The isoquinoline structural core is present in scores of natural and synthetic products possessing many interesting pharmacological activities,including cytotoxic,antimicrobial,antimalarial and anti-HIV properties ^{[1, 2, 3, 4]}. The potent biological activities of various isoquinoline alkaloids have drawn much attention from various research groups in designing and synthesizing the pharmacophore.

One of the most powerful methodologies to synthesize the isoquinoline core is the acid-catalyzed Pictet-Spengler reaction ^{[5, 6]}. The protocol involves the cyclization of iminium ions derived from the condensation of β-arylethylamine derivatives with aldehydes (Scheme 1). Modifications of the original strategy by increasing the electrophilicity of the iminium intermediates using a sulfonyl or acyl group attached to the starting β-arylethylamines have been developed ^{[7, 8, 9, 10, 11, 12, 13, 14, 15]}. The practice of using sulfonyl,as an auxiliary group,showed superior reactivity to the use of an acyl component ^[15],and has received much interest owing to its promising properties,such as stability under a wide range of reaction conditions and the ease of purification ^[16]. It should benoted that the N-sulfonyl-1,2,3,4-tetrahydroisoquinolines could be directly converted to both 1,2,3,4-tetrahydroisoquinolines and isoquinolines (Scheme 1). The 1,2,3,4-tetrahydroisoquinolines can be readily achieved by reductive desulfonylation ^{[14, 17, 18, 19]},and isoquinolines can be practically derived through tandem β-elimination and aromatization as well ^{[20, 21]}. However,many of the Pictet-Spengler procedures suffer from disadvantages,such as the use of corrosive,sensitive and expensive catalysts,and harsh acidic conditions,in addition to the tedious preparation of catalysts and protecting carbonyls. To avoid these limitations,a novel and mild synthetic procedure has been developed for the synthesis of the isoquinoline core.

Scheme 1

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Scheme 1.1,2,3,4-Tetrahydroisoquinolines and isoquinolines fromN-sulfonyl-1,2,3,4-tetrahydroisoquinolines.

Heteropolyacids (HPAs) have gained much attention as versatile catalysts in organic synthesis owing to their environmentally friendly property,high catalytic activities,commercial availability,high stability toward humidity and air,and ease of handling ^{[22, 23, 24, 25]}. They have been applied to the synthesis of many attractive products,particularly heterocyclic compounds. In general,the most common Keggin-type HPAs were mainly utilized as catalysts due to their availability and chemical stability and are normally stronger than the conventional Lewis acids (e.g.,AlCl₃) and mineral acids (e.g.,H₂SO₄ and HCl). The acid strength of a series of Keggin-type HPAs decreases as follow: H₃[PW₁₂O₄₀]>H₄[SiW₁₂O₄₀]>H₃[PMo₁₂O₄₀]>H₄[SiMo₁₂O₄₀] ^[24]. Herein,we wish to report the synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinolines by the eco-friendly Pictet-Spengler strategy using commercially available tungstophosphoric acid (H₃[PW₁₂O₄₀]) as a catalyst.

Melting points were determined using a Griffin melting point apparatus and were uncorrected. Column chromatography was carried out using silica gel 60 (70-230 mesh ASTM). Analytical thin-layer chromatography (TLC) was performed with silica gel 60F₂₅₄aluminum sheets. ¹H NMR and¹³C NMR spectra were recorded on a Bruker AVANCE 300 NMR spectrometer (operating at 300 MHz for ¹H NMR and 75 MHz for ¹³C NMR). FTIR were obtained using a universal attenuated total reflectance attached on a PerkinElmer Spectrum One spectrometer. Mass spectra were recorded on a Bruker Daltonics (microTOF).

A mixture of N-sulfonylphenylethylamine 1 (0.5 mmol),aldehyde 2 (0.6 mmol),and H₃[PW₁₂O₄₀]·aq (144 mg,0.05 mmol) in acetonitrile (2 mL) was stirred under refluxing for 0.5-48 h. The reaction mixture was concentrated in vacuum and purified by silica gel column chromatography to obtain N-sulfonyl-1,2,3,4-tetrahydroisoquinoline 3 .

¹H NMR spectra of 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-phenylisoquinoline (3a),1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-isoquinoline (3b), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-methylisoquinoline (3c),1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-bromophenyl)-isoquinoline (3f),1,2,3, 4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-nitrophenyl)-isoquinoline (3g),1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-hydroxyphenyl)-isoquinoline (3h), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-methoxyphenyl)-isoquinoline (3i),1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(2-hydroxyphenyl)-isoquinoline (3j),1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(4-hydroxy-3-methoxyphenyl)-isoquinoline (3k), 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-(3-hydroxy-4-methoxyphenyl)-isoquinoline (3l),and 1,2,3,4-tetrahydro-2-[(4-methylphenyl)sulfonyl]-isoquinoline (3s) were consistent with those reported in the literatures ^{[26, 27]}.

Yield: 89%.¹H NMR (300 MHz,CDCl₃):δ 0.90-1.85 (m,7H, CH₂CH₂CH₃),2.30 (s,3H,ArCH₃),2.32-2.40 (m,2H,C4),3.32-3.45, 3.75-3.90 (m,2H,C3),3.74,3.84 (2s,6H,2×OCH₃),4.87 (dd,1H,J= 9.3,4.3 Hz,C1),6.30,6.48 (2s,2H,C5-ArH,C8-ArH),7.08 (d,2H,J= 8.1 Hz,C3 ' -ArH₂),7.55 (d,2H,J= 8.1 Hz,C2 ' -ArH₂). ¹³ C NMR (75 MHz,CDCl₃):δ 13.8,19.8,21.4,25.7,38.5,39.7,55.8,56.0,56.2, 109.7,111.4,124.6,127.0,129.1,129.3,138.1,142.9,147.4,147.7. IR (UATR,cm^-1 ): 1612,1518,1322,1158,1120. TOF-MS: m/z 390.1726; Calcd. for C₂₁H₂₈NO₄S: 390.1734.

Yield: 68%. Mp: 122-124℃. ¹H NMR (300 MHz,CDCl₃):δ 1.00- 2.02 (m,11H,CyH),2.25 (s,3H,ArCH₃),2.26-2.57 (m,2H,C4), 3.44-3.70 (m,2H,C3),3.73,3.82 (2s,6H,2×OCH₃),4.49 (d,1H, J= 8.8 Hz,C1),6.27,6.45 (2s,2H,C5-ArH,C8-ArH),7.00 (d,2H, J= 8.0 Hz,C3' -ArH₂),7.44 (d,2H,J= 8.0 Hz,C2' -ArH₂). ¹³C NMR (75 MHz,CDCl₃):δ 21.3,25.3,26.2,26.3,30.4,30.7,55.8,56.1,61.8, 111.4,111.5,125.2,127.1,127.5,129.1,137.4,142.7,146.5,147.9. IR (UATR,cm^-1 ): 1611,1514,1336,1158,1114. TOF-MS: m/z 452.1865; Calcd. for C₂₄H₃₁NNaO₄S: 452.1866.

Yield: 88%. Mp: 141-142℃. ¹H NMR (300 MHz,CDCl₃):δ 2.84 (t,2H,J= 5.8 Hz,C4),3.45 (t,2H,J= 5.8 Hz,C3),3.83 (s,6H,2×OCH₃),4.28 (s,2H,C-1),6.52,6.55 (2s,2H,C5-ArH,C8-ArH),8.02 (d, 2H,J= 8.9 Hz,C2' -ArH₂),8.37 (d,2H,J= 8.9 Hz,C3'-ArH₂). ¹³ C NMR (75 MHz,CDCl₃):δ 28.2,43.8,47.1,55.9,56.0,108.8,111.4,122.6, 124.3,124.7,128.7,143.1,147.9,148.1,150.1. IR (UATR,cm^-1): 1610,1518,1347,1164,1117. TOF-MS:m/z401.0776; Calcd. for C₁₇H₁₈N₂NaO₆S: 401.0778.

Yield: 68%. Mp 128-129℃. ¹H NMR (300 MHz,CDCl₃):δ 2.50- 2.60 (m,2H,C4),3.20-3.34,3.72-3.90 (m,2H,C3),3.73,3.79 (2s, 6H,2×OCH₃),6.17 (s,1H,C1),6.40,6.43 (2s,2H,C5-ArH,C8-ArH), 7.12-7.28 (m,5H,C2' -ArH2,C3'-ArH2,C4'-ArH),7.80 (d,2H, J= 8.8 Hz,C2'' -ArH₂),8.12 (d,2H,,J= 8.8 Hz,C3'' -ArH₂). ¹³C NMR (75 MHz,CDCl₃):δ 26.5,39.1,55.9,56.0,59.3,110.6,111.1,123.9, 125.1,125.3,128.1,128.5,128.8,140.7,146.8,147.8,148.5,149.6. IR (UATR,cm^-1): 1609,1529,1348,1162,1117. TOF-MS: m/z 477.1091; Calcd for C₂₃H₂₂N₂NaO₆S: 477.1091.

Yield: 12%. Mp: 279-2818C.¹H NMR (300 MHz,CDCl₃):δ 2.45- 2.65 (m,2H,C4),3.20-3.35,3.70-3.90 (m,2H,C3),3.73,3.76,3.79 (3s,9H,3×OCH3),6.13 (s,1H,C1),6.39,6.41 (2s,H,C5-ArH,C8-ArH),6.76 (d,2H,J= 8.7 Hz,C3'-ArH₂),7.07 (d,2H,J= 8.7 Hz,C2'-ArH₂),7.79 (d,2H,J= 8.9 Hz,C2''-ArH₂),8.11 (d,2H,J= 8.9 Hz,C3'' -ArH₂). ¹³C NMR (75 MHz,CDCl₃):d26.5,38.9,55.3,55.9,56.0,58.8, 110.6,111.1,113.7,123.9,125.2,128.1,130.0,132.9,147.0,147.8, 148.5,149.6,159.4. IR (UATR,cm^-1): 1608,1510,1347,1248,1162. TOF-MSm/z: 485.1382; Calcd. for C₂₄H₂₅N₂O₇S: 485.1377.

Initially,the Pictet-Spengler reaction of 4-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-benzenesulfonamide 1a ^[28] with benzaldehyde using H₃[PW₁₂O₄₀]·aq was optimized in various solvents such as water,ethanol,dichloromethane and acetonitrile as demonstrated in Table 1. The best result was obtained using acetonitrile as solvent. Increasing the amount of catalyst did not show any significant effect on the outcome of the reaction (Table 1, entry 4 vs entry 5); however,the shorter reaction time was realized by elevating the reaction temperature to furnish the anticipated 1,2,3,4-tetrahydro-6,7-dimethoxy-2-[(4-methylphenyl)sulfonyl]-1-phenylisoquinoline 3a in 86% yield within 12 h (Table 1,entry 6).

Table 1

Table 1 Reaction ofN-sulfonylphenylethylamine1awith benzaldehyde using H3[PW12O40]aq as a catalyst in different reaction conditions.

Table 1 Reaction ofN-sulfonylphenylethylamine1awith benzaldehyde using H3[PW12O40]·aq as a catalyst in different reaction conditions.

The formation of the desired isoquinoline (3a) was confirmed by ¹H NMR spectra which showed the absence of the NH proton, while the singlet of methine proton displayed at δ 6.19 indicated that the cyclized product 3a was formed. The structure was consistent with that reported in the literature ^[26].

The success of forming3aencouraged us to extend the reaction of the activated benzene sulfonamide (1a) with other aldehydes2, as summarized in Table 2. The reactions were performed under similar conditions to provide tetrahydroisoquinoline analogs3in moderate to good yields. It was clear that the reaction could be applied to both aliphatic and aromatic aldehydes. The reaction proceeded smoothly with aromatic aldehydes bearing both electron-withdrawing (Br,NO₂) and electron-donating groups (OH,OCH₃); however,the latter required longer reaction time to consume1a. The scope of the reaction was further studied using salisaldehyde to determine the steric effect ofortho-substituted aromatic aldehydes. The reaction gradually proceeded to afford the cyclized product with low yield (Table 2; entry 10). The less reactive 3,4,5-trimethoxy benzaldehyde (Table 2; entry 13) gave no cyclized product along with the recovery of starting material. Moreover,the reaction could not tolerate the use of heterocyclic aldehydes,such as pyridine-3-carboxaldehyde and indole-3-carboxaldehyde (Table 2; entries 14-15) even with prolonged reaction times of up to 48 h. Both methyl and nitro substituted (R²) benzene sulfonamides (1aand1b) were determined as suitable substrates for the Pictet-Spengler procedure under these reaction conditions. It was found that the methyl analogs were more reactive than the nitro counterparts (entry 1vsentry 17 and entry 9vsentry 18). When the benzene sulfonamide bearing no methoxy activating group (1c) was used as the substrate,the cyclization reaction was achieved only with paraformaldehyde (entry 19).

Table 2

Table 2 Tungstophosphoric acid hydrate catalyzed reaction of N-sulfonylphenylethylamines 1 with various aldehydes 2.

Table 2 Tungstophosphoric acid hydrate catalyzed reaction of N-sulfonylphenylethylamines 1 with various aldehydes 2.

The synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinolines promoted by silica-supported HPA catalysts has been shown; however,the reaction scope was narrow ^{[13, 14]}. The approach could be applied only toN-sulfonyl-1,2,3,4-tetrahydroisoquinolines containing no substituent at position 1 using trioxane as the carbonyl component. Mechanistically,HPA plays an essential role in this Pictet-Spengler reaction by protonation of the carbonyl oxygen of aldehyde,thus the formation of the iminium intermediate was accelerated ^[29].

It is worth noting that various N-sulfonyl-1,2,3,4-tetrahydroisoquinolines have been reported as potent cytotoxic agents ^[26], and their analogs are synthetic intermediates in the preparation of various biologically active molecules ^{[18, 28]} including a simple natural isoquinoline alkaloid,salsolidine ^[19].

We have presented a novel,simple and greener protocol for the synthesis ofN-substituted-1,2,3,4-tetrahydroisoquinolinesviathe modified Pictet-Spengler reaction ofN-(2-phenylethyl)-benzenesulfonamides with various aldehydes using tungstophosphoric acid hydrate as an influential catalyst. Significantly,the method offers several attractive advantages such as readily availability, non-corrosive conditions,as well as a simple experimental procedure.

We gratefully acknowledge the research grant from Srinakharinwirot University (B.E. 2555). This project is supported by Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative.