Facile synthesis of thiazole, thiazine and isoindole derivatives via EDA approach and conventional methods

Article abstract of DOI:10.5560/ZNB.2013-3117

The reactivity of N-amidinothiourea (1) as an electron donor towards several electron-accepting functional groups via electron-donor-acceptor (EDA) interaction has been studied. Thus on treatment of 1 with either 1,1,2,2-tetracyanoethylene (TCNE, 2), 2,3-

Full text of DOI:10.5560/ZNB.2013-3117

Facile Synthesis of Thiazole, Thiazine and Isoindole Derivatives via EDA
Approach and Conventional Methods
Kamal M. El-Shaieb, Mohamed A. Ameen, Fathy F. Abdel-latif, and Asmaa H. Mohamed
Chemistry Department, Faculty of Science, Minia University, El-Minia, A. R. Egypt
Reprint requests to Dr. Kamal M. El-Shaieb. Fax: +2-086-2342601.
E-mail: kmelshaieb@yahoo.com
Z. Naturforsch. 2013, 68b, 905 – 912 / DOI: 10.5560/ZNB.2013-3117
Received April 17, 2013
The reactivity of N-amidinothiourea (1) as an electron donor towards several electron-accepting
functional groups via electron-donor-acceptor (EDA) interaction has been studied. Thus on treat-
ment of 1 with either 1,1,2,2-tetracyanoethylene (TCNE, 2), 2,3-dicyano-1,4-naphthoquinone
(DCNQ, 4), 2,3,5,6-tetrabromo-1,4-benzoquinone (BHL-p, 6), 2,3-dichloro-1,4-naphthoquinone
(DCHNQ, 8), 2,3,5,6-tetrachloro-1,4-benzoquinone (CHL-p, 13), 2,3-dicyano-5,6-dichloro-1,4-
benzoquinone (DDQ, 15), 2-dicyanomethyleneindan-1,3-dione (CNIND, 17), 2-(2-oxoindolin-3-
ylidene)malononitrile (19), and/or dimethyl acetylenedicarboxylate (DMAD, 21), the reaction pro-
ceeds to give thiazole and thiazine derivatives, respectively. However, isoindole derivatives 24 and
26 were formed on heating of 1 with either tetrabromophthalic anhydride and/or o-phthalaldehyde,
respectively. The products were fully characterized according to their spectral data. The mechanisms
of formation of the products have been rationalized.
Key words: N-Amidinothiourea, Thiazoles, Thiazines, Isoindole, EDA Interaction
Introduction
Amidinothiourea has several potential coordinating
kinases (CDKs) [11] and glycogen synthase kinase-3
(GSK-3) [12].
Preparation of 1,3-thiazoles can be readily ac-
modes since it can act as an N,N- or S,N-donor lig- complished using both classical and non-classical
and due to thiol-thioketo tautomerism [1, 2]. Amidino- approaches, for example: (a) the Hantzsch synthe-
thiourea and its derivatives are important industrial sis [13, 14], (b) via thiazolines by condensation of
and biological compounds. Recently, amidinothiourea aldehydes with a cysteine derivative followed by ox-
derivatives have been reported to be non-toxic and idation [15], (c) the reaction of N-amidinothiourea
are used in many pharmaceutical applications [3]. In with α-bromoketones [16], (d) the condensation of α-
the field of medicine they are well-known stimula- halomethyl ketimines with thioamides [17], and (e) the
tors of intestinal peristalsis and have been used for reaction of ethyl diazopyruvate with thioamides [18].
the clinical treatment of bowel paresis in peritoni- Despite the existing approaches to 1,3-thiazoles, there
tis. Their derivatives have also been very promis- is still a need for new general procedures, especially
ing in clinical trials as immunostimulants and tu- considering the potential opportunities in parallel and
mor cell inhibitors [4]. The richness of the phar- combinatorial chemistry [19]. As part of our ongoing
macopeia in compounds containing heterocyclic sys- research program on heterocyclic compounds which
tems is the basis of a continuing search for versa- may serve as leads for designing novel antitumor
tile processes towards these key structural elements. agents, we were particularly interested in quinazoline,
The 1,3-thiazole ring has been identified as a cen- diazepine, thiazole, and thiazine derivatives [20 – 25].
tral structural element of a number of biologically
active natural products [5 – 7] and of pharmacologi- Results and Discussion
cally active substances [8, 9]. Among various thiazole-
containing anticancer drug candidates [10], some are
We report herein general, rapid, and effective pro-
reported to be potential inhibitors of cyclin-dependent cedures for the synthesis of thiazole derivatives by
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K. M. El-Shaieb et al. · Synthesis of Thiazole, Thiazine and Isoindole Derivatives
HN
NH2
N
S
N
O
9
l
C
O
O
Cl
Cl
DMF
r.
