Synthesis of 3,5,5-trisubstituted 4-hydroxy-4H,5H-1,2,4-oxadiazoles through the condensation of N-hydroxyamidoximes and ketones or aldehydes

Article abstract of DOI:10.1002/ejoc.201500083

An interesting class of heterocyclic compounds, 1,2,4-oxadiazoles and their derivatives have attracted the attention of chemists because of their use in the development of new pharmaceuticals and functional materials. Herein, a catalyst-free reaction of N-hydroxyamidoxime with various ketones or aldehydes has been investigated. The reaction was carried out in methanol under mild conditions and gave 3,5,5-trisubstituted 4-hydroxy-4H,5H-1,2,4-oxadiazole derivatives in excellent yields. The structure of product 3f was confirmed by single-crystal X-ray diffraction studies.

Full text of DOI:10.1002/ejoc.201500083

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FULL PAPER
DOI: 10.1002/ejoc.201500083
Synthesis of 3,5,5-Trisubstituted 4-Hydroxy-4H,5H-1,2,4-oxadiazoles through
the Condensation of N-Hydroxyamidoximes and Ketones or Aldehydes
Ning Liu,*[a] Lian-Jie Zhai,[a] Peng Lian,[a] Hui Li,[a] and Bo-Zhou Wang[a]
Keywords: Synthetic methods / Cyclization / Condensation / Nitrogen heterocycles / Aldehydes / Ketones
An interesting class of heterocyclic compounds, 1,2,4-oxadi-
azoles and their derivatives have attracted the attention of
chemists because of their use in the development of new
pharmaceuticals and functional materials. Herein, a catalyst-
free reaction of N-hydroxyamidoxime with various ketones
or aldehydes has been investigated. The reaction was carried
out in methanol under mild conditions and gave 3,5,5-trisub-
stituted 4-hydroxy-4H,5H-1,2,4-oxadiazole derivatives in ex-
cellent yields. The structure of product 3f was confirmed by
single-crystal X-ray diffraction studies.
However, up until the present time, reports of the synthe-
sis of 4H,5H-1,2,4-oxadiazoles are relatively rare.[13]
Nicolaides and co-workers synthesized 4-phenyl-4H,5H-
1,2,4-oxadiazole, which exhibited a good overall profile of
biological activity.[14] Desherces and co-workers developed
an HCl-catalyzed condensation reaction of electron-
deficient N-hydroxyamidoximes with aldehydes to forming
3,5-disubstituted 4-hydroxy-4H,5H-1,2,4-oxadiazoles in
50% yield.[15] Morrocchi and Aurich, respectively, reported
the synthesis of 3,5,5-trisubstituted 4-hydroxy-4H,5H-1,2,4-
oxadiazoles by using the reaction of nitrile oxides with
hydroxylamines, which gave the desired products in low
yields (20%-43%).[16] Investigations of new synthetic meth-
ods for the synthesis of 4H,5H-1,2,4-oxadiazoles have been
stagnant in the last 30 years. This prompted us to explore
a more robust method, by which the construction of
4H,5H-1,2,4-oxadiazoles can be performed under mild con-
ditions with improved yields. Herein, we present a general
and highly efficient method that proceeds through the con-
densation of N-hydroxyamidoximes and ketones (alde-
hydes) at room temperature under catalyst-free conditions.
Introduction
Since the first synthesis of 1,2,4-oxadiazoles 125 years
ago by Tiemann and Krüger,[1] numerous compounds that
contain this five-membered heterocycle have been obtained.
Many of them have already been extensively studied be-
cause of their significant pharmacological properties as
anticancer,[2] antioxidant,[3] anti-inflammatory,[4] antibacte-
rial,[5] and anti-HIV agents.[6] Recently, Carbone isolated
the natural product phidianidine A (Figure 1), which is
characterized by the presence of a 1,2,4-oxadiazole ring.[7]
1,2,4-Oxadiazoles have also been used in the field of liquid
crystals[8] as well as with organic light-emitting diodes
(OLEDs).[9] Because of their high nitrogen content, appro-
priate balance of oxygen, and enhanced explosive perform-
ance, 1,2,4-oxadiazoles can be utilized in the design of new
energetic materials.[10] Previous studies have indicated that
1,2,4-oxadiazoles are important synthons in the preparation
of heterocycles through rearrangement reactions.[11] Over
the past few decades, quite a few general synthetic methods
for the preparation of 1,2,4-oxadiazoles have been devel-
oped and thoroughly summarized in several publications.[12]
Results and Discussion
During the purification process for the preparation of 3-
aminofurazan-4-carboximidamide (1a), we found that a
new product was formed when 1a was added to a solution
of butanone at 20 °C. This product was subsequently char-
acterized as 3a. To optimize the reaction conditions, 1a and
butanone (2a) were selected as the model substrates. Under
the previously mentioned conditions (Table 1, Entry 1),
there was complete conversion, and the desired product was
obtained within 15 min in 97% yield. When MeCN, tetra-
hydrofuran (THF) and dimethyl sulfoxide (DMSO) were
used as alternative solvents, significantly diminished yields
were obtained (Table 1, Entries 3–5). An excellent yield was
Figure 1. Representative natural product with a 1,2,4-oxadiazole
unit.
