Facile synthesis of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles from acylthiourea

Article abstract of DOI:10.1016/j.tetlet.2011.09.048

Facile and selective synthesis of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles starting from N-acylthioureas has been demonstrated. The regio-selectivity is achieved by simply selecting an appropriate base used for the generation of hydroxyl amine fro

Full text of DOI:10.1016/j.tetlet.2011.09.048

Tetrahedron Letters 52 (2011) 6170–6173
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles
from acylthiourea
⇑
Gundala Chennakrishnareddy, Hazra Debasis, Rapai Jayan, Sulur G. Manjunatha
Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Off Bellary Road, Hebbal, Bangalore 560 024, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2011
Revised 7 September 2011
Accepted 10 September 2011
Available online 16 September 2011
Facile and selective synthesis of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles starting from N-acy-
lthioureas has been demonstrated. The regio-selectivity is achieved by simply selecting an appropriate
base used for the generation of hydroxyl amine from the corresponding hydrochloride salt. This method
also avoids the use of toxic cyanogen bromide. The structure of the synthesized oxadiazoles has been
resolved by tandem mass spectral studies.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,2,4-Oxadiazoles
Acylisothiocyanate
Acylthiourea
Hydroxylamine hydrochloride
Oxadiazoles, show wide range of application as drugs in phar-
maceuticals.1,2 Conventionally, 3,5-disubstituted 1,2,4-oxadiazoles
are synthesized by coupling of amidoximes with activated car-
bonyl compounds, yielding O-acyl amidoximes followed by dehyd-
rative cyclization carried out under harsh conditions (Scheme 1).3
Alternatively, these are synthesized by the reaction of acylami-
dines with hydroxylamine4 as shown in Scheme 1.
Though there are many literature reports for the preparation of
3,5-aryl/alkyl 1,2,4-oxadiazoles,5 relatively less is known on 3-aryl/
alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles synthesis,6 which are
also pharmaceutically important molecules.7 The most common
methods for the preparation of the latter not only involve the use
of toxic and corrosive cyanogen bromide but are also inefficient,
poor yields being generally obtained (Scheme 2).8 In this Letter,
we report a cyanogen bromide-free, simple and selective method
for the synthesis of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiaz-
oles from N-acyl thiourea derivatives.
At the beginning of our study, commercially available benzoy-
lisothiocyanate 1a was coupled with piperidine 2a in CHCl3 at
room temperature for 1 h to yield the N-benzoyl-N0,N0-piperidine
thiourea 3a (Scheme 3).9 Addition of hexane to the reaction mix-
ture gave 3a as a solid and was separated by simple filtration in
89% yield. 4a was S-methylated using methyl iodide and potassium
carbonate (K2CO3) at room temperature (25 °C) in THF to get the
corresponding S-methylated acylthiourea 4a in 85% yield.10
In an attempt to synthesize hydroxy guanidine 5a, S-methyl-
ated acylthiourea 4a was treated with a solution of hydroxylamine
prepared by neutralizing hydroxylamine hydrochloride with meth-
anolic potassium hydroxide.11 Surprisingly, the reaction yielded
two compounds in 80% overall yield, which were separated in
equal amounts (ꢀ1:1) by column chromatography.
While the molecular mass of the two isolated compounds were
the same, the mass spectra of neither of the compounds matched
with that of the expected 5a. In fact, the mass spectra of the iso-
lated compounds were matching with that of the cyclized product,
that is, 1,2,4-oxadiazole 7a. The NMR spectra of the two com-
pounds also showed no significant difference indicating that the
compounds are structurally similar. Based on these results, struc-
tures of 7a and 8a were proposed for the two compounds, respec-
tively. This was later confirmed by tandem mass spectral analysis
(Fig. 1).12 The reaction protocol was repeated with the morpholine
analog 4b under similar reaction conditions resulting in the oxadi-
azoles 7b and 8b, respectively, in equal amounts.
The formation of both 7a and 8a is possible only if hydroxyl-
amine is reacting with 4a at both N and O ends. This would be pos-
sible when a strong base such as methanolic KOH is used for the
generation of free base from hydroxylamine hydrochloride as this
could possibly generate NH2Oꢁ (aminoxide anion) along with
hydroxylamine. Hydroxylamine could react at the nitrogen end
to give 7a while aminoxide ion could react at the oxygen end to
give 8a (Scheme 3).
