Electrophilic fluorination with N,N′-difluoro-2,2′-bipyridinium salt and elemental fluorine

Article abstract of DOI:10.1016/S0022-1139(02)00327-5

NNpm-Difluoro-22pm-bipyridiniu m bis(tetrafluoroborate) (MEC-31) was shown to be a highly reactive electrophilic fluorinating agent with the highest effective fluorine content in its class. We have developed the perfect recycled fluorination system with MEC-31 for the lower-cost industrial fluorination and for an environment. MEC-31 can be completely recycled including the counter-anion. We found the fluorination of 2-naphthol in liquid CO₂ with MEC-31 in the presence of catalytic amount of NaOTf proceeded quantitatively without the generation of by-product. In the fluorination of 1,3-dicarbonyl compounds with elemental fluorine, we found the introduction method of fluorine gas would be very important in order to make a reaction efficient. As fluorination goes on, the quantity of 1,3-dicarbonyl compounds of the starting material is reduced gradually, and therefore the quantity of fluorine must be reduced by the method to control the flow rate or the concentration of fluorine gas diluted with nitrogen, together the fluorination to proceed efficiently.

Full text of DOI:10.1016/S0022-1139(02)00327-5

Journal of Fluorine Chemistry 120 (2003) 173–183
0
0
Electrophilic fluorination with N,N -difluoro-2,2 -bipyridinium
salt and elemental fluorine
*
Kenji Adachi , Yutaka Ohira, Ginjiro Tomizawa, Sumi Ishihara, Satoshi Oishi
Research and Development Department No. 2, Chemical Division, Daikin Industries Limited,
3
Miyukigaoka, Tsukuba-shi, Ibaraki 305-0841, Japan
Received 9 September 2002; received in revised form 28 October 2002; accepted 11 November 2002
Abstract
0
0
N,N -Difluoro-2,2 -bipyridinium bis(tetrafluoroborate) (MEC-31) was shown to be a highly reactive electrophilic fluorinating agent with the
highest effective fluorine content in its class. We have developed the perfect recycled fluorination system with MEC-31 for the lower-cost industrial
fluorination and for an environment. MEC-31 can be completely recycled including the counter-anion. We found the fluorination of 2-naphthol in
2
liquid CO with MEC-31 in the presence of catalytic amount of NaOTf proceeded quantitatively without the generation of by-product.
In the fluorination of 1,3-dicarbonyl compounds with elemental fluorine, we found the introduction method of fluorine gas would be very
important in order to make a reaction efficient. As fluorination goes on, the quantity of 1,3-dicarbonyl compounds of the starting material is
reduced gradually, and therefore the quantity of fluorine must be reduced by the method to control the flow rate or the concentration of fluorine
gas diluted with nitrogen, together the fluorination to proceed efficiently.
#
2002 Elsevier Science B.V. All rights reserved.
0
0
Keywords: Fluorination; Fluorinating agent; Electrophilic; N,N -Difluoro-2,2 -bipyridinium salt; N-Fluoropyridinium salt; Fluorine; Recycle; 1,3-Dicarbonyl
compounds
0
0
1
. Introduction
N,N -difluoro-2,2 -bipyridinium bis(tetrafluoroborate) (MEC-
1) [1], counter-anion-bound fluorinating agents (MEC-01,
3
When introducing fluorine atoms to organic compounds,
-02, -03, -04B, -05) as an electrophilic fluorinating agent [2].
Besides these agents, a lot of electrophilic fluorinating agents
with an N–F moiety are known [3,4] (Scheme 1).
the characteristics of the original compound changes con-
siderably, due to its high electronegativity, strong bonding
forces with carbon, and lipophilicity effect, etc. By utilizing
the peculiar characteristics of the fluorine atom, recently the
introduction of fluorine into the fields of medicine, agricul-
tural chemicals, and new materials such as liquid crystals is
widely practiced.
And we have the corresponding industrial fluorination
technologies, elemental fluorine [5,6], IF /Et N-3HF [7,8],
and SF [9–11], for bulk supply of the new fluorocompounds
5
3
4
that are synthesized with the fluorinating agents for
researching new compounds.
We have been trying to advance various technical devel-
opments in order to introduce fluorine atoms into organic
compounds, and have classified these technologies into
fluorinating agents for researching new compounds and
industrial fluorination technologies.
