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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