Having this in mind we thought of using a milder base, such as
sodium acetate for generating hydroxylamine free base from
NH2OHꢂHCl. This approach would avoid the formation of the inter-
mediate 6a that would lead to 8a. Indeed, the reaction of 4a with
NH2OHꢂHCl in the presence of NaOAc, provided the desired oxadiaz-
ole 7a in 80% yield with no unwanted regioisomer 8a. Encouraged
⇑
Corresponding author. Tel.: +91 80 66213000; fax: +91 80 23622011.
E-mail address: manjunath.sulur@astrazeneca.com (S.G. Manjunatha).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.048

CHCl3, rt, 1 h
89%
MeI, K2
CO3
G. Chennakrishnareddy et al. / Tetrahedron Letters 52 (2011) 6170–6173
6171
O
NH2
1
N
O
X
R
R
NH2OH
O
1
R
N
R
N
CR N(CH )
3 2
N
cyclization
cyclization
OH
amidoximes
1
R
acylamidines
Scheme 1. Preparation of 3,5-disubstituted 1,2,4-oxadiazoles.
O
N
O
R2
R2
R1
R2
R1
R2
R1
N
OH
CNBr
NH2OH
X
R
NH
N
CN
N
N
R
N
R1
cyclization
NH2
Scheme 2. Conventional method for the preparation of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles.
C H3
N
O
S
O
S
O
N
N
N
H
N
HN
O
C
S
THF, 0 °C - rt, 2 h, 85%
2a
4a
1a
3a
NH2
N
OH
H2NOH. HCl
MeOH, base
O
HN
O
O
N
N
O
N
N
N
N
N
N
N
0 °C - rt, 1 h, 80%
7a
8a
6a
5a
base = KOH, 7a:8a ~1:1
base = NaOAc, 7a
Scheme 3. Synthesis of 5-phenyl-3-(1-piperidyl)-1,2,4-oxadiazole.
by the above results, the reactions were repeated with different acy-
lisothiocyanates and primary or secondary amines to prepare a ser-
ies of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles 7a–h (Table
1). Some of the acylisothiocyanates 1, which were not commercially
available, were generated in situ by the reaction of ammoniumthi-
ocyanate with the corresponding acyl chlorides 9. The reaction of
acylisothiocyanates with different amines using reported protocol9
provides the corresponding acylthioureas 3 in 80–90% yield. In a
subsequent step, the produced acylthiourea 3 was treated with
methyl iodide to provide the corresponding S-methylated deriva-
tives 4 in 80–85% yield (Scheme 4).13 The S-methylated derivatives
were found to be stable for couple of weeks at ambient temperature.
O
N
N O
R2
R2
R
R
N
N
N
N
R1
R1
7
8
O+
O+
R2
N
R
R1
Figure 1. Proposed LC–MSMS fragmentation pathway of isomers 7 and 8.
Table 1
Synthesis of different oxadiazoles 7 from the corresponding S-methylated acylthioureas 4
H2NOH. HCl
S
O
O
N
NaOAc, MeOH
1
1
R
R
R
N
R
N
0 °C - rt, 1-2 h
7
4
Entry
R
R1
Oxadiazole (7)
Yield of 7 from 4 (%)
O
N
N
N
N
a
80
N
N
N
O
b
O
80
N
O
(continued on next page)

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G. Chennakrishnareddy et al. / Tetrahedron Letters 52 (2011) 6170–6173
Table 1 (continued)
Entry
R
R1
Oxadiazole (7)
O
Yield of 7 from 4 (%)
N
N
c
d
e
f
76
N
N
O
N
N
N
N
Br
77
78
75
72
79
O
N
N
O
Br
O
N
NAc
N
N
NAc
O
N
O
N
N
NBoc
NBoc
N
N
NBoc
N
g
h
N
NBoc
O
N
N
N
N
H
H
References and notes
amine (R1-H)
NH SCN
4
O
O
1. Clapp, L. B. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: New York, 1976; Vol. 20, pp 65–116.
2
S
C
2. (a) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.; MacLeod, A.; Knight, A.;
Merchant, K.; Moseley, J.; Saunders, J.; Swain, C. J.; Wong, E.; Springer, J. P. J.
