Regioselective synthesis of thiadiazolo[3,2-a]benzimidazole-5,8-diones

Article abstract of DOI:10.3184/030823409X12556199325887

Regioselective synthesis of the novel 7-hydroxy-2-(alkylsulfanyl)-6- undecyl[1,3,4]thiadiazolo[3,2-a]benzimidazole-5,8-diones was achieved by the reaction of 2,5-dihydroxy-6-undecyl-1,4-bezoquinone (embelin) with 5-(alkyl/aralkyl/phenacylsulfanyl)-1,3,4-t

Full text of DOI:10.3184/030823409X12556199325887

JOURNAL OF CHEMICAL RESEARCH 2009
NOVEMBER, 679–681
RESEARCH PAPER 679
Regioselective synthesis of thiadiazolo[3,2-a]benzimidazole-5,8-diones
Vakiti Srinivas and Vedula Rajeswar Rao*
Department of Chemistry, National Institute of Technology, Warangal-506 004, A.P., India
Regioselective synthesis of the novel 7-hydroxy-2-(alkylsulfanyl)-6-undecyl[1,3,4]thiadiazolo[3,2-a]benzimidazole-
5,8-diones was achieved by the reaction of 2,5-dihydroxy-6-undecyl-1,4-bezoquinone (embelin) with 5-(alkyl/aralkyl/
phenacylsulfanyl)-1,3,4-thiadiazol-2-amines in refluxing acetic acid.
Keywords: embelin, benzoquinone, thiadiazole, heterocyclic fused
Quinones are ubiquitous in nature. They are implicated in
numerous cellular functions and are involved in mechanisms
of electron and hydrogen transfers. Quinones form a large
class of antitumour agents approved for clinical use, and
many other antitumour quinones are in different stages of
clinical and preclinical development.1 The efficiency of the
quinones in inhibiting cancer cell growth is believed to stem
from their participation in key cellular redox mechanisms
with consequent generation of highly reactive oxygen species
(ROS). It is found that the ROS modify and degrade nucleic
acids and proteins within the cells.2,3
One of the most simple 1,4-benzoquinones isolated from
natural sources is embelin (1). Embelin (1) is isolated as the
main secondary metabolite from species of the Myrsinaceae4,5
and Oxalidaceae6 families. Compound 1 shows a diversity of
relevant biological activities such as chemopreventive effect
against DENA/PB-induced hepatocarcinogenesis in Wistar
rats,7 anti-fertility effects,8 and in vitro cytotoxic activity
against B16 and XC cell lines.9 In addition, recent studies
have shown that embelin is a fairly potent, nonpeptidic, cell-
permeable inhibitor of XIAP (X-linked inhibitor of apoptosis
protein), and it represents a promising lead compound for
designing an entirely new class of anticancer agents that
target the BIR3 domain of XIAP.10,11 These antecedents
justify the interest in evolving newer synthetic methods for
the construction of embelin derivatives.
embelin derivatives. In continuation of our earlier work,12-14
on the synthesis of heterocyclics fused quinones from
naturally occurring quinones, we now report the synthesis
of the novel 7-hydroxy-2-(alkylsulfanyl)-6-undecyl[1,3,4]
thiadiazolo[3,2-a]benzimidazole-5,8-dione (3) in a single step
(Scheme 1).
The embelin (1) used in the reactions was obtained from
Oxalis erythrorhiza following the procedure described in
ref. 4. The various 5-(alkyl/aralkyl/phenacylsulfanyl)-1,3,4-
thiadiazol-2-amines 2 were synthesised by the reaction of
2-amino-5-mercapto-1,3,4-thiadiazole with alkyl, aralkyl,
phenacyl halides.
5-(Alkyl/aralkyl/phenacylsulfanyl)-1,3,4-thiadiazol-2-amines
is believed to exist in two tautomeric structures 2 and 5. It has
been shown that in thiadiazole system, the more nucleophilic
site is the cyclic secondary nitrogen at position 3. In the course
of the reaction of 5-(alkyl/aralkyl/phenacylsulfanyl)-1,3,4-
thiadiazol-2-amines with embelin, the secondary nitrogen
with its nonbonding electrons attack on less sterically hindred
carbonyl carbon of quinone 4. Subsequent elimination of
water molecule followed by oxidative cyclisation in situ
furnished the product 3. Further the disappearance of the
characteristic signal of vinylic proton at 5.90 (s, 1H) of
embelin (1) confirms the structure (3).
