Convenient and efficient synthesis of disubstituted piperazine derivatives by catalyst-free, atom-economical and tricomponent domino reactions

Article abstract of DOI:10.1039/c4ra14811h

One-pot, atom-economical, catalyst-free and tri-component domino reactions are applied to the diversity-oriented synthesis (DOS) of disubstituted piperazine derivatives under mild conditions with moderate to high yields. This protocol exhibits potential a

Full text of DOI:10.1039/c4ra14811h

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Convenient and efficient synthesis of disubstituted
piperazine derivatives by catalyst-free, atom-
economical and tricomponent domino reactions†
Cite this: RSC Adv., 2015, 5, 10768
Received 18th November 2014
Accepted 6th January 2015
Hong-Ru Dong, Zi-Bao Chen, Rong-Shan Li, Heng-Shan Dong* and Zhi-Xiang Xie*
DOI: 10.1039/c4ra14811h
www.rsc.org/advances
One-pot, atom-economical, catalyst-free and tri-component domino
The new classes of hybrid anticancer drugs were obtained by
reactions are applied to the diversity-oriented synthesis (DOS) of selective functionalization of the piperazine scaffold following
disubstituted piperazine derivatives under mild conditions with fragment-based drug design. The piperazine nucleus and its
moderate to high yields. This protocol exhibits potential applicability in substituted products play an important role in anticancer (the
the synthesis of pharmaceuticals, liquid crystals, complexes, etc. invention compounds are useful for the treatment of cancers
Because of its operational simplicity and convenience, it may be including glioblastomas, lung cancers, colon cancers, gastric
suitable for application in large-scale synthesis.
(stomach) cancer, breast cancer, esophageal cancer, and pros-
tate cancer, liver cancer, breast cancer, leukemia, lymphoma,
kidney cancer, skin cancer, pancreatic cancer.) activity and
3
Some reactions and synthetic methodologies, for example
cascade, tandem, one-pot, multicomponent domino reactions,
atom-economical, catalyst-free, ring opening, supramolecular
self-assembly, diversity-oriented synthesis (DOS) and
functional-oriented synthesis (FOS), are increasingly applied to
the construction of natural and designed molecules. Such
processes, in which ideally a single event triggers the conversion
of a starting material to a product which then becomes a
substrate for the next reaction until termination leads to a
stable nal product, are highly desirable not only due to their
elegance, but also because of their efficiency and economy in
terms of reagent consumption and purication. Oen, these
one-pot multistep procedures are accompanied by dramatic
increases in molecular complexity and impressive selectivity.
The discovery of new molecular diversity from nature and the
demand for more efficient and environmentally benign chem-
ical processes dictates and invites the further development of
such synthetic strategies and tactics as we move into a new age
pharmacological properties. The arylpiperazine framework is
observed in agreat deal of compounds of pharmaceutical
interest. In 2001, the MDDR (MDL Drug Data Report) listed
2
271 phenylpiperazines which totaled 65 structures in clinical
4
trials or higher across 23 therapeutic areas. The piperazine or
piperazinone core also presents in the compounds that are
possessing anti-fungal, anti-depressant, anti-malarial, anti-
5
migraine, anti-diabetic, anti-thrombotic, anti-aggregating, etc.
Piperazine derivatives are important intermediates in organic
synthesis and can be used as the building blocks in pharma-
ceutical and ne chemical industries. Some disubstituted
6
piperazine derivatives are applications in liquid crystals, com-
7
plexe, coatings, sealing materials, adhesives and hot-melt
8
9
adhesive, self-assembled monolayer in an electronic device,
10
novel charge-transfer polymers in solar cells et al., non-
aqueous gel ion conductor compositions used in batteries,
self-assembly of supra-molecular polymer materials, antistatic
agents and vulcanization accelerators, etc.
11
12
13
1
of chemical synthesis.
Aromatic ring, aromatic heterocyclic ring and its derivatives
are the parent structure of many nature products. Most of the
heterocyclic nucleuses use exhibit remarkable pharmacological
Piperazine ring and its derivatives present in many nature
2
products, such as anticancer Aspernigerin (Scheme 1), etc.
College of Chemistry and Chemical Engineering, State Key Laboratory of Applied
Organic Chemistry, Institute of Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, P. R. China. E-mail: donghengshan@lzu.edu.cn; xiezx@lzu.edu.cn;
Fax: +86 0931 8912582
†
Electronic supplementary information (ESI) available: Experimental procedure,
1
13
characterization data, H and C NMR spectra, X-ray crystal data of products.
CCDC 1019130. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra14811h
Scheme 1 Aspernigerin.
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DABCO is less, it is a catalyst and main product 4b is obtained.
When the amount of DABCO is more than 0.6 equivalent, it acts
as a reactant and gives major product 4a. The reaction is shown
in Scheme 2. The results of the reaction using different amount
of DABCO are shown in Fig. 1.
The new class derivatives for selective functionalization of
the aromatic ring scaffold. Some novel disubstituted piperazine
derivatives were synthesized by substituted aromatic acids
(Table 1).
Scheme 2 Synthesis conditions of title compound 4a.
Table 1 Synthesis of some novel aryl piperazine derivatives
Entry
Ar-COOH
4-Br-C
2-Cl-C
Yields (%)
Fig. 1 The yield of title compound 4a is changed by quantity of
DABCO added.
1
2
3
4
6
H
4
-COOH
1a (86%)
1
b (11%)
2a (86%)
b (9%)
3a (72%)
b (16%)
4a (82%)
b (12%)
6
H
4
-COOH
2
b-C10
H
7
-OCH
2
COOH
activities. The new classes of hybrid derivatives were obtained
by selective of the heterocyclic ring scaffold. The 1H-1,2,3-tri-
azole derivative is a heterocyclic compounds with wide biolog-
3
a-C10H
7
-COOH
4
1
4
ical activity and applications in many elds. The triazole ring
nucleus also exhibits remarkable pharmacological activities
and selective functionalization of the heterocyclic ring scaf-
5
6
7
8
9
a-C10H -CH COOH
5a (62%)
6a (43%)
7a (89%)
8a (59%)
7
2
2-CH
4-F-C
Ph-CH]CH-COOH
3
COO-C
6
H
4
-COOH
6
H
4
-COOH
15
fold. Amino acid is the smallest unit formation of protein and
polypeptide, and the most of amino acids was chiral. Some
4-NC-C
6
H
4
-COOH
-COOH
9a (57%)
10
4-CH O-C
3
6
H
4
10a (75%)
11a (79%)
12a (84%)
13a (64%)
14a (74%)
15a (85%)
16a (81%)
17a (75%)
18a (89%)
19a (74%)
20a (66%)
21a (69%)
22a (72%)
23a (75%)
24a (74%)
25a (65%)
26a (31%)
27a (68%)
28a (89%)
29a (71%)
30a (66%)
31a (55%)
32a (79%)
33a (77%)
34a (45%)
35a (39%)
35b (25%)
amino acids are used for important chiral tool sources in chiral 11
synthesis or asymmetric synthesis. Proteins and peptides are 12
Ph-CH(OH)-COOH
2-Br-C -COOH
6
H
4
1
1
1
1
3
4
5
6
2-CH
3-CH
3
O-C
O-C
6
H
H
4
-COOH
-COOH
chiral, enzyme and cell is also composed of chiral proteins. The
cancer or some diseases is caused by some enzymes or cells.
Hence, to inhibit these enzymes or cells, the chiral drugs was
required.
3
6
4
3-Cl-C
2-F-C
3-CH -C H -COOH
6
H
4
-COOH
6
4
H -COOH
17
3
6
4
In the one-pot, atom-economical, catalyst-free, supra- 18
Ph-COOH
Ph-CH COOH
3-CH -C -COOH
2,4-DiCl-C -OCH
-OCH COOH
19
20
21
22
2
molecular homo- and hetero-synthon, ring opening and tri-
component domino reactions are being applied to the
diversity-oriented synthesis and construction progress of
3
6 4
H
6
H
3
2
COOH
C
6
H
3
2
designed molecules. In the processes, the conversion of a 23
starting material to a product is highly desirable, efficient and 24
a-C10H -OCH COOH
7
2
4-I-C
2-I-C
6
H
4
-COOH
-COOH
25
26
27
28
6
H
4
economic in terms of reagent consumption and purication.
These multistep, one-pot procedures are accompanied by
dramatic increases in molecular complexity and impressive
3 6 4
2-CH COO-C H -COOH
Nicotinic acid
5-Bromopyridine-3-COOH
Quinoline-2-COOH
Pyrazine-2-COOH
(Tetrazol-1-yl)acetic acid
Furan-2-COOH
selectivity, and are suitable for application in scale the 29
synthesis. To examine the yield of diversity-oriented synthesis 30
3
3
3
3
1
2
3
4
(
DOS), atom-economical, one-pot and tri-component domino
reactions, we chose the 1-naphthoic acid (4), dimethyl acetylene
dicarboxylate (DMAD) as a model substrate. The yield of 4a and
4
Picolinic acid
4-Br-C
6
H
4
-COOH, R ¼ –CH
3
b is examined by the change of 1,4-diazabicyclo[2.2.2]octane 35
4-Br-C H -COOH, R ¼ –Et
6
4
(DABCO) mol%. Finally result shows, when the amount of
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Table 2 Synthesis of some novel 1H-1,2,3-triazolyl piperazine derivatives
Entry
Ar-COOH
Yields (%)
3
6
1-(4-Chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
36a (68%)
3
6b (25%)
37
38
39
40
41
42
43
44
5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid
37a (71%)
38a (64%)
39a (82%)
40a (60%)
36a (63%)
42a (35%)
43a (49%)
44a (67%)
1-(4-Ethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
5-Methyl-1-(naphthalen-2-yl)-1H-1,2,3-triazole-4-carboxylic acid
1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
1-(4-Chlorophenyl)-5-methoxy-1H-1,2,3-triazole-4-carboxylic acid
1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid
reaction of hetero-synthon a attacks DMAD was happened and
the corresponding zwitterionic intermediate b and c were given.
When the aromatic acid anion b attacks DABCO cationic
intermediate c, a reaction of nucleophilic substitution was
reacted and the nal products 1a–52a is obtained. If reaction
Table 3 Synthesis of some novel (un)substituted amino carboxylic
acid piperazine derivatives
Scheme 3 The target compound 42a and 43a.
Some novel disubstituted piperazine derivatives were
synthesized by substituted 1,2,3-triazolyl acids (Table 2).
When 1-[1-(1-aryl-5-methyl-1H-1,2,3-triazole-4-carboyloxyl) ethan-
2-yl]-4-[(E)-1,2-(dimethoxycarbonyl)ethen-1-yl]piperazine derivatives
were synthesized, novel compounds 42a and 43a were obtained by
the reaction of 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-
carboxylic acid, DABCO, dimethyl but-2-ynedioate. Compound 43a
is a normal product, but 1-{2-[2-diazo-3-(E)-(2-bromophenylimino)
butyroyloxyl]ethan-1-yl}-4-[(dimethoxycarbonyl)-ethen-1-yl]piperaine
Entry
Ar-COOH
Yields (%)
4
2a is a compound involving diazo compound by showing strong IR
ꢀ
1
16
absorption at 2125 cm . The structures are shown in Scheme 3.
Some target compounds were synthesized by amino acid or 46
45
2-(Phenylamino)benzoic acid
(ꢁ)-5-Oxopyrrolidine-2-carboxylic acid
2-(Benzamido)acetic acid
2-(1H-Indol-3-yl)acetic acid
1H-Indole-2-carboxylic acid
45a (89%)
46a (68%)
47a (90%)
48a (61%)
49a (77%)
substituted amino acid. The reaction is shown in Table 3.
When the target compounds were synthesized by some
amino carboxylic acid, the products with bis(E)-1,2-
47
4
4
8
9
(
dimethoxycarbonyl)ethen-1-yl compounds 50a, 51a and 52a 50
were obtained (Scheme 4).
A proposed mechanism of this reaction is shown (in 51
50a (69%)
51a (55%)
17
Scheme 5) based on the previous investigation. Initially,
reaction of Ar-COOH (dimeric supra-mol. homo-synthon) 1 and
DABCO form a DABCO aromatic acid salt (supra-mol. hetero-
synthon) a. Then, an intermolecular nucleophilic addition
52
52a (78%)
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Fig. 3 The p–p accumulation structure of 40a supra-molecular.
Scheme 4 The target compound 50a, 51a and 52a.
The supra-molecular structure of compound 40a is shown in
Fig. 3.
In summary, catalyst-free, one-pot, atom-economical, supra-
molecular homo- and hetero-synthon, ring opening and tri-
component domino reactions are applied to diversity-oriented
synthesis (DOS) of disubstituted piperazine derivatives under
mild conditions with moderate to high yields. This protocol
exhibits potential applicability in the synthesis of pharmaceu-
ticals and natural products, because of the operational
simplicity, the convenient and available reactants. The target
compounds are synthesized for an organic whole structure of
procaine part and anticancer drugs heterocyclic compounds.
We should point out that the target compounds is of low
expenditure and novel in biological and pharmacological elds,
and suitable for application in the industrial scale synthesis.
Scheme 5 Plausible mechanism for the reaction.
Acknowledgements
We are grateful to acknowledge nancial support from Lanzhou
University SKLAOC.
Notes and references
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