Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents: The substituent effect

Article abstract of DOI:10.1016/j.jfluchem.2011.05.009

We have investigated the different chlorodifluoromethyl aryl ketones 1a-1g and sulfones 2a-2h as difluorocarbene reagents for O- and N- difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-difluoromethylations.

Full text of DOI:10.1016/j.jfluchem.2011.05.009

Journal of Fluorine Chemistry 132 (2011) 521–528
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents:
The substituent effect
*
Fei Wang, Laijun Zhang, Ji Zheng, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We have investigated the different chlorodifluoromethyl aryl ketones 1a–1g and sulfones 2a–2h as
difluorocarbene reagents for O- and N-difluoromethylations. It was found that the sulfone reagents 2
were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the
different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethyla-
tion reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we
found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl
sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-
difluoromethylations.
Received 7 April 2011
Received in revised form 3 May 2011
Accepted 5 May 2011
Available online 19 May 2011
Keywords:
Difluorocarbene
Difluoromethylation
Chlorodifluoromethyl ketone
Chlorodifluoromethyl sulfone
Substituent effect
ß 2011 Elsevier B.V. All rights reserved.
1. Introduction
[5]. Thereafter, we found that chlorodifluoromethyl phenyl sulfone
(PhSO2CF2Cl, 2a) can also serve as a more efficient non-ODS-based
Since the pioneering study by Hine et al. in the late 1950s [1],
difluorocarbene (:CF2) has become one of the most important
fluorinated reactive intermediates in modern organic chemistry
[2,3]. Owing to the interaction of the lone pairs of its fluorine
substituents with the carbene center, difluorocarbene is a relatively
stabilized carbene species (with a singlet ground state) and is
therefore less reactive than other dihalocarbenes [3]. Over the past
half century, it has been realized that the reactivity of difluor-
ocarbene is significantly influenced by the way it is generated, and as
a result, enormous efforts have been devoted to seek new methods
and/or reagentsforgenerationofreactivedifluorocarbenespeciesfor
practical organic synthesis [2,3]. One of the important synthetic
applications of difluorocarbene species is the difluoromethylation of
O-, N-, S-, C-, and P-nucleophiles, using CHClF2, ClCF2CO2Na,
ClCF2CO2CH3, CF2Br2, CF3CO2Na, FSO2CF2CO2H, CF3ZnBr, and CHF2I
as difluorocarbene precursors [2–5]. The difluoromethyl group
(CF2H)has been proposed both asanisostereofOH (or CH2OH) group
[6] and as a more lipophilic hydrogen donor (than typical donors
such as OH and NH), which makes it an interesting group with
respect to the design of bioactive molecules [7]. In 2006, we reported
that2-chloro-2,2-difluoroacetophenone(PhCOCF2Cl, 1a)canbeused
difluorocarbene reagent for O- and N-difluoromethylations [8]. The
different reactivity between 1a and 2a as difluorocarbene precursors
inspired us to investigate the relationship between the structure of
difluorocarbene reagents [including chlorodifluoromethyl aryl
ketones (1, ArCOCF2Cl) and chlorodifluoromethyl aryl sulfones (2,
ArSO2CF2Cl)] and their reactivity in O-difluoromethylations.
2. Results and discussion
A series of chlorodifluoromethyl aryl ketones 1a–1g were
prepared by using the previously known method [9]. Therefore, we
carried out the O-difluoromethylation reactions by using biphenyl-
4-ol (3c) as a model compound. The reaction condition of O-
difluoromethylation was similar to our previous report [5].
Potassium hydroxide (25 wt% in H2O) was used both as a base
to deprotonate phenol (3a) and as an activating agent to react with
1 to generate difluorocarbene species. CH3CN–H2O (1:1, v/v)
system was used as the mixed solvent for the reaction. As shown in
Table 1 and Fig. 1, the reaction between 3c and 1 gave product 4c in
63–86% yields. By comparing the chemical yields of the reactions at
different temperatures (50 8C and 80 8C), we found that the
reaction temperature did not have a significant impact on the
reaction (Fig. 1). We also compared the product yields of the
reactions with different difluorocarbene reagents 1a–1g under the
same reaction condition, and found that reagents 1a–1g bearing
different substitution groups (R = H, Me, OMe, halo, CF3, etc.) on the
phenyl ring showed similar reactivity, as evidenced by the fact that
as
a
non-ozone-depleting substance-based (non-ODS-based)
difluorocarbene precursor for O-difluoromethylation of phenols
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail addresses: jinbohu@mail.sioc.ac.cn, jinbohu@sioc.ac.cn (J. Hu).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.05.009

522
F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
Table 1
Difluoromethylation with different reagents 1.
