Synthesis of polyheteroatomic heterocycles:
relevance of microwave-assisted reactions
Daniele Canestrari
Instituto Superior Técnico, Universidade Técnica de Lisboa
May 2014
Abstract. Heterocyclic structures,
components of a large number of molecules,
have been studied since the mid-1800s due to
their wide occurrence in nature, such as in the
Heme and Chlorophyll A, and the discovery
of their usefulness in organic chemistry,
creating an interesting new branch, which
continues today. From the first applications of
simple heterocycles in main fields of research,
such as in medicine, pharmaceutical,
agrochemical and energy materials,
polyheteroatomic heterocycles have achieved
a remarkable position in the development of
new products for clinical use with most
advantageous features that allow different
interactions with the biological target, not
always possible with a simple heterocyclic
ring. And this is the real aim of this thesis,
based on a new research project on particular
polyheteroatomic heterocyclic systems,
namely 1,2,5-oxadiazoles, also called
furazans, five-membered rings likely to be
useful for the architectural structure of new
drugs. Furthermore, this work wants to
propose possible innovative methods to
synthesize furazans from acyclic substrates in
order to obtain specific heterocycles with
particular substituents on the ring. Even more
importantly, our attention has focused on the
possibility to exploit microwave-assisted
organic synthesis (MAOS) for its ability to
optimize strategies both from the point of
view of the time and of the yield.
Key words. Polyheteroatomic heterocycles,
1,2,5-oxadiazoles, furazans, aminofurazan
synthesis, microwave-assisted reactions.
Introduction
Two hundred years ago, the chemical science
was an undivided field; around 1900 a
division into inorganic, organic and physical
chemistry became necessary. Over the years,
a progressive segmentation into
subdisciplines, very often interconnected, has
become necessary. Heterocycles included
inside compounds have been studied since
half of 1800s due to their wide occurrence in
nature; however the heterocyclic chemistry
was born as a branch of organic chemistry
only after the Second World War.
Heterocycles are by far one of the largest and
most significant classes of organic
compounds, mainly because they are the basis
of life. This is not an overstatement if we
think that the majority of macromolecules
constituting living organisms are built around
heterocyclic motifs, such as Heme and
Chlorophyll A, which are the oxygen carriers
in animals and plants, respectively (Fig. 1).
Fig. 1 Representation of the pigments of life: Heme and
Chlorophyll A.
Moreover, heterocycles are inextricably
interlaced into the life processes and the vital
interest of the pharmaceutical and
agrochemical industries in heterocycles is
often connected with their natural occurrence.
The large majority of drugs (Fig. 2) and
biologically active compounds, like
antitumor, antibiotic, anti-inflammatory,
antidepressant, antimalarial, anti-HIV,
antimicrobial, antibacterial, antifungal,
antiviral, antidiabetic, hypnotics, and
vasopressor modifiers agents, include
synthetic heterocycles as central structural
moiety.
Fig. 2: Some of the top brand name small molecules drugs.
Chemistry of heterocyclic compounds is so
vast that it is almost impossible to summarize
their several ways of synthesis. However,
from a conceptual point of view, it is possible
to divide the preparation of
polyfunctionalized heterocycles using two
major strategies (Scheme 1), or combination
of both of these:
I. Incorporation of functional group in a pre-
existing heterocycle.
II. Ring construction through cyclization of
acyclic precursors.
Scheme 1: Possible strategies for the synthesis of
polysubstituted heterocycles.
Nowadays, formation of cyclic core followed
by incorporation of further functionalization
is a frequent approach to access heterocycles.
