Electrophilic monofluoromethylation of O-, S-, and N-nucleophiles with chlorofluoromethane

Article abstract of DOI:10.1016/j.tet.2007.08.043

CH₂ClF has been found to be a useful electrophilic monofluoromethylating agent for a variety of O-, S-, and N-nucleophiles. The reaction is not sensitive to the radical scavenger such as nitrobenzene, which strongly supports an S_N2 m

Full text of DOI:10.1016/j.tet.2007.08.043

Tetrahedron 63 (2007) 10569–10575
Electrophilic monofluoromethylation of O-, S-, and
N-nucleophiles with chlorofluoromethane
*
Wei Zhang, Lingui Zhu and Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 13 July 2007; revised 10 August 2007; accepted 14 August 2007
Available online 16 August 2007
Abstract—CH2ClF has been found to be a useful electrophilic monofluoromethylating agent for a variety of O-, S-, and N-nucleophiles. The
reaction is not sensitive to the radical scavenger such as nitrobenzene, which strongly supports an SN2 mechanism rather than an SET mech-
anism. Although most of these products (fluoromethyl ethers, sulfides, and amines) can be isolated with good purity, some of these compounds
do intend to decompose (via defluorination) during storage. The electrophilic monofluoromethylation of carbon-nucleophiles was attempted
with CH2ClF, CH2FI, or FCH2OTs as monofluoromethylating agents, but with no success.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
electrophilic difluoromethylation chemistry with S-(difluoro-
methyl)diarylsulfonium tetrafluoroborate reagent, which is
able to incorporate an electrophilic CF2H group into cer-
tain nucleophiles such as sulfonic acids, tertiary amines,
imidazole derivatives, and phosphines.7
Electrophilic fluoroalkylation reactions, which are usually
different from regular electrophilic alkylations in hydrocar-
bon chemistry, represent one of the unique aspects of organo-
fluorine chemistry.1 For instance, while the bimolecular
nucleophilic substitution (SN2) reaction between a nucleo-
phile (Nuꢀ, such as a thiophenoxide) and methyl iodide
can proceed very readily (Scheme 1, Eq. 1), the similar
SN2 type of reaction between a nucleophile and trifluoro-
methyl iodide has been proven to be unsuccessful (Scheme
1, Eq. 2).2 This is mainly due to the fact that, in sharp contrast
to normal alkyl halides, for perfluoroalkyl halides (RfX) the
electronegativities of perfluoroalkyl groups (Rf) are higher
than those of halogen atoms (X) and thus nucleophiles
attack at halogen instead of the halogen-substituted carbon.3
To overcome this problem, several novel electrophilic
trifluoromethylating agents such as (trifluoromethyl)-
aryliodonium salts and (trifluoromethyl)chalcogen salts
have been developed by Yagulpol’skii et al.,4 Umemoto
et al.,1 and others.5,6 On the other hand, the electrophilic di-
fluoromethylation (the direct transfer of a ‘CF2H+’ building
block into a nucleophile) has been a long-standing challenge,
and indeed, the currently known methods for introducing
a difluoromethyl moiety to oxygen-, sulfur-, phosphorus-,
and nitrogen-nucleophiles are mainly based on de facto
electrophilic difluoromethylations with difluorocarbene re-
agents.2,3 Recently, Prakash et al. reported the first real
δ+
δ−
SN2
I−
Nu−
Nu
+
CH3
+
+
CH3
I
δ−
CF3
SN2
X
δ+
I
I−
Nu−
Nu−
Nu
Nu
+
+
CF3
δ+
FCH2
δ−
Cl
SN2
Cl−
CH2F
+
?
Scheme 1.
Compared with electrophilic trifluoroalkylation and difluoro-
methylation (both de facto and real ones), much less has
been known about electrophilic monofluoromethylation
(the electrophilic transfer of ‘CH2F+’ building block).
In 1953, Olah and Pavlath reported the first example of
electrophilic monofluoromethylation—the acid-catalyzed
monofluoromethylation of benzene with fluoromethanol
(FCH2OH).8 However, during the following 32 years, the
electrophilic monofluoromethylation was almost neglected.9
Since 1985, several examples of electrophilic monofluoro-
methylation of oxygen-, sulfur-, nitrogen-, and carbon-
nucleophiles have been reported, by use of CH2FI,10
CH2FBr,11 CH2FCl,11e,12 or CH2FOSO2R (R¼CF3, CH3,
tolyl)11d,13 as monofluoromethylating agents. However,
most of these electrophilic monofluoromethylations are
[18F]-labeled fluoromethylation, and it has been pointed
Keywords: Fluorine; Electrophilic; Monofluoromethylation; SN2 reaction.
