(3+2) annulation of amidinothioureas with binucleophile: Synthesis and antimicrobial activity of 3-phenylamino-5-aryl/alkyl-1,2, 4-oxadiazole derivatives

Article abstract of DOI:10.1002/jhet.1873

Herein, we report an efficient method for preparation of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole by (3+2) annulation of amidinothioureas with binucleophilic hydroxylamine hydrochloride in the presence of mercury (II) chloride. Desired 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole was prepared in good to moderate yields. On the basis of the literature precedence, the mechanism for the formation of 3-phenylamino- 5-aryl/alkyl-1,2,4-oxadiazole is proposed. The synthesized compounds were tested for their antimicrobial activity and showed promising inhibition of Gram-positive bacteria (Staphylococcus aureus) and fungi (Candida albicans).

Full text of DOI:10.1002/jhet.1873

1752
(3+2) Annulation of Amidinothioureas with Binucleophile: Synthesis
and Antimicrobial Activity of 3-Phenylamino-5-aryl/alkyl-1,2,
4-oxadiazole Derivatives
Vol 51
a
b
c
d
d
d,e
*
Swapnil G. Yerande, Amruta B. Ghaisas, Kiran M. Newase, Wei Wang, Kan Wang, and Alexander Dömling
aAcoris Research Ltd, 3A International Biotech Park, Hinjewadi, Pune 411 057 India
bDepartment of Pharmaceutical chemistry, Progressive Education Society’s, Modern College of Pharmacy, Sector 21,
Yamunanagar, Nigdi, Pune 411044 (M.S.), India
cBanasthali Vidyapith, P.O. Banasthali Vidyapith, Rajasthan 304022, India
dDepartment of Pharmaceutical Sciences, University of Pittsburgh, Pennsylvania 15261
eDepartment of Pharmaceutical Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
*
E-mail: swapnil_yerande@acorisresearch.com
Received June 29, 2012
DOI 10.1002/jhet.1873
Published online 12 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
NH
R2
N
NH2OH.HCl,TEA,
HgCl2, DMF
R1 NH
N
2
H
N C
R1
S
Acetone, 0 °C
N
N
N
3
N
R1
60-80 %
44-70 %
R2
O
S
R2
1
4
R1 = C6H5, 2-CH3C6H4, 4-CH3C6H4, 2-OCH3C6H4, 4-OCH3C6H4, 4-ClC6H4,4-BrC6H4,COC6H5
R2 = CH3, C6H5
Herein, we report an efficient method for preparation of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole
by (3+2) annulation of amidinothioureas with binucleophilic hydroxylamine hydrochloride in the presence
of mercury (II) chloride. Desired 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole was prepared in good to
moderate yields. On the basis of the literature precedence, the mechanism for the formation of 3-phenylamino-
5-aryl/alkyl-1,2,4-oxadiazole is proposed. The synthesized compounds were tested for their antimicrobial
activity and showed promising inhibition of Gram-positive bacteria (Staphylococcus aureus) and fungi
(Candida albicans).
J. Heterocyclic Chem., 51, 1752 (2014).
INTRODUCTION
leads to the formation of 5-amino (primary or secondary)-
1,2,4-oxadiazole derivatives [20]. The most common method
for the preparation of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-
oxadiazoles not only involve the use of toxic and corrosive
cyanogen bromide but are also inefficient, and poor yields
are being generally obtained [21a]. Recently, the synthesis
of 3-aryl/alkylamino 5-aryl/alkyl-1,2,4-oxadiazoles has been
reported from N-acyl thiourea derivatives [21b].
Despite numerous reports on their syntheses, to date, a
highly efficient route to these 3-phenylamino-5-aryl/alkyl-
1,2,4-oxadiazole derivatives remains a challenge. In this
context, a general and concise route for their synthesis
would be a valuable tool for the exploration of chemistry
and biology of these heterocycles.
