Dual behavior of monothiocarbohydrazones in the cyclization with diethyl acetylene dicarboxylate (DEAD): Synthesis of substituted 1,3-thiazolidin-4-ones

Article abstract of DOI:10.1080/17415993.2011.608799

Aliphatic aldehydes and cyclohexanone reacted with thiocarbohydrazide to give exclusively 6-substituted-1,2,4,5-tetrazinane-3-thiones, which readily underwent cyclization with diethyl acetylene dicarboxylate to afford condensed thiazolidinones. On the other hand, cyclopentanone and cycloheptanone reacted under a similar sequence of reaction conditions to give 3-amino thiazolidin-4-ones. [image omitted].

Full text of DOI:10.1080/17415993.2011.608799

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Dual behavior of
monothiocarbohydrazones in the
cyclization with diethyl acetylene
dicarboxylate (DEAD): synthesis of
substituted 1,3-thiazolidin-4-ones
Hasan I. Tashtoush a , Fatima Abusahyon a , Mohanad Shkoor a
Mahmoud Al-Talib a
&
a Chemistry Department, Yarmouk University, Irbid, Jordan
Published online: 22 Aug 2011.
To cite this article: Hasan I. Tashtoush , Fatima Abusahyon , Mohanad Shkoor & Mahmoud Al-
Talib (2011) Dual behavior of monothiocarbohydrazones in the cyclization with diethyl acetylene
dicarboxylate (DEAD): synthesis of substituted 1,3-thiazolidin-4-ones, Journal of Sulfur Chemistry,
32:5, 405-412, DOI: 10.1080/17415993.2011.608799
To link to this article: http://dx.doi.org/10.1080/17415993.2011.608799
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Journal of Sulfur Chemistry
Vol. 32, No. 5, October 2011, 405–412
Dual behavior of monothiocarbohydrazones in the cyclization
with diethyl acetylene dicarboxylate (DEAD): synthesis of
substituted 1,3-thiazolidin-4-ones
Hasan I. Tashtoush, Fatima Abusahyon, Mohanad Shkoor and Mahmoud Al-Talib*
Chemistry Department, Yarmouk University, Irbid, Jordan
(Received 7 June 2011; final version received 26 July 2011)
Aliphatic aldehydes and cyclohexanone reacted with thiocarbohydrazide to give exclusively 6-substituted-
1,2,4,5-tetrazinane-3-thiones, which readily underwent cyclization with diethyl acetylene dicarboxylate to
afford condensed thiazolidinones. On the other hand, cyclopentanone and cycloheptanone reacted under a
similar sequence of reaction conditions to give 3-amino thiazolidin-4-ones.
CO2Et
S
when R2 = H, R1 aliphatic
R2+R1 = CH2(CH2)3CH2
O
N
N
NH
HN
S
CO2Et
CO2Et
R1 R2
EtOH
HN
HN
NH
NH
+
CO2Et
Δ
R1 R2
S
when R2+R1 = CH2(CH2)nCH2, n=2 or 4
O
N
N
N
R1
NH2
R2
Keywords: tetrazinanethiones;thiocarbohydrazide;monothiocarbohydrazone;electron-deficientalkynes;
thiazolidinone
1. Introduction
Condensed 4-thiazolidinones have attracted the attention of organic chemists and pharmacolo-
gists due to the biological significance associated with the thiazolidinone nucleus. On the other
hand, the synthesis of spiro compounds has always been a challenge and attraction due to their
pharmacological activities. 4-Thiazolidinones are embedded in the structures of various synthetic
pharmaceuticals displaying a broad spectrum of biological activities (1), including antimicrobial
(2), antifungal (3), antimalarial (4), antiviral (5), antibacterial (5), antioxidant (6), anti-HIV (7),
*Corresponding author. Email: mahmoud_talib@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2011.608799
http://www.tandfonline.com

