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Article

Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids

by
Masahiro Yoshida
*,
Ryunosuke Imaji
and
Shinya Shiomi
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-cho, Tokushima 770-8514, Japan
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(12), 2917; https://doi.org/10.3390/molecules29122917
Submission received: 6 June 2024 / Revised: 17 June 2024 / Accepted: 17 June 2024 / Published: 19 June 2024
(This article belongs to the Special Issue Advances in Heterocyclic Synthesis)
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Abstract

:
1,2-Dihydroisoquinolines are important compounds due to their biological and medicinal activities, and numerous approaches to their synthesis have been reported. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines. In this study, a palladium-catalyzed cascade cyclization–coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. When N-acetyl diphenyl-substituted trisubstituted allenamide and phenylboronic acid were treated with 10 mol% of Pd(OAc)2, 20 mol% of P(o-tolyl)3, and 5 equivalents of NaOH in dioxane/H2O (4/1) at 80 °C, the reaction proceeded to afford a substituted 1,2-dihydroisoquinoline. The reaction proceeded via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained using this methodology because the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step.

Graphical Abstract

1. Introduction

Isoquinolines and their derivatives, especially 1,2-dihydroisoquinolines, are among the important structure classes of chemical substances. A wide variety of natural products and biologically active pharmacophores have been reported [1,2,3,4,5,6,7,8], such as acetoneberberine IK-2 (I) [5], cribrostatin 4 (II) [6], N-carboxymethyl compound III for a carrier for brain-specific delivery [7], and nitro-substituted 1,2-dihydroisoquinoline IV as an HIV-1 inhibitor [8]. For this reason, numerous approaches to the synthesis of 1,2-dihydroisoquinolines have been developed (Figure 1) [9,10,11,12,13,14,15,16,17,18,19,20,21,22].
Allenamides are powerful and versatile synthetic building blocks in organic synthesis, extensively utilized as reaction substrates to produce a variety of synthetically useful organic molecules [23,24]. Among them, palladium-catalyzed cascade cyclization of ortho-haloaryl-substituted allenamides provides efficient approaches for the synthesis of N-heterocyclic compounds (Scheme 1, eq 1) [25,26,27,28,29,30,31,32,33,34,35,36,37]. The key intermediate in this strategy is the π-allylpalladium species, which is generated by an oxidative addition and allene insertion sequence. Diverse nucleophiles or organic main group element compounds are applied to undergo subsequent allylic substitution reactions, yielding a variety of substituted heterocycles. Considerable effort has been devoted to developing methods for the synthesis of various N-heterocyclic compounds, but few examples using polysubstituted allenamides have been reported, presumably due to the difficulty of synthesizing polysubstituted allenamides. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides were conveniently synthesized from readily available propargylamines with high efficiency (Scheme 1, eq. 2) [38]. In light of this research background, we focused on the utility of this methodology for the synthesis of substituted 1,2-dihydroisoquinolines via the palladium-catalyzed cascade cyclization of ortho-haloaryl-substituted allenamides with arylboronic acids. Although similar transformation using arylboronic acids has been previously reported for the synthesis of indole and isoquinolinone derivatives [32,33], no examples using polysubstituted allenamides as the substrates were reported. Herein, we describe a synthesis of highly substituted 1,2-dihydroisoquinolines via the palladium-catalyzed reaction of trisubstituted allenamides containing a o-bromoaryl moiety with arylboronic acids (Scheme 1, eq 3).

