Dimethyldithioimidocarbonates-mediated heterocyclizations: Synthesis of imidazolidines and benzheterocycles as potent antitubercular agents

Article abstract of DOI:10.1080/10426500601088721

A new series of thiadiazolylimidazolidines, thiadiazolylbenzimidazoles, thiadiazolylbenzoxazoles, and thiadiazolylbenzothiazoles were synthesized by heterocyclization reactions of dimethyldithioimidocarbonate of properly substituted thiadiazoles with vari

Full text of DOI:10.1080/10426500601088721

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Phosphorus, Sulfur, and Silicon
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Dimethyldithioimidocarbonates-
Mediated Heterocyclizations:
Synthesis of Imidazolidines and
Benzheterocycles as Potent
Antitubercular Agents
Vinayak S. Hegde a , Gundurao D. Kolavi a , Ravi S.
Lamani a & Imtiyaz Ahmed M. Khazi a
a Department of Chemistry , Karnatak University ,
Dharwad, India
Published online: 24 Feb 2007.
To cite this article: Vinayak S. Hegde , Gundurao D. Kolavi , Ravi S. Lamani & Imtiyaz
Ahmed M. Khazi (2007) Dimethyldithioimidocarbonates-Mediated Heterocyclizations:
Synthesis of Imidazolidines and Benzheterocycles as Potent Antitubercular Agents,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:4, 911-920, DOI:
10.1080/10426500601088721
To link to this article: http://dx.doi.org/10.1080/10426500601088721
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Phosphorus, Sulfur, and Silicon, 182:911–920, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601088721
Dimethyldithioimidocarbonates-Mediated
Heterocyclizations: Synthesis of Imidazolidines and
Benzheterocycles as Potent Antitubercular Agents
Vinayak S. Hegde
Gundurao D. Kolavi
Ravi S. Lamani
Imtiyaz Ahmed M. Khazi
Department of Chemistry, Karnatak University, Dharwad, India
A new series of thiadiazolylimidazolidines, thiadiazolylbenzimidazoles, thiadia-
zolylbenzoxazoles, and thiadiazolylbenzothiazoles were synthesized by heterocy-
clization reactions of dimethyldithioimidocarbonate of properly substituted thia-
diazoles with various binucleophiles. The structures of all the newly synthesized
compounds were elucidated and they were screened for antitubercular activity
against Mycobacterium tuberculosis H Rv using the BACTEC 460 radiometric
37
system, where few compounds have shown more than 90% inhibition at MIC of
<6.25 μg/mL in the preliminary screening level. They were also screened for their
antibacterial activity against Escherichia coli and Bacillus cirrhosis, and antifun-
gal activity against Aspergillus niger and Penicillium worthmanni. Some of the
compounds have shown promising in vitro antibacterial and antifungal activities.
Keywords Antitubercular activity; antimicrobial activity; Dimethyldithioimidocarbon-
ates; thiadiazolylimidazolidines; thiadiazolyl-benzheterocycles
INTRODUCTION
Thiadiazole derivatives are useful compounds having pharmaco-
logical and biological activities1−6 such as antimicrobial,1−3 anti-
inflammatory,4,5 anticonvulsant,6 antihypertensive7 and anticancer8,9
activities. Furthermore, benzfused heterocycles. Particularly benzimi-
dazoles, benzoxazoles, and benzothiazoles, are of considerable chemi-
cal and biological interest.10−13 A combination of such two biodynamic
Received July 23, 2006; accepted October 5, 2006.
We sincerely thank Tuberculosis Antimicrobial Acquisition and Coordinating Facility
(National Institute of Allergy and Infectious Diseases (NIAID), Maryland National Insti-
tutes of Health (NIH), Bethesda, Maryland, Tuberculosis Antimicrobial Acquisition and
Coordinating Facility (TAACF), Birmingham, Alabama) for anti-tuberculosis evaluations
and Dr. Uday Muddapur for antibacterial and antifungal screening. We also thank Prof.
C. S. Mahajanashetti for valuable suggestions and encouragement.
Address correspondence to Imtiyaz Ahmed M. Khazi, Department of Chemistry,
Karnatak University, Dharwad, 580003, India. E-mail:drimkogchem@gmail.com
911

