[3+2]-cycloaddition of in situ generated nitrile imines and acetylene for assembling of 1,3-disubstituted pyrazoles with quantitative deuterium labeling

Article abstract of DOI:10.1021/acs.joc.8b00155

A novel synthetic methodology for the preparation of 1,3-disubstituted pyrazoles from in situ generated nitrile imines and acetylene is reported. The reactions are performed in a simple two-chamber reactor. One part of the reactor is loaded with hydrazonoyl chloride precursors of active nitrile imine species and a base. The other part is used to generate acetylene from CaC₂ and water. Partitioning of the reactants improves the yields of desired pyrazoles up to 99% and simplifies their isolation to a simple procedure of solvent evaporation. The approach requires no complex equipment and utilizes inexpensive, safe, and easy to handle calcium carbide as a starting material. A model deuterium incorporation is carried out according to the developed methodology, producing a series of novel 4,5-dideuteropyrazoles with excellent deuterium enrichment. Theoretical calculations on reaction mechanism and characterization of possible intermediate structures were performed.

Full text of DOI:10.1021/acs.joc.8b00155

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
[3 + 2]-Cycloaddition of in Situ Generated Nitrile Imines and
Acetylene for Assembling of 1,3-Disubstituted Pyrazoles with
Quantitative Deuterium Labeling
Vladimir V. Voronin,† Maria S. Ledovskaya,† Evgeniy G. Gordeev,‡ Konstantin S. Rodygin,†
and Valentine P. Ananikov*,†,‡
†Saint Petersburg State University, Universitetsky prospect 26, Peterhof 198504, Russia
‡N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect 47, Moscow,119991, Russia
S
* Supporting Information
ABSTRACT: A novel synthetic methodology for the preparation of
1,3-disubstituted pyrazoles from in situ generated nitrile imines and
acetylene is reported. The reactions are performed in a simple two-
chamber reactor. One part of the reactor is loaded with hydrazonoyl
chloride precursors of active nitrile imine species and a base. The
other part is used to generate acetylene from CaC2 and water.
Partitioning of the reactants improves the yields of desired pyrazoles
up to 99% and simplifies their isolation to a simple procedure of
solvent evaporation. The approach requires no complex equipment
and utilizes inexpensive, safe, and easy to handle calcium carbide as a
starting material. A model deuterium incorporation is carried out
according to the developed methodology, producing a series of novel
4,5-dideuteropyrazoles with excellent deuterium enrichment. Theoretical calculations on reaction mechanism and character-
ization of possible intermediate structures were performed.
of acetylene (Scheme 1A). Recently, a methodology based on
calcium carbide as an acetylene source was proposed for
synthetic applications.13 Generated in situ from CaC2 and
water, acetylene can be successfully utilized as a starting
material in various nucleophilic addition and cross-coupling
reactions giving rise to vinyl ethers,14 vinyl sulfides,15 vinyl
indoles,16 enaminones,17 acetylenic alcohols,18 and aryl- and
diarylacetylenes.19 Besides, 1,3-dipolar cycloaddition of the
calcium carbide-derived acetylene to azides,20 diazo com-
pounds,21 and nitrile oxides22 is possible. Calcium carbide has a
number of advantages over the gaseous acetylene, and it is
more safe and convenient to handle. However, introducing
calcium carbide and water straight into the reaction mixture is
incompatible with functioning of base- or water-sensitive
systems (Scheme 1A).
This study reports 1,3-dipolar cycloaddition of nitrile imines
to the unsubstituted acetylene, where both components of the
studied [3 + 2]-cycloaddition reaction (nitrile imines and
acetylene) are generated in situ. A two-chamber reactor is
employed in order to separate the water-sensitive nitrile imines
from the acetylene-generating mixture (Scheme 1B). Using the
developed approach, 1,3-disubstituted pyrazoles are obtained,
and 4,5-dideuteropyrazoles are synthesized for the first time.
Overall, cycloaddition of nitrile imines to the unsubstituted
INTRODUCTION
■
Pyrazoles are important N-heterocyclic compounds that find
extensive use in the pharmaceutical industry.1 Several pyrazole
derivatives have been found to possess analgesic,2 antimicro-
bial,3 anti-inflammatory,4 antidiabetic,5 antidepressant, anti-
convulsant,6 anticancer, and antituberculosis activity.7 Celecox-
ib, sulfaphenazole, lonazolac, mepiprazole, and rimonabant are
pyrazole-based commercially available drugs. Substituted
pyrazole derivatives have also been employed as ligands for
the transition-metal-catalyzed cross-coupling reactions.8 Due to
the multiple important applications of pyrazoles, advanced
methodologies for their synthesis are currently in demand.
The 1,3-dipolar cycloaddition is a conventional synthetic
route to five-membered heterocycles, widely used because of its
high efficiency and versatility.9 In particular, 1,3-dipolar
cycloaddition reaction between the triple carbon−carbon
bond and nitrile imines, generated in situ from hydrazonoyl
halides and a base, leads to pyrazole products.10 Various
acetylene derivatives are commonly applied to set up these
reactions, but these do not include the acetylene itself. To put it
more generally, synthetic applications of the simplest alkyne,
acetylene, are poorly developed as compared with the chemistry
of substituted alkynes. High risks of explosion, handling
difficulties, flammability, and specific high-pressure equipment
requirements11 complicate experiments that involve acetylene
gas supplied in high-pressure cylinders.12,13 These obstacles
may introduce several difficulties in the laboratory applications
Received: January 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00155
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The Journal of Organic Chemistry
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Scheme 1. Comparison of Different Acetylene Sources and
Protocols (A) and the Developed Synthetic Procedure (B)
Table 1. Optimization of Reaction Conditions for Pyrazole
Synthesis
a
b
amount of 3a,
CaC2, H2O,
mmol mmol
mg/mL of
solvent
yield
(conversion), %
c
entry
solvent
1
MeOH
DMF
0.875
0.875
0.875
0.875
0.875
0.875
0.875
0.875
0.525
0.7
1.75
1.75
1.75
1.75
1.75
1.75
1.75
1.75
1.05
1.4
100
100
100
100
100
100
100
100
100
100
100
35
14 (100)
25 (100)
56 (100)
74 (100)
69 (100)
76 (100)
79 (100)
79 (100)
56 (68)
2
3
4
5
6
7
8
9
Et2O
toluene
CH2Cl2
CCl4
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
d
10
11
12
13
14
15
16
17
18
74 (88)
1.05
2.1
70 (100)
62 (100)
74 (100)
78 (100)
71 (100)
99 (100)
93 (100)
70 (100)
0.875
0.875
0.875
0.875
1.5
1.75
1.75
1.75
1.75
5.5
70
150
200
50
ef
,
acetylene, especially allowing quantitative deuteration of the
products, is a novel point of this study. Certain problems that
complicate this type of synthesis are solved by utilization of the
two-chamber reactor, which was not employed in reactions
with calcium carbide before.
eg
,
1.5
5.5
50
egh
, ,
1.5
5.5
50
a
Reaction conditions: 3a (0.35 mmol, except entries 12−18, solvent (1
b
mL), CaC2, water, 20 °C, 48 h). 0.12, 0.25, 0.53, 0.70, and 0.175
mmol quantities of 3a were used for entries 12, 13, 14, 15, and 16−18,
respectively. NMR conversions and yields, except entry 16 where
c
RESULTS AND DISCUSSION
■
d
yield of pure product is shown. 0.7 mmol of Et3N was added.
Initial materials, hydrazonoyl chlorides 3a−y, were obtained
from commercially available carboxylic acids and hydrazines
according to the standard procedures described elsewhere
(Scheme 2).23 4-tert-Butyl-N′-phenylbenzohydrazonoyl chlor-
e
f
Reactions were conducted in the two-chamber reactors. 0.35 mmol
g
of Et3N was used as a base. 0.438 mmol of Ca(OH)2 was used as a
base. 0.875 mmol of H2O was added to the reactant part of the two-
chamber reactor.
h
Scheme 2. Synthesis of Hydrazonoyl Chlorides 3a−y
Table 1) and chlorinated solvents (entries 5−7, Table 1). The
best result was achieved in CHCl3 as a solvent at the 3a
concentration of 100 mg/mL with 2.5 equiv of CaC2 (entry 7,
Table 1). Using Et3N as an additional base did not improve the
pyrazole yield under the studied conditions (entry 8, Table 1).
