Chinese Chemical Letters  2015, Vol.26 Issue (02):251-254   PDF    
An efficient synthesis of benzo[b]benzofurano[2,3-e]-[1,6]naphthyridine-8-ones
Dao-Lin Wang , Dan Wu, Wei Zhao, Yong-Yang Wang, Jian-Ying Wu    
College of Chemistry and Chemical Engineering, Liaoning Key Laboratory of Synthesis and Application of Functional Compound, Bohai University, Jinzhou 121003, China
Abstract: An efficient method for the synthesis of benzo[b]benzofurano[2,3-e][1,6]naphthyridine-8-one derivatives has been developed via Pictet-Spengler reaction of 4-(3-aminobenzofuran-2-yl)quinoline- 2-ones, which could be obtained from alkylation of 4-bromomethylquinoline-2-ones with salicylonitrile and subsequent Thorpe-Ziegler isomerization, with aromatic aldehydes under p-TsOH as catalyst in good yields.
Key words: 4-Bromomethylquinoline-2-one     Salicylonitrile     Benzo[b]benzofurano[2,3-e][1,6]naphthyridine-8-one     Thorpe-Ziegler isomerization     Pictet-Spengler reaction    
1. Introduction Nitrogen-containing heterocycles are ubiquitous in both natural products and pharmaceuticals; therefore,new,selective methods for their preparation are an important focus of research. The Pictet-Spengler reaction [1],as it is practiced nowadays,has been one of the most prominent strategies for carbon-carbon bond formation in synthetic organic chemistry with excellent functional group tolerance,regio- and stereo-selectivity. In this respect,the modified Pictet-Spengler reaction has attained considerable importance for the synthesis of various products and novel heterocycles of biological interest [2].

The [1, 6]naphthyridine and their fused analogs are an important pharmacophore present in many natural [3] and designed synthetic products of therapeutic applications. They are associated with a wide spectrum of biological activities such as anticancer [4],anti- HIV-1 [5],antimicrobial [6] and cytotoxic activity [7]. Therefore,the synthesis of [1, 6]naphthyridine derivatives has aroused great interest in organic and medicinal communities [8, 9, 10, 11, 12].

On the other hand,benzofuran derivatives have attracted widespread interest in view of their presence in natural products, and their biological and pharmacological activities [13]. The benzofuran nucleus is a central component of a diverse class of heterocyclic natural and synthetic products that possess a broad range of biological activities [14].

As a result of our continued synthetic interest in the nitrogencontaining fused heterocycles [15],herein,we report a simple and convenient synthetic approach toward novel benzo[b]benzofurano[ 2,3-e][1, 6]naphthyridine-8-one derivatives via modified Pictet- Spengler reaction (Scheme 1).

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Scheme 1. Syntheses of benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-ones.
2. Experimental 2.1. Preparation of 4-(3-aminobenzofuran-2-yl)quinoline-2-ones (3)

To a solution of 4-bromomethylquinoline-2-one 1a [16a] or 1b [16b] (20.0 mmol) in DMF (25 mL) was added salicylonitrile 2 (2.38 g,30.0 mmol) and anhydrous potassium carbonate (5.52 g, 40.0 mmol). The mixture was heated at 100 ℃ for 5 h. After cooling to room temperature,then water (50 mL) was added and stirred for 20 min. The solid was filtered and recrystallized from HOAc to give 3.

3a: Yield 83%. Mp 196-198 ℃. IR (KBr,cm-1): n 3456,3363 (NH2),1687 (C=O). 1H NMR (400 MHz,CDCl3): d 3.68 (s,3H),5.75 (s,2H),7.11 (s,1H),7.24-7.27 (m,2H),7.31-7.32 (m,2H),7.37- 7.41 (m,1H),7.59-7.63 (m,1H),7.72 (d,1H,J = 7.6 Hz),8.14 (d,1H, J = 8.0 Hz). Anal. Calcd. for C18H14N2O2: C 74.47,H 4.86,N 9.65. Found: C 74.58,H 4.98,N 9.73.

