble under the reaction conditions,
but with addition of methanol, its solubility increased sufficiently
to allow reaction. Compound 1c could be isolated, but proved
Scheme 2. Our initial results with fluoroform.

36
C.S. Thomoson et al. / Journal of Fluorine Chemistry 168 (2014) 34–39
Table 1
Products and yields for preparation of N-CF2H compounds.
N
N
N
N
N
N
N
N
N
N
NO2
SMe
CF2H
CF2H
CF2H
CF2H
CF2H
1a,50%
1b,(45%)
1c,(42%)
1d,(71%)
1e,(93%)
N
N
N
N
N
MeO
N
N
N
CF2H
MeO
CF2H
CF2H
1f-b
1f-a
1g-b
CF2H
1g-a
(67%)
1:1 ratio
(
66%)
1:1 ratio
Cl
Cl
N
N
N
N
N
CF2H
N
N
1i-b
CF2H
,(72%)
1i-a
CF2H
1h
(95%)
2:1 ratio
Table 2
Products and yields with nitrophenol substrates.
Table 3
Products and yields from substituted hydroxypyridines.
OCF2H
OCF2H
NO2
OCF2H
Cl
OCF2H
OCF2H
Br
Cl
N
OCF2H
O2N
O2N
N
Cl
, (51%)
N
3b,(50%)
3c
3d, (53%)
2a
2b
2c
, (69%)
, (83%)
OCF2H
, 37%
OCF2H
Cl
HF2CO
OCF2H
OCF2H
Cl
N
OCF2H
N
Cl
N
F
O2N
2f,
2d
,(40%)
NO2
2e,(85%)
NO2
3f
3g
,(65%)
, (48%)
3e, (54%)
Table 4
Product and yields from enolate, C-nucleophiles.
O
O
NC CF2H
O
O
Scheme 4. Methanol cosolvent improves nitrophenol reaction.
CF2H
4b
, 30%
4a
,51%
Scheme 5. Reaction with 3-hydroxypyridine.
3. Conclusions
The results obtained in this work have demonstrated that
fluoroform, a non-ozone-depleting, nontoxic, and inexpensive gas,
can beused asthedifluorocarbenesource ina convenient processfor
conversion of imidazoles and benzimidazoles to their difluoro-
methylated derivatives. Additionally, fluoroform can be used to
prepare difluoromethoxypyridine derivatives under similar condi-
tions. Nitrophenols are less reactive under these conditions, but the
addition of co-solvent (methanol) greatly improves yields. Overall,
these two-phase, very clean reactions, carried out at moderate
2.4. Enolate substrates
Carbon nucleophiles in the form of tertiary enolates were
also investigated (Table 4). Modest yields were obtained that
were consistent with similar results from the literature [22].

C.S. Thomoson et al. / Journal of Fluorine Chemistry 168 (2014) 34–39
37
temperatures and atmospheric pressure, provide moderate to good
4.2.5. 1-(Difluoromethyl)-5-methyl-1H-benzo[d]imidazole and 1-
yields of difluoromethylated products, which should make this
process very competitive with other methods for preparing these
important compounds.
(difluoromethyl)-6-methyl-1H-benzo[d]imidazole (1f)
1H NMR:
d 8.07 (s, 1H), 8.05 (s, 1H), 7.65–7.61 (m, 2H), 7.45 (m,
2H), 7.30 (t, 2JHF = 61 Hz, 2H), 7.22–7.10 (m, 2H), 2.50 (s, 3H), 2.48
2
(s, 3H); 19F NMR:
d
À93.7 (d, JFH = 61 Hz, 2F), À93.9 (d,
2JFH = 61 Hz, 2F); The NMR data were consistent with those
4. Experimental
previously reported [10].