Variations of the amount of CaC2 (entries 9−11, Table 1) and
concentration of 3a (entries 12−15, Table 1) did not improve
the product yield.
We supposed that Ca(OH)2 formed in situ upon reaction of
CaC2 with water was a suboptimal base for this reaction, and its
excess, as well as the presence of water in the reaction mixture,
promoted collateral processes and decreased the yields of the
desired pyrazole. To check this hypothesis, we separated CaC2
and water from the substrate and used Et3N as a milder base.
The reaction was carried out in a two-chamber reactor. One
part of the reactor was loaded with a solution of hydrazonoyl
chloride 3a and Et3N in chloroform, while the other part was
loaded with CaC2, a layer of chloroform, and water. The
chloroform layer prevented the reaction of calcium carbide with
water from proceeding too fast and ensured slow release of
acetylene under stirring. Acetylene evolving from the calcium
carbide chamber readily dissolved in the reaction mixture in the
other chamber, provided that the reactor was hermetically
sealed. The NMR shift of acetylene (δ = 1.91 ppm) was
detected in the 1H NMR spectra of the reaction mixture after 1
h. In this way, gaseous acetylene was introduced into the
ide (3a) was chosen as a model substrate since it could be
readily obtained from 4-tert-butylbenzoyl chloride and phenyl-
hydrazine. Moreover, a characteristic signal of the tert-butyl
group facilitated NMR monitoring of the reactions.
Several types of settings and various conditions were
examined for the reaction of the hydrazonoyl chlorides with
acetylene generated from CaC2. At first, we attempted to
perform pyrazole synthesis by mixing all the components in the
same vessel. We assumed that calcium carbide reacting with the
water would simultaneously provide the source of both
acetylene and Ca(OH)2 which could act as a base for the
dipole generation. Various reaction conditions were examined
to obtain the corresponding product, 3-(4-tert-butylphenyl)-1-
phenyl-1H-pyrazole (4a), in good yield. We screened different
solvents, substrate concentrations, and amounts of calcium
carbide. In highly polar solvents, like MeOH and DMF, the
pyrazole yield was low (entries 1 and 2; Table 1), and a better
yield was obtained in ether (entry 3, Table 1). Good yields of
the desired product were obtained using toluene (entry 4,
B
DOI: 10.1021/acs.joc.8b00155
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Article
a
Table 2. Preparation of 1,3-Disubstituted Pyrazoles in the Two-Chamber Reactors
a
Reaction conditions: 3 (0.2 mmol), Et3N (0.4 mmol), CaC2 (100 mg), water (0.1 mL), CHCl3 (1 mL in each vessel), 20 °C, 48 h.
reaction mixture without using separate equipment. At the
same time, a contact of the reactants with the CaC2/water
system was avoided due to usage of the two-chamber reactor.
Triethylamine turned out to be a good base for the dipole
generation. After its addition to a solution of 3a in chloroform,
the resulting mixture was analyzed by electrospray ionization
mass spectrometry (ESI-MS), and the corresponding nitrile
imine was detected (m/z = 251.1547 [M + H]+).
The reaction in the two-chamber reactor was studied, and
pyrazole 4a was obtained in high yield after 48 h (Table 1, entry
16). The product did not require special purification: washing
with water and evaporation of the solvent resulted in a pure
compound. Two control experiments were carried out using
Ca(OH)2 and Ca(OH)2/H2O systems as a base in the two-
chamber reactor. When Ca(OH)2 was added to the reactant
chamber, a high yield of 4a was observed (Table 1, entry 17).
However, the product yield significantly decreased in the case
of addition of the Ca(OH)2/H2O system (Table 1, entry 18).
Therefore, the absence of water is an important factor to
achieve better product yields (the experiment confirmed that
the direct addition of calcium carbide and water to the reactant
solution should be avoided). Spatial partitioning of nitrile imine
and generation of acetylene by means of the two-chamber
reactor solved this problem and prevented the contact of the
active dipole with water.
yields can be achieved, but the acetylene consumption was
several times higher compared with the reaction in the two-
chamber reactor because of gas losses in the supply system.
Taking into account a low price of calcium carbide and the
technical simplicity of the proposed method, the suggested
usage of a two-chamber reactor would be a procedure of choice
for carrying out this reaction.
With this simple and efficient procedure in hand, a
considerable scope of various hydrazonoyl chloride substrates
was examined. In particular, a number of N′-arylbenzohy-
drazonoyl chlorides with various substituents at aryl fragments
were tested, and most of them afforded good or quantitative
yields of the desired pyrazoles (Table 2). The method worked
well for alkyl-, halogeno-, methoxy-, and nitro-derivatives.
Quantitative yields were obtained for 3-(4-(tert-butyl)phenyl)-
and 3-(4-methoxyphenyl)-1-phenylpyrazoles 4a, 4b, methyl-
and dimethyl-derivatives 4c, 4d, 4f, 4g, 4r, 4s, and
diphenylpyrazole 4h. Bromo-, chloro-, fluoro-, and dichloro-
derivatives 4i−k, 4m, 4u−w, and 4y were prepared in good or
quantitative yields. 3-(4-Nitrophenyl)-1-phenyl-, 3-phenyl-1-(4-
tolyl)-, and 1-(3-(trifluoromethyl)phenyl)-3-phenylpyrazoles
were also obtained in high yields (Table 2). Moderate yields
were obtained for 2-methyl-, 2,4-dichloro-, and 2-iodo-N′-
phenylbenzohydrazonoyl chlorides 3e, 3l, and 3n only. N′-
Phenylpropionohydrazonoyl chloride (3p) and hydrazonoyl
chloride 3q derived from ibuprofen also showed excellent
results and were converted to the corresponding pyrazoles 4p
Additionally, reaction of 3a with gaseous acetylene from a
standard external gas supply system was carried out. Similar
C
DOI: 10.1021/acs.joc.8b00155
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a
Table 3. Preparation of 4,5-Dideuteropyrazoles
a
Reaction conditions: 3 (0.2 mmol), Et3N (0.4 mmol), CaC2 (100 mg), D2O (0.1 mL), CDCl3 (1 mL in each vessel), 20 °C, 48 h.
Scheme 3. Pyrazole Synthesis by 1,3-Dipolar Cycloaddition Reaction
Table 4. Activation Energies (ΔE⧧, ΔH⧧, ΔG⧧, kcal/mol) and Reaction Energies (ΔE, ΔH, ΔG, kcal/mol) for 1,3-Dipolar
Cycloaddition Reaction (see Scheme 3) in Chloroform Media
ΔE‡
ΔH‡
ΔG‡
ΔE
ΔH
ΔG
I (R = H, R′ = H)
5.5
5.3
5.3
4.9
5.3
7.0
5.3
5.6
5.6
5.3
5.7
5.4
5.4
5.0
5.5
7.1
4.8
5.8
5.7
5.4
16.8
16.2
16.3
16.4
16.2
17.6
16.6
16.2
16.4
16.1
−113.1
−112.7
−112.7
−112.3
−114.0
−114.8
−113.6
−112.4
−112.5
−113.2
−108.4
−107.9
−108.1
−107.7
−109.3
−110.0
−109.0
−107.8
−107.9
−108.5
−94.3
−94.3
−94.4
−93.7
−95.4
−96.3
−95.6
−94.3
−94.5
−94.7
II (R = Me, R′ = H)
III (R = t-Bu, R′ = H)
IV (R = OMe, R′ = H)
V (R = Cl, R′ = H)
VI (R = NO2, R′ = H)
VII (R = H, R′ = Me)
VIII (R = H, R′ = Br)
IX (R = H, R′ = Cl)
X (R = H, R′ = F)
and 4q in a good and quantitative yield, respectively. Therefore,
the scope of application of our method can be extended to
other substrates derived from aliphatic carboxylic acids,
including pharmacologically active compounds. In total, 25
disubstituted pyrazoles have been successfully prepared from
the corresponding hydrazonoyl chloride precursors, and 16 of
them have been isolated in excellent yields and purity without
any additional purification.
In order to further evaluate a potential practical application
of the developed procedure the reaction was carried out in a
larger scale using 800 mg of hydrazonoyl chloride 3a and 1.6 g
of CaC2 to produce pure 4a in 95% yield (731 mg).
reaction with active dipoles to give the corresponding
dideuterated cycloadducts. This approach allowed us to obtain
novel 4,5-dideuteropyrazoles. Chloroform and water within the
reactor were replaced with CDCl3 and deuterium oxide,
respectively, in order to prevent D−H exchange between
D2O or C2D2 and the solvent. Several substrates were studied
using the developed procedure. In all cases, the expected 4,5-
dideuteropyrazoles were isolated in excellent yields with high
deuterium enrichment (Table 3). Content of the 4,5-
dideuterated pyrazoles in obtained isotopic mixtures exceeded
95% for all products. Synthesized 4,5-dideuteropyrazoles 5 were
stable and easy to purify without a noticeable change in the
isotope purity.
