Multisubstituted pyrazole synthesis via [3?+?2] cycloaddition/rearrangement/N[sbnd]H insertion cascade reaction of α-diazoesters and ynones

Article abstract of DOI:10.1016/j.cclet.2020.11.053

The cascade reactions of alkyl α-diazoesters and ynones using Al(OTf)₃ as the catalyst are described. A series of 4-substituted pyrazoles were obtained via [3 + 2] cycloaddition, 1,5-ester shift, 1,3-H shift, and N[sbnd]H insertion process. Deuterium labelling experiments, kinetic studies and control experiments were carried out for the rationalization of the mechanism.

Full text of DOI:10.1016/j.cclet.2020.11.053

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Multisubstituted pyrazole synthesis via [3 + 2]
cycloaddition/rearrangement/N<ce:glyph name="sbnd"/>H insertion
cascade reaction of α-diazoesters and ynones
Peng Zhao, Zi Zeng, Xiaoming Feng, Xiaohua Liu
PII:
S1001-8417(20)30694-X
https://doi.org/10.1016/j.cclet.2020.11.053
CCLET 5993
DOI:
Reference:
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Chinese Chemical Letters
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Revised Date:
Accepted Date:
17 September 2020
16 November 2020
18 November 2020
Please cite this article as: Zhao P, Zeng Z, Feng X, Liu X, Multisubstituted pyrazole synthesis
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via [3 + 2] cycloaddition/rearrangement/N<ce:glyph name=sbnd/>H insertion cascade
reaction of α-diazoesters and ynones, Chinese Chemical Letters (2020),
doi: https://doi.org/10.1016/j.cclet.2020.11.053
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Communication
Multisubstituted pyrazole synthesis via [3+2] cycloaddition/rearrangement/N-H
insertion cascade reaction of -diazoesters and ynones
Peng Zhao, Zi Zeng, Xiaoming Feng, Xiaohua Liu*
a Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
Graphical abstract
The cascade reactions of alkyl -diazoesters and ynones via [3+2] cycloaddition, 1,5-ester shift, 1,3-H shift, and N-H insertion
process using Al(OTf)3 as the catalyst are described. Deuterium labelling experiments, kinetic studies and control experiments
were carried out for the rationalization of the mechanism.
ABSTRACT
The cascade reactions of alkyl -diazoesters and ynones using Al(OTf)3 as the catalyst are described. A series of 4-substituted pyrazoles were obtained via [3+2]
cycloaddition, 1,5-ester shift, 1,3-H shift, and N-H insertion process. Deuterium labelling experiments, kinetic studies and control experiments were carried out
for the rationalization of the mechanism.
Keywords: Pyrazole, Cascade reaction, -Diazoester, Ynone, Al(OTf)3
Pyrazole-containing derivatives have exhibited promising
biological activities [1], and several newly approved small
molecule drugs, such as elexacaftor, erdafitinib, cilastatin,
remogliflozin etabonate, bear this kind of two nitrogen atoms-
based aromatic heterocycle (Scheme 1a) [2]. A fruitful synthetic
approach to substituted pyrazoles has been disclosed during the
past two decades (Scheme 1b) [3]. These methods included the
construction of two C-N bonds via condensation of 1,3-
dicarbonyl compounds or ynones with hydrazines (path i) [4],
simultaneous formation of one C-N bond and one C-C bond via
[3+2] cycloaddition of 1,3-dipoles (path ii), i.e., hydrazones or α-
diazo compounds with alkynes or alkenes-bearing electron-
withdrawing groups. In addition, the direct N-N bond formation
to install into multisubstituted pyrazoles from nitriles via metal-
imido intermediates was also available (path iii) [5]. An example
of forming one C-N bond via intramolecular cyclization of
vinyldiazoacetates was discovered recently (path iv) [6].
group. When α-diazoarylacetate was used as the 1,3-dipole to
react with methyl propiolate, 4-aryl-3,5-diester substituted
pyrazole was isolated as the major product. This cycloaddition-
migration cascade rendered the convenient introduction of
substituted group into pyrazole-ring. As an ongoing research
about the reactions of α-diazo carbonyl compounds in the
presence of Lewis acids or transition-state metal catalysts [9], we
found that Al(OTf)3 could promote the formation of four-
substituted pyrazoles from alkyl α-diazoacetates and ynones. The
reaction was found to proceed by a [3+2] cycloaddition, 1,5-ester
shift and 1,3-H shift, then a N-H insertion cascade. Herein, we
wish to report the one-pot synthesis of N-alkyl 3-alkyl-4-ester-5-
benzoyl substituted pyrazoles.
-Diazoesters compounds are prominent building blocks for
organic synthesis [7]. Cycloaddition reactions of diazo
compounds with dipolarophiles bearing carbon-carbon double or
triple bond to convert into pyrazolines and pyrazoles derivatives
(Scheme 1b, path ii) have received considerable interest [8]. One
elegant example was InCl3 catalyzed cycloaddition between
diazocarbonyl compounds to alkynes in water initiated by Li’s
———
 Corresponding author.
E-mail address: liuxh@scu.edu.cn (X. Liu), xmfeng@scu.edu.cn (X. Feng)

c 2a (4.0 equiv.) was used.
d DCE (CH2ClCH2Cl, 0.8 mL) was used.
With the optimized reaction condition in hand, we turned to
explore the substrate scope of the catalytic system (Scheme 2). A
wide range of terminal alkynones with benzoyl group bearing
both electron-withdrawing and electron-donating substituents at
the para-, meta-, or ortho-positions, all reacted smoothly with
ethyl 2-diazopropanoate 2a to form the corresponding pyrazole
products 3b-3o in moderate yield. It was found that the methyl-
substituent at para-position was better than ortho- and meta-
positions. The structure of the product 3f was confirmed by
single-crystal X-ray diffraction analysis. The supplementary
crystallographic data of 3f (CCDC: 1984363) can be obtained
free of charge from The Cambridge Crystallographic Data Centre.
Functional substituents such as halogens, alkyl groups, and esters
were well tolerated. Furthermore, ynones bearing 3-furyl or 3-
thiophyl group also proved to be suitable substrates, affording 3p
in 40% yield and 3q in 44% yield. Subsequently, the substrate
scope with respect to the -diazoesters was examined. The length
of α-alkyl chain attached to α-diazoesters had a huge effect on the
yield (3r and 3s), and the corresponding NH-pyrazole was
isolated as the major product (53% yield) when methyl 2-
diazobutanonate was used (see Supporting information for
details). Next, by changing the esters group of diazopropanoate
from methyl to isopropyl group, the yield decreased to 36% yield
(3t). Notably, the catalytic system was also suitable for the
diazoacetate. It has some effect on the yield when the ester group
changed into isopropyl or tertbutyl group with larger steric
hindrance (35%-64% yield, 3u-3y).
Scheme 1. Representative pyrazole-containing drugs and general
methods for the construction of pyrazole rings.
We initiated our study by selection proper catalysts for the
reaction between alkynone 1a with ethyl 2-diazopropanoate 2a. It
was found that the four substituted pyrazole 3a was detected as
the major product, along with three-substituted pyrazole 4a and
other unidentified byproducts (for details see the Supporting
information). In the presence of 10 mol% of Al(OTf)3 at 35 °C,
the product 3a was obtained in 31% yield and 4a in 8% yield
(Table 1, entry 1). Stronger Lewis acids, such as Sc(OTf)3,
In(OTf)3, and Fe(OTf)3 could afforded the pyrazole 3a with low
yields (entries 2-4), but the reaction in the presence of other
metal salts was messy. The yield of the product 3a increased to
61% at 80 °C in DCE (entry 5). At this reaction temperature, only
trace product 3a can be detected when BF3·Et2O or Ti(OiPr)4 was
selected as the catalyst (entries 6 and 7). A better yield can be
achieved by increasing the amount of diazoester 2a (entry 8).
Furthermore, when reducing the amount of solvent, the pyrazole
3a could be isolated in a yield of 73%, as well as the pyrazole 4a
in 20% yield (entry 9). It was noteworthy that the reaction did not
occur without a Lewis acid catalyst at high reaction temperature
(entry 10).
Table 1
Optimization of reaction conditions.a
Entry Lewis acid
T (oC)
35
35
35
35
80
80
80
80
solvent
CH2Cl2
CH2Cl2
CH2Cl2
Yield 3a/4a (%) b
31/8
19/12
20/trace
15/trace
61/6
trace/-
trace/-
71/22
73/20
n.d.
1
2
3
4
5
6
Al(OTf)3
Sc(OTf)3
In(OTf)3
Fe(OTf)3
Al(OTf)3
BF3·Et2O
Ti(OiPr)4
Al(OTf)3
CH2Cl2
Scheme 2. Substrate scope. Unless otherwise noted, the reactions
were performed with 1 (0.1 mmol), 2 (0.4 mmol), and Al(OTf)3 (10
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
o
mol%) in DCE (0.8 mL) at 80 C for 24 h under nitrogen. Yields of
7
isolated product 3.
8 c
9 d
10
Al(OTf)3
-
80
80
Based on this outcome, we tried to test the one-pot
enantioselective N-H insertion to yield optically active product 3.
Many kinds of chiral ligands, such as BINAP, Box, Pybox were
used, the products were isolated in moderate yield but no
enanatioselectivity (for details, see the Supporting information).
n.d. = no detected.
a Unless otherwise noted, the reactions were performed with 1a (0.1
mmol), 2a (2.0 equiv.), and Lewis acid (10 mol%) in solvent (1.0 mL)
for 24 h.
b Isolate yield.

Besides, a series of chiral N,N′-dioxide ligands that was
developed in our group were screened, only the ligand L-PiEt2-
1-Ad derived from (S)-pipecolic acid could get an
enantioselectivity of 16% ee (Scheme 3, Eq. 1).
Scheme 4. Control experiments.
Scheme 3. Other reactions.
In view that two molecules of α-diazoesters transferred into
the product 3, we next subjected two different α-diazoesters into
the catalyst system. As shown in Eq. 2, the reaction of alkynoe
1a, 2-diazopropanoate 2a, and 2-diazo-2-phenylacetate 2j
delivered the desired pyrazole 5a, which is generate via [3+2]
cycloaddition of 2a and N-H insertion into 2j. When ethyl 2-
diazoacetate and diazophenylacetate 2j were mixed with ynone
1a, the pyrzaole product 5b was observed, which is the N-H
insertion product with 2j (Eq. 3). These results were different
from previous synthesis of pyrazoles using α-diazoarylacetate
and methyl propiolate, in which diazophenylacetate participated
in cycloaddition, following 1,5-phenyl shift and without further
N-H insertion reaction [10]. To show the synthetic utility of the
cascade reactions, the gram scale experiment was performed.
Alkynone 1a (4.0 mmol) reacted with ethyl 2-diazopropanoate 2a
(16.0 mmol), providing the desired product 3a in 66% yield
(0.944g) (Eq. 4).
Next, deuterium-labelling experiments were carried out to
probe into the rearrangement processes. The deuterium-labelled
alkynone [D1]1a (88% D) or deuterated additives (D2O) were
examined in the cascade reactions (Scheme 4, Eq. 5). When
[D1]1a was used for the reaction in either the absence or
presence of additive water, the product [D1]3a had low
deuterium ratio at the chiral center. This data suggest that the
proton does not originate from the alkynone. When 1a or [D1]1a
was used with deuterated additives (D2O) in the reaction, [D1]3a
is detected in dramatically increased deuterium ratio. It
demonstrates that the proton can originate from external sources
(trace amount of water containing in the catalytic system) for the
two proton shift steps. Nevertheless, the extra water additive
(exceeded 1.0 equiv.) decreased the isolated yield of the product
3a.
Scheme 5. Plausible mechanism.
Kinetic experiments were conducted with 1a and 2a through
the operando IR instrument (for detail, see the Supporting
information). According to the initial rates based on various
concentrations of each component involved in the reaction, the
reaction showed clear first-order dependence on the substrate 1a,
2a and the catalyst Al(OTf)3. Int. C was synthesized based
previous reported [11], and was used to react with 2a at standard
conditions to give the product 3a with 43% yield (Scheme 4, Eq.
6). No product detected without a catalyst. These feature of
kinetics and control experiments indicate that the cycloaddition
of diazo substrate, ynone in the assistance of Al(OTf)3 is likely
the rate-limiting step.
Based on the above experiments, the mechanism of this
reaction was proposed (Scheme 5). Firstly, Al(OTf)3 actives
alkynone 1 by coordinating its benzoyl group to lower the
LUMO of alkyne, then cycloaddition with alkyl α-diazoacetate
affords the key 3-methyl-3H-pyrazole-3-carboxylate A. The ester
group has higher migratory aptitude than methyl group or
hydrogen, and then 1,5-ester shift leads to the formation of minor
trisubstituted pyrazole 4 or the major intermediate B. The
structure of the product 4a was confirmed by single-crystal X-ray
diffraction analysis. The supplementary crystallographic data of
4a (CCDC: 2008350) can be obtained free of charge from The
Cambridge Crystallographic Data Centre. Water assisted
intermolecular 1,3-proton shift yields the N-H pyrazole Int C.
The NH-based pyrazole C from methyl 2-diazobutanonate and
ynone 1a was detected as the major product (see Scheme S1 in
Supporting information for details). Finally, a Lewis acid assisted
N-H insertion occurs readily to give the final product of N-alkyl
3-alkyl-4-ester-5-benzoyl substituted pyrazole 3.
In summary, we have developed an Al(OTf)3-promoted [3+2]
cycloaddition/rearrangement/N-H insertion cascade reaction of
alkynones and -diazoesters. The reaction afforded a series of

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Conflict of interest
There are no conflicts to declare
.
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Acknowledgments
This work is supported by the National Natural Science
Foundation of China (Nos. 21625205 and U19A2014).
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