Cyclization of β-Chlorovinyl Thiohydrazones into Pyridazines: A Mechanistic Study

Article abstract of DOI:10.1002/ejoc.201801118

Extensive experimental and theoretical investigations on the isomerization and heterocyclizations of β-chlorovinyl thiohydrazones derived from oxamic acid thiohydrazides and β-chlorovinyl aldehydes were performed to elucidate the reaction mechanism of pyr

Full text of DOI:10.1002/ejoc.201801118

A Journal of
Accepted Article
Title: Cyclization of β-chlorovinyl thiohydrazones into pyridazines: A
mechanistic study
Authors: Anna S. Komendantova, Artem N. Fakhrutdinov, Leonid G.
Menchikov, Alexey Yu. Sukhorukov, Igor V. Zavarzin, and
Yulia Volkova
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801118
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European Journal of Organic Chemistry
10.1002/ejoc.201801118
FULL PAPER
Cyclization of β-chlorovinyl thiohydrazones into pyridazines:
A mechanistic study
[
a]
[a]
[a]
[a]
Anna S. Komendantova, Artem N. Fakhrutdinov, Leonid G. Menchikov, Alexey Yu. Sukhorukov,
[
a]
[a]
Igor V. Zavarzin, and Yulia A. Volkova*
Abstract: Extensive experimental and theoretical investigations on
the isomerization and heterocyclizations of β-chlorovinyl
thiohydrazones derived from oxamic acid thiohydrazides and
β-chlorovinyl aldehydes were performed to elucidate the reaction
mechanism of pyridazines formation. We showed that model
β-chlorovinyl thiohydrazone undergoes multiple isomerization
reactions in solution induced by thione-thiol tautomerism and Z/E-
isomerization at the C=N bond. Mechanistic rationalization along
with computational studies demonstrated that pyridazine is
predominantly generated from the Z-thiol isomers via 6π-
electrocyclization of the thiohydrazone-derived 2,3-diazatriene
intermediate. The autocatalytic character of cyclization accelerated
1
by the formation of acid was demonstrated by means of H NMR
monitoring.
Scheme 1. Cyclization of β-chlorovinyl aldehydes with oxamic acid
thiohydrazides to form pyridazines.
Introduction
The proposed approach demonstrates high product yields,
functional group tolerance, and good scope for aliphatic and
aromatic substrates, including complex natural products.15 We
Pyridazines comprise an important class of six-membered
nitrogen-containing heterocycles with a broad spectrum of
biological activities.1 Highly functionalized pyridazines are used
assumed that the transformation of β-chlorovinyl aldehydes I is
initiated by the formation of the 2,3-diazahexatriene intermediate
V (tautomer of β-chlorovinyl thiohydrazones IV) that readily
undergoes 6π-electrocyclization via the formation of
dihydropyridazine VI (Scheme 1). However the proposed
mechanism was controversial since the β-chlorovinyl
as
аntihypertensive drugs
(hydralazine,
dihydralazine,
2
3
endralazine) and antidepressants (pipofezine, minaprine). The
frequent presence of the pyridazine moiety in medicinally
4
5
relevant compounds, dyes and ligands for metal catalysts and
its wide use in crystal engineering6 have inspired the
development of many novel methods for their preparation.7
Thus, the Michael-type addition/nucleophilic cyclization of cyano
16
thiohydrazones were not isolated and characterized. The key
intermediates, by-products and factors that influence on
pyridazines formation were unclear. Here, we report the results
of extensive experimental and preliminary theoretical
mechanistic investigation on the condensation of β-chlorovinyl
aldehydes with oxamic acid thiohydrazides giving pyridazines.
The special focus was made on the isomerization and
tautomerism of β-chlorovinyl thiohydrazone intermediates, which
is the source of their unique reactivity.
compounds,8
ring-closing
olefin
metathesis,9
tandem
1
0
Staudinger–diaza-Wittig reactions of 2-diazo-2-vinylcarbonyls,
catalytic hydrogenation-aldolization of aldehydes,11 and
heterocyclization of diarylmaleic anhydrides12 have been
employed to prepare highly diverse pyridazine derivatives.
On the other hand (β-halo)vinyl compounds have been always
considered as convenient and readily available reagents in
organic synthesis, including synthesis of N-heterocycles.13 In
particular, we have developed a general synthesis of 3-
Results and Discussion
carbamide-substituted
pyridazines
(III)
via
tandem
imination/heterocyclization of β-chlorovinyl aldehydes (I) with
oxamic acid thiohydrazides (II) (Scheme 1).14
In order to gain insight into the reaction mechanism, we
performed H NMR, pH, IR and UV-monitoring experiments and
1
some QM calculations (see the Supporting information). The IR
and UV techniques were found poorly efficient, while NMR-
monitoring has allowed to get constituent data on reaction. The
condensation of cyclohexene-based β-chlorovinyl aldehyde 1
with 4-methoxyphenyl substituted oxamic acid thiohydrazide 2
giving pyridazine 4 was studied as a model reaction (Scheme
[
a]
N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russia.
