Regioselective Synthesis of Highly Functionalized Pyrazoles from N-Tosylhydrazones

Article abstract of DOI:10.1021/acs.orglett.9b00561

A regioselective synthesis of highly functionalized pyrazoles from N-tosylhydrazones was developed. The reaction was general for a wide range of substrates and demonstrated excellent tolerance to a variety of substituents, and the method has been successfully applied to the formal synthesis of ibrutinib.

Full text of DOI:10.1021/acs.orglett.9b00561

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Synthesis of Highly Functionalized Pyrazoles from
N‑Tosylhydrazones
Qian Zhang and Meng Tang*
School of Pharmacy, Lanzhou University, Lanzhou 730000, P.R. China
S
* Supporting Information
ABSTRACT: A regioselective synthesis of highly functionalized pyrazoles
from N-tosylhydrazones was developed. The reaction was general for a wide
range of substrates and demonstrated excellent tolerance to a variety of
substituents, and the method has been successfully applied to the formal
synthesis of ibrutinib.
Scheme 1. Approaches toward aminopyrazoles
yrazoles and their derivatives constitute an important class
of compounds that are extensively used in the agro-
P
chemical, material, and pharmaceutical industry.1 Synthesis of
pyrazoles has received considerable attention from organic
chemists.2
Reactivity of aminopyrazoles as a functional motif is
frequently applied to the preparation of pharmacologically
active agents, such as ibrutinib and sildenafil (Figure 1).3 The
Figure 1. Structure of ibrutinib and sildenafil.
addition and cyclization between monosubstituted hydrazines
and alkoxyacrylonitriles or acrylonitriles has been a classical
reaction toward aminopyrazoles (Scheme 1, a).3,4 However,
the lack of commercially available monosubstituted hydrazines
and somewhat limited substrate scope greatly reduces the
attractiveness of this method. Commonly, R1 is limited to
methyl and phenyl. Furthermore, the initial nucleophilic attack
of the more nucleophilic substituted nitrogen of alkyl
hydrazines or the unsubstituted nitrogen of aryl hydrazines
to either the nitrile or activated olefin results in two isomers, 3-
aminopyrazole and 5-aminopyrazole, respectively. In general,
the 5-aminopyrazole isomer is favored. To control the site
selectivity, Fandrick et al. have developed a Michael
equilibration model in the condensation reactions in 2015.4b
In continuation of our ongoing interest in the synthesis of
pyrazoles,5 herein, we present a new approach for the
regioselective synthesis of highly functionalized pyrazoles
from N-tosylhydrazones6 via a tandem process of nucleophilic
addition and intramolecular cyclization (Scheme 1, b). N-
Alkylation tosylhydrazones could be prepared according to our
reported procedure in a one-pot reaction easily.5b,7
We initiated the investigation for a reaction of N-methyl
tosylhydrazone (1a) with malononitrile, and the results are
summarized in Table 1. The reaction was initially conducted in
the presence of AlBr3 in DCE at room temperature, after 24 h,
pyrazole 2a was obtained in 33% yield (entry 1). In order to
accelerate the reaction rate and improve the yield, the reaction
was performed at reflux temperature, and the yield was
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00561
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Screening the Reaction Conditions
Table 2. Synthesis of 5-Aminopyrazoles.
b
entry
acid
AlBr3
AlBr3
AlCl3
AlCl3
SnCl4
BF3·OEt2
TiCl4
Sc(OTf)3
FeCl3
HCl
solv
time (h)
yield (%)
c
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
CH2Cl2
toluene
THF
24
1
0.5
1
3.5
5
5
5
5
5
5
5
0.5
5
6
33
80
83
61
61
19
25
19
trace
trace
63
62
40
2
3
4
d
5
6
7
8
9
10
11
12
13
14
AlCl3
AlCl3
AlCl3
AlCl3
NR
72
e
15
AlCl3
DCE
a
Reactions were performed with 1a (0.30 mmol), malononitrile (0.75
mmol), and acid (0.75 mmol) in 4 mL of solvent at reflux
b
c
temperature. Isolated yields. The reaction was performed at room
d
e
temperature. 0.5 mmol of AlCl3 was used. The reaction was
performed with 1a (3.0 mmol), malononitrile (7.5 mmol), and AlCl3
(7.5 mmol) in 20 mL of DCE at reflux temperature.
improved to 80% within 1 h (entry 2). Encouraged by the
results, we screened other reaction conditions. First, a variety
of different acids were tested in the reaction. The use of AlCl3
resulted in 83% yield, and the reaction could reach completion
within 0.5 h (entry 3). Decreasing the amount of AlCl3
resulted in lower yield (entry 4). SnCl4 gave 61% yield
(entry 5), and other acids led to lower yields (entries 6−10).
Of the solvents screened, CHCl3, CH2Cl2, and toluene could
give moderate yields (entries 11−14). To investigate the
reaction’s practical utility, we also performed the reaction with
3 mmol of 1a, and the yield was not affected (entry 15).
With our optimized conditions in hand, several N-
tosylhydrazones 1 were applied to the reaction to test the
generality and scope of the method. Different R1 substituents
were first evaluated in the reaction. As shown in Table 2,
hydrogen (2b), ethyl (2c), benzyl (2d), allyl (2e), propargyl
(2f), carbonitrile (2g), ester (2h), and phenyl8 (2i) were all
applicable and gave the corresponding 5-aminopyrazole
derivatives in good to high yields. Additionally, the electronic
effect on the aromatic ring of R2 had little influence on the
reaction,and N-tosylhydrazones derived from benzaldehyde
featuring ortho-, meta-, and para-substituents as well as
electron-withdrawing (2j, 2k, 2l, 2m) or electron-donating
(2n, 2o, 2p) substituents worked well to furnish the
corresponding pyrazole derivatives. Furthermore, N-tosylhy-
drazones derived from 2-furaldehyde, 2-thienaldehyde, and
aliphatic aldehyde were also appropriate on the reaction, and
products 2q, 2r, and 2s were prepared in moderate yields. In
some cases, the yields were lower, but no byproducts could be
confirmed in the current state.
a
Reactions were performed with 1 (0.30 mmol), malononitrile (0.75
mmol), and AlCl3 (0.75 mmol) in DCE (4 mL) at reflux temperature.
pentane-2,4-dione, and the corresponding products 6,7-
dihydro-1H-indazol-4(5H)-ones (2t, 2u, and 2v) and 1H-
pyrazole-4-one (2w) were obtained in moderate yields
(Scheme 2). No self-condensation products of 1,3-diketones
were detected. In addition, 6,7-dihydro-1H-indazol-4(5H)-
ones have been reported in connection with the preparation of
antitumor agents.9 Ethyl 2-cyanoacetate was also suitable for
the reaction, and 5-amino-4-ester-pyrazoles (2x, 2y, and 2z)
were obtained in good yields (Scheme 3).10
Compared to the previously reported reactions toward
aminopyrazoles from monosubstituted hydrazines, our reaction
conditions showed good compatibility with different sub-
stituents. The reaction was effective for a wide scope of
substrates, and a series of highly functionalized pyrazole
derivatives were synthesized in good yields. More importantly,
the use of monosubstituted hydrazines was unnecessary, and
R1 was no longer limited to methyl and phenyl. Hydrogen,
alkyl, benzyl, allyl, propargyl, carbonitrile, ester, and phenyl
were all applicable, malononitrile, cyclohexane-1,3-dione,
pentane-2,4-dione, and ethyl 2-cyanoacetate were all suitable
And then, we investigated any other active methylene
compounds to expand the scope of the reaction under similar
conditions. First, 1,3-diketones were evaluated. To our delight,
the reaction was general for cyclohexane-1,3-dione and
B
DOI: 10.1021/acs.orglett.9b00561
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Organic Letters
Letter
Scheme 2. Synthesis of 6,7-Dihydro-1H-indazol-4(5H)-one
and 1H-Pyrazole-4-one
Scheme 5. Proposed Pathway for Aminopyrazole Formation
malononitrile to N-tosylhydrazone iminium salt 4 resulting in 5
by the loss of a p-toluenesulfinic acid anion and then a 1,3-H
shift producing intermediate 6, which subsequently went
through an intramolecular cyclization and 1,3-H shift to form
pyrazoles 2.
Scheme 3. Synthesis of 5-Amino-4-ester-pyrazoles
In summary, we have established a simple and efficient
procedure for the regioselective preparation of highly function-
alized pyrazole derivatives. This strategy proceeded smoothly
with complete regioselectivity, and the protocol was applied to
a wide range of substrates and demonstrated excellent
tolerance to a variety of functional groups. R1 was no longer
limited to methyl and phenyl, and the reaction should facilitate
the exploration of new pyrazole-related pharmaceuticals. The
method has been successfully applied to the formal synthesis of
ibrutinib.
for the reaction, and the reaction proceeded with complete
regioselectivity.
The potential utility of this reaction was exhibited by a
synthesis of the key intermediate of ibrutinib (Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00561.
■
S
Scheme 4. Formal Synthesis of Ibrutinib
Experimental procedures, characterization data, and
copies of NMR spectra for all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tangmeng@lzu.edu.cn.
ORCID
Meng Tang: 0000-0003-4398-3900
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
Ibrutinib is a first-in-class Bruton tyrosine kinase (BTK)
inhibitor. Since its approval for relapsed chronic lymphocytic
leukemia (CLL) by the FDA in 2013, ibrutinib has generally
been found to have a favorable safety and efficacy profile in all
categories of patients with CLL and has been approved for four
different cancers and chronic graft-versus-host disease.11 The
N-tosylhydrazone 3 was synthesized from 4-phenoxybenzalde-
hyde and TsNHNH2 in almost quantitative yield and applied
in the newly developed cyclization reaction with malononitrile
to give the known intermediate 2aa12 in 53% yield, completing
the formal synthesis of ibrutinib.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the NSFC (No. 21772073).
■
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DOI: 10.1021/acs.orglett.9b00561
Org. Lett. XXXX, XXX, XXX−XXX