Palladium-catalyzed amino group arylation of 1,3-disubstituted 1H-pyrazol-5-amine based on Buchwald–Hartwig reaction

Article abstract of DOI:10.1007/s10593-021-02961-z

[Figure not available: see fulltext.] An efficient Pd-catalyzed C–N bond formation for the synthesis of different pyrazole derivatives using XPhos as a ligand and KOH as a base is presented. The developed procedure can be successfully applied for the synthesis of 5-N-aryl-1,3-disubstituted 1H-pyrazol-5-amines. Contrary to previously described procedures, this one proceeds in one step utilizing commercially available aminopyrazoles and aryl halides. Thus, a series of 5-N-aryl-1,3-disubstituted 1H-pyrazol-5-amines were obtained with satisfactory yields under optimized reaction conditions.

Full text of DOI:10.1007/s10593-021-02961-z

DOI 10.1007/s10593-021-02961-z
Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
Palladium-catalyzed amino group arylation
of 1,3-disubstituted 1H-pyrazol-5-amine
based on Buchwald–Hartwig reaction
Mateusz Kucharek1*, Andrzej Danel2
1 Department of Biotechnology and General Technology of Food,
Faculty of Food Technology, University of Agriculture in Krakow,
122 Balicka St., Krakow 30-149, Poland; e-mail: mateusz.kucharek@urk.edu.pl
2 Faculty of Materials Engineering and Physics, Cracow University of Technology,
1 Podchorążych St., Krakow 30-048, Poland; e-mail: rrdanela@cyf-kr.edu.pl
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted February 12, 2021
2021, 57(6), 633–639
Accepted after revision March 24, 2021
An efficient Pd-catalyzed C–N bond formation for the synthesis of different pyrazole derivatives using XPhos as a ligand and KOH as a
base is presented. The developed procedure can be successfully applied for the synthesis of 5-N-aryl-1,3-disubstituted 1H-pyrazol-
5-amines. Contrary to previously described procedures, this one proceeds in one step utilizing commercially available aminopyrazoles
and aryl halides. Thus, a series of 5-N-aryl-1,3-disubstituted 1H-pyrazol-5-amines were obtained with satisfactory yields under optimized
reaction conditions.
Keywords: 5-N-arylaminopyrazoles, palladium catalyst, arylation, cross coupling.
Nitrogen-containing heterocycles probably are the largest
and most studied family of organic compounds. Among
them, pyrazole derivatives, e.g., 5-N-arylaminopyrazoles,
have attracted our interest due to their application as key
constituents in the synthesis of luminophores to obtain
organic light emitting diodes (OLEDs). One of the known
method for the synthesis of 5-N-arylaminopyrazoles
includes a reaction of β-oxothioanilides with arylhydrazines
developed by Pocar and coworkers.1 Lately, Dodd and
Martinez published another methodology for the synthesis
of substituted 5-aryl/alkylaminopyrazoles where β-keto-
anilides reacted with phenyl/benzylhydrazine in the
presence of Lawesson's reagent.2 Bernhammer and Huynh
used 1,3-diphenylpyrazol-5-one, aniline hydrochlorides,
and phosphorus pentoxide under microwave irradiation to
obtain 1,3-diphenyl-5-phenylaminopyrazoles.3
and K2CO3 resulted in the formation of (pyrazol-5-yl)-
aminobenzoic acid, which was subsequently transformed
into 4-hydroxy-1H-pyrazolo[3,4-b]quinoline – a starting
material for potential antimalarial compounds.8 Moreover,
the synthesis of 1,3-diphenyl-5-(N-phenylamino)pyrazole
using 5-amino-1,3-diphenylpyrazole and aryl halides as
starting materials in the presence of 1,10-phenanthroline
and catalytic amount of CuI was published.9 Buchwald and
others have developed a series of catalysts used for effi-
cient arylation of some aminoheterocycles such as 2-amino-
benzimidazoles, aminopyridines, aminodiazines, amino-
triazines, etc.10–15 It should be mentioned that the same
catalysts can be used for the arylation of aminopyrazoles,
although this type of reaction was relatively little studied.
