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Synthesis of new pyran and pyranoquinoline derivatives
⁎Corresponding author. Tel.: +216 97 238 298. anis_romdhane@yahoo.fr (Anis Romdhane)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Various 2-amino-4H-pyran-3-carbonitriles 1 and 2 were successfully synthesized, via a one-pot three-component condensation reaction of arylaldehyde and malononitrile with methyl acetoacetate and 8-hydroxyquinoline, respectively in moderate yields. These key intermediates 1 and 2 undergo rapid condensation with formic acid and acetic anhydride to give, respectively the corresponding pyranes 3–6 and pyranopyrimidinones 7 and 8. All the synthesized compounds were completely characterized by 1H NMR, 13C NMR, IR and ES-HRMS.
Keywords
2-Amino-4H-pyran-3-carbonitriles
Multicomponent reaction
Pyranes
Pyranopyrimidinones
1 Introduction
Six-membered heterocyclic compounds containing oxygen such as 4H-pyrans constitute an important class of biologically active natural and synthetic products, playing a fundamental role in bioorganic chemistry and continue to attract interest (Abe et al., 2005; Sibi and Zimmerman, 2006).
In fact, pyrans and fused pyrans are biologically interesting compounds with antimicrobial (Hussein et al., 2012), antifungal (Chattapadhyay and Dureja, 2006), antitumor (Wang et al., 2011), anticoagulant, diuretic, spasmolitic and antianaphylactic activities (De Simone et al., 2004; Safari et al., 2012; Bonsignore et al., 1993; Heravi et al., 2008; Andreani and Lapi, 1960). Furthermore, 4H-pyrans represent building blocks of a series of natural products (Hatakeyama et al., 1988; Singh et al., 1996). A number of 2-amino-4H-pyrans are used as photoactive materials (Armesto et al., 1989), pigments (Rideout et al., 1976) and potentially biodegradable agrochemicals (Kumar et al., 2009).
On the other hand, heterocyclic systems containing a quinoline nucleus represent an important group of compounds in medicinal chemistry, they are ubiquitous substructures associated with biologically active natural products (Jonckers et al., 2002; Balamurugan et al., 2010). Some quinoline compounds, especially those with a pyranoquinoline core, constitute the basic skeleton of a number of alkaloids, such as flindersine, oricine and verprisine. They have demonstrated a significant range of biological effects such as anti-allergic, psychotropic, anti-inflammatory and antibacterial activities (Magesh et al., 2004).
Several methods for the preparation of pyran derivatives have been reported (Perkin, 1868; Singh et al., 1996; Khafagy et al., 2002). Recently, the domino-Knoevenagel–hetero-Diels–Alder (DKHDA) reaction has been described as an important protocol for the synthesis of pyran moiety by reaction of resorcinol with α,β-unsaturated aldehydes (Lee et al., 2005a, 2008b) or by reaction of barbituric acid with aromatic aldehydes followed by condensation with ethyl vinyl ether (Palasz, 2012).
Another recent method was reported as the most efficient, simple and useful synthetic method for the synthesis of pyran systems via the one-pot three component reaction of arylaldehydes, active methylene compounds and electron rich compound under basic conditions (Shestopalov et al., 2004; Sangani et al., 2012; Banothu and Bavanthula, 2012).
Our research has been devoted to the development of a new class of heterocyclic systems which incorporate the pyran moiety with the hope that they may be biologically active. Herein and as a continuation of our previous work on the synthesis of fused-pyrans scaffolds using enaminonitriles (Romdhane et al., 2012; Ben Said et al., 2013), we report here the synthesis of 2-amino-4H-pyran-3-carbonitriles 1–2 (a–b), via the one-pot three component reaction described above, and their use as precursor in the synthesis of a variety of new pyranic systems 4–8 (a–b).
2 Results and discussion
Our approach to the target heterocycle firstly started by the synthesis of 2-amino-4H-pyran-3-carbonitriles 1 and 2 via a one-pot three-component condensation between equimolar amounts of arylaldehyde, malononitrile and methyl acetoacetate and 8-hydroxyquinoline, respectively, in ethanol catalyzed by sodium carbonate (Mohammed et al., 2009) (scheme 1).
Synthetic pathway to 2-amino-4H-pyran-3-carbonitriles 1–2 (a–b).
According to some previous works (Wang et al., 2006; Seshy Babu et al., 2008; Ziarani et al., 2011), the reaction process of pyran type 1, chosen as an illustration example, is supposed to be the results in two stages of condensation, involving first the Knoevenagel condensation between aromatic aldehyde and malononitrile in the presence of Na2CO3 which yields the formation of arylidenemalononitrile A. The consequent Michael’ addition of enolic form of methylacetoacetate on an electron deficient carbon of cyanoolefin A takes place and final ring closing leads to the formation of 2-amino-4H-pyran-3-carbonitriles 1 (scheme 2).
Proposed mechanism for 2-amino-4H-pyran-3-carbonitriles 1 (a–b).
The above-mentioned pyrans 1 and 2 which contain the β-enaminonitrile moiety represent a class of intermediates which are known to be highly reactive and used as precursors for the synthesis of newly fused pyran compounds (Bedair et al., 2001; Zaki et al., 1999; Maalej et al., 2011).
The so formed pyrans 1 and 2 were characterized by their IR, 1H and 13C NMR spectra. Thus the IR spectrum of compound 1a chosen as an illustration example showed an absorption band at 2215 cm−1 due to the cyano group, while the NH2 stretching bands appeared at 3415 and 3327 cm−1. The structure was also supported by 1H NMR evidences thought the presence of three singlets relating to methyl protons (CH3, 2.31 ppm), methoxy protons (CH3O, 3.50 ppm) and the uncoupled proton (H4, 4.32 ppm). We also observed a D2O exchangeable broad singlet at δ 6.88 ppm due to the NH2 group and sets of signals, between 7.27 and 7.32 ppm, relative to aromatic protons for which chemical shifts and multiplicities were in good agreement with the proposed structure. Unambiguous proofs for the obtained product 1a aroused from its 13C spectrum data (see experimental part). In fact, on this spectrum we revealed essentially the signals attributable to carbons C4 (38.9 ppm), C3 (57.7 ppm), −CN (120.1 ppm) and particularly C2 (157.1 ppm) which was consistent with the strong deshielding effects caused by heteroatom’s proximity. Finally, the mass spectrum (ES–HRMS) of this compound showed a protonated molecular ion peak [M + H]+ at m/z 271.1004 in agreement with the molecular formula (C15H15N2O3)+.
Interaction of 1 or 2 with excess formic acid under reflux for 30 min gave 3 and 4, respectively (scheme 3). A logical explanation for the formation of these compounds is acid-induced hydrolysis of the enamine function in pyrans 1 and 2.
Synthetic pathway to derivatives 3–8 (a–b).
The newly formed products 3 and 4 were characterized by their IR, 1H and 13C NMR spectra. Supporting evidence for the suggested structures comes from their infrared spectra (1730–1760 cm−1 for a lactone and 2250–2220 cm−1 for the cyano group, but no absorption frequency was detected in the NH2 region).
Furthermore, the 1H NMR spectra of these compounds were compatible with the proposed structures. Thus taking derivative 4a (Ar⚌Ph) as an illustrative example, the 1H NMR spectrum showed, in addition to the signals of the aromatic protons attributable to the phenyl and quinoline groups between 7.24 and 8.87 ppm, the presence of two doublets (1H, J = 6.9 Hz) at 3.94 and 4.23 ppm assigned to the protons coupled together H3 and H4, respectively and the disappearance of the exchangeable broad singlet signal corresponding to the NH2 group, confirming the disappearance of the double bond C2–C3 following the hydrolysis of the enamine function in synthon 2a.
The 13C NMR of the same compound showed, in addition to the signals relating to the nitrile group (119.2 ppm) and aromatic carbons (122.6–152.6 ppm), the presence of a new signal at 162.8 ppm attributable to the carbonyl function (C2) (due to the disappearance of the double bond C2–C3) and the displacement of two signals at 41.3 and 56.8 ppm relative to carbons C4 and C3, respectively. The mass spectrum (ES–HRMS) of the same compound showed protonated molecular ion peak [M + H]+ at m/z 301.0899 in concordance with the molecular formula (C19H13N2O2)+.
While heating of 1 or 2 with formic acid under reflux for 6 h afforded the new pyran derivatives 5 and 6, respectively. Indeed, under these more vigorous conditions, the nitrile group had evidently also been hydrolyzed to the corresponding carboxylic acid, which underwent facile decarboxylation, to give the observed new products 5 and 6. We note that the reflux of the isolated cyanide pyranone types 3 and 4 for 6 h in the presence of formic acid, leads to the same structures 5 and 6, respectively (scheme 3).
Similarly, the structure of the isolated products 5 and 6 was confirmed on the basis of their spectral data. Taking for example the case of product 6a, the IR spectrum shows a characteristic absorption band of a carbonyl group at 1750 cm−1 but no absorption frequency was detected in the CN and NH2 regions. In the 1H NMR spectrum, we note essentially, the appearance of a muliplet at 3.11 ppm (2H) and a triplet (J = 7.8 Hz) at 5.08 ppm (1H) assigned to the protons H3 and H4, respectively in agreement with the proposed structure. The 13C NMR spectrum of this compound showed essentially the appearance of a signal at 38.9 ppm attributable to the methylene carbon (C3) and a deshielded signal at 173.2 ppm assigned to the carbonyl of the lactam function, we note also the disappearance of the signal of the nitrile group (120.8 ppm). Moreover, the mass spectrum (ES–HRMS) of the same compound showed a pseudo-molecular ion peak [M + H]+ at m/z 276.0946 in agreement with the molecular formula (C18H14NO2)+.
Finally, compounds 1 and 2 were further converted into pyranopyrimidino derivatives 7 and 8 by condensation with acetic anhydride in the presence of a catalytic amount of polyphosphoric acid (PPA) under reflux for one hour (Scheme 3). From a mechanistic point of view, the reaction process is assumed to follow a two-step pathway. Primly, pyrans 1 (or 2) should react with acetic anhydride to afford, the non-isolable intermediate 7′ (or 8′) which cyclize in 7″ (or 8″) after a nucleohpilic attack of the nitrile group. Intramolecular rearrangement of the so formed intermediate led to new pyrimidinones 7 (or 8) (scheme 4).
Proposed mechanism for the synthesis of compounds 7–8 (a–b).
The formation of the pyrimidino ring involving the participation of both amino and cyano groups was evident if we consider the absence of these latter’s function IR absorption bands and the appearance of new absorption band due to the (C⚌N) group at 1617–1625 cm−1. Further, the 1H NMR spectra of derivatives 7 and 8 exhibited a characteristic singlet (3H) at δ 2.32–2.49 ppm which corresponds to protons of the new methyl group introduced at the −2 position in the pyrimidino moiety by the acetic anhydride. On the other hand, the broad singlet (1H) observed at δ 11.57–12.22 ppm for these derivatives was assigned to the mobile proton of the NH function.
Unambiguous proofs for the obtained products 7 and 8 aroused from their 13C data (see experimental part). Particularly the shift-values attributed to the quaternary carbons (C⚌N) (160.4–165.7 ppm) and (C⚌O) (162.2–167.2 ppm) were consistent with the proposed structures. On the other hand, the high resolution mass spectra (ES-HR-MS) showed essentially the correct protonated molecular ion peaks [M + H]+ for all synthesized compounds 7–8(a–b), which were in good agreement with the assigned structures.
3 Conclusion
In conclusion, this work reports the synthesis of 2-amino-4H-pyran-3-carbonitriles 1 and 2, via the simple and useful one pot three component reaction of arylaldehyde, malononitrile and methylacetoacetate (or 8-hydroxyquinole). In the second part of this work we have described the successful access to some new pyranic compounds 3–8 starting from precursors 1 and 2.
4 Materials and methods
4.1 Materials and reagents
Melting points were determined on an Electrothermal 9002 melting point apparatus and are uncorrected. IR spectra were recorded on a FTS-6000 BIO-RAD apparatus. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded in deuterated CDCl3 and DMSO-d6 on a Bruker AC-300 using non deuterated solvents as internal reference. All chemical shifts were reported as δ values (ppm) and coupling constants (J) were expressed in Hz. High Resolution Mass Spectra (HR-ES-MS) were obtained with Micromass LCT (ESI technique, positive mode) spectrometers. All reactions were monitored by TLC using aluminum sheets of sds silica gel 60 F254, 0.2 mm. Column chromatography was performed on an sds silica gel (70–230 mesh) using petroleum ether and ethyl acetate mixture as eluents.
4.2 Synthesis
4.2.1 General procedure of synthesis of 2-amino-3-cyanopyrans 1 and 2
To a stirred stoichiometric mixture of arylaldehyde (10 mmol), malononitrile (10 mmol) and methyl acetoacetate or 8-hydroxyquinoline (10 mmol) in absolute ethanol (30 mL), anhydrous potassium carbonate (2 g) was added and stirring continued at room temperature for 3 h. The solvent was largely evaporated, the mixture was diluted with cold water and left to stand at room temperature for 45 min. The precipitated solid was collected by filtration, washed with cold water, then dried and crystallized from ethanol to afford 1 and 2, respectively.
4.2.2 Methyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (1a)
White solid, yield: 78%, mp: 161–163 °C (ethanol). IR (KBr, cm−1) ν: 2215 (CN), 3415, 3327 (NH2). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.31 (s, 3H, CH3), 3.50 (s, 3H, OCH3), 4.32 (s, 1H, H4), 6.88 (s, 2H, NH2), 7.27–7.32 (m, 5H, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.5 (CH3), 38.9 (C4), 51.8 (OCH3), 57.7 (C3), 107.5 (C5), 120.1 (CN), 127.2 (C3′,5′), 128.8 (C2′,6′), 145.1 (C1′), 157.1 (C2), 158.9 (C6), 166.5 (C⚌O). HR-ES-MS [M + H]+ calcd for (C15H15N2O3)+: 271.1004, found: 271.1012.
4.2.3 Methyl 6-amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-4H-pyran-3-carboxylate (1b)
White solid, yield: 81%, mp: 165–167 °C (ethanol). IR (KBr, cm−1) ν: 2220 (CN), 3423, 3335 (NH2). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.24 (s, 3H, CH3), 3.50 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.22 (s, 1H, H4), 6.89 (s, 2H, NH2), 6.99–7.12 (m, 5H, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.2 (CH3), 38.3 (C4), 51.5 (OCH3), 53.7 (OCH3), 57.2 (C3), 107.2 (C5), 119.7 (CN), 126.9 (C3′,5′), 129.1 (C2′,6′), 144.8 (C1′), 156.5 (C2), 158.4 (C6), 166.0 (C⚌O). HR-ES-MS [M + H]+ calcd for (C16H17N2O4)+: 301.1110, found: 301.1118.
4.2.4 2-Amino-4-phenyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile (2a)
White solid, yield: 68%, mp: 196–198 °C (ethanol). IR (KBr, cm−1) ν: 2225 (CN), 3526, 3445 (NH2). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 4,95 (s, 1H, H4), 7.12 (s, 2H, NH2), 7.22–7.39 (m, 5H, Harom.), 7.57–7.66 (m, 3H, H5,6,8), 8.33 (d, 1H, J = 8.4 Hz, H7), 8.94 (d, 1H, J = 4.2 Hz, 1H, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 41.1 (C4), 56.2 (C3), 120.8 (CN), 122.3, 122.5, 123.9, 127.3, 127.4, 128.1, 129.1, 136.4, 137.8, 143.3, 146.1, 150.6 (C9), 160.6 (C2). HR-ES-MS [M + H]+ calcd for (C19H14N3O)+: 300.1059, found: 300.1066.
4.2.5 2-Amino-4-(4-methoxyphenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile (2b)
White solid, yield: 52%, mp: 217–219 °C (ethanol). IR (KBr, cm−1) ν: 2217 (CN), 3430, 3330 (NH2). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 3.70 (s, 3H, OCH3), 4.90 (s, 1H, H4), 6.37 (d, J = 8.4 Hz, 2H, H3′,5′), 7.20 (m, 5H, NH2 + H2′,6′,5), 7.59 (m, 2H, H8,6), 8.32 (d, 1H, J = 8.4 Hz, H7), 8.95 (d, 1H, J = 4.2 Hz, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 41.7 (C4), 53.7 (OCH3), 56.3 (C3), 120.7 (CN), 121.9, 122.3, 123.7, 127.1, 127.5, 128.3, 129.2, 136.2, 137.9, 144.0, 146.5, 151.2 (C9), 161.3 (C2). HR-ES-MS [M + H]+ calcd for (C20H16N3O2)+: 330.1164, found: 330.1153.
4.3 General procedure of synthesis of 2-amino-3-cyanonaphtopyranes 3–6 (a–b)
A mixture of compound 1 or 2 (10 mmol) and redistilled acetic anhydride (25 mL) was refluxed for 30 min (or 6 h). After cooling, the precipitated white solid product was filtered off and washed thoroughly and recrystallized from ethanol to yield 3 and 4, respectively (or 5 and 6, respectively) as white solid.
4.3.1 Methyl 5-cyano-3,4-dihydro-2-methyl-6-oxo-4-phenyl-4H-pyran-3-carboxylate (3a)
White solid, yield: 76%, mp: 218–220 °C (ethanol). IR (KBr, cm−1) ν: 1730 (C⚌O), 2220 (CN). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.18 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 3.74 (d, J = 6.9 Hz, 1H, H5), 4.21 (d, J = 6.9 Hz, 1H, H4), 7.12–7.34 (m, 5H, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.6 (CH3), 30.4 (C4), 39.2 (C5), 51.6 (OCH3), 105.9 (C3), 117.3 (CN), 126.7, 127.9, 129.4, 138.0, 148.4 (C2), 158.9 (C6), 166.3 (C⚌O). HR-ES-MS [M + H]+ calcd for (C15H14NO4)+: 272.0845, found: 272.0854.
4.3.2 Methyl 5-cyano-3,4-dihydro-2-methyl-4-(4-methoxyphenyl)-6-oxo-4H-pyran-3-carboxylate (3b)
White solid, yield: 64%, mp: 230–232 °C (ethanol). IR (KBr, cm−1) ν: 1745 (C⚌O), 2235 (CN). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.22 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 3.71 (s, 3H, COOCH3), 3.82 (d, J = 6.9 Hz, 1H, H5), 4.18 (d, J = 6.9 Hz, 1H, H4), 7.27 (d, 2H, J = 8.4 Hz, Harom), 7.32 (d, 2H, J = 8.4 Hz, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.6 (CH3), 31.2 (C4), 40.9 (C5), 53.7 (OCH3), 55.6 (OCH3), 105.9 (C3), 115.2, 117.3 (CN), 128.7, 135.8, 148.2 (C2), 152.9, 160.2 (C6), 166.5 (C⚌O). HR-ES-MS [M + H]+ calcd for (C16H16NO5)+: 302.0950, found: 302.0956.
4.3.3 3,4-Dihydro-2-oxo-4-phenyl-2H-pyrano[3,2-h]quinoline-3-carbonitrile (4a)
White solid, yield: 78%, mp: 152–154 °C (ethanol). IR (KBr, cm−1) ν: 1750 (C⚌O), 2247 (CN). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 3.94 (d, J = 6.9 Hz, 1H, H3), 4.23 (d, J = 6.9 Hz, 1H, H4), 7.24–7.41 (m, 5H, Harom.), 7.53–7.67 (m, 3H, H5,6,8), 8.31 (d, 1H, J = 8.4 Hz, H7), 8.87 (d, 1H, J = 4.2 Hz, 1H, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 41.3 (C4), 56.8 (C3), 119.2 (CN), 122.6, 123.1, 124.1, 126.3, 127.5, 128.4, 129.1, 131.5, 136.4, 141.8, 143.3, 146.6, 152.6 (C9), 162.8 (C2). HR-ES-MS [M + H]+ calcd for (C19H13N2O2)+: 301.0899, found: 301.0907.
4.3.4 3,4-Dihydro-4-(4-methoxyphenyl)-2-oxo-2H-pyrano[3,2-h]quinoline-3-carbonitrile (4b)
White solid, yield: 52%, mp: 216–218 °C (ethanol). IR (KBr, cm−1) ν: 1760 (C⚌O), 2250 (CN). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 3.72 (s, 3H, OCH3), 3.89 (d, J = 6.9 Hz, 1H, H3), 4.21 (d, J = 6.9 Hz, 1H, H4), 6.28 (d, J = 8.4, 2H, H2′,6′), 6.83 (d, J = 8.4, 2H, H3′,5′), 7.39 (d, J = 8.4, 1H, H5), 7.56 (m, 2H, H6,8), 8.31 (d, J = 8.1 Hz, 1H, H7), 8.81 (d, J = 4.2 Hz, 1H, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 42.3 (C4), 51.8 (C3), 55.7 (OCH3), 114.8, 117.3 (CN), 121.6, 123.1, 127.1, 127.3, 129.5, 130.6, 135.5, 136.4, 141.8, 146.9, 152.6 (C9), 158.2, 164.3 (C2). HR-ES-MS [M + H]+ calcd for (C20H15N2O3)+: 331.1004, found: 331.1012.
4.3.5 Methyl 3,4-dihydro-2-methyl-6-oxo-4-phenyl-4H-pyran-3-carboxylate (5a)
White solid, yield: 73%, mp: 215–217 °C (ethanol). IR (KBr, cm−1) ν: 1745 (C⚌O). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.31 (s, 3H, CH3), 2.97 (m, 2H, H5), 3.76 (s, 3H, OCH3), 4.21 (m, 1H, H4), 7.12–7.34 (m, 5H, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 17.9 (CH3), 35.3 (C5), 38.2 (C4), 52.3 (OCH3), 107.9 (C3), 126.7, 128.1, 129.7, 141.2, 147.8 (C2), 162.9 (C6), 167.3 (C⚌O). HR-ES-MS [M + H]+ calcd for (C14H15O4)+: 247.0892, found: 247.0899.
4.3.6 Methyl 3,4-dihydro-4-(4-methoxyphenyl)-2-methyl-6-oxo-4H-pyran-3-carboxylate (5b)
White solid, Yield: 66%, mp: 226–228 °C (ethanol). IR (KBr, cm−1) ν: 1755 (C⚌O). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.23 (s, 3H, CH3), 2.78 (m, 2H, H5), 3.56 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.14 (m, 1H, H4), 7.07 (d, 2H, J = 8.4 Hz, Harom), 7.32 (d, 2H, J = 8.4 Hz, Harom). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 17.6 (CH3), 34.7 (C5), 39.7 (C4), 52.3 (OCH3), 55.2 (OCH3), 108.2 (C3), 115.7, 128.9, 136.1, 148.1 (C2), 152.3, 158.9 (C6), 166.3 (C⚌O). HR-ES-MS [M + H]+ calcd for (C15H17O5)+: 277.0998, found: 277.1005.
4.3.7 3,4-Dihydro-4-phenylpyrano[3,2-h]quinolin-2-one (6a)
White solid, yield: 86%, mp: 182–184 °C (ethanol). IR (KBr, cm−1) ν: 1750 (C⚌O). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 3.11 (m, 2H, H3), 5.08 (t, J = 7.8 Hz, 1H, H4), 7.12–7.38 (m, 7H, Harom), 7.50 (m, 1H, H6), 8.29 (d, J = 8.4 Hz, 1H, H7), 8.84 (d, J = 3.9 Hz, 1H, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 39.1 (C3), 48.9 (C4), 117.5, 121.8, 126.4, 126.5, 127.2, 127.3, 127.9, 128.6, 136.3 (C7), 138.4 (C10a), 144.2, 148.5 (C10b), 149.7 (C9), 173.2 (C2). HR-ES-MS [M + H]+ calcd for (C18H14NO2)+: 276.0946, found: 276.0953.
4.3.8 3,4-Dihydro-4-(4-methoxyphenyl)pyrano[3,2-h]quinolin-2-one (6b)
White solid, Yield: 63%, mp: 171–173 °C (ethanol). IR (KBr, cm−1) ν: 1755 (C⚌O). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 3.07 (m, 2H, H3), 3.75 (s, 3H, OCH3), 5.03 (t, J = 7.5 Hz, 1H, H4), 6.18 (d, J = 8.7, 2H, Harom), 6.81 (d, J = 8.4, 2H, Harom), 7.38 (d, J = 8.4, 1H, H5), 7.54 (m, 2H, Harom), 8.32 (d, J = 8.1 Hz, 1H, H7), 8.83 (d, J = 3.3 Hz, 1H, H9). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 38.9 (C3), 42.3 (C4), 54.9 (OCH3), 113.6, 121.4, 124.7, 125.1, 126.3, 127.1, 128.1, 137.7 (C7), 137.4 (C10a), 147.8, 148.8 (C10b), 157.5 (C9), 160.5, 172.9 (C2). HR-ES-MS [M + H]+ calcd for (C19H16NO3)+: 306.1052, found: 306.1059.
4.4 General procedure of synthesis of pyrano[2,3-d]pyrimidines 7–8 (a–b)
Acetic anhydride (20 mL) was added to the pyran 1 or 2 (10 mmol), then orthophosphoric acid (5 mL) was added carefully and the resulting hot mixture was refluxed for 3 h. After cooling, the mixture was diluted with cold water when a solid formed which was collected by filtration, washed several times with cold water and crystallization from ethanol.
4.4.1 Methyl 2,7-dimethyl-4-oxo-5-phenyl-3H-pyrano[2,3-d]pyrimidine-6-carbox-ylate (7a)
White solid, yield: 75%, mp: 149–151 °C (ethanol). IR (KBr, cm−1) ν: 1620 (C⚌N). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.31 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.60 (s, 3H, OCH3), 4.92 (s, 1H, H5), 7.05–7.33 (m, 5H, Harom), 12.11 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.9, 21.2, 36.3 (C5), 51.7 (OCH3), 101.8 (C4a), 108.3 (C6), 126.9 (C4′), 128.1 (C3′,5), 128.4 (C2′,6′), 143.6 (C1′), 158.4 (C7), 158.2 (C8a), 161.1 (C4), 165.2 (C2), 166.7 (C⚌O). HR-ES-MS [M + H]+ calcd for (C17H17N2O4)+: 313.1110, found: 313.1115.
4.4.2 Methyl 2,7-dimethyl-5-(4-methoxyphenyl)-4-oxo-3H-pyrano[2,3-d]pyrimidine-6-carboxylate (7b)
White solid, yield: 78%, mp: 154–156 °C (ethanol). IR (KBr, cm−1) ν: 1615 (C⚌N). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.30 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.63 (s, 1H, H5), 7.06 (d, 2H, J = 8.4 Hz, Harom), 7.32 (d, 2H, J = 8.4 Hz, Harom), 12.22 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 18.9, 23.2, 37.1 (C5), 52.3 (OCH3), 55.7 (OCH3), 102.1 (C4a), 108.9 (C6), 117.2, 129.7, 133.6, 152.3, 156.9, 158.3, 162.1, 165.7 (C2), 167.2 (C⚌O). HR-ES-MS [M + H]+ calcd for (C18H19N2O5)+: 343.1216, found: 343.1210.
4.4.3 2-Methyl-5-phenyl-4H-pyrano[3,2-h]quinolino[2,3-d]pyrimidin-4-one (8a)
White solid, yield: 78%, mp: 194–196 °C (ethanol). IR (KBr, cm−1) ν: 1625 (—C⚌N). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.47 (s, 3H, CH3), 5.48 (s, 1H, H5), 7.23 (d, J = 8.7 Hz, 1H, H6), 7.21–7.32 (m, 5H, Harom), 7.62 (m, 1H, H9), 7.63 (d, J = 8.7 Hz, 1H, H7), 8.37 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H, H8), 8.96 (dd, J = 4.2 Hz, J = 1.5 Hz, 1H, H10), 11.57 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 25.6, 42.8 (C5), 93.3 (C4a), 117.6, 121.6, 126.8, 126.3, 127.1, 127.5, 128.2, 128.8, 136.8, 137.9, 142.3, 150.2, 151.7, 158.7, 160.4, 162.2 (C⚌O). HR-ES-MS [M + H]+ calcd for (C18H19N2O5)+: 342.1164, found: 342.1157.
4.4.4 2-Methyl-5-(4-methoxyphenyl)-4H-pyrano[3,2-h]quinolino[2,3-d]pyrimidin-4-one (8b)
White solid; yield: 68%, mp: 183–185 °C (ethanol). IR (KBr, cm−1) ν: 1617 (—C⚌N). 1H NMR (DMSO-d6, 300 MHz): δ (ppm) = 2.32 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 5.29 (s, 1H, H5), 7.12 (d, 2H, J = 8.4 Hz, Harom), 7.31 (d, 2H, J = 8.4 Hz, Harom), 7.38 (d, J = 8.1 Hz, 1H, H6), 7.58 (m, 1H, H9), 7.65 (d, J = 8.1 Hz, 1H, H7), 8.31 (d, J = 7.5 Hz, 1H, H8), 8.95 (d, J = 3.5 Hz, 1H, H10), 11.68 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 22.5, 54.4 (C5), 52.3 (OCH3), 98.4 (C4a), 117.5, 121.3, 126.7, 126.5, 127.3, 127.4, 128.4, 128.9, 136.9, 138.2, 142.6, 150.3, 152.1, 156.7, 161.3, 164.2 (C⚌O). HR-ES-MS [M + H]+ calcd for (C22H18N3O3)+: 372.1270, found: 372.1263.
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