Utility of 3-(thiophen-2-yl)prop-2-enoyl isothiocyanate in heterocyclic synthesis

Article abstract of DOI:10.1177/1747519819862176

Convenient syntheses of quinazoline, benzothiazole, thiadiazole, imidazole, and thiourea derivatives starting from 3-(thiophen-2-yl)prop-2-enoyl isothiocyanate are described. The structures of the synthesized compounds are confirmed from their microanalytical and spectral data. Some of the products are examined for their antibacterial activity against Gram-positive and Gram-negative bacteria and fungi.

Full text of DOI:10.1177/1747519819862176

862176CHL0010.1177/1747519819862176Journal of Chemical ResearchEl-Sayed et al.
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Journal of Chemical Research
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Utility of 3-(thiophen-2-yl)prop-2-enoyl
isothiocyanate in heterocyclic synthesis
https://doi.org/10.1177/1747519819862176
DOI: 10.1177/1747519819862176
journals.sagepub.com/home/chl
Amira A El-Sayed , Saad R Atta-Allah and Magdy M Hemdan
Abstract
Convenient syntheses of quinazoline, benzothiazole, thiadiazole, imidazole, and thiourea derivatives starting from
3-(thiophen-2-yl)prop-2-enoyl isothiocyanate are described. The structures of the synthesized compounds are confirmed
from their microanalytical and spectral data. Some of the products are examined for their antibacterial activity against
Gram-positive and Gram-negative bacteria and fungi.
Keywords
3-(thiophen-2-yl)prop-2-enoyl isothiocyanate, benzothiazoles, imidazoles, quinazolines, thiadiazoles, thioureas
been reported.13–16 In this investigation, we utilized a het-
Introduction
erocyclic α,β-unsaturated acyl isothiocyanate in order to
Extensive studies on the chemistry of aroyl isothiocy-
synthesize several heterocyclic compounds expected to
anates have established the value of these reagents as
starting materials for the syntheses of a wide variety of
heterocyclic compounds and thiourea derivatives.1–11
Highly reactive α,β-unsaturated acyl isothiocyanates can
Department of Chemistry, Faculty of Science, Ain Shams University,
Cairo, Egypt
be useful intermediates in organic synthesis, because
their multiple bonds can participate in cyclization reac-
tions.12 In addition, intramolecular cyclization of α,β-
unsaturated acylthioureas, formed in the reaction of
Corresponding author:
Amira A El-Sayed, Department of Chemistry, Faculty of Science, Ain
Shams University, Abbasia, Cairo 11566, Egypt.
α,β-unsaturated acyl isothiocyanates and amines, have Email: amira_aa47@hotmail.com

2
Journal of Chemical Research 00(0)
Scheme 1. Synthesis of quinazolines 3a,b.
demonstrate antibacterial activity against Gram-positive the Z counterpart could be attributed to its higher stability
and Gram-negative bacteria and fungi.
because of hindrance. On the contrary, compound 3a exists
exclusively as the E-isomer, since its configuration is based
on the higher value of the CH=CH coupling constant
(J=15.6Hz). The mass spectra of the synthesized compounds
Results and discussion
In the current study, transformations of 3-(thiophen-2-yl) revealed mass ions in accord with their proposed structures
prop-2-enoyl isothiocyanate (1)7 has been performed, leading (see the experimental analysis section). The formation of
to the novel derivatives of quinazoline, benzothiazole, thiadi- quinazoline derivatives 3 obviously proceeds via cyclization
azole, imidazole, and thiourea derivatives. Thus, addition of of thiourea derivative 2 by removing a molecule of water.