Patel and coworkers synthesized a series of 3-amino-
pyrazole derivatives in the search of potential brain
penetrant inhibitors using Pd2(dba)3–Xantphos system with
the product yields varied within 7–66%.16 Buchwald and
Ueda applied the same protocol for arylation of some
3-aminopyrazole and 3-aminoindazole derivatives.10 The
Recently, many synthetic procedures employing Cu- and
Pd-mediated C–N bond formation have been published.4–7
Thus, the reaction of o-iodobenzoic acid and 3-amino-
5-methyl-2-phenylpyrazole in the presence of Cu catalyst
0009-3122/21/57(6)-0633©2021 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
Table 1. Screening of ligands for the synthesis of compound 1a
reaction was carried out in the presence of Pd2(dba)3–
t-BuBrettPhos system. The yields of the obtained deriva-
tives ranged from 80 to 92%. Some pyrazole derivatives as
modulators of the 5-HT2A serotonin receptors were
synthesized employing Pd2(dba)3–BINAP catalyzed coupling
of 3-amino-2,5-dimetylpyrazole with various substituted
aryl bromides or arylboronic acids.17
The purpose of our research is the synthesis of 5-N-aryl-
aminopyrazoles as valuable precursors of 1H-pyrazolo-
[3,4-b]quinolines – potential OLED luminophores or
fluorescence sensors.18–20 However, there are not many
examples of the synthesis of this type of compounds in the
literature. Recently the methodology for the synthesis of
5-(o-nitrophenyl)amino-1,3-disubstituted pyrazole deriva-
tives as precursors of 1H-pyrazolo[3,4-b]quinoxalines
was described.21 Thus, commercially available 5-amino-
pyrazoles under Pd2(dba)3–BINAP catalysis undergo
arylation reaction with 5-substituted 2-iodonitrobenzenes.21
Several other examples of the arylation of 5-amino-
pyrazoles found in the literature were based on the
procedures developed by Buchwald. Such an example is
the synthesis of 1,3-dimethyl-5-(3-nitrophenyl)amino-
pyrazole which was obtained by the reaction of 3-chloro-
nitrobenzene with 5-amino-1,3-dimethylpyrazole in the
presence of Pd(0) and biarylphosphine ligand (BrettPhos)
in 97% yield.22 Mitchell and coworkers presented an
effective synthesis of 5-N-arylaminopyrazole derivative as
a potential inhibitor of the Janus kinase A2. The reaction
was carried out in the presence of Pd2(dba)3–Xantphos
system with the yield of 79%.23
Entry
Ligand
Yield of compound 1a, %
1
2
3
4
5
6
BINAP
P(Tol)3
49
Not observed
Not observed
Traces
DavePhos
CyJohnPhos
JohnPhos
XPhos
71
79
model reaction conditions: 1,3-diphenyl-1H-pyrazol-5-amine
(1 equiv), aryl halide (1.1 equiv), Pd2(dba)3 (1 mol %), and
KOH (1 equiv) (Table 2). Product 1a was formed in
reaction with iodobenzene in the presence of XPhos with
79% yield (Table 2, entry 3), however in the presence of
JohnPhos product 1a was not obtained (Table 2, entry 5).
Coupling reaction conditions were ineffective in the
presence of chlorobenzene for both ligands (Table 2,
entries 2, 4). Based on the obtained results, XPhos was
selected as a more versatile ligand for this transformation.
Later on, the influence of the base on the coupling
reaction was investigated. Model reaction was carried out
under the standard conditions in the presence of different
inorganic bases, and product 1a was isolated by column
chromatography on silica gel. Base screening results are
presented in Table 3. In the reaction with KOH and K2CO3,
product 1a formed with satisfactory yields of 79 and 77%,
respectively (Table 3, entries 1, 2). In the case of K3PO4
(Table 3, entry 3) the product was obtained with 68% yield.
It is worth to mention that in the reaction using t-BuOK
In the present study, we investigated arylation reaction
of various 1,3-disubstituted 5-aminopyrazoles with available
para-substituted aryl halides catalyzed by Pd2(dba)3 and
phosphine ligand XPhos. The ortho- and meta-substituted
aryl halide derivatives will be tested during our further
investigations.
As the first step of our investigation, the conditions
described before17 were modified and applied to the model
reaction of bromobenzene and 1,3-diphenyl-1H-pyrazol-
5-amine. Initially, different organic phosphine ligands in
presence of Pd2(dba)3 and KOH as a base were tested in
order to optimize the conditions of the process. The results
are summarized in Table 1. In the presence of BINAP as a
ligand, product 1a was obtained with 49% yield (Table 1,
entry 1), moreover some byproducts caused difficulties
during purification. The model reaction was also proceeded
under modified conditions of Buchwald and coworkers.24
Thus, in presence of P(Tol)3 and DavePhos the formation
of the desired product 1a was not observed (Table 1,
entries 2, 3, respectively). Similarly, in the presence of
CyJohnPhos ligand only traces of product 1a were
observed by TLC (Table 1, entry 4). Higher conversion
was obtained in the reactions with JohnPhos and XPhos,
resulting in 71 and 79% yield of compound 1a, respec-
tively (Table 1, entries 5 and 6). Based on preliminary
results, JohnPhos and XPhos were selected for the further
optimization of the Pd-catalyzed reaction.
Table 2. Screening of aryl halides for the synthesis
of compound 1a
Entry
Ligand
XPhos
Aryl halide
PhBr
PhCl
Yield of compound 1a, %
1
2
3
4
5
79
Traces
XPhos
XPhos
PhI
79
JohnPhos
JohnPhos
PhCl
Not observed
Traces
PhI
Table 3. Screening of inorganic bases for the synthesis
of compound 1a
Entry
Base
Mp of compound 1a, °C Yield of compound 1a, %
1
2
3
4
KOH
K2CO3
K3PO4
t-BuOK
155
79
154–155
152–153
77
68
With two effective ligands in hand, XPhos and
JohnPhos, chloro- and iodobenzenes were tested under the
Traces, not isolated
634

Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
Table 4. Optimization of the ligand, catalyst, and base amount
for the synthesis of compound 1a
(Table 3, entry 4) product 1a was identified by TLC, but
purification by column chromatography was unsuccessful.
