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

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07 June 2024

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07 June 2024

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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. In this study, a palladium-catalyzed cascade cyclization-coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids is described. The reaction proceeds via intramolecular cyclization, followed by transmetallation with the arylboronic acid of the resulting allylpalladium intermediate. A variety of 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.
Keywords: 
allenamide
;  
cascade reaction
;  
palladium catalyst
;  
cyclization
;  
coupling
;  
organoboronic compound
;  
1
;  
2-dihydroisoquinoline
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

supplementary.pdf (1.89MB )

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 a 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 in synthesizing polysubstituted allenamides. Recently, we reported a facile synthesis of trisubstituted allenamides via N-acetylation followed by DBU-promoted isomerization, where various substituted allenamides can be 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. Herein, we describe a palladium-catalyzed cascade cyclization-coupling of trisubstituted allenamides containing a bromoaryl moiety with arylboronic acids, concisely yielding a variety of substituted 1,2-dihydroisoquinolines (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 arylaldehyde, monosubstituted alkyne and o-bromobenzyl amine gave the propargylamines 1a–1e, which were subjected to the reaction with acetic anhydride and DBU [38], according to our procedure, 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, 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 76% yield when the reaction temperature was raised to 100 ºC (entry 6). The product was produced in 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 (Table 2). When 4-methoxyphenylboronic acid (3b) was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ab was obtained in 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 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 85% yield. When 1-naphtylboronic acid (3i) was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ai was produced in 67% yield.
Table 2. Reactions using allenamide 2a with various arylboronic acids 3.
Table 2. Reactions using allenamide 2a with various arylboronic acids 3.
Preprints 108639 i002
Table 2. b–2e with various substituents and phenylboronic acid (3a) are summarized in Table 3. When the substrate 2b, having a 4-fluorophenyl group at the 1-position, was subjected to the reaction, the corresponding 1,2-dihydroisoquinoline 4ba was obtained in 55% yield. The reaction of allenamide 2c, which have a 1,3-benzodioxole moiety, proceeded to afford the cyclized product 4ca in 80% yield. The substrates 2d and 2e, containing a 4-fluoro- and 4-methoxyphenyl group at the 3-posion, also reacted with 3a to produce the corresponding substituted products 4da (4ag) and 4ea (4ab) in 66% and 72% yields, respectively.
Table 3. Reactions using various allenamides 2 with phenylboronic acid (3a).
Table 3. Reactions using various allenamides 2 with phenylboronic acid (3a).
Preprints 108639 i003
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. This is 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 occurs, forming hydroxypalladium species D [39]. This species undergoes 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 Merck 60F245). 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., Inc.). NMR spectra were recorded on Bruker AVANCED III HD-500 (1H: 500 MHz, 13C: 125 MHz) spectrometer using tetramethylsilane (1H NMR at 0.00 ppm) and CDCl3 (13C NMR at 77.16) as a reference standard. Chemical sifts 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).

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) was added phenylacetylene (766 mg, 7.50 mmol), 2-bromobenzylamine (1.40 g, 7.50 mmol) and CuBr (143 mg, 1.00 mmol) at rt under argon atmosphere. The reaction mixture was then stirred under reflux condition for 2 h. The reaction was quenched with sat. NH4Cl. The aq. mixture was extracted with AcOEt. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by 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%; 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%; 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%; 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%; 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%; 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) were added Ac2O (0.40 mL, 4.18 mmol) and DBU (0.62 mL, 4.18 mmol) at 0 °C under 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 brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by 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%; 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%; 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%; 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%; 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%; 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) were added 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) at rt under argon atmosphere. The reaction mixture was stirred for 3 h at 80 °C. The reaction mixture was added water and extracted with AcOEt. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (hexane/AcOEt = 7/1) to afford the 1,2-dihydroisoquinoline 4aa (53.2 mg, 88%).

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

Yield 88%; 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% from 2a with 3b, and yield 72% 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%; 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%; 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%; 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%; 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% from 2a with 3g, and yield 66% 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%; 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%; 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%; 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%; 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 have 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. A variety of 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.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org, 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) 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

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not applicable.

References

  1. Bentley, K.W. The Isoquinoline Alkaloids, vol. 1; Harwood Academic Publishers: Australia, 1998. [Google Scholar]
  2. Scholz, D.; Schmidt, H.; Prieschl, E.E.; Csonga, R.; Scheirer, W.; Weber, V.; Lembachner, A.; Seidl, G.; Werner, G.; Mayer, P.; Baumruker, T. Inhibition of FcεRI-Mediated Activation of Mast Cells by 2,3,4-Trihydropyrimidino[2,1-a]Isoquinolines. J. Med. Chem. 1998, 1998. 41, 1050–1059. [Google Scholar] [CrossRef]
  3. Ramesh, P.; Reddy, N.S.; Venkateswarlu, Y. A New 1,2-Dihydroisoquinoline from the Sponge Petrosiasimilis. J. Nat. Prod. 1999, 62, 780–781. [Google Scholar] [CrossRef] [PubMed]
  4. Deore, R.R.; Chen, G.S.; Chen, C.-S.; Chang, P.-T.; Chuang, M.-H.; Chern, T.-R.; Wang, H.-C.; Chern, J.-W. 2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid with inbuilt β-N-hydroxy-γ-keto-acid pharmacophore as HCV NS5B polymerase inhibitors. Curr. Med. Chem. 2012, 19, 613–624. [Google Scholar] [CrossRef]
  5. Inoue, K.; Kulsum, U.; Chowdhury, S.A.; Fujisawa, S.; Ishihara, M.; Yokoe, I.; Sakagami, Hi. Tumor-specific Cytotoxicity and Apoptosis-inducing Activity of Berberines. Anticancer Res. 2005, 25, 4053–4059. [Google Scholar] [PubMed]
  6. Gonzalez, J.F.; de la Cuesta, E.; Avendano, C. Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino-[3,2-b]-3-benzazocines. Bioorg. Med. Chem. 2007, 15, 112–118. [Google Scholar] [CrossRef] [PubMed]
  7. Mahmoud, S.; Sheha, M.; Aboul-Fadl, T.; Farag, H. 1,2-Dihydroisoquinoline-N-acetic Acid Derivatives as New Carriers for Brain-specific Delivery II: Delivery of Phenethylamine as Model Drug. Arch. Pharm. Pharm. Med. Chem. 2003, 336, 258–263. [Google Scholar] [CrossRef]
  8. Tandon, V.; Urvashi; Yadav, P.; Sur, S.; Abbat, S.; Tiwari, V.; Hewer, R.; Papathanasopoulos, M.A.; Raja, R.; Banerjea, A.C.; Verma, A.K.; Kukreti, S.; Bharatam, P.V. Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors. ACS Med. Chem. Lett. 2015, 6, 1065–1070. [Google Scholar] [CrossRef]
  9. Hajinasiri, R. A review of the synthesis of 1,2-dihydroisoquinoline, [2,1-a] isoquinoline and [5,1-a] isoquinoline since 2006. Tetrahedron 2022, 104, 132576. [Google Scholar] [CrossRef]
  10. Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Synthesis of 1,2-dihydroisoquinolines via the reaction of ortho-alkynylarylimines with bis-π-allylpalladium. Tetrahedron Lett. 2004, 4, 7339–7341. [Google Scholar] [CrossRef]
  11. Asao, N.; Yudha S, S.; Nogami, T.; Yamamoto, Y. Direct Mannich and Nitro-Mannich Reactions with Non-Activated Imines: AgOTf-Catalyzed Addition of Pronucleophiles to ortho-Alkynylaryl Aldimines Leading to 1,2-Dihydroisoquinolines. Angew. Chem. Int. Ed. 2005, 44, 5526–5528. [Google Scholar] [CrossRef]
  12. Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. Concise Synthesis of 1,2-Dihydroisoquinolines and 1H-Isochromenes by Carbophilic Lewis Acid-Catalyzed Tandem Nucleophilic Addition and Cyclization of 2-(1-Alkynyl)arylaldimines and 2-(1-Alkynyl)arylaldehydes. J. Org. Chem. 2007, 72, 4462–4468. [Google Scholar] [CrossRef] [PubMed]
  13. Su, S.; Porco Jr., J.A. 1,2-Dihydroisoquinolines as Templates for Cascade Reactions To Access Isoquinoline Alkaloid Frameworks. Org. Lett. 2007, 9, 4983–4986. [Google Scholar] [CrossRef] [PubMed]
  14. Chen, Z.; Yang, X.; Wu, J. AgOTf-catalyzed tandem reaction of N’-(2-alkynylbenzylidene)hydrazide with alkyne. Chem. Commun. 2009, 3469–3471. [Google Scholar] [CrossRef] [PubMed]
