I2-Triggered N-O cleavage of ketoxime acetates for the synthesis of 3-(4-pyridyl)indoles

Article abstract of DOI:10.1039/c8ob02230e

A facile and complementary [3 + 2 + 1] annulation of aryl ketoxime acetates and 3-formylindoles to give pyridine derivatives is reported. The condensation reaction demonstrated that I₂ was capable of triggering N-O bond cleavage of ketoxime ace

Full text of DOI:10.1039/c8ob02230e

Organic &
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I2-Triggered N–O cleavage of ketoxime acetates
for the synthesis of 3-(4-pyridyl)indoles†
Cite this: Org. Biomol. Chem., 2018,
16, 9030
Qinghe Gao, *a Yakun Wang,a Qianqian Wang,b Yanping Zhu,c Zhaomin Liua and
Jixia Zhanga
A facile and complementary [3 + 2 + 1] annulation of aryl ketoxime acetates and 3-formylindoles to give
pyridine derivatives is reported. The condensation reaction demonstrated that I2 was capable of triggering
N–O bond cleavage of ketoxime acetates to generate iminyl radicals via a single electron transfer
pathway. This direct and operationally simple protocol provides a fundamental platform to synthesize
3-(4-pyridyl)indoles with high functional group compatibility and high regioselectivity.
Received 10th September 2018,
Accepted 1st November 2018
DOI: 10.1039/c8ob02230e
rsc.li/obc
However, most of the reported methods for the synthesis of
3-(4-pyridyl)indoles have suffered from limited diversity of pro-
Introduction
The construction of bis-heterocyclic scaffolds is highly appreci- ducts and the requirement of multistep procedures.5a,6 Herein,
ated in modern drug discovery to achieve specific drug– we sought to develop an efficient and complementary strategy
receptor interactions.1 Heteroaryl-indoles are such an unpre- to directly obtain a diverse range of 3-(4-pyridyl)indoles.
cedented class of bis-heterocycles. For example, pimprinine
Recently, transition-metal catalysis has been demonstrated
displayed a range of biological activities such as antiepileptic as a powerful tool for breaking the N–O bond of oximes to give
activity, monoamine oxidase inhibition, and anticonvulsant iminyl radicals through single-electron reduction and for-
activity.2 Meridianin D analogues showed antibiofilm activity mation of various multisubstituted heterocycles.7 The strategy
against MRSA and increased colistin efficacy in Gram-negative of using readily available ketoximes bearing α-protons to con-
bacteria.3 Pyrazolyl–indole has been reported to be a strong struct pyridines is appealing.8 Guan and co-workers developed
inhibitor of hCA XII.4 Especially, recent studies revealed that Cu- and Fe-catalyzed coupling reactions of ketoxime acetates
incorporation of the pyridine nucleus into the C3 position of and aldehydes, wherein both the nitrogen and α-carbon atoms
indoles leaded to diverse biological activities such as antiproli- were incorporated into the final pyridine rings (Scheme 1a).9
ferative activity, inhibition of IMPDH and Rho-kinase5 (Fig. 1). However, the introduction of important indolyl into pyridine
was not reported via this approach, which substantially limited
the accessible substitution patterns of the resulting pyridines.
Fig. 1 Selected bioactive heteroaryl-indoles.
aSchool of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003,
P. R. China. E-mail: gao_qinghe@xxmu.edu.cn
bSchool of International education, Xinxiang Medical University, Xinxiang,
Henan 453003, P. R. China
cSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug
Evaluation, Ministry of Education, Collaborative Innovation Center of Advanced Drug
Delivery System and Biotech Drugs in Universities of Shandong, Yantai University,
Shandong, Yantai 264005, P. R. China
†Electronic supplementary information (ESI) available. CCDC 1844843. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02230e
Scheme 1 Synthesis of pyridines from ketoximes and aldehydes.
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Very recently, our group disclosed a metal-free pyridine- into the effect of the loading of I2 disclosed that reducing the
forming reaction, in which two molecules of ketoxime amount of I2 was negative to the results (entries 11 and 12). By
acetates are condensed with triethylamine as the C1 source replacing I2 with NIS or NH4I, the desired product was isolated
(Scheme 1b).10 Inspired by the reaction, we now report an in 59% and 42% yields, respectively (entries 13 and 14).
I2-triggered effective formation of indole-linked pyridines However, no desired product was obtained in the presence of
through [3 + 2 + 1] annulation of aryl ketoxime acetates and KI, or TBAI (entries 16 and 17), and no reaction occurred in
3-formylindoles (Scheme 1c). The method features simple and the absence of iodine reagents, indicating that I2 is essential
mild reaction conditions and enables the regioselective syn- for the reaction (entry 18). Surprisingly, the yield of 3a was
thesis of a broad range of 3-(4-pyridyl)indoles.
improved to 82% when using pyridine instead of Et3N as the
electron donor (entry 23). Note that the reaction, when per-
formed using Et3N as an electron donor, was accompanied by
homocoupling of 1a to produce methyl-containing pyridine as
a byproduct.10 Moreover, this reaction could still proceed suc-
cessfully when conducted at 110 °C (entry 25).
