Nickel-Catalyzed Electrochemical Reductive Homocouplings of Aryl and Heteroaryl Halides: A Useful Route to Symmetrical Biaryls

Article abstract of DOI:10.1055/s-0036-1589100

Due to their widespread presence in functional materials and pharmaceuticals, biaryls are of fundamental importance in organic chemistry. Methods for the synthesis of symmetrical biaryls generally involve both metallic reduction and transition-metal catalysis. In this work, we show that electroreduction can also constitute a very relevant way to achieve the nickel-catalyzed reductive synthesis of symmetrical biaryl compounds. Therefore, it is demonstrated that both aryl and heteroaryl halides undergo reductive coupling to furnish the corresponding symmetrical biaryls in fair to excellent yields. Reactions are performed under very mild conditions thus ensuring important functional group tolerance.

Full text of DOI:10.1055/s-0036-1589100

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
paper
A
en
R. Rahil et al.
Paper
Synthesis
Nickel-Catalyzed Electrochemical Reductive Homocouplings of
Aryl and Heteroaryl Halides: A Useful Route to Symmetrical
Biaryls
Rima Rahil
Stéphane Sengmany*
Erwan Le Gall
Eric Léonel*
Électrochimie et Synthèse Organique, Université Paris Est,
ICMPE (UMR 7182), CNRS, UPEC, 2–8 rue Henri Dunant,
94320 Thiais, France
sengmany@icmpe.cnrs.fr
leonel@icmpe.cnrs.fr
Received: 13.06.2017
Accepted after revision: 02.08.2017
Published online: 12.09.2017
tive conditions. Mostly employed reductants are finely dis-
persed metallic species like powdered manganese,10 mag-
nesium,11 or zinc.12 However, such methods can present
substantial drawbacks like stoichiometric use of transition-
DOI: 10.1055/s-0036-1589100; Art ID: ss-2017-n0393-op
Abstract Due to their widespread presence in functional materials and
pharmaceuticals, biaryls are of fundamental importance in organic
chemistry. Methods for the synthesis of symmetrical biaryls generally
involve both metallic reduction and transition-metal catalysis. In this
work, we show that electroreduction can also constitute a very relevant
way to achieve the nickel-catalyzed reductive synthesis of symmetrical
biaryl compounds. Therefore, it is demonstrated that both aryl and het-
eroaryl halides undergo reductive coupling to furnish the correspond-
ing symmetrical biaryls in fair to excellent yields. Reactions are per-
formed under very mild conditions thus ensuring important functional
group tolerance.
Me
OH
OH OH
O
HN
Me
Me
OH
OH OMe
HO
HO
O
O
Me
Me
OMe OH
HO
Me
Me
OH OH
O
Cephalochromine
(anti-tumor agent)
Key words homocoupling, electrochemistry, biaryl compounds, nick-
el, catalysis
NH
Michellamine B
(anti-HIV)
OH Me
Due to their ubiquitous presence in both natural and
synthetic compounds, biaryls play a pivotal role in modern
organic chemistry. In this context, symmetrical biaryls are
privileged structural motifs that are widely spread in func-
tional materials1 and natural products displaying biological
activities.2 They also find applications as useful building
blocks in multistep synthesis or as metal ligands in asym-
metric catalysis3 (Figure 1). These remarkable properties
have aroused intensive efforts from chemists to develop the
most efficient and straightforward ways to achieve Csp2–
Csp2 coupling. Therefore, since the seminal copper-mediat-
ed coupling reaction of aryl halides described by Ullmann
more than a century ago,4 a considerable number of works
have been reported for the synthesis of biaryls.5 Although
the oxidative C–C coupling of arylmetal reagents currently
represents a possible alternative to reductive couplings,6
most reported works involve homocouplings of aryl halides
or pseudo-halides using transition-metal catalysis, espe-
cially palladium,7 nickel,8 or cobalt catalysis,9 under reduc-
PPh2
PPh2
+
Me +N
Cl–
N
Me
Cl–
Paraquat
(herbicide)
BINAP
(ubiquitous chiral ligand)
O
O
O
O
O
O
O
O
OMe
O
O
O
O
CO2Me
Paracyclophane
(metallic cations complexant)
MeO2C
O
O
S
S
S
S
OMe
α-DDB
S
S
(hepatic disease treatment)
2,2'-Bidithieno[3,2-b:2',3'-d]thiophene
(organic conductor)
Figure 1 Applications of some selected symmetrical biaryl compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

B
R. Rahil et al.
Paper
Synthesis
metal species, long reaction times, mandatory thermal acti-
vation, or significant scope limitations. Therefore, general
and reliable methods allowing aryl halide Csp2–Csp2 homo-
coupling under mild conditions remain desirable. Although
electrochemical reduction potentially constitutes a very
relevant alternative to classical metallic reduction, only a
limited number of works describe the formation of sym-
metrical biaryls by electroassisted reductive coupling of
aryl halides or pseudo-halides.13 However, such methods
may also apply in a global perspective of waste reduction
and sustainable chemistry development. We reported re-
cently that cross-coupling reactions can be efficiently car-
ried out between aza-haloaromatic compounds and aryl or
heteroaryl halides using an electrochemical procedure em-
ploying a sacrificial anode and a nickel pre-catalyst.14 In
continuation of these works, we demonstrate herein that
electroreduction can represent a very mild alternative to
metallic reductants in nickel-catalyzed homocouplings of
aryl or heteroaryl halides leading to symmetrical biaryl
species.
The main objective of this work was to implement a
general method able to efficiently furnish symmetrical bi-
aryls starting from aryl or heteroaryl halides. For environ-
mental and economic reasons, the use of an only catalytic
amount of the transition-metal catalyst was a prerequisite
condition for the viability of the project. Therefore, optimi-
zation of the reaction conditions were carried out on 4-bro-
moanisole which was subjected to electrochemical reduc-
tion on nickel foam, at room temperature, using catalytic
amounts of nickel(II) complexes. The results are presented
in Table 1.
First experiments were carried out using DMF as the
solvent, Fe/Ni (64:36) as the anode and catalytic NiBr2·xH2O
as the pre-catalyst (Table 1, entries 1 and 2). Stoichiometric
LiCl was added to the reaction mixture. Indeed, it was antic-
ipated that LiCl could play a dual role in the reaction, firstly
Table 1 Optimization of the Electrochemical Homocouplinga
Ni foam cathode
anode, Ni catalyst
supporting electrolyte
MeO
Br
MeO
OMe
solvent, r.t.
constant current intensity
1c
Entry
Anode
Current intensity Solvent
(A)
Catalyst (mol%)
Supporting electrolyte Time (h)
(equiv)
Yield (%)b
1
2
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Fe/Ni
Inox
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NiBr2·xH2O (5)
NiBr2·xH2O (10)
NiBr2·xH2O (10)
NiBr2bpy (5)
LiCl (1)
3.5
3.5
5
–
–
LiCl (1)
3
NaI (1)
–
4
LiCl (1)
2.5
2
65
88
73
90
86
73
–
5
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
–
LiCl (1)
6
LiCl (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
NaI (0.5)
2
7
2
8
3
9
8
10
11
12
13
14
15
16
17
18
19
20
21
3.5
2.5
3
NiBr2·xH2O (10) + bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (10)
NiBr2bpy (5)
78
56
30
42
80
50
69
77
62
52
24
DMF/py (9:1)
MeCN
NMP
5
8
DMAc
PC
3
9
DMF
3
Fe
DMF
2.3
2
Zn
DMF
Ni
DMF
5
Fe
DMF
3
a Reaction conditions: metal rod anode, nickel foam cathode, 4-bromoanisole (5 mmol), supporting electrolyte (2.5–5 mmol), Ni complex (5–10 mol%), solvent
(40 mL), I = 0.05–0.2 A, r.t.
b Isolated yield.
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R. Rahil et al.
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Synthesis
by acting as a supporting electrolyte and secondly by stabi-
lizing the in situ generated organometallic species.15 Under
such conditions, no coupling product was observed in the
reaction mixture, all starting material remaining uncon-
verted. This was also the case with NaI as the supporting
electrolyte (entry 3). However, when NiBr2·xH2O was re-
placed by NiBr2bpy complex (5 mol%), good amounts of
coupling product were observed in the presence of stoichio-
metric LiCl (entry 4); by increasing NiBr2bpy to 10 mol%,
the yield increased to 88% (entry 5). A noticeable loss of ef-
ficiency was noticed when LiCl was lowered to 0.5 equiv
(entry 6). However, an important improvement of the reac-
tion efficiency was observed when LiCl was replaced by NaI
(entry 7). In this case, an excellent 90% chemical yield was
obtained using 0.5 equiv of NaI. It is obvious that under in-
tensiostatic conditions, modulation of the current intensity
could result in both chemical and faradic yields variations.
Therefore, current intensity was decreased successively to
0.1 A (entry 8) and 0.05 A (entry 9); in these cases, the
chemical yield slightly decreased whereas faradic yield re-
mained comparable. Given the noticeable rise of the reac-
tion time under these conditions, we chose to keep the
0.2 A intensity for the rest of the study. We next wanted to
ensure that the use of a catalyst is mandatory. Thus, a con-
trol experiment carried out without nickel salts resulted in
a failure; no coupling products were detected in the reac-
tion mixture (entry 10). Interestingly, the presence of water
was not identified as a possible reason for the failures re-
ported in entries 1–3. Indeed, an experiment involving Ni-
Br2·xH2O in the presence of additional 2,2′-bipyridine (bpy,
1:1) proceeded fairly well thus revealing that the presence
of a nickel ligand is a crucial element of the reaction system
(entry 11). In addition, the opportunity of operating from
simple commercial NiBr2·xH2O and additional bpy could
represent a very useful and reliable alternative to the use of
a preformed NiBr2bpy complex. In the following part of the
study, we assessed the effect of solvent nature on the fate of
the reaction (entries 12–16). Thus, while all the tested polar
solvents16 allow the electrochemical reaction to proceed,
heterogeneous results are obtained. For instance, these re-
sults indicate that N,N-dimethylacetamide (DMAc) can be
used in the process in replacement of DMF as well (cf. entry
15 with entry 7). It can also be noted that for toxicity and
ecological (bio-sourcing) reasons, propylene carbonate (PC)
can be favorably used as the solvent as well, albeit with
more limited yield (entry 16). Finally, we examined the ef-
fect of the anode nature on the reaction efficiency
(entries 17–20). Again, we observed that a range of metals
can be used as the anode material. However, it was noticed
that the use of iron affords the best result (entry 18). How-
ever, efficiency is strongly correlated with the amount of
NiBr2bpy in the reaction mixture. Indeed, a significant drop
of the reaction yield was observed when decreasing the
amount of NiBr2bpy from 10 mol% to 5 mol% (cf. entry 18
with entry 21). Other additional experiments (not reported
in Table 1) involved halides other than 4-bromoanisole.
