Cascade reactions of diazocarbonyl compounds with pyridinium aroylmethylides accompanied by water or benzoic acid elimination in the cyclocondensation step

Article abstract of DOI:10.1007/s11172-011-0056-4

The reaction of pyridinium aroylmethylides with diazocarbonyl compounds proceeds as a multistep process involving three ylide molecules and one diazo compound molecule. As a result, intermediate functionally substituted azines, if they contain carbonyl gr

Full text of DOI:10.1007/s11172-011-0056-4

Russian Chemical Bulletin, International Edition, Vol. 60, No. 2, pp. 345—351, February, 2011
345
Cascade reactions of diazocarbonyl compounds
with pyridinium aroylmethylides accompanied by water
or benzoic acid elimination in the cyclocondensation step
a
a
b
a
D. V. Dorokhov, D. N. Platonov, K. Yu. Suponitsky, and Yu. V. Tomilov
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6390. Eꢀmail: tom@ioc.ac.ru
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
8 ul. Vavilova, 119991 Moscow, Russian Federation
2
The reaction of pyridinium aroylmethylides with diazocarbonyl compounds proceeds as
a multistep process involving three ylide molecules and one diazo compound molecule. As
a result, intermediate functionally substituted azines, if they contain carbonyl groups and reacꢀ
tive methylene fragment, undergo intramolecular cyclocondensation to form triꢀ and tetrasubꢀ
stituted pyridazines. Depending on stereochemistry of cyclic ketols formed, water or benzoic
acid is eliminated to form tetraꢀ or trisubstituted pyridazines, respectively. The regularities of
reactions of pyridinium ylides with diazo compounds are discussed depending on the nature of
substituents in the both substrates and reaction conditions.
Key words: methyl diazoacetate, diazoacetophenone, pyridinium ylides, pyridazines, adꢀ
dition and elimination reactions, NMR spectra.
Pyridinium ylides containing the carbonyl or carboxyl
group at the ylidic carbon atom react with diazocarbonyl
compounds involving three ylide molecules in the reacꢀ
tion to form 1,4,5,6ꢀtetrahydropyridazineꢀ3,4,5,6ꢀtetraꢀ
cesses involving pyridinium ylides 1 and diazo compounds
containing carboxyl or carbonyl groups differ, as a rule, by
the heterocyclization step (Scheme 1). In the case of inꢀ
termediately formed diazadiene 2 containing four ester
groups, cyclization proceeds through the corresponding
1
,2
3,4
carboxylates or polysubstituted pyridazines. The proꢀ
Scheme 1
R = OMe (a), Me (b), Ph (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 338—344, February, 2011.
066ꢀ5285/11/6002ꢀ345 © 2011 Springer Science+Business Media, Inc.
1

346
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Dorokhov et al.
eneꢀhydrazone 3, in which the nucleophilic moiety of the
molecule attacks the electronꢀdeficient C atom of the double
bond to form tetrahydropyridazine tetracarboxylate 4
lower than that for tautomers 5c. This ratio did not change
with a change in the type of solvent; however, it changed
noticeably inside each pair of products, indicating that the
content of their tautomeric forms depends on the nature
of solvents used. Since we failed to isolate from this mixꢀ
ture the minor product in the analytically pure state beꢀ
(
see Ref. 1). If diazadiene 2 contains the conjugated carꢀ
bonyl group, cyclization proceeds directly at this group
and affords, after elimination of the H O molecule, tetraꢀ
2
substituted pyridazines 5 and/or 5´ (see Ref. 4 and Scheme 1).
Ylides were generated, as a rule, by the dehydrohalogeꢀ
nation of the corresponding pyridinium salts with wet poꢀ
tassium carbonate in acetonitrile. For the reaction of pyriꢀ
dinium benzoylmethylide (1c) with methyl diazoacetate
cause of close values of R , we attempted to increase the
f
yield of the minor compound by changing the reaction
conditions. It turned out that the desired result can easily
be achieved by using water as the main solvent. For inꢀ
stance, the dissolution of phenacylpyridinium bromide,
MDA, and potassium carbonate (molar ratio 3 : 1 : 6) in
a water—acetonitrile (10 : 1) mixture and storage of the
reaction mixture at 20 °С for 2 days gave the former minor
compound as the main product. Appropriate crystals of
the main compound were obtained by double recrystalliꢀ
zation from chloroform, and the structure of the comꢀ
pound was determined by Xꢀray diffraction analysis.
It turned out that the obtained compound was trisubꢀ
stituted pyridazine 6c that differs from pyridazine 5c by
the absence of the benzoyl substituent in position 4 of the
pyridazine cycle (Scheme 3). Moreover, a comparison of
(
MDA), we found along with the predominant formation
1
4
of pyridazine 5 (R = Ph, R = OMe) the presence of one
more compound, whose amount changed noticeably deꢀ
pending on the water content in the reaction mixture.
In the present work, we studied in detail the influence
of water on the composition of the reaction products of
some carbonylꢀcontaining ylides with MDA and with
diazoacetophenone and determined the structures of the
compounds formed.
