Uncatalyzed one-pot synthesis of highly substituted pyridazines and pyrazoline-spirooxindoles via domino SN/condensation/aza-ene addition cyclization reaction sequence

Article abstract of DOI:10.1021/co400005y

A previously unknown class of highly substituted pyridazines and pyrazoline-spirooxinoles are easily prepared by an uncatalyzed one-pot three-component approach incorporating a domino SN/condensation/aza-ene addition cyclization reaction sequence. 1,1-Dihydrazino-2-nitroethylene (DHNE) which is generated in situ from the nucleophilic substitution (SN) reaction of hydrazine and 1,1-bis(methylthio)-2-nitroethylene (BMTNE), allowed to be condensed with active 1,2-dicarbonyl compounds followed by an intramolecular aza-ene addition cyclization to obtain the titled products depending on the type of 1,2-dicarbonyl. All reactions are easily performed and proceed with high efficiency under very simple and mild conditions without any catalyst and give good yields avoiding time-consuming, costly syntheses, and tedious workup and purification of products.

Full text of DOI:10.1021/co400005y

Research Article
pubs.acs.org/acscombsci
Uncatalyzed One-Pot Synthesis of Highly Substituted Pyridazines
and Pyrazoline-Spirooxindoles via Domino SN/Condensation/
Aza-ene Addition Cyclization Reaction Sequence
Nasrin Zohreh and Abdolali Alizadeh*
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
S
* Supporting Information
ABSTRACT: A previously unknown class of highly sub-
stituted pyridazines and pyrazoline-spirooxinoles are easily pre-
pared by an uncatalyzed one-pot three-component approach
incorporating a domino SN/condensation/aza-ene addition
cyclization reaction sequence. 1,1-Dihydrazino-2-nitroethylene
(DHNE) which is generated in situ from the nucleophilic
substitution (SN) reaction of hydrazine and 1,1-bis(methylthio)-2-nitroethylene (BMTNE), allowed to be condensed with active
1,2-dicarbonyl compounds followed by an intramolecular aza-ene addition cyclization to obtain the titled products depending
on the type of 1,2-dicarbonyl. All reactions are easily performed and proceed with high efficiency under very simple and
mild conditions without any catalyst and give good yields avoiding time-consuming, costly syntheses, and tedious workup and
purification of products.
KEYWORDS: 1,2-diaza heterocycles, spirooxindole, pyrazoline, pyridazine, one-pot reactions, domino reactions,
nitro ketene dithioacetal, isatin, benzil, 1,2-dicarbonyls, aza-ene reaction
pharmacological activities.27,28 Several biologically active
INTRODUCTION
■
natural and unnatural compounds consist of heterocycles
Among the currently used strategies to find the new biologically
containing an N−N bond in six membered rings such as
active heterocyclic compounds, one-pot multicomponent reac-
well-known piperazic acid and 1-Azafagomine.29−35 In this
tions (MCRs) are used to increase the molecular complexity
class of compounds, 1,4-dihydropyridazines are of particular
and diversity with minimum time, labor, cost, and waste
interest because of their activities as cardiovascular and
production.1−5 These benefits are highlights for multi-
spasmolytic agents that can be correlated with those of 1,4-
component domino reactions, which involve in situ production
dihydropyridine.36,37 Conventional methods for pyridazine
of an intermediate with a strategic reactive site for subsequent
synthesis are based on the reaction of hydrazine or its
transformations.6,7
Spiroheterocycles are of considerable interest because the
derivatives with 1,4-dicarbonyls38−44 and different types of
[2 + 4] hetero Diels−Alder reaction.45−50 Synthetic methods
based on Ugi four-component reaction51 and electrophilic
conformational restriction associated to the structural rigidity
affects considerably their biological activity.8 Among them,
hydrazination of enolates52−57 are most interesting recent
spirooxindoles,9−14 are the central structural frameworks
methods for the preparation of 1,4-dihydropyridines.
which are present in numerous bioactive natural products
In view of the above introduction and prompted by our on-
going investigations on the construction of diaza-heterocycles,58−62
and alkaloids with biological and clinical activities such as
spirotryprostatin A, pteropodine,15 gelsemine,16 and horsfi-
we tried to design a practical and efficient multicomponent domino
protocol for the preparation of two new classes of highly func-
tionalized previously unknown 1,2-diazaheterocycles, pyrazoline-
line.17
Spirooxindole-pyrazolines are one of the interesting classes
of spirooxindoles on which significantly less research has been
done compared to the spirooxindole-pyrrolidine. Surprisingly,
to the best of our knowledge there are three18−20 procedures
for the synthesis of spirooxindole-pyrazolines, and all of them
require at least two steps, starting from the condensation of
isatin and a reactive methylene nucleophile. In a very recent
work, one-pot synthesis of pyrazolophthalazinyl-spirooxindoles
has been reported in the presence of nickel chloride in poly-
ethylene glycol 600 as catalyst.21
spirooxindoles and pyridazines, using 1,1-dihydrazino-2-
nitroethylene (DHNE) as intermediate.
RESULTS AND DISCUSSION
■
Recently, we have become interested in the application of
ketene aminal intermediates resulting from the reaction of
1,1-bis(methylthio)-2-nitroethylene (BMTNE) and nitrogen
Pyridazines and fused pyridazines with their reduced
derivatives are important subclasses of diaza-six-membered
heterocycles that possess synthetic utility22−26 and important
Received: January 11, 2013
Revised: April 11, 2013
© XXXX American Chemical Society
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nucleophiles such as diamines or ammonia for the synthesis of
interesting heterocycles in one-pot processes.63−66 Following
this lead and to achieve a diaza-intermediate to employ in one-
pot synthesis of diaza heterocycles, we first evaluated the
reaction of hydrazine and BMTNE under different conditions.
The maximum yield of 1,1-dihydrazino-2-nitroethylene (DHNE)
3 was obtained when the reaction was performed in EtOH at
room temperature for 7 h with 2.6:1 ratio of hydrazine:BMTNE
(Table 1).
Table 2. Optimization Conditions for the Formation of
Pyrazoline-Spirooxindole 5{1}
a
b
entry
solvent
T (°C)
t (h)
5a yield (%)
1
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
r.t
0.5
1
52
77
85
85
70
51
25
58
24
66
66
2
r.t
Table 1. Optimization Conditions for the Formation of
Intermediate 1,1-Dihydrazino-2-nitroethylene (DHNE)
3
r.t
1.5
2
4
r.t
5
reflux
r.t
1.5
1.5
1.5
4
6
7
H2O
reflux
r.t
8
H2O
a
entry
solvent
T (°C)
t (h)
molar ratio 1:2
yield (%)
9
CH2Cl2
MeCN
MeCN
r.t
8
1
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
r.t
5
5
2:1
2:1
51
39
10
11
r.t
7
2
reflux
r.t
reflux
7
3
7
2:1
65
a
b
1:2 ratio of DHNE 3:isatin 4{1}. Isolated yield.
4
r.t
9
2:1
65
5
r.t
14
9
2:1
15
of 5. Procedure 2 avoids the isolation of the intermediate
BHNE (3) and should save time of execution and solvent
amounts, and afford better yields.67 These two procedures are
summarized in Scheme 2. With the optimized conditions in
hand, we performed a one-pot pseudofive component reac-
tion with 2.6 equiv of hydrazine hydrate, 1 equiv of BMTNE
2, and 2 equiv of isatin 4{1}. As expected, the reaction
proceeds smoothly in EtOH at room temperature after 7 h to
produce spirooxindole-pyrazoline 5{1} in 67% yield (Table 3,
Entry 1).
7
r.t
2:1
70
8
H2O
r.t
7
2.2:1
2.2:1
2.6:1
3:1
73
9
EtOH
EtOH
EtOH
CH2Cl2
r.t
7
78
10
11
12
r.t
7
80
r.t
7
80
r.t
7
3:1
trace
a
Isolated yields.
In the next stage, we decided to perform the reaction of isatin
and the resulting 1,1-dihydrazino-2-nitroethylene 3 to evaluate
the formation of pyrazoline-spirooxindoles. Thus, a mixture of
isatin 4{1} and 1,1-dihydrazino-2-nitroethylene 3 underwent a
bis-condensation/aza-ene addition cyclization reaction through
different conditions. The best result and maximum 85% yield of
pyrazoline-spirooxindole 5{1} was obtained when the reaction
proceeded in EtOH at room temperature for 1.5 h (Table 2).
Notably, performing the above reaction using equivalent ratio
of reactants gave the corresponding pyrazoline-spirooxindole
5{1} in nearly 45% and roughly half of unreacted 1,1-dihydrazino-
2-nitroethylene 3 was recovered at the end of the reaction while
no pyrazoline-spirooxindole 6 was obtained based on NMR
investigation of reaction mixture (Scheme 1).
Subsequently, we examined the scope and limitation of both
of strategies by varying the isatin component. Different types
of isatin such as 5-bromo, 5-nitro, and N-alkylisatins were used.
As depicted in Table 3, both of procedures are general toward
the isatin component. In addition, the yield of the one-pot,
multicomponent reaction (Procedure 2) is higher than the total
yield of procedure 1 in all examples (Table 3).
After this successful endeavor with the synthesis of pyrazoline-
spirooxindole 5 using the DHNE intermediate 3 and isatin 4, our
attention turned to the use of 1,2-diarylethanediones (benzils) in
both procedures. Comparing to the isatins, benzyls have two
reactive ketonic carbonyls in 1,2 positions. Taking this difference
between isatin and benzil into account and considering the
behavior of DHNE and ketene aminal intermediates that
show nucleophilicity on two sites, we performed the reaction of
DHNE and benzil 6{1} to obtain pyridazines. As expected,
under optimum condition (Table 4, Entry 4), the reaction of
Despite the success in the synthesis of pyrazoline-spirooxindoles
5 using the above two-components per reaction, two step pro-
cedure (Procedure 1), we decided to evaluate a one-pot pseudo
five-component reaction procedure (Procedure 2) for the synthesis
Scheme 1. Outcome of the Equimolecular Reaction of DHNE (3) and Isatin 4{1}
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Scheme 2. Two- and One-Step Procedures for the Synthesis of Pyrazoline-Spirooxindoles 5
Scheme 3. Outcome of the Reaction of DHNE (3) and Benzil 6{1} with a Ratio 1:2
Scheme 4. Two- and One-Step Procedures for the Synthesis of Hydrazino-1,4-dihydropyridazinole 7
Scheme 5. One-Pot Synthesis of Hydrazinopyridazines Fused Phenathrenequinone 10 or Acenaphthoquinone 11 via Domino
SN/Condensation/Addition Cyclization Reaction
DHNE 3 and 1,2-diphenylethanedione 6{1} (benzil) produced
hydrazino-1,4-dihydropyridazinole 7{1} in 82% yield.
Interestingly, the reaction with 1:2 ratio of DHNE and benzil
6{1} did not produce pyridazine 8 unlike the case of isatin even
at high temperature and extended reaction times. Half of the
benzil was recovered at the end of the reaction while the yield
of pyridazine 7{1} did not change (Scheme 3).
Then, we explored a one-pot, pseudo four-component
domino SN/condensation/addition cyclization reaction (Scheme 4,
procedure 2) for the synthesis of hydrazino-1,4-dihydropyr-
idazinole 7. With the optimized conditions for the two reac-
tions of procedure 1 in hand, we performed a one-pot pseudo
four-component reaction of 2.6:1:1 ratio of hydrazine 1,
BMTNE 2, and benzil 6{1}. The reaction mixture underwent
a domino SN/condensation/addition cyclization processes
in EtOH at room temperature to afford the hydrazino-1,4-
dihydropyridazinole 7{1} in 78% yield after 8 h (Table 5, Entry 1).
Both of procedures are summarized in Scheme 4. It must be
noted again that obviously, the one-pot synthesis of hydrazine-
1,4-dihydropyridazinol is the preferred procedure.
Then, various benzils with different substituents were utilized
under the same one-pot reaction conditions to examine the
scope and limitations of both procedures. It was found that
only benzils carrying electron-withdrawing groups (such as F,
Cl, and NO2, entries 3−8) or weak electron-donating groups
(such as Me, entry 2) show similar reactivity and react effi-
ciently to yield the desired products in both procedures (Table 5).
Application of substituted benzils with an electron-donating
C
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a
Table 3. Pyrazoline-Spirooxindoles 5 Synthesized by the Procedures Shown in Scheme 2
a
Conditions for procedure 1: ratio of DHNE:isatin is 1:2/EtOH/1.5 h in all entries; conditions for procedure 2: ratio of hydrazine:BMTNE:isatin is
b
c
2.6:1:2/EtOH/7 h in all entries. total yield of 5 obtained by procedure 1. Isolated yield obtained by DHNE-isatin reaction in procedure 1 (step 2).
d
Isolated yield obtained by one-pot domino SN/condensation/addition cyclization reaction (procedure 2).
group such as OMe or Br (Entries 9,10) even in the presence of
a NO2 group (entries 11−13) did not lead to the desired product
at all. In these cases, after appropriate time, 1,1-dihydrazino-2-
nitroethylene intermediate and all of the related benzil were
recovered unchanged.
We subsequently changed the 1,2-diketone component from sub-
stituted benzils 6 to reactive quinones. Interestingly, the one-pot
reaction of hydrazine 1, 1,1-bis(methylthio)-2-nitroethylene and
acenaphthoquinone 8 or phenanthrenequinone 9 produces poly-
cyclic 3,4-acenaphthoquino-6-hydrazino-5-nitro-1,4-dihydro-4-pyri-
dazinol 10 or aromatic 3,4-([9,10]-phenanthrene)-6-hydrazino-5-
nitro-pyridazine 11 under the same reaction conditions (Scheme 5).
The molecular structure of all synthetic compounds 5{1−8},
7{1−8}, 10, and 11 were elucidated from their mass spec-
1
trometric analyses, IR, and high-field H NMR and 13C NMR.
The mass spectrum of 5{1} displayed the molecular ion peak at
m/z = 319 with low intensity. In the IR spectrum, stretching
frequencies of five NH groups appear as two broad bands in the
region of 3100−3500 cm−1. Absorption bands at 1715, 1616,
1558, and 1340 cm−1 are related to NCO, CN, CC, and
NO2 groups, respectively, and indicate the most important
1
functional groups of the product. The H NMR spectrum of
5{1} exhibited four singlets at δ = 6.13, 10.79, 11.21, and 13.37 ppm
and were assigned as NH protons, as all were exchangeable
D
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Table 4. Optimization Conditions for the Formation of
Hydrazino-1,4-dihydropyridazinole 7{1}
Scheme 7
a
b
Entry
Solvent
T (°C)
t (h)
Yield of 7{1}(%)
1
2
3
4
5
6
7
8
9
10
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
r.t
r.t
r.t
r.t
35
45
r.t
r.t
r.t
r.t
1
70
79
87
93
93
93
76
64
10
47
spectrum, stretching frequencies of OH, NH2, and two NH
groups appear as broad bands in 3471, 3348, 3170, 3066 cm−1.
Absorption bands at 1620, 1532, and 1404 cm−1 are clearly
attributed to CC, and NO2 groups, respectively, and indicate
1.5
2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
the most important functional groups of the product. The H
NMR spectrum of 7{1} exhibited four singlets at δ = 4.52, 7.03,
8.33, and 12.73 ppm and were assigned as NH2, two NH
and OH protons, respectively, as all were exchangeable with
D2O. The OH and second NH resonate downfield because of
intramolecular hydrogen bonding with the NO2 group.
MeCN
CH2Cl2
MeOH
a
b
1
Observation of 12 distinct signals in the H-decoupled 13C
1:1 ratio of DHNE 3:benzil 6{1}. Isolated yield.
NMR spectrum of 7{1} is in agreement with the proposed
structure. There are two characteristic signals at δ = 81.8 and
96.6 ppm corresponding to the C−OH and C-NO2. In the H
NMR spectrum of 11 there are only two D2O exchangeable
singlets at δ = 6.82 and 15.95 ppm attributed to the NH and
NH2 (see Supporting Information for characterization data of
all compounds).
Although no detailed mechanistic studies have been carried
out at this point, a rationale mechanism for both of the one-
pot procedures are outlined in Scheme 6. This mechanism
is proposed knowing the chemical behavior of isatin,68 1,2-
diketones such as benzils, and also ketene aminal intermediate
3. Based on this mechanism, DHNE 3 readily prepared in situ
from the addition of 2:1 ratio of hydrazine 1 and BMTNE 2 via
a SN2 reaction followed by loss of 2 equiv of MeSH. In the
presence of isatin 4 which contained a highly active ketonic
carbonyl, condensation reaction of DHNE 3 and 2 equiv of
isatin followed by loss of 2 equiv of H2O affords vinyl bis-
hydrazone intermediate 12. Finally, intermediate 12 converts to
1
with D2O. The first signal is due to the two NH protons of the
pyrazoline ring. The second and third signals are attributed to
the two NH groups of isatins and are not present when N-alkyl
isatins are used. The latter is related to the NHNC which
resonates downfield because of intramolecular hydrogen
bonding with the NO2 group, in addition of conjugation with
CCNO2. Observation of 18 distinct signals in the 1H-
decoupled 13C NMR spectrum of 5{1} is in agreement with the
proposed structure. In the aliphatic region there is one char-
acteristic signal at δ = 74.3 ppm corresponding to the C-3 spiro
carbon. Signals of two amidic carbonyls appear at δ = 162.5 and
164.2 ppm. It is proposed that intramolecular hydrogen bond-
ing results in the formation of the Z-isomer around the CN
bond in the products 5.
The mass spectrum of 7{1} displayed the molecular ion peak
at m/z = 325 with low intensity. Ion peaks at m/z = 308 and
279 are related to the loss of OH and NO2 fragments. In the IR
Scheme 6. Proposed Mechanism for the Formation of Pyrazoline-Spirooxinoles 5 and Pyridazines 7
E
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the product 5 via an intramolecular aza-ene addition cyclization
reaction.
6-hydrazino-5-nitro-3,4-diaryl-1,4-dihydropyridazin-4-ol prod-
uct 7 (Scheme 7).
In the case of phenanthrenequinone, the pyridazinole inter-
mediate 7 oxidized to hydrazinopyridazine 11 via an aromatiza-
tion process (Scheme 7).
On the other hand, in the presence of benzil with two active
ketonic CO, NH2 of DHNE 3 condensed with one reactive
carbonyl of benzil 6 followed by loss of 1 equiv of H2O to
afford vinyl hydrazone 13. Since the other carbonyl of the
benzil moiety is still highly reactive in intermediate 13, an
intramolecular aza-ene addition cyclization process followed
by imine-enamine tautomerization leads to the formation of
CONCLUSION
■
Overall, we have succeeded in developing a novel, convenient,
and efficient synthesis of new spirooxindole-pyrazolines and
a
Table 5. Hydrazino-1,4-Dihydropyridazine 7 Synthesized by the Procedures Shown in Scheme 4
F
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Table 5. continued
a
Conditions for procedure 1: ratio of DHNE and benzil is 1:1/EtOH/2.5 h in all entries; conditions for procedure 2: ratio of hydrazine, BMTNE
b
c
d
and benzil is 2.6:1:1/EtOH/8 h in all entries. The bold bonds refer to the bonds formed in the reaction. Total yield of 7 in procedure 1. Isolated
e
yield of product 7 in DHNE-benzil reaction. Isolated yield of one-pot domino SN/condensation/addition cyclization reaction (procedure 2).
f
Almost all benzil recovered unchanged in addition of DHNE 3
1,4-dihydro pyridazinoles from readily available and inexpensive
starting materials. Both one-pot procedures proceed through
domino SN/condensation/aza-ene addition cyclization reac-
tions. Our work presents a very simple reaction which is
performed under neutral conditions without any catalyst that
leads to the formation of four and five chemical bonds in 1,4-
dihydropyridazines and spirooxindole-pyrazolines. All products
were easily isolated (filtration or crystallization) and obtained in
moderately good yields. The optimized one-pot procedure is
noteworthy, when compared to the stepwise procedure, be-
cause of its ease of execution, flexibility, and substantial mini-
mization of waste, labor, time, and cost. From the structural
viewpoint, the products are polynitrogen and fully substituted
compounds that will be suitable for further elaboration.
Potential uses of the reaction in synthetic and medicinal chem-
istry might be quite significant.
spectra at room temperature were determined in DMSO-d6.
Chemical shifts are reported in parts per million (δ) downfield
from an internal tetramethylsilane reference. Coupling con-
stants (J values) are reported in hertz (Hz), and spin multi-
plicities are indicated by the following symbols: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet). Elemental
analyses for C, H, and N performed using a Heraeus CHN-O-
Rapid analyzer. Mass spectra were recorded on a FINNIGAN-
MATT 8430 mass spectrometer operating at an ionization
potential of 20 or 70 eV. All chemicals were purchased from
Merck or Aldrich and were used without further purification.
General Procedure for the Preparation of 1,1-
Dihydrazino-2-nitroethylene (DHNE) 3. To a magnetically
stirred 50 mL flask containing 1,1-bis(thiomethyl)-2-nitro-
ethylene (0.85 g, 5 mmol) in EtOH (10 mL) was added
NH2NH2 (80% aq, 0.8 g, 13 mmol). After 7 h, the precipitated
product 3 was filtered and washed with cold EtOH (2 mL) and
dried under vacuum for 2 h.
EXPERIMENTAL PROCEDURES
■
General Procedure for the Preparation of Com-
pounds 5{1−8} (for example 5{1}). Procedure 1: To a mag-
netically stirred 10 mL flask containing 1,1-dihydrazino-2-
nitroethylene (0.16 g, 1 mmol) in EtOH (3 mL) was added
isatin (0.30 g, 2 mmol). After 1.5 h, the precipitated product
General Information. Melting points measured on an
Electrothermal 9100 apparatus. IR spectra were recorded
as KBr pellets on a Shimadzu IR-460 spectrometer. H NMR
1
(500 MHz) and 13C NMR (125 MHz) spectra were obtained
using a Bruker DRX-500 AVANCE spectrometer. All NMR
G
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all-carbon quaternary stereocenters. Synthesis 2006, 2006, 369−396.
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5{1} was filtered and washed with cold EtOH (2 mL). Procedure
2: To a magnetically stirred 10 mL flask containing 1,1-
bis(thiomethyl)-2-nitroethylene (0.17 g, 1 mmol) in EtOH
(3 mL) was added NH2NH2 (80% aq, 0.16 g, 2.6 mmol). After
6 h, isatin (0.30 g, 2 mmol) was added to the reaction mixture,
and stirring was allowed to continue for 1 h. After the com-
pletion of the reaction, the precipitated product was filtered and
washed with cold EtOH.
General Procedure for the Preparation of Com-
pounds 7{1−8} (for example 7{1}). Procedure 1: To a
magnetically stirred 10 mL flask containing 1,1- dihydrazino-2-
nitroethylene (0.16 g, 1 mmol) in EtOH (3 mL) was added
benzil (0.21 g, 1 mmol). After 2.5 h, the precipitated product
7{1} was filtered and washed with cold EtOH (2 mL).
Procedure 2: To a magnetically stirred 10 mL flask containing
1,1-bis(thiomethyl)-2-nitroethylene (0.17 g, 1 mmol) in EtOH
(4 mL) was added NH2NH2·H2O (80% aq, 0.16 g, 2.6 mmol).
After 6 h, benzil (0.21 g, 1 mmol) was added to the reaction
mixture, and stirring was allowed to continue for 2 h. After the
completion of the reaction (monitoring by TLC), the pre-
cipitated product was filtered and washed with cold EtOH (1 mL)
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ASSOCIATED CONTENT
* Supporting Information
■
S
The experimental details and the spectroscopic data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Zhang, X. N.; Li, Y. X.; Zhang, Z. H. Nickel chloride-catalyzed
one-pot three-component synthesis of pyrazolophthalazinylspiroox-
indoles. Tetrahedron 2011, 67, 7426−7430.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+98)-21-8288. Tel: (+86)-21-82884402. E-mail:
aalizadeh@modares.ac.ir or abdol_alizad@yahoo.com.
■
(22) Coates, W. J. Pyridazines and their benzo derivatives. In
Comprehensive heterocyclic chemistry II; Katritzky, A. R.; Rees, C. W.;
Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K., 1996; pp 1−91.
Notes
̌
(23) Kolar, P.; Tisler, M. Recent advances in the chemistry of
pyridazines. In Advances in heterocyclic chemistry; Alan, R. K., Ed.;
Academic Press: New York, 1999; Vol. 75, pp 167−241.
The authors declare no competing financial interest.
(24) Mat
F.; Tapolcsan
́
yus, P.; Maes, B. U. W.; Riedl, Z.; Hajos
́
́
, G.; Lemier
́
́
yi, P.; Monsieurs, K.; Elias, O.; Dommisse, R. A.;
̀
e, G. L.
ABBREVIATIONS
SN, Nucleophilic substitution; BMTNE, 1,1-bis(methylthio)-2-
nitroethylene; DHNE, 1,1-dihydrazino-2-nitroethylene
■
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