E-mail:yavolkova@gmail.com
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/
).17 In special experiments, TsOH (10 mol%) was added to
promote the intermediate formation of thiohydrazone 3.
2
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European Journal of Organic Chemistry
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General aspects. The model reaction toward 4 as the major
product was performed at room temperature in non-polar, polar,
aprotic, and protic solvents (octane, CHCl , EtOH, DMSO) under
3
an inert argon atmosphere and in the presence of ambient
oxygen (see the Supporting information for the yields and
experimental details for product 4).18 In all cases, the formation
of 4 was detected and was accompanied by the elimination of
elemental sulfur. The EI mass spectra of crude reaction mixtures
+
of 1 with thiohydrazide 2 showed molecular ion peaks M of both
8
product 4 (285 m/z) and S (256 m/z). The quantitative
elimination of sulfur was proved by its isolation by column
chromatography. Balancing a chemical reaction equation with
respect to the extrusion of elemental sulfur suggested the
formation of hydrochloric acid as another side product of the
reaction (Scheme 2). This is consistent with the pH monitoring of
the reaction by the virtue of the fact that the pH of the reaction
mixtures decreased to strongly acidic values during the course
of the reaction (for detailed pH monitoring see the Supporting
Information). An analysis of the published data showed that the
ring contraction of N-heterocycles through extrusion of elemental
sulfur are scarce.19 Nevertheless, several studies reported the
simultaneous elimination of elemental sulfur and the acid HHal,20
including heterocyclization of halogenated thiohydrazones. Two
principal opportunities for the formation of HHal and S as side
products via the stepwise elimination of components and via the
one-step elimination of HSHal that decomposes under the
reaction conditions are likely.21
Figure 1. Isomerization of β-chlorovinyl thiohydrazones.
Thiohydrazone isomerization. In contrast to classical
hydrazones, three major Lewis structure formulas provided by
an extra C=S group can contribute to thiohydrazone 3 real
structure, namely thione A, thiol B, and thiadiazoline structure
C22 generated through the intramolecular ring closure of thiol B
(
Figure 1, line a). The geometry of the С=С-Cl bond in 3 is cis
locked, but cis-trans isomerization at N=C-H and N=С-SH
double bonds can be induced by the thione-thiol tautomerization,
elevated temperature and reversibility of the iminium bond
formation (Figure 1, line b). Therefore thiohydrazone 3 can
undergo multiple isomerization reactions in solution.
Next, it was found that model reaction can be stopped at the
step of the hydrazone 3 formation after a short-term treatment of
Surprisingly, the solution-state structure of compound
established by detailed NMR studies, showed that, in relatively
3
aldehyde
temperature (rt) in ethanol supplemented with 10 mol% TsOH
Scheme 2). Compound 3 was isolated in 91% yield in the pure
1 with oxamic acid thiohydrazide 2 at room
non-polar CDCl
3
, hydrazone 3 exists exclusively as E-3-thione
1
isomer (Figure 2). The H NMR spectrum shows characteristic
singlets at δ 12.21, 10.07, and 8.68 ppm assigned to thioamide
NH, amide NH, and imine CH, respectively.
(
form after the removal of TsOH by washing. Thiohydrazone 3
o
was found to be stable during storage at +4 C in the solid state
6
By contrast, in polar DMSO-d hydrazone 3 was found to exist
within several weeks and was used in NMR monitoring
experiments without additional purification. Nucleophilic addition
of thiohydrazide 2 to the double bond of β-chlorovinyl aldehyde 1
was not detected under these conditions, which is attributed to
the low reactivity of the chlorovinyl center in nucleophilic addition
reactions.
as a mixture of three isomers (Figure 3). The C=N bond trans:cis
isomers E-3-thione and Z-3-thione and also cyclic 3-
thiadiazoline were detected (Figure 1, A and C). In the H NMR
1
Figure 2. Representative parts of the 1H NMR spectra of hydrazone 3 in
3
CDCl at 298K recorded 30 min after dissolution.
Scheme 2. Model reaction
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European Journal of Organic Chemistry
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1H NMR monitoring in DMSO-d
and CDCl
. The real-time
6
3
1
monitoring of the heterocyclization by H NMR spectroscopy was
used to evaluate the consumption of each isomer of
thiohydrazone 3 at any point of time and then to calculate the
total conversion since side processes in the model reaction are
minimized. The cyclization of 3 to pyridazine 4 (Figures 4 and 5)
was performed in an NMR tube at rt to slow down the reaction
rate, allowing the quantification of the initial rate of formation of
product 4. The effect of isomerization of thiohydrazone 3 on the
course of the reaction was estimated by comparing the NMR
data in DMSO-d
Figure 4 presents a typical series of 1H NMR spectra for the
conversion of hydrazone 3 to pyridazine 4 in DMSO-d , which
6 3
and CDCl solutions.