The possible mechanism for the formation of 3 is proposed
in Scheme 2. Compound 3 was shown to have quinone moiety
intact by its behaviour towards Zn/AcOH in a reduction and
re-aerial oxidation test.
In view of broad biological activities of embelin derivatives,
we became interested in developing novel heterocyclic fused
O
S
O
R
N
H3C(H2C)10
HO
N
N
H3C(H2C)10
HO
OH
+
AcOH
N
N
S
S
R
H2N
S
O
O
1
2
3
3
a
b
R
methyl
ethyl
H2
C
HB
HA
c
HX
d
e
f
benzyl
p-Nitrobenzyl
phenacyl
g
h
i
p-Methylphenacyl
p-Methoxyphenacyl
p-Chlorophenacyl
p-Bromophenacyl
j
Scheme 1
* Correspondent. E-mail: vrajesw@yahoo.com
PAPER: JC090681

680 JOURNAL OF CHEMICAL RESEARCH 2009
7-Hydroxy-2-(ethylsulfanyl)-6-undecyl[1,3,4]thiadiazolo[3,2-a]
benzimidazole-5,8-dione (3b): Brown solid, yield 90%, m.p.
119–120°C. IR: nmax 1614 (quinonoid C=O), 2852 (CH) and 3313
(OH)cm-1.1HNMRd(DMSO-d6)0.85(t,3H,CH3),1.22–1.34(m,18H,
–(CH2)9-), 3.35 (q, 2H, SCH2), 1.40 (t, 3H, CH3), 2.25 (t, 2H, –CH2-),
and 12.58 (s, 1H, OH). Anal. Calcd for C21H29N3O3S2: C, 57.90; H,
6.71; N, 9.65; S, 14.72. Found: C, 57.86; H, 6.67; N, 9.62; S, 14.68%.
7-Hydroxy-2-(allylsulfanyl)-6-undecyl[1,3,4]thiadiazolo[3,2-a]
benzimidazole-5,8-dione (3c): Brown solid, yield 92%, m.p. 101–
102°C. IR: nmax 1614 (quinonoid C=O), 2848 (CH) and 3317 (OH)
In summary, we have described a convenient one-step
synthesis of 7-hydroxy-2-(alkylsulfanyl)-6-undecyl[1,3,4]
thiadiazolo[3,2-a]benzimidazole-5,8-dione
3
via hetero-
cyclisation of embelin 1 with 5-(alkyl/aralkyl/phenacyl-
sulfanyl)-1,3,4-thiadiazol-2-amines 2.
Experimental
“
Melting points were determined in open capillaries with a cintex”
melting point apparatus, Mumbai, India. Melting points were
uncorrected and CHNS analysis was performed using Carlo Erba EA
1108 automatic elemental analyser. The purity of the compounds was
checked by TLC plates (E.Merek, Mumbai, India), IR spectra (KBr)
1
cm-1. H NMR d (DMSO-d6) 0.84 (t, 3H, CH3), 1.25–1.35 (m, 18H,
–(CH2)9-), 2.25 (t, 2H, –CH2-), 3.86 (d, J = 5.1 Hz, 2H, S–CH2), 5.14
(d, J = HX, HA, J = 8 Hz, HA of allyl group), 5.28 (d, J = HX, HB,
J = 16.8 Hz, HB of allyl group), 5.90–6.00 (m, 1H, HX), and 12.60 (s,
1H, OH). Anal. Calcd for C22H29N3O3S2: C, 59.03; H, 6.53; N, 9.39;
S, 14.33. Found: C, 58.96; H, 6.50; N, 9.35; S, 14.30%.
1
were recorded on a BrukerWM-4(X) spectrometer (577 model). H
NMR spectra were recorded on a Bruker WM-300 MHz spectrometer
in d ppm using TMS as internal standard. Mass spectra (EI-MS) were
determined on Perkin Elmer (SCIEX API-2000, ESI) at 12.5eV.
7-Hydroxy-2-(benzysulfanyll)-6-undecyl[1,3,4]thiadiazolo[3,2-a]
benzimidazole-5,8-dione (3d): Brown solid, yield 94%, m.p. 113–
114°C. IR: nmax 1614 (quinonoid C=O), 2852 (CH) and 3313 (OH)
Synthesis of 7-hydroxy-2-(alkyl/aralkyl/phenacylsulfanyl)-6-undecyl-
[1,3,4]thiadiazolo[3,2-a]benzimidazole-5,8-dione 3; general procedure
Amixture of embelin 1 (10 mmol) and 5-(alkyl/aralkyl/phenacylthio)-
1,3,4-thiadiazol-2-amines 2 (10 mmol) was dissolved in glacial
acetic acid (15 mL) and the solution was refluxed for 4 h, cooled and
treated with ice cold water. The solid separated was filtered dried and
crystallised from ethanol.
1
cm-1. H NMR d (DMSO-d6) 0.85 (t, 3H, CH3), 1.23–1.36 (m, 18H,
–(CH2)9-), 2.25 (t, 2H, –CH2-), 4.47 (s, 2H, SCH2), 7.27–7.40 (m,
5H, ArH) and 12.58 (s, 1H, OH). Anal. Calcd for C26H31N3O3S2: C,
62.75; H, 6.28; N, 8.44; S, 12.89. Found: C, 62.71; H, 6.23; N, 8.41;
S, 12.86%.
7-Hydroxy-2-(p-nitrobenzylsulfanyl)-6-undecyl[1,3,4]thiadiazolo-
[3,2-a]benzimidazole-5,8-dione (3e): Brown solid, yield 91%, m.p.
139–140°C. IR: nmax 1614 (quinonoid C=O), 2853 (CH) and 3311
(OH) cm-1. 1H NMR d (DMSO-d6) 0.85 (t, 3H, CH3), 1.22–1.34 (m,
18H, –(CH2)9-), 2.27 (t, 2H, –CH2-), 5.77 (s, 2H, SCH2), 7.67 (d, 2H,
J = 8.4 Hz, ArH), 8.04 (d, 2H, J = 6.4 Hz, ArH) and 12.61 (s, 1H,
OH). Anal. Calcd for C26H30N4O5S2: C, 57.54; H, 5.57; N, 10.32; S,
11.82. Found: C, 57.51; H, 5.54; N, 10.30; S, 11.79%.
7-Hydroxy-2-(methylsulfanyl)-6-undecyl[1,3,4]thiadiazolo[3,2-a]
benzimidazole-5,8-dione (3a): Brown solid, yield 95%, m.p. 111–
112°C. IR: nmax 1648 (quinonoid C=O), 2850 (CH) and 3315 (OH)
1
cm-1. H NMR d (CDCl3) 0.87 (t, 3H, end CH3), 1.20–1.40 (m, 18H,
–(CH2)9-), 2.20 (s, 3H, SCH3), 2.35 (t, 2H, allylic CH2), and 11.77 (s,
1H, OH). EI-MS 421 (M+). Anal. Calcd for C20H27N3O3S2: C, 56.98; H,
6.46; N, 9.92; S, 15.21. Found: C, 56.94; H, 6.41; N, 9.89; S, 15.18%.
O
H3C(H2C)10
HO
OH
N
N
+
S
R
H2N
S
O
1
2
O
O
O
R
S
H3C(H2C)10
HO
OH
NH
H3C(H2C)10
HO
OH
S
HN
HN N
+
N
N
HO
S
5
4
S
R
OH
O
OH
H3C(H2C)10
O
H3C(H2C)10
O
H3C(H2C)10
O
O
H
O
O
H
N H
N
S
N
N
N
NH
NH
N
N
S
S
R
S
S
R
S
R
O
S
N
R
H3C(H2C)10
HO
N
N
S
O
3
Scheme 2
PAPER: JC090681

JOURNAL OF CHEMICAL RESEARCH 2009 681
7-Hydroxy-2-(phenacylsulfanyl)-6-undecyl[1,3,4]thiadiazolo-
[3,2-a]benzimidazole-5,8-dione (3f): Brown solid, yield 96%, m.p.
172–173°C. IR: nmax 1614 (quinonoid C=O), 1694 (ketone C=O),
2852 (CH) and 3313 (OH) cm-1. 1H NMR d (DMSO-d6) 0.85 (t, 3H,
CH3), 1.31–1.46 (m, 18H, –(CH2)9-), 2.30 (t, 2H, –CH2-), 5.05 (s, 2H,
SCH2), 7.58 (m, 2H, ArH), 7.70 (m, 1H, ArH), 8.05 (m, 2H, ArH) and
12.58 (s, 1H, OH). Anal. Calcd for C27H31N3O4S2: C, 61.69; H, 5.94;
N, 7.99; S, 12.20. Found: C, 61.64; H, 5.91; N, 7.75; S, 12.00%.
7-Hydroxy-2-(p-methylphenacylsulfanyl)-6-undecyl[1,3,4]thiadiazolo-
[3,2-a]benzimidazole-5,8-dione (3g): Brown solid, yield 93%, m.p.
