Efficient one-pot synthesis of substituted 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2008.09.057

A convenient one-pot method for the preparation of substituted 2-amino-1,3,4-oxadiazoles has been developed. The method is a significant improvement over previously reported syntheses. Reaction of carboxylic acids with thiosemicarbazides afforded the corresponding oxadiazoles in moderate to good yields. In general, the products precipitated from the reaction mixture, and were collected by filtration. In most of the cases, no chromatographic separations were required. To explore the scope and limitations of this reaction, various aliphatic, aromatic, and heteroaromatic carboxylic acids were reacted with different substituted thiosemicarbazides. The influence of R¹ and R² substituents on the reaction yield and additional results demonstrating the versatility of this method are presented.

Full text of DOI:10.1016/j.tetlet.2008.09.057

Tetrahedron Letters 49 (2008) 6709–6711
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Tetrahedron Letters
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Efficient one-pot synthesis of substituted 2-amino-1,3,4-oxadiazoles
z
*
Eugene L. Piatnitski Chekler , Hassan M. Elokdah , John Butera
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-pot method for the preparation of substituted 2-amino-1,3,4-oxadiazoles has been
developed. The method is a significant improvement over previously reported syntheses. Reaction of car-
boxylic acids with thiosemicarbazides afforded the corresponding oxadiazoles in moderate to good
yields. In general, the products precipitated from the reaction mixture, and were collected by filtration.
In most of the cases, no chromatographic separations were required. To explore the scope and limitations
of this reaction, various aliphatic, aromatic, and heteroaromatic carboxylic acids were reacted with dif-
ferent substituted thiosemicarbazides. The influence of R1 and R2 substituents on the reaction yield
and additional results demonstrating the versatility of this method are presented.
Received 29 August 2008
Revised 9 September 2008
Accepted 10 September 2008
Available online 15 September 2008
Keywords:
Oxadiazole
Kinase inhibitor
One-pot cyclization
Ó 2008 Elsevier Ltd. All rights reserved.
2-Amino-1,3,4-oxadiazoles belong to a chemical class that dis-
plays diverse biological activity depending on the specific substitu-
tion within the molecule.1 An aminooxadiazole analog is currently
undergoing phase II clinical evaluation for the treatment of diabe-
tes.1e The amino group and the adjacent azole nitrogen may be
engaged in hydrogen bond donor-acceptor interactions similar to
ones observed for ATP molecule as well as for various kinase inhib-
itors.2 As a result of these potential interactions, 2-amino-1,3,4-
oxadiazole motif became a kinase targeting scaffold.2b,c Our goal
was to develop a convenient synthetic protocol for a quick assem-
bly of 2-amino-1,3,4-oxadiazole core.
R2NCS
O
H2N NH2
R1
R1 COOH
HN NH2
1
1'
HN R2
R2
Coupling
Agent
O S
R1
O
N
H
N
R1
HN NH
N
4
3
Scheme 1. Literature method to prepare 2-amino-1,3,4-oxadiazoles.
A variety of synthetic methods for the preparation of 2-amino-
1,3,4-oxadiazoles have been reported. One of the most common
procedures involves the cyclization of 2-acyl-hydrazinecarbothioa-
mide 4 in the presence of a coupling agent to result in oxadiazole 3
(Scheme 1).3 The preparation of the intermediate 4 requires a
multi-step synthesis starting from the corresponding carboxylic
acid or ester that contains the R1 groups and an isothiocyanate or
an isocyanate that incorporates the R2 groups.4 The cyclization of
2-acyl-hydrazinecarbothioamide 4 is complicated by 2-amino-
1,3,4-thiodiazole formation. Thiodiazole can be inseparable from
the desirable oxadiazole, and may become a major side product
depending on the reaction conditions.5 The cyclization step usually
requires elevated temperatures and extensive purification of the
product. In addition, mercury salts are often used as coupling
agents to improve the yield of the key cyclization step. The use
of toxic materials is highly undesirable particularly when the pro-
cedure has to be repeated in parallel fashion to generate a library of
targets. The overall sequence reported in literature (Scheme 1)
often results in low yield of the desired 2-aminooxadiazoles.
