Novel and efficient cyclization procedure for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles without using any ring-closing reagents

Article abstract of DOI:10.1080/00397911.2010.548891

A novel method for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles via direct ring closure of 1,6-disubstituted-2,5-dithioureas in dimethylformanide without using any ring-closing reagents has been accidentally discovered. Repeated and extended experiments confirmed that this is a very simple and efficient way to synthesize these kinds of fine chemicals. A series of novel 2,5-disubstituted-1,3,4-thiadiazoles have been synthesized via this method in good yields.

Full text of DOI:10.1080/00397911.2010.548891

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Novel and Efficient Cyclization
Procedure for the Synthesis of 2,5-
Disubstituted-1,3,4-thiadiazoles Without
Using Any Ring-Closing Reagents
Qi Lin a , You-Ming Zhang a , Man-Lin Li a & Tai-Bao Wei a
a Key Laboratory of Eco-environment-Related Polymer Materials,
Ministry of Education of China, Gansu Key Laboratory of Polymer
Materials, College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu, China
Accepted author version posted online: 08 May 2012. Version of
record first published: 18 Jul 2012
To cite this article: Qi Lin, You-Ming Zhang, Man-Lin Li & Tai-Bao Wei (2012): Novel and Efficient
Cyclization Procedure for the Synthesis of 2,5-Disubstituted-1,3,4-thiadiazoles Without Using Any
Ring-Closing Reagents, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:22, 3251-3260
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Synthetic Communications1, 42: 3251–3260, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.548891
NOVEL AND EFFICIENT CYCLIZATION PROCEDURE
FOR THE SYNTHESIS OF 2,5-DISUBSTITUTED-1,3,4-
THIADIAZOLES WITHOUT USING ANY RING-CLOSING
REAGENTS
Qi Lin, You-Ming Zhang, Man-Lin Li, and Tai-Bao Wei
Key Laboratory of Eco-environment-Related Polymer Materials, Ministry of
Education of China, Gansu Key Laboratory of Polymer Materials, College of
Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu, China
GRAPHICAL ABSTRACT
Abstract A novel method for the synthesis of 2,5-disubstituted-1,3,4-thiadiazoles via direct
ring closure of 1,6-disubstituted-2,5-dithioureas in dimethylformanide without using any
ring-closing reagents has been accidentally discovered. Repeated and extended experiments
confirmed that this is a very simple and efficient way to synthesize these kinds of fine
chemicals. A series of novel 2,5-disubstituted-1,3,4-thiadiazoles have been synthesized via
this method in good yields.
Keywords 2,5-Dithiobiurea; microwave-assisted synthesis; ring-closure; 1,3,4-thiadiazole
INTRODUCTION
Substituted 1,3,4-thiadiazoles have attracted significant interest in medicinal
chemistry because they have a wide range of pharmaceutical and biological activities,
including anticancer,[1] anti-HIV,[2] antitubercular,[3] antimicrobial,[4] antifungal,[5]
anti-inflammatory,[6] anticonvulsant,[7] and antihypertensive[8] activities. In addition,
1,3,4-thiadiazoles have become very useful compounds in many fields of technology
Received September 9, 2010.
Address correspondence to Tai-Bao Wei, Gansu Key Laboratory of Polymer Materials, College of
Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, Gansu, China.
E-mail: weitaibao@126.com
3251

