A diversified assembly of 1,2,4-oxadiazol-3-amines: Metallic thiophile catalyzed chemoselective one-pot reaction of aryl isothiocyanates, amidines/guanidines, and hydroxylamine

Article abstract of DOI:10.1055/s-0032-1317504

An efficient one-pot synthesis of 1,2,4-oxadiazol-3-amines from simple starting materials, isothiocyanates, amidines/guanidines, and hydroxylamine, is described. The reaction is facilitated by metallic-thiophile-assisted desulfurization of in situ formed amidino- or guanidinothiourea to give chemoselectively N-hydroxyguanidine intermediates that give exclusively various 1,2,4-oxadiazol-3-amines in good to excellent yields. The reaction mechanistic pathway may proceed through an intramolecular 5-exo-trig cyclization.

Full text of DOI:10.1055/s-0032-1317504

3378▌
PAPER
paper
A Diversified Assembly of 1,2,4-Oxadiazol-3-amines: Metallic Thiophile
Catalyzed Chemoselective One-Pot Reaction of Aryl Isothiocyanates,
Amidines/Guanidines, and Hydroxylamine1
MCR Synthesis of 1,2,4-Oxadiazol-3-amines
Hitesh B. Jalani, V. Sudarsanam, Kamala K. Vasu*
Department of Medicinal Chemistry, B.V. Patel Pharmaceutical Education and Research Development (PERD) Centre,
Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India
Fax +91(79)27450449; E-mail: kamkva@gmail.com
Received: 05.06.2012; Accepted after revision: 07.09.2012
In loving memory of my grandfather, S. J. Jalani
that means there is a level of complexity associated with
this simplicity. General interest in these small-ring hetero-
cycles has made them valuable synthetic targets for vari-
ous biological screening. As a result, various synthetic
Abstract: An efficient one-pot synthesis of 1,2,4-oxadiazol-3-
amines from simple starting materials, isothiocyanates, ami-
dines/guanidines, and hydroxylamine, is described. The reaction is
facilitated by metallic-thiophile-assisted desulfurization of in situ
formed amidino- or guanidinothiourea to give chemoselectively N- methods have been developed for their synthesis. 1,2,4-
hydroxyguanidine intermediates that give exclusively various
1,2,4-oxadiazol-3-amines in good to excellent yields. The reaction
mechanistic pathway may proceed through an intramolecular 5-exo-
inhibition,2 muscarinic agonism,3 histamine H3 antago-
trig cyclization.
Oxadiazole are an important class of small-ring heterocy-
cles with biological properties such as tyrosine kinase
nism,4 anti-inflammatory action,5 antitumor activity,6 and
monoamine oxidase inhibition;7 recently the FDA have
Key words: 1,2,4-oxadiazol-3-amine, metallic thiophile, chemose-
lectivity, N-hydroxyguanidine
approved the drug Azilsartan (Figure 1). Additionally,
1,2,4-oxadiazoles are also widely used for the design of
dipeptidomimetics as peptide building blocks.8,9
Small-ring heterocyclic compounds, particularly five-
Various methods for the synthesis of 1,2,4-oxadiazoles
membered rings with more than two hetero atoms, are an
are available and these include: (i) condensation of ami-
attractive target for organic chemists; the development of
doximes with derivatives of carboxylic acids followed by
simple and diverse synthetic methods for their preparation
remains a challenge. Although the synthesis of these small
cyclization to 1,2,4-oxadiazoles, (ii) cyclization of N-ac-
ylamidoximes, (iii) 1,3-dipolar cycloaddition of nitrile
heterocycles appears simple, they require complex pattern
oxides to nitriles, (iv) electrocyclic ring closure of ni-
of functionalization, transformation, and rearrangement
H
N
NO2
O
O
H
O
N
N
N
N
O
N
O
N
O
O
N
N
O
H
N
fluvinazole
NH2
tryptase inhibitor
5-HT3 antagonist
NH2
N
O
N
N
O
O
N
N
O
O
N
HN
NH
O
N
O
O
N
O
N
O
H
efficient muscarinic agent
Azilsartan Medoxomil
imolamine
Figure 1 Selected examples of some biologically important 1,2,4-oxadiazoles
SYNTHESIS 2012, 44, 3378–3386
Advanced online publication: 09.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317504; Art ID: SS-2012-N0491-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
MCR Synthesis of 1,2,4-Oxadiazol-3-amines
3379
trenoids, and (v) oxidation of 4,5-dihydro-1,2,4- benzamidine (2a), with hydroxylamine hydrochloride (4)
oxadiazoles10,11 and other derivatives of 1,2,4-oxadia- in the presence of triethylamine (2 equiv) catalyzed by
zoles.12 A few reports are available on the synthesis of 3- mercury(II) chloride in N,N-dimethylformamide (r.t., 3–4
aryl-1,2,4-oxadiazol-5-amine13 and 1,2,4-oxadiazole-3,5- h); the expected product 5a was obtained as a pure com-
diamine.14
pound in 84% yield. The reaction conditions were opti-
mized with respect to the solvent, and it was found that the
reaction proceeded smoothly in N,N-dimethylformamide.
The reaction was then performed and optimized as a se-
quential one-pot procedure using 4-chlorophenyl isothio-
cyanate (1a), N,N-diethylbenzamidine (2a), and
hydroxylamine hydrochloride (4).
Great effort has been devoted to the design of multicom-
ponent reactions,15 a powerful tool for the construction of
organic molecules that permits the formation of several
bonds in a single reaction. Multicomponent reactions are
of interest for the formation of complex molecules from
either simple starting materials or precursors without the
need to isolate intermediates.
