One-Pot and Two-Chamber Methodologies for Using Acetylene Surrogates in the Synthesis of Pyridazines and Their D-Labeled Derivatives

Article abstract of DOI:10.1002/asia.202100562

Acetylene surrogates are efficient tools in modern organic chemistry with largely unexplored potential in the construction of heterocyclic cores. Two novel synthetic paths to 3,6-disubstituted pyridazines were proposed using readily available acetylene surrogates through flexible C₂ unit installation procedures in a common reaction space mode (one-pot) and distributed reaction space mode (two-chamber): (1) an interaction of 1,2,4,5-tetrazine and its acceptor-functionalized derivatives with a CaC₂?H₂O mixture performed in a two-chamber reactor led to the corresponding pyridazines in quantitative yields; (2) [4+2] cycloaddition of 1,2,4,5-tetrazines to benzyl vinyl ether can be considered a universal synthetic path to a wide range of pyridazines. Replacing water with D₂O and vinyl ether with its trideuterated analog in the developed procedures, a range of 4,5-dideuteropyridazines of 95–99% deuteration degree was synthesized for the first time. Quantum chemical modeling allowed to quantify the substituent effect in both synthetic pathways.

Full text of DOI:10.1002/asia.202100562

doi.org/10.1002/asia.202100562
Full Paper
One-Pot and Two-Chamber Methodologies for Using Acetylene
Surrogates in the Synthesis of Pyridazines and Their D-Labeled
Derivatives
[a]
[a, b]
[a, b]
Maria S. Ledovskaya, Mikhail V. Polynski,
and Valentine P. Ananikov*
Abstract: Acetylene surrogates are efficient tools in modern
organic chemistry with largely unexplored potential in the
construction of heterocyclic cores. Two novel synthetic paths
to 3,6-disubstituted pyridazines were proposed using readily
available acetylene surrogates through flexible C2 unit
installation procedures in a common reaction space mode
pyridazines in quantitative yields; (2) [4+2] cycloaddition of
1,2,4,5-tetrazines to benzyl vinyl ether can be considered a
universal synthetic path to a wide range of pyridazines.
Replacing water with D O and vinyl ether with its trideuter-
2
ated analog in the developed procedures, a range of 4,5-
dideuteropyridazines of 95–99% deuteration degree was
synthesized for the first time. Quantum chemical modeling
allowed to quantify the substituent effect in both synthetic
pathways.
(one-pot) and distributed reaction space mode (two-cham-
ber): (1) an interaction of 1,2,4,5-tetrazine and its acceptor-
functionalized derivatives with a CaC À H O mixture per-
2
2
formed in a two-chamber reactor led to the corresponding
Introduction
Nitrogen heterocycles are one of the most important structural
motives in drug design and development because of the wide
[1]
range of diversities and biological activities they possess.
More than 75% of the FDA-approved drugs currently available
on the market contain a nitrogen heterocycle as a core
[2]
fragment. The number of biologically active nitrogen hetero-
[1,2]
cycles is constantly growing, with a significant demand in the
synthesis of new structures.
Pyridazines, six-membered heterocycles containing a unique
and valuable NÀ N structural motif, are widely present in a
variety of natural products and pharmaceutically active com-
Figure 1. Selected examples of valuable pyridazines.
[3]
pounds (Figure 1). Among them, Sulfachloropyridazine pos-
[3c]
sesses antibiotic activity, Hydralazine has anti-hypertensive
[
3d,g]
activity,
agent,
Pyridazomycin is an antibiotic and antifungal
[
3e,f]
[4]
Minaprine and relatives are AchE inhibitors, and a
The potential of pyridazines in the construction of drugs is
not the only way of their application. The pyridazine moiety
was also efficiently applied as a main skeleton unit in
[5]
range of pyridazines demonstrate anti-inflammatory activity.
Recently, a number of 3,6-disubstituted pyridazines demon-
strated antitumor activities, what forces us to admit a high
potency of the pyridazine cycle in the construction of new
pharmaceuticals. The pyridazine ring was specifically ranked by
pharmaceutical companies as one of the best potential hetero-
[6]
[8]
fluorescent dyes. Substituted pyridazines have demonstrated
high potential in the creation of chemical multicolor fluorescent
[8b]
sensors due to their sensitivity to pH. Taking into account the
abovementioned considerations, the development of simple
and efficient methods for the synthesis of structurally diversified
pyridazines is in high demand.
[7]
cycles for the design of new drugs.
In this article, we thoroughly investigated the interaction
between 1,2,4,5-tetrazines and acetylene surrogates, a calcium
carbide-water mixture and benzyl vinyl ether. The [4+2]
cycloaddition of 1,2,4,5-tetrazines to unsaturated carbon-carbon
bonds and sequential nitrogen elimination (and benzyl alkohol,
if benzyl vinyl ether was used as an acetylene surrogate) can
lead to the formation of a pyridazine moiety (Figure 2A). We
proposed and compared two different strategies for using
acetylene surrogates (Figure 2A) depending on the
compatibility of reaction components. We demonstrated that a
[
a] Dr. M. S. Ledovskaya, Dr. M. V. Polynski, Prof. Dr. V. P. Ananikov
Institute of Chemistry
Saint Petersburg State University
Universitetsky prospect 26, Saint Petersgburg 198504 (Russia)
E-mail: val@ioc.ac.ru
b] Dr. 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 available on the WWW under
https://doi.org/10.1002/asia.202100562
Chem Asian J. 2021, 16, 1–13
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
strated recently for obtaining mechanistic insight into cyclo-
addition reactions and exploring/optimizing synthetic
procedures, including those catalyzed by transition metal
[
14]
[15]
complexes and organocatalysts, as well as classic concerted
[16,17]
cycloadditions.
Results and Discussion
The use of calcium carbide in organic chemistry is very
promising: CaC is a nontoxic solid material that can be easily
2
handled (unlike acetylene itself) and can be applied in a
[18]
diversity of synthetic transformations.
However, there are
some leaks in the application of calcium carbide as a source of
acetylene. CaC is a solid and almost inert material insoluble in
2
organic solvents that can only react with water at room
temperature, releasing acetylene and calcium hydroxide. This
fact means that a number of possible chemical transformations
of one-pot carbide-derived acetylene are limited by water- and
base-insensitive reactions.
Figure 2. (A) Two strategies for using acetylene surrogates in the synthesis
of pyridazines. (B) The proposed methodology for using surrogates of
acetylene-d in the synthesis of highly deuterated 4,5-dideuteropyridazines.
2
In previous studies, we proposed applying a two-chamber
reactor to separate water- and base-sensitive substrates from
[19]
calcium carbide and water.
Using this methodology, we
successfully synthesized a range of pyrazoles and their labeled
[
19a]
derivatives, 4,5-dideuteropyrazoles, from calcium carbide.
Additionally, we started an investigation of CaC reactivity in
practically desirable and efficient “one vessel” approach can be
2
1
3
designed for either type of reactive C unit by implementation
Diels-Alder reactions, obtaining 3,6-dichloropyridazine-4,5- C
2
2
[19b]
in a one-pot or two-chamber manner (see inserted graphics in
Figure 2). The results of this study suggest two simple,
economical and efficient synthetic paths to 3,6-disubstituted
pyridazines and demonstrate a range of applicability of both
methods.
in quantitative yield.
The second way to perform water- and base-sensitive
[
20]
reactions with acetylene is to replace it with vinyl ethers.
Vinyl ethers are readily available and relatively nontoxic
compounds with well-known physical characteristics that can
[
20–21]
The substitution of hydrogen atoms in a drug molecule to
deuterium is a novel opportunity to alter its physical and
be used as safe and easily dosed acetylene surrogates.
From a certain point of view, vinyl ethers can be described as
simple and safe reagents compared to acetylene itself. Using
vinyl ethers entirely excludes intermediate gas formation and
excessive pressure in the reaction vessel. Previously, we
successfully demonstrated that primary vinyl ethers can be
[9]
chemical properties and to improve the pharmaceutical
[10]
activity of a specific molecule. This property of deuterium
underlies a great variety of mechanistic studies in chemistry
[
10–11]
and pharmacokinetic profile evaluation in medicine.
The
[
20]
substitution of hydrogen to deuterium allowed to alter reaction
selectivities in total syntheses and to enhance the metabolic
stability of a specific VMAT2 inhibitor (Tetrabenazine, which was
modified by a replacement of six hydrogen atoms with
used as acetylene surrogates in the synthesis of pyrazoles.
First, the possibility of direct one-pot synthesis of pyrida-
zines from calcium carbide and 1,2,4,5-tetrazines 1a–j was
investigated. However, 1,2,4,5-tetrazines 1a–d are base-sensi-
tive compounds, so only trace amounts of the desired
pyridazines 2a, b were observed in the reaction mixtures, and
2c, d were not detected in the reaction mixtures at all (Table 1,
entries 1–4). Pyridine-substituted tetrazine 1e reacted with
[
12]
deuterium atoms), allowing less frequent drug dosing.
view of recent advances in this field,
In
[12–13]
the development of
new synthetic paths to deuterium-labeled compounds, partic-
ularly heterocycles, is very demanding.
The application of deuterated acetylene surrogates in the
developed procedures (CaC À D O mixture or benzyl D -vinyl
CaC2, giving 2e in 19% yield (Table 1, entry 5). CaC reactivity
2
towards 1,2,4,5-tetrazines containing electron donating groups
(EDG) was also poor: 3,6-dimethoxy-1,2,4,5-tetrazine 1f did not
react, 3-chloro-6-methoxy-substituted derivative 1g gave 2g in
5% yield (Table 1, entry 6,7). Better results were observed at
continuous heating (21 days) of 1h in the presence of the
CaC À H O mixture – the yield of pyridazine 2h was 35%
2
2
3
ether, see Figure 2B) led to 4,5-dideuteropyridazines. For the
first time, were proposed two simple and economical synthetic
paths to D -labeled pyridazines, which allowed high levels of
2
deuteration (95–99%) to be achieved in only one synthetic step
and did not require any harsh reagents or complex equipment.
For the first time, a complete reaction space involving both
acetylene and its surrogate (Figure 2) was explored here with
quantum-chemical modeling and correlated with the experi-
ment. High validity of computational modeling was demon-
2
2
(Table 1, entry 8). The reaction of 1i with carbide-derived
acetylene led to the formation of 2i in 70% yield, and 2j was
obtained in only 5% yield (Table 1, entry 9,10). All processes
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
1
00% yields in the reactions of active 1,2,4,5-tetrazines 1a–e
Table 1. The reactions of 1,2,4,5-tetrazines with acetylene surrogates.
with acetylene.
