Electrocyclic Ring-Opening of 1,2,4-Oxadiazole[4,5-a]piridinium Chloride: a New Route to 1,2,4-Oxadiazole Dienamino Compounds

Article abstract of DOI:10.1002/open.201900230

1,2,4-Oxadiazole[4,5-a]piridinium chloride adds nucleophiles to undergo electrocyclic ring opening affording 1,2,4-oxadiazole dienamino derivatives. These pyridinium salts represent a special class of Zincke salts that are prone to rearrange when treated

Full text of DOI:10.1002/open.201900230

DOI: 10.1002/open.201900230
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Electrocyclic Ring-Opening of 1,2,4-Oxadiazole[4,5-a]
piridinium Chloride: a New Route to 1,2,4-Oxadiazole
Dienamino Compounds
[a]
Stefano Carella, Misal Giuseppe Memeo,* and Paolo Quadrelli*
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1
,2,4-Oxadiazole[4,5-a]piridinium chloride adds nucleophiles to
to give the pyridones. The pivotal tuning of the experimental
conditions leads to a straightforward synthesis of valuable 1,2,4-
oxadiazole dienamine derivatives. The mechanism is also
discussed in the light of NMR experiments and theoretical
calculations.
undergo electrocyclic ring opening affording 1,2,4-oxadiazole
dienamino derivatives. These pyridinium salts represent a
special class of Zincke salts that are prone to rearrange when
treated with primary amines or in the presence of bicarbonate
1. Introduction
1
,2,4-Oxadiazoles are valuable heterocycles extensively studied
both from the synthetic and applicative point of view by
numerous research organic chemistry groups. The synthesis of
these heterocycles can be accomplished through conventional
and unconventional methodologies and several methods are
[1]
reported in the literature.
The great deal of interest in 1,2,4-oxadiazoles derives from
their biological activities and the use in drug discovery often as
hydrolysis-resisting bioisosteric replacements for amide or ester
functionalities because of their electronic properties. Some
derivatives can also act as a bioisostere of the carboxylic acid
function in retinoid structures. Compounds containing the
oxadiazole ring were found to be anti-inflammatory or antiviral
agents, agonists of muscarinic receptors, peptidomimetics,
Figure 1. Structural features of some 1,2,4- and 1,3,4-oxadiazole compounds.
[1,2]
antitumor agents.
Many oxadiazole-based biologically active compounds share
some specific structural features (Figure 1). Often, the oxadia-
zole rings are linked through a spacer (alkylic, aromatic,
containing ether or ester functionalities, ect.) to a second
[
7]
1,3,4-oxadiazoles have been synthetized via a [3+2] cyclo-
addition reaction of nitrile oxides with allylic alcohol, exhibiting
anti-inflammatory activities in carrageenan-induced edema
[3]
[8]
heterocyclic moiety. This is, for instance, the case of the
linezolid-like 1,2,4-oxadiazole derivatives whose antibacterial
activities were evaluated using Gram-positive and -negative
(comparable to ibuprofen). Similarly, bis-1,3,4-oxadiazoles,
synthetized by oxidative cyclization of Schiff bases, were
screened for in vitro antibacterial activities.
Following up the interest relaying on 1,2,4-oxadiazole
derivatives, we reconsidered under a new light the approach
to 1,2,4-oxadiazoles based on 1,3-dipolar cycloadditions of
nitrile oxides. These 1,3-dipoles of type 2 are traditionally in situ
generated from the corresponding hydroxymoyl chlorides of
type 1 in the presence of bases, typically tertiary amines
[9]
[4]
pathogens. Oxadiazole-based derivatives can find application
[5]
[10]
in the treatment of type-II diabete and as anticancer
[6]
compounds. A series of novel ether-linked bis(heterocyclic)
[
a] Dr. S. Carella, Dr. M. G. Memeo, Prof. P. Quadrelli
Department of Chemistry
[11]
(
Scheme 1). When instead, nucleophilic aromatic bases, such
University of Pavia
Viale Taramelli 12, 27100 – Pavia (Italy)
E-mail: misalgmemeo@gmail.com
paolo.quadrelli@unipv.it
as pyridine, are used the formation of the furoxan dimers 3, is
in competition with the formation of zwitterion 4.
This intermediate is formed in a low stationary concen-
tration, and is involved into the dimerization process that leads
to dioxadiazines 5 or undergoes a further cycloaddition, leading
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201900230
©
2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution Non-Commercial NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
[12]
to a stable bis-cycloadduct 7. Aside from reversion to the
reactants, the zwitterion 4 can enter also an electrocyclic
closure to the monocycloadduct 6, in equilibrium with the
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Scheme 3. Synthesis of the 1,2,4-oxadiazole[4,5-a]pyridinium salt.
Scheme 1. Nitrile oxide formation from chloroximes 1 and pyridine and
subsequent dimerization and cycloaddition processes.
using the 2-bromo-pyridine 10b with similar results in terms of
yields. The structure relies upon the corresponding analytical
and spectroscopic data. Compound 9 is a solid colorless
compound, having m.p. 197–8°C (from chloroform), and shows
1
at the H NMR spectrum (DMSO) highly deshielded signals
corresponding to the pyridine moiety; the proton H5 in the
heterocycle is found at δ 9.26 as a doublet (J=7 Hz) while the
H7 is found at δ 8.93 as a double doublet (J=7 and 8 Hz).
Slightly shielded are the other protons H6 and H8, found at δ
Scheme 2. Nitrile oxide reactions with 2-substituted pyridines and reaction
pathway to 5-substituted 1,2,4-oxadiazoles. FG, functional groups.
8
.12 and 8.82, respectively, coupled with the adjacent protons,
as expected.
An indirect confirm of the reported structure of 9 came
reactants and unstable towards cycloreversion. A further cyclo-
addition of nitrile oxide leads to the stable bis-cyclocadducts
from the hydrolysis experiments. The salt 9 is stable for days in
water solution but unstable in the presence of bases. When
[13,14]
7
.
By replacing pyridine with 2-hydroxypyridine, adduct 8
can be obtained and upon heating in acidic conditions a stable
treated with 5% solution NaHCO , compound 9 gives rise to
3
[12]
salt of type 9 is formed (Scheme 1).
oxadiazole ring opening reaction and just after ten minutes the
insoluble adduct 8 starts separating off the water solution. After
one day the reaction is nearly quantitative and the adduct 8
was isolated in 93% yield, identical to the product obtained
Expanding our investigation on the reactivity of nitrile
oxides with 2-substituted pyridines, we envisioned the study of
benzonitrile oxide (BNO) 2 (Scheme 2, R=Ph), identifying an
unexpected route to 5-dienamino substituted 1,2,4-oxadiazoles
when in the presence of a nucleophile of type R’-Z.
The scope of this methodology towards these derivatives is
presented and investigated in the light of the mechanism
proposed, with the aim to set up the protocol for obtaining
single products with reliable and positive impacts on the
synthetic ground.
upon
hydroxypyridine.