406 H.I. Tashtoush et al.
R1
S
S
H
N
H
N
O
H+
R2
H2N
NH2
H2N
N
R1
R2
+
N
H
N
H
N
H
N
H
N
H
R1
N
H
R2
S
1
A
B
HN NH
N
HN
N
R2
R1
R2
R1
S
NHNH2
S
NH2
D
C
Scheme 1. Chain–ring and ring–ring tautomerism of monothiocarbohydrazones.
anti-convulsant (8), antitumor (9), anti-inflammatory (10), herbicidal (11) and many others (12).
Imino thiazolidine-4-ones are widely studied for their interesting activities. The impressive chem-
istry of these compounds was reviewed (see review (13)). The great importance of these moieties
provoked us to study the synthesis of condensed spiro thiazolidinones.
Thiocarbohydrazide has been widely used in the synthesis of heterocyclic compounds with
biological and pharmacological interest. The subject has recently been reviewed (14).
It has been reported that thiocarbohydrazide condenses with carbonyl compounds to form
the linear monothiocarbohydrazones “true hydrazones” A, which have the tendency to undergo
reversible ring–chain tautomerism to form 1,2,4,5-hexahydrotetrazine-3-thione B, the latter
undergoes ring–ring equilibrium with 4-amino-1,2,4-triazolidine-3-thione C and 2-hydrazino-
4,3-dihydro-1,3,4-thiadiazole D via A (15) (Scheme 1). Some generalizations have been made
on the influence of the presence of a monothiocarbohydrazone on a specific tautomeric config-
uration or on an unequal mixture of certain tautomers (for NMR study of the tautomerization,
see (16)).
2. Results and discussion
The acid-catalyzed condensation of thiocarbohydrazide 1 with equimolar amounts of aliphatic
aldehydes and alicyclic ketones in an alcoholic solution furnished the corresponding monoth-
iocarbohydrazones. It is apparent from the observed NMR data that these monothiocarbohy-
drazones adopt the cyclic structures corresponding to 6-alkyl-1,2,4,5-tetrazinane-3-thiones 3a–g
(Scheme 2). The observed tautomeric structures of these compounds are consonant with previous
studies (15–17).
1,2,4,5-Tetrazinane-3-thiones 3a–d and f underwent cyclization with diethyl acetylene dicar-
boxylate (DEAD) (4), in ethanol under reflux, to afford the condensed thiazolidinones 5a–d and
f, respectively (Scheme 3).
In contrast, the cyclization of 3e and g with DEAD under similar reaction conditions
resulted in the regioselective formation of 3-amino-thiazolidin-4-ones 5e and g exclusively
(Scheme 4).
Broad signals at δ = 4.78 ppm and at δ = 4.80 ppm integrated for two hydrogens and are readily
assigned to the NH2 protons of 5e and g, respectively. Two signals corresponding to imino carbons
were also observed in both 13C-NMR spectra, whereas only one sp2 imino carbon signal and two
signals for two different NH protons were detected for 5f.

Journal of Sulfur Chemistry 407
S
S
O
H+
i
HN
HN
NH
NH
H2N
NH2
+
N
H
N
H
R1
R2
R1 R2
2
1
3
i: EtOH, reflux, 3hr
2,3 R1
R2
H
Yield of
3 (%)a
91
a
-C3H7
b
c
d
e
f
-C4H9
-C6H13
-CH(CH3)2
[CH2(CH2)2CH2]
H
H
H
87
92
88
b
b
b
[CH2(CH2)3CH2]
[CH2(CH2)4CH2]
g
a
b
: yields of isolated products,
: compounds are reported, see references (15-17)
Scheme 2. Synthesis of 3a–g.
CO2Et
S
CO2Et
S
EtOH
HN
HN
NH
NH
O
+
N
N
NH
Δ
HN
CO2Et
R1 R2
R1 R2
3a-d,f
4
5a-d,f
3,5 R1
R2
Yield of
5 (%)
a
a
-C3H7
H
77
b
c
d
f
-C4H9
-C6H13
-CH(CH3)2
H
H
H
81
79
72
88
[CH2(CH2)3CH2]
a
: yields of isolated products
Scheme 3. Synthesis of condensed thiazolidinones 5a–d,f.
This discrepancy is attributed to the tendency of these monothiocarbohydrazones to undergo
ring–chain tautomerization in solution. It is well established that cyclohexanone monothiocar-
bohydrazone exists exclusively in the heterospirocyclic configuration 3f, whereas other alicyclic
carbonyl compounds exist mainly in cyclic forms (16).
These results led us to presume that the initial reaction step is the nucleophilic addition of the
linear monothiocarbohydrazone sulfur atom of the tautomer A at the triple bond of DEAD to
give intermediate B; the subsequent intramolecular cyclization and expulsion of EtOH then give
5e and g. The other regioisomer resulting from the cyclization of tautomer C was not detected.
It is expected that the tautomer A is mainly present due to the conjugation of the double bonds
(Scheme 5).

408 H.I. Tashtoush et al.
CO2Et
O
S
CO2Et
CO2Et
S
EtOH
HN
HN
NH
NH
+
N
N
N
Δ
NH2
n
n
3e,g
5e,g
R2
4
3,5
n
R1
Yield of
a
5 (%)
e
g
1
3
[CH2(CH2)2CH2]
[CH2(CH2)4CH2]
72
75
a
: yields of isolated products
Scheme 4. Regioselective formation of 3-amino-thiazolidin-4-ones 5e and g.
S
SH
H
N
n
HN
HN
NH
NH
N
n:1,3
N
H2N
H2N
N
N
N
H
n
SH
A
C
n
O
OEt
3e,g
EtO
O
EtO2C
S
H2N
N
NH2
EtO
HN
S
O
N
N
n
N
N
O
B
n
EtO
O
-EtOH
CO2Et
N
N
S
N
O
H2N
5e,g
Scheme 5. Plausible mechanism of the regioselective formation of 3-amino-thiazolidin-4-ones
5e and g.
3. Conclusion
The cyclization of DEAD with monothiocarbohydrazones of aliphatic aldehydes and cyclo-
hexanone gave exclusively condensed 1,3-thiazolidin-4-ones, while monothiocarbohydrazones
derived from cyclopentanone and cycloheptanone afforded 3-amino-thiazolidin-4-ones. This dual
behavior is probably due to ring–chain tautomerization.

Journal of Sulfur Chemistry 409
4. Experimental
Melting points were determined on an electrothermal-digital melting point apparatus and were
uncorrected. 1H-NMR spectra were determined using Bruker Avance 400 spectrometer in deuter-
ated chloroform, with tetramethylsilane (TMS) as an internal standard. 13C-NMR spectra were
recorded on Brucker Avance 400 spectrometer. Infrared spectra (IR) were recorded on Perkin
Elmer FT-IR SP-2000 spectrometer as potassium bromide (KBr) pellets. Mass spectra were deter-
mined on a sector field double focusing unit VG7070 E mass spectrometer. All newly synthesized
compounds gave satisfactory results following elemental analyses. Elemental analyses were done
in the Institute of Chemistry of University of Rostock. Chemicals were purchased from Aldrich
and Fluka and were used without further purification.
4.1. General procedure for the synthesis of tetrazinethiones 3a–g
To a solution of 1 (10 mmol) in absolute ethanol (25 ml), with catalytic amount of HOAc, 10 mmol
of aliphatic aldehydes and/or cyclic ketones 2a–g were added. The reaction mixture was stirred
under reflux for 3 h. The resulting precipitate was collected, washed with ethanol and ether and
finally dried to afford the desired products.
4.1.1. 6-Propyl-1,2,4,5-tetrazinane-3-thione (3a)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 9.15 (s, 2H, NH); 4.71 (s, 2H, NH); 3.40 (s, 1H, CH);
1.44 (m, 2H, CH2); 1.30 (m, 2H, CH2); 0.86 (t, J3 = 6.5, 3H, CH3). 13C-NMR (CDCl3/TMS) δ
(ppm): 173.0; 66.3; 32.3; 18.9; 14.5. Ms (m/z, rel. int. (%)): 160 (M+, 5); 117 (M+–C3H7, 12);
106 (M+–C4H6, 56); 43 (M+–C2H5N4S, 100). IR (cm−1) KBr disc: 3180 (N–H), 1528 (N–H),
yellowish solid, m.p. 158–160◦C, yield (91%).
4.1.2. 6-Butyl-1,2,4,5-tetrazinane-3-thione (3b)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 9.15 (s, 2H, NH); 4.70 (bs, 2H, NH); 3.59 (m, 1H,
CH); 1.34–1.25 (m, 6H, CH2); 0.86 (t, J3 = 6.7, 3H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm):
173.1; 66.6; 29.9; 27.8; 22.4;14.3. Ms (m/z, rel. int. (%)): 174 (M+, 73); 143 (M+–N2H3, 38); 130
(M+–CS, 5); 117 (M+–C4H9, 100); 100 (M+–C5H12N3, 20). IR (cm−1) KBr disc: 3192 (N–H),
1529 (N–H), yellowish solid, m.p. 157–159◦C, yield (87%).
4.1.3. 6-Hexyl-1,2,4,5-tetrazinane-3-thione (3c)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 9.15 (s, 2H, NH); 4.70 (bs, 2H, NH); 3.39 (m, 1H, CH);
1.34–1.23 (m, 10H, CH2); 0.84 (t, J3 = 6.8, 3H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 173.0;
66.6; 31.6; 30.2; 29.0; 25.6; 22.5; 14.4. Ms (m/z, rel. int. (%)): 202 (M+, 25); 171(M+–N2H3,
20); 117(M+–C6H13, 59); 43 (M+–C3H7, 100). IR (cm−1) KBr disc: 3267 (N–H), 1529 (N–H),
pale yellowish solid, m.p. 166–168◦C, yield (92%).
4.1.4. 6-Isopropyl-1,2,4,5-tetrazinane-3-thione (3d)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 9.14 (s, 2H, NH); 4.70 (bs, 2H, NH); 3.14 (m, 1H, CH);
1.60–1.51 (m, 1H, CH); 0.92 (d, J3 = 6.8, 6H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 173.3;
71.8; 28.7; 19.7. Ms (m/z, rel. int. (%)): 160 (M+, 100); 145 (M+–CH3, 35); 118 (M+–C3H6,

