Primary Vinyl Ethers as Acetylene Surrogate: A Flexible Tool for Deuterium-Labeled Pyrazole Synthesis

Article abstract of DOI:10.1002/ejoc.202000674

A novel synthetic path to 1,3-disubstituted pyrazoles and their deuterated derivatives was developed. It is based on the reaction of vinyl ethers with hydrazonoyl chlorides in the presence of triethylamine. The reaction mechanism, clarified by the joint experimental and computational study, involves 1,3-dipolar cycloaddition of the in situ generated nitrile imines to vinyl ethers and subsequent cleavage of alcohol from the formed alkoxypyrazoline. The results highlight the possibility of using vinyl ethers as acetylene surrogate and provide a novel access to pyrazoles, 4,5-dideuteropyrazoles and their regioselectively labeled derivatives, 5-deuteropyrazoles.

Full text of DOI:10.1002/ejoc.202000674

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Primary Vinyl Ethers as Acetylene Surrogate: a Flexible Tool for
Deuterium-Labeled Pyrazole Synthesis
Authors: Maria Ledovskaya, Vladimir Voronin, Mikhail Polynski, Andrey
Lebedev, and Valentine P. Ananikov
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000674
Link to VoR: https://doi.org/10.1002/ejoc.202000674
01/2020

10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Primary Vinyl Ethers as Acetylene Surrogate: a Flexible Tool for
Deuterium-Labeled Pyrazole Synthesis
Maria S. Ledovskaya,[a] Vladimir V. Voronin,[a] Mikhail V. Polynski,[a,b] Andrey N. Lebedev[a] and
Valentine P. Ananikov*[a,b]
[a]
[b]
M.S. Ledovskaya, V.V. Voronin, M.V. Polynski, A.N. Lebedev, Prof. Dr. V.P. Ananikov
Institute of Chemistry
Saint Petersburg State University
Universitetsky prospect 26, Peterhof, 198504, Russia
E-mail: val@ioc.ac.ru
M.V. Polynski, Prof. Dr. V.P. Ananikov
N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences
Leninsky prospect 47, Moscow, 119991, Russia
Supporting information for this article is given via a link at the end of the document.
Abstract: A novel synthetic path to 1,3-disubstituted pyrazoles and
their deuterated derivatives was developed. It is based on the
reaction of vinyl ethers with hydrazonoyl chlorides in the presence of
triethylamine. The reaction mechanism, clarified by the joint
experimental and computational study, involves 1,3-dipolar
cycloaddition of the in situ generated nitrile imines to vinyl ethers and
subsequent cleavage of alcohol from the formed alkoxypyrazoline.
The results highlight the possibility of using vinyl ethers as acetylene
growing demand for deuterium-labeled compounds and the
interest in new methods for isotope labeling.
Studying vinyl ethers, we stumbled across an interesting
opportunity of applying them as acetylene surrogates. The idea
was tested in a synthesis of non-labeled, dideuterated and
regioselectively labeled 5-deuteropyrazoles (Scheme 1, [c]). In
this study, for the first time was proposed a detailed mechanistic
investigation of the reaction between vinyl ethers and in situ
generated nitrile imines, resulting into the novel synthetic
approach to 1,3-disubstituted pyrazoles and their mono- and
dideuterated derivatives.
surrogate and provide
a
novel access to pyrazoles, 4,5-
dideuteropyrazoles and their regioselectively labeled derivatives, 5-
deuteropyrazoles.
Scheme 1. Аcetylene surrogates in chemical processes.
Introduction
With the triple bond prone to additions and two active C-
bonded protons, acetylene is invaluable for
a variety of
transformations.[1] However, its synthetic potential cannot be
fully implemented because bulk gaseous acetylene is flammable
and explosive.[1a, 1c] Safer replacements for acetylene have been
proposed, including dihaloethanes,[2] vinylene carbonate,[3]
mono-functionalized ethylenes,[4] substituted alkynes with a
potent leaving group,[5] and some other molecules.[6] Application
of some of these acetylene surrogates may imply an additional
step (to get rid of the leaving group) or/and involve the use of
specific reagents for activation (Scheme 1, [a]).[2-6]
Among the acetylene surrogates, calcium carbide
represents a highly efficient and convenient acetylene source. It
reacts with water to produce acetylene. This procedure can be
safely performed on any scale and is perfect for the in situ
acetylene generation in laboratory settings.[7] It provides a
convenient access to pyrazoles and 4,5-dideuteropyrazoles
(when using D2O instead of water, Scheme 1, [b]).[8] Despite its
convenience, deuteration with CaC2 is of limited scope and
requires application of aprotic or deuterated solvents to achieve
high levels of deuterium incorporation.[8-9]
Results and Discussion
A
preliminary 1H NMR investigation of the reaction
mixtures with a variety of nitrile imine sources, hydrazonoyl
chlorides, and vinyl ethers in the presence of base demonstrated
the possibility for their direct transformation to pyrazoles, but not
pyrazolines, as we could expect (as depicted in Table 1). This
transformation seemed very promising, so we decided to
investigate it in detail. The readily available tert-butyl substituted
hydrazonoyl chloride 1a was reacted with benzyl vinyl ether 2a
in different solvents (Table 1, Entries 1-14) and the best results
were observed in benzene (Table 1, Entries 8,9). After varying
concentration of 2a (Table 1, Entries 6, 9-11) and reaction time
(Table 1, Entries 9, 14), the best conditions were founded. The
spectral yield of 3a reached 93% at 80 °C starting from 70 mg/ml
concentration of 2a (Table 1, Entry 9).
The importance of deuterated substances in chemistry,[10]
medical biology[11] and physics[12] is undeniable.[13] D-labeled
compounds allow studying reaction mechanisms[14] and altering
reaction selectivities[15] in total syntheses of complex
pharmaceuticals. They are extensively used in pharmacokinetic
studies.[11, 16] The first deuterated drug, deutetrabenazine, has
been recently approved by FDA.[17] This milestone reflects the
1
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10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of the reaction conditions.
[a] Reaction conditions: 1a-m (1.5 mmol), 2a (1.0 mmol), benzene (2.0 ml),
triethylamine (1.5 mmol), 80 °C, 24 h. [b] Isolated yields are given. [c] The
reaction time was 48 h.
Concentration
of 2a, mg/ml
Yield of
Entry
Solvent
T, ° C
Time, h
3a, %[b]
1
2
CH2Cl2
CHCl3
20
20
20
20
20
20
70
70
70
50
100
70
70
70
35
35
50
50
50
50
50
50
80
80
80
80
80
80
96
96
96
96
96
96
96
96
24
24
24
24
24
12
7
10
We have previously proposed a methodology for the
synthesis of D3-vinyl ethers from the mixture of alcohol, calcium
carbide and D2O.[18] To its certain disadvantage, the procedure
depends on the use of DMSO-d6 as a solvent and a substrate for
the D3-vinyl group formation. Besides, DMSO-d6 has been
shown to participate in side H-D exchange processes with active
protons e.g. the CH2 protons in benzyl alcohol.[18] As vinylations
can be also carried out in 1,4-dioxane[19] which do not enter in
any role to the hydrogen exchange processes,[20] we attempted
to use 1,4-dioxane as a solvent instead of DMSO to avoid the
undesirable H-D exchange and make the procedure more
economic. We modified the procedure by diluting a small
amount of DMSO-d6 with 1,4-dioxane. The modified procedure
afforded benzyl D3-vinyl ether 2b in 94% yield with 96% isotopic
purity (Scheme 2, see Supporting Information for details). No
side exchange processes involving the CH2 protons in benzyl
group were observed during the procedure.
