Intramolecular Cyclization of Vinyldiazoacetates as a Versatile Route to Substituted Pyrazoles

Article abstract of DOI:10.1055/s-0040-1707111

Vinyldiazo compounds undergo a thermal electrocyclization to form pyrazoles in yields of up to 95percent. The reactions are operationally simple, use readily available starting materials, require no intervention of a catalyst, and enable the synthesis of mono-, di- A nd tri-substituted pyrazoles. With the ability to produce highly substituted pyrazoles and the flexibility in installing various types of substituents, this method constitutes a new entry to this valuable heterocyclic scaffold and may be of interest to all branches of the chemical industry.

Full text of DOI:10.1055/s-0040-1707111

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
de
D. Drikermann et al.
Letter
Synlett
Intramolecular Cyclization of Vinyldiazoacetates as a Versatile
Route to Substituted Pyrazoles
Denis Drikermanna
PhCF3
N2
HN N
R3
R3
Valerie Kerndla
Helmar Görlsb
Ivan Vilotijevic*a
R1
R1
reflux, <10 min
O
R2
O
R2
R1 = H, alkyl, aryl
2 = H, alkyl, aryl, CO2Me, OTBS
R3 = alkyl, benzyl
35 examples
up to 95% yield
0
0
0
0-0
0
0
1-6
1
9
9-0
6
3
2
R
a Friedrich-Schiller-University Jena, Institute of Organic and
Macromolecular Chemistry, Humboldtstraße 10, 07743 Jena,
Germany
ivan.vilotijevic@uni-jena.de
b Friedrich-Schiller-University Jena, Institute of Inorganic and
Analytical Chemistry, Humboldtstraße 8, 07743 Jena,
Germany
In memory of Prof. Dr. Ludwig Knorr, professor at Friedrich-
Schiller-University Jena (1889–1921)
Received: 13.03.2020
Accepted after revision: 14.04.2020
Published online: 05.05.2020
Knorr et al., 1883
Ph NH2
Ph
N
N
R
O
O
R
neat
N
H
DOI: 10.1055/s-0040-1707111; Art ID: st-2020-b0150-l
Δ, 2 h
R
R
Abstract Vinyldiazo compounds undergo a thermal electrocyclization
to form pyrazoles in yields of up to 95%. The reactions are operationally
simple, use readily available starting materials, require no intervention
of a catalyst, and enable the synthesis of mono-, di- and tri-substituted
pyrazoles. With the ability to produce highly substituted pyrazoles and
the flexibility in installing various types of substituents, this method
constitutes a new entry to this valuable heterocyclic scaffold and may
be of interest to all branches of the chemical industry.
Chen et al., 2014
Ph
Ph
N
Ph
Ph
NH2
N
Cu(OAc)2 (2 equiv)
120 °C, 6–8 h
Me
CO2Me
N
MeO2C
EtO2C
Me
Legros et al., 2009
H
N
EtO2C
N2
CO2Et
neat
N
20 °C, 30 min
H
H
CO2Et
Key words pyrazoles, vinyldiazoacetates, vinyldiazo compounds, cy-
clization, electrocyclization
This work
H
R1
R2
N2
N
PhCF3
N
R1
CO2R3
First prepared by Ludwig Knorr in 1883,1 pyrazoles and
their derivatives are common structural motifs in chemical,
agricultural, pharmaceutical and related industries. This
heterocyclic scaffold is a part of numerous biologically ac-
tive molecules with anti-inflammatory, antipsychotic, anti-
depressant and anticancer activity.2 Beside the condensa-
tion of hydrazine derivatives with 1,3-dicarbonyl com-
pounds, similar to Knorr’s synthesis,3 numerous synthetic
pathways to pyrazoles have been reported.4 Recent exam-
ples include multicomponent reactions5 and dipolar cyc-
loadditions of diazo compounds,6 nitrile imines7 or azome-
thine imines8 with alkynes and other unsaturated sub-
strates (Scheme 1). Although numerous synthetic routes to
pyrazoles exist, the regioselective synthesis of densely
functionalized pyrazoles remains a challenge.
Cyclization of vinyldiazoacetates could provide an alter-
native general pathway for the direct synthesis of pyrazoles
with a variety of substituents present on all three carbon
atoms of the pyrazole (Scheme 1). The feasibility of this ap-
proach is supported by previous reports of base-free ther-
mal cyclization of vinyldiazo compounds9 and the observa-
tion of pyrazoles as side products in Lewis acid, Rh(II)-,
reflux, <10 min
R2
CO2R3
2
1
Scheme 1 Selected previous work on the synthesis of pyrazoles and an
outline of our strategy to prepare pyrazoles via cyclization of vinyldiazo
compounds
Cu(II)-, Co(II)-, Au(I)-, Ag(I)- or base-catalyzed reactions
that utilize vinyldiazoacetates as starting materials.10 The
latter observations were echoed in our work on catalytic in-
sertions of metal carbenoids derived from vinyldiazoace-
tates into heteroatom-H bonds, where pyrazoles were ob-
served as side products alongside the desired allylic bo-
ranes (Scheme 2, a).11 Considering the ease of access to
various vinyldiazoacetates via diazo-transfer to ,-unsatu-
rated esters, we realized that the cyclization of these com-
pounds could allow for an operationally simple and general
entry to highly substituted pyrazoles. We thus set off to try
to identify catalysts that would promote such cyclizations,
establish the procedure for the synthesis of differentially
substituted pyrazoles and systematically study the reaction
scope.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Drikermann et al.
Letter
Synlett
Keeping in mind the observation that pyrazoles are
formed as side products in the presence of a Cu(I) catalyst,
BOX ligands and a phosphine-borane adduct (Scheme 2, a),
attempts were made to use each of these as a catalyst or a
reagent individually. Cu(I) salts, BOX ligands and nucleop-
hilic phosphines12 all proved to be less efficient than the
simple thermally induced cyclization of the vinyldiazoace-
tate 1a (Scheme 2, b).
Table 1 Optimization of the Reaction Conditions: Solvent, Tempera-
ture and Concentration
solvent
temperature
concentration
N2
HN
N
Ph
CO2Me
Ph
CO2Me
1a
2a
Entry
Solvent
[1a] (mol/L)
Temp (°C)
Yield (%)
1
2
THF
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
1.20
0.25
0.25
66
111
84
59
73
70
46
63
75
66
68
75
81
89
91
87
(a)
5 mol% Cu(MeCN)4PF6
6 mol% BOX ligand
6 mol% NaBArF
Bu3P BH3
N2
PBu3
BH2
PhMe
DCE
H
HN
R1
N
CO2R2
3
R1
CO2R2
R1
CO2R2
CHCl3, 60 °C, 30 min
up to 92% yield
up to 25% yield
4
MeOH
tBuOH
DMSO
65
(b)
Ph
cat. BOX ligand or
cat. Cu(I) salt or
5
83
N2
HN
N
highest yields
observed without
catalyst/additive
6
120
120
120
81
CO2Me
Ph
CO2Me
cat. PBu3 or
no catalyst
7
PhMe/DMPU (1:1)
DMPU
1a
2a
8
Scheme 2 (a) The observation of the cyclization of vinyldiazoacetates
during Cu(I)-catalyzed B–H insertions. (b) Initial search for catalysts to
promote the cyclization of vinyldiazoacetates.
9
C6F6
10
11
12
13
PhCF3
102
102
115
144
PhCF3
With a better understanding of the fact that these reac-
tions proceed as thermally promoted cyclizations of the vi-
nyldiazo 1,5-dipole and require no intervention of a cata-
lyst, focus was shifted to optimization of the reaction con-
ditions by identifying the solvent, temperature,
concentration and the time required for full conversion.
Considering the charge separation in the starting vinyldia-
zoacetate and the redistribution of electron density in the
transition states for the cyclization, predicting the solvent
effects was not intuitive.
Standard laboratory solvents and solvent mixtures were
employed at refluxing temperatures in the search for the
optimum medium for the rearrangement (Table 1). The for-
mation of pyrazole 2a from the corresponding vinyldiazo-
acetate was observed in all the tested solvents. Non-polar
solvents and polar protic solvents afforded the desired
product in moderate to good yields (entries 1–5). Better
yields were generally observed in polar, aprotic solvents
(entries 6–13), with pyridine, 2,6-lutidine and trifluorotol-
uene giving the highest yields of 91%, 87% and 81%, respec-
tively. Reactions in trifluorotoluene proceeded with signifi-
cantly higher rate, requiring less than 10 minutes to com-
plete and allowing for the product to directly precipitate
out of the solution, which is why trifluorotoluene was used
in further optimization. Somewhat counterintuitively, in-
creasing the concentration of vinyldiazoacetate in the reac-
tion mixture to 1.2 M led to an improvement of the isolated
yield to 89% with reaction times of less than 10 minutes,
which suggests that the intramolecular cyclization readily
outperforms any possible bimolecular pathways.
C6H5N
2,6-lutidine
The vinyldiazoacetates required for the studies of the
reaction scope could be easily prepared via Regitz diazo
transfer13 to the corresponding ,-unsaturated ester using
DBU as the base and p-ABSA as the diazo transfer reagent.
To address any ambiguity about the structure of the result-
ing vinyldiazo compound with respect to the possibility of
diazo transfer to C2 or to C4 with transposition of the dou-
ble bond, a heavier crystalline analog of the diazo transfer
product 1r was subjected to X-ray crystallography, which
indicated that only the observed and isolated isomer was
indeed the desired aryl-substituted vinyldiazoacetate (Fig-
ure 1). This was further corroborated by the alternative
pathway to the vinyldiazoacetate 1x via the palladium-cat-
alyzed coupling of (E)-(2-iodovinyl)benzene with ethyl dia-
zoacetate.14 A set of vinyldiazoacetates, including unsubsti-
tuted, 3- and 4-substituted, as well as 3,4- and 4,4-disubsti-
tuted vinyldiazoacetates, was prepared to test the reaction
scope. Under the optimized reaction conditions, the corre-
sponding unsubstituted, 3-substituted and 3,4-disubstitut-
ed 1H-pyrazole-5-carboxylates were obtained in yields of
up to 95% (Schemes 3 and 4). The reactions were carried
N2
OMe
O
F3C
1r
Figure 1 Structural conformation of the product of diazo transfer to
C2 of ,-unsaturated ester 1r
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
D. Drikermann et al.
Letter
Synlett
out on 0.5–2.0 mmol scale, however, further scale up was
avoided out of safety concerns related to the stability of dia-
zoacetates.15
N2
OR2
N
HN
R1
0.5 mmol scale
OR2
R1
PhCF3, reflux
<10 min
O
O
1, c = 1.2 M
2
Differently substituted aryl groups were installed at C4
of the vinyldiazoacetates in order to evaluate the electronic
effects these substituents had on the reaction outcome
(Scheme 3). Vinyldiazoacetates carrying an electron-rich
aryl substituent at the ortho, meta or para position resulted
in good yields (2a–i, 64–93%), similar to those of the phe-
nyl-substituted diazo compound 1a. Halogen-substituted
aryl groups were well tolerated and the corresponding pyr-
azoles 2j–o suitable for further cross-coupling could be ob-
tained in yields of 72–77%. The structure of product 2m was
unambiguously assigned by X-ray crystallography (Scheme
3). Pyrazoles carrying an electron-deficient aryl substituent
at the C4 position (2r–t) were isolated in 70–79% yield, thus
demonstrating that the yields obtained in these reactions
were not strongly influenced by the electronic nature of the
substituents. Furans and thiophenes were also well tolerat-
ed and the corresponding pyrazoles 2p and 2q were ob-
tained in 80% and 68% yield, respectively. Alkyl substituents
also allowed for the synthesis of pyrazoles, albeit in lower
yields owing to the lower stability of the diazoacetate and a
more diverse network of possible side reactions. When an
n-butyl group was present as the C4 substituent the corre-
sponding pyrazole 2v was isolated in a yield of 48%. When a
t-butyl-substituted vinyldiazoacetate was employed, the
cyclization product was not observed, presumably due to
steric crowding at the reactive C4 carbon atom. Even a non-
substituted vinyldiazoacetate underwent the cyclization to
produce monosubstituted pyrazole 2u in 56% yield. In addi-
tion to the methyl esters, a variety of other alkyl and aryl
esters were tolerated, including benzylic and bulky t-butyl
esters, with the isolated yields of the corresponding pyra-
zoles ranging from 74% to 85% (2x–ab).
