Diaza-wittig reactions of diketoesters phosphazines: Synthesis of tetrasubstituted fluoroalkyl-containing pyridazines

Full text of DOI:10.1134/S1070428011080240

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 8, pp. 1252−1255. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © M.B. Supurgibekov, N.S. Yanyuk, V.A. Nikolaev, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 8, pp. 1232−1235.
SHORT
COMMUNICATIONS
diaza-Wittig Reactions of Diketoesters Phosphazines:
Synthesis of Tetrasubstituted Fluoroalkyl-Containing Pyridazines
M. B. Supurgibekov, N. S. Yanyuk, and V. A. Nikolaev
St. Petersburg State University, St. Petersburg,198504 Russia
e-mail: vnikola@VN6646.spb.edu
Received January 28, 2011
DOI: 10.1134/S1070428011080240
diketones IIc, IId. In the preparation of the phosphazines
from diazoketoesters I we applied the triphenylphosphine
(IIIа) commonly used in the Staudinger reaction [11–13]
and more nucleophilic [14] tris(dimethylamino)phosphine
(IIIb).
Pyridazines attract much attention due to their biologi-
cal activity [1], some of them are used in the treatment
of Parkinson, Alzheimer, and other neurodegenerative
diseases [2, 3]. Therefore the development of new meth-
ods of preparation of this class compounds is an urgent
problem of the synthetic organic chemistry.
The reaction of diazoketoesters Iа, Ib with ketoester
IIа was carried out similarly to procedure [10] using PPh3.
It presumably proceeded with the intermediate forma-
tion of triphenylphosphazines IVа, IVb and was of low
efficiency. The monitoring of the reaction progress by
1Н NMR spectroscopy showed that under these conditions
a fairly complex mixture of products formed containing
alongside the target compounds also a diazoacetic ester
phosphazine and the other reaction products, and accord-
ing to the data of 1Н NMR spectrum of the reaction mix-
ture the yield of pyridazines V did not exceed 30–32%.
In keeping with published reports 3,4,6-trisubstituted
pyridazines can be synthesized in good yields from
2-vinyl derivatives of 2-diazoketones by the intramo-
lecular diaza-Wittig reaction [4–9]. The only example
of the synthesis of the tetrasubstituted pyridazine with
the use of analogous procedure was described in [10],
where by the diaza-Wittig reaction of the posphazine of
4-diazopyrrolidinetrione with ethyl acetoacetate bicyclic
pyrrolo[3,4-c]pyridazine was obtained.
The aim of our study was the elucidation of the pos-
sibility to obtain 3,4,5,6-tetrasubstituted pyridazines by
the intermolecular diaza-Wittig reaction of phosphazines
of acyclic diazoketoesters with 1,3-diketones and ke-
toesters .
CO2Me
F3C
O
N
F3C
CF3
CH2Cl2
Iа, Ib
+
PPh3
PPh3 IIa
_H2O,
N
N
RO2C
RO2C
N
_O PPh3
We used as diazo substrates methyl and ethyl
2-diazo-3-oxo-4,4,4-trifluorobutanoates (Iа, Ib), аnd
as 1,3-dicarbonyl compounds ketoesters IIa, IIb and
IVа, IVb
Vа, Vb
The relatively low yield of pyridazines V and the
occurrence of the side processes in the reaction with
the use of the triphenylphosphine is apparently due to
the ready dissociation of the triphenylphosphazines IV
formed in the first stage into the initial components, PPh3
and diazoketoesters I [5, 12, 13]. This decreases the ef-
ficiency of the subsequent diaza-Wittig reaction, and
in the presence in the reaction mixture of a little water
formed in the stage of condensation it makes possible the
O
O
O
O
F3C
R
F3C
OR
N2
Iа, Ib
IIа_IId
I, R = Me (а), Et (b); II, R = OMe (а), OEt (b), Me (c),
t-Bu (d).
1252

diaza-WITTIG REACTIONS OF DIKETOESTERS PHOSPHAZINES
1253
parallel proceses: the hydrolysis of fluoroalkyl-containing
diazoketoesters I [5] and/or of phosphazines IVа, IVb
[13, 14]. In this connection in further experiments
phosphine IIIb was used since it provided phosphazines
more stable against thermolysis and hydrolysis [9].
(yield of pyridazine VIа in the presence of Et3N was 14%
in contrast to 46% in the absence of the base).
By the more detailed investigation of the composition
of the reaction mixtures we established that alongside
the target pyridazines VI they contained the products of
deacylation of the latter, trisubstituted pyridazines VII
(up to 25–37% by the data of 1Н NMR). The hydrolytic
cleavage of the acetyl group occurs evidently owing to
the presence of water formed in the stage of the condensa-
tion. It is also presumable that this process is catalyzed by
bases for the yields of the 5-acetyl-substituted pyridazines
essentially decrease in the presence of bases.At the same
time the addition into the reaction mixture of drying
agents (CaSO4 or MgSO4) led to the increased yields of
tetrasubstituted pyridazines VI and to decreased yields
of deacylated products VII (yields of pyridazine VIа in
the presence of calcium sulfate and without it were 39
and 11% respectively).
The reaction of diazoketoesters Iа, Ib with tris(di-
methylamino)phosphine (IIIb) proceeded with heat evo-
lution and furnished as a result phosphazines IVc, IVd in
95–97% yield. The analysis of the 1Н NMR spectra of the
reaction mixture showed that in contrast to the reaction
with PPh3, phosphine IIIb reacted with diazoketoesters
I virtually quantitatively and irreversibly. The structure
of phosphazines IVc, IVd was confirmed by 1Н and 13С
NMR spectra, their purity, by the elemental analyses, and
in further experiments phosphazines IVc, IVd were used
without additional purification.
The reaction of phosphazines IVc, IVd with ketoester
IIа was carried out at 18–20°С over 72 h or at heating in
dichloromethane (39–40°С) within 6 h.After the workup
of the reaction mixture and chromatographic purification
pyridazines Va, Vb were isolated in preparative yields
of 44–50%.
It was also shown that the reaction of phosphazine
IVа with diketone IId containing in its structure the steri-
cally loaded tert-butyl group provided the corresponding
pyridazine VId in a low yield (9%).
The structure of pyridazines Vа, Vb and VIа, VIb was
established from 1Н, 13С NMR spectra, their composition,
from elemental analyses. The signals of atoms С3 at 152.8,
153.1 and of С6 at 148.7 and 148.6 q (2JC–F 35.9 Hz) in
the spectra of pyridazines Vа, Vb, and also 152.8, 153.1
F3C
O
Iа, Ib
+
P(NMe2)3
N
CH2Cl2
0_5oC
P(NMe2)3
RO2C
N
IVc, IVd
2
(C3), 148.1 q (C6, JC–F 35.9 Hz) in the spectra of VIа,
IIa, CH2Cl2
_H2O,
Vа,Vb
VIb are located in the region of the 13С NMR spectra
characteristic of unsubstituted [15] and trisubstituted
pyridazines [5, 7, 9].
_O P(NMe2)3
Investigating the reactions of phosphazines IVа, IVb
with diketone IIc we varied reaction time and temperature
to estimate the effect of these variations on the efficiency
of the formation of 5-acetyl-substituted pyridazines VIа,
VIb.
The presence of the signals from the ester and acetyl
carbonyl groups in the 13С NMR spectra of pyridazines
Vа, Vb and VIа, VIb at 162.6, 162.2 and 194.2, 194.4 ppm
respectively shows that the condensation of the 1,3-di-
carbonyl fragment forming the cyclic pyridazine system
does not affect these groups but occurs chemoselectively
at the carbonyl group linked to the trifluoromethyl group.
The highest yields of pyridazines VIа, VIb (35–46%
by the data of Н NMR) were obtained in the reaction
1
carried out in acetonitrile at the temperature of the reac-
tion mixture 80–81°С in the presence of dehydrating
agents (magnesium or calcium sulfates). The increased
temperature of the reaction mixture favors the higher
yield of bis(trifluoromethyl)-substituted pyridazines VI
(yield of pyridazine VIа at 80°С 46% compared with
11% at 39–40°С). Yet the attempts to use weak organic or
inorganic bases (Et3N, Na2CO3, K2CO3) for the intensifi-
cation of the condensation stage resulted in a significant
decrease in the yield of tetrasubstituted pyridazines VI
Hence we established for the first time that the reaction
of phosphazines of fluoroalkyl-containing diazoketoesters
with fluorinated acyclic 1,3-diketones and ketoesters
provides by a tandem process (diaza-Wittig reaction and
condensation) tetrasubstituted fluoroalkyl-containing
pyridazines. This method makes it possible to obtain
5-alkoxycarbonyl- and 5-acetyl-4,6-bis(trifluoromethyl)-
substituted pyridazines in the preparative yields up to
50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

SUPURGIBEKOV et al.
1254
(3H, OCH3). 13C NMR spectrum, δ, ppm: 37.4 d (СH3,
H3C
F3C
O
2JC–P1.7 Hz), 51.5 (OCH3), 117.7 q (CF3, 1JC–F 291.2 Hz),
140.0 d (С=N, 3JC–P 50.9 Hz), 164.8 (COOMe), 174.8 q
(CO, 2JC–F 31.9 Hz). Found, %: С 36.67, 36.64; Н 6.17,
6.13; N 19.04, 19.05. С11H21F3N5O3P. Calculated, %:
С 36.77; Н 5.89; N 19.49.
CF3
IIb
Vа, Vb
_H2O,
_O P(NMe2)3
N
RO2C
N
VIа, VIb
Ethyl 2-[tris(dimethylamino)phosphoranilidene]
azino-3-oxo-4,4,4-trifluorobutanoate (IVd) was ob-
tained from 0.17 g (0.8 mmol) of diazoketoester Ib and
0.13 g (0.8 mmol) of phosphine IIIb. Yield 300 mg
(97%), yellow crystals, mp 64–66°C (from mixture Et2O−
petroleum ether), Rf 0.48 (ethyl acetate). 1Н NMR spec-
trum, δ, ppm: 1.31 t (3Н, СН2СН3, 3JН–Н 7.1 Hz), 2.71 d
F3C
MeO2C
CF3
H2O
_AcOH
N
N
VIIа
R = Me (а), Et (b)
3
3
The use in the reaction of tris(dimethyl)amino-
phosphazines provided higher yields of pyridazines
than the application of the triphenylphosphazine analogs
readily dissociating in solution. The presence in the
reaction mixture of organic or inorganic bases (Et3N,
Na2CO3, K2CO3) decreases the yields of tetrasubstituted
pyridazines apparently due to the hydrolytic cleavage
of the 5-acetyl group from the molecule of the initially
formed pyridazine.
(18Н, СН3, JP–H 8.9 Hz), 4.30 q (2Н, СН2СН3, JН–Н
7.1 Hz). 13C NMR spectrum, δ, ppm: 14.71 (OCH2CH3),
37.4 d (СH3, 2JC–P1.7 Hz), 60.5 (OCH2), 117.8 q (CF3,
3
1JC–F 291.2 Hz), 140.6 d (С=N, JC–P 51.9 Hz),
2
164.5 (COOMe), 174.8 q (CO, JC–F 31.9 Hz). Found,
%: С 38.57, 38.76; Н 6.20, 6.22; N 18.52, 18.39.
С12H23F3N5O3P. Calculated, %: С 38.61; Н 6.21; N 18.76.
Pyridazine Vb. A mixture of 0.89 g (2.38 mmol) of
phosphazine IVd, 0.81 g (4.8 mmol) of ketoester IIа, and
0.5 g of anhydrous MgSO4 in 5 ml of dichloromethane
was stirred at room temperature for 72 h (TLC monitor-
ing), the solvent was distilled off in a vacuum (10–12 mm
Hg), the residue (~1.5 g) in 2 ml of the mixture MeOBu-t
and petroleum ether was filtered through a bed of silica gel
(5 g), elution with the mixture MeOBu-t and petroleum
ether, 1:1 (40 ml). The residue after the removal of the
solvent was distilled in a vacuum.
Phosphazines IVc,IVd. General procedure. To
a solution of 0.8–1.5 mmol of diazo compound Ia, Ib in
5–7 ml of dichloromethane cooled with ice was added
dropwise within 10–15 min 0.8–1.5 mmol of phosphine
IIIb in 5–7 ml of dichloromethane. The reaction mix-
ture of yellow color was stirred at room temperature
for 10 min, the solvent was completely distilled off
in a vacuum (10–12, next 0.1–0.5 mm Hg), obtained
phosphazines IVc, IVd (practically pure substances
according to 1Н NMR data) were used in further experi-
ments without additional purification.
5-Methoxycarbonyl-4,6-bis(trifluoromethyl)-3-
ethoxycarbonylpyridazine (Vb). Yield 406 mg (50%),
colorless crystals, mp 52–54°C (from mixture Et2O−pe-
troleum ether), bp 65–75°C (0.1 mm Hg), Rf 0.60 (pe-
For the preparation of analytically pure phosphazines
IVc, IVd the residue after the removal of solvent was
applied to a small column packed with silica gel (5.5 g),
elution with a mixture of petroleum ether with ethyl ac-
etate, 1:1 (20 ml). The eluate was dried with anhydrous
magnesium sulfate, the residue after the removal of
solvents was recrystallized from a mixture of Et2O and
petroleum ether.
1
troleum ether–ethyl acetate, 2:1). Н NMR spectrum,
δ, ppm: 1.45 t (3Н, СН2СН3, 3JН–Н 7.1 Hz), 4.05 s (3Н,
OСН3), 4.58 q (2Н, СН2СН3, 3JН–Н 7.1 Hz). 13C NMR
spectrum, δ, ppm: 13.8 (OCH2CH3), 54.6 (OCH3), 60.1
1
(OCH2), 120.2 q (CF3, JC–F 276.8 Hz), 120.8 q (CF3,
1JC–F 277.0 Hz), 124.9 q (C4, 2JC–F 35.9 Hz), 128.9 (C5),
148.6 q (C6, 2JC–F 35.7 Hz), 153.1 (C3), 161.2 (COOEt),
162.2 (COOMe). Найdе-но, %: С 38.36, 38.02; H 2.61,
2.45; N 8.16, 8.24. С11Н8F6N2O4. Calculated, %: С 38.15;
Н 2.33; N 8.09.
Methyl 2-[tris(dimethylamino)phosphoranilidene]
azino-3-oxo-4,4,4-trifluorobutanoate (IVc) was ob-
tained from 0.3 g (1.5 mmol) of diazoketoester Ia and
0.25 g (1.5 mmol) of phosphine IIIb. Yield 517 mg
(96%), yellow crystals, mp 82.5–84°C (from mixture
Et2O−petroleum ether), Rf 0.33 (ethyl acetate). 1Н NMR
spectrum, δ, ppm: 2.71 d (18Н, СН3, 3JP–H 8.9 Hz), 3.83 s
Pyridazines VIа, VIb. General procedure. To
a solution of 2.55 mmol of phosphazine IVc, IVd in
5 ml of acetonitrile was added 0.78 g (5.1 mmol) of
trifluoroacetylacetone (IIb), ~1 g of anhydrous MgSO4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

diaza-WITTIG REACTIONS OF DIKETOESTERS PHOSPHAZINES
1255
or CaSO4, and the mixture was stirred at 79–80°С over
20–50 h till the phosphazines IVc, IVd disappeared
from the reaction mixture (TLC monitoring). The dry-
ing agent was filtered off, the solvent was distilled off
from the filtrate at 20 mm Hg, unreacted ketone IIb was
distilled off at 1–2 mm Hg, the residue was subjected to
chromatography on a column packed with 8 mg of silica
gel, gradient elution with a mixture of MeOBu-t with
petroleum ether.
and Institute of Organic Chemistry (Leipzig University,
Germany) for the financial support of this study.
REFERENCES
1. Tisler, M. and Stanovnik, B., Adv. Heterocycl. Chem., 1990,
vol. 49, p. 385; Joule, J.A., Mius, K., and Smith., G.F.,
Heterocyclic chemistry, NewYork : Chapman & Hall, 1994.
2. Oreland, L., Acta Neurol. Scand. Suppl., 1991, vol. 136,
p. 60.
5-Acetyl-4,6-bis(trifluoromethyl)-3-ethoxy-
carbonylpyridazine (VIb). Yield 330 mg (39%),
colorless crystals, mp 69–70.5°C (from mixture
Et2O−petroleum ether), Rf 0.53 (petroleum ether–ethyl
3. Yasuhiro, N., Satoko, N., Takako, M., Isao, K., Masaki, M.,
Shinji, M., Hiroshi, K., Kazuo, K., and Tomiichiro, O.,
British, J. Pharm., 2002, vol. 137, p. 676.
4. Guillaume, M., Janousek, Z., and Viehe, H.G., Synthesis,
1995, p. 920.
5. Galiullina, S.V., Zakharova, V.M., Kantin, G.P., and
Nikolaev, V.A., Zh. Org. Khim., 2007, vol. 43, p. 609.
6. Zakharova, V.M. and Nikolaev, V.A., Synthesis, 2005,
p. 2871.
7. Nikolaev, V.A. and Zakharova, V.M., J. Fluor. Chem., 2007,
vol. 128, p. 507.
8. Supurgibekov, M.B., Hennig, L., Schulze, V., and
Nikolaev, V.A., Zh. Org. Khim., 2008, vol. 44, p. 1724.
9. Supurgibekov, M.B., Zakharova, V.M., Sieler, J., and
Nikolaev, V.A., Tetrahedron Lett., 2011, vol. 52, p. 341.
10. Poshcenrieder, H. and Stachel, H., J. Heterocycl. Chem.,
1995, vol. 32, p. 1457.
11. Staudinger, H. and Meyer, I., Helv. Chim. Acta, 1919, vol. 2,
p. 635; Regitz, M., Eistert, B., Heck, G., and Schwall, H.,
Meth. Org. Chem. (Houben-Wehl), 1968, vol. 10, p. 877.
12. Korobitzina, I.K. and Rodina, L.L., Meth. Chim., 1974,
vol. 6, p. 306.
13. Zalesov, V.V., Pulina, N.A., andAndreichikov, Yu.S., Khim.
Zh. Ural’sk. Univ., 1995, vol. 2, p. 135; Aitbaev, I.A.,
Dubitskii, V.V., and Rodina, L.L., Sovremennye problemy
organicheskoi khimii (Contemporary Problems of Prganic
Chemistry), St. Petersburg: Izd. SPbGU, 1998, vol. 12,
p. 182.
14. Weygand, F. and Bestmann, H.J., Angew. Chem., 1960,
vol. 72, p. 535; Miyamoto, T. and Matsumoto, J.I., Chem.
Pharm. Bull., 1988, vol. 36, p. 1321; Zhu, S., Zhu, S., and
Liao, Y., J. Fluor. Chem., 2004, vol. 125, p. 1071.
15. Pretsch, E., Buhlmann, P., and Affolter, C., Structure De-
termination of Organic Compounds, Springer-Verlag, 2000.
16. Banks, R.E., Barlow, M.G., and Nickho-Amiry, M.,
J. Fluor. Chem., 1997, vol. 82, p. 171; Burdon, J. and
McLoughlim, V.C.R., Tetrahedron, 1964, vol. 20, p. 2163.
1
acetate, 2 : 1). Н NMR spectrum, δ, ppm: 1.46 t (3Н,
СН2СН3, 3JН–Н 7.3 Hz), 2.67 s (3Н, СН3), 4.59 q (2Н,
3
СН2СН3, JН–Н 7.3 Hz). 13C NMR spectrum, δ, ppm:
13.7 (OCH2CH3), 31.3 (OCH3), 64.3 (OCH2), 120.6 q
1
1
(CF3, JC–F 276.3 Hz), 121.1 q (CF3, JC–F 277.3 Hz),
124.1 q (C4, JC–F 35.9 Hz), 136.7 (C5), 148.1 q
2
2
(C6, JC–F 35.7 Hz), 153.3 (C3), 162.3 (COOEt), 194.4
(COMe). Found, %: С 40.25, 40.18; H 2.53, 2.59; N 8.64,
8.73. C11H8F6N2O3. Calculated, %: С 40.01; Н 2.44;
N 8.48.
1H and 13C NMR spectra were registered on a spec-
trometer Bruker 300, operating frequencies 300 (1H)
and 75.5 MHz (13C), solvent CDCl3, internal reference
TMS. Elemental analyses were carried out on an analyzer
Heraeus CHNO RapidAnalyser. Reaction mixtures were
separated by column chromatography on neutral Silicagel
L 40/100 (Aldrich) in the gradient mode, eluents ethyl
acetate or the mixture of petroleum ether and MeOBu-t
in various ratios. The reaction progress was monitored
and Rf was measured by TLC on Silufol UV-254 pates
(Kavalier, Czechia). Diazodicarbonyl compounds Ia, Ib
were obtained from commercial ethyl or methyl 4,4,4-tri-
fluorooxobutanoates by the diazotransfer reaction [5],
fluoro-containing 1,3-dicarbonyl compounds IIа–IIc
were obtained by Claisen condensation [16].
ACKNOWLEDGMENTS
The authors express their deep gratitude to DAAD
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011