3
CHCl3
13
4
CH3CN
toluene
benzene
CHCl3
47
5
45
6
47
7
63
8
benzene
benzene
benzene
benzene
CH3CN
toluene
benzene
75
9
93 (90)
83
10
11
12
13
14
86
71
70
77
[a] Reaction conditions: 1a (1.5 equiv), 2a (6-30 μl, 0.045-0.225 mmol), solvent
(300 μl), triethylamine (1.5 equiv), temperature, time. [b] Spectral yields are
given; the isolated yield for Entry 9 is shown in parentheses.
With the optimized conditions in hand, we tested a scope
of hydrazonoyl chlorides 1a-m to obtain the corresponding
pyrazoles 3a-m (see Table 2 for the details). Among them, 3-(4-
tert-butyl)phenyl-, 3-(4-tolyl)-, 3-(4-methoxyphenyl)- and 3-(4-
bromophenyl)-substituted N-phenylpyrazoles 3a-c and 3e were
obtained in 90-99% isolated yields, and 1,3-diphenylpyrazole 3d
was obtained in 96% yield. To achieve full conversion of benzyl
vinyl ether 2a in the reaction with nitro-substituted hydrazonoyl
chloride 1f, the reaction time was increased to 48 h to afford the
desired pyrazole 2f in 91% yield. The yield of 3-(3,4-
dichlorophenyl)- derivative 3g was high, 88%. N-(4-Tolyl)- and
N-(4-bromophenyl)-functionalized pyrazoles 3h and 3i were
obtained in 88% and 89% yields, respectively. The yields of N-
(4-fluorophenyl) derivatives 3j and 3m were nearly quantitative.
Scheme 2. Synthesis of benzyl D3-vinyl ether 2b.
Reaction conditions: CaC2 (2.0 mmol), benzyl alcohol (0.7 mmol), KOtBu (0.7
mmol), KF (0.9 mmol), DMSO-d6 (120 μl), D2O (4.0 mmol), 1,4-dioxane (1.0
ml), 110 oC, 4 h.
Benzyl D3-vinyl ether 2b (synthesized from the readily
available benzyl alcohol, calcium carbide and D2O by the
upgraded D3-vinylation procedure) was reacted with various
hydrazonoyl chlorides to afford 4,5-dideuteropyrazoles 4a-m
(Table 3). Among them, the donor-substituted 4,5-D2-pyrazoles
4a-c, 4,5-dideutero-1,3-diphenylpyrazole 4d, and a bromo-
derivative 4e were obtained in 93-99% isolated yields. The yield
of nitro-substituted dideuteropyrazole 4f was good, 85%. 4,5-D2-
pyrazoles 4h and 4i were obtained in 96% and 90% yields,
respectively. The yield of 4,5-dideutero-1,3-di(4-tolyl)pyrazole 4k
was moderate (66%), whereas 4m was obtained in nearly
quantitative yield.
1,3-Di(4-tolyl)pyrazole
3k
and 3-(4-methoxyphenyl)-1-(4-
tolyl)pyrazole 3l were obtained in good yields (77% and 89%,
respectively).
Table 2. A scope of products for the transformation with benzyl vinyl ether.[a,b]
2
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10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Table 3. A scope for the transformation of benzyl D3-vinyl ether 2b.[a,b]
Table 4. NMR study of the reaction mixtures.
Ratio[b]
Time,
h
Entry
Substrate (R1)
T, °C
2a
5
6
3
1a (4-tBuC6H4)
40
80[c]
20
24
24
68
3
0
0
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
32
97
1
2
1a
1b (4-MeC6H4)
120
24
15
0
0
85
3
1b
40
80[c]
0
100
100
41
4
1b
24
0
0
5
1c (4-MeOC6H4)
20
120
24
17
4
42
0
6
1c
40
80[c]
96
7
1c
24
0
0
100
16
8
1d (Ph)
20
120
24
16
5
68
0
9
1d
40
80[c]
95
10
11
12
13
14
15
16
17
18
19
[a] Reaction conditions: 1a-m (1.5 mmol), 2b (1.0 mmol), benzene (2.0 ml),
triethylamine (1.5 mmol), 80 °C, 24 h. [b] Isolated yields are given; deuterium
incorporation corresponds to the level observed for 2b (96%). [c] The reaction
time was 48 h.
1d
24
0
0
100
11
1e (4-BrC6H4)
20
120
24
28
23
22
21
0
61
15
1
1e
40
62
1e
40
48
77
1e
40
80[c]
120
24
<1
0
79
1e
100
22
Further, the study of the reaction mechanism was
performed. For this purpose, reaction mixtures with six selected
hydrazonoyl chlorides 1a-f and benzyl vinyl ether 2a were
investigated by 1H NMR at various conditions (Table 4). In some
cases, pyrazoline intermediate was revealed and it was
invariably detected as a single regioisomer 5. The alternative
regioisomer 6 was not observed. The reactions with alkylphenyl-
substituted hydrazonoyl chlorides 1a and 1b were too fast to
allow “catching” the intermediate, with only the starting vinyl
ether 2a and the final aromatic products 3a,b observed in the
reaction mixture (Table 4, Entries 1-5). The use of 4-
methoxyphenyl- or phenyl-substituted substrates allowed
observation of intermediates, respectively, 5c and 5d by 1H
NMR at room temperature (Table 4, Entry 6,9). At elevated
temperatures these intermediates were not detected in the
reaction mixtures (Table 4, Entries 6-11).
1f (4-NO2C6H4)
50
72
22
10
9
56
81
13
1f
1f
50[c]
80[c]
72
9
24
78
1f
80[c]
48
7
0
ND
93
20
[a] Reaction conditions: 1a-f (0.224 mmol), 2a (0.15 mmol), CHCl3 (300 μl),
triethylamine (0.224 mmol), time, temperature. [b] Molar percents for the
components are given. [c] The reactions were carried out in benzene.
With the results of NMR investigation in our hands, we
performed a series of regioselective D-labeling experiments.
Decyl 1-deuterovinyl ether 8 was synthesized by consequent
lithiation of decyl vinyl ether 7 and treatment of the resulting
organolithium compound by D2O (Scheme 3, upper line). At first,
the reaction of decyl vinyl ether 7 with hydrazonoyl chlorides
was investigated. The reactivity of decyl vinyl ether 7 under
optimized conditions was exceptionally good: tert-butyl- and
nitrophenyl-substituted substrates 1a and 1f were transformed
into pyrazoles 3a and 3f in 94 and 93% yields, respectively
(Scheme 3). After that, decyl 1-deuterovinyl ether 8 was applied
in cycloaddition reactions under optimized conditions, giving 5-
The use of substrates 1e and 1f with 4-bromo- and 4-
nitrophenyl substituents allowed detection of corresponding
1
intermediates 5 even under heating (Table 4, Entries 12-20). H
NMR signals for the CH(OBn) group in 5e and 5f were observed
at 5.95 ppm (dd, J = 8.7, 2.3 Hz) and 6.04 ppm (dd, J = 8.7, 2.3
Hz), respectively. 1H NMR signals for pyrazoline CH2-group
proton in 5e and 5f were observed at 3.24 ppm (dd, J = 18.3, 2.3
Hz) and 3.30 ppm (dd, J = 18.5, 2.3 Hz), respectively; the
signals for the second proton of CH2 group partially overlapped
with the standard. The mixture with 4-nitrophenyl derivative 1f
deuteropyrazoles
9
in up to 95% yields with 100%
regioselectivity (Scheme 3). Thus, the proposed methodology
turned out to be highly suitable for the regioselective synthesis
of 5-deuterated pyrazoles in mild conditions.
was additionally examined by HRMS-ESI, and
a peak
corresponding to the intermediate 5f was clearly detected
(C22H19N3O3Na+, m/z 396.1304).
3
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10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Scheme 3. Application of decyl vinyl ether 7 and its D-labeled derivative 8 for
the synthesis of pyrazoles 3 and 5-deuteropyrazoles 9.[a]
pre-addition intermediate (10' or 10'') is endergonic, as
estimated at the ωB97X-V/def2-TZVP-gCP//GFN2-xTB level.