4.1. General information
4.2.6. 1-(Difluoromethyl)-5-methoxy-1H-benzo[d]imidazole and 1-
The NMR spectra for 1H, 13C, and 19F were recorded in CDCl3 at
300, 75.46, and 282 MHz, respectively, with chemical shifts being
reported in parts per million downfield from the respective
internal standards (TMS for proton and carbon and CFCl3 for
fluorine spectra). HRMS data were obtained on a DSQ MS
instrument.
(difluoromethyl)-6-methoxy-1H-benzo[d]imidazole (1g)
1H NMR: 8.39 (s, 1H), 8.31 (s, 1H), 7.92 (t, 2JHF = 60, 1H), 7.91 (t,
d
2JHF = 60 Hz, 1H), 7.65–7.61 (m, 2H), 7.28 (m, 2H), 7.02–6.98 (m,
2
2H), 3.88 (s, 3H), 3.87 (s, 3H) 19F NMR:
d
À93.5 (d, JFH = 59 Hz),
2
À94.1 (d, JFH = 59 Hz). The NMR data were consistent with those
previously reported [10].
4.2. Preparation of 1-(difluoromethyl)-1H-benzo[d]imidazole (1d)
4.2.7. 1-(Difluoromethyl)-1H-benzo[d][1,2,3]triazole (1h)
Liquid: 1H NMR:
d 8.18–8.12 (m, 1H), 8.07–7.61 (m, 3H),
7.55–7.47 (m, 1H); 19F NMR:
data were consistent with those previously reported [13,23].
d
À96.4 (d, 2JFH = 59 Hz, 2F); The NMR
Using the apparatus previously described for method B [21],
potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water
(2.52 g) were added to the reaction vessel and the mixture was
allowed to stir until the potassium hydroxide was almost
completely dissolved. Then, 1H-benzimidazole (0.35 g, 3 mmol)
was added and the mixture stirred for 30 min, after which
acetonitrile (10 mL) was added via syringe and the mixture
stirred at room temperature. Fluoroform was then bubbled
slowly into the mixture for 2 h, after which the resulting mixture
was stirred for one additional hour. Analysis as described for
method B revealed that 5.6 g (26.8 equiv) of CHF3 had been
condensed in the trap, with a total of 3 g (14.6 equiv) having
been consumed in the reaction. After being quenched with water
and extracted with ethyl acetate, the ethyl acetate layer was
4.2.8. 1-(Difluormethyl)-3-chloroindazole (1i)
1H NMR
d 7.67 (m, 2H), 7.54 (t, J = 1 Hz, 1H), 7.35 (t, J = 6.3 Hz,
d
1H);19FNMR:
À94.7(d, 2JFH = 57 Hz,2F), À95.2(d, 2JFH = 57 Hz,2F).
(ESI-DART) m/z calcd for C7H4N2F2Cl 232.0579; found [M+H]+
203.0182.
4.3. Preparation of 1-(difluoromethoxy)-4-nitrobenzene (2a)
Using the apparatus previously described for method B [21],
potassium hydroxide (2.52 g, 45 mmol, 15 equiv), water (2.52 g),
and methanol (1 g) were added to the reaction vessel and the
mixture was allowed to stir until the potassium hydroxide was
almost completely dissolved. Then, 4-nitrophenol (0.52 g, 3 mmol)
was added and the mixture stirred for 30 min, after which
acetonitrile (10 mL) was added via syringe and the mixture stirred
at room temperature. Fluoroform was then bubbled slowly into the
mixture for 2 h, after which the resulting mixture was stirred for
one additional hour. After being quenched with water and
extracted with ethyl acetate, the ethyl acetate layer was washed
with a saturated solution on sodium hydroxide, separated and
concentrated. Additional impurities were removed via column
chromatography on silica gel using an 80:20 mixture of hexanes/
methylene chloride to give an 83% yield of the liquid product, 1-
washed with
a saturated solution on sodium hydroxide,
separated and concentrated, and additional impurities were
removed via column chromatography on silica gel using an 80:20
mixture of hexanes/methylene chloride to give a 71% yield of
the liquid product, 1-(difluoromethyl)-1H-benzo[d]imidazole
2
(1d): 1H NMR:
d
8.48 (s, 1H), 7.98 (t, JHF = 54, 1H), 7.79–7.75
(m, 2H), 7.43–7.38 (m, 2H); 19F NMR:
d
À95.6 (d, 2JFH = 60 Hz, 2F);
The NMR data were consistent with those previously reported
[13,23].