6
shows the consumption of all three isomers within 48 h and the
simultaneous formation of pyridazine 4 as the major product.
The time intervals between two measurements were adjusted
during the progress of the reaction, ranging from 5 min to 1 h,
with regard to decreasing cyclization rate. The 1H NMR
Figure 3. Representative parts of the 1H NMR spectra of hydrazone 3 in
DMSO-d at 298K recorded 30 min after dissolution.
6
spectrum of hydrazone 3 recorded in DMSO-d
sample preparation demonstrated that there was
thiadiazoline/E-3-thione mixture in a 2.1 : 1 ratio. Already within
0 min, the reaction mixture comprised 3-thiadiazoline, E-3-
6
5 min after the
a
3-
spectrum, these isomeric forms are characterized by two signals
from thioamide NH at δ 13.69 and 13.48 ppm and three signals
assigned to amide NH at δ 10.29, 10.25, and 9.95 ppm. A
singlet at 6.58 ppm attributed to the CH group of 3-thiadiazoline
form was found to correlate with amine NH at δ 8.76 ppm. The
tautomers E-3-thione and 3-thiadiazoline were found to be the
major isomers, meanwhile Z-3-thione is the minor isomer.
3
thione, and Z-3-thione in a 12.6 : 6 : 1 ratio. The convincing
evidence for the formation of pyridazine 4 (higher than 5%) was
obtained only 3 h after the beginning of the experiment, the ratio
of 3-thiadiazoline/E-3-thione/Z-3-thione isomers being shifted to
4
.8 : 2.3 : 1. During the course of the reaction, the excess of 3-
thiadiazoline with respect to E-3-thione increased from 2.1 to
.1, while the percentage of Z-3-thione first increased almost by
The observed solvent effects on isomerization of thiohydrazone
4
3
are attributed to the nucleophilic cyclization of E-3-thione to
cyclic 3-thiadiazoline facilitated in polar solvents.23 The
a factor of 4.5, with the maximum concentration being achieved
within 5 h, followed by its decrease up to complete consumption
in 43 h.26
3-thiadiazoline can easily undergo the ring-opening to form Z-3-
thione, reachable also from E-3-thione via rotation about the
carbon−nitrogen double bond.24 Others isomers expected for 3,
such as cis/trans 3-thiols (Figure 1, B), were not detected by
NMR spectroscopy as short-lived species, which are involved in
fast (on the NMR time scale) exchange. In fact, the total
energies calculated by DFT for Z-3-thiols predicted the same.
The isomerization equilibrium for hydrazone 3 suggested based
on NMR data, DFT calculations, and literature precedents is
generalized in Scheme 3. E-3-Thione isomerizes to cyclic 3-
thiadiazoline via intramolecular S-nucleophilic addition to the
imine bond.25 This process is reversible and favored by polar
solvents, such as DMSO. In the presence of acids (HCl, TsOH)
and water, E-3-thione is able to isomerize to Z-3-thione via the
acid-catalyzed Z/E isomerization of imines. The tautomeric shift
in E-and Z-3-thiones gives rise to unstable E,E-, E,Z-, Z,Z-, Z,E-
3-thiols. The “hub” of the isomerization equilibrium is 3-
thiadiazoline, which can undergo the ring opening giving all
isomeric thiones and thiols.
Scheme 3. Isomerization equilibrium for β-chlorovinyl thiohydrazone 3.
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European Journal of Organic Chemistry
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Figure 4. Real-time monitoring of chemical reactions by 1H NMR spectroscopy in DMSO-d
at 298 K and the kinetic plot of the consumption of thiohydrazone 3
6
isomers along with accumulation of pyridazine 4.
1
By contrast, the H NMR spectra of thiohydrazone 3 recorded 3
Table 1. Influence of bases on the reactiona,b
3
h after dissolution in CDCl did not show any significant changes
(
Figure 5). Only E-3-thione was reliably identified at a constant
concentration. A decrease in the percentage of E-3-thione in the
reaction mixture and a broadening of the signals were observed
during the subsequent two hours, which were attributed to the
establishment of the isomerization equilibrium.27 The convincing
evidence for the formation of pyridazine 4 was obtained 5 h after
the beginning of the experiment. The complete conversion of 3
to pyridazine 4 was achieved within the subsequent 33 h.
The autocatalytic character of the reaction is unambiguously
evidenced by the induction period observed in chloroform as
well as by an increase in the rate in the course of the reaction.
We assume that hydrochloric acid that is eliminated in the
course of heterocyclization acts as a catalyst, thus affecting
entry
1
Conditions
yield of 4, %
yield of 5, %
Et
3
Et
3
Et
3
N (1 equiv), rt, air, 48 h
-
-
isomerization of thiohydrazone
3
and accelerating the
2
3
4
N (1 equiv), reflux, air, 1.5 h
N (1 equiv), reflux, inert, 1.5 h
<5
-
40
-
transformation of E-3-thione into the reactive isomer that
2
8
undergoes cyclization. For instance, the addition of 10 mol%
2
9
acid to a solution of hydrazone 3 in CDCl
3
resulted in
elimination of the induction period and the immediate onset of
No base, reflux, air, 1.5 h
36
<5
1
the formation of product 4 (for detailed H NMR monitoring see
the Supporting information). Moreover, such bases as Et
Table 1), K CO or DBU added in an equimolar amount to a
solution of hydrazone compromised the reaction (for
experimental details see the Supporting Information).