Results and Discussion
We have earlier shown3,4 that the reaction of MDA
with pyridinium acetylmethylides in acetonitrile via the
dehydrobromination of acetonylꢀ or phenacylpyridinium
bromides by K CO containing ~20 mol.% H O affords
Scheme 3
2
3
2
substituted pyridazineꢀ3ꢀcarboxylates 5b,c in 65—71%
yields. Since position 6 of the pyridazine cycle of the both
compounds has the reactive methylene moiety, in soluꢀ
tion they exist as ketone and enol forms. According to the
1
13
Н and С NMR spectra, the enol form substantially
predominates in chloroform, whereas in DMSO the keꢀ
tone form prevails (Scheme 2).
Scheme 2
R = Me (b), Ph (c)
In the case of the reaction of MDA with pyridinium
1
ylide 1c, the Н NMR spectrum (CDCl ) of the reaction
3
mixture contains, along with singlet signals at δ 4.68 (CH2
group of the ketone form) and 5.77 (=CH group of the
4
enol form) corresponding to pyridazine 5c, singlets at
δ 4.77 and 5.89 with the total integral intensity fourfold
Ar = Ph (c), 4ꢀFC H4 (d), 4ꢀBrC H (e)
6
6 4

Triꢀ and tetrasubstituted pyridazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
347
a
b
C(16)
C(16)
O(3)
O(2)
C(22)
C(23)
O(3)
C(15)
C(3)
O(4)
C(18)
O(2)
C(15)
C(21)
C(20)
C(3)
C(5)
C(4) C(17)
N(2)
N(1)
C(19)
N(2)
N(1)
C(4)
C(17)
C(25)
C(5)
C(18)
C(26)
C(27)
C(19)
C(20)
C(24)
C(7)
C(6)
H(1)
O(1)
C(6)
C(7)
C(28)
O(1)
C(22)
C(29)
C(21)
C(8)
C(8)
C(9)
C(9)
C(14)
C(13)
C(14)
C(13)
C(10)
C(11)
C(10)
C(11)
C(12)
C(12)
Fig. 1. General view of molecules 5c (a) and 6c (b) in representation of atoms as thermal ellipsoids (р = 50%).
the С(6)—С(7) and С(7)—С(8) bond lengths showed that
in single crystal trisubstituted pyridazine 6c exists in the
enamine form (Fig. 1, b, Table 1), whereas tetrasubstiꢀ
tuted pyridazine 5c exists in the enol form (Fig. 1, a,
Table 1). The Xꢀray diffraction data for crystals of both
pyridazines showed that in molecule 5c the С(6)—С(7)
bond is longer than the С(7)—С(8) bond, while an oppoꢀ
site dependence is observed for molecule 6c.
bromination of acetonylpyridinium bromide with K CO
2 3
in a water—acetonitrile (9 : 1) mixture did not result in the
formation of trisubstituted pyridazine and, moreover,
3
pyridazine 5b described earlier was formed in 10—12%
yield only. It is most likely that pyridinium acetylmethylꢀ
ide 1b is much more easily hydrolyzed with water than
ylide 1c and has no time to react with diazo compound.
Then we studied the reaction of MDA with pꢀsubstiꢀ
tuted pyridinium benzoylmethylides 1d,e generated by deꢀ
hydrobromination of the corresponding phenacylpyridinꢀ
ium bromides with K CO . Acetonitrile or water containꢀ
Unlike the solid phase, in solution both pyridazines 5c
and 6c exist as the corresponding mixtures of the ketone
and enol forms, whose ratio is determined by the nature of solꢀ
2
3
1
13
vents used. The H and C NMR spectra exhibit a correlaꢀ
tion of chemical shifts and integral intensities of signals of
the protons and carbon atoms in the fragments COCH2
and (HO)C=CH for each pair of tautomers (Table 2).
We did not observe an analogous process leading to the
formation of trisubstituted pyridazines in the case of pyriꢀ
dinium acetylmethylide 1a. An attempt to carry out the
reaction of MDA with ylide 1b generated by the dehydroꢀ
ing ~10% acetonitrile were used to provide solubility of
the reactants. As should be expected, for the reaction in
acetonitrile the major reaction products were tetrasubstiꢀ
tuted pyridazines 5d or 5e (see Scheme 3 and Table 3),
which were isolated (purity >95%) by double recrystalliꢀ
zation from methanol.
When the reaction was carried in water, unlike unsubsꢀ
tituted pyridinium benzoylmethylide 1c, although the
amount of trisubstituted pyridazines 6d,e increased but
insignificantly (see Table 3), which did not allow us to
separate them completely from tetrasubstituted pyridazines
5d,e. The structures of pyridazines 6d,e were determined
Table 1. Bond lengths in molecules of pyridꢀ
azines 5c and 6c
1
13
by the Н and С NMR spectra, subtracting the signals of
pyridazines 5d or 5e, respectively, and comparing the reꢀ
mained signals with the signals of pyridazine 6c. In soluꢀ
tion both tetraꢀ (5d,e) and trisubstituted pyridazines 6d,e
exist as ketoꢀenol tautomers, the equilibrium between
which in chloroform is shifted to enol forms (see Table 2).