Despite the good results in the synthesis of pyridazines 2a–
e, their electron donating group-containing analog synthesis
was still challenging. Summarizing the results of the experi-
ments including calcium carbide usage as a surrogate of
acetylene, one can propose that the CaC À H O mixture should
2
2
be replaced with a neutral analog to avoid 1,2,4,5-tetrazine
decomposition at elevated temperatures (most of the tetrazines
Entry Product
The source of C
2
H
2
-fragment, product
1
2
[a]
[
R , R ]
yield [%]
decomposed in the presence of Ca(OH) ). Recently, we demon-
2
CaC
2
À H
2
O Benzyl vinyl
strated that benzyl vinyl ether can be used as an acetylene
[
d]
ether
[20]
[b]
[c]
surrogate in 1,3-dipolar cycloaddition reactions. In this way,
pyrazoles were obtained in up to quantitative yields in a one-
pot manner. This path seemed very promising, so we decided
to investigate the chemical behavior of benzyl vinyl ether in the
reactions with 1,2,4,5-tetrazines. The reactivity of benzyl vinyl
ether towards tetrazines 1a–e was good: at heating for 1–48 h,
the corresponding pyridazines were obtained in good to
quantitative yields (Table 1, entries 1–5). The results of less
reactive tetrazine testing were exceptionally good: the yields of
one-pot
Y/H-tube
1
2
1
2
3
4
5
6
7
8
9
R =R =H (2a)
traces
traces
0
0
19
NR
5
99 (99)
99 (99)
99 (99)
99 (99)
99 (99)
traces
6
90
99
80
99
1
2
R =R =Cl (2b)
1
2
R =R =Br (2c)
1
2
R =R =CO
2
Me (2d)
1
2
[e]
R =R =2-Py (2e)
99 (95)
95 (83)
95 (90)
1
2
R =R =OMe (2f)
1
2
R =OMe, R =Cl (2g)
1
2
[f]
R =NEt
2
, R =Cl (2h)
35 (30)
70
traces
4
30
1
2
R =R =Ph (2i)
96 (91)
3
1
-chloro-6-methoxy-, diphenyl- and bis(3,5-dimethyl-1H-pyrazol-
-yl)-substitutioned pyridazines 2g, 2i, and 2j, respectively,
1
0
5
1
97 (93)
were almost quantitative (Table 1, entries 7, 9, and 10). In this
case, it took 5–10 days to achieve full conversion of the
corresponding 1,2,4,5-tetrazine. Even 3,6-dimethoxy-1,2,4,5-tet-
razine 1f reacted with benzyl vinyl ether, giving dimethoxy-
substituted pyridazine 2f in 95% yield within 14 days (Table 1,
entry 6). The less reactive 3-chloro-6-diethylamino-1,2,4,5-tetra-
zine 1h reacted with an excess of benzyl vinyl ether in the
[
a] Isolated yield shown in parentheses. [b] The reaction was performed in
a sealed tube using 0.3 mmol of 1a–j, 2 mmol of CaC , 4 mmol of water,
2
and 1,4-dioxane (0.6 ml) at 100°C for 5 d. [c] The substrate part was
loaded with 0.3 mmol of 1a–j and 1.0 ml of 1,4-dioxane, benzene or
nd
CHCl
3
, in the 2 part were placed 2 mmol of CaC
2
, 4 mmol of water and a
solvent – 1,4-dioxane, benzene or CHCl
1
3
(0.6 ml), rt, 5–7 d. [d] 0.3 mmol of
a–j, benzyl vinyl ether (0.6 mmol), 1,4-dioxane or benzene (0.6 mmol),
1
00°C, 1 h–21 d (TLC/NMR-control). [e] 2-Py is 2-pyridyl. [f] 30 μl of Et
3
N
was added to the reaction mixture.
presence of Et N, producing pyridazine 2h in 30% yield within
3
3
weeks (Table 1, entry 8). Triethylamine was used for benzyl
vinyl ether protection from decomposition in the presence of
[18i]
1
h.
The resulting pyridazines can be easily isolated with
were accompanied by side reactions, so we decided to explore
another method of acetylene generation.
standard protocols, so this synthetic path is totally suitable for
the synthesis of electron donating group-substituted pyrida-
zines, which cannot be obtained from calcium carbide using a
two-chamber reactor.
Since some of the studied 1,2,4,5-tetrazines can decompose
in direct contact with the CaC À H O mixture, we decided to use
2
2
a two-chamber reactor for acetylene generation. In previous
studies, we demonstrated that a two-chamber reactor is highly
By studying the NMR spectra of the reaction mixtures, we
noted that with increasing reaction time, the content of benzyl
vinyl ether decreased, but it could not be connected directly
with product formation. At the same time, acetaldehyde
dibenzyl acetal was detected in the NMR spectra of the reaction
mixtures. And, the contents of acetal increased over time. A
small admixture of it was detected after ~15 h in the reaction
mixtures, and a more significant quantity was observed with an
increase in reaction time. We proposed that the interaction of
tetrazine 1 with benzyl vinyl ether leads to the formation of
intermediate [1!2] (Scheme 1, top). According to the literature,
[19]
recommended for base- and water-sensitive substrates, so we
tested the scope of 1,2,4,5-tetrazines in reactions with calcium
carbide in a two-chamber reactor. The reactions of tetrazines
1
a–e with carbide-derived acetylene in a two-chamber reactor
proceeded smoothly, giving the corresponding pyridazines 2a–
in quantitative yields (Table 1, entries 1–5). However,
e
acetylene is an unactivated alkyne, so its reactivity towards
EDG-substituted 1,2,4,5-tetrazines 1f–h, 3,6-diphenyl-1,2,4,5-
tetrazine 1i and 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-
tetrazine 1j was low: the desired pyridazines 1f–j were
obtained in only up to 6% yields (Table 1, entries 6–10).
Therefore, we could conclude that this method is suitable for
the synthesis of pyridazine 2a and its electron withdrawing
group (EWG)-containing derivatives. The introduction of any
electron-donating substituent retarded the cycloaddition reac-
tion. A significant advantage of two-chamber reactor applica-
tion is that the procedure of product isolation can be simplified
to solvent removal, giving the opportunity to reach nearly
[
17d,22]
this process is a synchronous concerted cycloaddition,
which is followed by the elimination of a molecule of benzyl
alcohol, nitrogen and a desired pyridazine 2. The next
possibility was that upon heating, benzyl alcohol can react with
the vinyl moiety, leading to acetaldehyde dibenzyl acetal
formation (Scheme 1, bottom). This is consistent with previously
[
23]
reported data on the conversion of vinyl ethers to acetales.
An additional experiment demonstrated that heating the
mixture of benzyl vinyl ether and benzyl alcohol in dioxane to
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
with pyridine-containing substrate 1e required only 1 hour to
achieve full conversion, 1a–d reacted with 4 in up to 2 days,
and 100% conversion of 1i and 1j was achieved in five days.
Tetrazines, which contained strong electron donating substitu-
ents, required noticeably more time and additional portions of
benzyl trideuterovinyl ether 4 to achieve full conversion of
tetrazine. Therefore, 3-chloro-6-methoxy-1,2,4,5-tetrazine 1g
reacted with 4 in 10 days, and dimethoxy-substituted tetrazine
1
f required 14 days to achieve high conversion of the substrate.
Analysing the results, summarized in Table 1, we concluded
that inasmuch as 1h required 21 days to achieve moderate
conversion using any acetylene surrogate. The best choice was
to apply a CaC À D O mixture in a one-pot manner to synthesize
Scheme 1. The proposed reaction mechanism and side product formation.
2
2
1
00°C for 48 h lead to the formation of acetaldehyde dibenzyl
3h due to an easier purification procedure: a single admixture
of starting material presence, but not a mixture of 3h with 1h,
4 and its side products. Therefore, a direct interaction of the
CaC À D O mixture and 1h at heating led to 3h in 35% yield
acetal.
Due to the abovementioned considerations, an additional
portion of benzyl vinyl ether was added to the reaction
mixtures with electron donating group-substituted compounds
2
2
and 96% deuterium incorporation value.
1
f–h because the latter required more time to achieve full
We performed quantum chemical modeling of the cyclo-
addition of acetylene and benzyl vinyl ether to 1,2,4,5-tetrazines
conversion of tetrazine than 1a–e, 1i, j.
1
2
Since an excess of acetylene surrogates was used in the
developed procedures, it was necessary to investigate the
problem of starting materials and waste recyclability. Regarding
calcium carbide, a number of rational decisions have been
proposed previously. Calcium carbide reacts with water,
producing acetylene and calcium hydroxide. In previous works,
(Figure 3). The same substituents R and R were selected in the
model reaction as were used in the experiments. The proposed
cage-like intermediates A and B can be formed via the
cycloaddition preceded by the formation of prereaction com-
plexes 1’ and 1“. In both pathways, transition states, TS1 and
TS2, corresponding to the concerted addition were found. We
it was proposed to reuse Ca(OH) in the synthesis of a new
selected the quantum chemical semiempirical method GFN2-
2
[18b]
[26]
portion of calcium carbide.
Undoubtedly, it is not a single
xTB
for geometry optimizations and vibrational frequency
way of its utilization. Recently, it was proposed to use calcium
hydroxide, which was produced from CaC in the production of
construction materials.
calculations, as it reproduced the geometries obtained by DFT
[20]
calculations. Single-point energy evaluations at the ωB97X-V/
def2-TZVP-gCP and RIJCOSX-PBE0-D4/def2-TZVP levels followed
geometry optimizations. Below, we abbreviate ωB97X-V/def2-
TZVP-gCP//GFN2-xTB and RIJCOSX-PBE0-D4/def2-TZVP//GFN2-
xTB as ωB97X-V/TZ//XTB2 and PBE0-D4/TZ//XTB2, respectively.
The formation of weakly bound preaddition complexes 1’
and 1“ was an endergonic process due to the loss of transla-
tional entropy. In the case of the acetylene path, the formation
of the model van der Waals complex 1’ is endergonic by at least
6.6 kcal/mol and up to 10.8 kcal/mol, according to the calcu-
lations at the ωB97X-V/TZ//XTB2 level (Table 3, PBE0-D4/TZ//
XTB2: 7.0 and 10.8 kcal/mol). The formation of 1’’ is in many
cases even more endergonic, reaching 14.4 kcal/mol for
2
,
[24]
During our study, it was noted that it is possible to separate
the desired pyridazine product from the uncovered benzyl vinyl
ether, benzyl alkohol and from the aforementioned side
product, acetaldehyde dibenzyl acetal. Certainly, uncovered
benzyl vinyl ether can be collected and reused. Acetaldehyde
dibenzyl acetal easily transforms to benzyl alkohol, and the
latter can be reused in the synthesis of benzyl vinyl ether.
Furthermore, we applied the developed procedures for the
construction of D -labeled pyridazines. In this way, 1,2,4,5-
2
tetrazine 1a and its electron withdrawing group-containing
derivatives 1b–e reacted with calcium carbide and D O in a
2
1
2
two-chamber reactor, giving desired 4,5-dideuteropyridazines
R =R =H (Table 3, PBE0-D4/TZ//XTB2: 12.3 kcal/mol). Since the
preaddition complex formation was markedly endergonic, we
considered the sum of the Gibbs free energies in processes 1!
TS1 and 1!TS2 as the proper and experimentally relevant free
energy of activation in the cycloaddition stage, not 1’!TS1 and
1”!TS2, see below.
