Superior reactivity of thiosemicarbazides in the synthesis of 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1021/jo0618730

(Chemical Equation Presented) A facile and general protocol for the preparation of 2-amino-1,3,4-oxadiazoles is reported. This method relies on a tosyl chloride/pyridine-mediated cyclization of a thiosemicarbazide, which is readily prepared by acylation o

Full text of DOI:10.1021/jo0618730

Superior Reactivity of Thiosemicarbazides in the
Synthesis of 2-Amino-1,3,4-oxadiazoles
Sarah J. Dolman,*,† Francis Gosselin,† Paul D. O’Shea,† and
Ian W. Davies‡
Department of Process Research, Merck Frosst Centre for
Therapeutic Research, 16711 Route Transcanadienne, Kirkland,
Que´bec, Canada H9H 3L1, and Department of Process
Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
sarah_dolman@merck.com
FIGURE 1. Some pharmaceutical products which contain the oxa-
diazole core.
ReceiVed September 11, 2006
properties,7 and 2-hydroxyphenyl-1,3,4-oxadiazoles behave as
hypnotics and sedatives.8 The widespread use of 1,3,4-oxadia-
zoles as a scaffold in medicinal chemistry as demonstrated by
these examples establishes this moiety as a member of the
privileged structures class. However, despite their common use,
most reported methods to prepare 1,3,4-oxadiazoles suffer from
harsh conditions or stoichiometric formation of an intractable
byproduct. Typically, 2-amino-1,3,4-oxadiazoles are prepared
by cyclization of the corresponding acyclic semicarbazide or
thiosemicarbazide derivatives (Scheme 1). As part of an ongoing
research program, we were interested in the development of a
robust and general method to access functionalized 2-amino-
1,3,4-oxadiazoles.
A facile and general protocol for the preparation of 2-amino-
1,3,4-oxadiazoles is reported. This method relies on a tosyl
chloride/pyridine-mediated cyclization of a thiosemicarba-
zide, which is readily prepared by acylation of a given
hydrazide with the appropriate isothiocyanate. Cyclization
of the thiosemicarbazide consistently outperforms the analo-
gous semicarbazide cyclization under these conditions, for
18 distinct examples. Utilizing this protocol, we have
prepared 5-alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles in
78-99% yield.
SCHEME 1. 2-Amino-1,3,4-oxadiazoles Are Accessible from
the Semicarbazide or Thiosemicarbazide
Approaches based on cyclo-dehydration of semicarbazides
are generally used and typically require harsh reagents such as
POCl3 or concentrated sulfuric acid.10 Alternatively, reagents
9
1,3,4-Oxadiazoles are commonly utilized pharmacophores due
to their metabolic profile and ability to engage in hydrogen
bonding. In particular, marketed antihypertensive agents such
as tiodazosin1 and nesapidil2 as well as antibiotics such as
furamizole3 contain the oxadiazole nucleus (Figure 1). 2-Amino-
1,3,4-oxadiazoles have demonstrated biological activity as
muscle relaxants4 and antiomitotics,5 while 2,5-diaryl-1,3,4-
oxadiazoles are known to be platelet aggregation inhibitors.6
5-Aryl-2-hydroxymethyl-1,3,4-oxadiazoles have shown diuretic,
analgesic, antiinflammatory, anticonvulsive, and antiemetic
that activate one carbonyl group to promote cyclization have
been used. Such reagents include phosphonium salts11 and
Burgess-type reagents;12 however, these reagents result in
significant byproduct formation and have typically been re-
stricted to use in solid-phase synthesis strategies. When thi-
(7) Thomas, J. Ger. Offen. 2403357, 1974; Chem. Abstr. 1974, 81,
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(8) Adelstein, G. W.; Yen, C. H.; Dajani, E. Z.; Bianchi, R. G. J. Med.
Chem. 1976, 19, 1221-1225.
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M. A.; Sit, S.-Y.; Romine, J. I.; Marin, S. W.; Ward, S. A.; McGovern, R.
T.; Clarke, W.; Russell, J.; Antal-Zimanyi, I. Bioorg. Med. Chem. 2004,
12, 507-521. (b) Demina, M.; Sarapulova, G.; Borisova, A.; Larina, L.;
Medvedeva, A. Rus. J. Org. Chem. 2003, 10, 1522-1524. (c) Hamad, A.-
S. S.; Hashem, A. I. J. Heterocycl. Chem. 2002, 39, 1325-1328.
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Kimpe, N.; Sackus, A. Tetrahedron 2006, 62, 3309-3319. (b) Lee, C. H.;
Cho, H. I.; Lee, K.-J. Bull. Korean Chem. Soc. 2001, 22, 1153-1155.
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Lett. 1999, 40, 3275-3278. (b) Brain, C. T.; Brunton, S. A. Synlett 2001,
3, 382-384.
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Research Laboratories.
(1) (a) Partyka, R. A.; Crenshaw, R. R. 1,3,4-Oxadiazole amides. U.S.
Patent 4001238, 1977. (b) Vardan, S.; Mookherjee, S.; Eich, R. Clin. Pharm.
Ther. 1983, 34, 3, 290-296.
(2) (a) Theime, P. C.; Franke, A.; Denke, D.; Lehmann, H. D.; Gries, J.
Ger. Offen. 1981, 29. (b) Schlecker, R.; Thieme, P. C. Tetrahedron 1988,
44, 3289-3294.
(3) (a) Hirao, I. Nippon Kagaku Zasshi 1967, 88, 574-575. (b) Ogata,
M.; Atobe, H.; Kushida, H.; Yamamoto, K. J. Antibiot. 1971, 24, 443-
451.
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(5) Ghirian, D.; Schwatz, I.; Simiti, I. Farmacia 1974, 22, 141.
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10.1021/jo0618730 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/15/2006
9548
J. Org. Chem. 2006, 71, 9548-9551

osemicarbazides are used as oxadiazole precursors, H2S scav-
engers, such as stoichiometric mercuric13 or lead oxide,14 can
be used to effect cyclization. A common, more environmentally
benign alternative is activation of sulfur through iodine-mediated
oxidation in the presence of base.15 Selective activation of the
sulfur moiety followed by cyclization has been achieved by
coupling reagents such as DCC16 and EDC17 as well as highly
reactive alkylating agents such as methyl iodide18 and ethyl
bromoacetate.19
Recently, the Boger group reported an intriguing method to
prepare 2-amino-1,3,4-oxadiazoles via cyclo-dehydration of an
ester semicarbazide mediated by tosyl chloride and base at room
temperature.20 We were attracted to this strategy due to the low
cost of reagents and mild reaction conditions. However, when
we used the reported conditions with semicarbazide 1a, we
observed less than 5% conversion to oxadiazole 2, even after
48 h. After some modification, we were able to obtain a modest
23% conversion after 20 h at reflux in THF with pyridine as
base (Scheme 2). In an effort to improve reactivity, we turned
our attention to the thiosemicarbazide analogue. We envisioned
that due to the polarizability of sulfur vs oxygen the related
thiosemicarbazide could also be activated toward cyclization
by tosyl chloride, affording an intermediate more predisposed
to cyclization. Gratifyingly, when thiosemicarbazide 1b was
treated with tosyl chloride and pyridine in THF at reflux, >99%
conversion to the desired oxadiazole was observed within 5 h.
Encouraged by this result, we set out to examine the generality
of this reaction. Thus, a variety of semicarbazides, and the
related thio analogues, were prepared in order to directly
compare their reactivity in the tosyl chloride/pyridine mediated
cyclization protocol.