3252
Q. LIN ET AL.
such as lubricating compositions,[9] dyes,[10] liquid-crystalline materials,[11] and
optical materials.[12] Therefore, the development of efficient methods for the
synthesis of 1,3,4-thiadiazoles is an important issue.
Since Guha[13] reported the ring closure of hydrazodithio-dicarbonamide (viz.
2,5-dithiobiurea) to produce 1,3,4-thiadiazoles in 1922, a variety of methods for the
preparation of 1,3,4-thiadiazoles have been developed.[14] For example, the cycliza-
tion of a 1,2-diacylhydrazine or its thia analog in the presence of coupling reagents
is the most common procedure for the synthesis of 1,3,4-thiadiazoles.[14] However,
the classical synthesis of 1,3,4-thiadiazoles usually involves rather harsh reaction
conditions and employ phosgene=thiophosgene,[14,15] thionyl chloride,[15] phosphorus
oxychloride,[16] acetic anhydride,[13] phosphorus pentasulfide,[17] or sulfuric acid[3] as
ring-closing reagents. Although a number of groups have developed alternative
milder cyclization procedures for the synthesis of thiadiazoles recently,[18–21] which
often use relatively uncommon or sophisticated ring-closing reagents such as pro-
pylphosphonic anhydride(T3P),[18] phosphorus pentasulfide in alumina (P4S10=
Al2O3),[19] Lawesson’s reagent,[20] and disulfur dichloride.[22] In view of this and
because we are interested in the synthesis of organic functional compounds,[23–25]
we want to develop a convenient and efficient procedure to synthesize 1,3,4-thiadia-
zoles without using potentially problematic reagents and nongeneral conditions.
In our previous works,[24] when we recrystallized 1,6-diethoxycarbonyl-2,5-
dithiourea (DTU 1) in dimethylformamide (DMF), the hot solution of the DTU 1
emitted H2S gas unexpectedly, which indicated that the DTU 1 had some unexpected
reactions under these conditions. After carefully analyzing the product of this unex-
pected result, we found that the DTU 1 underwent a ring-closure reaction and
yielded 2,5-diethoxycarbonylamino-1,3,4-thiadiazole (DTZ 1), which was confirmed
by single-crystal x-ray analysis.[24] This is an exciting accidental discovery, as the
Scheme 1. Reagents and conditions: (i) BTC, 40 ꢀC, 3 h; (ii) KSCN, CH2Cl2, PEG-400, rt, 4 h; (iii) 85%
NH2NH2 ꢁ H2O, rt, 4 h; and (iv) DMF, reflux 0.5–1 h or MWI 5–10 min.

THIADIAZOLE SYNTHESIS WITHOUT RING-CLOSING REAGENT
3253
Table 1. Molecular structures of DTZ 1–14
Entry
Compound
DTZ 1
DTZ 2
DTZ 3
DTZ 4
DTZ 5
DTZ 6
DTZ 7
DTZ 8
DTZ 9
DTZ 10
DTZ 11
DTZ 12
DTZ 13
DTZ 14

3254
Q. LIN ET AL.
1,6-diethoxycarbonyl-2,5-dithioureas could cyclized to 2,5-diethoxycarbonylamino-
1,3,4-thiadiazole without using any ring-closing reagents in refluxing DMF.
To expand this result, we investigated the cyclization abilities of other 1,6-
disubstituted-2,5-dithioureas under the same conditions. Each 1,6-disubstituted-2,5-
dithioureas (DTU 1-14, as shown in Scheme 1) could cyclized into the corresponding
2,5-disubstituted-1,3,4-thiadiazoles (DTZ 1-14, Scheme 1 and Table 1) in refluxing
DMF without using any ring-closing reagents. It is worth mentioning that DTU
1–13 are 1,6-diacylsubstituted-2,5-dithioureas but DTU 14 is a 1,6-diarylsubstituted-
2,5-dithiourea, which indicated that this novel cyclization procedure is applicable not
only for the preparation of 2,5-diacylamidosubstituted-1,3,4-thiadiazoles but also for
2,5-diarylaminosubstituted-1,3,4-thiadiazoles.
In addition, we also investigated this method under microwave irradiation
(MWI) conditions and found MWI could obviously promote these cyclization
reactions. For example, the cyclization reactions need 30–60 min under reflux
conditions in oil bath but only need 5–10 min under MWI conditions. Moreover,
the substituted groups showed direct influence on the reaction times; for example,
electron-withdrawing groups such as substituted dithioureas (such as DTU 8 and 9)
need longer reaction times. For instance, DTU 8 and 9 need ca. 10 min under MWI
conditions, whereas the DTU 1 or 2 only need ca. 5 min under the same conditions.
1
The cyclization processes of DTU to DTZ were confirmed by H NMR. As
shown in Fig. 1, before the cyclization, owing to its molecular structure, DTU 13
1
formed six-membered intermolecular hydrogen bonds.[25] The H NMR chemical
Figure 1. 1H NMR spectra of DTU and DTZ. From bottom to top are DTU 13, DTZ 13, DTU 14, and
DTZ 14, respectively.

