Indian Journal of Chemistry-B
Vol. 44B, September 2005, pp. 1887-1893

Novel fluoro substituted benzo[b]pyran with anti-lung cancer activity

Abou El-Fotooh G Hammam*, Osama I Abd El-Salam, Ashraf M Mohamed & Nagla Abdel Hafez

Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo-12622, Egypt

E-mail: Abo_elfotooh@yahoo.com

Received 4 January 2005; accepted (revised) 8 June 2005

6-Fluorobenzo[b]pyran-4-one 1 on condensation with aromatic aldehydes yields 3-arylmethylene-6-fluoro-2,3-dihydrobenzo[b]pyran-4-ones 2 which on treatment with phenylhydrazine and thiourea gives the pyrazole and pyrimidine thione derivatives 3 and 4, respectively. Compound 4 reacts with chloroacetic acid in acetic acid-acetic anhydride mixture to afford the thiazolopyrimidines 5 which on condensation with aromatic aldehyde furnish the corresponding arylmethylene­thiazolopyrimidine derivatives 6. The product 6 could be prepared directly by the action of chloroacetic acid and the proper aldehyde on 4 in the presence of acetic acid-acetic anhydride mixture. Product 2 reacts with malononitrile in the presence of ammonium acetate or piperidine to afford the pyridine- and pyran- 7 and 8 derivatives, respectively. Also, compound 1 on treatment with arylmethylenecyanoacetamide yields the pyridone derivatives 9. Condensation of 1 with malononitrile affords the yliedinemalononitrile 10, which on reaction with p-chlorobenzaldehyde-ammonium acetate or arylmethylene-cyano­acetamide yields the pyridine derivative 11 (isomer of 8) and the dicarbonitrile derivative 12, respectively. The synthesized compounds have been tested against three cell lines of human cancer (lung, breast and CNS cancer), and these compounds show anticancer activity at low concentration as compared to reference drug 5-fluorodeoxyuridine.

Keywords: 6-Fluorobenzo[b]pyran-4-one, pyran-4-ones, phenylhydrazine, thiourea, pyrimidine thione, thiazolopyrimidines, arylmethylene­thiazolopyrimidine derivatives, dicarbonitrile derivative, human cancer, anticancer activity

IPC: Int.Cl.7 C 07 D // A 61 P 35/00

 

In continuation to our drug research program1-8, the present work is aimed towards the construction of novel heterocyclic compounds of anticipated utility as anti-cancer agents. Since fluorine-containing compounds are of promising pharmacological acti­vities which are originated from their unique high thermal stabilities and lipophilicity9, some novel fluoro-substituted benzo[b]pyran compounds are synthesized, which exhibited higher anti-cancer activities (specially as anti-lung cancer) when compared with our previous work dealing with the unsubstituted benzo[b]pyran derivatives, which showed moderate anti-cancer activities6.

Results and Discussion

6-Fluorobenzo[b]pyran-4-one 1 was condensed with the proper aldehyde in the presence of ethanolic potassium hydroxide to yield 3-arylmethylene-6-fluoro-2,3-dihydrobenzo[b]pyran-4-one derivatives 2 (Scheme I). Product 2d showed IR absorption at 1660 cm-1 (C=O) and its 1H  NMR (CDCl3) showed a singlet at d 7.8 and a multiplet at d 7.5-6.9 for the benzylic proton (1H) and aromatic protons (6H), respectively, two singlets at d 3.9 for the two methoxy groups (6H) and a singlet at d 3.7 for the pyran protons (2H). The mass spectrum of 2d showed the molecular ion peak [M+] at m/z 314 (100%, base peak) and a peak at m/z 177 (36%) for [M+ - C6H3 (OCH3)2-3,4].