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128;
e-mail: jinbohu@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.043

10570
W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
out that the yields of some reactions were not reproducible
due to the unstable nature of the monofluoromethylated
products.10d
temperature was raised to 80 ꢁC (see Table 1, entry 7). Fur-
thermore, we found that other polar non-protic solvents such
as DMSO and NMP were also suitable for the reaction
(Table 1, entries 9 and 10).
Intrigued by the biological importance of incorporating
monofluoromethyl group into organic molecules, recently
we reported the first nucleophilic monofluoromethylation
using PhSO2CH2F reagent.14 Thereafter, nucleophilic
monofluoromethylation has been studied by several different
research groups.15 We have been interested in the electro-
philic monofluoromethylation using inexpensive and readily
available chlorofluoromethane (CH2ClF, 1), with the follow-
ing aims: (1) to explore the substrate scope of electrophilic
monofluoromethylation reactions; (2) to ascertain the reac-
tion mechanism (SN2 or SET, see Scheme 1, Eq. 3); (3) to
determine the stability of the monofluoromethylated
products. In this article, we wish to report our results in these
studies.
To ascertain the mechanism of this electrophilic monofluoro-
methylation with CH2ClF, we added a radical scavenger
(1.0 equiv of nitrobenzene) in the reaction mixture and
found that the radical scavenger did not show inhibition
effect of the monofluoromethylation reaction (Table 1, com-
pare entries 11 and 5). This observation strongly indicates
that the current electrophilic monofluoromethylation pro-
ceeded via a nucleophilic substitution (very possibly through
Table 2. Electrophilic monofluoromethylation of phenyl derivatives 2 with
CH2ClF
Entry
1
Substrate
Product
Yielda (%)
86b
OH
OCH2F
2. Results and discussion
2a
3a
OCH2F
OH
2.1. With oxygen-nucleophiles
2
3
90
93
In the preliminary studies, we chose phenol 2a as a model
compound to optimize the reaction conditions (Table 1).
The typical experimental procedure is as follows: compound
2a (2 mmol) and the base were stirred in a pressure tube for
15 min, then the chlorofluoromethane (1) was bubbled into
the solution for a period of 15 min (ca. 15 mmol) at the
room temperature. The tube was then sealed and the reaction
mixture was heated to the desired temperature for additional
3 h. When K2CO3 was used as a base, the reaction was
unsuccessful and no desired product 3a was detected by the
19F NMR spectroscopy (Table 1, entry 1). By using KOH
as a base in CH3CN, we only obtained the product 3a in
<10% yield (Table 1, entries 2 and 3). When DMF was
used as a solvent, the product yield was increased to 53%
(Table 1, entry 4). It was found that NaH in DMF gave better
results (with 74% yield) at room temperature (Table 1, entry
5). The best yield (86%) was obtained when the reaction
3b
2b
OH
OCH2F
2c
3c
OH
Cl
OCH2F
Cl
4
5
6
86
95
87
Cl
Cl
2d
3d
Ph
OH
Ph
OCH2F
OCH2F
3e
2e
OH
3f
OCH2F
2f
OH
I
7
8
88
92
Table 1. Screening the reaction conditions
I
3g
2g
CH2F
OH
O
Br
Br
base
solvent, 3 h
+
CH2ClF
OH
Br
OCH2F
Br
2a
1
3a
2h
3h
Br
Br
Entry
Base
Base/2a
Solvent
T (ꢁC)
Yielda (%)
OH
OCH2F
OCH2F
1
2
3
4
5
6
7
8
K2CO3
KOHb
KOHb
KOHb
NaH
KOH
NaH
NaH
1.1:1
2.0:1
4.0:1
2.0:1
1.1:1
2.0:1
1.1:1
1.1:1
1.1:1
1.1:1
1.1:1
Ether
CH3CN
CH3CN
DMF
DMF
DMF
DMF
THF
DMSO
NMP
DMF
rt
rt
rt
rt
n.r
<10
<10
53
74
64
86
22
83
84
9
87
3i
2i
OH
rt
80
80
80
80
80
rt
10
91
92
2j
3j
9
10
NaH
NaH
NaH
OH
Br
OCH2F
Br
11
11c
78
Cl
Cl
2k
3k
Determined by 19F NMR spectroscopy.
KOH (30 wt % in H2O).
Nitrobenzene of 1.0 equiv was added.
a
b
c
a
Isolated yield.
