Synthesis of chiral pyrazolone and spiropyrazolone derivatives through squaramide-catalyzed reaction of pyrazolin-5-ones with o-quinone methides

Article abstract of DOI:10.1021/acs.orglett.8b00025

A bifunctional squaramide-catalyzed reaction of pyrazolin-5-ones with o-quinone methides in situ generated from 2-(1-tosylalkyl)phenols has been successfully developed, providing a facile access to chiral pyrazolones with high enantioselectivities. In addition, the chiral spiropyrazolones with adjacent tertiary and quaternary stereogenic centers can also be obtained through cascade chlorination/cyclization of the chiral pyrazolones.

Full text of DOI:10.1021/acs.orglett.8b00025

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chiral Pyrazolone and Spiropyrazolone Derivatives
through Squaramide-Catalyzed Reaction of Pyrazolin-5-ones with
o‑Quinone Methides
Ji Zhou, Wen-Jun Huang, and Guo-Fang Jiang*
State Key Lab of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. China
S
* Supporting Information
ABSTRACT: A bifunctional squaramide-catalyzed reaction of pyrazolin-5-ones with o-quinone methides in situ generated from
2-(1-tosylalkyl)phenols has been successfully developed, providing a facile access to chiral pyrazolones with high
enantioselectivities. In addition, the chiral spiropyrazolones with adjacent tertiary and quaternary stereogenic centers can also
be obtained through cascade chlorination/cyclization of the chiral pyrazolones.
mong the various nitrogen-containing heterocyclic com-
pounds, prazolones and their derivatives are important
molecular skeletons that widely occur in natural products and
pharmaceutical agents.1 Although the pyrazolone moiety is not
a common feature of biologically active natural products, a
broad range of synthetic pyrazolone derivatives exhibit
significant pharmacological activities (Figure 1). For example,
spiropyrazolone heterocyclic molecules is still considered an
arduous challenge owing to the difficulties in controlling the
diastereo- and enantioselectivities, and only sporadic examples
have been reported regarding the direct use of simple 4-
unsubstituted pyrazolones.9 Moreover, the methodology to
acquire different types of enantiopure pyrazolones including the
spirocyclic ones with a multistereogenic center through a
cascade reaction is still rare. Hence, development of more
efficient catalytic asymmetric strategies for the synthesis of
chiral prazolones and their derivatives remains highly desirable.
It is fairly well-known that the o-quinone methides (o-QMs)
are a pivotal class of key intermediates in various biological
processes10 and have been regarded as highly reactive chemical
motifs.11 As part of our ongoing interest toward the utilization
of o-QMs,12 we focused on asymmetric cascade reactions of in
situ generated o-QMs. Accordingly, we envisioned the
combination of 2-(1-tosylalkyl)phenols and pyrazolin-5-ones
would enable synthesis of chiral pyrazolone derivatives, even
spiropyrazolones, in the presence of inorganic bases and
bifunctional organocatalysts (Scheme 1). The bifunctional
organocatalyst could be used for deprotonation of pyrazolones
to form the nucleophilic species in the chiral environment, and
those intermediates then react with the in situ generated o-QMs
via Michael addition to get adducts, which could further
convert to spiropyrazolones catalyzed by a bifunctional
organocatalyst in the presence of N-chlorosuccinimide (NCS)
and base through cascade chlorination/cyclization. Herein, we
present a facile bifunctional squaramide-catalyzed synthesis of
chiral pyrazolone and spiropyrazolone derivatives via the in situ
A
Figure 1. Pyrazolone drugs and bioactive compounds.
the C. I. Acid Yellow 11 is used as a reactive dye in the chemical
industry;2 metamizole is considered as the strongest antipy-
retic;3 and the prazolone derivatives A and B act as an
antibacterial agent and P38 inhibitor, respectively.4,5
Pyrazolin-5-ones are unique scaffolds with availability of
many reactive centers, which enable further modifications and
transformations to access new valuable compounds. Undoubt-
edly, the enantioselective synthesis of the structurally diverse
pyrazolone derivatives employing the pyrazolin-5-ones stands at
the forefront, and many methods have been reported over the
past few years.6 Although various simple C−C and C−X7 bond
formations as well as cascade sequences8 involving the
pyrazolin-5-one derivatives provide diversely functionalized
pyrazolones, the highly enantiocontrolled construction of
Received: January 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Strategy for the Synthesis of Chiral Pyrazolones
Based on o-Quinone Methides (o-QMs) with Pyrazolin-5-
ones
Table 1. Optimization of Reaction Parameters for Michael
Addition
a
generated o-QMs with pyrazolin-5-ones in excellent diastereo-
and enantioselectivities under the basic conditions.