Examining the use of various thiophiles showed that silver
nitrate (1.1 equiv) gave the best results and gave 1,2,4-
oxadiazole 5a in 91% yield (Table 1, entry 1), an im-
proved yield over the use of mercury(II) chloride, which
gave 5a in 84% (entry 2). Elemental iodine was also an ef-
ficient thiophile (entry 3) giving 5a in 76% yield. Thio-
philes such as lead nitrate, lead acetate, copper sulfate,
and mercury acetate were also capable of producing 5a,
but with lower yields and with the presence of impurities
(entries 4–7). As mercury(II) chloride is also known for its
toxicity and should be avoided for the synthesis of biolog-
ically important molecules, the more environmentally
friendly silver nitrate or elemental iodine would be pre-
ferred over mercury(II) chloride.
The reaction of isothiocyanates with N,N-diethylacetami-
dine (2c), N,N-diethylbenzamidines (2a,b,e), or 1,1,3,3-
tetramethylguanidine (2d) gives amidino- or guanidino-
thioureas in good yields under mild conditions.16,17 The
thiourea functionality (NH–CS–NH) of amidino- or gua-
nidinothioureas can be converted into a carbodiimide
(N=C=N) using various desulfurizing agents (thiophiles
or thiophilic metal salts); thiophilic metal salts [typically
Hg(II), Cu(I), or Ag(I)] are the most commonly used re-
agents for guanidine18 formation. The reaction of various
nucleophiles like amines, carboxamidines, hydrazines,
and hydroxylamine with carbodiimides results in the for-
mation of functionalized guanidines. These guanidines
can be manipulated to give diverse heterocycles, such as The results of the optimization of the thiophiles in hand,
thiazoles,19 imidazoles,20 triazines,21 and triazoles.22
the effect of the leaving groups on reaction was examined.
The use of different amine leaving groups (R3 NH) in the
2
Utilizing the synthetic potential of amidino- or guanidino-
thioureas, substituted triazines, and triazoles were synthe-
sized using binucleophiles such as carboxamidines
[HN=C(NH2)–Ar]21 and hydrazines.22 Therefore we en-
visaged that the carbodiimide intermediate from the amid-
ino- or guanidinothioureas could give novel 1,2,4-
oxadiazoles upon nucleophilic addition of hydroxylamine
catalyzed by a thiophile to give N-hydroxyguanidines that
further undergo cyclization through intramolecular C–O
bond formation.
amidine was examined (Table 2). Starting from N,N-di-
ethylbenzamidine (2a) and N,N-dimethylbenzamidine,
both diethylamine and dimethylamine were found to be
good leaving groups at room temperature. Various amine
leaving groups, such as morpholine, benzylamine, and
isopropylamine (used to prepare amidines of benzonitrile)
were found to be less suitable for this reaction as they re-
quired higher temperatures and gave 5a in lower yields.
Unsuccessful attempts were also made to react alkyl and
aroyl isothiocyanates with amidines or guanidines to give
N-alkyl- and N-aroyl-substituted amidino- or guanidino-
thioureas followed by reaction with a thiophile for the
synthesis of N-alkyl- and N-aroyl-1,2,4-oxadiazol-3-
amines. This failure may be due to the decreased acidity
of the amine proton in the case of alkyl amidinothioureas;
this is similar to the case of benzoyl amidinothioureas,
where the amine proton is part of the amide function and
hence does not allow the desulfurization.
Herein, we report an efficient and diversified protocol for
the synthesis of 1,2,4-oxadiazol-3-amines 5 in excellent
yields via metallic thiophile-catalyzed desulfurization of
in situ formed amidinothioureas 3 to give carbodiimides
that react chemoselectively with hydroxylamine hydro-
chloride in the presence of triethylamine (Scheme 1). The
1,2,4-oxadiazol-3-amines 5 were readily isolated without
chromatography.
We began by reacting amidinothiourea 3a, synthesized
from 4-chlorophenyl isothiocyanate (1a) and N,N-diethyl-
R2
2. NH2OH·HCl (4),
Et3N, AgNO3, r.t.,
3–4 h
NR3R3
R2
NR3R3
N
1. DMF, 20–25 °C, 1 h
R1
N
C
S
O
N
+
R1
R2
R1
HN
N
N
N
S
H
2
H
1
3
5
Scheme 1 One-pot synthesis of 1,2,4-oxadiazol-3-amines
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3378–3386

3380
H. B. Jalani et al.
PAPER
Table 1 Thiophile Optimization for 1,2,4-Oxadiazol-3-amine 5a Synthesis
N=C=S
N
S
2. NH2OH·HCl (4),
Et3N, thiophile, r.t.
Cl
Cl
N
1. DMF, 20–25 °C, 1 h
N
N
O
+
HN
N
N
N
H
H
Cl
2a
3a
5a
1a
Entry
Thiophile (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
AgNO3 (1.1)
HgCl2 (1.0)
3
91
84
76
41
46
31
36
3
I2 (1.1)
6
Pb(NO3)2 (1.0)
Hg(OAc)2 (1.0)
CuSO4·SiO2 (1.0)
Pb(OAc)2 (1.0)
20
14
24
29
a Isolated products without chromatography.
Table 2 Reaction of 4-Chlorophenyl Isothiocyanate (1a) with N-
Substituted Benzamidines in the Synthesis of 5a; Effect of Leaving
Groups on Reaction Parameters
To explore whether this process was efficient for
guanidinothioureas23 for the synthesis of 1,2,4-oxadia-
zole-3,5-diamines, reaction of aryl isothiocyanates 1 and
1,1,3,3-tetramethylguanidine (2d) performed giving
N5,N5-dimethyl-1,2,4-oxadiazole-3,5-diamines 5j–l in
good yields; in the course of reaction, one dimethylamino
(NMe2) group is removed. The structure of 5l was con-
firmed by X-ray crystallography (Figure 2).
