Phase transfer catalyzed synthesis of thiosemicarbazide and bis-thiosemicarbazide derivatives of 2-ethoxybenzoic acid

Article abstract of DOI:10.1080/10426500490464078

Reaction of aryloxyacetic acid hydrazide or arenedioxydiacetic acid hydrazide with 2-ethoxybenzoy chloride and ammonium thiocyanate under the condition of solid-liquid phase transfer catalysis using polyethylene glycol-400 (PEG-400) as the catalyst yielded the corresponding thiosemicarbazide or bisthiosemicarbazide derivatives of 2-ethoxybenzoic acid in good-to-excellent yield.

Full text of DOI:10.1080/10426500490464078

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Phosphorus, Sulfur, and Silicon and the Related
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PHASE TRANSFER CATALYZED SYNTHESIS OF
THIOSEMICARBAZIDE AND bis-THIOSEMICARBAZIDE
DERIVATIVES OF 2-ETHOXYBENZOIC ACID
Tai-Bao Wei a , You-Ming Zhang a , Hai Wang a & Li-Ming Gao a
a Department of Chemistry , Lanzhou, Gansu, P.R. China
Published online: 16 Aug 2010.
To cite this article: Tai-Bao Wei , You-Ming Zhang , Hai Wang & Li-Ming Gao (2004) PHASE TRANSFER CATALYZED SYNTHESIS OF
THIOSEMICARBAZIDE AND bis-THIOSEMICARBAZIDE DERIVATIVES OF 2-ETHOXYBENZOIC ACID, Phosphorus, Sulfur, and Silicon and
the Related Elements, 179:8, 1539-1544, DOI: 10.1080/10426500490464078
To link to this article: http://dx.doi.org/10.1080/10426500490464078
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Phosphorus, Sulfur, and Silicon, 179:1539–1544, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490464078
PHASE TRANSFER CATALYZED SYNTHESIS
OF THIOSEMICARBAZIDE AND
BIS-THIOSEMICARBAZIDE DERIVATIVES
OF 2-ETHOXYBENZOIC ACID
Tai-Bao Wei, You-Ming Zhang, Hai Wang, and Li-Ming Gao
Department of Chemistry, Northwest Normal University,
Lanzhou, Gansu, P.R. China
(Received November 6, 2003; accepted December 16, 2003)
Reaction of aryloxyacetic acid hydrazide or arenedioxydiacetic acid
hydrazide with 2-ethoxybenzoy chloride and ammonium thiocyanate
under the condition of solid–liquid phase transfer catalysis using
polyethylene glycol-400 (PEG-400) as the catalyst yielded the cor-
responding thiosemicarbazide or bisthiosemicarbazide derivatives of
2-ethoxybenzoic acid in good-to-excellent yield.
Keywords: Bis-thiosemicarbazide; phase transfer catalysis; thiosemi-
carbazide
INTRODUCTION
A series of 1,4-disubstituted thiosemicarbazide and their related het-
erocyclic compounds have been found to possess many important bio-
logical activities. Some thiosemicarbazides have been found to be use-
ful as herbicides, insecticides and plant-growth regulators.1 In view
of these observations and in continuation of our earlier work on the
synthesis of plant-growth regulators,2−6 we now report a convenient
and efficient method for the preparation of thiosemicarbazide and bis-
thiosemicarbazide derivatives of 2-ethoxybenzoic acid under the condi-
tion of solid–liquid phase transfer catalysis using polyethylene glycol-
400 (PEG-400) as the catalyst.
This work was supported by Natural Science Foundation (No. 20371040) of China, the
Foundation (031-A21-004) of Gansu province, and the Foundation (No. 02-18) of North-
west Normal University, which are gratefully acknowledged.
Address correspondence to You-Ming Zhang, Department of Chemistry, Northwest
Normal University, Lanzhou 730070, Gansu, P.R. China. E-mail: kejichu@nwnu.edu.cn
1539

