The Suzuki-Miyaura Cross-Coupling Reaction of Halogenated Aminopyrazoles: Method Development, Scope, and Mechanism of Dehalogenation Side Reaction

Article abstract of DOI:10.1021/acs.joc.6b02306

The efficient Suzuki-Miyaura cross-coupling reaction of halogenated aminopyrazoles and their amides or ureas with a range of aryl, heteroaryl, and styryl boronic acids or esters has been developed. The method allowed incorporation of problematic substrates: aminopyrazoles bearing protected or unprotected pyrazole NH, as well as the free amino or N-amide group. Direct comparison of the chloro, bromo, and iodopyrazoles in the Suzuki-Miyaura reaction revealed that Br and Cl derivatives were superior to iodopyrazoles, as a result of reduced propensity to dehalogenation. Moreover, the mechanism and factors affecting the undesired dehalogenation side reaction were revealed.

Full text of DOI:10.1021/acs.joc.6b02306

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Article
The Suzuki-Miyaura cross-coupling reaction of halogenated aminopyrazoles:
method development, scope, and mechanism of dehalogenation side reaction
Lukas Jedinak, Renáta Zátopková, Hana Zemánková, Alena Šustková, and Petr Canka#
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02306 • Publication Date (Web): 08 Dec 2016
Downloaded from http://pubs.acs.org on December 8, 2016
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The Suzuki-Miyaura cross-coupling reaction of halogenated aminopyrazoles: method
development, scope, and mechanism of dehalogenation side reaction
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Lukáš Jedinák,a Renáta Zátopková,b Hana Zemánková,b Alena Šustková,b and Petr Cankařb*
a Institute of Molecular and Translation Medicine, Faculty of Medicine, Palacký University, Hněvotínská 5, 77900
Olomouc, Czech Republic
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b Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, 77146 Olomouc,
Czech Republic
Email: petr.cankar@upol.cz
ABSTRACT
The efficient SuzukiꢀMiyaura crossꢀcoupling reaction of halogenated aminopyrazoles and their
amides or ureas with a range of aryl, heteroaryl, and styryl boronic acids or esters has been
developed. The method allowed incorporation of problematic substrates: aminopyrazoles bearing
protected or unprotected pyrazole NH, as well as the free amino or Nꢀamide group. Direct
comparison of the chloro, bromo, and iodopyrazoles in the SuzukiꢀMiyaura reaction revealed that
Br and Cl derivatives were superior to iodopyrazoles, as a result of reduced propensity to
dehalogenation. Moreover, the mechanism and factors affecting the undesired dehalogenation
side reaction were revealed.
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INTRODUCTION
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The SuzukiꢀMiyaura crossꢀcoupling reaction is useful method allowing chemists to generate
effectively more complex molecules from simpler fragments through the formation of sigma
carbon – carbon bond.1,2 This, among other reasons, caused that the SuzukiꢀMiyaura reaction has
been implemented as a valuable tool for the synthesis of biologically active molecules, fine
chemicals, and natural products.3,4 On the other hand, several limitations and challenges occurred
when the SuzukiꢀMiyaura and other transition metal catalyzed reactions were used in conjunction
with heterocyclic compounds.5ꢀ7 Given importance of heterocyclic systems for medicinal
chemistry, many research groups spent great effort to implement transition metal catalyzed
transformations into the syntheses and modifications of heteroarenes.8ꢀ10
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In this context, there are two major problems with respect to the SuzukiꢀMiyaura reaction: (1)
coordination of the heterocyclic substrate/product to the metal center resulting in the inhibition or
deactivation of the catalyst,11,12 and (2) instability and/or poor reactivity of some boronic acids
(e.g. 2ꢀheteroaryl and pyridyl boronic acids) leading to the undesired side reactions, such as
protodeboronation and oxidative homo coupling.13 The first issue has been largely solved by the
use of new advanced palladium (pre)catalysts and ligands,14ꢀ18 while the development of
alternative organoboron reagents, particularly MIDA esters19 and trifluoroborates,20 solved the
second issue. Nevertheless, the problems associated with electrophilic coupling partners,
particularly electronꢀrich heteroaryl halides, and understanding the mechanism of their side
reactions received inadequate attention. The reductive homo coupling and especially
dehalogenation of (hetero)aryl halides accompanied many CꢀC a CꢀN crossꢀcoupling reactions,
which consequently led to lower yields and complicated isolation of product.21,22
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We were interested in the synthesis of the 4ꢀsubstituted aminopyrazoles, especially 4ꢀstyryl
aminopyrazoles due to their structural similarity to 4ꢀarylazo pyrazoles, which were found as the
potent inhibitors of cyclinꢀdependent kinases.23 However, a parallel synthesis of 4ꢀaryl
aminopyrazoles using traditional step by step methods appeared less efficient in comparison to
the synthetic strategies based on transition metal catalyzed crossꢀcoupling chemistry. Moreover,
the access to 4ꢀstyryl aminopyrazoles via traditional methods seemed to be difficult. Therefore
we spent an effort on the development of a SuzukiꢀMiyaura crossꢀcoupling method for 4ꢀ
halogenated aminopyrazoles, which are challenging coupling partners for such reaction.24
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Attention was paid to achieve two main targets: (1) manage substrate scope as broad as possible
with respect to the both coupling partners, and (2) reach high conversion to a coupling product by
suppression of impurities formation in order to simplify product purification. Herein, we reported
our results on the SuzukiꢀMiyaura reaction using halogenated aminopyrazoles as problematic
substrates for metal catalyzed crossꢀcoupling reactions. In addition, we provided a deeper insight
into the undesired and not well understood dehalogenation side reaction of NH containing
heteroaromatic compounds. Despite the dehalogenation of simple aromatic halides can proceed
through the βꢀelimination of alkoxypalladium complexes,25,26 this mechanism is not the
predominant pathway in the case of NH containing heteroarenes.
Table 1. Optimization of reaction conditions
entry
1
solvent
base
[Pd]
ligand
XPhos
T (°C)
100
X
3aa
1a
4a
89
Dioxane
K2CO3
Pd(OAc)2
Br
2
1
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2
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Dioxane
EtOH
MeCN
DMF
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
CsF
XPhos Pd G2
Pd(OAc)2
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
SPhos
BINAP
dppf
100
90
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
16
57
20
4
18
11
8
60
24
62
94
59
48
79
74
40
65
41
30
8
4
Pd(OAc)2
90
5
Pd(OAc)2
100
90
0
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6
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Pd(OAc)2
33
5
0
7
Pd(OAc)2
90
35
0
8
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Pd(OAc)2
90
16
18
8
9
Pd(OAc)2
90
0
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20
Pd(OAc)2
90
33
16
0
Pd(OAc)2
90
9
Pd(OAc)2
PAd2Bu
IPr
90
50
44
89
33b
27c
36
88d
87d
11d
PEPPSI
90
14
0
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos Pd G2
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
90
90
0
59
63
18
7
90
0
70
42
0
135
135
135
0
6
0
84
Structures od ligands and precatalysts
PPh2
Fe
Ph2P
XPhos Pd G2
XPhos
SPhos
rac-BINAP
dppf
PEPPSI-IPr
a HPLC yield (%) determined from the crude reaction mixture (see Supporting Information for more details). b 3
equivalents of K2CO3. c 4 equivalents of K2CO3. d Reaction was carried out in a microwave reactor for 20 minutes.
