Mild synthesis of 5-(9-ethyl-9H-carbazol-3-yl)-N-aryl-1,3,4-thiadiazol-2- amines

Article abstract of DOI:10.1007/s11164-012-0538-5

An efficient synthetic method for heterocycles containing both carbazole and 1,3,4-thiadiazole moieties is described. 9-Ethyl-9H-carbazol-3-carbaldehyde reacted with 4-arylthiosemicarbazides, with acetic acid as catalyst, to give 1-(9-ethyl-9H-carbazol-3-yl)methylene-4-arylthiosemicarbazides, which were further treated with manganese dioxide at room temperature in acetone to give 5-(9-ethyl-9H-carbazol-3-yl)-N-aryl-1,3,4-thiadiazol-2-amines in good to high yield. This procedure has the advantages of mild conditions, easy separation, and simple manipulation. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0538-5

Res Chem Intermed (2012) 38:2223–2228
DOI 10.1007/s11164-012-0538-5
Mild synthesis of 5-(9-ethyl-9H-carbazol-3-yl)-N-aryl-
1,3,4-thiadiazol-2-amines
•
Zheng Li Yulin Xing
Received: 18 February 2012 / Accepted: 17 March 2012 / Published online: 3 April 2012
Ó Springer Science+Business Media B.V. 2012
Abstract An efficient synthetic method for heterocycles containing both carbazole
and 1,3,4-thiadiazole moieties is described. 9-Ethyl-9H-carbazol-3-carbaldehyde
reacted with 4-arylthiosemicarbazides, with acetic acid as catalyst, to give 1-(9-ethyl-
9H-carbazol-3-yl)methylene-4-arylthiosemicarbazides, which were further treated
with manganese dioxide at room temperature in acetone to give 5-(9-ethyl-9H-car-
bazol-3-yl)-N-aryl-1,3,4-thiadiazol-2-amines in good to high yield. This procedure
has the advantages of mild conditions, easy separation, and simple manipulation.
Keywords Thiadiazole Á Carbazole Á Thiosemicarbazide Á Synthesis
Introduction
1,3,4-Thiadiazole derivatives are of interest in medicine and agriculture because of their
wide range of biological activity, for example antibacterial [1], fungicidal [2],
anticancer [3–6], antitubercular [7], anti-inflammatory [8], leishmanicidal [9], herbi-
cidal [10], insecticidal [11], and anti-depressant [12]. Compounds bearing a carbazole
moiety have antiproliferative [13, 14], cytotoxic [15], antimitotic [16], and antimicro-
bial [17] activity. Compounds bearing both 1,3,4-thiadiazole and carbazole moieties,
especially, have anticancer [3], antimicrobial, anticonvulsant, and anti-inflammatory
[18] activity, and are also used as optoelectronic [19] and polymeric [20] materials.
Reported methods for the preparation of 1,3,4-thiadiazole heterocycles include
1. Dehydration of acylthiosemicarbazides in the presence of acids (HOAc, H2SO4,
CH3SO3H) [21, 22] or other dehydrating agents (PEG-OPOCl2, DCC, TMSCl,
p-TsCl, PPh3, SOCl2, and PCl5) [23, 24];
Z. Li (&) Á Y. Xing
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070,
Gansu, People’s Republic of China
e-mail: lizheng@nwnu.edu.cn
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2. Condensation of diacylhydrazines in the presence of P2S5 or Lawesson reagent
[25];
3. Dehydrogenating cyclization of thiosemicarbazones in the presence of FeCl3 or
Br2 [26, 27]; and
4. Reaction of aldehydes with sulfur and hydrazine hydrate under microwave
irradiation [28].
However, the most methods suffer from the drawbacks of difficult separation and
release of corrosive and odorous hydrogen sulfide.
In this paper we report an efficient method with manganese dioxide as a mild
oxidizing agent for synthesis of a series of new heterocyclic compounds containing
both carbazole and 1,3,4-thiadiazole moieties.
Results and discussion
Reaction of carbazole with bromoethane in the presence of potassium hydroxide
gave 9-ethyl-9H-carbazole in high yield. 9-Ethylcarbazole on treatment with
phosphorus oxychloride and N,N-dimethylformamide under reflux for 2 h afforded
9-ethyl-9H-carbazol-3-carbaldehyde with high selectivity (no 3,6-dicarbaldehyde
by-product was observed). 9-Ethyl-9H-carbazol-3-carbaldehyde reacted with 4-
arylthiosemicarbazides, with acetic acid as catalyst, to give 1-(9-ethyl-9H-carbazol-
3-yl)methylene-4-arylthiosemicarbazides (1a–g), which were further treated with
manganese dioxide at room temperature in acetone to give 5-(9-ethyl-9H-carbazol-
3-yl)-N-aryl-1,3,4-thiadiazol-2-amines (2a–g) in good to high yield (Scheme 1;
Table 1).
CHO
POCl3/DMF
C2H5Br/KOH
r.t., acetone
N
C2H5
N
N
H
C2H5
S
R
H
C
N NH2
N
H
HOAc/ethanol
S
R
H
N N C NH
R
MnO2
r.t., acetone
S
H
N
N
N
N
N
C2H5
C2H5
2a-g
1a-g
Scheme 1
123

Mild synthesis
2225
Table 1 Synthesis of
Compounds 1a–g and 2a–g
Compound
R
Reaction time (h) m.p. (°C) Yield (%)
1a
1b
1c
1d
1e
1f
H
1
1
206–208
224–226
199–201
218–221
202–204
206–208
214–216
246–248
164–166
210–212
200–202
238–240
212–214
258–260
93
86
90
92
89
86
87
71
80
75
73
62
69
70
2-CH3
4-CH3
4-CH3O
4-Cl
1
1
1
3-Br
1
1g
2a
2b
2c
2d
2e
2f
4-Br
1
H
15
9
2-CH3
4-CH3
16
4-CH3O 18
4-Cl
3-Br
4-Br
18
18
14
2g
Yields refer to isolated product
It was observed that compounds 1a–g bearing electron-donating groups (methyl,
methoxyl) on aromatic rings were obtained in higher yield than those bearing
electron-withdrawing groups (chloro, bromo). In addition, the solvent used was
important for synthesis of products 2a–g. Many solvents were tested for the
reactions. Ethanol and dichloroethane gave low yield because of the poor solubility
of the reactants. The reactions could proceed smoothly in DMF, but separation of
the products could be a problem. However, it was found acetone was an acceptable
solvent for the reactions and gave the products in good to high yield.
Other cyclizing agents were also investigated for formation of 1,3,4-thiadiazole
rings. It was found that ferric chloride also gave the products. However, the
reactions had to be conducted under reflux and gave the products in lower yield.
1
The structures of compounds 1a–g and 2a–g were determined by H NMR, IR,
1
and elemental analysis. The H NMR spectra of compounds 1a–g in DMSO-d6
contained –CH= group proton peaks at d = 8.63–8.65 ppm and –NH– group proton
peaks at d = 9.95–10.14 and 11.72–11.91 ppm. The 1H NMR spectra of
compounds 2a–g contained –NH– proton peaks at d = 10.42–10.63 ppm. The IR
spectra of compounds 1a–g showed characteristic absorption at 3,115–3,350 cm-1
and 1,191–1,225 cm-1, attributable to imino and thiocarbonyl groups, respectively.
IR spectra of compounds 2a–g showed the characteristic absorption of –NH– groups
at 3,225–3,262 cm-1
.
Conclusion
In summary, an efficient synthetic method for a series of compounds containing
both carbazole and thiadiazole moieties has been developed. This procedure has
features of mild conditions and easy work-up.
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Z. Li, Y. Xing
Experimental
IR spectra were recorded as KBr pellets on a Digilab FTS 3000 FTIR
1
spectrophotometer. H NMR spectra were recorded on a Mercury-400BB instru-
ment using (CD3)2SO as solvent and Me4Si as internal standard. Elemental analysis
was performed with a Vario E1 elemental analysis instrument. Melting points were
measured with an electrothermal melting point apparatus. 4-Arylthiosemicarbazides
[29] and 9-ethyl-9H-carbazole-3-carbaldehyde [30] were prepared by methods
reported in the literature.
Preparation of 1-(9-ethyl-9H-carbazol-3-yl)methylene-4-
arylthiosemicarbazides (1a–g)
A mixture of 4-arylthiosemicarbazide (2 mmol), 9-ethyl-9H-carbazole-3-carbalde-
hyde (2 mmol), and acetic acid (0.2 mmol) in 20 mL ethanol was heated under
reflux for 1 h. The progress of the reaction was monitored by TLC. After
completion of the reaction, the precipitate was isolated by filtration and washed with
ethanol (3 9 5 mL), and the solid was recrystallized from DMF–H2O to give the
corresponding product. The analytical data for compounds 1a–g are given below.
1a: 1H NMR (DMSO-d6, 400 MHz) d 11.83 (s, 1H, NH), 10.07 (s, 1H, NH), 8.64
(s, 1H, –CH=), 7.21–8.35 (m, 12H, Ar–H), 4.48 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.33
3
(t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,238, 3,141 (N–H), 1,201 (C=S).
Anal. Calcd. for C22H20N4S: C, 70.94; H, 5.41; N, 15.04. Found: C, 70.85; H, 5.39;
N, 15.10.
1b: 1H NMR (DMSO-d6, 400 MHz) d 11.79 (s, 1H, NH), 9.95 (s, 1H, NH), 8.63
(s, 1H, –CH=), 7.20–8.33 (m, 11H, Ar–H), 4.45 (q, 3J = 7.2 Hz, 2H, –CH2–), 2.24
3
(s, 3H, CH3), 1.32 (t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,296, 3,167
(N–H), 1,198 (C=S). Anal. Calcd. for C23H22N4S: C, 71.47; H, 5.74; N, 14.50.
Found: C, 71.60; H, 5.76; N, 14.48.
1c: 1H NMR (DMSO-d6, 400 MHz) d 11.80 (s, 1H, NH), 9.96 (s, 1H, NH), 8.65
3
(s, 1H, –CH=), 7.17–8.35 (m, 11H, Ar–H), 4.47 (q, J = 7.2 Hz, 2H, –CH2–),
2.25(s, 3H, CH3), 1.32 (t, 3J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,284, 3,170
(N–H), 1,191 (C=S). Anal. Calcd. for C23H22N4S: C, 71.47; H, 5.74; N, 14.50.
Found: C, 71.38; H, 5.73; N, 14.49.
1d: 1H NMR (DMSO-d6, 400 MHz) d 11.72 (s, 1H, NH), 9.99 (s, 1H, NH), 8.64
(s, 1H, –CH=), 6.94–8.34 (m, 11H, Ar–H), 4.48 (q, 3J = 7.2 Hz, 2H, –CH2–), 3.78
3
(s, 3H, –OCH3), 1.33 (t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,294, 3,137
(N–H), 1,216 (C=S). Anal. Calcd. for C23H22N4OS: C, 68.63; H, 5.51; N, 13.92.
Found: C, 68.56; H, 5.53; N, 13.84.
1e: 1H NMR (DMSO-d6, 400 MHz) d 11.85 (s, 1H, NH), 10.10 (s, 1H, NH), 8.65
(s, 1H, –CH=), 7.23–8.34 (m, 11H, Ar–H), 4.49 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.34
3
(t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,350, 3,127 (N–H), 1,214 (C=S).
Anal. Calcd. for C22H19ClN4S: C, 64.93; H, 4.71; N, 13.77. Found: C, 65.00; H,
4.73; N, 13.80.
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Mild synthesis
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1f: 1H NMR (DMSO-d6, 400 MHz) d 11.90 (s, 1H, NH), 10.12 (s, 1H, NH), 8.64
(s, 1H, –CH=), 7.23–8.33 (m, 11H, Ar–H), 4.50 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.35
3
(t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,335, 3,130 (N–H), 1,220 (C=S).
Anal. Calcd. for C22H19BrN4S: C, 58.54; H, 4.24; N, 12.41. Found: C, 58.38; H,
4.25; N, 12.44.
1g: 1H NMR (DMSO-d6, 400 MHz) d 11.91 (s, 1H, NH), 10.14 (s, 1H, NH), 8.64
(s, 1H, –CH=), 7.24–8.36 (m, 11H, Ar–H), 4.51 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.33
3
(t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,327, 3,115 (N–H), 1,225 (C=S).
Anal. Calcd. for C22H19BrN4S: C, 58.54; H, 4.24; N, 12.41. Found: C, 58.62; H,
4.22; N, 12.39.
Preparation of 5-(9-ethyl-9H-carbazol-3-yl)-N-aryl-1,3,4-thiadiazol-2-amines
(2a–g)
Manganese dioxide (2 mmol) was added to compound 1a–1g (1 mmol) in 20 mL
acetone and 1 mL DMF. The suspension was stirred at room temperature for an
appropriate time (indicated in Table 1). The progress of the reaction was monitored
by TLC. After completion of the reaction, the resulting mixture was filtered to
remove the solid. The filtrate was concentrated and the pure product was obtained
by chromatography using petroleum ether–ethyl acetate (4:1) as eluent. The
analytical data for compounds 2a–g are given below.
2a: Yellow solid. 1H NMR (DMSO-d6, 400 MHz) d 10.49 (s, 1H, NH),
7.00–8.62 (m, 12H, Ar–H), 4.47 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.31 (t, 3J = 7.2 Hz,
3H, –CH3). IR (KBr, m, cm-1): 3,231 (N–H). Anal. Calcd. for C22H18N4S: C, 71.32;
H, 4.90; N, 15.12. Found: C, 71.14; H, 4.89; N, 15.09.
1
2b: Red–brown solid. H NMR (DMSO-d6, 400 MHz) d 10.43 (s, 1H, NH),
3
6.98–8.61 (m, 11H, Ar–H), 4.46 (q, J = 7.2 Hz, 2H, –CH2–), 2.36 (s, 3H, –CH3),
1.30 (t, 3J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,227 (N–H). Anal. Calcd. for
C23H20N4S: C, 71.85; H, 5.24; N, 14.57. Found: C, 71.77; H, 5.23; N, 14.54.
2c: Purple solid. 1H NMR (DMSO-d6, 400 MHz) d 10.42 (s, 1H, NH), 7.01–8.60
3
(m, 11H, Ar–H), 4.45 (q, J = 7.2 Hz, 2H, –CH2–), 2.37 (s, 3H, –CH3), 1.30 (t,
3J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,225 (N–H). Anal. Calcd. for
C23H20N4S: C, 71.85; H, 5.24; N, 14.57. Found: C, 71.95; H, 5.26; N, 14.56.
2d: Yellow solid. 1H NMR (DMSO-d6, 400 MHz) d 10.52 (s, 1H, NH),
7.09–8.63 (m, 11H, Ar–H), 4.47 (q, 3J = 7.2 Hz, 2H, –CH2–), 3.81 (s, 3H,
3
–OCH3),1.32 (t, J = 7.2 Hz, 3H, –CH3). IR (KBr, m, cm-1): 3,237 (N–H). Anal.
Calcd. for C23H20N4OS: C, 68.98; H, 5.03; N, 13.99. Found: C, 69.06; H, 5.01; N,
13.97.
2e: White solid. 1H NMR (DMSO-d6, 400 MHz) d 10.63 (s, 1H, NH), 7.21–8.64
3
3
(m, 11H, Ar–H), 4.48 (q, J = 7.2 Hz, 2H, –CH2–), 1.34 (t, J = 7.2 Hz, 3H,
–CH3). IR (KBr, m, cm-1): 3,262 (N–H). Anal. Calcd. for C22H17ClN4S: C, 65.26;
H, 4.23; N, 13.84. Found: C, 65.33; H, 4.22; N, 13.81.
2f: Yellow solid. 1H NMR (DMSO-d6, 400 MHz) d 10.62 (s, 1H, NH), 7.22–8.63
3
(m, 11H, Ar–H), 4.49 (q, J = 7.2 Hz, 2H, –CH2–), 1.34 (t, J = 7.2 Hz, 3H,
3
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Z. Li, Y. Xing
–CH3). IR (KBr, m, cm-1): 3,259 (N–H). Anal. Calcd. for C22H17BrN4S: C, 58.80;
H, 3.81; N, 12.47. Found: C, 58.86; H, 3.85; N, 12.51.
2g: Yellow solid. 1H NMR (DMSO-d6, 400 MHz) d 10.62 (s, 1H, NH),
7.25–8.64 (m, 11H, Ar–H), 4.48 (q, 3J = 7.2 Hz, 2H, –CH2–), 1.34 (t, 3J = 7.2 Hz,
3H, –CH3). IR (KBr, m, cm-1): 3,260 (N–H). Anal. Calcd. for C22H17BrN4S: C,
58.80; H, 3.81; N, 12.47. Found: C, 58.74; H, 3.83; N, 12.45.
Acknowledgments The authors thank the National Natural Science Foundation of China (21162024)
for financial support of this work.
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