Convenient preparation of unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles promoted by Dess-Martin reagent

Article abstract of DOI:10.1016/j.tetlet.2009.02.054

2,5-Disubstituted 1,3,4-oxadiazoles have been conveniently prepared by oxidative cyclization of N-acyl-N′-aryliden-hydrazines promoted by an excess of Dess-Martin periodinane under mild conditions (23 examples, up to 92% isolated yields).

Full text of DOI:10.1016/j.tetlet.2009.02.054

Tetrahedron Letters 50 (2009) 1886–1888
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Convenient preparation of unsymmetrical 2,5-disubstituted
1,3,4-oxadiazoles promoted by Dess–Martin reagent
*
Cristian Dobrota˘ , Codrußta C. Paraschivescu, Ioana Dumitru, Mihaela Matache, Ion Baciu, Lavinia L. Rußta˘
University of Bucharest, Department of Chemistry, Division of Organic Chemistry, Sßoseaua Panduri, No. 90–92, Sector 5, 050657 Bucharest, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
2,5-Disubstituted 1,3,4-oxadiazoles have been conveniently prepared by oxidative cyclization of N-acyl-
N0-aryliden-hydrazines promoted by an excess of Dess–Martin periodinane under mild conditions (23
examples, up to 92% isolated yields).
Received 12 December 2008
Revised 28 January 2009
Accepted 3 February 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3,4-Oxadiazoles
Oxidative cyclization
Dess–Martin periodinane
Heterocycles
Among five-membered aromatic heterocycles, 1,3,4-oxadiaz-
oles1 are of particular interest, since some of the members belong-
ing to this class display various biological activities: 5-HT-receptor
antagonists,2 muscarinic receptor agonists,3 benzodiazepine recep-
tor agonists,4 or tyrosinase inhibitors.5
Besides the dehydration of diacylhydrazines, oxidative cycliza-
tion of aldehyde N-acylhydrazones is the most known method to
prepare unsymmetrically 2,5-disubstituted 1,3,4-oxadiazoles
(Scheme 1), and several reagents have been reported to mediate
the named transformation: ceric ammonium nitrate,6 chloramine
T,7 tetravalent lead reagents,8 potassium permanganate under
microwaves conditions,9 ferric chloride,10 bromine/sodium ace-
tate,11 or yellow mercuric oxide/iodine.12
In recent years, hypervalent iodine-containing reagents have
been successfully utilized to prepare 1,3,4-oxadiazoles, namely
iodobenzene diacetate13 or bis(trifluoroacetoxy)-iodobenzene.14
Besides these trivalent iodine-based reagents, some pentavalent
iodine-containing compounds, (i.e., the 1,1,1-triacetoxy-1,1-dihy-
dro-1,2-benziodoxol-3(1H)-one 115—the Dess–Martin periodinane,
DMP, as well as its synthetic precursor 1-hydroxy-1,2-benziodox-
ol-3(1H)-one 1-oxide—IBX) have proven their usefulness as agents
for oxidative cyclizations. Lately, a growing number of reports have
revealed their ability to mediate the synthesis of heterocycles from
various intermediates based on single-electron transfer (SET) pro-
cesses.16–18 Therefore, we have decided to attempt the preparation
of 1,3,4-oxadiazoles in the presence of DMP via the oxidative cycli-
zation pathway.
To the best of our knowledge, preparation of 1,3,4-oxadiazoles
utilizing DMP as the reagent has not been reported yet. Herein
we report our first results regarding the preparation of unsymmet-
rically 2,5-disubstituted 1,3,4-oxadiazoles from aldehyde N-acyl-
hydrazones mediated by DMP. N0-benzylidene-N-benzhydrazide
2a was chosen as a model substrate, in order to test the effective-
ness of the process. We found that placing 2a in the presence of an
excess of 1 at room temperature resulted in the formation of the
desired 2,5-diphenyl-oxadiazole 3a with complete consumption
of the starting material in a few hours. The best solvent for the pro-
cess was proved to be dichloromethane, while the amount of the
oxidant required for a satisfactory yield of product was 2.5 equiv
with respect to the substrate (Table 1, entries 1–3).
Although the conversion of 1a was complete even when using
1.5 equiv of reagent (Table 1, entry 1), the yield of the isolated
product decreased, probably due to the slow degradation of the
substrate under the action of AcOH liberated from the oxidative
process. The reaction also takes place in other polar nonprotic sol-
vents, but more slowly and less efficiently (Table 1, entries 4 and
5).
Having these preliminary observations in hand, we have syn-
thesized a series of aldehyde N-acylhydrazones 2a–w in order to
test the scope of their oxidative cyclization. These substrates are
easily accessible in high yields and purity from aroylhydrazides
and aldehydes. Thus, we had subjected this series of acylhydra-
zones 2 to the optimized reaction conditions.
