Fluorinations of unsymmetrical diaryliodonium salts containing: Ortho -sidearms; Influence of sidearm on selectivity

Article abstract of DOI:10.1039/d0ob01401j

Activated aromatics were reacted with two different fluoroidoane reagents 1 and 2 in the presence of triflic acid to prepare only the para-substituted diaryliodonium salts. With fluoroiodane 1 the unsymmetrical diaryliodonium salts contained an ortho-propan-2-ol sidearm, whereas the alcohol sidearm was eliminated to form an ortho-styrene sidearm in the reaction with fluoroiodane 2. Only the diaryliodonium salts containing a styrene sidearm were fluorinated successfully to deliver para-fluorinated aromatics in good yields.

Full text of DOI:10.1039/d0ob01401j

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/D0OB01401J
ARTICLE
Fluorinations of unsymmetrical diaryliodonium salts containing
Received 00th January 20xx,
ortho-sidearms; influence of sidearm on selectivity
Ahmed M. H. Abudken,a,b Eric G. Hope,a Kuldip Singha and Alison M. Stuart*a
Activated aromatics were reacted with two different fluoroidoane reagents 1 and 2 in the presence of triflic acid to prepare
only the para-substituted diaryliodonium salts. With fluoroiodane 1 the unsymmetrical diaryliodonium salts contained an
ortho-propan-2-ol sidearm, whereas the alcohol sidearm was eliminated to form an ortho-styrene sidearm in the reaction
with fluoroiodane 2. Only the diaryliodonium salts containing a styrene sidearm were fluorinated successfully to deliver
para-fluorinated aromatics in good yields.
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Introduction
Fluoroaromatics constitute an important class of organic
compounds because of their commercial applications in
pharmaceuticals, agrochemicals, liquid crystals and positron
emission tomography (PET).1 Fluorine-18 (18F) is the most
commonly used radionuclide for PET, mainly due to its half-life
of 110 minutes, and this has created a demand for new methods
for the late-stage radiofluorination of aromatics. Consequently,
the number of synthetic methods available for the preparation
of aromatic fluorides has increased dramatically over the last
eight years,2 and the synthesis of aryl carbon-fluorine bonds
from fluoride normally requires pre-functionalisation of the
aromatic with either boron,3 tin,4 N-arylsydnone5 or
hypervalent iodine.6-13
The fluorination of unsymmetrical diaryliodonium salts was
first reported in 1995 by Pike6 and it has now become a well-
established method for the introduction of [18F]fluoride into
aromatics.7 Since fluoride normally attacks the most electron-
deficient aromatic ring, an effective strategy for directing
fluoride into the desired aryl ring is to use an unsymmetrical
aryl(spectator)iodonium salt where the spectator group is an
electron-rich aromatic such as 4-methoxyphenyl or 2-thienyl.6-9
There is also an “ortho effect” in these fluorinations which
overcomes the electronic effect. If one of the aromatic rings
contains an ortho-substituent such as methyl, it will direct the
fluorination to that ring. Sanford has shown that ortho-
selectivity can be reversed by using a copper catalysed
fluorination of aryl(mesityl)iodonium salts and the reaction is
highly selective for fluorination to occur at the less sterically
hindered arene, even with highly electron-rich aromatics.10,11
Scheme 1 Preparation of fluoroiodane reagents and diaryliodonium salts
Recently, she described a two-step procedure involving an SEAr
reaction between activated aromatics, MesI(OH)(OTs) and
TMSOTf to generate aryl(mesityl)iodonium triflates which were
used in situ in a copper-mediated radiofluorination with
[18F]KF.10c Despite the presence of two ortho-methoxy groups,
2,4,6-trimethoxyphenyl was introduced by Chun in 2019 as an
excellent new spectator group in the high-temperature
radiofluorinations of aryl(2,4,6-trimethoxyphenyl)iodonium
triflates where the aryl group was fluorinated with extremely
high chemoselectivity.12 Iodonium ylides, (diacetoxyiodo)-
arenes and iodoarenes oxidised by m-CPBA have also been
investigated as precursors to [18F]fluoroarenes.13
In 2013 we reported the preparation of the hypervalent
iodine(III) reagent 1 from cheap sources of nucleophilic fluoride
(Scheme 1) and its application as a new fluorinating reagent for
the fluorination of 1,3-diketones, 1,3-ketoesters and 1,3-
ketoamides.14a Since then, the reaction scope of fluoroiodane
1
has extended significantly from the difluorinations of styrenes
and cyclopropanes, to intramolecular fluorocyclisations of
unsaturated alcohols, amines, amides and carboxylic acids, as
well as to radiofluorinations.14-16 Most of these reactions,
aSchool of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
Email: Alison.Stuart@le.ac.uk
however, required
fluoroiodane reagent
a
1
transition metal to activate the
by coordinating to the fluorine atom.17
bCollege of Pharmacy, Al-Qadisiyah University, Al-Qadisiyah, Iraq.
