Reactions of 1,2,4-Oxadiazole[4,5-a]piridinium Salts with Alcohols: the Synthesis of Alkoxybutadienyl 1,2,4-Oxadiazoles

Article abstract of DOI:10.1002/open.201900376

1,2,4-Oxadiazole[4,5-a]piridinium salts add alcohols and alkoxides to undergo electrocyclic ring opening affording alkoxybutadienyl 1,2,4-oxadiazole derivatives. The pyridinium salts represent a special class of Zincke salts that are prone to rearrange to give alkoxybutadienyl 1,2,4-oxadiazoles when treated with suitable nucleophiles or, alternatively, to give pyridones in the presence of bicarbonate. The pivotal tuning of the experimental conditions leads to a straightforward synthesis of valuable 1,2,4-oxadiazole derivatives. The mechanism is also discussed in the light of previous observations.

Full text of DOI:10.1002/open.201900376

DOI: 10.1002/open.201900376
Full Papers
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Reactions of 1,2,4-Oxadiazole[4,5-a]piridinium Salts
with Alcohols: the Synthesis of Alkoxybutadienyl
1,2,4-Oxadiazoles
Mattia Moiola, Marco Leusciatti, and Paolo Quadrelli*[a]
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1,2,4-Oxadiazole[4,5-a]piridinium salts add alcohols and alkox-
ides to undergo electrocyclic ring opening affording alkoxybu-
tadienyl 1,2,4-oxadiazole derivatives. The pyridinium salts
represent a special class of Zincke salts that are prone to
rearrange to give alkoxybutadienyl 1,2,4-oxadiazoles when
treated with suitable nucleophiles or, alternatively, to give
pyridones in the presence of bicarbonate. The pivotal tuning of
the experimental conditions leads to a straightforward synthesis
of valuable 1,2,4-oxadiazole derivatives. The mechanism is also
discussed in the light of previous observations.
1. Introduction
excellent yield the 5-dienamino derivatives of type 4
(Scheme 1). The scope of this methodology, thoroughly inves-
tigated in the light of the mechanism proposed, aimed to set
up the protocol for obtaining single products with reliable and
positive impacts on the synthetic field.
Expanding our investigation on the reactivity of nitrile
oxides and 2-substituted pyridines as well as that of their
oxadiazole-pyridinium salts, we studied the chemical behavior
of these latters in the presence of alcohols and alkoxides
identifying an interesting route to 5-alkoxybutadienyl substi-
tuted 1,2,4-oxadiazoles of type 5 (Scheme 2). Scope and
limitations of the protocol are discussed in the light of the
proposed mechanism.
The great interest in 1,2,4-oxadiazoles[1] in organic synthesis can
be ascribed both to the versatility of these heterocycles with
respect to their preparationf and elaboration in other synthons
as well as to their biological activities, specifically in drug
discovery where oxadiazoles are often hydrolysis-resisting
bioisosteric replacements for amide or ester functionalities.
Some derivatives can also act as bioisosteres of the carboxylic
acid functionality.[2] Compounds containing the oxadiazole ring
were found to be anti-inflammatory or antiviral agents, agonists
of muscarinic receptors, peptidomimetics, antitumor agents[3] or
partial agonists for a class of peroxisome proliferator-activated
receptors.[4] Moreover, 1,2,4- and 1,3,4-oxadiazoles containing
flexible alkoxy chains were also found to display liquid
crystalline and emissive properties.[5]
A number of conventional and unconventional methodologies
and several methods are reported in the literature regarding the
synthesis of these heterocycles.[1,2] In the search of new method
for the preparation of functionalized 1,2,4-oxadiazoles, we pursued
in our traditional interest in the 1,3-dipolar cycloaddition approach
through nitrile oxide chemistry.[6]
2. Results and Discussion
3-Phenyl-1,2,4-Oxadiazole[4,5-a]piridinium chloride 3 was pre-
pared according to the known procedure.[7] Compound 3 is
stable for days in water solution but unstable in the presence of
5% solution NaHCO3 affording the insoluble N-substituted 2-
pyridone 6 through oxadiazole ring-opening reaction.[7] The
Recently, we have detailed the remarkable behavior of the
1,2,4-oxadiazole[4,5-a]piridinium salts 3 with amines;[7] synthe-
sized from nitrile oxides of type 2 and suitably 2-substituted
pyridines, the 1,2,4-oxadiazole[4,5-a]piridinium salts 3 undergo
an electrocyclic ring-opening in the presence of in situ
generated amines (from their hydrochlorides) to afford in
[a] Dr. M. Moiola, Dr. M. Leusciatti, Prof. Dr. P. Quadrelli
Department of Chemistry
Scheme 1. Benzonitrile oxide reactions with 2-substituted pyridines and
reaction pathway to 5-dienamino 1,2,4-oxadiazoles. FG, functional groups.
