HNO made-easy from photochemical cycloreversion of novel 3,5-heterocyclic disubstituted 1,2,4-oxadiazole-4-oxides

Article abstract of DOI:10.1016/j.tet.2013.06.067

A variety of symmetric and asymmetric 3,5-heterocyclic disubstituted 1,2,4-oxadiazole-4-oxides have been prepared through cycloaddition of aromatic and heteroaromatic nitrile oxides to heteroaromatic amidoximes. A library of novel, fully characterized, 1,

Full text of DOI:10.1016/j.tet.2013.06.067

Tetrahedron 69 (2013) 7387e7394
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
HNO made-easy from photochemical cycloreversion of novel
3,5-heterocyclic disubstituted 1,2,4-oxadiazole-4-oxides
,
,
,
,
z
Misal Giuseppe Memeo a y, Daniele Dondi a y, Barbara Mannucci b z, Federica Corana b
,
,
Paolo Quadrelli a
*
a
ꢀ
Dipartimento di Chimica, Universita degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Centro Grandi Strumenti, Universita degli Studi di Pavia, Via Bassi 21, 27100 Pavia, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2013
Received in revised form 30 May 2013
Accepted 17 June 2013
Available online 2 July 2013
A variety of symmetric and asymmetric 3,5-heterocyclic disubstituted 1,2,4-oxadiazole-4-oxides have
been prepared through cycloaddition of aromatic and heteroaromatic nitrile oxides to heteroaromatic
amidoximes. A library of novel, fully characterized, 1,2,4-oxadiazole-4-oxides has been obtained as
valuable precursors, upon photochemical activation, of new nitrosocarbonyl intermediates. The photo-
chemical cycloreversion of the 1,2,4-oxadiazole-4-oxides was investigated from the computational point
of view and the hydrolysis of the generated nitrosocarbonyl intermediates in water constituted the way
for an easy-made HNO generation process because of the photochemical behavior of the parent
compounds.
Keywords:
1,2,4-Oxadiazole-4-oxide
Nitrosocarbonyl intermediates
HNO generation
Ó 2013 Elsevier Ltd. All rights reserved.
DFT calculations
Photochemical cycloreversion
1. Introduction
have been recently synthetized and in particular their barbituric
acid and pyrazolone derivatives efficiently generated HNO at
Nitrogen oxides are the critical components of a number of
physiological processes1 and they gained a wide interest with re-
spect to the treatment of heart failure2 and as a preconditioning
agent for the mitigation of ischemia-reperfusion injury.3 The dis-
covery that nitric oxide (NO) as endothelial derived relaxation
factor (EDRF) led to an increase of research in the field.4 The main
problem of studying NO is the diverse array of the nitrogen oxides
that must be considered; one of the most overlooked because of its
chemical simplicity is HNO (nitroxyl or nitroxyl hydride according
to IUPAC nomenclature). Due to its fleeting nature, HNO affords
a dimer (hyponitrous acid), which decomposes to nitrous oxide and
water2 and the direct observation is limited to the gas-phase5 and
matrix studies.6
physiological conditions (pH 7.4, 37 ꢀC) with half-lifes of 0.7 and
9.5 min, respectively.10 Strictly related, a wide range of N,O-bis-
acylated hydroxylamine derivatives with chloro and arenesulfonyl
leaving groups have been prepared and the generation of HNO
optimized under physiological conditions, with tunable half-lives
as a function of the substituents.11 In addition to these methods,
acyl nitroso compounds (ReCOeNO) 1 also display the ability to
generate HNO in the presence of nucleophiles.12
Nitrosocarbonyls are well known and versatile intermediates for
organic synthesis due to their high reactivity.13 Some application of
these fleeting intermediates, stable for at least 180 ms, arised from
their typical reactivity as p2 components in Hetero DielseAlder
(HDA) cycloadditions as well as super-enophiles, affording valuable
structures easily convertible into molecules useful for the prepa-
ration of nucleosides analogues or natural products.14 Traditionally,
nitrosocarbonyls are generated through periodate oxidation of
hydroxamic acids 2 and instantly trapped by dienes (Scheme 1).12
Apart from the oxidation of hydroxamic acids 2 with the more
soluble tetra-alkylammonium periodate salts, other oxidative con-
ditions have been developed15 as well as transition metal catalyzed16
and PhI(OAc)2 oxidations.17 Thermal cycloreversion of the HDA
adducts 3 offers an alternative source of these intermediates, which
can be trapped with different dienes.18 Recently we developed two
alternative entries to nitrosocarbonyls through the mild oxidation of
There is a number of methods to generate HNO from different
donors, such as Angeli’s salt for a fast release of HNO,7 Piloty’s acid8
that releases HNO only at high pH values and isopropylamine
NONOate (IPA/NO),9 that is, an NO donor at lower pH values. Novel
N-substituted hydroxylamines with carbon-based leaving groups
* Corresponding author. Tel.: þ39 0382 987315; fax: þ39 0382 987323; e-mail
address: paolo.quadrelli@unipv.it (P. Quadrelli).