2. Results and Discussion

Trisubstituted allenamides for the palladium-catalyzed cascade cyclization were prepared as shown in Scheme 2. The three-component reaction of commercially available arylaldehyde, monosubstituted alkyne, and o-bromobenzyl amine yielded the propargylamines 1a–1e, which were subjected to reaction with acetic anhydride and DBU, according to our procedure [38], to afford the corresponding trisubstituted allenamides 2a–2e in moderate to good yields, respectively.
The initial attempts for the palladium-catalyzed cascade reaction were carried out using the N-acetyl diphenyl-substituted trisubstituted allenamide 2a with phenylboronic acid (3a) (Table 1). When 2a and 3a were treated with 5 mol% of Pd(OAc)2, 10 mol% of P(o-tolyl)3, and 5 equivalents of NaOH in dioxane/H2O (4/1) at 80 °C [39], the expected reaction proceeded, affording a substituted 1,2-dihydroisoquinoline 4aa in 78% yield (entry 1). Upon examining the catalyst amounts (entries 2 and 3), it was found that increasing the amounts to 10 mol% of Pd(OAc)2 and 20 mol% of P(o-tolyl)3 increased the yield to 88% (entry 3). Reaction temperatures were then investigated (entries 4–6). The yield of 4aa was 86% when the reaction was carried out at 50 °C (entry 4), but a significant decrease in yield was observed when the temperature was lowered to 25 °C (entry 5). The product was obtained in a 76% yield when the reaction temperature was raised to 100 °C (entry 6). The product was produced in a 70% yield when PPh3 was used (entry 7), but the yield decreased to 19% when PCy3 was used (entry 8). The reactions using bidentate ligands such as DPPE and DPPF also proceeded, giving 4aa in 47% and 70% yields, respectively (entries 9 and 10).
We next carried out a study on the substrate scope using various arylboronic acids 3b–3i with 2a (Figure 2). When 4-methoxyphenylboronic acid (3b) was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ab was obtained in an 82% yield. Arylboronic acids 3c and 3d, having dimethoxyphenyl groups, reacted with 2a to produce the products 4ac and 4ad in 98% and 86% yields, respectively. The reaction of 3e, having a tert-butyl group, also proceeded to give the product 4ae in a 92% yield. The corresponding products 4af and 4ag were obtained in good yields from the reactions using 4-chloro- and 4-fluorophenyl boronic acids 3f and 3g, respectively. The reaction using 4-acetylphenylboronic acid (3h) afforded the product 4ah in an 85% yield. When 1-naphtylboronic acid (3i) was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ai was produced in a 67% yield.
The reactions using trisubstituted allenamides 2b–2e with various substituents and phenylboronic acid (3a) are summarized in Figure 3. When the substrate 2b, with a 4-fluorophenyl group at the 1-position, was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ba was obtained in a 55% yield. The reaction of allenamide 2c, which had a 1,3-benzodioxole moiety, proceeded to afford the cyclized product 4ca in an 80% yield. The substrates 2d and 2e, containing a 4-fluoro- and 4-methoxyphenyl group at the 3-position, also reacted with 3a to produce the corresponding substituted products 4da (4ag) and 4ea (4ab) in 66% and 72% yields, respectively.
A plausible mechanism for the cyclization process is shown in Scheme 3. The reaction was initiated with the oxidative addition of the aryl bromide moiety of the allenamide 2 to palladium, generating arylpalladium intermediate A [25,26,27,28,29,30,31,32,33,34,35,36,37]. This was followed by an intramolecular allene insertion process (B) to generate the π-allyl-palladium intermediate C [25,26,27,28,29,30,31,32,33,34,35,36,37]. Then, ligand exchange of palladium complex C with hydroxide ion occurred, forming hydroxypalladium species D [39]. This species underwent transmetallation with the arylborate complex via intermediate E to produce the substituted 1,2-dihydroisoquinoline 4.

3. Materials and Methods

All commercially available reagents were used without further purification. All reactions were performed in glassware equipped with a septum under the positive pressure of argon. The reaction mixture was magnetically stirred. Concentration was performed under reduced pressure. The heating experiments were conducted under an oil bath as a heat source. The reactions were monitored by TLC. TLC was performed on pre-coated plates (0.25 mm, silica gel 60F245, Merck & Co., Inc., Kenilworth, NJ, USA). Spots were visualized by exposure to UV light or by immersion into a solution of 10% phosphomolybdic acid in ethanol, followed by heating at ca. 200 °C. Column chromatography was performed on silica gel (40–50 μm, Kanto Chemical Co. Lit., Nihonbashi, Tokyo, Japan). NMR spectra were recorded on a Bruker AVANCED III HD-500 (1H: 500 MHz, 13C: 125 MHz) spectrometer (Bruker Corporation, Billerica, MA, USA) using tetramethylsilane (1H NMR at 0.00 ppm) and CDCl3 (13C NMR at 77.16) as a reference standard. Chemical shifts were reported in ppm. The following abbreviations were used to denote peak multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sept, septet; m, multiplet; br, broadened. Mass spectra and high-resolution mass spectra were recorded on JEOL JMS-700 mass spectrometers (double-focusing magnetic sector) (JEOL Ltd., Tokyo, Japan).

3.1. General Procedure for the Three-Component Reaction of Arylaldehyde, Alkyne and Amine in Scheme 2: Synthesis of Propargylamine 1a

To a solution of benzaldehyde (531 mg, 5.00 mmol) in toluene (6 mL), phenylacetylene (766 mg, 7.50 mmol), 2-bromobenzylamine (1.40 g, 7.50 mmol) and CuBr (143 mg, 1.00 mmol) were added at rt under an argon atmosphere. The reaction mixture was then stirred under reflux conditions for 2 h. The reaction was quenched with sat. NH4Cl. The aq. mixture was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a crude product, which was purified by means of silica gel column chromatography (hexane/AcOEt = 30/1 to 10/1) to afford propargylamine 1a (1.71 g, 4.54 mmol, 90%).

