A novel strategy for the construction of azole heterocycles via an oxidative desulfurization approach using iodobenzene and oxone

Article abstract of DOI:10.1055/s-0031-1290439

The oxidative desulfurization approach has been utilized for the construction of oxadiazole and thiadiazole heterocycles using iodobenzene and Oxone. The use of iodobenzene and the inexpensive readily available oxidant Oxone makes the reaction system simp

Full text of DOI:10.1055/s-0031-1290439

1970▌
LETTER
lAetteNr ovel Strategy for the Construction of Azole Heterocycles via an Oxidative
Desulfurization Approach Using Iodobenzene and Oxone®
Synthesis of Oxadiazole and Thiadiazole Heterocycles
Kavitkumar N. Patel, Nikhil C. Jadhav, Prashant B. Jagadhane, Vikas N. Telvekar*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400 019, India
Fax +91(22)33611020; E-mail: vikastelvekar@rediffmail.com
Received: 18.05.2012; Accepted after revision: 18.06.2012
desulfurization to form N-(4-bromophenyl)-5-(4-chloro-
Abstract: The oxidative desulfurization approach has been utilized
phenyl)-2-amino-1,3,4-oxadiazole 2a in the presence of
for the construction of oxadiazole and thiadiazole heterocycles us-
iodobenzene and Oxone® in methanol as a solvent; but
only a 50% yield was observed after prolonged reaction
time. In the initial studies, we found that, on addition of 1
mol of triethylamine, the time for the reaction substantial-
ly decreased to 90 minutes but still with 50% yield. To in-
crease the yield we studied different ratios of reagent and
observed that a 90% yield could be achieved in 40 minutes
with 2 mol of iodobenzene, 4 mol of Oxone®, and 2 mol
of triethylamine in methanol. Acetonitrile and dichloro-
methane were also suitable solvents for this transforma-
tion, but the highest yield was observed with methanol.
ing iodobenzene and Oxone®. The use of iodobenzene and the inex-
pensive readily available oxidant Oxone® makes the reaction
system simple and versatile for desulfurization.
Key words: desulfurization, hypervalent iodine, iodobenzene, Ox-
one®, thiosemicarbazide, oxadiazole
Nitrogen-containing heterocycles are found ubiquitously
in nature,1a and many synthetic bioactive compounds con-
tain nitrogen heterocycles.1b Among these, azoles are an
important class of heterocycles in medicinal chemistry.
Within this group of heterocycles, 1,3,4-oxadiazole and
1,3,4-thiadiazole derivatives have been widely exploited
for various properties anti-inflammatory,1c anticancer,1d
and antimicrobial activity.1e
S
H
O
N
Br
N
H
NH
I
N
N
Oxone®
N
O
There are several methods described in the literature for
the synthesis of 2-amino derivatives of 1,3,4-oxadiazole
using cyclodehydration2a and cyclodesulfurization2b ap-
proaches. Similarly, synthesis of 2,5-diamino-1,3,4-thia-
diazoles has been accomplished by cyclization of
bisdiarylthioureas.2a,b These approaches suffer the disad-
vantages of requiring harsh reaction conditions, produc-
tion of byproducts, and use of corrosive and toxic
reagents.2c–e An iodine and K2CO3 combination has been
used for desulfurization in the synthesis of oxadiazoles,