3
N
[
a] Thiohydrazone 3 (158 mg, 0.45 mmol) in CHCl
3
(1.6 mL) under specified
(
2
3
conditions. [b] Isolated yield.
3
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European Journal of Organic Chemistry
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FULL PAPER
Figure 5. Real-time monitoring of chemical reactions by 1H NMR spectroscopy in CDCl
along with accumulation of pyridazine 4.
at 298 K and the kinetic plot for the consumption of E-3-thiohydrazone
3
In the presence of 1 equiv. of Et
temperature, the reaction did not proceed (Table 1, entry 1). The
reaction performed in the presence of Et N under reflux in CHCl
afforded pyridazine 4 in a dramatically low yield (less 5%, Table
, entry 2). 1,3,4-Thiadiazole 5 derived by the oxidation of 3-
3
N
in CHCl
3
at room
conditions. Hereby formation of strained seven-member ring -
6,7-dihydro-1,3,4-thiadiazepine as an alternative Ad
A
N
3
3
intermediate is unlikely. Finally, the 1,3,4-thiadiazepines of type
II are known to be stable compounds losing sulfur only under
harsh conditions.32,33 It is in consist with the calculated free
energies for the cyclization of intermediate B to fused thiirane D.
The activation barrier for this step was predicted to be 34.0
kcal/mol, that fails to meet the requirements of reaction taking
place at rt.
1
thiadiazoline tautomer with ambient air (Table 1, entries 2,3) was
isolated as the major reaction product in 40% yield (Table 1,
entries
thiohydrazone 3 under the same conditions in the absence of
Et N gave pyridazine 4 in 36% yield (Table 1, entry 4). Only
2
and 3).30 As a comparison, the cyclization of
3
trace amounts of 1,3,4-thiadiazole 5 were detected in this
experiment.
Proposed cyclization mechanisms. Heterocyclization of E-3-
thione into pyridazine 4 via the intramolecular attack of the S-
nucleophile on the electrophilic chlorovinyl center (Scheme 4) is
the most obvious mechanism.16,31 However it was excluded from
consideration due to the following experimental reasons. Firstly,
chlorovinyl center of thiohydrazone 3 was found poorly reactive
in nucleophilic addition reactions. Thus addition of N-
nucleophiles to solutions of 3 in chloroform and DMSO at rt did
not result in the formation of any coupling products. Secondly,
using NMR (Figure 3) and experiments with bases (Table 1) it
was shown that Ad
N
ring closure into five-member ring
intermediate 3-thiadiazoline occurs smoothly under mild
Scheme 4. Key intermediates of thiohydrazone
pyridazine 4.
3 AdN cyclization into
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European Journal of Organic Chemistry
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To gain insights on the reaction mechanism we turned to others
isomers of thiohydrazone 3. We assumed that most unstable Z-
3
-thiols can serve as the 2,3-diazahexatirene synthon that is
able to undergo 6π-electrocyclization.34 Their 6π-electron planes
formed by a chlorovinyl unit and two C=N double bonds. No-frills
electrocyclization reactions of Z,E- and Z,Z-3-thiols should
involve disrotatory ring closure giving rise to dihydropyridazine D
or D’, respectively (Scheme 5). Conrotatory mode of cyclization
is unlikely, because the reaction is not senstive to light and
smoothly occurs in the dark. The cyclization induced by
N
hydrochloric acid elimination from intermediate D via the S 2
mechanism should afford the fused thiirane intermediate E
followed by the extrusion of molecular sulfur to form product 4.32
Intermediate E can also be generated through HCl elimination
from dihydropyridazine D’ via the S
the direct elimination of HSCl from intermediates D or D’ via E
or E driven by aromatization can produce pyridazine 4 in one
step.
N
1 mechanism. Alternatively,
1
2
DFT calculations on the proposed reaction pathway were
performed as described in the Experimental Section. The free
energy profile for the first step of the reaction with 3-thiols as the
active species is shown in Figure 6, and additional
computational details, such as total energies, enthalpies, and
Gibbs Free energies for all isomers of mentioned compounds in
gas phase, chlorophorm and DMSO, are summarized in the
Supporting Information. Most importantly, it was found that the
electrocyclic ring closures of Z,E-3-thiol and Z,Z-3-thiol to
intermediates D and D’ via TS1 and TS2 are exergonic (1-13
kcal/mol) and occur with reasonably low activation barriers of
Figure 6. Free energy profile (kcal/mol) for the first step of the reaction with 3-
thiols as the active promoting species in the gas phase (in DMSO) and the
computed structures of the key stationary points.
20.4–26.4 kcal/mol (18.6-26.4 kcal/mol in DMSO). Calculations
performed for the conversions of dihydropyridines D or D’ to
pyridazine 4 via intermediate B predicted exothermic HCl and S
elimination processes. Interestingly, that the elimination of HSCl
from D or D’ is significantly exothermic (46–50 kcal/mol for the
8
stepwise elimination of HCl and 1/8S vs 33–37 kcal/mol for the
one-step HSCl elimination) and occurs with low activation
energies of 8.1–14.6 kcal/mol. The catalytic amounts of
Brønsted acids can accelerate 6π-electrocyclizations by
3
5
protonation of intermediates. This correlate with experimentally
shown autocatalytic character of reaction. Therefore,
comprehensive DFT calculations taking into account the
protonation of all reagents, intermediates and products will be
subject of further theoretical investigations focused on complete
elucidation of proposed mechanism.
Conclusions
The cyclization of β-chlorovinyl aldehydes and oxamic acid
thiohydrazides to 3-carbamide-substituted pyridazines was
studied both experimentally and theoretically. It was shown that
the heterocyclization proceeds at room temperature and is
accompanied by the extrusion of elemental sulfur and
acidification. Thiohydrazone proved to be the first-step
intermediate that undergoes isomerization in solution mediated
by thione–thiol tautomerization and cis–trans isomerization at
N=С-SH and N=C-H double bonds. The isomeric composition of
thiohydrazone was found to be strongly dependent on the
solvent polarity, which facilitates the thione–thiol tautomerism
and E/Z-isomerism. In dimethyl sulfoxide, E-thione, Z-thione,
and tautomeric thiadiazoline were detected by 1H NMR, while
only E-thione was observed in chloroform. Additionally, in
chloroform, the autocatalytic character of the reaction induced
Scheme 5. Proposed mechanistic pathways for the cyclization of
thiohydrazone 3 to pyridazine 4.
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European Journal of Organic Chemistry
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FULL PAPER
by hydrochloric acid that was revealed. The additives of acids
were found to accelerate the reaction, while the additives of
bases inhibit the formation of pyridazine and switch the reaction
pathway to 1,3,4-thiadiazole. On the brighter note they show for
the first time the potential of β-chlorovinyl thiohydrazones as 2,3-
diazahexatriene synthons thus giving rise to a novel type of α,β-
unsaturated thiohydrazones reactivity. Preliminary computational
results on the 6π-electrocyclic ring closure of β-chlorovinyl
thiohydrazone to pyridazine suggests that this pathway is
thermodynamically allowed and the calculated energy barriers
were found to be reasonably low. The full DFT calculations
taking into account protonation and an exploration of a solvates
must await additional studies.
(OMe), 114.6 (2×CH), 131.0 (2×CH), 131.0 (C), 156.6 (C), 158.0 (C=O),
1
68.1 (C=S). ESI-MS m/z: [M]+ 225.
(
2-(2-((2-Сhlorocyclohex-1-en-1-yl)methylene)hydrazinyl)-N-(4-
methoxyphenyl)-2-thioxoacetamide (3). Oxamic acid thiohydrazide 2
56 mg, 0.25 mmol) was added to a solution of chlorovinyl aldehyde 1 (42
(
mg, 0.29 mmol) and p-toluenesulfonic acid monohydrate (5 mg, 10
mol%) in ethanol (1 mL). The reaction mixture was stored at rt for 15 min
until the complete conversion of the intermediates (TLC monitoring). The
solvent was removed under reduced pressure and the residue was
dissolved in CH2Cl2 (15 mL). The organic layer was washed with water (3
× 10 mL) and dried over Na2SO4 for 30 min. Solvent distillation afforded a
product as a red-brown viscous substance in 91% yield (80 mg, 85-75%
1H NMR purity), which was used without additional purification.36 Rf
.71 (1:1 EtOAc: petroleum ether, visualized by 254 nm UV light). 1
=
H
0
Therefore, the study provides novel insights into the
isomerization of functionalized thiohydrazones and their
reactivity, revealing potential of α,β-unsaturated thiohydrazones
as 2,3-diazahexatriene synthons. Proven combination of
experimental and theoretical methods may be useful for
elucidation of others reactions mechanisms going through α,β-
unsaturated thiohydrazone intermediates.
NMR (600 MHz, CDCl3, recorded 1 h after dissolution, E-3-thione): δ
1.67-1.76 (m, 4Н, 2СН2), 2.49-2.56 (m, 4Н, 2СН2), 3.78 (s, 3Н, OCH3),
6
.86 (d, 2H, J = 9.00 Hz, Ar), 7.56 (d, 2H, J = 9.00 Hz, Ar), 8.68 (s, 1Н,
CH), 10.07 (s, 1H, CONH), 12.21 (s, 1H, CSNH). 13C {1H} NMR (125
MHz, CDCl3, E-3-thione): δ 21.3 (CH2), 23.4 (CH2), 25.5 (CH2), 35.5
(CH2), 55.5 (OCH3), 114.3 (2×CH), 121.5 (2×CH), 129.4 (C=), 129.8 (C),
1
43.5 (Cl-C=), 154.1 (CH), 155.5 (C=O), 157.2 (C), 180.6 (C=S). 1H NMR
(
600 MHz, DMSO-d6, recorded 1 h after dissolution for the mixture of
three isomers): δ 1.50-1.68 (m, 4Н, 2СН2), 2.28-2.48 (m, 4Н, 2СН2), 3.66
s, 3Н, OCH3, 3-thiadiazoline), 3.69 (s, 3Н, OCH3, E-3-thione), 6.58 (s,
(
Experimental Section
1
6
H, CH, 3-thiadiazoline), 6.83 (d, 2H, J = 9.00 Hz, Ar, 3-thiadiazoline),
.90 (d, 2H, J = 9.00 Hz, Ar, E-3-thione), 7.56 (d, 2H, J = 9.00 Hz, Ar, 3-
General information. Routine NMR measurements were performed on a
Bruker Avance 400 spectrometer. The 1H NMR (400, 500, and 600 MHz)
chemical shifts are given in ppm (δ) relative to TMS as the internal
standard (0 ppm). The coupling constants, J values, are given in Hertz
thiadiazoline), 7.65 (d, 2H, J = 9.00 Hz, Ar, E-3-thione), 8.44 (s, 1Н, СH,
Z-3-thione), 8.76 (s, 1Н, NH, 3-thiadiazoline), 8.97 (s, 1Н, СH, E-3-
thione), 9.95 (s, 1H, CONH, 3-thiadiazoline), 10.25 (s, 1H, CONH, Z-3-
thione), 10.29 (s, 1H, CONH, E-3-thione), 13.48 (s, 1H, CSNH, Z-3-
thione), 13.69 (s, 1H, CSNH, E-3-thione). 13C { H} NMR (125 MHz,
DMSO-d6, E-3-thione): δ 21.3 (CH2), 23.5 (CH2), 25.6 (CH2), 35.4 (CH2),
55.7 (OCH3), 114.4 (2×CH), 122.1 (2×CH), 130.1 (C=), 131.2 (C), 142.2
(Cl-C=), 154.5 (CH), 156.0 (C), 158.6 (C=O), 184.2 (C=S). 13C { H} NMR
(125 MHz, DMSO-d6, Z-3-thione): δ 21.2 (CH2), 23.3 (CH2), 25.1 (CH2),
35.2 (CH2), 55.4 (OCH3), 114.3 (2×CH), 121.6 (2×CH), 129.2 (C=), 132.0
(C), 141.5 (Cl-C=), 147.7 (CH), 156.6 (C), 162.9 (C=O), 193.4 (C=S). 13C
{1H} NMR (125 MHz, DMSO-d6, 3-thiadiazoline): δ 21.9 (CH2), 23.7
(CH2), 24.6 (CH2), 34.2 (CH2), 55.6 (OCH3), 72.4 (CH), 114.2 (2×CH),
122.2 (2×CH), 128.0 (C=), 131.8 (C), 133.1 (C=N), 139.7 (Cl-C=), 156.0
Hz). The 13C NMR (100, 125, and 150 MHz) chemical shifts are
1
(
referenced to the internal solvent signals (central peak is at δ 77.2 ppm in
CDCl3 and at δ 39.52 ppm in DMSO-d6). HRMS were acquired by
electrospray ionization (ESI) using a TOF analyzer. The melting points
are uncorrected. All commercial reagents and solvents were used as
received. All reactions were monitored by TLC on GF 254 silica gel
coated plates. Column chromatography was performed on silica gel 60
1
(230-400 mesh). Parent 2-сhlorocyclohex-1-enecarbaldehyde (1) and 2-
hydrazinyl-N-(4-methoxyphenyl)-2-thioxoacetamide (2) were prepared
according to the published procedures.14,15
(
C), 157.9 (C=O). IR (CHCl3): 3000 (NH), 2941, 2856 (CH), 1720 (CO),
-
1
-Chlorocyclohex-1-enecarbaldehyde (1). The procedure14 was
1676, 1617, 1594, 1513, 1466, 1417, 1352, 1340 cm . IR (DMSO): 3337,
2
3
274 (NH), 2965, 2930, 2831 (CH), 1643, 1606, 1543, 1516, 1463, 1404,
followed using cyclohexanone (3.0 mL, 29.0 mmol), POCl3 (4.4 mL, 46.9
mmol), and DMF (4.6 mL, 59.6 mmol). Workup afforded product as a
colorless, low-boiling liquid (3.12 g, 75% yield), which was purified by
column chromatography (eluent - petroleum ether/diethyl ether, 50:1)
immediately before next step. Rf = 0.66 (1:5 EtOAc: petroleum ether,
visualized by 254 nm UV light). 1H NMR (500 MHz, CDCl3): δ 1.63 (m,
-1
+
1365, 1247, 1222, 1102, 1027, 813 cm . HRMS (ESI-TOF) m/z: [M + H]
Calcd for C C16H18ClN3O2S 352.0881; Found 352.0878.