[a] Xi’an Modern Chemistry Research Institute,
Xi’an, Shanxi 710065, P. R. China
E-mail: flackliu@sina.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500083.
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N. Liu, L.-J. Zhai, P. Lian, H. Li, B.-Z. Wang
FULL PAPER
Table 1. Optimization of condensation reaction of 1a with but- achieved when the quantity of 2a was increased to 10 equiv.
anone (2a).[a]
(Table 1, Entry 2). Notably, the use of MeOH as a solvent
led to a dramatic increase in the reaction efficiency, and
only 1.5 equiv. of 2a was needed (Table 1, Entry 6). Both
EtOH and 2-propanol were less effective than MeOH as
solvents (Table 1, Entries 7 and 8). In addition, a decrease
in the amount of 2a (1.2 equiv.) resulted in a decrease of
Entry Solvent
n1a/n2a
Time
Yield [%][b]
the reaction yield (Table 1, Entry 9).
Under the optimized reaction conditions, a range of
ketones and aldehydes were then treated with 3-amino-fur-
azan-4-carboximidamide (1a), and the results show that
sterics played an important role in the outcome of the reac-
tion. For example, reactions with 2b–2d proceeded
smoothly to give the corresponding products in 91–98%
yield, whereas the condensation of 2e and 2f led to slightly
lower yields, even with longer reaction times (Table 2, En-
tries 1–5). Cyclic and heterocyclic ketones were also suc-
cessfully applied to this method. The reaction of 1a with
2g–2j proceeded smoothly to furnish the desired products
1
2
3
4
5
6
7
8
9
butanone
MeCN
MeCN
THF
DMSO
MeOH
EtOH
1:22.4
1:10
15 min
50 min
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
1.5 h
97
92
47
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.2
31
n.d.[c]
97
95
58
84
2-propanol
MeOH
[a] Unless otherwise specified, the reactions were performed by
using 1a (3 mmol) and solvent (6 mL). [b] Isolated product yields.
[c] n.d.: not determined.
Table 2. Condensation of 1a with various ketones and aldehydes.[a]
[a] The reactions were performed by using 1a (3 mmol) and the ketone/aldehyde (4.5 mmol) in MeOH (6 mL) at 20 °C. [b] Isolated product
yields. [c] dr = 45:55. [d] dr = 53:47.
2
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Condensation of N-Hydroxyamidoximes and Ketones (Aldehydes)
in 85–95% yield (Table 2, Entries 6–9). Unfortunately, the Table 3. Condensation of 1b with ketones and aldehydes.[a]
employed conjugated ketones proved to be incompatible
with this methodology. For example, no desired product
was obtained from the reaction of 1a with acetophenone.
The respective condensation reactions between 1a and 2-
cyclohexen-1-one and acetylacetone gave complicated mix-
tures. We propose that a conjugated structure might de-
crease the electrophilicity of the ketone carbonyl moiety.
However, the reaction of ethyl acetoacetate with 1a afforded
the desired product in 67% yield, although it did require a
longer reaction time (Table 2, Entry 10). Aldehydes exhib-
ited a higher reactivity than ketones, and a shorter reaction
time was required. However, the reaction of 1a with 2l–2n
gave the corresponding products in 69–84% yield because
of the occurrence of side reactions (e.g., a small amount of
byproduct from the addition of the NH2 to the CHO
group). In the case of products 3j and 3n, it is of note that
mixtures were formed with diastereomeric ratios (dr) of
45:55 and 53:47, respectively.
The reactions of the less nucleophilic pyrazine-2-carbox-
imidamide (1b) with ketones or aldehydes were also investi-
gated. In the reaction of 1b with 2b, the use of an excess
amount of acetone as the solvent was found to promote
the transformation, whereas extended reaction times were
required when MeOH was the solvent (Table 3, Entries 1
and 2). A poor yield (30%) was obtained for the reaction
with 2f, which is attributed to its steric hindrance (Table 3,
Entry 3). Ketones 2c, 2g, and 2d as well as acetaldehyde 2l
exhibited good reactivity with 1b to form 3q–3t in 73–85%
yield (Table 3, Entries 4–7).
The more nucleophilic benzenecarboximidamide (1c) ex-
hibited different reactivity when employed in this reaction.
In an earlier study, Desherces reported that the reaction of
1c with benzophenone resulted in no condensation prod-
uct.[15] We found that the reaction of 1c with 2b provided
the condensation product in high yield (90%) when
0.5 equiv. HCl was used as a catalyst along with an excess
amount of acetone as the solvent (Table 4, Entry 2). In con-
trast, the reaction gave no product under the standard con-
ditions (Table 4, Entry 1). This may be explained by the
electron-donating effect of the benzene ring, which de-
creases the acidity of the oximino group. However, when
2.0 equiv. 2b or 2g were employed in MeOH as the solvent,
their respective reactions only proceeded in moderate yields,
even after long reaction times (10–12 h; Table 4, Entries 3
and 4).
