C-H Arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1016/j.cclet.2015.09.011

Synthesis of a series of new 3,6-diaryl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles (5a-o) was achieved by phophine free, C-H arylative cross-coupling of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (4a-o) with suitably substituted iodoanilines using 1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand. The requisite triazolothiadiazoles (4a-o) were obtained by the condensation of 4-amino-1,2,4-triazole-3-thiol (3) with suitably substituted aromatic acids in the presence of phosphoryl chloride.

Full text of DOI:10.1016/j.cclet.2015.09.011

G Model
CCLET 3435 1–4
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
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Original article
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C–H arylation using acyl thiourea ligands: Applications in the
synthesis of 3,6-diaryl-[1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles
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Q1 Aamer Saeed *, Pervaiz Ali Channar, Qasir Iqbal, Jamaluddin Mahar
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
A R T I C L E I N F O
A B S T R A C T
Article history:
Synthesis of a series of new 3,6-diaryl-[1,2,4-]triazolo[3,4-b] [1,3,4]thiadiazoles (5a–o) was achieved by
phophine free, C–H arylative cross-coupling of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (4a–o)
with suitably substituted iodoanilines using 1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand.
The requisite triazolothiadiazoles (4a–o) were obtained by the condensation of 4-amino-1,2,4-triazole-
Received 17 June 2015
Received in revised form 5 August 2015
Accepted 19 August 2015
Available online xxx
3-thiol (3) with suitably substituted aromatic acids in the presence of phosphoryl chloride.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Keywords:
Published by Elsevier B.V. All rights reserved.
[
1,2,4-]triazolo[3,4-b] [1,3,4]thiadiazoles
Acyl thiourea
C–H arylative coupling
N,N-Dimethylacetamide
7
8
1. Introduction
catalyzed C–H halogenation [9], efficient synthesis of 2-arylqui- 32
nazolines via copper-catalyzed dual oxidative benzylic C–H 33
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Carbon–carbon coupling reactions are among the most
powerful synthetic tools used in the synthesis of complex
molecules such as natural products. Mizoroki and Heck indepen-
dently reported the first carbon–carbon bond-forming reaction
that followed a Pd(0)/Pd(II) catalytic cycle. It involved the coupling
of aryl or vinyl halides and activated alkenes in the presence of a
base [1,2]. Conversely, there has long been an increasing interest in
the transition metal-catalyzed functionalization of relatively
unactivated carbon-hydrogen (C–H) bonds for the new C–C, C–
O, or C–S bond formation. This approach is straightforward,
environmentally friendly and avoids the use of protective/leaving
groups, thus significantly shortening the synthetic routes [3,4]. The
C–H activation finds applications in the synthesis of natural
products, functional materials, and pharmaceuticals. Some recent
examples include the palladium-catalyzed enantioselective C–H
arylation in the synthesis of P-stereogenic compounds [5],
palladium(II)-catalyzed directed trifluoromethylthiolation of
aminations of methylarenes [10] have also been reported.
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Thiourea derivatives have long been employed as organocata- 35
lysts for various organic transformations. These ligands have also 36
been used in palladium catalyzed Heck and Suzuki–Miyaura cross 37
0
coupling reactions [11,12]. N,N -Monosubstituted acyclic thiourea 38
and 1-aroyl-3-arylthiourea ligands have been utilized as highly 39
active phosphine-free catalysts for palladium catalyzed Heck 40
reactions of aryl iodides or bromides with styrenes and acrylates. 41
The 1-aroyl-3-arylthiourea ligands giving best results included the 42
simple 1-benzoyl-3-phenylthiourea and 1-(4-bromobenzoyl)-3- 43
(4-bromophenyl)thiourea with bulky bromo-substituents [13].
44
Substituted triazolo[3,4-b][1,3,4]thiadiazoles are the key struc- 45
tural motifs of numerous compounds with activity relevant to 46
biological and medicinal chemistry [14,15]. Therefore, there is an 47
unrelenting strong requirement for developing new strategies for 48
the synthesis of these heterocycles.