N-(4-Methoxyphenyl)-5,6,7,8-tetrahydrophthalazine-1-carboxamide
(4). Oxamic acid thiohydrazide 2 (52 mg, 0.23 mmol) was added to a
solution of chlorovinyl aldehyde (39 mg, 0.27 mmol) and p-
toluenesulfonic acid monohydrate (5 mg, 10 mol%) in an appropriate
solvent (0.8 mL). The reaction mixture was stored at rt for 15 min until the
complete conversion of thiohydrazide and then heated (reflux for EtOH,
CHCl3, and octane; 60 oC for DMSO) for 30 min – 4 h min until the
2
2
2
H), 1.75 (m, 2H), 2.26 (tt, J = 6.0, 2.5 Hz, 2H), 2.56 (tt, J = 6.0, 2.5 Hz,
1
H), 10.20 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 21.0 (CH2), 23.2 (CH2),
3.7 (CH2), 35.9 (CH2), 133.5 (C), 151.3 (C), 191.1 (CHO). ESI-MS m/z:
+
[
M] 144.
1
complete conversion of the hydrazone ( H NMR monitoring). The
2
-Hydrazinyl-N-(4-methoxyphenyl)-2-thioxoacetamide
(2).
The
1
4,15
resulting mixture was cooled to room temperature and the solvent was
removed under reduced pressure (EtOH, CHCl3, and octane) or washed
off with water (DMSO). The product was obtained as pale-yellow solid
procedure
was followed using chloroacetanilide (1.0 g, 5.0 mmol),
sulfur (1.0 g, 31.3 mmol), morpholine (3.5 mL), hydrazine hydrate (1.5
mL), and DMF (8.5 mL). Workup afforded analytically pure compound as
a pale yellow solid (0.91 g, 83%). Rf = 0.23 (1:5 EtOAc: petroleum ether,
(23 mg, 35% in octane; 48 mg, 74% in EtOH; 45 mg, 70% in CHCl3; 37
o
o
28
1H
mg, 57% in DMSO). Rf = 0.71 (1:1 EtOAc: petroleum ether, visualized by
visualized by 254 nm UV light); mp 159-160 C (mplit 161-163 C).
54 nm UV light); mp 164-165 C. 1H NMR (600 MHz, DMSO-d6): δ 1.77-
o
2
NMR (500 MHz, DMSO-d6): δ 3.75 (s, 3H, OMe), 6.91 (d, J = 8.83 Hz,
H), 7.70 (d, J = 8.83 Hz, 2H), 10.10 (br.s, 1H, NH) (the signals of the
1.81 (m, 4Н, 2СН2), 2.79-2.82 (m, 2Н, СН2), 2.93 (m, 2Н, СН2), 3.78 (s,
2
NHNH2 were not observed). 13C NMR (125 MHz, DMSO-d6): δ 55.7
3Н, OCH3), 6.96 (d, 2H, J = 9.00 Hz, Ar), 7.73 (d, 2H, J = 9.00 Hz, Ar),
.03 (s, 1Н, CHpyridazine), 10.68 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): δ
9
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European Journal of Organic Chemistry
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FULL PAPER
2
0.9 (CH2), 21.9 (CH2), 26.0 (CH2), 26.9 (CH2), 55.6 (OCH3), 114.3
Acknowledgements
(2×CH), 121.6 (2×CH), 130.9 (C), 140.2 (C), 140.8 (C), 150.6
CHpyridazine), 153.1 (C), 156.7 (C), 161.9 (CO). ESI-MS m/z: [M]+ 283.
(
This research was financially supported by the Russian Science
Foundation (Projects 14-50-00126 - chemistry). High-resolution
mass spectra were recorded in the Department of Structural
Studies of the N. D. Zelinsky Institute of Organic Chemistry,
Moscow.
5
-(2-Chlorocyclohex-1-en-1-yl)-N-(4-methoxyphenyl)-1,3,4-
thiadiazole-2-carboxamide (5). A solution of thiohydrazone 3 (158 mg,
.45 mmol) and Et3N (62 μL, 0.45 mmol) in CHCl3 (1.6 mL) was refluxed
0
under an air atmosphere for 1.5 h until the complete conversion of the
starting material (TLC monitoring). The resulting mixture was cooled to
room temperature, the solvent was removed under reduced pressure,
and the product was isolated by column chromatography using petroleum
ether/ethyl acetate, 5:1, as eluent, to obtain a product as pale-yellow
solid (67 mg, 40% yield). Rf = 0.49 (1:1 EtOAc: petroleum ether,
Keywords: Electrocyclic reactions, Hydrazones, Aldehydes,
Pyridazines, β-Chlorovinyl thiohydrazone, Isomerization
o
1
[1]
(a) M. Y. Jaballah, R. T. Serya, K. Abouzid, Drug. Res. 2017, 67, 138-
visualized by 254 nm UV light); mp 167-170 C. H NMR (300 MHz,
CDCl3): δ 1.83-1.86 (m, 4H, 2СН2), 2.67-2.69 (m, 2H, СН2), 2.94-2.97
148. (b) M. Asif, Curr. Med. Chem. 2012, 19, 2984-2991. (c) G. Heinisch, H.
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(
m, 2H, СН2), 3.82 (s, 3H, OMe), 6.94 (d, J = 8.80 Hz, 2H, Ar), 7.64 (d, J
8.80 Hz, 2H, Ar), 9.12 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): δ 21.9
=
(
CH2), 23.3 (CH2), 29.6 (CH2), 35.7 (CH2), 55.5 (OMe), 114.4 (2×CH),
[2]
[3]
[4]
R. Shi, US 2017/0095474, 2017.
1
1
1
7
21.6 (2×CH), 126.3 (C), 130.0 (C), 138.9 (C), 155.8 (C), 157.0 (C),
64.6 (C), 169.0 (CO). IR (KBr): 3232 (NH), 2952, 2937, 2870 (CH),
740 (CO), 1670, 1513, 1442, 1384, 1249, 1231, 1102, 1030, 943, 833,
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-
1
Na]+ Calcd for
54 cm . HRMS (ESI-TOF) m/z: [M
+
C
C16H16ClN3O2SNa 372.0544; Found 372.0534.
Organometallics 2001, 20, 4418-4423. (b) T. Guo, S. Dechert, S. Meyer, F.
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2
6, 145-148. (b) S. Varughese, S. M. Draper, Cryst. Growth Des. 2010, 10,
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3
043. (b) P. Majumdar, A. Pati, M. Patra, R. Behera, A. K. Behera, Chem.
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L of dibromomethane as the internal standard.
[
Computational methods. All calculations were performed using the
Gaussian 09 program package.37 The optimized geometries of all
stationary points on the potential energy surface were first obtained by
the density functional theory (B3LYP38) with the 6-31G39 basis set and
semiempirical method PM640. After geometry optimization, vibrational
analysis was carried out to ensure that the imaginary frequency is zero
for the ground states and one for the transition states. Intrinsic reaction
coordinate (IRC) analysis was performed to ensure that the transition
states connect suitable intermediates.41 Solvent effects on the reaction
energies and activation barriers were evaluated using single-point
polarized continuum model (PCM)42 calculations for DMSO (ε = 46.826)
and chloroform (ε = 4.7113) with optimized gas-phase geometries at the
B3LYP/6-31+G** level of theory. Each transition state connecting the
corresponding reactant and product was confirmed by following the
intrinsic reaction coordinate43 (IRC) path in both directions.
Thermochemical data obtained in the gas phase at both levels of theory
were used with the appropriate single-point solvation energies to
calculate the Gibbs free energies of solvation. The 3D conformers of Z,E-
and Z,Z-3-thiols were generated using the FROG2 server.44 It gave 24
structures, which were optimized with the PM6 semiempirical method.39
After the removal of duplicates, 4 unique most stable structures were
obtained (2 structures for Z,E-3-thiols and 2 structures for Z,Z-3-thiols,
see Supporting information). The difference ΔΔfH0 between the lowest
and the highest standard formation enthalpy of conformers is 4.7
[
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2
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[
17] β-Chlorovinyl moiety stereochemistry has no significant influence on the
reaction rate (see Supporting information).
18] 2-Chlorocyclohex-1-enecarbaldehyde
methoxyphenyl)-2-thioxoacetamide react smoothly in the dark, under
[
1
and
2-hydrazinyl-N-(4-
2
irradiation with ultraviolet lamp and in the presence of TEMPO. This suggests
that reaction mechanism is not radical. Moreover, under an inert atmosphere
of argon the principal result was still the formation of 4 as the major product,
what excluded oxidation with oxygen as a key step of reaction (for product 4
yields see Supporting information).
-
1
kcal⋅mol . Then calculations for the first step of heterocyclization (3-thiols
to intermediates A,A’ and C, Scheme 4) were performed at the B3LYP/6-
31+G(d,p) level.
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European Journal of Organic Chemistry
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[
3
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[
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European Journal of Organic Chemistry
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
α,β-Unsaturated thiohydrazones
Anna S. Komendantova, Artem N.
Fakhrutdinov, Leonid G. Menchikov, Igor
V. Zavarzin, Yulia A. Volkova*
Page No. – Page No.
Cyclization of β-chlorovinyl
thiohydrazones into pyridazines: A
mechanistic study
Here, we report the results of extensive experimental and some theoretical
mechanistic investigation on the condensation of β-chlorovinyl aldehydes with
oxamic acid thiohydrazides giving pyridazines.
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