Photochemical isomerization of aryl hydrazones of 1,2,4-oxadiazole derivatives into the corresponding triazoles

Article abstract of DOI:10.1039/c2pp25073j

The photochemical version of the Boulton-Katritzky reaction has been studied, examining the behaviour of the arylhydrazones of 3-benzoyl-5-X-1,2,4- oxadiazoles. The effect of several modifications of the substrates structure (the E and/or Z structures of

Full text of DOI:10.1039/c2pp25073j

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PAPER
Photochemical isomerization of aryl hydrazones of 1,2,4-oxadiazole
derivatives into the corresponding triazoles†
Maurizio D’Auria,*a Vincenzo Frenna,b Salvatore Marullo,b Rocco Racioppi,a Domenico Spinellic and
Licia Viggiania
Received 22nd March 2012, Accepted 21st May 2012
DOI: 10.1039/c2pp25073j
The photochemical version of the Boulton–Katritzky reaction has been studied, examining the behaviour
of the arylhydrazones of 3-benzoyl-5-X-1,2,4-oxadiazoles. The effect of several modifications of the
substrates structure (the E and/or Z structures of arylhydrazones, the possible presence of substituents in
the arylhydrazono moiety, and the nature of substituents at C-5 of the 1,2,4-oxadiazole ring) on the course
of the photochemical rearrangement has been examined.
Introduction
Generally speaking the syntheses of heterocycles can be
achieved via two general schemes:1 (a) from one (or more) open
chain compounds, the obtaining of the ring can be realised
through the formation of one (or more) new bond (e.g., a C–C, a
C–X, or a X–Y); (b) from a first heterocyclic compound a differ-
ent heterocyclic system can be got through a ring-into-ring
rearrangement.
Ring-into-ring rearrangements can occur via ring-expansion or
-contraction as well as maintaining the same number of atoms in
the ring. All of these kinds of transformations can be realised in
both polar and non-polar conditions. Among these last kind of
reactions an important role is played by the photochemical
routes.
As a matter of fact the isomerisation of pentatomic hetero-
cyclic compounds is one of the most important photochemical
reactions of this type of compounds.2 At least five mechanisms
can be invoked in order to justify the photochemical isomerisa-
tion of pentatomic aromatic heterocycles: (1) the ring contrac-
tion–ring expansion route (RCRF) (Scheme 1, A); (2) the
internal cyclization–isomerisation route (ICI) (Scheme 1, B); (3)
the van Tamelen–Whitesides general mechanism (VTW)
(Scheme 1, C); (4) the zwitterion–tricycle route (ZT) (Scheme 1,
D); (5) the fragmentation–readdition route (FR) (Scheme 1, E).
1,2,4-Oxadiazoles are reactive substrates for some photoche-
mical transformations giving 1,3,4-ozadiazoles or isomerised
Scheme 1 Possible mechanisms for the photochemical isomerisation
of pentatomic heterocyclic compounds.
aDipartimento di Chimica “A. M. Tamburro”, Università della
Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy.
E-mail: maurizio.dauria@unibas.it
bDipartimento di Scienze e Tecnologie Molecolari e Biomolecolari,
1,2,4-oxadiazoles, as shown by Vivona et al.3 More recently, the
Università di Palermo, Viale delle Scienze, Parco d’Orleans 2, 90128
Palermo, Italy
same authors reported that irradiated 1,2,4-oxadiazoles can inter-
cDipartimento di Chimica “G. Ciamician”, Università di Bologna, Via
act with a double bond (CvC) giving both inter- and intra-mole-
Selmi 2, 40126 Bologna, Italy
cular reactions (Scheme 2).4 Considering that the intramolecular
†Electronic supplementary information (ESI) available. See DOI:
reaction of styrene derivatives with a hydrazone to give the
10.1039/c2pp25073j
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Experimental section
(2,5-Diphenyl-2H-1,2,3-triazol-4-yl)benzamide
Compound 1a (35 mg) was dissolved in 1 : 1 dioxane–water
mixture (20 ml). The mixture was deoxygenated by nitrogen
bubbling and irradiated with a Photochemical Multirays Reactor
(Helios-Italquartz, Milan, Italy) equipped with ten 15 W lamp
whose output was centered at 366 nm. After 96 h the mixture
was diluted with brine and extracted with chloroform. The
organic layers were collected and dried (Na2SO4). The solvent
was evaporated and the crude product was chromatographed on
silica gel. Elution with 5 : 4.5 : 0.5 methylene chloride–hexanes–
ethyl acetate gave 17 mg (49%) of 2a: m.p. 191 °C (lit.9
Scheme 2 Photochemical conversion of 1,2,4-oxadiazoles and intra-
molecular reaction of a styrene derivative with a hydrazone.
