Pd/Cu-catalyzed C-H arylation of 1,3,4-thiadiazoles with (hetero)aryl iodides, bromides, and triflates

Article abstract of DOI:10.1021/jo301401q

The direct C-H arylation of 1,3,4-thiadiazoles with a wide range of (hetero)aryl iodides, bromides, and triflates is described using a Pd/Cu-catalyzed protocol. The methodology is compatible with substrates possessing electron-donating or electron-withdrawing substituents and also tolerates sterically hindered aryl halides. The utility of the developed protocol is demonstrated by a one-pot C-H arylation-Suzuki coupling sequence.

Full text of DOI:10.1021/jo301401q

Subscriber access provided by DUKE UNIV
Note
Pd/Cu-Catalyzed C-H Arylation of 1,3,4-Thiadiazoles
with (Hetero)aryl Iodides, Bromides and Triflates
Dipak D. Vachhani, Abhishek Sharma, and Erik Van der Eycken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301401q • Publication Date (Web): 07 Sep 2012
Downloaded from http://pubs.acs.org on September 9, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Pd/Cu-Catalyzed C-H Arylation of 1,3,4-Thiadiazoles with (Hetero)aryl
Iodides, Bromides and Triflates
7
8
9
Dipak D. Vachhani,† Abhishek Sharma†‡ and Erik Van der Eycken†*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry,
KU Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium.
‡Current Address: Department of Chemistry, University of Illinois at Urbana-Champaign,
Urbana, Illinois, 61801, United States
* E-mail: erik.vandereycken@chem.kuleuven.be
________________________________________________________________________________
The direct C-H arylation of 1,3,4-thiadiazoles with a wide range of (hetero)aryl iodides,
bromides and triflates is described using a Pd/Cu-catalyzed protocol. The methodology is
compatible with substrates possessing electron-donating or electron-withdrawing substituents
and also tolerates sterically hindered aryl halides. The utility of the developed protocol is
demonstrated by a one-pot C-H arylation-Suzuki coupling sequence.
_____________________________________________________________________________
1,3,4-Thiadiazoles represent an important class of five-membered heterocycles possessing
diverse biological properties1 including adenosine1a/histamine1b receptor antagonists,
antidiabetic,1c antidepressant1d and anticancer1e activities. Moreover, they have also found
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
applications in material science2 and for the synthesis of heterocycles fused3 with peptides. Thus
it would be highly desirable if direct functionalization strategies could be developed for this
heteroarene, thereby enabling the late stage decoration of the thiadiazole core.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In recent years, transition-metal-catalyzed direct C-H arylation has emerged as a promising
4
stratgey for the construction of biaryl units. In this context, a diverse range of N- and/or O-
containing heteroarenes has been arylated using aryl halides/pseudohalides.4c-d,5 However, the
scope of C-H arylation of various heterocyclic systems still needs to be evaluated. In particular,
S-containing heterocycles pose a significant challenge due to the poisoning effect of sulfur,6
although thiazoles, thiophenes have been found to undergo direct C-H arylations.7 To the best of
our knowledge, a direct arylation of 1,3,4-thiadiazoles with aryl halides has not been reported till
date. We describe herein, a Pd/Cu-catalyzed direct C-H arylation of various 1,3,4-thiadiazoles
using a wide range of aryl iodides/bromides as well as triflates.