Bond
d/Å
5
c
6c
C(6)—C(7)
C(7)—C(8)
N(1)—C(6)
N(1)—N(2)
C(8)—O(1)
1.442(2)
1.368(2)
1.354(2)
1.338(1)
1.338(2)
1.389(3)
1.412(3)
1.369(2)
1.347(2)
1.278(2)
4
As mentioned earlier, the formation of pyridazine 5
proceeds via successive addition of three molecules of ylide 1
to a diazo ester molecule. As a result, diazadiene 2 formed

348
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Dorokhov et al.
Table 2. Chemical shifts of the key signals of the ketone and enol forms of triꢀ and tetrasubstituted pyridazines in the Н and 13С NMR
1
spectra (CDCl3)
Comꢀ Ketone : enol
pound
1Н NMR, δ
13С NMR, δ
Ketone
CH2 H(4) OMe
Enol
Ketone
Enol
=CH =C(OH) HC(4)
=CH H(4) OMe
CH2 HC(4) C(6)
C(6)
5
6
6
5
6
5
6
c (Ref. 4) 1 : 4
4.68
—
3.91
5.77
—
3.88
44.5
—
157.1
89.2
88.1
87.6
88.5
87.3
88.9
87.6
178.7
179.8
178.6
179.2
180.2
178.4
179.4
—
156.8
156.1
156.2
155.2
155.3
156.4
155.5
c
1 : 5
1 : 1.4
1 : 5.5
1 : 7.3
1 : 7.2
1 : 8
4.81 8.10 4.09
4.90 8.02 3.97
4.65
4.77 8.08 4.08
4.63 3.98
4.77 8.08 4.10
6.16 7.73 4.02
6.07 7.68 3.91
5.65
6.01 7.67 4.03
5.67 3.90
6.04 7.69 4.06
44.4 127.7 158.8
44.6 127.9 159.4
44.4
44.3 128.0 158.8
44.4 159.4
44.2 126.2 159.1
126.1
126.9
—
126.2
—
c*
d
—
3.95
—
3.89
—
156.9
d
e
e
—
—
—
126.3
*
Spectra in (CD ) SO.
3 2
undergoes cyclization of the aldol condensation type. The
cyclization can afford two diastereomeric ketols or their
anions 7 and 8 (see Scheme 3), which are responsible for
the formation of substituted pyridazines 5 and 6 due to the
elimination of water or benzoic acid.
intramolecular cyclocondensation of 5ꢀmethylꢀ1,3,5,7ꢀ
tetraphenylheptꢀ2ꢀeneꢀ1,7ꢀdione to 5ꢀmethylꢀ1,3,5ꢀtriꢀ
phenylcyclohexaꢀ1,3ꢀdiene.
4
It has been shown earlier that the reaction of pyridinꢀ
ium benzoylmethylide 1c with diazoacetophenone in
acetonitrile (the amount of water in the reaction mixture
did not exceed 5%) affords only 3,4ꢀdibenzoylꢀ6ꢀphenꢀ
acylꢀ5ꢀphenylpyridazine 10, which exists in solution as
ketoꢀenol tautomers. Unlike the reaction with methyl
diazoacetate, performing the same reaction in a waꢀ
ter—acetonitrile mixture (volume ratio 9 : 1) exerts no
principal effect on the formation of pyridazine 10, but the
Since we could not observe ketol formation in the reacꢀ
tion mixture, it is difficult to make certain conclusions
about the step of their aromatization to pyridazines. Howꢀ
ever, taking into account that the cyclization of the anion
of triketones 2c—e leads to the generation of stereoisoꢀ
meric anions 7 and 8, we may assume that the formed
nucleophilic oxygen atom will further attack the neighꢀ
boring proton (isomer 7) or benzoyl group (isomer 8) folꢀ
lowed by the cisꢀelimination of hydroxyl or benzoate and
the formation of tetraꢀ or trisubstituted pyridazines 5 or 6.
Meanwhile, if ketols themselves are formed due to cyclizaꢀ
tion, their deprotonation will give the same anions 9c—e,
from which only tetrasubstituted pyridazines 5c—e are
formed after hydroxyl group elimination. Indeed, pyridꢀ
azines 5c—e are the major reaction products in most cases.
Thus, the composition of the final pyridazines can depend on
both stereochemistry of the intermediate ketols and diverse
variants of their aromatization, which is determined, to
a certain extent, by the nature (polarity) of solvents used.
The possibility of elimination of benzoic acid moleꢀ
1
13
Н and С NMR spectra make it possible, in this case, to
observe also the formation of trisubstituted pyridazine 11,
whose yield is 5—6% (Scheme 4). In a CDCl solution,
3
Scheme 4
5
cule instead of H O has earlier been established for the
2
Table 3. Yields and the ratio of pyridazines 5c—e and 6c—e
depending on the solvent nature
Product
Ar
Solvent
Yield
Ratio
(%)
5 : 6
5
5
5
c + 6c
d + 6d
e + 6e
Ph
MeCN
70
73
69
72
68
70
0.4 : 1
0.1 : 3.9
5.3 : 1
2.8 : 1
0.5 : 1
1.9 : 1
H O
2
4ꢀC H F
MeCN
6
4
H O
2
4ꢀC H Br
MeCN
6
4
H O
2

Triꢀ and tetrasubstituted pyridazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
349
pyridazine 11, as well as pyridazine 10, exists as ketone
and enol forms in a ratio of ~1 : 6.
