Synthesis of Triazole-Fused Phenanthridines through Pd-Catalyzed Intramolecular Phenyl C-H Activation of 1,5-Diaryl-1,2,3-triazoles

Article abstract of DOI:10.1055/s-0037-1611859

An efficient method for the synthesis of triazole-fused phenanthridines from 1,5-diaryl-1,2,3-triazoles under palladium catalysis has been developed. The reaction proceeds through Pd-catalyzed intramolecular phenyl C-H activation of 1,5-diaryl-1,2,3-triazoles. This method provides a concise and efficient pathway to construct triazolo[1,5-f]phenanthridine derivatives in excellent yields.

Full text of DOI:10.1055/s-0037-1611859

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
J. Wang et al.
Letter
Synlett
Synthesis of Triazole-Fused Phenanthridines through Pd-Cata-
lyzed Intramolecular Phenyl C–H Activation of 1,5-Diaryl-1,2,3-tri-
azoles
Y
Jiazhuang Wang§
Jianhua Yang§
Xuxin Fu
R1
R1
R2
N
N
Pd(OAc)2, PCy3, CsOPiv
N
N
N
N
toluene, 130 °C
82–95% yield
Guiping Qin
Tiebo Xiao*
Yubo Jiang*
R2
X
C–H functionalization
X = halogen, Y = H;
X = H, Y = halogen
R1, R2 = H, Me, MeO
Triazole-fused phenanthridine
14 examples
Faculty of Science, Kunming University of Science and
Technology, South Jingming Road 727, Kunming 650500,
P. R. of China
xiaotb@kmust.edu.cn
ybjiang@kmust.edu.cn
§Both authors contributed equally.
Received: 01.05.2019
O
Accepted after revision: 20.05.2019
Published online: 19.06.2019
DOI: 10.1055/s-0037-1611859; Art ID: st-2019-l0244-l
O
O
N
OMe
S
OMe
O
Pt
Abstract An efficient method for the synthesis of triazole-fused
phenanthridines from 1,5-diaryl-1,2,3-triazoles under palladium cataly-
sis has been developed. The reaction proceeds through Pd-catalyzed in-
tramolecular phenyl C–H activation of 1,5-diaryl-1,2,3-triazoles. This
method provides a concise and efficient pathway to construct triazo-
lo[1,5-f]phenanthridine derivatives in excellent yields.
N
O
R
O
N
N
I
N
N
N
O
R
OBn
OMe
OMe
anti-breast cancer
OC8H17
OMe
xychelerythrine
used in OLED
S
Key words palladium catalyst, site-selective reactions, C–H activa-
tion, 1,5-diaryl-1,2,3-triazoles, fused phenanthridines
OC8H17
C8H17
O
S
N
N
RO
OR
Phenanthridine, an important nitrogen heterocycle dis-
covered by Pictet and Ankersmit from the pyrolysis conden-
sation of benzaldehyde and aniline,[1] is a common pharma-
cophore existing in various natural alkaloids.[2] It has been
widely applied in prosperous research areas including med-
icine,[3] materials,[4] and biological technology (Figure 1).[5]
Additionally, it also has served as a vital intermediate for
constructing complicated molecules in organic synthesis.[6]
Because of these attractive applications, extensive efforts
have been devoted to the development of concise and ver-
satile methods for the synthesis of phenanthridines and
their derivatives.[7]
Moreover, the 1,2,3-triazole motif, which is considered
to be a safe bioequivalent surrogate for amide, is another
functional core abundantly present in many fields. As many
1,2,3-triazole-containing compounds possess particular
medicinal activities including anti vibrio cholerae, anticon-
vulsant, anti-inflammatory, antitubercular, antifungal, anti-
malarial, anti-vitiligo, and anti-cancer, this kind of struc-
tures have played an outstanding role in medicinal research
O
Ph
S
O
C8H17
OC8H17
O
used in bioimaging
n
OC8H17
used as liquid crystal
(R = 5-undecyl)
used in solar cells
Figure 1 Typical applications of phenanthridine derivatives
and development.[8] The synthesis of 1,2,3-triazole deriva-
tives has also been an interesting target in material research
for applications such as energetic molecules, ions recogni-
tion, solar cells, sorbents, liquid crystals, and fluorescent
probes.[9] Furthermore, these heterocycles are commonly
found as catalysts, ligands, and core intermediates in the
field of organic synthesis.[10]
Those booming applications have attracted much atten-
tion and vigorously accelerated the development of new
strategies for constructing 1,2,3-triazole derivatives in re-
cent years. Except for the traditional 1,3-dipolar addition,
methods involved Cu[11] or Ru[12] catalysts regioselectively
delivering the 1,4- or 1,5-disubstituted isomer, respectively.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Wang et al.