In continuation of our longstanding interest in the synthesis and diversification of novel
heterocycles bearing biaryl units,8 we initiated our studies with the direct C-H arylation of 2-
phenyl-1,3,4-thiadiazole (1a, 0.5 mmol) with phenyl iodide (2a, 2 equiv) under concerted
metalation-deprotonation (CMD) conditions7d,9 using Pd(OAc)2 (5 mol%), PPh3 (10 mol%),
Cs2CO3 (2 equiv) and pivalic acid (30 mol%) as additive in DMA. However, after heating the
above reaction mixture at 105 oC for 12 h, the desired product 3a could only be obtained in 15%
yield (Table 1, entry 1). Replacement of DMA with dioxane enhanced the yield to 30% (Table 1,
entry 2) while DME as solvent led to a lower yield (Table 1, entry 3). Further, the use of K2CO3
as base provided 3a in only trace amounts (Table 1, entry 4). Screening of various other ligands
and Pd-catalysts (Table 1, entries 5-8) failed to further improve the reaction. Interestingly,
replacement of pivalic acid by CuI (10 mol%) as additive substantially enhanced the yield of 3a
2
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
Table 1. Optimization of the direct arylation of 2-Phenyl-1,3,4-thiadiazole.a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
solvent
DMA
base
Pd/Ligand
additive
yieldb (%)
15
1
Cs2CO3
Pd(OAc)2
/PPh3
Pivalic acid
2
3
4
5
Dioxane
DME
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Pd(OAc)2
/PPh3
Pivalic acid
Pivalic acid
Pivalic acid
Pivalic acid
30
Pd(OAc)2
/PPh3
28
Dioxane
Dioxane
Pd(OAc)2
/PPh3
Pd(OAc)2
/dppp
traces
27
6
Dioxane
Cs2CO3
Pd(OAc)2
/Xantphos
Pivalic acid
30
7
8
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Pd(OAc)2
/CyJohnphos
Pd(PPh3)Cl2
Pivalic acid
Pivalic acid
CuI
traces
7
9
Pd(OAc)2
/Xantphos
Pd(OAc)2
/ PPh3
84 (73)c
54
10
11
12
CuI
Pd(OAc)2
/Xantphos
-
CuI
27d
CuI
nde
aGeneral Conditions: 1a (0.5 mmol), Pd-catalyst (5 mol%), ligand (10 mol%), base (2 equiv), additive: pivalic acid (30 mol%),
o
CuI (10 mol%), solvent (2 mL), 2a (2 equiv), 105 C, 12 h. Yield of isolated product. Yield of the reaction under focused
b
c
microwave irradiation (105oC, 100 W), 50 min. Pd(OAc)2 (2 mol%), Xantphos (4 mol%) and CuI (4 mol%) were used. eNot
detected.
d
(84%, Table 1, entry 9). The use of PPh3 in place of Xantphos under these new conditions
decreased the reaction performance (54% yield, Table 1, entry 10). Further, the replacement of
conventional heating with microwave irradiation resulted in reduced reaction time (50 min) but
afforded comparatively lower yield of 3a (73%, Table 1, entry 9). On the other hand, direct
arylation of 1a did not proceed in the absence of Pd using CuI as the sole catalyst (Table 1, entry
12).
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
Having established the optimum conditions, the substrate scope was next examined. The
protocol was found to be broadly applicable for C-H arylation of thiadiazoles bearing electron
donating or withdrawing substituents on phenyl ring (Table 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Substrate scope of the Pd/Cu-catalyzed direct arylation of 1,3,4-thiadiazoles.a
entry substrate (1)
Ar-X (2)
product (3)
yieldb (%)
84
1
2a
3a
1a
1a
2
60
79
2b
3b
3
4
1a
1a
2c
3c
traces
76
2d
2e
3d
5
6
3e
1a
1a
81
79
2f
2g
2c
3f
7
8
1a
3g
74
38
3h
1b
1b
3i
9
2h
2i
10
1b
3j
51
4
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
11
71
2c
2j
3k
1c
9
1b
1c
1c
12
13
69
78
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3l
2g
3m
3n
14
74
2e
15
16
17
49
79
1a
2k
3o
1a
1a
2l
3p
ndc
2m
3q
3a
18
72
2n
2o
1a
19
20
39
24
3r
1c
1a
2p
3s
1a
21
ndc
2q
3t
aConditions: 1 (0.5 mmol), Pd(OAc)2 (5 mol%), Xantphos (10 mol%), Cs2CO3 (2 equiv), CuI (10 mol%), 2 (2 equiv)
in dioxane (1.5 mL), 105 oC, 12 h. bYield of isolated product. cNot detected.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
4
5
6
7
8
The arylation could be accomplished efficiently using aryl iodides/bromides as well as triflates.