3b: Yield 80%. Mp 169-171 ℃. IR (KBr,cm-1): n 3425,3376 (NH2),1692 (C=O). 1H NMR (400 MHz,CDCl3): d 5.52 (s,2H),6.96 (s,1H),7.21-7.26 (m,2H),7.37-7.38 (m,2H),7.53-7.54 (m,2H), 7.90 (d,1H,J = 7.6 Hz),8.12 (d,1H,J = 8.0 Hz),11.74 (s,1H). Anal. Calcd. for C17H12N2O2: C 73.90,H 4.38,N 10.14. Found: C 74.03,H 4.47,N 10.26.

2.2. Preparation of benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-one derivatives

A mixture of 4-(3-aminobenzofuran-2-yl)quinoline-2-one 3a or 3b (1.0 mmol),aromatic aldehyde (1.0 mmol) and p-toluenesulfonic acid (p-TsOH) (19 mg,0.1 mmol) in DMF (20 mL) was heated for 8-13 h at 120 ℃. At the end of the reaction,the reaction mixture was cooled to room temperature,and then water (20 mL) was added to the mixture and stirred for 30 min. The solid was filtered and recrystallized from DMF to afford the corresponding products (5a-l) [17].

3. Results and discussion

The authors demonstrated that the benzo[b]benzofurano[2,3- e][1, 6]naphthyridine-8-ones can be readily synthesized from 4- bromomethylquinoline-2-ones by treatment with salicylonitrile, followed by cyclization of the intermediate amine by attack of aldehydes under Pictet-Spengler condition (Scheme 1).

In this study,the key intermediate amine,synthesis for benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-ones,4-(3-aminobenzo- furan-2-yl)quinoline-2-ones 3 was obtained by the condensation of 4-bromomethylquinoline-2-ones 1 with salicylonitrile 2 via Thorpe-Ziegler isomerization [18] in good yield. Its structure was determined from the spectral data as well as elemental analysis. The presence of an amino group in 3 was demonstrated by NMR spectroscopy and chemical transformations. Thus,a two-proton broadened singlet at 5.52-5.75 ppm is observed in the 1H NMR spectra of substituted quinoline-2-one 3, which corresponds to the amino group. In addition,in the IR spectra of 3,N-H asymmetric and symmetric stretching vibrations of amino groups appeared as two weak absorption bands at 3425- 3456 cm-1 and 3363-3376 cm-1,respectively. In an initial endeavor,we selected benzaldehyde 4a as model aryl benzaldehyde to react with equimolar amounts of intermediate amine 3a for the preparation of benzo[b]benzofurano[2,3- e][1, 6]naphthyridine-8-one 5a and investigated the optimal reaction conditions.

As shownin Table 1,the amine 3a was treatedwithbenzaldehyde 4a under traditional Pictet-Spengler protocol [2],thus,the use of p-TsOH and TFA as catalysts. Interestingly,the cyclization resulting in benzo[b]benzofurano[2, 3, e][1, 6]naphthayridine-8-one 5a was successfully synthesized under all of the above conditions,and best result involving complete conversion was obtained only when reaction was carried out in 10% p-TsOH in DMF at 120 ℃. The crude product exhibiting >96% purity on HPLC was purified using recrystallized from DMF furnishing a new product in 79% isolated yield. Its structure was demonstrated by NMR spectroscopy and chemical transformations.

Table 1
Optimization of reaction conditions on the synthesis of benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-one 5a.a

Under the optimized conditions,a wide range of aromatic aldehydes 4 underwent this one-pot condensation with of 4-(3- amino-benzofuran-2-yl)quinoline-2-ones 3 to give the corresponding benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-ones 5 under Pictet-Spengler reaction.

Encouraged by the above result,we investigated the scope of this reaction using various aldehydes (Table 2). A variety of electron-rich (entries 2-7 and 9-11) and electron-deficient aromatic aldehydes (entries 8 and 12) are effectively transformed to the corresponding naphthyridines in the presence of p-TsOH in good yields (74%-85%).

Table 2
Synthesis of benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-one 5.

All the products were characterized by IR,1H NMR,13CNMR and elemental analysis. And all the data is consistent with the desired structures.