THIADIAZOLE SYNTHESIS WITHOUT RING-CLOSING REAGENT
3255
shifts of the N–Hb appeared in low field at 14.01 ppm; however, the N–Ha appeared
at 12.03 ppm. After DTU 13 was refluxed in DMF under MWI for 5 min, N–Hb pro-
tons underwent a de-H2S process, the resonances for N–Hb disappeared, and the
resonances for N–Ha shifted to 12.74 ppm, which confirmed that the DTU 13 under-
1
went a ring-closure process and formed DTZ 13. Similarly, the H NMR chemical
shifts of the N–Hb and N–Ha protons on DTU 14 were at 9.88 and 9.68 ppm, respect-
ively. After DTU 14 was refleuxed in DMF for 5 min under MWI, the resonances for
N–Hb disappeared, and the resonances for N–Ha shifted to 9.86 ppm, which
confirmed that the DTU 14 underwent a ring-closing process and formed DTZ 14.
CONCLUSION
In conclusion, a novel method for the synthesis of 2,5-disubstituted-1,3,4-
thiadiazoles without using any ring-closing reagents has been developed. This
method has the following merits: First, the intermediates are easy to synthesize
and do not need purification; second, the cyclization procedure does not need any
ring-closing reagents, and classical ring-closing reagents are often noxious, corrosive,
uncommon, or sophisticated reagents; and finally, this cyclization reaction is very
efficient, needing only a few minutes to yield the thiadiazoles in good to excellent
yields. Therefore, this methodology could act as a very efficient general procedure
for the preparation of a wide range of symmetrical 2,5-disubstituted-1,3,4-
thiadiazoles derivatives. On the other hand, if the 1,6-positions of dithioureas were
substituted with different groups, the cyclization product of the dithioureas are
unsymmetrical 2,5-disubstituted-1,3,4-thiadiazoles.
EXPERIMENTAL
Melting points were measured on an X-4 digital melting-point apparatus
(uncorrected). 1H and 13C NMR spectra were recorded with a Mercury-400BB
1
spectrometer at 400 and 100 MHz respectively. H chemical shifts are reported in
parts per million (ppm) downfield from tetramethylsilane (TMS, d scale) with the
solvent resonances as internal standards. All NMR spectra were referenced to
solvent. The infrared (IR) spectra were performed on a Digilab FTS-3000 Fourier
transform (FT)–IR spectrophotometer. All reagents were commercially available
and were used as received unless otherwise stated.
The synthesis route is showed in Scheme 1. DTU 1 and 2 were synthesized
according to a similar method, which we reported previously.[23e,24a] DTU 3–13 were
synthesized in three steps starting from substituted-benzoic acid. DTU 14 was
synthesized via the reaction of phenyl isothiocyanate with hydrazine.
General Procedure for DTU 3-13
Reacting 3 mmol of substituted-benzoic acid with 1.5 mmol of triphosgene
(BTC) in 10 mL CH2Cl2 using 0.05 mL DMF as catalyst at 40 ꢀC for 3 h gave the
corresponding substituted benzoyl chloride, which did not need separation. Then
we added 4 mmol drying powdered KSCN and 0.1 mL PEG-400 into the reaction
solution, stirred it at room temperature for 3 h, and filtered out the inorganic salts.