49
The significance and utilization of the theories mentioned 50
above together with the availability of our library of diverse 1-acyl- 51
3-arylthiourea derivatives [16], encouraged us to explore the C–H 52
activated coupling of 6-aryl [1,2,4]triazolo [3,4-b][1,3,4]thiadia- 53
zole with different aryl iodides in the presence of 1-(2-naphthoyl)- 54
3
unactivated C(sp )–H bonds [10], cobalt catalyzed low tempera-
ture CH alkenylations with alkenyl acetates, phosphates, carbo-
nates or carbamates [6] and photocatalytic CH activation by
hydrogen-atom transfer [7]. Moreover, direct C–H amination for
indole synthesis from N-Ts-2-styrylaniline derivatives catalyzed
by copper salt [8], multi-substituted arenes via palladium
3-(4-bromophenyl)thiourea.
55
2. Experimental
56
*
Corresponding author.
Melting points were recorded using a digital Gallenkamp 57
1
E-mail addresses: asaeed@qau.edu.pk, aamersaeed@yahoo.com (A. Saeed).
(SANYO) model MPD.BM 3.5 apparatus and are uncorrected.
H
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http://dx.doi.org/10.1016/j.cclet.2015.09.011
1
001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A. Saeed, et al., C–H arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-
[
1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.011

G Model
CCLET 3435 1–4
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A. Saeed et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
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NMR and C NMR spectra were determined at 300 MHz and
75 MHz, respectively, using a Bruker AM-300 spectrophotometer.
FTIR spectra were recorded on a Bio-Rad-Excalibur Series Mode FTS
3000 MX spectrophotometer. Mass Spectra (EI, 70 eV) on a GC-MS,
Agilent Technologies 6890N and an inert mass selective detector
5973 mass spectrometer Technologies and elemental analyses
were conducted using a LECO-183 CHNS analyzer. Thin layer
chromatography (TLC) was conducted on 0.25 mm silica gel plates
(60 F254, Merck).
(d, 1H, J = 7.5 Hz, Ar-H) 7.90–7.24 (m, 5H, J = 9 Hz, Ar-H), 2.41 (s,
121
122
123
124
125
126
127
128
129
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186
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3
3H, ArCH
(C 55 N), 132.9, 131.7, 130.1, 130.0, 129.8, 129.6, 128.5, 127.7 (ArCs),
21.55 (CH ), Anal. Calcd. for C16 S: C, 65.73; H, 4.14; N, 19.16;
3 6
). C NMR (75.5 MHz, DMSO-d ): d 167.0, 140.9, 133.0
3
14 4
H N
S, 10.97; found: C, 65.71; H, 4.16; N, 19.15; S, 10.98. EI-MS m/z:
+
292.0 (M , 100).
3-(4-Chlorophenyl)-6-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thia-
f
diazole (5d): Light yellow solid; R = 0.66 (petroleum ether:ethyl
ꢀ1
acetate = 7:3) IR (KBr, cm ): 2921 (Ar, C–H str), 2851 (methyl, C–H
str), 1602 (nitro N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C str), 1185
1
6
6
8
9
2.1. Synthesis of 6-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
(Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-d
6
):
d
7.73
(4a–o)
(d, 2H, J = 7.8 Hz, ArH), 7.47 (d, 2H, J = 7.8 Hz, ArH), 7.39–7.42 (m,
1
3
5
H, J = 9 Hz, Ar-H). C NMR (75.5 MHz, DMSO-d
146.3 (C 55 N), 143.9, 131.9, 129.5, 128.3, 127.8, 124.6, 123.5, 114.5
(ArCs). Anal. Calcd. for C1s ClN S: C, 57.60; H, 2.90; N, 17.91; S,
6
): d 165.2, 151.0,
70
71
72
73
74
75
76
77
4-Amino-4H-1,2,4-triazole-3-thiole (1 equiv.) (3) was taken in
a two-necked round bottom flask equipped with magnetic stirrer
and suitable benzoic acid (1 equiv.) was added followed by the
dropwise addition of the POCl
refluxed at 180 8C for 10 h. On completion, the reaction mixture
was cooled and neutralized with NaHCO and the solids obtained
H
9
4
10.25; found: C, 57.62; H, 2.88; N, 17.90; S, 10.26. EI-MS m/z: 312.0,
+
3
(10 mL). The reaction mixture was
314.0 (M , 100).