3
a–e in quantitative yields and excellent deuterium incorpo-
ration values (98–99%, Table 2, entries 1–5). The reaction was
performed in 1,4-dioxane to prevent undesirable deuterium-
[20,25]
hydrogen exchange.
To obtain D -labeled pyridazines from the less active 1,2,4,5-
2
tetrazines, benzyl trideuterovinyl ether 4 was synthesized by a
The free energy change in step 1’!TS1 depends signifi-
cantly on the electron-donating/withdrawing effect of the
substituents (Table 3). Electron withdrawing substituents facili-
tate the addition of acetylene. The lowest free energy of 5.7
[18j,20]
previously reported procedure.
The interaction of 4 with
tetrazines 1e–j led to the corresponding 4,5-dideuteropyrida-
zines in up to quantitative yields and 95–98% deuteration
degree (Table 2, entries 5–10). Moving from the most reactive
1
2
was observed with R =R =COOMe, according to the calculations
at the ωB97X-V/TZ//XTB2 level. In contrast, the addition to
3
,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine 1e to the less reactive 3-
dimethoxy-1,2,4,5-tetrazine 1f and 3-chloro-6-diethylamino-
,2,4,5-tetrazine 1h, we observed a significant decrease in the
reaction rates. The reaction of benzyl trideuterovinyl ether 4
1
2
1,2,4,5-tetrazine with R =R =NEt was hampered, and ΔG
2
1’!TS1
1
was equal to 34.7 kcal/mol.
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
Table 2. The construction of 4,5-dideuteropyridazines using acetylene
Table 2. continued
surrogates.
[
a]
[b]
[c]
Entry
Product
Method
Time
Yield
IP
[a]
[b]
[c]
Entry
1
Product
Method
Time
7d
Yield
IP
1
a–j, 4 (0.6 mmol), 1,4-dioxane (0.6 mmol), 100°C, 1 h–21 d (TLC/NMR-
control). Method C: One-pot procedure using 0.3 mmol of 1h, 2 mmol of
CaC
, 4 mmol of D
2
O, 1,4-dioxane (0.6 ml), 100
°
C, 21 d. [b] Isolated yield
A
99 (99)
99 (99)
99
99
2
shown in parentheses. [c] IP is a degree of deuterium incorporation. [d] Py
is 2-pyridyl; the deuteration degree may be underestimated due to
overlapping NMR signals.
2
3
4
5
6
7
8
9
A
7d
First and foremost, ΔG1
correlates well with experimen-
!TS1
A
7d
99 (99)
99 (99)
99
tal observations. The reaction time was approximately seven
days (see Table 3). Taken within the framework of the transition
state theory, a reference value of ~26.5 kcal/mol corresponds to
a reaction kinetic constant that, in turn, allows for a reaction to
[27]
1
2
A
7d
98
proceed in several days. With R =R equal to H, Cl, Br, COOMe,
and Pyr, the reaction proceeds to full conversion. In line with
this, ΔG1
is equal to 24.2, 28.5, 28.2, 12.3, and 23.5 kcal/mol,
!TS1
according to the calculations at the ωB97X-V/TZ//XTB2 level.
9
9
9 (99)/
9 (98)
[d]
A/B
B
5d/1 h
14d
10d
21d
5d
98/98
98
1
2
ΔG1
with R =R =Br is slightly greater than the threshold
!TS1
1
2
value. However, acetylene‘s cycloaddition to 1 with R =R equal
to H, Cl, Br, COOMe, Pyr proceeds with free activation energies
of 20.8, 24.7, 24.5, 12.3, and 21.0 kcal/mol, according to the
modeling at the PBE0-D4/TZ//XTB2 level.
95 (87)
96 (80)
35 (30)
99 (96)
1
2
1
2
1
The cases of R =OMe and R =Cl, R =R =Ph, R =NEt and
2
2
1
2
R =Cl, and R =R =C H N are borderline, as ΔG is above the
5
7
2
1!TS1
threshold of ~26.5 kcal/mol by several kcal/mol in these cases.
Indeed, only minor reactivity was observed in the experiments
described above in Table 1. Note that 1,2,4,5-tetrazine with
B
97
1
2
R =R =NEt is expected to be unreactive.
2
A similarly strong substituent effect was confirmed by
quantum chemical modeling of the benzyl vinyl ether path (see
C
96
Table 4). ΔG1
varied from 9.3 (6.0) kcal/mol with the
“!TS2
withdrawing COOMe to 40.2 (36.8) kcal/mol with the highly
donating NEt , as calculated at the ωB97X-V/TZ//XTB2 and
2
B
95
PBE0-D4/TZ//XTB2 levels. Combining ΔG1
with the ender-
”!TS2
gonic ΔG1
kinetic feasibility.
can give us an estimation of the reaction‘s 1!2
!1“
Note that the addition of benzyl vinyl ether was performed
at a significantly higher temperature of 100°C and reaction
1
0
B
5d
99 (95)
97
times up to 21 days (Table 1). We avoided thermochemical
calculations at 100°C because the reaction was performed in
solution. Consequentially, we needed to model solvent effects.
The selected SMD approach (solvation model based on
[electron] density) was parameterized to estimate the Gibbs
free energy of solvation of organic substances under standard
[
1
a] Method A: The substrate part was loaded with 0.3 mmol of 1a–j and
.0 ml of 1,4-dioxane; in the 2 part 2 mmol of CaC
nd
2
, 4 mmol of water
and 1,4-dioxane (0.6 ml) were placed; rt, 5–7 d. Method B: 0.3 mmol of
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
Figure 3. Model formations of cycloaddition intermediates in the acetylene (left) and benzyl vinyl ether (right) paths. Representative optimized structures of
transition states are shown with the interatomic distances between bonding atoms.
Table 3. Free energies of the transformations along the acetylene path (Figure 3, left) in kcal/mol.
1
2 [a]
R , R
ΔG1!1’
ΔG1’!TS1
ΔG1!TS1
ΔG1’!A
ΔG1!A
ΔG1!2
[
b]
[c]
Br
Cl
COOMe
H
NEt
OMe
Ph
9.3 (9.0)
8.9 (8.6)
6.6 (7.0)
18.8 (15.6)
19.6 (16.1)
5.7 (5.4)
28.2 (24.5)
28.5 (24.7)
12.3 (12.3)
24.2 (20.8)
45.5 (40.9)
35.0 (30.5)
29.7 (26.1)
23.5 (21.0)
38.3 (33.7)
32.0 (27.8)
32.7 (29.1)
À 34.5 (À 36.4)
À 34.2 (À 35.8)
À 45.1 (À 46.2)
À 36.8 (À 40.6)
À 7.5 (À 6.9)
À 25.1 (À 27.4)
À 25.3 (À 27.2)
À 38.5 (À 39.2)
À 26.0 (À 30.5)
3.3 (4.0)
À 114.8 (À 111.7)
À 113.0 (À 109.9)
À 125.6 (À 120.7)
À 107.0 (À 104.2)
À 91.1 (À 88.1)
10.8 (10.1)
10.8 (10.9)
9.1 (8.9)
8.8 (8.7)
7.1 (7.2)
9.2 (9.1)
8.9 (8.7)
10.4 (10.2)
13.4 (10.6)
34.7 (30.0)
25.9 (21.5)
20.8 (17.5)
16.4 (13.8)
29.1 (24.6)
23.2 (19.1)
22.3 (18.9)
2
À 24.9 (À 26.0)
À 27.4 (À 28.3)
À 35.4 (À 36.2)
À 16.9 (À 17.4)
À 28.4 (À 29.9)
À 34.2 (À 33.8)
À 15.8 (À 17.1)
À 18.6 (À 19.6)
À 28.3 (À 29.0)
À 7.7 (À 8.2)
À 105.3 (À 102.1)
À 103.2 (À 99.7)
À 116.0 (À 112.2)
À 100.3 (À 97.3)
À 108.6 (À 105.5)
À 110.9 (À 107.2)
2
-Pyridyl
NEt
OMe, Cl
2
, Cl
À 19.5 (À 21.2)
À 23.9 (À 23.6)
[
d]
C
5
H
7
N
2
[a] The para-substituent, see Figure 3; [b] without parentheses: computed at the RIJCOSX-ωB97X-V/def2-TZVP-gCP//GFN2-xTB level; [c] in parentheses:
RIJCOSX-PBE0-D4/def2-TZVP; SMD was used to account for bulk solvent effects (1,4-dioxane); [d] 3,5-dimethyl-1H-pyrazol-1-yl.
Table 4. Free energies of the transformations along the benzyl vinyl ether path (Figure 3, right), in kcal/mol.
1
2 [a]
R , R
ΔG1!1“
ΔG1”!TS2
ΔG1!TS2
ΔG1“!B
ΔG1!B
ΔGB!A
ΔG1!2
[
b]
[c]
Br
Cl
COOMe
H
NEt
OMe
10.1 (9.9)
8.7 (8.5)
8.2 (8.5)
14.4 (12.3)
9.8 (10.2)
7.7 (8.3)
8.8 (8.8)
6.3 (6.2)
8.3 (9.0)
10.5 (7.9)
13.4 (10.2)
9.3 (6.0)
20.5 (17.8)
22.1 (18.7)
17.5 (14.5)
19.4 (16.1)
49.9 (47.0)
35.0 (31.0)
29.2 (25.4)
21.9 (18.5)
28.9 (25.7)
À 19.4 (À 16.5)
À 18.2 (À 15.0)
À 26.7 (À 22.3)
À 24.4 (À 21.4)
18.5 (23.1)
À 9.3 (À 6.7)
À 9.5 (À 6.5)
À 18.5 (À 13.8)
À 10.0 (À 9.1)
28.2 (33.4)
0.5 (4.5)
7.7 (5.3)
7.7 (5.3)
3.5 (0.6)
7.5 (4.7)
À 1.4 (À 3.4)
7.3 (4.4)
6.0 (3.2)
1.4 (À 1.2)
6.3 (3.5)
À 91.2 (À 85.7)
À 89.4 (À 83.8)
À 102.1 (À 94.7)
À 83.5 (À 78.2)
À 67.6 (À 62.0)
À 81.8 (À 76.0)
À 79.7 (À 73.7)
À 92.5 (À 86.2)
À 76.7 (À 71.3)
5.0 (3.8)
2
40.2 (36.8)
27.3 (22.7)
20.4 (16.6)
15.6 (12.3)
20.6 (16.8)
À 7.2 (À 3.8)
Ph
À 9.9 (À 5.6)
À 1.1 (3.2)
2
C
-Pyridyl
H N
5 7 2
À 12.4 (À 8.0)
À 14.9 (À 10.0)
À 6.1 (À 1.8)
À 6.6 (À 1.0)
[
d]
[
a] The substituents, see Figure 3; [b] without parentheses: computed at the RIJCOSX-ωB97X-V/def2-TZVP-gCP//GFN2-xTB level; [c] in parentheses: RIJCOSX-
PBE0-D4/def2-TZVP; SMD was used to account for bulk solvent effects (1,4-dioxane); [d] 3,5-dimethyl-1H-pyrazol-1-yl.