.
2 h
,
t
N
C
8
r
r
B
B
O
CN
CN
NC
r
r
B
S
O
S
O
NH
NH
NH
N
NC
2
r
B
r
B
N
C
6
N
H
H2N
N
NH2
DMF
B
NH2
H
DMF
r.
r.
.
6 h
,
t
S
N
NH2
HN
O
7
.
,
t
2 h
1
3
O
CN
CN
DMF
r.
.
2 h
,
t
4
O
O
S
N
N
H
NH2
HN
O
5
Scheme 1. Reactions of N-amidinothiourea (1) with π acceptors.
1
the reaction of N-amidinothiourea (1) with some se- teristic for cyano groups. The H NMR spectrum of
lected electron-accepting functional groups. We have the product 5 exhibits beside the signals due to the
found that on treatment of 1 with the electron acceptor aromatic protons in their expected positions three sin-
2 in DMF at room temperature, a blue CT complex glet signals at δ = 6.55, 6.95 and 7.93 ppm due to
was formed, and a reddish brown precipitate started the NH2 and NH groups. Moreover, the l3C NMR
to settle. After completion of the reaction (TLC test), spectrum shows the existence of twelve distinct car-
the product was filtered, dried and recrystallized from bon atoms. Two of them resonate at δ = 154.21 and
1,4-dioxane to give the thiazole derivative 3 in good 156.17 ppm referred to (C–NH2) and C=N carbon
yield (Scheme 1). The IR spectrum of 3 exhibits strong atoms, respectively.
absorption bands at ν = 3332, 3250 and 3165 cm−1
The two carbonyl carbon atoms have been detected
belonging to stretching vibrations of NH2 and NH at δ = 168.40 and 168.55 ppm. Both MS and ele-
groups, while the absorption at 2198 cm−1 backs the mental analysis confirm the molecular formula of 5 as
cyano group. The 1H NMR spectrum of 3 reveals three C12H8N4O2S.
characteristic relatively sharp singlets at δ = 6.88, 7.05
Similarly, the substrate 1 reacted with 2,3-dichloro-
and 8.15 ppm, which refer to NH2 and NH groups. 1,4-naphthoquinone (8) to give the naphtha-thiazole
Moreover, the mass spectrum of 3 exhibits a molec- derivative 9 (Scheme 1). A rational pathway for the
ular ion peak at m/z = 192 along with the base peak at formation of the thiazole derivative 3 is illustrated in
m/z = 175 which is assigned to [M–NH3]+. The ele- Scheme 2.
mental analysis established the molecular formula of 3
as C6H4N6S.
We suggest that the non-bonding electron pair of the
sulfur atom attacks on one of the most electrophilic
Stirring of 1 with the acceptor 4 in DMF at room centers in 2 which is the C=C unit leading to the for-
temperature led to the formation of the thiazole deriva- mation of the adduct 10. This adduct loses a molecule
tive 5. The IR spectrum of the product 5 displays strong of HCN to give the adduct 11. The intermediate 12 was
absorption maxima at ν = 3452 and 3122 cm−1 in- formed upon nucleophilic attack of the electron pair of
dicating the presence of NH2 and NH groups, and the amino group to the olefinic carbon atom carrying
the CO groups absorb at ν = 1666 cm−1. Further- the two cyano groups. Another molecule of HCN is
more, the IR spectrum reveals no absorption charac- eliminated to form the final product 3 (Scheme 2).
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907
N
C
NC
..
NH
NH2
CN
CN
S
NC
CN
SH
NH
NH
−
CN
H
HCN
H2N
H2N
NC
N
..
NH2
+
S
CN
NH2
N
H2N
N
N
N
C
C
10
11
N
C
2
1
H2N
N
S
NH
HN
−
HCN
H
NH2
HN
HN
NC
N
CN
S
3
CN
N
C
12
Scheme 2. Rational pathway for the formation of product 3.
N
S
C
N
N H
2
N H
H N
O
N
H
2 0
NC
CN
DMF
r. .
O
t
h
6
,
N
H
19
O
O
Cl
Cl
Cl
N H
2
CN
H N
O
O
O
S
NH
C
N
O
H
N
l
l
C
C
S
Cl
N
17
13
N
H2N
N
NH2
CN
DMF
r. .
DMF
3
H
N
H
N H
S
N
2
t
5 h
,
r. .
t
h
,
1
H N
O
O
C
NC
1 8
1 4
DMF
3
O
O
r. .
t
h
,
Cl
Cl
15
N
C
H N
N
N
C
O
N H
N
S
2
l
C
1 6
Scheme 3. Reactions of 1 with CHL-p, DDQ, CNND and 19.
On treatment of 1 with either 2,3,5,6-tetrachloro- 1H NMR spectrum shows five singlet signals at δ =
1,4-benzoquinone (13), 2,3-dicyano-5,6-dichloro-1,4- 6.64, 7.71, 8.33, 10.73, and 11.18 ppm attributed to
benzoquinone (DDQ, 15), 2-dicyanomethyleneindan- CH, NH2 and NH groups. Both mass and elemen-
1,3-dione (CNIND, 17), and 2-(2-oxoindolin-3- tal analysis confirm the molecular formula of 20 as
ylidene)malononitrile (19), the thiazole derivatives 14, C12H10N6OS.
16, 18, and 20, respectively, were obtained (Scheme 3).
We then examined the reaction of N-amidino-
The indolinothiazolidine derivative 20 was formed thiourea (1) with dimethyl acetylenedicarboxylate
on treatment of 1 with the indoline derivative 19. The (DMAD, 21) in the presence of p-toluenesulfonic acid
structure of compound 20 was assigned using spectro- (p-TSA) to give the thiazine derivative 22 (Scheme 4).
scopic tools such as IR, 1H NMR and mass spectrome- The structure of 22 was established on the basis of the
try, in addition to elemental analysis. Its IR spectrum 1H and 13C NMR data. The 1H NMR spectrum of the
revealed three absorption bands at ν = 3320 – 3185 product shows only four singlet signals belonging to
(NH2 and NH), 2180 (CN) and 1720 cm−1 (CO). The protons of CH3, the thiazine CH and NH2, whereas, the
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K. M. El-Shaieb et al. · Synthesis of Thiazole, Thiazine and Isoindole Derivatives
r
B
O
r
r
B
B
r
r
B
O
e
M
O
S
CO2
N
r
r
B
NH
S
HN
NH
MeO2C
C
C CO2Me
O
r
B
NH2
S
N
NH2
21
23
H2N
N
H
1
NH2
B
-
EtOH,p TSA
AcOH
, refl.,
2 h
H2N
N
O
2 h
refl.,
O
B
22
24
Scheme 4. Reaction of 1 with DMAD and tetrabromophthalic anhydride (23).
S
HN
N
NH
NH2
NH
HN
S
N
H2N
29
OHC
CHO
EtOH, p-TSA
refl., 2 h
27
CHO
S
OHC
CHO
NH
S
NH2
NH
CHO
N
NH
25
27
OHC
HN
S
H2N
N
NH2
EtOH, p-TSA
N
EtOH, p-TSA
NH
N
H
refl., 3 h
refl., 2 h
28
1
26
Scheme 5. Reaction of 1 with o-phthalaldehyde (25) and terephthalaldehyde (27).
NH
S
NH
S
H
CHO
NH
S
H
H2N
N
H
1
NH2
H
O
H2N
N
H
N
H
CHO
H2N
N
H
N
−
O
H
2O
HO
27
30
31
NH
S
HN
NH2
S
NH
N
NH
O
H
O
− shift
-
−
H2O
1,3 H
S
N
H2N
N
H
N
N
NH
26
33
32
Scheme 6. Rational pathway for the formation of the isoindole derivative 26.
l3C NMR spectrum shows seven distinct peaks. Both analysis confirm the molecular formula of the product
MS and elemental analysis confirm the molecular for- as C10H8N4S. A rational pathway for the formation of
mula of 22 as C7H8N4O3S.
compound 26 is as shown in Scheme 6.
Condensation of 1 with o-phthalaldehyde (25) in
In this case we suggested that the amino group
ethanol under reflux conditions led to the formation of attacks one of the formyl carbon atoms by its non-
the triazinoisoindole derivative 26 (Scheme 5). bonding electron pair leading to the formation of the
The structure of the product was deduced from its intermediate 30 which yields the azomethine 31 af-
spectral data and elemental analysis. The 1H NMR ter losing a molecule of water. The azomethine ni-
spectrum of compound 26 reveals, beside the aromatic trogen atom attacks by its lone pair of electrons the
protons, a deshielded singlet at δ = 4.84 ppm as the second formyl group’s carbon atom to give the cy-
result of the methylene protons. The IR spectrum re- cloadduct 32 which undergoes rearrangement through
veals the absence of the absorption maxima for the 1,3-hydride shift to give adduct 33 which is suitable
carbonyl groups. Both mass spectrum and elemental for being attacked by the second amino group to form
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909
the end product 26 after losing another water molecule NMR (75 MHz, [D6]DMSO): δ = 109.57 (C), 115.79 (CN),
117.34 (CN), 159.70 (C), 164.84 (C), 168.12 (C) ppm. – MS
(EI, 70 eV): m/z(%) = 192 (34) [M]+, 191 (35) [M–1]+, 175
(100) [M–NH3]+, 159 (23), 146 (20), 136 (38), 129 (32), 102
(46), 89 (47), 77 (48), 63 (22), 44 (56). – C6H4N6S (192.02):
calcd. C 37.49, H 2.10, N 43.73, S 16.68; found C 37.27, H
2.02, N 43.53, S 16. 48.
(Scheme 6).
Conclusion
In this study we investigated the ability of N-
amidinothiourea (1) to react with some selected
electron-accepting functional groups of compounds
like tetracyanoethylene etc. The reactions proceed to
give novel thiazole and thiazine derivatives in good
yields. The structure of the products was apparent from
their mass spectrum, which displayed the molecular
Synthesis of (E)-1-(4,9-dioxonaphtho[2,3-d]thiazol-
2(3H,4H,9H)-ylidene)guanidine (5)
To a solution of 2,3-dicyano-1,4-napthoquinone (DCNQ,
4) (208 mg, 1 mmol) dissolved in DMF (5 mL), a solution
of N-amidinothiourea (1) (118 mg, 1 mmol) dissolved in
DMF (5 mL) was added slowly. The initially orange solution
turned to brown, then to yellowish green. The solution was
stirred for 2 h at room temperature. After completion of the
reaction, the formed yellow precipitate was collected and re-
crystallized from DMF-EtOH to form the thiazole derivative
5. Yellowish-green crystals (yield: 65%), m. p. > 300 ◦C. –
IR (film): ν = 3452, 3122, 3093, 1666 cm−1. – 1H NMR
(300 MHz, [D6]DMSO): δ = 6.55 (s, 2H, NH2), 6.95 (s, 1H,
NH), 7.48 – 7.68 (m, 2H, Ar-H), 7.93 (s, 1H, NH), 7.05 – 8.28
(m, 2H, Ar-H) ppm. – 13C NMR (75 MHz, [D6]DMSO):
δ = 120.59 (CH), 121.14 (CH), 122.25 (CH), 124.42 (CH),
129.74 (C), 131.85 (C), 135.75 (C), 154.21 (C), 156.17
(C), 168.40 (C=O), 168.55 (C=O) ppm. – MS (EI, 70 eV):
m/z(%) = 272 (4) [M]+, 270 (4) [M–2]+, 268 (3), 250 (4),
240 (100), 224 (2), 212 (8), 195 (8), 171 (34), 149 (6), 130
(7), 116 (7), 104 (51), 83 (100), 76 (56). – C12H8N4O2S
(272.04): calcd. C 52.93, H 2.96, N 20.58, S 11.78; found
C 52.70, H 2.89, N 20.35, S 11.56.
1
ion peaks at the appropriate m/z values. The H and
13C NMR spectroscopic data, as well as IR spectra,
are in agreement with the proposed structures. Sug-
gested mechanisms for the formation of the products
have been rationalized.
Experimental Section
General. All reagents were purchased from Alfa Aesar
and Fluka companies and were used without further purifica-
tion. Melting points were measured with a Gallenkamp ap-
paratus and are uncorrected. The reactions and purity were
monitored by TLC on aluminum plates coated with sil-
ica gel with fluorescent indicator (Merck, 60 F254) using
chloroform-acetone (7 : 3) as an eluent. The IR spectra were
recorded on a Jasco FTIR-450 Plus IR spectrophotometer.
The NMR spectra were obtained on a JHA-LAA 400 WB-
FT spectrometer (300 MHz for 1H NMR, 75 MHz for 13C
NMR) with [D6]DMSO as a solvent. Chemical shifts are
quoted in δ and are referenced to TMS. The mass spectra
were recorded on a Trace GC 2000/Finnegan Mat SSQ 7000
and a Shimadzu GCMS-QP-1000EX mass spectrometer at
70 eV. Elemental analyses were carried out with a Vario EL
III CHNOS.
Synthesis of (E)-1-(5,6-dibromo-4,7-dioxobenzo[d]thiazol-
2(3H,4H,7H)-ylidene)guanidine (7)
To a well-stirred solution of 2,3,5,6-tetrabromo-1,4-ben-
zoquinone (6) (227 mg, 1 mmol) in DMF (5 mL), a solution
of 1 (118 mg, 1 mmol) in DMF (5 mL) was added slowly.
The yellow color of the reaction mixture gradually turned
to red. A grey precipitate started to be formed. The reaction
mixture was stirred for 2 h at room temperature, the precip-
Synthesis of
(E)-1-(4,5-dicyanothiazol-2(3H)-ylidene)guanidine (3)
To a magnetically stirred solution of tetracyanoethylene itate was collected and crystallized by using a mixture of
(2) (128 mg, 1 mmol) in DMF (5 mL), a solution of 1 DMF-EtOH. Grey powder (yield: 60%), m. p. 240 – 242 ◦C.
(118 mg, 1 mmol) in DMF (5 mL) was added. The color of – IR (film): ν = 3421 – 3379, 3220, 3109, 1624 cm−1. – 1H
the solution changed to red, then to reddish brown. The re- NMR (300 MHz, [D6]DMSO): δ = 8.09 (s, 2H, NH2), 8.53
action mixture was stirred at room temperature for 6 h. After (s, 1H, NH), 9.12 (s, 1H, NH) ppm. – 13C NMR (75 MHz,
completion of the reaction (followed by TLC), the formed [D6]DMSO): δ = 154.20 (C), 155.36 (C), 161.74 (C), 163.38
precipitate was collected by filtration, washed and recrys- (C), 168.14 (C), 168.56 (C), 177.64 (C), 206.60 (CO), 206.78
tallized by using a mixture of DMF-EtOH to afford the (CO) ppm. – MS (EI, 70 eV): m/z(%) = 382/380/378 (5/9/4)
thiazole derivative 3. Reddish-brown crystals (yield: 69%), [M]+, 372 (10), 354 (15), 339 (4), 240 (100), 224 (2), 212 (8),
m. p. 300 ◦C (dec.). – IR (film): ν = 3332, 3250, 3165, 199 (8), 171 (34), 149 (6), 130 (7), 116 (7), 104 (51), 83 (100),
2198 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 6.88 76 (56). – C8H4Br2N4O2S (380.02): calcd. C 25.28, H 1.06,
(s, 2H, NH2), 7.05 (s, 1H, NH), 8.15 (s, 1H, NH) ppm. – 13
C
N 14.74, S 8.44; found C 25.10, H 1.01, N 14.50, S 8.25.
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Synthesis of (E)-1-(4-chloro-5-oxonaphtho[1,2-d]thiazol-
2(5H)-ylidene)guanidine (9)
60%), m. p. 172 – 174 ◦C. – IR (film): ν = 3435 – 3332,
3238, 2253, 1641 cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 7.08 (s, 2H, NH2), 7.14 (s, 1H, NH) ppm. – MS (EI,
70 eV): m/z(%) = 292 (5) [M+2]+, 291 (25) [M+1]+, 276
(6), 263 (6), 252 (6), 236 (4), 220 (3), 208 (3), 191 (3), 176
(3), 164 (20), 147 (35), 134 (100), 118 (27), 104 (10), 91
(15), 83 (3), 77 (10). – C10H3ClN6OS (289.98): calcd. C
41.32, H 1.04, N 28.91, S 11.03; found C 41.11, H 1.00, N
28.80, S 10.81.
To a round-bottom flask containing a solution of
2,3-dichloro-1,4-naphthoquinone (DCHNQ, 8) (227 mg,
1 mmol) in DMF (5 mL), a solution of 1 (118 mg, 1 mmol)
in DMF (5 mL) was added slowly with stirring; the yellow
solution turned to red, then to brown. A brown precipitate
started to be formed. The reaction mixture was stirred for 2 h
at room temperature, the precipitate was collected and crys-
tallized from acetonitrile. Brown crystals (yield: 60%), m. p.
Synthesis of (E)-1-(50-cyano-1,3-dioxo-1,3-dihydrospiro-
[indene-2,40-thiazolidin]-20-ylidene)guanidine (18)
284 – 286 ◦C. – IR (film): ν = 3421, 3317, 3074, 1666 cm−1
.
– 1H NMR (300 MHz, [D6]DMSO): δ = 7.87 – 8.14 (m, 4H,
Ar-H), 8.40 (s, 2H, NH2), 8.51 (s, 1H, NH) ppm. – 13C NMR
(75 MHz, [D6]DMSO): δ = 120.67 (CH), 121.07 (CH),
121.13 (CH), 121.66 (CH), 124.26 (C), 126.80 (C), 149.29
(C), 153.27 (C), 164.97 (C=N), 165.55 (C=N), 173.99
(C=N), 178.64 (C=O) ppm. – MS (EI, 70 eV): m/z(%) =
292 (14) [M+2]+, 291 (2) [M+1]+, 290 (2) [M]+, 275
(4), 276 (3), 260 (5), 232 (9), 223 (6), 188 (17), 163 (17),
144 (13), 132 (28), 123 (7), 104 (48), 99 (15), 76 (100). –
C12H7ClN4OS (290.00): calcd. C 49.57, H 2.43, N 19.27, S,
11.03; found C 49.34, H 2.36, N 19.03, S 10.82.
To a well-stirred solution of 2-dicyanomethyleneindan-
1,3-dione (CNIND, 17) (208 mg, 1 mmol) dissolved in DMF
(10 mL), a solution of 1 (118 mg, 1 mmol) dissolved in DMF
(10 mL) was added dropwise with constant stirring. The
color of the reaction mixture changed from yellow to reddish
brown. The reaction mixture was stirred at room temperature
for 5 h. The formed precipitate was collected by filtration
and recrystallized from DMF-EtOH. Brown crystals (yield:
63%), m. p. 320 ◦C. – IR (film): ν = 3360, 3200, 2130, 1700,
1600 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 6.40 (s,
1H, CH), 7.51 – 7.94 (m, 7H, ArH, NH, NH2), 8.30 (s, 1H,
NH) ppm. – MS (EI, 70 eV): m/z(%) = 301 (10) [M+2]+,
300 (15) [M+1]+, 299 (38) [M]+, 281 (20), 252 (18), 224
(5), 195 (5), 160 (5), 147 (20), 135 (100), 101 (3), 84 (100).
– C13H9N5O2S (299.05): calcd. C 52.17, H 3.03, N 23.40, S
10.71; found C 51.99, H 2.96, N 23.20, S 10.50.
Synthesis of (E)-1-(5,6-dichloro-4,7-dioxobenzo[d]thiazol-
2(3H,4H,7H)-ylidene)guanidine (14)
To a magnetically stirred solution of 2,3,5,6-tetrachloro-
1,4-benzoquinone (13) (245 mg, 1 mmol) in DMF (5 mL),
a solution of 1 (118 mg, 1 mmol) in DMF (5 mL) was added;
the yellow color of the solution changed to red, then to
reddish brown. The reaction mixture was stirred at room
temperature for 3 h. After completion of the reaction (TLC
analysis), the formed precipitate was collected by filtration,
washed and recrystallized from DMF to afford the product
14. Reddish brown crystals (yield: 68%), m. p. 360 ◦C. – IR
(film): ν = 3282, 3178, 3101, 1666 cm−1. – MS (EI, 70 eV):
m/z(%) = 292/290/288 (4/6/11) [M]+, 270 (10), 250 (4),
233 (7), 223 (3), 203 (6), 188 (6), 176 (4), 167 (2), 144
(7), 132 (16), 104 (63), 93 (10), 76 (12). – C8H4Cl2N4O2S
(291.11): calcd. C 33.01, H 1.38, N 19.25, S 11.01; found C
32.80, H 1.31, N 19.12, S 10.80.
Synthesis of (E)-1-(50-cyano-2-oxospiro[indoline-
3,40-thiazolidin]-20-ylidene)guanidine (20)
A solution of 1 (118 mg, 1 mmol) in dry ethyl ac-
etate (10 mL) was added dropwise to a solution of 2-(2-
oxoindolin-3-ylidene)malononitrile (19) (195 mg, 1 mmol)
in 10 mL of the same solvent. The reaction mixture was
heated under reflux for 6 h. Dark-brown crystals precipi-
tated, were filtered, washed with ethanol and dried to give
the product 20. Brown powder (yield: 70%), m. p. > 360 ◦C.
1
– IR (film): ν = 3320, 3185, 2180, 1720 cm−1. – H NMR
(300 MHz, [D6]DMSO): δ = 6.64 (s, 1H), 6.67 – 7.36 (m,
4H), 7.71 (s, 2H, NH2), 8.33 (s, 1H, NH), 10.73 (s, 1H, NH),
11.18 (s, 1H, NH) ppm. – MS (EI, 70 eV): m/z(%) = 286
(3) [M]+, 232 (11), 200 (26), 195 (85), 186 (6), 170 (100),
168 (38), 141 (20), 131 (48), 115 (36), 98 (10), 74 (22). –
C12H10N6OS (286.06): calcd. C 50.34, H 3.52, N 29.35, S
11.20; found C 50.32, H 3.45, N 29.16, S 10.98.
Synthesis of (E)-1-(7-chloro-4,5-dicyano-6-
oxobenzo[d]thiazol-2(6H)-ylidene)guanidine (16)
To a solution of 2,3-dicyano-5,6-dichloro-1,4-benzo-
quinone (DDQ, 15) (227 mg, 1 mmol) in 10 mL of DMF,
a solution of 1 (118 mg, 1 mmol) in 10 mL of DMF was
added slowly; the initially yellow solution turned to dark blue
and then to reddish brown. The solution was stirred for 3 h at
room temperature. A brown precipitate was formed, which
Synthesis of methyl 2-((diaminomethylene)amino)-
4-oxo-4H-1,3-thiazine-6-carboxylate (22)
A mixture of equimolar amounts of N-amidinothiourea
after completion of the reaction (TLC control) was collected (1) (118 mg, 1 mmol) and dimethyl acetylenedicarboxylate
and recrystallized from 1,4-dioxane. Brown crystal (yield: (21) (142 mg, 1 mmol) in the presence of a catalytic amount
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911
of p-TSA was refluxed in absolute ethanol (20 mL) for 2 h. ppm. – MS (EI, 70 eV): m/z(%) = 216 (100) [M]+, 199 (16),
The resulting precipitate obtained after cooling was filtered 174 (7), 157 (41), 130 (20), 126 (36), 103 (38), 89 (13), 76
off, dried, and recrystallized from ethanol. Yellow powder (26). – C10H8N4S (216.05): calcd. C 55.54, H 3.73, N 25.91,
(yield: 85%), m. p. 250 – 252 ◦C (dec.). – IR (film): ν = S, 14.83; found C 55.34, H 3.67, N 25.76, S 14.69.
3477 – 3345, 3061, 1670, 1655 cm−1. – 1H NMR (300 MHz,
Synthesis of (E)-N-((4-formylbenzylidene)carbamothioyl)-
guanidine (28)
[D6]DMSO): δ = 3.72 (s, 3H, CH3), 6.59 (s, 1H, CH), 7.56
(s, 2H, NH2), 8.36 (s, 2H, NH2) ppm. – 13C NMR (75 MHz,
[D6]DMSO): δ = 52.08 (CH3), 113.41(CH), 148.79 (C),
160.47 (C), 168.24 (C), 178.61 (C), 180.64 (C) ppm. – MS
(EI, 70 eV): m/z(%) = 228 (2) [M]+, 210 (2), 180 (4), 166
(3), 152 (6), 141 (3), 127 (4), 101 (4), 90 (3), 84 (100). –
C7H8N4O3S (228.03): calcd. C 36.84, H 3.53, N 24.55, S
14.05; found C 36.61, H 3.44, N 24.34, S 13.85.
Equimolar quantities of terephthalaldehyde (27) (134 mg,
1 mmol) and 1 (118 mg, 1 mmol) in the presence of a cat-
alytic amount of p-TSA in absolute ethanol (20 mL) were
heated under reflux. A yellow precipitate commenced to
be formed after 30 min. The reaction was continued un-
der reflux conditions for 2 h. After completion of the re-
action (monitoring by TLC), the precipitate was filtered
off and recrystallized from DMF-EtOH. Yellow powder
(yield: 81%), m. p. > 360 ◦C. – IR (film): ν = 3364, 3182,
1689, 1643 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.09 – 7.54 (m, 4H, Ar-H), 7.92 (s, 1H, NH), 7.94 (s, 1H,
NH), 8.12 (s, 2H, NH2), 10.01 (CH=N), 10.11 (CHO) ppm.