University of Pavia
Viale Taramelli 12, 27100 – Pavia (Italy)
E-mail: paolo.quadrelli@unipv.it
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201900376
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This
is an open access article under the terms of the Creative Commons Attri-
bution Non-Commercial License, which permits use, distribution and re-
production in any medium, provided the original work is properly cited and
is not used for commercial purposes.
Scheme 2. Reaction of the salt 3 with alcohols to afford 5-alkoxybutadienyl
1,2,4-oxadiazoles 5.
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reaction takes place almost immediately and is quantitative
after one day (Scheme 3).[8–10] Acylation of compound 6 with
acetic anhydride or benzoyl chloride afforded the O-acyl
derivatives 7a, b, respectively in 63% and 62% yields,
according to the well-established methods for amidoximes
acylation reported in literature.[11]
The behavior of salt 3 with slightly basic water solutions
somewhat suggests to investigate the reactions with alcohols
and alkoxides.
The salt 3 is soluble in methanol and in general in polar
solvents and indefinitely stable in their solutions. However, when
1–2 equivalents Et3N are added to the methanol solution,
compound 3 disappears after few hours to leave the meth-
oxybutadienyl-1,2,4-oxadiazole derivative 5a (15% yield) and the
hydroximic ester 8 as major product (75% yield) (Scheme 4).
The structures of the reaction products were attributed on
the basis of the corresponding analytical and spectroscopic
data. The 1H NMR (CDCl3) of the methoxybutadienyl-1,2,4-
oxadiazole 5a shows the typical signals diene moiety; in the
inset of Scheme 4 the chemical shifts of 5a are reported
showing that the Hb and Hd proton signals are quite shielded
as expected for an alkoxydiene with respect to the Ha and Hc
signals. The geometry of the double bond was determined on
the basis of the relative coupling constants (J); The double
bond close to the oxadiazole ring has a typical (Z) geometry
with a J=11 Hz while the vinyl ether portion has a larger J=
13 Hz, accounting for a (E) configuration.
With the aim to set-up properly the reaction conditions in
order to obtain as single product of the reaction the alkoxybuta-
dienyl-1,2,4-oxadiazole derivatives of type 5, we took advantage of
the method applied for the reaction with amines,[7] i.e. by
suspending the salt 3 in benzene as solvent in the presence of
4 mmol of alcohols and adding 5 mmol Et3N to establish a low-
concentration equilibrium with the nucleophilic species
(Scheme 5). The reactions proceed slowly and take 2 day for
complete disappearance of the salt 3, affording the desired
products 5a–e in very good yields (80–92%). From the crude
mixtures traces of the corresponding hydroximic ester of type 8
could be detected not isolable due to their very low amounts.
The structures of products 5b–e were attributed on the
basis of the corresponding analytical and spectroscopic data. In
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the H NMR (CDCl3) spectra the trend shown for compound 5a
is confirmed for the new products regarding the diene moieties.
The signals of the protons located on the (Z) double bond are
found shielded in the range δ 5.4–7.0 ppm with coupling
constant values J=11 Hz. On the other side, she signals of the
protons located on the (E) double bond are found slightly
deshielded in the range δ 6.0–7.5 ppm with coupling constant
values J=13 Hz. A complete characterization is reported in the
experimental section.
The obtained results clearly show a different behavior of the
salt 3 in dependence of the concentration of alcohols; upon
increasing the MeOH/Benzene ratio (1%, 5%, 20%, 50% V/V) in
the reactions with salt 3, the yields of compound 5a decrease
steadily (NMR determinations) to reach the 8% for compound
5a and 79% for compound 8 in pure MeOH as solvent,
consistent with previous results.
The hydroximic ester 8 shows in its 1H NMR (CDCl3)
spectrum the typical pyridine proton array, quite deshieded and
with increasing J values moving from Ha to the Hd, as expected
for this type of heterocycles. In the specific case, the structure
of 8 was furtherly demonstrated upon catalytic hydrogenation
that afforded quantitatively an equimolecular mixture of 2-
pyridone 9 and methyl benzimidate[12] 10.
