Synthesis of thiadiazoles and 1,2,4-triazoles derived from cyclopropane dicarboxylic acid

Article abstract of DOI:10.3390/10091153

New heterocyclic derivatives of cyclopropane dicarboxylic acid comprising thiadiazole and 1,2,4-triazole moieties are reported. Reaction of 1,1-cyclopropane dicarboxylic acid (1) with thiosemicarbazide and phosphorous oxychloride resulted in 1,1-bis (2-am

Full text of DOI:10.3390/10091153

Molecules 2005, 10, 1153-1160
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Thiadiazoles and 1,2,4-Triazoles Derived from
Cyclopropane Dicarboxylic Acid .
A. Hussain K. Sharba*, Rida H.Al-Bayati , Nadjet Rezki and Mohammed R. Aouad
Department of Chemistry, College of Science, Al-Mustansirya University, Baghdad, Iraq.
*
Author to whom correspondence should be addressed; e-mail: hussainirk@yahoo.com
Received: 29 June 2005; in revised form: 29 August 2005 / Accepted: 30 August 2005 / Published: 30
September 2005
Abstract: New heterocyclic derivatives of cyclopropane dicarboxylic acid comprising
thiadiazole and 1,2,4-triazole moieties are reported. Reaction of 1,1-cyclopropane
dicarboxylic acid (1) with thiosemicarbazide and phosphorous oxychloride resulted in
1,1-bis (2-amino-1,3,4-thiadiazol-5- yl)cyclopropane (2). Cyclopropane dicarboxylic acid
thiosemicarbazide (6) was converted into 1,1-bis(3-thio-4H-1,2,4-triazol-5-yl) cyclo-
propane (7) by ring closure in an alkaline medium. The thiadiazole 2 and the triazole 7
were converted into a variety of derivatives.
Keywords: Bis-thiadiazolylcyclopropane, bis–triazolylcyclopropane, azomethines,
Mannich bases.
Introduction
Thiadiazoles, oxadiazoles and triazoles are five–membered rings associated with diverse biological
and pharmacological properties [1]. For example, triazole derivatives are active as antibacterial,
antiviral and insecticidal agents [2]. Substituted 1,2,4-triazoles have been associated with activities
such as anti-inflammatory and diuretic agents and as plant grown regulators [3]. Esters of 1,1-
cyclopropane dicarboxylic acid are important insecticidal agents [4]. In continuation of our interest in
the chemistry of 1,1-cyclopropane dicarboxylic acid, thiadiazole and 1,2,4-triazole derivatives of this
acid have been prepared by conventional synthetic techniques.

Molecules 2005, 10
1154
Results and Discussion
1,1-Cyclopropane dicarboxylic acid was obtained from diethylmalonate and 1,2-dibromoethane.
When the acid was treated with thiosemicarbazide and phosphorous oxychloride (Scheme 1), 1,1-
bis(2-amino-1,3,4-thiadiazol-5-yl) cyclopropane (2) was obtained in good yield. The IR spectrum
-
1
indicated the presence of a C=N function (1605 cm ) and the NMR spectrum showed a singlet at δ
.29 ppm due to the NH protons and a multiplet at 1.08 – 1.51 ppm for the cyclopropane ring protons.
Reaction of the aminothiadiazole 2 with aromatic aldehydes produced new Schiff bases 3a-c in
3
2
high yield (Scheme 1, Table 1). Propynylation of 2 with propargyl chloride, followed by reaction with
formaldehyde and secondary amines afforded the Mannich bases 5a-c (Scheme 1, Table 1).
Scheme 1
HOOC
COOH
1
POCl , H NNHCSNH
2
3
2
N
N
N
N
H N
S
S
NH2
2
2
ArCHO
BrCH C
CH
2
N
N
N
N
N
N
N
N
ArHC=N
S
S
N=CHAr
NHCH C CH
2
HC
CCH HN
S
S
2
3
a-c
Ar = C H , p-Cl-C H , p-NO -C H
4
4
6
5
6
4
2
6
R NH, HCHO
2
N
N
N
N
R NCH C
CCH HN
S
S
NHCH C CCH NR
2
2 2
2
2
2
5
a-c
R = N(CH ) , piperidine, morpholine
3
3