3.2. N-(2-Bromobenzyl)-1,3-diphenylprop-2-yn-1-amine (1a)

Yield 90% (1.71 g, 4.54 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.62 (d, 2H, J = 7.5 Hz), 7.53 (d, 1H, J = 7.5 Hz), 7.52–7.46 (m, 4H), 7.38–7.29 (m, 7H), 4.82 (s, 1H), 4.06 (d, 1H, J = 6.6 Hz), 4.04 (d, 1H, J = 6.6 Hz), 1.92 (s, 1H); 13C-NMR (125 MHz, CDCl3): δ 140.2, 138.9, 132.9, 131.8 (2C), 130.6, 128.8, 128.6 (2C), 128.3 (2C), 128.2, 127.9, 127.8 (2C), 127.5, 124.3, 123.2, 89.0, 85.9, 54.0, 51.3; HRMS (EI) m/z calcd for C22H18NBr [M]+ 375.0623, found 375.0626.

3.3. N-(2-Bromobenzyl)-1-(4-fluorophenyl)-3-phenylprop-2-yn-1-amine (1b)

Yield 99% (2.09 g, 5.31 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.58 (dd, 1H, J = 9.0 and 5.5 Hz), 7.52–7.46 (m, 4H), 7.43 (d, 1H, J = 7.5 Hz), 7.31–7.25 (m, 3H), 7.23 (t, 1H, J = 7.5 Hz), 7.06–6.99 (m, 3H), 4.77 (s, 1H), 4.03 (d, 1H, J = 6.6 Hz), 4.01 (d, 1H, J = 6.6 Hz), 1.91 (s, 1H); 13C-NMR (125 MHz, CDCl3): δ 162.3 (d, J = 244 Hz), 138.7, 135.9, 132.8. 131.7 (2C), 130.5, 129.4, 129.3 (2C, d, J = 7.9 Hz), 128.7, 128.3 (2C), 127.4, 124.1, 122.9, 115.3 (2C, d, J = 21.6 Hz), 88.7, 86.1, 53.2, 51.1; HRMS (EI) m/z calcd for C22H17NBrF [M]+ 393.0528, found 393.0534.

3.4. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-bromobenzyl)-3-phenylprop-2-yn-1-amine (1c)

Yield 71% (581 mg, 1.38 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.55 (d, 1H, J = 8.0 Hz), 7.49–7.46 (m, 3H), 7.33–7.27 (m, 4H), 7.15–7.11 (m, 2H), 7.07 (d, 1H, J = 8.0 Hz), 6.79 (d, 1H, J = 8.0 Hz), 5.96 (s, 2H), 4.74 (s, 1H), 4.07 (d, 1H, J = 6.6 Hz), 4.03 (d, 1H, J = 6.6 Hz), 1.60 (brs, 1H); 13C-NMR (125 MHz, CDCl3): δ 147.9, 147.3, 138.9, 134.3, 132.9, 131.8 (2C), 130.7, 128.8, 128.4 (2C), 128.3, 128.2, 127.6, 124.3, 123.1, 121.1, 108.4, 108.1, 89.0, 85.9, 53.8, 51.3; HRMS (EI) m/z calcd for C23H18NO2Br [M]+ 419.0521, found 419.0524.

3.5. N-(2-Bromobenzyl)-3-(4-fluorophenyl)-1-phenylprop-2-yn-1-amine (1d)

Yield 69% (1.45 g, 3.67 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.59 (d, 2H, J = 7.5 Hz), 7.48 (d, 1H, J = 8.0 Hz), 7.43–7.39 (m, 3H), 7.33 (t, 2H, J = 7.5 Hz), 7.25 (t, 1H, J = 7.5 Hz), 7.20 (t, 1H, J = 7.5 Hz), 7.03 (dt, 1H, J = 7.5 and 8.0 Hz), 6.96–9.91 (m, 2H), 4.78 (s, 1H), 4.04 (d, 1H, J = 6.6 Hz), 4.00 (d, 1H, J = 6.6 Hz), 1.93 (s, 1H); 13C-NMR (125 MHz, CDCl3): δ 162.3 (d, J = 247 Hz), 140.0, 138.8, 133.5 (2C, d, J = 8.8 Hz), 132.7, 130.4, 128.6, 128.5 (2C), 127.8, 127.6 (2C), 127.4, 124.1, 119.1, 115.5 (2C, d, J = 21.6 Hz), 88.7, 84.7, 53.9, 51.2; HRMS (EI) m/z calcd for C22H17NBrF [M]+ 393.0528, found 393.0524.

3.6. N-(2-Bromobenzyl)-3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-amine (1e)

Yield 94% (1.00 g, 2.49 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.61 (d, 2H, J = 7.0 Hz), 7.51 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 8.0 Hz), 7.42 (d, 2H, J = 9.0 Hz), 7.33 (t, 2H, J = 7.0 Hz), 7.28–7.22 (m, 2H), 7.07 (t, 1H, J = 8.0 Hz), 6.81 (d, 2H, J = 9.0 Hz), 4.80 (s, 1H), 4.06 (d, 1H, J = 6.6 Hz), 4.04 (d, 1H, J = 6.6 Hz), 3.73 (s, 3H)1.92 (brs, 1H); 159.5, 140.3, 138.9, 133.1 (2C), 132.8, 130.5, 128.7, 128.5 (2C), 127.8, 127.7 (2C), 127.4, 124.1, 115.2, 113.9 (2C), 87.5, 85.8, 55.2, 54.0, 51.2; HRMS (EI) m/z calcd for C23H20NOBr [M]+ 405.0728, found 405.0725.

3.7. General Procedure for the One-pot Synthesis of Trisubstituted Allenamide in Scheme 2: Synthesis of Allenamide 2a

To a solution of propargylamine 1a (314 mg, 0.835 mmol) in toluene (7 mL), Ac2O (0.40 mL, 4.18 mmol) and DBU (0.62 mL, 4.18 mmol) were added at 0 °C under an argon atmosphere. The reaction mixture was stirred at same temperature for 24 h. The reaction was quenched with 1 M HCl. The aq. mixture was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a crude product, which was purified by means of silica gel column chromatography (hexane/AcOEt = 8/1) to afford the allnenamide 2a (349 mg, 0.834 mmol, 99%).

3.8. N-(2-Bromobenzyl)-N-(1,3-diphenylpropa-1,2-dien-1-yl)acetamide (2a)

Yield 99% (349 mg, 0.834 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.46 (d, 1H, J = 7.9 Hz), 7.40–7.31 (m, 4H), 7.26–7.20 (m, 5H), 7.07 (t, 1H, J = 7.6 Hz), 7.03–7.00 (m, 3H), 6.62 (s, 1H), 5.23 (d, 1H, J = 15.3 Hz), 4.72 (d, 1H, J = 15.3 Hz), 2.23 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 206.9, 171.5, 136.3, 132.7, 132.6, 131.9, 130.0, 129.1 (2C), 128.8 (2C), 128.7, 128.6, 128.3, 127.7 (2C), 127.5, 125.5 (2C), 123.8, 115.8, 101.9, 49.6, 22.2; HRMS (EI) m/z calcd for C24H20BrNO [M]+ 417.0728, found 417.0730.

3.9. N-(2-Bromobenzyl)-N-(1-(4-fluorophenyl)-3-phenylpropa-1,2-dien-1-yl)acetamide (2b)

Yield 75% (220 mg, 0.500 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.46 (d, 1H, J = 7.9 Hz), 7.32–7.29 (m, 2H), 7.26–7.22 (m, 4H), 7.09–6.98 (m, 6H), 6.61 (s, 1H), 5.23 (d, 1H, J = 15.5 Hz), 4.68 (d, 1H, J = 15.5 Hz), 2.24 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 206.6, 171.4, 162.9 (d, J = 247 Hz), 136.2, 132.7, 130.2, 128.9 (2C), 128.8, 128.7, 128.5, 128.4, 127.7 (2C), 127.6, 127.4 (2C, d, J = 8.8 Hz), 123.9, 116.3 (2C, d, J = 21.6 Hz), 115.0, 102.1, 49.4, 22.2; HRMS (EI) m/z calcd for C24H19NOBrF [M]+ 435.0634, found 435.0632.

3.10. N-(1-(Benzo[d][1,3]dioxol-5-yl)-3-phenylpropa-1,2-dien-1-yl)-N-(2-bromobenzyl)acetamide (2c)

Yield 59% (145 mg, 0.313 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.46 (d, 1H, J = 8.0 Hz), 7.26–7.21 (m, 4H), 7.08–6.98 (m, 4H), 6.84–6.80 (m, 3H), 6.58 (s, 1H), 5.97 (s, 2H), 5.21 (d, 1H, J = 15.5 Hz), 4.71 (d, 1H, J = 15.5 Hz), 2.24 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 206.4, 171.4, 148.6, 148.2, 136.3, 132.7, 132.0, 130.0, 128.9, 128.8 (2C), 128.3, 127.6 (2C), 127.5, 126.6, 123.8, 119.2, 115.7, 108.8, 106.0, 101.9, 101.5, 49.5, 22.1; HRMS (EI) m/z calcd for C25H20NO3Br [M]+ 461.0627, found 461.0622.

3.11. N-(2-Bromobenzyl)-N-(3-(4-fluorophenyl)-1-phenylpropa-1,2-dien-1-yl)acetamide (2d)

Yield 88% (259 mg, 0.590 mmol); yellow oil; 1H-NMR (500 MHz, CDCl3): δ 7.45 (d, 1H, J = 8.0 Hz), 7.40–7.37 (m, 2H), 7.34–7.31 (m, 1H), 7.24 (d, 1H, J = 8.0 Hz), 7.07–7.00 (m, 2H), 6.95–6.87 (m, 6H), 6.60 (s, 1H), 5.31 (d, 1H, J = 15.5 Hz), 4.64 (d, 1H, J = 15.5 Hz), 2.24 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 206.6, 171.5, 162.6 (d, J = 247 Hz), 136.3, 132.7, 132.5, 130.0, 129.3, 129.2 (3C), 128.8 (2C, d, J = 8.8 Hz), 128.0, 127.9, 127.6, 125.6 (2C), 123.9, 115.9 (2C, d, J = 21.6 Hz), 100.8, 49.5, 22.2; HRMS (EI) m/z calcd for C24H19NOBrF [M]+ 435.0634, found 435.0638.