The proposed mechanism of the process is summarized in Scheme 2. The present synthetic sequence was initiated by an Oalkylation of 4-bromomethylquinoline-2-ones 1 with salicylonitrile 2 giving rise to the 4-(2-cyanophenoxymethyl)quinoline-2- ones A. An intramolecular carbanion addition across the nitrile was brought about by ethers A via Thorpe-Ziegler reaction,and isomerization,resulting in the formation of 4-(3-aminobenzofuranyl) quinoline-2-ones 3. Next,substrates 3 were exposed to the cationic p-cyclization [19] with aldehydes as one-carbon electrophiles of imine intermediates B under Pictet-Spengler cyclization, which resulted closure at the C3 position of quinoline-2-ones to give benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-ones 5.

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Scheme 2. A proposed mechanism for the formation of 5.
4. Conclusion

In summary,we have developed an efficient synthesis of benzo[b]benzofurano[2, 3, e][1, 6]naphthyridine-8-ones intwosteps with good yields. The synthetic approach involves Thorpe-Ziegler isomerization of 4-bromomethylquinoline-2-ones followed by a Pictet-Spengler cyclization of the corresponding 4-(3-aminobenzofuran- 2-yl)quinoline-2-ones with different benzaldehyde derivatives. This pathway could afford a large series of quinolines fused heterocycles with potential biological properties.

Acknowledgment

We are grateful for financial support from the Science and Technology Department of Liaoning Province (No. 2011220022).

References
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[17] Physical and spectral (IR, NMR, Anal.) data: 5a: Mp 280-282 8C. IR (KBr, cm-1): 1680 (C5O). 1H NMR (400 MHz, CDCl3): 3.69 (s, 3H), 7.42-7.54 (m, 8H), 7.63-7.71 (m, 2H), 7.78 (d, 1H, J=8.4 Hz), 8.37 (d, 1H, J=7.6 Hz), 9.37 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.3, 112.1, 112.5, 114.5, 114.9, 116.7, 122.7, 123.2, 124.1, 124.6, 127.6, 127.9, 128.1, 128.4, 129.7, 129.9, 131.9, 132.3, 139.9, 143.9, 158.3, 159.2, 159.9. Anal. Calcd. for C25H16N2O2: C 79.77, H 4.28, N 7.44. Found: C 79.84, H 4.38, N 7.56; 5b: Mp 284-286 8C. IR (KBr, cm-1): 1684 (C5O). 1H NMR (400 MHz, CDCl3): 2.45 (s, 3H), 3.71 (s, 3H), 7.30-7.32 (m, 2H), 7.42-7.50 (m, 5H), 7.64-7.71 (m, 2H), 7.79 (d, 1H, J=8.0 Hz), 8.38 (d, 1H, J=7.6 Hz), 9.38 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 21.7, 30.5, 112.1, 112.4, 114.4, 114.9, 115.8, 116.5, 122.2, 122.5, 123.1, 123.9, 124.4, 127.8, 128.3, 128.9, 129.8, 131.7, 132.0, 139.8, 143.6, 158.3, 159.6, 160.2. Anal. Calcd. for C26H18N2O2: C 79.98, H 4.65, N 7.17. Found: C 80.15, H 4.79, N 7.26; 5c: Mp 285-287 8C. IR (KBr, cm-1): 1675 (C5O). 1H NMR (400 MHz, CDCl3): 3.66 (s, 3H), 3.69 (s, 3H), 6.99-7.01 (m, 1H), 7.14-7.15 (m, 1H), 7.46-7.50 (m, 5H), 7.65-7.67 (m, 2H), 7.79 (d, 1H, J=8.4 Hz), 8.44 (d, 1H, J=7.6 Hz), 8.40 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.2, 55.4, 110.4, 110.6, 112.0, 112.4, 114.3, 114.8, 118.1, 120.6, 121.0, 122.4, 122.9, 123.8, 124.4, 128.4, 128.9, 129.6, 129.8, 131.6, 131.9, 139.9, 143.9, 156.6, 158.1, 159.9. Anal. Calcd. for C26H18N2O3: C 76.83, H 4.46, N 6.89. Found: C 76.94, H 4.58, N 6.96; 5d: Mp 289-290 8C. IR (KBr, cm-1): 1684 (C5O). 1H NMR (400 MHz, CDCl3): 3.71 (s, 3H), 3.86 (s, 3H), 7.01 (s, 1H), 7.07 (d, 1H, J=7.6 Hz), 7.40-7.43 (m, 2H), 7.45-7.51 (m, 3H), 7.68-7.71 (m, 2H), 7.80 (d, 1H, J=8.4 Hz), 8.40 (d, 1H, J=7.6 Hz), 9.39 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.3, 55.3, 113.1, 113.4, 113.9, 114.4, 114.9, 115.8, 116.6, 120.6, 121.0, 122.5, 123.1, 123.9, 124.4, 127.8, 128.5, 129.0, 129.6, 129.8, 130.1, 139.9, 143.7, 158.3, 159.2, 159.9. Anal. Calcd. for C26H18N2O3: C 76.83, H 4.46, N 6.89. Found: C 76.96, H 4.57, N 6.99; 5e: Mp 293-295 8C. IR (KBr, cm-1): 1686 (C5O). 1H NMR (400 MHz, CDCl3): 3.71 (s, 3H), 3.87 (s, 3H), 7.03 (d, 2H, J=7.6 Hz), 7.62-7.66 (m, 5H), 7.69-7.71 (m, 2H), 7.77 (d, 1H, J=8.4 Hz), 8.38 (d, 1H, J=7.6 Hz), 9.37 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.3, 55.1, 112.1, 112.4, 113.2, 113.4, 114.4, 114.8, 116.4, 122.4, 122.6, 123.0, 123.9, 124.4, 129.5, 129.8, 130.0, 131.7, 132.0, 139.8, 143.6, 158.3, 159.2, 160.2. Anal. Calcd. for C26H18N2O3: C 76.83, H 4.46, N 6.89. Found: C 76.98, H 4.54, N 7.02; 5f:Mp 296-298 8C. IR (KBr, cm-1): 1673 (C5O). 1H NMR (400 MHz, CDCl3): 3.73 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 6.98-6.99 (m, 1H), 7.01-7.02 (m, 2H), 7.07-7.08 (m, 3H), 7.09-7.12 (m, 2H), 7.14 (d, 1H, J=7.6 Hz), 8.44 (d, 1H, J=7.6 Hz), 9.40 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.5, 55.7, 55.9, 110.4, 110.6, 111.7, 112.1, 112.4, 114.4, 114.9, 115.7, 116.5, 121.0, 121.5, 122.6, 123.1, 124.0, 124.5, 129.6, 129.8, 131.9, 132.2, 143.7, 148.4, 158.3, 158.9, 160.0. Anal. Calcd. for C27H20N2O4: C 74.30, H 4.62, N 6.42. Found: C 74.45, H 4.74, N 6.58; 5g: Mp >300℃. IR (KBr, cm-1): 1675 (C5O). 1H NMR (400 MHz, CDCl3): 3.67 (s, 3H), 3.74 (s, 3H), 3.93 (s, 3H), 3.97 (s, 3H), 6.64 (s, 1H), 7.11 (s, 1H), 7.46-7.48 (m, 4H), 7.71-7.76 (m, 2H), 7.82-7.84 (m, 1H), 9.43 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.3, 55.1, 112.1, 112.4, 113.2, 113.4, 114.4, 114.8, 116.4, 122.4, 122.6, 123.0, 123.9, 124.4, 129.5, 129.8, 130.0, 131.7, 132.0, 139.8, 143.6, 158.3, 159.2, 160.2. Anal. Calcd. for C28H22N2O5: C 72.09, H 4.75, N 6.01. Found: C 72.14, H 4.83, N 6.13; 5h: Mp >300℃. IR (KBr, cm-1): 1687 (C5O). 1H NMR (400 MHz, CDCl3): 3.73 (s, 3H), 7.47-7.53 (m, 7H), 7.66-7.68 (m, 2H), 7.81 (d, 1H, J=8.4 Hz), 8.35 (d, 1H, J=8.0 Hz), 9.40 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CDCl3): 30.5, 112.2, 112.5, 112.7, 114.5, 114.9, 120.7, 122.0, 122.3, 122.7, 123.2, 124.0, 127.7, 128.3, 129.4, 129.6, 129.8, 129.9, 144.2, 144.3, 158.2, 158.3, 168.3. Anal. Calcd. for C25H15ClN2O2: C 73.08, H 3.68, N 6.82. Found: C 73.16, H 3.84, N 6.94; 5i: Mp >300℃. IR (KBr, cm-1): 3410 (NH), 1689 (C5O). 1H NMR (400 MHz, CF3CO2D): 7.59-7.68 (m, 5H), 7.71-7.78 (m, 3H), 7.96-8.01 (m, 3H), 8.32 (d, 1H, J=8.4 Hz), 9.57 (d, 1H, J=8.4 Hz). 13C NMR (100 MHz, CF3CO2D): 112.7, 113.7, 115.1, 115.6, 116.1, 121.0, 121.3, 126.6, 127.0, 127.3, 127.8, 129.1, 129.3, 131.0, 133.9, 134.8, 135.4, 137.1, 145.4, 153.5, 158.5, 159.6. Anal. Calcd. for C24H14N2O2: C 79.55, H 3.89, N 7.73. Found: C 79.67, H 3.95, N 7.89; 5j: Mp >300℃. IR (KBr, cm-1): 3427 (NH), 1679 (C5O). 1H NMR (400 MHz, CF3CO2D): 2.49 (s, 3H), 7.42-7.48 (m, 4H), 7.60 (d, 1H, J=8.0 Hz), 7.77-7.79 (m, 2H), 7.96-8.07 (m, 3H), 8.33 (d, 1H, J=8.0 Hz), 9.57 (d, 1H, J=8.4 Hz). 13C NMR (100 MHz, CF3CO2D): 18.2, 112.7, 113.7, 114.9, 115.6, 121.0, 121.3, 126.6, 127.2, 127.9, 128.5, 129.1, 129.2, 133.9, 134.8, 134.9, 135.3, 137.1, 142.4, 145.2, 153.8, 158.4, 159.7. Anal. Calcd. for C25H16N2O2: C 79.77, H 4.28, N 7.44. Found: C 79.85, H 4.41, N 7.53; 5k: Mp >300℃. IR (KBr, cm-1): 3415 (NH), 1676 (C5O). 1H NMR (400 MHz, CF3CO2D): 4.01 (s, 3H), 7.22 (d, 2H, J=8.0 Hz), 7.58-7.62 (m, 3H), 7.70-7.72 (m, 2H), 7.74-7.78 (m, 3H), 8.33 (d, 1H, J=7.6 Hz), 9.56 (d, 1H, J=8.4 Hz). 13C NMR (100 MHz, CF3CO2D): 55.1, 113.9, 114.3, 114.8, 122.2, 122.5, 125.5, 126.2, 126.4, 126.5, 126.7, 130.3, 130.4, 130.6, 135.1, 136.0, 136.1, 136.6, 138.3, 146.4, 154.2, 159.6, 160.9. Anal. Calcd. for C25H16N2O3: C 76.52, H 4.11, N 7.14. Found: C 76.63, H 4.27, N 7.28; 5l: Mp >300℃. IR (KBr, cm-1): 3424 (NH), 1683 (C5O). 1H NMR(400 MHz, CF3CO2D): d 7.53-7.73 (m, 5H), 7.50-7.76 (m, 2H), 7.96-8.07 (m, 3H), 8.33 (d, 1H, J=8.0 Hz), 9.56 (d, 1H, J=8.0 Hz). 13C NMR (100 MHz, CF3CO2D): d 113.5, 114.6, 116.1, 116.6, 122.0, 122.3, 128.6, 128.9, 129.1, 129.4, 130.1, 130.2, 135.0, 135.8, 136.0, 136.4, 138.1, 138.7, 146.4, 153.2, 159.5, 160.4. Anal. Calcd. for C24H13ClN2O2: C 72.64, H 3.30, N 7.06. Found: C 72.76, H 3.46, N 7.15.
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