Entry
Leaving group Temp (°C)
Time (h)
Yielda (%)
(R3 NH)
2
1
2
3
4
5
Et2NH
25
25
40
45
50
3
91
85
46
42
39
Me2NH
morpholine
BnNH2
3
The reaction of the in situ formed amidinothiourea 3 with
a thiophile in the presence of a base, first converts them
into the carbodiimide (N=C=N) structure 6, which is read-
ily attacked by nucleophiles such as hydroxylamine. The
proposed mechanism (Scheme 2) shows the example of
silver nitrate as the metallic thiophile. The nucleophilic
nitrogen atom of amidine 2 attacks the electron-deficient
thiocarbonyl of isothiocyanate 1 to give amidinothiourea
3 in an addition reaction. In the reaction of 3 with silver
nitrate, sulfur is regarded as a strong nucleophile which at-
tacks the Ag+1 ion and thereby forms Ag–S bond after the
abstraction of a proton by triethylamine. The lone pair of
electrons on the nitrogen of the diethylamino group in 6
form an iminium structure and allow C–S bond breakage
and this results in the formation of carbodiimide interme-
diate 7 with the elimination of the silver sulfide complex.
The carbodiimide intermediate 7 is attacked by the free
amino group of hydroxylamine (due to excess base pres-
ent in the reaction mixture) on the central carbon to give
N-hydroxyguanidine 8 by C–N bond formation. The inter-
molecular acid–base reaction further converts 8 into 9. Si-
multaneously the electron-withdrawing quaternary
nitrogen attached to the imine carbon is a strong electro-
phile and attracts the lone pair of electrons of hydroxy
group. This results in an intramolecular 5-exo-trig cycli-
17
20
28
i-PrNH2
a Isolated products without chromatography.
With the optimized process in hand, the generality of this
protocol was examined using aryl isothiocyanates substi-
tuted with electron-donating and electron-withdrawing
groups (Table 3).
The utility of this reaction for the production of an N-un-
substituted 1,2,4-oxadiazole was examined. Reaction of
trityl isothiocyanate (1d) with N,N-diethyl-4-methylbenz-
imidamide (2d) in N,N-dimethylformamide at 45–50 °C
for 5–6 hours gave the tritylated amidinothiourea 3d in
situ (entry 4), which was reacted with hydroxylamine hy-
drochloride in presence of silver nitrate and triethylamine
to give 5-(4-tolyl)-N-trityl-1,2,4-oxadiazol-3-amine (5d)
(entry 4). Deprotection of the trityl group was achieved
using trifluoroacetic acid to give 5-(4-tolyl)-1,2,4-oxadia-
zol-3-amine in 64% yield, which was confirmed by NMR
and mass spectra.
Synthesis 2012, 44, 3378–3386
© Georg Thieme Verlag Stuttgart · New York

PAPER
MCR Synthesis of 1,2,4-Oxadiazol-3-amines
3381
N
N
2
N
S
N
R2
N
S
R2
HN
C
H
R1
R2
N
R2
N
N
H
S
R1
Ag
R1
NO3
N
S
R1
N
H
N
3
1
NEt3
NO3
NO3
R1
N
N
N
R1
C
N N
N
C
N
N
R2
R2
R2
R1
HNEt3
– AgS
N
OH
Et3NH
N
S
N
H
7
8
Ag
NO3
OH
H
Et3N
H
H NEt3
6
– NEt3
NO3
R2
O
H
N
H
N
N
R2
R1
R1
N
N
R1
N
N
N
R2
R1
NO3
H
N
C
N
N
– HNO3
– NEt3
N
O
N
H
– HNEt2
– NEt3
R2
H
N
O
N
H
11
5
H
9
O
NEt3
H
10
NEt3
H
Scheme 2 Plausible mechanism of 1,2,4-oxadiazoles formation by 5-exo-trig cyclization
zation with C–O bond formation to give 10. Further re- vantages of this method are: (1) Simple reaction
moval of diethylamine in 11 in the presence of excess conditions performed at ambient temperature. (2) Product
triethylamine gives the corresponding 1,2,4-oxadiazol-3- isolation in the form of precipitates with very good purity.
amines 5.
(3) This method provides N-aryloxadiazoles with alkyl,
aryl, or dimethylamino substitution at C5. (4) Free amino
group can be generated at C3 of the oxadiazole. These ver-
satile variations in the synthesis of 1,2,4-oxadiazoles us-
ing this protocol could be an interesting alternative to
other approaches. This reaction is applicable to a variety
of isothiocyanates and tolerates various substituents.
1,2,4-Oxadiazol-3-amines compounds synthesized using
this protocol could be of use for the generation of com-
pound libraries for biological screening. Further work to
explore the reaction of amidinothioureas with other mo-
lecular species to generate various biologically interesting
heterocyclic compounds are in progress.