In contrast, we report a highly efficient one-pot protocol to pre-
pare the substituted 2-amino-1,3,4-oxadiazoles that often does not
require any chromatographic purification. The procedure does not
require an anhydrous solvent, inert gas atmosphere, or use of mer-
cury salts, and it is amendable for high-throughput parallel synthe-
sis. We established our methodology by synthesizing literature
known 2-amino-1,3,4-oxadiazoles utilizing commercially available
carboxylic acids and thiosemicarbazides. An initial attempt to dis-
cover a robust method to synthesize aminooxadiazoles was dis-
closed as a single example in our early work.3a Here, we describe
a general protocol where R1 and R2 groups represent a broad
spectrum of aliphatic, aromatic, and heteroaromatic substituents
(Table 1). A carboxylic acid 1 and a thiosemicarbazide 2 are mixed
in dichloromethane at room temperature with several equivalents
of EDCI (Scheme 2). A typical procedure for the preparation of
oxadiazole 3 involves filtering of the product precipitate that
crystallizes from the reaction mixture in analytically pure form
* Corresponding author. Tel.: +1 484 865 8180; fax: +1 484 865 9399.
E-mail address: piatnits@gmail.com (E. L. Piatnitski Chekler).
z
In memory of our deceased colleague, Hassan M. Elokdah.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.057

6710
E. L. Piatnitski Chekler et al. / Tetrahedron Letters 49 (2008) 6709–6711
Table 1
greater solubility in organic solvents. We found that the resin-
Oxadiazoles prepared using a novel process
bound EDCI reagent provides a useful alternative in these transfor-
mations. An attempt to develop a robust procedure to synthesize
the oxadiazoles in efficient manner using solid phase reagents
was reported.15,19,21 However, reported unfavorable reaction con-
ditions and the limited commercial availability of starting material
make our method more attractive and more amendable to parallel
synthesis. The corresponding oxadiazole derivative remains in
solution while the resin can be easily removed upon completion
of the reaction. 2-Aminooxadiazoles 15 and 16 that are relatively
more soluble in dichloromethane than other oxadiazoles with
aromatic R2 groups were subjected to the new conditions using
resin-based EDCI reagent in DMF as a solvent. The isolation of
oxadiazoles 15 and 16 from the solid phase reaction mixture
required chromatographic purification with the isolated yields
higher than in the corresponding solution phase processes (53%
and 61%, respectively).
We hypothesized that mechanistically the reaction proceeds
through the formation of intermediate 4, which undergoes cycliza-
tion to furnish target 3 (Scheme 1). To confirm that, we prepared
and isolated intermediate 4, where R1 and R2 = phenyl, and then
subjected it to the same reaction conditions with 1.5 equiv of EDCI
(Scheme 2). Re-subjecting intermediate 4 to the reaction condi-
tions resulted in the formation of the same product in slightly bet-
ter yields than in the one-pot protocol. Similar transformations
have been reported in the literature using harsher reaction condi-
tions.15,19 These studies suggest that the title reaction is a combi-
nation of two processes, where the initial EDCI-promoted amide
coupling to form intermediate 4 is followed by a cyclization to
yield 2-aminooxadiazole 3.
An additional simplification of the reaction protocol comes from
a one-pot sequential formation of thiosemicarbazide 2 followed by
addition of carboxylic acid 1 and coupling agent. The limited num-
ber of commercially available thiosemicarbazides 2 may narrow
down the scope of the described methodology while the precursor
isothiocyanates are more readily available. Thus, the thiosemicar-
bazide is formed by a standard protocol of reacting isothiocyanate
with hydrazine at reflux in DCM. Once the reaction is completed,
the reaction mixture is cooled down, and required reagents are
added to render the desired 2-aminooxadiazole derivatives using
the above-described protocol. Two title compounds 8 and 14 were
produced using this three-step one-pot protocol in 60% and 61%
yields, respectively.
HN R2
O
N
R1
R2
N
Compd
R1
Yielda (%)
Ref.
