Protecting-Group-Free Synthesis of 1-Phenylisoquinolin-4-ols

Oct 24, 2017 - A protecting-group-free synthetic approach to 1-phenylisoquinolin-4-ols was developed by the intramolecular thermal cyclization of meth...
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Protecting-Group-Free Synthesis of 1‑Phenylisoquinolin-4-ols: Thermal Cyclization of Methyl 2‑[(Diphenylmethylidene)amino]acetates Ying-Hui Chen,† Chin-Hung Lai,‡ Kumaraswamy Sorra,§ and Ta-Hsien Chuang*,† †

School of Pharmacy, China Medical University, Taichung 40402, Taiwan Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung 40201, Taiwan § Medicinal Chemistry Laboratory, Gunapati Venkata Krishnareddy Biosciences Private Limited, Hyderabad 500076, India ‡

S Supporting Information *

ABSTRACT: A protecting-group-free synthetic approach to 1phenylisoquinolin-4-ols was developed by the intramolecular thermal cyclization of methyl 2-[(diphenylmethylidene)amino]acetates. R1 and R2 substituents were found to affect the required reaction temperatures, time, and yields of the cyclized products. The reactivity of the Schiff bases increased upon introduction of α-benzoyl and α-ester groups (R2). The cyclization yield also depended on the position of the R1 substituents on the phenyl groups. by bulky substituents (e.g., diphenyl, fluorenylidene, etc.).12 Herein, we disclose a concise strategy to construct isoquinolin4-ol systems via the pericyclic annulations of conjugated iminoketenes. We speculated that 1-phenylisoquinolin-4-ol derivatives 1 could be produced by the intramolecular electrocyclic reactions of (diphenylmethylidene)aminoketenes 2, generated in situ from methyl 2-[(diphenylmethylidene)amino]acetates 3 upon loss of methanol (Scheme 1).

I

soquinolines comprise many natural products and are important building blocks in pharmaceuticals.1 Over the past several decades, only a few methodologies have allowed access to isoquinolin-4-ol derivatives. The isomerization of isoquinoline N-oxides with p-toluenesulfonyl chloride, followed by hydrolysis,2 as well as the oxidation of dihydroisoquinolines3,4 are shortcuts to isoquinolin-4-ols if the isoquinoline starting materials are commercially available. Moreover, the most typical method to construct isoquinoline rings with a 4hydroxyl group is the Bischler−Napieralski cyclization of protected N-(2-oxo-2-phenylethyl)benzamides with ethylene glycol, followed by removal of the ketal-protecting group.5 In addition, isoquinolin-4-ols can also be synthesized from Ntoluenesulfonyl benzylaminoacetyl chlorides via intramolecular Friedel−Crafts cyclization and subsequent deprotection and aromatization.6 Recently, Wei and Zhang reported the Yb(OTf)3-catalyzed ring opening/Friedel−Crafts cyclization of N-protected aziridines, followed by elimination of ptoluenesulfonic acid under basic conditions, producing 1phenylisoquinolin-4-ols.7 Although these methods have been developed to synthesize isoquinolin-4-ol derivatives, a concise method that does not involve the use of protecting groups is still needed. Ketenes are highly reactive intermediates and have a wide range of uses, such as key intermediates in natural product synthesis8 and in the preparation of β-lactam antibacterial agents via Staudinger synthesis.9 A reactive cumulene CC O can be produced by the Wolff rearrangement of αdiazocarbonyl derivatives, dehalogenation of α-haloacetyl halides, dehydrohalogenation of acyl chlorides, or decomposition of ketene dimers, among other routes.8,10−13 Notably, ketenes can be stabilized by conjugation with double bonds and © 2017 American Chemical Society

Scheme 1. Strategy for Synthesis of Isoquinolin-4-ols 1

Initially, unsubstituted methyl 2-[(diphenylmethylidene)amino]acetate (3aI) was chosen as a model substrate to determine the feasibility of the intramolecular thermal cyclization. First, Schiff base 3aI, a possible methyleneaminoketene 2aI precursor, was synthesized by the transimination of a commercially available benzophenone imine (4a, R1 = H) with glycine methyl ester hydrochloride (5I, R2 = H) in 75% yield by the modified O’Donnell method.14 Schiff base 3aI was hydrolyzed during silica-gel column chromatography but could be purified by vacuum distillation. To our delight, a solution of 3aI in diphenyl ether afforded desired cyclization product 1aI Received: September 6, 2017 Published: October 24, 2017 12849

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

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The Journal of Organic Chemistry in 51% yield upon refluxing under N2 for 1 h. Additionally, the reaction was performed in refluxing diphenyl ether under a maximum power of 300 W for 50 min using a focused microwave reactor, but 1aI was obtained in lower yield (45%). Hence, conventional heating was selected over microwave heating in the following thermal cyclization. The preliminary results prompted us to design and prepare unsubstituted methyl 2-[(diphenylmethylidene)amino]-2-benzoylacetate (3aII, R2 = Bz) and dimethyl 2-[(diphenylmethylidene)amino]malonate (3aIII, R2 = CO2CH3) to investigate the effects of R2 on the thermal cyclization of 3 and expand the applications of the developed method. Similarly, transimination of 4a with methyl 2-amino-2benzoylacetate hydrochloride (5II,15 prepared from methyl 5phenyl-1,3-oxazole-4-carboxylate (8)16) or commercially available dimethyl aminomalonate hydrochloride (5III) gave the corresponding Schiff bases 3aII and 3aIII. Interestingly, 3aIII was stable on silica gel and could be obtained in 85% isolated yield, but 3aII was unstable under the chromatographic conditions. Hence, we attempted to use unpurified 3aII in the following reaction to simplify the process. Refluxing a solution of 3aII in diphenyl ether for 1 h gave 3-benzoyl-1phenylisoquinolin-4-ol 1aII in 72% yield. Moreover, the thermal cyclization of 3aIII was complete within 40 min under the same conditions and produced methyl 4-hydroxy-1phenylisoquinoline-3-carboxylate 1aIII (76%) as well as its decarboxylation derivative 1aI (6%). The thermal cyclization results revealed that the reactivity of Schiff bases 3aII and 3aIII was enhanced by the introduction of α-benzoyl or α-ester groups, po ssibly because t he ket en e mo iety in (diphenylmethylidene)aminoketene 2 could be activated by electron-withdrawing groups (Bz and CO2CH3), thus potentially facilitating the intramolecular electrocyclic reaction. The aforementioned examples encouraged us to further investigate the effects of R1 on the phenyl groups on the thermal cyclization of methyl 2-[(diphenylmethylidene)amino]acetates 3I−III. A series of Schiff bases 3bI−3fI, 3bII−3fII, and 3bIII−3fIII were synthesized using the strategy shown in Scheme 2. First, benzophenone imines 4b−f were prepared from the appropriate benzonitriles 6b−f and Grignard reagents 7b−f. Benzophenone imines 4b−f were hydrolyzed to the corresponding benzophenones during silica-gel chromatography; however, they could be easily purified by vacuum distillation. Transimination of 4b−f with 5I−III produced the corresponding Schiff bases 3bI−3fI (57−97% yields), 3bII−3fII,17 and 3bIII−3fIII (62−85% yields) in good yields. With Schiff bases 3bI−3fI, 3bII−3fII, and 3bIII−3fIII in hand, the thermal cyclization of 3 was investigated. The effects of the substituents on reaction temperature, time, and yield are summarized in Table 1. Unfortunately, upon refluxing a solution of 3bI, 3dI, or 3fI in diphenyl ether, the corresponding cyclized products 1bI, 1dI, and 1fI were not obtained (entries 2, 4, and 6). Additionally, when the Schiff base with 4′methylphenyl groups (3eI) was refluxed in diphenyl ether, 6methyl-1-(4-methylphenyl)isoquinolin-4-ol (1eI) could be obtained in 30% yield (entries 5). Notably, the thermal cyclization of 3cI, bearing 3′-methoxyphenyl groups on the imine double bond, was complete within 45 min and produced 1-phenylisoquinolin-4-ols 1cI and 1cI′ in a good combined yield (72 and 12%, respectively) (entry 3). The results could imply that the thermal cyclization of methyl 2[(diphenylmethylidene)amino]acetate 3I could be promoted

Scheme 2. Synthesis of Schiff Bases 3I, 3II, and 3III

by 3′-methoxy groups on the phenyl rings and could produce 7methoxy-1-(3-methoxyphenyl)isoquinolin-4-ol (1cI) in the best yield, in addition to minor steric isomer 1cI′, due to the greater steric hindrance at the C-2′ position. On the contrary, the thermal cyclization of 3I might be hindered due to the introduction of methoxyl or fluoro substituents at the C-2′ or C-4′ positions of the phenyl rings. A similar trend in R1 effects, albeit better yields, compared to those of the 3I series was observed in the thermal cyclizations of 3II (compare entries 1 and 7, entries 3 and 9, and entries 5 and 11). Moreover, even in the case of 3bII, 3dII, and 3fII bearing 2′-OCH3, 4′-OCH3, and 4′-F on the phenyl rings, respectively, their intramolecular electrocyclic reactions gave the corresponding 1-phenylisoquinolin-4-ols 1bII, 1dII, and 1fII in 23, 37, and 45% yields, respectively (entries 8, 10, and 12). Obviously, methyl 2-[(diphenylmethylidene)amino]acetates with conjugated α-benzoyl groups (3II) might be suitable methyleneaminoketene precursors and could facilitate the intramolecular electrocyclic reactions to produce 3-benzoyl1-phenylisoquinolin-4-ol derivatives (1II). Next, the thermal cyclizations of dimethyl 2[(diphenylmethylidene)amino]malonates 3III were investigated. The thermal cyclization of 3aIII could be performed at lower temperatures than 3aI and 3aII, and decarboxylation side product 1aI was not isolated at temperatures lower than 240 °C (entries 14−16). When the reaction was performed at 220 °C, 3aIII was obtained in the best yield (87%, entries 15). Hence, the thermal cyclizations of 3bIII−3fIII were conducted at 220 °C to evaluate the effects of R1 on the thermal cyclizations of 3III (entries 17−21). To our delight, the thermal cyclizations of 3cIII and 3eIII produced the corresponding methyl 4hydroxy-1-phenylisoquinoline-3-carboxylates 1cIII (91% yield, entry 18) and 1eIII (86% yield, entry 20) in excellent yields. Furthermore, as shown in entries 17, 19, and 21, Schiff bases 3bIII, 3dIII, and 3fIII with deactivating phenyl groups on the imine double bond gave the desired cyclic products 1bIII, 1dIII, and 1fIII in moderate yields (69, 67, and 67%, 12850

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

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The Journal of Organic Chemistry Table 1. Yields of Thermal Cycloadducts 1I, 1II, and 1III

entry

3

R2

temp (°C)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

3aI 3bI 3cI 3dI 3eI 3fI 3aII 3bII 3cII 3dII 3eII 3fII 3aIII 3aIII 3aIII 3aIII 3bIII 3cIII 3dIII 3eIII 3fIII

H H H H H H Bz Bz Bz Bz Bz Bz CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3

reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux reflux 240 220 200 220 220 220 220 220

time (h) 1 1 45 1 1 1 1 90 1 90 75 1 40 70 3 9 3 90 3 2 3

min

min min min min min

min

1dIII, and 1fIII). Therefore, methyl 2-[(diphenylmethylidene)amino]acetates with a methoxycarbonyl group at C-1 (3III) could be better precursors for 1-phenylisoquinolin-4-ols 1I via thermal cyclization, followed by hydrolysis and decarboxylation. Finally, unsymmetrical Schiff base 3gIII was also synthesized to determine the scope and limitations of the thermal cyclization. A mixture of geometric isomers (E)- and (Z)3gIII was obtained upon transimination of (3-methoxyphenyl)(4-methoxyphenyl)methanimine with 5III; the (E)-3gIII/(Z)3gIII ratio was 1/3 based on 2D NMR analysis. Surprisingly, heating geometric isomers 3gIII in diphenyl ether at 220 °C for 1 h gave regioselective cycloadducts 1gIII and 1gIII′ in 96 and 4% yields, respectively (eq 2). A remarkably high product

1 (%)a 1aI 51 1bI −b 1cI 72c 1dI −b 1eI 30 1fI −b 1aII 72d 1bII 23d 1cII 79d 1dII 37d 1eII 45d 1fII 45d 1aIII 76e 1aIII 74 1aIII 87 1aIII 81 1bIII 69 1cIII 91 1dIII 67 1eIII 86 1fIII 67

selectivity for this thermal cyclization could result from the isomerization of (E)- and (Z)-3gIII, which might occur after the proton transfer between the diester methine and benzhydryl carbon. In summary, we developed a synthetic strategy for the production of 1-phenylisoquinolin-4-ol derivatives via the thermal cyclization of Schiff bases 3. Notably, 3II and 3III could be better precursors than 3I to give the corresponding cycloadducts 1II and 1III probably via the intramolecular electrocyclic reaction of (diphenylmethylidene)aminoketenes. As such, C-3-unsubstituted 1-phenylisoquinolin-4-ol derivatives 1I could be obtained by the one-pot hydrolysis and decarboxylation of 1III, especially when 1-phenylisoquinolin4-ols 1I cannot be obtained in good yields from the thermal cyclization of 2-[(diphenylmethylidene)amino]acetates 3I.

a

Isolated yields of 1. bThe corresponding products were not isolated. 5-Methoxy-1-(3-methoxyphenyl)isoquinolin-4-ol (1cI′) was obtained in 12% yield. dCombined yield over two steps from 4 and 5II. e Decarboxylation product 1aI was produced in 6% yield. c

respectively). Based on the above results, methyl 2[(diphenylmethylidene)amino]acetates with conjugated αester groups 3III could be good methyleneaminoketene precursors and could be amenable to the intramolecular electrocyclic reaction, producing 1-phenylisoquinolin-4-ol derivatives in excellent to moderate yields. Moreover, methyl 4-hydroxy-1-phenylisoquinoline-3-carboxylates 1aIII−1fIII could be hydrolyzed and decarboxylated upon heating with 37% hydrochloric acid in 1,4-dioxane at 120 °C overnight to give the corresponding 1-phenylisoquinolin-4ols 1aI−1fI in 93−99% yields (eq 1). 1-Phenylisoquinolin-4-ols 1bI, 1dI, and 1fI could not be obtained by the thermal cyclization of Schiff bases 3bI, 3dI, and 3fI (entries 2, 4, and 6 in Table 1), but 1bI, 1dI, and 1fI could be produced by hydrolysis followed by decarboxylation from the corresponding methyl 4-hydroxy-1-phenylisoquinoline-3-carboxylates (1bIII,

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EXPERIMENTAL SECTION

All reagents and solvents were purchased from commercial sources and were used as received without further purification. Melting points (°C) were uncorrected. 1H, 13C, and 19F NMR spectra were recorded on 500 and 600 MHz FT-NMR spectrometers. All chemical shifts (δ) were expressed in parts per million using tetramethylsilane as the internal standard. IR spectra were reported in wave numbers (cm−1) using an FT-IR spectrometer. Mass spectra were recorded on a double-focusing spectrometer. High-resolution electron ionization mass spectra (HREI-MS) were recorded on a high-resolution E/B mass spectrometer using a double-focusing magnetic-sector mass analyzer and orbitrap mass analyzer for HREI-MS measurements. Elemental analyses were performed using a conventional elemental analyzer. Flash chromatography was performed on 230−400 mesh silica gel. 12851