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RESULTS AND DISCUSSION
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Searching for optimal reaction conditions started with compound 1a that contains free pyrazole
NH, as well as primary amino group; all these features make compound 1a challenging substrate
for the SuzukiꢀMiyaura crossꢀcoupling reaction. Indeed, when 1a was reacted with pꢀtolylboronic
acid 2a in the presence of K2CO3, and a catalytic amount of Pd(OAc)2 and XPhos, only 2% of the
product 3a was detected by LCMS (Table 1, entry 1). The product was accompanied with 1% of
the starting material 1a and 89% of the dehalogenated pyrazole 4. In agreement with our previous
results, the use of precatalyst XPhos Pd G2 instead of Pd(OAc)2 increased the product formation
to 16% (entry 2).27 This can be further improved to 57% if the reaction is performed with
Pd(OAc)2/XPhos in a mixture of EtOH/H2O (entry 3), while DMF and MeCN gave
unsatisfactory results (entries 4 and 5). The use of various bases such as Cs2CO3, CsF, and K3PO4
resulted only in diminished conversion or increased dehalogenation (entries 6 – 8). The
combination of Pd(OAc)2 and SPhos gave only 18% of the product 3a (entry 9). Bidentate
phosphine ligands BINAP and dppf furnished even lower amount of 3a (entries 10 and 11).
Trialkyl phosphine ligand PAd2Bu provided comparable result to XPhos (50% of 3a, entry 12).
From a range of available NHCꢀPd catalysts, we tested 3ꢀchloropyridyl stabilized Pd(II)
precatalyst known as PEPPSI, which contained IPr as a supporting ligand. However, PEPPSIꢀIPr
did not provide any improvement giving the mixture of 3a, 1a and 4 in a ratio of 44:14:30 (entry
13).
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The nature of the palladium preꢀcatalyst (or Pd source) is of significance for the efficient crossꢀ
coupling, as it determines the formation and availability of the active LnPd(0) species.28 If the
active ligated Pd(0) is formed readily and under mild conditions, it can diminish unwanted side
reactions of both coupling partners, such as protodeboronation and oxidative homocouping of
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boronic acids, and dehalogenation of aryl halides. When the XPhos derived precatalyst XPhos Pd
G2 was used instead of Pd(OAc)2 in EtOH/H2O, the amount of the product 3a considerably
increased to 89% (entry 14). LCMS of the reaction mixture showed that the starting material 1a
was completely consumed and dehalogenated pyrazole 4 was formed in 8% after 20 hours.29
Increasing the amount of a base, or decreasing reaction temperature to 70 °C resulted in the
increased dehalogenation (entries 15 and 16), or incomplete conversion of the starting material
(entry 17). The reaction time was reduced to 20 minutes, when the reaction was heated in a
microwave reactor at 135 °C (entry 18).30 Subsequently, 88% of the product 3a and 7% of
dehalogenated pyrazole 4 were formed. The coupling product 3a was then isolated in 78% yield
from either entry 14 or entry 18.
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Finally, the reactivity of chloro 1b and iodo 1c pyrazoles was compared to bromo derivative 1a.
On heating in a microwave reactor at 135 °C for 20 minutes, chlorinated pyrazole 1b displayed
nearly the same reactivity as 1a, providing 87% of the coupling product 3a and 6% of
dehalogenated pyrazole 4 (entry 19). On the other hand, iodo derivative 1c showed the increased
tendency to deiodination, furnishing 84% of dehalogenated pyrazole 4 (entry 20) and only 11%
of product 3a.
Under the optimized conditions (Table 1, entry 18), the scope of the Suzuki reaction between
pyrazole 1a and various aryl, heteroaryl, and styryl boronic acids was examined (Table 2).
Boronic acids bearing electronꢀdonating groups reacted smoothly furnishing biaryls 3b and 3c in
high yields. Moreover, high yield of 3c demonstrated that the reaction is somewhat tolerant to
sterically hindered boronic acids. Note that pyrazole 1a itself is “ortho” disubstituted. Likewise,
the coupling of pyrazole 1a with styrylboronic acid 2d gave stilbeneꢀlike structure 3d in 84%
isolated yield. As expected, electronꢀpoor boronic acid 2e gave lower conversion, as well as a
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portion of unreacted starting material 1a and dehalogenated pyrazole 4. Thus, biaryl 3e bearing
strongly electronꢀwithdrawing pꢀCF3 group was isolated in only 30% yield.
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In order to evaluate the Suzuki reaction of 1a with heteroaromatic nucleophiles, we selected
representatives of oxygen, sulfur, and nitrogen containing heteroarenes. The coupling with 2ꢀ
thienylboronate 2f afforded the respective biaryl product 3f in 57% yield. A better result was
achieved with 3ꢀfuranyl boronic acid 2g, which afforded biaryl 3g in 74% yield on coupling with
pyrazole 1a. Unfortunately, MIDA ester of problematic 4ꢀpyridylboronic acid 2h gave traces of
coupling product 3h, which precluded its isolation. Various solvents and additives, such as CuI
and Cu(OAc)2, were employed in order to improve the product conversion; however, neither one
improved the conversion of 3h significantly.31
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Table 2. Scope of the Suzuki-Miyaura reaction using pyrazole 1a
entry
1
nucleophile
product
yield (%)
78
2
3
87
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NIa
a Not isolated.
Table 3. Scope of the Suzuki-Miyaura reaction using pyrazole 5
entry
product
method
A
X
Br
Cl
I
yield
79
77
1
2
3
83
4
B
Br
88
5
6
A
B
I
84
89
Br
7
8
A
B
I
60
70
Br
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A
B
I
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Br
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12
A
B
I
83
85
Br
Method A: pyrazole 5 (1 mmol), K2CO3 (2 mmol), boronic acid (2 mmol), Xphos Pd G2 (1 mol%), XPhos (2 mol%),
dioxane/H2O, 100 °C, 24h. Method B: pyrazole 5a (1 mmol), K2CO3 (2 mmol), boronic acid (2 mmol), Xphos Pd G2
(1 mol%), XPhos (2 mol%), EtOH/H2O, µW 120 °C, 20 minutes.
In the next step, we examined the SuzukiꢀMyiaura reaction of halogenated pyrazoles 5a-c
without substitution at Cꢀ3 (Table 3). These pyrazoles are structurally related to our previously
reported ones, where Me or Ph was attached to this position.27 We found that pyrazoles 5a-c were
less reactive in the Suzuki reaction and less susceptible to the dehalogenation (with respect to C3ꢀ
substituted pyrazoles from the reference 27). Initially, the optimized reaction conditions from
reference 27 were applied (method A). This method led to the incomplete consumption of
brominated and chlorinated pyrazoles 5a and 5b, while iodide 5c was completely consumed
during the reaction. For instance, when chloride 5a or bromide 5b reacted with pꢀtolylboronic
acid 2a in a mixture of dioxane/H2O at 100 °C (method A), biaryl 6a was isolated in 77% and
79%, respectively (entries 1 and 2). In both cases, unreacted starting material 5a/5b was observed
in a reaction mixture even after 24h. On the other hand, using the same conditions, iodide 5c was
completely consumed, providing 6a in 83% yield (entry 3). The reaction rate can be further
accelerated by elevating the temperature to 120 °C and switching a solvent system to EtOH/H2O
(method B). Method B was derived from the optimized conditions in Table 1 However, we found
that the reaction temperature for the substrate 5a can be slightly lower (120 °C) than 135 °C
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required for pyrazole 1a. The full conversion of bromide 5b was achieved after just 20 minutes,
providing biaryl 6a in 88% yield (entry 4).