Hereunder, we would like to explain fluorinating agents
for researching new fluorocompounds, MEC-31, and direct
fluorination with elemental fluorine for industrial fluorina-
tion technology.
Fluorinating agents for researching new compounds are
safe, easy to handle, and widely used agents. By using our
agents for the direct fluorination of developing compounds,
various fluorocompounds are able to be easily obtained, and
research can proceed more rapidly than developing a new
synthesis route for the fluorocompounds. At present, we have
2. Results and discussion
2.1. Powerful electrophilic fluorinating agent: MEC-31
0
0
(N,N -difluoro-2,2 -bipyridinium bis(tetrafluoroborate))
2
.1.1. Synthesis of MEC-31
MEC-31 can be synthesized in one pot by introducing BF3
*
Corresponding author. Tel.: þ81-298-58-5074; fax: þ81-298-58-5082.
0
E-mail address: kenji.adachi@daikin.co.jp (K. Adachi).
gas into 2,2 -bipyridine at 0 8C and then by introducing
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 3 2 7 - 5

174
K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
Scheme 1.
2.1.3. Effect of additive: sodium
trifluoromethanesulfonate
If the reaction is slow, the addition of catalytic amount of
sodium trifluoromethanesulfonate is very effective. Depend-
ing on the counter-anions of the salt, the solubility of MEC-
31 into organic solvents increases remarkably, and there
Scheme 2.
are cases where the reaction time is shortened for some
substrates as shown in Table 2.
fluorine gas diluted with nitrogen to 25 vol.%. MEC-31 can
be separated easily by filtration alone, because it has the
characteristic of being able to crystallize well and it is
created as precipitated crystals during the reaction. The
isolation yield is 89% (Scheme 2).
2.1.4. Comparison with other isomers
MEC-31 has a molecular structure of the two N-fluor-
opyridinium salts combined at the ortho position, and
through this combination, we succeeded in enhancing the
fluorinating power greatly. Fig. 1 shows the formation curves
of fluorocompound 2 for the comparison of the reactivity of
2
N,N -difluoro-2,2 -bipyridinium salts
.1.2. Fluorination of various nucleophiles with
0
0
0
MEC-31 is a stable crystal without explosive features and
its melting point is 166–168 8C with decomposition. Fluor-
ination can be performed in a glass reactor, and it is easy to
each N,N -difluorobipyridinium bis(triflate), through the
fluorination of 2-acetylcyclohexanone 1. The reaction was
done in CD CN at 50 8C in NMR tube and the yield of 2 was
3
0
0
19
remove N,N -dihydro-2,2 -bipyridinium bis(tetrafluorobo-
rate) generated after the reaction, from desired fluorinated
compounds, as the salt is dissolved in diluted hydrochloric
determined by F NMR using fluorobenzene as an internal
0
standard. A volume of 0.5 mmol of N,N -difluorobipyridi-
nium bis(triflate) was used for the fluorination of 1 mmol
of the substrate 1. In the case of N-fluoropyridinium
triflate 13, 1 mmol was used for 1 mmol of the substrate
1. From this result, relative reactivity was determined to be
0
0
acid. As shown in Table 1, N,N -difluoro-2,2 -bipyridinium
salts can be applied to the fluorination of various kinds of
substrates. They have the tendency to bring good results, in
yield and selectivity, etc. to the aryl compounds and enol
ether compounds. It is understood that as the structures of
N,N -difluoro-2,2 -bipyridinium salts include electron-defi-
cient aromatic ring, they will form the p-complex with the
compounds which are rich in electrons.
0
4 > 10 > 11 ffi 12 @ 13. The lowest reactivity of the 4,4 -
isomer 12, which has strong p-electron conjugation effect,
indicates the p-electron conjugation effect to be unessential
for fluorination. The highest reactivity of the 2,2 -isomer 4
0
0
0
would be due to the N–F moieties being the most deficient in
electrons by the strong electron-withdrawing effect of other
N-fluoropyridinium moieties in the ortho position at a close
We have to note, however, the fact that the mechanism of
carbene formation causes the decomposition of MEC-31 and
the fluorination of substrates does not proceed, when we use
highly reactive nucleophiles or solvents which have highly
nucleophilic nature (such as water or DMSO, etc.), as shown
in Scheme 3 [12,13]. At first, the absorption of hydrogen at
the ortho position occurs by highly reactive nucleophiles to
generate the carbene 7. The carbene 7 reacts with nucleo-
0
distance. In isomers (10–12) except the 2,2 -isomer 4,
though the reactivity of the first fluorine atom was relatively
high, the reactivity of the second fluorine atom decreased
remarkably, as is shown in Fig. 1, it is the same level as N-
fluoropyridinium triflate 13. On the other hand, in the case of
0
2,2 -isomer 4, the difference of reactivity between the first
0
philes to form 3,3’-substituted 2,2 -bipyridine derivatives.