Moreover, the sterically hindered o-tolyl bromide (2e) or o-phenyl bromobenzene (2p) were
tolerated (Table 2, entries 5, 14, 20) while the aryl halide possessing bulkier 2,6-diisopropyl
substitution was not compatible (Table 2, entry 21). On the other hand, no reaction was observed
using aryl halides bearing highly polar substituents like nitro (Table 2, entry 4) or carboxylic acid
(Table 2, entry 17) presumably due to catalyst inactivation.10 Importantly, the use of heteroaryl
halides comprising thiophene, pyridine or even indole moities (Table 2, entries 7, 9, 10 and 13)
was found to be feasible, thereby, enabling a facile diversification into biologically important
biheterocyclic frameworks.11
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Encouraged by the good tolerance for the above conditions of the 4-chloro-phenyl substituent
(Table 2, entries 2, 12-14 and 19), we became interested to introduce further diversity employing
this moiety. A one-pot C-H arylation-Suzuki coupling sequence was envisaged, wherein, after
the initial formation of 3b, p-tolylboronic acid 4, (1.5 equiv), Pd(OAc)2 (5 mol%), SPhos (10
mol%), K3PO4 (2 equiv) THF/water (3:1) (2 mL) were added and the mixture was heated at 105
oC for 8h. To our great satisfaction, this one-pot approach successfully afforded the
corresponding 5a in 58% overall yield (Table 3, entry 1).12 Analogously, the 5b could be
synthesized in 70% overall yield (Table 3, entry 2).
On the basis of experimental observations as as well as some earlier reports,13 a plausible
mechanism of this Pd/Cu-catalyzed direct arylation of thiadiazoles might involve a base assisted
cupration of the thiadiazole to give the aryl-Cu species I (Scheme 1).13 Subsequently, I
undergoes transmetalation with an aryl-Pd complex (II formed by the oxidative addition of Pd0
6
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
Table 3. One-pot sequential C-H Arylation-Suzuki coupling of 1,3,4-thiadiazoles.a
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yieldb
entry
substrate (1)
Ar-X (2)
product (5)
(%)
2b
1
58
1a
5a
N
N
2e
S
2
70
1c
5b
aConditions: 1 (0.5 mmol), Pd(OAc)2 (5 mol%), Xantphos (10 mol%), Cs2CO3 (2 equiv), CuI (10 mol%), 2 (1.5 equiv) in
dioxane (1.5 mL), 105 oC, 12 h; then p-tolylboronic acid (1.5 equiv), K3PO4 (2 equiv), Pd(OAc)2 (5 mol%), S-phos (10 mol%),
THF/water (3:1) (2 mL), 105 oC, 8h. Yield of isolated product.
b
to aryl halide) to give intermediate III which undergoes reductive elimination to furnish the
product with concomitant release of both the Pd and Cu-catalyst.
Scheme 1. Plausible mechanism for the Pd/Cu-catalyzed direct C-H arylation of 1,3,4-
thiadiazoles.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
6
7
8
9
In conclusion, we have elaborated a hitherto unknown direct C-H arylation of substituted
1,3,4-thiadiazoles using a Pd/Cu-catalyzed protocol. This is applicable for the facile coupling of
2-substituted 1,3,4-thiadiazoles with a wide range of aryl halides/triflates bearing electron
donating/withdrawing groups or ortho substituents. Moreover, heteroaryl halides bearing
thiophene, pyridine and indole moeities could also be successfully employed. Interestingly, a
one-pot direct arylation–Suzuki coupling sequence was found to be feasible, thereby furnishing a
convenient access to polyarylated thiadiazoles.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
Materials:
The various 1,3,4-thiadiazoles were synthesized according to a known literature procedure.14 The
aryl halides, reagents and catalysts were obtained from commercial sources and used as such. For
thin layer chromatography, analytical TLC plates (70-230 mesh silica gel) were used. Column
chromatography was performed using silica gel (60-120 mesh size). Anhydrous solvents were
purchased from commercial sources and stored over molecular sieves. The chromatographic
solvents used for isolation/purification of compounds were distilled prior to use. The
chromatographic solvents are mentioned as volume:volume ratios. Reactions were typically run
in oven-dried screw-cap vial under inert atmosphere.
Apparatus:
1
13
NMR spectra were recorded at 300 MHz (1H) and 75.5 MHz (13C). The H and C chemical
shifts are reported in parts per million relative to tetramethylsilane using the residual solvent
signal as the internal reference. The following abbreviation were used to designate chemical shift
multiplicities: s = singlet, bs = broad singlet, d = doublet, dd = double doublet, t = triplet, m =
8
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
multiplet. The 13C NMR spectra are proton decoupled. High-resolution mass spectra were
recorded by using double-focusing magnetic sector analyzer and at an ion source temperature
150−250 °C as required. High resolution EI-mass spectra were performed with a resolution of
10,000.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Microwave Irradiation Experiment: All microwave irradiation experiments were carried out in
a dedicated CEM-Discover monomode microwave apparatus, operating at a frequency of
2.45GHz with continuous irradiation power from 0 to 300 W with utilization of the standard
absorbance level of 300W maximum power. The reactions were carried out in 10-mL glass
tubes, sealed with Teflon septum and placed in the microwave cavity. Initially, microwave
irradiation of required watts was used and the temperature is being ramped from room
temperature to the desired temperature. Once this was reached the reaction mixture was held at
this temperature for the required time. The reaction mixture was continuously stirred during the
reaction. The temperature was measured with an IR sensor on the outer surface of the process
vial. After the irradiation period, gas jet cooling cooled the reaction vessel rapidly to ambient
temperature.