Letter
Synlett
Recently, the direct modification of 1,2,3-triazole deriva-
tives has emerged as another indispensable access to the
functionalized target molecules, especially to complex
structures. Prominently, the 1,2,3-triazole ring-directed C–H
bond functionalizations to furnish C–C, C–O, C–N, C–halo-
gen bonds with high efficiency and selectivity[13] served as
an elegant bridge to late-stage diversification of ‘click com-
pounds’. As hybridization of different pharmacophores
from various bioactive substances into a single molecule is
an encouraging strategy in the discovery of new drugs, the
fusion of 1,2,3-triazole and phenanthridine rings has also
attracted attention, recently. In 2014, Wen and co-workers
described a copper-catalyzed formation of triazolophenan-
thridines through a cascade reaction with cyclic diaryliodo-
niums, sodium azide, and alkynes as the starting materials
(Scheme 1, a).[14] In 2016, Likhar reported a palladium-cata-
lyzed one-pot synthesis of triazolo[1,5-f]phenanthridines
from 1,4-diaryl 1,2,3-triazoles and aryl halides (Scheme 1,
b).[15] The group of Fan disclosed a convenient preparation
of triazolophenanthridines through a Pd-catalyzed C–H
arylation reaction (Scheme 1, c).[16] Notably, it is the C(5)–H
bond of the heterocycle which was involved in the ring-
closing step in both two methods b and c in Scheme 1. And
it is worth mentioning that a Pd-catalyzed intermolecular
cross-coupling of triazole bromide with a heterocyclic C–H
group has been reported by Doucet and co-workers. Only
one example of intramolecular cyclization was involved, in
which a structurally complicated PdCl(C3H5)(dppb) catalyst
was used under a relatively higher temperature.[17] Herein,
we report an efficient Pd-catalyzed cyclization process to
synthesize triazolophenanthridines, in which 1,5-diaryl-
1,2,3-triazoles were applied as the substrates and the or-
tho-C–H bond of N(1)- or C(5)-aryl was selectively arylat-
ed in the cyclization process (Scheme 1, d).
azolo[1,5-f]phenanthridine (2a) was detected when the re-
action was conducted at 130 °C in toluene as a solvent for
24 hours with use of the substrate 1a (0.3 mmol), zero-va-
lent Pd(PPh3)4 or Pd2(dba)3 (0.1 equiv), and K3PO4 (3 equiv)
(Table 1, entries 1–2). Application of two-valent palladium
catalysts such as Pd(PPh3)2Cl2 and Pd(OAc)2 in the reaction
led to significant improvements with an acceptable isolated
yield of 42% (Table 1, entries 3–4). The structure of the
product 2a was unambiguously confirmed by single-crystal
X-ray diffraction analysis.[18] Among the next solvents
screened, toluene was the most effective, whereas other
solvents including DMSO, DMF, and dimethylacetamide
(DMA) seemed ineffective in the system (Table 1, entries 5–
7). Further screening of the bases showed that Cs2CO3 was
better than others, including K3PO4 and K2CO3, delivering
the target molecules with 65% yield (Table 1, entries 8–9).
Subsequently, we investigated the effects of ligands and
Table 1 Optimization of the Reaction Conditionsa
conditions
N
N
N
N
N
N
130 °C
Br
1a
2a
Entry
Catalyst
Base
K3PO4
Ligand
Solvent
Yield (%)b
1
2
Pd(PPh3)4
Pd2(dba)3
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
toluene
toluene
toluene
toluene
DMSO
DMF
–
–
K3PO4
–
3
K3PO4
–
26
42
22
–
4
K3PO4
–
5
K3PO4
–
An initial investigation of the reaction conditions was
conducted by using 5-(2-bromophenyl)-1-(p-tolyl)-1H-
1,2,3-triazole (1a) as the starting material. We investigated
the effects of catalysts, bases, ligands, and solvents, as sum-
marized in Table 1. No target molecule 9-methyl- [1,2,3]tri-
6
K3PO4
–
7
K3PO4
–
DMA
–
8
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOPiv
NaOPiv
CsOPiv
CsOPiv
–
toluene
toluene
toluene
58
65
70
32
76
91
93
82
86
92
9
–
10
11
12
13c
14
15
16d
17e
PPh3
(p-Tol)3Ph toluene
N
–OTf
N
NaN3
+
+
R
I
N
R
Br
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
toluene
toluene
toluene
toluene
toluene
toluene
a
H
c
(Ref. 14)
(Ref. 16)
N
N
I
N
H
b
H
d
R
N
X
+
N
a Reaction conditions unless noted: 5-(2-bromophenyl)-1-(p-tolyl)-1H-
1,2,3-triazole 1a (0.3 mmol), catalyst (0.03 mmol), ligand (0.06 mmol),
and base (0.9 mmol) were added to solvent (2 mL) and stirred at 130 °C for
N
H
(Ref. 15)
This work
N
N
N
R
24 h.