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

Note

The Journal of Organic Chemistry

MHz, CDCl3) δ 2.39 (6H, s), 7.20 (4H, d, J = 8.0 Hz), 7.46 (4H, d, J = 8.0 Hz), 9.41 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 21.3 (2 × C), 128.3 (4 × C), 128.8 (4 × C), 136.7 (2 × C), 140.3 (2 × C), 178.0; IR (KBr) 3279, 1636 cm−1; ESIMS m/z (rel. int.) 210 (100, [M + H]+); HRESIMS m/z calcd for C15H16N 210.1277; found 210.1284 [M + H]+. Bis(4-fluorophenyl)methanimine (4f): 21 Yield 88% (1.912 g); yellow syrup; 1H NMR (500 MHz, CDCl3) δ 7.10 (4H, t, J = 8.5 Hz), 7.40−7.70 (4H, m), 9.63 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 115.4 (4 × C, d, J = 22 Hz), 130.4 (4 × C), 135.1, 164.1 (2 × C, d, J = 249 Hz), 176.1; 19F NMR (470 MHz, CDCl3) δ −109.6; IR (KBr) 3279, 1620 cm−1; ESIMS m/z (rel. int.) 218 (100, [M + H]+); HRESIMS m/z calcd for C13H10F2N 218.0776; found 218.0778 [M + H]+. General Procedure for the Preparation of Schiff Bases 3aI− 3fI, 3aII−3fII, and 3aIII−3fIII. A mixture of benzophenone imine 4a−f (5.0 mmol) and glycine methyl ester hydrochloride 5I−III (6.0 mmol) was refluxed overnight in DCM (50 mL) under N2. After being cooled, the reaction mixture was filtered by suction and the solid was rinsed with DCM (10 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with Et2O (50 mL), washed with water (3 × 10 mL), dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure to give the crude products 3I−III. 3aI−3fI and 3aIII−3fIII could be purified by Kügelrohr bulb-to-bulb distillation, recrystallization, or chromatography using silica gel to give the pure products. However, unpurified Schiff bases 3aII−3fII were used in the following reaction. The full spectral data of 3aI−3fI and 3aIII−3gIII are as follows. Methyl 2-[(Diphenylmethylidene)amino]acetate (3aI): 14 Purified by vacuum distillation (120 °C, 0.1 Torr); yield 75% (0.950 g); white solid, mp 42.0−42.5 °C; 1H NMR (500 MHz, CDCl3) δ 3.74 (3H, s), 4.22 (2H, s), 7.19 (2H, d, J = 7.5 Hz), 7.31−7.36 (2H, m), 7.38−7.43 (1H, m), 7.43−7.50 (3H, m), 7.64−7.69 (2H, m); 13C NMR (125 MHz, CDCl3) δ 51.9, 55.6, 127.6 (2 × C), 128.0 (2 × C), 128.6 (2 × C), 128.7 (2 × C), 128.8, 130.4, 135.9, 139.2, 171.0, 171.9; IR (KBr) 1744, 1605 cm−1; ESIMS m/z (rel. int.) 254 (100, [M + H]+); HRESIMS m/z calcd for C16H16NO2 254.1176; found 254.1180 [M + H]+. Methyl 2-{[Bis(2-methoxyphenyl)methylidene]amino}acetate (3bI): Purified by recrystallization from hexane−EtOAc; yield 57% (0.893 g); white granule, mp 73−73.5 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.53 (3H, s), 3.75 (3H, s), 3.81 (3H, s), 4.02 (2H, s), 6.81 (1H, d, J = 8.2 Hz), 6.88−6.95 (2H, m), 6.98 (1H, t, J = 7.5 Hz), 7.02 (1H, dd, J = 7.5, 1.7 Hz), 7.29−7.34 (2H, m), 7.61 (1H, dd, J = 7.5, 1.7 Hz); 13C NMR (125 MHz, CDCl3) δ 51.8, 55.3, 55.4, 55.7, 110.6, 112.0, 120.3, 120.6, 126.8, 128.3, 129.9, 130.4, 130.5, 131.2, 155.6, 157.6, 168.7, 171.5; IR (KBr) 1759, 1612 cm−1; ESIMS m/z (rel. int.) 313 (100, [M + H]+); HRESIMS m/z calcd for C18H20NO4 314.13868; found 314.13875 [M + H]+. Methyl 2-{[Bis(3-methoxyphenyl)methylidene]amino}acetate (3cI): Purified by recrystallization from hexane−EtOAc; yield 97% (1.520 g); pale yellow solid, mp 55−56 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.74 (3H, s), 3.78 (3H, s), 3.81 (3H, s), 4.22 (2H, s), 6.70 (1H, s), 6.74 (1H, d, J = 7.7 Hz), 6.94−6.98 (2H, m), 7.15 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.34−7.39 (2H, m); 13C NMR (125 MHz, CDCl3) δ 51.9, 55.2, 55.3, 55.5, 112.9, 113.2, 114.4, 116.7, 119.7, 121.8, 128.9, 129.8, 137.2, 140.4, 159.4, 159.7, 171.0, 171.5; IR (KBr) 1751, 1597 cm−1; ESIMS m/z (rel. int.) 314 (100, [M + H]+); HRESIMS m/z calcd for C18H20NO4 314.1387; found 314.1388 [M + H]+. Methyl 2-{[Bis(4-methoxyphenyl)methylidene]amino}acetate (3dI): Purified by vacuum distillation (120 °C, 0.1 Torr); yield 94% (1.473 g); pale yellow syrup; 1H NMR (500 MHz, CDCl3) δ 3.74 (3H, s), 3.82 (3H, s), 3.86 (3H, s), 4.22 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.60 (2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ 51.9, 55.3 (2 × C), 55.5, 113.3 (2 × C), 114.0 (2 × C), 128.2, 129.3 (2 × C), 130.5 (2 × C), 132.5, 159.8, 161.5, 171.2, 171.4; IR (KBr) 1744, 1605 cm−1; ESIMS m/z (rel. int.) 314 (100, [M + H]+); HRESIMS m/z calcd for C18H20NO4 314.1387; found 314.1395 [M + H]+.