General procedure for arylation of 1,3,4-thiadiazole.
Synthesis of 2,5-diphenyl-1,3,4-thiadiazole (Table 2, 3a)
1a (81 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), Xantphos (28.9 mg, 0.05 mmol),
Cs2CO3 (326 mg, 1.0 mmol) and CuI (9.5 mg, 0.05 mmol) were taken in a 10 mL oven-dried
screw-cap vial and 2a (204 mg, 1 mmol), 1,4-Dioxane (1.5 mL) were added to it. The reaction
o
tube was evacuated-backfilled with argon (5 cycles), sealed and subsequently heated at 105 C
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
9
for 12h. After completion of the reaction (confirmed by mass and TLC analysis), poured in to
water (50 mL) and extracted by ethyl acetate (2x50 mL). The combined organic layer was
washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was
subjected to silica gel column chromatography (using 5-10 % EtOAc in heptane as eluant) to
afford 3a as a white solid (100 mg, 84% yield), m.p. 131-133 oC, 1H NMR (300 MHz, CDCl3): δ
8.06-7.96 (m, 4H), 7.55-7.44 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 168.1, 131.0, 130.1, 129.1,
127.9. HRMS (EI): calcd for C14H10N2S: 238.0565, found: 238.0553
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The above procedure was also used for heteroarylation of various other 1,3,4-thiadiazoles
(Table 2, 3b-r).
2-(4-chlorophenyl)-5-phenyl-1,3,4-thiadiazole (Table 2, 3b)
o
1
White solid, m.p. 179-181 C, 81 mg, yield 60 %, H NMR (300 MHz, CDCl3): δ 8.06-7.88 (m,
4H), 7.58-7.39 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 168.3, 166.8, 137.2, 131.2, 129.9, 129.4,
129.2, 129.1, 129.0, 128.6, 127.9. HRMS (EI): calcd for C14H9ClN2S: 272.0175, found:
272.0168
2-phenyl-5-p-tolyl-1,3,4-thiadiazole (Table 2, 3c)
10
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
o
1
3
4
White solid, m.p. 123-124 C, 99 mg, yield 79 %, H NMR (300 MHz, CDCl3): δ 8.07-7.97 (m,
5
6
13
2H), 7.91 (d, J = 7.74 Hz, 2H), 7.53-7.46 (m, 3H), 7.30 (d, J = 7.53 Hz, 2H), 2.42 (s, 3H). C
7
8
9
NMR (75 MHz, CDCl3): δ 168.2, 167.7, 141.5, 131.5, 130.2, 129.8, 129.1, 127.9, 127.89,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
127.84, 127.4, 21.5 . HRMS (EI): calcd for C15H12N2S: 252.0721, found: 252.0719
2-phenyl-5-o-tolyl-1,3,4-thiadiazole (Table 2, 3e)
o
1
Creamish white solid, m.p. 55-57 C, 96 mg, yield 76 %, H NMR (300 MHz, CDCl3): δ 8.08-
7.98 (m, 2H), 7.74 (d, J = 7.53 Hz, 1H), 7.55-7.47 (m, 3H), 7.44-7.28 (m, 3H), 2.65 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 168.6, 167.4, 137.3, 131.6, 131.1, 130.7, 130.4, 130.1, 129.2, 127.9,
126.3, 21.7. HRMS (EI): calcd for C15H12N2S: 252.0721, found: 252.0731.