The possibility forming 1,2,4-oxadiazol-5-amine is ruled
out by the fact that: (1) hydroxylamine (pKa ~6) is a
unique α-nucleophile,24 in neutral to slightly basic condi-
tion its NH2 group will act as a nucleophile. (2) Hydrox-
ylamine can be converted into N-hydroxyguanidine on
reaction with substituted carbodiimides.25 (3) The X-ray
crystal structure of compound 5l26 (Figure 2) reveals that
the 4-tolyl amino group is directly attached to C3 of the
1,2,4-oxadiazole ring, while the dimethylamino group is
present on C5. The X-ray single crystal structure of 5l
(Table 3, entry 12) confirms the chemoselectivity of hy-
droxylamine giving the guanidine system predominantly
over the isourea system. This evidence confirms that NH2
group of hydroxylamine attacks the carbodiimide (C–N
bond) to give 1,2,4-oxadiazol-3-amines 5a–t exclusively.
All reactions were carried out at r.t. in dried glassware. Glassware
was dried at 90 °C in a hot air oven and cooled to r.t. prior to use.
All solvents were used without further purification unless otherwise
mentioned, as such from the suppliers. All reactions were monitored
by TLC plates (aluminum oxide 60 F254, neutral) and analyzed
with 254 nm UV light. Melting points were determined of isolated
product without purification and are uncorrected. NMR spectra
were recorded on Bruker FT-NMR, 300 and 400 MHz relative to re-
sidual DMSO-d6 as an internal reference (1H NMR: δ = 2.5 (3 H),
3.3 (H2O); 13C NMR: δ = 39). The mass data were obtained on a
Perkin-Elmer HRMS instrument. Infrared spectra were recorded on
Bruker FT-IR spectrophotometer. Single crystal X-ray analysis was
carried out on Bruker Smart Apex CCD Diffractometer.
Figure 2 ORTEP presentation of 5l (Table 3, entry 12); ellipsoids set
at 30% probability
N,N-Diethylacetamidine (2c)19b,27
MeCN (37.12 g, 0.9 mol) was cooled to 10 °C and AlCl3 (60 g) was
added portionwise over 30 min, maintaining the temperature be-
tween 10 °C and 30 °C. Et2NH (33.44 g, 0.45 mol) was added por-
tionwise with cooling over 20 min; the internal temperature was
maintained below 35 °C. The mixture was then cooled to 10 °C, and
further AlCl3 (60 g) was added, followed by Et2NH (33.44 g, 0.45
In conclusion, we have developed an efficient chemose-
lective three-component one-pot synthesis of novel 1,2,4-
oxadiazol-3-amines from simple starting materials cata-
lyzed by a thiophile in good to excellent yields. The ad-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3378–3386

3382
H. B. Jalani et al.
PAPER
Table 3 Synthesis of 3-Amino-1,2,4-oxadiazoles from Aryl Isothiocyanates, Amidines or 1,1,3,3-Tetramethylguanidine, and Hydroxylamine
Hydrochloride
R2
NR3R3
R2
2. NH2OH·HCl (4),
Et3N, AgNO3, r.t.,
3–4 h
NR3R3
N
1. DMF, 20–25 °C, 1 h
N
R1
N
C
S
+
O
R1
R1
HN
R2
N
N
N
S
H
H
2
1
3
5
Entry
Isothiocyanate
Amidine or guanidine
Product
Yielda (%) of 5
1
R1
2
R2
R3
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
1
1a
1b
1c
1d
1b
1c
1a
1e
1f
4-ClC6H4
4-MeC6H4
Ph
2a
2a
2a
2b
2c
2c
2c
2c
2c
2d
2d
2d
2a
2a
2b
2b
2b
2e
2b
2e
Ph
5a
5b
5c
5db
5e
5f
91
78
83
62
82
80
89
66
82
80
86
67
64
78
75
76
87
78
72
67
2
Ph
3
Ph
4
CPh3
4-MeC6H4
Me
5
4-MeC6H4
Ph
6
Me
7
4-ClC6H4
2,4-(MeO)2C6H3
4-FC6H4
Ph
Me
5g
5h
5i
8
Me
9
Me
10
11
12
13
14
15
16
17
18
19
20
1c
1a
1b
1g
1h
1i
NMe2
NMe2
NMe2
Ph
5j
4-ClC6H4
4-MeC6H4
3-MeOC6H4
2-MeC6H4
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
Ph
5k
5l
5m
5n
5o
5p
5q
5r
5s
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-MeC6H4
4-MeC6H4
2-MeC6H4
1b
1a
1b
1c
1c
Ph
5t
a Isolated products without chromatography.
b This was detritylated with TFA for characterization.
mol) as before. The mixture was heated and the internal temperature
was maintained at 120 °C for 30 min and then at 140–145 °C for 1
h. The mixture was cooled to 70 °C and poured onto ice with stir-
ring, the temperature was not allowed to rise above 15 °C. CH2Cl2
(400 mL) was added, followed by slow addition of a soln of NaOH
(162 g) in H2O (400 mL). The mixture was stirred for 15 min and
then the CH2Cl2 layer was separated; the aqueous layer was extract-
ed with further CH2Cl2 (400 mL). The CH2Cl2 extracts were com-
bined and dried (anhyd Na2SO4), and the solvent was distilled off.
The residual N,N-diethylacetamidine was vacuum distilled; bp 50–
55 °C/6.7–8 mbar.
cooling over 20 min; the internal temperature rose to 60–70 °C. The
mixture was cooled to 10 °C, and further anhyd AlCl3 (21.5 g) was
added, followed by Et2NH (11.77 g) as before. The internal temper-
ature was maintained at 120 °C for 30 min, and then at 140–145 °C
for 1 h. The mixture was cooled to 70 °C and poured onto ice with
stirring, the temperature was not allowed to rise above 15 °C.
