One-pot and catalyst-free synthesis of thiosemicarbazones via multicomponent coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2009.02.134

A novel and efficient procedure for the synthesis of thiosemicarbazones has been achieved via a multicomponent and catalyst-free reaction of phenyl or p-chlorophenyl isothiocyanate, hydrazine, and aldehydes or ketones. The method afforded 20 thiosemicarba

Full text of DOI:10.1016/j.tetlet.2009.02.134

Tetrahedron Letters 50 (2009) 2090–2093
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One-pot and catalyst-free synthesis of thiosemicarbazones via
multicomponent coupling reactions
*
Silvio Cunha , Tiago Lima da Silva
Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, Salvador 40170-290, BA, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient procedure for the synthesis of thiosemicarbazones has been achieved via a multi-
component and catalyst-free reaction of phenyl or p-chlorophenyl isothiocyanate, hydrazine, and alde-
hydes or ketones. The method afforded 20 thiosemicarbazones in good yields and short reaction time.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 November 2008
Revised 13 February 2009
Accepted 16 February 2009
Available online 24 February 2009
Keywords:
Thiosemicarbazones
Three-component reactions
Presently, synthetic organic chemists are faced with environ-
mental concerns that demand new procedures and/or procedure
improvements where atom economy, minimal waste production,
and energy/cost-effective preparations should be prime consider-
ations.1 In this scenario, multicomponent reactions represent an
advanced approach to achieve efficient target and diversity-ori-
ented synthesis.2
stop-and-go approaches involving isolation and purification of
each prepared intermediate, which are time, solvent, and energy
consuming procedures.5,6
We disclose herein our results concerning the first one-pot, cat-
alyst-free synthesis of thiosemicarbazones via multicomponent
coupling reactions of hydrazine, isothiocyanates, and oxo
compounds.
Thiosemicarbazones and their metal complexes derivatives are
an essential structural unit with a wide range of biological and
pharmacological properties such as anticancer and antimicrobial
activities, Figure 1.3 Besides, thiosemicarbazones are versatile
building blocks in the synthesis of densely substituted heterocy-
cles.4 Despite of these important characteristics the available
synthetic methodologies for this class of thiocompound are
The most successful routes to access thiosemicarbazones
consist of step-by-step reactions of hydrazine with different
H2N
H
Route A
Route C
N
H
CS2
S
Route B
S
S
C
N
H2N
R1
R3
N
SH
CH3I
O
NH2
N
S
H
S
R2
N
H
S
N
H
N
N
H
N
H
N
H
N
H
R3
N
R1
H2N
H2N
N
H
Triapine
Tiacetazone
N
H
N
H
SCH3
H2NR3
N
(anticancer)
(turberculostatic)
R2
S
H
H
S
S
N
N
H
R1
N
R3
O
H2N
R1
C
N
N
H
N
H
N
R2
O
R3
N-Methyl-isatine-β-4-4´-diethyl-thiosemicarbazone
O
(antiviral)
S
R1
R3
R2
N
Figure 1. Representative bioactive thiosemicarbazones.
N
N
R2
H
H
* Corresponding author. Tel.: +55 71 32836814; fax: +55 71 32343166.
E-mail address: silviodc@ufba.br (S. Cunha).
Figure 2. Synthetic routes to thiosemicarbazones.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.134

S. Cunha, T. L .d. Silva / Tetrahedron Letters 50 (2009) 2090–2093
R3
2091
compound such as aldehydes or ketones, whereas in route B the
same reagents react in an inverse order of events to provide the re-
quired thiosemicarbazone. In the four-step pathway presented in
route C, hydrazine reacts with carbon disulfide followed by reac-
tion with methyl iodide affording methyl hydrazinecarbodithioate,
and sequential nucleophilic substitution with amines followed by
condensation with the appropriate oxo compound affords the thi-
osemicarbazone, Figure 2. As one can see, routes A–B are degener-
ated operations1a and they present less steps than route C. Thus,
we reasoned that they should be appropriate to test a multicompo-
nent synthetic approach to thiosemicarbazones.
R1
O
H2N
H
S
N
H
2
+
C
+
R2
N
3a-b
1
MeOH
reflux
R3
S
R1
N
N
N
H
R2
4a-t
H
To acquire the best reaction condition two reaction controls
were performed at room temperature employing only one pair of
each electrophilic and nucleophilic reagent. In the first reaction,
benzaldehyde and hydrazine were reacted in methanol, and in
the second one phenyl isothiocyanate was reacted with hydrazine.
Scheme 1.
electrophiles, Figure 2. In the two-step route A, hydrazine reacts
with isothiocyanates followed by reaction with appropriate oxo
Table 1
Isolated thiosemicarbazones yields
Entry
Compound
Structure
Time (h)
24
Yield (%)
87
S
N
1
4a
N
H
N
H
OH
S
S
2
3
4
5
4b
4c
4d
4e
N
24
24
24
24
50
54
51
75
N
H
N
H
OMe
N
N
H
N
H
CH3O
S
N
N
H
N
H
N
S
N
N
H
N
H
O2N
S
6
7
8
4f
12
6
80
71
86
N
N
H
N
H
S
N
4g
4h
Cl
N
H
N
H
OMe
OH
HO
S
24
N
N
N
H
H
MeO
S
9
4i
4j
12
8
61
N
N
N
H
H
O
O
S
N
10
98
N
N
H
H
(continued on next page)

2092
S. Cunha, T. L .d. Silva / Tetrahedron Letters 50 (2009) 2090–2093
Table 1 (continued)
Entry
Compound
Structure
Time (h)
8
Yield (%)
72
O
S
N
11
4k
N
H
N
H
S
N
S
12
13
4l
24
24
52
47
N
N
H
H
N
N
4m
N
N
H
H
S
S
14
15
4n
4o
8
1
60
66
N
H
N
H
N
O
H
Cl
N
N
H
N
H
Cl
CH3O
S
16
4p
3
56
N
N
H
N
H
Cl
O2N
S
17
18
19
20
4q
4r
4s
4t
1
24
3
57
65
25
66
N
N
H
N
H
Cl
O
O
S
N
N
H
N
H
Cl
O
S
S
N
N
N
H
H
Cl
N
3
N
H
N
H
N
H
O
Only in the last reaction we observed the consumption of the re-
agent. However, when both reaction mixtures were heated under
reflux all reagents were consumed. These experiments indicated
that to the three-multicomponent approach, the reaction must be
performed under heating condition. Thus, we initiated our study
exploring the possibility of a multicomponent reaction toward
thiosemicarbazones by mixing in the same pot 1 equiv of benzal-
dehyde, phenyl isothiocyanate, and hydrazine in methanol under
reflux, according to Scheme 1. In this condition compound 4a
was obtained in good yield (87%).
In search of an environmentally safe solvent, ethanol and iso-
propanol were investigated. Contrary to our expectation, the
three-component reaction showed to be very sensitive to solvent
variation, because when these solvents were employed at room
temperature or under reflux no formation of thiosemicarbazone
4a was observed. However, in these experiments phenyl thiosem-
icarbazide was detected by TLC. The reason to the no formation of
the thiosemicarbazone is not entirely understood. A possible
explanation to this fact may be the more acid character of metha-
nol in comparison to ethanol and isopropanol (pKa 15.5, 15.9, and
17.1, respectively7). This acid character should be responsible for
the carbonyl activation, which is necessary to the attack by the
nucleophilic R–NH2 species present in the reaction media in the
routes A and B shown in Figure 2.
With the optimal condition in hand, we extended the reaction to
other oxo compounds, and results are indicated in Table 1. A repre-
sentative spectrum of monosubstituted (entries 1–7) and disubsti-
tuted (entries 8–10) aldehydes afforded thiosemicarbazones from
modest to excellent isolated yields. Therein, the method was ade-
quate to multigram preparation also, and compound 4b was synthe-
sized in 52% yield (8g) employing 60 mmol of each reagent, a yield
comparable to the 2 mmol scale preparation (entry 2). The method
is also useful for heteroaromatic and a,b-unsaturatedaldehydes(en-
tries 11 and 12, respectively), and to some aromatic ketones (entries
13 and 14). However, when cyclohexanone was reacted a complex
mixture was formed. To understand the scope and limitation of this

S. Cunha, T. L .d. Silva / Tetrahedron Letters 50 (2009) 2090–2093
2093
S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126,
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Chem. 2008, 16, 446–456.
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MacMillan, D. W. C. Synlett 2007, 1477–1498.
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multicomponent reaction, the method was extended to benzoyl and
butyl isothiocyanate, but we could not isolate the desired thiosemi-
carbazones. However, the method was successfully applied to p-
chloro-phenyl isothiocyanate (Table 1, entries 15–20).
In conclusion, this study shows for the first time that three-
component coupling reaction involving aryl isothiocyanates,
hydrazine, and oxo compounds can be conveniently employed as
a direct, catalyst-free synthetic route to a broad spectrum of thio-
semicarbazones. Since the experimental conditions8 are extremely
simple, inexpensive, and very mild, we hope that this approach
would be useful in the context of synthesis of molecular library
for pharmacological applications. Besides, because thiosemicarba-
zone itself can participate in multicomponent reactions9 we are
investigating the application of the conditions here described in
more complex situations, and additional studies of our research
group will be described in due time.
8. General synthetic procedure: 2 mmol of hydrazine, 2 mmol isothiocyanate, and
2 mmol of aldehyde or ketone in 10 mL of MeOH were heated under reflux at the
indicated time in Table 1. After this time, the reaction was treated as indicated in
each case. For 4a–p the solid was decanted and triturated with cold methanol;
4s was recrystallized from acetonitrile; 4q,r,t were purified from silica-gel
column chromatography (hexane/ethyl acetate 7:3; dichloromethane; and
hexane/ethyl acetate 6:4, respectively). Spectral data for new compound: 4i
brown solid, mp 165.5–166.7 °C (recrystallized from ethanol). IR (KBr): 3306,
Acknowledgments
3135, 1547, 1513, 1261, 1206 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 11.73 (s,
;
1H), 9.81 (s, 1H), 7.97 (s, 1H), 7.57 (dd, 2H, J 7.2 Hz, J 1.5 Hz), 7.44–7.16 (m, 6H),
6.83 (s, 1H), 2.20 (s, 3H) ppm; 13C NMR (DMSO-d6): d 176.0, 148.9, 139.4, 137.6,
136.7, 134.7, 129.7, 128.8, 128.4, 128.1, 125.8, 125.5, 13.2 ppm; 4j greenish
solid, mp 179.4–180.2 °C (recrystallized from ethanol), IR (KBr): 3305, 3132,
The authors gratefully acknowledge the financial support of
Conselho Nacional de Desenvolvimento Científico e Tecnológico—
CNPq and Fundação de Amparo à Pesquisa do Estado da Bahia—FA-
PESB. We also thank CNPq for fellowship to T.L.S., and a research
fellowship to S.C., and Professor Mauricio Victor for the comments.
1552, 1501, 1251, 1194 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 11.69 (s, 1H),
;
10.07 (s, 1H), 8.06 (s, 1H), 7.82 (d, 1H, J 1.2 Hz), 7.55 (d, 2H, J 7.8 Hz), 7.40–7.31
(m, 4H), 7.22–7.02 (m, 2H), 6.94 (d, 1H, J 7.8 Hz), 6.11 (s, 1H), 6.07 (s, 1H) (E–Z
mixture 2:1) ppm; 13C NMR (DMSO-d6): d 175.7, 149.0, 148.0, 142.6, 139.0,
128.5, 128.1, 127.9, 126.0, 125.2, 124.2, 108.1, 105.5, 101.4 ppm; 4l brown solid,
mp 184.7–186.5 °C (recrystallized from ethanol), IR (KBr): 3326, 3144, 1550,
References
1507, 1273, 1204 cmÀ1 1H NMR(300 MHz, DMSO-d6): d 11.63 (s, 1H), 9.97 (s,
;
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2H, J 7.5 Hz), 7.21–7.16 (m, 2H), 6.95 (d, 1H, J 8.4 Hz), 3.81 (s, 3H) ppm;. 13C NMR
(DMSO-d6): d 175.4, 149.7, 146.6, 143.3, 139.0, 127.9, 126.8, 125.4, 125.0, 120.6,
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