Efficient Suzuki-Miyaura mono-arylation of symmetrical diiodo(hetero)arenes

Article abstract of DOI:10.1016/j.tetlet.2018.04.015

A reliable protocol for converting 1,4-diiodo-2,3,5,6-tetrafluorobenzene into 1-(hetero)aryl-4-iodo-2,3,5,6-tetrafluorobenzene derivatives has been lacking in the literature. We have identified optimal conditions to achieve this conversion in good yields and have minimized formation of the bis-coupling product. The newly identified protocol involving the use of a syringe pump has been extended to other symmetrical diiodo(hetero)arenes.

Full text of DOI:10.1016/j.tetlet.2018.04.015

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient Suzuki-Miyaura mono-arylation of symmetrical diiodo(hetero)
arenes
Alexander Sapegin a, Mikhail Krasavin a,b,
⇑
a Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
b Immanuel Kant Baltic Federal University, Kaliningrad 236016, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A reliable protocol for converting 1,4-diiodo-2,3,5,6-tetrafluorobenzene into 1-(hetero)aryl-4-iodo-
2,3,5,6-tetrafluorobenzene derivatives has been lacking in the literature. We have identified optimal
conditions to achieve this conversion in good yields and have minimized formation of the bis-coupling
product. The newly identified protocol involving the use of a syringe pump has been extended to other
symmetrical diiodo(hetero)arenes.
Received 17 March 2018
Revised 30 March 2018
Accepted 9 April 2018
Available online xxxx
Ó 2018 Elsevier Ltd. All rights reserved.
Keywords:
Polyfluorinated aromatics
1,4-Diiodo-2,3,5,6-tetrafluorobenzene
Coupling reactions
Monocoupling
Halogen bond
Crystal engineering
1,4-Diiodo-2,3,5,6-tetrafluorobenzene (DITFB, 1) is a building
block of special significance for several reasons. Firstly, it is widely
used in the construction of polyfluorinated organic compounds.1
The latter have been employed as principal components of organic
light-emitting diodes,2 thin-film transistors,3 and various
supramolecular self-assembly systems.4 The 2,3,5,6-tetrafluo-
rophenyl moiety (which can be derived from DITFB) has been used
as powerful tag for observing intermolecular interactions by 19F
NMR.5 Oligomeric chains containing an array of 2,3,5,6-tetraflu-
oro-4-iodophenyl groups have been reported to efficiently trans-
port anions across lipid bilayer membranes.6 The most recent
and perhaps the most exciting applications of DITFB and its deriva-
tives is their use in the design and assembly of a special case of
so-called molecular containers, namely, halogen-bonded
supramolecular capsules with host-guest binding properties.7
Halogen bonds (XB) in general have been receiving increasing
attention in the last few years as a major non-covalent interaction
that can complement or be viewed as an alternative to hydrogen
bonds (HB).8 Similar to the latter, XB can help form novel crystal
structures9 and be involved in forming specific interactions of
small molecule ligands with their protein targets, which is
particularly important from a medicinal chemistry and drug design
perspective.10 This, in turn, requires
a wealth of validated
approaches to prepare various derivatives of DITFB. However, as
we recently demonstrated,1 reliable methods to derivatize 1 via
metal-catalyzed monocoupling reactions are surprisingly lacking
in the current literature. For instance, Suzuki-Miyaura monocou-
pling reactions (yielding 2) reported in the literature are always
accompanied by the formation of a significant amount of bis-
coupling product 3 (Fig. 1).11
Our recent interest in finding new ‘tamed’ solid forms of active
pharmaceutical ingredients via co-crystallization with halogen
bond donors such as DITFB and its derivatives drew our attention
to this obvious void in the current synthetic methodology. Herein,
we report an efficient protocol for a high-yielding Suzuki-Miyaura
monocoupling of DITFB with (hetero)arene boronic acids
and demonstrate its transferrability to other symmetrical diiodo
(hetero)arene substrates.
Our initial experiments towards finding the optimal conditions
for the Suzuki-Miyaura monocoupling were conducted with 1 and
⇑
Corresponding author at: Laboratory of Chemical Pharmacology, Institute of
Chemistry, Saint Petersburg State University, 26 Universitetskyi prospect, Peterhof
198504, Russian Federation.
E-mail address: m.krasavin@spbu.ru (M. Krasavin).
Fig. 1. DITFB and its derivatization via Suzuki-Miyaura coupling.
https://doi.org/10.1016/j.tetlet.2018.04.015
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sapegin A., Krasavin M. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.015