Determined by 19F NMR spectroscopy.
b

W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
10571
Table 3. Electrophilic monofluoromethylation of thiols 4 with CH2ClF
SN2) mechanism, rather than halophilic or single electron
transfer (SET) mechanism.16
NaH
+
R
SH
CH2ClF
R
SCH2F
DMF, 80 °C / 0 °C, 3h
4
1
5
By using the optimized reaction condition, we studied the
scope of the electrophilic monofluoromethylation reactions
with oxygen-nucleophiles. The results are summarized in
Table 2. Avarietyofstructurallydiversephenolderivatives2a–
2k were smoothly monofluoromethylated by CH2ClF in the
presence of NaH in DMF solvent to give the corresponding
products 3a–3k in excellent yields (86–95%). The reaction
was compatible with bromo- and iodo-substituted phenols
(Table 2, entries 7–9, and 11) to give products 3g–3i, 3k,
which are possible for further elaboration through transition
metal-catalyzed cross-coupling reactions. In addition, we
used the naphthalen-1-ylmethanol (Fig. 1, 2l) and diphenyl-
methanol (Fig. 1, 2m) as the O-nucleophile in the reaction,
and it was found that the yields determined by 19F NMR
spectroscopy were 73% (for the reaction with 2l, 19F NMR
d ꢀ152.6 (t, J¼56.8 Hz)) and 96% (for the reaction with
2m, 19F NMR d ꢀ152.7 (t, J¼56.4 Hz)), respectively. How-
ever, wewerenotable to isolatethese two monofluoromethyl-
ated ether products through silica gel chromatography due to
the instability of these two products (defluorination was ob-
served). Furthermore, aliphatic alcohol 2n was also found
to be able to react with CH2ClF under similar reaction condi-
tion, but with lower yield (22%, monitored by 19F NMR).
Entry
1
Substrate
Product
Yielda (%)
72
SH
SCH2F
5a
4a
SH
SCH2F
2
3
75
74
O2N
O2N
5b
4b
SH
SCH2F
5c
4c
Cl
Cl
SH
Cl
SCH2F
4
80
Cl
5d
4d
SH
SCH2F
5
70
86
4e
5e
N
SCH2F
N
SH
N
N
N
6b
N
N
N
OH
OH
4f
5f
N
SH
N
SCH2F
N
N
OH
SH
7b
64
82
13
12
N
N
N
N
Ph
5g
Ph
4g
2l
2m
2n
4i
N
S
N
Figure 1. Compounds 2l–2n and 4i.
SH
SCH2F
8b
S
5h
4h
2.2. With sulfur-nucleophiles
a
Isolated yield.
Chlorofluoromethane was bubbled into the solution at 0ꢁC, then the mix-
ture was warmed to room temperature gradually and stirred overnight.
b
We further examined the electrophilic monofluoromethyl-
ation reaction with sulfur-nucleophiles. The results are sum-
marized in Table 3. It was found that under similar reaction
condition (CH2ClF/NaH/DMF, 80 ꢁC, 3 h), thiophenol and
its derivatives showed high reactivity toward monofluoro-
methylation with CH2ClF, and corresponding monofluoro-
methylated sulfide products were obtained in high yields
(72–80%, Table 3, entries 1–4). Interestingly, phenylmetha-
nethiol (4e), 1-tert-butyl-1,2,3,4-tetrazole-5-thiol (4f),
1-phenyl-1,2,3,4-tetrazole-5-thiol (4g), and 2-benzothiazole-
thiol (4h) were all able to be efficiently monofluoro-
methylated by CH2ClF in 64–86% yield (Table 3, entries
5–8). However, we found that the simple aliphatic thiol 4i
(see Fig. 1) did not show reactivity toward CH2ClF under
similar reaction condition.
have high tendency to undergo dehydrofluorination reac-
tions.17 The electrophilic monofluoromethylation of tertiary
amines with CH2ClF (to give fluoromethylated ammonium
salts) with low yields has been reported.12 However, we
were not aware of any reports on the electrophilic mono-
fluoromethylation of secondary amines to give fluorometh-
ylated tertiary amines. As shown in Table 4, a variety of
structurally diverse N-heterocyclic compounds 6a–6i were
readily monofluoromethylated to give the corresponding
N-CH2F-containing products 7a–7i. We found that products
7f–7i were difficult to isolate due to their tendency of de-
composition (during purification) and/or their high volatility.
It is noteworthy that the stability of products 5a and 5c was
quite low. For example, we found that when the liquid com-
pound 5c was stored in a refrigerator for 15 days, it polymer-
ized to give a white solid material.
