Access and modulation of substituted 1-methyl-1,6-dihydropyrazolo[3,4-c]pyrazoles

Article abstract of DOI:10.1039/d1ra00314c

Despite the pharmacological potential of the pyrazolo[3,4-c]pyrazoles, only a few methods of preparation and direct functionalization of this moiety have been described. We report herein a convenient design of new pyrazolo[3,4-c]pyrazoles with a high therapeutic impact. The effective chosen strategy consists of hydrazine condensations and C-N Ullmann-type cross-coupling reactions with microwave activation. Moreover, chemoselective bromination of the newly formed bipyrazoles followed by Suzuki-Miyaura cross-coupling reactions allowed the synthesis of a variety of modulated heterobicycles.

Full text of DOI:10.1039/d1ra00314c

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Access and modulation of substituted 1-methyl-
1,6-dihydropyrazolo[3,4-c]pyrazoles†
Cite this: RSC Adv., 2021, 11, 9756
ab
a
b
Nicu-Cosmin Ostache,
Marie-Aude Hiebel,
Adriana-Lumini¸ta Fınaru,
ˆ
Hassan Allouchi,c Gerald Guillaumeta and Franck Suzenet
a
*
´
Despite the pharmacological potential of the pyrazolo[3,4-c]pyrazoles, only a few methods of preparation
and direct functionalization of this moiety have been described. We report herein a convenient design of
new pyrazolo[3,4-c]pyrazoles with a high therapeutic impact. The effective chosen strategy consists of
hydrazine condensations and C–N Ullmann-type cross-coupling reactions with microwave activation.
Moreover, chemoselective bromination of the newly formed bipyrazoles followed by Suzuki–Miyaura
cross-coupling reactions allowed the synthesis of a variety of modulated heterobicycles.
Received 13th January 2021
Accepted 23rd February 2021
DOI: 10.1039/d1ra00314c
rsc.li/rsc-advances
These methods, while apparently abundant, exhibit none-
theless several major limitations such as a narrow functional
Introduction
group tolerance, a lack of further modulation, a non-convergent
strategy, multiple steps and complex starting materials (Scheme
1a). In order to overcome these difficulties, we hereby present
an efficient one-pot approach and a robust process in the design
of novel pyrazolo[3,4-c]pyrazoles, using the 5-bromo-1-methyl-
1H-pyrazole-4-carbaldehyde21,22 (1) (Scheme 1b). The rst
modulation arises from the use of diverse aromatic hydrazines,
followed by a C–N Ullmann-type cross-coupling reaction under
microwave irradiation, leading to compound 2. Chemoselective
bromination of the formed bipyrazole ensures the formation of
further functionalized scaffolds by a Suzuki–Miyaura cross-
coupling. The main text of the article should appear here with
headings as appropriate.
Fused bicyclic heterocycles are ubiquitous in nature. The most
prominent include biological macromolecules (DNA and RNA
with their purine bases), proteins and peptides, as well as
physiologically important biomolecules (serotonin, melatonin
etc.).1 In contrast, bicyclic heterocycles containing a nitrogen–
nitrogen (N–N) bond are relatively rare in nature, but none-
theless prevalent in the pharmaceutical industry.2 Such a class
is well represented by the ring-contracted [5:5] bicyclic aromatic
rings. Among this group, the pyrazolo[3,4-c]pyrazole nucleus
stands out from the little attention it was given, despite previous
reports of interesting biologically activities.3–7 Differences in the
distribution of ring electron densities and in spatial orientation
between [5:5] bicyclic aromatic rings and their [6:5] and [6:6]
analogs could explain these interesting therapeutic effects.8
The synthesis of this bicyclic scaffold are scarcely found in
the literature and are almost exclusively based on an existing
pyrazole motif.9–11 The desired bicyclic framework is aerward
obtained either according to a mononuclear heterocyclic rear-
rangement1,8 (known as Boulton–Katritzky rearrangement –
Route A), an annulation strategy (Route B)12–17 or other miscel-
laneous methods (using isothiocyanates,18 nitrilimines,9 aryl-
semicarbazides19 or 2-cyano-N-methyl-acrylamide20).
Results and discussion
The one-pot sequence for the synthesis of the bipyrazole 2a
relies on previous studies on similar heterocycles.23–26 The
a
´
´
Institut de Chimie Organique et Analytique (ICOA), Universite d'Orleans, UMR CNRS
´
7311, BP 6759, 45067 Orleans Cedex 2, France. E-mail: franck.suzenet@univ-orleans.
fr
bCenter of Applied Chemistry and Process Engineering (CAIP), University “Vasile
˘ ˘
˘
Alecsandri” of Bacau, Calea Mara¸ses¸sti, Bacau, 600115, Romania
c
`
´
Synthese et Isolement de Molecules BioActives (SIMBA), EA 7502, Laboratoire de
´
Chimie Physique, Universite de Tours, 31, Avenue Monge, 37200 Tours, France
† Electronic supplementary information (ESI) available. CCDC 1994906. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1ra00314c
Scheme 1 State of the art and retrosynthetic approach.
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Table 1 Optimization for the cyclization step
essential for the cyclization giving access to the optimized
reaction conditions (Table 1, entries 6–8).
Next, the scope and generality of the cyclization step were
examined (Table 2). Nonetheless, the condensation of various
monosubstituted aromatic hydrazines requires two different
reaction conditions, depending on the nature of the arylhy-
drazines. When salt free arylhydrazines are involved, a catalytic
amount of acid is used (1) while under their hydrochloride salt
form, a stoichiometric amount of sodium acetate is required
(1*).
Hydrazines bearing electron-donating (Table 2, entries 1–3)
or electron-withdrawing groups (Table 2, entries 4 and 5) were
equally well tolerated since the corresponding pyrazolo[3,4-c]
pyrazoles (2a–e) were isolated with good to excellent yields over
the two steps. Regarding the uoro substituent position (ortho,
meta or para) on the aromatic ring, a slight effect was observed
in favor of the meta position (Table 2, entries 6–8). Furthermore,
heterocyclic hydrazines were found to be an accessible partner
for the annulation step (Table 2, entry 9).
t
Entry DMEDA (mol%) CuI (mol%) (min) T (ꢀC) Yielda (%)
1
2
3
4
5
6
7
8
10
10
20
5
5
5
10
2.5
2.5
—
30
30
30
30
60
30
30
60
120
150
150
150
150
150
150
150
36
64 (30)b (47)c
56
64d
5
73
10
—
—
28 (0)c
13 (0)c
76
—
2.5
a
b
Isolated yield aer silica gel chromatography purication. Yield
obtained with conventional heating. Result obtained with 5-chloro-1-
methyl-1H-pyrazole-4-carbaldehyde as starting material. Traces of
c
d
The scope of the reaction is unfortunately limited to aryl
starting material present.
hydrazines since hydrazine lead to
a
bis-condensated
compound, and alkylhydrazines to degradation or a lack of
conversion.
condensation step occurred quantitatively with a slight excess
of phenylhydrazine. Aer a change of solvent and addition of
the Ullmann-type catalysts, the expected fused heterocycle was
obtained in an encouraging yield (Table 1, entry 1).
Increasing the reaction temperature to 150 ꢀC allowed
a signicant yield improvement (Table 1, entries 2). The amount
of catalyst and ligand was investigated and reducing to half the
initial quantities lead to an identical yield, alongside traces of
starting material (Table 1, entries 3–4). The chlorinated
analogue was tried but gave lower yield. In order to increase the
conversion to its fullest, the reaction time was doubled (Table 1,
entry 5). Finally, the sole use of copper catalyst was proven to be
We aerwards focused our attention on the insertion of
a second point of diversity through a bromination step followed
by a Suzuki–Miyaura cross-coupling reaction. The bromide was
selectively introduced on C3.27 The ratio of the mono-
brominated (3a) and dibrominated (3a0) compounds was opti-
mized through diverse reaction conditions (Table 3).
A partial conversion was noticed, with the formation
a mixture of a mono- and dibrominated analogue when using
a slight excess of halogenation agent (Table 3, entry 1). Deter-
mined by this result, the amount of NBS was increased up to 1.5
equivalents, action that lead to a total conversion and an
increased yield of the monobrominated bicycle of 69% (Table 3,
entries 2 and 3). In order to render the reaction faster,
conventional heating was replaced by microwave irradiation.
Better results were attained aer only 2 hours of reaction time
(Table 3, entry 4).
Table 2 Scope for the annulation step
Aer establishing the best reaction conditions which allow
the major formation of the monobrominated bipyrazole, the
Table 3 Optimization for the bromination step
Entry
R-NH-NH2
Product (yield%)
1
2
3
4
5
6
7
8
9
Ph
2a (76, 69bb)
2b (64)
a
4-CH3-C6H4
4-CH3O-C6H4
4-CN-C6H4
4-CF3-C6H4
4-F-C6H4
3-F-C6H4
2-F-C6H4
4-Pyridine
2c (46, 62c)
2d (76)
a
a
2e (54, 50d)
2f (62)
2g (85)
2h (46)
2i (46)
t
a
Entry NBS (eq.) Heating
(h) 3aa (%) 3a0a (%) 2aa (%)
a
a
1
2
3
4
1.1
1.3
1.5
1.5
Conventional 24 27
Conventional 24 45
Conventional 24 69
10
13
19
17
40
26
0
a
Hydrazine used in a hydrochloride salt form. b Reaction performed on
1.00 g of 1. c Reaction performed on 2.40 g of 1. d Reaction performed on
1.45 g of 1.
mWave
2
77
0
a
Isolated yield aer silica gel chromatography purication.
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Table 4 Reactivity study of bipyrazoles towards the bromination step Table
5
Generalization for the Suzuki–Miyaura cross-coupling
reaction
Entry
R
NBS (eq.) Heating
t
3b/ca (%) SMa (%)
Entry
SM (R1)
R2
Yield (%)
1
2
3
4
5
6
7
8
1.0
mWave
mWave
mWave
Conventional 4 h
mWave 4 h
Conventional 24 h
Conventional 72 h
Conventional 24 h
15 min 47
15 min 49
30 min 50
9
0
8
0
0
42
10
21
1
2
3
4
5
6
7
8
3a (R1 ¼ H)
4-CH3-C6H4
3-CH3-C6H4
2-CH3-C6H4
Ph
4-CH3O-C6H4
4-CF3-C6H4
4-CN-C6H4
3-F-C6H4
3-Thiophene
4-Pyridine
Styril
4-CN-C6H4
4-Pyridine
4-CH3O-C6H4
4-CN-C6H4
4-Pyridine
4-CH3O-C6H4
4-CH3-C6H4
83
89
86
92
90
86
72
90
85aa
78
64
75
76
80
68
79
94
86
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-CH3O 1.2
1.0
1.0
1.5
1.5
1.5
2.0
55
92
58
82
73
4-CF3
a
9
Isolated yield aer silica gel chromatography purication.
10
11
12
13
14
15
16
17
18
3b (R1 ¼ OCH3)
3c (R1 ¼ CF3)
impact of the electronic nature of a substituent on the aromatic
moiety was investigated (Table 4).
When the substituent present on the aromatic ring is
electron-rich in nature, 15 minutes of microwave irradiation
and a stoichiometric amount of NBS allowed the synthesis of
the halogenated compound with a correct yield, alongside
traces of starting material, as well as an inseparable mixture of
mono and dibrominated by-products (Table 4, entry 1). Neither
a slight bromination agent excess, nor longer reaction times
allowed results superior to 50% (Table 4, entries 2 and 3).
However, switching to conventional heating lead to the identi-
cation of the optimal conditions, as well as obtaining a slightly
higher yield of the expected molecule of 55% (Table 4, entry 4).
When the aromatic ring from position 6 is substituted by an
electron-withdrawing substituent, the bromination reaction
performed under microwave irradiation turned out to be highly
chemoselective. It required 1.5 equivalents of NBS generating total
conversion and an excellent yield of a monobrominated hetero-
cycle aer 4 hours of reaction time (Table 4, entry 5). Conventional
heating was also studied, but despite increased amounts of NBS
and longer reaction times, incomplete conversion and lower yield
values were noticed (Table 4, entries 6–8).
a
2 h of mWave irradiation necessary for total conversion.
Suitably, independent of the electronic nature of the functional
group present on the aromatic moiety, the Suzuki–Miyaura
cross-coupling reaction allowed very good to excellent yields
(Table 5, entries 12–18).
Compound 4n was found appropriate for X-ray single crys-
tallography, which conrmed that the bromination and
Subsequently, two different reaction conditions developed by
our group for the Suzuki–Miyaura coupling reaction were tested,
both of which proved to be effective (see ESI† for details).22,28
The scope of the Suzuki–Miyaura cross-coupling reaction was
next examined (Table 5). To our delight, both electron-rich (Table
5, entries 1, 4 and 5) and electron-poor boronic acid partners
(Table 5, entries 6–8) lead towards the expected product in good to
excellent yields, without any impact of the position of the
substituent on the aromatic ring (Table 5, entries 1–3). Addition-
ally, heterocyclic and even styryl boron derivatives were equally
compatible with this transformation (Table 5, entries 9–11).
Lastly, the electronic impact of the aryl substituent at the N6
position of the pyrazolo[3,4-c]pyrazoles 3b and 3c was explored.
Fig. 1 ORTEP representation of pyrazolo[3,4-c]pyrazole 4n.
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subsequent cross-coupling reaction take place at the C-3 posi-
tion on the pyrazolo[3,4-c]pyrazoles (Fig. 1).29
Synthetic procedures
Synthesis of starting material compound 1. Copper(II)
bromide (6.3 g, 0.0283 mol) and tert-butyl nitrite (4.2 mL, 0.0354
mol) were combined in acetonitrile (50 mL). Commercial ethyl
5-amino-1-methyl-1H-pyrazole-4-carboxylate (4.0 g, 0.0236 mol)
was slowly added portionwise, and the reaction was maintained
le at room temperature for 30 minutes. The mixture was
cooled to room temperature, poured into aqueous hydrochloric
acid (6 N, 160 mL), diluted with dichloromethane (150 mL), and
stirred for 10 min. The aqueous layer was extracted with
dichloromethane (3 ꢁ 100 mL), and the combined organic
layers were dried over magnesium sulfate, ltered, and
concentrated in vacuo. The crude obtained needed no further
purication and was engaged in the next step. Yield: 96% (5.33
Conclusions
In summary, the quick access towards variously functionalized
pyrazolo[3,4-c]pyrazoles is herein described, starting from 5-
bromo-1-methyl-1H-pyrazole-4-carbaldehyde
approach relies on the use of substituted aromatic hydrazines
engaged in efficient one-pot sequences. Thus the formed
bipyrazoles were subsequently modulated by chemoselective
bromination followed by high-yielding Suzuki–Miyaura cross-
coupling reactions.
(1).
The
1
ꢀ
g). Light yellow solid. Mp: 38–39 C. H NMR (400 MHz, chlo-
roform-d): d 7.79 (s, 1H), 4.19 (q, J ¼ 7.1 Hz, 2H), 3.78 (s, 3H),
1.23 (t, J ¼ 7.1 Hz, 3H). 13C NMR (101 MHz, chloroform-d):
d 161.4 (C]O), 141.6 (CH), 117.7 (C), 113.6 (C), 60.1 (CH2), 37.8
(N–CH3), 14.1 (CH3). IR n (cmꢂ1): 2995, 2974, 2931, 2871, 1709,
1528, 1470, 1389, 1214, 1173, 1214, 1173, 1040, 770. HRMS
(ESI): (m/z) [M + H]+ calculated for [C7H1079BrN2O2]+ 232.9920;
found 232.9917, calculated for [C7H1081BrN2O2]+ 234.9900;
found 234.9897. A solution of ethyl 5-bromo-1-methyl-1H-
pyrazole-4-carboxylate (5.33 g, 0.0228 mol) in anhydrous tetra-
hydrofuran (75 mL) at 0 ꢀC was treated with diisobutylalumi-
num hydride (1 M solution in tetrahydrofuran, 58 mL, 0.0571
mol), and the mixture was allowed to warm to room tempera-
ture and stir for 2 hours. A cold saturated aqueous sodium
potassium tartrate solution was added, and stirring was
continued for 4 hours. The aqueous layer was extracted with
dichloromethane, and the combined organic layers were dried
over magnesium sulfate, ltered, and concentrated under
reduced pressure. The resulted crude mixture needed no further
purication and was engaged in the next step. Yield: 94% (4.14
Experimental section
Materials and methods
All reagents and organic solvents were purchased from
commercial suppliers and were used without further purica-
tion. Microwave assisted reactions were carried out in a Biotage
Initiator microwave synthesis instrument and temperatures
were measured by an IR sensor. Solvents mentioned as dry were
puried with a dry station GT S100 immediately prior to use.
The reactions were monitored by thin-layer chromatography
(TLC) analysis using 0.2 mm precoated Kieselgel 60 F254
(Merck) silica gel plates visualized with a Macherey Nagel UV254
lamp. Column chromatography was performed on silica gel 60
(230–400 mesh, 40–63 mm). Solvent ratios for chromatography
and are reported as v/v ratios and are indicated for each
compound. Melting points (mp [ꢀC]) were taken on samples in
open capillary tubes and are uncorrected on an IA9200 Thermo
Scientic Electrothermal Melting Point apparatus/instrument.
Infrared analyses were determined on a Thermo Scientic
ATR Nicolet iS10 and interpreted using OMNIC soware. 1H
NMR and 13C NMR spectra were recorded either on a Bruker
ULTRASHIELD® PLUS 400 MHz spectrometer (13C, 100 MHz) or
on a Bruker AVANCE 250 MHz (13C, 62.9 MHz) spectrometer, as
solutions in deuterated solvents. Unless otherwise indicated,
chemical shis (d) are reported in parts per million (ppm)
values, and coupling constants (J) are reported in Hertz. Peak
multiplicities are designated by the following abbreviations: s ¼
singlet; d ¼ doublet; t ¼ triplet; q ¼ quartet; m ¼ multiplet; dd
¼ double doublet, br ¼ broadened. High-resolution mass
spectrometry analyses (HRMS) were performed on a Maxis
Bruker 4G Spectrometer. X-ray diffraction data were collected
on Xcalibur CCD area detector diffractometer equipped with
1
g). Colorless solid. Mp: 55–56 ꢀC. H NMR (400 MHz, chloro-
form-d): d 7.48 (s, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 2.53 (s, 1H). 13
C
NMR (101 MHz, chloroform-d): d 139.3 (CH), 120.9 (C), 113.7
(C), 55.6 (CH2), 37.6 (N–CH3). IR n (cmꢂ1): 3255, 2947, 2896,
2848, 2741, 1554, 1413, 1398, 1322, 1189, 1012, 995, 880. HRMS
(ESI): (m/z) [M + H]+ calculated for [C5H879BrN2O]+ 190.9815;
found 190.9815, calculated for [C5H881BrN2O]+ 192.9794, found
192.9796.
A solution of 5-(bromo-1-methyl-1H-pyrazol-4-yl)
methanol(III) (4.14 g, 0.0216 mol) in dichloromethane (25 mL)
was treated with activated manganese(IV) oxide (18.8 g, 0.216
mol) and the mixture was stirred at room temperature for 24
hours. Aerwards, the reaction mixture was ltered on Celite®
and the lter pad washed with dichloromethane. The recovered
ltrates were then concentrated under reduced pressure to yield
the crude compound that required no further purication.
˚
monochromatized Mo-Ka radiation (0.71073 A) at 296 K. The
data collection, unit cell renement, and data reduction were
performed using the CrysAlis Pro, Oxford Diffraction Ltd. so-
ware package. Analytical numeric absorption correction using
a multifaceted crystal model based on expressions derived was
carried. The positions of non-H atoms were determined and
renement by SHELXS-2014 program. Non-hydrogen atoms
were rst rened isotropically followed by anisotropic rene-
ment by full matrix least-squares calculations based on F2 using
SHELXL-2014 program.
1
ꢀ
Yield: 97% (4.01 g). Light yellow solid. Mp: 75–76 C. H NMR
(400 MHz, chloroform-d): d 9.78 (s, 1H), 7.97 (s, 1H), 3.94 (s, 3H).
13C NMR (101 MHz, chloroform-d): d 183.4 (C]O), 141.0 (CH),
121.7 (C), 119.7 (C), 37.6 (N–CH3). IR n (cmꢂ1): 2953, 2920, 2852,
1655, 1524, 1501, 1454, 1419, 1388, 1368, 1190, 1094, 763.
HRMS (ESI): (m/z) [M + H]+ calculated for [C5H679BrN2O]+
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188.9658; found 188.9653, calculated for [C5H681BrN2O]+
190.9638, found 190.9634.
ꢁ CH), 130.0 (CH), 128.0 (CH), 127.6 (CH), 124.1 (2 ꢁ CH), 121.0
(C), 37.7 (N–CH3). IR n (cmꢂ1): 3056, 2942, 1682, 1595, 1508,
1457, 1436, 1372, 1189, 1112, 1034, 1004, 990, 969, 844, 759,
715, 696. HRMS (ESI): (m/z) [M + H]+ calculated for [C11H11N4]+
199.0978; found 199.0978.
General procedures
Synthesis of 1-methyl-6-arylpyrazolo[3,4-c]pyrazoles 2a–i. To
1-Methyl-6-(p-tolyl)-1,6-dihydropyrazolo[3,4-c]pyrazole
(2b).
a
stirred solution of 5-bromo-1-methyl-1H-pyrazole-4-
Prepared as described in the general procedure A (4-methyl-
phenylhydrazine hydrochloride: 92 mg, 0.58 mmol; NaOAc:
48 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3: 146 mg,
1.06 mmol). Yield: 64% (72 mg). Beige solid. Column chroma-
carbaldehyde 1 (100 mg, 0.529 mmol, 1.0 eq.) in ethanol (2
mL) a few drops of glacial acetic acid and the desired hydrazine
(1.1 eq., 0.58 mmol) were added. If the hydrazine is found under
its hydrochloric form salt, a stoichiometric amount of sodium
acetate (1.1 eq., 0.58 mmol) is added to the mixture instead of
the glacial acetic acid. This mixture was reuxed for 18 h and
aerwards concentrated under reduced pressure. The crude was
solubilized in DMF (3 mL), transferred to a dry tube and then
potassium carbonate (146 mg, 1.06 mmol, 2.0 eq.) and copper
iodide (2.5 mg, 0.013 mmol, 2.5 mol%) were added to the
mixture. The tube was evacuated, backlled with dry argon
three times and then sealed. The reaction mixture was then
heated at 150 ꢀC for 1 hour under microwave irradiation.
Solvent removal and purication by silica gel column chroma-
tography using appropriate solvents afforded the expected
bicyclic compound.
Synthesis of 3-bromo-1-methyl-6-arylpyrazolo[3,4-c]pyrazoles
3a, 3b and 3c. To a stirred solution of 1-methyl-6-aryl-pyrazolo
[3,4-c]pyrazole (2a, 2c or 2e) (100 mg, 1.0 eq.) in acetonitrile (2
mL) the correspondent amount of NBS is added. Depending on
the nature of the substituent, the mixture is le under stirring at
reux or under microwave irradiation (sealed tube) for the given
time. The reaction mixture is aerwards extracted with
dichloromethane (3 ꢁ 10 mL) and water. The organic layers
collected were washed with a saturated solution of Na2S2O3,
dried over MgSO4 and evaporated under reduced pressure. The
crude product was puried by silica gel column chromatog-
raphy using appropriate solvents.
1
tography eluents: PE/EtOAc ¼ 8/2. Mp: 88–89 ꢀC. H NMR (400
MHz, acetone-d6): d 7.59 (s, 1H), 7.52 (d, J ¼ 8.2 Hz, 2H), 7.44 (s,
1H), 7.37 (d, J ¼ 8.2 Hz, 2H), 3.81 (s, 3H), 2.41 (s, 3H). 13C NMR
(101 MHz, acetone-d6): d 149.1 (C), 137.9 (C), 137.4 (C), 130.6 (2
ꢁ CH), 129.6 (CH), 127.5 (CH), 124.2 (2 ꢁ CH), 120.8 (C), 37.5
(N–CH3), 21.0 (CH3). IR n (cmꢂ1): 3108, 3041, 2918, 2854, 1711,
1604, 1583, 1515, 1436, 1416, 1376, 1365, 1216, 1198, 1108,
1036, 999, 977, 843, 819, 720. HRMS (ESI): (m/z) [M + H]+
calculated for [C12H13N4]+ 213.1134; found 213.1136.
1-(4-Methoxyphenyl)-6-methyl-1,6-dihydropyrazolo[3,4-c]pyr-
azole (2c). Prepared as described in the general procedure A (4-
methoxyphenylhydrazine hydrochloride: 102 mg, 0.58 mmol;
NaOAc: 48 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3:
146 mg, 1.06 mmol). Yield: 46% (56 mg). Light orange oil.
Column chromatography eluents: PE/EtOAc ¼ 8/2. 1H NMR (400
MHz, chloroform-d): d 7.57 (s, 1H), 7.46 (s, 1H), 7.44 (d, J ¼
8.9 Hz, 2H), 7.01 (d, J ¼ 8.9 Hz, 2H), 3.86 (s, 3H), 3.77 (s, 3H). 13
C
NMR (101 MHz, chloroform-d): d 159.3 (C), 148.7 (C), 131.6 (C),
129.1 (CH), 127.6 (CH), 125.7 (2 ꢁ CH), 119.4 (C), 114.6 (2 ꢁ
CH), 55.7 (O–CH3), 36.9 (N–CH3). IR n (cmꢂ1): 3001, 2935, 2837,
1600, 1585, 1514, 1444, 1421, 1370, 1299, 1246, 1182, 1137,
1109, 1035, 1013, 994, 969, 832, 718, 704. HRMS (ESI): (m/z) [M +
H]+ calculated for [C12H13N4O]+ 229.1083; found 229.1085.
4-(6-Methylpyrazolo[3,4-c]pyrazol-1(6H)-yl)benzonitrile
(2d).
Prepared as described in the general procedure A (4-cyanophe-
nylhydrazine hydrochloride: 99 mg, 0.58 mmol; NaOAc: 48 mg,
0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3: 146 mg, 1.06
mmol). Yield: 76% (90 mg). Light brown solid. Column chro-
matography eluents: PE/EtOAc ¼ 7/3. Mp: 154–155 ꢀC. 1H NMR
(250 MHz, chloroform-d): d 7.82 (d, J ¼ 8.9 Hz, 2H), 7.72–7.67
(m, 3H), 7.52 (s, 1H), 3.94 (s, 3H). 13C NMR (63 MHz, chloro-
form-d): d 148.1 (C), 142.1 (C), 133.7 (2 ꢁ CH), 131.6 (CH), 128.3
(CH), 122.8 (2 ꢁ CH), 121.0 (C), 118.2 (CN), 110.6 (C), 38.1 (N–
CH3). IR n (cmꢂ1): 3133, 3104, 2924, 2853, 2224, 1605, 1591,
1512, 1438, 1411, 1378, 1344, 1287, 1185, 1172, 1110, 1032, 996,
967, 837, 711, 704. HRMS (ESI): (m/z) [M + H]+ calculated for
[C12H10N5]+ 224.0930; found 224.0930.
Synthesis of 1-methyl-3-aryl-6-arylpyrazolo[3,4-c]pyrazoles
4a–r. To a stirred solution of 3-bromo-1-methyl-6-aryl-pyrazolo
[3,4-c]pyrazoles (3a, 3b or 3c) (100 mg, 1.0 eq.) and corre-
sponding boronic acid (1.5 eq.) in a mixture (3 mL) of dioxane,
ethanol and water (3 : 1 : 0.5), a solution of cesium carbonate
(1.3 eq.) in 0.5 mL of water was added. The tube was argon
ushed three times and then Pd(PPh3)4 (1.25 mol%) was added.
The tube was again argon ushed, sealed and microwave irra-
diated at 140 ꢀC for 1 h. The reaction mixture was then ltrated
on Celite®, rinsed and extracted with EtOAc (3 ꢁ 10 mL). The
organic layers collected were washed, dried on MgSO4, ltered
and evaporated. The crude obtained was puried by silica gel
column chromatography using appropriate solvents, affording
the desired compound.
1-Methyl-6-(4-(triuoromethyl)phenyl)-1,6-dihydropyrazolo[3,4-
c]pyrazole (2e). Prepared as described in the general procedure A
(4-(triuoromethyl)-phenylhydrazine: 103 mg, 0.58 mmol; CuI:
2.5 mg, 0.013 mmol; K2CO3: 146 mg, 1.06 mmol). Yield: 54% (77
mg). Light yellow solid. Column chromatography eluents: DCM/
EtOAc ¼ 95/5. Mp: 89–90 ꢀC. 1H NMR (400 MHz, chloroform-d):
d 7.78 (d, J ¼ 8.5 Hz, 2H), 7.68 (d, J ¼ 8.5 Hz, 2H), 7.66 (s, 1H),
7.50 (s, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, chloroform-d):
1-Methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
(2a).
Prepared as described in the general procedure A (phenyl-
hydrazine: 63 mg, 57 mL, 0.58 mmol, CuI: 2.5 mg, 0.013 mmol;
K2CO3: 146 mg, 1.06 mmol). Yield: 76% (80 mg). Orange oil.
Column chromatography eluents: PE/EtOAc ¼ 8/2. 1H NMR (400
MHz, acetone-d6): d 7.67 (d, J ¼ 7.9 Hz, 2H), 7.62 (s, 1H), 7.58 (t, J
¼ 7.9 Hz, 2H), 7.45 (s, 1H), 7.43 (t, J ¼ 7.9 Hz, 1H), 3.85 (s, 3H).
13C NMR (101 MHz, acetone-d6): d 149.1 (C), 139.8 (C), 130.2 (2
2
d 148.2 (C), 141.4 (C), 130.9 (CH), 129.2 (q, JC–F ¼ 33.0 Hz, C),
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1
128.1 (CH), 126.8 (q, JC–F ¼ 3.8 Hz, 2 ꢁ CH), 123.8 (q, JC–F
¼
K2CO3: 146 mg, 1.06 mmol). Yield: 46% (49 mg). White yellow
272.1 Hz, CF3), 122.9 (2 ꢁ CH), 120.6 (C), 37.8 (N–CH3). 19F NMR solid. Column chromatography eluents: EtOAc/MeOH ¼ 95/5.
(235 MHz, chloroform-d): d ꢂ62.4. IR n (cmꢂ1): 3106, 2923, 2854, Mp: 105–106 ꢀC. 1H NMR (400 MHz, chloroform-d): d 8.75
1616, 1597, 1523, 1507, 1143, 1318, 1193, 1180, 1157, 1118, (br s, 2H), 7.68 (s, 1H), 7.53 (br s, 2H), 7.50 (s, 1H), 4.00 (s, 3H).
1107, 1065, 1031, 999, 970, 872, 839, 823, 714, 690. HRMS (ESI): 13C NMR (101 MHz, chloroform-d): d 151.2 (2 ꢁ CH), 147.9 (C),
(m/z) [M + H]+ calculated for [C12H10F3N4]+ 267.0852; found 145.3 (C), 131.8 (CH), 128.3 (CH), 121.2 (C), 116.1 (2 ꢁ CH), 38.5
267.0852.
(N–CH3). IR n (cmꢂ1): 3088, 3036, 2943, 1682, 1647, 1587, 1569,
1-(4-Fluorophenyl)-6-methyl-1,6-dihydropyrazolo[3,4-c]pyrazole
1508, 1440, 1417, 1381, 1191, 1115, 1030, 1009, 993, 696, 842,
(2f). Prepared as described in the general procedure A (4-uo- 820, 715. HRMS (ESI): (m/z) [M + H]+ calculated for [C10H10N5]+
rophenylhydrazine hydrochloride: 95 mg, 0.58 mmol; NaOAc: 200.0930; found 200.0930.
48 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3: 146 mg,
3-Bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
1.06 mmol). Yield: 62% (71 mg). Colorless oil. Column chro- (3a). Prepared as described in the general procedure B (1-
matography eluents: PE/EtOAc ¼ 8/2. 1H NMR (400 MHz, methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole 2a: 100 mg,
chloroform-d): d 7.60 (s, 1H), 7.51 (dd, J ¼ 8.9, 4.7 Hz, 2H), 7.48 0.5 mmol; NBS: 1.5 eq., 135ꢀ mg, 0.75 mmol; MeCN: 2 mL;
(s, 1H), 7.24–7.16 (dd, J ¼ 8.9, 8.8 Hz, 2H), 3.80 (s, 3H). 13C NMR microwave irradiation at 100 C for 2 h). Yield: 77% (108 mg).
(101 MHz, chloroform-d): d 161.9 (d, 1JC–F ¼ 248.0 Hz, C), 148.5 Light orange oil. Column chromatography eluents: PE/EtOAc ¼
(C), 134.7 (d, 4JC–F ¼ 3.1 Hz, C), 129.8 (CH), 127.8 (CH), 125.7 (d, 95/5. 1H NMR (400 MHz, chloroform-d): d 7.60 (s, 1H), 7.55–7.50
3JC–F ¼ 8.6 Hz, 2 ꢁ CH), 119.8 (C), 116.5 (d, 2JC–F ¼ 23.1 Hz, 2 ꢁ (m, 4H), 7.41 (t, J ¼ 8.6 Hz, 1H), 3.79 (s, 3H). 13C NMR (101 MHz,
CH), 37.1 (N–CH3). IR n (cmꢂ1): 3111, 3066, 2943, 1701, 607, chloroform-d): d 148.8 (C), 138.1 (C), 129.6 (2 ꢁ CH), 129.1 (CH),
1594, 1513, 1443, 1417, 1371, 1218, 1190, 1218, 1190, 1152, 128.1 (CH), 123.8 (2 ꢁ CH), 119.9 (C), 113.1 (C–Br), 37.6 (N–
1033, 999, 969, 838, 815, 718, 701. HRMS (ESI): (m/z) [M + H]+ CH3). IR n (cmꢂ1): 3066, 2928, 1726, 1594, 1506, 1457, 1431,
calculated for [C11H10FN4]+ 217.0884; found 217.0884.
1-(3-Fluorophenyl)-6-methyl-1,6-dihydropyrazolo[3,4-c]pyrazole
(2g). Prepared as described in the general procedure A (3-uo- 277.0083; found 277.0084, calculated for [C11H1081BrN4]+
1367, 1238, 1148, 1079, 1038, 1008, 983, 905, 840, 759, 715, 696.
HRMS (ESI): (m/z) [M + H]+ calculated for [C11H1079BrN4]+
rophenylhydrazine hydrochloride: 95 mg, 0.58 mmol; NaOAc: 279.0064, found 279.0065.
48 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3: 146 mg,
3-Bromo-6-(4-methoxyphenyl)-1-methyl-1,6-dihydropyrazolo
1.06 mmol). Yield: 85% (98 mg). Colorless solid. Column [3,4-c]pyrazole (3b). Prepared as described in the general
1
ꢀ
chromatography eluents: PE/EtOAc ¼ 8/2. Mp: 103–104 C. H procedure
B
(1-(4-methoxyphenyl)-6-methyl-1,6-dihydropyr-
NMR (400 MHz, chloroform-d): d 7.62 (s, 1H), 7.51–7.42 (m, 2H), azolo[3,4-c]pyrazole 2c: 100 mg, 0.43 mmol; NBS: 78 mg,
7.36–7.29 (m, 2H), 7.09 (d, J ¼ 8.8 Hz, 1H), 3.88 (s, 3H). 13C NMR 0.43 mmol, 1.0 eq.; MeCN: 2 mL; conventional heating at reux
(101 MHz, chloroform-d): d 163.0 (d, 1JC–F ¼ 248.4 Hz, C), 148.2 for 4 h). Yield: 55% (74 mg). Colorless oil. Column chroma-
3
3
1
(C), 140.0 (d, JC–F ¼ 10.2 Hz, CH), 130.7 (d, JC–F ¼ 9.2 Hz, C), tography eluents: PE/EtOAc ¼ 9/1. H NMR (400 MHz, chloro-
130.2 (CH), 127.9 (CH), 120.2 (C), 118.6 (d, 4JC–F ¼ 3.2 Hz, CH), form-d): d 7.54 (s, 1H), 7.41 (d, J ¼ 8.9 Hz, 2H), 7.00 (d, J ¼
114.4 (d, JC–F ¼ 21.1 Hz, CH), 110.9 (d, JC–F ¼ 24.7 Hz, CH), 8.9 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H). 13C NMR (101 MHz,
37.5 (N–CH3). IR n (cmꢂ1): 3091, 2992, 2934, 2853, 1161, 1595, chloroform-d): d 159.5 (C), 149.0 (C), 131.0 (C), 128.5 (CH), 125.8
1509, 1464, 1429, 1414, 1379, 1199, 1171, 1148, 1113, 1081, (2 ꢁ CH), 119.4 (C), 114.7 (2 ꢁ CH), 112.8 (C–Br), 55.7 (O–CH3),
1030, 970, 869, 784, 712. HRMS (ESI): (m/z) [M + H]+ calculated 37.2 (N–CH3). IR n (cmꢂ1): 3107, 2936, 2836, 1600, 1585, 1514,
2
2
for [C11H10FN4]+ 217.0884; found 217.0883.
1462, 1366, 1299, 1246, 1150, 1040, 904, 832, 716. HRMS (ESI):
1-(2-Fluorophenyl)-6-methyl-1,6-dihydropyrazolo[3,4-c]pyrazole
(2h). Prepared as described in the general procedure A (2-uo- 307.0189, calculated for [C12H1281BrN4O]+ 309.0169, found
(m/z) [M + H]+ calculated for [C12H1279BrN4O]+ 307.0189; found
rophenylhydrazine hydrochloride: 95 mg, 0.58 mmol; NaOAc: 309.0168.
48 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; K2CO3: 146 mg,
3-Bromo-1-methyl-6-(4-(triuoromethyl)-1,6-dihydrophenyl)pyr-
1.06 mmol). Yield: 46% (53 mg). Light brown solid. Column azolo[3,4-c]pyrazole (3c). Prepared as described in the general
chromatography eluents: PE/EtOAc ¼ 8/2. Mp: 57–58 ꢀC. 1H procedure
B (1-methyl-6-(4-(triuoromethyl)phenyl)-1,6-dihy-
NMR (400 MHz, acetone-d6): d 7.72–7.67 (m, 2H), 7.61–7.53 dropyrazolo[3,4-c]pyrazole 2e: 100 mg, 0.37 mmol; NBS: 101 mg,
(ddd, J ¼ 8.2, 8.1, 4.7 Hz, 1H), 7.48–7.40 (m, 3H), 3.71 (s, 3H). 13
C
0.56ꢀmmol, 1.5 eq.; MeCN: 2 mL; microwave irradiation at
1
NMR (101 MHz, acetone-d6): d 157.1 (d, JC–F ¼ 248.7 Hz, C), 100 C for 4 h). Yield: 92% (120 mg). Colorless solid. Column
3
1
ꢀ
150.1 (C), 131.0 (d, JC–F ¼ 7.8 Hz, CH), 130.8 (CH), 129.2 (C), chromatography eluents: PE/EtOAc ¼ 7/3. Mp: 132–133 C. H
127.6 (CH), 127.5 (CH), 126.1 (d, 3JC–F ¼ 3.9 Hz, CH), 120.1 (C), NMR (400 MHz, chloroform-d): d 7.79 (d, J ¼ 8.3 Hz, 2H), 7.66 (d,
117.4 (d, 2JC–F ¼ 19.5 Hz, CH), 36.2 (s, N–CH3). IR n (cmꢂ1): 3113, J ¼ 8.3 Hz, 2H), 7.62 (s, 1H), 3.85 (s, 3H). 13C NMR (101 MHz,
3075, 2924, 2852, 1607, 1515, 1494, 1479, 1463, 1445, 1432, chloroform-d): d 148.5 (C), 140.9 (C), 130.2 (CH), 129.7 (q, 2JC–F
¼
¼
3
1
1417, 1370, 1260, 1216, 1187, 1103, 1025, 1000, 972, 846, 836, 33.2 Hz, C), 126.9 (q, JC–F ¼ 3.7 Hz, 2 ꢁ CH), 123.7 (q, JC–F
755, 725, 717, 704. HRMS (ESI): (m/z) [M + H]+ calculated for 272.2 Hz, CF3), 123.1 (2 ꢁ CH), 120.6 (C), 113.4 (C–Br), 38.1 (N–
[C11H10FN4]+ 217.0884; found 217.0882.
1-Methyl-6-(pyridin-4-yl)-1,6-dihydropyrazolo[3,4-c]pyrazole
CH3). 19F NMR (235 MHz, chloroform-d): ꢂ62.5. IR n (cmꢂ1):
3108, 2924, 2853, 1613, 1596, 1583, 1523, 1500, 1438, 1416,
(2i). Prepared as described in the general procedure A (4- 1320, 1249, 1151, 1107, 1065, 1034, 1009, 904, 838. HRMS (ESI):
hydrazinopyridine: 64 mg, 0.58 mmol; CuI: 2.5 mg, 0.013 mmol; (m/z) [M + H]+ calculated for [C12H979BrF3N4]+ 344.9957; found
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344.9958, calculated for [C12H981BrF3N4]+ 346.9937, found methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole 3a: 100 mg,
346.9938. 0.36 mmol; phenylboronic acid: 66 mg, 0.54 mmol, 1.5 eq.;
1-Methyl-6-phenyl-3-(p-tolyl)-1,6-dihydropyrazolo[3,4-c]pyrazole Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; Pd(PPh3)4: 5.5 mg,
(4a). Prepared as described in the general procedure C (3- 0.004 mmol, 1.25 mol%). Yield: 92% (91 mg). Colorless solid.
bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
Column chromatography eluents: PE/EtOAc ¼ 9/1. Mp: 133–
3a: 100 mg, 0.36 mmol; 4-methylphenylboronic acid: 74 mg, 135 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.92 (d, J ¼ 8.3 Hz,
0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; 2H), 7.85 (s, 1H), 7.58 (d, J ¼ 7.3 Hz, 2H), 7.52 (t, J ¼ 8.3 Hz, 2H),
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 83% (87 mg). 7.46 (t, J ¼ 7.3 Hz, 2H), 7.43–7.33 (m, 2H), 3.86 (s, 3H). 13C NMR
Light brown solid. Column chromatography eluents: PE/EtOAc (101 MHz, chloroform-d): d 149.3 (C), 139.6 (C), 138.4 (C), 132.5
¼ 9/1. Mp: 126–127 ꢀC. 1H NMR (400 MHz, acetone-d6): d 7.98 (s, (C), 130.1 (CH), 129.5 (2 ꢁ CH), 128.8 (2 ꢁ CH), 128.3 (CH),
1H), 7.87 (d, J ¼ 8.0 Hz, 2H), 7.70 (d, J ¼ 7.4 Hz, 2H), 7.60 (t, J ¼ 127.7 (CH), 126.1 (2 ꢁ CH), 123.7 (2 ꢁ CH), 117.3 (C), 37.4 (N–
7.4 Hz, 2H), 7.45 (t, J ¼ 7.4 Hz, 1H), 7.28 (d, J ¼ 8.0 Hz, 2H), 3.88 CH3). IR n (cmꢂ1): 3089, 3056, 2923, 2852, 1595, 1504, 1455,
(s, 3H), 2.37 (s, 3H). 13C NMR (101 MHz, acetone-d6): d 150.1 (C), 1418, 1208, 1081, 1016, 988, 907, 758. 694. HRMS (ESI): (m/z) [M
139.6 (C), 139.3 (C), 138.5 (C), 131.0 (C), 130.6 (CH), 130.3 (2 ꢁ + H]+ calculated for [C17H15N4]+ 275.1291; found 275.1289.
CH), 130.2 (2 ꢁ CH), 128.1 (CH), 126.6 (2 ꢁ CH), 124.3 (2 ꢁ CH),
3-(4-Methoxyphenyl)-1-methyl-6-phenyl-1,6-dihydropyrazolo
118.0 (C), 37.8 (N–CH3), 21.3 (CH3). IR n (cmꢂ1): 3013, 2919, [3,4-c]pyrazole (4e). Prepared as described in the general
1854, 1596, 1510, 1496, 1459, 1416, 1310, 1295, 1278, 1206, procedure C (3-bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo
1087, 1040, 1017, 1002, 990, 909, 820, 766, 753, 724, 696. HRMS [3,4-c]pyrazole 3a: 100 mg, 0.36 mmol; 4-methoxyphenyl-
(ESI): (m/z) [M + H]+ calculated for [C18H17N4]+ 289.1447; found boronic acid: 83 mg, 0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg,
289.1446.
1-Methyl-6-phenyl-3-(m-tolyl)-1,6-dihydropyrazolo[3,4-c]pyr-
0.47 mmol, 1.3 eq.; Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%).
Yield: 90% (99 mg). Light brown solid. Column chromatography
1
ꢀ
azole (4b). Prepared as described in the general procedure C (3- eluents: PE/EtOAc ¼ 8/2. Mp: 108–109 C. H NMR (400 MHz,
bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
chloroform-d): d 7.84 (d, J ¼ 8.8 Hz, 2H), 7.82 (s, 1H), 7.57 (d, J ¼
3a: 100 mg, 0.36 mmol; 3-methylphenyl-boronic acid: 74 mg, 8.0 Hz, 2H), 7.54 (t, J ¼ 8.0 Hz, 2H), 7.40 (t, J ¼ 8.0 Hz, 1H), 6.99
0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; (d, J ¼ 8.8 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H). 13C NMR (101 MHz,
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 89% (93 mg). chloroform-d): d 159.9 (C), 149.4 (C), 139.6 (C), 138.5 (C), 130.2
White yellow solid. Column chromatography eluents: PE/EtOAc (CH), 129.5 (2 ꢁ CH), 127.7 (CH), 127.5 (2 ꢁ CH), 125.4 (C),
¼ 9/1. Mp: 137–138 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.85 123.7 (2 ꢁ CH), 117.1 (C), 114.3 (2 ꢁ CH), 55.4 (O–CH3), 37.4 (N–
(s, 1H), 7.75 (s, 1H), 7.70 (d, J ¼ 7.7 Hz, 1H), 7.59 (d, J ¼ 7.6 Hz, CH3). IR n (cmꢂ1): 3052, 2999, 2941, 2837, 1596, 1538, 1506,
2H), 7.54 (t, J ¼ 7.6 Hz, 2H), 7.41 (t, J ¼ 7.6 Hz, 1H), 7.36 (t, J ¼ 1458, 1439, 1417, 1245, 1173, 1109, 1087, 1024, 1011, 989, 908,
7.7 Hz, 1H), 7.19 (d, J ¼ 7.7 Hz, 1H), 3.88 (s, 3H), 2.44 (s, 3H). 13
C
827, 841, 792. HRMS (ESI): (m/z) [M + H]+ calculated for
NMR (101 MHz, chloroform-d): d 149.4 (C), 139.9 (C), 138.6 (C), [C18H17N4O]+ 305.1396; found 305.1396.
138.5 (C), 132.5 (C), 130.3 (CH), 129.6 (2 ꢁ CH), 129.2 (CH),
1-Methyl-6-phenyl-3-(4-(triuoromethyl)phenyl)-1,6-dihydropyr-
128.8 (CH), 127.8 (CH), 126.6 (CH), 123.8 (2 ꢁ CH), 123.5 (CH), azolo[3,4-c]pyrazole (4f). Prepared as described in the general
117.4 (C), 37.5 (N–CH3), 21.6 (CH3). IR n (cmꢂ1): 3059, 2920, procedure C (3-bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo
2851, 1596, 1579, 1505, 1456, 1417, 1315, 1196, 1172, 1081, [3,4-c]pyrazole 3a: 100 mg, 0.36 mmol; 4-triuoro-
1039, 1025, 1014, 939, 825, 838, 796, 762. HRMS (ESI): (m/z) [M + methylphenylboronic acid: 103 mg, 0.54 mmol, 1.5 eq.;
H]+ calculated for [C18H17N4]+ 289.1447; found 289.1447.
Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; Pd(PPh3)4: 5.5 mg,
1-Methyl-6-phenyl-3-(o-tolyl)-1,6-dihydropyrazolo[3,4-c]pyrazole 0.004 mmol, 1.25 mol%). Yield: 86% (107 mg). Colorless solid.
(4c). Prepared as described in the general procedure C (3- Column chromatography eluents: PE/EtOAc ¼ 8/2. Mp: 136–
bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
137 ꢀC. 1H NMR (400 MHz, chloroform-d): d 8.01 (d, J ¼ 8.1 Hz,
3a: 100 mg, 0.36 mmol; 2-methylphenyl-boronic acid: 74 mg, 2H), 7.85 (s, 1H), 7.71 (d, J ¼ 8.1 Hz, 2H), 7.61–7.51 (m, 4H), 7.43
0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; (t, J ¼ 8.1 Hz, 1H), 3.89 (s, 3H). 13C NMR (101 MHz, chloroform-
2
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 86% (90 mg). d): d 149.4 (C), 138.3 (C), 138.0 (C), 136.0 (C), 130.3 (q, JC–F
¼
Colorless solid. Column chromatography eluents: PE/EtOAc ¼ 32.5 Hz, C), 129.8 (CH), 129.6 (2 ꢁ CH), 128.0 (CH), 126.2 (2 ꢁ
8/2. Mp: 134–135 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.71– CH), 125.9 (q, 3JC–F ¼ 3.8 Hz, 2 ꢁ CH), 124.3 (q, 1JC–F ¼ 272.0 Hz,
7.66 (m, 2H), 7.59 (d, J ¼ 7.3 Hz, 2H), 7.53 (t, J ¼ 7.3 Hz, 2H), 7.40 CF3), 123.9 (2 ꢁ CH), 117.4 (C), 37.6 (N–CH3). 19F NMR (235
(t, J ¼ 7.3 Hz, 1H), 7.32–7.28 (m, 3H), 3.88 (s, 3H), 2.61 (s, 3H). MHz, chloroform-d): d ꢂ62.5. IR n (cmꢂ1): 3113, 3063, 2950,
13C NMR (101 MHz, chloroform-d): d 149.1 (C), 140.6 (C), 138.9 1616, 1590, 1590, 1575, 1540, 1495, 1169, 1110, 1082, 1041,
(C), 136.7 (C), 132.2 (C), 131.5 (CH), 131.0 (CH), 129.9 (CH), 1010, 990, 955, 854, 845. HRMS (ESI): (m/z) [M + H]+ calculated
129.8 (2 ꢁ CH), 128.5 (CH), 128.0 (CH), 126.3 (CH), 124.1 (2 ꢁ for [C18H14F3N4]+ 343.1165; found 343.1166.
CH), 119.5 (C), 37.8 (N–CH3), 21.7 (CH3). IR n (cmꢂ1): 3059, 3039,
4-(1-Methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazol-3-yl)
2953, 2923, 1597, 1526, 1507, 1457, 1414, 1379, 1302, 1270, benzonitrile (4g). Prepared as described in the general procedure
1206, 1074, 1041, 1010, 989, 908, 846, 760. HRMS (ESI): (m/z) [M
C
(3-bromo-1-methyl-6-phenyl1,6-dihydro-pyrazolo[3,4-c]pyr-
+ H]+ calculated for [C18H17N4]+ 289.1447; found 289.1447.
azole 3a: 100 mg, 0.36 mmol; 4-cyanophenyl- boronic acid:
1-Methyl-3,6-diphenyl-1,6-dihydropyrazolo[3,4-c]pyrazole (4d). 80 mg, 0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.;
Prepared as described in the general procedure C (3-bromo-1- Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 72% (78 mg).
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Colorless solid. Column chromatography eluents: PE/EtOAc ¼ (2 ꢁ CH), 129.5 (CH), 128.0 (CH), 123.8 (2 ꢁ CH), 120.3 (2 ꢁ
1
7/3. Mp: 203–204 C. H NMR (400 MHz, chloroform-d): d 8.00 CH), 117.5 (C), 37.7 (N–CH3). IR n (cmꢂ1): 3034, 2925, 1609,
ꢀ
(d, J ¼ 8.4 Hz, 2H), 7.85 (s, 1H), 7.74 (d, J ¼ 8.4 Hz, 2H), 7.61– 1594, 1556, 1506, 1432, 1407, 1388, 1323, 1291, 1204, 1094,
7.52 (m, 4H), 7.44 (t, J ¼ 8.0 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 1019, 1002, 992, 917, 826. HRMS (ESI): (m/z) [M + H]+ calculated
MHz, chloroform-d): d 149.5 (C), 138.2 (C), 137.4 (C), 137.0 (C), for [C16H14N5]+ 276.1243; found 276.1244.
132.8 (2 ꢁ CH), 129.7 (2 ꢁ CH), 129.7 (CH), 128.1 (CH), 126.5 (2
(E)-1-Methyl-6-phenyl-3-styryl-1,6-dihydropyrazolo[3,4-c]pyr-
ꢁ CH), 124.0 (2 ꢁ CH), 119.0 (CN), 117.4 (C), 111.5 (C), 37.7 (N– azole (4k). Prepared as described in the general procedure C (3-
CH3). IR n (cmꢂ1): 3056, 2943, 2226, 1592, 1581, 1502, 1435, bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
1417, 1296, 1281, 1206, 1081, 1041, 1019, 990, 908, 844. HRMS 3a: 100 mg, 0.36 mmol; trans-2-phenylvinylboronic acid: 81 mg,
(ESI): (m/z) [M + H]+ calculated for [C18H14N5]+ 300.1243; found 0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.;
300.1244.
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 64% (70 mg).
Light brown solid. Column chromatography eluents: PE/EtOAc
3-(3-Fluorophenyl)-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-
c]pyrazole (4h). Prepared as described in the general procedure C ¼ 8/2. Mp: 140–141 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.84
(3-bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
(s, 1H), 7.60–7.47 (m, 6H), 7.37 (q, J ¼ 7.8 Hz, 3H), 7.27 (t, J ¼
3a: 100 mg, 0.36 mmol; 3-uorophenyl-boronic acid: 76 mg, 7.4 Hz, 1H), 7.18 (d, J ¼ 18.5 Hz, 1H), 7.14 (d, J ¼ 18.5 Hz, 1H),
0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; 3.79 (s, 3H). 13C NMR (101 MHz, chloroform-d): d 149.0 (C),
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 90% (95 mg). 139.9 (C), 138.3 (C), 136.7 (C), 132.8 (CH), 130.0 (CH), 129.5 (2 ꢁ
Beige solid. Column chromatography eluents: PE/EtOAc ¼ 8/2. CH), 128.8 (2 ꢁ CH), 128.1 (CH), 127.7 (CH), 126.6 (2 ꢁ CH),
Mp: 97–98 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.83 (s, 1H), 123.7 (2 ꢁ CH), 120.2 (CH), 116.6 (C), 37.3 (N–CH3). IR n (cmꢂ1):
7.67 (d, J ¼ 7.7 Hz, 1H), 7.62 (d, J ¼ 9.8 Hz, 1H), 7.59–7.50 (m, 4H), 3100, 3061, 3030, 2946, 1591, 1580, 1505, 1494, 1429, 1304,
7.45–7.39 (m, 2H), 7.04 (dd, J ¼ 8.5, 8.2 Hz, 1H), 3.87 (s, 3H). 13
C
1261, 1201, 1046, 1013, 1001, 989, 961, 906, 874, 852, 744. HRMS
1
NMR (101 MHz, chloroform-d): d 163.3 (d, JC–F ¼ 245.5 Hz, C), (ESI): (m/z) [M + H]+ calculated for [C19H17N4]+ 301.1447; found
149.4 (C), 138.4 (C), 138.3 (C), 134.8 (d, 3JC–F ¼ 8.3 Hz, C), 130.4 (d, 301.1449.
3JC–F ¼ 8.4 Hz, CH), 129.9 (CH), 129.6 (2 ꢁ CH), 127.9 (CH), 123.8
4-(6-(4-Methoxyphenyl)-1-methyl-1,6-dihydropyrazolo[3,4-c]
pyrazol-3-yl)benzonitrile (4l). Prepared as described in the
(2 ꢁ CH), 121.9 (d, 4JC–F ¼ 2.8 Hz, CH), 117.3 (C), 115.1 (d, 2JC–F
¼
2
21.3 Hz, CH), 112.8 (d, JC–F ¼ 22.8 Hz, CH), 37.5 (N–CH3). 19F general procedure C (3-bromo-6-(4-methoxyphenyl)-1-methyl-
NMR (235 MHz, chloroform-d): d ꢂ112.9. IR n (cmꢂ1): 3054, 2931, 1,6-dihydropyrazolo[3,4-c]pyrazole 3c: 100 mg, 0.32 mmol; 4-
2850, 1595, 1580, 1507, 1481, 1449, 1411, 1297, 1183, 1082, 1018, cyanophenylboronic acid: 72 mg, 0.48 mmol, 1.5 eq.; Cs2CO3:
990, 881, 831. HRMS (ESI): (m/z) [M + H]+ calculated for 138 mg, 0.42 mmol, 1.3 eq.; Pd(PPh3)4: 5 mg, 0.004 mmol,
[C17H14FN4]+ 293.1197; found 293.1197.
1.25 mol%). Yield: 75% (81 mg). Colorless solid. Column
1
ꢀ
1-Methyl-6-phenyl-3-(thiophen-3-yl)-1,6-dihydropyrazolo[3,4-c]
chromatography eluents: PE/EtOAc ¼ 7/3. Mp: 186–187 C. H
pyrazole (4i). Prepared as described in the general procedure C NMR (400 MHz, chloroform-d): d 7.99 (d, J ¼ 8.3 Hz, 2H), 7.81 (s,
(3-bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
1H), 7.73 (d, J ¼ 8.3 Hz, 2H), 7.47 (d, J ¼ 8.9 Hz, 2H), 7.04 (d, J ¼
3a: 100 mg, 0.36 mmol; 3-thienylboronic acid: 70 mg, 8.9 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H). 13C NMR (101 MHz,
0.54 mmol, 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; chloroform-d): d 159.6 (C), 149.7 (C), 137.3 (C), 137.1 (C), 132.7
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 85% (86 mg). (2 ꢁ CH), 131.1 (C), 129.1 (CH), 126.4 (2 ꢁ CH), 126.0 (2 ꢁ CH),
Light brown solid. Column chromatography eluents: PE/EtOAc 119.0 (CN), 116.9 (C), 114.7 (2 ꢁ CH), 111.3 (C), 55.7 (O–CH3),
¼ 8/2. Mp: 100–101 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.78 37.3 (N–CH3). IR n (cmꢂ1): 3105, 3082, 3012, 2942, 2842, 2221,
(s, 1H), 7.68 (s, 1H), 7.61–7.50 (m, 5H), 7.43–7.38 (m, 2H), 3.84 1610, 1593, 1580, 1517, 1439, 1299, 1253, 1203, 1110, 1086,
(s, 3H). 13C NMR (101 MHz, chloroform-d): d 149.1 (C), 138.5 (C), 1045, 1017, 989, 910, 841, 826. HRMS (ESI): (m/z) [M + H]+
136.0 (C), 134.2 (C), 129.8 (CH), 129.5 (2 ꢁ CH), 127.7 (CH), calculated for [C19H16N5O]+ 330.1349; found 330.1353.
126.4 (CH), 125.9 (CH), 123.7 (2 ꢁ CH), 122.0 (CH), 117.4 (C),
6-(4-Methoxyphenyl)-1-methyl-3-(pyridin-4-yl)-1,6-dihydropyr-
37.3 (N–CH3). IR n (cmꢂ1): 3095, 3061, 2947, 1596, 1510, 1460, azolo[3,4-c]pyrazole (4m). Prepared as described in the general
1413, 1282, 1211, 1188, 1038, 1013, 1001, 951, 870, 793, 779. procedure C (3-bromo-6-(4-methoxyphenyl)-1-methyl-1,6-dihy-
HRMS (ESI): (m/z) [M + H]+ calculated for [C15H13N4S]+ 281.0855; dropyrazolo[3,4-c]pyrazole 3c: 100 mg, 0.32 mmol; 4-pyr-
found 281.0858.
1-Methyl-6-phenyl-3-(pyridin-4-yl)-1,6-dihydropyrazolo[3,4-c]
idinylboronic acid: 61 mg, 0.48 mmol, 1.5 eq.; Cs2CO3: 138 mg,
0.42 mmol, 1.3 eq.; Pd(PPh3)4: 5 mg, 0.004 mmol, 1.25 mol%).
pyrazole (4j). Prepared as described in the general procedure C Yield: 76% (76 mg). Colorless solid. Column chromatography
(3-bromo-1-methyl-6-phenyl-1,6-dihydropyrazolo[3,4-c]pyrazole
eluents: DCM/EtOAc ¼ 5/5. Mp: 198–199 ꢀC. 1H NMR (400 MHz,
3a: 100 mg, 0.36 mmol; 4-pyridinylboronic acid: 67 mg, chloroform-d): d 8.68 (d, J ¼ 6.2 Hz, 2H), 7.83 (s, 1H), 7.76 (d, J ¼
0.54 mmol 1.5 eq.; Cs2CO3: 153 mg, 0.47 mmol, 1.3 eq.; 6.2 Hz, 2H), 7.47 (d, J ¼ 8.9 Hz, 2H), 7.04 (d, J ¼ 8.9 Hz, 2H), 3.88
Pd(PPh3)4: 5.5 mg, 0.004 mmol, 1.25 mol%). Yield: 78% (78 mg). (s, 3H), 3.83 (s, 3H). 13C NMR (101 MHz, chloroform-d): d 159.6
Beige solid. Column chromatography eluents: PE/EtOAc ¼ 1/9. (C), 150.5 (2 ꢁ CH), 149.7 (C), 140.0 (C), 136.7 (C), 131.1 (C),
Mp: 158–159 ꢀC. 1H NMR (400 MHz, chloroform-d): d 8.68 129.1 (CH), 126.0 (2 ꢁ CH), 120.3 (2 ꢁ CH), 117.0 (C), 114.7 (2 ꢁ
(br s, 2H), 7.84 (s, 1H), 7.75 (br s, 2H), 7.58–7.47 (m, 4H), 7.41 (t, CH), 55.7 (O–CH3), 37.3 (N–CH3). IR n (cmꢂ1): 3067, 2951, 2847,
J ¼ 6.8 Hz, 1H), 3.86 (s, 3H). 13C NMR (101 MHz, chloroform-d): 1593, 1556, 1518, 1455, 1438, 1409, 1298, 1255, 1208, 1166,
d 150.3 (2 ꢁ CH), 149.3 (C), 139.8 (C), 138.1 (C), 136.7 (C), 129.6
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1108, 1094, 1017, 991, 917, 821. HRMS (ESI): (m/z) [M + H]+ 917, 846, 739. HRMS (ESI): (m/z) [M + H]+ calculated for
calculated for [C17H16N5O]+ 306.1349; found 306.1349.
[C17H13F3N5]+ 344.1117; found 344.1118.
3,6-Bis(4-methoxyphenyl)-1-methyl-1,6-dihydropyrazolo[3,4-c]
3-(4-Methoxyphenyl)-1-methyl-6-(4-(triuoromethyl)phenyl)-1,6-
pyrazole (4n). Prepared as described in the general procedure C dihydro pyrazolo[3,4-c]pyrazole (4q). Prepared as described in the
(3-bromo-6-(4-methoxyphenyl)-1-methyl-1,6-dihydropyrazolo general procedure C (3-bromo-1-methyl-6-(4-(triuoromethyl)
[3,4-c]pyrazole 3c: 100 mg, 0.32 mmol; 4-methoxyphenylboronic phenyl)-1,6-dihydro pyrazolo[3,4-c]pyrazole 3e: 100 mg,
acid: 75 mg, 0.48 mmol, 1.5 eq.; Cs2CO3: 138 mg, 0.42 mmol, 1.3 0.28 mmol; 4-methoxyphenylboronic acid: 67 mg, 0.43 mmol,
eq.; Pd(PPh3)4: 5 mg, 0.004 mmol, 1.25 mol%). Yield: 80% (88 1.5 eq.; Cs2CO3: 123 mg, 0.37 mmol, 1.3 eq.; Pd(PPh3)4: 4.5 mg,
mg). Colorless solid. Column chromatography eluent: DCM. 0.003 mmol, 1.25 mol%). Yield: 94% (102 mg). Colorless solid.
Mp: 212–213 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.84 (d, J ¼ Column chromatography eluents: PE/EtOAc ¼ 9/1. Mp: 205–
8.7 Hz, 2H), 7.78 (s, 1H), 7.47 (d, J ¼ 8.9 Hz, 2H), 7.02 (d, J ¼ 206 ꢀC. 1H NMR (400 MHz, chloroform-d): d 7.88–7.77 (m, 5H),
8.9 Hz, 2H), 6.99 (d, J ¼ 8.7 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 7.71 (d, J ¼ 8.4 Hz, 2H), 7.00 (d, J ¼ 8.7 Hz, 2H), 3.91 (s, 3H), 3.86
3.78 (s, 3H). 13C NMR (101 MHz, chloroform-d): d 160.1 (C), (s, 3H). 13C NMR (101 MHz, chloroform-d): d 160.0 (C), 149.2 (C),
2
159.6 (C), 150.0 (C), 139.8 (C), 131.8 (C), 129.9 (CH), 127.7 (2 ꢁ 141.4 (C), 140.0 (C), 131.4 (CH), 129.3 (q, JC–F ¼ 33.1 Hz, C),
CH), 126.1 (2 ꢁ CH), 125.8 (C), 116.9 (C), 114.9 (2 ꢁ CH), 114.6 127.5 (2 ꢁ CH), 126.8 (q, 3JC-F ¼ 3.7 Hz, 2 ꢁ CH), 125.0 (C), 123.0
1
(2 ꢁ CH), 56.0 (O–CH3), 55.7 (O–CH3), 37.2 (N–CH3). IR n (2 ꢁ CH), 121.2 (d, JC-F ¼ 272.1 Hz, CF3), 117.8 (C), 114.4 (2 ꢁ
(cmꢂ1): 3105, 3002, 2974, 2941, 1840, 1596, 1537, 1513, 1500, CH), 55.4 (O–CH3), 37.8 (N–CH3). 19F NMR (235 MHz, chloro-
1452, 1438, 1302, 1244, 1168, 1106, 1043, 1024, 1013, 907, 839, form-d): d ꢂ62.4. IR n (cmꢂ1): 3338, 3057, 2937, 2845, 1596,
824. HRMS (ESI): (m/z) [M + H]+ calculated for [C19H19N4O2]+ 1614, 1540, 1425, 1323, 1251, 1107, 1088, 1031, 1007, 858, 832,
335.1502; found 335.1505.
4-(1-Methyl-6-(4-(triuoromethyl)phenyl)-1,6-dihydropyrazolo
[3,4-c]pyrazol-3-yl)benzonitrile (4o). Prepared as described in the
721, 715. HRMS (ESI): (m/z) [M
[C19H16F3N4O]+ 373.1270; found 373.1268.
1-Methyl-3-(p-tolyl)-6-(4-(triuoromethyl)phenyl)-1,6-dihydro
+
H]+ calculated for
general procedure C (3-bromo-1-methyl-6-(4-(triuoromethyl) pyrazolo[3,4-c]pyrazole (4r). Prepared as described in the
phenyl)-1,6-dihydro pyrazolo[3,4-c]pyrazole 3e: 100 mg, general procedure C (3-bromo-1-methyl-6-(4-(triuoromethyl)
0.28 mmol; 4-cyanophenylboronic acid: 64 mg, 0.43 mmol, phenyl)-1,6-dihydro pyrazolo[3,4-c]pyrazole 3e: 100 mg,
1.5 eq.; Cs2CO3: 123 mg, 0.37 mmol, 1.3 eq.; Pd(PPh3)4: 0.28 mmol; 4-methylphenylboronic acid: 60 mg, 0.43 mmol,
4.5 mg, 0.003 mmol, 1.25 mol%). Yield: 68% (73 mg). 1.5 eq.; Cs2CO3: 123 mg, 0.37 mmol, 1.3 eq.; Pd(PPh3)4: 4.5 mg,
Colorless solid. Column chromatography eluents: PE/EtOAc 0.003 mmol, 1.25 mol%). Yield: 86% (89 mg). Colorless solid.
¼ 9/1. Mp: 226–227 ꢀC. 1H NMR (400 MHz, chloroform-d): Column chromatography eluents: PE/EtOAc ¼ 9/1. Mp: 204–
1
ꢀ
d 7.98 (d, J ¼ 8.4 Hz, 2H), 7.88 (s, 1H), 7.82 (d, J ¼ 8.6 Hz, 2H), 205 C. H NMR (400 MHz, chloroform-d): d 7.87 (s, 1H), 7.79
7.76–7.69 (m, 4H), 3.96 (s, 3H). 13C NMR (101 MHz, chloro- (d, J ¼ 7.8 Hz, 4H), 7.70 (d, J ¼ 8.4 Hz, 2H), 7.27 (d, J ¼ 7.8 Hz,
form-d): d 149.2 (C), 141.0 (C), 137.7 (C), 136.6 (C), 132.7 (2 ꢁ 2H), 3.92 (s, 3H), 2.40 (s, 3H). 13C NMR (101 MHz, chloroform-
CH), 130.7 (CH), 129.7 (q, 2JC–F ¼ 33.1 Hz, C), 126.9 (q, 3JC–F
¼
d): d 149.2 (C), 141.4 (C), 140.2 (C), 138.6 (C), 131.4 (CH), 129.6
1
3.7 Hz, 2 ꢁ CH), 126.5 (2 ꢁ CH), 123.8 (d, JC–F ¼ 272.2 Hz, (2 ꢁ CH), 129.5 (C), 129.3 (q, 2JC–F ¼ 33.0 Hz, C), 126.9 (q, 3JC–F
1
CF3), 123.3 (2 ꢁ CH), 118.9 (CN), 118.0 (C), 111.7 (C), 38.2 (N– ¼ 3.7 Hz, 2 ꢁ CH), 126.1 (2 ꢁ CH), 123.9 (q, JC–F ¼ 272.1 Hz,
CH3). 19F NMR (235 MHz, chloroform-d): d ꢂ62.5. IR n (cmꢂ1): CF3), 123.1 (2 ꢁ CH), 118.0 (C), 37.9 (N–CH3), 21.5 (CH3). 19F
3343, 2923, 1852, 2225, 1616, 1579, 1522, 1541, 1421, 1384, NMR (235 MHz, chloroform-d): d ꢂ62.4. IR n (cmꢂ1): 2926,
1315, 1168, 1103, 1038, 1013, 989, 955, 909, 839. HRMS (ESI): 1614, 1594, 1582, 1522, 1504, 1424, 1317, 1162, 1110, 1085,
(m/z) [M + H]+ calculated for [C19H13F3N5]+ 368.1117; found 1066, 1039, 1014, 990, 965, 952, 909, 842, 825, 737. HRMS
368.1116.
1-Methyl-3-(pyridin-4-yl)-6-(4-(triuoromethyl)phenyl)-1,6-
(ESI): (m/z) [M + H]+ calculated for [C19H16F3N4]+ 357.1249;
found 357.1247.
dihydro pyrazolo[3,4-c]pyrazole (4p). Prepared as described in the
general procedure C (3-bromo-1-methyl-6-(4-(triuoromethyl)
phenyl)-1,6-dihydro pyrazolo[3,4-c]pyrazole 3e: 100 mg,
0.28 mmol; 4-pyridinylboronic acid: 54 mg, 0.43 mmol, 1.5 eq.;
Cs2CO3: 123 mg, 0.37 mmol, 1.3 eq.; Pd(PPh3)4: 4.5 mg,
0.003 mmol, 1.25 mol%). Yield: 79% (79 mg). Colorless solid.
Column chromatography eluents: PE/EtOAc ¼ 5/5. Mp: 196–
197 ꢀC. 1H NMR (400 MHz, chloroform-d): d 8.69 (d, J ¼ 5.4 Hz,
Conflicts of interest
There are no conicts to declare.
Acknowledgements
2H), 7.90 (s, 1H), 7.82 (d, J ¼ 8.4 Hz, 2H), 7.76 (d, J ¼ 5.4 Hz, 2H), This work was supported by “Vasile Alecsandri” University of
7.71 (d, J ¼ 8.4 Hz, 2H), 3.96 (s, 3H). 13C NMR (101 MHz, Bacau (ERASMUS grants and CNFIS-FDI-0151/2017), Franco-
chloroform-d): d 150.5 (2 ꢁ CH), 149.2 (C), 141.0 (C), 139.5 (C), phone University Agency in Central and Eastern Europe
137.2 (C), 130.7 (CH), 129.7 (q, 2JC–F ¼ 33.1 Hz, C), 127.0 (q, 3JC–F (CE_124_FF_2016), Campus France (N 857352 B, N 902192 B)
1
¼ 3.7 Hz, 2 ꢁ CH), 123.8 (q, JC–F ¼ 272.2 Hz, CF3), 123.3 (2 ꢁ and the Eiffel Scholarship Program of Excellence (N 870738 C)
CH), 120.3 (2 ꢁ CH), 118.2 (C), 38.2 (N–CH3). 19F NMR (235 as well as partially supported by Orleans University, CNRS,
´
MHz, chloroform-d): d ꢂ62.5. IR n (cmꢂ1): 3067, 2952, 1614, Labex SynOrg (ANR-11-LABX-0029), Labex IRON (ANR-11-LABX-
´
1581, 1556, 1526, 1420, 1324, 1219, 1184, 1113, 1094, 1016, 992, 0018-01), region Centre-Val de Loire.
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16 R. A. Pawar and A. A. Patil, Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem., 1994, 33, 156.
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17 F. M. Abd El Latif, J. Indian Chem. Soc., 1994, 71, 631.
18 R. M. Mohareb, A. Habashi, N. S. Ibrahim and S. M. Sherif,
Synthesis, 1987, 228.
19 G. H. Elgemeie, H. A. Ali, A. H. Elghandour and
A. M. Hussein, Heterocycl. Commun., 2002, 8, 443.
20 S. Asadi, F. Alizadeh-Bami and H. Mehrabi, Arkivoc, 2020,
238.
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© 2021 The Author(s). Published by the Royal Society of Chemistry
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