Direct Preparation of N-Substituted Pyrazoles from Primary Aliphatic or Aromatic Amines

Article abstract of DOI:10.1021/acs.joc.1c00606

Despite a large number of synthesis procedures for pyrazoles known today, those directly employing primary amines as substrates are rare. Herein, we report an original method for the preparation of N-alkyl and N-aryl pyrazoles from primary aliphatic or aromatic amines as a limiting reagent of the reaction. The protocol utilizes no inorganic reagents and requires a short reaction time, mild conditions, and the use of structurally simple and commercially available starting reagents. During this study, pyrazoles containing a wide variety of N-substituents were obtained using the same procedure for both aliphatic and aromatic amines.

Full text of DOI:10.1021/acs.joc.1c00606

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Article
Direct Preparation of N‑Substituted Pyrazoles from Primary
Aliphatic or Aromatic Amines
Nurbey Gulia,* Marcin Małecki, and Sławomir Szafert
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ABSTRACT: Despite a large number of synthesis procedures for
pyrazoles known today, those directly employing primary amines as
substrates are rare. Herein, we report an original method for the
preparation of N-alkyl and N-aryl pyrazoles from primary aliphatic or
aromatic amines as a limiting reagent of the reaction. The protocol
utilizes no inorganic reagents and requires a short reaction time, mild
conditions, and the use of structurally simple and commercially available
starting reagents. During this study, pyrazoles containing a wide variety of
N-substituents were obtained using the same procedure for both aliphatic
and aromatic amines.
Scheme 1. Pyrazoles from Aliphatic Amines as a Limiting
Reagent
INTRODUCTION
■
Pyrazoles can be obtained by numerous synthetic methods,1−5
but their versatile applicability as pharmaceuticals,6,7 crop
protection chemicals,8,9 building blocks for organic and
inorganic chemistry10,11 still propels research to develop new
synthetic methodologies. Over the past decade, a new specific
application has appeared for N-substituted pyrazoles, i.e., as a
metal-coordinating directing group for transition-metal-cata-
lyzed reactions.12−18 A large number of such chemical
transformations significantly increase interest in pyrazole-
functionalized molecules. Preparation of N-substituted pyr-
azoles from primary amines as a limiting reagent and source of
N-substituent gives a wide variety of potential products that
might be further functionalized.15
In contrast to N-alkyl indazoles for which synthetic
methodology starting from primary aliphatic amines is well-
known and broadly used,19−21 N-alkyl pyrazoles are usually
synthesized from difficult to handle hydrazines or hydrazine
derivatives.2−4,22−24 With a great variety of synthetic methods
for N-alkyl pyrazoles, there are just two reports describing
primary aliphatic amine as a limiting reagent that introduces an
N-linked substituent into a product’s structure (Scheme
1).25,26 The known methods are limited because of multistep
functionalizations of diketone (A) or amination reagent
preparation (B). The drawback of the methodologically
elegant reaction B is, moreover, a complicated and time-
consuming procedure (Scheme 1).
this requires a further deprotection step.25,31,32 Transformation
with commercially available amination reagents that form
unprotected hydrazine has practical advantages. Here we
report a fast and straightforward method for the preparation of
pyrazoles from primary aliphatic and aromatic amines as
limiting reagents using bench-stable, commercially available
amination reagent.
RESULTS AND DISCUSSION
■
Initially, we tested reagents R1, R2, and R4, and we found that
only R1 gives the desired product under initial conditions.
Electrophilic amination of primary aliphatic amines is a well-
known strategy for the preparation of hydrazines.27−29
However, in all cases, a large excess of the amine is required
due to hydrazine’s enhanced nucleophilicity relative to the
corresponding origin amine.30 This problem might be solved
by utilizing N-protected electrophilic amination reagents that
form hydrazines that are stable under reaction conditions, but
Received: March 14, 2021
Published: July 1, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.joc.1c00606
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a
Solvent, temperature, time, and proportion of reagents
optimization with R1 allowed obtaining the desired N-alkyl
pyrazole 1a with 44% isolated yield (Table 1, for the full table,
Scheme 2. Scope of Amines
Table 1. Reaction Conditions and Amination Reagent
a
Optimization
b
entry R1−6 [equiv] additive [1.0 equiv] temp [°C]
yield [%]
e
f
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
R1 [1.5]
R1 [1.5]
R1 [1.5]
R1 [1.5]
R1 [1.1]
R1 [1.7]
R1 [1.5]
R1 [1.5]
R1 [1.5]
R1 [1.5]
R1 [1.5]
R1 [1.5]
R2 [1.5]
R3 [1.5]
R4 [1.5]
R5 [1.5]
0−85
0−85
0−110
0−50
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
0−85
54, 53, 44
c
17
49
41
47
48
48
51
51
53
56
46
d
H2O
AcOH
AcONa
K2CO3
DIPEA
e
23
e
41
e
0
e
0
g
e
R6 [1.5]
53
a
The yields refer to the isolated products. Reactions were carried out
using amines a−q (1.0 mmol), 1 (1.1 mmol), R1 (1.5 mmol), and
DMF (5.0 mL) at 0−85 °C in 1.5−2.0 h under air unless otherwise
a
Reactions were carried out using a (0.2 mmol, 1.0 equiv), 1 (0.22
mmol, 1.1 equiv), R1−6 (1.1−1.7 equiv), and DMF (1.0 mL, 0.2 M)
b
c
at a given temperature under air. GC yield. 1 was added after the
b
given. The experiment was conducted on a 3.0 mmol scale to give
0.243 g (1.35 mmol) of the 1a. The experiment was conducted on a
5.0 mmol scale to give 383 mg (1.71 mmol) of the 1g. The
experiment was conducted on a 0.5 mmol scale. The reaction was
d
mixture was heated to 80 °C. 0.3 mmol (1.5 equiv) of 1 was added.
NMR yield. Isolated yield. Wet R6 was used.
c
e
f
g
d
e
carried out for 16 h at 80 °C.
see Table S1). Adding all three reagents simultaneously at 0 °C
followed by their heating is critical to obtain the desired
product with a reproducible yield. Minor changes in the
reaction temperature or equivalents of reagents R1 and 1
slightly reduce the yield (Table 1, entries 3−7). The addition
of a stoichiometric amount of water, acetic acid, or weak basic
salts has a minor effect on yield, showing that the reaction is
not promoted by this species, and it is not sensitive to them
(Table 1, entries 8−12). The presence of diisopropylethyl-
amine (DIPEA) decreases the yield of 1a, which is probably an
effect of an R1 consumption for a side formation of 1,1-
diisopropyl-1-ethylhydrazonium salt (entry 12). Alternative
amination reagents R2−R6 were tried under optimized
conditions (Table 1, entries 13−17). The product was
obtained in 23%, 41%, and 53% yields for R2, R3, and R6,
respectively, and was not observed (1H NMR and GC−MS)
for reactions conducted with R4 and R5.
less hindered tertiary carbon gave yields close to 30% (1c, 1e,
1g, 1j, and 1k). Aromatic amines reacted under the same
condition and gave pyrazoles 1l−p generally with higher yields
(47−70%) than aliphatic amines. Compounds with electron-
donating and withdrawing substituent at phenyl ring (1m and
1n) and substituent in ortho position to an amine group (1p)
were successfully obtained. Besides ester, methoxy, and
haloarene functionalities, the reaction tolerates unprotected
N−H of indole and aliphatic O−H group. However, the target
product was not observed in the presence of unprotected
phenol (1q), probably due to competitive O-amination.
Syntheses of 1a and 1g were conducted on a 3.0 and 5.0
mmol scale, respectively, to underline the method’s synthetic
applicability. The structure of 1o was confirmed by X-ray
single-crystal analysis (Scheme 4).
A series of primary aliphatic and aromatic amines were
reacted under optimal conditions yielding corresponding
pyrazoles (Scheme 2). Reactions were typically carried out
on a 1 mmol scale. It was found that aliphatic amines with
quaternary carbon or sterically hindered tertiary carbon
adjacent to the amine group gave around 40% yields (1a, 1b,
1d, 1h, and 1i), whereas amines with neighboring secondary or
Reactivity of a series of diketones was tested in reaction with
tert-octylamine, and it was found that it strongly depends on
the electronic and steric properties of diketone’s substituents
(Scheme 3). 3,5-Dialkyl and 3,4,5-trialkyl pyrazoles (2b, 3b,
and 6b) were obtained in 37−43% yields, whereas 4b in only
24% even with 5.0 equiv of b. Reaction conducted with
diketone containing aryl substituent 5 under standard
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a
a
b
Scheme 3. Scope of Diketones
Scheme 4. Additional Experiments and X-ray Structures
a
The yields refer to the isolated products. Reactions were carried out
using amine b (1.0 mmol), diketones 2−8 (1.1 mmol), R1 (1.5
a
The reactions were carried out using 9 (0.1 mmol, 1.0 equiv), R1
(1.1 equiv), and DMF (0.5 mL); 10 (0.12 mmol, 1.2 equiv), a (1.0
equiv), and DMF (0.5 mL), at a given temperature under air.
mmol), and DMF (5.0 mL) at 0−85 °C for 1.5 h under air unless
b
otherwise given. The experiment was conducted on a 0.5 mmol scale
for 4b and a 0.2 mmol for 5b and 7−8b with 5.0 equiv of diketones.
b
ORTEP view of crystal structures of 1o (CCDC 2019272) and 5b
(CCDC 2019718). Thermal ellipsoids are drawn to encompass 50%
probability level.
conditions gave a 20% yield. However, the use of 5.0 equiv of 5
instead of standard 1.1 allowed for 5b with a 46% yield.
Sterically hindered 7 and electron-deficient 8 did not react
under the standard conditions and when they were used in 5.0
equiv excess (7b and 8b). Interestingly, for reactions with
diketones 5 and 6, only one isomer of pyrazoles 5b or 6b was
obtained. The other was observed in the crude reaction
mixture by GC−MS in a very small amount, but they were not
isolated in both cases. The structure of the obtained isomer 5b
was confirmed by X-ray single-crystal analysis (Scheme 4).
Additional experiments conducted for 9 and 10 showed that
both compounds are not intermediates in the reaction
(Scheme 4). This and selectivity of formed products from
unsymmetrical diketones (Scheme 3, 5b and 6b) that indicate
a nucleophilic attack of prior formed hydrazine on less
hindered carbonyl gave reason to believe that the reaction
starts from a nucleophilic attack of amine on II (Scheme 5).
Delivered during this step, hydrazine III is trapped by diketone
V before the next competitive attack on II. It is also consistent
with the fact that the addition of diketone 1 with a few minutes
delay caused a significantly lower yield (17%, Table 1, entry 2).
Relatively strong p-nitrobenzoic acid that forms in the first step
from R1 catalyzes the formation of hydrazone followed by
heterocyclization to give pyrazole in Knorr condensation
reaction. The observed moderate yield of the reaction explains
the formation of side products VI, VII, and IX (Scheme 5).
GC−MS of a crude mixture of 1a indicated corresponding
imine VI, and the product of hydrazine decomposition VII was
observed by the same method running reaction without
diketone (see Supporting Information). The product of
amination of pyrazole IX was not detected in reaction
mixtures. However, deprotonated pyrazole efficiently reacts
with R1,33 and the addition of the next portion of amination
reagent II decreases the yield of VIII, pointing to the
formation of IX (see Table S1, entries 5 and 9).
Scheme 5. Proposed Reaction Pathway and Side Product
Formation
delivers products with less effort. In this context, the
availability of R1 amination reagent from commercial sources
offers an extra advantage over the requiring five-step synthesis
of oxaziridine (15% overall yield). Alternatively, a known two-
step large-scale synthesis allows to obtain R1 from basic
reagents (81% overall yield).33
CONCLUSIONS
■
In conclusion, we have developed a new method for the
preparation of N-alkyl and N-aryl substituted pyrazoles directly
from primary aliphatic or aromatic amines and diketones,
applying readily accessible from commercial sources electro-
philic amination reagent R1. Despite the modest yields in some
cases, the use of an amine as the limiting reagent, the absence
of metals, short reaction times, and a simple procedure makes
this method practical for functionalizing amines, giving
pyrazoles containing a wide variety of N-substituents.
EXPERIMENTAL SECTION
■
In contrast to the multistep method of pyrazole synthesis
from amines, which in showed examples gave comparable
overall yields (Scheme 1, B),25 the presented method is
characterized by a short time and a simple procedure that
General Information. All reactions were carried out and purified
using standard, commercially available glassware. Chemicals for
reactions, workup, and chromatography were reagent grade or ACS
grade and were used as received. Silica gel 60 Å 0.04−0.06 mm
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(Macherey Nagel), Al2O3, basic/neutral alumina, Brockmann grade I,
3H). 13C{1H} NMR (126 MHz, CDCl3): δ 147.5, 139.2, 136.3, 127.4,
122.5, 122.1, 119.5, 118.6, 112.6, 111.3, 104.8, 49.4, 26.7, 13.7, 10.9.
IR (ATR, diamond, cm−1): 3215, 3184, 2931, 2856, 1551, 1454,
1352, 1232, 1107, 786, 765, 736. HRMS (ESI) m/z: [M + H]+ calcd
for C15H18N3, 240.1496; found, 240.1493.
1
60 mesh (Alfa Aesar), was used for product purifications. H NMR
and 13C NMR spectra were recorded using a 500 MHz Bruker Avance
1
spectrometer with an inverse broad-band probe. For all H NMR
spectra, the chemical shifts are given in ppm relative to the solvent
1
residual peaks (CDCl3, H = 7.26 ppm, 13C = 77.16 ppm). Coupling
3,5-Dimethyl-1-(tert-pentyl)-1H-pyrazole (1d). 2-Methylbutan-2-
amine d (116 μL, 1.00 mmol), 2,4-pentanedione 1 (114 μL 1.10
mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and
DMF (5.0 mL) were used. The reaction was run at 85 °C (reaction
block) for 1.5 h. Workup A and chromatography (silica gel, hexane−
EA 30%) were applied to obtain 60 mg (0.361 mmol, 36%) of 1d as a
constants are given in hertz (Hz). 13C NMR spectra were measured
with proton decoupling. HRMS spectra were recorded using Bruker
Apex ultra FT-ICR (ESI) or Shimadzu q-TOF LCMS 9030 with an
ESI ion source. GC−MS (EI) data were recorded using an Agilent
GCMSD 7820A/5977B system. IR spectra were recorded using a
Thermo Scientific Nicolet iS10 FTIR (ATR, diamond).
1
yellowish volatile liquid. H NMR (500 MHz, CDCl3): δ 5.75 (s,
1H), 2.33 (s, 1H), 2.16 (s, 1H), 1.85 (q, J = 7.4 Hz, 1H), 1.56 (s,
2H), 0.71 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
145.0, 138.7, 107.7, 62.1, 34.8, 28.0, 14.5, 13.5, 8.4. HRMS (ESI) m/
z: [M + Na]+ calcd for C10H18N2Na, 189.1363; found, 189.1359. IR
(ATR, diamond, cm−1): 2970, 1550, 1416, 1356, 1304, 1251, 1210,
1107, 1025, 776.
General Procedure. Amine (1.00 mmol) was dissolved in DMF
(5.0 mL) in an 8−10 mL screw cap (silicon/PTFE septum) vial
equipped with a small (10 mm × 6 mm) stir bar. The mixture was
cooled in an ice−NaCl cooling bath. Then, prepared samples of O-(4-
nitrobenzoyl)hydroxylamine (274 mg, 1.50 mmol) and diketone
(1.10 mmol) were added one by one. The vial was immediately
closed, shaken, and placed into a reaction pie block preheated on a
stirrer to 85 °C for the reaction time given for a compound. In
workup A, the crude mixture was poured into 1 M NaOH (100 mL)
and extracted with DCM (3 × 30 mL). The organic phase was washed
with brine (2 × 50 mL), dried with anhydrous MgSO4, and filtered,
and the solvent was evaporated. The product was purified using
column chromatography under conditions given for a compound. In
workup B, the crude mixture was treated with triethylamine (0.5 mL),
and DMF was partially evaporated under a nitrogen flow. The residue
was adsorbed on silica gel and purified using column chromatography
under conditions given for a compound.
1-Dodecyl-3,5-dimethyl-1H-pyrazole (1e). Dodecylamine e (185
mg, 1.00 mmol), 2,4-pentanedione 1 (114 μL 1.10 mmol), O-(4-
nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and DMF (5.0
mL) were used. The reaction was run at 85 °C (reaction block) for
1.5 h. Workup A and chromatography (silica gel, hexane−EA 0−30%)
were applied to obtain 87 mg (0.33 mmol, 33%) of 1e as a yellowish
oil. 1H NMR (500 MHz, CDCl3): δ 5.74 (s, 1H), 3.92−3.88 (m, 2H),
2.19 (s, 6H), 1.78−1.70 (m, 2H), 1.23 (s, 18H), 0.86 (t, J = 7.0 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3): δ 147.0, 138.3, 104.6, 48.7,
31.9, 30.5, 29.6, 29.5, 29.5, 29.3, 29.2, 26.7, 22.6, 14.1, 13.4, 11.0.
HRMS (ESI) m/z: [M + H]+ calcd for C17H33N2, 265.2639; found,
265.2636. IR (ATR, diamond, cm−1): 2928, 2854, 1670, 1611, 1553,
1466, 1378, 1310, 1023,774.
1-(3,3-Dimethylbutan-2-yl)-3,5-dimethyl-1H-pyrazole (1a). 3,3-
Dimethylbutan-2-amine a (134 μL, 1.00 mmol), 2,4-pentanedione 1
(114 μL, 1.10 mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg,
1.50 mmol), and DMF (5.0 mL) were used. The reaction was run at
85 °C (reaction block) for 1.5 h. Workup A and chromatography
(basic alumina grade I, pentane−Et2O 0−60%) were applied to obtain
80 mg (0.44 mmol, 44%) of 1a as a colorless volatile liquid. For a
large-scale experiment, dimethylbutan-2-amine a (410 μL, 3.00
mmol), 2,4-pentanedione 1 (342 μL, 3.30 mmol), O-(4-
nitrobenzoyl)hydroxylamine (820 mg, 4.50 mmol), and DMF (20
1-Cyclohexyl-3,5-dimethyl-1H-pyrazole (1f).34 Cyclohexanamine
f (115 μL 1.00 mmol), 2,4-pentanedione 1 (114 μL 1.10 mmol), O-
(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and DMF (5.0
mL) were used. The reaction was run at 85 °C (reaction block) for
1.5 h. Workup A and flash chromatography (silica gel, hexane−THF
0−100%) were applied to obtain 63 mg (0.35 mmol, 35%) of 1f as a
1
yellowish oil. H NMR (500 MHz, CDCl3): δ 5.74 (s, 1H), 3.92−
3.88 (m, 2H), 2.19 (s, 6H), 1.78−1.70 (m, 2H), 1.23 (s, 18H), 0.86
(t, J = 7.0 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 147.0,
138.3, 104.6, 48.7, 31.9, 30.5, 29.6, 29.5, 29.5, 29.3, 29.2, 26.7, 22.6,
14.1, 13.4, 11.0.
1
mL) were used to obtain 243 mg (1.35 mmol, 45%) of 1a. H NMR
(500 MHz, CDCl3): δ 5.72 (s, 1H), 3.85 (q, J = 6.9 Hz, 1H), 2.22 (s,
3H), 2.21 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H), 0.93 (s, 9H). 13C{1H}
NMR (126 MHz, CDCl3): δ 146.5, 138.9, 104.0, 61.0, 36.4, 27.2,
15.9, 13.9, 12.0. IR (ATR, diamond, cm−1): 2955, 2870, 1553, 1456,
1419, 1373, 1365, 1255, 1075, 974, 773. HRMS (ESI) m/z: [M + H]+
calcd for C11H21N2, 181.1700; found, 181.1706.
6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-methylheptan-2-ol (1g). 6-
Amino-2-methylheptan-2-ol g (741 mg, 5.00 mmol), 2,4-pentane-
dione 1 (568 μL, 5.48 mmol), O-(4-nitrobenzoyl)hydroxylamine
(1.37 mg, 7.52 mmol), and DMF (50 mL) were used. The reaction
was run at 80 °C (reaction block) for 2 h. Workup A and
chromatography (basic alumina grade I, hexane−THF 0−80%) were
applied to obtain 383 mg (1.71 mmol, 34%) of 1g as a yellowish oil.
1H NMR (500 MHz, CDCl3): δ 5.71 (s, 1H), 4.15−4.03 (m, 1H),
2.20 (s, 3H), 2.19 (s, 3H), 2.05−1.93 (m, 1H), 1.74−1.63 (m, 1H),
1.51 (s, 1H), 1.40 (m, 2H overlap with d, J = 6.7 Hz, 3H), 1.31−1.24
(m, 1H), 1.19−1.14 (m, 1H), 1.13 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3): δ 147.2, 138.2, 104.5, 70.9, 53.7, 43.4, 37.1, 29.4, 29.3,
21.3, 21.3, 13.8, 11.2. IR (ATR, diamond, cm−1): 3392 (OH), 2969,
2932, 2868, 1552, 1454, 1423, 1375, 1158, 773. HRMS (ESI) m/z:
[M + H]+ calcd for C13H25N2O, 225.1962; found, 225.1959.
1-Adamantan-1-yl-3,5-dimethyl-1H-pyrazole (1h).15 1-Adaman-
tylamine h (151,25 mg, 1.00 mmol), 2,4-pentanedione 1 (114 μL 1.10
mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and
DMF (5.0 mL) were used. The reaction was run at 85 °C (reaction
block) for 1.5 h. Workup A and chromatography (silica gel, hexane−
EA 30%) were applied to obtain 97 mg (0.42 mmol, 42%) of 1h as a
3,5-Dimethyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole (1b).
Compound 1b was synthesized according to the general procedure
using 2,4,4-trimethylpentan-2-amine b (161 μL, 1.00 mmol), 2,4-
pentanedione 1 (114 μL 1.10 mmol), O-(4-nitrobenzoyl)-
hydroxylamine (273 mg, 1.50 mmol), and DMF (5.0 mL). The
reaction was run at 85 °C (reaction block) for 1.5 h. Workup A and
chromatography (silica gel, hexane−EA 0−30%) were applied to
1
obtain 79 mg (0.38 mmol, 38%) of 1b as a yellowish oil. H NMR
(500 MHz, CDCl3): δ 5.70 (s, 1H), 2.32 (s, 3H), 2.12 (s, 3H), 1.76
(s, 2H), 1.62 (s, 6H), 0.71 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3): δ 144.6, 138.7, 108.1, 62.5, 53.3, 31.5, 31.0, 30.7, 15.0, 13.5.
HRMS (ESI) m/z: [M + Na]+ calcd for C13H24N2Na, 231.1832;
found, 231.1851. IR (ATR, diamond, cm−1): 2949, 1550, 1447, 1417,
1357, 1234, 1094, 1024, 776, 603.
3-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1H-indole (1c). Trypt-
amine c (160 mg, 1.00 mmol), 2,4-pentanedione 1 (114 μL, 1.10
mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and
DMF (5.0 mL) were used. The reaction was run at 85 °C (reaction
block) for 1.5 h. Workup A and chromatography (basic alumina grade
I, hexane−THF 5−100%) were applied to obtain 72 mg (0.30 mmol,
30%) of 1c as a yellowish solid. 1H NMR (500 MHz, CDCl3): δ 8.34
(s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23−7.16
(m, 1H), 7.15−7.08 (m, 1H), 6.84 (d, J = 2.3 Hz, 1H), 5.74 (s, 1H),
4.23 (t, J = 7.4 Hz, 2H), 3.25 (t, J = 7.4 Hz, 2H), 2.28 (s, 3H), 1.95 (s,
1
yellowish oil. H NMR (500 MHz, CDCl3): δ 5.78 (s, 1H), 2.43 (s,
3H), 2.27 (d, J = 3.1 Hz, 6H), 2.20 (s, 6H), 1.74 (s, 6H). 13C{1H}
NMR (126 MHz, CDCl3): δ 145.3, 138.6, 108.0, 60.4, 42.3, 36.3,
30.0, 15.1, 13.6.
3,5-Dimethyl-1-(1-phenylethyl)-1H-pyrazole (1i).15 1-Phenyle-
than-1-amine i (127 μL, 1.00 mmol), 2,4-pentanedione 1 (114 μL
1.10 mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol),
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and DMF (5.0 mL) were used. The reaction was run at 80 °C
(reaction block) for 1.5 h. Workup A and chromatography (silicagel
hexane−EA 30%) were applied to obtain 76 mg (0.38 mmol, 38%) of
mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and
DMF (5.0 mL) were used. The reaction was run at 85 °C (reaction
block) for 1.5 h. Workup A and chromatography (silica gel, hexane−
EA 0−30%) were applied to obtain 155 mg (0.70 mmol, 70%) of 1o
as a red oil. 1H NMR (500 MHz, CDCl3): δ 7.90 (d, J = 8.7 Hz, 1H),
7.88−7.82 (m, 3H), 7.59 (dd, J = 8.7, 2.1 Hz, 1H), 7.54−7.43 (m,
2H), 6.02 (s, 1H), 2.35 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3): δ 148.5, 133.1, 132.7, 129.5, 128.2, 127.9, 127.1,
126.9, 123.6, 123.1, 107.5, 12.9, 12.4. HRMS (ESI) m/z: [M + Na]+
calcd for C15H14N2Na 245.1050; found, 245.1045. IR (ATR,
diamond, cm−1): 3053, 2920, 2852, 1633, 1508, 1379, 1266, 857,
815, 783, 472.
1
1i as a yellowish oil. H NMR (500 MHz, CDCl3): δ 7.28−7.12 (m,
1H), 7.05−7.00 (m, 1H), 5.76 (s, 1H), 5.27 (q, J = 7.1 Hz, 1H), 2.21
(s, 1H), 2.02 (s, 1H), 1.84 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3): δ 146.9, 143.0, 138.9, 128.5, 127.1, 125.9, 105.5, 57.3,
21.7, 13.7, 11.1.
Ethyl 2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-phenylpropanoate (1j).
Ethyl phenylalaninate35 j (193 mg, 1.00 mmol), 2,4-pentanedione 1
(114 μL, 1.10 mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg,
1.50 mmol), and DMF (5.0 mL) were used. The reaction was run at
85 °C (reaction block) for 1.5 h. Workup B and chromatography
(neutral alumina grade I, hexane−THF 0−40%) were applied to
obtain 73 mg (0.27 mmol, 27%) of 1j as a colorless oil. 1H NMR (500
MHz, CDCl3): δ 7.22−7.15 (m, 3H), 7.01−6.96 (m, 2H), 5.69 (s,
1H), 4.76 (dd, J = 9.8, 5.2 Hz, 1H), 4.20 (qd, J = 7.1, 2.2 Hz, 2H),
3.58−3.47 (m, 2H), 2.25 (s, 3H), 1.83 (s, 3H), 1.21 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (75 MHz, CDCl3): δ 169.4, 148.4, 140.3, 137.6,
129.2, 128.5, 126.8, 105.1, 62.0, 61.8, 37.4, 14.2, 13.9, 10.7. IR (ATR,
diamond, cm−1): 2980, 2925, 1745 (CO), 1557, 1455, 1262, 1210,
1173, 1028, 752, 701. HRMS (ESI) m/z: [M + H]+ calcd for
C16H21N2O2, 273.1598; found, 273.1597.
1-(5-Bromo-2-methylphenyl)-3,5-dimethyl-1H-pyrazole (1p). 5-
Bromo-2-methylaniline p (191 mg, 1.00 mmol), 2,4-pentanedione 1
(114 μL, 1.10 mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg,
1.50 mmol), and DMF (5.0 mL) were used. The reaction was run at
80 °C (reaction block) for 16 h. Workup A and chromatography
(basic alumina grade I, hexane−THF 0−30%) were applied to obtain
1
149 mg (0.56 mmol, 56%) of 1p as a yellowish oil. H NMR (500
MHz, CDCl3): δ 7.45 (dd, J = 8.2, 2.1 Hz, 1H), 7.39 (d, J = 2.1 Hz,
1H), 7.17 (d, J = 8.2 Hz, 1H), 5.96 (s, 1H), 2.27 (s, 3H), 2.06 (s,
3H), 2.01 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 149.2,
140.4, 140.0, 135.6, 132.2, 132.1, 131.1, 119.2, 105.5, 17.0, 13.7, 11.4.
IR (ATR, diamond, cm−1): 2954, 2924, 2857, 1594, 1556, 1496,
1424, 1360, 1036, 823, 782. HRMS (ESI) m/z: [M + H]+ calcd for
C12H14N2Br, 265.0335; found, 265.0335.
1-(Bicyclo[2.2.1]heptan-2-yl)-3,5-dimethyl-1H-pyrazole (1k).
Bicyclo[2.2.1]heptan-2-amine k (60 μL, 0.50 mmol), pentane-2,4-
dione 1 (56 μL 0.55 mmol), O-(4-nitrobenzoyl)hydroxylamine (136
mg, 0.75 mmol), and DMF (2.5 mL) were used. The reaction was run
at 85 °C for 1.5 h. Workup A and chromatography (silica gel,
hexane−THF 0−30%) were applied to obtain 33 mg (0.18 mmol,
35%) of 1k as a yellowish oil. 1H NMR (500 MHz, CDCl3): δ 5.79 (s,
1H), 3.97−3.96 (m, 1H), 2.42 (s, 1H), 2.37−2.29 (m, 1H), 2.23 (s,
1H), 2.21 (s, 1H), 2.08−2.02 (m, 1H), 1.73−1.70 (m, 1H), 1.63−
1.50 (m, 1H), 1.25−1.11 (m, 2H). 13C{1H} NMR (126 MHz,
CDCl3): δ 146.2, 138.4, 105.2, 60.6, 43.5, 37.7, 36.0, 35.8, 28.8, 27.7,
13.9, 11.5. IR (ATR, diamond, cm−1): 2951, 2923, 1553, 1452, 1378,
1290, 1258, 1023, 802, 773. HRMS (ESI) m/z: [M + H]+ calcd for
C12H19N2, 191.1543; found, 191.1549.
3,4,5-Ttrimethyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole
(2b). 2,4,4-Trimethylpentan-2-amine b (161 μL, 1.00 mmol), 3-
methylpentane-2,4-dione 2 (128 μL 1.10 mmol), O-(4-nitrobenzoyl)-
hydroxylamine (273 mg, 1.50 mmol), and DMF (5 mL) were used.
The reaction was run at 85 °C (reaction block) for 1.5 h. Workup A
and chromatography (silica gel, hexane−EA 0−30%) were applied to
1
obtain 95 mg (0.43 mmol, 43%) of 2b as a yellowish oil. H NMR
(500 MHz, CDCl3): δ 2.30 (s, 1H), 2.21−2.08 (m, 1H), 1.86 (s, 1H),
1.82 (s, 1H), 1.68 (s, 2H), 0.77 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 143.3, 135.2, 113.1, 62.3, 53.2, 31.5, 30.7, 29.5, 13.1, 11.8,
8.0. IR (ATR, diamond, cm−1): 2954, 2252, 2669, 1669, 1568, 1540,
1415, 1050, 905, 729 HRMS (ESI) m/z: [M + Na]+ calcd for
C14H26N2Na, 245.1989; found, 245.1987.
3,5-Dimethyl-1-phenyl-1H-pyrazole (1l).18 Aniline l (94 μL, 1.0
mmol), 2,4-pentanedione 1 (114 μL 1.10 mmol), O-(4-nitrobenzoyl)-
hydroxylamine (273 mg, 1.50 mmol), and DMF (5.0 mL) were used.
The reaction was run at 85 °C (reaction block) for 1.5 h. Workup A
and chromatography (silica gel, hexane−EA 30%) were applied to
3,5-Diethyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole (3b).
2,4,4-Trimethylpentan-2-amine b (161 μL, 1.00 mmol), heptane-
3,5-dione 3 (150 μL 1.1 mmol), O-(4-nitrobenzoyl)hydroxylamine
(273 mg, 1.50 mmol), and DMF (5 mL) were used. The reaction was
run at 85 °C (reaction block) for 1.5 h. Workup A and
chromatography (silica gel, hexane−EA 0−30%) were applied to
1
obtain 68 mg (0.47 mmol, 47%) of 1l as a yellowish oil. H NMR
(500 MHz, CDCl3): δ 7.34 (d, J = 4.4 Hz, 4H), 7.24 (dq, J = 8.7, 4.4
Hz, 1H), 5.91 (s, 1H), 2.22 (d, J = 10.9 Hz, 6H). 13C{1H} NMR (126
MHz, CDCl3): δ 148.9, 139.9, 139.3, 128.9, 127.2, 124.7, 106.9, 13.5,
12.3.
1
obtain 88 mg (0.37 mmol, 37%) of 3b as a yellowish oil. H NMR
(500 MHz, CDCl3): δ 5.87 (s, 1H), 2.77 (q, J = 7.4 Hz, 2H), 2.56 (q,
J = 7.6 Hz, 2H), 1.80 (s, 2H), 1.68 (s, 7H), 1.26 (t, J = 7.4 Hz, 3H),
1.18 (t, J = 7.6 Hz, 3H), 0.73 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3): δ 150.8, 145.5, 103.6, 62.6, 53.5, 31.6, 31.3, 30.7, 21.9, 21.6,
14.4, 13.6. HRMS (ESI) m/z: [M + H]+ calcd for C15H29N2
237.2326; found, 237.2323. IR (ATR, diamond, cm−1): 3001, 2929,
1545, 1465, 1365, 1253 1227, 1089, 956, 773.
1-(4-Methoxyphenyl)-3,5-dimethyl-1H-pyrazole (1m).18 4-Me-
thoxyaniline m (123 mg, 1.00 mmol), 2,4-pentanedione 1 (114 μL
1.10 mmol), O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol),
and DMF (5.0 mL) were used. The reaction was run at 85 °C
(reaction block) for 1.5 h. Workup A and chromatography (silica gel,
hexane−EA 30%) were applied to obtain 112 mg (0.55 mmol, 55%)
of 1m as a brown oil. 1H NMR (500 MHz, CDCl3): δ 7.33−7.27 (m,
2H), 6.96−6.90 (m, 2H), 5.94 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3): δ 158.7, 148.5, 139.4, 133.1,
126.4, 114.1, 106.2, 55.5, 13.5, 12.1.
4-Ethyl-3,5-dimethyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole
(4b). 2,4,4-Trimethylpentan-2-amine b (67 mg, 0.50 mmol), 3-
ethylpentane-2,4-dione 4 (336 μL, 2.50 mmol), O-(4-nitrobenzoyl)-
hydroxylamine (136 mg, 0.75 mmol), and DMF (2.5 mL) were used.
The reaction was run at 85 °C (reaction block) for 1.5 h. Workup A
and chromatography (basic alumina grade I, hexane-(DCM-MeOH
10%) 0−20%) were applied to obtain 28 mg (0.118 mmol, 26%) of
1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazole (1n).36 4-Fluoroa-
niline n (95 μL, 1.0 mmol), 2,4-pentanedione 1 (114 μL 1.10 mmol),
O-(4-nitrobenzoyl)hydroxylamine (273 mg, 1.50 mmol), and DMF
(5.0 mL) were used. The reaction was run at 85 °C (reaction block)
for 1.5 h. Workup A and chromatography (silica gel, hexane−EA
30%) were applied to obtain 115 mg (0.60 mmol, 60%) of 1n as a
1
4b as a colorless oil. H NMR (500 MHz, CDCl3): δ 2.33−2.28 (m,
5H), 2.16 (s, 3H), 1.82 (s, 2H), 1.69 (s, 6H), 1.00 (t, J = 7.6 Hz, 3H),
0.75 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ 142.9, 135.1,
120.4, 62.4, 53.4, 31.7, 31.2, 30.9, 17.0, 15.6, 13.0, 12.0. IR (ATR,
diamond, cm−1): 2956, 2925, 2855, 1463, 1366, 1355, 1272, 1256,
1235. HRMS (ESI) m/z: [M + H]+ calcd for C15H29N2, 237.2326;
found, 237.2326.
1
yellowish oil. H NMR (500 MHz, CDCl3): δ 7.39−7.33 (m, 2H),
7.15−7.06 (m, 2H), 5.96 (s, 1H), 2.25 (d, J = 10.3 Hz, 6H). 13C{1H}
NMR (126 MHz, CDCl3): δ 161.6 (d, J = 247.0 Hz), 149.1, 139.5,
136.1 (d, J = 3.0 Hz), 126.6 (d, J = 8.6 Hz), 115.9 (d, J = 22.8 Hz),
106.9, 13.5, 12.2.
3-Methyl-5-phenyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole
(5b). 2,4,4-Trimethylpentan-2-amine b (26 mg, 0.20 mmol), 1-
phenylbutane-1,3-dione 5 (162 mg, 1.0 mmol), O-(4-nitrobenzoyl)-
3,5-Dimethyl-1-(naphthalen-2-yl)-1H-pyrazole (1o). Naphthalen-
2-amine o (143 mg, 1.00 mmol), 2,4-pentanedione 1 (114 μL 1.10
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hydroxylamine (55 mg, 0.30 mmol), and DMF (1 mL) were used.
The reaction was run at 85 °C (reaction block) for 1.5 h. Workup A
and chromatography (silica gel, hexane−EA 0−30%) were applied to
REFERENCES
■
(1) Mykhailiuk, P. K. Fluorinated Pyrazoles: From Synthesis to
Applications. Chem. Rev. 2021, 121 (3), 1670−1715.
(2) Neto, J. S. S.; Zeni, G. Alkynes and Nitrogen Compounds:
Useful Substrates for the Synthesis of Pyrazoles. Chem. - Eur. J. 2020,
26 (37), 8175−8189.
1
obtain 25 mg (0.092 mmol, 46%) of 5b as a white solid. H NMR
(500 MHz, CDCl3): δ 7.67−7.26 (m, 5H), 5.88 (s, 1H), 2.26 (s, 3H),
1.78 (s, 2H), 1.46 (s, 6H), 0.79 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3): δ 144.6, 143.3, 135.0, 130.5, 128.1, 127.6, 109.3, 64.1, 54.8,
31.8, 31.5, 30.7, 13.5, 13.5. IR (ATR, diamond, cm−1): 2955, 1545,
1498, 1442, 1395, 1365, 1253, 1196, 793, 704. HRMS (ESI) m/z: [M
+ Na]+ calcd for C18H26N2Na, 293.1989; found, 293.1989.
5-Isobutyl-3-methyl-1-(2,4,4-trimethylpentan-2-yl)-1H-pyrazole
(6b). 2,4,4-Trimethylpentan-2-amine b (161 μL, 1.00 mmol), 6-
methylheptane-2,4-dione 6 (173 μL, 1.10 mmol), O-(4-nitrobenzoyl)-
hydroxylamine (273 mg, 1.50 mmol), and DMF (5.0 mL) were used.
The reaction was run at 85 °C (reaction block) for 2 h. Workup A
and chromatography (basic alumina grade I, hexane−THF 0−20%)
were applied to obtain 97 mg (0.37 mmol, 37%) of 6b as a yellowish
oil. 1H NMR (500 MHz, CDCl3): δ 5.84 (s, 1H), 2.61 (d, J = 7.1 Hz,
2H), 2.20 (s, 3H), 2.03−1.94 (m, 1H), 1.83 (s, 2H), 1.69 (s, 6H),
1.01 (d, J = 6.6 Hz, 6H), 0.77 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3): δ 144.6, 143.3, 106.6, 62.8, 53.8, 37.9, 31.7, 31.5, 30.9, 28.5,
23.1, 13.8. IR (ATR, diamond, cm−1): 2954, 2870, 1546, 1468, 1425,
1387, 1363, 1241, 1021, 777, 600. HRMS (ESI) m/z: [M + H]+ calcd
for C16H31N2, 251.2482; found, 251.2481.
(3) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A.
From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of
Pyrazoles. Chem. Rev. 2011, 111 (11), 6984−7034.
(4) Fustero, S.; Simón-Fuentes, A.; Sanz-Cervera, J. F. Recent
Advances in the Synthesis of Pyrazoles. A Review. Org. Prep. Proced.
Int. 2009, 41 (4), 253−290.
(5) Dadiboyena, S.; Nefzi, A. Synthesis of Functionalized
Tetrasubstituted Pyrazolyl Heterocycles − A Review. Eur. J. Med.
Chem. 2011, 46 (11), 5258−5275.
(6) Bennani, F. E.; Doudach, L.; Cherrah, Y.; Ramli, Y.; Karrouchi,
K.; Ansar, M.; Faouzi, M. E. A. Overview of Recent Developments of
Pyrazole Derivatives as an Anticancer Agent in Different Cell Line.
Bioorg. Chem. 2020, 97, 103470.
(7) Kucu̧ kguzel, Ş. G.; Şenkardes,̧ S. Recent Advances in Bioactive
̈ ̈ ̈
Pyrazoles. Eur. J. Med. Chem. 2015, 97, 786−815.
(8) Ma, Y.; Yang, L.; Liu, X.; Yang, J.; Sun, X. Development of
Celecoxib-Derived Antifungals for Crop Protection. Bioorg. Chem.
2020, 97, 103670.
(9) Lamberth, C. Pyrazole Chemistry in Crop Protection. Hetero-
cycles 2007, 71 (7), 1467−1502.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00606.
■
sı
̆
̆
(10) Pettinari, C.; Tabacaru, A.; Galli, S. Coordination Polymers and
Metal−Organic Frameworks Based on Poly(Pyrazole)-Containing
Ligands. Coord. Chem. Rev. 2016, 307, 1−31.
1
Copies of H and 13C spectra of products, X-ray data,
(11) Halcrow, M. A. Pyrazoles and PyrazolidesFlexible Synthons
in Self-Assembly. Dalton Trans. 2009, No. 12, 2059−2073.
(12) Zhang, C.; Chen, S.; Ye, C.-X.; Harms, K.; Zhang, L.; Houk, K.
N.; Meggers, E. Asymmetric Photocatalysis by Intramolecular
Hydrogen-Atom Transfer in Photoexcited Catalyst−Substrate Com-
plex. Angew. Chem., Int. Ed. 2019, 58 (41), 14462−14466.
(13) Lutter, F. H.; Grokenberger, L.; Perego, L. A.; Broggini, D.;
Lemaire, S.; Wagschal, S.; Knochel, P. Regioselective Functionaliza-
tion of Aryl Azoles as Powerful Tool for the Synthesis of
Pharmaceutically Relevant Targets. Nat. Commun. 2020, 11 (1), 4443.
(14) Onodera, S.; Ishikawa, S.; Kochi, T.; Kakiuchi, F. Direct
Alkenylation of Allylbenzenes via Chelation-Assisted C−C Bond
Cleavage. J. Am. Chem. Soc. 2018, 140 (31), 9788−9792.
(15) Gulia, N.; Daugulis, O. Palladium-Catalyzed Pyrazole-Directed
sp3 C−H Bond Arylation for the Synthesis of β-Phenethylamines.
Angew. Chem., Int. Ed. 2017, 56 (13), 3630−3634.
additional experiments details, and full optimization
table (PDF)
Accession Codes
CCDC 2019272 (1n), and 2019718 (4b) contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
Nurbey Gulia − Faculty of Chemistry, University of Wrocław,
50-383 Wrocław, Poland; orcid.org/0000-0001-6518-
1197; Email: nurbey.gulia@chem.uni.wroc.pl
■
(16) Moselage, M.; Li, J.; Kramm, F.; Ackermann, L. Ruthenium-
(II)-Catalyzed C−C Arylations and Alkylations: Decarbamoylative
C−C Functionalizations. Angew. Chem., Int. Ed. 2017, 56 (19), 5341−
5344.
(17) Boerth, J. A.; Hummel, J. R.; Ellman, J. A. Highly
Stereoselective Cobalt(III)-Catalyzed Three-Component C−H
Bond Addition Cascade. Angew. Chem., Int. Ed. 2016, 55 (41),
12650−12654.
(18) Kwak, S. H.; Gulia, N.; Daugulis, O. Synthesis of Unsym-
metrical 2,6-Diarylanilines by Palladium-Catalyzed C−H Bond
Functionalization Methodology. J. Org. Chem. 2018, 83 (10),
5844−5850.
(19) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Consecutive
Condensation, C−N and N−N Bond Formations: A Copper-
Catalyzed One-Pot Three-Component Synthesis of 2H-Indazole.
Org. Lett. 2011, 13 (13), 3542−3545.
(20) Genung, N. E.; Wei, L.; Aspnes, G. E. Regioselective Synthesis
of 2H-Indazoles Using a Mild, One-Pot Condensation−Cadogan
Reductive Cyclization. Org. Lett. 2014, 16 (11), 3114−3117.
(21) Zhu, J. S.; Li, C. J.; Tsui, K. Y.; Kraemer, N.; Son, J.-H.;
Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J. Accessing Multiple
Classes of 2H-Indazoles: Mechanistic Implications for the Cadogan
and Davis−Beirut Reactions. J. Am. Chem. Soc. 2019, 141 (15),
6247−6253.
Authors
Marcin Małecki − Faculty of Chemistry, University of
Wrocław, 50-383 Wrocław, Poland; orcid.org/0000-
0002-1406-1897
Sławomir Szafert − Faculty of Chemistry, University of
Wrocław, 50-383 Wrocław, Poland; orcid.org/0000-
0002-0570-8847
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00606
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the National Science
Centre Poland (NCN 2017/26/D/ST5/00112 and NCN
2018/31/M/ST5/00450) for financial support of this research.
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(22) Niesobski, P.; Klukas, F.; Berens, H.; Makhloufi, G.; Janiak, C.;
̈
Muller, T. J. J. De Novo Ring-Forming Consecutive Four-Component
Syntheses of 4-Pyrazolyl-1,2,3-triazoles from (Triisopropylsilyl)-
butadiyne as a C4 Building Block. J. Org. Chem. 2018, 83 (8),
4851−4858.
(23) Zhu, C.; Zeng, H.; Liu, C.; Cai, Y.; Fang, X.; Jiang, H.
Regioselective Synthesis of 3-Trifluoromethylpyrazole by Coupling of
Aldehydes, Sulfonyl Hydrazides, and 2-Bromo-3,3,3-trifluoropropene.
Org. Lett. 2020, 22 (3), 809−813.
(24) Wang, H.; Ning, Y.; Sun, Y.; Sivaguru, P.; Bi, X. Cycloaddition
of Trifluoroacetaldehyde N-Triftosylhydrazone (TFHZ-Tfs) with
Alkynes for Synthesizing 3-Trifluoromethylpyrazoles. Org. Lett.
2020, 22 (5), 2012−2016.
(25) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D.
Oxaziridine-Mediated Amination of Primary Amines: Scope and
Application to a One-Pot Pyrazole Synthesis. Org. Lett. 2005, 7 (4),
713−716.
(26) Wang, S.; Li, Y.; Bi, X.; Liu, Q. Synthesis of 1,3,4-Trisubstituted
Pyrazoles from α-(1,3-Dithian-2-yl) Enamine Ketones via [4 + 1]
Cyclization. Synlett 2015, 26 (13), 1895−1899.
(27) Ragnarsson, U. Synthetic Methodology for Alkyl Substituted
Hydrazines. Chem. Soc. Rev. 2001, 30 (4), 205−213.
(28) Gever, G.; Hayes, K. Alkylhydrazines. J. Org. Chem. 1949, 14
(5), 813−818.
(29) Audrieth, L. F.; Diamond, L. H. Preparation of N-Substituted
Hydrazines by Modification of the Raschig Synthesis. J. Am. Chem.
Soc. 1954, 76 (19), 4869−4871.
(30) Nigst, T. A.; Antipova, A.; Mayr, H. Nucleophilic Reactivities of
Hydrazines and Amines: The Futile Search for the α-Effect in
Hydrazine Reactivities. J. Org. Chem. 2012, 77 (18), 8142−8155.
(31) Polat, D. E.; Brzezinski, D. D.; Beauchemin, A. M. Formation of
Complex Hydrazine Derivatives via Aza-Lossen Rearrangement. Org.
Lett. 2019, 21 (12), 4849−4852.
(32) Sarnowski, M. P.; Kang, C. W.; Elbatrawi, Y. M.; Wojtas, L.;
Del Valle, J. R. Peptide N-Amination Supports β-Sheet Conforma-
tions. Angew. Chem., Int. Ed. 2017, 56 (8), 2083−2086.
(33) Parlanti, L.; Discordia, R. P.; Hynes, J.; Miller, M. M.; O'Grady,
H. R.; Shi, Z. Amination of Heterocyclic Compounds with O-
Benzoylhydroxylamine Derivatives. Org. Lett. 2007, 9 (19), 3821−
3824.
(34) Klein, J. F.; Pommelet, J. C.; Chuche, J.; Elguero, J.; Goya, P.;
Martinez, A. SO2 Extrusion in 1,2,6-Thiadiazine 1,1-Dioxides: A
Novel Synthesis of Pyrazoles. Can. J. Chem. 1993, 71 (3), 410−412.
(35) Lin, H.; Wang, C.; Bannister, T. D.; Kamenecka, T. M. Site-
Selective γ-C(sp3)−H and γ-C(sp2)−H Arylation of Free Amino
Esters Promoted by a Catalytic Transient Directing Group. Chem. -
Eur. J. 2018, 24 (38), 9535−9541.
(36) Yang, C.-H.; Li, S.-W.; Chi, Y.; Cheng, Y.-M.; Yeh, Y.-S.; Chou,
P.-T.; Lee, G.-H.; Wang, C.-H.; Shu, C.-F. Heteroleptic Cyclo-
metalated Iridium(III) Complexes Displaying Blue Phosphorescence
in Solution and Solid State at Room Temperature. Inorg. Chem. 2005,
44 (22), 7770−7780.
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J. Org. Chem. 2021, 86, 9353−9359