y
Tel.: þ39 0382 987315; fax: þ39 0382 987323.
z
Tel.: þ39 0382 987532; fax: þ39 0382 987323.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.067

7388
M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
The nitrile oxides were generated in situ by adding the aromatic
and heteroaromatic hydroximoyl chlorides 6AeG, prepared
according to the literature procedures,25 to stirred solutions of
heteroaromatic amidoximes26 7aeg (1 equiv) and distilled trie-
thylamine (1.1 equiv) in dichloromethane (DCM). After keeping the
reactions for 48 h at room temperature, the solutions were washed
with brine and the organic phases dried over anhydrous sodium
sulfate. Evaporation of the solvent afforded the residues, from
which the products were isolated. The primary cycloadducts 8
spontaneously aromatize with loss of ammonia affording the 1,2,4-
oxadiazole-4-oxides 5. Separation of the oxides 5 from minor
amounts of unreacted amidoximes and the furoxans, which derive
from the competing dimerization of the nitrile oxides and are sig-
nificantly faster running in TLC, could be easily achieved by column
chromatography. 1,2,4-Oxadiazole-4-oxides 5Bb and 5Dd are
known compounds25b while all the other products were new and
fully characterized through analytical and spectroscopic methods.
In the same manner 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 5Aa
was prepared as reference compound for the HNO generation.
The yields, physical constants, and significant NMR data of the
new 1,2,4-oxadiazole-4-oxides 5 are gathered in Table 1. The
structures were also confirmed by their smooth deoxygenation
with triethylphosphite in boiling benzene affording quantitatively
the corresponding 1,2,4-oxadiazoles 9, which are known com-
pounds.27 In the syntheses of the crossed N-oxides 5 (Table 1, en-
tries 1e4), small amounts of the 3,5-diphenyl-1,2,4-oxadiazole-4-
oxide 5Aa were obtained (2e10%) in good keeping with the cyclic
mechanism previously demonstrated.24
We evaluated the effect of the presence of heterocyclic rings of
different nature in position 3 and 5 of the 1,2,4-oxadiazole ring with
respect to the electronic transitions, photochemically promoted
and active in the fragmentation of the 1,2,4-oxadiazole-4-oxide
into nitrile and nitrosocarbonyl moieties. The UV patterns of the
newly prepared 1,2,4-oxadiazole-4-oxides 5 have been achieved by
recording the UV spectra in acetonitrile solutions. Table 2 reports
the main absorptions (lmax) and the molar extinction coefficients
(ε) for each compound.
With respect to the phenyl group as substituent (entry 1), the
placement of heterocyclic rings modifies quite remarkably the UV
absorption in the 1,2,4-oxadiazole-4-oxides 5. When heterocyclic
substituents are located in position 5 of the 1,2,4-oxadiazole ring
a red-shift in the l1 UV band generally occurred in the range
23e36 nm (entries 2e7). The presence of a heterocyclic ring in
position 3 of the 1,2,4-oxadiazole ring does not affect much the l1
UV absorption (entries 8e10), being strongly related to the sub-
stituent in 5. The l2 UV absorption, however, undergoes small
variation just around the canonical value of the phenyl di-
substituted compound 5Aa (240ꢁ3 nm) when the phenyl ring in
the position 5 is replaced by a heterocyclic ring (entries 2e10).
Remarkable blue- and red-shifts are observed for the l2 UV ab-
sorption when the phenyl ring in the position 3 of the 1,2,4-
oxadiazole ring is replaced by the pyridine rings (entries 8e10:
from ꢂ12 nm to þ22 nm). It seems quite clear that substitution in
position 3 affects mainly the high energy transitions while the
substitution in position 5 of the 1,2,4-oxadiazole ring influences the
Scheme 1.
nitrile oxides 4 with N-methylmorpholine-N-oxide (NMO)19 and the
clean photolysis and thermolysis of 1,2,4-oxadiazole-4-oxides 5.20
The last method, in particular, belongs to the acyl nitroso (nitro-
socarbonyl) compounds generation by photolysis of several classes of
precursors including 9,10-dimethylanthracene adducts and nitro-
diazo compounds allowing for the photo-controllable NO and HNO
donors and their release mechanism.21
The photochemical cleavage of these heterocycles is indeed the
cleanest and softest method for the generation of nitrosocarbonyl
intermediates and raised the interest of research groups involved in
the chemistry of nitric oxide (NO) and nitroxyl (HNO). In particular,
Toscano and co-workers reported the first direct observation of the
nitrosocarbonyl benzene generated through the photochemical
cleavage of the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 5 by time-
resolved infrared (TRIR) spectroscopy and monitored its reaction
with diethyl amine and cyclopentadiene, reporting the detection of
HNO.22
Historically, our group is engaged in the chemistry of 1,2,4-
oxadiazole-4-oxides23 5 and the recent emerging interests for
these encouraged us to develop a small library of 1,2,4-oxadiazole-
4-oxides, symmetrically and unsymmetrically substituted with
five- and six-membered heterocyclic rings, with the aim of better
tuning of the nitrosocarbonyl generation and modulating the re-
leasing of HNO upon the photochemical activation of the parent
heterocycle. The photochemical cycloreversion of the 1,2,4-
oxadiazole-4-oxides was also investigated from a computational
point of view in order to shine some light on this clean generation
of the nitrosocarbonyl intermediates.
2. Results
2.1. The synthesis of 1,2,4-oxadiazole-4-oxides
We have prepared the 3,5-heterocyclic disubstituted 1,2,4-
oxadiazole-4-oxides 5 according to the established procedure
through the 1,3-dipolar cycloaddition of nitrile oxides to amidox-
imes as sketched in Scheme 2.24
_
R
O
R
OH
R
R
Cl
R
NH
OH
+
N
- NH3
N
Et3N, DCM
r.t., 48 h
+
n/p* transition of the N-oxide bond with a remarkable bath-
NH
N
N
N
ochromic shift.28 These features allowed for the tunable generation
of HNO from 1,2,4-oxadiazole-4-oxides under mild and convenient
conditions.
N
OH
R
O
5
O
6
7
8
(EtO)3P
C6H6,
R1
Ph
R2
Ph
2-Py
3-Py
4-Py
2-Thio
2-Pyr
2-Fur
A
a
b
c
d
e
f
R
2.2. Photochemical cycloreversion of 1,2,4-oxadiazole-4-
oxides: a computational study
B
C
D
E
F
2-Py
3-Py
4-Py
2-Thio
2-Pyr
2-Fur
N
N
R
O
9
The nitrosocarbonyl photochemical generation from 1,2,4-
oxadiazole-4-oxides represents the first step toward the HNO
generation and is sketched in Scheme 3; for this reason we have
G
g
Scheme 2.

M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
7389
Table 1
_
The yields, physical constants, and significant NMR data of the 1,2,4-oxadiazole-4-
oxides 5
Ph
O
Ph
O
+
Solvent
h , 2 hrs
N
5
R1
R2
Mp (ꢀC)
Yield (%)
29
1H NMR (
d, ppm, CDCl3)
Ph-CN
+
1
2
Ab
Ph
164e166
Ph: 7.61 (m, 3H)
8.52 (m, 2H)
2-Py: 7.61 (m, 1H)
8.04 (dt, 1H)
8.92 (m, 1H)
9.36 (dt, 1H)
N
N
O
Ph
2-Py
O
5AA
1A
Scheme 3.
Ac
Ph
122e123
35
Ph: 7.62 (m, 3H)
8.51 (m, 2H)
3-Py
3-Py: 7.62 (m, 1H)
8.90 (d, 1H)
The 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 5AA was used as
9.12 (d, 1H)
9.75 (s, 1H)
Ph: 7.66 (m, 3H)
8.47 (m, 2H)
model structure and Fig. 1 shows the enthalpic profile connecting
the intermediates and Transition Structures (TSs) along with the
energy values (kcal/mol) nearby the structures.
3
4
5
6
7
Ad
Ae
Af
Ph
203e206
116e119
160e163
111e114
169e173
38
30
27
32
45
4-Py
4-Py: 7.62 (m, 1H)
8.49 (AA0BB0, 1H)
8.97 (AA0BB0, 1H)
Ph: 7.62 (m, 3H)
8.55 (m, 2H)
2-Thio: 7.38 (dd, 1H)
7.88 (dd, 1H)
8.19 (dd, 1H)
Ph: 7.62 (m, 3H)
8.50 (m, 2H)
2-Pyr: 6.53 (dd, 1H)
7.23 (m, 2H)
11.98 (b, 1H)
Ph: 7.62 (m, 3H)
8.51 (m, 2H)
Ph
2-Thio
2-Pyr
2-Fur
Ph
Ag
Bb
Ph
2-Fur: 6.81 (d, 1H)
7.82 (s, 1H)
8.18 (d, 1H)
2-Py: 7.61 (m, 1H)
8.01 (m, 1H)
2-Py
8.93 (m, 1H)
8.98 (dt, 1H)
2-Py
2-Py: 7.61 (m, 1H)
8.01 (m, 1H)
8.93 (m, 1H)
9.35 (dt, 1H)
8
9
Cc
3-Py
4-Py
132e134
32
29
3-Py: 7.49 (m, 1H)
8.88 (m, 1H)
8.22 (m, 1H)
9.17 (s, 1H)
3-Py: 7.49 (m, 1H)
8.84 (m, 1H)
8.52 (d, 1H)
9.48 (s, 1H)
4-Py: 8.05 (AA0BB0, 1H)
8.87 (AA0BB0, 1H)
4-Py: 8.13 (AA0BB0, 1H)
8.94 (AA0BB0, 1H)
Fig. 1. Enthalpic profile of the photocatalyzed cycloreversion of 5AA. Numbers are
enthalpic differences in kcal/mol.