.
Entrya
Reagent
Temp. (8C)
Yield (%)b
1
2
R = H (1a)
50
80
50
80
50
80
50
80
50
80
50
80
50
80
64
66
74
71
68
78
76
67
71
86
76
80
63
67
R = H (1a)
3
R = p-Me (1b)
R = p-Me (1b)
R = o-Me (1c)
R = o-Cl (1d)
R = p-Cl (1d)
R = p-Cl (1d)
R = p-F (1e)
4
5
6
7
8
9
10
11
12
13
14
R = p-F (1e)
R = p-N(Me)2 (1f)
R = p-N(Me)2 (1f)
R = p-CF3 (1g)
R = p-CF3 (1g)
a
For all classes, the reactant ratio 3c:1:KOH = 1:1.5:16.
Yield was determined by 19F NMR spectroscopy.
b
Table 2
Difluoromethylation with different reagents 2.
.
Entrya
Reagent
Temp. (8C)
Yield (%)b
1
2
R = H (2a)
50
80
50
80
50
80
50
80
50
80
50
80
50
80
50
80
73
77
52
65
29
36
90
91
83
86
76
73
79
81
91
91
R = H (2a)
3
R = p-Me (2b)
R = p-Me (2b)
R = p-OMe (2c)
R = p-OMe (2c)
R = p-Cl (2d)
R = p-Cl (2d)
R = p-Br (2e)
R = p-Br (2e)
R = o-Cl,p-Cl (2f)
R = o-Cl,p-Cl (2f)
R = p-F (2g)
4
5
6
7
8
9
10
11
12
13
14
15
16
R = p-F (2g)
R = p-NO2 (2h)
R = p-NO2 (2h)
a
For all classes, the reactant ratio 3c:2:KOH = 1:1.5:16.
Yield was determined by 19F NMR spectroscopy.
b
the product 4c was obtained in similar yields (both for 50 8C and
80 8C) (Fig. 1). It indicates that for chlorodifluoromethyl aryl
ketones 1a–1g, the different substituents on the aryl group of
reagents did not significantly affect their reactivity as the
difluorocarbene reagents for O-difluoromethylation.
For comparison, we prepared a variety of structurally diverse
chlorodifluoromethyl phenyl sulfones 2a–2h following the
known procedure [8]. As shown in Table 2 and Fig. 2, the
difluoromethylation power of each sulfone reagent was examined
using 3c as a model substrate under the similar reaction conditions
as our previous report [8], except that the reactant ratio
3c:2:KOH = 1:1.5:16. When we investigated the temperature
effect, it showed that the yield of 3c was not sensitive to reaction
temperature, with only slightly higher yields obtained at 80 8C
(than those at 50 8C) in most cases. However, unlike the reactions
Fig. 1. Difluoromethylation with different reagents 1.

F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
523
Table 3
with reagents 1a–1g (Table 1 and Fig. 1), the different substituents
on reagents 2a–2h had a remarkable effect on the product yields
(Table 2 and Fig. 2). As shown in Fig. 2, the product yield is
increasing along the order R = H, p-OMe, p-Me, H, p-F, p-Br, p-Cl,
s
values for several substituents.
Substituent (R)
p-OMe p-Me
À0.27 À0.17
H
0
p-F
p-Br p-Cl
p-NO2
Hammett constant (s)
0.06 0.23 0.23 0.78
and p-NO2. Since Hammett constant (
indicate the relative electronic effect of different substituents on
the phenyl ring, we listed the para values for different substituents
s value) can be used to
s
With the two efficient difluorocarbene reagents 2d and 2h in
(as shown in Table 3) [10]. It was found that an electron-donating
group (with a negative spara value) resulted in a decrease of
product yield, while an electron-withdrawing group (with a
hand, we carefully examined the scope of the O-difluoromethyla-
tion reaction with these two reagents. The results are summarized
in Table 4. Reagent 2d and 2h were found to be powerful in
reacting with a variety of structurally diverse phenol derivatives to
give aryl difluoromethyl ethers in good to excellent yields (entries
1–13). Naphthols were also successfully difluoromethylated to
give the corresponding products in good yields (entries 12 and 13).
It should be mentioned that, in most cases, only 1.5 equivalents of
reagent 2g or 2h were used, and the corresponding difluoro-
positive spara value) led to an increase of product yield. As shown in
Fig. 2 and Table 3, the tendency of product yields is consistent with
that of the spara values. Finally, para-chloro and para-nitro
substituted chlorodifluoromethyl phenyl sulfones 2d and 2h
behaved as the two most efficient difluorocarbene reagents in
this category.
Table 4
O-Difluoromethylation with reagent 2d or 2h.
.
Entrya
Substrate
Reactant
Product
Yield (%)b
1
2
3
4
5
6
7
8
2d
2h
2h
2h
2h
2d
2d
2d
4a R = H
76c
77
93
90
93
80c
85
66
4b R = p-tBu
4c R = p-Ph
4d R = o-NO2
4e R = p-NO2
4f R = p-OMe
4g R = p-l
4h R = p-Cl
9
2d
99
10
2d
86
11
2d
97
12
2d
2h
90
13
76
a
For all cases, the reactant ratio 3:2:KOH =1:1.5:16.
Isolated yield.
Yield was determined by 19F NMR spectroscopy.
b
c

524
F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
Scheme 1.
should also be realized that the difluorocarbene is a reactive
intermediate and possesses only a very short life-time, which
suggests that a quick generation of: CF2 at low temperature may
not be beneficial to the desired difluoromethylation reaction that
involves a high activation energy and requires a high reaction
temperature [2].
Fig. 2. Difluoromethylation with different reagents 2.
methylated ethers were obtained in better yields than those of the
reported reactions using other difluorocarbene reagents [5,8,11].
p-Chlorophenyl chlorodifluoromethyl sulfone 2d was also
applied in the N-difluoromethylation of different N-heterocyclic
compounds, and the corresponding N-difluoromethylated tertiary
amines were obtained in moderate yields (Table 5).
The difluorocarbene can be readily captured by phenoxides
(ArOÀ) to give the difluoromethyl ethers via anionic intermediates
(ArOCF2À). In Table 1 and Fig. 1, we found that the change of
different substituents on the phenyl ring of 1a–1g did not show a
remarkable impact on the product yield; however, in Table 2 and
Fig. 2, we realized that the substituent effect on chlorodifluor-
omethyl aryl sulfones 2a–2h were more significant. This can be
explained by the fact that the reactions between chlorodifluor-
omethyl aryl ketones 1 and hydroxide is generally much faster
than the those with chlorodifluoromethyl aryl sulfones 2 [5,8].
Indeed, the generation of difluorocarbene from ketones 1 and KOH
was so facile that a low temperature (À78 8C) condition was
required during the reaction set-up stage (see Section 4) [5].
Therefore, the electronic effect of different substituents on 1 had
little effect on the product yield of the difluoromethylation reaction.
However, since sulfones 2 are more stable and the generation of
The mechanism for O-difluoromethylation using 1 or 2 is
proposed in Scheme 1 [5]. Chlorodifluoromethyl anion (CF2ClÀ) is
generated from reagent 1 or 2 under the nucleophilic attack by
hydroxide ion, and the CF2ClÀ species readily undergoes
a-
elimination of a chloride ion to release difluorocarbene (:CF2) [12].
It should be noted that chlorodifluoromethyl anion is a highly
unstable species, and its decomposition to difluorocarbene and
chloride anion was known to proceed swiftly without significant
activation barrier [12,13]. Therefore, the generation of:CF2 from 1
or 2 and hydroxide can be reasonably regarded as one step. It
Table 5
N-Difluoromethylation with reagent 2d.
.
Entrya
1
Substrate
Reactant
Product
Yield (%)b
57
2d
2
3
2d
2d
56
68
4
2d
34
a
For all cases, the reactant ratio 5:2d:KOH = 1:1.5:16.
b
Isolated yield.

F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
525
difluorocarbene from sulfones 2 is much slower, the electronic effect
4.2.1. 4-(Difluoromethoxy)biphenyl (4c)
of different substituents on 2 showed a significant influence on the
product yields (Table 2 and Fig. 2). It is reasonable to see that an
electron-withdrawing group on sulfone 2 facilitates the generation
of difluorocarbene species through the attack of a hydroxide ion,
resulting in a beneficial effect for the chemical outcome of the
difluoromethylation reaction. The relative stability and the substit-
uent effect of ketones 1 and sulfones 2 also explain why a large
excessamount ofketonereagents1(5 equiv.)weregenerallyused to
obtain satisfactory yield of difluoromethylated products [5].
White solid; 1H NMR:
d 7.56 (t, J = 8.1 Hz, 4H), 7.44 (t, J = 7.2 Hz,
2H), 7.39–7.32 (m, 1H), 7.19 (d, J = 7.8 Hz, 2H), 6.55 (t, J = 74.1 Hz,
1H); 19F NMR:
d
À80.2 (d, J = 73.7 Hz, 2F); MS (EI, m/z, %): 220 (M+,
75.93), 170 (100.00). The characterization data was consistent with
the previous report [8].
4.2.2. 1-tert-Butyl-4-(difluoromethoxy)benzene (4b)
3. Conclusions
In conclusion, we have investigated structurally different
chlorodifluoromethyl aryl ketones 1a–1g and sulfones 2a–2h as
difluorocarbene reagents for O- and N-difluoromethylations. It was
found that the sulfone reagents 2 were generally more efficient in
difluoromethylation than the ketone reagents 1. Furthermore, while
the different substituents on ketone reagents 1 did not show a
remarkable impact on the difluoromethylation reaction, the
substituent effect on the sulfone reagents 2 was much more
significant. Finally, we found that p-chlorophenyl chlorodifluor-
omethyl sulfone 2dand p-nitrophenyl chlorodifluoromethylsulfone
2h were among the most powerful difluorocarbene reagents in O-
difluoromethylations. p-Chlorophenyl chlorodifluoromethyl sul-
fone 2d was also applied in the N-difluoromethylation of different
N-heterocyclic compounds, and the corresponding N-difluoro-
methylated tertiary amines were obtained in moderate yields.
Colorless liquid; 1H NMR:
J = 8.9 Hz, 2H), 6.48 (t, J = 74.1 Hz, 1H), 1.31 (s, 9H); 19F NMR:
À80.4 (d, J = 74.4 Hz, 2F); MS (EI, m/z, %): 200 (M+, 17.27), 185
(100.00). The characterization data was consistent with the
previous report [8].
d 7.37 (d, J = 8.9 Hz, 2H), 7.05 (d,
d
4.2.3. 1-(Difluoromethoxy)-2-nitrobenzene (4d)
4. Experimental
Light yellow liquid; 1H NMR:
d 7.98–7.91 (m, 1H), 7.68–7.59 (m,
Unless otherwise mentioned, solvents and reagents were
purchased from commercial sources and used as received. 1H
NMR spectra were recorded on Bruker 300 or Mercury 300
spectrometers with Me4Si as internal standard. 19F NMR spectra
were recorded on Bruker 300 or Mercury 300 spectrometers with
CFCl3 as external standard. 13C NMR spectra were recorded on
Avance 500 or DPX-400 spectrometers. Mass spectra were obtained
on a spectrometer. High-resolution mass data were recorded on a
high-resolution mass spectrometer in the EI, ESI or MALDI mode.
1H), 7.44–7.36 (m, 2H), 6.63 (t, J = 72.9 Hz, 1H); 19F NMR:
d
À81.3 (d,
J = 72.6 Hz, 2F); MS (EI, m/z, %): 189 (M+, 82.16), 139 (100.00). The
characterization data was consistent with the previous report [8].
4.2.4. 1-(Difluoromethoxy)-4-nitrobenzene (4e)
4.1. Typical procedure for difluoromethylation of 3 using 1
Light yellow liquid; 1H NMR:
J = 9.0 Hz, 2H), 6.64 (t, J = 72.0 Hz, 1H); 19F NMR:
J = 72.3 Hz, 2F); MS (EI, m/z, %): 189 (100.00), 109 (91.91). The
characterization data was consistent with the previous report [8].
d 8.28 (d, J = 9.0 Hz, 2H), 7.26 (d,
d
À6.64 (d,
Into a pressure tube containing a mixture of biphenyl-4-ol 3c
(170 mg, 1.0 mmol) and aqueous KOH (3 mL, 25 wt%, ca. 16 mmol),
was added 1a (963 mg, 5.0 mmol) (dissolved in CH3CN (3 mL)) at
À78 8C. The reaction tube was sealed and heated to 50 8C (or 80 8C)
for 4 h. After the addition of 3 mL of water, the reaction mixture
4.2.5. 1-(Difluoromethoxy)-4-iodobenzene (4g)
was extracted with 5 mL of Et2O. The yield was determined by 19
F
NMR spectroscopy using PhCF3 as internal standard (64% for 50 8C;
66% for 80 8C).
4.2. Typical procedure for difluoromethylation of 3 (or 5) using 2
Colorless liquid; 1H NMR:
d 7.67 (d, J = 8.7 Hz, 2H), 6.89 (d,
J = 8.7 Hz, 2H), 6.48 (t, J = 73.8 Hz, 1H); 19F NMR:
d
À80.4 (d,
Into a reaction tube containing mixture of biphenyl-4-ol 3c
(170 mg, 1.0 mmol) and aqueous KOH (3 mL, 25% wt%, ca.
16 mmol), was added 2g (340 mg, 1.5 mmol; dissolved in 3 mL
of CH3CN) at À78 8C. The reaction tube was sealed immediately,
and the mixture was heated to 80 8C for 4 h. After the addition of
3 mL of water, the reaction mixture was extracted with 5 mL of
Et2O. The yield was determined by 19F NMR spectroscopy using
PhCF3 as internal standard (91%). The organic phase was washed
with brine, and then dried over anhydrous MgSO4. After the
solution was filtered and the solvent was evaporated under
vacuum, the residue was subjected to silica gel column chroma-
tography to give product 4c (205 mg, 93%).
J = 73.6 Hz, 2F); MS (EI, m/z, %): 270 (M+, 33.27), 58 (100.00). The
characterization data was consistent with the previous report [8].
4.2.6. 1-Chloro-4-(difluoromethoxy)benzene (4h)
Colorless liquid; 1H NMR:
J = 8.7 Hz, 2H), 6.48 (t, J = 73.5 Hz, 1H); 19F NMR:
d
7.33 (d, J = 8.7 Hz, 2H), 7.07 (d,
À80.4 (d,
d

526
F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
J = 74.0 Hz, 2F); MS (EI, m/z, %): 178 (M+, 33.40), 128 (100.00), 130
(32.16). The characterization data was consistent with the
previous report [8].
4.2.11. 1-(Difluoromethoxy)naphthalene (4m)
4.2.7. 2,4-Dichloro-1-(difluoromethoxy)benzene (4i)
Colorless liquid; 1H NMR:
1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60–7.38 (m, 3H), 7.22–7.16 (m, 1H),
d
8.22À8.16 (m, 1H), 7.89À7.83 (m,
6.66 (t, J = 74.1 Hz, 1H); 19F NMR:
d
À79.1 (d, J = 74.0 Hz, 2F); MS
(EI, m/z, %): 194 (M+, 72.21), 144 (100.00), 115 (93.41). The
Colorless liquid; 1H NMR:
d
7.48À7.44 (m, 1H), 7.28À7.16 (m,
2H), 6.51 (t, J = 72.6 Hz, 1H); 19F NMR:
d
À82.1 (d, J = 73.4 Hz, 2F);
characterization data was consistent with the previous report [8].
MS (EI, m/z, %): 212 (M+, 32.96), 162 (100.00). The characterization
data was consistent with the previous report [8].
4.2.12. 1-(Difluoromethyl)-1H-benzo[d]imidazole (6a)
4.2.8. 4-Allyl-1-(difluoromethoxy)-2-methoxybenzene (4j)
Light yellow liquid; 1H NMR:
d 8.14 (s, 1H), 7.90–7.81 (m, 1H),
7.66–7.57 (m, 1H), 7.56–7.12 (m, 3H); 19F NMR:
d
À92.9 (d,
J = 60.1 Hz, 2F); MS (EI, m/z, %): 168 (M+, 100.00), 118 (62.21). The
Colorless liquid; IR (film): 2980, 1641, 1599, 1511, 1467, 1421,
1382, 1274, 1216, 1123, 1935, 919 cmÀ1 1H NMR:
; d 7.07 (d,
characterization data was consistent with the previous report [8].
J = 8.2 Hz, 2H), 6.80–6.25 (m, 3H), 6.02–5.87 (m, 1H), 5.14–5.10 (m,
1H), 5.09–5.06 (m, 1H), 3.86 (s, 3H), 3.36 (d, J = 6.9 Hz, 2H); 19F
4.2.13. 1-(Difluoromethyl)-1H-benzo[d][1,2,3]triazole (6b)
NMR:
d
À80.6 (d, J = 78.6 Hz, 2F); 13C NMR:
d 150.9, 138.9, 136.9,
122.2, 120.2, 116.3 (t, J = 258.3 Hz), 112.9, 55.9, 39.9; MS (EI, m/z,
%): 214 (M+, 100.00), 91 (55.30), 147 (53.70); HRMS (EI): calcd. for
C
11H12O2F2: 214.0805; found: 214.0807.
4.2.9. 1,3-Dibromo-2-(difluoromethoxy)-5-methylbenzene (4k)
Light yellow liquid; 1H NMR:
d 8.18–8.12 (m, 1H), 8.07–7.61 (m,
3H), 7.55–7.47 (m, 1H); 19F NMR:
d
À96.4 (d, J = 59.0 Hz, 2F); MS
(ESI): m/z 170.2 (M+H+). The characterization data was consistent
with the previous report [7].
4.2.14. 1-(Difluoromethyl)-2-phenyl-1H-imidazole (6c)
White solid; Mp. 41 8C; IR (film): 1735, 1588, 1554, 1463, 1383,
1257, 1127, 1089, 1068, 849, 746, 582, 562 cmÀ1; 1H NMR:
7.39
(s, 2H), 6.57 (t, J = 74.4 Hz, 1H), 2.32 (s, 3H). 19F NMR:
À80.3 (d,
J = 74.4 Hz, 2F); 13C NMR:
143.6, 139.1, 133.6, 117.7, 116.7 (t,
d
d
d
J = 262.8 Hz), 20.3; MS (EI, m/z, %): 314 (M+, 22.79), 266(100.00);
HRMS (EI): calcd. for C8H6OF2Br2: 313.8753; found: 313.8755;
anal. calcd. for C8H6OF2Br2: C, 30.41; H, 1.91; found: C, 30.55; H,
1.75.
Light yellow 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, J = 59.8 Hz, 2F); MS
(EI, m/z, %): 194 (M+, 78.17), 193 (100.00). The characterization
4.2.10. 1-Bromo-2-(difluoromethoxy)naphthalene (4l)
data was consistent with the previous report [8].
4.2.15. 4-Benzoyl-1-(difluoromethyl)-5-methyl-2-phenyl-1H-
pyrazol-3(2H)-one (6d)
White solid; Mp. 55–56 8C; IR (film): 1504, 1383, 1359, 1231,
1121, 1105, 993, 935, 811, 741, 526 cmÀ1
;
1H NMR:
d
8.29 (d,
J = 8.4 Hz, 1H), 7.88–7.81 (m, 2H), 7.68–7.51 (m, 2H) 7.43–7.36 (m,
1H), 6.63 (t, J = 73.8 Hz, 1H); 19F NMR:
À80.1 (d, J = 73.8 Hz, 2F);
13C NMR:
146.0, 132.7, 132.2, 129.2, 128.2, 128.1, 127.1, 126.5,
d
Light yellow liquid; 1H NMR:
d 7.85–7.78 (m, 2H), 7.69–7.57
d
120.5, 118.9, 116.2 (t, J = 241.3 Hz), 114.7; MS (EI, m/z, %): 272 (M+,
78.09), 222 (100.00); HRMS (EI): calcd. for C11H7OF2Br: 271.9648;
found: 271.9651; anal. calcd. for C11H7OF2Br: C, 48.38; H, 2.58;
found: C, 48.19; H, 2.59.
(m, 3H), 7.56–7.37 (m, 5H), 6.73 (t, J = 73.2 Hz, 1H), 2.23 (s, 3H);
19F NMR:
d
À82.3 (d, J = 73.6 Hz, 2F); MS (ESI): m/z 329.2 (M+H+).
The characterization data was consistent with the previous
report [8].

F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
527
4.3. Typical procedure for preparation of reagents 1
J = 333.5 Hz), 21.9; MS (EI, m/z, %): 240 (M+, 0.30), 91 (100.00), 155
(52.65); HRMS (EI): calcd. for C8H7O2SF2Cl: 239.9823; found:
239.9825; anal. calcd. for C8H7O2SF2Cl: C, 39.93; H, 2.93; found: C,
39.98; H, 2.94.
The reagents 1 were prepared following the previous report [9].
4.3.1. 2-Chloro-2,2-difluoro-1-(4-fluorophenyl)ethanone (1e)
4.4.2. 1-(Chlorodifluoromethylsulfonyl)-4-methoxybenzene (2c)
Colorless liquid; IR (film): 2928, 1719, 1602, 1510, 1247, 1159,
White solid; Mp. 49–50 8C; IR (film): 2992, 1595, 1498, 1353,
988, 894, 747, 601 cmÀ1; 1H NMR:
d 8.21–8.08 (m, 2H), 7.22–7.11
1276, 1168, 1123, 1074, 839, 802, 667, 575, 543 cmÀ1; 1H NMR:
d
(m, 2H); 19F NMR:
d
À61.5 (s, 2F), À100.8 (s, 1F); 13C NMR:
d 179.7
7.96 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 3.94 (s, 3H); 19F
(t, J = 29.0 Hz), 166.9 (d, J = 257.6 Hz), 133.5 (d, J = 9.7 Hz), 125.7 (d,
J = 3.0 Hz), 120.0 (t, J = 303.0 Hz), 116.3 (d, J = 221.6 Hz); MS (EI, m/
z, %): 208 (M+, 4.40), 104 (100.00); HRMS (EI): calcd. for C8H4OF3Cl:
207.9903; found: 207.9899.
NMR:
d
À63.8(s, 2F); 13C NMR:
d 166.1, 133.6, 126.4 (t,
J = 329.5 Hz), 121.0, 115.1, 55.9; MS (EI, m/z, %): 256 (M+, 1.43),
171 (100.00); HRMS (EI): calcd. for C8H7O3F2SCl: 255.9773; found:
255.9774; anal. calcd. for C8H7O3F2SCl: C, 37.44; H, 2.75; found: C,
37.58; H, 2.75.
4.3.2. 2-Chloro-1-(4-(dimethylamino)phenyl)-2,2-difluoroethanone
(1f)
4.4.3. 1-Bromo-4-(chlorodifluoromethylsulfonyl)benzene (2e)
White solid; Mp. 68 8C; IR (film): 3094, 1571, 1393, 1368, 1117,
Yellow solid; Mp. 59 8C; IR (film): 2921, 1681, 1602, 1542,
1011, 930, 738, 590, 560 cmÀ1
; d 7.89 (d, J = 8.7 Hz, 2H),
1H NMR:
1387, 1153, 977, 888, 742 cmÀ1
;
1H NMR:
d
7.99 (d, J = 8.8 Hz,
2H), 6.65 (d, J = 8.8 Hz, 2H), 3.09 (s, 6H); 19F NMR:
À59.1 (s, 2F);
13C NMR:
178.9 (t, J = 26.8 Hz), 154.4, 132.9 (d, J = 2.2 Hz), 120.9
7.81 (d, J = 8.7 Hz, 2H); 19F NMR:
d
À62.3(s, 2F); 13C NMR:
d 133.2,
d
132.5, 132.4, 129.6, 126.2 (t, J = 233.5 Hz); MS (EI, m/z, %): 304 (M+,
5.46), 155 (100.00); HRMS (EI): calcd. for C7H4O2F2ClS (MÀBr):
224.9589; found: 224.9589; anal. calcd. for C7H4O2F2ClBrS: C,
27.52; H, 1.32; found: C, 27.90; H, 1.62.
d
(t, J = 303.8 Hz), 116.2, 110.7 (t, 32.0 Hz), 39.9; MS (EI, m/z, %):
233 (M+, 18.44), 148 (100.00); HRMS (EI): calcd. for
10H10ONF2Cl: 233.0419; found: 233.0417; anal. calcd. for
10H10ONF2Cl: C, 51.41; H, 4.31; N, 5.99; found: C, 51.41; H,
C
C
4.4.4. 2,4-Dichloro-1-(chlorodifluoromethylsulfonyl)benzene (2f)
4.24; N, 5.90.
4.3.3. 2-Chloro-2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethanone
(1g)
Colorless liquid; IR (film): 3097, 1573, 1552, 1381, 1188, 1151,
1126, 1098, 929, 824, 613, 577, 543, 485 cmÀ1; 1H NMR:
d 8.11 (d,
J = 8.4 Hz, 1H), 7.69–7.50 (m, 2H); 19F NMR:
NMR:
d
À60.7 (s, 2F); 13C
Colorless liquid; IR (film): 1726, 1415, 1330, 1320, 1166, 1139,
d
144.1, 137.5, 136.4, 133.3, 128.5, 127.8, 126.9 (t,
1070, 992, 896, 758 cmÀ1; 1H NMR:
d 8.28 (d, J = 8.2 Hz, 2H), 7.85
J = 345.0 Hz); MS (EI, m/z, %): 294 (M+, 7.87), 209 (100.00), 145
(79.68); HRMS (EI): calcd. for C7H3O2F2Cl3: 293.8887; Found:
293.8890; Anal. Calcd. for C7H3O2F2Cl3: C, 28.45; H, 1.02; Found: C,
28.94; H, 0.98.
(d, J = 8.6 Hz, 2H); 19F NMR:
d
À62.2 (s, 2F), À64.3 (s, 3F); 13C NMR:
d
180.3 (t, J = 29.1 Hz), 136.3 (q, J = 33.5 Hz), 132.2, 130.9, 126.0 (d,
J = 13.7 Hz), 124.6, 119.9 (t, J = 230.0 Hz); MS (EI, m/z, %): 173
(100.00), 145 (73.18), 239 (3.42); HRMS (EI): calcd. for C9H4OF5Cl:
257.9871; found: 257.9871.
4.4.5. 1-(Chlorodifluoromethylsulfonyl)-4-fluorobenzene (2g)
4.4. Typical procedure for preparation of reagents 2
The reagents 2 were prepared according to literature [8].
4.4.1. 1-(Chlorodifluoromethylsulfonyl)-4-methylbenzene (2b)
White solid; Mp. 30 8C; IR (film): 3110, 1591, 1494, 1370,
1248, 1187, 1160, 1121, 1079, 930, 844, 664, 574, 530 cmÀ1 1H
;
NMR:
d
8.14À8.06 (m, 2H), 7.36 (d, J = 8.1 Hz, 2H); 19F NMR:
d
À63.5 (s, 2F), À98.4 (s, 1F); 13C NMR:
d 167.6 (d, J = 259.8 Hz),
134.3 (d, J = 10.4 Hz), 126.5 (d, J = 3.0 Hz), 126.2 (t, J = 333.5 Hz),
117.4 (d, J = 33.1 Hz); MS (EI, m/z, %): 208 (M+, 4.40), 104
(100.00); HRMS (EI): calcd. for C7H4O2F3SCl: 243.9573; found:
243.9572; anal. calcd. for C7H4O2F3SCl: C, 34.37; H, 1.65; found:
C, 34.45; H, 1.77.
White solid; Mp. 66–67 8C; IR (film): 1592, 1357, 1178, 1124,
1114, 1077, 933, 813, 657, 571,530 cmÀ1 1H NMR:
; d 7.90 (d,
J = 7.8 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 2.50 (s, 3H); 19F NMR:
d
À62.9(s, 2F); 13C NMR:
d 148.1, 131.2, 130.4, 127.4, 126.4 (t,

528
F. Wang et al. / Journal of Fluorine Chemistry 132 (2011) 521–528
A Critical Review, ACS, Washington, DC, 1995;
Acknowledgements
(f) M. Hudlicky (Ed.), Chemistry of Organic Fluorine Compounds, Ellis Horwood,
New York, 1976;
We gratefully acknowledge the National Natural Science
Foundation of China (20772144, 20825209, 20832008) and the
Chinese Academy of Sciences for financial support.
(g) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 105 (2005) 827–856.
[4] J. Hu, W. Zhang, F. Wang, Chem. Commun. (2009) 7465–7478.
[5] L. Zhang, J. Zheng, J. Hu, J. Org. Chem. 71 (2006) 9845–9848, and the references
cited therein.
[6] (a) G.K.S. Prakash, A.K. Yudin, D. Deffieux, M. Bradley, R. Bau, G.A. Olah, J. Am.
Chem. Soc. 119 (1997) 1572–1581, and the references cited therein;
(b) R. Sasson, A. Hagooly, S. Rozen, Org. Lett. 5 (2003) 769–771;
(c) G.K.S. Prakash, J. Hu, Y. Wang, G.A. Olah, Org. Lett. 6 (2004) 4315–4317;
(d) Y. Li, J. Hu, Angew. Chem. Int. Ed. 44 (2005) 5882–5886.
[7] J.A. Erickson, J.I. McLoughlin, J. Org. Chem. 60 (1995) 1626–1631.
[8] J. Zheng, Y. Li, L. Zhang, J. Hu, G.J. Meuzelaar, H.-J. Federsel, Chem. Commun. (2007)
5149–5151.
[9] Y. Kodama, H. Yamane, M. Okumura, M. Shiro, T. Taguchi, Tetrahedron 51 (1995)
12217–12228.
[10] T.H. Lowry, K.S. Richardson, Mechanism and Theory in Organic Chemistry, 3rd
ed., Harper & Row, New York, 1987.
References
[1] In his seminal reports in 1950s, Hine called difluorocarbene as ‘‘difluoromethy-
lene’’. See reports:
(a) J. Hine, K. Tanabe, J. Am. Chem. Soc. 79 (1957) 2654–2655;
(b) J. Hine, J.J. Porter, J. Am. Chem. Soc. 79 (1957) 5493–5496;
(c) J. Hine, D.C. Duffey, J. Am. Chem. Soc. 81 (1959) 1131–1136.
[2] (a) L.S. Brahms, W.P. Dailey, Chem. Rev. 96 (1996) 1585–1632;
(b) W.R. Dolbier Jr., M.A. Battiste, Chem. Rev. 103 (2003) 1071–1098.
[3] (a) K. Uneyama, Organofluorine Chemistry, Blackwell, New Delhi, 2006;
(b) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH, Weinheim, 2004;
[11] W. Zhang, F. Wang, J. Hu, Org. Lett. 11 (2009) 2109–2112.
[12] F. Wang, W. Zhang, J. Zhu, H. Li, K.-W. Huang, J. Hu, Chem. Commun. 47 (2011)
2411–2413.
(c) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004;
(d) T. Hiyama (Ed.), Organofluorine Compounds: Chemistry and Applications,
Springer, New York, 2000;
[13] J.A. Paulino, R.R. Squires, J. Am. Chem. Soc. 113 (1991) 1845.
(e) M. Hudlicky, A.E. Pavlath (Eds.), Chemistry of Organic Fluorine Compounds. II.