Sergeev 2020

Russian Chemical Reviews
PAPER
Recent advances in the chemistry of pyridazine — an important

representative of six-membered nitrogen heterocycles
To cite this article: Pavel G. Sergeev and Valentin G. Nenajdenko 2020 Russ. Chem. Rev. 89 393
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P.G.Sergeev, V.G.Nenajdenko
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
https://doi.org/10.1070/RCR4922
Recent advances in the chemistry of pyridazine Ð an important

representative of six-membered nitrogen heterocycles
Pavel G. Sergeev, Valentin G. Nenajdenko*
Department of Chemistry, M.V.Lomonosov Moscow State University,

Leninskie Gory 1, stroenie 3, 119991 Moscow, Russian Federation
The review is devoted to recent advances in the chemistry of pyridazine Ð a six-membered heterocycle containing two
nitrogen atoms in adjacent positions. The practical significance of title compounds is demonstrated and published data of the
last decade devoted to them are considered systematically. The modern synthetic approaches to pyridazine derivatives are
described in detail, analyzed and classified according to the precursor molecules involved in ring closure. The chemical
properties of pyridazines are considered, including both reactions of the diazine ring and reactions of various substituents
attached to the ring. Particular attention is given to the application of some pyridazine derivatives as pharmaceuticals,
optical materials and ligands for catalysis.
The bibliography includes 180 references.
Contents
1. Introduction 394
2. Formation of the pyridazine ring 395
2.1. Formation of one bond 395
2.2. Formation of two bonds 397
2.2.1. Formation of two bonds from [4+2] fragments 397
2.2.2. Formation of two bonds from [3+3] fragments 400
2.3. Formation of three bonds 401
2.4. Ring expansion 404
2.5. Cycloaddition 405
3. Pyridazine ring reactivity 406
3.1. Electrophilic attack on pyridazine nitrogen atoms 407
3.2. Reactivity of pyridazine carbon atoms 408
3.3. Reduction reactions 409
3.4. Radical reactions 409
3.5. Cycloaddition reactions 409
3.6. Reactions of hydropyridazines 409
4. Reactivity of substituents in the pyridazine ring 410
4.1. Alkyl groups 410
4.2. Carboxy and ester groups 411
4.3. Cyano groups 411
4.4. Amino groups 412
4.5. Hydrazino groups 413
4.6. Hydroxy and oxo groups 414
4.7. Thiol and thione groups 415
4.8. Halogen atoms 416
4.8.1. Replacement of a halogen by a metal 416
4.8.2. Replacement of a halogen atom in cross-coupling reactions 417
4.8.3. Nucleophilic aromatic substitution in pyridazines 417
4.9. Organometallic derivatives of pyridazines 419
4.10. Pyridazine N-oxides 420
4.11. Supramolecular complexes with pyridazines 421
5. Applications of pyridazines 421
6. Conclusion 426
Received 20 June 2019 # 2020 Uspekhi Khimii, ZIOC RAS, Russian Academy of Sciences and IOP Publishing Limited
394 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
1. Introduction N
N
Pyridazines (1,2-diazines) are among the most important N

N N N N
six-membered nitrogen heterocyclic compounds, which are
of enormous interest, first of all, because of their biological Pyridine Pyridazine Pyrimidine Pyrazine
activity. Indeed, about 9% of unique structures of pharma-
ceutical products approved by the US Food and Drug N
Administration (FDA) contain heterocycles that are N
N N
depicted in Fig. 1; most often, the drug products contain
pyridine and pyrimidine moieties.1 Isoquinoline Quinoline Quinazoline
Pyridazines rarely occur in nature; therefore, they have
not attracted much attention of researchers for a long time. Figure 1. Six-membered nitrogen heterocycles and their benzan-
Since the 1970s, the popularity of pyridazines started to nulated analogues often present in the molecules of pharmaceutical
increase, which finally resulted in the synthesis of a variety agents.1
of derivatives, which are successfully used in pharmaceutics
and agrochemistry (Fig. 2). Some pharmaceutical products
based on pyridazines are actively applied in medicine: Hydralazine was also noted as one of the most frequently
indeed, the drugs Hydralazine and Azelastine were included used components for combination drugs based on hydro-
in the list of Top 200 Brand Name Drugs by Prescription chlorothiazide.3
(2016), while Lynparza occupied the 162th line in the list of The number of studies on pyridazines published in the
Top 200 Brand Name Drugs by Retail Sales (2018).2 last decade is rather large. Mention should be made of a
group of reviews,4 ± 14 which analyze numerous studies and
P.G.Sergeev. Graduate of the Department of Chemistry, Moscow State
identify future trends in the 1,2-diazine chemistry. Consid-
University. ering the analyzed and systematically arranged data, we
E-mail: sergeevpg@gmail.com defined parts of the present review. They are devoted to the
Current research interests: olefination, heterocyclic compounds. synthesis of pyridazines, reactivity of fully conjugated and
V.G.Nenajdenko. Doctor of Chemical Sciences, Professor, Head of the non-conjugated rings and substituents at the diazine system.
Division of Organic Chemistry of the same Department. Practical applications of these compounds are considered
Telephone: +7(495)939±2276, e-mail: nenajdenko@gmail.com separately.
Current research interests: organofluorine chemistry, chirality, peptide
The following abbreviations are used in the review:
synthesis, cyclic imines, click chemistry, multicomponent reactions,
p-ABSA Ð 4-acetamidobenzenesulfonyl azide,
olefination, heterocyclic compounds.
Aliquat 336 Ð methyltrioctylammonium chloride
Translation: Z.P.Svitanko (Starks catalyst),
a
H 2N F Et
NH O
N Me O N
O N
N N
N N N O CO2H
N
Hydralazine O
NH
N Cinoxacin
Cl
O N N
O Cl H
O N
HN Lynparza Azelastine
N
N OMe O
N MeHN(O)C
N H
N N Telatinib Cl
S S H
+ N
N O N N Me
N N MeO
H2N O
N N
COÿ2
Vatalanib N
Cefozopran N O
Pimobendan H
b
But
Cl F Cl MeO OMe
O O N
N
Me
O Me N O But O
HN N Cl N N
N
Cl F3C HO2C S Ph
Diclomezine Flufenpyr Pyridaben Dimidazon
Figure 2. Pyridazine derivatives used in pharmaceutics (a) and agrochemistry (b).

Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 395
Boc Ð tert-butoxycarbonyl, two or three bonds; on ring expansion; and on cycloaddi-

BQ Ð benzoquinone, tion.
Cbz Ð benzyloxycarbonyl,
COD Ð (1Z,5Z)-cycloocta-1,5-diene, 2.1. Formation of one bond
DABCO Ð 1,4-diazabicyclo[2.2.2]octane, The synthetic routes to pyridazine derivatives based on the
dba Ð dibenzylideneacetone, formation of only one bond can be subdivided into four
DBU Ð 1,8-diazabicyclo[5.4.0]undec-7-ene, groups according to the position of this bond in the
DCB Ð 1,2-dichlorobenzene, resulting ring: C(4)7C(5), C(3)7C(4), N(2)7C(3) or
DCE Ð 1,2-dichloroethane, N(1)7N(2) bond (Fig. 3).
DIAD Ð diisopropyl azodicarboxylate,
DIB Ð di(acetoxy)iodobenzene,
C(4)7C(5)
DIBAL-H Ð diisobutylaluminium hydride, C(3)7C(4)
DIPEA Ð N,N-diisopropylethylamine,
DMA Ð dimethylacetamide, N(2)7C(3) N N
DMAP Ð 4-dimethylaminopyridine,
N(1)7N(2)
DME Ð 1,2-dimethoxyethane,
DPP Ð diphenyl phosphate,
DPPA Ð diphenylphosphoryl azide, Figure 3. Approaches to the assembly of the pyridazine ring via
dppf Ð 1,10 -bis(diphenylphosphino)ferrocene, the formation of one bond (here and below, the forming bond is
dppp Ð 1,3-bis(diphenylphosphino)propane, designated by the dashed line).
ERG Ð electron-releasing group,
esp Ð 3,30 -(1,3-phenylene)bis(2,2-dimethylpropanoic
acid), Examples of C(4)7C(5) cyclization implementing this
EWG Ð electron-withdrawing group, synthetic strategy for the synthesis of pyridazinones 1 and 2
Fu Ð furyl, via the Claisen condensation of the appropriate substrates
HATU Ð bis(dimethylamino)methylene-1H-1,2,3-tria- were reported.17, 18 (Scheme 1).
zolo[4,5-b]pyridinium 3-oxide,
HMPT Ð hexamethylphosphoramide, Scheme 1
IBX Ð 2-iodoxybenzoic acid, OH
R CO2Et
Mes Ð mesityl (2,4,6-trimethylphenyl), R CO2Et
AcONa
MS Ð molecular sieves, N DMF, 150 8C
NH N
MW Ð microwave radiation, N O
Naph Ð naphthyl, CO2Et H
O
NMIL Ð nanomagnetic ionic liquid, 1 (38% ± 95%)
NMP Ð N-methyl-2-pyrrolidone,
1,10-Phen Ð 1,10-phenanthroline, R = Ph, Het, Bui, cyclo-C5H9 , cyclo-C6H11 , cyclo-C4H7CH2 , ButCH2
PIFA Ð bis(trifluoroacetoxy)iodobenzene,
PPA Ð polyphosphoric acid, Me Me O
Py Ð pyridyl, OEt
SnCl2
RL Ð Lawesson's reagent [2,4-bis(4-methoxyphenyl)- N N OEt N
N PhNO2, D N N
1,3,2,4-dithiadiphosphetane 2,4-disulfide], N N
H CO2Et H
rt Ð room temperature, 2 (80%)
TBS Ð tert-butyldimethylsilyl,
TCCA Ð trichloroisocyanuric acid,
TEMPO Ð (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, The metathesis reaction was proposed as an original
TFA Ð trifluoroacetic acid, C(4)7C(5) method for the synthesis of pyridazin-3(2H)-
TFDA Ð trimethylsilyl fluorosulfonyldifluoroacetate, ones 3 and 4 (Scheme 2).19 An important circumstance is
THF Ð tetrahydrofuran, the application of second-generation Grubbs catalysts,
Th Ð thienyl, HG-II and Zhan-1B, characterized by easy handling, com-
TMP Ð 2,2,6,6-tetramethylpiperidine, mercial availability and high substrate tolerance. In some
TMS Ð trimethylsilyl, cases, the yield of the reaction products slightly increased
Ts Ð p-toluenesulfonyl (tosyl), upon O-alkylation of the initial compounds.
UST Ð ultrasonic treatment. The formation of the C(3)7C(4) bond in 2-methyl-
phthalazin-1(2H)-ones 5 containing substituents in the ben-
zene ring can be accomplished in the presence of
2. Formation of the pyridazine ring palladium(II) acetate via intramolecular oxidative C7H/
A variety of synthetic approaches to the assembly of C7H cross-coupling involving benzoquinone or by the
pyridazine systems were comprehensively covered in the Heck reaction with the corresponding iodide (Scheme 3;
literature.1, 5 Methods for the synthesis of pyrimidines, the positions of the substituents in the substrate are indi-
pyrazines, pyridazines and triazines based on transition cated).20
metal catalysis are described in detail.15 A special review 16 A simple, but efficient method for cyclization of the
is devoted to the preparation of a-trifluoromethylpyrida- N(2)7C(3) bond is refluxing of 1,2,5-thiadiazole-3,4-dicar-
zines. All methods for the synthesis of these compounds boxylic acid dihydrazide in concentrated formic acid, result-
available from the literature can be divided into the following in closing of the pyridazinedione and thiadiazole fused
ing large groups: methods based on the formation of one, system 6 (Scheme 4).21
396 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 2
R3
HG-II (10 mol.%), O O
CH2Cl2, D
R3 R3
O NH or Zhan-1B (10 mol.%) NH DBU NH
N CH2Cl2 N 20 8C N
R1
Ts R2 Ts R2 MesN NMes
R1 R1 Cl
R2 HG-II = Ru ;
3 (60% ± 86%) Cl
Et3O+BFÿ
4 or Me3O+BFÿ
4, PriO
CH2Cl2, D
(R1 = R2 = H)
MesN NMes
R3 Cl
OAlk O Zhan-1B = Ru
Cl
AlkO N HG-II (10 mol.%) R3 ButOK R3
N NH PriO SO2NMe2
CH2Cl2, D THF, 0 8C
N N N
Ts Ts
4 (74% ± 88%)
Alk = Me, Et; R1, R2 = H, Me; R3 = H, Me, CF3, Ph, OEt; Mes is 2,4,6-trimethylphenyl (mesityl), Ts is p-toluenesulfonyl (tosyl),
DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene
Scheme 5
Scheme 3 R2
O O
R1
Me Me
N a or b N
NH
N N (Ar1 = 3-R2C6H4)
R1
Z Z N N Ar2
R R Ar1 a
N 7 (72% ± 85%)
5 (24% ± 85%)
R4 CO2Me
N2 Ar2 X
(a) Pd(OAc)2 , BQ, AcOH, 120 8C (for R = H; Z = H, 4-MeO, 4-Br,
3-Me, 2-Me, 3,4-Me2 , 3,4-(MeO)2 , 3,5-Me2 , 3,4-benzo); R3 NH
(b) Pd(OAc)2 , AcOK, DMF, 130 8C (for R = H, Me, Ph; Z = 2-I); R3
(Ar1 = N N Ar2
BQ is benzoquinone R4
X
8 (61% ± 94%)
Scheme 4 (a) 25% H2SO4, D; Ar1 = Ph, 3-MeOC6H4 , 2-Th,

O O HN NH benzofuran-2-yl, benzo[b]thiophen-2-yl; R1 = Ph, CO2Me;
H2NHN NHNH2 O O R2 = H, OMe; R3 = R4 = H, R37R4 is benzo;
80% HCO2H
X = S, O; Th is thienyl
D
N N N N
S S MeO MeO
..
6 (90%)
CO2Me CO2Me
H+ *H+
N NH
An unusual method for the N(2)7C(3) assembly of the
pyridazine ring giving rise to pyrrolo[3,4-c]pyridazines 7 +
N Ar2
+
N Ar2
and 8 is refluxing of 4-diazopyrrole-2-carboxylates in an 7
N N
acid medium (Scheme 5).22 After protonation of the pyrrole
nitrogen atom, the pyridazine ring is closed via an electro- MeO
philic attack by the positively charged diazo group on the CO2Me
electron-releasing aromatic moiety (shown for
Ar1 = 3-MeOC6H4). NH
4-Hydroxypyridazines 9 and 10 were prepared by the N N
diaza-Wittig reaction according to the N(2)7C(3) synthetic Ar2
strategy (Scheme 6).23 ± 25 The essence of the reaction is
oxidation of substituted a-diazo-b-keto-d-hydroxybutanes
with 2-iodoxybenzoic acid (IBX) and subsequent diazine The next efficient step towards improvement of this
ring closure on treatment with phosphine. In the develop- procedure was the use of organocatalysis. Phospholene
ment of this method, the Bun3 P7Pri2 O system was demon- oxide served as the catalyst; in the first step it was reduced
strated to be more beneficial for phosphorylation than the with diphenylsilane to give the corresponding phospholene,
hexamethylphosphorous triamide (HMPT)7CH2Cl2 sys- which was introduced into the diaza-Wittig reaction. The
tem, since it provides higher product yields and tolerates a back phospholene oxidation into phospholene oxide closed
larger number of electron-withdrawing groups (EWG), such the catalytic cycle. The modified procedure provided higher
as carbonyl and sulfonic groups, in the initial molecule. product yields for all types of substrates used in the reaction
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 397
Scheme 6
1) IBX,
MeCN, D
OH 2) Bun3 P, OH O OH
R2 EWG Pri2 O, 20 8C 1) IBX, MeCN, D R2 EWG
EWG
R1 Me O
N 2) P N
N R2 N2 Ph N
R1 R1
9 (35% ± 85%) Ph2SiH2, PhMe, 100 8C 10 (42% ± 92%)
Me O
IBX P
7Bun3 PO Ph
O O
O EWG
EWG O O R1
R2 Bun3 P
EWG R2 N
N R1 N
O N Ph
R1 R2 N2 P
PBun3
Me
Ph2SiH2
Me
P Ph
EWG = CO2Me, C(O)Ar, C(O)Het, SO2Ph; R1 = Alk, Ar, Het; R2 = H, Me
Scheme 7 Scheme 8
Ar Ar
SO2Ar SO2Ar SO2Ar
R2 R2
O Bun3 P N
NH
N2 Pri2 O, 20 8C N N N N N
N
a b
R3 R3
CO2R1 CO2R1 R1 R1 R1
R2
11 (54% ± 87%) R2 R2
13 (31%751%) 14 (41% ± 96%)
R1 = Me, Et; R2 = R3 = H, OMe; R27R3 is benzo
Ph Ph (a) Pd(OAc)2 , BIPHIMIP, TsOH, BQ, THF, 45 8C (5-exo-trig);