À
conditions of 25°C and 1 atm. A temperature change of +75°C
can significantly alter the solubility of potentially volatile
organic substances. Therefore, performing SMD calculations in
our case can introduce errors that cannot be estimated yet. We
thus used standard free energies of activation to roughly
estimate the reactivity of benzyl vinyl ether in cycloaddition to
synthesis with benzyl vinyl ether are required to facilitate BzO
+
and H elimination. See a related discussion in our previous
work.
A value of 33 kcal/mol can be taken as a roughly estimated
[20]
¼6
reference for ΔG that corresponds to a reaction proceeding in
several days at 100°C, according to the Eyring transition state
[27]
1
,2,4,5-tetrazines relative to that of acetylene. However, one
theory. Table 4 demonstrates that almost all 1,2,4,5-tetrazines
can react with benzyl vinyl ether. The only exception is highly
unreactive 3,6-bis(diethylamino)-1,2,4,5-tetrazine. Therefore,
should note that the presented values are for a comparison
only. Note that elevated temperatures in the heterocycle
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
subquantitative yields of approximately 90% with benzyl vinyl
ether could be a result of possible side reactions. Additionally,
elevated temperatures allow activation of almost all 1,2,4,5-
tetrazines in the cycloaddition except for the most unreactive.
Considering the last columns in Tables 3 and 4, we see that
the whole reaction 1!2 is highly exergonic with ΔG
below
1!2
~
90 kcal/mol along the acetylene path and ~62 kcal/mol along
the benzyl vinyl ether path. The expected thermodynamic
driver of the reaction is the elimination of N , which has a
2
strong chemical bond. ΔG
in Table 4 also demonstrates that
B!A
the transition from the right to left pathway via the elimination
of BnOH immediately after cycloaddition is moderately unfavor-
able in most cases. However, at elevated temperatures, such a
pathway cannot be excluded.
We conducted a virtual Hammett study to quantify the
substituent effect in the cycloadditions of acetylene and benzyl
vinyl ether and the whole reaction 1!2. A standard linear
dependence of reaction (activation) free energy on the
substituent effect was assumed (correspondingly, ΔG and
rxn
¼
6
ΔG ). Additionally, we assumed that the total substituent effect
of R and R could be approximated by the sum of individual
Hammett constants for para-substituents, s and s . Therefore,
1
2
1
2
R
P
R
P
6¼
a linear approximation of DGrxn and DG should be valid:
�
ꢀ
R1
P
R
2
R
1
R
2
6¼
DGrxn or DG ¼ c
s
þ sP þ DG , sP þ sP ¼ sP,
(1)
P
0
where DG is the intercept value corresponding to the reaction
0
1
2
R
R
1
2
(
activation) free energy when sP ¼ sP ¼ 0, i.e., R =R =H. The
obtained approximations for ΔG1 ΔG , ΔG , and ΔG
1!
!A,
1!B
1!TS1
TS2, as well as the computed ωB97X-V/TZ//XTB2 level values, are
depicted in Figure 4.
1
2
R
R
6¼
Figure 4. Correlation of the sum sP þ sP with DGrxn and DG . Scatter plots
show the values calculated at the ωB97X-V/TZ//XTB2 level (solvent effects
included). Linear approximations of DGrxn and DG according to equa-
Table 5 summarizes the results of linear fits. Good correla-
2
tions were obtained in all cases, with R values exceeding 0.83.
6
Root-mean-square deviations are significant, however. We
suppose that many factors, e.g., substituent steric effects,
cannot be captured by simple equation (1). Formulating a
tion (1) are also shown.
general multivariate linear model is beyond the scope of the Conclusions
present study and would require a separate mechanistic and
QSAR study.
A significant electronic substituent effect on the formation
To summarize, two convenient and cost-efficient paths to 3,6-
disubstituted pyridazines and their 4,5-dideuterated analogs of
high levels of deuterium incorporation were proposed. Most of
the described 4,5-dideuteropyridazines were obtained for the
first time. Calcium carbide and benzyl vinyl ether are both
suitable for use as acetylene surrogates in [4+2] cycloaddition
with 1,2,4,5-tetrazines.
of intermediates A and B, whole reaction 1!2, and the free
energy of activation is evident. The obtained absolute values of
6
cP exceed 10.9 and 18.2 kcal/mol for DG of acetylene and
benzyl vinyl ether. The difference of 10–20 kcal/mol can
significantly change the kinetic feasibility, as seen in the
experiments described above.
P 0
Table 5. Summary of the linear fitting. c , DG , MD, and RMSD are in kcal/mol.
1
!TS1
1!A
1!2 [via A]
1!TS2
1!B
1!2 [via B]
2
[a]
[b]
R
0.83 (0.85)
0.92 (0.90)
0.90 (0.91)
0.90 (0.90)
À 14.2 (À 14.2)
27.2 (23.9)
3.2 (3.2)
0.90 (0.87)
À 18.2 (À 18.8)
À 2.9 (0.8)
4.1 (5.0)
0.89 (0.90)
c
P
À 12.4 (À 10.9)
29.3 (25.8)
3.5 (2.8)
À 16.8 (À 17.6)
À 20.8 (À 22.2)
3.2 (3.8)
À 13.6 (À 13.1)
À 109.0 (À 105.6)
2.9 (2.7)
À 13.4 (À 12.9)
À 85.7 (À 79.8)
3.2 (2.9)
DG
RMSD
0
[
c]
[
a] Without parentheses: the values computed at the RIJCOSX-ωB97X-V/def2-TZVP-gCP//GFN2-xTB level were used for the linear fits; [b] in parentheses:
RIJCOSX-PBE0-D4/def2-TZVP values were used; [c] root-mean-square deviation.
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
7
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
1
13
The calcium carbide-water (D O) mixture demonstrated
on Bruker Avance III ( H 400 MHz; C 101 MHz) and Bruker Avance
1 13
2
5
00 ( H 500 MHz; C 126 MHz) spectrometers. Chemical shifts δ are
reported in ppm relative to residual CHCl ( H, δ=7.26) and CDCl
C, δ=77.16) as internal standards. 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–
excellent reactivity towards 1,2,4,5-tetrazine and 1,2,4,5-tetra-
zines, which contain electron withdrawing substituents: the
reaction proceeded well at room temperature, leading to 3,6-
disubstituted pyridazines and 4,5-dideuteropyridazines, respec-
tively, in quantitative yields. The reaction of calcium carbide
and water with 1,2,4,5-tetrazine demonstrated the best results
in distributed reaction space mode (two-chamber reactor). A
two-chamber reactor allowed separation of a source of basic
1
3
3
1
3
(
(
4
00 Mesh), which was previously treated with triethylamine.
calcium hydroxide, a mixture CaC À H O, and base-sensitive
2
2
Computational Details
tetrazines. The application of a two-chamber reactor simplified
the isolation procedure to solvent evaporation, making the
synthesis of EWG-containing pyridazines and 4,5-dideuteropyr-
idazines of 98–99% deuteration degree from 1,2,4,5-tetrazines
and calcium carbide exceptionally convenient and environ-
mentally friendly.
[29]
[26]
We used ORCA 4.2.1.
GFN2-xTB
was selected to perform
geometry optimizations and vibrational frequency calculations.
Vibrational mode analysis was performed with a finite differences
procedure (“NUMFREQ”). Thermochemical corrections were com-
puted within the ideal gas and QR-RHO approximations.
modified version (which allows for thermochemical calculations
involving XTB-optimized structures) of the Otherm script by the
Duarte group was used to conduct all thermochemical calculations
[
30]
A
[
31]
Concerning benzyl vinyl ether and benzyl D -vinyl ether, we
3
can consider this approach reliable for the efficient synthesis of
a wide range of pyridazines and 4,5-dideuteropyridazines. The
use of benzyl vinyl ether and its deuterated analog led us to
propose a convenient one-pot methodology, since vinyl ethers
are compatible with any 1,2,4,5-tetrazines. Benzyl vinyl ether
except those involving N and HC�CH molecules representing the
2
D
symmetry group. For thermochemical calculations involving
h
1
the latter two molecules, the original ORCA 4.2.1 was used.
Acetylene and nitrogen were treated as ideal gases in the standard
state in thermochemical calculations. All other intermediates and
transition states were considered as solutes (1 M).
and benzyl D -vinyl ether demonstrated excellent reactivity in
3
[
3
4+2] cycloaddition to less active 3,6-diphenyl-1,2,4,5-tetrazine,
,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine, which has
All transition states had one imaginary mode corresponding to (un)
binding of an acetylene or benzyl vinyl ether molecule. According
to the vibrational mode analysis, all intermediates, reaction
products, and reactants had no imaginary modes. Solvent effects
bulky substituents, and even to electron donating group-
containing 1,2,4,5-tetrazines. Using the developed procedures, a
number of pyridazines and 4,5-dideuteropyridazines of 95–98%
deuteration degree were obtained in up to 99% yields.
[32]
were accounted for by using SMD.
SMD calculations were
[33]
performed at the M06-2X/6-31+G* level,
as in our previous
[20]
related work.
information.
Calculated data are included in the supporting
The strong substituent effect was confirmed and quantified
by quantum chemical calculations. The cycloaddition of
acetylene to disubstituted 1,2,4,5-tetrazines was performed
under ambient conditions, which, with the strong substituent
effect, led to a limited scope, i.e., 1,2,4,5-tetrazines bearing
electron-donating substituents were unreactive. Using benzyl
vinyl ether as an acetylene surrogate allowed us to perform the
reaction at elevated temperatures, which alleviates the sub-
stituent effect in the cycloaddition, widening the synthetic
methodology‘s scope. No significant mechanistic difference
between the one-pot and two-chamber methods was found in
quantum chemical calculations. The latter method is, however,
significantly more versatile since it allows reactions at higher
temperatures.
Single-point energy evaluations at optimized geometries were
[34]
[35]
performed with two DFT functionals, PBE0 and ωB97X-V. In
[36]
PBE0 calculations, the D4 dispersion correction was included. In
ωB97X-V calculations, the nonlocal correlation term was calculated
[
37]
self-consistently (“SCNL”). Geometrical counterpoise corrections
were computed using the original code by the Grimme group. The
[
38]
RIJCOSX approximation was used to speed up calculations. The
[39]
[40]
def2-TZVP
and Def2/J
basis sets were selected. In all DFT
calculations, Kohn-Sham matrices were recalculated in each KS-SCF
iteration (“directresetfreq 1”). Dense integration grids were used,
“
GRID6”, “GridX6”, and “vdwgrid3”; also, the “NOFINALGRID” option
was switched on. Tight convergence criteria, “TightSCF,” were
selected in KS-SCF procedures.
All electronic energies, enthalpies, and free energies are included in
the supporting information. Linear regression was performed using
A linear model including only the electronic substituent
[41]
the scikit-learn library.
effect is suboptimal and gives significant deviations.
