Chemoselective Synthesis of 5-Alkylamino-1H-pyrazole-4-carbaldehydes by Cesium- and Copper-Mediated Amination

Article abstract of DOI:10.1002/ejoc.201500505

Microwave-assisted synthesis of new 5-alkylamino-pyrazole-4-carbaldehydes was performed efficiently, with yields up to 99 and short reaction times. Nucleophilic substitution of primary alkylamines with activated 5-chloro-1-(2-pyridyl)pyrazole-4-carbaldehyde was mediated by the "cesium effect". The amination of deactivated 1-aryl-5-chloropyrazole-4-carbaldehydes was also assisted by the cesium ion and catalyzed by copper(I). Hereby is described an efficient protocol for the chemoselective synthesis of new 5-alkylaminopyrazole-4-carbaldehydes from 5-chloropyrazole-4-carbaldehydes and primary alkylamines in one step to give products with good to excellent yields and short reaction times. Unexpectedly, under these reaction conditions the corresponding alkylimine formation was not observed.

Full text of DOI:10.1002/ejoc.201500505

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500505
Chemoselective Synthesis of 5-Alkylamino-1H-pyrazole-4-carbaldehydes by
Cesium- and Copper-Mediated Amination
Jessica Orrego-Hernández,[a] Justo Cobo,[b] and Jaime Portilla*[a]
Keywords: Pyrazoles / Cesium / Copper / Chemoselectivity / Amination reactions
Microwave-assisted synthesis of new 5-alkylamino-pyrazole-
4-carbaldehydes was performed efficiently, with yields up to
99% and short reaction times. Nucleophilic substitution of
primary alkylamines with activated 5-chloro-1-(2-pyridyl)-
pyrazole-4-carbaldehyde was mediated by the “cesium ef-
fect”. The amination of deactivated 1-aryl-5-chloropyrazole-
4-carbaldehydes was also assisted by the cesium ion and cat-
alyzed by copper(I).
useful, as it can act as a catalyst in C–N bond formation
in pyrazole rings.[11] Accordingly, and continuing with our
studies toward the development of synthetic methodologies
for the construction of new derivatives of pyrazoles,[4a,4c,12]
we now describe an efficient protocol for the chemoselective
synthesis of new 5-alkylaminopyrazole-4-carbaldehydes
from 5-chloropyrazole-4-carbaldehydes and primary
amines mediated by cesium and copper(I) in good to excel-
lent yields. Unexpectedly, under these reaction conditions
the corresponding imine formation was not observed.
Introduction
Derivatives of 5-aminopyrazole have been found to play
an important role as biologically active compounds.[1] As
such, they are considered building-blocks of high interest
for pharmaceutical agents[2] and agrochemicals.[3] In ad-
dition, 5-aminopyrazoles are important intermediates for
obtaining useful polyheterocycles.[4] Both 5-aminopyrazoles
and 5-aminopyrazole-4-carbaldehydes are key precursors
for the synthesis of structures that have found applications
as antitumor agents[5] and in the treatment of osteoarthri-
tis.[6] Hence, the development of methods for the synthesis
of 5-alkylaminopyrazole-4-carbaldehydes can be seen as an
important research goal in organic chemistry. Typically,
methods for the synthesis of 5-aminopyrazoles focus on re-
actions between acrylonitrile derivatives[4c] or, in some
cases, β-enaminones[7] with structures containing the
hydrazine moiety. In addition, methods for the synthesis of
5-aminopyrazole-4-carbaldehydes are based on reacting 5-
chloropyrazole-4-carbaldehydes with secondary amines,
aromatic amines, or with the N–H group in heterocyclic
compounds.[8] To the best of our knowledge, there is only
one report for the reaction of primary alkylamines with 5-
chloropyrazole-4-carbaldehydes, with electron-withdrawing
groups to favor the reaction.[9]
Results and Discussion
Our initial attempt to synthesize 5-alkylaminopyrazole-
4-carbaldehydes began with cyclohexylamine (2a), freshly
synthesized 5-chloropyrazole-4-carbaldehyde (1a) (see Sup-
porting Information), and sodium hydroxide, in dimethyl-
formamide (DMF) and with a microwave reactor at 160 °C
for 10 min. Results for this initial test generated the desired
product 3a in a 20% yield (Table 1, entry 1). Increasing the
reaction time to 20 min did not increase the yield (Table 1,
entry 2). When dimethyl sulfoxide was used as solvent at
160 °C for 10 min, the yield of 3a decreased instead
(Table 1, entry 3). Likewise, the use of conventional heating
at 150 °C for 12 h in DMF provided the desired product in
a low yield (15%).
The use of potassium hydroxide did not increase the re-
action yield (Table 1, entry 5); these latest conditions are
similar to those recently reported by Reekie et al.,[8c] this
was possibly due to the higher acidity of aniline relative
to that of primary alkylamines. The addition of potassium
carbonate did not favor the formation of product 3a
(Table 1, entry 6). A significant improvement in the yield
of 3a was observed when 1 equiv. of cesium carbonate was
employed with both microwave (98%) and conventional
heating (80%) (Table 1, entries 7–9). It is noteworthy to
mention that a high reaction yield was observed when
It has been reported that cesium salts can act as efficient
mediators in chemoselective N-alkylation of amines. This
phenomenon has been named the “cesium effect” due to
the fact that cesium ions are “naked” in polar aprotic sol-
vents, thus increasing the nucleophilicity of primary
amines.[10] It has also been reported that copper(I) iodide is
[a] Departamento de Química, Universidad de los Andes
Carrera 1 N° 18A- 12, Bogotá, Colombia
E-mail: jportill@uniandes.edu.co
[b] Departamento de Química Orgánica e Inorgánica,
Universidad de Jaén
23071 Jaén, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500505.
5064
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of 5-Alkylamino-1H-pyrazole-4-carbaldehydes
Table 1. Optimization of the reaction conditions for the synthesis
Once the optimal conditions for obtaining 3a were
achieved (Table 1, entry 9), the primary amine was varied
in order to produce a series of 5-alkylaminopyrazole-4-car-
baldehydes; excellent yields starting from 1a were obtained
(Table 2, 3a–e). The success of this reaction can be ex-
plained by the electron-withdrawing nature of the 2-pyridyl
group in 5-chloropyrazole-4-carbaldehyde (1a), which fa-
vors the nucleophilic aromatic substitution reaction.
of 5-alkylaminopyrazole-4-carbaldehyde 3a.[a]
Table 2. Substrate scope of alkylamines for the synthesis of 5-alk-
ylamino-pyrazole-4-carbaldehydes 3a–e under optimized condi-
tions.[a]
Entry
Base
Solvent
Temp.
[°C]
Time
[min]
Yield
[%][f]
1
2
3
4
5
6
7
8
9
NaOH[b]
NaOH[b]
NaOH[b]
NaOH[b]
KOH[b]
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
160[d]
160[d]
160[d]
150[e]
160[d]
160[d]
160[d]
150[e]
150[d]
10
20
10
720
10
10
10
720
10
20
20
15
15
20
0
98
80
98
[b]
K2CO3
[b]
Cs2CO3[b]
Cs2CO3[c]
Cs2CO3
[a] Reaction conditions: 1a (0.45 mmol), 2a (0.56 mmol), solvent
(2 mL). [b] 1 equiv. of base. [c] 0.2 equiv. of base. [d] Run in a mi-
crowave vial (10 mL) sealed and placed in a microwave reactor
(100 W). [e] Conventional heating. [f] Isolated yields.
0.2 equiv. of cesium carbonate was used under microwave
irradiation (Table 1, entry 9). These preliminary results
showed that cesium carbonate and microwave heating play
a crucial role for improving the results. Under these reac-
tion conditions, a high selectivity towards the substitution
on the aromatic ring instead of imine formation is observed.
Surprisingly, the slight excess of amine used in the experi-
mental procedure did not react with the aldehyde. We have
hypothesized that these results can be explained by the ef-
[a] Reaction conditions: 1a (0.45 mmol), 2a–e (0.56 mmol), Cs2CO3
(0.09 mmol), DMF (2 mL). Reaction times are shown in parenthe-
ses.
Subsequently, we investigated the scope of the method in
fect of cesium carbonate in a polar aprotic solvent such as order to obtain 5-alkylamino-1-arylpyrazole-4-carb-
DMF.[9]
aldehydes 3f–l (Table 4) from 1-aryl-5-chloropyrazole-4-
As it has been already established, the cesium ion forms carbaldehydes 1b,c containing either a phenyl or 4-chloro-
complexes with primary amines whose hydrogen atoms are phenyl group on the nitrogen N-1. Unfortunately, the de-
acidic enough to be abstracted by the carbonate ion, lead- sired products 3f–l did not form under these reaction condi-
ing to the respective cesium amide [2a]– Cs+.[10] This ionic tions. These aryl groups do not have the electron-with-
amide is a good nucleophile for aromatic nucleophilic drawing ability that the 2-pyridyl group does, which ex-
substitution at the 5-chloropyrazole-4-carbaldehyde (1a), plains these results. For this reason, finding optimal condi-
which occurs through an addition–elimination sequence tions for the reaction of pyrazoles 1b,c with primary amines
(Scheme 1).
is a remarkable achievement, since they are electron-rich
Scheme 1. Possible reaction mechanism for nucleophilic aromatic substitution of 5-chloropyrazole-4-carbaldehyde (1a) with cyclohex-
ylamine (2a).
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J. Orrego-Hernández, J. Cobo, J. Portilla
SHORT COMMUNICATION
heteroaromatic compounds and generally do not react with Table 4. Substrate scope of alkylamines for the synthesis of 5-alk-
ylamino-pyrazole-4-carbaldehydes 3f–l under optimized condi-
nucleophiles.
tions.[a]
To accomplish our objective, we optimized the reaction
conditions by using primary amine 2a with freshly synthe-
sized 5-chloro-4-formylpyrazole (1b) (see Supporting Infor-
mation). In this latest study, it was found that copper salts
favored the amination reaction and the expected product 3f
was obtained (Table 3, entries 1–12). Copper(I) compounds,
such as CuI, CuBr, and Cu2O, were found to be more ef-
ficient compared to the copper(II) salt Cu(OAc)2. On the
basis of these results, it is possible to say that the catalytic
species in this reaction is the copper(I) ion. Moreover, the
results showed that the employed base also plays an impor-
tant role in the reaction. Better yields were obtained when
cesium carbonate was used instead of potassium carbonate
or sodium carbonate. These results can be explained by the
previously mentioned “cesium effect”.[9] In addition to the
use of copper(I) salts and cesium carbonate, the selection
of the solvent and the type of heating are also key to achiev-
ing an increase in the reaction yield for 3f. We found that
the use of DMF as solvent and microwave-assisted heating
increased the reaction yield (Table 3, entries 4, 8, 12). In
general, the best results were obtained when CuI was used
as catalyst, cesium carbonate as base, DMF as solvent, and
microwave as the heating source (Table 3, entry 4). Once the
optimal conditions were established, various primary
amines (2a–e) were studied. The 5-alkylaminopyrazole-4-
carbaldehydes were obtained from 1b,c in moderate yields
(Table 4, 3f–l).
[a] Reaction conditions: 1b,c (0.45 mmol), 2a–e (0.56 mmol),
Cs2CO3 (0.45 mmol), DMF (2 mL). Temperature and time of reac-
tion are shown in parentheses.
Table 3. Optimization of the reaction conditions for the synthesis
of 5-alkylaminopyrazole-4-carbaldehyde 3f.[a]
ordination of the cesium amide [2a]–Cs+ by transmetalation
with the catalytically active species of copper(I) (Scheme 2).
Once the coordination complex A is formed, oxidative ad-
dition occurs to form the intermediate species of CuIII B.
Subsequently, the amination product 3f is obtained by a
Entry Catalyst
Base
Solvent Temp.
[°C]
Time
[min]
Yield
[%][d]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
Na2CO3 DMF
K2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
140[b]
140[b]
150[c]
140[b]
15
15
720
15
15
15
15
15
15
15
15
15
0[e]
13[e]
27[e]
50[e]
22[e]
15[e]
0[e]
Cs2CO3 DMSO 140[b]
Cs2CO3 toluene 140[b]
Cu(OAc)2 K2CO3 DMF
Cu(OAc)2 Cs2CO3 DMF
CuBr
CuBr
Cu2O/Cu K2CO3 DMF
Cu2O/Cu Cs2CO3 DMF
140[b]
140[b]
140[b]
140[b]
140[b]
140[b]
18[e]
30[e]
38[e]
12[f]
48[f]
9
K2CO3 DMF
Cs2CO3 DMF
10
11
12
[a] Reaction conditions: 1b (0.45 mmol), 2a (0.56 mmol), 1 equiv.
of base, solvent (2 mL). [b] Run in a microwave vial (10 mL) sealed
and placed in a microwave reactor (100 W). [c] Conventional heat-
ing. [d] Isolated yields. [e] 10 mol-% catalyst loading. [f] 10 mol-%
Cu2O and 20 mol-% Cu.
A possible reaction mechanism for the formation of 5-
Scheme 2. Proposed reaction mechanism for catalytic amination of
alkylaminopyrazol-4-carbaldehydes 3f–l begins with the co- 5-chloropyrazole-4-carbaldehyde (1b).
5066 Eur. J. Org. Chem. 2015, 5064–5069
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Synthesis of 5-Alkylamino-1H-pyrazole-4-carbaldehydes
reductive elimination followed by a regeneration of the hydropyrazolo[3,4-b]quinolines and their analogues in one
active CuI catalyst (Scheme 2).[13] It is possible to hypothe- step, which is vastly preferable over other reported
size that copper chloride does not perform well as catalyst multistep methods.[15]
due to its higher stability and lower dissociation. It was also
noted that increasing the amount of CuI in the reaction tandem reactions that begins with the formation of the sub-
mixture did not lead to higher yield for 3f. stituted product 3f, which tautomerizes to produce C. Sub-
The formation of 5 can be explained by a sequence of
Searching for better reaction conditions for the forma- sequently, a 1,5-sigmatropic rearrangement of hydrogen oc-
tion of 5-alkylaminopyrazoles 3f–l, we employed ethanol curs to form alcohol D. Intermediate D undergoes imine/
as the solvent as well as higher temperatures. These latest enamine tautomerization to form tautomer F. Then, tauto-
experiments gave results that support our previous state- mer F forms the dihydropyridine ring G, which aromatizes
ments on the role of the solvent (Scheme 3). For example, to the pyridine ring (compound 5 in Scheme 4). In this reac-
by using 5-chloropyrazole-4-carbaldehyde (1b) in the pres- tion, temperature plays an important role, since under these
ence of two equivalents of cyclohexylamine 2a, an equiva- reaction conditions the sigmatropic rearrangement and tau-
lent of cesium carbonate, ethanol as solvent, and microwave tomerization are favored, which leads to the formation of
heating, (Z)-4-[(cyclohexylamino)methylene]-1-phenyl-1H- compound 5.
pyrazolone (4) was isolated in 65% yield. Compound 4
The reactions of 5-chloropyrazole-4-carbaldehydes 1a–c
comes from the formation of the imine and subsequent sub- with aniline as primary arylamine were examined under the
stitution of the chlorine atom with a hydroxyl group from optimized conditions. The results are shown in Table 5. The
the reaction medium. This result experimentally supports product of substitution, 6a, was produced with good yield,
our hypothesis that the solvent plays an important role in confirming the influence of the electron-withdrawing nature
the chemoselectivity of the reaction.
of the 2-pyridyl group in the substitution reaction of 5-
Employing 5-chloropyrazole-4-carbaldehyde (1b) in the chloropyrazole-4-carbaldehyde (1a). By contrast, the yields
presence of two equivalents of cyclohexylamine (2a), one were low when 1-aryl-5-chloropyrazole-4-carbaldehydes
equivalent of cesium carbonate, DMF as solvent, and mi- 1b,c were used. For instance, compounds 6b and 6c were
crowave heating at 250 °C afforded 3-methyl-1-phenyl-1H- formed in 16% and 20% yield, respectively. Furthermore,
pyrazolo[3,4-b]quinoline (5) in 80% yield (Scheme 3). Al- these reactions occur in competition with the formation of
though compound 5 has previously been reported in the the corresponding imines 7b,c, which were also isolated
literature,[14] these new reaction conditions can have a syn- with low yields. These results can be explained by the low
thetic advantage, since it is possible to obtain tetra- electron-withdrawing ability of the corresponding aryl
Scheme 3. Synthesis of products 4 and 5. Reaction conditions: 1b (0.45 mmol), 2a (0.90 mmol), Cs2CO3 (0.45 mmol). i: Ethanol (2 mL),
160 °C, 150 W, 30 min; ii: DMF (2 mL), 250 °C, 190 W, 30 min.
Scheme 4. Proposed mechanism to prepare 3-methyl-1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline (5).
Eur. J. Org. Chem. 2015, 5064–5069
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J. Orrego-Hernández, J. Cobo, J. Portilla
SHORT COMMUNICATION
groups on the pyrazole ring. In this case, imine formation
was observed probably as a result of the stabilization of the
conjugate product.
Experimental Section
General Procedure for the Synthesis of 5-Alkylamino-1-(pyridin-2-
yl)-1H-pyrazole-4-carbaldehydes 3a–e: A mixture of pyrazole 1a
(0.100 g, 0.45 mmol, 1 equiv.), the appropriate amine (0.56 mmol,
1.3 equiv.), cesium carbonate (0.029 g, 20 mol-%, 0.2 equiv.), and
DMF (2 mL) was placed in a reaction tube of a CEM DiscoverTM
instrument containing a magnetic stirring bar. The tube was sealed
with a plastic microwave septum and was irradiated at 160 °C for
10–25 min at 100 W. The resulting crude product was partitioned
between dichloromethane and water. The organic layer was washed
with water, then brine, and dried with anhydrous sodium sulfate.
Subsequently, the solvent was removed under vacuum, and the resi-
due was purified by silica gel flash chromatography (DCM) to af-
ford compounds 3a–e.
Table 5. Results obtained for the reaction of 5-chloro-1-arylpyr-
azole-4-carbaldehydes 1a–c with aniline.
General Procedure for the Synthesis of 5-Alkylamino-1-aryl-1H-pyr-
azole-4-carbaldehydes 3f–l: A mixture of pyrazole 1b,c (0.45 mmol,
1 equiv.), the appropriate amine (0.56 mmol, 1.3 equiv.), cesium
carbonate (0.147 g, 0.45 mmol, 1 equiv.), copper(I) iodide
(0.0086 g, 10 mol-%, 0.1 equiv.), and DMF (2 mL) was placed in a
reaction tube of a CEM DiscoverTM instrument containing a mag-
netic stirring bar. The tube was sealed with a plastic microwave
septum, and it was then irradiated at 80–140 °C for 15–35 min at
100 W. The resulting crude product was partitioned between
dichloromethane and water. The organic layer was washed with
water, then brine, and dried with anhydrous sodium sulfate. Sub-
sequently, the solvent was removed under vacuum, and the residue
was purified by silica gel column chromatography using DCM/Ac-
OEt (50:1 v/v) as eluent to afford compounds 3f–l.
Synthesis of (Z)-4-[(Cyclohexylamino)methylene]-3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one (4):[4] A mixture of pyrazole 1b (0.0992 g,
0.45 mmol, 1 equiv.), cyclohexylamine 2a (0.0892 g, 0.90 mmol,
2 equiv.), cesium carbonate (0.147 g, 0.45 mmol, 1 equiv.), and
2 mL of ethanol was placed in a reaction tube of a CEM Dis-
coverTM instrument containing a magnetic stirring bar. The tube
was sealed with a plastic microwave septum and was irradiated at
160 °C for 30 min at 150 W. The resulting crude product was con-
centrated in vacuo, and the residue was purified by silica gel col-
umn chromatography using DCM/AcOEt (50:1 v/v) as eluent to
afford compound 4 as white crystals.
[a] Reaction conditions: 1a (0.45 mmol), aniline (0.59 mmol),
Cs2CO3 (0.09 mmol), DMF (2 mL), 160 °C, 20 min. [b] 1b,c
(0.45 mmol), aniline (0.59 mmol), CuI (10 mol-%), Cs2CO3
(0.45 mmol), DMF (2 mL), 140 °C, 20 min.
Synthesis of 3-Methyl-1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-
b]quinoline (5): A mixture of pyrazole 1b (0.0992 g, 0.45 mmol,
1 equiv.), cyclohexylamine 2a (0.0892 g, 0.90 mmol, 2 equiv.),
cesium carbonate (0.147 g, 0.45 mmol, 1 equiv.), and DMF (2 mL)
was placed in a reaction tube of a CEM DiscoverTM instrument
containing a magnetic stirring bar. The tube was sealed with a plas-
tic microwave septum and was irradiated at 250 °C for 30 min at
190 W. The resulting crude product was partitioned between
dichloromethane and water. The organic layer was washed with
water, then brine, and dried with anhydrous sodium sulfate. Sub-
sequently, the solvent was removed under vacuum, and the residue
was purified by silica gel column chromatography (DCM) to afford
compound 5 as pale-yellow crystals.
The structures of new 5-alkylamino-1H-pyrazole-4-carb-
aldehydes 3a–l and compounds 4–7 were appropriately es-
tablished by the usual spectroscopic methods. Single-crystal
X-ray diffraction analysis of compounds 3a and 4 were used
to corroborate the postulated structures.[16]
Conclusions
In conclusion, we have reported a novel and efficient
method for the chemoselective synthesis of new 5-alkyl-
aminopyrazole-4-carbaldehydes mediated by cesium and
copper(I). Primary alkylamines and 5-chloropyrazole-4-
carbaldehydes were used as starting materials in a suitable
solvent and at appropriate temperatures. The chemoselec-
tive formation of C–N bonds was achieved in one step to
give products with good to excellent yields and short reac-
tion times. In addition, two unexpected products (4 and 5)
were also isolated; the formation of 5 provides a new route
for the easy access to new pyrazolo[3,4-b]pyridines.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedure and spectroscopic data for all
1
products. H NMR and 13C NMR spectra and mass spectra (IE)
of all compounds; HPLC–HRMS analysis data for compounds 3a–
l, 4, 5, 6a–c, and 7a,b.
Acknowledgments
The authors are grateful to the Departamento de Química and Fac-
ultad de Ciencias of Universidad de los Andes, the University of
5068
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Synthesis of 5-Alkylamino-1H-pyrazole-4-carbaldehydes
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Received: April 21, 2015
Published Online: July 8, 2015
Eur. J. Org. Chem. 2015, 5064–5069
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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