Acid-catalyzed tandem reaction for the synthesis of pyridine derivatives via C=C/C(sp3)-N bond cleavage of enones and primary amines

Article abstract of DOI:10.1039/c7ra00780a

A one-pot acid-catalyzed tandem reaction has been developed without any metallic reagents or extra oxidants. This reaction involves a C=C bond cleavage of enones via a “masked” reverse Aldol reaction, and C(sp³)-N bond cleavage of primary amines to provide nitrogen sources for the assembly of pyridine derivatives in high yields with excellent functional group tolerance.

Full text of DOI:10.1039/c7ra00780a

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Acid-catalyzed tandem reaction for the synthesis of
pyridine derivatives via C]C/C(sp3)–N bond
cleavage of enones and primary amines†
Cite this: RSC Adv., 2017, 7, 13123
*
Zhong-Yuan Mao, Xiao-Yun Liao, Heng-Shan Wang, Chun-Gu Wang, Ke-Bin Huang
*
and Ying-Ming Pan
Received 18th January 2017
Accepted 17th February 2017
A one-pot acid-catalyzed tandem reaction has been developed without any metallic reagents or extra
oxidants. This reaction involves a C]C bond cleavage of enones via a “masked” reverse Aldol reaction,
and C(sp3)–N bond cleavage of primary amines to provide nitrogen sources for the assembly of pyridine
derivatives in high yields with excellent functional group tolerance.
DOI: 10.1039/c7ra00780a
rsc.li/rsc-advances
substrates for building pyridines.11–13 For instance, Wang and
colleagues accomplished an impressive work that highly
Introduction
substituted pyridines were efficiently constructed via a Ru-
catalyzed dehydrative [4 + 2] cycloaddition of enamides and
alkynes (Scheme 1c).11 Cui's group disclosed a base-promoted
synthesis of polysubstituted pyridines from 1-arylethylamines
and ynones through the b-C(sp3)–H functionalization of
enaminones (Scheme 1d).12 Recently, Jiang, Yi and Dhavale
groups respectively reported the synthesis of 2,4,6-trisubsti-
tuted pyridines from ketones and amines (Scheme 1e).13
Nevertheless, it is rarely reported to construct pyridine rings
via C(sp3)–N bond cleavage of diverse primary amines provi-
ding the nitrogen source. Therefore, we herein present a rou-
te through tandem reverse Aldol reaction/condensation/
cyclization/aromatization for the formation of pyridine deriva-
tives via C]C/C(sp3)–N bond cleavage of enones/primary
amines. This new reaction system avoids the use of costly
catalyst and extra oxidant with broad functional group tolerance
at the cost of a catalytic amount of Brønsted acid in the absence
of any transitional metal (Scheme 1f).
Construction of N-heterocycles is one of the most signicant
areas in synthetic organic chemistry. Among them, the devel-
opment of efficient methods for building the pyridine motif has
attracted considerable attention since pyridine forms the
structural core of numerous natural products,1 pharmaceuti-
cals,2 and functionalized materials.3 During the past decades,
abundant methodologies have been disclosed for the
construction of pyridine rings, in which a variety of nitrogen-
containing substrates were used as building blocks.4,5 As we
know, the nitrogen source of pyridine rings can be provided by
compounds containing C^N, C]N and C–N bonds.6 Among
them, the metal-mediated [2 + 2 + 2] cycloaddition reaction
constitutes a powerful tool for the synthesis of pyridines from
nitriles and alkynes.7 In addition, the transition-metal-catalyzed
intermolecular reactions of compounds bearing a C]N group
(imines, oximes, oxime esters, etc.) and carbon–carbon unsat-
urated compounds (e.g., alkynes, alkenes, acrylic acids) have
been extensively studied and have become a fascinating method
to construct pyridines.8–10 For example, Cheng8 and Ellman9
groups respectively reported the Rh-catalyzed C–H functionali-
zation of a,b-unsaturated ketoximes with alkynes to produce
substituted pyridines (Scheme 1a). Another Rh-catalyzed C–H
functionalization of unsaturated oxime esters with alkenes or
acrylic acids was reported by Rovis' group (Scheme 1b).10
Moreover, compounds tethered with C(sp2)–N and C(sp3)–N
bonds have also been widely utilized as nitrogen-containing
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources,
School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University,
Guilin 541004, People's Republic of China. E-mail: hkg2003@163.com;
panym2013@hotmail.com
† Electronic supplementary information (ESI) available: Experimental procedure,
spectral data for all products, and X-ray crystallographic les (CIF) for 3a and 3k.
CCDC 1498096 and 1498097. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c7ra00780a
Scheme 1 Comparison of previous study and our work.