Thus, we observe that no reaction occurs with 4-chloroan-
isole whereas a 67% yield is obtained with 4-iodoanisole as
the starting aryl halide. Consequently, an optimized proto-
col (corresponding to the conditions reported in entry 7)
was defined as follows: the aryl bromide is dissolved in
DMF and the electrochemical reactions are conducted at
room temperature in an undivided electrochemical cell fit-
ted with an iron/nickel rod, surrounded by a nickel foam as
the cathode, in the presence of NiBr2bpy (10 mol%) as a cat-
alyst precursor, and NaI (0.5 equiv) as the supporting elec-
trolyte, under a constant current intensity of 0.2 A.
The scope of the reaction with aryl bromides was exam-
ined under these optimized experimental conditions; the
results are presented in Table 2.
Table 2 Electrochemical Homocoupling of Aryl Halides: Scope of the
Reactiona
Ni cathode
Fe/Ni anode
NiBr2bpy (10 mol%)
X
NaI (0.5 equiv)
DMF, r.t., 0.2 A
FG
FG
FG
1a–o
Entry
ArX
Time (h)
Product
Yield (%)b
58
1
2
Br
I
4
3
1a
1a
56
77
90
56
Br
3
4
5
3
2
3
1b
1c
1d
Me
MeO
Br
Br
OMe
6
7
8
4
3
3
1e
1f
62
75
56
MeS
Me2N
F
Br
Br
Br
1g
Br
c
9
3.5
–
–
Cl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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Synthesis
Table 2 (continued)
the yield varies depending on the steric effect. Methyl 2-
bromobenzoate and 2-bromoanisole give moderate to good
yields (entries 5 and 12). In the case of 1-bromo-2-(trifluo-
romethyl)benzene, the coupling is less efficient probably
due to steric hindrance of trifluoromethyl group17 (entry
17). 1-Bromo-2-chlorobenzene affords the expected biaryl
as the minor product (entry 9). In this case, we noticed the
formation of a complex mixture due to further couplings
with dichlorobiphenyl, leading to oligomeric products bear-
ing 3 to 4 aromatic rings. This result is quite surprising as it
indicates that under these conditions, aromatic C–Cl bond
is activated by nickel hence contradicting one of our prelim-
inary experiments revealing that chlorobenzene is ineffi-
cient in the reaction (see above).
Extension of the reaction to heteroaryl halides required
additional experiments. Indeed, the electrochemical proce-
dures proved more substrate-dependent than with aryl ha-
lides, particularly in regard with the nature of the heteroat-
om and the position of the halogen. Results are presented in
Table 3.
Entry
ArX
Time (h)
Product
Yield (%)b
76
10
EtO2C
Br
2.5
2.5
1h
Br
11
1i
73
MeO2C
Br
CO2Me
12
13
14
3
2
2
1j
80
54
51
1k
1l
NC
Br
Br
NC
Br
15
16
17
2
1m
1n
1o
52
87
34
Table 3 Electrochemical Homocoupling of Heteroaryl Halidesa
MeOC
F3C
Ni cathode
Fe/Ni anode
NiBr2bpy (10 mol%)
Br
3
X
Het
Het
Het
NaI (0.5 equiv)
DMF, r.t., 0.2 A
FG
FG
FG
1p–t
Br
CF3
Entry
1
HetArX
Time (h)
Product
Yield (%)b
43 (48)c
3.5
Br
5
3
1p
a Reaction conditions: iron/nickel (64:36) rod anode, nickel foam cathode,
aryl halide (5 mmol), NaI (2.5 mmol), NiBr2bpy complex (10 mol%), DMF
(40 mL), I = 0.2 A, r.t.
S
b Isolated yield.
Br
2
3
1q
18 (51)c
c Product not isolated (complex mixture).
N
N
2.5
2
–
– (trace)c
Cl
Br
As previously indicated, the use of aryl iodides proved
possible, as attested by the similar yields obtained starting
from bromobenzene (Table 2, entry 1) and iodobenzene
(entry 2). However, for commercial availability and eco-
nomic reasons, most of the following experiments were
carried out starting from bromides. The reaction proved
general and exhibited good functional tolerance given the
possible use of a large range of substituted aryl halides. In-
deed, aryl bromides bearing alkyl (entry 3), ether (entries 4
and 5), thioether (entry 6), amine (entry 7), halide (entries
8 and 9), ester (entries 10–12), nitrile (entries 13 and 14),
ketone (entry 15), or trifluoromethyl (entries 16 and 17)
groups (or functions) undergo the reaction in fair to excel-
lent yields. Such an extended range of electron-donating or
electron-withdrawing groups likely indicates that the reac-
tion is not under electronic control. The position of the sub-
stituent at meta and para position has little influence on
the fate of the reaction (cf. entries 10 and 11 with 13 and
14). However, when the substituent is at the ortho position,
N
N
N
4
5
1r
1s
30 (58)c
– (18c, 64d)
MeO
Cl
2
N
N
Cl
6
2
1t
63 (91)c
N
a Reaction conditions: iron/nickel (64:36) rod anode, nickel foam cathode,
heteroaryl halide (5 mmol), NaI (2.5 mmol), NiBr2bpy complex (10 mol%),
DMF (40 mL), I = 0.2 A, r.t.
b Isolated yield.
c Supporting electrolyte = LiCl (2.5 mmol), DMF/pyridine (9:1).
d Reaction conditions: iron/nickel (64:36) rod anode, nickel foam cathode,
3-chloro-6-methoxypyridazine (10 mmol), Bu4NBr/Bu4NI (1:1, 0.2 mmol),
NiBr2·xH2O (5 mol%), DMF/pyridine (50:50, 50 mL), I = 0.05 A, r.t.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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Starting from heteroaryl halides and using NaI as the
supporting electrolyte, the coupling was achieved with 3-
bromothiophene (Table 3, entry 1), 3-bromopyridine
(entry 2), 5-bromopyrimidine (entry 4), and 2-chloroquin-
oline (entry 6) in low to fair yield. However, 2-chloropyra-
zine (entry 3) and 3-chloro-6-methoxypyridazine (entry 5)
did not furnish the corresponding biaryl compounds. Sur-
prisingly, a significant improvement of the reaction could
be observed by using a DMF/pyridine (9:1) medium (in-
stead of DMF alone) as the reaction solvent in conjunction
with LiCl as the supporting electrolyte (instead of NaI). In
most cases, yields could be significantly increased under
these conditions even if the formation of the bipyridazine
1s remained difficult to achieve and required the use of
more specifically optimized reaction conditions to increase
the reaction yield up to 64% (entry 5).
The noticeable improvement of the reaction efficiency
in a DMF/pyridine medium, especially with nitrogen-con-
taining compounds, may likely indicate that competitive
complexation of nickel occurs in the presence of the newly
formed azaaromatic biaryl compounds which are likely
bind to nickel and lock the overall catalytic cycle. Pyridine
may probably act as suitable nickel ligand and would dis-
place the azaaromatic biaryl compounds hence restoring
the catalytic activity of nickel.
Ar[Ni]III(X)Ar complex (step d). A reductive elimination
(step e) furnishes the desired coupling product Ar-Ar. This
event would also furnish a [Ni]IX species, which is further
reduced electrochemically to regenerate [Ni]0 (step f).
In conclusion, the electrochemical method presented
herein for the electrochemical homocoupling of aryl or het-
eroaryl halides appears as a relevant and reliable alternative
to the more conventional corresponding chemical reaction.
Main features of the electrochemical process are important
functional group tolerance, limited reaction times, no req-
uisite thermal activation, and possible use of only catalytic
amounts of the transition metal for catalysis.
Solvents and reagents were purchased from commercial suppliers
and were used without further purification. (2,2′-Bipyridine)nickel
bromide (NiBr2bpy) was prepared from NiBr2·xH2O and 2,2′-bipyr-
idyl.19 Reactions were monitored by gas chromatography (GC) using a
chromatograph fitted with a capillary column (l = 5 m, i.d. = 0.32 mm,
depth of film (d.f.) = 0.5 μm). Melting points (mp) were measured in
unsealed capillary tubes. Infrared spectra (FTIR) were recorded in ATR
mode. NMR spectra were recorded in CDCl3 at 400 MHz (1H), 100
MHz (13C), and 376 MHz (19F). NMR spectra were calibrated using the
residual solvent signal. Mass spectra [MS in electron-impact (EI+) ion-
ization mode] were measured with a GC-MS spectrometer fitted with
a capillary column (l = 25 m, i.d. = 0.25 mm, d.f. = 0.25 μm). Purifica-
tion was carried out manually by flash chromatography on silica gel
(70–200 μm). Compounds that have been previously described in the
literature are linked to the corresponding bibliographic references
and their CAS registry number.
We have recently confirmed by cyclic voltamperometry
the presence of [Ni]I complexes in related electrochemical
mechanisms leading to dissymmetrical biaryls.14c Based on
both previous results and literature,18 we can propose the
following reaction mechanism, which takes into account
the crucial role of a transient [Ni]I species in the catalytic
cycle (Scheme 1).
Electrochemical Homocouplings; General Procedure
DMF (40 mL), NaI (375 mg, 2.5 mmol), and 1,2-dibromoethane (100
μL, 1.16 mmol) were added to an undivided electrochemical cell, fit-
ted with an iron/nickel (64/36) anode, and surrounded by a nickel
foam as the cathode (surface: 40 cm2, porosity: 500 μm, Goodfellow).
The mixture was electrolyzed under argon at a constant current in-
tensity of 0.2 A at r.t. for 15 min. The current was then stopped, then
NiBr2bpy (187 mg, 0.5 mmol) and aryl or heteroaryl halide (5 mmol),
were sequentially added. The solution was electrolyzed at 0.2 A until
the starting aryl or heteroaryl halide had been totally consumed (2–5
h). Sat. aq EDTA-Na2 solution (50 mL) was added, and the resulting
solution was extracted either with EtOAc (for aryl halides) or with
CH2Cl2 (for heteroaryl halides) (3 × 50 mL). The combined organic lay-
ers were washed with brine (50 mL), dried (MgSO4), filtered, and con-
centrated under vacuum. The crude product was purified by flash
chromatography (silica gel, 70–200 μm).
[Ni]II
2e–
(a)
Ar
X
[Ni]0
e–
X
(f)
(b)
[Ni]I
Ar [Ni]IIX
e–
Ar Ar
(c)
(e)
X–
X
Ar [Ni]I
Ar [Ni]III Ar
(d)
Ar
X
Biphenyl (1a)20
Scheme 1 Probable reaction mechanism (ligands are omitted for clari-
[CAS Reg. No. 92-52-4]
ty)
White solid; yield: 225 mg (58%); mp 67 °C (Lit.20 67–69 °C); GC
(50 °C, 6 °C/min): tR = 5.0 min.
In this putative catalytic cycle, NiBr2bpy pre-catalyst is
first reduced to [Ni]0 complex by cathodic dual electron
transfer (step a). Nickel(0) then undergoes an oxidative ad-
dition to the C–X bond of the aryl halide ArX to give an in-
termediate Ar[Ni]IIX complex (step b). The monoelectronic
reduction of this intermediate (step c), followed by a second
oxidative addition to the aromatic halide, leads to a
IR (neat, ATR): 3032, 1476, 1428, 1005, 725, 693, 609, 458 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.60 (dd, J = 8.1, 1.0 Hz, 4 H), 7.45 (t, J =
7.6 Hz, 4 H), 7.35 (t, J = 7.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 141.2, 128.8, 127.3, 127.2.
MS (EI+): m/z (%) = 155 (12), 154 ([M]•+, 100), 153 (45), 152 (38), 151
.
(11), 76 (8), 63 (6).
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R. Rahil et al.
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Synthesis
3,3′-Dimethylbiphenyl (1b)20
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.8 Hz, 4 H), 6.83 (d, J = 8.4
Hz, 4 H), 2.99 (s, 12 H).
[CAS Reg. No. 612-75-9]
13C NMR (100 MHz, CDCl3): δ = 149.1, 130.0, 127.0, 113.3, 41.0.
MS (EI+): m/z (%) = 241 (17), 240 ([M]•+, 100), 239 (7), 226 (6), 225
Pale yellow oil; yield: 350 mg (77%); GC (60 °C, 6 °C/min): tR = 8.8 min.
IR (neat, ATR): 1604, 1473, 1091, 878, 770, 696, 625, 449 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.49–7.43 (m, 4 H), 7.38 (t, J = 7.6 Hz, 2
H), 7.22 (d, J = 7.5 Hz, 2 H), 2.48 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 141.0, 138.0, 128.6, 127.9, 127.8,
124.2, 21.5.
.
(37), 224 (13), 223 (7), 198 (10), 196 (7), 183 (7), 152 (7), 119 (16).
4,4′-Difluorobiphenyl (1g)22
[CAS Reg. No. 398-23-2]
White solid; yield: 265 mg (56%); mp 87 °C (Lit.22 89–90 °C); GC
(60 °C, 6 °C/min): tR = 3.80 min.
MS (EI+): m/z (%) = 183 (17), 182 ([M]•+, 100), 181 (23), 168 (9), 167
(55), 166 (24), 165 (41), 153 (5), 152 (18), 115 (5), 89 (7).
IR (neat, ATR): 1593, 1483, 1221, 1156, 1108, 818, 502 cm–1
.
4,4′-Dimethoxybiphenyl (1c)20
1H NMR (400 MHz, CDCl3): δ = 7.49 (ddd, J = 8.3, 5.3, 2.6 Hz, 4 H),
7.16–7.08 (m, 4 H).
[CAS Reg. No. 2132-80-1]
13C NMR (100 MHz, CDCl3): δ = 162.4 (d, J = 246.4 Hz), 136.4 (d, J = 3.3
Hz), 128.6 (d, J = 8.2 Hz), 115.7 (d, J = 21.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –115.8.
White solid; yield: 480 mg (90%); mp 172–174 °C (Lit.20 175–176 °C);
GC (60 °C, 6 °C/min): tR = 13.06 min.
IR (neat, ATR): 3014, 2839, 1603, 1495, 1466, 1436, 1273, 1242, 1182,
1039, 1011, 822, 779, 548, 515 cm–1
.
MS (EI+): m/z (%) = 191 (16), 190 ([M]•+, 100), 189 (35), 188 (29), 170
1H NMR (400 MHz, CDCl3): δ = 7.49 (d, J = 8.8 Hz, 4 H), 6.97 (d, J = 8.8
(11), 169 (6), 94 (5).
Hz, 4 H), 3.85 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.7, 133.5, 127.8, 114.2, 55.4.
Diethyl Biphenyl-4,4′-dicarboxylate (1h)7b
[CAS Reg. No. 47230-38-6]
White solid; yield: 570 mg (76%); mp 107 °C (Lit.7b 111 °C); GC (60 °C,
MS (EI+): m/z (%) = 215 (16), 214 ([M]•+, 100), 201 (13), 200 ([M –
CH3]•+, 96), 173 (8), 172 (43), 156 (9), 139 (6), 128 (17).
6 °C/min): tR = 20.4 min.
2,2′-Dimethoxybiphenyl (1d)21
IR (neat, ATR): 2980, 1706, 1606, 1367, 1272, 1179, 1103, 1020, 845,
751, 696, 500 cm–1
.
[CAS Reg. No. 4877-93-4]
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.2 Hz, 4 H), 7.68 (d, J = 8.2
Hz, 4 H), 4.41 (q, J = 7.1 Hz, 4 H), 1.42 (t, J = 7.1 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 144.3, 130.2, 130.0, 127.2, 61.1,
White solid; yield: 300 mg (56%); mp 152–153 °C (Lit.21 152–154 °C);
GC (60 °C, 6 °C/min): tR = 19.21 min.
IR (neat, ATR): 2931, 2835, 1456, 1254, 1237, 1022, 763 cm–1
.
14.4.
1H NMR (400 MHz, CDCl3): δ = 7.32 (td, J = 8.2, 1.8 Hz, 2 H), 7.24 (dd,
J = 7.4, 1.7 Hz, 2 H), 7.01 (dd, J = 7.4, 0.9 Hz, 2 H), 6.97 (d, J = 8.2 Hz, 2
H), 3.76 (s, 6 H).
MS (EI+): m/z (%) = 281 (20), 267 (8), 265 (6), 225 (8), 209 (26), 208
(16), 207 ([M]•+, 100), 193 (10), 191 (14), 165 (6), 135 (8), 91 (6), 73
(10), 55 (14), 50 (6).
13C NMR (100 MHz, CDCl3): δ = 157.1, 131.5, 128.6, 127.9, 120.4,
111.1, 55.7.
Dimethyl Biphenyl-3,3′-dicarboxylate (1i)6b
MS (EI+): m/z (%) = 215 (17), 214 ([M]•+, 100), 199 (16), 184 (31), 183
(14), 182 (6), 181 (15), 171 (7), 169 (6), 168 (14), 156 (11), 155 (10),
153 (6), 152 (5), 141 (6), 139 (12), 128 (14), 115 (7).
[CAS Reg. No. 1751-97-9]
White solid; yield: 490 mg (73%); mp 100 °C (Lit.6b 102–103 °C); GC
(60 °C, 6 °C/min): tR = 17.8 min.
4,4′-Bis(methylthio)biphenyl (1e)6a
IR (neat, ATR): 1727, 1716, 1437, 1264, 1107, 1080, 740, 692, 574 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 2 H), 8.13–7.99 (m, 2 H), 7.86–
7.79 (m, 2 H), 7.54 (t, J = 7.7 Hz, 2 H), 3.96 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.9, 140.4, 131.6, 130.9, 129.0,
[CAS Reg. No. 10075-90-8]
White solid; yield: 380 mg (62%); mp 189–190 °C (Lit.6a 188–189 °C);
GC (60 °C, 6 °C/min): tR = 13.82 min.
IR (neat, ATR): 3027, 2916, 1593, 1476, 1415, 1098, 803, 484 cm–1
.
128.8, 128.3, 52.3.
MS (EI+): m/z (%) = 271 (17), 270 ([M]•+, 98), 240 (15), 239 ([M –
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.5 Hz, 4 H), 7.32 (d, J = 8.5
Hz, 4 H), 2.52 (s, 6 H).
OCH3]•+, 100), 211 (8), 196 (5), 179 (7), 165 (8), 152 (26).
13C NMR (100 MHz, CDCl3): δ = 137.5, 137.4, 127.2, 127.0, 15.9.
MS (EI+): m/z (%) = 248 (13), 247 (18), 246 ([M]•+, 100), 234 (7), 232
Dimethyl Biphenyl-2,2′-dicarboxylate (1j)23
[CAS Reg. No. 5807-64-7]
White solid; yield: 540 mg (80%); mp 73 °C (Lit.23 69.7–71.4 °C); GC
(10), 231 (68), 217 (9), 184 (13), 152 (8), 139 (5).
(60 °C, 6 °C/min): tR = 12.6 min.
N,N,N′,N′-Tetramethylbiphenyl-4,4′-diamine (1f)22
IR (TF-ATR, neat): 2950, 1719, 1572, 1431, 1249, 1133, 1053, 760,
[CAS Reg. No. 366-29-0]
Yellow oil; yield: 450 mg (75%); mp 192 °C (Lit.22 193–194 °C); GC
(50 °C, 6 °C/min): tR = 20.5 min.
707, 563 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 7.8, 1.4 Hz, 2 H), 7.54 (td,
J = 7.5, 1.4 Hz, 2 H), 7.43 (td, J = 7.7, 1.3 Hz, 2 H), 7.21 (dd, J = 7.6, 0.9
Hz, 2 H), 3.62 (s, 6 H).
IR (neat, ATR): 3097, 1607, 1504, 1335, 1223, 1193, 803, 759, 594, 509
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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13C NMR (100 MHz, CDCl3): δ = 167.4, 143.3, 131.5, 130.2, 129.9,
2,2′-Bis(trifluoromethyl)biphenyl (1o)26
129.3, 127.2, 51.8.
MS (EI+): m/z (%) = 212 (16), 211 ([M – CO2Me]•+, 100), 196 (18), 195
(5), 180 (9), 168 (7), 152 (10), 139 (8).
[CAS Reg. No. 567-15-7]
Colorless oil; yield: 250 mg (34%); GC (60 °C, 6 °C/min): tR = 11.18
min.
IR (neat, ATR): 1314, 1170, 1110, 1078, 1034, 768 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 7.4 Hz, 2 H), 7.58–7.50 (m, 4
H), 7.31 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 137.5, 131.6, 130.7, 128.8 (q, J = 30.2
Hz), 128.1, 126.0 (d, J = 2.4 Hz), 123.9 (q, J = 274.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –58.1.
.
Biphenyl-4,4′-dicarbonitrile (1k)7b
[CAS Reg. No. 1591-30-6]
Off-white solid; yield: 244 mg (54%); mp 195 °C (Lit.7b 223 °C); GC
(60 °C, 6 °C/min): tR = 15.6 min.
IR (neat, ATR): 2225, 1660, 1630, 1490, 1395, 815, 543 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.6 Hz, 4 H), 7.69 (d, J = 8.6
Hz, 4 H).
13C NMR (100 MHz, CDCl3): δ = 143.5, 132.9, 128.0, 118.4, 112.4.
.
MS (EI+): m/z (%) = 291 (16), 290 ([M]•+, 100), 269 (5), 251 (15), 221
(18), 219 (8), 202 (11), 201 (60).
MS (EI+): m/z (%) = 205 (18), 204 ([M]•+, 100), 203 (14), 177 (14), 176
3,3′-Bithiophene (1p)20
(10), 150 (6).
[CAS Reg. No. 3172-56-3]
Off-white solid; yield: 200 mg (48%); mp 128–132 °C (Lit.20 130–
131 °C); GC (50 °C, 6 °C/min): tR = 5.9 min.
Biphenyl-3,3′-dicarbonitrile (1l)22
[CAS Reg. No. 396-64-5]
Off-white solid; yield: 260 mg (51%); mp 190 °C (Lit.22 200–201 °C);
GC (50 °C, 6 °C/min): tR = 16.7 min.
IR (neat, ATR): 3097, 1333, 1199, 1085, 842, 760, 697, 595 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 2.8, 1.4 Hz, 2 H), 7.37–7.32
.
(m, 4 H).
IR (neat, ATR): 3066, 2227, 1693, 1574, 1470, 893, 786, 685, 561, 478
13C NMR (100 MHz, CDCl3): δ = 137.2, 126.4, 126.1, 119.8.
MS (EI+): m/z (%) = 168 (9), 167 (10), 166 ([M]•+, 100), 165 (8), 134
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 2 H), 7.80 (d, J = 7.9 Hz, 2 H),
7.71 (d, J = 7.7 Hz, 2 H), 7.61 (t, J = 7.8 Hz, 2 H).
(15), 122 (5), 121 (32), 108 (5), 77 (5), 69 (5).
13C NMR (100 MHz, CDCl3): δ = 140.2, 131.8, 131.5, 130.7, 130.1,
118.4, 113.5.
MS (EI+): m/z (%) = 205 (15), 204 ([M]•+, 100), 203 (13), 178 (5), 177
(16), 176 (13), 150 (6), 75 (5).
3,3′-Bipyridine (1q)20
[CAS Reg. No. 581-46-4]
Brown oil; yield: 200 mg (51%); GC (50 °C, 6 °C/min): tR = 6.03 min.
IR (neat, ATR): 1664, 1586, 1425, 1024, 998, 793, 710, 615 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.81 (dd, J = 2.4, 0.8 Hz, 2 H), 8.63 (dd,
J = 4.8, 1.6 Hz, 2 H), 7.86 (ddd, J = 7.9, 2.3, 1.7 Hz, 2 H), 7.39 (ddd, J =
7.9, 4.8, 0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 149.3, 148.2, 134.5, 133.5, 123.8.
MS (EI+): m/z (%) = 157 (12), 156 ([M]•+, 100), 155 (44), 130 (6), 119
1,1′-(Biphenyl-3,3′-diyl)bis(ethan-1-one) (1m)24
[CAS Reg. No. 94113-07-2]
Pale yellow solid; yield: 310 mg (52%); mp 118 °C (Lit.24 121–122 °C);
GC (60 °C, 6 °C/min): tR = 16.8 min.
IR (neat, ATR): 1680, 1594, 1400, 1351, 1252, 960, 790, 587 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 2 H), 7.97 (d, J = 7.7 Hz, 2 H),
7.82 (d, J = 7.7 Hz, 2 H), 7.58 (t, J = 7.7 Hz, 2 H), 2.68 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 198.0, 140.8, 137.8, 131.8, 129.3,
127.8, 126.9, 26.8.
MS (EI+): m/z (%) = 239 (11), 238 ([M]•+, 63), 224 (16), 223 ([M – CH3]•+,
.
(17), 128 (15), 102 (9), 101 (6), 76 (7), 75 (8), 74 (7), 50 (6).
5,5′-Bipyrimidine (1r)27
[CAS Reg. No. 56598-46-0]
Off-white solid; yield: 230 mg (58%); mp 196–197 °C (Lit.27 196–
197 °C); GC (50 °C, 6 °C/min): tR = 8.15 min.
100), 195 (6), 153 (10), 152 (17), 150 (5), 76 (6).
IR (neat, ATR): 3024, 2923, 1666, 1548, 1395, 1173, 725, 635 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.33 (s, 2 H), 8.99 (s, 4 H).
13C NMR (100 MHz, CDCl3): δ = 159.0, 154.9, 128.5.
.
3,3′-Bis(trifluoromethyl)biphenyl (1n)25
[CAS Reg. No. 580-82-5]
Colorless oil; yield: 630 mg (87%); GC (60 °C, 6 °C/min): tR = 3.9 min.
MS (EI+): m/z (%) = 159 (11), 158 ([M]•+, 100), 104 (27), 77 (6), 76 (7),
75 (6), 50 (16).
IR (neat, ATR): 1318, 1117, 1074, 919, 794, 700, 674 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C8H7N4: 159.0665; found:
159.0665.
1H NMR (400 MHz, CDCl3): δ = 7.84 (s, 2 H), 7.78 (d, J = 7.7 Hz, 2 H),
7.67 (d, J = 7.8 Hz, 2 H), 7.60 (t, J = 7.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.6, 131.5 (q, J = 32.4 Hz), 130.5 (q,
J = 1.1 Hz), 129.5, 124.1 (q, J = 272.4 Hz), 124.7 (q, J = 3.8 Hz), 124.0 (q,
J = 3.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –62.7.
MS (EI+): m/z (%) = 291 (14), 290 ([M]•+, 100), 271 (14), 240 (6), 221
6,6′-Dimethoxy-3,3′-bipyridazine (1s)28
[CAS Reg. No. 24049-46-5]
White solid; yield: 700 mg (64%); mp 238–239 °C (Lit.28 237–238 °C;
GC (50 °C, 6 °C/min): tR = 22.26 min.
IR (neat, ATR): 3073, 2957, 2923, 2854, 1594, 1459, 1394, 1282, 994,
(8), 219 (5), 201 (23), 152 (5).
848, 599 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

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R. Rahil et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.61 (d, J = 9.3 Hz, 2 H), 7.12 (d, J = 9.3
Hz, 2 H), 4.20 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.5, 152.5, 127.4, 118.2, 55.1.
Hoehner, M. C. Synlett 1994, 211. (e) Zhang, S.; Zhang, D.;
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(5) (a) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
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3327.
MS (EI+): m/z (%) = 219 (15), 218 ([M]•+, 100), 217 (72), 190 (7), 189
(34), 175 (31), 161 (6), 147 (28), 119 (11), 91 (5), 76 (9), 74 (5), 65
(11), 63 (5).
HRMS (ESI+): m/z [M + H]+ calcd for C10H11N4O2: 219.0877; found:
219.0876.
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2,2′-Biquinoline (1t)29
[CAS Reg. No. 119-91-5]
Brown solid; yield: 580 mg (91%); mp 194 °C (Lit.29 192–194 °C); GC
(50 °C, 6 °C/min): tR = 22.9 min.
IR (neat, ATR): 3098, 1495, 828, 737, 595, 482 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.86 (d, J = 8.6 Hz, 2 H), 8.34 (d, J = 8.6
Hz, 2 H), 8.25 (d, J = 8.5 Hz, 2 H), 7.89 (d, J = 8.1 Hz, 2 H), 7.77 (ddd, J =
8.4, 6.9, 1.4 Hz, 2 H), 7.65–7.52 (m, 2 H).
.
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13C NMR (100 MHz, CDCl3): δ = 156.1, 147.9, 136.9, 129.9, 129.6,
128.5, 127.7, 127.0, 119.5.
MS (EI+): m/z (%) = 257 (22), 256 ([M]•+, 100), 255 (79), 253 (6), 227
(6), 207 (5), 128 (17), 127 (8), 114 (7), 101 (10), 75 (7).
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Acknowledgment
The financial support of this work by the CNRS and the Université
Paris-Est Créteil is gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589100.
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