To better understand the reactivity of salt 3 and for sake of
comparison with free amine reactions previously reported,7 we
investigated the reactions with the methoxide anion; the
reaction was conducted by using
a 30% w/w solution
MeOÀ Na+/MeOH (2 equiv.) in a benzene suspension of salt 3.
After one day at room temperature the worked-up reaction
mixture was submitted to chromatographic separation to
obtain the products whose structures are shown in Scheme 6.
Compound 5a was isolated in modest yield (6%) along with
the new products 11 and 12 derived from the multiple addition
of the methoxide anion to the diene moiety, respectively
Scheme 3. Reaction of salt 3 with NaHCO3 5% water solution and acylation
reactions of compound 6.
Scheme 5. Reactions of the salt 3 with alcohols/Et3N in benzene suspen-
sions.
Scheme 4. Reaction of the salt 3 with methanol in the presence of Et3N and
hydrogenation reaction of compound 8.
Scheme 6. Reaction of salt 3 with MeOÀ Na+/MeOH in benzene as solvent.
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obtained in 10% and 34% yields, and an oxidative cleavage
product 13 in 36% yield. For products 11–13 the structures
were attributed on the basis of their analytical and spectro-
quantitatively satisfactory as previously demonstrated.[7] How-
ever, we reasonably propose the mechanism in Scheme 7 on
the basis of the product outcome.
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scopic data. Specifically in the H NMR (CDCl3) of compound 11
The formation of the hydromic esters of type 8 from
alcoholic solutions of 3 can be explained on the basis of the
proposed mechanism proposed in Scheme 8. At high concen-
tration of alcohols or in pure alcohols as solvents, the reaction
proceeded by addition to the electrophilic carbon atom C3 of
the oxadiazole ring of 3 to give the intermediate 16 that, in the
presence of organic bases, neutralized the pyridinium salt
affording the hydroximic esters 8a–e. In some cases, the syn
and anti stereosiomers of 8 around the C=N double bond could
be observed in the crude; the structure of 8 corresponds to the
isolated compound.
Finally, Scheme 9 shows the proposed mechanism account-
ing the formation of the adducts 11 and 12. The structures of
these compounds do suggest the mechanism starting from the
primary adduct 5a that is prone to add a methoxide ion to give
the intermediate 17 that gains its neutrality by extracting a
proton from the solvent (MeOH) leaving product 11. This latter
is again prone to add a second methoxide ion in the same
manner to afford the intermediate 18 before rearranging to
product 12 in a similar way.
the presence of a single double bond is testified by the
presence of two signals at δ 6.56 and 7.10 coupled with a J=
16 Hz, accounting for a (E) geometry of the C=C double bond,
while two methoxy groups are found at δ 3.40, geminally linked
to the acetalic CH whose proton resonate at δ 4.57. The parent
compound 12 possesses as additional methoxy group (δ 3.41)
and a methylene adjacent to the oxadiazole ring whose proton
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are found at δ 3.19. Finally, in the H NMR (CDCl3) of the α,β-
unsaturated aldehyde 13 the aldehyde proton is found at
δ 9.90 as a doublet, coupled with the C=C double bond protons
found at δ 7.37 and 7.43.
The use of stronger bases seems to erode the reaction
selectivity that is clearly guarantee by the ROH/R3N/Benzene
methodology conditions.
The results here reported add intriguing aspects in the
reactivity of the oxadiazole-pyridinium salts 3 with nucleophiles.
These monocycloadducts obtained through
a
pseudo-
pericyclic[13] addition of nitrile oxides to pyridine derivatives are
a special type of Zincke salts[14] whose electrocyclic ring-
opening is triggered by nucleophilic addition.[15] We have
already accounted for this type of mechanism, detailing the
various stereochemical features in a previous work using
different amines as nucleophiles to conduct these synthetic
transformations.[7]
The presence in the reaction mixture of the α,β-unsaturated
aldehyde 13 can be ascribed to oxidation occurring on
compound 5a; this phenomenon was also observed when 5a
was left in solution in open air (TLC monitor).
The use of pyridines for the preparation acyclic and
heterocyclic compounds belonging to several classes of organic
compounds remains a valuable topic of research and the
application of the chemistry of Zincke salts[16] renovates a
protocol dating back more than one century.[17] 1,2,4-Oxadia-
zole[4,5-a]piridinium salts of type 3 belong to the wide family
of Zincke salts and display a remarkable chemical behavior,
interesting and valuable on both mechanistic and applicative
points of view. They can be easily prepared from a variety of 2-
halogen substituted pyridines and aromatic or aliphatic nitrile
oxides[18] expanding the synthetic possibilities from a single
molecule to obtain variable functionalized oxadiazole deriva-
tives.
In our previous work we summarized the reactivity of salts 3
with amines in connection with the competitive dimerization
processes involving the nitrile oxides, evidencing the com-
pound stability aspects determining the accessibility of specific
reaction pathways.[7] Hereby, we wish to conclude giving
another comprehensive picture of the reactivity of salts 3 with
The results shown in Scheme 5 can be easily explained in
the light of previous observations: alcohols add the position 5
of the pyridinium salt 3 with the assistance of an organic base
to give the adduct 14 that undergoes disrotatory electrocyclic
ring-opening to afford the intermediate 15. This latter partially
isomerizes to give the stable isolated compounds 5a–e in (E,Z)
configurations (Scheme 7).
As these reactions proceeded at the earlier stage slower
than the analogous reaction with amines, we found difficult to
monitor experimentally the reaction pathway through NMR.
Attempts were made but the output was not qualitatively and
Scheme 7. Nucleophilic addition of alcohols to the salt 3 with disrotatory
mechanism outcome of adduct 14 to give intermediate 15 and subsequent
(Z)–(E) isomerization.
Scheme 8. Proposed mechanism for compounds 8a–e formation.
Scheme 9. Proposed mechanism for the formation of compounds 11 and 12.
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(Hz): b, broad; s, singlet; bs, broad singlet; d, doublet; t, triplet; q,
quartet; m, multiplet. IR spectra (nujol mulls) were recorded on a
spectrophotometer Perkin-Elmer RX-1 available at the Department
and absorptions (ν are in cmÀ 1. Column chromatography and tlc:
silica gel H60 and GF254, respectively; eluents: cyclohexane/ethyl
acetate 9:1 to pure ethyl acetate.
alcohols and alkoxides as the experimental results here exposed
allow to design (Scheme 10).
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When the 1,2,4-Oxadiazole[4,5-a]piridinium chloride 3 is
suspended in benzene and an amount of alcohols is added in
the presence of an organic base, a disrotatory electrocyclic ring-
opening starts from the adduct 14 affording the intermediate
15 that enters (Z)–(E) isomerization process to give the final
compounds 5. Important rule to trigger this reaction pathway:
the amount of alcohols must remains below 1%. Upon the
increasing this amount a competitive reaction pathway is
enforced and speed-up by the alcohol concentration to give as
major product the hydroximic ester 8.
On the other side, the use of alkoxides, stronger bases even
in low concentration, still activate the electrocyclic ring-opening
but the alkoxybutadienyl derivatives undergo a further addition
to the diene moiety, cancelling the reaction selectivity
previously observed.
Starting and Reference Materials
2-Hydroxypyridine, 2-chloropyridine, were purchased from Sigma-
Aldrich (Merck). The alcohols used in this work were also purchased
from Sigma-Aldrich (Merck).
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Benzhydroximoyl chloride was obtained by treatment of benzaldox-
ime with sodium hypochlorite.[18] Addition of a slight excess of Et3N
to a DCM solution of benzhydroximoyl chloride furnished in situ
BNO.
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.
3. Conclusions
Reaction of Salt 3 in Methanol with Triethylamine
To sum up, a comparison with the salt 3 behaviour with amines
seems to give a neat preference on the synthetic ground to the
reactions with nitrogen containing derivatives rather than the
alcohols. In particular the stability of secondary amine deriva-
tives is indefinite while the alkoxybutadienyl derivative some-
what suffer a long-term oxidative degradation to aldehydes and
related compounds.
Other targets and planned investigations will promise
further developments in this topic as well as the use of some of
these oxadiazole derivatives in biological investigations.