Molecules 2005, 10
Table 1 Properties of 1,1- bis-(1,3,4- thiadiazolyl) cyclopropane derivatives.
1155
N
N
N
N
S
NR2
R N
S
2
Spectral data
UV, λmax
Comp.
No.
Yield
0
IR cm-1
R
mp C
%
38
45
40
(EtOH)
1
6
1
3
1
3
1
605 (C=N), 3165, 3280 (NH
2
),
2
H
214-217
201-204
199-201
290
60 (C-S-C)
630 (C=N), 2940-2980 (C-H),
020 (C-HAr), 830 (C-Cl)
620 (C=N), 2900-2920 (C-H),
025 (C-HAr), 1345,1520 (NO
620 (C=N), 3130 (N-H), 2120
3
b
c
=CHC
=CH-C
6
H
4
-Cl-p
293
263
3
6
H
4
NO -p
2
2
)
4
2
CH C ≡ CH
243-246
60
260
(C≡C), 3240 (≡C-H), 1180 (C-N),
760 (C-S-C),
1
620 (C=N), 3190 (N-H), 1220
5
a
CH
2
C≡C-CH
2
N(CH
3
)
2
230-232
237-298
48
54
298
300
(
C-N)
610 (C=N), 3250 (NH), 2125
C≡C), 650 (C-S -C)
1
(
CH C CCH2
N
O
5b
2
5c
1610 (C=N), 3250 (N-H), 1180
C-N)
CH C CCH2
N
2
233-235
50
345
(
All compounds gave satisfactory CHN analysis .
On the other hand, oxidative cyclization of the 1,1-bis-cyclopropane dicarboxylic acid
thiosemicarbazide 6 with aqueous sodium hydroxide (Scheme 2) afforded 1,1-bis(3-thio-4H-1,2,4-
triazol-5-yl) cyclopropane (7), which exists in two tautomeric forms [5,6], the thiol 7a and the thione
-
1
7
b, as indicated by the presence of the characteristic S-H stretching at 2620 cm (7a) or the C=S
-
1
-1
stretching at 1220 cm (7b), in addition to the absorption bands at 1615 cm for the C=N stretching
-
1
and 3120 cm for N-H stretch. The NMR spectrum of 7 shows two singlets at 3.7 ppm and 3.8 ppm
for the N-H [6] and S-H [8] protons of the triazole ring, respectively, and a multiplet at 0.9 – 1.1 ppm
for the cyclopropane ring protons [9].
Reaction of 7 with chloroacetic acid yielded 8 which on treatment with thionyl chloride and
hydrazine hydrate afforded the acid hydrazide 9. Condensation with aromatic aldehydes in absolute
ethanol gave the Schiff bases 10a-c. Introduction of a propynylic function by reaction with propargyl
chloride in alkaline medium followed by the Mannich reaction with paraformaldehyde and secondary
amines gave the Mannich bases 11a-c (Scheme 2, Table 2).

Molecules 2005, 10
1156
Scheme 2
1
SOCl , H NNNCSNH
2
2
2
H NSCHNHNOC
CONHNHCSNH2
2
6
NaOH
N
N
N
N
1
. HC CCH Cl
2
ClCH COOH
HS
N
H
N
H
SH
2
2
. R NH, HCHO
2
7
N
N
N
N
N
N
N
N
R NCH C
CCH2S
N
H
N
H
SCH C
2
CCH NR2
HOOCCH2S
N
H
N
H
SCH
COOH
2
2
2
2
1
1a-c
8
NR = piperidine, morpholine, cyclohexylamine
2
1
. SOCl2
2
. N H · H O
2
4
2
N
N
N
N
H NNHNCOCH S
N
N
SCH CONHNH
2 2
2
2
H
H
9
ArCHO
N
N
N
N
ArCH=NNHCOCH2S
N
N
H
SCH CONHN=CHAr
2
H
1
0a-c
Ar = p-Cl-C H , p-NO -C H , p-Br-C H
4
6
4
2
6
4
6
The structures of all derivatives of the thiotriazole 7 were proven on the basis of melting points
mp), thin layer chromatography (TLC) and spectral data. The IR spectra of compound 9 exhibited a
(
-
1
-1
C=O stretching vibration near 1675 cm and NH,NH
2
stretching vibrations at 3180–3200 cm .
The Schiff bases 10a-c (Table 2) display in their IR carbonyl and azomethine absorptions near
-
1
-1
-1
1
680 cm and 1625 cm , respectively, in addition to aromatic C=C at 1600 cm and =C-H at 3080
-
1
cm . The formation of the Mannich bases 11 was confirmed by the presence of a weak absorption
-
1
near 2120 cm for C ≡ C and at 1260-1280 due to C-N stretching.

Molecules 2005, 10
Table 2 Properties of 1,1- bis (3- thiol -4H–1,2,4-triazol- 5–yl) cyclopropanes.
1157
N
N
N
N
SR
RS
S
S
Spectral
data
UV, λmax
Comp.
No.
R
Mp°C
Yield %
IR cm-1
(EtOH)
2
(
2
860 (C-H), 3120 (N-H), 1615
C=N), 2620 (S-H), 1220 (C=S).
970, 2910 (C-H), 3500-3000
(COOH), 1630 (C=N), 1670 (C=O),
7
H
270
58
45
223.5
8
HOOC-CH
2
237-39
290
305.5
297.5
308
770 (C-S-C) .
2990, 2920 (C-H), 1640 (C=O),
9
H
2
NNHCOCH
2
217-20
203-05
209-211
48
50
48
1610 (C=N), 3180 (N-H), 3200
NH ) .
200 (N-H), 3080 (C-Har), 2890,
2930 (C-Hal), 1600 (C=N), 1665
C=O), 790 (C-Cl) .
150 (N-H), 3020 (C-Har), 2920
(C-Hal), 1610 (C=N), 1665 (C=O),
(
3
2
10a
p-ClC
6
H
4
CH=NNHCOCH
2
(
3
1
0b
p-NO
2
C
6
H
4
CH=NNHCOCH
2
1
540,1325 (C-NO
2
)
3220 (N-H), 3100 (C-Har), 2970
1
0c
p-BrC
6
H
4
CH=NNHCOCH
2
215-17
249-50
46
48
315
237
(C-Hal), 1630 (C=N), 1670 (C=O),
650 (C-Br) .
3150 (N-H), 2120 (C ≡C,w), 1605
N
N
CH C CCH2
11a
2
(C=N), 1275 (C-N) .
3200 (N-H), 2110 (C ≡C,w), 1610
1
1b
256-57
259-60
50
47
302
301
O
CH C CCH2
2
(C=N), 1260 (C-N) .
3165 (N-H), 2115 (C ≡C,w), 1610
11c
(C
6
H
11
)
2
NCH
2
C ≡ CCH
2
(C=N), 1280 (C-N) .
All compounds gave satisfactory CHN analysis .

Molecules 2005, 10
1158
Experimental
General
Melting points were determined in open capillary tubes on a Gallenkamp melting point apparatus
and are uncorrected. The IR spectra were recorded by KBr discs with a Pye-Unicam SP3-100
1
spectrometer. UV spectra were recorded with Hitachi 2000 spectrophotomer. H-NMR spectra were
recorded on a Hitachi – Perkin- Elmer 60 – MHz NMR spectrometer in CDCl
3
– DMSO-d with TMS
6
as an internal standard. Elemental analyses were done on a Carlo- Erba Analyzer type 1106. Starting
chemical compounds were obtained from Fluka or Aldrich. Characterization data of the products is
given in Tables 1 and 2.
Preparation of 1,1-Bis (2-amino-1,3,4-thiadiazol-5-yl) cyclopropane (2).
A mixture of 1,1-cyclopropane dicarboxylic acid [10]) (0.01 mole), thiosemicarbazide (0.02 mole)
and phosphorous oxychloride (5 mL) was gently refluxed for 30 minutes. After cooling water (10 mL)
was added and the reaction mixture was refluxed for four hours and filtered. The solution was
neutralized with KOH and the precipitate was filtered and recrystallized from ethanol.
Preparation of compounds 3a-c.
The corresponding aryl aldehyde (0.1 mole) was added to a stirred solution of compound 2 (0.1
mole) in absolute ethanol (30 mL) and the mixture was refluxed for 2 hours. After cooling the mixture
was filtered and the solid recrystallized for methanol.
Preparation of 1,1- bis(3-aminoprop-2-ynyl-1,3,4–thiadiazol-5-yl) cyclopropane (4) .
Propargyl bromide (0.02 mole) was added dropwise to a stirred solution of compound 2 (0.01
mole) and triethylamine (0.01 mole) in ethanol (25 mL). The mixture was refluxed for 2 hours then the
solvent was evaporated and the product was collected and crystallized from ethanol-water.
Preparation of Mannich bases 5a–c.
To a solution of compound 4 (0.025 mole) in dry dioxane (50 mL) was added paraformaldehyde
(
0.05 mole), the appropriate secondary amine (0.05 mole) and catalytic amount (0.05 g) of cuprous
0
chloride. The reaction mixture was heated for 2 hours at 90 C. After cooling the mixture was filtered
and poured on to ice-water and the precipitite was filtered and crystallized from chloroform.
Preparation of 1,1-cyclopropane dicarboxylic acid thiosemicarbazide (6).
A mixture of compound 1 (0.01 mole) and thionyl chloride (10 mL) was refluxed gently for 7
hours. Excess thionyl chloride was removed under vaccum to give red-brown oil of the acid chloride

