Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides

Article abstract of DOI:10.1039/c0ob00790k

Lithium-bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by S _NAr substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of

Full text of DOI:10.1039/c0ob00790k

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 2294
www.rsc.org/obc
PAPER
Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type
rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides†
Julia Ponce Gonza´lez, Mark Edgar, Mark R. J. Elsegood‡ and George W. Weaver*
Received 27th September 2010, Accepted 22nd November 2010
DOI: 10.1039/c0ob00790k
Lithium–bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated
benzofurans or benzothiophenes respectively by SNAr substitution of the adjacent fluorine in the
perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy
and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid-4-yl ether,
lithiation promoted a Smiles-type rearrangement which led to formation of
4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray
crystallography.
Aromatic nucleophilic substitution in per- and poly-fluorinated
arenes1,2 is a valuable method for constructing highly func-
tionalised heterocycles and aromatics.3 Such compounds have
been widely investigated by Chambers4 and Sandford5 and have
been used as scaffolds for drug discovery.6 The mechanistic and
synthetic potential of fluorinated arenes has been reviewed.7 There
is considerable interest in ring closing reactions of substituted
polyfluoroarenes as a way of rapidly generating usefully function-
alised polycyclic compounds.8,9 As part of our investigations in
this area we have studied ring closure by lithiation of bromoaryl
ethers and sulfides containing a perfluoroarene ring. Reaction of
a lithiated binaphthyl with hexafluorobenzene has recently been
used in an elegant synthesis of a fluorinated helicene by Piers.10
In our study, lithiation of the easily prepared 2-bromophenyl
tetrafluoropyridin-4-yl ether 2 (Scheme 1) was expected to form
the pyrido-fused benzofuran derivative 3 by lithium–bromine
exchange and then intramolecular substitution of the fluorine at C-
3 of the pyridine ring to close the furan ring. However treatment of
the tetrafluoropyridyl ether 2 with n-butyllithium in THF at low
temperature afforded a compound which was not the expected
1
tricyclic furan 3. IR and H NMR spectroscopy indicated the
presence of an alcohol group (dH 5.01, exchangeable with D2O)
while the 19F NMR spectrum showed signals for two pairs of
fluorine atoms indicating that the tetrafluoropyridine ring was
intact. The product was identified as the 2-(tetrafluoropyridin-
4-yl)phenol 4 and the structure was confirmed by X-ray crys-
tallography (Fig. 1, Table 1) indicating that the reaction had
Department of Chemistry, Loughborough University, Loughborough, UK,
LE11 3TU
† CCDC reference numbers 794854–794860. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0ob00790k
‡ For correspondence regarding the X-ray crystallography.
Scheme 1 Formation and Smiles-type rearrangement of ether 2.
2294 | Org. Biomol. Chem., 2011, 9, 2294–2305 This journal is
The Royal Society of Chemistry 2011
©

View Article Online
1
2
Table 1 Crystallographic data for compounds 4, 7· C7H8, 8, 22, 32A, 32B, and 34
1
2
Compound
Formula
4
7· C7H8
8
22
32A
32B
34
C11H5F4NO
C23H12Br3F2NS3· C11H4F3NS
C18H8F2O2
C18H8BrF3S2
C18H8BrF3S2
C18H8F2S2
1 C7H8
2
Formula weight 243.16
722.31
Triclinic
¯
P1
239.21
Triclinic
¯
P1
294.24
Monoclinic
P21/n
425.27
Monoclinic
P21/c
425.27
Monoclinic
P21/c
326.36
Monoclinic
P21/c
Crystal system
Tetragonal
Space group
I41cd
Unit cell dimensions
˚
a (A)
13.0912(7)
13.0912(7)
23.1759(12)
90
90
90
3971.9(4)
16
150(2)
7.0016(12)
10.9436(19)
17.466(3)
92.675(3)
99.643(3)
90.003(3)
1317.9(4)
2
7.2230(8)
7.9584(9)
9.1866(10)
100.979(2)
97.143(2)
113.863(2)
462.01(9)
2
6.198(2)
6.525(2)
15.416(5)
90
97.211(4)
90
618.5(3)
2
150(2)
0.6942
1.580
9.8845(5)
15.6680(8)
10.3729(5)
90
92.2845
90
1605.18(14)
4
150(2)
0.71073
1.760
15.1514(9)
12.9717(8)
8.1916(5)
90
103.5221(9)
90
1565.34(16)
4
150(2)
7.823(2)
3.9110(12)
21.623(7)
90
92.499(4)
90
660.9(3)
2
150(2)
0.71073
1.640
˚
b (A)
˚
c (A)
a (◦)
b (◦)
g (◦)
3
˚
V (A )
Z
Temp. (K)
150(2)
0.71073
1.820
150(2)
0.71073
1.720
˚
Radiation, l (A) 0.71073
0.71073
1.805
2.921
Dc (g cm-3)
1.627
0.156
Absorption
4.861
0.362
0.123
2.848
0.417
coefficient (mm-1)
Crystal size (mm) 0.59 ¥ 0.22 ¥ 0.20 0.62 ¥ 0.23 ¥ 0.05 0.47 ¥ 0.15 ¥ 0.03 0.07 ¥ 0.01 ¥ 0.01 0.84 ¥ 0.13 ¥ 0.10 0.70 ¥ 0.29 ¥ 0.03 0.56 ¥ 0.12 ¥ 0.02
2qmax (◦)
56.66
12777
57.74
14248
54.16
7449
45.98
2656
56.66
16379
61.14
18058
52.86
4059
Reflections
measured
Unique
1268, 0.0208
8971, 0.0439
6373
3593, 0.0249
3172
907, 0.0501
588
3987, 0.0336
3119
4770, 0.0410
3675
1347, 0.0623
1022
reflections, Rint
Reflections with 1158
F2 > 2s(F2)
Transmission
factors
0.914 to 0.969
155
0.153 to 0.793
354
0.849 to 0.989
146
0.992 to 0.999
101
0.196 to 0.756
217
0.234 to 0.918
217
0.800 to 0.992
100
Number of
parameters
R1 [F2 > 2s(F2)] 0.0305
0.0547
0.1632
1.03 and -0.88
0.0343
0.0881
0.37 and -0.19
0.0949
0.2902
0.97 and -0.32
0.0378
0.0976
1.02 and -0.68
0.0355
0.1012
0.56 and -0.40
0.0559
0.1366
0.50 and -0.31
wR2 (all data)
0.0849
Largest difference 0.16 and -0.16
peak and hole
-3
˚
(e A )
◦
˚
Fig. 1 Crystal structure of 4 showing p ◊ ◊ ◊ p stacking and H-bond intermolecular interactions. O(8)–H(8) ◊ ◊ ◊ N(4¢) = 2.02 A, angle at H(8) = 168 .
