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Journal Name DOI: 10.1039/C6RA08871F

ARTICLE

Facile synthesis of 3-amino-5-aryl -1,2,4-oxadiazoles via

PIDA-mediated intramolecular oxidative cyclization
Received 00th January 20xx,

RSC Advances Accepted Manuscript

Accepted 00th January 20xx
Kuan Lu , Liancheng Duan, Bo xuan Xu, Weile Yin, Di Wu, Yanfang Zhao*, and Ping Gong*
Published on 31 May 2016. Downloaded by University of Wollongong on 31/05/2016 15:54:52.

DOI: 10.1039/x0xx00000x
www.rsc.org/
A mild and efficient method for the synthesis of 3-amino-5-aryl-1,2,4-oxadiazole by intramolecular
cyclization using PhI(OAc)2 (PIDA) as an oxidant is developed. Various 3-amino-5-aryl-1,2,4-oxadiazoles are
prepared in moderate to good yields, and the PIDA-mediated N–O bond formation mechanism is suggested. In
view of the readily available starting materials, operational simplicity, high functionality tolerance, and low
toxicity, this protocol provides a novel synthetic strategy for 1,2,4-oxadiazoles.

N,5-Diphenyl-1,2,4-oxadiazol-3-amine using N aOCl as an

Introduction
1,2,4-O xadiazole derivatives exist in natural products and are
widely applied as drugs in pharmaceuticals. T hey are
important five-membered heterocy cles w ith diverse biological
activities, such as immuneregulatory 1, diuret ic 2, anti-
inflammatory 3 and anti-diabet ic 4 activities. M oreover, they are
widely us ed as bioisost eres of other het erocy cles to improve
activity and stability 5.
oxidant wit h a good yield1 0. Recently, isot hiocy anate has been
used as a starting material to synthes ize 3-amino-5-aryl-
1,2,4-oxadiazoles by tandem cyclizing amidinothioureas w ith
hydroxy lamine hydrochloride in moderat e to high yields 11.
Bes ides , G. C. Tron report ed a novel strat egy to obtain
1,2,4-oxadiazoles via a M ulticomp onent Reaction, follow ed
by M itsunobu-Beckmann Rearrangement 12 . How ever, most of
the above-mentioned methods used unavailable st arting
materials or toxic agents (cyanamide 8,10 , H gCl21 1a , CS211 b),
which resulted in poor yields. Therefore, developing an
effective and environment-friendly method t o synthes ize
3-amino-5- aryl-1,2,4-oxadiazoles pres ents a challenge. In t his
paper, w e report an efficient and mild protocol for the
synthesis of 3-amino-1,2,4-oxadiazoles in moderat e to good
yields by cy clizing aromatic N-acylguanidines with PhI(O A c) 2
(PID A) which is applied in the synt hes is of 1,3,4-oxadiazole13
(Scheme 1)

Figu re 1 S tru ctu res of some biologically acti ve 1,2,4-

oxadi azole deri vati ves
M any synthetic methods for synthes izing 3,5-aryl/alkyl
1,2,4-oxadiazoles have been report ed6 . How ever, limit ed
knowledge exists on how to synthesiz e 3-amino-5-aryl-
1,2,4-oxadiazoles , w hich are important privileged structures
for drug optimiz atio n7. 3-A mino-5-aryl-1,2,4-oxadiazoles are
usually prepared from acyl chloride and toxic cyanamide,
thereby yielding N-cyanobenzamide, follow ed by cy clizing
with hydroxylamine hydrochloride under a harsh condit ion 8,
or cycliz ing carboxy lic est er wit h hydroxy guanidine in a low
yield9. N . G ötz. report ed a mild method to synthes ize

S cheme 1 Selected synthetic methods for 3-amino-1,2,4-

oxadiazoles
Key Laboratory of Structure-Based Drug Design and Discovery ( Shenyang
Pharmaceutical University), Ministry of Education, 103 W enhua Road, Shenyang
110016, PR China.
†Electronic Supple menta ry In for mation (ESI ) available: [details o f any
supplementary in for mation available should be included her e]. Se e
DOI: 10.1039/x0 xx00000x

