Copper-Promoted Coupling of Propiophenones and Arylhydrazines for the Synthesis of 1,3-Diarylpyrazoles

Article abstract of DOI:10.1055/s-0039-1690835

Synthesis of 1,3-diarylpyrazoles from commercial substrates and/or simple transformations is still underrated. In this report, we have developed a method for copper-promoted coupling of propiophenones and arylhydrazines. The reactions afforded substituted pyrazoles in the presence of TEMPO oxidant, acetic acid additive, and DMF solvent. A number of functionalities were compatible with reaction conditions, including halogens, methoxy, trifluoromethyl, and nitro groups. An indazole could be obtained if an electron-poor propiophenone was used.

Full text of DOI:10.1055/s-0039-1690835

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
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T. L. Pham et al.
Letter
Synlett
Copper-Promoted Coupling of Propiophenones and Arylhydrazines
for the Synthesis of 1,3-Diarylpyrazoles
Thuyet L. D. Pham
Tien M. Nguyen
Khuong A. Tran
Ha V. Dang
Ar
N
N
O
Cu(OAc)2 (0.25–1.3 equiv)
TEMPO (4 equiv)
R2
R2
ArNHNH2 (4 equiv)
acetic acid (1 equiv)
DMF, 140 °C, 48 h
R1
R1
Nam T. S. Phan
Ha V. Le*
11 examples
R1, R2 = Cl, Br, CF3, Me, Ph
47–78% yield
R1 = 3-NO2
Tung T. Nguyen*
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2-
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9
1
2-9
9
8
1
Ph
N
N
Faculty of Chemical Engineering, HCMC University of Technology,
VNU-HCM, 268 Ly Thuong Kiet, District 10, Ho Chi Minh City,
Vietnam
R2
R2 = Me or Et
lvha@hcmut.edu.vn
tungtn@hcmut.edu.vn
NO2
Received: 19.01.2020
Su (2016)
Accepted after revision: 04.02.2020
Published online: 26.02.2020
DOI: 10.1055/s-0039-1690835; Art ID: st-2019-l0390-l
O
O
ArNH2, Cu(OAc)2
R
NHAr
(1)
2,2'-bipyridine
TEMPO
Abstract Synthesis of 1,3-diarylpyrazoles from commercial substrates
and/or simple transformations is still underrated. In this report, we have
developed a method for copper-promoted coupling of propiophenones
and arylhydrazines. The reactions afforded substituted pyrazoles in the
presence of TEMPO oxidant, acetic acid additive, and DMF solvent. A
number of functionalities were compatible with reaction conditions, in-
cluding halogens, methoxy, trifluoromethyl, and nitro groups. An inda-
zole could be obtained if an electron-poor propiophenone was used.
1
Our work
Ar
N
N
O
R
R
ArNHNH2, Cu(OAc)2
TEMPO
(2)
1
2
Scheme 1 Dehydrogenative coupling of propiophenones with amine
Key words copper, 1,3-diarylpyrazoles, TEMPO, oxidative, dehydroge-
nucleophiles
nation
Dehydrogenation of aliphatic ketones and isosteres is a
growing methodology that allows for the synthesis of hith-
erto demanding molecules.1 Perhaps the Saegusa–Ito oxida-
tion is the earliest method for yielding enones from silyl
enol ethers.1a,b Since then, developments of methods that
do not require the use of hygroscopic silyl halides have
been attempted. Palladium-, platinum-, and rhodium-cata-
lyzed desaturation of cyclic and acyclic carbonyl com-
pounds is known.1c–f Notably, only a few first-row metals
are used to facilitate the transformation. Ueno and Kuwano
firstly reported a method for nickel-catalyzed dehydrogena-
tive amination of ethyl ketones.1g Su later presented a cou-
pling of propiophenones 1 with many nucleophiles includ-
ing sulfonamides, amides, amines, and phenols.1h The
transformation was promoted by a combination of copper
catalyst and TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl)
oxidant (Scheme 1, eq 1). Multiple dehydrogenation of ali-
phatic carbonyls and alcohols is also precedented.1i Notably,
metal-free oxidation of allylic sp3 C–H bonds has been re-
ported.1j To our surprise, there have not been any examples
that leverage the advantages of the available methods for
the synthesis of valuable heterocycles.
Pyrazoles are prevalent in many natural products,2a use-
ful chemicals,2b–d and functional materials.2e–g Scorpionate
ligands comprising sterically hindered pyrazoles play a
prominent role in stabilizing metal complexes used in catal-
ysis.2h–k Synthesis of densely 1,3-diarylated pyrazoles 2 is
notoriously challenging and has attracted substantial atten-
tion of synthetic chemists. Conventional cycloaddition of
1,3-dicarbonyl compounds and arylhydrazines often suffers
from the formation of regioisomeric products.3 Conse-
quently, well-tailored starting materials are required to ob-
tain the selectivities.4 Beller has reported a condensation of
butoxypropenones, in situ formed via a Heck coupling of
aryl bromides and vinyl butyl ether, with phenylhydrazines
to afford moderate yields of 1,3-diarylpyrazoles.4a The
group of Panda has developed an iron-catalyzed reaction of
diarylhydrazones and vicinal diols.4b Oxime acetates of
propiophenones could be used to couple with aromatic
amines and paraformaldehyde under copper catalysis to
yield disubstituted pyrazoles.4c Coupling N–H bonds in 3-
substituted pyrazoles, which are commercially limited,
with aryl iodides or boronic acids is also possible.5 It would
be much more beneficial if commercial substrates are di-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. L. Pham et al.
Letter
Synlett
rectly used, thus shortening synthetic schemes. Our hy-
pothesis was that a copper-catalyzed dehydrogenative cou-
pling of propiophenones 1 and arylhydrazines could afford
1,3-disubstituted pyrazoles 2 (Scheme 1, eq 2), since cop-
per(II) complexes are known to facilitate desaturation of
phenyl alkyl ketones1i and -amination of carbonyl com-
pounds.1h If successful, our method would offer a rapid
route for the synthesis of 1,3-diarylpyrazoles. It should be
noted that such a method has not been reported in the lit-
erature.
ted (entry 9). The presence of copper(II) acetate was crucial
to achieve a substantial conversion of propiophenone 1a
(entry 10). Using a stoichiometric amount of copper(II) ace-
tate gave 81% isolated yield of product 2aa (entry 11). It
should be noted that -amination of C–H bonds in propio-
phenone 1a did not occur under these reaction conditions.6
Scope of the transformation was next studied and is
presented in Scheme 2. Positions of the substituents some-
what affected the yields of 1,3-diarylpyrazoles. If a catalytic
amount of Cu(OAc)2 was used, para-substituted substrates
such as 4′-methoxy, 4′-chloro, 4′-bromo, and 4′-methyl
propiophenones coupled with phenylhydrazine to give the
sluggish crude reaction mixtures (2ba, 2da, 2fa, and 2ga).
Some intermediates such as enones or dihydropyrazoles
were detected (by GC–MS). In those entries, excess
Cu(OAc)2 was often required. Meanwhile, the reactions of
meta-substituted propiophenones were far easier and only
needed a catalytic amount of Cu(OAc)2 (2ca and 2ea).7 Oth-
er aliphatic ketones were also investigated. Condensation of
butyrophenone and phenylhydrazine afforded a 1,3,5-tri-
substituted pyrazole 2ha in 60% yield. Benzylic sp3 C–H
bonds were active, yielding a highly dense diaryl pyrazole
On the basis of previous results,1h,i we decided to use
Cu(OAc)2 in combination with TEMPO for the synthesis of
2aa from the corresponding starting materials. The reaction
optimization was carried out with regard to solvent, cata-
lyst, and oxidant (Table 1). Alcoholic solvents such as glyc-
erol and ethylene glycol were inferior to DMF (entries 1–3).
In contrast to other copper-catalyzed dehydrogenation of
carbonyl compounds,1h,i 1,2-dichlorbenzene only afforded a
trace amount of product 2aa (entry 4). Copper(II) acetate
was more active than copper(II) bromide and copper(I) io-
dide (entries 5 and 6). Only TEMPO and the hydroxy deriva-
tive were competent oxidants (entry 7), while running the
reaction under air as the sole oxidant gave an indole (entry
8). The byproduct was of the competitive Fischer process. A
moderate yield of 2aa was obtained if acetic acid was omit-
Ph
N
Cu(OAc)2 (1 equiv)
TEMPO (4 equiv)
O
N
Table 1 Optimization Resultsa
R2
R1
R2
PhNHNH2 (4 equiv)
acetic acid (1 equiv)
DMF, 140 °C, 48 h
R1
Ph
N
N
O
catalyst (25 mol%)
oxidant (4 equiv)
Ph
N
N
Ph
N
Ph
N
N
N
PhNHNH2 (3a, 4 equiv)
acetic acid (1 equiv)
solvent, 140 °C, 48 h
Cl
1a
2aa
O
Entry Solvent
Catalyst
Oxidant
Yield of 2aa (%)
2aa, 76%
2ba, 65%
2ca,a 70%
Ph
Ph
Ph
1
2
3
4
5
6
7
glycerol
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
60
41
70
<5
60
12
N
N
N
N
N
N
ethylene glycol
DMF
F3C
Cl
Br
2ea,a 59%
2fa,c 67%
2da,b 56%
1,2-dichlorobenzene Cu(OAc)2
Ph
N
Ph
N
DMF
DMF
DMF
CuBr2
Ph
N
N
N
N
CuI
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
none
4-OH-TEMPOb 65
8c,d DMF
none
<5
31
<5
81
2ga,b,c 78%
Ph
2ha,a,b 60%
2ia,d 55%
9e
10
11f
DMF
DMF
DMF
TEMPO
TEMPO
TEMPO
Ph
N
Ph
N
CF3
N
N
N
Cl
N
Cu(OAc)2
a Reaction conditions: Acetophenone (1a, 0.2 mmol), phenylhydrazine (3a,
0.8 mmol), catalyst (0.05 mol), oxidant (0.8 mmol), acetic acid (0.2 mmol),
solvent (1 mL), 140 °C, 48 h. Yields of 2aa are GC yields using diphenyl ether
internal standard.
2ja, <5%
2ka, <5%
2la, <5%
Scheme 2 Reaction scope with respect to propiophenones. Reagents
and conditions: Phenyl ketone (1 mmol), phenylhydrazine (4 mmol),
Cu(OAc)2 (1 mmol), TEMPO (4 mmol), acetic acid (0.2 mmol), DMF (5
mL), 140 °C, 48 h. Isolated yields are given. a Cu(OAc)2 (0.25 mmol) was
used. b Average yields of two independent runs. c Cu(OAc)2 (1.3 mmol)
was used. d CuBr2 (0.25 mmol) instead of Cu(OAc)2.
b 4-OH-TEMPO = 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxy.
c Air is the sole oxidant.
d Major product is 3-methyl-2-phenyl-1H-indole.
e No acetic acid.
f Cu(OAc)2 (0.2 mmol) was used, yield is isolated yield.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
T. L. Pham et al.
Letter
Synlett
2ia in 55% yield. At this moment, our conditions were limit-
ed to sterically hindered ortho-substituted propiophe-
nones.8
zole 8, followed by another copper/TEMPO co-promoted
oxidation of C–C bond to furnish the pyrazole 2aa. For some
entries, such ene–imine11 and dihydropyrazole intermedi-
ates were detected by GC–MS.12
Notably, if 3′-nitropropiophenone coupled with phenyl-
hydrazine under the reaction conditions, indazole 4a was
isolated in a moderate yield (Scheme 3). Similarly, 3′-nitro-
acetophenone was also a competent substrate, affording the
corresponding indazole 4b in 57% yield. Synthesis of such
biorelated indazoles is rare and often requires the prefunc-
tionalization of carbonyl compounds.9 One should be noted
that Chang and co-workers have reported a relevant iodine-
mediated cyclization of hydrazones to afford fully substitut-
ed indazoles.9c However, the scope was limited to those not
containing -C–H bonds. It was envisaged that under our
reaction conditions, the nitro group plays a role as a direct-
ing group for intramolecular amination,10 after the forma-
tion of imine intermediate, to afford the product.
O
Cu(OAc)2 (1.3 equiv)
TEMPO (4 equiv)
R
N
Ph
N
+
acetic acid (1 equiv)
DMF, 140 °C, 48 h
Ph
R-NHNH2
I
CF3
Cl
N
N
N
N
N
N
Ph
Ph
Ph
2ab,a 47%
2ad, complex mixture
2ac, 71%
F3C
CF3
N
N
N
N
N
Ph
Cu(OAc)2 (25 mol%)
TEMPO (4 equiv)
O
N
N
Ph
Ph
R
R
PhNHNH2 (4 equiv)
acid acetic (1 equiv)
DMF, 140 °C, 48 h
2af, <5%
2ae, <5%
Scheme 4 Scope of arylhydrazines. Reagents and conditions: 3′-Nitro-
propiophenone (1 mmol), arylhydrazine (4 mmol), Cu(OAc)2 (1.3
mmol), TEMPO (4 mmol), acetic acid (1 mmol), DMF (5 mL), 140 °C, 48 h.
Isolated yields are given. a Hydrochloride salt was used.
NO2
NO2
R = Et, 4a, 51%
R = Me, 4b, 57%
Scheme 3 Synthesis of indazoles. Reagents and conditions: 3′-Nitro-
propiophenone or 3′-nitroacetophenone (1 mmol), phenylhydrazine (4
mmol), Cu(OAc)2 (0.25 mmol), TEMPO (4 mmol), acetic acid (1 mmol),
DMF (5 mL), 140 °C, 48 h. Isolated yields are given.
In conclusion, we report a method for the synthesis of
1,3-diarylpyrazoles from propiophenones and arylhydra-
zines. Reactions proceeded in the presence of copper(II) ac-
etate TEMPO oxidant, acetic acid promoter, and DMF sol-
vent. Functionalities such as halogens, methoxy, and triflu-
oromethyl groups were compatible with reaction
conditions. An indazole was isolated if 3-nitropropiophe-
none was used. The method is a promising candidate for the
synthesis of densely substituted pyrazoles from commer-
cial, simple substrates.
We next studied the scope of arylhydrazines. The result
is shown in Scheme 4. A hindered ortho-chloro phenylhy-
drazine coupled with propiophenone to furnish 47% yield
of the pyrazole 2ab. A 71% yield of the pyrazole (2ac) con-
taining trifluoromethyl group was obtained. It should be
noted that the reaction of 4-iodophenylhydrazine gave the
desired product 2ad, albeit in an inseparably complex mix-
ture. Neither a very electron-poor phenylhydrazine (2ae)
nor a substrate derived from heterocycle (2af) was active
under our conditions. Attempts to expand the scope with
respect to arylhydrazine are ongoing.
Ph
Cu(OAc)2
TEMPO
N
N
NHPh
N
–H2O
2aa
3a
1a +
8
A brief mechanism was proposed based on a relevant re-
sult reported by Su and co-workers.1h Given that indazole 4
was obtained if a very electron-poor propiophenone was
used, the coupling of aryl ethyl ketones and arylhydrazines
possibly proceeds via the formation of hydrazones, such as
5, in the presence of acetic acid (Scheme 5). Copper(II)-pro-
moted activation of -C–H bonds6 in 5 followed by a single-
electron transfer between 6 and TEMPO would afford the
enone 7. Running the ‘homocoupling’ of propiophenone 1a
(in the absence of phenylhydrazine 3a) yielded a dimer,
somewhat showing the involvement of intermediate 6 in
the mechanism. The oxidation of C–C bond (5 → 6) is likely
the rate-limiting step, via the formation of 4, and strongly
affected by electronic properties of the substituents. An in-
tramolecular Michael addition would give the dihydropyra-
5
HX
Michael
addition
CuIIX2
H2O
+
N
H
NHPh
CuXLn
N
NHPh
N
CuIX
+
N
N
O
OH
7
TEMPO
NHPh
N
+
N
O
6
TEMPO
Scheme 5 Plausible mechanism
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
T. L. Pham et al.
Letter
Synlett
Funding Information
(4) (a) Schrank, J.; Wu, X.-F.; Neumann, H.; Beller, M. Chem. Eur. J.
2012, 18, 4827. (b) Panda, N.; Jena, A. K. J. Org. Chem. 2012, 77,
9401. (c) Tang, X.; Huang, L.; Yang, J.; Xu, Y.; Wu, W.; Jiang, H.
Chem. Commun. 2014, 50, 14793. (d) Voronin, V. V.; Ledovskaya,
M. S.; Gordeev, E. G.; Rodygin, K. S.; Ananikov, V. P. J. Org. Chem.
2018, 83, 3819. (e) Pünner, F.; Sohtome, Y.; Sodeoka, M. Chem.
Commun. 2016, 52, 14093.
This research is funded by the Ho Chi Minh City University of Tech-
nology – VNU-HCM (grant number T-KTHH-2018-100).
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ty(T-K
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Supporting Information
(5) (a) Xu, Z.-L.; Li, H.-X.; Ren, Z.-G.; Du, W.-Y.; Xu, W.-C.; Lang, J.-P.
Tetrahedron 2011, 67, 5282. (b) Mallia, C. J.; Burton, P. M.;
Smith, A. M. R.; Walter, G. C.; Baxendale, I. R. Beilstein J. Org.
Chem. 2016, 12, 1598.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690835.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(6) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Wei, L.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2013, 155, 16074.
References and Notes
(7) 3-(3-Chlorophenyl)-1-phenyl-1H-pyrazole (2ca)
– Typical
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Chem. Soc. 2011, 133, 14566. (d) Li, H.; Jiang, Q.; Jie, X.; Shang,
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R.; Kuwano, R. Angew. Chem. Int. Ed. 2009, 48, 4543. (h) Jie, X.;
Shang, Y.; Zhang, X.; Su, W. J. Am. Chem. Soc. 2016, 138, 5623.
(i) Shang, Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su, W. Nat.
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Metwally, M. A. Eur. J. Med. Chem. 2010, 45, 3692.
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Procedure
To a 16 mL vial was added 3′-chloropropiophenone (169 mg,
1 mmol), phenylhydrazine (432 mg, 4 mmol), Cu(OAc)2 (46 mg,
0.25 mmol), TEMPO (624 mg, 4 mmol), acetic acid (60 mg,
1 mmol), and DMF (5 mL). The vial was placed into a preheated
oil bath (140 °C) and vigorously stirred for 48 h. The reaction
mixture was cooled to room temperature, quenched with brine
(10 mL), then extracted with EtOAc (3 × 15 mL). Combined
organic phases were dried over Na2SO4, filtered, and concen-
trated. Crude product was purified by flash column chromatog-
raphy (hexanes/EtOAc, 10:1) to obtain 179 mg (70%) of a white
solid. This compound is known.4c
1H NMR (500 MHz, CDCl3):  = 7.90 (d, J = 2.5 Hz, 1 H), 7.86 (t, J =
1.9 Hz, 1 H), 7.71 (tt, J = 7.6, 1.2 Hz, 3 H), 7.45–7.37 (m, 2 H),
7.29 (t, J = 7.8 Hz, 1 H), 7.27–7.21 (m, 2 H), 7.19 (s, 1 H), 6.70 (d,
J = 2.5 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3):  = 151.6,
135.0, 134.7, 129.9, 129.5, 128.2, 128.0, 126.6, 125.9, 123.9,
119.2, 105.2 ppm. One carbon signal could not be located.
(8) Small amounts of dehydrogenation products were observed by
GC–MS analysis.
(9) (a) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552.
(b) Esmaeili-Marandi, F.; Saeedi, M.; Mahdavi, M.; Yavari, I.;
Foroumadi, A.; Shafiee, A. Synlett 2014, 25, 2605. (c) Wei, W.;
Wang, Z.; Yang, X.; Yu, W.; Chang, J. Adv. Synth. Catal. 2017, 359,
3378.
(10) One reviewer recommended the use of 4′-nitropropiophenone;
however, only the starting material was recovered. For NO2-
directed intermolecular amination, see selected example:
Kumar, S.; Rathore, V.; Verma, A.; Prasad, C. D.; Kumar, A.;
Yadav, A.; Jana, S.; Sattar, M.; Meenakshi; Kumar, S. Org. Lett.
2015, 17, 82.
(11) For selected example of intermolecular ene–imine cycloaddi-
tion, see: Li, Z.; Hu, B.; Wu, Y.; Fei, C.; Deng, L. Proc. Natl. Acad.
Sci. U.S.A. 2018, 115, 1730.
(12) Attempts to isolate possible intermediates are ongoing.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D