Table 4. Selected crystallographic data for pyridazines 5c and 6c
Thus, we showed that the cascade reactions of pyridinꢀ
ium benzoylmethylides with methyl diazoacetate and
diazoacetophenone afford not only tetrasubstituted pyridꢀ
azines (due to water elimination from intermediate ketols
in the step of cyclocondensation), but also trisubstituted
pyridazines, viz., products of elimination of benzoic acids,
which is determined, most likely, by both different stereoꢀ
chemistry of formed cyclic ketols and different modes of
their aromatization.
Parameter
5c
6c
C20H N O
3
332.35
100(2)
Triclinic
Pꢀ1
Molecular formula
Molecular weight
Т/К
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
C27H20N O
2
4
16
2
436.45
100(2)
Triclinic
Pꢀ1
9.9116(11)
7.4968(10)
10.5403(12)
12.2947(13)
65.012(2)
89.898(2)
67.270(2)
1053.6(2)
2
1.376
0.93
456
1.86—28.99
10.3702(14)
10.7176(15)
78.362(3)
85.591(3)
74.434(3)
785.93(19)
2
1.404
0.96
348
1.94—28.43
Experimental
γ/deg
3
V/Å
Z
1Н and 13С NMR spectra were recorded on Bruker AVANCE
II 300 (300 and 75.5 MHz) and Bruker DRXꢀ500 (500 MHz and
–
3
dcalc/g cm
μ/cm
F(000)
–
1
1
25.3 MHz, respectively) spectrometers for CDCl solutions conꢀ
3
taining 0.05% Me Si as an internal standard. Mass spectra were
4
Scan range,
obtained on a Finnigan MAT INCOSꢀ50 instrument (EI, 70 eV,
direct inlet). Thin layer chromatography was carried out on Siliꢀ
cagel 60 (Merck) plates with development in an iodine chamber.
Column chromatography (silica gel 60, 0.040—0.063 mm,
Merck) was used for preparative separation. Solvents were disꢀ
tilled prior to use. Diazoacetophenone was synthesized accordꢀ
ing to a standard procedure by treatment of benzoyl chloride
θ/deg
Number of measured
reflections
Number of independent
reflections
Rint
Number of refined
parameters
Number of reflections
with I ≥ 2σ(I)
Completeness of reflection
array (%)
12574
5552
9032
3919
0.0225
299
0.0683
227
6
,7
with diazomethane.
4ꢀHalosubstituted phenacylpyridinium
bromides were synthesized by quaternization of pyridine by the
corresponding αꢀbromoꢀ4ꢀfluoroꢀ or ꢀbromoacetophenones in
acetone.8 Methyl 4ꢀbenzoylꢀ6ꢀbenzoylmethylꢀ5ꢀphenylpyridꢀ
4480
99.1
1883
99.4
4
azineꢀ3ꢀcarboxylate (5c) was synthesized by us earlier.
Xꢀray diffraction studies of pyridazines 5c and 6c were carꢀ
ried out on a SMART APEX II CCD diffractometer (MoKαꢀ
radiation, graphite monochromator, ω scan mode) at 100 K.
The starting arrays of measured intensities were processed using
GOOF
1.036
0.0426
0.965
0.0549
a
R (F) on reflections
1
with I ≥ 2σ(I)
2
b
wR (F ) on all reflections
0.1124
0.475/–0.247
0.1060
0.234/–0.219
9
2
the APEX2 program. The structures were solved by a direct
Residual electron density
method and refined by fullꢀmatrix least squares in the anisotroꢀ
pic approximation for nonꢀhydrogen atoms on F2hkl. Hydrogen
atoms were placed in geometrically calculated positions, except
for the hydrogen atoms at the nitrogen and oxygen atoms, whose
positions were localized from the difference electron density
synthesis and then were normalized to the distance 0.90 Å for the
N atoms and 0.85 Å for the O atoms. All hydrogen atoms were
min/max)/e•Å–
3
(
a
b
R = ∑|F – |F ||/∑(F );
1
o
c
o
2
2 2
2 2 1/2
wR = (∑[w(F – F ) ]/∑[w(F ) ]
2
o
c
o
.
Target pyridazines 5c—e were isolated as orange crystals by douꢀ
ble recrystallization from methanol.
refined using the riding model (Uiso(H) = nU (C,N), where
eq
n = 1.5 for the carbon atoms of the methyl groups, n = 1.2 for
other C atoms and nitrogen atoms). The structures were decodꢀ
ed and refined using the SHELXTL program.10 Selected crystalꢀ
lographic data and refinement parameters are listed in Table 4.
Methyl 4ꢀaroylꢀ6ꢀaroylmethylꢀ5ꢀarylpyridazineꢀ3ꢀcarboxyꢀ
lates (5c—e) (general procedure). Potassium carbonate (1.04 g,
Methyl 4ꢀ(4ꢀfluorobenzoyl)ꢀ6ꢀ(4ꢀfluorobenzoyl)methylꢀ5ꢀ(4ꢀ
fluorophenyl)pyridazineꢀ3ꢀcarboxylate (5d). A mixture of pyridꢀ
azines 5d and 6d in the molar ratio 5.3 : 1 were obtained from
4ꢀfluorophenacylpyridinium bromide (0.89 g, 3 mmol) and meꢀ
thyl diazoacetate (0.10 g, 1 mmol) in acetonitrile (see Table 3).