Electronic Supplementary Information (ESI) available: Experimental procedures,
NMR spectra. CCDC 2013356-2013360. For ESI and crystallographic data in CIF or
other electronic form see DOI: 10.1039/x0xx00000x
We have now established that 1 can be activated by hydrogen
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Table 1 Preparation of diaryliodonium salts 4 from fluoroiodane reagent 1
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DOI: 10.1039/D0OB01401J
Scheme 2 Metathesis reactions using NaBF4 (aq)
were applied to the less activated aromatic, 2-bromoanisole,
the diaryliodonium salt 4d was obtained in a moderate 58%
yield. After further optimisation (see Table S3 in ESI), the yield
increased to 86% when 2-bromoanisole was reacted with
fluoroiodane
1
and 3 equivalents of triflic acid in acetonitrile at
o
0 C for 2 hours. The optimised protocol was applied to other
less activated aromatics such as diphenyl ether, methyl-2-
methoxybenzoate and m-xylene to form the unsymmetrical
diaryliodonium salts 4e, 4f and 4g in moderate to good yields
(22-69%). All the diaryliodonium triflates were obtained as
stable, white powders which were purified simply by washing
with hexane and diethyl ether.
a
The triflate counteranions in the unsymmetrical
diaryliodonium salts 4 were exchanged easily by stirring the salt
in dichloromethane with aqueous sodium tetrafluoroborate at
room temperature for 18 hours (Scheme 2). This simple
Reaction conditions: substrate (0.72 mmol), fluoroiodane 1 (1.07 mmol), triflic acid
b
(1.07 mmol) and dry CH3CN (2 mL) at RT for 1 h; Reaction conditions: substrate (0.72
mmol), fluoroiodane 1 (1.07 mmol), triflic acid (2.16 mmol) and dry CH3CN (2 mL) at 0 °C
for 2 h.
procedure delivered the diaryliodonium tetrafluoroborates
good yields (79-91%).
5 in
bonding to hexafluoroisopropanol and crucially, it removed the
need for transition metals.14d
A new analogue of the fluoroiodane reagent 1, where one
We were interested in preparing fluorinated aromatics using
of the methyl groups was replaced by a phenyl group, was then
prepared by a five-step synthesis (see ESI). The phenyl group
was introduced to encourage the alcohol sidearm in the
diaryliodonium salts to eliminate and form an alkene in
conjugation with two aromatic rings under the strong acidic
conditions used in their synthesis. Hence, a new class of
unsymmetrical diaryliodonium salts containing an ortho-
styrene sidearm was prepared by reacting a series of activated
fluoroiodane
classes of unsymmetrical diaryliodonium salts containing ortho-
sidearms, and , by a site selective SEAr reaction between
activated aromatics and the fluoroiodane reagents and with
1 and here, we report the preparation of two new
5
7
1
2
triflic acid (Scheme 1). We will also discuss the fluorinations of
these unsymmetrical diaryliodonium salts using Sanford’s
copper catalysed conditions to reverse the “ortho effect” and
fluorinate selectively the activated aromatics.
aromatics with fluoroiodane
2
and triflic acid in acetonitrile at 0
in
oC for 2 hours. After stirring the diaryliodonium triflates
6
dichloromethane with an aqueous solution of sodium
tetrafluoroborate, the diaryliodonium tetrafluoroborates 7a to
7h were produced in good yields (74-89%) over the two steps
(Scheme 3). The reaction worked particularly well with less
activated aromatics such as diphenyl ether, methyl-2-
methoxybenzoate and m-xylene delivering the diaryliodonium
Results and Discussion
Initially, anisole was reacted with fluoroiodane
equivalents of triflic acid in acetonitrile at room temperature to
form exclusively the para-substituted diaryliodonium triflate 4a
in 86% yield in just 1 hour at room temperature (Table 1). 1,3-
Dimethoxybenzene and mesitylene were reacted with
1 and 1.5
triflates 6b
respectively) than the same reactions with fluoroiodane
where the salts, 4e 4f and 4g, were obtained in 69%, 22% and
, 6f and 6g in better yields (85%, 90% and 89%
fluoroiodane
1 and triflic acid to form the diaryliodonium salts
1
4b and 4c in 91-92% yield. When the same reaction conditions
,
2 | J. Name., 2012, 00, 1-3
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Scheme 3 Preparation of diaryliodonium salts 7 from fluoroiodane reagent 2 and the overall yields for the two steps are reported
51% yields respectively. In the reaction between benzyl phenyl diisopropylethylamine (Hunig’s base) were used to ensure
ether and fluoroiodane , the benzyl protecting group was complete conversion to products 9a and 10a which were
2
removed under the strong acidic conditions producing the p- isolated in excellent yields after stirring the crude products with
phenol salt 6c and subsequently 7c in 59% overall yield after an aqueous solution of sodium tetrafluoroborate. The last step
anion exchange. Interestingly, the first general procedure for was essential because without it, some of the salt was obtained
preparing para-hydroxy substituted diaryliodonium salts was with a chloride counteranion which affected the subsequent
only reported in 2018 by Zhdankin using Koser’s reagent, fluorinations.
triisopropylsiloxyarenes and triflic acid to deprotect the aryl silyl
ethers.18 Some arenes, however, were incompatible with the
reaction (Scheme 3) including 1,3-dimethoxybenzene, 1,2-
dimethoxybenzene, 1-methoxy-2-methylbenzene, acetanilide
and N-methylindole.
The diaryliodonium tetrafluoroborate 5a was also prepared
in one-step by the direct reaction between anisole,
fluoroiodane reagent
1 and the Lewis acid, boron trifluoride
(Scheme 4). Unfortunately, this reaction did not work with less
activated aromatics such as 2-bromoanisole. When anisole was
reacted with fluoroiodane reagent
alcohol sidearm did not undergo elimination and the
diaryliodonium tetrafluoroborate 8a containing 1-
2 and boron trifluoride, the
a
phenylethan-1-ol sidearm was formed in 90% yield. Before
attempting to fluorinate these unsymmetrical diaryliodonium
salts, the free hydroxy groups in 5a and 8a were protected with
MOMCl (Scheme 4). An excess of both MOMCl and N,N-
Figure 1 Molecular structure of 5a containing a propan-2-ol sidearm and showing 50%
displacement ellipsoids. Selected bond lengths and angles: I(1)-C(1) 2.132(3) Å; I(1)-C(10)
2.087(3) Å; I(1)···O(1) 2.576(2) Å; C(10)-I(1)-C(1) 98.35(10) °; O(1)···I(1)-C(10) 169.24(8) °.
Scheme 4 Preparation of diaryliodonium tetrafluoroborates, 5a and 8a, and protection of alcohol sidearm
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Table 2 Preliminary fluorinations of unsymmetrical diaryliodonium salts 7a, 9a and 10a
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DOI: 10.1039/D0OB01401J
Entry Substrate
Ar Group
[Cu]
(equiv)
0
12a
(%)a
0
13
(%)a
53
7
1
2
3
4
5
6
7a
7a
0.2
0
39
0
9a
8
9a
0.2
0
0
74
6
10a
10a
0
0.2
0
65
Figure 2 Molecular structure of 8a containing a 1-phenylethan-1-ol sidearm and showing
50% displacement ellipsoids. Selected bond lengths and angles: I(1)-C(1) 2.134(3) Å; I(1)-
C(15) 2.088(3) Å; I(1)···O(1) 2.589(2) Å; C(15)-I(1)-C(1) 97.12(11) °; O(1)···I(1)-C(15)
168.84(8) °.
a Determined by GC and 19F NMR spectroscopy with internal standards.
triflate 6a and tosylate 11a that both contain the same o-
styrene sidearm are presented in the ESI. In this series of
diaryliodonium salts, the I(1)-C(1) bond lengths (2.102(3)-
2.118(4) Å) are very similar to the I(1)-C(15) bond lengths
(2.094(3)-2.100(4) Å) and the C(15)-I(1)-C(1) bond angles range
from 92.8(1) to 98.0(1)˚. The C(7)-C(8) bond lengths are
1.314(5)-1.331(5) Å which is typical for an alkene C=C bond
length (1.322 Å)19 and the bond angles around C(7) are normal
for an sp2 hybridised carbon atom. There is secondary bonding
between the iodine and the oxygen atoms of the tosylate and
triflate counteranions in 11a and 6a respectively. There are two
intramolecular interactions in 11a, I(1)···O(4) = 2.721(3) Å and
I(1A)···O(2) = 2.850(3) Å, as well as two intermolecular
interactions, I(1)···O(2A) = 2.805(3) Å and I(1A)···O(3A) =
2.859(3) Å. The intramolecular and intermolecular interactions
in 6a are slightly weaker with the triflate anion, I(1)···O(3) =
2.930(2) Å and I(1)···O(4) = 3.094(3) Å respectively. An
intramolecular interaction (3.023(3) Å) between F(3) of the
Solid-State Structures
The solid-state structures of 5a containing a propan-2-ol
sidearm and 8a containing a 1-phenylethan-1-ol sidearm are
shown in Figures 1 and 2. The I(1)-C(1) (2.132(3) and 2.134(3) Å)
and I(1)-C(10)/C(15) (2.087(3) and 2.088(3) Å) bond lengths are
practically identical for the two diaryliodonium salts. The
distinct C(15)/C(10)-I(1)-C(1) bond angles are typical for the
pseudo T-shape of diaryliodonium salts and range from 97.1(1)
to 98.4(1) °. In both solid-state structures there is a strong
intramolecular interaction between I(1) and O(1) (2.576(2) and
2.589(2) Å) with an O(1)···I(1)-C(10) bond angle of 169 ˚.
Figure 3 shows the solid-state structure of 7a containing an
o-styrene sidearm and the X-ray crystal structures of the related
tetrafluoroborate counteranion and I(1) is also present in 7a
.
Fluorinations
Initially, the unsymmetrical diaryliodonium salts 7a, 9a and 10a
were reacted with potassium fluoride (1.1 equivalent) and 18-
crown-6 (0.4 equivalent) in DMF at 60 °C for 18 hours both with
and without [Cu(MeCN)4]BF4 (0.2 equivalent), as reported by
Sanford in the fluorination of aryl(mesityl)iodonium salts (Table
2).10a Without the copper catalyst the ortho-effect dominated in
the fluorination of 7a (entry 1) and the aryl group containing the
ortho-styrene sidearm was fluorinated producing 1-fluoro-2-(1-
phenylvinyl)benzene 13a in 53% yield with byproduct 4-
iodoanisole formed in 72% yield. However, the ortho-effect was
reversed in the copper-catalysed fluorination and the desired
product, 4-fluoroanisole 12a, was delivered in a moderate 39%
yield (entry 2). Surprisingly, when the unsymmetrical salts, 9a
and 10a, were fluorinated in the absence of copper, there was
Figure 3 Molecular structure of 7a containing an o-styrene sidearm and showing 50%
displacement ellipsoids. Selected bond lengths and angles: I(1)-C(1) 2.118(4) Å; I(1)-C(15)
2.099(4) Å; I(1)···F(3) 3.023(3) Å; C(15)-I(1)-C(1) 95.26(14) °; F(3)···I(1)-C(15) 171.38(13) °.
4 | J. Name., 2012, 00, 1-3
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Table 3 Optimisation of fluorination conditions
Table 4 Fluorinations of unsymmetrical diaryliodonium salts
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DOI: 10.1039/D0OB01401J
Entry Substrate
Product
12
13a
12:13a
(%)a
(%)a
Entry Substrate
Cu catalyst
Time
(h)
18
18
18
18
4
4
4
4
12a
(%)a
45
43
50
60
65
1
13a 12a:13a
(%)a
1
2b
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
6a
11a
[Cu(MeCN)4]BF4
[Cu(MeCN)4]BF4
[Cu(MeCN)4]OTf
Cu(OTf)2
Cu(OTf)2
No catalyst
Cu(OTf)2
5
5
7
9
6
90:10
90:10
88:12
87:13
92:8
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
65
61
20
87
66
82
63
23
6
6
92:8
91:9
80
1
1:99
97:3
34
13
0
100:0
94:6
Cu(OTf)2
1
93:7
a Determined by GC with an internal standard. b 1 Equivalent of TEMPO in the dark.
6
very little fluorination but there was still a strong ortho-effect
with 4-iodoanisole being obtained in 79% and 85% yield
respectively (entries 3 and 5). Under the copper-catalysed
conditions (entries 4 and 6) fluorination was observed, but the
ortho-effect was not reversed and the aryl groups containing
the ortho-sidearms were fluorinated in 74 and 65% yields
respectively. Presumably, the presence of the oxygen atoms in
the sidearms of 9a and 10a, which had strong interactions with
the iodine atom in the solid-state structures, were affecting the
selectivity of these fluorinations.