3-(4-Nitrophenyl)-6-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thia-
3
f
diazole (5e): Yellow solid; R = 0.56 (petroleum ether:ethyl
ꢀ1
were filtered and recrystallized from water and ethanol (8:2) to
afford products (4a–o) in 69–81% yields.
acetate = 7:3); IR (KBr, cm ): 2921 (Ar, C–H str), 2851 (methyl,
C–H str), 1602 (nitro N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C str),
1
1
185 (Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-d
6
):
7
7
8
9
2.2. Synthesis of 3-aryl-6-phenyl[1,2,4]triazolo[3,4-
d
7.36 (d, 2H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-H); 7.39–
1
3
b][1,3,4]thiadiazoles (5a–o)
7.42 (m, 5H, J = 9 Hz, Ar-H). C NMR (75.5 MHz, DMSO-d
66.2, 153.0, 146.4 (C 55 N), 145.9, 132.9, 129.6, 127.3, 126.8, 126.6,
124.5, 115.5 (ArCs); Anal. Calcd. for C1s S: C, 55.72; H, 2.81;
6
): d
1
8
8
8
8
8
8
8
8
8
8
9
9
9
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0
Pd(OAc)
2
(5 mol%) and thiourea ligand (3 mol%) were added to
9 5 2
H N O
1
2
3
4
5
6
7
8
9
0
1
2
3
4
15 mL of DMA (15 mL) and stirred well under argon. Then, CaO
(1.5 equiv.) followed by that of corresponding triazolo-thiadiazole
(4a–o) (1.0 equiv.) were added to the reaction mixture and
refluxed at 140 8C for 1 h. After cooling to room temperature 4-
iodoaniline derivative (1.0 equiv.) was added and the mixture
refluxed for 15–20 h. The reaction progress was monitored by TLC
analysis using a solvent system (methanol:chloroform = 0.5:9.5) or
(ethyl acetate: n-hexane = 6:4). On completion, the reaction
mixture was poured into 50 mL of water. The water layer was
extracted twice with 25 mL of DCM, dried (anhydrous sodium
sulphate) filtered and concentrated. The products were purified by
recrystallization or by column extraction using n-hexane/ethyl
acetate (3:1) to yield the 3,6-diphenyl-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazoles (5a–o).
N, 21.66, S, 9.92; found: C, 55.70; H, 2.83; N, 21.65; S, 9.93. EI-MS
+
m/z: 323 (M , 100).
4-(6-Phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)benze-
f
namine (5f): Light brown; R = 0.62 (petroleum ether:ethyl
ꢀ
1
acetate = 7:3); IR (KBr, cm ): 3064 (Ar, C–H str), 2923 (methyl,
1
C–H str), 1518 (C 55 N str), 1465 (Ar, C 55 C str), 971 (Ar-H bend); H
6
NMR (300 MHz, DMSO-d ): d 8.03 (d, 2H, J = 8.0 Hz, ArH), 7.96 (d,
2H, J = 7.5 Hz, ArH), 7.66–6.72 (m, 5H, J = 9 Hz, Ar-H), 5.69 (s, 2H,
1
3
NH
146.3, 132.7, 129.5, 129.0, 127.1, 129.1, 113.6, 112.3 (ArCs). Anal.
Calcd. for C1s S: C, 61.42; H, 3.78; N, 23.87; S, 10.93; found: C,
2 6
). C NMR (75.5 MHz, DMSO-d ): d 165.7, 152.4, 150.8 (C 55 N),
11 5
H N
+
61.40; H, 3.80; N, 23.86; S, 10.94. EI-MS m/z: 293 (M , 100).
6-Phenyl-3-(pyridin-4-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
f
zole (5g): Yellow solid; R = 0.66 (petroleum ether:ethyl acetate
ꢀ
1
2
5
3,6-Diphenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (5a): Yel-
7:3); IR (KBr, cm ): 3080 (sp CH), 1626 (C 55 N), 1505 (C 55 C), 1266
1
6
7
8
low solid, R
f
= 0.67 (petroleum ether:ethyl acetate = 7:3); IR (KBr,
cm ): 1605 (N 55 O str), 1514 (C 55 N str), 1494 (Ar, C 55 C str), 1185
(N–N 55 C triazolo-thiadiazole), 669 (C-S-C), H NMR (DMSO-d
6
):
8.84–8.25 (m, 4H, Py), 8.10–7.65 (m, 5H, J = 9 Hz; Ar-H). C NMR
(75.5 MHz, DMSO-d ): 167.5 150.7, 143.7, (C 55 N), 133.1 132.4,
129.7, 128.8, 127.4, 126.4, 126.3, 119.4, (ArCs). Anal. Calcd. for
S, C, 60.20; H, 3.25; N, 25.07; S, 11.48; found: C, 60.22; H,
d
ꢀ1
13
1
(Ar, C–C str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-d
7.52–7.45 (m, 5H, J = 9.0 Hz, Ar-H), 7.39–7.42 (m, 5H, J = 9.0 Hz, Ar-
H), C NMR (75.5 MHz, DMSO-d
131.9, 131.9, 130.4, 130.05, 129.9, 129.7, 128.6, 127.8 (ArCs), Anal.