CH2Cl2 (200 mL) was added, followed by slow addition of a soln of
NaOH (38.64 g) in H2O (200 mL). The mixture was stirred 15 min
and then the CH2Cl2 layer was separated; the aqueous layer was ex-
tracted with further CH2Cl2 (200 mL). The CH2Cl2 extracts were
combined and dried (anhyd Na2SO4), and the solvent was distilled
off. The residual N,N-diethylbenzamidine (2a) was vacuum dis-
tilled. The same procedure was followed for N,N-diethyl-4-methyl-
benzamidine (2b) and N,N-diethyl-2-methylbenzamidine (2e).
N,N-Diethylbenzamidine (2a); Typical Procedure19b,27
PhCN (30 g) was cooled to 10 °C and anhyd AlCl3 (21.5 g) added
portionwise over the course of 30 min, maintaining the temperature
between 10 °C and 30 °C. Et2NH (11.77 g) was added rapidly with
Synthesis 2012, 44, 3378–3386
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MCR Synthesis of 1,2,4-Oxadiazol-3-amines
3383
Aryl Isothiocyanates 1; General Procedure19b,28
13C NMR (400 MHz, DMSO-d6): δ = 117.0, 121.0, 123.5, 127.5,
128.9, 133.0, 139.9, 165.5, 172.6.
HRMS (EI): m/z [M]+ calcd for C14H11N3O: 237.2566; found:
237.2568.
A soln of the aniline (0.0392 mol) and Et3N (0.129 mol) in THF (25
mL) was cooled to 0–5 °C. CS2 (0.0431 mol) was added to the cold
mixture through an addition funnel over 1 h. The mixture was al-
lowed to stir at r.t. for 15–18 h (TLC monitoring, MeOH–hexane–
EtOAc, 0.5:3:1.5). The dithiocarbamate salt was filtered and
washed with hexane (2 × 25 mL). The air dried dithiocarbamate salt
was dissolved in CHCl3 (40 mL) and Et3N (0.0392 mol) was added
to the mixture. The mixture was stirred at 0–5 °C for 10 min, ethyl
chloroformate (0.047) was added, and the mixture was stirred at r.t.
for 1.5 h; 3 M HCl was added and the mixture was stirred for 10
min. The CHCl3 layer was separated and dried (anhyd Na2SO4). The
organic layer was evaporated to give the isothiocyanate with 90–
95% purity. Impure isothiocyanates were purified by column chro-
matography (hexane).
5-(4-Tolyl)-1,2,4-oxadiazol-3-amine (5d, R1 = H)
Tritylated oxadiazole 5d (R1 = CPh3; 0.1 mol) was dissolved in an-
hyd CH2Cl2 (10 × the volume) at r.t. To this soln TFA (0.3 mol) was
added and the mixture was stirred for 12 h. After complete deprot-
ection of the trityl group (TLC), the mixture was evaporated to re-
move the CH2Cl2 and treated with sat. NaHCO3 soln. The separated
solid was filtered, dissolved in CH2Cl2, and dried (Na2SO4), and the
solvent was removed by distillation. The residue was treated with
Et2O to give the pure detritylated solid.
Cream solid; yield: 390 mg (62%); mp 186–189 °C.
Substituted 3-Amino-1,2,4-oxadiazoles 5a–t; General Proce-
dure
IR (KBr): 3345, 3197, 2919, 1659, 1562, 1422, 1116, 826, 761
cm–1.
To a hot air dried round-bottom flask, aryl isothiocyanate 1 (2.0
mmol), amidine 2 (2.0 mmol), and DMF (20 mL) were added at 20–
25 °C and the mixture was stirred for 1 h. Et3N (5.0 mmol) was add-
ed to the mixture followed by slow addition of NH2OH·HCl (4; 2.0
mmol) at r.t. with stirring. The mixture resulted in turbid suspension
due to the formation of Et3N·HCl. A fine powder of AgNO3 (2.2
mmol) was added slowly to this suspension and the mixture was
stirred for 3–4 h at r.t. (As the addition of AgNO3 began, initiation
of the desulfurization was observed by the formation of black
precipitate.) When the reaction was complete (TLC monitoring:
EtOAc–hexane, 2:8), the mixture was filtered through a celite bed
and the celite bed was washed with CH2Cl2. The filtrate was evap-
orated on a Büchi rotavapor to remove the traces of solvent. The fil-
trate was cooled and poured into cold H2O, the mixture was stirred,
and the precipitate was collected on a Büchner funnel. (In the case
of a suspension, the mixture was extracted.) The precipitate was
then dissolved in either CH2Cl2 or EtOAc and dried (anhyd MgSO4)
and concentrated under reduced pressure. The residue was treated
with hexane and/or Et2O to give the pure compound.
1H NMR (400 MHz, DMSO-d6): δ = 2.38 (s, 3 H), 6.34 (s, 2 H,
NH2), 7.38–7.40 (d, J = 8.0 Hz, 2 H), 7.85–7.87 (d, J = 8.0 Hz, 2 H).
13C NMR (400 MHz, DMSO-d6): δ = 21.1, 121.3, 127.2, 129.8,
142.8, 168.9, 173.0.
HRMS (EI): m/z [M]+ calcd for C9H9N3O: 175.1873; found:
175.1875.
5-Methyl-N-(4-tolyl)-1,2,4-oxadiazol-3-amine (5e)
Off white solid; yield: 500 mg (82%); mp 160–163 °C.
IR (KBr): 3304, 3047, 2918, 1561, 1413, 1336, 1048, 907, 804, 740,
624 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.22 (s, 3 H), 2.48 (s, 3 H),
7.08–7.10 (d, J = 8.4 Hz, 2 H), 7.32–7.34 (d, J = 8.0 Hz, 2 H), 9.60
(s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 11.8, 20.2, 116.9, 129.2,
129.5, 137.5, 165.1, 174.5.
HRMS (EI): m/z [M]+ calcd for C10H11N3O: 189.2138; found:
189.2140.
N-(4-Chlorophenyl)-5-phenyl-1,2,4-oxadiazol-3-amine (5a)
Cream solid; yield: 630 mg (91%); mp 181–184 °C.
5-Methyl-N-phenyl-1,2,4-oxadiazol-3-amine (5f)
IR (KBr): 3413, 3060, 1561, 1407, 1337, 1091, 823, 740, 687 cm–1.
Grey solid; yield: 220 mg (80%); mp 110–113 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.33–7.35 (d, J = 8.8 Hz, 2 H),
7.50–7.52 (d, J = 8.8 Hz, 2 H), 7.57–7.72 (m, 3 H), 8.02–8.04 (d,
J = 7.2 Hz, 2 H), 10.18 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 118.5, 123.5, 124.7, 127.5,
128.7, 129.2, 133.0, 138.9, 165.3, 172.7.
HRMS (EI): m/z [M]+ calcd for C14H10ClN3O: 271.7017; found:
271.7030.
IR (KBr): 3291, 3133, 2919, 1572, 1450, 1344, 1082, 896, 786, 692,
648 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.49 (s, 3 H), 6.90–6.93 (m, 1
H), 7.27–7.31 (m, 2 H), 7.43–7.45 (d, J = 8.0 Hz, 2 H), 9.73 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 11.8, 116.8, 120.8, 128.8,
140.0, 165.1, 174.7.
HRMS (EI): m/z [M]+ calcd for C9H9N3O: 175.1873; found:
175.1876.
5-Phenyl-N-(4-tolyl)-1,2,4-oxadiazol-3-amine (5b)
Cream solid; yield: 290 mg (78%); mp 116–119 °C.
N-(4-Chlorophenyl)-5-methyl-1,2,4-oxadiazol-3-amine (5g)
IR (KBr): 3284, 2919, 1568, 1415, 1347, 1072, 809, 737, 688 cm–1.
Buff grey solid; yield: 520 mg (89%); mp 159–163 °C.
1H NMR (400 MHz, DMSO-d6): δ = 2.24 (s, 3 H), 7.12–7.14 (d,
J = 8.4 Hz, 2 H), 7.38–7.40 (d, J = 8.4 Hz, 2 H), 7.61–7.72 (m, 3 H),
8.05–8.07 (d, J = 6.4 Hz, 2 H), 9.91 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 20.2, 117.0, 123.6, 127.5,
129.3, 129.4, 129.8, 132.9, 137.4, 165.5, 172.5.
HRMS (EI): m/z [M]+ calcd for C15H13N3O: 251.2832; found:
251.2840.
IR (KBr): 3314, 3061, 2776, 1604, 1419, 1337, 1084, 809, 737, 614
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.48 (s, 3 H), 7.34–7.36 (d,
J = 8.8 Hz, 2 H), 7.44–7.46 (d, J = 8.8 Hz, 2 H), 9.92 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 11.8, 118.4, 124.5, 128.7,
138.9, 164.9, 174.9.
HRMS (EI): m/z [M]+ calcd for C9H8ClN3O3: 209.6323; found:
209.6331.
N,5-Diphenyl-1,2,4-oxadiazol-3-amine (5c)
Light yellow solid; yield: 320 mg (83%); mp 130–133 °C.
N-(2,4-Dimethoxyphenyl)-5-methyl-1,2,4-oxadiazol-3-amine
(5h)
IR (KBr): 3408, 3061, 1563, 1443, 1342, 1113, 742, 686 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 6.93–6.97 (m, 1 H), 7.31–7.35
(m, 1 H), 7.50–7.52 (d, J = 8.0 Hz, 2 H), 7.62–7.65 (m, 2 H), 7.69–
7.72 (m, 1 H), 8.06–8.08 (d, J = 7.2 Hz, 2 H), 10.03 (s, 1 H).
Cream solid; yield: 180 mg (66%); mp 104–107 °C.
IR (KBr): 3432, 3083, 2949, 1577, 1422, 1209, 1034, 890, 793, 562
cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3378–3386

3384
H. B. Jalani et al.
PAPER
1H NMR (400 MHz, DMSO-d6): δ = 2.45 (s, 3 H), 3.73 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 6.49–6.51 (d, J = 8.8 Hz, 1 H), 6.60–
6.61 (d, J = 2.4 Hz, 1 H), 7.51–7.53 (d, J = 8.8 Hz, 1 H), 8.08 (s, 1
H).
13C NMR (400 MHz, DMSO-d6): δ = 11.8, 55.2, 55.7, 99.1, 104.0,
120.2, 121.8, 150.2, 155.5, 165.8, 174.7.
13C NMR (400 MHz, DMSO-d6): δ = 54.8, 103.2, 106.3, 109.7,
123.6, 127.5, 129.3, 129.6, 132.9, 141.1, 159.9, 165.5, 172.6.
HRMS (EI): m/z [M]+ calcd for C15H13N3O2: 267.2826; found:
267.2834.
5-Phenyl-N-(2-tolyl)-1,2,4-oxadiazol-3-amine (5n)
Light yellow crystals; yield: 600 mg (78%); mp 74–76 °C.
HRMS (EI): m/z [M]+ calcd for C11H13N3O: 235.2392; found:
235.2398.