Apparently, the loss in translational entropy upon its formation is
greater than the gain in enthalpy upon its binding to 2a. Due to
the relative instability of 10' or 10'', we estimated 10⟶TS1 and
10⟶TS2 as the activation free energy of cycloaddition.
Scheme 4. Model paths for the transformation of in situ generated nitrile imine
to pyrazole (1⟶3); see Figures 1 and S37 as an example of optimized
structures.
[a] Reaction conditions are specified in Tables 2,3; isolated yields are given in
the scheme. [b] The reaction time was 48 h.
We obtained independent evidence for the prevalence of
1⟶5⟶3 path by performing quantum chemical modeling of the
underlying cycloaddition process. Two possible paths are shown
in Scheme 4. The modeled process starts with formation of two
alternative pre-addition intermediates (10' or 10'' at Scheme 4).
On a qualitative level, cycloaddition regioselectivity can be
explained by the consideration of Lewis’ structures of 10' and
10''. In 10' and, as well as in TS1, the negatively charged N
atom interacts with the electron-deficient carbon atom adjacent
to the withdrawing substituent -OBn. Analysis of Mulliken
charges in 10' and 10'' corroborates this qualitative prediction,
see Figure 1. For simplicity, we computed Mulliken charges at
the ZINDO/S//GFN2-xTB level of theory for the case of R = H.
Clearly, electrostatic interaction in 10' facilitates the formation of
the transition state TS1.
Figure 1. Optimized geometries at the GFN2-xTB level of the pre-
cycloaddition intermediates 10' and 10'' and Mulliken charges (in a.u) at the
ZINDO/S//GFN2-xTB level (dotted lines connect the bonding atoms.).
Concerted dipolar cycloaddition proceeds via a five-
membered ring transition state (TS1 or TS2 at Scheme 4). The
reaction product is formed by elimination of benzyl alcohol at the
final stage (5⟶3 or 6⟶3). We compared thermodynamics and
kinetics of 10⟶5 and 10⟶6. Calculated Gibbs free energies of
the benzyl vinyl ether addition to nitrile imine 10 (a
dehydrohalogenated derivative of 1) in benzene (with solvation
accounted for by SMD) are given in Table 5. Formation of the
4
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10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Table 5. Free energies (kcal/mol) calculated for the transformations shown in Scheme 4, as modeled at the ωB97X-V/def2-TZVP-gCP//GFN2-xTB level with SMD
for benzene (see Supporting Information for the results of B97-3c-based modeling).
[b]
R[a]
10⟶10'
10'⟶5
10⟶TS1
5⟶3
10⟶10''
10''⟶6
10⟶TS2
6⟶3
∆∆Grxn
∆∆G≠[c]
Entry
1
2
3
4
5
Br
H
5.8
6.3
6.2
6.3
6.1
-64.0
-63.2
-62.7
-65.1
-62.8
22.8
22.3
23.8
21.3
23.8
-18.6
-18.7
-18.5
-19.3
-18.2
8.0
7.3
7.6
6.1
7.1
-61.7
-59.9
-59.6
-61.0
-59.1
28.0
29.0
28.7
27.1
28.4
-23.2
-23.0
-23.0
-23.4
-23.0
0.1
2.4
1.8
4.3
2.6
5.2
6.6
4.8
5.8
4.6
Me
NO2
OMe
[a] The para-substituent, see Scheme 4; [b] ∆∆Grxn is the difference between ∆G10 6 and ∆G10 5; [c] ∆∆G≠ is the difference between ∆G10 TS2 and ∆G10
⟶
TS1
.
⟶
⟶
⟶
The calculated activation free energies of cycloaddition
ranged from 21.3 to 23.8 kcal/mol for TS1 and from 27.1 to 28.4
kcal/mol for TS2 (Table 5). More detailed structural information
is given in Supporting Information. The left path in Scheme 4
proceeds over a barrier below 24 kcal/mol, which allows
cycloaddition at room temperature within hours.[21] By contrast,
the right path in Scheme 4 at ambient conditions is kinetically
forbidden.
In all modeled cases, cycloaddition was highly exergonic.
Formation of intermediate 5 was thermodynamically preferred
over formation of 6 in all cases except R = Br. Both kinetic and
thermodynamic favorability of 5 is consistent with the lack of
detectable 6 in the experimental mixtures. At the same time, the
strong preference for 5 explains the perfect regioselectivity of
deuteration (Scheme 3).
As shown by Hammett equation-based analysis, nature of
the substituent moderately affects the cycloaddition kinetics
(Figure 2). Slopes of the Hammett plots for 10⟶TS1 and
10⟶TS2 are -2.3 and -1.5 kcal/mol per σ unit, respectively,
which is flat, considering that the corresponding intercepts are
23.0 and 28.4 kcal/mol. For the favored path 1⟶5⟶3 via TS1,
the effect is more pronounced, which indicates more facile
formation of 5 for the substrates with electron-withdrawing
substituents, e.g. R = NO2, compared to the substrates with
donating substituents.
dehydrobenzylation by using the implicit solvent approach at the
selected level of theory. The existence of both E1 and E2 should
not be excluded in further studies. For now, we will accept a post
hoc explanation corroborated by experimental evidence and
given below.
The increased kinetic stability of
5 with electron-
withdrawing para-substituents is consistent with the E1
elimination mechanism, if we assume the validity of the
Brønsted–Evans–Polanyi principle to estimate the activation
energy Ea for this stage:
Ea ∝ ∆H5
,
⟶
5'
Table 6 shows that relative enthalpy of the endothermic
BnO− dissociation ∆H5
becomes more pronounced as the
⟶
5'
electron-withdrawing effect of
R increases. The electron-
withdrawing NO2- and Br-substituents destabilize the conjugated
cation 5' and therefore may hamper the 5⟶3 transition.
Some extra single-point energy evaluations were
performed
to
independently
estimate
kinetics
and
thermodynamics of the elementary reactions depicted in
Scheme 4. Switching computational method to B97-3c//GFN2-
xTB significantly reduced the exergonic effects of 1'⟶5 and
1''⟶6 cycloadditions by +17.0 kcal/mol on average (depending
on the substituent R, see Supporting Information).
A
concomitant average decrease in the free energy of activation
for cycloaddition stage was -6.4 kcal/mol. The B97-3c is a
computationally cheap yet accurate method, according to
benchmarks;[23] nevertheless, calculations with the ωB97X-V
functional can be significantly more accurate for the prediction of
cycloaddition thermodynamics.[24] It should also be noted, that
both levels of theory give, qualitatively, the same results.
Therefore, the computations at the B97-3c//GFN2-xTB level,
presented in Supporting Information, generally confirm the
proposed mechanism.
Figure 2. Effect of the substituent on the activation free energy of
cycloaddition. Least squares regression lines are given in red and blue.
Hammett parameters were adopted from [22]
.
Table 6. Dissociation of BnO− from
5
and the corresponding reaction
enthalpies.
R
∆H5
σ [b]
[a]
Entry
⟶
5'
1
2
3
4
5
Br
H
4.0
1.9
0.9
6.6
0
0.23
0.0
The final stage, dehydrobenzylation, is highly exergonic
irrespective of the para-substituent R and the path, 5⟶3 or
6⟶3 (Table 5). At the same time, we saw that with the electron-
withdrawing NO2-group in 1f, intermediate 5 accumulated in the
system and persisted even at an elevated temperature of 80 °C.
A similar effect, though less pronounced, was observed for 1e.
We could not locate neither E1 nor E2 transition states of
Me
−0.17
0.78
−0.27
NO2
OMe
[a] Calculated at the ωB97X-V/def2-TZVP-gCP//GFN2-xTB level.
[b] The Hammett σ values were adopted from ref. [22]
5
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Transition state structures were determined as follows. First, a
coarse reaction path was generated by invoking the NEB procedure with
initial path generation at the GFN2-xTB level.[30] The highest energy point
in the reaction path was used for transition state optimization at the
GFN2-xTB level. All transition states exhibited one imaginary mode with
vibration vector directed along the reaction path, according to post-
optimization normal mode analysis.
To summarize, transformation 10⟶3, as a whole, is a
thermodynamically favorable and kinetically feasible process
that takes 10⟶5⟶3 pathway. Accordingly, excellent yields have
been obtained in almost all cases under elevated temperatures
(Tables 2,3 and Scheme 3). The nature of para-substituent R in
1 has opposite effects on the kinetics of cycloaddition and
dehydrobenzylation stages.
Single-point calculations with the B97-3c method[23] were
performed for quick evaluation of energies for the GFN2-xTB-optimized
geometries. Resolution of the identity (RI) approximation[31] and,
accordingly, the auxiliary basis set def2-mTZVP/J[23] were used in the
B97-3c calculations. Tight convergence criteria were set for the KS-SCF
procedure (“TightSCF” option). We selected a dense integration grid for
the energy evaluations (GRID6) and switched off the FINALGRID option.
Single-point energy evaluations at the ωB97X-V/def2-TZVP-gCP
level[32] was also performed. In these calculations, we applied the
RIJCOSX approximation and, implicitly, used the Def2/J auxiliary basis
set.[33] The non-local dispersion energy terms were evaluated self-
consistently. The “GridX9” and “vdwgrid4” parameters were set; all other
parameters were used without change from the previous settings.
Mulliken charges were computed in single-point calculations within
the restricted Hartree-Fock formalism at the ZINDO/S level[34] using the
structures optimized with the GFN2-xTB method, as described above.
Tight convergence criteria were set in the SCF procedure by setting the
“TightSCF” option.
Conclusion
The article provides detailed analysis of the reaction
between vinyl ethers and in situ generated nitrile imines. The
interaction leads to 5-alkoxydihydropyrazoles, which are rapidly
converted to pyrazoles. A reaction mechanism was confirmed by
NMR study and computational study, which demonstrated the
excellent regioselectivity of the first step, [3+2] cycloaddition
reaction leading to the formation of intermediate, 5-
alkoxydihydropyrazole.
The mechanistic investigation resulted in the development
of the novel access to 1,3-disubstituted pyrazoles, 4,5-
dideuteropyrazoles
and
regioselectively
labeled
5-
Bulk solvent effects were accounted for by applying the SMD
model.[35] The M06-2X functional and the 6-31+G** basis set[36] were
used in KS-SCF equation solving. Due to the absence of 6-31+G**
parameters for Br, we selected the LANL2DZ basis set[37] in this case;
hence, a certain decrease in accuracy may be expected for the
molecules with Br substituents. In SMD calculations, the RIJCOSX
approximation and the Def2/J basis set were used. The grid density and
convergence criteria were used without change from the previous
settings. The Gibbs free energies of solvation were calculated as a
difference between the total energies of molecules with the SMD option
switched on and off. Free energies of species in solution ( ) were
calculated according to equation given below:
deuteropyrazoles. The application of only 1 equivalent of
deuterated substrate and no necessity in deuterated solvent for
the synthesis of D-labeled pyrazoles means high cost efficiency
of the approach.
As a side chain of the work, an economic and efficient
procedure for benzyl D3-vinyl ether synthesis was proposed.
Transformation of the readily available calcium carbide,
deuterium oxide and benzyl alcohol in the presence of a base
and a small admixture of DMSO-d6, with 1,4-dioxane as a
solvent, leads to benzyl D3-vinyl ether in excellent yield and with
≥96% deuterium incorporation. Probably, further use of this
approach can afford a wide range of D3-vinyl derivatives with no
side exchange processes.
,
Where
V/def2-TZVP-gCP level,
corrections computed with GFN2-xTB method within the ideal gas, quasi-
rigid rotor, and harmonic oscillator approximations,[29] and
is the
is the total energy of a molecule A computed at the ωB97X-
is the sum of thermochemical
correction term that is equal to 1.89 kcal/mol. The latter term accounts for
the change of the system state from the ideal gas at 298 K and 1 atm to
the 1 M solution.
Optimized geometries and visualizations of imaginary modes (for
transition states) are available in XYZ format in Supporting Information
(zip archive). Additional calculations were performed to confirm a good
correspondence between geometries optimized with DFT (B97-3c) and
tight binding (GFN2-xTB) methods (described in Supporting Information).
Experimental Section
General: All chemicals were purchased from Sigma Aldrich, Alfa Aesar
and Acros Organics in reagent grade or better quality and used without
further purification. Hydrazonoyl chlorides were synthesized by the
procedure reported previously.[25] D-vinyl ether was synthesized by the
method of Basu and Marnett.[26] NMR spectra were recorded on a Bruker
Avance III spectrometer (1H 400 MHz; 13C 101 MHz, 19F 376 MHz).
Chemical shifts are reported in ppm relative to residual CHCl3 (1H,
=
7.26) and CDCl3 (13C, = 77.16) as internal standard. High-resolution
mass spectra (HRMS) were recorded on a Bruker micrOTOF 10223
spectrometer using electrospray ionization (ESI). Reactions were
monitored by TLC analysis using Merck UV-254 plates. Preparative
column chromatography was performed on Merck silica gel 60 (230-400
Mesh) that was previously treated with triethylamine.
General procedure for the synthesis of pyrazoles
The reaction tube was loaded with 1.0 mmol of vinyl ether 2, 7 or 8 and
hydrazonoyl chloride 1a-o (1.5 mmol). Then, 2 ml of dry benzene and 1.5
mmol of triethylamine were added, the tube was sealed and heated at
80 °C for 24 hours. After, the solvent was evaporated, and the resulting
pyrazole was purified by column chromatography (SiO2, hexane/ethyl
acetate 10:1).
Computational details
ORCA 4.2.1 program package[27] was used to perform restricted
Kohn-Sham and Hartree-Fock calculations. Only (S)-enantiomers were
modeled. Gas-phase geometry optimizations were performed at the
GFN2-xTB level of theory.[28] Vibrational frequency analysis was
conducted to check whether the obtained geometries were true energy
minima, and no imaginary frequencies were encountered. The calculated
vibrational frequencies were used in the calculations of gas-phase Gibbs
free energies within the ideal gas-QRRHO approximation.[29]
3-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole 3a. Using the general
procedure 3a was obtained in 90 % yield (248 mg). Rf 0.38. Beige solid;
m.p. 103-105 °С (lit. 103-105 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.94 (d,
J = 2.5 Hz, 1H, Hpyr), 7.86 (d, J = 8.5 Hz, 2H), 7.80-7.77 (m, 2H), 7.49-
7.45 (m, 4H), 7.29 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H, Hpyr), 1.38
t
(s, 9H, Bu). 13C NMR (101 MHz, CDCl3) δ 153.1 (C), 151.2 (C), 140.4
(C), 130.5 (C), 129.5 (2CH), 128.0 (CH), 126.3 (CH), 125.73 (2CH),
125.69 (2CH), 119.1 (2CH), 105.1 (CHpyr), 34.8 (C(CH3)3), 31.5 (3CH3).
HRMS (ESI) Calcd. for C19H21N2+ [M+H]+ 277.1699, found 277.1693.