A methanol solution (20 mL) of the pyridinium salt 3 1.0 g
(4.3 mmol) is left under stirring at room temperature and 1 mL
(7.2 mmol) of freshly distilled triethylamine is added dropwise. After
a couple of hours (TLC monitoring), methanol is removed at
reduced pressure and the residues were taken up with benzene to
ensure precipitation of insoluble chlorides. The organic phase was
then evaporated to dryness and the residue were submitted to
chromatographic separation to isolate the products 5a and 8 that
were fully characterized.
5-((1Z,3E)-4-Methoxybuta-1,3-dien-1-yl)-3-phenyl-1,2,4-oxadiazole 5a,
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0.15 g (15%), dark yellow oil. IR: νC=N 1680, νC-O 1290 cmÀ 1. H-NMR
(C6D6) δ: 3.12 (s, 3H, OCH3); 5.90 (d, 1H, J=11 Hz, Hd); 6.05 (dd, 1H,
J=13, 11 Hz, Hb); 6.50 (d, 1H, J=13 Hz, Hc); 7.20 (m, 3H+1H, arom.
and Ha); 8.33 (m, 2H, arom.). 13C-NMR (DMSO) δ: 59.8, 105.7, 120.9,
125.3, 128.8, 129.9, 131.5, 137.8, 141.4, 146.1, 159.8. Anal. Calcd for
C13H12N2O2 (228.25): C, 68.41; H, 5.30; N, 12.27. Found: C, 67.50; H,
5.35; N, 12.25.
Experimental Section
All melting points (Mp) are uncorrected. Elemental analyses were
1
done on a elemental analyzer available at the Department. H and
13C 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
Methyl N-(pyridin-2-yloxy)benzimidate 8, 0.74 g (75%), yellow oil. IR:
νC=N 1630, νOMe 1100 cmÀ 1. 1H-NMR (CDCl3) δ: 4.03 (s, 3H, OCH3); 6.97
(dd, 1H, J=7, 5 Hz, Hb); 7.30 (d, 1H, J=8 Hz, Hd); 7.50 (m, 3H,
arom.); 7.70 (dd, 1H, J=8, 7 Hz, Hc); 7.85 (m, 2H, arom.); 8.25 (d, 1H,
J=5 Hz, Ha). 13C-NMR (DMSO) δ: 52.5, 96.1, 126.4, 126.9, 128.6,
130.5, 146.4, 152.5, 166.9, 176.9. Anal. Calcd for C13H12N2O2 (228.25):
C, 68.41; H, 5.30; N, 12.27. Found: C, 67.29; H, 5.38; N, 12.30.
Catalytic Hydrogenation of 8
A solution of the compound 8 210 mg (1.3 mmol) in 75 mL ethanol
96% are hydrogenated with 50 mg Pd/C 10% at room temperature
(H2 absorption 27 mL in 30 minutes). The catalyst is then removed
by filtration and the solvent evaporated at reduced pressure to
leave an oily residue. Upon addition of diethyl ether a crystalline
solid corresponding to the 2-pyridone 9 separates off, found
identical with an authentic specimen. The organic phase was then
evaporated to dryness to leave an oil identified as the methyl
benzimidate[12] 10.
Scheme 10. Mechanistic chart: from pyridinium salts 3 to alkoxybutadienyl
oxadiazoles 5 through electrocyclic ring-opening. With high alcohol
concentration competitive reaction affords the hydroximic ester 8. With
alkoxide ions, subsequent addition to the diene moiety furnishes the
methoxy derivatives 11 and 12.
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3-Phenyl-5-(2,4,4-trimethoxybutyl)-1,2,4-oxadiazole 12, 0.85 g (34%),
General Procedure for the Reactions of 3with Alcohols and
Triethylamine in Benzene
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straw yellow solid, m.p. 98 C (dec.). IR: νC-O 1127 cmÀ 1
.
1H-NMR
°
(CDCl3) δ: 1.96 (dd, 2H, J=7, 6 Hz, CH2); 3.19 (d, 2H, J=7 Hz, CH2);
3.37 (s, 6H, OCH3); 3.41 (s, 3H, OCH3); 3.91 (dd, 1H, J=12, 6 Hz,
CHÀ O); 4.62 (t, 1H, J=6 Hz, OÀ CHÀ O); 7.50 (m, 3H, arom.); 8.10 (m,
2H, arom.). 13C-NMR (CDCl3) δ: 31.1, 36.8, 52.4, 52.7, 57.0, 74.8, 101.2,
126.9, 128.3, 130.6, 130.7, 175.9, 176.8. Anal. Calcd for C15H20N2O4
(292.34): C, 61.63; H, 6.90; N, 9.58. Found: C, 61.58; H, 6.85; N, 9.65.