1-6) were prepared in 78-89% yield from thiosemicarbazide
precursors. In contrast, semicarbazide precursors showed sig-
nificantly lower conversion under the same conditions for all
examples. 2-Benzylamino-oxadiazoles with both linear and
branched alkyl groups in the 5-position (entries 7-12) were
readily prepared in 85-93% yield. Oxadiazoles with either
electron-donating or electron-withdrawing alkyl groups in the
5-position were prepared in 95-99% yield from thiosemicar-
bazides; less than 30% conversion was observed for the
corresponding semicarbazides (entries 13-18). A variety of
5-aryl- and 5-heteroaryloxadiazoles were also prepared in high
yield, with 2-benzylamino (entries 19-26), 2-tert-butylamino
(entries 27-32), and 2-phenylamino (entries 33-36) substitu-
ents. It is interesting to note that while semicarbazides in general
afforded less than 30% conversion after 20 h, a few examples
(entries 4, 10, and 26) did show greater than 50% conversion.
However, in each of these cases, the analagous thiosemicarba-
zide (entries 3, 9, 25) proceeded to >95% conversion within
3.5 h.
Semicarbazides and thiosemicarbazides were readily prepared
by acylation of commercially available hydrazides with the
requisite isocyanate or isothiocyanate.21 Although most thi-
osemicarbazides can be readily purified by precipitation from
the crude acylation reaction mixture, this is unnecessary.22 Thus,
when the crude slurry from acylation of a given hydrazide with
isothiocyanate was treated with tosyl chloride and pyridine at
reflux in THF, the requisite oxadiazole was obtained in 83-
85% yield after workup and HCl salt formation (Scheme 3).
This two-step, one-pot procedure provides access to a variety
of 2-amino-oxadiazoles in an efficient manner.
SCHEME 3. One-Pot Acylation/Cyclization
SCHEME 2. Cyclization of Semicarbazides 1a and 1b
We found that for various semicarbazides and thiosemicar-
bazides higher reactivty of the thio analogue is a general trend,
as shown in Table 1. 5-Benzyloxadiazoles with primary,
secondary, and tertiary alkylamines in the 2-position (entries
In summary, this work has established that tosyl chloride
effectively activates thiosemicarbazides toward cyclization to
afford the related 2-amino-1,3,4-oxadiazoles. Thiosemicarba-
zides have consistently exhibited a higher rate of cyclization
than the corresponding semicarbazides. This methodology
provides an efficient preparation for a variety of 5-alkyl- and
5-aryl-2-amino-1,3,4-oxadiazoles. As an additional feature, the
parent thiosemicarbazides can be prepared in situ and used
without purification in the subsequent cyclization step, thereby
making the synthesis a convenient two-step, one-pot process.
This process provides a means to rapidly prepare a wide variety
of oxadiazoles as part of any high-throughput screening program
or a robust method for use in development.
(13) (a) Rostom, S. A.; Shalaby, M. A.; El-Demellawy, M. A. Eur. J.
Med. Chem. 2003, 38, 959-974. (b) Wang, X.; Li, Z.; Wei, B.; Yang, J.
Synth. Commun. 2002, 32, 1097-1103.
(14) Yale, H. L.; Losee, K. J. Med. Chem. 1966, 9, 478-483.
(15) (a) Hiremath, S. P.; Biradir, J. S.; Kudari, S. M. J. Ind. Chem. Soc.
1984, 61, 74-76. (b) Amir, M.; Kumar, S. Ind. J. Heterocycl. Chem. 2004,
14, 51-54. (c) Amir, M.; Khan, M. S. Y.; Zaman, M. S. Ind. J. Chem.
Sect. B 2004, 43B, 2189-2194.
(16) (a) Ahmed, M. M.; Aboulwafa, O. M.; Kader, O. Monatsch. Chem.
1989, 120, 571-574. (b) Aboulwafa, O. M.; Omar, A.; Mohsen, M. E.
Sulfur Lett. 1992, 14, 181-188. (c) Coppo, F. T.; Evans, K. A.; Graybill,
T. L.; Burton, G. Tetrahedron Lett. 2004, 45, 3257-3260.
(17) Severinsen, R.; Kilbrun, J. P.; Lau, J. F. Tetrahedron 2005, 61,
5565-5575.