Molecules 2005, 10
1159
which was dissolved in dry benzene (25 mL) and thiosemicarbazide (0.02 mole) was added. The
reaction mixture was refluxed for 2-3 hours. The product was filtered and recrystallized from ethanol .
Preparation of 1,1-bis(3-thio-1,2,4-triazol-5-yl) cyclopropane (7).
A stirring mixture of 6 (0.01 mole) and sodium hydroxide (0.01 mole, as 4% solution) was
refluxed for 4 hours. After cooling the solution was decolorized with activated carbon and filtered. The
filtrate was acidified with hydrochloric acid and the precipitate was filtered and recrystallized from
ethanol – water.
Preparation of compound 8.
To a stirring solution of α–chloroacetic acid (0.01 mole ) in 10% sodium hydroxide (10 ml) was
added a solution of compound 7 in 10% sodium hydroxide (10 ml) .The reaction mixture was refluxed
for 3 hours . After cooling the solution was acidified with coc. HCl and the product was collected and
recrystallized from ethanol.
Preparation of compound 9.
A mixture of compound 8 (0.002 mole) and thionyl chloride (8 mL) was refluxed for 2 hours.
Excess thionyl chloride was removed in vacuo and the resulting acid chloride was crystallized from
methanol. This was dissolved in pyridine (10 mL) and hydrazine hydrate (2 mL) was added dropwise
with cooling. The reaction mixture was stirred overnight at room temperature then it was heated for 2
hours at 80 °C. Excess pyridine was removed in vacuo and product 9 was crystallized from ethanol-
water
.
Preparation of Schiff bases 10 a-c.
These compounds were prepared following the same procedure used in preparation of compounds
a –c.
3
Preparation of Mannich bases 11a-c.
These compounds were prepared by the same procedure used for compounds 5a-c.
References and Notes
1- Mori, I; Iwasaki, G.; Kimura, Y.; Matsunaga, S.; Ogawa, A., Nakano, T.; Buser, H-P.; Hatano., M.;
Tada, S.; Hayakawa, K. J. Am. Chem.Soc. 1995, 117, 4411.
2
- Horst, W.; Marion, T.; Emil, T. East German Pat. Appl. DD 205,868, 1978; [Chem. Abstr. 1980,
92, 41963 j].
3
- Elise, C. Sci. News 1993, 143, 255.
4- Dekimpe, N.; De Buyck, L. Bull. Soc.Chem. Belg. 1977, 86, 55.

Molecules 2005, 10
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5
6
7
8
9
1
- Becker, H.G.O.; Withaner, J.; Sauder, N.; West, G. J. Prakt. Chem. 1989, 311, 646.
- Nargund, L.V.G.; Redely, G.R.N.; Hariprasad, H. Indian J. Chem. 1996 , 35B, 499.
- Ewiss, N.F.; Bahajap, A.A.; El- Sherbini, E.A. J. Heterocyclic Chem. 1986, 23, 1458.
- Goswami, B.N.; Skataky, J.C.; Baruah, J.N. J. Heterocyclic Chem. 1984, 21, 1225.
- Kothari, P.J.; Sirgh, S.P.; Parmer, V.I. Stenberg, S.S. J. Heterocyclic Chem. 1980, 17, 1393.
0- Prepared according to the method in the literature: Czurny, M.R.; Semmel, M.F. Org. Synth. 1975,
0, 66.
6
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