DABCO-catalyzed highly regioselective synthesis of novel 4H-pyrano[2,3- b]quinoline derivatives: three‑component domino strategy

doi:10.21203/rs.3.rs-3121221/v1

Download PDF

Research Article

DABCO-catalyzed highly regioselective synthesis of novel 4H-pyrano[2,3- b]quinoline derivatives: three‑component domino strategy

https://doi.org/10.21203/rs.3.rs-3121221/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

A highly regioselective multicomponent synthesis via DABCO-mediated knoevenagel condensation/heterocyclization sequence has been executed. An efficient and fast-track protocol has been used for preparing O-heterocyclic compounds under metal-free conditions. The one pot three-component reaction of 2-chloroquinoline-3-carbaldehyde and two diverse cyclic active methylenes (dimedone and barbituric acid) for the synthesis of 4H-pyrano[2,3-b]quinoline has been accomplished under mild condition. The strategy included herein shows significant advantages including a facile process with easy purification, excellent yields, wide applicability, available substrates and cost-effective and eco-friendly solvent and catalyst.

regioselective

multicomponent

metal-free

knoevenagel condensation

heterocyclization

pyranoquinoline

Heterocyclic rings are the main core of the natural products scaffold [1–4]. As an example, polyfunctionalized heterocyclic compounds are extensively utilized in the pharmaceutical discoveries and chemical processes [5–7].

Multicomponent reactions (MCRs) are one of the most popular strategy for the synthesis of organic targets, especially complex heterocyclic libraries [8–10]. The development of efficient multi-component reactions for the construction of heterocyclic frameworks to have distinctive and special features plays an important role for huge numbers of synthetic products [11–13]. MCRs are one-pot, simple procedure with short reaction time and other notable features through which complex structures can be produced with novel reactions in cost-effective manner [10, 14–20].

Quinoline as a nitrogen-containing vital scaffold has become a versatile heterocyclic compound in drug and organic synthesis due to its biological and pharmaceutical activities [21, 22]. Quinoline constitutes the essential segment of natural products with pharmacological properties [23]. Also, it is used as a main template for the synthesis of medicinal compounds [24]. A broad range of biological and pharmaceutical activities of synthetic derivatives containing quinoline scaffold has attracted the attention of chemical researchers. Therefore, scholars have presented copious synthetic methods to construct functionalized quinolines scaffold [25–29].

Various types of polyfunctional quinoline derivatives are synthesized using 2-chloroquinoline-3-carbaldehydes as a synthon [30–32]. Notably, over the last two decades, a wide range of derivatives of quinoline-fused heterocyclic compounds such as pyrrolo[3,4-b]quinolinone [33], pyrazoloquinolines [34], tetrazoloquinolines [35], pyranoquinolinones [36], thiopyranoquinolines [37], dihydrodibenzo[1, 8]naphthyridinones [38], pyrimido[1, 8]naphthyridines, chromenoquinolinyl-pyrimidines [39], pyrazolopyrano-quinolinyl-pyrimidines [40], and oxazepinoquinolines [41] have been reported.

As polycyclic O-heterocycles, pyranoquinoline frames have also attracted considerable attention as a major class of alkaloids [42]. The skeleton of pyranoquinoline contains both cores of dihydropyran and quinoline which shown great biological activity [43, 44].

The efficient synthesis of pyranoquinolines has been of focus for several decades to be improved through introducing novel synthetic methods [45–48]. So far, various strategies have been reported for the construction of pyranoquinolines [49–54].

Because of its diversity and specific features, remarkable efforts have been dedicated to pyranoqunoline. For example, synthesis of 80-member library of novel pyrano-[4,3-b]quinolines by using palladium-coupling reactions of 4-iodopyrano[4,3-b]-quinoline [55], synthesis of medicinally relevant 4H-pyrano[3,2-c]quinoline scaffold [56], and functionalized spiro[indoline-3,4'-pyrano[3,2-h]quinolines [57].

Recently, the synthesis and biological screening of pyrano[3,2‑c]quinolone analogues as anti-inflammatory and anticancer agents was reported by Upadhyay et al. [58]. Also, a novel and convenient procedure for the synthesis of multifunctional quinolinopyranpyrazole frameworks via multicomponent reaction was reported by Bakthadoss et al. [59].

One approach to synthesize these molecules involves variety of condensation reactions of 2-chloroquinoline-3-carbaldehyde derivatives with methylene active due to its unique structural features [60–64]. Cyclic active methylenes have emerged as a brilliant synthon to synthesis a series of polyfunctionalized heterocyclic derivatives [65–70]. 1,3-Cyclodiones are significant active methylenes involving in a broad range of chemical properties. The 1,3-cyclodiones such as dimedone and barbituric acid mostly serves as commonly-used and versatile nucleophile in the reactions of C-C and C-O bond formation, especially the knoevenagel condensation [71–81]. Enole-keto forms of active 1,3-cyclodiones leading to domino knoevenagel condensation/heterocyclization reactions to achieve O-heterocyclic compounds through intramolecular O-cyclization [39, 40]. So far, several reports have been published on the condensation reaction of 2-chloroquinoline-3-carbaldehydes with cyclic active methylenes, which led to the synthesis of polycyclic structures, such as pyranoquinolines [40], quinolinyl-pyranopyrazole, quinolinyl-pyrazolo pyrano pyrimidine [64, 82], quinolinyl pyranochromenones [83], and quinolinyl-xanthene [84] through intramolecular O-cyclization. Despite the extensive applicability of cyclic active methylenes as nucleophiles in heterocyclization reactions, their utilization in regioselective 4H-pyrano[2,3-b]quinoline synthesis have been rarely reported.