N
N
N
HN
HN
HN
CO2Me
CO2Me
CO2Me
Ph
2a, 94%
2b, 92%
2c, 77%
N
N
N
HN
HN
HN
CO2Me
Ph
CO2Me
CO2Me
2d, 78%
2e, 64%
2f, 93%
N
N
N
HN
HN
HN
CO2Me
CO2Me
CO2Me
MeO
OMe
2i, 76%
2g, 69%
2h, 82%
MeO
HN
N
N
N
HN
HN
CO2Me
CO2Me
CO2Me
F
F
Cl
2j, 74%
2k, 77%
2l, 72%
N
HN
CO2Me
Br
2m, 73%
N
HN
CO2Me
CO2Me
2n, 77%
I
N
N
N
Cl HN
HN
HN
CO2Me
CO2Me
O
S
Cl
Cl
2o, 73%
2p, 80%
2q, 68%
N
N
N
HN
HN
HN
CO2Me
CO2Me
MeO2C
CO2Me
F3C
F3C
After establishing the reaction scope for disubstituted
pyrazoles, the focus was shifted to the synthesis of trisub-
stituted pyrazoles (Scheme 4, a). Both alkyl and aryl groups
can be introduced at C3 of the vinyldiazoacetate, although
with slightly lower yields (Scheme 4, a). Electron-with-
drawing groups such as esters were also well tolerated (2af,
62%), as were electron donors such as the silyl enol ether in
2ag (51%).
Finally, we set out to explore if vinyldiazo compounds
featuring an electron-withdrawing group other than a sim-
ple ester would be competent cyclization substrates for pro-
duction of the corresponding pyrazoles. Attempts to accom-
modate a nitrile, diethylamide, fluoride, trifluoromethyl or
acetate instead of the ester failed and the corresponding vi-
nyldiazo compounds could not be isolated in satisfactory
yields. However, the ester could be substituted by a carbox-
ylic acid, as in 2ah, or a ketone, as in 2ai (Scheme 4, b). In
the synthesis of the methyl-ketone-substituted pyrazole,
the diazo transfer reaction proved selective for the allylic
2r, 79%
2s, 70%
2t, 78%
CF3
N
N
N
HN
HN
HN
CO2Bn
CO2Me
CO2Me
H
2u, 56%
2v, 48%
2w, 0%
HN
OtBu
HN
N
N
N
OEt
O
OBn
HN
O
O
2y, 82%
2x, 78%
2z, 76%
Br
F
F
F
O
F
N
N
HN
O
HN
F
O
O
Br
2aa, 85%
2ab, 74%
Scheme 3 Reaction scope for the synthesis of disubstituted pyrazoles
methylene over the -methyl group of the ketone, and the
corresponding diazo compound underwent efficient cy-
clization to the pyrazole 2ai in 64% yield. The cyclization to
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
D. Drikermann et al.
Letter
Synlett
include C–C cleavage, therefore leaving a simple thermally
induced electrocyclization as the most plausible mechanis-
tic scenario.
R3
R'
N2
N
HN
PhCF3, reflux
R3
R1
R1
O
<10 min
R2
1ac
O
R2
2ac, R' = H
In summary, thermal 6 electrocyclization of vinyldia-
zoacetates to 3H-pyrazoles followed by a 1,5-proton shift is
an effective strategy for the synthesis of trisubstituted 1H-
pyrazoles with substituents on all three carbon atoms. The
reactions are operationally simple, require no catalyst and
proceed with high rates at elevated temperature.16 The re-
action scope is broad with both alkyl and aryl substituents
tolerated at positions 4 and 5 of the pyrazoles. An electron-
withdrawing group: an ester, a carboxylic acid or a ketone,
is required in the vinyldiazo compound and is installed at
position 3 of the pyrazole. The reactions proceed in good
yields regardless of the electronic properties of the substit-
uents and afford a variety of pyrazoles that are of interest in
different branches of the chemical industry.
(a)
(b)
N
N
N
HN
OH
HN
HN
CO2Me
CO2Me
Ph
Ph
Tol
O
Me
Ph
2ad, 45%
2ae, 36%
2ah, 95% (2 steps)
N
N
N
HN
Me
HN
HN
CO2Me
CO2Me
Ph
H
Ph
O
CO2Me
OTBS
2af, 62%
2ag, 51%
2ai, 64%
(c)
PhCF3, reflux
10 min
Me N2
No cyclization
No cyclization
Ph
CO2Me
1aj
PhCF3, reflux
10 min
Et
N2
Funding Information
CO2Me
1ak
This research was funded by the Carl-Zeiss-Stiftung (endowed profes-
sorship to I.V.), Friedrich-Schiller-Universität Jena, the Ernst Ludwig
Ehrlich Foundation (graduate fellowship to D.D.) and the State of
Thuringia (2015 FGI0021) co-supported by the European Regional
Et
N2
N
PBu3
HN
CO2Me
CO2Me
1ak
PhCF3, reflux
Et
2ak
Development Fund (ERDF).
C
arl-Z
e
i
s-Stiftu
n
g
(F)ri
e
dri
c
h-S
c
h
i
l
er-U
n
i
v
ersität
J
e
n
a
()Ernst
L
u
d
w
i
g
E
hrl
i
c
h
F
o
u
n
d
ati
o
n
(S)tateof
T
h
uri
n
g
i
a
(2
0
1
5
F
G
I
0
0
2
1)Euro
p
e
a
n
R
e
g
i
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n
a
lD
e
v
e
l
o
p
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F
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n
d
()
Scheme 4 (a) Synthesis of trisubstituted pyrazoles. (b) Accommodat-
ing electron-withdrawing groups other than esters at C2. (c) 4,4-Disub-
stituted and Z-vinylacetates do not readily undergo cyclization.
Acknowledgment
We thank Dr. Peter Bellstedt and Dr. Nico Ueberschaar (FSU Jena) for
their support with NMR and MS analysis.
form 1H-pyrazole-3-carboxylic acid 2ah proceeded with
high rates and prevented isolation of the vinyldiazoacetic
acid during basic hydrolysis of the ester precursor. This in-
dicated that diazo transfer and cyclization could be accom-
plished as a one-pot process in the presence of the base and
excess diazo transfer reagent. Overall yields for the tested
one-pot process were lower, presumably due to the limited
choice of solvents that would enable high yields in both the
diazo transfer and cyclization processes.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707111.
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References and Notes
(1) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2597.
Cyclization attempts with 4,4-disubstituted vinylacetate
1aj and the Z-configured vinyldiazoacetate 1ak under the
optimized conditions did not afford any of the desired cy-
clized 3H- or 1H-pyrazole products (Scheme 4, c). The Z-vi-
nyldiazoacetate, however, did form the corresponding pyra-
zole in the presence of Lewis bases such as nucleophilic
phosphines that promoted Z/E isomerization. Based on
these experiments, it can be speculated that the reactions
likely proceed as thermal 6 electrocyclizations to 3H-pyra-
zoles followed by a 1,5-proton shift. We consider C–N bond
cleavage an unlikely scenario as it would irreversibly pro-
duce dinitrogen. A simple crossover experiment, in which a
1:1 mixture of two vinyldiazoacetates with different C4 and
ester substituents was used, demonstrated that these reac-
tions did not proceed via a dissociative pathway that would
(2) (a) Liu, J.-J.; Zhao, M.-y.; Zhang, X.; Zhao, X.; Zhu, H.-L. Mini-Rev.
Med. Chem. 2013, 13, 1957. (b) Czarnomysy, R.; Surażyński, A.;
Muszynska, A.; Gornowicz, A.; Bielawska, A.; Bielawski, K.
J. Enzyme Inhib. Med. Chem. 2018, 33, 1006. (c) Hura, N.; Naaz,
A.; Prassanawar, S. S.; Guchhait, K. S.; Panda, D. ACS Omega
2018, 3, 1955. (d) Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.;
Mabkhot, Y. N.; Al-aizari, F. A.; Ansar, M. Molecules 2018, 23,
134.
(3) (a) Kidwai, M.; Jain, A.; Poddar, R. J. Organomet. Chem. 2011,
696, 1939. (b) Vaddula, R. B.; Varma, S. R.; Leazer, J. Tetrahedron
Lett. 2013, 54, 1538. (c) Venkateswarlu, V.; Kour, J.; Kumar, K. A.
A.; Verma, K. P.; Reddy, L. G.; Hussain, Y.; Tabassum, A.;
Balgotra, S.; Gupta, S.; Hudwekar, D. A.; Vishwakarma, A. R.;
Sawant, D. S. RSC Adv. 2018, 8, 26523. (d) Wang, H.; Sun, X.;
Zhang, S.; Liu, G.; Wang, C.; Zhu, L.; Zhang, H. Synlett 2018, 29,
2689. (e) Yang, G.-P.; He, X.; Yu, B.; Hu, C.-W. Appl. Organomet.
Chem. 2018, 32, e4532.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
D. Drikermann et al.
Letter
Synlett
(4) (a) Kumar, V.; Kaur, K.; Gupta, K. G.; Sharma, K. A. Eur. J. Med.
Chem. 2013, 69, 735. (b) Pizzuti, L.; Barschak, G. A.; Stefanello,
M. F.; Farias, D. M.; Lencina, C.; Roesch-Ely, M.; Cunico, W.;
Moura, S.; Pereira, C. M. P. Curr. Org. Chem. 2014, 18, 115.
(c) Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman New J. Chem.
2017, 41, 16.
(5) (a) Chen, B.; Zhu, C.; Tang, Y.; Ma, S. Chem. Commun. 2014, 50,
7677. (b) Pires, S. C.; de Oliveira, D. H.; Pontel, M. R. B.;
Kazmierczak, C. J.; Cargnelutti, R.; Alves, D.; Jacob, G. R.;
Schumacher, F. R. Beilstein J. Org. Chem. 2018, 14, 2789. (c)
Preeti; Singh, N. K. Org. Biomol. Chem. 2018, 16, 9084.
(d) Mamaghani, M.; Nia, R. H. Polycyclic Aromat. Compd. 2019, 1.
(6) (a) Aggarwal, K. V.; de Vicente, J.; Bonnert, V. R. J. Org. Chem.
2003, 68, 5381. (b) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-
Delpon, D. Green Chem. 2009, 11, 156. (c) Pramanik, M. M. D.;
Kant, R.; Rastogi, N. Tetrahedron 2014, 70, 5214.
(7) (a) Chandanshive, Z. J.; Bonini, F. B.; Gentili, D.; Fochi, M.;
Bernardi, L.; Franchini, C. M. Eur. J. Org. Chem. 2010, 6440.
(b) Voronin, V. V.; Ledovskaya, S. M.; Gordeev, G. E.; Rodygin, S.
K.; Ananikov, P. V. J. Org. Chem. 2018, 83, 3819. (c) Yavari, I.;
Taheri, Z.; Naeimabadi, M.; Bahemmat, S.; Halvagar, R. M.
Synlett 2018, 29, 918.
(8) (a) Nájera, C.; Sansano, M. J.; Yus, M. Org. Biomol. Chem. 2015,
13, 8596. (b) Bakthadoss, M.; Agarwal, V. ChemistrySelect 2018,
3, 6960.
(9) (a) Brewbaker, L. J.; Hart, H. J. Am. Chem. Soc. 1969, 91, 711.
(b) Padwa, A.; Kulkarni, S. Y.; Zhang, Z. J. Org. Chem. 1990, 55,
4144. (c) Supurgibekov, B. M.; Cantillo, D.; Kappe, O. C.; Surya
Prakash, G. K.; Nikolaev, A. V. Org. Biomol. Chem. 2014, 12, 682.
(d) O’Connor, N. R.; Bolgar, P.; Stoltz, M. B. Tetrahedron Lett.
2016, 57, 849. (e) Bien, J.; Davulcu, A.; DelMonte, A. J.;
Fraunhoffer, J. K.; Gao, Z.; Hang, C.; Hsiao, Y.; Hu, W.; Katipally,
K.; Littke, A.; Pedro, A.; Qiu, Y.; Sandoval, M.; Schild, R.; Soltani,
M.; Tedesco, A.; Vanyo, D.; Vemishetti, P.; Waltermire, E. R. Org.