3-Py
4-Py
The photochemical fragmentation of the 1,2,4-oxadiazole-4-
oxide 5AA occurs at the excited state of triplet 5AA_T located
46.9 kcal/mol above the ground state. Once 5AA_T is formed, two
competitive reactions can be followed. At a higher value of acti-
vation energy (13.2 kcal/mol) TS10 represents the transition
structure of the deoxygenation pathway leading (IRC) to the 1,2,4-
oxadiazole 9AA. The lower path at 3.6 kcal/mol leads to the in-
termediate 12 where the NeO bond of the oxadiazole ring is broken
through the TS11. The open intermediate 12 is remarkably stabi-
lized at 28.2 kcal/mol below the triplet state 5AA_T and, through an
easy passage located 8.6 kcal/mol above, the TS12 leads (IRC) to the
final compounds, benzonitrile and nitrosocarbonyl benzene 1A.
These results nicely account for the presence of small but de-
tectable amounts of the oxadiazole 9AA in all the reactions in-
volving the photochemical fragmentation of 5AA in the presence of
nucleophiles, dienes or olefins as trapping agents of the nitro-
socarbonyl intermediates. The deoxygenation pathway has a higher
activation enthalpy with respect to the stepwise fragmentation of
the heterocyclic ring. However, the gap of 9.6 kcal/mol can be easily
passed under the normal experimental conditions the reactions are
conducted.
Dd
202e203
Table 2
Absorptions (lmax) and molar extinction coefficients (ε) of the 1,2,4-oxadiazole-4-
oxides 5 in acetonitrile solutions
Entry
5
R1
R2
l1
ε
1 104
l2
ε2 104
1
2
3
4
5
6
7
8
9
10
Aa
Ab
Ac
Ad
Ae
Af
Ag
Bb
Cc
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-Py
3-Py
4-Py
Ph
319
0.89
0.61
1.04
0.95
1.11
1.53
1.48
0.68
1.03
1.54
240
239
237
243
244
241
243
228
234
262
2.15
1.34
2.65
2.56
1.75
1.54
2.04
1.19
2.53
3.22
2-Py
3-Py
4-Py
2-Thio
2-Pyr
2-Fur
2-Py
3-Py
4-Py
343 (þ24)
342 (þ23)
355 (þ36)
355 (þ36)
350 (þ31)
348 (þ29)
344 (þ25)
341 (þ22)
351 (þ32)
Dd
investigated the cycloreversion process from the theoretical point
of view by performing DFT calculation at the B3LYP/6-31G (d,p)
level, which gives satisfactory geometries and reliable energies for
the photocatalyzed reaction.29
In Fig. 2 we have also shown the three TSs constituting the
passes in deoxygenation and cycloreversion processes.

7390
M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
studies on its biological activity. HNO has an half-life of approxi-
mately 2e3 min at physiological pH and temperature; it rapidly
dimerizes2,4 in a second-order process to give N2O through a 1,2-
proton shift from dimer 10 affording the hydroxy derivative 11
that collapses to N2O with loss of water.20,23
In all the cases the headspace analyses revealed the presence of
N2O, as a marker of HNO, detected by plotting the mass chro-
matogram of the characteristic ion m/z 30 (deriving from molecular
ion by loss of nitrogen). The retention time of N2O was found at
12.63 min. Standard solutions were prepared from pure N2O, by
dissolving an exact volume of the gas in 10 mL water, and imme-
diately analyzed through headspace analysis. Water could in prin-
ciple be considered as a nucleophile able alone to decompose the
nitrosocarbonyl intermediate and promote the evolution of HNO.
For this reason a variety of 1,2,4-oxadiazole-4-oxides, symmetri-
cally and unsymmetrically substituted with different heterocycles,
have been photolyzed in pure water only, under the same experi-
mental conditions and analyzed for the production of HNO.
Table 3 reports the yields of N2O derived from water hydrolysis
of the photochemical generated nitrosocarbonyl intermediate.
ꢁ
Fig. 2. Side views of TS10, TS11, and TS12. Bond distances are in A and dotted lines
represent the breaking bonds.
Table 3
It is worthwhile to note that the deoxygenation path involves
TS10 where the NeO bond of the N-oxide group is about to be
cleaved out of the average plane of the oxadiazolic ring. In TS11 the
NeO bond of the oxadiazolic ring is cleaved with occurring tilting of
the open fragment. TS12 clearly shows the two final compounds on
the way of their formation after the cleavage of the last CeN bond of
the former oxadiazolic ring.