Calcd. for C15 S: C, 64.73; H, 3.62; N, 20.13; S, 11.52; found: C,
6
):
d
6
d
9
13
00
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
6
):
d
167.04, 141.9, 133.3 (C 55 N),
14 9 5
C H N
+
3.86; N, 25.09; S, 11.46. EI-MS m/z: 279 (M , 100).
H
N
10 4
3-(4-Chlorophenyl)-6-(4-nitrophenyl)-[1,2,4]triazolo[3,4-
+
64.71; H, 3.64; N, 20.13; S, 11.52. GC-MS m/z: 278.0 (M , 100).
f
b][1,3,4]thiadiazole (5h): Yellow solid; R = 0.33 (petroleum
1
6-Phenyl-3-m-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
ether:ethyl acetate 7:3); IR (KBr, cm ): 2921 (Ar C–H str), 2851
(5b): Yellow solid, R
f
= 0.66 (petroleum ether:ethyl acetate = 7:3);
(methyl C–H str), 1602 (nitro N 55 O str), 1510 (C 55 N str), 1492 (Ar,
ꢀ
1
1
IR (KBr, cm ): 2921 (Ar, C–H str), 2851 (methyl, C–H str), 1602
C 55 C str), 1185 (Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz,
(nitro N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C str), 1185 (Ar C–F
str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-d
J = 1.2 Hz), 7.68–7.54 (m, 1H, Ar-H), 7.42–7.30 (m, 2H, Ar-H), 7.39–
7.42 (m, 5H, J = 9 Hz, Ar-H), 2.42 (s, 3H, ArCH
(75.5 MHz, DMSO-d ): 167.04, 141.9, 133.3 (C 55 N), 131.9,
131.9, 130.4, 130.05, 129.9, 129.7, 128.6, 127.8 (ArCs), 21.58
(CH ), Anal. Calcd. for C16 S: C, 65.73; H, 4.14; N, 19.17; S,
DMSO-d
H); 7.73 (d, 2H, J = 7.8 Hz, ArH), 7.47 (d, 2H, J = 7.8 Hz, ArH).
NMR (75.5 MHz, DMSO-d ): 166.5, 149.1, 143.5, (C 55 N), 1425,
139.3, 137.1, 136.2, 133.7 130.4, 129.2, 122.4, (ArCs). Anal. Calcd.
for C15 ClN S, C, 50.36; H, 2.25; N, 19.57 S, 8.96; found: C,
6
): d 7.36 (d, 1H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-
1
13
6
):
d
7.70 (d, 1H,
C
6
d
13
3
).
C NMR
6
d
H
8
5 2
O
+
50.34; H, 2.27; N, 19.56; S, 8.97. EI-MS m/z: 357 (M , 100).
3
H
14
N
4
3-(4-Chlorophenyl-)-6-(4-chlorophenyl)-[1,2,4-]triazolo[3,4-
10.96; found: C, 65.71; H, 4.16; N, 19.15; S, 10.98. EI-MS m/z: 292.0
b][1,3,4]thiadiazole (5i): White solid; R
ethyl acetate 7:3); IR (KBr, cm ): 3080 (sp CH), 1626 (C 55 N), 1505
f
= 0.68 (petroleum ether:-
+
ꢀ1
2
(M , 100).