an equimolar amount of anthranilic acid to a solution of
Treatment of isothiocyanate 1 with o-aminothiophenol in
3-(thiophen-2-yl)prop-2-enoyl isothiocyanate (1) in boiling dry acetonitrile afforded benzothiazole derivative 5 in a good
acetonitrile produced thiourea derivative 2. Heating the yield. However, the reaction of isothiocyanate 1 with o-ami-
adduct 2 in acetic anhydride for 1h afforded quinazoline nophenol and/or o-phenylenediamine gave the open adducts
derivative 3a (Scheme 1). Moreover, when compound 2 was 4b and 4c, respectively. Boiling compound 5 in ethanolic
heated in acetic anhydride for 3h, quinazoline 3b was obtained sodium hydroxide solution furnished a mixture of 2-amino-
in a good yield. Compound 3b has been also formed by heat- 1,3-benzothiazole 6 and acrylic acid derivative 7. On the
ing quinazoline 3a in acetic anhydride for 3h. The infrared contrary, compounds 4b and 4c produced acrylic acid deriva-
(IR) spectra of compounds 2 and 3 showed absorption fre- tive 7 on treatments with ethanolic sodium hydroxide
quencies for NH, CO, and C=S groups, as well as an absorp- (Scheme 2). The structures of compounds 4–7 were substan-
tion for the OH group of compound 2. Their 1H NMR spectra tiated from their microanalytical and spectral data. Thus,
displayed signals for aromatic protons besides NH protons in their IR spectra showed bands correlating with their func-
the downfield region that were exchangeable with D2O. In tional groups (see the experimental analysis section). Further
addition, olefinic protons were observed for compounds 2 and support for the assigned structures of compounds 4–7 was
1
1
3a. Inspection of the H NMR spectrum of compound 2 gained from their H NMR spectra, which exhibit signals
showed the existence of extra signals corresponding to characteristic for aromatic protons and NH protons (com-
olefinic as well as acidic protons, with an integration ratio of pounds 4–6) in addition to OH protons for compounds 4b
70:30. This is good proof for its existence as a mixture of E/Z and 7 in the downfield region that were exchanged following
stereoisomers in the ratio 2:1. The second olefinic proton of a D2O shake. The configurational assignment of compounds
the Z-isomer is hidden under the multiplets due to the aro- 4, 5, and 7 as the E-configured isomers was based on the
matic signals. The higher ratio of the E-isomer compared with coupling constants of their olefinic protons, which were in

El-Sayed et al.
3
NH2
XH
O
+
R
N=C=S
1
MeCN/reflux
S
S
H
O
H
H
N
H
H
N
H
N
N
H
H
S
S
O
SH
XH
S
4b) X =O
(84%)
(78%)
=
4c) X NH
H
H
N
N
NaOH/EtOH
H
NH2
XH
SH
O
SH
OH
+
S
4a
O
7
-H
2S
N
NH
O
H
S
S
5
(78%)
H
EtOH
NaOH /
S
NH2
+
7
(32%)
N
6
(43%)
Scheme 2. Reactions of isothiocyanate 1 with o-aminothiophenol, o-aminophenol, and o-pheneylene diamine.
the expected range of trans isomers. The formation of com- good yield. On the contrary, refluxing of the compound 10 in
pound 5 can be explained on the basis of nucleophilic attack ethanolic hydrochloric acid solution afforded a mixture of
of the amino group of the o-aminothiophenol on the isothio- 2-thioxoimidazolidin-4-one (12) and acid 7 (Scheme 3). The
cyanato carbon atom of 1 producing non-isolable thiourea IR spectra of compounds 8–10 and 12 showed absorption fre-
derivative 4a, which then cyclizes to afford compound 5 via quencies correlating with NH and CO groups, in addition to
1
removal of H2S. The highly nucleophilic character of the sul- CN groups for compounds 8 and 9. Their H NMR spectra
fur atom of the SH group is responsible for the ease of cycli- displayed signals corresponding to CH2 protons, while the
zation of 4a in comparison to 4b and 4c. Compounds 6 and 7 NH protons were in the downfield region and were exchange-
were obtained as the result of amide hydrolysis of the corre- able with D2O. The appearance of two doublet signals with
sponding compounds.
higher coupling constants values, in the range (J=15.4–15.6Hz),
The interaction of isothiocyanate 1 and 2-cyanoacetohy- suggests the existence of compounds 8, 9, and 10 as the
drazide and/or ethyl glycinate HCl produced adducts 8 and E-configured isomers. Further evidence for the assigned
10, respectively. Heating of the adduct 8 in ethanolic hydro- structures of the synthesized compounds 8–10 and 12 was
chloric acid solution afforded thiadiazole derivative 9 in a gained from their mass spectral data, which revealed the

4
Journal of Chemical Research 00(0)
O
R
N=C=S
1
O
C
H
OC2
5
H2N
CN
H2N
N
H
O
O
C
H
O
C
R
OC2
5
H
H
R
CN
N
N
NH
N
H
C
NH
O
O
S
S
8
(85%)
10 (81%)
HCl/EtOH
HCl/EtOH
S
O
N
N
HN
R
O
N
N
CH2CN
H
S
9
(73%)
R
O
11
O
H
N
S
+
7
N
H
12 (47%)
Scheme 3. Reactions of isothiocyanate 1 with 2-cyanoacetohydrazide and ethyl glycinate.
