One-Pot Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles Using Catalytic System NaOH?DMSO

Article abstract of DOI:10.1134/S1070428018080213

One-pot convenient process was developed for the production of 3,5-disubstituted 1,2,4-oxadiazoles by reaction of amidoximes with anhydrides or acyl chlorides in a system NaOH?DMSO. The reaction proceeds at room temperature with high yields.

Full text of DOI:10.1134/S1070428018080213

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 8, pp. 1250–1255. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © V.E. Pankrat’eva, T.V. Sharonova, M.V. Tarasenko, S.V. Baikov, E.R. Kofanov, 2018, published in Zhurnal Organicheskoi Khimii,
2018, Vol. 54, No. 8, pp. 1236–1241.
One-Pot Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles Using
Catalytic System NaOH‒DMSO
V. E. Pankrat’evaa, T. V. Sharonovaa, M. V. Tarasenkob,*
S. V. Baikovc, and E. R. Kofanovb
a Transfer Center of Pharmaceutical Technology, Ushinski Yaroslavl State Pedagogical University, Yaroslavl, 150000 Russia
b Yaroslavl State Technical University, Moskovskii pr. 88, Yaroslavl, 150023 Russia
*е-mail: mkarunnaya@mail.ru
c St. Petersburg State University, St. Petersburg, 199034 Russia
Received September 20, 2017
Abstract—One-pot convenient process was developed for the production of 3,5-disubstituted 1,2,4-
oxadiazoles by reaction of amidoximes with anhydrides or acyl chlorides in a system NaOH‒DMSO. The
reaction proceeds at room temperature with high yields.
DOI: 10.1134/S1070428018080213
1,2,4-Oxadiazole derivatives exhibit versatile pharma-
ceutical properties [1–3]. Among them compounds were
found with antibacterial activity [4, 5], in particular,
tuberculocidal action (1а) [6], antitumor agents [7],
neuroprotectors [8], agonists of sphingosine-1-phosphate
receptors (S1P) [9], as well as inhibitors of glycogen
phosphorylase [10] and of carbonic anhydrase isoform
II (CAII) [11]. 1,2,4-Oxadiazole moiety is present in
well-known drugs against coughing (libexine [12] and
oxalomine [13]), and also in pharmaceutical ataluren
(Translarna®) 1b used in the treatment of Duchenne
muscular dystrophy [14].
The majority of existing procedures of the synthesis
of 1,2,4-oxadiazoles (amidoximes condensation with
carbonic acids derivatives [18–21], 1,3-dipolar
cycloaddition [22], oxidative addition of amides to
nitriles [23], and oxidation of N-substituted
amidoximes [24]) require reagents heating to elevated
temperature that in some cases results in
decomposition of target compounds and side products
formation. One solution to this problem is performing
the synthesis of 1,2,4-oxadiazole ring in a superbasic
system MОН‒DMSO [25]. This provides a possibility
to prepare various 3,5-disubstituted-1,2,4-oxadiazoles in
good yields at room temperature. Starting compounds
for this reaction are О-acylamidoximes that usually are
not isolated in the free state for the necessity of heir
preparation and purification complicates the synthesis.
1,2,4-Oxadiazole derivatives are used in making
new materials, in particular, of fluorescent dyes (1с)
[15–17] (Scheme 1).
Scheme 1.
Lately we successfully used the system NaOH‒
DMSO in the reaction of amidoximes with esters,
carboxylic acids, and cyclic anhydrides [26–28]. In
this study we carried out the reaction of amidoximes
with acylating agents, anhydrides and acyl chlorides,
in a system MОН‒DMSO. The procedure was
optimized using a reaction of 4-methylbenzamidoxime
2a with acetic anhydride 3a in the system NaОН‒
DMSO (Table 1). The reaction of amidoximes with
acylating agents according to published descriptions
contains two successive stages: О-acylation of
amidoxime 2 and cyclodehydration of intermediate
Me
N
O
Me
N
O
O
N
O
N
H
S
N
1a
N
O
F
N
O
HOOC
N
1b
O
EtO
O
1c
1250

ONE-POT SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-OXADIAZOLES USING CATALYTIC
1251
Scheme 2.