2
A. Sapegin, M. Krasavin / Tetrahedron Letters xxx (2018) xxx–xxx
Table 1
Screening of reaction conditions for the Suzuki-Miyaura coupling of DITFB.
Entry
Solvent
Base
T (°C)
1:4a
2a:3a
Yield 2a (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN/H2O (2:1)
MeCN/H2O (2:1)
MeCN/H2O (2:1)
MeCN/H2O (2:1)
MeCN/H2O (2:1)
MeCN/H2O (2:1)
THF
THF
THF
THF
MeOH
MeOH
MeOH
MeOH
i-PrOH
Na2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
LiOH
NaOH
K2CO3
Cs2CO3
LiOH
t-BuOK
Na2CO3
K2CO3
Cs2CO3
LiOH
77
77
77
77
77
77
77
77
77
70
70
70
55
70
70
70
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1.5:1
1.25:1
1.1:1
1.1:1
10:1
10:1
5:1
10:1
5:1
5
8
16
30
44
40
23
51
33
10
27
37
18
19
9
30
5:1
10:0.8
10:3
10:4.2
5:1
10:2.3
2:1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2:1
10:1
10:1
10:1.5
2:1
10:0.7
–
–
–
10:1
2:1
5:1
10:1
10:3
5:2
5:2
10:1
70
82
75
13
LiOH
Toluene
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
110
110a
100
100
100
100
95
No reaction
No reaction
No reaction
Toluene/MeOH
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane/H2O (2:1)
1,4-Dioxane/MeOH (2:1)
1,4-Dioxane/MeOH (2:1)
1,4-Dioxane/MeOH (2:1)
1,4-Dioxane/MeOH (2:1)
1,4-Dioxane/MeOH (2:1)
23
26
54
79
54
41
37
74
95
95
95
95b
a
Reaction conducted in a microwave reactor.
Solution of 4a in 1,4-dioxane added to the reaction mixture over 10 h using a syringe pump.
b
phenylboronic acid (4a) using 0.05 equiv. of Pd(PPh3)4 and 3 equiv.
of base. The influence of solvent, base and temperature were inves-
tigated using a 2-fold excess of 4a over 1 (Table 1, entries 1–25).
The use of aprotic solvents (MeCN, THF, 1,4-dioxane, toluene) led
to low conversions or no reaction at all. In the case of toluene, addi-
tion of MeOH did not improve the situation (Entry 20). The best
results were achieved in MeOH (Entry 17), aqueous MeCN (Entry
8), aqueous 1,4-dioxane (Entry 24) or 1,4-dioxane/MeOH (Entry
25). The latter experiment gave the best result and was further
optimized with the aim of lowering the excess of 1 used in the
reaction (Table 1, entries 26–29). Gradual lowering of the 1:4a
ratio, unfortunately, led to a similar drop in the 2a:3a ratio and
the isolated yield of 2a. However, when we chose to add a solution
of 4a in 1,4-dioxane to the reaction mixture slowly over 10 h using
a syringe pump, both the 2a:3a ratio and the isolated yield of 2a
improved. This approach only utilized a 10% excess of 1 (Entry
29). These conditions were considered optimal and were employed
to prepare other monoaryl derivatives of 1 while the reaction time
was shortened to 12 h (Table 2).12
Table 2
1-(Hetero)aryl-4-iodo-2,3,5,6-tetrafluorobenzenes 4a–4k prepared in this work.a,b
Entry
1
Ar(OH)2
Compound
Isolated yield (%)
74
2
3
79
61
The monocoupling reaction was largely unaffected by electronic
or steric effects as electron-rich (e.g., 4d) and electron-poor (e.g.,
4i) boronic acids as well as the ones possessing ortho-substituents
(4g and 4h) gave comparable results.
Encouraged by these results, we wondered if the same protocol
would be applicable to other symmetrical diiodo(hetero)arene
templates 5a–c. The results of these experiments are provided in
Please cite this article in press as: Sapegin A., Krasavin M. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.015

A. Sapegin, M. Krasavin / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2 (continued)
Table 3 (continued)
Entry
4
Ar(OH)2
Compound
Isolated yield (%)
77
Entry Substrate Ar(OH)2
Compound
Isolated
yield (%)
4
5a
70
5
6
7
54
54
50
5
6
7
5b
5b
5b
83
77
80
8
5b
69
9
5c
5c
64
67
8
62
10
9
73
59
11
12
5c
5c
51
42
10
a
11
57
Boronic acid was added via a syringe pump over 10 h.
<10% of the bis-coupling product formed in each reaction as judged by crude 1
b
H
NMR spectroscopy.
a
Table 3 and demonstrate the universal nature of this method,
involving the use of a syringe pump, for carrying out the Suzuki-
Miyaura monocoupling.
Boronic acid was added via a syringe pump over 10 h.
<10% of the bis-coupling product formed in each reaction as judged by crude 1
b
H
NMR spectroscopy.
In summary, we have reported a practical method to conduct
the Suzuki-Miyaura reaction of (hetero)arene boronic acids and
DITFB which provided good yields of the desired monocoupling
product and minimized (<10% by crude 1H NMR spectroscopy) for-
mation of the undesired bis-coupling by-product. These conditions
appear to be widely applicable as they provided good monocou-
pling product yields in case of other symmetrical diiodo (hetero)
arenes. The synthesized iodo-substituted biaryls will be tested as
halogen bond donors; the results of these studies will be reported
in due course.
Table 3
1-(Hetero)aryl-4-iodo-2,3,5,6-tetrafluorobenzenes 4a–4k prepared in this work.a,b
Acknowledgement
This work was supported by the Russian Science Foundation
(project grant 17-73-20185).
Entry Substrate Ar(OH)2
Compound
Isolated
yield (%)
1
2
3
5a
5a
5a
79
68
51
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.04.015.
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