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
1-phenyl-3-(4-tolyl)-1H-pyrazole 3b. Using the general procedure 3b
was obtained in 99 % yield (231 mg). Rf 0.35. Beige solid; m.p. 92-93 °С
(lit. 92-94 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.5 Hz, 1H,
Hpyr), 7.84 (d, J = 8.1 Hz, 2H), 7.80-7.77 (m, 2H), 7.50-7.45 (m, 2H),
7.31-7.25 (m, 3H), 6.75 (d, J = 2.5 Hz, 1H, Hpyr), 2.41 (s, 3H, CH3). 13C
NMR (101 MHz, CDCl3) δ 153.1 (C=N), 140.4 (C), 137.9 (C), 130.5 (C),
129.50 (2CH), 129.46 (2CH), 128.0 (CH), 126.3 (CH), 125.9 (2CH),
(CHPh+CHpyr), 125.9 (2CH), 119.2 (2CH), 104.9 (CHpyr), 21.1 (CH3).
HRMS (ESI) Calcd. for C16H15N2+ [M+H]+ 235.1230, found 235.1230.
1-(4-bromophenyl)-3-phenyl-1H-pyrazole 3i. Using the general
procedure 3i was obtained in 89 % yield (265 mg). Rf 0.29. Beige solid;
m.p. 133-134 °С (lit. 133-134 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.93-
7.90 (m, 3H), 7.67 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.44 (t, J
= 7.5 Hz, 2H), 7.37-7.33 (m, 1H), 6.79 (d, J = 2.5 Hz, 1H, Hpyr). 13C NMR
(101 MHz, CDCl3) δ 153.4 (C=N), 139.4 (C), 133.0 (C), 132.6 (2CH),
128.8 (2CH), 128.4 (CH), 128.0 (CH), 126.0 (2CH), 120.5 (2CH), 119.6
(C), 105.6 (CHpyr). HRMS (ESI) Calcd. for C15H12N2Br+ [M+H]+ 299.0178,
found 299.0176.
+
119.1 (2CH), 105.0 (CHpyr), 21.4 (CH3). HRMS (ESI) Calcd. for C16H15N2
[M+H]+ 235.1230, found 235.1230.
3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole 3c. Using the general
procedure 3c was obtained in 97 % yield (242 mg). Rf 0.23. Beige solid;
m.p. 101-103 °С (lit. 101-103°С).[8] 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 2.5 Hz, 1H, Hpyr), 7.86 (d, J = 8.8 Hz, 2H, C6H4), 7.77 (d, J = 7.7 Hz,
2H, H2,6(Ph)), 7.46 (t, J = 8.0 Hz, 2H, H3,5(Ph)), 7.30-7.26 (m, 1H, H4(Ph)),
6.98 (d, J = 8.8 Hz, 2H, C6H4), 6.71 (d, J = 2.5 Hz, 1H, Hpyr), 3.86 (s, 3H,
OCH3). 13C NMR (101 MHz, CDCl3) δ 159.8 (C), 152.9 (C), 140.4 (C),
129.5 (2CH), 128.0 (CH), 127.2 (2CH), 126.3 (CH), 126.1 (C), 119.1
(2CH), 114.2 (2CH), 104.7 (CHpyr), 55.4 (OCH3). HRMS (ESI) Calcd. for
C16H15N2O+ [M+H]+ 251.1179, found 251.1173.
1-(4-fluorophenyl)-3-phenyl-1H-pyrazole 3j. Using the general
procedure 3j was obtained in 99 % yield (240 mg). Rf 0.29. Beige solid;
m.p. 91-93 °С (lit. 90-92 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.93-7.90 (m,
2H), 7.88 (d, J = 2.5 Hz, 1H, Hpyr), 7.76-7.70 (m, 2H), 7.44 (t, J = 7.5 Hz,
2H), 7.37-7.33 (m, 1H), 7.19-7.13 (m, 2H), 6.77 (d, J = 2.5 Hz, 1H, Hpyr).
13C NMR (101 MHz, CDCl3) δ 161.2 (d, J = 245.6 Hz, CF), 153.2 (C=N),
136.8 (d, J = 2.9 Hz, C), 133.1 (C), 128.8 (2CH), 128.23 (CH), 128.22
(CH), 126.0 (2CH), 120.9 (d, J = 8.3 Hz, 2CH), 116.3 (d, J = 23.0 Hz,
2CH), 105.2 (CHpyr). HRMS (ESI) Calcd. for C15H12N2F+ [M+H]+ 239.0979,
found 239.0975.
1,3-diphenyl-1H-pyrazole 3d. Using the general procedure 3d was
obtained in 96 % yield (211 mg). Rf 0.33. Beige solid; m.p. 82-84 °С (lit.
82-85 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 3H), 7.80-7.77
(m, 2H), 7.50-7.43 (m, 4H), 7.38-7.33 (m, 1H), 7.32-7.28 (m, 1H), 6.79 (d,
J = 2.5 Hz, 1H, Hpyr). 13C NMR (101 MHz, CDCl3) δ 153.1(C=N), 140.4
(C), 133.3 (C), 129.5 (2CH), 128.8 (2CH), 128.14 (CH), 128.09 (CH),
126.4 (CH), 126.0 (2CH), 119.2 (2CH), 105.1 (CHpyr). HRMS (ESI) Calcd.
for C15H13N2+ [M+H]+ 221.1073, found 221.1072.
1,3-di(4-tolyl)-1H-pyrazole 3k. Using the general procedure 3k was
obtained in 77 % yield (191 mg). Rf 0.35. White solid; m.p. 138 ° С. 1H
NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.5 Hz, 1H, Hpyr), 7.81 (d, J = 8.1
Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.27-7.22 (m, 4H), 6.72 (d, J = 2.5 Hz,
1H, Hpyr), 2.39 (s, 6H, 2CH3). 13C NMR (101 MHz, CDCl3) δ 152.8 (C=N),
138.1 (C), 137.9 (C), 136.3 (C), 130.4 (C), 130.0 (2CH), 129.5 (2CH),
128.1 (CHpyr), 125.9 (2CH), 119.2 (2CH), 104.7 (CHpyr), 21.4 (CH3), 21.1
3-(4-bromophenyl)-1-phenyl-1H-pyrazole 3e. Using the general
procedure 3e was obtained in 93 % yield (277 mg). Rf 0.30. Beige solid;
m.p. 123-125 ° С (lit. 122-124 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.95 (d,
J = 2.5 Hz, 1H, Hpyr), 7.79 (d, J = 8.5 Hz, 2H), 7.77-7.75 (m, 2H), 7.55 (d,
J = 8.5 Hz, 2H), 7.47 (t, J = 8.0 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 6.75 (d,
J = 2.5 Hz, 1H, Hpyr). 13C NMR (101 MHz, CDCl3) δ 152.0 (C=N), 140.3
(C), 132.3 (C), 131.9 (2CH), 129.6 (2CH), 128.3 (CH), 127.5 (2CH),
126.7 (CH), 122.1 (C), 119.2 (2CH), 105.1 (CHpyr). HRMS (ESI) Calcd.
for C15H12N2Br+ [M+H]+ 299.0178, found 299.0174.
+
(CH3). HRMS (ESI) Calcd. for C17H17N2 [M+H]+ 249.1386, found
249.1374.
3-(4-methoxyphenyl)-1-(4-tolyl)-1H-pyrazole 3l. Using the general
procedure 3l was obtained in 89 % yield (235 mg). Rf 0.24. White solid;
1
m.p. 157-158 ° С. H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.5 Hz, 1H,
Hpyr), 7.85 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.2
Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.5 Hz, 1H, Hpyr), 3.85 (s,
3H, OMe), 2.39 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 159.7 (C),
152.6 (C=N), 138.1 (C), 136.1 (C), 130.0 (2CH), 128.0 (CHpyr), 127.3
(2CH), 126.1 (C), 119.1 (2CH), 114.2 (2CH), 104.4 (CHpyr), 55.5 (OMe),
21.1 (CH3). HRMS (ESI) Calcd. for C17H17N2O+ [M+H]+ 265.1335, found
265.1335.