1
191 °C); H NMR (CDCl3, 500 MHz), δ: 8.11 (d, J = 7.5 Hz,
2 H), 7.98 (bs, 1 H), 7.94 (d, J = 7.5 Hz, 2 H), 7.34 (d, J =
7.0 Hz, 2 H), 7.61 (dd, J1 = J2 = 7.5 Hz, 1 H), 7.53 (dd, J1 = J2
= 7.5 Hz, 2 H), 7.51 (dd, J1 = J2 = 7.5 Hz, 2 H), 7.44 (dd, J1 =
J2 = 7.0 Hz, 2 H), 7.40 (dd, J1 = J2 = 7.0 Hz, 1 H), and
7.38 ppm (dd, J1 = J2 = 7.5 Hz, 1 H). The 13C NMR, CDCl3, δ:
142.72, 140.40, 139.81, 133.43, 132.68, 129.84, 129.46, 129.08,
129.04, 128.82, 127.72, 127.25, and 118.83 ppm. HRMS, m/z,
340.1330 (Calcd for C21H16N4O: 340.1324).
Scheme 3 The Boulton–Katritzky rearrangement (the structure of the
transition state is depicted in Fig. 1).
Reaction of 1a in AcCN
Compound 1a (40 mg) was dissolved in acetonitrile (20 ml).
The mixture was deoxygenated by nitrogen bubbling and ir-
radiated with a Photochemical Multirays Reactor (Helios-
Italquartz, Milan, Italy) equipped with ten 15 W lamps whose
output was centered at 366 nm. After 24 h the solvent was evap-
orated. The crude product was chromatographed on silica gel.
The elution with 5 : 4.5 : 0.5 methylene chloride–hexanes–ethyl
acetate gave 20 mg (50%) of 2a.
Fig. 1 The structure proposed by some of us for the transition state of
the uncatalyzed path of the BKR is depicted in the instance of the hydra-
zone of 3-formyl-1,2,4-oxadiazole.
corresponding dihydropyrazoles has been reported (Scheme 2),5
we decided to test the possibility to obtain a photochemical iso-
merization of some arylhydrazones of 3-benzoyl-1,2,4-oxa-
diazoles into 1,2,5-triazoles.
Reaction of 1b in benzene
Compound 1b (36 mg) was dissolved in benzene (20 ml). The
mixture was deoxygenated by nitrogen bubbling and irradiated
with a Photochemical Multirays Reactor (Helios-Italquartz,
Milan, Italy) equipped with ten 15 W lamp whose output was
centered at 366 nm. After 90 h the solvent was evaporated. The
crude product was chromatographed on silica gel. The elution
with 5 : 4.5 : 0.5 methylene chloride–hexanes–ethyl acetate gave
25 mg (72%) of 2a.
The conversion we like to realise is the photochemical version
of the well-known Boulton–Katritzky rearrangement (BKR,
Scheme 3):6
a ring-into-ring (really an azole-into-azole)
rearrangement able to open the way to the synthesis of a number
of azoles starting from pentatomic heterocycles containing an
oxygen–nitrogen bond in the ring and a –X = Y–ZH system (in
some instance also a –X–Y–ZH can work) at the C-3 carbon
atom doubly bonded to the cyclic nitrogen N-2. As a matter of
fact ‘the scope of the Boulton–Katritzky scheme, as claimed by
L’abbé,7 has not been fully exploited, and new reactions are fre-
quently reported’. This statement is quite old, but the results we
report here show it is true after a long time.
BKRs have been investigated by some of us, looking at the
effect of the structure of the involved hydrazones, of the solvent
used, and of the experimental conditions (proton concentration
in protic solvents and the presence of bases or acids in aprotic
solvents) on the course of the reaction. Changing the experimen-
tal conditions, different reaction mechanisms can be operating
(base-catalyzed, uncatalyzed, and acid-catalyzed pathways have
been evidenced). In every instance the rearrangement seems to
occur as a SNi process via a quasi-aromatic transition state with
ten π-electrons involved in a bicyclic structure (Fig. 1).8
[2-(3-Chlorophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl]urea
Compound 1d (62 mg) was dissolved in acetonitrile (15 ml).
The mixture was deoxygenated by nitrogen bubbling and ir-
radiated with a Photochemical Multirays Reactor (Helios-
Italquartz, Milan, Italy) equipped with ten 15 W lamp whose
output was centered at 366 nm. After 24 h the solvent was
evaporated and the crude product was chromatographed on silica
gel. The elution with 1 : 1 hexanes–ethyl acetate gave 17 mg
1
(27%) of 2b: m.p. 274–275 °C (lit.,7 274–275 °C); H NMR,
500 MHz, DMSO-d6, δ: 8.56 (s, 1 H), 8.04 (s, 1 H), 7.99 (d, J =
8.4 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H), 7.62 (dd, J = 8.4 Hz,
1 H), 7.55–7.40 (m, 4 H), and 6.25 ppm (s, 2 H). 13C NMR,
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DMSO-d6, δ: 159.04, 145.97, 145.40, 142.85, 136.94, 134.42,
132.07, 129.63, 129.15, 126.22, 125.85, 120.43, and
119.33 ppm. HRMS, m/z: 313.0725 (Calcd for C15H12ClN5O:
313.0730).
[2-(3-Chlorophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl]urea
Compound 1e (70 mg) was dissolved in acetonitrile (15 ml).
The mixture was outgassed with nitrogen and irradiated with a
Photochemical Multirays Reactor (Helios-Italquartz, Milan,
Italy) equipped with ten 15 W lamp whose output was centered
at 366 nm. After 24 h the solvent was evaporated and the crude
product was chromatographed on silica gel. The elution with
1 : 1 hexanes–ethyl acetate gave 39 mg (56%) of 2b.
[2-(4-Cyanophenyl)-5-phenyl-2H-1,2,3-triazol-4-yl]benzamide
50 mg of 1f (0.14 mmol) were dissolved in 10 ml of acetonitrile,
and irradiated for 18 h in a multirays apparatus (Helios-Ital-
quartz, Milan, Italy) equipped with twelve 8 W UV lamps with
output centred at 310 nm. The solution was then evaporated to
afford 80 mg of crude mixture, which was chromatographed on
silica gel (eluant: petroleum ether–EtOAc 9 : 1 to 8 : 2) to obtain
1
20 mg (40%) of pure 2d. H NMR (CDCl3, 400 MHz): δ 8.23
(d, 2 H, J = 8.8 Hz), 7.91 (d, 2 H, J = 6.8 Hz), 7.79 (3 H, m),
7.61–7.43 (8H, m). 13C NMR, CDCl3, δ: 143.74, 142.32,
141.86, 133.91, 133.76, 133.13, 129.68, 129.34, 129.28, 129.16,
129.05, 128.83, 128.69, 128.62, 127.73, 127.35, 119.00, 118.57,
114.15, and 110.95 ppm. ESI-MS: 366 (M+ + H).
