Reaction of 1,2,3-oxadiazole 3-oxides

Article abstract of DOI:10.3987/COM-12-S(N)127

1,2,3-Oxadiazole 3-oxides with an alkoxymethyl group at the 5-position were reduced by reacting them with sodium borohydride to produce 4,5-dihydro-1,2,3-oxadiazole 3-oxides in good yields, which were further transformed into substituted diazene N-oxides by reacting with Grignard reagents.

Full text of DOI:10.3987/COM-12-S(N)127

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1039 - 1044. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 30th September, 2012, Accepted, 8th November, 2012, Published online, 9th November, 2012
DOI: 10.3987/COM-12-S(N)127
REACTION OF 1,2,3-OXADIAZOLE 3-OXIDES
Takumichi Sugihara,* Akira Murakawa, Chiemi Sawanaka, Megumi Seki,
Natsuki Iio, Ayano Iizuka, Takuya Oohora, and Shinobu Honzawa
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied
Life Sciences (NUPALS), Higashi-jima, Niigata 956-8603, Japan
This manuscript is dedicated to Nobel Laureate Professor Ei-ichi Negishi on the
occasion of his ‘Ki-Ju’.
Abstract – 1,2,3-Oxadiazole 3-oxides with an alkoxymethyl group at the
5-position were reduced by reacting them with sodium borohydride to produce
4,5-dihydro-1,2,3-oxadiazole 3-oxides in good yields, which were further
transformed into substituted diazene N-oxides by reacting with Grignard reagents.
Oxadiazoles are five-membered heteroaromatic compounds consisting of two carbons, two nitrogens, and
one oxygen with two double bonds; they are used as mother nuclei and/or subunits of pharmaceutical
drugs, such as butalamine, fasiplon, oxolamine, pleconaril, and raltegravir. Oxadiazoles have four
isomers: 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-isomers. Although the later three are stable under ambient
temperature, the first one 1 is unstable and is easily tautomerized to -diazocarbonyl compounds 2 (Eq.
1).1
R2
R2
R2
N N
N N
N
N
(Eq. 1)
R1
R1
R1
O
O
O
1

2
1,2,3-oxadiazoles
-diazocarbonyl compounds
We have developed a new and convenient method of synthesizing 1,2,3-oxadiazole 3-oxides 3 by reacting
alkynyllithiums with nitric oxide at atmospheric pressure and low temperatures (Eq. 2).2 The reaction is
clean and fast, producing 3 in good yield when oxygen contamination is eliminated completely.
H
O
NO (bubbling)
THF, -78 °C
N
N
R
Li
(Eq. 2)
R
then H2O
(70-90%)
O
3
1,2,3-oxadiazole 3-oxides

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HETEROCYCLES, Vol. 86, No. 2, 2012
Most N-oxides of nitrogen-containing heteroaromatic compounds are unstable when heated.
1,2,5-Oxadiazole 2-oxides are the same, decomposing into nitrile oxides and isocyanates easily.3 In
contrast, their isomers 1,2,3-oxadiazole 3-oxides 3 are thermally stable and are not decomposed after
refluxing in xylene for 10 h; however, 1,2,3-oxadiazoles 1 are less stable than 1,2,5-isomers. If the stable
and easily accessible 1,2,3-oxadiazole 3-oxides 3 are reduced, this will become a new method of
producing -diazocarbonyls,-aminocarbonyls, and -amino alcohols. Thus, we started to study the
reaction of 1,2,3-oxadiazole 3-oxides 3 with various reducing agents.
The introduction of phenyl substituents into the starting molecules facilitates handling and reaction
checking. Thus, five types of 1,2,3-oxadiazole 3-oxide with phenyl substituents, i.e.,
5-phenyl-1,2,3-oxadiazole
3-oxide
3a,
5-(2-phenylethyl)-1,2,3-oxadiazole
3-oxide
3b,
5-phenoxymethyl-1,2,3-oxadiazole 3-oxide 3c, 5-(3-phenoxypropyl)-1,2,3-oxadiazole 3-oxide 3d, and
5-(3-benzyloxypropyl)-1,2,3-oxadiazole 3-oxide 3e were synthesized from the corresponding alkynes
according to the previous method2 and used for studying their reactivity.
First, catalytic hydrogenation in the presence of palladium on activated carbon was applied to 3a-e, since
one of their isomers, 1,2,5-oxadiazole 2-oxide, was reported to deoxygenate under the same conditions.4
The results are summarized in Table 1.
O
Me
O
H2 (1 atm), Pd-C (cat.)
solvent, 20 °C
N
N
R
R
O
3
4
Table 1. Hydrogenation of 3 in the presence of 10% of palladium on activated carbona
Substrate
R
Time
(h)
Product
Yield (%)
Entry
Solvent
3
1
2
3
4
5
6
7
a
a
a
b
c
Ph
Ph
Ph
MeOHb
2
1
1
2
2
2
2
4a
4a
4a
4b
5e
98
96
82
91
98
87
78
MeOH-CH2Cl2 (1 : 3 v/v)c
d
CH2Cl2
PhCH2CH2
PhOCH2
PhOCH2CH2CH2
PhCH2OCH2CH2CH2
MeOHb
MeOHb
MeOHb
MeOHb
d
e
4d
6f
a
A mixture of 1.00 mmol of 3 and 10.0 mg of 10% of palladium on activated carbon in the solvent was
stirred at 20 °C under atmospheric pressure of hydrogen. b 30 mL of methanol was used. c A mixture of 1.0
mL of methanol and 3.0 mL of dichloromethane was used. d 4.0 mL of dichloromethane was used. e Phenol
5 was produced as the sole and isolable product. f 5-Hydroxy-2-pentanone 6 was produced.
1,2,3-Oxadiazole 3-oxides 3 are slightly solved in methanol, and thus, whether a large amount of
methanol or the addition of dichloromethane is required to carry out the reaction in solution. A mixture of

HETEROCYCLES, Vol. 86, No. 2, 2012
1041
3a and a catalytic amount of palladium on activated carbon in methanol was stirred at 20 °C under
atmospheric pressure of hydrogen for 2 h. Unfortunately, the desired 1,2,3-oxadiazole 1a (R1 = Ph, R2 =
H) or their tautomers, -diazocarbonyl compound 2a, were not obtained, and the simple carbonyl
compound 4a was produced in an almost quantitative yield (Entry 1). Changing the solvent to a mixture
of methanol and dichloromethane shortened the reaction time (Entry 2); however the reaction in
dichloromethane lowered the yield of 4a (Entry 3). 1,2,3-Oxadiazole 3-oxides having 2-phenylethyl and
3-phenoxypropyl groups 3b and 3d were also reduced smoothly to produce 4b and 4d, respectively
(Entries 4 and 6), whereas the reaction of 3c produced phenol 5 in an almost quantitative yield (Entry 5).
The hydrogenation of 1-phenoxyacetone under the same conditions did not produce phenol 6, and no
5-methyl-1,2,3-oxadiazole 3-oxide was obtained after the reaction. Therefore, the hydrogenolytic removal
of the 5-methylene-1,2,3-oxadiazole 3-oxide part seemed to be faster than the reduction of this part, and
the resulting 5-methyl-1,2,3-oxadiazole 3-oxide might be transformed into acetone under the same
conditions. Both the hydrogenation of the 1,2,3-oxadiazole 3-oxide part and the hydrogenolytic cleavage
of the arylmethyl part proceeded at the same time when 3e was reacted to give 5-hydroxy-2-pentanone in
a good yield (Entry 7). 1,2,3-Oxadiazole 3-oxides 3 were prepared from their parent terminal alkynes
under basic conditions, and the reduction of the resulting 3 to the carbonyl compounds 4 was carried out
under neutral conditions. Thus, the overall reaction from alkynes to carbonyl compounds 4 appeared to be
an alternative to the Markovnikov-type ‘formal hydration’ of alkynes and could be carried out under basic
to neutral conditions. The Markovnikov-type hydration of the terminal alkynes is generally carried out
under acidic conditions as shown in Scheme 1. Thus, the present overall transformation becomes an
alternative to the conventional method.
O
n-BuLi (1.1 eq.)
NO (bubbling)
N
N
'formal hydration' of alkynes
under basic or neutral conditions
R
H
R
THF, -78 °C
-78 °C
then H2O
O
3
H2 (1 atm)
Pd-C (cat.)
MeOH, rt
Me
Hg(OAc)2 (0.1 eq.)
10% H2SO4 aq.-MeOH (1 : 2 v/ v), rt
R
O
4
hydration of alkynes under acidic conditions
Scheme 1
Catalytic hydrogenation produced neither the desired 2 nor 3, and thus we switched to conventional
reducing agents having nucleophilic hydrides. The reaction of 3a-e with lithium aluminum hydride

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HETEROCYCLES, Vol. 86, No. 2, 2012
produced a number of compounds, and thus mild boron-based reducing agents were chosen and reacted
with 3. The results are summarized in Table 2.
O
O
reducing agent (5.0 eq.)
solvent, 0~25 °C
N
N
N
N
R
R
O
O
3
7
Table 2. Reaction of 3 with some boron-based reducing agentsa
Reducing
Agent
Substrate
R
Time
(h)
Product
Yield (%)
Entry
Solvent
3
1
2
3
4
5
a
b
c
c
c
c
d
e
f
Ph
NaBH4
NaBH4
NaBH4
MeOHb
MeOHb
MeOHb
5
5
5
3
5
5
5
5
3
3
3
3
3a
3b
7c
7c
7c
3c
3d
3e
7f
99
99
83
PhCH2CH2
PhOCH2
PhOCH2
PhOCH2
NaBH4
MeOH-CH2Cl2 (1 : 3 v/v)c
MeOHd
97
NaBH3(CN)
BH3•THFf
NaBH4
34e
98
6
PhOCH2
THFg
7
8
9
10
11
12
PhOCH2CH2CH2
PhCH2OCH2CH2CH2
(4-CH3O)C6H4OCH2
PhCH2OCH2
Ph3C-OCH2
MeOHb
100
100
92
96
88
NaBH4
NaBH4
NaBH4
NaBH4
MeOHb
MeOH-CH2Cl2 (1 : 3 v/v)c
MeOH-CH2Cl2 (1 : 3 v/v)c
MeOH-CH2Cl2 (1 : 3 v/v)c
MeOH-CH2Cl2 (1 : 3 v/v)c
g
h
i
7g
7h
7i
PhCH2CH2CH2OCH2
NaBH4
95
a A solution of 1.00 mmol of 1 was added to 5.00 mmol of the reducing agent at 0 °C and then the mixture
b
c
was warmed to 25 °C. 30 mL of methanol was used. A mixture of 1.0 mL of methanol and 3 mL of
d
dichloromethane was used. A mixture of 29 mL of methanol and 1.0 mL of hydrochloric acid was used.
e
f
The starting compound 3c was also recovered in 43% yield. 20.0 mmol of acetic acid was added when
the reaction was stopped. g 6.0 mL of THF was used.
The reaction of 3a, 3b, 3d, and 3e with excess sodium borohydride in methanol did not proceed, which
led to the recovery of these compounds in quantitative yields (Entries 1, 2, 7, and 8). In contrast, the
reaction of 3c with excess sodium borohydride in methanol proceeded smoothly to produce 7c in a good
yield (Entry 3).5,6 A comparison of Entries1-3 and 7 revealed that the position of the oxygen atom in the
side chain plays an important role in the successful reduction of the carbon-carbon double bond by
reaction with sodium borohydride. Changing the solvent from methanol to a mixture of methanol and
dichloromethane could reduce the amount of solvent used and make the reaction clean (Entry 4). When
sodium cyanoborohydride and borane-tetrahydrofuran complex were used instead of sodium borohydride,
7c was also produced in moderate yield in the former case (Entry 5), and 3c was recovered in quantitative
yields in the latter case (Entry 6), respectively. Thus, sodium borohydride was important to reduce the
carbon-carbon double bond in 1,2,3-oxadiazole 3-oxides. The efficient reduction of the carbon-carbon
double bond also proceeded by changing the substituent on methanol from a phenyl group to

HETEROCYCLES, Vol. 86, No. 2, 2012
1043
4-methoxyphenyl, benzyl, triphenylmethyl, and 3-phenylpropyl groups (Entries 9-12);5 thus, the presence
of aryloxymethyl and alkoxymethyl groups at the 5-position of 1,2,3-oxadiazole 3-oxides seemed to be
important for the reduction.7
Although 5-phenoxymethyl-1,2,3-oxadiazole 3-oxide 3c was reacted with neither n-butyllithium nor
ethylmagnesium chloride, its reduced form 4,5-dihydro-5-phenoxymethyl-1,2,3-oxadiazole 3-oxide 7c
was reacted with certain Grignard reagents to produce diazene N-oxides 8. The results of the reaction with
a couple of organometallic regents are summarized in Table 3.
O
O
R3 M (1.5~3.0 eq.)
THF, 0 °C-rt, 2 h
Ph O
Ph O
N
N
N
N R3
O
OH
8a e
7c
-
Table 3. Reaction of 7c with organometallic reagents
Entry
R3
Me
Et
i-Pr
t-Bu
n-Bu
Et
M
(eq.)
1.5
1.5
2.0
3.0
1.5
3.0
Yield (%)
1
2
3
4
5
6
MgCl
MgCl
MgCl
MgCl
Li
8a
25
72
60
98
8b
8c
7c
8e
7c
a
☆
ZnClb
99
a
b
A complex mixture was produced. EtZnCl was prepared by mixing
equimolar amounts of Et2Zn and ZnCl2 at ambient temperature.
Although the reaction of 7c with methylmagnesium chloride was sluggish to produce 8a in moderate
yield (Entry 1),5 that with ethylmagnesium chloride proceeded smoothly to produce unsymmetrical
diazene N-oxide 8b in good yield (Entry 2).5,8 The isopropyl group could also be introduced into the
nitrogen atom (Entry 3).5 However, nothing happened when tert-butylmagnesium chloride was used
(Entry 4). The reaction with n-butyllithium gave a complex mixture (Entry 5) and that with ethylzinc
chloride recovered the starting compound 7c in an almost quantitative yield (Entry 6). In addition, nothing
happened when 3c was reacted with ethylmagnesium chloride. Thus, the reduction of the double bond of
1,2,3-oxadiazole 3-oxides 3c and the reaction with Grignard reagents having primary and secondary alkyl
groups are important for the success of the desired substitution reaction.
We elucidated herein some reactivity of 1,2,3-oxadiazole 3-oxides 3 and developed a new route to
unsymmetrical diazene N-oxides by reacting with sodium borohydride and then with Grignard reagents.
The resulting 7 and 8 are considered as the precursors of substituted -aminoalcohols, which are

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HETEROCYCLES, Vol. 86, No. 2, 2012
important mother nuclei of sympathomimetic drugs. Further development is now under way, and the
dream that ‘medicines can be made from a pollutant (nitric oxide)’ will come true soon in the near future.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
REFERENCES (AND NOTES)
1. J. A. Joule, K. Mills, and G. F. Smith, ‘Heterocyclic Chemistry, 3rd ed.,’ Chapman & Hall, London,
1995.
2. T. Sugihara, K. Kuwahara, A. Wakabayashi, H. Takao, H. Imagawa, and M. Nishizawa, Chem.
Commun., 2004, 216.
3. J. A. Chapman, J. Crosby, C. A. Cummings, R. A. C. Rennie, and R. M. Paton, J. Chem. Soc., Chem.
Commun., 1976, 240.
4. T. K. Kim, J. H. Choe, B. W. Lee, and K.-H. Chung, Bull. Korean Chem. Soc., 2012, 33, 2765.
5. All new compounds were characterized by spectroscopic methods (IR, 1H- and 13C-NMR, MS).
6. The spectroscopic data of the typical compound 7c are as follows: IR (KBr) 1590, 1499, 1473, 1239,
996 cm-1; 1H NMR (400 MHz, CDCl3)  4.22 (dd, J = 3.6, 10.8 Hz, 1 H), 4.30 (dd, J = 4.4, 10.8 Hz,
1 H), 4.65 (d, J = 9.2 Hz, 2 H), 5.34 (ddt, J = 3.6, 4.4, 9.2 Hz, 1 H), 6.92 (ddd, J = 1.2, 2.0, 8.0 Hz, 2
13
H), 7.03 (dd, J = 1.2, 7.6 Hz, 1 H), 7.32 (ddd, J = 2.0, 7.6, 8.8 Hz, 2 H); C NMR  63.41, 66.39,
78.67, 114.60, 122.09, 129.68, 157.57; MS (EI) m/z 194 (M+), 134 (100%), 119, 94, 77, 65. HR-MS
(EI) calcd. for C9H10N2O3 (M+) 194.0692, found 194.0694.
7. The investigation to clarify the reaction mechanism is now under way.
8. The spectroscopic data of the typical compound 8b are follows: IR (KBr) 3442, 297, 2937, 1598,
1588, 1497, 1458, 1424, 1317, 1244, 1078, 1044, 754, 692 cm-1; 1H NMR (400 MHz, CDCl3)  1.31
(t, J = 7.4 Hz, 3 H), 3.52 (tq, J = 1.1, 7.4 Hz, 2 H), 3.76 (d, J = 4.7 Hz, 1 H), 4.02 (dd, J = 6.1, 9.6 Hz,
1 H), 4.12 (d, J = 4.6, 9.6 Hz, 1 H), 4.41 (ddt, J = 1.1, 8.1, 13.2 Hz, 1 H), 4.49 (ddt, J = 1.1, 2.9, 13.2
Hz, 1 H), 4.58 (m, 1 H), 6.91 (ddd, J = 1.2, 2.4, 8.8 Hz, 2 H), 6.99 (dd, J = 1.2, 7.2 Hz, 1 H), 7.30
(ddd, J = 2.4, 7.2, 8.8 Hz, 2 H); 13C NMR  11.74, 46.72, 67.61, 68.56, 71.25, 114.43, 121.34,
129.48, 158.07; MS (EI) m/z 224 (M+), 207, 131 (100%), 107, 94, 77, 65. HR-MS (EI) calcd. for
C11H16N2O3 (M+) 224.1162, found 224.1152.