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Table 2 Scope of [N] sources for the reactiona
Results and discussion
We initiated our research on the model reaction of enone 1a with
primary amine 2a for screening optimum reaction conditions
(Table 1). The desired product 3a was obtained in 51% isolated
yield upon treatment ofꢀa 1 : 1 mixture of 1a and 2a with 5 mol%
TfOH in xylene at 100 C for 2 h (Table 1, entry 1). We subse-
quently varied the reaction temperature from 100 to 130 ꢀC,
[N] source
R3
R4
R5
Yield of 3ab (%)
ꢀ
which showed that 130 C is optimal for this protocol (Table 1,
2b
2c
2d
2e
2f
2g
2h
2i
4-MeOC6H4
4-F3CC6H4
2-Furyl
2-Thienyl
Bn
Et
Me
i-Pr
i-Bu
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Me
95
88
81
86
77
56
40
63
67
71
n.r.c
entries 2–4). Compared with 5 mol% TfOH, the yield of 3a was
not distinctly improved as the amount of TfOH was increased to
10 mol% (Table 1, entry 5). When TfOH was replaced by other
acids (e.g., PhCO2H, AcOH, PivOH, HCl, TFA, TsOH, MsOH), the
yield of 3a remarkably decreased (Table 1, entries 6–12). Without
any acids, TLC analysis indicated no desired product formation
(Table 1, entry 13). Furthermore, several different solvents were
also surveyed (e.g., DMF, DMSO, NMP, MeCN and 1,4-dioxane),
and the results revealed that xylene is the optimal solvent for this
reaction (Table 1, entry 4 vs. entries 14–18).
With the optimal reaction conditions in hand, we proceeded
to explore the nitrogen source scope for this reaction, as shown
in Table 2. The aromatic methylamines (2b–2f) as nitrogen
sources gave the desired pyridine 3a in high yields. Moreover,
treatment of 1a with various aliphatic amines (2g–2k) produced
3a in 40–71% yields, but tert-butylamine (2l) could not provide
the nitrogen atom for the synthesis of pyridine 3a. These results
indicate that at least one hydrogen atom at a-position of amino
is necessary for this reaction.
2j
2k
2l
3-Heptyl
Me
H
Me
a
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), TfOH (5 mol%) and
xylene (1 mL) for 2 h. b Isolated yield. c No reaction.
Subsequently, the scope of enones was investigated under
the optimal conditions (Table 3). Enones containing one or
more electron-withdrawing groups (EWG ¼ F, Cl, Br, CF3, CN,
t
NO2) or electron-donating groups (EDG ¼ Me, Bu, N(Me)2,
OMe) on the phenyl ring (R1) are both well-tolerated and
afforded excellent yields (80–93%, 3b–3l). Variation of the
electronic properties of the substituents on the aromatic ring
(R2) has little inuence on the reaction efficiency (3m–3r).
Notably, 4,40-dihalogen substituted aryl enone also proceeded
smoothly with 85% yield (3s). Gratifyingly, enones bearing
heterocycle and fused ring reacted efficiently as well to give the
corresponding product 3t–3w in 78–86% yields. With respect to
aromatic rings, the alkyl-substituted enones were also tolerated
in this transformation, generating the corresponding 2,4,6-
trisubstituted pyridines 3x and 3y in 61% and 72% isolated
yields, respectively. Unfortunately, benzalacetone failed to
afford the desired product 3z. The structures of 3a and 3k were
unambiguously conrmed by single-crystal X-ray diffraction
analysis (Fig. 1).14
Table 1 Optimization of the reaction conditionsa
Entry
Acid
Solvent
Temp. (ꢀC)
Yieldb (%)
1
2
3
TfOH
TfOH
TfOH
TfOH
TfOH
PhCO2H
AcOH
PivOH
HCl
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
DMF
100
110
120
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
51
72
85
92
93
33
37
28
68
87
76
81
n.d.d
46
33
39
70
82
With the aim of evaluating the practicality of this catalytic
process, a gram-scale experiment was performed with 1a (10
mmol) and 2a (15 mmol was added in two portions), yielding
the corresponding product 3a in 72% (Scheme 2).
To gain insight into the mechanism of this new reaction, we
conducted several control experiments (Scheme 3). When the
model substrates 1a, and 2a were reacted under argon atmo-
4
5c
6
7
8
9
10
11
12
13
14
15
16
17
18
TFA
TsOH
MsOH
—
TfOH
TfOH
TfOH
TfOH
TfOH
ꢀ
sphere in xylene at 130 C, we failed to obtain the product 3a.
The reaction of 1a with 2a under oxygen atmosphere resulted in
the formation of 3a with 91% isolated yield. The results
replacing air with Ar or O2 demonstrated that molecular oxygen
is essential as an oxidant for this transformation. Under the
standard conditions, the reaction of 4 with 1a and 2a afforded
3a in 89% isolated yield, and the reaction of 5 with 1a and 2a
afforded 6, 3a and 3n, indicating that acetophenone should be
a reactive intermediate in this process.
DMSO
NMP
CH3CN
1,4-Dioxane
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), acid (5 mol%) and
solvent (1 mL) for 2 h. b Isolated yield. c 10 mol% TfOH. d Not detected.
