A one Step Synthesis of 4-Methyl-3,4-Dihydro-2H,5H-Pyrano[3,2-C]Quinolin-2,5[6H]- Diones and Their Biological Activities

A one Step Synthesis of 4-Methyl-3,4-Dihydro-2H,5H-Pyrano[3,2-C]Quinolin-2,5[6H]- Diones and Their Biological Activities

Dr. N. Venkatesh Kumar Chemistry Section, Dept. of Applied Sciences Higher College of Technology, Al Khuwair

Muscat, Sultanate of Oman

Dr. S. P. Rajendran

Dept. of Chemistry, Bharathiar University Coimbatore, Tamil Nadu

India

AbstractA novel one step methodology for the synthesis of pyranoquinolines has been developed from 4-hydroxy-2(1H)- quinolone being endowed with both nucleophilic and electrophilic properties. Michael addition followed by cyclization gave an angular isomer 4-methyl-3,4-dihydro-2H,5H- pyrano[3,2-c]quinolin-2,5[6H]-diones starting from 4-hydroxy- 2(1H)-quinolone with crotonic acid and pyridine. The reaction was then extended to synthesize further derivatives of angular pyranoquinolones. Structures of all the products have been established by spectral and elemental analysis data.

Key words One step synthesis, Michael addition, 4-hydroxy- 2(1H)-quinolone, 4-methyl-3,4-dihydro-2H,5H pyrano[3,2c] quinolin-2,5[6H]-diones, Biological activity.

1. INTRODUCTION

   The synthesis of pyranoquinolines have gained more interest in recent years as they constitute the parent ring structure of pyranoquinoline alkaloids, which occur in the plant family rutaceae1. They have interesting pharmacological activities1, like anticoagulant2, coronary constricting3, optically brightening4 and biological activity5. 4-hydroxy-2(1H)-quinolone is a versatile and convenient precursor for the synthesis of a wide variety of heterocyclic compounds6-1. We have reported13-16 the synthesis of a series of 3,5-di substituted pyrano[2,3-b]quinolin-2-ones starting from 2-chloro-3-formylquinolines and 2-chloro-3-formyl-4- phenyl/ methylquinolones respectively as well as the angular pyrano quinolines starting from 4-hydroxy-2(1H)-quinolone. In continuation of our studies and in view of pharmacological activities of pyranoquinolines we herewith report the synthesis of new unreported derivatives of 4-methyl-3,4- dihydro-2H,5H -pyrano[3,2-c]quinolin-2,5[6H]-diones [Scheme I]

2. MATERIALS AND METHODS

   Melting points were determined on a Boetius microheating table and are uncorrected. IR spectra were recorded on a Perkin-Elmer-597 Infrared spectrophotometer as KBr pellets. 1H NMR spectra were recorded on a AMX 400 spectrometer in CDCl3. The coupling constants (J) were expressed in Hz. Mass spectra were recorded on a Jeol D 300 mass spectrometer. Carlo Erba 106 and Perkin-Elmer model 240B CHN analyser performed elemental analysis and the values are within the permissible limits (± 0.5 %).

   4-hydroxy-2(1H)-quinolone have been prepared by known procedures17. The hitherto unknown derivatives of 4-methyl- 3,4-dihydro-2H,5H-pyrano[3,2-c]quinolin-2,5[6H]-diones synthesized were reported in Table I and their biological activities in Table II.

   ANTIBACTERIAL ACTIVITY18

   The compounds (2a-g) were screened for their antibacterial activities against Escherichia coli, Bacillus subtilis and Aeromonas hydrophilla were determined by agar diffusion technique18,19. The bacteria were cultured in nutrient agar medium and used as inoculum for the study. Bacterial cells were swabbed onto nutrient agar medium (prepared from NaCl 5.0 g, peptone 10.0 g, beef extract 10.0 g and distilled water) in petri plates. The compounds to be tested were dissolved in chloroform to a final concentration of 1, 2 and 4

   % and soaked in filter paper discs. These discs were placed on the already seeded plates and incubated at 37±20C for 24

   1. The zones of inhibition around the discs were measured after 24 h. Streptomycin was used as standards to compare the antibacterial activity of the compounds (2a-g) (Table II).

      General Procedure: Synthesis of 4-methyl-3,4-dihydro- 2H,5H-pyrano[3,2-c]quinolin-2,5[6H]-diones (2a-g):

      A mixture of 4-hydroxy-2(1H)-quinolone (1 g), crotonic acid (1 g), and pyridine (1 ml) was refluxed for 12 hours in an oil bath at 1200 1300C. Excess of crotonic acid and pyridine was removed by distillation. The reaction mixture was cooled, added to ice-cooled water (50 ml) and acidified with HCl when 4-methyl-3,4-dihydro-2H,5H-pyrano[3,2- c]quinolin-2,5 [6H]-diones separated as yellow precipitate. The precipitated product was then filtered, washed with water, dried and chromatographed over silica gel. The petrol- ethyl acetate (20:1) elute fractions furnished the pure compound, which on crystallization from petrol-acetone mixture afforded 2(a-g). M.P., Yield, IR and analytical data of 2(a-g) are given in Table I.

      Scheme I:

      Mechanism: Scheme II: Probable pathway for the formation of 2

3. RESULTS AND DISCUSSION

   The presence of hydroxyl group at C-4 in 4-hydroxy- 2(1H)-quinolone activates the nucleophilic carbon at C-3 which prompts to react with a Michael type acceptor giving the expected product 4-methyl-3,4-dihydro-2H,5H- pyrano[3,2-c] quinolin-2,5[6H]-diones, 2a in 60 % yield which melts at 252-2540C. The IR spectra showed very sharp peaks. The peak at 1720 cm-1 was assigned to the pyrone ring. It possesses stronger absorption at 1665 cm-1 (corresponds to an angular isomer) in the carbonyl region, which is attributable to amide-carbonyl stretching. 2- quinolones possess stronger carbonyl absorption at higher wavelength than 4-quinolones20,21. The 1H NMR spectra showed very sharp signals in which the proton at position C-4 appeared as sextet at 3.62 of value J=7 Hz. The hydrogen at position C-3 observed as doublet of doublet at 2.68 of value J=8.0 and 7.5Hz respectively. The signal due to methyl protons at C-4 showed a singlet at 1.24. The hydrogens at C-7 and C-10 showed a doublet at 7.50 and 7.78 of value J=7.9Hz and J=8.0Hz respectively. We observed a triplet for C8-H and C9-H at 7.32 of value J=8.1Hz. A broad singlet was obtained at 12.01 corresponds to NH. The mass spectra also showed intense molecular ion peak at m/e 229. The plausible mechanism has been proposed for the formation of 4-methyl-3,4-dihydro-2H,5H-pyrano[3,2-c]quinolin-2,5[6H]- diones, an angular isomer in Scheme II. The reaction sequence leading to 2a was then extended to synthesize compounds 2(b-g) and similar results were obtained.

   ANTIBACTERIAL ACTIVITY

   The antibacterial activity of the test solution containing new compounds with their inhibition zone furnished in Table II and the antibiotic streptomycin was used as a standard. According to the observation, the toxicity increases with the increase in concentration of the test solution containing new compounds. Among the different synthetic compounds, 2f and 2g seem to be very much active against the pathogens under study and it is evidenced by their inhibitory zone. Generally the methoxy derivatives are much active against the bacterial species than compared with other derivatives. Even though, all the compounds are active against various pathogens, but their effectiveness did not reach the conventional bacteriostatic streptomycin. This may be due to cellular integrity of the microbes and/or non-effectiveness of these compounds against microbial metabolism18.

   Table I. Physical and Spectroscopic data of (2a-g)a:

   (Yield		Calcul.	Found (%)	max	() ppm	m/z
   %)		(%)		(cm-1)		70ev
   						(m+)
   2a252-254		C 68.65	C 68.60	1720	6.57 (s, 1H, C4-H); 2.68 (dd, 2H, J=8,
   (60)		H 3.89	H 3.85	1665	7.5, C3-H); 1.24 (s, 3H, C4-CH3); 7.50	229
   		N 6.06	N 6.05		(d, 1H, J=7.9, C7-H); 7.78 (d, 1H, J=8,
   					C10-H); 7.32 (t, 2H, J=8.1, C8-H & C9-
   					H); 12.01 (bs, 1H, NH)
   2b	243-245	C 69.70	C 69.68	1718	2.70 (s, 3H, C8-CH3); 6.65 (s, 1H, C4-
   	(55)	H 4.60	H 4.59	1658	H); 2.65 (dd, 2H, J=8, 7.5, C3-H); 1.30	243
   		N 5.81	N 5.80		(s, 3H, C4-CH3); 7.40 (d, 1H, J=8, C7-
   					H); 7.80 (d, 1H, J=8, C10-H); 7.35 (d,
   					1H, J=8.1, C9-H); 12.10 (bs, 1H, NH)
   2c	231-233	C 69.79	C 69.67	1716	2.72 (s, 3H, C7-CH3); 6.60 (s, 1H, C4-
   	(55)	H 4.60	H 4.58	1658	H); 2.70 (dd, 2H, J=8.2, 7.6, C3-H); 1.35	243
   		N 6.14	N 5.80		(s, 3H, C4-CH3); 7.75 (d, 1H, J=8.1,
   					C10-H); 7.30- 7.35 (m, 2H, C8-H & C9-
   					H); 12.12 (bs, 1H, NH)
   2d	255-257	C 65.37	C 65.36	1722	3.75 (s, 3H, C9-OCH3); 6.70 (s, 1H, C4-
   	(55)	H 4.31	H 4.30	1665	H); 2.82 (dd, 2H, J=7.9, 7.4, C3-H); 1.40	259
   		N 5.45	N 5.44		(s, 3H, C4-CH3); 7.50 (d, 1H, J=7.6, C7-
   					H); 7.75 (d, 1H, J=7.8, C10-H); 7.45 (d,
   					1H, J=8, C8-H); 11.75 (bs, 1H, NH)
   2e	268-270	C 65.36	C 65.37	1725	3.75 (s, 3H, C8-OCH3); 6.65 (s, 1H, C4-
   	(55)	H 4.30	H 4.31	1670	H); 2.70 (dd, 2H, J=8.2, 7.7, C3-H); 1.40	259
   		N 5.44	N 5.45		(s, 3H, C4-CH3); 7.50 (d, 1H, J=8.1, C7-
   					H); 7.70 (d, 1H, J=7.9, C10-H); 7.45 (d,
   					1H, J=7.9, C9-H); 11.85 (bs, 1H, NH)
   2f	262-264	C 62.70	C 62.72	1725	3.78 (s, 3H, C7-OCH3); 6.60 (s, 1H, C4-
   	(55)	H 4.53	H 4.56	1665	H); 2.70 (dd, 2H, J=8.1, 7.6, C3-H); 1.35	259
   		N 4.87	N 4.88		(s, 3H, C4-CH3); 7.65 (d, 1H, J=8.2,
   					C10-H); 7.35- 7.40 (m, 2H, C8-H & C9-
   					H); 11.90 (bs, 1H, NH)
   2g	257-259	C 65.36	C 65.37	1715	3.75 (s, 3H, C7-OCH3); 3.95 (s, 3H,
   	(55)	H 4.30	H 4.31	1660	C10-OCH3); 6.55 (s, 1H, C4-H); 2.75	289

   Compd. M.p. 0C

   Elemental analyses IRb

   1H NMRc MS

   N 5.43

   N 5.45

   (dd, 2H, J=8.1, 7.6, C3-H); 1.45 (s, 3H,

   C4-CH3); 7.40- 7.45 (m, 2H, C8-H &

   C9-H); 11.95 (bs, 1H, NH)

   Compd

   1. recrystallized from Petrol-Acetone mixture b) as KBr pellets c) as CDCl3 solvent

      Table II. Antibacterial activity data of (2a-g)a: Organisms Diameter of inhibition zone in mm

      Aeromonas hydrophilla Bacillus subtilis Escherichia coli

      	1 %	2 %	4 %	1 %	2 %	4 %	1 %	2 %	4 %
      2a	–	4.0	6.0	3.0	4.0	4.8	3.0	3.5	5.0
      2b	4.0	6.0	6.0	3.5	4.0	4.5	4.0	4.2	5.1
      2c	–	–	–	4.1	4.5	5.0	4.5	5.0	6.0
      2d	1.0	5.1	7.7	5.5	6.6	7.5	5.1	6.2	6.8
      2e	3.1	3.8	5.9	5.2	6.7	8.3	4.0	6.0	8.1
      2f	4.0	6.0	8.1	4.5	7.2	9.2	5.0	7.1	13.6
      2g	6.0	7.0	14.2	4.0	6.0	13.1	4.4	8.2	15.2

      1. The mean of three replicate values

4. CONCLUSION

We have demonstrated that 4-hydroxy-2(1H)-quinolone is successfully used to synthesize newer derivatives of angular pyranoquinolones in one step method through Michael addition. The expected Michael addition was followed by cyclization, involving the nucleophilic oxygen at C-4 and electrophilic carbonyl carbon in the side chain afforded the product 2(a-g), which was carefully isolated after chromatographic purification. The overall results showed that the derivatives of angular pyranoquinolones are active against the bacterial species. But it could not reach the effectiveness of the conventional bactericide, streptomycin.

ACKNOWLEDGMENT

One of the authors (NVK) is grateful to Ministry of Manpower (Higher College of Technology) Muscat, Sultanate of Oman and Bharathiar University, Coimbatore for providing the facilities, SIF, ESC, Bangalore and IICT, Hyderabad for supporting the spectral studies. We gratefully acknowledge Mr. P.M. Ayyasamy and Prof. K. Lakshmana Perumalswamy, Division of Microbiology, Department of Environmental Sciences, Bharathiar University, Coimbatore for their help in studying the antibacterial activities.

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