Synthesis of fluorinated aromatic compounds by one-pot benzyne generation and nucleophilic fluorination

Article abstract of DOI:10.1071/CH13548

The fluorination of substituted benzenes using fluoride ions under mild reaction conditions has been one of the most important challenges for the synthesis of biologically active fluorinated aromatic compounds; however, only a few synthetically useful methods are known. In this paper, it is reported that the nucleophilic fluorination of benzynes, generated from either 2-(trialkylsilyl)phenyl nonafluorobutanesulfonates or 2-(trialkylsilyl)phenols, meets this challenge. In particular, the fluorination starting from 2-(trialkylsilyl)phenols for fabricating aryl fluorides involves three sequential reactions in one-pot: the nonaflylation of phenols, benzyne generation, and nucleophilic fluorination of the benzynes. The regioselectivities of these reactions are controlled by the substituents at the C3-position of the benzynes. CSIRO 2014.

Full text of DOI:10.1071/CH13548

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 475–480
Full Paper
http://dx.doi.org/10.1071/CH13548
Synthesis of Fluorinated Aromatic Compounds by One-Pot
Benzyne Generation and Nucleophilic Fluorination
A B C
, ,
B
B
Takashi Ikawa,
Shigeaki Masuda, Tsuyoshi Nishiyama,
B
A B C
, ,
Akira Takagi, and Shuji Akai
A
Graduate School of Pharmaceutical Sciences, Osaka University,
Yamadaoka, Suita, Osaka 565-0871, Japan.
B
School of Pharmaceutical Sciences, University of Shizuoka,
Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan.
C
Corresponding authors. Email: ikawa@phs.osaka-u.ac.jp; akai@phs.osaka-u.ac.jp
The fluorination of substituted benzenes using fluoride ions under mild reaction conditions has been one of the most
important challenges for the synthesis of biologically active fluorinated aromatic compounds; however, only a few
synthetically useful methods are known. In this paper, it is reported that the nucleophilic fluorination of benzynes,
generated from either 2-(trialkylsilyl)phenyl nonafluorobutanesulfonates or 2-(trialkylsilyl)phenols, meets this challenge.
In particular, the fluorination starting from 2-(trialkylsilyl)phenols for fabricating aryl fluorides involves three sequential
reactions in one-pot: the nonaflylation of phenols, benzyne generation, and nucleophilic fluorination of the benzynes. The
regioselectivities of these reactions are controlled by the substituents at the C3-position of the benzynes.
Manuscript received: 10 October 2013.
Manuscript accepted: 21 November 2013.
Published online: 24 December 2013.
Introduction
On the other hand, the nucleophilic addition to benzynes has
been long used for the synthesis of multisubstituted aromatic
compounds.[11] However, the nucleophilic addition of a fluoride
ion to benzynes has been rarely achieved, probably because
the reaction between a ‘hard’ fluoride ion and a ‘soft’ benzyne’s
triple bond is less favourable compared with those of
other nucleophiles. Only a few reports have been published
in the literature, in which most of the examples resulted in very
low yields of fluorinated products.[12] Recently, Yoshida et al.
have published a remarkable method for the synthesis of aryl
fluorides by the fluorostannylation of benzynes using
Bu3SnF.[13a] However, this method requires a toxic tin reagent
and an excess of additional fluoride sources. Lee et al. recently
reported a silver-mediated benzyne fluorination using AgBF4;
however, a glove box was used for handling the hygroscopic
silver reagent.[13b]
Therefore, there is an urgent need to develop alternative
fluorination methods for aromatic compounds in a more easy-
to-operate manner by using less toxic reagents. In this study, we
report a novel one-pot synthesis of fluorinated aromatic com-
pounds 4 from 2-(trialkylsilyl)phenols 1 using a combination of
nonafluorobutanesulfonyl fluoride (NfF) and Bu4NF(t-BuOH)4,
that includes nonaflylation of 1, generation of benzynes 3,[14,15]
and nucleophilic fluorination of 3 (Scheme 1).