A
comprehensive QSAR study of the reaction mechanism will be a
future project.
General procedure A: The synthesis of pyridazines and
D -pyridazines using calcium carbide in a two-chamber
2
reactor
Experimental Section
The reaction was performed in a two-chamber reactor of reversed
Y-tube type or H-tube type. The substrate part of the two-chamber
reactor was loaded with 0.3 mmol of 1a–e and 1.0 ml of 1,4-
General
dioxane, benzene or CHCl (1,4-dioxane in the case of deuterated
3
All chemicals were purchased from Sigma Aldrich, Alfa Aesar and
Acros Organics in reagent grade or better quality and used without
further purification. Tetrazines 1a–c,
procedures reported previously.
by a previously reported procedure. NMR spectra were recorded
nd
pyridazine synthesis). In the 2 part of the reactor, 2 mmol of CaC2
and a solvent (0.6 ml) were placed. Then, 4 mmol of water (or D O)
2
j
were synthesized by
D -vinyl ether was synthesized
20]
was added carefully to the carbide vessel. The reactor was
thoroughly sealed with a cup, and the stirring was started carefully
[
19b,28]
3
[
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
8
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
+
+
at small speeds (100 rpm) to avoid vigorous acetylene formation
and undesirable transfer of water to the substrate part. When the
release of acetylene almost stopped, the stirring was gradually
intensified (up to 1400 rpm), and the reaction mixture was stirred at
room temperature for the next 5–7 days. Then, the contents of the
substrate part were carefully collected using a syringe, and the
solvent was evaporated to give pure pyridazine 2a–e or 3a–e.
(2OMe). HRMS (ESI) Calcd. for C H N O [M+H] 141.0659, found
141.0659.
6
9
2
2
3
-Chloro-6-methoxypyridazine 2g was synthesized by procedure
B, yield 43 mg (90%). Colorless solid. M.p. 86–87°C (lit. 88–
[48] 1
8
6
8.5°C).
H NMR (400 MHz, CDCl ) δ 7.35 (d, J=9.2 Hz, 1H, H-4),
3
13
.95 (d, J=9.2 Hz, 1H, H-5), 4.11 (s, 3H, OMe). C NMR (101 MHz,
4
5
CDCl ) δ 164.6 (C), 151.2 (C), 130.9 (CH ), 120.2 (CH ), 55.3 (OMe).
3
+
+
HRMS (ESI) Calcd. for C H ClN O [M+H] 145.0163, found
5
6
2
145.0166.
General procedure B: The application of benzyl vinyl ether
and benzyl D -vinyl ether as C H /C D surrogates in the
3
2
2
2
2
3-Chloro-6-diethylaminopyridazine 2h was synthesized by proce-
[
49]
synthesis of pyridazines and D -pyridazines
°
2
dure C, yield 55 mg (30%). Orange viscous oil (lit. m.p. 51–53 C).
1
H NMR (400 MHz, CDCl ) δ 7.14 (d, J=9.6 Hz, 1H, H-4), 6.71 (d, J=
3
The reaction tube was loaded with 0.3 mmol of 1a–j, 0.6 mmol of
9
.6 Hz, 1H, H-5), 3.56 (q, J=7.1 Hz, 4H, 2CH ), 1.20 (t, J=7.1 Hz, 6H,
2
benzyl vinyl ether or benzyl D -vinyl ether 4 and 0.6 ml of 1,4-
3
13
2
1
CH3). C NMR (101 MHz, CDCl ) δ 157.3 (C), 145.2 (C), 128.7 (CH),
3
dioxane. After sealing, it was heated to 100°C until 100%
conversion of tetrazine was achieved (TLC/NMR-control). If neces-
sary, an additional portion of benzyl vinyl ether or 4 can be poured
into the reaction mixture to achieve full conversion. Then, the
solvent was evaporated, and the resulting pyridazines 2a–j and
+
13.9 (CH), 43.2 (2CH ), 12.8 (2CH ). HRMS (ESI) Calcd. for C H ClN
2
3
8
13
3
+
[
M+H] 186.0793, found 186.0791.
3
,6-Diphenylpyridazine 2i was synthesized by procedure B, yield
[
50] 1
63 mg (91%). Colorless solid. M.p. 217–218 C (lit. 219–220 C).
°
°
H
3
a–j were purified by column chromatography (SiO , hexane/ethyl
2
NMR (400 MHz, CDCl
3
) δ 8.18–8.15 (m, 4H), 7.94 (s, 2Hpyridazine), 7.58–
1
3
acetate 10:1).
7.49 (m, 6H). C NMR (101 MHz, CDCl ) δ 157.8 (2C
), 136.2
3
pyridazine
(
2 C), 130.2 (2CH), 129.2 (4CH), 127.1 (4CH), 124.4 (2CHpyridazine).
+ +
HRMS (ESI) Calcd. for C H N [M+H] 233.1073, found 233.1077.
1
6
13
2
General procedure C: The synthesis of 2h and 3h from
calcium carbide in a one-pot manner
3
,6-Bis(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine 2j was synthe-
sized by procedure B, yield 75 mg (93%). Colorless solid. M.p. 170–
172 C (lit. 178–180 C).
[
51]
1
The reaction tube was loaded with 0.3 mmol of 1h, 2 mmol of CaC2
°
°
H NMR (400 MHz, CDCl ) δ 8.21 (s,
3
13
and 0.6 ml of 1,4-dioxane. Then, water or D O (4 mmol) was
2
2H
), 6.05 (s, 2Hpyrazole), 2.74 (s, 6H, 2Me), 2.30 (s, 6H, 2Me).
C
pyridazine
carefully added, the tube was sealed, and the reaction mixture was
NMR (101 MHz, CDCl ) δ 155.0 (2 C), 151.3 (2 C), 142.4 (2 C), 122.9
3
stirred at 100°C for 21 days. After this, the product was isolated by
(
2CHpyridazine), 110.1 (2CH
), 14.9 (2Me), 13.7 (2Me). HRMS (ESI)
pyrazole
+
+
column chromatography (SiO , hexane/ethyl acetate 10:1).
2
Calcd. for C H N Na [M+Na] 291.1329, found 291.1329.
14 16 6
Pyridazine 2a was synthesized by procedure A, yield 24 mg (99%).
4
,5-Dideuteropyridazine 3a was synthesized by procedure A, yield
[
42] 1
Colorless oil (lit. m.p. À 6.4°C).
H NMR (400 MHz, CDCl ) δ 9.17 (t,
J=3.5 Hz, 2H, H ), 7.46 (t, J=3.5 Hz, 2H, H ). C NMR (101 MHz,
CDCl ) δ 151.8 (2CH=N), 126.4 (2CH). HRMS (ESI) Calcd. for
1
3
24 mg (99%). Colorless oil. H NMR (400 MHz, CDCl ) δ 9.13 (s,
3
13
3,6
4,5 13
2
H). C NMR (101 MHz, CDCl ) δ 151.6 (2CH), 126.0 (t, J=25.7 Hz,
3
+ +
3
2CD). HRMS (ESI) Calcd. for C H D N Na [M+Na] 105.0392, found
4 2 2 2
+
+
C H N Na [M+Na] 103.0267, found 103.0263.
4
4
2
105.0391
,6-Dichloro-4,5-dideuteropyridazine 3b was synthesized by pro-
3
,6-Dichloropyridazine 2b was synthesized by procedure A, yield
[43] 1
3
4 mg (99%). Colorless solid. M.p. 69°C (lit. 69°C).
H NMR
13
4
(
(
°
cedure A, yield 45 mg (99%). Beige solid. M.p. 65–67 C. C NMR
13
400 MHz, CDCl ) δ 7.52 (s, 2H). C NMR (101 MHz, CDCl ) δ 156.1
3 3
+ +
(101 MHz, CDCl ) δ 156.1 (C), 130.1 (t, J=27.0 Hz, 2CD). HRMS (ESI)
Calcd. for C HD N Cl [M+H] 150.9793, found 150.9791.
3
+
+
2 C), 130.5 (2CH). HRMS (ESI) Calcd. for C H Cl N
[M+H]
4
3
2
2
4
2
2
2
148.9668, found 148.9669.
3
,6-Dibromo-4,5-dideuteropyridazine 3c was synthesized by pro-
1
3
3
,6-Dibromopyridazine 2c was synthesized by procedure A, yield
°
cedure A, yield 71 mg (99%). Yellow solid. M.p. 108–110 C. C NMR
[44] 1
7
1 mg (99%). Orange solid. M.p. 95–97°C (lit. 115–116°C).
H
(101 MHz, CDCl ) δ 147.7 (2 C), 133.0 (t, J=27.1 Hz, 2CD). HRMS
3
13
+
+
NMR (400 MHz, CDCl ) δ 7.53 (s, 2H). C NMR (101 MHz, CDCl ) δ
3
3
(ESI) Calcd. for C HD N Br [M+H] 240.8763, found 240.8767.
4
2
2
2
+
+
1
47.7(2 C), 133.5 (2CH). HRMS (ESI) Calcd. for C H Br N [M+H]
4 3 2 2
Dimethyl 4,5-dideuteropyridazine-3,6-dicarboxylate 3d was syn-
thesized by procedure A, yield 59 mg (99%). Colorless solid. M.p.
238.8637, found 238.8633.
1
13
Dimethyl pyridazine-3,6-dicarboxylate 2d was synthesized by
procedure A, yield 58 mg (99%). Colorless solid. M.p. 191–193°C (lit.
°
1
82–184 C. H NMR (400 MHz, CDCl ) δ 4.10 (s, 6H). C NMR
3
(101 MHz, CDCl ) δ 164.1 (2CO Me), 152.8 (2 C), 128.0 (t, J=26.8 Hz,
3
2
[
45] 1
95–196°C).
H NMR (400 MHz, CDCl ) δ 8.33 (s, 2H), 4.10 (s, 6H,
3
+
+
1
2
1
1
2CD), 53.8 (2OMe). HRMS (ESI) Calcd. for C H D N O [M+H]
199.0682, found 199.0682.
8
7
2
2
4
13
OMe). C NMR (101 MHz, CDCl ) δ 164.1 (2CO Me), 152.9 (2 C),
28.5 (2CH), 53.8 (2OMe). HRMS (ESI) Calcd. for C H N O [M+H]
97.0557, found 197.0557.
3
2
+
+
8
9
2
4
4
,5-Dideutero-3,6-di(pyridin-2-yl)pyridazine 3e was synthesized
by procedure A, yield 70 mg (99%). Colorless solid. M.p. 175–177°C.
1
3
,6-Di(pyridin-2-yl)pyridazine 2e was synthesized by procedure A,
H NMR (400 MHz, CDCl ) δ 8.74 (d, J=8.0 Hz, 2H), 8.71 (d, J=
3
yield 69 mg (99%). Colorless solid. M.p. 177–178°C (lit. 178–
4.6 Hz, 2H), 7.88 (td, J=7.8, 1.7 Hz, 2H), 7.38 (ddd, J=7.3, 4.9,
[46] 1
79°C).
