Protecting Group-Controlled Remote Regioselective Electrophilic Aromatic Halogenation Reactions

Article abstract of DOI:10.1021/acs.joc.9b03322

Being able to utilize a protecting group to influence remote regiocontrol offers a simple alternative approach to direct late-stage functionalization of complex organic molecules. However, protecting groups that have the ability to influence reaction regi

Full text of DOI:10.1021/acs.joc.9b03322

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Article
Protecting Group Controlled Remote Regioselective
Electrophilic Aromatic Halogenation Reactions
William David George Brittain, and Steven L. Cobb
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03322 • Publication Date (Web): 07 May 2020
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The Journal of Organic Chemistry
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Protecting Group Controlled Remote Regioselective Electrophilic
Aromatic Halogenation Reactions
William D. G. Brittain,*,† and Steven L. Cobb *,†
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†Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, United Kingdom Department
Supporting Information Placeholder
(Scheme 1a).27 It was found that the TFP protecting group could be
ABSTRACT: Being able to utilise a protecting group to influence
readily installed and cleaved from a range of phenol containing
compounds. The TFP group was also found to be stable to a wide
range of commonly employed reaction conditions.27 Unlike most
of its alternatives the TFP group has somewhat of a unique position
as being a phenol protecting group which is highly electron
deficient.28-32 Due to this we envisaged that a TFP protected phenol
would be less reactive in electrophilic substitution reactions (SEAr)
compared with either free phenols, alkyl ether protected phenols
(e.g. -OMe) or even non-phenolic rings (e.g. benzene). If this was
indeed found to be the case, the reactivity difference afforded by
remote regiocontrol offers a simple alternative approach to direct
late-stage functionalisation of complex organic molecules.
However, protecting groups that have the ability to influence
reaction regioselectivity remote to their local chemical
environment are not widely reported in the literature. Herein, we
report the development of remote regioselective electrophilic
aromatic substitution (SEAr) reactions that are enabled via the
application of the tetrafluoropyridyl (TFP) phenol protecting
group. We demonstrate that through sequential reactions and
protection/deprotection of the TFP group, substitution patterns
which do not conform to classical SEAr regioselectivity rules can
be readily accessed.
TFP protection would provide
a straightforward route to
differentiate and regioselectively modify a specific ring in systems
where multiple aromatic rings were present (Scheme 1b).
A) Our Previous Work
F
INTRODUCTION
O
F
F
OH
PFP, K2CO3
Despite the fact that there has been an impressive increase in the
number of reported “protecting group free” syntheses of natural
products,1-7 and other complex organic molecules the fact remains
that in the majority of cases the use of protecting groups is still
required. While the primary role of a protecting group in complex
organic synthetic pathways is to mask the reactivity of a particular
functionality they are often utilised to also control chemical
reactivity or reaction regioselectivity. For example, nitrogen
containing protecting groups such as amidines and imines have
been used in C-H activation reactions,8-11 and groups such as tert-
butyldiphenylsilyl (TBDPS) can be employed to add steric bulky
to modulate the accessibility/ reactivity of functional groups in their
proximity.12 In all of the aforementioned synthetic transformations
the protecting group used imparts a localised effect and the
subsequent reductions, additions, couplings occur near to or
adjacent to the protecting group. Conversely, reports of protecting
groups being able to influence reaction reactivity or selectively
distal from their position have not been widely disclosed in the
literature.13-19 In fact, in order to carry out transformations under
remote regiocontrol bespoke directing groups typically need to be
installed into the desired substrates and their subsequent removal
from the resultant products can require complex synthetic
manipulations.20-23 Having the ability to use a simple protecting
group to influence remote regiocontrol would offer an alternative
approach to direct late-stage functionalisation methods that
typically rely on selective activation of the site of the reaction.24-26
R
R
N
KF, 18-C-6,
Methyl thioglycolate
F
TFP
Introduction of the tetrafluoropyridyl protecting group for phenols
B) This Work
E
E
TFPO
OH
HO
OH
E+
E+
E
E
E
HO
OH
TFPO
OH
E
Classical product
TFP mediated product
Tetrafluoropyridyl protecting group overcomes inherent regioselectivity
Scheme 1. a) Our previous work on the utilisation of TFP
moieties as protecting groups for phenols. b) This work, the
selective electrophilic aromatic substitution of multi-aromatic
systems.
As part of a program of work in our laboratory to develop new
multi-functional protecting groups we recently reported the use of
the tetrafluoropyridyl (TFP) group for the protection of phenols
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spectroscopy and selected reaction products were isolated to
determine the regiochemistry (see ESI, S13 – S56).
Table 1. Iodination condition screening of TFP aryl ether (1a) and
anisole (2a).
1
2
3
4
5
6
7
8
9
Conditions
Table 2. Comparison of reactivity and regioselectivity between
substituted OMe- and OTFP-containing compounds.
O
R
I
O
R
1a
R = TFP
2a
= Me
A
B
NIS, TFA, rt, 1 h
O
R
O
R
OR
Entry
1
Conditions
Conv
(%)a
31
Yield (%)b
-
AgSO4, I2, 50 °C
I
R = TFP
= Me
2 h
1a
AgSO4 (1.2 equiv.), I2 (1.2 equiv.),
MeOH, 50 °C, 2 h
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Conv/
Entry
1
Starting Material
Major Product
2
3
1a
1a
NIS (1.1 equiv.), TFA, rt, 1 h
NIS (1.1 equiv.), TFA (0.3 equiv.),
MeCN, rt, 1 h
94
<1
80
-
Yield (%)
OTFP
I
I
OTFP
A 81/68
B 7/-
4
5
1a
2a
NIS (1.1. equiv), CF₃SO₃H, rt, 1 h
AgSO4 (1.2 equiv.), I2 (1.2 equiv.),
MeOH, 50 °C, 2 h
87
-
Me
Me
1b
3b
>99
98
OTFP
OTFP
A 94/74
B 15/-
6
7
2a
2a
NIS (1.1 equiv.), TFA, rt, 1 h
NIS (1.1 equiv.), TFA (0.3 equiv.),
MeCN, rt, 1 h
>99
68
96
-
2
3
Me
Me
1c
3c
I
8
2a
NIS (1.1. equiv), CF₃SO₃H, rt, 1 hc
-
-
A 79/65
B <1/-
Me
OTFP
a) Conversion determined by inspection of 1H NMR spectra. b) Yield following
purification by column chromatography. c) A mixture of regioisomeric products
was observed, therefore, conversion was not determined.
Me
OTFP
1d
1e
3d
OTFP
OTFP
Herein, we detail our investigations into how tetrafluoropyridyl
aryl ethers (TFP-ethers) can be utilised to give remote
regioselectivity control in electrophilic aromatic substitutions. Our
study demonstrates that TFP-ethers can be utilised to allow for
efficient access to unsymmetrical biphenols, bisphenols and
biaryls.33 The methodology reported overcomes the statistical
product distribution which is a common drawback of the typical
approaches used to access such compounds (e.g. cross-coupling).34
A >99/91
B 25/-a
4
I
3e
I
OTFP
OTFP
A 78/62
B 17/-
5
6
RESULTS AND DISCUSSION
1f
To begin the study, the electrophilic iodination of TFP-aryl-ether
1a was carried out under a range of conditions.35-38 Reaction
3f
1
conversion was monitored using H NMR spectroscopy (see ESI,
S2) and only the para-iodo regioisomer was isolated. To compare,
the iodination of anisole 2a was carried out under the same
conditions. From this comparative study it was observed that the
TFP ether 1a was significantly less reactive than its methyl ether
counterpart 2a across all of the conditions employed. For example,
in the presence of silver sulfate and iodine (Table 1, Entries 1 and
5) the TFP ether 1a had only reached a conversion of 31% after two
hours, while anisole 2a had been completely consumed to give the
iodinated product in the same time period. In order to rationalise
these observations computational electron density distribution
calculations were carried out (see ESI, S181). These showed that
the positions which would typically undergo electrophilic aromatic
substitution (ortho/para) were less electron-rich in the TFP phenol
1a compared to the anisole 2a, supporting the initial hypothesis and
rationalising why a difference in reaction rate was observed.
I
OMe
OMe
OMe
A >99/62
B >99/68
Me
Me
2b
4b
OMe
I
A >99/64
B >99/78
7
8
Me
Me
4c
2c
I
A >99/64
B >99/81
Me
OMe
Me
OMe
2d
4d
OMe
OMe
A -/-b
9
B >99/77
To probe the substrate scope for iodination, a comparative study
between a range of substituted TFP-phenols and methyl-protected
phenols was undertaken. We selected methyl- substituted
compounds 1b-d to study the regioselectivity of the reactions. To
investigate the differences in reactivity between the various
substrates, two sets of reaction conditions were chosen, one in
which both OTFP and OMe compounds reacted rapidly (NIS, TFA,
rt, 1h) and one in which the OTFP was significantly less reactive
than OMe (AgSO4, I2, MeOH, 50 °C, 2 h). As with the previous
I
2e
2f
4e
I
OMe
OMe
A >99/59
B >99/63
10
4f
a) A mixture of two regioisomeric products were observed in the crude 1H
NMR spectra of the reaction mixture, but the major component was unreacted
SM. b) A complex mixture was observed in the crude 1H NMR spectra of the
reaction mixture.
1
study, conversion of the reactions was measured using H NMR
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quantitative conversion to the iodo compound was seen for the
1
2
3
4
5
6
OMe derivative (2d) no conversion was obtained for the OTFP
compound (1d) (Table 2, Entries 3 and 8). It was observed that the
regiochemical outcomes of the iodination reactions were the same
regardless of which protecting group was employed. This result is
not unexpected given the previously calculated electron density
distribution profiles for 1a and 2a (see ESI, S181).
Table 3. Scope of selective iodination reaction.
I
TFPO
TFPO
NIS, TFA
1 h, rt
OR
OR
R = H/Me
R = H/Me
After it had been confirmed that a range of TFP-protected
phenols could undergo iodination, a competition experiment
utilising a compound containing two phenol rings, one protected
with a TFP group and one with a methylated phenolic oxygen, was
undertaken. The orthogonally protected biphenol 5a was
synthesized in one step. 5a was then exposed to iodination
conditions (TFA, NIS, rt, 1h), which were shown to readily iodinate
both OMe and OTFP substrates. From the 1H NMR spectrum
obtained it was clear that mono-substitution had occurred and that
one regioisomer 6a (>95%) had formed (Table 3, Entry 1). 6a was
purified and its regiochemistry confirmed by 2D NMR (see ESI,
S84 – S87). As hypothesised iodination had only occurred on one
of the aromatic rings and ortho to the methoxy group (Table 3,
Entry 1). This demonstrated that even under conditions in which
both OTFP and OMe aryl rings could undergo electrophilic
aromatic substitution, the reaction occurred selectively on the
OMe-substituted ring. When the OTFP group was moved to the
meta position relative to the central C-C biaryl bond (5b) iodination
still occurred selectively only on the OMe-substituted ring (6b)
(Table 3, Entry 2). It was also found that in a competition
experiment, between an OTFP-protected phenol ring and a free
phenolic ring, substitution occurs selectively on the free phenolic
ring (Table 3, Entries 3 and 4). Substitution occurred ortho to the
oxygen in the case of compound 5c and para to the oxygen in
compound 5d (Table 3, Entries 3 and 4). We also studied iodination
of bis-phenols, where the two phenolic rings are not directly
attached to each other.39-42 This is an important class of compounds,
7
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9
Yield
(%)b
Entry
1
Starting Material
Major Producta
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TFPO
OMe
TFPO
OMe
93
96
I
5a
6a
OMe
OMe
2
3
TFPO
TFPO
TFPO
TFPO
I
5b
6b
OH
OH
87
84
I
5c
6c
OTFP
OTFP
I
4
HO
HO
6d
5d
I
5
6
80
68
TFPO
TFPO
OH
TFPO
OH
5e
5f
6e
6f
especially in the polymer arena (e.g. bis-phenol A (BPA)).43-45
A
I
series of bis-phenol TFP derivatives were synthesised (5e-g) and
subsequently iodinated to give the mono-iodinated products (Table
3, Entries 5-7). As previously seen for the biphenol systems
regioselective substitution occurred adjacent to the phenolic
oxygen to give 6e-g. The structures of 6e-g were confirmed by 2D
NMR correlations (see ESI, S109 – S127). It is worth noting that
when unprotected BPA was exposed to the same iodination
reaction conditions (NIS, TFA, rt) an inseparable mixture of mono-
and di-iodinated products in addition to unfunctionalised BPA was
generated (see ESI, S179 – S180). We were also able to selectively
modify a TFP-protected BINOL (5h) to regioselectively generate
6h (Table 3, Entry 8). To complete our study we wanted to probe
the reactivity difference between a TFP-phenolic ring and an
unmodified phenyl ring. To do this test substrate 5i was synthesised
in one step from 4-phenylphenol as previously reported. Iodination
of 5i resulted in the regioselective formation of compound 6i in
87% yield (Table 3, Entry 9). 6i would not be the expected
regioisomer if the iodination reaction was carried out in the absence
of the TFP protecting group or on the OMe protected system.
Importantly, the formation of 6i demonstrates that TFP protection
offers a route to selectively modify phenyl rings in the presence of
phenols which is currently challenging to do given the electronic
make up of these two aromatic systems. In order to lend further
evidence to a methyl substituted phenyl ring being more activated
that an OTFP ether we conducted a competition experiment, We
took a mixture of TFP-ether 1a (1 equiv.) and toluene (1 equiv.)
and exposed them to iodination conditions (TFA, NIS (1 equiv.)).
Following the reaction we measured the product distribution by 1H
NMR (see ESI S176).It was clear that 1a had not reacted and
instead 4-iodotoluene was generated as the major product. To
confirm this we spiked our NMR sample of our reaction mixture
OH
TFPO
OH
I
7
8
58
88
TFPO
OH
TFPO
I
OH
5g
6g
OH
OH
OTFP
OTFP
5h
5i
6h
6i
TFPO
I
TFPO
MeO
9
87
63
MeO
10
I
5j
6j
a) Regiochemistry of product determined by 2D NMR analysis. b) Isolated yield
following flash column chromatography.
Across the series, it was observed that under silver sulfate-
mediated conditions all OMe derivatives (2b-f) were significantly
more reactive than their OTFP (1b-f) counterparts. For example, in
the cases of 4-methyl compounds 1d and 2d where complete
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with 4-iodotoluene, clear overlap of the signals confirmed our
In addition aryl species, 5f and 6f were further modified (Scheme
1
2
3
4
5
6
7
8
original spectral assignment (see ESI S177). We also conducted the
iodination of compound 5j, the OMe analogue of 5i, this reaction
gave compound 6j with substitution occurring ortho to the OMe
group in 63% yield. This further demonstrated that the installation
of the OTFP group allows access to substitution patterns which
require selective modification away from the most electron rich
ring.
2). By exposing the mono-iodo-TFP-bisphenol A derivative 6f to
Suzuki-Miyaura cross-coupling conditions, the tri-aryl compound
11, with one free phenolic oxygen and two orthogonally protected
phenolic oxygens, was produced in 74% yield (Scheme 2). The
TFP group could be easily removed from compound 5f using a
modified version of our previously reported conditions7 to give
mono-iodo-bisphenol A 9 in 81% yield (Scheme 2). Other
electrophiles could also be employed, for example, bromination of
compound 5f occurred smoothly to give a single regioisomeric
product 7a in 74% yield (Scheme 2), consistent with the
regioselecitivity observed for iodination. We then brominated
compound 7a again under the same previous conditions to give us
the di-bromo compound 7b. The regiochemistry of this compound
was found to be analogous to that of the di-iodo compound 8.
Having established the ability of the TFP group to clearly control
the regioselectivity of SEAr reactions we looked to use the
methodology to sequentially add multiple electrophiles in a
controlled and regioselectively manner. A second iodination
reaction was carried out on compound 6f. The second iodine was
added selectively onto the same ring as the first, ortho to the free
phenolic oxygen, giving di-iodo compound 8 in 57% yield (Scheme
2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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33
34
35
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60
The regiochemistry of 8 was confirmed by obtaining a crystal
structure and further evidenced by 2D NMR spectra (see ESI, S158
– S163).46 This result showed that even when an aromatic ring
already contained a deactivating group like iodine it was still more
reactive in SEAr reactions than the TFP-protected phenol ring. This
is the first example, to the best of our knowledge, of the synthesis
of an unsymmetrical bis-phenol system in which two electrophiles
have been added selectively and sequentially to the same phenolic
ring. Removal of the TFP group from 5f and then subsequent
iodination, allowed us to selectively install a single iodine on to
each of the phenolic rings giving 10 in 73% yield (Scheme 2). The
synthesis of 8 and 10 clearly demonstrated the application of the
TFP protecting group as a useful tool to control the regiochemical
outcome of SEAr reactions in more complex systems. In addition
the synthesis of 8 highlights that the TFP approach allows access
to substitution patterns which do not conform to classical SEAr
regioselectivity rules for multi-aryl systems.
CONCLUSIONS
In conclusion, we have demonstrated that through installation of
a tetrafluoropyridyl (TFP) moiety on a phenolic ring, the aromatic
system’s reactivity towards electrophilic aromatic substitutions can
be significantly reduced. The methodology reported allows for
precise and remote regiocontrol of SEAr reactions without the
requirement for a bespoke directing group. The TFP group can
perform dual functions, acting as both a protecting and a directing
group which can give, substitution patterns which do not conform
to classical regioselectivity rules for multi-aryl systems. The
simplicity of the TFP protecting group approach to control remote
regioselectivity in electrophilic aromatic substitutions makes it
highly amenable to a wide range of areas within the broad field of
synthetic chemistry.
EXPERIMENTAL SECTION
General Methods. All starting materials and reagents were bought
from commercial sources and used as received. All reference
anisoles and methoxynaphthols were purchased from Fluorochem
UK and their NMR spectra recorded as received. All reactions apart
from where noted were carried out in air using non-dried solvents
or reagents. All flash column chromatography was carried out
using silica purchased from Sigma Aldrich using the solvent system
Scheme 2. TFP regiocontrolled synthesis of unsymmetric aryl
systems.
NBS
TFPO
OH
TFPO
NBS, HFIP,
OH
HFIP, 1 h, rt
74%
7a
5f
Br
1
noted. H NMR spectra were recorded at 400, 600 and 700 MHz
1 h, rt
63%
NIS
using Bruker Avance III, Varian VNMRS-600 and Varian
VNMRS-700 spectrometers. 13C NMR spectra were recorded at
101, 151 and 176 MHz using Bruker Avance III, Varian VNMRS-
600 and Varian VNMRS-700 spectrometers. 19F NMR spectra were
recorded at 376 MHz using a Bruker Avance III spectrometer. In
cases where it was required 2D NMR techniques were used to
confirm compound identity. Chemical shifts are reported in ppm
and are referenced to residual solvent peaks; CHCl3 (1H 7.26 ppm,
13C 77.0 ppm) and CH3CN (1H 1.96 ppm, 13C 118.3). Mass spectra
were collected on a Waters TQD mass spectrometer and accurate
mass spectra were collected on a Waters LCT Premier XE mass
spectrometer using a QTOF mass analyser. Infrared absorption
spectra were recorded using a Perkin Elmer Frontier FTIR
spectrometer fitted with an ATR attachment. Melting points were
carried out in triplicate and an average of the values taken and
reported as a range using a Stuart SMP10 melting point apparatus.
Melting points were carried out directly on material purified by
flash column chromatography
TFA, rt, 1 h
68%
Br
TFPO
TFPO
OH
7b
8
Br
I
I
NIS
TFA, rt, 3 h
57%
TFPO
OH
6f
OH
I
Thiophenol, KF
MeCN, rt, 18 h
81%
I
HO
9
OH
OH
B(OH)2
NIS
TFA, rt, 1 h
73%
OMe
MeO
Pd(PPh3)4,
K2CO3,
I
I
General Procedures
1,4-Dioxane : Water
74%
HO
OH
10
11
General Procedure for the Synthesis of Tetrafluoropyridyl
Ethers. To a stirred solution of phenol (1 equiv.) in acetonitrile (20
mL) was added pentafluoropyridine (1.05 equiv.) and potassium
OTFP
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carbonate (1.05 equiv.). The reaction mixture was stirred at room
2,3,5,6‐tetrafluoro‐4‐(naphthalen‐2‐yloxy)pyridine (1f) The title
1
2
3
4
5
6
7
8
temperature for 16 h. After this time the reaction mixture was
filtered and concentrated under reduced pressure. The resulting
residue was purified directly by flash column chromatography
(100% hexane to 25% EtOAc/75% hexane).
compound was synthesised according to the general procedure for
the synthesis of tetrafluoropyridyl ethers from 3.47 mmol of the
corresponding naphthol as a white crystalline solid (0.987 g) in
97% yield. 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.87 (m, 2H), 7.78
(appd, J = 8.1 Hz, 1H), 7.59 – 7.48 (m, 2H), 7.39 – 7.32 (m, 2H);
19F NMR (376 MHz, CDCl3) δ -88.3 – -88.5 (m, 2F), -154.0 – -
154.2 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 153.5, 145.0 –
144.8 (m), 144.5 – 144.3 (m), 143.7 – 143.4 (m), 137.2 – 136.9 (m),
135.7 – 135.4 (m), 133.7, 130.9, 130.5, 127.9, 127.3, 127.2, 125.7,
117.2, 112.2; IR νmax (ATR)/cm-1 1647, 1628, 1480, 1208, 1153,
1124, 1061, 976, 817, 747, 472; HRMS (ESI-) calcd for [M-H]-
C15H6NOF4- = 292.0386 found = 292.0376; MP 94-95 °C.
General Procedure for Suzuki-Miyaura Cross-Coupling. A
solution of tetrafluoropyridyl-iodo-phenol (1 equiv.) and
corresponding boronic acid were dissolved in 1,4-dioxane (10 mL)
and the solution degassed by bubbling nitrogen for 1 h. At the same
time a solution of K2CO3 (3 equiv.) in water was also degassed by
bubbling nitrogen for 1 h. After this time, Pd(PPh3)4 (5 mol%) was
added to the dioxane solution and the resulting mixture degassed
for a further 10 min. The K2CO3 water solution was then transferred
via syringe to the dioxane solution and the resulting mixture was
heated at reflux for 12 h. The reaction mixture was then cooled and
concentrated under reduced pressure. The resulting residue was
taken up in EtOAc (50 mL) and washed with H2O (25 mL), the
organic layer was dried over MgSO4, filtered and concentrated. The
recovered residue was then subjected to flash column
chromatography (100% hexane to 20% EtOAc/80% hexane).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3,5,6-tetrafluoro-4-(4-iodophenoxy)pyridine (product Table 1)
Iodination was carried out as detailed in the general procedure A
from 0.82 mmol of the corresponding tetrafluoropyridyl phenol as
a white crystalline solid (0.242 g) in 80% yield. Characterisation
was consistent with our previously reported literature values.27 1
H
NMR (400 MHz, CDCl3) δ 7.71 (d, J = 9.0 Hz, 2H), 6.86 (d, J =
9.0 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -87.9 – -88.1 (m, 2F),
-153.9 – -154.1 (m, 2F); IR νmax (ATR)/cm- 1645, 1460, 1198,
1072, 970, 807, 485.
General Procedure for Iodination Using Conditions A. To a
stirred solution of TFP ether or methoxy ether (1 equiv.) in TFA (2
mL) was added NIS (1.1 equiv) and the resulting solution stirred
for 1h at rt. After this time the reaction mixture was concentrated
under reduced pressure. The resulting residue was taken up in
EtOAc (30 mL) and washed with 1M sodium thiosulfate solution.
The organic fraction was then dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by flash column
chromatography.
2,3,5,6‐tetrafluoro‐4‐(4‐iodo‐2‐methylphenoxy)pyridine
(3b)
Iodination was carried out as detailed in the general procedure A
from 0.39 mmol of the corresponding tetrafluoropyridyl phenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a white crystalline solid
(0.101 g) in 68% yield. 1H NMR (600 MHz, CDCl3) δ 7.62 – 7.58
(m, 1H), 7.48 – 7.43 (m, 1H), 6.55 (d, J = 8.5 Hz, 1H), 2.32 (s, 3H,
CH3); 19F NMR (376 MHz, CDCl3) δ -88.1 – -88.5 (m, 2F), -155.2
– -155.4 (m, 2F); 13C{1H} NMR (151 MHz, CDCl3) δ 154.3, 145.1
– 144.8 (m), 144.6 – 144.3 (m), 143.5 – 143.2 (m), 140.4, 136.8 –
136.5 (m), 136.1, 135.1 – 134.8 (m), 130.6, 117.5, 88.8, 15.6; IR
νmax (ATR)/cm-1 2927, 1641, 1471, 1222, 1170, 1121, 1064, 971;
HRMS (ESI-) calcd for [M-H]- C12H5NOF4I- = 381.9352 found =
381.9352; MP 69-70 °C.
General Procedure for Iodination Using Conditions B. A
solution of AgSO4 (1.2 equiv.) and iodine (1.2 equiv.) was stirred
in MeOH (10 mL) at 50 °C for 10 min. After this time the TFP ether
or methoxy ether (1 equiv.) was added and the resulting solution
stirred at 50 °C for 2 h. Following this the reaction mixture was
filtered and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography.
2,3,5,6‐tetrafluoro‐4‐(4‐iodo‐3‐methylphenoxy)pyridine
(3c)
2,3,5,6-tetrafluoro-4-phenoxypyridine (1a) The title compound
was synthesised according to the general procedure for the
synthesis of tetrafluoropyridyl ethers from 10.6 mmol of the
corresponding phenol as a clear oil (2.52 g) in 97% yield. 1H NMR
(400 MHz, CDCl3) δ 7.45 – 7.38 (m, 2H), 7.28 – 7.22 (m, 1H), 7.09
(appd, J = 8.1 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -88.6 – -
88.8 (m, 2F), -154.2 – -154.4 (m, 2F); 13C{1H} NMR (176 MHz,
CDCl3) δ 155.8, 145.0 – 144.7 (m), 144.5 – 144.3 (m), 143.6 –
143.3 (m), 137.0 – 136.8 (m), 135.5 – 135.3 (m), 130.0, 125.1,
116.6; IR νmax (ATR)/cm-1 1641, 1591, 1469, 1192, 1068, 971, 741,
Iodination was carried out as detailed in the general procedure A
from 0.39 mmol of the corresponding tetrafluoropyridyl phenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a clear colourless oil
(0.111 g) in 74% yield. 1H NMR (600 MHz, CDCl3) δ 7.76 (d, J =
8.6 Hz, 1H), 6.95 (d, J = 3.1 Hz, 1H), 6.61 (dd, J = 8.6, 3.1 Hz, 1H),
2.42 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -88.1 – -88.3 (m, 2F),
-154.0 – -154.2 (m, 2F); 13C{1H} NMR (151 MHz, CDCl3) δ 156.0,
145.1 – 144.8 (m), 144.1 – 143.8 (m), 143.7, 143.5 – 143.2 (m),
140.0, 137.1 – 136.8 (m), 135.4 – 135.1 (m), 117.9, 115.7, 95.3,
28.2; IR νmax (ATR)/cm-1 2925,1642, 1466, 1222, 1158, 1072,
1015, 972; HRMS (ESI-) calcd for [M-H]- C12H5NOF4I- = 381.9352
found = 381.9357.
-
687; HRMS (ESI-) calcd for [M-H]- C11H4NOF4 = 242.0229 found
= 242.0218.
2,3,5,6‐tetrafluoro‐4‐(naphthalen‐1‐yloxy)pyridine (1e) The title
compound was synthesised according to the general procedure for
the synthesis of tetrafluoropyridyl ethers from 3.47 mmol of the
corresponding naphthol as a cream coloured solid (0.979 g) in 96%
2,3,5,6‐tetrafluoro‐4‐(2‐iodo‐4‐methylphenoxy)pyridine
(3d)
Iodination was carried out as detailed in the general procedure A
from 0.39 mmol of the corresponding tetrafluoropyridyl phenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a clear colourless oil
(0.097 g) in 65% yield. 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.70
(m, 1H), 7.18 – 7.13 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 2.36 (s, 3H);
19F NMR (376 MHz, CDCl3) δ -88.6 – -88.8 (m, 2F), -155.2 – -
155.4 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 153.1, 145.0 –
144.8 (m), 144.6 – 144.4 (m), 143.6 – 143.3 (m), 140.4, 137.4,
136.3 – 135.9 (m), 134.9 – 134.5 (m), 130.4, 117.1, 86.0, 20.3; IR
νmax (ATR)/cm-1 2926, 1640, 1477, 1218, 1203, 1071, 972; HRMS
(ESI-) calcd for [M-H]- C12H5NOF4I- = 381.9352 found = 381.9354.
1
yield. H NMR (400 MHz, CDCl3) δ 8.29 – 8.23 (m, 1H), 7.98 –
7.91 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.66 – 7.59 (m, 2H), 7.45 –
7.38 (m, 1H), 6.92 (dd, J = 7.6, 0.9 Hz, 1H); 19F NMR (376 MHz,
CDCl3) δ -88.3 – -88.6 (m, 2F), -154.3 – -154.5 (m, 2F); 13C{1H}
NMR (176 MHz, CDCl3) δ 151.8, 145.0 – 144.7 (m), 143.6 – 143.4
(m), 137.0 – 136.8 (m), 135.5 – 135.3 (m), 134.8, 127.9, 127.2,
126.8, 125.2, 125.1, 125.0, 121.1, 110.2; IR νmax (ATR)/cm-1 1642,
1498, 1476, 1388, 1092, 967, 766, 560; HRMS (ESI-) calcd for [M-
H]- C15H6NOF4- = 292.0386 found = 292.0369; MP 81-83 °C.
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Page 6 of 12
2,3,5,6‐tetrafluoro‐4‐[(4‐iodonaphthalen‐1‐yl)oxy]pyridine (3e)
2‐iodo‐1‐methoxy‐4‐methylbenzene (4d) Iodination was carried
1
2
3
4
5
6
7
8
Iodination was carried out as detailed in the general procedure A
from 0.34 mmol of the corresponding tetrafluoropyridyl naphthol
and purified by flash column chromatography (100% hexane to
20% EtOAc/80% hexane) to give the product as a white crystalline
solid (0.129 g) in 91% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 –
8.23 (m, 1H), 8.18 – 8.14 (m, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.75 –
7.65 (m, 2H), 6.67 (d, J = 8.1 Hz, 1H); 19F NMR (376 MHz, CDCl3)
δ -87.7 – -88.0 (m, 2F), -153.8 – -154.1 (m, 2F); 13C{1H} NMR
(101 MHz, CDCl3) δ 152.6, 145.7 – 145.2 (m), 144.5 – 144.1 (m),
143.2 – 142.8 (m), 137.8 – 137.2 (m), 136.1, 135.3, 135.1 – 134.6
(m), 132.5, 129.1, 127.7, 125.7, 121.8, 111.1, 94.4; IR νmax
(ATR)/cm-1 1641, 1594, 1473, 1085, 962, 761, 580; HRMS (ESI-)
Calculated for [M-H]- C15H5NOF4I- = 417.9352 found = 417.9363;
MP 78-79 °C.
out as detailed in the general procedures (A/B) from A = 1.64 mmol
B = 0.85 mmol of the corresponding methoxy phenol as a clear
colourless oil (A 0.260 g, 64%) (B 0.165 g, 81%). All
characterisation data were consistent with previously reported
literature values.47 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.61 (m,
1H), 7.14 – 7.10 (m, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H),
2.28 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 156.1, 139.8,
132.0, 130.0, 110.8, 85.8, 56.5, 20.0; IR νmax (ATR)/cm-1 2920,
2836, 1489, 1276, 1248, 1049, 1019, 802, 730, 548.
9
1‐iodo‐4‐methoxynaphthalene (4e) Iodination was carried out as
detailed in the general procedure B from 0.64 mmol of the
corresponding methoxynaphthalene as a brown oil (0.138 g) in
77% yield. All characterisation data were consistent with
previously reported literature values.49 1H NMR (400 MHz, CDCl3)
δ 8.28 (appd, J = 9.1 Hz, 1H), 8.07 (appd, J = 7.9 Hz, 1H), 7.98 (d,
J = 8.2 Hz, 1H), 7.63 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.55 (ddd, J =
8.2, 6.9, 1.3 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 4.00 (s, 3H);13C{1H}
NMR (101 MHz, CDCl3) δ 156.3, 136.9, 134.7, 131.8, 128.2,
126.7, 126.0, 122.5, 105.6, 88.2, 55.7; IR νmax (ATR)/cm-1 2932,
2836, 1586, 1417, 1366, 1258, 1240, 1084, 805, 755, 616.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3,5,6‐tetrafluoro‐4‐[(1‐iodonaphthalen‐2‐yl)oxy]pyridine (3f)
Iodination was carried out as detailed in the general procedure A
with the following modification. Following flash column
chromatography (100% hexane to 20% EtOAc/80% hexane) the
recovered solid was recrystallised from hexane. The reaction was
carried out on 0.68 mmol of the corresponding tetrafluoropyridyl
phenol this gave the product as a white crystalline solid in a 62%
(0.174 g) yield. 1H NMR (400 MHz, CDCl3) δ 8.27 – 8.21 (m, 1H),
7.90 – 7.83 (m, 2H), 7.71 – 7.65 (m, 1H), 7.61 – 7.54 (m, 1H), 7.18
(d, J = 8.9 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ -88.4 – -88.6
(m), -155.2 – -155.4 (m); 13C{1H} NMR (101 MHz, CDCl3) δ
152.6, 145.7 – 145.2 (m), 144.5 – 144.0 (m), 143.3 – 142.8 (m),
137.7 – 137.3 (m), 136.1, 135.3, 135.1 – 134.6 (m), 132.5, 129.1,
127.7, 125.7, 121.8, 111.1, 94.4; IR νmax (ATR)/cm-1 1642, 1473,
1203, 984, 961, 815, 762, 521; HRMS (ESI-) calcd for [M-H]-
C15H5NOF4I- = 417.9352 found = 417.9363; MP 121-123 °C.
1‐iodo‐2‐methoxynaphthalene (4f) Iodination was carried out as
detailed in the general procedures (A/B) from A = 1.26 mmol B =
0.64 mmol of the corresponding methoxynaphthalene as a cream
coloured solid (A 0.214 g, 59%) (B 0.131 g, 63%). All
characterisation data were consistent with previously reported
literature values.49 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.8
Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.80 – 7.74 (m, 1H, ArH), 7.57
(ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.41 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H),
7.24 (d, J = 8.9 Hz, 1H), 4.05 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 156.65, 135.65, 131.20, 130.39, 129.92, 128.21, 128.14,
124.37, 112.95, 87.72, 57.26; IR νmax (ATR)/cm-1 3007, 2970,
1618, 1264, 1059, 1022, 887, 801, 743, 512.
1‐iodo‐4‐methoxybenzene (product Table 1) Iodination was
carried out as detailed in the general procedures (A/B) from 1.85
mmol of the corresponding anisole as a white solid with the
following yields (A 0.419 g, 96%) (B 0.423 g, 98%). All
characterisation data were consistent with previously reported
literature values.47 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6
Hz, 1H), 6.85 (d, J = 3.0 Hz, 1H), 6.51 (dd, J = 8.6, 3.0 Hz, 1H),
3.80 (s, 3H), 2.42 (s, 3H);13C{1H} NMR (101 MHz, CDCl3) δ
159.9, 142.4, 139.3, 115.9, 113.4, 89.7, 55.3, 28.3; IR νmax
(ATR)/cm-1 2933, 2836, 1598, 1568, 1471, 1236, 1167, 1011,
1045, 797, 589, 440.
2,3,5,6‐tetrafluoro‐4‐({4'‐methoxy‐[1,1'‐biphenyl]‐4‐yl}oxy)pyrid
ine (5a) The title compound was synthesised according to the
general procedure for the for Suzuki-Miyaura cross-coupling from
0.27 mmol of the corresponding tetrafluoropyridyl phenol iodide as
a white crystalline solid (0.090 g) in 96% yield.1H NMR (400 MHz,
CDCl3) δ 7.57 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.13
(d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H); 19F NMR
(376 MHz, CDCl3) δ -88.5 – -88.7 (m, 2F), -154.1 – -154.3 (m, 2F);
13C{1H} NMR (176 MHz, CDCl3) δ 159.3, 154.8, 145.0 – 144.7
(m), 144.6 – 144.4 (m), 143.6 – 143.4 (m), 138.1, 137.0 – 136.8
(m), 135.6 – 135.3 (m), 132.4, 128.2, 128.0, 117.0, 114.3, 55.3; IR
νmax (ATR)/cm-1 2972, 1642, 1600, 1478, 1067, 968, 813; HRMS
4‐iodo‐1‐methoxy‐2‐methylbenzene (4b) Iodination was carried
out as detailed in the general procedures (A/B) from A = 1.64 mmol
B = 0.82 mmol of the corresponding methoxy phenol as a white
solid (A 0.251 g, 62%) (B 0.135 g, 68%). All characterisation data
were consistent with previously reported literature values.48 1H
NMR (400 MHz, CDCl3) δ 7.49 – 7.43 (m, 2H,), 6.61 (d, J = 8.3
Hz, 1H), 3.82 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 157.7, 138.98, 135.5, 129.5, 112.2, 82.5, 55.4, 15.9; IR
νmax (ATR)/cm-1 2971, 2837, 1486, 1476, 1242, 1027, 805, 614.
-
(ESI-) calcd for [M-H]- C18H10NO2F4 = 348.0648 found =
348.0646; MP 156-157 °C.
2,3,5,6‐tetrafluoro‐4‐({4'‐methoxy‐[1,1'‐biphenyl]‐3‐yl}oxy)pyrid
ine (5b) The title compound was synthesised according to the
general procedure for the for Suzuki-Miyaura cross-coupling from
0.27 mmol of the corresponding tetrafluoropyridyl phenol iodide as
1
1‐iodo‐4‐methoxy‐2‐methylbenzene (4c) Iodination was carried
out as detailed in the general procedures (A/B) from A = 1.64 mmol
B = 0.85 mmol of the corresponding methoxy phenol as a clear
colourless oil (A 0.257 g, 64%) (B 0.157 g, 78%). All
characterisation data were consistent with previously reported
literature values.48 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6
Hz, 1H), 6.85 (d, J = 3.0 Hz, 1H), 6.51 (dd, J = 8.6, 3.0 Hz, 1H),
3.80 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
159.9, 142.4, 139.3, 115.9, 113.4, 89.7, 55.3, 28.3; IR νmax
(ATR)/cm-1 2933, 2836, 1598, 1568, 1471, 1236, 1167, 1011,
1045, 797, 589, 440.
a white crystalline solid (0.085 g) in 91% yield. H NMR (400
MHz, CDCl3) δ 7.52 (d, J = 8.9 Hz, 2H), 7.48 – 7.40 (m, 2H), 7.28
– 7.23 (m, 1H), 7.06 – 6.96 (m, 3H), 3.88 (s, 3H); 19F NMR (376
MHz, CDCl3) δ -88.4 – -88.6 (m, 2F), -154.0 – -154.2 (m, 2F);
13C{1H} NMR (176 MHz, CDCl3) δ 159.7, 156.2, 145.0 – 144.8
(m), 144.5 – 144.3 (m), 143.6 – 143.4 (m), 143.3, 137.1 – 136.1
(m), 135.6 – 135.3 (m), 132.2, 130.2, 128.2, 123.5, 115.0, 114.5,
114.3, 55.4; IR νmax (ATR)/cm-1 3034, 2844, 1603, 1581, 1462,
-
1282, 966, 837, 782; HRMS (ESI-) calcd for [M-H]- C18H10NO2F4
= 348.0648 found = 348.0631; MP 98-100 °C.
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The Journal of Organic Chemistry
4'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐biphenyl]‐4‐ol (5c)
4‐(1‐phenyl‐1‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}et
1
2
3
4
5
6
7
8
The title compound was synthesised according to the general
procedure for the for Suzuki-Miyaura cross-coupling from 1.08
mmol of the corresponding tetrafluoropyridyl phenol iodide as a
white crystalline solid (0.355 g) in 98% yield. 1H NMR (400 MHz,
CDCl3) δ 7.56 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.13
(d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.80 (brs, 1H); 19F
NMR (376 MHz, CDCl3) δ -88.5 – -88.7 (m, 2F), -154.1 – -154.3
(m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 155.3, 154.8, 138.0,
132.7, 128.3, 128.2, 117.0, 115.8. Note: Quaternary fluoropyridyl
carbons were not observed; IR νmax (ATR)/cm-1 3378, 1642, 1599,
1459, 1202, 1167, 968, 822, 510; HRMS (ESI-) calcd for [M-H]-
C17H8NO2F4- = 334.0491 found = 334.0485; MP 125-127 °C.
hyl)phenol (5g) The title compound was synthesised according to
the general procedure for the synthesis of tetrafluoropyridyl ethers
from 3.44 mmol of the corresponding bisphenol with the following
modification. In order to prevent two TFP groups from being
added, the equivalents of pentafluoropyridine and potassium
carbonate were decreased to 0.9 equiv. The compound was purified
using flash column chromatography (100% hexane to 100%
toluene). This gave the product as a colourless oil (0.718 g) in 48%
1
yield. H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 3H), 7.27 –
7.21 (m, 1H), 7.10 (appt, J = 7.4 Hz, 4H), 6.96 (d, J = 8.6 Hz, 4H),
6.77 (d, J = 8.6 Hz, 2H), 4.82 (brs, 1H), 2.17 (s, 3H); 19F NMR (376
MHz, CDCl3) δ -88.6 – -88.8 (m, 2F), -154.1 – -154.3 (m, 2F);
13C{1H} NMR (101 MHz, CDCl3) δ 153.9, 153.8, 148.9, 146.4,
143.0 – 142.7 (m), 141.0, 137.6 – 137.2 (m), 135.1 – 134.6 (m),
130.3, 129.9, 128.5, 128.0, 126.2, 115.9, 114.8, 51.5, 30.7. Note:
Two quaternary fluoropyridyl carbons were not observed; IR νmax
(ATR)/cm-13367, 2982, 1642, 1598, 1470, 1204, 1171, 972, 829,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐biphenyl]‐2‐ol (5d)
The title compound was synthesised according to the general
procedure for the synthesis of tetrafluoropyridyl ethers from 1.07
mmol of the corresponding biphenol as a clear oil (0.199 g) in 56%
1
-
701; HRMS (ESI-) calcd for [M-H]- C25H16NO2F4 = 438.1117
yield. H NMR (400 MHz, CDCl3) δ 7.51 – 7.36 (m, 3H), 7.29 –
7.18 (m, 3H), 7.00 – 6.89 (m, 2H), 5.00 (brs, 1H); 19F NMR (376
MHz, CDCl3) δ -89.4 – -89.6 (m, 2F), -155.0 – -155.3 (m, 2F);
13C{1H} NMR (176 MHz, CDCl3) δ 153.4, 152.8, 144.7 – 144.4
(m), 143.3 – 143.0 (m), 136.1 – 135.8 (m), 134.7 – 134.3 (m),
132.4, 130.8, 130.1, 130.0, 127.3, 126.2, 122.6, 120.8, 118.1,
115.9; IR νmax (ATR)/cm-1 3448, 1642, 1471, 1187, 1067, 974, 752;
found = 438.1102.
[R]-
2'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐binaphthalene]‐2‐
ol (5h) The title compound was synthesised according to the
general procedure for the synthesis of tetrafluoropyridyl ethers
from 1.75 mmol of the corresponding BINOL with the following
modification. In order to prevent two TFP groups from being
added, the equivalents of pentafluoropyridine were decreased to 0.9
equiv. The compound was purified using flash column
chromatography using a mixture of hexane and toluene 2:1. This
-
HRMS (ESI-) calcd for [M-H]- C17H8NO2F4 = 334.0491 found =
334.0500.
4‐({4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}methyl)phenol
(5e) The title compound was synthesised according to the general
procedure for the synthesis of tetrafluoropyridyl ethers from 5.0
mmol of bis(4-hydroxyphenyl)methane with the following
modification. In order to prevent two TFP groups from being
added, the equivalents of pentafluoropyridine and potassium
carbonate were decreased to 0.9 equiv. The compound was purified
using flash column chromatography (100% hexane to 100%
toluene). This gave the product as a colourless oil (0.792 g) in 45%
yield. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.8 Hz, 2H), 7.06
(d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.6 Hz,
2H), 4.71 (brs, 1H), 3.93 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -
88.7 – -88.9 (m, 2F), -154.3 – -154.5 (m, 2F); 13C{1H} NMR (176
MHz, CDCl3) δ 154.2, 154.0, 145.0 – 144.7 (m), 144.8 – 144.5 (m),
143.6 – 143.3 (m), 138.6, 137.0 – 136.7 (m), 135.5 – 135.2 (m),
132.8, 130.2, 130.0, 116.7, 115.4, 40.2; IR νmax (ATR)/cm-1 3363,
1642, 1497, 1193, 1133, 1068, 972, 815; HRMS (ESI-) calcd for
[M-H]- C18H10NO2F4 = 348.0648 found = 348.0661.
1
gave the product as a clear oil (0.485 g) in 64% yield. H NMR
(400 MHz, CDCl3) δ 8.14 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 8.2 Hz,
1H), 7.86 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.63 – 7.55
(m, 2H), 7.47 – 7.32 (m, 3H), 7.31 – 7.22 (m, 2H), 7.03 (d, J = 8.4
Hz, 1H), 4.90 (s, 1H); 19F NMR (376 MHz, CDCl3) δ -90.1 – -90.4
(m, 2F), -154.3 – -154.6 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3)
δ 152.8, 151.8, 144.8 – 144.5 (m), 144.2 – 143.8 (m), 142.8 – 142.5
(m), 135.9 – 135.4 (m), 134.4 – 134.0 (m), 133.5, 132.9, 131.8,
131.6, 131.0, 129.0, 128.6, 128.5, 128.2, 128.1, 128.1, 127.0,
126.5, 125.6, 125.3, 119.1, 118.9, 117.3, 112.1; IR νmax (ATR)/cm-1
3524, 1641, 1474, 1203, 1081, 972, 815, 729; HRMS (ESI-) calcd
for [M-H]- C25H12NO2F4- = 434.0804 found = 434.0787.
2,3,5,6‐tetrafluoro‐4‐({3'‐iodo‐4'‐methoxy‐[1,1'‐biphenyl]‐4‐yl}o
xy)pyridine (6a) The title compound was synthesised according to
the general procedure for iodination using conditions A from 0.14
mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a cream coloured solid
(0.065 g) in 93% yield. 1H NMR (700 MHz, CDCl3) δ 7.97 (d, J =
2.3 Hz, 1H), 7.52 – 7.47 (m, 3H), 7.10 (d, J = 8.7 Hz, 2H), 6.88 (d,
J = 8.5 Hz, 1H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -88.3
– -88.6 (m, 2F), -154.0 – -154.2 (m, 2F); 13C{1H} NMR (176 MHz,
CDCl3) δ 157.8, 155.1, 145.0 – 144.8 (m), 144.5 – 144.2 (m), 143.6
– 143.4 (m), 137.9, 137.1 – 136.8 (m), 136.6, 135.5 – 135.3 (m),
134.4, 128.3, 128.0, 117.0, 111.0, 86.5, 56.5; IR νmax (ATR)/cm-1
2840, 1643, 1595, 1477, 1272, 1207, 1072, 977, 804; HRMS (ESI+)
calcd for [M]+ C18H10NO2F4I+ = 474.9692 found = 474.9674 MP
93-95 °C.
4‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}propan‐2‐yl)
phenol (5f) The title compound was synthesised according to the
general procedure for the synthesis of tetrafluoropyridyl ethers
from 4.38 mmol of the corresponding BPA with the following
modification. In order to prevent two TFP groups from being
added, the equivalents of pentafluoropyridine and potassium
carbonate were decreased to 0.9 equiv. The compound was purified
using flash column chromatography using a mixture of hexane and
toluene 2:1. This gave the product as a colourless oil (0.704 g) in
48% yield. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.9 Hz, 2H),
7.11 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.8
Hz, 2H), 4.89 (br s, 1H), 1.68 (s, 6H); 19F NMR (376 MHz, CDCl3)
δ -88.7 – -88.9 (m, 2F), -154.2 – -154.4 (m, 2F); 13C{1H} NMR
(176 MHz, CDCl3) δ 153.7, 153.4, 148.0, 145.0 – 144.7 (m), 144.7
– 144.5 (m), 143.6 – 143.3 (m), 142.5, 137.0 – 136.8 (m), 135.6 –
135.3 (m), 128.3, 127.9, 116.1, 114.8, 42.0, 30.9; IR νmax
(ATR)/cm-1 3352, 1641, 1497, 1202, 1170, 1066, 972, 830, 554;
HRMS (ESI-) calcd for [M-H]- C20H14NO2F4- = 376.0961 found =
376.0938.
2,3,5,6‐tetrafluoro‐4‐({3'‐iodo‐4'‐methoxy‐[1,1'‐biphenyl]‐3‐yl}o
xy)pyridine (6b) The title compound was synthesised according to
the general procedure for iodination using conditions A from 0.23
mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a clear oil (0.109 g) in
96% yield. 1H NMR (700 MHz, CDCl3) δ 7.97 (d, J = 2.3 Hz, 1H),
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Page 8 of 12
7.49 (dd, J = 8.4, 2.3 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 – 7.34
(0.615 g) in 68% yield. 1H NMR (700 MHz, CDCl3) δ 7.50 (d, J =
1
2
3
4
5
6
7
8
(m, 1H), 7.21 (t, J = 2.1 Hz, 1H), 6.98 – 6.96 (m, 1H), 6.88 (d, J =
8.4 Hz, 1H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -88.3 – -
88.5 (m, 2F), -154.0 – -154.2 (m, 2F); 13C{1H} NMR (176 MHz,
CDCl3) δ 158.1, 156.2, 145.0 – 144.7 (m), 144.4 – 144.2 (m), 143.6
– 143.4 (m), 141.7, 138.0, 137.0 – 136.8 (m), 135.5 – 135.3 (m),
134.2, 130.3, 128.2, 123.6, 115.2, 115.0, 111.0, 86.5, 56.5; IR νmax
(ATR)/cm-1 2934, 2842, 1642, 1469, 1270, 1250, 1164, 1070, 972,
692; HRMS (ESI-) calcd for [M-H]- C18H9NO2F4I- = 473.9614
found = 473.9637; MP 86-87 °C.
2.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 8.5 Hz, 2.3 Hz,
1H), 6.94 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.5 Hz, 1H), 5.17 (brs,
1H), 1.62 (s, 6H); 19F NMR (376 MHz, CDCl3) δ -88.6 – -88.8 (m,
2F), -154.1 – -154.4 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ
153.8, 152.9, 147.2, 145.0 – 144.7 (m), 144.7 – 144.4 (m), 143.6 –
143.3 (m), 137.1 – 136.7 (m), 136.0, 135.6 – 135.2 (m), 129.0,
128.2, 116.2, 114.6, 85.6, 41.9, 30.9; IR νmax (ATR)/cm-1 1644,
1501, 1484, 1224, 1175, 1126, 1070, 979; HRMS (ESI-) calcd for
[M-H]- C20H13NO2F4I- = 501.9927 found = 501.9909; MP 87-89
°C.
9
3‐iodo‐4'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐biphenyl]‐4
‐ol (6c) The title compound was synthesised according to the
general procedure for iodination using conditions A from 0.17
mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a clear oil (0.068 g) in
87% yield. 1H NMR (700 MHz, CDCl3) δ 7.84 (d, J = 2.2 Hz, 1H),
7.49 (d, J = 8.8 Hz, 2H), 7.43 (dd, J = 8.4, 2.2 Hz, 1H), 7.09 (d, J
= 8.8 Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H), 5.35 (brs, 1H); 19F NMR
(376 MHz, CDCl3) δ -88.3 – -88.5 (m, 2F), -154.0 – -154.2 (m, 2F);
13C{1H} NMR (176 MHz, CDCl3) δ 155.1, 154.5, 145.0 – 144.8
(m), 144.4 – 144.2 (m), 143.6 – 143.4 (m), 137.0 – 136.7 (m),
136.6, 136.5, 135.5 – 135.3 (m), 134.5, 117.1, 115.3, 86.2; IR νmax
(ATR)/cm-1 3444, 1647, 1475, 1215, 1164, 1075, 971, 816, 513;
HRMS (ESI-) calcd for [M-H]- C17H7NO2F4I- = 459.9458 found =
459.9472; MP 113-115 °C.
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2‐iodo‐4‐(1‐phenyl‐1‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]ph
enyl}ethyl)phenol (6g) The title compound was synthesised
according to the general procedure for iodination using conditions
A from 0.68 mmol of the corresponding tetrafluoropyridyl
bisphenol and purified by flash column chromatography (100%
hexane to 20% EtOAc/80% hexane) to give the product as a clear
oil (0.223 g) in 58% yield. 1H NMR (700 MHz, CDCl3) δ 7.35 (d,
J = 2.2 Hz, 1H), 7.28 (appt, J = 7.7 Hz, 2H), 7.22 (appt, J = 7.3 Hz,
1H), 7.09 – 7.04 (m, 4H), 6.97 – 6.91 (m, 3H), 6.88 (d, J = 8.5 Hz,
1H), 5.24 (brs, 1H), 2.12 (s, 2H); 19F NMR (376 MHz, CDCl3) δ -
88.5 – -88.7 (m, 2F), -154.1 – -154.3 (m, 2F); 13C{1H} NMR (176
MHz, CDCl3) δ 154.0, 153.1, 148.2, 145.8, 145.0 – 144.7 (m),
144.5 – 144.3 (m), 143.6 – 143.4 (m), 143.0, 137.9, 137.0 – 136.8
(m), 135.5 – 135.3 (m), 130.8, 130.2, 128.4, 128.1, 126.4, 116.1,
114.3, 85.6, 51.3, 30.7; IR νmax (ATR)/cm-1 3484, 1641, 1470,
1205, 1171, 1071, 972, 700; HRMS (ESI-) calcd for [M-H]-
C25H15NO2F4I- = 564.0084 found = 564.0082.
5‐iodo‐2'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐biphenyl]‐2
‐ol (6d) The title compound was synthesised according to the
general procedure for iodination using conditions A from 0.31
mmol of the corresponding tetrafluoropyridyl bisphenol as a clear
6‐iodo‐2'‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]‐[1,1'‐binaphthal
ene]‐2‐ol (6h) The title compound was synthesised according to the
general procedure for iodination using conditions A from 1.15
mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a clear oil (0.570 g) in
88% yield. 1H NMR (700 MHz, CDCl3) δ 8.17 (d, J = 1.8 Hz, 1H),
8.10 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 9.0
Hz, 1H), 7.57 – 7.52 (m, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.47 (dd, J
= 8.9 Hz, 1.7 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.28 (d, J = 8.5 Hz,
1H), 7.21 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H); 19F NMR
(376 MHz, CDCl3) δ -89.5 – -89.7 (m, 2F), -154.4 – -154.6 (m, 2F);
13C{1H} NMR (176 MHz, CDCl3) δ 152.6, 152.1, 136.7, 135.4,
133.3, 131.9, 131.9, 131.7, 130.4, 129.9, 128.6, 128.3, 126.6,
125.8, 125.3, 118.3, 118.3, 118.2, 112.5, 88.7. Note: Quaternary
fluoropyridyl carbons were not observed; IR νmax (ATR)/cm-1 1640,
1583, 1477, 1204, 974, 819, 736; HRMS (ESI-) calcd for [M-H]-
C25H11NO2F4I- = 559.9771 found = 559.9771.
1
oil (0.119 g) in 84% yield. H NMR (700 MHz, CDCl3) δ 7.53 –
7.49 (m, 2H), 7.47 – 7.43 (m, 1H), 7.39 – 7.37 (m, 1H), 7.37 – 7.32
(m, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 5.04
(brs, 1H); 19F NMR (376 MHz, CDCl3) δ -88.6 – -88.8 (m, 2F), -
154.6 – -154.9 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 153.2,
152.9, 144.9 – 144.5 (m), 144.4 – 144.1 (m), 143.5 – 143.1 (m),
139.1, 138.7, 136.3 – 136.0 (m), 134.9 – 134.5 (m), 132.3, 130.5,
126.2, 125.7, 125.3, 118.2, 117.5, 82.4; IR νmax (ATR)/cm-1 3672,
1651, 1474, 1271, 1184, 1042, 983, 873, 759, 741, 615; HRMS
(ESI-) calcd for [M-H]- C17H7NO2F4I- = 459.9458 found =
459.9451; MP 109-111 °C.
2‐iodo‐4‐({4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}methyl
)phenol (6e) The title compound was synthesised according to the
general procedure for iodination using conditions A from 0.44
mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 100%
toluene) to give the product as a clear oil (0.167 g) in 80% yield.
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.1 Hz, 1H), 7.19 (d, J
= 8.7 Hz, 2H), 7.07 (dd, J = 8.3, 2.1 Hz, 1H), 7.02 (d, J = 8.7 Hz,
2H), 6.95 (d, J = 8.3 Hz, 1H), 5.31 (brs, 1H), 3.91 (s, 2H); 19F NMR
(376 MHz, C DCl3) δ -88.6 – -88.8 (m, 2F), -154.2 – -154.4 (m,
2F); 13C{1H} NMR (176 MHz, CDCl3) δ 154.3, 153.4, 145.0 –
144.7 (m), 144.7 – 144.4 (m), 143.6 – 143.4 (m), 138.2, 137.8,
137.0 – 136.8 (m), 135.5 – 135.3 (m), 134.8, 130.7, 130.3, 116.8,
115.1, 85.8, 39.6; IR νmax (ATR)/cm-1 3489, 1641, 1468, 1194,
1068, 971, 815; HRMS (ESI-) calcd for [M-H]- C18H9NO2F4I- =
473.9614 found = 473.9595.
2,3,5,6‐tetrafluoro‐4‐({4'‐iodo‐[1,1'‐biphenyl]‐4‐yl}oxy)pyridine
(6i) The title compound was synthesised according to the general
procedure for iodination using conditions A from 0.21 mmol of the
corresponding tetrafluoropyridyl ether with the following
modification. A catalytic amount of acetonitrile was added to the
reaction mixture to solubilise the starting material. The product was
purified by flash column chromatography (100% hexane to 10%
EtOAc/90% hexane). This gave the title compound as a white solid
(0.081 g) in 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
8.5, 2H), 7.58 (d, J = 8.9, 2H), 7.32 (d, J = 8.5, 2H), 7.15 (d, J =
8.9, 2H); 19F NMR (376 MHz, CDCl3) δ -88.2 – -88.4 (m, 2F), -
153.9 – -154.1 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 155.5,
145.0 – 144.8 (m), 144.3 – 144.1 (m), 143.6 – 143.4 (m), 139.3,
138.0, 137.2, 137.1 – 136.8 (m), 135.6 – 135.3 (m), 128.8, 128.5,
117.1, 93.3; IR νmax (ATR)/cm-1 1641, 1493, 1472, 1168, 1064,
969, 809, 762; HRMS (ESI-) calcd for [M-H]- C17H7NOF4I- =
443.9509 found = 443.9514; MP 109-110 °C.
2‐iodo‐4‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}prop
an‐2‐yl)phenol (6f) The title compound was synthesised according
to the general procedure for iodination using conditions A from
1.86 mmol of the corresponding tetrafluoropyridyl bisphenol and
purified by flash column chromatography (100% hexane to 20%
EtOAc/80% hexane) to give the product as a cream coloured solid
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The Journal of Organic Chemistry
-
3‐iodo‐4‐methoxy‐1,1'‐biphenyl (6j) The title compound was
calcd for [M-H]- C20H12NO2F4I2 = 627.8894 found = 627.8912;
1
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3
4
5
6
7
8
synthesised according to the general procedure for iodination using
conditions A from 0.54 mmol from 4-methoxybiphenyl and
purified by flash column chromatography (100% hexane to 10%
EtOAc/90% hexane) to give the product as a white solid (0.105 g)
MP 141-143 °C.
4‐[2‐(4‐hydroxyphenyl)propan‐2‐yl]‐2‐iodophenol (9) To
solution
a
of
1
2‐iodo‐4‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}prop
an‐2‐yl)phenol (0.230 g, 0.46 mmol) in MeCN (10 mL) was added
potassium fluoride (0.053 g, 0.92 mmol) and thiophenol (0.152 g,
1.38 mmol) and the resulting reaction mixture stirred at rt for 18 h.
After this time the reaction mixture was concentrated under
reduced pressure and the recovered residue purified directly by
flash column chromatography (100% hexane to 25% EtOAc/75%
hexane). This gave the title product as a clear oil (0.132 g) in 81%
yield. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 2.3 Hz, 1H), 7.11
– 7.06 (m, 3H), 6.89 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H),
5.37 (brs, 1H), 1.63 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
153.5, 152.6, 145.4, 142.5, 136.1, 129.1, 127.9, 114.9, 114.5, 85.5,
41.6, 31.0; IR νmax (ATR)/cm-1 3248, 1644, 1595, 1511, 1500,
1489, 1224, 1177, 820, 560; HRMS (ESI-) calcd for [M-H]-
C15H14O2I- = 353.0039 found = 353.0041.
in 63% yield. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.3 Hz,
1H), 7.60 – 7.53 (m, 3H), 7.45 (appt, J = 7.6 Hz, 2H), 7.36 (appt, J
= 7.3 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 3.95 (s, 3H); 13C {1H}
NMR (151 MHz, CDCl3) δ 157.6, 139.3, 138.0, 135.8, 128.8,
128.1, 127.1, 126.7, 111.0, 86.4, 56.5; IR νmax (ATR)/cm-1 2933,
2834, 1595, 1480, 1282, 1250, 1054, 1016, 813, 760; HRMS (ESI+)
calcd for [M]+ C13H11OI- = 309.9855 found = 309.9856; MP 86-87
°C.
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2‐bromo‐4‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}pr
opan‐2‐yl)phenol (7a) To a solution of compound 5f (0.200 g, 0.53
mmol) in hexafluoroisopropanol (2 mL) was added NBS (0.095 g,
0.53 mmol) and the resulting reaction mixture was stirred at rt for
1 h. The reaction mixture was then concentrated under reduced
pressure and the recovered residue was purified directly with flash
column chromatography (100% hexane to 100% toluene). This
gave the desired compound as a colourless oil (0.179 g) in 74%
yield. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 2.3 Hz, 1H), 7.24
(d, J = 8.9 Hz, 1H), 7.06 (dd, J = 8.5 Hz, 2.3 Hz, 1H), 6.98 (d, J =
8.9 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H), 5.43 (brs, 1H), 1.67 (s, 6H);
19F NMR (376 MHz, CDCl3) δ -88.6 – -88.8 (m, 2F), -154.2 – -
154.3 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 153.8, 150.3,
147.2, 145.0 – 144.7 (m), 144.6 – 144.4 (m), 144.1, 143.6 – 143.4
(m), 137.0 – 136.8 (m), 135.6 – 135.3 (m), 129.9, 128.2, 127.8,
116.2, 115.7, 109.9, 42.1, 30.9; IR νmax (ATR)/cm-1 3516, 2971,
1641, 1465, 1203, 1171, 1065, 973, 825; HRMS (ESI-) calcd for
[M-H]- C20H13NO2F4Br- = 454.0066 found = 454.0071.
4‐[2‐(4‐hydroxy‐3‐iodophenyl)propan‐2‐yl]‐2‐iodophenol (10)
The title compound was synthesised according to the general
procedure for iodination using conditions A from 0.40 mmol of the
corresponding mono-iodo-BPA this gave the desired product as a
clear oil (0.141 g) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 7.52
(d, J = 2.3 Hz, 2H), 7.06 (dd, J = 8.5 Hz, 2.3 Hz, 2H), 6.91 (d, J =
8.5 Hz, 2H), 5.24 (brs, 2H), 1.61 (s, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 152.9, 144.6, 136.0, 129.0, 114.7, 85.6, 41.5, 31.0; IR
νmax (ATR)/cm-1 3478, 2966, 1645, 1489, 1226, 1165, 1077, 1018,
979; HRMS (ESI-) calcd for [M-H]- C15H13O2I2 = 478.9005 found
= 478.9018.
-
2,6‐dibromo‐4‐(2‐{4‐[(2,3,5,6‐tetramethylpyridin‐4‐yl)oxy]pheny
l}propan‐2‐yl)phenol (7b) To a solution of compound 7 (0.050 g,
0.12 mmol) in hexafluoroisopropanol (2 mL) was added NBS
(0.021 g, 0.12 mmol) and the resulting mixture was stirred at rt for
1 h. The reaction mixture was then concentrated under reduced
pressure and the recovered residue was purified directly with flash
column chromatography (100% hexane to 100% toluene). This
gave the desired compound as a white solid (0.040 g) in 63% yield.
1H NMR (400 MHz, CDCl3) δ 7.29 (s, 2H), 7.22 (d, J = 8.8 Hz,
2H), 7.00 (d, J = 8.8 Hz, 2H), 5.80 (brs, 1H), 1.66 (s, 6H); 19F NMR
(376 MHz, CDCl3) δ -88.47 – -88.69 (m, 2F), -154.07 – -154.26
(m, 2F); 13C{1H} NMR (151 MHz, CDCl3) δ 154.0, 147.4, 146.4,
145.0, 144.6 – 144.4 (m), 143.4 – 143.2 (m), 137.2 – 136.9 (m),
135.4 – 135.2 (m), 130.4, 128.2, 116.4, 109.6, 42.1, 30.8. Note:
One quaternary fluoropyridyl carbon was not observed; IR νmax
(ATR)/cm-1 3500, 2870, 1641, 1499, 1474, 1205, 1173, 1069;
Synthesis
of
4'‐methoxy‐5‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}
propan‐2‐yl)‐[1,1'‐biphenyl]‐2‐ol (11) The title compound was
synthesised according to the general procedure for the for Suzuki-
Miyaura cross-coupling from 0.54 mmol of the corresponding
tetrafluoropyridyl phenol iodide. The compound was purified using
flash column chromatography (100% hexane to 100% toluene) to
1
give the product as a brown oil (0.192 g) in 74% yield. H NMR
(400 MHz, CDCl3) δ 7.37 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.9 Hz,
2H), 7.11 – 7.06 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.9
Hz, 2H), 6.90 (d, J = 8.6 Hz, 1H), 5.10 (brs, 1H), 3.88 (s, 3H), 1.70
(s, 6H); 19F NMR (376 MHz, CDCl3) δ -88.7 – -88.9 (m, 2F), -
154.2 – -154.5 (m, 2F); 13C{1H} NMR (176 MHz, CDCl3) δ 159.3,
153.7, 150.5, 148.0, 142.5, 130.2, 129.4, 128.5, 128.3, 127.2,
127.1, 116.2, 115.2, 114.7, 55.4, 42.1, 31.0; IR νmax (ATR)/cm-1
2966, 1642, 1603, 1475, 1202, 1170, 1066, 975, 832; HRMS (ESI-)
calcd for [M-H]- C27H20NO3F4- = 482.1379 found = 482.1368.
-
HRMS (ESI-) calcd for [M-H]- C20H12Br2F4NO2 = 531.9171 found
= 531.9171; MP 115-117 °C.
2,6‐diiodo‐4‐(2‐{4‐[(2,3,5,6‐tetrafluoropyridin‐4‐yl)oxy]phenyl}p
ropan‐2‐yl)phenol (8) To a solution of compound 6f (0.600 g 1.19
mmol) in TFA (1mL) was added NIS (0.295 g, 1.31 mmol) and the
resulting reaction mixture stirred at room temperature for 3 h. After
this time the reaction mixture was concentrated under reduced
pressure and then directly to flash column chromatography (100%
hexane to 100% toluene). This gave the target compound 8 as a
colourless crystalline solid (0.425 g) in a 57% yield. 1H NMR (400
MHz, CDCl3) δ 7.50 (s, 2H), 7.22 (d, J = 9.0 Hz, 2H), 7.00 (d, J =
9.0 Hz, 2H), 5.66 (brs, 1H), 1.64 (s, 6H); 19F NMR (376 MHz,
CDCl3) δ -88.5 – -88.7 (m, 2F), -154.1 – -154.3 (m, 2F); 13C{1H}
NMR (176 MHz, CDCl3) δ 153.9, 151.7, 146.5, 146.4, 145.0 –
144.7 (m), 144.6 – 144.4 (m), 143.6 – 143.4 (m), 137.6, 137.0 –
136.8 (m), 135.5 – 135.3 (m), 128.2, 116.4, 82.1, 41.8, 30.8; IR νmax
(ATR)/cm-1 1643, 1591, 1489, 1248, 1076, 740; HRMS (ESI-)
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Copies of 1H, 19F and 13C NMR spectra for synthesized
compounds, NMR data for reaction screening, computational
data, X-ray analysis of 3f and 8 (PDF)
X-ray crystal data of 3f and 8 (CIF)
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15.
Barros, M. T.; Matias, P. M.; Maycock, C. D.; Ventura, M. R.,
AUTHOR INFORMATION
Aziridines as a Protecting and Directing Group. Stereoselective Synthesis
1
2
3
4
5
6
7
8
Corresponding Author
of (+)-Bromoxone. Org. Lett. 2003, 5 (23), 4321-4323.
16.
Gandeepan, P.; Ackermann, L., Transient Directing Groups for
*s.l.cobb@durham.ac.uk
*william.d.brittain@durham.ac.uk
Transformative C–H Activation by Synergistic Metal Catalysis. Chem
2018, 4 (2), 199-222.
17.
Li, S.; Wang, H.; Weng, Y.; Li, G., Carboxy Group as a Remote
Notes
and Selective Chelating Group for C-H Activation of Arenes. Angew Chem
Int Ed Engl 2019, 58 (51), 18502-18507.
The authors declare no competing financial interests.
18.
M. T. Mihai, B. D. Williams, R. J. Phipps., Para-Selective C-H
Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with
a Bulky Countercation. J. Am. Chem. Soc 2019, 141, 15477-15482.
ACKNOWLEDGMENT
9
19.
Lee, B.; Mihai, M. T.; Stojalnikova, V.; Phipps, R. J., Ion-Pair-
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SLC and WDGB would like to acknowledge the Biotechnology and
Biological Sciences Research Council [BB/P003656/1] and
Durham University’s Medical Research Council Confidence in
Concept scheme for financial support [MC-PC-17157]. Dr Mark
Fox is thanked for carrying out computational calculations. Dr Juan
A. Aguilar and Catherine Heffernan are thanked for NMR
spectroscopy support. Dr Dmitry S. Yufit is thanked for help in the
collection of X-ray crystal data and solving of the reported crystal
structure.
Directed Borylation of Aromatic Phosphonium Salts. J. Org. Chem. 2019,
84 (20), 13124-13134. .
20.
Liu, Z.; Li, X.; Zeng, T.; Engle, K. M., Directed, Palladium(II)-
Catalyzed Enantioselective anti-Carboboration of Alkenyl Carbonyl
Compounds. ACS Catal. 2019, 9 (4), 3260-3265.
21.
Nimmagadda, S. K.; Liu, M.; Karunananda, M. K.; Gao, D.-W.;
Apolinar, O.; Chen, J. S.; Liu, P.; Engle, K. M., Catalytic, Enantioselective
α-Alkylation of Azlactones with Nonconjugated Alkenes by Directed
Nucleopalladation. Angew. Chem. Int. Ed. 2019, 58 (12), 3923-3927.
22.
Maji, A.; Bhaskararao, B.; Singha, S.; Sunoj, R. B.; Maiti, D.,
Directing group assisted meta-hydroxylation by C–H activation. Chem Sci
2016, 7 (5), 3147-3153.
23.
Xu, X.; Luo, J., Transition Metal-Catalyzed Directing-Group-
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