(18) Fulop, F.; Semega, E.; Dombi, G.; Bernath, G. J. Heterocycl. Chem.
1990, 27, 951-955.
(19) Kucukguzel, S. G.; Oruc, E. E.; Rollas, S.; Sahin, F.; Ozbek, A.
Eur. J. Med. Chem. 2002, 37, 197-206.
(20) (a) Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliot, G. I.; Miller, M.
M.; Boger, D. L. Org. Lett. 2005, 7, 4539-4542. (b) Yuan, Z. Q.; Ishikawa,
H.; Boger, D. L. Org. Lett. 2005, 7, 741-744. (c) Wolkenberg, S. E.; Boger,
D. L. J. Org. Chem. 2002, 67, 7361-7364. (d) Wilkie, G. D.; Elliot, G. I.;
Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack,
S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292-11294.
(21) (a) Suni, M. M.; Nair, V. A.; Joshua, C. P. Tetrahedron 2001, 57,
2003-2009. (b) Robert-Piessard, S. C.; Leger, J. M.; Kumar, P.; Le Baut,
G.; Brion, J. D. J. Chem. Res., Synop. 1989, 3, 60-61. (c) Kane, J. N.
Synthesis 1987, 10, 912-914. (d) Colanceska-Ragenovic, K.; Dimova, V.;
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(22) Cyclization of crude thiosemicarbazides has previously been
reported: Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G.
Tetrahedron Lett. 2004, 45, 3257-3260.
J. Org. Chem, Vol. 71, No. 25, 2006 9549

TABLE 1. Preparation of 2-Amino-oxadiazoles via Tosyl Chloride-Mediated Cyclizationa
a Reaction conditions: substrate treated with 1.2 equiv of TsCl and 2.1 equiv of pyridine in THF at 65-70 °C for 20 h. b Conversion determined by
relative HPLC (A%) vs authentic standard. c Assay yield determined by HPLC vs authentic standard. d Isolated yield after trituration in THF/MTBE. e Isolated
yield of HCl salt after treatment of THF solution of free base with 1 equiv of ethereal HCl and addition of MTBE. f Isolated yield after purification via
column chromatography on silica gel.
tosyl chloride (1.57 g, 8.22 mmol), and pyridine (1.16 mL, 14.4
mmol) were combined in THF (30 mL) in a 100 mL round-bottom
flask fitted with a magnetic stir bar, reflux condenser, and nitrogen
inlet. The solution was heated in a 70 °C oil bath to bring the
mixture to reflux for 20 h and then cooled to room temperature.
An aliquot of the crude reaction mixture indicated complete
conversion (no thiosemicarbazide visible by LC) to the oxadiazole,
with 97% assay yield. EtOAc (20 mL) and 1 N HCl (20 mL) were
added; the mixture was vigorously stirred for 5 min, and then the
aqueous layer was removed. The aqueous layer was back-extracted
with EtOAc (20 mL), and then the combined organic layers were
flushed with heptane (2 × 75 mL) and the material was concentrated
to an orange slurry. The material was dissolved in ∼10 mL of THF
and filtered over Solka-Floc. HCl (3.43 mL, 2.0 M in diethyl ether)
was added to the solution. After the mixture was stirred for 30
min at room temperature, a thin slurry was obtained. MTBE was
added dropwise to the slurry (25 mL) and the resultant mixture
stirred for an additional 25 min. The slurry was filtered to afford
1.74 g of shiny white powder (84% yield): 1H NMR (400 MHz,
Experimental Section
Representative Procedure for Stepwise Oxadiazole Prepara-
tion. N-Benzylphenylacetic Acid Thiosemicarbazide (1b). Phenyl
acetic acid hydrazide (2.0 g, 13.3 mmol) and benzyl isothiocyanate
(1.77 mL, 13.3 mmol) were combined in THF (50 mL) at room
temperature. The resultant solution was stirred for 18 h, and then
volatiles were removed in vacuo to afford an off-white solid. The
solid was suspended and triturated in MTBE (50 mL) for 1 h and
then filtered to afford 3.80 g (95% yield) of the desired thiosemi-
carbazide; 1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H) 9.35 (s,
1H) 8.51 (s (br), 1H) 7.25 (m, 10H) 4.73 (d, J ) 6.0 Hz, 2H) 3.47
(s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 169.9 139.2 135.4 129.3
128.1 128.0 127.0 126.5 46.7; HPLC tR 6.78 min; mp 170.1-171.0
°C; IR 3336.3 (s), 3201.9 (s), 3030.4 (s), 1948.5 (w), 1683.2 (s),
1653.5 (s), 1604.6 (m), 1555.2 (s), 1492.8 (s), 1378.1 (s), 1292.5
(s), 1186.8 (s), 1074.5 (s); HRMS calcd for C16H17N3OS 300.1171,
found 300.1174.