Yields of N2O upon irradiation of the 1,2,4-oxadiazole-4-oxides 5 in water
Entry
5
R1
R2
N2O (%)
1
2
3
4
5
6
7
8
9
Aa
Ab
Ac
Ad
Ae
Af
Ag
Bb
Cc
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-Py
3-Py
4-Py
Ph
50
21
46
11
91
99
98
39
43
1
2-Py
3-Py
4-Py
2-Thio
2-Pyr
2-Fur
2-Py
3-Py
4-Py
2.3. Hydrolysis of the nitrosocarbonyl intermediates and HNO
generation
10
Dd
Samples of the newly prepared 1,2,4-oxadiazole-4-oxides 5, along
with a sample of 5Aa as reference compound, have been used for the
photochemical generation of HNO.11 Solutions of 3,5-diphenyl-1,2,4-
oxadiazole-4-oxide 5Aa have been prepared at a concentration of
1.22ꢃ10ꢂ3 M in water as solvent (10 mL). These solutions were ex-
posed to sun-light under stirring for 2 h. GC/MS headspace analyses
(see Experimental section) were performed for the detection of N2O
obtained through the reactions reported in Scheme 4.
Compared with the 50% yield of N2O obtained with the 3,5-
diphenyl substituted compound 5Aa, the yields in the other cases
span a wide range of values. The presence of the pyridine rings,
variably oriented with respect to the 1,2,4-oxadiazole ring, do not
give great improvements in N2O generation as the yields are all
below 50%. In some cases (entries 4 and 10) where the 4-pyridyl
derivatives were photolyzed, the N2O yields were extremely low.
These results are in deep contrast with those obtained from the 3-
pyridyl-substituted 1,2,4-oxadiazole-4-oxides 5Ac,Cc (entries 3 and
9). The N2O yields were 46 and 43%, respectively, for 5Ac and 5Cc,
close to value observed for the diphenyl-substituted 5Aa. Some
comments can be made on these results, obtained by irradiating
organic compounds in water as solvent. Trying to simplify the
complexity of concurrent and in some cases competitive mecha-
nisms operating, and since the UV spectra of the asymmetric
compounds 5Ab,Ac,Ad and the symmetric compounds 5Bb,Cc,Dd
are almost identical, we can fix our attention to the hydrolysis step
of the nitrosocarbonyl intermediates photochemically generated,
sketched in the inset of Scheme 5.
_
Ph
O
Ph
O
O
Ph
O
+
Solvent
, 2 hrs
H O
N
h
+
HNO
Ph-CN
+
A
B
N
N
OH
Ph
O
5AA
1A
_
_
H
O
+
_
O
H
O
+
+
N
N
N
N
1,2-shift
2
H
N
O
N
N
+ H O
_
O
H
+
O
H
10
11
Scheme 4.
The 4-pyridyl substituted 1,2,4-oxadiazole-4-oxides 5Ad,Dd
generate the same nitrosocarbonyl intermediate 1d that un-
dergoes hydrolysis in water to afford the carboxylic acid 12d and
HNO. The main question is: on which nitrosocarbonyl structure
does the water undergo nucleophilic addition followed by loss of
HNO to afford the corresponding carboxylic acid? Looking at the
structure 1d it seems quite clear the importance of the presence of
exocyclic conjugation with the pyridine ring and the relative
tautomeric equilibria as well as the presence of charged structures.
The topic has been thoroughly investigated30 and can be referred
as the population level of the possible tautomeric structures in the
The dimerization of HNO in aqueous solution has been recently
investigated from the theoretical point of view on the basis of DFT
calculations.30 The cumbersome property for studying HNO, its fast
dimerization leading to the rapid formation of N2O, can be con-
sidered surprisingly far from being well understood. Scheme 4 re-
ports one of the possible pathways of dimerization.11,21,22
As stated above, it is commonly accepted that the presence of
HNO can be derived from the presence of N2O; the lack of a specific
and convenient trap and/or detection for HNO limits somewhat the

M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
7391
the mechanism of aminolysis by secondary amines is strictly bi-
molecular. For a given amine, the rate of aminolysis is also de-
pendent on the structure of the acyl nitroso compound. The authors
in fact reported the importance of electronic effects; when a p.ClPh
group was inserted in the nitrosocarbonyl structure, the generation
reaction was two to three times faster than in the case of the simple
nitrosocarbonyl benzene with diethyl amine. Aminolysis of acyl
nitroso compounds has been studied for a long time and King and
co-workers examined the production of HNO along with the
preparation of amides by using both oxidation of hydroxamic acids
and the thermal cycloreversion of N-benzoyl-2,3-oxazanorborn-5-
ene.32 Direct HNO detection remains a difficult task and gas chro-
matographic analysis of the reaction headspace of these reaction
mixtures demonstrates the formation of N2O. This remains a valid
demonstration of HNO formation.33
Our results can be summarized in a few points: 1) The versatility
of the synthetic method to prepare 1,2,4-oxadiazole-4-oxides based
on the cycloaddition of nitrile oxides to amidoximes is the most
general way for the synthesis of these heterocycles; although yields
are moderate because of interfering side reactions, the main side-
product is amidoxime itself, which enters the cyclic mechanism
affording the same class of heterocycles. This protocol is applicable
to a variety of nitrile oxides and amidoximes and we have prepared
a selection of heterocyclic substituted derivatives 5 and others are
actually under evaluation. 2) The insertion of heterocyclic ring with
different aromatic features affects somewhat the photochemical
behavior of the 1,2,4-oxadiazole-4-oxides 5 and the UV absorption
band responsible for the fragmentation of the 1,2,4-oxadiazole-4-
oxides can be easily modulated and properly tuned up by varying
the substituent mainly in the position 5 of the heterocyclic ring. 3)
Scheme 5.
