Cyclization of protected N-acylhydroxyguanidine to 3-amino-1,2,4-oxadiazole

Article abstract of DOI:10.1016/j.tetlet.2011.08.074

The acid mediated cyclization of a protected N-acylhydroxyguanidine into the corresponding 3-amino-1,2,4-oxadiazole and confirmation of its structure by single crystal X-ray crystallography is reported herein. The yield of the cyclization is comparable to

Full text of DOI:10.1016/j.tetlet.2011.08.074

Tetrahedron Letters 52 (2011) 5750–5751
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Cyclization of protected N-acylhydroxyguanidine to 3-amino-1,2,4-oxadiazole
Jamie B. Côté a, , Andrew Roughton a, Joanna Nasielski a, Jeff Wilson a, Ji Chang You b, Judd M. Berman a,
⇑
a Dalton Medicinal Chemistry Inc., 349 Wildcat Road, Toronto, Ontario, Canada M3J 2S3
b National Research Laboratory of Molecular Virology, Department of Pathology, College of Medicine, The Catholic University of Korea and Avixgen Inc.,
Seocho-gu Banpo-dong 505, Seoul 137-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The acid mediated cyclization of a protected N-acylhydroxyguanidine into the corresponding 3-amino-
1,2,4-oxadiazole and confirmation of its structure by single crystal X-ray crystallography is reported
herein. The yield of the cyclization is comparable to literature reports utilizing alternative procedures.
Importantly, these new conditions provide complementary chemoselectivity to current synthetic proce-
dures which may be useful for the synthesis of 3-amino-1,2,4-oxadiazoles in general.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 August 2011
Revised 12 August 2011
Accepted 13 August 2011
Available online 26 August 2011
Keywords:
N-Acylhydroxyguanidine
3-Amino-1,2,4-oxadiazole
Acylthiourea
Cyclization
Heterocycle
Substituted 1,2,4-oxadiazole heterocycles (generic structure
with IUPAC numbering shown in Fig. 1) are of interest to medicinal
and organic chemists as they are present in a number of biologi-
cally active compounds.1,2
triethylamine to afford 3 in excellent yield.7 Treatment of 3 with acid
did not provide the N-hydroxyguanidine as expected.7 The only
isolated product from this reaction was determined by single crystal
X-ray analysis to be 3-amino-1,2,4-oxadiazole 4 (Fig. 2).8 The mech-
anism of this cyclization reaction can be rationalized as depicted in
Scheme 2. Following literature precedent for acid-mediated cleav-
age of tetrahydropyranyloxy ether-protected guanidines7, we trea-
ted intermediate 3 with trifluoroacetic acid. Protonation of the
tetrahydro-2H-pyran-2-yl (THP) hydroxyl group and tautomeriza-
tion of the guanidine moiety could lead to 5, with subsequent cleav-
age of the THP group and protonation of the carbonyl oxygen atom
leading to 6. Nucleophilic addition of the N-hydroxyguanidine
hydroxyl group of 6 onto the benzoyl moiety (leading to 7), with
subsequent elimination of H2O and deprotonation, could lead to
3-amino-1,2,4-oxadiazole 4.
For example, a 3-amino-1,2,4-oxadiazole ring was recently
identified for the first time in a natural product, phidianidine A
(Fig. 1), isolated from a marine organism.1 Further, 1,2,4-oxadiaz-
oles are used in medicinal chemistry programs as prodrugs and
bioiososteres of amides or esters.2–4 Tropane derivative RTI-126
is reported to have five times greater biological activity than that
of cocaine.2 The synthesis and biological activity of 1,2,4-oxadiaz-
ole compounds have been recently reviewed.4 There are numerous
syntheses of 3-amino-1,2,4-diazoles reported in the literature but
none of the reported methods are truly general.4,5 The syntheses
typically utilize high temperatures (ꢀ10 h at reflux) in acid or base
to cyclize hydroxylamine with an acylthiourea. Here we report a
room temperature, acid-catalyzed cyclization reaction to yield 3-
amino-1,2,4-oxadiazoles. The low temperature utilized may allow
for the synthesis of novel 3-amino-1,2,4-diazoles that are other-
wise not accessible using hitherto reported methods.
The synthesis of 3-amino-1,2,4-oxadiazoles that we have devel-
oped proceeds in three steps with an overall yield of 30% (unoptim-
ized), compared favorably with the reported values from alternate
4
N
R1
5
R2
Our synthesis commenced with the commercially available acid
chloride 1 (Scheme 1). The acylthioisocyanate of 1 was prepared
in situ using a literature procedure6 and converted to acylthiourea
2 by reaction with 1-naphthylamine. Intermediate 2 was treated
with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, EDCI, and
3
1O
N
2
N
H
N
H
N
O
NH2
NH
N
N
N
N
O
Br
N
H
⇑
Corresponding author. Tel.: +1 416 661 2102; fax: +1 416 616 2108.
phidianidine A
RTI-126
E-mail address: jberman@dalton.com (J.M. Berman).
Present address: The Hunter Group Ltd, 25 Allaura Boulevard, Aurora, Ontario,
Canada L4G 3N2.
Figure 1. Examples of a 1,2,4-oxadiazole-containing natural product (phidianidine
A) and biologically active compound (RTI-126).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.074

J. B. Côté et al. / Tetrahedron Letters 52 (2011) 5750–5751
5751
NH2
(1.1 eq)
O
S
COCl
KSCN (1.2 eq)
N
H
N
H
acetone, 56 °C, 2 h
6
1
2
NH2OTHP (1.8eq), EDC I(1.6 eq)
NEt3 (3.5 eq)
CH2Cl2, rt, 18 h
99%
OTHP
TFA:CH2Cl2:anisole
(1:1:0.25)
O
N
O
HN
N
N
H
N
N
rt, 2 h
H
47%
4
3
Scheme 1. Synthesis of 3-amino-1,2,4-oxadiazole 4 (THP = tetrahydro-2H-pyran-2-yl).
Acknowledgment
We thank Dr. Alan J. Lough, Director of X-ray Facility, Depart-
ment of Chemistry, University of Toronto, for obtaining the X-ray
crystal structure data and generating the ORTEP depiction of com-
pound 4.
References and notes
1. Carbone, M.; Li, Y.; Irace, C.; Mollo, E.; Castelluccio, F.; Di Pascale, A.; Cimino, G.;
Santamaria, R.; Guo, Y.-W.; Gavagnin, M. Org. Lett. 2011, 13, 2516–2519.
2. Caroll, F. I.; Abraham, P.; Kuzemko, M. A.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J.
Med. Chem. 1993, 36, 2886–2890.
3. Bock, M. G.; Smith, R. L.; Blaine, E. H.; Cragoe, E. J., Jr. J. Med. Chem. 1986, 29,
1540–1544.
4. Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337–4348.
5. (a) Anikova, S. V.; Boboshko, L. G.; Mikhailov, V. O.; Zubritskii, M. Y.; Kovalenko,
V. V.; Palamrchuk, G. V.; Zubatyuk, R. I.; Shishkin, O. V. Zhurnal Organichoi to
Farmatsevtichnoi Khimii 2010, 8, 71–78; (b) Boboshko, L. G.; Zubritskii, M. Y.;
Kovalenko, V. V.; Mikhailov, V. A.; Popov, A. F.; Rybakov, V. B.; Savelova, V. A.;
Taran, N. A. Zhurnal Organichoi to Farmatsevtichnoi Khimii 2007, 5, 61–70; (c)
Ebenreth, A.; Pech, R.; Boehm, R. Pharmazie 1992, 47, 556–557; (d) Palumbo, P.
A.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron 2008, 64, 4004–4010;
(e) Goetz, N.; Zeeh, B. Synthesis 1976, 4, 268–270; (f) Adib, M.; Jahromi, A. H.;
Tavoosi, N.; Mahdavi, M.; Bijanzadeh, H. R. Tetrahedron Lett. 2006, 47, 2965–
2967.
Figure 2. ORTEP depiction of the structure of 3-amino-1,2,4-oxadiazole 4, as
determined by single crystal X-ray analysis (spheroids depict nitrogen (blue),
oxygen (red) or carbon (white); small circles depict hydrogen).
H
O
O
O
O
N
O
6. Lin, T.-C.; Lai, C.-C.; Chiu, S.-H. Org. Lett. 2009, 11, 613–616.
7. Martin, N. I.; Woodward, J. J.; Winter, M. B.; Beeson, W. T.; Marletta, M. A. J. Am
Chem. Soc. 2007, 129, 12563–12570.
HN
N
H
R1
N
O
O
R2
R2
R2
R1
N
R1
N
H
N
H
O
H
N
H
6
N
H
H
8. Synthesis of 5-(4-(tert-butyl)phenyl)-N-(naphthalen-1-yl)-1,2,4-oxadiazol-3-
amine (4): (Z)-4-(tert-butyl)-N-(N0-(naphthalen-1-yl)-N-((tetrahydro-2H-pyran-
2-yl)oxy)carbamimidoyl)benzamide (Intermediate 3; 0.44 g, 0.98 mmol) was
stirred at room temperature (rt) in a mixture of dichloromethane (5 mL) and
anisole (2.5 mL). Trifluoroacetic acid (5 mL) was added. The mixture was stirred
for ꢀ2 h at rt and was then stored for 16 h at ꢁ20 °C. The mixture was
concentrated by rotoevaporation and high vacuum to yield a crude brown oil
that was subjected to ISCO semi-automated Flash Chromatography on silica gel
(40 g), eluting with a gradient of 0?20% EtOAc in hexanes. The resulting white
solid (159 mg) was stirred in 3 mL of hot hexanes, with full solution provided by
the addition of minimal dichloromethane. The mixture was concentrated to ½
volume and allowed to stand at rt overnight. Crystals were collected by vacuum
filtration, washed with cold hexanes and dried, yielding 79 mg of white needles.
Compound 4: 1H NMR (400 MHz, CDCl3): d 8.13(d, 1H), 8.09 (d, 2H), 8.01 (d, 1H),
7.92 (d, 1H), 7.64–7.54 (m, 6H), 7.29 (s, 1H), 1.40 (s, 9H); chemical purity, 99%
(AUC at 254 nm); LCMS: m/z 343.9 (M+H+); mp: 118–119 °C; X-ray
crystallography: A clear needle-like crystal of 0.65 ꢂ 0.14 ꢂ 0.08 mm3 was used
for data collection. X-ray diffraction was measured using radiation with a
wavelength of 0.71073 Å at 150(1) K. The crystal showed a monoclinic crystal
system, space group P21/c. Crystal data are: Z = 4, a = 11.4037(3) Å,
b = 20.0328(12) Å, c = 7.9932(6) Å, b = 101.299(3)°, V = 1790.64(18) Å3, density
3
5
O N
N
O N
N
R2
H
R2
R1
N
O
N
H
H
H R1
H
4
H2O,
H+
7
Scheme 2. Proposed mechanism for acid catalyzed cyclization (R1 = 4-tert-butyl-
phenyl; R2 = 1-naphthyl).
methods. However, the lower reaction temperature identified here
is a clear advantage for this method over previously reported
methods and may prove useful for the synthesis of 3-amino-
1,2,4-oxadiazoles containing sensitive functional groups.
(calcd) = 1.274 mg/m3, absorption coefficient 0.080 mmꢁ1
.