H NMR (400 MHz, CDCl ) δ 8.77–8.72 (m, 4H), 8.69 (s,
3
13
1
2
2
0.8 Hz, 2H). C NMR (101 MHz, CDCl ) δ 158.2 (2 C), 153.5 (2 C),
149.5 (2CH), 137.3 (2CH), 124.85 (2CH), 124.83 (t, JC- D+ =26.2 Hz,
2CD), 121.8 (2CH). LCMS (ESI-TOF) Calcd. for C H D N [M+H]
3
H
), 7.90 (td, J=7.8, 1.8 Hz, 2H), 7.40 (ddd, J=7.5, 4.8, 1.1 Hz,
pyridazine
13
+
H). C NMR (101 MHz, CDCl ) δ 158.3 (2 C), 153.5 (2 C), 149.5
3
1
4
9
2
4
(
2CH), 137.4 (2CH), 125.3 (2CH), 124.9 (2CH), 121.9 (2CH). HRMS (ESI)
237.1104, found 237.1109.
+ +
Calcd. for C H N [M+H] 235.0978, found 235.0980.
14
11
4
4
,5-Dideutero-3,6-dimethoxypyridazine 3f was synthesized by
3
3
1
2
,6-Dimethoxypyridazine 2f was synthesized by procedure B, yield
procedure B, yield 37 mg (87%). Colorless solid. Start sublimating at
5 mg (83%). Colorless solid. M.p. 98–100°C (lit. m.p. 103.6–
1
13
4
0 C. M.p. 98 C. H NMR (400 MHz, CDCl ) δ 4.05 (s, 6H, 2OMe).
°
°
C
3
[
47] 1
04.8°C).
H NMR (400 MHz, CDCl ) δ 6.92 (s, 2H, 2CH), 4.05 (s, 6H,
3
NMR (126 MHz, CDCl ) δ 162.1 (2 C), 121.1 (t, J =25.9 Hz, 2CD),
3
C-D
1
3
OMe). C NMR (126 MHz, CDCl ) δ 162.2 (2 C), 121.5 (2CH), 54.7
3
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
9
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
+
+
5
4.7 (2OMe). HRMS (ESI) Calcd. for C H D N O [M+H] 143.0784, Acknowledgements
6
7
2
2
2
found 143.0785.
We gratefully acknowledge financial support from the Russian
Science Foundation (Project N 19-73-10032). The authors express
their gratitude to the Resource Centres of Saint Petersburg State
University: Magnetic Resonance Research Centre and Chemical
Analysis and Materials Research Centre.
3
-Chloro-4,5-dideutero-6-methoxypyridazine 3g was synthesized
1
o
by procedure B, yield 35 mg (80%). Colorless solid. M.p. 89°C. H
13
NMR (400 MHz, CDCl ) δ 4.12 (s, 3H, OMe). C NMR (101 MHz,
3
4
CDCl ) δ 164.6 (C), 151.2 (C), 130.5 (t, J =26.6 Hz, CD ), 119.8 (t, J
3
5
C-D
C+ -
=
26.3 Hz, CD ), 55.4 (OMe). HRMS (ESI) Calcd. for C H D ClN O
5 4 2 2
+
D
[M+H] 147.0289, found 147.0291.
3
-Chloro-6-diethylamino-4,5-dideuteropyridazine 3h was synthe-
sized by procedure C, yield 17 mg (30%). Orange solid. M.p. 46–
1
Conflict of Interest
4
8°C. H NMR (400 MHz, CDCl ) δ 3.56 (q, J=7.1 Hz, 4H, 2CH ), 1.20
3
2
13
(
t, J=7.1 Hz, 6H, 2CH ). C NMR (101 MHz, CDCl ) δ 157.0 (C), 145.1
C), 128.5 (t, J =26.4 Hz, CD), 113.9 (t, J =26.0 Hz), 43.3 (2CH ),
3
3
(
C-D
C-D
2
The authors declare no conflict of interest.
+
+
12.8 (2CH ). HRMS (ESI) Calcd. for C H D ClN [M+H] 188.0918,
3 8 11 2 3
found 188.0916.
Keywords: acetylene · cycloaddition · deuterium · labeling ·
pyridazine
4
,5-Dideutero-3,6-diphenylpyridazine 3i was synthesized by pro-
cedure B, yield 67 mg (96%). Colorless solid. M.p. 220–222°C. H
1
1
3
NMR (400 MHz, CDCl ) δ 8.18–8.15 (m, 4H), 7.57–7.48 (m, 6H).
C
3
NMR (101 MHz, CDCl ) δ 157.8 (2C
), 136.2 (2 C), 130.2 (2CH),
3
pyridazine
1
29.2 (4CH), 127.1 (4CH), 124.0 (t, J =25.5 Hz, 2CD). HRMS (ESI)
C-D
+ +
[1] a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
Calcd. for C H D N [M+H] 235.1199, found 235.1200.
16
11
2
2
5845–5859; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2
014, 57, 10257–10274; c) Z. Ye, S. Adhikari, Y. Xia, D. Mingji, Nat.
4
,5-Dideutero-3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine 3j
Commun. 2018, 9, 721; d) M. A. Walker, Expert Opin. Drug Discovery
was synthesized by procedure B, yield 77 mg (95%). Colorless solid.
2
014, 9, 1421–433; e) T. Y. Zhang, Adv. Heterocycl. Chem. 2017, 121, 1–
1
M.p. 171–172°C. H NMR (400 MHz, CDCl ) δ 6.06 (s, 2Hpyrazole), 2.75
3
12; f) M. Henary, C. Kananda, L. Rotolo, B. Savino, E. A. Owens, G.
13
(
(
(
s, 6H, 2Me), 2.31 (s, 6H, 2Me). C NMR (101 MHz, CDCl ) δ 155.0
2 C), 151.3 (2 C), 142.5 (2 C), 122.6 (t, J =27.8 Hz, 2CD), 110.1
2CHpyrazole), 14.9 (2CH ), 13.7 (2CH ). LCMS (ESI-TOF) Calcd. for
3
Cravotto, RSC Adv. 2020, 10, 14170–14197; g) L. K. M. O. Goni, M. A.
Jafar Mazumder, M. A. Quraishi, M. Mizanur Rahman, Chem. Asian J.
2021, 16, 1324–1364.
C-D
3
3
+
+
C H D N [M+H] 271.1635, found 271.1639.
[2] a) N. Kerru, L. Gummidi, S. Maddila, K. K. Gangu, S. B. Jonnalagadda,
Molecules 2020, 25, 1909; b) S. K. Parida, S. K. Hota, R. Kumar, S. Murarka,
Chem. Asian J. 2021, 16, 879–889; c) M. M. Heravi, V. Zadsirjan, RSC Adv.
2020, 10, 44247–44311; d) B. Seifinoferest, A. Tanbakouchian, B. Larijani,
M. Mahdavi, Asian J. Org. Chem. 2021, 10, 1319–1344; e) F. O.
Rodriguez del Rey, P. E. Floreancig, Org. Lett. 2021, 23, 150–154; f) S.
Dongbang, D. N. Confair, J. A. Ellman, Acc. Chem. Res. 2021, 54, 1766–
1
4
15
2
6
3
,6-Dimethoxy-1,2,4,5-tetrazine 1f: To the round bottom flask
were placed 120 mg of 3,6-dichloro-1,2,4,5-tetrazine 1b, 150 mg of
sodium methoxide and 2 ml of dry methanol. The reaction mixture
was stirred at room temperature for 24 hours, then the solvent was
evaporated, and the product was purified by flash chromatography
1
778; g) V. García-Vázquez, L. Hoteite, C. P. Lakeland, D. W. Watson,
(
SiO , hexane/ethyl acetate 10:1), giving pure 1f as a red crystals
2
[52] 1
J. P. A. Harrity, Org. Lett. 2021, 23, 2811–2815; h) M.-J. Yi, H.-X. Zhang, T.-
F. Xiao, J.-H. Zhang, Z.-T. Feng, L.-P. Wei, G.-Q. Xu, P.-F. Xu, ACS Catal.
2021, 11, 3466–3472; i) D. K. Lang, R. Kaur, R. Arora, B. Saini, S. Arora,
Anti-Cancer Agents Med. Chem. 2020; 20, 2150–2168.
(
100 mg, 89%). M.p. 65°C (lit. 62°C).
H NMR (400 MHz, CDCl ) δ
3
13
4
.22 (s, 6H). C NMR (101 MHz, CDCl ) δ 166.5 (2 C), 56.8 (2OMe).
3
+ +
HRMS (ESI) Calcd. for C H N O Na [M+Na] 165.0383, found
4
6
4
2
1
65.0390.
[3] a) C. G. Wermuth, MedChemComm 2011, 2, 935–941; b) P. G. Sergeev,
V. G. Nenajdenko, Russ. Chem. Rev. 2020, 89, 393–429; c) S. Fanning, J.
Wang, N. Leonard, in Encyclopedia of Food Safety (Ed.: Y. Motarjemi),
Academic Press, Waltham, 2014, pp. 39–44; d) F. Chast, in The Practice
of Medicinal Chemistry (Third Edition) (Ed.: C. G. Wermuth), Academic
Press, New York, 2008, pp. 1–62; e) H. Bockholt, J. M. Beale, J. Rohr,
Angew. Chem. Int. Ed. 1994, 33, 1648–1651; Angew. Chem. 1994, 106,
3
-Chloro-6-methoxy-1,2,4,5-tetrazine 1g: To the round bottom
flask were placed 80 mg of 3,6-dichloro-1,2,4,5-tetrazine 1b, 30 mg
of sodium methoxide and 2 ml of 1:1 mixture dry methanol/1,4-
dioxane. The reaction mixture was stirred at room temperature for
2
hours, the solvent was evaporated, and the product was purified
1
733–1735; f) R. Grote, Y. Chen, A. Zeeck, Z. X. Chen, H. Zähner, P.
by flash chromatography (SiO , hexane/ethyl acetate 10:1), giving
2
Mischnick-Lübbecke, W. A. König, J. Antibiot. 1988, 41, 595–601; g) A.
Schroeder Henry, Circulation 1952, 5, 28–37; h) M. Imran, M. Asif, Russ. J.
Bioorg. Chem. 2020, 46, 745–767; i) P. J. Rayner, M. J. Burns, E. J. Fear,
S. B. Duckett, Magn. Reson. Chem. 2021, Early View, DOI: 10.1002/
mrc.5152.
pure 1g as orange crystals (72 mg, 93%). M.p. 60–62°C (lit. 66–
[53]
1
13
6
8°C).
H NMR (400 MHz, CDCl ) δ 4.33 (s, 3H). C NMR (101 MHz,
3
CDCl ) δ 167.1 (C), 164.6 (C), 57.5 (OMe). HRMS (ESI) Calcd. for
C H N OClNa [M+Na] 168.9888, found 168.9893.