3-(4-nitrophenyl)-1-phenyl-1H-pyrazole 3f. Using the general
procedure 3f was obtained in 91 % yield (241 mg). Rf 0.15. Beige solid;
m.p. 134-136 °С (lit. 134-136 °С).[8] 1H NMR (400 MHz, CDCl3) δ 8.29 (d,
J = 9.0 Hz, 2H), 8.07 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 2.5 Hz, 1H, Hpyr),
7.80-7.77 (m, 2H), 7.52-7.47 (m, 2H), 7.37-7.33 (m, 1H), 6.87 (d, J = 2.5
Hz, 1H, Hpyr). 13C NMR (101 MHz, CDCl3) δ 150.7 (C=N), 147.4 (C),
140.0 (C), 139.5 (C), 129.7 (2CH), 128.8 (CH), 127.2 (CH), 126.4 (2CH),
124.3 (2CH), 119.4 (2CH), 106.0 (CHpyr). HRMS (ESI) Calcd. for
C15H11N3O2Na+ [M+Na]+ 288.0743, found 288.0739.
1-(4-fluorophenyl)-3-(4-tolyl)-1H-pyrazole 3m. Using the general
procedure 3m was obtained in 99 % yield (250 mg). Rf 0.33. Colorless
solid; m.p. 119-121 ° С. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.5 Hz,
1H, Hpyr), 7.81 (d, J = 8.1 Hz, 2H), 7.74-7.70 (m, 2H), 7.25 (d, J = 8.6 Hz,
2H), 7.15 (t, J = 8.6 Hz, 2H), 6.74 (d, J = 2.5 Hz, 1H, Hpyr), 2.40 (s, 3H,
CH3). 13C NMR (101 MHz, CDCl3) δ 161.1 (d, J = 245.5 Hz, CF), 153.2
(C=N), 138.0 (C), 136.8 (d, J = 2.8 Hz, C), 130.3 (C), 129.5 (2CH), 128.1
(CHpyr), 125.8 (2CH), 120.8 (d, J = 8.3 Hz, 2CH), 116.3 (d, J = 22.9 Hz,
2CH), 105.0 (CHpyr), 21.41 (CH3). 19F NMR (376 MHz, CDCl3) δ -116.3
3-(3,4-dichlorophenyl)-1-phenyl-1H-pyrazole 3g. Using the general
procedure 3g was obtained in 88 % yield (254 mg). Rf 0.28. Beige solid;
m.p. 94-97 °С (lit. 95-97 °С).[8] 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
1.9 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H, Hpyr), 7.77-7.72 (m, 3H), 7.50-7.46
(m, 3H), 7.32 (t, J = 7.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H, Hpyr). 13C NMR
(101 MHz, CDCl3) δ 150.8 (C=N), 140.1 (C), 133.4 (C), 133.0 (C), 131.9
(C), 130.7 (CH), 129.6 (2CH), 128.5 (CH), 127.7 (CH), 126.9 (CH), 125.1
+
ppm. HRMS (ESI) Calcd. for C16H14FN2 [M+H]+ 253.1136, found
253.1135.
+
(CH), 119.3 (2CH), 105.2 (CHpyr). HRMS (ESI) Calcd. for C15H11N2Cl2
[M+H]+ 289.0294, found 289.0292.
4,5-dideutero-3-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole 4a. Using
the general procedure 4a was obtained in 95 % yield (264 mg). Rf 0.38.
Beige solid; m.p. 101-102 °С (lit. 100-102 °С).[8] 1H NMR (400 MHz,
CDCl3) δ 7.91-7.89 (m, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.52-7.46 (m, 4H),
3-phenyl-1-(4-tolyl)-1H-pyrazole 3h. Using the general procedure 3h
was obtained in 88 % yield (206 mg). Rf 0.34. Beige solid; m.p. 110-112 °
С (lit. 111-112 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.95-7.93 (m, 2H),
7.91 (d, J = 2.5 Hz, 1H, Hpyr), 7.66 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 7.5 Hz,
2H), 7.37-7.32 (m, 1H), 7.27 (d, J = 8.2 Hz, 2H), 6.76 (d, J = 2.5 Hz, 1H,
Hpyr), 2.40 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 152.8 (C=N),
138.2 (C), 136.3 (C), 133.4 (C), 130.0 (2CH), 128.8 (2CH), 128.0
t
7.30 (t, J = 7.4 Hz, 1H), 1.41 (s, 9H, Bu). 13C NMR (101 MHz, CDCl3) δ
153.0 (C), 151.1 (C), 140.4 (C), 130.5 (C), 129.5 (2CH), 127.6 (t, J = 27.6
Hz, CD), 126.3 (CH), 125.71 (2CH), 125.66 (2CH), 119.0 (2CH), 104.7 (t,
J = 26.6 Hz, CD), 34.7 (C(CH3)3), 31.4 (3CH3). HRMS (ESI) Calcd. for
C19H19D2N2+ [M+H]+ 279.1825, found 279.1824.
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
4,5-dideutero-1-phenyl-3-(4-tolyl)-1H-pyrazole 4b. Using the general
procedure 4b was obtained in 99 % yield (234 mg). Rf 0.35. Beige solid;
m.p. 92-94 °С (lit. 93-94 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J =
8.1 Hz, 2H), 7.79-7.76 (m, 2H), 7.49-7.45 (m, 2H), 7.31-7.24 (m, 3H),
2.41 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 153.1 (C=N), 140.4 (C),
137.9 (C), 130.5 (C), 129.51 (2CH), 129.47 (2CH), 127.7 (t, J = 27.8 Hz,
CD), 126.3 (CH), 125.9 (2CH), 119.1 (2CH), 104.7 (t, J = 26.5 Hz, CD),
21.4 (CH3). HRMS (ESI) Calcd. for C16H12D2N2Na+ [M+Na]+ 259.1175,
found 259.1175.
J = 26.6 Hz, CD). HRMS (ESI) Calcd. for C15H9D2BrN2Na+ [M+Na]+
323.0123, found 323.0126.
4,5-dideutero-1,3-di(4-tolyl)-1H-pyrazole 4k. Using the general
procedure 4k was obtained in 66 % yield (170 mg). Rf 0.35. Beige solid;
m.p. 140-142 °С. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H),
7.65 (d, J = 8.4 Hz, 2H), 7.27-7.23 (m, 4H), 2.40 (s, 6H, 2CH3). 13C NMR
(101 MHz, CDCl3) δ 152.8 (C=N), 138.2 (C), 137.8 (C), 136.2 (C), 130.5
(C), 130.0 (2CH), 129.5 (2CH), 127.7 (t, J = 28.3 Hz, CD), 125.9 (2CH),
119.1 (2CH), 104.4 (t, J = 26.9 Hz, CD), 21.4 (CH3), 21.1 (CH3). HRMS
(ESI) Calcd. for C17H14D2N2Na+ [M+Na]+ 273.1331, found 273.1325.
4,5-dideutero-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazole 4c. Using
the general procedure 4c was obtained in 97 % yield (244 mg). Rf 0.23.
Beige solid; m.p. 100-101 °С (lit. 100-101°С).[8] 1H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 8.8 Hz, 2H, C6H4), 7.78-7.76 (m, 2H), 7.47 (t, J =
8.0 Hz, 2H, H3,5(Ph)), 7.28 (t, J = 7.5 Hz, 1H, H4(Ph)), 6.99 (d, J = 8.8 Hz,
2H, C6H4), 3.86 (s, 3H, OCH3). 13C NMR (101 MHz, CDCl3) δ 159.7 (C),
152.8 (C), 140.4 (C), 129.5 (2CH), 127.7 (t, J = 28.2 Hz, CD), 127.2
(2CH), 126.2 (CH), 126.1 (C), 119.0 (2CH), 114.2 (2CH), 104.3 (t, J =
26.9 Hz, CD), 55.4 (OCH3). HRMS (ESI) Calcd. for C16H12D2N2ONa+
[M+Na]+ 275.1124, found 275.1116.