(b) Pd(OAc)2 , BIPHIMIP, BQ, THF, 45 8C (6-endo-trig);
OH 1) IBX, MeCN, D N R1 = Ar, Het, n-C5H11; R2 = H, Ph; R17R2 = o-C6H4CH2CH2 , (CH2)5
N2 Me O N
2) P
Ph
CO2Et CO2Et BIPHIMIP = PPh2
Ph2SiH2, PhMe, 100 8C N PPh2
12 (83%)
N
and expanded the range of substrates from carbonyl-con-

taining to phenylsulfonyl-containing derivatives. Scheme 9
Substituted phthalazines 11 and 12 were obtained by the 7O O7
diaza-Wittig reaction under the same conditions HO R R OH HNO3, TFA +
N N+
(Scheme 7).25, 26 N N or N2O4 R R
Depending on the conditions, Pd-catalyzed C7H oxi-
+
dative cyclization of allyl-N-sulfonylhydrazones may follow N N O7 +
O N N
two pathways (Scheme 8).27 When the reaction is carried O O7
out in the presence of p-toluenesulfonic acid, 5-exo-trig- 15 (56% ± 75%)
cyclization is the preferred pathway, giving 5-vinylpyrazo- R = H, Me, Cl, Ph, 4-O2NC6H4 , O2N;
lines 13 in moderate yields. When Pd(OAc)2 in combination TFA is trifluoroacetic acid
with a phosphine ligand and an oxidant is used, 6-endo-trig-
cyclization takes place, implementing the N(2)7C(3)
approach, resulting in the formation of 6-methylidenetetra- atomic fragments ([5+1]); tetra- and diatomic fragments
hydropyridazines 14 in moderate to quantitative yields. ([4+2]); and two triatomic fragments ([3+3]). Examples of
The preparation of unusual 1,2,5-oxadiazolo[3,4-d ]pyr- [5+1] assembly are considered in several reviews.1, 5, 9 This
idazine 1,5,6-trioxides 15 according to the N(1)7N(2) approach is mainly used to prepare cinnolines by diazotization
strategy was described (Scheme 9).28 Interesting examples of anilines that have a reactive electron-releasing group
of pyridazine ring closure via oxidative N7N bond for- containing at least two carbon atoms in the ortho-position to
mation are also considered in the review.29 the amino group. The other methods are considered below.
2.2. Formation of two bonds 2.2.1. Formation of two bonds from [4+2] fragments
The synthesis of pyridazines by formation of two bonds can be The possible retrosynthetic approaches for the assembly of
accomplished in three ways: starting from penta- and mono- pyridazines from tetra- and diatomic groups are depicted in
398 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
(c) C(4)7C(5)+N(1)7C(6) (d ) N(1)7N(2)+C(5)7C(6) Scheme 11
(b) C(3)7C(4)+C(5)7C(6) R1 N R1 O R1 N
NH NH
(a) N(1)7C(6)+N(2)7C(3)
N N a CO2Pri b
O O
Figure 4. Approaches to the assembly of the pyridazine ring via
cyclization of tetra- and diatomic fragments ([4+2]).
R2 R2 R2
16 (62% ± 80%) 17 (68% ± 77%)
Fig. 4. As will be shown below, strategies involving the
R1 O R1 N
formation of N(1)7C(6) and N(2)7C(3) (pathway a) or NH
C(4)7C(5) and N(1)7C(6) bonds (pathway c) are used CO2Pri a or b O
most often for assembly of the pyridazine system. In most
cases, a synthetic chart starting from hydrazine and the
corresponding 1,4-dicarbonyl compounds (in the former
case) or appropriate diatomic (C2) components is most
convenient. Methods based on the formation of the 18 [67% ± 68% (for conditions a),
C(3)7C(4) and C(5)7C(6) bonds (pathway b) can be 37% ± 39% for conditions b)]
implemented by means of cycloaddition reactions, for
(a) NH2NH2 . H2O (1 equiv.), AcOH (0.5 equiv.), CH2Cl2 , 60 8C;
example, the Diels ± Alder reaction (see Section 2.5). The
(b) NH2NH2 . H2O (10 equiv.), AcOH (10 equiv.), CH2Cl2 , 60 8C;
least beneficial approach is the formation of N(1)7N(2)
and C(5)7C(6) bonds (pathway d ), because the one-step R1 = CO2Pri, 4-ClC6H4; R2 = Ar, Bn
process is faced with certain synthetic difficulties (it is easier
to use starting compounds with a ready N7N group:
hydrazines, hydrazones, diazo compounds and so on). trisubstituted double bond is more stable than a disubsti-
The pyridazine synthesis from 1,4-dicarbonyl com- tuted one. This accounts for the formation of 4,5-dihydro-
pounds and hydrazines is one of the most facile and efficient pyridazin-3(2H)-ones 18 as the only products.
methods implementing the N(1)7C(6)+N(2)7C(3) strat- The 6-exo-dig-cyclization of g-alkynones with hydrazine
egy (Scheme 10). The applicable sources of carbonyl group activated by indium(III) triflate was proposed for the syn-
in the precursors include both typical aldehyde, ketone, thesis of 3,4,6-trisubstituted pyridazines 19 and 20 (Sche-
ester, carboxyl and nitrile functions and their synthetic me 12).43 In the case of substrates containing a benzoyl or
equivalents, such as the 1,1-dibromomethyl or 1,1,1-tri- tosyl group as R2, this group was eliminated, thus giving
chloromethyl group of (Z)-2,4,4,4-tetrachlorobut-2-enal, 4-unsubstituted products.
which was converted to 3,5-dichloropyridazine.30, 31 The The condensation of 6-hydrazinyluracil and substituted
reaction is carried out with hydrazine or its salts.32 ± 34 glyoxals with the formation of C(4)7C(5) and N(1)7C(6)
Ethanol or acetic acid is usually used as the solvent. When
the 1,4-dicarbonyl compound contains a saturated moiety Scheme 12
between the carbonyl groups, oxidative aromatization is R3
NH2NH2, N
required; the oxidants used for this purpose include N R3
In(OTf)3
DMSO,35 bromine in an acid,36, 37 hydrogen peroxide in an O
dioxane, 20 8C R1
acid, phenyldiazonium chloride 38 and copper(II) chloride.39
It was shown that the use of microwave radiation (MW) R1 R4
increases the reaction rate and the yields of products.40, 41 In R2 19 (31%785%)
some cases, a base such as potassium carbonate or piper-
idine may be added for additional activation.42 N Me
O NH2NH2, N
In(OTf)3
Scheme 10 dioxane, 20 8C
R1 R1 Ts
R2 R2 20 (72%)
O NH2 [O] N
+
O NH2 72 H2O N
R3 R3 R1 = Ar, Het; R2 = R4 = Ar, Het, CO2Et; R4 = H: R2 = Bz, Ts;
R4 R4 R3 = H, Me, Et
R3 R3
H+
H2N N
..
The features of cyclization of several oxostyryl buta- In(OTf)3 *H+ N In(OTf)2

N
noates with hydrazine (Scheme 11) have been studied.34 It
was shown that the reactant ratio has a considerable R1 R1 7
OTf
influence on the reaction: taking starting compounds in R2 R2 In(OTf)3
equimolar amounts results in conventional closure of the
non-aromatic 4,5-dihydropyridazin-3(2H)-one ring (16), R3 R3
H
while a tenfold excess of hydrazine brings about isomer- N N
N *H+ N
ization to give 4,6-disubstituted pyridazin-3(2H)-one 17. O2
When a cyclohexenyl substituent is present in the initial R1 R1
1,4-dicarbonyl compound, isomerization does not take R2 R4
place regardless of the hydrazine amount, because the
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 399
bonds was proposed for the synthesis of pyrimido[4,5-c]pyr- Scheme 16

idazine-5,7(1H,6H)-dione derivatives 21 and 22 Cl
(Scheme 13).44 It was shown that regioselectivity of the R1 R2 R1 R1 R2
a b
reaction varies depending on the conditions: the reaction
N N N
conducted in 1,2-dichloroethane (DCE) yields only the N R3 N N NH2
3-substituted isomer, whereas the use of water and sodium C(O)NH2
25 (32% ± 87%) 26 (33% ± 90%)
acetate results in the formation of a mixture of 3- and
4-substituted isomers.
(a) 1) R2CH2C(O)R3, DIPEA, CHCl3 , 20 8C; 2) MeONa, MeOH, D;
Scheme 13 (b) 1) R2CH2CN, DIPEA, CHCl3 , 20 8C; 2) MeONa, MeOH, D;
O
O R1 = Me, Ph; R3 = Me: R2 = CO2Alk, C(O)NHAr, SO2Ar, C6H4NO2-4,
OH
Me R
N 2-Th; R27R3 = C(O)(CH2)3; DIPEA is N,N-diisopropylethylamine
OH
H2N a or b
N N O
H ring closure under the action of sodium methoxide and by
Me
O R O aromatization, resulting in the formation of 3,4,6-substi-
R Me Me tuted pyridazines 25 and 26.
N N
+ By using 4,4-dichloro-1,2-diazabuta-1,3-diene as the
N N
N N O N N O C(2)7N(2) component in the reactions with malononitrile
and dimethyl malonate, one can prepare heterocyclization
Me Me
products 27 and 28. The reaction includes condensation of
21 22
two carbon acid molecules and subsequent heterocycliza-
tion (Scheme 17).48
(a) DCE, D (19%785% total yield, 21 : 22 = 1 : 0);
(b) AcONa, H2O, D (43% ± 65% total yield, 21 : 22 from 1 : 0 to 2 : 5); Scheme 17
R = Me, But, Ar
NC CN MeO2C CO2Me
Cl Cl
A similar strategy with esters of dibasic oxoacids being Ar1 CN a b Ph CO2Me
used as the C(2)-component was applied to prepare com- Ar1 N
pounds 23 (Scheme 14).45 After hydrolysis of the ester N N
N NH2 N N O
group, these products were evaluated as dihydropteroate Ar2
synthase inhibitors. Ar2 Ph
27 (56% ± 98%) 28 (85%)
Scheme 14
R3 (a) NCCH2CN, NaH, THF, 20 8C;
R1 CO2R5 R1 O R3 (b) MeO2CCH2CO2Me, NaH, THF, 20 8C (for Ar1 = Ar2 = Ph)
R4
N O N R4
NH2 MeOH N
H2N N N or H2O, D
H2N N N 2-Hydrazones of 1,2,3-tricarbonyl derivatives can serve
R2 R2
as C(2)7N(2) components, while carbon acids with an
activated methylene group or alkyl acetylenedicarboxylate
23 (22% ± 95%)
can be utilized as the C(2) fragments. These reagents were
R1 = NH2 , OH; R2 = Me,
Bn; Me; R3 = H, used to prepare pyridazines 29 and 30 (Scheme 18).49 ± 51
R4 = CO2H, CO2Et, CH2CO2H, CH2CO2Me, CH2CO2Et; Similar methods accompanied by ultrasonic treatment
R5 = Me, Et (UST) were employed to obtain pyridazines 31 and 32
(Scheme 19).52
Arylhydrazones of 2-oxo-1,3-dinitriles and -1,3-dicar-
A series of pyrazolo[3,4-c]pyridazine derivatives 24 were bonyl compounds can react with cyanoacetylurea to afford
prepared from ethyl 2-arylhydrazono-3-oxobutyrates and pyridazine heterocycles 33 ± 35 (Scheme 20).53 After attack
potassium cyanoacetohydroxamate in moderate yields on the hydrazone by the acyl or nitrile group of the
(Scheme 15).46 cyanoacetylurea anion, the pyridazine ring can be closed
1,2-Diazabuta-1,3-dienes can act as the C(2)7N(2) either at the amide group of the initial compound with
component by reacting with compounds containing an elimination of urea, yielding products 34a,b, or at the nitrile
active methylene group (Scheme 16).47 The reaction group (33, 35). In the latter case, cyclization with the urea
includes displacement of the chlorine atom followed by residue additionally takes place. The reaction route depends
Scheme 15
KO
KO HO
NH NH NH NH HN N
O
CN CN Ar O Ar
N Ar O O H+ O N N
Me N
H NH4OAc, AcOH, N Ar N 7H2O N
CO2Et PhH, D Me N Me Me
H CO2Et
CO2Et CO2Et
24 (26% ± 38%)
400 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 18 on the substituent in the benzene ring of the aromatic

R2 R2 R2 moiety.
R1 R4 R1 R1 CO2Me An unusual compound to be used as the C(2)-compo-
R4 R5 O a
nent is (N-phenyliminovinylidene)triphenylphosphorane,
N N N which was employed to prepare heterocycle 36
N X NH N CO2Me
(Scheme 21).54
R3 R3 R3
29 (59% ± 89%) 30 (79% ± 91%) Scheme 21
Ph Ph
(a) MeO2CC:CCO2Me, PPh3 , DCE, 20 8C;
NH N NPh
R1 = C(O)Ar, C(O)Het; R2 = H, Me, Ph; R3 = Ar, Het; N a N
R4 = CN, Bz; R5 = CN, CO2Et; X = NH, O
PPh3
O O
O O
Scheme 19 Ph
O
N N
O NPh
N
O NH O = =C=NPh,
(a) Ph3P C
Ar 2 36 (75%) PhMe, D
O
R17EWG R2
2.2.2. Formation of two bonds from [3+3] fragments
a, or b, or c
N The concept of pyridazine ring assembly from two triatomic
O N X fragments ([3+3]) may imply two possible types of
Ar 2 coupling Ð formation of C(3)7C(4)+N(1)7C(6) bonds
CO2Me 31 (83% ± 90%) and N(1)7N(2)+C(4)7C(5) bonds (Fig. 5). However, the
latter approach is less preferred since the N7N bond
or
O formation is energetically unfavourable (see Section 2.2.1).
CO2Me
R3
CN
d or e N C(3)7C(4)+N(1)7C(6)
O N R4
Ar 2
N N
32 (74% ± 80%) N(1)7N(2)+C(4)7C(5)
(a) US, PhMe; (b) US, PyH; (c) US, Ac2O;

(d ) US, PPh3 , CH2Cl2; (e) US, DABCO, EtOH; Figure 5. Approaches to the assembly of the pyridazine ring from
Ar = 4-MeC6H4 , 4-F3CC6H4; EWG = CO2H, CO2Et, CN; [3+3] fragments.
R1 = CH2CN, CH2CO2Et, CH2Bz, CH2NHBz, CH PPh3; =
R2 = CN, CO2Et, Bz, NHBz, H; R3 = CO2Me, CN; R4 = CO2Me, H;
X = O, NH; Py is pyridyl, DABCO is 1,4-diazabicyclo[2.2.2]octane In the synthesis of dihydropyridazines 37, 2-oxoalde-
hyde hydrazones can act as the C7N(2) components, with
alkylidenemalononitriles being used as the C(3) -compo-
nents (Scheme 22).55 When a 2-cyanophenyl substituent is
Scheme 20 present in the starting arylhydrazone, additional cyclization
NC CN CN takes place, giving rise to fused polyheterocyclic system 38.
N H 2N A regioselective method for the synthesis of pyridazines
NHAr N
H from chalcone epoxides and diazodicarbonyl compounds
NC Et3N, EtOH, D H2N N N
Ar has been reported (Scheme 23).56 The diazodicarbonyl com-
O O NH pound is deacylated under the action of the ethoxide anion,
O
33 (65%) and then the diazo ester anion nucleophilically attacks the
NH
COMe chalcone epoxide. The resulting intermediate eliminates a
O MeOC COMe
COMe Me water molecule, then the ethoxide anion cleaves the epoxide
NH2 N
N Me ring, and the enolate attacks the diazo group to yield
NHAr N or O N 5-hydroxy-4,6-diarylpyridazine-3-carboxylates 39.
PyH, EtOH, D N Ar
NC Ar A synthetic route to pyrrolo[1,2-b]pyridazines 40 based
HN N
on 1H-pyrrole-1-amine derivatives and also involving chal-
O
O cones has been developed (Scheme 24).57 The reaction
34
(33% ± 50%) 35 (95%) mechanism includes a nucleophilic attack on the pyrrole
ring, isopropyl group migration and aromatization of the
system.
Ar = 4-MeOC6H4 (33, 34a), 4-O2NC6H4 (34b), 4-ClC6H4 (35) Furo[3,4-d ]pyrazolo[1,2-a]tetrahydropyridazinones 41
were prepared via a cyclization7intramolecular [3+3]
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 401
Scheme 22 Scheme 25
Ph R1
+
N
N N Ph 7N
O Ph R1
O
Ar2
Me + L, Me2SAuCl, AgOTf N
Ph CN O
N O R2 MeCN, 20 8C N
Ph
N N NHAr1
a CN a N N Me O
(Ar1 = 2-NCC6H4, Me R2
O Ph
Ar2 = Ph) Ar2 41 (83% ± 95%,
O
CN R1 = Ar, Het; R2 = Ph, 4-MeOC6H4; 65% ± 96% ee)
Me CN
Me
N Ar Ar
N N N
N NH2 O O Me
Ph2P O P
NH2 Ar1 O O Me
L = (Ar = 3,5-Me2C6H3)
37 (74% ± 85%) Pri Ar
Ar
38 (77%)
(a) PyH, dioxane, D; Ar1 = Ph, 4-ClC6H4; enantioselectivity: the enantiomeric excess (ee) reaches
Ar2 = Ph, 4-MeC6H4 , 4-ClC6H4 95%.
2.3. Formation of three bonds

cycloaddition tandem process involving 2-(alkyn-1-yl)alk-2- The approaches to the formation of the pyridazine system
en-1-ones and azomethine imines in the presence of a chiral via the formation of three bonds can be divided into three
Au catalyst generated in situ (Scheme 25).58 The target groups according to the number of atoms in the fragments
products can be obtained in high yields and with high that close the ring: [2+2+2], [1+2+3] and [1+1+4]
Scheme 23
N CO2R
O O N
O NaOH
+ CO2R
Me EtOH, 20 8C Ar1 Ar2
Ar1 Ar2
N2 OH
R = Me, Et
39 (30% ± 40%)
7 O O O H
+ O7 O7 OH
N Ar2
O N OR Ar1 Ar2 EtOH Ar1 Ar2
O
+ OR + OR Ar1 + OR
Ar1 Ar2 N N N
N N H N
O7 O O
EtO7
O O7
OH
Ar1 Ar2 Ar1 Ar2
Ar1 Ar2
N OR + OR
N N N
N CO2R N
O O
Scheme 24
O Ph
O O Ph N
Ph Ph O H
Ph N Ph N
H a H Ar1 Ar2 H3O+
Ar Pri
N
7CO2, 7PhNH2
Ar Pri Ar Pri
N N N Ar2
NHBoc NH2
Ar1
Ph Ph Ph Pri Ph Pri
Pri +
Ar .. Pri Ar + Ar2 Ar Ar2 [O] Ar Ar2
N N N N
7H+
N Ar2 N N N
Ar1 H+ Ar1 Ar1 Ar1

(a) TsOH, PhMe ± cyclo-C6H12 (3 : 2), D; Boc is tert-butoxycarbonyl 40 (59%784%)
402 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
[2+2+2] [1+2+3]
a c d e
N N N N N N N N
N(1)7C(6)+N(2)7C(3)+C(4)7C(5) N(1)7C(6)+C(3)7C(4)+ N(1)7C(6)+N(2)7C(3)+ N(1)7C(6)+C(3)7C(4)+
C(5)7C(6) C(3)7C(4) C(4)7C(5)
b f g h
N N N N N N N N
N(1)7N(2)+C(3)7C(4)+C(5)7C(6) N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+C(3)7C(4)+

C(4)7C(5) C(5)7C(6) C(4)7C(5)
[1+1+4]
i j k l
N N N N N N N N
C(3)7C(4)+C(4)7C(5)+ N(2)7C(3)+C(3)7C(4)+ N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+N(2)7C(3)+

C(5)7C(6) C(4)7C(5) C(3)7C(4) N(1)7C(6)
Figure 6. Approaches to the assembly of the pyridazine ring by the formation of three bonds.
protocols (Fig. 6). Considering all possible combinations Scheme 27

R
gives 12 pathways (a ± l ), six of which (b, f ± h, k, l ) imply
O N X
energetically unfavourable formation of N7N bonds. R
Methods based on the [1+1+4] protocol (i, j ) N
R N N X
associated with C7C bond formation may be difficult to O O N
implement in a multicomponent reaction. Thus, four strat- O NH2NH2 N
Ar Ar
egies can be listed for the three-component synthesis of R
pyridazines associated with the formation of O
N(1)7C(6)+N(2)7C(3)+C(4)7C(5) bonds (a); R = Me, Et; X = O, S 44 (43% ± 93%)
N(1)7C(6)+C(3)7C(4)+C(5)7C(6) bonds (c); C(O)NH2
O C(O)NH2
N(1)7C(6)+N(2)7C(3)+C(3)7C(4) bonds (d ); or
C(O)Me Me
N(1)7C(6)+ C(3)7C(4) + C(4)7C(5) bonds (e). OH
Ar
A simple example corresponding to formation of NH2NH2,
N
N(1)7C(6), N(2)7C(3) and C(4)7C(5) bonds is the OH DBU, H2O, Ar N
20 8C
preparation of pyridazin-3(2H)-ones 42 and 43 from appro- 45 (78% ± 93%)
priate ketones, glyoxylic acid and hydrazine
(Scheme 26).59, 60
Similarly, the reactions of arylglyoxals and hydrazine N(1)7C(6)+N(2)7C(3)+C(4)7C(5) strategy is the syn-
with barbituric or thiobarbituric acid or acetoacetamide are thesis of 3,6-substituted pyridazines 46 and 47 from readily
accompanied by the formation of 3-arylpyrimido[4,5-c]- available methyl ketones and 1,3-dicarbonyl compounds
pyridazine-5,7(6H,8H)-diones (or their thio analogues) 44 with the participation of hydrazine (Scheme 28).64 A dis-
or 6-aryl-3-methylpyridazine-4-carboxamides 45 tinctive feature of this method is efficient intermediate
(Scheme 27).61 ± 63 An interesting case corresponding to the elimination of one acyl group of the dicarbonyl precursor
induced by excess hydrazine. The use of ethyl benzoylace-
Scheme 26 tates results, in all cases, in the selective formation of
HOCCO2H,
O pyridazinone 46, irrespective of the nature of substituents
NH2NH2
O R3 in the benzoyl moiety.
K2CO3
N Me N N NH The formation of the pyridazine ring of compounds 48
42 (29%) according to the N(1)7C(6)+C(3)7C(4)+C(5)7C(6)
strategy occurs via condensation of 2-[4-(2-thienyl)pyrimi-
H din-2-ylthio]acetohydrazide, benzaldehyde and malononi-
O N O
N trile (Scheme 29).65
1) (HO)2CHCO2H, AcOK
2) NH2NH2 . H2O
One more example of using this strategy is the synthesis
of pyridazine-3-carboxamide derivatives 49 by reacting
N oxamic acid thiohydrazides with chlorovinylaldehydes
N obtained from the corresponding ketones through the
CO2R
CO2R Vilsmeier ± Haack reaction. The subsequent 6p-electrocyclic
R = Et, Bn 43 (55% ± 72%) closure of the pyridazine ring is accompanied by elimination
of molecular sulfur (Scheme 30).66, 67
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 403
Scheme 28 Scheme 31
N NH NHAr
Me O
Ph O O
Me N
Me H N
O O O a
a 46 (61% ± 75%)
+ H H
R1 Me R2 R3 N N AcO
R1 R2 H
50 (67% ± 92%)
47 (60% ± 89%)
NHAr
Me O
(a) 1) CuO, I2 , DMSO, 70 8C; 2) NH2NH2 . H2O, ButOH, D; O
46: R1 = Ph, R2 = OEt: R3 = Ar, 2-Fu; Me N
H a N
47: R1 = Ar, Het; R2, R3 = Me, Ph, 4-MeOC6H4; Fu is furyl
H H
O O N N HO H
R1 R2 NH NH R1 R2 NH2NH2 51 (79% ± 91%)
..
2 2
R3 R3 Me OH Me
O O N
Me H a
N N N
N N
R1 R2 H H H
R1 R2 + R3C(O)NHNH 2
O O NHAr
H
R3 + 52 (67% ± 73%) Me
7
O N2H3 Me
Me OH Me H
Me
Me H a N
Scheme 29 H
N
1) PhCHO, CN H H H
O CH2(CN)2, Ph
O O O NHAr 53 (51% ± 82%)
PyH, EtOH, D CN H
NH2 N
R N 2) 10% HCl R N
H
H (a) 1) POCl3 , DMF, CH2Cl2 , D; 2) H2NNHC(S)C(O)NHAr, TsOH
NH O
N
NC Ph NC Ph 1) H2O NC Ph
underwent the Wagner7Meerwein rearrangement, which
2) HCl
.. N N N resulted in compound 53.
R N R N R N .
H H HCl A palladium-catalyzed reaction was used to implement
48 (75%) the approach involving formation of the
S
N S
N(1)7C(6)+N(2)7C(3)+C(3)7C(4) bonds for the syn-
R= thesis of 4-aminophthalazinones 54 (Scheme 32, substituent
N
positions in the substrate are indicated).68
An example of the N(1)7C(6) + C(3)7C(4) + C(4)7
C(5) strategy is a reaction catalyzed by activated magne-
Scheme 30 sium oxide or phosphotungstic acid. Under these condi-
O Cl tions, methylglyoxal arylhydrazones, benzaldehydes and
a CHO b
1,3-dicarbonyl compounds react to afford dihydropyrida-
R1 R1
R2 R2
Scheme 32
C(O)NHR3 NHR3 O
R1n
N R1n R3
HS N O N CO2Me R3 a N
Cl N + R27NC + HN
7HCl, 7S8 Y N
R1 Y
R1 X NH2
R2 HN
R2 R2
49 (26% ± 89%)
(a) Pd(OAc)2 , Xantphos, MW, DMSO, 150 8C; 54 (29% ± 99%)
(a) POCl3 , DMF, CH2Cl2 , D; (b) H2NNHC(S)C(O)NHR3, TsOH; X = Cl, Br, I, OTf; Y = CH, N; R1n = H, 5-Cl,
R1, R2 = Alk; R17R2 = (CH2)3 , (CH2)4 , (CH2)5 , (CH2)2CH(Ph)CH2 , 4-F, 5-CF3 , 4,5-benzo, 4-Me, 3-OMe,
(CH2)2CH(But)CH2 , (CH2)2N(CO2Et)CH2 , (CH2)2OCH2; R3 = Ar, Bn 5-OMe, 5-NH2 , 4-morpholino, 4-(NHCH2C6H4F-4);
R2 = But, CMe2CH2But; R3 = H, Me, Ph, 4-F3CC6H4;
Me Me
This method was successfully used to modify a number
of steroids to give annulated pyridazines 50 ± 53 Xantphos =
(Scheme 31). It is worth noting that in the case of 3-keto- O
PPh2 PPh2
17a-methyl-17b-hydroxyandrostane, the substrate also
404 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 33 Scheme 35
O
ArCHO, O O O
H NH2NH2 BF3 . OEt2
Me N N Y XCH2CN O n n
O EtOH, D HN CH2Cl2, 20 8C
a or b N
OMe H OH
58 (97% ± 98%)
Ar X Ar X O O O O
O O MnO2
n
NH2 or NH HN DMF, D HN
N (n = 2) N
Me N N Me N N Z
59 (96% ± 73%) 60 (47%)
Ph
n = 1, 2
55 (65% ± 95%)
56 (70% ± 88%)
Benzoyl-g-butyrolactones and hydrazine also served as
(a) Et3N, MgO, MeCN, D; (b) Et3N, H3PW12O40 , MeCN, rt; the starting compounds for the synthesis of pyridazinones;
X = CN, CO2Et; Y = H, CN, CO2Et; Z = O, NH first, they were converted to 6-aryl-5-hydroxymethyl-
4,5-dihydropyridazin-3(2H)-ones 61 (Scheme 36).72 The
Ar X O Ar
H subsequent ring aromatization giving 6-aryl-5-hydroxyme-
Me X thylpyridazin-3(2H)-ones 62 was induced by oxidation with
N Me
N manganese dioxide under acetyl protection of the hydroxyl
N O N
Ar0 H N group.
N
27 2+ 27 2+ Ar0
O Mg O Mg Scheme 36
O27 Mg 2+
O
N NH N NH
O Ar O Ar Ar a b
H O Ar O Ar O
X X O
Me Me
HOH2C HOH2C
N N
N NH N NH2 61 (20%) 62 (19%)
Ar0 Ar0 (a) NH2NH2 , EtOH, D;
(b) 1) Ac2O, PyH, 20 8C; 2) MnO2 , CHCl3 , D; 3) 2 M HCl, D
zine derivatives 55 and 56 (Scheme 33).69 The authors

proposed a possible reaction mechanism. The simple strategy of assembly of the pyridazine core
An interesting reaction with formation of the using the hydrazine N(2) component and a five-membered
N(1)7C(6), C(3)7C(4) and C(4)7C(5) bonds of the pyr- oxygen-containing heterocycle may be a part of the syn-
idazine system is depicted in Scheme 34.70 The reaction of thesis of functionalized pyrazolopyridazine-5,8-diones 63
(tert-butyl-NNO-azoxy)acetonitrile with N,N-dimethylace- and 64 (Scheme 37).73
tamide dimethylacetal followed by treatment with silica gel A similar idea was utilized to prepare 1H-pyra-
affords derivative 57. zolo[1,2-a]pyridazine-5,8-diones 65, containing amino and
cyano groups (Scheme 38).74 Maleic or phthalic anhydride
Scheme 34 was allowed to react with hydrazine, and the pyrazole
O7 moiety was assembled from malononitrile and aldehydes.
+ But
But N CN N Catalysis by the nanomagnetic ionic liquid (NMIL), com-
O7 N
+ a + SiO2 posed of Fe3O4@SiO2 bearing surface-grafted piperidinium
But N CN N
N Me O7 MeOH, 25 8C cations and surrounded by benzene-1,3-disulfonate anions,
(63%) CN {Fe 3 O4 @SiO 2@(CH 2 )3 7 +NH(CH 2 ) 5} 2[C 6 H 4(SO ÿ
3 ) 2 -1,3],
O7 NH2 was the key issue of the synthesis. Apparently, the NMIL
But N +
particles activate the electrophilic groups of the reactants
N N (a) 1) MeC(OMe)2NMe2 ,
+ owing to the presence of positively charged pyridinium
N 0 ? 20 8C; 2) 1 M HCl,
Me O7 groups.
0 ± 5 8C
CN The synthesis of nickel(II) complexes with 10,20-dimesi-
57 (99%)
tyl-5,15-diazaporphyrin 66 was accompanied by the forma-
tion of derivatives 67 as by-products, resulting from the
2.4. Ring expansion rearrangement of one pyrrole ring of the ligand to give a
The expansion of the hydroxyfuranone ring continues the pyridazine moiety (Scheme 39).75 The key goal of that study
synthetic strategy towards pyridazines based on the [4+2] was to prepare unrearranged complexes, the yield of which
fragment; in this case, the furan ring acts as the C(4) was subsequently increased by complete elimination of the
component, while the N(2) component is again represented formation of by-products; therefore, the preparative value
by hydrazine (Scheme 35).71 After the formation of the of this process is moderate. Nevertheless, this transforma-
tetrahydropyridazinone system, dehydration and oxidation tion can be of interest for further research, since the
can be conducted one after the other with successive products represent a new class of complex compounds
formation of compounds 58 ± 60. potentially possessing interesting physical properties.
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 405
O O Scheme 37
R3
O CO2 R2 O
O
CO2R2 O CO2R2
R4 R3
N O
+
O N
CO2R2 + R1 N C7 CO2R2
N .H .H N
NH2NH2 2O, NH2NH2 2O,
R4
HN EtOH7Me2CO (1 : 1) CO2R2 EtOH7Me2CO (1 : 1) HN
O R1 O R2
63 (59% ± 72%) 64 (54% ± 73%)
R1 = Alk, Bn; R2 = Me, Et, But; R3 = R4 = H; R37R4 is benzo, tetrachlorobenzo
2.5. Cycloaddition
Scheme 38 As noted above, a facile approach to the formation of the
pyridazine ring implementing the C(3)7C(4)+C(5)7C(6)
O O NH2
CH2(CN)2,
strategy is the use of cycloaddition reactions. The inverse
R2 R2 electron demand Diels7Alder reaction of 1,2,4,5-tetrazines
NH2NH2 . H2O N
R1CHO + O CN is used most often. For example, 3,6-substituted pyridazines
NMIL, 110 8C N
R3 R3 68 were obtained in this way (Scheme 40).76 When the
O O R1 reaction is carried out in refluxing acetonitrile, the second
65 (60% ± 94%) tetrazine equivalent serves as the oxidant.
R1 = Ar, CH2Bn, 2-Naph; R2 = R3 = H; R27R3 is benzo; Scheme 40

Naph is naphthyl; NHCO2Bn
R R
A27 N+ H
+ NHCO2Bn
N
+ H N N N (1 or 2 equiv.) N
H H A27
N N a or b N
+
N Fe3O4 N ÿ
NMIL = + [A27 = C 6H4(SO3 )2-1,3]
A +
27 H R R 68 (68% ± 92%)
H
N H +N
+
H N (a) 1) CH2Cl2 , 20 8C; 2) PIFA (for R = CO2Me);
A27
(b) MeCN, D (for R = 2-Py);
PIFA is bis(trifluoroacetoxy)iodobenzene
Scheme 39 Two procedures used for the synthesis of 4-[(1H-indol-

Br
3-yl)methyl]pyridazine-3,6-dicarboxylates 69 were com-
Br
N pared: first, a combination of the Diels7Alder and Fischer
N NaN3
R Ni R reactions and second, a combination of Tebbe methylena-
N DMF, 110 8C
N tion and the Diels7Alder reaction (Scheme 41).77 The total
Br yield of the product was found to be higher in the latter
Br case.
N N
Scheme 41
N N N N
CO2Me
R Ni R+R Ni R
O OMe
N N N N N MeO2C
a b
N N N
N N
CO2Me R Boc
66 (12%) X 67 (13% ± 20%)
69
R = Mes; X = O, NH
(a) 1) 3,6-di(methoxycarbonyl)tetrazine, dioxane, 20 8C;
R R 2) PhNHNH2 , AcOH, MeOH (for R = H, 9% yield);
R R
Ni Ni (b) 1) m-chlorobis(cyclopentadienyl)(dimethylaluminium)-m-
N N 7N2 N N methylenetitanium (Tebbe reagent), THF, 740 ? 20 8C;
N
2) 3,6-di(methoxycarbonyl)tetrazine, dioxane, 20 8C (for R = Boc,
X N3 NH2 43% yield)
..
N
The Diels7Alder reaction was also applied to synthesize
N N
conjugated compounds 70, which were utilized in the design
R Ni R of electrochromic copolymers (Scheme 42).78
N N A deoxyuridine triphosphate derivative containing a
N vinyl group in position 5 was used as an unusual substrate
X = N3 , NH2 , Br for the assembly of the pyridazine ring (Scheme 43).79
NH
Compound 71 produced in the reaction with 3,6-di(2-pyri-
406 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 42 Scheme 44
R O R1 O R1
O N O NH K2CO3, CsF N Ar1

Br N N Br N MeCN, 20 8C N
X X
X
Ph2O, 160 8C Ar1 Ar1
N N
72 (88% ± 98%)
R
O R2 O R2 O R2
O N O
NH NH K2CO3, CsF N Ar3
Br X X Br + N
N N MeCN, 20 8C
X X
N N Ar2 Ar3 Ar2
70 (56% ± 73%) 73 (86% ± 98%)
X = O, S; R = n-C6H13 , CH2CH(C8H17-n)C10H21-n X = Br, Cl; R1 = Me, Ar, 2-Fu; R2 = Me, Ph; Ar1 = Ph, 4-NCC6H4 ,
4-MeC6H4 , 3,4-Cl2C6H3 , 2-Naph; Ar2 = 4-PhC6H4 , 2-Naph, 4-NCC6H4 ,
Scheme 43 4-O2NC6H4 , 4-ClC6H4 , 3,4-Cl2C6H3; Ar3 = 4-PhC6H4 , 4-MeC6H4
O
NH N N O R
O
O O O R R
N N N Ar N [4+2]
7O P O P O P O N O N + N R
O a
O7 O7 O7
Ar
OH R N
O N O R
O R O R
HN R N Ar H+
N F7 N 7 Ar N Ar
O O O N N N
7O P O P O P O O N Ar N R Ar
O Ar
O7 O7 O7
O
71 (80%) OH
(a) O2 (air), dioxane, H2O, 20 8C; R = 2-Py Scheme 45

Ar Ar
NH R2 TEMPO N R2
N N
+ argon, PhMe, 80 8C R3
dyl)tetrazine could find use in polymerase chain reaction for R3
R1 Me R1
fluorescence determination and visualization of cellular
74 (41% ± 88%)
DNA. A similar synthetic strategy was described for a
library of DNA-encoded compounds.80 R1 = Me, But, Ar, 2-Th; R2 = CO2Alk, CO2Bn, CO2Ph, C(O)NHPh,
An interesting method was proposed for the synthesis of
Ar, Het; R3 = H, Me
tetrahydropyridazines, namely, cyclodimerization of
a-halo-N-acylhydrazones (Scheme 44).81, 82 The reaction
mechanism includes conversion of the substrate, under the An unusual synthetic route to 5-fluorine-substituted
action of a base, to substituted 1,2-diazabuta-1,3-diene, pyridazines 76 includes a series of successive [2+1] and
which further undergoes [4+2] cycloaddition, eliminates [3+2] cycloadditions involving terminal alkynes, difluoro-
an acyl group and a nitrogen molecule after an attack by carbene and diazocarbonyl compounds (Scheme 47).85 The
the fluoride anion and adds a proton to give 1-acyl- conditions of generation of difluorocarbene varied depend-
3,6-diaryl-1,4,5,6-tetrahydropyridazines 72. It was found ing on the degree of electron deficiency of alkynes.86
that this protocol can be rather easily modified to enable
cross-cyclodimerization involving two different a-halo-N-
acylhydrazones taken in 2 : 1 ratio. In this case, the reaction
3. Pyridazine ring reactivity
gives product 73 as a single regioisomer. The key structural feature of pyridazines determining their
A similar method for the synthesis of substituted tetra- reactivity is the presence of two neighbouring nitrogen
hydropyridazines 74 is also based on the Diels7Alder atoms in the aromatic six-membered ring (Scheme 48).
reaction; however, in this case, the formation of diazabuta- This causes relative intertness of pyridazines towards elec-
diene is facilitated by the use of (2,2,6,6-tetramethylpipe- trophilic substitution reactions and higher reactivity
ridin-1-yl)oxyl (TEMPO) (Scheme 45).83 towards nucleophilic substitution reactions compared with
The cascade process based on [4+2] cycloaddition with pyridine derivatives, which contain only one nitrogen atom
the subsequent nucleophilic attack by the pyrazole moiety in the aromatic ring. The electrophilic attack is directed to
on the formed 4,5-dihydropyridazine ring results in the only one nitrogen atom, as the positive charge on this atom
diastereoselective formation of product 75 (Scheme 46).84 deactivates the second nitrogen atom. Pyridazines are
The minor diastereomer 750 is one of the other three weaker bases (pKa H = 2.3) than pyridines (pKa H = 5.2),
possible isomers. because the second nitrogen atom has a destabilizing action
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 407
Scheme 46
CO2Me N+
MeO2C MeO2C Ar Ar
NH
N N Me N N N
O N N
O N ON O ON O
N Me Ph CO2Me
CO2Me N *H+ CO2Me CO2Me
Ph Me Ph N + Ph N
MeCN, D Ph CO2Me NH NH
N O N O7
HO N N N N
HO
N Me Me
Ar N
Ar N Ar CO2Me CO2Me
75 (64% ± 88%) 750 (minor
diastereomer)
dr from 75 : 25 to 85 : 15
Scheme 47
F F F F F
F F
CF2 R2O2C N2
R1 R1 R1
..
R1 a or b Et3N, 20 8C H .. N
N N
R1 N R2O2C N N
R2O2C H R2O2C
76 (14% ± 86%)
(a) TMSCF3 , NaI, THF, 110 8C; (b) TFDA, NaF, diglyme, 120 8C; R1 = Ar, Het, Bn, cyclo-C3H5 , cyclo-C6H11 , CH2OAc, CH2CH2NBoc2 ,
CH(CH2CH2)2NTs; R2 = Et, Bn, But; TMS is trimethylsilyl, TFDA is trimethylsilyl fluorodisulfonyldifluoroacetate
Scheme 48
Scheme 49
N O
+ R1
..
N R2
H R2X, NaH N
O DMF, 20 8C N
H+
NH NH2 77 (67% ± 80%)

RX RCO3H R1
+ N + N
..
..
N N N N O
..
N
.. ArI, CuI,
R X7 O7 Ar
NH2 Cs2CO3 N
R1
X Nu NH2 N
Nu7 ,
NH2 NH2
N N
N N DMF, 110 8C 77 (16% ± 80%)
ERG ERG Nu7 is nucleophile,
E+ E+ is electrophile, R1 = H, OMe, Me, Cl,morpholino; R2 = Me, Bn, All; X = Br, I
E ERG is electron-
N N
N N releasing group
The possibility of electrophilic attack on the nitrogen
atoms in the pyridazine system opens the route to imid-
azo[1,2-b]pyridazines 80 and 81 (Scheme 51).90, 91
on the formed pyridazinium cation. However, this does not A method was proposed for the synthesis of 6-chloro-
prevent the formation of salts with alkyl halides or N-oxides 1,2,4-triazolo[1,5-b]pyridazines 82 by addition of nitrile to
with peroxy acids. 3-aminopyridazine catalyzed by CuI and ZnII salts, followed
by intramolecular oxidative formation of the N7N bond
3.1. Electrophilic attack on pyridazine nitrogen atoms (Scheme 52).92
Examples of introducing alkyl substituents to pyridazine The key step of the synthesis of ferroceno[d ]pyridazine
nitrogen atoms are found in the literature quite often. derivatives 83, potential antitumour agents, is the closure of
Typical cases are nucleophilic substitution followed by the imidazoline or tetrahydropyrimidine rings at the pyr-
deprotonation of the diazinium salt.17, 32, 40 A modification idazine C7N bond via the Appel or Mitsunobu reaction of
of this technique with the use of ultrasonic treatment is substituted hydroxyalkylaminoferroceno[d ]pyridazines
known.87 There are examples of selective N-alkylation and (Scheme 53).93 The influence of diastereomer configuration
N-arylation of 4-aminophthalazin-1(2H)-ones to give on the yields of reaction products was studied. For example,
4-amino-2-aryl(alkyl)phthalazin-1(2H)-ones 77 both by the if the R1 or R2 group in the aliphatic moiety of the starting
classical procedure and in the presence of a Cu catalyst compound is phenyl, partial dehydrogenation products 84
(Scheme 49).68 were isolated.
Diazinium salts 78 and 79 were isolated and the former The condensation of 3,6-dihydroxypyridazine, acetyle-
were found to exhibit antibacterial properties 88, 89 nedicarboxylate and isonitrile was proposed for the syn-
(Scheme 50). thesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives
85 (Scheme 54).94
408 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
OH Scheme 50
OH O R1 R1 BFÿ
4
OH R2 R2
R1 O Cl N Et3O+BFÿ N
4
N OH
+ MeOH, Me2CO, N CH2Cl2, 20 8C N+
N R3 R3 Et
MW or US, D
Cl7 Cl Cl
Cl 78 (85% ± 95%) 79 (68%785%)
78: R1 = H, Me, 4-BrC6H4 , 4-MeC6H4; R2 = R3 = H; 79: R1 = Cl, 2,4-Me2-pyrazol-1-yl; R2 = R3 = H; R27R3 is benzo
Scheme 51
O
O X
N Cl HN O
N Cl Br
N R N O N Cl
R N
EtOH, D a or b HN
N H2N N
80 (45% ± 72%) 81 (45% ± 77%)
(a) Na2HPO4 , DMA; (b) K3PO4 , DMA, 80 8C; R = Me, F3C, 4-MeC6H4 , 4-F3CC6H4; X = Cl, Br; DMA is dimethylacetamide
Scheme 54
Scheme 52
R1 R1 OH O NHR1
CO2R2
H2N R2C N, CuBr,
1,10-Phen, ZnI2 N N Me2CO N
+ + R1 NC CO2R2
R2 N 20 8C N
N I2, KI, K2CO3, N N N
N Cl Cl CO2R2
DCB, 130 8C CO2R2
82 (18% ± 63%) OH O
85 (70% ± 86%)
R1 = H, MeO; R2 = Me, Ar, Het;
1,10-Phen is 1,10-phenanthroline, DCB is 1,2-dichlorobenzene R1 = But, cyclo-C6H11 , Bn, CH2CO2Et, CMe2CH2But, 2,6-Me2C6H3;
R2 = Me, Et, But
N Scheme 53
N
Scheme 55
HN R2 a or b
Fe n O O
R1 NH NH
HO a
R
R3 R
N N
N NHAlk
N R3
N N NH2 N
R2
N 86 (69% ± 82%) Ar
N + Fe Ph
Fe n
R1
(a) ArCHO, AlkNC, TsOH . H2O, DMSO, 70 8C; R = H, 6-Me, 7-Me
83 (15%770%) 84 (17%729%)
(a) CBr4 , PPh3 , CH2Cl2 , 20 8C; (b) DIAD, PPh3 , THF, 20 8C; Scheme 56
R1 = H, Me, Pri, Bn, Ph; R2 = H, Ph, CH(OH)Ph; R3 = H, Ph; Br
n = 0, 1; for 84: R1 = Ph, R2 = R3 = H; R2 = Ph, Br2, NaHCO3
Cl NH2 Cl NH2
R1 = R3 = H; DIAD is diisopropyl azodicarboxylate MeOH, 20 8C
N N N N
87 (57%)
It was shown that 4-aminophthalazin-1(2H)-ones
undergo the Groebke ± BienaymeÂ ± Blackburn reaction to
give 3-amino-2-arylimidazo[2,1-a]phthalazin-6(5H)-ones 86 Examples of nucleophilic attack on the pyridazine ring
(Scheme 55).68 were also reported. The synthesis of 4-aminopyridazin-
3(2H)-ones 88 by the reaction of pyridazinones with hydra-
3.2. Reactivity of pyridazine carbon atoms zine is a well-known and reliable method for introducing an
Many interesting cases of electrophilic attack on the pyr- amino group into the pyridazine ring (Scheme 57).96
idazine carbon atoms were considered in previous The enantioselective functionalization of pyridazines
reviews.1, 5 A classical example of such reactions is bromi- with alkenes into position 4 was accomplished to give
nation of 3-amino-6-chloropyridazine 87 (Scheme 56).95 substituted (S)-4-(1-arylethyl)pyridazines 89. The reaction
The reaction pathway is dictated by more pronounced proceeds in the presence of a Cu catalyst, a chiral bis-phos-
electron-donor properties of the amino group compared to phine ligand and methyldimethoxysilane (Scheme 58). 97
chlorine. The organocopper derivative formed intermediately upon
alkene hydrocupration acts as the nucleophile.
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 409
Scheme 57 Scheme 60
R R
R R NH2 NHCO2Bn NHCO2Bn
N Zn
X N X N HN
a AcOH
O O N
Y N N NH Y N N NH
Z Z R 93 (64% ± 67%)
R 68
88 (65% ± 90%)
R = CO2Me, 2-Py
(a) NH2NH2 . H2O, D; X, Y = CH, N; Z = CH, N, C(O); R = H, Me
Scheme 61
Scheme 58 Cl Cl Cl
Ar Ar R
R2 R2 N a N b N NHCbz
R1 R1 R1 N N N
a O2
N N PhMe, N CO2Et CO2Et CO2Et
N N 20 8C N
94 (37% ± 45%) 95
SiMe(OMe)2 89 (48% ± 58%,
93% ± 98% ee) (a) RCO2H, (NH4)2S2O8 , AgNO3 , H2SO4 (conc.), H2O, 70 8C;
(b) CbzNHCH2CO2H, (NH4)2S2O8 , AgNO3 , TFA, H2O, 70 8C;
(a)(E)-R2CH =
CHAr, HSiMe(OMe)2 , Cu(OAc)2 , (S,S)-Ph-BPE,
R = Bn, Pri; Cbz is benzyloxycarbonyl
THF, 208C; R1 = H, OMe; R2 = H, CH2OMe;
Ph Cl
Ph
(S,S)-Ph-BPE = P S2O2ÿ
8 N
P Cl Cl
Ph N
Ph Ag2+ Ag+ R
. CO2Et N N
RCO2H R +
7CO2 H+, [O] N N
R
An efficient method for introduction of the cyano group
CO2Et CO2Et
into the pyridazine ring is the Reissert ± Henze reaction
(Scheme 59).98 It is noteworthy that in the case of 4-fluo-
robenzyl substituent, only derivative 90 tosylated into the
benzylic position was isolated. The reaction regioselectivity of 4,5-dicyanopyridazine to various substrates with subse-
depending on substituents present in the ring was studied quent transformations is described in detail in a review 99
and the conditions of the preparation of 3-cyanopyridazines (Scheme 62).
91 and 92 were optimized; the total yield of these products Pyridazine derivatives alkylated at the nitrogen atom
varied from 58% to 80% and their ratio varied from 1 : 0.8 with a-halocarbonyl compounds can be involved in
to 1 : 28. 1,3-dipolar cycloaddition. For example, this method was
used to synthesize pyrrolo[1,2-b]pyridazines 99 ± 103
3.3. Reduction reactions (Scheme 63).100 ± 102 The 1,3-dipole was generated from the
The reduction of pyridazine derivatives 68 with zinc in corresponding pyridazinium bromide under the action of a
acetic acid follows an unusual pathway. In this case, base.
reductive contraction of the pyridazine ring to a pyrrole
ring takes place, giving benzyl(4,5,6,7-tetrahydro-2H-isoin- 3.6. Reactions of hydropyridazines
dol-5-yl)carbamates 93 (Scheme 60).76 The exocyclic double bond in methylidenetetrahydropyri-
dazines can undergo exo7endo migration and, after that,
3.4. Radical reactions the corresponding dihydropyridazines are easily aromatized
In some cases, carbon substituents are introduced into to give substituted pyridazines 104 (Scheme 64).103
position 5 of the pyridazine ring using the Minisci nucleo- A large number of derivatives 105 ± 115 containing a
philic radical substitution. For example, derivatives 94 and hexahydropyridazine moiety were prepared for studying
95 were synthesized in this way (Scheme 61).36, 95 their ability to inhibit the inducible NO-synthase
(Schemes 65, 66).104 The synthesis of the starting com-
3.5. Cycloaddition reactions pounds shown in Scheme 66 was reported by the same
Pyridazines undergo cycloaddition reactions. The prepara- research group in an earlier publication.105
tion of compounds 96 ± 98 based on the [4+2] cycloaddition
Scheme 59
Ts CN R
R N
TMSCN, TsCl N TMSCN, TsCl R
N N + N
DBU, AlCl3, N DBU, AlCl3,
N THF, 10 8C THF, 10 8C N
F CN
90 (64%) (R = 4-FC6H4CH2)
91 92
R = Me, Et, Pri, But, PhCH =CH, Ph, MeO, EtO, Pr O, CF CH O, PhO, BocNH, piperidino, morpholino
i
3 2
410 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 62
R5 CN
R5 R6
CN R1 R2 or
X R5 R6 R6 CN
NC
CN 97 (11% ± 99%)
R3 R4 N
R1 R2 Ph
N
X CN Ph Ph
R3 R4
NC
96 (21% ± 99%) Ph Ph
NC
Ph
X = (CH2)n (n = 1, 2, 3), CH2OCH2 , CH2N(Ac)CH2 , CH2SCH2 , CH2O, C(O)O 98 (77%)
Scheme 63
R1 O O
N R1 R1
H
O N Ph CN d
N N N
c NC N NC N
a or b
N R1
Ph C(O)Ar
Br7 C(O)Ar C(O)Ar
O N
103 (50% ± 69%)
99 (45% ± 85%) + R4
N C(O)Ar
CO2Me R1
R1
R1 R2
CO2Me R5 N N
H R4 N R4 N
N a or b R3 a or b
MeO2C N
a or b
R5 C(O)Ar R5 C(O)Ar
MeO2C C(O)Ar R1 102 (10% ± 83%)
100 (35% ± 43%) H
N
R2 N (a) Et3N, CHCl3 , D or MW; (b) KF, Aliquat 336, MW;
(c) DMF, 20 8C; (d ) CoCr2O7 . 4 PyH, DMF, 90 8C; R1 = H, Me;
R3 C(O)Ar R2 = CN, CO2Me, CF3 , CO2CH2CF3; R3 = H, CO2Alk;
101 (20% ± 76%) R4 = CO2Alk, CF3; R5 = H, CO2Alk; Aliquat 336 is methyltrioctylammo-
nium chloride (Starks catalyst)
Scheme 64
SO2Ar SO2Ar
N Me
4. Reactivity of substituents in the pyridazine ring
N N Me N
N CHCl3 N AcONa 4.1. Alkyl groups
20 8C THF, 65 8C R1 The a-position of alkyl substituents in pyridazines is acti-
R1 R1 vated. A standard approach to functionalization of alkyl
R2
R2 R2 groups is halogenation, for example, as in the synthesis of
104 (40% ± 96%)
3,6-bis(chloromethyl)pyridazine 116 (Scheme 67).106
R1 = Ar, 2-Naph, n-C5H11; R2 = H, Ph; The cyclization involving 3-methylpyridazine-4-carbox-
R17R2 = o-C6H4CH2CH2 , (CH2)5 amides and Vilsmeier reagents was successfully carried out
O Scheme 65
d
N
S N
N a
S O
N
108 (9%)
S CH2N[(CO)2C6H4-o]
105 (82%)
NH . HCl
e N
a NH N
CH2N[(CO)2C6H4-o]
S HN
H 109 (5%)
O Ar N N b
N c
N
N f N N
Ar O
107 (19%) 106 (62%) N N
110 (13%)
(a) CS2 , PyH, MeOH, 80 ± 90 8C; (b) ArC(O)NH2 , (HCHO)n , EtOH, D (for Ar = 4-O2NC6H4);
(c) CS2 , PyH, MeOH, 20 8C; (d ) o-C6H4(CO)2NK, 30% HCHO (aq.), MW;
(e) o-C6H4(CO)2NH, 30% HCHO (aq.), PyH, EtOH, D; (f ) o-C6H4(CO)2NK, 30% HCHO (aq.), H2O, D
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 411
S Scheme 66
a N
N R1
N
NR1
113 (3% ± 71%)
N a or b
S
N S S NHMe S NHMe
111 (23% ± 75%)
N NHR1 a or d N N
N N
S NH (R1 = Me)
N c 114 (10%)
N H
N (R1 = H) S S
2
R3 R N N
N N
112 (10% ± 81%) d
N N
(R1 = H)
115 (15%)
(a) 30% HCHO (aq.), MeOH, D; (b) 30% HCHO (aq.), 20 8C;
(c) R2C(O)R3, TsOH, D; (d) (HCHO)n , MS, 140 ± 150 8C; 111: R1 = H, Ph; 112: R2, R3 = Alk, Ar; 113: R1 = Me, Ph;
MS are molecular sieves
Me Scheme 67
TCCA Cl Scheme 69
N CHCl3, D N Cl N NH
N Me N
N NH N NH Ar1 O
116 (46%) a b
Ar1 O Ar1 O O
TCCA is trichloroisocyanuric acid NH
HOH2C 62 HO2C Ar2 NH
118 (5% ± 20%)
to prepare compound 117 (Scheme The reaction was 68).63 (a) 1) MnO2 , THF, 20 8C; 2) AgNO3 , EtOH, H2O, 20 8C;
facilitated by enhanced acidity of the methyl group at the 3) 10% NaOH (aq.), 20 8C;
electron-withdrawing pyridazine ring; considering this fact, (b) 1) DPPA, Et3N, PhMe, 80 8C; 2) Ar2NH2 , THF, D;
a possible reaction mechanism was proposed. DPPA is diphenylphosphoryl azide
Scheme 68
H example, ethyl 5-fluoro-6-phenylpyridazine-3-carboxylic
O NH2 O N
1) POCl3, DMF, 75 8C acid was converted to derivatives 119 ± 122 (Scheme 70).85
Me 2) NaHCO3, H2O O Amides 123 and 124 were prepared using
bis(dimethylamino)methylene-1H-1,2,3-triazolo[4,5-b]pyri-
N N dinium 3-oxide (HATU), which generates an activated ester
Ar N Ar N
during the reaction, and the ester readily reacts with the
117 (61% ± 78%)
required amine (Scheme 71).95
..
An interesting method for functionalization of pyrida-
O NH2 Cl7 O NH2 zine-3-carboxylic acids is the palladium-catalyzed cross-
Cl Cl7
7
+
NMe2 + coupling accompanied by decarboxylation, which resulted
CH2 NMe2 in the synthesis of a number of substituted 3-(het)arylpyr-
N N
idazines 125 (Scheme 72).107
Ar N Ar N
H
4.3. Cyano groups
O N O N For cyanopyridazines, examples of nitrile group displace-
Cl +
Cl7
NMe2 ment by the nucleophilic aromatic substitution mechanism
O were reported. This aspect was considered in sufficient
NaHCO3,
N H2O
N
detail for 4,5-dicyanopyridazine in a review 99 (Scheme 73);
Ar N Ar N this approach resulted in the preparation of compounds
117 126 ± 129.
The last steps of the synthesis of 4-oxo-1,4-dihydropyr-
idazine-3-carboxamide and its methylated analogue include
4.2. Carboxy and ester groups hydrolysis of the nitrile group giving the corresponding
Ureidopyridazinone derivatives 118 were synthesized using amides 130 (Scheme 74).108
the strategy consisting of stepwise oxidation of 5-hydroxy- Reactions of urea and hydroxylamine with 4-cyanodihy-
methylpyridazinones 62 to the corresponding acids, con- dropyridazinones were investigated (Scheme 75).109 By
version of the acids to acyl azides and application of Curtius using hydroxylamine, it is possible to prepare hydroxamic
rearrangement (Scheme 69).72 acid amide 131. In the case of urea, the attack on the cyano
The presence of the ester group in pyridazines can serve group is followed by ring closure involving the oxo group of
for the preparation of a broad range of derivatives. For pyridazinone to give compound 132.
412 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 70
F F
NH N
O DIBAL-H
Ph Ph
CH2Cl2, 778 8C BunLi, THF, 778 8C
F O N N
N N
119 (79%) 121 (53%)
EtO2C Ph
F N N F
HO DIBAL-H MgBr
Ph Ph
CH2Cl2, 778?20 8C THF, 778 8C
N N O N N
120 (63%) 122 (71%)
DIBAL-H is diisobutylaluminium hydride
Scheme 74
Scheme 71
R
NBoc R
R2 N
R2 N
N
a N N
R1 CO2Et O a
R1 CN O
N N TBSO
N N O HO C(O)NH2
O
123, 124 O O O
HO OH
(a) 1) NaOH, MeOH, 30 8C; 2) BocN(CH2CH2)2NH, HATU, DIPEA, Me Me 130 (51% ± 55%)
DMF, 308C; 123: R1 = Cl, R2 = Bn (58%);
(a) 1) H2O2 , Et3N, MeOH; 2) TFA (aq.); R = H, Me;
124: R1 = N(CH2CH2CH2CHBn)-cyclo, R2 = CH2NHCbz (72%)
TBS = ButMe2Si
Scheme 72
Ar(Het)X, Scheme 75
R2 R3 Pd(PPh3)4, R2 R3 H
Cu2O, Li2CO3 N O
CO2H R1 Ar(Het) NH2OH . HCl, AcONa N
R1 DMA, 160 8C
N N N N AcOH, D N
H Ph OH
(Ar = Ph)
125 (15% ± 95%) N O
N 131 (82%) NH2
X = Cl, Br, I; R1 = H, Ph; R2 = H, Me, Ph; R3 = H, Me Ar CN H H

N N O
(NH2)2CO, EtOH, D N
(Ar = Ph, 4-ClC6H4) N
Complex heterocyclic system 133 containing a pyrida- Ar
zine ring was synthesized (Scheme 76).110 The thiophene NH2
ring was assembled with the participation of the cyano and 132 (75%783%)
thio groups at the pyridazine system.
The thiophene ring of molecule 134 was assembled on
the basis of substituted pyridazin-3(2H)-one with methyl 4.4. Amino groups
and cyano groups in neighbouring positions (Scheme 77).50 Amino groups in pyridazines are readily alkylated, which
Probably, the reaction proceeds efficiently owing to the high was utilized to prepare N-benzyl-N-methyl-4-bromo-6-
acidity of the methyl group. chloropyridazine-3-amine 135. The same reaction can serve
for the preparation of fused nitrogen heterocycles.
For example, 4,5-diaminopyridazinone and pyridazinone-
Scheme 73
CN R2
N N N
OH
CN
N R1 N
(R1 = H, Me; N
N R2 = H, Me, Ph) N
R2 CN
R1 N 128 (44%) O
126 (88% ± 99%) N
CN N CN
CN R4R5NH R3 N R3
N
N N
N
NR4R5
127 (48% ± 100%)
129 (23% ± 91%)
R1 = H, Me; R2 = H, Me, Ph; R3 = H, Me, Ph, NMe2; R4, R5 = Alk
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 413
Scheme 76 Scheme 80
N Ar Ar
C n
N N X HN Ph
NH Cl CO2Et N n
PhMe, MW, 110 8C HN N N

EtOH, D
S X
S
H2N Ph 140 (25% ± 45%)
CN
H 2N CO2Et N N
ArSO2Cl
133 (86%) ArO2SHN Ph
PyH, 0 8C
N N
141 (80% ± 85%)
Scheme 77 X = O, S; n = 0, 1, 2
Me CN
Me O
Me S
X
N Et3N, EtOH, D The reactions of 3-amino-6-phenylpyridazine with sub-
N N N
N H stituted isocyanates, isothiocyanates and sulfonyl chlorides
Ph Ar
O open the way towards the corresponding ureas and their
S NH2 thio analogues 140 and sulfonamides 141 (Scheme 80).112
Me O The acylation of the 3-amino-4-cyanopyridazine deriva-
Me X tive with acetic anhydride (Scheme 81) 55 does not stop after
N
N N N acylation of the amino group. The neighbouring cyano
N H group is also subjected to the nucleophilic attack, resulting
Ph Ar
O in closure of the ring, which undergoes the Dimroth
134 (55% ± 58%)
X = O, NH rearrangement. This gives rise to the pyrimidine moiety
fused to pyridazine, that is, compound 142.
3-carboxylic acid in polyphosphoric acid (PPA) are con- Scheme 81

verted to 1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one Ph Ph
136 (Scheme 78).95, 96 N N N N
Ph Ph
Scheme 78 Ac2O
1) BnBr, NaH,
NH2 THF NMeBn Ac CN D Ac CN
OH
..
Br 2) MeI, NaH, Br
N THF N N N
N NH2 N N Me
N N
Ph Ph
Cl Cl 135 (46%)
Ph Ph
H N N N N
NH2 HO2C O N
N N NH N
O Ph NH Ph O
HN PPA, D HN N
NH2 N NH Ac Ac
O O 136 (87%) O NH
N N
N N Me N N Me
The preparation of polymers exhibiting photoelectric Ph Ph 142 (77%)
properties was based on thiophene derivatives of pyrazi-
no[2,3-d]pyridazine 137 and [1,2,5]thiadiazolo[3,4-d]pyrid-
azine 138 (Scheme 79).111 The synthesis was started from 4.5. Hydrazino groups
[1,2,5]oxadiazolo[3,4-d]pyridazine, which was converted to An example of reactions of hydrazino groups at the pyr-
4,5-diaminopyridazine 139. idazine ring routinely used in organic synthesis is the
formation of hydrazides, such as compound 143.113 The
Scheme 79
O
N N
S Br
Br S N N
a
H2N NH2 S
N N N N
S Br
S Br b S Br
c
S Br S N N S
Br N N Br N N
137 (83%) 139 (81%) 138 (53%)
(a) (NH4)2SO4 , NaBH4 , EtOH, 20 8C; (b) (CHO)2 , AcOH, D; (c) SOCl2 , Et3N, CH2Cl2 , D
414 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
reaction of a similar hydrazine with chalcones is accompa- Scheme 84

Ar1 N
nied by closure of a five-membered ring, thus giving a
N
dihydropyrazole derivatives 144 (Scheme 82).114 N
Cl N
R Ar1 NHNH2
Scheme 82
N Cl 146 (20% ± 60%)
Cl N
H2NHN Cl N
Cl Ar1 N
Br N HN NH b
N c
O
N N
Et3N, CH2Cl2, 20 8C O N Cl N Ar1
N N
Br N Ar2 NH
Cl
143 (39%) Cl 147 (20% ± 90%) N
Cl N
H2NHN O Ar2 S
Ar2
N Ar1 148 (85% ± 90%)
Ar1
N N N
NaOH, EtOH, D N N
(a) RC(OEt)3 , AcOH, D; (b) 1) Ar2CHO, AcOH, EtOH, D; 2) PhNO2;
Ph Ph (c) CS2 , PyH, D; R = H, Me, Et
144 (40% ± 73%)
pyridazine core (Scheme 85).117 It was found that some of

The reaction of 6-chloro-3-hydrazinylpyridazine with the obtained compounds possess antibacterial activity.
acyl halides followed by refluxing with POCl3 leads to
triazole ring closure, resulting in the formation of 4.6. Hydroxy and oxo groups
N-cycloalkyltriazolo[4,3-b]pyridazine derivatives 145 The most frequently encountered transformation of the oxo
(Scheme 83).115 Among these compounds, Pim-1 kinase group in pyridazinones is deoxohalogenation, most often,
inhibitors were found. deoxochlorination with the participation of phosphorus(V)
oxochloride (Scheme 86). Bromination of the oxo group in
Scheme 83 pyridazinones was also reported; an example is the synthesis
of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine 154.21 A
NHNH2 N N
a b mixture of phosphorus tribromide and bromine, which
N N
N N N generates in situ more reactive phosphorus pentabromide,
Cl N Cl N RHN N acts as the brominating agent.
Ar Ar
Closure of four types of heterocycles 155 ± 158 coupled
145 (11% ± 66%)
to the pyridazine system was described (Scheme 87).24 The
(a) 1) ArC(O)Cl, MeCN, 20 8C; 2) POCl3 , MeCN, 80 8C;
synthesis is accompanied by intramolecular nucleophilic
(b) RNH2 , 708C; R = cyclo-C3H5, CH2C3H5-cyclo, cyclo-C4H7 ,
Scheme 86
cyclo-C6H11 R1 R1
R2 O R2 Cl
POCl3
5-Aryl-6-chloro-3-hydrazinopyridazine derivatives were NH N
used to close a conjugated 1,2,4-triazole ring in reactions R3 N R3 N
with electrophiles such as orthoesters, substituted benzalde- HN NH N N
hydes and carbon disulfide (Scheme 84).116 Triazolo[4,3-b]- O O PBr3, Br2 Br Br
pyridazines 146 ± 148 were thus formed in moderate to high 105 8C
yields. N N N N
The hydrazine moiety served as the basis for the syn- S S
thesis of a number of fused systems 149 ± 153 containing a 154 (75%)
Scheme 85
H
N H O O Y
R1 N R2 Me Me
Me N
Me N
a NH f N NHR3
N O N N
N c NH O N O N
N N
O N
NHNH2 O Me Me
Me
Me
Me 153 (76%788%)
149 (64% ± 78%) N
N 151 (76% ± 82%)
O N
H N N (a) R1C(O)CH2Br, AcOH, D (for R1 = Me, Ph);
N O Me
N Me X (b) AcONa, (CO2Et)2 , D;
Me N
d or e (c) R2C(O)Cl (for R2 = Me, 4-MeOC6H4);
N
N O b N (d ) BrCH2CO2Et or (CO2Et)2 , D
N O
O N (for X = CCH2Br, CCO2Et);
Me
(e) NaNO2 (aq.), AcOH (for X = N);
Me 152 (62% ± 75%) ( f ) RNCY, K2CO3 , Me2CO, D
150 (66%) (for Y = O, S; R3 = cyclo-C6H11, Ar)
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 415
Scheme 87
1) POCl3, 95 8C 1) POCl3, 95 8C HN N
HN N 2) H2NCH2CH2NH2, 2) NH2NH2 . H2O,
R2 R1
EtOH, D EtOH, D
R2
R1 N
N OH O R3 N
R3 N 157 (75% ± 87%)
R2
155 (77% ± 82%) R1
CO2R4
1) POCl3, 95 8C N
O N R3 N 1) POCl3, 95 8C S
2) H2NOH . HCl,
2) HSCH2CO2R4,
R2 R1 EtOH ± PyH (5 : 1), D R2 R1
EtOH, D
3) NaH, THF, 40 8C N
N
R3 N R3 N
156 (46%761%) 158 (33% ± 52%)
R1 = OMe, Ar, 2-Th; R2 = H, Me; R3 = Et, Pri, cyclo-C6H11 , Ph, 2-FC6H4 , 2-Th; R4 = Me, Et
attack on the acyl groups at the C(3) atom of the starting Scheme 89
pyridazine containing a hydroxy group in position 4. O S
RL,
4.7. Thiol and thione groups NH PhMe, D NH
N N
3,7-Dimethylisoxazole[4,5-d]pyridazine-4(5H)-thione (159) N N
was prepared by the reaction of a similar 4-chloro-substi- 161 (72%)
tuted pyridazine with thiourea (Scheme 88).117 Then this
product was subjected to dimerization to give disulfide 160. HetCH2Br, K2CO3, S Het
DMF, 20 8C
Scheme 88 N
N
Me Cl Me S
(NH2)2CS, NaHSO4 (aq.), N 162 (49% ± 99%)
N Me2CO, D NH NaNO2
N N
N N H2O, 20 8C
O O
Me Me
159 (78%) Scheme 90
Me N N
N R2 R1 R3
NH RL, NH
S O THF, D H2N OH
S O Fe S n
Me Fe
Hg(OAc)2, THF, 20 8C
N
N N Me
N 163
O N
N 164 (90%)
Me 160 (82%) N
Fe NH n
R2
The reaction of pyridazinones with the Lawesson's R1 R1 = H, Me, Pri, Bn, Ph;
reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphe- HO R2 = H, Ph, CH(OH)Ph;
tane 2,4-disulfide, RL] was used for the synthesis of thio- R3 R3 = H, Ph; n = 0, 1
(16% ± 57%)
pyridazines, for example, 6-(2-pyridyl)pyridazine-3(2H)-
Scheme 91
OR2 Me
CN PO(OR2)2 CN CN
O
Ph S Ph SR2 Ph
R1 R1 Ph Ph
+ + +
NH R2ONa, R2OH, D N NH
Ph N Ph N Ph N N NH
Ph N Ph N
165 166 167 168
R1 R2 Yield (%)
165 166 167 168
CO2Me, CO2Et Me, Et 15 35 35 7

=
C(Me) CH2 Et 15 25 7 15
CN, 4-MeOC6H4 , pyrrolidino, Et 15 30 ë 35 7 7
phthalimido
416 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
thione 161 (Scheme 89).118 The subsequent alkylation for magnesium, which was followed by attack on position 5
afforded a series of 3-alkylthio-6-(2-pyridyl)pyridazines by the electrophile; however, the methoxy group was
162 possessing neuroprotective properties as EAAT2 pro- replaced by the hydrocarbon group of the Grignard reagent,
tein activators. thus being converted to compounds 171 (see Scheme 92).
The synthesis of a series of substituted ferroceno[d]pyr- 2-Benzyl-4-bromo-5-methoxypyridazin-3(2H)-one was
idazines is based on conversion of pyridazinone 163 to also reacted with benzoyl chloride; however, the prepara-
thione 164 followed by displacement of the sulfur atom via tion of the desired 4-benzoyl-2-benzyl-5-methoxypyridazin-
the reaction with amino alcohols in the presence of mercu- 3(2H)-one (169b ) required the use of transmetallation in the
ry(II) acetate (Scheme 90).93 presence of CuCN, because the standard procedure resulted
The reaction of 3-thioxo-5,6-diphenyl-2,3-dihydropyri- in the double substitution product at the carbonyl group Ð
dazine-4-carbonitrile with the Horner ± Wadsworth ± compound 172. Transmetallation in the presence of MnBr2
Emmons reagents gives product mixture 165 ± 168 gave homocoupling product 173 in a good yield (see
(Scheme 91),119 which is attributable to the thione7thiol Scheme 92).
equilibrium. An unusual influence of conditions on the reactions with
formylating agents, giving products of bromine and
4.8. Halogen atoms methoxy group displacement 174 and 175, was found; the
The reactions involving halogen atoms present as substitu-
ents in the ring are among the most developed trends of Scheme 93
pyridazine chemistry. The high popularity of these methods Bn O Bn O
is due to the convenience of preparation of starting com- N N
a
pounds and to high diversity and efficiency of the trans- N OMe N OMe
formations, first of all, reactions with organometallic com-
pounds,120 cross-coupling and nucleophilic aromatic sub- X Y 177 (64% ± 77%)
stitution.
N Cl N
4.8.1. Replacement of a halogen by a metal H2N N b or c H2N N
X N X N
The reactivity of organomagnesium derivatives of halopyr-
idazin-3(2H)-ones towards a broad range of electrophiles N N
Ar Ar
was studied in detail (Scheme 92).121, 122 In the case of
pyridazinones containing a bromine atom in position 4, 178 (44% ± 95%)
bromine was replaced by magnesium, and this was followed
by regioselective electrophilic attack giving substitution (a) H2, K2CO3, Pd/C, EtOAc, rt (for X = H, Y = Cl; X = Cl, Y = H);
products at position 4 Ð compounds 169a,b and 170. For (b) H2, Pd/C, AcOH, 50 8C; (c) H2, Pd/C, Et3N, DMF, rt (for X = CH, N)
5-substituted pyridazinones, bromine was also exchanged
Scheme 92
O O O O O O
Bn Br Bn E Bn Br Bn E Bn OMe Bn R2
N a or b N N a N N a N
N N N N N N
OMe OMe Br Br Br E
169a,b (32% ± 95%) 170 (44% ± 80%) 171 (18% ± 99%)
(a) 1) R1MgCl, THF, 720 8C; 2) electrophile, 720 8C; 3) NH4Cl (aq.); (b) 1) BunMgCl, THF, 720 8C; 2) CuCN, 720 8C; 3) PhC(O)Cl, 720 8C;
4) NH4Cl (aq.) [for E = Bz (169b)]; electrophile = D2O, H2O, PhCHO, Ph2CO, PhC(O)CO2Me, DMF, cyclo-(CH2)5NCHO, TsCN, MeSSMe,
Me2SO4 , I2; 169a, 170, 171: E = D, H, PhCH(OH), Ph2C(OH), PhC(OH)CO2Me, CHO, CN, SMe, Me, I; R1 = Bun, Pri, Ph, Mes; R2 = R1, OMe
Bn O O Bn Bn O O Bn
OH 1) BunMgCl, THF, 720 8C O 1) BunMgCl, THF, 720 8C
N N N N
2) PhC(O)Cl, 720 8C Bn 2) MnBr2, 0 8C
N N 3) NH4Cl (aq.) Br N N
N
Ph 3) PhC(O)Cl, 710 8C
O O N 4) NH4Cl (aq.) O O
OMe
Me Me Me Me
172 (59%) 173 (62%)
O O O O O O O
Bn Bn Br Bn Bn OMe Bn NMe2
N c N d N N e N
N N N N N O
NR2 OMe SMe Br
174 (46%756%) 176 (26%) 175 (96%)
(c) 1) BunMgCl, THF, 720 8C; 2) R2NCHO; 3) MeOH, 20 8C; 4) NH4Cl (aq.); R2N = Me2N, (CH2)5N;
(d ) 1) BunMgCl, THF, 720 8C; 2) DMF, 720 8C; 2) NaSMe, 720 8C; 3) NH4Cl (aq.);
(e) 1) MesMgBr, THF, 720 8C; 2) DMF, 720 8C; 3) MeOH, rt; 4) NH4Cl (aq.)
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 417
addition of NaSMe to the reaction medium gave rise to Palladium carbene complexes 181 and 182 were pre-
methylthio derivative 176 (see Scheme 92). pared from pyridazinium salts. Their molecules contain an
Examples of efficient catalytic hydrogenolysis of the exocyclic Pd7C bond with respect to the pyridazine ring
C7Cl bond involving palladium were reported, such as (Scheme 96).89
syntheses of compounds 177 and 178 (Scheme 93).123, 124
4.8.3. Nucleophilic aromatic substitution in pyridazines
4.8.2. Replacement of a halogen atom in cross-coupling reactions The nucleophilic aromatic substitution is often used for the
Cross-coupling is an efficient method frequently used for synthesis of pyridazine derivatives. Quite a few such reac-
functionalization of pyridazines.125 Examples of using tions with the participation of various N-nucleo-
Suzuki7Miyaura,90, 95, 126, 127 Buchwald ± Hartwig,21, 128 philes,35, 60, 113, 130 ± 132 O-nucleophiles 91, 95, 133 ± 136 and
Stille, 126 Negishi 129, 124, 127 and Ullmann reactions 21 were S-nucleophiles 137 are known. There are examples of selec-
reported. The Suzuki7Miyaura reaction makes it possible tive successive nucleophilic substitution in which halogen
to accomplish selective one-pot exchange of different chlor- atoms located in different positions of the pyridazine ring
ine atoms in 6-chloro-2-chloromethylimidazo[1,2-b]pyrida- are displaced to give several N-phenyl-6-chloro-5-phenoxy-
zine for aryl groups to give products 179 (Scheme 94).129 It pyridazine-3-amines 183 and imidazo[1,2-b]pyridazine
is possible to introduce two different aryl groups by dis- derivatives 184 (Scheme 97).128, 138 The course of substitu-
placing chlorine atoms in both the benzylic position and tion is determined by higher reactivity of the halogen atom
pyridazine ring. in position 5 compared to position 3.
A combination of the Suzuki7Miyaura reaction and Nucleophilic substitution involving the fluorine atom at
aminocarbonylation for pyridazines containing both bro- the pyridazine ring can be utilized in reactions with N-, O-,
mine and chlorine atoms gives rise to compounds 180; S- and C-nucleophiles (Scheme 98).85 This approach pro-
however, the overall yields of the target products do not
exceed 27% (Scheme 95).95
Scheme 97
Scheme 94 Cl Cl Ar2HN OAr1
1) Ar1B(OH)2, Pd(PPh3)4, a
Na2CO3, DME, H2O N
N Cl 2) Ar2B(OH) , Na CO N Ar1 N N Cl
2 2 3 N Cl
183 (20% ± 35%)
N N
Cl N Ar2 N
179 (48% ± 62%) Br NBoc
N O N
Ar1 = Ph, 4-FC6H4 , 3-Fu; Ar2 = Ph, 4-MeOC6H4, 3-Th b
N N
Cl N RO N
Scheme 95
Ar 184 (51% ± 68%)
Br O
BnMeN (a) 1) Ar1OH, NaH, DMF; 2) Ar2NH2 , HCl, EtOH;
a
BnMeN Cl N N N (b) 1) O(CH2CH2)2CHCH2NH2 , DIPEA, EtOH, D;
N N 2) Boc2O, DMAP, THF, 50 8C; 3) ROH, NaH, NMP, rt;
180 (10%727%) NH R = cyclo-C6H11, Ar; DMAP is 4-dimethylaminopyridine
(a) 1) ArB(OH)2 , Pd(dppf)Cl2 . CH2Cl2 , Cs2CO3 , dioxane, H2O, Scheme 98

30 8C; 2) CO, BocN(CH2CH2)2NH, Pd(OAc)2, dppp, K3PO4 , Et3N, R1 R2
N
DMF, 110 8C; 3) TFA, CH2Cl2; Ar = Ph, Het; dppp is 1,3-bis(di-
phenylphosphino)propane Ph
N
Scheme 96 EtO2C N
R3 + 185 (95% ± 99%) XR3

R3 BFÿ
4
R1 a or b Ph
R1 N R1R2NH MeCN
N Pd(PPh3)4
N BFÿ N
N+ Me2CO, 20 8C R2 Et
4 F EtO2C N
R2 Et
Ph3P Pd PPh3 Ph 186 (59% ± 77%)
Cl
Cl N R4 EWG
181 (61% ± 80%) EtO2C N
c Ph
R1 = R2 = H; R17R2 is benzo; R3 = Cl, 3,5-dimethylpyrazol-1-yl
N
Cl EtO2C N
Cl BFÿ
4 187 (60% ± 88%)
N
N Pd2(dba)3
+ N (a) R3XH, TFA, rt (for R3 = CH2C3H5-cyclo, X = O);
N Et4NCl, PPh3, Et
Et Me2CO, 20 8C (b) R3XNa, MeCN, 100 8C (for R3 = Et, X = S);
Ph3P Pd Cl
Cl (c) R4CH2(EWG), DBU, DMSO, 80 8C (for R4 = CO2Me, H;
Cl EWG = CO2Me, NO2); R1R2NH = PhMeNH, morpholino
dba is dibenzylideneacetone 182 (40%)
418 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
vides an efficient synthesis of a variety of pyridazine Scheme 100

derivatives 185 ± 187.
Cl N N NH2
The nucleophilic substitution in 4,7-dibromo[1,2,5]thia-
N
diazolo[3,4-d]pyridazine was studied in detail N N N
a b
(Scheme 99).21 Reactions for several O-, N- and S-nucleo- N N N
philes were carried out to give products 188 ± 194. For O-
and N-nucleophiles and for the synthesis of symmetrical
EtO2C EtO2C EtO2C
and unsymmetrical pyridazine derivatives, conditions for
the displacement of only one bromine atom were selected. 195 (81%) 196 (85%)
Cl PBun3 NH2
Scheme 99 N
OR1 Br OR2 N N N
c d
c, or d, N N
N N N N
N a or b N or e N
S S S
N N N N
N N CO2Et CO2Et CO2Et
OR1 Br Br 197 (43%) 198 (82%)
188 (69% ± 82%) 189 (80% ± 82%)
(a) NaN3 , DMF, 60 8C; (b) 1) Bun3 P, PhMe, 110 8C;
NR3R4 Br NR3R4 2) H2O7MeCN (1 : 1), 80 8C; (c) NaN3 , Bun3 P, DMSO, 120 8C;
N N N (d ) H2O7MeCN (1 : 1), 70 8C
N f N g N
S S S
N N N N
N N
product, which could not be reduced with tri-n-butylphos-
NR3R4 Br Br
phine. Nevertheless, by simultaneous use of sodium azide
190 (78% ± 90%) 191 (75% ± 86%) and tri-n-butylphosphine, resulting in the formation of
(a) R1ONa, MeOH, 20 8C (for R1 = Me); (b) R1ONa, DMF, 90 8C Scheme 101
(for R1 = Ph); (c ) R2ONa, H2O, CHCl3, 20 8C (for R2 = H);
(d ) R2ONa, MeOH, 20 8C (for R2 = Me); (e) R2ONa, THF, 20 8C NMeBn NMeBn
(for R2 = Ph); (f ) R3R4NH, Et3N, MeCN, 80 8C; NR1R2 NMeBn OR3
N N
(g) R3R4NH, Et3N, CH2Cl2 , 20 8C (for R3, R4 = H, Alk, Ar) Br
N a N b N
Br SR5 N
N N O N O N
N R5SH N Cl
S S NH NH
N NaH, THF N
N N
199 (10% ± 16%) 200 (9% ± 18%)
Br SR5
192 (85% ± 90%)
(a) 1) R1R2NH, CsF, DIPEA, DMSO, 110 8C;
R5 = Ph, n-C6H13 , n-C12H25 2) CO, BocN(CH2CH2)2NH, Pd(OAc)2, dppp, K3PO4 , Et3N, DMF, 110 8C;
3) TFA, CH2Cl2; (b) 1) R3OH, NaH, DMF, 30 8C;
O 2) CO, BocN(CH2CH2)2NH, Pd(OAc)2, dppp, K3PO4 , Et3N, DMF, 110 8C;
O O
3) TFA, CH2Cl2; R17R2 = (CH2)4 , (CH2CH2)2O, (CH2CH2)2NMe;
H N R1 = Me: R2 = CH2CH2OMe, Bn; R3 = Pri, CHMeEt, CH2Bui,
N N N
N CH2Bn, CH2CH2N(CH2CH2)2O
PhSH N
N N N N S
S NaH, THF S Et3N, N N
N N N N MeCN, D Scheme 102
N R1 Cl
SPh Br N Cs2CO3
C(O)NHR3 + MeCN, D
N N
193 (90%) 194 (87%) R2 Cl THP
H
O
R1 R3
For the introduction of an amino group into the R2
O N
pyridazine ring, a different procedure was successfully N
used, instead of displacement of the chlorine atom; in N
N + N
particular, on treatment with sodium azide, the 4-chloroph- N THP
N
thalazine derivative underwent nucleophilic substitution O N THP O
and tetrazole ring closure to afford compound 195. This R1 R2
R3 O
product was efficiently reduced in the presence of tri-n- 201 (14% ± 43%) 202 (40% ± 74%)
butylphosphine (owing to the tetrazole7azide tautomer-
ism) giving ethyl 2-(4-aminophthalazin-1-yl)acetate 196 R4
(Scheme 100).139 It is worth noting that this method proved R1 = R2 = H; R17R2 = ; R3 = Alk, Ar; R4 = H, F, MeO;
to be inapplicable for analogous 3-chloropyridazine, THP is tetrahydropyran-20-yl
because tetrazole ring closure furnished a more stable
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 419
iminophosphorane 197, it was possible to synthesize amino Scheme 104

derivative 198, although in a lower yield. O O
In the preparation of two libraries of compounds (199 Bn Bn R
N RMgX N Br2
and 200), the nucleophilic SAE substitution at the most THF, 720 8C
N N 720 8C
activated position 5 was followed by aminocarbonylation Mg
of the C(3) atom (Scheme 101).95 X X
The reactions of protected 4,5-dichloropyridazin-3(2H)-
one with pyrrole-2- and indole-2-carboxamides have been O O
reported 140 (Scheme 102). In all cases, mixtures of regioiso- Bn R NH4Cl (aq.)
Bn R
N N
meric nucleophilic substitution products 201, 202 were
N N
obtained. Br
X X
4.9. Organometallic derivatives of pyridazines 204 (20%783%)
Organometallic derivatives of pyridazines open the route to
a relatively convenient and often selective insertion of X = H, Cl; R = Pri, Bun, Ph, 4-MeC6H4 , 4-MeOC6H4 , 2-MeOC6H4 ,
electrophiles into the C7H bond.122, 124, 141 The reactions 3,5-Cl2C6H3
of 5-halo-substituted pyridazinones and alkylmagnesium
halides with a number of electrophiles giving products 203
were studied (Scheme 103). It was noted that bromo deriv- an electrophile (Br2) convenient for the formation of a good
atives react with a smaller number of electrophiles than leaving group in the intermediate compound was the key
chloro derivatives. Indeed, the latter are able to react with issue. A version of this reaction representing oxidative
Br2 , ICl and MeSO2SMe with replacement of hydrogen at nucleophilic substitution resulted in a series of 4-substituted
the pyridazine C(4) atom by the alkyl group of a Grignard pyridazin-3(2H)-ones 204.
reagent. The reaction mixture was found to contain no The same authors 124 described the strategy of so-called
5-bromo or 5-iodo derivatives, which is due to higher lactam directed ortho-C7H metallation. According to this
nucleofugality of bromine and iodine atoms compared to
chlorine. Scheme 105
The accumulation of experimental data and determina- O O
tion of the reaction mechanism culminated in the successful Bn Bn E
N a or b N
use of this reaction in the selective alkylation of substituted
N N
pyridazinones into position 4 (Scheme 104). The choice of Y Y
X X
Scheme 103 205 (37% ± 91%)
O 1) RMgX, THF, 720 8C O
2) electrophile, 720 8C
Bn Bn R
N 3) NH4Cl (aq.) N (a) 1) TMPMgCl . LiCl, THF, 720 8C; 2) electrophile, 720 8C;
3) NH4Cl (aq.) [for electrophile = MeSSO2Me, PhCHO,
N N
X E furfural, PhC(O)CO2Me, PhC(O)Cl; E = SMe, PhCH(OH),
203 (14% ± 93%) 2-FuCH(OH), PhC(OH)CO2Me, Bz];
(b) 1) TMPZnCl . LiCl, THF, 20 8C; 2) Br2 or I2 , 20 8C (for E = Br, I);
R = Pri, Bun, Ph; X = Cl, Br: electrophile = D2O, PhCHO, X, Y = H, Cl; Cl, H;
PhC(O)CO2Me, furfural; E = D, PhCH(OH), PhC(OH)CO2Me, Me Me
TMP(M)Cl . LiCl = [(M) = Mg, Zn]
2-FuCH(OH); X = Cl: electrophile = Br2 , ICl; E = Cl; Me N Me
electrophile = MeSO2SMe, E = SMe (M)Cl . LiCl
F Scheme 106
F
F Ph
Ph
I Ph I2 Br
N
EtO2C N CuCN . 2 LiCl N
N EtO2C N
EtO2C N
TMPMgCl 209 (95%)
206 (73%)
O F
F F O
Ph
PhS Ph ClMg Ph Cl Ph
PhSO2SPh Ph
CuCN . 2 LiCl N
N N EtO2C N
EtO2C N EtO2C N
210 (84%)
207 (94%)
CO2Et
F
CHO F
Ph 3-IC6H4CO2Et, ZnCl2
Ph
O Pd(dba)2, P(Fu-2)3
N
N N
O EtO2C N
208 (58%)
211 (41%)
420 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
strategy, the hydrogen atom in position 4 of pyridazinone is Scheme 109

replaced by a metal atom on treatment with Knochel ± a
R R
Hauser bases (which are less nucleophilic than Grignard +
N N
reagents) and, after that, the intermediate is reacted in situ
with an electrophile to give the corresponding substitution O7 ArO2S N
products 205 (Scheme 105). 215 (56% ± 60%)
Ethyl 5-fluoro-6-phenylpyridazine-3-carboxylate was
employed as a versatile building block in the synthesis of (a) 1) Me2SO4 , KOH, CH2Cl2 , 708C; 2) pyrrole, Rh2(esp)2 , 0 8C;
various pyridazine derivatives. The above strategy resulted 3) NaBH3CN, AcOH, 0 8C; 4) ArSO2Cl, PyH, 0 8C;
in the synthesis of a number of modified pyridazines R = H, CN; Ar = 4-MeOC6H4
206 ± 210 in high yields (Scheme 106).85 Negishi coupling
was also carried out (see Section 4.8.2), and product 211
was isolated in a moderate yield. Pyridazine N-oxides can be used for the synthesis of
alkyl-, 7-aryl- and 7-styrylindoles. Efficient transannulation
4.10. Pyridazine N-oxides was described.143 The key reaction steps included opening
The efficient synthesis of pyridazine N-oxides was reported of the pyridazine ring, Rh-catalyzed elimination of nitrogen
(Scheme 107).142 The oxidation of nitrogen atoms is due to with intermediate formation of metallocarbene and the
the formation of hypofluorous acid, one of the most potent reaction of the metallocarbene with pyrroles, resulting in
oxidants, in the fluorine ± water ± acetonitrile system. This substituted indoles 214 (Scheme 108).
method is suitable for the synthesis of both N-oxides 212 This reaction was applied for the synthesis of 7-arylin-
and N,N 0 -dioxides 213. dolines 215, which possess anticancer activity (Scheme 109).
The saturated moiety was formed during the subsequent
reduction and N-sulfonylation of the pyrrole ring.
Scheme 107 3,5-Diamino-4,6-dinitropyridazine 1-oxide (216) was
F2/N2 + H2O + MeCN investigated as a compound with high detonation properties
R2 R2 R2
(Scheme 110).31 The last steps of the synthesis included
R3 HOF . MeCN R3 R3 + O7 nitration of 3,5-dimethoxypyridazine 1-oxide and replace-
N N N
+ + ment of methoxy groups by amino groups on treatment with
N N N
O7 + O7 ammonia.
R1 R1 R1 The photochemical method for direct synthesis of
212 (15% ± 100%) 213 (0% ± 85%) 1H-pyrazoles 217 from pyridazine N-oxides demonstrated
a good efficiency for a range of different substrates, which
R1 = H, Me, Cl, Br; R2 = H, Me, Cl, Br, CN; R3 = H, Me
Scheme 108
R6
O R5 R6
R3 + O7 N
N R3 R3
Me2SO4 R4
N R5
R2 70 8C, 2 h N2 Rh2(esp)2, DPP, N
R2 CH2Cl2, 0 8C R2
R1 R1 R4
R1
7OH, Me2SO4
214 (5% ± 70%)
7H2O
OH O
..
OH R6
R3 OMe R3 7 OMe
N N R3
N N R5
R2 R2 O N
R6 R2
R1 a R1 R4
R3 R1
O
R3 [Rh] R5 6p
R2 N
N2 O R1 R4 OH
R6 R6
R2
O R2 R3
R1
R3 + R5 R5
R2 7 N R2 N
[Rh] R1 [Rh] R4 R4
R2 R1
R1 R6
R1 = H, Me, CH2Bn, Ar, 2-Naph, (E)-CH CHAr; =
R2, R3, R4, R5 = H, Me; R6 = H, Me, Et;
R5
N [Rh] = Rh2(esp)2; esp is 3,30 -(1,3-phenylene)-bis(2,2-di-
methylpropanoic acid), DPP is diphenyl phosphate
(a) Z ± E- isomerization, (7MeO7) R4
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 421
Scheme 110 Scheme 111
OMe OMe NH2 Ar

Ar Ar
a or b O2N c O2N
N N N
+ + N hn (350 nm) N2 N
N N+ N + R
MeO O7 MeO O7 H2N O7 N THF, 65 8C O N
O7 H
NO2 NO2 O
R R
216 (95%) 217 (15%794%)
(a) 20% oleum, 100% HNO3 , 50 8C (25% ë 30% yield); R = N(CH2CH2)2X (X = CH2 , O, S, NH), N(CH2)4 , N(CH2)3 , NHPh,
(b) 20% oleum, NaNO3 , 60 8C (13% yield); NHBn, NHAll, NHCH(Me)CH(OH)Ph, OAlk, OCH(Me)CH CH2 , =
(c) NH3 (aq.), MeCN, D OPh, OCH2C:CH, SEt
F
finally furnished compound 218, a promising NK-3 receptor OMe

antagonist, in a high yield (Scheme 111).144
N
4.11. Supramolecular complexes with pyridazines N
N
Macrocyclic [2]rotaxane moieties 219 and 220 were pre- N
H
pared on the basis of pyridazines (Scheme 112).145 The O
formation of complex 219 with unsubstituted pyrene pro- 218 (90%)
ceeded via pyrene coordination, the formation of a dication
and ring closure. [2]Rotaxane 220 was obtained in a similar
way, with the linear part being also constructed from pyrene pyridazine structures. A large number of examples of
with long-chain substituents containing an alkyne and applications of pyridazines as pharmacologically active
polyether moieties and triphenyl anchors at the chain ends. agents are given in reviews.1, 5, 9, 147 Pyridazine derivatives
often demonstrate antitumour activities; therefore, they are
expected to be used against a broad range of cancer
5. Applications of pyridazines diseases. The key mechanism of action of these compounds
A study 146 is devoted to evaluation of the practical signifi- is inhibition of various kinases. Among them, mention
cance and description of the most favourable properties of should be made of Bruton tyrosine kinase inhibitors
Scheme 112
+ +
N N R N N
N N N N
Br Br
R R
+
R
2 PFÿ
6
N N +
N N +
+ +
N N N N
O 219, 220
R = H (219, 92%), X (220, 84%); X = O 2
CPh3
Structures 221 ± 226

N N
N
N Me
N N OMe
R N NHPri N N F
N N N N
NH2 N NH
N S
N Me
N Me
N MeO Me
MeO
221 222 223
R = Me, CH2CH2OH
O H O H
O N
N
N N N N
N Me N
N
N 18F
N
N 18F
N F 225 F 226
N O X
Y
N N
224 H H
X = N, Y = CH; X = CH, Y = N
422 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
OMe Structures 227 ± 229
N
N
N N
O N O N
N
MeO N
N F NH2
S N
S NMe2 N
F F O O H N N
F N
228 (Omipalisib) NH
N
O
HN
227 (Relugolix) HN OMe 229 (Bemcentinib)
(221),113 LRRK2 kinase inhibitors (222) 148 and g-secretase combination therapy of patients with neurocutaneous mel-
modulators (223).149 Compounds 224 show considerable anocytosis (NCM).153 Compound 229 (Bemcentinib, R428,
antiproliferative activity, especially against A549 and H460 BGB324) is the first low-molecular-weight AXL kinase
non-small cell lung cancer.150 Derivatives 225 and 226 inhibitor of this class, which was proposed for the treatment
demonstrated good efficiency towards inhibition of Trk of some types of cancer such as non-small cells lung cancer
receptors and, when labelled with 18F isotopes, they proved (NSCLC), triple negative breast cancer (TNBC), acute
to be potential PET imaging agents (PET is positron myeloid leukemia (AML), myelodysplastic syndrome
emission tomography).151 This fact was successfully con- (MDS), melanoma and metastatic pancreatic cancer.154, 155
firmed by experiments in rats, in particular, their specific Currently, this agent is in phase II clinical trials.
binding in brain areas rich in TrkB/C receptors was identi- Quite a few pyridazine derivatives demonstrate interest-
fied. ing physical properties. A review 156 describes the applica-
Special mention should be made of some pharmacolog- tion of pyridazine-based p-conjugated structures as
ically active agents, which were obtained in the last decade functional materials possessing luminescent and nonlinear-
and are in various phases of clinical trials. The agent optical properties in organic electronics and for the develop-
Relugolix (RVT-601, TAK-385, 227) is a gonadotropin- ment of liquid crystals. Particular attention was given to
releasing hormone antagonist (GnRH) applied for the supramolecular complexes for the molecular recognition,
treatment of uterine fibroid.152 Currently, this compound membrane transport of drugs and design of macrostructures
is in phase III clinical trials for the treatment of endome- and devices at the molecular level. Films fabricated from
triosis and prostate cancer. The agent Omipalisib polymers 230 possess interesting optical properties, in
(GSK2126458, GSK458, 228), a potent and selective particular, high refractive indices and birefringence.137 Pol-
PI3K/mTOR signaling pathway inhibitor, was evaluated in ymers 231 were synthesized and found 78 to have high
phase I clinical trials in subjects with solid tumours, optical contrast, high switching speed and high colouration
lymphoma and idiopathic pulmonary fibrosis and can be efficiency. For donor-acceptor polymer semiconductors
regarded as a new drug candidate for direct use or in a 232, physical and electrochemical properties were thor-

C8H17-n n-H C O OC12H25-n
S 25 12
n-H21C10 C12H25-n
N n-H21C10
S N R1 O N O
O O O N O
n
230
S S S R2 S S
N N
N N S
x 17x
n
N N n
231 232
S S R3 x = 0.1, 0.3, 0.5
S
n
C8H17-n n-H17C8 Et
n-H21C10 C10H21-n
233 Bun
Et
S
O O O O O
S Bun S
S S O
R1 = N N , N N ; R2 = , ;
S S S Et
O O O O S O
O Et Bun
Bun S
S Et Bun
R3 = , S ,
S Et
S S
O Bun
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 423

MeO OMe R R
N N
R R R R
N N N N N
236 R Ph
237
MeO OMe N
N N R
234
Ph R= N ,
Ph N N Ph N N N
R 238
Ph Ph
Ph Ar
Me N N N N
N
235 Me N
N N
239
Me N N N N N
S
OH
N N N N Me N
240 F F N
B N OH
Bun2 N N N O N S
N
Ph N
N N NBun2
241 243
N 242
N
Ar
oughly studied, which demonstrated good prospects for the pound 240 in comparison with asymmetric derivative
use of these compounds in the design of organic thin-film 239.163 This interesting feature was used for the design of a
transistors and solar cells.157 Three types of polymers 233 film based on polymethyl methacrylate, which is applied to
were studied as p-type semiconductors and proposed as detect organic solvents on the basis of their polarity.
appropriate materials for the manufacture of organic field Bipyridazine 241 also showed good fluorescent properties,
effect transistors.158 clear-cut solvatochromism and was considered promising
Luminescent characteristics of compound 234 were for the design of organic light emitting diodes; the com-
studied in solution and in the solid state.159 Protonation of pound was found to function as a ligand giving stable
the pyridazine ring induces a change in the luminescence complexes with Cu2+, Pt2+, Ni2+ and Ir3+ (Ref. 164).
intensity and a colour change from blue (l = 406 nm) to Compounds 242 forms coloured complexes with the Cu2+
orange-red (l = 630 nm). The results made it possible to ions.165 Boron-containing blue fluorophore 243 demon-
design a sensing film possessing high sensitivity to trifluoro- strated fluorescent properties in solution and in the solid
acetic acid, which is efficiently controlled by UV radiation. state and was proposed for the introduction of biological
A similar sensitivity to acids was shown for compound 235, labels and design of sensors.166
which was also proposed for determination of organic Dihydropyridazines 244 can be used for selective and
acids.160 The synthesis and study of luminescence character- sensitive detection of fluorine ions (Scheme 113).167 The
istics of compounds 236 and 237 were reported; in addition, NH protons in these structures are sufficiently acidic for
the single crystal structure of unsymmetrical pyridazine 236 deprotonation under the action of fluoride anion, which
was thoroughly investigated, and relatively high thermal leads to a considerable colour change due to charge deloc-
stability was established.161 Similar compounds 238 were alization and to accompanying fluorescence quenching.
employed for the fabrication of green phosphorescent Large Stokes shifts, high quantum yields and long fluores-
organic light-emitting diodes.162 Bis-pyridazines 239 and cence lifetimes make these compounds suitable for the
240 were studied for photophysical properties; a higher design of potential efficient chemosensors.
solvatochromic sensitivity was found for symmetrical com-
Scheme 113
R R R R
N TBAF N N 7 N
O O O O
NH MeCN N 7HF N7 N
H
R R R R
F7
244
R = CO2Me, 2-Py (244)

424 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429

OH OC CO
OC CO Re CO
O
HO
HO O Re CO O N
Cl Cl
OH N O N
Cl Cl RO
N N Re
Et H CO
Re
CO OC CO
245 OC CO 246
OH
OH O
HO O
HO O
OH O N
HO OH OH
Me HO OH N N
O O O
R = HO , HO Me , HO N N
HO N O O
O HO O N
OH HO N OH O
OH OH
O
O
HO
HO O
OH N N
O N
R2 R1 F F F F
Ar Me
N R2 N
N N N N N N
Ar N Ar = R1 Me N Me N
Ir Ir Ir
R1 R2 (R1 = F, R2 = H; F F F
O O
R1 = R2 = F)
N N N
N N N
R2 R1 F F F
Ar Me Me
247 248 249
F F
But But
N N
Me
N O
Me N N N
Ir
F Ir Ir
O +
Cl
N Me
N N N
But But
F
Me
250
251
Good photophysical properties may be inherent in not physical properties. For example, cationic complex 251
only organic molecules based on pyridazine, but also in shows broadband emission in the red region
their complexes with transition metals. A review 168 is (l = 520 ± 720 nm). This complex exhibited the ability to
devoted to the studies of photophysical characteristics of penetrate into cells and concentrate in mitochondria. How-
luminescent binuclear rhenium(I) complexes containing ever, its application as a fluorescence biolabel is hampered
1,2-diazine ligands. Luminescent glycosylated luminophores by high dark toxicity.
245 and 246 based on binuclear rhenium complexes were Bidentate ligands based on pyridazine-3,6-dicarbalde-
reported.169 The photophysical properties were studied in hyde imines have been reported.174, 175 It was found that
detail and assays on internalization of human cervical two types of complexes (252 and 253) can be distinguished;
adenocarcinoma cells were carried out. The complexes in one type of complexes, silver atoms are in a tetrahedral
have high cell permeability, selectivity to various organelles, environment of nitrogen atoms. Similar derivatives were
low cytotoxicity and fast internalization. All this makes applied to prepare palladium complexes 254 and 255.
compounds 245 and 246 appropriate agents for the use in Pyridazine-3,6-dicarbaldehyde imines were found to behave
cell imaging. as both tetradentate and bidentate ligands.
Iridium(III) complexes 247 ± 250 were studied as poten- Pyridazine-based bis-carbene ligands are often used to
tial materials for organic light-emitting diodes prepare complexes of various transition metals, for exam-
(OLEDs).170 ± 173 Compounds 247 were demonstrated to ple, compounds 256 and 257.106 The RuII, PdII, NiII and CuI
have enhanced luminescent and electrochemical character- complexes (258 ± 261) with a bis-carbene ligand containing
istics with increase in the number of fluorine atoms in the pyridazine and pyridine moieties were studied in detail. 176
ligands in comparison with unsubstituted precursor. The The most interesting structure is inherent in copper(I)
binuclear iridium complexes are also of interest for their complex 261 containing a triangular Cu3 core at the centre.
Russ. Chem. Rev., 2020, 89 (4) 393 ± 429 425

4+
Ar Ar
N N
2+ Ar N N N N Ar
Ar N Ag N N Ag N Ar Pd Pd
Ar N N N N Ar R Cl R
N N
Ag Ag 2 BFÿ
4 4 BFÿ
4 254
N N
Ar N N N N Ar
Ar N Ag N N Ag N Ar
N N Ar N N N N Ar
252 Pd
Ar Ar
253
X Y 255
252, 253: Ar = 4-MeC6H4 , 4-MeOC6H4 , 2-PhC6H4 , 2,4-Me2C6H3 , 3,5-Cl2C6H3;
254, 255: R = Cl, Me; Ar = 2,6-Pri2C6H3; X = Y = Cl; X = Me, Y = Cl; X = Cl, Y = Me
2+
R R
+
N N 3+
N N
N M N N L L N
N N N N
N N PFÿ
N M N 2 PFÿ R R
6
6
Ru Ru 3 PFÿ
6
Rh Cl
N N
N N L L
COD
R R
256 257 258
M = Cu, Ag, Au L = MeCN
2+ 3+
N N
N N
N N N
2 PFÿ
6
Pd Pd N
N N O
N
259
N N
2+ N
N N N 3 PFÿ
N 6
N Cu N
N N
N
OMe N
Ni 2 PFÿ Cu Cu
OMe 6 N O
N
N N
N N
N N N N
N N
N N N N
N
N
260
O
261
Scheme 115
Scheme 114
ButO2H, O OH 263 (2 mol.%),
OR
258 (1 mol.% ± 2 mol.%) AgBF4 (2 mol.%)
R2 R2
R1 NaI, MeCN, 20 8C R1 + ROH
80 8C
O
262 (58% ± 92%) (68% ± 91%)
R = Et, Prn, Pri, Bui, iso-C5H11, CH(CH2)6
R1 = Ar; R2 = Ph, Prn, 2-Th;
Me
R17R2 = C6H47N(Me), C6H47N(Bn)
N N
263 = N N N N
Mes Me
Au Cl
Ruthenium(II) complex 258 was efficiently utilized for Cl
Cl
catalytic oxidation of several alkenes and substrates con-
taining double bonds to diketones 262 (Scheme 114).
Other examples of application of pyridazine-containing Rhenium catalyst 264 with a pyridazine moiety in the
catalysts in organic synthesis are also known. For example, ligand was developed for epoxidation of cyclooctene in the
gold-containing catalyst 263 was favourable for efficient presence of tert-butyl hydroperoxide (Scheme 116).178
ether formation reaction (Scheme 115). 177
426 Russ. Chem. Rev., 2020, 89 (4) 393 ± 429
Scheme 116 The review was written with the financial support of the
O
Russian Foundation for Basic Research (Projects
ButO 2H, 264 (1 mol.%)
No. 16-29-10669, 18-53-34002).
CHCl3, 50 8C
Me References
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Russian Chemical Reviews

Recent advances in the chemistry of pyridazine — an important

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This content was downloaded from IP address 129.180.1.217 on 03/05/2020 at 07:14

Recent advances in the chemistry of pyridazine Ð an important

Department of Chemistry, M.V.Lomonosov Moscow State University,

Pyridazines (1,2-diazines) are among the most important N

Figure 2. Pyridazine derivatives used in pharmaceutics (a) and agrochemistry (b).

Boc Ð tert-butoxycarbonyl, two or three bonds; on ring expansion; and on cycloaddi-

Scheme 4 (a) 25% H2SO4, D; Ar1 = Ph, 3-MeOC6H4 , 2-Th,

EWG = CO2Me, C(O)Ar, C(O)Het, SO2Ph; R1 = Alk, Ar, Het; R2 = H, Me

Ph Ph (a) Pd(OAc)2 , BIPHIMIP, TsOH, BQ, THF, 45 8C (5-exo-trig);

and expanded the range of substrates from carbonyl-con-

(c) C(4)7C(5)+N(1)7C(6) (d ) N(1)7N(2)+C(5)7C(6) Scheme 11

The features of cyclization of several oxostyryl buta- In(OTf)3 *H+ N In(OTf)2

bonds was proposed for the synthesis of pyrimido[4,5-c]pyr- Scheme 16

Scheme 18 on the substituent in the benzene ring of the aromatic

(a) US, PhMe; (b) US, PyH; (c) US, Ac2O;

2.3. Formation of three bonds

Ar1 H+ Ar1 Ar1 Ar1

N(1)7N(2)+C(3)7C(4)+C(5)7C(6) N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+C(3)7C(4)+

C(3)7C(4)+C(4)7C(5)+ N(2)7C(3)+C(3)7C(4)+ N(1)7N(2)+N(2)7C(3)+ N(1)7N(2)+N(2)7C(3)+

protocols (Fig. 6). Considering all possible combinations Scheme 27

zine derivatives 55 and 56 (Scheme 33).69 The authors

R1 = Ar, CH2Bn, 2-Naph; R2 = R3 = H; R27R3 is benzo; Scheme 40

Scheme 39 Two procedures used for the synthesis of 4-[(1H-indol-

O N O NH K2CO3, CsF N Ar1

(a) O2 (air), dioxane, H2O, 20 8C; R = 2-Py Scheme 45

NH NH2 77 (67% ± 80%)

78: R1 = H, Me, 4-BrC6H4 , 4-MeC6H4; R2 = R3 = H; 79: R1 = Cl, 2,4-Me2-pyrazol-1-yl; R2 = R3 = H; R27R3 is benzo

X = Cl, Br, I; R1 = H, Ph; R2 = H, Me, Ph; R3 = H, Me Ar CN H H

PhMe, MW, 110 8C HN N N

3-carboxylic acid in polyphosphoric acid (PPA) are con- Scheme 81

reaction of a similar hydrazine with chalcones is accompa- Scheme 84

pyridazine core (Scheme 85).117 It was found that some of

165 166 167 168

CO2Me, CO2Et Me, Et 15 35 35 7

(a) 1) ArB(OH)2 , Pd(dppf)Cl2 . CH2Cl2 , Cs2CO3 , dioxane, H2O, Scheme 98

R3 + 185 (95% ± 99%) XR3

vides an efficient synthesis of a variety of pyridazine Scheme 100

iminophosphorane 197, it was possible to synthesize amino Scheme 104

strategy, the hydrogen atom in position 4 of pyridazinone is Scheme 109

Scheme 110 Scheme 111

OMe OMe NH2 Ar

finally furnished compound 218, a promising NK-3 receptor OMe

Structures 221 ± 226

OMe Structures 227 ± 229

Structures 230 ± 233

Structures 234 ± 243

R = CO2Me, 2-Py (244)

Structures 245 ± 251

Structures 252 ± 261

28. V.A.Ogurtsov, P.V.Dorovatovskii, Y.V.Zubavichus, 60. A.V.Borisov, V.V.Voloshchuk, M.A.Nechayev,

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