Oxadiazoles represent an important class of heterocyclic
compounds, and their rich chemistry has been widely
reviewed over the years [1,2]. 3,5-Disubstituted 1,2,4-
oxadiazole is a versatile template and has wide utility in
the medicinal chemistry. These classes of compound have
been reported to be b-tryptase inhibitors [3], apoptosis
inducers [4–6], reverse transcriptase inhibitors [7],
gamma-aminobutyric acid modulators [8], avb3 receptor
antagonists [9], and cannabinoid receptor 2 agonists [10].
1,2,4-Oxadiazole ring system is widely used as an amide,
ester, and isothiourea bioisostere because of its hydrolytic
stability. Such a kind of bioisosteric replacement of amide
group of peptide is an extensively explored area in the field
of peptidomimetics [11–14]. 5-Amino-1,2,4-oxadiazole
scaffold has been a part of widely investigated vasodilating
drug imolamine [15], which is used in the treatment of
angina pectoris, and fulvinazole [16], which has shown
antischistosomal activity (Fig. 1).
RESULTS AND DISCUSSION
With the aforementioned background and keeping in
mind some recent reports [22–24], we hypothesized that
amidinothioureas 2, which are prepared by reaction of
corresponding isothiocyanate and N,N-diethyl-benza/
acetamidine, would react with binucleophilic hydroxylamine
hydrochloride in the presence of mercury (II) chloride
catalyzed desulfurization/elimination reaction to give
3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole derivatives
Different synthetic methods have been reported for the
synthesis of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole
derivatives. The displacement of amidoxime-derived 5-
chloro-1,2,4-oxadiazole with primary or secondary amine
gave access to 5-amino-1,2,4-oxadiazole derivatives [17–19].
Reaction of hydroximoyl chloride with guanidine derivatives
© 2014 HeteroCorporation

November 2014
(3+2) Annulation of Amidinothioureas with Binucleophile: Synthesis and Antimicrobial
Activity of 3-Phenylamino-5-aryl/alkyl-1,2,4-oxadiazole Derivatives
1753
desulfurization of amidinothiourea 2 was observed visually
on the basis of the formation of a black precipitate of mercury
sulfite. This reaction after careful filtration of mercury sulfite
precipitate and conventional workup gave a mere 10% yield
of the desired 4.
After careful experimentation, 1.0 equiv of amidinothiourea
2 with 1.1 equiv of hydroxylamine hydrochloride in the
presence of 1.1 equiv of mercury (II) chloride and 3.2 equiv
TEA in DMF gave the desired 3-phenylamino-5-aryl/alkyl-
1,2,4-oxadiazole derivatives in moderate to good yields. The
generality of this new synthetic method was investigated by
employing the aforementioned optimized conditions. The
results are summarized in Scheme 1.
Figure 1. Drugs containing 1,2,4 oxadiazole scaffold.
4 (Scheme 1). This proposed reaction will allow us to
perform this (3+2) annulation and would give access to a
wide range of substitution patterns in oxadiazole
derivatives.
The isolated 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole
derivatives (4a–4i) were characterized by spectroscopic
Towards this aim, an initial attempt was made, by refluxing
the reaction mixture containing amidinothiourea 2 and
hydoxylamine hydrochloride in methanol, but we did not
see any progress in the reaction. Even the addition of TEA
(2 equiv) does not lead to a formation of a product. Having
obtained disappointing results with the aforementioned
method, we turned our attention towards the polar aprotic
solvent DMF. Reactions of amidinothiourea 2 and hydoxyla-
mine hydrochloride when carried out in DMF using TEA
as a base at room temperature and at 80ꢀC did not gave
target 4. Then, we carried out the same reaction in the
presence of strong thiophile mercury (II) chloride. Here, the
1
methods. Disappearance of diethylamine peak in H nmr
spectrum present in amidinothiourea 2 indicated the forma-
tion of 4a. Further, observation of a [M]+ ion peak of
175.0740 in HRMS, corresponding to the molecular formula
C14H11ON3, and seven-line 13C nmr spectrum with the
characteristic carbon resonances at d 165.22 and 174.86
confirmed the structure of 4a.
