Tetramethylammonium fluoride tetrahydrate-mediated transition metal-free coupling of aryl iodides with unactivated arenes in air

Article abstract of DOI:10.1248/cpb.c19-00452

Biaryls are important compounds with widespread applications in many fields. Tetramethylammonium fluoride tetrahydrate was found to promote the biaryl coupling of aryl iodides bearing electron-withdrawing substituents with unactivated arenes. The reaction takes place at temperatures between 100 and 150°C and can be applied to a wide range of aromatic and heteroaromatic rings, affording the products in moderate to high yields. The reaction does not require strong bases or expensive additives that are employed in the existing methods and can be conducted in air and moisture without any precautions.

Full text of DOI:10.1248/cpb.c19-00452

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Vol. 67, No. 10
Communication to the Editor
homolytic aromatic substitution (HAS) mechanism, wherein
the aryl radicals generated by dehalogenation of haloarenes
add to the unactivated arenes to afford cyclohexadienyl-type
radicals. These radicals almost always undergo rearomatiza-
tion (Chart 1). Furthermore, base-mediated biaryl coupling
reactions that proceed via benzyne26–28) or radical reaction
mechanism have been developed recently. As a pioneering
work of biaryl synthesis via radical pathway, in 2008, Itami
and colleagues presented a t-BuOK-mediated biaryl coupling
of aryl halides and electron-deficient heterocycles involv-
ing base-promoted homolytic aromatic substitution (BHAS),
in which strong bases acted as a single electron donor to
haloarenes, resulting in the generation of aryl radicals.29)
The subsequent works30–51) reported that some additives,
such as 1,10-phenanthroline,30,32,40,50) 1,2-dimethylethylenedi-
Tetramethylammonium Fluoride
Tetrahydrate-Mediated Transition
Metal-Free Coupling of Aryl Iodides
with Unactivated Arenes in Air
Kanako Nozawa-Kumada,* Kosuke Nakamura,
Satoshi Kurosu, Yuki Iwakawa, Charline Denneval,
Masanori Shigeno, and Yoshinori Kondo*
Graduate School of Pharmaceutical Sciences, Tohoku University;
6–3 Aoba, Aramaki, Aoba-ku, Sendai 980–8578, Japan.
Received May 29, 2019; accepted July 22, 2019
Biaryls are important compounds with widespread applica-
tions in many fields. Tetramethylammonium fluoride tetrahy- amine,31) proline,37) alcohols,42,49)p-tolylsulfonyl hydrazide,44)
and urea51)etc. were effective in the coupling reaction in
drate was found to promote the biaryl coupling of aryl iodides
bearing electron-withdrawing substituents with unactivated
arenes. The reaction takes place at temperatures between 100
and 150°C and can be applied to a wide range of aromatic
and heteroaromatic rings, affording the products in moderate
to high yields. The reaction does not require strong bases or
expensive additives that are employed in the existing methods
and can be conducted in air and moisture without any pre-
cautions.
the presence of an inorganic base (t-BuOK or t-BuONa).
Other base-mediated coupling such as CsOH-52) and lithium
bis(trimethylsilyl)amide (LiHMDS)-53)mediated coupling reac-
tions have also been reported. Although these methods are
efficient for the construction of biaryls, most of these reactions
require to be conducted under an inert atmosphere because of
the strong bases. In 2014, Ryu and colleagues reported that
the Bu4NBH3CN-mediated biaryl synthesis under photoirra-
diation in air proceeded via a BHAS-based mechanism.54) It
is considered that the reaction is promoted by oxygen. In the
same year, Guo and colleagues developed the photoinduced
coupling reaction in air using a catalytic amount of N,N,N′,N′-
tetramethylethylenediamine (TMEDA).55) Though the reac-
Key words biaryl; tetramethylammonium fluoride tetrahy-
drate; transition-metal-free coupling
Introduction
Biaryls, compounds containing the aryl–aryl bond, are used tions can be easily carried out in air, such reactions have been
in various fields such as pharmaceuticals, agrochemicals, and rarely reported (Chart 2).
materials science.1,2) Hence, much effort has been devoted
Our group has developed transition metal-free reactions in-
to the development of new synthetic methods for these com- volving C–C bond formation by amide bases generated in situ
pounds. To date, transition metal-catalyzed cross-coupling from fluoride and aminosilane.56–61) Very recently, we reported
reactions have been the most commonly employed method to the amide base-mediated biaryl coupling of aryl iodides and
prepare biaryls via C–C bond formation.3–5) However, these arenes.62) Tetramethylammonium fluoride (TMAF) and hexa-
methods require organometallic reagents, which are usually methyldisilazane (HMDS) were used to generate the amide
unstable and need to be synthesized first. For instance, the base in situ. During the investigation, it was found that the
direct C–H arylation of arenes with aryl halides has attracted coupling of 2-nitroiodobenzene with benzene was driven by
considerable attention, and the synthesis has been extensively TMAF in the absence of HMDS. It has already been reported
reported using several transition metals (Pd, Rh, Ru, Ir, and that the dehalogenation of 2-nitrohalobenzenes proceeds with
Cu).6–16) However, the development of cheap and environment- CsF in N,N-dimethylformamide (DMF) via a single electron
friendly methods is in high demand.
transfer to the substrate63); however, a coupling reaction with
As an alternative method, a transition metal-free coupling arenes in the presence of fluoride has not yet been developed.
of haloarenes with unactivated arenes for the construction In this study, we further investigated the coupling of aryl
of biaryls has been achieved using radical sources such as iodides with unactivated arenes using a fluoride, wherein
Bu3SnH and (Me3Si)3SiH.17–25) The reaction proceeds via a the unactivated arenes acted as the solvents. The reaction
Chart 1. Transition Metal-Free Biaryl Synthesis via HAS
*To whom correspondence should be addressed. e-mail: kumada@m.tohoku.ac.jp; ykondo@m.tohoku.ac.jp
© 2019 The Pharmaceutical Society of Japan

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Chem. Pharm. Bull.
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Table 2. Coupling Reaction of Aryl Iodides with Unactivated Arenes
Chart 2. This Work
Table 1. Effects of Reaction Conditions on the Formation of the Biaryl
Product
Entry
Fluoride (equiv.)
Yield (%)[a]
1[b]
2[b]
3
TMAF (3.0)
TMAF⋅4H2O (3.0)
TMAF⋅4H2O (3.0)
TMAF⋅4H2O (3.0)
TBAF⋅3H2O (3.0)
KF (3.0)
30
30
82(74)[c]
4[d]
76
50
0
5
6
7
CsF (3.0)
0
8
TMAF⋅4H2O (1.0)
TMAF⋅4H2O (2.0)
TMAF⋅4H2O (3.0)
38
45
23
9
10[e]
[a] Determined by 1H-NMR using 1,1,2-trichloroethane as an internal standard. [b]
Carried out under Ar atmosphere. [c] Isolated yield is given in parentheses. [d] Car-
ried out under O2 atmosphere. [e] Reaction temperature=100°C.
proceeded smoothly in air in the presence of tetraalkylam-
monium fluoride hydrate. This method did not require strong
bases or expensive additives and could be conducted in air
and moisture without any precautions.
Results and Discussion
We first studied the coupling of the substrate 2-nitroiodo-
benzene, 1a, with benzene as solvent (Table 1). When the
coupling reaction was conducted in Ar atmosphere in the
presence of TMAF, which was used as a fluoride source in our
previous work,62) biaryl product 2a was obtained in low yield
(entry 1). The use of TMAF·4H2O, which is air stable, gave
the same yield (entry 2). Subsequently, the reaction was car-
ried out in air using TMAF·4H2O, and this improved the yield
of 2a (entry 3). The yield of 2a was higher in O2 atmosphere
as compared with that in Ar atmosphere, suggesting that O2
promoted the desired reaction (entry 4).24,54) The reaction
could also be carried out effectively in air in the presence of
tetrabutylammonium fluoride trihydrate (TBAF·3H2O) (entry
5). However, the reaction did not proceed at all in the presence
[a] Reaction conditions: 1 (0.20mmol), 2 (1.0mL), TMAF·4H2O (0.60mmol),
120°C, 24h, air. [b] Reaction temperature=150°C. [c] With BHT (3.0eq) and
K2CO3 (1.2eq) at 110°C. [d] o:m:p=1.0:0.37:0.41. [e] o:m:p=1.0:1.4:1.0. [f]
C1:C2=1.0:0.34. [g] C1:C2=1.0:1.5. [h] Reaction temperature=100°C.
of alkali metal fluorides (entries 6 and 7). A drop in the yield with benzene proceeded by the aromatic nucleophilic substitu-
was observed on reducing the amount of TMAF·4H2O (entries tion of the substrate with the hydroxide ion (OH−) and resulted
8 and 9). In addition, lowering of the reaction temperature to in the formation of 4-nitrophenol in 70% yield. The addition
100°C decreased the yield (entry 10).
of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) and K2CO3 could
Next, we investigated the substrate scope of the reaction prevent this undesirable reaction, and the yield of the biaryl
using the optimal reaction conditions (Table 2). The coupling product 2c was increased (entry 3).
of 3-iodonitrobenzene 1b with benzene required higher tem-
When iodobenzonitriles were employed, the reactions pro-
peratures (entry 2). The coupling of 4-iodonitrobenzene 1c ceeded at 150°C in low yields (entries 4 and 5). We further in-

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Acknowledgments This work was financially supported
by the Japan Society for the Promotion of Science (JSPS)
KAKENHI Grant No. 17K15418. This work was also support-
ed by Grand for Basic Science Research Projects from The
Sumitomo Foundation, the Platform Project for Supporting
Drug Discovery and Life Science Research funded by Japan
Agency for Medical Research and Development (AMED),
Tohoku University Center for Gender Equality Promotion
(TUMUG), and Morinomiyako Project for Empowering
Women in Research.
Conflict of Interest The authors declare no conflict of
interest.
Supplementary Materials The online version of this ar-
ticle contains supplementary materials.
Chart 3. Intramolecular Cyclization of Aryl Halides
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