With the optimized reaction conditions in hand, the gener-
ality and scope of this facile and complementary [3 + 2 + 1]
annulation for the synthesis of 3-(4-pyridyl)indoles was
explored. The reaction demonstrated a wide substrate scope of
the ketoxime acetates (Scheme 2). Aryl ketone O-acetyloximes
bearing electron-neutral (e.g., 4-Me, 4-H), electron-rich (e.g.,
4-OMe, 3,4-OCH2O), and electron-deficient (e.g., 3-NO2) groups
on the phenyl ring were converted to the corresponding pro-
ducts in good yields (71–89%; 3a–3e). The reaction of 1a could
Results and discussion
On the basis of our previous work,10,11 initial experiments
were carried out with 4-methylacetophenone oxime acetate
(1a) and 1H-indole-3-carbaldehyde (2a) in the presence of I2
and Et3N in chlorobenzene at 130 °C (Table 1). To our delight,
the desired 3-(4-pyridyl)indole (3a) was obtained in 65% yield
(entry 1). Different solvents such as toluene, 1,4-dioxane,
CH3CN, NMP, THF, DCE, DMF, and DMSO were screened first
(entries 2–9), revealing that 1,4-dioxane was superior to chloro-
benzene for this transformation. Subsequently, investigation
Table 1 Optimization of reaction conditionsa
Entry
[I]
Donor
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
NIS
NH4I
CuI
KI
TBAI
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et2NH
DABCO
DBU
Quinoline
Py
PhCl
Toluene
1,4-Dioxane
CH3CN
NMP
THF
DCE
DMF
DMSO
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
65
60
76
72
n.d.
69
23
48
n.d.
77
63
39
59
42
9
10c
11d
12e
13
14
15
16
17
18
19
20
21
22
23
24
25f
26g
13
n.r.
Trace
n.r.
68
64
43
41
82
23
82
I2
I2
I2
I2
I2
I2
I2
I2
Py
Py
73
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), [I] (0.5 mmol),
donor (0.5 mmol), solvent (2 mL), at 130 °C. b Isolated yield; n.d. = no
desired product; n.r. = no reaction. c I2 (0.75 mmol). d I2 (0.25 mmol).
e I2 (0.1 mmol). f At 110 °C. g At 100 °C.
Scheme 2 Scope of ketoxime acetates. Reaction conditions:
1
(1.0 mmol), 2a (0.5 mmol), I2 (0.5 mmol) and pyridine (0.5 mmol) in 1,4-
dioxane (2 mL) at 110 °C. Isolated yield. a Conducted on 10 mmol scale,
isolated yield.
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be scaled up to 10 mmol scale without a problem. In general,
acetophenone oxime acetates with an electron-donating group
showed higher reactivity than those with an electron-withdraw-
ing group. Much to our satisfaction, the optimized conditions
were mild enough to allow a broad range of halogenated (e.g.,
4-Cl, 4-Br, 3,4-Cl2) substrates to be reacted (61–69%; 3f–3h).
Naphthalen-2-yl ethanone oxime acetate was also a suitable
substrate for this reaction to provide the target product (3i) in
59% yield. Meanwhile, the optimized conditions could be
applied to thiophene-2-yl methyl ketoxime acetate and thio-
phene-3-yl methyl ketoxime acetate, delivering the annulation
products in 65% and 72% yields, respectively (3j–3k). It is note-
worthy that ketoxime acetate derived from α-tetralone under-
went the desired reaction to afford the symmetrical indolyl
pyridine (3l) in good yield (74%). In addition, ortho-methyl
substituted substrates reacted smoothly and resulted in the
target pyridine (3m) in 52% yield. Unfortunately, no reaction
occurred when alkyl ketoxime acetate 3,3-dimethylbutan-2-one
oxime acetate was employed as the substrate.
Scheme 4 Scope of aldehydes and ketoxime acetates. Reaction con-
ditions:
1 (1.0 mmol), 4 (0.5 mmol), I2 (0.5 mmol) and pyridine
(0.5 mmol) in 1,4-dioxane (2 mL) at 110 °C. Isolated yield.
The scope of this reaction was subsequently extended to the
representative 3-formylindoles (Scheme 3). Indoles substituted
with various useful substituents such as methyl, methoxy, ben-
zyloxy, and halogens (F and Cl) at the C5, C6, and C7 positions
of the aromatic ring showed good reactivity with acetophenone
oxime acetate 1b, leading to the corresponding pyridines
3n–3v in 54–77% yields. In the case of a 6-methyl substituted
substrate, the structure of the desired product (3o) was unam-
biguously confirmed by single-crystal X-ray diffraction (CCDC
1844843†). These results indicated that the position of the sub-
stituents on the aromatic ring of the indoles had little effect
on the yields of the products. Notably, the strong electron-
withdrawing groups 6-COOCH3 and 7-NO2 could be accessed
through this route to generate the desired products (41–71%;
3w–3x). In addition, the protocol was also effective with an
N-protected indole, furnishing the expected product (3y) in
69% yield.
Next, we were naturally interested in the general scope of
the present reaction system using other types of aldehydes. As
expected, several (het)aryl aldehydes (4) and ketoxime acetates
were subjected to the procedure, and the corresponding pyri-
dines (5) were obtained in 57–81% yields (Scheme 4). However,
no reaction occurred when isobutyraldehyde was used as the
substrate.
To understand the role of molecular iodine in this process,
an inhibition experiment for the radical was carried out. As
expected, when TEMPO was introduced into the reaction
system, the formation of 3a was completely suppressed
(Scheme 5a). This result indicated that molecular iodine was
capable of reducing the N–O bond of the ketoxime acetates to
generate iminyl radicals via a single-electron transfer (SET)
process. Finally, we investigated the cross reaction between
two representative substrates 4-methylacetophenone oxime
acetate (1a) and acetophenone oxime acetate (1b) under stan-
dard conditions. Fortunately, all the products were successfully
Scheme 3 Scope of 3-formylindoles. Reaction conditions: 1b
(1.0 mmol), 2 (0.5 mmol), I2 (0.5 mmol) and pyridine (0.5 mmol) in 1,4-
dioxane (2 mL) at 110 °C. Isolated yield.
