O-arylation of iodophenols with 2-fluorobenzaldehyde under microwave conditions

Article abstract of DOI:10.2174/15701808113106660096

The arylation of 4-iodo-, 2-iodo- and 3-iodophenols with 2-fluorobenzaldehyde may be carried out in the presence of K₂CO ₃ in DMF as the solvent under microwave conditions. The arylation of 4-iodophenole was promoted by the use of triethylbenzylammonium chloride (TEBAC) as the phase transfer catalyst. In the other model reactions, the use of TEBAC was harmful. By-products formed by isomerization and disproportionation were also detected.

Full text of DOI:10.2174/15701808113106660096

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114
Letters in Drug Design & Discovery, 2014, 11, 114-120
O-Arylation of Iodophenols with 2-Fluorobenzaldehyde Under Microwave
Conditions
Erika Bálinta, Mónika Kállaib, Orsolya Kovácsb, Hedvig Bölcskeic and György Keglevichb,*
aMTA-BME Research Group for Organic Chemical Technology, 1521 Budapest, Hungary
bDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest,
Hungary
cGedeon Richter Plc., 1475 Budapest 10, PO Box 27, Hungary
Abstract: The arylation of 4-iodo-, 2-iodo- and 3-iodophenols with 2-fluorobenzaldehyde may be carried out in the pres-
ence of K2CO3 in DMF as the solvent under microwave conditions. The arylation of 4-iodophenole was promoted by the
use of triethylbenzylammonium chloride (TEBAC) as the phase transfer catalyst. In the other model reactions, the use of
TEBAC was harmful. By-products formed by isomerization and disproportionation were also detected.
Keywords: 2-Flourobenzaldehyde, Iodophenols, Arylation, Microwave, Phase transfer catalysis.
1. INTRODUCTION
the non-opioid analgesic “2-[3-(3-chloro-5-fluorophenoxy)-
phenyl]-pyrimidine-4-carboxamide” (II) [4] and others (e.g.
III) [5] were also described. These compounds are NaV1.2
sodium channel blockers. Later further derivatives of VGSC
blockers were published, where the phenoxyphenyl moiety
was combined with a substituted pyridine unit IV and V [6,
7] and other derivatives were also described [8-10]. The
main diseases areas were ischemic neuronal damage, neu-
rodegenerative problems, Alzheimer’s disease, amyotrophic
lateral sclerosis (ALS), Parkinson’s disease, various types of
pain, manic depression.
Phenoxyphenyl moieties are useful building blocks in the
field of voltage gated sodium channel (VGSC) blockers. For
example’s sake the well-known analgesic and antiepilepti-
cum I was synthesized by the O-arylation of 4-fluorophenol
with 4-F-benzaldehyde in N,N-dimethylacetamide heating
with K2CO3, the next step was the reaction with semicar-
bazide hydrochloride and NaOAc refluxing in EtOH/H2O [1,
2]. Ilyin and his coworkers studied I as a state dependent
blocker of mammalian voltage gated sodium channels [3].
F
NH
NH2
N
N
O
F
NH
O
N
I
CONH2
O
O
IV
N
Cl
O
N
N
O
NH2
F
II
F
N
N
F
O
N
O
V
O
Compounds with phenoxyphenyl moiety containing a
thiazolodione unit (VI) was also introduced [11]. The indica-
tions were various types of pain, irritable bowel syndrome
(IBS), epilepsy, etc.
III
Compound I became a starting point for further VGSC
blockers. Later its ring closed derivatives [4, 5], including
O
F
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and Eco-
nomics, 1521, Budapest, Hungary; Tel: 36-1-4631111/5883;
N
S
O
Fax: 36-1-4633648; E-mail: gkeglevich@mail.bme.hu
O
VI
1875-628X/14 $58.00+.00
©2014 Bentham Science Publishers

O-Arylation of Iodophenols
Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1 115
MW
T, 2 h
TEBAC
K2CO3
O
O
O
O
OH
O
O
F
O
+
1.05
+
+
+
solvent
I
I
I
2
3
4
1
OH
O
OH
OH
I
O
I
+
+
+
I
I
I
7
5
6
8-1
Scheme (1). O-Arylation of 4-Iodophenol (1) Under MW Conditions.
Microwave (MW) irradiation [12–14] and phase transfer
catalysis (PTC) [15] represent attractive methods in
environmentally friendly chemistry. A few O-alkylations of
phenol derivatives were described, where there was no need
to use a phase transfer catalyst under MW irradiation [16–
19]. It is noted that MW-assisted heterogeneous phase C-
alkylations did not require the use of phase transfer catalyst
either [20-24]. However, in most cases, the combination of
the MW and phase transfer catalytic techniques offered
additional advantages [25]. Both S–L and L–L two phase
alkylations of phenols were performed under combined
MW–PTC techniques, the former using K2CO3/KOH [26] or
K2CO3/NaOH [27] without any solvent, the latter utilizing
NaOH/H2O [28]. We found that in the S–L phase alkylation of
phenols applying K2CO3 under solvent-free conditions, MW
and PTC synergized each other [29, 30]. This was also true for
other O-alkylations [31, 32]. Applying alkyl halides, the
situation was similar for the O-alkylation of naphtholes. How-
ever, the benzylations could be performed best in acetonitrile
solutions in the absence of phase transfer catalyst [33].
product (4) and 8% of the diiodo components (5). The ethers
2-5 all together represented 62%. The remaining 38%
covered 19% of unreacted 4-iodophenol (1), 8% of 2-
iodophenol (6) and 11% of phenol (7) (Table 1/Entry 1). The
use of 5% or 10% of TEBAC, on the one hand, increased the
proportion of the desired diaryl ether (2) to 46% and 65%,
respectively, on the other hand led to “cleaner” reactions.
The different mono- and diiodo isomers 3 and 5 represented
only 6/7%, and no dehalogenated product (4) could be
detected (Table 1/Entries 2 and 3). However, the conversions
remained incomplete. The thermal comparative experiment
led to a lower conversion (41%), but in respect of the diaryl
ethers, the reaction was more selective: beside the 41% of 2,
only 7% of the diiodo components (5) were formed (Table
1/Entry 4). Elevation of the reaction temperature to 140 °C
led to a complex mixture containing almost all possible
components (2-5, 1, 6 and 7) in quantities of 6-36% (Table
1/Entry 5). Then, we performed the arylations in solvents. In
acetonitrile, again a complex mixture was obtained, no mat-
ter if 5% of TEBAC was added in or not. The only positive
observation was that the proportion of the diaryl ether
products (2-5) amounted to 85% (Table 1/Entry 6). The use
of DMF as the solvent, especially in the presence of
increasing amount of TEBAC was very efficient (Table
1/Entries 7-9). The proportion of the expected product 2 in
the presence of DMF as the solvent was 67% (Table 1/Entry
7). Adding 5% and 10% of the catalyst, the proportion of
iodophenyl 2-formylphenyl ether 2 was 80% and 92%, re-
spectively (Table 1/Entries 8 and 9). In the latter case, only
8% of the 2-iodo isomer (3) was present as an additional
component meaning that the best option is to carry out the
reaction in the presence of K2CO3 and 10% of TEBAC in
DMF at 120 °C. The thermal control experiment gave ether
(2) in a conversion of 76%. It is noteworthy that only 24% of
unreacted 4-iodophenol (1) was present beside product 2
(Table 1/Entry 10). However, the conversion remained un-
changed even after a prolonged heating.
In this paper, the arylation of 4-, 2- and 3-iodophenols is
studied with 2-fluorobenzaldehyde under MW and PTC
conditions.
2. RESULTS AND DISCUSSION
The first model reaction was the arylation of 4-
iodophenol (1) with 2-fluorobenzaldehyde in the presence of
K2CO3 with or without triethylbenzylammonium chloride
(TEBAC) in the absence or presence of solvent under MW
conditions. In general, it was found that beside the expected
4-iodophenyl 2-formylphenyl ether (2), the 2-iodo isomer
(3), the dehalogenated ether (4) and variations of the diiodo
ethers (5) were also formed (Scheme 1). The unreacted 4-
iodophenol (1) appeared also as 2-iodophenol (6), phenol (7)
and, in a few cases, as diiodophenols (marked generally by
structure 8).
