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A New Approach for the Synthesis of Some Pyridine and Pyridone Derivatives

0. H. Hishmat*'f, M. M. Y. Zohair**, and J. A. A. Miky** * National Research Center, Dokki, Cairo, Egypt.

** Faculty of Science, Al-Azhar University (Girls), Egypt

Z. Naturforsch. 38b, 1690-1694 (1983); received June 28, 1983

Pyridones, Pyridines

Both visnaginone and khellinone react with malononitrile, ethyl cyanoacetate or cyano-acetamide in presence of ammonium acetate to give substituted furobenzopyrans or furo-benzopy ridones.

However, the reaction of visnaginone and khellinone with aldehydes, and malononitrile in presence of ammonium acetate leads to the formation of the corresponding 2-amino-4,6-disubstituted pyridine 3-carbonitriles. The latter compounds are also obtained by treating the respective chalcones with malononitrile and ammonium acetate.

3-Substituted 1,3-diketobutyrates form with malononitrile or with cyanoacetamide and ammonium acetate the 2-amino-4,6-disubstituted pyridine-3-carbonitriles or the 4,6-di-substituted cyanopyridones, respectively.

Benzofuran derivatives possess marked biological properties [1, 2], On the other hand substituted pyridines show acaricidal, insecticidal and herbicidal activities [3-5]. A compound having both pyridine and benzofuran moieties can be expected to possess marked biological activities. We report in this paper the synthesis of some such type of com-pounds.

In this investigation both Visnaginone (4-me-thoxy-6-hydroxy-5-benzofuranyl methyl ketone) (la) and Khellinone (4,7-dimethoxy-6-hydroxy-5-benzofuranyl methyl ketone) (lb) were used as the starting material, they react with malononitrile in presence of ammonium acetate to form 6-cyano-7-imino-4-methoxy-5-methyl-7H-furo[3,2-g] [1]-benzopyran (2 a) and 6-cyano-7-imino-4,9-dime-thoxy-5-methyl-7H-furo[3,2-g] [l]benzopyran (2b), respectively.

OCH OCH3 CH3

l a : R = H 2 a : R = H ; X = NH lb : R = OCH3 2b : R = OCH3; X = NH

2c : R = H ; X = O 2d: R = OCHs; X = O

+ Reprint requests to Prof. Dr. O. H. Hishmat. 0340-5087/83/1200-1690/$ 01.00/0

Both 2 a and 2 b give no colour reaction with aqueous ferric chloride solution. The structure was confirmed by the infrared spectra which revealed the presence of a - C = N group at 2200 cm -1 and 2250 cm -1, respectively. The NH absorption of the imino group appears at 3350 cm -1 and 3400 cm -1. The C = N absorption occurs at 1620 cm -1 and 1650 cm -1, respectively.

When 2 b was refluxed with acetic acid, the imino group at position 7 was hydrolyzed to the corre-sponding coumarin derivative, namely 6-cyano-4,9-dimethoxy-5-methyl-7 H-furo[3,2-g] [1] benzopyran-7-one (2d). The infrared spectrum of 2d reveals the presence of a - C = N group at 2210 cm -1 and a 0 = 0 group at 1730 cm-1.

Compound 2d was also obtained by treating Khellinone (lb) with ethyl cyanoacetate in presence of ammonium acetate or piperidine. In a similar manner, visnaginone (la) forms 6-cyano-4-me-thoxy-5-methyl-7H-furo [3,2-g] [1] benzopyran-7-one (2 c) when treated with ethyl cyanoacetate.

The reaction of either Visnaginone (la) or Khelli-none (lb) with cyano acetamide in presence of ammonium acetate leads to the formation of the corresponding pyridone derivatives (3a-b) or the possible isomers (4a-b). The infrared spectrum of 3 a taken as an example reveals the presence of the pyridone C = 0 at 1700 cm-1. The C s N group appears at 2200 cm-1 and the NH at 3180 cm-1. Mixed melting point of 3 a with 2 c or with 2 a gave a depression.

O. H. Hishmat et al. • Synthesis of Some Pyridine and Pyridone Derivatives 1691

a: R = H b: R = OCHg

The reaction of Visnaginone (la) or Khellinone (lb) with aldehydes, i.e. acetaldehyde, benzalde-hyde, p-nitrobenzaldehyde, or p-fluorobenzalde-hyde and malononitrile in presence of ammonium acetate leads to the formation of the corresponding 2-amino - 4,6 - disubstituted pyridine - 3 - carbonitrile derivatives (5a-g or the possible isomer 6a-g). The infrared spectra of 5 b and 5 c taken as an example reveal the presence of C=N group at 2200 cm-1. The C=N absorption appears at 1615 cm -1 for 5 b and at 1630 cm"1 for 5 c. Both the NH and OH groups appear as a very broad peak between 3000-3600 cm-1 in both compounds. The compounds give a positive ferric chloride reaction.

a: R = H; R' = CH3 b: R = H; R = CßHs c: R = H; R* = C6H4N02-?? d: R = OCH3; R( - CH3 e: R = OCH3; R* = C6H5 f: R = OCH3; Rx = C6H4N02 ^ g: R = OCH3; R* = C6H4F-^

at 3360 cm-1 for 6 b and at 3340 cm"1 for 6 c, re-spectively.