Deuterated acetylene C2D2, easily generated in the reaction
of CaC2 with D2O, was subsequently engaged in the studied
D
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Figure 1. (A) Mapped surface of the molecular electrostatic potential for nitrile imines I, IV, VI, and X. (B) Molecular structures of nitrile imine,
transition state, and product of the 1,3-dipolar cycloaddition reaction for I with Gibbs energies (ΔG, kcal/mol) in chloroform media. Calculations
were carried out at the PBE1PBE/6-311+G(d,p)&D3BJ&SMD level.
It should be noted that the developed methodology is handy
and practically relevant. The reaction may be performed in
standard glassware (either a two-chamber reactor or a widely
available H-tube reactor;24 see photos in Supporting
Information). The reaction with calcium carbide is easy to
implement in any conventional chemical laboratory: it requires
no dedicated equipment as in the case of acetylene gas.
For an insight into the reaction mechanism, theoretical
calculations of the intermediate structures and the reaction
pathway were carried out to estimate the role of substituents in
aryl fragments (Figures S1−S3, Table S1). To address this
question and to analyze electronic structures, theoretical
calculations were performed at the PBE1PBE/6-311+G(d,p)
level with D3BJ corrections for the dispersion interactions and
SMD continuum model for the effect of solvent.
considered as bond orders for C−C and C−N bonds.25 Total
delocalization index for the N2 atom (calculated as a sum of δ
values) is 3.44 for molecule I, wherein the δ value for the N1−
N2 bond is 1.57; that is, multiplicity of this bond is expressed to
a greater extent as compared with multiplicity calculated by the
Wiberg bond indices (1.36) (Figure S1). It should be noted
that variation of the R substituent results in more considerable
changes of the electronic parameters of the −N1N2C3−
nitrilimine group as compared with variation of the R′
substituent. For example, NBO charges of the N1 atom are
−0.360, −0.387, −0.323, and −0.361 for molecules I (R = H,
R′ = H), IV (R = OMe, R′ = H), VI (R = NO2, R′ = H), and X
(R = H, R′ = F), respectively (Figure S1).
The 1,3-dipolar cycloaddition reaction proceeds over the
concerted transition states with C−C and C−N bonds formed
simultaneously. Small activation barriers (∼16−17 kcal/mol)
and large driving force values (>90 kcal/mol) were found
computationally (Table 4). Indeed, the studied reactions should
easily proceed at room temperature. Very similar activation
barriers and reaction energies for the studied substituted
substrates confirm a general scope for substituents with
different electronic effect.
In conclusion, a novel highly efficient protocol for the
synthesis of 1,3-disubstituted pyrazoles in excellent yields is
reported. The procedure is based on 1,3-dipolar cycloaddition
between nitrile imines and acetylene, generated in situ from
calcium carbide. Using a simple two-chamber reactor, a
procedure with a controlled and spatially isolated acetylene
generation was developed. The process appears to be a 1,3-
dipolar cycloaddition reaction proceeding over the concerted
transition state, and theoretical calculations confirmed good
functional group tolerance at the key cycloaddition step.
Replacing water with D2O allowed formation of 4,5-
dideuteropyrazoles with high levels of deuterium incorporation.
The key stage of the whole process is 1,3-dipolar cyclo-
addition of nitrile imine to acetylene. Several substrate
molecules with different substituents were considered (Scheme
3, Table 4, and Figure 1). We took the electronic structure of
the unsubstituted nitrilimine molecule (R = H, R′ = H) as a
reference point (Figure 1).
Quantum-chemical calculations of atomic charges, bond
orders, natural bond orbitals, and molecular electrostatic
potentials confirmed that the −N1N2C3− nitrilimine group
is a dipole with the positive charge localized within the C3
carbon atom region and the negative charge localized within the
N1 nitrogen atom region (Figures 1A and S1), wherein the
natural bond orbital charge of the nitrogen atom N2 is rather
small. It should be noted that the total Wiberg bond index for
the N2 nitrogen atom is 3.59 for molecule I (R = H, R′ = H);
that is, the N2 atom forms a double bond with the C3 carbon
atom and “one and a half” bond with the N1 nitrogen atom.
Therefore the N1−N2−C3 fragment may be considered to
involve a contribution from the cumulene structure. The
Wiberg bond indices are in good agreement with the Bader
delocalization indices (δ). Delocalization indices may be
E
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°C).31 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.98 (d, J = 2.2
Hz, 1H), 7.74 (dd, J = 8.5, 2.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H),
7.35−7.31 (m, 2H), 7.18−7.16 (m, 2H), 6.98 (t, J = 7.3 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 142.9, 134.5, 133.2, 133.0, 130.4,
129.6 (2C), 128.0, 125.4, 122.2, 121.9, 113.7 (2C). HRMS (ESI)
EXPERIMENTAL SECTION
■
General. Chemicals were purchased from Sigma-Aldrich, Alfa
Aesar, and Acros Organics in reagent grade or better quality and
checked by NMR before use. Calcium carbide (granulated, technical,
≥75% purity) was obtained from Sigma-Aldrich. NMR spectra were
recorded on a Bruker Avance III spectrometer (1H 400 MHz; 13C 101
MHz, 19F 376 MHz). Chemical shifts δ are reported in ppm relative to
residual CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.16) as internal
standards. High-resolution mass spectra (HRMS) were recorded on a
Bruker micrOTOF 10223 spectrometer using electrospray ionization
(ESI). A mass spectrum of 3x was measured on a high-resolution time-
of-flight Bruker maXis instrument using atmospheric pressure chemical
ionization (APCI-MS). Reactions were monitored by TLC analysis
using Merck UV-254 plates. Preparative column chromatography was
performed on Merck silica gel 60 (230−400 Mesh) pretreated with
triethylamine.
+
Calcd for C13H10Cl3N2 [M + H]+ 298.9904, found 298.9898.
2-Fluoro-N-phenylbenzohydrazonoyl Chloride (3m). Obtained
from 576 mg (2.5 mmol) of 2-fluoro-N′-phenylbenzohydrazide, yield
447 mg (72%). White solid; mp 77−80 °C (lit. 82−83.5 °C).32 1H
NMR (400 MHz, CDCl3) δ 8.12 (s, 1H, NH), 7.73 (td, J = 7.7, 1.7
Hz, 1H), 7.39−7.29 (m, 3H), 7.22−7.12 (m, 4H), 6.98−6.94 (m, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 159.9 (d, J = 256.3 Hz), 143.3,
130.8 (d, J = 8.6 Hz), 130.3 (d, J = 1.1 Hz), 129.5 (2C), 124.1 (d, J =
3.8 Hz), 123.3 (d, J = 10.0 Hz), 121.5, 118.9 (d, J = 5.7 Hz), 116.7 (d,
J = 22.0 Hz), 113.7 (2C). 19F NMR (376 MHz, CDCl3) δ −112.12
ppm. HRMS (ESI) Calcd for C13H10ClFN2Na+ [M + Na]+ 271.0409,
found 271.0410.
Calculation Details. All structures were optimized by the
PBE1PBE26 method with 6-311+G(d,p)27 basis set. Dispersion
interaction was accounted for by Grimme D3BJ28 empirical
corrections. Vibrational analysis was performed for all structures, and
vibrational spectra of all transition states had one imaginary frequency
corresponding to 1,3-dipolar cycloaddition. The intrinsic reaction
coordinate calculations (IRCs) were carried out for the verification of
the founded transition state structures. Influence of the solvent
medium (chloroform) was modeled by the SMD continuum model.29
All structures were optimized considering the solvent effects. The
calculations were performed by the Gaussian 16 program package.30
Visualization of the molecular structures and MESP surfaces was
performed by GaussView 6.0 software.