2-(4-methoxyphenyl)-5-phenyl-1,3,4-thiadiazole (Table 2, 3f)
White solid, m.p. 136-137 oC, 108 mg, yield 81 %, 1H NMR (300 MHz, CDCl3): δ 8.05-7.98 (m,
13
2H), 7.96 (d, J = 8.46 Hz, 2H), 7.57-7.43 (m, 3H), 7.01 (d, J = 8.46 Hz, 2H), 3.88 (s, 3H). C
NMR (75 MHz, CDCl3): δ 167.8, 167.3, 161.9, 130.9, 130.2, 129.4, 129.1, 127.8, 122.8, 114.5,
55.4. HRMS (EI): calcd for C15H12N2OS: 268.0670, found: 268.0653
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
2-phenyl-5-(pyridine-3-yl)-1,3,4-thiadiazole (Table 2, 3g)
5
6
7
N
N
8
9
S
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
White solid, m.p. 147-149 C, 94 mg, yield 79 %, H NMR (300 MHz, CDCl3): δ 9.19 (s, 1H),
13
8.75 (d, J = 3.96 Hz, 1H), 8.38 (d, J = 7.89 Hz, 1H), 8.10-7.95 (m, 2H), 7.60-7.40 (m, 4H). C
NMR (75 MHz, CDCl3): δ 168.8, 164.7, 151.8, 148.8, 134.7, 131.4, 129.7, 129.2, 128.0, 126.5,
123.9. HRMS (EI): calcd for C13H9N3S: 239.0517, found: 239.0503
2,5-dip-tolyl-1,3,4-thiadiazole (Table 2, 3h)
o
1
White solid, m.p. 146-148 C, 98 mg, yield 74 %, H NMR (300 MHz, CDCl3): δ 7.89 (d, J =
8.10 Hz, 4H), 7.29 (d, J = 7.92 Hz, 4H), 2.42 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 167.8,
141.4, 129.8, 127.7, 21.5. HRMS (EI): calcd for C16H14N2S: 266.0878, found: 266.0858
2-(1H-indol-5-yl)-5-p-tolyl-1,3,4-thiadiazole (Table 2, 3i)
Pale brown solid, m.p. 263-266 oC, 55 mg, yield 38 %, 1H NMR (300 MHz, CDCl3): δ 11.49 (s,
1H), 8.22 (s, 1H), 7.90 (d, J = 7.53 Hz, 2H), 7.78 (d, J = 8.64 Hz, 1H), 7.57 (d, J = 8.28 Hz, 1H),
7.49 (bs, 1H), 7.39 (d, J = 7.92 Hz, 2H), 6.61 (bs, 1H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3):
12
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
δ 169.1, 166.4, 141.1, 137.4, 129.9, 127.9, 127.4, 127.3, 127.0, 120.6, 120.5, 120.4, 112.3, 102.2,
5
6
20.9. HRMS (EI): calcd for C17H13N3S: 291.0830, found: 291.0833
7
8
9
2-(thiophen-2-yl)-5-p-tolyl-1,3,4-thiadiazole (Table 2, 3j)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pale yellow solid, m.p. 125-127 oC, 66 mg, yield 51 %, 1H NMR (300 MHz, CDCl3): δ 7.87 (d,
J = 8.10 Hz, 2H), 7.58 (d, J = 3.57 Hz, 1H), 7.49 (d, J = 4.89 Hz, 1H), 7.29 (d, J = 8.07 Hz, 2H),
7.13 (dd, J = 4.71, 3.93 Hz, 1H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 167.5, 161.4,
141.6, 132.5, 129.8, 129.4, 129.1, 127.9, 127.8, 127.2, 21.5. HRMS (EI): calcd for C13H10N2S2:
258.0285, found: 258.0295
2-(4-chlorophenyl)-5-p-tolyl-1,3,4-thiadiazole (Table 2, 3k)
N
N
S
Cl
o
1
White solid, m.p. 184-186 C, 102 mg, yield 71 %, H NMR (300 MHz, CDCl3): δ 7.95 (d, J =
8.46 Hz, 2H), 7.90 (d, J = 8.10 Hz, 2H), 7.47 (d, J = 8.46 Hz, 2H), 7.30 (d, J = 8.10 Hz, 2H),
2.43 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 168.5, 166.4, 141.7, 137.0, 129.9, 129.4, 129.0,
128.7, 127.8, 127.2, 21.5. HRMS (EI): calcd for C15H11ClN2S: 286.0331, found: 286.0331
2-(4-fluorophenyl)-5- p-tolyl-1,3,4-thiadiazole (Table 2, 3l)
N
N
F
S
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
o
1
3
White solid, m.p. 177-178 C, 77 mg, yield 57 %, H NMR (300 MHz, CDCl3): δ 8.00 (dd, J =
8.37, 5.28 Hz, 2H), 7.89 (d, J = 7.92 Hz, 2H), 7.30 (d, J = 7.92 Hz, 2H), 7.19 (t, J = 8.46 Hz,
2H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 168.3, 166.4, 166.0, 162.6, 141.6, 129.9,
129.88, 129.80, 127.8, 127.3, 126.6, 126.5, 116.5, 116.2, 21.5. HRMS (EI): calcd for
C15H11FN2S: 270.0627, found: 270.0629.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(4-chlorophenyl)-5-(pyridin-3-yl)-1,3,4-thiadiazole (|Table 2, 3m)
o
1
White solid, m.p. 179-181 C, 106 mg, yield 78 %, H NMR (300 MHz, CDCl3): δ 9.18 (s, 1H),
13
8.75 (bs,1H), 8.37 (d, J = 7.89 Hz, 1H), 7.98 (d, J = 8.10 Hz, 2H), 7.55-7.42 (m, 3H). C NMR
(75 MHz, CDCl3): δ 167.5, 164.9, 152.0, 148.8, 137.6, 134.7, 129.5, 129.1, 128.2, 126.3, 124.0, .
