Chinese Chemical Letters  2016, Vol.27 Issue (02): 261-264   PDF    
Synthesis of novel benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine-8-ones via Pictet-Spengler cyclization
Dao-Lin Wang , Xiao-Ce Shi, Yong-Yang Wang, Jian Ma    
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 novel benzo[b]pyrimido[4',5':5,4]thieno[2,3e]-[1,6]naphthyridine-8-one derivatives via Pictet-Spengler cyclization is reported. The reaction of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones, which could be obtained from Thorpe-Ziegler isomerization of 4-bromomethylquinoline-2-ones and 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine, with aromatic aldehydes in the presence of BF3 OEt2 gives pyrimidothieno[1,6]naphthyridines in good yields.
Key words: 4-Bromomethylquinoline-2-one     5-Cyano-6-thioxopyrimidine     Pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine     Thorpe-Ziegler reaction     Pictet-Spengler reaction    
1. Introduction

1,6-Naphthyridine derivatives,nitrogen heterocycles containing two pyridine rings,are widely distributed in nature [1],and they are considered to be "privileged structures" in drug discovery. In particular,functionalized [1, 6]naphthyridines and their benzo/ hetero-fused analogues have displayed a wide range of physiological activities,such as anticancer [2],anti HIV-1 [3],antimicrobial [4] and cytotoxic activities [5]. Consequently,various methods havebeen reported for the synthesis of these compounds including multi component reactions [6],metal-catalyzed reactions [7],cycloaddition reactions [8] and other approaches [9].

The Pictet-Spengler reaction [10] has become one of the most prominent strategies for carbon-carbon bond formation in synthetic organic chemistry with excellent functional group tolerance,regio- and stereo-selectivity. From this perspective,the modified Pictet-Spengler reactions are attained considerable important for the synthesis of various products and novel heterocycles of biological interest [11].

In addition,pyrimidine derivatives and pyrimidine-fused compounds are of interest in medicinal chemistry and chemical biology due to their wide range of biological activities [12]. On account of the pharmaceutical interest in these compounds,the development of highthroughput methodologies for the synthesis of novel pyrimidine-fused heterocyclic scaffolds is in continuous expansion [13].

In our previous studies [14] we reported the synthesis of fused nitrogen-containing ring systems. As part of our program to develop new methods for the construction of important heterocycles using Pictet-Spengler reaction,herein,a convenient approach for the synthesis of novel benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1, 6]naphthyridine derivatives from readily accessible 4-bromomethyl quinoline-2-one [15] using Pictet-Spengler reactions a key step is described (Scheme 1).

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Scheme 1.Syntheses of benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine-8-ones.
2. Experimental 2.1. Preparation of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline- 2-ones (3)

To a solution of 4-bromomethylquinoline-2-one 1 (20.0 mmol) in DMF (25 mL) was added 5-cyano-1,6-dihydro-4-methyl-2- phenyl-6-thioxopyrimidine 2 [16] (6.81 g,30.0 mmol) and anhydrous potassium carbonate (5.52 g,40.0 mmol). The mixture was heated at 80 ℃ for 5 h. After cooling to room temperature,water (50 mL) was added and stirred for 20 min. The solid was filtered and recrystallized from HOAc to give 3.

3a: 82%. Mp > 300 ℃. IR (KBr,cm-1): v 3403,3373 (NH2),1686 (C=O). 1H NMR (400 MHz,CF3CO2D): δ 2.51 (s,3H),3.01 (s,3H),4.27 (s,3H),7.67-7.70 (m,3H),7.77-7.81 (m,2H),7.97-7.99 (m,2H),8.25-8.30 (m,2H). 13C NMR (100 MHz,CF3CO2D): δ 16.8,18.9,32.3,115.9,116.7,121.3,123.7,124.0,125.8,127.7,128.1,128.3,129.5,129.6,134.9,136.2,137.2,138.7,
139.8,144.3,154.7,160.5. Anal. Calcd. for C24H20N4OS: C 69.88,H 4.98,N 13.58,S 7.35. Found: C 69.97,H 5.14,N 13.73,S 7.46.

3b: 86%. Mp > 300 ℃. IR (KBr,cm-1): v 3441,3445 (NH2),1682 (C=O). 1H NMR (400 MHz,CF3CO2D): δ 3.32 (s,3H),3.90 (s,3H),4.28 (s,3H),7.33 (s,1H),7.68-7.78 (m,5H),8.08-8.09 (m,1H),8.29-8.31 (m,2H). 13CNMR(100 MHz,CF3CO2D): δ 16.8,32.5,=.2,107.9,116.7,118.6,123.0,123.7,124.1,127.7,128.1,128.3,129.5,129.6,132.9,135.0,138.7,143.6,
154.7,158.6,159.7. Anal. Calcd. for C24H20N4O2S: C 67.27,H 4.70,N 13.07,S 7.48. Found: C 67.38,H 4.85,N 13.15,S 7.59.

2.2. Preparation of benzo[b]pyrimido[40,50:5,4]thieno[2,3e][1, 6]- naphthyridine-8-one derivatives

A mixture of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline- 2-one 3 (1.0 mmol),aromatic aldehyde 4 (1.0 mmol) and BF3-OEt2 (14.2 mg,0.1 mmol) in DMF (15 mL) was heated for 4-12 h at 100 ℃. After the completion of the reaction judged by TLC analysis,the reaction mixture was cooled to room temperature. Water (30 mL) was added and the mixture was stirred for 30 min. The solid was filtered and recrystallized from DMF to afford the corresponding products (5a-k)1(1 Physical and spectral (IR, NMR, Anal.) data:
5a: Mp > 300 8C. IR (KBr, cm-1): v 1670 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 2.69 (s, 3H), 3.38 (s, 3H), 3.75 (s, 3H), 7.44-7.45 (m, 1H), 7.56-7.58 (m, 7H), 7.71- 7.72 (m, 2H), 8.59 (s, 1H), 8.67-8.69 (m, 2H). 13C NMR (100 MHz, CF3CO3D): δ 21.2, 23.1, 30.4, 115.1, 116.8, 117.4, 121.5, 123.2, 127.4, 127.7, 128.0, 128.6, 128.8, 128.9, 131.2, 132.4, 132.9, 137.0, 137.9, 138.2, 143.2, 150.7, 159.9, 160.8, 162.4, 166.2, 170.6. Anal. Calcd. for C31H22N2OS: C 74.68, H 4.45, N 11.24, S 6.43. Found: C 74.79, H 4.54, N 11.37, S 6.58.
5b: Mp > 300 8C. IR (KBr, cm-1): v 1674 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 2.51 (s, 3H), 2.66 (s, 3H), 3.43 (s, 3H), 3.77 (s, 3H), 7.36-7.38 (m, 2H), 7.44-7.46 (m, 1H), 7.58-7.64 (m, 6H), 8.62 (s, 1H), 8.69 (m, 2H). 13C NMR (100 MHz, CF3CO3D): δ 19.1, 19.5, 30.9, 39.1, 112.2, 113.2, 114.9, 116.0, 116.8, 117.4, 118.7, 127.1, 127.4, 128.5, 129.0, 129.6, 129.8, 131.4, 131.9, 135.9, 137.2, 137.8, 138.5, 140.9, 143.9, 144.1, 157.3, 159.6. Anal. Calcd. for C32H24N4OS: C 74.98, H 4.72, N 10.93, S 6.26. Found: C 75.14, H 4.86, N 11.08, S 6.42.
5c: Mp > 300 8C. IR (KBr, cm-1): v 1681 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 2.39 (s, 3H), 3.00 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 6.99-7.03 (m, 2H), 7.21-7.25 (m, 1H), 7.37-7.39 (m, 1H), 7.47-7.50 (m, 1H), 7.54-7.58 (m, 4H), 8.21 (s, 1H), 8.60-8.61 (m, 2H). 13C NMR (100 MHz, CF3CO3D): δ 20.8, 23.8, 29.6, 55.4, 112.4, 114.5, 117.2, 118.5, 118.7, 122.1, 124.2, 125.2, 127.4, 128.5, 128.6, 128.8, 129.7, 130.6, 132.0, 132.5, 136.5, 137.4, 138.2, 141.5, 142.8, 159.8, 160.2, 161.1, 163.7, 167.3. Anal. Calcd. for C32H24N4O2S: C 72.71, H 4.58, N 10.60, S 6.07. Found: C 72.86, H 4.69, N 10.73, S 6.19.
5d:Mp > 300 8C. IR (KBr, cm-1): v 1684 (C=O). 1H NMR (400 MHz, CF3COOD): δ 2.67 (s, 3H), 3.34 (s, 3H), 4.09 (s, 3H), 7. 18-7.22 (m, 4H), 7.47-7.49 (m, 1H), 7.63- 7.69 (m, 3H), 7.74-7.82 (m, 4H). 13C NMR (100 MHz, CF3COOD): δ 19.2, 30.8, 39.1, 112.2, 113.2, 115.0, 116.0, 116.5, 116.7, 117.0, 121.1, 126.4, 126.5, 127.9, 128.3, 128.6, 129.7, 129.8, 135.3, 135.4, 136.4, 136.5, 137.0, 137.9, 140.8, 156.5,161.6. Anal. Calcd. for C31H21ClN4OS: C 69.85, H 3.97, N 10.51, S 6.02. Found: C 69.98, H 4.15, N 10.67, S 6.11.
5e: Mp > 300 8C. IR (KBr, cm-1): v 1689 (C=O). 1H NMR (400 MHz, CF3COOD): δ 2.72 (s, 3H), 3.22 (s, 3H), 3.33 (s, 3H), 7.21-7.29 (m, 1H), 7.28-7.29 (m, 2H), 7.64- 7.65 (m, 1H), 7.72-7.86 (m, 5H), 8.19-8.21 (m, 1H), 8.41-8.44 (m, 1H), 8.71 (s, 1H). 13C NMR(100 MHz, CF3CO3D): δ 30.8, 33.3, 39.0, 112.2, 115.1, 115.4, 116.0, 116.5 (d, J = 23.5 Hz), 116.6, 117.1, 120.7 (d, J = 8.2 Hz), 126.5, 126.8, 127.8, 128.6, 129.7, 129.9, 130.7, 130.8, 135.4, 135.7, 136.6, 137.2, 141.4, 145.8 (d, J = 2.5 Hz), 156.6 (d, J = 243.4 Hz), 160.0. Anal. Calcd. for C31H21FN4OS: C 72.08, H 4.10, N 10.85, S 6.21. Found: C 72.27, H 4.27, N 10.96, S 6.37.
5f: Mp > 300 8C. IR (KBr, cm-1): v 1672 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 4.06 (s, 3H), 4.13 (s, 3H), 4.27 (s, 3H), 7.28-7.31 (m, 2H), 7.82-7.86 (m, 5H), 7.92- 7.96 (m, 3H), 8.45-8.44 (m, 3H). 13C NMR (100 MHz, CF3CO3D): δ 31.2, 55.1, 55.6, 110.4, 112.2, 113.3, 114.4, 115.0, 116.1, 117.3, 117.6, 120.2, 122.8, 127.2, 127.8, 128.8, 129.8, 131.0, 134.4, 135.7, 141.9, 144.3, 156.8, 157.0, 160.2, 160.9, 161.4. Anal. Calcd. for C31H22N4O2S: C 72.35,H4.31, N10.89, S 6.23. Found: C 72.53,H4.50, N 10.95, S 6.39.
5g:Mp > 300 8C. IR (KBr, cm-1): v 1678 (C=O). 1H NMR (400 MHz, CF3CO3D3): d 3.53 (s, 3H), 3.65 (s, 3H), 4.28 (s, 3H), 4.51 (s, 3H), 7.87-7.92 (m, 3H), 8.03-8.05 (m, 4H), 8.15-8.21 (m, 2H), 8.70-8.74 (m, 3H). 13C NMR (100 MHz, CF3CO3D): δ 31.1, 33.4, 39.0, 55.4, 110.3, 113.2, 117.3, 117.4, 118.5, 119.5, 121.9, 123.6, 126.1, 127.5, 128.0, 128.6, 128.9, 129.3, 129.4, 129.7, 133.0, 134.7, 135.8, 142.6, 143.3, 157.0, 157.2, 159.7. Anal. Calcd. for C32H24N4O2S: C 72.71, H 4.58, N 10.60, S 6.07. Found: C 72.86, H 4.74, N 10.72, S 6.15.
5h: Mp > 300 8C. IR (KBr, cm-1): v 1685 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 3.29 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.15 (s, 3H), 7.25-7.27 (m, 1H), 7.38-7.40 (m, 3H), 7.64-7.67 (m, 2H), 7.75-7.78 (m, 1H), 7.83-7.85 (m, 1H), 7.91-7.94 (m, 1H), 8.25-8.27 (m, 2H), 8.50-8.52 (m, 1H). 13C NMR (100 MHz, CF3CO3D): δ 31.9, 32.2, 54.9, 55.0, 108.7, 114.4, 117.6, 118.5, 122.0, 122.2, 123.3, 124.1, 124.8, 127.8, 128.2, 128.5, 129.4, 129.5, 130.6, 132.6, 132.8, 134.8, 144.1, 144.2, 154.4, 158.4, 159.2, 160.1. Anal. Calcd. for C32H24N4O3S: C 70.57, H 4.44, N 10.29, S 5.89. Found: C 70.70, H 4.62, N 10.41, S 5.94.
5i: Mp > 300 8C. IR (KBr, cm-1): v 1688 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 2.19 (s, 3H), 3.33 (s, 3H), 4.10 (s, 3H), 4.15 (s, 3H), 7.04-7.07 (m, 2H), 7.15-7.18 (m, 2H), 7.64-7.73 (m, 4H), 7.91-7.92 (m, 1H), 8.19-8.22 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H). 13C NMR (100 MHz, CF3CO3D): δ 31.5, 33.0, 39.5, 55.9, 110.7, 112.6, 113.6, 115.4, 116.4, 117.7, 118.1, 120.8, 122.8, 127.5, 128.1, 128.8, 128.9, 129.1, 130.1, 130.9, 134.6, 135.9, 138.3, 141.3, 141.6, 157.1, 157.2, 162.8. Anal. Calcd. for C32H24N4O3S: C 70.57, H 4.44, N 10.29, S 5.89. Found: C 70.68, H 4.56, N 10.43, S 5.97.
5j: Mp > 300 8C. IR (KBr, cm-1): v 1683 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 3.34 (s, 3H), 4.10 (s, 3H), 4.16 (s, 3H), 6.61-6.63 (m, 1H), 6.69-6.72 (m, 1H), 7.28- 7.30 (m, 1H), 7.65-7.74 (m, 4H), 7.91-7.92 (m, 1H), 8.20-8.23 (m, 2H), 8.27-8.30 (m, 1H), 8.42-8.44 (m, 1H). 13C NMR (100 MHz, CF3CO3D): δ 34.0, 55.0, 55.5, 107.6, 110.4, 115.0, 115.2, 117.2 (d, J = 23.2 Hz), 117.9, 118.2, 121.1 (d, J = 8.4 Hz), 121.5, 126.3, 127.9, 128.0, 128.6, 129.5, 129.7, 130.7, 130.8, 133.8, 135.3, 140.3, 147.0 (d, J = 2.3 Hz), 156.4, 156.6 (d, J = 243.1 Hz), 160.1. Anal. Calcd. for C31H21FN4O2S: C 69.91, H 3.97, N 10.52, S 6.02. Found: C 70.15, H 4.16, N 10.68, S 6.13.
5k: Mp > 300 8C. IR (KBr, cm-1): v 1692 (C=O). 1H NMR (400 MHz, CF3CO3D): δ 3.39 (s, 3H), 4.10 (s, 3H), 4.16 (s, 3H), 6.57-7.65 (m, 5H), 7.75-7.77 (m, 1H), 7.89- 7.90 (m, 1H), 8.09-8.12 (m, 2H), 8.21-8.27 (m, 3H). 13C NMR (100 MHz, CF3CO3D): δ 31.4, 52.5, 55.4, 107.8, 112.1, 112.2, 113.2, 115.0, 116.1, 116.7, 118.7, 119.4, 121.7, 123.8, 127.5, 128.0, 129.5, 133.5, 134.6, 137.5, 141.3, 147.2, 148.1, 154.1, 156.7, 158.7, 159.6. Anal. Calcd. for C31H21NO4S: C 66.54, H 3.78, N 12.51, S 5.73. Found: C 66.68, H 3.89, N 12.73, S 5.87.).

3. Results and discussion

In this letter,we have presented a new and efficient method for the synthesis of benzo[b]pyrimido[4',5':5,4]thieno[2,3- e][1, 6]naphthyridine-8-ones can be readily synthesized from 4-bromomethylquinoline-2-ones and 5-cyano-1,6-dihydro-4- methyl-2-phenyl-6-thioxopyrimidine,by using a Thorpe-Ziegler isomerization and Pictet-Spengler reaction (Scheme 1).

In this study,the key intermediate amine 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3 was obtained by the condensation of 4-bromomethylquinoline-2-ones 1 with 5-cyano- 1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 2 via a Thorpe-Ziegler isomerization [17] in good yield. Its structure was determined from the spectral data as well as elemental analysis.

To examine the Pictet-Spengler reaction of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3 with various aldehydes 4,we chose 4-(3-aminopyrimido[4,5-d]thieno-2-yl)-6- methylquinoline-2-one (3a) and benzaldehyde (4a) as model substrates to optimize the reaction conditions (Scheme 2). The results are summarized in Table 1.

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

Table 1
Optimization of reaction conditions on the synthesis of benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine-8-one 5aa.

We have examined the influence of catalysts and solvents in the reaction. When the reaction of 3a and 4a was carried out in DMF at 100 ℃ for 4 h in the presence of BF3-OEt2 (10 mol%) the targeted compound benzo[b]pyrimido [4',5':5,4]thieno [2,3-e][1, 6]- naphthyridine-8-one 5a was obtained in 78% yield (Table 1,entry 1). However,when H2SO4 (10 mol%) was employed as a catalyst,the desired product 5a was obtained in 53% yield at 100 ℃ for 4 h in DMF (entry 2). When the same reaction was carried out in the presence of p-TsOH (10 mol%) for 8 h,63% yield of the product was obtained (entry 3). The yield of the product was slightly increased when the reaction was carried out in the presence of TFA (10 mol%) for 6 h in refluxing toluene,but did not exceed than that of BF3-OEt2 (10 mol%) (entry 4). To improve the yield,different solvents and reaction temperature were evaluated. The results revealed that DMF provided much better results than toluene,THF,DMSO and CH3CN (entries 5-10). We then varied the amount of catalyst loading. A yield of 69% of the product was obtained when the reaction was carried out with 5 mol% BF3-OEt2 for 4 h in refluxing toluene (entry 11). Increasing the amount of catalyst loading (15 mol%) did not improve the yield of the product (entry 12). Among the various conditions employed,the reaction in DMF at 100 ℃ in the presence of 10 mol% BF3-OEt2 catalyst was found to give the best results (Table 1,entry 1).

Under the optimized conditions,a wide range of aromatic aldehydes 4 underwent this one-pot condensation with of 4-(3-amino pyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3 to give the corresponding benzo[b]pyrimido[4',5':5,4]thieno[2,3- e][1, 6]naphthyridine-8-ones 5.

Encouraged by the above results,we investigated the scope of this reaction using various aromatic aldehydes (Table 2). A variety of electron-rich (entries 2,3 and 7-9) and electron-deficient aromatic aldehydes (entries 4,5,10 and 11) are effectively transformed to the corresponding naphthyridines in the presence of BF3-OEt2 in good yields (70%-85%).

Table 2
Synthesis of benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine-8-ones 5.

On the other hand,aliphatic aldehydes and ketones failed to the Pictet-Spengler cyclization and this may be attributed to the relatively poor electrophilicity of the imines derived from aliphatic aldehydes and ketones.

All the products were characterized by IR,1HNMR,13CNMRand elemental analysis. And all the data are consistent with the proposed structures.

A proposed mechanism of the process is summarized in Scheme 2. The present synthetic sequence was initiated by an S-alkylation of 4-bromomethylquinoline-2-ones 1 with 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine 2 giving rise to the thioethers A. An intramolecular carbanion addition across the nitrile occurred via a Thorpe-Ziegler isomerization reaction,resulting in the formation of 4-(3- aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones 3. Next,substrates 3 underwent a cationic π-cyclization with aldehydes as one-carbon electrophiles in imine intermediates B under Pictet- Spengler cyclization conditions,which resulted in the closure at the C3 position of quinoline-2-ones to give pentacyclic benzo[b]- pyrimido[4',5':5,4]thieno[2,3-e][1, 6]naphthyridine-8-ones ring system 5.

4. Conclusion

In summary,we have developed an efficient method for the synthesis of pharmacologically important,functionalized 1,6- naphthyridine derivatives in two steps. The synthetic approach involves a Thorpe-Ziegler isomerization of 4-bromomethylquinoline- 2-ones followed by a Pictet-Spengler cyclization of the corresponding 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline- 2-ones with aromatic aldehydes in the presence of BF3-OEt2. This method has the advantages of using utilizes easily accessible starting materials,mild reaction conditions,straightforward product isolation and good yields.

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