Scheme 4 Photochemical rearrangement of 1,2,4-oxadiazoles.
Table 1 Photochemical rearrangement of 1,2,4-oxadiazoles
1,2,4-
Entry Oxadiazole
Irradiation
time [h]
Yields
Product [%]
Solvent
[2-(4-Methoxyphenyl)-5-phenyl-2H-1,2,3-triazol-4-yl]benzamide
1
1a
Dioxane–
96
2a
49
water
Acetonitrile 24
50 mg of 1g (0.13 mmol) were dissolved in 10 ml of acetonitrile,
and irradiated for 18 h in a multirays apparatus (Helios-Ital-
quartz, Milan, Italy) equipped with twelve 8 W UV lamps with
output centred at 310 nm. The solution was then evaporated to
afford 50 mg of crude mixture, which was chromatographed on
silica gel (eluant: petroleum ether–EtOAc 9 : 1 to 8 : 2) to obtain
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2a
2b
2c
2c
2d
2e
50
72
—
27
56
40
44
Benzene
Benzene
Acetonitrile 24
Acetonitrile 24
Acetonitrile 18
Acetonitrile 18
90
90
1g
1
22 mg (44%) of pure 2e. H NMR (CDCl3, 400 MHz): δ 8.04
(s, 1 H), 7.96 (d, 2 H, J = 9.2 Hz), 7.89 (d, 2 H, J = 7.2 Hz),
7.77 (d, 2 H, J = 7.2 Hz), 7.56 (t, 1 H, J = 7.6 Hz), 7.46 (t, 2 H,
J = 7.6 Hz), 7.41–7.34 (m, 3 H), 6.96 (d, 2 H, J = 9.2 Hz), 3.84
(s, 3 H). 13C NMR, CDCl3, δ: 159.27, 142.27, 139.85, 133.64,
133.49, 132.68, 129.93, 129.10, 129.05, 127.71, 127.21, 120.34,
114.54, and 55.76 ppm. ESI-MS: 371 (M+ + H).
possible. On the contrary, in benzene (in the absence of added
bases) the kinetic constant for the uncatalyzed rearrangement
could not be calculated, because it is too low.10 The irradiation
wavelength was selected on the basis of the UV spectrum of the
substrate. The Z isomer 1a gave the triazole 2a with 50% yield.
1
The H NMR in CDCl3 showed a doublet at δ 8.11 (J = 7.5 Hz,
2 H), aromatic ortho protons, a broad singlet at δ 7.98 (1 H), the
NH proton, a doublet at δ 7.94 (J = 7.5 Hz, 2 H) and a doublet
at δ 7.34 (J = 7.0 Hz, 2 H), aromatic ortho protons, a doublet of
doublet at δ 7.61 (J1 = J2 = 7.5 Hz, 1 H), a doublet of doublet at
δ 7.53 (J1 = J2 = 7.5 Hz, 2 H), a doublet of doublet at δ 7.51 (J1
= J2 = 7.5 Hz, 2 H), a doublet of doublet at δ 7.44 (J1 = J2 = 7.0
Hz, 2 H), a doublet of doublet at δ 7.40 (J1 = J2 = 7.0 Hz, 1 H),
and a doublet of doublet at δ 7.38 ppm (J1 = J2 = 7.5 Hz, 1 H),
corresponding to meta and para protons. The 13C NMR showed
signals at δ 142.72, 140.40, 139.81, 133.43, 132.68, 129.84,
129.46, 129.08, 129.04, 128.82, 127.72, 127.25, and
118.83 ppm. All these data are in agreement with the proposed
Results and discussion
We tested the photochemical behavior of the 1,2,4-oxadiazoles 1
(Scheme 4, Table 1). The solvents used in these experiments
were selected after an experiment in the dark, to avoid an uncata-
lyzed thermal reaction. In fact, the polar 1 : 1 dioxane–water
mixture was able to act as a donor as well as an acceptor of
hydrogen bonds and, then, was able to promote the uncatalyzed
process. In this solvent mixture, the kinetic constant for the un-
catalyzed process has been measured: the calculated period of
half life for 1a is in the range of 1000–150 h in the temperature
range 293–313 K.8 Then, a thermal reaction using this solvent is
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structure. It is noteworthy that the E-isomer 1b gave the relevant
triazole 2a in 72% yield. Furthermore, if the reaction is per-
formed using gassed solutions, the presence of the by-product 3
can be detected in reasonable yields (20%). This by-product
probably derives from a reaction of oxygen with the excited state
of the oxadiazole allowing the attack of the CvN bond of the
hydrazone.