4-Nitro-N-phenylbenzohydrazonoyl Chloride (3o). Obtained from
643 mg (2.5 mmol) of 4-nitro-N′-phenylbenzohydrazide, yield 535 mg
1
(78%). Red solid; mp 158−159 °C. H NMR (400 MHz, CDCl3) δ
8.27−8.23 (m, 3H), 8.08−8.04 (m, 2H), 7.37−7.33 (m, 2H), 7.22−
7.20 (m, 2H), 7.04−7.00 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 147.8, 142.6, 140.3, 129.7 (2C), 126.8 (2C), 123.9 (2C), 122.4,
122.3, 114.0 (2C). HRMS (ESI) Calcd for C13H10N3O2ClNa+ [M +
Na]+ 298.0354, found 298.0344.
N-Phenylpropionohydrazonoyl Chloride (3p). Obtained from 493
mg (3 mmol) of N′-phenylpropionohydrazide, yield 350 mg (64%).
Red solid; mp 38−42 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H),
7.29−7.25 (m, 2H), 7.06 (d, J = 7.6 Hz, 2H), 6.89 (t, J = 7.3 Hz, 1H),
2.67 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 144.1, 129.4 (2C), 129.0, 120.7, 113.2 (2C), 32.7,
Experimental Details and Spectral Data for Hydrazonoyl
Chlorides. Hydrazonoyl chlorides were prepared in 62−89% yields by
a procedure reported previously.23c
+
11.6. HRMS (ESI) Calcd For C9H11N2 [M − Cl]+ 147.0917, found
147.0920.
4-(tert-Butyl)-N-phenylbenzohydrazonoyl Chloride (3a). Ob-
2-(4-Isobutylphenyl)-N-phenylpropanehydrazonoyl Chloride
(3q). Obtained from 741 mg (2.5 mmol) of 2-(4-isobutylphenyl)-
N′-phenylpropanehydrazide, yield 574 mg (73%). Brown oil. 1H NMR
(400 MHz, CDCl3) δ 7.68 (s, 1H), 7.29−7.26 (m, 2H), 7.21 (d, J =
8.1 Hz, 2H), 7.12−7.06 (m, 4H), 6.92−6.88 (m, 1H), 3.97 (q, J = 7.0
Hz, 1H), 2.46 (d, J = 7.2 Hz, 2H), 1.95−1.78 (m, 1H), 1.63 (d, J = 7.1
Hz, 3H), 0.91 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ 144.1, 140.7, 138.9, 130.8, 129.4 (4C), 127.4 (2C), 120.8, 113.3
tained from 2.684 g (10 mmol) of 4-tert-butyl-N′-phenylbenzohy-
1
drazide, yield 2.237 g (78%). Beige solid; mp 55−57 °C. H NMR
(400 MHz, CDCl3) δ 8.01 (s, 1H), 7.88−7.85 (m, 2H), 7.46−7.43 (m,
2H), 7.35−7.30 (m, 2H), 7.20−7.17 (m, 2H), 6.95 (tt, J = 7.6, 1.1 Hz,
1H), 1.36 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.7, 143.6,
131.9, 129.5 (2C), 126.4 (2C), 125.5 (2C), 125.0, 121.2, 113.5 (2C),
34.9, 31.4 (3C). HRMS (ESI) Calcd for C17H19ClN2Na+ [M + Na]+
309.1129, found 309.1148.
+
(2C), 48.7, 45.2, 30.3, 22.5, 19.8. HRMS (ESI) Calcd for C19H24ClN2
[M + H]+ 315.1623, found 315.1616.
2-Methyl-N-phenylbenzohydrazonoyl Chloride (3e). Obtained
from 453 mg (2 mmol) of 2-methyl-N′-phenylbenzohydrazide, yield
N-(2-Tolyl)benzohydrazonoyl Chloride (3r). Obtained from 566
mg (2.5 mmol) of N′-2-tolylbenzohydrazide, yield 410 mg (67%).
White solid, mp 64−66 °C (lit. 64.5−66 °C).32 1H NMR (400 MHz,
CDCl3) δ 7.99−7.97 (m, 3H), 7.57 (d, J = 8.1 Hz, 1H), 7.46−7.38 (m,
3H), 7.26 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.4
Hz, 1H), 2.33 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 141.4,
134.6, 130.7, 129.4, 128.6 (2C), 127.5, 126.6 (2C), 125.7, 121.3, 120.9,
113.4, 17.0. HRMS (ESI) Calcd for C14H14ClN2+ [M + H]+ 245.0840,
found 245.0839.
1
304 mg (62%). Yellow oil. H NMR (400 MHz, CDCl3) δ 8.04 (s,
1H), 7.66−7.63 (m, 1H), 7.32−7.26 (m, 5H), 7.14−7.11 (m, 2H),
6.95−6.91 (m, 1H), 2.59 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 143.6, 136.9, 134.5, 131.3, 129.7, 129.5 (2C), 129.1, 126.0, 123.8,
+
121.2, 113.4 (2C), 22.0. HRMS (ESI) Calcd for C14H14ClN2 [M +
H]+ 245.0840, found 245.0847.
3,4-Dimethyl-N-phenylbenzohydrazonoyl Chloride (3f). Obtained
from 601 mg (2.5 mmol) of 3,4-dimethyl-N′-phenylbenzohydrazide,
yield 440 mg (68%). Beige solid; mp 97−99 °C. 1H NMR (400 MHz,
CDCl3) δ 7.95−7.93 (m, 3H), 7.44−7.35 (m, 3H), 7.08 (d, J = 8.1 Hz,
1H), 7.00 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 2.29 (s, 3H), 2.24 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 141.6, 137.8, 134.8, 130.5, 129.4,
129.1, 128.5 (2C), 126.5 (2C), 124.0, 115.0, 111.0, 20.2, 19.1.
N-(3-Tolyl)benzohydrazonoyl Chloride (3s). Obtained from 566
mg (2.5 mmol) of N′-2-tolylbenzohydrazide, yield 415 mg (68%).
Colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.96−7.93
(m, 2H), 7.45−7.36 (m, 3H), 7.22 (t, J = 7.7 Hz, 1H), 7.03 (s, 1H),
7.00 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 2.38 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.5, 139.5, 134.6, 129.4, 129.3,
128.5 (2C), 126.5 (2C), 124.6, 122.2, 114.2, 110.8, 21.7. HRMS (ESI)
+
HRMS (ESI) Calcd for C15H16ClN2 [M + H]+ 259.0997, found
259.0999.
+
Calcd for C14H14ClN2 [M + H]+ 245.0840, found 245.0849.
3,5-Dimethyl-N-phenylbenzohydrazonoyl Chloride (3g). Ob-
tained from 601 mg (2.5 mmol) of 3,5-dimethyl-N′-phenylbenzohy-
N-(3-(Trifluoromethyl)phenyl)benzohydrazonoyl Chloride (3x).
Obtained from 700 mg (2.5 mmol) of N′-(3-(trifluoromethyl)-
phenyl)benzohydrazide, yield 560 mg (75%). White solid, mp 85−87
°C. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.95−7.92 (m, 2H),
7.46−7.40 (m, 5H), 7.32 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.6 Hz,
1H).13C{1H} NMR (101 MHz, CDCl3) δ 143.9, 134.2, 132.0 (q, J =
32.2 Hz), 130.0, 129.8, 128.6 (2C), 126.7 (2C), 126.5, 124.3 (q, J =
272.4 Hz), 117.7 (q, J = 3.8 Hz), 116.6, 110.2 (q, J = 3.9 Hz). 19F
NMR (376 MHz, CDCl3) δ −62.82 ppm. HRMS (APCI) Calcd for
1
drazide, yield 455 mg (70%). Beige solid; mp 44−47 °C. H NMR
(400 MHz, CDCl3) δ 8.00 (s, 1H), 7.56 (s, 2H), 7.36−7.31 (m, 2H),
7.21−7.19 (m, 2H), 7.03 (s, 1H), 6.98−6.94 (m, 1H), 2.40 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.6, 138.1 (2C), 134.5, 131.2,
129.5 (2C), 125.2, 124.5 (2C), 121.2, 113.6 (2C), 21.5. HRMS (ESI)
+
Calcd for C15H16ClN2 [M + H]+ 259.0997, found 259.1004.
3,4-Dichloro-N-phenylbenzohydrazonoyl Chloride (3k). Obtained
from 700 mg (2.5 mmol) of 3,4-dichloro-N′-phenylbenzohydrazide,
yield 629 mg (84%). Pale yellow solid; mp 119−121 °C (lit. 121−122
+
C14H11ClF3N2 [M + H]+ 299.0557, found 299.0555.
F
DOI: 10.1021/acs.joc.8b00155
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N-(2,6-Dichlorophenyl)benzohydrazonoyl Chloride (3y). Ob-
tained from 700 mg (2.5 mmol) of N′-(2,6-dichlorophenyl)-
benzohydrazide, yield 590 mg (79%). White solid, mp 66−69 °C
(lit. 69.5−70.5 °C).33 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H),
7.96−7.93 (m, 2H), 7.43−7.39 (m, 3H), 7.34 (d, J = 8.1 Hz, 2H), 6.94
(t, J = 8.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 137.2, 134.2,
129.9, 129.4 (2C), 128.6 (2C), 127.7, 126.8 (2C), 125.6 (2C), 123.9.
127.0, 126.3, 126.0, 119.0 (2C), 108.1, 21.6. HRMS (ESI) Calcd for
+
C16H15N2 [M + H]+ 235.1230, found 235.1233.
3-(3,4-Dimethylphenyl)-1-phenyl-1H-pyrazole (4f). Yield 49 mg
1
(99%). Beige solid; mp 76−77 °C. H NMR (400 MHz, CDCl3) δ
7.94 (d, J = 2.5 Hz, 1H), 7.79−7.74 (m, 3H), 7.65 (d, J = 7.8 Hz, 1H),
7.49−7.45 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H),
6.75 (d, J = 2.5 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 153.3, 140.4, 136.9, 136.6, 130.8, 130.0, 129.5
(2C), 128.0, 127.1, 126.3, 123.5, 119.2 (2C), 105.0, 20.0, 19.7. HRMS
+
HRMS (ESI) Calcd for C13H10Cl3N2 [M + H]+ 298.9904, found
298.9915.
+
(ESI) Calcd for C17H17N2 [M + H]+ 249.1386, found 249.1394.
General Procedure for the Synthesis of Pyrazoles. The first
vessel of the two-chamber reactor was loaded with the calcium carbide
(100 mg). Then, the corresponding hydrazonoyl chloride (0.2 mmol)
was loaded to the second vessel, and 1.0 mL of CHCl3 was added to
each part. Next, triethylamine (0.4 mmol) was added to the
hydrazonoyl chloride solution, and distilled water (0.1 mL) was
poured into the carbide vessel. The reactor was immediately sealed,
and the mixture was stirred at room temperature for 48 h. After
completing the reaction, the contents of the second vessel were
collected by a syringe, washed thrice with water, dried with Na2SO4,
and filtered, and then the solvent was removed on a rotary evaporator.
Pyrazoles 4a−d, 4f−k, 4m, 4q−s, and 4u,v did not require special
purification and were obtained in individual form after drying of
reaction mixture. The products 4e,l, 4n−p, 4t, and 4w−y were purified
by column chromatography using hexane−ethyl acetate as an eluent
(eluent compositions for each compound are given below). For
deuterated pyrazoles 5, D2O and CDCl3 were used instead of water
and chloroform. All compounds 5 were isolated without chromato-
graphic purification. Isotopic purity of the synthesized products was in
the range of 95−99%.
3-(3,5-Dimethylphenyl)-1-phenyl-1H-pyrazole (4g). Yield 49 mg
(99%). Beige solid; mp 65−67 °C. H NMR (400 MHz, CDCl3) δ
1
7.94 (d, J = 2.5 Hz, 1H), 7.79−7.77 (m, 2H), 7.56 (s, 2H), 7.49−7.45
(m, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.76 (d, J = 2.5 Hz,
1H), 2.40 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.3, 140.4,
138.3 (2C), 133.0, 129.9, 129.5 (2C), 128.0, 126.4, 123.8 (2C), 119.2
(2C), 105.2, 21.5 (2C). HRMS (ESI) Calcd for C17H17N2+ [M + H]+
249.1386, found 249.1396.
1,3-Diphenyl-1H-pyrazole (4h). Yield 44 mg (99%). Beige solid;
mp 82−85 °C (lit. 80−82 °C).33 1H NMR (400 MHz, CDCl3) δ
7.97−7.93 (m, 3H), 7.81−7.77 (m, 2H), 7.50−7.43 (m, 4H), 7.38−
7.35 (m, 1H), 7.30 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 140.4, 133.3, 129.5 (2C),
128.8 (2C), 128.15, 128.09, 126.4, 126.0 (2C), 119.2 (2C), 105.1.
+
HRMS (ESI) Calcd for C15H13N2 [M + H]+ 221.1073, found
221.1081.
3-(4-Bromophenyl)-1-phenyl-1H-pyrazole (4i). Yield 59 mg
(99%). Beige solid; mp 122−124 °C (lit. 124−126 °C).35 1H NMR
(400 MHz, CDCl3) δ 7.95 (d, J = 2.5 Hz, 1H), 7.81−7.75 (m, 4H),
7.57−7.54 (m, 2H), 7.49−7.45 (m, 2H), 7.31 (t, J = 7.4 Hz, 1H), 6.75
(d, J = 2.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.0, 140.3,
132.3, 131.9 (2C), 129.6 (2C), 128.3, 127.5 (2C), 126.7, 122.1, 119.2
(2C), 105.1. HRMS (ESI) Calcd for C15H12N2Br+ [M + H]+
299.0178, found 299.0183.
3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole (4j). Yield 50.5 mg
(99%). Beige solid; mp 119−120 °C (lit. 118 °C).33 1H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 2.5 Hz, 1H), 7.87−7.85 (m, 2H), 7.78−
7.75 (m, 2H), 7.50−7.46 (m, 2H), 7.42−7.39 (m, 2H), 7.33−7.29 (m,
1H), 6.75 (d, J = 2.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
151.9, 140.2, 133.9, 131.8, 129.6 (2C), 128.9 (2C), 128.3, 127.2 (2C),
126.7, 119.2 (2C), 105.1. HRMS (ESI) Calcd for C15H12N2Cl+ [M +
H]+ 255.0684, found 255.0673.
3-(4-(tert-Butyl)phenyl)-1-phenyl-1H-pyrazole (4a). Yield 55 mg
1
(99%). Beige solid; mp 103−105 °C. H NMR (400 MHz, CDCl3) δ
7.94 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.9 Hz,
2H), 7.49−7.45 (m, 4H), 7.29 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 2.5 Hz,
1H), 1.37 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 151.2,
140.4, 130.5, 129.5 (2C), 128.0, 126.3, 125.74 (2C), 125.69 (2C),
119.1 (2C), 105.1, 34.8, 31.5. HRMS (ESI) Calcd for C19H21N2+ [M +
H]+ 277.1699, found 277.1709.
3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole (4b). Yield 49.5 mg
(99%). Beige solid; mp 101−103 °C (lit. 102−104 °C).33 1H NMR
(400 MHz, CDCl3) δ 7.93 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.6 Hz,
2H), 7.78−7.76 (m, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.28 (t, J = 7.8 Hz,
1H), 6.97 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 152.9, 140.4, 129.5 (2C),
128.0, 127.2 (2C), 126.3, 126.1, 119.0 (2C), 114.2 (2C), 104.7, 55.4.
HRMS (ESI) Calcd for C16H15N2O+ [M + H]+ 251.1179, found
251.1183.
3-(3,4-Dichlorophenyl)-1-phenyl-1H-pyrazole (4k). Yield 58 mg
1
(99%). Beige solid; mp 95−97 °C. H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.76−7.71 (m, 3H),
7.50−7.46 (m, 3H), 7.32 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 150.7, 140.1, 133.4, 133.0, 131.8,
130.7, 129.6 (2C), 128.5, 127.7, 126.8, 125.1, 119.3 (2C), 105.2.
1-Phenyl-3-(4-tolyl)-1H-pyrazole (4c). Yield 46.5 mg (99%). Beige
solid; mp 92−94 °C (lit. 91−92 °C).34 1H NMR (400 MHz, CDCl3) δ
7.94 (d, J = 2.5 Hz, 1H), 7.83−7.77 (m, 4H), 7.49−7.45 (m, 2H),
7.31−7.24 (m, 3H), 6.75 (d, J = 2.5 Hz, 1H), 2.40 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 153.1, 140.4, 137.9, 130.5, 129.53 (2C),
129.48 (2C), 128.0, 126.3, 125.9 (2C), 119.1 (2C), 105.0, 21.4.
+
HRMS (ESI) Calcd for C15H11N2Cl2 [M + H]+ 289.0294, found
289.0293.