912
V. S. Hegde et al.
molecules is expected to increase the biological potency of the molecule
in concern. In recent years much attention has been devoted to the
synthesis of heterocycles as antitubercular and antimicrobial agents.
The treatment of mycobacterial infections, especially tuberculosis, has
become an important problem due to the emergence of monodrug and
multidrug resistance.13 It has been reported that the thiadiazole deriva-
tives showed good activity against Mycobacterium tuberculosis.15−17
RESULTS AND DISCUSSION
The new key intermediate dimethyl 5-(benzyl/3-pyridyl)-1,3,4-
thiadiazol-2-yldithioimidocarbonates (2a,b) were synthesized from
corresponding 2-amino-5-(benzyl/3-pyridyl)thiadiazoles (1a,b)18,19
by the reaction with carbon disulfide and methyl iodide in alkaline
medium (Scheme 1). The products are characterized by the absence
of υN
in the IR spectra and by the presence of a singlet for six
H
protons (at δ 2.6 for 2a and δ 2.74 for 2b) due to two equivalent SCH3
1
groups in H NMR spectra. The rest of the protons resonated in the
expected region. Furthermore, compound 2b was confirmed by a 13C
NMR spectrum, which exhibited a characteristic signal at δ 16.4 due
to carbon of two magnetically equivalent SCH3 groups.
The intermediates dimethyldithioimidocarbonates (2a,b) were
treated with ethylenediamine in DMF to yield corresponding imida-
zolidine derivatives (3a,b). The products obtained possessed the strong
SCHEME 1 Reagents and conditions: (a) i. aq. NaOH (20 M),CS2, 0◦C/DMF, ii.
CH3I, 0◦C; (b) ethylene diamine/DMF, 120◦C, 6 h; (c) 2-phenelenediamine/DMF,
120◦C, 6–8 h; (d) 2-aminophenol/DMF, 120◦C, 8 h; (e) 2-aminothiophenol/DMF,
120◦C, 6–8 h.

Synthesis of Imidazolidines and Benzheterocycles
913
υN around the 3330 cm−1 band in IR spectra, and the 1H NMR spec-
H
tra displayed a D2O exchangeable broad singlet in the region δ 7.3 to
7.7 assigned for two equivalent NH protons; a singlet around δ 3.6 for
4 protons was observed indicating the fact that both hydrogens are lo-
cated (Figure 1) on ring nitrogens, thus making the protons CH2CH2
of imidazolidine equivalent. Furthermore the 13C NMR spectrum of im-
idazolidine 3b showed a characteristic signal at δ 37.5 for CH2-CH2
confirming both carbons are equivalent in accordance with the 1H NMR
report. Compound 3b is also confirmed by mass (ESI) spectrum.
Similarly, when intermediate dimethyldithioimidocarbonates (2a,b)
were reacted with binucleophiles viz. o-phenylenediamine, 2-
aminophenol and 2-amino thiophenol afforded corresponding benzimi-
dazoles (4a,b), benzoxazoles (5a,b), and benzothiazoles (6a,b), respec-
tively. From the 1H NMR spectrum of benzimidazole (4b), it is clear that
both NH protons are equivalent. This is due to the reason as described
in the case of imidazolidine derivatives (3a,b). Furthermore, this is
1
supported by the fact that, in the H NMR spectra of benzimidazole
derivatives (4a,b), C5-H, and C6-H of benzimidazole ring was observed
as a doublet at δ 7.2 and C4, C7-H was observed as a doublet at δ 7.4.
The 1H NMR and 13C NMR spectra of all benzheterocycles are in total
agreement with the assigned structures. The mass spectrum of benzox-
azole derivative 5a showed a molecular ion peak at 308.1 (100%), which
corresponds to its molecular weight (308.37). The new heterocyclic sys-
tems (3–6) were successfully constructed by the 4+1 approach, and the
evolution of methanethiol (MeSH) was observed during the course of
heterocyclization reactions.
BIOLOGICAL ACTIVITY
The in vitro antimycobacterial activity was assayed by Tuberculo-
sis Antimicrobial Acquisition and Coordinating Facility (Birmingham,
Alabama, USA), an antitubercular drug discovery program. Primary
screening was conducted at 6.25 μg/mL against M. tuberculosis H37Rv
(ATCC 27294) in BACTEC 12B20,21 medium using a broth microdilu-
tion assay,22the Microplate Alamar Blue Assay (MABA). Compounds
exhibiting fluorescence were tested in the BACTEC 460 radiometric
FIGURE 1 The delocalization of hydrogens over nitrogen atoms.