Y
I
b Isolated yield.
H
c 3 equiv of PivOH added.
d 2 equiv of CsOPiv added.
e 4 equiv of CsOPiv added.
Scheme 1 Synthesis of triazolophenanthridines
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
J. Wang et al.
Letter
Synlett
found that the yield could be further improved when PCy3
was employed, and a satisfying yield of 76% was obtained
(Table 1, entry 12). To our delight, the yield was remarkably
raised to 91% when we added 3.0 equiv of trimethylacetic
acid (PivOH) to the system (Table 1, entry 13). To test
whether it was the CsOPiv generated in situ from Cs2CO3
and PivOH, CsOPiv was added directly instead, and an excel-
lent yield of 93% was acquired (Table 1, entry 14). Another
pivalate, namely NaOPiv, was also tested in this transforma-
tion and it seemed inferior to CsOPiv (Table 1, entry 15).
Additionally, the amount of CsOPiv was also examined, and
reducing the amount of CsOPiv to 2.0 equiv or increasing it
to 4.0 equiv could not raise the yield evidently (Table 1, en-
tries 16–17). After further optimization, the best results
were obtained by using 10 mol% Pd(OAc)2, 20 mol% PCy3
and 3.0 equiv of CsOPiv in toluene at 130 °C for 24 hours,
affording the desired compound 2a in 93% yield (Table 1,
entry 14).
Having the optimized conditions in hand, we then in-
vestigated the scope of this protocol utilizing various 1,5-
diaryl-1,2,3-triazoles bearing ortho-halogen atoms on the
5-aryl ring (Table 2). The reactions were found to be quite
efficient and tolerated electron-donating groups such as
methyl or methoxy, furnishing the expected triazolo-
phenanthridines in good yields (84–95%). The position of
the methyl group in the N-1 phenyl ring of the 1,2,3-tri-
azole had little effect on the reaction, and the desired prod-
ucts could be obtained in excellent yields (Table 2, 1a–d). As
expected, when 5-(2-bromophenyl)-1-(m-tolyl)-1H-1,2,3-
triazole (1d) was used as a substrate, the isomer products
Table 3 Scope of 5-(ortho-Halogenaryl)-1-aryl-1,2,3-triazolesa,b
X
N
Pd(OAc)2, PCy3, PivOCs
N
N
N
N
N
toluene, 130 °C
X = Cl, Br, I
R2
R2
Table 2 Scope of 5-(ortho-Halogenaryl)-1-aryl-1,2,3-triazolesa,b
1
2
Substrates
Products
Substrates
Products
R1
R1
N
Br
Br
N
Pd(OAc)2, PCy3, CsOPiv
N
N
N
N
toluene, 130 °C
X = Cl, Br
N
N
N
N
N
N
N
N
N
N
N
N
X
1
2
MeO
MeO
1k
Cl
1g
2g, 85%
Substrates
Products
Substrates
Products
2k, 93%
*
Br
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
2d + 2d*c, 84%
Br
1a
2a, 93%
2b, 92%
1h
1l
2g, 84%
1d
MeO
(56:44)
I
Br
N
MeO
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
Br
2g, 95%
1m
1i
2i, 93%
1b
2b, 95%
2e, 85%
1e
Br
Br
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
*
Cl
Br
2j + 2j*c , 88%
1n
2n, 82%
1j
1f
2a, 84%
2c, 86%
1c
(56:44)
a Reaction conditions: 1,5-diaryl-1,2,3-triazole 1 (0.3 mmol), Pd(OAc)2
a Reaction conditions: 1,5-diaryl-1,2,3-triazole 1 (0.3 mmol), Pd(OAc)2
(0.03 mmol), PCy3 (0.06 mmol), and CsOPiv (0.9 mmol) were added to tol-
uene (2 mL) and stirred at 130 °C for 24 h.