4.2.1. 1-(difluoromethyl)-1H-imidazole (1a)
1H NMR
d 7.81 (s, 1H), 7.20 (t, J = 1 Hz, 1H), 7.15 (s, 1H), 7.10 (t,
2JHF = 61 Hz, 1H); 19F NMR:
d
À92.5 (d, 2JFH = 61 Hz). The NMR data
(difluoromethoxy)-4-nitrobenzene (2a): 1H NMR:
d 8.28 (d,
2
J = 9 Hz, 2H), 7.26 (d, J = 9 Hz, 2H), 6.64 (t, JHF = 72 Hz, 1H); 19F
were consistent with those previously reported [13].
NMR:
d
À82.6 (d, 2JFH = 72.3 Hz, 2F). The NMR data were consistent
4.2.2. 1-(Difluoromethyl)-2-phenyl-1H-imidazole (1b)
with those previously reported [13].
Liquid; 1H NMR:
d
7.64–7.48 (m, 5H), 7.42–7.38 (m, 1H), 7.28–6.86
(m, 2H); 19F NMR:
d
À89.7 (d, 2JFH = 60 Hz, 2F); The NMR data were
4.3.1. 1-(Difluoromethoxy)-2-nitrobenzene (2b)
Liquid: 1H NMR:
d 7.98–7.91 (m, 1H), 7.68–7.59 (m, 1H), 7.44–
consistent with those previously reported [13].
2
7.36 (m, 2H), 6.63 (t, JHF = 73 Hz, 1H); 19F NMR:
d
À81.3 (d,
2JFH = 73 Hz, 2F). The NMR data were consistent with those
4.2.3. 1-(Difluoromethyl)-2-nitro-1H-imidazole (1c)
1H NMR:
d
7.35 (d, 2JHF = 60 Hz, 1H), 7.00 (d, J = 2 Hz, 1H), 6.67
previously reported [13].
2
(s, 1H); 19F NMR:
d
À95.7 (d, JFH = 59 Hz, 2F); 13C NMR:
d 128.2,
125.5, 110.6, 107.8 (t, JCF = 210 Hz). The sample decomposed upon
4.3.2. 1-(Difluoromethoxy)-2-chloro-4-nitrobenzene (2c)
1H NMR:
d 8.07 (m, 1H), 7.96 (t, J = 2 Hz, 1H), 7.56 (t, 8 Hz), 7.46
attempts to isolate.
(m, 1H), 7.33 (t, 2JHF = 73 Hz, 1H); 19F NMR:
d
À84.7 (d, 2JFH = 73 Hz,
1
2F) 13C NMR:
d 126.1, 124, 119.3, 116.1 (t, JCF = 261 Hz).
4.2.4. 1-(Difluoromethyl)-2-thiomethoxy-1H-benzo[d]imidazole (1e)
1H NMR:
d
7.79 (t, 2JHF = 59 Hz, 1H), 7.63 (m, 2H), 7.32 (m, 2H),
HRMS (EI) m/z calcd for C7H4O3NF2Cl 222.9841; found
222.9848.
2
2.82 (s, 3H); 19F NMR:
d
À97.2 (d, JFH = 59 Hz, 2F); 13C NMR:
d
151.3, 143.8, 133.1, 123.6, 123.3, 118.6, 111.0, 109.6 (t,
1JCF = 210 Hz).
