Amphiphile catalysed selective synthesis of 4-amino alkylated-1H-pyrazol-5-ol via Mannich aromatization preferred to the Knoevenagel-Michael type reaction in water

Article abstract of DOI:10.1039/c4ra11961d

An economic and efficient amphiphile (SDS) catalysed one pot synthesis of the aromatized 4-amino alkylated-1H-pyrazol-5-ol via a Mannich type reaction that is preferable compared to a Knoevenagel-Michael type reaction, i.e. aromatic aldehyde, secondary amine and 3-methyl-1-phenyl-5-pyrazolinone in water, has been developed. In this selective Mannich aromatization, the reaction proceeds via a micelle stabilized imine intermediate, followed by the nucleophilic addition of 3-methyl-1-phenyl-5-pyrazolinone and aromatization in water.

Full text of DOI:10.1039/c4ra11961d

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Amphiphile catalysed selective synthesis of 4-
amino alkylated-1H-pyrazol-5-ol via Mannich
aromatization preferred to the Knoevenagel–
Michael type reaction in water†
Cite this: RSC Adv., 2014, 4, 57953
Received 8th October 2014
Accepted 17th October 2014
ab
Atul Kumar,
Shivam Maurya,ab Maneesh Kumar Guptaa and Ratnakar Dutt Shuklaa
*
DOI: 10.1039/c4ra11961d
www.rsc.org/advances
An economic and efficient amphiphile (SDS) catalysed one pot
Water, essential for life, is an ultimate green solvent involved
synthesis of the aromatized 4-amino alkylated-1H-pyrazol-5-ol via a in biochemical reactions; however, it is still not frequently used
Mannich type reaction that is preferable compared to a Knoevenagel– as a sole solvent for organic synthesis due to solubility issues as
Michael type reaction, i.e. aromatic aldehyde, secondary amine and 3- solubility is a prerequisite for reactivity. Using amphiphiles5 is
methyl-1-phenyl-5-pyrazolinone in water, has been developed. In this the best solution to overcome this problem. Amphiphiles not
selective Mannich aromatization, the reaction proceeds via a micelle only provide a micellar lipophilic core for water insoluble
stabilized imine intermediate, followed by the nucleophilic addition of organic reactants but also accelerate the reaction by micellar
3-methyl-1-phenyl-5-pyrazolinone and aromatization in water.
catalysis6 in water.
One pot amphiphile catalysed Mannich aromatization,
involving 3-methyl-1-phenyl-5-pyrazolinone, is still rarely
mentioned in literature, whereas the Knoevenagel condensa-
tion followed by a Michael type addition of various nucleophiles
or with itself is extensively reported.7 Using this methodology,
in 1959, Ahmed Mustafa et al.8 reported the action of secondary
amines on 1-phenyl-3-methyl-4-arylidene-5-pyrazolones and
synthesized 4-amino aryl methyl-5-methyl-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (10) in a moderate yield.
We wish to report here a highly efficient and economic
procedure for the preparation of 4-amino alkylated-1H-pyrazol-
5-ol derivatives via a one pot three-component Mannich type
reaction, using amphiphile (SDS) in aqueous media in excellent
yield (Scheme 1).