Scheme 5 Key step in the photochemical rearrangement of 1,2,4-
oxadiazoles.
On the contrary, the oxadiazole 1c, where the phenyl substitu-
ent at C-5 of the oxadiazole ring is absent, while a chlorine sub-
stituent is present on the Z-hydrazonic part of the molecule, did
not give any rearrangement product (Scheme 4, Table 1): only
decomposition products were observed. A theoretical expla-
nation of this behaviour can be formulated (see below), this be-
haviour could be a further example of the observed increased
stability of the 5-aryl substituted 1,2,4-oxadiazoles (diaryloid
effect).8,11 In fact, the 5-phenyl substituted oxadiazole deriva-
tives 1a and 1b gave the photochemical transposition, while the
5H (unsubstituted at C-5) derivative 1c decomposed under the
same reaction conditions.
An effect similar to that exerted by the 5-phenyl group12 on
the stability of the substrate was found when the arylhydrazones
of 5-amino substituted 1,2,4-oxadiazoles have been tested.
Confirming this assumption, the Z-arylhydrazonic oxadiazole
1d, where an amino group is present at C-5 on the oxadiazole
ring, gave the corresponding triazole 2c in 27% yield (Scheme 4,
Fig. 2 Frontier orbitals involved in the photochemical rearrangement
of 1,2,4-oxadiazole 1a.
1
Table 1). The H NMR spectrum in DMSO-d6 showed a singlet
giving only decomposition compounds. To answer this question
we performed some DFT and TD-DFT calculations by using
B3LYP/6-31-G+(d,p) on Gaussian 09.14
at δ 8.56 (1 H), a singlet at δ 8.04 (1 H), a doublet at δ 7.99 (J =
8.4 Hz, 1 H), a doublet at δ 7.88 (J = 7.2 Hz, 2 H), a doublet of
doublet at δ 7.62 (J = 8.4 Hz, 1 H), a multiplet in the range at δ
7.55–7.40 (4 H), and a singlet at δ 6.25 ppm (2 H). The
13C NMR spectrum showed signals at δ 159.04, 145.97, 145.40,
142.85, 136.94, 134.42, 132.07, 129.63, 129.15, 126.22, 125.85,
120.43, and 119.33 ppm. All these data are in agreement with
the proposed structure and data reported.9
Furthermore, the relevant E-isomer 1e gave the corresponding
triazole 2c in 56% yield (Scheme 4, Table 1). It is noteworthy
that the E-isomers 1b and 1e gave better results than the corres-
ponding Z-isomers 1a and 1d. These results merit an explanation
considering that the reaction has to occur on the Z-isomer. It
could be explained considering that we obtained also decompo-
sition products in these reactions. Probably, the Z-isomers were
less stable towards the by-products formation than the corre-
sponding E-isomers.
Finally, we tested the reaction on homologues of the com-
pound 1a, bearing an electron-withdrawing group (CN, com-
pound 1f, Scheme 4, Table 1) or an electron-releasing
group (OCH3, compound 1g, Scheme 4, Table 1) in the aryl-
hydrazono moiety. Both these compounds reacted giving the
corresponding triazoles. However, both the substituents induced
lower yields of the corresponding triazoles than the unsubstituted
derivative.