Med. Chem. 1989, 32, 2282; (b) Srivastava, R. M.; Lima, A. D. A.; Viana, O. S.;
Silva, M. J. D. C.; Catanho, M. T. J. A.; de Morais, J. O. F. Bioorg. Med. Chem. 2003,
11, 1821; (c) Messer, W. S., Jr.; Abuh, Y. F.; Liu, Y.; Periyasamy, S.; Ngur, D. O.;
Edgar, M. A. N.; El-Assadi, A. A.; Sbeih, S.; Dunbar, P. G.; Roknich, S.; Rho, T.;
Fang, Z.; Ojo, B.; Zhang, H.; Huzl, J. J., III; Nagy, P. I. J. Med. Chem. 1997, 40, 1230.
3. Augustine, J. K.; Akabote, V.; Hegde, S. G.; Alagarsamy, P. J. Org. Chem. 2009, 74,
5640.
4. Lin, Y. I.; Lang, S. A., Jr.; Lovell, M. F.; Perkinson, N. A. J. Org. Chem. 1979, 44,
4160.
5. (a) Kayukova, L. A. Pharm. Chem. J. 2005, 39, 539; (b) Crestey, F.; Lebargy, C.;
Lasne, M.-C.; Perrio, C. Synthesis 2007, 3406; (c) Wang, Y.; Miller, R. L.; Sauer, D.
R.; Djuric, S. W. Org. Lett. 2005, 7, 925; (d) Ronsisvalle, G.; Guerrera, F.; Siracusa,
M. A. Tetrahedron 1981, 37, 1415.
R
Cl
R
N
THF, rt, 1 h
THF, 0 °C, 30 min
1
9
O
S
S
O
MeI, K2CO3
THF, 0 °C - rt, 2-3 h
1
1
R
N
R
R
N
R
H
4
3
Scheme 4. Synthesis of S-methylated acylthioureas 4 starting from corresponding
acyl chlorides 9.
6. (a) Whitfield, L. L., Jr.; Papadopoulos, E. P. J. Heterocycl. Chem. 1981, 18, 1197;
(b) Makara, G. M.; Schell, P.; Hanson, K.; Moccia, D. Tetrahedron Lett. 2002, 43,
5043; (c) Kurz, T.; Lolak, N.; Geffken, D. Tetrahedron Lett. 2007, 48, 2733; (d)
Buscemi, S.; Vivona, N.; Caronna, T. Synthesis 1995, 917; (e) Suyama, T.; Suzuki,
N.; Nishimura, M.; Saitoh, Y.; Ohkoshi, H.; Yamaguchi, J.-I. Bull. Chem. Soc. Jpn.
2005, 78, 873; (f) Wheeler, H. L.; Merriam, H. F. J. Am. Chem. Soc. 1901, 23, 283.
7. (a) Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley, E. A.; Iversen, L. L.; Kneen,
C.; MacLeod, A. M.; Merchant, K. J.; Snow, R. J.; Baker, R. J. Med. Chem. 1990, 33,
1128; (b) Saunders, J.; MacLeod, A. M.; Merchant, K.; Showell, G. A.; Snow, R. J.;
Street, L. J.; Baker, R. J. Chem. Soc. Chem. Commun. 1988, 1618.
8. (a) Alper, P.; Azimioara, M.; Cow, C.; Epple, R.; Jiang, S.; Lelais, G.; Michellys, P. -
Y.; Mutnick, D.; Nikulin, V.; Westcott-Baker, L. WO-2009038974; 2009.; (b)
Alan, M. B.; Roger, J. B.; David, S. C.; Andrew, L.; Philip, A. M.; Charles, J. O. D.;
James, S. S.; Paul, R. O. W.; Dan, A. B.; Ojvind, P. D.; Kjell, E. J.; Hanna, D. L. M. US
20110065706A1; 2011 references cited there in.