5
6
7
8
9
Benzyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Benzyl
Allyl
70
61
56
67
51
53
49
48
57
60
42
32
69
73
75
74
66
67
72
6
7
7
8
8
9
10
11
12
13
14
15
16
17
17
18
19
19
20
4-Pyridyl
3-Pyridyl
Phenyl
2-Pyridyl
2-Thiophenyl
2-Benzthiazolyl
2-Indolyl
3-Indolyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Methyl
4-Methylphenyl
3-Chlorophenyl
4-Nitrophenyl
4-Bromophenyl
2,4-Difluorophenyl
4-Ethoxycarbonylphenyl
2-Nitrophenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
a
Yields calculated based on the amount of initially precipitated material using
soluble EDCI reagent. Additional amount of material remained in the solution.
S
HN R2
H2N
R2
2
O
N
H
N
H
N
R1 COOH
R1
N
3
EDCI
1
3 equivalents
S
H2N
R2
2
EDCI
N
H
N
H
1.5 equivalents
R2
O S
R1
EDCI
N
1.5 equivalents
H
4
HN NH
Scheme 2. One-pot and stepwise processes towards 2-amino-1,3,4-oxadiazoles.
In summary, we have described a protocol for a rapid assembly
of 2-amino-1,3,4-oxadiazoles from thiosemicarbazides (or isothio-
cyanates) and carboxylic acids. The proposed reaction mechanism
for this process involves the formation of acylthiosemicarbazide as
an intermediate. The selected oxadiazole class representatives
exhibited activity against kinase and non-kinase targets.
that often passes elemental analysis criteria (see Supplementary
data). Only oxadiazole 16 required an additional purification using
column chromatography. The key element of this procedure is the
use of EDCI (or EDAC) as a coupling reagent. The isolated yields of
compounds 5–15 and 17–23 varied depending on the compound
solubility in the reaction solvent, dichloromethane, or DMF. The
reported yields (Table 1) reflect only the amounts of products that
crystallized from the reaction mixture without further purification.
Thus, highly crystalline products with both R1 and R2 as aromatic
groups tend to render the higher yields compared to oxadiazoles
with an aliphatic R2 component.
Over the years, N-(3-dimethylaminopropyl)-N’-ethylcarbodiim-
ide (EDCI) has emerged as a reagent of choice for amide coupling
reactions. The use of this coupling reagent in this efficient
procedure leads to a convenient process that does not require an
elaborate purification. However, the best results in this one-
pot multi-step condensation were achieved when the product
had limited solubility in the organic solvent. This may potentially
limit the application of the described method to highly crystalline
or less soluble compounds. It became our goal to develop an
alternative procedure to prepare oxadiazoles with potentially
Acknowledgments
We thank Dr. Avdhoot Velankar and Mr. X. Ouyang formerly of
ImClone Systems for helpful discussions at early stages of this
work. We acknowledge Dr. B. Blass for helpful suggestions. We
thank Wyeth Discovery Analytical Chemistry Department for
characterizing our compounds.
Supplementary data
Experimental details, proton and carbon NMR spectra, mass
spectrometry data, HPLC chromatograms for all compounds, and
elemental analysis data for selected compounds. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2008.09.057.

E. L. Piatnitski Chekler et al. / Tetrahedron Letters 49 (2008) 6709–6711
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60, 175; (c) Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org. Chem.
2006, 25, 9548–9551.
References and notes
5. Hassan, A. A.; El-Shaieb, K. M.; Shaker, R. M.; Doepp, D. Heteroat. Chem. 2005,
16, 12.
6. Madhavan, R.; Srinivasan, V. R. Indian J. Chem. 1969, 7, 760–765.
7. Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur. J. Med. Chem. 1996, 31, 819–
825.
8. Marcewicz-Rojewska, B.; Bilinski, S. Acta Pol. Pharm. 1980, 37, 159–167.
9. Gumien, D. Biuletyn Informacyjny Instytutu Lekow 1983, 30, 179–186.
10. Sawhney, S. N.; Singh, J.; Bansal, O. P. Indian J. Chem. 1975, 13, 804–807.
11. Hiremath, S. P.; Bajji, A. C.; Biradar, J. S. Proc. Natl. Acad. Sci., India Sec. A: Phys.
Sci. 1992, 62, 161–166.