BNO
generation
in
the
presence
of
2-
[12–14]
The reaction can be speed up by using
1
5% NaOH solution; completion is reached after
(monitoring by TLC) and the final pyridine 8 can be obtained as
a solid compound by addition of 5% HCl solution or bubbling
=
2
hour
CO to neutralize the solution.
2
The salt 9 is stable in methanol solution as well as in other
organic solvents. Once evaluated the instability of 9 in a basic
environment, we then tested the chemical behavior in the
presence of organic bases, such as ammonia and amines. To
ensure a low concentration of free bases in solution (vide infra)
and monitor the competitive formation of different compounds,
the reactions were performed by adding triethylamine (2 equiv.)
to an excess of amines hydrochlorides (1.5 equiv.) (Scheme 4).
The in situ-formed amines smoothly react with 9 yielding
unexpected products, the (1E,3E)-4-(3-phenyl-1,2,4-oxadiazol-5-
yl)buta-1,3-dien-1-amines 11a–j, isolated by simple evaporation
of the alcoholic solvent, washing of the dichloromethane (DCM)
organic solution with water and final evaporation of the dried
organic phase. The products 11a–j were recrystallized by
proper solvents and obtained in general in nearly quantitative
yields, with a few exceptions as reported in Table 1.
2. Results
Supported by our previous findings (Scheme 1), we commenced
to study the BNO cycloaddition reaction in the presence of
variously functionalized pyridines (FG=halogen and amino
groups).
Upon in situ generation of BNO 2 in a benzene solution with
an excess of 2-chloro-pyridine 10a (2–5 equiv.), the BNO dimer
3
,4-diphenylfuroxan 3 was obtained in nearly quantitative yields
(Scheme 3). When the same reaction is conducted in polar and
protic solvents (e.g. MeOH) in the presence of the same excess
pyridine 10a, the furoxan formation is circumvented and, upon
evaporation of the solvent, the salt 9 is obtained as solid
compound in 71% yield. The synthesis can be carried on by
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Scheme 4. Synthesis of the 4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
amines 11a–j.
Table 1. Yields, Mp.s (solvent) of compounds 11a–j.
1
Figure 2. H NMR spectrum (DMSO) of morpholino derivative 11j.
Entry 11
R
R’
Yield (%) m.p. (°C)
(Solvent)
We have conducted the reaction between the pyridinium
salt 9 and the 2-amino-pyridine or N-methylamino-pyridine
2.5 equiv.) under the previously described experimental con-
ditions. After 2 days, the reaction mixture was washed with
water and the dried organic phase was submitted to chromato-
graphic separation to isolate the expected products of type
12a,b (Scheme 5).
1
2
a
b
c
d
e
f
H
H
Me
H
H
H
72
94
2
>100 (dec.) iPr O
Me
Me
Et
nPr
iPr
94–96
iPr O
2
(
3
4
98
66
90
99–101
>95 (dec.)
82–84
EtOH
EtOH
Et O
2
5
6
H
89
88–89
2
iPr O
7
8
9
10
g
h
i
H
CH
2
Ph 87
115–117
115–116
88–89
EtOH
À (CH
2
2
)
)
4
À
98
99
99
MeOH
MeOH
MeOH
À (CH
5
À
j
À (CH CH ) O
2
2 2
138–139
The structures of compounds 11a–j are based upon the
corresponding analytical and spectroscopic data. The most
1
relevant and diagnostic feature in the H NMR spectra is the
sequence of four olefinic protons found in the range 5.00–8.70
Scheme 5. From salt 9, the synthesis of the N-[(1E,3E)-4-(3-phenyl-1,2,4-
oxadiazol-5-yl)buta-1,3-dien-1-yl]pyridin-2-amines 12a,b.
δ. From all the reported compounds, the representative case of
1
the morpholine derivative 11j is shown in the H NMR spectrum
(DMSO) of Figure 2. Typically, protons of type Ha and Hb are
doublets quite deshielded, close to the aromatic protons
region.
The products were isolated in 95% and 98% yields,
respectively for 12a and 12b and their structures rely upon the
corresponding analytical and spectroscopic data. In particular
the H NMR spectra showed the typical dienamine structure
already observed in compounds 11 along with the aromatic
Conversely, the Hd (doublets) and Hc (triplets or double
doublets) protons are found up-field below 6.50 δ. More details
on the spectroscopic characterizations of compounds 11a–j can
be found in the experimental section. The reactions can be also
conducted with free amines although with lower yields and the
reactions appear dirtier since the high concentration of the
bases somewhat activates a competitive decomposition proc-
ess. Concerning the stability of the synthesized compounds,
products from primary amines are less stable both in the solid
state and in solution and degrade to unspecified fragments. In
particular, the ammonia derivative 11a decomposes rapidly in
solution, e.g. during the acquisition of the NMR spectra, and
undergoes rapid oxidation when left to open air.
1
signals attributable to the pyridine moiety. Figure 3 shows the
H NMR spectrum (DMSO) of the compound 12a with the main
1
attributions. More insight on the mechanism and synthetic
suitability came from the experiments performed directly
between both 2-amino-pyridine and N-methylamino-pyridine
and in situ generated BNO, in polar solvents (MeOH or CHCl3)
(Scheme 6). After a couple of days, the worked-up mixtures
afforded the desired compounds.
Compounds 12a,b were isolate in 30% and 25% yield,
respectively, along with the dioxadiazine 5 (8%) from the
dimerization of BNO under basic conditions,
[15,16]
In order to expand the synthetic scope of the reaction
leading to dienamino heterocycles of type 11, we also
considered the use of heterocyclic amines, starting from the 2-
amino-pyridines.
the 3,5-
diphenyl-1,2,4-oxadiazole-4-oxide 13 (15%) whose formation is
clearly attributable to the BNO cycloaddition to the correspond-
ing amidoxime derived from aminopyridine addition to BNO
[
17]
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Scheme 6. Synthesis of the N-[(1E,3E)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-
,3-dien-1-yl]pyridin-2-amines 12a,b from 2-amino-pyridine or N-meth-
ylamino-pyridine and BNO.
1
1
Figure 3. H NMR spectrum (DMSO) of amino-pyridine derivative 12a.
and the pyridine adduct 8 (43%) as a result of the addition of
OH to the salt 9 that is the reaction intermediate of the whole
pericyclic process (see also Scheme 3).
À
Scheme 7 shows the nucleophilic addition of the amines to
the electrophilic carbon C5 of the pyridinium ring of 9, that
triggers the pivotal step represented by the disrotatory electro-
cyclic ring opening of the not isolable intermediate 14 leading
to compounds 11/12. Since the stereochemistry of the obtained
products of type 11/12 does not correspond to the primary
expected ones (dienamines 15 and 16 were not isolated),
according to the pericyclic reaction selection rules, we decided
to further investigate the ring-opening step.
We monitored the reaction following the formation and
disappearance of the intermediates generated by the nucleo-
philic addition to the salt 9 as well as the final products by NMR
technique, in CD OD as solvent. Here we report the case of the
3
reaction of 9 with dimethylamine as representative of the
behavior of all the amines used as reported in Scheme 4 and
Table 1.
At the very beginning of the reaction (t=0 h) the fast
electrocyclic ring opening of 14 affords the compound (E,Z)-16c
as major component of the reaction mixture while the (Z,Z)-
1
Figure 4. H NMR spectra of the reaction between the pyridinium salt 9 and
3
dimethylamine in CD OD at t=0, 1 h, 6 h, 12 h and 24 h.
1
5c, also detectable, remains the minor component and rapidly
disappears (Figure 4). The structure attribution is based on the
Scheme 7. Electrocyclic ring opening mechanism in the reactions between the oxadiazole-pyridinum salt 9 with amines and isomerization of dienamino
derivatives.
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Figure 5. Formation of compound 11j with time performed from salt 9 in
the presence of morpholine in MeCN as solvent at 25°C.
Figure 6. Reactions of the salt 9 with morpholine in CHCl
at 68% of (E,Z)/(E,E) isomerization, with and without norbornene.
3
as solvent at 60°C
Table 2. Isomeric ratios and life times of intermediates from electrocyclic
ring opening reactions of the salt 9 with amines.
the cyclic ones (entries 7, 8), reasonably because of the steric
demand of the piperidine or morpholine rings. The surviving E/
Z isomer slowly converts into the E/E compound within the
time of few days. Cyclic amines (pyrrolidine, pyperidine and
mopholine) react faster at the beginning of the reactions that
are speed up in methanol rather than in chloroform.
To monitor the kinetic of the process we followed the
reaction of the salt 9 with amines by HPLC analyses and
Figure 5 shows the formation of compound 11j with time
performed in the presence of morpholine in acetonitrile (for
analytical reasons).
A quantitative conversion requires 3.09 mmol/L of the
product 11j and this theoretical value is nearly reached after
day (6000 min). In order to verify if the morpholine adduct
1j is the solely product of the reaction we have conducted a
faster reaction in chloroform at 60°C, also in the presence of
Figure 6 reports two plots of reactions of 9 with morpholine
at the 68% of (E,Z)/(E,E) isomerization. The nearly identical
pattern confirms that the morpholine addition occurs only at
the position 5 of the pyridinium ring leading to the dienamino
products of type 11 excluding any competitive cycloreversion
reaction. As a consequence, Scheme 8 shows the allowed and
forbidden paths for secondary amines. Addition to the carbon
C8a of the pyridinium ring (red arrows) leading to 17, does not
occur at all.
When primary amines are used, the detection and in some
cases the isolation of 2-amino-pyridines bearing the substituent
corresponding to the primary amine could be explained by
invoking a competitive process as shown in the blue box of
Scheme 8: it leads to the undetectable and not-isolable
intermediate 18 that evolves through base deprotonation to 19
and final fragmentation into the 2-substituted pyridine and
BNO. The BNO presence in the reaction mixture is confirmed by
the detection of dimerization products whose formation under
basic conditions was already accounted through several
[a]
[a]
Entry RR’NH
Z,Z/E,Z
Z,Z
life time
E,Z/E,E
E,Z/E,E
conv. time
[b]
[b]
1
2
3
4
5
6
7
8
a R=R’=H
b R=H, R’=Me
c R=R’=Me
d R=H, R’=Et
e R=H, R’=nPr
f R=H, R’=iPr
1/8
1/6
1/3
1.6/1
1.3/1
1/1
1/1
1/1
3 h
2 h
1 h
12 h
8 h
8 h
50 min.
40 min.
2/1
2/1
9/1
10/1
8/1
8/1
10/1
60/1
2 d
2 d
3 d
3 d
2 d
2 d
2 d
3 d
i R=R’=À (CH
2
)
5
À
j R=R’=
À (CH
2
CH
2
)
2
OÀ
[
a]. Isomeric ratio determined as an average of the heights of the olefinic
1
3
signals in the H NMR spectra recorded in CD OD: 9, 10 mg; amines, 2
equivs. (if liquid, an excess if gas). [b]. Lifetime; time for complete
disappearance signals of isomer at hand.
4
1
coupling constants clearly readable and measured from the
NMR spectra. In particular, the intermediate (Z,Z)-15c showed
two J of 11 and 12 Hz consistent for a (Z,Z) configuration of the
two C=C double bonds. On the other hand, the intermediate
norbornene as scavenger of the BNO.
(
E,Z)-16c showed two J of 13 and 11 Hz consistent for a (E,Z)
configuration.
After 1 h the (E,Z)-16c is the only product observed still
growing from the reactants. From this point on the reaction
proceeds slowly and after 6 h a little amount of the final
product, (E,E)-11c is found. Compound (E,E)-11c showed a
typical C=C (E,E) configuration due to the J of 13 and 15 Hz; it
slowly increases in the reaction mixture in 12 h time and
overtakes the (E,Z)-16c isomer only after 24 h. Reaction
completion occurs after 4 days with complete disappearance of
the salt 9 and full conversion in the final products. Table 2
gathers the data relative to analogous NMR experiments
(
CD OD) conducted for almost all the amines used for the
3
synthesis of compounds 11, showing different kinetics for the
different nucleophiles.
Referring to entry 3, the Z/Z isomer is the minor component
of the mixtures formed just after the electrocyclic ring opening.
Isomer Z/Z life time ranges from few hours in the cases of
aliphatic amines (entries 1–6) to 40–50 minutes in the cases of
[14–17]
reported mechanisms.
To confirm the previous observa-
tions, a few experiments were conducted on the 5-methyl-1,2,4-
oxadiazole-[4,5-a]-pyridinium 21 (Scheme 9).
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5
5
Scheme 8. Secondary and primary amines addition mechanisms to salt 9.
3
. Discussion
The results here reported clearly show the intriguing reactivity
of the 1,2,4-oxadiazole-pyridinium salts of type 9. These
monocycloadducts obtained through a pseudo-pericyclic
addition of nitrile oxides to pyridine derivatives deserve a
remarkable interest, not only from the mechanistic point of
view but also synthetically. The ring-opening of Zincke salts
dates back over a century and the activation of pyridines as
their pyridinium salts triggers the nucleophilic addition at the 2-
[
19]
[
20]
Scheme 9. Reactions of the 5-methyl-1,2,4-oxadiazole-[4,5-a]-pyridinium
chloride 21 with ammonia, bicarbonate and ammonia in the presence of
norbornene.
[21]
and 5-positions leading to dienamino derivatives.
Being
synthetically remarkable, in recent years this methodology
found application in the synthesis of nitrogen heterocycles by
the conversion of pyridinylÀ anilines into indoles and a plausible
mechanism was proposed to occur conceivably through an
electrocyclic pathway. The authors did not investigate the
mechanism that was proposed to be simply ionic followed by
alkene geometrical isomerization. The literature on this point
only corroborates the nucleophilic addition step, ring opening
The salt 21 was prepared according to the well-established
procedure from 2-chloro-2-picoline and BNO. The structure of
[22]
2
1 is consistent with the corresponding analytical and spectro-
1
scopic data; in the H NMR spectrum (DMSO), besides the
typical aromatic signals, a singlet at δ 2.30 corresponds to the
[
23]
methyl group. The salt 21 smoothly reacts with NaHCO 5%
and alkene isomerization.