5
93:7
7
92:8
7g
21
75:25
47:53
The fluorination of 7a was optimised by screening the
reaction conditions, different solvents, copper catalysts and
fluorinating reagents (see ESI for full details). Increasing the
7h
26
a Determined by 19F NMR spectroscopy with an internal standard
o
reaction temperature to 80 C in entry 1 (Table 3) improved
but this was probably due to the free hydroxy group in the salt.20
In the copper-catalysed fluorinations of 7d to 7f, the fluorinated
aromatics 12d to 12f were produced in good (66%) to excellent
(82%-87%) yields and with high selectivities (93:7). As expected,
the selectivity dropped to 75:25 in the fluorination of 7g
because of the presence of the ortho-methyl group in the
activated aromatic, but 2,4-dimethylfluorobenzene 12g was still
formed in a good 63% yield. The selectivity was reduced further
to 47:53 in the fluorination of 7h due to the bigger ethyl
substituent in the ortho-position and the desired fluorinated
aromatic 12h was only obtained in a low 23% yield.
both the yield of 4-fluoroanisole 12a to 45% and the selectivity
of the reaction to 90:10. Since the use of TEMPO has proved
beneficial for the fluorinations of some diaryliodonium salts,7 1
equivalent of TEMPO was used in entry 2 but it had no effect on
the reaction. Both [Cu(MeCN)4]OTf and Cu(OTf)2 were good
catalysts with Cu(OTf)2 providing 4-fluoroanisole in 60 % yield.
The yield improved to 65% and the selectivity increased to 92:8
by reducing the reaction time to 4 hours in entry 5. The
uncatalysed reaction in entry 6 proceeded in an excellent 80%
yield but with the opposite selectivity (1:99). Finally, the effects
of changing the counteranion from tetrafluoroborate 7a to
triflate 6a (entry 7) and tosylate 11a (entry 8) were investigated
under the optimised reaction conditions but only low yields of
4-fluoroanisole 12a were obtained.
Conclusions
Having established optimum conditions, each of the
diaryliodonium tetrafluoroborates, 7a to 7h, were fluorinated
using potassium fluoride and 20 mol% Cu(OTf)2 in DMF at 80 oC
for 4 h (Table 4). The salts, 7a and 7b, produced the desired p-
fluorinated aromatics, 12a and 12b, in good yields (61-65%)
with excellent selectivities (91:9). However, p-fluorophenol 12c
was only obtained in a low 20% yield in the fluorination of 7c
In summary, this paper describes a convenient synthesis of
para-fluorinated aromatics from activated aromatics and
fluoroiodane reagent
2. Initially, two new classes of
unsymmetrical diaryliodonium salts containing ortho-sidearms
were prepared by a site selective SEAr reaction between
activated aromatics and two different fluoroiodane reagents
1
and with triflic acid. With fluoroiodane the unsymmetrical
2
1
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11 (a) A. Yamaguchi, H. Hanaoka, T. Higuchi and Y. Tsushima, J.
Nucl. Med., 2018, 59, 815; (b) A. YamDagOuI:c1h0i.,10H3V.9ieH/wDa0AnrOtaicBole0k1Oa4n,0li1nTJe.
Higuchi and Y. Tsushima, J. Label. Compd. Radiopharm., 2020,
63, 368.
diaryliodonium salts contained an ortho-propan-2-ol sidearm,
whereas the alcohol sidearm was eliminated to form an ortho-
styrene sidearm in the reaction with fluoroiodane
counteranion exchange, only the diaryliodonium tetrafluoro-
borates containing a styrene sidearm reacted selectively with
2. After
12 Y.-D. Kwon, J. Son and J.-H. Chun, J. Org. Chem., 2019, 84
,
7
3678.
13 (a) B. H. Rotstein, N. A. Stephenson, N. Vasdev and S. H. Liang,
potassium fluoride under copper-catalysed conditions to form
para-fluorinated aromatics 12 in good yields (61-87%).
Nat. Commun., 2014,
5
, 4365; (b) J. Cardinale, J. Ermert, S.
, 17293; (c) M.
Humpert and H. H. Coenen, RSC Adv., 2014,
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B. Haskali, S. Telu, Y.-S. Lee, C. L. Morse, S. Lu and V. W. Pike,
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Conflicts of interest
There are no conflicts to declare.
14 (a) G. C. Geary, E. G. Hope, K. Singh and A. M. Stuart, Chem.
Commun., 2013, 49, 9263; (b) G. C. Geary, E. G. Hope, K. Singh
and A. M. Stuart, RSC Adv., 2015, 5, 16501; (c) G. C. Geary, E.
G. Hope and A. M. Stuart, Angew. Chem. Int. Ed. Engl., 2015,
54, 14911; (d) H. Minhas, W. Riley, A. M. Stuart and M.
Urbonaite, Org. Biomol. Chem., 2018, 16, 7170.
Acknowledgements
AMHA would like to thank The Higher Committee for Education
Development in Iraq (HCED) and the University of Al-Qadisiyah
for the PhD scholarship.
15 (a) N. O. Ilchenko, B. O. A. Tasch and K. J. Szabó, Angew. Chem.
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