3-(2,4-Dichlorophenyl)-1-phenyl-1H-pyrazole (4l). The crude
material was purified by column chromatography (n-hexane/EtOAc
20:1) to give the product as colorless solid; mp 88−90 °C. Yield 39.5
+
HRMS (ESI) Calcd for C16H15N2 [M + H]+ 235.1230, found
1
mg (68%). H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.5 Hz, 1H),
235.1245.
7.92 (d, J = 8.4 Hz, 1H), 7.77−7.75 (m, 2H), 7.50−7.45 (m, 3H),
7.33−7.30 (m, 2H), 7.01 (d, J = 2.5 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 149.8, 140.1, 134.2, 133.1, 131.6, 130.8, 130.2, 129.6
(2C), 127.5, 127.4, 126.8, 119.3 (2C), 109.0. HRMS (ESI) Calcd for
1-Phenyl-3-(3-tolyl)-1H-pyrazole (4d). Yield 46.5 mg (99%). Beige
solid; mp 68−70 °C (lit. oil).34 1H NMR (400 MHz, CDCl3) δ 7.95
(d, J = 2.5 Hz, 1H), 7.80−7.77 (m, 3H), 7.72 (d, J = 7.7 Hz, 1H),
7.50−7.45 (m, 2H), 7.36−7.28 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.77
(d, J = 2.5 Hz, 1H), 2.44 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
153.2, 140.4, 138.4, 133.1, 129.5 (2C), 129.0, 128.7, 128.1, 126.6,
126.4, 123.2, 119.2 (2C), 105.2, 21.6. HRMS (ESI) Calcd for
+
C15H11N2Cl2 [M + H]+ 289.0294, found 289.0308.
3-(2-Fluorophenyl)-1-phenyl-1H-pyrazole (4m). Yield 47 mg
1
(99%). Beige solid; mp 59−61 °C. H NMR (400 MHz, CDCl3) δ
8.19 (td, J = 7.7, 1.8 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.80−7.78 (m,
2H), 7.50−7.46 (m, 2H), 7.34−7.29 (m, 2H), 7.23 (td, J = 7.6, 1.2 Hz,
1H), 7.16 (ddd, J = 11.3, 8.2, 1.1 Hz, 1H), 6.94 (dd, J = 3.9, 2.5 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5 (d, J = 249.8 Hz),
147.8 (d, J = 1.1 Hz), 140.3, 129.6 (2C), 129.5 (d, J = 8.6 Hz), 128.7
(d, J = 3.6 Hz), 127.8 (d, J = 2.2 Hz), 126.6, 124.4 (d, J = 3.5 Hz),
121.1 (d, J = 11.8 Hz), 119.3 (2C), 116.2 (d, J = 22.1 Hz), 108.6 (d, J
= 10.5 Hz). 19F NMR (376 MHz, CDCl3) δ −115.95 ppm. HRMS
(ESI) Calcd for C15H12N2F+ [M + H]+ 239.0979, found 239.0987.
+
C16H15N2 [M + H]+ 235.1230, found 235.1237.
1-Phenyl-3-(2-tolyl)-1H-pyrazole (4e). The crude material was
purified by column chromatography (n-hexane/EtOAc 100:1) to give
the product as yellow oil. Yield 25 mg (54%).
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 2.5 Hz, 1H), 7.79−7.76
(m, 2H), 7.68−7.64 (m, 1H), 7.49−7.44 (m, 2H), 7.31−7.27 (m, 4H),
6.65 (d, J = 2.5 Hz, 1H), 2.59 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 153.6, 140.4, 136.4, 133.0, 131.1, 129.5 (2C), 129.4, 128.0,
G
DOI: 10.1021/acs.joc.8b00155
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-(2-Iodophenyl)-1-phenyl-1H-pyrazole (4n). The crude material
was purified by column chromatography (n-hexane/EtOAc 100:1) to
give the product as white solid; mp 93−95 °C. Yield 44.5 mg (64%).
1H NMR (400 MHz, CDCl3) δ 8.00−7.98 (m, 2H), 7.79−7.76 (m,
2H), 7.66 (dd, J = 7.7, 1.7 Hz, 1H), 7.49−7.38 (m, 3H), 7.32−7.28
(m, 1H), 7.06 (td, J = 7.7, 1.7 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 154.7, 140.29, 140.25, 138.45,
131.0, 129.7, 129.6 (2C), 128.3, 127.0, 126.6, 119.3 (2C), 108.7, 97.2.
HRMS (ESI) Calcd for C15H12N2I+ [M + H]+ 347.0040, found
347.0050.
105.6. HRMS (ESI) Calcd for C15H12N2Br+ [M + H]+ 299.0178,
found 299.0187.
1-(4-Chlorophenyl)-3-phenyl-1H-pyrazole (4v). Yield 50.5 mg
(99%). Beige solid; mp 129−130 °C (lit. 132−133 °C).33 1H NMR
(400 MHz, CDCl3) δ 7.92−7.90 (m, 3H), 7.74−7.70 (m, 2H), 7.46−
7.41 (m, 4H), 7.37−7.34 (m, 1H), 6.78 (d, J = 2.5 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 153.4, 138.9, 133.0, 131.9, 129.6 (2C),
128.8 (2C), 128.3, 128.0, 126.0 (2C), 120.2 (2C), 105.5. HRMS (ESI)
Calcd for C15H12N2Cl+ [M + H]+ 255.0684, found 255.0688.
1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole (4w). The crude materi-
al was purified by column chromatography (n-hexane/EtOAc 40:1) to
give the product as white solid; mp 90−92 °C (lit. 87−88 °C).34 Yield
3-(4-Nitrophenyl)-1-phenyl-1H-pyrazole (4o). The crude material
was purified by PTLC (n-hexane/EtOAc 10:1) to give the product as
orange solid; mp = 134−136 °C (lit. 138−140 °C).33 Yield 41 mg
(77%). 1H NMR (400 MHz, CDCl3) δ 8.31−8.28 (m, 2H), 8.10−8.06
(m, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.80−7.77 (m, 2H), 7.53−7.48 (m,
2H), 7.37−7.33 (m, 1H), 6.88 (d, J = 2.5 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 150.6, 147.4, 140.0, 139.5, 129.7 (2C), 128.8,
127.2, 126.3 (2C), 124.2 (2C), 119.4 (2C), 106.01. HRMS (ESI)
1
45.5 mg (96%). H NMR (400 MHz, CDCl3) δ 7.93−7.90 (m, 2H),
7.88 (d, J = 2.5 Hz, 1H), 7.76−7.70 (m, 2H), 7.46−7.42 (m, 2H),
7.37−7.34 (m, 1H), 7.19−7.13 (m, 2H), 6.77 (d, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 161.2 (d, J = 245.7 Hz), 151.2,
136.8 (d, J = 2.8 Hz), 133.1, 128.8 (2C), 128.23, 128.22, 125.9 (2C),
121.0 (d, J = 8.2 Hz, 2C), 116.3 (d, J = 23.2 Hz, 2C), 105.2 (C). 19F
NMR (376 MHz, CDCl3) δ −116.13 ppm. HRMS (ESI) Calcd for
C15H12N2F+ [M + H]+ 239.0979, found 239.0989.
+
Calcd for C15H12N3O2 [M + H]+ 266.0924, found 266.0918.
3-Ethyl-1-phenyl-1H-pyrazole (4p).36 The crude material was
purified by column chromatography (gradient elution n-hexane/
EtOAc 100:1 to 20:1) to give the product as orange oil. Yield 28.5 mg
(83%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 2.4 Hz, 1H), 7.68−
7.65 (m, 2H), 7.45−7.39 (m, 2H), 7.26−7.22 (m, 1H), 6.28 (d, J = 2.4
Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.7, 140.4, 129.4 (2C), 127.3, 126.0,
119.0 (2C), 106.1, 21.8, 14.0. HRMS (ESI) Calcd for C11H13N2+ [M +
H]+ 173.1073, found 173.1069.