– MS (EI, 70 eV): m/z(%) = 234 (7) [M]+, 199 (6), 162 (5),
133 (31), 105 (15), 77 (20). – C10H10N4OS (234.06): calcd.
C 51.27, H 4.30, N 23.91, S 13.69; found C 51.04, H 4.23, N
23.66, S 13.76.
Synthesis of 4,5,6,7-tetrabromo-N-carbamothioyl-
1,3-dioxoisoindoline-2-carboximidamide (24)
A mixture of 1 (118 mg, 1 mmol) and tetrabromophthalic
anhydride (TBPA, 23) (463 mg, 1 mmol) in glacial acetic
acid (15 mL) was heated for 2 h. After completion of the re-
action a precipitate was formed. It was collected by filtration
and recrystallized from 1,4-dioxane. Yellow powder (yield:
83%), m. p. 278 – 280 ◦C. – IR (film): ν = 3249, 1777,
1731 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 6.91
(s, 2H, NH2), 7.08 (s, 1H, NH), 7.25 (s, 1H, NH) ppm. – 13
C
Synthesis of (E,Z)-N,N0-(1,4-phenylenebis-
NMR (75 MHz, [D6]DMSO): δ = 120.75 (C), 120.78 (C),
120.80 (C), 128.80 (C), 131.20 (C), 162.43(C=N), 168.24
(CO), 170.94 (CO), 181.24 (C=S) ppm. – MS (EI, 70 eV):
m/z(%) = 558 (25) [M–2]+, 566 (58), 522 (15), 493 (5), 459
(2), 431 (100), 387 (5), 353 (4), 340 (7), 326 (85), 296 (5),
282 (5), 255 (4), 91 (10). – C10H4Br4N4O2S (559.68): calcd.
C 21.30, H 0.72, N 9.94, S 5.69; found C 21.09, H 0.67, N
9.81, S 5.59.
(methanylylidene))carbamothioyldiguanidine (29)
Compound 1 (236 mg, 2 mmol) and terephthalaldehyde
(27) (134 mg, 1 mmol) in the presence of a catalytic amount
of p-TSA were heated in absolute ethanol (20 mL) under re-
flux. A yellow precipitate was formed after 30 min. The re-
action was continued for 2 h. After completion of the reac-
tion (TLC analysis), the precipitate was filtered off, washed,
dried and recrystallized from DMF-EtOH. Yellow powder
(yield: 79%), m. p. 276 – 278 ◦C. – IR (film): ν = 3452,
3220, 3058, 1627 cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 6.91 – 7.15 (m, 4H, Ar-H), 7.51 (s, 2H, 2NH), 7.61 (s,
Synthesis of 2-imino-2,3-dihydro-
[1,3,5]triazino[2,1-a]isoindole-4(6H)-thione (26)
Equimolar amounts of N-amidinothiourea (1) and o- 2H, 2NH), 8.02 (s, 4H, 2NH2), 10.04 (s, 1H), 10.13 (s, 1H)
phthalaldehyde (25) were heated in absolute ethanol (20 mL) ppm. – 13C NMR (75 MHz, [D6]DMSO): δ = 125.75 (C),
under reflux conditions for 3 h (the reaction was followed by 126.98 (C), 128.24 (C), 130.07 (C), 138.31 (C), 138.69 (C),
TLC). The resulting precipitate was filtrated off and recrys- 148.83 (C), 168.24 (C), 157.86 (C), 192.59 (C), 192.96 (C)
tallized from DMF-EtOH. Grey powder (yield: 80%), m. p. ppm. – MS (EI, 70 eV): m/z(%) = 334 (5) [M]+, 396 (35),
200 – 202 ◦C. – IR (film): ν = 3317 – 3228, 1627 cm−1. – 277 (7), 235 (10), 172 (100), 107 (38), 91 (96), 79 (25). –
1H NMR (300 MHz, [D6]DMSO): δ = 4.84 (s, 2H, CH2), C12H14N8S2 (334.08): calcd. C 43.10, H 4.22, N 33.51, S
7.45 – 7.52 (m, 4H, ArH), 7.84 (s, 1H, NH), 7.97 (s, 1H, NH) 19.18; found C 42.88, H 4.15, N 33.22, S 18.99.
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K. M. El-Shaieb et al. · Synthesis of Thiazole, Thiazine and Isoindole Derivatives
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