HRMS (EI): calcd for C13H8ClN3S: 273.0127, found: 273.0132
2-(4-chlorophenyl)-5-o-tolyl-1,3,4-thiadiazole (Table 2, 3n)
o
1
White solid, m.p. 134-135 C, 106 mg, yield 74 %, H NMR (300 MHz, CDCl3): δ 7.98 (d, J =
8.46 Hz, 2H), 7.73 (d, J = 7.53 Hz, 1H), 7.49 (d, J = 8.49 Hz, 2H), 7.44-7.28 (m, 3H), 2.64 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 167.6, 167.3, 137.3, 137.1, 131.6, 130.7, 130.5, 129.4,
129.1, 129.0, 128.6, 126.3, 21.6. HRMS (EI): calcd for C15H11ClN2S: 286.0331, found: 286.0353
14
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
4-(5-phenyl-1,3,4-thiadiazol-2-yl)benzonitrile (Table 2, 3o)
5
6
7
N
N
8
9
CN
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
White solid, m.p. 210-211 C, 64 mg, yield 49 %, H NMR (300 MHz, CDCl3): δ 8.14 (d, J =
13
8.28 Hz, 2H), 8.07-7.96 (m, 2H), 7.79 (d, J = 8.49 Hz, 2H), 7.59-7.45 (m, 3H). C NMR (75
MHz, CDCl3): δ 169.4, 165.9, 134.1, 132.9, 131.6, 129.6, 129.3, 128.3, 128.1, 127.9, 118.0,
114.4. HRMS (EI): calcd for C15H9N3S: 263.0517, found: 263.0523
2-phenyl-5-(3-(trifluoromethyl)phenyl)-1,3,4-thiadiazole (Table 2, 3p)
o
1
White solid, m.p. 125-127 C, 121 mg, yield 79 %, H NMR (300 MHz, CDCl3): δ 8.28 (s, 1H),
8.22 (d, J = 7.92 Hz, 1H), 8.08-7.94 (m, 2H), 7.77 (d, J = 7.92 Hz, 1H), 7.65 (t, J = 7.71 Hz,
1H), 7.58-7.41 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 168.8, 166.4, 132.0, 131.5, 131.4, 131.1,
130.9, 129.8, 129.83, 129.29, 129.19, 128.0, 127.9, 127.6, 127.5, 125.4, 124.7, 124.70, 124.6,
124.5, 121.8. HRMS (EI): calcd for C15H9F3N2S: 306.0439, found: 306.0412.
2-(4-chlorophenyl)-5-(pyridin-2-yl)-1,3,4-thiadiazole (Table 2, 3r)
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
o
1
3
White solid, m.p. 203-205 C, 53 mg, yield 39 %, H NMR (300 MHz, CDCl3): δ 8.67 (d, J =
4.53 Hz, 1H), 8.39 (d, J = 7.89 Hz, 1H), 7.99 (d, J = 8.46 Hz, 2H), 7.88 (t, J = 7.35 Hz, 1H), 7.49
(d, J = 8.49 Hz, 2H), 7.41 (t, J = 5.28 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 170.2, 168.7,
149.8, 149.0, 137.3, 137.2, 129.4, 129.1, 128.7, 125.4, 121.0 . HRMS (EI): calcd for
C13H8ClN3S: 273.0127, found: 273.0119
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(biphenyl-2-yl)-5-phenyl-1,3,4-thiadiazole (Table 2, 3s)
1
Colorless viscous liquid, 37 mg, yield 24 %, H NMR (300 MHz, CDCl3): δ 8.19-8.11 (m, 1H),
7.85-7.75 (m, 2H), 7.58-7.47 (m, 3H), 7.44-7.35 (m, 7H), 7.33-7.27 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 169.5, 166.8, 141.9, 139.7, 130.8, 130.3, 130.1, 130.0, 129.8, 129.0, 128.6, 128.2,
127.9, 127.7. HRMS (EI): calcd for C20H14N2S: 314.0878, found: 314.0880
General procedure for one-pot sequential C-H arylation-Suzuki coupling of 1,3,4-
thiadiazole.