correct molecular ion peaks and some important peaks that the ratio of 2:1. The appearance of the two hydrogen atoms
were in accord with their proposed structures. The formation of the NH2 group as two broad singlets was good evidence
of compound 9 is understood to occur via cyclization of the for their magnetic non-equivalence. This suggests the exist-
openadduct8withremovalofamoleculeofwater. Compound ence of compound 13 as its chelated form as shown in
12 is formed by acid-catalyzed hydrolysis of compound 10 Scheme 5. The 1H NMR spectrum of compound 14 showed
through removal of an ethanol molecule to afford the non- that it existed as the E-configured isomer (see the experimen-
isolable intermediate 11, followed by hydrolysis.
tal analysis section).
Refluxing a solution of the isothiocyanate 1 in acetonitrile
The mechanism of formation of compound 13 can be
in the presence of a few drops of distilled water gave a mix- visualized as shown in Scheme 5. The formation of com-
ture of thiourea derivative 13 and the acid 7. On the contrary, pound 14 is thought to occur via attack of the nitrogen atom
the amide derivative 14 was obtained upon heating of a solu- of the piperidine molecule on the carbonyl group of 1, fol-
tion of 1 in acetonitrile in the presence of piperidine (Scheme lowed by isothiocyanato group displacement.
4). The assigned structures for compounds 13 and 14 were
gained from their IR, which displayed NH, NH2, and C=O
absorptions for compound 13 and a C=O frequency for com-
pound 14. Analysis of the 1H NMR spectrum of compound The prepared heterocyclic compounds 2, 3, 5, 7, 8, and 9
13 revealed its existence as a mixture of E/Z stereoisomers in were examined for their antibacterial activity against
Antimicrobial activity

El-Sayed et al.
5
Scheme 4. Formation of compounds 13 and 14.
Scheme 5. The mechanism of formation of compound 13.
Gram-positive bacteria (Bacillus cereus and Staphylococcus to monitor the progress of all reactions and the homogene-
aureus), Gram-negative bacteria (Escherichia coli and ity of the synthesized compounds. 3-(Thiophen-2-yl)prop-
Pseudomonas aeruginosa) and fungi (Candida albicans 2-enoyl isothiocyanate (1) was synthesized as described in
and Aspergillus fumigatus).17,18 Compounds 2, 3, and 5 the literature.7
proved to be good antimicrobial agents, as shown in Table
1 and Figure 1.
Reactions of isothiocyanate (1) with the
different nucleophiles; general procedure
Experimental analysis
To a solution of isothiocyanate 1 (3mmol) in dry acetoni-
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. The elemental analy-
ses were recorded on a Perkin-Elemer 2400 CHN elemental
analyzer (USA). The IR spectra were recorded on a FTIR
Maltson (infinity series) spectrophotometer LABX
trile (30mL) was added anthranilic acid (3mmol). The
reaction mixture was refluxed for 3h and cooled to room
temperature. The precipitated solid product was collected
and recrystallized to give compound 2. The same procedure
was performed with o-aminothiophenol, o-aminophenol,
o-phenylenediamine, 2-cyanoacetohydrazide, ethyl glyci-
nate, distilled water, and piperidine. The progress of all
reactions and the homogeneity of the synthesized com-
pounds were monitored by TLC. The solid obtained for
each reaction was recrystallized from a suitable solvent to
give the corresponding compound.
1
(Canada) as KBr disks. The H NMR spectra were meas-
ured using a Varian Gemini 300-MHz spectrometer LABX
(Canada), with chemical shifts (δ) expressed in ppm down-
field from tetramethylsilane (TMS) as the internal standard,
in DMSO-d6. Mass spectra were determined on a Shimadzu
GC-MSQP 1000 EX instrument (Japan) operating at 70eV.