  15. Guo, Z.; Cai, M.; Jiang, J.; Yang, L.; Hu, W. Rh2(OAc)4-AgOTf Cooperative Catalysis in Cyclization/Three-Component Reactions for Concise Synthesis of 1,2-Dihydroisoquinolines. Org. Lett. 2010, 12, 652–655. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, M.; Zhang, H.-J.; Ruan, W.; Wen, T.-B. Construction of Isoquinolin-1(2H)-ones by Copper-Catalyzed Tandem Reactions of 2-(1-Alkynyl)benzaldimines with Water. Eur. J. Org. Chem. 2015, 5914–5918. [Google Scholar] [CrossRef]
  17. Chaudhari, T.Y.; Ginotra, S.K.; Yadav, P.; Kumar, G.; Tandon, V. Regioselective synthesis of functionalized dihydroisoquinolines from: O -alkynylarylaldimines via the Reformatsky reaction. Org. Biomol. Chem. 2016, 14, 9896–9906. [Google Scholar] [CrossRef] [PubMed]
  18. Gao, Y.-N.; Shi, F.-C.; Xu, Q.; Shi, M. Enantioselective Synthesis of Isoquinolines: Merging Chiral-Phosphine and Gold Catalysis. Chem. Eur J. 2016, 22, 6803–6807. [Google Scholar] [CrossRef] [PubMed]
  19. De Abreu, M.; Tangm, Y.; Brachet, E.; Selkti, M.; Michelet, V.; Belmony, P. Silver-catalyzed tandem cycloisomerization/hydroarylation reactions and mechanistic investigations for an efficient access to 1,2-dihydroisoquinolines. Org. Biomol. Chem. 2021, 19, 1037–1046. [Google Scholar] [CrossRef] [PubMed]
  20. Wu, Y.-J.; Chen, J.-H.; Teng, M.-Y.; Li, X.; Jiang, T.-Y.; Huang, F.-R.; Yao, Q.-J.; Shi, B.-F. Cobalt-Catalyzed Enantioselective C-H Annulation of Benzylamines with Alkynes: Application to the Modular and Asymmetric Syntheses of Bioactive Molecules. J. Am. Chem. Soc. 2023, 145, 24499–24505. [Google Scholar] [CrossRef]
  21. Seoane-Carabel, F.; Alonso-Marañón, L.; Sarandeses, L.A.; Sestelo, J.P. Synthesis of 1H-Isochromenes and 1,2-Dihydroisoquinolines by Indium(III)-Catalyzed Cycloisomerization of ortho-(Alkynyl)benzyl Derivatives. Synthesis 2023, 55, 1714–1723. [Google Scholar]
  22. Umeda, R.; Ishida, T.; Mori, S.; Yashima, H.; Yajima, T.; Osaka, I.; Takata, R.; Nishiyama, Y. Rhenium-catalyzed synthetic method of 1,2-dihydroisoquinolines and isoquinolines by the intramolecular cyclization of 2-alkynylaldimines or 2-alkynylbenzylamines. Tetrahedron 2024, 154, 133854. [Google Scholar] [CrossRef]
  23. Wei, L.L.; Xiong, H.; Hsung, R.P. The Emergence of Allenamides in Organic Synthesis. Acc. Chem. Res. 2003, 36, 773–782. [Google Scholar] [CrossRef] [PubMed]
  24. Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R.P. Allenamides: A Powerful and Versatile Building Block in Organic Synthesis. Chem. Rev. 2013, 113, 4862–4904. [Google Scholar] [CrossRef] [PubMed]
  25. Braun, M.-G.; Katcher, M.H.; Doyle, A.G. Carbofluorination via a palladium-catalyzed cascade reaction. Chem. Sci. 2013, 4, 1216–1220. [Google Scholar] [CrossRef]
  26. Xiong, W.; Cheng, R.; Wu, B.; Wu, W.; Qi, C.; Jiang, H. Palladium-catalyzed regioselective cascade reaction of carbon dioxide, amines and allenes for the synthesis of functionalized carbamates. Sci. China: Chem. 2020, 63, 331–335. [Google Scholar] [CrossRef]
  27. Higuchi, Y.; Mita, T.; Sato, Y. Palladium-Catalyzed Intramolecular Arylative Carboxylation of Allenes with CO2 for the Construction of 3-Substituted Indole-2-carboxylic Acids. Org. Lett. 2017, 19, 2710–2713. [Google Scholar] [CrossRef] [PubMed]
  28. Zhu, X.; Li, R.; Yao, H.; Lin, A. Palladium-Catalyzed Allenamide Carbopalladation/Allylation with Active Methine Compounds. Org. Lett. 2021, 23, 4630–4634. [Google Scholar] [CrossRef] [PubMed]
  29. Wang, D.-C.; Yang, T.-T.; Qu, G.-R.; Guo, H.-M. Substrate-Dependent Regioselectivity: Pd/PTC Cooperatively Catalyzed Domino Heck/Allylation of Allenamides with α-Carbon of Carbonyl Compounds. J. Org. Chem. 2022, 87, 14284–14298. [Google Scholar] [CrossRef] [PubMed]
