HETEROCYCLES

Communication | Regular issue | Vol. 92, No. 12, 2016, pp. 2141-2144
Received, 28th September, 2016, Accepted, 28th October, 2016, Published online, 11th November, 2016.

■ A Facile One-Pot Synthesis of Chromeno[4,3-b][1,5]-Naphthyridines

Dong Wang, Dao-Lin Wang,* Xiao-Ce Shi, and Jian-Hua Qian

Liaoning Key Laboratory of Synthesis and Application of Functional Compound, College of Chemistry & Chemical Engineering, Bohai University, Jinzhou 121001, China

Abstract

A simple and efficient synthesis of chromeno[4,3-b][1,5]naphthyridine derivatives were accomplished in high yields via the one-pot three-component reaction of 4-hydroxycoumarin, arylaldehyde and 3-aminopyridine in aqueous media catalyzed by sulfamic acid.

Naphthyridines and their polycyclic derivatives are an important pharmacophore present in many natural1 and designed synthetic products of therapeutic applications. They are associated with a wide spectrum of biological activities such as anticancer,2 anti-HIV-1,3 and cytotoxic activity.4 Therefore, there has been increasing interest in developing facile methodologies for synthesis of naphthyridine framework of medicinal relevance.5
On the other hand, the coumarin moiety is abundant in various natural and synthetic products and has applications in both medicinal chemistry and optoelectronics.6 Coumarin-fused polycyclic heterocyclic molecules have very interesting properties and therefore the development of new methods for facile accessto these molecules has received much attention.7 4-Hydroxycoumarin is one of the most widely explored and readily available substrates in organic synthesis.8
As part of our current studies on the development of new routes to heterocyclic systems,9 we now report an efficient and clean synthetic method for the synthesis of chromeno[4,3-b][1,5]naphthyridines in aqueous media catalyzed by sulfamic acid (SA) (Scheme 1).

When the reaction of 4-hydroxycoumarin 1, arylaldehyde 2, and 3-aminopyridine 3 was performed in water in the presence of SA at 100 °C, high yields of chromeno[4,3-b][1,5]naphthyridine derivatives 4 were obtained and representative examples are shown in Table 1.
The effect of electrons and the nature of substituents on the aromatic ring did not show obvious effects in terms of yields under this reaction condition. The reaction proceeded smoothly under refluxing water to give the corresponding products 4 in high yields. Benzaldehyde and other aromatic aldehydes containing electron-withdrawing groups (such as halogen, nitro group) or electron-donating groups (such as methyl, methoxy, and hydroxy group) were employed and reacted well to give the corresponding chromeno- [4,3-b][1,5]naphthyridine derivatives in good to excellent yields.

The products 4 were completely characterized by IR, NMR, and elemental analyses. The analyses were in agreement with their structures. The IR spectra for 4a exhibited sharp bands at 3356 cm-1 (NH) and 1657 cm-1 (C=O). The 1H NMR spectrum of 4a exhibited a singlet identified methane (6.32) along with multiplets (7.10~7.86) for aromatic protons. The NH proton resonance at 7.88 disappeared after addition of D2O to the DMSO-d6 solution of 4a.
We proposed the following reaction mechanism for this reaction (Scheme 2). First, an imine A is formed via condensation of aldehyde 2 with 3-aminopryidine 3. Then Povarov reaction of the 4-hydroxycoumarin moiety with the imine A to give a cyclized intermediate C. Subsequently, double bond isomerization furnishes the final product 4.

In summary, we have successfully developed an efficient green chemistry method for the synthesis of chromeno[4,3-b][1,5]naphthyridines via the one-pot three-component reaction. This method has the advantages of high yields, mild reaction conditions, easy work-up, inexpensive reagents and environmentally friendly procedure.

ACKNOWLEDGEMENTS
This work was partially supported by innovation team project of Liaoning Province Education Department (Grant No. 2015001).

References

1. H. Nakamura, J. Kobayashi, and Y. Ohizumi, Tetrahedron Lett., 1982, 23, 5555. CrossRef
2. J. J. Bowling, H. K. Pennaka, K. Ivey, S. Wahyuono, M. Kelly, R. F. Schinazi, F. A. Valeriote, D. E. Graves, and M. T. Hamann, Chem. Biol. Drug Des., 2008, 71, 205. CrossRef
3. W. Gul, N. L. Hammond, M. Yousaf, J. J. Bowling, R. F. Schinazi, S. S. Wirtz, G. de C. Andrews, C. Cuevas, and M. T. Hamann, Bioorg. Med. Chem., 2006, 14, 8495. CrossRef
4. L. W. Deady, M. L. Rogers, L. Zhuang, B. C. Baguley, and W. A. Denny, Bioorg. Med. Chem., 2005, 13, 1341. CrossRef
5. (a) Y. Takahashi, T. Kubota, A. Shibazaki, T. Gonoi, J. Fromont, and J. Kobayashi, Org. Lett., 2011, 13, 3016; CrossRef (b) L. Caixia, T. Xuli, L. Pinglin, and L. Guoqiang, Org. Lett., 2012, 14, 1994; CrossRef (c) R. M. Singh, R. Kumar, N. Sharma, and M. Asthana, Tetrahedron, 2013, 69, 9443. CrossRef
6. (a) J. Chen, W. Liu, J. Ma, H. Xu, J. Wu, X. Tang, Z. Fan, and P. Wang, J. Org. Chem., 2012, 77, 3475; CrossRef (b) I. A. Khan, M. V. Kulkarni, M. Gopal, M. S. Shahabuddin, and C.-M. Sun, Bioorg. Med. Chem. Lett., 2005, 15, 3584. CrossRef
7. (a) C.-H. Lin and D.-Y. Yang, Org. Lett., 2013, 15, 2802; CrossRef (b) K. Islama, D. K. Dasa, E. Akrama, and A. T. Khan, Synthesis, 2015, 47, 2745. CrossRef
8. (a) G. M. Ziarani and P. Hajiabbasi, Heterocycles, 2013, 87, 1415; CrossRef (b) J.-C. Jung and O.-S. Park, Molecules, 2009, 14, 4790. CrossRef
9. (a) D.-L. Wang, J.-Y. Wu, D. Wu, and Y.-Y. Wang, Chin. J. Org. Chem., 2015, 35, 200; CrossRef (b) D.-L. Wang, D. Wu, W. Zhao, Y.-Y. Wang, and J.-Y. Wu, Chin. Chem. Lett., 2015, 26, 251; CrossRef (c) D.-L. Wang, T. Zhou, J.-J. Xing, J.-H. Qiang, and L. Liu, Heterocycles, 2016, 92, 733. CrossRef
10. The general procedure is represented as follow: A suspension of a mixture of 4-hydroxycoumarin 1 (1 mmol), arylaldehyde 2 (1 mmol), 3-aminopyridine 3 (1 mmol) and SA (20 mg, 0.2 mmol) was stirred in water (20 mL) at 100 °C. After completion monitored by TLC, the reaction mixture was allowed to cool to room temperature. The crystalline power formed recrystallized from DMF to give pure 4 (yield of the products is summarized in Table 1). Selected data of compound. 4a: mp 246-248 °C; IR (KBr): ν 3356 (NH), 1657 cm-1 (C=O); 1H NMR (400 MHz, DMSO-d6): δ 6.32 (1H, s), 7.10-7.19 (3H, m), 7.28-7.30 (2H, m), 7.32-7.34 (4H, m), 7.54-7.56 (2H, m), 7.86 (1H, d, J = 8.0 Hz), 7.88 (1H, s). 13C NMR (100MHz, DMSO-d6): δ 36.0, 104.5, 116.3, 118.7, 124.0, 124.3, 127.0, 129.0, 132.2, 134.7, 137.5, 152.7, 162.7, 165.2, 166.0. Anal. Calcd for C21H14N2O2: C 77.29, H 4.32, N 8.58. Found: C 77.37, H 4.43, N 8.65. 4b: mp 279-281°C; IR (KBr): ν 3363 (NH), 1651 cm-1 (C=O). 1H NMR (400 MHz, DMSO-d6): δ 2.25 (3H, s, CH3), 6.30 (1H, s), 7.03 (4H, m), 7.31-7.38 (4H, m), 7.58-7.62 (2H, m), 7.88 (1H, s), 7.89-7.91 (1H, m). 13C NMR (100 MHz, DMSO-d6): δ 21.0, 36.0, 104.5, 116.3, 118.7, 124.0, 124.3, 127.0, 129.0, 132.2, 134.7, 137.5, 152.7, 162.7, 165.2, 166.0. Anal. Calcd for C22H16N2O2: C 77.63, H 4.74, N 8.23. Found: C 77.72, H 4.79, N 8.34. 4d: mp 265-267 °C; IR (KBr): ν 3362 (NH), 1652 cm-1 (C=O). 1H NMR (400MHz, DMSO-d6): δ 3.64 (3H, s, OCH3), 6.30 (1H, s), 6.65 (1H, s), 6.72-6.74 (2H, m), 7.13 (1H, t, J = 8.0Hz), 7.28-7.35 (4H, m), 7.56-7.60 (2H, m), 7.88 (1H, s), 7.89-7.90 (1H, m). 13C NMR (100MHz, DMSO-d6): δ 36.4, 55.2, 104.2, 110.0, 110.2, 113.7, 116.2, 119.1, 119.6, 123.9, 124.4, 129.4, 132.0, 152.7, 159.5, 165.1, 166.6. Anal. Calcd for C22H16N2O3: C 74.15, H 4.53 N 7.86. Found: C 74.27, H 4.66, N 7.94. 4j: mp 268-270 °C; IR (KBr): ν 3372 (NH), 1663 cm-1 (C=O). 1H NMR (400MHz, DMSO-d6): δ 6.31 (1H, s), 7.16-7.18 (2H, m), 7.26-7.38 (6H, m), 7.57-7.62 (2H, m), 7.87 (1H, s), 7.90-7.91 (1H, m). 13C NMR (100MHz, DMSO-d6): δ 36.1, 104.2, 116.3, 118.6, 124.1, 124.4, 128.3, 129.1, 130.4, 132.2, 140.0, 152.7, 165.0, 166.2. Anal. Calcd for C21H13ClN2O2: C 69.91, H 3.63, N 7.76. Found: C 69.98, H 3.69, N 7.85.