An Expeditious Room Temperature Stirring Method for the Synthesis of Isoxazolo[5,4-b]quinolines
An Expeditious Room Temperature Stirring Method for the Synthesis of Isoxazolo[5,4-b]quinolines
Journal of the Korean Chemical Society. 2011. Oct, 55(5): 805-807
Copyright © 2011, The Korean Chemical Society
  • Received : June 29, 2011
  • Accepted : July 27, 2011
  • Published : October 20, 2011
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Kirti S. Niralwad
Bapurao B. Shingate
Murlidhar S. Shingare

The synthesis of different derivatives of isoxazolo[5,4-b]quinoline by the cyclization reaction of various substituted oximes of quinoline using mild base at ambient temperature. The formation of isoxazolo[5,4-b]quinoline, as a consequence of cheaper and more readily available K 2 CO 3 and DMF participating in the reaction, is documented.
Heterocyclic compounds are widely distributed in nature. They are essential to life and play a vital role in the metabolism of living cells. These compounds have been an asset to combat various diseases, disorders and provide essential commodities for the survival of mankind. Among various known heterocyclic systems, quinolines represent one of the most successful yet poorly understood classes of drugs.
As the earlier reported method the 2-chloroquinoline-3-carbaldehyde were prepared from acetanilide in good yields by the action of Vilsmeier’s reagent in phosphoryl chloride solution. The reaction is shown to involve successive conversion of the acetanilide into an imidoyl chloride and then an N-(α-chlorovinyl)aniline. The latter enamine is diformylated at its α-position and subsequently cyclised to the 2-chloroquinoline-3-carbaldehydes. 1
Quinoline ring system 2 is an essential structural fragment of a large number of natural and synthetic compounds possessing a wide variety of pharmacological activities. 3 , 4 Quinoline have occupied a unique position in the design and synthesis of novel biologically active compounds since they are often used as antiallergic, 5 antiproliferative, 6 antiparasitic, 7 antinflammatory, antiasthmatic, antituberculosis, antibacterial, antihypertensive, antitumor and most notably antimalarial agents. 8 , 9
Quinolines are found in numerous commercial products, including pharmaceuticals, fragrances and dyes. In the recent past, quinoline compounds were extensively studied for the development of new therapeutic agents that led to the development of some molecules, such as quinoline alkaloids, namely quinine, chloroquine, mepacrine, and pamaquine which are used as efficient drugs for the treatment of malaria. 10 - 17
In particular 2-chloroquinoline-3-carbaldehyde has been used as a key intermediate for the synthesis of variety of medicinally valuable compounds. 18
Literature survey revealed that isoxazolo[5,4- b ]quinoline have received much interest in the field of chemistry because it is associated with diverse pharmaceutical and agrochemical application. 19
In a report M. Kidwai et al . 20 have synthesized isooxazolo[5,4- b ]quinoline by the reaction of hydroxylamine hydrochloride with ethanolic solution of 2-chloro-3-quinoline-carboxaldehyde in the presence of acetic acid under reflux condition for 1 h, The resulting compounds were screened for their biological activity and found to be promising analgesic agents.
The methods employed for the synthesis of isooxazolo [5,4- b ]quinoline are very few. Consequently, there is still needs to develop a more efficient, simple, milder and high yield protocol for the synthesis of isooxazolo[5,4- b ]quinoline.
Melting points were determined in open capillaries in a paraffin bath and are uncorrected. IR spectra were recorded on a Bruker spectrophotometer using KBr discs, and the absorption bands are expressed in cm -1 . 1 H-NMR spectra were recorded on a Varian AS 400 MHz spectrometer in CDCl 3 /DMSO-d 6 , chemical shifts (δ) are in ppm relative to TMS, Mass spectra were taken on a Macro mass spectrometer (Waters) by electro-spray method (ES).
All the synthesized compounds were characterized by spectral data and compared (MS, NMR, and IR) with authentic sample. This comparison revealed that the compounds synthesized by this newly developed method were exactly similar in all aspects to the reference compounds. The developed methodology is simple and a good contribution in the field of chemistry.
- Spectral Data for representative compounds
Isoxazolo[5,4-b]quinoline (7): 1622 (C=N str.), 1600, 1576, 1462 (Ar-C=C); 1 H NMR (Acetone-d 6 ): 7.7-8.27 (m, 3H, Ar-H), 8.55 (s, 1H, 3-H).
4-methylisoxazolo[5,4-b]quinoline (8): 1640 (C=N str.), 1585, 1560, 1474 (Ar-C=C str.); 1 H NMR (Acetone-d 6 ): 2.44 (s, 3H, CH 3 ), 7.42-8.1 (m, 4H, At-H), 8.57 (s, 1H, 3-H).
- General procedure
Synthesis of compounds 3(a-h): A mixture of an ethanolic solution of 2-chloroquinoline-3-carbaldehyde (1 mmol), hydroxyl amine hydrochloride (1.5 mmol), and sodium acetate (1.5 mmol) were placed in a round bottom flask. This mixture was stirred at room temperature for the precised time. After the completion of reaction as monitored by TLC; 20 mL ice cold water was added to the reaction mixture and product was extracted by chloroform (2×25 mL). The chloroform was distilled out on rota-evaporator under reduced pressure to afford the pure products. The compound formed was then stirred with DMF and K 2 CO 3 which on cyclization gives the corresponding products 3(a-h) . All the synthesized compounds were characterized by spectral data and compared (MS, NMR, and IR) with authentic sample.
In continuation of our research work on the development of novel synthetic methodologies 21 herein, we have developed methodology for the synthesis of isooxazolo [5,4- b ]quinoline using K 2 CO 3 which makes use of mild catalyst in dimethyl formaldehyde.
Firstly, we have carried out the reaction of 2-chloro-3-quinoline-carboxaldehyde with hydroxyl amine hydrochloride in presence of sodium acetate stirred at room temperature for 4-10 min. to give the product 2 ( 1 ).
Here we have observed that the oxime group was produced very smoothly with hydroxyl amine hydrochloride and sodium acetate at room temperature, the results are shown in ( 1 ).
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Synthesis of various oximes of quinoline from 2-chloro-3-quinoline-carboxaldehyde
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aIsolated yield.
Screening of catalysts on the model reaction (3a)
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aIsolated yield
Synthesis of isoxazolo[5,4-b]quinoline
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aIsolated yield
We also screened a number of different catalysts on the model reaction. When the reaction was carried out in the presence of Cs 2 CO 3 , KOH, DBU under stirring condition it gave lower yield of product. However, when the same reaction was conducted using potassium carbonate as a catalyst it gave excellent yields of product in short reaction time ( 2 , entry 4).
After optimizing the conditions, the generality of this method was examined by the reaction of various oximes of quinoline using K 2 CO 3 and DMF gave the corresponding product 3(a-h) in 3 .
In conclusion the K 2 CO 3 and DMF was found to be mild and effective catalyst for synthesis of different derivatives of isoxazolo[5,4- b ]quinoline by the cyclization of various substituted oximes of quinoline at ambient temperature. We believed that, synthesis of isoxazolo[5,4- b ]quinoline using base will be a valuable contribution in the field of chemistry as compared to the existing processes.
The authors are thankful to University Grant Commission, New Delhi, for awarding the fellowship and to The Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad-431 004, MS, India for providing the laboratory facility.
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