Efficient Synthesis of Five Types of Heterocyclic Compounds via Intramolecular Elimination Using Ultrasound-Static Heating Technique

Article abstract of DOI:10.1002/asia.201800682

An experimental technique, ultrasound-static heating, has been developed for the efficient synthesis of heterocyclic compounds. The technique involves ultrasonic irradiation and static heating processes. First, the ultrasonic irradiation process is performed to form an intermediate of the heterocyclic compound under mild conditions and the subsequent static heating process (heating the intermediate under solvent-free conditions without stirring) produces the target heterocyclic compounds via intramolecular elimination.

Full text of DOI:10.1002/asia.201800682

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Efficient Synthesis of Five Types of Heterocyclic Compounds
via Intramolecular Elimination Using Ultrasound-Static Heating
Technique
Authors: Tao Jiang, HongFei Jiang, Xueyang Dong, Xin Jin, Danyang
Zhu, Ruijuan Yin, Rilei Yu, Shengbiao Wan, and Lijuan Zhang
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To be cited as: Chem. Asian J. 10.1002/asia.201800682
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Efficient Synthesis of Five Types of Heterocyclic Compounds via
Intramolecular Elimination Using Ultrasound-Static Heating
Technique
Hongfei Jiang,[a] Xueyang Dong,[a] Xin Jin,[a] Danyang Zhu,[a] Ruijuan Yin,[a],[b] Rilei Yu,[a],[b] Shengbiao
Wan,[a] Lijuan Zhang,[c] Tao Jiang*[a],[b]
Abstract: A novel experimental technique, ultrasound–static heating,
has been developed for the efficient synthesis of heterocyclic
compounds. The technique involves ultrasonic irradiation and static
heating processes. The ultrasonic irradiation process is performed to
form an intermediate of the heterocyclic compound under mild
condition and the subsequent static heating process (heating the
intermediate under solvent-free conditions without stirring) is an
efficient way of producing the target heterocyclic compound via
intramolecular elimination.
workers in 2004. [3] They discovered that this method was greatly
superior to the conventional ways using solvents.
We have greatly improved the static heating technique. In this
paper, we synthesize five types of heterocyclic compounds
including pyrazolone, imidazopyridine, thiazolopyrimidine,
thiadiazol and pyrimidine derivatives. In our work, we applied
static heating technique in some reactions that require FeCl3 or
K2CO3 as the catalyst. Through this work, we found that U-SH
technique can be widely applied to cyclo-condensation reactions
via intramolecular elimination for the preparation of heterocyclic
compounds.
Heterocyclic compounds, including the majority of drugs, novel
materials, natural or synthetic dyes and nucleic acids etc, widely
exist in nature. Much effort has been devoted to synthesizing
various heterocyclic compounds.[1] However, the reaction process
of reactants in solution usually leads to complicated side reactions
which result in the generation of by-products. New methods or
strategic means should be adopted for the efficient synthesis of
heterocyclic compounds .
Most heterocyclic compounds are synthesized by cyclo-
condensation reactions (besides cycloaddition reactions), starting
with more than one reactants combining via a key intermediate,
which later on undergoes intramolecular elimination reaction to
generate targeted heterocyclic compound.[2] We have found that
these two consecutive steps can be efficiently carried out by using
an ultrasonic irradiation followed by static heating. We call this
novel technique ultrasound-static heating (U-SH).
U-SH technique involves two steps (Figure 1). Firstly, reactants
(A and B) react under ultrasonic irradiation to form the
intermediate (A–B) under mild conditions with little or no solvent.
Secondly, the intermediate undergoes intramolecular elimination
through a static heating process to form the desired heterocyclic
compound (C). ‘Static heating’ here implies heating the
intermediate together with other reagents (e.g. catalyst etc, if any)
under solvent-free conditions without stirring.
Figure 1. Methods for synthesizing heterocyclic compounds.
Static heating is a novel solvent-free methodology. Conventional
solvent-free methods are performed using some form of agitation,
e.g. mechanochemistry (grinding), microwaves, ultrasound or
magnetic stirring.[4] However, stirring is not essential for
intramolecular reactions and so the static heating process can be
successfully carried out without stirring. Static heating may, of
course, be performed using reactants in the solid state. Therefore,
it is more propitious to intramolecular reactions, such as
intramolecular elimination reactions and intramolecular
cyclization reactions, and can efficiently prevent intermolecular
side-reactions between reactant molecules.
To our knowledge, the technique of heating the reactants (rather
than intermediate) under solvent-free conditions were firstly
adopted by Francesco Fringuelli, Ferdinando Pizzo and their co-
[a]
Dr. H.F. Jiang, X.Y. Dong, X. Jin, Ms. D.Y. Zhu, Dr. R.J. Yin, Dr.
R.L. Yu, Prof. S.B. Wan, Prof. T. Jiang
Key Laboratory of Marine Drugs, Chinese Ministry of Education,
School of Medicine and Pharmacy
Initially, we applied U-SH technique to the synthesis of pyrazolone
derivatives, which are involved in various physiological and
biochemical processes.[5] A large number of studies have been
aimed at obtaining various pyrazolone derivatives.[6] The
conventional synthetic route to pyrazolone derivatives involve
condensation wherein hydrazine derivatives are refluxed with β-
dicarbonyl compounds in a suitable solvent (e.g. acetic acid,
Ocean University of China
Qingdao, 266003, P.R. China
E-mail: jiangtao@ouc.edu.cn
Dr. R.J. Yin, R.L. Yu, Prof. T. Jiang
Laboratory for Marine Drugs and Bioproducts
Qingdao National Laboratory for Marine Science and Technology
Qingdao, 266237, P.R. China
[b]
[c]
Prof. L.J. Zhang
Institute of Cerebrovascular Diseases, Affiliated Hospital of Qingdao
University Medical College, Qingdao, 266500, P. R. China
Supporting information for this article is given via a link at the end of
the document.
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toluene, ethanol or methanol).[7] The method usually persists long
reaction time (over 24 hours in some cases) with low yields (due
to side reactions) and difficulty in choosing suitable solvent. For
example, our attempt to synthesize 1-(4-carboxyphenyl)-3-
stable and their structures could be confirmed by NMR analysis
(supporting information S9-S10). However, the compounds 3c-g
that formed were less stable under the experimental conditions
and partially transformed to the corresponding 4c-g compounds
during the ultrasonic irradiation process. The intermediate 3 was
used directly in the next step to synthesize 4. All of the
intermediates 3b-g reacted smoothly during the static heating
process at appropriate reaction temperature to give the
corresponding targeted heterocyclic compounds 4b-g with
moderate to excellent isolated yield (49-100%).[9]
methyl-5-pyrazolone
(4a,
Table 1)
by
refluxing
4-
hydrazinobenzoic acid (1a) with acetoacetic ester (2a) in various
solvents (acetic acid, toluene or ethanol) only yielded the
intermediate 3a and no 4a was detected. However, when DMSO
was used as solvent (which has a higher boiling point), the target
compound 4a was detected along with various by-products. The
poor solubility of 4a and these by-products made the subsequent
purification process very difficult. Using microwave and ultrasonic
solvent-free methods may be able to greatly improve the yield,
however, there is still no conclusion about the intermediates and
adaptability of the reaction.[8]
The reaction temperature required in the static heating process
varies with the substituent group in the N-1 position. In general,
compounds with phenyl groups in the N-1 position (3a-f) require
a
higher reaction temperature than those with aliphatic
substituents (3g). Similarly, those with strongly electron-
withdrawing substituents on the benzene ring (3a, 3b) require
higher reaction temperatures than those with halo substituent
groups (3c) and electron-donating groups (1d, 1e, 1f) on the
benzene ring.
Table 1. The synthesis of pyrazolone derivatives 4a-g using the U-SH
technique
Other β-dicarbonyl derivatives, including ethyl-3-cyclopropyl-3-
oxopropionate (2h), ethyl benzoylacetate (2i), ethyl-2-
methylacetoacetate (2j), methyl acetoacetate (2k) and methyl
isobutyrylacetate (2l), all reacted with 1d via the U-SH technique
and gave the desired products 4h-l with excellent isolated yield
(Table 2).
Table 2. The synthesis of pyrazolone derivatives 4h-m using the U-SH
technique
ꢀ
ꢀ
[a] Isolated yield. [b] Reaction time is 1 h. [c] Reaction conditions: 150 °C,
2 h. [d] Reaction conditions: 70 °C, 5 h. [e] Reaction conditions: 50 °C, 1 h.
We found that our U-SH technique could be used to synthesize
4a with high efficiency. We started by synthesizing the key
intermediate 3a using ultrasonic irradiation. (Compound 1a was
reacted with 2a at room temperature under ultrasonic irradiation
without the use of any solvent and 3a was produced with an
excellent yield of 100%.) The solid state compound 4a was
subsequently achieved by using static heating at 150 °C for
2 hours via an intramolecular elimination reaction (the removal of
an ethanol molecule). The target cyclic compound 4a was
obtained with nearly 100% isolated yield without any by-products
detected (Table 1).
The U-SH technique was used to synthesize other pyrazolone
derivatives (Table 1). Various hydrazine derivatives were used to
react with ethyl acetoacetate. The hydrazine derivatives, which
included phenylhydrazine derivatives with electron withdrawing
groups (1a, 1b), halo substituent groups (1c), electron donating
groups (1d, 1e, 1f) and aliphatic hydrazine (1g), all reacted with
2a smoothly under ultrasonic irradiation and to give the
corresponding intermediates 3a-g. Intermediates 3a and 3b are
Although 1d and 2m (ethyl-4,4,4-trifluoroacetoacetate) reacted
together under ultrasonic irradiation and gave the expected
intermediate 3m smoothly, the 3m (table 3) did not react further
during the static heating process to produce the desired 4m, even
when it was heated to high temperature (up to 130 °C). By
analysing the structure of 3m using NMR, it was found that there
is an intramolecular hydrogen bond between CF3 and OH groups
in 3m (Figure 2). As shown in Figure 2, the proton chemical shift
of hydroxyl group was up to 9.09 ppm, which is markedly higher
than those found for hydrogen atoms in ordinary hydroxyl groups.
Once the intramolecular hydrogen bond is formed, the elimination
of ethanol is not energetically favourable, and so pyrazolone
production is suppressed.
In order to destroy the intramolecular hydrogen bond in compound
3m, we used FeCl3 (a Lewis acid) as a catalyst to promote the
synthesis of 4m. The electron-deficient center Fe3+ was an proton
acceptor and could weaken the intramolecular hydrogen bond
between CF3 and OH groups in 3m, thus, 3m reacted to produce
the desired 4m and gave 4n as by-product.[10] To make the static
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heating technique applicable to the synthesis of 4m, we used
silica gel (as commonly used in column chromatography) as a
support that 3m and FeCl3 would homogeneously absorb on the
surface of silica gel. The mixture was subsequently heated at
70 °C for 2 h without adding solvent and stirring the mixture. The
desired product 4m was produced with an isolated yield of 55%
(Table 3). It is noteworthy that a sizeable amount of the 3m was
also converted to compound 4n (38% isolated yield). This
compound is produced during the static heating process by the
removal of a water molecule rather than an ethanol molecule.
Increasing the temperature used in the static heating process
made the removal of water molecule more favourable and
increases the proportion of 4n among products.
temperature was increased slightly to 100 °C and heat treatment
prolonged to 10 hours, a reasonable amount of 3b was converted
to 4b (50%, Entry 2 in Table 4). However, when a temperature of
110 °C was used, the 3b was totally converted to 4b in 10 hours
(Entry 3 in Table 4). Further increases in temperature allowed the
reaction time to be reduced. Thus, reaction temperatures of 120
and 150 °C allowed complete conversion to be achieved in 6 and
2 hours, respectively (Entry 4 and Entry 5 in Table 4).
Table 4. The FeCl3-mediated synthesis of 4m under static heating
conditions.
Entry
Temp. (°C)
Time (h)
Yieldꢀ
(%)[a]
1
2
3
4
5
90
3
0
100
110
120
150
10
10
6
50
100
100
100
2
[a] ꢀIsolated yield.
Following the successful application of U-SH technique in the
synthesis of pyrazolone derivatives, we applied this technique in
the synthesis of other heterocyclic compounds.Firstly, we
synthesized an imidazopyridine derivative, 2-phenylimidazo[1,2-
a]pyridine (8), under ultrasonic irradiation condition. The
imidazopyridine derivatives are a class of drugs defined by their
chemical structure.[11] Compound 8 was usually synthesized from
2-aminopyridine (5) and 2-bromoacetophenone (6) by using
ethanol as the solvent through an imine intermediate (7), the
addition of excess alkali (e.g. NaHCO3) could stimulate this
reaction.[12] By using this method, 8 could be obtained with
moderate yield (90%) in 6 hours (Scheme S1 in supporting
information). However, we found that ultrasonic irradiation
condition could be much more efficient for the synthesis of 8. The
compound 5 and 6 in the flask was added a small quantity of
methanol as solvent.[13] And then the mixture reacted at ultrasonic
irradiation condition for 1h at 30 °C could produce the desired 8
with 98% isolated yield (Scheme 1). Ultrasonic reaction was able
to shorten reaction time and improve the yield for the synthesis of
8 without static heating in this synthesis.
Figure 2. The 1H NMR spectrum of 3m.
Table 3. The FeCl3-mediated synthesis of 4m under static heating
conditions.
Entry
Temp. (°C)
Catalyst
Time
(h)
Yieldꢀ (%)[a]
4m
0
4n
0
1
2
3
130
70
none
8
2
2
FeCl3/silica gel
FeCl3/silica gel
55
0
38
83
100
[a] ꢀIsolated yield.
The conversion of compound 3b to compound 4b was performed
at different temperatures to investigate the optimum reaction
conditions required during the static heating process (Table 4).
The reaction temperature and reaction time are the key factors
that influence the reaction. At 90 °C, no 4b was detected after
3 hours of static heating (Entry 1 in Table 4). When the
Scheme 1. The synthesis of thiazolopyrimidine derivative 8 using the U-SH
technique.
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Secondly, U-SH technique was applied for the synthesis of
thiazolopyrimidine derivative, which play an important role in
various physiological activities.[14] For example, the compound 12
(Scheme 2) is a useful kinase inhibitor and is used to treat, for
example, P38 kinase-associated conditions. 12 can be
synthesized from the corresponding thiazole intermediate 11
which, in turn, can be synthesized from the starting compounds 9
and 10 (Scheme S2 in supporting information).[15]
Scheme 3. The synthesis of the thiadiazol derivative 16 using the U-SH
technique.
The synthetic method previously used to prepare 12 involves
the use of the high boiling point solvent diphenyl ether. However,
the solvent’s high boiling point and toxicity means that the work
up processes required to isolate and purify the desired product 12
are difficult to perform. However, U-SH technique was found to be
an efficient method for the preparation of 12. In this case, 9 and
10 reacted under ultrasonic irradiation for 50 minutes at 60 °C
producing 11 at a very high isolated yield of 96%.[16] In the
subsequent static heating process, the 11 was placed in a flask
and statically heated to 200 °C for 1 hour. The crude product was
purified using column chromatography giving the target
compound 12 with an isolated yield of 67%. Overall, taking into
account the two steps used, the U-SH technique produces 12 with
a yield of 64%. In contrast, the previous synthetic method has an
overall yield of 37%. Thus, compared with the previous synthetic
method, the U-SH technique is a far more efficient, economical
and environmentally friendly method of synthesis.
Fourthly, we applied the U-SH technique to the efficient
synthesis of Meridianin derivative (Meridianins are marine
alkaloids isolated from the south Atlantic tunicate Aplidium
meridianum [18]) 20. The intermediate 19 was synthesized from 17
and 18 under ultrasonic irradiation at 50 °C for 2 h. The
intramolecular cyclization reaction (from 19 to 20) requires
potassium carbonate as a catalyst to facilitate the deprotection of
the tosyl-protecting group. Therefore, to make the static heating
process work for this reaction, potassium carbonate was used
directly as a support and compound 19 was absorbed onto its
surface. The potassium carbonate was heated to 100 °C for
6 hours. The procedure produced the desired 20 with an isolated
yield of 56% and during static heating, the cyclization reaction and
deprotection reaction proceeded simultaneously. (Scheme 4).
