Azines from one-pot reaction of thiosemicarbazones

Article abstract of DOI:10.1080/17415993.2016.1210146

Thermolysis and/or microwave irradiation of thiosemicarbazones gave the corresponding isothiocyanates, which on addition of either activated nitriles or aldehydes furnished various types of azines. The mechanism was discussed. The structures of products were proved by MS, IR, NMR, and elemental analyses (Image presented).

Full text of DOI:10.1080/17415993.2016.1210146

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Azines from one-pot reaction of
thiosemicarbazones
Ashraf A. Aly, Alaa A. Hassan, Alan B. Brown, Mohamoud A. A. Ibrahim & El-
Shimaa S. M. AbdAl-Latif
To cite this article: Ashraf A. Aly, Alaa A. Hassan, Alan B. Brown, Mohamoud A. A. Ibrahim & El-
Shimaa S. M. AbdAl-Latif (2016): Azines from one-pot reaction of thiosemicarbazones, Journal
of Sulfur Chemistry, DOI: 10.1080/17415993.2016.1210146
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Date: 26 July 2016, At: 02:36

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1210146
Azines from one-pot reaction of thiosemicarbazones
Ashraf A. Alya, Alaa A. Hassana, Alan B. Brownb, Mohamoud A. A. Ibrahima and
El-Shimaa S. M. AbdAl-Latifa
aChemistry Department, Faculty of Science, Minia University, El-Minia, Egypt; bChemistry Department,
Florida Institute of Technology, Melbourne, FL, USA
ABSTRACT
ARTICLE HISTORY
Received 18 May 2016
Accepted 4 July 2016
Thermolysis and/or microwave irradiation of thiosemicarbazones
gave the corresponding isothiocyanates, which on addition of either
activated nitriles or aldehydes furnished various types of azines. The
mechanism was discussed. The structures of products were proved
by MS, IR, NMR, and elemental analyses.
KEYWORDS
Thiosemicarbazones;
thermolysis; microwave
irradiation; isothiocyanates;
azines
1. Introduction
Azines are useful synthetic intermediates,[1] and many possess important and unexpected
biological activities.[2] Methods for synthesis of unsymmetrical azines have received
much attention. Recently, a few new methods have been reported: alkylidene group
exchange between azines and imines,[3] reaction of N-(diethoxyphosphinyl)hydrazones
with carbonyl compounds,[4] and reaction of zirconium ‘metalloazines’ and aldehydes.[5]
However, none of these methods is simple, and most require elevated temperatures [6]
and complex catalysts.[7] Thiosemicarbazones and semicarbazones react with various
π-acceptors and ions, because of the presence of several nucleophilic centers: nitrogen,
azomethine-CH, and sulfur.[8] Recently, we reported an approach to the synthesis of
6-imino-1,3,4-thiadiazines, pyrimidine-2-thiones, and thiazolidines, via the reaction of
thiosemicarbazones with various π-acceptors [5,9–11]; therefore, we now describe our
unexpected finding of azine formation from the thermolysis of thiosemicarbazones with
different aldehydes and/or activated nitriles in a one-pot reaction.
CONTACT Ashraf A. Aly
ashrafaly63@yahoo.com
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
A. A. ALY ET AL.
2. Results and discussion
Reaction of thiosemicarbazones 1a–c with activated nitriles 2a,b in DMF at 120°C for
10–15 h, catalyzed by triethylamine, afforded the corresponding azines 3a–c (70–76%,
Scheme 1, Table 1). The long reflux times led us to assess the reaction under microwave
irradiation (MW); in a few minutes, we obtained the same products 3a–c in 80–90% yields
(Scheme 1, Table 1). However, the reaction of 1d with either 2a or 2b produced a dimer
assigned as 4 (Scheme 2). Based on the TLC analysis, we believed that thermolysis of
thiosemicarbazones 1a–c in DMF under prolonged heating produced intermediates that
subsequently reacted with the activated nitriles to produce the azines 3a–c.
Therefore, we let thiosemicarbazide (5) react with aldehydes 6a–c in DMF, catalyzed
by acetic acid. When TLC indicated conversion to thiosemicarbazones 1a–c, benzalde-
hyde (6a) was added; the same azines 3a–c were obtained in 70–80% yields (Scheme 3),
Scheme 1. Reactions of thiosemicarbazones 1a–c with activated nitriles 2a,b.
Table 1. Structure of azines 3a–c, m.p. and yield (%) obtained by Method II in Scheme 1.
Entries
R1
m.p.
Product structure
Yield (%) by Method II
3a
C6H5
138°C (lit. 93–94°C [12])
80
3b
3c
4-CH3C6H4
120–121°C (lit .123°C [7]
85
90
4-CH3OC6H4 148–150°C (lit. 145–147°C [9])
Scheme 2. Reaction of 1d with activated nitriles 2a or 2b under MW – synthesis of disulfide 4.