On the basis of the literature [25,26] precedence for the
formation of guanidine from thiourea, two mechanistic
pathways can be postulated for the formation of 3-phenyla-
mino-5-aryl/alkyl-1,2,4-oxadiazole derivatives (Scheme 2).
Scheme 1. Synthesis of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole derivatives from several functionalized amidinothioureas.
NH
R2
N
NH2OH.HCl,TEA,
HgCl2, DMF
H
2
H
N
N
Acetone, 0 °C
N
N
N
R1
R2
N
R1
C
S
R1
N
4
60-80 %
44-70 %
O
S
R2
1
3
R1 = C6H5, 2-CH3C6H4, 4-CH3C6H4, 2-OCH3C6H4, 4-OCH3C6H4, 4-ClC6H4,4-BrC6H4,
COC6H5
R2 = CH3, C6H5
NH
NH
NH
N
N
N
N
N
N
O
CH3
O
O
4a - 44 %
4b - 70 %
4c - 69 %
NH
O
NH
N
O
N
O
N
N
N
N
O
O
4d - 51 %
NH
4e - 52 %
NH
4f - 56 %
NH
O
Cl
Br
N
N
N
N
N
O
N
O
O
4g - 50 %
4h - 50 %
4i - 62 %
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1754
S. G. Yerande, A. B. Ghaisas, K. M. Newase, W. Wang, K. Wang, and A. Dömling
Vol 51
Scheme 2. Plausible mechanism for the formation of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazole.
S
R2
R1
N
H
N
N
3
Hg2+
Hg2+
R2
Pathway A
S
Pathway B
R1
N
H
N
N
NH2OH.HCl
NEt3
NEt3
-HgS
5
Hg2+
N
R1
C
H
N
S
N
N
7
N
N
R1
R2
NH2 R2
HO
6
OH
R2
NEt3
-HgS
NH2OH.HCl
NEt3
N
R1
N
H
N
8
N
NEt3
-HNEt2
O
N
R2
R1
N
N
H
4
Figure 3. Antifungal activity of 3-phenylamino-5-aryl/alkyl-1,2,4-
oxadiazole.
Figure 2. Antimicrobial activity of 3-phenylamino-5-aryl/alkyl-1,2,4-
oxadiazole.
Both of which should involve an initial activated species 5
formed by complexion of amidinothiourea 2 with Hg2+. In
the absence of mercury chloride, the desired product did
not form. In pathway A, amidinothiourea 2 may undergo
nucleophilic attack from hydroxylamine hydrochloride in
the presence of TEA to form intermediate 6, followed
by elimination of diethylamine to afford target product 4.
Alternatively, in pathway B, 5 undergoes desulfurization to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
(3+2) Annulation of Amidinothioureas with Binucleophile: Synthesis and Antimicrobial
Activity of 3-Phenylamino-5-aryl/alkyl-1,2,4-oxadiazole Derivatives
1755
form a carbodiimide intermediate 7, which is trapped by
hydroxylamine hydrochloride in the presence of TEA, and
subsequent elimination of diethylamine by nucleophilic
oxygen will give the target product 4.
was maintained at the same temperature for 20 min. The reaction
was then monitored by TLC, and after completion, precipitate of
mercury sulfite was filtered through celite bed. The filtrate was
then poured in cold water and stirred for 10 min. The precipitated
product was filtered and was purified by column chromatography
using suitable combination of hexane and ethyl acetate.
All the newly synthesized 3-phenylamino-5-aryl/alkyl-
1,2,4-oxadiazoles were tested for their antibacterial and
antifungal activity [27–29]. The antimicrobial activity
was compared with standard drug azithromycin, and
the antifungal activity was compared with standard drug
fluconazole (Figs 2 and 3). Overall in a series, activity
against fungus was more compared with bacteria. Electron-
donating substitution in the phenylamino ring at the third
position of 1,2,4-oxadiazole is favorable for antifungal
activity. The series showed minimum or no activity against
Gram-negative bacteria (Escherichia coli and Pseudomonas
aeruginosa). When compared with standard azithromycin,
compound 4e showed better antimicrobial activity against
Gram-positive Staphylococcus aureus.
CAUTION: HgCl2 is very toxic, and both the reagent and
the crude product must be manipulated carefully. Although the
byproduct of the reaction, HgS, is highly water insoluble, the
solid residue retained in the short celite column must be disposed
of in a suitable flask. The appropriate disposal of celite and SiO2
used in the purification process must also be considered.
Characterization. 5-Methyl-N-phenyl-1,2,4-oxadiazol-3-
amine (4a). White solid, mp 124–126ꢀC, Rf: 0.52 (hexane/ethyl
acetate 1.5:0.35), IR (KBr, cmÀ1: 3413, 3346, 3010, 2952, 2882,
1863, 1577, 1509, 1467, 1266.), 1H nmr (600 MHz, CDCl3)
d [ppm]: 2.5 (s, 3H, –CH3); 6.75 (s, 1H, –NH–); 7–7.5 (m, 5H,
ArH). 13C nmr (150 MHz, CDCl3) d [ppm]: 12.43, 117.28,
122.11, 129.27, 138.91, 165.22, and 174.86. MS [M+]: 175,
HRMS (TOF MS ES+) calcd. for C9H9ON3 [M]+ 175.0759,
found 175.0740.
N,5-Diphenyl-1,2,4-oxadiazol-3-amine (4b). White solid, mp
132–134ꢀC, Rf: 0.64 (hexane/ethyl acetate 1.5:0.35), ir (KBr, cmÀ1
:
CONCLUSION
3411, 3073, 2921, 2551, 1723, 1566, 1447, 900, 733, 691.), 1H nmr
(600MHz, CDCl3) d [ppm]: 6.9 (s, 1H, –NH–); 7.1–8.1 (m, 10H,
ArH). 13C nmr (150MHz, CDCl3) d [ppm]: 117.29, 122.23,
124.09, 128.03, 129.07, 132.79, 138.95, 165.66, and 173.66. MS
[M+]: 237, HRMS (TOF MS ES+) calcd. for C14H11ON3 [M]+
237.0902, found 237.0911.
In conclusion, we have developed a convenient synthesis
of 3-phenylamino-5-aryl/alkyl-1,2,4-oxadiazoles from readily
available starting materials under mild conditions. The reac-
tion is applicable to a wide range of substituted isothiocya-
nates and N,N-diethylamidines. Because of the importance
of these compounds in medicinal chemistry, the present
reaction may prove to be an efficient means for library
construction. Some of the compounds from this series have
shown promising antifungal and antimicrobial activities.
Further extension of this chemistry towards the synthesis of
other heterocycles can be easily envisioned and currently is
being explored in our laboratory.
5-Phenyl-N-o-tolyl-1,2,4-oxadiazol-3-amine (4c).
White
solid, mp 80–81ꢀC, Rf: 0.68 (hexane/ethyl acetate 1.5:0.35), ir
(KBr, cmÀ1: 3448, 3041, 2999, 1905, 1785, 1572, 1585, 1462,
1343, 1254, 1118.), 1H nmr (600 MHz, CDCl3) d [ppm]: 2.36
(s, 3H, –CH3); 6.55 (s, 1H, –NH–); 7–8.2 (m, 9H, ArH). 13C
nmr (150 MHz, CDCl3) d [ppm]: 17.71, 117.99, 122.40, 124.14,
124.77, 128.00, 129.08, 130.46, 133.132.77, 137.23, 165.89,
and 173.66. MS [M+]: 251. HRMS (TOF MS ES+) calcd. for
C15H13ON3 [M]+ 251.1072, found 251.1055.
5-Phenyl-N-p-tolyl-1,2,4-oxadiazol-3-amine (4d).
White
solid, mp 116–118ꢀC, Rf: 0.6 (hexane/ethyl acetate 1.5:0.35), ir
EXPERIMENTAL
(KBr, cmÀ1: 3286, 3208, 2921, 2364, 1978, 1608, 1566, 1405,
1
General methods. All reactions were performed under air
atmosphere. All other reagents and solvents are purchased from
Avara chemicals Hyderabad, India and used without further
purification. TLC was performed on precoated aluminum plate
with silica gel 60 F254 available from Merck. Flash column
chromatography was performed using SiO2 60 (particle size
0.040–0.055 mm, 230–400 mesh) Proton and carbon nmr
spectra were obtained on Bruker Avance 600 MHz nmr
spectrometer. Chemical shifts are reported as d values in parts
per million (ppm) as referenced to a residual solvent. 1H nmr
spectra are tabulated as follows: chemical shift, multiplicity
(s, singlet; m, multiplet); HRMS were obtained at the University
of Pittsburgh Mass Spectrometry facility. The antimicrobial
and antifungal activities were tested as per the reported
protocol [27–29].
1118, 936, 811, 743, 691, 582.), H nmr (600 MHz, CDCl3) d
[ppm]: 2.32 (s, 3H, –CH3); 6.75 (s, 1H, –NH–); 7.2–8.2 (m,
9H, ArH). 13C nmr (150 MHz, CDCl3) d [ppm]: 20.70, 117.37,
124.16, 128.01, 129.05, 129.76, 131.64, 132.73, and 136.47.
MS [M+]: 251, HRMS (TOF MS ES+) calcd. for C15H13ON3
[M]+ 251.1018, found 251.1049.
3-(2-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazole (4e). White
solid, mp 88–90ꢀC, Rf: 0.69 (hexane/ethyl acetate 1.5:0.35), ir
(KBr, cmÀ1: 3448, 3020, 2848, 2364, 2035, 1865, 1572, 1457,
1363, 1249, 1108, 1020, 910, 733, 619, 504.), 1H nmr (600MHz,
CDCl3) d [ppm]: 3.9 (s, 3H, –OCH3); 7.3 (s, 1H, –NH–); 6.9–7.1
and 7.5–8.2 (m, 9H, ArH). 13C nmr (150 MHz, CDCl3) d [ppm]:
55.72, 109.83, 117.12, 121.26, 121.64, 124.24, 128.00, 128.75,
129.05, 132.69, 147.10, 165.57, and 173.47. MS [M+]: 267,
HRMS (TOF MS ES+) calcd. for C15H13O2N3 [M]+ 267.1048,
found 267.1015.
General procedure for the synthesis of 3-phenylamino-5-
aryl/alkyl-1,2,4-oxadiazole (4). Amidinothiourea 3 (1.0 equiv)
was taken in DMF in a round bottom flask. To it, hydroxylamine
hydrochloride (1.1 equiv) was added followed by TEA (3.2equiv).
The reaction mixture was then cooled between 0ꢀC and 5ꢀC, and
mercury (II) chloride (1.1 equiv) was added to it. Reaction mixture
N-(4-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazol-3-amine
(4f). White solid, mp 106–108ꢀC, Rf: 0.46 (hexane/ethyl acetate
1.5:0.35), ir (KBr, cmÀ1: 3291, 3223, 3129, 2780, 1726, 1384,
1294, 1254, 1091, 978, 906, 759, 655.), 1H nmr (600MHz,
CDCl3) d [ppm]: 3.8 (s, 3H, –OCH3); 6.7 (s, 1H, –NH–); 6.9–8.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. G. Yerande, A. B. Ghaisas, K. M. Newase, W. Wang, K. Wang, and A. Dömling
Vol 51
(m, 9H, ArH). 13C nmr (150MHz, CDCl3) d [ppm]: 55.58, 114.52,
119.05, 124.18, 127.99, 129.03, 132.41, 132.70, 155.03, 165.96,
and 173.58. MS [M+]: 267, HRMS (TOF MS ES+) calcd. for
C15H13O2N3 [M]+ 267.1048, found 267.0997.
M. A.; Wendt, J. A.; Chen, B. B.; Stenmark, H. G.; Wu, H.; Spangler,
D. P.; Clare, M.; Desai, B. N.; Khanna, I. K.; Nguyen, M. N.; Duffin,
T.; Engleman, W.; Finn, M. B.; Freeman, S. K.; Hanneke, M. L.; Keene,
J. L.; Klover, J. A.; Nickols, G. A.; Nickols, M. L.; Steininger, C. N.;
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M. W.; Nguyen, H. Q.; Patel, V. F.; Tomlinson, S. A.; White, R. D.;
Xia, X.; Hitchcock, S. A. J. Med Chem 2008, 51, 5019.
N-(4-Chlorophenyl)-5-phenyl-1,2,4-oxadiazol-3-amine
(4g).
White solid, mp 180–182ꢀC, Rf: 0.53 (hexane/ethyl
acetate 1.5:0.35), ir (KBr, cmÀ1: 3416, 3093, 1889, 1514, 1410,
1
1098, 1009, 936, 821, 780, 701.), H nmr (600MHz, CDCl3) d
[ppm]: 6.75 (s, 1H, –NH–); 7.2–8.2 (m, 9H, ArH). 13C nmr
(150 MHz, CDCl3) d [ppm]: 118.53, 123.99, 127.13, 128.04,
139.11, 129.25, 132.90, 137.54, 165.46, and 173.84. MS [M+]:
271, 273, HRMS (TOF MS ES+) calcd. for C14H10ON3Cl [M]+
271.0472, found 271.0502.
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[21] (a) Alan, M. B.; Roger, J. B.; David, S. C.; Andrew, L.; Philip,
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N-(4-Bromophenyl)-5-phenyl-1,2,4-oxadiazol-3-amine (4h). White
solid, mp 194–196ꢀC, Rf: 0.4 (hexane/ethyl acetate 1.5:0.2), ir
(KBr, cmÀ1: 3911, 3416, 3093, 2884, 2593, 2364, 1889, 1554,
1405, 1077, 1009, 736, 816, 775, 665.), 1H nmr (600 MHz,
CDCl3) d [ppm]: 6.75 (s, 1H, –NH–); 7.2–8.2 (m, 9H, ArH).
13C nmr (150 MHz, CDCl3) d [ppm]: 114.53, 118.92, 123.97,
128.05, 129.12, 132.18, 132.92, 138.03, 165.43, and 173.86.
MS [M+]: 315, 317, HRMS (TOF MS ES+) calcd. for
C14H10ON3Br [M]+ 314.9945, found 315.0001.
N-(5-Phenyl-1,2,4-oxadiazol-3-yl)benzamide (4i). White solid,
mp118–120ꢀC, Rf: 0.7 (hexane/ethyl acetate 1:1), ir (KBr, cmÀ1
:
3244, 2776, 2364, 2182, 1686, 1630, 1488, 1291, 1159, 1098, 926,
1
712, 660.), H nmr (600 MHz, CDCl3) d [ppm]: 7.2–8.2 (m, 10H,
ArH); 8.7 (s, 1H, –NH–). 13C nmr (150 MHz, CDCl3) d [ppm]:
123.62, 127.57, 128.12, 129.00, 129.16, 132.51, 132.97, 133.17,
163.21, and 174.97. HRMS (TOF MS ES+) calcd. for C15H11O2N3
[M]+ 288.0749, found 288.0760.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet