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Cyanoacetanilides intermediates in heterocyclic synthesis. Part 6: Preparation of some hitherto unknown 2-oxopyridine, bipyridine, isoquinoline and chromeno[3,4-c]pyridine containing sulfonamide moiety
1st Heterocyclic Update
*Corresponding author at: Chemistry Department, Faculty of Science & Arts, K K U, Mohail Assir, Saudi Arabia. Tel.: +966 536 563 810 m_eltayyeb@hotmail.com (Mohamed A. Salem)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Available online 23 November 2013
Peer review under responsibility of King Saud University.
Abstract
Treatment of cyanoacetanilide derivative 1 with tetracyanoethylene (2) in dioxane/triethylamine furnished 2-pyridone derivative 6. Aminopyridine 9 was obtained by cyclization of compound 1 with ketene dithioacetal 7/EtONa. Cyclocondensation of 1 with malononitrile and/or acetylacetone (1:1 M ratio) gave pyridine derivatives 11 and 13. Ternary condensation of compound 1, aliphatic aldehydes and malononitrile (1:1:1 M ratio) yielded the 2-pyridones 20a and b. Bipyridines 22a–c were prepared by refluxing of compound 21 with active methylene reagents. Cyclization of chromene derivatives 24 and 28 with malononitrile produced the novel chromeno[3,4-c]pyridine 26 and pyrano[3′,2′:6,7]chromeno[3,4-c]pyridine 29.
Keywords
Cyanoacetanilide
2-Pyridone
Bipyridine
Isoquinoline and chromeno[3,4-c]pyridines
1 Introduction
Among the wide variety of heterocycles that have been explored developing pharmaceutically important molecules like pyridines, cyano-pyridines have played an important role in the heterocyclic chemistry. Pyridine derivatives have occupied a unique position in medicinal chemistry. The naturally occurring B6-vitamins (Dawane et al., 2010) pyridoxine, pyrodoxal, pyridoxamine, and codecarbaxylase contain a pyridine nucleus. In addition to this, many naturally occurring and synthetic compounds containing the pyridine scaffold possess interesting pharmacological properties (Temple and Rener, 1992; Konda and Khedkar, 2010; Hossan et al., 2012). Among them, 2-amino-3-cyanopyridines have been identified as IKK-β inhibitors (Murata et al., 2003). The synthesis of 2-pyridone derivatives is of continued interest in the field of heterocyclic chemistry. Topical reviews have appeared in the literature over the last years about the synthesis of the 2-pyridone ring (Pemberton et al., 2006; Ciufolini and Chan, 2007). These heterocycles attracted attention because of their applications as bioactive compounds for example as a promising class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) (Medina-Franco et al., 2007; Bernardino et al., 2006), as antibacterial (Suksrichavalit, 2009) antifungal (Leal and Rodrigues, 2008), anticancer agents (Romagnoli et al., 2008) and anticonvulsant agents (Farag et al., 2012). Moreover, such derivatives have recently become important due to their structural similarity to nucleosides (Yang et al., 2006; Rajeswaran and Srikrishnan, 2008). Also, sulphanilamide effectiveness extends to acute chronic Gram negative and Gram positive infections. For example, sulfapyridine (N1-2-pyridylsulfanilamide) is a chemotherapeutic agent for the treatment of pneumococcal and other bacterial infections. It is also used for broncho-pneumonia and upper respiratory infections, even though currently it has been largely supplanted by sulfadiazine and sulfamerazine due to its high toxicity (El-Salam et al., 2005). Application of N-substituted cyanoacetamides as CH-acids (Dyachenko et al., 2008) allows introduction of an additional diversity point into the final 2-pyridone molecule via the amide group (Gorobets et al., 2004) or, depending on the reaction conditions, leads to N1-substituted 3-cyano-2-pyridones (Yermolayev et al., 2009). Cyanoacetanilide derivatives are important and versatile reagents, which have especially been used for the synthesis of polyfunctionalized three-, five- and six-membered rings and condensed heterocycles (Fadda et al., 2008; Dyachenko et al., 2008). Cyanoacetanilides are poly-functional compounds that possess both electrophilic and nucleophilic properties (Fadda et al., 2012). Two nucleophilic centers in cyanoacteanilides are localized on NH and C-2. Also, cyanoacetanilides possess two electrophilic positions (Dyachenko et al., 2008), which are associated with C-1 and C-3 (Fig. 1). In view of the above observations and in continuation of our program on the chemistry of cyanoacetanilide derivatives (Ammar et al., 2005a,b, 2008, 2011, 2006, 2009, 2013; Salem, 2009; Salem et al., 2011; Helal et al., 2013), we report herein the synthesis of the versatile hitherto unknown 2-pyridone, bipyridine, isoquinoline and chromeno-[3,4-c]pyridine derivatives containing sulfonamide moiety from the readily accessible cyanoaceta-nilide derivative 1.