0
and second fluorinations was very small. N-Hydropyridi-
nium moiety generated after the first fluorination is less
electron-withdrawing than N-fluoropyridinium moiety. But,
0
When the nucleophile is water, 3,3 -dihydroxy-2,2 -bipyr-
idine 9 was generated in high yield (Scheme 3).
Scheme 3.

Table 1
0
0
Fluorination of various nucleophiles with N,N -difluoro-2,2 -bipyridinium salt
a
b
Run
Nucleophile
Salt of ‘‘F’’
Additive (mmol)
None
Solvent
Conditions
Reflux, 3 h
Product
Yield (%)
À
1
BF (MEC-31)
CH
3
CN
71
82
4
À
BF
4
2
3
1
NaOTf (0.1)
TfOH (0.1)
CH
3
3
CN
CN
Reflux, 10 min
Reflux, 48 h
2
À
BF
4
Dibenzoylmethane
CH
Dibenzoylfluoromethane
Dibenzoyldifluoromethane
10
76
À
BF
4
4
None
CH
3
CN
Reflux, 8 h
73
À
BF
4
5
6
None
None
CH
3
3
CN
CN
Reflux, 8 h
Reflux, 8 h
76
À
BF
4
Phenol
CH
o-Fluorophenol
p-Fluorophenol
39
33
5
2
,4-Difluorophenol
À
BF
4
7
8
9
Phenol
NaOTf (0.1)
None
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
Reflux, 5 h
Reflux, 9 h
Reflux, 48 h
Reflux, <5 min
RT, 10 min
o-Fluorophenol
p-Fluorophenol
39
31
6
2
,4-Difluorophenol
À
BF
4
Anisole
o-Fluoroanisole
p-Fluoroanisole
40
28
8
2
,4-Difluoroanisole
À
BF
4
Phenylurethane
Resorcinol
2-Naphthol
None
o-Fluorophenylurethane
p-Fluorophenylurethane
48
32
5
2
,4-Difluorophenylurethane
À
BF
4
1
1
0
1
None
4-Fluroresorcinol
72
10
3
4
2
,6-Difluroresorcinol
-Fluroresorcinol
À
BF
4
None
HCOOH
AcOH
1-Fluoro-2-naphthol
,1-Difluoro-2-naphthalenone
61
18
1
À
BF
4
À
BF
4
1
2
3
trans-PhCH¼CHCH
3
None
None
Reflux, <15 min
Reflux, <10 min
PhCH(OAc)CHFCH
1-Fluoro-2-tetralone
3
51
38
1
2-Tetralone
CH
3
CN
À
BF
4
14
NaHCO
3
(0.25)
CH
3
CN
70 8C, 1 h
82

Table 1 (Continued )
a
b
Run
Nucleophile
Salt of ‘‘F’’
Additive (mmol)
Solvent
Conditions
RT, 30 min
Product
Yield (%)
À
BF
4
15
NaHCO
3
(0.25)
CH CN
3
65
À
À
1
6
7
4-Chlorophenol
TfO (4)
TfO
None
None
ClCH
ClCH
2
CH
CH
2
Cl
Cl
82 8C, 20 h
82 8C, 20 h
4-Chloro-2-fluorophenol
40
50
1
Methyl 4-hydroxy-benzoate
2
2
Methyl 3-fluoro-4-hydroxy-benzoate
À
18
TfO
None
ClCH
2
CH
2
Cl
82 8C, 20 h
58
2
3
a
0
0
0
0
Runs 1–15 [1]. For runs 16 and 17, the reaction was carried out in 2 ml of 1,2-dichloroethane using 0.5 mmol of a nucleophile and 0.6 mmol of N,N -difluoro-2,2 -bipyridinium
bis(trifluoromethanesulfonate). For run 18, the reaction was carried out in 2 ml of 1,2-dichloroethane using 0.5 mmol of a nucleophile and 0.3 mmol of N,N -difluoro-2,2 -bipyridinium
bis(trifluoromethanesulfonate).
b
Determined by 19F NMR using fluorobenzene as an internal standard, based on the amount of a nucleophile used.