1
6-Phenyl-3-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
(Ar, C 55 C), 1266 (N–N 55 C triazolo-thiadiazole), 669 (C-S-C),
NMR (DMSO-d ): 7.73 (d, 2H, J = 7.8 Hz, ArH), 7.47 (d, 2H,
J = 7.8 Hz, ArH), 7.73 (d, 2H, J = 7.8 Hz, ArH), 7.47 (d, 2H, J = 7.8 Hz,
H
(5c): Yellow solid; R
f
= 0.68 (petroleum ether:ethyl acetate = 7:3);
6
d
ꢀ
1
IR (KBr, cm ): 3064 (Ar, C–H str), 2923 (methyl, C–H str), 1517
1
13
(C 55 N str), 1466 (Ar, C 55 C str), 971 (Ar-H bend); H NMR
ArH), C NMR (75.5 MHz, DMSO-d
6
): d 165.5, 149.3, 144.5, (C 55 N),
6
(300 MHz, DMSO-d ): d 8.28 (d, 2H, J = 7.5 Hz, Ar-H), 8.10
134.5, 133.3, 132.1, 131.2, 130.7 129.4, 129.2, 128.4 (ArCs). Anal.
Please cite this article in press as: A. Saeed, et al., C–H arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-
1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.011
[

G Model
CCLET 3435 1–4
A. Saeed et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
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8 2 4
Calcd. for C15H Cl N S, C, 51.89; H, 2.32; N, 16.14; S, 9.23; found: C,
+
51.86; H, 2.35; N, 16.15; S, 9.22 EI-MS m/z: 345.0, 347.0 (M , 100).
3-(4-Nitrophenyl-)-6-(4-nitrophenyl)-[1,2,4-]triazolo[3,4-
f
b][1,3,4]thiadiazole (5j): Reddish brown solid R = 0.26 (petroleum
ꢀ1
ether:ethyl acetate = 7:3); IR (KBr, cm ): 2921 (Ar C–H str), 2851
(methyl C–H str), 1602 (N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C
1
str), 1185 (Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-
d
6
):
7.36 (d, 1H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-H); C NMR
(75.5 MHz, DMSO-d ): 166.3, 152.0, 146.5 (C 55 N), 145.8, 136.9,
133.6, 130.3, 129.8, 128.6, 122.5, 121.5 (ArCs). Anal. Calcd. for
S: C, 48.91; H, 2.19; N, 22.82; S, 8.71; found: C, 48.89; H,
d 7.36 (d, 1H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-H);
1
3
6
d
1s 8 6 4
C H N O
+
2.21; N, 22.80; S, 8.73. EI-MS m/z: 368 (M , 100).
6-(4-Nitrophenyl)-3-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazole (5k): Yellow solid;
acetate = 7:3); IR (KBr, cm ): 2921 (Ar C–H str), 2851 (methyl
f
R = 0.37 (petroleum ether:ethyl
Scheme 1. Synthesis of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4a–o).
ꢀ1
C–H str), 1602 (N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C str), 1185
1
(Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-d
6
):
d
7.36
3-(4-Nitrophenyl-)-6-(2-chlorophenyl)-[1,2,4-]triazolo[3,4-
235
(d, 1H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-H); 7.43 (d, 2H,
J = 7.5 Hz, Ar-H), 8.13 (d, 1H, J = 7.5 Hz, Ar-H), 2.43 (s, 3H, ArCH ).
166.0, 143.9, 134.0 (C 55 N), 133.9,
132.7, 131.1, 130.5, 129.7, 129.4, 128.3, 127.7 (ArCs), 22.55 (CH ),
Anal. Calcd. for C16 S: C, 56.96; H, 3.29; N, 20.76, S, 9.50;
f
b][1,3,4]thiadiazole (5n): Light yellow solid, R = 0.31 (Petroleum 236
ꢀ
1
3
ether: ethyl acetate = 7:3); IR (KBr, cm ): 2921 (Ar C–H str), 2851 237
13
C NMR (75.5 MHz, DMSO-d
6
):
d
(methyl C–H str), 1602 (N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C 238
1
3
str), 1185 (Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO- 239
H
11
N
5
O
2
d
6
):
7.28–7.31 (m, 4H, J = 9 Hz, Ar-H). C NMR (75.5 MHz, DMSO-d
165.5, 149.3, 144.5, (C 55 N), 142.4, 138.3, 137.3, 136.6, 133.8, 132.8, 242
131.8 130.4, 129.2, 122.4, (ArCs); Anal. Calcd. for C15 ClN S, C, 243
50.36; H, 2.25; N, 19.57 S, 8.96 found: C, 50.34; H, 2.27; N, 19.57; S, 244
d 7.36 (d, 1H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H, J = 8.4 Hz, Ar-H), 240
1
3
found: C, 56.94; H, 3.31; N, 20.74; S, 9.52. EI-MS m/z: 337.0, 339.0
6
):
d
241
+
(M , 100).