Process Res. Dev. 2018, 22, 1393.
(10) (a) Ito, K.; Maruyama, J. Heterocycles 1984, 22, 1057. (b) Ito, K.;
Maruyama, J. J. Heterocycl. Chem. 1988, 25, 1681. (c) Davies, H.
M. L.; Hougland, W. P.; Cantrell, W. R. Jr. Synth. Commun. 1992,
22, 971. (d) Antos, M. J.; Francis, B. M. J. Am. Chem. Soc. 2004,
126, 10256. (e) Qian, Y.; Xu, X.; Wang, X.; Zavalij, J. P.; Hu, W.;
Doyle, P. M. Angew. Chem. Int. Ed. 2012, 51, 1. (f) Cui, S.; Zhang,
Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4, 3912. (g) Supurgibekov,
B. M.; Prakash, G. K. S.; Nikolaev, A. V. Synthesis 2013, 45, 1215.
(h) Guo, H.; Zhang, D.; Zhu, C.; Li, J.; Xu, G.; Sun, J. Org. Lett.
2014, 16, 3110. (i) Deng, Y.; Jing, C.; Doyle, P. M. Chem. Commun.
2015, 51, 12924. (j) Xu, G.; Zhu, C.; Gu, W.; Li, J.; Sun, J. Angew.
Chem. Int. Ed. 2015, 54, 883. (k) Martin, C. S.; Vohidov, F.; Wang,
H.; Knudsen, E. S.; Marzec, A. A.; Ball, T. Z. Bioconjugate Chem.
2017, 28, 659. (l) Roizen, L. J.; Jones, C. A.; Smith, C. R.; Virgil, C.
S.; Stoltz, M. B. J. Org. Chem. 2017, 82, 13051. (m) Zhao, M.-N.;
Zhang, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Sci. Bull. 2017,
62, 493. (n) Craig, A. R.; Smith, C. R.; Roizen, L. J.; Jones, C. A.;
Virgil, C. S.; Stoltz, M. B. J. Org. Chem. 2018, 83, 3467. (o) Zhang,
X.; Zheng, Y.; Qiu, L.; Xu, X. Org. Biomol. Chem. 2018, 16, 70.
(11) Drikermann, D.; Mößel, S. R.; Al-Jammal, W. K.; Vilotijevic, I.
Org. Lett. 2020, 22, 1091.
(f) Nikolaev, A. V.; Cantillo, D.; Kappe, O. C.; Medvedev, J. J.;
Prakash, G. K. S.; Supurgibekov, B. M. Chem. Eur. J. 2016, 22, 174.
(g) Moslin, R.; Zhang, Y.; Wrobleski, T. S.; Lin, S.; Mertzman, M.;
Spergel, S.; Tokarski, S. J.; Strnad, J.; Gillooly, K.; McIntyre, K. W.;
Zupa-Fernandez, A.; Cheng, L.; Sun, H.; Chaudhry, C.; Huang, C.;
D’Arienzo, C.; Heimrich, E.; Yang, X.; Muckelbauer, K. J.; Chang,
C.; Tredup, J.; Mulligan, D.; Xie, D.; Aranibar, N.; Chiney, M.;
Burke, R. J.; Lombardo, L.; Carter, H. P.; Weinstein, S. D. J. Med.
Chem. 2019, 62, 8953.
(13) Pavlyuk, O.; Teller, H.; McMills, M. C. Tetrahedron Lett. 2009, 50,
2716.
(14) Ye, F.; Qu, S.; Zhou, L.; Peng, C.; Wang, C.; Cheng, J.; Hossain, L.
M.; Liu, Y.; Zhang, Y.; Wang, Z.-X.; Wang, J. J. Am. Chem. Soc.
2015, 137, 4435.
(15) Green, P. S.; Wheelhouse, M. K.; Payne, D. A.; Hallett, P. J.;
Miller, W. P.; Bull, A. J. Org. Process Res. Dev. 2020, 24, 67.