* Corresponding author at present address: Technische Universität München,
Lichtenbergstr. 4, 85747 Garching, Germany. Tel.: +49 089 289 13 206.
E-mail address: cristian.dobrota@ch.tum.de (C. Dobrota˘).
In all cases, the conversion of the substrates was complete with-
in 4 h in dichloromethane, while the use of DMF required over-
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.054

˘
1887
C. Dobrota et al. / Tetrahedron Letters 50 (2009) 1886–1888
O
O
H
N
N
N
R2
R2
oxidative cyclization
dehydrative cyclization
N
R1
R1
N
H
N
H
R2
R1
O
H
O
Scheme 1. The main synthetic pathways of access to 1,3,4-oxadiazoles.
night reactions. Chromatographic analysis of the crude mixture
indicated the presence of the desired 1,3,4-oxadiazole as the main
product, usually with excellent purity, easily separable from the
iodinated by-products formed during the reaction. The results ob-
tained are summarized in Table 2.
We have firstly studied variations of the nature of the aldehyde
moiety participating in the formation of oxadiazoles 3, preserving
the same aroyl part (i.e., benzoyl, Table 2, entries 1–10). Thus, we
have observed that the best results were obtained with hydrazones
derived from aromatic aldehydes possessing electron-donating
groups. The solvent of choice was dichloromethane. For the cases
where the substrate was poorly soluble in dichloromethane, DMF
was a suitable alternative, although the presence of an electron
withdrawing group on the aromatic ring decreased the yield (Table
2, entry 8). The benzoyl hydrazones bearing an aliphatic chain in
the aldehyde part gave very low yields (entries 9 and 10) probably
due to the decomposition of the substrate during the reaction.
Hydrazones derived from some heterocyclic aldehydes gave good
yields (Table 2, entries 5–7). However, the cyclization of furyl
derivative 2d led to the desired oxadiazole 3d in modest yield (Ta-
ble 2, entry 4).
Table 1
Screening of conditions for the oxidative cyclization of 2a to 2,5-diphenyl-1,3,4-
oxadiazole 3a in presence of 1
OAc
OAc
AcO
O
N
N
I
DMP (1)
Ph
N
Ph
N
H
O
Ph
Ph
O
r.t.
H
O
3 a
2 a
1
Subsequently, we have tested several N-aroyl-N0-aryliden-
hydrazines bearing substituted benzoyl as well as some heterocy-
clic aromatic groups (Table 2, entries 11–20). The yields obtained
were usually good to excellent, improvements being noticed in
the case of the furyl- or nitro derivatives.
Entry
Solvent
Equiv of 1
Reaction time
Yield (%)
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DMF
1.5
2
2.5
2
4
4
4
6
12
72
83
92
71
59
Very recently, we have reported the synthesis of a series of
2,5-disubstituted 1,3,4-oxadiazoles bearing the 3-chloro-ben-
2
Table 2
Oxidative cyclization of 2 to 2,5-disubstituted-1,3,4-oxadiazoles 3 in presence of DMP
OAc
AcO
O
OAc
N
N
I
DMP (1)
N
R2
R1
N
H
R2
O
R1
O
r.t.
H
O
2 a-w
3 a-w
1
Entry
R1
R2
Solvent
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3d
3p
3q
3r
92
87
73
42
82
83
85
53
28
17
87
76
56
69
55
81
88
51
79
74
72
80
65
48
81
4-MeO–C6H4–
4-Br–C6H4–
2-Furyl
2-Thienyl
4-Pyridyl
3-Thienyl
3-O2N–C6H4–
Pr
Ph
Ph
iPr
4-Cl–C6H4–
4-Cl–C6H4–
4-Cl–C6H4–
4-O2N–C6H4–
4-O2N–C6H4–
2-Furyl
2-Furyl
2-Furyl
4-Pyridyl
4-Pyridyl
3-Chloro-benzo[b]thien-2-yl
3-Chloro-benzo[b]thien-2-yl
3-Chloro-benzo[b]thien-2-yl
3-Chloro-benzo[b]thien-2-yl
3-Chloro-benzo[b]thien-2-yl
4-MeO–C6H4–
Ph
2-O2N–C6H4–
4-MeO–C6H4–
4-Br–C6H4–
Ph
DMF
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
4-MeO–C6H4–
3-MeO-4-BnO–C6H3–
4-MeO–C6H4–
Ph
3f
3s
3t
3u
3v
3w
Ph
4-MeO–C6H4–
3-MeO-4-BnO–C6H3–
2-O2N–C6H4–
3-Thienyl
CH2Cl2
a
General procedure: Substrate (0.5 mmol) and DMP (0.5 g) are placed in a dried flask and purged twice with vacuum/argon cycles. Dry solvent (10 mL) is syringed and
stirring is started, obtaining a clear solution, which develops quickly a color depending on the substrate. After 4 h (of 12 h for DMF as solvent), the mixture is evaporated, the
residue is taken in ethyl acetate and washed with water and brine. The organic phase is dried, concentrated, and purified by chromatography on silica. Spectroscopic and
physical data for known products agreed with those reported.20

˘
C. Dobrota et al. / Tetrahedron Letters 50 (2009) 1886–1888
1888
12. Faidallah, H. M.; Sharshira, E. M.; Basaif, S. A.; A-Ba-Oum, A. E.-K. Phosphorus,
Sulfur Silicon Relat. Elem. 2002, 177, 67–79.
13. (a) Yang, R.-Y.; Dai, L.-X. J. Org. Chem. 1993, 58, 3381–3383; (b) Rao, V. S.;
Sekhar, K. Synth. Commun. 2004, 34, 2153–2157.
14. (a) Shang, Z. Synth. Commun. 2006, 36, 2927–2937; (b) Shang, Z.; Reiner, J.;
Chang, J.; Zhao, K. Tetrahedron Lett. 2005, 46, 2701–2704.
15. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287; (b) Dess, D.
B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
16. Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261–8263.
zo[b]thien-2-yl (BBT) group by the dehydration of corresponding
diacylhydrazines.19 In the course of this study, we have encoun-
tered difficulties in obtaining several BBT-containing 1,3,4-oxadi-
azoles (i.e., some nitro-phenyl or pyridyl derivatives) via the
dehydrative cyclization. Therefore, we decided to attempt the
preparation of some BBT-containing 1,3,4-oxadiazoles using the
oxidative cyclization promoted by 1 (Table 2, entries 21–25).
To our satisfaction, we observed that most of the substrates
tested reacted smoothly in dichloromethane and gave the de-
sired oxadiazoles in good yields. Again, the use of DMF as sol-
vent was required in order to prepare the nitro derivative 3v
in moderate yield.
17. Janza, B.; Studer, A. J. Org. Chem. 2005, 70, 6991–6993.
18. Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.;
Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233–2244. and the references cited
therein.
19. Paraschivescu, C. C.; Dumitrascu, F.; Draghici, C.; Ruta, L. L.; Matache, M.; Baciu,
I.; Dobrota, C. Arkivoc 2008, xiii, 198–206.
20. Compound 3g: mp 121–122 °C; rF 0.3 (CH2Cl2); IR (KBr, cmꢀ1) 1596, 1551, 1488,
1448, 1266, 860, 723, 688; 1H NMR (400 MHz, CDCl3) 8.12–8.1 (m, 3H), 7.73
(dd, 1H, J = 5.2 Hz, J = 1.2 Hz), 7.55–7.50 (m, 3H), 7.47 (dd, 1H, J = 5.2 Hz,
J = 3.2 Hz); 13C NMR (100 MHz, CDCl3) 163.94, 161.3, 131.65, 129.03 (2C),
127.41, 127.39, 126.88 (2C), 126.04, 125.27, 123.83; MS (CI,%) calcd 228.04,
found 229 (100, MH)+; Anal. Calcd for C12H8N2OS: C, 63.14; H, 3.53; N, 12.27.
Found: C, 63.19; H, 3.60; N, 12.33. Compound 3q: mp 124–126 °C; rF 0.3
In summary, we have demonstrated that the preparation of
unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles via the oxida-
tive cyclization of N-acyl-N0-aryliden-hydrazines may be effec-
tively accomplished utilizing the DMP, and this method stands as
a
feasible alternative for convenient access to this class of
)
(AcOEt/pentanes 3:7); IR (KBr, cmꢀ1 1603, 1507, 1283, 1250; 1H NMR
heterocycles.
(400 MHz, CDCl3) 7.65 (d, 1H, J = 2 Hz), 7.60 (dd, 2H, J = 8 Hz, J = 2 Hz), 7.45–
7.35 (m, 3H), 7.33–7.29 (m, 1H), 7.19 (d, 1H, J = 4 Hz), 6.98 (d, 1H, J = 8.4 Hz),
6.60 (dd, 1H, J = 4 Hz, J = 2 Hz), 5.22 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz,
CDCl3) 164.04, 157.24, 151.39, 150.06, 145.64, 139.69, 136.38, 128.77 (2C),
128.22, 127.35 (2C), 120.48, 116.55, 113.89, 113.56, 112.24, 110.11, 71.02,
56.34; MS (CI,%) calcd 348.1, found 348 (98, M+), 257(100); Anal. Calcd for
C20H16N2O4: C, 68.96; H, 4.63; N, 8.04. Found: C, 69.00; H, 4.61; N, 8.07.
Compound 3t: mp 165–167 °C; rF 0.6 (CH2Cl2); IR (KBr, cmꢀ1) 1613, 1588, 1499,
1260; 1H NMR (400 MHz, CDCl3) 8.10 (d, 2H, J = 8.8 Hz), 7.97–7.94 (m, 1H),
7.86–7.84 (m, 1H), 7.53–7.51 (m, 2H), 7.03 (d, 2H, J = 8.8 Hz), 3.89 (s, 3H); 13C
NMR (100 MHz, CDCl3) 164.85, 162.71, 159.26, 138.13, 136.96, 129.08 (2C),
127.76, 125.79, 123.57, 123.3, 122.8, 119.25, 116.04, 114.69 (2C), 55.58; MS(CI,
%) calcd 342.02, found 343.5 (38, (37Cl)M+), 341.5(100, (35Cl)M+), 250.7(61),
194.7(35), 135(66); Anal. Calcd for C17H11ClN2O2S: C, 59.56; H, 3.23; N, 8.17.
Found: C, 59.51; H, 3.28; N, 8.19. Compound 3u: mp 167–169 °C; rF 0.45
Acknowledgments
The authors thank the Romanian Ministry for Education and Re-
search for financial support by a Grant CEEX-VIASAN 43/2005. We
also thank Mrs. Ulrike Ammari (Mikroanalytisches Labor, LSAC,
Technische Universität München) for performing the elemental
analyses.
References and notes
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)
(CH2Cl2/MeOH 98:2); IR (KBr, cmꢀ1 1605, 1582, 1509, 1277; 1H NMR
(400 MHz, CDCl3) 7.98–7.96 (m, 1H), 7.88–7.85 (m, 1H), 7.71 (s, 1H), 7.67 (d,
1H, J = 8.4 Hz), 7.54–7.52 (m, 2H), 7.47–7.43 (m, 2H), 7.39 (t, 2H, J = 7.2 Hz),
7.32 (t, 1H, J = 7.2 Hz), 7.01 (d, 1H, J = 8.4 Hz), 5.25 (s, 2H), 4.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) 164.88, 159.37, 151.58, 150.09, 138.17, 136.69, 136.37,
128.79, 128.23, 127.8, 127.33, 125.82, 123.64, 123.32, 122.82, 120.76, 119.19,
116.44, 113.62, 110.22, 71.03, 56.36; MS(CI,%) calcd 448.06, found 449.6 (2,
(
37Cl)M+), 447.6(5, (35Cl)M+), 343.8 (19), 295.9 (30), 257.9 (21), 241.9 (97),
211.8 (100), 196.9 (26), 194.9(76); Anal. Calcd for C24H17ClN2O3S: C, 64.21; H,
3.82; N, 6.24. Found: C, 64.19; H, 3.87; N, 6.27. Compound 3v: mp 205–207 °C;
rF 0.7 (CH2Cl2); IR (KBr, cmꢀ1) 1582, 1533, 1353, 1286, 1044, 753, 725; 1H NMR
(400 MHz, DMSO-d6) 8.25–8.23 (m, 1H), 8.2–8.18 (m, 1H), 8.01–7.97 (m, 3H),
7.9–7.83 (m, 1H), 7.69–7.64 (m, 2H); 13C NMR (100 MHz, DMSO-d6) 160.78,
159.8, 148.0, 137.54, 135.92, 133.78 (2C), 131.41, 128.5, 126.51, 124.86,
123.68, 123.33, 122.9, 118.19, 116.38; MS(CI,%) calcd 357.00, found 358.6 (22,
(
37Cl)M+), 356.7(64, 35Cl)M+), 194.9(100), 167 (26); Anal. Calcd for
(
C16H8ClN3O3S: C, 53.71; H, 2.25; N, 11.74. Found: C, 53.78; H, 2.22; N, 11.80.
Compound 3w: mp 122–124 °C; rF 0.5 (CH2Cl2); IR (KBr, cmꢀ1) 1583, 1486,
1308, 1266, 1246, 854, 758, 725; 1H NMR (400 MHz, CDCl3) 8.18 (dd, 1H,
J = 2.9 Hz, J = 1.2 Hz), 7.99–7.96 (m, 1H), 7.89–7.86 (m, 1H), 7.77 (dd, 1H,
J = 5 Hz, J = 1.2 Hz), 7.55–7.53 (m, 2H), 7.50 (dd, 1H, J = 5 Hz, J = 2.9 Hz); 13C
NMR (100 MHz, CDCl3) 161.56, 159.14, 138.21, 136.95, 128.31, 127.88, 127.65,
126.26, 125.86, 124.92, 123.38, 122.83, 118.97; MS(CI,%) calcd 317.9, found
320.7 (42, (37Cl)MH+), 318.7(100, (35Cl)MH+); Anal. Calcd for C14H7ClN2OS2: C,
52.74; H, 2.21; N, 8.79. Found: C, 52.70; H, 2.26; N, 8.83.
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