TfOH mediated intermolecular electrocyclization for the synthesis of pyrazolines and its application in alkaloid synthesis

Article abstract of DOI:10.1039/c8ra05702h

TfOH mediated easy access to interesting pyrazolines starting from an aldehyde, phenylhydrazine and styrene has been developed. The scope of this synthetic methodology has been explored by synthesizing various 1,3,5-trisubstituted pyrazolines in very good yields with very high regioselectivity. The origin of regioselectivity has been explained by comparing the stability of possible intermediate carbocations. The synthetic utility of a green solvent has been explored by synthesizing some of pyrazolines in a DES medium. The synthetic application of the present methodology is employed in the synthesis of a pyrazoline alkaloid.

Full text of DOI:10.1039/c8ra05702h

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TfOH mediated intermolecular electrocyclization
for the synthesis of pyrazolines and its application
in alkaloid synthesis†
Cite this: RSC Adv., 2018, 8, 30071
*
*
Sesuraj Babiola Annes, Pothiappan Vairaprakash
and Subburethinam Ramesh
TfOH mediated easy access to interesting pyrazolines starting from an aldehyde, phenylhydrazine and
styrene has been developed. The scope of this synthetic methodology has been explored by
synthesizing various 1,3,5-trisubstituted pyrazolines in very good yields with very high regioselectivity.
The origin of regioselectivity has been explained by comparing the stability of possible intermediate
carbocations. The synthetic utility of a green solvent has been explored by synthesizing some of
pyrazolines in a DES medium. The synthetic application of the present methodology is employed in the
synthesis of a pyrazoline alkaloid.
Received 4th July 2018
Accepted 6th August 2018
DOI: 10.1039/c8ra05702h
rsc.li/rsc-advances
Pyrazoles and pyrazolines are known to exhibit interesting method for accessing pyrazolines, but this method falls behind
biological and photo-physical behaviours. The biological activ- due to a greater number of synthetic steps involved.31–34
ities of pyrazoles/pyrazolines have been discussed in several Recently Wang et al. disclosed a methodology proceeding via
reviews.1–4 A few representative examples of biologically and
medicinally important pyrazoles and pyrazolines are given in
Fig. 1.5–7 In particular, considerable interest has been focused
on 1,3,5-trisubstituted pyrazoline derivatives due their potential
pharmacological activities including (i) antitubercular activity
against the H37Rv strain of Mycobacterium,9 (ii) anti-
proliferative activity,8,10 (iii) antibacterial activity,11–13 (iv) anti-
obesity effect in an animal model of the potent cannabinoid
CB1 receptor antagonist,14 (v) pre-emergent herbicide activity
against various kinds of weeds,15 and (vi) ACE-inhibitory activity
with 0.123 mM IC504.16 Pyrazoline derivatives show enhanced
biological activity compared with their corresponding pyr-
azoles.17 In addition, the pyrazoline motif is known to exhibit
photo-luminescent behaviour due to intra-molecular charge
transfer (ICT) in the excited state and also shows hole transport
behaviour.18–24
Various synthetic approaches have been developed to access
these biologically important 1,3,5-trisubstituted pyrazoline/
pyrazole compounds.25–28 The most general synthetic approach
proceeding via a reaction of 1,3-dicarbonyl compounds with
arylhydrazines results in poor regioselectivity.3,29,30 A synthetic
method which employs appropriate chalcones and arylhy-
drazines has been considered to be the most widely accepted
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed
University, Thanjavur, Tamil Nadu, India. E-mail: vairaprakash@scbt.sastra.edu;
ramesh_s@scbt.sastra.edu; Fax: +91-4362-264120; Tel: +91-4362-264101-3614; +91-
4362-264101-3791
† Electronic supplementary information (ESI) available: Experimental details,
supporting data and NMR spectra (1H and 13C) are provided. See DOI:
10.1039/c8ra05702h
Fig.
1 Representative examples of medicinally important 1,3,5-
trisubstituted pyrazolines and pyrazoles.
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a three component [3 + 2] cycloaddition using 20 mol% enhancement of the yield (Table 1, entries 1–5). Due to it being
Cu(OTf)2 at elevated temperature.35 The development of less hazardous among the screened solvents, acetonitrile was
synthetic methodology to prepare active pharmaceutical ingre- used as a solvent for further screening of other non-metal
dients (APIs) would preferably involve (i) high regioselectivity, catalysts including TfOH, PhIOAc, NaI, NBS, CAN, L-proline,
(ii) diversity in substrates, (iii) the least number of synthetic CH(OMe)3, TFA, p-TSA and MeSO3H (Table 1, entries 6–13).
steps involved and (iv) attaining target compounds, free of TfOH was found to be the most effective in mediating electro-
metal traces. Hence, a regioselective tandem one-pot intermo- cyclization and pyrazoline 4a was obtained in 82% yield (Table
lecular electrocyclization reaction under metal free condition to 1, entry 12). It is presumed that TfOH alone is capable of
access 1,3,5-trisubstituted pyrazolines would be of great forming an intermediate carbocation I-1 via hydride abstraction
+
importance.
from hydrazone by the superacid species TfOH2 (Scheme 1).36,37
In this regard, we are disclosing a general, metal free and The use of other solvents such as H2O, DMF, DMSO and ethanol
green synthetic methodology to access diverse pyrazoline did not result in product formation, as TfOH might be deacti-
derivatives with various functionalities including –NO2, –OH vated by these solvents (see ESI, Table S1†).
and aliphatic groups using arylhydrazines, aldehydes and
We have observed very good regioselectivity in the formation
styrenes. We have obtained the corresponding pyrazoline of pyrazolines mediated by TfOH. Mechanistically, the carbo-
products in very good yields with enhanced regioselectivity. In cation I-1 can interact with either of the alkenyl carbons in
addition, we have employed this synthetic methodology in the styrene resulting in two types of cationic intermediates: (i) the
synthesis of
pyrazoline).
a
pyrazoline alkaloid (1,5-diphenyl-3-styryl-2- most stable benzylic carbocation I-2 and (ii) the least stable
primary carbocation I-3. The stability of the benzylic carboca-
In our initial studies to attempt metal free conditions, iodine tion I-2 over the primary carbocation I-3 directs the reaction
mediated intermolecular electrocyclization of tolualdehyde 1a, pathway towards the formation of a 5-phenyl substituted
phenylhydrazine 2a and styrene 3 was explored (Table 1). The product 4a over a 4-phenyl substituted product 5a (Scheme 1).
use of a substoichiometric amount of iodine (0.2 equiv.) yielded
The scope of this synthetic methodology has been studied by
the corresponding pyrazoline 4a in 25% yield (Table 1, entry 1). varying the substrates. Both aromatic and aliphatic aldehydes
Increasing the amount of iodine did not result in considerable reacted well under the reaction conditions and their corre-
sponding pyrazolines were obtained in yields of up to 86%
Table 1 Optimization of reaction conditions in the synthesis of pyr-
azoline 4aa
Entry
Additive (equiv.)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
I2 (0.2)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
PhI(OAc)2 (0.2)
NaI (1.0)
NBS (1.0)
CAN (1.0)
L-Proline (0.3)
CH(OMe)3 (1.0)
TfOH (1.0)
TFA (1.0)
CH3CN
CH3CN
Toluene
H2O
24
24
24
24
24
24
24
24
24
24
24
7
25
34
40
35
Trace
ND
ND
ND
ND
ND
ND
82
EtOAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
24
24
24
ND
18
13
p-TSA (1.0)
MeSO3H (1.0)
a
A solution of tolualdehyde 1a (1.0 mmol) and phenylhydrazine 2a (1.0
mmol) in solvent (1.0 mL) was treated with additive followed by styrene
3 (1.0 mmol) and stirred. b Isolated yield; ND ¼ not detected.
Scheme 1 Origin of regioselectivity in the formation of pyrazoline 4a.
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Table 2 Synthesis of various pyrazolines 4a–ma
pyrazolines 4h and 4i were obtained in poor yields due to the
strong electron withdrawing effect of the –NO2 group via –I and
–R (Table 2, entries 8 and 9). In every case, the obtained regio-
selectivity was very high and benzylic cation intermediate I-2
derived compounds were obtained as the only products.
Using this methodology, we have attempted the synthesis of
bis-pyrazoline
6 from terephthalaldehyde 1m. The bis-
pyrazoline 6 was obtained in very low yield, which is also in
accordance with the proposed mechanism depicted in Scheme
1. The formation bis-pyrazoline 6 was expected to proceed via
a bis-benzylic cation I-4 (Scheme 2), which is highly destabilized
by conjugation between two cationic sites. Thus, formation of
the bis-benzylic cation I-4 is less probable and resulted in the
observed poor yield of bis-pyrazoline 6 (18%) even aer 48 h of
reaction time. Bis-pyrazoline 6 was structurally characterized by
NMR spectroscopy and high resolution mass spectrometry
(HRMS) analysis.
We wanted to apply this synthetic methodology in the
synthesis of a pyrazoline alkaloid. Many species of the genus
Euphorbia are medicinally important and known to treat
various ailments including gonorrhea, skin diseases, gastroin-
testinal disorders, migraines and anaphylaxis.38–41 Alkaloid 7
Entry
R ¼
Ar ¼
Product
Yieldb (%)
1
2
3
4
5
6
7
8
4-Me–C6H4– 1a
4-MeO–C6H4– 1b
3-MeO–C6H4– 1c
C6H5– 1d
4-Br–C6H4– 1e
4-Cl–C6H4– 1f
4-F–C6H4– 1g
4-NO2–C6H4– 1h
2-NO2–C6H4– 1i
2-HO–C6H4– 1j
CH3CH2CH2– 1k
(CH3)2CH– 1l
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
C6H5– 2a
4-Me–C6H4– 2b
4a
4b
4c
4d
4e
4f
4g
4h
4i
82
73
57
63
61
58
39
24
45
82
86
58
82
9
10
11
12
13
4j
4k
4l
4-Me–C6H4– 1a
4m
a
A solution of aldehyde 1a–l (1.0 mmol) and arylhydrazine 2a, 2b (1.0
mmol) in CH3CN (1.0 mL) was treated with TfOH followed by styrene (1,5-diphenyl-3-styryl-2-pyrazoline) was isolated from aerial
3 (1.0 mmol) and stirred. b Isolated yield.
(Table 2). The yields were in accordance with the stability of the
corresponding benzylic cations I-1. In the reactions employing
aromatic aldehydes with electron donating groups, pyrazolines
were obtained in very good yields (Table 2, entries 1 and 2), as I-
1 might receive additional stability from electron donating
substituents. The methoxy group in the meta position did not
play a considerable role in stabilizing the benzylic carbocation I-
1, hence the yield of the corresponding pyrazoline 4c was
moderate (Table 2, entry 3). Analogous to this, products were
obtained in moderate yields for aldehydes with halogen
substitution (Cl and Br) and without any substitution, as there
is neutrality between the electron withdrawing effect through –I
and the electron releasing effect through +R in H/Cl/Br–
substituted aldehydes (2, entries 4–6). The high electronega-
tivity of uorine destabilizes I-1, hence its corresponding pyr-
azoline 4g was obtained in low yield (Table 2, entry 7). Similarly,
Scheme 2 Synthesis of bis-pyrazoline 7 from terephthalaldehyde.
Scheme 3 Application in alkaloid synthesis: synthesis of alkaloid 7.
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Table 3 Synthesis of various pyrazolines in DES mediaa
Conflicts of interest
There are no conicts to declare.
Acknowledgements
S. R. sincerely thanks DST-SERB, the Government of India, New
Delhi for nancial support under the DST INSPIRE Faculty
Program (Grant No. DST/INSPIRE/04-I/2017/000002). B. A.
thanks SASTRA Deemed University for the research fellowship.
Entry R ¼
Ar ¼
Product
Yieldb (%)
1
2
3
4
4-Me–C6H4– 1a
2-HO–C6H4– 1j
CH3CH2CH2– 1k
C6H5–CH]CH– 1n 4-Me–C6H4– 2b Alkaloid 7 54
C6H5– 2a
C6H5– 2a
C6H5– 2a
4a
4j
4k
45
61
45
a
A mixture of aldehyde (1.0 mmol) arylhydrazine (1.0 mmol) and
b
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