Electrophilic or nucleophilic substitution are
often used, and recently organometallic C-H
functionalization has been developed.1
Until now, it was developed the general
theme of the heterocycles, their main features
and their importance for the formation of
natural and synthetic compounds. However,
this is only the beginning because the
heterocyclic chemistry is open to a more
complex world that looks over the simple
heterocycles and their derivatives. So, now
we have to consider the particular case where
more than one heteroatom is present in a five-
membered ring. Five-membered ring
heterocycles containing two carbon atoms,
two nitrogen atoms, and one oxygen atom,
known as oxadiazoles, are of considerable
interest in different areas of medicinal and
pesticide chemistry and also polymer and
material science.2 Oxadiazole rings can exist
in different regioisomeric forms: two 1,2,4-
isomers (if asymmetrically substituted), a
1,3,4-isomer, a 1,2,5-isomer and two 1,2,3-
isomers (if asymmetrically substituted), but
the latter is unstable and reverts to the
diazoketone tautomer3 (Fig. 3a). They display
interesting hydrogen bond acceptor
properties, and it will be shown that the
regioisomers exhibit significantly different
hydrogen bonding potentials. The level of
interest is clearly shown, as over the past ten
years the number of patent applications
containing oxadiazole rings has increased
considerably (Fig. 3b).
Fig. 3: (a) Two 1,2,4-oxadiazoles (if asymmetrically
substituted), 1,3,4-oxadiazole, one 1,2,5-oxadiazole and two
1,2,3-oxadiazioles (if asymmetrically substituted). (b) The
number of patent applications containing oxadiazoles has
increased significantly between 2000 and 2008.4
As seen above in the graphic of published
patents and in the examples of commercially
available drugs reported, the less common
oxadiazole used to synthetize new and
efficient pharmaceutical products are the
1,2,5-oxadiazoles, both for problems that may
be encountered during their synthesis and for
choosing appropriate substituents to make
more and more active this compounds. On
these basis, our research begins with the wish
to know and discover as soon as possible a
great variety of synthetic methods and to
promote also this not well known class of
oxadiazoles in the medicinal and clinical
fields. Initially, we have to say that in
literature there is not an abundant number of
papers or patents which describe exhaustively
the employment of furazans for the formation
of biological5 and agrochemical products.
6,7
So, we have got few examples to start our
work with necessary knowledge on the
chemical and physical characteristics8 and the
different methods to synthetize simple
furazans or their derivatives. The first
synthesis appeared was made with
phenylfurazan (2), a 1,2,5-oxadiazole
derivative, by steam distillation of
phenylglyoxime (1) (Scheme 2)9 and later
accomplished the dehydration in sulfuric
acid10
but the yield by both methods was
poor.
Scheme 2: First synthesis of phenylfurazanes.
Starting from this point, the scientific research
has developed more and more works on the
furazan’s world, taking into account the
different stabilities of 1,2,5-oxadiazoles, both
in the reaction conditions and as thermal
decomposition. In general, furazans are not
very stable compounds because they give ring
opening rapidly and easily, so they become
difficult products to prepare and isolate. The
earliest reports concerning the thermolytic
cleavage of a furazan ring date from 1888
when it was noted that heating
diphenylfurazan (4) at temperatures higher
than 200 ºC afforded benzonitrile together
with some phenyl isocyanate (7).11
Similar
formation of phenyl isocyanate from the
thermolysis of diphenylfuroxan (5) suggested
a common pathway with the known
benzonitrile oxide (6) as intermediate
(Scheme 3).12
Scheme 3: Thermal fragmentation of furazans and furoxans.
Microwaves-assisted organic synthesis
(MAOS)
Since the first published reports in 1986,13
the
use of Microwaves heating to “accelerate”
organic chemical transformations has gained a
considerable attention.14
The application of
Microwave Irradiation (MW) has already
established its valuable potential in organic15
and medicinal chemistry16
worldwide. In
particular, in the pharmaceutical industries
MW-assisted synthesis is used extensively as
frontline methodology in most discovery
programs.17
Although at the beginning, a slow
uptake of the technology was necessary for
the lack of controllability and reproducibility,
more than 2000 article have been published
since now in the area of microwave-assisted
organic synthesis (MAOS). The attention on
Microwave Heating is due essentially to its
ability to increase reaction rate, along with the
capability to reduce side reaction, increase
yield and improve reproducibility. The ability
of this type of electromagnetic wave to
enhance reaction potential is based on the
efficient heating of material by “microwave
dielectric heating” effect. This effect depends
on the ability of a specific material to absorb
microwave energy and convert it into heat.