Pyrazole scaffolds have been considered as an important
framework in pharmaceutical1a,b and agrochemical industri-
es.1c,d Various pyrazole substructure derivatives nd applica-
tions in therapeutical areas such as antimicrobials, anti-
inammatory agents, central nervous system, analgesics and
oncology drugs. Various leading clinical and commercial drugs
containing pyrazole include celecoxib2a (Cox-2 inhibitor),
rimonabant2b (anorectic anti-obesity drug), PNU-32945 2c (HIV-1
reverse transcriptase inhibitor), Lonazolac2d (NSAID), and
Zoniporide2e (NHE-1 inhibitor, Fig. 1). Pyrazole also acts as a
constituent and receptor in transition metal3a and supramo-
lecular chemistry,3b respectively. Therefore, identifying new
approaches for the efficient synthesis of different pyrazole
scaffolds with diverse substitution patterns is still a challenging
task, involving various synthetic steps or multicomponent
reactions.3c,d
Our preliminary work has been based on organocatalysis as
well as multicomponent reactions (MCRs) using a green
approach for the synthesis of various biologically important
heterocyclic compounds.9 Inspired from this, we attempted to
Out of the various multicomponent reactions, Mannich
reaction provides the most important and powerful synthetic
methodology for the construction of novel diverse nitrogen
containing biologically active organic scaffolds, that has been
reported using organic solvent4a,b as well as in water.4c,d
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Sector 10, Jankipuram Extension, Lucknow-226031, India
bAcademy of Scientic & Innovative Research (AcSIR), New Delhi, India. E-mail:
dratulsax@gmail.com
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, copies of 1H and 13C NMR spectra and
Chiralpak IA HPLC for compounds. See DOI: 10.1039/c4ra11961d
Fig. 1 Some pyrazole containing drugs.
RSC Adv., 2014, 4, 57953–57957 | 57953
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Communication
only bis-product (12) (Table 1, entries 3–8). The addition of
catalytic amounts of silica-supported acids (SiO2–Cl and HClO2–
SiO2) was also not suitable for the reaction medium, affording
bis-product (12) with trace amounts of 11a (Table 1, entries 9
and 10). Moving towards the solid supported Brønsted acids
(Cell SA, Star SA & SSA), eco-friendly and reusable catalysts also
led the reaction to achieve bis-products very efficiently (Table 1,
entries 11–13). However, when we carried out the reaction in
water using DBSA (acting as surfactant as well as Brønsted acid)
in heating conditions, surprisingly, we obtained the product
(11a) in higher amounts (28%) compared to any another catalyst
used (Table 1, entry 14).
This result encouraged us to optimize the reaction condi-
tions by using a different type of amphiphilic surfactant to
improve the yield of the desired product. In order to study the
effect of surfactants (non-ionic, cationic, anionic), the reaction
was carried out in water using benzaldehyde, 3-methyl-1-
phenyl-5-pyrazolinone, and piperidine (summarised in Table 2).
Non-ionic surfactants (Triton-X-100, Tween 80, Tween 20
and Triton CF-10) were not found very effective and provided
poor to average yield of the required product (41–53%) (Table 2,
entries 1–4). It has been seen that in the case of non-ionic
surfactants, on increasing the temperature, a decrease in
head-group hydration occurs. Thus, these surfactants separate
out as a pure phase from the aqueous solution, nally affecting
the yield of the product. The product 11a was also obtained, but
in poor yield, when cationic surfactants like CTAB, TBAB and
TBAF (acting as phase transfer catalysts10e) were employed
(Table 2, entries 5–7). A Lewis acid surfactant, i.e. Sc(DS)3, was
also not suitable for the reaction medium (Table 2, entries 8).
Fortunately, when we used SDS as an anionic surfactant in
water, in heating conditions, both the yield and the reaction
time were improved (Table 2, entry 9). However, the product
formation and time factor were not adequate when SDS was
employed at r.t. (Table 2, entry 13). Considering this observa-
tion, we increased the amount of SDS from 15 to 20 mol% and
Scheme 1
synthesize 4-amino alkylated-1H-pyrazol-5-ol derivatives using
SDS in water.
Previously, in the absence of a catalyst, solvents using
MeOH, EtOH, ACN, DMF, benzene, toluene afforded 8 10a,b
efficiently. In heating conditions, dioxane, which is used as a
solvent, also afforded 11a in trace amount along with 8.
Considering this observation and in order to choose a better
solvent–catalyst system, we carried out the reaction in dioxane
by using a variety of catalysts (Table 1).
Starting from the catalytic amount of Brønsted acid using
MSA and PTSA did not improve the yield of the desired product
(11a). The bis-product10c,d (12) was obtained in this case as
major product (Table 1, entries 1 and 2). All the non-metal/
metal/heteropoly Lewis acids (BF3$Et2O, FeCl3, ZrCl4, cop-
per(II) triate, zinc(II) triate and PMA) used in the reaction gave
Table 1 Effect of the catalyst on the synthesis of 11a,e
Entry
Catalystb
Solvent
Yield of 12/8 (%)c
Yield of 11a (%)c
1
2
3
4
5
6
7
8
MSA
PTSA
BF3$Et2O
FeCl3
ZrCl4
Copper(II) triate
Zinc(II) triate
PMA
SiO2–Cl
HClO2–SiO2
CellSA
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Water
60/18
58/20
59/24
54/20
70/21
53/21
57/22
70/11
52/24
62/22
72/11
70/12
74/10
42/—
12
11
—
—
—
—
—
—
Trace
Trace
9
10
9
9
10
11
12
13
14
StarSA
SSA
DBSAd
28
a
Reaction conditions: the reaction was conducted with benzaldehyde (1 mmol), 3-methyl-1-phenyl-5-pyrazolinone (1 mmol), piperidine (1.2 mmol)
in solvent (2 ml) at r.t. b 10 mol% were used. c Isolated yield. d Reaction mixture was heated to 80 ꢀC. e Abbreviations used in Table: MSA ¼ Methane
sulphonic acid; PTSA ¼ p-Toluene sulfonic acid; PMA ¼ Phosphomolybdic acid; CellSA ¼ Cellulose sulphuric acid; StarSA ¼ Starch sulphuric acid;
SSA ¼ Silica sulphuric acid; DBSA ¼ p-Dodecylbenzenesulfonic acid.
57954 | RSC Adv., 2014, 4, 57953–57957
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 2 Effect of amphiphilic surfactants on the synthesis of 11a,i
Entry
Surfactantb
Time (h)
Yield of 11a/12 (%)c
1
2
3
4
5
6
7
8
Triton X-100
Tween 80
Tween 20
Triton CF-10
CTAB
8.5
8.5
8.5
8.5
5.0
5.5
5.5
6.5
2.0
4.5
4.5
4.0
4.5
2.0
2.0
2.0
53/trace
52/trace
48/trace
41/trace
52/trace
54/trace
53/trace
41/12
68/—
55/30
58/33
57/27
TBAB
TBAF
Sc(DS)3
SDS
9
10
11
12
13
14
15
16
SDS/PMAd
SDS/DBSAd
SDS/XSAd
SDSe
Fig. 2 A quick comparison of used surfactants on the basis of HLB
values.
42/10
52/—
78/—
91/—
SDSf
SDSg
SDSh
a
The reaction was conducted with benzaldehyde (1 mmol), 3-methyl-1-
phenyl-5-pyrazolinone (1 mmol), piperidine (1.2 mmol) in water (2 ml)
b
c
d
at 80 ꢀC. 10 mol% were used. Isolated yield. 10 : 12 mol% were
used. The reaction was conducted at r.t. 5 mol% catalyst. 15
mol% catalyst. 20 mol% catalyst. Abbreviations used in Table:
Triton-X-100 ¼ [C14H22O(C2H4O)n] where n ¼ 9–10; Tween 80 ¼
Polyoxyethylene(20)sorbitanmonooleate (Polysorbate 80); Tween 20 ¼
Polyoxyethylene(20)sorbitanmonolaurate (Polysorbate 20); Triton CF-
e
f
g
h
i
10
Cetyltrimethylammonium bromide; TBAB ¼ Tetra-n-butylammonium
bromide; TBAF Tetra-n-butylammonium uoride; Sc(DS)3
¼
Benzyl-polyethylene glycol tert-octylphenyl ether; CTAB
¼
¼
¼
Scandium tris(dodecyl sulphate); SDS ¼ Sodium dodecyl sulphate;
PMA ¼ Phosphomolybdic acid; DBSA ¼ p-dodecylbenzenesulfonic
acid; XSA ¼ Xanthan sulphuric acid.
Scheme 3 Effect of SDS on the reaction medium.
Amphiphilic properties of the surfactant largely depend
upon HLB values11 for its hydrophilic and lipophilic character. A
high HLB value of the surfactant indicates a strongly hydro-
philic character, whereas a low value is an indication of a
strongly hydrophobic nature. According to the HLB scale, the
classication of used surfactants presented in Table 2 is shown
in Fig. 2. The large HLB value of SDS shows that it is readily
soluble in water compared to other surfactants and as an ionic
Scheme 2
also decreased it to 5 mol% at 80 ꢀC and, therefore, we
demonstrated that the yield of product 11a increased from 78%
to 91% (Table 2, entries 15 & 16) and decreased to 52% (Table 2,
entry 14), respectively. Moreover, we also employed the combi-
nation of anionic surfactant along with various acids by using
SDS/PMA, SDS/DBSA and SDS/XSA (Table 2, entries 10–12) but
the product formation was not satisfactory.
Therefore, SDS was proved to be the best amphiphile for the
formation of substituted 4-amino alkylated-1H-pyrazol-5-ol
derivatives using water as a solvent (Table 2, entry 16)
(Scheme 2).
Scheme 4 Acid catalysed formation of the bis product.
RSC Adv., 2014, 4, 57953–57957 | 57955
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Communication
surfactant its CMC is not much affected by the increase in an imine. The water molecule, generated due to imine forma-
temperature employed in organic synthesis.12
tion, is easily expelled from the lipophilic interior pocket to the
Previously, the mechanism for the direct esterication of outward side of the micelle.13b Therefore, the equilibrium
carboxylic acids with alcohols has been reported by Kobayashi position14 shis towards the imine side. SO3Oꢁ of SDS activates
et al.13a using a surfactant-type Brønsted acid catalyst in water. 3-methyl-1-phenyl-5-pyrazolinone by the formation of
a
Inspired from this fact, we proposed a plausible mechanism, as hydrogen bond with the pyrazolic OH, favouring the nucleo-
shown in Scheme 3.
philic addition towards imine followed by aromatization15 (no
SDS is an amphiphilic surfactant, which forms micelles in need for further steps), giving the required substituted amino
water in which hydrophilic ends arrange themselves outward alkylated-1H-pyrazol-5-ol (Mannich type of product). Supported
and lipophilic ends arranges themselves to the inward side of by the computational study, the molecular volume of the imine
ꢀ3
the micelles. In the lipophilic pocket of a micelle, the corre- intermediate is approximately 170 A (calculated by Discovery
sponding aldehyde and secondary amine easily enter forming studio 2.0) and according to Berkowitz et al.,16 the reported
ꢀ
hydrodynamic radius of the micelle (SDS) is about 22.0 A
ꢀ3
(volume 44 620 A ). Therefore, this reveals that the imine
intermediate is small enough to occupy the space inside the
lipophilic core of SDS micelles.
Table 3 SDS catalysed the synthesis of 11a,b
In the absence of SDS, a secondary amine acting as a base,
abstracts a proton from 3-methyl-1-phenyl-5-pyrazolinone, the
position next to carbonyl nally attacks the activated carbonyl of
the aromatic aldehyde to form the arylidenepyrazolone inter-
mediate10a,b (Knoevenagel type). Again arylidenepyrazolone,
which acts as a Michael acceptor, reacts with another molecule
of 3-methyl-1-phenyl-5-pyrazolinone in the presence of a base,
which nally leads to the formation of the 4,40-(aryl methylene)
bis (1-H-pyrazol-5-ol)7,10c–e (Michael type) (Scheme 4).