(16) Methyl 5-Phenyl-1H-pyrazole-3-carboxylate (2a); Typical
Procedure
A mixture of cinnamic alcohol (3.35 g, 25.0 mmol, 1.00 equiv),
formic acid (2.83 mL, 75.0 mmol, 3.00 equiv), acetic anhydride
(7.09 mL, 75.0 mmol, 3.00 equiv), tris(dibenzylideneace-
tone)dipalladium(0) (114 mg, 0.5 mol%) and Xantphos (289 mg,
2.0 mol%) was suspended in toluene (15 mL) and heated to 80 °C
for 12 h.17 The mixture was filtered through a short pad of silica
and washed with ethyl acetate. The volatiles were removed
under reduced pressure to give a crude product. The product
could be purified by column chromatography (dry loading, 10–
20% v/v ethyl acetate/petroleum ether) and isolated as a yellow
solid (3.45 g, 85% yield). A suspension of the crude carboxylic
acid from the previous step (3.00 g, 18.5 mmol, 1.00 equiv),
Cs2CO3 (3.01 g, 9.25 mmol, 0.50 equiv) and MeI (2.30 mL, 37.0
mmol, 2.00 equiv) in acetone (150 mL) was heated at 80 °C for 3
h.[18] Silica gel was added and the solvent was evaporated. After
column chromatography purification (dry loading, 5–20% v/v
ethyl acetate/petroleum ether), methyl (E)-4-phenylbut-3-
enoate (3a) was isolated as a yellow oil (2.29 g, 70% yield). To a
solution of p-ABSA (4.09 g, 17.0 mmol, 1.50 equiv) and ester 3a
(2.00 g, 11.3 mmol, 1.00 equiv) in dry acetonitrile (0.10 M) at
0 °C under a N2 atmosphere was slowly added DBU (3.37 mL,
22.6 mmol, 2.00 equiv) over a period of 30 min. After the addi-
tion was complete, the mixture was allowed to warm to RT
overnight and then quenched by addition of sat. NH4Cl solution.
The aqueous layer was extracted with ethyl acetate (3 × 150
mL), and the combined organic phase was dried over MgSO4,
concentrated and the crude residue purified by column chro-
matography (5–20% v/v ethyl acetate/petroleum ether) to give
methyl (E)-2-diazo-4-phenylbut-3-enoate (1a) as a dark red oil
(2.29 g, 72% yield).[13] A solution of vinyldiazo compound 1a
(101 mg, 0.50 mmol, 1.00 equiv) in benzotrifluoride (0.42 mL,
1.20 M) was heated to reflux until complete consumption of the
vinyldiazo compound was observed (<10 min). Silica gel was
then added and the solvent was evaporated. The product was
purified by column chromatography (dry loading, 50–70% v/v
ethyl acetate/petroleum ether) and pyrazole 2a was isolated as
an off-white solid (95.2 mg, 94%). The analytical data matched
with the literature.[10d]
(12) (a) Miyamoto, T.; Matsumoto, J. Chem. Pharm. Bull. 1988, 36,
1321. (b) Miyamoto, T.; Matsumoto, J. Chem. Pharm. Bull. 1990,
38, 3211. (c) Nikolaev, A. V.; Zakharova, M. V.; Hennig, L.; Sieler,
J. J. Fluorine Chem. 2007, 128, 507. (d) Supurgibekov, B. M.;
Zakharova, M. V.; Sieler, J.; Nikolaev, A. V. Tetrahedron Lett.
2011, 52, 341. (e) Bel Abed, H.; Mammoliti, O.; Bande, O.; Van
Lommen, G.; Herdewijn, P. J. Org. Chem. 2013, 78, 7845.
1H NMR (250 MHz, CDCl3):  = 7.89–7.76 (m, 2 H), 7.51–7.37 (m,
3 H), 7.14 (s, 1 H), 3.97 (s, 3 H).
(17) Fu, M.-C.; Shang, R.; Cheng, W.-M.; Fu, Y. Chem. Eur. J. 2017, 23,
8818.
(18) Eissler, S.; Nahrwold, M.; Neumann, B.; Stammler, H.-G.;
Sewald, N. Org. Lett. 2007, 9, 817.
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