Scheme 5 Control experiments.
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Significantly, this work provides an example for applying mole-
cular iodine as a promising alternative to transition metal cata-
lysts for single-electron reduction coupling reactions. Further
mechanistic investigations and exploration of new transform-
ations of oxime acetates with I2 are underway and will be
reported in due course.
Experimental
General information
All reagents were commercially available and used without
further purification. TLC analysis was performed using pre-
coated glass plates. Column chromatography was performed
using silica gel (200–300 mesh). 1H spectra were recorded in
DMSO-d6/CDCl3 on 400 MHz NMR spectrometers and reso-
nances (δ) are given in parts per million relative to tetramethyl-
silane. 13C spectra were recorded in DMSO-d6/CDCl3 on
100 MHz NMR spectrometers and resonances (δ) are given in
ppm. HRMS were obtained on a Bruker 7-tesla FT-ICR MS
equipped with an electrospray source. The X-ray crystal-struc-
ture determinations of 3o were obtained on a Bruker SMART
APEX CCD system. Melting points were determined using XT-4
apparatus and not corrected.
Scheme 6 Proposed mechanism.
identified by HRMS analysis of the crude reaction extract, and
the ratio of 3a, 3b and 3z was further calculated using 1H NMR
analysis (Scheme 5b).
On the basis of the above results and previous reports,12
a
possible mechanism has been proposed using acetophenone
oxime acetate (1b) and 3-formylindole (2a) as examples
(Scheme 6). Initially, the single-electron reduction of the N–O
bond of ketoxime acetate 1b with molecular iodine produced
the iminyl radical intermediate A and hypervalent iodine
species (I+).10 Subsequently, the highly active iminyl radical A
was reductively quenched by an electron donor to generate the
corresponding anion B which could isomerize to a strong
nucleophile α-carbanion C.11 Then, nucleophilic addition of C
to the formyl of 2a and dehydration would afford the imine
intermediate E. Next, condensation of the intermediate E with
a second ketoxime acetate 1b gave an aza-hexa-1,3,5-triene
intermediate F. Finally, the intermediate F underwent sequen-
tial thermal electrocyclization and rapid oxidative aromatiz-
ation reactions to provide the desired product 3b. Another
possible pathway involves Michael addition of species C to the
α,β-unsaturated imine E followed by intramolecular imine/
enamine condensation and oxidative aromatization.
General procedure for the synthesis of 3
A mixture of ketoxime acetates 1 (1.0 mmol), 1H-indole-3-car-
baldehydes 2 (0.5 mmol), iodine (0.5 mmol), and pyridine
(0.5 mmol) in 1,4-dioxane (2 mL) was stirred at 110 °C. After
disappearance of the reactant (monitored by TLC), 50 mL of
water was added to the mixture, and then extracted with EtOAc
3 times (3 × 50 mL). The extract was washed with 10% Na2S2O3
solution (w/w), dried over anhydrous Na2SO4 and evaporated.
The residue was purified by column chromatography on silica
gel (eluent: petroleum ether/EtOAc) to afford the product 3.
General procedure for the synthesis of 5
A mixture of ketoxime acetates 1 (1.0 mmol), aldehydes 4
(0.5 mmol), iodine (0.5 mmol), and pyridine (0.5 mmol) in
1,4-dioxane (2 mL) was stirred at 110 °C. After disappearance
of the reactant (monitored by TLC), 50 mL of water was added
to the mixture, and then extracted with EtOAc 3 times (3 ×
50 mL). The extract was washed with 10% Na2S2O3 solution
(w/w), dried over anhydrous Na2SO4 and evaporated. The
residue was purified by column chromatography on silica gel
(eluent: petroleum ether/EtOAc) to afford the product 5.
Conclusions
In summary, we have developed a facile and efficient I2-trig-
3-(2,6-Di-p-tolylpyridin-4-yl)-1H-indole (3a). Yield 82%
gered [3 + 2 + 1] annulation of aryl ketoxime acetates and 3-for- (153.3 mg); white solid; mp 231–234 °C; 1H NMR (400 MHz,
mylindoles to produce diverse 3-(4-pyridyl)indoles that are DMSO-d6): δ (ppm) 11.79 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.21
challenging to prepare by traditional methods. With the easily (d, J = 8.0 Hz, 4H), 8.15 (s, 2H), 8.13–8.08 (m, 1H), 7.58–7.50
accessible starting materials, operational simplicity, functional (m, 1H), 7.36 (d, J = 8.0 Hz, 4H), 7.26–7.22 (m, 2H), 2.39 (s,
group compatibility and high regioselectivity, the present 6H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.1, 145.4,
method not only effectively complements other existing and 138.4, 137.2, 136.5, 129.3, 126.7, 126.5, 124.8, 121.9, 120.5,
emerging methods for pyridine synthesis but also enables the 119.3, 115.0, 113.4, 112.3, 20.9; HRMS (ESI): m/z [M + Na]+
construction of a diverse array of indole-linked pyridines. calcd for C27H22N2Na: 397.1675; found: 397.1676.
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3-(2,6-Diphenylpyridin-4-yl)-1H-indole (3b). Yield 79%
3-(2,6-Bis(3,4-dichlorophenyl)pyridin-4-yl)-1H-indole
(3h).