3
+
+
3
3
4
[
4] a) P. Ciapetti, B. Giethlen, in The Practice of Medicinal Chemistry (Fourth
Edition) (Eds.: C. G. Wermuth, D. Aldous, P. Raboisson, D. Rognan),
Academic Press, San Diego, 2008, pp. 181–241; b) A. Dorababu, Bioorg.
Chem. 2019, 93, 103299.
3
-Chloro-6-diethylamino-1,2,4,5-tetrazine 1h: To the round bot-
tom flask 80 mg of 3,6-dichloro-1,2,4,5-tetrazine 1b and 1 ml of dry
,4-dioxane were placed. To the resulting mixture, 50 μl of triethyl-
1
[
5] a) C. Barberot, A. Moniot, I. Allart-Simon, L. Malleret, T. Yegorova, M.
Laronze-Cochard, A. Bentaher, M. Médebielle, J.-P. Bouillon, E. Hénon, J.
Sapi, F. Velard, S. Gérard, Eur. J. Med. Chem. 2018, 146, 139–146; b) E. M.
Ahmed, M. S. A. Hassan, A. A. El-Malah, A. E. Kassab, Bioorg. Chem. 2020,
amine and 120 μl of pure diethylamine were added. The reaction
mixture was stirred at room temperature for 24 hours, and then
5
ml of water and 5 ml of chloroform were added to the reaction
vessel. The organic layer was separated, and the aqueous layer was
95, 103497.
extracted three times with small portions of CHCl . The combined
organic extracts were washed twice with water and then dried over
Na SO . After solvent removal, pure 1h was obtained as an orange-
red viscous oil (140 mg, 94%). H NMR (400 MHz, CDCl ) δ 3.76 (q,
[6] A. Sabt, W. M. Eldehna, T. Al-Warhi, O. J. Alotaibi, M. M. Elaasser, H.
Suliman, H. A. Abdel-Aziz, J. Enzyme Inhib. Med. Chem. 2020, 35, 1616–
1630.
3
2
4
1
[7] Z. Liu, J. Lou, J. Xiao, Org. Lett. 2021, 23, 1606–1610.
3
[
53] 13
[8] a) Q. Mei, R. Sheng, W. Cheng, J. Zhang, P. Wang, Q. Mei, P. Chen, B.
Tong, Dalton Trans. 2020, 49, 13797–13804; b) M. Li, Y. Yuan, Y. Chen,
ACS Appl. Mater. Interfaces 2018, 10, 1237–1243.
[9] a) N. E. Tayar, H. van de Waterbeemd, M. Gryllaki, B. Testa, W. F. Trager,
Int. J. Pharm. 1984, 19, 271–281; b) M. Turowski, N. Yamakawa, J. Meller,
J=7.1 Hz, 4H, 2CH ), 1.27 (t, J=7.1 Hz, 6H, 2CH ).
C NMR
2
3
(
101 MHz, CDCl ) δ 159.8 (C), 159.1 (C), 42.8 (2CH ), 12.5 (2CH ).
3
2
3
+
+
HRMS (ESI) Calcd. for C H N ClNa [M+Na] 210.0517, found
6
10
5
210.0517.
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
10
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
K. Kimata, T. Ikegami, K. Hosoya, N. Tanaka, E. R. Thornton, J. Am. Chem.
Soc. 2003, 125, 13836–13849; c) C. L. Perrin, Y. Dong, J. Am. Chem. Soc.
k) A. Hosseini, P. R. Schreiner, Org. Lett. 2019, 21, 3746–3749; l) R. Fu, Z.
Li, Org. Lett. 2018, 20, 2342–2345; m) S. P. Teong, Y. Zhang, J. Biores.
Bioprod. 2020, 5, 96–100; n) K. S. Rodygin, I. Werner, V. P. Ananikov,
ChemSusChem 2017, 11, 292–298; o) L. Gao, Z. Li, Org. Chem. Front.
2020; p) J. Demaerel, C. Veryser, W. M. De Borggraeve, React. Chem. Eng.
2020, 5, 615–631; q) A. Y. Dubovtsev, N. V. Shcherbakov, D. V. Dar’in,
V. Y. Kukushkin, J. Org. Chem. 2020, 85, 745–757; r) L. Gao, Z. Liu, X. Ma,
Z. Li, Org. Lett. 2020, 22, 5246–5250; s) D. Li, S. Qiu, Y. Chen, L. Wu,
ChemistrySelect 2020, 5, 12034–12037; t) H. Lu, Z. Li, Adv. Synth. Catal.
2019, 361, 4474–4482; u) S. A. Metlyaeva, K. S. Rodygin, K. A. Lotsman,
D. E. Samoylenko, V. P. Ananikov, Green Chem. 2021, 23, 2487–2495;
v) D. A. Shabalin, A. Y. Dubovtsev, E. Y. Schmidt, B. A. Trofimov, Chemis-
trySelect 2020, 5, 3434–3437; w) X. Ma, Z. Li, Synlett 2021, 32, 631–635;
x) R. Fu, Y. Lu, G. Yue, D. Wu, L. Xu, H. Song, C. Cao, X. Yu, Y. Zong, Org.
Lett. 2021, 23, 8, 3141–3145; y) H. Lu, Z. Li, Eur. J. Org. Chem. 2020, 845–
851.
2
007, 129, 4490–4497; d) C. L. Perrin, B. K. Ohta, J. Kuperman, J.
Liberman, M. Erdélyi, J. Am. Chem. Soc. 2005, 127, 9641–9647.
10] a) S. L. Harbeson, R. D. Tung, in Annu. Rep. Med. Chem., Vol. 46 (Ed.: J. E.
Macor), Academic Press, 2011, pp. 403–417; b) J. Yang, in Deuterium
[
[
(
Ed.: J. Yang), Elsevier, 2016, pp. 31–97.
11] a) M. Shigenobu, K. Takenaka, H. Sasai, Angew. Chem. Int. Ed. 2015, 54,
572–9576; Angew. Chem. 2015, 127, 9708–9712; b) J.-H. Chu, C.-C.
9
Chen, M.-J. Wu, Organometallics 2008, 27, 5173–5176; c) M. Miyashita,
M. Sasaki, I. Hattori, M. Sakai, K. Tanino, Science 2004, 305, 495; d) A. E.
Mutlib, Chem. Res. Toxicol. 2008, 21, 1672–1689.
[
12] a) G. S. Timmins, Expert Opin. Ther. Pat. 2014, 24, 1067–1075; b) A.
Mullard, Nat. Rev. Drug Discovery 2018, 17, 81; c) C. Schmidt, Nat.
Biotechnol. 2017, 35, 493.
[
13] a) J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed. 2018,
5
7, 1758–1784; Angew. Chem. 2018, 130, 1774–1802; b) T. Pirali, M.
[19] a) V. V. Voronin, M. S. Ledovskaya, E. G. Gordeev, K. S. Rodygin, V. P.
Ananikov, J. Org. Chem. 2018, 83, 3819–3828; b) M. S. Ledovskaya, V. V.
Voronin, K. S. Rodygin, V. P. Ananikov, Org. Chem. Front. 2020, 7, 638–
647.
Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 2019, 62, 5276–5297;
c) H. I. M. Amin, C. Raviola, A. A. Amin, B. Mannucci, S. Protti, M. Fagnoni,
Molecules 2019, 24, 2164; d) Z. Zhan, X. Peng, Y. Sun, J. Ai, W. Duan,
Chem. Res. Toxicol. 2018, 31, 1213–1218; e) C. Taglang, D. E. Korenchan,
C. von Morze, J. Yu, C. Najac, S. Wang, J. E. Blecha, S. Subramaniam, R.
Bok, H. F. VanBrocklin, D. B. Vigneron, S. M. Ronen, R. Sriram, J.
Kurhanewicz, D. M. Wilson, R. R. Flavell, Chem. Commun. 2018, 54, 5233–
[20] M. S. Ledovskaya, V. V. Voronin, M. V. Polynski, A. N. Lebedev, V. P.
Ananikov, Eur. J. Org. Chem. 2020, 2020, 4571–4580.
[21] a) M. S. Ledovskaya, V. V. Voronin, K. S. Rodygin, Russ. Chem. Rev. 2018,
87, 167–191; b) V. V. Voronin, M. S. Ledovskaya, A. S. Bogachenkov, K. S.
Rodygin, V. P. Ananikov, Molecules 2018, 23, 2442; c) S. D. Schnell, M.
Schilling, J. Sklyaruk, A. Linden, S. Luber, K. Gademann, Org. Lett. 2021,
23, 2426–2430.
[22] a) J. Cioslowski, J. Sauer, J. Hetzenegger, T. Karcher, T. Hierstetter, J. Am.
Chem. Soc. 1993, 115, 1353–1359; b) D. V. Sadasivam, E. Prasad, R. A.
Flowers, D. M. Birney, J. Phys. Chem. A 2006, 110, 1288–1294; c) D. L.
Boger, R. P. Schaum, R. M. Garbaccio, J. Org. Chem. 1998, 63, 6329–6337;
d) A. Hamasaki, R. Ducray, D. L. Boger, J. Org. Chem. 2006, 71, 185–193;
e) L. R. Domingo, M. T. Picher, J. A. Sáez, J. Org. Chem. 2009, 74, 2726–
2735; f) J. M. J. M. Ravasco, J. A. S. Coelho, J. Am. Chem. Soc. 2020, 142,
4235–4241; g) B. Rickborn, In Organic Reactions, (Ed. L. A. Paquette)
John Wiley & Sons, Inc., Hoboken, NJ, 1998, pp 224–286; h) D. Brown, S.
Muranjan, Y. Jang, R. Thummel, Org. Lett. 2002, 4, 1253–1256; i) Y. Xu, T.
Åkermark, V. Gyollai, D. Zou, L. Eriksson, L. Duan, R. Zhang, B. Åkermark,
L. Sun, Inorg. Chem. 2009, 48, 2717–2719.
5
4
236; f) A. C. Reyes, T. L. Amyes, J. P. Richard, Biochemistry 2018, 57,
338–4348; g) K. Parcella, K. Eastman, K.-S. Yeung, K. A. Grant-Young, J.
Zhu, T. Wang, Z. Zhang, Z. Yin, D. Parker, K. Mosure, H. Fang, Y.-K. Wang,
J. Lemm, X. Zhuo, U. Hanumegowda, M. Liu, K. Rigat, M. Donoso, M.
Tuttle, T. Zvyaga, Z. Haarhoff, N. A. Meanwell, M. G. Soars, S. B. Roberts,
J. F. Kadow, ACS Med. Chem. Lett. 2017, 8, 771–774; h) C. Gerlach, M.
Wüst, J. Agric. Food Chem. 2017, 65, 10775–10780.
[
14] a) S. J. Li, D. C. Fang, Organometallics 2018, 37, 1373–1380; b) H.
Ben El Ayouchia, L. Bahsis, H. Anane, L. R. Domingo, S. E. Stiriba, RSC
Adv. 2018, 8, 7670–7678; c) R. Saha, S. Mondal, A. Chatterjee, P. Pal, K.