  30. Hédouin, J.; Carpentier, V.; Renard, R.M.Q.; Schneider, C.; Gillaizeau, I.; Hoarau, C. Regioselective Pd-Catalyzed Carbopalladation/Decarboxylative Allylic Alkynylation of ortho-Iodoallenamides with Alkynyl Carboxylic Acids. J. Org. Chem. 2019, 84, 10535–10545. [Google Scholar] [CrossRef]
  31. Shen, Q.-W.; Wen, W.; Guo, Q.-X. Chiral Aldehyde–Palladium Catalysis Enables Asymmetric Synthesis of α-Alkyl Tryptophans via Cascade Heck-Alkylation Reaction. Org. Lett. 2023, 25, 3163–3167. [Google Scholar] [CrossRef]
  32. Grigg, R.; Sansano, J.M.; Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D. Palladium catalysed tandem cyclisation-anion capture processes. Part 3. Organoboron anion transfer agents. Tetrahedron 1997, 53, 11803–11826. [Google Scholar] [CrossRef]
  33. Fuwa, H.; Sasaki, M. A strategy for the synthesis of 2,3-disubstituted indoles starting from N-(o-halophenyl)allenamides. Org. Biomol. Chem. 2007, 5, 2214–2218. [Google Scholar] [CrossRef] [PubMed]
  34. Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Palladium-Catalyzed Multistep Reactions Involving Ring Closure of 2-Iodophenoxyallenes and Ring Opening of Bicyclic Alkenes. Org. Lett. 2006, 8, 621–623. [Google Scholar] [CrossRef] [PubMed]
  35. Chen, X.; Qiu, G.; Liu, R.; Chen, D.; Chen, Z. Divergent oriented synthesis (DOS) of aza-heterocyclic amides through palladium-catalyzed ketenimination of 2-iodo-N-(propa-1,2-dien-1-yl)anilines. Org. Chem. Front. 2020, 7, 890–895. [Google Scholar] [CrossRef]
  36. Hédouin, J.; Schneider, C.; Gillaizeau, I.; Hoarau, C. ; Palladium-Catalyzed Domino Allenamide Carbopalladation/Direct C–H Allylation of Heteroarenes: Synthesis of Primprinine and Papaverine Analogues. Org. Lett. 2018, 20, 6027–6032. [Google Scholar] [CrossRef] [PubMed]
  37. Xue, Q.; Pu, Y.; Zhao, H.; Xie, X.; Zhang, H.; Wang, J.; Yan, L.; Shang, Y. Palladium-catalysed aryl/monofluoroalkylation of allenamides: access to fluoroalkyl indoles and isoquinolones. Chem. Commun. 2024, 60, 3794–3797. [Google Scholar] [CrossRef] [PubMed]
  38. Hirokane, T.; Watanabe, S.; Matsumoto, K.; Yoshida, M. A facile synthesis of trisubstituted allenamides by DBU-promoted isomerization of propargylamides. Tetrahedron Lett. 2020, 61, 152146. [Google Scholar] [CrossRef]
  39. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. [Google Scholar] [CrossRef]
Preprints 108639 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.
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Preprints 108639 sch001
Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.
Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.
Preprints 108639 sch001
Preprints 108639 sch002
Scheme 2. Synthesis of trisubstituted allenamides.
Scheme 2. Synthesis of trisubstituted allenamides.
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Preprints 108639 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.
Preprints 108639 sch003
Table 1. Initial attempts using allenamide 2a with phenylboronic acid (3a).
Table 1. Initial attempts using allenamide 2a with phenylboronic acid (3a).
Preprints 108639 i001
Entry Palladium Catalyst Phosphine Ligand Temperature (°C) Yield (%)
1 Pd(OAc)2 (5 mol%) P(o-tolyl)3 (10 mol%) 80 78
2 Pd(OAc)2 (5 mol%) P(o-tolyl)3 (20 mol%) 80 85
3 Pd(OAc)2 (10 mol%) P(o-tolyl)3 (20 mol%) 80 88
4 Pd(OAc)2 (10 mol%) P(o-tolyl)3 (20 mol%) 50 86
5 Pd(OAc)2 (10 mol%) P(o-tolyl)3 (20 mol%) 25 30
6 Pd(OAc)2 (10 mol%) P(o-tolyl)3 (20 mol%) 100 75
7 Pd(OAc)2 (10 mol%) PPh3 (20 mol%) 80 70
8 Pd(OAc)2 (10 mol%) PCy3 (20 mol%) 80 19
9 Pd(OAc)2 (10 mol%) DPPE (10 mol%) 80 47
10 Pd(OAc)2 (10 mol%) DPPF (10 mol%) 80 70
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