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9
In this context, iodinated pyrazole 5c (method A) or brominated pyrazole 5a (method B) were
coupled with a set of representative boronic acids yielding biaryls 6a-e (Table 3). In all cases, the
reaction using bromide 5b, higher temperature (120 °C), and a solvent system EtOH/H2O
provided higher yields of the respective coupling products. This was applied for the coupling of
sterically hindered boronic acid (entries 5 vs. 6), styrylboronic acid (entries 7 vs. 8), and
heteroarylboronic acid (entries 11 vs. 12). The lower reactivity of the electron poor boronic acid
resulted in the increased dehalogenation, therefore biaryl 6d containing CF3 group was isolated in
53% (method A, entry 9) and 62% yield (method B, entry 10), respectively.
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Up to this point, we have explored the Suzuki coupling of aminopyrazoles featuring endocyclic
NꢀMe vs NꢀH (Table 2 vs. Table 3 and ref. 24), exocyclic NH2 vs. NHꢀAc (ref. 27 and Table 2),
and varying the Cꢀ3 substitution (Table 3 and ref. 27). Finally, we wished to explore the effect of
diverse substituents connected to the amino group on the crossꢀcoupling reaction. Therefore we
synthesized 4ꢀbrominated aminopyrazoles 7a-h and one chlorinated derivative 7i bearing diverse
Nꢀamide substitution in two steps using readily available starting materials (Scheme 1). The
crossꢀcoupling of pyrazole amides 7a-d and boronic acids (or esters in some cases) required just
20 minutes and 110 °C (Table 4), which was somewhat lower temperature compared to
unsubstituted pyrazoles 1a-c (see Tables 1 and 2 for comparison).32
Scheme 1. Preparation and structures of pyrazoles 7a-i
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R1COOH, T3P or
R1COCl or
N
N
N
R1=C=O
O
N
6
7
8
9
R1
N
H2N
N
then NBS or NCS
H
X
7a-i
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N
N
N
N
N
N
O
O
O
N
O
N
N
N
N
H
X
H
H
H
Br
Br
Br
S
MeO
7c
7d
7a: X = Br
7i: X = Cl
7b
N
N
N
N
N
O
N
O
N
O
N
O
N
N
N
N
N
H
N
H
H
H
H
Br
Br
Br
Br
N
N
O
7f
7g
7h
7e
Table 4 Scope of the Suzuki-Miyaura reaction using pyrazoles 7a-i
8a (80%) from 7a: X = Br
8a (78%) from 7i: X = Cl
8b (83%) from 7a: X = Br
8c (79%) from 7a: X = Br
8d (78%) from 7a: X =
Br
8e (76%)a from 7a: X = Br
8f (82%) from 7b: X = Br
8g (75%) from 7b: X = Br
8h (83%)
from 7b: X = Br
8i (80%)b from 7b: X = Br
8j (88%) from 7c: X = Br
8n (85%) from 7c: X = Br
8k (87%) from 7c: X = Br
8o (46%) a from 7c: X = Br
8l (87%) from 7c: X =
Br
8m (86%)a from 7c: X = Br
8p (70%) from 7d: X =
Br
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8q (28%) from 7d: X = Br
8u (77%) from 7i: X = Cl
9a (77%)c from 7g: X = Br
9e (63%)c from 7h: X = Br
8r (59%) from 7d: X = Br
8s (NI) from 7e: X = Br
8t (NI) from 7f: X = Br
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N
O
N
N
H
MeO
OMe
8v (85%) from 7i: X = Cl
8w (NI)e from 7i: X = Cl
8w (90%)e from 7a: X = Br
N
N
O
N
N
H
H
9b (44%)c from 7g: X = Br
9c (76%)c from 7g: X = Br
9d (50%)c from 7g: X =
Br
9f (89%)c from 7h: X = Br
9g (45%)c,d from 7h: X = Br
9h (81%)c from 7h: X =
Br
a Pinacol ester was used. b MIDA ester was used. c Reaction temperature 60 °C. d Reaction time 40 minutes.
e Potassium 3ꢀmethoxyphenyltrifluoroborate was used.
We speculated that bulky substituents around CꢀBr can potentially hinder the crossꢀcoupling
reaction. To our delight, phenyl, cyclopropyl, and tertꢀbutylcarboxamides 7a-c reacted smoothly
with a range of electronꢀrich, electronꢀpoor, sterically hindered, and heteroaryl boronic acids
producing biaryls 8a-n in high yields (75 – 88%). The exception was the coupling with pinacol
ester of 3ꢀpyridylboronic acid, which gave a lower yield of the respective product 8o (46%).
Amides 7d-f featuring substituent with additional coordinating heteroatoms possessed a negative
effect on the reaction. Thus biaryls 8p, 8q, and 8r bearing lateral 2ꢀthienyl scaffold were obtained
from the amide 7d in diminished yields (70, 28 and 59%, respectively). Lateral pyridine
substituent of 7e displayed pronounced inhibitory effect on the reaction; therefore the coupling of
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7e with pꢀtolylboronic acid furnished only traces of the respective product 8s, which precluded its
isolation. To examine whether the catalyst inhibition, apparently caused by pyridine ring
nitrogen, can be reversed, we synthesized Nꢀoxide 7f and employed it in the reaction with pꢀ
tolylboronic acid.33 Even in this case, unfortunately, only traces of the respective biaryl 8t were
detected. Using both amides 7e and 7f, we tested the possibility of CuI and Cu(OAc)2 coꢀ
catalysis, as well as a combination of solvents (DMF, iꢀPrOH) and additives (N,Nꢀ
diethanolamine); however, none of these attempts increased the conversion of respective products
8s and 8t significantly.31
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Chlorinated pyrazole 7i gave upon coupling with pꢀtolylboronic acid biaryl 8a in 78% yield,
which is close to the yield achieved with its brominated analog 7a (80%). Chlorinated pyrazole 7i
proved to be efficient coupling partner with aryl boronic acids bearing sensitive functional
groups, such as hydroxyl and amino group. Thus, biaryls 8u and 8v containing –OH and –NH2
groups were obtained in 77 and 85% yield, respectively. The reaction of 7i with potassium 3ꢀ
methoxyphenyltrifluoroborate gave a mixture of dehalogenated compound, starting material and
product 8w in the ratio of 1:1:2. The chromatographic separation on silica gel did not allow to
separate compound 7i from 8w. When brominated derivative 7a was used instead of 7i, the
staring material was completely consumed and the major product detected in a crude mixture was
8w, which was subsequently isolated in 90% yield.
Urea derivatives 7g and 7h were found unstable under the reaction condition (110 °C) resulting
in partial hydrolysis of the carboxamide function. Consequently around 30 – 40% of the free
amine product was observed. Hydrolytic instability of 7g and 7h at 110 °C stimulated us to
explore, whether a lower reaction temperature preserves the carboxamide group and still
maintains the effective coupling with various boronic acids. To our delight, the reaction of 7g and
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7h with electronꢀneutral, electronꢀrich, and heterocyclic boronic acids went to completion in just
20 minutes even at 60 °C, giving biaryls 9a, 9c, 9e-f, and 9h in 77 – 89% yields. Under the same
conditions, sterically hindered and electronꢀpoor boronic acids gave an incomplete conversion of
the starting material, leading to biaryls 9b, 9d, and 9g in diminished yields (44 – 50%). Note that
sterically hindered 2ꢀmethoxyphenyl boronic acid gave considerably higher yield than oꢀtolyl
boronic acid, which could be explained by the beneficial electronꢀdonating effect of the methoxy
group.
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During our study, a majority of crossꢀcoupling reactions went to completion; nevertheless all of
them were accompanied with undesired dehalogenation, ranging from ~ 5 to 20% (and more with
pyridylboronates). Unwanted dehalogenation of aryl halides affects Suzuki reaction, as well as
other important crossꢀcouplings; therefore, the recognition of factors causing this side reaction, as
well as understanding its mechanism is of importance for the synthetic community.34
Cleavage of the Cꢀhalogen and forming of the CꢀH bond is obviously a reductive process; hence
one can suspect that the palladium and/or boronic acid are involved in this transformation. In
order to identify factors causing the dehalogenation, we performed experiments with brominated
pyrazole 1a (Table 5). The compound 1a was heated with two equivalents of K2CO3 resulting in
the formation of the dehaloganated pyrazole 4 in 90% (entry 1), and the staring material was
completely consumed. The preliminary observation suggested that the dehalogenation can be a
base promoted process and motivated us to further explore this phenomenon. The same situation
occurred when strong base KOH was used (entry 2). In this case the detected amount of pyrazole
4 was slightly lower presumably due to a partial decomposition. On the other hand, weaker base
KOAc led only to a partial dehalogenation, leaving 61% of staring material 1a untouched (entry
3). In order to minimize the possibility that a low amount of palladium or other heavy metal in
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the inorganic base can distort the result,35 we repeated the experiment with trace metal basis
K2CO3 (entry 4). Complete consumption of the pyrazole 1a occurred and the dehalogenated
pyrazole 4 was formed in 89% even with K2CO3 of 99.995% purity. These findings also
explained why the higher amount of K2CO3 during optimization resulted in the increased
dehalogenation (Table 1, entries 15 and 16).
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The influence of other reaction components on the dehalogenation was also investigated. When
pyrazole 1a was heated with two equivalents of boronic acid 2a, only traces of the dehalogenated
pyrazole 4 were detected together with 95% of the starting material (entry 5). The catalytic
amount of palladium, either Pd(0) or Pd(II), had a little effect on the dehalogenation (entries 6
and 7). In the control experiment, when compound 1a was heated without any additive, no
detectable dehalogenation occurred (entry 8).
Table 5. The evaluation of factors causing dehalogenation
entry
Additive
K2CO3
KOH
equivalents
4 (%)a
90
1a (%)a
1
2
3
4
5
6
7
8
2
0
0
2
82
KOAc
2
2
36
61
0
b
K2CO3
89
2
traces
1
95
95
91
>95
2a
XPhos Pd G2
Pd2dba3/XPhos
none
0.01
0.01/0.02
none
6
0
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a HPLC yield (%) determined from the crude reaction mixture (see Supporting Information for more details). b Trace
metal basis K2CO3 was used.
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Generally, cleavage of the CꢀBr bond can release the bromine atom as a cation, anion, or radical.
Considering that the dehalogenation is promoted by a base, Br+ seems to be a reasonable leaving
group, while the formation of bromine radical and anion is unlikely. The plausible mechanism of
the baseꢀpromoted dehalogenation leading to pyrazole 4 is depicted in Scheme 2. Deprotonation
of 1a leads to the anion 10 and its resonance contributor 11 that can accept a proton from a
solvent to form 4ꢀH tautomer 12. Rearomatization by releasing of Br+ species from 12 generates
the anion 13, which after protonation gives dehalogenated pyrazole 4. Likewise, Nꢀmethyl
analogs (e.g. 5 or 7) are expected to deprotonate the amidic NH bond.
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Scheme 2.
When Nꢀmethyl pyrazole 14 was heated with two equivalents of K2CO3, no dehalogenation
product 15 was observed (Scheme 3). Consequently, >95% of starting material 14 remained
unchanged, as was revealed by the HPLC analysis of a crude reaction mixture. The propensity of
14 toward base promoted dehalogenation suggested that the presence of more acidic azole NꢀH or
amide NꢀH is required for the proposed mechanism to be operative.
Scheme 3.
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In order to prove that mildly oxidizing Br+ species are formed during dehalogenation of 1a, we
heated thoroughly degassed mixture of pyrazole 1a, K2CO3, and thiophenol in EtOH/H2O to 110
°C under microwave irradiation. As a result, dehalogenated pyrazole 4 and disulfide 16 were
formed quantitatively (Scheme 4). When the same experiment was repeated without pyrazole 1a,
more than 98% of thiophenol remained unchanged. Traces of disulfide 16 were detected,
presumably as a consequence of the presence of residual oxygen. The same experiment was
repeated in the presence of pyrazole 4, in order to prove that it cannot act as an oxidizing agent,
and thiophenol remained practically unchanged (see Supporting Information for more details).
Pyrazole 1a and K2CO3 were also heated in a presence of 4ꢀmethoxystyrene, anisole, or phenol in
order to trap suggested Br+ species. However, any electrophilic addition or substitution was not
observed.
Scheme 4. Oxidation of thiophenol by released Br+ species
H
N
K2CO3
EtOH/H2O
N
S
SH
S
4
+
H2N
+
W, 110 °C
20 min
Br
16
1a
> 98% by LCMS
The proposed mechanism corresponds to the observed ratio of pyrazoles 1, 3a, and 4 (Table 1,
entries 18ꢀ20), where iodopyrazole 1c predominantly underwent dehalogenation. This can be
explained by the increased iodine susceptibility to oxidation. Our explanation, that deprotonation
of mildly acidic NH is involved in a mechanism leading to the dehalogenation, agrees with the
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observation of others. For instance, Nꢀunprotected indoles were reported to suffer from unwanted
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dehalogenation, which was suppressed by the protection of indole nitrogen.36
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CONCLUSION
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Overall, we have developed the efficient SuzukiꢀMiyaura crossꢀcoupling of various boronic
acids/esters with 4ꢀhalogenated aminopyrazoles featuring the free endocyclic pyrazoleꢀNH/amino
group, NꢀMe/NHꢀacetyl, NꢀMe/NHꢀamides, and NHꢀureas. The use of palladacylce XPhos Pd G2
in a combination with K2CO3 and user friendly solvent system EtOH/H2O afforded diverse
(hetero)biaryls generally in high yields. Additionally, the presented method allowed the
preparation of 4ꢀstyryl aminopyrazoles, which are otherwise difficult to access by standard
methods. The reaction temperature is strongly dependent on the pyrazole substrate. While some
pyrazoles bearing substituents on both pyrazole NH and amino group can be coupled almost
quantitatively after 20 minutes at 60 °C, unsubstituted pyrazoles required 135 °C for the same
reaction time. The crossꢀcoupling reactions were accompanied with undesired dehalogenation,
which was primarily caused by a base and its mechanism was proposed on the basis of our
experimental observations.
EXPERIMENTAL SECTION
All reactions were carried out under inert atmosphere of nitrogen or argon. All starting materials,
reagents and catalysts were purchased from commercial sources. Solvents were distilled,
degassed, and stored under inert atmosphere. Reactions were monitored by LCMS using Cꢀ18
column and MeCN – 1 mM AcONH4 buffer as a mobile phase. Product purifications were
performed with silica gel (40 ꢀ200 mesh). NMR spectra were recorded with 400 MHz
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spectrometer and chemical shifts are reported in ppm relative to a residual solvent peak. Accurate
mass spectra were measured using ESIꢀTOF detector.
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8
9
General procedure for the cross-coupling of pyrazole 1a (Table 2). A mixture of pyrazole 1a
(0.174 g, 1.0 mmol), boronic acid (2.0 mmol), and K2CO3 (0.276 g, 2.0 mmol) in EtOH (4 mL)
and water (1 mL) was thoroughly degassed with a stream of nitrogen. Then, XPhos (0.009 g, 0.02
mmol) and XPhos Pd G2 (0.008 g, 0.01 mmol) were added and the microwave vial containing the
mixture was capped and inserted into microwave reactor. The reaction mixture was irradiated
(setup: variable power, maximum of 300W, 135 °C) for 20 min. After that, the mixture was
filtered through a Celite, washed with EtOAc, and concentrated under reduced pressure.
Purification of the crude via column chromatography (MeOHꢀEt3NꢀDCM 100:0.5:0 to 100:0.5:3)
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1
afforded desired pyrazole as an oil or solid, which was characterized by H, 13C NMR and
HRMS. In some cases, a product was crystallized from appropriate solvents before measurement
of a melting point.
3ꢀmethylꢀ4ꢀ(4ꢀpꢀtolyl)ꢀ1Hꢀpyrazolꢀ5ꢀamine (3a). The compound 3a is known; however no
analytical data were reported.37 Title compound was prepared according the general procedure
from pyrazole 1a and 4ꢀtolylboronic acid 2a. Purification via column chromatography afforded
1
title product as a white solid (0.146 g, 78%); mp 80 – 82 °C (DCM – hexanes); H NMR (400
MHz, CD3COOD) δ (ppm) = 7.28 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 2.37 (s, 3H), 2.3
13
(s, 3H); C NMR (100 MHz, CD3COOD) δ (ppm) = 149.8, 143.2, 138.4, 130.7, 129.9, 127.8,
106.2, 21.2, 10.5 ppm; HRMS (ESI): calcd for C11H13N3 [M + H]+ 188.1182, found 188.1183.
4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀamine (3b). Pyrazole 3b is a known compound and
its analytical data were in accordance with the literature.38 Title compound was prepared
according the general procedure from pyrazole 1a and 4ꢀmethoxyphenylboronic acid 2b.
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Purification via column chromatography afforded title product as a white solid (0.176 g, 87%);
5
6
1
mp 139 – 141 °C (DCM – hexanes); H NMR (400 MHz, DMSOꢀd6) δ (ppm) = 11.32 (br.s, 1H,
7
8
9
NH), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.32 (br.s, 2H, NH2), 3.75 (s, 3H), 2.13
13
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(s, 3H); C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 156.9, 152.1, 135.2, 129.1, 126.3, 114.0,
104.4, 55.0, 10.8; HRMS (ESI): calcd for C11H13ON3 [M + H]+ 204.1131, found 204.1131.
4ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀamine (3c). Pyrazole 3c is a known compound and
39
its NMR data were in accordance with the literature.
We were not able to crystallize the
compound, albeit it was reported as a solid melting from 67 to 68 °C. Title compound was
prepared according the general procedure from pyrazole 1a and 2ꢀmethoxyphenylboronic acid 2c.
Purification via column chromatography afforded title product as a pale brown oil (0.166 g,
82%); 1H NMR (400 MHz ,DMSOꢀd6) δ (ppm) = 7.24 (td, J = 7.5 Hz, 1.8 Hz, 1H), 7.15 (dd, J =
7.5 Hz, 1.8 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.95 (td, J = 7.5 Hz, 1.0 Hz, 1H), 3.76 (s, 3H), 2.02
13
(s, 3H); C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 156.3, 151.4, 138.3, 130.9, 127.4, 122.2,
120.4, 111.3, 101.5, 55.1, 10.9; HRMS (ESI): calcd for C11H13ON3 [M + H]+ 204.1131, found
204.1132.
(E)ꢀ4ꢀ(4ꢀmethoxystyryl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀamine (3d). Title compound was prepared
according the general procedure from pyrazole 1a and (E)ꢀ(4ꢀmethoxystyryl)boronic acid 2d.
Purification via column chromatography afforded title product as a beige solid (0.192 g, 84%);
mp 171 – 175 °C (DCM – hexanes); 1H NMR (400 MHz, CD3COOD) δ (ppm) = 7.44 (d, J = 8.8
Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 16.6 Hz, 1H), 6.74 (d, J = 17.1 Hz, 1H), 3.80 (s,
3H), 2.41 (s, 3H); 13C NMR (100 MHz, CD3COOD) δ (ppm) = 159.3, 149.0, 142.1, 130.4, 128.4,
127.2, 114.0, 113.8, 102.6, 54.6, 10.1; HRMS (ESI): calcd for C13H15ON3 [M + H]+ 230.1288,
found 230.1289.
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3ꢀmethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrazolꢀ5ꢀamine (3e). The compound 3e is known;
however no analytical data were reported.40 Title compound was prepared according the general
procedure from pyrazole 1a and 4ꢀ(trifluoromethyl)phenylboronic acid 2e. Purification via
column chromatography afforded title product as a pale yellow solid (0.072 g, 30%); mp 114 –
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119 °C (DCM – hexanes), H NMR (400 MHz, DMSOꢀd6) δ (ppm) = 7.68 (d, J = 8.2 Hz, 2H),
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7.57 (d, J = 8.2 Hz, 2H), 2.21 (s, 3H); C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 151.1, 138.8,
138.0, 127.9, 125.3 (q, J = 4 Hz), 124.9 (q, J = 32 Hz), 124.6 (q, J = 272 Hz), 102.8, 11.5; HRMS
(ESI): calcd for C11H10N3F3 [M + H]+ 242.0900, found 242.0900.
3ꢀmethylꢀ4ꢀ(5ꢀmethylthiophenꢀ2ꢀyl)ꢀ1Hꢀpyrazolꢀ5ꢀamine (3f). Title compound was prepared
according the general procedure from pyrazole 1a and 4,4,5,5ꢀtetramethylꢀ2ꢀ(5ꢀmethylthiophenꢀ
2ꢀyl)ꢀ1,3,2ꢀdioxaborolane 2f. Purification via column chromatography afforded title product as a
white solid (0.110 g, 57%); mp 118 – 122 °C (DCM – hexanes); 1H NMR (400 MHz, DMSOꢀd6)
δ (ppm) = 11.45 (br.s, 1H, NH), 6.77 (d, J = 3.1 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H) 4.56 (br.s, 2H,
NH2), 2.42 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 151.4, 137.2, 135.6,
133.5, 125.5, 122.6, 98.8, 14.8, 11.5; HRMS (ESI): calcd for C9H11N3S [M + H]+ 194.0746,
found 194.0748.
4ꢀ(furanꢀ3ꢀyl)ꢀ3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀamine (3g). Title compound was prepared according the
general procedure from pyrazole 1a and furanꢀ3ꢀylboronic acid 2g. Purification via column
chromatography afforded title product as a white solid (0.122 g, 74%); mp 93 – 96 °C (DCM –
hexanes); 1H NMR (400 MHz, DMSOꢀd6) δ (ppm) = 11.31 (br.s, 1H, NH), 7.72 (dd, J = 1.6 Hz,
0.8 Hz, 1H), 7.67 (dd, J = 1.8 Hz, 1.6 Hz, 1H), 6.68 (dd, J = 1.8 Hz, 0.8 Hz, 1H), 4.45 (br.s, 2H,
13
NH2), 2.18 (s, 3H); C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 151.1, 142.8, 137.5 (overlapped
Cꢀ2 of furan and Cꢀ3 of pyrazole), 117.7, 109.7, 95.6, 11.5; HRMS (ESI): calcd for C8H9ON3 [M
+ H]+ 164.0818, found 164.0820.
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General procedure for the cross-coupling of pyrazoles 5 (Table 3). Method A: A mixture of
pyrazole 5c (0.265 g, 1.0 mmol), boronic acid (2.0 mmol), and K2CO3 (0.276 g, 2.0 mmol) in
dioxane (4 mL) and water (1 mL) was thoroughly degassed with a stream of nitrogen. Then,
XPhos (0.009 g, 0.02 mmol) and XPhos Pd G2 (0.008 g, 0.01 mmol) were added and the sealed
tube inserted into a preheated oil bath to 100 °C. The reaction mixture was stirred at 100 °C for
24h. After that, the mixture was filtered through a Celite, washed with EtOAc, and concentrated
under reduced pressure. Purification of the crude via column chromatography (MeOHꢀDCM
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100:0 to 100:3) afforded desired pyrazole as an oil or solid, which was characterized by H, C
NMR and HRMS. In some cases, a product was crystallized from appropriate solvents before
measurement of a melting point.
Method B: A mixture of pyrazole 5a (0.174 g, 1.0 mmol), boronic acid (2.0 mmol), and K2CO3
(0.276 g, 2.0 mmol) in EtOH (4 mL) and water (1 mL) was thoroughly degassed with a stream of
nitrogen. Then, XPhos (0.009 g, 0.02 mmol) and XPhos Pd G2 (0.008 g, 0.01 mmol) were added
and the microwave vial containing the mixture was capped and inserted into microwave reactor.
The reaction mixture was irradiated (setup: variable power, maximum of 300W, 120 °C) for 20
min. After that, the mixture processed the same way as in the method A.
Nꢀ(1ꢀmethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)acetamide (6a). Title compound was prepared from 4ꢀ
tolylboronic acid 2a and pyrazole 5c (Method A, 0.190 g, 83%) or pyrazole 5a (Method B, 0.201
1
g, 88%). Entry 3: white solid; mp 147 ꢀ 148 °C (DCM ꢀ hexanes); H NMR (400 MHz, DMSOꢀ
d6) major conformer
δ (ppm) = 9.88 (s, 1H), 7.71 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.18 (d, J =
8.1 Hz, 2H), 3.61 (s, 3H), 2.29 (s, 3H), 2.10 (s, 3H), minor conformer
δ
(ppm) = 9.36 (s, 1H),
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7.82 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 3.71 (s, 3H), 1.55 (s, 3H); C
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NMR (100 MHz, DMSOꢀd6):
δ
(ppm) = 170.0, 136.0, 135.3, 132.2, 129.4, 129.3, 125.9, 115.7,
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35.5, 22.6, 20.7; HRMS (ESI): calcd for C13H15ON3 [M + H]+ 230.1288, found 230.1289.
Nꢀ(1ꢀmethylꢀ4ꢀ(oꢀtolyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)acetamide (6b). Title compound was prepared from 2ꢀ
methylphenylboronic acid 2i and pyrazole 5c (Method A, 0.192 g, 84%) or pyrazole 5a (Method
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B, 0.203 g, 89%), and obtained as a colourless oil. Entry 5: H NMR (400 MHz, DMSOꢀd6)
major conformer
δ (ppm) = 9.72 (s, 1H), 7.50 (s, 1H), 7.24 ꢀ 7.12 (m, 4H), 3.63 (s, 3H), 2.22 (s,
3H), 2.00 (s, 3H); minor conformer
δ (ppm) = 9.81 (s, 1H), 9.30 (s, 1H), 7.58 (s, 1H), 3.73 (s,
3H), 1.46 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6):
δ
(ppm) = 169.9, 137.6, 135.9, 133.3, 131.6,
130.2, 129.7, 126.9, 125.7, 115.3, 35.7, 22.4, 20.2; HRMS (ESI): calcd for C13H15ON3 [M + H]+
230.1288, found 230.1289.
(E)ꢀNꢀ(1ꢀmethylꢀ4ꢀstyrylꢀ1Hꢀpyrazolꢀ5ꢀyl)acetamide (6c). Title compound was prepared from
(E)ꢀstyrylboronic acid 2j and pyrazole 5c (Method A, 0.144 g, 60%) or pyrazole 5a (Method B,
1
0.168 g, 70%). Entry 7: white solid; mp 107 ꢀ 109 °C (DCM ꢀ hexanes); H NMR (400 MHz,
DMSOꢀd6):
δ (ppm) = 9.91 (s, 1H), 7.77 (s, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz,
2H), 7.21 (t, J = 7.3 Hz, 1H), 6.89 (d, J = 16.5 Hz, 1H), 6.82 (d, J = 16.5 Hz, 1H), 3.60 (s, 3H),
13
2.14 (s, 3H); C NMR (100 MHz, DMSOꢀd6):
δ (ppm) = 169.5, 137.5, 135.1, 133.9, 128.7,
126.9, 125.7, 125.4, 118.1, 113.4, 35.7, 22.7; HRMS (ESI): calcd for C14H15N3O [M + H]+
242.1288, found 242.1288.
Nꢀ(1ꢀmethylꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)acetamide (6d). Title compound was
prepared from 4ꢀ(trifluoromethyl)phenylboronic acid 2e and pyrazole 5c (Method A, 0.150 g,
53%) or pyrazole 5a (Method B, 0.175 g, 62%). Entry 9: white solid; mp 141 ꢀ 142 °C (DCM ꢀ
hexanes); 1H NMR (400 MHz, DMSOꢀd6):
δ
(ppm) = 10.02 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 9.3
13
Hz, 2H), 7.70 (d, J = 9.3 Hz, 2H), 3.65 (s, 3H), 2.13 (s, 3H); C NMR (100 MHz, DMSOꢀd6):
δ
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(ppm) = 169.9, 136.6, 136.5, 133.2, 126.4 (q, J = 32 Hz), 126.2, 125.6 (q, J = 4 Hz), 124.5 (q, J =
271 Hz), 114.3, 35.5, 22.6; HRMS (ESI): calcd for C13H12F3N3O [M + H]+ 284.1005, found
284.1004.
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Nꢀ(1ꢀmethylꢀ4ꢀ(thiophenꢀ3ꢀyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)acetamide (6e). Title compound was prepared
from thiophenꢀ3ꢀylboronic acid 2k and pyrazole 5c (Method A, 0.183 g, 83%) or pyrazole 5a
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(Method B, 0.187 g, 85%). Entry 11: white solid; mp 111 ꢀ 113 °C (DCM ꢀ hexanes); H NMR
(400 MHz, DMSOꢀd6) major conformer:
δ (ppm) = 9.90 (s, 1H), 7.75 (s, 1H), 7.56 (dd, J = 5.0,
3.0 Hz, 1H), 7.48 (dd, J = 3.0, 1.3 Hz, 1H), 7.32 (dd, J = 5.0, 1.3 Hz, 1H), 3.61 (s, 3H), 2.13 (s,
3H); 13C NMR (100 MHz, DMSOꢀd6):
δ
(ppm) = 169.8, 136.1, 132.4, 132.1, 126.2, 126.1, 118.7,
111.8, 35.5, 22.6; HRMS (ESI): calcd for C10H11OSN3 [M + H]+ 222.0696, found 222.0696.
Synthesis of halogenated pyrazoles 7a-h (Scheme 1)
Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ4ꢀmethoxybenzamide (7a). DIPEA (6.97 mL, 40.0
mmol) was added to the mixture of 1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀamine (2.22 g, 20.0 mmol), 4ꢀ
methoxybenzoic acid (3.34 g, 22.0 mmol), and DMAP (0.25 g, 2.0 mmol) in acetonitrile (20 mL).
The solution was cooled in an ice water bath and T3P (50% in EtOAc, 14.3 mL, 24.0 mmol) was
added dropwise. Resulting mixture was stirred at room temperature for 18 hours. After that, Nꢀ
bromosuccinimide (3.91 g, 22.0 mmol) was added in one portion and the mixture was stirred for
another 4 hours. Then the mixture was diluted with water and extracted with EtOAc (3x60 mL).
After removing solvents under reduced pressure the residue was crystallized first from DCM –
hexanes, then from MeOH – H2O yielding title product as white needles (4.46 g, 69%); mp 174 ꢀ
176 °C (MeOH ꢀ H2O); 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 10.16 (s, 1H), 7.99 (d, J = 8.8
Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.62 ꢀ 3.59 (m, 3H), 2.13 (s, 3H); 13C NMR (100
MHz, DMSOꢀd6): δ (ppm) = 165.8, 163.0, 144.7, 135.6, 130.4, 125.3, 114.4, 90.9, 56.0, 36.6,
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12.9; HMRS (ESI): calcd for C13H14BrN3O2 [M + H]+ 324.0342 and 326.0322, found 324.0344
and 326.0319.
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Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)pivalamide (7b). Compound 7b was prepared from
pivalic acid using the same procedure as for compound 7a. Purification via a column
chromatography (SiO2, 0 – 4 % MeOH in DCM) and subsequent crystallization from MeOH ꢀ
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H2O yielded title product as a white solid (3.22 g, 59%); mp 104 ꢀ 106 °C (MeOH ꢀ H2O); H
NMR (400 MHz, DMSOꢀd6): δ (ppm) = 9.36 (s, 1H), 3.52 (s, 3H), 2.10 (s, 3H), 1.24 (s, 9H); 13C
NMR (100 MHz, DMSOꢀd6): δ (ppm) = 177.7, 144.0, 135.1, 90.2, 38.7, 35.7, 27.1. HRMS (ESI):
calcd for C10H16BrN3O [M + H]+ 274.0555 and 276.0535, found 274.0554 and 276.0534.
Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)cyclopropanecarboxamide (7c). Compound 7c was
prepared from cyclopropanecarboxylic acid using the same procedure as for compound 7a.
Purification via a column chromatography (SiO2, 0 – 4 % MeOH in DCM) and subsequent
crystallization from MeOH ꢀ H2O (charcoal) yielded title product as a white solid (3.92 g, 76%);
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mp 161 – 163 °C (MeOH – H2O); H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 10.10 (s, 1H),
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3.53 (s, 3H), 2.09 (s, 3H), 1.82 (tt, J = 4.7, 7.9 Hz, 1H), 0.89 ꢀ 0.78 (m, 4H); C NMR (100
MHz, DMSOꢀd6): δ (ppm) = 172.8, 144.0, 134.8, 89.3, 36.2, 13.5, 12.3, 7.6; HRMS (ESI): calcd
for C9H12BrN3O [M + H]+ 258.0237 and 260.0216, found 258.0240 and 260.0215.
Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)thiopheneꢀ2ꢀcarboxamide (7d). Pyrazole 7d is
commercially available; however no reference exists for this compound. Pyrazole 7d was
prepared from thiopheneꢀ2ꢀcarboxylic acid using the same procedure as for compound 7a.
Purification via a column chromatography (SiO2, 0 – 4 % MeOH in DCM) and subsequent
crystallization from DCM ꢀ hexanes yielded title product as a white solid (3.70 g, 62%); mp 152
– 153 °C (DCM – hexanes); 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 10.38 (s, 1H), 8.02 (d, J
= 3.4 Hz, 1H), 7.93 (dd, J = 4.9, 1.0 Hz, 1H), 7.26 (dd, J = 4.9, 3.8 Hz, 1H), 3.62 (s, 3H), 2.14 (s,
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3H); 13C NMR (100 MHz, DMSOꢀd6) δ (ppm) = 160.4, 144.4, 137.7, 134.3, 132.9, 130.4, 128.4,
90.5, 36.2, 12.4; HRMS (ESI): calcd for C10H10BrN3OS [M + H]+ 299.9801 and 301.9780, found
299.9802 and 301.9776.
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Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)isonicotinamide (7e). Compound 7e was prepared
from isonicotinic acid using the same procedure as for compound 7a. The crude product was
crystallized first from EtOAc ꢀ toluene, then from MeOH ꢀ H2O yielding title product as a pale
1
yellow crystalline solid (3.35 g, 57%); mp 80 – 82 °C (MeOH ꢀ H2O); H NMR (400 MHz,
DMSOꢀd6): δ (ppm) = 10.68 (s, 1H), 8.83 (dd, J = 4.4, 1.6 Hz, 2H), 7.90 (dd, J = 4.4, 1.6 Hz,
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2H), 3.64 (s, 3H), 2.14 (s, 3H); C NMR (100 MHz, DMSOꢀd6): δ (ppm) = 164.5, 150.6, 144.5,
139.7, 134.1, 121.6, 90.4, 36.2, 12.4; HRMS (ESI): calcd. for C11H11BrN4O [M + H]+ 295.0189
and 297.0169, found 295.0190 and 297.0165.
4ꢀ((4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)carbamoyl)pyridine 1ꢀoxide (7f). Compound 7f was
prepared from 4ꢀcarboxypyridine 1ꢀoxide using the same procedure as for compound 7a. The
crude product was purified via crystallization from EtOAc – hexanes yielding pale yellow solid
1
(1.79 g, 29%); mp 129 – 131 °C (EtOAc – hexanes); H NMR (400 MHz, DMSOꢀd6): δ (ppm) =
13
10.56 (s, 1H), 8.39 (d, J = 7.3 Hz, 2H), 7.97 (d, J = 7.3 Hz, 2H), 3.62 (s, 3H), 2.13 (s, 3H); C
NMR (100 MHz, DMSOꢀd6): δ = 162.7, 144.5, 139.2, 134.2, 127.7, 125.4, 90.3, 36.2, 12.4;
HRMS (ESI): calcd for C11H11BrN4O2 [M + H]+ 311.0138 and 313.0118, found 311.0139 and
313.0114.
1ꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ3ꢀphenylurea (7g). The compound 7g is known from
a patent literature; however no synthetic procedure and analytical data were reported. To the
solution of 1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀamine (1.11 g, 10.0 mmol) in THF (10 mL) was added
phenyl isocyanate (1.19 mL, 11.0 mmol), and the mixture was heated at ~ 66 °C for 24h under
nitrogen atmosphere. Then the mixture was cooled to ambient temperature and Nꢀ
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bromosuccinimide (1.96 g, 11.0 mmol) was added. After stirring for 4h at ~ 20 °C, the mixture
was diluted with water and extracted to EtOAc (3x40 mL). The crude product was purified via
crystallization from DCM – hexanes, then from MeOH – H2O, yielding white crystalline solid
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(2.15 g, 70%); mp 278 – 280 °C; H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 8.99 (s, 1H), 8.21
(s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.28 (t, J = 8,6 Hz, 2H), 6.98 (t, J = 8.6 Hz, 1H), 3.62 (s, 3H),
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2.11 (s,3 H); C NMR (400 MHz, DMSOꢀd6): δ (ppm) = 153.1, 144.4, 139.9, 135.7, 129.3,
122.7, 119.0, 90.6, 36.6, 12.9; HMRS (ESI): calcd for C12H13BrN4O [M + H]+ 309.0351 and
311.0331, found 309.0347 and 311.0322.
Nꢀ(4ꢀbromoꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)piperidineꢀ1ꢀcarboxamide (7h). To the mixture of 1,3ꢀ
dimethylꢀ1Hꢀpyrazolꢀ5ꢀamine (2.22 g, 20.0 mmol) and DABCO (4.39 g, 36.0 mmol) in DCM (80
mL) was added the solution of piperidineꢀ1ꢀcarbonyl chloride (4.48 mL, 36 mmol) in DCM (40
mL) dropwise over 45 minutes. The mixture was stirred at ambient temperature for 14h. Then it
was washed with water (3x50 mL), dried over Na2SO4, and evaporated under reduced pressure.
The residue was crystallized from DCM – hexanes yielding a white crystalline solid (2.48 g, 11.2
mmol, 56%), which was then dissolved in acetonitrile (60 mL). To the solution intermediate urea
was added Nꢀbromosuccinimide (2.09 g, 11.76 mmol) and the mixture was stirred at ambient
temperature for 3h. Then the mixture was diluted with water and extracted to EtOAc (3x50 mL).
Combined organic extracts were washed with 10% NaHCO3 (2x20 mL), dried over Na2SO4, and
concentrated under reduced pressure. The residue was crystallized from EtOAc – hexanes to
yield title product as a white crystalline solid (2.78 g, 83%, 46% over two steps); mp 150 – 152
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°C (EtOAc – hexanes); H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 8.38 (s, 1H), 3.53 (s, 3H),
3.44 ꢀ 3.37 (m, 4H), 2.09 (s, 3H), 1.63 ꢀ 1.56 (m, 2H), 1.53 ꢀ 1.45 (m, 4H); 13C NMR (100 MHz,
DMSOꢀd6): δ (ppm) = 154.5, 143.6, 136.4, 90.3, 44.9, 35.7, 25.4, 24.0, 12.4; HRMS (ESI): calcd
for C11H17BrN4O [M + H]+ 301.0659 and 303.0638, found 301.0659 and 303.0634.
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Nꢀ(4ꢀchloroꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ4ꢀmethoxybenzamide (7i). To a mixture of 1,3ꢀ
dimethylꢀ1Hꢀpyrazolꢀ5ꢀamine (1.11 g, 10.0 mmol) in acetonitrile (20 mL), 4ꢀmethoxybenzoic
acid (1.67 g, 11.0 mmol), DMAP (0.12 g, 1.0 mmol), and DIPEA (3.5 mL, 20.0 mmol) were
added. The solution was cooled in an ice water bath and T3P (50% in EtOAc, 7.2 mL, 12.0
mmol) was added dropwise. Resulting mixture was stirred at room temperature for 18 hours.
After that, Nꢀchlorosuccinimide (1.47 g, 11.0 mmol) was added in one portion and the mixture
was stirred for another 4 hours. Then the mixture was diluted with water and extracted with
EtOAc (3x60 mL). After removing solvents under reduced pressure, the residue was purified via
a column chromatography (silica gel, DMC – MeOH 100:2). Then the compound was
crystallized from MeOH – H2O in order to remove any residual succinimide. Title product 7i was
obtained as a white crystalline solid (1.60 g, 57% over two steps); mp 180 – 181 °C (MeOH ꢀ
H2O); 1H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 10.19 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.08 (d,
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J = 8.6 Hz, 2H), 3.85 (s, 3H), 3.59 (s, 3H), 2.14 (s, 3H); C NMR (100 MHz, DMSOꢀd6): δ
(ppm) = 165.3, 162.5, 142.6, 133.3, 129.9, 124.7, 113.9, 103.5, 55.5, 36.1, 11.5; HRMS (ESI):
calcd for C13H14N3O2 [M + H]+ 280.0847, found 280.0844.
General procedure for the cross-coupling of pyrazoles 7a-i (Table 4). A mixture of respective
pyrazole 7 (1.0 mmol), boronic acid 2 (2.0 mmol), and K2CO3 (0.276 g, 2.0 mmol) in EtOH (4
mL) and water (1 mL) was thoroughly degassed with a stream of nitrogen. Then, XPhos (0.009 g,
0.02 mmol) and XPhos Pd G2 (0.008 g, 0.01 mmol) were added and the microwave vial was
inserted into microwave reactor. The reaction mixture was irradiated (setup: variable power, a
maximum of 300W, 110 or 60 °C) for 20 min. After that, the mixture was filtered through a
Celite, washed with EtOAc, and concentrated under reduced pressure. Purification of the crude
via column chromatography (MeOHꢀDCM 100:0 to 100:3) afforded the desired pyrazole as an oil
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or solid, which was characterized by H, C NMR and HRMS. In some cases, a product was
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Nꢀ(1,3ꢀdimethylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ4ꢀmethoxybenzamide (8a). Title compound was
prepared according the general procedure using pyrazole 7a and 4ꢀtolylboronic acid 2a at 110 °C.
The crude material was purified via a column chromatography to yield title product as a white
solid (0.268 g, 80%). Title compound was also prepared from chloro derivative 7i in 78% yield.
Reported analytical data belong to the sample prepared from 7a: mp 209 – 210 °C (DCM ꢀ
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hexanes); H NMR (400 MHz, DMSOꢀd6): δ (ppm) = 10.06 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H),
7.23 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.60 (s,
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3H), 2.26 (s, 3H), 2.23 (s, 3H); C NMR (100 MHz, DMSOꢀd6): δ (ppm) = 166.2, 162.4, 143.4,
135.3, 133.2, 129.8, 129.7, 128.0, 125.1, 115.0, 113.8, 55.5, 20.7, 13.2; HRMS (ESI): calcd for
C20H21N3O2 [M + H]+ 336.1705, found 336.1707.
4ꢀmethoxyꢀNꢀ(4ꢀ(4ꢀmethoxyphenyl)ꢀ1,3ꢀdimethylꢀ1Hꢀpyrazolꢀ5ꢀyl)benzamide
(8b).
Title
compound was prepared from pyrazole 7a and 4ꢀmethoxyphenylboronic acid 2b at 110 °C. The
crude material was purified via a column chromatography to yield title product as a white solid
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(0.291 g, 83%); mp 175 ꢀ 177 °C (DCM ꢀ hexanes); H NMR (400 MHz, DMSOꢀd6): δ (ppm) =
10.05 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.93 (d,
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J = 8.3 Hz, 2H), 3.83 (s, 3H), 3.72 (s, 3H), 3.59 (s, 3H), 2.22 (s, 3H); C NMR (100 MHz,
DMSOꢀd6): δ (ppm) = 166.2, 162.4, 157.7, 143.3, 133.0, 129.8, 129.2, 125.1, 124.9, 114.9, 114.0,
113.8, 55.5, 55.0, 35.0, 13.2; HRMS (ESI): calcd for C20H21N3O3 [M + H]+ 352.1654, found
352.1656.
Nꢀ(1,3ꢀdimethylꢀ4ꢀ(oꢀtolyl)ꢀ1Hꢀpyrazolꢀ5ꢀyl)ꢀ4ꢀmethoxybenzamide (8c). Title compound was
prepared according the general procedure using pyrazole 7a and 2ꢀmethylphenylboronic acid 2i
at 110 °C. The crude material was purified via a column chromatography to yield title product as
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