Some complex pyrano[2,3-b]-quinolines were synthesized via intramolecular domino knoevenagel/hetero diels-alder reactions by Bhuyan and et al. [85]. It is noteworthy that Shiri and co-workers reported new series of 4H-pyrano[2,3-b]quinoline by intramolecular O-cyclization of pyrazolone cyclic active methylenes [39, 86]. New methodology for synthesis of bio-active functionalized 1,4-dihydropyrazolo-[4`,3`:5,6]pyrano[2,3-b]quinolines via alkylation/annulation sequence was reported by Zhang and co-workers [44]. Alizadeh and et al. reported novel functionalized pyrano[2,3‑b]quinoline derivatives via Wittig reagent and the active methylene compounds [87].

Inspiring by these reports, in our previous research, we have synthesized a series of regioselective polycyclic structures by DABCO [86]. In continuance of our interest in the MCRs and quinolines, herein, we report a facile and efficient procedure for the synthesis of new fused quinolines O-heterocycles by using 2-chloroquinoline-3-carbaldehyde 1, diverse active methylenes 2, and 3 under multi-component process.

Toward this end, the synthesis of new 4H-pyrano[2,3-b]quinoline derivatives through intramolecular O-cyclization of cyclic active methylenes with high regioselectivity has been investigated (Scheme 1).

Inspired by our previous works, and due to the unique structural and chemical properties of DABCO [88–91], we used DABCO as a reactive and selective catalyst for the synthesis of 4H-pyrano[2,3-b]quinoline derivatives.

Initially, the key starting material, 2-chloroquinoline-3-carbaldehydes 1a-f [85], were prepared. Subsequently a mixture of 2-chloroquinoline-3-carbaldehyde 1a, dimedone 2a and barbituric acid 3 was refluxed in the EtOH by adding DABCO as a catalyst. The progress of the reaction was monitored by TLC (Ethyl acetate- MeOH: 9:1). After 2h, the reaction was completed and a cream precipitate was obtained in 95% yield. As seen in Scheme 2, it is possible to synthesize four products according to potential nucleophilic-electrophilic sites in the three consecutive stages of knoevenagel condensation/ michael addition/ O-intramolecular cyclization. According to our strategy, product 4a has been obtained with high selectivity and efficiency. DABCO seems to have directed the reaction path towards the formation of the desired product 4a as a basic catalyst with a specific structure [88–91]. In the next step, in order to be ensured the choice of optimal conditions, the reaction was carried out under different solvents and catalysts. As shown in Table 1, EtOH as a solvent and DABCO as a catalyst with a stoichiometric amount showed the best results in terms of yield, purity, and selectivity.

The structure of the newly product 4a was confirmed by FT-IR, ¹H-NMR, ¹³C-NMR and Ms Spectra.

This compound exhibited characteristic IR stretching frequencies in the 3417 and 3230 regions which are attributed to OH and NH, respectively. Also, three signals of C = O groups in 1729 (ketone), 1668 (amide), 1652 (amide) cm^− 1 were clearly observed. The ¹H-NMR spectrum exhibited two key singlet peaks attributed to methyl at δ = 0.91 (3H) and 1.02 (3H) ppm. Four doublet signals at δ = 2.01–2.04 (1H), 2.24–2.27 (1H), 2.35–2.38 (1H) and 2.55–2.58 (1H) ppm, related to the CH₂ groups of dimedone. CH of the pyran ring is confirmed by singlet peak at δ = 4.49 (1H) ppm. Other signals including triplet at 7.11–7.14 (1H), doublet at 7.21–7.23 (1H), triplet at 7.39–7.42 (1H), doublet at 7.68–7.69 (1H) and singlet at 7.80 (1H) ppm are corresponding to five aromatic protons. Two protons attributed to the NH, appeared as two singlet at δ = 10.60 and δ = 11.49 ppm.

The ¹³C-NMR data showed two methyl groups in the aliphatic region at 26.5 and 29.4 ppm. Also, other signals in the aliphatic regions related to quaternary carbon (4°) 31.5 ppm and two methylene groups δ = 32.3 and 50.7 ppm. Methyne carbon appeared at 86.9 ppm due to magnetic anisotropy.

Other peaks were observed at 111.5 to 161.1 ppm relevant to aromatic carbons. Peaks attributed to 2 amides and keto groups at 163.9, 164.8 and 196.8 ppm respectively, corresponding to structure 4a. Mass spectrum has confirmed the formation of the 4H-pyrano[2,3-b]quinoline 4a clearly.

Next, we employed various 2-chloroquinoline-3-carbaldehyde bearing either electron-withdrawing or electron-donating groups 1b-f, dimedone 2a and barbituric acid 3 to produce functionalized 4H-pyrano[2,3-b]quinolines derivatives under optimal condition. As shown in Table 2, 4H-pyrano[2,3-b]quinolines 4a-f were synthesized with different yields.

To establish the scope of this process using another cyclic active methylene derivative. Toward this end, under the same strategy, functionalized 4H-pyrano[2,3-b]quinolines 7g-l in good yields (80–89%) were synthesized when 1, 3-cyclohexanedione was used as cyclic active methylene.

Outstandingly, by simple and proficient methodology, we have established new series of regioselective functionalized 4H-pyrano[2,3-b]quinolines 4a-l in good to high yields (80–95%) (Table 2,3).

The plausible mechanism of these regioselective domino reactions is proposed, as shown in Scheme 3. The initial, intermediate A is formed undergoes knoevenagel condensation of 2-chloroquinoline-3-carbaldehyde 1 with dimedone 2. In following barbituric acid was added to intermediate A through michael addition and intermediate B was formed. Subsequently, desired product 4 is produced through intramolecular O-cyclization.

In conclusion, we have designed and synthesized a novel series of functionalized 4H-pyrano[2,3-b]quinolone derivatives by utilizing an efficient one-pot three-component reaction strategy. We have established a new simple and effective procedure for the regioselective synthesis of functionalized pyranoquinolines derivatives from facile domino metal free knoevenagel /heterocyclization reaction. The most important features of this reaction are operational simplicity, inexpensiveness, and commercially availability of engaging materials. From environmental point of view all solvents used in all steps from synthesis to purification are green. Remarkably, C-O bond formation has been performed under metal-free conditions with high selectivity.

A mixture of 2-chloroquinoline-3-carbaldehydes 1 (1 mmol) dimedone 2 (1 mmol), barbituric acid 3, and DABCO (1 mmol) as catalyst were taken in ethanol (5 mL) under reflux condition for appropriate periods as indicated in Tables 2 and 3. After completion of the reaction as indicated by TLC (Ethyl acetate: MeOH: 9:1), the reaction mixture was filtered off, and the residue solid washed by hot EtOH/H₂O (1:1) to afford pure compounds.

Spectral data for selected products 4a-l

5-(3,3-dimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4a): Cream powder, mp: 304–306 ºC, yield: 95%; FT-IR (KBr) (ν_max, cm^− 1); 3417, 3230, 1729, 1668, 1652; ¹HNMR (300 MHz, DMSO-d₆): δ 0.91 (s, 3H, CH₃), 1.02 (s, 3H, CH₃), 2.01–2.04 (d, J = 9.0 Hz, 1H, CH), 2.24–2.27 (d, J = 9.0 Hz, 1H, CH), 2.35–2.38 (d, J = 9.0 Hz, 1H, CH), 2.55–2.58 (d, J = 9.0 Hz, 1H, CH), 4.49 (s, 1H, CH), 7.11–7.14 (t, J = 4.5 Hz, 1H, Ar CH), 7.21–7.23 (d, J = 6.0 Hz, 1H, Ar CH), 7.39–7.42 (t, J = 4.5 Hz, 1H, Ar CH), 7.68–7.69 (d, J = 3.0 Hz, 1H, Ar CH), 7.80 (s, 1H, Ar CH), 10.60 (s, 1H, NH), 11.49 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 26.5, 29.4, 31.5, 32.3, 50.7, 86.9, 111.5, 114.9, 119.6, 122.2, 128.2, 130.1, 132.0, 138.6, 139.3, 151.7, 151.8, 156.4, 161.1, 163.9, 164.8, 196.8; Anal. calc. for C₂₂H₁₉N₃O₅: C, 65.18; H, 4.72; N, 10.37%, found: C, 64.95; H, 4.68; N, 10.28%; MS (EI, 70 eV) m/z: 405(M⁺).

6-hydroxy-5-(3,3,9-trimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4b): Cream powder, mp: 310–312 ºC, yield: 92%; FT-IR (KBr) (ν_max, cm^− 1): 3648, 3250, 1730, 1670, 1660; ¹HNMR (300 MHz, DMSO-d₆): δ 0.92 (s, 3H, CH₃), 1.04 (s, 3H, CH₃), 2.02–2.08 (d, J = 18 Hz, 1H, CH), 2.26 (s, 1H, CH), 2.33 (s, 3H, CH₃), 2.40 (s, 1H, CH), 2.56–2.62 (d, J = 18 Hz, 1H, CH), 4.49 (s, 1H, CH), 7.13–7.16 (d, J = 9 Hz, 1H, Ar CH), 7.25–7.27 (d, J = 6.0 Hz, 1H, Ar CH), 7.50 (s, 1H, Ar CH), 7.78 (s, 1H, Ar CH), 9.91 (s, 1H, OH), 10.98 (s, 1H, NH), 11.46 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 20.9, 26.4, 29.3, 31.4, 32.3, 50.6, 87.5, 111.8, 114.9, 119.5, 127.7, 131.1, 131.3, 131.4, 136.7, 139.3, 149.9, 151.3, 154.2, 161.0, 136.4, 164.3, 196.6; Anal. calc. for C₂₃H₂₁N₃O₅: C, 65.86; H, 5.05; N, 10.02%, found: C, 65.74; H, 4.96; N, 9.98%; MS (EI, 70 eV) m/z: 419(M⁺).

6-hydroxy-5-(9-methoxy-3,3-dimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4c): Cream powder, mp: 314–316 ºC, yield: 88%; FT-IR (KBr) (ν_max, cm^− 1): 3420, 3150, 1693, 1653, 1624; ¹HNMR (300 MHz, DMSO-d₆): δ 0.93 (s, 3H, CH₃), 1.04 (s, 3H, CH₃), 2.03–2.09 (d, J = 18 Hz, 1H, CH), 2.26–2.31 (d, J = 15 Hz, 1H, CH), 2.35–2.41 (d, J = 18 Hz, 1H, CH), 2.56–2.62 (d, J = 18 Hz, 1H, CH), 3.78 (s, 3H, OCH₃), 4.49 (s, 1H, CH), 7.07–7.09 (d, J = 6 Hz, 1H, Ar CH), 7.17–7.20 (d, J = 9 Hz, 1H, Ar CH), 7.29 (s, 1H, Ar CH), 7.82 (s, 1H, Ar CH), 10.93 (s, 1H, NH), 11.43 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 26.5, 29.3, 31.5, 32.3, 50.6, 55.9, 87.4, 109.5, 111.7, 116.3, 119.6, 120.1, 131.7, 133.2, 139.3,150.0, 153.1, 154.4, 154.5, 160.6, 163.4, 164.3, 196.6; Anal. calc. for C₂₃H₂₁N₃O₆: C, 63.44; H, 4.86; N, 9.65%, found: C, 63.28; H, 4.75; N, 9.53%; MS (EI, 70 eV) m/z: 435(M⁺).

6-hydroxy-5-(3,3,7-trimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4d): Cream powder, mp: 319–321 ºC, yield: 90%; FT-IR (KBr) (ν_max, cm^− 1); 3475, 3171, 1699, 1673, 1644; ¹HNMR (300 MHz, DMSO-d₆): δ 0.93 (s, 3H, CH₃), 1.05 (s, 3H, CH₃), 2.03–2.09 (d, J = 18 Hz, 1H, CH), 2.27 (s, 1H, CH), 2.32 (s, 1H, CH), 2.37 (s, 3H, CH₃), 2.58–2.63 (d, J = 15 Hz, 1H, CH), 4.52 (s, 1H, CH), 7.04–7.09 (t, J = 7.5 Hz, 1H, Ar CH), 7.27–7.29 (d, J = 6.0 Hz, 1H, Ar CH), 7.55–7.57 (d, J = 6.0 Hz, 1H, Ar CH), 7.85 (s, 1H, Ar CH), 10.64 (s, 1H, NH), 10.97 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 19.0, 26.7, 29.3, 31.2, 32.3, 50.6, 87.5, 111.9, 119.5, 122.0, 123.4, 126.4, 131.2, 131.3, 137.0, 140.1, 149.9, 154.4, 161.5, 163.4, 164.2, 196.6; Anal. calc. for C₂₃H₂₁N₃O₅: C, 65.86; H, 5.05; N, 10.02%, found: C, 65.73; H, 4.96; N, 9.97%; MS (EI, 70 eV) m/z: 419(M⁺).

5-(9-bromo-3,3-dimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4e): Cream powder mp: 316–318 ºC, yield: 82%; FT-IR (KBr) (ν_max, cm^− 1): 3500, 3120, 1720, 1692, 1672; ¹HNMR (400 MHz, DMSO-d₆): δ 0.92 (s, 3H, CH₃), 1.04 (s, 3H, CH₃), 2.04–2.08 (d, J = 16 Hz, 1H, CH), 2.27–2.31 (d, J = 16 Hz, 1H, CH), 2.36–2.40 (d, J = 16 Hz, 1H, CH), 2.57–2.61 (d, J = 16 Hz, 1H, CH), 4.51 (s, 1H, CH), 7.18–7.20 (d, J = 8 Hz, 1H, Ar CH), 7.57–7.59 (d, J = 8 Hz, 1H, Ar CH), 7.87 (s, 1H, Ar CH), 8.02 (s, 1H, Ar CH), 10.98 (s, 1H, NH), 11.67 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 26.5, 29.3, 31.3, 32.3, 50.6, 87.3, 111.7, 113.7, 117.2, 121.3, 130.2, 132.7, 132.9, 137.7, 138.3, 149.9, 154.3, 160.8, 163.4, 164.4, 196.5; Anal. calc. for C₂₂H₁₈BrN₃O₅: C, 54.56; H, 3.75; N, 8.68%, found: C, 54.41; H, 3.64; N, 8.56%; MS (EI, 70 eV) m/z: 483(M⁺).

5-(9-chloro-3,3-dimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4f): Cream powder, mp: 315–317 ºC, yield: 85%; FT-IR (KBr) (ν_max, cm^− 1): 3425, 3170, 1720, 1692, 1659; ¹HNMR (400 MHz, DMSO-d₆): δ 0.92 (s, 3H, CH₃), 1.03 (s, 3H, CH₃), 2.04–2.08 (d, J = 16 Hz, 1H, CH), 2.26–2.30 (d, J = 16 Hz, 1H, CH), 2.36–2.40 (d, J = 16 Hz, 1H, CH), 2.57–2.61 (d, J = 16 Hz, 1H, CH), 4.51 (s, 1H, CH), 7.24–7.26 (d, J = 6 Hz, 1H, Ar CH), 7.45–7.47 (d, J = 6 Hz, 1H, Ar CH), 7.88 (s, 2H, Ar CH), 10.96 (s, 1H, NH), 11.67 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 26.5, 29.3, 31.3, 32.3, 50.6, 87.3, 111.7, 116.9, 120.7, 126.0, 127.2, 130.0, 132.9, 137.3, 138.4, 150.0, 154.4, 160.8, 163.4, 164.4, 196.5; Anal. calc. for C₂₂H₁₈ClN₃O₅: C, 60.07; H, 4.12; N, 9.55%, found: C, 59.91; H, 4.07; N, 9.47%; MS (EI, 70 eV) m/z: 439(M⁺).

6-hydroxy-5-(1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4g): Orangish powder, mp: 313–315 ºC, yield: 87%; FT-IR (KBr) (ν_max, cm^− 1): 3497, 3099, 1724, 1688, 1644; ¹HNMR (300 MHz, DMSO-d₆): δ 1.77–1.87 (m, 1H, CH), 1.92–2.02 (m, 1H, CH), 2.26 (s, 2H, CH₂), 2.59 (s, 2H, CH₂), 4.54 (s, 1H, CH), 7.18–7.21 (d, J = 9 Hz, 1H, Ar CH), 7.54–7.57 (d, J = 9 Hz, 1H, Ar CH), 7.84 (s, 1H, Ar CH), 7.98 (s, 1H, Ar CH), 10.91 (s, 1H, OH), 11.53 (s, 1H, NH), 11.81 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 20.3, 26.9, 31.0, 36.9, 87.5, 112.9, 113.7, 117.2, 121.3, 130.2, 132.7, 133.3, 137.6, 138.2, 149.9, 154.2, 160.7, 163.4, 166.0, 196.8; Anal. calc. for C₂₀H₁₅N₃O₅: C, 63.66; H, 4.01; N, 11.14%, found: C, 63.54; H, 3.96; N, 11.02%; MS (EI, 70 eV) m/z: 377(M⁺).

6-hydroxy-5-(9-methoxy-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4h): Orangish powder, mp: 315–317 ºC, yield: 86%; FT-IR (KBr) (ν_max, cm^− 1): 3470, 3170, 1715, 1695, 1669; ¹HNMR (300 MHz, DMSO-d₆): δ 1.81–1.88 (m, 1H, CH), 1.93–1.98 (m, 1H, CH), 2.21–2.31 (m, 2H, CH₂), 2.58–2.60 (m, 2H, CH₂), 3.79 (s, 3H, OCH₃), 4.54 (s, 1H, CH), 7.05–7.09 (dd, J = 3 Hz, J = 9 Hz, 1H, Ar CH), 7.18–7.21 (d,, J = 9 Hz, 1H, Ar CH), 7.26 (s, 1H, Ar CH), 7.81 (s, 1H, Ar CH), 10.88 (s, 1H, OH), 11.28 (s, 1H, NH), 11.79 (s, 1H, NH);¹³CNMR (75 MHz, DMSO-d₆): δ 20.3, 26.9, 31.2, 36.9, 55.9, 87.6, 109.4, 112.9, 116.3, 119.6, 120.1, 132.0, 133.1, 139.1, 149.9, 154.2, 154.5, 160.6, 163.4, 165.9, 196.8; Anal. calc. for C₂₁H₁₇N₃O₆: C, 61.91; H, 4.21; N, 10.31%, found: C, 61.79; H, 4.14; N, 10.23%; MS (EI, 70 eV) m/z: 407(M⁺).

6-hydroxy-5-(9-methyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4i): Orangish powder, mp: 323–325 ºC, yield: 86%; FT-IR (KBr) (ν_max, cm^− 1): 3300, 3200, 1718, 1669, 1610; ¹HNMR (300 MHz, DMSO-d₆): δ 1.77–1.87 (m, 1H, CH), 1.92–1.99 (m, 1H, CH), 2.23–2.27 (m, 2H, CH₂), 2.32 (s, 3H, CH₃), 2.56–2.60 (m, 2H, CH₂), 4.53 (s, 1H, CH), 7.13–7.16 (d, J = 9 Hz, 1H, Ar CH), 7.23–7.25 (d, J = 6 Hz, 1H, Ar CH), 7.46 (s, 1H, Ar CH), 7.77 (s, 1H, Ar CH), 10.84 (s, 1H, OH), 11.26 (s, 1H, NH), 11.76 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 20.3, 20.9, 26.9, 31.2, 36.9, 87.6, 112.9, 114.9, 119.5, 127.7, 131.0, 131.4, 131.6, 136.6, 139.2, 149.9, 154.2, 160.9, 163.4, 165.9, 196.8; Anal. calc. for C₂₁H₁₇N₃O₅: C, 64.45; H, 4.38; N, 10.74%, found: C, 64.30; H, 4.31; N, 10.68%; MS (EI, 70 eV) m/z: 391(M⁺).

6-hydroxy-5-(7-methyl-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)pyrimidine-2,4(1H,3H)-dione (4j): Orangish powder mp: 302–304 ºC, yield: 89%; FT-IR (KBr) (ν_max, cm^− 1): 3463, 3169, 1699, 1671, 1638; ¹HNMR (300 MHz, DMSO-d₆): δ 1.77–1.85 (m, 1H, CH), 1.91-2.00 (m, 1H, CH), 2.19–2.31 (m, 2H, CH₂), 2.36 (s, 3H, CH₃), 2.56–2.63 (m, 2H, CH₂), 4.54 (s, 1H, CH), 7.03–7.08 (t, J = 7.5 Hz, 1H, Ar CH), 7.26–7.29 (d, J = 9 Hz, 1H, Ar CH), 7.53–7.56 (d, J = 9 Hz, 1H, Ar CH), 7.82 (s, 1H, Ar CH), 10.52 (s, 1H, OH), 10.92 (s, 1H, NH), 11.86 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 19.0, 20.4, 26.9, 30.9, 36.9, 87.5, 112.9, 119.5, 122.0, 123.3, 126.4, 131.3, 131.4, 136.9, 139.9, 149.9, 154.2, 161.4, 163.4, 165.9, 196.7; Anal. calc. for C₂₁H₁₇N₃O₅: C, 64.45; H, 4.38; N, 10.74%, found: C, 64.31; H, 4.31; N, 10.67%; MS (EI, 70 eV) m/z: 391(M⁺).

5-(9-chloro-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4k): Orangish powder, mp: 313–315 ºC, yield: 82%. FT-IR (KBr) (ν_max, cm^− 1): 3450, 3180, 1718, 1696, 1668; ¹HNMR (300 MHz, DMSO-d₆): δ 1.77–1.88 (m, 1H, CH), 1.93-2.00 (m, 1H, CH), 2.21–2.31 (m, 2H, CH₂), 2.60 (s, 2H, CH₂), 4.56 (s, 1H, CH), 7.25–7.28 (d, J = 9 Hz, 1H, Ar CH), 7.43–7.46 (d, J = 9 Hz, 1H, Ar CH), 7.85 (s, 1H, Ar CH), 10.92 (s, 1H, OH), 11.54 (s, 1H, NH), 11.82 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 20.3, 26.9, 31.0, 36.9, 87.5, 112.8, 116.9, 120.7, 125.9, 127.2, 130.0, 133.3, 137.3, 138.2, 149.9, 154.2, 160.7, 163.3, 166.0, 196.7; Anal. calc. for C₂₀H₁₄ClN₃O₅: C, 58.33; H, 3.43; N, 10.22%, found: C, 58.21; H, 3.36; N, 10.14%; MS (EI, 70 eV) m/z: 411(M⁺).

5-(9-bromo-1-oxo-2,3,4,12-tetrahydro-1H-chromeno[2,3-b]quinolin-12-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4l): Orangish powder, mp: 332–334 ºC, yield: 80%. FT-IR (KBr) (ν_max, cm^− 1): 3480, 3184, 1715, 1668, 1696; ¹HNMR (300 MHz, DMSO-d₆): δ 1.78–1.88 (m, 1H, CH), 1.92–2.02 (m, 1H, CH), 2.21–2.31 (m, 2H, CH₂), 2.55–2.62 (m, 2H, CH₂), 4.55 (s, 1H, CH), 7.19–7.22 (d, J = 9 Hz, 1H, Ar CH), 7.54–7.57 (d, J = 9 Hz, 1H, Ar CH), 7.83 (s, 1H, Ar CH), 7.98 (s, 1H, Ar CH), 10.73 (s, 1H, NH), 11.52 (s, 1H, NH); ¹³CNMR (75 MHz, DMSO-d₆): δ 20.3, 26.9, 31.0, 36.9, 87.5, 112.9, 113.7, 117.2, 121.3, 130.2, 132.6, 133.3, 137.6, 138.1, 149.5, 154.3, 160.7, 163.4, 166.0, 196.8; Anal. calc. for C₂₀H₁₄BrN₃O₅: C, 52.65; H, 3.09; N, 9.21%, found: C, 52.52; H, 2.98; N, 9.15%; MS (EI, 70 eV) m/z: 457(M⁺).

Acknowledgements The Research Department of the Chemistry and Chemical Engineering Research Center of Iran is acknowledged for financial support.

Authors’ contributions MH done investigation; validation; and writing-original draft preparation.

The conceptualization, formal analysis and manuscript writing were reviewed under the guidance of AAM.

MRM has provided instrument facility.

Funding Not applicable.

Availability of data and materials Data available on reasonable request.

Declarations

Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval Not applicable.

K. Kumar and H. Waldmann, Angewandte Chemie International Edition, 48, 18 (2009)
M.S. Butler and A.D. Buss, Biochemical Pharmacology, 71, 7 (2006)
K. Grabowski, K.-H. Baringhaus and G. Schneider, Natural Product Reports, 25, 5 (2008)
D.J. Newman and G.M. Cragg, Future medicinal chemistry, 1, 8 (2009)
R. Zhong, A.C. Lindhorst, F.J. Groche and F.E. Kühn, Chemical Reviews, 117, 3 (2017)
R. Dua, S. Shrivastava, S. Sonwane and S. Srivastava, Advances in Biological Research, 5, 3 (2011)
I. Ali, M. Nadeem Lone, Z. A Al-Othman, A. Al-Warthan and M. Marsin Sanagi, Current drug targets, 16, 7 (2015)
E. Ruijter, R. Scheffelaar and R.V. Orru, Angew. Chem. Int. Ed., 50, 28 (2011)
B. Ganem, Accounts of chemical research, 42, 3 (2009)
B.H. Rotstein, S. Zaretsky, V. Rai and A.K. Yudin, Chemical reviews, 114, 16 (2014)
A. Domling, W. Wang and K. Wang, Chemical reviews, 112, 6 (2012)
N. Elders, D. van der Born, L.J. Hendrickx, B.J. Timmer, A. Krause, E. Janssen, F.J. de Kanter, E. Ruijter and R.V. Orru, Angewandte Chemie, 121, 32 (2009)
G. van der Heijden, E. Ruijter and R.V. Orru, Synlett, 24, 06 (2013)
B. Jiang, T. Rajale, W. Wever, S.-J. Tu and G. Li, Chemistry – An Asian Journal, 5, 11 (2010)
A. Dömling, W. Wang and K. Wang, Chemical Reviews, 112, 6 (2012)
R.C. Cioc, E. Ruijter and R.V.A. Orru, Green Chemistry, 16, 6 (2014)
S. Brauch, S.S. van Berkel and B. Westermann, Chemical Society Reviews, 42, 12 (2013)
T. Zarganes-Tzitzikas, A.L. Chandgude and A. Dömling, The Chemical Record, 15, 5 (2015)
C. de Graaff, E. Ruijter and R.V.A. Orru, Chemical Society Reviews, 41, 10 (2012)
J.D. Sunderhaus and S.F. Martin, Chemistry – A European Journal, 15, 6 (2009)
A. Marella, O.P. Tanwar, R. Saha, M.R. Ali, S. Srivastava, M. Akhter, M. Shaquiquzzaman and M.M. Alam, Saudi Pharmaceutical Journal, 21, 1 (2013)
B.S. Matada, R. Pattanashettar and N.G. Yernale, Bioorganic & Medicinal Chemistry, 32, (2021)
T.J. Egan, Expert Opinion on Therapeutic Patents, 11, 2 (2001)
O. Afzal, S. Kumar, M.R. Haider, M.R. Ali, R. Kumar, M. Jaggi and S. Bawa, European Journal of Medicinal Chemistry, 97, (2015)
P. Prasad, P.G. Shobhashana and M.P. Patel, Royal Society Open Science, 4, 11 (2017)
G.A. Ramann and B.J. Cowen, in Molecules(2016)
J.B. Bharate, R.A. Vishwakarma and S.B. Bharate, RSC Advances, 5, 52 (2015)
S.M. Prajapati, K.D. Patel, R.H. Vekariya, S.N. Panchal and H.D. Patel, RSC Advances, 4, 47 (2014)
S. Eswaran, A.V. Adhikari, I.H. Chowdhury, N.K. Pal and K.D. Thomas, European Journal of Medicinal Chemistry, 45, 8 (2010)
B.F. Abdel-Wahab and R.E. Khidre, Journal of Chemistry, 2013, (2013)
M.A. Massoud, W.A. Bayoumi, A.A. Farahat, M.A. El-Sayed and B. Mansour, ARKIVOC: Online Journal of Organic Chemistry, 2018, (2018)
W.S. Hamama, M.E. Ibrahim, A.A. Gooda and H.H. Zoorob, RSC advances, 8, 16 (2018)
M. Abd-El Maksoud, H. Tawfik, S. Maigali, F. Soliman, M. Moharam and M. Dondeti, Der Pharma Chemica, 8, 13 (2016)
P. Muthumani, S. Venkataraman, R. Meera, N. Govind, N.C.P. Devi and B. Kameswari, Pharma Chem, 2, (2010)
C.B. Sangani, J.A. Makawana, Y.-T. Duan, Y. Yin, S.B. Teraiya, N.J. Thumar and H.-L. Zhu, Bioorganic & Medicinal Chemistry Letters, 24, 18 (2014)
V. Nadaraj and S.T. Selvi, International Journal of Engineering, Science and Technology, 3, 4 (2011)
M.B. Kanani and M.P. Patel, RSC advances, 4, 54 (2014)
L. Fu, W. Lin, M.-H. Hu, X.-C. Liu, Z.-B. Huang and D.-Q. Shi, ACS Combinatorial Science, 16, 5 (2014)
M. Shiri, R. Pourabed, V. Zadsirjan and E. Sodagar, Tetrahedron Letters, 57, 49 (2016)
M. Shiri, M. Heydari and V. Zadsirjan, Tetrahedron, 73, 15 (2017)
M. Ghandi, N. Zarezadeh and A. Abbasi, Molecular diversity, 20, (2016)
P.G. Shobhashana, P. Prasad and M.P. Patel, HETEROCYCLIC LETTERS, 7, 3 (2017)
G. Mariappan, B. Saha, L. Sutharson, G. Ankits, L. Pandey and D. Kumar, J. Pharm. Res, 3, 12 (2010)
X. Xiao, B. Shao, J. Li, Z. Yang, Y.-J. Lu, F. Ling and W. Zhong, Chemical Communications, 57, 38 (2021)
M. Sekar and K.R. Prasad, Journal of natural products, 61, 2 (1998)
R.A. Corral and O.O. Orazi, Tetrahedron Letters, 8, 7 (1967)
L. Puricelli, G. Innocenti, G.D. Monache, R. Caniato, R. Filippini and E. Cappelletti, Natural Product Letters, 16, 2 (2002)
J.L. Marco and M.C. Carreiras, Mini reviews in medicinal chemistry, 3, 6 (2003)
T. Godet, C. Vaxelaire, C. Michel, A. Milet and P. Belmont, Chemistry–A European Journal, 13, 19 (2007)
J. Marco-Contelles, R. León, M.G. López, A.G. García and M. Villarroya, European journal of medicinal chemistry, 41, 12 (2006)
I. Butenschön, K. Möller and W. Hänsel, Journal of medicinal chemistry, 44, 8 (2001)
P.K. Kalita, B. Baruah and P.J. Bhuyan, Tetrahedron letters, 47, 44 (2006)
J. Barluenga, H. Vázquez-Villa, A. Ballesteros and J.M. Gonzàlez, Journal of the American Chemical Society, 125, 30 (2003)
J. Barluenga, H. Vázquez-Villa, I. Merino, A. Ballesteros and J.M. Gonzalez, Chemistry–A European Journal, 12, 22 (2006)
T. Aggarwal, M. Imam, N.K. Kaushik, V.S. Chauhan and A.K. Verma, ACS Combinatorial Science, 13, 5 (2011)
A.N. Vereshchagin, M.N. Elinson, R.F. Nasybullin, F.V. Ryzhkov, S.I. Bobrovsky, I.S. Bushmarinov and M.P. Egorov, Helvetica Chimica Acta, 98, 8 (2015)
R.-G. Shi and C.-G. Yan, Chinese Chemical Letters, 27, 4 (2016)
K.D. Upadhyay, N.M. Dodia, R.C. Khunt, R.S. Chaniara and A.K. Shah, ACS medicinal chemistry letters, 9, 3 (2018)
M. Bakthadoss, V. Vinayagam, V. Agarwal and D.S. Sharada, ChemistrySelect, 4, 27 (2019)
V. Ramesh, B. Ananda Rao, P. Sharma, B. Swarna, D. Thummuri, K. Srinivas, V.G.M. Naidu and V. Jayathirtha Rao, European Journal of Medicinal Chemistry, 83, (2014)
A.J. Patel, A.B. Dholakia and V.C. Patel, Synthetic Communications, 51, 2 (2021)
B. Paplal, S. Nagaraju, P. Veerabhadraiah, K. Sujatha, S. Kanvah, B. Vijaya Kumar and D. Kashinath, RSC Advances, 4, 97 (2014)
P. Shrivas, R. Pandey, S. Zodape, A. Wankhade and U. Pratap, Research on Chemical Intermediates, 46, 5 (2020)
R.H. Vekariya, K.D. Patel and H.D. Patel, Research on Chemical Intermediates, 42, 5 (2016)
S. Asadi and G. Mohammadi Ziarani, Molecular diversity, 20, (2016)
R. Pluskota and M. Koba, Mini Reviews in Medicinal Chemistry, 18, 15 (2018)
Z. Zhao, X. Dai, C. Li, X. Wang, J. Tian, Y. Feng, J. Xie, C. Ma, Z. Nie and P. Fan, European Journal of Medicinal Chemistry, 186, (2020)
G. Mustafa, M. Zia-ur-Rehman, S.H. Sumrra, M. Ashfaq, W. Zafar and M. Ashfaq, Journal of Molecular Structure, (2022)
M. Asif, M. Imran and A. Husain, Journal of the Chilean Chemical Society, 66, 2 (2021)
X. Bao, X. Wang, J.-M. Tian, X. Ye, B. Wang and H. Wang, Organic & Biomolecular Chemistry, (2022)
D. Arora, J. Dwivedi, S. Kumar and D. Kishore, Synthetic Communications, 48, 2 (2018)
H. Kiyani, Current Organic Synthesis, 15, 8 (2018)
M. M Heravi, V. Zadsirjan, B. Fattahi and N. Nazari, Current Organic Chemistry, 20, 16 (2016)
K. Nikoofar and F.M. Yielzoleh, Journal of Saudi Chemical Society, 22, 6 (2018)
P. Teli, N. Sahiba, A. Sethiya, J. Soni and S. Agarwal, Journal of Heterocyclic Chemistry, 58, 7 (2021)
K.T. Mahmudov, M.N. Kopylovich, A.M. Maharramov, M.M. Kurbanova, A.V. Gurbanov and A.J. Pombeiro, Coordination Chemistry Reviews, 265, (2014)
R.G. Sans and M.G. Chozas, Die Pharmazie, 43, 12 (1988)
G.M. Ziarani, F. Aleali and N. Lashgari, RSC advances, 6, 56 (2016)
R.Y. Levina and F.K. Velichko, Russian Chemical Reviews, 29, 8 (1960)
K. Nikoofar and Z. Khademi, Mini-Reviews in Organic Chemistry, 14, 2 (2017)
A. Olyaei and M. Sadeghpour, Synthetic Communications, 52, 23 (2022)
M. Bakherad, A. Keivanloo, M. Gholizadeh, R. Doosti and M. Javanmardi, Research on Chemical Intermediates, 43, 2 (2017)
M. Kidwai and S. Saxena, Synthetic Communications, 36, 18 (2006)
V. Krishnakumar, B.K. Mandal, F.-R. Nawaz Khan and E.D. Jeong, Tetrahedron Letters, 55, 27 (2014)
B. Baruah and P.J. Bhuyan, Tetrahedron, 65, 34 (2009)
M. Heydari, A.A. Mohammadi and M. Mosleh, Molecular Diversity, (2022)
A. Alizadeh and A. Rostampoor, Journal of the Iranian Chemical Society, 19, 4 (2022)
L. Liang, E. Li, X. Dong and Y. Huang, Organic letters, 17, 19 (2015)
Y. Li, R. Tian and S. Du, RSC advances, 7, 5 (2017)
H. Meshram, G.S. Kumar, P. Ramesh and B.C. Reddy, Tetrahedron Letters, 51, 19 (2010)
S.N. Murthy, B. Madhav and Y. Nageswar, Tetrahedron Letters, 51, 40 (2010)

Tables 1-3 is available in the Supplementary Files section.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

DABCO-catalyzed highly regioselective synthesis of novel 4H-pyrano[2,3- b]quinoline derivatives: three‑component domino strategy

Status:

Version 1

Abstract

Introduction

Results and discussion

Conclusion

General procedure for the synthesis of 4H-pyrano[2,3-b]quinoline derivatives 4a-l

Spectral data for selected products 4a-l

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1