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Syntheses of sydnonyl-substituted α, β-unsaturated ketones and
1,3-dihydro-indol-2-ones by Knoevenagel reaction
Mei-Hsiu Shiha*, Cheng-Ling Wua and Mou-Yung Yehb
a
Department of Chemical Engineering, Southern Taiwan University of Technology, Tainan, Taiwan 710, R.O.C.
b
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan 701, R.O.C
A convenient method for the preparation of sydnonyl-substituted α, β-unsaturated ketones, based on Knoevenagel condensation, is presented. Although well known, this reaction has never been utilized in the condensation involving sydnone derivatives.
Thus, 3-aryl-4-formylsydnones (1) are reacted with active methylene compounds such as acetylacetone (2a), ethyl acetoacetate (2b), diethyl malonate (2c), malononitrile (4a), ethyl cyanoacetate (4b) and cyanoacetamide (4c) by modified Knoevenagel
condensation to afford multifunctional derivatives. Also, sydnonyl-substituted 1,3-dihydro-indol-2-one derivatives 10 were synthesized successfully by condensing 3-aryl-4-formylsydnones (1) with oxindoles 9.
Introduction
3-Aryl-4-formylsydnones (1) had been reported to proceed the Claisen-Schmidt reaction with acetophenone to give α, β-unsaturated
ketones in the presence of sodium hydroxide. Since the sydnone ring of compounds 1 is sensitive to strong base and easy to be
decomposed, the yield of the reaction was not good. Accordingly, a convenient method for the preparation of sydnonylsubstituted α,
β-unsaturated ketones, based on Knoevenagel condensation is reported here. Furthermore, taking the special pharmacological and
biological activities of indole derivatives into account, the sydnonyl substituted 1,3-dihydro-indol-2-ones 10 were also synthesized in
good yield by the condensation of 3-aryl-4- formylsydnones (1) with oxindoles 9.
Results and discussion
In this study, compounds 1 were reacted with active methylene compounds using piperidine /acetic acid buffer system. However, the
sydnone ring itself is sensitive to acids, bases and heat. Sydnone compounds are sometimes decomposed during reaction and/or
Figure 1. Crystal structure of compound 5h.
Figure 2. Crystal structure of compound 5j.
work-up. Initially, the Knoevenagel condensations were controlled at low temperature by successive addition of sydnones, methylene
compounds, piperidine and acetic acid in order, but still, the starting materials 1 were unavoidably decomposed. Several tests
The pyrazoles or pyrazolines have been found to have a variety applications in medicine and are known as potent antibiotic or
established glacial acetic acid was first added to the ice-cooled solution of sydnone 1. Then, the ice-cooled solution of the active
antioxidizing agents. The condensation products, 2-(3-arylsydnon-4-ylmethylene)malononitriles (5a-5d), were each treated with
methylene compound with piperidine was slowly added to this acidic solution and the mixture was stirred to precipitate the desired
hydrazine hydrate, phenylhydrazine and methylhydrazine to afford the desired sydnonyl substituted pyrazoline derivatives. However,
material as solid. The solvent effect was obvious during the reaction, too. Using isopropyl alcohol rather than ethanol improved the
the isolated products were not pyrazolines but compounds 7 (Scheme 3). Various cyclizations of α, β-unsaturated carbonyl compounds
yield of the precipitated solid because the solubility of the condensation product in the former solvent was lower than that in the latter.
with amidines were reported to yield pyrimidone or pyrimidine derivatives. However, the reaction of compounds (5e-5h) with
Consequently, under optimal experimental condition, compounds 1 reacted with activated methylene compounds such as acetylacetone
guanidine hydrochloride yielded 3-arylsydnones (8), not the desired pyrimidones (Scheme 3).
H
(2a), ethyl acetoacetate (2b) and diethyl malonate (2c) in isopropyl alcohol to give condensation products 3a-3l in high yields (Scheme
H
1).
O
CH3COCH2COCH3
2a
piperidine, 4-7 h
Ar
CH3
N
N
H
N
CH3CO2H
CH3COCH2COOEt
2b
O
OEt
N
N
OEt
H
+
N
O
O
N
NH
CN
N
O
O
O
3e-3h
N
Ar
yield: 78-73%
H2N
NH2 . HCl
pyrimidone
derivatives
5e-5h
OEt
H
Scheme 3.
Ar
Scheme 1.
1a: Ar =C6H5;
1b: Ar = p-CH3C6H4;
OEt
N
N
piperidine, 12-24 h
O
O
8
O
EtOCOCH2COOEt
2c
H
Ar
O
CH3
Ar
piperidine, 8-10 h
pyrazole or pyrazoline
derivatives
R = H, CH3, C6H5
H
Ar
O
O
7
5a-5d
O
O
N
O
O
O
O
O
1a-1d
yield: 84-74%
RNHNH2
6
CN
N
R
N
C
N
CH3
H
O
3a-3d
N
C
Ar
N
C N
Ar
CN
H
O
O
O
3i-3l
5a, 5e: Ar = C6H5;
5b, 5f: Ar = p-CH3C6H4; 5c, 5g: Ar = p-CH3OC6H4; 5d, 5h: Ar = p-C2H5OC6H4
yield: 75-65%
In this report, Knoevenagel condensation could directly be applied to synthesize the desired sydnonyl-substituted heterocycles through
the reaction of compounds 1 with suitable reagents. For example, ropinirole, 4-(2-(dipropylamino)ethyl)-1,3-dihydro-2H-indol-2-one,
1c: Ar = p-CH3OC6H4;
1d: Ar = p-C2H5OC6H4
is a potent anti-Parkinson’s disease drug developed by Smith Kline Beecham Pharmaceuticals. Furthermore, chemists are still
enthusiastically pursuing the syntheses of such indole derivatives. Along this line, we proceeded to this work and reported the
When active methylene compounds that contain cyano group, such as malononitrile (4a), ethyl cyanoacetate (4b) and cyanoacetamide
syntheses of sydnonyl-substituted 1,3-dihydro-indol-2-one derivatives 10a-10h by the modified Knoevenagel condensation of
(4c), were allowed to react with compounds 1 in buffer systems containing piperidine and acetic acid, to afford the desired products
3-aryl-4-formylsydnones (1) with oxindole (9a) and 5-chlorooxindole (9b), respectively (Scheme 4). The yields of synthesized indole
5a-5l successfully in good yields, too (Scheme 2). All these products were spectroscopically characterized. Among these new
derivatives 10a-10h are very high. The structure of compound 10a was also verified by X-ray analysis and is displayed in Fig. 3.
compounds 5a-5l, the yellow crystals 5h and 5j were analytically pure and suitable for X-ray structure analyses. Figures 1 and 2 show
O
the molecular structures of compounds 5h and 5j. The products 5e-5l are E-isomers exclusively, based on the direct determination on
O
5h and 5j, and spectral comparisons. As the results, the high yields and high (E)-stereoselectivity of our reaction make it as attractive
Ar
H
N
as existing methodologies. On the basis of the reaction time and the corresponding yields of these active methylene species with
O
Unlike other heteroaromatic aldehydes in
O
+
N
compounds 1 suggests that their reactivity order are in the sequence of 2a > 2b > 2c and 4a > 4b > 4c. All the above reactions are
initiated at ice-cold condition followed by stirring in the room temperature till completion.
H
1a~1d
O
H
R
N
H
N
Ar
CH3CO2H
piperidine
9a-9b
N
N
O
O
10a-10h
R
the Knoevenagel condensation were carried out in the presence of base and solvent refluxing temperature, the current sydnone system
Scheme 4. 1a: Ar = C6H5; 1b: Ar = p-CH3C6H4; 1c: Ar = p-CH3OC6H4; 1d : Ar = p-C2H5OC6H4;
was processed in the mild condition and often resulted in a better yield.
Ar
CNCH2CN
4a
yield: 92-78%
O
O
5a-5d
O
O
OEt
H
H
CH3CO2H
CNCH2CO 2Et
4b
Ar
CN
N
piperidine, 4-5 h
N
O
1a-1d
CN
N
N
piperidine, 3-4 h
N
9b: R = C
CN
H
Ar
9a: R = H;
N
O
O
5e-5h
O
O
piperidine, 12-24 h
Ar
CN
N
N
O
5i-5l
F igure 3. Crystal structure of compound 10a.
NH2
H
CNCH2CONH2
4c
yield: 91-78%
Conclusion
yield: 77-65%
3-Aryl-4-formylsydnones (1) reacted with active methylene compounds containing carbonyl or cyano group by modified Knoevenagel
condensation to give multifunctional derivatives in good yields. The high yields and complete (E)-stereoselectivity of this reaction
O
make it an attractive addition to existing methodologies. The cyclization reaction of the condensation compounds are now underway. In
this report, Knoevenagel condensation could be directly applied to synthesize the desired sydnonyl-substituted indole heterocycles
Scheme 2.
1a: Ar = C6H5;
1b: Ar = p-CH3C6H4;
1c: Ar = p-CH3OC6H4;
1d : Ar = p-C2H5OC6H4
through the reaction of compounds 1 with suitable reagents such as oxindole and 5-chlorooxindole