However, the synthesis of 20 in the solvent of ethanol at 90 °C
gave 20 with relatively low yield of 15% (Scheme S4 in supporting
information). The reaction produced 3-acetylindole as the main
by-product and the large amount of 3-acetylindole produced
made the task of isolating and purifying the 20 very difficult. It is
rather remarkable that the by-product 3-acetylindole was not
detected in this process. This means that the potassium
carbonate on its own was not able to induce the conversion of 17
to 3-acetylindole and that it was the addition of the protic solvent
that promoted the generation of the by-product.
Scheme 2. The synthesis of thiazolopyrimidine derivative 12 using the U-SH
technique.
Thirdly, we applied the novel technique to the synthesis of a
thiadiazol derivative 16 (Scheme 3), a novel and potent protein
kinase CK2 inhibitor and can be synthesized starting from 13 and
14 using FeCl3 as the catalyst.[17] According to the literature, the
reported method of 16 synthesis employs ethanol and water as
solvents (and FeCl3 as catalyst) producing the target molecule 16
with a yield of 26% (Scheme S3 in supporting information). Many
by-products were detected.
Scheme 4. The synthesis of the meridianin derivative 20 using the U-SH
technique.
In our synthesis, 13 and 14 were reacted together under
ultrasonic irradiation for 1 hour at room temperature. The
intermediate 15 was generated with high purity and could be used
in the next step (static heating) without further purification. Then
compound 15 and FeCl3 absorbed onto the surface of silica gel
reacted under static heating condition at 70 °C for 30 minutes.
The desired product 16 was obtained with an isolated yield of 60%.
In the previous synthetic method employing solvents, a large
amount of by-products produced during the FeCl3-catalyzed
intramolecular cyclization reaction. However, static heating is able
to efficiently avoid some of these intermolecular side reactions so
that the yield of the desired product 16 is greatly improved.
In summary, we have developed a new technique, U-SH, that
is a convenient and efficient method for organic synthesis. The
technique has proved to be a feasible method of synthesizing
some well-known heterocyclic compounds. Furthermore, it
improves the yields of these compounds compared to synthetic
routes employing solvents. The technique uses little or no solvent
and requires no stirring device. The static heating technique is
specifically efficient for intramolecular reactions and can
effectively prevent the production of by-products induced by
intermolecular side reactions. We believe that the U-SH technique
may be usable in many more synthetic roles. The static heating
technique could also have a broader range of application in many
other areas, e.g. in industry.
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The authors are grateful for financial support granted by NSFC-
Shandong Joint Fund (U1706213, U1406403), Innovation Project
from Qingdao National Laboratory for Marine Science and
Technology (No.2015ASKJ02), the Fundamental Research
Funds for the Central Universities (No. 201512007,201762011 for
R.Y.), and Taishan Scholar Project Fund of Shandong Province.
During the static heating processes, the reaction mixture of 4a and 4b
synthesises were solid state and 4a and 4b were obtained with excellent
isolated yield of 100%. However, the reaction mixture of 4c-g
synthesises were liquid state, some intermolecular side-reactions might
occur during those processes and led to the moderate to excellent yield
of them.
Keywords: ultrasound • static heating • heterocyclic compounds
• solvent-free • non-stirred
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Hongfei Jiang, Xueyang Dong, Xin Jin,
Danyang Zhu, Ruijuan Yin, Rilei Yu,
Shengbiao Wan, LiJuan Zhang, Tao
Jiang*
Page No. – Page No.
Efficient Synthesis of Five Types of
Heterocyclic Compounds via
Text for Table of Contents
Intramolecular Elimination Using
Ultrasound-Static Heating Technique
A novel experimental technique, ultrasound–static heating (U-SH technique), has been developed for the efficient synthesis of five
types of heterocyclic compounds. The technique involves ultrasonic irradiation process, forming an intermediate of the heterocyclic
compound synthesis, and static heating process (heating the intermediate under solvent-free conditions without stirring), an efficient
way of producing the target heterocyclic compound via intramolecular elimination to produce the desired heterocyclic compounds.
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