Finally, intermediates 4, upon treatment with NH2OHꢂHCl in the
presence of NaOAc provided 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-
oxadiazole 7a–h in 70–80% yield (Table 1).13
Based on these results, we believe that 7 or 8 can be synthesized
selectively just by modifying the strength of the base. Work is un-
der progress for the selective synthesis of 8 using this protocol.
We have demonstrated a facile and selective synthesis of 3-aryl/
alkylamino 5-aryl/alkyl 1,2,4-oxadiazoles 7 starting from the cor-
responding acyl chlorides in good yields. The reactions proceed
via in situ generated hydroxy guanidines 5. The protocol avoids
the use of toxic cyanogen bromide. The structures of the regioi-
somers have been confirmed by tandem mass spectral studies.
9. Bai, L.; Li, S.; Wang, J.-X.; Chen, M. Synth. Commun. 2002, 32, 127.
10. Sambrook, M. R.; Beer, P. D.; Wisner, J. A.; Paul, R. L.; Cowley, A. R.; Szemes, F.;
Drew, M. G. B. J. Am. Chem. Soc. 2005, 127, 2292.
11. Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285.
12. Detection of the mixture of isomers were performed on an Agilent HPLC
coupled through an Electrospray interphased to an Agilent 6520 Accurate-
Mass Q-TOF LC/MS. Accurate mass TOF-LC mass detected two isomers 7a and
8a with M+H ions as 230.1288, 230.1289, respectively, and molecular formula
generated as C13H15N3O with mass error less than 2.0 ppm for both. However,
accurate mass Q-TOF LC–MS/MS shows fragmentation having unique product
ion pattern via 230.1289, 105.0339 for 7a and 230.1288, 112.0760 for 8a.
Corresponding molecular formula generated for the product ions were formyl
carbocation, C7H5O and N-formyl carbocation, C6H10NO, respectively, with a
mass error less than 5.0 ppm.
Acknowledgments
We thank Bill Moss, R. Sridharan, Vinod Kumar, Santhosh Unni,
Anthony Bristow, and Sudhir Nambiar for useful discussion and
manuscript preparation. This Letter refers to ATP No. 11/0733 from
AstraZeneca.
Supplementary data
13. General procedure for the preparation of acylthioureas 3a–h: Ammoniumthiocya
nate (11 mmol) was added to a solution of acyl chlorides 9 (10 mmol) in THF
(10 mL) at 0 °C and stirred for 30 min. Substituted amine 2 (11 mmol) was
added to the above reaction mixture and was stirred at rt for about an hour
until completion (monitored by TLC). The solvent was removed in vacuo and
Supplementary data associated (mass, 1H and 13C spectra for 7a,
7b, 8a, and 8b) with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2011.09.048.

G. Chennakrishnareddy et al. / Tetrahedron Letters 52 (2011) 6170–6173
6173
the remaining mass was dissolved in ethylacetate. The organic layer was
washed with 10% NaHCO3 solution, 10% HCl, brine, and dried over anhydrous
Na2SO4. The solvents were removed under reduced pressure to afford the
products as solids in 80–90% yield.
Procedure for the preparation of S-methylated acylthioureas 4a–h: To a stirring
solution of acylthioureas 3 (10 mmol) in THF (10 mL), MeI (30 mmol) was
added followed by K2CO3 (11 mmol) at 0 °C. The resulting reaction mixture
was stirred at room temperature for 2–3 h. After completion of the reaction
(monitored by TLC), THF was evaporated and the residue was diluted with
ethylacetate. The organic layer was washed with water and brine and dried
over anhydrous Na2SO4. The organic layer was concentrated and yielded the
crude compounds in 80–85% yield, which were taken for further reaction
without any purification.
General procedure for the preparation of 3-aryl/alkylamino 5-aryl/alkyl 1,2,4-
oxadiazoles (7a–h): NaOAc (30 mmol) was added to NH2OHꢂHCl (30 mmol) in
MeOH (10 mL) and stirred at 0 °C. After 20 min, S-methylated acylthioureas 4
(10 mmol) in MeOH (10 mL) was added to the above reaction mixture and was
stirred for 1–2 h. After completion of the reaction (monitored by TLC), solvent
was removed in vacuo and the reaction mass was dissolved in ethylacetate.