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2295
©

View Article Online
Scheme 2 Formation and cyclisation of sulfide 6.
Fig. 2 Crystal structure of 7 showing halogen ◊ ◊ ◊ halogen interactions. Toluene of crystallisation omitted for clarity.
proceeded by a Smiles type11,12 rearrangement rather than SNAr
reaction at the 3-position of the pyridine ring. The structure
of the biaryl 4 showed a unique hydrogen bond between the
phenolic OH group and the weakly basic tetrafluoropyridine
nitrogen, resulting in zig-zag chains of molecules. The torsion
angle between the two aryl rings is 56.05(3)◦. Molecules p ◊ ◊ ◊ p
substitution of the fluorine atom at 3-position of the pyridine
ring.
Reaction of pentafluoropyridine and sodium 2-bromoben-
zenethiolate in DMF (Scheme 2) gave the corresponding sulfide
6 (50%) together with a small amount (18%) of the product
of trisubstitution 7. The latter was identified as the 2,4,5-
tri(2-bromophenylthio)-3,6-difluoropyridine, and the substitution
pattern, which differs13 from that usually found14 for pentafluo-
ropyridine, was shown by the 19F NMR spectrum (dF 45.6 and
99.0), and was confirmed by X-ray crystallography (Fig. 2, Table
˚
stack with centroid–centroid separations of 3.864 and 4.021 A and
˚
a shortest contact of 3.620 A for N(4) ◊ ◊ ◊ C(12¢). Treatment of the
phenol 4 with sodium hydride in DMF gave the fused benzofuran
5 quantitatively with the phenoxide oxygen effecting nucleophilic
2296 | Org. Biomol. Chem., 2011, 9, 2294–2305
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
˚
˚
Fig. 3 Crystal structure of 8 showing fluorine ◊ ◊ ◊ fluorine {F(3) ◊ ◊ ◊ F(6¢¢) = 2.800 A} and H-bond {C(12¢)–H(12¢) ◊ ◊ ◊ N(5) = 2.54 A; angle at H(12¢) =
◦
˚
157 } intermolecular interactions. Not shown: p ◊ ◊ ◊ p stacking interactions parallel to a with a spacing of a/2 = 3.61 A.
1). Compound 7 crystallised as the hemi-toluene solvate and
exhibits no p ◊ ◊ ◊ p stacking but two types of halogen ◊ ◊ ◊ halogen
˚
interactions (F(3) ◊ ◊ ◊ Br(3¢) = 3.248; Br(3) ◊ ◊ ◊ Br(3¢¢) = 3.880 A).
None of the 2,4-disubstituted product was isolated. Lithiation of
sulfide 6 (Scheme 2) gave a pyrido-fused benzothiophene in 79%
yield, which was shown by X-ray crystallography (Fig. 3, Table 1)
to be compound 8 rather than the alternatively fused tricycle 10.
In this case direct intramolecular substitution of the C-3 fluorine
in the pyridine ring occurred rather than Smiles rearrangement,
which would have formed thiolate 9 that could have undergone
ring closure to form isomer 10.
In the case of the ether 2, reaction of the lithiated intermediate 11
(Scheme 3) must have proceeded with a Smiles-type rearrangement
(path B) with attack at the ipso position occurring, even though
this would involve the strained four-membered intermediate 13.
Smiles rearrangements involving five-membered intermediates
have been reported for perfluoroarene derivatives,15 and a rad-
ical Smiles rearrangement has been described by Zard16 which
proceeds through a four-membered cyclic intermediate. Dudley17
has recently reported a rearrangement of 2-benzyloxypyridines
to 2-pyridyl carbinols on treatment with LDA which involves
a 3-membered intermediate. Attack at the ipso position in 11
must occur to avoid the unfavourable repulsion effect18–20 the 6-
fluoro substituent would have on the pyridyl anion 12 if attack
at C-3 occurred (path A). In the case of the lithiated thioether
15 (Scheme 4), the stabilising effect21 of the sulfur atom at C-4
must outweigh the destabilising influence of the fluorine at C-
Scheme 3 Possible reaction pathways for lithiated ether 11.
6 allowing attack at C-3 through a less strained five-membered
intermediate (17 ↔ 18), rather than attack at C-4 forming 16.
The longer C–S bonds in 15 may also make it harder to close the
four-membered ring in 16. It is not clear why the initially formed
phenoxide 14 (Scheme 3), generated in the lithiation promoted
Smiles rearrangement of 2, did not cyclise to 5 under the reaction
conditions, but complexation of the alkoxide by lithium in the
relatively non-polar THF may have diminished its reactivity.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2297
©

View Article Online
Scheme 4 Mechanism of formation of 8.
Scheme 5 Reaction of hexafluorobenzene with 2-bromophenol.
