Synthesis of Asymmetrical 2,6-Diarylpyridines from Linear α,β,γ,δ-Unsaturated Ketones by Addition of Ammonium Formate Followed by Annulation

Article abstract of DOI:10.1055/s-0037-1610725

A simple and efficient method has been established for the synthesis of asymmetrical 2,6-diarylpyridines by cyclization of α,β,γ,δ-unsaturated ketones with ammonium formate under air atmosphere. The reaction is metal-free and operationally convenient from readily available starting materials. Thirty-three examples have been presented, most of which show good yields.

Full text of DOI:10.1055/s-0037-1610725

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
Y. Gao et al.
Paper
Synthesis
Synthesis of Asymmetrical 2,6-Diarylpyridines from Linear
,,,-Unsaturated Ketones by Addition of Ammonium Formate
Followed by Annulation
Yejun Gaoa,b
Rener Chen*a
Yongmin Ma*a,b
O
metal-free
+
HCOONH4
Ar1
N
Ar2
Ar1
Ar2
toluene, heat
33 examples, up to 92% yield
a School of Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P. R. China
cre@tzc.edu.cn
yongmin.ma@tzc.edu.cn
b School of Pharmaceutical Science, Zhejiang Chinese Medical
University, Hangzhou 310053, P. R. China
In memory of Professor Yongmin Zhang (1932–2019)
Received: 05.06.2019
Accepted after revision: 24.07.2019
Published online: 08.08.2019
,,,-Unsaturated compounds used as Michael accep-
tors remain a challenge due to the difficulty in simultane-
ously controlling the regioselectivity (1,2-, 1,4- as well as
1,6-addition).16 Over the last few years, Hayashi and co-
workers have established rhodium- and iridium-catalyzed
protocols that selectively perform 1,6-addition on the 2,4-
dien-1-ones.17 Selective 1,6-additions have also been re-
ported with Grignard reagents, trialkylaluminums, and ar-
ylboronic acids utilizing copper-, iron-, and palladium-
based catalysts.18 In contrast, Alexakis et al. employed
Grignard reagents to selectively yield 1,4-adducts with
copper-based catalysts.19 Pullarkat developed an efficient
palladium-catalyzed regioselective 1,4-conjugate addition
of arylboronic acids to 2,4-dien-1-ones.20 More recently,
Fletcher and co-worker reported copper-catalyzed asym-
metric 1,4-addition of alkylzirconium species to ,,,-un-
saturated dienones and ynenones.21 In our continuing ef-
forts on the synthesis of pyridine derivatives through annu-
lation of readily available starting materials,14,22 we
attempted the Michael addition of linear ,,,-unsaturat-
ed dienones using ammonium formate as a nucleophile
without any additives. Interestingly, 1,4-adducts were not
afforded. The formed 1,2- or 1,6-Michael addition interme-
diates were simultaneously cyclized to the pyridines. Here-
in, we reported a new transformation of ,,,-unsaturat-
ed compounds with ammonium formate for the synthesis
of asymmetrical 2,6-diarylpyridines in a metal-free system.
We initiated our investigation by choosing 1,5-diphenyl-
penta-2,4-dien-1-one (1a) as our model substrate. We ex-
amined the effect of ammonia sources, solvents, mole ratios
of ammonia source to the substrate 1a, and temperatures
on the transformation. In the presence of 5 equivalents of
ammonium chloride, 1a was converted to 2,6-diphenylpyri-
dine (2a) in 65% in toluene at 110 °C in 16 hours (Table 1,
entry 1). Instead of ammonium chloride, an improved yield
of 2a was afforded when ammonium acetate was applied as
DOI: 10.1055/s-0037-1610725; Art ID: ss-2019-h0317-op
Abstract A simple and efficient method has been established for the
synthesis of asymmetrical 2,6-diarylpyridines by cyclization of ,,,-
unsaturated ketones with ammonium formate under air atmosphere.
The reaction is metal-free and operationally convenient from readily
available starting materials. Thirty-three examples have been present-
ed, most of which show good yields.
Key words regioselectivity, Michael addition, annulations, 2,4-dien-
1-one, asymmetrical pyridine
Pyridine is one of the most important heterocycles and
the pyridine structures are widely found in many natural
products,1 functional materials,2 electrochemicals,3 agro-
chemicals,4 pharmaceutical drugs,5,6 and organocatalysis.7
As a sequence, the development of effective methods for
constructing the pyridine skeleton has attracted consider-
able attention and a wide range of versatile methods have
been developed in the past decades, which include the
Hantzsch synthesis,8 the Vilsmeier–Haack reaction,9 the
Chichibabin reaction,10 the Bohlmann–Rahtz synthesis,11
and the Krohnke synthesis.6,12 These methods or their mod-
ified procedures are very useful and general for the synthe-
sis of symmetrical pyridines. In addition, more attentions
were focused recently on the synthesis of unsymmetrical
pyridines and various methodologies such as transition-
metal-catalyzed reaction13 and metal-free condensation re-
actions of amines with carbonyl compounds14,15 have been
established. Although a lot of methods for building the pyr-
idine motif have been achieved, simple and effective meth-
odologies for the synthesis of symmetrical and asymmetri-
cal pyridines using easily accessible starting materials are
still highly desirable.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Gao et al.
Paper
Synthesis
the ammonia source into the reaction system (entry 2). To
our delight, the yield of 2a could be increased to 85% when
the reaction was carried out with ammonium formate (en-
try 3). In contrast, the reaction failed when ammonia or
methylamine solution was applied as the ammonia source.
The effect of solvents on the reaction was then investigated.
Apart from toluene, DMSO, DMF, and N,N-dimethylacet-
amide (DMAC) were examined and significantly lower
yields were achieved compared to that with toluene (en-
tries 6–8). Surprisingly, very low yield of 2a was detected in
xylene and chlorobenzene, respectively (entries 9 and 10).
The influence of the amount of ammonium formate on the
yield was also examined. It was found that only a trace
amount of 2a was afforded when the mole ratio of ammoni-
um formate to 1a was decreased to 1 (entry 11). When in-
creasing the amount of ammonium formate to 3 equiva-
lents, the yield of 2a was increased to 28% (entry 12). Fur-
ther increasing the amount of ammonium formate from 5
equivalents to 7 equivalents or more did not significantly
improve the yield (entry 13 vs 3). In addition, the yield of
the desired product was dramatically decreased with lower
reaction temperatures (entries 14–16). On the other hand,
increasing the reaction temperature to 130 °C did not im-
prove the yield (entry 17). Based on these results, it was
proposed that the optimal reaction conditions were 1a (1
mmol) and ammonium formate (5 mmol) in toluene (3 mL)
at 110 °C in an open air for 16 hours.
Table 1 Optimization of Reaction Conditionsa
O
N
1a
2a
+ nitrogen source
Entry
Solvent
Ammonia source (equiv) Temp (°C)
Yield (%)
1
2
toluene
toluene
toluene
toluene
toluene
DMSO
NH4Cl (5)
110
110
110
110
110
110
110
110
110
110
110
110
110
20
65
NH4OAc (5)
74
3
HCOONH4 (5)
NH3·H2O (5)
MeNH2 (5)
85, traceb
0
4
5
0
6
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (1)
HCOONH4 (3)
HCOONH4 (7)
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (5)
HCOONH4 (5)
62
7
DMF
42
8
DMAC
23
9
xylene
10
10
11
12
13
14
15
16
17
PhCl
trace
trace
28
toluene
toluene
toluene
toluene
toluene
toluene
toluene
87
0
70
40
90
75
With the optimal reaction condition established, we
progressed to explore the substrate scope of 1,5-diarylpen-
ta-2,4-dien-1-ones in order to evaluate the reaction gener-
ality. The data are summarized in Scheme 1. We first pro-
ceeded to screen the substituent effect by variation of the
aryl group at the carbonyl carbon (-position). To test the
effect of steric hindrance on the reaction output, both elec-
tron-donating groups (EDG, for example, Me and OMe) and
electron-withdrawing groups (EWG, for example, F, Cl, and
Br) at the ortho-, meta- and para-positions of the phenyl
group at the carbonyl site of the 2,4-dien-1-ones 1 (1b–f,g–
k,m–q) were introduced. It was found that the reaction ex-
hibited satisfactory tolerance of the substrates containing
either EDG or EWG. The average yields of product 2 con-
taining EDG (Me and OMe) and EWG (F, Cl, and Br) are sim-
ilar, indicating that the electronic nature of the aryl group
on the 2,4-dien-1-ones had no significant influence on the
yield. In contrast, the reaction of ortho-substituted 1 (2b–f)
proceeded in lower yields compared with those of meta-
and para-substituted analogues (2g–k and 2m–q). The re-
sult demonstrates that the steric hindrance has appreciable
influence on the product yield. In addition, the reaction of
substrate containing an OH (1l) or NMe2 (1s) group also
proceeded smoothly but with moderate yields (38% and
36%, respectively). On the other hand, a strong electron-
withdrawing nitro-substituted 2,4-dien-1-one (1t) was in-
efficient for the preparation of the desired product.
130
84
a Reaction conditions: 1a (1 mmol), ammonia source and solvent (3 mL) at
the indicated reaction conditions for 16 h.
b Reaction under N2 atmosphere.
The reaction generality of disubstituted phenyl and het-
erocyclic 2,4-dien-1-ones was also investigated. In a similar
fashion to monosubstituted analogues, the di-substituted
phenyl 2,4-dien-1-ones (1u–x) were well tolerable for the
transformation and the corresponding 2,6-diarylpyridines
were afforded in moderate yields (65–70%). Compared to
those of monosubstituted analogues, the yields for disubsti-
tuted 2,6-diarylpyridines are slightly lower. This can be
clarified by the steric hindrance effect. When naphthyl and
heterocyclic 2,4-dien-1-ones were employed, the transfor-
mation was also successful under the standard reaction
conditions and the corresponding 2,6-disubstituted pyri-
dines 2y–ab were produced in moderate to good yields.
The scope of substituted phenyl group at -position of
the 2,4-dien-1-ones in this novel reaction was also exam-
ined (Scheme 1). The 2,4-dien-1-ones bearing either EDG
such as 4-Me and 4-OMe or EWG such as 4-Br at the -phenyl
group, underwent the reaction smoothly to provide the
corresponding 2,6-diarylpyridines 2ac–ae in moderate to
good yields.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
Y. Gao et al.
Paper
Synthesis
under basic conditions (NaOH/EtOH), was found to be con-
verted to the corresponding product 2ag in a moderate
yield (Equation 2).
O
R1
R2
toluene
1
N
O
R2
R1
standard
conditions
110 °C
+ HCOONH4
2
1ag
R
R
N
N
N
2g, R = Me, 85%
2h, R = OMe, 80%
2i, R = F, 82%
2j, R = Cl, 80%
2k, R = Br, 87%
2l, R = OH, 38%
2a, R = H, 85%
2ag, yield: 25%
2b, R = Me, 75%
2c, R = OMe, 73%
2d, R = F, 80%
2e, R = Cl, 78%
2f, R = Br, 76%
Equation 2 Synthesis of 2-phenyl-6-(4-phenylbuta-1,3-dien-1-yl)pyri-
dine (2ag)
In order to demonstrate the suitability of this new syn-
thetic method on an enlarged scale, a scale-up experiment
(12 mmol) was carried out to prepare 2q. The reaction of
the starting material 1q and ammonium formate under
standard conditions proceeded smoothly to afford the cor-
responding product 2q in 86% yield (Scheme 2) without a
significant loss of efficiency (1 mmol scale, 92%).
N
N
R
R
2u, R = 2,4-Me2, 70%
2v, R = 3,4-Cl2, 65%
2w, R = 3-Br, 4-F, 66%
2m, R = Me, 91%
2n, R = OMe, 89%
2o, R = F, 82%
2p, R = Cl, 84%
2q, R = Br, 92%
2r, R = n-Pr, 77%
2s, R = NMe2, 36%
2t, R = NO2, 0%
2x, R = 3,4-OCH2O-, 70%
O
standard
conditions
N
Br
1q, 12 mmol
N
Br
N
R
R1
R2
+ HCOONH4
2q, 86%
2y, R = 1-naphthyl, 63%
2z, R = 2-naththyl, 68%
2aa, R = 2-furyl, 83%
2ab, R = 3-thienyl, 44%
2ac, R1 = R2 = 4-Me, 64%
2ad, R1 = 4-OMe, R2 = 3-Cl, 57%
2ae, R1 = R2 = 4-Br, 73%
Scheme 2 Gram-scale synthesis of 2q
Based on the results of our experiments, a plausible
mechanism for the reaction is proposed (Scheme 3). Initial-
ly, at high temperature conditions, the thermal decomposi-
tion of ammonium formate produces ammonia source. The
electrophilicity of the 2,4-dien-1-one 1 allows it to react
with the resulting ammonia source. As 1,4-adducts were
not observed, nucleophilic attack at the -position of 2,4-
dien-1-one is ruled out, leaving two other possibilities,
namely 1,6- (path a) and 1,2-addition (path b). The result-
ing intermediate A or its tautomeric form A′ from path a
performs an annulation by nucleophilic attack of amine on
the carbonyl group followed by elimination of one molecule
of water to afford intermediate C. Intermediate C can also
be produced from intermediate B, where the nitrogen of
imine attacks the -C to form a six-membered ring. In the
presence of oxygen, the 2,3-dihydropyridine C is readily
oxidized to lead to the formation of final product 2. In fact,
oxygen is necessary for the transformation, as the desired
product failed to be formed under nitrogen atmosphere
(Table 1, entry 3).
Scheme 1 Scope of the substrates. Reagents and conditions: 1 (1
mmol), HCOONH4 (5 mmol), toluene (3 mL), 110 °C, 16 h. Isolated
yields are shown.
In addition, several aliphatic linear ,,,-unsaturated
ketones such as -methyl, -ethyl, and -methyl 2,4-dien-1-
ones were attempted to investigate for the annulation reac-
tion. However, only the aliphatic 2,4-dien-1-one on carbon-
yl carbon 1af was successfully synthesized and only 20%
yield of the desired product 2af was achieved for this cyc-
loaddition under the standard conditions (Equation 1). Fur-
thermore, 1,9-diphenylnona-1,3-6,8-tetraen-5-one (1ag),
which was synthesized from cinnamaldehyde and acetone
O
standard conditions
N
1af
2af, yield: 20%
Equation 1 Synthesis of 2-(tert-butyl)-6-phenylpyridine
(2af)
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
Y. Gao et al.
Paper
Synthesis
HCOONH4
NH2
O
NH3
O
Ar2
Δ
Ar2
Ar1
Ar2
path a
Ar1
Ar2
[O]
– H2O
O
A'
N
NH3
N
A
Ar1
Ar2
Ar1
Ar1
NH
path b
– H2O
C
1
2
Ar1
Ar2
B
Scheme 3 Proposed mechanism
In summary, a simple and efficient method for the
Michael addition of 1,5-diarylpenta-2,4-dien-1-ones 1 with
an ammonium source has been developed for the synthesis
of 2,6-diarylpyridines 2. The method has the advantages of
toleration of a wide range of substituents, operational sim-
plicity, no additives, high yields, high regioselectivity, and
readily available starting materials. This method can be
readily extended to a large scale and has potential to be ap-
plied to industrial synthesis.
1H NMR (400 MHz, CDCl3):  = 8.10–8.05 (m, 2 H), 7.80 (t, J = 7.8 Hz, 1
H), 7.69 (dd, J = 7.9, 1.0 Hz, 1 H), 7.50–7.44 (m, 3 H), 7.43–7.39 (m, 1
H), 7.35 (dd, J = 7.6, 1.0 Hz, 1 H), 7.31 (s, 3 H), 2.49 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.81, 156.50, 140.52, 139.47,
136.96, 136.12, 130.88, 129.80, 128.88, 128.66, 128.26, 127.01,
125.87, 122.39, 118.20, 20.70.
EI-MS: m/z = 246 [M + H]+.
2-(2-Methoxyphenyl)-6-phenylpyridine (2c)23
Pale yellow oil; yield: 191 mg (73%).
1H NMR (400 MHz, CDCl3):  = 8.10 (dd, J = 7.1, 1.5 Hz, 2 H), 8.01 (dd,
J = 7.7, 1.8 Hz, 1 H), 7.82 (dd, J = 7.8, 1.1 Hz, 1 H), 7.75 (t, J = 7.8 Hz, 1
H), 7.64 (dd, J = 7.7, 1.1 Hz, 1 H), 7.49–7.44 (m, 2 H), 7.42–7.35 (m, 2
H), 7.11 (td, J = 7.5, 1.1 Hz, 1 H), 7.00 (dd, J = 8.3, 1.1 Hz, 1 H), 3.87 (s, 3
H).
13C NMR (101 MHz, CDCl3):  = 157.24, 156.80, 155.50, 139.77,
136.37, 131.52, 129.94, 129.29, 128.77, 128.65, 127.01, 123.56,
121.11, 118.35, 111.48, 55.67.
All reagents and solvents were used from commercial sources, unless
otherwise stated. All raw materials are obtained from commercial
sources or synthesized and used as such. All experiments were con-
ducted in the air. Precoated plates (silica gel 60 PF254, 0.25 mm or 0.5
mm) were used for TLC. Column chromatography was carried out on
silica gel (240–400 mesh) with petroleum ether (PE) and EtOAc as
eluent. The 1H and 13C NMR spectra of the 200/400/600 MHz and
50/100/125 MHz NMR spectrometers were recorded in CDCl3/DMSO-d6,
respectively. Chemical shifts are reported as  peaks. Melting points
are uncorrected. Mass spectra were obtained using an LC-MS (ESI)
mass or GC-MS mass spectrometer.
EI-MS: m/z = 262 [M + H]+.
2-(2-Fluorophenyl)-6-phenylpyridine (2d)
Pale yellow oil; yield: 199 mg (80%).
1H NMR (400 MHz, CDCl3):  = 8.10 (td, J = 7.9, 1.9 Hz, 1 H), 8.03–7.98
(m, 2 H), 7.68–7.62 (m, 2 H), 7.56 (dd, J = 6.3, 2.5 Hz, 1 H), 7.40–7.35
(m, 2 H), 7.32–7.28 (m, 1 H), 7.25 (ddd, J = 8.1, 5.1, 2.0 Hz, 1 H), 7.19–
7.15 (m, 1 H), 7.05 (ddd, J = 11.5, 8.1, 1.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 160.83 (d, J = 249.8 Hz), 157.04,
152.85, 139.39, 137.20, 131.33 (d, J = 3.0 Hz), 130.36, 130.45, 129.06,
128.76, 127.00, 124.51 (d, J = 3.5 Hz), 122.93, 119.01, 116.22 (d, J =
23.2 Hz).
2,6-Diarylpyridines; 2,6-Diphenylpyridine (2a); Typical Procedure
1,5-Diphenylpenta-2,4-dien-1-one (1a; 234 mg,
1 mmol) and
HCOONH4 (315 mg, 5 mmol) were added to a solution of toluene (3.0
mL), and the reaction mixture was stirred in a tube at 110 °C for 16 h.
The reaction was monitored by TLC. Once the reaction was complete,
the mixture was treated with H2O (15.0 mL) and EtOAc (8.0 mL). The
organic and aqueous layers were then separated, and the aqueous lay-
er was extracted with EtOAc (3 × 8 mL). The combined organic ex-
tracts were dried (Na2SO4), the solvent was removed under reduced
pressure, and the remaining residue was purified by column chroma-
tography; yield: 196 mg (85%); white solid; mp 95–96 °C (Lit.23 mp
81–82 °C).
1H NMR (400 MHz, CDCl3):  = 8.26–8.20 (m, 4 H), 7.88 (dd, J = 8.5, 7.1
Hz, 1 H), 7.76 (d, J = 7.8 Hz, 2 H), 7.60–7.55 (m, 4 H), 7.53–7.48 (m, 2
H).
13C NMR (101 MHz, CDCl3):  = 156.87, 139.51, 137.53, 129.02,
128.72, 127.04, 118.68.
EI-MS: m/z = 232 [M + H]+.
HRMS (ESI): m/z calcd for C17H13FN [M + H]+: 250.1027; found:
250.1033.
2-(2-Chlorophenyl)-6-phenylpyridine (2e)23
Pale yellow oil; yield: 207 mg (78%).
1H NMR (400 MHz, CDCl3):  = 8.09–8.05 (m, 2 H), 7.78 (t, J = 7.8 Hz, 1
H), 7.70 (ddd, J = 7.9, 4.8, 1.5 Hz, 2 H), 7.58 (dd, J = 7.7, 1.0 Hz, 1 H),
7.49–7.43 (m, 3 H), 7.41–7.38 (m, 1 H), 7.37–7.29 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 157.13, 156.60, 139.46, 139.38,
136.68, 132.37, 131.92, 130.25, 129.59, 129.06, 128.78, 127.12,
127.04, 123.18, 119.11.
2-Phenyl-6-(o-tolyl)pyridine (2b)23
EI-MS: m/z = 266 [M + H]+.
White solid; yield: 184 mg (75%); mp 61–62 °C.
2-(2-Bromophenyl)-6-phenylpyridine (2f)24
Pale yellow oil; yield: 235 mg (76%).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
Y. Gao et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.11–8.04 (m, 2 H), 7.79 (t, J = 7.8 Hz, 1
H), 7.69 (td, J = 7.8, 1.1 Hz, 2 H), 7.62 (dd, J = 7.7, 1.8 Hz, 1 H), 7.52 (dd,
J = 7.6, 1.0 Hz, 1 H), 7.49–7.43 (m, 2 H), 7.42–7.37 (m, 2 H), 7.26–7.22
(m, 1 H).
1H NMR (400 MHz, CDCl3):  = 8.30 (t, J = 2.0 Hz, 1 H), 8.14–8.08 (m, 2
H), 8.01 (dt, J = 7.8, 1.4 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.9
Hz, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.54–7.46 (m, 3 H), 7.42 (t, J = 7.3 Hz,
1 H), 7.32 (t, J = 7.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 158.05, 157.00, 141.45, 139.36,
136.69, 133.46, 131.76, 129.71, 129.04, 128.76, 127.56, 127.15,
122.99, 121.99, 119.13.
13C NMR (101 MHz, CDCl3):  = 157.01, 155.19, 141.55, 139.21,
137.70, 131.91, 130.26, 130.11, 129.22, 128.81, 127.05, 125.54,
123.09, 119.27, 118.72.
EI-MS: m/z = 310 [M + H]+.
HRMS (ESI): m/z calcd for C17H13BrN [M + H]+: 310.0226; found:
310.0218.
2-Phenyl-6-(m-tolyl)pyridine (2g)
3-(6-Phenylpyridin-2-yl)phenol (2l)
White solid; mp 60–61 °C; yield: 207 mg (85%).
Pale yellow oil; yield: 94 mg (38%).
1H NMR (400 MHz, CDCl3):  = 8.17–8.12 (m, 2 H), 7.97 (d, J = 1.8 Hz, 1
H), 7.92 (d, J = 7.7 Hz, 1 H), 7.79 (dd, J = 8.4, 7.2 Hz, 1 H), 7.67 (d, J = 7.8
Hz, 2 H), 7.50 (dd, J = 8.2, 6.6 Hz, 2 H), 7.46–7.35 (m, 2 H), 7.25 (s, 1 H),
2.46 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.02, 156.81, 139.54, 139.44,
138.29, 137.42, 129.74, 128.94, 128.67, 128.58, 127.70, 127.01,
124.12, 118.75, 118.61, 21.62.
1H NMR (400 MHz, CDCl3):  = 8.59 (d, J = 2.3 Hz, 1 H), 7.98–7.94 (m, 2
H), 7.65 (d, J = 8.1 Hz, 1 H), 7.54 (dd, J = 8.1, 2.3 Hz, 1 H), 7.46 (t, J = 7.4
Hz, 2 H), 7.39 (t, J = 7.3 Hz, 1 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.23 (ddd, J =
8.4, 6.9, 1.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 155.45, 149.91, 139.90, 139.15,
137.25, 135.00, 128.89, 128.80, 128.75, 128.73, 126.79, 126.52,
120.38.
HRMS (ESI): m/z calcd for C18H15N [M + H]+: 245.1204; found:
245.1212.
HRMS (ESI): m/z calcd for C17H14NO [M + H]+: 248.1070; found:
248.1077.
2-(3-Methoxyphenyl)-6-phenylpyridine (2h)
White solid; yield: 209 mg (80%); mp 82–83 °C (Lit.23 mp 83–85 °C).
2-Phenyl-6-(p-tolyl)pyridine (2m)
White solid; yield: 223 mg (91%); mp 92–93 °C (Lit.25 mp 91–92 °C).
1H NMR (400 MHz, CDCl3):  = 8.23–8.19 (m, 2 H), 8.11 (d, J = 8.2 Hz, 2
H), 7.88–7.83 (m, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.56 (t, J = 7.4 Hz, 2 H),
7.49 (t, J = 7.3 Hz, 1 H), 7.36 (d, J = 7.7 Hz, 2 H), 2.48 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 156.85, 156.73, 139.45, 139.06,
137.55, 136.58, 129.45, 129.00, 128.70, 127.08, 126.95, 118.45, 21.34.
1H NMR (400 MHz, CDCl3):  = 8.15 (dd, J = 7.1, 1.8 Hz, 2 H), 7.83–7.75
(m, 2 H), 7.71–7.66 (m, 3 H), 7.53–7.47 (m, 2 H), 7.45–7.38 (m, 2 H),
6.98 (dd, J = 8.2, 2.5 Hz, 1 H), 3.91 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.01, 156.74, 156.54, 140.98,
139.40, 137.47, 129.66, 128.98, 128.68, 126.97, 119.40, 118.79,
114.58, 112.54, 55.38.
EI-MS: m/z = 262 [M + H]+.
EI-MS: m/z = 246 [M + H]+ .
2-(3-Fluorophenyl)-6-phenylpyridine (2i)
2-(4-Methoxyphenyl)-6-phenylpyridine (2n)
Pale yellow oil; yield: 204 mg (82%).
White solid; yield: 232 mg (89%); mp 131–133 °C (Lit.25 mp 132–133
°C).
1H NMR (400 MHz, CDCl3):  = 8.19–8.12 (m, 3 H), 8.00 (dt, J = 7.0, 1.9
Hz, 1 H), 7.82 (t, J = 7.8 Hz, 1 H), 7.71 (dd, J = 7.9, 0.9 Hz, 1 H), 7.66 (dd,
J = 7.8, 0.9 Hz, 1 H), 7.53–7.48 (m, 2 H), 7.46–7.43 (m, 1 H), 7.42–7.39
(m, 2 H).
1H NMR (400 MHz, CDCl3):  = 8.18 (td, J = 8.8, 1.8 Hz, 4 H), 7.84 (t, J =
7.8 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 2 H), 7.48 (t, J =
7.3 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 2 H), 3.93 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.04, 155.34, 141.29, 139.21,
137.69, 134.82, 129.94, 129.18, 128.97, 128.78, 127.18, 127.02,
125.04, 119.25, 118.71.
13C NMR (101 MHz, CDCl3):  = 160.61, 156.65, 156.47, 139.38,
137.63, 131.91, 129.04, 128.71, 128.40, 127.10, 118.13, 118.07,
114.10, 55.41.
HRMS (ESI): m/z calcd for C17H13FN [M + H]+: 250.1027; found:
EI-MS: m/z = 262 [M + H]+.
