Synthesis of 3-trifluoromethyl-1,4-dihydropyridazines by the PTSA-catalyzed reaction of α,β-unsaturated aldehydes with (E)-1-phenyl-2-(2,2,2- trifluoroethylidene)

Article abstract of DOI:10.1055/s-0031-1290608

A facile and efficient method for the synthesis 3-trifluoromethyl-1,4- dihydropyridazine from a variety of readily available ,-unsaturated aldehyde and (E)-1-phenyl-2-(2,2,2-trifluoroethylidene)hydrazine was developed. The reaction proceeded under mild co

Full text of DOI:10.1055/s-0031-1290608

LETTER
935
Synthesis of 3-Trifluoromethyl-1,4-dihydropyridazines by the
PTSA-Catalyzed Reaction of a,b-Unsaturated Aldehydes with
(E)-1-Phenyl-2-(2,2,2-trifluoroethylidene)
3
-Trifluoromethyl-
a
1,4-dihydro
i
pyrida
b
z
ines o Xie, Jiangtao Zhu, Zixian Chen, Shan Li, Yongming Wu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 LingLing Road, Shanghai 200032, P. R. of China
Fax +86(21)54925192; E-mail: ymwu@sioc.ac.cn
Received 19 December 2011
available trifluoroacetaldehyde ethyl hemiacetal with
phenylhydrazine with a,b-unsaturated aldehyde under
catalysis of p-toluenesulfonic acid. Initially, we chose
cinnamaldehyde and (E)-1-phenyl-2-(2,2,2-trifluoroeth-
Abstract: A facile and efficient method for the synthesis 3-trifluo-
romethyl-1,4-dihydropyridazine from a variety of readily available
a,b-unsaturated aldehyde and (E)-1-phenyl-2-(2,2,2-trifluoroeth-
ylidene)hydrazine was developed. The reaction proceeded under
mild conditions and gave the expected 1,4-dihydropyridazine prod- ylidene)hydrazine, which was obtained in turn by conden-
ucts in moderate to high yields.
sation of the commercially available trifluoro-
acetaldehyde ethyl hemiacetal with phenylhydrazine, as
the model reaction to optimize the reaction conditions. Ul-
timately, the optimization conditions were ascertained as
p-toluenesulfonic acid as catalyst and in toluene as sol-
vent.
Key words: pyridazine, 3,3-sigmatropic rearrangement, electro-
cyclic rearrangement, hydrazine, heterocycles
Pyridazines and its derivatives represent an important
class of heterocycles which deserve chemists’ attention.1
The first representatives of the pyridazine ring system
were described as early as the end of the 19th century.2
However, since the 60s of the last century the pyridazines
found various industrial applications, for example, as
pharmaceuticals or agrochemicals, thus motivated further
investigations of their synthesis, reactivity, physicochem-
ical properties, and biological activity. Since the late
1980s, many bioactive natural products containing py-
ridazine rings have been discovered, and their structures
were identified. A broad diversity of pharmacological ac-
tivities has been reported for pyridazine derivatives.
Scheme 1 shows the structures of some pyridazine-
derived molecules made their way into the market: the
calcium-sensitizing ionotropic agent levosimendan (1),
the antihypertensive agent cadralazine (2), the cardiotonic
vasodilator pimobendan (3), and the analgesic/anti-in-
flammatory agent emorfazone (4).3 Since the incorpora-
tion of fluorine and/or fluorine-containing groups into an
organic molecule often drastically alters the chemical,
physical, and biological properties of the parent com-
pound, it is only logical to conclude that the above-men-
tioned modification necessitates the invention of novel
reagents and materials endowed with fluorine-imparting
properties.
Me
O
OH
Me
Et
N
NH
N
H
NC
N
EtO
N
N
N
N
N
N
H
H
CN
O
1
2
Me
O
O
OEt
NH
N
O
N
MeO
N
H
N
N
Me
4
3
Figure 1 Representatives of some pyridazine-derived molecules in
medicinal chemistry
Having established suitable reaction conditions, the scope
and generality of this methodology were explored. As
shown in Table 1, most substrates examined provided
moderate to good yields under the standard reaction con-
ditions. To our delight, when crotonaldehyde was used as
a substrate in place of cinnamaldehyde, the reaction also
proceeded well and afforded 4-methyl-1-phenyl-3-(trifluo-
romethyl)-1,4-dihydropyridazine (7a) in 80% yield
(Table 1, entry 1). In an effort to understand the scope of
The report of the preparation of 1,4-dihydropyridazine the reaction, the effect of various substituents on the ben-
ring is rare.4 Herein, we wish to report a method for the zene ring of cinnamaldehyde was examined. Generally,
synthesis of multisubstituted 3-trifluoromethyl 1,4-dihy- electron-donating substituents, such as methyl (Table 1,
dropyridazine by the reaction of fluorinated hydrazine entry 3) and methoxy (Table 1, entry 4) would reduce the
which was obtained by condensation of commercially yield, while electron-withdrawing substituents, including
trifluoromethyl (Table 1, entry 8) and nitro (Table 1, entry
13) would enhance the yield.
SYNLETT 2012, 23, 935–937
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1290608; Art ID: W77711ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
2
When the substituents on the benzene ring were halogens
such as fluoro (Table 1, entries 5 and 12), chloro (Table 1,

936
H. Xie et al.
LETTER
yet found a suitable experiment to distinguish these possi-
bilities. In the electrocyclic mechanism, the condensation
of cinnamaldehyde with fluorinated hydrazine leads to the
6p-electron cation intermediate C. Then through the elec-
trocyclic rearrangement, six-membered-ring cation inter-
mediate D is formed. Finally, the intermediate D loses a
proton, and the product 7b is obtained. In the other possi-
ble reaction pathway, through 3,3-sigmatropic rearrange-
ment, intermediate A is converted into intermediate E.
Eventually, the product 7b is obtained by the condensa-
tion of intermediate F. Comparing and analyzing these
two possible mechanisms, the conspicuous difference is
the mode of the carbon–carbon bond formation, one is
through the electrocyclic reaction, the other is the 3,3-sig-
matropic rearrangement.
Table 1 PTSA-Catalyzed Synthesis of 3-Trifluoromethyl-1,4-
dihydropyridazine5
Ph
H
N
N
O
PTSA
N
N
Ph
+
toluene, r.t., 12 h
R
H
CF3
F3C
5
6
R
7
Entry
1
R
Yield (%)
7a 80
7b 86
7c 71
7d 54
7e 80
7f 80
Me
Ph
2
3
4-MeC6H4
4-MeOC6H4
4-FC6H4
4
In summary, a facile and efficient method for the synthe-
sis of 3-trifluoromethyl-1,4-dihydropyridazine from a va-
riety of readily available a,b-unsaturated aldehyde and
(E)-1-phenyl-2-(2,2,2-trifluoroethylidene)hydrazine was
developed. The reaction proceeded under mild conditions
and gave the expected 1,4-dihydropyridazine products in
good to high yields. Additional studies on the asymmetric
reactions of the trifluoromethylated N-monosubstituted
hydrazone with a,b-unsaturated aldehyde are under way.
5
6
4-ClC6H4
4-BrC6H4
4-F3CC6H4
4-NCC6H4
7
7g 80
7h 88
7i 78
8
9
10
11
12
13
14
4-MeO2CC6H4
4-AcC6H4
2-FC6H4
7j 76
7k 78
7l 82
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
3-O2NC6H4
2-thienyl
7m 86
7n 61
Acknowledgment
The authors gratefully acknowledge generous financial support
from National Science Foundation of China (No. 21172239).
entry 6), and bromo (Table 1, entry 7), the reaction
worked also well and provided high yields. It is worth-
while to note that when the arene ring is 2-thienyl
(Table 1, entry 14), it could afford 7n in 61% yield. As for
nitrile- (Table 1, entry 9), ester- (Table 1, entry 10), and
acetyl-substituted (Table 1, entry 11) substrates, the reac-
tion could also proceed well and shows wide functional-
group tolerance.
References and Notes
(1) (a) Kolar, P.; Tiler, M. In Advances in Heterocyclic
Chemistry, Vol. 75; Katritzky, A. R., Ed.; Academic Press:
San Diego, 2000, 167. (b) Brown, D. J. In Chemistry of
Heterocyclic Compounds, Vol. 57; Taylor, E. C.; Wipf, P.,
Eds.; Wiley: New York, 2000, 1. (c) Maes, B. U. W.;
Lemière, G. L. F. In Comprehensive Heterocyclic
Chemistry, 3rd ed., Vol. 8; Aitken, A., Ed.; Elsevier:
Amsterdam, 2008, 1.
There are two possible mechanisms for this reaction, elec-
trocyclic rearrangement mechanism and 3,3-sigmatropic
rearrangement mechanism (Scheme 1), but we have not
Ph
Ph
N
Ph
N
electrocyclic
reaction
H2O
N
– H2O
CF3
N
N
N
Ph
N
Ph
HN
– H+
Ph
N
H+
O
CF3
HO
CF3
N
N
N
Ph
Ph
Ph
CF3
CF3
CF3
B
C
D
Ph
Ph
Ph
Ph
N
Ph
HN
Ph
N
– H2O
CF3
A
HO
HO
O
N
N
N
CF3
CF3
Ph
Ph
Ph
E
G
F
Scheme 1 Two possible mechanisms
Synlett 2012, 23, 935–937
© Thieme Stuttgart · New York

LETTER
3-Trifluoromethyl-1,4-dihydropyridazines
937
(2) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1885, 299.
(b) Fischer, E. Justus Liebigs Ann. Chem. 1886, 147.
(c) Tauber, E. Ber. Dtsch. Chem. Ges. 1895, 451.
(3) (a) Tišler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1968,
211. (b) Hunston, R. N.; Parrick, J.; Shaw, C. J. G. In Rodd’s
Chemistry of Carbon Compounds, Vol. 4; Coffey, S., Ed.;
Elsevier: Amsterdam, 1989, 1.
(4) (a) Mathew, T.; Keller, M.; Hunkler, D.; Pinzbach, H.
Tetrahedron Lett. 1996, 4491. (b) Mathew, T.; Tonne, J.;
Sedelmeier, G.; Grund, C.; Keller, M.; Hunkler, D.; Knothe,
L.; Pinzbach, H. Eur. J. Org. Chem. 2007, 2133.
(5) General Procedure for the Fluorination of 1,4-
Dihydropyridazine
stirred at r.t. for 12 h. The mixture was partitioned between
EtOAc and H2O, the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel and
crystallized from PE (boiling range 60–90 °C) to provide 7b.
General Analytical Data of Compound 7b
1H NMR (300 MHz, CDCl3): d = 7.41–7.22 (m, 9 H), 7.15–
7.11 (m, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 5.22 (dd, J1 = 7.6
Hz, J2 = 5.3 Hz, 1 H), 4.40 (d, J = 5.3 Hz, 1 H). 19F NMR
(282 MHz, CDCl3): d = –67.7 (s). 13C NMR (100 MHz,
CDCl3): d = 143.6, 142.8, 132.9 (q, J = 34.2 Hz), 129.3,
128.9, 127.5, 124.6, 123.9, 121.5 (q, J = 275.3 Hz), 119.6,
116.2, 104.7, 36.5. IR (KBr): 3060, 2912, 2843, 1666, 1599,
1493, 1480, 1289, 1271, 1223, 1173, 1129, 1076, 983, 755,
697 cm–1. MS (EI): m/z (%) = 302 (20)[M+], 225 (100), 205
(9), 105 (5), 77 (25). HRMS: m/z calcd for C17H13F3N2:
302.1031; found: 302.1030.
A Schlenk tube was charged with PTSA (19 mg, 0.1 mmol),
evacuated and backfilled with nitrogen. Toluene (5.0 mL),
cinnamaldehyde (132 mg, 1.0 mmol), and (E)-1-phenyl-2-
(2,2,2-trifluoroethylidene)hydrazine (5, 188 mg, 1.0 mmol)
was successively added. Then the reaction mixture was
© Thieme Stuttgart · New York
Synlett 2012, 23, 935–937

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