3
solution in water to afford quantitatively the pyridone 22 whose
structure was confirmed by the spectroscopic analyses. When
the salt 21 was treated with ammonia in chloroform as solvent
at room temperature the addition of the base occurs on the
C8a carbon atom leading to the 5-amino-2-picoline 23 (40%)
and the benzamidoxime 24 (37%), found identical to known
However we wish to summarize here through Scheme 10
the complex picture of the reactions involved that were
accounted by the experimental results exposed in this work.
The addition of amines to the flat pyridinium ion can occur on
both sides of the heterocyclic ring leading to the not-isolable
adduct 14. Before discussing the disrotatory electrocyclic ring-
opening, a conformational analysis of 14 was conducted
through DFT calculations at the B3LYP/6-31G* level. We have
optimized at the lowest energy level the four possible con-
formers of adduct 14a (R=R’=H): adducts 14eq and 14eq’ are
mirror images with the NH group in the equatorial position at
the C5 carbon atom in conformational equilibrium with the
axial enantiomeric structures 14ax and 14ax’. The theoretical
calculations demonstrated that only the axial conformer
structures 14ax and 14ax’ correspond to energy minima (see
calculated structures in Scheme 10) and the equatorial con-
formers cannot be located not only at this level of theory but
authentic samples as a product of the addition of NH to
3
[17,18]
[24]
BNO.
Moreover, when the salt 21 is allowed to react with
ammonia in the presence of excess norbornene in chloroform
solution at room temperature, besides the 5-amino-2-picoline
2
3 (30%) and the benzamidoxime 24 (5%), the BNO norbor-
2
nene cycloadduct 25 was isolated in 49% yield. As clearly
shown, the methyl on the C5 of the pyridinium ring forbids the
nucleophilic addition at the same carbon atom and activates
the cycloreversion pathway of the salt 21.
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Scheme 10. Nucleophilic addition of amines to the salt 9 with disrotatory mechanism outcome from adduct 14.
the (E,Z)-(E,E) isomerization that occurs in a longer time scale
see Table 2) to afford the final dienamino derivative 11a. We
(
have also located the two Transition Structures (TS) connecting
the structures 14 with the intermediates (Z,Z)-15a and (E,Z)-16a
(Scheme 11) (B3LYP 6-31+g(d,p) M06). TS_A can be reached
from both 14ax and 14ax’ and is found at 13.86 kcal/mol
above. IRC data confirmed that TS_A connects 14ax and 14ax’
with intermediate (E,Z)-16a. The route to (Z,Z)-15a passes at
higher energy, 25.47 kcal/mol above 14ax and 14ax’ through
TS_B (Figure 7).
Regarding the (Z,E)-isomerization process, the literature
reports some examples of this processes but nothing strictly
[
22,25]
related to the structures at hand.
Figure 7. DFT calculated TSs for the electrocyclic ring-opening of com-
pounds 14. Numbers near the structure are relative energies in kcal/mol.
Scheme 12 shows in a simple and straightforward manner
how compounds of type (Z,Z)-15 can easily isomerize to (E,Z)-16
through the zwitterion 15’ and the conformer 15’’ derived from
rotation around the CÀ C bond as indicated by the blue arrow.
Similarly occurs for the slow isomerization that converts 16 into
the final products of type 11 or 12.
even higher or even introducing constraints during the
optimization runs. Structures 14ax and 14ax’ only differ by
0
.22 kcal/mol. Adducts 14ax and 14ax’ can undergo disrotatory
electrocyclic ring-opening following the orientations indicated by
the curly arrows; for each structure two pathway are possible, 4. Conclusions
leading to either the (Z,Z)-15a or (E,Z)-16a intermediates.
According to the NMR investigations and Table 2 results,
both the ring-opening orientation are allowed: the (Z,Z) path
suffers of steric problems since this pathway locates the amine
substituents inward the 6π array, presumably causing steric
clashes with the oxadiazole ring. From the NMR experiments,
the (Z,Z)/(E,Z) ratio ranges from 1/8 to 1/1 upon increasing the
steric demand of the amines. Significantly, at the same
concentration level of (Z,Z)/(E,Z) intermediates, the life time
decreases upon the steric requirements of the bases (Table 2,
entries 6–8). On the other hand, the (E,Z) path is preferred and
Pyridinium salts of type 9 belong to the wide family of the
[26]
Zincke salts.
In a recent perspective article, Vanderwal
accounted for the use of pyridines for the preparation acyclic
and heterocyclic compounds belonging to several classes of
organic compounds through the valuable and century-old
[
27]
Zincke ring-opening reaction.
Moreover, Zincke reaction
found applications in the synthesis of spin-lanbels TEMPO
[28]
[29]
derivatives,
materials and nanomaterials,
preparation of
[30]
ligands for Pd-catalyzed reactions, up to the application in
[31]
the drug synthesis.
1
6a is more stable than 15a by 2.29 kcal/mol. The final step is
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Scheme 11. DFT (B3LYP/6-31G*) calculated structures of key intermediates and products. Numbers near the structure are relative energies in kcal/mol.
Hydrogen-bonding distance (dashed line) is expressed in Å.
Scheme 12. Isomerization mechanism of compounds 15.
The 1,2,4-oxadiazole[4,5-a]piridinium chlorides 9 represent a
special category of Zincke salts displaying a unique chemical
behavior, interesting and valuable on both mechanistic and
applicative points of view. First of all, these salts are easy to
prepare in high yields and from a variety of halogen-substituted
pyridines 10 (Scheme 13). Further substituents on the pyridine
ring can decorate the diene moiety in final products of type 11.
Moreover, the nitrile oxides 2 can be also selected from a wide
range of aromatic and aliphatic derivatives and easily generated
from the corresponding hydroxymoyl chlorides 1 and in some
case they are stable enough to simplify the reaction
Finally the choice of the amines that trigger to electrocyclic
ring-opening determines the structure of the diene-end moiety.
For these reasons a number of elements can be properly tuned-
up to design the desired structure of the final compounds of
type 11, thus expanding the synthetic scope of the reaction. In
this view, the overall mechanism and chemical behavior of
these pyridinium salts must be taken into account also for the
synthetic design of the desired products.
At the end, Scheme 14 summarizes the reactivity of salts 9
and the connections with the various chemical species as we
have reported in this work from the experiments conducted
that disclosed the intriguing chemistry of these compounds,
[32]
conditions.
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offering a chart to the different reaction pathways. Pyridinium
salts 9 can be prepared either from halogen-substituted
pyridine 10 or from 2-amino-pyridines. In this latter case
dienamine products 12 are formed when the 2-amino-pyridine
are used in excess. Through electrocyclic ring-opening triggered
by amines or 2-amino-pyridines the dienamino compounds 11
and 12 are obtained. However, the salts 9 are prone to
decompose when treated with primary amines or in the
presence of bicarbonate to give the pyridone 8. A cyclo-
reversion process is also active leading to the pyridine and
nitrile oxides that dimerize to the dioxadiazines 5 and the 1,2,4-
oxadiazole-4-oxides 13 when in the presence of amines.
The best way to prepare the products of type 11 is
definitively the separate preparation of the salt 9 and then
submit the salt to treatment with amines as hydrochloride salts
in the presence of triethylamine to ensure a low concentration
of the free base and to gain high yields of the desired products.
Slightly different is the behavior of 2-amino-pyridines that,
being less nucleophilic, can be used without passing through
their hydrochloride salts and compounds 12 can be easily
isolated in optimum yields. The tuning of the experimental
conditions is the key point to have a straightforward synthesis
of valuable dienamine derivatives.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Samples of some of the synthetized compounds were sent
[33]
to the NIAID (NIH, USA) for in-vitro tests against a variety of
viruses for a primary antiviral evaluation. Products 11h–j and
12a were tested against the Herpesviridae family, Varicella-
Zoster virus, (VZV), from the Hepatic virus HBV, Respiratory
Viruses such as Influenza A virus H1N1 (IV/H1N1), Adenovirus-5
(AD5), from the Togavidae family, Chikungunya virus (CV), from
the Flaviridae group, Yellow Fever Virus (YFV), from the
Bunyaviridae family, Punta Toro Virus (PTV), and from the
Papovaviridae the Human Papilloma Virus (HPV). Compounds
11h–j and 12a were found inactive against all the viruses
tested with slight differences. Other targets and planned
investigations will promise further developments.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
Scheme 13. Synthetic pathway to pyridinium salts 9 and dienamines 11.
Scheme 14. Mechanistic chart: from pyridinium salts 9 to dienamine products 11 and 12 through electrocyclic ring-opening. Nitrile oxide dimerization
processes to furoxans 3, dioxadiazines, 5 and 1,2,4-oxadiazole-4-oxides 13 and decomposition pathway of salts 9 under basic conditions to pyridines 8.
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Experimental Section
All melting points (Mp) are uncorrected. Elemental analyses were
Calcd for C12
H
9
N
2
OCl (232.67): C, 61.95; H, 3.90; N, 12.04. Found: C,
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
61.96; H, 3.89; N, 12.06.
1
done on a elemental analyzer available at the Department. H and
1
3
C NMR spectra were recorded on a 300 MHz spectrometer
solvents specified). Chemical shifts are expressed in ppm from
internal tetramethylsilane (δ) and coupling constants (J) are in Hertz
Hz): b, broad; s, singlet; bs, broad singlet; d, doublet; t, triplet; m,
Synthesis of the 1-[(hydroxyimino)(phenyl)methyl]
pyridin-2(1H)-one 8
(
(
To a solution of 46 mg (0.2 mmol) of the salt 9 in 2 mL of water,
1 mL 80.6 mmol) of NaHCO 5% were added. The reaction was left
under stirring at room temperature and after 10 minutes the
pyridine 8 starts separating off the solution. After one day, the solid
is filtrated, dried and characterized.
multiplet. IR spectra (nujol mulls) were recorded on a spectropho-
tometer Perkin-Elmer RX-1 available at the Department and
3
À 1
absorptions (ν) are in cm . Column chromatography and tlc: silica
gel H60 and GF254, respectively; eluents: cyclohexane/ethyl acetate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
9
:1 to pure ethyl acetate. UV spectra were recorded on a Perkin-
1
-[(Hydroxyimino)(phenyl)methyl]pyridin-2(1H)-one 8, 40 mg (93%),
Elmer Lambda 16 UV Spectrophotometer in acetonitrile as solvent.
HPLC analyses were carried out by means of a WATERS 1525
instrument, equipped with an UV2487 detector (λ=254 nm) both
controlled by Breeze software and a RP C-18 Intersil ODS-2 column:
a mixture of H O/CH CN 60:40 was used as eluent. Quantitative
colourless crystals from water, m.p. 201–203°C. IR: ν
1703, νC=N
C=O
À 1
1
1
653 cm . H-NMR (DMSO) δ: 6.35 (t, 1H, J=8 Hz, pyridone); 6.51
(d, 1H, J=9 Hz, phenyl); 7.44 (s, 5H, phenyl); 7.46 (d, 1H, J=9 Hz,
13
pyridone); 7.57 (dd, 1H, J=8, 1 Hz, pyridone); 12.04 (s, 1H, OH). C-
NMR (DMSO) δ: 105.7; 120.9; 125.3; 128.8; 129.9; 131.5; 137.8; 141.4;
146.1; 159.8. Anal. Calcd for C12
2
3
determinations were conducted using the 5,5-dimethyl-3-phenyl-
,5-dihydroisoxazole as internal standard.
H N O (214.22): C, 67.28; H, 4.71; N,
10 2 2
4
13.08. Found: C, 67.26; H, 4.70; N, 13.07.
Starting and Reference Materials
-Hydroxypyridine, 2-chloropyridine, 2-bromopyridine, 2-aminopyr-
General Procedure for the Reaction of the Salt 9 with Primary
and Secondary Amines
2
idine, 2-methylaminopyridine and 2-amino-6-methylpyridine were
purchased from Sigma-Aldrich (Merck). Ammonia and all the
primary and secondary amines used in this work were also
purchased from Sigma-Aldrich (Merck). The corresponding
hydrochloride salts were synthesized from standard procedures.
A solution of the pyridinium salt 9 is prepared with 1.4 g (6 mmol)
in 50 mL of methanol. To this solution 9 mmol of the amine
hydrochlorides, dissolved in 20 mL of methanol, were added
followed by 2 mL (14.2 mmol) of freshly distilled triethylamine
dropwise. The reaction mixtures were left under stirring at room
temperature for 5 days. After this period of time, methanol is
removed at reduced pressure and the residues were taken up with
toluene to ensure precipitation of insoluble chlorides. The organic
phases were then washed with water and dried over anhydrous
Na SO . Upon evaporation of the solvent, solid residues were
Benzhydroximoyl chloride was obtained by treatment of benzaldox-
ime with sodium hypochlorite. Addition of a slight excess of Et N
to a DCM solution of benzhydroximoyl chloride furnished in situ
BNO.
[
32]
3
2
4
Solvents and all the other reagents were purchased from Sigma-
Aldrich (Merck) and used without any further purification with the
single exception of triethylamine that was carefully distilled and
used in all the reactions, when requested.
submitted to chromatographic isolation and the solid compounds
were recrystallized from proper solvents to afford the final products
11a–j that were fully characterized.
