Metal-Free Selective Synthesis of 1,4-Dihydropyridazines from Hydroxypyrrolines and Hydrazines

Article abstract of DOI:10.1002/ejoc.201700589

An efficient and selective synthesis of 1,4-dihydropyridazines through the acid-catalyzed recyclization of 5-hydroxy-Δ¹-pyrrolines with hydrazines has been developed. The scope of this reaction was thoroughly explored, resulting in the generation of a library of 1,4-dihydropyridazines in good to excellent yields (25 examples, 67–100 % yields).

Full text of DOI:10.1002/ejoc.201700589

A Journal of
Accepted Article
Title: Metal-Free Selective Synthesis of 1,4-Dihydropyridazines from
Hydroxypyrrolines and Hydrazines
Authors: Boris A. Trofimov
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10.1002/ejoc.201700589
European Journal of Organic Chemistry
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Metal-Free Selective Synthesis of 1,4-Dihydropyridazines from
Hydroxypyrrolines and Hydrazines
Dmitrii A. Shabalin,[a] Marina Yu. Dvorko,[a] Evgeniya E. Zolotareva,[a] Igor’ A. Ushakov,[a] Alexander V.
Vashchenko,[a] Elena Yu. Schmidt,[a] and Boris A. Trofimov*[a]
Abstract: An efficient and selective synthesis of 1,4-
dihydropyridazines by the acid-catalyzed recyclization of 5-hydroxy-
Δ1-pyrrolines with hydrazines has been developed. The scope of this
reaction was thoroughly explored resulting in the generation of a
library of title compounds in good to excellent yields (25 examples,
67-100% yields).
moiety in a one molecule makes these compounds perspective
building blocks for construction of various pyrroline ensembles.
As part of our ongoing research in this direction, we have
unexpectedly found regioselective recyclization of 3,3-dimethyl-
5-hydroxy-2-phenyl-Δ1-pyrroline (1a) with phenylhydrazine (2a)
to form pharmaceutically attractive 1,4-dihydropyridazine 3aa
(Scheme 1).
Introduction
1,4-Dihydropyridazine structural unit could be referred to a
privileged scaffold[1] for the drug discovery because of two main
reasons. First, it is the aza-analog of 1,4-dihydropyridine which
is generally considered as the motif for important cardiovascular
drugs, namely, calcium antagonists including nifedipine,
Scheme 1. Unexpected formation of 1,4-dihydropyridazine 3aa from 5-
hydroxy-Δ1-pyrroline 1a and phenylhydrazine (2a).
nitrendipine,
amlodipine,
etc.[1,2]
Indeed,
some
1,4-
dihydropyridazine derivatives have already demonstrated
a
Therefore, in the present work we aimed to thoroughly
investigate the applicability of the reaction between 5-hydroxy-
Δ1-pyrrolines and hydrazines for the selective synthesis of 1,4-
dihydropyridazines.
potential use as antihypertensive, coronary insufficiency
therapeutic and spasmolytic agents,[3] and as inhibitors of ocular
inflammation induced by lens protein, endotoxin, and
interleukin-1.[4] The various routes to 1,4-dihydropyridazines are
known.[5] Among them are reaction between 1,2-diaza-1,3-
butadienes and activated methine compounds,[6] cycloaddition of
1,2,4,5-tetrazines with different dienophiles,[7] reaction of
activated alkenes with hydrazones,[8] and some miscellaneous
synthesis.[9] One of the most common approach is the reaction
of 1,4-dicarbonyl compounds with hydrazines.[10] However, in
reviews concerning dihydropyridazine chemistry[5,11] it has been
emphasized that not all reactions of 1,4-dicarbonyl compounds
with hydrazines proceed as simply as assumed. Depending on
the reaction conditions and structural factors, problems of
chemo- and regioselectivity usually emerge. The former relates
to the simultaneous formation of the mono- and bishydrazones,
N-aminopyrroles, and 1,4-dihydropyridazines, and the latter
refers to the different reactivity of carbonyl groups of
unsymmetrical 1,4-dicarbonyl compounds.
Results and Discussion
At the outset of our study, we have examined the reaction of 3,3-
dimethyl-5-hydroxy-2-phenyl-Δ1-pyrroline
(1a)
with
phenylhydrazine (2a) as a model (Scheme 1). As shown in
Table 1, the 1,4-dihydropyridazine 3aa was obtained in 34%
yield along with a large number of unidentified products in the
presence of trifluoroacetic acid (TFA, 10 mol%) in acetonitrile at
room temperature (Entry 3). Without acid catalyst, the
recyclization of 1a with 2a in acetonitrile at room temperature
(Entry 1) as well as under reflux (Entry 2) does not almost occur.
Pleasingly, the selectivity of reaction of 1a with 2a toward the
target product was improved up to 75% yield of 3aa, when TFA
and refluxing were applied together (Entry 4). Stepwise
decreasing of the reaction time from 3 h to 1 h allowed to reach
89% yield of 3aa (Entries 4-7) that indicated the poor stability of
1,4-dihydropyridazines under the studied reaction conditions at
prolonged heating. An increase in TFA loading from 10 mol% to
Recently, we have developed
a general method for the
synthesis of stable 5-hydroxy-Δ1-pyrrolines by the reaction of
easily accessible aryl isoalkyl ketoximes with acetylene in the
presence of inexpensive KOH/DMSO superbase catalytic
system.[12] Combination of reactive hydroxyl group and pyrroline
20 mol% resulted in
a
slightly lower yield of 1,4-
dihydropyridazine 3aa (84%, Entry 9). However, if 5 mol% of
TFA (Entry 8) or 10 mol% of stronger Brønsted acids like
trifluoromethanesulfonic (Entry 10) and p-toluenesulfonic (Entry
11) acids were used the yield of 3aa deteriorated significantly
(down to 71, 72 and 56%, respectively). Among the solvents
tested, acetonitrile provided the best results, while other solvents
such as benzene, ethanol, and dimethyl sulfoxide afforded lower
[a]
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the
Russian Academy of Sciences
1 Favorsky St., 664033 Irkutsk, Russian Federation
E-mail: boris_trofimov@irioch.irk.ru
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700589
European Journal of Organic Chemistry
FULL PAPER
yields (Entries 12-14). Hence, the arbitrary optimal conditions
were determined to perform the reaction of 3,3-dimethyl-5-
hydroxy-2-phenyl-Δ1-pyrroline (1a) with phenylhydrazine (2a) in
acetonitrile with TFA (10 mol%) under reflux for 1 h (Table 1,
entry 6).
was carried out for 30 min, the yield of 1,4-dihydropyridazine
3ad was improved up to 75%.