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T.-B. Wei et al.
2-Ethoxybenzoyl chloride (1) is readily available by the reaction of
2-ethoxybenzoic acid with thionyl chloride. Its treatment with am-
monium thiocyannte under the condition of solid–liquid phase trans-
fer catalysis using 3% PEG-400 as the catalyst gave 2-ethoxybenzoyl
isothiocyanate (2). This compound does not need to be isolated
and reacts immediately with various aryloxyacetic acid hydrazide
or arenedi-oxydiacetic acid hydrazide to afford the corresponding
SCHEME 1

Thiosemicarbazide Derivatives
1541
thiosemicarbazide and bis-thiosemicarbazide derivatives (3), (4), and
(5) in good-to-excellent yields (Scheme 1).
Acyl isothiocyanates have been available under the condition of
liquid–liquid phase transfer catalysis using tetrabutyl ammonium bro-
mide as PTC (phase transfer catalyst); however, in the presence of
water, hydrolysis of the acyl chloride may occur, and the yield of the
acyl isothiocyanate may be decreased.9 Harrison has also reported
that polymer-supported thiocyanate reacting with benzoyl chloride in
benzene yielded benzoyl isothiocyanate, but the preparation of the
polymer-supported reagent required long reaction times and vacuum
condition.10 Therefore, the reaction was then operated under solid–
liquid phase transfer catalysis condition using PEG-400 as PTC. It was
found that 2-ethoxybenzoyl chloride was quantitatively converted to
the corresponding acyl isocyanate (2). This intermediate reacts with
aryloxyacetic acid hydrazides or arenedioxy diacetic acid hydrazides to
give the title compounds (3), (4), and (5) in high yield.
According to our experiment resultes,2−6 the production is a gen-
eral method that may be applied to the preparation of most acylisoth-
iocyanates by the reaction of different acyl chloride with ammonium
thiocyanate. We tentatively propose the mechanism shown in Scheme 2.
SCHEME 2
In conclusion, this one-pot procedure is a facile and convenient
method for the synthesis of 1,4-disubstituted thiosemicarbazide deriva-
tives under solid–liquid phase transfer catalysis conditions, with the
advantages of mild conditions, simple operation, short reaction times,
and high yield. The catalyst PEG-400 is inexpensive, relatively non-
toxic, highly stable, and easily available.
EXPERIMENTAL
Infrared (IR) spectra were recorded using KBr pellets on an Alpha
Centauri Fourier Transform Infrared (FTIR) spectrophotometer and

1542
T.-B. Wei et al.
1H-NMR spectra on Brucke AC-80 instrument. DMSO-d6 was used
as solvent and TMS as internal standard. Elemental analyses were
performed on a Perkin-Elmer-2400 CHN Element analyzer instru-
ment. Melting points were observed in an open capillary tube and were
uncorrected.
General Procedure for the Preparation of Compounds 3
Powdered ammonium thiocyanate (4.5 mmol) 2-ethoxybenzoyl chloride
(3 mmol) 0.054 g PEG-400 (3% with respect to ammonium thiocyanate)
and 15 ml of dichloro-methane were placed in a dried round-bottomed
flask containing a magnetic stirret bar and stirred at room temperature
for 1 h. Then aryloxyacetic acid hyddrazide (2.9 mmol) was added, and
the mixture was stirred for 0.5 h. The corresponding thiosemicarbazide
precipitates immediately. The product is filtered, wash with water to
remove inorganic salts, dried, and recrystallized from DMF-EtOH-H2O
to give products (3).
Using 6 mmol 2-ethoxybenzoyl chloride, 9 mmol NH4SCN, and
2.9 mmol 1.4-phenylenedioxydiacetic acid hydrazide or 1.3-phenyl-
enedioxydiaceticacid hydrazide, compounds 4 and 5 were prepared
similarly.
Compound 3a
85% Yield; m.p., 128–130◦C; IR (KBr, cm−1): 3450, 3287, 334, 3143
(N H), 2980, 2866 (CH2, CH3), 1671, 1684 (C O), 1163 (C S), 1617,
1599, 1515, 1473 (C C), 1251, 1030 (Ar O ); 1H-NMR (80MH2, DMSO-
d6): 1.48 (t, 3H, CH3), 2.23 (s, 3H, CH3), 4,39 (q, 2H, CH2), 4.67
(ArOCH2), 6.64–7.98 (m, 8H, Ar H), 11.01 (s, 1H, N H), 11.36 (s, 1H,
N H), 12.35 (s, 1H, N H); Anal. Calc. for C19H21N3O4S: C, 58.80, H,
5.46; N, 10.84. Found: C, 58.94; H, 5.37; N, 10.89.
Compound 3b
80% yield; m.p., 154–156◦C; IR (KBr, cm−1): 3290, 3143 (N H), 2980,
2856 (CH3, CH2); 1679, 1686 (C O), 1159 (C S), 1600, 1587, 1486
1
(C C), 1257, 1013 (Ar o ); H-NMR (80MHz, DMSO-d6): 1.49 (t, 3H,
CH3), 2.28 (S, 3H, CH3), 4.31 (q, 2H, CH2), 4.69 (S, 2H, ArOCH2), 6.75–
7.98 (m, 8H, Ar H), 11.02 (S, 1H, N H), 11.38 (S, 1H, N H), 12.27 (S,
1H, N H); Anal. Calc. for C19H21N3O4S: C, 58.80; H, 5.46; N, 10.84.
Found: C, 58.77; H, 5.49; N, 10.81.
Compound 3c
86% yield; m.p., 178–180◦C; IR (KBr, cm−1): 3295, 3150 (N–H), 2989,
2890 (CH3, CH2); 1650, 1686 (C O), 1163 (C S), 1599, 1560, 1487