140–141°C. IR: nmax 1613 (quinonoid C=O), 1681 (ketone C=O),
Conclusion
In conclusion, we have found a novel unexpected product
formation of 7-hydroxy-2-(alkylsulfanyl)-6-undecyl[1,3,4]
thiadiazolo[3,2-a]benzimidazole-5,8-dione 3 via heterocyclisation
of embelin 1 with 5-(alkyl/aralkyl/phenacylsulfanyl)-1,3,4-
thiadiazol-2-amines 2.
The authors are thankful to UGC, New Delhi for the sanction
of the project (F.No. 32-201/2006 (SR)). We also thank the
Director, NIT Warangal for providing research facilities.
1
2852 (CH) and 3312 (OH) cm-1. H NMR d (DMSO-d6) 0.85 (t, 3H,
CH3), 1.32–1.44 (m, 18H, –(CH2)9-), 2.31 (t, 2H, –CH2-), 2.40 (s, 3H,
p-methyl), 5.00 (s, 2H, SCH2), 7.38 (m, 2H, ArH), 7.90 (m, 2H, ArH)
and 12.58 (s, 1H, OH). Anal. Calcd for C28H33N3O4S2: C, 62.31; H,
6.16; N, 7.79; S, 11.88. Found: C, 62.28; H, 6.13; N, 7.75; S, 11.84%.
7-Hydroxy-2-(p-methoxyphenacylsulfanyl)-6-undecyl[1,3,4]-
thiadiazolo[3,2-a]benzimidazole-5,8-dione (3h): Brown solid, yield
97%, m.p. 159–160°C. IR: nmax 1612 (quinonoid C=O), 1676 (ketone
C=O), 2852 (CH) and 3312 (OH) cm-1. 1H NMR d (DMSO-d6) 0.82
(t, 3H, CH3), 1.35–1.43 (m, 18H, –(CH2)9-), 2.30 (t, 2H, –CH2-), 3.80
(s, 3H, OCH3), 5.00 (s, 2H, SCH2), 7.10 (d, 2H, J = 8 Hz, ArH),
8.00 (d, 2H, J = 8 Hz ArH) and 12.58 (s, 1H, OH). Anal. Calcd for
C28H33N3O5S2: C, 60.52; H, 5.99; N, 7.56; S, 11.54. Found: C, 60.50;
H, 5.96; N, 7.53; S, 11.50%.
7-Hydroxy-2-(p-chlorophenacylsulfanyl)-6-undecyl[1,3,4]-
thiadiazolo[3,2-a]benzimidazole-5,8-dione (3i): Brown solid, yield
90%, m.p. 170–171°C. IR: nmax 1614 (quinonoid C=O), 1680 (ketone
C=O), 2853 (CH) and 3313 (OH) cm-1. 1H NMR d (DMSO-d6) 0.85
(t, 3H, CH3), 1.32–1.46 (m, 18H, –(CH2)9-), 2.31 (t, 2H, –CH2-),
5.05 (s, 2H, SCH2), 7.65 (m, 2H, ArH), 8.10 (m, 2H, ArH) and 12.58
(s, 1H, OH). Anal. Calcd for C27H30ClN3O4S2: C, 57.90; H, 5.40; N,
7.50; S, 11.45. Found: C, 57.84; H, 5.38; N, 7.47; S, 11.41%.
7-Hydroxy-2-(p-bromophenacylsulfanyl)-6-undecyl[1,3,4]-
thiadiazolo[3,2-a]benzimidazole-5,8-dione (3j): Brown solid, yield
92%, m.p. 165–166°C. IR: nmax 1614 (quinonoid C=O), 1680 (ketone
C=O), 2852 (CH) and 3312 (OH) cm-1. 1H NMR d (DMSO-d6) 0.85
(t, 3H, CH3), 1.35–1.44 (m, 18H, –(CH2)9-), 2.30 (t, 2H, –CH2-), 5.00
(s, 2H, SCH2), 7.80 (m, 2H, ArH), 8.00 (m, 2H, ArH) and 12.58 (s,
1H, OH). Anal. Calcd for C27H30BrN3O4S2: C, 53.64; H, 5.00; N,
6.95; S, 10.61. Found: C, 53.58; H, 4.97; N, 6.93; S, 10.56%.
Received 13 July 2009; accepted 24 September 2009
Paper 09/0681 doi: 10.3184/030823409X12556199325887
Published online: 16 November 2009
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PAPER: JC090681