3-(4-Nitrophenyl-)-6-(3,4,5-trimethoxyphenyl)-[1,2,4-]tria-
H
8
5 2
O
f
zolo[3,4-b][1,3,4]thiadiazole (5l): Yellow solid, R = 0.37 (petro-
ꢀ1
+
leum ether:ethyl acetate = 7:3); IR (KBr, cm ): 2921 (Ar C–H
8.96 EI-MS m/z: 357.0, 359.0 (M , 100).
245
246
str), 2851 (methyl C–H str), 1602 (N 55 O str), 1510 (C 55 N str), 1492
3-(4-Chlorophenyl)-6-p-tolyl-[1,2,4]triazolo[3,4-b][1,3,4]thia-
1
(Ar, C 55 C str), 1185 (Ar C–F str), 990 (Ar-H bend); H NMR
f
diazole (5o): Yellow solid, R = 0.68 (Petroleum ether: ethyl 247
ꢀ1
(300 MHz, DMSO-d
6
):
d
7.36 (d, 2H, J = 8.1 Hz, Ar-H), 8.36 (d, 2H,
acetate = 7:3) IR (KBr, cm ): 3064 (Ar C–H str), 2923 (methyl 248
1
J = 8.4 Hz, Ar-H); 6.63 (s, 2H, 3,4,5-trimethoxybenzyl-H), 3.61
C–H str), 1517 (C 55 N str), 1466 (Ar, C 55 C str), 971 (Ar-H bend); H 249
1
3
(s, 6H, 3,5-di–CH
DMSO-d ): 167.3, 151.0, 143.5 (C 55 N), 151.8, 151.5, 146.9,
141.6, 136.3, 129.8, 125.6, 122.5, 106.9 (ArCs). 56.7, 56.4, 54.2
(OCH ), Anal. Calcd. for C18 S: C, 52.30; H, 3.66; N, 16.94;
3
O), 3.82 (s, 3H, 4-CH
3
O), C NMR (75.5 MHz,
NMR (300 MHz, DMSO-d
6
): d 8.28 (d, 2H, J = 7.5 Hz, Ar-H), 8.10 250
6
d
(d, 1H, J = 7.5 Hz, Ar-H), 7.73 (d, 2H, ArH, J = 7.8 Hz), 7.47 (d, 2H, 251
1
3
J = 7.8 Hz, ArH), 2.41 (s, 3H, CH
167.0, 140.9, 133.0 (C 55 N), 132.9, 131.7, 130.1, 130.0, 129.8, 129.6, 253
128.5, 127.3, (ArCs), 21.5 (CH ); Anal. Calcd. for C16 11ClN S: C, 254
58.80; H, 3.39; N, 17.14; S, 9.81 found: C, 58.78; H, 3.41; N, 17.12; S, 255
3
), C NMR (75 MHz, DMSO-d
6
):
d
252
3
15 5 5
H N O
S, 7.76; found: C, 52.28; H, 3.68; N, 16.92; S, 7.78. EI-MS m/z: 413
3
H
4
+
(M , 100).
+
3-(4-Nitrophenyl-)-6-(4-pyridyl)-[1,2,4-]triazolo[3,4-
9.83. EI-MS m/z: 326 (M , 100).
256
f
b][1,3,4]thiadiazole (5m): Yellow solid; R = 0.3 (Petroleum ether:
ꢀ
1
ethyl acetate = 7:3); IR (KBr, cm ): 2921 (Ar, C–H str), 2851
3. Results and discussion
257
(methyl C–H str), 1602 (N 55 O str), 1510 (C 55 N str), 1492 (Ar, C 55 C
1
str), 1185 (Ar C–F str), 990 (Ar-H bend); H NMR (300 MHz, DMSO-
The synthesis of coupling partners 6-aryl-[1,2,4]triazolo[3,4- 258
b][1,3,4]thiadiazoles (4a–o) was achieved according to the 259
synthetic strategy outlined in Scheme 1. Formic acid (1) was 260
treated with thiocarbohydrazide (2) using dry ethanol as a solvent 261
to afford 4-amino-1,2,4-triazole-3-thiole (3), which was further 262
reacted with suitably substituted aromatic acids in the presence of 263
1
3
d
6
):
NMR (75.5 MHz, DMSO-d
132.5, 129.6, 128.9, 127.5, 126.3, 120.4, (ArCs). Anal. Calcd. for
S, C, 51.85; H, 2.49; N, 25.91, S, 9.89 found: C, 51.83; H,
d
7.92, 8.76 (m, 4H, Py), 7.24–7.28 (m, 4H, J = 12 Hz; Ar-H).
C
6
): 166.5 151.7, 142.7, (C 55 N), 133.2,
d
14 8 6 2
C H N O
+
2.51; N, 25.90; S,9.90. EI-MS m/z: 324 (M , 100).
Scheme 2. Coupling of 4a–o to aryl iodides leading to 3,6-diaryl-[1,2,4-]triazolo[3,4-b] [1,3,4] thiadiazoles (5a–o).
Please cite this article in press as: A. Saeed, et al., C–H arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-
1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.011
[

G Model
CCLET 3435 1–4
4
A. Saeed et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
1
Table 1
and C 55 N functions, respectively. In the H NMR spectral data for all
286
287
288
289
290
291
292
293
Optimization table for the synthesis of 5a.
the compounds, the characteristic thiazolyl proton disappeared
and only aromatic protons were found. The C NMR spectral data
show deshielded signals for C 55 N of thiazole and triazole in the
range of d 164.6–162.0 and d 159.9–158.3, respectively, due to the
neighboring sulfur and nitrogen atoms. The purity and homoge-
neity of all compounds were confirmed by their sharp melting
points and analytical TLC.
1
3
Entry
Ligand (mol%)
Base
CO
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
0.010
0.010
0.010
0.010
0.015
0.020
0.025
0.030
K
2
3
DMF
DMF
DMF
DMA
DMA
DMA
DMA
DMA
16–20
14–20
12–16
12–15
12–15
15–20
15–20
15–20
54
57
59
62
74
78
84
89
NaOAc
CaO
CaO
CaO
CaO
CaO
CaO
4. Conclusion
294
The present study offers an efficient and convenient phosphine-
free C–H activated arylation of the triazol-H of triazolo-thiadiazoles
using thiourea/Pd catalysis. The yields are satisfactory and the
thiourea ligand used is thermally stable, insensitive to air and
moisture, and tunablebymodifyingthesubstituentsonthearylring.
295
296
297
298
299
Table 2
3
,6-Diaryl-[1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles 5a–o produced via Scheme 1.
1
2
Entry
Product
R
R
Mp (8C)
Yield (%)
1
2
3
4
5
5
6
7
8
9
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
185
166
120
150
200
250
300
235
229
200
220
230
236
238
227
78
80
81
84
79
81
78
78
84
79
80
86
84
78
87
3-CH
4-CH
4-Cl
3
References
300
3
4-NO
4-NH
2
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326
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328
329
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332
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334
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[
[
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5h
5i
2-pyridyl
4-Cl
4-NO
4-Cl
2
4-Cl
5j
4-NO
4-NO
4-NO
4-NO
4-NO
2
2
2
2
2
4-NO
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5k
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3
4-Cl
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[
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285
phosphoryl chloride to afford the targeted compounds (5a–o)
(Scheme 2).
The phophine-free Pd-catalyzed cross-coupling of (4a–o) with
suitably substituted aryl iodides was carried out in the presence of
1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand to afford
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palladium catalyzed C–H halogenation, Chin. Chem. Lett. 25 (2014) 667–669.
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[
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targeted
compounds
3,6-diaryl-[1,2,4-]triazolo[3,4-
b][1,3,4]thiadiazoles (5a–o) in 78%-89% yields. The reaction
conditions for the synthesis of compound 5a were optimized
originally by screening for the best solvent, base, refluxing time,
mol percent of thiourea ligand constant (entries 4–8) and then the
optimum mol percent of ligand was established (Table 1).
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0
[
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H NMR spectroscopy, ESI-MS spectra and elemental analysis
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data of the targeted compounds fully accorded with their assigned
structures.
The FTIR spectra of all compounds showed strong absorptions
around 3016, 2959 cm for C–H stretchings, in addition to the
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ꢀ
1
1
ꢀ1
peaks at 3115–3100 cm and 1618–1605 cm assignable to C 55 C
(2015) 59–66.
Please cite this article in press as: A. Saeed, et al., C–H arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-
1,2,4-]triazolo[3,4-b][1,3,4]thiadiazoles, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.011
[