Thiosemicarbazide Derivatives
1543
(C C), 1033, 1249 (Ar O ); 1H-NMR (80MH2, DMSO-d6): 1.48 (t, 3H,
CH3), 2.24 (S, 3H, CH3), 4.31 (q, 2H, CH2), 4.74 (S, 2H, ArOCH2), 6.77–
7.99 (m, 8H, Ar H), 10.96 (S, 1H, N H), 11.38 (S, 1H, N H), 12.41 (S,
1H, N H); Anal. Calc. for C19H21N3O4S: C, 58.80; H, 5.46; N, 10.84.
Found: C, 58.89; H, 5.40; N, 10.93.
Compound 3d
88% Yield; m.p., 158–160◦C; IR (KBr, cm−1): 3273, 3134, 3132 (N H),
2904, 2853 (CH2, CH3), 1664, 1684 (C O), 1163 (C S), 1601, 1559, 1469
1
(C C), 1248, 1038 (ArO ); H-NMR (80MH2, DMSO-d6): 1.48 (t, 3H,
CH3), 4.31 (q, 2H, CH2), 4.73 (S, 2H, ArOCH2), 6.97–7.97 (m, 8H, ArH),
11.06 (S, 1H, N H), 11.36 (S, 1H, N H), 12.24 (S, 1H, N H); Anal Calc.
for C18H18ClN3O4S: C, 53.00; H, 4.48; N, 10.30. Found: C, 53.21; H, 4.49;
N, 10.28.
Compound 3e
93% Yield; m.p., 202–204◦C; IR (KBr, cm−1): 3297, 3148 (N H), 2980,
2929, 2890, 2853 (CH2CH3), 1656, 1694 (C O), 1157 (C S), 1600, 1577,
1487 (C C), 1263, 1036 (ArO ); 1H-NMR (80MH2, DMSO-d6): 1.48 (t,
2H, CH3), 4.20–4.28 (q, 2H, CH2), 4.86 (S, 2H, ArOCH2), 7.20–7.97 (m,
8H, Ar H), 11.08 (S, 1H, N H), 11.35 (S, 1H, N H) 12.43 (S, 1H, N H);
Anal Calc. for C18H18ClN3O4S: C, 53.00; H, 4.48; N, 10.30. Found: C,
53.26; H, 4.47; N, 10.21.
Compound 3f
80% Yield; m.p., 208–210◦C; IR (KBr, cm−1): 3325, 3301, 3162, 3123
(N H), 2988, 2998, 2849 (CH3, CH2), 1654, 1697 (C O), 1163 (C S),
1611, 1594, 1484 (C C), 1535, 1358 (NO2), 1036, 1251 (ArO ); 1H-NMR
(80MH2, DMSO-d6): 1.48 (t, 3H, CH3), 4.29 (q, 2H, CH2), 4.91 (S, 2H,
ArOCH2), 7.02–8.26 (m8H, Ar H), 11.20 (S, 1H, N H), 11.35 (S, 1H,
N H), 12.24 (S, 1H, N H); Anal Calc. for C18H18N4O6S: C, 51.67; H,
4.34; N, 13.39. Found: C, 51.82; H, 4.33; N, 13.47.
Compound 3g
74% Yield; m.p., 216–218◦C; IR (KBr, cm−1): 3317, 3291, 3160, 3137
(N H), 2986, 2951, 2867 (CH2, CH3), 1654, 1697 (C O), 1159 (C S),
1613, 1598, 1508, 1487 (C C), 1033, 1250 (Ar O ); 1H-NMR (80MH2,
DMSO-d6): 1.49 (t, 3H, CH3), 4.23 (q, 2H, CH2), 4.85 (S, 2H, ArOCH2)
6.96–8.37 (m, 11H, Ar H) 11.12 (S, 1H, N H), 11.36 (S, 1H, N H) 12.40
(S, 1H, N H); Anal Calc. for C22H21N3O4S: C, 62.39; H, 5.00; N, 9.92.
Found: C, 62.45; H 4.97; N, 9.78.