4,5-dideutero-1-(4-fluorophenyl)-3-(4-tolyl)-1H-pyrazole 4m. Using the
general procedure 4m was obtained in 99 % yield (250 mg). Rf 0.33.
Beige solid; m.p. 119-121 ° С. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J =
8.1 Hz, 2H), 7.75-7.69 (m, 2H), 7.26 (d, J = 7.9 Hz, 2H), 7.18-7.12 (m,
2H), 2.41 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 161.1 (d, J = 245.5
Hz, CF), 153.1 (C=N), 138.0 (C), 136.7 (d, J = 2.8 Hz, C), 130.3 (C),
129.5 (2CH), 127.8 (d, J = 28.8 Hz, CD), 125.8 (2CH), 120.8 (d, J = 8.3
Hz, 2CH), 116.2 (d, J = 23.0 Hz, 2CH), 104.7 (d, J = 26.8 Hz, CD), 21.4
(CH3). 19F NMR (376 MHz, CDCl3) δ -116.3 ppm. HRMS (ESI) Calcd. for
C16H11D2FN2+ [M+H]+ 255.1261, found 255.1262.
4,5-dideutero-1,3-diphenyl-1H-pyrazole 4d. Using the general
procedure 4d was obtained in 97 % yield (213 mg). Rf 0.33. Beige solid;
m.p. 83-84 °С (lit. 83-85 °С).[8] 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J =
7.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.50-7.44 (m, 4H), 7.37 (t, J = 7.3
Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 153.0
(C=N), 140.3 (C), 133.3 (C), 129.5 (2CH), 128.8 (2CH), 128.1 (CH),
127.8 (t, J = 29.2 Hz, CD), 126.4 (CH), 125.9 (2CH), 119.1 (2CH), 104.8
5-deutero-3-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole 9a. Using the
general procedure 9a was obtained in 90 % yield (250 mg). Deuterium
incorporation corresponded to 8 (91%). Rf 0.38. Beige solid; m.p. 99-
101 °С. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.5 Hz, 0.09H, residual
H-5), 7.89 (d, J = 8.5 Hz, 2H), 7.81-7.77 (m, 2H), 7.51-7.45 (m, 4H), 7.32-
+
(t, J = 27.1 Hz, CD). HRMS (ESI) Calcd. for C15H11D2N2 [M+H]+
t
7.27 (m, 1H), 6.76 (s, 1H, H-4), 1.40 (s, 9H, Bu). 13C NMR (101 MHz,
223.1199, found 223.1202.
CDCl3) δ 153.1 (C=N), 151.2 (C), 140.4 (C), 130.5 (C), 129.5 (2CH),
127.7 (t, J = 28.6 Hz, CD), 126.3 (CH), 125.71 (2CH), 125.67 (2CH),
119.1 (2CH), 104.9 (CHpyr), 34.8 (CMe3), 31.5 (CMe3). HRMS (ESI)
Calcd. for C19H20DN2+ [M+H]+ 278.1762, found 278.1759.
3-(4-bromophenyl)-4,5-dideutero-1-phenyl-1H-pyrazole 4e. Using the
general procedure 4e was obtained in 93 % yield (280 mg). Rf 0.29.
Beige solid; m.p. 124-125 °С (lit. 123-125 °С).[8] 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 8.6 Hz, 2H), 7.78-7.74 (m, 2H), 7.56 (d, J = 8.6 Hz,
2H), 7.47 (t, J = 8.0 Hz, 2H), 7.33-7.28 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 151.9 (C=N), 140.2 (C), 132.2 (C), 131.9 (2CH), 129.6 (2CH),
128.0 (t, J = 27.0 Hz, CD), 127.5 (2CH), 126.6 (CH), 122.0 (C), 119.2
5-deutero-1,3-diphenyl-1H-pyrazole 9d. Using the general procedure
9d was obtained in 95 % yield (210 mg). Deuterium incorporation
corresponded to 8 (91%). Rf 0.33. Beige solid; m.p. 78-80 °С. 1H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 7.8 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H),
7.50-7.44 (m, 4H), 7.37 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 6.79
(s, 1H, H-4). 13C NMR (101 MHz, CDCl3) δ 153.0 (C=N), 140.3 (C), 133.3
(C), 129.5 (2CH), 128.8 (2CH), 128.1 (CH), 127.9 (t, J = 27.2 Hz, CD),
126.4 (CH), 126.0 (2CH), 119.1 (2CH), 105.0 (CHpyr). HRMS (ESI) Calcd.
for C15H12DN2+ [M+H]+ 222.1136, found 222.1133.
(2CH), 104.8 (t,
J = 27.2 Hz, CD). HRMS (ESI) Calcd. for
C15H9BrD2N2Na+ [M+Na]+ 323.0123, found 323.0134.
4,5-dideutero-3-(4-nitrophenyl)-1-phenyl-1H-pyrazole 4f. Using the
general procedure 4f was obtained in 85 % yield (228 mg). Rf 0.15. Beige
solid; m.p. 135-137 °С. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.6 Hz,
2H), 8.05 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.7 Hz,
2H), 7.34 (t, J = 7.4 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 150.5 (C),
147.3 (C), 139.9 (C), 139.5 (C), 129.6 (2CH), 128.5 (t, J = 27.7, CD),
127.1 (CH), 126.3 (2CH), 124.2 (2CH), 119.3 (2CH), 105.6 (d, J = 27.3
Hz, CD). HRMS (ESI) Calcd. for C15H9D2N3O2Na+ [M+Na]+ 290.0869,
found 290.0867.
5-deutero-3-(4-nitrophenyl)-1-phenyl-1H-pyrazole 9f. Using the
general procedure 9f was obtained in 89 % yield (237 mg). Deuterium
incorporation corresponded to 8 (91%). Rf 0.15. Beige solid; m.p. 137-
139 °С. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.7 Hz, 2H), 8.06 (d, J
= 8.7 Hz, 2H), 8.00 (d, J = 2.5 Hz, 0.09H, residual H-5), 7.77 (d, J = 8.0
Hz, 2H), 7.50 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 6.86 (s, 1H, H-
4). 13C NMR (101 MHz, CDCl3) δ 150.6 (C=N), 147.4 (C), 140.0 (C),
139.5 (C), 129.7 (2CH), 128.6 (t, J = 28.4 Hz, CD), 127.1 (CH), 126.3
(2CH), 124.2 (2CH), 119.3 (2CH), 105.9 (CHpyr). HRMS (ESI) Calcd. for
C15H10DN3O2Na+ [M+Na]+ 289.0806, found 289.0806.
4,5-dideutero-3-phenyl-1-(4-tolyl)-1H-pyrazole 4h. Using the general
procedure 4h was obtained in 96 % yield (227 mg). Rf 0.34. Beige solid;
m.p. 104-106 °С. 1H NMR (400 MHz, CDCl3) δ 7.96-7.93 (m, 2H), 7.67 (d,
J = 8.4 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.28-
7.26 (m, 2H), 2.41 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 152.7
(C=N), 138.1 (C), 136.2 (C), 133.4 (C), 130.0 (2CH), 128.7 (2CH), 128.0
(CH), 127.7 (t, J = 27.9 Hz, CD), 125.9 (2CH), 119.1 (2CH), 104.5 (t, J =
1-(4-bromophenyl)-5-deutero-3-phenyl-1H-pyrazole 9i. Using the
general procedure 9i was obtained in 91 % yield (273 mg). Deuterium
incorporation corresponded to 8 (91%). Rf 0.30. Beige solid; m.p. 135-
26.8 Hz, CD), 21.0 (CH3). HRMS (ESI) Calcd. for C16H13D2N2 [M+H]+
+
1
137 °С. H NMR (400 MHz, CDCl3) δ 7.93-7.90 (m, 2.09H, 2HAr and the
237.1355, found 237.1356.
residual H-5), 7.66 (d, J = 8.9 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.45 (t, J
= 7.5 Hz, 2H), 7.38-7.34 (m, 1H), 6.78 (s, 1H, H-4). 13C NMR (101 MHz,
CDCl3) δ 153.4 (C=N), 139.3 (C), 133.0 (C), 132.5 (2CH), 128.8 (2CH),
128.3 (CH), 127.7 (t, J = 28.7 Hz, CD), 126.0 (2CH), 120.4 (2CH), 119.5
(C), 105.4 (CHpyr). HRMS (ESI) Calcd. for C15H10DBrN2Na+ [M+Na]+
322.0061, found 322.0066.