but lower yields were observed.3 Recently, IBX/triethyl-
amine-mediated desulfurization has been reported for the
synthesis of oxadiazoles and thiadiazoles from the corre-
sponding thiosemicarbazides and bis(diarylthioureas).4
However, the potentially explosive nature of IBX led us to
consider desulfurization of thiosemicarbazide and bis(di-
arylthiourea) substrates using an iodine-based system.
H
Et3N
r.t.
Cl
2a
Cl
Br
1a
Scheme 1 Oxidative desulfurization of the thiosemicarbazide 1a us-
ing iodobenzene/Oxone® in methanol
In order to study substrate scope, various thiosemicarba-
zides were surveyed, and the results are summarized in
Table 1.6
Table 1 Oxidative Desulfurization of the Thiosemicarbazidea
S
iodobenzene
Oxone®
N
H
N
R1
O
N
N
H
NH
R1
N
R2
Et3N
O
H
R2
1a–i
2a–i
It has been reported that the hydroxy(phenyl)iodonium
ion, which is an active iodine species, can be generated in
situ using iodobenzene and Oxone® at room temperature.5
As part of our studies on hypervalent iodine systems, we
considered that this in situ generated species could be
used for desulfurization. Thus for our initial study, N-(4-
bromophenyl)-2-(4-chlorobenzoyl)hydrazine-carbothio-
amide 1a was used as a model substrate (Scheme 1). We
observed that thiosemicarbazide 1a underwent oxidative
Entry
Substrate 1
Product 2 Yield (%)b
S
H
O
N
N
NH
Br
H
1
2a
91
Cl
1a
SYNLETT 2012, 23, 1970–1972
Advanced online publication: 26.07.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290439; Art ID: ST-2012-D0435-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Oxadiazole and Thiadiazole Heterocycles
1971
Table 1 Oxidative Desulfurization of the Thiosemicarbazidea
Table 1 Oxidative Desulfurization of the Thiosemicarbazidea
(continued)
(continued)
S
S
iodobenzene
Oxone®
iodobenzene
Oxone®
N
N
N
H
H
N
R1
R1
O
N
O
N
N
H
NH
R1
N
H
NH
R1
N
N
R2
R2
Et3N
O
Et3N
O
H
H
R2
R2
1a–i
2a–i
1a–i
2a–i
Entry
Substrate 1
Product 2 Yield (%)b
Entry
Substrate 1
Product 2 Yield (%)b
S
S
H
H
O
N
O
N
N
H
NH
N
NH
H
9
2i
77
2
2b
2c
2d
2e
2f
85
78
76
72
84
Br
Br
1i
a Reaction conditions: Oxone® (4 mol), iodobenzene (2 mol), Et3N
(2 mol), MeOH, r.t.
1b
S
H
N
b Isolated yields after column chromatography and structures were
confirmed by comparison of IR, 1H NMR, and mp with literature re-
ports.
O
N
H
NH
3
4
5
6
To extend the scope of this desulfurization protocol, the
same reactant system was applied to bisdiarylthiourea 3a,
forming thiadiazole 4a in good yield, and results with a
range of substrates are summarized in Table 2. The yield
and rate of reaction showed no notable correlation with
the nature of substitution of the benzene rings.
OMe
OMe
Br
1c
S
H
N
O
N
H
NH
Table 2 Oxidative Desulfurization of the Bisdiarylthioureaa
S
S
Cl
OMe
NH
HN
R
N
N
NH
R
1d
PhI (2 equiv)
H
H
S
Oxone® (4 equiv)
H
N
O
Et3N (2 equiv)
MeOH
N
H
R
R
3a–d
N
N
N
N
H
S
OMe
Br
H
4a–d
1e
S
Entry
Substrate 3
Product 4
Yield (%)b
H
N
O
N
H
NH
S
S
HN
N
H
N
H
NH
OMe
1
4a
90
OMe
O
OMe
S
1f
OMe
OMe
NH
H
N
3a
N
NHEt
S
S
H
O2N
7
8
2g
2h
85
81
HN
N
H
N
H
2
4b
90
1g
S
H
O
N
Br
Br
N
H
NH
3b
Ph
1h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1970–1972