(136.7 mg); white solid; mp 225–228 °C; 1H NMR (400 MHz, Yield 69% (167 mg); brown solid; mp 179–181 °C; 1H NMR
DMSO-d6): δ (ppm) 11.81 (s, 1H), 8.32 (d, J = 7.6 Hz, 5H), (400 MHz, DMSO-d6): δ (ppm) 11.81 (s, 1H), 8.43 (s, 2H), 8.30
8.22 (s, 2H), 8.14 (d, J = 4.4 Hz, 1H), 7.64–7.53 (m, 5H), (d, J = 4.4 Hz, 1H), 8.24–8.15 (m, 4H), 8.08 (d, J = 7.2 Hz, 1H),
7.52–7.45 (m, 2H), 7.29–7.21 (m, 2H); 13C NMR (100 MHz, 7.74–7.67 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.28–7.17 (m, 2H);
DMSO-d6) δ (ppm) 156.3, 145.6, 139.2, 137.2, 129.0, 128.7, 13C NMR (100 MHz, DMSO-d6) δ (ppm) 153.6, 146.1, 139.3,
126.8, 126.6, 124.8, 121.9, 120.6, 119.4, 115.7, 113.3, 112.3; 137.2, 131.7, 131.6, 130.7, 128.4, 127.2, 126.8, 124.6, 121.9,
HRMS (ESI): m/z [M + H]+ calcd for C25H19N2: 347.1543; found: 120.5, 119.5, 116.3, 112.8, 112.3; HRMS (ESI): m/z [M + H]+
347.1545.
calcd for C25H15Cl4N2: 482.9984; found: 482.9988.
3-(2,6-Bis(4-methoxyphenyl)pyridin-4-yl)-1H-indole (3c).
3-(2,6-Di(naphthalen-2-yl)pyridin-4-yl)-1H-indole (3i). Yield
Yield 89% (180.6 mg); white solid; mp 224–227 °C; 1H NMR 59% (131.5 mg); yellow solid; mp 219–221 °C; 1H NMR
(400 MHz, DMSO-d6): δ (ppm) 11.78 (s, 1H), 8.27 (d, J = 7.6 Hz, (400 MHz, DMSO-d6): δ (ppm) 11.86 (s, 1H), 8.93 (s, 2H), 8.57
5H), 8.16–8.02 (m, 3H), 7.56 (d, J = 5.6 Hz, 1H), 7.25 (d, J = (d, J = 8.4 Hz, 2H), 8.43 (s, 2H), 8.40 (d, J = 2.4 Hz, 1H),
3.6 Hz, 2H), 7.11 (d, J = 8.4 Hz, 4H), 3.83 (s, 6H); 13C NMR 8.26–8.21 (m, 1H), 8.17 (d, J = 7.2 Hz, 2H), 8.12 (d, J = 8.8 Hz,
(100 MHz, DMSO-d6) δ (ppm) 160.1, 155.9, 145.3, 137.2, 131.9, 2H), 8.01 (d, J = 6.8 Hz, 2H), 7.63–7.55 (m, 5H), 7.32–7.25 (m,
128.1, 126.4, 124.9, 121.9, 120.5, 119.4, 114.2, 114.1, 113.6, 2H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.3, 145.7,
112.4, 55.2; HRMS (ESI): m/z [M + H]+ calcd for C27H23N2O2: 137.3, 136.7, 133.3, 133.2, 128.7, 128.2, 127.6, 126.7, 126.6,
407.1754; found: 407.1757.
126.4, 126.1, 124.8, 122.0, 120.6, 119.5, 116.2, 113.4, 112.4;
3-(2,6-Bis(benzo[d][1,3]dioxol-5-yl)pyridin-4-yl)-1H-indole (3d). HRMS (ESI): m/z [M + H]+ calcd for C33H23N2: 447.1856; found:
1
Yield 87% (188.8 mg); yellow solid; mp 210–214 °C; H NMR 447.1859.
(400 MHz, DMSO-d6): δ (ppm) 11.76 (s, 1H), 8.28 (s, 1H),
3-(2,6-Di(thiophen-2-yl)pyridin-4-yl)-1H-indole (3j). Yield
8.10 (s, 1H), 8.07 (s, 2H), 7.87 (s, 3H), 8.84 (s, 1H), 7.53 (d, J = 65% (116.3 mg); brown solid; mp 165–169 °C; 1H NMR
4.4 Hz, 1H), 7.23 (d, J = 2.8 Hz, 2H), 7.08 (d, J = 7.6 Hz, 2H), (400 MHz, DMSO-d6): δ (ppm) 11.82 (s, 1H), 8.28 (s, 1H),
6.12 (s, 4H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 155.5, 8.19–8.05 (m, 3H), 7.98 (s, 2H), 7.66 (d, J = 4.4 Hz, 2H), 7.55 (d,
148.1, 147.9, 145.4, 137.2, 133.7, 126.5, 124.8, 121.9, 120.9, J = 5.2 Hz, 1H), 7.29–7.10 (m, 4H); 13C NMR (100 MHz, DMSO-
120.5, 119.5, 114.7, 113.4, 112.3, 108.4, 107.0, 101.3; HRMS d6) δ (ppm) 151.8, 145.4, 144.6, 137.2, 128.4, 128.3, 126.8,
(ESI): m/z [M + H]+ calcd for C27H19N2O4: 435.1339; found: 125.4, 124.7, 122.0, 120.6, 119.5, 113.5, 112.7, 112.4; HRMS
435.1338.
(ESI): m/z [M + Na]+ calcd for C21H14N2NaS2: 381.0491; found:
3-(2,6-Bis(3-nitrophenyl)pyridin-4-yl)-1H-indole (3e). Yield 381.0492.