3.12. N-(2-Bromobenzyl)-N-(3-(4-methoxyphenyl)-1-phenylpropa-1,2-dien-1-yl)acetamide (2e)

Yield 84% (275 mg, 0.613 mmol); white solid; mp 123.5–157.2 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.45 (d, 1H, J = 7.5 Hz), 7.38–7.28 (m, 6H), 7.08–7.00 (m, 2H), 6.93 (d, 2H, J = 9.0 Hz), 6.75 (d, 2H, J = 9.0 Hz), 6.59 (s, 1H), 5.23 (d, 1H, J = 15.5 Hz), 4.69 (d, 1H, J = 15.5 Hz), 3.78 (s, 3H), 2.25 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 206.1, 171.6, 159.7, 136.3, 132.9, 132.6, 129.9, 129.1 (2C), 128.9 (2C), 128.7, 128.5, 127.5, 125.5 (2C), 124.1, 123.8, 115.5, 114.3 (2C), 101.4, 55.4, 49.6, 22.2; HRMS (EI) m/z calcd for C25H22NO2Br [M]+ 447.0834, found 447.0830.

3.13. General Procedure for the Palladium-Catalyzed Cascade Reaction of Allenamide with Arylboronic Acid: Synthesis of 1,2-dihydroisoquinoline 4aa

To a stirred solution of allenamide 2a (60.1 mg, 0.144 mmol) in 1,4-dioxane (2.4 mL) and H2O (0.6 mL), phenylboronic acid (3a) (26.3 mg, 0.216 mmol), Pd(OAc)2 (3.2 mg, 0.0144 mmol), P(o-tolyl)3 (8.7 mg, 0.0287 mmol), and NaOH (28.8 mg, 0.720 mmol) were added at rt under an argon atmosphere. The reaction mixture was stirred for 3 h at 80 °C. Water was added to the reaction mixture, which was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a crude product, which was purified by means of silica gel column chromatography (hexane/AcOEt = 7/1) to afford the 1,2-dihydroisoquinoline 4aa (53.2 mg, 0.128 mmol, 88%).

3.14. 1-(4-Benzhydryl-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4aa)

Yield 88% (53.2 mg, 0.128 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.33–7.31 (m, 5H), 7.26–7.15 (m, 12H), 7.06 (t, 1H, J = 7.5 Hz), 6.94 (t, 1H, J = 7.5 Hz), 5.76 (s, 1H), 4.99 (s, 2H), 1.56 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 142.6 (2C), 138.5, 137.7, 135.3, 132.2, 129.7, 129.4 (3C), 129.3, 129.0, 128.9, 128.7, 128.4, 128.3 (3C), 127.6, 127.2, 126.5 (3C), 126.4, 125.1, 51.4, 46.5, 24.4; HRMS (EI) m/z calcd for C30H25NO [M]+ 415.1936, found 415.1935.

3.15. 1-(4-((4-Methoxyphenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ab/4ea)

Yield 82% (52.9 mg, 0.119 mmol) from 2a with 3b, and yield 72% (42.1 mg, 0.095 mmol) from 2e with 3a; colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.35–7.28 (m, 6H), 7.24–7.20 (m, 4H), 7.18–7.14 (m, 4H), 7.06 (t, 1H, J = 7.5 Hz), 6.95 (t, 1H, J = 7.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 5.71 (s, 1H), 5.02–4.93 (m, 2H), 3.78 (s, 3H), 1.51 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 158.1, 142.9, 138.3, 137.7, 135.3, 134.5, 132.3, 130.4 (2C), 129.7, 129.3 (3C), 129.2, 128.8, 128.7, 128.3 (3C), 127.6, 127.2, 126.4, 126.3, 125.1, 113.7 (2C), 55.3, 50.6, 46.5, 24.4; HRMS (EI) m/z calcd for C31H27NO2 [M]+ 445.2042, found 445.2041.

3.16. 1-(4-((3,5-Dimethoxyphenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ac)

Yield 98% (66.9 mg, 0.141 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.36–7.31 (m, 5H), 7.27–7.22 (m, 5H), 7.18–7.15 (m, 2H), 7.07 (t, 1H, J = 7.5 Hz), 6.97 (t, 1H, J = 7.5 Hz), 6.42 (s, 2H), 6.31 (s, 1H), 5.68 (s, 1H), 5.03 (d, 1H, J = 13.5 Hz), 4.93 (d, 1H, J = 13.5 Hz), 3.68 (s, 6H), 1.56 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 160.7, 145.0, 142.3, 138.5, 137.7, 135.3, 132.2, 129.7 (2C), 129.4 (2C), 129.0, 128.9, 128.7 (2C), 128.3 (2C), 127.6 (2C), 127.2, 126.4 (2C), 125.0, 107.9 (2C), 98.1, 55.3 (2C), 51.5, 46.5, 24.4; HRMS (EI) m/z calcd for C32H29NO3 [M]+ 475.2147, found 475.2148.