We then investigated reaction of hexafluorobenzene 19 with 2-
bromophenol or 2-bromobenzenethiol in the presence of sodium
hydride. With the phenol it proved difficult to isolate the mono-
substitution product 21 (Scheme 5). Replacement of the 4-fluorine
atom in the first-formed product occurred, and the major product
formed was the 1,4-bis ether 20. Only by using ten equivalents
of hexafluorobenzene could we isolate the mono-ether 21 in a
moderate 58% yield, and 20 was still formed in trace amounts.
Since bis-ether 20 could be readily formed in quantity, we decide
to investigate lithiation of this substrate (Scheme 6). Treatment
of 20 with two equivalents of n-butyllithium in THF at -78 ◦C
followed by warming to room temperature gave, after aqueous
work-up and crystallisation, a non-phenolic, high melting (279–
280 ◦C) crystalline product in low yield (19%). 1H and 19F NMR
spectroscopy showed the compound to be a symmetrical molecule
with four proton resonances and a single fluorine signal (dF
14.7 ppm). X-Ray crystallography showed the product to be the
centro-symmetric pentacyclic fused bis furan 22 (Fig. 4, Table 1).
The small, thin, weakly diffracting crystals required synchrotron
radiation for data collection. The molecules pack in a herring-bone
fashion exhibiting both halogen ◊ ◊ ◊ halogen and p ◊ ◊ ◊ p stacking
interactions.
27 would demonstrate direct cyclisation occurred, whereas forma-
tion of 28 would show that Smiles rearrangement had preceded
cyclisation. Unfortunately this experiment was inconclusive with
a complex mixture forming from which no identifiable products
could be obtained. Treatment of the pentafluorophenyl ether 21
(Scheme 7) with n-butyllithium gave a fluorinated benzofuran in
moderate yield (66% crude, 25% after crystallisation). Since excess
n-butyllithium was employed in this reaction addition of an n-
butyl group to the fluorinated ring also occurred. The structure of
the product was assigned as the 3-butyl derivative 29 (numbering
shown) with the butyl group adding most likely para to carbon
rather than oxygen (giving 30) assuming the addition occurred
after ring closure. The low melting point (48 ◦C) of this compound
precluded formation of suitable crystals for X-ray diffraction
analysis, but detailed analysis of the long range carbon–fluorine
coupling constants22 in the 13C NMR spectrum supported the
assignment of the structure as 29. Calculation of the Mulliken
charges in 1,2,3,4-tetrafluorodibenzofuran (structure optimised
using Gaussian 03 at the B3LYP/6-31G* level)23 indicated C-3
(+0.261) to be slightly more electrophilic than C-4 (+0.258) also
supporting assignment as 29. The values for C-1 and C-4 were
+0.250 and +0.255 respectively.
It is not clear if this compound is formed by direct SNAr
substitution of the adjacent fluorine atoms (20 → 22), or if Smiles
rearrangement has taken place first at both ether linkages, forming
the bis-phenoxide 26 which could have undergone ring closure to
22. None of the other possible products of cyclisation which could
have shed light on to whether cyclisation occurred directly 23, with
rearrangement 24, or with a combination of both 25, were isolated.
An experiment to determine if rearrangement occurred during
this reaction was carried out by treating bis-ether 20 with a single
equivalent of n-butyllithium with the expectation that isolation of
Reaction of 2-bromobenzenethiol (two equivalents), sodium hy-
dride and hexafluorobenzene in DMF gave the 1,4-disubstitution
product 31 (Scheme 8) in 81% crude yield (70% after crys-
tallisation). The monosubstitution product could not be formed
even when a large excess of hexafluorobenzene was employed.
Treatment of 31 with a single equivalent of n-butyllithium af-
forded the 2-(bromophenylthio)-1,3,4-trifluorodibenzothiophene
32 showing that cyclisation had occurred without initial Smiles
rearrangement as was observed for the pyridyl ether. None of the
isomer 33 was detected. The structure of the dibenzothiophene
2298 | Org. Biomol. Chem., 2011, 9, 2294–2305
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
˚
Fig. 4 Crystal structure of 22 showing stepped chains via fluorine ◊ ◊ ◊ fluorine {F(1) ◊ ◊ ◊ F(1¢) = 2.833 A} interactions and head-to-tail p ◊ ◊ ◊ p interactions
˚
˚
{centroid ◊ ◊ ◊ centroid = 3.902 A, closest atom ◊ ◊ ◊ atom separations ca. 3.42 A}.
Scheme 6 Cyclisation of bis-ether 20 to benzo[1,2-b:4,5-b¢]bis[b]benzofuran 22.
Scheme 7 Reaction of bromophenyl pentafluorophenyl ether 21 with n-BuLi.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2299
©

View Article Online
Fig. 5 Crystal structure of 32A showing p ◊ ◊ ◊ p and halogen ◊ ◊ ◊ halogen interactions.
In 32B there are no halogen ◊ ◊ ◊ halogen interactions, although
˚
there is an F(6) ◊ ◊ ◊ S(1¢) = 3.260 A short contact; however there
are more p ◊ ◊ ◊ p interactions: ring C(15)–C(20) with its symmetry
˚
equivalent (centroid ◊ ◊ ◊ centroid = 3.716 A) and head-to-tail
interactions between the three fused rings and their symmetry
˚
equivalents (centroid ◊ ◊ ◊ centroid = 3.586 A).
When the bis-sulfide 31 was treated with two equivalents
of n-butyllithium (Scheme 9) cyclisation occurred between
both bromophenyl groups and the central fluorinated ben-
zene ring to give the pentacyclic 6,12-difluorobenzo[1,2-b:4,5-
b¢]bis[b]benzothiophene 34 in high yield (95%). No evidence for
formation of any of the other possible cyclisation products (35, 36
or 37) was obtained. The benzo[1,2-b:4,5-b¢]bis[b]benzothiophene
ring system has recently been synthesised by acid catalysed ring
closure of a methylsulfinyl group onto an adjacent benzene ring.24
The structure of 34 was confirmed by X-ray crystallography (Fig.
7, Table 1) supporting ring closure by direct SNAr reaction at C-2
and C-5 without initial rearrangement. The crystals of 34 were very
thin and flexible and the crystal structure showed p ◊ ◊ ◊ p stacking
˚
parallel to b with the closest atom ◊ ◊ ◊ atom contact being 3.50 A.
In conclusion we have shown that lithiation of aryloxy- or
arylthio-substituents on perfluorinated arenes can be used to
rapidly build up usefully functionalised polycyclic structures.
Cyclisation can occur by direct attack of the initially formed
carbanion on the neighbouring position by SNAr reaction, and
this seems to be the norm for groups attached through a sulfur
atom. In the case of fluoroaryl ethers Smiles-type rearrangement
of the initially formed carbanion can occur, although the scope of
this process needs to be investigated further. The crystal structures
of key examples reveal a fine balance between halogen ◊ ◊ ◊ halogen
and p ◊ ◊ ◊ p stacking interactions and polymorphism in one case.
Further work on the mechanistic aspects of these reactions, and
results on the cyclisation of corresponding perfluoroarylamines
will be reported in due course.
Scheme 8 Direct cyclisation of bis-sulfide 31 with 1 equivalent of n-BuLi.
32 was confirmed by X-ray crystallography which showed that
the sulfur atoms retained their original 1,4-relationship. The
compound crystallised as two monoclinic polymorphs (32A –
rod-shaped crystals and 32B – plate-shaped) (Fig. 5 and 6,
Table 1). Both polymorphs have 3D supramolecular structures,
but the balance of p ◊ ◊ ◊ p and halogen ◊ ◊ ◊ halogen interactions
differs. In 32A there are both types: Br(1) ◊ ◊ ◊ Br(1¢¢) = 3.268,
˚
F(3) ◊ ◊ ◊ F(3¢¢¢) = 2.879 A and centroid ◊ ◊ ◊ centroid separations
We thank Loughborough University for support, the Socrates
Programme which allowed JPG to study in Loughborough and
˚
of 3.688 and 3.547 A for ring C(15)–C(20) with its symmetry
equivalent and ring C(8)–C(13) with ring C(2¢)–C(7¢) respectively.
2300 | Org. Biomol. Chem., 2011, 9, 2294–2305
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Fig. 6 Crystal structure of 32B showing p ◊ ◊ ◊ p and fluorine ◊ ◊ ◊ sulfur interactions.
Scheme 9 Cyclisation of 31 to benzo[1,2-b:4,5-b¢]bis[b]benzothiophene 34.
the EPSRC National Mass Spectrometry service at the University
of Swansea, and John Kershaw and Sheena Grainger (Loughbor-
ough University) for recording mass spectra. We also thank STFC
for beam time at Daresbury Laboratory where Drs J.E. Warren and
P.J. Rizkallah provided scientific support.
dichloromethane which was distilled from CaH2, and THF which
was distilled from sodium and benzophenone. Light petroleum
refers to the fraction boiling between 40–60 C. Sodium hydride
◦
was a 60% dispersion in mineral oil. A 1.6 or 2.5 M solution of n-
butyllithium in hexane was used. Melting points were determined
on a Stuart Scientific SMP3 melting point apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer
Paragon 1000 FT-IR spectrophotometer on NaCl plates. 1H
(400 MHz), 13C (100 Hz) and 19F (376 MHz) NMR spectra
were recorded on a Bruker DPX-400 instrument. 19F NMR
spectra are referenced to hexafluorobenzene as internal standard.
Experimental
General
Commercial dry solvents were used in all reactions except for
light petroleum and ethyl acetate which were distilled from CaCl2,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2301
©

View Article Online
Fig. 7 Crystal structure of 7 showing p ◊ ◊ ◊ p stacking parallel to b.
Spectra were obtained from solutions in CDCl3 unless otherwise
specified. Chemical shifts are given in parts per million (ppm)
and J values in hertz (Hz). Assignments were made using a
combination of COSY, HMQC and HMBC analysis. Mass spectra
were recorded on a Jeol SX102 high resolution mass spectrometer,
a ThermoFisher ExactiveTM Orbitrap instrument equipped with
dH (400 MHz, CDCl3) 6.99 (1H, dd, J 1.2 and 8), 7.08, (1H, dt,
J 1.2 and 7.6), 7.26 (1H, dt, J 1.6 and 7.6), 7.58 (1H, dd, J 1.6
and 8)
dF (376 MHz, CDCl3) 6.5–6.9 (2F, m), 73.5–73.7 (2F, m)
m/z (FAB) 321/323 (MH+)
Found 320.9420, C11H579BrF4NO requires 320.9412
R
an Advion TriVersa NanoMateꢀ, or were run by the EPSRC MS
Service at the University of Wales, Swansea. TLC using silica as
absorbent was carried out with aluminium backed plates coated
with silica gel (Merck Kieselgel 60 F254), and TLC using alumina
as absorbent was carried out with aluminium backed plates
coated with neutral aluminium oxide (Merck 150 F254,TypeT).
Silica gel (Merck Kieselgel 60 H silica) was used for column
chromatography.
4-(2-Hydroxyphenyl)tetrafluoropyridine 4
A solution of 4-(2-bromophenoxy)tetrafluoropyridine 2 (1.05 g,
0.0033 mol) in anhydrous THF (7 mL) was stirred at -78 ◦C
and treated dropwise with a solution of n-butyllithium in hexanes
(2.5 M, 1.5 mL, 0.0037 mol). The solution turned orange and
then faded to yellow over 50 min. The mixture was stirred and
allowed to warm to room temperature overnight. Water (10 mL)
was added and the mixture extracted with ether (3 ¥ 20 mL).
Brine was added to break up the emulsion which formed during
extraction. The combined ether layers were dried over MgSO4,
filtered and evaporated to give a yellow oil (0.9 g) which crystallised
on standing. Recrystallisation from dichloromethane and light
petroleum gave off-white crystals of the title compound (0.25 g,
31%).
4-(2-Bromophenoxy)tetrafluoropyridine 2
2-Bromophenol (3.46 g, 0.02 mol) was added dropwise to a
stirred suspension of sodium hydride (1.0 g, 0.025 mol) in DMF
(40 mL) at ice-bath temperature. When gas evolution had stopped
pentafluoropyridine (3.38 g, 0.02 mol) was added dropwise and
the resulting turbid yellow solution stirred at room temperature
overnight for 19 h. Water (100 mL) was added and the mixture
extracted with ether (250 mL). The organic layer was dried over
MgSO4, filtered and evaporated to give the title compound as a
yellow oil (5.96 g, 92%).
mp 138–141 ◦C
n
max/cm-1 (film) 3380 br. (OH), 3070, 2957, 2927, 2567, 1915,
1842, 1790, 1642, 1590, 1472, 1291, 1263, 1214, 1073, 888, 752.
dH (400 MHz, CDCl3) 5.02 (1H, bs, exch., OH) 6.90 (1H, dd, J
0.8 and 8.4), 7.12, (1H, dt, J 0.8 and 7.6), 7.22 (1H, d, J 7.6), 7.35
(1H, dt, J 1.6 and 8.4)
n
max/cm-1 (film) 3069, 2925, 2853, 2565, 2033, 1842, 1641, 1576,
1473, 1443, 1259, 1214, 1073.
dF (376 MHz, CDCl3) 20.7–20.9 (2F, m), 70.7–70.9 (2F, m)
2302 | Org. Biomol. Chem., 2011, 9, 2294–2305
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
m/z (FAB) 244 (MH+)
1,3,4-Trifluorobenzo[b]thieno[3,2-c]pyridine 8
Found 244.0328, C11H6F4NO requires 244.0307
A stirred solution of 4-(2-bromobenzenethio)tetrafluoropyridine
6 (0.31 g, 0.9 mmol) in anhydrous THF (3 mL) was cooled to
-78 ◦C and treated dropwise with n-butyllithium in hexanes (2.5
M, 0.4 mL, 1.0 mmol). The solution turned maroon in colour
and then brown. The mixture was allowed to warm to room
temperature overnight with stirring during which time it changed
to yellow in colour. Water was added, precipitating a solid, and the
mixture exhaustively extracted with ether re-dissolving the solid
material. Evaporation of the ether afforded a solid (0.2 g) which
was dissolved in dichloromethane, and the solution washed with
saturated aqueous sodium carbonate to remove acidic material.
Evaporation of the organic phase gave the benzothienopyridine 8
as a yellow solid (0.17 g, 79%).
1,3,4-Trifluorobenzo[b]furo[2,3-c]pyridine 5
4-(2-Hydroxypheny)tetrafluoropyridine 4 (0.23 g, 0.95 mmol) was
added to a stirred suspension of sodium hydride (0.04 g, 1.0 mmol)
in anhydrous DMF (10 mL). The mixture was heated at 100 C
◦
for 3 h. After cooling water (25 mL) was added, and the mixture
was extracted with ether (50 mL). The organic extract was dried
over MgSO4, filtered and evaporated to give 5 as a pale yellow
solid (0.2 g, quant.), mp 136–137 ◦C (from dichloromethane/light
petroleum).
n
max/cm-1 (film) 1657, 1492, 1474, 1444, 1415, 1252, 1165, 1098,
973.
dH (400 MHz, CDCl3) 7.45 (1H, m), 7.62–7.68, (2H, m), 8.07
mp 151–153 ◦C (from dichloromethane–light petroleum)
n
max/cm-1 1656, 1618, 1547, 1479, 1439, 1253, 1026, 913.
(1H, d, J 8)
dH (400 MHz, CDCl3) 7.52–7.56 (2H, m), 7.883–7.85 (1H, m)
8.26–8.28 (1H, m)
dF (376 MHz, CDCl3) 8.0 (1F, dd, J 20.3 and 29.0), 62.4 (1F,
dd, J 11.3 and 20.3), 84.8 (1F, dd, J 11.3 and 29.0)
m/z (EI) 239 (M+)
dF (376 MHz, CDCl3) 6.7 (1F, dd, J 21.6 and 33.5), 60.1 (1F,
dd, J 12.4 and 19.9), 69.0 (1F, dd, J 12.8 and 33.5).
m/z (EI) 223 (M+)
Found 223.0242, C11H4F3NO requires 223.0245
Found 239.0017, C11H4F3NS requires 239.0016
Reaction of pentafluoropyridine with 2-bromobenzenethiol
2-Bromobenzenethiol (0.27 g, 2.1 mmol) was added dropwise
to a stirred suspension of sodium hydride (0.10 g, 2.5 mmol)
in DMF (4 mL) at ice-bath temperature. When gas evolution
had stopped pentafluoropyridine (0.34 g, 2 mmol) was added
dropwise. The mixture turned momentarily bright yellow and
then faded to colourless. The solution was stirred at room
temperature for 24 h. Water (15 mL) was added and the
mixture extracted with ether (3 ¥ 15 mL). The organic layers
were dried over MgSO4, filtered and evaporated to give a
pale yellow malodorous oil (0.76 g). The oil was dissolved in
dichloromethane and the solution washed with saturated Na2CO3
(aq) and then 5% HCl(aq). Evaporation of the organic layer gave
a less odorous brown oil (0.62 g) which was chromatographed
over silica. Elution with light petroleum–dichloromethane (5 : 1)
gave 4-(2-bromobenzenethio)tetrafluoropyridine 6 as a colourless
crystalline solid (0.34 g, 50%).
Reaction of 2-bromophenol with hexafluorobenzene
2-Bromophenol (0.75 g, 4.3 mmol) was added dropwise to a
suspension of sodium hydride (0.20 g, 5 mmol) in anhydrous
DMF (8 mL) at 0 ◦C. Hexafluorobenzene (0.40 g, 2.2 mmol)
was added dropwise and the resulting mixture stirred at 50 ◦C
overnight. The cooled mixture was diluted with water (20 mL)
and extracted with ether (3 ¥ 40 mL). Evaporation of the organic
extracts gave a yellow oil (1.2 g) which was treated with light
petroleum. On cooling afforded colourless crystals of 1,4-di(2-
bromophenoxy)tetrafluorobenzene 20 (0.3 g, 31%) were formed.
mp 113–115 ◦C
n
max/cm-1 1576, 1510, 1471, 1444, 1313, 1264, 1218.
dH (400 MHz, CDCl3) 6.75 (2H, dd, J 1.4, 8.0), 6.97 (2H, dt, J
1.4, 7.6), 7.19 (2H, dt, J 1.6, 7.6), and 7.58 (2H, dd, J 1.6, 8.0).
dF (376 MHz, CDCl3) 8.3 (4F, apparent t)
mp 47–48 ◦C
n
max/cm-1 1699, 1682, 1652, 1627, 1558, 1463, 1235.
dH (400 MHz, CDCl3) 7.23 (2H, m), 7.47 (1H, dd, J 1.5, 7.6),
7.59 (1H, dd, J 1.5, 7.6).
m/z (FAB) 490/492/494 (M+)
Found 489.8834, C18H879Br2F4O2 requires 489.8827
When the above reaction was conducted using 10 equivalents
of hexafluorobenzene 2-bromophenyl pentafluorophenyl ether 21
was obtained in 58% yield as a colourless oil (0.40 g from a
2 mmol scale reaction) after chromatography over silica using
light petroleum as eluent.
dF (376 MHz, CDCl3) 25.4–25.6 (2F, m), 71.9–72.0 (2F, m).
m/z (EI) 337/339 (M+)
Found 339.9177, C11H479BrF4NS requires 336.9184
Further
elution
gave
2,4,5-tri(2-bromobenzenethio)-
difluoropyridine 7 as a pale yellow solid (0.24 g, 18%)
mp 97–98 ◦C
n
max/cm-1 1733, 1717, 1699, 1683, 1653, 1576, 1558, 1516, 1474,
1319, 1265, 1221.
n
max/cm-1 1652, 1635, 1557, 1505, 1471, 1387.
dH (400 MHz, CDCl3) 6.77 (1H, dd, J 0.8, 8.0), 6.97 (1H, dt, J
1.6, 7.2), 7.09 (2H, m), 7.17 (1H, m), 7.23 (1H, dt, J 2.0, 8.0), 7.31
(2H, m), 7.45 (1H, dd, J 1.2, 8.0), 7.51 (1H, dd, J 1.2, 7.6), 7.58
(1H, dd, J 1.6, 7.6), 7.63 (1H, dd, J 1.2, 8.0).
dH (400 MHz, CDCl3) 6.74 (1H, dd, J 1.2, 8.0), 7.05 (1H, dt, J
1.2, 8.0), 7.26 (1H, dt, J 1.6, 8.0), and 7.66 (1H, dd, J 1.6, 8.0).
dF (376 MHz, CDCl3) 0.42–0.56 (2F, m), 2.83 (1F, tt, J 1.5,
22.2), 8.37–8.46 (2F, m).
dF (376 MHz, CDCl3) 45.6 (1F, d, J 21.1 Hz), 99.0 (1F, d, J 21.1
Hz).
m/z (EI) 338/340 (M+)
Found 337.9370, C12H479BrF5O requires 337.9366
The disubstituted product 20 was also isolated (0.005 g, 1%) on
further elution.
m/z (FAB) (MNa+) 696–703
Found 697.7512, C23H1279Br281Br F2NNa32S3 requires 697.7522
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2303
©

View Article Online
6,12-Difluorobenzo[1,2-b:4,5-b¢]bis[b]benzofuran 22
temperature overnight. The cooled mixture was diluted with water
(25 mL) and extracted with ether (3 ¥ 50 mL). Evaporation of the
organic extracts gave a yellow solid (0.85 g) with a pungent odour.
Crystallisation from dichloromethane–light petroleum afforded
pale yellow crystals of the title compound 31 (0.74 g, 70%).
mp 138 ◦C
A solution of the bis ether 20 (0.3 g, 0.6 mmol) in anhydrous THF
◦
(2 mL) was stirred at -84 C and treated with n-butyllithium in
hexanes (2.5 M, 0.5 mL, 1.25 mmol). The solution turned brown
in colour and then faded to yellow after 1 h. After 2 h the mixture
was warmed to room temperature and treated with water (2 mL).
Extraction with dichloromethane (x 3) and evaporation of the
organic phases gave a pale brown solid (0.2 g). Recrystallisation
from dichloromethane–light petroleum gave colourless needles of
the benzo-bis-benzofuran 22 (0.033 g, 19%).
n
max/cm-1 (film) 1686, 1652, 1639, 1558, 1464, 1446, 1259.
dH (400 MHz, CDCl3) 7.15–7.19 (2H, m), 7.24–7.27 (1H, m),
7.62 (1H, dd, J 1.2, 8.4).
dF (376 MHz, CDCl3) 31.1 (4F, s)
m/z (EI) 522/524/526 (M+)
mp 279–280 ◦C
m/z (FAB) 523 (MH+) Found 523.8343, C18H879Br2F4S2 requires
523.8350
n
max/cm-1 1652, 1557, 1539, 1436, 1418, 1306, 1246.
dH (400 MHz, CD2Cl2) 7.39 (1H, dt, J 0.8, 8.0), 7.51 (1H, dt, J
1.2, 8.4), 7.59 (1H, d, J 8.4), and 8.09 (1H, dd, J 0.8, 8.0).
dC (100 MHz, CD2Cl2) 111.81 (C-4,10), 114.48 (dd, J 8, 12, C-
6a,12a), 121.86 (C-6b,12b), 122.86 (t, J 2, C-1,7), 123.71 (C-2,8),
128.39 (C-3,9), 137.90 (dd, J 7, 251 Hz, C-6,12), 138.81 (dd, J 8,
10, C-5a,11a), 156.69 (C-4a,10a)
Reactions of bis-sulfide 31 with n-butyllithium
A solution of bis-sulfide 31 (1.18 g, 2.2 mmol) in dry THF (6 mL)
was stirred at -78 C and treated dropwise with n-butyllithium
in hexanes (2.5 M, 1.8 mL, 2.5 mmol). The solution turned
dark brown in colour. The mixture was allowed to warm to
room temperature over 48 h and was then treated with water
(10 mL). Extraction with ether (¥3) and evaporation of the
organic phases gave a brown solid (0.91 g) which was crystallised
from dichloromethane–light petroleum to give colourless crys-
tals of 2-(2-bromobenzenethio)-1,3,4-trifluorodibenzothiophene
32 (0.17 g, 23%).
dF (376 MHz, DMSO-d6) 14.7 (2F, s)
m/z (EI) 294 (M+)
Found 294.0495, C18H8F2O2 requires 294.0492
Reaction of 2-bromophenyl pentafluorophenyl ether 21 with
n-butyllithium
A solution of 2-bromophenyl pentafluorophenyl ether 21 (1.1 g,
mp 172–173 ◦C
◦
3 mmol) in dry THF (15 mL) was stirred at -78 C and treated
n
max/cm-1 (film) 1558, 1481, 1440, 1250.
with n-butyllithium in hexanes (2.5 M, 3.1 mL, 7.8 mmol). The
solution turned dark red in colour and then faded to orange after
30 min. The mixture was allowed to warm to room temperature
over night and was then treated with water (10 mL). Extraction
with ether (3 ¥ 40 mL) and evaporation of the organic phases
gave a yellow oil (0.52 g) which was chromatographed over silica.
Elution with light petroleum gave colourless crystals of 3-n-butyl-
1,2,4-trifluorodibenzofuran 29 (0.20 g, 24%).
dH (400 MHz, CDCl3) 6.83 (1H, d, J 8.0), 7.05 (1H, dt, J 1.2,
8.0), 7.14 (1H, dt, J 1.2, 8.0), 7.52–7.60 (3H, m), 7.89–7.92 (1H,
m), 8.34–8.38 (1H, m).
dF (376 MHz, CDCl3) 17.6 (1F, dd, J 17.6, 24, F-3), 27.3 (1F, d,
J 24, F-4), 45.8 (1F, d, J 17.6, F-1),
m/z (EI) 424/426 (M+)
Found 423.9211, C18H879BrF3S2 requires 423.9203
mp 48–49 ◦C
Reaction with 2.2 equivalents of n-butyllithium
n
max/cm-1 (film) 3739, 3628, 2958, 2928, 2863, 1708, 1690, 1676,
1648, 1551, 1534, 1479, 1449, 1300, 1262.
The above reaction using bis-sulfide (0.957 g, 0.0018 mmol) and 2.2
equivalents of n-butyllithium (2.5 M, 1.6 mL), and extraction with
dichloromethane instead of ether afforded 6,12-difluorobenzo[1,2-
b:4,5-b¢]bis[b]benzothiophene 34 as an orange brown solid (0.6 g,
95%). Recrystallisation from dichloromethane–light petroleum
gave fine pale yellow needles.
dH (400 MHz, CDCl3) 0.98 (3H, t, J 7.6, CH3), 1.44 (2H, sext.,
J 7.6, CH2), 1.68 (2H, quin., J 7.6, CH2), 2.89 (2H, tt, J 2.0, 7.6,
CH2), 7.41 (1H, dt, J 0.8, 7.6), 7.53 (1H, dt, J 1.2, 8.4), 7.60 (1H,
td, J 1.0, 8.4), and 8.03 (1H, ddd, J 0.8, 1.2, 7.6).
dC (100 MHz, CDCl3) 13.76 (CH3), 22.34 (CH2-3), 22.96 (CH2-
1), 31.82 (CH2-2), 111.87 (C-6), 113.46 (td, J 3.5, 6.3, C-9b), 118.54
(dd. J 18.2, 19.6, C-3), 121.67 (td, J 2.3, 4.6, C-9a), 122.65 (C-9),
123.64 (C-8), 128.13 (C-7), 139.18 (ddd, J 2.0, 7.8, 14.1, C-4a),
140.96 (ddd, J 4.0, 16.1, 248.7, C-1), 141.57 (ddd, J 3.7, 7.1, 244.7,
C-4), 144.19 (ddd, J 6.3, 12.0, 240.3, C-2), 156.22 (C-5a).
dF (376 MHz, DMSO-d6) 13.6 (1F, t, J 19.5), 14.5 (1F, d, J
21.1), 18.6 (1F, d, J 19.2).
mp 287 ◦C
n
max/cm-1 (film) 3318, 3105, 3039, 1649, 1608, 1560, 1503, 1433,
1468, 1325, 1252, 1222.
dH (400 MHz, CDCl3) 7.46–7.51 (2H, m), 7.82–7.84 (1H, m),
8.40–8.43 (1H, m).
dF (376 MHz, CDCl3) 37.9 (2F, s).