410 H.I. Tashtoush et al.
10); 104 (M+–C4H8, 46). IR (cm−1) KBr disc: 3207 (N–H), 1515 (N–H), yellowish solid, m.p.
159–161◦C, yield (88%).
4.2. General procedure for the preparation of compounds 5a–g
To a solution of 3a–g (5 mmol) in absolute methanol (10 ml), DEAD (5 mmol) was added. The
reaction mixture was stirred under reflux for about 12 h. The reaction mixture was cooled and the
resulting solid was collected by filtration and recrystallized from chloroform/ether and dried.
4.2.1. Ethyl 2-(6-oxo-3-propyl-3,4-dihydro-2H-thiazolo[3,2-b][1,2,4,5]tetrazin-7(6H)-
ylidene)acetate (5a)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.90 (s, 1H, CH); 5.63 (s, 1H, NH); 4.55 (bs, 1H, NH);
4.30 (q, J3 = 7.1, 2H, CH2); 4.11–4.03 (m, 1H, CH); 1.66 (m, 4H, CH2); 1.36 (t, J3 = 7.1, 3H,
CH3); 1.15 (t, J3 = 7.2, 3H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 166.2; 158.8; 140.4; 136.1;
115.6; 66.8; 61.6; 32.8; 17.9; 14.2; 13.9. Ms (m/z, rel. int. (%)): 284 (M+, 49); 269 (M+–CH3,
17); 241 (M+–C3H7, 100); 213 (M+–C4H9N, 49); 85 (C4H10N+2 , 48). IR (cm−1) KBr disc: 3327
◦
=
(N–H), 1677 (C O). Yellowish solid, m.p. 167–169 C, yield (77%).
4.2.2. Ethyl 2-(3-butyl-6-oxo-3,4-dihydro-2H-thiazolo[3,2-b][1,2,4,5]tetrazin-7(6H)-
ylidene)acetate (5b)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.9 (s,1H,CH); 5.5 (s, 1H, NH); 4.49 (bs, 1H, NH);
4.30 (q, J3 = 7.1, 2H, CH2); 4.11–4.03 (m, 1H, CH); 1.70–1.35 (m, 6H, CH2); 1.30 (t, J3 = 7.1,
3H, CH3); 0.91 (t, J3 = 7.0, 3H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 166.2; 158.7; 140.4;
136.1; 115.6; 67.1; 61.6; 30.5; 26.5; 22.5; 14.2; 13.7. Ms (m/z, rel. int. (%)): 298 (M+, 19); 283
(M+–CH3, 8); 269 (M+–C2H5, 27); 241 (M+–C4H9, 100); 169 (M+–C7H13O2, 10); 103 (M+–
◦
C4H7O, 20). IR (cm−1) KBr disc: 3326 (N–H), 1737 (C O). Yellowish solid, m.p. 161–163 C,
yield (81%).
=
4.2.3. Ethyl 2-(3-hexyl-6-oxo-3,4-dihydro-2H-thiazolo[3,2-b][1,2,4,5]tetrazin-7(6H)-
ylidene)acetate (5c)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.92 (s, 1H, CH); 5.59 (s, 1H, NH); 4.49 (bs, 1H, NH);
4.34–4.27(q, J3 = 7.1, 2H, CH2); 4.08–4.03 (m, 1H, CH); 1.69–1.49 (m, 10H, CH2); 1.37 (t,
J3 = 7.1, 3H, CH3); 0.90 (t, J3 = 6, 3H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 166.2; 158.7;
140.4; 136.1; 115.6; 67.1; 61.6; 31.4; 30.8; 29.0; 24.4; 22.5; 14.2; 13.9. Ms (m/z, rel. int. (%)):
326 (M+, 54); 269 (M+–C4H9, 70); 256 (M+–C5H10, 100); 242 (M+–C6H13, 70)◦; 85 (C6H1+3,100).
IR (cm−1) KBr disc: 3325 (N–H), 1679 (C O). Yellowish solid, m.p. 146–148 C, yield (79%).
=
4.2.4. Ethyl 2-(3-isopropyl-6-oxo-3,4-dihydro-2H-thiazolo[3,2-b][1,2,4,5]tetrazin-7(6H)-
ylidene)acetate (5d)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.92 (s, 1H, CH); 5.60 (s, 1H, NH); 4.50 (bs, 1H, NH);
4.31(q, J3 = 7.1, 2H, CH2); 3.92–3.85 (m, 1H, CH); 2.02–1.90 (m, 1H, CH); 1.12 (t, J3 = 7.1,
3H, CH3); 0.91 (d, J3 = 6.2, 6H, CH3). 13C-NMR (CDCl3/TMS) δ (ppm): 166.2; 158.7; 140.5;
135.9; 115.5; 71.4; 61.6; 29.2; 17.6; 17.4; 14.2. Ms (m/z, rel. int. (%)): 284 (M+, 40); 269 (M+–
CH3, 10); 256 (M+–C2H5, 8); 241 (M+–CH(CH3)2, 49); 85(C4H10N2+, 48). IR (cm−1) KBr disc:
◦
=
3283 (N–H), 1704 (C O). Yellowish solid, m.p. 153–156 C, yield (72%).

Journal of Sulfur Chemistry 411
4.2.5. Ethyl 2-(3-amino-2-(cyclopentylidenehydrazono)-4-oxothiazolidin-5-ylidene)
acetate (5e)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.88 (s, 1H, CH); 4.78 (sbr, 2H, NH2); 4.28 (q, J3 = 7.1,
2H, CH2); 2.60–2.09 (m, 8H, CH2); 1.33 (t, J3 = 7.1, 3H, CH3). 13C-NMR (CDCl3/TMS) δ
(ppm): 181.5; 165.7; 162.0; 154.2; 139.7; 116.8; 61.6; 33.5; 30.4; 24.8; 25.7; 14.2. Ms (m/z,
rel. int. (%)): 296 (M+, 100); 280 (M+–NH2, 11); 267 (M+–C2H5, 25); 214 (M+–C5H8N, 35);
169 (M+–C6H7O3, 20). IR (cm−1) KBr disc: 3327 (N–H), 1700 (C O). Yellowish solid, m.p.
=
123–126◦C, yield (72%).
4.2.6. Ethyl 2-(6ꢀ-oxospiro[cyclopentane-1,3ꢀ-thiazolo[3,2-b][1,2,4,5]tetrazine]-
7ꢀ(2ꢀH,4ꢀH,6ꢀH)-ylidene)acetate (5f)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.89 (s, 1H, CH); 5.57 (s, 1H, NH); 4.52 (s, 1H, NH);
4.29 (q, J3 = 7.1, 2H, CH2); 1.73–1.50 (m, 10H, CH2); 1.32 (t, J3 = 7.1, 3H, CH3). 13C-NMR
(CDCl3/TMS) δ (ppm): 166.2; 159.1; 140.6; 134.6; 115.3; 66.7; 61.5; 32.0; 25.4; 21.8; 14.2.
Ms (m/z, rel. int. (%)): 310 (M+, 100); 294 (M+–O, 10); 237 (M+–C3H5O2, 13); 214 (M+–
◦
C6H10N, 20). IR (cm−1) KBr disc: 3326 (N–H), 1706 (C O). Yellowish solid, m.p. 166–168 C,
yield (88%).
=
4.2.7. Ethyl 2-(3-amino-2-(cycloheptylidenehydrazono)-4-oxothiazolidin-5-ylidene)
acetate (5g)
1H-NMR (CDCl3/TMS) δ (ppm), J (Hz): 6.89 (s, 1H, CH); 4.80 (sbr, 2H, NH); 4.50 (q, J3 = 7.1,
2H, CH2); 2.65 (m, 4H, CH2); 2.01–1.30 (m, 8H, CH2); 1.30 (t, J3 = 7.1, 3H, CH3). 13C-NMR
(CDCl3/TMS) δ (ppm): 181.5; 165.7; 162.0; 154.1; 139.7; 116.9; 61.6; 33.5; 30.4; 24.8; 14.2.
Ms (m/z, rel. int. (%)): 324 (M+, 1); 230 (M+–C7H12, 100); 202 (M+–C7H12N2, 57); 214 (M+–
◦
C7H14N3, 53). IR (cm−1) KBr disc: 3323 (N–H), 1719 (C O).Yellowish solid, m.p. 126–130 C,
yield (75%).
=
Acknowledgements
Deanship of research and graduate studies atYarmouk University is acknowledged for the financial support. Professor Dr
Peter Langer of University of Rostock is highly acknowledged for providing laboratory facilities.
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