Recrystallization from methanol gave 0.25 g (52%) of pyridazine
5d, m.p. 195—197 °С. Found (%): C, 65.88; H, 3.50; N, 5.82.
C H F N O . Calculated (%): C, 66.12; H, 3.49; N, 5.71.
6
mmol) containing ~20 wt.% water was added to a solution of
methyl diazoacetate (100 mg, 1 mmol) and 4ꢀfluoroꢀ or 4ꢀfluoꢀ
rophenacylpyridinium bromide (3 mmol) in acetonitrile (30 mL)
with vigorous stirring for 16 h at 20 °С. Then the reaction mixꢀ
ture was evaporated to 1/3 of the starting volume, water (50 mL)
was added, extracted with CH Cl (3×30 mL), and dried with
2
7
17
3
2
4
1
H NMR (CDCl ), δ: enol form (85%): 3.89 (s, 3 Н, ОМе); 5.65
3
(s, 1 Н, =СН); 7.02, 7.11, and 7.65 (all m, 3 C H ); 15.9 (br.s,
6
4
1 Н, ОН); ketone form (15%): 3.95 (s, 3 Н, ОМе); 4.65 (s, 2 Н,
3
3
СН ); 6.86 (br.dd, 2 Н, 2 Н , J
≈ J
= 8.7 Hz); 7.59 and
H,F
2
2
2
m
H,H
3
4
anhydrous MgSO . The solvent was removed in vacuo, the resiꢀ
7.90 (both m, 2 Н each, 4 H , J
= 8.7 Hz, J
= 5.5 Hz);
4
o
H,H
H,F
due was washed with methanol (15 mL), and the obtained prodꢀ
uct was analyzed using Н and С NMR spectroscopy (the total
other signals from aromatic protons lie in the range of signals of
1
13
13
the protons of the enol form. C NMR (CDCl ), δ: enol form:
3
yield and the ratio of pyridazines 5 and 6 are given in Table 3).
53.5 (OMe); 88.5 (=СН); 115.6, 116.1 and 116.3 (all d, Сm,

350
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Dorokhov et al.
2JC,F ≈ 22.0); 126.9, 132.5 and 133.4 (all д, С , 4JC,F ≈ 3.0);
СН ); 8.08 (s, 1 Н, Н(4)); 7.10—7.90 (m, 2 Ph of both tautoꢀ
i
2
3
13
1
1
1
29.2, 131.2 (br.s) and 131.4 (all d, С , J
≈ 9.0); 136.6 and
mers). C NMR (CDCl ), δ: enol form: 53.0 (OMe); 88.1 (=СН);
o
C,F
3
37.8 (C(4) and С(5)); 140.3 (С(3)); 155.2 (С(6)); 163.0 (COO);
63.1, 164.7, and 166.0 (all d, С , J = 248—254); 179.2
126.1 (С(4)); 126.7, 128.2, 128.3, and 129.1 (С and С ); 129.7
o
m
and 130.8 (C ); 134.8 and 137.8 (C ); 140.5 (С(5)); 143.0 (С(3));
p
C,F
p
i
(
1
1
(
1
=COH); 190.5 (C=O); ketone form: 44.4 (CH ); 53.7 (OMe);
156.1 (С(6)); 163.6 (COO); 179.8 (=COH); ketone form: 44.4
2
2
15.8, 116.1, and 116.4 (all d, С , J
≈ 20); 132.4, 133.2, and
(CH ); 53.1 (OMe); 127.7 (С(4)); 126.8, 128.6, 128.9, and 129.3
m
C,F
2
4
34.2 (all d, С , J
≈ 2.9 Hz); 131.0, 131.2 (br.s) and 131.5
(С and С ); 130.7 and 133.4 (C ); 133.3 and 136.2 (C ); 141.9
i
C,F
o
m
p
i
3
all d, С , J
≈ 9.0 Hz); 136.7 and 138.2 (C(4) and С(5));
C,F
(С(5)); 150.8 (С(3)); 158.8 (С(6)); 164.5 (COO); 194.5 (C=O);
o
13
47.2 (С(3)); 156.9 (С(6)); 163.0, 164.5 and 166.1 (all d, Сp,
C NMR (DMSOꢀd ), δ: enol form: 53.2 (OMe); 87.6 (=СН);
6
J
= 248—254 Hz); 164.5 (COO); 190.6 and 194.0 (C=O).
126.1 (С(4)); 126.7, 128.9, 129.0 and 129.6 (С and С ); 130.2
o m
and 131.4 (C ); 134.6 and 137.6 (C ); 140.4 (С(5)); 144.0 (С(3));
p i
156.2 (С(6)); 163.3 (COO); 179.0 (=COH); ketone form: 44.6
C,F
9
1
F NMR (282 MHz, CDCl ): enol form: –103.6, –109.0, and
3
3
4
–
110.7 (all tt, 1 F each, J
≈ 8.7 Hz, J
≈ 5.5 Hz); ketone
H,F
H,F
3
form: –103.5, –104.2, and –111.3 (all tt, 1 F each, J
≈ 8.7 Hz,
(CH ); 53.4 (OMe); 127.9 (С(4)); 128.5, 128.8, 129.2, and 129.3
H,F
2
4
JH,F ≈ 5.5 Hz).