3256
Q. LIN ET AL.
The filtrate is the solution of corresponding substituted benzoyl isothiocyanate,
which did not need separation. We added 1.4 mmol of 85% hydrazine into the filtrate
solution and stirred it in room temperature for 1 h, which yielded the precipitate of
corresponding DTU.
General Procedure for DTU 14
Reacting 1.5 mmol of 85% hydrazine with 3 mmol of phenyl isothiocyanate in
10 mL CH2Cl2 at room temperature for 3 h yielded the precipitate of DTU 14.
General Procedure for DTZ 1–14
The DTU 1–14 did not need purification. We refluxed 2 mmol of DTU 1–14 in
3 mL DMF for 0.5–1 h or refluxed it under MWI for 5–10 min, poured the solution
into 5 mL H2O to yield the precipitate of corresponding DTZ 1–14, and recrystal-
lized them in DMF-EtOH to obtain pure products.
2,5-Diethoxylcarbonylamino-1,3,4-thiadiazole (DTZ 1). Yield 97%
mp > 300 ꢀC; 1H NMR (200 Hz, DMSO-d6): d ¼ 11.73 (s, 2H, NH), 4.18 (q,
J ¼ 7.2 Hz, 4H, CH2), 1.23 (t, J ¼ 7.0 Hz, 6H, CH3); IR (KBr): 3423, 3139, 1717,
1582, 1542, 1484, 1238, 1237, 765 cmꢂ1. Anal. calcd. for C8H12N4O4S: C, 36.92;
H, 4.65; N, 21.53. Found: C, 36.97; H, 4.43; N, 21.29.
2,5-Dibenzamido-1,3,4-thiadiazole (DTZ 2). Yield 85% mp > 300 ꢀC; 1H
NMR (400 Hz, DMSO-d6): d ¼ 12.75 (s, 2H, NH), 8.11–8.13 (m, 4H, ArH),
7.64–7.66 (m, 2H, ArH), 7.53–7.63 (m, 4H, ArH); 13C NMR (DMSO-d6):
d ¼ 164.99, 156.01, 132.85, 131.70, 128.67, 128.37; IR (KBr): 3472, 3115, 1670,
1554, 1445, 1311, 1251, 694 cmꢂ1; Anal. calcd. for C16H12N4O2S: C, 59.25; H,
3.73; N, 17.27. Found: C, 59.51; H, 3.61; N, 17.30.
2,5-Bis(2-chlorobenzamido)-1,3,4-thiadiazole (DTZ 3). Yield 82%; mp
1
292–294 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.93 (s, 2H, NH), 7.46–7.70 (m,
8H, ArH); 13C NMR (DMSO-d6): d ¼ 164.82, 154.98, 133.98, 132.16, 130.37,
129.87, 129.57, 127.30; IR (KBr): 3382, 3141, 1683, 1561, 1510, 1434, 1308,
733 cmꢂ1. Anal. calcd. for C16H10Cl2N4O2S: C, 48.87; H, 2.56; N, 14.25. Found:
C, 48.67; H, 2.29; N, 14.35.
2,5-Bis(3-chlorobenzamido)-1,3,4-thiadiazole (DTZ 4). Yield 85%; mp
1
296–298 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.92 (s, 2H, NH), 8.09–8.20 (m,
2H, ArH), 8.08 (dd, J ¼ 4.8, 1.6 Hz, 2H, ArH), 7.72–7.75 (m, 2H, ArH), 7.59–7.63
(m, 2H, ArH); 13C NMR (100 Hz, DMSO-d6): d ¼ 163.76, 155.89, 133.70, 133.44,
132.57, 130.60, 128.13, 127.10. IR (KBr): 3414, 3149, 1669, 1558, 1523, 1433,
1309, 1245, 1083, 670 cmꢂ1. Anal. calcd. for C16H10Cl2N4O2S: C, 48.87; H, 2.56;
N, 14.25. Found: C, 49.10; H, 2.41; N, 14.38.
2,5-Bis(4-chlorobenzamido)-1,3,4-thiadiazole (DTZ 5). Yield 81%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.87 (s, 2H, NH), 8.13–8.16 (m,
3H, ArH), 7.96–8.02 (m, 1H, ArH), 7.60–7.67 (m, 4H, ArH); 13C NMR (100 Hz,
DMSO-d6): d ¼ 162.31, 152.82, 137.41, 130.39, 130.29, 129.45, 128.16, 128.73; IR

THIADIAZOLE SYNTHESIS WITHOUT RING-CLOSING REAGENT
3257
(KBr): 3453, 3176, 1668, 1559, 1530, 1444, 1310, 1247, 1088, 667 cmꢂ1. Anal. calcd.
for C16H10Cl2N4O2S: C, 48.87; H, 2.56; N, 14.25. Found: C, 48.94; H, 2.37; N, 14.13.
2,5-Bis(4-iodobenzamido)-1,3,4-thiadiazole
(DTZ
6). Yield
85%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.82 (s, 2H, NH), 7.68–7.97 (m,
8H, ArH); 13C NMR (100 Hz, DMSO-d6): d ¼ 162.31, 152.82, 138.18, 137.60,
137.56, 130.21, 129.62, 128.67; IR (KBr): 3453, 3093, 1669, 1566, 1443, 1315,
1258, 1097, 684 cmꢂ1. Anal. calcd. for C16H10I2N4O2S: C, 33.35; H, 1.75; N, 9.72.
Found: C, 33.62; H, 1.75; N, 9.79.
2,5-Bis(4-bromobenzamido)-1,3,4-thiadiazole (DTZ 7). Yield 87%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.90 (s, 2H, NH), 8.00–8.06 (m,
4H, ArH), 7.71–7.78 (m, 4H, ArH); IR (KBr): 3452, 3097, 1670, 1566, 1444, 1315,
1255, 1084, 679 cmꢂ1. Anal. calcd. for C16H10Br2N4O2S: C, 39.86; H, 2.09; N,
11.62. Found: C, 39.91; H, 1.86; N, 11.52.
2,5-Bis(3-fluorobenzamido)-1,3,4-thiadiazole (DTZ 8). Yield 80%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.91 (s, 2H, NH), 7.94–8.01 (m,
2H, ArH), 7.83, (d, J ¼ 9.2 Hz, 1H, ArH), 7.39–7.67 (m, 5H, ArH); IR (KBr):
3446, 3121, 3086, 1665, 1574, 1525, 1475, 1318, 1251, 1107, 741 cmꢂ1. Anal. calcd.
for C16H10F2N4O2S: C, 53.33; H, 2.80; N, 15.55. Found: C, 53.19; H, 2.61; N, 15.71.
2,5-Bis(4-fluorobenzamido)-1,3,4-thiadiazole (DTZ 9). Yield 85%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.82 (s, 2H, NH), 8.22 (s, 4H,
ArH), 7.42 (s, 4H, ArH); IR (KBr): 3457, 3077, 1675, 1582, 1504, 1313, 1238,
1150, 1093, 676 cmꢂ1. Anal. calcd. for C16H10F2N4O2S: C, 53.33; H, 2.80; N,
15.55. Found: C, 53.15; H, 2.56; N 15.63.
2,5-Bis(4-methylbenzamido)-1,3,4-thiadiazole (DTZ 10). Yield 86%;
mp > 300 ꢀC; 1H NMR (400 Hz, DMSO-d6): d ¼ 12.64 (s, 2H, NH), 8.00 (d,
J ¼ 8.0 Hz, 4H, ArH), 7.35 (d, J ¼ 8.0 Hz, 4H, ArH), 2.38 (s, 6H, CH3); 13C NMR
(100 Hz, DMSO-d6): d ¼ 166.91, 152.50, 143.20, 129.26, 128.87, 128.40, 21.61; IR
(KBr): 3449, 3158, 1666, 1607, 1564, 1505, 1449, 1302, 1256, 1084, 681 cmꢂ1; Anal.
calcd. for C18H16N4O2S: C, 61.35; H, 4.58; N, 15.90. Found: C, 61.40; H, 4.43; N,
16.07.
2,5-Bis(4-ethoxybenzamido)-1,3,4-thiadiazole (DTZ 11). Yield 89%;
mp > 300 ꢀC; 1H NMR (400 Hz, DMSO-d6): d ¼ 12.50 (s, 2H, NH), 8.09 (d,
J ¼ 8.0 Hz, 4H, ArH), 7.05 (d, J ¼ 8.4 Hz, 4H, ArH), 4.10 (q, J ¼ 6.8 Hz, 4H,
CH2), 1.34 (t, J ¼ 7.2 Hz, 6H, CH3); IR (KBr): 3460, 3119, 1667, 1594, 1509, 1312,
1245, 1039, 681 cmꢂ1. Anal. calcd. for C20H20N4O4S: C, 58.24; H, 4.89; N, 13.58.
Found: C, 58.06; H, 4.68; N, 13.49.
Bis(1-naphthamido)-1,3,4-thiadiazole (DTZ 12). Yield 87%; Mp > 300 ꢀC;
1H NMR (400 Hz, DMSO-d6): d ¼ 13.00 (s, 2H, NH), 8.32 (d, J ¼ 8.0 Hz, 2H,
ArH), 8.15 (d, J ¼ 8.0 Hz, 2H, ArH), 8.05 (d, 2H, J ¼ 7.2 Hz, ArH), 7.96 (d,
J ¼ 6.4 Hz, 2H, ArH), 7.60–7.68 (m, 6H, ArH); 13C NMR (100 Hz, DMSO-d6):
d ¼ 166.87, 155.53, 133.21, 131.63, 130.98, 129.85, 128.55, 127.52, 127.24, 126.61,
124.99, 124.95; IR (KBr): 3450, 3150, 1647, 1558, 1510, 1505, 1379, 1295, 1093,