presence of aqueous solvation. A tentative interpretation of the
results at hand relies upon the water promoted equilibrium be-
tween the structure 1d and the quinonic form 1d0 (Scheme 4). The
structure 1d0 must be considered when the mechanism of water
addition to the carbonyl group is in action. Formation of the hy-
drated adduct 13 is somewhat slowed down by the quinonic form
1d0 because of the reduced electrophilicity of the carbon atom in
the enolic form.
A similar behavior is expected in the cases of the 2-pyridyl de-
rivatives 5Ab,Bb.
On the other hand, amazing results were obtained with the five-
membered ring heterocycles (entries 5e7). The 1,2,4-oxadiazole-4-
The red-shift in UV absorption band corresponding to the n/p*
oxides 5Ae,Af,Ag showed l
1 UV absorption bands red-shifted in the
transition of the N-oxide bond allowed performing the photo-
chemical cleavage of the oxadiazole ring in an easy way and avoi-
ded the use of UV lamps, making the protocol simpler, shortening
the reaction times and improving the yields. Water as solvent is
overall preferred and easily employed since the heterocycles at
hand displayed a nice and probably improvable solubility in the
solvent. 4) The analytical protocol was accurate and as much as
possible beyond any reasonable doubt. The yields of N2O were
calculated using an external calibration performed on standard
solutions of different concentrations of the gas.
range 348e355 nm and reacted almost quantitatively to afford
HNO. Hydrolysis in water of the corresponding nitrosocarbonyl
intermediates is very efficient and the MS analysis of the reaction
solution allowed identifying benzonitrile and the heterocyclic (fu-
ran, pyrrole, and thiophene) carboxylic acids in nearly quantitative
yields. In these cases furan, pyrrole, and thiophene do not decrease
the electrophilicity of the carbonyl group and water addition pro-
ceeds rapidly (Fig. 3).31
In conclusion, photolysis of 1,2,4-oxadiazole-4-oxides repre-
sents the mildest and most convenient method for the generation
of HNO easy-made in aqueous solutions with potential relevant
applications in biology and medicine.
4. Experimental section
4.1. General
All melting points are uncorrected. Elemental analyses were done
on a C. Erba 1106 elemental analyzer available in our Department. IR
spectra (Nujol mulls) were recorded on an FTIR PerkineElmer RX-1.
1H and 13C NMR spectra were recorded on a Bruker AVANCE 300 in
the specified deuterated solvents. Chemical shifts are expressed in
parts per million (d) from internal tetramethylsilane. Column chro-
Fig. 3. Laboratory system of irradiation for the generation of HNO.
matography and TLC: silica gel 60 (0.063e0.200 mm) (Merck); elu-
ant cyclohexane/ethyl acetate from 9:1 to 1:1. MPLC: Biotage FMP
apparatus equipped with KP-SIL columns, eluant cyclohexane/ethyl
acetate from 9:1 to 7:3. The identification of samples from different
experiments was secured by mixed mps and superimposable IR
spectra. UV spectra were recorded on a PerkineElmer Lambda-16
spectrophotometer in acetonitrile solutions. GC/MS headspace
analysis was performed on a Thermo Scientific DSQII single quad-
rupole GC/MS system.
3. Discussion and conclusions
This HNO made-easy protocol opens the way to future de-
velopments to prepare novel compounds for a rapid and efficient
generation of HNO. Previous results in the field reported by Toscano
and co-workers21a indicated that the mechanism of acyl nitroso
aminolysis by primary amines involves general base catalysis, while

7392
M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
4.2. Materials
(CDCl3,
d
): Ph: 7.62 (m, 3H) 8.50 (m, 2H); 2-Pyr: 6.53 (dd, J 3.0,
1.5 Hz, 1H) 7.23 (m, 2H) 11.98 (b, 1H). 13C NMR (CDCl3,
d): 111.5,
Nitriles, aldehydes, solvents, and all the reagents required for
the preparation of the starting materials are from SigmaeAldrich
and were used without purification.
112.8, 114.1, 120.7, 123.6, 127.7, 128.5, 132.2, 156.3, 158.2. Elemental
Analysis: calcd for C12H9N3O2 (MW¼227.22) C, 63.43; H, 3.99; N,
18.49. Found: C, 63.5; H, 4.0; N, 18.5.
4.3.7. 3-Phenyl-5-(2-furyl)-1,2,4-oxadiazole-4-oxide
32%; mp 111e114 ꢀC (from ethanol). IR ( C]N) 1602 cmꢂ1. 1H NMR
(CDCl3, ): Ph: 7.62 (m, 3H) 8.51 (m, 2H); 2-Fur: 6.81 (d, J 2.0 Hz, 1H)
7.82 (s, 1H) 8.18 (d, J 2.0 Hz, 1H). 13C NMR (CDCl3,
): 112.9, 118.2,
120.8, 128.0, 128.8, 132.7, 136.0, 147.1, 159.5. Elemental Analysis:
calcd for C12H8N2O3 (MW¼228.20) C, 63.16; H, 3.53; N, 12.28.
Found: C, 63.3; H, 3.3; N, 12.5.
5Ag. Yield
4.3. Preparation of the 3,5-disubstituted 1,2,4-oxadiazole-4-
oxides 5
n
d
d
To a stirred solution of heteroaromatic amidoximes 7 (7 mmol)
and distilled triethylamine (7 mmol) in anhydrous DCM (70 mL),
solutions of the aromatic and heteroaromatic hydroximoyl chlo-
rides 6 (7 mmol) in the same solvent (70 mL) were added dropwise.
After keeping the reaction mixtures for two days at room temper-
ature, the organic phases were washed twice with brine and dried
over anhydrous Na2SO4. Upon evaporation of the solvent, the res-
idues were submitted to chromatographic separation to isolate the
desired compounds. 1,2,4-Oxadiazole-4-oxides 5Aa, 5Bb, and 5Dd
are known compounds.25b
4.4. Deoxygenation with trimethyl phosphite
A solution of the 1,2,4-oxadiazole-4-oxides 5 and trimethyl
phosphite (2 equiv) in benzene (30 mL) was heated at reflux for 2 h.
Evaporation of the solvent afforded the crude 1,2,4-oxadiazoles 9,
which were crystallized from suitable solvent. All the 1,2,4-
oxadiazoles are known compounds and are identical with samples
obtained by thermal cyclization of the O-acyl amidoximes (toluene,
reflux overnight) following well-established procedures.19
4.3.1. 3,5-Di(3-pyridyl)-1,2,4-oxadiazole-4-oxide 5Cc. Yield 32%; mp
132e134 ꢀC (from ethanol). IR ( C]N) 1587 cmꢂ1. 1H NMR (CDCl3,
n
d
): 3-Py: 7.49 (m, 1H) 8.88 (m, 1H) 8.22 (m, 1H) 9.17 (s, 1H); 3-Py:
7.49 (m, 1H) 8.84 (m, 1H) 8.52 (d, J 5.0 Hz, 1H) 9.48 (s, 1H). 13C NMR
(CDCl3, ): 123.5, 123.8, 134.5, 134.9, 135.3, 148.2, 148.4, 149.1,
151.9, 153.4, 160.7. Elemental Analysis: calcd for 12H8N4O2
4.5. UV spectra of 1,2,4-oxadiazole-4-oxides 5
d
C
The UV spectra of the 1,2,4-oxadiazole-4-oxides 5 were pre-
pared by dissolving samples of the solid compounds in acetonitrile
to have concentrations around 10ꢂ5 M and the spectra were
(MW¼240.22) C, 60.00; H, 3.36; N, 23.32. Found: C, 60.1; H, 3.3; N,
23.5.
recorded on
a PerkineElmer Lambda-16 spectrophotometer
4.3.2. 3-Phenyl-5-(2-pyridyl)-1,2,4-oxadiazole-4-oxide 5Ab. Yield
29%; mp 164e166 ꢀC (from ethanol). IR ( C]N) 1577 cmꢂ1. 1H NMR
n
equipped with the PECSS Software pkg Ver. 4.5. Table 2 reports the
absorptions (lmax) and molar extinction coefficients (ε) of the 1,2,4-
oxadiazole-4-oxides 5 in acetonitrile solutions.
(CDCl3,
J 8.1, 2.0 Hz, 1H) 8.92 (m, 1H) 9.36 (dt, J 8.1, 1.0 Hz, 1H). 13C NMR
(CDCl3, ): 120.6, 122.8, 126.7, 127.8, 128.5, 132.4, 137.1, 139.7,
150.4, 160.5, 166.7. Elemental Analysis: calcd for 13H9N3O2
d): Ph: 7.61 (m, 3H) 8.52 (m, 2H); 2-Py: 7.61 (m, 1H) 8.04 (dt,
d
C
4.6. N2O quantification via GC/MS headspace analysis
(MW¼239.23) C, 65.27; H, 3.79; N, 17.56. Found: C, 65.4; H, 3.8; N,
17.5.