Preparation of Methyl 2-Amino-2-benzoylacetate Hydrochloride (5II). Triethylamine (17.5 mL, 125.5 mmol) and 4(dimethylamino)pyridine (305.5 g, 2.5 mmol) were added to a mixture of methyl isocyanoacetate (95%, 5.22 g, 50.0 mmol) and benzoyl chloride (8.44 g, 60.0 mmol) in THF (60 mL) cooled in an ice bath. The reaction mixture was refluxed overnight under N2. After being cooled, the resulting mixture was filtered by suction and the solid was rinsed with EtOAc. The filtrate was diluted with EtOAc (200 mL), washed with water (3 × 20 mL), dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with hexane−EtOAc (5:1, v/v) as the eluent to give pure methyl 5-phenyl1,3-oxazole-4-carboxylate (8):16 Yield 94% (9.550 g); white solid, mp 79−80 °C; 1H NMR (500 MHz, CDCl3) δ 3.95 (3H, s), 7.45−7.51 (3H, m), 7.92 (1H, s), 8.06−8.11 (2H, m); 13C NMR (125 MHz, CDCl3) δ 52.2, 126.3, 126.5, 128.3 (2 × C), 128.4 (2 × C), 130.5, 148.9, 155.6, 162.3; IR (KBr) 1721, 1558 cm−1; EIMS (70 eV) m/z (rel. int.) 203 (100, M+), 172 (77), 135 (80); HREIMS (70 eV) m/z calcd for C11H9NO3 203.0582; found 203.0585 [M]+. Acetyl chloride (9.4 mL, 132.2 mol) was slowly added to a solution of 8 (3.05 g, 15.0 mmol) in MeOH (50 mL) cooled in an ice bath under N2. The mixture was allowed to reach room temperature and then refluxed overnight. After being cooled, the resulting mixture was evaporated under reduced pressure, and the residue was triturated with acetone (10 mL) at room temperature to give pure methyl 2-amino-2benzoylacetate hydrochloride (5II):15 Yield 85% (2.928 g); white solid, mp 164 °C (sublimation); 1H NMR (500 MHz, DMSO-d6) δ 3.66 (3H, s), 6.22 (1H, s), 7.60 (2H, t, J = 7.4 Hz), 7.75 (1H, t, J = 7.4 Hz), 8.15 (2H, d, J = 7.4 Hz), 9.28 (3H, br s); 13C NMR (125 MHz, DMSO-d6) δ 53.9, 56.9, 129.1 (2 × C), 129.9 (2 × C), 133.8, 135.2, 164.7, 189.6; IR (KBr) 3441, 2963, 1751, 1690 cm−1; ESIMS m/z (rel. int.) 194 (100, [M − Cl−]+); HRESIMS m/z calcd for C10H12NO3 194.0812; found 194.0820 [M − Cl−]+. General Procedure for the Preparation of Benzophenone Imines 4b−f. Commercially available phenylmagnesium bromide 7b−f (12.0 mmol) solution in THF was slowly added to a solution of benzonitrile 6b−f (10.0 mmol) in THF (15 mL) at room temperature. The reaction mixture was refluxed overnight under N2. After being cooled, the resulting mixture was quenched with ice water (10 mL) and diluted with EtOAc (50 mL). The EtOAc layer was washed with water (3 × 10 mL), dried with anhydrous MgSO4, filtered, and evaporated under reduced pressure. The residue was distilled (120 °C, 0.1 Torr) with a Kügelrohr bulb-to-bulb distillation apparatus to give the desired pure products 4b−f. The full spectral data of 4b−f are as follows. Bis(2-methoxyphenyl)methanimine (4b): 18 Yield 79% (1.906 g); pale yellow needles, mp 87.5−88 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.74 (6H, s), 6.91−6.96 (4H, m), 7.23−7.29 (2H, m), 7.34 (2H, td, J = 7.9, 1.8 Hz), 9.79 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 55.6 (2 × C), 111.3 (2 × C), 120.4 (2 × C), 129.2 (2 × C), 130.1 (2 × C), 130.4 (2 × C), 157.4 (2 × C), 174.2; IR (KBr) 3287, 1597 cm−1; ESIMS m/z (rel. int.) 242 (100, [M + H]+); HRESIMS m/z calcd for C15H16NO2 242.1176; found 242.1185 [M + H]+. Bis(3-methoxyphenyl)methanimine (4c): 18 Yield 98% (2.364 g); yellow syrup; 1H NMR (500 MHz, CDCl3) δ 3.82 (6H, s), 7.01 (2H, d, J = 8.3 Hz), 7.05−7.21 (4H, m), 7.31 (2H, t, J = 8.3 Hz), 9.48 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 55.3 (2 × C), 113.3 (2 × C), 116.2 (2 × C), 121.0 (2 × C), 129.2 (2 × C), 140.6 (2 × C), 159.4 (2 × C), 178.0; IR (KBr) 3256, 1589 cm−1; ESIMS m/z (rel. int.) 242 (100, [M + H]+); HRESIMS m/z calcd for C15H16NO2 242.1176; found 242.1184 [M + H]+. Bis(4-methoxyphenyl)methanimine (4d): 19 Yield 68% (1.640 g); white solid, mp 128−129 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.85 (6H, s), 6.90−6.94 (4H, m), 7.53 (4H, br. s), 9.35 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 55.3 (2 × C), 113.5 (4 × C), 130.1 (4 × C), 132.2 (2 × C), 161.2 (2 × C), 177.0; IR (KBr) 3256, 1589 cm−1; ESIMS m/z (rel. int.) 242 (100, [M + H]+); HRESIMS m/z calcd for C15H16NO2 242.1176; found 242.1184 [M + H]+. Bis(4-methylphenyl)methanimine (4e): 20 Yield 95% (1.988 g); white granule, mp 48−48.5 °C (hexane−EtOAc); 1H NMR (500 12852

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

Note

The Journal of Organic Chemistry Methyl 2-{[Bis(4-methylphenyl)methylidene]amino}acetate (3eI): 22 Purified by vacuum distillation (120 °C, 0.1 Torr); yield 69% (0.971 g); yellow syrup; 1H NMR (500 MHz, CDCl3) δ 2.35 (3H, s), 2.41 (3H, s), 3.73 (3H, s), 4.21 (2H, s), 7.05 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.55 (2H, d, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.3 (2 × C), 51.9, 55.5, 127.6 (2 × C), 128.7 (2 × C), 128.8 (2 × C), 129.2 (2 × C), 133.0, 136.8, 138.6, 140.6, 171.3, 172.0; IR (KBr) 1744, 1605, 1435 cm−1; ESIMS m/z (rel. int.) 282 (100, [M + H]+); HRESIMS m/z calcd for C18H20NO2 282.1489; found 282.1487 [M + H]+. Methyl 2-{[Bis(4-fluorophenyl)methylidene]amino}acetate (3fI): 23 Purified by vacuum distillation (120 °C, 0.1 Torr); yield 82% (1.186 g); white solid, mp 85−85.5 °C; 1H NMR (500 MHz, CDCl3) δ 3.75 (3H, s), 4.19 (2H, s), 7.02 (2H, t, J = 8.7 Hz), 7.12− 7.22 (4H, m), 7.61−7.66 (2H, m); 13C NMR (125 MHz, CDCl3) δ 52.0, 55.5, 115.1 (2 × C, d, J = 22 Hz), 116.0 (2 × C, d, J = 22 Hz), 129.7 (2 × C, d, J = 8 Hz), 130.8 (2 × C, d, J = 8 Hz), 131.4 (d, J = 3 Hz), 135.4 (d, J = 3 Hz), 162.9 (d, J = 248 Hz), 164.4 (d, J = 250 Hz), 169.8, 170.8; 19F NMR (470 MHz, CDCl3) δ −111.3, −110.0; IR (KBr) 1759, 1597 cm−1; ESIMS m/z (rel. int.) 290 (100, [M + H]+); HRESIMS m/z calcd for C16H14F2NO2 290.0987; found 290.0988 [M + H]+. Dimethyl 2-[(Diphenylmethylidene)amino]malonate (3aIII): Purified by column chromatography using hexane−EtOAc (5:1 v/v); yield 85% (1.324 g); white solid, mp 60.0−60.5 °C; 1H NMR (500 MHz, CDCl3) δ 3.77 (3H, s), 3.78 (3H, s), 4.90 (1H, s), 7.16−7.21 (2H, m), 7.34 (2H, t, J = 7.5 Hz), 7.41 (1H, t, J = 7.5 Hz), 7.44−7.49 (3H, m), 7.70 (2H, d, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ 52.8 (2 × C), 69.3, 127.7 (2 × C), 128.0 (2 × C), 128.7 (2 × C), 129.1, 129.2 (2 × C), 130.9, 135.3, 138.8, 167.6 (2 × C), 174.0; IR (KBr) 1751, 1612 cm−1; ESIMS m/z (rel. int.) 312 (100, [M + H]+); HRESIMS m/z calcd for C18H18NO4 312.1230; found 312.1241 [M + H]+. Dimethyl 2-{[Bis(2-methoxyphenyl)methylidene]amino}malonate (3bIII): Purified by column chromatography using hexane−EtOAc (2:1 v/v); yield 71% (1.320 g); yellow granule, mp 112−113 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.46 (3H, s), 3.76 (9H, s), 4.86 (1H, s), 6.79 (1H, d, J = 8.3 Hz), 6.87−6.94 (2H, m), 6.96−7.03 (2H, m), 7.28−7.36 (2H, m), 7.72 (1H, dd, J = 7.6, 1.7 Hz); 13C NMR (125 MHz, CDCl3) δ 52.7 (2 × C), 55.3, 55.7, 69.4, 110.4, 112.0, 120.3, 120.7, 126.1, 128.5, 130.1, 130.8, 130.9, 131.1, 155.4, 157.8, 167.6 (2 × C), 171.0; IR (KBr) 1744, 1605 cm−1; ESIMS m/z (rel. int.) 372 (100, [M + H]+); HRESIMS m/z calcd for C20H22NO6 372.1442; found 372.1444 [M + H]+. Dimethyl 2-{[Bis(3-methoxyphenyl)methylidene]amino}malonate (3cIII): Purified by column chromatography using hexane−EtOAc (5:1 v/v); yield 85% (1.579 g); pale yellow syrup; 1 H NMR (500 MHz, CDCl3) δ 3.78 (6H, s), 3.79 (3H, s), 3.80 (3H, s), 4.91 (1H, s), 6.72 (1H, s), 6.75 (1H, d, J = 7.4 Hz), 6.95−7.01 (2H, m), 7.20 (1H, d, J = 7.8 Hz), 7.25 (1H, t, J = 7.8 Hz), 7.34−7.40 (2H, m); 13C NMR (125 MHz, CDCl3) δ 52.8 (2 × C), 55.2, 55.3, 69.3, 112.9, 113.8, 114.9, 117.0, 119.7, 122.2, 128.9, 129.8, 136.5, 139.9, 159.4, 159.6, 167.5 (2 × C), 173.6; IR (KBr) 1751, 1597 cm−1; ESIMS m/z (rel. int.) 372 (100, [M + H]+); HRESIMS m/z calcd for C20H22NO6 372.1442; found 372.1447 [M + H]+. Dimethyl 2-{[Bis(4-methoxyphenyl)methylidene]amino}malonate (3dIII): Purified by column chromatography using hexane−EtOAc (4:1 v/v); yield 85% (1.578 g); pale yellow syrup; 1 H NMR (500 MHz, CDCl3) δ 3.77 (6H, s), 3.80 (3H, s), 3.85 (3H, s), 4.93 (1H, s), 6.84 (2H, d, J = 8.8 Hz), 6.97 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 7.65 (2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ 52.6 (2 × C), 55.1, 55.2, 69.2, 113.2 (2 × C), 113.9 (2 × C), 127.4, 129.2 (2 × C), 130.9 (2 × C), 131.9, 159.9, 161.7, 167.8 (2 × C), 173.1; IR (KBr) 1751, 1597 cm−1; ESIMS m/z (rel. int.) 372 (100, [M + H]+); HRESIMS m/z calcd for C20H22NO6 372.14416; found 372.14421 [M + H]+. Dimethyl 2-{[Bis(4-methylphenyl)methylidene]amino}malonate (3eIII): Purified by column chromatography using hexane−EtOAc (10:1 v/v); yield 62% (1.053 g); white solid, mp 82−82.5 °C; 1H NMR (500 MHz, CDCl3) δ 2.36 (3H, s), 2.41 (3H, s), 3.78 (6H, s),