 

 

 

Scheme I

 

 

Compounds 2 were reacted with phenylhydrazine in ethanol using triethylamine as a catalyst to yield 3-aryl-8-fluoro-2-phenyl-2, 3, 3a, 4-tetrahydrobenzo[b]­py­rano­[4,3-c]pyrazole derivatives 3a-c (Scheme I, Table I). The IR spectra of the products 3 showed peaks at 1675 and 1668 cm-1 (C=N). The 1H NMR (DMSO-d6) of product 3a showed the following signals at d 7.70-6.90 (12 H, m, ArH), 4.9 (1 H, d, Ha), 4.6 (1 H, m, Hb), 4.5 (1 H, d, Hc), 4.3 (1 H, m, Hd) and 2.33 (3H, s, CH3). The mass spectrum of product 3c showed peaks at m/z 422 (100%, base peak) [M+], 424 (97.65%) [M+ +2] due to the presence of bromine atom and 267 (12%) [M+- C6H4Br-4]. Both the IR and 1H NMR spectral data (Table II) showed the absence of NH group indicating that the formation of the cyclized product 3A is tentatively favoured over the isomeric structure 3B.

 

 

 

Table I ¾ Physical data of prepared compounds

Compd

Ar

m.p.
(Solvent)

Mol. formula
(Mol. Wt)

 Calcd % (Found)

C

H

N

2a

4-CH3.C6H4

165-67
(EtOH)

C17H12FO2
(267.27)

76.11
(76.06

4.88
4.82

-
-)

2b

4-F.C6H4

149-51
(EtOH)

C16H10F2O2
(272.25)

70.59
(70.56

3.70
3.68

-
-)

2c

4-Cl.C6H4

209-11
(EtOH)

C16H10ClFO2
(288.7)

66.56
(66.52

3.49
3.47

-
-)

2d

3,4-(OCH3)2. C6H3

199-201
(EtOH)

C18H15FO4
(314.31)

68.78
(68.72

4.81
4.76

-
-)

2e

4-Br.C6H4

206-08
(dioxane)

C16H10BrFO2
(333.15)

57.68
(57.59

3.03
2.95

-
-)

3a

4-CH3.C6H4

119-21
(dioxane)

C23H19FN2O
(358.41)

77.08
(77.00

5.34
5.26

7.82
7.88)

3b

4-F.C6H4

124-26
(EtOH)

C22H16F2N2O
(362.37)

72.92
(72.86

4.45
4.38

7.73
7.68)

3c

4-Br.C6H4

150-52
(dioxane)

C22H16BrFN2O
(423.28)

62.43
(62.34

3.81
3.76

6.62
6.70)

4a

4-CH3.C6H4

203-05
(EtOH)

C18H15FN2OS
(326.39)

66.24
(66.18

4.63
4.58

8.58
8.52)

4b

4-F.C6H4

274-76
(dioxane)

C17H12F2N2OS
(330.35)

61.81
(61.76

3.66
3.64

8.48
8.44)

4c

4-Cl.C6H4

245-47
(dioxane)

C17H12ClFN2OS
(346.81)

58.87
(58.82

3.49
3.43

8.08
7.98)

4d

3,4-(OCH3)2. C6H3

142-44
(EtOH)

C19H17FN2O3S
(372.41)

61.28
(61.18

4.60
4.56

7.52
7.48)

4e

4-Br.C6H4

259-61
(dioxane)

C17H12BrFN2OS
(391.26)

52.19
(52.12

3.09
3.10

7.16
7.12)

5a

4-Cl.C6H4

123-25
(EtOH)

C19H12ClFN2O2S
(386.83)

58.99
(58.88

3.13
3.10

7.24
7.30)

5b

3,4-(OCH3)2. C6H3

114-16
(EtOH)

C21H17FN2O4S
(412.43)

61.16
(61.10

4.15
4.10

6.79
6.81)

6a

4-F.C6H4,
X= Br

189-191
(dioxane)

C26H15BrF2N2O2S
(537.38)

58.11
(57.99

2.81
2.74

5.21
5.18)

6b

4-Cl.C6H4,
X= Cl

140-42
(EtOH)

C26H15Cl2FN2O2S
(509.38)

61.31
(61.24

2.97
2.93

5.50
5.45)

6c

3,4-(OCH3)2. C6H3,
X= OCH3-4

130-32
(EtOH)

C29H23FN2O5S
(530.57)

65.65
(65.52

3.58
3.54

5.28
5.23)

7a

4-F.C6H4

309-11
(dioxane)

C19H12F2N2O2
(338.31)

67.45
(67.36

3.58
3.54

8.28
8.22)

7b

4-Cl.C6H4

303-05
(dioxane)

C19H12ClFN2O2
(354.76)

64.33
(64.28

3.41
3.38

7.90
7.95)

7c

3,4-(OCH3)2. C6H3

179-81
(EtOH)

C21H17FN2O4
(380.37)

66.31
(66.22

4.50
4.48

7.36
7.32)

8a

4-Cl.C6H4

135-37
(EtOH)

C19H11ClFN3O
(351.76)

64.87
(64.82

3.15
3.11

11.95
11.96)

8b

3,4-(OCH3)2. C6H3

218-20
(dioxane)

C21H16FN3O3
(377.37)

66.84
(66.76

4.27
4.23

11.14
11.15)

9a

4-CH3.C6H4

310-12
(dioxane)

C20H13FN2O2
(332.33)

72.28
(72.22

3.94
3.89

8.43
8.45)

9b

4-F.C6H4

305-07
(dioxane)

C19H10F2N2O2
(336.29)

67.86
(67.75

3.00
2.98

8.33
8.28)

9c

4-Cl.C6H4

299-301
(dioxane)

C19H10ClFN2O2
(352.75)

64.69
(64.63

2.86
2.81

7.94
7.97)

9d

3,4-(OCH3)2. C6H3

158-60
(EtOH)

C21H15FN2O4
(378.35)

66.66
(66.60

4.00
3.98

7.40
7.42)

10

-

296-98
(dioxane)

C12H7FN2O
(214.20)

67.29
(67.25

3.29
3.24

13.08
13.10)

11

4-Cl.C6H4

153-55
(dioxane)

C19H11ClFN3O
(351.76)

64.87
(64.82

3.15
3.10

11.95
11.97)

12

4-Cl.C6H4

254-56
(dioxane)

C21H11ClFN3O
(375.78)

67.12
(67.10

2.95
2.92

11.18
11.16)

 

 

 

 

Table II ¾ Spectral data of compounds having anticancer activity

Compd

1H NMR
 (
d, ppm)

Solvent*

MS
m/z (%)

3b

7.7-6.9 (m, 12H, Ar-H), 4.9 (d, 1H, Ha), 4.6 (m, 1H, Hb), 4.5 (d, 1H, Hc), 4.3 (m, 1H, Hd).

C

362 (M+, base peak, 100%), 267 (M+- C6H4-F, 45%).

3c

7.71-6.91 (m, 12H, Ar-H), 4.92 (d, 1H, Ha), 4.7 (m, 1H, Hb), 4.6 (d, 1H, Hc), 4.4 (m, 1H, Hd).

D

422 (M+, base peak, 100%), 424 (M++2, 97.65%), 267 (M+- C6H4-Br, 0.3%).

4c

9.8 (s, 1H, NH, D2O exchangeable), 8.0 (s, 1H, NH, D2O exchangeable), 7.8-6.9 (m, 7H, Ar-H), 5.2 (s, 1H, pyrimidine-H), 4.8 (d, 1H, pyran-H), 4.6 (d, 1H, pyran-H).

D

394 (M+, base peak, 100%), 235 (M+- C6H4-Cl, 35%).

4d

9.9 (s, 1H, NH, D2O exchangeable), 8.1 (s, 1H, NH, D2O exchangeable), 7.7-6.9 (m, 6H, Ar-H), 4.9 (s, 1H, pyrimidine-H), 4.8 (d, 1H, pyran-H), 4.7 (d, 1H, pyran-H), 3.9 (s, 6H, 2 x OCH3).

C

372 (M+, base peak, 100%), 238 (M+- C6H3(OCH3)2, 40%).

5a

7.4-6.9 (m, 7H, Ar-H), 5.5 (s, 1H, pyrimidine-H), 4.8 (d, 1H, pyran-H), 4.6 (d, 1H, pyran-H), 3.7 (s, 2H, thiazole-H).

C

388 (M++2, 42%), 386 (M+, base peak, 100%), 275 (M+- C6H4-Cl, 41%).

6c

7.8-6.9 (m, 11H, Ar-H+benzylic-H), 5.5 (s, 1H, pyrimidine-H), 4.6 (d, 1H, pyran-H), 4.1 (d, 1H, pyran-H), 4.0 (s, 2H, thiazole-H), 3.9 (s, 3H, OCH3), 3.7 (s, 6H, 2 x OCH3).

C

530 (M+, base peak, 100%), 392 (M+- C6H3(OCH3)2, 30%).

7c

7.8-6.8 (m, 6H, Ar-H), 4.7 (s, 2H, NH2, D2O exchangeable), 4.5 (d, 1H, pyran-H), 4.3 (m, 1H, pyran-H), 4.1 (s, 1H, pyran-H), 3.9 (s, 6H, 2 x OCH3).

C

380 (M+, base peak, 100%), 242 (M+- C6H3(OCH3)2, 40%).

8a

7.51-6.8 (m, 7H, Ar-H), 4.8 (s, 2H, NH2, D2O exchangeable), 4.6 (s, 2H, pyran-H).

C

353 (M++2, 46%), 351 (M+, base peak, 100%), 240 (M+- C6H4-Cl, 17%).

8b

7.51-6.8 (m, 6H, Ar-H), 4.8 (s, 2H, NH2, D2O exchangeable), 4.5 (s, 2H, pyran-H), 3.8 (s, 6H, 2 x OCH3).

D

377 (M+, base peak, 100%), 239 (M+- C6H3(OCH3)2, 55%).

9a

12.8 (br s, 1H, NH, D2O exchangeable), 7.6-6.9 (m, 7H, Ar-H), 4.5 (s, 2H, pyran-H), 3.5 (s, 3H, OCH3).

D

332 (M+, base peak, 100%), 240 (M+- C6H4OCH3, 55%).

9b

12.8 (br s, 1H, NH, D2O exchangeable), 7.7-6.8 (m, 7H, Ar-H), 4.4 (s, 2H, pyran-H).

D

336 (M+, base peak, 100%), 241 (M+- C6H4-Cl, 25%).

9c

12.5 (br s, 1H, NH, D2O exchangeable), 7.6-6.8 (m, 7H, Ar-H), 4.5 (s, 2H, pyran-H).

D

354 [(M++2), base peak, 100%], 352 (M+, 35%), 241 (M+- C6H4-Cl, 9%).

9d

12.5 (br s, 1H, NH, D2O exchangeable), 7.6-6.8 (m, 6H, Ar-H), 4.6 (s, 2H, pyran-H), 3.8 (s, 6H, 2 x OCH3).

C

378 (M+, base peak, 100%), 352 (M+- C≡N, 10%).

10

7.6 (m, 3H, Ar-H), 3.4 (t, 2H, OCH2), 2.9 (s, 2H, =C-CH2).

D

214 (M+, base peak, 100%), 188 (M+- C≡N, 21%).

11

7.8-6.9 (m, 7H, Ar-H), 5.5 (s, 2H, NH2, D2O exchangeable), 4.9 (s, 2H, pyran-H).

D

353 (M++2, 31%), 351 (M+, base peak, 100%), 240 (M+- C6H4-Cl, 7%).

12

7.5-7.1 (m, 7H, Ar-H), 6.25 (s, 2H, NH2, D2O exchangeable), 4.7 (s, 2H, pyran-H).

D

375 (M+, 10%), 340 (M+ - Cl, base peak, 100%), 264 (M+- C6H4-Cl, 30%).

*Solvent: C= CDCl3, D= DMSO-d6

 

 

     Compound 2 was condensed with thiourea in ethanolic potassium hydroxide to yield 4-aryl-9-fluoro-2, 3, 4, 5-tetrahydrobenzo[b]thiopyrano[4,3-d]­pyri­midine-2(1H)-thione derivatives 4. Compound 4 showed IR absorptions at 3434-3259 cm-1 (NH). The 1H NMR (DMSO-d6) of 4a showed two singlets at d 9.8 and 8.0 (2 H, NH, exchanged with D2O), a multiplet at d 7.8-6.9 (7H, ArH), a singlet at d 5 for the pyrimidine proton and two doublets at d 4.8 and 4.6 for the pyran protons. The mass spectrum of product 4e showed peaks at m/z 392 (100%, base peak) [M+ + 2] and 235 (27%) [M+- C6H4Br-4]. Pyrimidine thione derivatives 4 were reacted with chloroacetic acid in the presence of fused sodium acetate and acetic acid-acetic anhydride mixture to give 4-aryl-10-fluoro-2,3,5,6-tetrahydro­benzo[b]­pyr­a-­ no­[4,3-d]thiazolo[3,2-a]pyrimidin-3-ones 5. The IR spectra of 5 showed peaks at 1722 cm-1 (C=O). The 1H NMR (DMSO-d6) of 5b showed a multiplet at d 7.8-6.9 (6H, ArH), a singlet at d 5.6 for the pyrimidine proton, a singlet at d 4.0 (2H) for the thiazole ring protons, two doublets at d 4.8 and 4.6 for the pyran protons and a singlet at d 3.9 for the two methoxy groups (6H). The mass spectrum of 5b showed the molecular ion peak [M+] at m/z 412 (100, base peak), and a peak at m/z 275 (24%) for [M+- C6H3 (OCH3)2-3,4]. The formation of the linear cyclized products 5A is tentatively favoured over the angular structure 5B due to the chemical shift of the pyrimidine proton which was deshielded by about d 0.6 relative to the pyrimidine proton of compounds 4.

Product 5 was condensed with the proper aromatic aldehydes in refluxing acetic anhydride to afford 4-aryl-2-arylmethylene-10-fluoro-2,3,5,6-tetrahydro­be­n­­zo[b]-pyrano[4,3-d]thiazolo[3,2-a]pyrimidin-3-one derivatives 6 (Method A). Compounds 6 were prepared directly by the action of chloroacetic acid and the proper aromatic aldehydes on 4 in the presence of fused sodium acetate and acetic acid-acetic anhydride mixture (Method B). The IR spectra of compounds 6 showed absorption peaks at 1700-1710 cm-1 (C=O). The 1H NMR (DMSO-d6) of 6b showed signals at d 7.80-6.90 (m, 11H, Ar-H + benzylic-H), 5.5 (s, 1H, pyrimidine-H, 4.6 (d, 1H, pyran-H) and 4.1 (d, 1H, pyran-H). The mass spectrum of 6a showed the molecular ion peak [M+] at m/z 537 (100%, base peak) and other peaks at m/z 539 (11%) for [M++2], 443 (20%) for [M+ - C6H4F-4] and 415 (41%) for [443-(C=O)].

Compounds 2 reacted with malononitrile in ethanol in the presence of piperidine at room temperature to yield 2-amino-4-aryl-9-fluoro-4,5-dihydrobenzo­[b]pyr­ano[4,3-b]pyran-3-carbonitrile derivatives 7. The IR spectra of product 7 showed peaks at 3401-3345 (NH2) and 2223-2219 cm-1. The 1H  NMR (CDCl3) of 7a showed signals at d 7.70-6.75 (m, 7 H, ArH), 4.7 (s, 2 H, NH2, exchangeable with D2O), 4.5 (d, 1 H, Ha), 4.3 (1 H, m, Hb) and 4.1 (1 H, d, Hc).

Also, compounds 2 were condensed with malo­nonitrile and ammonium acetate in the presence of triethyl amine to afford 2-amino-4-aryl-9-fluoro-5H-benzo­[b]pyrano-[4,3-b]pyridine-3-carbonitrile deri­va­tives 8. Its spectral data are given in Table II.

Compound 1 was reacted with the proper arylmethylenecyanoacetamide derivatives to yield 4-aryl-9-fluoro-1,2-dihydro-2-oxo-benzo[b]pyrano[4,3-b]pyridine-3-carbonitrile derivatives 9 (Scheme I). Its spectral data are given in Table II.

On the other hand, condensation of 1 with malo­nonitrile gave 2-(6-fluorobenzo[b]pyran-4-yildine)­malononitrile 10. Product 10 on reaction with p-chlorobenzaldehyde and ammonium acetate in acetic acid gave 2-amino-4-(4-chlorophenyl)-9-fluoro-5H-benzo[b]pyrano[3,4-c]pyridine-1-carbonitrile5,6 11.

Compounds 10 were condensed with arylmethyl­ene­cyanoacetamide in ethanol in the presence of triethyl amine to yield 2-amino-4-aryl-9-fluoro-5H-dibenzo[b,d]pyrano-1,3-dicarbonitrile 12 [see original reference]10 The spectral data of compounds 10-12 are given in Table II.

Biological activity

Some of the synthesized heterocyclic compounds were screened for their anticancer activity. Each compound was tested at five different concentrations against 3 cell lines of human cancer which are Lung, Breast and CNS cancer. The results expressed as log10GI50, which the drug concentration (M) is causing a 50% reduction in the net protein increase in control cells during the drug incubation, are collected in Table III. An inspection of these data shows that the majority of the compounds tested exhibit lung anticancer activity at low concentration comparable with that of 5-fluorodeoxyuridine (log10GI50= -4.7) used as the reference compound11.

 

 

Table III ¾ In vitro tumor cell growth inhibition data against different tumor/cell lines

Compd

Panel/cell line

Activity

Lung cancer
NCI-H460

Breast cancer
MCF7

CNS cancer
SF-268

 

3b

1

56

85

active

4c

16

81

83

active

4d

5

21

43

active

5b

49

36

92

active

6c

25

37

77

active

7c

22

37

63

active

8a

17

60

72

active

8b

0

24

54

active

9a

13

53

79

active

9b

79

83

104

inactive

9c

18

77

88

active

9d

90

57

108

inactive

10

23

59

70

active

11

17

60

72

active

12

20

98

89

active

 

Experimental Section

Melting points are uncorrected and are taken on Electrothermal IA 9000 Series digital melting point apparatus. Microanalyses were performed by the Central Services Laboratory, NRC. IR spectra were recorded on a CarlZeiss spectrophotometer model “UR 10” using KBr; 1H NMR spectra on a Varian Gemini 200 MHz using TMS as an internal standard; and mass spectra on a Finnigan SSQ-7000 mass spectrometer. Purity of the products was checked by TLC on silica gel aluminum sheets 60F254 (E. Merck).

3-Arylmethylene-6-fluoro-2,3-dihydrobenzo­[b]­pyran-4-ones 2. A solution of KOH [5.6 g (100 mmoles) in 5 mL H2O] was added to a mixture of 6-fluorobenzo[b]pyran-4-one 1 (16.6 g, 100 mmoles) and the aromatic aldehydes (100 mmoles) in ethanol (50 mL), and the reaction mixture was stirred at room temperature for half-an-hour. The formed yellow precipitate was filtered off, washed thoroughly with water, dried and crystallized from ethanol to give 2 (Table I).

3-Aryl-8-fluoro-2-phenyl-2,3,3a,4-tetrahydro­be­n­zo[b]pyrano[4,3-c]pyrazoles 3. A suspension of 2 (2 mmoles) in gl. acetic acid (10 mL) was treated with phenylhydrazine (0.2 mL º 0.22 g, 2 mmoles). The reaction mixture was refluxed for 2hr, poured onto water and the solid formed was separated by filtration and crystallized from ethanol to yield 3 (Table I).

4-Aryl-9-fluoro-2,3,4,5-tetrahydroben­zo[b]thio­pyrano[4,3-d]pyrimidine-2(1H)-thiones  4. To a mixture of 2 (10 mmoles) and thiourea (1 g, 13 mmoles) in ethanol (50 mL), was added a solution of KOH [(1 g, 18 mmoles in H2O (1 mL)]. The mixture was refluxed for 4 hr, poured onto water and the solid formed was filtered off, dried and crystallized from dioxane to get 4 (Table I).

4-Aryl-10-flouro-2,3,5,6-tetrahydrobenzo[b]­pyr­a­no[4,3-d]thiazolo[3,2-a]-pyrimidin-3-ones 5. A mixture of 4 (10 mmoles), chloroacetic acid (1 g, 11 mmoles), fused sodium acetate (4 g, 49 mmoles), acetic acid (40 mL) and acetic anhydride (20 mL) was refluxed for 4 hr, cooled and poured onto water. The solid formed was collected by filtration, washed with water, dried and crystallized from ethanol to get 5 (the product didn’t dissolve in a sodium hydroxide solution) (Table I).

     4-Aryl-2-arylmethylene-10-fluoro-2,3,5,6-tetra­hydrobenzo[b]pyrano[4,3-d]thiazolo[3,2-a]pyri­mi­din-9-ones 6.          Method A ¾ Equimolar amount (10 mmoles) of compound 5 and the appropriate aromatic aldehyde, gl. acetic acid (30 mL), acetic anhydride (10 mL) and fused sodium acetate (3 g, 37 mmoles) were refluxed for 1hr, cooled and poured onto cold water. The solid formed was collected by filtration and crystallized from proper solvent to get 6b,c (Table I).

Method B ¾ A mixture of 4 (10 mmoles), chloroacetic acid (1.39 g, 10 mmoles), fused sodium acetate (2 g, 24 mmoles), acetic acid (30 mL), acetic anhydride (10 mL) and the proper aromatic aldehyde (10 mmoles) was refluxed for 3 hr. The reaction mixture was cooled and poured onto cold water. The solid formed was collected by filtration, dried and crystallized from the proper solvent to get 6 (Table I).

2-amino-4-aryl-9-fluoro-4,5-dihydro­benzo[b]­py­r­a­no[4,3-b]pyrane-3-carbonitriles 7. A mixture of  2 (10 mmoles) and malononitrile (0.66 g, 10 mmoles), and piperidine (2 mL) in ethanol (100 mL) was stirred at room temperature for 1 hr. Excess solvent was distilled off under reduced pressure and the residue obtained was dissolved in acetic acid and poured onto ice-water. The separated solid was collected by filtration, dried and crystallized from the proper solvent to afford 7 (Table I).

2-Amino-4-aryl-9-fluoro-5H-benzo[b]pyrano-[4,3-bpyridine-3-carbonitriles 8. A few drops of TEA were added to a mixture of 2 (3 g, 10 mmoles), malononitrile (0.66 g, 10 mmoles) and ammonium acetate (0.62 g, 80 mmoles) in absolute ethanol (50 mL). The reaction mixture was refluxed for 8 hr, allowed to cool and poured gradually while stirring onto cold water. The solid formed was collected by filtration, dried and crystallized from the proper solvent to get 8 (Table I).

4-Aryl-9-fluoro-1,2-dihydro-2-oxobenzo[b]­pyra­no­[4,3-b]pyridine-3-carbonitriles 9. To a mixture of 1 (1.66 g, 10 mmoles) and the proper arymethylene­cyanoacetamide derivatives (10 mmoles) in ethanol (50 mL), a few drops of TEA were added and the reaction mixture was refluxed for 8hr, allowed to cool, then poured onto ice-water. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to give 9, respectively (Table I).

2-(6-Fluorobenzo[b]pyran-4-yildine)malo­noni­trile 10. A mixture of 1 (1.66 g, 10 mmoles), malononitrile (0.66 g, 10 mmoles) and b–alanine (50 mg) in ethanol (25 mL) was refluxed for 3hr. The reaction mixture was cooled and poured onto cold water. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to get 10 (Table I).

2-Amino-4-(4¢-chlorophenyl)-9-fluoro-5H-ben­zo­­[b]pyrano[3,4-c]-pyridine-1-carbonitrile 11. A mix­ture of 10 (1.07 g, 5 mmoles), 4-chloro­benzalde­hyde (0.7 g, 5 mmoles) and ammonium acetate (1.4 g, 20 mmoles) in ethanol (50 mL) was refluxed for 5hr. The reaction mixture was cooled and poured onto ice-water. The solid formed was filtered off, washed thoroughly with water, dried and crystallized from the proper solvent to afford 11 (Table I).

2-Amino-4-(4¢-chlorophenyl)-9-fluoro-5H-diben­zo[b,d]pyrano-1,3-dicarbonitrile 12. To a mixture of 10 (1.66 g, 10 mmoles), arylmethylene­cyanoaceta­mide derivative (2.06 g, 10 mmoles) in ethanol (50 mL), a few drops of TEA were added. The reaction mixture was refluxed for 8hr, cooled and poured onto ice-water. The solid formed was filtered off, washed with water, dried and crystallized from the proper solvent to yield 12 (Table I).

Acknowledgement

Authors thank the United States National Institute of Health (NIH)/National Cancer Institute (NCI) and specially Dr V L Narayanan and his team, for the inhibition of tumor growth measurements reported in this paper.

 

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