Chakrabarty, G. K. Das, J. Organomet. Chem. 2021, 937, 121744–121744;
d) C. Wang, Y. Zhou, X. Bao, J. Org. Chem. 2017, 82, 3751–3759; e) F. Yu,
Z. Zhou, J. Song, Y. Zhao, RSC Adv. 2021, 11, 2744–2755; f) Y. Lin, T.
Zhou, W. Guo, Z. Teng, Y. Xia, Dalton Trans. 2019, 48, 5698–5704.
15] a) B. Yuan, H. Zhou, Y. Yu, X. Guo, Y. Zhao, F. Zhang, H. Zhou, H. Huang,
R. He, New J. Chem. 2021, 45, 131–140; b) M. Y. Ovchinnikov, T. A.
Yangirov, A. N. Lobov, R. M. Sultanova, S. L. Khursan, J. Phys. Chem. B
[
[23] a) J. A. Schneider, K. Yoshihara, J. Org. Chem. 1986, 51, 1077–1079;
b) M. J. van Vliet, J. Visscher, A. W. Schwartz, Nucleosides Nucleotides
1994, 13, 2113–2124; c) J. H. Freudenberger, Y. Matsui, M. Orchin, Chem.
Lett. 1982, 11, 1811–1814.
[24] B. A. Akinyemi, B. O. Orogbade, C. W. Okoro, J. Cleaner Prod. 2021, 279,
123693.
2
017, 121, 6601–6609.
[
16] a) G. Molteni, A. Ponti, Molecules 2021, 26, 928–928; b) W. Yahia, A.
Khorief Nacereddine, M. Liacha, A. Djerourou, Int. J. Quantum Chem.
2
018, 118; c) C. Wang, C. Flinn, Y. Zhao, RSC Adv. 2017, 7, 36623–36631;
d) D. Hallooman, M. Ríos-Gutiérrez, L. Rhyman, I. A. Alswaidan, L. R.
Domingo, P. Ramasami, RSC Adv. 2018, 8, 27406–27416; e) A. Amoah, R.
Tia, E. Adei, Tetrahedron 2020, 76, 131422–131422; f) Y. Yao, W. Yang, Q.
Lin, W. Yang, H. Li, L. Wang, F. Gu, D. Yang, Org. Chem. Front. 2019, 6,
[25] M. F. Hawthorne, J. J. Miller, J. Am. Chem. Soc. 1958, 80, 754–754.
[26] C. Bannwarth, S. Ehlert, S. Grimme, J. Chem. Theory Comput. 2019, 15,
1652–1671.
[27] H. Ryu, J. Park, H. K. Kim, J. Y. Park, S. T. Kim, M. H. Baik, Organometallics
2018, 37, 3228–3239.
3360–3364; g) K. Abbiche, N. Acharjee, M. Salah, M. Hilali, A. Laknifli, N.
Komiha, K. Marakchi, J. Mol. Model. 2020, 26, 1–12; h) A. Morales-
Bayuelo, J. Sánchez-Márquez, G. Jana, P. K. Chattaraj, Struct. Chem. 2020,
[28] a) J. Sauer, D. K. Heldmann, J. Hetzenegger, J. Krauthan, H. Sichert, J.
Schuster, Eur. J. Org. Chem. 1998, 1998, 2885–2896; b) M. Abdo, S. P.
Brown, J. R. Courter, M. J. Tucker, R. M. Hochstrasser, A. B. Smith 3rd,
Org. Lett. 2012, 14, 3518–3521.
3
2
1, 1745–1756; i) R. Jasiński, E. Jasińska, E. Dresler, J. Mol. Model. 2017,
3, 1–9; j) C. Sobhi, A. Khorief Nacereddine, A. Djerourou, M. Ríos-
Gutiérrez, L. R. Domingo, J. Phys. Org. Chem. 2017, 30, e3637-e3637.
17] a) Y. Wang, D. Wei, W. Zhang, ChemCatChem 2018, 10, 338–360; b) K.
Selvaraj, S. Chauhan, K. Sandeep, K. C. K. Swamy, Chem. Asian J. 2020,
[29] F. Neese, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73–78.
[30] S. Grimme, Chem. Eur. J. 2012, 18, 9955–9964.
[
[31] GitHub
– duartegroup/otherm: thermochemical contributions from
1
5, 2380–2402; c) R. Jasiński, E. Dresler, Organika 2020, 1; d) T. Deb, J.
ORCA calculations https://github.com/duartegroup/otherm (accessed
March 22, 2021).
Tu, R. M. Franzini, Chem. Rev. 2021, ASAP Articles, DOI: 10.1021/
acs.chemrev.0c01013.
[32] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378–6396.
[
18] a) K. S. Rodygin, M. S. Ledovskaya, V. V. Voronin, K. A. Lotsman, V. P.
Ananikov, Eur. J. Org. Chem. 2021, 2021, 43–52; b) K. S. Rodygin, Y. A.
Vikenteva, V. P. Ananikov, ChemSusChem 2019, 12, 1483–1516; c) D.
Scharnagel, I. Escofet, H. Armengol-Relats, M. E. de Orbe, J. N. Korber,
A. M. Echavarren, Angew. Chem. Int. Ed. 2020, 59, 4888–4891; Angew.
Chem. 2020, 132, 4918–4921; d) K. J. Ardila-Fierro, C. Bolm, J. G.
Hernández, Angew. Chem. Int. Ed. 2019, 58, 12945–12949; Angew. Chem.
[33] a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241; b) W. J.
Hehre, K. Ditchfield, J. A. Pople, J. Chem. Phys. 1972, 56, 2257–2261;
c) M. M. Francl, W. J. Pietro, W. J. Hehre, J. S. Binkley, M. S. Gordon, D. J.
DeFrees, J. A. Pople, J. Chem. Phys. 1982, 77, 3654–3665; d) V. A.
Rassolov, J. A. Pople, M. A. Ratner, T. L. Windus, J. Chem. Phys. 1998, 109,
1223–1229.
2
019, 131, 13079–13083; e) R. Matake, Y. Adachi, H. Matsubara, Green
[34] C. Adamo, V. Barone, J. Chem. Phys. 1999, 110, 6158–6170.
[35] N. Mardirossian, M. Head-Gordon, Phys. Chem. Chem. Phys. 2014, 16,
9904–9924.
[36] E. Caldeweyher, S. Ehlert, A. Hansen, H. Neugebauer, S. Spicher, C.
Bannwarth, S. Grimme, J. Chem. Phys. 2019, 150, 154122.
[37] H. Kruse, S. Grimme, J. Chem. Phys. 2012, 136, 154101–154101.
[38] F. Neese, F. Wennmohs, A. Hansen, U. Becker, Chem. Phys. 2009, 356,
98–109.
Chem. 2016, 18, 2614–2618; f) Z. Liu, Z. Li, Eur. J. Org. Chem. 2021, 2021,
3
2
02–308; g) S. Liu, S. Yin, Z. Zhang, H. Liu, M. Liu, B. Han, ChemistrySelect
020, 5, 3644–3646; h) S. P. Teong, A. Y. H. Chua, S. Deng, X. Li, Y.
Zhang, Green Chem. 2017, 19, 1659–1662; i) V. V. Voronin, M. S.
Ledovskaya, K. S. Rodygin, V. P. Ananikov, Org. Chem. Front. 2020, 7,
1
334–1342; j) M. S. Ledovskaya, V. V. Voronin, K. S. Rodygin, A. V.
Posvyatenko, K. S. Egorova, V. P. Ananikov, Synthesis 2019, 51, 3001;
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
11
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
[
[
[
39] F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297–3297.
40] F. Weigend, Phys. Chem. Chem. Phys. 2006, 8, 1057–1057.
41] F. Pedregosa, G. Varoquaux, A. Gramfort, V. Michel, B. Thirion, O. Grisel,
M. Blondel, P. Prettenhofer, R. Weiss, V. Dubourg, J. Vanderplas, A.
Passos, D. Cournapeau, M. Brucher, M. Perrot, E. Duchesnay, J. Mach.
Learn. Res. 2011, 12, 2825–2830.
[50] A. Padwa, A. Rodriguez, M. Tohidi, T. Fukunaga, J. Am. Chem. Soc. 1983,
105, 933–943.
[51] G. L. Rusinov, R. I. Ishmetova, N. I. Latosh, I. N. Ganebnych, O. N.
Chupakhin, V. A. Potemkin, Russ. Chem. Bull. 2000, 49, 355–362.
[52] R. I. Ishmetova, N. I. Latosh, I. N. Ganebnykh, N. K. Ignatenko, S. G.
Tolshchina, G. L. Rusinov, Russ. J. Org. Chem. 2009, 45, 1102–1107.
[53] A. Kotschy, Z. Novák, B. Bostai, M. Csékei, K. Lorincz, Heterocycles 2003,
60, 2653–2668.
[42] W. Hückel, W. Jahnentz, Ber. Dtsch. Chem. Ges. 1942, 75, 1438–1446.
[43] H. Feuer, H. Rubinstein, J. Org. Chem. 1959, 24, 811–813.
[44] E. A. Steck, R. P. Brundage, L. T. Fletcher, J. Am. Chem. Soc. 1954, 76,
3
225–3226.
[
45] G. Özer, N. Saraçoglu, M. Balci, J. Heterocycl. Chem. 2003, 40, 529–533.
[
46] R. Hoogenboom, B. C. Moore, U. S. Schubert, J. Org. Chem. 2006, 71,
4
903–4909.
[
47] K. M. Clapham, A. S. Batsanov, R. D. R. Greenwood, M. R. Bryce, A. E.
Smith, B. Tarbit, J. Org. Chem. 2008, 73, 2176–2181.
Manuscript received: May 25, 2021
[
[
48] E. A. Steck, R. P. Brundage, J. Am. Chem. Soc. 1959, 81, 6511–6514.
49] G. Pifferi, F. Parravicini, C. Carpi, L. Dorigotti, J. Med. Chem. 1975, 18,
Revised manuscript received: June 18, 2021
Accepted manuscript online: June 21, 2021
Version of record online: ■■■, ■■■■
7
41–746.
Chem Asian J. 2021, 16, 1–13
www.chemasianj.org
12
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Full Paper
FULL PAPER
Two novel synthetic paths to 3,6-
disubstituted pyridazines and 4,5-
dideuteropyridazines from 1,2,4,5-
tetrazines and acetylene surrogates
Dr. M. S. Ledovskaya, Dr. M. V.
Polynski, Prof. Dr. V. P. Ananikov*
were proposed. CaC demonstrated
1 – 13
2
excellent results in reactions with
One-Pot and Two-Chamber Meth-
odologies for Using Acetylene Sur-
rogates in the Synthesis of Pyrida-
zines and Their D-Labeled
Derivatives
1
,2,4,5-tetrazine and acceptor-substi-
tuted derivatives, and benzyl (D3-)
vinyl ether was found to be a better
choice for reactions with donor-sub-
stituted tetrazines. Competitive ex-
periments and quantum chemical
calculations were performed for
mechanistic study.