As a counter-check we have looked at the course of the reac-
tion in the dark observing with all of the examined substrates
that no reaction occurs in comparable times, thus obtaining
results in line with pre-visions based on some of our previous
kinetic results.6,10,13
Considering compound 1a, it showed an excited singlet state
at 382 nm. The energy of the singlet state is 74.90 kcal mol−1
.
The triplet state showed an energy of 35.38 kcal mol−1. In the
case of the compound 1c the first excited singlet state was found
with an energy of 79.77 kcal mol−1, while the triplet state
showed an energy of 35.33 kcal mol−1. There was no substantial
difference between these two compounds.
The conversion of oxadiazole–triazole could be a photochemi-
cal electrocyclic reaction in a 6π system. The reaction has to
occur through a conrotatory process, as described in the
Scheme 5.
In order to verify this hypothesis, we verified whether our
compounds can give a conrotatory electrocyclic ring closure in
their excited singlet and triplet states. The reaction has to occur
through the interaction between the HSOMO and the LUMO
orbitals.15
The frontier orbitals of the excited singlet states in the oxadia-
zole derivatives 1a are depicted in Fig. 2.
We can see that, in the case of oxadiazole 1a, the HSOMO is
a π orbital centred on the oxadiazole ring, while, on the contrary,
in the LUMO is localized on all the molecule and also on the
hydrazone. The arrows indicate the atomic orbitals involved in
the reaction. We can see that the interaction between the
HSOMO and LUMO can occur through a conrotatory process.
In the case of 1c, the shape of the molecular orbitals is
inverted (Fig. 3). The HSOMO is localized on all the molecule,
while the LUMO is mainly localized on the oxadiazole ring.
In this case, considering the atomic orbitals involved, we can see
that the atomic coefficient on the LUMO is very low. This way,
we can explain the lack of reactivity observed with this
molecule.
On the basis of the results described above we attempted to
understand why compound 1a rearranges to give a triazole,
while compound 1c does not furnish rearrangement products,
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Fig. 3 Frontier orbitals in 1c.
Conclusion
In this paper we have shown that the uncatalyzed Boulton–
Katritzky rearrangement can be obtained by using a photochemi-
cal approach. The E-arylhydrazone of 3-benzoyl-1,2,4-oxadia-
zole (1b and 1e) were the better substrates in order to obtain the
corresponding 1,2,3-triazole derivatives. The 1,2,4-oxadiazole
derivatives have to be substituted at C-5 in order to realise the
reaction. The key step of the reaction can be considered an elec-
trocyclic conrotatory heterocyclization on a 6π system. This
hypothesis (see Scheme 5) is in good agreement with the pro-
posed transition state for the uncatalyzed polar rearrangement
(Fig. 1). The only difference we can find between the polar and
the photochemical process is that, in the photochemical pro-
cedure, the reaction occurs between the HSOMO and the LUMO
of the substrate, while, in the polar one, the reaction occurs
between the HOMO and the LUMO. Also in this case, a conrota-
tory process can occur. Furthermore, it is difficult to compare the
chemical yields of both the processes. In fact, we know that the
thermal uncatalyzed process is able to give the triazole in very
good yields,16 but the chemical yields of the uncatalyzed
thermal process to give 2a–e cannot be found in the literature.
The only datum we found is relative to compound 2c, which
could be obtained in 84% yield.12 Assuming that the thermal
process gives very good yields of the corresponding triazoles,
the photochemical process gave lower yields. Probably, consider-
ing that by products could not be isolated in the reaction
mixture, the photochemical process induces the decomposition
of the starting materials or of the products.
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photochemical isomerisation when a π orbital is available in a
correct position and the formation of another pentatomic hetero-
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8 D. Spinelli, A. Corrao, V. Frenna, N. Vivona, M. Ruccia and
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