K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
177
Table 2
equivalent reactivity with MEC-31. The effective fluorine
content means the value of fluorine atoms used for reactions
divided by molecular weight. This value is an indication for
evaluating the cost-effective industrial fluorination. MEC-31,
as stated above, has two active fluorine atoms in the molecule
keeping high reactivity and, therefore, shows an extremely
high value of effective fluorine content per unit weight, in com-
parison with the other fluorinating agents as shown in Table 3.
Effect of catalytic amount of NaOTf
þ
‘
‘F ’’
Additive
Time
Yield of
a
2
(%)
2.1.6. Perfect recycled system in fluorination with MEC-31
We have developed the perfect recycled system with
MEC-31 for the lower-cost industrial fluorination and for
an environment. MEC-31 can be completely recycled
including the counter-anion as shown in Fig. 2. After the
fluorination of 2-naphthol at 88% yield, MEC-31 itself is
–
<5 min
85
MEC-31
MEC-31
–
3 h
71
82
0
0
collected quantitatively in the form of N,N -dihydro-2,2 -
bipyridinium bis(tetrafluoroborate) (16). The salt 16 is easily
collected through filtration, due to good crystallization and
low solubility in solvents. The salt 16 can almost be quan-
titatively converted to MEC-31 again by fluorine gas and can
be used for the fluorination of substrates without isolation.
We consider this fluorination system by recycling MEC-31
as a form of fluorination technology for the next generation,
since it has less impact on the environment.
NaOTf (20 mol%)
10 min
a
Determined by 19F NMR using fluorobenzene as an internal standard.
as N-hydropyridinium moiety exerts a fairly strong electron-
withdrawing effect at the nearest ortho position, the reactivity
0
of the second fluorine in only 2,2 -isomer 4 will be kept too
0
high. Therefore, only the 2,2 -isomer 4 can be used in reactions
with high reactivity for both fluorine atoms in the molecule.
0
0
2.1.5. Effective fluorine content: comparison with
other fluorinating agents
2.1.7. Fluorination with N,N -difluoro-2,2 -bipyridinium
salts in liquid carbon dioxide
We compared the effective fluorine content of MEC-31 with
that of other electrophilic fluorinating agents having an almost
The reaction using carbon dioxide as a solvent, which is
nonpoisonous, and nonflammable which is extremely safe,
Fig. 1. Comparison of reactivity with other isomers.

178
K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
Table 3
Comparison of effective fluorine content
Molecular structure (trade name)
(
MEC-31)
(Selectfluor)
(Accufluor NFTh)
(FP-B800)
Molecular weight
Effective fluorine
content (g/kg)
367.8
103
354.3
54
321.8
59
253.8
75
reaction, the reaction was made in such a condition using 1.1
times of a mole for 2-naphthol. The reaction was done in an
autoclave at a room temperature in a pressured state for 12 h,
the pressure was reduced to normal pressure and carbon
dioxide was eliminated, then the yield of fluorination pro-
ducts was confirmed by 19F NMR using fluorobenzene as an
internal standard. During the reaction, the carbon dioxide
was not at a super critical state but merely at a liquid state.
As shown in Table 4, the products were the mixture of
1-fluoro-2-naphthol 17 and 1,1-difluoro-1H-naphthalen-2-
one 15, all of which were converted into 17 through the
reduction by H /Pd–C. From the result of run 1, when
2
Fig. 2. Perfect recycled system in fluorination with MEC-31.
fluorinating agent 4 was used in liquid carbon dioxide as
a solvent, 1-fluoro-2-naphthol was gained almost quantita-
tively without the generation of by-product after the reduc-
tion. On the other hand, when fluorination is made, as usual
at normal pressure using acetonitrile as a solvent, the yield
was a comparatively low (85%). Raw material, 2-naphthol
was not left all due to the side-reaction. We have found, in
comparison with runs 1 and 2, that the fluorination reaction
with N,N -difluoro-2,2 -bipyridinium salt, when using liquid
carbon dioxide as a solvent, was proceeding quite comple-
tely and that there was almost no sub-reactions. We also tried
the fluorination of 2-naphthol in liquid carbon dioxide as
well, with MEC-31, but this didn’t react at all (run 3). When
we added a catalytic amount of NaOTf, fluorination which
proceeded smoothly with a yield of compound 17 was 95%
after the reduction (run 4). The reason why MEC-31 did not
react is considered that solubility to the liquid carbon
easily eliminated, and easily recovered, is considered to be
excellent due to being gentle to environment just like non-
solvent reaction.