(1E,3E)-4-(3-Phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-amine
0.92 g (72%), yellow crystals from diisopropylether, m.p. >100
(dec.). IR: νC=N 1660 cm . H-NMR (DMSO) δ: 5.98 (t, 1H, J=12 Hz,
CH=); 6.37 (d, 1H, J=15 Hz, CH=); 7.30 (t, 5H, J=12 Hz, CH=); 7.53
11a,
°
C
À 1
1
Synthesis of the 1,2,4-oxadiazole[4,5-a]piridinium Chloride 9
To a methanol solution (40 mL) of 5.0 g (32 mmol) of benzhydrox-
ymoyl chloride 1, 6.0 g (10 mL, 53 mmol) of 2-chlropyridine were
added and the mixture was cooled at 0°C with an ice-bath.
(
d, 1H, J=15 Hz, CH=); 7.57 (m, 3H, phenyl); 8.03 (m, 2H, phenyl).
C-NMR (DMSO) δ: 103.9; 106.2; 126.7; 128.7; 131.2; 142.2; 143.8;
13
1
67.3; 167.6; 176.3. Anal. Calcd for C H N O (213.24): C, 67.59; H,
1
2
11
3
Triethylamine (30 mmol, 4.8 mL) dissolved in 20 mL methanol was
added dropwise under stirring and the solution turns from colour-
less to pale yellow. The reaction is left under stirring for 6 h; after
this period of time, methanol is removed at reduced pressure and
the residue is taken up with benzene to dissolve the pyridine
excess. Upon filtration, the crude salt 9 is obtained along with the
triethylamine hydrochloride. Purification of 9 is secured by dissolv-
ing the salt mixture with chloroform and leaving to crystallized the
pyridinium salt 9 in colourless crystals. The product was submitted
to complete characterization.
5.20; N, 19.71. Found: C, 67.58; H, 5.18; N, 19.70.
(1E,3E)-N-Methyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
amine 11b, 1.28 g (94%), yellow crystals from diisopropylether, m.p.
À 1
1
94–96°C. IR: ν
1640 cm . H-NMR (CDCl ) δ: 2.84 (d, 3H, J=7 Hz,
C=N
3
NÀ CH
); 4.30 (b, 1H, NH); 5.38 (t, 1H, J=12 Hz, CH=); 6.08 (d, 1H, J=
3
15 Hz, CH=); 6.88 (dd, 1H, J=12, 7 Hz, CH=); 7.41 (m, 3H, phenyl);
1
3
7.53 (dd, 1H, J=15, 12 Hz, CH=); 8.10 (m, 2H, phenyl). C-NMR
(DMSO) δ: 96.1; 126.4; 126.9; 128.6; 130.5; 146.4; 152.5; 166.9; 176.9.
Anal. Calcd for C13H N O (227.26): C, 68.70; H, 5.77; N, 18.49. Found:
13 3
C, 68.72; H, 5.76; N, 18.48.
Similarly, the reaction can be performed by using 2-bromopyridine
following the same experimental procedure and getting analogous
results.
(1E,3E)-N,N-Dimethyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
amine 11c, 1.42 g (98%), yellow crystals from ethanol, m.p. 99–
À 1
1
1
01°C. IR: ν
1641 cm . H-NMR (DMSO) δ: 2.91 (s, 6H, NÀ Me );
C=N
2
1
,2,4-Oxadiazole[4,5-a]piridinium chloride 9, 5.29 g (71%), colourless
5.29 (t, 1H, J=12 Hz, CH=); 5.92 (d, 1H, J=15 Hz, CH=); 7.18 (d, 1H,
J=15 Hz, CH=); 7.49 (t, 1H, J=12 Hz, CH=); 7.55 (m, 3H, phenyl);
À 1
1
crystals from chloroform, m.p. 197–198°C. IR: ν
1633 cm . H-
C=N
NMR (DMSO) δ: 7.83 (t, 2H, J=7 Hz, phenyl); 7.92 (t, 1H, J=7 Hz,
phenyl); 8.03 (d, 2H, J=7 Hz, phenyl); 8.12 (t, 1H, J=6 Hz, pyridine);
8.82 (d, 1H, J=8 Hz, pyridine); 8.93 (dd, 1H, J=7, 8 Hz, pyridine);
13
7
1
.66 (m, 2H, phenyl). C-NMR (DMSO) δ: 95.4; 96.0; 126.4; 126.9;
28.6; 130.5; 146.4; 152.5; 166.9; 176.9. Anal. Calcd for C H N O
14
15
3
(241.29): C, 69.69; H, 6.27; N, 17.41. Found: C, 69.71; H, 6.26; N,
13
9.26 (d, 1H, J=7 Hz, pyridine). C-NMR (DMSO) δ: 110.4; 122.7;
25.2; 128.8; 130.0; 130.1; 130.7; 134.0; 147.6; 155.5, 161.2. Anal.
17.39.
1
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(
1
IR: ν
1E,3E)-N-Ethyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-amine
General Procedure for the Reaction of the Salt 9 with
2-aminopyridine and 2-(N-methylamino)-pyridine
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1d, 0.96 g (66%), yellow crystals from ethanol, m.p. >95°C (dec.).
À 1
1
1618 cm . H-NMR (DMSO) δ: 1.12 (m, 3H, CH ); 3.47 (m,
3
C=N
A solution of the pyridinium salt 9 is prepared with 1.0 g (4.3 mmol)
in 80 mL of methanol. To this solution 2.5 equivalents of the 2-
aminopyridine and 2-(N-methylamino)-pyridine, dissolved in 20 mL
of methanol, were added dropwise. The reaction mixtures were left
under stirring at room temperature for 5 days. After this period of
time, methanol is removed at reduced pressure and the residues
were taken up with DCM. The organic phases were washed with
water and dried over anhydrous Na SO . Upon evaporation of the
2H, NÀ CH ); 5.38 (t, 1H, J=12 Hz, CH=); 5.86 (d, 1H, J=15 Hz, CH=);
2
7.08 (t, 1H, J=15 Hz, CH=); 7.17 (t, 1H, J=12 Hz, CH=); 7.54 (m, 3H,
13
phenyl); 7.98 (m, 2H, phenyl). C-NMR (DMSO) δ: 21.7; 95.0; 126.4;
27.3; 128.8; 129.2; 129.5; 147.6; 167.2; 177.4. Anal. Calcd for
C H N O (241.29): C, 69.69; H, 6.27; N, 17.41. Found: C, 69.70; H,
1
1
4
15
3
6
.25; N, 17.40.
(
1E,3E)-4-(3-Phenyl-1,2,4-oxadiazol-5-yl)-N-propylbuta-1,3-dien-1-
2
4
amine 11e, 1.38 g (90%), yellow crystals from diethylether, m.p. 82–
solvent, solid residues were submitted to chromatographic isolation
and the solid compounds were recrystallized from proper solvents
to afford the final products 12a,b that were fully characterized.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
À 1
1
8
4°C. IR: ν
1660 cm . H-NMR (CDCl ) δ: 0.96 (t, 3H, J=7 Hz,
C
=
N
3
CH ); 1.60 (m, 2H, CH ); 3.07 (bs, 2H, J=7 Hz, NÀ CH ); 4.40 (bs, 1H,
3
2
2
NH); 5.38 (t, 1H, J=12 Hz, CH=); 6.03 (d, 1H, J=15 Hz, CH=); 6.80
(dd, 1H, J=15, 8 Hz, CH=); 7.44 (m, 3H, phenyl); 7.48 (d, 1H, J=
N-[(1E,3E)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-yl]pyridin-
13
2-amine 12a, 1.19 g (95%), yellow crystals from ethanol, m.p. 184–
1
5 Hz, CH=); 8.10 (m, 2H, phenyl). C-NMR (DMSO) δ: 24.7; 45.4;
À 1
1
1
85°C. IR: ν
1647 cm . H-NMR (DMSO) δ: 6.03 (t, 1H, J=12 Hz,
9
7.3; 126.8; 127.3; 128.9; 130.9; 146.6; 148.6; 167.2; 177.3. Anal.
C=N
CH=); 6.33 (d, 1H, J=15 Hz, CH=); 6.87 (m, 2H, pyridine and CH=);
7.57 (m, 3H, phenyl); 7.65 (m, 2H, pyridine and CH=); 8.03 (m, 3H,
phenyl and pyridine); 8.21 (d, 1H, J=5 Hz, pyridine); 10.09 (d, 1H,
J=12 Hz, NH). C-NMR (DMSO) δ: 102.8; 105.1; 110.0; 116.5; 126.8;
126.9; 129.1; 131.2; 138.2; 139.0; 145.1; 148.1; 152.7; 167.6; 176.4.
Anal. Calcd for C H N O (290.32): C, 70.33; H, 4.86; N, 19.30. Found:
Calcd for C H N O (255.31): C, 70.56; H, 6.71; N, 16.46. Found: C,
15
17
3
7
0.57; H, 6.70; N, 16.44.
1
3
(
1E,3E)-N-Isopropyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
amine 11f, 1.36 g (89%), yellow crystals from diiosopropylether,
À 1
1
m.p. 88–89°C. IR: ν
1618 cm . H-NMR (CDCl ) δ: 1.20 (d, 6H, J=
C=N
3
17 14
4
7
Hz, CH ); 3.55 (m, 1H, NÀ CH); 4.31 (m, 1H, NH); 5.38 (t, 1H, J=
C, 70.34; H, 4.87; N, 19.32.
3
12 Hz, CH=); 6.03 (d, 1H, J=15 Hz, CH=); 6.75 (dd, 1H, J=15, 8 Hz,
N-Methyl-N-[(1E,3E)-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
CH=); 7.50 (m, 3H, phenyl); 7.55 (d, 1H, J=15 Hz, CH=); 8.08 (m, 2H,
13
yl]pyridin-2-amine 12b, 1.28 g (98%), yellow crystals from ethanol,
phenyl). C-NMR (DMSO) δ: 23.6; 25.2; 96.3; 126.8; 127.3; 129.0;
30.9; 147.1; 151.8; 167.3; 177.2. Anal. Calcd for C H N O (255.31):
À 1
1
m.p. 157–158°C. IR: ν
1620 cm . H-NMR (DMSO) δ: 3.38 (s, 3H,
1
C=N
15
17
3
NÀ CH ); 6.03 (t, 1H, J=12 Hz, CH=); 6.37 (d, 1H, J=15 Hz, CH=); 7.03
C, 70.56; H, 6.71; N, 16.46. Found: C, 70.55; H, 6.72; N, 16.47.
3
(dd, 1H, J=7, 6 Hz, pyridine); 7.56 (d, 1H, J=9 Hz, pyridine); 7.58
(m, 4H, phenyl and CH=); 7.77 (m, 2H, pyridine); 8.04 (m, 2H,
(
1E,3E)-N-Benzyl-4-(3-phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-
1
3
amine 11g, 1.58 g (87%), yellow crystals from ethanol, m.p. 115–
phenyl); 8.30 (d, 1H, J=12 Hz, CH=). C-NMR (DMSO) δ: 32.0; 103.5;
104.5; 109.7; 117.4; 126.8; 126.9; 129.1; 131.2; 138.6; 142.1; 145.5;
147.8; 154.4; 167.6; 176.4. Anal. Calcd for C H N O (304.35): C,
À 1
1
1
17°C. IR: ν
1646 cm . H-NMR (DMSO) δ: 4.29 (d, 1H, J=6 Hz,
C=N
NÀ CH ); 5.43 (t, 1H, J=12 Hz, CH=); 5.89 (d, 1H, J=15 Hz, CH=); 7.26
2
18 16
4
13
(
m, 7H, phenyl, CH=); 7.53 (m, 3H, phenyl); 7.97 (m, 2H, phenyl). C-
71.04; H, 5.30; N, 18.41. Found: C, 71.03; H, 5.29; N, 18.41.
NMR (DMSO) δ: 96.3; 126.8; 127.1; 127.2; 127.3; 128.5; 128.6; 128.9;
129.0; 131.0; 147.2; 167.3; 177.2. Anal. Calcd for C19 O (303.36):
H N
17 3
C, 75.23; H, 5.65; N, 13.85. Found: C, 75.25; H, 5.64; N, 13.85.
Reaction followed at the NMR Between the Pyridinium salt 9
and Dimethylamine in CD OD
3
3-Phenyl-5-[(1E,3E)-4-(pyrrolidin-1-yl)buta-1,3-dien-1-yl]-1,2,4-oxadia-
zole 11h, 1.57 g (98%), yellow crystals from methanol, m.p. 115–
1
Pyridinium salt 9 (35 mg, 0.15 mmol) was dissolved in 1 mL CD OD
3
À 1
1
16°C. IR: ν
1630 cm . H-NMR (DMSO) δ: 1.86 (bs, 4H,
and an excess dimethylmine was added. 1H NMR spectra were
recorded after 1, 6, 12 and 24 h (see Figure 4) to monitor the
reaction and evolution of intermediates and reaction products.
Similarly it was done for the reactions conducted in CDCl3.
C=N
pyrrolidine); 3.29 (bs, 4H, CH À NÀ CH pyrrolidine); 5.22 (t, 1H, J=
2
2
1
2 Hz, CH=); 5.90 (d, 1H, J=15 Hz, CH=); 7.35 (d, 1H, J=12 Hz,
13
CH=); 7.52 (m, 4H, phenyl, CH=); 7.99 (m, 2H, phenyl). C-NMR
DMSO) δ: 24.7; 96.5; 97.3; 126.8; 127.3; 129.0; 130.9; 145.7; 148.6;
167.2; 177.3. Anal. Calcd for C H N O (267.33): C, 71.89; H, 6.41; N,
(
16
17
3
15.72. Found: C, 71.90; H, 6.43; N, 15.73.
HPLC Quantitative Analyses on the Reaction Between the
Pyridinium Salt 9 and Morpholine
3
-Phenyl-5-[(1E,3E)-4-(piperidin-1-yl)buta-1,3-dien-1-yl]-1,2,4-oxadia-
zole 11i, 1.67 g (99%), yellow crystals from methanol, m.p. 88–89°C.