Thin-layer chromatography (TLC) was run using TLC alu-
minum sheets coated with silica gel F254 (Merck, England)
(E, Z)-2-(3-(3-(thiophen-2-yl)acryloyl)thioureido)ben-
zoic acid (2): Yellow crystals, 87%; m.p. 187–189°C

6
Journal of Chemical Research 00(0)
Table 1. Antimicrobial Activity Data.
Compound Inhibition zone diameter (cm/gm sample)
B. cereus (G+) S. aureus (G+) E. coli (G–) P. aeruginosa (G–) C. albicans (fungi) A. fumigatus (multicellular fungi)
2
3
5
7
8
9
S
F
20
20
12
13
12
19
25
–
24
23
10
17
16
25
30
–
35
33
22
23
24
35
40
–
21
20
13
12
11
19
25
–
15
14
9
8
8
15
–
20
10
11
4
6
5
13
–
15
S: septrin DS (antibacterial agent); F: Fungistatin (antifungal agent); B. cereus: Bacillus cereus; S. aureus: Staphylococcus aureus; E. coli: Escherichia coli; P.
aeruginosa: Pseudomonas aeruginosa; C. albicans: Candida albicans;A. fumigatus:Aspergillus fumigatus.
Figure 1. Graphical Representation of Antimicrobial Activity.
(EtOH); IR (KBr): 3400 (br. OH), 3272 (NH), 3052 (ArH),
(E)-1-(2-hydroxyphenyl)-3-(3-(thiophen-2-yl)acryloyl)
1666 (CO), 1592 (C=C), 1162 (CS), 754cm−1 δ4H; 1H NMR thiourea (4b): Yellow crystals, 84%, m.p. 214–216°C
(300MHz) (DMSO-d) δ 7.17 (m, 1H), 7.36 (t, 1H, (EtOH); IR (KBr) υ: 3480 (br OH), 3334 (NH), 3038 (ArH),
J=6.8Hz), 7.54–7.64 (m, 2H), 7.80–7.97 (m, 2H), 8.10 (d, 1666 (CO), 1600, 1558 (C=C), 1198 (C=S), 740cm−1; H
1
1H, J=7.6Hz), 3.49 (br s, 1H, 1NH, exchangeable), For the NMR (300MHz) (DMSO-d6) δ 6.83 (d, 1H, CH=,
E-isomer: 6.83 (d, 1H, CH=, J=15.4Hz), 7.94 (d, 1H, J=15.6Hz), 6.82 (m, 1H, ArH), 6.93 (d, 1H, J=8.1Hz),
CH=, J=15.4Hz), 11.55 (br s, 1H, 1NH, exchangeable), 7.05 (t, 1H, J=7.2Hz), 7.18 (t, 1H, J=4.5, 3.6Hz), 7.53 (d,
13.09 (br s, 1H, 1OH, exchangeable); For Z-isomer: 6.53 1H, J=3.6Hz), 7.76 (d, 1H, J=4.8Hz), 7.94 (d, 1H, CH=,
(d, 1H, CH=, J=11.2Hz), 7.76 (d, 1H, CH=, J=4.8Hz), J=15.6Hz), 8.56 (d, 1H, J=8.4Hz), 10.18 (br s, 1H,
10.72 (br s, 1H, 1NH, exchangeable), 12.19 (br s, 1H, 1OH, NHCS, exchangeable), 11.41 (br s, 1H, CONHCS,
exchangeable); MS (70eV): m/z (%): 332 (M+, absent), exchangeable), 12.93 (br s, 1H, 1OH, exchangeable); MS
314 (M+-H2O, 13), 298 (M+-H2S, 4), 171 (2), 162 (54), 146 (70eV): m/z (%): 304 (M+, 4), 271 (M+-SH, 9), 167 (4),
(3), 137 (100), 119 (21), 109 (51), 92 (22), 65 (61), 63 (36); 152 (6), 137 (100), 136 (7), 109 (64), 108 (15), 78 (18), 108
Anal. calcd for C15H12N2O3S2 (332.40): C, 54.20; H, 3.64; (28), 65 (59); Anal. calcd for C14H12N2O2S2 (304.39): C,
N, 8.43; found C, 53.82; H, 3.51; N, 8.57.
55.24; H, 3.97; N, 9.20; found C, 55.37; H, 3.86; N, 8.96.
(E)-N-(3,1-benzothiazol-2-yl)-3-(thiophen-2-yl)acryla-
(E)-1-(2-aminophenyl)-3-(3-(thiophen-2-yl)acryloyl)
mide (5): Colorless crystals, 78%; m.p. 245–247°C (EtOH); thiourea (4c): Yellow crystals; 78%, m.p. 179–181°C
IR (KBr) υ: 3236 (NH), 3067 (ArH), 1660 (CO), 1598 (C=C), (EtOH); IR (KBr) υ: 3382, 3300, 3132 (NH), 3063 (ArH),
751cm−1 δ4H; 1H NMR (300MHz) (DMSO-d6) δ 6.71 (d, 1H, 1674 (CO), 1612 (C=C), 1170 (C=S), 744cm−1 δ4H; H
1
CH=, J=15.4Hz), 7.44 (d, 1H, CH=, J=15.4Hz), 7.18–8.00 NMR (300MHz) (DMSO-d6) δ 5.01 (br s, 2H, NH2,
(m, 7H, ArH), 12.51 (br s, 1H, 1NH, exchangeable); MS exchangeable), 6.59 (t, 1H, J=8.1Hz), 6.77 (d, 1H,
(70eV): m/z (%): 286 (M+, 11), 258 (M+-CO, 6), 226 (2), 151 J=8.1Hz), 6.83 (d, 1H, CH=, J=15.6Hz), 7.00 (t, 1H,
(3), 150 (8), 149 (28), 137 (99), 109 (100), 108 (28), 83 J=7.5Hz), 7.14 (t, 1H, J=3.9, 4.8Hz), 7.31 (d, 1H,
(12),65 (84);Anal. calcd for C14H10N2OS2 (286.37): C, 58.72; J=7.8Hz), 7.53 (m, 1H, J=3.8Hz),7.75 (d, 1H, J=5.1Hz),
H, 3.52; N, 9.78; found C, 58.65; H, 3.16; N, 9.54.
7.92 (d, 1H, CH=, J=15.3Hz), 11.43 (br s, 1H, NHCS,

El-Sayed et al.
7
exchangeable), 11.99 (br. s, 1H, CONHCS, exchangeable);
MS (70eV): m/z (%): 303 (M+, 6), 302 (M+-H, 3), 270
(M+-SH, 8), 269 (8), 153 (26), 152 (11), 150 (70), 137
(100), 134 (14), 133 (15), 109 (76), 108 (27),78 (11),65
(78); Anal. calcd for C14H13N3OS2 (303.40): C, 55.42; H,
4.32; N, 13.85; found C, 55.16; H, 4.09; N, 13.63.
Formation of compounds 3a and 3b
A solution of compound 2 (1g) in acetic anhydride (10mL)
was refluxed for 1h. The solid product obtained was fil-
teredoffandrecrystallizedtogivecompound3a. Compound
3b was obtained after 3h of refluxing compound 2 in acetic
anhydride. In addition, compound 3a was refluxed in acetic
anhydride for 3h to afford 3b.
(E)-3-(3-(thiophen-2-yl)acryloyl)-2-thioxo-2,3-dihydro-
quinazolin-4(1H)-one (3a): Colorless crystals 83%, m.p.
240–242°C (EtOH); IR (KBr) υ: 3222, 3191, 3100 (NH),
3058 (ArH), 1685 (CO), 1622 (C=C), 1153 (CS), 746cm−1
δ4H; 1H NMR (300MHz) (DMSO-d6) δ 6.73 (d, 1H, CH=,
J=15.3Hz), 7.17 (t, 1H, J=4.5Hz),7.52 (t, 2H, J=7.2Hz),
7.62 (d, 1H, J=7.8Hz), 7.74 (d, 1H, J=4.8Hz), 7.88 (d,
1H, J=5.8Hz), 7.89 (d, 1H, CH=, J=15.6Hz), 8.06 (d, 1H,
J=7.8Hz), 12.02 (br s, 1H, 1NH, exchangeable); MS
(70eV) m/z (%): 314 (M+, 27), 205 (7), 177 (65), 145 (32),
137 (100), 120 (67), 109 (76), 103 (18), 83 (12), 65 (37);
Anal. calcd for C15H10N2O2S2 (314.38):C, 57.31; H, 3.21;
N, 8.91; found C, 57.12; H, 2.97; N, 8.76.
(E)-1-(2-cyanoacetyl)-4-(3-(thiophen-2-yl)acryloyl)thi-
osemicarbazide (8): Pale yellow crystals, 85%, m.p. 210°C
(with decomposition), (EtOH); IR (KBr) υ: 3291, 3181,
3102 (NH), 3073, 3017 (ArH), 2930, 2903 (alkyl-H), 2260
(CN), 1679 (CO), 1614, (C=C), 1180 (C=S)cm−1; 1H NMR
(300MHz) (DMSO-d6) δ 3.84 (s, 2H, CH2), 6.75 (d, 1H,
CH=, J=15.6Hz), 7.13 (t, 1H, J=4.8, 3.9Hz), 7.54 (d, 1H,
J=3.0Hz), 7.75 (d, 1H, J=5.4Hz), 7.91 (d, 1H, CH=,
J=15.6Hz), 11.15 (br s, H, NHCS, exchangeable), 11.62
(br s, H, NHCO, exchangeable), 12.44 (br s, H, CONHCS,
exchangeable); MS (70eV): m/z (%): 294 (M+,8), 276
(M+-H2O, 4), 249 (5), 235 (6), 209 (8), 154 (8), 137 (100),
109 (88), 99 (25), 65 (35); Anal. calcd for C11H10N4O2S2
(294.35): C, 44.88; H, 3.42; N, 19.03; found C, 44.66; H,
3.19; N, 18.72.
3-acetyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one
(3b): Colorless crystals, 76%, m.p. 269–271°C (EtOH); IR
(KBr) υ: 3211, 3197 (NH), 3062 (ArH), 2918 (alkyl-H),
1658 (CO), 1278 (CS), 766cm−1 δ4H; 1H NMR (300MHz)
(DMSO-d6) δ 2.14 (s, 3H, CH3CO), 7.52 (t, 1H, J=8.1,
6.9Hz), 7.59 (d, 1H, J=8.1Hz),7.87 (t, 1H, J=6.9Hz),
8.04 (d, 1H, J=7.8Hz), 11.87 (br s, 1H, 1NH, exchangea-
ble); MS (70eV): m/z (%): 220 (M+, 38), 221 (M++1, 6),
205 (M+-CH3, 7), 179 (18), 178 (100), 162 (54), 150 (46),
145 (38), 120 (67), 90 (74),63 (68); Anal. calcd for
C10H8N2O2S (220.25): C, 54.53; H, 3.66; N, 12.72; found
C, 54.61; H, 3.48; N, 12.43.
(E)-ethyl
2-(3-(3-(thiophen-2-yl)acryloyl)thioureido)
acetate (10): Colorless crystals, 81%, m.p. 162–164°C,
(EtOH); IR (KBr) υ: 3208, 3150 (NH), 3048 (ArH), 2973
(alkyl-H), 1750 (COester), 1678 (COamide), 1616 (C=C), 1116
(C=S)cm−1; 1H NMR (300MHz) (DMSO-d6) δ 1.32 (t, 3H,
CH3, J=7.2), 4.27 (q, 2H, OCH2, J=7.2), 4.45 (s, 2H,
NCH2CO), 6.19 (d, 1H, CH=, J=15.4Hz), 7.09–7.44 (m,
3H), 7.92 (d, 1H, CH=, J=14.6Hz), 8.68 (br s, 1H, NHCS,
exchangeable), 11.08 (br s, H, CONHCSNH, exchangea-
ble); MS (70eV): m/z (%): 298 (M+, 8), 253 (M+-OEt, 1),
138 (9), 137 (100), 109 (34), 83 (39), 65 (31); Anal. calcd
for C12H14N2O3S2 (298.38): C, 48.30; H, 4.73; N, 9.39;
found C, 48.41; H, 4.63; N, 9.11.
(E/Z)-1-(3-(thiophen-2-yl)acryloyl)thiourea
(13):
Formation of compounds 6 and 7
Colorless crystals, 41%, m.p. 222–224°C, (EtOH); IR
(KBr) υ: 3320, 3232, 3164 (NH), 3043 (ArH), 1684 (CO),
1590 (C=C), 1158 (C=S)cm−1; 1H NMR (300MHz)
(DMSO-d6) δ 7.15 (t, 1H, J=3.9Hz), 7.50 (d, 1H,
J=3.3Hz), 7.73 (d, 1H, J=4.5Hz), 9.38, 9.77 (two br. s,
2H, NH2, exchandeable), 11.13 (br s, 1H, CONHCS,
exchangeable), For E-isomer: 6.74 (d, 1H, CH=,
J=15.6Hz), 7.84 (d, 1H, CH=, J=15.3Hz), For Z-isomer:
6.60 (d, 1H, CH=, J=12.6 Hz), 8.04 (d, 1H, CH=,
J=7.8Hz); MS (70eV): m/z (%): 212 (M+, 34), 179 (M+-
SH, 10), 152 (2), 137 (100), 109 (57), 83 (4), 65 (47); Anal.
calcd for C8H8N2OS2 (212.29): C, 45.26; H, 3.80; N, 13.20;
found C, 44.88; H, 3.63; N, 12.86.
(E)-1-(piperidin-1-yl)-3-(thiophen-2-yl)prop-2-en-1-
one (14): Colorless crystals, 79%, m.p. 244–246°C,
(EtOH); IR (KBr) υ: 3098 (ArH), 2940, 2860 (alkyl-H),
1630 (CO), 1574 (C=C)cm−1; 1H NMR (300MHz)
(DMSO-d6) δ 1.37–1.72 (m, 6H, 3 CH2-piperidyl), 3.43–
3.62 (m, 4H, 2 CH2-piperidyl), 6.94 (d, 1H, CH=,
J=15.0Hz), 7.12–7.18 (m, 1H, thienyl), 7.4.2–7.51 (m,
1H, thienyl), 7.64 (d, 1H, CH=, J=12.4Hz), 7.65 (m, 1H,
thienyl); MS (70eV): m/z (%): 221 (M+, 12), 137 (100),
109 (86), 83 (9), 65 (31); Anal. calcd for C12H15NOS
(221.32): C, 65.12; H, 6.83; N, 6.33; found C, 65.36; H,
6.71; N, 6.12.
A solution of compound 5 (1g) in ethanol (30mL) and 3-M
sodium hydroxide (5mL) was refluxed for 1h. The reaction
mixture was concentrated under vacuum and then cooled to
room temperature. To an ice-cold solution of the reaction
mixture was added 3-M hydrochloric acid. The precipitated
solid was collected to give a mixture of compounds 6 and 7,
which were separated by fractional crystallization. A simi-
lar procedure was performed in the case reactions of com-
pounds 4b and 4c.
2-amino-3,1-benzothiazole (6): Colorless crystals,
43%, m.p. 124–126 °C (m.p. 126–128 °C) 16 (light petro-
leum 60–80°C); IR (KBr) υ: 3394, 3270 (NH2), 3055
1
(ArH), 1642 (C=N), 741cm−1 δ4H; H NMR (300MHz)
(DMSO-d6) δ 6.99 (t, 1H, J=7.5, J=7.8Hz), 7.19 (t, 1H,
J=7.2Hz, J=7.8Hz), 7.32 (d, 1H, J=8.1Hz), 7.40 (br s,
2H, NH2, exchangeable), 7.63 (d, 1H, J=7.5Hz); MS
(70eV) m/z (%): 150 (M+, 100), 133 (2), 123 (23), 118 (5),
108 (5), 96 (26), 82 (5); Anal. calcd for C7H6N2S (150.20):
C, 55.97; H, 4.03; N, 18.65; found C, 55.69; H, 3.81; N,
18.23.