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Table 3 Scope of enonesa
Scheme 2 Gram scale synthesis.
Scheme 3 Control experiments.
The above results have led us to propose a reaction mecha-
nism, which is depicted in Scheme 4 using 3a as a representa-
tive example. Originally with Brønsted acid catalysis, the reverse
Aldol reaction of 1a proceeds to give acetophenone, which
reacts with 2a to obtain the dehydrative condensation product
imine A. Then, 1,4-addition of imine A to another molecule of
1a generates intermediate B. Subsequent intramolecular
nucleophilic addition and dehydration of intermediate B
affords 1,4-dihydropyridine C. Finally, aerobic oxidative C(sp3)–
N bond cleavage of dihydropyridine C leads to its aromatization,
with the latter being the driving force of this oxidation.
According to the mechanism proposed in Scheme 4, the
reaction of (E)-chalcone to acetophenone and benzaldehyde is
reversible, the decomposition of C would give the desired
pyridine and benzaldehyde. If substituted BnNH2 (such as
p-tolylmethanamine) was used, “unsymmetric” chalcone would
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), TfOH (5 mol%) and
xylene (1 mL) for 2 h. Isolated yields are shown.
Fig. 1 X-ray crystal structures of 3a (CCDC 1498096) and 3k (CCDC
1498097).
Scheme 4 Possible mechanism.
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(chloroform d 77.00) or tetramethylsilane (TMS d 0.00) was used
as a reference. High resolution mass spectra (HRMS) were
recorded on the Exactive Mass Spectrometer equipped with ESI
ionization source.
General experimental procedure for the synthesis of
pyridines 3
The reaction mixture of enones 1 (0.5 mmol), primary amines 2
(0.5 mmol) and TfOH (5 mol%) in xylene (1 mL) was stirred at
130 ꢀC for 2 h in test tube, and periodically monitored by TLC.
Upon completion, the crude product was cooled to room
temperature and then directly separated by ash column
chromatography on silica gel to give the pure product 3.
2,4,6-Triphenylpyridine (3a). White solid (71 mg, 92%), mp
137.0–137.8 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.29 (d, J ¼ 7.1 Hz,
Fig. 2 ESI-MS based analysis during the formation of 3a.
4H), 7.94 (s, 2H), 7.79 (d, J ¼ 7.0 Hz, 2H), 7.62–7.48 (m, 9H); 13
C
NMR (100 MHz, CDCl3) d 157.4, 150.1, 139.5, 138.9, 129.0, 129.0,
128.9, 128.6, 127.1, 127.1, 117.0; HRMS (ESI) for C23H18N ([M +
H]+): calcd 308.1434, found 308.1432.
generated. As a result, the generated “unsymmetric” chalcone
would react with acetophenone and benzyl amine to form
pyridines with 4-different substituent. In fact, we did not obtain
the 4-different substituent pyridines, because it is adverse that
ketones with aldehydes perform an Aldol reaction at this reac-
2,6-Diphenyl-4-(p-tolyl)pyridine (3b). White solid (69 mg,
86%), mp 118.5–120.2 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.29 (d, J
¼ 7.1 Hz, 4H), 7.93 (s, 2H), 7.70 (d, J ¼ 8.1 Hz, 2H), 7.62–7.56 (m,
ꢀ
4H), 7.54–7.49 (m, 2H), 7.38 (d, J ¼ 7.9 Hz, 2H), 2.49 (s, 3H); 13
C
tion temperature (130 C).
ESI/MS experiments were performed to gain evidence for the
possible intermediates in the proposed mechanism. A mixture
of 1a (0.5 mmol), 2a (0.5 mmol) and TfOH (5 mol%) in xylene (1
mL) was reacted at 130 ꢀC for 15 min and 50 mL of the mixture
was used for the ESI analysis in MeOH. The ESI/MS analyses
showed three peaks at m/z 210.1269, m/z 418.2148, and m/z
400.1953 which were respectively identied as imine A, inter-
mediate B, and dihydropyridine C (Fig. 2).
NMR (100 MHz, CDCl3) d 157.3, 149.9, 139.6, 139.0, 135.9, 129.7,
128.9, 128.6, 127.1, 126.9, 116.8, 21.2; HRMS (ESI) for C24H20N
([M + H]+): calcd 322.1590, found 322.1590.
2,6-Diphenyl-4-(3-(triuoromethyl)phenyl)pyridine (3c). Pale
yellow solid (78 mg, 83%), mp 125.8–127.5 ꢀC; 1H NMR (400
MHz, CDCl3) d 8.22 (d, J ¼ 7.1 Hz, 4H), 7.99 (s, 1H), 7.93 (d, J ¼
7.7 Hz, 1H), 7.88 (s, 2H), 7.75 (d, J ¼ 7.8 Hz, 1H), 7.67 (t, J ¼
7.7 Hz, 1H), 7.56–7.45 (m, 6H); 13C NMR (100 MHz, CDCl3)
2
d 157.8, 148.8, 140.0, 139.2, 131.6 (q, JC–F ¼ 32.6 Hz) 130.53,
129.7, 129.3, 128.8, 127.2, 125.6 (q, 3JC–F ¼ 3.7 Hz), 124.0 (q, 1JC–F
Conclusions
3
¼ 270.8 Hz), 124.0 (q, JC–F ¼ 3.8 Hz), 117.0; HRMS (ESI) for
24H17NF3 ([M + H]+): calcd 376.1308, found 376.1306.
In summary, we have demonstrated an expedient approach for
the synthesis of 2,4,6-trisubstituted pyridines via sequential
reverse Aldol reaction/dehydrative condensation/addition–
cyclization/aromatization, catalyzed by Brønsted acid. The use
of naturally abundant air as an oxidant, readily available start-
ing materials including the nitrogen source, and experimentally
convenient catalytic process are the additional advantages of
the present protocol. Further investigations on the synthetic
applications of this reaction are ongoing in our laboratory.
C
4-(4-Chlorophenyl)-2,6-diphenylpyridine (3d). White solid
1
ꢀ
(73 mg, 85%), mp 124.3–125.6 C; H NMR (400 MHz, CDCl3)
d 8.21 (d, J ¼ 7.0 Hz, 4H), 7.84 (s, 2H), 7.68 (d, J ¼ 8.5 Hz, 2H),
7.56–7.47 (m, 8H); 13C NMR (100 MHz, CDCl3) d 157.6, 148.9,
139.3, 137.4, 135.1, 129.3, 129.1, 128.7, 128.4, 127.1, 116.7;
HRMS (ESI) for C23H17NCl ([M + H]+): calcd 342.1044, found
342.1042.
4-(2,6-Diphenylpyridin-4-yl)benzonitrile (3e). White solid
1
ꢀ
(74 mg, 89%), mp 190.8–192.3 C; H NMR (400 MHz, CDCl3)
d 8.19 (d, J ¼ 7.0 Hz, 4H), 7.78 (d, J ¼ 8.8 Hz, 6H), 7.57–7.45 (m,
6H); 13C NMR (100 MHz, CDCl3) d 157.6, 147.9, 143.2, 138.9,
132.7, 129.3, 128.7, 127.7, 127.0, 118.4, 116.6, 112.5; HRMS (ESI)
Experimental
General experimental details
Unless otherwise noted, commercial reagents were used for C24H17N2 ([M + H]+): calcd 333.1386, found 333.1385.
without further purication. All manipulations were performed
4-(2,6-Diphenylpyridin-4-yl)-N,N-dimethylaniline (3f). Pale
under an air atmosphere unless otherwise statement. Reaction yellow solid (70 mg, 80%), mp 120.1–121.8 ꢀC; 1H NMR (400
temperatures were controlled using IKAmag temperature MHz, CDCl3) d 8.26 (d, J ¼ 7.1 Hz, 4H), 7.91 (s, 2H), 7.72 (d, J ¼
modulator. Column chromatography was performed on silica 8.9 Hz, 2H), 7.56 (t, J ¼ 7.4 Hz, 4H), 7.51–7.45 (m, 2H), 6.86 (d, J
gel (300–400 mesh). NMR spectra were obtained using a Bruker ¼ 8.9 Hz, 2H), 3.05 (s, 6H); 13C NMR (100 MHz, CDCl3) d 157.2,
400 MHz spectrometer. Chemical shis were reported in parts 151.0, 149.8, 140.0, 128.7, 128.6, 127.7, 127.1, 125.9, 115.9,
per million (ppm), and the residual solvent peak was used as an 112.4, 40.2; HRMS (ESI) for C25H23N2 ([M + H]+): calcd 351.1856,
internal reference: proton (chloroform
d 7.26), carbon found 351.1844.
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4-(4-(tert-Butyl)phenyl)-2,6-diphenylpyridine (3g). White
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4-Phenyl-2,6-di-p-tolylpyridine (3n). White solid (79 mg,
solid (80 mg, 88%), mp 87.2–88.3 ꢀC; 1H NMR (400 MHz, CDCl3) 94%), mp 162.8–163.9 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.15 (d, J
d 8.39 (d, J ¼ 7.5 Hz, 4H), 8.02 (s, 2H), 7.80 (d, J ¼ 8.3 Hz, 2H), ¼ 8.1 Hz, 4H), 7.87 (s, 2H), 7.77 (d, J ¼ 7.0 Hz, 2H), 7.58–7.47 (m,
7.67 (t, J ¼ 8.0 Hz, 6H), 7.58 (t, J ¼ 7.2 Hz, 2H), 1.54 (s, 9H); 13
C
3H), 7.36 (d, J ¼ 8.0 Hz, 4H), 2.47 (s, 6H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3) d 157.2, 152.0, 149.8, 139.5, 135.9, 128.8, CDCl3) d 157.3, 150.0, 139.2, 138.9, 136.8, 129.4, 129.0, 128.8,
128.5, 127.0, 126.7, 125.9, 116.8, 34.5, 31.2; HRMS (ESI) for 127.1, 127.0, 116.5, 21.27; HRMS (ESI) for C25H22N ([M + H]+):
C
27H26N ([M + H]+): calcd 364.2060, found 364.2045.
calcd 336.1747, found 336.1739.
4-(4-Methoxyphenyl)-2,6-diphenylpyridine (3h). White solid
2,6-Bis(4-methoxyphenyl)-4-phenylpyridine (3o). White solid
1
1
ꢀ
ꢀ
(77 mg, 91%), mp 102.5–104.0 C; H NMR (400 MHz, CDCl3) (82 mg, 89%), mp 129.5–131.3 C; H NMR (400 MHz, CDCl3)
d 8.28 (d, J ¼ 7.2 Hz, 4H), 7.89 (s, 2H), 7.72 (d, J ¼ 8.8 Hz, 2H), d 8.15 (d, J ¼ 8.8 Hz, 4H), 7.72 (s, 2H), 7.68 (d, J ¼ 7.0 Hz, 2H),
7.58 (t, J ¼ 7.4 Hz, 4H), 7.51 (t, J ¼ 7.3 Hz, 2H), 7.07 (d, J ¼ 8.8 Hz, 7.50–7.39 (m, 3H), 7.01 (d, J ¼ 8.8 Hz, 4H), 3.80 (s, 6H); 13C NMR
2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d 160.3, 157.2, (100 MHz, CDCl3) d 160.4, 156.7, 149.7, 139.1, 132.2, 128.9,
149.4, 139.6, 131.0, 128.9, 128.6, 128.2, 127.0, 116.4, 114.4, 55.2; 128.6, 128.2, 127.0, 115.4, 113.9, 55.1; HRMS (ESI) for
HRMS (ESI) for C24H20ON ([M + H]+): calcd 338.1539, found
338.1537.
C
25H22O2N ([M + H]+): calcd 368.1645, found 368.1644.
2,6-Bis(3-chlorophenyl)-4-phenylpyridine (3p). White solid
1
ꢀ
4-(3-Bromophenyl)-2,6-diphenylpyridine (3i). White solid (80 mg, 85%), mp 180.5–181.6 C; H NMR (400 MHz, CDCl3)
1
ꢀ
(79 mg, 82%), mp 106.3–107.5 C; H NMR (400 MHz, CDCl3) d 8.20–8.14 (m, 2H), 8.04 (ddd, J ¼ 6.2, 2.9, 1.7 Hz, 2H), 7.83 (s,
d 8.22 (d, J ¼ 7.0 Hz, 4H), 7.89 (t, J ¼ 1.8 Hz, 1H), 7.84 (s, 2H), 2H), 7.74–7.69 (m, 2H), 7.57–7.41 (m, 7H); 13C NMR (100 MHz,
7.66 (ddd, J ¼ 7.7, 1.7, 1.0 Hz, 1H), 7.61 (ddd, J ¼ 8.0, 1.9, 1.0 Hz, CDCl3) d 156.0, 150.4, 141.0, 138.3, 134.8, 129.9, 129.2, 129.1 (2),
1H), 7.56–7.52 (m, 4H), 7.49–7.45 (m, 2H), 7.40 (t, J ¼ 7.9 Hz, 127.1 (2), 125.1, 117.5; HRMS (ESI) for C23H16NCl2 ([M + H]+):
1H); 13C NMR (100 MHz, CDCl3) d 157.6, 148.6, 141.2, 139.3, calcd 376.0654, found 376.0644.
131.9, 130.6, 130.2, 129.2, 128.7, 127.1, 125.8, 123.2, 116.9;
HRMS (ESI) for C23H17NBr ([M + H]+): calcd 386.0539, found (75 mg, 87%), mp 117.3–118.5 C; H NMR (400 MHz, CDCl3)
386.0538.
2,6-Bis(2-uorophenyl)-4-phenylpyridine (3q). White solid
1
ꢀ
d 8.16 (t, J ¼ 7.3 Hz, 2H), 7.96 (s, 2H), 7.68 (d, J ¼ 7.3 Hz, 2H),
4-(2-Nitrophenyl)-2,6-diphenylpyridine (3j). White solid 7.47–7.29 (m, 5H), 7.24 (t, J ¼ 7.4 Hz, 2H), 7.13 (dd, J ¼ 10.9,
1
(78 mg, 88%), mp 111.5–112.9 ꢀC; H NMR (400 MHz, CDCl3) 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 160.6 (d, 1JC–F ¼ 249.8
d 8.20–8.15 (m, 4H), 8.02 (dd, J ¼ 8.1, 1.1 Hz, 1H), 7.72–7.68 (m, Hz), 153.5 (d, 4JC–F ¼ 2.3 Hz), 149.3, 138.4, 131.3 (d, 4JC–F ¼ 2.8
1H), 7.63 (s, 2H), 7.62–7.57 (m, 1H), 7.54–7.49 (m, 5H), 7.48–7.43 Hz), 130.4 (d, 3JC–F ¼ 8.6 Hz), 129.0, 128.9, 127.4 (d, 2JC–F ¼ 11.3
3
3
(m, 2H); 13C NMR (100 MHz, CDCl3) d 157.3, 148.7, 147.3, 139.0, Hz), 127.2, 124.4 (d, JC–F ¼ 3.5 Hz), 121.3 (d, JC–F ¼ 9.7 Hz),
134.6, 132.9, 131.5, 129.4, 129.2, 128.7, 127.1, 124.5, 117.8; HRMS 116.1 (d, 2JC–F ¼ 23.1 Hz); HRMS (ESI) for C23H16NF2 ([M + H]+):
(ESI) for C23H17O2N2 ([M + H]+): calcd 353.1284, found 353.1284. calcd 344.1245, found 344.1234.
4-(2-Chloro-6-uorophenyl)-2,6-diphenylpyridine (3k). White
4-Phenyl-2,6-di-o-tolylpyridine (3r). White solid (70 mg,
solid (84 mg, 93%), mp 177.8–178.5 ꢀC; 1H NMR (400 MHz, 83%), mp 132.2–133.9 ꢀC; 1H NMR (400 MHz, CDCl3) d 7.77 (d, J
CDCl3) d 8.26–8.23 (m, 4H), 7.76 (s, 2H), 7.59–7.52 (m, 4H), 7.51– ¼ 7.0 Hz, 2H), 7.65 (s, 2H), 7.59–7.47 (m, 5H), 7.38–7.32 (m, 6H),
7.45 (m, 2H), 7.41–7.32 (m, 2H), 7.17 (ddd, J ¼ 9.3, 7.6, 1.9 Hz, 2.55 (s, 6H); 13C NMR (100 MHz, CDCl3) d 160.1, 148.7, 140.7,
1
1H); 13C NMR (100 MHz, CDCl3) d 160.0 (d, JC–F ¼ 250.1 Hz), 138.4, 135.8, 130.6, 129.8, 129.1, 129.0, 128.2, 127.1, 125.8,
157.0, 142.1, 139.2, 133.9 (d, 3JC–F ¼ 4.0 Hz), 130.1 (d, 2JC–F ¼ 9.4 120.0, 20.58; HRMS (ESI) for C25H22N ([M + H]+): calcd 336.1747,
3
Hz), 129.1, 128.7, 127.1, 126.9, 125.7 (d, JC–F ¼ 3.5 Hz), 120.1 found 336.1733.
4
2
(d, JC–F ¼ 1.0 Hz), 114.5 (d, JC–F ¼ 22.7 Hz); HRMS (ESI) for
4-(4-Chlorophenyl)-2,6-bis(4-uorophenyl)pyridine
(3s).
C
23H16NClF ([M + H]+): calcd 360.0950, found 360.0950.
White solid (80 mg, 85%), mp 207.0–208.2 ꢀC; 1H NMR (400
4-(3,4-Dimethoxyphenyl)-2,6-diphenylpyridine (3l). White MHz, CDCl3) d 8.19–8.13 (m, 4H), 7.76 (s, 2H), 7.68–7.62 (m,
solid (84 mg, 91%), mp 99.8–101.5 ꢀC; 1H NMR (400 MHz, 2H), 7.53–7.47 (m, 2H), 7.23–7.17 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 8.17 (d, J ¼ 7.4 Hz, 4H), 7.79 (s, 2H), 7.48 (t, J ¼ 7.5 Hz, CDCl3) d 163.7 (d, 1JC–F ¼ 248.9 Hz), 156.6, 149.2, 137.2, 135.4 (d,
3
4H), 7.41 (t, J ¼ 7.2 Hz, 2H), 7.25 (d, J ¼ 8.2 Hz, 1H), 7.19 (t, J ¼ 4JC–F ¼ 2.8 Hz), 129.4, 128.9 (d, JC–F ¼ 8.3 Hz), 128.4, 127.1,
2
3.0 Hz, 1H), 6.93 (d, J ¼ 8.3 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H); 13
C
116.3, 115.6 (d, JC–F ¼ 21.6 Hz); HRMS (ESI) for C23H15NClF2
NMR (100 MHz, CDCl3) d 157.3, 149.8, 149.8, 149.3, 139.5, 131.6, ([M + H]+): calcd 378.0856, found 378.0855.
128.9, 128.5, 127.0, 119.7, 116.6, 111.4, 110.1, 56.0, 55.9; HRMS
2,4,6-Tri(thiophen-2-yl)pyridine (3t). White solid (70 mg,
(ESI) for C25H22O2N ([M + H]+): calcd 368.1645, found 368.1645. 86%), mp 129.9–131.8 ꢀC; 1H NMR (400 MHz, CDCl3) d 7.70 (dd,
2,6-Bis(4-uorophenyl)-4-phenylpyridine (3m). White solid J ¼ 3.7, 1.1 Hz, 2H), 7.65 (s, 2H), 7.56 (dd, J ¼ 3.7, 1.1 Hz, 1H),
1
(77 mg, 90%), mp 178.1–178.4 C; H NMR (400 MHz, CDCl3) 7.43 (ddd, J ¼ 4.0, 2.9, 1.1 Hz, 3H), 7.17–7.13 (m, 3H); 13C NMR
ꢀ
d 8.22–8.14 (m, 4H), 7.80 (s, 2H), 7.72 (d, J ¼ 6.7 Hz, 2H), 7.58– (100 MHz, CDCl3) d 152.6, 144.6, 142.8, 141.2, 128.3, 127.9,
7.48 (m, 3H), 7.25–7.16 (m, 4H); 13C NMR (100 MHz, CDCl3) 127.8, 127.0, 125.4, 124.9, 113.1; HRMS (ESI) for C17H12NS3 ([M
d 163.6 (d, 1JC–F ¼ 248.6 Hz), 156.3, 150.3, 138.7, 135.5 (d, 4JC–F
¼
+ H]+): calcd 326.0126, found 326.0125.
3.1 Hz), 129.1, 129.0, 128.8 (d, 3JC–F ¼ 8.3 Hz), 127.1, 116.5, 115.5
2-(2,6-Diphenylpyridin-4-yl)quinoline (3u). Brown solid
(d, 2JC–F ¼ 21.5 Hz); HRMS (ESI) for C23H16NF2 ([M + H]+): calcd (70 mg, 78%), mp 167.2–168.9 C; H NMR (400 MHz, CDCl3)
1
ꢀ
344.1245, found 344.1245.
d 8.46 (s, 2H), 8.35–8.24 (m, 6H), 7.99 (d, J ¼ 8.6 Hz, 1H), 7.87 (d,
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J ¼ 8.1 Hz, 1H), 7.82–7.77 (m, 1H), 7.63–7.53 (m, 5H), 7.48 (t, J ¼
7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 157.6, 155.1, 148.3,
148.2, 139.5, 137.2, 130.0 (2), 129.0, 128.6, 127.8, 127.5, 127.2,
127.1, 118.6, 116.9; HRMS (ESI) for C26H19N2 ([M + H]+): calcd
359.1543, found 359.1528.
J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, 4, 2337; (e) D. F. Fisher and
R. Sarpong, J. Am. Chem. Soc., 2010, 132, 5926; (f) C. Yuan,
C.-T. Chang, A. Axelrod and D. Siegel, J. Am. Chem. Soc.,
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Med. Chem., 2011, 54, 3451.
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X.-C. Hang, T. Fleetham, E. Turner, J. Brooks and J. Li,
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T. Takeda and J. Kido, Adv. Mater., 2008, 20, 2125.
4-(Naphthalen-2-yl)-2,6-diphenylpyridine (3v). White solid
1
ꢀ
(73 mg, 82%), mp 251.8–252.9 C; H NMR (400 MHz, CDCl3)
d 8.24 (d, J ¼ 7.1 Hz, 4H), 7.97 (d, J ¼ 8.1 Hz, 2H), 7.86 (s, 2H),
7.63–7.45 (m, 11H); 13C NMR (100 MHz, CDCl3) d 156.9, 150.2,
139.4, 138.1, 133.8, 131.0, 129.1, 128.8, 128.7, 128.5, 127.1, 126.7
(2), 126.2, 125.4, 120.1, 117.1; HRMS (ESI) for C27H20N ([M +
H]+): calcd 358.1590, found 358.1589.
´
4 For partial reviews, see: (a) J. A. Varela and C. Saa, Chem. Rev.,
2003, 103, 3787; (b) I. Nakamura and Y. Yamamoto, Chem.
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Soc. Rev., 2007, 36, 1085; (e) B. Groenendaal, E. Ruijter and
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Synthesis, 2011, 3209.
2,6-Di(naphthalen-2-yl)-4-phenylpyridine (3w). White solid
1
ꢀ
(88 mg, 86%), mp 159.7–161.2 C; H NMR (400 MHz, CDCl3)
d 8.71 (s, 2H), 8.45 (dd, J ¼ 8.6, 1.7 Hz, 2H), 8.08–8.01 (m, 6H),
7.93 (dd, J ¼ 8.1, 4.3 Hz, 2H), 7.85–7.80 (m, 2H), 7.62–7.51 (m,
7H); 13C NMR (100 MHz, CDCl3) d 157.4, 150.2, 139.0, 136.9,
133.8, 133.5, 129.1, 129.0, 128.7, 128.4, 127.7, 127.2, 126.5,
126.2, 124.9, 117.4; HRMS (ESI) for C31H22N ([M + H]+): calcd
408.1747, found 408.1732.
5 (a) T. J. Donohoe, J. A. Basutto, J. F. Bower and A. Rathi, Org.
Lett., 2011, 13, 1036; (b) D. G. Stark, L. C. Morrill, P.-P. Yeh,
´
A. M. Z. Slawin, T. J. C. ORiordan and A. D. Smith, Angew.
4-Pentyl-2,6-diphenylpyridine (3x). Pale yellow oil (46 mg,
61%), mp 190.8–192.3 ꢀC; 1H NMR (400 MHz, CDCl3) d 8.04 (d, J
¼ 7.1 Hz, 4H), 7.39–7.34 (m, 6H), 7.31–7.26 (m, 2H), 2.62–2.54
(m, 2H), 1.64–1.54 (m, 2H), 1.33–1.18 (m, 4H), 0.80 (t, J ¼ 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 156.8, 153.1, 139.7, 128.7,
128.5, 127.0, 119.0, 35.7, 31.4, 30.2, 22.5, 13.9; HRMS (ESI) for
Chem., Int. Ed., 2013, 52, 11642; (c) T. Sakai and
R. L. Danheiser, J. Am. Chem. Soc., 2010, 132, 13203; (d)
M. Yoshida, T. Mizuguchi and K. Namba, Angew. Chem.,
Int. Ed., 2014, 53, 14550; (e) C.-H. Lei, D.-X. Wang, L. Zhao,
J. Zhu and M.-X. Wang, J. Am. Chem. Soc., 2013, 135, 4708;
(f) Z. Shi and T.-P. Loh, Angew. Chem., Int. Ed., 2013, 52,
8584; (g) Y. Jiang, C.-M. Park and T.-P. Loh, Org. Lett., 2014,
16, 3432; (h) F. Sha and X. Huang, Angew. Chem., Int. Ed.,
2009, 48, 3458; (i) K. Kral and M. Hapke, Angew. Chem., Int.
Ed., 2011, 50, 2434; (j) P. Huang, R. Zhang, Y. Liang and
D. Dong, Org. Lett., 2012, 14, 5196; (k) C. Allais, F. Lieby-
Muller, T. Constantieux and J. Rodriguez, Adv. Synth.
Catal., 2012, 354, 2537.
6 For some selected examples, see: (a) D. A. Colby,
R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2008,
130, 3645; (b) S. Duttwyler, C. Lu, A. L. Rheingold,
R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2012,
134, 4064; (c) T. K. Hyster and T. Rovis, Chem. Commun.,
2011, 47, 11846; (d) K. Parthasarathy and C.-H. Cheng, J.
Org. Chem., 2009, 74, 9359; (e) C.-Z. Luo, J. Jayakumar,
P. Gandeepan, Y.-C. Wu and C.-H. Cheng, Org. Lett., 2015,
17, 924; (f) T. Yamakawa and N. Yoshikai, Org. Lett., 2013,
15, 196; (g) Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013,
135, 3756; (h) G. Cheng, Y. Weng, X. Yang and X. Cui, Org.
Lett., 2015, 17, 3790.
C
22H24N ([M + H]+): calcd 302.1903, found 302.1894.
4-Cyclohexyl-2,6-diphenylpyridine (3y). White solid (56 mg,
1
ꢀ
72%), mp 97.3–98.9 C; H NMR (400 MHz, CDCl3) d 8.28–8.08
(m, 4H), 7.57 (s, 2H), 7.55–7.48 (m, 4H), 7.47–7.41 (m, 2H), 2.73–
2.60 (m, 1H), 2.01 (d, J ¼ 13.0 Hz, 2H), 1.93 (d, J ¼ 12.7 Hz, 2H),
1.83 (d, J ¼ 12.6 Hz, 1H), 1.63–1.42 (m, 4H), 1.40–1.31 (m, 1H);
13C NMR (100 MHz, CDCl3) d 158.0, 156.9, 139.9, 128.7, 128.5,
127.0, 117.6, 44.4, 33.7, 26.6, 26.0; HRMS (ESI) for C23H24N ([M +
H]+): calcd 314.1903, found 314.1894.
Acknowledgements
We would like to thank the National Natural Science Founda-
tion of China (21362002 and 81260472), Guangxi Natural
Science Foundation of China (2014GXNSFDA118007 and
2016GXNSFEA380001), State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources (CMEMR2014-
A02 and CMEMR2012-A20), the Fund of Guangxi Key Labora-
tory of Functional Phytochemicals Research and Utilization
(FPRU2015-2), and Guangxi's Medicine Talented Persons Small
Highland Foundation (1306).
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Notes and references
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crystallographic data for this paper.
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RSC Adv., 2017, 7, 13123–13129 | 13129