In glass vials (20 mL capacity) sealed with silicone/PTFE caps,
3 mg of the 1,2,4-oxadiazole-4-oxides 5 were suspended in 10 mL
of distilled water. The samples were exposed to sun-light for 2 h.
4.3.3. 3-Phenyl-5-(3-pyridyl)-1,2,4-oxadiazole-4-oxide
35%; mp 122e123 ꢀC (from ethanol). IR ( C]N) 1592 cmꢂ1. 1H NMR
(CDCl3, ): Ph: 7.62 (m, 3H) 8.51 (m, 2H); 3-Py: 7.62 (m,1H) 8.90 (d, J
5.0 Hz, 1H) 9.12 (d, J 5.0 Hz, 1H) 9.75 (s, 1H). 13C NMR (CDCl3,
):
5Ac. Yield
n
N2O produced was determined analyzing 200 mL of the headspace
d
and quantified using an external calibration. The emission of N2O
in samples was determined by external calibration. Standard so-
lutions were prepared from pure N2O purchased from Sigma-
eAldrich by dissolving an exact volume of the gas in 10 mL water.
The calibration samples were immediately analyzed through
headspace analysis. N2O yields are taken as an average of five
injections.
d
117.2, 120.7, 123.7, 128.1, 128.9, 132.8, 147.1, 153.5, 158.5, 160.8. Ele-
mental Analysis: calcd for C13H9N3O2 (MW¼239.23) C, 65.27; H,
3.79; N, 17.56. Found: C, 65.4; H, 3.8; N, 17.5.
4.3.4. 3-Phenyl-5-(4-pyridyl)-1,2,4-oxadiazole-4-oxide 5Ad. Yield
38%; mp 203e206 ꢀC (from ethanol). IR (
n
C]N) 1549 cmꢂ1. 1H NMR
N2O peak areas determined are plotted against the concentra-
tions of the different calibration levels. Ten calibration solutions
(CDCl3,
d
): Ph: 7.66 (m, 3H) 8.47 (m, 2H); 4-Py: 7.62 (m, 1H) 8.49
): 118.4, 120.6,
(AA0BB0, 1H) 8.97 (AA0BB0, 1H). 13C NMR (CDCl3,
d
were prepared and the N2O mmols were plotted versus the area of
126.7, 128.1, 128.9, 132.9, 151.1, 158.3, 161.2. Elemental Analysis:
calcd for C13H9N3O2 (MW¼239.23) C, 65.27; H, 3.79; N, 17.56.
Found: C, 65.3; H, 3.7; N, 17.6.
the response for the N2O peak (R2¼0.9971).
The injection in the GC/MS system was performed at 250 ꢀC
splitless for 2 min. The initial oven temperature of 35 ꢀC was main-
tained for 2 min, increased by 30 ꢀC/min to 200 ꢀC and held for 8 min.
4.3.5. 3-Phenyl-5-(2-thiophenyl)-1,2,4-oxadiazole-4-oxide
AThermo Scientific TG-BOND Msieve 5A 30 mꢃ0.32 mmꢃ30
mm film
5Ae. Yield 30%; mp 116e119 ꢀC (from ethanol). IR
(
n
C]N)
): Ph: 7.62 (m, 3H) 8.55 (m, 2H); 2-
Thio: 7.38 (dd, J 5.0, 4.0 Hz, 1H) 7.88 (dd, J 5.0, 1.1 Hz, 1H) 8.19
(dd, J 4, 1 Hz, 1H). 13C NMR (CDCl3,
): 119.2, 120.9, 127.9, 128.0,
128.4, 128.8, 130.7, 132.7, 133.4, 159.1. Elemental Analysis: calcd for
thickness PLOT column was used with helium as the carrier gas at
a constant flow-rate of 1.0 mL/min. The transfer line temperature was
200 ꢀCandtheionsourcetemperaturewas250ꢀC.Electronionization
mode was used with 70 eV and the ions were registered in full scan
mode in a mass range of m/z 16e300 amu.
1590 cmꢂ1 1H NMR (CDCl3,
. d
d
C
12H8N2O2S (MW¼244.27) C, 59.00; H, 3.30; N, 11.47. Found: C,
Quantification was carried out in Full Scan mode, using char-
acteristic ion m/z 30 as quantifier ion (Fig. 4).
58.9; H, 3.3; N, 11.5.
The chromatogram acquisition, detection of mass spectral peaks
and their waveform processing were performed using Xcalibur MS
Software Version 2.1 (Thermo Scientific Inc.).
4.3.6. 3-Phenyl-5-(2-pyrroyl)-1,2,4-oxadiazole-4-oxide
5Af. Yield
27%; mp 160e163 ꢀC (from ethanol). IR ( C]N) 1612 cmꢂ1. 1H NMR
n

M.G. Memeo et al. / Tetrahedron 69 (2013) 7387e7394
7393
Fig. 4. Mass chromatogram and EI mass spectrum of N2O.
Acknowledgements
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Supplementary data
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