IR (KBr): 3430, 3062, 2923, 1547, 1594, 1454, 1333, 1106, 893,
758, 682, 484 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.30 (s, 3 H), 6.96–6.99 (m, 1
H), 7.18–7.21 (m, 2 H), 7.60–7.71 (m, 4 H), 7.05–7.07 (d, J = 7.2
Hz, 2 H), 8.89 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 17.9, 120.6, 123.0, 123.7,
126.3, 127.5, 128.6, 129.3, 130.4, 132.8, 137.8, 166.6, 172.9.
HRMS (EI): m/z [M]+ calcd for C15H13N3O: 251.2832; found:
251.2839.
N-(4-Fluorophenyl)-5-methyl-1,2,4-oxadiazol-3-amine (5i)
Cream solid; yield: 400 mg (82%); mp 126–129 °C.
IR (KBr): 3304, 3074, 1690, 1509, 1342, 1206, 1042, 835, 738, 688
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.49 (s, 3 H), 7.12–7.14 (d,
J = 8.8 Hz, 2 H), 7.43–7.45 (d, J = 8.8 Hz, 2 H), 9.76 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 11.8, 115.5, 118.3, 136.5,
157.9, 165.0, 174.8.
HRMS (EI): m/z [M]+ calcd for C9H8FN3O: 193.1777; found:
193.1788.
N-(4-Methoxyphenyl)-5-(4-tolyl)-1,2,4-oxadiazol-3-amine (5o)
Cream solid; yield: 890 mg (75%); mp 125–129 °C.
IR (KBr): 3273, 3136, 2932, 2833, 1576, 1500, 1334, 1235, 1182,
1121, 833, 756, 655 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.40 (s, 3 H), 3.71 (s, 3 H),
6.90–6.92 (d, J = 8.0 Hz, 2 H), 7.40–7.44 (m, 4 H), 7.93–7.95 (d,
J = 8.0 Hz, 2 H), 9.74 (s, 1 H).
N5,N5-Dimethyl-N3-phenyl-1,2,4-oxadiazole-3,5-diamine (5j)
Off white solid; yield: 470 mg (80%); mp 170–174 °C.
IR (KBr): 3252, 3099, 2935, 1665, 1558, 1343, 1248, 922, 751, 694
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.04 (s, 6 H), 6.84–6.87 (m, 1
H), 7.22–7.23 (m, 2 H), 7.37–7.38 (d, J = 7.6 Hz, 2 H), 9.40 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 21.1, 55.1, 114.1, 118.3,
120.9, 127.4, 129.9, 133.3, 143.2, 153.8, 165.5, 172.5.
13C NMR (400 MHz, DMSO-d6): δ = 37.3, 116.7, 120.2, 128.6,
HRMS (EI): m/z [M]+ calcd for C16H15N3O2: 281.3092; found:
140.4, 165.4, 168.9.
281.3100.
HRMS (EI): m/z [M]+ calcd for C10H12N4O: 204.2285; found:
204.2292.
N,5-Di(4-tolyl)-1,2,4-oxadiazol-3-amine (5p)
Cream solid; yield: 900 mg (76%); mp 166–168 °C.
N3-(4-Chlorophenyl)-N5,N5-dimethyl-1,2,4-oxadiazole-3,5-di-
amine (5k)
IR (KBr): 3285, 3085, 2909, 1585, 1515, 1346, 1238, 1031, 826,
758, 462 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.23 (s, 3 H), 2.40 (s, 3 H),
7.11–7.13 (d, J = 8.0 Hz, 2 H), 7.38–7.40 (d, J = 8.0 Hz, 2 H), 7.42–
7.44 (d, J = 8.0 Hz, 2 H), 7.91–7.93 (d, J = 8.0 Hz, 2 H), 9.85 (s, 1
H).
Off white solid; yield: 520 mg (86%); mp 180–184 °C.
IR (KBr): 3280, 3118, 2931, 1663, 1410, 1329, 1236, 922, 755, 671
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.04 (s, 6 H), 7.28–7.30 (d,
J = 8.8 Hz, 2 H), 7.38–7.40 (d, J = 8.8 Hz, 2 H), 9.59 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 20.2, 21.1, 117.0, 120.9,
13C NMR (400 MHz, DMSO-d6): δ = 37.3, 118.2, 123.9, 128.5,
149.4, 165.2, 168.9.
127.4, 129.2, 129.7, 129.9, 137.5, 143.3, 165.5, 172.5.
HRMS (EI): m/z [M]+ calcd for C16H15N3O: 265.3098; found:
HRMS (EI): m/z [M]+ calcd for C10H11ClN4O: 238.6735; found:
265.3104.
238.6739.
N-(4-Chlorophenyl)-5-(4-tolyl)-1,2,4-oxadiazol-3-amine (5q)
Cream solid; yield: 500 mg (87%); mp 192–194 °C.
N5,N5-Dimethyl-N3-(4-tolyl)-1,2,4-oxadiazole-3,5-diamine (5l)
Off white solid; yield: 480 mg (67%); mp 139–143 °C.
IR (KBr): 3409, 3045, 2909, 1591, 1545, 1410, 1333, 1182, 886,
818, 756, 500 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.41 (s, 3 H), 7.37–7.39 (d,
J = 8.8 Hz, 2 H), 7.43–7.45 (d, J = 8.0 Hz, 2 H), 7.50–7.52 (d,
J = 8.8 Hz, 2 H), 7.94–7.96 (d, J = 8.0 Hz, 2 H), 10.17 (s, 1 H).
IR (KBr): 3281, 3123, 2926, 1663, 1418, 1338, 1241, 923, 756, 648
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.20 (s, 3 H), 3.03 (s, 6 H),
7.03–7.05 (d, J = 8.4 Hz, 2 H), 7.25–7.27 (d, J = 8.4 Hz, 2 H), 9.26
(s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 21.1, 118.5, 120.7, 124.6,
13C NMR (400 MHz, DMSO-d6): δ = 20.1, 37.3, 116.7, 128.9,
129.0, 138.0, 165.4, 168.8.
