Br?nsted acid-promoted hydroamination of unsaturated hydrazones: access to biologically important 5-arylpyrazolines

Article abstract of DOI:10.1039/d1ra03043d

A novel and efficient Br?nsted acid-promoted hydroamination of hydrazone-tethered olefins has been developed. A variety of pyrazolines have been easily obtained in good to excellent yields with high chemo- and regioselectivity under simple and mild conditions. This method represents a straightforward, facile, and practical approach toward biologically important 5-arylpyrazolines, which are difficult to access by previously reported radical hydroamination of β,γ-unsaturated hydrazones.

Full text of DOI:10.1039/d1ra03043d

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Brønsted acid-promoted hydroamination of
unsaturated hydrazones: access to biologically
Cite this: RSC Adv., 2021, 11, 17340
important 5-arylpyrazolines†
Han He,‡ Ning Xu,‡ Honglin Zhang, ‡ Bin Chen, Zhengnan Hu, Kang Guo,
*
Jianlin Chun, Shujun Cao and Yingguang Zhu
A novel and efficient Brønsted acid-promoted hydroamination of hydrazone-tethered olefins has been
developed. A variety of pyrazolines have been easily obtained in good to excellent yields with high
chemo- and regioselectivity under simple and mild conditions. This method represents a straightforward,
facile, and practical approach toward biologically important 5-arylpyrazolines, which are difficult to
access by previously reported radical hydroamination of b,g-unsaturated hydrazones.
Received 19th April 2021
Accepted 29th April 2021
DOI: 10.1039/d1ra03043d
rsc.li/rsc-advances
group developed a mild and efficient radical hydroamination of
b,g-unsaturated hydrazones for the synthesis of pyrazolines
Introduction
with stoichiometric amounts of PhI(OAc)2 as the oxidant and
DABCO as the base (Scheme 1a, method B).16b In 2019, the group
of Song reported the facile and metal-free access to pyrazolines
from b,g-unsaturated hydrazones via a radical pathway with the
use of the oxidant TBHP in n-Bu2O at 80 ꢀC under N2 atmo-
sphere (Scheme 1a, method C).16c The previously reported
hydroaminations14 of unsaturated hydrazones represent the
rapid, facile, and straightforward approaches to pyrazolines.
However, the substrates employed in such hydroamination
reactions are only b-unsubstituted unsaturated hydrazones,
thus providing the corresponding 5-methylpyrazolines through
a radical 5-exo-trig cyclization (Scheme 1a). In 2016, Chen et al.
The functionalization of olens is one of the most efficient and
powerful strategies to rapidly construct structurally diverse and
valuable molecules.1–3 In this context, the hydroamination of
olens has drawn considerable attention from chemists. Great
progress has been made in the transition-metal-catalyzed,4,5
acid-promoted,6,7 and miscellaneous8 hydroaminations of
olens.
Pyrazolines are an important class of ve-membered
nitrogen-containing heterocycles that present in many phar-
maceuticals and bioactive molecules.9,10 In this context, 5-aryl-
pyrazolines oen exhibit diverse and signicant biological
properties such as anti-cancer, anti-depressant, anti-infective,
and anti-convulsant activities, etc. (Fig. 1).11 Recently, the
elegant synthesis of pyrazolines from b,g-unsaturated hydra-
zones has been accomplished via a novel C–N bond-forming
cyclization strategy by the groups of Loh, Xiao, Han, and
others.12–16 Despite recent impressive advances, the examples of
the hydroamination of b,g-unsaturated hydrazones for the
construction of pyrazolines are rare.16 In 2014, Xiao and Chen
et al. disclosed a novel visible-light-driven photocatalytic
hydroamination of b,g-unsaturated hydrazones, in which the
generation of N-centered hydrazonyl radicals has been achieved
for the rst time by a visible-light photocatalytic oxidation
strategy (Scheme 1a, method A).16a Shortly aerwards, the same
Jiangsu Key Laboratory of Pesticide Science, Department of Chemistry, College of
Sciences, Nanjing Agricultural University, Nanjing 210095, China. E-mail: ygzhu@
njau.edu.cn
† Electronic supplementary information (ESI) available. CCDC 2018227 (2e)
contains the supplementary crystallographic data for this paper. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/d1ra03043d
Fig. 1 5-Arylpyrazoline-containing bioactive molecules.
‡ H. H., N. X., and H. Z. contributed equally.
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and following our continuous interest in the synthesis of N-
heterocycles,15f,g we herein report a novel Brønsted acid-
promoted hydroamination of b,g-unsaturated hydrazones to
afford a wide range of pyrazolines in generally excellent yields
and with high chemo- and regioselectivities through an ionic
pathway (Scheme 1d). It is noteworthy that the present method
provides a facile, mild, efficient, and practical access to bio-
logically signicant 5-arylpyrazolines.
Results and discussion
Our studies commenced with b-phenyl substituted b,g-unsatu-
rated hydrazone 1a as model substrate to optimize the reaction
conditions. To our delight, the desired product 5-arylpyrazoline
2a was obtained in 71% yield by the treatment of 1a with TsOH
(1.0 equiv.) in CH3CN at 50 ꢀC for 12 h (Table 1, entry 1). Other
Brønsted acids, including TsOH, TfOH, CH3SO3H, CF3COOH,
CH3COOH, H3PO4, HCl, HBr, HI, and H2SO4 were also tested
(Table 1, entries 2–10). Among the above acids examined, H2SO4
was found to be the best for this transformation, giving product
2a in 94% yield (Table 1, entry 10). The screening of solvents
showed that CH3CN was superior to other solvents, such as
CH2Cl2, EtOH, DMF, and THF (Table 1, entries 10–14).
Decreasing the amount of H2SO4 resulted in the lower yields of
Table 1 Optimization of reaction conditionsa
Entry
Acid (equiv.)
Solvent
Yieldb (%)
Scheme 1 Previous work and this work.
1
2
3
4
TsOH (1.0)
TfOH (1.0)
CH3SO3H (1.0)
CF3COOH (1.0)
CH3COOH (1.0)
H3PO4 (1.0)
HCl (1.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
C2H5OH
DMF
71
82
62
Trace
0
reported an impressive and elegant protocol for the preparation
of 1,6-dihydropyradazines from b-aryl substituted b,g-unsatu-
rated hydrazones, in which a novel visible-light photocatalytic
oxidative deprotonation electron transfer (ODET)/6-endo-trig
cyclization/TEMPO-mediation strategy was developed (Scheme
1b).17
5
6c
7d
8e
9f
0
0
HBr (1.0)
HI (1.0)
62
81
94
58
0
10g
11
12
13
14
15
16
17h
18
H2SO4 (1.0)
H2SO4 (1.0)
H2SO4 (1.0)
H2SO4 (1.0)
H2SO4 (1.0)
H2SO4 (0.2)
H2SO4 (0.5)
H2SO4 (1.0)
—
Given the fact that 5-arylpyrazolines display a broad spec-
trum of important biological activities, it is highly demanded to
develop mild, efficient, practical, and selective methods for the
construction of such type of pyrazolines. To test whether 5-
arylpyrazolines could be obtained from b-aryl substituted
unsaturated hydrazones, we synthesized b-phenyl substituted
unsaturated hydrazones (R2 ¼ Ts, Ph, Ac, Bz) and subjected
them to the previously reported radical hydroamination
methods.16 Surprisingly, no desired 5-phenylpyrazoline prod-
ucts were observed (Scheme 1c). Based on these observations
and considering the biological signicance of 5-arylpyrazolines,
we decided to explore new synthetic methods for the construc-
tion of the scaffolds. Inspired by the above breakthrough12–18
0
THF
18
29
65
14
0
CH3CN
CH3CN
CH3CN
CH3CN
a
All reactions were performed with 1a (0.20 mmol) and acid (0.20
mmol) in solvent (2 mL) at 50 ꢀC for 12 h unless otherwise noted.
b
e
c
d
Isolated yields. H3PO4 (85 wt% in water). HCl (36 wt% in water).
f
g
HBr (40 wt% in water). HI (55 wt% in water). H2SO4 (98 wt% in
h
water).
At
25
ꢀC.
Ts
¼
p-toluenesulfonyl,
Tf
¼
triuoromethanesulfonyl, DMF ¼ N,N-dimethyl formamide, THF ¼
tetrahydrofuran.
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2a (Table 1, entries 15 and 16). Additionally, the signicantly
With the optimized reaction conditions in hand, we subse-
decreased yield of 2a was obtained when the reaction was quently investigated the generality of the Brønsted acid-
conducted at a lower temperature (Table 1, entry 17). No reac- promoted hydroamination reaction. As exemplied in Scheme
tion occurred in the absence of a Brønsted acid, suggesting that 2, the present reaction can be extended to various b,g-unsatu-
the acid plays a crucial role in the transformation (Table 1, entry rated hydrazones to give the 5-aryl or 5-alkylpyrazoline products
18).
in 60–99% yield. Substrates with either electron-donating or
electron-withdrawing groups on the phenyl ring (R1) that is
attached to the C–N double bond were smoothly converted into
products 2a–2j in 73–99% yield. 2-Thienyl group was also well
tolerated to provide the product 2k in 81% yield. Notably,
substrates bearing alkyl groups (R1) at the C–N double bond
moiety also participated in the reaction to give the corre-
sponding products 2l–2q in 65–98% yield. The effect of the
substituents (R) at the alkene moiety on the reaction was next
investigated. It was found that electron-rich or electron-poor
aryl groups were well tolerated under the reaction conditions,
producing the 5-arylpyrazoline products 2r–2w in 85–98% yield.
Furthermore, substrates bearing alkyl groups at the alkene
moiety could also undergo the reaction to give the 5-alkylpyr-
azolines 2x and 2y in good yields. Nevertheless, no desired
product 2z was obtained when R group in the substrate was
changed to H atom. Additionally, the substrate bearing a gem-
dimethyl moiety adjacent to C]N bond could not produce the
corresponding pyrazoline product 2aa either. It is noteworthy
that N-aryl, N-acetyl, and N-benzoyl substituted unsaturated
hydrazones also smoothly participated in the transformation,
providing the corresponding 5-arylpyrazolines 2ab–2ae in 61–
92% yield.
The structure of product 2e (CCDC 2018227) was conrmed
by single-crystal X-ray diffraction analysis (Scheme 2). To
demonstrate the practical application of the method, a gram-
scale reaction was carried out under standard conditions and
afforded product 2a in 92% yield (1.08 g) (Scheme 2).
Scheme 2 Substrate scope. aAll reactions were performed with 1 (0.20
mmol) and conc. H2SO4 (0.20 mmol) in CH3CN (2 mL) at 50 ꢀC for 12 h
unless otherwise noted. b Isolated yields. c 3.0 mmol scale.
Scheme 3 Control experiments.
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amenability to gram-scale synthesis, which makes it particularly
attractive and is expected to nd potential applications in
organic synthesis and drug discovery.
Experimental
General information
All commercially available reagents were used without further
purication. Column chromatography was performed on silica
gel (200–300 mesh). 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded on a 400 MHz spectrometer.
Chemical shis (d) were reported in ppm, and coupling
constants (J) were given in Hertz (Hz). Data were reported as s ¼
singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, dd ¼ doublet of
doublets, m ¼ multiplet. High-resolution mass spectra (HRMS)
were recorded on an AB SCIEX Triple TOF 5600+ mass spec-
trometer. Melting points were uncorrected. Alkenyl hydrazone
substrates 1a–1ac were prepared according to the reported
methods.17,20
Scheme 4 Proposed mechanism.
To gain some insight into the reaction pathway, several
control experiments were conducted (Scheme 3). Upon the
addition of the radical scavenger butylated hydroxytoluene
(BHT, 3.0 equiv.) under standard reaction conditions, the
reaction still proceeded very well to give the desired product 2a
in 92% yield (Scheme 3a), suggesting that a radical pathway
could not be involved in this transformation. By the treatment
of 1a with conc. H2SO4 (1.0 equiv.) in CH3CN at 50 ꢀC for a much
shorter reaction time (0.5 h), two separable isomers Z-3 and E-3,
resulting from the isomerization of the terminal olen moiety
of 1a, were obtained in 29% and 57% yields, respectively
(Scheme 3b). Subsequent subjection of the isolated Z-3 or E-3 to
the standard reaction conditions afforded the product 2a in
90% and 84% yields (Scheme 3c). The results indicate that the
isomeric 3 could be the reaction intermediate, and an olen
isomerization process is very likely to be involved in the reac-
tion. No product was observed when isolated Z-3 or E-3 was
subjected to the standard reaction conditions in the absence of
H2SO4 (Scheme 3d), suggesting that the Brønsted acid plays an
important role in the formation of the pyrazoline product from
the intermediate.
Based on the above experimental results and previous
reports,12–19 a plausible reaction mechanism is proposed
(Scheme 4). Initial electrophilic attack on the C–C double bond
of hydrazone 1 by the proton generates carbocation A, which is
deprotonated to afford olen-isomerized intermediate B.19a–c
Subsequent protonation of the hydrazone moiety of B results in
cationic species C,18a,b which undergoes a 6p-azaelectrocycliza-
tion to provide intermediate D.19d–g Isomerization of D to E,19a,h
followed by the nal deprotonation to deliver pyrazoline
product 2.
General procedure for the hydroamination reaction
To a reaction tube equipped with a magnetic stir bar were added
alkenyl hydrazone 1 (0.20 mmol), conc. H2SO4 (11 mL, 0.20
mmolꢀ), and CH3CN (2.0 mL). The reaction mixture was stirred
at 50 C under nitrogen atmosphere for 12 h, cooled to room
temperature, and concentrated under reduced pressure. The
residue was puried by column chromatography on silica gel
(eluent : petroleum ether/ethyl acetate ¼ 10 : 1) to give product
2.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful for the nancial support from the National
Natural Science Foundation of China (21502096), the Natural
Science Foundation of Jiangsu Province (BK20150652), the
Student Research Training (SRT) Project of Nanjing Agricultural
University (S20190033), the Fundamental Research Funds for
the Central Universities (KJQN201629), and the “333 High Level
Talent Project” of Jiangsu Province.
Conclusions
Notes and references
In summary, we have developed a novel, facile, efficient, prac-
tical, and Brønsted acid-promoted hydroamination protocol
that enables the synthesis of various pyrazolines from b,g-
unsaturated hydrazones. Notably, the present method can be
applied to construct the biologically signicant 5-arylpyrazo-
lines that are difficult to access by the reported radical hydro-
aminations of b,g-unsaturated hydrazones. Preliminary
mechanistic investigations indicated that an ionic pathway
could be involved in this transformation. This reaction is
characterized by simple and mild conditions, broad substrate
scope, high yields, excellent chemo- and regioselectivities, and
˜
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