(С and С ); 129.6 and 134.0 (C ); 135.6 and 136.5 (C ); 141.6
o
m
p
i
Methyl 4ꢀ(4ꢀbromobenzoyl)ꢀ6ꢀ(4ꢀbromobenzoyl)methylꢀ5ꢀ(4ꢀ
bromophenyl)pyridazineꢀ3ꢀcarboxylate (5e). A mixture of pyridꢀ
azines 5e and 6e in the molar ratio 5 : 1 was obtained from
(С(5)); 150.8 (С(3)); 159.4 (С(6)); 164.5 (COO); 196.8 (C=O).
Reaction of methyl diazoacetate with 4ꢀfluorophenacylpyriꢀ
dinium bromide in an aqueous solution. A solution of methyl diazoꢀ
acetate (1.56 g, 9 mmol) in acetonitrile (2 mL) was added to
a solution of 4ꢀfluorophenacylpyridinium bromide (1.33 g,
4.5 mmol) in water (18 mL), and potassium carbonate (1.56 g,
9 mmol) containing 20% water was added. The reaction mixture
was stirred for 15 h at 20 °С, then extracted with ethyl acetate
4
ꢀbromophenacylpyridinium bromide (1.07 g, 3 mmol) and meꢀ
thyl diazoacetate (0.10 g, 1 mmol) (see Table 3). Recrystalliꢀ
zation from methanol gave 0.36 g (54%) of pyridazine 5e,
m.p. 214—216 °С. Found (%): C, 47.89; H, 2.67; N, 4.48.
C H Br N O . Calculated (%): C, 48.18; H, 2.55; N, 4.16.
2
7
17
3
2
4
1
H NMR (CDCl ), δ: enol form (88%): 3.90 (с, 3 Н, ОМе); 5.67
s, 1 Н, =СН); 7.00 (br.d, 2 Н, 2 Н , J = 8.2 Hz); 7.32—7.58
m, 2 C H and 2 Н ); 15.9 (br.s, 1 Н, ОН); ketone form (12%):
(3×20 mL), and dried with anhydrous MgSO . The solvents were
3
4
3
(
(
removed in vacuo, the solid residue was washed with methanol
(2 mL) at 0 °С, and 0.50 g of a mixture of pyridazines 5d and 6d
m
6
4
o
1
13
3
.98 (s, 3 Н, ОМе); 4.63 (s, 2 Н, СН ); 6.91 (br.d, 2 Н, 2 Н ,
were obtained, which were analyzed by Н and С NMR specꢀ
troscopy (the total yield and the ratio of pyridazines 5d and 6d
are given in Table 3). Then double recrystallization from chloroꢀ
form gave orangeꢀyellow crystals enriched in trisubstituted pyridꢀ
azine 6d to ~65%. Methyl 6ꢀ(4ꢀfluorobenzoyl)methylꢀ5ꢀ(4ꢀ
fluorophenyl)pyridazineꢀ3ꢀcarboxylate (6d) was identified by the
2
m
3
13
J = 8.2 Hz); 7.32—7.58 (m, 2 C H4 and 2 Н ). C NMR
6
o
(
CDCl ), δ: enol form: 53.5 (OMe); 88.9 (=СН); 124.3, 126.1,
3
and 129.4 (С ); 128.4, 130.0, 130.7 (br.s); 131.8, 132.1, and 132.3
p
(
С and С ); 129.8, 134.9, and 135.8 (С ); 136.4 and 137.7 (C(4)
o
m
i
and С(5)); 140.6 (С(6)); 156.4 (С(3)); 163.1 (COO); 178.4
=COH); 190.8 (C=O); ketone form: 44.4 (CH ); 53.7 (OMe);
1
13
(
H and C NMR spectra by subtracting the signals of the deꢀ
2
1
1
1
24.4, 126.2, and 129.6 (С ); 128.4, 129.8, 130.1, 130.7 (br.s);
scribed above pyridazine 5d. H NMR (CDCl ), δ: enol form
p
3
31.9 and 132.4 (С and С ); 130.2, 134.7, and 135.7 (С ); 136.2
(88%): 4.03 (s, 3 Н, ОМе); 6.01 (s, 1 Н, =СН); 7.00—7.29
(m, 6 Н, 4 H and 2 H ); 7.48 and 7.77 (both dd, 2 Н each, 4 H ,
o
m
i
and 137.5 (C(4) and С(5)); 145.0 (С(3)); 159.4 (С(6)); 163.3
m
p
o
(
COO); 190.7 and 193.0 (C=O).
JH,H = 8.9 Hz, JH,F = 5.6 Hz); 7.67 (s, 1 Н, Н(4)); 16.2 (ОН);
Methyl 6ꢀbenzoylmethylꢀ5ꢀphenylpyridazineꢀ3ꢀcarboxylate
6c). A solution of methyl diazoacetate (0.50 g, 5 mmol) in acetoꢀ
ketone form (12%): 4.08 (s, 3 Н, ОМе); 4.77 (s, 2 Н, СН );
2
(
7.00—7.31 (m, 6 Н, 4 Hm and 2 H ); 7.56 and 7.95 (both dd,
p
nitrile (11 mL) was added to a solution of phenacylpyridinium
bromide (4.17 g, 15 mmol) in water (100 mL), and potassium
carbonate (6.90 g, 50 mmol) containing 20% water was added by
portions of 1—1.5 g with stirring, waiting for the complete dissoꢀ
lution of each portion. The reaction mixture was stirred for 15 h
at 20 °С, extracted with ethyl acetate (3×50 mL), and dried with
2 Н each, 4 H , J
Н(4)). C NMR (CDCl ), δ: enol form: 53.3 (OMe); 87.3
(=СН); 115.5 and 116.5 (both d, С , J
(C(4)); 129.1 and 130.3 (both d, С , J
= 8.8 Hz, JH,F = 5.5 Hz); 8.08 (s, 1 Н,
o
H,H
1
3
3
2
≈ 21.5 Hz); 126.2
m
3
C,F
= 8.6 Hz); 131.7 and
C,F
o
4
133.2 (both d, С , J
≈ 3.0 Hz); 139.9 С(5)); 142.5 (С(3));
i
C,F
155.3 (С(6)); 163.5 (COO); 163.6 and 166.1 (both d, С , J
=
p
C,F
anhydrous MgSO . The solvents were removed in vacuo, the
= 250—254 Hz); 180.2 (=COH); ketone form: 44.3 (CH ); 53.6
4
2
2
solid residue was treated with hot methanol (15 mL), and cooled,
and an orange finely crystalline precipitate was filtered off. The
filtrate was evaporated to half a volume and cooled to –5 °С and
the precipitate formed was joined with the previous portion of
(OMe); 115.8 and 116.2 (both d, С , JC,F ≈ 21 Hz); 128.0
m
4
(С(4)); 133.2 and 134.2 (both d, С , J
≈ 3.0 Hz); 130.8 and
i
C,F
3
131.6 (both d, С , J
≈ 9.0 Hz); 138.2 С(5)); 147.2 (С(3));
o
C,F
158.8 (С(6)); 164.5 and 166.1 (both d, С , J
≈ 250 Hz); 164.5
C,F
p
1
19
the precipitate. The obtained product was analyzed by Н and
(COO); 194.3 (C=O). F NMR (282 MHz, CDCl ): enol form:
3
13
3
4
С NMR spectroscopy (the total yield and the ratio of pyridꢀ
–109.6 and –110.9 (both tt, 1 F each, J ≈ 8.7 Hz, J ≈ 5.5 Hz);
H,F H,F
3
azines 5c and 6c are given in Table 3). Then trisubstituted pyridꢀ
azine 6c was isolated as yellow crystals by double recrystallizaꢀ
tion from chloroform, m.p. 149—151 °С. Found (%): C, 72.64;
H, 4.91; N, 8.20. C20H16N O . Calculated (%): C, 72.28;
ketone form: –104.6 and –111.8 (both tt, 1 F each, J
≈ 8.6 Hz,
H,F
4
JH,F ≈ 5.5 Hz).
Reaction of methyl diazoacetate with 4ꢀbromophenacylꢀ
pyridinium bromide in an aqueous solution. Similarly to the previꢀ
ous experiment, the reaction of 4ꢀbromophenacylpyridinium broꢀ
mide (1.07 g, 3 mmol) and methyl diazoacetate (0.10 g, 1 mmol)
2
3
+
+
H, 4.85; N, 8.43. MS, m/z (I (%)): 332 [M] (3), 255 [М – Ph]
5), 227 [M – COPh]+ (10), 195 (7), 167 (15), 105 (100).
H NMR (CDCl ), δ: enol form (84%): 4.02 (s, 3 Н, ОМе); 6.16
rel
(
1
in an H O—MeCN mixture (14 mL, 9 : 1) afforded 0.61 g of
3
2
(
s, 1 Н, =СН); 7.73 (s, 1 Н, Н(4)); 7.37—7.55 (m, 2 Ph of both
a mixture of pyridazines 5e and 6e, which were analyzed using
the Н and С NMR spectra (the total yield and the ratio of
1
13
tautomers); 7.74 (d, 2 H, J = 7.9 Hz, H of one of Ph); 16.2
o
(
ОН); ketone form (16%): 4.09 (s, 3 Н, ОМе); 4.81 (s, 2 Н,
pyridazines 5e and 6e are listed in Table 3). Methyl 6ꢀ(4ꢀbromoꢀ

Triꢀ and tetrasubstituted pyridazines
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
351
benzoyl)methylꢀ5ꢀ(4ꢀbromophenyl)pyridazineꢀ3ꢀcarboxylate
pyridazine ring and phenyl groups); 158.8 (С(6)); 191.8, 193.8,
and 196.0 (C=O); enol form: 88.9 (=CH); 127.0—139.5 (C atoms
of pyridazine ring and phenyl groups); 147.6 (C(3); 153.9 (С(6));
182.0 (=COH); 189.6 and 193.4 (C=O).
1
13
(
6e) was identified by the H and C NMR spectra, subtracting
1
the signals of above described pyridazine 5e. H NMR (CDCl ),
3
δ: enol form (89%): 4.06 (s, 3 Н, ОМе); 6.04 (s, 1 Н, =СН); 7.36
and 7.69 (both d, 2 Н each, 2 Н and 2 Н , J = 8.3 Hz); 7.52 and
o
m
7
.62 (both d, 2 Н each, 2 Н and 2 Н , J = 8.4 Hz); 7.69 (s, 1 Н,
o m
References
H(4)); 16.2 (ОН); ketone form (11%): 4.10 (s, 3 Н, ОМе); 4.77
s, 2 Н, СН ); 7.25—7.70 (m, 8 Н, 2 C H ); 8.08 (s, 1 Н, Н(4)).
(
2
6
4
1
3
1. Yu. V. Tomilov, D. N. Platonov, D. V. Dorokhov, O. M.
Nefedov, Izv. Akad. Nauk, Ser. Khim., 2005, 984 [Russ. Chem.
Bull., Int. Ed., 2005, 54, 1008].
. Yu. V. Tomilov, D. N. Platonov, D. V. Dorokhov, I. V.
Kostyuchenko, Izv. Akad. Nauk, Ser. Khim., 2006, 108 [Russ.
Chem. Bull., Int. Ed., 2006, 55, 112].
. Yu. V. Tomilov, D. N. Platonov, D. V. Dorokhov, O. M.
Nefedov, Tetrahedron Lett., 2007, 48, 883.
. Yu. V. Tomilov, D. N. Platonov, D. V. Dorokhov, A. A.
Zhalnina, Izv. Akad. Nauk, Ser. Khim., 2008, 1228 [Russ.
Chem. Bull., Int. Ed., 2008, 57, 1252].
. D. Iwanov, T. Iwanov, Chem. Ber., 1944, 77, 173.
. F. Arndt, J. Amende, Chem. Ber., 1928, 61, 1124.
. W. Breadley, R. Robinson, J. Chem. Soc., 1928, 1301.
. L. N. Yakhontov, M. F. Marshalkin, in Sintezy geterotsikliꢀ
cheskikh soedinenii [Syntheses of Heterocyclic Compounds],
Erevan, 1979, vol. 11, p. 21 (in Russian).
9. APEX2 and SAINT, Bruker AXS, Inc., Madison (WI),
USA, 2005.
10. G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystalꢀ
logr., 2008, 64, 112.
C NMR (CDCl ), δ: enol form: 53.3 (OMe); 87.6 (=СН); 125.8
3
and 129.3 (С ); 126.3 (C(4)); 128.4, 130.0, 131.7 and 132.6
p
(
С and С ); 133.5 and 136.6 (С ); 139.6 С(5)); 142.9 (С(3));
o m i
2
1
55.5 (С(6)); 163.1 (COO); 179.4 (=COH); ketone form: 44.2
(
CH ); 53.5 (OMe); 124.2 and 128.3 (С ); 126.3 (С(4)); 129.9,
2 p
30.3, 131.8, and 132.2 (С and С ); 133.3 and 136.8 (С ); 137.0
o m i
1
3
4
С(5)); 145.0 (С(3)); 156.4 (С(6)); 163.2 (COO); 193.3 (C=O).
,4ꢀDibenzoylꢀ6ꢀphenacylꢀ5ꢀphenylpyridazine (10) and
ꢀbenzoylꢀ6ꢀphenacylꢀ5ꢀphenylpyrazine (11). Diazoacetophenone
0.15 g, 1 mmol) in acetonitrile (2 mL) was added to a solution of
3
3
(
phenacylpyridinium bromide (0.84 g, 3 mmol) in water (18 mL)
and then potassium carbonate (1.40 g, 8 mmol) containing 20%
water was added. The mixture was stirred for 48 h at 20 °С and
5
6
7
8
extracted with CH Cl2 (3×20 mL). The solvent was removed
2
in vacuo and the residue was washed with methanol (8 mL).
A mixture of compounds 10 and 11 in the ratio ~12 : 1 was
obtained in a yield of 0.33 g (~70%) as an orange finely crysꢀ
1
talline powder. Minor product 11 was identified by Н and
13
С NMR spectroscopy, subtracting the signals of pyridazine 10
see Ref. 4). 1Н NMR (СDCl ), δ: ketone form (15%): 4.77
s, 2 Н, СН ); 7.10—7.80 (m, 4 Ph of both tautomers); 7.86 and
(
(
3
2
3
8
5
.18 (both br.d, 4 Н, H (2 Ph), J = 8.0 Hz); enol form (85%):
o
.89 (s, 1 Н, СН); 7.10—7.80 (m, 4 Ph of both tautomers); 8.09
3
13
(
(
br.d, 2 Н, H , J = 8.2 Hz); 11.9 (br.s, 1 Н, ОН). С NMR
СDCl ): ketone form: 44.4 (СН ); 127.0—139.5 (C atoms of
Received October 12, 2010;
in revised form December 21, 2010
o
3
2