Conclusions
In conclusion, we have developed an economic, efficient and
green, amphiphile catalysed multicomponent reaction of
aromatic aldehydes, 3-methyl-1-phenyl-5-pyrazolinone and
secondary amines in aqueous media. SDS (sodium dodecyl
sulphate) was found to be a very useful amphiphile to catalyse
the reaction via an imine intermediate through which the
reaction proceeded in a more efficient and favourable manner
via Mannich aromatization preferable to a Knoevenagel–
Michael type reaction. The advantage of this method is to
improve conditions for the synthesis of substituted 4-amino
alkylated-1H-pyrazol-5-ol derivatives without the formation of a
bis product or any side product (Table 3).
Acknowledgements
S.M., M.K.G. & R.D.S. are thankful to CSIR-UGC for nancial
support. We thank the SAIF division, CDRI, for providing the
spectroscopic and analytical data, as well as acknowledge the
nancial support from CSIR-Network BSC0108. CDRI Commu-
nication no. 8832.
Notes and references
1 (a) C. M. Park and D. J. Jeon, Org. Biomol. Chem., 2012, 10,
a
Reaction conditions: the reaction was conducted with aromatic
aldehyde (1 mmol), 3-methyl-1-phenyl-5-pyrazolinone (1 mmol),
secondary amine (1.2 mmol) and SDS (20 mol%) in water (2 ml) at a
2613; (b) W. G. Bensen, Pain, 2003, 515; (c)
A. V. Ivachtchenko, et al., J. Med. Chem., 2011, 54, 8161; (d)
S. Okuno, A. Saito, T. Hayashi and P. H. Chan, J. Neurosci.,
2004, 24, 7879.
temperature of 80 ꢀC for 2 h. All products were characterised by 1H-
b
NMR, 13C-NMR, IR and Mass spectroscopy.
57956 | RSC Adv., 2014, 4, 57953–57957
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
2 (a) T. D. Penning, et al., J. Med. Chem., 1997, 40, 1347–1365;
(b) M. L. Isidro and F. Cordido, Mini-Rev. Med. Chem., 2009,
9, 664; (c) M. J. Genin, et al., J. Med. Chem., 2000, 43, 1034; (d)
R. Riedel, Arzneim. Forsch., 1981, 31, 655; (e) A. Guzman-
Perez, et al., Bioorg. Med. Chem. Lett., 2001, 11, 803.
8 A. Mustafa, et al., J. Am. Chem. Soc., 1959, 81, 6007.
9 (a) A. Kumar, D. Saxena and M. K. Gupta, Green Chem., 2013,
15, 2699; (b) A. Kumar, M. Kumar and M. K. Gupta, Green
Chem., 2012, 14, 2677; (c) A. Kumar, V. D. Tripathi and
P. Kumar, Green Chem., 2011, 13, 51; (d) A. Kumar,
M. Kumar, S. Maurya and R. S. Khanna, J. Org. Chem.,
2014, 79, 6905; (e) A. Kumar, G. Gupta and S. Srivastava,
Org. Lett., 2011, 13, 6366.
3 (a) S. O. Ojwach and J. Darkwa, Inorg. Chim. Acta, 2010, 363,
´
1947; (b) S. Nieto, J. Perez, L. Riera, V. Riera and D. Miguel,
Chem.–Eur. J., 2006, 12, 2244; (c) A. Domling, Chem. Rev.,
´
2006, 106, 17; (d) D. J. Ramon and M. Yus, Angew. Chem., 10 (a) R. Ramajayam, K.-P. Tan, H.-G. Liu and P.-H. Liang,
Int. Ed., 2005, 44, 1602.
Bioorg. Med. Chem., 2010, 18, 7849; (b) K. H. Mehta, et al.,
Chem.: Indian J., 2003, 1, 38; (c) D. Singh and D. Singh, J.
Chem. Eng. Data, 1984, 29, 355; (d) X. L. Li, Y. M. Wang,
B. Tian, M. Teruo and J. B. Meng, J. Heterocycl. Chem.,
1998, 35, 129; (e) H. J. Ledon, Org. Synth., 1988, 6, 414.
4 (a) S. Kobayashi, H. Kiyohara and M. Yamaguchi, J. Am.
Chem. Soc., 2011, 133, 708; (b) M. Hatano, T. Horibe and
K. Ishihara, J. Am. Chem. Soc., 2010, 132, 56; (c) R. H. Qiu,
S. F. Yin, X. W. Zhang, J. Xia, X. H. Xu and S. L. Luo, Chem.
Commun., 2009, 4759; (d) B. Huang, X. Yao and C.-J. Li, 11 (a) P. Krugliakov, Physicochemical Aspects and Applications,
Adv. Synth. Catal., 2006, 348, 1528.
Elsevier Science, Amsterdam, 2000; (b) F. Wang,
A. Klaikherd and S. Thayumanavan, J. Am. Chem. Soc.,
2011, 34, 13496; (c) F. Tu and D. Lee, J. Am. Chem. Soc.,
2014, 28, 9999.
5 (a) B. H. Lipshutz, G. T. Aguinaldo, S. Ghorai and
K. Voigtritter, Org. Lett., 2008, 10, 1325; (b) B. H. Lipshutz,
D. W. Chung and B. Rich, Org. Lett., 2008, 10, 3793; (c)
B. H. Lipshutz, S. Ghorai and G. T. Aguinaldo, Adv. Synth. 12 (a) D. A. Jaeger, J. R. Wyatt and R. E. Robertson, J. Org. Chem.,
Catal., 2008, 350, 953; (d) B. H. Lipshutz and B. R. Ta,
Org. Lett., 2008, 10, 1329; (e) B. H. Lipshutz and
A. R. Abela, Org. Lett., 2008, 10, 5329.
6 (a) F. M. Menger and C. E. Portnoy, J. Am. Chem. Soc., 1967,
89, 4698; (b) K. Fuji, T. Morimoto, K. Tsutsumi and
1985, 50, 1467; (b) R. P. Bonar-Law, J. Org. Chem., 1996, 61,
3623.
13 (a) K. Manabe, X.-M. Sun and S. Kobayashi, J. Am. Chem. Soc.,
2001, 123, 10101; (b) A. Kumar, M. K. Gupta, M. Kumar and
D. Saxena, RSC Adv., 2013, 3, 1673.
ˆ
K. Kakiuchi, Angew. Chem., 2003, 115, 2511; Angew. Chem., 14 T. Hatta, “Le Chatelier principle,” The New Palgrave: A
Int. Ed., 2003, 42, 2409. Dictionary of Economics, 1987, vol. 3, p. 155.
7 (a) E.-S. A. Aly, M. A. Abdo and A. A. El-Gharably, J. Chin. 15 (a) P. Liu, Y.-M. Pan, Y.-L. Xu and H.-S. Wang, Org. Biomol.
Chem. Soc., 2004, 51, 983; (b) M. N. Elinson, et al.,
Synthesis, 2008, 12, 1933; (c) S. Sobhani, A. R. Hasaninejad,
Chem., 2012, 10, 4696; (b) X. Xu, M. O. Ratnikov,
P. Y. Zavalij and M. P. Doyle, Org. Lett., 2011, 13, 6122.
M. F. Maleki and Z. P. Parizi, Synth. Commun., 2012, 42, 16 (a) C. D. Bruce, M. L. Berkowitz, L. Perera and
2245; (d) E. Mosaddegh, A. Hassankhani and
A. Baghizadehb, J. Chil. Chem. Soc., 2010, 55(4), 419.
M. D. E. Forbes, J. Phys. Chem. B, 2002, 106, 3788.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 57953–57957 | 57957