7518
J. Li et al. / Tetrahedron Letters 48 (2007) 7516–7519
Table 2. Synthesis of 7 via reaction of phenol 1a and 5 with 2 and
subsequent reduction with Zn dust
to high vacuum could result in loss of significant amount
of yield.
Entry ArOH Time (h)
Yield (%) of
bromophilic
substitution
Yield (%) of
Zn reductionc
In conclusion, we have described a practical and conve-
nient synthesis of aryl tetrafluoroethyl ethers from phe-
nols and 1,2-dibromotetrafluoroethane. The new
condition using the combination of Cs2CO3 as a base
and DMSO as a solvent for the nucleophilic substitution
of phenols with 1,2-dibromotetrafluoroethane not only
avoided preparation of moisture sensitive potassium
phenoxides, but also gave higher yields. This reaction
system could be adopted in other types of nucleophilic
replacement initiated by halophilic attack. The use of
aryl tetrafluoroethyl ethers in the synthesis of bioactive
compounds will be reported in due course.
6a
7a Totalb
1
2
3
4
5
6
1a
5a
5b
5c
5d
5e
5
5
10
5
2
89
84
89
80
85
94
5
4
5
4
5
5
94
88
94
84
90
99
87
85
85
82
82
86
13
a Percentage calculated based on 19F NMR.
b Isolated yield of 6 + 7.
c Isolated yield.
References and notes
OMe
OMe
Cs2CO3
+
CsHCO3
(1)
1. (a) Petrov, A. A. US Patent Appl. 2005/0065382, March 24,
2005; (b) Kuhn, D. G. US Patent Appl. 4 659 857, April 21,
1987; (c) Idoux, J. P.; Gibbs-Rein, K. S.; Gupton, J. T.;
Cunningham, G. N. J. Chem. Eng. Data 1988, 33, 385; (d)
Hamprecht, G. US Patent Appl. 4 832 879, May 23, 1989;
(e) Juerg, Z. PCT Int. Appl. WO95/09852, April 13, 1995;
(f) Kitazaki, T.; Tamura, N.; Tasaka, A.; Matsushita, Y.;
Hayashi, R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull.
1996, 44, 314; (g) Durley, R. C.; Grapperhaus, M. L.;
Massa, M. A.; Mischke, D. A.; Parnas, B. L.; Fobian, Y.
M.; Rath, N. P.; Honda, D. D.; Zeng, M.; Connolly, D. T.;
Heuvelman, D. M.; Witherbee, B. J.; Glenn, K. C.; Krul, E.
S.; Smith, M. E.; Sikorski, J. A. J. Med. Chem. 2000, 43,
4575; (h) Durley, R. C.; Grapperhaus, M. L.; Hickory, B.
S.; Massa, M. A.; Wang, J. L.; Spangler, D. P.; Mischke, D.
A.; Parnas, B. L.; Fobian, Y. M.; Rath, N. P.; Honda, D.
D.; Zeng, M.; Connolly, D. T.; Heuvelman, D. M.;
Witherbee, B. J.; Melton, M. A. B. J.; Glenn, K. C.; Krul,
E. S.; Smith, M. E.; Sikorski, J. A. J. Med. Chem. 2002, 45,
3891; (i) Reinhard, E. J.; Wang, J. L.; Durley, R. C.;
Fobian, Y. M.; Grapperhaus, M. L.; Hickory, B. S.; Massa,
M. A.; Norton, M. B.; Promo, M. A.; Tollefson, M. B.;
Vernier, W. F.; Connolly, D. T.; Witherbee, B. J.; Melton,
M. A.; Regina, K. J.; Smith, M. E.; Sikorski, J. A. J. Med.
Chem. 2003, 46, 2152.
O-
8
OH
5d
OMe
OMe
-CF2CF2Br
(2)
(3)
+
BrCF2CF2Br
+
O-
OBr
9
CF2=CF2
2
10
8
-CF2CF2Br
10
11
OMe
OMe
+
CF2=CF2
(4)
(5)
O-
8
OCF2CF2
-
11
12
OMe
OMe
OMe
OMe
+
+
-
O-
8
OCF2CF2
12
OMe
OBr
9
OCF2CF2Br
6d
OMe
-CF2CF2Br
(6)
(7)
(8)
+
+
BrCF2CF2Br
-
OCF2CF2
12
OCF2CF2Br
6d
2. Kamal, A.; Pratap, T. B.; Ramana, K. V.; Ramana, A. V.;
Babu, A. H. Tetrahedron Lett. 2002, 43, 7353.
3. (a) Rico, I.; Wakselman, C. J. Fluorine Chem. 1982, 20, 759;
(b) Li, X.; Pan, H.; Jiang, X. Tetrahedron Lett. 1984, 25,
4937; (c) Li, X.; Jiang, X.; Hu, J.; Fu, W. Pure & Appl.
Chem. 1987, 59, 1015.
4. Dolbier, W. R., Jr.; Medebielle, M.; Ait-Mohand, S.
Tetrahedron Lett. 2001, 42, 4811.
5. Typical procedure exemplified by the synthesis of 4-
cyanophenyl 2-bromotetrafluoroethyl ether (6e) (Table 2,
10
2
OMe
OMe
+
H2O or CsHCO3
-
OCF2CF2H
7d
OCF2CF2
12
OMe
OMe
OMe
OMe
+
Br
Br
OCF2CF2Br
14
O-
8
OBr
9
O-
13
entry 6):
A mixture of 4-cyanophenol (5e) (11.9 g,
100 mmol), 1,2-dibromotetrafluoroethane (2) (51.8 g,
200 mmol) and Cs2CO3 (48.9 g, 150 mmol) in dry DMSO
(100 mL) was heated to 50 ꢁC, under N2, with mechanical
stirring, for 13 h. After cooling to rt, H2O (300 mL) and
CH2Cl2 (300 mL) were added. The resulting mixture was
stirred at rt for 15 min. The organic phase was separated
and the aqueous phase was extracted with CH2Cl2
(100 mL). The combined organic extracts were washed
with H2O (2 · 300 mL), brine (300 mL) and dried over
Na2SO4. After filtration, the solution was concentrated in
vacuo to give a mixture of products 6e and 7e as a colorless
liquid at a ratio of 19:1 based on 19F NMR (29.5 g, 99%).
Scheme 3.
clean, fairly pure products 7 (>90% HPLC) were iso-
lated in every case simply after aqueous work up. With-
out further purification, we were able to use them for
potential drug candidate scale up synthesis. More pure
products could be obtained either by fine distillation
or column chromatography. It should be noted that
compounds 7 were highly volatile. Prolonged exposure