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Results and discussion Having identified the optimal react ion conditions, w e then
View Article Online
explored the s cope and generality of thisDOI:
oxidative annulation
10.1039/C6RA08871F
Init ially, w e attempted to establis h oxidative cyclizat ion to
reaction. T he res ults are s ummarized in Table 2. As can be
form an N–O bond, which provided an atom-economic
seen, the reactions proceeded s moothly with wide functional
method to synthes ize 3-amino-5-ary l-1,2,4-oxadiazoles. When
group tolerance, the corresponding products w ere obtained in
using N-carbamimidoylbenzamide 1a as a model substrate and
moderate to good yields ( 42%–79%). The reactivity of the
ter t-butyl hydroperoxide (T BHP , 70% aqueous solut ion) as an
substrates changed with the electronic propert ies of the
oxidant, no desired product w as detected when the reaction
substituents on the benzene rings. The pres ence of
was p erformed in 1,2-dichloroethane (D CE) at room
electron-w ithdraw ing groups on the phenyl ring, such as the
temp erature when a cat alytic amount of CuBr or Cu(O A c) 2
halide, nitro, CF 3 , and cyano group, increased the yield
was us ed under alkaline conditio ns (Table 1, entries 1–2).
(72%–79%, except for 2s ). The halogen group had a
Surpris ingly, the des ired oxadiazole 2a w as produced in 46%
negligible effect on the reaction, thus offering the poss ibility
isolat ed yield by using PID A as an oxidant w ithout catalyst
for further transformation by aromatic substitution or coupling

RSC Advances Accepted Manuscript

and bas e (Table 1, entry 3). On account of the low solubility in
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reaction. However, t he electron -donating groups, s uch as

DCE, further screening of the solvent s (T able 1, entries 4–6)
methyl- and methoxy-, caus ed a decrease in the yields (2e,
revealed that dimethylformamide (DM F) s erved as the most
2i–2k, 2r). The s ubstrates w ith both electron-withdraw ing and
suitable s olvent, w hich obt ained 2a in 69% yield (T able 1,
electron-donating groups on the phenyl ring reacted well in
entry 6). Inspired by this res ult, Pd(OA c)2 and Cu(O Ac)2 w as
good yields (2l, 73%; 2m, 75%). The number and pos itions of
chosen as catalysts respectively, but resulted in decreas ed
the substituents on aromatic rings had an insignificant
yields (Table 1, entries 8–9). Changing the P IDA molar rat io
influence on the conversion. H et eroaromatic structures w ere
from 1.5 equiv to 1.3 equiv reduced the yield of 2a from 69%
als o compet ent to acquire access to the corresponding
to 65% (Table 1, entries 6–7). No product formation w as
products in moderate yields ( 2t, 59%; 2u , 62%). M oreover,
obs erved when us ing molecular iodine as a cat alyst and T BHP
N-substitut ed substances were well tolerated and afforded the
or di-ter t-butyl peroxide (DT BP ) as an oxidant (Table 1,
corresponding products (2v-2y) in moderate to good yields. When
entries 10–11). Therefore, the optimal react ion conditions
N,N'-dibenzoylguanidine (1v) which can induce convulsion in the
were as follows: P ID A (1.5 equiv) as an oxidant in DM F at
brain14 was used, the corresponding product (2v) could be obtained
room temperature for 5 h.
in 78% yield.
a
Table 1 Optimization of Reaction Conditions Table 2 Substrate S cope for the S ynthesis of 3-Amino-1,2,4-
Oxadiazoles via Oxidative Cyclization a,b

b
Entry Catalyst Oxidant(equiv) Additive Solvent Yield(%)
d c
1 CuB r TBHP (2.0) K2 CO3 DCE n. d.

e
2 Cu(OAc)2 TBHP (2.0) K3 PO4 DCE n. d.

3 NO ONE PIDA (1.5) NO ONE DCE 46

4 NO ONE PIDA (1.5) NO ONE CH3CN 39

5 NO ONE PIDA (1.5) NO ONE MeOH 58

6 NO ONE PIDA (1.5) NO ONE DMF 69

7 NO ONE PIDA (1.3) NO ONE DMF 65

f
8 Pd(OAc)2 PIDA (1.5) NO ONE DMF 56

9 Cu(OAc)2 PIDA (1.5) NO ONE DMF 47

10 I2 TBHP (2.0) NO ONE DMF n. d.

11 I2 DTB P (2.0) NO ONE DMF n. d.

a
Reaction conditions : 1a (0.6 mmol, 3 mL of solvent), catalyst
(0.12 mmol), oxidant, at room temperature for 5 h. b isolated yields a
c
n.d. = not detected. d K2CO 3 (1.2 mmol) e K3PO 4 (1.8 mmol) f
Reaction conditions : 1 (0.6 mmol), PIDA (0.9.mmol) in DM F
Pd(OAc)2 (0.06 mmol).
at room temperature for 5 h. b is olated yields. c room
temp erature for 6 h.

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In order to exp lore the react ion mechanis m, control
experiments were conducted under standard reaction
conditions. When radical s cavengers, 2,2,6,6-tetramethyl-
piperidine N-oxide (T EM PO) and butylated hydroxytoluene
(BHT ), were added to the mixt ure, the reaction proceeded
smoothly and w as not inhibit ed, which indicated that this
reaction did not proceed via a radical mechanism (Scheme 2).
Published on 31 May 2016. Downloaded by University of Wollongong on 31/05/2016 15:54:52.
S cheme 2 Control experiments
Bas ed on the above res ults and previous studies 6a, 10, a
proposed mechanis m is illustrated in Scheme 3. First, the
starting mat erial 1a w as oxidized in the pres ence of PID A to
yield N-iodination int ermediate 3. Second, intermediat e 3 w as
deprot onated by the bas e (-O Ac) and transformed into
intermediat e 4a w hich w as identified as a res onance hybrid with
intermediat e 4b. Finally, intermediat e 4a underw ent
intramolecular cy clization t o obtain the des ired product 2a.
Anion intermediat e 4a w as stabiliz ed by the
electron-w ithdraw ing groups on the phenyl rings, w hich might
explain the relatively high yields of the product s.
S cheme 3 Proposed mechanism
Conclusion
In conclusion, w e have developed a novel and efficient
synthesis of 3-amino-5-aryl-1,2,4-oxadiaz oles via PID A-
mediated oxidat ive cycliz ation of available aromatic
N-acy lguanidines. A propos ed mechanis m is als o est ablis hed
in this study. T he reaction is operat ionally simply, and the
conditions are mild and suitable for a w ide range of subst rates.
This method provides a novel synthetic strategy for
1,2,4-oxadiazoles . An investigat ion on the applicat ion of thes e
compounds in medicinal chemistry is currently in progress.
This journal is © The Royal Society of Chemistry 20xx
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Acknowledgme nts View Article Online
DOI: 10.1039/C6RA08871F
This w ork w as supported by the Program for Innovative
Res earch T eam of the M inistry of Education and the Program
for Liaoning Innovat ive Res earch Team in U niversity.
References
1. R. M . H arris , B. I. Andrews , S. Clark, J. W. B. Cooke, J. C.
S. Gray, and S. Q. Q. N g, Org. Pr ocess. Res . D ev., 2013, 17,
1239-1246.
2. M . G. Bock, R. L. Smit h, E. H. Blaine, and E. J. Cragoe, J,
J. Med. Chem., 1986, 29, 8.
3. L. L. Xu, J . F . Zhu, X. L. Xu, J. Zhu, L. Li, M . Y. X i, Z. Y.
RSC Advances Accepted Manuscript
Jiang, M . Y. Zhang, F. Liu, M . C. Lu, Q. C. Bao, Q . Li, C.
Zhang, J. L. Wei, X. J. Zhang, L. S. Zhang, Q. D . You, and
H. P. Sun, J. Med. Chem., 2015, 58, 5419-5436.
4. J. S. Scott, A. M . Birch, K . J. Brocklehurst, A. Broo, H . S.
Brown, R. J . Butlin, D. S. Clarke, O. J. Davidsson, A.
Ert an, K. Goldberg, S. D. G roombridge, J. A. Hudson, D.
Laber, A. G. Leach, P. A . M acFaul, D. M cKerrecher, A.
Pickup, P. Schofield, P. H. Svensson, P . Sorme, and J.
Teague, J. Med. Chem., 2012, 55, 5361-5379.
5. (a) M . P. Bourbeau, A. Siegmund, J. G. A llen, H. Shu, C.
Fotsch, M . D. Bartberger, K.W. Kim, R. Komorowski, M .
Graham, J. Busby, M . H. Wang, J. M eyer, Y. Xu, K.
Salyers, M . Fielden, M . M . Véniant, and W. G u, J. Med.
Chem., 2013, 56, 10132-10141. (b) H . C. Shen, F . X .D ing,
S. Y. Wang, Q. L. D eng, X. P . Zhang, Y. L. Chen, G . C.
Zhou, S. Y. X u, H. S. Chen, X . C. Tong, V. Tong, K.
M itra, S. Kumar, C. Ts ai, A . S. Stevens on, L. Y. P ai, M . A.
Galicia, X . L. Chen, S. M . Soiss on, S. Roy, B. Zhang, J . R.
Tata, J. P. Berger, and S. L. Colletti, J. Med. Chem ., 2009,
52, 5009-5012
6. (a) W. G uo, K . B. H uang, F. H. J i, W. Q. Wua, and H .F.
Jiang, Chem . Comm un., 2015, 51, 8857-8860; (b) P. K.
Gupta, M . K. Hu ssain, M . Asad, R. K ant, R. M ahar, S. K.
Shukla, and K. H ajela, New. J. Chem ., 2014, 38, 3062; (c) F.
L. Zhang, Y. F . Wang, and S. Chiba, Or g. Biomol. Chem.,
2013, 11, 6003.
7 (a) P. C. Unangst, G. P . Shrum, D . T. Connor, R. D . Dy er,
and D . J. Schrier, J. Med. Chem. 1992, 35, 3691-3698; (b)
N. I. Z iedan , F . St efanelli , S. Fogli, and A . D . Westw ell,
Eur . J. Med. Chem. 2010, 45, 4523-4530.
8 A. M . P olozov, G. H ategan, H. Cao, A. S. K is elyov, W.
Zeller, and J . Singh, T etr ahedr on. L ett., 2010, 51, 575-578.
9 H. L. Wang , V. C. Cee, B. J . H erberich, C. L. M . J ackson, L.
B. A lan, N. T homas, L. H. Pettus, A. B. Reed, B. Wu, and
W. Ry an, WO Pat., 2012129338A1, 2012.
10 N. G ötz, and B. Zeeh, Synthesis . ,1976, 4, 268-270.
11 (a) S. G. Yerande, A . B. Ghais as, K. M . N ew as e, W.Wang,
K. Wang, and A. Dömling, J. H eter ocyclic. Chem., 2014,
51, 1752. (b) H. B, J alani, Sudars anam, and K . K. Vas u,
synthes is., 2012, 44, 3378-3386.
12 V. M ercalli, A. M assarotti, M . Varese, M . Giustiniano, F.
M eneghetti, E. Novellino, and G. C. Tron, J. Org. Chem., 2015,
80, 9652-9661.
13 B. N. Prasanna Kumar, K. N. M ohana, and L.M allesha, J.Chem.,
2013, Article ID 121029, 7 pages.
J. Nam e. , 2013, 00, 1 -3 | 3
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14 Nakae, and Isao, Neurosciences., 1981, 7, 205-17. View Article Online

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Graphical Abstract
DOI: 10.1039/C6RA08871F
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RSC Advances Accepted Manuscript