Synthesis of 2-(4’-methylbiphenyl-4-yl)-5-phenyl-1,3,4-thiadiazole (Table 3, 5a)
1a (81 mg, 0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), Xantphos (28.9 mg, 0.05 mmol),
Cs2CO3 (326 mg, 1.0 mmol) and CuI (9.5 mg, 0.05 mmol) were taken in a 10 mL oven-dried
screw-cap vial and 2a (178 mg, 0.75 mmol), 1,4-Dioxane (1.5 mL) were added to it. The reaction
o
tube was evacuated-backfilled with argon (5 cycles), sealed and subsequently heated at 105 C
for 12h. After completion of the reaction (confirmed by mass and TLC analysis), Pd(OAc)2 (5.6
16
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
mg, 0.025 mmol), S-phos (20.5 mg, 0.05 mmol), K3PO4 (212.2 mg, 1 mmol), p-tolylboronic acid
5
6
o
4 (102 mg, 0.75 mmol), and THF:water (3:1) 2 mL was added and heated at 105 C for 8h.
7
8
9
Subsequently, the reaction mixture was poured into water (50 mL) and extracted with ethyl
acetate (2x50 mL). The combined organic layer was washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was subjected to silica gel column
chromatography (using 5-10 % EtOAc in heptane as eluant) to afford 5a as a white solid (95 mg,
58% yield),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
1
White solid, m.p. 178-180 C, 95 mg, yield 58 %, H NMR (300 MHz, CDCl3): δ 8.07 (d, J =
8.28 Hz, 2H), 8.05-7.97 (m, 2H), 7.71 (d, J = 8.10 Hz, 2H), 7.55 (d, J = 7.92 Hz, 2H), 7.53-7.45
13
(m, 3H), 7.29 (d, J = 7.89 Hz, 2H), 2.41 (s, 3H). C NMR (75 MHz, CDCl3): δ 167.98, 167.94,
143.8, 138.0, 136.9, 131.1, 130.2, 129.7, 129.2, 128.7, 128.3, 127.9, 127.5, 126.9, 21.1. HRMS
(EI): calcd for C21H16N2S: 328.1034, found: 328.1037
The above procedure was also used for synthesis of 5b (Table 3).
2-(4’-methylbiphenyl-4-yl)-5-o-tolyl-1,3,4-thiadiazole (Table 3, 5b)
N
N
S
o
1
White solid, m.p. 156-158 C, 120 mg, yield 70 %, H NMR (300 MHz, CDCl3): δ 8.09 (d, J =
8.10 Hz, 2H), 7.80-7.66 (m, 3H), 7.56 (d, J = 7.92 Hz, 2H), 7.45-7.31 (m, 3H), 7.29 (d, J = 7.71
13
Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H). C NMR (75 MHz, CDCl3): δ 168.4, 167.2, 143.7, 138.0,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
3
4
5
6
137.3, 136.9, 131.6, 130.7, 130.3, 129.6, 129.2, 128.6, 128.3, 127.5, 126.9, 126.2, 21.7, 21.1.
HRMS (EI): calcd for C22H18N2S: 342.1191, found: 342.1203
7
8
9
Acknowledgements
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The authors wish to thank the F.W.O. [Fund for Scientific Research - Flanders (Belgium)] and
the Research Fund of the University of Leuven (KU Leuven) for financial support. D.D.V. is
grateful to EMECW13 (Erasmus Mundus External Cooperation Window Lot 13) for obtaining a
doctoral scholarship. A.S. is thankful to the F.W.O. for obtaining a Visiting Postdoctoral
Fellowship.
Supporting information
General experimental details and spectroscopic data of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Koezen, J. E. M.; Timmerman, H.; Vollinga, R. C.; Kunzel, J. F. V. D.; Groote, M. D.;
Visser, S.; Ijzerman, A. P. J. Med. Chem. 2001, 44, 749. (b) Rao, A. U.; Shao, N.; Aslanian, R.
G.; Chan, T. Y.; Degrado, S. J.; Wang, L.; McKittrick, B.; Senior, M.; West, R. E.; Williams, S.
M.; Wu, R.-L.; Hwa, J.; Patel, B.; Zheng, S.; Sondey, C.; Palani, A. ACS Med. Chem. Lett. ,
dx.doi.org/10.1021/ml200250t. (c) Lee, J.; Han Lee, S.; Jeong Seo, H.; Jung Son, E.; Lee, S. H.;
Jung, M. E.; Lee, M.W.; Han, H. K.; Kim, J.; Kang, J.; Lee, J. Bioorg. Med. Chem. 2010, 18
2178. (d) Clerici, F.; Pocar, D. J. Med. Chem. 2001, 44, 931. (e) Wei, M. X.; Feng, L.; Qiang Li,
X.; Zhang Zhou, X.; Shao, Z. H. Eur. J. Med. Chem. 2009, 44, 3340.
(2) (a) Ying, L.; Hsu, B. B.; Zhan, H.; Welch, G. C.; Zalar, P.; Perez, L. A.; Kramer, E.
J.; Nguyen, T. Q.; Heeger, A. J.; Wong, W. Y.; Bazan, G. C. J. Am. Chem. Soc. 2011, 133,
18
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
18538. (b) Yi, H.; Faifi, S. A.; Iraqi, A.; Watters, D. C.; Kingsley, J.; Lidzey, D. G. J. Mater.
5
6
Chem. 2011, 21, 13649.
7
8
9
(3) Katrizky, A. R.; Nachef, C. E.; Bajaj, K.; Kubik, J.; Haase, D. N. J. Org. Chem. 2010, 75,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6009.
(4) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,174. (b) Daugulis, O.; Do,
H. Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (c) Ackermann, L.; Vicente, R.; Kapdi, A.
R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 3850.
(5) Selected examples: (a) Kawano, T.; Yoshizumi, T.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2009, 11, 3072. (b) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J. E. Org.
Lett. 2010, 12, 3578. (c) Roy, D.; Mom, A.; Beauperin, M.; Doucet, H.; Hierso, J.-S. Angew.
Chem., Int. Ed. 2010, 49, 6459. (d) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130,
2926.
(6) (a) Bryan, S.; Braunger, J. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 121, 7198. (b)
Fernández-Rodríguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180.
(7) (a) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem. Int. Ed. 2007, 46, 7996. (b)
Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D.; Faul, M. M. J Am
Chem Soc. 2010, 132, 3674. (c) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You,
J. Angew. Chem. Int. Ed. 2009, 48, 3296. (d) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826. (e) Yang, F.; Xu, Z.; Wang, Z.; Yu, Z.; Wang R.
Chem. Eur. J. 2011, 17, 6321.
(8) (a) Beryozkina, T.; Appukkuttan, P.; Mont, N.; Van der Eycken, E. Org. Lett. 2006, 8, 487.
(b) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Chem. Eur. J. 2007, 13, 6452. (c) Mont,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
9
N.; Mehta V. P.; Appukkuttan, P.; Beryozkina, T.; Toppet, S.; Van Hecke, K.; Meervelt, L. V.;
Voet, A.; De Maeyer, M.; Van der Eycken, E. J. Org. Chem. 2008, 73, 7509. (d) Sharma, A.;
Vachhani, D.; Van der Eycken, E. Org. Lett. 2012, 14, 1854.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. (b) Gorelsky, S.
I.; Lapointe, D,; Fagnou, K. J. Org. Chem. 2012, 77, 658.
(10) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
(11) (a) Steel, P. J. Aromatic biheterocycles: syntheses, structures, and properties. Adv.
Heterocycl. Chem. 1996, 67, 1–117. and references therein, (b) Zhao, D.; You, J.; Hu, C. Chem.
Eur. J. 2011, 17, 5466.
(12) A similar reaction but without using Pd(OAc)2 in the second step led to a considerably
lower yield (10 %) of 5a.
(13) (a) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.; Larsen, R. D. J. Am. Chem.
Soc. 2010, 132, 3674. (b) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379.
(14) Gierczyk, B.; Zalas, M. Org. Prep. Proc. Int. 2005, 37, 213-222.
20
ACS Paragon Plus Environment