Fluorinated pharmaceuticals and agrochemicals have become
increasingly more important in the medicinal and agricultural
fields because the introduction of fluorine atom(s) into the drug
candidates often dramatically improves properties such as the
biological activity, bioavailability, and stability in blood.[1] Aryl
fluorides have played a pivotal role in the pharmaceutical sci-
ences, and fluorobenzene derivatives account for approximately
two-thirds of the fluorinated compounds of the best-selling
pharmaceuticals.[2] However, conventional fluorination reac-
tions of benzenes require harsh reaction conditions, and many
functional groups cannot tolerate these conditions.[3,4] There-
fore, most of the desired fluorinated aromatic compounds have
been synthesised from small fluorinated building blocks.[1]
Recently, Ritter et al. reported the silver-catalyzed fluorina-
tion reaction of aryl stannanes, which can be prepared from
phenols in the presence of various functional groups.[5] Further-
more, they developed a more synthetically useful direct fluori-
nation of phenols using PhenoFluor.[6,7] Buchwald et al.
reported the first palladium-catalyzed fluorination of aryl
triflates using BrettPhos as a ligand.[8] We have developed the
nucleophilic deoxyfluorination of one of the two hydroxy
groups of catechols using Deoxo-Fluor or Xtalfluor-E.[9] These
fluorination methods are important tools for drug discovery
because phenols and catechols are abundant in both natural and
synthetic biologically active compounds,[10] and the methods
enable late-stage fluorination.[5,6] However, these methods also
have several disadvantages such as high reaction temperature
and the use of expensive and/or hazardous reagents and catalysts.
Results and Discussion
First, the reaction conditions for the domino benzyne gener-
ation/nucleophilic fluorination were optimized using 4,5-
dimethoxy-2-(trimethylsilyl)phenyl nonaflate (2a) as the test
Journal compilation Ó CSIRO 2014
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476
T. Ikawa et al.
OH
Fꢁ
ONf
Fꢁ
F
NfF, Bu4NF
Fꢁ
MeCN
SiR3
SiR3
R1
R1
R1
R1
60ꢀC
1
2
3
4
F
S
F F
F
F
, SiR3 ꢂ SiMe3 (2) or Si(t-Bu)Me2 (2ꢃ)
Nf ꢂ
F
O
F
O F
F
Scheme 1. One-pot synthesis of fluorinated aromatic compounds 4 from 2-(trialkylsilyl)phenols 1.
Table 1. Optimization of reaction conditions
Fꢁ
MeO
MeO
ONf
MeO
MeO
OH
ONf
MeO
MeO
F
MeO
MeO
MeO
Fꢁ source
(OHꢁ)
ꢄ
Solvent
1 h
MeO
SiMe3
SiMe3
Fꢁ
2a
2a
3a
4a
5
Yield [%]A,B
Entry
Fꢀ source
Solvent
Conc. [M]
Temp [8C]
2a
4a
5
1
KF/18-crown-6
CsF
THF
0.1
60
60
99
86
0
0
0
0
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
0.1
0
0
3
Bu4NPh3SiF2
Me4NF
0.1
60
24
4
0.1
60
0
50
0
5
BnMe3NF
0.1
60
0
67
0
6
Bu4NF
0.1
60
0
47–74
79
3
7
8C
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
Bu4NF(t-BuOH)4
0.1
60
0
8
0.1
60
0
74
0
9
0.2
60
0
81
9
10
11
12
13
14
15
0.05
0.1
60
0
85
7
60
0
72
87 (64)D
13
7
THF
0.05
0.025
0.05
0.05
60
0
THF
60
0
78
14
0
THF
rt
0
82
THF
reflux
0
76
0
AConditions: 1.0 equiv. of 2a; 2.2 equiv. of Fꢀ source in solvent.
BDetermined by gas chromatography–mass spectrometry using n-decane as an internal standard.
C4,5-Dimethoxy-2-(trimethylsilyl)phenyl triflate (2a9) was used instead of 2a.
DIsolated yield.
substrate (Table 1). Inorganic fluoride sources such as KF/
18-crown-6 and CsF did not afford the fluorinated product 4a
even after long reaction durations (Table 1, entries 1 and 2).
In contrast, tetraalkylammonium fluorides such as tetra-
butylammonium difluorotriphenylsilicate (Table 1, entry 3),[16]
tetramethylammonium fluoride (Table 1, entry 4),[17] and ben-
zyltrimethylammonium fluoride (Table 1, entry 5),[18] all of
which were dried at 2008C under vacuum (0.25 Torr) for more
than 12 h before use, afforded 4a in poor (24 %) to moderate
the conditions using Bu4NF or Bu4NF(t-BuOH)4 (Table 1,
entries 6, 7, and 9–13). The reaction of the corresponding triflate
2a9 as the benzyne precursor afforded 4a in 74 % yield, similar
to that of nonaflate 2a (Table 1, entry 8). Further investigation of
the reaction conditions (solvents, substrate concentration, and
temperature, see: Table 1, entries 9–15) provided the optimized
conditions, i.e. Bu4NF(t-BuOH)4 in THF (0.05 M) at 608C
afforded 4a in 64 % isolated yield (Table 1, entry 12). In this
reaction, 2.2 equiv. of Bu4NF(t-BuOH)4 was used, where
1 equiv. of the fluoride ion was used for benzyne generation and
the remaining equivalent was used for nucleophilic fluorination.
Next, the scope and limitation of the fluorination of benzynes
3, generated in situ from various substituted nonaflates 2, was
explored. The nanoflates 2 were prepared in 71–94 % yields
by the nonaflylation of phenols 1 using NfF and NaH (Table 2).
2-(t-Butyldimethylsilyl)-4,5-dimethoxyphenyl nonaflate (2a99),
another good substrate, afforded 4a in 88 % yield (Table 2,
entry 1); the yield was similar to that using 2a under the same
reaction conditions (87 %, Table 1, entry 12). Not only symmet-
rical benzynes 3a and 3b, but also unsymmetrical benzynes
3c–g were generated and reacted with a fluoride ion to afford
fluorinated products 4a–g (Table 2, entries 1–7).
yields (67 %). The use of
a THF solution of tetra-
butylammonium fluoride (Bu4NF)[19,20] also afforded 4a;
however, the results were poorly reproducible (the yields varied
from 47 to 74 %, Table 1, entry 6). Finally, we found that Bu4NF
(t-BuOH)[421] was the best fluoride source for benzyne genera-
tion followed by its fluorination (Table 1, entry 7). This reaction
was highly reproducible and afforded 4a in ,80 % yields
because of the several advantages of Bu4NF(t-BuOH)4, such as
high nucleophilicity,[22] low hygroscopicity, and good solubility
in organic solvents.[21] Small amounts (#14 % yield) of a
by-product, 3,4-dimethoxyphenol (5a), was obtained, presum-
ably produced by the competitive nucleophilic addition of
contaminated water[19,23] to 4,5-dimethoxybenzyne (3a) under

Nucleophilic Benzyne Fluorination
477
Table 2. Synthesis of 2-(trialkylsilyl)phenyl nonafluorobutanesulfonates 2 and nucleophilic fluorination of benzynes 3 generated from 2
3
ONf
F
OH
Fꢁ
Bu4NF(t-BuOH)4
NaH, NfF
2
18-crown-6
THF, 60ꢀC
THF
60ꢀC for 1 h
1
5
SiR3
SiR3
R1
R1
R1
R1
2
3
4
1
Entry
1
2
2aꢃ
2b
Yield of 2A,B [%]
3
4
Yield of 4C,D [%]
MeO
MeO
ONf
MeO
MeO
MeO
F
85
88E
Si(t-Bu)Me2
MeO
3a
4a
BnO
BnO
BnO
F
BnO
BnO
ONf
2
3
87
67 (72)E
SiMe3
BnO
4b
3b
BnO
F
BnO
ONf
Si(t-Bu)Me2
BnO
94F
64
OBn
OBn
OBn
meta-4c
(meta-4c:ortho-4c ꢂ ꢅ20:1)
2cꢃ
3c
t-Bu
t-Bu
t-Bu
ONf
4
84
58
t-Bu
meta-4d
(meta-4d:ortho-4d ꢂ ꢅ20:1)
F
t-Bu
SiMe3
t-Bu
2d
3d
SiMe3
F
SiMe3
SiMe3
ONf
5
86G
34
SiMe3
MeO
ortho-4e
MeO
MeO
2e
3e
(meta-4e:ortho-4e ꢂ 1:1.6)
Si(t-Bu)Me2
Si(t-Bu)Me2
Si(t-Bu)Me2
ONf
O
6
77
44
F
meta-4f
O
O
SiMe3
O
O
O
2f
3f
(meta-4f:ortho-4f ꢂ 6.4 :1)
B(dan)
F
B(dan)
OTf
B(dan)
7H
71I
60
SiMe3
ortho-4g
(meta-4g:ortho-4g ꢂ 1:ꢅ20)
3g
2gꢆ
AReaction conditions: 1.0 equiv. of 1, 1.5 equiv. of NaH, 1.5 equiv. of nonafluorobutanesulfonyl fluoride (NfF), 1.0 equiv. of 18-crown-6 in THF (0.10 M).
BYield of nonaflylation of 1 unless otherwise stated.
CReaction conditions: 1.0 equiv. of 2, 2.2 equiv. of Bu4NF(t-BuOH)4 in THF (0.050 M).
DIsolated yield.
EYield was determined by gas chromatography analysis.
F2.0 equiv. of 18-crown-6 was added.
GYield of nonaflylation of 4-iodo-2,6-bis(trimethylsilyl)phenol (for details, see Supplementary Material).
HB(dan) ¼ 1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl.
IYield of the triflylation of the corresponding pinacol borate (for details, see Supplementary Material).

478
T. Ikawa et al.
Table 3. One-pot nucleophilic fluorination of benzynes 3 generated in situ from 2-(trialkylsilyl)phenols 1
(1) NfF, Cs2CO3
MeCN, 60ꢀC, 30 min
Fꢁ
OH
ONf
Fꢁ
SiR3
F
(2) Bu4NF(t-BuOH)4
18-crown-6, 60ꢀC, 1 h
SiR3
R1
R1
R1
R1
1
2
3
4
Entry
1
1
3
4
YieldA,B [%]
MeO
MeO
OH
MeO
MeO
MeO
F
F
60C
MeO
SiMe3
1a
3a
4a
BnO
BnO
BnO
BnO
BnO
BnO
OH
2
3
62
SiMe3
1b
1h
3b
4b
4h
Me
Me
OH
Me
Me
Me
Me
F
50C
SiMe3
3h
BnO
F
BnO
OH
Si(t-Bu)Me2
BnO
4
5
73
OBn
meta-4c
OBn
OBn
3c
1cꢃ
(meta-4c:ortho-4c ꢂ ꢅ20 :1)
t-Bu
t-Bu
t-Bu
OH
0D
SiMe3
t-Bu
t-Bu
F
t-Bu
3d
1d
meta-4d
AReaction conditions: 1.0 equiv. of 1, 1.5 equiv. of nonafluorobutanesulfonyl fluoride (NfF), 1.5 equiv. of Cs2CO3 in MeCN (0.10 M) at 608C for 30 min,
1.0 equiv. of Bu4NF(t-BuOH)4, and 0.60 equiv. of 18-crown-6 at 608C for 1 h.
BIsolated yield of 4.
CYield was determined by gas chromatography analysis using n-decane as an internal standard.
D1d was quantitatively recovered (determined by 1H NMR spectroscopy).
Nucleophilic additions of a fluoride ion to benzynes 3a–c
bearing alkoxy groups afforded aryl fluorides 4a–c in
higher yields (64–88 %, Table 2, entries 1–3) compared with
benzynes bearing alkyl groups 3d (58 %, Table 2, entry 4), silyl
groups 3e–3f (34 and 44 %, Table 2, entries 5 and 6), and boryl
group 3g (60 %, Table 2, entry 7). The substituents at the
C3-position of the benzynes significantly affected the regios-
electivities of the nucleophilic addition reactions, as
expected.[24,25] Thus, a fluoride ion selectively attacked the
C1-position of 3-alkoxybenzyne 3c, 3-(t-butyl)benzyne 3d,
and 3-(t-butyldimethylsilyl)benzyne 3f (Table 2, entries 3, 4,
and 6), and attacked the C2-position of 3-(trimethylsilyl)
benzyne 3e and 3-borylbenzyne 3g (Table 2, entries 5 and 7).
Next, our one-pot benzyne generation method using
2-(trimethylsilyl)phenols 1[14] was applied to this nucleophilic
fluorination (Table 3). After several optimizations of the reac-
tion conditions, we found that the reaction of 1, NfF (1.5 equiv.),
and Cs2CO3 (1.5 equiv.) in MeCN at 608C for 30 min before the
addition of Bu4NF(t-BuOH)4 (1.0 equiv.) and 18-crown-6
(0.60 equiv.)[26] achieved successive O-nonaflylation, benzyne
generation, and nucleophilic fluorination to afford fluorinated
compounds 4. 2-(Trimethylsilyl)phenols (1a, 1b, and 1h) and
2-(t-butyldimethylsilyl)phenol 1c99 were converted in situ into
2 after the first 30 min, and then transformed to 3 by the addition
of Bu4NF(t-BuOH)4 and 18-crown-6 to afford 4a–c and 4h in
good-to-moderate yields (Table 3, entries 1–4). The yields of
this one-pot synthesis of 4b and 4c from 1b and 1c99 (4b: 62 %;
4c: 73 %; Table 3, entries 2 and 4) are comparable or higher than
those of the stepwise nonaflylation and benzyne fluorination
(4b: 63 % from 1b (87 % for nonaflylation of 1b, 72 % for
fluorination of 2b); 4c: 60 % from 1c99 (94 % for nonaflylation of
1c99, 64 % for fluorination of 2c99); Table 2, entries 2 and 3), even
though the total yield of 4a by the one-pot synthesis (60 %,
Table 3, entry 1) was lower than that by the stepwise synthesis
(79 % from 1a (91 % for nonaflylation of 1a, 87 % for fluori-
nation of 2a), Table 1, entry 12). It is worth noting that this
one-pot process is complete within 90 min. Therefore, the
one-pot method in Table 3 should be beneficial for the step
economy and time saving. However, 2,4-di(t-butyl)phenol 1d
did not react with NfF under the same reaction conditions
(Table 3, entry 5). Further studies on the one-pot reaction are
under progress to expand its scope.
The trends of the regioselectivities in the nucleophilic flu-
orination of 3-substituted benzynes are summarized in
Fig. 1.[24,25,27] The completemeta-selectivityof3-alkoxybenzyne
3c (meta: ortho = .20: 1, Table 2, entry 3; and Table 3, entry 4)

Nucleophilic Benzyne Fluorination
479
Both electronic
and steric control
over Na2SO4. The organic phase was filtered and concentrated
under reduced pressure. The residue was purified by flash col-
umn chromatography on silica gel (hexane/EtOAc) to afford
2-(trialkylsilyl)phenyl nonafluorobutanesulfonate 2.
Steric control
Electronic control
B(dan)
t-Bu
OBn
3
δꢄ
δꢁ
Fꢁ
δꢄ
δꢁ
2
1
δꢄ
3c
Fꢁ
δꢁ
Fꢁ
General Procedure for Nucleophilic Fluorination
of Benzyne 3 Generated from 2-(Trialkylsilyl)phenyl
Nonafluorobutanesulfonate 2 (Table 2)
3g
3d
SiMe3
Si(t-Bu)Me2
A flame-dried flask was charged with 2-(trialkylsilyl)phenyl
nonafluorobutanesulfonate 2 (1.0 equiv.) and a stir bar, capped
with a rubber septum, and evacuated and back-filled with
nitrogen. Anhydrous THF (0.050 M) was added by a syringe,
and the mixture was heated to 608C. Bu4NF(t-BuOH)4
(2.2 equiv.) was quickly added by opening the septum. After
stirring at 608C for 1 h, the reaction mixture was cooled, and then
passed through a short pad of silica gel using EtOAc as the
solvent. The eluent was added to hexane and water, and the
aqueous phase was extracted twice with hexane. The combined
organic phase was washed with a saturated aqueous NaCl
solution. The organic phase was dried over anhydrous Na2SO4,
and the solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography on silica
gel (hexane, a mixture of hexane and EtOAc, or CH2Cl2) to
afford fluorinated product 4.
δꢄ
Fꢁ
δꢄ
δꢁ
δꢁ
Fꢁ
3e
3f
Fig. 1. Regioselectivities of fluorination of 3-substituted benzynes.
is most probably because of the additive effect of the electronic
(distortion) and steric effect of the alkoxy group.[24a] On the
other hand, the ortho-selectivities of 3-borylbenzyne 3g and
3-(trimethylsilyl)benzyne 3e can be understood by the electronic
(electron-donating inductive) effect of the silyl[24b,c] and
boryl[24d] substituents, which overcome the steric repulsion
between these substituents and the incoming fluoride ion. In
particular, the exclusive formation of ortho-adduct 4g by the
fluorination of 3-borylbenzyne 3g occurs probably because of the
small steric influence of the boryl group.[24d] In the cases of 3d
and 3f, very bulky t-butyl and t-butyldimethylsilyl groups seemed
to orient the nucleophilic additions at their meta-positions
(Table 2, entries 4 and 6), even though the alkyl and silyl groups
made their ortho-positions more electrophilic.[24b–d]
Notably, the ortho-selectivity of 3-(trimethylsilyl)benzyne
3e with a fluoride ion (meta : ortho ¼ 1 : 1.6, Table 2, entry 5)
was not as high as those of the reactions with primary amines
(meta : ortho ¼ 1 : 4.8–8.5).[24b] This result indicates that a fluo-
ride ion behaves as a bulkier nucleophile than amines, probably
because of its solvation.
General Procedure for the One-Pot Nucleophilic
Fluorination of Benzyne 3 Generated from 2-(Trialkylsilyl)-
phenol 1 (Table 3)
A flask was charged with Cs2CO3 (1.5 equiv.) and a stir bar,
capped with a rubber septum, and dried over a flame under
reduced pressure. After cooling, the flask was charged with
2-(trialkylsilyl)phenol 1 (1.0 equiv.), and the mixture was
evacuated and back-filled with nitrogen. Anhydrous MeCN
(0.10 M) and NfF (1.5 equiv.) were sequentially added through
the septum by a syringe. After the mixture was stirred at 608C
for 30 min, Bu4NF(t-BuOH)4 (1.0 equiv.) and 18-crown-6
(0.60 equiv.) were quickly added by opening the septum. The
resealed flask was heated at 608C for 1.0 h. The same work up
and purification procedure as mentioned in the general proce-
dure for Table 2 afforded fluorinated product 4.
Conclusion
In conclusion, a novel method for the synthesis of fluorinated
aromatic compounds by the nucleophilic addition of a fluoride
ion to benzynes is developed. The key features of this method
include: (i) the use of minimum amounts of the easy-to-handle
fluorinating reagent, Bu4NF(t-BuOH)4; (ii) the step economical
three sequential processes in one-pot[28] that include nona-
flylation, benzyne generation, and nucleophilic fluorination; and
(iii) the regioselective fluorination of benzynes controlled by the
substituent effects. Further improvement of the reaction effi-
ciency and its applications are now in progress in our laboratory.
Supplementary Material
Full experimental data, as well as 1H and 13C NMR spectra, are
available on the Journal’s website.
Acknowledgements
This work was supported by MEXT KAKENHI (Grant Numbers 23790017,
24390005, and 25460018). TI is also thankful for receiving the Special Grant
in University of Shizuoka for this study.
References
Experimental
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Nonafluorobutanesulfonate 2 (Table 2)
An oven-dried flask was charged with 2-(trialkylsilyl)phenol
1[14] (1.0 equiv.) and 18-crown-6 (1.0 equiv.), capped with a
rubber septum, and then evacuated and back-filled with argon.
Anhydrous THF (0.10 M) and NaH (60 % in mineral oil,
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was stirred for a few minutes. NfF (1.5 equiv.) was added using a
syringe, and the resulting mixture was stirred at 608C. After the
reaction was complete, water was added into the reaction mix-
ture. The mixture was extracted with hexane (this process was
repeated three times), and the combined organic phase was dried
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