The organic layer was washed with water, brine, and dried over anhydrous
Na2SO4. Thereafter, the organic layer was concentrated and the resulting
126.1, 126.9, 127.5, 129.5, 167.5, 170.0; LC–MS m/z calcd for C13H16N3O 230.1
(M+H+), found 230.1 (M+H+).
3-Phenyl-5-(1-piperidyl)-1,2,4-oxadiazole 8a: 1H NMR (400 MHz, CDCl3):
d
1.62–1.70 (m, 6H), 3.65–3.67 (m, 4H), 7.43–7.49 (m, 3H), 7.99–8.02 (m, 2H);
13C NMR (100 MHz, CDCl3): d 23.2, 24.0, 46.0, 123.8, 126.8, 127.8, 131.2, 169.8,
173.1; LC–MS m/z calcd for C13H16N3O 230.1 (M+H+), found 230.1 (M+H+).
4-(5-Phenyl-1,2,4-oxadiazol-3-yl)morpholine 7b: 1H NMR (400 MHz, CDCl3): d
3.35–3.37 (m, 4H), 3.72–3.75 (m, 4H), 7.39–7.48 (m, 3H), 7.97–7.99 (m, 2H);
13C NMR (100 MHz, CDCl3): d 46.3, 66.2, 124.6, 127.9, 128.9, 132.5, 170.7,
174.5; LC–MS m/z calcd for C12H14N3O2 232.1 (M+H+), found 232.1 (M+H+).
4-(3-Phenyl-1,2,4-oxadiazol-5-yl)morpholine 8b: 1H NMR (400 MHz, CDCl3): d
3.61–3.3.62 (m, 4H), 3.74–3.76 (m, 4H), 7.36–7.38 (m, 3H), 7.92 (m, 2H), ; 13C
NMR (100 MHz, CDCl3): d 45.9, 66.1, 127.2, 127.6, 128.6, 130.8, 165.5, 170.0;
LC–MS m/z calcd for C12H14N3O2 232.1 (M+H+), found 231.9 (M+H+).
5-Ethyl-3-(1-piperidyl)-1,2,4-oxadiazole 7c: 1H NMR (400 MHz, CDCl3): d 1.24–
1.28 (t, J = 7.52 Hz, 3H), 1.55 (br , 6H), 2.65–2.72 (q, J = 7.52 Hz, 2H), 3.32 (br,
4H); 13C NMR (100 MHz, CDCl3): d 10.7, 20.5, 24.2, 24.9, 46.9, 170.4, 179.4; LC–
MS m/z calcd for C9H16N3O 182.1 (M+H+), found 182.1 (M+H+).
4-[5-(4-Bromophenyl)-1,2,4-oxadiazol-3-yl]morpholine 7d: 1H NMR (400 MHz,
CDCl3): d 3.42 (m, 4H), 3.74 (m, 4H), 7.56–7.58 (m, 2H), 7.85 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 46.3, 66.2, 123.5, 127.4, 429.3, 132.3, 170.7, 173.7; LC–MS
m/z calcd for C12H13BrN3O2 311.1 (M+H+), found 311.1 (M+H+).
compound
7
was isolated, which was purified by flash column
chromatography (20% of EtOAc and hexane) to yield the title compounds in
70–80% yield.
Spectral data for selected compounds: 5-phenyl-3-(1-piperidyl)-1,2,4-oxadiazole
7a: 1H NMR (400 MHz, CDCl3): d 1.60–1.67 (m, 6H), 3.50–3.51 (m, 4H), 7.48–
7.57 (m, 3H), 8.07–8.09 (m, 2H); 13C NMR (100 MHz, CDCl3): d 22.6, 24.1, 45.9,
tert-Butyl 4-(5-isopropyl-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate 7f: 1H
NMR (400 MHz, CDCl3): d 1.27 (d, J = 7.2 Hz, 6H), 1.46 (s, 9H), 3.0 (m, 1H),
3.34 (t, 4H), 3.43 (t, 4H), 13C NMR (100 MHz, CDCl3): d 20.0, 27.7, 28.4, 44.4,
45.9, 80.1, 154.9, 170.1, 183.1; LC–MS m/z calcd for C14H25N4O3 297.2 (M+H+),
found 297.2 (M+H+).