71% (154.7 mg); brown solid; mp 258–260 °C; 1H NMR
3-(2,6-Di(thiophen-3-yl)pyridin-4-yl)-1H-indole (3k). Yield
(400 MHz, DMSO-d6): δ (ppm) 11.84 (s, 1H), 9.03 (s, 2H), 8.70 72% (128.9 mg); brown solid; mp 182–186 °C; 1H NMR
(d, J = 7.6 Hz, 2H), 8.36 (d, J = 2.8 Hz, 1H), 8.34 (s, 2H), 8.31 (d, (400 MHz, DMSO-d6): δ (ppm) 11.78 (s, 1H), 8.38 (d, J = 2.0 Hz,
J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 2H), 8.25 (d, J = 2.8 Hz, 1H), 8.16–8.12 (m, 1H), 8.08 (s, 2H),
7.82 (t, J = 8.0 Hz, 2H), 7.55–7.50 (m, 1H), 7.28–7.18 (m, 2H); 7.97 (d, J = 5.2 Hz, 2H), 7.70–7.66 (m, 2H), 7.57–7.52 (m, 1H),
13C NMR (100 MHz, DMSO-d6) δ (ppm) 154.0, 148.4, 146.4, 7.29–7.19 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ (ppm)
140.4, 137.2, 133.1, 130.3, 127.4, 124.6, 123.7, 122.0, 121.2, 152.8, 145.3, 142.4, 137.2, 126.8, 126.7, 126.5, 124.8,
120.6, 119.5, 116.9, 112.7, 112.3; HRMS (ESI): m/z [M + Na]+ 124.2, 121.9, 120.5, 119.6, 115.1, 113.1, 112.3; HRMS (ESI): m/z
calcd for C25H16N4NaO4: 459.1064; found: 459.1069.
[M − H]− calcd for C21H13N2S2: 357.0526; found: 357.0521.
3-(2,6-Bis(4-chlorophenyl)pyridin-4-yl)-1H-indole (3f). Yield
7-(1H-Indol-3-yl)-5,6,8,9-tetrahydrodibenzo[c,h]acridine (3l).
61% (126.5 mg); brown solid; mp 182–185 °C; 1H NMR Yield 74% (147.3 mg); brown solid; mp 133–136 °C; H NMR
(400 MHz, DMSO-d6): δ (ppm) 11.89 (s, 1H), 8.43 (s, 2H), 8.40 (400 MHz, DMSO-d6): δ (ppm) 11.52 (s, 1H), 8.47 (d, J = 7.2 Hz,
(s, 3H), 8.31 (s, 2H), 8.23–8.18 (m, 1H), 7.68 (d, J = 8.4 Hz, 4H), 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.40 (t, J =
7.64–7.59 (m, 1H), 7.35–7.28 (m, 2H); 13C NMR (100 MHz, 7.2 Hz, 2H), 7.34–7.28 (m, 2H), 7.23 (d, J = 7.2 Hz, 2H),
DMSO-d6) δ (ppm) 155.0, 145.9, 137.8, 137.2, 133.9, 128.7, 7.20–7.13 (m, 2H), 7.00 (t, J = 7.2 Hz, 1H), 2.86–2.73 (m, 4H),
128.6, 126.9, 124.7, 122.0, 120.6, 119.4, 115.8, 113.0, 112.3; 2.73–2.66 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ (ppm)
HRMS (ESI): m/z [M + H]+ calcd for C25H17Cl2N2: 415.0763; 149.1, 141.3, 137.8, 136.1, 134.9, 130.5, 128.6, 127.6, 126.8,
1
found: 415.0764.
126.5, 125.0, 124.7, 121.4, 119.4, 118.9, 111.9, 110.1, 27.5, 25.6;
3-(2,6-Bis(4-bromophenyl)pyridin-4-yl)-1H-indole (3g). Yield HRMS (ESI): m/z [M + H]+ calcd for C29H23N2: 399.1856; found:
64% (161.3 mg); brown solid; mp 223–225 °C; 1H NMR 399.1855.
(400 MHz, DMSO-d6): δ (ppm) 11.81 (s, 1H), 8.31 (d, J = 2.8 Hz,
3-(2,6-Di-o-tolylpyridin-4-yl)-1H-indole (3m). Yield 52%
1H), 8.28–8.20 (m, 6H), 8.14–8.09 (m, 1H), 7.73 (d, J = 8.4 Hz, (97.2 mg); white solid; mp 270–273 °C; 1H NMR (400 MHz,
4H), 7.56–7.51 (m, 1H), 7.28–7.19 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 11.74 (s, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.97
DMSO-d6) δ (ppm) 155.1, 145.9, 138.2, 137.2, 131.6, 128.9, (d, J = 7.6 Hz, 1H), 7.76 (s, 2H), 7.56–7.52 (m, 2H), 7.50 (d, J =
126.9, 124.7, 122.7, 122.0, 120.6, 119.4, 115.8, 113.0, 112.4; 7.6 Hz, 1H), 7.36–7.29 (m, 6H), 7.23–7.14 (m, 2H), 2.45 (s, 6H);
HRMS (ESI): m/z [M + H]+ calcd for C25H17Br2N2: 502.9753; 13C NMR (100 MHz, DMSO-d6) δ (ppm) 159.0, 144.3, 140.7,
found: 502.9758.
137.2, 135.4, 130.6, 129.7, 128.1, 126.5, 125.9, 124.7, 121.9,
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120.5, 119.1, 118.7, 112.9, 112.4, 20.4; HRMS (ESI): m/z 1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 159.0, 156.7,
[M + H]+ calcd for C27H23N2: 375.1856; found: 375.1856.