1-(4-bromophenyl)-4,5-dideutero-3-phenyl-1H-pyrazole 4i. Using the
general procedure 4i was obtained in 90 % yield (270 mg). Rf 0.29. Beige
solid; m.p. = 137-138 °С (lit. 137-138 °С).[8] 1H NMR (400 MHz, CDCl3) δ
7.93-7.89 (m, 2H), 7.66 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.45
(t, J = 7.4 Hz, 2H), 7.38-7.33 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
153.3 (C=N), 139.3 (C), 133.0 (C), 132.5 (2CH), 128.8 (2CH), 128.3 (CH),
127.7 (t, J = 28.4 Hz, CD), 126.0 (2CH), 120.4 (2CH), 119.5 (C), 105.2 (t,
5-deutero-1-(2,6-dichlorophenyl)-3-phenyl-1H-pyrazole 9o. Using the
general procedure 9o was obtained in 93 % yield (269 mg). Rf 0.23.
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
Deuterium incorporation corresponded to 8 (91%). Beige solid; m.p. 106-
108 °С. H NMR (400 MHz, CDCl3) δ 7.93-7.90 (m, 2H), 7.58 (d, J = 2.5
We gratefully acknowledge financial support from the Russian
Science Foundation (Project № 19-73-10032).
1
Hz, 0.09H, residual H-5), 7.48-7.41 (m, 4H), 7.36-7.32 (m, 2H), 6.82 (s,
1H, H-4). 13C NMR (101 MHz, CDCl3) δ 153.2 (C=N), 136.6 (C), 134.8
(2C), 133.0 (C), 132.8 (t, J = 28.9 Hz, CD), 130.7 (CH), 128.8 (2CH),
128.7 (2CH), 128.2 (CH), 126.1 (2CH), 104.0 (CHpyr). HRMS (ESI) Calcd.
for C15H9DCl2N2Na+ [M+Na]+ 312.0176, found 312.0181.
The authors express their gratitude to the Resource Centres of
Saint Petersburg State University: Magnetic Resonance
Research Centre, Chemical Analysis and Materials Research
Centre, Computing Centre.
General procedure for the synthesis of benzyl D3-vinyl ether 2b
Keywords: cycloaddition
isotopic labeling • vinyl ether
• deuterium • deuteropyrazole •
The reaction tube was loaded with 128 mg (2.0 mmol) of CaC2, 78 mg
(0.7 mmol) of KOtBu, 52 mg (0.9 mmol) of KF and 76 mg (72 μl, 0.7
mmol) of benzyl alcohol. Then, 1 ml of dry 1,4-dioxane, DMSO-d6 (120
μl), and 72 μl (4.0 mmol) of water were added, the tube was immediately
sealed and heated at 110 °C for 4 hours. After, the reaction mixture was
poured to 10 ml of water and extracted five times with 7 ml of hexane.
The combined organic extracts were washed three times with water,
dried over sodium sulfate and evaporated on rotary evaporated to give
benzyl D3-vinyl ether 2b in 94% yield (90 mg) as a colorless oil. 1H NMR
(400 MHz, C6D6) δ 7.18-7.04 (m, 5H, Ph), 4.45 (s, 2H, CH2). 13C NMR
(101 MHz, C6D6) δ 151.6 (t, J = 27.8 Hz, =CD), 137.5 (C), 128.6 (2CH),
127.9 (CH), 127.7 (2CH), 86.6 (quint, J = 24.3 Hz, =CD2), 70.0 (CH2).
HRMS (ESI) Calcd. for C9H7D3OAg+ [M+Ag]+ 243.9965, found 243.9967.
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Decyl 1-deuterovinyl ether 8. Was synthesized by the previously
reported procedure.[26] Yield 472 mg (75%). Colorless oil. 1H NMR (400
MHz, C6D6) δ 6.46 (dd, J = 14.4, 6.8 Hz, 0.09H, residual OCH=), 4.18 (s,
1H from =CH2), 3.96 (s, 1H from =CH2), 3.47 (t, J = 6.5 Hz, 2H, OCH2),
1.56-1.48 (m, 2H), 1.32-1.21 (m, 14H), 0.91 (t, J = 6.9 Hz, 3H, CH3). 13C
NMR (101 MHz, C6D6) δ 152.2 (t, J = 27.7 Hz, CD), 85.9 (CH2), 67.9
(CH2), 32.3 (CH2), 30.00 (CH2), 29.99 (CH2), 29.8 (2CH2), 29.5 (CH2),
26.4 (CH2), 23.1 (CH2), 14.4 (CH3). HRMS (ESI) Calcd. for C12H23DOAg+
[M+Ag]+ 294.0932, found 294.0940.
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solid, m.p. 121-123 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (br s, 1H, NH),
7.81 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.13-7.06 (m, 4H), 2.39
(s, 3H, CH3), 2.31 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 141.4 (C),
139.4 (C), 132.0 (C), 130.5 (C), 130.0 (2CH), 129.2 (2CH), 126.4 (2CH),
124.5 (C), 113.5 (2CH), 21.4 (CH3), 20.8 (CH3). HRMS (ESI) Calcd for
C15H15ClN2Na+ [M+Na]+ 281.0816, found 281.0807.
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solid, m.p. 134-135 °C. 1H NMR (400 MHz, CDCl3) δ 7.88-7.85 (m, 3H,
NH+2CHAr), 7.12 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.93 (d, J =
8.9 Hz, 2H), 3.86 (s, 3H, OCH3), 2.32 (s, 3H, CH3). 13C NMR (101 MHz,
CDCl3) δ 160.6 (C), 141.5 (C), 130.3 (C), 130.0 (2CH), 128.0 (2CH),
127.5 (C), 124.3 (C), 113.9 (2CH), 113.5 (2CH), 55.5 (OCH3), 20.8 (CH3).
+
HRMS (ESI) calcd for C16H19N2O2 [M–Cl+MeOH]+ 271,1441, found:
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271,1454.
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Colorless solid, m.p. 70-72 °C. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H,
NH), 7.80 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.14-7.09 (m, 2H),
7.01 (t, J = 8.7 Hz, 2H), 2.39 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ
157.9 (d, J = 238.8 Hz, CF), 140.0 (d, J = 2.2 Hz, C), 139.6 (C), 131.8 (C),
129.3 (2CH), 126.5 (2CH), 125.3 (C), 116.1 (d, J = 22.8 Hz, 2CH), 114. 6
(d, J = 7.6 Hz, 2CH), 21.4 (CH3). 19F NMR (376 MHz, CDCl3) δ -123.5
ppm.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000674
European Journal of Organic Chemistry
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10.1002/ejoc.202000674
European Journal of Organic Chemistry
FULL PAPER
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A novel synthetic path to 1,3-disubstituted pyrazoles, 4,5-dideuteropyrazoles and 5-deuteropyrazoles based on the interaction of the
readily available vinyl ethers and in situ generated nitrile imines was developed. The joint experimental and computational study
clarified the mechanism of the process and allowed us to propose a convenient access to regioselectively deuterated pyrazoles.
Keywords: cycloaddition • deuterium • deuteropyrazole • isotopic labeling • vinyl ether
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This article is protected by copyright. All rights reserved.