4.90 (1H, s), 7.06 (2H, d, J = 7.9 Hz), 7.13 (2H, d, J = 8.2 Hz), 7.25 (2H, d, J = 7.9 Hz), 7.58 (2H, d, J = 8.2 Hz); 13C NMR (125 MHz, CDCl3) δ 21.3, 21.4, 52.8 (2 × C), 69.4, 127.7 (2 × C), 128.8 (2 × C), 129.3 (2 × C), 129.4 (2 × C), 132.5, 136.5, 139.0, 141.3, 167.8 (2 × C), 174.2; IR (KBr) 1736, 1605 cm−1; ESIMS m/z (rel. int.) 340 (100, [M + H]+); HRESIMS m/z calcd for C20H22NO4 340.1543; found 340.1546 [M + H]+. Dimethyl 2-{[Bis(4-fluorophenyl)methylidene]amino}malonate (3fIII): Purified by column chromatography using hexane−EtOAc (5:1 v/v); yield 80% (1.390 g); yellow syrup; 1H NMR (500 MHz, CDCl3) δ 3.79 (6H, s), 4.83 (1H, s), 7.03 (2H, t, J = 8.6 Hz), 7.15− 7.21 (4H, m), 7.65−7.70 (2H, m); 13C NMR (125 MHz, CDCl3) δ 53.0 (2 × C), 69.3, 115.2 (2 × C, d, J = 22 Hz), 116.0 (2 × C, d, J = 22 Hz), 129.8 (2 × C, d, J = 8 Hz), 130.8 (d, J = 3 Hz), 131.4 (2 × C, d, J = 8 Hz), 135.0 (d, J = 3 Hz), 163.0 (d, J = 249 Hz), 164.7 (d, J = 251 Hz), 167.4 (2 × C), 171.9; 19F NMR (470 MHz, CDCl3) δ −110.7, −109.0; IR (KBr) 1744, 1597 cm−1; ESIMS m/z (rel. int.) 348 (100, [M + H]+); HRESIMS m/z calcd for C18H16F2NO4 348.1042; found 348.1043 [M + H]+. Di met hyl 2 - {[ (3 -Met hox yph e n y l ) ( 4 - m e t ho x y p h e n y l ) methylidene]amino}malonate (3gIII): Purified by column chromatography using hexane−EtOAc (1:1 v/v); yield 36% (0.669 g), a mixture of E- and Z-forms with a ratio of 1:3; pale yellow syrup. For the minor E-form: 1H NMR (500 MHz, CDCl3) δ 3.79 (6H, s), 3.80 (3H, s), 3.86 (3H, s), 4.96 (1H, s), 6.95−7.00 (3H, m), 7.12 (2H, d, J = 8.8 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.32 (1H, s); 13C NMR (125 MHz, CDCl3) δ 52.9 (2 × C), 55.4 (2 × C), 69.5, 114.0 (2 × C), 114.1, 117.0, 122.4, 127.4, 129.0, 129.4 (2 × C), 140.9, 159.4, 160.2, 167.8 (2 × C), 174.0. For the major Z-form: 1H NMR (500 MHz, CDCl3) δ 3.78 (6H, s), 3.80 (3H, s), 3.82 (3H, s), 4.87 (1H, s), 6.71 (1H, s), 6.74 (1H, d, J = 7.8 Hz), 6.85 (2H, d, J = 9.0 Hz), 6.95−7.00 (1H, m), 7.37 (1H, t, J = 7.8 Hz), 7.67 (2H, d, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 52.8 (2 × C), 55.3 (2 × C), 69.3, 113.0, 113.4 (2 × C), 114.9, 119.9, 129.9, 131.0 (2 × C), 131.4, 136.8, 159.7, 162.0, 167.9 (2 × C), 173.1; IR (KBr) 1751, 1597 cm−1; ESIMS m/z (rel. int.) 372 (100, [M + H]+); HRESIMS m/z calcd for C20H22NO6 372.1442; found 372.1446 [M + H]+. General Procedure for the Thermal Cyclization of Schiff Bases 3. A solution of methyl 2-[(diphenylmethylidene)amino]acetate 3 (1 mmol) in diphenyl ether (5 mL) was heated under N2 (reaction temperature and time shown in Table 1). The resulting mixture was allowed to cool to room temperature until the complete conversion of the Schiff base 3 was observed by TLC. The resulting solution was directly purified by chromatography using silica gel and hexane−EtOAc as the eluent, affording pure 1-phenylisoquinolin-4-ol 1. The full spectral data of 1aI, 1cI, 1cI′, 1eI, 1aII−1fII, 1aIII−1gIII, and 1gIII′ are as follows. 1-Phenylisoquinolin-4-ol (1aI): 24 Eluted with hexane−EtOAc (1:1 v/v); yield 51% (113 mg); white needles, mp 252−254 °C. (acetone); 1 H NMR (500 MHz, acetone-d6) δ 7.47 (1H, t, J = 7.4 Hz), 7.52 (2H, t, J = 7.4 Hz), 7.62 (1H, t, J = 8.0 Hz), 7.65 (2H, d, J = 7.4 Hz), 7.75 (1H, t, J = 8.0 Hz), 8.04 (1H, d, J = 8.0 Hz), 8.22 (1H, s), 8.31 (1H, d, J = 8.0 Hz), 9.41 (1H, br s); 13C NMR (125 MHz, acetone-d6) δ 122.4, 127.2, 127.5, 128.0, 128.2, 128.6, 128.9 (2 × C), 129.0, 129.6, 130.8 (2 × C), 141.1, 148.5, 152.6 ; IR (KBr) 3456, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 221 (64, M+), 220 (100), 165 (21). Anal. Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.24; H, 5.05; N, 6.33. 7-Methoxy-1-(3-methoxyphenyl)isoquinolin-4-ol (1cI): Eluted with hexane−EtOAc (1:1 v/v); yield 72% (202 mg); pale yellow granule, mp 201−203 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 3.79 (3H, s), 3.81 (3H, s), 5.21 (1H, br s), 6.97−7.01 (1H, m), 7.18−7.21 (2H, m), 7.26−7.30 (2H, m), 7.39 (1H, t, J = 8.1 Hz), 8.11−8.14 (1H, m), 8.18 (1H, s); 13C NMR (125 MHz, CDCl3) δ 55.3, 55.4, 105.1, 114.7, 114.9, 121.8, 122.3, 123.4, 124.2, 125.1, 129.1, 129.2, 139.6, 149.3, 150.5, 158.9, 159.5; IR (KBr) 3395, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 281 (100, M+), 280 (61), 266 (27), 250 (29); HREIMS (70 eV) m/z calcd for C17H15NO3 281.1052; found 281.1054 [M]+. 12853

