Unprecedented synthesis of 1,2,3-triazolo-cinnolinone via Sonogashira coupling and intramolecular cyclization

Article abstract of DOI:10.1039/C8OB01152D

An unprecedented copper mediated one-pot sequential synthesis of 1,2,3-triazolo cinnolinone derivatives from 2-halo-phenyl triazoles and terminal alkynes has been reported. Under the optimized reaction conditions, a broad range of substituted triazoles and alkynes were found to participate in this transformation, thus affording unknown 1,2,3-triazolo cinnolinone derivatives in moderate to excellent yields. This method proceeds through sequential C-C coupling followed by an annulation cascade sequence in the same vessel under atmospheric air as the sole oxidant, thus representing a simple, efficient and atom economical approach for the synthesis of aza-cinnolinones.

Full text of DOI:10.1039/C8OB01152D

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Unprecedented Synthesis of 1,2,3-Triazolo-Cinnolinone via
Sonogashira Coupling and Intramolecular Cyclization
Avnish Kumar,a,b Dharmendra Kumar Tiwari,c Balasubramanian Sridhar,d and Pravin R. Likhar*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper mediated an unprecedented one pot sequential synthesis
of 1,2,3-triazolo cinnolinone derivatives from 2-halo-phenyl
triazoles and terminal alkynes has been reported. Under the
optimized reaction conditions, a broad range of substituted
triazoles and alkynes were found to participate in this
transformation, thus affording unknown 1,2,3-triazolo cinnolinone
derivatives in moderate to excellent yield. This method proceeds
through sequential C-C coupling followed by annulation cascade
sequence in the same vessel under atmospheric air as the sole
oxidant, thus representing
a simple, efficient and atom
economical approach to aza-cinnolinones.
Figure 1. Biologically active cinnoline derivatives.
The cinnoline and its derivatives are an important class of
nitrogen-containing heterocyclic compounds, frequently
encountered in various biologically and pharmaceutically
important molecules,[1] displaying a broad range of biological
properties such as anticancer, anti-inflammatory, antifungal,
LRRK2 inhibitor, LXR agonist, GABAA modulator, antibacterial
(Fig.-1).[2] These derivatives also exhibit luminescent and
survey revealed that arylhydrazones, arylhydrazines,
arenediazonium salts, and aryl phenylallylidenehydrazone are
the most preferred starting materials for the synthesis of
cinnoline derivatives, as they are already embedded with two
nitrogen atoms.[7-9] Although, the hydrazones, hydrazines and
diazonium salts have been employed as starting materials in
various organic transformation reactions but the commercial
unavailability, stability and handling issues are some serious
drawbacks associated with these materials. Therefore, a direct
access to biologically important cinnoline derivatives from
simpler starting materials remains an important research
objective.
fluorescent
properties
for
cell-based
imaging[3]
,
antitrypanosomiasis activity, and inhibitory activity towards
Bruton’s tyrosine kinase and antiallergic activities.[4a-e] In
addition, they also have useful electrochemical, n-channel
semiconductors properties and play an important role in
organic synthesis.
Owing to their chemical and physical properties numerous
elegant methods have been developed for the synthesis of
heterofusedcinnolines in recent past.[5-6] A careful literature
The 1,2,3-triazoles are some of the most prevalent structural
motifs in several biologically active organic compounds,
electronic materials and agrochemicals.[10] In particular, the
transition metal catalyzed functionalization of triazoles
through C-H activation has emerged as a powerful tool for
construction of complex compounds, which are usually difficult
to synthesize by conventional methods.[11] In this regard, Wu
and coworkers, recently developed oxidative annulation
between triazoles and internal alkynes, catalyzed by
[Cp*RhCl2]2 and Cu(OAc)2·H2O through sequential triazole-
directed C-H activation followed by C−C, C−N, and C−O bond
formation processes in one-pot to access mesoionic
triazoloisoquinolium derivatives (Scheme-1).[12] On the other
hand, we recently reported a palladium catalyzed double C-H
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o
functionalizations of 2-iodophenyl triazoles to afford a variety (2.0 mol%), CuI (2.0 mol%) in Et3N (3.0 mL) at 50 C for 6 h
of triazolo[1,5-f]phenanthridines.[13] As a part of our continued (table-1 entry 9). After the standardization of Sonogashira
research interest in triazole chemistry, here in we disclose our coupling, the product 3aa’ was isolated and subjected to
highly unexpected findings for the synthesis of unknown 1,2,3- annulations reaction with different conditions. Initially, the
triazolo[1,2-a]cinnolin-1-one from 2-iodo-phenyl-triazoles and hypothesis was based on palladium catalyzed C-H activation of
alkynes through sequential Sonogashira coupling and 1,2,3-triazole followed by annulations to obtained 4aa from
annulation reactions in one pot (scheme-1).
3aa’. In order to get the desired 4aa several reactions were
tried, unfortunately, all our efforts were found unsuccessful.
Interestingly, when we treated 3aa’ (1.0 mmol) with Cu(OAc)2
(1.0 mmol) and Et3N (2.0 mmol) in toluene (3.0 mmol) at 120
°C for 12 h, we observed trace amount of 3aa which was
confirmed by ESI-MS. This observation was needed to optimize
for good yield of 3aa (Table-2). To our delight, when ligand (L1,
10 mol%) was introduced with Cu(OAc)2 a higher yield (56%) of
the desired 3aa was obtained (entry-2). Among the various
bases screened for the annulations reaction, only sodium
acetate gave superior yield (61%) than the triethylamine
Table 2. Optimization studies for cyclization.a
Scheme-1: Previous report along with present study
We started our investigation by optimizing the reaction
conditions for both Sonogashira and annulations reactions
separately (table-1 & 2), however, at later the stage, both the
steps were telescoped in a one-pot.