m/z (EI) 326 (M+)
m/z (EI) 278 (M+)
Found 326.0036, C18H8F2S2 requires 326.0036
Found 278.0915, C16H13F3O requires 278.0919
Crystallography
1,4-Di(2-bromobenzenethio)tetrafluorobenzene 31
For each sample, a crystal was mounted in oil on a glass fibre
and fixed in the cold nitrogen stream on a Bruker APEX 2 CCD
diffractometer equipped with Mo-Ka radiation and a graphite
monochromator, except for 22 which was measured at Daresbury
Laboratory SRS, Station 9.8 due to tiny crystal size and weak
2-Bromobenzenethiol (0.78 g, 4 mmol) was added dropwise to
a stirred suspension of sodium hydride (0.20 g, 5 mmol) in
anhydrous DMF (8 mL). Hexafluorobenzene (0.38 g, 2 mmol) was
added dropwise and the resulting yellow mixture stirred at room
2304 | Org. Biomol. Chem., 2011, 9, 2294–2305
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
diffraction.25 Intensity data were measured by thin-slice w-scans
and corrected for Lp and absorption effects. Data were reduced
using the SAINT25 program. The structures were determined by
the direct methods routine in the SHELXS-97 program and refined
by full-matrix least-squares methods, on F2, in SHELXL-97.26
The non-hydrogen atoms were refined with anisotropic thermal
parameters. H atoms were constrained.
9 M. R. Cargill, K. E. Linton, G. Sandford, D. S. Yufit and J. A. K.
Howard, Tetrahedron, 2010, 66, 2356–2362.
10 D. J. Morrison, T. K. Trefz, W. E. Peirs, R. McDonald and M. Parvez,
J. Org. Chem., 2005, 70, 5309–5312.
11 W. J. Evans and S. J. Smiles, J. Chem. Soc., 1935, 181.
12 W. E. Truce, E. M. Kreider and W. W. Brand, Org. React., 1970, 18, 99
(Review).
13 R. E. Banks, W. Jondi and A. E. Tipping, J. Chem. Soc., Chem.
Commun., 1989, 1268.
For 4 the absolute structure could not be reliably determined due
to the lack of anomalous scatters, so Friedel pairs were merged.
Crystals of 7 were non-merohedrally twinned into two domains
related by a 180◦ rotation about real axis [1 0 0].27 The occupancies
of the two domains refined to 0.8744 : 0.1256(6). Crystals of 8
were non-merohedrally twinned into two domains related by a
180◦ rotation about reciprocal axis [0 0 1].27 The occupancies
of the two domains refined to 0.6215 : 0.3785(8). Compound 32
grows as either rods (32A) or plates (32B) which are polymorphic.
Although both crystallise in space group P21/c, the unit cell
shapes are entirely different and the p ◊ ◊ ◊ p and halogen-halogen
interactions are also different (see discussion). Crystals of 34
were extremely thin and flexible which led to some absorption
correction difficulties and less than ideal anisotropic displacement
parameters. Crystal data and refinement results are collated in
Table 1.
14 R. D. Chambers and C. R. Sargent, Adv. Heterocycl. Chem., 1981, 28,
1.
15 T. N. Gerasimova and E. F. Kolchina, J. Fluorine Chem., 1994, 66, 69.
16 E. Bacque, M. El Qacemi and S. Z. Zard, Org. Lett., 2005, 7, 3817–3820.
17 J. Yang and G. B. Dudley, J. Org. Chem., 2009, 74, 7998.
18 R. D. Chambers, J. S. Waterhouse and D. L. H. Williams, J. Chem.
Soc., Perkin Trans. 2, 1977, 585–588.
19 R. D. Chambers, M. J. Seabury, D. L. H. Williams and N. Hughes, J.
Chem. Soc., Perkin Trans. 1, 1988, 255–257.
20 R. D. Chambers, P. A. Martin, G. Sandford and D. L. H. Williams, J.
Fluorine Chem., 2008, 998–1002.
21 C. F. Bernasconi and K. W. Kittredge, J. Org. Chem., 1998, 63, 1944–
1953.
22 G. C. Levy, R. L. Lichter and G. L. Nelson, Carbon-13 Nuclear
Magnetic Resonance Spectroscopy, John Wiley & Sons Ltd., New York,
1980.
23 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J.
W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J.
J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B.
Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski,
B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.
L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian 03, Revision B.03,
Gaussian, Inc., Pittsburgh PA, 2003.
References
1 G. Brooke, J. Fluorine Chem., 1997, 86, 1.
2 R. D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford,
2004.
3 M. W. Cartwright, E. L. Parks, G. Pattison, R. Slater, G. Sandford, D. S.
Yufit, J. A. K. Howard, J. A. Christopher and D. D. Miller, Tetrahedron,
2010, 66, 3222–3227.
4 R. D. Chambers, P. R. Hoskin, G. Sandford, D. S. Yufit and J. A. K.
Howard, J. Chem. Soc., Perkin Trans. 1, 2001, 2788–2795.
5 E. L. Parks, G. Sandford, J. A. Christopher and D. D. Miller, Beilstein
J. Org. Chem., 2008, 4(45).
6 M. R. Cartwright, J. A. Christopher, D. D. Miller, G. Sandford, R.
Slater, P. W. Smith and A. Vong, Chim. Oggi, 2007, 25, 40–44.
7 H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119–2193.
8 C. A. Hargreaves, G. Sandford, J. Bousbaa, D. S. Yufit, J. A. K. Howard,
J. A. Christopher and D. D. Miller, Tetrahedron, 2007, 63, 7027–
7035.
24 P. Gao, D. Beckmann, H. N. Tsao, X. Feng, V. Enkelmann, W. Pisula
and K. Mu¨llen, Chem. Commun., 2008, 1548–1550.
25 SAINT and APEX 2 software for CCD diffractometers, 2006, Bruker
AXS Inc., Madison, WI, USA.
26 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
A64, 112–122.
27 G. M. Sheldrick, Twinabs software, 2007, University of Go¨ttingen.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2294–2305 | 2305
©