The methods of using molecular fluorine, xenon difluor-
ide, and CF CHFCF N(C H ) are reported, in fluorination
3
2
2 5 2
with carbon dioxide as a solvent [14]. It is reported that
fluorination of saturated hydrocarbon using xenon difluoride
proceeds at 30% yield under the violent conditions of 105 8C
and 5000 psia (340 atm). There is, however, no example of
the fluorination in carbon dioxide using electrophilic fluor-
inating agent that has N–F bonding.
0
0
We have tried fluorinating 2-naphthol in carbon dioxide,
0
0
0
with N,N -difluoro-2,2 -bipyridinium bis(triflate) (4) and
0
MEC-31. Because N,N -difluoro-2,2 -bipyridinium salt can
be used as two active fluorine atoms in the molecule for a
Table 4
0
0
Fluorination with N,N -difluoro-2,2 -bipyridinium salts in liquid CO
2
Run
Fluorinating
agent (mmol)
Solvent
Additive
(mmol)
Yield of
17 (%)
Yield of
15 (%)
Yield of 17 by
reduction (%)
1
2
3
4
4
CO
CH
CO
CO
2
3
2
2
–
10
89
99
4
CN
–
30
56
85
MEC-31
MEC-31
–
No reaction
Trace
No reaction
95
No reaction
95
NaOTf (0.10)

K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
179
dioxide was quite low, and the addition of catalyst NaOTf
caused salt exchanges which increased it’s solubility and
proceeded the reaction smoothly.
N,N -Dihydro-2,2 -bipyridinium salt generated after the
fluorination reaction can be easily recovered almost quanti-
tatively through filtration after dissolving fluorinated com-
pounds with the addition of an organic solvent such as ether,
can be used as an industrial agent for relatively simple
compounds that have a clearly identified reactive site.
Particularly, in the fluorination of 1,3-dicarbonyl com-
pounds, molecular fluorine is quite effective and can achieve
monofluorination in a high yield [15–18].
However, there is a problem in that the usual method in
the fluorination of 1,3-dicarbonyl compounds required more
excess amount of fluorine (more than 2 equivalents (eq.)) for
the consumption of the starting material [15–17]. The use of
more excess fluorine is not economical for the industrial
production, and excess fluorine becomes not only wasteful,
but also it may cause more sub-reactions. For the purpose of
resolving this problem, we have studied the effect of the flow
rate and the concentration of fluorine gas diluted with
nitrogen and the solvent effect in the fluorination of 1,3-
dicarbonyl compound [18].
0
0
0
0
etc. The recovered N,N -dihydro-2,2 -bipyridinium salt can
be returned to fluorinating agent again, by reacting it with
fluorine gas as already stated, and it is possible to recycle.
2.2. Industrial fluorination technologies: direct
fluorination with elemental fluorine
Elemental fluorine (F ) is, needless to say, a tremendously
2
dangerous gas due to it’s reactivity, corrosiveness, poisonous
characteristics, and regarding the handling of it and the
control of it’s reactions. Therefore, special technology
and know-how is required. Elemental fluorine is, generally,
not suited for the fluorination of complex compounds that
contain functional groups that can be oxidized easily, but it
2.2.1. Flow rate effect of fluorine gas
At first, we have studied the effect of the flow rate of
fluorine gas diluted with nitrogen in the fluorination of
methyl 3-oxovalerate (18) when formic acid was used as
Table 5
Comparison between constant and descending flow rate
a
Run
18 (mmol)
Solvent
F
2
concentration
F
2
flow rate
F
2
(eq.)
Time (min)
Product ratio
Yield (%)
(
%)
(ml/min)
19/(19 þ 18) (%)
1
9
20
21
1
2
80
80
HCOOH
HCOOH
10
10
190
2.5
1.65
256
300
97
73
75
3
2
11
11
190 ! 40
100
a
Determined by 19F NMR using fluorobenzene as an internal standard.
Fig. 3. Flow rate and concentration of F
2
gas at run 2 in Table 5.
Fig. 4. Comparison between constant and descending flow rate.

180
K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
a reaction solvent [18]. We have studied the relationship
among the amount of introduced fluorine gas, the product
ratio (percentage expressed by the ratio of a methyl 2-fluoro-
efficiently, the increment of reaction time was very small
in spite of the decreased flow rate of fluorine. Table 5 shows
the yield of 19 and that of by-products 20, 21 determined by
19F NMR using fluorobenzene as an internal standard. The
yield of the desired compound 19 was improved a little, but a
large effect in yield improvement was not confirmed. But,
the complete consumption of the starting material 18 is very
important for the industrial production of 19, because, the
separation of 18 from the desired compound 19 is not easy.
The separation of by-products 20 and 21 is relatively easy by
extraction and distillation.
3
-oxovalerate (19) and the total quantity of 18 plus 19,
measured by gas chromatography) of the desired compound
9, and the time required to introduce fluorine gas. We
1
compared the fluorination of 18 at a constant flow rate and
constant concentration and that at a constant concentration
and descending flow rate as shown in Fig. 3, to know the flow
rate effect of fluorine gas when introduced into a reaction
flask. A reaction was carried out as follows: a solution of
2
1
1
7 ml of formic acid and dissolved starting material 18
0.4 g (80 mmol) was cooled to 6 8C, then while stirring,
0% fluorine gas diluted with nitrogen was introduced at a
2.2.2. Concentration effect of fluorine in nitrogen gas
Similar results were obtained by controlling the concen-
tration of fluorine gas diluted with nitrogen. By the method
shown in Fig. 5, at a constant flow rate, we compared the
case where the concentrations of fluorine gas were changed
in descending order with the case where the concentration of
fluorine gas was kept constant. As a result, we could attain
fluorination reaction more efficiently with less fluorine
consumption as in run 3 in Table 6 and Fig. 5 using the
descending concentration method rather than in run 1 at a
constant concentration. The case of run 2 where fluorine was
constant flow rate (190 ml/min) and at descending flow rate
method shown in Fig. 3. From the results shown in Table 5
and Fig. 4, we found that in run 2 at controlled flow rate we
could achieve the reaction with less consumption of fluorine
than that of run 2 at a constant flow rate. At constant flow
rate, the starting material 18 is still remained even when
2.5 eq. of fluorine gas was introduced, and in the case of the
descending flow rate method, 18 was perfectly consumed at
an equivalent of 1.65 of it. As the reaction proceeded
Table 6
Comparison between constant and descending concentration
a
Run
18 (mmol)
Solvent
F
2
concentration
F
2
flow rate
F
2
(eq.)
Time (min)
Product ratio
Yield (%)
(
%)
(ml/mm)
19/(19 þ 18) (%)
1
9
20
21
1
2
3
50
50
50
HCOOH
HCOOH
HCOOH
10
100
100
100
2.5
2.0
2.0
304
485
402
94
96
97
66
72
71
2
3
2
11
11
11
5
10 ! 3
a
Determined by 19F NMR using fluorobenzene as an internal standard.
Fig. 5. Flow rate and concentration of F
2
gas at run 3 in Table 6.
Fig. 6. Comparison between constant and descending concentration.

K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
181
Table 7
Comparison of solvent effect
a
Run
18 (mmol)
Solvent
F
2
concentration
F
2
flow rate
F
2
(eq.)
Time (min)
Product ratio
Yield (%)
(
%)
(ml/mm)
19/(19 þ 18) (%)
1
9
20
21
b
1
80
80
80
HCOOH
10
10
10
190 ! 40
190 ! 70
190 ! 60
1.65
1.86
1.4
300
258
189
100
100
100
75
61
80
2
6
3
11
21
15
2
3
HCOOH:CH
HCOOH:CH
3
CN (1:5)
CN (2:1)
3
a
Determined by 19F NMR using fluorobenzene as an internal standard.