1. (a) Blouin, M.; Grimm, E. L.; Gareau, Y.; Gagnon, M.; Juteau, H.; Laliberte, S.;
Mackay, B.; Friesen, R. WO 2006099735, 2006; (b) Barth, F.; Congy, C.; Gueule,
P.; Rinaldi-Carmona, M.; Van Broeck, D. WO 2006087480, 2006; (c) Birch, A. M.;
Bowker, S. S.; Butlin, R. J.; Donald, C. S.; McCoull, W.; Nowak, T.; Plowright, A.
WO 2006064189, 2006; (d) Leber, J. D.; Li, M.; Lee, J.; Aubart, K. M.;
Christensen, S. B. WO 2005032550, 2005; (e) Handlon, A. L.; Akwabi-
Ameyaw, A.; Brown, K.; De Anda, F.; Drewry, D.; Fang, J.; Irsula, O.; Li, G.;
Linn, J. A.; Milliken, N. O.; Ramanjulu, J. Abstracts of Papers, 226th ACS National
Meeting, 2003; (f) Madhavan, R.; Srinivasan, V. R. Indian J. Chem. 1969, 7, 760–
765.
2. (a) Biwersi, C. M.; Warmus, J. S.; Zhang, L. Y.; Barrett, S. D.; Kaufman, M. D.;
Plummer, M. S.; Reed, J. E. WO 2004056789, 2004; (b) Kiselyov, A. S.;
Semenova, M.; Semenov, V. V.; Piatnitski, E.; Ouyang, S. Bioorg. Med. Chem.
Lett. 2006, 16, 2559; (c) Piatnitski, E. L.; Kiselyov, A. S.; Doody, J.; Hadari, Y. R.;
Ouyang, S.; Chen, X. WO 2004052280, 2004; (d) Black, S. L.; Kaufman, M. D.;
Ortwine, D. F.; Plummer, M. S.; Quin, J.; Rewcastle, G. W.; Shahripour, A. B.;
Spicer, J. A.; Whitehead, C. E. WO 2005000818, 2005.
12. Kelarev, V. I.; Shvekhgeimer, G. A.; Lunin, A. F. Khim. Geterotsikl. 1984, 1271–
1276.
13. Dehuri, S. N.; Pradhan, P. C.; Nayak, A. Indian J. Chem. Sect. B: Org. Chem.
Including Med. Chem. 1983, 22B, 815–816.
14. Dehuri, S. N.; Pradhan, P. C.; Nayak, A. J. Indian Chem. Soc. 1983, 60, 475–478.
15. Coppo, Frank T.; Evans, Karen A.; Graybill, Todd L.; Burton, George. Tetrahedron
Lett. 2004, 45, 3257–3260.
16. Bilinski, S.; Bielak, L.; Chmielewski, J.; Marcewicz-Rojewska, B.; Musik, I. Acta
Pol. Pharm. 1989, 46, 343–349.
17. Gierczyk, B.; Nowak-Wydra, B.; Grajewski, J.; Zalas, M. Magn. Reson. Chem.
2007, 45, 123–127.
18. Simiti, I.; Ghiran, D. Farmacia (Bucharest, Romania) 1971, 19, 199–205.
19. Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323–5349.
20. Gehlen, H.; Drohla, R. J. Prakt. Chem. (Leipzig) 1969, 311, 539–548.
21. Brain, C. T.; Brunton, S. A. Synlett 2001, 382–384.
3. (a) Ouyang, X.; Piatnitski, E. L.; Pattaropong, V.; Chen, X.; He, H.-Y.; Kiselyov, A.
S.; Velankar, A.; Kawakami, J.; Labelle, M.; Smith, L.; Lohman, J.; Lee, S. P.;
Malikzay, A.; Fleming, J.; Gerlak, J.; Wang, Y.; Rosler, R. L.; Zhou, K.; Mitelman,
S.; Camara, M.; Surguladze, D.; Doody, J. F.; Tuma, M. C. Bioorg. Med. Chem. Lett.
2006, 16, 1191–1196; (b) Hiremath, S. P.; Biradar, J. S.; Kudari, S. M. J. Indian
Chem. Soc. 1984, 61, 74–76.
4. (a) Dumciute, J.; Martynaitis, V.; Holzer, W.; Mangelinckx, S.; De Kimpe, N.;
Sackus, A. Tetrahedron 2006, 62, 3309; (b) Amir, M.; Kumar, S. Pharmazie 2005,