The composition of the reaction mixtures depended on
the conditions: the use of catalyst and solvent, as well as
temperature (Table 1). Carrying out the arylation at 120 °C
for 2 h without TEBAC and solvent, a quite complex
mixture was formed including 42% of the expected product
(2), 4% of the 2-iodo isomer (3), 8% of the dehalogenated
One can see that especially the solvent-free and MW-
assisted arylations were complicated by isomerization and
disproportionation side reactions. The 4-iodophenyl product
(2) could be isomerized to the 2-iodo species (3) and the
expected product (2) could be disproportionated to

116 Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1
Bálint et al.
Table 1. O-Arylation of 4-Iodophenol (1) Under MW and Thermal Conditions.
Composition of the Reaction Mixtures (%)a
ꢀ
Mode of
Heating
T
Entry
TEBAC
Solvent
ꢀ
(°C)
2
3
4
5
1
6
7
8-1
ethers
phenols
1
2
MW
MW
MW
ꢀ
–
5%
10%
10%
–
–
–
120
120
120
120
140
120
120
120
120
120
42
46
65
41
36
48
67
80
92
76
4
3
8
0
8
3
5
7
6
5
1
2
0
0
62
52
19
21
15
30
8
8
8
2
4
8
8
2
2
0
0
11
12
5
0
7
38
48
28
52
40
15
22
9
3
–
2
0
72
6
4
–
0
0
48
8
10
0
5
MW
MW
MW
MW
MW
ꢀ
–
6
12
18
9
60
24
5
6
–
MeCN
DMF
DMF
DMF
DMF
14
1
85b
78
2
0
7
–
14
4
4
2
8
5%
10%
10%
2
7
91
2
1
9
8
0
100
76c
0
0
0
0
10
0
0
24
0
0
24
aOn the basis of GC and GC-MS measurements.
bNo change in the presence of 5% of TEBAC.
cNo change after a prolonged reaction time of 3 h.
MW
120 °C, 2 h
TEBAC
K2CO3
O
O
O
O
OH
O
O
F
O
I
1.05
+
+
+
+
solvent
I
I
3
6
2
4
O
OH
OH
OH
I
O
+
+
+
I
I
I
I
5
7
1
8-2
Scheme (2). O-Arylation of 2-Iodophenol (6) Under MW Conditions.
dehalogenated ether 4 and to diiodo derivatives 5. The same
kind of side reactions occurred with 4-iodophenol (1) to
form by-products (6-8). It is also obvious that the presence
of TEBAC, and what is more important, the use of DMF as
the solvent promoted a clear-cut, quite selective arylation.
Without MW irradiation no complete conversion could be
attained. The thermal experiments were more selective, but
led to incomplete conversions. Hence, the positive role of
MW irradiation is unambiguous.
The results are listed in Table 2. Regarding the solvent-
free accomplishments, the composition was more favourable
in the absence of TEBAC as compared to the case when it
was present. In the absence of catalyst, 50% of the expected
product (3) was formed along with a 29% portion of the
other diaryl ethers (2, 4 and 5) (Table 2/Entry 1). At the
same time, in the presence of TEBAC, 32% of product 3 and
11% of diaryl ethers 2, 4 and 5 were formed (Table 2/Entry
2). It can also be seen that without the catalyst, the ratio of
the phenolic components (6, 1, 7, and 8) was 21%, while
with TEBAC, the proportion of phenols was 57%. All these
experiences suggests that in contrast with the reaction of 4-
iodophenol (1), in the case of the arylation of 2-iodophenol
(6), the presence of TEBAC is harmful, as less of the
expected diaryl ether (3) was formed. In acetonitrile without
TEBAC, the 2-iodophenyl aryl ether 3 was formed in 55%,
while the other diaryl ethers (2, 4 and 5) only in a small
quantity (5%) (Table 2/Entry 3). In DMF, the arylation was
The next model reaction was the arylation of 2-iodophenol
(6) with the same arylating agent, 2-fluorobenzaldehyde. The
situation was similar to the previous case: beside the expected
product of 2-iodophenyl 2-formylphenyl ether (3), the 4-iodo
derivative (2), the dehalogenated and the diiodo products (4
and 5) were also formed as a result of isomerization and
disproportionation (Scheme 2). The 4-iodophenol (1), phenol
(7) and diiodophenols (8) were also formed.

O-Arylation of Iodophenols
Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1 117
Table 2. O-Arylation of 2-Iodophenol (6) Under MW Conditions.
Composition of the Reaction Mixtures (%)a
Entry
TEBAC
Solvent
ꢀ
ꢀ
3
2
4
5
6
1
7
8-2
ethers
phenols
1
2
3
4
5
6
–
5%
–
–
50
32
55
85
59
76
4
3
7
4
3
2
0
0
18
4
79
43
14
33
32
11
23
15
0
8
1
0
0
0
7
8
6
0
0
0
0
8
1
0
0
0
21
57
40
11
23
15
–
MeCN
DMF
DMF
DMF
1
1
60
–
-
2
89
5%
10%
14
0
0
73b
76b
0
aOn the basis of GC and GC-MS measurements.
bThe reaction mixture contained 4-9% of 2-iodophenyl benzyl ether.
MW
120 °C, 120 min
TEBAC
O
O
OH
F
O
K2CO3
1.05
+
solvent
I
9
I
10
Scheme (3). O-Arylation of 3-Iodophenol (9) Under MW Conditions.
Table 3. O-Arylation of 3-Iodophenol (9) Under MW Conditions.
Composition of the Reaction Mixture (%)a
Entry
TEBAC
Solvent
Unknown
by-product
9
10
1
2
3
4
–
5%
–
–
–
14
30
27
9
80
66
6
4
–
–
MeCN
DMF
73
–
89b
aOn the basis of GC and GC-MS measurements.
bThe reaction mixture contained 2% of 2-phenoxy benzaldehyde (4).
more selective and the conversion was higher. 85% of
product 3 was formed at a conversion of 89% (Table 2/Entry
4). It was not, however, possible to obtain a complete
conversion. It was also observed that performing the O-
arylation in the presence of TEBAC, the proportion of the
main product (3) and the conversion were somewhat lower
(Table 2/Entries 5 and 6). Moreover, a new by-product 2-
iodophenyl benzyl ether coming from the reaction of 2-
iodophenol with TEBAC was also formed. It is again seen
that the catalyst does not enhance a complete and clear-cut
arylation.
presence of the catalyst. In the present stage of our work, the
reason for this experience is unknown.
The last series of reaction involved the arylation of 3-
iodophenol (9). As compared to the previous models, this
reaction way much simpler (Scheme 3). Only a few by-
products were formed and identified.
In the absence of catalyst and solvent, 80% of the
expected product, 3-iodophenyl 2-formylphenyl ether (10)
was formed. The conversion was 86% (Table 3/Entry 1). In
the presence of TEBAC, the proportion of 10 and the con-
version were lower (Table 3/Entry 2). In acetonitrile solution
without catalyst, 73% of diaryl ether 10 was formed without
any by-product (Table 3/Entry 3). The best experiment was,
when the arylation was performed in DMF. This occasion,
the main product (10) was formed in 89%. Beside this, 9%
of the starting material (9) and 2% of 2-phenoxy
In the above series, the best reaction was when the two
reactants met in DMF solution in the absence of TEBAC. It
is surprising that while in the arylation of 4-iodophenol (1)
the use of TEBAC is clearly advantageous, the arylation of
2-iodophenol (6) becomes more complex and reluctant in the

118 Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1
Bálint et al.
OH
OH
OH
OH
I
120 °C, 2 h
+
+
I
I
I
7
1
6
8
Scheme (4). Disproportionation of 4-Iodophenol (1).
Table 4. Disproportionation of 4-Iodophenol (1) at 120 °C for 2 h.
K2CO3
TEBAC
(5%)
Entry
Mode of Heating
Solvent
1
6
7
8
(1 equiv.)
1
2
3
4
5
MW
ꢀ
+
+
–
–
–
–
–
+
–
15
17
29
27
0
41
33
0
15
23
0
–
MW
MW
MW
MeCN
MeCN
MeCN
100
51
+
+
13
11
21
19
15
17
53
benzaldehyde (4) formed by dehalogenation were present
(Table 3/Entry 4).
3. EXPERIMENTAL
3.1. General
It can be said that similarly to the case of the arylation of
2-iodophenol (6), the arylation of 3-iodophenol (7) is also
disfavored in the presence of TEBAC as the catalyst.
The chemicals were purchased from Sigma-Aldrich com-
pany.
The arylations were carried out in a CEM Discover [300
W] microwave reactor equipped with a pressure controller
using 20–30 W irradiation.
As it was stated above, the reaction mixtures were
analyzed by GC and GC-MS. Most of the results listed in
Tables 1–3 are the average of 2-3 independent experiments.
The main and desired iodophenyl 2-formylphenyl ethers 2, 3
and 10 were obtained by column chromatography from the
best experiments that were the runs marked by Table 1/Entry
9, Table 2/Entry 4 and Table 3/Entry 4, respectively. Diaryl
ethers 2, 3 and 10 were obtained in yields of 75-85% in pure
GC was carried out on an HP5890 series 2 GC-FID
chromatograph, using a 15 m ꢁ 0.18 mm Restek, Rtx-5
column with a film layer of 0.20 μm. The temperature of the
column was initially held at 40 °C for 1 min, followed by
programming at 25 °C/min. up to 300 °C, and a final period
at 300 °C (isothermal) for 10 min. The temperature of the
injector was 290 °C, and of the FID detector 300 °C. The
carrier gas was N2.
1
forms and were identified by 13C and H NMR, as well as
mass spectral data. Compound 2 was briefly mentioned in the
literature [34] without characterization, while species 10 was
1
characterized only by H NMR spectral data [35]. The other
GC-MS was also carried out on an Agilent 6890 N-GC-
5973 N-MSD chromatograph, using a 30 m ꢁ 0.25 mm
Restek, Rtx-5SILMS column with a film layer of 0.25 μm.
The initial temperature of column was 45 °C for 1 min, fol-
lowed by programming at 10 °C/min. up to 310 °C and a
final period at 310 °C (isothermal) for 17 min. The
temperature of the injector was 250 °C. The carrier gas was
He and the operation mode was splitless.
13C and 1H NMR spectra were obtained in CDCl3
solution on a Bruker AV-300 spectrometer operating at 75.5
and 300 MHz, respectively. Chemical shifts are downfield
relative to 85% H3PO4 and TMS.
components, formed in most of the cases as minor components,
were identified on the basis of mass spectrometry.
Finally, the isomerization and disproportionation reaction
of 4-iodophenol (1) was studied in “blinde probe”
experiments. The possible reaction course is shown in
Scheme 4. The results are summarized in Table 4. It can be
seen that disproportionation takes place both under MW ir-
radiation and on conventional heating, no matter if a solvent
is used or not. In acetonitrile, the conversion of 4-iodophenol
was only 51%. No transformation occurred in the absence of
K2CO3. The use of 5% of TEBAC did not affect the outcome
of the reaction. To the best of our knowledge, we are the first
to observe these troublesome side reactions. It is also noted
that in case of suitably fast concurrent arylations, the side
reactions may be depressed.
Mass spectra were obtained using a Q-TOF Premier mass
spectrometer in positive electrospray mode.
3.2. General Procedure for O-Arylation of Iodophenols
with 2-Fluorobenzaldehyde under MW Conditions
In conclusion, the arylations of iodophenols with 2-
fluorobenzaldehyde were optimized under MW conditions.
DMF as the solvent was advantageous in all cases, but
TEBAC as the phase transfer catalyst enhanced the arylation
only in the reaction with 4-iodophenol (1).
A mixture of 0.22 g (1.0 mmol) of 2-, 3- or 4-iodophenol,
0.11 mL (1.1 mmol) of 2-fluorobenzaldehyde, 0.14 g (1.0
mmol) of potassium carbonate and in certain cases 11.4 mg

O-Arylation of Iodophenols
Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1 119
(0.050 mmol) of TEBAC in a closed vial was irradiated in a
CEM Discover microwave reactor at 120-140 °C for 2 hours.
The reaction mixture was taken up in 25 mL of ethyl acetate
and the suspension was filtered. Evaporation of the volatile
components provided the crude product that was passed
through a thin (ca. 2–3 cm) layer of silica gel using ethyl
acetate as the eluant to give an oil that was analysed by GC–
MS or GC.
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(CDCl3): ꢂ 6.83 (d, J = 8.6 Hz, 2H, C2’H), 6.91 (d, J = 8.3
Hz, 1H, C3H), 7.23 (t, J = 7.6 Hz, 1H, C5H), 7.54 (t, J = 7.9
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Hz, 1H, C6H), 10.46 (s, 1H, C(O)H); [M+Na]+
346.9547, C13H9O2NaI requires 346.9545.
=
found
2-iodophenyl 2-formylphenyl ether (3) Yield: 75%; 13
C
NMR (CDCl3): ꢂ 89.2 (C2’), 117.3 (C6’), 120.5 (C3), 123.5
(C5), 126.3 (C1), 126.5 (C4’), 128.6 (C5’), 129.9 (C6), 135.7
1
(C4), 140.3 (C3’), 155.4 (C1’), 159.4 (C2), 189.3 (C=O); H
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403.
NMR (CDCl3): ꢂ 6.75 (d, J = 8.3 Hz, 1H, C6’H), 6.96 (d, J =
7.5 Hz, 1H, C3H), 6.99 (t, J = 7.9 Hz, 1H, C4’H), 7.20 (t, J =
7.4 Hz, 1H, C5H), 7.37 (t, J = 8.1 Hz, 1H, C5’H), 7.50 (t, J =
8.2 Hz, 1H, C4H), 7.91 (d, J = 7.8 Hz, 1H, C3’H), 7.97 (d, J =
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7.7 Hz, 1H, C6H), 10.59 (s, 1H, C(O)H); [M+Na]+
346.9551, C13H9O2NaI requires 346.9545.
=
found
3-iodophenyl 2-formylphenyl ether (10) Yield: 81%;
13C NMR (CDCl3): ꢂ 94.4 (C3’), 118.4 (C6’), 118.9 (C3),
124.0 (C5), 127.0 (C1), 128.1 (C2’), 128.7 (C5’), 131.3 (C6),
133.3 (C4’), 135.8 (C4), 157.0 (C1’), 159.0 (C2), 188.9 (C=O);
1H NMR (CDCl3): ꢂ 6.92 (d, J = 8.3 Hz, 1H, C6’H), 7.00–
7.14 (m, 2H, C3H, C5’H), 7.23 (t, J = 8.3 Hz, 1H, C5H), 7.41
(s, 1H, C2’H), 7.52 (t, J = 8.7 Hz, 1H, C4H), 7.56 (d, J = 7.4
Hz, 1H, C4’H), 7.94 (d, J = 7.7 Hz, 1H, C6H), 10.45 (s, 1H,
C(O)H); ꢂ[35] (CDCl3) 6.90-7.96 (m, 8H), 10.48 (s, 1H);
[M+Na]+found = 346.9551, C13H9O2NaI requires 346.9545.
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CONFLICT OF INTEREST
The authors confirm that this article content has no
conflicts of interest.
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ACKNOWLEDGEMENTS
The above project was supported by the Hungarian
Scientific and Research Fund (OTKA No K83118).

120 Letters in Drug Design & Discovery, 2014, Vol. 11, No. 1
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[28]
Received: September 24, 2013
Revised: October 21, 2013
Accepted: October 29, 2013