(E)-3-(thiophen-2-yl)acrylic acid (7): Colorless crystals,
32%, m.p. 144–146°C (m.p. 145–148°C) (EtOH); IR
19
(KBr) υ: 3085–2584 (br OH), 3085 (ArH), 1675 (CO),
1614 (C=C)cm−1; 1H NMR (300MHz) (DMSO-d6) δ 6.17

8
Journal of Chemical Research 00(0)
(d, 1H, CH=, J=15.6Hz), 7.12–7.15 (m, 1H, ArH), 7.50 (d,
1H, J=3.6Hz),7.66–7.68 (m, 1H, ArH), 7.73 (d, 1H, CH=,
J=15.9Hz), 12.33 (br s, 1H, 1OH, exchangeable); MS
(70eV) m/z (%): 154 (M+, 100), 137 (65), 121 (56), 109
(52), 97 (27), 65 (32); Anal. calcd for C7H6O2S (154.19): C,
54.53; H, 3.92; found C, 54.22; H, 3.67.
Conclusion
The synthetic utilization of α,β-unsaturated acyl isothiocy-
anate is based on the different reactivities of both centers
toward nucleophiles. It is observed from all the reactions
mentioned that the nucleophilic attack proceeds at the iso-
thiocyanato group rather than at the α,β-unsaturated system,
which reflects the higher reactivity of the former. Compounds
2, 3, and 9 are the more active antimicrobial agents.
Formation of compounds 9 and 12
A solution of compound 8 or 10 (1 g) in ethanol (30 mL)
and 3-M hydrochloric acid (5 mL) was refluxed for 2 h.
The reaction mixture was evaporated in vacuo to ca
half-volume. A solution of 10% sodium carbonate was
added until effervescence ceased. The precipitated solid
was filtered off and recrystallized to give compounds 9
or 12.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
(E)-N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)-3-
(thiophen-2-yl)acrylamide (9): Pale yellow crystals, 73%,
m.p. 296–298°C, (dioxane); IR (KBr) υ: 3242, 3155, 3111
(NH), 3022 (ArH), 2909, 2830 (alkyl-H), 2250 (CN), 1670
(CO), 1611 (C=N), 1565 (C=C)cm−1; 1H NMR (300MHz)
(DMSO-d6) δ 4.52 (s, 2H, CH2), 6.66 (d, 1H, CH=,
J=15.6Hz), 7.18 (dd, 1H, J=3.6, 4.8Hz), 7.54 (d, 1H,
J=3.6Hz), 7.63 (d, 1H, J=4.8Hz), 7.95 (d, 1H, CH=,
J=15.3Hz), 12.74 (br s, 1H, 1NH, exchangeable); MS
(70eV) m/z (%): 276 (M+, 5), 243 (2), 152 (51), 139 (6),
134 (100), 124 (16), 109 (74), 83 (22); Anal. calcd for
C11H8N4OS2 (276.34): C, 47.81; H, 2.92; N, 20.27; found
C, 47.53; H, 2.76; N, 19.99.
2-thioxoimidazolidin-4-one (12): Buff crystals, 47%,
m.p. 227–229 °C, (m.p. 229–231 °C) 20 (EtOH); IR (KBr):
3282, 3185 (NH), 2970, 2912, 2830 (alkyl-H), 1715
(CO), 1161 (C=S) cm−1; 1H NMR (300 MHz) (DMSO-d6)
δ 4.07 (s, 2H, CH2), 9.79 (br s, 1H, NHCS, exchangea-
ble), 11.59 (br s, 1H, CONHCS, exchangeable); MS
(70 eV): m/z (%): 116 (M+, 100),88 (M+-CO, 22), 83
(M+-SH, 1) 72 (5), 60 (26); Anal. calcd for C3H4N2OS
(116.14): C, 31.02; H, 3.47; N, 24.12; found C, 30.69; H,
3.24; N, 23.78.
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Amira A El-Sayed
https://orcid.org/0000-0002-0840-4806
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Microbacterial activity
The newly synthesized heterocyclic compounds listed in
Table 1 were tested for their antibacterial activity against
Gram-positive bacteria (Bacillus cereus and Staphylococcus
aureus), Gram-negative bacteria (Escherichia coli and
Pseudomonas aeruginosa), and fungi (Candida albicans
and Aspergillus fumigatus) at a concentration of 100μg/mL
in dimethyl sulfoxide (DMSO). Nutrient agar and potato
dextrose agars were used to culture the bacteria and fungi,
respectively. The plates were inculcated by the bacteria or
fungi and incubated for 24h at 37°C for bacteria and for
72h at 28°C for fungi, and then the inhibition zones of
microbial growth surrounding the filter paper disk (5mm)
were measured in millimeters.