Benzyl(5-benzyl[1,3,4]oxadiazol-2-yl)amine‚HCl (2). N-Ben-
zylphenylacetic acid thiosemicarbazide 1b (2.05 g, 6.85 mmol),
9550 J. Org. Chem., Vol. 71, No. 25, 2006

DMSO-d6) δ 7.99 (t, J ) 6.0 Hz, 1H) 7.30 (m, 10H) 4.31 (d, J )
6.0 Hz, 2H) 4.04 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 163.7
158.5 138.8 135.1 128.7 128.3 127.3 127.1 127.0 46.0 30.9; HPLC
tR 7.79 min; mp 157.0 - 157.5 °C; IR 2948.7 (m), 2550.5 (m),
1734.8 (s), 1714.7 (s), 1638.3 (s), 1496.8 (m), 1453.8 (m), 1415.1
(w), 1214.4 (w), 1011.0 (m); HRMS calcd for C16H15N3O 266.1293,
found 266.1290.
Representative Procedure for One-Pot Oxadiazole Prepara-
tion. Benzyl(5-benzyl[1,3,4]oxadiazol-2-yl)amine‚HCl (2). Phe-
nylacetic acid hydrazide (2.17 g, 14.4 mmol) and benzyl isothio-
cyanate (1.92 mL, 14.4 mmol) were combined in THF (50 mL) in
a 100-mL round-bottom flask at room temperature and stirred for
18 h. Tosyl chloride (3.30 g, 17.3 mmol) and pyridine (2.45 mL,
30.3 mmol) were added to the reaction mixture. The flask was fitted
with a reflux condenser and nitrogen inlet and submerged into a
70 °C oil bath. The solution was heated to reflux in an oil bath for
20 h and then cooled to room temperature. An aliquot of the crude
reaction mixture indicated complete conversion (no thiosemicar-
bazide visible by LC) to the oxadiazole, with 97% assay yield.
EtOAc (50 mL) and 1 N HCl (50 mL) were added; the mixture
was vigorously stirred for 5 min, and then the aqueous layer was
removed. The aqueous layer was back-extracted with EtOAc (50
mL), and then the combined organic layers were flushed with
heptane (2 × 150 mL) and the material was concentrated to an
orange slurry. The material was dissolved in ∼35 mL of THF and
filtered over Solka-Floc. HCl (14.4 mL, 1.0 M in diethyl ether)
was added to the solution. After the mixture was stirred 30 min at
room temperature, a thin slurry was obtained. MTBE was added
dropwise to the slurry (70 mL) and the resultant mixture stirred an
additional 25 min. The slurry was filtered to afford 3.70 g of shiny
white powder (85% yield). Spectral data matched that found for
material prepared via a stepwise procedure.
Acknowledgment. We thank Greg Hughes, Austin Chen,
and Jason Burch for useful comments in the preparation of this
manuscript.
Supporting Information Available: Experimental procedures
and characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0618730
J. Org. Chem, Vol. 71, No. 25, 2006 9551