Reactivity of cyanoacetanilide 1.
2 Results and discussion
The key intermediate, 2-cyano-N-(4-sulfamoylphenyl)-acetamide 1 (Ammar et al., 2008) was prepared in high yield (92%) by the reaction of sulfanilamide with ethyl cyanoacetate in refluxing m-xylene (Scheme 1).
Synthesis of cyanoacetanilide 1.
The active methylene in the cyanoacetanilide 1 underwent nucleophilic addition reaction to the double bond of tetracyanoethylene (TCNE) (2) via a Michael type addition reaction, by refluxing in dioxane containing few drops of triethylamine where a substance its structure should be either 3 or 6 was produced. The actual structure of the product was assigned as 4-(6-Amino-3,4,5-tricyano-2-oxopyridin-1(2H)-yl)-benzenesulfonamide 6 based on its 1HNMR spectroscopic data which showed two NH2 signals and was devoid of an imino group signal which should appear if the reaction product was 3. Moreover 3 was excluded as reaction product since the 1HNMR lacked the pyran H-4 signal which should appear at approximately δ = 4–5 ppm (Scheme 2). The structure of compound 6 was established on the basis of its elemental analysis and spectral data. Its infrared spectrum revealed absorption bands at 3320, 3306, 2222 and 1682 cm−1 due to amino, nitrile and carbonyl function groups, respectively. Also, its mass spectrum showed a molecular ion peak at m/z 340 (10.1%) which is characteristic for the molecular formula C14H8N6O3S together with base peak at m/z 55. In a similar manner, cyclization of compound 1 with bis(methylsulfanyl)-methylene malononitrile (7) by refluxing in ethanol in the presence of sodium ethoxide furnished the 4-(6-amino-3,5-dicyano-4-(methylthio)-2-oxopyridin-1(2H)-yl)benzenesulfonamide 9. The molecular structure of 9 was confirmed on the basis of its analytical and spectral data. The infrared spectrum of the isolated product showed characteristic bands at 3322, 3208, 2212 and 1652 cm−1 assigned for amino, nitrile and carbonyl function groups, respectively. The 1HNMR spectrum (DMSO-d6) revealed absorption at δ = 2.84 ppm attributed for methylsulfanyl protons in addition to two amino and aromatic protons. The formation of 9 is assumed to proceed via an intramolecular cyclization of the non-isolable Michael adduct 8 and loss of methyl mercaptan (Ammar et al., 2006) (Scheme 2).
Synthesis of 2-pyridone derivatives 6 and 9.
The reactivity of 1 toward some active methylene reagents was investigated. Thus, compound 1 reacted with malononitrile (1:1 M ratio) in an oil bath at 160 °C to yield a single product that was identified as 4-(4,6-diamino-5-cyano-2-oxopyridin-1(2H)-yl)benzenesulfonamide 11 on the basis of its elemental analysis and spectral data. Its mass spectrum showed a molecular ion peak at m/z 305 (9.26%) together with base peak at m/z 65. The formation of 11 is assumed to proceed via the Michael addition of 1 to cyano function group of malononitrile to form the acyclic Michael adduct 10 followed by in situ cyclization to the pyridine skeleton, Scheme 3. Cyclocondensation of compound 1 with acetylacetone furnished 4-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzenesulfonamide 13, via intramolecular hetero-cyclization of the non-isolable intermediate 12 by loss of water (Ammar et al., 2005a) (Scheme 3).
Synthesis of 4,6-disubstituted-2-pyridone derivatives 11 and 13.
The reaction of compound 13 with some electrophilic reagents was examined. Condensation of compound 13 with dimethylformamide-dimethylacetal (DMF-DMA) at reflux temperature in m-xylene afforded N,N-dimethylaminomethylene derivative 15 rather than the expected product 14 based on the elemental and spectral analyses of the isolated product. The infrared spectrum showed no absorption due to the amino function group. Also, the 1HNMR spectrum of compound 15 revealed a singlet at δ = 3.18 ppm due to N(CH3)2 in addition to the two methyl, methine and aromatic protons. Cyclocondensation of compound 13 with 2-(4-methoxybenzylidene)malono-nitrile 16 in refluxing ethanol in the presence of sodium ethoxide afforded the isoquinoline derivative 18. The structure of 18 was established on the basis of elemental and spectral data. The formation of 18 is assumed to proceed via Michael addition of the methyl function group of 13 to the activated double bond of 16 to form Michael adduct 17 followed by intramolecular cyclization and loss of hydrogen cyanide under the reaction conditions to yield 18 (Scheme 4).
Synthesis of dimethylaminomethylene and isoquinolinone derivatives 15 and 18.
Ternary condensation of compound 1, formaldehyde and malononitrile (1:1:1 M ratio) at reflux temperature in ethanol in the presence of piperidine afforded the 2-pyridone derivative 20a (Scheme 5). The structure of compound 20a was elucidated on the basis of its analytical and spectral data. Its mass spectrum showed a molecular ion peak at m/z 315 (3.76%) together with base peak at m/z 92 which is characteristic for aniline moiety minus hydrogen. The plausible reaction mechanism for the formation of pyridine 20a is illustrated in Scheme 5. In a similar manner, cyclization of compound 1 with acetaldehyde and malononitrile (1:1:1 M ratio) yielded the novel 2-pyridone derivative 20b. Its mass spectrum revealed a molecular ion peak at m/z 329 which is base peak in the spectrum. Knoevenagel Condensation of compound 1 with terephthalaldehyde (2:1 M ratio) in ethanolic piperidine at reflux temperature furnished the bis(benzylidene) derivative 21 in high yield. Refluxing of compound 21 with active methylene reagents in ethanol in the presence of piperidine yielded the novel bis(aminopyridone) derivatives 22a–c (Scheme 5). Assignment of structures 22 was confirmed on the basis of their elemental and spectral data. Mass spectrum of compound 22a showed a molecular ion peak at m/z 704 (15%) and the base peak was found in the spectrum at m/z 114. the formation of 22 is assumed to proceed via the initial Michael addition of the active methylene function group of 1 to the activated double bond of 21 to form Michael adduct which cyclized and auto-oxidation under the reaction conditions yielded 22. Additionally, the structures of 22 were established chemically through the reaction of compound 1 with 1,4-bis-(benzylidene) derivatives 23 (2:1 M ratio) by refluxing in dioxane in the presence of piperidine (Scheme 5).
Synthesis of 6-aminopyridine and bipyridine derivatives 20 and 22a–c.
It has been reported that compounds with a chromene backbone have a wide range of biological properties (Mladenovíc et al., 2010, 2009; Nawrot and Nawrot, 2006; Nandgaonkar et al., 2005). Thus, condensation of cyanoacetanilide derivative 1 with salicylaldehyde 24 using ammonium acetate as a catalyst in refluxing ethanol gave 2-imino-N-(4-sulfamoylphenyl)-2H-chromene-3-carboxamide 25 (Scheme 6). Moreover, the resulting chromene derivatives have latent functional constituents, which have the potential for further chemical transformations that give new routes for the preparation of substituted, polycondensed chromene derivatives. Reaction of chromene 25 with malononitrile in refluxing ethanol containing a catalytic amount of piperidine afforded the novel chromeno[3,4-c]pyridine derivative 27 in high chemical yield. The molecular structure of 27 was established through analytical and spectral data. Its infrared spectrum showed absorption bands at 3442, 3350, 3238 and 2204 cm−1 due to amino and cyano function groups, respectively. Also, its mass spectrum revealed a molecular ion peak at m/z = 407 (3.04%). The formation of 27 was assumed to proceed via the Michael addition of the active methylene function of malononitrile to the activated double bond center in 25 to yield the acyclic Michael adduct 26 which cyclize and aromatize through auto-oxidation under the reaction conditions (Elgemeie and El-Ghandour, 1990). In a similar manner, cyclization of compound 1 with 7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromene-6-carbaldehyde (28) afforded the 2,8-dihydropyrano[3,2-g]chromene 29 which was allowed to react with malononitrile in the presence of piperidine to yield the pyrano[3′,2′:6,7]-chromeno[3,4-c]pyridine derivative 30. The mass spectrum of compound 30 showed a molecular ion peak at m/z 519 (M+; 2.74%) together with base peak at m/z 92.![Synthesis of chromene-3-carboxamides 25 and 29 and chromeno-[3,4-c]pyridine derivatives 27 and 30.](/content/184/2014/7/5/img/10.1016_j.arabjc.2013.11.026-fig7.png)
Synthesis of chromene-3-carboxamides 25 and 29 and chromeno-[3,4-c]pyridine derivatives 27 and 30.
3 Experimental
3.1 General methods
Melting points were determined on a digital Gallen-Kamp MFB-595 instrument and are uncorrected. IR spectra (KBr) were measured on a Shimadzu 440 spectrometer. 1HNMR spectra were recorded in deuterated dimethylsulfoxide (DMSO-d6) on a Varian Gemini 300 (300 MHz) spectrometer using TMS as an internal standard; chemical shifts are reported as δ units. Mass spectra were performed on a Shimadzu GSMS-QP 1000 Ex mass spectrometer at 70 eV. The elemental analyses were carried out at the Microanalytical Center, Cairo University, Cairo (Egypt).
3.1.1 4-(6-Amino-3,4,5-tricyano-2-oxopyridin-1(2H)-yl)benzene-sulfonamide (6)
A mixture of cyanoacetanilide derivative 1 (0.01 mol), tetracyanoethylene (2) (0.01 mol), and triethylamine (0.5 mL) in dioxane (20 ml) was heated under reflux for 3 h, then allowed to cool. The solid product was collected and recrystallized from acetic acid. Brown crystals: Yield 50%, mp 284–286 °C; Anal. Calcd. for C14H8N6O3S: C, 49.41; H, 2.37; N, 24.69. Found: C, 49.36; H, 2.28; N, 24.61; IR (KBr, cm−1): 3320, 3306 (NH2), 2222 (C≡N), 1682 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 7.42–8.51 (m, 8H, Ar-H+2NH2); MS m/z (% relative intensity): 340 (M+1; 10.1), 286 (13.13), 173 (11.1), 111 (20.2), 107 (23.2), 85 (38.3), 71 (38.3) and 55 (100).
3.1.2 4-(6-Amino-3,5-dicyano-4-(methylthio)-2-oxopyridin-1(2H)-yl)benzenesulfon-amide (9)
A mixture of cyanoacetanilide derivative 1 (0.01 mol), bis(methylsulfanyl)-methylenemalononitrile (7) (0.01 mol), and sodium ethoxide (1 g sodium in 10 ml ethanol) in ethanol (30 ml) was heated under reflux for 3 h. The reaction mixture was cooled and poured into ice acidified with HCl. The solid product was filtered off and recrystallized from acetic acid. Buff crystals: Yield 70%, mp > 300 °C; Anal. Calcd. for C14H11N5O3S2: C, 46.53; H, 3.07; N, 19.38. Found: C, 46.41; H, 2.95; N, 19.25; IR (KBr, cm−1): 3322, 3208 (NH2), 2212 (C≡N), 1652 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 2.84 (s, 3H, SCH3), 7.55–8.44 (m. 8H, Ar-H+2NH2).13CNMR (300 MHz, DMSO-d6, δ/ppm): 14.2 (SCH3), 60.8 (Pyridine-C5), 88.2 (Pyridine-C3), 116.0 (2C≡N), 120.9, 128.8, 134.9, 136.5 (phenyl-C), 158.0 (Pyridine-C6), 159.90 (Pyridine-C2), 174.90 (Pyridine-C4).
3.1.3 4-(4,6-Diamino-5-cyano-2-oxopyridin-1(2H)-yl)benzene-sulfonamide (11)
A mixture of anilide 1 (0.01 mol) and malononitrile (0.01 mol) with a few drops of piperidine in an oil bath was heated for 1 h at 160 °C, then allowed to cool. The solid product was collected and recrystallized from dimethyl-formamide. Brown crystals: Yield 65%, mp > 300 °C; Anal. Calcd. for C12H11N5O3S: C, 47.21; H, 3.63; N, 22.94. Found: C, 47.10; H, 3.54; N, 22.83; IR (KBr, cm−1): 3316, 3176 (NH2), 2202 (C≡N), 1658 (C⚌O); MS m/z (% relative intensity): 305 (M+; 9.26), 228 (10.1), 183 (11.1), 72 (38.8), 108 (58.3), 69 (64.3) and 65 (100).
3.1.4 4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)benzenesulfonamide (13)
Equimolar amounts of 1 (0.01 mol) and acetylacetone (0.01 mol) with a few drops of piperidine in an oil bath were heated for 1 h at 160 °C, then allowed to cool. The solid product was collected and recrystallized from dioxane. White crystals: Yield 75%, mp > 300 °C; Anal. Calcd. for C14H13N3O3S: C, 55.43; H, 4.32; N, 13.85. Found: C, 55.31; H, 4.26; N, 13.74; IR (KBr, cm−1): 3316, 3150 (NH2), 3078 (CH-arom.), 2924 (CH-aliph.), 2226 (C≡N), 1652 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 1.98, 2.40 (2s, 6H, 2CH3), 6.52 (s, 1H, pyridine-H5), 7.54–8.01 (m, 6H, Ar-H+SO2NH2).13CNMR (300 MHz, DMSO-d6, δ/ppm): 20.0, 22.0 (2CH3), 106.0 (Pyridine-C5), 116.0 (Pyridine-C3), 118.0 (C≡N), 122.0, 129.3, 136.3, 140.0 (phenyl-C), 143.3 (Pyridine-C6), 155.0 (Pyridine-C4), 158.0 (Pyridine-C2).
3.1.5 N′-((4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)phenyl)-sulfonyl)-N,N-di-methylformimidamide (15)
A mixture of 13 (0.01 mol) and dimethylformamide–dimethylacetal (0.01 mol) in m-xylene (30 mL) was heated under reflux for 6 h. The reaction mixture was concentrated and the obtained product was collected and recrystallized from ethanol. Reddish-brown crystals: Yield 50%, mp 240–242 °C; Anal. Calcd. for C17H18N4O3S: C, 56.97; H, 5.06; N, 15.63. Found: C, 56.89; H, 5.10; N, 15.67; IR (KBr, cm−1): 3010 (CH-arom.), 2934 (CH-aliph.), 2214 (C≡N), 1640 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 1.98, 2.51 (2s, 6H, 2CH3), 3.18 (s, 6H, N(CH3)2), 6.50 (s, 1H, pyridine-H), 7.52–7.99 (m, 4H, Ar-H), 8.31 (s, 1H, methine-H). 13CNMR (300 MHz, DMSO-d6, δ/ppm): 20.0, 22.7 (2CH3), 35.0 (N(CH3)), 107.5 (Pyridine-C5), 118.0 (Pyridine-C3), 116.9 (C≡N), 123.0, 127.0, 137.0, 140.0 (phenyl-C), 141.0 (Pyridine-C6), 146.5 (Pyridine-C4), 157.0 (Pyridine-C2), 166 (N⚌C-N(CH3)2)
3.1.6 4-(8-Amino-7-cyano-6-(4-methoxyphenyl)-3-methyl-1-oxo-isoquinolin-2(1H)-yl) benzenesulfonamide (18)
To a solution of 13 (0.01 mol) in ethanol (30 mL), α-cyano-4-methoxyphenyl cinnamonitrile (16) (0.01 mol) and sodium ethoxide (1 g sodium in 10 mL EtOH) were added. The mixture was refluxed for 6 h and poured into crushed ice and acidified with HCl. The solid product was filtered off and recrystallized from acetic acid. Yellow crystals: Yield 45%, mp > 300 °C; Anal. Calcd. for C24H20N4O4S: C, 62.60; H, 4.38; N, 12.17. Found: C, 62.54; H, 4.29; N, 12.20; IR (KBr, cm−1): 3306, 3210 (NH2), 2222 (C≡N), 1682 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 1.20 (s, 3H, CH3), 3.65 (s, 2H, NH2), 3.80 (s, 3H, OCH3), 6.72–8.07 (m, 12H, Ar-H+SO2NH2).
3.1.7 General procedure for the preparation of pyridine derivatives 20a,b
A mixture of anilide 1 (0.01 mol), appropriate aldehyde (0.01 mol), and malononitrile (0.01 mol) in ethanol (30 mL) containing piperidine (0.5 mL) was heated under reflux for 3 h. The resulting solid was filtered off and recrystallized from common solvents to afford products (20a and b).
3.1.8 4-(6-Amino-3,5-dicyano-2-oxopyridin-1(2H)-yl)benzenesulfonamide (20a)
Compound 20a was obtained in 73% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C13H9N5O3S: C, 49.52; H, 2.88; N, 22.21. Found: C, 49.44; H, 2.79; N, 22.16; IR (KBr, cm−1): 3324, 3264 (NH2), 2218 (C≡N), 1684 (C⚌O); MS m/z (% relative intensity): 315 (M+; 3.76), 224 (5.39), 172 (72.8), 156 (81.7), 92 (100) and 76 (25.3).
3.1.9 4-(6-Amino-3,5-dicyano-4-methyl-2-oxopyridin-1(2H)-yl)-benzene-sulfonamide (20b)
Compound 20b was obtained in 67% yield, mp > 300 °C (dioxane), Anal. Calcd. for C14H11N5O3S: C, 51.06; H, 3.37; N, 21.27. Found: C, 51.10; H, 3.26; N, 21.18; IR (KBr, cm−1): 3366, 3200 (NH2), 2224 (C≡N), 1668 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 2.43 (s, 3H, CH3), 7.31 (s, 2H, NH2), 7.53–7.99 (m, 6H, Ar-H+NH2); MS m/z (% relative intensity): 329 (M+; 100), 249 (42), 198 (9.1), 172 (2.3), 156 (12) and 92 (23.9).
3.1.10 3,3′-(1,4-Phenylene)bis(2-cyano-N-(4-sulfamoylphenyl)acrylamide) (21)
To a solution of 1 (0.02 mol) in ethanol (30 mL), terephthalaldehyde (0.01 mol) and piperidine (0.5 mL) were added. The mixture was refluxed and solid product which was produced on heating was filtered off and recrystallized from acetic acid. Brown crystals: Yield 80%, mp 284–286 °C; Anal. Calcd. for C26H20N6O6S2: C, 54.16; H, 3.50; N, 14.58. Found: C, 54.10; H, 3.43; N, 14.51; IR (KBr, cm−1): 3400, 3272 (NH2), 2227 (C≡N), 1654 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 7.35–8.19 (m, 16H, Ar-H+2SO2NH2), 8.42 (s, 2H, 2 benzylidene-H), 10.74 (hump, 2H, 2NH); MS m/z (% relative intensity): 576 (M+; 3.62), 537 (10.34), 350 (20.4), 264 (13.5), 185 (100), 172 (59.1) and 92 (60.2).
3.1.11 General procedure for the preparation of Bis(2-pyridone) derivatives (22a–c)
3.1.11.1 Method A
A mixture of 21 (0.01 mol), active methylene compound (0.02 mol) and piperidine (0.5 mL) in ethanol (30 mL) was heated under reflux for 3 h, the solid product which produced on heating was collected and recrystallized from common solvents to afford products 22a–c.
3.1.11.2 Method B
A mixture of 23 (0.01 mol), cyanoacetanilide derivative 1 (0.02 mol) and piperidine (0.5 mL) in dioxane (30 mL) was heated under reflux for 3 h. The product which produced on heating was collected and recrystallized to give 22a–c.
3.1.12 4,4′-(4,4′-(1,4-Phenylene)bis(6-amino-3,5-dicyano-2-oxopyridine-4,1-(2H)-diyl)) dibenzenesulfonamide 22a
Compound 22a was obtained in 70% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C32H20N10O6S2: C, 54.54; H, 2.86; N, 19.88. Found: C, 54.42; H, 2.78; N, 19.76; IR (KBr, cm−1): 3210, 3198 (NH2), 2218 (C≡N), 1654 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 3.37 (s, 4H, 2 NH2), 7.60–8.03 (m, 16H, Ar-H+2SO2NH2); MS m/z (% relative intensity): 704 (M+; 15), 640 (24.5), 390 (28.6), 374 (20.4), 248 (34.6), 234 (20.4), 208 (71.5), 142 (22.5) and 114 (100).
3.1.13 Diethyl 4,4′-(1,4-phenylene)bis(2-amino-5-cyano-6-oxo-1-(4-sulfamoyl-phenyl)-1,6-dihydropyridine-3-carboxylate) 22b
Compound 22b was obtained in 75% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C36H30N8O10S2: C, 54.13; H, 3.79; N, 14.03. Found: C, 54.20; H, 3.80; N, 13.94; IR (KBr, cm−1): 3330, 3250 (NH2), 2226 (C≡N), 1722, 1692 (2C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 1.31 (t, 6H, 2CH3), 4.34 2 (q, 4H, 2 CH2), 7.32 (s, 4H, 2 SO2NH2), 7.84–8.48 (m, 16H, Ar-H+2NH2).
3.1.14 4,4′-(1,4-Phenylene)bis(2-amino-5-cyano-6-oxo-1-(4-sulfamoyl-phenyl)-1,6-di-hydropyridine-3-carboxamide) 22c
Compound 22c was obtained in 60% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C32H24N10O8S2: C, 51.89; H,3.27; N, 18.91. Found: C, 51.81; H, 3.30; N, 18.83; IR (KBr, cm−1): 3350, 3300 (NH2), 2222 (C≡N), 1658 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 7.34 (hump, 4H, 2 SO2NH2), 7.86–8.18 (m, 16H, Ar-H+NH2), 8.41 (s, 2H, NH2), 10.75 (hump, 2H, NH2).
3.1.15 Synthesis of 2-iminochromene-3-carboxamide derivatives 25 and 30
3.1.15.1 General procedure
A mixture of compound 1 (0.01 mol), requisite aldehyde [salicylaldehyde or 7-hydroxy-2-methyl-4-oxo-4H-chromene-6-carboxaldehyde (29)] (0.01 mol) and ammonium acetate (1 g) was refluxed in ethanol (30 mL) for 1 h. The solid product which produced on heating was collected and recrystallized from common solvents to afford products 25 and 30.
3.1.16 2-Imino-N-(4-sulfamoylphenyl)-2H-chromene-3-carboxamide (25)
Compound 25 was obtained in 80% yield, mp 260–262 °C (dioxane), Anal. Calcd. for C16H13N3O4S: C, 55.97; H, 3.82; N, 12.24. Found: C, 55.84; H, 3.72; N, 12.08; IR (KBr, cm−1): 3322, 3232 (NH2), 1682 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 7.14–7.85 (m, 10H, Ar-H+SO2NH2), 8.57 (s, 1H, chromene-H), 9.22, 13.07 (2s, 2H, 2NH).
3.1.17 2-Imino-5-methoxy-8-methyl-6-oxo-N-(4-sulfamoylphenyl)-2,6-dihydro-pyrano [3,2-g]chromene-3-carboxamide (29)
Compound 30 was obtained in 70% yield, mp 290–291 °C (dioxane), Anal. Calcd. for C21H17N3O7S: C, 55.38; H, 3.76; N, 9.23. Found: C, 55.23; H, 3.70; N, 9.16; IR (KBr, cm−1): 3312, 3218 (NH2), 1654 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 2.31 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 6.12 (s, 1H, H-7), 6.85 (s, 1H, H-10), 7.09–7.83 (m, 6H, Ar-H+SO2NH2), 8.56 (s, 1H, pyran-H), 9.45, 12.75 (2br, 2H, 2NH).
3.1.18 General procedure for the preparation of chromeno[3,4-c]pyridine derivatives 27 and 30
A mixture of 25 or 30 (0.01 mol), malononitrile (0.01 mol) and piperidine (0.5 mL) in ethanol (30 mL) was heated under reflux for 3 h. The solid product which produced on heating was collected by filtration and recrystallized from common solvents to afford products 27 and 30.
3.1.19 4-(2-Amino-1-cyano-5-imino-4-oxo-4,5-dihydro-3H-chromeno[3,4-c]-pyridin-3-yl)benzenesulfonamide (27)
Compound 27 was obtained in 84% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C19H13N5O4S: C, 56.01; H, 3.22; N, 17.19. Found: C, 56.05; H, 3.16; N, 17.21; IR (KBr, cm−1): 3442, 3350, 3238 (NH/NH2), 2204 (C≡N), 1664 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 6.98–8.72 (m, 12H, Ar-H+2NH2), 9.51 (s, 1H, NH); MS m/z (% relative intensity): 407 (M+; 3.04), 368 (13.68), 299 (6.9), 149 (13.07), 97 (38.6), 71 (63.8) and 57 (100).
3.1.20 4-(2-Amino-1-cyano-5-imino-12-methoxy-9-methyl-4,11-di-oxopyrano-[3′,2′:6,7]chromeno[3,4-c]pyridin-3(4H,5H,11H)-yl)-benzenesulfonamide (30)
Compound 30 was obtained in 69% yield, mp > 300 °C (dimethylformamide), Anal. Calcd. for C24H17N5O7S: C, 55.49; H, 3.30; N, 13.48. Found: C, 55.42; H, 3.24; N, 13.60; IR (KBr, cm−1): 3336, 3200 (NH2), 2938 (CH-aliph.), 2210 (C≡N), 1648 (C⚌O); 1H NMR (300 MHz, DMSO-d6, δ/ppm): 2.22 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.29 (s, 1H, H-7), 6.81 (s, 1H, H-10), 7.14–8.49 (m, 8H, Ar-H+2NH2), 9.41 (s, 1H, NH); MS m/z (% relative intensity): 519 (M+; 2.74), 521 (M+2; 3.5), 363 (6.38), 239 (7.9), 184 (8.46), 160 (8.5), 156 (60.0), 144 (7.6), 92 (100) and 65 (98.48).
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