The condensation products were characterized by 1H
NMR, 13C NMR, and IR spectroscopy as well as HRMS
and elemental analyses. The structure of representative
product 3f was further confirmed by X-ray crystallography
(Figure 2), which confirmed that a 4-hydroxy-4H,5H-1,2,4-
oxadiazole ring was formed. The bond lengths of C-3–N-4
[1.265(4) Å] and C-3–N-5 [1.405(3) Å] are close to the
lengths of a typical C–N double bond and C–N single
[a] Unless otherwise specified, the reactions were performed by
using pyrazine-2-carboximidamide (1b, 3 mmol), the ketone/alde-
hyde (7.5 mmol), and MeOH (6 mL). [b] Isolated product yields.
[c] Acetone (6 mL) was used as the solvent.
A proposed mechanism for the reaction involves the ad-
bond, respectively. The torsion angle of C-3–N-5–C-4–O-2 dition of the N-hydroxyamidoxime (i.e., 1a or 1b) to the
is 10.3°, which indicates that the 1,2,4-oxadiazole ring is ketone (aldehyde) to form intermediate A, which is then
slightly twisted out of plane, which results in a loss of con- transformed into C through an intramolecular proton
jugation.
transfer and dehydration. The intramolecular cyclization of
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N. Liu, L.-J. Zhai, P. Lian, H. Li, B.-Z. Wang
FULL PAPER
Table 4. Condensation of 1c with ketones.[a]
Scheme 1. Proposed mechanism for the condensation of the N-
hydroxyamidoxime (i.e., 1a and 1b) and the ketone (aldehyde).
Conclusions
In summary, we have developed a simple and highly ef-
ficient process for the condensation of N-hydroxyamid-
oximes and ketones (aldehydes). This method is carried out
under mild conditions, requires no catalyst, and displays a
broad substrate scope. This investigation enables the rapid
and concise construction of 4H,5H-1,2,4-oxadiazoles that
are of substantial interest in medicinal and pharmaceutical
chemistry. Further efforts to expand the substrate scope and
their applications are now in progress.
Experimental Section
General Methods: All reactions were carried out in oven-dried vials
under air. Compounds 1a[17] and 1c[18] were obtained as previously
reported. All other solvents and reagents were obtained from com-
mercial vendors and used as received. The 13C and 1H NMR spec-
troscopic data were recorded with a Bruker Advance 500 MHz
spectrometer. [D6]DMSO was used as the NMR solvent with
tetramethylsilane (TMS) as an internal standard. IR spectra were
obtained by using KBr pellets on a Nicolet NEXUS870 infrared
spectrometer in the range of 4000–400 cm–1. High resolution mass
spectra (HRMS) were obtained with a Thermo Fisher SCIEN-
TIFIC EXACTIVE [ESI, atmospheric pressure chemical ionization
(APCI)]. Elemental analysis for carbon, hydrogen, and nitrogen
contents were carried out with an Elementary vario EL-III micro-
analyzer. Flash column chromatographic purifications of the prod-
ucts were accomplished by forced-flow chromatography on silica
gel (200–300 mesh). Compounds 3a–3c and 3e are unstable at room
temperature, and most of them can decompose within 24 h. These
compounds can be stored for several months at –18 °C. The dia-
stereomeric ratios of 3j and 3n were determined by 1H NMR spec-
troscopic analysis (500 MHz) of the reaction mixture.
[a] Unless otherwise specified, the reactions were performed by
using benzenecarboximidamide (1c, 3 mmol), the ketone (6 mmol),
and solvent (6 mL). [b] Isolated product yields. [c] Acetone (6 mL)
was used as the solvent. [d] HCl (1.5 mmol) was added. [e] MeOH
was used as the solvent.
Figure 2. X-ray crystal structure of 3f. Hydrogen atoms are omitted
for clarity. Thermal ellipsoids are set to 50% probability. Selected
bond lengths [Å] and bond angles [°]: C-3–N-4 [1.265(4)], C-3–N-
5 [1.405(3)], N-5–O-3 [1.440(3)], C-3–N-5–C-4–O-2 [10.3(3)], O-2–
N-4–C-3–N-5 [2.4(4)].
X-ray Crystallography of 3f: A thin plate (0.36ϫ0.28ϫ0.14 mm2)
was mounted on a MiteGen MicroMesh by using a small amount
of Cargille immersion oil. Diffraction data were collected at
296(2) K on an Oxford Diffraction Gemini S Ultra diffractometer
by using Mo-Kα radiation (λ = 0.71073 Å). The structure was
solved by direct methods using the SHELXS-97 program[19] and
refined against F2 by the full-matrix least-squares method using the
SHELXL-97 program.[20]
intermediate C affords the final product 3 (Scheme 1). The
mechanism for the condensation of 1c with acetone in the
presence of an acid can be rationalized as illustrated by
Desherces.[15]
Synthesis of Pyrazine-2-carboximidamide (1b): A 500 mL, three-
necked, round-bottomed flask was charged NH2OH·HCl (13.9 g,
4
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Condensation of N-Hydroxyamidoximes and Ketones (Aldehydes)
0.2 mol), NaOMe (10.8 g, 0.2 mol), and methanol (300 mL). H, NH2), 2.71–2.82 (m, 2 H, CH2), 2.00–2.14 (m, 2 H, CH2), 1.54
Chloroximinopyrazine (15.7 g, 0.1 mol) was added slowly by sy-
ringe at room temperature. After the resulting solution was stirred
at room temperature for 1 h, additional NaOMe (5.4 g, 0.05 mol)
was slowly added. The reaction mixture was stirred for another 1 h
at 30 °C. Upon completion of the reaction, the resulting solid was
collected by filtration, washed with cold water, and dried under
vacuum at 30 °C for 2 h to provide 1b (11.4 g, 74%).
(s, 3 H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 155.31,
150.92, 141.19, 136.06, 128.30, 128.10, 125.81, 104.27, 38.00, 29.32,
18.90 ppm. IR (KBr): ν = 3427, 3327, 1647, 1606, 1530, 1454, 1381,
˜
1119, 957 cm–1. HRMS: calcd. for C13H15N5O3 [M]+ 289.1175;
found 289.1174. C13H15N5O3 (289.29): calcd. C 53.97, H 5.23, N
24.21; found C 54.32, H 5.18, N 24.04.
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-isobutyl-5-methyl-4H,5H-
1,2,4-oxadiazole (3e): Pink solid. 1H NMR (500 MHz, [D6]DMSO):
δ = 9.77 (s, 1 H, OH), 6.32 (s, 2 H, NH2), 1.85–1.93 (m, 1 H, CH),
1.69–1.70 (m, 2 H, CH2), 1.45 (s, 3 H, CH3), 0.96 (d, J = 6.5 Hz,
6 H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 155.28,
150.87, 136.09, 104.81, 44.25, 23.93, 23.59, 23.41, 18.81 ppm. IR
General Procedure to Prepare Products 3a–3t (Preparation of 3a): A
round-bottomed flask was charged with 3-amino-N,NЈ-dihydroxy-
furazan-4-carboximidamide (0.477 g, 3 mmol), butanone (0.324 g,
4.5 mmol), and MeOH (6 mL). The reaction mixture was stirred at
20 °C for 1.5 h. The solvent was evaporated under vacuum, and the
residue was purified by column chromatography (silica gel, 30%
CH3COOEt/petroleum ether) to afford 3a (0.620 g, 97%).
(KBr): ν = 3433, 3330, 2956, 1647, 1607, 1531, 1382, 1114,
˜
959 cm–1. HRMS: calcd. for C9H15N5O3 [M]+ 241.1175; found
241.1180. C9H15N5O3 (241.25): calcd. C 44.81, H 6.27, N 29.03;
found C 44.75, H 6.24, N 29.36.
General Procedure to Prepare Products 3u–3v (Preparation of 3u):
A round-bottomed flask was charged with benzenecarboximid-
amide (1c, 0.456 g, 3 mmol), acetone (0.348 g, 6 mmol), HCl
(0.055 g, 1.5 mmol), and MeOH (6 mL). The reaction mixture was
stirred at 20 °C for 12 h. The solvent was evaporated under vac-
uum, and the residue was purified by column chromatography (sil-
ica gel, 50% CH3COOEt/petroleum ether) to afford 3u (0.357 g,
62%).
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-isopropyl-5-methyl-4H,5H-
1,2,4-oxadiazole (3f): Pink solid. 1H NMR (500 MHz, [D6]DMSO):
δ = 9.79 (s, 1 H, OH), 6.31 (s, 2 H, NH2), 1.97 (quint, J = 6.5 Hz,
1 H, CH), 1.40 (s, 3 H, CH3), 1.02 (d, J = 6.5 Hz, 3 H, CH3), 0.98
(d, J = 6.5 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO):
δ = 155.83, 151.35, 136.57, 107.66, 35.28, 17.20, 15.26 ppm. IR
(KBr): ν = 3431, 3328, 2971, 1728, 1646, 1607, 1533, 1385, 1128,
Pyrazine-2-carboximidamide (1b): Yellow solid. 1H NMR
(500 MHz, [D6]DMSO): δ = 10.74 (s, 1 H, NH), 8.79 (m, 1 H,
pyrazine), 8.65 (m, 2 H, pyrazine), 8.54 (b, 2 H, OH) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 154.59, 147.06, 144.50, 144.21,
˜
957 cm–1. HRMS: calcd. for C8H13N5O3 [M]+ 227.1018; found
227.1024. C8H13N5O3 (227.22): calcd. C 42.29, H 5.77, N 30.82;
found C 42.07, H 5.69, N 31.08.
143.91 ppm. IR (KBr): ν = 3516, 3141, 3007, 1622, 1461, 1370,
˜
3-(3-Aminofurazan-4-yl)-4-hydroxy-1-oxa-2,4-diazaspiro[4.5]dec-2-
ene (3g): White solid. H NMR (500 MHz, [D6]DMSO): δ = 9.74
(s, 1 H, OH), 6.33 (s, 2 H, NH2), 1.80–1.85 (m, 2 H, CH2), 1.68–
1.77 (m, 4 H, CH2), 1.57–1.62 (m, 2 H, CH2), 1.46–1.49 (m, 2 H,
CH2) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 155.38, 151.00,
1135, 1109, 944 cm–1. HRMS: calcd. for C5H6N4O2 [M]+ 154.0491;
found 154.0488. C5H6N4O2 (154.13): calcd. C 38.96, H 3.92, N
36.85; found C 39.11, H 3.87, N 36.64.
1
3-(3-Aminofurazan-4-yl)-5-ethyl-4-hydroxy-5-methyl-4H,5H-1,2,4-
1
136.63, 103.54, 30.77, 24.28, 22.73 ppm. IR (KBr): ν = 3465, 3348,
˜
oxadiazole (3a): Pink solid. H NMR (500 MHz, [D6]DMSO): δ =
2940, 1634, 1602, 1519, 1446, 1384, 1107, 949 cm–1. HRMS: calcd.
for C9H13N5O3 [M]+ 239.1018; found 239.1014. C9H13N5O3
(239.23): calcd. C 45.18, H 5.48, N 29.27; found C 45.38, H 5.42,
N 29.34.
9.79 (s, 1 H, OH), 6.32 (s, 2 H, NH2), 1.71–1.85 (m, 2 H, CH2),
1.46 (s, 3 H, CH3), 0.97 (t, J = 8.0 Hz, 3 H, CH3) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 155.28, 150.88, 136.11, 104.96, 29.28,
18.21, 7.91 ppm. IR (KBr): ν = 3469, 3341, 1636, 1604, 1528, 1376,
˜
1124, 958, 821 cm–1. HRMS: calcd. for C7H11N5O3 [M]+ 213.0862;
found 213.0866. C7H11N5O3 (213.20): calcd. C 39.44, H 5.20, N
32.85; found C 39.85, H 5.22, N 32.82.
3-(3-Aminofurazan-4-yl)-4-hydroxy-1,8-dioxa-2,4-diazaspiro[4.5]-
1
dec-2-ene (3h): White solid. H NMR (500 MHz, [D6]DMSO): δ =
9.91 (s, 1 H, OH), 6.36 (s, 2 H, NH2), 3.72–3.81 (m, 4 H, OCH2),
1.95–2.00 (m, 2 H, CH2), 1.82–1.87 (m, 2 H, CH2) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 155.33, 150.92, 136.42, 100.89, 64.25,
3-(3-Aminofurazan-4-yl)-4-hydroxy-5,5-dimethyl-4H,5H-1,2,4-oxa-
diazole (3b): Pink solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.81
(s, 1 H, OH), 6.33 (s, 2 H, NH2), 1.49 (s, 6 H, CH3) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 155.29, 150.93, 136.27, 102.82,
31.41 ppm. IR (KBr): ν = 3465, 3336, 2916, 1634, 1605, 1528, 1360,
˜
1227, 1176, 1088, 888, 828 cm–1. HRMS: calcd. for C8H11N5O4
[M]+ 241.0811; found 241.0808. C8H11N5O4 (241.21): calcd. C
39.84, H 4.60, N 29.03; found C 39.60, H 4.62, N 28.92.
21.78 ppm. IR (KBr): ν = 3467, 3339, 1636, 1604, 1523, 1375, 1103,
˜
949, 800 cm–1. HRMS: calcd. for C6H9N5O3 [M]+ 199.0705; found
199.0707. C6H9N5O3 (199.17): calcd. C 36.18, H 4.55, N 35.16;
found C 36.14, H 4.51, N 34.85.
3-(3-Aminofurazan-4-yl)-4-hydroxy-1-oxa-7-thia-2,4-diazaspiro[4.4]-
1
non-2-ene (3i): White solid. H NMR (500 MHz, [D6]DMSO): δ =
10.29 (s, 1 H, OH), 6.36 (s, 2 H, NH2), 3.00–3.30 (m, 2 H, SCH2),
2.91–2.98 (m, 2 H, SCH2), 2.28–2.44 (m, 2 H, CH2) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = 155.31, 153.37, 135.86, 112.12,
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-methyl-5-pentyl-4H,5H-1,2,4-
oxadiazole (3c): Pink solid. H NMR (500 MHz, [D6]DMSO): δ =
9.77 (s, 1 H, OH), 6.32 (s, 2 H, NH2), 1.68–1.80 (m, 2 H, CH2),
1.46 (s, 3 H, CH3), 1.37–1.43 (m, 2 H, CH2), 1.28–1.29 (m, 4 H,
CH2), 0.87 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 155.83, 151.40, 136.66, 105.20, 36.73, 31.79,
1
34.44, 34.29, 26.75 ppm. IR (KBr): ν = 3471, 3335, 3248, 1632,
˜
1603, 1518, 1424, 1106, 944, 877 cm–1. HRMS: calcd. for
C7H9N5O3S [M]+ 243.0426; found 241.0431. C7H9N5O3S (243.24):
calcd. C 34.56, H 3.73, N 28.79; found C 34.69, H 3.64, N 28.93.
23.32, 22.44, 19.26, 14.30 ppm. IR (KBr): ν = 3435, 3331, 2955,
˜
1646, 1607, 1530, 1382, 1119, 939 cm–1. HRMS: calcd. for
C10H17N5O3 [M]+ 255.1331; found 255.1326. C10H17N5O3 (255.28):
calcd. C 47.05, H 6.71, N 27.43; found C 46.88, H 6.68, N 27.15.
N-[3-(3-Aminofurazan-4-yl)-4-hydroxy-1-oxa-2,4-diazaspiro[4.5]dec-
2-en-8-yl]acetamide (3j): White solid. 1H NMR (500 MHz, [D6]-
DMSO): δ = 9.88 (s, 0.5 H, OH), 9.79 (s, 0.5 H, OH), 7.89 (d, J =
8.0 Hz, 0.5 H, NH), 7.84 (d, J = 8.0 Hz, 0.5 H, NH), 6.34 (s, 2 H,
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-methyl-5-phenethyl-4H,5H-
1,2,4-oxadiazole (3d): White solid. 1H NMR (500 MHz, [D6]- NH2), 3.69–3.74 (m, 1 H, CH), 1.94–2.03 (m, 2 H, CH2), 1.73–1.87
DMSO): δ = 9.92 (s, 1 H, OH), 7.17–7.30 (m, 5 H, Ph), 6.35 (s, 2 (m, 5 H, CH2, CH3), 1.49–1.64 (m, 2 H, CH2) ppm. 13C NMR
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Pages: 8
N. Liu, L.-J. Zhai, P. Lian, H. Li, B.-Z. Wang
NMR (125 MHz, [D6]DMSO): δ = 157.68, 146.34, 145.25, 144.36,
FULL PAPER
(125 MHz, [D6]DMSO): δ = 168.70, 155.32, 151.09, 136.72, 103.11,
45.91, 45.22, 28.64, 28.32, 28.26, 28.10, 22.65 ppm. IR (KBr): ν =
142.42, 107.20, 35.45, 17.34, 17.29, 15.45 ppm. IR (KBr): ν = 3251,
˜
˜
3469, 3343, 3238, 2941, 1658, 1627, 1546, 1370, 1144, 1127, 948,
857 cm–1. HRMS: calcd. for C11H16N6O4 [M]+ 296.1233; found
296.1229. C11H16N6O4 (296.29): calcd. C 44.59, H 5.44, N 28.36;
found C 44.72, H 5.51, N 28.60.
2970, 2878, 1599, 1443, 1367, 1135, 1018, 954 cm–1. HRMS: calcd.
for C10H14N4O2 [M]+ 222.1117; found 222.1114. C10H14N4O2
(222.25): calcd. C 54.04, H 6.35, N 25.21; found C 53.87, H 6.29,
N 25.43.
Ethyl 2-[3-(3-Aminofurazan-4-yl)-4-hydroxy-5-methyl-4H,5H-1,2,4- 4-Hydroxy-5-methyl-5-pentyl-3-(pyrazin-2-yl)-4H,5H-1,2,4-oxadi-
1
oxadiazol-5-yl]ethanoate (3k): White solid. H NMR (500 MHz,
[D6]DMSO): δ = 9.98 (s, 1 H, OH), 6.33 (s, 2 H, NH2), 4.07 (quart, (s, 1 H, OH), 9.03 (m, 1 H, pyrazine), 8.77–8.79 (m, 2 H, pyrazine),
azole (3q): White solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.56
J = 7.0 Hz, 2 H, CH2), 2.91 (d, J = 15.0 Hz, 1 H, CH2), 2.81 (d, J
= 15.0 Hz, 1 H, CH2), 1.67 (s, 3 H, CH3), 1.18 (d, J = 7.0 Hz, 3 H,
CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 168.68, 155.85,
151.30, 136.50, 102.79, 60.68, 41.21, 20.07, 14.41 ppm. IR (KBr):
1.67–1.81 (m, 2 H, CH2), 1.38–1.53 (m, 5 H, CH2, CH3), 1.25–1.34
(m, 4 H, CH2), 0.87 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 157.17, 145.79, 144.70, 143.76, 141.86,
104.21, 36.49, 31.30, 22.87, 21.89, 18.92, 13.75 ppm. IR (KBr): ν =
˜
ν = 3465, 3359, 2986, 1728, 1633, 1525, 1375, 1204, 1028 cm–1. 3280, 2954, 2871, 1599, 1455, 1361, 1164, 1135, 1019, 930 cm–1.
˜
HRMS: calcd. for C9H13N5O5 [M]+ 271.0917; found 271.0924. HRMS: calcd. for C12H18N4O2 [M]+ 250.1430; found 250.1433.
C9H13N5O5 (271.23): calcd. C 39.85, H 4.83, N 25.82; found C
39.67, H 4.90, N 25.98.
C12H18N4O2 (250.30): calcd. C 57.58, H 7.25, N 22.38; found C
57.44, H 7.27, N 22.53.
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-methyl-4H,5H-1,2,4-oxadi- 4-Hydroxy-3-(pyrazin-2-yl)-1-oxa-2,4-diazaspiro[4.5]dec-2-ene (3r):
1
azole (3l): Pink solid. H NMR (500 MHz, [D6]DMSO): δ = 10.09 White solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.52 (s, 1 H,
(s, 1 H, OH), 6.36 (s, 2 H, NH2), 5.45 (quart, J = 6.0 Hz, 1 H, OH), 9.07 (m, 1 H, pyrazine), 8.76–8.78 (m, 2 H, pyrazine), 1.81–
CH), 1.47 (d, J = 5.5 Hz, 3 H, CH3) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 155.31, 151.47, 135.98, 98.14, 16.16 ppm. IR
1.85 (m, 2 H, CH2), 1.67–1.77 (m, 4 H, CH2), 1.62–1.64 (m, 2 H,
CH2), 1.47–1.49 (m, 2 H, CH2) ppm. 13C NMR (125 MHz, [D6]-
(KBr): ν = 3439, 3330, 1647, 1606, 1525, 1388, 1170, 1100, 1062, DMSO): δ = 157.17, 145.74, 144.71, 143.79, 142.04, 102.99, 30.95,
˜
945 cm–1. HRMS: calcd. for C5H7N5O3 [M]+ 185.0549; found
185.0553. C5H7N5O3 (185.14): calcd. C 32.44, H 3.81, N 37.83;
found C 32.58, H 3.72, N 37.64.
