Direct perfluoroalkylation of non-activated aromatic C-H bonds of phenols

Article abstract of DOI:10.1016/j.tetlet.2008.04.106

A simple procedure for the perfluoroalkylation of the aromatic ring of phenols under mildly basic conditions is described. Treatment of a variety of phenols with perfluoroalkyl iodide in the presence of the radical initiator V-70L and Cs₂CO₃ provided the corresponding perfluoroalkylated products in moderate to good yields. Generally, the reaction proceeded smoothly at room temperature to yield regioselectively perfluoroalkylated products.

Full text of DOI:10.1016/j.tetlet.2008.04.106

Tetrahedron Letters 49 (2008) 4189–4191
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Direct perfluoroalkylation of non-activated aromatic C–H bonds of phenols
*
Masato Matsugi , Masakazu Hasegawa, Shohei Hasebe, Shohei Takai, Ryusuke Suyama, Yusuke Wakita,
Kanako Kudo, Hiromi Imamura, Toshiya Hayashi, Seiichi Haga
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple procedure for the perfluoroalkylation of the aromatic ring of phenols under mildly basic condi-
tions is described. Treatment of a variety of phenols with perfluoroalkyl iodide in the presence of the
radical initiator V-70L and Cs2CO3 provided the corresponding perfluoroalkylated products in moderate
to good yields. Generally, the reaction proceeded smoothly at room temperature to yield regioselectively
perfluoroalkylated products.
Received 14 March 2008
Revised 3 April 2008
Accepted 7 April 2008
Available online 23 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Perfluoroalkyl substituted compounds have been widely used
as, among others, convenient materials for surfactants, lubricating
oil, agricultural chemicals, drugs and polymers.1 More recently,
techniques for the separation of fluorous compounds from organic
compounds have become increasingly popular2 and many syn-
thetic strategies based on fluorous chemistry have been reported.3
In the field of transition metal catalyzed reactions, fluorous aro-
matics have been recognized as useful ligands for the design of sev-
eral catalysts. The fluorophilic nature of these catalysts has enabled
fluorous separation techniques to be used as a method of choice for
the highly efficient purification of reaction mixtures and the recov-
ery of the catalysts.4 In order to capitalize upon the aforemen-
tioned applications, development of methods for the effective
and easy introduction of a perfluoroalkyl group into aromatic
molecules represents an important research endeavour. The direct
perfluoroalkylation of a target molecule serves as one of the most
powerful tools for synthesizing fluorinated aromatics. Existing
methods developed to introduce perfluoroalkyl groups onto aro-
matic rings involve either the direct perfluoroalkylation of haloge-
nated aromatics via coupling reactions or the use of electrophilic
perfluoroalkylating agents.5 However, except for a few free-radical
reactions, there are few reports of the direct introduction of per-
fluoroalkyl groups into a non-activated C–H bond on aromatic
rings.6 Herein, we report a simple method for the direct perflu-
oroalkylation of phenols under mildly basic conditions. The novel
perfluoroalkylation protocol described herein involves the use of
a radical initiator V-70L (Fig. 1),7 which allows the reaction to be
carried out at room temperature,8 and cesium carbonate as the
mild base. The reaction furnishes regioselectively perfluoroalkyl-
ated phenol compounds in moderate to high yields.
Me
OMe
Me
Me
N
NC
N
Me
CN
MeO
Me
Me
Figure 1.
V-70L (1 eq)
C8F17I (1.5 eq)
V-70L (1 eq)
C8H17I (1.5 eq)
Cs2CO3 (8 eq)
OH
OH
OC8H17
CHO
Cs2CO3 (8 eq)
CHO
CHO
DMF
rt, 20 h
DMF
rt, 20 h
C8F17
3
2a
1a
92%
o
: 36%;
p
: 16%; o/p : 25%
Scheme 1. C-alkylation versus O-alkylation of salicylaldehyde 1a.
2.46 mmol) and perfluorooctyl iodide (2.01 g, 3.68 mmol) in DMF
(16 ml) were added V-70L (758 mg, 2.46 mmol) and cesium car-
bonate (6.41 g, 19.7 mmol) at room temperature. The mixture
was stirred for 20 h at ambient temperature. After the addition of
aq. HCl (1.0 M), the reaction mixture was extracted with diethyl-
ether. The organic layer was concentrated and the three regioiso-
mers of perfluorooctylated compound 2a (ortho; para; and ortho/
para dialkylated) were purified by column chromatography over
silica gel eluting with AcOEt/hexane 1/20 and obtained in 36%,
16%, and 25%, respectively.9
It is noteworthy that no O-alkylated compound was observed in
the 1H NMR of the crude product. On the other hand, when octyl
iodide (non-fluorous) was used instead of the corresponding per-
fluorooctyl iodide, the corresponding O-octylated compound 310
was exclusively obtained as shown in Scheme 1 in 92% yield.
As part of our reaction optimization studies, we screened a vari-
ety of bases and found cesium carbonate to be the most effective
base in terms of product yields. It was essential to use V-70L at
A representative experiment is illustrated in Scheme 1 with sal-
icylaldehyde 1a as the substrate. To a solution of 1a (300 mg,
* Corresponding author.
E-mail address: matsugi@ccmfs.meijo-u.ac.jp (M. Matsugi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.106

4190
M. Matsugi et al. / Tetrahedron Letters 49 (2008) 4189–4191
Table 1
Direct perfluoroalkylation of phenol derivatives
V-70L (1 eq)
RfI (3 eq)
OH
OH
Cs2CO3 (8 eq)
R5
R4
R1
R2
R5
R4
R1
Rf
R2
DMF
rt, 20 h
R3
R3
2a-g
1a-g
Entry
Substrate
Rf
Orientationa
Yieldb (%)
1
2
3
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1a: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = H
1b: R1 = CHO, R2 = H, R3 = H, R4 = OMe, R5 = H
1c: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = OMe
1d: R1 = CHO, R2 = H, R3 = H, R4 = H, R5 = Me,
1e: R1 = CN, R2 = H, R3=H, R4 = H, R5 = H
1f: R1 = NO2, R2 = H, R3 = H, R4 = H, R5 = H
1g: R1 = H, R2 = H, R3 = NO2, R4 = H, R5 = H
C4F9
o:p:o/p = 38:4:58
o:p:o/p = 13:0:87
o:p:o/p = 46:0:54
o:19; o/p:39
o:4; o/p:50
o:26; o/p:49
o:20; o/p:47
o:36; p:16; o/p:25
o:23; p:4; o/p:44
p:50
C6F13
C8F17
C10F21
c
4
—
d
5
C8F17
o:p:o/p = 49:22:29
o:p:o/p = 31:trace:69
o:p:o/p = 1:99:trace
—
6e
7
C8F17
C8F17
C8F17
C8F17
C8F17
C8F17
C8F17
8
9
10
11f
12
p:59
p:37
—
o:p:o/p = 0:0:100
o:p:o/p = 51:16:33
o:o/o = trace:100
o/p:76
o:42; p:13; o/p:16
o/o:77
a
Determined by crude 1H NMR.
b
c
d
e
f
Isolated yield after chromatography or crystallization.
Orientation could not be determined due to the low solubility of the crude product.
1.5 equiv of 1a was used.
The condition without V-70L was used at 70 °C.
The reaction was conducted for 10 h at 70 °C.
room temperature for the reaction to go to completion. When the
reaction was conducted at temperatures higher than 70 °C, perflu-
oroalkylation proceeded without the initiator. However, a product
mixture rich in an o/p-di-substituted adduct was obtained. (Table
1, entry 5). We also examined the effect of solvent on the reaction
and found DMF to be the best. DMSO was also a suitable solvent for
the reaction, but in general gave lower isolated yields of the de-
sired adducts than DMF. We also found that electron withdrawing
functionality such as formyl or nitro groups was required to
achieve the successful perfluoroalkylation. When non-substituted
phenol or alkyl phenols were used as substrates, a complex mix-
ture of products was obtained. A summary of our reaction optimi-
zation and substrate scope for the perfluroalkylation experiments
is summarized in Table 1.
for the oxidative coupling of aromatics. An investigation into the
mechanism for this reaction is currently in progress and will be
reported in due course.
Acknowledgements
We thank Professor Dennis P. Curran, University of Pittsburgh,
for the useful discussion and Professor Shuji Akai, University of
Shizuoka, for the elemental analysis of the fluorous compounds
2. We also thank Wako Pure Chemical Industries Ltd for funding
this work.
References and notes
The perfluoroalkyl groups were directly introduced onto the
aromatic ring in either the o-orientation or the p-orientation with
respect to the hydroxyl group. Notable observations are that when
3 equiv of perfluoroiodide is used with respect to the phenol, two
alkylated products are obtained namely the o-mono perfluoroalky-
lated and o/p-di-substituted compounds (entries 1–4). On the
other hand, three compounds, o-mono perfluoroalkylated, p-mono
perfluoroalkylated and o/p-di-perfluoroalkylated, were obtained
when the perfluoroalkyl iodide of 1.5 equiv was used (entry 5).
Interestingly, the reaction using substrate 1b provided the high
p-selectivity in spite of using excess amounts of perfluorooctyl
iodide (entry 7). When both o-positions of the hydroxyl group were
occupied, the regioselective perfluoroalkylation occurred at the p-
position (entries 8 and 9). When 2-cyanophenol was used as the
substrate, both o-position and p-position were substituted in the
same condition (entry 10). Although the presence of a nitro group
on the aromatic ring attenuated its reactivity, moderate yields
were still obtained under the standard conditions, and elevating
the reaction temperature only showed a moderate improvement
(entries 11 and 12).
1. Recent examples: (a) Onuki, Y.; Kimura, H. Toraiborojisuto 2007, 52, 273–278;
(b) Sinclair, E.; Kim, S. K.; Akinleye, H. B.; Kannan, K. Environ. Sci. Technol. 2007,
41, 1180–1185; (c) Loos, R.; Wollgast, J.; Huber, T.; Hanke, G. Anal. Bioanal.
Chem. 2007, 387, 1469–1478; (d) Yi, W.; Cai, C.; Wang, X. Eur. J. Org. Chem.
2007, 3445–3448; (e) Zuev, V. V.; Bertini, F.; Audisio, G. Polym. Degrad. Stab.
2006, 91, 512–516.
2. Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–11865.
3. Highlights of Applications in Synthesis and Catalysis. In The Handbook of
Fluorous Chemistry; Gladysz, J., Horváth, I., Curran, D. P., Eds.; Wiley-VCH:
Weinheim, 2004; pp 175–365.
4. (a) Schneider, S.; Bannwarth, W. Angew. Chem., Int. Ed. 2000, 39, 4142–4145;
(b) Tian, Y.; Yang, Q. C.; Mak, T. C. W.; Chan, K. S. Tetrahedron 2002, 58, 3951–
3961; (c) Matsugi, M.; Curran, D. P. J. Org. Chem. 2005, 70, 1636–1642; (d) Yi,
W.; Cai, C.; Wang, X. Eur. J. Org. Chem. 2007, 3445–3448.
5. For examples: (a) Takamasa, F.; Ojima, I. J. Fluorine Chem. 1983, 22, 541–556;
(b) Crich, D.; Hao, X.; Lugas, M. Tetrahedron 1999, 55, 14261–14268; (c)
Betzemeier, B.; Lhermitte, F.; Knochel, P. Synlett 1999, 489–491; (d) Brink, G.-J.
T.; Vis, J. M.; Arends, I. W. C. E.; Sheldon, R. A. Tetrahedron 2002, 58, 3977–3983.
6. (a) Tordeux, M.; Langlois, B.; Wakselman, C. J. Chem. Soc., Perkin Trans. 1 1990,
2293–2299; (b) Baciocchi, E.; Muraglia, E. Tetrahedron Lett. 1993, 34, 3799–
3800; (c) Bravo, A.; Bjorsvik, H.-R.; Fontana, F.; Liguori, L.; Mele, A.; Minisci, F. J.
Org. Chem. 1997, 62, 7128–7136; (d) Huang, W.; Ying, W.; Zhang, H.; Liu, J. Chin.
J. Chem. 1993, 11, 272–279.
7. 2,20-Azobis(2,4-dimethyl-4-methoxyvaleronitrile) is commercially available
from Wako Pure Chemicals Ltd, Japan, and the abbreviation in brackets [V-70]
is its trade name. This compound is a mixture of diastereomeric isomers whose
melting points are 58 and 107 °C, and should be stored below ꢀ10 °C to prevent
any decomposition. V-70L is the isomer, which shows low melting point. The
typical procedure to separate the diastereomers is shown below: V-70 (5.0 g) in
Et2O (25 ml) was stirred at 10 °C for 30 min to precipitate only V-70H (1.8 g;
In summary, a new method for the direct perfluoroalkylation of
an aromatic sp2 carbon in phenol derivatives has been developed.
The reaction proceeds under mildly basic conditions at room tem-
perature and does not require reagents that are typically needed

M. Matsugi et al. / Tetrahedron Letters 49 (2008) 4189–4191
4191
content of 100% from 1H NMR). On the other hand, the filtrate, upon cooling to
ꢀ10 °C for 2 days, gave crystallized V-70L (0.7 g; content of 100% from 1H NMR);
V-70L: mp ca. 58 °C (dec.); 1H NMR (CDCl3) d 1.29 (s, 12H), 1.64 (s, 12H), 2.26 (d,
2H, J = 11 Hz), 2.42 (d, 2H, J = 11 Hz), 3.21 (s, 6H).
J = 7.6 Hz), 7.79 (2H, m), 9.96 (1H, s), 11.85 (1H, s); 19F NMR (466 MHz,
CDCl3) ppm ꢀ126.0 (2F), ꢀ122.6 (2F), ꢀ121.8 (2F), ꢀ121.7 (2F), ꢀ121.5 (2F),
ꢀ121.3 (2F), ꢀ108.9 (2F), ꢀ80.6 (3F); p-compound: pale yellow crystals; mp
57.0–58.0 °C; 1H NMR (270 MHz, CDCl3) d: 7.13 (1H, dd, J = 8.9, 2.3 Hz), 7.70–
7.74 (1H, m), 7.82 (1H, d, J = 2.2 Hz), 9.97 (1H, s), 11.3 (1H, s); 19F NMR
(466 MHz, CDCl3) ppm ꢀ126.0 (2F), ꢀ122.6 (2F), ꢀ121.7 (6F), ꢀ121.1 (2F),
ꢀ110.1 (2F), ꢀ80.6 (3F), ꢀ80.6 (3F); o/p-compound: white crystals; mp 78.5–
79.5 °C; 1H NMR (270 MHz, acetone-d6) d: 8.10 (1H, d, J = 2.0 Hz), 8.61 (1H, d,
J = 2.0 Hz), 10.3 (1H, s); 19F NMR (466 MHz, CDCl3) ppm ꢀ126.7 (4F), ꢀ123.2
(4F), ꢀ122.4 (4F), ꢀ122.3 (6F), ꢀ122.0 (2F), ꢀ121.8 (2F), ꢀ121.6 (2F), ꢀ110.6
(2F), ꢀ109.3 (2F), ꢀ81.6 (6F).
8. (a) Kita, Y.; Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.; Matsugi, M.
Tetrahedron Lett. 1997, 38, 3549–3552; (b) Kita, Y.; Gotanda, K.; Sano, A.; Oka,
M.; Murata, K.; Suemura, M.; Matsugi, M. Tetrahedron Lett. 1997, 38, 8345–
8348; (c) Kita, Y.; Gotanda, K.; Murata, K.; Suemura, M.; Sano, A.; Yamaguchi,
T.; Oka, M.; Matsugi, M. Org. Process Res. Dev. 1998, 2, 250–254; (d) Kita, Y.;
Sano, A.; Yamaguchi, T.; Oka, M.; Gotanda, K.; Matsugi, M. J. Org. Chem. 1999,
64, 675–678; (e) Gotanda, K.; Matsugi, M.; Suemura, M.; Ohira, C.; Sano, A.;
Oka, M.; Kita, Y. Tetrahedron 1999, 55, 10315–10324.
10. Peng, S.; Zhao, H.; Xie, Q.; Qi, H.; Huang, L. Huaxue Shiji 2003, 25, 241–242. O-
alkylated compound 3: colourless oil; 1H NMR (270 MHz, CDCl3) d: 0.86–0.91
(3H, m), 1.29–1.51 (12H, m), 1.80–2.04 (2H, m), 7.49–7.56 (1H, m), 7.74–7.85
(1H, m), 10.52 (1H, s)..
9. Pozzi, G.; Cavazzini, M.; Cinato, F.; Montanari, F.; Quici, S. Eur. J. Org. Chem.
1999, 1947–1955. Perfluorooctylated compounds 2a: o-compound: white
crystals; mp 73.0–74.0 °C; 1H NMR (270 MHz, CDCl3) d: 7.16 (1H, t,