O
O
OH
N
N
Me
Me
Me
N
O
solvent
MOH, DMSO
20oC
O
O
+
O
20oC, 2 h
Me
NH2
NH2
N
Me
Me
Me
2a
3a
4a
5a
Scheme 3.
O
O
O
N
O
OH
R2
N
1. CH2Cl2, 20oC, 2 h
R3
+
N
2. NaOH, DMSO,
20oC, 1 h
R1
NH2
2a_2c
R2
R1
5b_5e
3b_3e
2, R1 = Me (a), Br (b), NO2 (с); 3, R2 = Et (b), Ph (c), i-Pr (d), OBoc (e); 5, R1 = Br, R3 = Et (b); R1 = Me, R3 = Ph (c);
R1 = NO2, i-Pr (d); R1 = Me, R3 = OH (e).
compound 4 to 1,2,4-oxadiazole 5 (Scheme 2) [29].
Since NaOH accelerates the cyclodehydration stage [30],
it was added 2 h after the beginning of the process.
amidoxime 2a with acetyl chloride 6a. Unlike the
reaction involving anhydrides it was necessary to use
bases in the stage of acylation with acyl chlorides (to
bind the forming HCl), NaHCO3 was applied as a base.
In the reaction of starting reagents 2a and 6a in DMSO
1,2,4-oxadiazole 5a was obtained in a very low yield.
Acylation in dichloromethane (similarly to the reaction
with anhydrides) in the presence of NaHCO3 followed
by removal of the solvent and treatment of the residue
with a mixture NaОН‒DMSO at room temperature led
Hence the experiment consisted of two operations:
amidoxime 2a was mixed with acetic anhydride 3a in
DMSO, then NaОН was added. To obtain a complete
conversion of О-acylamidoxime in 1,2,4-oxadiazole
10 min [25] was insufficient, a mixture was isolated of
the intermediate О-acylamidoxime 4a and 1,2,4-
oxadiazole 5a, the latter prevailing (Table 1, run
no. 1). The increased time of the second stage made it
possible to obtain compound 5а in 62% yield without
impurity of О-acylamidoxime 4а (Table 1, run no. 2).
Further we explored the influence of the nature of the
used hydroxide, reagents amount (of the base and the
anhydride), and the reaction time on the yield of 1,2,4-
oxadiazole 5а (Table 1, runs nos. 3‒9). As alternative
for DMSO in the first stage of О-acylamidoxime 4а
formation we tested three solvents: dichloromethane,
acetone, and acetonitrile (Table 1, runs nos. 10‒12).
The reason of this choice was firstly because of
good solubility of the intermediate О-acylamidoxime,
and secondly of the simplicity of solvent
elimination. At the reaction in dichloromethane
we succeeded to raise the yield of compound 5а to
83%.
Table 1. Study of reaction between 4-methylbenzamid-
oxime 2а with acetic anhydride 3а (1 : 1)
Run
no.
Solvent in the Time of the
Yield of
MOH, equiv
first stageа second stage, h 5а, %
1
2
3
4
5
6
7
8
9
NaOH (2.0)
NaOH (2.0)
NaOH (2.5)
NaOH (3.0)
LiOH (2.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0.2
1
34
62
62
55
63
60
65a
64
65
83
74
69
1
1
1
1
KOH (2.0)
NaOH (2.0)
1
NaOH (2.0)
NaOH (2.0)
2
In keeping with this procedure we synthesized a
series of 3,5-disubstituted-1,2,4-oxadiazoles using
anhydrides and amidoximes as starting compounds
(Scheme 3).
24
10 NaOH (1.0) CH2Cl2
11 NaOH (1.0) Acetone
1
1
1
At the investigation of the reaction of amidoximes
with acyl chlorides 6 we used as model the reaction of
12 NaOH (1.0)
MeCN
a
Time of the first stage 2 h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 8 2018

PANKRAT’EVA et al.
1252
Scheme 4.
OH
N
O
N
O
i or ii
+
Me
Me
Cl
N
NH2
Me
Me
2a
6a
5a
i: 1. NaHCO3, DMSO, 20°С, 2 h; 2. NaOH, DMSO, 20°С, 1 h, yield 31%;
ii: 1. NaHCO3, CH2Cl2, 20°С, 2 h; 2. NaOH, DMSO, 20°С, 1 h, yield 77%.
Table 2. Synthesis of 1,2,4-oxadiazoles 5с and 5e–5ma
to the formation of compound 5a in 77% yield
1. 6b_6k, NaHCO3,
(Scheme 4).
OH
N
O
N
CH2Cl2, 20oC, 2 h
R2
Finally we applied the developed procedure to the
synthesis of a series of 3,5-disubstituted 1,2,4-oxa-
diazoles from various acyl chlorides 6b–6k (Table 2).
This procedure is applicable to the synthesis of 1,2,4-
oxadiazoles both with aromatic (heteroaromatic) and
aliphatic substituents.
N
NH2
2. NaOH, DMSO,
20oC, 1 h
R1
R1
5c, 5e_5m
2a, 2d, 2e
O
O
O
O
O
Me
Cl
Cl
Cl
Pn
Cl
Ph
Cl
EtO
O
Me
6d
The developed procedure makes it possible to
prepare in a good yield and a satisfactory purity a wide
set of potential biologically active 3,5-disubstituted
1,2,4-oxadiazoles from available starting compounds
(amidoximes, acyl chlorides, and anhydrides) in a low
toxic solvent DMSO at room temperature.
6c
6b
6e
6f
NO2
O
O
O
Cl
Cl
Cl
Cl
Cl
O
S
6g
6h
6i
6j
O
Cl
EXPERIMENTAL
1Н and 13С NMR spectra were registered on a spec-
trometer Bruker Avance DRX-400 (400 and 100 MHz
respectively). As internal reference the signals served
of residual protons and carbon atoms of the solvent:
2.50 (1Н) and 39.52 (13С) ppm for solutions in DMSO-
d6; 7.26 (1Н) and 77.16 (13С) ppm for solutions in
CDCl3. TLC was performed on Sulifol 201S plates,
eluent petroleum ether‒ethyl acetate, 2 : 1 v/v. Melting
points were measured on an apparatus IA 9000
SERIES Digital Melting point. Mass spectra were
taken on an instrument Shimadzu LCMS-2020 Single
Quadru-pole Liquid (electrospray ionization, ESI).
High resolution mass spectra were recorded on an
instrument Bruker maXis HRMS-ESI-QTOF.
6k
Acyl chlo- Reaction
R1
R2
Yield, %
ride
products
6b
5c
Me
Me
H
Ph
75
74
61
6c
5e
5f
OH
i-Pr
6d
6e
6f
5g
5h
Me
Me
65
72
Pentyl
Cl
6g
6h
5i
5j
Me
76
84
NO2
OMe
Reaction of 4-methylbenzamidoxime (2а) with
acetic anhydride (3а) in DMSO. In 2 mL of DMSO
was mixed 348 mg (2 mmol) of amidoxime 2а and
0.19 mL (2 mmol) of acetic anhydride 3а. The reaction
mixture was stirred at room temperature for 2 h (Table 1),
powdered MOH was added, and the obtained
dispersion was stirred for desired time at room
temperature. Then to the reaction mixture 20 mL of
cold water was added and the formed precipitate was
filtered off.
6i
6j
5k
5l
H
67
78
O
S
Me
6k
5m
H
79
а
Reagents and solvents: 2 mmol of 2, 2 mmol of 6, 2.2 mmol of
NaHCO3, 2 mmol of NaOH, 10 mL of CH2Cl2, 1.5‒2 mL of
DMSO.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 8 2018

ONE-POT SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-OXADIAZOLES USING CATALYTIC
1253
1
Reaction of 4-methylbenzamidoxime (2а) with
acetyl chloride (6а) in DMSO. In 2 mL of DMSO
was dissolved 348 mg (2 mmol) of amidoxime 2а, the
solution was cooled to 0°С and by portions maintaining
the reaction mixture temperature below 5°С 0.15 mL
(2 mmol) of acetyl chloride 6а and 185 mg (2.2 mmol)
of NaHCO3 was added. The reaction mixture was
warmed to room temperature, stirred for 2 h, and
80 mg (2 mmol) of powdered NaOH was added. The
reaction mixture was stirred for 1 h at room temperature,
then to the reaction mixture 20 mL of cold water was
added and the formed precipitate was filtered off.
(mp 38–40°С [28]). Н NMR spectrum (DMSO), δ,
ppm: 1.34 t (3Н, СН3, J 7.6 Hz), 2.98–3.05 m (2Н),
7.77 d (2Harom, J 8.6 Hz), 7.94 d (2Harom, J 8.6 Hz). 13С
NMR spectrum (DMSO), δ, ppm: 10.8 (СН3), 20.1
(СН2), 125.4 (Сarom), 126.0 (Сarom), 129.3 (Сarom), 131.8
(Сarom), 132.7 (Сarom), 167.1 (С3), 181.6 (С5). Mass
spectrum: m/z 253 [M + H]+.
3-(4-Methylphenyl)-5-phenyl-1,2,4-oxadiazole
(5c). Yield 387 mg (82%) (a), 354 mg (75%) (b);
white powder, mp 102–103°С (mp 102–103°С [28]).
1Н NMR spectrum (DMSO), δ, ppm: 2.38 s (3H, СН3),
7.38 d (2Harom, J 8.0 Hz), 7.64 t (2Harom, J 7.4 Hz),
7.72 t (1Harom, J 7.4 Hz), 7.96 d (2Harom, J 8.1 Hz),
8.15 d (2Harom, J 7.1 Hz). 13С NMR spectrum (DMSO),
δ, ppm: 21.2 (СН3), 123.4 (Сarom), 123.5 (Сarom), 127.1
(Сarom), 127.9 (Сarom), 129.6 (Сarom), 127.9 (Сarom),
129.6 (Сarom), 129.8 (Сarom), 133.3 (Сarom), 141.6
(Сarom), 168.3 (С3), 175.3 (С5). Mass spectrum: m/z
237 [M + H]+.
1,2,4-Oxadiazoles (5а–5m). General procedure.
a. In 10 mL of dichloromethane 2 mmol of amidoxime
2 was dissolved and 2 mmol of anhydride 3 was added.
The reaction mixture was stirred at room temperature
for 2 h, then it was washed with 10 mL of NaHCO3
solution and 10 mL of water, the organic layer was
dried with Na2SO4 and evaporated at a reduced
pressure. The residue was dissolved in 1.5‒2 mL of
DMSO and 80 mg (2 mmol) of preliminary ground
NaOH was added. The reaction mixture was stirred at
room temperature for 1 h and diluted with 20 mL of
cold water. The formed precipitate was filtered off.
5-Isopropyl-3-(4-nitrophenyl)-1,2,4-oxadiazole
(5d). Yield 382 mg (82%) (a), light yellow powder,
mp 129–130°С (mp 128–130°С [25]). Н NMR spec-
trum (DMSO), δ, ppm: 1.40 d (6Н, СН3, J 6.9 Hz),
3.36–3.43 m (1Н, СН), 8.26 d (2Нarom, J 9.0 Hz), 8.40
d (2Нarom, J 9.0 Hz). 13С NMR spectrum (DMSO), δ,
ppm: 19.8 (СН3), 26.9 (СН), 124.5 (Сarom), 128.5
(Сarom), 132.0 (Сarom), 149.2 (Сarom), 166.3 (С3), 185.0
(С5). Mass spectrum: m/z 234 [M + H]+.
1
b. In 10 mL of dichloromethane was dissolved 2 mmol
of amidoxime 2, 185 mg (2.2 mmol) of NaHCO3 was
added. The reaction mixture was cooled to 0°С and by
portions maintaining the reaction mixture temperature
below 5°С 2 mmol of acyl chloride 3 was added. The
reaction mixture was warmed to room temperature,
stirred for 2 h, then it was washed with 10 mL of
NaHCO3 solution and 10 mL of water, the organic layer
was dried with Na2SO4 and evaporated at a reduced
pressure. The residue was dissolved in 1.5‒2 mL of
DMSO and 80 mg (2 mmol) of preliminary ground
NaOH was added. The reaction mixture was stirred at
room temperature for 1 h and diluted with 20 mL of
cold water. The formed precipitate was filtered off.