1544
T.-B. Wei et al.
Compound 3h
95% Yield; m.p., 206–208◦C; IR (KBr, cm−1) 3447, 3155, 3134 (N H),
2986, 2873 (CH2CH3), 1656, 1696 (C O), 1163 (C S), 1600, 1514, 1485
1
(C C), 1037, 1257 (ArO ); H-NMR (80MH2, DMSO-d6): 1.47 (t, 3H,
CH3), 4.27 (q, 2H, CH2), 4.86 (S, 2H, ArOCH2), 7.03–7.89 (m, 11H,
Ar H), 11.15 (S, 1H, N H), 11.38 (S, 1H, N H), 12.28 (S, 1H, N H);
Anal Calc. for C22H21N3O4S: C, 62.39; H, 5.00; N, 9.92. Found: C, 62.33;
H, 5.07; N, 9.95.
Compound 4
65% Yield; m.p., 229–230◦C; IR (KBr, cm−1): 3313, 3211, 3133 (N H),
2980, 2912, 2829 (CH3, CH2), 1658, 1684 (C O), 1159 (C S), 1599,
1
1576, 1485 (C C), 1031, 1251 (ArO ); H-NMR (80MH2, DMSO-d6):
1.49 (t, 6H, 2CH3), 4.41 (q, 4H, 2CH2), 4.65 (S, 4H, ArO2CH2), 6.91–
8.04 (m, 12H, Ar H), 11.09 (S, 2H, N H2), 11.37 (S, 2H, N H2), 12.16
(S, 2H, N H2); Anal Calc. for C30H32N6O8S2: C, 53.88; H, 4.82; N, 12.57.
Found: C, 53.97; H, 4.78; N, 12.61.
Compound 5
60% Yield; m.p., 221–222◦C; IR (KBr, cm−1): 3363, 3149 (N H), 2985,
2939 (CH3, CH2), 1658, 1689 (C O), 1160 (C S), 1600, 1559, 1486
1
(C C), 1033, 1251 (ArO ); H-NMR (80MH2, DMSO-d6): 1.49 (t, 6H,
2 CH3), 4.23 (q, 4H, 2CH2) 4.73 (S, 4H, ArO2CH2), 6.69–7.98 (m, 12H,
Ar H), 11.07 (S, 2H, N H2) 11.34 (S, 2H, N H2), 12.21 (S, 2H, N H2).
Anal Calc for C30H32N6O8S2: C, 53.88; H, 4.82; N, 12.57. Found: C,
53.93; H, 4.86; N, 12.64.
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