A Straightforward Approach toward Multifunctionalized Pyridazines via Imination/Electrocyclization

Article abstract of DOI:10.1021/acs.orglett.5b01718

A facile synthesis of functionalized 3-carbamide pyridazines starting from readily available chlorovinyl aldehydes and oxamic acid thiohydrazides via cascade imination/electrocyclization is reported. In the presence of p-toluenesulfuric acid, various ketones have been efficiently incorporated into the pyridazine derivatives through a two-step sequence involving a Vilsmeier-Haack reaction and imination. The synthetic value of this method has been demonstrated by efficient synthesis of steroidal pyridazines.

Full text of DOI:10.1021/acs.orglett.5b01718

Letter
pubs.acs.org/OrgLett
A Straightforward Approach toward Multifunctionalized Pyridazines
via Imination/Electrocyclization
Alexander V. Komkov, Anna S. Komendantova, Leonid G. Menchikov, Elena I. Chernoburova,
Yulia A. Volkova,* and Igor V. Zavarzin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russia
S
* Supporting Information
ABSTRACT: A facile synthesis of functionalized 3-carbamide pyridazines starting from readily available chlorovinyl aldehydes
and oxamic acid thiohydrazides via cascade imination/electrocyclization is reported. In the presence of p-toluenesulfuric acid,
various ketones have been efficiently incorporated into the pyridazine derivatives through a two-step sequence involving a
Vilsmeier−Haack reaction and imination. The synthetic value of this method has been demonstrated by efficient synthesis of
steroidal pyridazines.
pyridines 216b and cyclization of 1-dimethyamine-2,4-azahexa-
yridazines are an important structural subunit found in a
Pvariety of biologically active agents, including a number of trienes 3 to give pyrimidines 418 should be mentioned. To the
natural products (e.g., Pyridazomycin1 and Azamerone2) and
best of our knowledge, diazahexatrienes in the synthesis of
pyridazines are unknown to date.
major drugs (e.g., antihypertensive - hydralazine, dihydralzine,
endralazine;3 antidepressants - pipofezine, minaprine).4 The
prevalence of the pyridazine motif in medicinally relevant
compounds,5 dyes,6 ligands for metal catalysts,7 and crystal
engineering8 has inspired the development of many novel
methods for their preparation.9 However, there are only limited
protocols for assembling 3-carbonyl substituted pyridazine
derivatives, important intermediates in organic synthesis.10
Traditional methods include diaza-Wittig reactions of 1,3-
diketones,11 addition of diazo compounds to Morita−Baylis−
Hillman carbonates,12 [4 + 2] cycloaddition of substituted
1,2,3-triazines,13 cascade reactions of pyridiniumylides,14 and
cycloaddition of 1,2,4,5-tetrazine with alkynes.15 Despite the
impressive progress made in this area, it is still a great challenge
to synthesize functionalized pyridazines from readily available
and easily varied starting materials using a simple procedure.
Known methods suffer from the requirements of a stringent
anaerobic procedure, harsh conditions, and limited substrate
scope.
Reasonably, we proposed a 2,3-diazahexatrienyl system
bearing a carbonyl group along with a good leaving group
can be effective for 3-carboxy pyridazine construction (Scheme
1). Initial sourcing of 2,3-azahexatrienyl synthons possessing a
carboxy moiety clued us to hydrazones of oxamic acid
thiohydrazides.19 Distinctive thione−thiol tautomerism togeth-
er with the SH good leaving group character made them highly
promising substrates for transformations. The presence of a
chlorine atom in their structure could favor the aromatization
step, whereby we intensely examined β-chlorohydrazones 5 as
precursors for pyridazines 6. Note that hydrazones 5 are readily
available from ketones by the Vilsmeier−Haack reaction and
subsequent imination with oxamic acid thiohydrazides.
We initiated our investigation on the model reaction of
chlorovinyl aldehyde 8a derived from 2-hexanone (7a) with
hydrazide 9a in the presence of TsOH (10 mol %) to optimize
various reaction parameters. Full data concerning the
optimization of temperature (rt → 120 °C), solvent (toluene,
CHCl3, CH3CN, EtOH, 2-methoxyethanol), and amounts of
the reagents are presented in the Supporting Information. It
was found the principal result was the formation of pyridazines
10a as the major product in all cases (Scheme 2).
On the other hand, electrocyclic processes are valued for
their mild reaction conditions, excellent functional group
tolerance, and ability to produce six-membered aromatic
rings. There have been a number of reports over the past
decade demonstrating the utility of azahexatrienes for synthesis
of pyridines,16 1,2-dihydropyridines,17and pyrimidines.18 In
particular, transformations of 1-ethoxy-4-azahexatrines 1 into
Received: June 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01718
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Letter
a c
−
Scheme 1. Azahexatrienes in the Synthesis of Carboxy
Substituted Azaheterocycles
Scheme 3. Substrate Scope of Cyclization
Scheme 2. Initial Probe Experiment
Heterocyclization proceeded smoothly even at room temper-
ature, and complete conversion of the starting material was
achieved within 18 h with a good yield of pyridazine 10a.
Solvent effect was not observed; reactions in toluene and 2-
methoxyethanol gave comparable yields of product 10a (80%
and 83%, respectively). The best result was obtained by
performing the reaction in refluxing 2-methoxyethanol for 5
min to afford compound 10a in 84% yield (Scheme 3).
With optimal reaction conditions in hand, we studied the use
of various ketones 7b−l as well as different hydrazides 9b−d to
synthesize a variety of 3-carbomide-4,5-disubstituted pyrida-
zines derivatives (Scheme 3). Three general procedures
differing in temperature (A, 120 °C; B, 80 °C; C, rt) and