An anhydrous benzene suspension (100 mL) of the pyridinium salt
3 0.7 g (3 mmol) is left under stirring at room temperature and
4 mmol of selected alcohols (methanol, absolute ethanol, n-
propanol, isopropanol, n-butanol) are added along with 5 mmol of
freshly distilled triethylamine. After a couple of days (TLC monitor-
ing), the insoluble salts are filtered and the solvent is removed at
reduced pressure to leave oily residues that were purified by
chromatography or distillation and fully characterized.
(E)-3-(3-Phenyl-1,2,4-oxadiazol-5-yl)acrylaldehyde 13, 0.62 g (36%),
1
straw yellow solid, m.p. 89–91 C. IR: νC=O 1688, νC=N 1664 cmÀ 1. H-
°
NMR (CDCl3) δ: 7.37 (dd, 1H, J=16, 8 Hz, CH=); 7.43 (d, 1H, J=
16 Hz, CH=); 7.40 (m, 3H, arom.); 8.20 (m, 2H, arom.); 9.90 (d, 1H, J=
8 Hz, CHO). 13C-NMR (DMSO) δ: 120.9, 125.3, 128.8, 129.9, 131.5,
137.8, 141.4, 146.1, 159.8, 199.2. Anal. Calcd for C11H8N2O2 (200.20):
C, 66.00; H, 4.03; N, 13.99. Found: C, 66.08; H, 4.05; N, 14.05.
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5-((1Z,3E)-4-Ethoxybuta-1,3-dien-1-yl)-3-phenyl-1,2,4-oxadiazole 5b,
1
0.65 g (90%), dark yellow oil. IR: νC=N 1681, νC-O 1289 cmÀ 1. H-NMR
(CDCl3) δ: 0.95 (t, 3H, J=7 Hz, CH3), 3.05 (q, 2H, J=7 Hz, CH2), 4.22
(s, 3H, OCH3); 5.40 (dd, 1H, J=11 Hz, Hd); 6.05 (d, 1H, J=13 Hz, Hb);
6.83 (dd, 1H, J=13, 11 Hz, Hc); 7.49 (m, 3H+1H, arom. and Ha);
8.09 (m, 2H, arom.). 13C-NMR (CDCl3) δ: 24.7, 45.4, 59.8, 97.3, 126.8,
127.3, 129.0, 130.9, 146.7, 148.6, 167.2, 177.3. Anal. Calcd for
C14H14N2O2 (242.28): C, 69.41; H, 5.82; N, 11.56. Found: C, 69.40; H,
5.85; N, 11.55.
Acknowledgments
5-((1Z,3E)-4-Propoxybuta-1,3-dien-1-yl)-3-phenyl-1,2,4-oxadiazole 5c,
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.
0.71 g (92%), yellow oil. IR: νC=N 1660, νC-O 1290 cmÀ 1 1H-NMR
.
(CDCl3) δ: 1.03 (t, 3H, CH3); 1.80 (sx, 2H, CH2); 3.93 (t, 2H, OCH2); 6.07
(d, 1H, J=11 Hz, Hd); 6.67 (dd, 1H, J=13, 1 Hz, Hb); 7.05 (m, 1H+
1H, Ha,c); 7.40 (m, 3H, arom.); 8.39 (m, 2H, arom.). 13C-NMR (DMSO)
δ: 10.7, 24.7, 59.8, 97.3, 126.8, 127.3, 128.9, 130.9, 146.7, 148.5,
167.3, 177.3. Anal. Calcd for C15H16N2O2 (256.31): C, 70.30; H, 6.29; N,
10.93. Found: C, 70.20; H, 6.25; N, 10.95.
Keywords: Nitrile oxides · 1,3-dipolar cycloadditions · Zincke
salts · oxadiazoles · alkoxybutadienyl derivatives
5-((1Z,3E)-4-Isopropoxybuta-1,3-dien-1-yl)-3-phenyl-1,2,4-oxadiazole
5d, 0.70 g (91%), yellow oil. IR: νC=N 71 νC-O 1290 cmÀ 1 1H-NMR
.