3258
Q. LIN ET AL.
651 cmꢂ1. Anal. calcd. for C24H16N4O2S: C, 67.91; H, 3.80; N, 13.20. Found: C,
67.83; H, 3.64; N 13.49.
2,5-Bis(Furan-2-carboxamido)-1,3,4-thiadiazole (DTZ 13). Yield 81%;
1
mp > 300 ꢀC; H NMR (400 Hz, DMSO-d6): d ¼ 12.74 (s, 2H, NH), 7.95–8.05 (m,
2H, furan-H), 7.69, (d, J ¼ 3.6 Hz, furan-H), 6.77 (dd, J ¼ 1.6, 2.0 Hz, 2H, furan-H);
13C NMR (100 Hz, DMSO-d6): d ¼ 162.32, 155.26, 147.53, 145.35, 117.12, 112.45; IR
(KBr): 3447, 3132, 3004, 1676, 1590, 1532, 1491, 1449, 1316, 1269, 836, 735, 678 cmꢂ
1. Anal. calcd. for C12H8N4O4S: C, 47.37; H, 2.65; N, 18.41. Found: C, 47.59; H,
2.87; N, 18.24.
2,5-Diphenylamino-1,3,4-thiadiazole
(DTZ
14). Yield
95%;
mp
253–255 ꢀC; 1H NMR (400 Hz, DMSO-d6): d ¼ 9.86 (s, 2H, NH), 7.55–7.57 (m,
4H, ArH), 7.31 (t, J ¼ 7.6 Hz, 4H, ArH), 6.93 (td, J ¼ 7.2, 1.2 Hz, 2H, ArH); 13C
NMR (100 Hz, DMSO-d6): d ¼ 155.67, 141.19, 128.97, 121.01, 116.78; IR (KBr):
3230, 3187, 3028, 1603, 1550, 1482, 1443, 1312, 1252, 746, 692 cmꢂ1. Anal. calcd.
for C14H12N4S: C, 62.66; H, 4.51; N, 20.88. Found: C, 62.40; H, 4.74; N, 20.76.
ACKNOWLEDGMENTS
This work was supported by the NSFC (Nos. 21064006, 21161018) and Gansu
Natural Science Foundation (No. 1010RJZA018).
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