Pyridinium salt 9 (18 mg, 0.08 mmol) was dissolved in 25 mL CH CN
3
À 1
1
IR: νC=N 1635 cm . H-NMR (DMSO) δ: 1.54 (m, 6H, piperidine); 3.23
and 9.5 mg (0.08 mmol) of morpholine were added along with
12 mg of internal standard. The reaction was conducted at 25°C.
HPLC analyses were done at fixed times and the plot of the reaction
is reported in Figure 5.
(
m, 4H, CH À NÀ CH piperidine); 5.44 (t, 1H, J=12 Hz, CH=); 5.91 (d,
2
2
1
H, J=15 Hz, CH=); 7.10 (d, 1H, J=12 Hz, CH=); 7.53 (m, 4H, phenyl,
13
CH=); 7.99 (m, 2H, phenyl). C-NMR (DMSO) δ: 23.6; 25.2; 48.8; 95.8;
6.3; 126.8; 127.3; 128.9; 130.9; 147.1; 151.8; 167.3; 177.2. Anal.
Calcd for C H N O (281.35): C, 72.57; H, 6.81; N, 14.94. Found: C,
9
17
19
3
72.58; H, 6.82; N, 14.96.
HPLC Quantitative Analyses on the Reaction Between the
Pyridinium Salt 9 and Morpholine with and without
Norbornene at 60°C in Chloroform as Solvent
Pyridinium salt 9 (18 mg, 0.08 mmol) was dissolved in 25 mL CHCl
3
and increasing amounts of morpholine ([Morpholine/[9]=3, 6, 9,
18, 27, 36) were added along with 12 mg of internal standard in
separated reactions. The reactions were conducted at 60°C with
and without excess norbornene. All the experiments were stopped
at the 68% of conversion and HPLC analyses were performed. The
plot of the reaction is reported in Figure 6.
4
-[(1E,3E)-4-(3-Phenyl-1,2,4-oxadiazol-5-yl)buta-1,3-dien-1-yl]morpho-
line 11j, 1.68 g (99%), yellow crystals from methanol, m.p. 138–
À 1
1
139°C. IR: ν
1635 cm . H-NMR (DMSO) δ: 3.25 (m, 4H, morpho-
C=N
line); 3.63 (m, 4H, morpholine); 5.51 (t, 1H, J=12 Hz, CH=); 6.00 (d,
1
H, J=15 Hz, CH=); 7.08 (d, 1H, J=12 Hz, CH=); 7.53 (m, 4H, phenyl,
13
CH=); 7.98 (m, 2H, phenyl). C-NMR (DMSO) δ: 66.0; 97.7; 97.9;
27.2; 127.5; 129.4; 131.4; 146.9; 151.8; 167.7; 177.4. Anal. Calcd for
C H N O (283.33): C, 67.83; H, 6.05; N, 14.83. Found: C, 67.84; H,
1
1
6
17
3
2
6
.03; N, 14.85.
ChemistryOpen 2019, 8, 1209–1221
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1219
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Full Papers
Synthesis of the 3-Phenyl-5-methyl-1,2,4-Oxadiazole[4,5-a]
piridinium Chloride 21
isolated in 30% and found identical to a commercially available
reference compound (Sigma-Aldrich A75706) along with the
benzamidoxime 24 (5%), also identical to a reference compound
available in our laboratory. Finally, the cycloadduct of BNO to
norbornene 25 was isolated in 49% yield, identical to an authentic
sample prepared in our laboratory according to the known
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
To a methanol solution (40 mL) of 5.0 g (32 mmol) of benzhydrox-
ymoyl chloride 1, 8.0 mL (67 mmol) of 6-chloro-2-picoline were
added and the mixture was cooled at 0°C with an ice-bath.
Triethylamine (30 mmol, 4.8 mL) dissolved in 20 mL methanol was
added dropwise under stirring and the solution turns from colour-
less to pale yellow. The reaction is left under stirring overnight;
after this period of time, methanol is removed at reduced pressure
and the residue is taken up with benzene to dissolve the picoline
[34]
procedures.
excess. Upon filtration, the crude salt 21 is obtained along with the Acknowledgements
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
triethylamine hydrochloride. Purification of 21 is secured by
dissolving the salt mixture with chloroform and leaving to crystal-
lized the pyridinium salt 21 in colourless crystals. The product was
submitted to complete characterization.
Financial support by the University of Pavia, MIUR is gratefully
acknowledged. We also thank “VIPCAT – Value Added Innovative
Protocols for Catalytic Transformations” project (CUP:
E46D17000110009) for valuable financial support.
3
-Phenyl-5-methyl-1,2,4-Oxadiazole[4,5-a]piridinium
chloride
°
21,
4
.74 g (60%), colourless crystals from ethanol, m.p. 205 C (dec.). IR:
À 1
1
νC=N 1643 cm . H-NMR (DMSO) δ: 2.02 (s, 3H, CH ); 7.85 (m, 2H,
3
phenyl); 7.90 (m, 1H, phenyl); 8.03 (d, 2H, phenyl); 8.12 (t, 1H, J=
Conflict of Interest
6
Hz, pyridine); 8.83 (d, 1H, J=9 Hz, pyridine); 8.91 (t, 1H, J=7 Hz,
13
pyridine). C-NMR (DMSO) δ: 18.5; 110.4; 122.7; 125.2; 128.8; 130.0;
30.7; 134.0; 147.6; 155.5; 161.2. Anal. Calcd for C H N OCl
1
The authors declare no conflict of interest.
13
11
2
(246.70): C, 63.29; H, 4.49; N, 11.36. Found: C, 63.28; H, 4.48; N,
11.37.
Keywords: nitrile oxides · 1,3-dipolar cycloadditions · Zincke
salts · oxadiazoles · dienamino derivatives
Synthesis of the 1-[(hydroxyimino)(phenyl)
methyl]-6-methylpyridin-2(1H)-one 22
To a solution of 10 mg (0.43 mmol) of the salt 21 in 20 mL of water,
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1
0
ν
-[(Hydroxyimino)(phenyl)methyl]-6-methylpyridin-2(1H)-one
22,
.10 g (98%), colourless crystals from water, m.p. 217°C (dec.). IR:
À 1
1
1705, ν
1642 cm . H-NMR (DMSO) δ: 2.02 (s, 3H, CH ); 6.27
3
C=O
C=N
(
d, 1H, J=6 Hz, pyridone); 6.33 (d, 1H, J=9 Hz, pyridone); 7.45 (s,
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13
1
1
8.5; 105.3; 117.3; 124.9; 129.0; 129.9; 131.4; 141.1; 144.7; 145.3;
60.6. Anal. Calcd for C H N O (228.25): C, 68.41; H, 5.30; N, 12.27.
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13
12
2
2
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[
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organic phase was dried and the residue, obtained upon evapo-
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3
3
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3
3
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218, n/a.
ChemistryOpen 2019, 8, 1209–1221
www.chemistryopen.org
1221
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA