4-Arylation of N-Acylamino- and Aminopyrazoles by the Suzuki-Miyaura Cross-Coupling Reaction

Article abstract of DOI:10.1002/ejoc.201600072

Halogenated aminopyrazoles have rarely been utilized in metal-catalysed cross-coupling reactions mainly due to the complexation of the aminopyrazoles to the metal center, which deactivates the catalyst. In this paper we reveal that the appropriate combination of palladium source and ligand enables efficient Suzuki-Miyaura cross-coupling reactions with even challenging substrates such as halogenated aminopyrazoles. The combination of Pd(OAc)₂ and XPhos allowed efficient coupling of halogenated N-acetylaminopyrazoles, whereas XPhos Pd G2 was needed when unprotected aminopyrazoles were used. Generally, the halogenated aminopyrazoles underwent facile cross-coupling reactions with a range of aryl-, heteroaryl-, and styrylboronic acids and esters. The resulting biaryl, bisheteroaryl, or arylalkenyl derivatives were obtained in good-to-high isolated yields.

Full text of DOI:10.1002/ejoc.201600072

DOI: 10.1002/ejoc.201600072
Full Paper
Aminopyrazole Cross-Coupling
4-Arylation of N-Acylamino- and Aminopyrazoles by the
Suzuki–Miyaura Cross-Coupling Reaction
Lukáš Jedinák[a] and Petr Cankař*[a]
Abstract: Halogenated aminopyrazoles have rarely been util- cient coupling of halogenated N-acetylaminopyrazoles, whereas
ized in metal-catalysed cross-coupling reactions mainly due to
the complexation of the aminopyrazoles to the metal center,
which deactivates the catalyst. In this paper we reveal that the
appropriate combination of palladium source and ligand ena-
bles efficient Suzuki–Miyaura cross-coupling reactions with
even challenging substrates such as halogenated aminopyr-
azoles. The combination of Pd(OAc)2 and XPhos allowed effi-
XPhos Pd G2 was needed when unprotected aminopyrazoles
were used. Generally, the halogenated aminopyrazoles under-
went facile cross-coupling reactions with a range of aryl-, hete-
roaryl-, and styrylboronic acids and esters. The resulting biaryl,
bisheteroaryl, or arylalkenyl derivatives were obtained in good-
to-high isolated yields.
Introduction
inhibition of the catalyst.[21,22] In particular, five-membered ni-
trogen-rich heterocycles bearing an unprotected amino group
were found problematic coupling partners in palladium-cata-
lyzed cross-coupling reactions.[23–26] However, the development
of more robust catalysts has overcome this obstacle, allowing
the cross-coupling of the previously challenging substra-
tes.[27–31]
Recently, we reported 4-substituted aminopyrazoles as potent
and selective inhibitors of cyclin-dependent kinases, namely
CDK2, CDK4, and CDK9.[1–4] These compounds displayed anti-
proliferative activity, which was proven on several cancer cell
lines, including MCF7, K562, and RPMI-8226. To further explore
the structure–activity relationship (SAR) and potentially find
new compounds with improved CDK inhibition activity, we
were interested in the synthesis of amino- and N-acylamino-
pyrazoles with diverse substituents at the 4-position of the pyr-
azole ring.
Classically, 4-substituted aminopyrazoles can be prepared by
traditional methods starting from the corresponding substi-
tuted acyclic precursors.[5–10] Although these traditional meth-
ods still hold their value, they usually suffer from limited sub-
strate scope and require multiple steps, which make them unat-
tractive for parallel syntheses.[11–15] Therefore, we sought a
more efficient and general method for the rapid elaboration of
the 4-substituted aminopyrazole scaffold. Among various or-
ganic reactions, the Pd-catalyzed Suzuki–Miyaura cross-cou-
pling reaction has enjoyed great attention as it enables straight-
forward and efficient syntheses of olefins, styrenes, and biaryls,
has broad substrate scope, and uses relatively low-toxic and
bench-stable organoboron reagents.[16]
Despite the tremendous progress in the development of ef-
fective palladium-based catalytic systems, only isolated exam-
ples of the Suzuki–Miyaura reaction with halogenated amino-
or N-acylaminopyrazoles have been published to date.[32,33] The
reported procedures often employed less effective catalytic sys-
tems based on [Pd(PPh3)4], which provided the biaryl product in
low yield. Furthermore, no systematic study including reaction
optimization and exploration of the substrate scope has been
disclosed.[34] Poorly explored cross-coupling methodologies in
this field and the potential bioactivity of the target arylated
aminopyrazoles encouraged us to further explore the arylation
of aminopyrazole derivatives at the 4-position. Herein, we
present our results of the Pd-catalyzed C–C cross-coupling reac-
tions of pyrazoles with a range of aryl-, heteroaryl-, and styryl-
boronic acids or esters. In addition, we have compared the re-
activity of 4-chloro-, 4-bromo-, and 4-iodo-aminopyrazoles in
the Suzuki–Miyaura reaction.
Previously, Pd-catalyzed Suzuki–Miyaura cross-coupling reac-
tions involving heteroaromatic substrates represented a sub-
stantial challenge,[17–20] presumably due to the complexation of
a starting material and/or product to the metal resulting in the
Results and Discussion
We initiated our study with the model reaction involving pyraz-
ole 1a and boronic acid 2a. The reaction was performed in a
mixture of dioxane and water, K2CO3 was used as base, and
Pd(OAc)2 as the palladium source. The reaction mixture was
heated in an oil bath at 100 °C for 18 h (Table 1). In the first
stage, distinct supporting ligands were evaluated in combina-
tion with Pd(OAc)2, including bulky trialkylphosphines, biden-
tate phosphines, biphenyl-based phosphines, and an NHC-
[a] Department of Organic Chemistry, Faculty of Science, Palacky University
Olomouc,
17. listopadu 1192/12, 771 46 Olomouc, Czech Republic
E-mail: cankar@orgchem.upol.cz
www.orgchem.upol.cz
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600072.
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Table 1. Optimization of the reaction parameters[a] (PEPPSI = [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride).
Entry
[Pd]
Ligand
Base
Solvent
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PEPPSI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
XPhos Pd G2
10 % Pd/C
[Pd2dba3]
PCy3
PAd2Bu
dppp
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
48
62
51
33
64
33
74
69
45
32
66
73
67
dppf
BINAP
SPhos
XPhos
Aphos
IPr
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
CsF
Cs2CO3
K3PO4
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
57
43[c]
66[d]
54[e]
68
toluene
iPrOH
66
64
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
59[f]
26[g]
75[h]
75
63
71
[a] Reagents and conditions: 1a (0.5 mmol), 2a (1.0 mmol), base (1.0 mmol), organic solvent (2 mL), H2O (0.5 mL), ligand (0.01 mmol), [Pd] (0.005 mmol),
100 °C, 18 h. [b] Isolated yield. [c] 1 equiv. of K2CO3 was used. [d] 3 equiv. of K2CO3 was used. [e] 4 equiv. of K2CO3 was used. [f] T = 80 °C. [g] T = 40 °C. [h]
Reaction time 8 h.
based catalyst (Table 1, entries 1–9). For example, trialkylphos-
Next, other reaction parameters, such as the nature of the
phine PCy3, which was earlier reported as an efficient support- base, solvent system, temperature, and reaction time, were opti-
ing ligand for Suzuki reactions involving heteroarenes,[35] gave mized. A few other inorganic bases and one organic base were
product 3a in only 48 % yield, together with 9 % of recovered tested (entries 10–14), however, none of them gave better re-
starting material 1a and 25 % of debrominated pyrazole 4 (en- sults than K2CO3. The amount of base was found to be critical.
try 1). Better results were obtained by using PAd2Bu, BINAP, One equivalent of K2CO3 led to the incomplete consumption of
APhos, and XPhos, with XPhos being the best of all the tested the starting material, whereas 3 or 4 equivalents of K2CO3 led
ligands, affording the desired product 3a in 74 % yield.
to an increase in the rate of hydrodehalogenation (entries 15–
17). Comparison of different solvent systems (entries 18–20) re-
vealed a mixture of dioxane and water to be optimal for the
reaction. We envisioned that a lower reaction temperature
could potentially suppress the undesired hydrodehalogenation,
however, the impurity 4 was formed even at 40 °C. Moreover,
the yield of product 3a decreased due to the incomplete
conversion of the starting pyrazole 1a (entries 21 and 22).
Pleasingly, the reaction time could be reduced to 8 hours
without affecting the yield (entry 23). Other palladium sources,
Notably, LCMS analyses of the crude reaction mixtures gener-
ally showed product 3a, starting material 1a, debrominated
pyrazole 4, which results from the reductive hydrodehalogena-
tion of the starting material, boronic acid 2a, and biphenyl 5,
which results from the oxidative homocoupling of the boronic
acid. For cases in which the product was isolated in lower yields
(e.g., entries 4, 6, and 10), a substantial amount of the starting
material 1a and/or the hydrodehalogenated pyrazole 4 was de-
tected. The most effective supporting ligand, XPhos, led to the
complete consumption of the starting material 1a, leaving de- such as [Pd2dba3], XPhos Pd G2, and 10 % Pd/C, were
brominated compound 4 as the sole impurity derived from the also effective for the transformation (entries 24–26). Of
parent pyrazole.
these Pd sources, the XPhos-derived precatalyst XPhos Pd G2
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gave compound 3a in the highest yield of 75 % (entry 24), acylpyrazoles 1a–d with aryl-, heteroaryl-, and styrylboronic ac-
which is comparable to the catalytic activity of Pd(OAc)2. ids and esters 2a–q (Table 2). Generally, the coupling products
Therefore, we chose the less-expensive Pd(OAc)2 for further
were obtained in moderate-to-high isolated yields with both
studies.
bromides 1a and 1c. Both electron-donating and -withdrawing
With the optimized conditions in hand, we explored the groups at the para position of the respective phenylboronic
scope of the cross-coupling reaction by using halogenated N- acids (2c,d for EWG, 2e,f for EDG) were compatible with the
Table 2. Scope and limitation of the Suzuki reaction using N-acylaminopyrazoles.
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Table 2. (Continued).
[a] Only traces of the respective biaryl were detected by LCMS. [b] The reaction was performed in DMF/iPrOH (10:1) with 0.5 equiv. of Cu(OAc)2.
reaction. Notably, the ortho-substituted phenylboronic acids 2g boron nucleophile was found to be more problematic. Only tra-
and 2h reacted equally well, producing sterically hindered bi- ces of the desired heterobiaryl 3y were detected by LCMS when
aryls 3m–p in yields of 77–88 %. On the other hand, ortho- 3-pyridylboronic acid (2o) was employed in the cross-coupling
disubstituted boronic acid 2i failed to give the cross-coupling reaction. At first, we considered that the low solubility of 2o in
product when treated with pyrazole 1a under the optimized dioxane/H2O could potentially hamper the reaction with 1c,
conditions. Gratifyingly, (E)-styrylboronic acids 2j–l were suc- hence we switched to other solvent systems, including DMF/
cessfully coupled with pyrazoles 1a and 1c allowing the prepa- H2O and DMF/iPrOH. However, this only increased the rate of
ration of compounds 3q–t in yields of 78–86 %. The cross-cou- hydrodehalogenation and no improvement was observed in
pling of the styrylboronic acids proceeded with the retention the conversion to 3y. The problem was solved by using the
of stereochemistry; compounds 3q–t adopted the E configura- pinacol ester of 3-pyridylboronic acid (2p), which furnished the
tion, as determined from the values of vicinal coupling constant desired heterobiaryl 3y in a moderate yield of 58 %. The MIDA
of the olefinic protons (3J ≈ 16 Hz).
ester of 4-pyridylboronic acid (2q) gave only traces of product
3z. We believe that 4-pyridylboronates could behave similarly
to their 2-pyridyl counterparts in that they are susceptible to
protodeboronation.[36] Inspired by the previously reported pro-
cedures dealing with the “2-pyridyl problem”, we switched to a
Carbon–carbon cross-coupling reactions involving hetero-
arylboronic acids or their derivatives with heteroaryl halides are
versatile transformations in medicinal chemistry. Therefore, we
appreciated that the coupling of pyrazoles 1a and 1c with 2-
benzothienylboronic acid (2m) and the MIDA ester of 2-furyl- different solvent system (DMF/iPrOH) and added 0.5 equiv. of
boronic acid (2n) delivered heterobiaryls 3u–x in good yields of Cu(OAc)2;[37] the co-catalysis with copper allowed us to isolate
76–84 %. On the other hand, the use of pyridine as an organo- biaryl 3z in a poor yield of 29 %.
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Figure 1. Reactivity of Cl-, Br-, and I-substituted pyrazoles 1a,b,e in the Suzuki–Miyaura cross-coupling reaction.
Similarly to the bromides 1a and 1c, the chlorides 1b and
1d proved to be eligible electrophiles for the reaction, provid-
ing the respective heterobiaryls 3b, 3e, 3h, 3j, 3m, 3o, 3w, and
3x in yields of 77–90 %. Generally, the yields achieved with
chlorides 1b and 1d were comparable or even better than
those obtained with bromides 1a and 1c. This prompted us to
further investigate the reactivity of chloride 1b, bromide 1a,
and iodide 1e with p-tolylboronic acid (2a). The formation of
biaryl 3a was studied by HPLC over the course of 8 hours, and
the results are depicted in Figure 1. Under the optimized condi-
tions, the cross-coupling reactions with both chloride 1b and
bromide 1a proceeded with approximately 70 % conversion
after 1 h. Conversions of 82 % for the bromide and 84 % for the
chloride were achieved after 4 h. At that point, the starting
materials 1a and 1b were completely consumed and the prod-
uct 3a was accompanied by approximately 13 % of the hydro-
dehalogenated pyrazole 4. On the other hand, iodide 1e exhib-
ited a greater propensity for hydrodehalogenation, which led
to a higher amount of impurity 4 (39 %).
To extend the scope of the procedure to pyrazoles bearing
an unprotected amino group, we turned our attention to the
cross-coupling of pyrazole 6a and p-tolylboronic acid (2a)
(Scheme 1). Disappointingly, only a small amount of the desired
product 7a was observed together with unreacted starting ma-
Scheme 1. Suzuki–Miyaura cross-coupling reaction of unprotected aminopy-
razole 6a.
terial 6a and hydrodebrominated pyrazole 8. We assumed that 6a and 6b. Various boronic acids or esters bearing an electron-
strong complexation of the metal to the substrate terminated donating (2e) and -withdrawing functionality (2d), ortho-substi-
the reaction. This inhibition can be eliminated by the proper tuted boronic acids (2g,h), and heterocyclic moieties (2p–t)
choice of palladium source. For example, 2-aminobiphenyl- were all compatible with the reaction, affording the desired
based palladacycles (e.g., XPhos Pd G2) combined with bulky products 7b–j in yields of 60–79 %. The coupling of pyrazole
electron-rich phosphines have been reported to be superior to 6b and 4-pyridylboronic acid MIDA ester (2q) was co-catalyzed
traditional Pd sources such as [Pd2dba3] or Pd(OAc)2.[38] Fortu- with Cu(OAc)2, as in the previous series of reactions (see
nately, this was the case, switching to the precatalyst XPhos Pd Table 2). This modification was necessary to obtain good con-
G2 allowed us to isolate the NH2-unprotected biaryl 7a in 76 % version, although the biaryl 7k was still only obtained in a low
yield. This modified procedure was then applied to the synthe- yield of 36 %. When styrylboronic acid (2j) was treated with
sis of biaryls 7b–k (Table 3) from unprotected aminopyrazoles pyrazole 6a, the starting material 6a was completely consumed
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Table 3. Scope of the Suzuki–Miyaura cross-coupling reaction using unpro-
tected aminopyrazoles.
to give a complex mixture of unidentified compounds. This was
presumably due to side-reactions between the unprotected
amino group and the styryl moiety.
Alternatively, unprotected aminopyrazoles 7 could be ob-
tained from their N-acetyl analogues 3 by a simple hydrolysis
of the amide group. As an example, pyrazole 7a was easily pre-
pared in high yield from the corresponding amide 3a using
KOH in a mixture of ethanol and water (Scheme 2). This alterna-
tive approach avoids the use of the more expensive XPhos Pd
G2.
Scheme 2. Hydrolysis of the N-acetamide group in 3a.
Conclusions
An efficient method for the Suzuki–Miyaura reactions of 4-halo-
genated pyrazoles bearing an N-acylamino and unprotected
amino functionality has been developed. The reported proce-
dure enables the efficient cross-coupling reaction of 4-chloro-,
4-bromo-, and 4-iodopyrazoles with a range of aryl-, heteroaryl-,
and styrylboronic acids and/or esters. The chloro- and bromo-
pyrazoles were found to be superior electrophilic coupling part-
ners, as the iodo derivative suffers from considerable hydrodei-
odination. The cross-coupling products bearing the N-acylam-
ino group on the pyrazole ring were generally obtained in high
yields with Pd(OAc)2 and XPhos as the catalytic system. On the
other hand, the use of the precatalyst XPhos Pd G2 instead of
Pd(OAc)2 was found to be essential for the efficient cross-cou-
pling reaction of bromopyrazoles containing a free amino
group. This procedure with its broad substrate scope has al-
lowed the rapid synthesis of a library of functionalized amino-
pyrazoles and N-acylaminopyrazoles, which have the potential
to evince significant protein kinase inhibitory activity.
Experimental Section
General: Boronic acids and esters, precatalysts, ligands, 1,3-di-
methyl-1H-pyrazol-5-amine, and 1-methyl-3-phenyl-1H-pyrazol-5-
amine were bought from commercial suppliers. Solvents were puri-
fied by standard techniques and deoxygenated with a stream of
nitrogen immediately before use. All reactants and catalysts were
weighed in air and then transferred to a sealed tube. All cross-
coupling reactions were performed in a sealed tube, which was
thoroughly flushed with a stream of nitrogen before closing with a
screw cap. The reaction tube was then inserted into a preheated oil
bath. Progress of the reaction was monitored by LCMS and TLC
(Kiesegel 60, visualization by UV). Crude products were purified by
column chromatography on silica gel. Mixtures of dichloromethane
and methanol were used as eluents. Purified products were charac-
terized by NMR spectroscopy and HRMS. The NMR spectra were
recorded with a Jeol 400 MHz spectrometer in deuteriated chloro-
form or DMSO. Chemical shifts are reported in ppm and referenced
to the residual solvent peak. HRMS data were recorded with an
[a] 0.5 equiv. of Cu(OAc)2 were added.
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Orbitrap Elite HRMS operating in the positive full scan mode in the
range of m/z = 200–900.
orated under reduced pressure (evaporated twice with toluene to
remove residual acetic acid). The crude product was crystallized
twice, first from a mixture of dichloromethane/hexanes, then from
MeOH/H2O to remove residual succinimide. The title product 1d
was obtained as a white fine powder (2.09 g, 84 %), m.p. 156–158 °C
Preparation of Halogenated Pyrazoles 1a–e and 6a,b
N-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (1a): A mix-
ture of 1,3-dimethyl-1H-pyrazol-5-amine (5.55 g, 50.0 mmol) and
acetic anhydride (5.25 mL, 55.0 mmol) in DCM (40 mL) was stirred
at ambient temperature for 18 h. Then the mixture was cooled to
0 °C and bromine (2.71 mL, 52.5 mmol) was added dropwise. After
stirring the mixture for 3 h at ambient temperature, the reaction
1
(MeOH/H2O). H NMR (400 MHz, [D6]DMSO): δ = 2.12 (s, 3 H), 3.68
(s, 3 H), 7.38 (td, J = 7.3, 1.3 Hz, 1 H), 7.46 (dd, J = 7.5, 7.3 Hz, 2 H),
7.81 (dd, J = 7.5, 1.3 Hz, 2 H), 10.06 (s, 1 H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 22.5, 36.6, 101.8, 126.4, 128.1, 128.6, 131.7, 134.7,
143.8, 169.5 ppm.
was quenched with 2
N K2CO3 (30 mL) and 1 N Na2S2O3 (10 mL).
N-(4-Iodo-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (1e): A mix-
ture of 1,3-dimethyl-1H-pyrazol-5-amine (0.555 g, 5.0 mmol) and
acetic anhydride (0.565 mL, 6.0 mmol) in MeCN (30 mL) was stirred
at ambient temperature for 18 h. Then iodine (3.036 g, 12.0 mmol)
was slowly added in several portions and the resulting mixture was
The organic layer was separated and the aqueous layer extracted
with ethyl acetate (2 × 20 mL). The combined organic layers were
dried with Na2SO4 and concentrated under vacuum. The residue
was purified by crystallization from a mixture of DCM and toluene.
Pyrazole 1a was obtained as white needles (10.5 g, 91 %), m.p. 122–
123 °C (DCM/toluene). 1H NMR (400 MHz, [D6]DMSO): major con-
former: δ = 2.06 (s, 3 H), 2.09 (s, 3 H), 3.54 (s, 3 H), 9.86 (s, 1 H) ppm;
minor conformer: δ = 1.73, 2.12, 3.64, 9.28 ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 12.3, 22.4, 36.1, 89.4, 134.8, 144.1, 169.2 ppm. HRMS
(ESI-TOF): calcd. for C7H11BrN3O [M + H]+ 232.0080; found 232.0091,
234.0064.
stirred at ambient temperature for an additional 3 d. Then 2
N K2CO3
(15 mL) and 1 Na2S2O3 (15 mL) were added and the mixture
N
was thoroughly shaken until all unreacted iodine was reduced. The
organic layer was separated and the aqueous layer extracted with
ethyl acetate (2 × 30 mL). The combined organic layers were dried
with Na2SO4 and the solvents removed under reduced pressure.
The crude product was triturated with water (20 mL), filtered, and
washed with water (ca. 20 mL) to yield the iodopyrazole 1e as a
N-(4-Chloro-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (1b):
A
1
white powder (0.865 g, 62 %), m.p. 144–146 °C. H NMR (400 MHz,
mixture of 1,3-dimethyl-1H-pyrazol-5-amine (1.110 g, 10.0 mmol)
and acetic anhydride (1.13 mL, 12.0 mmol) in DCM (20 mL) was
stirred at ambient temperature for 20 h. Then the mixture was im-
mersed in an ice–water bath and N-chlorosuccinimide (1.469 g,
11.0 mmol) was added. The resulting mixture was warmed to room
temperature and stirred for an additional 4 h. The solvent was re-
moved under reduced pressure and the residue was purified by
column chromatography (silica gel, 0–3 % MeOH in DCM). Crystalli-
zation from a mixture of DCM and toluene afforded pyrazole 1b as
[D6]DMSO): δ = 2.06 (s, 3 H), 2.08 (s, 3 H), 3.56 (s, 3 H), 9.79 (s, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 14.0, 22.5, 36.1, 59.9,
138.4, 147.5, 169.2 ppm. HRMS (ESI-TOF): calcd. for C7H11IN3O [M +
H]+ 279.9941; found 279.9941.
4-Bromo-1,3-dimethyl-1H-pyrazol-5-amine (6a): A mixture of 1,3-
dimethyl-1H-pyrazol-5-amine (0.22 g, 2.0 mmol), and N-bromosuc-
cinimide (0.37 g, 2.1 mmol) in DCM (10 mL) was stirred at ambient
temperature for 19 h. Then the mixture was washed with aqueous
sodium carbonate and the aqueous layer extracted with dichloro-
methane (2 × 10 mL). The combined organic layers were dried with
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, iPrOH/hexanes, gra-
dient from 2:100 to 4:100). The bromopyrazole 6a was obtained as
1
white needles (1.458 g, 78 %), m.p. 140–142 °C. H NMR (400 MHz,
[D6]DMSO): δ = 2.07 (s, 3 H), 2.09 (s, 3 H), 3.53 (s, 3 H), 9.89 (s, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 11.4, 22.4, 36.1, 102.6,
133.0, 142.5, 169.3 ppm. HRMS (ESI-TOF): calcd. for C7H11ClN3O [M
+ H]+ 188.0585; found 188.0586.
1
a yellow oil (0.29 g, 77 %). H NMR (400 MHz, [D6]DMSO): δ = 1.95
N-(4-Bromo-1-methyl-3-phenyl-1H-pyrazol-5-yl)acetamide (1c):
(s, 3 H), 3.48 (s, 3 H), 5.26 (br. s, 2 H) ppm. 13C NMR (100 MHz,
A
mixture of 1-methyl-3-phenyl-1H-pyrazol-5-amine (5.25 g,
[D6]DMSO): δ = 12.3, 34.9, 74.0, 143.1, 144.5 ppm.
30.33 mmol) and acetic anhydride (3.72 mL, 39.42 mmol) in DCM
(100 mL) was stirred at ambient temperature for 22 h. Then the
mixture was cooled in an ice bath and bromine (1.72 mL,
33.36 mmol) was added dropwise. The mixture was stirred for 3 h
4-Bromo-1-methyl-3-phenyl-1H-pyrazol-5-amine (6b): A mixture
of 1-methyl-3-phenyl-1H-pyrazol-5-amine (1.73 g, 10.0 mmol) and
N-bromosuccinimide (1.78 g, 10.0 mmol) was stirred in DCM (20 mL)
at ambient temperature for 18–24 h. Then the mixture was washed
with aqueous sodium carbonate. The organic layer was dried with
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, eluting with 0–2 %
MeOH in dichloromethane). The title compound 6b was obtained
as a pink solid (1.91 g, 76 %), m.p. 89–92 °C. 1H NMR (400 MHz,
[D6]DMSO): δ = 3.64 (s, 3 H), 5.47 (s, 2 H), 7.32 (t, J = 7.3 Hz, 1 H),
7.40 (t, J = 7.3 Hz, 2 H), 7.77 (d, J = 7.3 Hz, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 35.5, 72.1, 126.5, 127.6, 128.2, 132.9,
144.5, 145.8 ppm. HRMS (ESI-TOF): calcd. for C10H11BrN3 [M + H]+
252.0135; found 252.0135, 254.0108.
at 5 °C. The reaction was then quenched with 2
N K2CO3 (30 mL)
and 1 Na2S2O3 (10 mL). The organic layer was separated and
N
the aqueous layer extracted with dichloromethane (3 × 50 mL). The
combined organic layers were dried with Na2SO4 and concentrated
under vacuum. The crude product was crystallized from a mixture
of DCM and toluene to yield pyrazole 1c as a white crystalline solid
1
(8.53 g, 96 %), m.p. 183–184 °C (DCM/toluene). H NMR (400 MHz,
[D6]DMSO): δ = 2.12 (s, 3 H), 3.70 (s, 3 H), 7.39 (t, J = 7.5 Hz, 1 H),
7.46 (t, J = 7.5 Hz, 2 H), 7.82 (d, J = 7.5 Hz, 2 H), 10.01 (s, 1 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 22.4, 36.6, 88.1, 126.7, 128.1,
128.5, 132.1, 136.3, 145.4, 169.4 ppm. HRMS (ESI-TOF): calcd. for
C12H13BrN3O [M + H]+ 294.0237; found 294.0211, 296.0183.
General Procedure for the Synthesis of Biaryls or Arylalkenyls
N-(4-Chloro-1-methyl-3-phenyl-1H-pyrazol-5-yl)acetamide (1d):
3a–z by the Suzuki–Miyaura Reaction: See Table 2. The corre-
A
mixture of 1-methyl-3-phenyl-1H-pyrazol-5-amine (1.73 g, sponding pyrazole 1 (1.0 mmol), boronic acid 2 (2.0 mmol), potas-
10.0 mmol) and acetic anhydride (1.13 mL, 12.0 mmol) in dichloro-
methane (0 mL) was stirred at a room temperature for 18 h, then
sium carbonate (0.272 g, 2.0 mmol), and XPhos (0.009 g,
0.020 mmol) were weighed into a pressure tube. Dioxane (3 mL)
the mixture was cooled in an ice–water bath and N-chlorosuccinim- and water (1 mL) were successively added to the reaction flask. The
ide (1.47 g, 11.0 mmol) was added in one portion. The reaction
mixture was stirred at room temperature for another 18 h and evap-
mixture was then degassed for 5 min by using a needle connected
to a nitrogen supply. Then Pd(OAc)2 (0.002 g, 0.010 mmol) was
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added while maintaining a flow of nitrogen. The tube was quickly
closed with a screw cap and inserted into an oil bath preheated to
100 °C. The mixture was stirred at approximately 700 rpm for 8 h.
After that, the mixture was filtered through Celite, washed with
EtOAc, and partitioned between EtOAc and water. The organic layer
was separated, dried with Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (DCM/MeOH, 100:0–100:3) to give the desired biaryl. The
title product was sufficiently pure according to NMR and HPLC–MS
analyses; however, it was further crystallized from a mixture of DCM
and hexanes or other solvent systems before measurement of the
melting point.
hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.06
(s, 3 H), 3.72 (s, 3 H), 7.31–7.35 (m, 5 H), 7.39 (d, J = 8.8 Hz, 2 H),
8.20 (d, J = 8.8 Hz, 2 H), 9.97 (s, 1 H) ppm; minor conformer: δ =
1.56 (s), 3.82 (s), 7.45 (d, J = 8.8 Hz), 8.25 (d, J = 8.8 Hz), 9.49
(NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.9, 36.1, 113.1,
124.2, 128.2, 128.3, 129.0, 130.3, 133.3, 135.7, 140.1, 146.3, 147.3,
170.7 ppm. HRMS (ESI-TOF): calcd. for C18H17N4O3 [M + H]+
337.1295; found 337.1297.
N-{1,3-Dimethyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-
yl}acetamide (3g): White solid (0.261 g, 88 %), m.p. 177–178 °C
(DCM/hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer:
δ = 2.04 (s, 3 H), 2.22 (s, 3 H), 3.57 (s, 3 H), 7.51 (d, J = 7.9 Hz, 2 H),
7.75 (d, J = 7.9 Hz, 2 H), 9.84 (s, 1 H) ppm; minor conformer: δ =
1.51 (s, 3 H), 2.25 (s, 3 H), 3.67 (s, 3 H), 7.57 (d, J = 7.9 Hz, 2 H), 7.79
(d, J = 7.9 Hz, 2 H), 9.40 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
major conformer: δ = 13.2, 22.5, 35.1, 113.1, 124.4 (q, J = 272 Hz),
125.4 (q, J = 4 Hz), 126.5 (q, J = 32 Hz), 128.5, 133.8, 137.1, 143.7,
170.1 ppm. HRMS (ESI-TOF): calcd. for C14H15F3N3O [M + H]+
298.1162; found 298.1145.
N-[1,3-Dimethyl-4-(p-tolyl)-1H-pyrazol-5-yl]acetamide
(3a):
White solid (0.180 g, 74 %), m.p. 108–110 °C (DCM/hexanes). 1H
NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.01 (s, 3 H), 2.17
(s, 3 H), 2.30 (s, 3 H), 3.53 (s, 3 H), 7.16–7.22 (m, 4 H), 9.70 (s, 1
H) ppm; minor conformer: δ = 1.48 (s, 3 H), 2.19 (s, 3 H), 2.31 (s, 3
H), 3.64 (s, 3 H), 9.26 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 13.1, 20.1, 22.4, 35.0, 114.4, 128.0, 129.0, 129.6, 133.0, 135.3,
143.2, 170.1 ppm. HRMS (ESI-TOF): calcd. for C14H18N3O [M + H]+
244.1444; found 244.1434.
N-{1-Methyl-3-phenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyraz-
ol-5-yl}acetamide (3h): White solid (0.294 g, 82 %), m.p. 176–
178 °C (DCM/hexanes). 1H NMR (400 MHz, [D6]DMSO): major con-
former: δ = 2.04 (s, 3 H), 3.69 (s, 3 H), 7.26–7.32 (m, 5 H), 7.34 (d,
J = 8.3 Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 9.88 (s, 1 H) ppm; minor
conformer: δ = 1.54 (s), 3.80 (s), 7.40 (d, J = 8.3 Hz), 7.74 (d, J =
8.3 Hz), 9.42 (s, NH) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 22.4,
35.6, 113.1, 124.4 (q, J = 272 Hz, CF3), 125.3 (q, J = 4 Hz), 127.1 (q,
J = 32 Hz), 127.6, 127.7, 128.4, 129.6, 133.0, 135.0, 136.7, 146.6,
170.3 ppm. HRMS (ESI-TOF): calcd. for C19H17F3N3O [M + H]+
360.1318; found 360.1319.
N-[1-Methyl-3-phenyl-4-(p-tolyl)-1H-pyrazol-5-yl]acetamide
(3b): White solid (0.244 g, 80 %), m.p. 174–176 °C (toluene). 1H NMR
(400 MHz, [D6]DMSO): δ = 2.02 (s, 3 H), 2.30 (s, 3 H), 3.67 (s, 3 H),
7.03 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 7.9 Hz, 2 H), 7.23–7.31 (m, 3 H),
7.33–7.36 (m, 2 H), 9.76 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 20.7, 22.4, 35.5, 114.4, 127.3, 127.3, 128.2, 129.0, 129.0, 129.3,
133.6, 134.5, 135.8, 146.1, 170.3 ppm. HRMS (ESI-TOF): calcd. for
C
19H20N3O [M + H]+ 306.1601; found 306.1601.
N-(1,3-Dimethyl-4-phenyl-1H-pyrazol-5-yl)acetamide (3c): Color-
less oil that solidified upon standing (0.183 g, 80 %), m.p. 120–
1
N-[4-(4-Methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl]acet-
amide (3i): White solid (0.220 g, 85 %), m.p. 185–186 °C (DCM/
123 °C. H NMR (400 MHz, CDCl3): major conformer: δ = 2.12 (s, 3
H), 2.24 (s, 3 H), 3.66 (s, 3 H), 7.22 (d, J = 7.5 Hz, 2 H), 7.28 (t, J =
7.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.58 (s, 1 H) ppm; minor
conformer: δ = 1.67 (s, 3 H), 2.30 (s, 3 H), 3.71 (s, 3 H), 7.17 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): major conformer: δ = 12.8, 22.8,
35.5, 115.6, 126.8, 128.6, 128.7, 132.0, 132.5, 144.8, 170.5 ppm; mi-
nor conformer: δ = 13.2, 20.3, 34.9, 116.7, 127.0, 128.4, 128.8, 131.6,
132.9, 145.7, 173.0 ppm. HRMS (ESI-TOF): calcd. for C13H16N3O [M +
H]+ 230.1288; found 230.1280.
1
toluene). H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.02
(s, 3 H), 2.16 (s, 3 H), 3.53 (s, 3 H), 3.76 (s, 3 H), 6.96 (d, J = 8.8 Hz,
2 H), 7.20 (d, J = 8.8 Hz, 2 H), 9.69 (s, 1 H) ppm; minor conformer:
δ = 1.50 (s, 3 H), 2.18 (s, 3 H), 3.64 (s, 3 H), 3.77 (s, 3 H), 6.99 (d, J =
8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H), 9.24 (br. s, 1 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): major conformer: δ = 13.1, 22.4, 35.0, 55.1,
114.0, 114.2, 124.8, 129.3, 132.9, 143.1, 157.7, 170.1 ppm; minor
conformer: δ = 13.1, 20.5, 34.6, 114.8, 124.4, 129.3, 133.9, 143.6,
157.9, 171.4 ppm. HRMS (ESI-TOF): calcd. for C14H18N3O2 [M + H]+
260.1394; found 260.1379.
N-(1-Methyl-3,4-diphenyl-1H-pyrazol-5-yl)acetamide (3d): White
solid (0.241 g, 83 %), m.p. 198–201 °C (DCM/hexanes). 1H NMR
(400 MHz, [D6]DMSO): major conformer: δ = 2.03 (s, 3 H), 3.68 (s, 3
H), 7.13–7.16 (m, 2 H), 7.25–7.30 (m, 4 H), 7.32–7.36 (m, 4 H), 9.81
(s, 1 H) ppm; minor conformer: δ = 1.55 (s), 3.79 (s), 9.33 (s,
N-[4-(4-Methoxyphenyl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]-
acetamide (3j): White solid (0.292 g, 91 %), m.p. 160–162 °C (DCM/
NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.4, 35.6, 114.5, hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.02
126.7, 127.3, 127.4, 128.2, 128.4, 129.2, 132.3, 133.5, 134.6, 146.2, (s, 3 H), 3.67 (s, 3 H), 3.75 (s, 3 H), 6.91 (d, J = 8.8 Hz, 2 H), 7.06 (d,
170.3 ppm. HRMS (ESI-TOF): calcd. for C18H18N3O [M + H]+ 292.1445;
found 292.1445.
J = 8.8 Hz, 2 H), 7.24–7.31 (m, 3 H), 7.33–7.36 (m, 2 H), 9.75 (s, 3
H) ppm; minor conformer: δ = 1.55 (s), 3.77 (s), 3.78 (s), 6.95 (d, J =
8.8 Hz), 7.11 (d, J = 8.8 Hz), 9.27 (s, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO): major conformer: δ = 22.4, 35.5, 55.0, 113.9, 114.3,
124.4, 127.2, 127.3, 128.2, 130.3, 133.6, 134.4, 146.0, 158.1,
170.3 ppm; minor conformer: δ = 20.7, 35.2 ppm. HRMS (ESI-TOF):
calcd. for C19H20N3O2 [M + H]+ 322.1550; found 322.1550.
N-[1,3-Dimethyl-4-(4-nitrophenyl)-1H-pyrazol-5-yl]acetamide
(3e): Yellow solid (0.211 g, 77 %), m.p. 162–164 °C (DCM/hexanes).
1H NMR (400 MHz, CDCl3): major conformer: δ = 2.22 (s, 3 H), 2.30
(s, 3 H), 3.73 (s, 3 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.60 (br. s, 1 H), 8.17
(d, J = 8.8 Hz, 2 H) ppm; minor conformer: δ = 1.71 (s, 3 H), 2.36 (s,
3 H), 3.79 (s, 3 H), 7.31 (br. s, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 8.25 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): major conformer:
δ = 13.0, 23.0, 35.7, 114.1, 123.9, 129.0, 132.2, 139.3, 144.9, 146.1,
170.3 ppm; minor conformer: δ = 13.6, 20.4, 35.2, 124.2, 128.7,
131.4, 138.8, 145.9 ppm. HRMS (ESI-TOF): calcd. for C13H15N4O3 [M
+ H]+ 275.1139; found 275.1137.
N-[4-(4-Hydroxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl]acet-
amide (3k): White solid (0.169 g, 69 %), m.p. 110–112 °C (acetone/
1
DCM). H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.01 (s,
3 H), 2.14 (s, 3 H), 3.62 (s, 3 H), 6.78 (d, J = 8.3 Hz, 2 H), 7.07 (d, J =
8.3 Hz, 2 H), 9.37 (s, 1 H), 9.65 (s, 1 H) ppm; minor conformer: δ =
1.50 (s, 3 H), 2.16 (s, 3 H), 3.62 (s, 3 H), 6.80 (d, J = 8.3 Hz, 2 H), 7.12
N-[1-Methyl-4-(4-nitrophenyl)-3-phenyl-1H-pyrazol-5-yl]acet- (d, J = 8.3 Hz, 2 H), 9.19 (s, 1 H), 9.43 (br. s, 1 H) ppm. 13C NMR
amide (3f): Yellow solid (0.302 g, 90 %), m.p. 142–144 °C (DCM/
(100 MHz, [D6]DMSO): major conformer: δ = 13.1, 22.4, 35.0, 114.5,
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115.3, 123.1, 129.3, 132.7, 143.0, 155.9, 170.2 ppm; minor conformer:
δ = 13.2, 20.6, 34.6, 115.5, 129.4, 143.5, 156.0, 171.5 ppm. HRMS
(ESI-TOF): calcd. for C13H16N3O2 [M + H]+ 246.1237; found 246.1224.
2.32 (s, 3 H), 3.62 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): major
conformer: δ = 13.9, 22.7, 35.2, 110.4, 119.0, 125.5, 125.7, 126.8,
128.6, 134.3, 137.9, 144.0, 169.5 ppm. HRMS (ESI-TOF): calcd. for
C15H18N3O [M + H]+ 256.1444; found 256.1430.
N-[4-(4-Hydroxyphenyl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]-
acetamide (3l): White solid (0.221 g, 72 %), m.p. 251–252 °C (acet-
one/hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer: δ =
2.02 (s, 3 H), 3.66 (s, 3 H), 6.73 (d, J = 8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz,
2 H), 7.22–7.30 (m, 3 H), 7.34–7.37 (m, 2 H), 9.41 (s, 1 H), 9.71 (s, 1
H) ppm; minor conformer: δ = 1.56 (s), 3.77 (s), 6.76 (d, J = 8.8 Hz),
6.99 (d, J = 8.8 Hz), 9.23 (s), 9.49 (s) ppm. 13C NMR (100 MHz,
[D6]DMSO): major conformer: δ = 22.4, 35.5, 114.6, 115.3, 122.7,
127.1, 127.2, 128.2, 130.4, 133.7, 134.3, 145.9, 156.3, 170.3 ppm; mi-
nor conformer: δ = 20.7, 35.2, 115.6 ppm. HRMS (ESI-TOF): calcd. for
C18H18N3O2 [M + H]+ 308.1394; found 308.1393.
(E)-N-(1-Methyl-3-phenyl-4-styryl-1H-pyrazol-5-yl)acetamide
(3r): White solid (0.257 g, 81 %), m.p. 78–80 °C (DCM/hexanes). H
1
NMR (400 MHz, [D6]DMSO): δ = 2.16 (s, 3 H), 3.67 (s, 3 H), 6.78 (d,
J = 16.7 Hz, 1 H), 6.96 (d, J = 16.7 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H),
7.33 (t, J = 7.5 Hz, 2 H), 7.37–7.42 (m, 3 H), 7.47 (t, J = 7.5 Hz, 2 H),
7.59 (m, 2 H), 10.04 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 22.6, 35.7, 110.5, 118.5, 125.8, 127.2, 127.7, 127.8, 128.0, 128.6,
128.7, 133.6, 134.3, 137.5, 147.4, 169.8 ppm. HRMS (ESI-TOF): calcd.
for C20H20N3O [M + H]+ 318.1601; found 318.1600.
(E)-N-[4-(4-Methoxystyryl)-1,3-dimethyl-1H-pyrazol-5-yl]acet-
amide (3s): White solid (0.237 g, 83 %), m.p. 157–159 °C (DCM/
N-[4-(2-Methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl]acetam-
ide (3m): White solid (0.222 g, 86 %), m.p. 66–70 °C. 1H NMR
(400 MHz, [D6]DMSO): major conformer: δ = 1.97 (s, 3 H), 2.00 (s, 3
H), 3.54 (s, 3 H), 3.72 (s, 3 H), 6.95 (td, J = 7.3, 1.0 Hz, 1 H), 7.04 (d,
J = 7.8 Hz, 1 H), 7.07 (dd, J = 7.3, 1.6 Hz, 1 H), 7.29 (td, J = 7.3,
1.6 Hz, 1 H), 9.49 (s, 1 H) ppm; minor conformer: δ = 1.54 (s), 3.64
(s), 9.06 (s) ppm. 13C NMR (100 MHz, [D6]DMSO): major conformer:
δ = 13.1, 22.4, 35.2, 55.1, 111.2, 120.2, 121.1, 128.3, 130.9, 133.8,
144.5, 156.7, 169.7 ppm; minor conformer: δ = 12.9, 20.3, 34.7, 55.2,
112.3, 119.5, 120.7, 128.8, 131.2, 134.8, 145.0, 156.8, 171.5 ppm.
HRMS (ESI-TOF): calcd. for C14H18N3O2 [M + H]+ 260.1394; found
260.1394.
1
hexanes). H NMR (400 MHz, [D6]DMSO): δ = 2.12 (s, 3 H), 2.27 (s, 3
H), 3.51 (s, 3 H), 3.76 (s, 3 H), 6.67 (d, J = 16.7 Hz, 1 H), 6.72 (d, J =
16.7 Hz, 1 H), 6.91 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 8.8 Hz, 2 H), 9.86
(s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 13.9, 22.6, 35.2,
55.1, 110.7, 114.1, 116.8, 125.3, 126.9, 130.6, 133.9, 143.7, 158.4,
169.5 ppm. HRMS (ESI-TOF): calcd. for C16H20N3O2 [M + H]+
286.1550; found 286.1520.
(E)-N-{4-[4-(Trifluoromethyl)styryl]-1,3-dimethyl-1H-pyrazol-5-
yl}acetamide (3t): White solid (0.278 g, 86 %), m.p. 188–190 °C
(DCM). 1H NMR (400 MHz, [D6]DMSO): δ = 2.14 (s, 3 H), 2.31 (s, 3
H), 3.53 (s, 3 H), 6.80 (d, J = 16.6 Hz, 1 H), 7.05 (d, J = 16.6 Hz, 1 H),
7.67 (d, J = 8.6 Hz, 2 H), 7.71 (d, J = 8.6 Hz, 2 H), 9.94 (s, 1 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 13.8, 22.7, 35.3, 110.1, 122.0,
123.6, 124.4 (q, J = 271 Hz), 125.4 (q, J = 4 Hz), 126.1, 126.6 (q, J =
32 Hz), 134.9, 142.1, 144.4, 169.5 ppm. HRMS (ESI-TOF): calcd. for
N-[4-(2-Methoxyphenyl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]-
acetamide (3n): White foam (0.282 g, 88 %), m.p. 70–74 °C. 1H NMR
(400 MHz, [D6]DMSO): major conformer: δ = 1.98 (s, 3 H), 3.41 (s, 3
H), 3.67 (s, 3 H), 6.92–6.97 (m, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 7.06
(dd, J = 7.3, 1.6 Hz, 1 H), 7.18–7.25 (m, 3 H), 7.29–7.33 (m, 3 H), 9.58
(s, 1 H) ppm; minor conformer: δ = 1.61 (s), 3.50 (s), 3.78 (s), 9.12
(s) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.4, 35.7, 54.8, 110.8,
111.5, 120.4, 121.3, 126.0, 127.0, 128.0, 128.9, 131.2, 134.4, 135.1,
146.6, 151.0, 170.0 ppm. HRMS (ESI-TOF): calcd. for C19H20N3O2 [M
+ H]+ 322.1550; found 322.1550.
C
16H17F3N3O [M + H]+ 324.1318; found 324.1290.
N-[4-(Benzo[b]thiophen-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl]-
acetamide (3u): White solid (0.225 g, 79 %), m.p. 149–152 °C (DCM/
hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.14
(s, 3 H), 2.38 (s, 3 H), 3.58 (s, 3 H), 7.30 (dd, J = 7.5, 6.9 Hz, 1 H), 7.36
(dd, J = 7.5, 6.9 Hz, 1 H), 7.39 (s, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.93
(d, J = 7.5 Hz, 1 H), 9.98 (s, 1 H) ppm; minor conformer: δ = 1.65 (s),
3.68 (s), 9.42 (s) ppm. 13C NMR (100 MHz, [D6]DMSO): major con-
former: δ = 14.0, 22.7, 35.1, 108.5, 119.7, 122.0, 123.0, 123.8, 124.4,
133.9, 134.5, 138.1, 139.8, 143.7, 170.0 ppm; minor conformer: δ =
12.3, 22.4, 36.1 ppm. HRMS (ESI-TOF): calcd. for C15H16N3OS [M +
H]+ 286.1009; found 286.1009.
N-[1,3-Dimethyl-4-(o-tolyl)-1H-pyrazol-5-yl]acetamide (3o):
White foam (0.187 g, 77 %). 1H NMR (400 MHz, [D6]DMSO): major
conformer: δ = 1.93 (s, 3 H), 1.94 (s, 3 H), 2.07 (s, 3 H), 3.55 (s, 3 H),
7.03 (dd, J = 7.3, 1.6 Hz, 1 H), 7.17 (td, J = 7.3, 1.6 Hz, 1 H), 7.22 (td,
J = 7.3, 1.6 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 9.61 (s, 1 H) ppm;
minor conformer: δ = 1.51 (s), 1.97 (s), 2.11 (s), 3.66 (s), 9.23 (s) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 12.5, 19.6, 22.4, 35.3, 114.1,
125.5, 127.2, 129.9, 130.8, 131.8, 133.7, 137.0, 143.7, 169.6 ppm.
HRMS (ESI-TOF): calcd. for C14H18N3O [M + H]+ 244.1444; found
244.1445.
N-[4-(Benzo[b]thiophen-2-yl)-1-methyl-3-phenyl-1H-pyrazol-5-
yl]acetamide (3v): White solid (0.263 g, 76 %), m.p. 196–198 °C
(DCM/hexanes). 1H NMR (400 MHz, [D6]DMSO): δ = 2.10 (s, 3 H),
3.71 (s, 3 H), 7.19 (s, 1 H), 7.27–7.39 (m, 5 H), 7.45–7.53 (m, 2 H),
7.77 (dd, J = 6.7, 1.5 Hz, 1 H), 7.90 (dd, J = 7.6, 1.0 Hz, 1 H), 9.99 (s,
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.6, 35.8, 107.7,
122.2, 122.5, 123.4, 124.1, 124.4, 127.9, 128.0, 128.4, 132.9, 133.8,
135.6, 139.3, 139.7, 147.0, 170.2 ppm. HRMS (ESI-TOF): calcd. for
C20H18N3OS [M + H]+ 348.1165; found 348.1166.
N-[1-Methyl-3-phenyl-4-(o-tolyl)-1H-pyrazol-5-yl]acetamide
(3p): White foam (0.247 g, 81 %), m.p. 80–84 °C. 1H NMR (400 MHz,
[D6]DMSO): major conformer: δ = 1.90 (s, 3 H), 1.95 (s, 3 H), 3.70 (s,
3 H), 7.09–7.12 (m, 1 H), 7.19–7.31 (m, 8 H), 9.66 (s, 1 H) ppm; minor
conformer: δ = 1.60 (s), 3.81 (s), 9.29 (s) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 19.7, 22.3, 35.7, 113.9, 125.8, 125.9, 127.2, 127.7,
128.3, 130.0, 130.7, 132.3, 134.0, 134.9, 137.1, 145.8, 169.9 ppm.
HRMS (ESI-TOF): calcd. for C19H20N3O [M + H]+ 306.1601; found
306.1602.
N-[4-(Furan-2-yl)-1,3-dimethyl-1H-pyrazol-5-yl]acetamide (3w):
Prepared from pyrazole 1a and the MIDA ester of furan-2-ylboronic
acid (2n). White solid (0.184 g, 84 %), m.p. 139–141 °C (DCM/hex-
1
(E)-N-(1,3-Dimethyl-4-styryl-1H-pyrazol-5-yl)acetamide (3q):
anes). H NMR (400 MHz, [D6]DMSO): δ = 2.09 (s, 3 H), 2.28 (s, 3 H),
White solid (0.199 g, 78 %), m.p. 143–145 °C (DCM/hexanes). 1H 3.54 (s, 3 H), 6.35 (dd, J = 3.2, 0.7 Hz, 1 H), 6.52 (dd, J = 3.2, 1.8 Hz,
NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.14 (s, 3 H), 2.30
(s, 3 H), 3.53 (s, 3 H), 6.74 (d, J = 16.7 Hz, 1 H), 6.89 (d, J = 16.7 Hz, (100 MHz, [D6]DMSO): δ = 13.8, 22.6, 35.1, 104.8, 105.8, 111.1,
1 H), 7.65 (dd, J = 1.8, 0.7 Hz, 1 H), 9.87 (s, 1 H) ppm. 13C NMR
1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.49 (d, J =
7.5 Hz, 2 H), 9.92 (s, 1 H) ppm; minor conformer: δ = 1.71 (s, 3 H),
132.9, 141.2, 142.8, 147.3, 169.7 ppm. HRMS (ESI-TOF): calcd. for
C11H14N3O2 [M + H]+ 220.1081; found 220.1081.
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N-[4-(Furan-2-yl)-1-methyl-3-phenyl-1H-pyrazol-5-yl]acetamide H), 6.90 (d, J = 8.8 Hz, 2 H), 7.04 (d, J = 8.8 Hz, 2 H), 7.18–7.24 (m,
(3x): Prepared from pyrazole 1c and the MIDA ester of furan-2-
3 H), 7.2–7.31 (m, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
ylboronic acid (2n). Pale-yellow solid (0.216 g, 77 %), m.p. 131– 34.6, 55.0, 101.2, 114.0, 126.1, 126.7, 127.1, 127.9, 130.6, 134.5, 144.7,
1
134 °C (DCM/hexanes). H NMR (400 MHz, [D6]DMSO): δ = 2.08 (s,
3 H), 3.68 (s, 3 H), 6.34 (dd, J = 3.4, 0.7 Hz, 1 H), 6.53 (dd, J = 3.4,
1.8 Hz, 1 H), 7.30–7.45 (m, 5 H), 7.63 (dd, J = 1.8, 0.7 Hz, 1 H), 9.93
(s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.5, 35.8, 105.1,
107.8, 111.3, 127.2, 127.7, 128.2, 133.3, 135.3, 142.2, 145.7, 146.5,
169.9 ppm. HRMS (ESI-TOF): calcd. for C16H16N3O2 [M + H]+
282.1237; found 282.1237.
145.7, 157.3 ppm. HRMS (ESI-TOF): calcd. for C17H18N3O [M + H]+
280.1444; found 280.1444.
1,3-Dimethyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-amine
(7c): White solid (0.163 g, 64 %), m.p. 109–111 °C (DCM/hexanes).
1H NMR (400 MHz, [D6]DMSO): δ = 2.10 (s, 3 H), 3.52 (s, 3 H), 5.33
(s, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 12.9, 33.5, 100.4, 124.5 (q, J =
271 Hz), 124.6 (q, J = 32 Hz), 125.2 (m), 127.7 (q, J = 7 Hz), 138.9,
143.2, 144.5 ppm. HRMS (ESI-TOF): calcd. for C12H13F3N3 [M + H]+
256.1056; found 256.1056.
N-[1-Methyl-3-phenyl-4-(pyridin-3-yl)-1H-pyrazol-5-yl]acetam-
ide (3y): Prepared from pyrazole 1c and 3-pyridylboronic acid pin-
acol ester (2p). White solid (0.169 g, 58 %), m.p. 188–189 °C (DCM/
hexanes). 1H NMR (400 MHz, [D6]DMSO): major conformer: δ = 2.04
(s, 3 H), 3.71 (s, 3 H), 7.29–7.33 (m, 5 H), 7.37 (ddd, J = 7.9, 4.8,
0.9 Hz, 1 H), 7.53 (dt, J = 7.9, 2.2 Hz, 1 H), 8.34 (d, J = 2.2 Hz, 1 H),
8.47 (dd, J = 4.8, 1.3 Hz, 1 H), 9.92 (s, 1 H) ppm; minor conformer:
δ = 1.59 (s), 3.82 (s) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 22.4,
35.7, 111.2, 123.6, 127.4, 127.6, 128.3, 128.4, 133.1, 135.1, 136.4,
146.6, 147.7, 149.5, 170.2 ppm. HRMS (ESI-TOF): calcd. for C17H17N4O
[M + H]+ 293.1397; found 293.1397.
1-Methyl-3-phenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-
amine (7d): White solid (0.202 g, 64 %), m.p. 168–170 °C (DCM/
1
hexanes). H NMR (400 MHz, [D6]DMSO): δ = 3.66 (s, 3 H), 5.38 (s, 2
H), 7.21–7.28 (m, 5 H), 7.31 (dd, J = 8.7, 0.6 Hz, 2 H), 7.63 (dd, J =
8.6, 0.5 Hz, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 34.6, 99.9,
124.6 (q, J = 271 Hz, CF3), 125.2 (q, J = 4 Hz), 125.4 (q, J = 32 Hz),
127.2, 127.6, 128.2, 129.4, 134.0, 138.5, 145.4, 146.4 ppm. HRMS (ESI-
TOF): calcd. for C17H15F3N3 [M + H]+ 318.1213; found 318.1212.
N-[1-Methyl-3-phenyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl]acetam-
ide (3z): Prepared from pyrazole 1a and 4-pyridylboronic acid MIDA
ester (2q). The reaction was performed in a mixture of DMF and 2-
propanol (5 mL, 10:1) in the presence of Cu(OAc)2 (0.031 g,
0.5 mmol). Biaryl 3z was obtained after purification by column chro-
matography as a white solid (0.064 g, 29 %), m.p. 184–186 °C (DCM/
4-(2-Methoxyphenyl)-1-methyl-3-phenyl-1H-pyrazol-5-amine
(7e): White solid (0.184 g, 66 %), m.p. 182–184 °C (MeOH/H2O). H
1
NMR (400 MHz, [D6]DMSO): δ = 3.61 (s, 3 H), 3.64 (s, 3 H), 4.78 (s, 2
H), 6.87 (dd, J = 7.40, 1.2 Hz, 1 H), 6.96 (dd, J = 7.40, 1.69 Hz, 1 H),
7.03 (dd, J = 8.3, 0.9 Hz, 1 H), 7.11–7.21 (m, 3 H), 7.22–7.29 (m, 3
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 34.6, 55.0, 98.1, 111.5,
120.4, 122.5, 126.4, 126.5, 127.8, 127.9, 132.0, 134.9, 145.1, 146.1,
156.9 ppm. HRMS (ESI-TOF): calcd. for C17H18N3O [M + H]+ 280.1444;
found 280.1444.
1
hexanes). H NMR (400 MHz, [D6]DMSO): δ = 2.07 (s, 3 H), 3.71 (s, 3
H), 7.14 (dd, J = 4.6, 1.6 Hz, 2 H), 7.30–7.35 (m, 5 H), 8.51 (dd, J =
4.6, 1.6 Hz, 2 H), 10.02 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 22.5, 35.7, 111.9, 123.6, 127.7, 127.9, 128.5, 132.9, 135.3, 140.3,
146.9, 149.6, 170.3 ppm. HRMS (ESI-TOF): calcd. for C17H17N4O [M +
H]+ 293.1397; found 293.1397.
1,3-Dimethyl-4-(o-tolyl)-1H-pyrazol-5-amine (7f): Pale-yellow
solid (0.158 g, 79 %), m.p. 103–105 °C (DCM/hexanes). 1H NMR
(400 MHz, [D6]DMSO): δ = 1.84 (s, 3 H), 2.0 (s, 3 H), 3.51 (s, 3 H),
4.73 (s, 2 H), 6.99–7.05 (m, 1 H), 7.09–7.16 (m, 2 H), 7.18–7.23 (m, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 12.5, 19.7, 34.0, 101.7,
125.5, 126.4, 129.9, 131.2, 133.2, 137.3, 143.2, 143.6 ppm. HRMS (ESI-
TOF): calcd. for C12H16N3 [M + H]+ 202.1339; found 202.1339.
General Procedure for the Synthesis of Biaryls 7a–i by the Suz-
uki–Miyaura Reaction: See Table 3. The corresponding pyrazole
(1.0 mmol), boronic acid (2.0 mmol), potassium carbonate (0.272 g,
2.0 mmol), and XPhos (0.009 g, 0.020 mmol) were weighed into a
pressure tube and dioxane (3 mL) and water (1 mL) were added
successively. The mixture was degassed for 5 min by using a needle
connected to a nitrogen supply. XPhos Pd G2 (0.008 g, 0.010 mmol)
was added while maintaining a flow of nitrogen. The tube was
quickly closed with a screw cap and inserted into an oil bath pre-
heated to 100 °C. The mixture was stirred at approximately 700 rpm
for 8 h. After that, the mixture was filtered through Celite, washed
with EtOAc, and partitioned between EtOAc and water. The organic
layer was separated, dried with Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatogra-
phy on silica gel (DCM/MeOH, 100:0–100:5) to give the desired bia-
ryl. The title product was sufficiently pure according to NMR and
HPLC–MS; however, it was further crystallized from a mixture of
DCM and hexanes or other solvent systems before measurement of
the melting point.
1,3-Dimethyl-4-(thiophen-3-yl)-1H-pyrazol-5-amine (7g): White
solid (0.137 g, 71 %), m.p. 93–95 °C (DCM/hexanes). 1H NMR
(400 MHz, [D6]DMSO): δ = 2.09 (s, 3 H), 3.50 (s, 3 H), 5.07 (s, 2 H),
7.21 (dd, J = 4.7, 1.0 Hz, 1 H), 7.23 (dd, J = 3.1, 1.0 Hz, 1 H), 7.54 (d,
J = 4.7, 3.1 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 13.6,
34.0, 97.8, 117.9, 125.4, 127.2, 134.3, 142.9, 143.7 ppm. HRMS (ESI-
TOF): calcd. for C9H12N3S [M + H]+ 194.0746; found 194.0746.
4-(Furan-3-yl)-1-methyl-3-phenyl-1H-pyrazol-5-amine (7h): Pre-
pared from pyrazole 6b and furan-3-ylboronic acid (2s). Pale-yellow
solid (0.160 g, 67 %), m.p. 142–144 °C (DCM/hexanes). 1H NMR
(400 MHz, [D6]DMSO): δ = 3.63 (s, 3 H), 5.10 (s, 2 H), 6.17 (t, J =
1.6 Hz, 1 H), 7.22–7.27 (m, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.42–7.46
(m, 2 H), 7.61–7.64 (m, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 34.6, 92.0, 111.6, 117.3, 127.0, 127.2, 128.0, 134.5, 139.1, 142.9,
145.0, 146.3 ppm. HRMS (ESI-TOF): calcd. for C14H14N3O [M + H]+
240.1131; found 240.1132.
1,3-Dimethyl-4-(p-tolyl)-1H-pyrazol-5-amine (7a): White solid
(0.152 g, 76 %), m.p. 100–102 °C (DCM/hexanes). 1H NMR (400 MHz,
[D6]DMSO): δ = 2.04 (s, 3 H), 2.30 (s, 3 H), 3.51 (s, 3 H), 4.98 (s, 2 H),
7.12–7.18 (m, 4 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 13.2,
20.7, 34.0, 101.8, 127.8, 129.1, 131.4, 133.6, 142.8, 143.6 ppm. HRMS
(ESI-TOF): calcd. for C12H16N3 [M + H]+ 202.1056; found 202.1056.
1-Methyl-4-(5-methylthiophen-2-yl)-3-phenyl-1H-pyrazol-5-
amine (7i): Prepared from pyrazole 6b and 4,4,5,5-tetramethyl-2-(5-
methylthiophen-2-yl)-1,3,2-dioxaborolane (2t). White solid (0.188 g,
70 %), m.p. 121–123 °C (DCM/hexanes). 1H NMR (400 MHz,
[D6]DMSO): δ = 2.36 (d, J = 1.0 Hz, 3 H), 3.58 (s, 3 H), 5.12 (s, 2 H),
6.61 (d, J = 3.4 Hz), 6.70 (dd, J = 3.4, 1.0 Hz, 1 H), 7.15–7.25 (m, 3
H), 7.34–7.39 (m, 2 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
15.0, 34.7, 94.3, 125.7, 126.3, 127.0, 127.1, 128.0, 132.9, 134.0, 138.3,
4-(4-Methoxyphenyl)-1-methyl-3-phenyl-1H-pyrazol-5-amine
1
(7b): White solid (0.167 g, 60 %), m.p. 139–142 °C (MeOH/H2O). H
NMR (400 MHz, [D6]DMSO): δ = 3.64 (s, 3 H), 3.75 (s, 3 H), 4.96 (s, 2
Eur. J. Org. Chem. 2016, 2013–2023
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145.8, 146.3 ppm. HRMS (ESI-TOF): calcd. for C15H16N3S [M + H]+
270.9941; found 270.9941.
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6350.
1-Methyl-3-phenyl-4-(pyridin-3-yl)-1H-pyrazol-5-amine (7j): Pre-
pared from pyrazole 6b and 3-pyridylboronic acid pinacol ester
(2p). White solid (0.150 g, 60 %), m.p. 140–142 °C (DCM/hexanes).
1H NMR (400 MHz, [D6]DMSO): δ = 3.66 (s, 3 H), 5.33 (s, 2 H), 7.21–
7.28 (m, 5 H), 7.32 (ddd, J = 7.8, 4.7, 0.7 Hz, 1 H), 7.50 (dd, J = 7.8,
1.6 Hz, 1 H), 8.32 (d, J = 1.6 Hz, 1 H), 8.39 (dd, J = 4.7, 1.4 Hz, 1
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 34.6, 97.9, 123.5, 127.1,
127.4, 128.1, 130.0, 134.1, 136.4, 145.4, 146.4, 149.9 ppm. HRMS (ESI-
TOF): calcd. for C15H15N4 [M + H]+ 251.1291; found 251.1291.
1-Methyl-3-phenyl-4-(pyridin-4-yl)-1H-pyrazol-5-amine (7k):
Prepared from pyrazole 6b and 4-pyridylboronic acid MIDA ester
(2q). The reaction was carried out in the presence of Cu(OAc)2
(50 mol-%). Product 7k was isolated as a pale-yellow solid (0.090 g,
36 %), m.p. 193–195 °C (DCM/hexanes). 1H NMR (400 MHz,
[D6]DMSO): δ = 3.62 (s, 3 H), 5.48 (s, 2 H), 7.03 (d, J = 4.5 Hz, 2 H),
7.22–7.27 (m, 5 H), 8.36 (d, J = 4.5 Hz, 2 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 34.6, 98.6, 123.3, 127.3, 127.7, 128.2, 134.0, 141.7,
145.6, 146.7, 149.5 ppm. HRMS (ESI-TOF): calcd. for C15H15N4 [M +
H]+ 251.1291; found 251.1291.
Hydrolysis of N-Acetamide 3a: A mixture of pyrazole 3a (0.243 g,
1.0 mmol) and KOH (0.168 g, 3.0 mmol) in EtOH/H2O (2:1, 6 mL)
was heated at reflux with a condenser for 48 h. Then the reaction
mixture was diluted with EtOAc and brine and the organic layer
was separated. The aqueous layer was extracted twice with EtOAc
and the combined organic layers were dried with Na2SO4. The crude
product was purified by column chromatography to yield the biaryl
7a as a white solid (0.178 g, 89 %). Analytical data are identical to
those of the same compound prepared by the Suzuki coupling reac-
tion using XPhos Pd G2.
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Acknowledgments
This work was supported by the Czech National Program for
Sustainability (project LO1304).
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Lett. 2010, 20, 1293.
Keywords: Homogeneous catalysis · C–C coupling · Cross-
coupling · Nitrogen heterocycles
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Received: January 19, 2016
Published Online: March 24, 2016
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