3.17. 1-(4-((3,4-Dimethoxyphenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ad)

Yield 86% (57.2 mg, 0.120 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.36–7.30 (m, 4H), 7.26–7.21 (m, 7H), 7.18–7.14 (m, 1H), 7.07 (t, 1H, J = 8.0 Hz), 6.96 (t, 1H, J = 7.5 Hz), 6.83 (d, 1H, J = 8.5 Hz), 6.78 (d, 1H, J = 8.5 Hz), 6.73 (s, 1H), 5.69 (s, 1H), 5.04 (d, 1H, J = 13.5 Hz), 4.90 (d, 1H, J = 13.5 Hz), 3.86 (s, 3H), 3.69 (s, 3H), 1.55 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 148.7, 147.6, 142.8, 138.3, 137.7, 135.4, 134.9, 132.3, 129.6 (2C), 129.2 (2C), 128.9, 128.7 (2C), 128.3 (2C), 127.6 (2C), 127.2, 126.5, 126.4, 125.1, 121.7, 112.8, 110.9, 56.0, 55.9, 51.0, 46.5, 24.4; HRMS (EI) m/z calcd for C32H29NO3 [M]+ 475.2147, found 475.2148.

3.18. 1-(4-((4-(tert-Butyl)phenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ae)

Yield 92% (63.3 mg, 0.134 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.34–7.30 (m, 5H), 7.28–7.24 (m, 2H), 7.22–7.20 (m, 5H), 7.16 (d, 4H, J = 8.5 Hz), 7.06 (t, 1H, J = 7.5 Hz), 6.95 (t, 1H, J = 7.5 Hz), 5.73 (s, 1H), 5.09 (d, 1H, J = 14.0 Hz), 4.88 (d, 1H, J = 14.0 Hz), 1.52 (s, 3H), 1.30 (s, 9H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 149.2, 142.9, 139.2, 138.3, 137.8, 135.3, 132.3, 129.7 (2C), 129.3 (2C), 129.2, 129.0 (2C), 128.8, 128.7 (2C), 128.2 (2C), 127.7, 127.1, 126.5, 126.3, 125.2 (2C), 125.0, 50.9, 46.5, 34.5, 31.5 (3C), 24.4; HRMS (EI) m/z calcd for C34H33NO [M]+ 471.2562, found 471.2559.

3.19. 1-(4-((4-Chlorophenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4af)

Yield 96% (62.0 mg, 0.138 mmol); white solid; mp 205.5–233.9 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.33–7.31 (m, 5H), 7.27–7.20 (m, 7H), 7.17–7.14 (m, 4H), 7.08 (t, 1H, J = 8.0 Hz), 6.96 (t, 1H, J = 8.0 Hz), 5.71 (s, 1H), 5.05 (d, 1H, J = 14.0 Hz), 4.90 (d, 1H, J = 14.0 Hz), 1.50 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.26, 142.1, 141.2, 137.5, 135.3, 132.2, 131.9, 130.7 (2C), 129.6, 129.2 (2C), 129.0, 128.8, 128.6 (2C), 128.5 (2C), 128.4, 127.4, 127.3 (2C), 126.7 (2C), 126.5, 125.2, 50.9, 46.5, 24.4; HRMS (EI) m/z calcd for C30H24NOCl [M]+ 449.1546, found 449.1546.

3.20. 1-(4-((4-Fluorophenyl)(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ag/4da)

Yield 81% (50.8 mg, 0.117 mmol) from 2a with 3g, and yield 66% (46.2 mg, 0.107 mmol) from 2d with 3a; white solid; mp 154.9–200.0 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.35–7.31 (m, 5H), 7.28–7.24 (m, 3H), 7.22–7.16 (m, 5H), 7.07 (t, 1H, J = 7.5 Hz), 6.98–6.96 (m, 4H), 5.72 (s, 1H), 5.07 (d, 1H, J = 14.0 Hz), 4.89 (d, 1H, J = 14.0 Hz), 1.51 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.2, 161.3 (d, J = 244 Hz), 142.4, 138.6, 138.3, 137.6, 135.3, 132.0, 130.8 (2C, d, J = 7.9 Hz), 129.6, 129.2 (2C), 129.0, 128.8, 128.7, 128.5 (2C), 127.4 (2C), 127.3, 126.6 (2C), 126.5, 125.2, 115.1 (2C, d, J = 21.7 Hz), 50.7, 46.5, 24.4; HRMS (EI) m/z calcd for C30H24NOF [M]+ 433.1842, found 433.1846.

3.21. 1-(4-((2-Acetyl-3-phenyl-1,2-dihydroisoquinolin-4-yl)(phenyl)methyl)phenyl)ethan-1-one (4ah)

Yield 85% (55.5 mg, 0.121 mmol); white solid; mp 205.9–220.7 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.83 (d, 3H, J = 8.5 Hz), 7.33–7.29 (m, 11H), 7.16 (t, 2H, J = 7.0 Hz), 7.07 (t, 1H, J = 7.5 Hz), 6.95 (t, 1H, J = 7.5 Hz), 5.79 (s, 1H), 5.10 (d, 1H, J = 14.0 Hz), 4.88 (d, 1H, J = 14.0 Hz), 2.55 (s, 3H), 1.51 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 197.8, 171.2, 148.4, 141.7, 139.0, 137.5, 135.5, 135.3, 131.9, 129.7, 129.6 (2C), 129.4 (2C), 129.3, 129.2, 129.1, 128.8, 128.6 (2C), 128.4 (2C), 128.2, 127.4, 127.2, 126.8, 126.6, 125.2, 51.5, 46.5, 26.7, 24.4; HRMS (EI) m/z calcd for C32H27NO2 [M]+ 457.2042, found 457.2037.

3.22. 1-(4-(Naphthalen-1-yl(phenyl)methyl)-3-phenylisoquinolin-2(1H)-yl)ethan-1-one (4ai)

Yield 67% (45.3 mg, 0.0973 mmol); colorless oil; 1H-NMR (500 MHz, CDCl3): δ 7.81 (d, 2H, J = 8.0 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.54–7.51 (m, 4H), 7.41–7.37 (m, 4H), 7.28–7.17 (m, 3H), 7.10 (d, 2H, J = 7.0 Hz), 7.01 (t, 2H, J = 7.5 Hz), 6.92 (t, 2H, J = 7.0 Hz), 6.18 (s, 1H), 5.00 (d, 1H, J = 13.0 Hz), 4.89 (d, 1H, J = 13.0 Hz), 1.50 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.3, 143.5, 139.1, 138.3, 137.8, 135.4, 133.9, 132.5, 132.1, 129.7, 129.6 (2C), 129.5, 129.0, 128.9 (2C), 128.7 (2C), 128.5, 128.4, 127.9, 127.8, 127.1, 126.4 (2C), 125.8, 125.5, 125.2 (2C), 125.0, 124.5, 49.5, 46.4, 24.3; HRMS (EI) m/z calcd for C34H27NO [M]+ 465.2093, found 465.2096

3.23. 1-(4-Benzhydryl-3-(4-fluorophenyl)isoquinolin-2(1H)-yl)ethan-1-one (4ba)

Yield 55% (42.2 mg, 0.0973 mmol); white solid; mp 211.4–229.1 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.32–7.29 (m, 2H), 7.27–7.22 (m, 9H), 7.20–7.14 (m, 3H), 7.06 (t, 1H, J = 7.5 Hz), 7.00 (t, 2H, J = 8.0 Hz), 6.95 (t, 1H, J = 7.5 Hz), 5.69 (s, 1H), 4.97 (s, 2H), 1.53 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.2, 162.8 (d, J = 250 Hz), 142.4 (2C), 137.4, 135.3, 133.7, 132.1, 131.5 (2C), 129.3 (3C), 129.2 (2C, d, J = 7.9 Hz), 128.4 (3C), 127.6 (2C), 127.3, 126.6 (3C), 125.1, 115.9 (2C, d, J = 21.6 Hz), 51.4, 46.5, 24.5; HRMS (EI) m/z calcd for C30H24NOF [M]+ 433.1842, found 433.1843.

3.24. 1-(4-Benzhydryl-3-(benzo[d][1,3]dioxol-5-yl)isoquinolin-2(1H)-yl)ethan-1-one (4ca)

Yield 80% (67.1 mg, 0.146 mmol); white solid; mp 183.1–250.2 °C (CHCl3); 1H-NMR (500 MHz, CDCl3): δ 7.26–7.24 (m, 8H), 7.19–7.16 (m, 3H), 7.13 (d, 1H, J = 7.0 Hz), 7.03 (t, 1H, J = 7.0 Hz), 6.93 (t, 1H, J = 7.0 Hz), 6.83–6.80 (m, 2H), 6.71 (d, 1H, J = 8.0 Hz), 5.95 (s, 2H), 5.79 (s, 1H), 4.94 (s, 2H), 1.60 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 171.4, 148.1, 147.9, 142.5 (2C), 138.0, 135.2, 132.3, 131.7, 131.4 (2C), 129.4 (3C), 128.3 (3C), 127.5 (2C), 127.1, 126.4 (3C), 125.0, 123.8, 109.8, 108.4, 101.5, 51.5, 46.5, 24.4; HRMS (EI) m/z calcd for C31H25NO3 [M]+ 459.1834, found 459.1835.

4. Conclusions

The studies described above resulted in the synthesis of substituted 1,2-dihydroisoquinolines through a palladium-catalyzed cascade cyclization–coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids. Under the optimum reaction conditions, using 10 mol% of Pd(OAc)2, 20 mol% of P(o-tolyl)3, and 5 equivalents of NaOH in dioxane/H2O (4/1) at 80 °C, a variety of highly substituted 1,2-dihydroisoquinolines were concisely obtained. Since the allenamides, as reaction substrates, were prepared from readily available propargylamines in one step, this reaction could provide a useful methodology for the synthesis of 1,2-dihydroisoquinoline derivatives. 1H-NMR and 13C-NMR characterization of all our synthetic compounds supported the identified structures, the details of which can be found in the Supporting Information section.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29122917/s1, Copies of the 1H NMR and 13C NMR spectra for all new compounds.

Author Contributions

Conceptualization, M.Y.; formal analysis, R.I. and S.S.; investigation, R.I.; resources, M.Y.; data curation, R.I. and S.S.; writing—original draft preparation, M.Y.; writing—review and editing, M.Y. and S.S. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported in part by a Grant-in-Aid for Scientific Research (C), grant number JP23K06042, from the Japan Society for the Promotion of Science (JSPS) and Transformative Research Areas (A); and grant number JP22H05338 from the Ministry of Education, Culture, Sports, Science & Technology (MEXT).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author/s.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 02917 g001
Figure 1. Structure of biologically active molecules containing 1,2-dihydroisoquinoline moiety.
Figure 1. Structure of biologically active molecules containing 1,2-dihydroisoquinoline moiety.
Molecules 29 02917 g001
Molecules 29 02917 sch001
Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.
Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.
Molecules 29 02917 sch001
Molecules 29 02917 sch002
Scheme 2. Synthesis of trisubstituted allenamides.
Scheme 2. Synthesis of trisubstituted allenamides.
Molecules 29 02917 sch002
Molecules 29 02917 g002
Figure 2. Reactions using allenamide 2a with various arylboronic acids 3.
Figure 2. Reactions using allenamide 2a with various arylboronic acids 3.
Molecules 29 02917 g002
Molecules 29 02917 g003
Figure 3. Reactions using various allenamides 2 with phenylboronic acid (3a).
Figure 3. Reactions using various allenamides 2 with phenylboronic acid (3a).
Molecules 29 02917 g003
Molecules 29 02917 sch003
Scheme 3. Proposed mechanism for the production of 1,2-dihydroisoquinoline 4.
Scheme 3. Proposed mechanism for the production of 1,2-dihydroisoquinoline 4.
Molecules 29 02917 sch003
Table 1. Initial attempts using allenamide 2a with phenylboronic acid (3a).
Table 1. Initial attempts using allenamide 2a with phenylboronic acid (3a).
Molecules 29 02917 i001
EntryPalladium CatalystPhosphine LigandTemperature (°C)Yield (%)
1Pd(OAc)2 (5 mol%)P(o-tolyl)3 (10 mol%)8078
2Pd(OAc)2 (5 mol%)P(o-tolyl)3 (20 mol%)8085
3Pd(OAc)2 (10 mol%)P(o-tolyl)3 (20 mol%)8088
4Pd(OAc)2 (10 mol%)P(o-tolyl)3 (20 mol%)5086
5Pd(OAc)2 (10 mol%)P(o-tolyl)3 (20 mol%)2530
6Pd(OAc)2 (10 mol%)P(o-tolyl)3 (20 mol%)10075
7Pd(OAc)2 (10 mol%)PPh3 (20 mol%)8070
8Pd(OAc)2 (10 mol%)PCy3 (20 mol%)8019
9Pd(OAc)2 (10 mol%)DPPE (10 mol%)8047
10Pd(OAc)2 (10 mol%)DPPF (10 mol%)8070
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MDPI and ACS Style

Yoshida, M.; Imaji, R.; Shiomi, S. Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids. Molecules 2024, 29, 2917. https://doi.org/10.3390/molecules29122917

AMA Style

Yoshida M, Imaji R, Shiomi S. Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids. Molecules. 2024; 29(12):2917. https://doi.org/10.3390/molecules29122917

Chicago/Turabian Style

Yoshida, Masahiro, Ryunosuke Imaji, and Shinya Shiomi. 2024. "Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids" Molecules 29, no. 12: 2917. https://doi.org/10.3390/molecules29122917

APA Style

Yoshida, M., Imaji, R., & Shiomi, S. (2024). Synthesis of Substituted 1,2-Dihydroisoquinolines by Palladium-Catalyzed Cascade Cyclization–Coupling of Trisubstituted Allenamides with Arylboronic Acids. Molecules, 29(12), 2917. https://doi.org/10.3390/molecules29122917

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