914
V. S. Hegde et al.
TABLE I The In Vitro Antitubercular Activity of
Compounds Against M. tuberculosis H37Rv
Compound
no.
MIC
in μg/mL
%
Assay
Inhibition
Activity
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
Alamar
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
>6.25
88
73
77
37
77
74
93
95
53
61
—
—
—
—
—
—
+
+
—
—
system. Compounds affecting <90% inhibition in the primary screen
were not further evaluated. Compounds demonstrating at least 90%
inhibition in preliminary screening were tested at lower concentrations
by serial dilution against M. tuberculosis H37Rv to determine the MIC
using MABA. Compounds 5a and 5b exhibited excellent inhibitory ac-
tivity of 93% and 95%, respectively, which were selected for further
screening, where it exhibited promising inhibitory activity of 58% and
39%, respectively.
Preliminary antituberculosis activity data (Table I) reveals that in-
termediate dimethyl-5-alkyl/aryl-1,3,4-thiadiazol-2-yldithioimidocar-
bonates (2a,b) are very active, and out of all heterocyclized deriva-
tives, only benzoxazole derivatives (5a,b) have shown very good activity
against M. tuberculosis H37Rv at <6.25 μg/mL. Other compounds have
shown moderate activity.
Biological significance of all the derivatives was also established by
screening them against two bacterial strains Bacillus cirrohsis and
Escherichia coli and two fungal species Aspergillus niger and Peni-
cillium wortmannii by the cup plate method19 at the concentration
25–100 μg/mL using DMF as a solvent. Norfloxacin and Greseoful-
vin, respectively, were used as standards. In general, antimicrobial
activity data (Table II) revealed that among all the newly syn-
thesized compounds, pyridine-substituted (at C-5 position of thia-
diazole ring) compounds have shown very good antibacterial and
antifungal activity at 100 μg/mL concentration and moderate activ-
ity at a lower concentration of 25 μg/mL. In particular, benzimidazole
derivatives (4a,b) have shown good antibacterial activity at a higher
concentration.

915

916
V. S. Hegde et al.
In conclusion the preliminary in vitro antituberculosis, antibacterial,
and antifungal screening results of novel imidazolidine and benzhete-
rocycle derivatives of 1,3,4-thiadiazole reported in the present article
reveal that many of the compounds from the series have emerged as po-
tent antitubercular, antibacterial, and antifungal agents endowed with
moderate to good activity. Possible improvements in the activity can be
further achieved by slight modifications in the new heterocyclic systems
reported in this article. Our findings will have an impact on chemists
and pharmacists for further investigations in this field in search of po-
tent antitubercular and antimicrobial agents.
EXPERIMENTAL
Melting points were determined using an electric melting point appara-
tus (Shital scientific industries, Mumbai) and are uncorrected. IR spec-
tra (KBr) were run on a Nicolet impact 410 FT-IR spectrometer (νmax in
cm−1). 1H NMR and 13C NMR spectra were recorded in CDCl3, DMSO-
d6, and TFA with TMS as an internal standard (chemical shift in δ,
ppm and J values in Hz) on a Brucker 300 MHz FTNMR spectrometer.
Mass spectra were recorded on Thermo-Finnigan-MAT, Bremen (Model
MAT8200) spectrometer. Electrospray ionization mass spectrum (ESI-
MS) was recorded on a Quattro LCZ (Walters-Micromass, Manchester),
and elemental analyses were carried out on a Heraus CHN rapid ana-
lyzer. Purity of the compound was checked by TLC. Nomenclature was
made using Chemsketch software. All the reagents were of laboratory
reagent quality and were used after purification.
Preparation of Dimethyl 5-(benzyl/3-pyridyl)-1,3,4-thiadiazol-
2-yldithio imidocarbonates (2a,b): General Procedure
To
a well-stirred solution of 2-amino-5-(benzyl/3-pyridyl)-1,3,4-
thiadiazole 2 (10 mmol) in dimethylformamide (8 mL) were added
sodium hydroxide solution (20 M, 4 mL), carbon disulfide (1.52 g,
20 mmol), and methyl iodide (3.384 g, 24 mmol) in sequence at an in-
terval of 30 min at 0–5◦C. Stirring was continued for 4 h, during which
the temperature was slowly raised to r.t. The mixture was then poured
into cold water, and the resulting sticky solid was extracted with chlo-
roform, washed with water and dried over anhydrous sodium sulphate.
The solvent was removed under diminished pressure, and the residual
solid was recrystallized from a chloroform-hexane mixture to yield the
corresponding dimethyldithioimidocarbonate (2a,b) in moderate yields
as crystalline solids.

Synthesis of Imidazolidines and Benzheterocycles
917
Dimethyl 5-benzyl-1,3,4-thiadiazol-2-yldithioimidocarbonate
(2a)
Pale yellow needles (chloroform + hexane), yield 61%, m.p. 88–90◦C;
1
IR (KBr) υcm−1: 3052, 2977, 2925, 1608, 1574; H NMR (300 MHz,
CDCl3) δ: 2.59 (s, 6H, SCH3), 4.35 (s, 2H, CH2), 7.25–7.36 (m, 5H,
phenyl). Anal. calcd. for C12H13N3S3: C, 48.78; H, 4.44; N, 14.22. Found:
C, 48.93; H, 4.50; N, 14.08%.
Dimethyl 5-pyridin-3-yl-1,3,4-thiadiazol-2-
yldithioimidocarbonate (2b)
Bright yellow granules, m.p. 130–132◦C; IR (KBr) υcm−1: 3038, 2978,
1
2919, 1583, 1568; H NMR (300 MHz, CDCl3) δ: 2.74 (s, 6H, SCH3),
7.47 (dd, J
= 4.8 Hz, J
= 3.1 Hz, 1H, C5-H, pyridine), 8.29 (d,
H5H4
H5H6
J =4.8 Hz, 1H, C6-H, pyridine), 8.68 (d, J = 4.4 Hz, 1H, C4-H, pyri-
dine), 9.08 (s, 1H, C2-H, pyridine); 13C NMR (75 MHz, CDCl3) δ: 16.4,
124.2, 127.4, 134.6, 148.6, 151.7, 162.9, 169.0 and 177.1. Anal. calcd.
for C10H10N4S3: C, 42.53; H, 3.57; N, 19.84. Found: C, 42.76; H, 3.61; N,
19.70%.
Preparation of 5-(benzyl/3-pyridyl)-N-imidazolidin-2-ylidene-
1,3,4-thiadiazol-2-amine (3a,b): General Procedure
A mixture of 2 (2 mmol) and ethylenediamine (0.14 g, 2.4 mmol) in
dimethylformamide (10 mL) was heated to 120◦C for 6 h. The solid
that separated after cooling was collected by filtration, washed with aq.
ethanol, dried, and recrystallized from ethanol.
5-Benzyl-N-imidazolidin-2-ylidene-1,3,4-thiadiazol-
2-amine (3a)
Colorless cubes (ethanol), yield 65%, m.p. 198–200◦C; IR (KBr)
1
υcm−1: 3343, 2976, 1626, 1558; H NMR (300 MHz, CDCl3) δ: 3.67 (s,
4H, imidazolidine), 4.23 (s, 2H, CH2), 7.24–7.35 (m, 5H, phenyl), 7.72
(s, 2H, NH, D2O exchangeable); 13C NMR (75 MHz, CDCl3) δ: 37.3,
42.7, 127.4, 129.10, 129.14, 137.9, 161.5, 161.6 and 176.4. Anal. calcd.
for C12H13N5S: C, 55.58; H, 5.05; N, 27.01. Found: C, 55.74; H, 5.17; N,
26.88%.
N-Imidazolidin-2-ylidene-5-pyridin-3-yl-1,3,4-thiadiazol-
2-amine (3b)
Colorless needles (ethanol), yield 61%, m.p. 254–256◦C; IR (KBr)
υcm−1: 3335, 3046, 2962, 1618, 1572, 1527; 1H NMR (300 MHz,
CDCl3) δ: 3.58 (s, 4H, imidazolidine), 7.35 (s, 2H, NH, D2O exchange-
able), 7.47 (dd, J
= 4.8 Hz, J
= 7.3 Hz, 1H, C5-H, pyridine),
H5H4
H5H6

918
V. S. Hegde et al.
8.29 (d, J = 7.8 Hz, 1H, C6-H, pyridine), 8.68 (d, J = 4.4 Hz, 1H, C4-H,
pyridine), 9.08 (s, 1H, C2-H, pyridine); MS (ESI): 247.07 (M+H), 269.05
(M+Na), 515.12 (2M+Na). Anal. calcd. for C10H10N6S: C, 48.77; H, 4.09;
N, 34.12. Found: C, 48.94; H, 4.17; N, 33.96%.
Preparation of N-{5-(benzyl/3-pyridyl)-1,3,4-thiadiazol-2-yl}-
1H-benzimidazol-2-amine (4a,b): General Procedure
A mixture of 2 (2 mmol) and o-phenylenediamine (0.26 g, 2 mmol) was
heated (120◦C) in dimethylformamide (10 mL) for 8 h. The separated
solid was collected by filtration, washed with aqueous alcohol, dried,
and recrystallized from a suitable solvent.
N-(5-Benzyl-1,3,4-thiadiazol-2-yl)-1H-benzimidazol-
2-amine (4a)
Colorless needles (DMF), yield 72%, m.p. 264–268◦C; IR (KBr)
υcm−1: 3228, 3060, 2976, 1608, 1576, 1544; 1H NMR (300 MHz, DMSO-
d6+ TFA) δ: 4.28 (s, 2H, CH2), 7.22–7.67 (m, 9H, benzimidazole). Anal.
calcd. for C16H13N5S: C, 62.52; H, 4.26; N, 22.78. Found: C, 62.41; H,
4.31; N, 22.63%.
N-(5-Pyridin-3-yl-1,3,4-thiadiazol-2-yl)-1H-
benzimidazol-2-amine (4b)
Bright yellow solid (DMF), yield 75%, m.p. >300◦C; IR (KBr) υcm−1
:
3242, 3054, 1616, 1585, 1547; 1H NMR (300 MHz, DMSO-d6) δ: 7.15 (d,
J = 3.3 Hz, 2H, C5, C6-H, benzimidazole), 7.39 (d, J = 3.3 Hz, 2H, C4,
C7-H, benzimidazole), 7.55 (t, J = 7.0 Hz, 1H, C5-H, pyridine), 8.23 (d,
J = 6.9 Hz, 1H, C6-H, pyridine), 8.66 (d, J = 6.9 Hz, 1H, C4-H, pyri-
dine), 9.04 (s, 1H, C2-H, pyridine), 12.06 (br s, 2H, NH, D2O exchange-
able); 13C NMR (75 MHz, DMSO-d6+ TFA) δ: 110.0, 113.1, 113.8, 117.6,
121.4, 124.5, 127.4, 129.2, 130.4, 141.3, 142.7, 146.0, 147.3 and 155.1.
Anal. calcd. for C14H10N6S: C, 57.13; H, 3.42; N, 28.55. Found: C, 57.25;
H, 3.30; N, 28.38%.
Preparation of N-{5-(benzyl/3-pyridyl)-1,3,4-thiadiazol-2-yl}-
1,3-benzoxazol-2-amine (5a,b): General Procedure
A mixture of dimethyldithioimidocarbonate 2 (2 mmol) and 2-
aminophenol (0.26 g, 2.4 mmol) in dimethylformamide (12 mL) was
heated at 120◦C for 8 h. The separated solid was collected by filtration,
washed with aqueous alcohol, dried and recrystallized from a methanol-
dimethylformamide mixture.