Table 2. Reaction of 5-hydroxy-Δ1-pyrroline 1a with hydrazines 2a-n.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Me
Entry
1
Catalyst (mol%)
none
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhH
T [°C]
rt
t [h]
8
Yield [%][b]
Me
Me
Me
Me
Ph
traces
traces
34
Me
Ph
Ph
N
N
N
N
N
N
Ph
2
none
82
rt
3
Me
Me
3
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (10)
TFA (5)
3
3aa (89%)
3ab (75%)[c]
3ac (75%)[c]
4
82
82
82
82
82
82
82
82
80
78
80
3
75
Me
Me
Me
Me
Me
Me
Ph
5
2
80
Ph
Ph
N
N
Me
Me
N
N
N N
6
1
89
7
0.5
1
69
F
Cl
3ad (75%)[c,d]
3ae (93%)[c]
3af (78%)[c]
8
71
Me
Me
Me
9
TFA (20)
TfOH (10)
TsOH∙H2O (10)
TFA (10)
TFA (10)
TFA (10)
1
84
Me
Ph
Me
Ph
Me
Ph
N
N
N
N
10
11
12
13
14
1
72
N
N
1
56
Br
NO2
CN
1
43
3ag (77%)[c]
3ah (83%)[c,e]
3ai (73%)[f]
EtOH
1
50
Me
Me
Me
Me
Me
Ph
Me
Ph
DMSO
1
5
Ph
N
N
NO2
NO2
N
N
N
N
N
[a]
Reaction
conditions:
5-hydroxy-Δ1-pyrroline
1a
(0.5
mmol),
phenylhydrazine (2a, 0.5 mmol), catalyst, solvent (3 mL). [b] Isolated yield.
3aj (traces)[f]
3ak (86%)[c]
With the conditions established, the scope of the reaction was
first explored with respect to the diversely substituted hydrazines
(Table 2). It should be noted that if hydrazines were used in the
form of hydrochloride salts, the recyclization was successfully
performed even without addition of TFA (products 3ab-3ah and
3ak, Table 2).
3al (79%)
Me
Me
Ph
N
N
CH2Ph
3am (see text)[g]
3an (79%)[g]
3ao (traces)
As follows from Table 2, hydrazines with alkyl, aryl and hetaryl
substituents are amenable for the recyclization of 5-hydroxy-Δ1-
pyrroline 1a to 1,4-dihydropyridazines in good to excellent yields.
The substituent pattern has the expected influence on the
studied process. Thus, when using arylhydrazines with electron-
donor methyl group in the phenyl ring under chosen arbitrary
optimal reaction conditions, the yields of the corresponding 1,4-
dihydropyridazines dropped to 75% (3ab and 3ac) in
comparison with unsubstituted phenylhydrazine (89% yield for
3aa). The introduction of second methyl group to the phenyl ring
leads to formation of the corresponding product 3ad in 66% yield.
[a] Reaction conditions: 5-hydroxy-Δ1-pyrroline 1a (0.5 mmol), hydrazine or
hydrazine hydrochloride 2 (0.5 mmol), with or without TFA (10 mol%), MeCN
(3 mL), reflux, 1 h. [b] Isolated yields are given. [c] Hydrazine hydrochloride
without addition of TFA was used. [d] Reaction time was 30 min. [e] Reaction
time was 3 h. [f] Reaction time was 5 h. [g] Reaction time was 15 min.
On the contrary, the reaction of 5-hydroxy-Δ1-pyrroline 1a with
arylhydrazines bearing electron-withdrawing substituents in the
phenyl ring naturally required a longer time, e.g. 3 h for 4-
cyanophenylhydrazine (2h) and 5 h for 4-nitrophenylhydrazine
(2i). The use of 2,4-dinitrophenylhydrazine (2j) as a nucleophile
shed light on the recyclization mechanism, since only traces of
the desired 1,4-dihydropyridazine 3aj were detected (1H NMR),
and the main product was dihydrazone 4 (63%, Scheme 2).
Noteworthy, when tosylhydrazine 2o was introduced in the
reaction with 5-hydroxy-Δ1-pyrroline 1a for 1 h the latter was fully
consumed, although only traces of 1,4-dihydropyridazine 3ao
This
contradiction
between
increasing
of
hydrazine
nucleophilicity and decreasing of the product yield could be
explained by faster formation of 1,4-dihydropyridazine and its
further transformation. Indeed, when the reaction between 5-
hydroxy-Δ1-pyrroline 1a and 2,4-dimethylphenylhydrazine (2d)
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10.1002/ejoc.201700589
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were observed (1H NMR) in complex reaction mixture.
Apparently, more electron-withdrawing tosyl substituent (in
comparison with 2,4-dinitrophenyl substituent) significantly
decrease the nucleophilicity of both amino functions, thus
precluding even initial ring opening (no dihydrazone of type 4
was detected).
up to 3 h. This is apparently associated with both the electron-
donor effect of 2,5-dimethylphenyl substituent reducing
electrophilicity of carbon atom of the imine function and the
shielding effect of ortho-methyl group hindering interaction with
acid catalyst and nucleophile.
Table 3. Reaction of 5-hydroxy-Δ1-pyrrolines 1 with hydrazines 2.[a,b]
Ph
Ph
Scheme
dinitrophenylhydrazine (2j).
2.
Reaction
of
5-hydroxy-Δ1-pyrroline
1a
with
2,4-
N
N
N
N
Ph
N
N
Ph
Me
F
The violation of regioselectivity has not been observed for the
recyclization of 5-hydroxy-Δ1-pyrroline 1a with alkylhydrazines
as it could be expected from increasing of nucleophilicity of
secondary nitrogen atom (NH), bearing σ-donor alkyl group
instead of electron-withdrawing aryl group. Ethylhydrazine (2m)
and benzylhydrazine (2n) were successfully tested in the studied
reaction affording the corresponding 1,4-dihydropyridazines in
good yields for 15 min (Table 2). Despite the good yield of 1-
3ba (82%)
3bc (95%)[c]
3be (91%)[c]
Ph
Ph
Ph
N
N
N
N
N N
NO2
Cl
CN
3bf (95%)[c]
3bh (92%)[c,d]
3bi (70%)[e]
1
ethyl-1,4-dihydropyridazine 3am, observed in H NMR spectrum
of the reaction mixture, the isolated yield of 3am was
insignificant (ca. 6%) due to its instability upon isolation and
storage.
Me
Me
Ph
Ph
N
N
Me
N
N
The reaction of 5-hydroxy-Δ1-pyrroline 1a with hydrazine hydrate
N
N
N
Ph
(2o) for
1 h led to formation of the corresponding 1,4-
dihydropyridazine 3ao in trace amounts (1H NMR). Increasing
the reaction time did not improve the yield of 3ao apparently due
to the known tautomeric equilibrium between 1,4- and 4,5-
dihydropyridazines and inclination of the latter to be transformed
into dimer, trimer and polymeric products (Scheme 3).[13]
3bk (88%)[c]
3bl (84%)
3ca (78%)
Me
Ph
Me
Me
Me
O
N
N
N
N
Ph
N
N
Ph
Ph
Me
3da (100%)
3ea (72%)[d]
3fa (67%)
[a] Reaction conditions: 5-hydroxy-Δ1-pyrroline 1b-f (0.5 mmol), hydrazine or
hydrazine hydrochloride 2 (0.5 mmol), with or without TFA (10 mol%), MeCN
(3 mL), reflux, 1 h. [b] Isolated yields are given. [c] Hydrazine hydrochloride
without addition of TFA was used. [d] Reaction time was 3 h. [e] Reaction time
was 5 h.
Scheme 3. Reaction of 5-hydroxy-Δ1-pyrroline 1a with hydrazine hydrate (2o).
The structures of all synthesized compounds
3
were
Further, we have investigated the reactivity of diversely
substituted 5-hydroxy-Δ1-pyrrolines 1b-f in the reaction with
hydrazines 2 (Table 3). Generally, the yields of spiro-fused 1,4-
dihydropyridazines are higher than those of 4,4-dimethyl-1,4-
dihydropyridazines that is explicated neither by electronic nor by
steric influence of spiro-fused cyclohexyl ring but by easy
isolation of the target products after treatment of the reaction
mixture with diethyl ether and, therefore, by the absence of
column chromatography purification step. In the case of 5-
hydroxy-Δ1-pyrroline 1e, having 2,5-dimethylphenyl substituent
at the carbon-nitrogen double bond, acceptable yield of 3ea
(72%) was obtained only when the reaction time was increased
unambiguously proven by 1H, 13C NMR spectroscopy (2D COSY,
NOESY, HMBC, HSQC techniques were also employed in some
cases) and X-ray diffraction study of their representative, 3ai
(Figure 1) and 3da (Figure 2).
A
tentative mechanism for recyclization of 5-hydroxy-Δ1-
pyrrolines with hydrazines to form 1,4-dihydropyridazines is
depicted in Scheme 4. Protonation of the starting 5-hydroxy-Δ1-
pyrroline 1 (with TFA or hydrogen chloride, when hydrazine
hydrochloride salts are used) leads to formation of cation A,
which reacts with hydrazine 2 to afford protonated pyrrolidine B.
Further ring opening gives linear intermediate C, which cyclizes
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10.1002/ejoc.201700589
European Journal of Organic Chemistry
FULL PAPER
to 3-hydroxy-2,3,4,5-tetrahydropyridazine D via intramolecular
nucleophilic substitution of ammonium moiety by the NH-
function of hydrazine. Dehydration of intermediate D ends the
formation of 1,4-dihydropyridazine 3. This mechanism is in an
agreement with the abovementioned reaction between 2,4-
dinitrophenylhydrazine (2j) and 5-hydroxy-Δ1-pyrroline 1a
resulting in dihydrazone 4 (Scheme 2), formation of which is
explained by decrease of nucleophilicity of the NH-function
conjugated with 2,4-dinitrophenyl ring that eventually prevents
intramolecular cyclization of intermediate C (Scheme 4).
Figure
2.
ORTEP
diagram
of
1-(4-methylphenyl)-3-phenyl-2,3-
diazaspiro[5.5]undeca-1,4-diene (3da) as determined by X-ray analysis.
Thermal ellipsoids set at 50% probability.
Conclusions
In conclusion, we have presented a selective synthesis of
pharmaceutically perspective 1,4-dihydropyridazines based on
the acid-catalyzed recyclization of available 5-hydroxy-Δ1-
pyrrolines with hydrazines. The reaction is operationally simple
and tolerant to a variety of substituted hydrazines and 5-
hydroxy-Δ1-pyrrolines, and provides desired heterocycles in
good to excellent preparative yields.
Scheme 4. A tentative mechanism for recyclization of 5-hydroxy-Δ1-pyrrolines
with hydrazines.
Experimental Section
General information. All chemicals and solvents were purchased from
commercial sources and used without further purification. Starting 5-
hydroxy-Δ1-pyrrolines 1a-e were prepared by literature method,[12] and 5-
hydroxy-Δ1-pyrroline 1f was synthesized from furyl isopropyl ketoxime
and phenylacetylene (for details see SI). Commercial acetonitrile was
dried with 4Å MS before use. Thin layer chromatography was carried out
on Merck silica gel 60 F254 pre-coated aluminium foil sheets (eluent:
hexane/diethyl ether 1:1) and were visualized using UV light (254 nm).
Flash column chromatography was carried out using slurry packed
Sigma Aldrich silica gel (SiO2), 70-230 mesh, pore size 60 Å, eluting with
benzene. IR spectra were recorded on
a
Bruker Vertex-70
spectrophotometer as thin films dispersed from CDCl3 or KBr pellets.
NMR spectra were recorded on Bruker DPX-400 and AV-400
spectrometers (400.1 MHz for 1H, 100.6 MHz for 13C, and 40.5 MHz for
15N). Chemical shifts (δ) are quoted in parts per million (ppm). The
residual solvent peak, δH 7.27 and δC 77.10 for CDCl3, δH 2.50 and δC
39.50 for DMSO-d6, δH 1.94 and δC 118.26 for CD3CN, was used as a
reference. Coupling constants (J) are reported in Hertz (Hz). The
multiplicity abbreviations used are: s singlet, d doublet, t triplet, q quartet,
m multiplet, br broad signal. Signal assignment was achieved by analysis
of COSY, NOESY, HMBC, and HSQC experiments if required. Melting
Figure 1. ORTEP diagram of 4,4-dimethyl-1-(4-nitrophenyl)-3-phenyl-1,4-
dihydropyridazine (3ai) as determined by X-ray analysis. Thermal ellipsoids
set at 50% probability.
points (uncorrected) were measured on
a Kofler micro hot-stage
apparatus. The CHN microanalyses were performed on a Flash EA 1112
Series elemental analyzer.
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Atomic coordinates, bond lengths, bond angles and thermal parameters
for compounds 3ai and 3da have been deposited at the Cambridge
Crystallographic Data Centre (CCDC) and allocated the deposition
numbers CCDC 1542500, 1542502. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1-(4-Fluorophenyl)-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3ae): purification by Method B; yield 0.130 g, 93%; an orange oil; 1H
NMR (400.1 MHz, CDCl3): δ = 7.57-7.55 (m, 2H, Ph), 7.40-7.34 (m, 5H,
Ar, Ph), 7.04-7.00 (m, 2H, Ar), 6.72 (d, J = 7.3 Hz, 1H, H6), 4.78 (d, J =
7.3 Hz, 1H, H5), 1.29 (s, 6H, Me) ppm; 13C NMR (100.6 MHz, CDCl3): δ =
158.7 (d, J = 240.5 Hz), 150.2, 141.5 (d, J = 2.3 Hz), 137.7, 129.2, 128.3,
127.9, 125.1, 116.9 (d, J = 7.7 Hz), 115.6 (d, J = 22.5 Hz), 109.7, 32.6,
28.8 ppm; IR (film): νmax = 2963, 2928, 2867, 1648, 1505, 1327, 1288,
1219, 1104, 1005 cm-1; elemental analysis calcd (%) for C18H17FN2: C
77.12, H 6.11, F 6.78, N 9.99; found: C 76.92, H 5.87, F 7.03, N 9.74.
General procedure for the synthesis of 1,4-dihydropyridazines 3. A
mixture of 5-hydroxy-Δ1-pyrroline 1 (0.5 mmol), hydrazine or hydrazine
hydrochloride salt
2 (0.5 mmol), TFA (10 mol%, if needed) and
acetonitrile (3 mL) was refluxed for appropriate time (see Table 2 and 3).
The residue after solvent evaporation was purified by Method A (flash
column chromatography, SiO2, eluent - benzene) or Method B (treatment
with diethyl ether and further evaporation of ether solution).
1-(4-Chlorophenyl)-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3af): purification by Method A; yield 0.116 g, 78%; an orange oil; Rf =
0.87 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.56-
7.55 (m, 2H, Ph), 7.41-7.39 (m, 3H, Ph), 7.34 (d, J = 8.9 Hz, 2H, Ar), 7.27
(d, J = 8.9 Hz, 2H, Ar), 6.75 (d, J = 7.4 Hz, 1H, H6), 4.82 (d, J = 7.4 Hz,
1H, H5), 1.29 (s, 6H, Me) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 150.9,
143.4, 137.5, 129.2, 129.0, 128.4, 128.0, 127.0, 124.4, 116.4, 110.5,
32.8, 28.8 ppm; IR (film): νmax = 2962, 2925, 2861, 1650, 1595, 1491,
1360, 1286, 1103, 1004 cm-1; elemental analysis calcd (%) for
C18H17ClN2: C 72.84, H 5.77, Cl 11.95, N 9.44; found: C 73.01, H 5.89, Cl
11.78, N 9.23.
4,4-Dimethyl-1,3-diphenyl-1,4-dihydropyridazine (3aa): purification by
Method A; yield 0.116 g, 89%; an yellow oil; Rf = 0.87 (hexane/diethyl
ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.62-7.60 (m, 2H, Ph), 7.46-
7.41 (m, 5H, Ph), 7.35-7.33 (m, 2H, Ph), 7.05-7.02 (m, 1H, Ph), 6.83 (d, J
= 7.4 Hz, 1H, H6), 4.81 (d, J = 7.4 Hz, 1H, H5), 1.32 (s, 6H, Me) ppm; 13
C
NMR (100.6 MHz, CDCl3): δ = 150.2, 144.9, 137.8, 129.3, 129.1, 128.2,
127.9, 124.8, 122.1, 115.4, 109.9, 32.7, 28.9 ppm; 15N NMR (40.5 MHz,
CDCl3): δ = −215.4, −64.9 ppm; IR (film): νmax = 2963, 2927, 2868, 1650,
1598, 1495, 1328, 1285, 1243, 1107, 1004 cm-1; elemental analysis
calcd (%) for C18H18N2: C 82.40, H 6.92, N 10.68; found: C 82.23, H 6.74,
N 10.74.
1-(3-Bromophenyl)-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3ag): purification by Method A; yield 0.132 g, 77%; an orange oil; Rf =
0.86 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.61-
7.59 (m, 1H, Ar), 7.56-7.54 (m, 2H, Ph), 7.41-7.40 (m, 3H, Ph), 7.31-7.29
(m, 1H, Ar), 7.19-7.15 (m, 1H, Ar), 7.12-7.10 (m, 1H, Ar), 6.76 (d, J = 7.4
Hz, 1H, H6), 4.84 (d, J = 7.4 Hz, 1H, H5), 1.29 (s, 6H, Me) ppm; 13C NMR
(100.6 MHz, CDCl3): δ = 151.4, 145.9, 137.4, 130.3, 129.2, 128.4, 128.0,
4,4-Dimethyl-1-(3-methylphenyl)-3-phenyl-1,4-dihydropyridazine
(3ab): purification by Method A; yield 0.103 g, 75%; an orange oil; Rf =
0.89 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.59-
7.57 (m, 2H, Ph), 7.40-7.38 (m, 3H, Ph), 7.27-7.26 (m, 1H, Ar), 7.21-7.20
(m, 2H, Ar), 6.84-6.82 (m, 1H, Ar), 6.80 (d, J = 7.2 Hz, 1H, H6), 4.77 (d, J
= 7.2 Hz, 1H, H5), 2.36 (s, 3H, Me), 1.28 (s, 6H, Me) ppm; 13C NMR
(100.6 MHz, CDCl3): δ = 150.0, 144.9, 138.9, 137.8, 129.2, 128.9, 128.2,
127.9, 124.9, 123.0, 116.1, 112.5, 109.6, 32.7, 28.8, 21.7 ppm; IR (film):
νmax = 2962, 2924, 2866, 1650, 1598, 1492, 1331, 1289, 1242, 1108,
1004 cm-1; elemental analysis calcd (%) for C19H20N2: C 82.57, H 7.29, N
10.14; found: C 82.69, H 7.30, N 10.08.
124.7, 124.1, 123.1, 118.2, 113.5, 110.9, 32.8, 28.8 ppm; IR (film): νmax
=
2963, 2927, 2866, 1653, 1589, 1478, 1331, 1288, 1237, 1102, 1013,
1001 cm-1; elemental analysis calcd (%) for C18H17BrN2: C 63.35, H 5.02,
Br 23.42, N 8.21; found: C 63.12, H 5.14, Br 23.68, N 8.20.
1-(4-Cyanophenyl)-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3ah): purification by Method A; yield 0.119 g, 83%; an yellow oil; Rf =
0.63 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.58 (d,
J = 9.0 Hz, 2H, Ar), 7.55-7.53 (m, 2H, Ph), 7.45 (d, J = 9.0 Hz, 2H, Ar),
7.42-7.41 (m, 3H, Ph), 6.82 (d, J = 7.5 Hz, 1H, H6), 4.97 (d, J = 7.5 Hz,
1H, H5), 1.31 (s, 6H, Me) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 153.5,
147.2, 137.0, 133.3, 129.0, 128.7, 128.0, 122.8, 119.6, 114.4, 113.0,
103.9, 33.0, 28.8 ppm; IR (film): νmax = 2966, 2928, 2870, 2219, 1602,
1509, 1393, 1337, 1292, 1174, 1106, 1002 cm-1; elemental analysis
calcd (%) for C19H17N3: C 79.41, H 5.96, N 14.62; found: C 79.51, H 5.67,
N 14.92.
4,4-Dimethyl-1-(4-methylphenyl)-3-phenyl-1,4-dihydropyridazine
(3ac): purification by Method A; yield 0.103 g, 75%; an orange oil; Rf =
0.86 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.59-
7.57 (m, 2H, Ph) 7.40-7.38 (m, 3H, Ph), 7.31 (d, J = 8.3 Hz, 2H, Ar), 7.13
(d, J = 8.3 Hz, 2H, Ar), 6.77 (d, J = 7.3 Hz, 1H, H6), 4.75 (d, J = 7.3 Hz,
1H, H5), 2.32 (s, 3H, Me), 1.29 (s, 6H, Me) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 149.6, 142.8, 137.9, 131.5, 129.6, 129.2, 128.1, 127.9, 125.1,
115.5, 109.3, 32.6, 28.9, 20.7 ppm; IR (film): νmax = 2961, 2924, 2863,
1648, 1612, 1512, 1360, 1283, 1241, 1107, 1005 cm-1; elemental
analysis calcd (%) for C19H20N2: C 82.57, H 7.29, N 10.14; found: C
82.43, H 7.08, N 10.23.
4,4-Dimethyl-1-(4-nitrophenyl)-3-phenyl-1,4-dihydropyridazine (3ai):
purification by Method A; yield 0.112 g, 73%; an yellow powder; m.p.
121-123 °C; Rf = 0.68 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz,
CDCl3): δ = 8.20 (d, J = 9.3 Hz, 2H, Ar), 7.56-7.54 (m, 2H, Ph), 7.45 (d, J
= 9.3 Hz, 2H, Ar), 7.45-7.43 (m, 3H, Ph), 6.88 (d, J = 7.5 Hz, 1H, H6),
5.04 (d, J = 7.5 Hz, 1H, H5), 1.32 (s, 6H, Me) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 154.7, 148.7, 141.6, 136.9, 129.0, 128.9, 128.1, 125.6, 122.6,
114.0, 113.6, 33.2, 28.8 ppm; IR (film): νmax = 2975, 2952, 2934, 1649,
1592, 1501, 1315, 1289, 1106, 1007 cm-1; elemental analysis calcd (%)
for C18H17N3O2: C 70.34, H 5.58, N 13.67; found: C 70.53, H 5.49, N
13.39.
1-(2,4-Dimethylphenyl)-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3ad): purification by Method A; yield 0.109 g, 75%; an orange oil; Rf =
0.87 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.54-
7.52 (m, 2H, Ph), 7.35-7.33 (m, 3H, Ph), 7.30-7.27 (m, 1H, Ar), 7.03-7.01
(m, 2H, Ar), 6.37 (d, J = 7.2 Hz, 1H, H6), 4.62 (d, J = 7.2 Hz, 1H, H5),
2.31 (s, 6H, Me), 1.29 (s, 6H, Me) ppm; 13C NMR (100.6 MHz, CDCl3): δ
= 148.3, 143.2, 137.8, 135.4, 132.4, 131.7, 129.2, 129.7, 127.9, 127.8,
127.2, 124.2, 106.4, 32.1, 28.2, 20.9, 18.3 ppm; IR (film): νmax = 2959,
2924, 2865, 1647, 1503, 1458, 1094, 1006 cm-1; elemental analysis
calcd (%) for C20H22N2: C 82.72, H 7.64, N 9.65; found: C 82.61, H 7.87,
N 9.44.
4,4-Dimethyl-1-(2-naphtyl)-3-phenyl-1,4-dihydropyridazine
(3ak):
purification by Method A; yield 0.134 g, 86%; a beige powder; m.p. 92-
94 °C; Rf = 0.83 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3):
δ = 7.81-7.78 (m, 4H, Naphtyl), 7.71-7.69 (m, 1H, Naphtyl), 7.66-7.64 (m,
2H, Ph), 7.47-7.43 (m, 4H, Naphtyl, Ph), 7.38-7.34 (m, 1H, Naphtyl), 6.97
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700589
European Journal of Organic Chemistry
FULL PAPER
(d, J = 7.4 Hz, 1H, H6), 4.88 (d, J = 7.4 Hz, 1H, H5), 1.35 (s, 6H, Me)
ppm; 13C NMR (100.6 MHz, CDCl3): δ = 150.7, 142.6, 137.8, 134.3,
129.9, 129.3 (2C), 129.0, 128.3, 128.0, 127.7, 127.3, 126.5, 124.8, 124.0,
117.0, 110.6, 32.9, 29.0 ppm; IR (film): νmax = 3056, 2962, 2931, 2870,
1629, 1594, 1510, 1471, 1361, 1327, 1288, 1102, 1008 cm-1; elemental
analysis calcd (%) for C22H20N2: C 84.58, H 6.45, N 8.97; found: C 84.35,
H 6.38, N 8.81.
67-69 °C; 1H NMR (400.1 MHz, CDCl3): δ = 7.47-7.44 (m, 2H, Ph), 7.40-
7.34 (m, 5H, Ar, Ph), 7.03-6.99 (m, 2H, Ar), 6.78 (d, J = 7.3 Hz, 1H, H4),
5.16 (d, J = 7.3 Hz, 1H, H5),1.67-1.52 (m, 9H, Cy), 1.22-1.16 (m, 1H, Cy)
ppm; 13C NMR (100.6 MHz, CDCl3): δ = 158.6 (d, J = 240.4 Hz), 151.0,
141.6 (d, J = 2.3 Hz), 137.5, 129.4, 128.0, 127.8, 125.9, 116.8 (d, J = 7.7
Hz), 115.6 (d, J = 22.5 Hz), 105.3, 37.8, 34.6, 25.9, 21.1 ppm; IR (film):
νmax = 2929, 2856, 1640, 1608, 1506, 1446, 1330, 1288, 1221 cm-1;
elemental analysis calcd (%) for C21H21FN2: C 78.72, H 6.61, F 5.93, N
8.74; found: C 78.50, H 6.61, F 6.00, N 8.71.
4,4-Dimethyl-3-phenyl-1-(2-pyridinyl)-1,4-dihydropyridazine
(3al):
purification by Method A; yield 0.104 g, 79%; a pale yellow powder; m.p.
61-63 °C; Rf = 0.78 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz,
CDCl3): δ = 8.27-8.24 (m, 1H, Py), 7.73 (d, J = 7.7 Hz, 1H, H6), 7.59-7.56
(m, 4H, Ph, Py), 7.41-7.39 (m, 3H, Ph), 6.88-6.84 (m, 1H, Py), 4.89 (d, J
= 7.7 Hz, 1H, H5), 1.32 (s, 6H, Me) ppm; 13C NMR (100.6 MHz, CDCl3): δ
= 154.8, 152.3, 147.2, 137.8 (2C), 129.1, 128.3, 127.9, 121.4, 117.0,
110.7, 109.4, 32.9, 29.3 ppm; IR (film): νmax = 2963, 2924, 2866, 1661,
1589, 1466, 1441, 1327, 1294, 1101, 1000 cm-1; elemental analysis
calcd (%) for C17H17N3: C 77.54, H 6.51, N 15.96; found: C 77.54, H 6.36,
N 15.91.
3-(4-Chlorophenyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3bf): purification by Method B; yield 0.160 g, 95%; a pale yellow powder;
m.p. 108-110 °C; 1H NMR (400.1 MHz, CDCl3): δ = 7.46-7.44 (m, 2H, Ph),
7.40-7.39 (m, 3H, Ph), 7.34 (d, J = 9.0 Hz, 2H, Ar), 7.26 (d, J = 9.0 Hz,
2H, Ar), 6.80 (d, J = 7.3 Hz, 1H, H4), 5.21 (d, J = 7.3 Hz, 1H, H5), 1.71-
1.52 (m, 9H, Cy), 1.22-1.16 (m, 1H, Cy) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 151.6, 143.4, 137.2, 129.2, 128.8, 127.9, 127.7, 126.8, 125.0,
116.2, 105.9, 37.7, 34.5, 25.7, 20.9 ppm; IR (film): νmax = 2929, 2856,
1643, 1595, 1492, 1447, 1331, 1288, 1249, 1091 cm-1; elemental
analysis calcd (%) for C21H21ClN2: C 74.88, H 6.28, Cl 10.52, N 8.32;
found: C 74.86, H 6.45, Cl 10.58, N 8.52.
1-Ethyl-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine (3am): 1H NMR
(400.1 MHz, CD3CN): δ = 7.45-7.43 (m, 2H, Ph), 7.36-7.33 (m, 3H, Ph),
6.32 (d, J = 7.2 Hz, 1H, H6), 4.50 (d, J = 7.2 Hz, 1H, H5), 3.47 (q, J = 7.1
Hz, 2H, Et), 1.20 (t, J = 7.1 Hz, 3H, Et), 1.13 (s, 6H, Me) ppm; 13C NMR
(100.6 MHz, CD3CN): δ = 148.1, 139.4, 130.3, 130.0, 128.7, 106.8, 51.5,
32.4, 28.3, 14.3 ppm.
3-(4-Cyanophenyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3bh): purification by Method B; yield 0.150 g, 92%; a pale yellow
1
powder; m.p. 128-130 °C; H NMR (400.1 MHz, CDCl3): δ = 7.57 (d, J =
8.9 Hz, 2H, Ar), 7.44 (d, J = 8.9 Hz, 2H, Ar), 7.43-7.38 (m, 5H, Ph), 6.87
(d, J = 7.4 Hz, 1H, H4), 5.38 (d, J = 7.4 Hz, 1H, H5), 1.72-1.57 (m, 9H,
Cy), 1.23-1.12 (m, 1H, Cy) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 154.4,
147.2, 136.8, 133.3, 129.1, 128.3, 127.9, 123.7, 119.7, 114.4, 108.7,
103.8, 38.2, 34.7, 25.6, 21.0 ppm; IR (film): νmax = 2928, 2856, 2219,
1601, 1508, 1340, 1290 cm-1; elemental analysis calcd (%) for C22H21N3:
C 80.70, H 6.47, N 12.83; found: C 80.47, H 6.41, N 12.54.
1-Benzyl-4,4-dimethyl-3-phenyl-1,4-dihydropyridazine
(3an):
purification by Method A; yield 0.109 g, 79%; an yellow oil; Rf = 0.85
(hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.49-7.46
(m, 2H, Ph), 7.37-7.29 (m, 8H, Benzyl, Ph), 6.25 (d, J = 7.3 Hz, 1H, H6),
4.72 (s, 2H, CH2), 4.50 (d, J = 7.3 Hz, 1H, H5), 1.21 (s, 6H, Me) ppm; 13
NMR (100.6 MHz, CDCl3): δ = 147.9, 138.7, 138.1, 129.3, 129.2, 128.5,
127.9 (2C), 127.8, 127.3, 106.5, 60.1, 32.0, 28.3 ppm; IR (film): νmax
C
=
3-(4-Nitrophenyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene (3bi):
purification by Method A; yield 0.121 g, 70%; an yellow powder; m.p.
146-148 °C; Rf = 0.66 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz,
CDCl3): δ = 8.19 (d, J = 9.3 Hz, 2H, Ar), 7.45 (d, J = 9.3 Hz, 2H, Ar),
7.44-7.40 (m, 5H, Ph), 6.93 (d, J = 7.4 Hz, 1H, H4), 5.45 (d, J = 7.4 Hz,
1H, H5), 1.73-1.56 (m, 9H, Cy), 1.24-1.12 (m, 1H, Cy) ppm; 13C NMR
(100.6 MHz, CDCl3): δ = 155.6, 148.7, 141.5, 136.6, 129.1, 128.5, 128.0,
2960, 2925, 2860, 1645, 1545, 1454, 1441, 1355, 1309, 1184, 1091,
1007 cm-1; elemental analysis calcd (%) for C19H20N2: C 82.57, H 7.29, N
10.14; found: C 82.68, H 7.31, N 10.38.
1,3-Diphenyl-2,3-diazaspiro[5.5]undeca-1,4-diene (3ba): purification
by Method A; yield 0.124 g, 82%; a beige powder; m.p. 78-80 °C; Rf =
0.89 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.48-
7.46 (m, 2H, Ph), 7.44-7.39 (m, 5H, Ph), 7.34-7.30 (m, 2H, Ph), 7.03-6.99
(m, 1H, Ph), 6.87 (d, J = 7.3 Hz, 1H, H4), 5.19 (d, J = 7.3 Hz, 1H, H5),
1.71-1.52 (m, 9H, Cy), 1.20-1.17 (m, 1H, Cy) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 151.1, 145.0, 137.7, 129.5, 129.1, 128.0, 127.8, 125.6, 122.1,
115.4, 105.5, 37.9, 34.8, 25.9, 21.1 ppm; IR (film): νmax = 2928, 2855,
1642, 1598, 1498, 1328, 1288, 1255 cm-1; elemental analysis calcd (%)
for C21H22N2: C 83.40, H 7.33, N 9.27; found: C 83.64, H 7.31, N 9.03.
125.5, 123.5, 113.6, 109.9, 38.4, 34.8, 25.6, 21.0 ppm; IR (film): νmax
=
2928, 2856, 1592, 1502, 1325, 1296, 1113 cm-1; elemental analysis
calcd (%) for C21H21N3O2: C 72.60, H 6.09, N 12.10; found: C 72.38, H
6.26, N 11.98.
3-(2-Naphtyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3bk):
purification by Method A; yield 0.154 g, 88%; a pale peach powder; m.p.
99-101 °C; Rf = 0.84 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz,
CDCl3): δ = 7.80-7.75 (m, 4H, Naphtyl), 7.69-7.67 (m, 1H, Naphtyl), 7.51-
7.50 (m, 2H, Ph), 7.43-7.41 (m, 4H, Naphtyl, Ph), 7.35-7.31 (m, 1H,
Naphtyl), 7.00 (d, J = 7.3 Hz, 1H, H4), 5.26 (d, J = 7.3 Hz, 1H, H5), 1.73-
1.53 (m, 9H, Cy), 1.24-1.15 (m, 1H, Cy) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 151.4, 142.6, 137.6, 134.3, 129.8, 129.5, 128.9, 128.1, 127.9,
127.7, 127.3, 126.4, 125.7, 123.9, 116.9, 110.5, 106.0, 38.0, 34.8, 25.9,
21.1 ppm; IR (film): νmax = 2929, 2855, 1628, 1599, 1510, 1471, 1449,
1327, 1288, 1227 cm-1; elemental analysis calcd (%) for C25H24N2: C
85.19, H 6.86, N 7.95; found: C 85.41, H 6.93, N 7.73.
3-(4-Methylphenyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3bc): purification by Method B; yield 0.150 g, 95%; a pale yellow
powder; m.p. 102-104 °C; 1H NMR (400.1 MHz, CDCl3): δ = 7.48-7.47 (m,
2H, Ph), 7.40-7.39 (m, 3H, Ph), 7.32 (d, J = 8.4 Hz, 2H, Ar), 7.13 (d, J =
8.4 Hz, 2H, Ar), 6.83 (d, J = 7.3 Hz, 1H, H4), 5.14 (d, J = 7.3 Hz, 1H, H5),
2.32 (s, 3H, Me), 1.70-1.51 (m, 9H, Cy), 1.20-1.17 (m, 1H, Cy) ppm; 13C
NMR (100.6 MHz, CDCl3): δ = 150.4, 142.9, 137.7, 131.4, 129.5 (2C),
127.9, 127.8, 125.8, 115.4, 104.7, 37.7, 34.7, 25.9, 21.1, 20.6 ppm; IR
(film): νmax = 2927, 2856, 1641, 1612, 1512, 1446, 1327, 1286, 1247 cm-
1; elemental analysis calcd (%) for C22H24N2: C 83.50, H 7.65, N 8.85;
found: C 83.30, H 7.76, N 8.63.
1-Phenyl-3-(2-pyridinyl)-2,3-diazaspiro[5.5]undeca-1,4-diene
(3bl):
purification by Method A; yield 0.127 g, 84%; a pale yellow powder; m.p.
135-137 °C; Rf = 0.76 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz,
CDCl3): δ = 8.28-8.26 (m, 1H, Py), 7.74 (d, J = 7.6 Hz, 1H, H4), 7.58-7.56
(m, 2H, Py), 7.48-7.44 (m, 2H, Ph), 7.41-7.39 (m, 3H, Ph), 6.89-6.84 (m,
1H, Py), 5.33 (d, J = 7.6 Hz, 1H, H5), 1.72-1.50 (m, 9H, Cy), 1.20-1.11 (m,
3-(4-Fluorophenyl)-1-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3be): purification by Method B; yield 0.146 g, 91%; a beige powder; m.p.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700589
European Journal of Organic Chemistry
FULL PAPER
1H, Cy) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 155.0, 153.4, 147.3,
137.7, 137.5, 129.3, 128.0, 127.8, 122.6, 117.0, 109.5, 106.0, 37.8, 35.0,
25.7, 20.8 ppm; IR (film): νmax = 2928, 2856, 1647, 1587, 1457, 1440,
1335, 1292 cm-1; elemental analysis calcd (%) for C20H21N3: C 79.17, H
6.98, N 13.85; found: C 79.45, H 6.95, N 13.72.
This work was supported by the President of the Russian
Federation (programs for the support of leading scientific
schools, Grant No. NSh-7145.2016.3). We acknowledge Baikal
Analytical Center for collective use of SB RAS for the equipment.
Keywords: Synthetic methods • Nitrogen heterocycles • Ring
expansion • Hydrazines • Spiro compounds
4,4-Dimethyl-3-(4-methylphenyl)-1-phenyl-1,4-dihydropyridazine
(3ca): purification by Method A; yield 0.108 g, 78%; an yellow oil; Rf =
0.89 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.48 (d,
J = 7.8 Hz, 2H, Ar), 7.43-7.41 (m, 2H, Ph), 7.34-7.30 (m, 2H, Ph), 7.20 (d,
J = 7.8 Hz, 2H, Ar), 7.02-6.98 (m, 1H, Ph), 6.80 (d, J = 7.2 Hz, 1H, H6),
4.77 (d, J = 7.2 Hz, 1H, H5), 2.40 (s, 3H, Me), 1.29 (s, 6H, Me) ppm; 13C
NMR (100.6 MHz, CDCl3): δ = 150.1, 144.9, 138.1, 134.9, 129.1 (2C),
[1]
M. E. Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin. Chem. Biol.
2010, 14, 347-361.
[2]
[3]
D. J. Triggle, Cell. Mol. Neurobiol. 2003, 23, 293-303.
a) G. Frankowiak, H. Meyer, F. Bossert, A. Heise, S. Kazda, K. Stoepel,
R. Towart, E. Wehinger, US 4348395, 1982; b) B. Loev, H. Jones, J. R.
Shroff, US 4435395, 1984; c) A. Vogel, US 4491581, 1985.
G. C. Y. Chiou, Q. S. Yao, T. Okawara, J. Ocul. Pharm. 1994, 10, 577-
586.
128.6, 124.7, 122.0, 115.2, 109.9, 32.7, 28.9, 21.3 ppm; IR (film): νmax
=
2959, 2923, 2859, 1649, 1597, 1496, 1461, 1329, 1285, 1242, 1106,
1006 cm-1; elemental analysis calcd (%) for C19H20N2: C 82.57, H 7.29, N
10.14; found: C 82.73, H 7.16, N, 9.93.
[4]
[5]
[6]
A. M. Abdelmoniem, I. A. Abdelhamid, Curr. Org. Chem. 2016, 20,
1512-1546.
1-(4-Methylphenyl)-3-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3da): purification by Method B; yield 0.158 g, 100%; a beige powder;
a) O. A. Attanasi, P. Filippone, C. Fiorucci, F. Mantellini, Synlett 1997,
12, 1361-1362; b) O. A. Attanasi, P. Filippone, C. Fiorucci, E. Foresti, F.
Mantellini, J. Org. Chem. 1998, 63, 9880-9887; c) G. Pitacco, O. A.
Attanasi, L. De Crescentini, G. Favi, F. Felluga, C. Forzato, F.
Mantellini, P. Nitti, E. Valentin, E. Zangrando, Tetrahedron: Asymmetry
2010, 21, 617-622.
1
m.p. 109-111 °C; H NMR (400.1 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz,
2H, Ar), 7.37 (d, J = 8.4 Hz, 2H, Ar), 7.33-7.29 (m, 2H, Ph), 7.21-7.19 (m,
2H, Ph), 7.01-6.99 (m, 1H, Ph), 6.86 (d, J = 7.3 Hz, 1H, H4), 5.17 (d, J =
7.3 Hz, 1H, H5), 2.40 (s, 3H, Me), 1.71-1.52 (m, 9H, Cy), 1.24-1.14 (m,
1H, Cy) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 151.1, 145.0, 137.8,
134.8, 129.4, 129.1, 128.5, 125.5, 122.0, 115.3, 105.4, 37.9, 34.8, 25.9,
21.3, 21.2 ppm; IR (film): νmax = 2927, 2856, 1643, 1597, 1495, 1448,
1329, 1286, 1250 cm-1; elemental analysis calcd (%) for C22H24N2: C
83.50, H 7.65, N 8.85; found: C 83.71, H 7.44, N 8.62.
[7]
[8]
a) E. G. Kovalev, I. Y. Postovskii, G. L. Rusinov, I. L. Shegal, Chem.
Heterocycl. Compd. 1981, 17, 1063-1076; b) A. M. Prokhorov, D. N.
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1-(2,5-Dimethylphenyl)-3-phenyl-2,3-diazaspiro[5.5]undeca-1,4-diene
(3ea): purification by Method A; yield 0.119 g, 72%; an orange oil; Rf =
0.89 (hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.42-
7.38 (m, 2H, Ph), 7.33-7.29 (m, 2H, Ph), 7.17-7.09 (m, 3H, Ar), 7.01-6.98
(m, 1H, Ph), 6.89 (d, J = 7.2 Hz, 1H, H4), 5.16 (d, J = 7.2 Hz, 1H, H5),
2.37 (s, 3H, Me), 2.24 (s, 3H, Me), 1.68-1.48 (m, 7H, Cy), 1.39-1.33 (m,
2H, Cy), 1.19-1.10 (m, 1H, Cy) ppm; 13C NMR (100.6 MHz, CDCl3): δ =
150.8, 145.2, 136.8, 134.5, 133.6, 130.2, 130.1, 129.1, 128.6, 126.0,
121.9, 115.3, 105.0, 38.7, 34.0, 25.9, 21.2, 21.1, 20.3 ppm; IR (film): νmax
= 2928, 2856, 1597, 1496, 1451, 1326, 1291 cm-1; elemental analysis
calcd (%) for C23H26N2: C 83.59, H 7.93, N 8.48; found: C 83.71, H 7.68,
N 8.28.
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3-(2-Furyl)-4,4-dimethyl-1,5-diphenyl-1,4-dihydropyridazine
(3fa):
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Chang, J. Org. Chem. 2016, 81, 8112-8120.
purification by Method A; yield 0.110 g, 67%; an orange oil; Rf = 0.87
(hexane/diethyl ether 1:1); 1H NMR (400.1 MHz, CDCl3): δ = 7.85 (d, J =
1.8 Hz, 1H, H5, Furyl), 7.49-7.47 (m, 2H, Ph), 7.40-7.35 (m, 7H, Ph),
7.08-7.05 (m, 1H, Ph),6.83-6.82 (m, 2H, H6, H3, Furyl), 6.49 (dd, J = 3.3,
1.8 Hz, 1H, H4, Furyl), 1.55 (s, 6H, Me) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 152.8, 144.3, 142.4, 141.0, 138.3, 130.3, 129.2, 128.0, 127.1,
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2016, 57, 3156-3159.
123.0, 122.5, 121.3, 115.5, 111.0, 110.5, 35.4, 26.8 ppm; IR (film): νmax
=
2969, 2923, 2873, 1645, 1596, 1552, 1496, 1331, 1258, 1224, 1172,
1037, 1010 cm-1; elemental analysis calcd (%) for C22H20N2O: C 80.46, H
6.14, N 8.53; found: C 80.34, H 6.25, N 8.62.
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Acknowledgements
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10.1002/ejoc.201700589
European Journal of Organic Chemistry
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Entry for the Table of Contents
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Dmitrii A. Shabalin, Marina Yu. Dvorko,
Evgeniya E. Zolotareva, Igor’ A.
Ushakov, Alexander V. Vashchenko,
Elena Yu. Schmidt, Boris A. Trofimov*
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Metal-Free Selective Synthesis of 1,4-
Dihydropyridazines from
Text for Table of Contents
Hydroxypyrrolines and Hydrazines
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