The experiment of run 1 is equal to that of run 2 in Table 5.
b
solvent shown in Table 7, at the almost same flow rate of
descending method shown in Fig. 3 and at a constant
concentration (10%) of fluorine gas. In all cases, the starting
material 18 was not detected at the end of the reaction. As a
result, we found that the mixed solvent of formic acid and
acetonitrile by the ratio of 2:1 raised the reaction efficiency
more than the single solvent of formic acid. The amount of
only 1.4 eq. of fluorine was necessary for the complete
consumption of 18. Besides, the yield of the desired com-
pound 19 increased to 80%. As observed in run 2, however,
when a portion of acetonitrile was increased, the reaction
efficiency was decreased, and the selectivity of the reaction
was decreased due to the fact that the yield of 19 was
extremely lower at 61% and the by-products 20 and 21
were increased to 6 and 21%. We, therefore, found the use of
a mixed solvent with an appropriate ratio of formic acid and
acetonitrile and controlling the introducing amount of fluor-
ine gas contributed to the efficient fluorination of 1,3-
dicarbonyl compound.
3. Experimental
Fig. 7. Comparison of solvent effect.
3.1. General
introduced in thin concentrations set from the beginning at a
constant quantity could attain almost the same result as in
run 3, but required more reaction time and was not efficient
for the industrial fluorination. Further, we observed that the
descending method with the reaction proceeding, for both
flow rate and concentration of fluorine gas, could also be
highly effective.
From above mentioned results, we found the introduction
method of fluorine gas would be very important in order to
make a reaction efficient in the fluorination of 1,3-dicarbo-
nyl compounds with elemental fluorine. As fluorination goes
on, the quantity of 1,3-dicarbonyl compounds of the starting
material is reduced gradually, and therefore the quantity of
introduced fluorine must be reduced together the fluorina-
tion to proceed efficiently. If it is not reduced, excessively
introduced fluorine becomes not only wasteful, but also it
may cause more sub-reactions.
1H and 19F NMR spectra were recorded at 200 or
500 MHz and 188 or 470 MHz, respectively. The solvents
for 19F NMR were same as those for H NMR, unless
otherwise noted. The 19F chemical shifts were given in
1
ppm downfield from CFCl as an internal standard. An
3
autoclave was used for the experiments of fluorination in
carbon dioxide. GC analyses were carried out on a Shimadzu
gas chromatograph with a column (2 m ꢀ 4 mm) packed
0
with DEGS (15%) on Uniport B. The synthesis of N,N -
difluorobipyridinium salts and the fluorination of various
0
nucleophiles with N,N -difluorobipyridinium salts were
done according to the methods stated in [1].
0
3.2. Fluorination with N,N -difluorobipyridinium salts in
carbon dioxide
0
2
-Naphthol 0.070 g (0.49 mmol) and N,N -difluoro-2,
0
2
.2.3. Solvent effect
We have studied the solvent effect in similar fluorination
reactions [18]. Namely, fluorination of 18 was done, with the
2 -bipyridinium bis(triflate) (4) 0.26 g (0.53 mmol)
were placed in 50 ml autoclave, and were sealed under a
decompressed state. It was cooled down to À70 8C, after

182
K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
Table 9
introducing carbon dioxide 15 g, then sealed again, and
stirred for 12 h at room temperature. It was cooled to 0 8C,
and carbon dioxide was discharged gradually. After water
was added to the reaction mixture, the mixture was
extracted with chloroform. The extract was washed with
saturated aqueous NaCl solution, dried with sodium sulfate
anhydride and was evaporated to dryness under reduced
pressure. The residue was column chromatographed on
silica gel using a 1:4 mixture of ethyl acetate and hexane
as an eluent to give the mixture of 1,1-difluoro-1H-
naphthalen-2-one (15) 783 mg (89%) and 1-fluoro-2-
naphthol (17) 77 mg (10%), as a brown solid. The mixture
Experimental procedure of run 3 in Table 6
F2 (eq.)
Flow rate of F2
gas (ml/min)
Concentration
2
of F gas (%)
0
.00
100
100
100
100
100
100
100
100
100
10
9
0.40
0.60
8
0
1
1
1
.80
.10
.40
.65
7
6
5
4
1.80
2.00
3
3
8
60 mg was dissolved in 3 ml of ethanol, 0.03 g of 5% Pd–
C was added, and was stirred for 8 h at room temperature in
the atmosphere of hydrogen. To the reaction mixture was
added 3 ml of chloroform, being filtered with celite, the
filtrate was evaporated to dryness under reduced pressure,
to give 780 mg (99%) of 1-fluoro-2-naphthol as light
yellow crystal. The spectral data were in agreement with
those of an authentic sample [1].