Finally, the influence of ligand, catalyst, and base
amount on the yield of compound 1a was investigated
(Table 4). The reduction of the ligand amount from 5 mol % to
3 and to 1 mol % resulted in decrease of the formation of
compound 1a to 59 and 50%, respectively (Table 4, entries 2,
3). Application of 5 mol % of Pd2(dba)3 instead of 1 mol %
did not influence the reaction yield (Table 4, entry 4)
comparing to the entry 3, where both catalyst and ligand
were used in amount of 1 mol % (Table 4). However, the
increase of catalyst amount up to 5 mol % resulted in the
formation of side products, which sophisticated the
isolation of pure product 1a (Table 4, entry 5). The same
effect was observed changing base amount from 1 to 3 and
to 5 equivalents (Table 4, entries 6, 7).
Taking into account experimental results, optimized
reaction conditions for the synthesis of substituted
aminopyrazoles were applied: XPhos (5 mol %), Pd2(dba)3
(1 mol %), KOH (1 equiv). Other reaction factors including
temperature, solvent, and reaction time were selected
according to the previously described procedure.24 Based
on the optimized reaction conditions, the synthesis of a
Pd2(dba)3,
mol %
XPhos,
mol %
KOH,
equiv
Entry
Yield of compound 1a, %
1
2
3
4
1
1
1
5
5
3
1
5
1
1
1
1
79
59
50
50
Identified with TLC,
not isolated
Identified with TLC,
not isolated
Identified with TLC,
not isolated
5
6
7
5
1
1
1
5
5
1
3
5
series of pyrazole derivatives 1a–v to prove the potency of
developed synthetic methodology was realized (Table 5).
In most cases, the product was obtained with satisfactory
yields from 53 to over 90%. The lowest yield (40%) was
obtained in the case of compound 1d which might be
explained by instability and possible decomposition of pro-
duct during purification process. Moreover, products with
p-OMe substituent 1c,l,p were found to be unstable on storage.
Table 5. Yields of 1,3-disubstituted N-aryl-1H-pyrazol-5-amines 1a–v
Aryl halide
Product
Yield, %
Aryl halide
Product
Yield, %
79
53
Ph
Ph
N
64
78
62
74
Br
40
60
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Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
Table 5 (continued)
Aryl halide
Product
Yield, %
77
Aryl halide
Product
Yield, %
88
Me
N
O2N
58
61
87
67
N
N
H
Ph
1q
Ph
N
Me
84
77
72
84
N
N
H
1s
Me
60
56
53
92
In case of R1 = NO2, optimized conditions were slightly
modified and the use of more polar solvent mixture such as
t-BuOH–H2O, 1:1 allowed to obtain product 1i with 77%
yield instead of 30% in PhMe/t-BuOH mixture. The
solvent system t-BuOH–H2O, 1:1 was also used in the
synthesis of all derivatives 1i,q,t containing NO2 group.
In conclusion, an efficient arylation method of disubsti-
tuted 1H-pyrazol-5-amines was developed using a protocol
based on the Buchwald–Hartwig methodology. The para-
substituted aryl halides and 1,3-disubstituted 1H-pyrazol-
5-amines were used as the substrates to obtain a series of
5-N-substituted 1H-pyrazol-5-amines with satisfactory
yields. The complex of XPhos and Pd2(dba)3 exhibited high
activity as the catalytic system in this transformation. The
developed one-step procedure requires less time, energy
and produces higher yields than previously reported
methods.
Experimental
1H and 13C NMR spectra were recorded on a Bruker
Avance III 400 MHz spectrometer (400 and 100 MHz,
respectively) in CDCl3 for compounds 1a,j–t and on a
Bruker Avance III 600 MHz spectrometer (600 and 150 MHz,
respectively) in CDCl3 for compounds 1b–i,u,v, using
residual CDCl3 signals or TMS as internal standard.
Elemental analyses were performed using a CHNS Vario
MICRO Cube analyzer combined with an electronic micro-
balance. Melting points were determined on a MEL-TEMP II
636

Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
apparatus. TLC was accomplished on 0.2 mm precoated
(3H, m, H Ar); 7.33–7.29 (1H, m, H Ar); 7.01 (2H, d,
J = 8.9, H Ar); 6.86 (2H, d, J = 8.9, H Ar); 6.32 (1H, s,
H Ar); 5.44 (1H, s, NH); 3.79 (3H, s, CH3).13C NMR
spectrum, δ, ppm: 154.9; 151.5; 144.1; 138.5; 135.9; 133.3;
129.5; 128.5; 127.9; 127.7; 125.6; 124.5; 119.1; 114.8;
91.0; 55.6. Found, %: C 77.25; H 5.44; N 12.53.
C22H19N3O. Calculated, %: C 77.40; H 5.61; N 12.31.
N-(4-Phenoxyphenyl)-1,3-diphenyl-1H-pyrazol-5-amine
plates of silica gel on TLC Al foils with fluorescence
indicator 254 nm purchased in Sigma Aldrich.
Visualization was made with a UV lamp Spectroline model
ENF-260C/FE (254 nm). Column chromatography was
carried out using 70–230 mesh ASTM silica gel purchased
in Merck KGaA.
Chemicals racemic 2,2'-bis(diphenylphosphino)-1,1'-bi-
naphthalene (97%), (2-biphenyl)di-tert-butylphosphine (97%),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (97%),
and 2-(dicyclohexylphosphino)biphenyl (97%) were purchased
from Sigma-Aldrich and used without additional purifi-
cation. Tri(o-tolyl)phosphine (97%) was purchased from
Merck-Schuchardt OHG and 2-dicyclohexylphosphino-
2'-(N,N-dimethylamino)biphenyl (98%) from Alfa Aesar.
Synthesis of 1,3-disubstituted N-aryl-1H-pyrazol-
5-amines 1a–v (General method). 1,3-Disubstituted
1H-pyrazol-5-amine (1 mmol) was dissolved in degassed
PhMe–t-BuOH, 5:1 mixture (5 ml) (t-BuOH–H2O, 1:1 for
compounds 1i,m,q,t) in Schlenck tube under Ar atmosphere.
Aryl halide (1.1 mmol) was added to the reaction mixture
followed by the addition of XPhos (5 mol %), Pd2(dba)3
(1 mol %), and KOH (1 mmol). The reaction mixture was
heated at 90°C for 24 h, cooled to room temperature, then
solids were filtrated off and the filtrate was evaporated. The
residue was purified by column chromatography on silica
gel (Al2O3 for compound 1v), eluent PhMe (for compounds
1a–d,f–i,k,m,n,r,s,u,v), CH2Cl2 (for compound 1e), or gradient
mixture of PhMe–EtOAc (for compounds 1j,l,o–q,t).
Products 1a,b,f,g,k,o,r,u were additionally recrystallized
from petroleum ether – EtOAc mixture.
1
(1d). Yield 162 mg (40%), light-red waxy solid. H NMR
spectrum, δ, ppm (J, Hz): 7.91–7.85 (2H, m, H Ar); 7.69–
7.64 (2H, m, H Ar); 7.50 (2H, t, J = 7.9, H Ar); 7.44–7.37
(3H, m, H Ar); 7.35–7.32 (3H, m, H Ar); 7.08 (1H, tt, J = 7.5,
J = 1.0, H Ar); 7.04–6.97 (6H, m, H Ar); 6.46 (1H, s,
H Ar); 5.57 (1H, s, NH). 13C NMR spectrum, δ, ppm:
158.1; 151.6; 151.1; 142.9; 138.7; 138.5; 133.3; 129.7;
129.5; 128.6; 128.1; 127.8; 125.6; 124.5; 122.7; 120.7;
117.9 (2C); 92.5. Found, %: C 80.45; H 5.29; N 10.45.
C27H21N3O. Calculated, %: C 80.37; H 5.25; N 10.41.
N'-(1,3-Diphenyl-1H-pyrazol-5-yl)-N,N-dimethylbenzene-
1,4-diamine (1e). Yield 215 mg (53%), yellow powder,
1
mp 99–103°C. H NMR spectrum, δ, ppm (J, Hz): 7.87–
7.81 (2H, m, H Ar); 7.71–7.62 (2H, m, H Ar); 7.53–7.48
(2H, m, H Ar); 7.41–7.35 (3H, m, H Ar); 7.33–7.28 (1H,
m, H Ar); 7.03 (2H, d, J = 8.5, H Ar); 6.77 (2H, d, J = 8.0,
H Ar); 6.26 (1H, s, H Ar); 5.43 (1H, s, NH); 2.93 (6H, s,
2CH3). 13C NMR spectrum, δ, ppm: 151.5; 145.1; 138.6;
133.5; 132.8; 129.5; 128.5; 127.8; 127.5; 125.6; 124.5;
120.1; 114.2; 89.8; 41.3. Found, %: C 77.98; H 6.28;
N 15.74. C23H22N4. Calculated, %: C 77.94; H 6.26; N 15.81.
N'-(1,3-Diphenyl-1H-pyrazol-5-yl)-N,N-diphenylbenzene-
1,4-diamine (1f). Yield 294 mg (62%), yellow powder,
1
N,1,3-Triphenyl-1H-pyrazol-5-amine (1a). Yield 245 mg
(79%), oil was crystallized upon standing in a freezer to
mp 157–158°C. H NMR spectrum, δ, ppm (J, Hz): 7.91–
7.84 (2H, m, H Ar); 7.69–7.64 (2H, m, H Ar); 7.55–7.47
(2H, m, H Ar); 7.45–7.37 (3H, m, H Ar); 7.36–7.30 (1H,
m, H Ar); 7.28–7.21 (4H, m, H Ar); 7.12–7.04 (6H, m,
H Ar); 7.02–6.92 (4H, m, H Ar); 6.49 (1H, s, H Ar); 5.57
(1H, s, NH). 13C NMR spectrum, δ, ppm: 151.5; 148.0;
142.7; 141.5; 138.5; 138.4; 133.3; 129.5; 129.1; 128.6;
128.0; 127.7; 126.7; 125.6; 124.5; 123.2; 122.1; 117.5;
92.2. Found, %: C 82.91; H 5.52; N 11.57. C33H26N4.
Calculated, %: C 82.82; H 5.48; N 11.71.
1
afford a light-yellow crystals, mp 152–155°C. H NMR
spectrum, δ, ppm (J, Hz): 7.91–7.86 (2H, m, H Ar); 7.68–
7.62 (2H, m, H Ar); 7.49 (2H, t, J = 7.8, H Ar); 7.41 (3H,
dd, J = 16.0, J = 8.0, H Ar); 7.36–7.32 (2H, m, H Ar); 7.29
(2H, dd, J = 8.3, J = 7.6, H Ar); 7.01 (1H, d, J = 7.7, H Ar);
6.96 (1H, t, J = 7.4, H Ar); 6.53 (1H, s, H Ar); 5.56 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 151.5; 142.9; 142.1;
138.4; 133.2; 129.5; 129.4; 128.5; 128.0; 127.7; 125.6;
124.4; 121.0; 115.9; 93.6. Found, %: C 81.06; H 5.54; N 13.40.
C21H17N3. Calculated, %: C 81.00; H 5.50; N 13.50.
N-[(1,1'-Biphenyl)-4-yl]-1,3-diphenyl-1H-pyrazol-5-amine
1
(1g). Yield 286 mg (74%), white solid, mp 177°C. H NMR
N-(4-Methylphenyl)-1,3-diphenyl-1H-pyrazol-5-amine
(1b). Yield 208 mg (64%), white powder, mp 78–79°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.89–7.82 (2H, m,
H Ar); 7.66–7.62 (2H, m, H Ar); 7.47 (2H, t, J = 7.9,
H Ar); 7.40 (2H, t, J = 7.6, H Ar); 7.36 (1H, t, J = 7.5,
H Ar ); 7.31 (1H, t, J = 7.4, H Ar); 7.09 (2H, d, J = 8.1,
H Ar); 6.92 (2H, d, J = 8.4, H Ar); 6.44 (1H, s, H Ar); 5.48
(1H, s, NH); 2.30 (3H, s, CH3). 13C NMR spectrum,
δ, ppm: 151.5; 142.9; 140.3; 138.5; 133.3; 130.8; 130.0;
129.5; 128.6; 127.9; 127.6; 125.6; 124.5; 116.5; 92.6; 20.6.
Found, %: C 81.28; H 5.94; N 12.78. C22H19N3. Calculated,
%: C 81.20; H 5.89; N 12.91.
spectrum, δ, ppm (J, Hz): 7.92–7.89 (2H, m, H Ar); 7.69–
7.65 (2H, m, H Ar); 7.59–7.57 (2H, m, H Ar); 7.56–7.53
(2H, m, H Ar); 7.52–7.48 (2H, m, H Ar); 7.46–7.41 (4H,
m, H Ar); 7.39 (1H, t, J = 7.5, H Ar); 7.37–7.30 (2H, m,
H Ar); 7.10–7.05 (2H, m, H Ar); 6.58 (1H, s, H Ar); 5.64
(1H, s, NH). 13C NMR spectrum, δ, ppm: 151.5; 142.3;
141.9; 140.6; 138.4; 134.0; 133.2; 129.5; 128.8; 128.6;
128.2; 128.0; 127.8; 126.7; 126.6; 125.6; 124.5; 116.2;
93.9. Found, %: C 83.75; H 5.48; N 10.77. C27H21N3.
Calculated, %: C 83.69; H 5.46; N 10.84.
N-(4-tert-Butylphenyl)-1,3-diphenyl-1H-pyrazol-5-amine
(1h). Yield 222 mg (60%), white solid, mp 142–143°C.
1H NMR spectrum, δ, ppm: 7.95–7.80 (2H, m, H Ar); 7.73–
7.59 (2H, m, H Ar); 7.54–7.45 (2H, m, H Ar); 7.44–7.36
(3H, m, H Ar); 7.35–7.31 (3H, m, H Ar); 7.01–6.97 (2H,
m, H Ar); 6.50 (1H, s, H Ar); 5.53 (1H, s, NH); 1.33 (9H,
N-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazol-5-amine
1
(1c). Yield 267 mg (78%), yellow waxy solid. H NMR
spectrum, δ, ppm (J, Hz): 7.86–7.83 (2H, m, H Ar); 7.68–
7.62 (2H, m, H Ar); 7.49 (2H, t, J = 7.9, H Ar); 7.41–7.35
637

Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
s, C(CH3)3). 13C NMR spectrum, δ, ppm: 151.5; 144.2;
H 6.10; N 16.72. C16H15N3. Calculated, %: C 77.08;
142.8; 140.1; 138.5; 133.3; 129.5; 128.5; 127.9; 127.7;
126.3; 125.6; 124.5; 116.1; 92.4; 34.2; 31.4. Found, %:
C 81.77; H 6.89; N 11.34. C25H25N3. Calculated, %:
C 81.71; H 6.86; N 11.43.
H 6.06, N 16.85.
3-Methyl-1-phenyl-N-(p-tolyl)-1H-pyrazol-5-amine (1o).
Yield 148 mg (56%), light-brown powder, mp 106–107°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.58–7.50 (2H, m,
H Ar); 7.44 (2H, t, J = 7.8, H Ar); 7.35–7.29 (1H, m,
H Ar); 7.07 (2H, d, J = 8.2, H Ar); 6.90–6.83 (2H, m,
H Ar); 5.94 (1H, s, H Ar); 5.45 (1H, s, NH); 2.31 (3H, s,
CH3); 2.29 (3H, s, CH3). 13C NMR spectrum, δ, ppm:
149.3; 142.1; 140.3; 138.5; 130.5; 129.9; 129.4; 127.2;
124.2; 116.3; 95.1; 20.5; 14.1. Found, %: C 77.62; H 6.57;
N 15.82. C17H17N3. Calculated, %: C 77.54; H 6.51;
N 15.96.
N-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazol-
5-amine (1p). Yield 246 mg (88%), yellow waxy solid.
1H NMR spectrum, δ, ppm (J, Hz): 7.59–7.53 (2H, m,
H Ar); 7.45 (2H, t, J = 7.9, H Ar); 7.37–7.30 (1H, m,
H Ar); 6.99–6.92 (2H, m, H Ar); 6.87–6.80 (2H, m, H Ar);
5.82 (1H, s, H Ar); 5.40 (1H, s, NH); 3.78 (3H, s, OCH3);
2.29 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 154.7;
149.3; 143.3; 138.5; 136.0; 129.4; 127.2; 124.2; 118.7; 114.7;
93.6; 55.6; 14.1. Found, %: C 73.16; H 6.15; N 14.89.
C17H17N3O. Calculated, %: C 73.10; H 6.13; N 15.04.
3-Methyl-N-(4-nitrophenyl)-1-phenyl-1H-pyrazol-
5-amine (1q). Yield 217 mg (87%), light-brown powder,
N-(4-Nitrophenyl)-1,3-diphenyl-1H-pyrazol-5-amine
(1i). Yield 274 mg (77%), yellow powder, mp 83°C
1
(decomp.). H NMR spectrum, δ, ppm: 8.16–8.10 (2H, m,
H Ar); 7.90–7.84 (2H, m, H Ar); 7.58–7.50 (2H, m, H Ar);
7.48–7.41 (4H, m, H Ar); 7.40–7.34 (2H, m, H Ar); 6.93–
6.86 (2H, m, H Ar); 6.64 (1H, s, H Ar); 6.14 (1H, s, H Ar).
13C NMR spectrum, δ, ppm: 151.7; 149.2; 140.7; 138.7;
138.0; 132.7; 129.5; 129.0; 128.7; 128.4; 128.2; 128.1;
126.2; 125.6; 125.3; 124.2; 113.7; 97.9. Found, %:
C 70.79; H 4.51; N 15.74. C21H16N4O2. Calculated, %:
C 70.77; H 4.53; N 15.72.
1,3-Dimethyl-N-phenyl-1H-pyrazol-5-amine (1j). Yield
109 mg (58%), light-yellow powder, mp 153–155°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.25–7.19 (2H, m,
H Ar); 6.87 (1H, t, J = 7.4, H Ar); 6.72 (2H, d, J = 7.6,
H Ar); 5.83 (1H, s, H Ar); 5.31 (1H, s, NH); 3.64 (3H, s,
NCH3); 2.25 (3H, s, CH3). 13C NMR spectrum, δ, ppm:
147.5; 144.7; 140.8; 129.4; 120.1; 114.6; 98.5; 34.6; 14.1.
Found, %: C 70.50; H 7.03; N 22.47. C11H13N3. Calculated, %:
C 70.56; H 7.00; N 22.44.
1,3-Dimethyl-N-(p-tolyl)-1H-pyrazol-5-amine (1k). Yield
122 mg (61%), light yellow-brown powder, mp 116–117°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.03 (2H, d, J = 8.2,
H Ar); 6.65 (2H, d, J = 8.4, H Ar); 5.79 (1H, s, H Ar); 5.19
(1H, s, NH); 3.63 (3H, s, NCH3); 2.27 (3H, s, CH3); 2.24
(3H, s, CH3). 13C NMR spectrum, δ, ppm: 147.4; 142.1;
141.4; 129.9; 129.6; 114.9; 97.8; 34.5; 20.4; 14.1. Found, %:
C 71.83; H 7.56; N 20.61. C12H15N3. Calculated, %:
C 71.61; H 7.51; N 20.88.
1
mp 173–176°C. H NMR spectrum, δ, ppm (J, Hz): 8.11
(2H, d, J = 9.1, H Ar); 7.49–7.36 (5H, m, H Ar); 6.85 (2H,
d, J = 9.2, H Ar); 6.16 (1H, s, H Ar); 6.13 (1H, s, NH);
2.34 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 149.6;
149.3; 140.6; 138.0; 137.9; 129.4; 127.8; 126.1; 124.0;
113.6; 100.2; 14.1. Found, %: C 65.45; H 4.84; N 18.78.
C16H14N4O2. Calculated, %: C 65.30; H 4.79; N 19.04
1-Methyl-N,3-diphenyl-1H-pyrazol-5-amine (1r). Yield
1
167 mg (67%), white powder, mp 148–150°C. H NMR
N-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-amine
(1l). Yield 182 mg (84%), white powder, mp 187–190°C.
1H NMR spectrum, δ, ppm: 6.87–6.66 (4H, m, H Ar); 5.73
(1H, s, H Ar); 5.50 (1H, s, NH); 3.76 (3H, s, OCH3); 3.61
(3H, s, NCH3); 2.23 (3H, s, CH3). 13C NMR spectrum,
δ, ppm: 153.9; 147.4; 142.7; 138.0; 116.9; 114.8; 96.3;
55.6; 34.4; 14.0. Found, %: C 66.22; H 6.90; N 19.46.
C12H15N3O. Calculated, %: C 66.34; H 6.96; N 19.34
1,3-Dimethyl-N-(4-nitrophenyl)-1H-pyrazol-5-amine
(1m). Yield 178 mg (77%), dark-brown waxy solid.
1H NMR spectrum, δ, ppm (J, Hz): 8.12 (2H, d, J = 9.1,
H Ar); 6.70 (2H, d, J = 9.2, H Ar); 6.01 (1H, s, H Ar); 5.94
(1H, s, NH); 3.65 (3H, s, NCH3); 2.27 (3H, s, CH3).
13C NMR spectrum, δ, ppm: 150.6; 148.0; 140.4; 137.7;
126.2; 113.1; 100.7; 34.8; 14.0. Found, %: C 56.97;
H 5.24; N 24.16. C11H12N4O2. Calculated, %: C 56.89;
H 5.21; N 24.12.
spectrum, δ, ppm (J, Hz): 7.81 (2H, d, J = 7.1, H Ar); 7.42
(2H, t, J = 7.5, H Ar); 7.36–7.22 (3H, m, H Ar); 6.93 (1H,
t, J = 7.4, H Ar); 6.80 (2H, d, J = 7.6 H Ar); 6.39 (1H, s,
H Ar); 5.37 (1H, s, NH); 3.79 (3H, s, NCH3).13C NMR
spectrum, δ, ppm: 150.1; 144.5; 141.5; 133.6; 129.5; 128.6;
127.6; 125.0; 120.4; 114.7; 96.4; 35.1. Found, %: C 77.14;
H 6.09; N 16.76. C16H15N3. Calculated, %: C 77.08;
H 6.06; N 16.85.
1-Methyl-3-phenyl-N-(p-tolyl)-1H-pyrazol-5-amine (1s).
Yield 190 mg (72%), light-yellow powder, mp 186–187°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.78 (2H, d, J = 7.1,
H Ar); 7.39 (2H, t, J = 7.5, H Ar); 7.33–7.27 (1H, m,
H Ar); 7.07 (2H, d, J = 8.2, H Ar); 6.71 (2H, d, J = 8.4,
H Ar); 6.33 (1H, s, H Ar); 5.26 (1H, s, NH); 3.76 (3H, s,
NCH3); 2.29 (3H, s, CH3). 13C NMR spectrum, δ, ppm:
150.0; 142.2; 142.0; 133.6; 130.0; 129.9; 129.0; 128.6;
128.2; 127.6; 125.3; 125.2; 115.2; 95.6; 35.0; 20.5. Found, %:
C 77.60; H 6.53; N 15.84. C17H17N3. Calculated, %:
C 77.54; H 6.51; N 15.96.
3-Methyl-N,1-diphenyl-1H-pyrazol-5-amine (1n). Yield
1
149 mg (60%), white powder, mp 122–123°C. H NMR
spectrum, δ, ppm (J, Hz): 7.58–7.54 (2H, m, H Ar); 7.46
(2H, t, J = 7.8, H Ar); 7.38–7.32 (1H, m, H Ar); 7.31–7.25
(2H, m, H Ar); 6.99–6.91 (3H, m, H Ar); 6.03 (1H, s,
H Ar); 5.54 (1H, s, NH); 2.35 (3H, s, CH3). 13C NMR
spectrum, δ, ppm: 149.3; 142.9; 141.3; 138.4; 129.4; 129.3;
127.3; 124.2; 120.8; 115.7; 96.1; 14.1. Found, %: C 77.17;
1-Methyl-N-(4-nitrophenyl)-3-phenyl-1H-pyrazol-
5-amine (1t). Yield 246 mg (84%), orange powder, mp 175–
179°C. H NMR spectrum, δ, ppm: 8.21–8.10 (2H, m,
H Ar); 7.82–7.78 (2H, m, H Ar); 7.46–7.41 (2H, m, H Ar);
7.38–7.33 (1H, m, H Ar); 6.79–6.74 (2H, m, H Ar); 6.48
(1H, s, H Ar); 6.06 (1H, s, NH); 3.79 (3H, s, CH3).
1
638

Chemistry of Heterocyclic Compounds 2021, 57(6), 633–639
4. Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
13C NMR spectrum, δ, ppm: 150.6; 150.5; 140.6; 138.5;
133.0; 128.7; 128.0; 126.2; 125.2; 113.2; 98.6; 35.3.
Found, %: C 65.38; H 4.84; N 18.86. C16H14N4O2.
Calculated, %: C 65.30; H 4.79; N 19.04.
3054.
5. Fischer, C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59.
6. Bhunia, S.; Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D.
Angew. Chem., Int. Ed. 2017, 56, 16136.
N-(Naphthalen-1-yl)-1,3-diphenyl-1H-pyrazol-5-amine
(1u). Yield 190 mg (53%), light-pink solid, mp 129–131°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.90–7.87 (3H, m,
H Ar); 7.84 (1H, d, J = 8.4, H Ar); 7.75–7.72 (2H, m,
H Ar); 7.56–7.45 (5H, m, H Ar); 7.43–7.39 (3H, m, H Ar);
7.39–7.32 (2H, m, H Ar); 7.28 (1H, d, J = 7.0, H Ar); 6.41
(1H, s, H Ar); 6.09 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 151.6; 143.0; 138.5; 138.4; 134.5; 133.2; 129.6;
128.8; 128.6; 128.0; 127.7; 126.2; 126.1; 125.8; 125.6;
125.2; 124.2; 122.3; 120.5; 112.6; 93.9. Found, %:
C 83.12; H 5.36; N 11.52. C25H19N3. Calculated, %:
C 83.08; H 5.30; N 11.63.
N-(Naphthalen-2-yl)-1,3-diphenyl-1H-pyrazol-5-amine
(1v). Yield 332 mg (92%), dark-yellow waxy solid.
1H NMR spectrum, δ, ppm (J, Hz): 7.95–7.89 (2H, m,
H Ar); 7.78–7.76 (2H, m, H Ar); 7.70–7.65 (3H, m, H Ar);
7.51–7.41 (5H, m, H Ar); 7.40–7.36 (4H, m, H Ar); 7.16
(1H, dd, J = 8.8, J = 2.4, H Ar); 6.63 (1H, s, H Ar); 5.71
(1H, s, NH). 13C NMR spectrum, δ, ppm: 151.6; 141.9;
140.7; 138.5; 134.5; 133.2; 129.5 (2C); 129.1; 128.6;
128.1; 127.8; 127.7; 126.8; 126.5; 125.7; 124.4; 123.7;
118.1; 110.2; 94.5. Found, %: C 83.16; H 5.23; N 11.61.
C25H19N3. Calculated, %: C 83.08; H 5.30; N 11.63.
7. Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116,
12564.
8. Crenshaw, R. R.; Luke, G. M.; Siminoff, P. J. Med. Chem.
1976, 19, 262.
9. Chang, E.-C.; Chen, C.-Y.; Wang, L.-Y.; Huang, Y.-Y.;
Yeh, M-Y.; Wong, F. F. Tetrahedron 2013, 69, 570.
10. Ueda, S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
10364.
11. Hanthorn, J. J.; Valgimigli, L.; Pratt, D. A. J. Am. Chem. Soc.
2012, 134, 8306.
12. Rauws, T. R. M.; Biancalani, C.; De Schutter, J. W.;
Maes, B. U. W. Tetrahedron 2010, 66, 6958.
13. Dao, P.; Jarray, R.; Le Coq, J.; Lietha, D.; Loukaci, A.;
Lepelletier, Y.; Hadj-Slimane, R.; Garbay, C.; Raynaud, F.;
Chen, H. Bioorg. Med. Chem. Lett. 2013, 23, 4552.
14. Wakabayashi, K.-I.; Imai, K.; Miyachi, H.; Hashimoto, Y.;
Tanatani, A. Bioorg. Med. Chem. 2008, 16, 6799.
15. Hornberger, K. R.; Badiang, J. G.; Salovich, J. M.; Kuntz, K. W.;
Emmitte, K. A.; Cheung, M. Tetrahedron Lett. 2008, 49,
6348.
16. Patel, S.; Harris, S. F.; Gibbons, P.; Deshmukh, G.; Gustafson, A.;
Kellar, T.; Lin, H.; Liu, X.; Liu, Y.; Liu, Y.; Ma, C.; Scearce-
Levie, K.; Ghosh, A. S.; Shin, Y. G.; Solanoy, H.; Wang, J.;
Wang, B.; Yin, J.; Siu, M.; Lewcock, J. W. J. Med. Chem.
2015, 58, 8182.
17. Strah-Pleynet, S.; Teegarden, B.; Unett, D. J. WO Patent
2006060762.
18. Tao, Y. T.; Balasubramaniam, E.; Danel, A.; Jarosz, B.;
Tomasik, P. Chem. Mater. 2001, 13, 1207.
19. Tomasik, P.; Funaki, J.; Imai, K.; Danel, A. Pol. J. Chem.
2003, 77, 1141.
20. Rurack, K.; Danel, A.; Rotkiewicz, K.; Grabka, D.; Spieles, M.;
Rettig, W. Org. Lett. 2002, 4, 4647.
21. Danel, A.; Wojtasik, K.; Szlachcic, P.; Gryl, M.; Stadnicka, K.
Tetrahedron 2017, 73, 5072.
22. Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
15914.
Supplementary information file containing 1H and 13C NMR
spectra of all synthesized compounds is available at the
journal website at http://link.springer.com/journal/10593.
This work was supported by Department of Chemistry,
Faculty of Food Technology, University of Agriculture in
Krakow, Poland (project No. 070012-D020).
References
1. Pocar, D.; Bianchetti, G.; Maiorana, S. Gazz. Chim. Ital.
23. Mitchell, D.; Cole, K. P.; Pollock, P. M.; Coppert, D. M.;
Burkholder, T. P.; Clayton, J. R. Org. Process Res. Dev. 2012,
16, 70.
1963, 93, 100.
2. Dodd, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45,
4265.
24. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
3. Bernhammer, J. C.; Huynh, H. V. Dalton Trans. 2012, 41,
8600.
639