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 3. One-pot synthesis of asymmetric azines 3a–c.
although after more prolonged heating (15–20 h) than in case of activated nitriles (Method
I in Scheme 1).
Because the formation of NH3 is observed during the reaction, we suggest the mech-
anism shown in Scheme 4. First, ammonia is released from thiosemicarbazones 1a–c to
form isothiocyanates 8 (Scheme 4). Subsequently, cycloaddition of 8 with the activated
nitriles 2a (or 2b) is proposed to form a four-membered intermediate 9, and finally 10 and
azines 3 are obtained by ring cleavage of 9. Derivatives of compound 10 were not obtained:
we propose that they hydrolyze into the activated nitriles (which are detected by TLC) and
carbon oxysulfide. A similar mechanism is proposed for the reaction of thiosemicarbazide
(5) with two equivalents of aldehyde 6a; in that case, carbon oxysulfide would form directly
(Scheme 5).
It was observed that triethylamine increased the yields of the products. We propose that
triethylamine deprotonates 1 forming the salt 7, which can easily decompose into 8 and
ammonia (Scheme 4). Benzaldehyde (6a) reacts with 8 forming the ring of 1,3-oxazetidine-
2-thione 11, which is easily cleaved into 3a–c and carbon oxysulfide (Scheme 5). Again and
Scheme 4. Proposed mechanism for formation of azines 3a–c from thiosemicarbazones 1a–c and
activated nitriles 2a or 2b.
Scheme 5. Proposed mechanism for formation of azines 3a–c from thiosemicarbazones 1a–c and
benzaldehyde (6a).

4
A. A. ALY ET AL.
Scheme 6. Reaction of thiosemicarbazones 1a–e with ‘the same’ aldehydes 6a–e to form symmetric
azines.
in case of 1d, the reaction proceeded to give 4 (Scheme 6). Interestingly, the reaction of
aldehydes 6a–e with thiosemicarbazones 1a–e derived from the same aldehydes afforded
the corresponding symmetric azines 3a,e–h in good yields (Scheme 6, Table 2).
Compound 3g was obtained after heating for 10 h (Method I) or assisted by MW for
6 min, recrystallized from EtOH and is the only new compound in the series 3a,e–h.
1
In the H NMR (Table 3), the doublets at δ = 7.35 and 7.04 must be H-5 and H-6;
H
the weak COSY correlation between δ = 7.35 and 7.41 presumably denotes the three-
H
bond relation between H-2 and H-6. Accordingly, the doublet at δ = 7.04 is assigned
H
Table 2. Structure of symmetric azines 3a,e–h, m.p. and yield (%).
Entries
R
m.p.
Product structure
Yield (%) by Method II
77
3a
C6H5
138°C (lit. 93–94°C
[12])
3e
3f
4-CH3–C6H4
4-CH3OC6H4
158–160°C (lit
159–160°C [13])
80
82
155–157°C (lit
179–181°C [6])
3g
3h
3,4-(CH2O–CH2)-C6H3 210–212°C
88
70
RCH = Cyclohexyl
40–45°C (lit 38.5°C
[14])

JOURNAL OF SULFUR CHEMISTRY
5
Table 3. NMR spectra of compound 3g.
1H NMR (DMSO-d6):
COSY
Assignment
=
8.60 (s; 2H)
7.41 (s; 2H)
HC
H-2
N
7.35
7.35 (d, J = 8.0; 2H)
7.04 (d, J = 8.0; 2H)
6.12 (s; 4H)
7.41, 7.04
7.35
H-6
H-5
CH2
13C NMR (DMSO-d6):
160.59
149.93
147.86
128.21
125.00
108.48
105.87
101.60
HSQC:
HMBC:
Assignment
=
C
C-4
N
7.41, 7.04, 6.12
7.04, 6.12
8.60, 7.04
8.60
C-3
C-1
C-6
C-5
C-2
CH2
7.35
7.04,
7.41
6.12
8.60, 7.35
HMBC:
N15-NMR (DMSO-d6):
359.66
HSQC:
8.60
Assignment
=
C
N
as H-5; by HSQC correlation, δ = 105.87 is C-2, δ = 108.48 is C-5, and δ = 125.00
C
C
C
is C-6. Both C-2 and C-6 give HMBC correlation with the singlet at δ = 8.60, which is
H
assigned as the imino proton; C-2 also correlates with H-6. Of the three remaining non-
protonated carbons, that at δ = 128.21 gives HMBC correlation with the imino proton,
C
and is assigned as C-1; the other two must be C-3 and C-4. Both give HMBC correlation
with H-5 and the CH2 protons at δ = 6.12. Carbon at δ = 149.93 also correlates weakly
H
C
with H-2; carbon at δ = 147.86 does not correlate with H-2. Thus, the correlation just
C
mentioned is assigned as the three-bond relation between C-4 and H-2, and the carbon
signals are assigned as per Table 3. The lone 15N signal appears at δ = 359.66, indicating
N
an sp2 nitrogen; it gives no HSQC correlation, but gives HMBC correlation with the imino
proton signal (presumably with the proton three bonds away).
3. Experimental design
Melting points are uncorrected. The IR spectra were recorded as KBr discs on a Shimadzu-
408 infrared spectrophotometer, Faculty of Science, Minia University. The TLC analysis
was performed on analytical Merck 9385 silica aluminum sheets (Kieselgel 60) with a
PF254 indicator. The NMR spectra were measured using a Bruker AV-400 spectrometer
at the Florida Institute of Technology, USA. Chemical shifts were expressed as δ (ppm)
with tetramethylsilane (TMS) as internal reference. The samples were dissolved in DMSO-
d6, s = singlet, d = doublet, dd = doublet of doublet and t = triplet. Mass spectra were
recorded on Varian MAT 312 instrument in EI mode (70 eV), Centre of National Research,
Dokki, Cairo, Egypt. Elemental analyses were carried out using a Varian Elementary device
in the National Research Center, Giza, Egypt, or by the Microanalytical Unit at the Cairo
University, Cairo, Egypt.

6
A. A. ALY ET AL.
3.1. Starting materials
Thiosemicarbazide (5), benzaldehyde (6a), p-methylbenzaldehyde (6b) and p-
methoxybenzaldehyde (6c), p-chlorobenzaldehyde (6d), piperonal (6e), cyclohexanone
(6f), ethyl 2-cyanoacetate and mlononitrile were commercially used from Fluka.
4. General procedure
4.1. Reaction of thiosemicarbazones 1a–c with activated nitriles 2a or 2b
(Method I)
A mixture of a thiosemicarbazone (1a–c, 10 mmol), an activated nitrile 2a or 2b (10 mmol),
and a few drops of triethylamine in DMF (30 mL) was heated at 120°C for 10–15 h; the
reaction was followed by the TLC analysis. After cooling, the precipitates 3a–c were allowed
to stand overnight, collected by suction filtration, washed with petroleum ether, and dried
at room temperature. Compounds 3a–c were identified by comparing their Rf values, mp,
and IR spectra to those of authentic samples (Table 1).
4.2. Microwave-irradiation-assisted reaction between thiosemicarbazones 1a–c
and activated nitriles 2a or 2b (Method II)
A mixture of a thiosemicarbazone (1a–c, 1 mmol) and an activated nitrile 2a or 2b
(1 mmol) in 4 mL of DMF together with two drops of triethyl amine were heated in a
microwave oven for 2–6 min. After cooling, the precipitates 3a–c were allowed to stand
overnight, collected by suction filtration, washed with petroleum ether, and dried at room
temperature.
Compound 4 was obtained, as a pale yellow precipitate from the reaction of 1d with
2a or 2b. It was recrystallized from CHCl3/MeOH, m.p. 166–168°C. IR (νmax): 3240–3210
(NH2,NH), 3030–3000 (Ar–CH), 1620 (C N) cm−1. 1H NMR (DMSO-d6): δ = 8.20 (s,
=
H
1
=
2H, 2 CH N), 6.80–6.65 (m, 8H, 2Ar-CH, 2NH2), 6.40–6.36 (dd, 4H, J = 7.0, 0.8 Hz). C
=
=
NMR (DMSO-d6): δ = 156.0 (2C N), 151.0 (2CH N), 138.4 (Ar–2C), 126.0, 124.30
C
(Ar–4CH), 122.60 (2Ar-C-Cl). Calcd for C16H14Cl2N6S2 (424.01): C, 45.18; H, 3.32; N,
19.76. Found: C, 45.00; H, 3.15; N, 19.60.
4.2.1. One-pot synthesis of azines 3a–c
A mixture of thiosemicarbazide (5, 0.91 g, 10 mmol) and an aldehyde 6a–c (1 mmol) in
DMF (20 mL) containing 10 drops of acetic acid was gently heated at 60°C for 0.5–1 h; the
reaction was followed by the TLC analysis. To the reaction mixture, another 10 mmol of
benzaldehyde (6a) was added and the mixture was heated at 100°C for 15–20 h. After cool-
ing, the precipitates 3a–c were allowed to stand overnight, collected by suction filtration,
washed with petroleum ether, and dried at room temperature.
4.2.2. Reaction of thiosemicarbazones 1a–e with aldehydes 6a–e
On applying the first procedure, symmetric azines 3a,e–hwere obtained as given in Table 2.

JOURNAL OF SULFUR CHEMISTRY
7
4.2.3. Anti-1,2-Bis(benzo[d][1,3]dioxol-5-ylmethylene)hydrazine (3g)
Orange crystals (EtOH), m.p. 210–212°C. Yield: 88%. IR (νmax): 3080–3040 (Ar–CH),
2980–2950 (Aliph-CH), 1620 (C N), 1110 (C–O) cm−1. NMR (DMSO-d6): Table 3. MS
(EI, 70 eV): m/z = 296 (100), 268 (56), 175 (18), 161 (26), 134 [( CH–C6H3–OCH2O) ,
=
+
=
10], 121 [(C6H3–OCH2O)+, 15], 77 (18). Calcd. for C16H12N2O4 (296.28): C, 64.86; H,
4.08; N, 9.46. Found: C, 65.00; H, 3.95; N, 9.60.
Acknowledgements
The NMR spectrometer at Florida Institute of Technology was purchased with the assistance of the
US National Science Foundation (CHE 03 42251).
Disclosure statement
No potential conflict of interest was reported by the authors.
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