The experiments of run 3 and 4 in Table 4 were done
according to the same method stated above, except for an
addition of sodium triflate (0.10 mmol) for run 4.
and the results are shown in Fig. 4. The equivalent numbers
of fluorine were calculated from the flow rate and the
concentration of fluorine. In run 2, the amount of fluorine
required for the complete consumption of the starting mate-
rial 18 was 132 mmol (1.65 eq.), and the reaction time was
300 min. After the reaction, the yields of 19, 20 and 21 were
determined by 19F NMR of the reaction mixture using 751 ml
(8 mmol) of fluorobenzene as an internal standard and the
results were shown in Table 5.
3.3. Fluorination of methyl 3-oxovalerate (18) with
fluorine gas
3.3.2. Runs 1–3 in Table 6
The solution of methyl 3-oxovalerate (18) 6.5 g
(50 mmol) dissolved in 17 ml of formic acid was cooled
3
.3.1. Runs 1 and 2 in Table 5
The solution of methyl 3-oxovalerate (18) 10.4 g
80 mmol) dissolved in 27 ml of formic acid was cooled
to 6 8C. Fluorine gas diluted with nitrogen to 5% for run 2,
10% for run 1 or changing concentration in accordance with
the method shown in Fig. 5 and Table 9 for run 3 was passed
through the stirred reaction mixture at a constant flow rate
(100 ml/min). The product ratio of 19 was determined by the
GC analysis of the reaction mixtures as mentioned above
and the results are shown in Figs. 6 and 7. After the reaction,
the yields of 19, 20 and 21 were determined by 19F NMR of
the reaction mixture using 469 ml (5 mmol) of fluorobenzene
as an internal standard and the results were shown in Table 6.
(
to 6 8C. Fluorine gas diluted with nitrogen to 10% was
passed through the stirred reaction mixture at a constant flow
rate (190 ml/min) for run 1, at a descending flow rate in
accordance with the method shown in Fig. 3 and Table 8.
The product ratio of the desired compound 19 was
determined by the GC analysis of the reaction mixtures
Table 8
Experimental procedure of run 2 in Table 5
3.3.3. Runs 2 and 3 in Table 7
Mixtures of formic acid and acetonitrile shown in Table 7
F
2
(eq.)
Flow rate of F
gas (ml/min)
2
Concentration
were used, and all the procedures were done similarly as
explained for run 1 in Table 7 (run 2 in Table 5), except
that the flow rates of fluorine gas were made in accordance
2
of F gas (%)
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
.00
.25
.50
.65
.70
.80
.90
.06
.12
.17
.20
.37
.40
.47
.52
.65
190
180
170
160
150
140
130
120
110
100
90
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Table 10
Experimental procedure of run 2 in Table 7
F
2
(eq.)
Flow rate of F
gas (ml/min)
2
Concentration
2
of F gas (%)
0.00
0.20
1.00
1.30
1.70
1.80
1.86
190
160
150
140
110
70
10
10
10
10
10
10
10
80
60
50
40
40
70

K. Adachi et al. / Journal of Fluorine Chemistry 120 (2003) 173–183
183
Table 11
Acknowledgements
Experimental procedure of run 3 in Table 7
F
2
(eq.)
Flow rate of F
gas (ml/min)
2
Concentration
The early study of MEC-31 and the fluorination of 1,
3-dicarbonyl compounds with fluorine gas were executed
under the direction of Dr. Teruo Umemoto during his term of
office in Daikin Industries Ltd.
2
of F gas (%)
0
0
0
0
1
1
1
1
1
1
.00
.55
.75
.95
.05
.10
.20
.30
.38
.40
190
175
160
145
130
115
100
70
10
10
10
10
10
10
10
10
10
10
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(
Chapter 1).
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reactive fluorinating agent MEC-31 having high effective
fluorine content by coupling double N-fluoropyridinium salt
at ortho position. And we found that MEC-31 can be
recycled easily for the lower-cost industrial fluorination
and for an environment. Besides that, the corresponding
industrial fluorination technologies are being sufficiently
developed such as the direct fluorination of 1,3-dicarbonyl
compounds with fluorine gas as mentioned above.
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various fields will be born through our fluorination technol-
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