156.3, 145.1, 139.2, 133.9, 129.0, 128.7, 128.5, 126.9, 125.0,
3-(2,6-Diphenylpyridin-4-yl)-5-methyl-1H-indole (3n). Yield 124.9, 115.6, 113.7, 113.6, 113.4, 113.3, 110.3, 110.0, 104.5,
77% (138.6 mg); brown solid; mp 187–190 °C; 1H NMR 104.2; HRMS (ESI): m/z [M + Na]+ calcd for C25H17FN2Na:
(400 MHz, DMSO-d6): δ (ppm) 11.66 (s, 1H), 8.30 (d, J = 7.6 Hz, 387.1268; found: 387.1271.
4H), 8.22 (d, J = 2.8 Hz, 1H), 8.17 (s, 2H), 7.85 (s, 1H), 7.57 (t,
3-(2,6-Diphenylpyridin-4-yl)-6-fluoro-1H-indole (3t). Yield
J = 7.6 Hz, 4H), 7.49 (t, J = 7.2 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 68% (123.7 mg); yellow solid; mp 223–226 °C; 1H NMR
7.06 (d, J = 8.0 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, (400 MHz, DMSO-d6): δ (ppm) 11.87 (s, 1H), 8.37–8.28 (m, 5H),
DMSO-d6) δ (ppm) 156.2, 145.8, 139.3, 135.5, 129.2, 129.0, 8.20 (s, 2H), 8.16–8.09 (m, 1H), 7.57 (t, J = 7.6 Hz, 4H), 7.49 (t,
128.8, 126.8, 126.6, 125.0, 123.6, 118.8, 115.7, 112.8, 112.1, J = 7.2 Hz, 2H), 7.38–7.32 (m, 1H), 7.14–7.06 (m, 1H); 13C NMR
21.6; HRMS (ESI): m/z [M + Na]+ calcd for C26H20N2Na: (100 MHz, DMSO-d6) δ (ppm) 160.2, 157.8, 156.3, 145.1, 139.2,
383.1519; found: 383.1518.
137.3, 137.2, 129.0, 128.7, 126.9, 121.7, 120.7, 120.6, 115.7,
3-(2,6-Diphenylpyridin-4-yl)-6-methyl-1H-indole (3o). Yield 113.6, 109.0, 108.8, 98.4, 98.2; HRMS (ESI): m/z [M + Na]+ calcd
63% (113.4 mg); brown solid; mp 157–160 °C; 1H NMR for C25H17FN2Na: 387.1268; found: 387.1270.
(400 MHz, DMSO-d6): δ (ppm) 11.64 (s, 1H), 8.31 (d, J = 7.2 Hz,
5-Chloro-3-(2,6-diphenylpyridin-4-yl)-1H-indole (3u). Yield
4H), 8.23 (d, J = 2.4 Hz, 1H), 8.19 (s, 2H), 7.99 (d, J = 8.4 Hz, 65% (123.8 mg); yellow solid; mp 219–221 °C; 1H NMR
1H), 7.57 (t, J = 7.6 Hz, 4H), 7.48 (t, J = 7.2 Hz, 2H), 7.32 (s, (400 MHz, DMSO-d6): δ (ppm) 11.98 (s, 1H), 8.34 (d, J = 2.4 Hz,
1H), 7.06 (d, J = 8.4 Hz, 1H), 2.45 (s, 3H); 13C NMR (100 MHz, 1H), 8.31 (d, J = 8.0 Hz, 4H), 8.14 (s, 2H), 8.04 (s, 1H), 7.56 (t,
DMSO-d6) δ (ppm) 156.2, 145.7, 139.3, 137.7, 131.1, 129.0, J = 7.6 Hz, 5H), 7.48 (t, J = 7.2 Hz, 2H), 7.28–7.20 (m, 1H);
128.7, 126.8, 126.0, 122.7, 122.3, 119.1, 115.5, 113.1, 112.1, 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.4, 144.9, 139.2,
21.3; HRMS (ESI): m/z [M + Na]+ calcd for C26H20N2Na: 135.7, 129.1, 128.7, 128.2, 126.9, 125.8, 125.1, 122.0, 118.4,
383.1519; found: 383.1520.
115.9, 113.9, 113.3; HRMS (ESI): m/z [M + Na]+ calcd for
3-(2,6-Diphenylpyridin-4-yl)-7-methyl-1H-indole (3p). Yield C25H17ClN2Na: 403.0972; found: 403.0976.
66% (118.8 mg); brown solid; mp 192–195 °C; 1H NMR
7-Chloro-3-(2,6-diphenylpyridin-4-yl)-1H-indole (3v). Yield
(400 MHz, DMSO-d6): δ (ppm) 11.75 (s, 1H), 8.34–8.29 (m, 5H), 59% (112.4 mg); brown solid; mp 168–171 °C; 1H NMR
8.21 (s, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.4 Hz, 4H), (400 MHz, DMSO-d6): δ (ppm) 12.15 (s, 1H), 8.39 (d, J = 2.8 Hz,
7.49 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 1H), 8.33 (d, J = 7.2 Hz, 4H), 8.22 (s, 2H), 8.10 (d, J = 8.0 Hz,
6.8 Hz, 1H), 2.55 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 1H), 7.56 (t, J = 7.4 Hz, 4H), 7.48 (t, J = 7.2 Hz, 2H), 7.33 (d, J =
δ (ppm) 156.2, 145.7, 139.2, 136.7, 129.0, 128.7, 126.8, 126.4, 7.6 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz,
124.5, 122.5, 121.6, 120.8, 116.9, 115.6, 113.7, 16.9; HRMS DMSO-d6) δ (ppm) 156.4, 144.9, 139.1, 134.0, 129.1, 128.7,
(ESI): m/z [M + H]+ calcd for C26H21N2: 361.1699; found: 127.8, 126.9, 126.7, 121.5(4), 121.5(1), 118.5, 116.7, 116.0,
361.1696.
