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

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.

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 palladiumcatalyzed reaction of trisubstituted allenamides containing a o-bromoaryl moiety with arylboronic acids (Scheme 1, eq 3).
Molecules 2024, 29, x FOR PEER REVIEW 2 of 12 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). .Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.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). .Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.

Results and Discussion
Scheme 1. Palladium-catalyzed cyclization of allenamides and synthesis of allenamides.

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.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(otolyl)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).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/H 2 O (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 PPh 3 was used (entry 7), but the yield decreased to 19% when PCy 3 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).

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 Scheme 3. Proposed mechanism for the production of 1,2-dihydroisoquinoline 4.

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 60F 245 , 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 ( 1 H: 500 MHz, 13 C: 125 MHz) spectrometer (Bruker Corporation, Billerica, MA, USA) using tetramethylsilane ( 1 H NMR at 0.00 ppm) and CDCl 3 ( 13 C 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).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.NH 4 Cl.The aq. mixture was extracted with AcOEt.The organic layer was washed with brine, dried over MgSO 4 , 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%).To a solution of propargylamine 1a (314 mg, 0.835 mmol) in toluene (7 mL), Ac 2 O (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 MgSO 4 , 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%).

Conclusions
The studies described above resulted in the synthesis of substituted 1,2dihydroisoquinolines 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/H 2 O (4/1) at 80 • C, a variety of highly substituted 1,2dihydroisoquinolines 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. 1 H-NMR and 13 C-NMR characterization of all our synthetic compounds supported the identified structures, the details of which can be found in the Supporting Information section.

3. 1 .
General Procedure for the Three-Component Reaction of Arylaldehyde, Alkyne and Amine in Scheme 2: Synthesis of Propargylamine 1a