Highly efficient method for the synthesis of 1,4-phenylenedithioureas under solvent- and catalyst-free conditions promoted by microwave irridiation

Article abstract of DOI:10.1080/00397911.2010.535941

A highly efficient method for the synthesis of 1,4-phenylenedithioureas promoted by microwave irridiation is reported. It is based on the nucleophilic addition reaction of 1,4-phenylenediisothiocyanate to aromatic amines under solvent- and catalyst-free conditions. The reaction has the advantages of short reaction time, good yields, and environmental acceptability. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.535941

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Highly Efficient Method for the Synthesis
of 1,4-Phenylenedithioureas Under
Solvent- and Catalyst-Free Conditions
Promoted by Microwave Irridiation
Li-Ping Zhang a , Xiao-Bo Shang a , Qing-Fen Wu a , Yang Zhang a
Jian-Ping Li a
a Key Laboratory for Yellow River and Huaihe River Water
&
Environment and Pollution Control, Ministry of Education, Henan
Key Laboratory of Environmental Pollution Control, Henan Normal
University, Xinxiang, China
Accepted author version posted online: 06 Sep 2011.Published
online: 16 Dec 2011.
To cite this article: Li-Ping Zhang , Xiao-Bo Shang , Qing-Fen Wu , Yang Zhang & Jian-Ping Li (2012):
Highly Efficient Method for the Synthesis of 1,4-Phenylenedithioureas Under Solvent- and Catalyst-
Free Conditions Promoted by Microwave Irridiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:7, 1045-1052
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Synthetic Communications1, 42: 1045–1052, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.535941
HIGHLY EFFICIENT METHOD FOR THE SYNTHESIS OF
1,4-PHENYLENEDITHIOUREAS UNDER SOLVENT- AND
CATALYST-FREE CONDITIONS PROMOTED BY
MICROWAVE IRRIDIATION
Li-Ping Zhang, Xiao-Bo Shang, Qing-Fen Wu, Yang Zhang,
and Jian-Ping Li
Key Laboratory for Yellow River and Huaihe River Water Environment and
Pollution Control, Ministry of Education, Henan Key Laboratory of
Environmental Pollution Control, Henan Normal University, Xinxiang,
China
GRAPHICAL ABSTRACT
Abstract A highly efficient method for the synthesis of 1,4-phenylenedithioureas promoted
by microwave irridiation is reported. It is based on the nucleophilic addition reaction of
1,4-phenylenediisothiocyanate to aromatic amines under solvent- and catalyst-free con-
ditions. The reaction has the advantages of short reaction time, good yields, and environ-
mental acceptability.
Keywords Microwave irradiation; 1,4-phenylenediisothiocyanate; 1,4-phenylene-
dithioureas; solvent- and catalyst-free conditions
INTRODUCTION
Thioureas have attracted much attention by virtue of their bioactivities as
pharmaceuticals and pesticides. Various thiourea derivatives and their metal com-
plexes exhibit analgesic,[1] anti-HIV,[2] anti-viral,[3] analgesic,[4] and antinociceptive
Received January 20, 2010.
Address correspondence to Jian-Ping Li, Key Laboratory for Yellow River and Huaihe River
Water Environment and Pollution Control, Ministry of Education, Henan Key Laboratory of
Environmental Pollution Control, Henan Normal University, Xinxiang 453007, China. E-mail: jplig@
163.com
1045

1046
L.-P. ZHANG ET AL.
activity.[5] Recently, the activity of bisthioureas againt several representative
pathogenic bacteria and fungi was investigated.[6] It can act as an organocatalyst[7,8]
and bind anions by formation of multiple hydrogen bonds.[9] Until now, several
methods for the preparation of phenylenedithioureas have been proposed.[10–14]
The classical method for the preparation of phenylenedithioureas always involves
many drawbacks and limitations such as poor yields, harsh reaction conditions,[15]
and toxic reagents.[13,16,17] Therefore, the development of efficient and high-yielding
methods for the synthesis of novel thioureas is of great importance in searching for
bioactive molecules as well as in synthetic chemistry.
Microwave (MW) irradiation has proven to be a very efficient technique to
accelerate different kinds of reactions.[17,18] The ability to rapidly heat reactions sig-
nificantly above the boiling point of the solvent has resulted in dramatic decreases in
reaction times and increases in reaction yields for a variety of chemical transforma-
tions.[19] Many of these reactions have been demonstrated to give good yields and to
shorten reaction times under MW irradiation as compared to traditional heating
methods.
RESULTS AND DISCUSSION
Based on this preliminary research, we proposed a new method by which the
synthesis of 1,4-phenylenedithioureas was carried out under solvent- and catalyst-
free conditions (Scheme 1). Greater yields and shorter reaction times were reached
under MW-assisted conditions compared with conventional heating. It has the
advantages of good yields, short reaction times, and environmental acceptability.
In our initial study, various reaction conditions including temperatures and sol-
vents were tested for the synthesis of 3a (Table 1). The reactions were carried out at
temperatures ranging from 10 ꢀC to 70 ꢀC (Table 1). It was found that the yield of 3a
was improved (93%) and the reaction time was shortened (2 min) at 60 ꢀC, whereas
the yield plateaued at 70 ꢀC (entry 6). Therefore, 60 ꢀC was chosen as the optimized
reaction temperature for all microwave-assisted reactions under study.
To compare the efficiency of MW irradiation with conventional heating proce-
dures in organic solvents, 1,4-phenylenediisothiocyanate was heated with 2 equiv of
4-methyl benzenamine in organic solvents at 60 ꢀC in an oil bath for 30 min. The
results were summarized in Table 2. It was found that MW irridiation gave the best
yield.
Scheme 1. Reactions of 1,4-phenylenediisothiocyanate with aromatic amines.

SYNTHESIS OF 1,4-PHENYLENEDITHIOUREAS
1047
Table 1. Influence of temperature and time on the reactiona
Entry
Temperature (ꢀC)
Time (min)
Yield of 3a (%)b
1
2
3
4
5
6
25
30
50
60
70
80
25
15
6
32
45
80
93
92
93
2
2
2
aThe power of MWI was 300 W.
bIsolated yield based on 1,4-phenylenediisothiocyanate.
Under the optimal MW conditions (300 W, 60 ꢀC), we then examined the
generality of the reaction by using 1,4-phenylenediisothiocyanate with a series of
aromatic amines. All the reactions proceeded smoothly to give the corresponding
1,4-phenylenedithioureas in good yields (75–93%). The results are summarized in
Table 3. A good yield was obtained when the substrates were well mixed.
The results in Table 3 show that the reaction can be favorably applied to aro-
matic amines with either electron-withdrawing groups or electron-donating groups.
Delicate electronic effects of amines on the reaction were observed: Those with
electron-donating groups reacted more rapidly and gave better yields (entries 1, 2,
Table 2. Solvent effects on the reactiona of 1 with 2a
Entry
1
Amine
Solvent
Time (min)
30
Yield of 3a (%)b
THF
55
2
3
4
EtOH
30
30
2
85
71
93
CH3COOEt
MW
aMaterials were heated up to 60 ꢀC in organic solvents.
bIsolated yield based on 1,4-phenylenediisothiocyanate.

1048
L.-P. ZHANG ET AL.
Table 3. The reactions between 1,4-phenylenediisothiocyanate and aromatic amines under microwave
irradiationa
Entry
Amine
Product
3a
Time (min)
Yield of 3 (%)b
1
2
2
3
93
92
3b
3
4
5
3c
3d
3e
2
8
4
91
89
91
6
7
3f
3
2
92
93
3g
8
3h
2
92
9
10
11
3i
3j
3
9
1
90
84
94
3k
12
3l
18
86
aThe power of MWI was 300 W at 60 ꢀC.
bIsolated yield based on 1,4-phenylenediisothiocyanate.

SYNTHESIS OF 1,4-PHENYLENEDITHIOUREAS
1049
7, and 11), whereas those with electron-poor groups on the benzene ring (entries 4,
10, and 12) required longer reaction times and gave poorer yields.
In conclusion, the present procedure provides an efficient methodology for the
synthesis of 1,4-phenylenedithioureas. The notable advantages offered by the
method are simple operation, fast and environmentally friendly reaction conditions,
and good yields of products.
EXPERIMENTAL
The reaction was carried out in a Sineo MW reactor with a heat setting (Sineo
Microwave Chemical Technology Co. Ltd. in Shang Hai). Melting points were deter-
mined with a XRC-1 micro-melting-point apparatus and were uncorrected. 1H NMR
and 13C NMR were measured on a Bruker DPX-400 M spectrometer at 400 MHz
and 100 MHz, respectively, using tetramethylsilane (TMS) as an internal standard.
Chemical shifts (d) were expressed in parts per million (ppm) from TMS, and coup-
ling constants J are given in hertz (Hz). High-resolution mass spectra (HRMS) were
taken on a Waters Q-TofMS=MS spectrometer. Column chromatography was per-
formed using silica gel (200–300 mesh, GF254). All reactions were monitored by
thin-layer chromatography (TLC). All reagents and solvents were purchased from
commercial sources and purified before use.
General Procedure
1,4-Phenylenediisothiocyanate was synthesized according to the literature.[20]
1,4-Phenylenediisothiocyanate (1 mmol) and aromatic amines (2 mmol) were
well mixed in a mortar. The resulting mixture was then placed into the microwave
reactor and heated to 60 ꢀC (constant microwave irradiation at 300 W). The progress
of the reaction was monitored by TLC (CH2Cl2=CH3OH). After completion of the
reaction, the reacion mixture was filtrated, washed with ethanol, and purified by
column chromatography.
Characterization Data for 3
1,4-Phenylene-bis[3-(4’-methylphenyl)thiourea] (3a)[13]. White powder;
1
mp 230–232 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.68 (s, 4H, NH), 7.42 (s, 4H,
ArH), 7.35 (d, 4H, J ¼ 8.4 Hz, ArH), 7.16 (d, 4H, J ¼ 8.4 Hz, ArH), 2.29 (s, 6H,
CH3). 13C NMR (100 MHz, DMSO-d6) d 180.0, 137.2, 136.3, 134.1, 129.3, 124.3,
124.2, 20.9.
1,4-Phenylene-bis[3-(4’-methoxylphenyl)thiourea] (3b)[13]. White pow-
1
der; mp 218–220 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.55 (s, 2H, NH), 9.52 (s,
2H, NH), 7.41 (s, 4H, ArH), 7.31 (s, 4H, ArH), 6.89 (d, 4H, J ¼ 6.4 Hz, ArH),
3.73 (s, 6H, CH3). 13C NMR (100 MHz, DMSO-d6) d 180.3, 157.0, 136.3, 132.6,
126.4, 124.2, 114.1, 55.7.
1,4-Phenylene-bis[3-(4’-ethoxylphenyl)thiourea] (3c)[13]. White powder;
1
mp 226–228 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.59 (s, 2H, NH), 9.55 (s, 2H,
NH), 7.411 (s, 4H, ArH), 7.32 (d, 4H, J ¼ 8.8 Hz, ArH), 6.89 (d, 4H, J ¼ 8.8 Hz,

1050
L.-P. ZHANG ET AL.
ArH), 4.01 (q, 4H, J ¼ 6.8 Hz, CH2), 1.32 (t, 6H, J ¼ 6.8 Hz, CH3). 13C NMR
(100 MHz, DMSO-d6) d 180.3, 156.2, 136.3, 132.5, 126.3, 124.2, 114.6, 63.6, 15.1.
1,4-Phenylene-bis[3-(4’-fluorophenyl)thiourea] (3d). White powder; mp
1
232–235 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.71 (s, 4H, NH), 7.48–7.44 (dd,
4H, J1 ¼ 5.2 Hz, J2 ¼ 8.8 Hz, ArH), 7.42 (s, 4H, ArH), 7.16 (t, 4H, J ¼ 8.8 Hz,
ArH). 13C NMR (100 MHz, DMSO-d6) d 180.3, 160.8, 158.4, 136.2, 126.6, 124.3,
115.5. HRMS: calcd. for C20H16S2N4F2 [M þNaþ] 437.0682, found 437.0681.
1,4-Phenylene-bis[3-(4’-chlorophenyl)thiourea] (3e)[21]. White powder;
1
mp 233–235 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.84 (s, 2H, NH), 9.82 (s, 2H,
NH), 7.50 (d, 4H, J ¼ 8.0 Hz, ArH), 7.41 (s, 4H, ArH), 7.36 (d, 4H, J ¼ 8.0 Hz,
ArH). 13C NMR (100 MHz, DMSO-d6) d 180.3, 155.8, 153.4, 137.2, 136.2, 126.2,
125.0, 124.4, 119.1, 116.9.
1,4-Phenylene-bis[3-(4’-bromophenyl)thiourea] (3f)[21]. White powder;
1
mp 222–224 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.85 (s, 2H, NH), 9.83 (s, 2H,
NH), 7.49 (d, 8H, J ¼ 8.4 Hz, ArH), 7.44 (s, 4H, ArH). 13C NMR (100 MHz,
DMSO-d6) d 179.9, 139.4, 136.2, 131.6, 125.9, 124.3, 116.7.
1,4-Phenylene-bis[3-(4’-iodophenyl)thiourea] (3g)[21]. Light brown pow-
1
der; mp 232–234 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.82 (s, 2H, NH), 9.79 (s,
2H, NH), 7.64 (d, 4H, J ¼ 8.4 Hz, ArH), 7.41 (s, 4H, ArH), 7.32 (d, 4H, J ¼ 8.4 Hz,
Hz, ArH). 13C NMR (100 MHz, DMSO-d6) d 179.8, 139.8, 137.5, 136.2, 126.0,
124.3, 88.9.
1,4-Phenylene-bis[3-(2’-methylphenyl)thiourea] (3h)[22]. White powder;
1
mp 230–232 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.63 (s, 2H, NH), 9.25 (s, 2H,
NH), 7.42 (s, 4H, ArH), 7.26-7.22 (m, 4H, ArH), 7.19–7.14 (m, 4H, ArH), 2.23 (s,
6H, CH3). 13C NMR (100 MHz, DMSO-d6) d 180.7, 138.2, 135.2, 130.8, 128.4,
126.5, 124.4, 18.3.
1,4-Phenylene-bis[3-(2’-chlorophenyl)thiourea] (3i)[23]. White powder;
1
mp 148–150 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.99 (s, 2H, NH), 9.38 (s, 2H,
NH), 7.62 (d,2H, J ¼ 7.6 Hz, ArH), 7.50–7.39 (m, 6H, ArH), 7.33 (t, 2H, J ¼ 7.6 Hz,
Hz, ArH), 7.24 (t, 2H, J ¼ 7.6 Hz, ArH).13C NMR (100 MHz, DMSO-d6) d 180.6,
136.8, 136.2, 130.3, 130.1, 129.9, 127.86, 127.6, 124.4.
1,4-Phenylene-bis[3-(3’-chloro-4’-fluorophenyl)thiourea]
(3j). White
powder; mp 184–186 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 9.95 (s, 2H, NH),
9.84 (s, 2H, NH), 7.77 (d, 2H, J ¼ 5.6 Hz, ArH), 7.42 (s, 4H, ArH), 7.38 (q, 4H,
J ¼ 8.8 Hz, ArH). 13C NMR (100 MHz, DMSO-d6) d 180.0, 138.9, 136.2, 128.7,
128.6, 125.6, 124.3. HRMS: calcd. for C20H14S2N4Cl2F2 [M þNaþ] 504.9903, found
504.9902.
1,4-Phenylene-bis[3-(3’,4’-dimethylphenyl)thiourea] (3k). White powder;
1
mp 182–184 ꢀC; H NMR (400 MHz, DMSO-d6): d 9.59 (s, 4H, NH), 7.41 (s, 4H,
ArH), 7.21 (s, 2H, ArH), 7.17 (d, 2H, J ¼ 8.0 Hz, ArH), 7.09 (d, 2H, J ¼ 8.4 Hz,
ArH), 2.20 (s, 6H, CH3), 2.20 (s, 6H, CH3). 13C NMR (100 MHz, DMSO-d6) d
179.9, 137.4, 136.6, 136.3, 133.0, 125.5, 124.2, 121.9, 19.9, 19.3. HRMS: calcd. for
C24H26S2N4 [M þNaþ] 457.1497, found 457.1496.

SYNTHESIS OF 1,4-PHENYLENEDITHIOUREAS
1051
1,4-Phenylene-bis[3-(a-naphthyl)thiourea] (3l). White powder; mp
204–207 ꢀC; 1H NMR (400 MHz, DMSO-d6): d 9.85 (s, 2H, NH), 9.75 (s, 2H,
NH), 7.97 (s, 4H, ArH), 7.86 (s, 2H, ArH), 7.54–7.47 (m, 12H, ArH). 13C NMR
(100 MHz, DMSO-d6) d 181.6, 136.5, 135.5, 134.4, 130.4, 128.6, 127.1, 126.6,
126.5, 126.1, 125.8, 124.6, 123.5. HRMS: calcd. for C28H22S2N4 [M þNaþ]
501.1184, found 501.1184.
ACKNOWLEDGMENTS
This work was supported by the National Natural Sciences Foundation of
China (20672031, 20802017, and 20872029), Innovative Research Team Program
in Science and Technology of Henan Province (2008IRTSTHN002 and
2006-HACET-06), and the Natural Science Foundation of Technology Commission
of Henan Province (0611021700).
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