Compounds 6 e, f and g were prepared by treating the chalcones (7a-c) with malononitrile in presence of ammonium acetate according to Sammour et al. [6], and Sakurai and Midorikawa [7] in 15% yield together with unchanged chalcone (7). When how-ever, the reaction was repeated using an excess of malononitrile and ammonium acetate, the yield was 55%.

OCH, C0CH=CHR

OCH,

a: R = C6H5 b: R = C6H4N02-J9 c: R = C6H4F-p

3-[4-Methoxy-6-hydroxy-5-benzofuranyl] (8 a) and 3-[4,6-dimethoxy-5-benzofuranyl]-l,3-diketo-butyrate (8 c) when fused with malononitrile in the presence of ammonium acetate give the corre-sponding 2-amino-4,6-disubstituted pyridine-3-car-bonitrile derivatives (9 a) and (9 b) or the possible isomers (10a) and (10b), respectively.

OCH, 2 5 C0CH2C0C00C,H

OR

a: R = R' = H b: R = CH3; R* = H c: R = H; Rv = OCH3

The reaction can proceed via the intermediate formation of the chalcones which react instantane-ously with malononitrile through a Michael reac-tion, with elimination of one molecule of water and two hydrogens.

The infrared spectra of 6a, 6b, 6c reveal the presence of a C = N group at 2200 cm -1 for 6 a, 6 b and 6c. The C=N group appears at 1620 cm -1 for 6a, at 1615 cm-1 for 6b and at 1600 cm-1 for 6c. The amino group absorption appears at 3140 cm-1

for 6 a, at 3190 cm-1 for 6 b and at 3160 cm-1 for 6 c. While the OH group occurs at 3450 cm-1 for 6 a,

a : R — R' = H b: R = CH3; Rv = H c : R = H; Rv = OCH3

The infrared spectra of 9 a and 9 b reveal the presence of C = N at 2200 and at 2205 cm"1, re-

COOC2H5

CN COOC2H5

CN

NH

1692 O. H. Hishmat et al. • Synthesis of Some Pyridine and Pyridone Derivatives 1692

spectively. The OH group absorption appears at 3400 cm-1 in the case of 9 a. The amino group absorption appears at 3200 cm-1 for 9 a and at 3320 cm-1 for 9b. The C=N absorption vibrations occur at 1650 cm-1 for both 9a and 9b. The ester C = 0 stretching vibrations occur as 1730 cm -1 for 9a and at 1740 cm-1 for 9b.

When 8 b is fused with cyano acetamide in the presence of ammonium acetate, it forms the re-spective disubstituted cyanopyridone derivative (11a) or the possible isomer (12a).

The infrared spectrum of 11a reveals a C = N group at 2200 cm"1; an ester 0 = 0 at 1740 cm-1

and the pyridone 0 = 0 at 1690 cm-1. Finally an NH group appears at 3250 cm-1.

a: R = CH3 ; R* = H b: R = H ; Rv = OCH3

In a similar manner, 3-[4,7-dimethoxy-6-hy-droxy-5-benzofuranyl] 1,3-diketobutyrate (8 c) re-acts with malononitrile or with cyano acetamide on fusion with ammonium acetate to give the cor-responding 2-amino-4,6-disubstituted pyridine-3-carbonitrile derivative (9 c or 10 c) and the disub-stituted pyridone derivative ( l ib or 12b), respec-tively.

The infrared spectrum of 9 c reveals the presence of an OH group at 3340 cm-1 and an NH group at 3200 cm -1 while the C=N group appears at 1640 cm -1 and the absorption at 2200 cm -1 indi-cates the C = N. Finally the ester 0 = 0 stretching occurs at 1735 cm-1.

Experimental

Melting points are not corrected. The infrared spectra were carried out in potassium bromide on a Unicam SP 1000 infra-red spectrophotometer. The PMR spectra were run in DMSO on a 90 MHz Proton Spectrum.

6-Cyano-7-imino-4-methoxy-5-methyl-7 H-furo-[3,2-g] [1] benzopyran (2 a)

A mixture of 1 g of 1 a, 1 g of malononitrile and 0.8 g of ammonium acetate was fused on a sand-bath (at 160-170 °C) for 1 h to form a brown semi-solid.

It was crystallized from ethanol as yellow crystals, m.p. 230 °C, yield ca. 80%. It gave no colour reac-tion with aqueous ferric chloride solution and a brown colour with concentrated sulphuric acid.

The same product was obtained, by refluxing a mixture of 0.01 mole of 1 a in 20 ml of ethanol with 0.01 mole of malononitrile and ammonium acetate (0.013 mole) in 65% yield. Analysis for C14H10N2O3 (254)

Calcd C 66.13 H 3.93 N 11.02, Found C 65.90 H 3.81 N 11.11.

6-Cyano-7-imino-4,9-dimethoxy-5-methyl-7 H-furo-[3,2-g] [1] benzopyran (2 b)

In a similar manner, when 1 g of 1 b was treated with 1 g of malononitrile in presence of ammonium acetate (0.8 g) as in the case of 2 a, 82% of 2b was obtained. It was crystallized from ethanol as yellow crystals, m.p. 220 °C. It gave a brown colour with concentrated sulphuric acid.

Compound 2 b was also formed by refluxing 1 g of lb, 1 g of malononitrile and 0.8 g of ammonium acetate in ethanol, in 63% yield. Analysis for CI5H12N204 (284)

Calcd C 63.38 H 4.22 N 9.85, Found C 63.15 H 4.51 N 9.49.

The PMR spectrum of 2 b taken as an example reveals d 1.55 s (3H, CHs), 3.85 s and 3.95 s (3H each, OCH3), 7.05 d (IH, J = 2Hz, C-3) and 7.65 d (IH, J = 2 Hz, C-2). MS, m/e M+ 284.

6-Cyano-4-methoxy-5-methyl-7H-furo[3,2-g] [1J-benzopyran-7-one (2 c)

A mixture of la (4 g), ethyl cyanoacetate (4.5 g) and ammonium acetate (4 g) was heated at 160 to 170 °C for 1 h. The brown melt obtained solidified, it was crystallized from butanol to give yellowish crystals m.p. 290 °C; yield ca. 85%.

Compound 2 a was also obtained in 70% yield by refluxing a mixture of l a (1 g), ethyl cyanoacetate (1.1 g) and few drops of piperidine in ethanol (20 ml) for 12 h. Analysis for C14H9NO4 (255)

Calcd C 65.88 H 3.53 N 5.49, Found C 66.10 H 3.91 N 5.82.

6-Cyano-4,9-dimethoxy- 5-methyl-7 H-furo -[3,2-g] [1] benzopyran-7-one (2d)

Compound 2d was obtained in 83% yield as in the case of 2c by heating a mixture of lb (4.5 g),

COOC2H5

CN

O. H. Hishmat et al. • Synthesis of Some Pyridine and Pyridone Derivatives 1693

ethyl cyanoacetate (4 g) and ammonium acetate (4 g) for 1 h at 160-170 °C. The brown solid formed was crystallized from butanol, m.p. 260 °C.

The same product was synthesized by refluxing a mixture of lb (1.1 g), ethyl cyanoacetate (1.1 g) and few drops of piperidine in ethanol (20 ml) for 12 h (yield ca. 71%).

Also refluxing 2 b (1 g) with glacial acetic acid (10 ml) for 2 h gave 2d. Analysis for C15HIIN0-o (285)

Calcd C 63.15 H 3.86 N4.91, Found C 62.79 H4 . l l N 4.68.

The PMR spectrum of 2d show <5 2.90 s (3 H, CH3), 4.15 s and 4.20 s (3H each, OCH3), 7.05 d (IH, J —2 Hz, C-3) and 7.75 d (IH, J = 2 Hz, C-2). MS, m/e M+ 285.

6-Cyano-4-methoxy-5-methyl-7 H-furo[3,2-g] -quinoline-7-one (3 a)

A mixture of la (1 g), cyanoacetamide (1 g) and 0.8 g of ammonium acetate was melted at 160 to 170 °C and kept at that temperature for 1 h. The brownish semi-solid obtained was crystallized from acetone to give yellow crystals of 3a, m.p. 305 °C; yield ca. 55%. Mixed m.p. with either 2a or 2c gave a depression.

Analysis for CI\HwN2OZ (254) Calcd C 66.13 H 3.93 N 11.02, Found C 65.89 H 3.67 N 10.88.

6-Cyano-4,9-dimethoxy-5-methyl-7 H-furo-[3,2-g] quinoline-7-one (3b)

Compound 3 b was synthesized as in the case of 3a by using l b (1 g), cyanoacetamide (1 g) and

ammonium acetate (0.8 g). The brown semi-solid obtained was crystallized from acetone as yellow crystals, m.p. 270 °C, yield ca. 52%. Analysis for C10H12N2O4 (284)

Calcd C 63.38 H 4.22 N 9.85, Found C 63.19 H4.19 N 9.67.

2-Amino-4,6-disubstituted pyridine-3-carbonitrile derivatives (5a-g) and (9a-c) General procedure

To la, l b or 8a-c (0.01 mole was added malono-nitrile (0.02 mole), the appropriate aldehyde (0.01 mole) and ammonium acetate (0.02 mole). The reaction mixture was heated at 160-170 °C for 1 h. The semi-solid so obtained was crystallized from a suitable solvent to give yellow crystals, 5 a-g give a pale green colour reaction with aqueous ferric chloride solution.

4,7-Dimethoxy-6-hydroxy-5- (p-nitroc innamoyl )-benzofuran (7 b)

To a mixture of lb (1 mole) and p-nitrobenz-aldehyde (1 mole) dissolved in 40 ml ethanol was added 20 ml of sodium hydroxide solution (10%). The reaction mixture was shaked for 30 min at room temperature then left overnight. Acidify with dilute hydrochloric acid and filter the solid and crystallize from ethanol as red crystals, m.p. 170 °C, yield ca. 72%. It gave pale green colour with aqueous ferric chloride solution and red colour with concentrated sulphuric acid.

Analysis for C^H^NO-, (369) Calcd C 61.78 H 4.06 N 3.79, Found C 61.63 H 3.89 N4.01.

Table. List of pyridine derivatives.

Com-pound No.

Yield [°C] [ % ]

Solvent of crystallisation Formula Carbon

Analysis Hydrogen Nitrogen

Calcd Found Calcd Found Calcd Found

5a 250 70 Butanol C16H15N3O3 (297) 64.65 64.39 5.05 4.88 14.14 13.83 5b 190 80 Dilute ethanol C2IHI7N303 (359) 70.196 69.86 4.74 4.49 11.69 11.65 5c 258-260 70 Butanol C2IHI6N405 (404) 62.38 62.60 3.96 3.93 13.86 13.59 5d 240 65 Butanol CL7HI7N304 (327) 62.38 62.19 5.199 5.40 12.85 13.10 5e* + 250 90 Ethanol C22HIGN304 (389) 67.86 68.10 4.88 5.20 10.79 10.49 5f* 310 70 Butanol C22HI8N406 (434) 60.83 60.59 4.15 3.88 12.9 12.86 5g* 240 70 Ethanol C22HI6N304F (405) 52.27 52.56 3.18 3.32 8.31 8.17 9a 240 55 Methanol CI8HI5N305 (353) 61.19 61.63 4.25 3.89 11.90 11.64 9b 240 50 Methanol C19H17N3O5 (367) 62.12 61.98 4.63 4.90 11.44 11.61 9c 180 61 Methanol CL9HI7N306 (383) 59.53 59.70 4.44 4.72 10.97 10.68

* 5e-g were also obtained by heating 7 a [8], 7 b, 7 c (0.05 mole) with malononitrile (0.05 mole) in presence of ammonium acetate (0.03 mole) for 4 h at 140-150° (6, 7), in 15% yield (m.p. and mixed m.p.). However, when the reaction was repeated using an excess of malononitrite (0.15 mole) the yield was increased to 55% (m.p. and mixed m.p.).

+ PMR of 5e, ö 3.90 s (3H, OCH3), 4.10 s (3H, OCH3), 5.10-5.25 broad peak (2H, NH2), 6.85 d (IH, J= 2 Hz, C-3), 7.45-7.75 m (6H, 5 aromatic and C-2) and 7.80 s (IH, C-5 of the pyridine moiety). MS, m/e M+ 387.

1694 O. H. Hishmat et al. • Synthesis of Some Pyridine and Pyridone Derivatives 1694

4,7-Dimethoxy-6-hydroxy-5-(p-fluoro cinnamoyl)-benzofuran (7 c)

Was prepared as above in the case of 7 b to give orange crystals, m.p. 125 °C, yield ca. 65% and gave pale yellowish green colour with aqueous ferric chloride solution.

Analysis for C19HI505F (342) Calcd C 66.66 H 4.38 F 5.55, Found C 66.63 H 3.99 F 5.74.

Disubstituted cyanopyridones ( l l a - b ) The same procedure was applied, using cyano

acetamide (1 g) instead of malononitrile with 8 b or 8c (1 g) in presence of ammonium acetate (0.8 g).

11a was crystallized from petroleum ether (b.p. 80-110 °C) as pale yellow crystals, m.p. 100 °C, yield ca. 50%. It gave no colour with aqueous ferric chloride solution.

Analysis for C^H^N^OE (368) Calcd C 61.95 H 4.34 N7.61, Found C 61.69 H4.17 N 8.09.

l ib was obtained as yellow crystals from petro-leum ether (b.p. 80-110 °C), m.p. 140 °C; yield ca. 55%. It gave a green colour with aqueous ferric chloride solution. Analysis for C19H16N20I (384)

Calcd C 59.37 H4.16 N 7.31, Found C 58.82 H 3.89 N 7.61.

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