solvent were applied in accordance with the intermediate
chlorovinyl aldehyde thermal stability.
It was found that this method is quite general since both
symmetrical and asymmetrical linear aliphatic ketones reacted
smoothly providing diverse pyridazines 10a−d in excellent
yields. Cyclic aliphatic ketones, such as cycloheptanone,
-hexanone, and -pentanone, produced the corresponding
pyridazines 10f−j in slightly lower yields (49−81%) that can
a
Reaction conditions: (A) aldehyde 8 (0.22 mmol), hydrazide 9 (0.22
mmol), and TsOH (10 mol %) in 2-methoxyethanol (2.5 mL) at 120
°C for 5−10 min; (B): aldehyde 8 (0.22 mmol), hydrazide 9 (0.22
mmol), and TsOH (10 mol %) in ethanol (2.5 mL) at refux for 5
min−2 h; (C) aldehyde 8 (0.22 mmol), hydrazide 9 (0.22 mmol), and
b
TsOH (10 mol %) in ethanol (2.5 mL) at rt overnight. Isolated yield.
c
Yield calculated with respect to intermediate chlorovinyl aldehyde
purity.
B
DOI: 10.1021/acs.orglett.5b01718
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
be attributed to decomposition side processes and low
solubility of products.
Scheme 4. Synthesis of Steroidal Pyridazines
In addition, a 4-tetrahydropyranone 7k, as well as a 4-
piperidone 7l, was tolerated under these reaction conditions.
Substituted 7,8-dihydro-5H-pyrano[3,4-d]pyridazine 10k and
5,6,7,8-tetrahydropyrido[3,4-d]pyridazine 10l were obtained in
57% and 66% yields. The reaction could also be performed with
aromatic ketones, namely, propiophenone 7e, producing the
corresponding product 10e in reasonable yield.
Diverse hydrazydes 9a−d bearing MeO, Me, CF3, Cl groups
in ortho-, meta-, and para-positions were well tolerated under
the reaction conditions to give the corresponding pyridazines
10m,n,p−q in moderate to good yields. In addition to
arylamides, benzyl derivative can also be employed to form
the corresponding 10r in 84% yield.
The structures of pyridazines 10 were confirmed by single
crystal X-ray analysis of the representative compound 10b
(Figure 1). The structures of 10j,k,m−o were supported by 2D
NMR (13C−1H HMBC and HSQC) techniques.
Scheme 5. Proposed Mechanistic Pathway
Figure 1. General view of X in representation of atoms by thermal
ellipsoids (p = 50%) for compound 10b.
Having established a framework of the method with relatively
simple molecules, we extended this method to complex natural
products. In this respect, we turned to steroids, one of the
largest and most diverse class of natural products.20
Heterosteroids bearing annulated azaheterocycles are known
to exhibit a wide range of biological activities, e.g.,
antiinflammatory,21 antimicrobial,22 antiproliferation,23 and
antitumor properties.24 We first examined 3β-hydroxyandrost-
5-en-17-one 11 and estrone 13 under standard conditions
(Scheme 4).
It was found that both compounds 11 and 13 were readily
transformed into the corresponding D-ring annulated steroidal
pyridazines 12 and 14 (82% and 79%, respectively) upon
subsequent treatment with Vilsmeier−Haack reagent and
oxamic acid thiohydrazides 9a,e in the presence of catalytic
amounts of TsOH (Scheme 4). A-Ring annulated steroidal
pyridazine 16 was obtained similarly from dihydrotestosterone
15 in 73% yield.
The possible mechanism for the formation of pyridazines 10
by the reaction of chlorovinyl aldehyde 8 with oxamic acid
thiohydrazides 9 is shown in Scheme 5 illustrating an example
of product 10b. Imination of the aldehyde 8b with 9a under
acid catalysis produces 2,3-azahexatirene intermediate 17. The
E/Z-geometric isomers and thiol−thione tautomers equilibrate
under the reaction conditions, and the Z-17-thiol isomer
undergoes 6π-electrocyclization to afford an intermediate
dihydropyridine 18. Rapid hydrochloric acid and molecular
sulfur elimination deliver the observed pyridazine product 10b.
The last step was confirmed experimentally since sulfur was
isolated in equimolar amounts in all reactions.
moiety in hydrazone 17b makes possible nucleophilic
cyclizations to occur. However, computational studies on
activation barriers and heat of the presented disrotatory
electrocyclization reaction were found to be without a rival
The mechanistic rationalization of the observed cyclization
remains, at least in part, speculative. The simultaneous presence
of a nucleophilic SH-center and electrophilic chlorovinyl
C
DOI: 10.1021/acs.orglett.5b01718
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Organic Letters
Letter
‡
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311+G(d,p) and semiempirical PM6].25
In summary, a novel effective approach to the synthesis of
pyridazines by the two-stage procedure from ketones was
described. The approach employs simple reactions comprising
(1) Vilsmeier−Haack reaction of enolizable ketone leading to
chlorovinyl aldehydes and (2) imination of the former with
oxamic acid thiohydrazides and cascade electrocyclization/
aromatization of the resulting 2,3-diazatriene affording highly
substituted pyridazines in moderate to excellent isolated yields
(32−89%). Starting materials are readily available, and
functional group tolerance is quite good. The ease of 2,3-
diazahexatriene system construction and the broad availability
of reagents imply that an extensive range of substituents can be
selectively incorporated in the pyridazine ring. The full
potential of this methodology and an exploration of a greater
variety of substituents must await additional studies.
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* Supporting Information
Detailed experimental procedures, spectral data for all products,
and the X-ray data for 10b (CIF). The Supporting Information
is available free of charge on the ACS Publications website at
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yavolkova@gmail.com.
Notes
The authors declare no competing financial interest.
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