250.1033.
2-(4-Fluorophenyl)-6-phenylpyridine (2o)
Yellow solid; yield: 204 mg (82%); mp 94–95 °C (Lit.23 mp 94–95 °C).
2-(3-Chlorophenyl)-6-phenylpyridine (2j)
Pale yellow oil; yield: 212 mg (80%).
1H NMR (400 MHz, CDCl3):  = 8.18–8.09 (m, 4 H), 7.85–7.75 (m, 1 H),
7.68 (d, J = 7.8 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.50 (td, J = 7.8, 7.3, 1.7
Hz, 2 H), 7.44 (td, J = 7.1, 1.6 Hz, 1 H), 7.18 (td, J = 8.6, 1.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 163.59 (d, J = 248.2 Hz), 156.35 (d, J =
107.7 Hz), 139.36, 137.62, 135.64, 129.09, 128.84, 128.74, 126.99,
118.61, 118.31, 115.71, 115.49.
1H NMR (400 MHz, CDCl3):  = 8.19–8.11 (m, 3 H), 7.99 (dt, J = 6.8, 1.9
Hz, 1 H), 7.80 (t, J = 7.8 Hz, 1 H), 7.70 (d, J = 6.9 Hz, 1 H), 7.64 (d, J = 7.7
Hz, 1 H), 7.50 (t, J = 7.4 Hz, 2 H), 7.45–7.38 (m, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.04, 155.34, 141.30, 139.22,
137.68, 134.82, 129.93, 129.18, 128.96, 128.78, 127.19, 127.02,
125.04, 119.24, 118.70.
EI-MS: m/z = 250 [M + H]+.
HRMS (ESI): m/z calcd for C17H13ClN [M + H]+: 266.0731; found:
2-(4-Chlorophenyl)-6-phenylpyridine (2p)23
266.0733.
White solid; yield: 223 mg (84%); mp 106–107 °C.
2-(3-Bromophenyl)-6-phenylpyridine (2k)
Pale yellow oil; yield: 269 mg (87%).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

F
Y. Gao et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.15–8.07 (m, 4 H), 7.81 (t, J = 7.8 Hz, 1
H), 7.70 (dd, J = 7.8, 1.0 Hz, 1 H), 7.66 (dd, J = 7.7, 1.0 Hz, 1 H), 7.53–
7.41 (m, 5 H).
13C NMR (101 MHz, CDCl3):  = 156.94, 155.57, 139.25, 137.86,
137.62, 135.06, 129.10, 128.85, 128.72, 128.24, 126.96, 118.91,
118.39.
2-(3,4-Dichlorophenyl)-6-phenylpyridine (2v)
Pale yellow oil; yield: 194 mg (65%).
1H NMR (400 MHz, CDCl3):  = 8.27 (d, J = 2.1 Hz, 1 H), 8.15–8.08 (m, 2
H), 7.96 (dd, J = 8.4, 2.1 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.72 (dd, J =
7.8, 0.9 Hz, 1 H), 7.64 (dd, J = 7.8, 0.9 Hz, 1 H), 7.61–7.55 (m, 1 H),
7.54–7.49 (m, 2 H), 7.47–7.42 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 157.15, 154.32, 139.39, 139.05,
137.78, 133.08, 132.99, 130.62, 129.27, 128.87, 128.80, 127.00,
126.04, 119.43, 118.46.
EI-MS: m/z = 266 [M + H]+.
2-(4-Bromophenyl)-6-phenylpyridine (2q)
White solid; yield: 284 mg (92%); mp 115–116 °C (Lit.25 mp 110–111
HRMS (ESI): m/z calcd for C17H12ClN [M + H]+: 300.0341; found:
°C).
300.0348.
1H NMR (400 MHz, CDCl3):  = 8.15–8.10 (m, 2 H), 8.05–8.00 (m, 2 H),
7.81 (t, J = 7.8 Hz, 1 H), 7.70 (dd, J = 7.8, 0.9 Hz, 1 H), 7.65 (dd, J = 7.8,
0.9 Hz, 1 H), 7.63–7.59 (m, 2 H), 7.53–7.48 (m, 2 H), 7.46–7.41 (m, 1
H).
13C NMR (101 MHz, CDCl3):  = 156.99, 155.64, 139.27, 138.35,
137.66, 131.83, 129.15, 128.76, 128.57, 126.99, 123.45, 119.00,
118.39.
2-(3-Bromo-4-fluorophenyl)-6-phenylpyridine (2w)
Pale yellow oil; yield: 216 mg (66%).
1H NMR (400 MHz, DMSO-d6):  = 8.53 (dd, J = 6.8, 2.2 Hz, 1 H), 8.28
(ddd, J = 8.8, 4.9, 2.5 Hz, 1 H), 8.20 (dd, J = 7.3, 1.7 Hz, 2 H), 8.00–7.96
(m, 2 H), 7.57–7.52 (m, 3 H), 7.49 (dq, J = 8.3, 3.0 Hz, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 159.38 (d, J = 247.3 Hz), 156.24,
153.61, 139.03, 138.88, 137.19, 131.88, 129.75, 129.30, 128.52,
128.44, 127.12, 119.67 (d, J = 36.8 Hz), 117.52 (d, J = 22.4 Hz), 109.14
(d, J = 21.2 Hz).
EI-MS: m/z = 310 [M + H]+.
2-Phenyl-6-(4-propylphenyl)pyridine (2r)
HRMS (ESI): m/z calcd for C17H12BrFN [M + H]+: 328.0132; found:
Pale yellow oil; yield: 210 mg (77%).
1H NMR (400 MHz, CDCl3):  = 8.17–8.13 (m, 2 H), 8.06 (d, J = 8.2 Hz, 2
H), 7.82–7.76 (m, 1 H), 7.66 (d, J = 8.3 Hz, 2 H), 7.49 (dd, J = 8.2, 6.5 Hz,
2 H), 7.43 (d, J = 7.2 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 2 H), 2.67–2.63 (m, 2
H), 1.72–1.66 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).
328.0123.
2-(Benzo[d][1,3]dioxol-5-yl)-6-phenylpyridine (2x)
White solid; yield: 193 mg (70%); mp 92–93 °C.
13C NMR (101 MHz, CDCl3):  = 156.94, 156.74, 143.77, 139.60,
137.41, 137.01, 128.92, 128.86, 128.67, 127.00, 126.89, 118.41,
118.33, 37.86, 24.55, 13.86.
1H NMR (400 MHz, CDCl3):  = 8.13 (dd, J = 7.0, 1.5 Hz, 2 H), 7.78 (t, J =
7.8 Hz, 1 H), 7.72 (d, J = 1.8 Hz, 1 H), 7.64 (ddd, J = 8.1, 3.3, 1.3 Hz, 2 H),
7.59 (d, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 2 H), 7.42 (t, J = 7.3 Hz, 1 H),
6.92 (d, J = 8.1 Hz, 1 H), 6.03 (s, 2 H).
HRMS (ESI): m/z calcd for C20H20N [M + H]+: 274.1590; found:
13C NMR (101 MHz, CDCl3):  = 156.65, 156.26, 148.47, 148.26,
139.46, 137.47, 134.02, 128.98, 128.69, 126.97, 120.96, 118.20,
118.06, 108.39, 107.51, 101.30.
274.1590.
N,N-Dimethyl-4-(6-phenylpyridin-2-yl)aniline (2s)
White solid; yield: 99 mg (36%); mp 175–178 °C (Lit.23 mp 176–178
HRMS (ESI): m/z calcd for C18H14NO2 [M + H]+: 276.1019; found:
°C).
276.1023.
1H NMR (400 MHz, CDCl3):  = 8.15 (dd, J = 8.3, 1.3 Hz, 2 H), 8.10–8.05
(m, 2 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.59 (ddd, J = 13.9, 7.8, 0.9 Hz, 2 H),
7.50–7.46 (m, 2 H), 7.42 (d, J = 7.4 Hz, 1 H), 6.86–6.80 (m, 2 H), 3.04 (s,
6 H).
13C NMR (101 MHz, CDCl3):  = 156.47, 149.40, 139.87, 137.21,
135.26, 128.90, 128.61, 127.87, 126.99, 126.59, 120.63, 117.21,
112.42, 40.58.
2-(Naphthalen-1-yl)-6-phenylpyridine (2y)23
Pale yellow oil; yield: 177 mg (63%).
1H NMR (400 MHz, CDCl3):  = 8.18–8.11 (m, 1 H), 7.99 (d, J = 7.3 Hz, 2
H), 7.78 (d, J = 9.0 Hz, 2 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1
H), 7.56 (dd, J = 7.1, 1.2 Hz, 1 H), 7.45–7.41 (m, 1 H), 7.38–7.31 (m, 5
H), 7.30–7.27 (m, 1 H).
13C NMR (101 MHz, CDCl3):  = 159.09, 156.93, 139.46, 138.83,
137.25, 134.11, 131.38, 129.06, 128.98, 128.80, 128.43, 127.70,
127.16, 126.43, 126.01, 125.91, 125.41, 123.49, 118.66.
EI-MS: m/z = 275 [M + H]+.
2-(2,4-Dimethylphenyl)-6-phenylpyridine (2u)
EI-MS: m/z = 282 [M + H]+.
Pale yellow oil; yield: 181 mg (70%).
1H NMR (400 MHz, CDCl3):  = 8.08 (d, J = 7.1 Hz, 2 H), 7.78 (t, J = 7.8
Hz, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.46 (t, J = 7.3 Hz, 2 H), 7.40 (dd, J =
7.5, 1.9 Hz, 2 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.14–7.09 (m, 2 H), 2.46 (s, 3
H), 2.38 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 159.88, 156.43, 139.58, 138.05,
137.81, 136.92, 135.99, 131.72, 129.85, 128.88, 128.68, 127.04,
126.63, 122.37, 117.97, 21.20, 20.71.
2-(Naphthalen-2-yl)-6-phenylpyridine (2z)24
Yellow solid; yield: 191 mg (68%); mp 101–103 °C.
1H NMR (400 MHz, CDCl3):  = 8.61 (s, 1 H), 8.33 (dd, J = 8.6, 1.8 Hz, 1
H), 8.22–8.18 (m, 2 H), 7.97 (t, J = 7.8 Hz, 2 H), 7.91–7.83 (m, 3 H), 7.72
(dd, J = 5.8, 2.9 Hz, 1 H), 7.55–7.49 (m, 4 H), 7.45 (t, J = 7.3 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 156.97, 156.71, 139.49, 137.56,
136.77, 133.71, 133.50, 129.03, 128.75, 128.72, 128.34, 127.68,
127.05, 126.47, 126.33, 126.23, 124.75, 118.94, 118.76.
HRMS (ESI): m/z calcd for C19H18N [M + H]+: 260.1434; found:
260.1439.
EI-MS: m/z = 282 [M + H]+.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

G
Y. Gao et al.
Paper
Synthesis
2-(Furan-2-yl)-6-phenylpyridine (2aa)
1H NMR (400 MHz, CDCl3):  = 8.12–8.07 (m, 2 H), 7.66 (t, J = 7.8 Hz, 1
H), 7.54 (dd, J = 7.8, 0.9 Hz, 1 H), 7.46 (t, J = 7.3 Hz, 2 H), 7.41–7.36 (m,
1 H), 7.28–7.25 (m, 1 H), 1.43 (s, 9 H).
13C NMR (101 MHz, CDCl3):  = 168.97, 155.37, 139.92, 136.76,
128.64, 128.58, 126.85, 117.35, 116.86, 30.25, 29.73.
Pale yellow oil; yield: 183 mg (83%).
1H NMR (400 MHz, CDCl3):  = 8.11–8.05 (m, 2 H), 7.77 (t, J = 7.8 Hz, 1
H), 7.62 (ddd, J = 14.2, 7.9, 1.0 Hz, 2 H), 7.54 (dd, J = 1.8, 0.9 Hz, 1 H),
7.51–7.46 (m, 2 H), 7.45–7.39 (m, 1 H), 7.20 (dd, J = 3.4, 0.9 Hz, 1 H),
6.55 (dd, J = 3.4, 1.7 Hz, 1 H).
HRMS (ESI): m/z calcd for C15H18N [M + H]+: 212.1434; found:
13C NMR (101 MHz, CDCl3):  = 156.99, 154.11, 149.24, 143.21,
139.25, 137.37, 129.05, 128.71, 127.00, 118.60, 116.80, 112.05,
108.78.
212.1431.
2-Phenyl-6-(4-phenylbuta-1,3-dien-1-yl)pyridine (2ag)
HRMS (ESI): m/z calcd for C15H12NO [M + H]+: 222.0913; found:
Pale yellow oil; yield: 71 mg (25%).
1H NMR (400 MHz, CDCl3):  = 8.08 (d, J = 7.6 Hz, 2 H), 7.70 (t, J = 7.8
Hz, 1 H), 7.65–7.60 (m, 1 H), 7.57 (d, J = 7.7 Hz, 1 H), 7.52–7.41 (m, 5
H), 7.35 (t, J = 7.5 Hz, 2 H), 7.28 (s, 1 H), 7.23 (s, 1 H), 7.09–6.99 (m, 1
H), 6.88–6.77 (m, 2 H).
222.0920.
2-Phenyl-6-(thiophen-3-yl)pyridine (2ab)23
Yellow solid; yield: 104 mg (44%); mp 72–74 °C.
13C NMR (101 MHz, CDCl3):  = 157.06, 155.36, 139.54, 137.18,
137.16, 135.22, 133.39, 132.22, 128.98, 128.72, 128.66, 127.94,
127.06, 127.02, 126.65, 120.51, 118.78.
HRMS (ESI): m/z calcd for C21H18N [M + H]+: 284.1434; found:
284.1438.
1H NMR (400 MHz, CDCl3):  = 8.14–8.10 (m, 1 H), 8.03 (ddd, J = 11.6,
3.0, 1.3 Hz, 1 H), 7.82–7.74 (m, 2 H), 7.70 (s, 1 H), 7.64–7.56 (m, 1 H),
7.54–7.46 (m, 2 H), 7.45–7.39 (m, 2 H), 7.32 (d, J = 0.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 156.84, 153.66, 142.46, 137.47,
129.01, 128.70, 127.14, 126.98, 126.51, 126.15, 123.67, 118.53,
116.65.
EI-MS: m/z = 238 [M + H]+.
Supporting Information
2,6-Di-p-tolylpyridine (2ac)
White solid; yield: 166 mg (64%); mp 157–159 °C (Lit.23 mp 157–159
°C).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610725.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
1H NMR (400 MHz, CDCl3):  = 8.04 (d, J = 8.2 Hz, 4 H), 7.75 (dd, J = 8.4,
7.2 Hz, 1 H), 7.62 (d, J = 7.7 Hz, 2 H), 7.29 (d, J = 7.9 Hz, 4 H), 2.41 (s, 6
References
H).
(1) (a) Ma, X. Q.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752.
(b) Vargas, D. F.; Larghi, E. L.; Kaufman, T. S. Nat. Prod. Rep. 2019,
36, 354. (c) Uredi, D.; Motati, D. R.; Watkins, E. B. Chem.
Commun. 2019, 55, 3270.
13C NMR (101 MHz, CDCl3):  = 156.75, 138.90, 137.35, 136.83,
129.41, 126.88, 118.06, 21.35.
EI-MS: m/z = 260 [M + H]+.
(2) (a) Rokesh, K.; Sakar, M.; Trong-On, D. Mater. Lett. 2019, 242, 99.
(b) Hang, X.-C.; Fleetham, T.; Turner, E.; Brooks, J.; Li, J. Angew.
Chem. Int. Ed. 2013, 52, 6753. (c) Cheng, G.; Weng, Y.; Yang, X.;
Cui, X. Org. Lett. 2015, 17, 3790.
(3) (a) McMillion, N. D.; Wilson, A. W.; Goetz, M. K.; Chang, M.-C.;
Lin, C.-C.; Feng, W.-J.; McCrory, C. C. L.; Anderson, J. S. Inorg.
Chem. 2019, 58, 1391. (b) Shi, H.; Wang, R.; Lou, M.; Jia, D.; Guo,
Y.; Wang, X.; Huang, Y.; Sun, Z.; Wang, T.; Wang, L. Electrochim.
Acta 2019, 294, 93. (c) Momblona, C.; Ertl, C. D.; Pertegas, A.;
Junquera-Hernandez, J. M.; Bolink, H. J.; Constable, E. C.;
Sessolo, M.; Orti, E.; Housecroft, C. E. J. Mater. Chem. C 2018, 6,
12679.
2-(3-Chlorophenyl)-6-(4-methoxyphenyl)pyridine (2ad)
White solid; yield: 168 mg (57%); mp 155–157 °C.
1H NMR (400 MHz, CDCl3):  = 8.17–8.15 (m, 1 H), 8.10 (d, J = 8.9 Hz, 2
H), 7.99 (dt, J = 7.0, 1.9 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.65 (dd, J =
7.9, 0.9 Hz, 1 H), 7.60 (dd, J = 7.8, 0.9 Hz, 1 H), 7.43–7.39 (m, 2 H), 7.02
(d, J = 8.9 Hz, 2 H), 3.88 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.62, 156.68, 155.17, 141.40,
137.59, 134.78, 131.84, 129.89, 128.87, 128.29, 127.16, 125.00,
118.47, 117.99, 114.12, 55.40.
HRMS (ESI): m/z calcd for C18H15ClNO [M + H]+: 296.0837; found:
(4) (a) Burriss, A.; Edmunds, A. J. F.; Emery, D.; Hall, R. G.; Jacob, O.;
Schaetzer, J. Pest. Manag. Sci. 2018, 74, 1228. (b) Guan, A.; Liu,
C.; Chen, W.; Yang, F.; Xie, Y.; Zhang, J.; Li, Z.; Wang, M. J. Agric.
Food Chem. 2017, 65, 1272. (c) Nauha, E.; Kolehmainen, E.;
Nissinen, M. CrystEngComm 2011, 13, 6531. (d) Nauha, E.;
Nissinen, M. J. Mol. Struct. 2011, 1006, 566.
(5) (a) Prachayasittikul, S.; Pingaew, R.; Worachartcheewan, A.;
Sinthupoom, N.; Prachayasittikul, V.; Ruchirawat, S.;
Prachayasittikul, V. Mini-Rev. Med. Chem. 2017, 17, 869.
(b) Ghobadian, R.; Mahdavi, M.; Nadri, H.; Moradi, A.; Edraki, N.;
Akbarzadeh, T.; Sharifzadeh, M.; Bukhari, S. N. A.; Amini, M. Eur.
J. Med. Chem. 2018, 155, 49. (c) Huang, Y.; Wang, Q.; Wu, Y.
J. Pharm. Sci. 2018, 107, 1633. (d) Zhou, Y.; Zhu, X.; Zhang, L.;
Tang, C.; Feng, B. Chem. Biol. Drug Des. 2019, 93, 67.
296.0839.
2,6-Bis(4-bromophenyl)pyridine (2ae)
White solid; yield: 283 mg (73%); mp 96–98 °C.
1H NMR (400 MHz, CDCl3):  = 8.00 (d, J = 8.6 Hz, 4 H), 7.81 (dd, J = 8.3,
7.3 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 2 H), 7.62 (d, J = 8.6 Hz, 4 H).
13C NMR (101 MHz, CDCl3):  = 155.79, 138.12, 137.81, 131.88,
128.53, 123.61, 118.72.
HRMS (ESI): m/z calcd for C17H12BrN [M + H]+: 387.9331; found:
387.9336.
2-(tert-Butyl)-6-phenylpyridine (2af)
Pale yellow oil; yield: 42 mg (20%).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
Y. Gao et al.
Paper
Synthesis
(6) Conlon, I. L.; Van Eker, D.; Abdelmalak, S.; Murphy, W. A.;
Bashir, H.; Sun, M.; Chauhan, J.; Varney, K. M.; Godoy-Ruiz, R.;
Wilder, P. T.; Fletcher, S. Bioorg. Med. Chem. Lett. 2018, 28, 1949.
(7) (a) Bertuzzi, G.; Sinisi, A.; Caruana, L.; Mazzanti, A.; Fochi, M.;
Bernardi, L. ACS Catal. 2016, 6, 6473. (b) Binnani, C.; Rai, R. K.;
Tyagi, D.; Mobin, S. M.; Singh, S. K. Eur. J. Inorg. Chem. 2018,
1435. (c) Greve, E.; Porter, J. D.; Dockendorff, C. Synthesis 2019,
51, 450. (d) Ramesh, R.; Arivazhagan, M.; Malecki, J. G.; Lalitha,
A. Synlett 2018, 29, 1897. (e) Zhang, Y.; Zhang, Y.; Sun, Y. L.; Du,
X.; Shi, J. Y.; Wang, W. D.; Wang, W. Chem. Eur. J. 2012, 18, 6328.
(8) (a) Xue, L.; Cheng, G.; Zhu, R.; Cui, X. RSC Adv. 2017, 7, 44009.
(b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645. (c) Evdokimov, N. M.; Magedov, I. V.; Kireev, A.
S.; Kornienko, A. Org. Lett. 2006, 8, 899. (d) Farooq, S.; Munawar,
M. A.; Ngani, Z. Curr. Org. Chem. 2018, 22, 2671. (e) Paplal, B.;
Nagaraju, S.; Sathish, K.; Kashinath, D. Catal. Commun. 2018,
103, 110.
(9) (a) Abdelwahab, A. B.; Hanna, A. G.; Kirsch, G. Synthesis 2017,
49, 2971. (b) Quiroga, J.; Diaz, Y.; Insuasty, B.; Abonia, R.;
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2010, 51, 2928. (c) Sun,
S. G.; Liu, Y. C.; Liu, Q.; Zhao, Y. L.; Dong, D. W. Synlett 2004,
1731. (d) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43,
2273. (e) Thomas, A. D.; Josemin; Asokan, C. V. Tetrahedron
2004, 60, 5069.
(10) (a) Lewis, D. E. Angew. Chem. Int. Ed. 2017, 56, 9660.
(b) Mastalir, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K. Tetra-
hedron Lett. 2016, 57, 333. (c) Sugimura, T.; Komatsu, A.; Koseki,
Y.; Usuki, T. Tetrahedron Lett. 2014, 55, 6343. (d) Usuki, T.;
Sugimura, T.; Komatsu, A.; Koseki, Y. Org. Lett. 2014, 16, 1672.
(e) Dagorn, F.; Yan, L.-H.; Gravel, E.; Leblanc, K.; Maciuk, A.;
Poupon, E. Tetrahedron Lett. 2011, 52, 3523. (f) Jin, F.; Li, Y. Catal.
Lett. 2009, 131, 545.
(11) (a) Bagley, M. C.; Glover, C. Molecules 2010, 15, 3211. (b) Bagley,
M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459. (c) Kantevari,
S.; Patpi, S. R.; Addla, D.; Putapatri, S. R.; Sridhar, B.; Yogeeswari,
P.; Sriram, D. ACS Comb. Sci. 2011, 13, 427. (d) Bagley, M. C.;
Dale, J. W.; Bower, J. Synlett 2001, 1149. (e) Bagley, M. C.; Dale, J.
W.; Hughes, D. D.; Ohnesorge, M.; Phillips, N. G.; Bower, J.
Synlett 2001, 1523. (f) Bashford, K. E.; Burton, M. B.; Cameron,
S.; Cooper, A. L.; Hogg, R. D.; Kane, P. D.; MacManus, D. A.;
Matrunola, C. A.; Moody, C. J.; Robertson, A. A. B.; Warne, M. R.
Tetrahedron Lett. 2003, 44, 1627.
Nandakumar, A.; Muralidharan, D.; Perumal, P. T. J. Comb. Chem.
2010, 12, 161. (d) Adib, M.; Tahermansouri, H.; Koloogani, S. A.;
Mohammadia, B.; Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47,
5957. (e) Fujimori, T.; Wirsching, P.; Janda, K. D. J. Comb. Chem.
2003, 5, 625.
(13) (a) Zhao, M.-N.; Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H.
Org. Lett. 2014, 16, 3082. (b) Bai, Y.; Tang, L.; Huang, H.; Deng,
G.-J. Org. Biomol. Chem. 2015, 13, 4404. (c) Manning, J. R.;
Davies, H. M. L. J. Am. Chem. Soc. 2008, 130, 8602. (d) Ohashi, M.;
Takeda, I.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133,
18018. (e) Midya, S. P.; Landge, V. G.; Sahoo, M. K.; Rana, J.;
Balaraman, E. Chem. Commun. 2018, 54, 90. (f) Huang, H.; Ji, X.;
Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (g) Neely, J. M.;
Rovis, T. J. Am. Chem. Soc. 2014, 136, 2735.
(14) Chen, J.; Ding, Y.; Gao, Y.; Zhou, D.; Hider, R.; Ma, Y. Chemistry
Select 2019, 4, 2404.
(15) (a) Liu, J.; Wang, C.; Wu, L.; Liang, F.; Huang, G. Synthesis 2010,
4228. (b) Pan, X.; Liu, Q.; Chang, L.; Yuan, G. RSC Adv. 2015, 5,
51183.
(16) (a) Csaky, A. G.; de la Herran, G.; Carmen Murcia, M. Chem. Soc.
Rev. 2010, 39, 4080. (b) Lear, M. J.; Hayashi, Y. ChemCatChem
2013, 5, 3499.
(17) (a) Nishimura, T.; Noishiki, A.; Hayashi, T. Chem. Commun. 2012,
48, 973. (b) Sawano, T.; Ashouri, A.; Nishimura, T.; Hayashi, T.
J. Am. Chem. Soc. 2012, 134, 18936. (c) Nishimura, T.; Yasuhara,
Y.; Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7872.
(18) (a) Chen, S.; Wu, L.; Shao, Q.; Yang, G.; Zhang, W. Chem.
Commun. 2018, 54, 2522. (b) Sugano, G.; Kawada, K.; Shigeta,
M.; Hata, T.; Urabe, H. Tetrahedron Lett. 2019, 60, 885. (c) Wu,
X.; Xie, F.; Ling, Z.; Tang, L.; Zhang, W. Adv. Synth. Catal. 2016,
358, 2510.
(19) Henon, H.; Mauduit, M.; Alexakis, A. Angew. Chem. Int. Ed. 2008,
47, 9122.
(20) Gan, K.; Ng, J. S.; Sadeer, A.; Pullarkat, S. A. Synlett 2016, 27, 254.
(21) Gao, Z.; Fletcher, S. P. Chem. Commun. 2018, 54, 3601.
(22) Gao, Y.; Zhou, D.; Ma, Y. ChemistrySelect 2018, 3, 9374.
(23) Yin, C.; Zhong, K.; Li, W.; Yang, X.; Sun, R.; Zhang, C.; Zheng, X.;
Yuan, M.; Li, R.; Lan, Y.; Fu, H.; Chen, H. Adv. Synth. Catal. 2018,
360, 3990.
(24) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc.
2011, 133, 6411.
(25) Sha, F.; Shen, H.; Wu, X.-Y. Eur. J. Org. Chem. 2013, 2537.
(12) (a) Sasaki, I.; Daran, J.-C.; Commenges, G. Beilstein J. Org. Chem.
2015, 11, 1781. (b) Jiang, B.; Hao, W.-J.; Wang, X.; Shi, F.; Tu, S.-J.
J. Comb. Chem. 2009, 11, 846. (c) Thirumurugan, P.;
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H