1972
K. N. Patel et al.
LETTER
Table 2 Oxidative Desulfurization of the Bisdiarylthioureaa
(continued)
Kennedy, J.; Kuipers, P.; Okonkwo, G.; Schrier, D.; Wright,
C. J. Med. Chem. 1993, 36, 1802. (d) Kumar, D.; Patel, G.;
Chavers, K.; Chang, K.; Shah, K. Eur. J. Med. Chem. 2011,
3085. (e) Aggarwal, N.; Kumar, R.; Dureja, P.; Khurana, J.
Chem. Biol. Drug Des. 2012, 79, 384.
S
S
HN
R
N
N
NH
R
PhI (2 equiv)
H
H
(2) (a) Dumciute, J.; Martynaitis, V.; Holzer, W.; Manelinckx,
S.; De Kimpe, N.; Sacaus, A. Tetrahedron 2006, 62, 3309.
(b) Dolman, S.; Gosselin, F.; Shea, P.; Davies, I. J. Org.
Chem. 2006, 71, 9548; and references cited therein.
(c) Demina, M.; Sarapulova, G.; Borisova, A.; Larina, L.;
Medvedeva, A. Russ. J. Org. Chem. 2003, 10, 1522.
(d) Rostom, S.; Shalaby, M.; El-Demellawy, M. Eur. J. Med.
Chem. 2003, 959. (e) Yale, H.; Losee, K. J. Med. Chem.
1966, 9, 478.
Oxone® (4 equiv)
Et3N (2 equiv)
MeOH
R
R
3a–d
N
N
N
N
H
S
H
4a–d
(3) Ghosh, H.; Yella, R.; Nath, J.; Patel, B. Eur. J. Org. Chem.
2008, 6189.
Entry
Substrate 3
Product 4
Yield (%)b
(4) Chaudhari, P.; Pathare, S.; Akamanchi, K. J. Org. Chem.
2012, 77, 3716.
(5) Zagulyaeva, A.; Banek, C.; Yusubov, M.; Zhdakin, V. Org.
Lett. 2010, 12, 4644.
S
S
HN
Cl
N
H
N
H
NH
(6) Typical Procedure for the Oxidative Desulfurization
A mixture of Oxone® (4 equiv) and iodobenzene (2 equiv) in
MeOH was stirred at r.t. for 20 min followed by addition of
Et3N (2 equiv) and substrate (1 equiv) at r.t. for 40 min. The
reaction mixture was diluted with H2O and then extracted
twice with EtOAc. The organic layer was washed succes-
sively with 10% NaHCO3 (2 × 20 mL), H2O (2 × 20 mL) and
dried over anhyd Na2SO4, filtered, and concen-trated under
reduced pressure to give the crude product. The product was
purified using silica gel column chromatography (30%
EtOAc–hexane).
3
4c
80
Cl
3c
S
S
HN
N
H
N
H
NH
4
4d
78
N-(4-Bromophenyl)-5-(4-chlorophenyl)-2-amino-1,3,4-
oxadiazole (2a)
3d
a Reaction conditions: Oxone® (4 mol), iodobenzene (2 mol), Et3N (2
mol), MeOH, r.t.
White solid, mp273–274 °C (lit.7a 272–274 °C). IR (KBr):
3318, 3032, 1551, 1435 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.49–7.53 (m, 4 H),7.61 (d, 2 H), 7.89 (d, 2 H), 4.10 (s,
1 H).
b Isolated yields after column chromatography and structures were
confirmed by comparison of IR, 1H NMR, and mp with literature re-
ports.
N-5-Diphenyl-1,3,4-oxadiazole-2-amine (2i)
White solid, mp 218–219 °C (lit.7a 217–219 °C). IR (KBr):
3371, 3043, 1549, 1452 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 6.92 (t, 1 H), 7.33 (dd, 2 H), 7.41 (m, 3 H), 7.58–7.62
(m, 2 H), 7.89 (m, 2 H), 8.91 (s, 1 H, NH).
In summary, we have utilized an in situ generated hyper-
valent iodine reagent system for the construction of the
azole heterocycles.
N2,N5-Bis(4-methoxyphenyl)-1,3,4-thiadiazole-2,5-
diamine (4a)
White solid, mp 234–236 °C (lit.7b 235–237 °C). IR (KBr):
3328, 1543, 1436, 1053 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 3.74 (s, 6 H), 7.04 (d, 4 H), 7.38 (d, 4 H), 8.21 (s, 2
H).
Acknowledgment
We thank University Grant Commission, New Delhi, India for pro-
viding fellowships to KNP and NCJ under the Special Assistant
Programme (UGC-SAP) and to PBJ under Rajiv Gandhi National
Fellowship programme (UGC-RGNF).
N2,N5-Diphenyl-1,3,4-thiadiazole-2,5-diamine (4d)
White solid, mp 238–240 °C (lit.7c 239–242 °C). IR (KBr):
3335, 1548, 1424, 1161 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 6.78 (d, 2 H), 7.15–7.47 (m, 6 H), 8.37 (s, 2 H).
(7) (a) Simiti, I.; Ghiran, D.; Schwartz, I. Arch. Pharm. Ber.
Dtsch. Pharm. Ges. 1971, 304, 230. (b) Joshua, C.; Annie,
V. J. Indian Chem. Soc. 1990, 759. (c) Yella, R.; Khatun, N.;
Rout, S.; Patel, B. Org. Biomol. Chem. 2011, 3235.
References
(1) (a) Lewis, J. Nat. Prod. Rep. 2000, 57. (b) Jansen, M.; Rabe,
H.; Strehle, A.; Dieler, S.; Debus, F.; Dannhardt, G.; Akabas,
M.; Lüddens, H. J. Med. Chem. 2008, 51, 4430.
(c) Boschelli, D.; Connor, D.; Bornemeier, D.; Dyer, R.;
Synlett 2012, 23, 1970–1972
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