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

Note

The Journal of Organic Chemistry

M+), 384 (100), 356 (53). Anal. Calcd for C24H19NO4: C, 74.79; H, 4.97; N, 3.63. Found: C, 75.03; H, 5.01; N, 3.75. 3-Benzoyl-6-methyl-1-(4-methylphenyl)isoquinolin-4-ol (1eII): Eluted with hexane−DCM (2:1 v/v); combined two-step yield 45% (160 mg); pale yellow needle, mp 189−190 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 2.44 (3H, s), 2.59 (3H, s), 7.31 (2H, d, J = 8.0 Hz), 7.47 (2H, t, J = 7.4 Hz), 7.50−7.57 (2H, m), 7.59 (2H, d, J = 8.0 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.33 (1H, s), 8.40 (2H, d, J = 7.4 Hz), 14.02 (1H, s); 13C NMR (125 MHz, CDCl3) δ 21.3, 21.9, 122.9, 127.2, 127.3, 127.7 (2 × C), 128.0, 129.0 (2 × C), 129.2, 129.8 (2 × C), 131.7 (2 × C), 132.3, 132.8, 136.4, 137.4, 138.2, 140.0, 150.3, 158.4, 198.3; IR (KBr) 1605, 1558 cm−1; EIMS (70 eV) m/z (rel. int.) 353 (78, M+), 352 (100), 324 (62), 312 (20); HREIMS (70 eV) m/z calcd for C24H19NO2: 353.1416; found 353.1409 [M]+. 3-Benzoyl-6-fluoro-1-(4-fluorophenyl)isoquinolin-4-ol (1fII). Eluted with hexane−DCM (1:1 v/v); combined two-step yield 45% (163 mg); pale yellow needle, mp 200−201 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.21 (2H, t, J = 8.6 Hz), 7.45−7.52 (3H, m), 7.58 (1H, t, J = 7.4 Hz), 7.65 (2H, dd, J = 8.6, 5.4 Hz), 8.10 (1H, dd, J = 9.2, 5.2 Hz), 8.17 (1H, dd, J = 9.2, 2.5 Hz), 8.37 (2H, d, J = 7.4 Hz), 13.92 (1H, s); 13C NMR (125 MHz, CDCl3) δ 108.3 (d, J = 23 Hz), 115.5 (2 × C, d, J = 22 Hz), 120.7 (d, J = 24 Hz), 126.6, 127.5, 127.8 (2 × C), 130.2 (d, J = 9 Hz), 131.1 (d, J = 9 Hz), 131.6 (2 × C), 131.7 (2 × C, d, J = 8 Hz), 132.7, 134.9 (d, J = 3 Hz), 137.0, 149.1, 157.8 (d, J = 4 Hz), 162.8 (d, J = 252 Hz), 163.0 (d, J = 247 Hz), 198.4; 19F NMR (470 MHz, CDCl3) δ −112.9, −107.0; IR (KBr) 1612, 1566 cm−1; EIMS (70 eV) m/z (rel. int.) 361 (80, M+), 360 (100), 332 (72); HREIMS (70 eV) m/z calcd for C22H13F2NO2 361.0914; found 361.0911 [M]+. Methyl 4-Hydroxy-1-phenylisoquinoline-3-carboxylate (1aIII): Eluted with hexane−EtOAc (5:1 v/v); yield 87% (243 mg); pale yellow granule, mp 172−173 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 4.06 (3H, s), 7.43−7.52 (3H, m), 7.62−7.69 (3H, m), 7.76 (1H, t, J = 8.3 Hz), 8.01 (1H, d, J = 8.3 Hz), 8.47 (1H, d, J = 8.3 Hz), 11.84 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 52.9, 112.0, 123.3, 127.5, 128.3 (2 × C), 128.4, 128.5, 129.7, 129.9 (2 × C), 130.0, 130.2, 138.9, 152.1, 155.9, 171.4; IR (KBr) 1659, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 279 (46, M+), 219 (100), 190 (40), 165 (14). Anal. Calcd for C17H13NO3: C, 73.11; H, 4.69; N, 5.02. Found: C, 73.36; H, 4.90; N, 5.02. Methyl 4-Hydroxy-8-methoxy-1-(2-methoxyphenyl)isoquinoline3-carboxylate (1bIII): Eluted with hexane−DCM (1:1 v/v); yield 69% (234 mg); white granule, mp 194−195 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 3.49 (3H, s), 3.59 (3H, s), 4.01 (3H, s), 6.85 (1H, d, J = 8.0 Hz), 6.97 (1H, d, J = 8.0 Hz), 7.01 (1H, t, J = 8.0 Hz), 7.27−7.36 (2H, m), 7.62 (1H, t, J = 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz), 11.78 (1H, s); 13C NMR (125 MHz, CDCl3) δ 52.8, 55.2, 55.5, 109.5, 110.4, 115.0, 120.0, 120.1, 123.0, 128.5, 129.2, 129.8, 130.3, 133.7, 147.7, 155.4, 157.0, 157.4, 171.3; IR (KBr) 1659, 1574 cm−1; EIMS (70 eV) m/z (rel. int.) 339 (96, M+), 308 (83), 279 (100), 236 (40), 207 (52). Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.24; H, 5.09; N, 4.10. Methyl 4-Hydroxy-7-methoxy-1-(3-methoxyphenyl)isoquinoline3-carboxylate (1cIII): Eluted with hexane−EtOAc (3:1 v/v); yield 91% (309 mg); white gradule, mp 155−156 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.83 (3H, s), 3.87 (3H, s), 4.05 (3H, s), 7.00 (1H, dd, J = 8.2, 2.4 Hz), 7.19−7.24 (2H, m), 7.35 (1H, d, J = 2.4 Hz), 7.37−7.43 (2H, m), 8.39 (1H, d, J = 9.1 Hz), 11.83 (1H, s); 13C NMR (125 MHz, CDCl3) δ 52.8, 55.4, 55.5, 106.5, 114.4, 115.1, 118.8, 121.4, 122.2, 123.1, 125.1, 129.4, 132.0, 140.5, 150.5, 156.1, 159.8, 161.0, 171.4; IR (KBr) 1659, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 339 (58, M+), 279 (100), 250 (23), 236 (32). Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.21; H, 5.05; N, 4.00. Methyl 4-Hydroxy-6-methoxy-1-(4-methoxyphenyl)isoquinoline3-carboxylate (1dIII): Eluted with hexane−DCM (1:1 v/v); yield 67% (228 mg); pale yellow needle, mp 231−233 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 3.88 (3H, s), 4.01 (3H, s), 4.06 (3H, s), 7.02 (2H, d, J = 8.6 Hz), 7.26−7.29 (1H, dd, J = 9.3, 2.5 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 2.5 Hz), 7.96 (1H, d, J = 9.3 Hz),