We have selected 1-(2-iodophenyl)-4-phenyl-1H-1,2,3-triazole
(
1a) and 1-hexyne as a model substrate for this one-pot, two
steps synthesis of the cinnolinone derivative. In order to
optimize the Sonogashira coupling several catalysts, ligands,
base, and solvents were screened Table-1. After several
optimizations efforts it was found that Sonogashira coupling
proceeds smoothly when 1a (1.0 mmol) and 2a
En
Metal
Base
(2 eq.)
Et3N
Solvent
Additiv
es
-
L (10
mol%)
--
L1
L1
L1
L1
L1
L2
Yield
%
b
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Trace
56
53
48
61
66
51
85
92
Et3N
-
iPr3N
K2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
(1.0 eq)
NaOAc
NaOAc
NaOAc
NaOAc
Table 1. Optimization studies for Sonogashira coupling.a
PivOH
PivOH
PivOH
PivOH
PivOH
L3
L4
L4
10
72
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2.H2
O
CuSO4.5H2O
Cu(OTf)2
CuI
DMF
DMSO
NMP
PivOH
PivOH
PivOH
PivOH
L4
L4
L4
L4
Trace
Trace
Trace
66
S.
No.
Pd catalyst
(2 mol%)
Base (2
equiv.)
Solvent
Yields %
(3aa’)a
1
2
Pd(OAc)2
Pd(OAc)2
K2CO3
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
-
toluene
toluene
toluene
THF
27b
35b
21b
78
toluene
15
16
17
18
19
20
21
22
23
24
25
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toulene
toluene
toluene
toluene
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
42
48
62
3
PdCl2
4
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
5
MeCN
DMF
66
AgOAc
trace
trace
trace
trace
45
6
57
Pd (OAc)2
Ni(OAc)2
Fe(OAc)3
(Ph3P)AuCl
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2 (10
mol%)
7
THF
88
92c
8
Et3N
88c
9
-
Et3N
96
60d
10
11
12
-
Et3N
78d
55e
Tracef
8e
-
Et3N
-
Et3N
Reagents and conditions:a 3aa’; (301 mg, 1.0 mmol); Cu(OAc)2 (1.0 mmol),
NaOAc (2.0 mmol), Ligand (L4; 10.0 mol%), PivOH (10.0 mol%) in toluene (3.0
mL), refluxed at 120 °C, for 12 h under air.(b) isolated yield; (c)when reaction was
performed at 140 °C;
mol% of Cu(OAc)2 was used. Ligands L1, L2, L3, L4 = ethane-1,2-diamine(en),
Reagents and conditions: 1a (1.0 mmol), 2a ( 1.2 mmol), Pd(PPh3)2Cl2 (2.0 mol
%), CuI (2.0 mol %) and Et3N (3.0 mL) at 50 °C, for 6 h, under N2.(a) isolated yield;
(d)
(b)when PPh3 was used; (c)when reaction was performed at 25 °C;
when 4.0
(d)
(e)
when reaction was performed at 100 °C;
when 10
mole% CuI was used; (e)when Cu(OAc)2 (2.0 mol%) was used; (f)when Cu(OAc)2
(1.0 mmol) was used.
1,10-phen, PPh3, dppm.
2 | J. Name., 2012, 00, 1-3
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Table-3 Substrate scope of the present studya
(entries 3-5). We next examine the effect of additives and
found that the addition PivOH (10.0 mol%) in same reaction
condition affording 3aa in 66% yield (entry-6). Since the ligand
plays an important role in this reaction we next screened the
effect of different ligands. Amongst, the different ligands were
tested (L2, L3, and L4) only L4 provided the best yield 92% of
3aa, indicating that phosphine ligands are more effective than
amines (entries 7-9). Furthermore, reducing the amount of
base from 2.0 equiv. to 1.0 equiv., furnished inferior yields of
desired 3aa (entry-10). Our urge to further improve the
reaction conditions resulted in checking the effect of polar
solvents such as DMF, DMSO and NMP and surprisingly, all of
them furnished 3aa only in trace amounts (entries 11-13),
indicating that toluene is the best choice as a solvent in
reaction. Different source copper such as Cu(OAc)2.H2O,
CuSO4.5H2O and Cu(OTf)2 were also screened but all of them
furnished 3aa in low yields (entry-14-16). We next screened
the role of Cu(I) salt as well as different metals such as AgOAc,
Pd(OAc)2, Ni(OAc)2,, Fe(OAc)3, and (Ph3P)AuCl however most of
them were found unsuccessful to induce the annulations
reaction except CuI and (Ph3P)AuCl which furnished 3aa in 62%
and 45% yields respectively (entry-17-22). Increasing or
decreasing the reaction temperature from 120 °C, also
resulted in a poor yield of 3aa (entry-23-24). Employing
catalytic amount of Cu(OAc)2 (10 mol%) furnished 3aa only in
trace amount indicating that the stoichiometric amount of
copper salt is required for this annulation reaction (entry-25).
The structure of 3aa was well characterized by 1H and 13C
NMR, HRMS and X-ray crystallography (fig. 2).
F
OMe
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
nBu
nBu
nBu
nBu
3aa; 82%b
3ba; 85%b
3ca; 81%b
3da; 73%b
S
N
O
O
O
N
O
CF3
N
N
N
N
N
N
N
N
N
N
N
nBu
nBu
n-Pentyl
OH
nBu
nBu
3ea; 71%b
3fa; 75%b
O
3hb; 82%b
3ga; 81%b
O
n-Octyl
O
N
O
N
N
N
N
N
N
N
N
N
N
N
OH
OH
nBu
OH
3jd; 71%b
3kd; 76%b
3la; 60%b
3ic; 69%b
nBu
O
O
O
N
O
N
N
N
N
N
N
N
N
N
N
N
Cl
OH
nBu
MeOOC
nBu
CN
nBu
3ma; 80%b
3na; 75%b
3oa; 72%b
3pd; 81%b
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
OH
3ac; 61%b
OMe
3ae; 66%b
3af; 70%b
O
3ag; 65%b
nBu
n-Octyl
O
O
N
N
N
N
N
N
N
N
N
nBu
3ka; 71%b
NHTs
3ah; 61%b
3ii; 0%
aRegents and conditions
: conditions-1: 1a-1p (1.0 mmol), 2a ( 1.2 mmol),
Pd(PPh3)2Cl2 (2.0 mol %), CuI (2.0 mol %) and Et3N (3.0 mL) at 50 °C, for 6 h,
under N2; condition 2: (after completion of reaction (monitored by TLC) Et3N was
evaporated and crude product was treated with Cu(OAc)2 (1.0 mmol), NaOAc
(2.0 mmol), Ligand (L4; 10.0 mol%), PivOH (10.0 mol%) in toluene (3.0 mL),
refluxed at 120 °C, for 12 h under air. bisolated yield; Condition-1: applied for
Sonogashira coupling and after evaporation of Et3N; condition-2 was applied for
annulation reaction in the same vessel.
Figure 2. ORTEP diagram of 3aa with atom-numbering scheme. Displacement ellipsoids
are drawn at the 30% probability level
After having standard conditions for both Sonogashira (table-1
entry-9) and annulation (table-2, entry-9) reactions in hand,
we turned our attention to cut short these two steps process
in same vessel without any workup and purification of
intermediate (3aa’). Therefore, 1a (1.0 mmol) and 2a (2.0
mmol) were treated with Pd(PPh3)2Cl2, (2.0 mol%), CuI (2.0
affording good to excellent yields of desired products. It is
worth mentioning that triazoles containing electron
withdrawing groups (1d-1e) furnished slightly lower yields
than those containing electron donating groups (1b-1c). 1,2,3-
trizoles substituted with naphthyl, thiopehenyl, and pyridyl
groups were also found to be suitable partner and smoothly
reacted with alkynes (2a-2b), furnishing required products
o
mol%) in Et3N (3.0 mL) at 50 C for 6 h. After consumption of
starting materials (monitored by TLC), Et3N was removed
under reduced pressure and residue was dissolved in toluene
(3.0 mL) and was refluxed with Cu(OAc)2 (1.0 mmol), ligand
(
3fa, 3ga and 3hb) in very good yields. Furthermore, cyclic and
acyclic substitution on 4-position of triazoles (1i-1l) were also
(L4, 10.0 mol%), additive (PivOH, 10.0 mol%) and NaOAc (2.0
found equally effective and produced the desired products
mmol) at 120 °C for 12 h, under air furnishing 3aa in 82% yield
in one pot.
(
3id-3kd and 3la) in good to moderate yields. We next
employed various p-substituted N-aryl-1,2,3-triazoles into this
one pot cascade reaction with aliphatic alkynes under standard
reaction conditions delivered the corresponding 1,2,3-triazol-
The scope of this strategy is exemplified by a diverse range of
substrates (table-3). Initially, various 1,4-disubstituted 1,2,3-
triazoles (1a-1p) containing both electron donating (EDGs) and
electron withdrawing groups (EWGs) were employed and
delightfully, all of them participated well in the reaction,
5-ones (3ma-3oa
& 3pd) in very good yields. Similarly, the
series of alkynes carrying cyclopropyl (2e), cyclohexyl (2f),
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propargyl alcohol (2c), 3-methoxyprop-1-yne (2g), N-tosyl Triazolo-Cinnolinone via tandem Sonogashira Coupling and
substituted but-1-yne (2h) and hexyne-1 (2a) were successfully intramolecular cyclization in one pot. This one pot process
reacted with 1a and 1k under optimized reaction conditions involves one C-C, C−N and C-O bond formations in the
produced corresponding cinnolinones derivatives in identical presence of palladium/copper catalysts system providing good
yields. Aryl alkyne (phenyl acetylene, 1i) was also employed in to moderate yields with both electron withdrawing and
this reaction under the standard condition, unfortunately, no releasing groups.
cyclized product
Sonogashira coupling product
applying optimized reaction conditions.
Based on our findings and literature report[14] a plausible
reaction mechanism for this one-pot tandem synthesis
of 1,2,3-Triazolo-Cinnolinone is depicted in scheme 2. The first
(
3ii
)
was observed. In this case only
(
3ii’ was recovered after
)
Acknowledgements
Avnish Kumar thanks to UGC, New Delhi for fellowship. DKT
thanks the Department of Science and Technology New Delhi
India for DST-INSPIRE Faculty award. The authors are grateful
to the Director, CSIR-IICT for providing the necessary
step
of
the
reaction
proceeds
through
well infrastructures
.
recognized Shonogashira coupling reaction. In the initial step,
palladium (II) in situ reduced to active form of Pd (0) which on
oxidative addition with 1a furnished palladium (II)
Experimental
All reagents were purchased from commercial suppliers and
used without further purification. The Shonogashira
experiment was carried out under nitrogen atmosphere and
annulations was carried out under air in one pot. All the
solvents used for the reaction were distilled before use. The
product purification by column chromatography was
accomplished using silica gel 100-200 mesh. Analytical TLC was
performed with Merck silica gel 60 F254 plates, and the
products
were
visualized
by
UV detection. The 1H NMR and 13C NMR spectra were
recorded on a Bruker-Avance (300 MHz); Inova (400 MHz)
and Avance (500 MHz) spectrophotometer using CDCl3 and
TMS as the internal standard. Chemical shifts (δ) are reported
in ppm using TMS as an internal standard, and spin -spin
1
coupling constants (J) are given in Hz. Multiplicities in the H
NMR spectra are described as: s = singlet, d = doublet, t =
triplet, q = quartet, qt = quintet, m = multiplet, bs = broad
singlet; coupling constants are reported in Hz. Low (MS) and
high (HRMS) resolution mass spectra were recorded on a
Waters 2695 and Thermo Scientific Exactive spectrometer
respectively and mass/charge (m/z) ratios are reported as
values in atomic mass units. The melting points of all the
compounds are uncorrected.
Scheme-2. Plausible reaction mechanism
intermediate
transmetallation reaction with copper acetylide
intermediate This intermediate
A
.
The
intermediate
A
undergoes
to
B
gives the
C
.
C
undergoes reductive
elimination to give the intermediate 3aa’ with regeneration of
Pd(0) species. The internal alkyne of 3aa’ gets activated by
copper to produce intermediate
D which is in turn
General procedure for 1,2,3-Triazolo-Cinnolinone:
intramolecularly attacked by the lone pair of the nitrogen
To a 50ml of round-bottom flask 1-(2-iodophenyl)-4-phenyl-
1H-1,2,3-triazole (1a) (1.0 mmol), Pd(PPh3)2Cl2 (2 mol%), CuI (2
mol%) in 3.0 ml of Et3N were taken under N2 atmosphere. The
reaction mixture was allowed to be stirred at 50 °C for 5 min.
To the above solution 1-hexyne (1.2 mmol) was added drop
wise over a period of 2 min and the mixture was stirred for
another 6h at same temperature. After consumption of
starting materials (monitored by TLC) the triethylamine was
removed under reduced pressure and the crude product was
dissolved in toluene (4 mL). This solution Cu(OAc)2 (1.0 mmol),
NaOAc (2.0 mmol), Ligand (L4; 10.0 mol%), PivOH (10.0 mol%)
was added and refluxed at 120 °C, for 12 h under air
(Condition-B). The reaction mixture was filtered through a pad
of celite. The mixture was diluted with ethylacetate (20 mL)
and was washed with water (10 ml), brine (10 mL) and sat.
sodium bircarbonate solution (10 mL). The organic layer was
dried over sodium sulphate and was evaporated under
reduced pressure to furnish the crude 3aa which was purified
atom of triazole to furnished E. which undergoes to Proto-
demetalation to afford intermediate F. The intermediate
oxidized by air to give the desired 3aa.
F gets
After having the optimized reaction conditions, we next
performed the large scale synthesis of 3aa by reacting 1a (5.0
mmol) with 2a (6.0 mmol) under optimized reaction conditions
and furnished the desired 3aa 85% yield of 3aa (scheme-3).
Scheme-3: large scale synthesis of 3aa
In conclusion, we have successfully developed simple and
efficient an unprecedented strategy for the synthesis of 1,2,3-
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over silica gel column chromatography to afford the pure 137.42, 132.91, 131.43, 131.14, 129.62, 127.95, 127.03,
product 3aa in 82% yield as a yellowish needles.
125.45, 121.31, 118.06, 115.17, 114.72, 110.30, 106.13, 55.35,
29.41, 28.26, 22.37, 13.85; IR (neat): 3448, 3036, 2992, 2951,
2866, 2831, 1654, 1600, 1458, 1411, 1352, 1297, 1223, 1154,
1093, 1048; HRMS (ESI, Orbitrap): calcd for C21H22O2N3 [M+H]+
Large scale synthesis of 3aa
:
To a stirred solution of 1-(2-iodophenyl)-4-phenyl-1H-1,2,3- is. 348.17065 and found is 348.16992.
triazole (1a) (5.0 mmol), Pd(PPh3)2Cl2 (2 mol%), CuI (2 mol%) in 5-butyl-2-(4-fluorophenyl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
15.0 ml of Et3N were taken under N2 atmosphere. To the one(3da):
above reaction mixture 6.0 mmol of 1-hexyne was added Yield: 73%; Yellow needles, m.p. 168 - 170 °C; 1H NMR (400
dropwise for 8 min and stirred for another 6 h at 50 °C MHz, CDCl3): δ 9.23 – 9.19 (m, 1H), 8.39 – 8.32 (m, 2H), 7.43
(condition-1). After the completion of reaction (monitored by (ddd, J = 9.6, 6.7, 3.7 Hz, 1H), 7.37 – 7.32 (m, 2H), 7.20 – 7.10
TLC), Tri ethyl anime was removed by reduced pressure and (m, 2H), 6.20 (s, 1H), 2.88 (t, J = 7.4 Hz, 2H), 1.79 (dt, J = 15.3,
crude product was further treated with Cu(OAc)2 (1.0 mmol), 7.5 Hz, 2H), 1.51 (dq, J = 14.6, 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz,
NaOAc (2.0 mmol), Ligand (L4; 10.0 mol%), PivOH (10.0 mol%) 3H); 13C NMR (100 MHz, CDCl3): δ 163.96, 161.49, 153.16,
in 10mL of toluene and refluxed at 120 °C, for 12 h under air 137.36, 132.83, 130.58, 127.92, 127.44, 127.36, 127.05,
(Condition-2). the reaction mixture was filtered out on cilite 126.33, 125.44, 121.30, 115.67, 115.46, 115.10, 105.98, 29.37,
pad and solvent was removed by reduced pressure, washed 28.22, 22.38, 13.86; 19F NMR (376 MHz, CDCl3) δ: -112.70 (s,
with brine, organic layer was extracted with EtOH/H2O (1:3). 1F); IR (neat): 3448, 3056, 2929, 2865, 1644, 1599, 1525, 1458,
The crude product was set to purification by silica gel column 1410, 1337, 1218, 1157, 942; HRMS (ESI, Orbitrap): calcd for
chromatography to afford the pure product 3aa in 84% (1.34g) C20H19ON3F [M+H]+ is 336.15067 and found is336.14979.
yield as a yellowish needles.
5-butyl-2-(2-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[1,2-
5-butyl-2-phenyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-one(3aa): a]cinnolin-1-one(3ea):
Yield: 82%; Yellow needles, m.p. 196 - 198 °C; 1H NMR (400 Yield: 71%; Yellow needles, m.p. 131 - 133 °C; 1H NMR (300
MHz, CDCl3):δ 9.24 (d, J = 8.3 Hz, 1H), 8.40 – 8.34 (m, 2H), 7.46 MHz, CDCl3): δ 9.22 (d, J = 8.2 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H),
(ddd, J = 11.3, 8.1, 3.3 Hz, 3H), 7.36 (dd, J = 10.7, 5.7 Hz, 3H), 7.84 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 – 7.42 (m,
6.21 (s, 1H), 2.90 (t, J = 7.64 Hz, 2H), 1.81 (dt, J = 15.2, 7.5 Hz, 2H), 7.37 (d, J = 4.2 Hz, 2H), 6.27 (s, 1H), 2.86 (t, J = 7.7 Hz, 2H),
2H), 1.52 (dq, J = 14.7, 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C 1.78 (dt, J = 15.2, 7.5 Hz, 2H), 1.55 – 1.41 (m, 2H), 0.98 (t, J =
NMR (100 MHz, CDCl3): δ 153.33, 137.37, 132.85, 131.24, 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.59, 137.59,
130.15, 129.78, 128.92, 128.56, 128.42, 128.24, 127.85, 132.95, 131.71, 131.31, 130.17, 128.47, 128.09, 127.84,
126.97, 125.84, 125.56, 125.41, 121.30, 120.48, 117.62, 127.13, 125.55, 122.67, 121.24, 120.87, 115.20, 106.72, 29.66,
115.09, 105.96, 29.38, 28.21, 22.39, 13.88; IR (neat): 3448, 28.26, 22.39, 13.74; 19F NMR (471 MHz, CDCl3) δ: -58.75 (s, 3F);
3069, 2953, 2925, 2863, 1645,1594, 1457, 1411, 1353, 1295, IR (neat): 3449, 3072, 2959, 2931, 2867, 2092, 1653, 1601,
1201, 946, 751; HRMS (ESI, Orbitrap): calcd for C20H20ON3 1494, 1455, 1409, 1313, 1171, 1127, 1032, 954; HRMS (ESI,
[M+H]+ is 318.16009 and found is 318.16107
5-butyl-2-(p-tolyl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-1
one(3ba):
Yield: 85%; Yellow needles, m.p. 162- 164 °C; 1H NMR (400 5-butyl-2-(naphthalen-1-yl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-
MHz, CDCl3): δ 9.21 (d, J = 8.3 Hz, 1H), 8.25 (d, J = 8.0 Hz, 2H), 1-one(3fa):
.
Orbitrap): calcd for C21H19ON3F3 [M+H]+ is 386.14747 and
found is 386.14855
.
7.40 (dd, J = 8.1, 3.3 Hz, 1H), 7.28 (dd, J = 15.6, 5.5 Hz, 4H), Yield: 75%; Yellow needles, m.p. 158 - 160 °C; 1H NMR (500
6.15 (s, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H), 1.82 – 1.73 (m, MHz, CDCl3):δ 9.29 (d, J = 8.3 Hz, 1H), 8.77 (d, J = 8.5 Hz, 1H),
2H), 1.56 – 1.44 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H); 13C NMR (125 8.44 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.63 – 7.51 (m,
MHz, CDCl3): δ 153.34, 138.22, 137.45, 132.89, 129.27, 127.79, 3H), 7.49 – 7.44 (m, 1H), 7.37 (dd, J = 4.1, 0.7 Hz, 2H), 6.26 (s,
127.31, 126.93, 125.52, 125.34, 121.43, 115.15, 105.57, 29.41, 1H), 2.94 (t, J = 7.7 Hz, 2H), 1.90 – 1.81 (m, 2H), 1.54 (dd, J =
28.25, 22.38, 21.51, 13.87; IR (neat): 3448, 2954, 2866, 1643, 15.0, 7.5 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
1526, 1410, 1338, 1306, 1209, 1032, 944; HRMS (ESI, CDCl3): δ 154.14, 137.41, 134.16, 132.94, 132.45, 130.79,
Orbitrap): calcd for C21H22ON3 [M+H]+ is 332.17574 and found 129.38, 128.69, 127.95, 127.87, 127.07, 126.56, 126.09,
is 332.17652.
125.95, 125.83, 125.45, 121.44, 115.31, 106.00, 29.66, 28.47,
22.46, 13.89; IR (neat): 3450, 2952, 2865, 1642, 1490, 1456,
1409, 1326, 1298, 1208, 1153; HRMS (ESI, Orbitrap): calcd for
5-butyl-2-(3-methoxyphenyl)-1H-[1,2,3]triazolo[1,2-
a]cinnolin-1-one(3ca):
Yield: 81%; Yellow needles, m.p. 100 - 102 °C; 1H NMR (500 C24H22ON3 [M+H]+ is 368.17574 and found is 368.17512.
MHz, CDCl3): δ 9.23 (dd, J = 8.3, 0.6 Hz, 1H), 7.99 (dd, J = 2.6, 5-butyl-2-(thiophen-2-yl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
1.5 Hz, 1H), 7.98 – 7.93 (m, 1H), 7.45 – 7.41 (m, 1H), 7.37 (t, J = one(3ga):
8.0 Hz, 1H), 7.34 – 7.32 (m, 2H), 6.92 (ddd, J = 8.2, 2.7, 0.9 Hz, Yield: 81%; Yellow needles, m.p. 152 - 154 °C; 1H NMR (500
1H), 6.20 (s, 1H), 6.20 (s, 1H), 3.91 (s, 3H), 2.89 (t, J = 7.6 Hz, MHz, CDCl3): δ 9.18 (d, J = 0.6 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.45
2H), 1.83 – 1.76 (m, 2H), 1.51 (dd, J = 14.9, 7.4 Hz, 2H), 1.02 (t, – 7.41 (m, 1H), 7.38 – 7.35 (m, 1H), 7.35 – 7.31 (m, 3H), 7.15
J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3):δ 159.77, 153.38, (dt, J = 6.8, 3.4 Hz, 1H), 6.19 (s, 1H), 2.87 (t, J = 7.6 Hz, 2H),
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1.78 (dt, J = 15.3, 7.5 Hz, 2H), 1.57 – 1.45 (m, 2H), 1.01 (t, J = 5-butyl-2-(2-hydroxyethyl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 152.14, 137.48, 1-one(3la):
127.95, 127.72, 127.15, 125.65, 125.44, 115.21, 108.49, Yield: 60%; Yellow needles, m.p. 123 - 125°C; 1H NMR (500
105.72, 100.23, 29.36, 28.21, 22.34, 13.85; IR (neat):3448, MHz, CDCl3): δ 9.10 (d, J = 8.5 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.38
3086, 2954, 2931, 2867, 1654, 1600, 1407, 1333, 1212, 1154, – 7.32 (m, 2H), 6.16 (s, 1H), 4.51 (t, J = 6.3 Hz, 1H), 4.02 (dd, J=
1037, 939; HRMS (ESI, Orbitrap): calcd for C18H18ON3S [M+H]+ 11.0, 6.1 Hz, 2H), 3.07 (t,J = 5.24 Hz, 2H), 2.83 – 2.79 (m, 2H),
is 324.11651 and found is 324.11574.
5-pentyl-2-(pyridin-2-yl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
one(3hb):
1.78 – 1.70 (m, 2H), 1.49 (dt, J = 14.9, 7.4 Hz, 2H), 0.99 (t, J =
7.4 Hz, 3H ); 13C NMR (125 MHz, CDCl3):δ 155.01, 137.40,
134.71, 132.28, 127.86, 127.28, 125.38, 121.47, 115.38,
Yield: 82%; Yellow needles, m.p. 168 - 170 °C; 1H NMR (400 105.04, 60.97, 29.75, 29.40, 28.25, 22.34, 13.83; IR (neat):
MHz, CDCl3):δ 9.26 (d, J = 8.0 Hz, 1H), 8.85 – 8.58 (m, 2H), 7.82 3325, 2962, 2933, 2868, 1632, 1598, 1459, 1412, 1373, 1333,
(t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.41 – 7.34 (m, 2H), 1286, 1213, 1161, 1066, 1036; HRMS (ESI, Orbitrap): calcd for
7.32 – 7.23 (m, 1H), 6.33 (s, 1H), 3.02 (t, J = 7.5 Hz, 2H), 1.88 – C16H20O2N3 [M+H]+ is286.15500 and found is 286.15421.
1.76 (m, 2H), 1.52 – 1.36 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H); 13C 5-butyl-8-methyl-2-phenyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
NMR (100 MHz, CDCl3): δ 153.78, 150.10, 149.01, 137.71, one(3ma):
136.69, 132.87, 130.79, 128.21, 127.16, 125.64, 122.81, Yield: 80%; Yellow needles, m.p. 158 - 160 °C; 1H NMR (400
122.17, 120.96, 115.09, 107.17, 31.26, 29.07, 25.49, 22.48, MHz, CDCl3): δ 9.08 (d, J = 8.4 Hz, 1H), 8.36 (dd, J = 8.3, 1.2 Hz,
14.00; IR (neat): 3448, 2929, 2858, 1655, 1583, 1459, 1402, 2H), 7.49 – 7.42 (m, 2H), 7.37 – 7.31 (m, 1H), 7.21 (dd, J = 8.4,
1343, 1298, 1149, 944, 788, 761; HRMS (ESI, Orbitrap):calcd 1.3 Hz, 1H), 7.10 (s, 1H), 6.12 (s, 1H), 2.84 (t, J = 7.5 Hz, 2H),
for C16H20O2N3 [M+H]+ is 286.15500 and found is 286.15421.
5-(hydroxymethyl)-2-octyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1- 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.14,
one(3ic): 137.23, 136.91, 131.20, 130.73, 130.28, 128.65, 128.54,
2.37 (s, 3H), 1.77 (dt, J = 15.3, 7.5 Hz, 2H), 1.56 – 1.41 (m, 2H),
Yield: 69%; Yellow needles, m.p. 130 - 132 °C; 1H NMR (500 128.15, 125.61, 125.54, 121.20, 114.96, 105.98, 29.38, 28.23,
MHz, CDCl3): δ 9.05 (d, J = 8.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.35 22.38, 21.20, 13.87; IR (neat): 3449, 3055, 2952, 2925, 2864,
– 7.29 (m, 2H), 6.26 (s, 1H), 4.74 (d, J = 6.0 Hz, 2H), 3.11 (s, 1H), 1645, 1573, 1489, 1455, 1398, 1352, 1320, 1227, 1153, 944;
2.73 (t, J = 7.7 Hz, 2H), 1.75 (dt, J = 15.4, 7.6 Hz, 2H), 1.37 – HRMS (ESI, Orbitrap): calcd for C21H22ON3 [M+H]+ is 332.17574
1.22 (m, 12H), 0.88 (td, J = 7.0, 2.0 Hz, 5H); 13C NMR (100 MHz, and found is332.17498.
CDCl3): δ 154.02, 137.48, 135.15, 132.77, 128.51, 127.16, Methyl
5-butyl-1-oxo-2-phenyl-1H-[1,2,3]triazolo[1,2-
125.98, 121.18, 115.37, 104.59, 59.85, 31.89, 29.73, 29.40, a]cinnoline-8-carboxylate(3na):
29.34, 29.25, 27.55, 24.54, 22.68, 14.13; IR (neat): 3450, 3315, Yield: 75%; Yellow needles, m.p. 198 - 200 °C; 1H NMR (400
2921, 2852, 1626, 1592, 1457, 1429, 1338, 1279, 1203, 1104, MHz, CDCl3): δ 9.23 (d, J = 8.7 Hz, 1H), 8.40 – 8.26 (m, 2H), 8.05
987; HRMS (ESI, Orbitrap): calcd for C16H20O2N3 [M+H]+is (dd, J = 8.7, 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.49 – 7.43 (m,
328.20195 and found is 328.20260.
2-cyclopropyl-5-(2-hydroxyethyl)-1H-[1,2,3]triazolo[1,2-
a]cinnolin-1-one(3jd):
2H), 7.39 – 7.33 (m, 1H), 6.20 (s, 1H), 3.93 (s, 3H), 2.87 (t,J =
7.45 Hz, 2H), 1.79 (dt, J = 15.3, 7.5 Hz, 2H), 1.57 – 1.45 (m, 2H),
1.02 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 165.94,
Yield: 71%; Yellow needles, m.p. 164 -166 °C; 1H NMR (400 153.55, 138.29, 135.59, 131.60, 129.76, 129.12, 128.63,
MHz, CDCl3):δ 8.92 (d, J = 7.7 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.23 128.55, 128.43, 126.78, 125.64, 121.46, 114.89, 105.36, 52.44,
(t, J = 6.9 Hz, 2H), 6.15 (s, 1H), 4.02 (t, J = 5.9 Hz, 2H), 3.01 (t, J 29.40, 28.18, 22.36, 13.85; IR (neat): 3449, 3068, 2924, 2860,
= 5.8 Hz, 2H), 2.03 – 1.97 (m,1H), 1.06 – 0.94 (m, 4H); 13C NMR 1714, 1667, 1602, 1438, 1301, 1210, 1108, 985; HRMS (ESI,
(125 MHz, CDCl3): δ 153.87, 137.72, 134.23, 132.40, 127.76, Orbitrap): calcd for C22H22O3N3 [M+H]+ is 376.16557 and found
126.99, 125.25, 121.50, 115.09, 105.98, 58.97, 33.65, 7.55, is 376.16665.
6.25; IR (neat): 3288, 3077, 2917, 2853, 1623, 1594, 1412, 5-butyl-1-oxo-2-phenyl-1H-[1,2,3]triazolo[1,2-a]cinnoline-8-
1326, 1100, 945, 762, 687; HRMS (ESI, Orbitrap): calcd for carbonitrile(3oa):
C15H16O2N3 [M+H]+is 270.12370 and found is 270.12417.
2-butyl-5-(2-hydroxyethyl)-1H-[1,2,3]triazolo[1,2-a]cinnolin-
1-one(3kd):
Yield: 72%; Yellow needles, m.p. 198 - 200 °C; 1H NMR (500
MHz, CDCl3): δ 9.28 (d, J = 8.6 Hz, 1H), 8.37 – 8.29 (m, 2H), 7.66
(dd, J = 8.6, 1.8 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.47 (t, J = 7.6
Yield: 76%; Yellow needles, m.p. 116 - 118 °C; 1H NMR (500 Hz, 2H), 7.38 (dd, J = 10.5, 4.3 Hz, 1H), 6.13 (s, 1H), 2.89 (t, J =
MHz, CDCl3): δ 8.93 (d, J = 8.1 Hz, 1H), 7.32 – 7.28 (m, 1H), 7.25 7.6 Hz, 2H), 1.84 – 1.75 (m, 2H), 1.56 – 1.47 (m, 2H), 1.03 (t, J =
(dt, J = 7.5, 2.6 Hz, 2H), 6.18 (s, 1H), 4.05 (s, 2H), 3.05 (t, J = 5.8 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.52, 139.59,
Hz, 2H), 2.66 – 2.57 (t, J = 7.6 Hz, 2H), 1.68 (dt, J = 15.3, 7.6 Hz, 135.21, 132.10, 131.22, 129.36, 128.88, 128.70, 125.73,
2H), 1.46 – 1.35 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (100 117.96, 115.60, 110.65, 103.92, 29.44, 28.17, 22.36, 13.82; IR
MHz, CDCl3): δ 154.05, 136.49, 134.31, 132.51, 127.78, 126.95, (neat): 3451, 2926, 2858, 2220, 1660, 1597, 1424, 1348, 1300,
125.25, 121.43, 115.01, 106.26, 58.91, 33.77, 29.60, 24.08, 1231, 1148, 927, 888; HRMS (ESI, Orbitrap): calcd for
22.45, 13.84; IR (neat): 3331, 2953, 2921, 2857, 1640, 1597, C21H19ON4 [M+H]+ is 343.15534 and found is 343.15644.
1457, 1408, 1332, 1305, 1046; HRMS (ESI, Orbitrap): calcd for 2-butyl-8-chloro-5-(2-hydroxyethyl)-1H-[1,2,3]triazolo[1,2-
C16H20O2N3 [M+H]+ is 286.15500 and found is 286.15419.
a]cinnolin-1-one(3pd):
6 | J. Name., 2012, 00, 1-3
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Yield: 81%; Yellow needles, m.p. 140 - 142 °C; 1H NMR (400 127.21, 126.14, 125.66, 120.95, 115.30, 105.96, 67.60, 59.59;
MHz, CDCl3): δ 8.84 – 8.79 (m, 1H), 7.27 – 7.20 (m, 2H), 6.10 (s, IR (neat): 3449, 3065, 2929, 1652, 1596, 1491, 1418, 1348,
1H), 4.05 (t, J = 5.7 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.90 (s, 1H), 1218, 1097, 1024, 847, 761; HRMS (ESI, Orbitrap):calcd for
2.66 – 2.61 (m, 2H), 1.69 (dt, J = 15.2, 7.6 Hz, 2H), 1.47 – 1.35 C18H16O2N3 [M+H]+is306.12370 and found is 306.12300.
(m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 4-methyl-N-(2-(1-oxo-2-phenyl-1H-[1,2,3]triazolo[1,2-
153.89, 137.02, 135.55, 132.49, 130.84, 127.52, 124.67, a]cinnolin-5 yl)ethyl)benzenesulfonamide (3ah):
123.21, 116.24, 105.04, 58.84, 33.77, 29.51, 24.12, 22.45, Yield: 61%; Yellow needles, m.p. 154 - 156 °C; 1H NMR (500
13.82; IR (neat): 3409, 3100, 2926, 2934, 2871, 1905, 1633, MHz, CDCl3) δ 9.07 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 5.2, 3.3 Hz,
1589, 1561, 1436, 1343, 1290, 1206, 1056; HRMS (ESI, 2H), 7.64 – 7.60 (m, 2H), 7.44 – 7.28 (m, 7H), 7.07 (d, J = 7.9 Hz,
Orbitrap): calcd for C16H19O2N3Cl [M+H]+ is 320.11603 and 2H), 6.17 (s, 1H), 5.11 (t, J = 6.2 Hz, 1H), 3.53 (dd, J = 12.5, 6.3
found is320.11636.
Hz, 2H), 3.05 (t, J = 6.2 Hz, 2H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3+DMSO): δ 152.97, 142.96, 137.26, 132.95, 129.78,
129.16, 128.43, 128.21, 128.00, 126.99, 126.51, 125.64,
5-cyclopropyl-2-phenyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
one(3ae):
Yield: 66%; Yellow needles, m.p. 160 - 162 °C; 1H NMR (500 125.37, 121.04, 114.72, 108.69, 30.76, 21.41; IR (neat): 3449,
MHz, CDCl3): δ 9.23 (d, J = 8.3 Hz, 1H), 8.39 (d, J = 7.3 Hz, 2H), 3184, 2924, 1643, 1597, 1491, 1456, 1330, 1159, 1077, 912,
7.47 (t, J = 7.7 Hz, 2H), 7.45 – 7.41 (m, 1H), 7.36 (dd, J = 11.8, 761; HRMS (ESI, Orbitrap):calcd for C18H16O2N3 [M+H]+ is
4.4 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 6.03 (s, 1H), 2.40 – 2.31 (m, 306.12370 and found is 306.12300
1H), 1.21 – 1.13 (m, 2H), 0.92 – 0.86 (m, 2H); 13C NMR (100 2,5-dibutyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-one(3ka):
MHz, CDCl3): δ 153.54, 139.13, 132.73, 131.55, 130.19, 128.57, Yield: 71%; Yellow needles, m.p. 181 - 183 °C; 1H NMR (400
128.27, 127.92, 126.99, 125.66, 125.46, 121.33, 115.19, MHz, CDCl3): δ 9.11 (d, J = 8.2 Hz, 1H), 7.41 – 7.35 (m, 1H), 7.32
103.37, 10.30, 6.86; IR (neat): 3449, 3066, 2924, 1657, 1597, – 7.25 (m, 2H), 6.05 (s, 1H), 2.82 – 2.72 (m, 4H), 1.80 – 1.69 (m,
1445, 1413, 1335, 1220, 1125, 1103, 1065, 945; HRMS (ESI, 4H), 1.53 – 1.40 (m, 4H), 0.98 (dd, J = 15.7, 7.4 Hz, 6H). 13C
Orbitrap): calcd for C19H16ON3 [M+H]+ is 302.12879 and found NMR (100 MHz, CDCl3): δ 154.33, 137.51, 136.47, 132.49,
is 302.12807.
127.42, 126.75, 125.02, 121.60, 115.11, 103.94, 77.45, 77.13,
76.81, 29.75, 29.38, 28.28, 27.24, 24.20, 22.44, 22.31, 14.12,
13.83; IR (neat): 3448, 3069, 2953, 2925, 2863, 1645, 1593,
5-cyclohexyl-2-phenyl-1H-[1,2,3]triazolo[1,2-a]cinnolin-1-
one(3af):
Yield: 70%; Yellow needles, m.p. 161- 163 °C; 1H NMR (500 1457, 1410, 1353, 1295, 1099, 944; HRMS (ESI, Orbitrap): calcd
MHz, CDCl3): δ 9.23 (d, J = 8.3 Hz, 1H), 8.36 (dd, J = 8.3, 1.2 Hz, for C18H24ON3 [M+H]+ is 298.19139 and found is 298.19177.
2H), 7.49 – 7.45 (m, 2H), 7.44 – 7.40 (m, 1H), 7.37 – 7.31 (m,
3H), 6.17 (s, 1H), 3.21 (ddd, J = 11.5, 7.4, 3.0 Hz, 1H), 2.17 (d, J
= 12.9 Hz, 2H), 1.95 – 1.91 (m, 2H), 1.87 – 1.82 (m, 1H), 1.60 –
1.42 (m, 4H), 1.33 (qt, J = 13.0, 3.7 Hz, 1H); 13C NMR (125 MHz,
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7.67 (d, J = 7.4 Hz, 1H), 7.49 (tt, J = 22.1, 7.3 Hz, 4H), 7.38 (t, J =
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Üꢀꢁꢂꢃꢄꢃꢅꢃꢀꢆꢃꢅ {ꢇꢀꢆꢈꢃꢉꢊꢉ ꢋꢌ ꢍꢎꢏꢎꢐꢑÇꢂꢊꢒꢓꢋꢔꢋꢑ/ꢊꢀꢀꢋꢔꢊꢀꢋꢀꢃ ꢕꢊꢒ
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