b
c
entry
solvent
cat.
yield (%)
ee (%)
At the outset, 2-(1-tosylalkyl)phenol 1a and pyrazolin-5-one
2a were chosen as model substrates for Michael addition. The
experiment was conducted in THF (tetrahydrofuran) by using
quinine 4a as catalyst and sodium carbonate as base. The
reaction proceeded smoothly to give the desired product 3aa in
72% yield with 4% ee (Table 1, entry 1). Encouraged by this
result, we continued to test the solvent effect (Table 1, entries
2−5), and 1,2-dichloroethane (DCE) was proven to be the
most favorable solvent in terms of enantioselectivity and yield.
Subsequently, a series of common bifunctional organocatalysts
were investigated (Table 1, entries 6−10). In contrast to
quinine 4a, bifunctional thiourea and squaramide catalysts gave
higher enantioselectivities. Obviously, quinine-based squara-
mide catalyst 4f was the best catalyst to deliver the target
product 3aa in 88% yield with 99% ee. Increasing the reaction
temperature gave no improvement of activity (Table 1, entry
11). Gratifyingly, the adduct 3aa was obtained in 96% yield
with 99% ee when 1.2 equiv of 1a was used (Table 1, entry 12).
Thus, the optimized conditions were established as quinine-
based squaramide catalyst 4f (10 mol %), sodium carbonate
(1.5 equiv), DCE, 30 °C, and 48 h.
With the optimal conditions identified, the substrate
generality with respect to both the 2-(1-tosylalkyl)phenol and
pyrazolin-5-one components was evaluated, and the results are
shown in Scheme 2. It indicates that a broad spectrum of 2-(1-
tosylalkyl)phenols and pyrazolin-5-ones were amenable to this
Michael addition, providing a diverse array of pyrazolones in
high yields with good enantioselectivities (up to 97% yield, 99%
ee).
First, the substrate scope with respect to the pyrazolin-5-one
partner was surveyed. When the methyl was changed to phenyl,
the transformation could furnish the corresponding adduct 3ac
in excellent enantioselectivity. However, for the ethyl group, the
corresponding adduct 3ab was obtained in lower enantiose-
lectivity for 83% ee. The influence of the steric and electronic
properties of substituents on the phenyl rings at the C3
position of pyrazolin-5-ones was exploited. Not surprisingly,
slightly lower enantioselectivity was observed upon increasing
the steric hindrance of phenyl ring (3af vs 3ae). Electron-
donating groups are favored to the control of enantioselectivity
apparently (3ad−af), fluorine on the phenyl ring decreased the
ee to moderate level 77% (3ag). Meanwhile, 2-naphthyl-
substituted pyrazolin-5-one 2h could be converted to 3ah in
1
THF
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
72
52
83
85
84
90
54
77
59
88
88
96
4
53
38
43
45
93
76
93
89
99
99
99
2
toluene
CHCl3
CH2Cl2
DCE
3
4
5
6
DCE
7
DCE
8
DCE
9
DCE
10
DCE
d
11
DCE
4f
e
12
DCE
4f
a
Conditions: 1a (0.10 mmol), 2a (0.10 mmol), cat. 4 (0.01 mmol),
Na2CO3 (0.12 mmol), solvent (1.5 mL), 30 °C, 48 h. Isolated yields.
Determined by chiral HPLC. 50 °C. 1a (0.12 mmol), 2a (0.10
mmol), cat. 4f (0.01 mmol), Na2CO3 (0.15 mmol), DCE (1.5 mL).
b
c
d
e
92% yield with 97% ee. In addition, when methoxy group was
placed in the para-position of phenyl ring on nitrogen, the
reaction also performed smoothly in 97% yield with 83% ee
(3ai).
Following the establishment of the broad generality of the
pyrazolin-5-one components, we continued to investigate into
the variation of the 2-(1-tosylalkyl)phenols. For 2-(1-tosylalkyl)
phenols 1b,c, the electronic property had a slight influence on
the enantioselectivities and yields. Furthermore, the reaction
proceeded smoothly with simple 2-(1-tosylalkyl) phenol 1d, 2-
(1-tosylalkyl)naphthols 1e, and the methoxy substituent
substrate 1f, though only moderate yield for 3da was obtained.
In addition, the alkyl-substituted substrate 1g could also
participate in this transformation as well and delivered the
desired product 3ga in 93% yield with moderate ee (43% ee).
Morever, the substrate with an electron-withdrawing group
bromo on the phenyl ring of the 2-(1-tosylalkyl)phenols (1h,
1i) could convert to the corresponding adducts in satisfying
results. Lastly, reaction of 2-(1-tosylalkyl)naphthols 1e with
pyrazolin-5-one 2c successfully gave the 3ec in 91% yield and
95% ee (Scheme 2).
To extend the utilization of this method, we have made
further efforts to synthesize the spiropyrazolones from adducts
3 through organocatalyzed chlorination and following intra-
molecular cyclization in the presence of base and organo-
B
DOI: 10.1021/acs.orglett.8b00025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope for Synthesis of Chiral
Pyrazolones*
Scheme 3. Substrate Scope for Synthesis of
Spiropyrazolones
a
a
Unless otherwise noted, all reactions were carried out under these
conditions: 3 (0.20 mmol), NCS (0.26 mmol), K2CO3 (0.24 mmol),
cat. 4h (0.02 mmol), DCE (3.0 mL), 50 °C, 5 h.
Scheme 4. Scale-up Experiment
Additionally, we have attempted the one-pot reaction of 2-
(1-tosylalkyl)phenol 1a with pyrazolin-5-one 2a for direct
access to the spiropyrazolones 5a. The excellent yields and
enantioselectivities could also be obtained, although the dr was
poor with or without organocatalyst 4h (Scheme 5), which may
be ascribed to the fact that the excess of 2-(1-tosylalkyl)phenol
affects the coordination of organocatalyst 4 with adducts 3 and
NCS.
*
Unless otherwise noted, all reactions were carried out under these
conditions: 1a (0.24 mmol), 2 (0.20 mmol), Na2CO3 (0.30 mmol),
cat. 4f (0.02 mmol), DCE (3.0 mL), 30 °C, 48 h. Cat. 4d was used.
PMP = 4-methoxyphenyl.
a
catalyst. According to the optimization of reaction parameters
(see the Supporting Information), it is worth noting that the
use of the bifunctional organocatalyst is essential for
diastereocontrol, which could remarkably increase the dr up
to 13:1 together with K2CO3 and NCS.7c
Scheme 5. One-Pot Reaction for the Synthesis of
Spiropyrazolone
Encouraged by the satisfying results above, we turned our
attention to the investigation of the generality regarding
different substituted adducts 3, and the results are depicted in
Scheme 3. Generally, various type of spiropyrazolones were
synthesized in high yields, excellent enantioselectivities as well
as diastereoselectivities (up to 98% yield, ee = 99%, dr >20:1)
under mild condition.
To further demonstrate the versatility of our method, the
scale-up reaction of 2-(1-tosylalkyl)phenol 1a and pyrazolin-5-
one 2a was performed. Reaction of 1.2 mmol of 1a and 1.0
mmol of 2a proceeded well under the standard reaction
conditions, affording the desired Michael addition product 3aa
in 95% yield (0.369 g) with 98% ee (Scheme 4) without any
loss of reactivity and enantioselectivty.
To determine the absolute configuration of products,
optically pure (2R,3S)-6-methoxy-3′-methyl-1′,3-diphenyl-3H-
spiro[benzofuran-2,4′-pyrazol]-5′(1′H)-one (+)-5a was ob-
tained as a colorless crystal after recrystallization from
dichloromethane/n-hexane, and the absolute configuration
was determined to be (2R,3S) based on the single-crystal X-
ray diffraction analysis. (For details, see the Supporting
Information.)
In summary, we have successfully realized a bifunctional
squaramide-catalyzed reaction of pyrazolin-5-ones with o-
C
DOI: 10.1021/acs.orglett.8b00025
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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ACS Publications website at DOI: 10.1021/acs.or-
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Experimental procedures, characterization data, and
NMR spectra (PDF)
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Accession Codes
CCDC 1579061 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
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Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
(10) (a) Quinone Methides; Rokita, S. E., Ed.; Wiley: Hoboken, 2009.
(b) Doria, F.; Nadai, M.; Folini, M.; Scalabrin, M.; Germani, L.; Sattin,
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■
Corresponding Author
*E-mail: gfjiang@hnu.edu.cn.
ORCID
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Ji Zhou: 0000-0003-1827-4686
Wen-Jun Huang: 0000-0001-8120-6286
Guo-Fang Jiang: 0000-0002-2295-7677
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National
Natural Science Foundation of China (51578224).
■
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DOI: 10.1021/acs.orglett.8b00025
Org. Lett. XXXX, XXX, XXX−XXX