2.4. With carbon-nucleophiles
Electrophilic monofluoromethylation with carbon-nucleo-
philes (C–C bond formation) could be a very useful reaction
for the synthesis of many fluoromethylated bioactive com-
pounds. Although there are several successful examples of
electrophilic monofluoromethylation of certain carbon-
nucleophiles with CH2ClF,12b CH2BrF,11c CH2FI,9 and
FCH2OH,8 these reports did not show the scope and
2.3. With nitrogen-nucleophiles
It is well-recognized that monofluoromethylated amines
bearing an a-H (RNHCH2F) are thermally unstable, they

10572
W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
Table 4. Electrophilic monofluoromethylation of nitrogen-nucleophiles 6
with CH2ClF
were observed. Fluoromethyl tosylate (FCH2OTs) was also
used as monofluoromethylating agent to react with 8a, and
no success was achieved. Under similar reaction condition
as those for Tables 2–4, the C-monofluoromethylation was
also found to be unsuccessful with compound 8d.
NaH
+
NH
CH2ClF
N CH2F
DMF, 80 °C,3h
6
1
7
Entry
1
Substrate
Product
Yielda (%)
(1) base, solvent
C-nucleophile
C-CH2F product
X
CH2F
N
HN
(2) CH2ClF
8
9
71
84
N
N
6a
O
O
O
O
O
7a
O
O
CH2F
N
OEt
H
N
O
N
OEt
2
N
N
8b
8a
8d
8c
6b
7b
N
Scheme 2.
N
CH2F
CH2F
N
O2N
O2N
H
N
7ca
3b
71
3. Conclusion
N
O2N
6c
In summary, we have shown that CH2ClF can be used as
a useful electrophilic monofluoromethylating agent for a
variety of O-, S-, and N-nucleophiles. The reaction is not
sensitive to the radical scavenger such as nitrobenzene, which
strongly supports an SN2 mechanism rather than an SET
mechanism. Although most of these products (fluoromethyl
ethers, sulfides, and amines) can be isolated with good pu-
rity, some of these compounds do intend to decompose
(via defluorination) during storage. The electrophilic mono-
fluoromethylation of carbon-nucleophiles was attempted
with CH2ClF, CH2FI, or FCH2OTs as monofluoromethylat-
ing agents, but in all cases the reaction did not occur. More
efficient electrophilic monofluoromethylating agent for
C-fluoromethylation is thus highly desired, and further efforts
aiming at this goal are currently underway in our laboratory.
N
7cb
CH2F
N
H
O
N
O
4b
N
50
71
N
6d
7d
O
O
Bz
Bz
5b
N
Ph
N
NH
Ph
N
CH2F
6e
7e
O
O
6
NH
N
CH2F
23c
80c
O
O
6f
7f
4. Experiment sections
4.1. General information
7
8
N
CH2F
N
H
6g
7g
CH2F
N
NH
6h
N
N
28c
46c
All solvents and reagents were purchased from commercial
sources and used as received. 1H, 13C, and 19F NMR spectra
were recorded on a 500, 400, or 300 MHz NMR spectrome-
ter. 1H NMR chemical shifts were determined relative to in-
ternal (CH3)4Si (TMS) at d 0.0 or to the signal of a residual
protonated solvent: CDCl3 d 7.26. 13C NMR chemical shifts
were determined relative to internal TMS at d 0.0. 19F NMR
chemical shifts were determined relative to CFCl3 at d 0.0.
Mass spectra were obtained on a mass spectrometer. High-
resolution mass data were recorded on a high-resolution
mass spectrometer in the EI, ESI, or MALDI mode.
7h
N
N
N
N
9
N
N
H
CH2F
6i
7i
a
Isolated yield.
Stirred overnight.
b
c
Determined by 19F NMR spectroscopy.
generality of the C-monofluoromethylation reaction. Based
on our above-mentioned study of O-, S-, and N-monofluoro-
methylation with CH2ClF, we attempted to apply the similar
reaction condition to the carbon-nucleophiles. As shown in
Scheme 2, we used several carbon pro-nucleophiles 8a–8d
as model compounds to test the C-monofluoromethylation
with CH2ClF. It was found that upon treatment of LDA in
THF at ꢀ78 ꢁC, compounds 8a–8c (corresponding carban-
ions) could not undergo electrophilic monofluoromethyl-
ation with CH2ClF. We also tried to use CH2FI (to replace
CH2ClF) as monofluoromethylating agent to react with 8a
and 8b, but in both cases no C-fluoromethylated products
4.2. General procedure
Naphthalen-2-ol 2b (288 mg, 2 mmol), DMF (4 mL), and
NaH (60 wt %, 88 mg, ca. 2.2 mmol) were stirred in a pres-
sure tube at room temperature for 15 min, then the chloro-
fluoromethane (1) was bubbled into the solution for
a period of 15 min (ca. 15 mmol). The tube was then sealed
and the reaction mixture was heated to 80 ꢁC for additional
3 h. Then to the mixture was added H2O (8 mL) and ex-
tracted with ethyl acetate (25 mLꢂ3), the combined organic

W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
10573
phase was washed with brine and dried over MgSO4. After
the removal of solvents under vacuum, the crude product
was further purified by silica gel column chromatography
to give the product 3b as a white solid. Yield: 90% (316 mg).