(CDCl3) δ: 1.20 (d, 6H, CH3); 4.40 (m, 1H, OCH); 6.07 (d, 1H, J=11 Hz,
Hd); 6.67 (dd, 1H, J=11, 1 Hz, Hb); 6.93 (d, 1H, J=13 Hz, Hc); 7.10
(dd, 1H, J=13, 1 Hz, Ha); 7.30 (m, 3H, arom.); 8.20 (m, 2H, arom.).
13C-NMR (DMSO) δ: 23.6, 25.2, 67.3, 96.3, 126.8, 127.3, 129.0, 130.9,
147.1, 151.8, 167.3, 177.2. Anal. Calcd for C15H1 6N2O2 (256.31): C,
70.30; H, 6.29; N, 10.93. Found: C, 70.33; H, 6.31; N, 10.91.
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Amsterdam, 2019.
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J. J. Vaquero, J. Barluenga, Ed.; Wiley-VCH, Eds.: 2011, pp. 1047–1252.
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Hashimoto, T. Yamaguchi, Bioorg. Med. Chem. Lett. 2017, 27, 3131–3134.
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(Eds. A. Padwa), J. Wiley & Sons, New York, 1984, p.291.
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1221.
5-((1Z,3E)-4-Butoxybuta-1,3-dien-1-yl)-3-phenyl-1,2,4-oxadiazole 5e,
0.75 g (92%), yellow oil. IR: νC=N 1640, νC-O 1290 cmÀ 1 1H-NMR
.
(CDCl3) δ: 0.99 (t, 3H, CH3); 1.30–1.70 (m, 4H, CH2); 4.00 (t, 2H, OCH2);
6.07 (dd, 1H, J=11, 1 Hz, Hd); 6.67 (dd, 1H, J=12, 11 Hz, Hb); 7.03
(m, 1H+1H, Ha,c); 7.30 (m, 3H, arom.); 8.20 (m, 2H, arom.). 13C-NMR
(DMSO) δ: 23.6, 25.1, 53.2, 66.9, 96.3, 126.8, 127.3, 128.9, 130.9,
147.1, 151.8, 167.2, 177.2. Anal. Calcd for C16H18N2O2 (270.33): C,
71.09; H, 6.71; N, 10.36. Found: C, 71.10; H, 6.70; N, 10.35.
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Gazz. Chim. Ital. 1990, 120, 1–7.
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Corsaro, Heterocycles 1995, 40, 515–520.
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Lenaers, R. Buyle, Bull. Soc. Chim. Belg. 1964, 73, 518–531; c) J. A.
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4190–4193.
Reaction of 3in Sodium Methoxide 30% Solution in benzene
Pyridinium salt 3 2.0 g (8.6 mmol) are suspended in anhydrous
benzene (100 mL) and 3.25 mL (17 mmol) MeONa/MeOH 30%
solution were added under stirring at room temperature. After one
day (TLC monitoring), the reaction is quenched with water and the
organic phase separated and dried over anhydrous Na2SO4. The
solvent is then removed at reduced pressure and the residue was
submitted to chromatographic separation to isolate the products
5a, 11, 12 and 13 that were fully characterized.
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2014, 43 4909–4921.
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[17] C. D. Vanderwal, J. Org. Chem. 2011, 76, 9555–9567.
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Heidelberg, 1971.
(E)-5-(4,4-Dimethoxybut-1-en-1-yl)-3-phenyl-1,2,4-oxadiazole
11,
0.22 g (10%), straw yellow oil. IR: νC=N 1665, νC-O 1071 cmÀ 1. 1H-NMR
(CDCl3) δ: 2.68 (dd, 2H, J=7, 6 Hz, CH2); 3.40 (s, 6H, OCH3); 4.57 (t,
1H, J=6 Hz, OÀ CHÀ O); 6.56 (d, 1H, J=16 Hz, CH=); 7.10 (dd, 1H, J=
16, 7 Hz, CH=); 7.49 (m, 3H, arom.); 8.11 (m, 2H, arom.). 13C-NMR
(CDCl3) δ: 36.6, 53.2, 102.8, 115.9, 126.8, 127.3, 128.7, 131.0, 141.4,
168.4, 174.4. Anal. Calcd for C14H16N2O3 (260.29): C, 64.60; H, 6.20; N,
10.76. Found: C, 64.50; H, 6.15; N, 10.85.
Manuscript received: December 31, 2019
Revised manuscript received: January 13, 2020
ChemistryOpen 2020, 9, 195–199
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