Synthesis of 6-(perfluoroalkyl)salicylates by [3+3] cyclization of 1,3-bis(silyl enol ethers) with 3-ethoxy-1-(perfluoroalkyl)prop-2-en-1-ones

Article abstract of DOI:10.1016/j.tet.2006.10.062

6-(Perfluoroalkyl)salicylates were prepared by [3+3] cyclization of 1,3-bis(silyl enol ethers) with 3-ethoxy-1-(perfluoroalkyl)prop-2-en-1-ones.

Full text of DOI:10.1016/j.tet.2006.10.062

Tetrahedron 63 (2007) 413–418
Synthesis of 6-(perfluoroalkyl)salicylates by [3D3] cyclization of
1,3-bis(silyl enol ethers) with 3-ethoxy-1-(perfluoroalkyl)prop-2-
en-1-ones
Mathias Lubbe,a Constantin Mamat,a Christine Fischerb and Peter Langera,b,
*
aInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu€r Katalyse e. V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 23 August 2006; revised 21 October 2006; accepted 23 October 2006
Available online 9 November 2006
Abstract—6-(Perfluoroalkyl)salicylates were prepared by [3+3] cyclization of 1,3-bis(silyl enol ethers) with 3-ethoxy-1-(perfluoroalkyl)-
prop-2-en-1-ones.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
(Perfluoroalkyl)arenes are important building blocks for the
synthesis of pharmaceuticals and new materials.1–3 Per-
fluoroalkyl groups are chemically and biologically inert
and are, therefore, not metabolized. A number of amphi-
philic perfluoroalkyl derivatives represent promising liquid
crystals.4 One of the most common methods for the synthesis
of (perfluoroalkyl)arenes relies on the reaction of iodoarenes
with (perfluoroalkyl)cuprates.5 However, the preparative
scope of this method is limited, since a number of side-
reactions are frequently observed and the starting materials
are often not readily available. Some years ago, Chan and
Brownbridge reported6 an elegant approach to salicylates
based on the cyclization of 1,3-bis(silyl enol ethers)7 with
3-(silyloxy)alk-2-en-1-ones.8 Recently, we developed a
convenient access to 2-acetyl- and 2-alkoxycarbonyl-3-(tri-
fluoromethyl)phenols by cyclization of 1,3-bis(silyl enol
ethers) with 4-ethoxy- and 4-silyloxy-1,1,1-trifluoroalk-3-
en-2-ones.9 In previous papers, Kostyuk and co-workers
reported the formation of 3,5-bis(trifluoromethyl)anilines
by reaction of enamines with 1,1,1,5,5,5-hexafluoroacetyl-
acetone.10 Herein, we report a new and efficient approach
to 6-(perfluoroalkyl)salicylates by [3+3] cyclization of 1,3-
bis(silyl enol ethers) with 3-ethoxy-1-(perfluoroalkyl)prop-
2-en-1-ones. These transformations provide a convenient
and regioselective synthesis of novel (perfluoroalkyl)sali-
cylates, which are not readily available by other methods,
from readily available starting materials.
The pyridine-mediated reaction of ethyl vinyl ether with
(perfluoroalkyl)carboxylic anhydrides 1 or (perfluoroalkyl)-
carboxylic chlorides 2 afforded the 3-ethoxy-1-(perfluoro-
alkyl)prop-2-en-1-ones 3a–j in 39–71% yield (Scheme 1,
Table 1). The reactions were carried out in analogy to the
synthesis of trifluoromethyl-substituted 3-(alkoxy)prop-2-
en-1-ones.11 (Perfluoroalkyl)carboxylic anhydrides12a and
chlorides12b are known and were prepared according to a lit-
erature method. The synthesis of 3-ethoxy-1-(perfluoro-
alkyl)prop-2-en-1-ones 3a–j has, except for 3a,13 not yet
been reported. Due to their rather unstable nature, 3a–j could
be characterized in most cases only by NMR experiments.
All products reside as a single E/Z-diastereomer; compari-
son of the values of the vicinal coupling constants with those
reported in the literature11c,13b suggest that the double bonds
possess an E-configuration.
O
O
O
EtO
O
RF
or
RF
1
EtO
RF
i
O
3a-j
Cl
RF
ii
2
OSiMe3
OR
Me3SiO
O
OH
OR
4a,b
RF
Keywords: Arenes; Cyclizations; Organic fluorine compounds; Silyl enol
ethers.
5a-m
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
Scheme 1. Synthesis of 5a–m, (i) CH2Cl2, pyridine, 0/20 ꢀC, 12 h; (ii)
TiCl4, CH2Cl2, ꢁ78/20 ꢀC, 20 h.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.062

414
M. Lubbe et al. / Tetrahedron 63 (2007) 413–418
Table 1. Products 3a–j, 5a–m and their yields
3. Experimental section
3
5
RF
R
% (3)a
% (5)a
3.1. General procedure for the synthesis of 3-ethoxy-1-
(perfluoroalkyl)prop-2-en-1-ones 3a–j
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
C3F7
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
56
40
41
72
52
71
59
40
39
39
52
71
59
41
43
53
58
52
47
38
40
26
24
48
40
52
C5F11
C6F13
C7F15
C8F17
C9F19
C10F21
C11F23
C13F27
C15F31
C8F17
C9F19
C10F21
To a CH2Cl2 solution (2.5 mL/mmol) of (perfluoroalkyl)-
carboxylic chloride 2 or (perfluoroalkyl)carboxylic anhy-
dride 1 (1.0 equiv) was added dropwise a CH2Cl2 solution
(1.5 mL/mmol) of pyridine (2.0 equiv) and of ethyl vinyl
ether (1.3 equiv) at 0 ꢀC. The temperature of the solution
was allowed to slowly rise to 20 ꢀC and the solution was
stirred at 20 ꢀC for 12 h. The solvent was removed in vacuo
and the residue was purified by kugelrohr distillation or by
column chromatography (silica gel, n-heptane/EtOAc¼
20:1). In the 13C NMR data, the carbon atoms attached to
the fluorine atoms were omitted, due to extensive couplings.
j
e
f
j
k
l
Et
Et
g
m
a
Isolated yields.
3.1.1. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,8-(undecafluoro)oct-1-
en-3-one (3b). Starting with a CH2Cl2 solution (4 mL) of
perfluorohexanoic anhydride (1b) (1.00 g, 1.6 mmol) and
a CH2Cl2 solution (4 mL) of pyridine (0.23 g, 3.2 mmol)
and ethyl vinyl ether (0.15 g, 2.1 mmol), 3b was isolated
by kugelrohr distillation (oven temperature¼110 ꢀC, 6 Torr)
as a colourless oil (240 mg, 40%); Rf ¼0.79 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.90 (d,
3J¼12.2 Hz, 1H, H-1), 5.93 (d, 3J¼12.2 Hz, 1H, H-2),
The TiCl4 mediated cyclization of 3a–j with 1,3-bis(silyl
enol ethers) 4a,b—prepared from methyl and ethyl aceto-
acetate—afforded the novel 6-(perfluoroalkyl)salicylates
5a–m (Scheme 1, Table 1). All products were formed with
very good regioselectivity. The regioselectivity can be
explained—following general observations by Chan6—by
TiCl4 mediated conjugate addition of the terminal carbon
atom of the 1,3-bis(silyl enol ether) onto 3a–j and subse-
quent cyclization by attack of the central carbon atom of
the bis(silyl enol ether) onto the carbonyl group. Satisfactory
yields were obtained for all products, but they decreased
with increasing length of the perfluoroalkyl group (which
can be explained by the decreasing solubility).
3
3
4.10 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.39 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼181.8
(C-3), 168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.2
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ88.7
(CF3), ꢁ121.0, ꢁ121.4, ꢁ122.5 (CF2), ꢁ126.1 (CF2CF3).
The synthesis of free 6-(perfluoroalkyl)salicylic acids was
studied next. Our initial attempts to hydrolyze the ester
5d by treatment with NaOH/H2O, NaOH/EtOH, NaOMe/
MeOH or trifluoroacetic acid (TFA) failed. Finally, we
have found that treatment of 5d with KOt-Bu/THF (stirring
for 3 days at 20 ꢀC) and subsequent acidic work-up afforded
the desired carboxylic acid 6a in 78% yield (Scheme 2, Table
2). Likewise, the 6-(perfluoroalkyl)salicylic acids 6b,c were
prepared from 5g and 5j, respectively.
3.1.2. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,9-(tridecafluoro)-
non-1-en-3-one (3c). Starting with a CH2Cl2 solution
(1 mL) of perfluoroheptanoic anhydride (1c) (180 mg,
0.47 mmol) and a CH2Cl2 solution (1 mL) of pyridine
(74 mg, 0.94 mmol) and ethyl vinyl ether (44 mg,
0.61 mmol), 3c was isolated by column chromatography as
a colourless oil (80 mg, 41%); Rf ¼0.83 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.91 (d,
3J¼12.2 Hz, 1H, H-1), 5.94 (d, 3J¼12.2 Hz, 1H, H-2), 4.11
(q, 3J¼7.0 Hz, 2H, OCH2CH3), 1.40 (t, 3J¼7.0 Hz, 3H,
OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼181.8 (C-3),
168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.3 (OCH2CH3).
19F NMR (CDCl3, 235 MHz): d¼ꢁ88.6 (CF3), ꢁ120.8,
ꢁ121.4, ꢁ122.2, ꢁ122.6 (CF2), ꢁ125.9 (CF2CF3).
O
OH
O
OH
i
OMe
OH
RF
RF
5d,g,j
6a-c
3.1.3. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-(penta-
decafluoro)dec-1-en-3-one (3d). Starting with a CH2Cl2
solution (10 mL) of perfluoroctanoic chloride (2a) (1.77 g,
4.10 mmol) and a CH2Cl2 solution (7 mL) of pyridine
(0.64 g, 8.20 mmol) and ethyl vinyl ether (0.38 g,
5.33 mmol), 3d was isolated by kugelrohr distillation (oven
temperature¼70 ꢀC, 0.2 Torr) as a colourless oil (1.15 g,
72%); Rf ¼0.71 (n-heptane/EtOAc¼1:1). 1H NMR (CDCl3,
250 MHz): d¼7.91 (d, 3J¼12.2 Hz, 1H, H-1), 5.94 (d,
3J¼12.2 Hz, 1H, H-2), 4.11 (q, 3J¼7.0 Hz, 2H, OCH2CH3),
1.40 (t, 3J¼7.0 Hz, 3H, OCH2CH3). 13C NMR (CDCl3,
63 MHz): d¼182.0 (C-3), 168.1 (C-2), 99.0 (C-1), 69.4
(OCH2CH3), 14.5 (OCH2CH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.6 (CF3), ꢁ120.9, ꢁ121.3, ꢁ121.9,
ꢁ122.3, ꢁ122.6 (CF2), ꢁ126.0 (CF2CF3). MS (CI, iso-
butane): m/z (%)¼469 ([M+1]+, 100), 99 (9).
Scheme 2. Synthesis of 6a–c, (i) (1) KOt-Bu, THF, 20 ꢀC, 3 days; (2) HCl,
H2O.
In conclusion, a variety of 6-(perfluoroalkyl)salicylates were
prepared by [3+3] cyclization of 1,3-bis(silyl enol ethers)
with 3-ethoxy-1-(perfluoroalkyl)prop-2-en-1-ones.
Table 2. Products 6a–c and their yields
5
6
RF
% (6)a
d
g
j
a
b
c
C7F15
C10F21
C15F31
78
80
86
a
Isolated yields.

M. Lubbe et al. / Tetrahedron 63 (2007) 413–418
415
3.1.4. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-
(heptadecafluoro)undec-1-en-3-one (3e). Starting with a
CH2Cl2 solution (7 mL) of perfluorononanoic chloride
(2b) (1.50 g, 3.10 mmol) and a CH2Cl2 solution (5 mL) of
pyridine (0.49 g, 6.2 mmol) and ethyl vinyl ether (0.29 g,
4.0 mmol), 3e was isolated by column chromatography
as a colourless oil (1.15 g, 72%); Rf ¼0.71 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.90 (d,
3J¼12.2 Hz, 1H, H-1), 5.93 (d, 3J¼12.2 Hz, 1H, H-2),
3.1.8. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,
13,13,14,14,15,15,16,16,16-(heptacosafluoro)hexadec-1-
en-3-one (3i). Starting with a CH2Cl2 solution (1.5 mL) of
perfluorotetradecanoic chloride (2f) (381 mg, 0.52 mmol)
and a CH2Cl2 solution (1.5 mL) of pyridine (82 mg,
1.04 mmol) and ethyl vinyl ether (48 mg, 0.68 mmol), 3i
was isolated by column chromatography as a colourless
solid (156 mg, 39%); Rf ¼0.75 (n-heptane/EtOAc¼1:1).
3
1H NMR (CDCl3, 250 MHz): d¼7.91 (d, J¼12.2 Hz, 1H,
3
3
3
3
4.09 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.38 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼181.8
(C-3), 168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.2
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ81.0
(CF3), ꢁ121.1, ꢁ121.4, ꢁ121.9, ꢁ122.4, ꢁ122.8 (CF2),
ꢁ126.2 (CF2CF3).
H-1), 5.95 (d, J¼12.2 Hz, 1H, H-2), 4.11 (q, J¼7.0 Hz,
2H, OCH2CH3), 1.41 (t, J¼7.0 Hz, 3H, OCH2CH3). 13C
3
NMR (CDCl3, 63 MHz): d¼168.0 (C-2), 98.8 (C-1), 69.2
(OCH2CH3), 14.4 (OCH2CH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.4 (CF3), ꢁ120.8, ꢁ120.8, ꢁ121.0,
ꢁ121.3, ꢁ122.0, ꢁ122.4 (CF2), ꢁ125.8 (CF2CF3).
3.1.5. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
(nonadecafluoro)dodec-1-en-3-one (3f). Starting with
a CH2Cl2 solution (4 mL) of perfluorodecanoic chloride
(2c) (1.00 g, 1.9 mmol) and a CH2Cl2 solution (4 mL) of
pyridine (0.30 g, 3.8 mmol) and ethyl vinyl ether (0.18 g,
2.4 mmol), 3f was isolated by column chromatography as
a colourless solid (754 mg, 71%); Rf ¼0.74 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.90 (d,
3J¼12.2 Hz, 1H, H-1), 5.94 (d, 3J¼12.2 Hz, 1H, H-2),
3.1.9. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,
13,13,14,14,15,16,16,17,17,18,18,18-(hentriconta-
fluoro)octadec-1-en-3-one (3j). Starting with a CH2Cl2
solution (1.5 mL) of perfluorohexadecanoic chloride (2g)
(458 mg, 0.55 mmol) and a CH2Cl2 solution (1.5 mL) of
pyridine (87 mg, 1.10 mmol) and ethyl vinyl ether (52 mg,
0.72 mmol), 3j was isolated by column chromatography as
a colourless solid (185 mg, 39%); Rf ¼0.75 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.91 (d,
3J¼12.2 Hz, 1H, H-1), 5.95 (d, 3J¼12.2 Hz, 1H, H-2),
3
3
4.10 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.39 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼181.8
(C-3), 168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.3
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.8
(CF3), ꢁ121.1, ꢁ121.4, ꢁ121.9, ꢁ122.3, ꢁ122.8 (CF2),
ꢁ126.1 (CF2CF3).
3
3
4.11 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.41 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼168.0
(C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.4 (OCH2CH3). 19F
NMR (CDCl3, 235 MHz): d¼ꢁ80.5 (CF3), ꢁ120.8,
ꢁ121.2, ꢁ121.5, ꢁ122.1, ꢁ122.4 (CF2), ꢁ125.9 (CF2CF3).
3.1.6. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,
13,13,13-(henicosafluoro)tridec-1-en-3-one (3g). Starting
with a CH2Cl2 solution (7 mL) of perfluoroundecanoic chlo-
ride (2d) (2.5 g, 4.3 mmol) and a CH2Cl2 solution (7 mL) of
pyridine (0.68 g, 8.6 mmol) and ethyl vinyl ether (0.52 g,
5.6 mmol), 3g was isolated by column chromatography as
a colourless solid (1.55 g, 59%); Rf ¼0.82 (n-heptane/
EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼7.91 (d,
3J¼12.2 Hz, 1H, H-1), 5.94 (d, 3J¼12.2 Hz, 1H, H-2),
3.2. General procedure for the synthesis of
6-(perfluoroalkyl)salicylates 5a–m
To a CH2Cl2 solution (2.5 mL/mmol) of 3-ethoxy-3-(per-
fluoroalkyl)alk-2-en-1-one 3 (1.0 equiv) and 1,3-bis(silyl
enol ether) 4a,b (1.3 equiv) was added TiCl4 (1.0 equiv) at
ꢁ78 ꢀC under argon atmosphere. The temperature of the so-
lution was allowed to slowly rise to 20 ꢀC and the solution
was stirred at this temperature for 12 h. To the solution
was added hydrochloric acid (10%) and the organic and
the aqueous layers were separated and the latter was ex-
tracted with CH2Cl2 (3ꢂ10 mL). The combined organic
layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-heptane/EtOAc¼20:1). In
the 13C NMR data, the carbon atoms attached to the fluorine
atoms were omitted, due to extensive couplings.
3
3
4.11 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.40 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz): d¼181.8
(C-3), 168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.3
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.7
(CF3), ꢁ121.0, ꢁ121.2, ꢁ121.7, ꢁ122.2, ꢁ122.6 (CF2),
ꢁ126.0 (CF2CF3).
3.1.7. 1-Ethoxy-4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,
13,13,14,14,14-(tricosafluoro)tridec-1-en-3-one (3h).
Starting with a CH2Cl2 solution (4 mL) of perfluorododeca-
noic chloride (2e) (1.50 g, 2.4 mmol) and a CH2Cl2 solution
(4 mL) of pyridine (0.38 g, 4.8 mmol) and ethyl vinyl ether
(0.22 g, 3.1 mmol), 3h was isolated by column chromato-
graphy as a colourless solid (628 mg, 40%); Rf ¼0.79
(n-heptane/EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz):
3.2.1. Methyl 6-(heptafluoropropyl)salicylate (5a). Start-
ing with 3a (402 mg, 1.5 mmol), 4a (521 mg, 2.0 mmol)
and TiCl4 (284 mg, 1.5 mmol) in CH2Cl2 (3 mL), 5a was
isolated as a colourless oil (195 mg, 41%); Rf ¼0.43 (n-hep-
tane/EtOAc¼1:1). A small amount of an unknown impurity
could not be separated. 1H NMR (CDCl3, 250 MHz):
3
3
3
d¼7.91 (d, J¼12.2 Hz, 1H, H-1), 5.95 (d, J¼12.2 Hz,
1H, H-2), 4.11 (q, 3J¼7.0 Hz, 2H, OCH2CH3), 1.41 (t,
3J¼7.0 Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 63 MHz):
d¼168.0 (C-2), 98.8 (C-1), 69.2 (OCH2CH3), 14.3
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5
(CF3), ꢁ120.9, ꢁ121.1, ꢁ121.5, ꢁ122.1, ꢁ122.4 (CF2),
ꢁ125.8 (CF2CF3).
d¼9.37 (s, 1H, OH), 7.50 (t, J¼8.5 Hz, 1H, H-4), 7.24–
7.17 (m, 2H, H-3, H-5), 3.93 (s, 3H, OCH3). 13C NMR
(CDCl3, 63 MHz): d¼169.0 (C]O), 159.1 (C-2), 132.8
(C-3), 129.0 (C-6), 121.6 (C-4), 120.6 (C-5), 115.9 (C-1),
52.8 (OCH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5
(CF3), ꢁ99.4 (ArCF2), ꢁ126.9 (CF2CF3). MS (EI, 70 eV):
m/z (%)¼320 (M+, 21), 288 (100, [M+ꢁMeOH]), 241 (8),

416
M. Lubbe et al. / Tetrahedron 63 (2007) 413–418
141 (37). HRMS (EI, 70 eV): calcd for C11H7F7O3 (M+)
320.02779, found 320.02728.
(CDCl3, 235 MHz): d¼ꢁ80.7 (CF3), ꢁ99.8 (ArCF2),
ꢁ117.7, ꢁ121.9, ꢁ122.6 (CF2), ꢁ126.0 (CF2CF3). MS (EI,
70 eV): m/z (%)¼570 (M+, 15), 538 (100, [M+ꢁMeOH]),
519 (11), 169 (12), 141 (64). HRMS (EI, 70 eV): calcd for
C16H7O3F17 (M+) 570.01183, found 570.01008. Anal. Calcd
for C16H7F17O3 (570.20): C, 33.70; H, 1.24. Found: C, 33.83;
H, 1.28.
3.2.2. Methyl 6-(undecafluoropentyl)salicylate (5b). Start-
ing with 3b (220 mg, 0.60 mmol), 4a (203 mg, 0.78 mmol)
and TiCl4 (114 mg, 0.60 mmol) in CH2Cl2 (1.2 mL), 5b
was isolated as a colourless solid (108 mg, 43%); mp¼
68–69 ꢀC; Rf ¼0.53 (n-heptane/EtOAc¼1:1). 1H NMR
(CDCl3, 250 MHz): d¼9.31 (s, 1H, OH), 7.51 (t, 3J¼
8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.93 (s, 3H,
OCH3). 13C NMR (CDCl3, 75 MHz): d¼168.9 (C]O),
159.1 (C-2), 132.8 (C-3), 127.5 (C-6), 121.7 (C-4), 120.8
(C-5), 114.7 (C-1), 52.8 (OCH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.4 (CF3), ꢁ99.6 (CF2Ar), ꢁ117.2,
ꢁ122.7 (CF2), ꢁ125.7 (CF2CF3). MS (EI, 70 eV): m/z
(%)¼420 (M+, 24), 388 (100, [M+ꢁMeOH]), 341 (10), 169
(21), 141 (61). HRMS (EI, 70 eV): calcd for C13H7F11O3
(M+) 420.02141, found 420.02112.
3.2.6. Methyl 6-(nonadecafluorononyl)salicylate (5f).
Starting with 3f (568 mg, 1.0 mmol), 4a (338 mg,
1.3 mmol) and TiCl4 (189 mg, 1.0 mmol) in CH2Cl2
(2.5 mL), 5f was isolated as a colourless solid (290 mg,
47%); mp¼109–110 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1).
1H NMR (CDCl3, 250 MHz): d¼9.28 (s, 1H, OH), 7.50 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.93 (s,
3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0 (C]O),
159.3 (C-2), 132.9 (C-3), 129.2 (C-6), 121.7 (C-4), 120.8
(C-5), 114.6 (C-1), 52.8 (OCH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.4 (CF3), ꢁ99.6 (CF2Ar), ꢁ116.9,
ꢁ121.5, ꢁ122.4 (CF2), ꢁ125.8 (CF2CF3). MS (EI, 70 eV):
m/z (%)¼620 (M+, 23), 588 (100, [M+ꢁMeOH]), 569 (20),
169 (18), 141 (75). HRMS (EI, 70 eV): calcd for
C17H7F19O3 (M+) 620.00863, found 620.00875. Anal. Calcd
for C17H7F19O3 (620.01): C, 32.92; H, 1.14. Found: C, 33.02;
H, 1.15.
3.2.3. Methyl 6-(tridecafluorohexyl)salicylate (5c). Start-
ing with 3c (80 mg, 0.19 mmol), 4a (65 mg, 0.25 mmol)
and TiCl4 (36 mg, 0.19 mmol) in CH2Cl2 (0.5 mL), 5c was
isolated as a colourless solid (47 mg, 53%); mp¼
75–76 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1). 1H NMR
(CDCl3, 250 MHz): d¼9.29 (s, 1H, OH), 7.50 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.93
(s, 3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0
(C]O), 159.1 (C-2), 132.9 (C-4), 129.1 (C-6), 121.7
(C-5), 120.8 (C-3), 114.8 (C-1), 52.8 (OCH3). 19F NMR
(CDCl3, 235 MHz): d¼ꢁ80.5 (CF3), ꢁ99.7 (CF2Ar),
ꢁ117.1 (CF2), ꢁ121.9 (CF2), ꢁ122.4 (CF2), ꢁ125.8
(CF2CF3). MS (EI, 70 eV): m/z (%)¼470 (M+, 17), 438
(100, [M+ꢁMeOH]), 419 (7), 169 (9), 141 (60). HRMS
(EI, 70 eV): calcd for C14H7O3F13 (M+) 470.01821, found
470.01904.
3.2.7. Methyl 6-(henicosafluorodecyl)salicylate (5g).
Starting with 3g (1.00 g, 1.6 mmol), 4a (547 mg, 2.1 mmol)
and TiCl4 (303 mg, 1.6 mmol) in CH2Cl2 (3.2 mL), 5g was
isolated as a colourless solid (405 mg, 38%); mp¼118–
119 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1). 1H NMR
(CDCl3, 250 MHz): d¼9.30 (s, 1H, OH), 7.50 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.94 (s,
3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0 (C]O),
159.3 (C-2), 132.9 (C-3), 129.3 (C-6), 121.8 (C-4), 120.8
(C-5), 114.6 (C-1), 52.8 (OCH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.5 (CF3), ꢁ99.5 (CF2Ar), ꢁ117.0,
ꢁ121.4, ꢁ122.4 (CF2), ꢁ125.8 (CF2CF3). MS (EI, 70 eV):
m/z (%)¼670 (M+, 16), 638 (100, [M+ꢁMeOH]), 619 (17),
169 (13), 141 (44). HRMS (EI, 70 eV): calcd for
C18H7F21O3 (M+) 670.00544, found 670.00601. Anal. Calcd
for C18H7F21O3 (670.21): C, 32.26; H, 1.05. Found: C, 32.70;
H, 1.18.
3.2.4. Methyl 6-(pentadecafluoroheptyl)salicylate (5d).
Starting with 3d (1.00 g, 2.1 mmol), 4a (1.12 g, 2.7 mmol)
and TiCl4 (0.40 g, 2.1 mmol) in CH2Cl2 (5.5 mL), 5d was
isolated as a colourless solid (650 mg, 58%); mp¼83–
84 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1). 1H NMR (CDCl3,
3
250 MHz): d¼9.28 (s, 1H, OH), 7.48 (t, J¼8.5 Hz, 1H,
H-4), 7.23–7.16 (m, 2H, H-3, H-5), 3.92 (s, 3H, OCH3).
13C NMR (CDCl3, 75 MHz): d¼169.1 (C]O), 159.1 (C-2),
132.9 (C-3), 129.2 (C-6), 121.8 (C-4), 120.9 (C-5), 115.2
(C-1), 52.9 (OCH3). 19F NMR (CDCl3, 235 MHz):
d¼ꢁ80.7 (CF3), ꢁ100.2 (CF2Ar), ꢁ117.3, ꢁ121.8, ꢁ122.5
(CF2), ꢁ126.0 (CF2CF3). IR (CHCl3, cmꢁ1): ~n ¼ 3277;
1685. MS (EI, 70 eV): m/z (%)¼520 (M+, 18), 488 (100,
[M+ꢁMeOH]), 461 (8, [M+ꢁCOOMe]). HRMS (EI,
70 eV): calcd for C15H7F15O3 (M+) 520.0150, found
520.0128.
3.2.8. Methyl 6-(tricosafluoroundecyl)salicylate (5h).
Starting with 3h (620 mg, 0.93 mmol), 4a (315 mg,
1.21 mmol) and TiCl4 (176 mg, 0.93 mmol) in CH2Cl2
(1.9 mL), 5h was isolated as a colourless solid (262 mg,
40%); mp¼119–120 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1).
1H NMR (CDCl3, 250 MHz): d¼9.30 (s, 1H, OH), 7.51 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.93 (s,
3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0 (C]O),
159.3 (C-2), 132.9 (C-3), 121.8 (C-4), 121.0 (C-5), 52.8
(OCH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5 (CF3),
ꢁ99.7 (CF2Ar), ꢁ117.1, ꢁ121.5, ꢁ122.5 (CF2), ꢁ125.9
(CF2CF3). MS (EI, 70 eV): m/z (%)¼720 (M+, 22), 688
(100, [M+ꢁMeOH]), 669 (25), 169 (13), 141 (47). HRMS
(EI, 70 eV): calcd for C19H7F19O3 (M+) 720.00224, found
720.00280.
3.2.5. Methyl 6-(heptadecafluorooctyl)salicylate (5e).
Starting with 3e (777 mg, 1.5 mmol), 4a (521 mg,
2.0 mmol) and TiCl4 (284 mg, 1.5 mmol) in CH2Cl2
(3 mL), 5e was isolated as a colourless solid (443 mg,
52%); mp¼102–104 ꢀC; Rf ¼0.50 (n-heptane/EtOAc¼1:1).
1H NMR (CDCl3, 250 MHz): d¼9.31 (s, 1H, OH), 7.51 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.94
(s, 3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0
(C]O), 159.3 (C-2), 132.9 (C-3), 129.2 (C-6), 121.7
(C-4), 120.8 (C-5), 114.6 (C-1), 52.8 (OCH3). 19F NMR
3.2.9. Methyl 6-(heptacosafluorotridecyl)salicylate (5i).
Starting with 3i (155 mg, 0.15 mmol), 4a (52 mg,
0.20 mmol) and TiCl4 (28 mg, 0.15 mmol) in CH2Cl2

M. Lubbe et al. / Tetrahedron 63 (2007) 413–418
417
(0.3 mL), 5i was isolated as a colourless solid (31 mg, 26%);
mp¼114–115 ꢀC; Rf ¼0.35 (n-heptane/EtOAc¼1:1).
ꢁ125.8 (CF2CF3). MS (EI, 70 eV): m/z (%)¼634 (M+, 12),
588 (100, [M+ꢁEtOH]), 569 (10), 169 (9), 141 (29).
HRMS (EI, 70 eV): calcd for C18H9O3F19 (M+) 634.02428,
found 634.025582.
A
small amount of an unknown impurity could not be sepa-
1
rated. H NMR (CDCl3, 250 MHz): d¼9.30 (s, 1H, OH),
7.50 (t, 3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3,
H-5), 3.93 (s, 3H, OCH3). 13C NMR (CDCl3, 75 MHz):
d¼169.0 (C]O), 159.2 (C-2), 132.9 (C-3), 121.7 (C-4),
120.8 (C-5), 52.8 (OCH3). 19F NMR (CDCl3, 235 MHz):
d¼ꢁ80.5 (CF3), ꢁ99.7 (ArCF2), ꢁ116.9 (CF2), ꢁ121.4,
ꢁ122.4 (CF2), ꢁ126.5 (CF2CF3). MS (EI, 70 eV): m/z
(%)¼820 (M+, 24), 788 (100, [M+ꢁMeOH]), 750 (62),
141 (64). HRMS (EI, 70 eV): calcd for C21H7O3F27 (M+)
819.99586, found 819.994578.
3.2.13. Ethyl 6-(henicosafluorodecyl)salicylate (5m).
Starting with 3g (230 mg, 0.37 mmol), 4b (203 mg,
0.48 mmol) and TiCl4 (70 mg, 0.37 mmol) in CH2Cl2
(1 mL), 5m was isolated as a colourless solid (130 mg,
52%); mp¼105–106 ꢀC; Rf ¼0.45 (n-heptane/EtOAc¼1:1).
A small amount of an unknown impurity could not be sepa-
rated. 1H NMR (CDCl3, 250 MHz): d¼9.21 (br s, 1H, OH),
7.49 (t, 3J¼8.5 Hz, 1H, H-4), 7.24–7.17 (m, 2H, H-3, H-5),
4.43 (q, 3J¼7.0 Hz, 2H, OCH2CH3), 1.36 (t, 3J¼7.0 Hz, 3H,
OCH2CH3). 13C NMR (CDCl3, 75 MHz): d¼168.5 (C]O),
158.9 (C-2), 132.6 (C-3), 128.9 (C-6), 121.6 (C-4), 121.0
(C-5), 115.5 (C-1), 62.7 (OCH2CH3), 13.4 (OCH2CH3).
19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5 (CF3), ꢁ99.7
(CF2Ar), ꢁ117.5 (CF2), ꢁ121.4 (CF2), ꢁ122.4 (CF2),
ꢁ125.8 (CF2CF3). MS (EI, 70 eV): m/z (%)¼684
(M+, 10), 638 (100, [M+ꢁEtOH]), 141 (18). HRMS (EI,
70 eV): calcd for C19H9O3F21 (M+) 684.02109, found
684.01984.
3.2.10. Methyl 6-(hentricontafluoropentadecyl)salicylate
(5j). Starting with 3j (185 mg, 0.21 mmol), 4a (71 mg,
0.27 mmol) and TiCl4 (38 mg, 0.21 mmol) in CH2Cl2
(0.5 mL), 5j was isolated as a colourless solid (45 mg,
24%); mp¼84–86 ꢀC; Rf ¼0.35 (n-heptane/EtOAc¼1:1).
1H NMR (CDCl3, 250 MHz): d¼9.30 (s, 1H, OH), 7.50 (t,
3J¼8.5 Hz, 1H, H-4), 7.24–7.18 (m, 2H, H-3, H-5), 3.93 (s,
3H, OCH3). 13C NMR (CDCl3, 75 MHz): d¼169.0
(C]O), 159.2 (C-2), 132.9 (C-3), 121.7 (C-4), 120.8
(C-5), 114.6 (C-1), 52.8 (OCH3). 19F NMR (CDCl3,
235 MHz): d¼ꢁ80.8 (CF3), ꢁ99.8 (ArCF2), ꢁ117.3 (CF2),
ꢁ121.6, ꢁ122.7 (CF2), ꢁ126.1 (CF2CF3). MS (EI, 70 eV):
m/z (%)¼920 (M+, 13), 888 (31, [M+ꢁMeOH]), 850 (100),
788 (43), 750 (58), 688 (13), 141 (33). HRMS (EI, 70 eV):
calcd for C23H7O3F31 (M+) 919.98947, found 919.98842.
3.3. General procedure for the synthesis of 6-(perfluoro-
alkyl)salicylic acids 6a–c
To a THF solution (20 mL/mmol) of 5 (1.0 equiv) was added
KOt-Bu (4.0 equiv) at 20 ꢀC and the solution was stirred for
3 days at 20 ꢀC. To the solution was added hydrochloric acid
(10%) until the solution reached pH¼1. The organic and the
aqueous layers were separated and the latter was extracted
with dichloromethane. The combined organic layers were
dried (Na2SO4), filtered, and the filtrate was concentrated
in vacuo. The residue was purified by chromatography (silica
gel, n-heptane/EtOAc¼1:1). In the 13C NMR data, the car-
bon atoms attached to the fluorine atoms were omitted,
due to extensive couplings.
3.2.11. Ethyl 6-(heptadecafluorooctyl)salicylate (5k).
Starting with 3e (160 mg, 0.31 mmol), 4b (170 mg,
0.62 mmol) and TiCl4 (59 mg, 0.31 mmol) in CH2Cl2
(0.8 mL), 5k was isolated as a colourless solid (84 mg,
46%); mp¼95–96 ꢀC; Rf ¼0.45 (n-heptane/EtOAc¼1:1). A
small amount of an unknown impurity could not be sepa-
1
rated. H NMR (CDCl3, 250 MHz): d¼9.21 (s, 1H, OH),
7.49 (t, 3J¼8.5 Hz, 1H, H-4), 7.24–7.17 (m, 2H, H-3,
H-5), 4.43 (q, 3J¼7.0 Hz, 2H, OCH2CH3), 1.36 (t,
3J¼7.0 Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 75 MHz):
d¼168.5 (C]O), 158.9 (C-2), 132.5 (C-3), 128.8 (C-6),
121.6 (C-4), 120.9 (C-5), 115.5 (C-1), 62.7 (OCH2CH3),
13.4 (OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5
(CF3), ꢁ99.8 (ArCF2), ꢁ117.5, ꢁ121.6, ꢁ122.4 (CF2),
ꢁ125.8 (CF2CF3). MS (EI, 70 eV): m/z (%)¼584 (M+,
14), 538 (100, [M+ꢁEtOH]), 519 (11), 169 (11), 141 (36).
HRMS (EI, 70 eV): calcd for C17H9O3F17 (M+)
584.02748, found 584.02769.
3.3.1. 6-(Pentadecafluoroheptyl)salicylic acid (6a). Start-
ing with 5d (110 mg, 0.21 mmol), KOt-Bu (94 mg,
0.84 mmol), THF (6.0 mL), 6a was isolated as a colourless
solid (83 mg, 78%); mp¼157 ꢀC (dec); Rf ¼0.24 (n-hep-
1
tane/EtOAc¼1:1). H NMR (CD3OD, 250 MHz): d¼7.33
3
(t, J¼7.9 Hz, 1H, H-4), 7.13–7.00 (m, 2H, H-3, H-5). 13C
NMR (CD3OD, 75 MHz): d¼173.5 (C]O), 156.5 (C-2),
130.2 (C-3), 126.8 (C-6), 120.6 (C-4), 119.8 (C-5), 112.4
(C-1). 19F NMR (CD3OD, 235 MHz): d¼ꢁ78.8 (CF3),
ꢁ102.0 (CF2Ar), ꢁ116.4, ꢁ118.8, ꢁ119.3, ꢁ120.2 (CF2),
ꢁ123.7 (CF2CF3). MS (EI, 70 eV): m/z (%)¼506 (M+,
18), 488 (100), 469 (11). HRMS (EI, 70 eV): calcd for
C14H5F15O3 (M+) 505.99863, found 505.99937.
3.2.12. Ethyl 6-(nonadecafluorononyl)salicylate (5l).
Starting with 3f (568 mg, 1.0 mmol), 4b (338 mg,
1.3 mmol) and TiCl4 (189 mg, 1.0 mmol) in CH2Cl2
(2.5 mL), 5l was isolated as a colourless solid (35 mg,
40%); mp¼103–104 ꢀC; Rf ¼0.45 (n-heptane/EtOAc¼1:1).
A small amount of an unknown impurity could not be sepa-
3.3.2. 6-(Henicosafluorodecyl)salicylic acid (6b). Starting
with 5g (55 mg, 0.08 mmol), KOt-Bu (36 mg, 0.32 mmol)
in THF (2.0 mL), 6b was isolated as a colourless solid
(42 mg, 80%); mp¼161 ꢀC (dec); Rf ¼0.24 (n-heptane/
EtOAc¼1:1). 1H NMR (CD3OD, 250 MHz): d¼7.29 (t,
3J¼8.2 Hz, 1H, H-4), 7.12–7.00 (m, 2H, H-3, H-5). 13C
NMR (CD3OD, 75 MHz): d¼170.2 (C]O), 156.2 (C-2),
131.3 (C-3), 120.6 (C-4), 119.6 (C-5). 19F NMR (CD3OD,
235 MHz): d¼ꢁ78.8 (CF3), ꢁ103.4 (CF2Ar), ꢁ117.1,
ꢁ119.1, ꢁ120.1 (CF2), ꢁ123.7 (CF2CF3).
1
rated. H NMR (CDCl3, 250 MHz): d¼9.19 (s, 1H, OH),
7.48 (t, 3J¼8.5 Hz, 1H, H-4), 7.23–7.16 (m, 2H, H-3, H-5),
3
3
4.42 (q, J¼7.0 Hz, 2H, OCH2CH3), 1.36 (t, J¼7.0 Hz,
3H, OCH2CH3). 13C NMR (CDCl3, 75 MHz): d¼169.0
(C]O), 159.3 (C-2), 132.9 (C-3), 129.2 (C-6), 121.7
(C-4), 120.8 (C-5), 114.6 (C-1), 52.8 (OCH2CH3), 13.4
(OCH2CH3). 19F NMR (CDCl3, 235 MHz): d¼ꢁ80.5
(CF3), ꢁ100.0 (CF2Ar), ꢁ117.6, ꢁ121.5, ꢁ122.4 (CF2),

418
M. Lubbe et al. / Tetrahedron 63 (2007) 413–418
4. (a) Liquid Crystals; Stegemeyer, H., Ed.; Steinkopff, Springer:
New York, NY, 1994; (b) Miethchen, R.; Hein, M. Carbohydr.
Res. 2000, 327, 169; (c) Hein, M.; Miethchen, R.;
3.3.3. 6-(Hentricontafluoropentadecyl)salicylic acid (6c).
Starting with 5k (40 mg, 0.04 mmol), KOt-Bu (18 mg,
0.16 mmol) in THF (2.0 mL), 6c was isolated as a colourless
solid (31 mg, 86%); mp¼168 ꢀC (dec); Rf ¼0.24 (n-heptane/
EtOAc¼1:1). 1H NMR (CD3OD, 250 MHz): d¼7.38
(t, 3J¼8.2 Hz, 1H, H-4), 7.14–7.02 (m, 2H, H-3, H-5).
19F NMR (CD3OD, 235 MHz): d¼ꢁ85.1 (CF3), ꢁ105.4
(CF2Ar), ꢁ119.1, ꢁ123.4, ꢁ123.6 (CF2), ꢁ127.1
(CF2CF3). Due to the low solubility of 6c, a 13C NMR
spectrum could not be obtained.
€
Schwabisch, D.; Schick, C. Liq. Cryst. 2000, 27, 163; (d)
€
Schwabisch, D.; Wille, S.; Hein, M.; Miethchen, R. Liq.
Cryst. 2004, 31, 1143.
5. Burton, D. J.; Yang, Z. Tetrahedron 1992, 48, 189.
6. Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534.
7. For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
8. For [3+3] cyclizations of 1,3-bis(silyl enol ethers) from our lab-
oratory, see: (a) Dede, R.; Langer, P. Tetrahedron Lett. 2004, 45,
9177; (b) Nguyen, V.; Langer, P. Tetrahedron Lett. 2005, 46,
1013; (c) Ahmed, Z.; Fischer, C.; Spannenberg, A.; Langer, P.
Tetrahedron 2006, 62, 4800; (d) Nguyen, V. T. H.; Bellur, E.;
Appel, B.; Langer, P. Synthesis 2006, 1103; (e) Nguyen,
V. T. H.; Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47,
113; (f) Ahmed, Z.; Langer, P. Tetrahedron Lett. 2006, 47, 417.
9. Mamat, C.; Pundt, T.; Schmidt, A.; Langer, P. Tetrahedron Lett.
2006, 47, 2183.
10. (a) Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.;
Chernega, A. N.; Pinchuk, A. M.; Tolmachev, A. A. Tetra-
hedron 2004, 60, 2361; (b) Volochnyuk, D. M.; Kostyuk,
A. N.; Sibgatulin, D. A.; Chernega, A. N. Tetrahedron 2005,
61, 2839.
11. (a) Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M.
Synthesis 1986, 1016; (b) Colla, A.; Martins, M. A. P.; Clar,
G.; Krimmer, S.; Fischer, P. Synthesis 1991, 483; (c) Hojo,
M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem.
Lett. 1976, 499.
12. (a) Husted, D. R.; Ahlbrecht, A. H. J. Am. Chem. Soc. 1953, 75,
1605; (b) Malik, A. A.; Sharts, C. M. J. Fluorine Chem. 1987,
34, 395.
Acknowledgements
We are grateful to Dr. Dirk Michalik for detailed NMR
studies.
References and notes
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Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993; (b)
Filler, R. Fluorine Containing Drugs in Organofluorine
Chemicals and their Industrial Application; Pergamon: New
York, NY, 1979; Chapter 6; (c) Hudlicky, M. Chemistry of
Organic Fluorine Compounds; Ellis Horwood: Chichester,
UK, 1992; (d) Fluorine in Medicine in the 21st Century;
Banks, R. E., Lowe, K. C., Eds.; Chemserve (UMIST):
Manchester, 1994.
2. (a) Ryckmans, T.; Balancon, L.; Berton, O.; Genicot, C.;
Lamberty, Y.; Lallemand, B.; Pasau, P.; Pirlot, N.; Quere, L.;
Talaga, P. Bioorg. Med. Chem. Lett. 2002, 12, 261; (b)
Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan, B.; Sawicki,
D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R. J. Med. Chem.
2000, 43, 3995.
13. (a) Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine
Chem. 1994, 69, 195; (b) Gorbunova, M. G.; Gerus, I. I.;
Kukhar, V. P. Synthesis 2000, 738.
€
3. Liedtke, J.; Loss, S.; Widauer, C.; Grutzmacher, H. Tetrahedron
2000, 56, 143.