3-(4-Methylphenyl)-1,2,4-oxadiazol-5-ol (5e).
Yield 303 mg (86%) (a), 261 mg (74%) (b); white
powder, mp 206–208°С (mp 207–208°С [28]). Н
NMR spectrum (DMSO), δ, ppm: 2.37 s (3Н, СН3),
7.37 d (2Нarom, J 7.8 Hz), 7.69 d (2Нarom, J 8.1 Hz),
12.82 br.s (1H, NH). 13С NMR spectrum (DMSO), δ,
ppm: 12.1 (СН3), 126.7 (Сarom), 127.6 (Сarom), 129.3
(Сarom), 146.5 (Сarom), 166.8 (С3), 178.0 (С5). Mass
spectrum: m/z 177 [M + H]+.
1
5-Isopropyl-3-phenyl-1,2,4-oxadiazole (5f). Yield
230 mg (61%) (b), colorless liquid [31]. Н NMR
5-Methyl-3-(4-methylphenyl)-1,2,4-oxadiazole
1
(5a). Yield 285 mg (83%) (a), 268 mg (77%) (b);
1
spectrum (DMSO), δ, ppm: 1.35 m (6Н, СН3), 3.25–
3.30 br.m (1Н, СН), 7.52 m (3Нarom), 7.97 m (2Нarom).
13С NMR spectrum (CDCl3), δ, ppm: 20.2 (СН3), 27.6
(СН), 127.1 (Сarom), 127.5 (Сarom), 128.8 (Сarom), 131.0
(Сarom), 168.2 (С3), 183.9 (С5). Mass spectrum: m/z
189 [M +H]+.
white powder, mp 77–79°С (mp 77–78°С [28]). Н
NMR spectrum (DMSO), δ, ppm: 2.37 s (3Н, СН3),
2.64 s (3Н, СН3), 7.36 d (2Нarom, J 7.9 Hz), 7.88 d
(2Нarom, J 7.9 Hz). 13С NMR spectrum (DMSO), δ,
ppm: 12.0 (СН3), 21.1 (СН3), 123.6 (Сarom), 126.9
(Сarom), 129.8 (Сarom), 141.4 (Сarom), 167.6 (С3), 177.2
(С5). Mass spectrum: m/z 175 [M + H]+.
3-(4-Methylphenyl)-5-cyclopropyl-1,2,4-oxadi-
azole (5g). Yield 192 mg (48%) (b), white powder, mp
54–55°С (mp 55–56°С [28]). 1Н NMR spectrum
3-(4-Bromophenyl)-5-ethyl-1,2,4-oxadiazole (5b).
Yield 319 mg (63%) (а), white powder, mp 39–40°С
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 8 2018

PANKRAT’EVA et al.
1254
(DMSO), δ, ppm: 1.13–1.19 m (2H, СН2), 1.21–1.30
m (2H, СН2), 2.33–2.40 m (4H, СН3, СН), 7.33 d
(2Harom, J 7.9 Hz), 7.84 d (2Harom, J 8.1 Hz). 13С NMR
spectrum (DMSO), δ, ppm: 7.7 (СН2), 10.4 (СН2,
СН3), 21.5 (СН), 124.0 (Сarom), 127.3 (Сarom), 130.1
(Сarom), 141.5 (Сarom), 167.7 (С3), 182.0 (С5). Mass
spectrum: m/z 201 [M + H]+.
148.8 (Сarom), 167.8 (С3), 168.4 (С5). Mass spectrum:
m/z 213 [M + H]+.
3-(-Methylphenyl)-5-(thiophen-2-yl)-1,2,4-oxadi-
azole (5l). Yield 281 mg (58%) (b), white powder, mp
91–92°С (mp 90–92°С [25]). 1Н NMR spectrum
(DMSO), δ, ppm: 2.40 s (3Н, СН3), 7.35–7.41 m
(3Нarom), 7.95 d (2Нarom, J 8.0 Hz), 8.10 d.d (2Нarom, J
15.0, 6.8 Hz). 13С NMR spectrum (DMSO), δ, ppm:
21.6 (СН3), 123.6 (Сarom), 125.1 (Сarom), 127.5 (Сarom),
129.7 (Сarom), 130.3 (Сarom), 133.2 (Сarom), 134.5
(Сarom), 142.2 (Сarom), 168.6 (С3), 171.4 (С5). Mass
spectrum: m/z 243 [M + H]+.
3-(4-Methylphenyl)-5-pentyl-1,2,4-oxadiazole
(5h). Yield 332 mg (72%) (b), dark red liquid [32]. 1Н
NMR spectrum (DMSO), δ, ppm: 0.90 t (3Н, СН3, J
6.3 Hz), 1.79 m (2H, СН2), 1.85 m (4Н, СН2), 2.39 s
(3H, СН3), 2.93 t (2Н, СН2, J 7.5 Hz), 7.31 d (2Harom
,
J 7.8 Hz), 7.88 d (2Harom, J 7.8 Hz). 13С NMR
spectrum (CDCl3), δ, ppm: 13.8 (СН3), 21.5 (СН2),
22.2 (СН2), 26.4 (СН2), 26.6 (СН2), 31.2 (СН), 124.2
(Сarom), 127.3 (Сarom), 129.5 (Сarom), 141.3 (Сarom),
168.3 (С3), 179.9 (С5). Mass spectrum: m/z 231 [M +
H]+.
(E)-3-Phenyl-5-(2-phenylethenyl)-1,2,4-oxadi-
azole (5m). Yield 392 mg (79%) (b), white powder,
1
mp 95–97°C (mp 92–93°C [33]). Н NMR spectrum
(DMSO), δ, ppm: 7.31 d (1H, =CH, J 16.4 Hz), 7.48–
7.51 m (3Harom), 7.57–7.59 m (3Harom), 7.83–7.84 m
(2Harom), 7.97 d (1H, =CH, J 16.4 Hz), 8.12–8.14 m
(2Harom). 13С NMR spectrum (DMSO), δ, ppm: 110.9
(HtCH=), 127.8 (Сarom), 128.8 (Сarom), 129.4 (Сarom),
129.6 (Сarom), 129.7 (Сarom), 131.2 (Сarom), 131.9
(Сarom), 135.3 (Сarom), 143.4 (PhCH=), 167.9 (С3),
174.1 (С5). Found: m/z 249.1022 [M + H]+.
C16H13N2O. Mcalc 249.1029.
3-(4-Methylphenyl)-5-(3-chlorophenyl)-1,2,4-
oxadiazole (5i). Yield 411 mg (76%) (b), white
1
powder, mp 85‒87°С. Н NMR spectrum (DMSO),
ppm: 2.41 s (3Н, СН3), 7.41 d (2Harom, J 8.0 Hz), 7.70 t
(1Нarom, J 7.9 Hz), 7.81 d (1Нarom, J 8.1 Hz), 7.99 d
(2Нarom, J 8.1 Hz), 8.15 t (2Нarom, J 7.1 Hz). 13С NMR
spectrum (DMSO), δ, ppm: 21.3 (СН3), 123.6 (Сarom),
125.8 (Сarom), 127.0 (Сarom), 127.5 (Сarom), 127.8
(Сarom), 130.3 (Сarom), 132.0 (Сarom), 133.5 (Сarom),
134.6 (Сarom.), 142.2 (Сarom), 168.8 (С3), 174.5 (С5).
Found: m/z 271.0622 [M + H]+. C15H12ClN2O. Mcalc
271.0633.
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d.d (1Нarom, J 3.6, 1.7 Hz), 7.57–7.64 m (3Harom), 7.65
d (1Нarom, J 3.6 Hz), 8.07 d.d (2Harom, J 7.8, 1.6 Hz),
8.17–8.19 m (1Harom). 13С NMR spectrum (DMSO), δ,
ppm: 113.5 (Сarom), 118.1 (Сarom), 126.3 (Сarom), 127.6
(Сarom), 129.7 (Сarom), 132.2 (Сarom), 139.5 (Сarom),
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ONE-POT SYNTHESIS OF 3,5-DISUBSTITUTED 1,2,4-OXADIAZOLES USING CATALYTIC
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