5-Methoxy-1-(3-methoxyphenyl)isoquinolin-4-ol (1cI′): Eluted with hexane−EtOAc (3:1 v/v); yield 12% (34 mg); pale yellow granule, mp 139−141 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.86 (3H, s), 4.10 (3H, s), 6.97−7.01 (2H, m), 7.14−7.20 (2H, m), 7.35−7.42 (2H, m), 7.68 (1H, d, J = 8.5 Hz), 8.24 (1H, s), 8.99 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 55.3, 56.4, 107.4, 114.0, 115.1, 118.6, 120.8, 122.4, 127.0, 128.6, 129.0, 129.2, 141.3, 148.4, 151.1, 155.4, 159.5; IR (KBr) 3356, 1605 cm−1; EIMS (70 eV) m/z (rel. int.) 281 (100, M+), 280 (48), 266 (45), 250 (16). Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.55; H, 5.67; N, 4.68. 6-Methyl-1-(4-methylphenyl)isoquinolin-4-ol (1eI): Eluted with hexane−EtOAc (1:1 v/v); yield 30% (75 mg); white needle, mp 279− 281 °C (EtOAc); 1H NMR (500 MHz, DMSO-d6) δ 2.37 (3H, s), 2.49 (3H, s), 7.29 (2H, d, J = 7.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 7.45 (2H, d, J = 7.0 Hz), 7.83 (1H, d, J = 8.3 Hz), 7.95 (1H, s), 8.06 (1H, s), 10.35 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ 21.1, 21.7, 120.5, 125.2, 126.3, 126.6, 128.2, 129.0 (2 × C), 129.8, 129.9 (2 × C), 137.1, 137.3, 138.8, 147.4, 150.6; IR (KBr) 3464, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 249 (100, M+), 248 (95), 234 (93); HREIMS (70 eV) m/z calcd for C17H15NO 249.1154; found 249.1155 [M]+. 3-Benzoyl-1-phenylisoquinolin-4-ol (1aII): 25 Eluted with hexane− EtOAc (10:1 v/v); combined two-step yield 72% (234 mg); pale yellow needle, mp 164−165 °C (hexane−EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.45−7.59 (6H, m), 7.71 (2H, d, J = 7.6 Hz), 7.74 (1H, d, J = 7.6 Hz), 7.80 (1H, t, J = 7.6 Hz), 8.13 (1H, d, J = 8.2 Hz), 8.41 (2H, d, J = 7.6 Hz), 8.59 (1H, d, J = 8.2 Hz), 14.07 (1H, s); 13C NMR (125 MHz, CDCl3) δ 123.9, 127.2, 127.3, 127.8 (2 × C), 128.3 (2 × C), 128.4, 129.1, 129.6, 129.7, 130.0 (2 × C), 130.9, 131.7 (2 × C), 132.5, 137.2, 139.1, 150.4, 158.8, 198.3; IR (KBr) 1659, 1597 cm−1; EIMS (70 eV) m/z (rel. int.) 325 (85, M+), 324 (100), 296 (75), 165 (21). Anal. Calcd for C22H15NO2: C, 81.21; H, 4.65; N, 4.30. Found: C, 81.15; H, 4.84; N, 4.11. 3-Benzoyl-8-methoxy-1-(2-methoxyphenyl)isoquinolin-4-ol (1bII): Eluted with hexane−EtOAc (10:1 v/v); combined two-step yield 23% (89 mg); pale yellow needle, mp 160−161 °C (hexane− EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.52 (3H, s), 3.62 (3H, s), 6.88 (1H, d, J = 8.2 Hz), 6.99−7.05 (2H, m), 7.32 (1H, t, J = 8.2 Hz), 7.35−7.44 (3H, m), 7.48 (1H, t, J = 7.4 Hz), 7.64 (1H, t, J = 8.2 Hz), 8.12 (1H, d, J = 8.2 Hz), 8.39 (2H, d, J = 7.4 Hz), 13.90 (1H, s); 13C NMR (125 MHz, CDCl3) δ 55.2, 55.6, 109.6, 111.0, 115.6, 120.0, 122.7, 127.2, 127.7 (2 × C), 128.4, 129.4, 130.1, 130.4, 131.8 (2 × C), 132.4, 133.7, 137.1, 146.1, 157.0, 157.3, 158.1, 197.9; IR (KBr) 1597, 1566 cm−1; EIMS (70 eV) m/z (rel. int.) 385 (100, M+), 384 (80), 354 (46), 312 (32), 135 (43). Anal. Calcd for C24H19NO4: C, 74.79; H, 4.97; N, 3.63. Found: C, 74.87; H, 5.03; N, 3.33. 3-Benzoyl-7-methoxy-1-(3-methoxyphenyl)isoquinolin-4-ol (1cII): Eluted with hexane−EtOAc (10:1 v/v); combined two-step yield 79% (305 mg); pale yellow needle, mp 136−137 °C (hexane− EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.79 (3H, s), 3.82 (3H, s), 6.97 (1H, d, J = 8.0 Hz), 7.23−7.27 (2H, m), 7.30 (1H, dd, J = 9.0, 2.3 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.40−7.46 (3H, m), 7.51 (1H, t, J = 7.4 Hz), 8.35−8.40 (3H, m), 14.09 (1H, s); 13C NMR (125 MHz, CDCl3) δ 55.2, 55.4, 106.4, 114.3, 115.0, 120.9, 122.0, 123.3, 125.7, 126.2, 127.6 (2 × C), 129.2, 131.5, 131.6 (2 × C), 132.2, 137.3, 140.6, 148.7, 159.0, 159.7, 161.6, 197.6; IR (KBr) 1659, 1589 cm−1; EIMS (70 eV) m/z (rel. int.) 385 (90, M+), 384 (100), 356 (51). Anal. Calcd for C24H19NO4: C, 74.79; H, 4.97; N, 3.63. Found: C, 74.90; H, 4.81; N, 3.38. 3-Benzoyl-6-methoxy-1-(4-methoxyphenyl)isoquinolin-4-ol (1dII): Eluted with hexane−DCM (2:1 v/v); combined two-step yield 37% (143 mg); pale yellow needle, mp 169−170 °C (hexane− EtOAc); 1H NMR (500 MHz, CDCl3) δ 3.85 (3H, s), 3.96 (3H, s), 7.00 (2H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 9.2, 2.4 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.53 (1H, t, J = 7.4 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 2.4 Hz), 7.99 (1H, d, J = 9.2 Hz), 8.39 (2H, d, J = 7.4 Hz), 13.91 (1H, s); 13C NMR (125 MHz, CDCl3) δ 55.3, 55.6, 101.9, 113.7 (2 × C), 122.6, 124.9, 127.4, 127.7 (2 × C), 129.2, 130.9, 131.1 (2 × C), 131.7 (2 × C), 131.8, 132.3, 137.3, 149.7, 157.6, 159.8, 160.3, 198.4; IR (KBr) 1605, 1566 cm−1; EIMS (70 eV) m/z (rel. int.) 385 (92, 12854

DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856

Note

The Journal of Organic Chemistry 11.76 (1H, s); 13C NMR (125 MHz, CDCl3) δ 52.9, 55.4, 55.7, 101.4, 113.8 (2 × C), 120.3, 122.2, 125.4, 129.5, 130.3, 131.2 (2 × C), 131.7, 151.5, 154.8, 159.9, 160.5, 171.5; IR (KBr) 1659, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 339 (50, M+), 279 (100), 236 (48). Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 66.98; H, 5.31; N, 4.03. Methyl 4-Hydroxy-6-methyl-1-(4-methylphenyl)isoquinoline-3carboxylate (1eIII): Eluted with hexane−EtOAc (1:1 v/v); yield 86% (264 mg); pale yellow needles, mp 231−232 °C (hexane− DCM); 1H NMR (500 MHz, CDCl3) δ 2.43 (3H, s), 2.56 (3H, s), 4.04 (3H, s), 7.29 (2H, d, J = 7.6 Hz), 7.46 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 7.6 Hz), 7.91 (1H, d, J = 8.5 Hz), 8.21 (1H, s), 11.77 (1H, s); 13C NMR (125 MHz, CDCl3) δ 21.2, 21.8, 52.8, 119.9, 122.2, 127.5, 128.3, 128.5, 129.0 (2 × C), 129.8 (2 × C), 132.1, 136.2, 138.1, 140.2, 152.0, 155.4, 171.4; IR (KBr) 1659, 1582 cm−1; EIMS (70 eV) m/z (rel. int.) 307 (46, M+), 247 (100), 232 (22). Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 73.91; H, 5.25; N, 4.47. Methyl 4-Hydroxy-6-fluoro-1-(4-fluorophenyl)isoquinoline-3-carboxylate (1fIII): Eluted with hexane−EtOAc (5:1 v/v); yield 67% (212 mg); white granule, mp 202−203 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 4.07 (3H, s), 7.15−7.25 (2H, m), 7.38−7.46 (1H, m), 7.56−7.65 (2H, m), 7.96−8.08 (2H, m), 11.77 (1H, br s); 13C NMR (125 MHz, CDCl3) δ 53.1, 107.8 (d, J = 23 Hz), 115.5 (2 × C, d, J = 22 Hz), 120.1 (d, J = 25 Hz), 120.5, 127.0, 130.3, 130.4 (d, J = 9 Hz), 131.7 (2 × C, d, J = 8 Hz), 134.7 (d, J = 3 Hz), 150.7, 155.1 (d, J = 4 Hz), 162.9 (d, J = 252 Hz), 163.1 (d, J = 247 Hz), 171.1; 19F NMR (470 MHz, CDCl3) δ −112.9, −106.7; IR (KBr) 1667, 1566 cm−1; EIMS (70 eV) m/z (rel. int.) 315 (45, M+), 255 (100), 226 (41). Anal. Calcd for C17H11F2NO3: C, 64.76; H, 3.52; N, 4.44. Found: C, 64.66; H, 3.67; N, 4.34. Methyl 4-Hydroxy-7-methoxy-1-(4-methoxyphenyl)isoquinoline3-carboxylate (1gIII): Eluted with hexane−DCM (1:1 v/v); yield 96% (325 mg); white needles, mp 179−180 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 3.81 (3H, s), 3.87 (3H, s), 4.03 (3H, s), 7.02 (2H, d, J = 8.5 Hz), 7.31 (1H, s), 7.32 (1H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.5 Hz), 8.31 (1H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) δ 52.6, 55.2, 55.3, 106.4, 113.8 (2 × C), 118.6, 121.1, 122.9, 125.0, 130.9 (2 × C), 131.7, 131.9, 150.3, 155.7, 159.7, 160.8, 171.3; IR (KBr) 1659, 1612 cm−1; EIMS (70 eV) m/z (rel. int.) 339 (71, M+), 279 (100), 264 (30), 236 (44). Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.53; H, 4.90; N, 4.08. Methyl 4-Hydroxy-6-methoxy-1-(3-methoxyphenyl)isoquinoline3-carboxylate (1gIII′): Eluted with hexane−DCM (1:1 v/v); yield 4% (14 mg); white needles, mp 174−175 °C (hexane−DCM); 1H NMR (500 MHz, CDCl3) δ 3.87 (3H, s), 4.02 (3H, s), 4.07 (3H, s), 7.00 (1H, dd, J = 8.0, 2.4 Hz), 7.15−7.20 (2H, m), 7.28 (1H, dd, J = 9.0, 2.4 Hz), 7.40 (1H, t, J = 8.0 Hz), 7.72 (1H, d, J = 2.4 Hz), 7.95 (1H, d, J = 9.0 Hz), 11.82 (1H, s); 13C NMR (150 MHz, CDCl3) δ 53.0, 55.4, 55.7, 101.3, 114.3, 115.3, 120.2, 122.4, 122.5, 125.4, 129.3, 129.5, 130.3, 140.3, 151.6, 155.2, 159.6, 160.7, 171.5; IR (KBr) 1659, 1589 cm−1; EIMS (70 eV) m/z (rel. int.) 339 (85, M+), 321 (38), 279 (100), 264 (27), 236 (49); HREIMS (70 eV) m/z calcd for C19H17NO5 339.1107; found 339.1111 [M]+. General Procedure for the One-Pot Hydrolysis and Decarboxylation of Esters 1III. A mixture of methyl 4-hydroxy-1phenylisoquinoline-3-carboxylate 1aIII−1fIII (0.7 mmol) and 37% hydrochloric acid (1 mL) in 1,4-dioxane (7 mL) was refluxed overnight. After being cooled, the reaction mixture was carefully neutralized with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with EtOAc (5 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a solid. The crude product was triturated with EtOAc (1 mL) at room temperature to give pure 1-phenylisoquinolin-4-ols 1aI−1fI. The full spectral data of 1bI, 1dI, and 1fI are as follows. 8-Methoxy-1-(2-methoxyphenyl)isoquinolin-4-ol (1bI): Yield 99% (195 mg); white granule, mp 257−259 °C (EtOAc); 1H NMR (500 MHz, acetone-d6) δ 3.53 (3H, s), 3.60 (3H, s), 6.92−6.99 (3H, m), 7.21 (1H, d, J = 7.0 Hz), 7.30 (1H, t, J = 7.0 Hz), 7.60 (1H, t, J = 8.2 Hz), 7.82 (1H, d, J = 8.2 Hz), 8.13 (1H, s), 9.20 (1H, br s); 13C NMR

(125 MHz, acetone-d6) δ 55.5, 55.8, 107.9, 110.4, 114.2, 120.3, 121.9, 127.2, 128.6, 130.0, 130.3, 130.4, 136.0, 147.9, 148.5, 157.9, 158.4; IR (KBr) 3422, 1601 cm−1; EIMS (70 eV) m/z (rel. int.) 281 (80, [M]+), 250 (100), 235 (26), 220 (23), 205 (21); HREIMS (70 eV) m/z calcd for C17H15NO3 281.1052; found 281.1058 [M]+. 6-Methoxy-1-(4-methoxyphenyl)isoquinolin-4-ol (1dI): Yield 99% (195 mg); white granule, mp 224−225 °C (EtOAc); 1H NMR (500 MHz, acetone-d6) δ 3.87 (3H, s), 3.97 (3H, s), 7.05 (2H, d, J = 8.7 Hz), 7.19 (1H, dd, J = 9.3, 2.6 Hz), 7.54 (1H, d, J = 2.6 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.97 (1H, d, J = 9.3 Hz), 8.10 (1H, s), 9.27 (1H, br s); 13 C NMR (125 MHz, acetone-d6) δ 55.6, 55.8, 100.3, 114.3 (2 × C), 120.5, 123.6, 127.5, 129.7, 130.9, 131.9 (2 × C), 133.6, 147.7, 152.0, 160.5, 160.7; IR (KBr) 3499, 1620 cm−1; EIMS (70 eV) m/z (rel. int.) 281 (100, [M]+), 280 (93), 266 (19), 250 (30); HREIMS (70 eV) m/ z calcd for C17H15NO3 281.1052; found 281.1057 [M]+. 6-Fluoro-1-(4-fluorophenyl)isoquinolin-4-ol (1fI): Yield 93% (167 mg); white granule, mp >300 °C (EtOAc); 1H NMR (500 MHz, acetone-d6) δ 7.28 (2H, t, J = 8.8 Hz), 7.45 (1H, td, J = 9.2, 2.7 Hz), 7.68 (2H, dd, J = 8.8, 5.5 Hz), 7.86 (1H, dd, J = 10.0, 2.7 Hz), 8.10 (1H, dd, J = 9.2, 5.5 Hz), 8.20 (1H, s), 9.62 (1H, br s); 13C NMR (125 MHz, acetone-d6) δ 106.0 (d, J = 22 Hz), 115.8 (2 × C, d, J = 22 Hz), 118.4 (d, J = 25 Hz), 125.3, 127.9, 130.6 (d, J = 10 Hz), 131.2 (d, J = 9 Hz), 132.7 (2 × C, d, J = 8 Hz), 137.1 (d, J = 3 Hz), 148.3 (d, J = 5 Hz), 151.5, 163.2 (d, J = 248 Hz), 163.5 (d, J = 244 Hz); 19F NMR (470 MHz, acetone-d6) δ −115.8, −110.7; IR (KBr) 3456, 1597 cm−1; EIMS (70 eV) m/z (rel. int.) 257 (74, [M]+), 256 (100), 201 (27); HREIMS (70 eV) m/z calcd for C15H9F2NO 257.0652; found 257.0662 [M]+.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02240. Copies of 1H and 13C NMR spectra of 1aI−1fI, 1cI′, 1aII−1fII, 1aIII−1gIII, 1gIII′, 3aI−3fI, 3aIII−3gIII, 4b−f, 5II, and 8 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ta-Hsien Chuang: 0000-0001-7850-9366 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the Ministry of Science and Technology, Taiwan (MOST 105-2113-M-039-002; MOST 106-2113-M-039-003; MOST 106-2738-M-039-001), for financial support. We are also grateful to the National Center for Computing, Taiwan, for their generosity with computing time.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02240 J. Org. Chem. 2017, 82, 12849−12856