1-(3-(Trifluoromethyl)phenyl)-3-phenyl-1H-pyrazole (4x). The
crude material was purified by column chromatography (n-hexane/
EtOAc 100:1) to give the product as beige solid; mp 70−71 °C. Yield
53.5 mg (93%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.99 (d,
J = 2.6 Hz, 1H, Hpyr), 7.96−7.94 (m, 3H), 7.60−7.53 (m, 2H), 7.48−
7.45 (m, 2H), 7.40−7.36 (m, 1H), 6.82 (d, J = 2.6 Hz, 1H). 13C{1H}
NMR (101 MHz, CDCl3) δ 153.7, 140.6, 132.8, 132.1 (q, J = 32.8
Hz), 130.1, 128.8 (2C), 128.5, 128.0, 126.0 (2C), 123.9 (q, J = 272.6
Hz), 122.8 (q, J = 3.7 Hz), 121.7, 115.8 (q, J = 4.0 Hz), 105.9. 19F
NMR (376 MHz, CDCl3) δ −62.71 ppm. HRMS (ESI) Calcd for
3-(1-(4-Isobutylphenyl)ethyl)-1-phenyl-1H-pyrazole (4q). Yield
1
60.5 mg (99%). Yellow oil. H NMR (400 MHz, CDCl3) δ 7.81 (d,
+
C16H12N2F3 [M + H]+ 289.0947, found 289.0945.
J = 2.4 Hz, 1H), 7.70−7.68 (m, 2H), 7.45−7.41 (m, 2H), 7.27−7.23
(m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 6.20 (d, J = 2.4 Hz, 1H), 4.29 (q, J
= 7.2 Hz, 1H), 2.46 (d, J = 7.2 Hz, 2H), 1.92−1.81 (m, 1H), 1.72 (d, J
= 7.2 Hz, 3H), 0.92 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.1, 142.9, 140.5, 139.6, 129.4 (2C), 129.2 (2C), 127.3
(2C), 126.0, 119.1 (2C), 106.1, 45.2, 39.1, 30.3, 22.6 (2C), 21.7.
1-(2,6-Dichlorophenyl)-3-phenyl-1H-pyrazole (4y). The crude
material was purified by column chromatography (n-hexane/EtOAc
40:1) to give the product as beige solid; mp 110−111 °C (lit. 109−
110 °C).37 Yield 51.5 mg (89%). H NMR (400 MHz, CDCl3) δ
1
7.91−7.89 (m, 2H), 7.58 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H),
7.44−7.40 (m, 2H), 7.37−7.31 (m, 2H), 6.82 (d, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 153.3, 136.7, 134.9 (2C), 133.1,
130.7, 128.9 (2C), 128.8 (2C), 128.2, 126.2 (2C), 104.2. One of the
carbon signals is overlapped by the other signals. HRMS (ESI) Calcd
+
HRMS (ESI) Calcd for C21H25N2 [M + H]+ 305.2012, found
305.2017.
3-Phenyl-1-(2-tolyl)-1H-pyrazole (4r).37 Yield 46.5 mg (99%).
1
Yellow oil. H NMR (400 MHz, CDCl3) δ 7.93−7.90 (m, 2H), 7.63
+
for C15H11N2Cl2 [M + H]+ 289.0294, found 289.0295.
(d, J = 2.4 Hz, 1H), 7.45−7.40 (m, 3H), 7.35−7.28 (m, 4H), 6.76 (d, J
= 2.4 Hz, 1H), 2.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
152.4, 140.2, 133.9, 133.5, 132.0, 131.5, 128.7 (2C), 128.5, 127.9,
126.8, 126.2, 125.9 (2C), 103.7, 18.4. HRMS (ESI) Calcd for
4,5-Dideutero-3-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole
(5a). Yield 55 mg (99%). Beige solid; mp 100−102 °C. 1H NMR (400
MHz, CDCl3) δ 7.87 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H),
7.49−7.45 (m, 4H), 7.29 (t, J = 7.4 Hz, 1H), 1.38 (s, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 153.0, 151.2, 140.4, 130.5, 129.5 (2C),
127.7 (t, J = 27.4 Hz), 126.3, 125.73 (2C), 125.69 (2C), 119.1 (2C),
104.7 (t, J = 26.2 Hz), 34.8, 31.5. HRMS (ESI) Calcd for
+
C16H15N2 [M + H]+ 235.1230, found 235.1232.
3-Phenyl-1-(3-tolyl)-1H-pyrazole (4s). Yield 46.5 mg (99%). Beige
solid; mp 71−73 °C (lit. oil).34 1H NMR (400 MHz, CDCl3) δ 7.95−
7.93 (m, 3H), 7.64 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.6
Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 7.5 Hz, 1H), 6.77 (d, J =
2.5 Hz, 1H), 2.45 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.0,
140.3, 139.6, 133.3, 129.3, 128.8 (2C), 128.2, 128.1, 127.3, 126.0 (2C),
120.0, 116.2, 105.0, 21.6. HRMS (ESI) Calcd for C16H15N2+ [M + H]+
235.1230, found 235.1238.
+
C19H19D2N2 [M + H]+ 279.1825, found 279.1831.
4,5-Dideutero-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole (5b).
1
Yield 50 mg (99%). Beige solid; mp 100−101 °C. H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 7.7 Hz, 2H),
7.46 (t, J = 7.9 Hz, 2H), 7.28 (t, J = 7.8 Hz), 6.98 (d, J = 8.8 Hz, 2H),
3.86 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.8, 152.8, 140.4,
129.5 (2C), 127.2 (2C), 126.3, 126.1, 119.0 (2C), 114.2 (2C), 104.4
(t, J = 26.8 Hz), 55.4. HRMS (ESI) Calcd for C16H13D2N2O+ [M +
H]+ 253.1304, found 253.1298.
3-Phenyl-1-(4-tolyl)-1H-pyrazole (4t). The crude material was
purified by column chromatography (n-hexane/EtOAc 100:1) to give
the product as colorless solid; mp 111−112 °C (lit. 110−111 °C).33
1
Yield 44.5 mg (95%). H NMR (400 MHz, CDCl3) δ 7.97−7.93 (m,
4,5-Dideutero-1-phenyl-3-(4-tolyl)-1H-pyrazole (5c). Yield 46.5
mg (98%). Beige solid; mp 93−94 °C. 1H NMR (400 MHz, CDCl3) δ
7.83 (d, J = 8.1 Hz, 2H), 7.78 (dd, J = 8.5, 0.8 Hz, 2H), 7.49−7.45 (m,
2H), 7.31−7.25 (m, 3H), 2.41 (s, 3H, CH3). 13C{1H} NMR (101
MHz, CDCl3) δ 153.1, 140.4, 137.9, 130.5, 129.51 (2C), 129.47 (2C),
127.7 (t, J = 28.5 Hz), 126.3, 125.9 (2C), 119.1 (2C), 104.7 (t, J =
3H), 7.68 (d, J = 8.4 Hz, 2H), 7.48−7.44 (m, 2H), 7.39−7.35 (m,
1H), 7.30−7.28 (m, 2H), 6.79 (d, J = 2.4 Hz, 1H), 2.43 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 152.7, 138.1, 136.1, 133.3, 129.9,
128.6, 127.9, 125.8, 119.1, 104.7, 21.0. Two signals are overlaid by the
other signals. HRMS (ESI) Calcd for C16H15N2+ [M + H]+ 235.1230,
found 235.1220.
+
26.4 Hz), 21.4. HRMS (ESI) Calcd for C16H13D2N2 [M + H]+
1-(4-Bromophenyl)-3-phenyl-1H-pyrazole (4u). Yield 60 mg
(99%). Beige solid; mp 133−134 °C (lit. 135−146 °C).34 1H NMR
(400 MHz, CDCl3) δ 7.93−7.90 (m, 3H), 7.68−7.64 (m, 2H), 7.60−
7.56 (m, 2H), 7.46−7.43 (m, 2H), 7.38−7.34 (m, 1H), 6.78 (d, J = 2.5
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.4, 139.3, 133.0,
132.6 (2C), 128.8 (2C), 128.3, 128.0, 126.0 (2C), 120.5 (2C), 119.6,
237.1355, found 237.1348.
4,5-Dideutero-1-phenyl-3-(3-tolyl)-1H-pyrazole (5d). Yield 47 mg
1
(99%). Beige solid; mp 69−71 °C. H NMR (400 MHz, CDCl3) δ
7.81−7.78 (m, 3H), 7.74 (d, J = 7.7 Hz, 1H), 7.51−7.45 (m, 2H),
7.37−7.29 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H, CH3).
13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 140.4, 138.4, 133.1, 129.5
H
DOI: 10.1021/acs.joc.8b00155
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2C), 128.9, 128.7, 127.7 (t, J = 28.8 Hz), 126.6, 126.4, 123.1, 119.1
(2C), 104.9 (t, J = 26.8 Hz), 21.6. HRMS (ESI) Calcd for
h) to avoid vigorous reaction of CaC2 with water. Then, the reaction
was stirred at room temperature for 72 h. After completion of the
reaction, the contents of the second vessel were collected by a syringe,
washed thrice with water, and dried over sodium sulfate. The resulting
solution was additionally passed through a layer of silica gel. The
evaporation of the solvent gave pure 4a (731 mg, 95%).
+
C16H13D2N2 [M + H]+ 237.1355, found 237.1355.
4,5-Dideutero-3-(3,4-dimethylphenyl)-1-phenyl-1H-pyrazole (5f).
1
Yield 49 mg (98%). Beige solid; mp 75−77 °C. H NMR (400 MHz,
CDCl3) δ 7.78 (dd, J = 8.5, 0.9 Hz, 2H), 7.74 (s, 1H), 7.65 (dd, J =
7.8, 1.3 Hz, 1H), 7.49−7.45 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.21 (d,
J = 7.8 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 153.2, 140.4, 136.9, 136.6, 130.8, 130.0, 129.5 (2C), 127.7
(t, J = 28.8 Hz), 127.1, 126.3, 123.5, 119.1 (2C), 104.7 (t, J = 26.8
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00155.
+
Hz), 19.9, 19.7. HRMS (ESI) Calcd for C17H15D2N2 [M + H]+
251.1512, found 251.1500.
4,5-Dideutero-1,3-diphenyl-1H-pyrazole (5h). Yield 44 mg (99%).
Beige solid; mp 83−85 °C. 1H NMR (400 MHz, CDCl3) δ 7.97−7.95
(m, 2H), 7.81−7.78 (m, 2H), 7.50−7.44 (m, 4H), 7.37 (t, J = 7.4 Hz,
1H), 7.30 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
153.0, 140.3, 133.3, 129.5 (2C), 128.8 (2C), 128.1, 127.8 (t, J = 28.4
Hz), 126.4, 126.0 (2C), 119.1 (2C), 104.8 (t, J = 26.7 Hz). HRMS
Photographs of the two-chamber reactor and experi-
ments, copies of 1H, 13C NMR, and 19F NMR spectra for
new compounds, and details on DFT calculations (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: val@ioc.ac.ru.
ORCID
■
+
(ESI) Calcd for C15H11D2N2 [M + H]+ 223.1199, found 223.1205.
3-(4-Bromophenyl)-4,5-dideutero-1-phenyl-1H-pyrazole (5i).
1
Yield 59.5 mg (99%). Beige solid; mp 123−125 °C. H NMR (400
MHz, CDCl3) δ 7.81−7.75 (m, 4H), 7.57−7.54 (m, 2H), 7.49−7.45
(m, 2H), 7.31 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 151.9, 140.2, 132.3, 131.9 (2C), 129.6 (2C), 127.5 (2C), 126.6,
122.1, 119.2 (2C), 104.8 (t, J = 27.3 Hz). HRMS (ESI) Calcd for
Valentine P. Ananikov: 0000-0002-6447-557X
Notes
The authors declare no competing financial interest.
+
C15H10BrD2N2 [M + H]+ 303.0283, found 303.0293.
3-(3,4-Dichlorophenyl)-4,5-dideutero-1-phenyl-1H-pyrazole (5k).
Yield 57 mg (98%). Beige solid; mp 102−104 °C. H NMR (400
ACKNOWLEDGMENTS
1
■
Experimental work was supported by Russian Science
Foundation (RSF grant 16-13-10301). Theoretical study was
supported by Russian Foundation for Basic Research (grant 17-
03-01148). The authors also express their gratitude to the
Resource Centers of Saint Petersburg State University:
Magnetic Resonance Research Centre; Chemical Analysis and
Materials Research Centre.
MHz, CDCl3) δ 8.02 (d, J = 2.0 Hz, 1H), 7.76−7.71 (m, 3H), 7.50−
7.46 (m, 3H), 7.32 (t, J = 7.4 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 150.7, 140.1, 133.4, 133.0, 131.8, 130.7, 129.6 (2C), 127.7,
126.8, 125.1, 119.2 (2C), 104.9 (t, J = 26.4). HRMS (ESI) Calcd for
+
C15H9Cl2D2N2 [M + H]+ 291.0419, found 291.0421.
4,5-Dideutero-3-(2-fluorophenyl)-1-phenyl-1H-pyrazole (5m).
1
Yield 47.5 mg (99%). Beige solid; mp 63−65 °C. H NMR (400
MHz, CDCl3) δ 8.19 (td, J = 7.7, 1.8 Hz, 1H), 7.80−7.78 (m, 2H),
7.48 (t, J = 8.0, Hz, 2H), 7.35−7.29 (m, 2H), 7.23 (td, J = 7.6, 1.2 Hz,
1H), 7.16 (ddd, J = 11.2, 8.2, 1.0 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.5 (d, J = 249.5 Hz), 147.7, 140.3, 129.6 (2C), 129.4 (d,
J = 8.4 Hz), 128.7 (d, J = 3.6 Hz), 127.6 (t, J = 29.4 Hz), 126.6, 124.4
(d, J = 3.5 Hz), 121.1 (d, J = 11.9 Hz), 119.3 (2C), 116.2 (d, J = 22.3
Hz). 19F NMR (376 MHz, CDCl3) δ −115.96 ppm. HRMS (ESI)
REFERENCES
■
(1) (a) Elguero, J. Comprehensive Heterocyclic Chemistry; Katritzky, A.
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+
Calcd for C15H10D2FN2 [M + H]+ 241.1105, found 241.1100.
4,5-Dideutero-3-(1-(4-isobutylphenyl)ethyl)-1-phenyl-1H-pyra-
1
zole (5q). Yield 59 mg (99%). Isotopic purity 99%. Yellow oil. H
NMR (400 MHz, CDCl3) δ 7.70−7.68 (m, 2H), 7.45−7.41 (m, 2H),
7.27−7.23 (m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 4.29 (q, J = 7.2 Hz, 1H),
2.46 (d, J = 7.2 Hz, 2H), 1.92−1.82 (m, 1H), 1.72 (d, J = 7.2 Hz, 3H),
0.92 (d, J = 6.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.0,
142.9, 140.5, 139.6, 129.4 (2C), 129.2 (2C), 127.3 (2C), 127.0 (t, J =
28.3 Hz), 126.0, 119.1 (2C), 105.7 (t, J = 26.6 Hz), 45.2, 39.1, 30.3,
(5) Faidallah, H. M.; Khan, K. A.; Asiri, A. M. J. Fluorine Chem. 2011,
132, 131.
+
22.6 (2C), 21.7. HRMS (ESI) Calcd for C21H23D2N2 [M + H]+
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Med. Chem. 2009, 44, 3480.
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Berliner, M. A. Tetrahedron Lett. 2006, 47, 3727.
307.2138, found 307.2131.
1-(4-Bromophenyl)-4,5-dideutero-3-phenyl-1H-pyrazole (5u).
Yield 59.5 mg (99%). Beige solid; mp 137−138 °C. H NMR (400
1
MHz, CDCl3) δ 7.93−7.91 (m, 2H), 7.68−7.64 (m, 2H), 7.59−7.56
(m, 2H), 7.46−7.43 (m, 2H), 7.38−7.34 (m, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 153.3, 139.3, 133.0, 132.6 (2C), 128.8 (2C),
128.3, 127.7 (t, J = 28.7 Hz), 126.0 (2C), 120.5 (2C), 119.5, 105.3 (t, J
+
= 26.7 Hz). HRMS (ESI) Calcd for C15H10BrD2N2 [M + H]+
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Gentili, D.; Locatelli, E.; Ricci, A. Synlett 2009, 2009, 2328.
303.0283, found 303.0277.
Synthesis of 4a in a Larger Scale. For this reaction, a 45 mL
capacity two-chamber reactor was utilized. The first vessel of the
reactor was loaded with 1.6 g of calcium carbide and 3.0 mL of CHCl3.
Then, 800 mg (2.79 mmol) of 4-(tert-butyl)-N-phenylbenzohydrazo-
noyl chloride 3a with 16.0 mL of CHCl3 was loaded to the second
vessel. Next, triethylamine (0.777 mL, 5.58 mmol) was added to the
hydrazonoyl chloride solution, and 1.6 mL of distilled water was
poured into the carbide vessel. The reactor was immediately sealed,
and the stirring was gradually turned on (from 300 to 1100 rpm for 2
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̧
I.-T.; Zimmermann, T.; Schuth, F. Chem. Rev. 2014,
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I
DOI: 10.1021/acs.joc.8b00155
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Article
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DOI: 10.1021/acs.joc.8b00155
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