There are two major mechanisms for the
conversion of electromagnetic energy into
heat: the dipole rotation and the ionic
conduction (Fig. 4). The first one is an
interaction in which polar molecules try to
align themselves with rapidly changing
electric field of the microwave, while the
second one occurs if there are free ions or
ionic species present in the substance being
heated. The electric field generates ionic
motion as the molecules try to orient
themselves to the rapidly changing field.
Fig. 4: The dipole rotation and the ionic conduction.
Moreover, the loss tangent (δ) is used to
compare the abilities of different solvents to
generate heat from microwaves.18
This
parameter is expressed as the ratio between
the dielectric constant ε’ and the loss factor
ε’’ (the capacity to convert the absorbed
energy into heat). Usually, solvents with high
Loss tangent value are generally used in order
to obtain high heating rates. Loss tangent
values for common solvents are shown in
Table 1. Ultimately, the ability of Microwave
Heating to promote reactions in a more
efficient way than thermal condition is due to
its spectacular capability to produce heat
directly from the intern of the reaction
vessel.19
This avoids the heat dissipation
typical of traditional thermal reactions and
allows a quicker rising of reaction
temperature (Fig. 5).
Solvent
Loss
Tangent
(δ)
Solvent
Loss
Tangent
(δ)
Ethylene
glycol 1.350 Water 0.123
Ethanol 0.941 Acetonitrile 0.062
DMSO 0.825 THF 0.047
Acetic
Acid 0.174 Hexane 0.020
Table 1: Loss Tangent (δ) for common solvents.
In addition, microwave irradiation allows the
so-called “superheating effect”, or rather the
ability to rapidly heat the reactions much
above the boiling point of the solvent.
Fig. 5: Microwaves Vs Oil bath heating.
These features ensure to decrease the time of
chemical transformation and consequently the
thermal stress of the system, enabling to
reduce catalyst/promoters loading, by-product
formation or reactant decomposition, increase
yields and sometimes the possibility to carry
on sluggish transformation. Actually, there is
also a debate centered around the question
whether the observed effect of microwave
irradiation can in all cases be rationalized by
the purely thermal/kinetic phenomena
described above, or whether some effect are
also connected to the so-called non-thermal
microwave effect. This effect should derive
from the fact that electromagnetic field could
induce molecule to undergo chemical
reaction, facilitating bond cleavage/formation.
Unfortunately, the definition of what
constitutes a non-thermal microwave effect is
somewhat vague and different scientific
communities may have different theories.20
Results and Discussion
Synthesis of aminofurazans from aroyl
cyanides
At the beginning, the first method that we
tested was focused on the synthesis of
aminofurazans, a well-defined category of
polyheteroatomic heterocycles. We started to
synthetize aminofurazans from a one-step
synthesis studied by Indian researchers
Lakhan and Singh,21
who made a screening of
reactions between aromatic an aroyl cyanide
(8) with a bifunctional nucleophile
hydroxylamine to give 3-amino-4-aryl-1,2,5-
oxadiazoles (10) (Scheme 4).
Scheme 4: Reaction scheme of one-step synthesis of
3-amino-4-aryl-1,2,5-oxadiazoles.
A second synthetic pathway is also feasible,
separating the previous scheme in two distinct
steps (Scheme 5). Undoubtedly, it involves
the formation of α-amino-α'-arylglyoxime (9)
as the key intermediate, actually isolated as
the end product of the first step, when the
dehydrating agent anhydrous sodium acetate
was not used. A plausible reaction mechanism
for one-step synthesis has been suggested as
shown in Scheme 6. Hydroxylamine may
react to the cyano group of 8 followed by
reaction at the carbonyl group, forming 9 as
Scheme 5: Reaction scheme of two-step synthesis of 3-amino-4-aryl-1,2,5-oxadiazoles.
product (Route A); alternatively, reaction of
hydroxylamine at the carbonyl group is
followed by its addition to the cyano group
leading to the same product 9 (Route B).
Then, in the presence of anhydrous sodium
acetate, the intermediate α-amino-α'-
arylglyoxime (9) undergoes cyclization with
dehydration readily to yield 3-amino-4-aryl-
1,2,5-oxadiazoles (10) as the final product.
the reaction to promote the nucleophile
addition of hydroxylamine on the carbonyl
group, as cerium(III) coordinates very easily
with the oxygen, making the carbonyl more
electrophilic (Scheme 7).22
With this change,
we also try to accelerate the reaction rate,
perhaps obtaining the final product at room
temperature, instead to use reflux, which
might carry to a thermal fragmentation of the
Scheme 6: Reaction mechanism of one-step synthesis of 3-amino-4-aryl-1,2,5-oxadiazoles.
For the first time, we attempted the same
procedure written in the article, following
every minimal particular and molar ratio,
using the commercially available and
economic benzoyl cyanide, as starting
material. Moreover, we also added
CeCl3·7H2O/CuI system (molar ratio 1:1) in
heterocycle formed. Attempts are also made
without catalyst system in different refluxing
solvents, like CH3CN, benzene and DMF,
which help us to avoid eventual nucleophilic
side reactions by the great amount of the
solvent that could act when the mixture is
under reflux (Table 2).
Scheme 7: Synthesis of 3-amino-4-phenyl-1,2,5-oxadiazoles
(12).
Entry Catalyst system
(eq.)
Solvent Temp.
(°C)
Time
(h)
Yields
(%)a
1 ---- EtOH
abs.
78,
reflux 6 0
2 CeCl3·7H2O/CuI
1.0:1.0 EtOH abs.
78, reflux
6 0
3 CeCl3·7H2O/CuI
1.0:1.0 CH3CN
82,
reflux 6 0
4 ----
Benzene (Dean-
Stark apparatus)
80,
reflux 24 0
5 ---- DMF 153,
reflux 24 0
a: the yields correspond to gas chromatography and mass
spectrometry analysis.
Table 2: Reaction conditions of synthesis of 12 with or
without CeCl3·7H2O/CuI system.
Unfortunately, all the tests with catalyst
system failed and there is not formation of our
expected product, but there are present a
series of by-products probably coming from
thermal decomposition of the furazan
eventually formed. In particular, it was
observed the nucleophilic addition of the
solvent on the carbonyl group, thanks to its
big quantity in the reaction mixture compared
with that of hydroxylamine and to the aptitude
of the cyano group to exit to the system of
benzoyl cyanide, as it is a good leaving group.
The main by-product is isocyanate (7),
coming from the rearrangement of nitrile
oxide fragment, as already demonstrated in
literature (Fig. 6).12
Fig. 6: Thermal fragmentation of a general phenylfurazan
and formation of isocyanate (7) by rearrangement.
Finally we changed route switching to the
other pathway proposed: the synthesis of (12)
in two separated steps, isolating the
corresponding glyoxime intermediate (13)
and trying with different conditions (Scheme
8 and Table 3).
Scheme 8: Synthesis of α-amino-α'-phenylglyoxime (13).
Entry Solvent Temp.
(°C)
Time
(h)
Yields
(%)a
1 EtOH abs. 78, reflux
24 0
2 t-BuOH 82,
reflux
24 0
a: the yields correspond to gas chromatography and mass
spectrometry analysis after 24 hours.
Table 3: Reaction conditions of synthesis of 13.
Therefore, after all these failed experiments,
we decided to give up this synthetic procedure
and explore other ways to obtain
aminofurazans.
Synthesis of aminofurazans from alkyl β-
aryl-β-oxopropionates
We initially tested the Russian method
proposed by Sheremetev and his research
group,23
to check if it is reasonable for the
synthesis of 3-amino-4-arylfurazans (10). The
procedure is very interesting, since it is a one-
pot process without isolation step of
intermediates and leads straightforward to the
final product through a multi-step mechanism.
The one-pot synthesis involves hydrolysis of
the corresponding ester of a β-aryl-β-oxo acid
(14), nitrosation at the activated methylene
group, and treatment of the resulting
intermediate (16) with an alkaline solution of
hydroxylamine in the presence of urea
afforded the target aminofurazan (10). The
suggested mechanism is shown in Scheme 9.
The starting esters of β-aryl-β-oxo acids are
commercially accessible or easily prepared,24
so we used our available ethyl 3-oxo-3-
phenylpropanoate or ethyl benzoylacetate, as
starting material.
Fortunately, our two preliminary tests with
this synthesis are satisfactory because we
obtained the target molecule, 3-amino-4-
phenylfurazan (12), starting from ethyl
benzoylacetate (27) (Scheme 10), in very
small amounts, which correspond to yields of
5% for the first attempt and 8% for the second
one, with the same condition (Table 4).
Probably, the second time we were more
careful in each step. Finally, the pure product
12 is obtained by recrystallization from
CHCl3-light petroleum (1:1).
Scheme 9: One-pot synthesis of 3-amino-4-arylfurazans (10).
Scheme 10: One-pot synthesis of 3-amino-4-phenylfurazans (12).
Entry NaOH
aq.
(eq.)
HClO4/NaNO2
(eq.)
NH2OH-
HCl
(eq.)
Urea
(eq.)
Reflux
temp.
(°C)
Time
(h)
Yields
(%)a
1 1.1 2.5:1.2 4 1.0 110 3 5
2 1.1 2.5:1.2 4 1.0 110 3 8
a: Yields are referred to isolated compounds.
Table 4: Reaction conditions for one-pot synthesis of 12.
Now, our new approach is to search where the
problem is inside the procedure and
understand why such little yields are obtained.
Surely, the first reason is the very high reflux
temperature in the last step that can
compromise the final yield of the product 12.
In fact, by gas chromatographic analysis, it is
demonstrated the presence of many
unidentified by-products after reflux time
(about 3 hours), due to thermal
decomposition. In addition, the second reason
could be the presence of some problems
arising from incorrect reagents quantities and
their molar ratio or unsuitable reaction
conditions, such as pH of the aqueous
mixture.
Synthesis of phenylfurazans through
protected oximes
Now, our novel strategy is built up to form
furazans avoiding high-temperature reflux
conditions and prolonged reaction times, that
favor inevitably formation of a great variety
of by-products because of thermal
decomposition. Therefore, the first idea we
thought, shown in the Scheme 11, is to create
a protection on the OH group of the initial α-
aldo oxime (24), so that a subsequent addition
of hydroxylamine hydrochloride in the
mixture leads exclusively to a nucleophilic
attack on the carbonyl group, producing the
corresponding protected glyoxime. At this
point, we can suppose that the final
cycloaddition to form the phenylfurazan
product (2) undergoes more spontaneously,
thanks to the protecting group, which acts as a
very suitable leaving group, also at room
temperature or with very mild warming
temperatures. Thus, we proceeded with our
method beginning with the first step, the
protection. We have to say that our synthetic
mechanism involves a mix of reagents and
media among all those cited above. In fact, we
tested two different sulfonyl groups, p-tosyl
one (Scheme 12) and mesyl one (Scheme 13),
using chloride derivatives as reagents; in
either cases, the base chosen was DMAP in
1:1 molar ratio with the starting oxime 24,
and Et3N dry was added in small amounts, as
co-solvent of CH2Cl2. The whole reaction was
processed at room temperature, as we
wanted.25
Scheme 11: The novel strategy to synthesis phenylfurazan (2).
Scheme 12: The protection step of 24 by p-toluenesulfonyl chloride (p-TsCl).
Scheme 13: The protection step of 24 by methanesulfonyl chloride (MsCl).
Unfortunately, in either attempts, the
protection does not occur and the reaction,
monitored by TLC, gas chromatography and
mass spectrometry screening, highlights no
variations during also long time (24-48
hours). It keeps substantially unchanged
reactant oxime (24) and p-TsCl, transformed
into acid (p-TsOH), but displaying an
increasing formation of by-products, which
were not identified. This probably means that
the protection of an oxime is more suitable
when we have α-keto oximes as starting
compounds, maybe because of some effects
of the substituent in α position that promote
the sulfonylation; while if we have α-aldo
oximes, the most reached outcomes are only
by-products without ever noticed the presence
of protected oximes, or even completely no
reaction at all.
Synthesis of of phenylfurazans with
ultrasound and microwave-assisted
reactions
For the first time, our approach is focused on
an easy chemical equipment and technique,
which has increasingly been used in organic
synthesis in recent years: chemical
applications of ultrasound threw doors open
to an exciting new field of research. A large
number of organic reactions can be carried
out in higher yield, shorter reaction time and
milder conditions under ultrasonic
irradiation.26
Also oximes can be synthetize
with this method and the oximation is a very
efficient method for reaching more rapidly
our intent to obtain furazans. Thus, we took
advantage by this innovative chemical
application of ultrasound to be employed
either on α-aldo oxime synthetized before,
that is 2-oxo-2-phenylacetaldehyde oxime
(24), or on the phenylglyoxale (29), which is
the parent material into compound 24
synthesis. In both cases, there are the presence
of at least one carbonyl group, where the
sonochemical technique can act in appropriate
way and the formation of phenylglyoxime (1)
as end product. Herein, we wish to check an
effortless sonochemical synthesis of oximes
in EtOH, in the presence of Na2SO4 or not,
with mild temperature (25-35 °C)27
(Scheme
14).
Scheme 14: Synthesis of phenylglyoxime (1) by
sonochemical application.
The outcome of these new approaches are
surprising. Either we start from compound
(24) or from compound (29), the results does
not change because we have always the
formation of phenylglyoxime (1). Yields are
low due to the presence of two important
unexpected compounds which arise after the
determined reaction time. The first, and
maybe the most significant, is phenylfurazan
(2), while the second is phenylglyoxylic
nitrile oxime (30) (Scheme 15). In Table 5,
there are all the other conditions of this
synthetic process.
Scheme 15: Unexpected results with sonochemical
synthesis.
a: the yields correspond to gas chromatography and mass
spectrometry analysis.
Table 5: Reaction conditions of synthesis of 1 by
sonochemical application and the other two determined
compounds: 2 and 30.
The big problem that we met is to recognize
which was compound 2 and which was
compound 30 due to their same molecular
weights, that is 146 g/mol. In fact, to mass
spectrometry analysis, there were two peaks
with identical m/z, but also fragmentations
were similar and plausible for both molecules.
With other accurate analysis, such as 1H-
NMR and 13
C-NMR, we could understand the
right compounds related to the right peaks.
After this misunderstanding, we could
continue our tests, also with the help of gas
chromatography analysis, since we obtained
all the information to identify all the reaction
compounds (Fig. 7).
Fig. 7: Complete gas chromatogram of all compounds of the
whole sonochemical reaction.
Therefore, after these interesting results, we
tried to process the same synthesis by
improving yields of phenylfurazan (2),
attempting to overcome the formation of
phenylglyoxylic nitrile oxime (30) by use the
microwave instrumentation (Scheme 16).
Scheme 16: Microwave-assisted reaction of phenylfurazan
(2).
In fact, as shown in Table 6, reaction time
decreases extremely, giving the same yields
of products in minor period. This procedure is
also possible to do with several different
solvents, also those that solubilize a little the
reagents, since in the microwave instrument,
elevated temperatures let hard solubility too,
but some of these solvents give any effective
products and only by-products. Anyway, it
remains the problem to obtain only furazan
(2) rather than compound (30); unfortunately,
still this innovative procedure is at the
beginning and needs to be improved to get
directly the desired furazan.
Entry Starting
substrate
NH2OH-
HCl
(eq.)
Na2SO4
(eq.)
Time
(h)
Yields
(%)a
1 2 30
1 (24) 1.25 1 5 5 45 45
2 (29) 2.50 1 24 4 45 41
3 (24) 5.00 ---- 24 7 35 30
a: All reactions were carried out by irradiation in a PowerMax cooling microwave oven with a reached power
between 70 and 150 W, depending on the solvent used.
b: the yields correspond to gas chromatography and mass spectrometry analysis.
Table 6: Reaction conditions of microwave-assisted synthesis of 2. There is also present compound 30.
Conclusions
During this thesis period, we focused our
attention on particularly efficient methods
found in literature to synthesis 3-amino-4-
phenylfurazans (12) and the simpler
phenylfurazans (2), trying to bring some
changes to processes that could improve the
yields of our target products. Thanks to
Russian procedure and the innovative one of
microwave-assisted organic synthesis
(MAOS), we reached our goal to obtain
compounds (12) and (2), respectively,
unfortunately with not excellent yields.
However, the microwave technique give the
best outcomes because it remarkably
increases the formation of phenylfurazan (2)
with yields of around 40% in very short
reaction times and in different reaction
conditions, such as using a great variety of
solvents. The continuous problem that
remains as a constant in this procedure is the
formation of phenylglyoxylic nitrile oxime
(30), which can be considered as an reaction
intermediate or as a degradation by-product
due to reaction conditions. So, future research
perspectives should investigate and
understand what it is the role of compound
(30) in the microwave-assisted process and,
consequently, act in direction of synthesis of
single furazan, increasing yields and reducing
formation of other by-products.
Experimental Section
Materials. All the reactions are monitored
through thin layer chromatography on Merck
silica gel plates Kieselgel 60 F254 and
through gaschromatography on a
gaschromatograph 6850 Agilent
Technologies, with capillary column (0,32
mm x 30 m) and stationary phase OV1
Agilent of 0,40-0,45 μm.
The separation and purification of compounds
are effectuated through flash chromatography
on silica gel Merck (0,040-0,063 mm).
Entry Starting
substrate
NH2OH-HCl
(eq.)
Na2SO4
(eq.)
Solvent Temp.
(°C)a
Time
(h)
Yields
(%)b
(2) (30)
1 (24) 1.25 1 EtOH/H2O Multistep (40-165)
1.5 0 90
2 (29) 2.50 1 EtOH/H2O 100 2 43 41
3 (29) 5.00 ---- EtOH/H2O 170 1 40 40
4 (29) 5.00 (without HCl)
---- EtOH 140 0.5 28 61
5 (24) 1.25 ---- EtOH 145 1 45 40
6 (29) 2.50 ---- THF 140 1 0 80
7 (29) 2.50 ---- CH3CN 140 0.5 ---- ----
8 (29) 2.50 ---- CH2Cl2 140 0.5 ---- ----
9 (29) 2.50 ---- DMF 200 0.5 0 85
Characterization of products is carried out by
mass spectrometry, infrared spectroscopy and 1H and
13C nuclear magnetic resonance. Mass
spectrum are obtained by a gaschromatograph
interfaced with a mass spectrometer Hewlett-
Packard GC/MS 6890N. The mass
spectrometer works with the EI method
(70eV); or with an HPLC-MS HEWLETT
PACKARD 1100MSD series model G1946A,
with a column C18 Lichrospher 100 and mass
spectrometer API-ES. IR spectrum are
obtained with an IR spectrophotometer
Perkin-Elmer 1310 in the 4000-600 cm-1
range. NMR spectrum are acquired with a
spectrometer Varian Mercury Plus 400,
operating at 400 MHz, using various
deuterated solvents. Chemical shifts are
expressed in δ (ppm) regard to the not
deuterated solvent. The following
abbreviations are used: s = singlet, br s =
broaded singlet, m = multiplet. Reactions
under microwave irradiations were performed
using BIOTAGE INITIATOR
MICROWAVE REACTOR with the
following technical features: temperature
range (40 – 250°C), heating rate (2-5°C/sec),
pressure range (0-20 bar), power range (0-
400W) with magnetron (2.4 GHz), and
variable magnetic stirrer. Substrates, reactants
and solvents are acquired from common
commercial sources and used as received or,
if necessary, purified by distillation.
3-amino-4-phenyl-1,2,5-oxadiazole (12)
Ethyl benzoylacetate (23) (500 mg, 2.6 mmol)
was added at 0 °C to a solution of NaOH (114
mg, 2.9 mmol) in water (2 ml) and the
resulting mixture was stirred for 16 h. Sodium
nitrite (215 mg, 3.1 mmol) was added and
then 20% HClO4 (0.36 ml, 6 mmol) was
slowly added dropwise at T <10 °C. After the
acid was added completely, the reaction
mixture was warmed to room temperature and
left for ~24 h. Then, a solution of NH2OH-
HCl (718 mg, 10.4 mmol) in water (2 ml) was
added dropwise with vigorous stirring. After
half the solution of hydroxylamine was added,
a solution of NaOH (468 mg, 11.7 mmol) in
water (2 ml) was simultaneously added
dropwise from a second dropping funnel at a
temperature no higher than 30 °C. Then a
mixture was heated to 95 °C over 3 h and urea
(156 mg, 2.6 mmol) was added in one portion.
The resulting mixture was refluxed for 6 h
and cooled. The precipitate that formed was
filtered off, washed with water, dried, and
recrystallized from CHCl3-light petroleum
(1:1). The product 12 was obtained as white
solid with a yield of 8%. IR (neat): 3408,
3377, 3324, 3245, 1630, 1526, 1477, 1456,
1411, 1318, 1297, 981, 775 cm-1
. 1H-NMR
(400 MHz, CDCl3): δ= 4.30 (br s, 2H), 7.51-
7.56 (m, 3H), 7.71-7.74 (m, 2H) ppm. 13
C-
NMR (100 MHz, CDCl3): δ= 125.82, 127.84,
129.68, 130.82, 147.11, 154.40 ppm. GC-MS
(EI, 70eV) m/z: 161 [M+], 131, 104, 91, 77,
58, 51, 39.
3-phenyl-1,2,5-oxadiazole (2) and
phenylglyoxylic nitrile oxime (30)
Ultrasounds-assisted procedure:
Phenylglyoxale (29) (160 mg, 1.2 mmol) or 2-
oxo-2-arylacetaldehyde oxime (24) (180 mg,
1.2 mmol) was dissolved in ethanol (6 ml). A
solution of hydroxylamine hydrochloride (207
mg, 3 mmol; H2O, 1.5 ml), anhydrous sodium
sulfate (1 mmol or without) were added. The
reaction mixture was irradiation in the water
bath of the ultrasonic cleaner at 25-35 °C for
an appropriate period (5 h for 24; 24 h for 29).
The mixture was filtered (if without NaSO4,
no filtration.) and the solvent was evaporated
under reduced pressure. The residue was
dissolved in CH2Cl2, washed with water, and
extracted with CH2Cl2. The combined organic
layers were dried over anhydrous MgSO4,
filtered, and evaporated to dryness under
reduced pressure. Purification was
accomplished by recrystallization or by
column chromatography on silica gel (200–
300 mesh), eluted with petroleum ether or a
mixture of petroleum ether and diethyl ether.
The product 2 was obtained as white solid
with a yield of 45%, while the product 30 was
obtained as white solid with a yield of 40%.
Microwave-assisted procedure:
Phenylglyoxale (29) (200 mg, 1.5 mmol) was
dissolved in ethanol (7.5 mL). A solution of
hydroxylamine hydrochloride (257 mg, 3.7
mmol; H2O, 1.5 mL) was added. The reaction
mixture was subjected to microwave
irradiation for 30 min at 140 °C. The reaction
was monitored by TLC until disappearance of
starting material. Once the reaction was
completed, the solvent was evaporated under
reduced pressure. The residue was dissolved
in CH2Cl2, washed with water, and extracted
with CH2Cl2. The combined organic layers
were dried over anhydrous MgSO4, filtered,
and evaporated to dryness under reduced
pressure. Purification was accomplished by
recrystallization or by column chromatogra-
phy on silica gel (200-300 mesh), eluted with
petroleum ether or a mixture of petroleum
ether and diethyl ether. The product 2 was
obtained as white solid with a yield of 40%,
while the product 30 was obtained as white
solid with a yield of 40%.
Characterization of 2: 1H-NMR (400 MHz,
CDCl3): δ= 7.52-7.54 (m, 3H), 7.84-7.88 (m,
2H), 8.56 (s, 1H) ppm. 13
C-NMR (100 MHz,
CDCl3): δ= 125.60, 127.68, 129.65, 131.34,
139.73, 154.65 ppm. GC-MS (EI, 70eV) m/z:
146 [M+], 119, 103, 91, 89, 76, 63, 51, 39.
Characterization of 30: 1H-NMR (400 MHz,
CDCl3): δ= 7.44-7.49 (m, 3H), 7.79-7.81 (m,
2H), 9.69 (br s, 1H) ppm. 13
C-NMR (100
MHz, CDCl3): δ= 109.52, 126.45, 129.24,
130.21, 131.45, 148.88 ppm. GC-MS (EI,
70eV) m/z: 146 [M+], 129, 116, 103, 89, 77,
63, 51, 39.
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