4.2.8. 1-Bromo-2-(fluoromethoxy)naphthalene (3i).
White solid. Mp: 71–72 ꢁC. IR (film): 3015, 1596, 1504,
1
1284, 1229, 1147, 1112, 972, 958, 802 cmꢀ1. H NMR:
d 8.25 (d, J¼8.4 Hz, 1H), 7.81 (d, J¼8.7 Hz, 2H), 7.60 (t,
J¼8.4 Hz, 1H), 7.39–7.49 (m, 2H), 5.83 (d, J¼54.6 Hz,
2H). 19F NMR: d ꢀ148.5 (t, J¼52.5 Hz, 1F). 13C NMR:
d 151.4, 132.9, 131.3, 129.2, 128.1, 127.9, 126.8, 125.6,
117.7, 111.6, 101.8 (d, J¼220.1 Hz). MS (EI, m/z, %): 254
(M+, 100.00). Anal. Calcd for C11H8BrFO: C, 51.79; H,
3.16. Found: C, 51.72; H, 3.21.
4.2.1. 2-(Fluoromethoxy)naphthalene (3b).10d White
1
solid. H NMR: d 7.79 (t, J¼8.7 Hz, 3H), 7.38–7.50 (m,
3H), 7.24–7.27 (m, 1H), 5.83 (d, J¼54.6 Hz, 2H). 19F
NMR: d ꢀ148.8 (t, J¼54.1 Hz, 1F).
4.2.2. 1-(Fluoromethoxy)naphthalene (3c). Colorless liq-
uid. IR (film): 3057, 2925, 1597, 1510, 1392, 1260, 1237,
4.2.9. 5-(Fluoromethoxy)-2,3-dihydro-1H-indene (3j).
Colorless liquid. IR (film): 2930, 1611, 1492, 1286, 1241,
1126, 979, 771 cmꢀ1
.
1H NMR: d 8.19–8.22 (m, 1H),
1
7.78–7.81 (m, 1H), 7.56 (d, J¼8.1 Hz, 1H), 7.46–7.51 (m,
2H), 7.37 (t, J¼7.8 Hz, 1H), 7.14 (d, J¼7.2 Hz, 1H), 5.86
(d, J¼54.3 Hz, 2H). 19F NMR: d –148.1 (t, J¼53.9 Hz,
1F). 13C NMR: d 152.8, 134.6, 127.6, 126.7, 125.9, 125.8,
125.7, 123.3, 121.8, 109.2, 101.1 (d, J¼217.8 Hz). MS
(EI, m/z, %): 176 (M+, 62.43), 115 (100.00). Anal. Calcd
for C11H9FO: C, 74.99; H, 5.15. Found: C, 74.98; H, 5.24.
1168, 1144, 1101, 975, 816 cmꢀ1. H NMR: d 7.14 (d,
J¼7.8 Hz, 1H), 6.96 (s, 1H), 6.85 (d, J¼8.1 Hz, 1H), 5.67
(d, J¼54.9 Hz, 2H), 2.83–2.91 (m, 4H), 2.03–2.13 (m,
2H). 19F NMR: d ꢀ147.9 (t, J¼54.7 Hz, 1F). 13C NMR:
d 155.7, 146.0, 139.3, 124.9, 114.8, 113.0, 101.3 (d,
J¼216.4 Hz), 33.1, 32.1, 25.8. MS (EI, m/z, %): 166 (M+,
49.20), 117 (100.00). HRMS (EI) calcd for C10H11FO:
166.0794. Found: 166.0788.
4.2.3. 2,4-Dichloro-1-(fluoromethoxy)benzene (3d).18
1
White solid. H NMR: d 7.42 (s, 1H), 7.23 (d, J¼8.7 Hz,
4.2.10. 2-Bromo-4-chloro-1-(fluoromethoxy)benzene
(3k). White solid. Mp: 59–60 ꢁC. IR (film): 3079, 1573,
1H), 7.14 (d, J¼8.7 Hz, 1H), 5.71 (d, J¼54.0 Hz, 2H). 19F
NMR: d ꢀ150.0 (t, J¼54.1 Hz, 1F).
1
1477, 1295, 1235, 1094, 967, 869, 808 cmꢀ1. H NMR:
d 7.58 (s, 1H), 7.27 (d, J¼8.7 Hz, 1H), 7.11 (d, J¼8.7 Hz,
1H), 5.71 (d, J¼54.0 Hz, 2H). 19F NMR: d ꢀ150.1 (t,
J¼53.0 Hz, 1F). 13C NMR: d 152.3, 133.1, 129.5, 128.7,
118.1, 113.8, 101.1 (d, J¼220.8 Hz). MS (EI, m/z, %): 238
(M+, 46.62), 63 (100.00). HRMS (EI) calcd for
C7H5BrClFO: 237.9196. Found: 237.9203.
4.2.4. 4-Phenyl-1-(fluoromethoxy)benzene (3e). White
solid. Mp: 72–73 ꢁC. IR (film): 3034, 1610, 1522, 1486,
1296, 1240, 1095, 950, 836, 758 cmꢀ1. 1H NMR: d 7.56 (d,
J¼8.1 Hz, 4H), 7.43 (t, J¼7.2 Hz, 2H), 7.33 (t, J¼7.2 Hz,
1H), 7.16 (d, J¼8.7 Hz, 2H), 5.75 (d, J¼54.6 Hz, 2H). 19F
NMR: d ꢀ148.9 (t, J¼53.9 Hz, 1F). 13C NMR: d 156.3,
140.4, 136.7, 128.8, 128.4, 127.1, 126.9, 117.0, 100.8 (d, J¼
217.4 Hz). MS (EI, m/z, %): 202 (M+, 100.00). Anal. Calcd
for C13H11FO: C, 77.21; H, 5.48. Found: C, 77.31; H, 5.52.
4.2.11. (Fluoromethyl)(phenyl)sulfane (5a).19 Colorless
liquid. H NMR: d 7.47–7.50 (m, 2H), 7.28–7.36 (m, 3H),
1
5.70 (d, J¼53.1 Hz, 2H). 19F NMR: d ꢀ182.0 (t, J¼
52.4 Hz, 1F).
4.2.5. 1-tert-Butyl-4-(fluoromethoxy)benzene (3f). Color-
less liquid. IR (film): 2965, 1612, 1515, 1365, 1299, 1232,
1187, 1091, 979, 834 cmꢀ1. 1H NMR: d 7.33 (d, J¼8.7 Hz,
2H), 7.01 (d, J¼8.7 Hz, 2H), 5.67 (d, J¼54.9 Hz, 2H), 1.30
(s, 9H). 19F NMR: d ꢀ147.9 (t, J¼52.7 Hz, 1F). 13C NMR: d
154.6, 146.3, 126.3, 116.2, 101.0 (d, J¼216.7 Hz), 34.2, 31.4.
MS (EI, m/z, %): 182 (M+, 18.05), 167 (100.00). HRMS (EI)
calcd for C11H15FO: 182.1107. Found: 182.1115.
4.2.12. (Fluoromethyl)(4-nitrophenyl)sulfane (5b).20 Yel-
1
low solid. H NMR: d 8.19 (d, J¼8.7 Hz, 2H), 7.57 (m,
J¼8.7 Hz, 2H), 5.85 (d, J¼52.2 Hz, 2H). 19F NMR:
d ꢀ185.2 (t, J¼53.9 Hz, 1F).
4.2.13. (Fluoromethyl)(o-tolyl)sulfane (5c). Colorless liq-
uid. H NMR: d 7.56–7.58 (m, 1H), 7.23–7.25 (m, 3H),
1
5.74 (d, J¼52.8 Hz, 2H), 2.44 (s, 3H). 19F NMR: d ꢀ182.7
(t, J¼52.2 Hz, 1F). It is an unstable compound.
4.2.6. 1-(Fluoromethoxy)-2-iodobenzene (3g). Colorless
liquid. IR (film): 2927, 1585, 1473, 1231, 1089, 1021, 984,
1
752 cmꢀ1. H NMR: d 7.79 (d, J¼7.8 Hz, 1H), 7.31 (t,
4.2.14. (2,6-Dichlorophenyl)(fluoromethyl)sulfane (5d).
Colorless liquid. IR (film): 2945, 1568, 1556, 1427, 1404,
J¼8.1 Hz, 1H), 7.10 (d, J¼8.1 Hz, 1H), 6.84 (t, J¼7.5 Hz,
1H), 5.71 (d, J¼54.3 Hz, 2H). 19F NMR: d ꢀ149.1 (t, J¼
54.7 Hz, 1F). 13C NMR: d 155.9, 139.7, 129.7, 125.3,
116.0, 101.1 (d, J¼219.8 Hz), 87.2. MS (EI, m/z, %): 252
(M+, 100.00). Anal. Calcd for C7H6FIO: C, 33.36; H, 2.40.
Found: C, 33.45; H, 2.31.
1321, 1189, 976, 779 cmꢀ1
.
1H NMR: d 7.44 (d, J¼
8.1 Hz, 2H), 7.27 (d, J¼8.1 Hz, 1H), 5.70 (d, J¼52.2 Hz,
2H). 19F NMR: d ꢀ185.8 (t, J¼52.2 Hz, 1F). 13C NMR: d
141.3, 131.0, 130.3, 128.9, 88.2 (d, J¼218.9 Hz). MS (EI,
m/z, %): 210 (M+, 100). Anal. Calcd for C7H5Cl2FS: C,
39.83; H, 2.39. Found: C, 40.00; H, 2.32.
4.2.7. 1,3-Dibromo-2-(fluoromethoxy)-5-methylbenzene
(3h). Colorless liquid. IR (film): 2989, 1590, 1488, 1457,
1410, 1244, 1080, 1049, 1000, 741 cmꢀ1. 1H NMR: d 7.35
(s, 2H), 5.67(d, J¼54.0 Hz, 2H), 2.28 (s, 3H). 19F NMR:
d ꢀ149.0 (t, J¼53.0 Hz, 1F). 13C NMR: d 148.6, 137.9,
133.3, 117.4, 103.9 (d, J¼224.3 Hz), 20.2. MS (EI, m/z,
%): 298 (M+, 100.00). Anal. Calcd for C8H7Br2FO: C,
32.25; H, 2.37. Found: C, 32.53; H, 2.37.
4.2.15. Benzyl(fluoromethyl)sulfane (5e).21 Colorless liq-
1
uid. H NMR: d 7.34–7.36 (m, 5H), 5.38 (d, J¼52.8 Hz,
2H). 19F NMR: d ꢀ189.2 (t, J¼51.6 Hz, 1F).
4.2.16. 1-tert-Butyl-5-(fluoromethylthio)-1H-tetrazole
(5f). White solid. Mp: 54–55 ꢁC. IR (film): 2982, 1476,
1399, 1373, 1336, 1289, 1227, 1139, 1104, 985, 720,

10574
W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
591 cmꢀ1. 1H NMR: d 6.25 (d, J¼49.8 Hz, 2H), 1.75 (s, 9H).
19F NMR: d ꢀ187.9 (t, J¼50.0 Hz, 1F). 13C NMR: d 149.6,
84.4 (d, J¼225.4 Hz), 61.7, 29.1. MS (EI, m/z, %): 190 (M+,
1), 57 (100). Anal. Calcd for C6H11FN2S: C, 37.88; H, 5.83;
N, 29.45. Found: C, 38.06; H, 5.49; N, 29.79.
51.3 Hz, 2H), 3.80 (t, J¼9.6 Hz, 2H), 2.96 (t, J¼9.6 Hz,
2H). 19F NMR: d ꢀ155.8 (t, J¼51.9 Hz, 1F). 13C NMR:
d 159.4, 148.6, 129.0, 119.2, 133.3, 98.3 (d, J¼221.4 Hz),
50.7, 30.5. MS (EI, m/z, %): 194 (M+, 35.64), 77 (100.00).
Anal. Calcd for C10H11FN2O: C, 61.85; H, 5.71; N, 14.42.
Found: C, 61.77; H, 5.78; N, 14.25.
4.2.17. 5-(Fluoromethylthio)-1-phenyl-1H-tetrazole (5g).
White solid. Mp: 86–87 ꢁC. IR (film): 2969, 1597, 1591,
1502, 1425, 1396, 1244, 1002, 982, 765, 719, 697, 689,
4.2.23. 4-Benzoyl-1-(fluoromethyl)-5-methyl-2-phenyl-
1,2-dihydropyrazol-3-one (7e). White solid. Mp:
85ꢀ86 ꢁC. IR (film): 3053, 1636, 1549, 1508, 1468, 1396,
992, 906 cmꢀ1. 1H NMR: d 7.81 (d, J¼8.1 Hz, 2H), 7.69 (d,
J¼8.7 Hz, 2H), 7.58 (t, J¼7.4 Hz, 1H), 7.44–7.51 (m, 4H),
7.37 (t, J¼7.2 Hz, 1H), 5.44 (d, J¼52.5 Hz, 2H), 2.26 (s,
3H). 19F NMR: d ꢀ149.9 (t, J¼52.5 Hz, 1F). 13C NMR:
d 190.4, 150.2, 138.8, 137.3, 132.8, 129.2, 128.5, 128.0,
123.7, 108.0, 104.0 (d, J¼228.9 Hz), 15.0. MS (EI,
m/z, %): 310 (M+, 58.58), 77(100.00). Anal. Calcd for
C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.68;
H, 4.88; N, 8.91.
555 cmꢀ1 1H NMR: d 7.53–7.61 (m, 5H), 6.22 (d,
.
J¼50.1 Hz, 2H). 19F NMR: d ꢀ188.4 (t, J¼49.8 Hz, 1F).
13C NMR: d 151.4, 133.1, 130.7, 130.0, 124.2, 83.9 (d,
J¼226.8 Hz). MS (EI, m/z, %): 211 ([M+H]+, 1), 46 (100).
Anal. Calcd for C8H7FN4S: C, 45.70; H, 3.36; N, 26.65.
Found: C, 45.81; H, 3.38; N, 26.32.
4.2.18. 2-(Fluoromethylthio)benzo[d]thiazole (5h). White
solid. Mp: 59–60 ꢁC. IR (film): 2930, 1467, 1455, 1431,
1
1411, 1322, 1311, 1005, 972, 766, 754,718, 674 cmꢀ1. H
NMR d 7.80–7.98 (m, 2H), 7.33–7.50 (m, 2H), 6.16 (d,
J¼50.7 Hz, 2H). 19F NMR d ꢀ186.7 (t, J¼51.1 Hz, 1F).
13C NMR d 62.4, 152.9, 135.8, 126.4, 125.0, 122.4, 121.2,
84.8 (d, J¼222.2 Hz). MS (EI, m/z, %): 199 (M+, 42), 135
(100). Anal. Calcd for C8H6FNS2: C, 48.22; H, 3.03; N,
7.03. Found: C, 48.36; H, 3.03; N, 7.04.
Acknowledgements
We thank the National Natural Science Foundation of China
(20502029), Shanghai Rising-Star Program (06QA14063),
and the Chinese Academy of Sciences (Hundreds-Talent
Program) for financial support. Zhejiang Lantian Co.
is gratefully acknowledged for providing us chlorofluoro-
methane.
4.2.19. 1-(Fluoromethyl)-2-phenyl-1H-imidazole (7a).
Yellow liquid. IR (film): 3394, 1506, 1483, 1468, 1394,
1
1284, 984, 776, 700 cmꢀ1. H NMR: d 7.70–7.73 (m, 2H),
7.47–7.51 (m, 3H), 7.18–7.20 (m, 2H), 5.88 (d, J¼
52.8 Hz, 2H). 19F NMR: d ꢀ157.9 (t, J¼54.1 Hz, 1F).
13C NMR: d 149.1, 129.6, 129.2, 128.8, 121.6, 83.3
(d, J¼198.2 Hz). MS (EI, m/z, %): 176 (M+, 100).
HRMS (EI): calcd for C10H9FN2: 176.0750. Found:
176.0754.
References and notes
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1
1460, 1371, 1268, 1219, 987, 973 cmꢀ1. H NMR: d 8.02
(s, 1H), 7.83–7.85 (m, 1H), 7.50–7.53 (m, 1H), 7.33–7.41
(m, 2H), 6.14 (d, J¼53.4 Hz, 2H). 19F NMR: d ꢀ163.7 (t,
J¼54.1 Hz, 1F). 13C NMR: d 144.0, 143.1, 133.2, 124.3,
123.5, 120.8, 109.5, 81.7 (d, J¼199.5 Hz). MS (EI, m/z,
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Orda, V. V. Synthesis 1978, 835–837; (b) Yagulpol’skii,
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1
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(s, 1H), 8.32–8.37 (m, 2H), 8.29 (s, 1H), 8.24 (s, 1H), 7.94
(d, J¼8.7 Hz, 1H), 7.64 (d, J¼8.7 Hz, 1H), 6.26 (d,
J¼52.5 Hz, 2H), 6.24 (d, J¼52.8 Hz, 2H). 19F NMR:
d ꢀ165.0 (t, J¼52.5 Hz, 1F), ꢀ165.5 (t, J¼52.4 Hz, 1F).
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1
1370, 1000, 751 cmꢀ1. H NMR: d 7.22ꢀ7.28 (m, 2H),
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W. Zhang et al. / Tetrahedron 63 (2007) 10569–10575
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