114.6; HRMS (ESI): m/z [M + H]+ calcd for C25H18ClN2:
3-(2,6-Diphenylpyridin-4-yl)-5-methoxy-1H-indole (3q). Yield 381.1153; found: 381.1152.
54% (101.5 mg); brown solid; mp 169–173 °C; 1H NMR
Methyl 3-(2,6-diphenylpyridin-4-yl)-1H-indole-6-carboxylate
(400 MHz, DMSO-d6): δ (ppm) 11.65 (s, 1H), 8.33–8.28 (m, 4H), (3w). Yield 41% (82.8 mg); brown solid; mp 240–243 °C; 1H
8.22 (d, J = 2.4 Hz, 1H), 8.16 (s, 2H), 7.56 (t, J = 7.4 Hz, 4H), NMR (400 MHz, DMSO-d6): δ (ppm) 12.19 (s, 1H), 8.53 (d, J =
7.51–7.46 (m, 3H), 7.43 (d, J = 8.8 Hz, 1H), 6.94–6.87 (m, 1H), 2.4 Hz, 1H), 8.32 (d, J = 7.6 Hz, 4H), 8.23–8.17 (m, 4H),
3.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.2, 7.85–7.81 (m, 1H), 7.57 (t, J = 7.4 Hz, 4H), 7.49 (t, J = 7.2 Hz,
154.4, 145.7, 139.2, 132.3, 129.0, 128.8, 127.1, 126.8, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ (ppm)
125.2, 115.5, 113.1, 113.0, 111.6, 101.4, 55.4; HRMS (ESI): m/z 167.0, 156.4, 144.8, 139.1, 136.5, 130.2, 129.1, 128.8, 128.2,
[M + Na]+ calcd for C26H20N2NaO: 399.1468; found: 399.1468.
126.9, 122.9, 121.1, 119.4, 115.9, 114.1, 113.9, 52.0; HRMS
5-(Benzyloxy)-3-(2,6-diphenylpyridin-4-yl)-1H-indole
(3r). (ESI): m/z [M + H]+ calcd for C27H21N2O2: 405.1598; found:
1
Yield 56% (126.5 mg); brown solid; mp 154–157 °C; H NMR 405.1596.
(400 MHz, DMSO-d6): δ (ppm) 11.69 (s, 1H), 8.29 (d, J = 7.2 Hz,
3-(2,6-Diphenylpyridin-4-yl)-7-nitro-1H-indole (3x). Yield
4H), 8.24 (d, J = 2.8 Hz, 1H), 8.12 (s, 2H), 7.61–7.55 (m, 5H), 71% (138.8 mg); red solid; mp 209–211 °C; 1H NMR (400 MHz,
7.52–7.44 (m, 5H), 7.37–7.28 (m, 3H), 7.04–6.97 (m, 1H), 5.26 DMSO-d6): δ (ppm) 12.47 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.40
(s, 2H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.3, 153.4, (d, J = 2.8 Hz, 1H), 8.36–8.30 (m, 4H), 8.25–8.18 (m, 3H), 7.56
145.7, 139.3, 137.9, 132.4, 129.0, 128.7, 128.4, 127.6, 127.3, (t, J = 7.4 Hz, 4H), 7.48 (t, J = 7.2 Hz, 2H), 7.42 (t, J = 8.0 Hz,
127.2, 126.8, 125.1, 115.5, 113.1(3), 113.0(9), 112.7, 102.9, 69.8; 1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 156.4, 143.9,
HRMS (ESI): m/z [M + H]+ calcd for C32H25N2O: 453.1961; 139.0, 133.0, 129.4, 129.3, 129.1, 129.0, 128.7, 128.1, 127.0,
found: 453.1962.
120.2, 119.3, 116.6, 115.3; HRMS (ESI): m/z [M + H]+ calcd for
3-(2,6-Diphenylpyridin-4-yl)-5-fluoro-1H-indole (3s). Yield C25H18N3O2: 392.1394; found: 392.1394.
69% (125.6 mg); yellow solid; mp 232–234 °C; 1H NMR
3-(2,6-Diphenylpyridin-4-yl)-1-methyl-1H-indole (3y). Yield
(400 MHz, DMSO-d6): δ (ppm) 11.91 (s, 1H), 8.37 (s, 1H), 8.33 69% (124.2 mg); yellow solid; mp 162–164 °C; 1H NMR
(d, J = 6.8 Hz, 4H), 8.16 (s, 2H), 7.83 (d, J = 10.0 Hz, 1H), 7.56 (400 MHz, CDCl3): δ (ppm) 8.32 (d, J = 7.6 Hz, 4H), 8.15 (d, J =
(d, J = 6.4 Hz, 5H), 7.49 (d, J = 6.4 Hz, 2H), 7.10 (t, J = 8.8 Hz, 7.6 Hz, 1H), 8.02 (s, 2H), 7.63 (t, J = 7.4 Hz, 4H), 7.58–7.52 (m,
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2H), 7.47–7.34 (m, 4H), 3.79 (s, 3H); 13C NMR (100 MHz, J = 3.6, 1.2 Hz, 1H), 7.40 (dd, J = 5.2, 0.8 Hz, 1H), 7.30 (d, J =
CDCl3) δ (ppm) 157.1, 144.7, 139.8, 137.6, 128.7, 128.6, 128.0, 8.0 Hz, 4H), 7.16–7.13 (m, 1H), 2.42 (s, 6H); 13C NMR
127.0, 125.6, 122.3, 120.6, 119.7, 116.5, 114.1, 109.9, 32.8; (100 MHz, CDCl3) δ (ppm) 157.5, 142.8, 142.1, 139.0, 136.6,
HRMS (ESI): m/z [M + H]+ calcd for C26H21N2: 361.1699; found: 129.4, 128.3, 126.9, 126.7, 125.1, 114.7, 21.3; HRMS (ESI): m/z
361.1701.
