HETEROCYCLES

Short Paper | Regular issue | Vol. 92, No. 3, 2016, pp. 552-559
Received, 20th December, 2015, Accepted, 21st January, 2016, Published online, 2nd February, 2016.
DOI: 10.3987/COM-15-13397

■ Synthesis of Novel Benzofuro-Fused Thiazolo[3,2-a]pyrimidinones via Pictet-Spengler Reaction

Dao-Lin Wang,* Dong Wang, Jian-Hua Qiang, and Lin Liu

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

Abstract

An efficient method for the preparation of novel benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-ones 5 is described. The key intermediate, 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]pyrimidin-5-one (3), was synthesized from 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1) with salicylonitrile (2) by Thorpe-Ziegler isomerization. Subsequent reaction of the intermediate amine with aromatic aldehydes via Pictet-Spengler reaction provided benzofuro-fused thiazolo[3,2-a]pyrimidines under sulfamic acid as catalyst in good yields.

Thiazolo[3,2-a]pyrimidine heterocyclic systems are the key chemical building blocks for numerous compounds that play important roles in the functioning of biologically active molecules.1 As one type of those heterocyclic rings, 5H-thiazolo[3,2-a]pyrimidin-5-ones are considered a promising class of bioactive heterocyclic compounds encompassing a diverse range of biological activities such as anticancer,2 antitumor,3 antiinflammatory,4 antinociceptive,5 antiviral,6 and antibiofilm properties.7 Owing to these remarkably broad pharmacological properties, a variety of synthetic methods have been reported for the preparation of thiazolo[3,2-a]pyrimidinone derivatives.6-10
In addition, benzofuran derivatives have attracted widespread interest in view of their presence in natural products, and their biological and pharmacological activities.11 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.12
As part of our continuing interest on the development of new synthetic methods for heterocyclic compounds,13 herein we report the synthesis of some new fused heterocyclic systems: benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-ones by the application of Pictet-Spengler reaction (Scheme 1).14

In this study, the key intermediate amine, 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]pyrimidin-5-one (3) was obtained by the condensation of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one15 (1) with salicylonitrile (2) via Thorpe-Ziegler isomerization,16 in 80% yield. Elemental analysis (C14H9N3O2S) and spectral data supported its structure. Its IR spectrum contains absorption peaks at 3450-3362 and 1682 cm-1, demonstrating the presence of NH2 and C=O funcitions, respecticely. Its 1H NMR spectrum (DMSO-d6) shows the presence of a D2O exchangeable broad singlet at δ 6.56 ppm (2H) which can be attributed to the NH2 protons and singlet peak at δ 6.16 corresponding to C6-H of thiazolo[3,2-a]pyrimidine nucleus. The multiplet between 7.27-8.01 ppm (6H) corresponding to the aromatic protons of benzene and thiazole nucleus.
In an initial endeavor, we selected benzadehyde 4a as model aromatic aldehyde to react with equimolar amounts of intermediate amine 3a for the preparation of benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one 5a and investigated the optimal reaction conditions. The reaction was carried out under neat conditions at 120 oC without and with different acid catalysts such as p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA), and sulfamic acid (SA) each 10 mol% in DMF. The maximum yield was obtained using SA. It can be seen that the reaction did not proceed even after 24 h in the absence of this catalyst (Table 1, entry 1). Although a lower catalyst loading of 5 mol% accomplished this condensation, 10 mol% of SA was optimal in terms of reaction time and isolated yield (Table 1, entry 4). Increasing the amount from 10 to 15 mol% has no effect on the product yield and reaction time (Table 1, entry 6).
In addition, various solvents such as HOAc, DMSO, glycol, toluene, and MeCN were screened for the optimal reaction conditions. The best catalytic activity was observed in DMF compared to other organic solvents (Table 1, entries 7-11).

With these optimized reaction conditions in hand, we then planned to examine the versatility of the methodology for the preparation of benzofuro-fused thiazolo[3,2-a]pyrimidines. The substrate scope of the SA catalyzed coupling of 1 with aromatic aldehydes 4 is shown in Table 2 and it was found that this protocol could be applied not only to the aromatic aldehydes with either electron-donating groups (e.g., methyl, methoxy) or electron-withdrawing groups (e.g., fluoro, chloro, and nitro groups), but also to heterocyclic aldehydes. Therefore, we concluded that the electronic nature of the substituents of aldehydes has no significant effect on this reaction.

On the basis of these results, a plausible mechanism for the construction of fused thiazolo[3,2-a]pyrimidinones is proposed (Scheme 2). The formation of ether A occurs through O-alkylation of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 1 and salicylonitrile (2). Then, the ether A occurred via Thorpe-Ziegler isomerization reaction to generate 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]pyrimidin-5-one (3). Next, the intermediate amine 3 underwent a cationic π-cyclization with aldehyde under Pictet-Spengler cyclization to form D, which effects aromatisation to give pentacyclic product 5.

In summary, we have developed an efficient synthesis of benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-ones in two steps with good yields in the presence of sulfamic acid. This method has the advantages of readily available starting materials, mild reaction conditions, and operational simplicity. Further study is underway to the scope of this methodology for some new fused heterocyclic systems.

EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. The NMR spectra were recorded with a Bruker Avance 400 spectrometer (400 MHz for 1H and 100 MHz for 13C) using TMS an internal reference. IR spectra were measured on Shimadzu FTIR-8300 spectrophotometer. C, H, and N analyses were performed by a HP-MOD 1106 microanalyzer. The preparation of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1) was according to the literature procedure.14 All other chemicals used in this study were commercially available.
Preparation of 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]pyrimidin-5-one (3): To a solution of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one 1 (2.01 g, 10.0 mmol) in DMF (25 mL) was added salicylonitrile (2) (1.19 g, 10.0 mmol) and anhydrous potassium carbonate (2.76 g, 20.0 mmol). The mixture was heated at 100 °C for 5 h (monitored by TLC). After cooling to rt, then water (50 mL) was added and stirred for 20 min. The solid was filtered and recrystallized from HOAc to give 3 (2.26 g, 80%). Yellow crystals; mp > 300 °C; IR (KBr): ν 3450, 3362 (NH2), 1682 cm-1 (C=O); 1H NMR (DMSO-d6): δ 6.16 (s, 1H, 6-H), 6.59 (s, 2H, NH2), 7.26-7.28 (m, 1H, Arom-H), 7.43-7.47 (m, 2H, Arom-H), 7.51 (d, 1H, J = 8.4 Hz, Ben-H), 7.93 (d, 1H, J = 8.0 Hz, Ben-H), 8.01 (d, 1H, J = 4.8 Hz, Thiazo-H). Anal. Calcd for C14H9N3O2S: C 59.35, H 3.20, N 14.83. Found: C 59.46, H 3.28, N 14.90.
Typical Procedure for the Preparation of 6-Aryl-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo- [3,2-a]pyrimidin-5-ones 5a-k. To a stirred solution of 7-(3-amino-2-benzofuran)-5H-thiazolo[3,2-a]- pyrimidin-5-one (3) (283 mg, 1.0 mmol), aromatic aldehyde (1.0 mmol), and NH2SO3H (10 mg, 0.1 mmol) in DMF (20 mL) was heated at 120 °C (monitored by TLC). At the end of the reaction, the reaction mixture was cooled to rt, and then water (20 mL) was added to the mixture and stirred for 30 min. The solid was filtered and recrystallized from DMF to give 5a-k.
6-Phenyl-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5a): Yellow crystals; mp > 300 °C; IR (KBr): ν 1670 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.45 (d, J = 4.8 Hz, 1H, Thiazo-H), 7.57-7.65 (m, 4H, Ben-H), 7.69-7.72 (m, 1H, Ben-H), 7.86-7.92 (m, 3H, Ben-H), 8.18 (d, J = 8.0 Hz, 1H, Ben-H), 8.21 (d, J = 4.8 Hz, 1H, Thiazo-H); 13C NMR (100 MHz, CF3CO2D): δ 107.7, 113.0, 114.2, 115.5, 121.7, 123.2, 126.3, 127.9, 128.9, 130.2, 132.3, 134.3, 135.5, 141.7, 142.7, 154.7, 156.9, 158.9, 168.7. Anal. Calcd for C21H11N3O2S: C 68.28, H 3.00, N 11.38. Found: C 68.36, H 3.07, N 11.46.
6-(4-Methylphenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5b): Yellow crystals; mp > 300 °C; IR (KBr): ν 1682 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 2.46 (s, 3H, CH3), 7.43-7.47 (m, 5H, Arom-H), 7.62-7.63 (m, 1H, Ben-H), 7.87-7.90 (m, 2H, Ben-H), 8.18-8.22 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 19.6, 107.5, 113.1, 114.3, 115.5, 121.7, 123.2, 126.3, 127.2, 128.0, 129.5, 134.3, 135.5, 141.4, 142.7, 144.4, 154.9, 157.3, 158.9, 168.5. Anal. Calcd for C22H13N3O2S: C 68.91, H 3.42, N 10.96. Found: C 68.98, H 3.53, N 11.04.
6-(2-Methoxyphenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5c): Yellow crystals; mp > 300 °C; IR (KBr): ν 1680 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 3.75 (s, 3H, OCH3), 7.15-7.22 (m, 2H, Arom-H), 7.39-7.42 (m, 1H, Ben-H), 7.47-7.50 (m, 1H, Ben-H), 7.63-7.72 (m, 2H, Ben-H), 7.86-7.94 (m, 2H, Ben-H), 8.19-8.26 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 54.8, 108.9, 111.4, 113.1, 114.3, 119.3, 121.1, 121.7, 123.2, 126.3, 128.9, 129.0, 134.3, 134.4, 135.9, 141.4, 142.0, 154.2, 154.3, 156.9, 158.8, 168.4. Anal. Calcd for C22H13N3O3S: C 66.15, H 3.28, N 10.52. Found: C 66.24, H 3.34, N 10.61.
6-(3-Methoxyphenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5d): Yellow crystals; mp > 300 °C; IR (KBr): ν 1686 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 4.02 (s, 3H, OCH3), 7.27 (d, 1H, J = 7.6 Hz, Ben-H), 7.32 (s, 1H, Ben-H), 7.39 (d, 1H, J = 8.0 Hz, Ben-H), 7.49 (d, 1H, J = 4.4 Hz, Thiazo-H), 7.61-7.68 (m, 2H, Ben-H), 7.70-7.97 (m, 2H, Ben-H), 8.23-8.26 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 55.2, 107.8, 113.0, 114.1, 115.3, 116.9, 121.3, 121.6, 123.1, 126.3, 130.6, 131.7, 134.3, 135.4, 135.5, 141.8, 142.7, 154.7, 155.7, 158.7, 158.9, 168.8. Anal. Calcd for C22H13N3O3S: C 66.15, H 3.28, N 10.52. Found: C 66.26, H 3.34, N 10.63.
6-(4-Methoxyphenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5e): Yellow crystals; mp > 300 °C; IR (KBr): ν 1678 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 4.02 (s, 3H, OCH3), 7.22 (d, 2H, J = 8.0 Hz, Ben-H), 7.50-7.51 (m, 1H, Benz-H), 7.63-7.68 (m, 3H, Arom-H), 7.87-7.95 (m, 2H, Ben-H), 8.23-8.25 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 54.9, 107.2, 113.0, 114.3, 114.6, 115.4, 121.8, 123.0, 123.4, 126.3, 130.5, 134.4, 135.9, 140.7, 141.6, 141.7, 154.3, 156.5, 159.0, 167.8. Anal. Calcd for C22H13N3O3S: C 66.15, H 3.28, N 10.52. Found: C 66.24, H 3.35, N 10.59.
6-(3,4-Dimethoxyphenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5f): Yellow crystals; mp > 300 °C; IR (KBr): ν 3316 (OH), 1682 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 3.94 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 7.11-7.28 (m, 3H, Ben-H), 7.50-7.66 (m, 2H, Arom-H), 7.82-7.90 (m, 2H, Ben-H), 8.14-8.25 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 55.0, 55.3, 107.5, 111.3, 112.3, 113.0, 114.3, 121.7, 122.8, 123.0, 123.3, 123.6, 126.3, 134.4, 135.7, 141.2, 142.1, 148.3, 151.9, 154.3, 155.9, 158.9, 168.2. Anal. Calcd for C23H15N3O4S: C 64.33, H 3.52, N 9.78. Found: C 64.42, H 3.63, N 9.84.
6-(2-Fluorophenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5g): Yellow crystals; mp > 300 °C; IR (KBr): ν 1681 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.33-7.36 (m, 1H, Ben-H), 7.45-7.51 (m, 2H, Arom-H), 7.59-7.61 (m, 1H, Ben-H), 7.69-7.75 (m, 1H, Ben-H), 7.78-7.89 (m, 1H, Ben-H), 7.90-7.97 (m, 2H, Ben-H), 8.25-8.27 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 109.0, 113.2, 114.2, 115.6, 116.0, 116.2, 121.8, 123.2, 124.9, 125.0, 126.4, 129.2, 134.4, 134.8, 134.9, 136.0, 150.6, 154.3, 158.4, 158.9, 168.9. Anal. Calcd for C21H10FN3O2S: C 65.11, H 2.60, N 10.85. Found: C 65.19, H 2.68, N 10.93.
6-(4-Fluorophenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5h): Yellow crystals; mp > 300 °C; IR (KBr): ν 1682 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.09-7.11 (m, 2H, Ben-H), 7.27-7.28 (m, 1H, Ben-H), 7.45-7.47 (m, 3H, Arom-H), 7.69-7.77 (m, 2H, Ben-H), 8.01-8.03 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 107.9, 113.1, 114.2, 115.5, 116.1, 116.3, 121.7, 123.2, 126.2, 128.2, 128.3, 130.6, 130.7, 134.3, 135.6, 154.5, 155.7, 158.9, 168.7. Anal. Calcd for C21H10FN3O2S: C 65.11, H 2.60, N 10.85. Found: C 65.18, H 2.69, N 10.93.
6-(4-Chlorophenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5i): Yellow crystals; mp > 300 °C; IR (KBr): ν 1686 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.45-7.58 (m, 6H, Arom-H), 7.88-7.91 (m, 2H, Ben-H), 8.19-8.20 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 107.8, 113.0, 114.2, 121.6, 123.1, 126.3, 128.3, 129.1, 129.3, 134.3, 135.2, 135.5, 139.6, 141.7, 142.6, 154.5, 155.5, 158.3, 168.7. Anal. Calcd for C21H10ClN3O2S: C 62.46, H 2.50, N 8.78. Found: C 62.54, H 2.58, N 8.86.
6-(4-Nitrophenyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5j): Yellow crystals; mp > 300 °C; IR (KBr): ν 1689 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.46 (d, 1H, J = 4.0 Hz, Thiazo-H), 7.64-7.68 (m, 1H, Ben-H), 7.85-7.95 (m, 4H, Ben-H), 8.18-8.21 (m, 2H, Arom-H), 8.47 (d, 2H, J = 8.0 Hz, Ben-H); 13C NMR (100 MHz, CF3CO2D): δ 108.4, 113.1, 114.3, 115.5, 121.7, 123.0, 123.8, 126.4, 129.8, 134.5, 135.8, 137.1, 142.4, 142.8, 149.4, 153.3, 154.3, 159.0, 169.2. Anal. Calcd for C21H10N4O4S: C 60.87, H 2.43, N 13.52. Found: C 60.93, H 2.52, N 13.59.
6-(2-Thienyl)-5H-benzofuro[3’,2’:2,3]pyrido[4,5:d]thiazolo[3,2-a]pyrimidin-5-one (5k): Yellow crystals; mp > 300 °C; IR (KBr): ν 1679 cm-1 (C=O); 1H NMR (400 MHz, CF3CO2D): δ 7.31-7.33 (m, 1H, Arom-H), 7.54 (d, 1H, J = 8.4 Hz, Ben-H), 7.69-7.71 (m, 2H, Arom-H), 7.88-7.91 (m, 2H, Ben-H), 7.96 (dd, 1H, J = 7.4, 8.4 Hz, Ben-H), 8.28-8.32 (m, 2H, Arom-H); 13C NMR (100 MHz, CF3CO2D): δ 108.0, 113.1, 114.5, 115.3, 122.0, 123.6, 126.4, 127.8, 128.6, 132.8, 133.3, 134.7, 136.3, 140.9, 141.1, 150.1, 153.7, 159.1, 167.6. Anal. Calcd for C19H9N3O2S2: C 60.79, H 2.42, N 11.19. Found: C 60.87, H 2.49, N 11.26.

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

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