127.5, 128.7, 129.9, 138.9, 143.5, 165.3, 172.8.
HRMS (EI): m/z [M]+ calcd for C15H12ClN3O: 285.7283; found:
HRMS (EI): m/z [M]+ calcd for C11H14N4O: 218.2551; found:
285.7289.
218.2559.
5-(2-Tolyl)-N-(4-tolyl)-1,2,4-oxadiazol-3-amine (5r)
Cream solid; yield: 600 mg (78%); mp 165–167 °C.
N-(3-Methoxyphenyl)-5-phenyl-1,2,4-oxadiazol-3-amine (5m)
Light yellow crystals; yield: 600 mg (64%); mp 101–104 °C.
IR (KBr): 3285, 3115, 2915, 2861, 1600, 1562, 1538, 1454, 1408,
1323, 1169, 908, 823, 761, 439 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.22 (s, 3 H), 2.65 (s, 3 H),
7.12–7.14 (d, J = 8.0 Hz, 2 H), 7.41–7.43 (m, 4 H), 7.53–7.57 (m, 1
H), 9.84 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 20.2, 21.2, 117.0, 122.9,
126.4, 129.2, 129.5, 129.7, 131.8, 132.2, 137.5, 138.2, 165.3, 173.1.
IR (KBr): 3437, 2937, 1580, 1500, 1450, 1347, 1167, 1042, 740,
691, 475 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 6.53–6.55 (m, 1
H), 7.06–7.10 (m, 1 H), 7.12 (s, 1 H), 7.20–7.24 (m, 1 H), 7.61–7.65
(m, 2 H), 7.69–7.72 (m, 1 H), 8.06–8.08 (d, J = 7.2 Hz, 2 H), 10.02
(s, 1 H).
Synthesis 2012, 44, 3378–3386
© Georg Thieme Verlag Stuttgart · New York

PAPER
MCR Synthesis of 1,2,4-Oxadiazol-3-amines
3385
HRMS (EI): m/z [M]+ calcd for C16H15N3O: 265.3098; found:
265.3099.
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Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven, R. F. V., Eds.;
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4, 243–309; and references cited therein.
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Mahdavi, M.; Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47,
2965. (b) Adib, M.; Mahdavi, M.; Mahmoodi, N.; Pirelahi,
H.; Bijanzadeh, H. R. Synlett 2006, 1765. (c) Kumita, I.;
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N-Phenyl-5-(4-tolyl)-1,2,4-oxadiazol-3-amine (5s)
Cream solid; yield: 560 mg (72%); mp 151–153 °C.
IR (KBr): 3405, 3054, 2915, 1585, 1500, 1423, 1330, 1230, 1192,
1115, 754, 692, 523, 462 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.40 (s, 3 H), 6.93–6.96 (m, 1
H), 7.30–7.34 (m, 2 H), 7.43–7.43 (d, J = 8.0 Hz, 2 H), 7.49–7.51
(d, J = 8.0 Hz, 2 H), 7.94–7.96 (d, J = 8.0 Hz, 2 H), 9.97 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 21.1, 117.0, 120.8, 120.9,
127.5, 128.8, 129.9, 140.0, 143.3, 165.5, 172.6.
HRMS (EI): m/z [M]+ calcd for C15H13N3O: 251.2832; found:
251.2840.
N-Phenyl-5-(2-tolyl)-1,2,4-oxadiazol-3-amine (5t)
Light cream solid; yield: 520 mg (67%); mp 118–120 °C.
(13) Adib, M.; Bagherzadeh, S.; Mahdavi, M.; Bijanzadeh, H. R.
Mendeleev Commun. 2010, 20, 50.
IR (KBr): 3330, 3138, 3077, 2931, 1630, 1600, 1446, 1338, 1100,
1038, 908, 754, 692, 615, 523, 454 cm–1.
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2733.
1H NMR (400 MHz, DMSO-d6): δ = 2.65 (s, 3 H), 6.93–6.97 (m, 1
H), 7.30–7.34 (m, 2 H), 7.40–7.46 (m, 2 H), 7.52–7.57 (m, 3 H),
7.99–8.01 (d, J = 7.6 Hz, 1 H), 9.97 (s, 1 H).
13C NMR (400 MHz, DMSO-d6): δ = 21.2, 117.0, 120.9, 122.9,
126.4, 128.8, 129.5, 131.8, 132.2, 138.2, 140.0, 165.2, 173.2.
HRMS (EI): m/z [M]+ calcd for C15H13N3O: 251.2832; found:
251.2848.
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Acknowledgment
We gratefully acknowledge the financial support for this work from
B. V. Patel PERD centre. We thank Dr. Manish Nivsarkar and Prof.
C. J. Shishoo, Directors B. V. Patel PERD centre for their constant
encouragement and support. Dr. Hitesh B. Jalani thanks PERD Cen-
tre for doctoral fellowship, Dr. E. Suresh of CSMCRI Bhavnagar
for single crystal X-ray analysis and Industries Commissioner (IC)
Gujarat for financial assistance to carry out the research work.
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(26) Compound 5l: Chemical formula C11H14N4O, gray crystal.
The crystal is of monoclinic shape and the symmetry group
present is C2/c. Crystallographic data for compound 5l have
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© Georg Thieme Verlag Stuttgart · New York
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© Georg Thieme Verlag Stuttgart · New York