4.3.3. 1-(Difluoromethoxy)-3-nitrobenzene (2d)
1H NMR
8.15 (m, 1H), 8.02 (m, 1H), 7.76 (t, 8 Hz), 7.65 (m,
(ESI-DART) m/z calcd for C9H8N2F2S 214.0376; found [M+H]+
d
2
2
1H), 7.20 (t, JHF = 73 Hz, 1H); 19F NMR:
d
À82.2 (d, JFH = 73 Hz,
215.0449.

38
C.S. Thomoson et al. / Journal of Fluorine Chemistry 168 (2014) 34–39
1
2F); 13C NMR:
263 Hz), 113.9.
d
151.6, 131.2, 125.5, 120.0, 116.2 (t, JCF
=
HRMS (ESI-DART) m/z calcd for C6H4CNF3 163.0245; found
[M+H]+ 164.0318.
HRMS (EI) m/z calcd for C7H5O3NF2 189.0234; found 189.0237.
4.4.4. 2-Difluoromethoxy-5-chloropyridine (3f)
1H NMR
d 8.09 (d, J = 5 Hz, 1H), 7.88 (t, J = 9 Hz, 1H), 7.40 (dd,
4.3.4. 1-(Difluoromethoxy)-3-nitro-4-chlorobenzene (2e)
J = 5 Hz, J = 8 Hz, 1H), 7.10 (t, 2JHF = 73 Hz, 1H); 19F NMR:
d
À82.6 (d,
1H NMR:
d 7.67 (d, J = 2 Hz, 1H), 7.55 (d, J = 9 Hz, 1H), 7.33 (m,
2JFH = 71 Hz, 2F); 13C NMR
d 156.5, 153.4, 143.6, 132.0, 122.7, 116.2
1H) 7.17 (t, 2JHF = 72 Hz, 1H); 19F NMR:
d
À83.3 (d, 2JFH = 72 Hz, 2F);
1
1
13C NMR:
116.1.
d
150.1, 133.0, 124.3, 122.0, 116.3 (t, JCF = 278 Hz),
(t, JCF = 262 Hz).
HRMS (GC-EI) m/z calcd for C6H4CNF2Cl 178.9949; found
178.9951.
HRMS (EI) m/z calcd for C8H4O3NF2Cl 203.0394; found
203.0390.
4.4.5. 2-Chloro-5-(difluoromethoxy)pyridine (3g)
1H NMR
7.94 (d, J = 3 Hz, 1H), 7.15 (dd, J = 3 Hz, J = 3 Hz, 1H),
d
4.3.5. 1-(Difluoromethoxy)-2-methyl-4-nitrobenzene (2f)
2
7.03 (d, J = 5 Hz, 1H), 6.23 (t, JHF = 72 Hz, 1H); 19F NMR:
d
À82.3
1H NMR:
d
8.12 (s, 1H), 8.09 (d, J = 9 Hz, 1H), 7.2 (d, J = 9 Hz, 1H),
(dd, 2JHF = 72 Hz, 2F); 13C NMR
116.1 (t, JCF = 259 Hz).
d 147.3, 146.9, 141.2, 130.5, 125.2,
2
6.65 (t, JHF = 72 Hz, 1H), 2.38 (s, 3H); 19F NMR:
d
À82.9 (d,
1
2JFH = 72 Hz, 2F); 13C NMR:
116.2 (t, JCF = 257 Hz).
d 154.5, 130.7, 126.4, 122.9, 117.5,
1
HRMS (ESI-DART) m/z calcd for C6H4CNF2Cl 178.9949; found
[M+H]+ 180.0022.
HRMS (EI) m/z calcd for C8H7CO3NF2 203.0394; found 203.0390.
4.4. Preparation of 2-bromo-3-(difluoromethoxy)pyridine (3d)
4.5. Preparation of diethyl 2-difluoromethoxy-2-phenylmalonate
(4a)
Using an apparatus previously described for method B [21],
potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water
(2.52 g) were added to the reaction vessel and the mixture was
allowed to stir until the potassium hydroxide was almost
completely dissolved. Then, 2-bromo-3-pyridinol (0.354 g,
3 mmol) was added and the mixture stirred for 30 min, after
which acetonitrile (10 mL) was added via syringe and the
mixture stirred at room temperature. Fluoroform was then
bubbled slowly into the mixture for 2 h, after which the
resulting mixture was stirred for one additional hour. After
being quenched with water and extracted with ethyl acetate, the
ethyl acetate layer was washed with a saturated solution on
sodium hydroxide, separated and concentrated. Additional
impurities were removed via column chromatography on silica
gel using an 80:20 mixture of hexanes/methylene chloride to
give a 53% yield of the liquid product, 2-bromo-3-difluoro-
Using the apparatus previously described for method B [21],
potassium hydroxide (2.52 g, 45 mmol, 15 equiv) and water
(2.52 g) were added to the reaction vessel and the mixture was
allowed to stir until the potassium hydroxide was almost
completely dissolved. Then, diethyl phenylmalonate (0.71 g,
3 mmol) was added and the mixture stirred for 30 min, after
which acetonitrile (10 mL) was added via syringe and the mixture
stirred at room temperature. Fluoroform was then bubbled slowly
into the mixture for 2 h, after which the resulting mixture was
stirred for one additional hour. After being quenched with water
and extracted with ethyl acetate, the ethyl acetate layer was
washed with a saturated solution on NaOH, separated and
concentrated to give diethyl difluoromethyl phenyl malonate, 4a
(50%): 19F NMR:
d
À128.2 (d, 2JFH = 55 Hz, 2F). The NMR data were
consistent with those previously reported [22].
methoxypyridine (3d): 1H NMR:
d 8.27 (d, J = 5 Hz, 1H), 7.59 (d,
2
J = 8 Hz, 1H), 7.26 (m, 1H) 6.59 (t, JHF = 72 Hz, 1H); 19F NMR:
d
4.5.1.
a-Difluoromethyl-diphenyl acetonitrile (4b)
À82.1 (d, 2JFH = 72 Hz, 2F); 13C NMR:
d
146.5, 134.5, 128.3, 124.3,
2
19F NMR
d
À119.3 (d, JFH = 54 Hz, 2F). The NMR data were
1
116.33 (t, JCF = 260 Hz).
consistent with those previously reported [22].
HRMS (ESI-DART) m/z calcd for C6H4CNF2Br 222.9444; found
[M+H]+ 223.9424.
Acknowledgment
4.4.1. 2-Difluoromethoxy-6-chloropyridine (3b)
The authors are pleased to acknowledge the support of this
research by Syngenta Crop Protection.
2
1H NMR:
d
8.24 (m, 1H), 7.99 (t, JHF = 72 Hz, 1H), 7.72 (d,
J = 14 Hz, 1H), 7.38 (d, J = 8 Hz, 1H); 19F NMR:
d
À88.7 (d,
2JFH = 72 Hz, 2F); 13C NMR:
1JCF = 254 Hz), 109.8.
d 158.3, 147.9, 143.1, 120.3, 114.4 (t,
References
HRMS (ESI-DART) m/z calcd for C6H4CNF2Cl 178.9949; found
[M+H]+ 180.0022, [M+NH4]+ 197.0288.
[1] D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308–319.
[2] G. Sandford, Philos. Trans. R. Soc.Lond. A 358 (2000) 455–471(Industrialaspects of F).
[3] (a) K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305;
(b) G.K.S. Prakash, S. Chacko, Curr. Opin. Drug Discov. Dev. 11 (2008) 793.
[4] S.M. Cheer, A. Prakash, D. Faulds, H.M. Lamb, Drugs 63 (2003) 101.
[5] D.J. Dumas, US Patent 5,990,315, 1999.
[6] N. Sato, M. Ando, S. Ishikawa, T. Nagase, K. Nagai, A. Kanatani, PCT Int. Pat. WO
2004/031175, 2004.
[7] H.T. Balaban, D.C. Oniciu, A.R. Katritzky, Chem. Rev. 104 (2004) 2777–2812.
[8] A. Jonczyk, E. Nawrot, M. Kisielewski, J. Fluorine Chem. 126 (2005) 1587–1591.
[9] V.P. Mehta, M.F. Greaney, Org. Lett. 19 (2013) 5036–5039.
[10] G.K.S. Prakash, S. Krishramoorthy, S.K. Ganesh, A. Kulkar, K. Haiges, G.A. Olah, Org.
Lett. 16 (2014) 54–57.
4.4.2. 2-Chloro-3-difluoromethoxypyridine (3c)
1H NMR:
d 8.23 (d, J = 5 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.28 (m,
2
2
1H), 6.82 (t, JHF = 73 Hz, 1H); 19F NMR:
d
À82.1 (d, JFH = 73 Hz,
2F); 13C NMR:
1JCF = 259 Hz).
d 176.1, 176.4, 146.0, 129.0, 124.0, 116.3 (t,
HRMS (ESI-DART) m/z calcd for C6H4CNF2Cl 178.9949; found
[M+H]+ 180.0022.
[11] V.G. Poludnenko, O.B. Didinskaya, A.F. Pozharskii, Chem. Heterocycl. Compd. 20
(1984) 422.
[12] J.W. Lyga, R.M. Patera, J. Fluorine Chem. 92 (1998) 141.
[13] (a) J. Zheng, Y. Li, L. Zhang, J. Hu, G.J. Meuzelaar, H.J. Federsel, Chem. Commun.
(2007) 5149;
(b) F. Wang, L. Zhang, J. Zheng, J. Hu, J. Fluorine Chem. 132 (2011) 521.
[14] W. Zhang, F. Wang, J. Hu, Org. Lett. 11 (2009) 2109.
[15] L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 52 (2013) 12390.
4.4.3. 2-Fluoro-3-(difluoromethoxy)pyridine (3e)
1H NMR
d 8.03 (d, J = 5 Hz, 1H), 7.63 (td, J = 8 Hz, J = 0.9, 1H),
7.19 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.58 (t, 2JHF = 73 Hz, 1H); 19F NMR:
À82.6 (dd, 2JFH = 72.5 Hz, 2JFF = 6 Hz, 2F), À81.4 (s, 1F); 13C NMR
d
d
1
143.8, 143.6, 132.7, 122.1, 122.0, 115.2 (t, JCF = 254 Hz).

C.S. Thomoson et al. / Journal of Fluorine Chemistry 168 (2014) 34–39
39
[16] A.K. Yudin, G.K.S. Prakash, D. Deffieux, M. Bradley, R. Bau, G.A. Olah, J. Am. Chem.
Soc. 119 (1997) 1572.
[17] A. Zanardi, M.A. Novikov, E. Martin, J. Benet-Buchholz, V.V. Grushin, J. Am. Chem.
Soc. 133 (2011) 20901–20913.
[18] P. Novak, A. Lishchynskyi, V.V.V.V. Grushin, J. Am. Chem. Soc. 134 (2012)
16167–16170.
[19] G.K.S. Prakash, P.V. Jog, P.T.D. Batamack, G.A. Olah, Science 338 (2012) 1324–1327.
[20] H. Kawai, Z. Yuan, E. Tokunaga, N. Shibata, Org. Biomol. Chem. 11 (2013)
1446–1450.
[21] C.S. Thomoson, W.R. Dolbier Jr., J. Org. Chem. 78 (2013) 8904–8908.
[22] E. Nawrot, A. Jonczyk, J. Fluorine Chem. 130 (2009) 456–459.
[23] G.K.S. Prakash, C. Weber, S. Chacko, G.A. Olah, Org. Lett. 9 (2007) 1863–1866.