Synthesis of Imidazolidines and Benzheterocycles
919
N-(5-Benzyl-1,3,4-thiadiazol-2-yl)-1,3-benzoxazol-2-amine (5a)
Pale yellow prisms (methanol + DMF), yield 69%, m.p. 282–286◦C;
1
IR (KBr) υcm−1: 3164, 3036, 1595, 1578, 1545; H NMR (300 MHz,
DMSO-d6) δ: 4.27 (s, 2H, CH2), 7.12–7.49 (m, 9H, benzoxazole), 13.95
(s, 1H, NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6 + TFA):
36.3, 110.6, 113.8, 116.0, 117.6, 121.4, 123.7, 125.2, 129.5, 129.6, 137.0,
138.2, 148.0 and 163.4; MS m/z (%): 308.0 (100), 270.1 (2.9), 248.0 (8.6),
177.0 (19.7), 160.1 (47.7). Anal. calcd. for C16H12N4OS: C, 62.32; H, 3.92;
N, 18.17. Found: C, 62.58; H, 3.81; N, 18.05%.
N-(5-Pyridin-3-yl-1,3,4-thiadiazol-2-yl)-1,3-benzoxazol-
2-amine (5b)
Pale yellow granules (methanol + DMF), yield 70%, m.p. >300◦C; IR
1
(KBr) υcm−1: 3320, 3072, 1609, 1572; H NMR (300 MHz, DMSO-d6+
TFA) δ: 7.31–7.48 (m, 4H, benzoxazole), 7.56 (t, J = 7.4 Hz, 1H, C5-H,
pyridine), 8.25 (d, J = 7.2 Hz, 1H, C6-H, pyridine), 8.66 (d, J = 7.0
Hz, 1H, C4-H, pyridine), 9.04 (s, 1H, C2-H, pyridine). Anal. calcd. for
C14H9N5OS: C, 56.94; H, 3.07; N, 23.71. Found: C, 57.18; H, 3.12; N,
23.56%.
Preparation of N-{5-(benzyl/3-pyridyl)-1,3,4-thiadiazol-2-yl}-
1,3-benzothiazol-2-amine (6a,b): General Procedure
A mixture of dimethyldithioimidocarbonate 2 (2 mmol) and 2-
aminothiophenol (0.3 g, 2.4 mmol) in dimethylformamide (12 mL) was
heated at 120◦C for 6–8 h. The solid that separated was collected by
filtration, washed with aqueous ethanol, dried, and recrystallized from
a suitable solvent.
N-(5-Benzyl-1,3,4-thiadiazol-2-yl)-1,3-benzothiazol-
2-amine (6a)
Light green granules (DMF), yield 64%, m.p. 264–266◦C; IR (KBr)
υcm−1: 3331, 3052, 1620, 1584, 1546; 1H NMR (300 MHz, DMSO-d6 +
TFA) δ: 4.32 (s, 2H, CH2), 7.15–7.52 (m, 9H, benzothiazole). Anal. calcd.
for C16H12N4S2: C, 59.23; H, 3.73; N, 17.27. Found: C, 59.48; H, 3.80; N,
17.12%.
N-(5-Pyridin-3-yl-1,3,4-thiadiazol-2-yl)-1,3-benzothiazol-
2-amine (6b)
Light green granules (DMF), yield 67%, m.p. 288–292◦C; IR (KBr)
1
υcm−1: 3326, 3048, 1622, 1585, 1545; H NMR (300 MHz, DMSO-d6)
δ: 7.26 (t, J = 7.5 Hz, 1H, C6-H, benzothiazole), 7.42 (t, J = 7.5 Hz,
1H, C5-H, benzothiazole), 7.54–7.91 (m, 3H, C4, C7-H, benzothiazole;

920
V. S. Hegde et al.
C5-H, pyridine), 8.31 (d, J = 7.2 Hz, 1H, C4-H, pyridine), 8.70 (d, J = 7.0
Hz, 1H, C6-H, pyridine), 9.10 (s, 1H, C2-H, pyridine), 13.23 (br s, 1H,
NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6 + TFA) δ: 109.8,
113.6, 117.5, 121.3, 122.5, 123.9, 127.1, 128.0, 130.3, 130.7, 140.5, 142.8,
143.2 and 154.8. Anal. calcd. for C14H9N5S2: C; 54.00, H, 2.91; N, 22.49.
Found: C; 54.26; H, 3.02; N, 22.34%.
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