(0.03 mmol), PCy3 (0.06 mmol), and CsOPiv (0.9 mmol) were added to tol-
uene (2 mL) and stirred at 130 °C for 24 h.
b Yield of isolated product after column chromatography.
c Isomer with a –CH3 group on the site marked with an asterisk.
b Yield of isolated product after column chromatography.
c Isomer with –CH3 group on the site marked with an asterisk.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
J. Wang et al.
Letter
Synlett
Br
Br
N
N
N
N
N
N
standard conditions
N
N
N
N
N
+
+
N
2 h
kH/kD = 1.22
D4
D5
d5-1h (0.15 mmol)
1h (0.15 mmol)
d4-2h
2h
Scheme 2 Kinetic isotope effect experiment
2d and 2d* were obtained in a whole yield of 84%, and the
ratio of 2d to 2d* was confirmed by H NMR spectroscopy
References and Notes
1
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as 56:44 (Table 2, 2d and 2d*). To our delight, when a com-
pound containing an unactivated ortho-C–Cl bond, namely
1,5-diaryl-1,2,3-triazole 1f, was employed as the substrate,
the desired product 2a could also be obtained in a good
yield of 84%.
(3) (a) Cheng, P.; Qing, Z.; Liu, S.; Liu, W.; Xie, H.; Zeng, J. Tetrahe-
dron Lett. 2014, 55, 6647. (b) Lasák, P.; Motyka, K.; Kryštof, V.;
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Subsequently, we investigated the substrates with an or-
tho-halogen atom on the N-1 phenyl ring shown in Table 3.
When a methyl group or methoxy group was present at any
site of the C-5 aryl ring (Table 3, 1g–k), the desired product
could be obtained in excellent yield (82–95%). Notably,
when substrate 1j with a meta-methyl group on the C-5
aryl was used as the substrate, the isomer products 2j and
2j* were also obtained in an overall yield of 88% (2j/2j* =
56:44, determined by 1H NMR spectroscopy). Moreover, rel-
evant chlorinated and iodized substrates were also suitable
for this transformation, delivering corresponding target
molecules 2g in yields of 84% and 95%, respectively, (Table 3,
1l and 1m). It is worth noting that 5-pyridyl substrate 1n
was well tolerated in the system, giving the product 2n in
82% yield.
To gain mechanistic insight into the reactions, a test of
the kinetic isotope effect (KIE) was conducted. The inter-
molecular KIE for 1a to d5-1a in the C–H direct arylation of
1,5-diaryl-1,2,3-triazoles was determined to be kH/kD = 1.22
by a competition experiment, indicating that the C–H bond
cleavage may not be the rate-determining step (Scheme 2).
In conclusion, a Pd(OAc)2-catalyzed process for the effi-
cient synthesis of triazolophenanthridines was achieved, in
which 1,5-diaryl-1,2,3-triazoles were applied as the sub-
strates.[19] A variety of substituted triazolophenanthridines
were prepared through this simple intramolecular cycliza-
tion with excellent yields.
Funding Information
The authors like to thank the National Natural Science Foundation of
China (No. 21662020) for the financial support.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611859.
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orti
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© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
J. Wang et al.
Letter
Synlett
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(18) CCDC 1857225 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(19) Synthesis of Triazolophenanthridines 2; General Procedure
To a 50 mL pressure tube, 1,5-diaryl-1,2,3-triazole were added 1
(0.3 mmol), Pd(OAc)2 (0.03 mmol), PCy3 (0.06 mmol), CsOPiv
(0.9 mmol), and toluene (2 mL) and the reaction mixture was
stirred at 130 °C for 24 h. After consumption of the 1,5-disub-
stitued 1,2,3-triazoles monitored by TLC analysis, the mixture
was treated with H2O (15 mL) and extracted with EtOAc (3 × 15
mL). The combined organic layers were washed with brine (3 ×
5 mL), dried with Na2SO4, and concentrated under reduced pres-
sure to afford a crude product. Purification by column chroma-
tography on silica gel with EtOAc-PE (1:8) afforded the desired
products 2.
(11) (a) Johansson, J.; Beke-Somfai, T.; Stålsmeden, A.; Kann, N.
Chem. Rev. 2016, 116, 14726. (b) Alonso, F.; Moglie, Y.; Radivoy,
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Chem. Rev. 2016, 116, 14726. (b) Hosseinnejad, T.; Mandavian, S.
Comput. Theor. Chem. 2018, 1143, 29. (c) Liu, P.; Clark, R.; Zhu, L.
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S.; Rasmussen, L.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V.
J. Am. Chem. Soc. 2008, 130, 8923.
9-Methyl-[1,2,3]triazolo[1,5-f]phenanthridine (2a)
White solid; yield: 65 mg (93%); mp 159.8–160.8 °C. IR (KBr):
3066, 2946, 2841, 1731, 1620, 1555, 1494, 1448, 1207, 1124,
1
1074, 1014, 826, 760, 584 cm–1. H NMR (600 MHz, CDCl3):  =
8.64 (d, J = 8.4 Hz, 1 H), 8.39 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.16
(s, 1 H), 8.10–8.03 (m, 1 H), 7.69–7.63 (m, 1 H), 7.61 (dd, J =
10.8, 4.1 Hz, 1 H), 7.51 (d, J = 8.3 Hz, 1 H), 2.58 (s, 3 H). 13C NMR
(150 MHz, CDCl3):  = 137.3, 131.3, 130.8, 129.2, 129.0, 128.6,
127.3, 127.2, 124.8, 123.5, 123.0, 121.9, 121.9, 116.9, 21.7.
HRMS (ESI+): m/z [M + H]+ calcd for C15H12N3: 234.1026; found:
234.1031.
[1,2,3]Triazolo[1,5-f]phenanthridine (2b)
(13) (a) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int. Ed.
2006, 45, 2619. (b) Zhao, F.; Liu, Y.; Yang, S.; Xie, K.; Jiang, Y. Org.
Chem. Front. 2017, 4, 1112. (c) Gu, Q.; Al Mamari, H.; Grczyk, K.;
Diers, E.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53, 3868.
(d) Shang, R.; Ilies, L.; Nakamura, E. Chem. Rev. 2017, 117, 9086.
(e) Bauer, M.; Wang, W.; Lorion, M.; Dong, C.; Ackermann, L.
Angew. Chem. Int. Ed. 2018, 57, 203. (f) He, P.; Tian, Q.; Kuang, C.
Org. Biomol. Chem. 2015, 13, 7146. (g) Fruchey, E.; Monks, B.;
Cook, S. J. Am. Chem. Soc. 2014, 136, 13130. (h) Wang, Z.; Tian,
Q.; Yu, X.; Kuang, C. Adv. Synth. Catal. 2014, 356, 961. (i) Zhao, F.;
Chen, Z.; Ma, X.; Huang, S.; Jiang, Y. Tetrahedron Lett. 2017, 58,
614. (j) Shi, S.; Kuang, C. J. Org. Chem. 2014, 79, 6105. (k) Wang,
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X.; Liu, W.; Wang, Z.; Shi, S.; Kuang, C. Org. Biomol. Chem. 2013,
11, 7830.
White solid; yield: 62 mg (95%); mp 187.2–188.4 °C. IR (KBr):
3047, 2944, 2843, 1944, 1790, 1724, 1617, 1558, 1447, 1220,
1125, 976, 822, 747, 526 cm–1 1H NMR (600 MHz, CDCl3):  =
.
8.75–8.73 (m, 1 H), 8.39–8.37 (m, 1 H), 8.36–8.33 (m, 1 H),
8.32–8.30 (m, 1 H), 8.04–8.01 (m, 1 H), 7.71–7.67 (m, 1 H),
7.65–7.57 (m, 3 H). 13C NMR (150 MHz, CDCl3):  = 131.4, 130.8,
129.5, 129.3, 128.6, 127.3, 127.2, 127.1, 124.6, 123.5, 122.9,
121.9, 121.6, 117.0. HRMS (ESI+): m/z [M + H]+ calcd for
C
14H10N3: 220.0869; found: 220.0872.
11-Methyl-[1,2,3]triazolo[1,5-f]phenanthridine (2c)
White solid; yield: 60 mg (86%); mp 142.1–143 °C. IR (KBr): 3045,
2948, 2849, 1957, 1786, 1710, 1623, 1564, 1512, 1449, 1393,
1226, 1126, 1079, 971, 854, 810, 756, 566 cm–1 1H NMR (600
.
MHz, CDCl3):  = 8.39 (dd, J = 3.0, 1.5 Hz, 1 H), 8.34 (t, J = 8.2 Hz,
1 H), 8.28 (t, J = 7.8 Hz, 1 H), 8.04 (dd, J = 9.2, 4.6 Hz, 1 H), 7.64–
7.57 (m, 2 H), 7.52 (d, J = 2.7 Hz, 1 H), 7.50–7.46 (m, 1 H), 3.17 (s,
3 H). 13C NMR (150 MHz, CDCl3):  = 133.2, 132.5, 132.5, 130.7,
130.3, 129.2, 128.5, 127.9, 126.5, 125.9, 124.3, 123.3, 123.2,
121.7, 121.3, 25.2. HRMS (ESI+): m/z [M + H]+ calcd for C15H12N3:
234.1026; found: 234.1029.
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Adv. 2016, 6, 43638.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E