Indian Journal of Chemistry Vol. 40B, July 2001, pp. 558-564 Synthesis of nove1 2,6-disubstituted-3-amino-4-trifluoromethylfuro- [2,3-b ]pyridines t K Srinivas, B Narsaiah*, P Shanthan Rao & J Madhusudana Rao Indian Institute of Chemical Technology, Hyderabad-5 7, India Received 4 February 2000; accepted (revised) 26 Februa 2001 A series of novel 2-acyl or benzoyl-3-amino-4-triuoromethyl-6-substituted furo[2,3-b]-pyridines have been synthesised from 4-tritluoromethyl-6-substituted- l ,2-dihydro-2-oxo-3-pyridine carbonitrile via 2-0-phenacyl or acetonyl-3-cyano- 4-tritluoromethyl-6-substituted pyridines. The furo[2,3-b]-pyridines are structurally analogous to indoles and quinolines I . They are known to have biological activity because the furo[2,3- b]pyridine . moiety is present in furo[2,3-b]quinoline alkaloids 2 isolated from some Rutaceae and makes the back- bone of furo[2,3- b]pyridine alkaloids 3 . The furo[2, 3-b]pyridine ring system have been claimed as potent herbicides 4 and as integral components of cephalo- sporine derivatives 5 . The furo[2,3-b]pyridines are mainly formed by the fusion of (n) deficient pyridine and a (n) excessive furan ring. The earlier reports on the synthesis of furo[2,3-b]pyridines are mainly fusion of furan ring to pyridines 6 - l o and pyridine ring to furan I I . Some of the reports are by intramolecular Diels-Alder cyclisation of 1, 2, 4-triazines 12 - 17 , 1, 3- pyrimidines 1 8 .19 and pyrazines 2 0 • 21 with dienophilic side chain and by rearrangement of azepines 22 • 23 . However, no report on fluorinated furo[2,3-b] - pyridine except under ref. lO is avai lable in literature. The fluorinated furo[2,3-b]-pyridines are supposed to have enhanced activity due to their lip ophilic nature. Therefore our continued interest on the synthesis of fluorinated pyridones 24 , fused pyridines such as pyrido[3',2' :4,5]furo[3,2-d]-1 ,3-pyrimi dines 2 5, pyrido- [3'2':4, 5]furo[3, 2-d]-1, 3 -oxazines 26 , N-allyl -2(lH) - pyridones 27 , prompted us to synthesise a series of novel fluorinated furo[2,3-b]pyridines. Results and Discussion We have shown earlier that when 4-trifluoro- methyl-6-substituted- l, 2-dihydro-2-oxo-pyridine car- *Corresponding author. E-mail:narsaiahbanda@ 1 23india.com t IlCT Communication No. 4444 bonitrile 1 24 was reacted with bromoethylacetate, exclusive O-alkylation products were formed. This 0- alkylation is mainly presumed to be due to the presence of bulky substituent in the ortho position of nitrogen in pyridone 2 8 and effect of trifluoromethyl group which profoundly enhances the aromaticity of the ring 2 9 • The O-alkylated products were cyclised using Thorpe Ziegler reaction 3 0 . Accordingly we have adopted the same methodolgy to synthesise a number of O-alkylated products 3a-p using 4-trifluoromethyl-6-substituted- l, 2-dihydro-2-oxo-pyridine 1 and phenacylbromide or chloroacetone and cyclised to 2, 6-disubstituted- 3-amino-4-trifluoromethylfuro[2, 3 -b]pyridines 4a-q (Scheme I). The infrared spectra of products 3 show the presence of the nitrile (C=N) function as a sharp peak R � 3 N I + XH 2 OR' H 2 3 ete I • K, . Nal Scheme I ) & 3 N . I R 0 COR' 4 (a )
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Indian Journal of Chemistry Vol. 40B, July 2001 , pp. 558-564
Synthesis of nove1 2,6-disubstituted-3-amino-4-trifluoromethylfuro[2,3-b ]pyridines t
K Srinivas, B Narsaiah*, P Shanthan Rao & J Madhusudana Rao
Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 4 February 2000; accepted (revised) 26 February 2001
A series of novel 2-acyl or benzoyl-3-amino-4-tritluoromethyl-6-substituted furo[2,3-b]-pyridines have been synthesised from 4-tritluoromethyl-6-substituted- l ,2-dihydro-2-oxo-3-pyridine carbonitrile via 2-0-phenacyl or acetonyl-3-cyano-4-tritluoromethyl-6-substituted pyridines.
The furo[2,3-b ]-pyridines are structurally analogous to indoles and quinolines I . They are known to have biological activity because the furo[2,3-b]pyridine
. moiety is present in furo[2,3-b]quinoline alkaloids2
isolated from some Rutaceae and makes the backbone of furo[2,3-b]pyridine alkaloids3. The furo[2, 3-b ]pyridine ring system have been claimed as potent herbicides4 and as integral components of cephalosporine derivatives5. The furo[2,3-b]pyridines are mainly formed by the fusion of (n) deficient pyridine and a (n) excessive furan ring. The earlier reports on the synthesis of furo[2,3-b ]pyridines are mainly fusion of furan ring to pyridines6- lo and pyridine ring to furan I I . Some of the reports are by intramolecular Diels-Alder cyclisation of 1 , 2, 4-triazines 12- 17, 1 , 3-pyrimidines 1 8. 1 9 and pyrazines20•2 1 with dienophilic side chain and by rearrangement of azepines22•23. However, no report on fluorinated furo[2,3-b]pyridine except under ref. l O is available in literature. The fluorinated furo[2,3-b ]-pyridines are supposed to have enhanced activity due to their lipophilic nature. Therefore our continued interest on the synthesis of fluorinated pyridones24, fused pyridines such as pyrido[3' ,2' :4,5]furo[3,2-d]- 1 ,3-pyrimidines25, pyrido[3'2':4, 5]furo[3, 2-d]- 1 , 3-oxazines26, N-allyl-2( lH)pyridones27, prompted us to synthesise a series of novel fluorinated furo[2,3-b ]pyridines.
Results and Discussion We have shown earlier that when 4-trifluoro
methyl-6-substituted- l , 2-dihydro-2-oxo-pyridine car-
*Corresponding author. E-mail :narsaiahbanda@ 1 23india.com tIlCT Communication No. 4444
bonitrile 124 was reacted with bromoethylacetate, exclusive O-alkylation products were formed. This 0-alkylation is mainly presumed to be due to the presence of bulky substituent in the ortho position of nitrogen in pyridone28 and effect of trifluoromethyl group which profoundly enhances the aromaticity of the ring29• The O-alkylated products were cyclised using Thorpe Ziegler reaction30.
Accordingly we have adopted the same methodolgy to synthesise a number of O-alkylated products 3a-p using 4-trifluoromethyl-6-substituted- l , 2-dihydro-2-oxo-pyridine 1 and phenacylbromide or chloroacetone and cyclised to 2, 6-disubstituted-3-amino-4-trifluoromethylfuro[2, 3-b ]pyridines 4a-q (Scheme I).
The infrared spectra of products 3 show the presence of the nitrile (C=N) function as a sharp peak
R
�3 N I + X-CH2-COR'
H 2
3
Acetone I • K2C OJ. Nal
Scheme I
3(a-p)
&3 NH2 ... I
R 0 COR'
4(a"<l)
SRINIVAS et al.: SYNTHESIS OF FURO[2,3,-b]PYRIDINES 559
in the region 2220-2250 cm" characterises these compounds as O-alkylated products. The products 4 show the presence of amine (NH2) function as two doublet shoulders at 3480 and 3360 cm- ' and disappearance of nitrile (C=N) at 2220 cm- ' .
The 'H NMR spectra of products 3 show the presence of active methylene protons as a sharp singlet in the range of 5 . 1 -5 .8 ppm which are absent in the spectra of products 4 where the presence of NH2 protons as broad singlet at 5 .9-6.4 ppm is observed. It indicates the formation of cyclised products. The aromatic protons in all the products
appeared in their appropriate aromatic regions. The mass spectra of the products showed the stable molecular ion with characteristic fragmentation patterns. The number of fragments shown by each product is given in detail in the experimental section together with the proper assignment. The number of compounds synthesised are tabulated in Table I.
Experimental Section General. Melting points were determined in open
glass capillaries on a Metler FP5 1 melting point apparatus and are uncorrected. 'H NMR spectra were
Table I-Physical data of compounds 3a-p and 4a-q. Product R R' Yield m.p.
(%) °C
3a p-CH3C6H4 CH3 94 163 3b p-OCH3C6H4 CH3 93 158 3c p-ClC6H4 CH3 98 155 3d P-FC6� CH3 89 143 3e C6HS C6HS 88 142 3f p-CH3C6H4 C�s 86 166 3g p-OCH3C6H4 C6Hs 88 147 3h p-ClC6� C6HS 89 162 3i C6Hs p-ClC6H4 89 204 3j
p-CH3C6H4 p-ClC6H4 88 1 88 3k p-OCH3C6H4 p-ClC6H4 95 178 31 p-ClC6H4 p-ClC6H4 87 193
3m C6HS P-OCH3C6H4 95 158 30 p-CH3C6H4 P-OCH3C6� 85 1 83 30 p-OCH3C6H4 P-OCH34H4 9 1 143 3p p-ClC6� P-OCH3C6� 97 124 4a C6HS CH3 88 147 4b P-CH3C6� CH3 83 1 86 4c P-OCH3C6� CH3 83 166 4d P-CI4� CH3 78 175 4e p-FC6H4 CH3 77 164 4f C6HS C6Hs 72 1 80 4g P-CH3C6� C6HS 84 195 4h P-OCH3C6H4 C6HS 8 1 1 6 1 4i p-ClC6H4 C6Hs 75 176 4
j C6HS p-ClC6� 7 1 203
4k p-CH3CnH4 p-C\C� 85 165 41 P-OCH3C6� p-ClC6� 66 1 87
4m p-ClC� p-ClC6H4 72 1 82 40 C�s p-OCH3C6H4 70 208 40 P-CH3C6� P-OCH3C6� 72 2 12 4p P-OCH3C6� . P-OCH3C� 76 177
4q p-CIC� P-OCH3C� 80 1 86
560 INDIAN J CHEM. SEC. B, JULY 2001
recorded on Varian Gemini (200 MHz) spectrometer llsing TMS as an internal standard, IR spectra on FfIR Schimadzu Perkin-Elmer 1 3 10 infrared spectrophotometer and mass spectra on a VG-micromass 7070H instrument at 70 eV. Elemental analyses were carried on a Vario-EL instrument.
The 4-trifluoromethyl-6-substituted- l , 2-dihydro-2-oxo-3-pyridine carbonitriles were prepared by a known25 procedure and all other reagents were obtained from commercial sources.
2-0-Acetonyl or substituted phenacyl-3-cyano-4-trifluoromethyl-6-substituted pyridines 3a-p: General procedure. The 3-cyano-4-trifluoromethyl-6-substituted-2( lH)pyridones (5 mmole) were dissolved in dry acetone (30 mL) and to the solution was added chloroacetone or substituted phenacylbromide (5.5 mmole), potassium carbonate ( 1 0 mmole) and sodium iodide (0.010 g). The reaction mixture was refluxed for 4hr at 60°C and cooled to room temperature. The acetone was removed in vacuo and the residue washed with n-hexane to remove unreacted chloroacetone or substituted phenacylbromide. The solid product was dissolved in water to remove excess potassium carbonate and the KCI or KBr salt formed in the reaction. The slurry was fi ltered, washed with water and dried to obtain good yield of product in pure form.
2 -0 -Aceto ny 1-3-cy ano -4- trifl u oromethy 1 -6-(p-methylphenyl)pyridine 3a: IH NMR (CDCI3) : 8 2.3 (s, 3H, CH3), 2.4 (s, 3H, COCH) , 5 . 1 (s, 2H, OCH2), 7.3 (d, 2H, aromatic H), 7.7 (s, IH, H-C(5», 7.8 (d, 2H, aromatic H) ppm; IR (KBr): 2234, 1 74 1 , 1 1 79 cm' l ; MS: mJz 334 (M+), 3 1 9, 3 1 5, 292 (base peak). Anal . Ca\cd for C I7H I 3F3N202: C, 6 1 .07 ; H, 3.9 1 ; N, 8.37. Found: C, 6 1 .04; H, 3 .89; N, 8.35%.
2-0-Acetonyl-3-cyano-4-trifluoromethyl-6-(pmethoxyphenyl)pyridinc 3b: IH NMR (CDCb): 8 2.3 (s, 3H, COCH3), 3.9 (s, 3H, OCH3), 5 . 1 (s, 2H, OCH2), 7.0 (d, 2H, aromatic H), 7.6 (s, I H, H-C(5» , 7.9 (d, 2H, aromatic H) ppm; IR (KBr): 2223, 1 733, 1 58 1 , 1 5 1 9, 1 1 37 cm' l ; MS : mJz 350 (M+),308, 43 (base peak). Anal. Ca\cd for CI7H I 3F3N203: C, 58.68; H, 3.74; N, 7.99. Found: C, 58 .24; H, 3.7 1 ; N, 7 .96%.
2-0-Acetonyl-3-cyano-4-trifluoromethyl-6-(pchlorophenyl) pyridine 3c: IH NMR (CDCh): 8 2.3 (s, 3H, COCH) , 5 . 1 (s, 2H, OCH2), 7 .4 (d, 2H,
aromatic H), 7.6 (s, I H, H-C(5», 7.8 (d, 2H, aromatic H) ppm; IR (KBr): 2227, 1 732, 1 582, 1 1 37 cm' l ; MS : rnJz 354 (M+), 339, 3 1 2, 43 (base peak) . Anal. Ca\cd for C16HIOF3N202: C, 54. 1 7 ; H, 2.84; N, 7.89. Found: C, 54. 1 5 ; H, 2.8 1 ; N, 7 .87%.
2-0-Acetonyl-3-cyano-4-trifluoromethyl-6-(ptluorophenyl) pyridine 3d: 'H NMR (CDCI) : 8 2.3 (s, 3H, COCH)) , 5 .3 (s, 2H, OCH2), 7.2-7 .3 (m, 2H, aromatic H), 7 .8 (s, I H, H-C(5», 8 . 1 -8.2 (m, 2H, aromatic H) ppm; IR (KBr): 2226, 1 730, 1 5 8 1 , 1 146 cm' l ; MS: rnJz 338 (M+) 323, 295, 43 (base peak). Anal. Ca\cd for CI6 H lO F4 N2 02: C, 56.8 1 ; H, 2.97; N, 8.28. Found: C, 56.78; H, 2.94; N, 8.26%.
2-0-Phenacyl-3-cyano-4-trifluoromethyl-6-phenylpyridine 3e: IH NMR (CDCI) : 8 5 .8 (s, 2H, OCH2), 7.3-8.0 (m, I 1H, aromatic H) ppm; IR (KBr) : 2224, 1 70 1 , 1 598, 1 566, 1 1 40 cm' l ; MS: rnJz 382 (M+), 277, 247, 77 (base peak). Anal. Ca\cd for C2 IH I3F)N202: C, 65.97; H,3.42; N,7.32. Found: C, 65.95; H, 3.39; N. 7.28%.
2-0-Phenacyl-3-cyano-4-trifluoromethyl-6-(pmethylphenyl)pyridine 3f: 'H NMR (CDCI3): 8 2.3 (s, 3H, CH3), 5.7 (s, 2H, OCH2), 7 . 1 (d, 2H, aromatic H), 7.4-7 .7 (m, 6H, aromatic H), 8.0 (d, 2H, aromatic H) ppm; IR (KBr): 2226, 1 705, 1 595, 1 560, 1 145 em" . MS: rnJz 396 (M+), 26 1 , 246, 105(base peak). Anal. Ca\cd for C22H ,sF3N202 : C, 66.66; H, 3.8 1 ; N, 7.06. Found: C, 66.62; H, 3 .79; N 7 .04%.
2-0-Phcnacyl-3-cyano-4-trifluoromethyl-6-(pmethoxyphenyl)pyridine 3g: 'H NMR(CDCI3) : 8 3.9 (s, 3H, OCH) , 5 .8 (s, 2H, OCH2), 6.9 (d, 2H, aromatic H), 7 .5-7.7 (m, 4H, aromatic H), 7.8 (d, 2H. aromatic H), 8.0 (d, 2H, aromatic H) ppm; IR (KBr) : 2226, 1 702, 1 595, 1 56 1 , 1 1 50 cm' l . ; MS : rnJz 4 12 (M+) 307, 277, 105 (base peak). Anal . Ca\cd for C22H '5F3N203 : C, 64.07; H, 3 .66; N, 6.79. Found: C, 64.05; H, 3.65; N, 6.75%.
2-0-Phenacyl-3-cyano-4-trifluoromethyl-6-(pchlorophenyl)pyridine 3h: 'H NMR(CDCI) : 8 5 .8 (s , 2H, OCR2), 7.3 (d, 2H, aromatic H) , 7.5-7.8 (m, 6H, aromatic H), 8.0 (d, 2H, aromatic H) ppm; IR(KBr): 223 1 , 1 700, 1 595, 1 1 5 1 cm" ; MS: rnJz 4 16 (M+), 3 1 1 , 28 1 , 246, 1 05 ' (base peak). Anal . Ca\cd for C2IH I2CIF3N202: C, 60.5 1 ; H, 2.90; N, 6.72. Found: C, 60.48; H, 2.89; N, 6.70%.
SRINIVAS et al.: SYNTHESIS OF FURO[2,3,-b]pYRIDINES 561
2-0-(p-Chlorophenacyl)-3-cyano-4-trifluoromethyl-6-phenylpyridine 3i: IH NMR(CDCh): 8 5 .8 (s, 2H, OCH2), 7.3-7.6 (m, 5H, aromatic H), 7.7 (s, I H, H-C(5)), 7.8 (d, 2H, aromatic H), 8 .0 (d, 2H, aromatic H) ppm; IR (KBr) : 2225, 1 698, 1 593, 1 1 89, 1 1 39 cm' l . MS: mlz 4 16 (M+),397, 1 39 (base peak), 1 1 1 . Anal. Calcd for C21H 12ClF3N202: C, 60.5 1 ; H, 2.90; N, 6.72. Found: C, 60.47; H, 2.88; N, 6.68%.
2-0-(p-Chlorophenacyl)-3-cyano-4-trifluoromethyl-6-(p-methylphenyl) pyridine 3j: IH NMR (CDCl3): 8 2.4 (s, 3H, CH3), 5.7 (s, 2H, OCH2), 7.2 (d, 2H, aromatic H), 7.5 (d, 2H, aromatic H), 7.6 (d, 2H, aromatic H), 7.7 (s, I H, H-C(5)), 7.9 (d, 2H, aromatic H) ppm; IR (KBr) : 2225, 1699, 1 593, 1 1 39 cm'l ; MS: mlz 430 (M+) 4 1 1 , 261 , 1 39 (base peak), 1 1 1 . Anal. Calcd for C22H 14CIF3N202: C, 6 1 .33; H, 3 .27; N, 6.50. Found: C, 6 1 .30; H, 3.25; N, 6.48%.
2-0-(p-Chlorophenacyl)-3-cyano-4-trifluoromethyl-6-(p-methoxyphenyl) pyridine 3k: IH NMR (CDCb): 8 3.9 (s, 3H, OCH3), 5 .7 (s, 2H, OCH2), 7.5 (d, 2H, aromatic H), 7 .6 (s, I H, H-C (5)), 7.7 (d, 2H, aromatic H), 7.9 (d, 2H, aromatic), 7.9 (d, 2H, aromatic H) ppm; IR (KBr): 2222, 1697, 1 592, 1 136 cm'l ; MS: mlz 446 (M+), 426, 277, 1 66, 1 39 (base peak), 1 1 1 . Anal. Calcd for C22H 14CIF3N203: C, 59. 1 3 ; H, 3. 1 5 ; N, 6.26. Found: C, 59. 10; H, 3 . 1 1 ; N, 6.23%.
2-0-(p-Chlorophenacyl)-3-cyano-4-trifluoromethyl-6-(p-chlorophenyl) pyridine 31: IH NMR (CDCb): 8 5.7 (s, 2H, OCH2), 7 .4 (d, 2H, aromatic H), 7.5 (d, 2H, aromatic H), 7:6 (s, I H, H-C(5» , 7.7 (d, 2H, aromatic H), 7.9 (d, 2H, aromatic H) ppm; IR (KBr): 2226, 1699, 1 593, 1 1 39 ; MS: mlz 450(M+). 43 1 , 1 39 (base peak), 1 1 1 . Analysis; Calc. for C2IH I ICIF3N202: C, 55 .89; H, 2.45; N, 6.20. Found: C, 55.86; H, 2.43 ; N, 6. 1 9.%
2-0-(p-Methoxyphenacyl)-3-cyano-4-trifluoromethyl-6-phenylpyridine 3m: IH NMR(CDCb): 8 3.9 (s, 3H, OCH3), 5 .7 (s, 2H, OCH2), 7 .0(d, 2H, aromatic H), 7 .3-7.5(m, 3H, aromatic H), 7 .7(s, I H, H-C(5» , 7 .8(d, 2H, aromatic H), 8 .0(d, 2H, aromatic H) ppm; IR(KBr): 2228, 1 738, 1 686, 1 596, l 1S 1 cm'l . MS: mlz 4 12(M+), 1 35 , 1 07, 77. Anal. Calcd for C22H 15F3N203: C,64.07; H, 3 .66; N, 6.79. Found: C, 64.05; H, 3.63; N,6.75%.
2-0-(p-Methoxyphenacyl)-3-cyano-4-trifluoromethyl-6-(p-methylphenyl) pyridine 3n: IH NMR (CDCh): 8 2.4(s, 3H, CH3), 3 .9(s, 3H, OCH3), 5.7(s, 2H, OCH2), 7.0(d, 2H, aromatic H), 7.2 (d, 2H, aromatic H), 7.6(s, I H, H-C(5» , 7.7(d, 2H, aromatic H), 8.0(d, 2H, aromatic H) ppm; IR (KBr): 2226, 1 688, 1 596, 1 15 1 cm' l ; MS: mlz 426 (M+). Anal. Calcd for C23H 17F3N203: C, 64.78; H, 4.0 1 ; N, 6.56. Found:C,64.75 ; H, 3 .99; N 6.54%.
2-0-(p-Methoxyphenacyl)-3-cyano-4-trifluoromethyl-6-(p-methoxyphenyl) pyridine 30: IH NMR (CDCb): 8 3.9 (s, 3H, OCH3), 3.9(s, 3H, OCH3), 5 .7(s, 2H, OCH2), 6.8(d, 2H, aromatic H), 7 .0(d, 2H, aromatic H), 7 .6(s, I H, H-C(5» , 7.8(d, 2H, aromatic H), 8 .0(d, 2H, aromatic H) ppm; IR(KBr): 2225, 1 735, 1 686, 1 594, 1 1 36 cm' l ; MS: mlz 442(M+), 277, 258, 1 35 (base peak) Anal. Calcd for C23H 17ClF3N204: C, 62.44; H, 3.87; N, 6.33. Found: C, 62.42; H, 3.85; N.6.30%.
2-0-(p-Methoxyphenacyl)-3-cyano-4-trifluoromethyl-6-(p-chlorophenyl) pyridine 3p: IH NMR (CDCb): 8 3 .9(s, 3H, OCH3), 5 .8 (s, 2H, OCH2), 7.0 (d, 2H, aromatic H), 7 .4(d, 2H, aromatic H), 7.7(s, I H, H-C(5» ,7.8(d,2H, aromatic), 8 .0(d, 2H, aromatic H) ppm; IR(KBr): 2226, 1 736, 1 688, 1 596, 1 1 36 cm'l ; MS: mlz 446(M+), 339, 1 35, 77. Anal. Calcd for C22H 14CIF3N203: C, 59. 1 3 ; H, 3 . 1 5; N, 6.26. Found: C, 59. 1 0; H, 3 . 12 ; N, 6.24%.
2-Acetyl or substituted benzoyl-3-amino-4-trifluoromethyl-6-substituted furo[2,3-b ]pyridines 4a-q. General procedure. The 2-0-acetonyl or substituted phenacyl-3-cyano-4-trifluoromethyl-6-substituted pyridine (4 mmole) was dissolved in dry N,Ndimethylformamide (6.5 mL) and potassium carbonate (8 mmole) was added. The reaction mixture was heated for 3hr with stirring, maintaining the temperature at 1 1O- 120°C. After cooling to room temperature it was poured into crushed ice. The separated solid product was filtered, washed with water and dried. The product was purified by passing over neutral alumina in chloroform.
2-Acetyl-3-amino-4-trifluoromethyl-6-phenylfuro[2,3-b]pyridine 4a: IH NMR (CDCb): 8 2.6(s, 3H, COCH3), 5 .9(s, br., 2H, NH2), 7.5-7.5(m, 3H, aromatic H) 7.9(s, I H, H-C(5» , 8.0-S. I (m, 2H, aromatic H)ppm; IR(KBr): 3445. 3340, 1642, 1 5 12,
562 INDIAN J CHEM. SEC. B. JULY 2001
1 1 8 1 em" ; MS: mlz 320 (M+), 305, 277, 228. Anal . Calcd for C'6H l l F3N202: C, 60.00; H, 3.46; N, 8.74. Found: C, 59.98; H, 3 .43; N, 8.70%.
2-Acetyl-3-amino-4-trifluoromethyl-6-(p-methylphenyl)furo[2,3-b]pyridine 4b: 'H NMR (CDCl) : 8 2.4 (s, 3H, CH3), 2.6(s, 3H, COCH3), 5 .9(s, br., 2H, NH2), 7 .3(d, 2H, aromatic H), 7 .9(s, I H, H-C(5» , 8.0(m, 2H, aromatic H) ppm; lR(KBr): 3480, 3363, 1644, 15 19, 1 122 em" ; MS: mlz 334 (M+), 3 1 9, 29 1 . Anal. Calcd for C ' 7H 1 3F3N202: C, 6 1 .07 ; H, 3.9 1 ; N, 8.37. Found: C, 6 1 .05 ; H, 3 .88; N, 8.36%.
2-Acetyl-3-amino-4-trifluoromethyl-6-(p-methoxyphenyl)furo[2,3-b]pyridine 4c: 'H NMR (CDCb): 8 2.6(s, 3H, COCH3), 3 .9(s, 3H, OCH3), 5 .9(s, br, 2H, NH2), 7.0(d, 2H, aromatic H),7.9(s, IH, H-C(5», 8 . 1 (d, 2H, aromatic H) ppm; lR(KBr) : 3520, 3346, 1647, 1 525, 1 1 1 6 em" ; MS: mlz 350 (M+), 335, 307. Anal . Calcd for C 1 7H 13F3N203: C, 58.28; H, 3.74; N, 7.99. Found: C, 58.26; H, 3 .7 1 ; N, 7.98%.
2-Acetyl-3-amino-4-trifluoromethyl-6-(p-chlorophenyl)furo[2,3-b]pyridine 4d: 'H NMR (CDCb): 8 2.6(s, 3H, COCH) , 5 .9(s, br, 2H, NH2), 7 .5(d,2H, aromatic H), 7.9(s, I H, H-C(5», 8. 1 (d, 2H, aromatic H) ppm; IR(KBr): 3526, 3363. 1 645, 1 5 19, 1 1 24 cm- ' . MS: mlz 354(M+), 339, 3 1 1 . Anal . Calcd for C'6H IOCIF3N202: C, 54. 17 ; H, 2.84; N, 7.89. Found: C, 54. 15 ; H, 2.8 1 ; N, 7.86%.
2-Acetyl-3-amino-4-trifluoromethyl-6-(p-fluorophenyl)furo[2,3-b ]pyridine 4e: 'H NMR (CDCb): 8 2.6 (s, 3H, COCH3), 5 .9(s, br., 2H, NH2), 7.3-7 .4(m, 2H, aromatic H), 7.9(s, I H, H-C(5» , 8. 1 -8 .2(d, 2H, aromatic H) ppm; IR (KBr) : 3520, 3345, 1 646, 1 520, 1 1 19 cm- ' ; MS: mlz 338(M+), 323, 295. Anal . Calcd for C'6HIOF4N202: C, 56.8 1 ; H. 2.97; N, 8.28. Found: C, 56.78; H, 2.96; N, 8.26%.
2-Benzoyl-3-amino-4-trifluoromethyl-6-phenylfuro[2,3-b]pyridine 4f: 'H NMR (CDCI3): 8 6.4 (br, s, 2H, NH2), 7.4 -7.7 (m, 6H, aromatic H), 8.0 (s, I H, H-C(5», 8 . 1 -8.4 (m, 4H, aromatic H) ppm; IR (KBr): 3280, 3340, 1 620, 1496, 1 1 7 1 cm-' ; MS: mlz 382 (M+), 277. Anal. Calcd for C2, H 1 3 F3 N2 O2: C, 65.97; H, 3 .42; N, 7.32. Found: C, 65.94; H, 3 .40; N, 7 .29%.
2-Benzoyl-3-amino-4-trifluoromethyl-6-(p-methylphenyl)furo[2,3-b]pyridine 4g: 'H NMR (CDCh): 0
2.49(s, 3H, CH3), 6.4 (br, s, 2H, NH2 exchangeable with D20), 7.3 (d, 2H, aromatic H), 7 .5-7.7 (m, 3H, aromatic H), 8.0 (s, I H,H-C(5» , 8 . 1 (d, 2H, aromatic H), 8.3 (d, 2H, aromatic H) ppm; IR(KBr) : 35 10, 3336, 1 623, 1 583 cm-' ; MS: mlz 396 (M+), 29 1 , 77(base peak), Anal . Calcd for C22H , sF3N202: C, 66.66; H, 3 .8 1 ; N, 7.06. Found: C, 66.64; H, 3.79; N, 7 .04%.
2-Benzoyl-3-amino-4-trifluoromethyl-6-(p-methoxyphenyl)furo[2,3-b ]-pyridine 4h: 'H NMR (CDC!3): 8 3 .9(s, 3H, OCH3), 6.3 (br, s, 2H, NH2), 7.0 (d, 2H, aromatic H), 7.5-7.6 (m, 3H, aromatic H), 7.9 (s, IH, H-C(5» , 8. 1 (d, 2H, aromatic H), 8.3 (d, 2H, aromatic H) ppm; lR (KBr) : 3475, 334 1 , 1 6 1 1 , 1 1 83 cm- ' ; MS: m/z 4 1 2(M+), 307, 77(base peak) Anal . Calcd for C22H ,sF3N203: C, 64.07; H, 3.66; N, 6.79. Found: C, 64.02; H, 3.64; N, 6.75%.
2-Benzoy 1-3-amino-4-trifluoromethyl-6-(p-chlorophenyl)furo[2,3-b]pyridine 4i: 'H NMR (CDCl) : 8 6.4 (br, s, 2H, NH2), 7 .4-7.7 (m, 5H, aromatic H), 7.9 (s, I H,H-C(5» , 8 . 1 (d,2H, aromatic H), 8.4(d, 2H, aromatic H) ppm; IR (KBr) : 3486, 3326, 1 624, 1 122 cm-' ; MS: m/z 4 16 (M+), 3 1 1 , 105 (base peak). Anal . Calcd. for C2 ,H 12CIF)N202: C, 60.5 1 , H, 2.90, N, 6.72. Found: C, 60.47; H, 2.87; N, 6.69%.
2-(p-Chlorobenzoyl)-3-amino-4-trifluoromethyl-6-phenyl furo[2,3-b]pyridine 4j : 'H NMR (CDCI) : 8 6.4 (br, s, 2H, NH2), 7 .4-7.7 (m, 5H, aromatic H), 8.0 (s, I H, H-C(5» , 8 . 1 (m, 4H, aromatic H) ppm; IR (KBr): 3476, 3338, 1 623, 1 587, 1 1 1 5 cm-' ; MS: mlz 4 16 (M+), 277, 1 39(base peak), 1 1 1 , Anal. Calcd. for C2,H '2ClF3N202: C, 60.5 1 ; H, 2.90; N, 6.72. Found: C, 60.49; H, 2.89; N, 6.68%.
2-(p-Chlorobenzoyl)-3-amino-4-trifluoromethyl-6-(p-methylphenyl)furo[2,3-b ]pyridine 4k: 'H NMR (CDCh): 8 2.5(s, 3H, CH3), 6.4 (br, s, 2H, NH2), 7.2-7.6 (m, 4H, aromatic H),7.9-8.3 (m, 5H aromatic H) ppm; IR (KBr): 3520, 3365, 1 626, 1 586, 1 1 1 6 cm- ' ; MS: mlz 430(M+), 3 1 9, 29 1 , 1 39 (base peak), Anal. Calcd. for C22H'4ClF3N2 O2 : C, 6 1 .33; H, 3.27; N, 6.50. Found: C, 6 1 .30; H, 3.25; N, 6.48%.
2-(p-Chlorobenzoyl)-3-amino-4-trifluoromethyl-6-(p-methoxyphenyl) furo[2,3-b ]-pyridine 41: 'H NMR (CDCb): 8 3 .9 (s, 3H, OCH) , 6.4 (br, s, 2H, NH2), 7.0 (d, 2H, aromatic H), 7.5 (d, 2H, aromatic
SRINIV AS et at.: SYNTHESIS OF FURO[2,3,-b]PYRIDINES 563
H), 7.9 (s, I H, H-C(5)), 8 . 1 (d, 2H, aromatic H), 8.2 (d, 2H, aromatic H) ppm; IR (KBr): 3505, 3339, 1 6 1 1 , 1 587, 1 1 29 cm - I . MS: mlz 446 (M+), 335, 307, Anal. Calcd for C22HI4CIF3N203: C, 59. 1 3 ; H, 3 . 1 5 ; N , 6.26. Found: C, 59. 1 1 ; H , 3 . 1 3 ; N , 6.24%.
2-(p-Chlorobenzoyl)-3-amino-4-trifluoromethyl-6-(p-chlorophenyl)furo[2,3-b ]-pyridine 4m: I H NMR (COCI3): 8 6.4 (br, s , 2H, NH2), 7.4-7 .6 (m, 4H, aromatic H), 7.9 (s, I H,H-C(5», 8. 1 (d, 2H, aromatic H), 8.2 (d, 2H, aromatic H) ppm; IR (KBr) : 35 13 , 337 1 , 1 627, 1 586, 1 1 1 7 cm- I ; MS: mlz 450(M+), 339, 3 1 1 , I I I (base peak) Anal. Calcd for C2 1 H I ICIF3N202: C, 55.89; H, 2.45 ; N, 6.20. Found: C, 55.85; H, 2.42; N, 6. 1 8%.
2-(p-Methoxybenzoyl)-3-amino-4-trifluoromethyl-6-phenylfuro[2,3-b]pyridine 4n: I H NMR (COCb): 8 3.9 (s, 3H, OCH3), 6.3 (br, s, 2H, NH2), 7.0 (d, 2H, aromatic H), 7.5-7.6 (m, 3H, aromatic H), 8.0 (s, 1 H, H-C(5», 8.2 (d, 2H, aromatic H), 8 .4 (d, 2H, aromatic H) ppm; IR(KBr): 35 1 9, 336 1 , 1624, 1 597, 1 1 1 9 cm-I . MS: mJz 4 1 2(M+), Anal. Calcd for C12HlsF)N203: C, 64.07; H, 3.66; N, 6.79. Found: C, 64.04; H, 3.64; N, 6.77%.
2-(p-Methoxybenzoyl)-3-amino-4-trifluoromethyl-6-(p-methylphenyl)furo[2,3-b ]pyridine 40: I H NMR (CDCI3) : 8 2.4(s, 3H, CH3), 3.9(s, 3H, OCH)), 6.3(br, s, 2H, NH2), 7 . 1 (d, 2H, aromatic H), 7.3 (d, 2H, aromatic H), 7.9 (s, IH, H-C(5)), 8 . 1 (d, 2H, aromatic H), 8.4 (d, 2H, aromatic H) ppm; IR (KBr) : 3465, 3336, 1 623, 1 596, 1 1 16 cm-I ; MS: mlz 426(M+) 3 19, 29 1 , Anal. Calcd. for C23H I7F3N203: C, 64.78 ; H, 4.0 1 ; N, 6.56. Found: C, 64.74; H, 3.99; N, 6.53%.
2-(p-Methoxybenzoyl)-3-amino-4-trifluoromethyl-6-(p-methoxyphenyl)furo[2,3-b ]pyridine 4p: I H NMR (COCl)): 8 3.9(s, 3H, OCH3) , 3 .9(s, 3H, OCH3), 6.3 (br, s, 2H, NH2), 7.0-7 . 1 (m, 4H, aromatic H), 7.9 (s, IH, H-C(5», 8 . 1 (d, 2H, aromatic H), 8.3 (d, 2H, aromatic H) ppm; IR (KBr): 3506, 334 1 , 1 604, 1 1 1 8 cm-I ; MS : mlz 442 (M+) 307, 1 70(base peak) Anal. Calcd. for C23H I7F3N204: C, 62.44; H, 3 .87 ; N, 6.33. Found: C, 62.40; H, 3 .85 ; N, 6.30%.
2-(p-Methoxybenzoyl)-3-amino-4-trifluoromethyl-6-(p-chlorophenyl)furo[2,3-b ]pyridine 4q: I H NMR (COCI3) : 8 3.9(s, 3H, OCH3) , 6.3 (br, s, 2H, NH2), 7.0 (d, 2H, aromatic H), 7.5 (d, 2H, aromatic
H), 7.9 (s, 1 H, H-C(5», 8 . 1 (d, 2H, aromatic H), 8.3 (d, 2H, aromatic H) ppm; IR (KBr) : 3359, 1 625, 1 598, 1 176 cm -I ; MS: mlz 446(M+), 339. Anal. Calcd for C22H
I4C1F3N203: C, 59. 1 3 ; H, 3. 1 5 ; N, 6.26.
Found: C, 59. 1 1 ; H, 3. 1 3 ; N, 6.24%.
Conclusion The synthesis of a series of new fluorinated
furo[2,3-bl-pyridines becomes a valuable addition to the fluorinated heterocycles. The activity studies are in progress and will be published separately.
Acknowledgement The authors are grateful to Dr K V Raghavan,
Director, nCT, for his constant encouragement. One of the authors K Srinivas is thankful to the CSIR, India for the research grant of SRF during the period of this work.
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