24.30, 22.70 ppm. IR (KBr): ν = 3225, 2930, 2852, 1602, 1449,
˜
1364, 1161, 1115, 1018, 948 cm–1. HRMS: calcd. for C11H14N4O2
[M]+ 234.1117; found 234.1124. C11H14N4O2 (234.26): calcd. C
56.40, H 6.02, N 23.92; found C 56.17, H 5.96, N 24.15.
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-isopropyl-4H,5H-1,2,4-oxadi-
azole (3m): Pink solid. 1H NMR (500 MHz, [D6]DMSO): δ = 10.34 4-Hydroxy-5-methyl-5-phenethyl-3-(pyrazin-2-yl)-4H,5H-1,2,4-oxa-
(s, 1 H, OH), 6.34 (s, 2 H, NH2), 5.19 (d, J = 5.5 Hz, 1 H, CH), diazole (3s): White solid. 1H NMR (500 MHz, [D6]DMSO): δ =
1.96 (sextet, J = 6.5 Hz, 1 H, CH), 0.99 (quart, J = 6.0 Hz, 6 H,
CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 155.29, 151.25,
9.70 (s, 1 H, OH), 9.07 (s, 1 H, pyrazine), 8.78–8.80 (m, 2 H, pyr-
azine), 7.23–7.30 (m, 4 H, Ph), 7.17–7.20 (m, 1 H, Ph), 2.74–2.85
135.68, 105.87, 30.65, 16.48, 16.26 ppm. IR (KBr): ν = 3459, 3348, (m, 2 H, CH2), 1.99–2.14 (m, 2 H, CH2), 1.55 (s, 3 H, CH3) ppm.
˜
1641, 1607, 1525, 1151, 1088, 941, 850 cm–1. HRMS: calcd. for
13C NMR (125 MHz, [D6]DMSO): δ = 157.27, 145.87, 144.71,
C7H11N5O3 [M]+ 213.0862; found 213.0857. C7H11N5O3 (213.20): 143.87, 141.76, 141.36, 128.28, 128.10, 125.75, 103.85, 38.42, 29.44,
calcd. C 39.44, H 5.20, N 32.85; found C 39.68, H 5.21, N 32.52.
19.10 ppm. IR (KBr): ν = 3285, 3027, 2948, 1599, 1454, 1431, 1363,
˜
1138, 1020, 932 cm–1. HRMS: calcd. for C15H16N4O2 [M]+
284.1273; found 284.1281. C15H16N4O2 (284.32): calcd. C 63.37, H
5.67, N 19.71; found C 63.50, H 5.65, N 19.62.
3-(3-Aminofurazan-4-yl)-4-hydroxy-5-(2,4,4-trimethylpentyl)-
4H,5H-1,2,4-oxadiazole (3n): Pink solid. 1H NMR (500 MHz, [D6]-
DMSO): δ = 10.20 (s, 0.5 H, OH), 10.15 (s, 0.5 H, OH), 6.35 (s, 2
H, NH2), 5.34–5.38 (m, 1 H, CH), 1.72–1.87 (m, 2 H, CH2), 1.59– 4-Hydroxy-5-methyl-3-(pyrazin-2-yl)-4H,5H-1,2,4-oxadiazole (3t):
1.65 (m, 1 H, CH), 1.28–1.34 (m, 1 H, CH2), 1.11–1.14 (m, 1 H, White solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.91 (s, 1 H,
CH2), 1.02 (d, J = 6.5 Hz, 3 H, CH3), 0.91 (m, 9 H, CH3) ppm. OH), 9.05 (m, 1 H, pyrazine), 8.78–8.80 (m, 2 H, pyrazine), 5.44–
13C NMR (125 MHz, [D6]DMSO): δ = 155.29, 151.40, 135.91,
5.47 (m, 1 H, CH), 1.48 (d, J = 6.0 Hz, 3 H, CH3) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 157.77, 146.00, 144.83, 143.79, 141.38,
98.06, 16.50 ppm. IR (KBr): ν = 3242, 2924, 2859, 1607, 1444,
˜
100.56, 50.59, 30.80, 29.71, 29.62, 24.97, 22.47 ppm. IR (KBr): ν =
˜
3470, 3351, 2958, 1638, 1605, 1522, 1364, 1134, 938 cm–1. HRMS:
calcd. for C1 2 H2 1 N5 O3 [M]+ 283.1644; found 283.1637. 1360, 1162, 1016 cm–1. HRMS: calcd. for C7H8N4O2 [M]+
C12H21N5O3 (283.33): calcd. C 50.87, H 7.47, N 24.72; found C 180.0647; found 180.0644. C7H8N4O2 (180.17): calcd. C 46.67, H
51.18, H 7.57, N 24.53.
4.48, N 31.10; found C 46.91, H 4.41, N 30.94.
4-Hydroxy-5,5-dimethyl-3-(pyrazin-2-yl)-4H,5H-1,2,4-oxadiazole 4-Hydroxy-5,5-dimethyl-3-phenyl-4H,5H-1,2,4-oxadiazole[16a] (3u):
1
(3o): White solid. H NMR (500 MHz, [D6]DMSO): δ = 9.61 (s, 1 white solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.37 (s, 1 H,
H, OH), 9.04 (m, 1 H, pyrazine), 8.77–8.79 (m, 2 H, pyrazine), 1.50
OH), 7.78–7.80 (m, 2 H, Ph), 7.46–7.50 (m, 3 H, Ph), 1.45 (s, 6 H,
(s, 3 H, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 157.23, CH3) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 158.79, 130.38,
145.83, 144.73, 143.78, 141.88, 102.36, 22.05 ppm. IR (KBr): ν = 128.53, 127.03, 126.35, 100.96, 22.13 ppm. IR (KBr): ν = 3224,
˜
3311, 2981, 2936, 1429, 1364, 1163, 1132, 1020, 926 cm–1. HRMS:
calcd. for C8H10N4O2 [M]+ 194.0804; found 194.0810. C8H10N4O2
(194.19): calcd. C 49.48, H 5.19, N 28.85; found C 49.55, H 5.07,
N 28.54.
˜
2983, 2861, 1450, 1371, 1354, 1217, 921, 693 cm–1. HRMS: calcd.
for C10H12N2O2 [M]+ 192.0899; found 192.0904. C10H12N2O2
(192.22): calcd. C 62.49, H 6.29, N 14.57; found C 62.67, H 6.26,
N 14.41.
4-Hydroxy-5-isopropyl-5-methyl-3-(pyrazin-2-yl)-4H,5H-1,2,4-oxa- 4-Hydroxy-3-phenyl-1-oxa-2,4-diazaspiro[4.5]dec-2-ene (3v): White
diazole (3p): White solid. 1H NMR (500 MHz, [D6]DMSO): δ = solid. 1H NMR (500 MHz, [D6]DMSO): δ = 9.26 (s, 1 H, OH),
9.54 (s, 1 H, OH), 9.04 (m, 1 H, pyrazine), 8.77–8.79 (m, 2 H,
7.81–7.82 (m, 2 H, Ph), 7.47–7.49 (m, 3 H, Ph), 1.61–1.80 (m, 8 H,
pyrazine), 1.94–2.00 (m, 1 H, CH), 1.41 (s, 3 H, CH3), 1.03 (d, J
CH2), 1.47 (s, 2 H, CH2) ppm. 13C NMR (125 MHz, [D6]DMSO):
= 6.5 Hz, 3 H, CH3), 0.99 (d, J = 6.5 Hz, 3 H, CH3) ppm. 13C δ = 158.66, 130.31, 128.52, 127.00, 126.57, 101.46, 31.04, 24.42,
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Date: 16-03-15 14:02:32
Pages: 8
Condensation of N-Hydroxyamidoximes and Ketones (Aldehydes)
G. Shanker, M. Nagaraj, A. Kocot, J. K. Vij, M. Prehm, C.
22.73 ppm. IR (KBr): ν = 3205, 2941, 2864, 1708, 1448, 1364, 1224,
˜
760, 689 cm–1. HRMS: calcd. for C13H16N2O2 [M]+ 232.1212;
found 232.1218. C13H16N2O2 (232.28): calcd. C 67.22, H 6.94, N
12.06; found C 67.54, H 6.85, N 11.82.
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Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra and X-ray crystal structure of 3f.
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Acknowledgments
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The authors gratefully acknowledge financial support by the
National Natural Science Foundation of China (NSFC) (grant
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the University of Science and Technology of China for the valuable
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Gui of the University of Vienna are also appreciated.
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Received: January 19, 2015
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 16-03-15 14:02:32
Pages: 8
N. Liu, L.-J. Zhai, P. Lian, H. Li, B.-Z. Wang
FULL PAPER
Heterocyclic Chemistry
N. Liu,* L.-J. Zhai, P. Lian, H. Li,
B.-Z. Wang ....................................... 1–8
Synthesis of 3,5,5-Trisubstituted 4-
Hydroxy-4H,5H-1,2,4-oxadiazoles through
the Condensation of N-Hydroxyamidox-
imes and Ketones or Aldehydes
A convenient method was developed for
the synthesis of 3,5,5-trisubstituted 4-
and ketones or aldehydes. These reactions
were efficiently carried out at room tem-
perature in the absence of a catalyst and
afforded the corresponding products in ex-
cellent yields.
hydroxy-4H,5H-1,2,4-oxadiazole
deriva-
tives that proceeds through the conden-
sation reaction of N-hydroxyamidoximes
Keywords: Synthetic methods
/ Cycliz-
ation / Condensation / Nitrogen hetero-
cycles / Aldehydes / Ketones
8
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