[M + H]+ calcd for C23H20NS: 342.1311; found: 342.1314.
4-Phenyl-2,6-di-p-tolylpyridine (5a). Yield 79% (132.3 mg);
white solid; mp 150–153 °C; 1H NMR (400 MHz, CDCl3):
δ (ppm) 8.10 (d, J = 8.0 Hz, 4H), 7.83 (s, 2H), 7.75–7.71 (m, Conflicts of interest
2H), 7.51 (t, J = 7.4 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.31 (d, J =
There are no conflicts to declare.
8.0 Hz, 4H), 2.42 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
157.3, 150.0, 139.2, 139.0, 136.8, 129.4, 129.0, 128.8, 127.2,
127.0, 116.5, 21.3; HRMS (ESI): m/z [M + Na]+ calcd for
C25H21NNa: 358.1566; found: 358.1566.
Acknowledgements
2,6-Bis(4-methoxyphenyl)-4-phenylpyridine (5b). Yield 81%
This work was supported by the National Natural Science
(148.6 mg); white solid; mp 158–161 °C; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.16 (d, J = 8.8 Hz, 4H), 7.78 (s, 2H), 7.76–7.71
(m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.04 (d,
J = 8.8 Hz, 4H), 3.89 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 160.5, 156.9, 150.2, 139.2, 132.1, 129.1, 128.9, 128.4,
127.2, 115.8, 114.0, 55.4; HRMS (ESI): m/z [M + H]+ calcd for
C25H22NO2: 368.1645; found: 368.1648.
Foundation of China (Grant 21702091). We also acknowledge
the University Key Research Projects of Henan Province
(Grants 19A350010, and 16A150022) and the Xinxiang
Innovative Technology Team (Grant CXTD17004).
Notes and references
4-(3,4-Dimethoxyphenyl)-2,6-di-p-tolylpyridine (5c). Yield
1
72% (142.2 mg); pink solid; mp 93–97 °C; H NMR (400 MHz,
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CDCl3): δ (ppm) 8.09 (d, J = 8.0 Hz, 4H), 7.78 (s, 2H), 7.32 (d,
J = 8.0 Hz, 5H), 7.23 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.99 (s,
3H), 3.96 (s, 3H), 2.43 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 157.3, 149.8(3), 149.7(9), 149.4, 138.9, 136.9, 132.0,
129.4, 127.0, 119.8, 116.2, 111.5, 110.1, 56.1, 56.0, 21.3; HRMS
(ESI): m/z [M + Na]+ calcd for C27H25NNaO2: 418.1778; found:
418.1780.
2,6-Di-p-tolyl-4-(3,4,5-trimethoxyphenyl)pyridine (5d). Yield
65% (138.1 mg); violet solid; mp 149–151 °C; 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.09 (d, J = 8.0 Hz, 4H), 7.77
(s, 2H), 7.32 (d, J = 8.0 Hz, 4H), 6.90 (s, 2H), 3.97 (s, 6H), 3.93
(s, 3H), 2.44 (s, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.4,
153.7, 150.3, 139.1, 138.8, 136.8, 135.2, 129.4, 127.0, 116.6,
104.5, 61.0, 56.4, 21.3; HRMS (ESI): m/z [M + Na]+ calcd for
C28H27NNaO3: 448.1883; found: 448.1881.
4-(2,6-Di-p-tolylpyridin-4-yl)benzonitrile (5e). Yield 60%
(108 mg); white solid; mp 211–215 °C; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.08 (d, J = 8.0 Hz, 4H), 7.81 (s, 4H), 7.78
(s, 2H), 7.32 (d, J = 8.0 Hz, 4H), 2.43 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 157.8, 148.0, 143.7, 139.4, 136.3,
132.8, 129.5, 127.9, 126.9, 118.5, 116.2, 112.5, 21.3; HRMS
(ESI): m/z [M + Na]+ calcd for C26H20N2Na: 383.1519; found:
383.1517.
2,6-Di-p-tolyl-4,4′-bipyridine (5f). Yield 57% (95.7 mg); black
solid; mp 190–193 °C; 1H NMR (400 MHz, CDCl3): δ (ppm)
8.78 (d, J = 3.6 Hz, 2H), 8.10 (d, J = 8.4 Hz, 4H), 7.83 (s, 2H),
7.65 (d, J = 5.6 Hz, 2H), 7.33 (d, J = 8.0 Hz, 4H), 2.44 (s, 6H);
13C NMR (100 MHz, CDCl3) δ (ppm) 157.9, 150.4, 147.2, 146.9,
139.4, 136.3, 129.5, 127.0, 121.7, 116.0, 21.3; HRMS (ESI): m/z
[M + H]+ calcd for C24H21N2: 337.1699; found: 337.1701.
4-(Thiophen-2-yl)-2,6-di-p-tolylpyridine (5g). Yield 74%
(126.2 mg); pink solid; mp 163–166 °C; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.07 (d, J = 8.4 Hz, 4H), 7.80 (s, 2H), 7.58 (dd,
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