Regio- and Stereoselective Electrophilic Cyclization Approach for the

Subscriber access provided by University of Sunderland

Article

Regio- and Stereoselective Electrophilic Cyclization Approach for the Protecting-Group-Free Synthesis of Alkaloids Lennoxamine, Chilenine, Fumaridine, 8-Oxypseudoplamatine and 2-O-Methyloxyfagaronine Tuanli Yao, Zhen Guo, Xiujuan Liang, and Lihan Qi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02154 • Publication Date (Web): 28 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Regio- and Stereoselective Electrophilic Cyclization Approach for the Protecting-Group-Free Synthesis of Alkaloids Lennoxamine, Chilenine, Fumaridine, 8-Oxypseudoplamatine and 2-O-Methyloxyfagaronine Tuanli Yao*,†,‡, Zhen Guo†, Xiujuan Liang† and Lihan Qi† †

College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an, 710021, China. ‡ Shaaxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi’an, 710021, China. Email: [email protected]

Abstract: A unified strategy for protecting-group-free synthesis of alkaloids lennoxamine, chilenine, fumaridine, 8-oxypseudoplamatine and 2-O-methyloxyfagaronine is reported. The core isoindolin-1-one and isoquinolin-1-one structures were built by a silver-catalyzed regio- and stereoselective cyclization of methyl 2-alkynylbenzimidates. The regioselectiveity of cyclization was achieved by utilizing the intrinsic functionality of alkaloids.

Introduction Isoindolin-1-ones1 and isoquinolin-1-ones2 are core structures in many pharmaceutical drugs and natural products. For example, isoindolobenzazepine alkaloids lennoxamine (1) and chilenine (2) were first found in the plants of the Chilean Berberis species (Figure 1).3 Fumaridine (3)4 was isolated with fumaramidine, fumaramine, narceineimide and isoquinoline alkaloids from creeper Fumaria parvifllora Lam (Fumariaceae), whose extracts are used in folk medicine as a blood purifier and an anthelmintic in Pakistan. Protoberberine alkaloid 8oxypseudoplamatine (4), which inhibits cell proliferation, was found in Stephama suberosa,

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Forman

(Menispermaceae).5

2-O-Methyloxyfagaronine

Page 2 of 22

(5)

is

an

analog

of

oxybenzo[c]phenanthridine alkaloids.6 Their unique structures and diverse biological activities have attracted much attention, therefore various synthetic approaches have been developed to reach these alkaloids and their analogs.

Figure 1. Alkaloids containing isoindolin-1-one or isoquinolin-1-one skeleton

Previous synthesis of lennoxamine (1) and chilenine (2) could be classified as either first assembly of the core isoindolin-1-one which was manipulated to form the benzazepine ring,7 or the reversed sequence.8 The only reported synthesis of fumaridine (3) involved HornerWadsworth-Emmons (HWE) olefination between phosphorylated isoindolinone and substituted benzaldehyde.9 Previous synthesis of 8-oxypseudopalmatine (4) generally started with construction of tetrahydroisoquinoline,10 dihydroisoquinoline11 or isoquinolinone.12 The development of a unified strategy to access these diverse natural products and their analogs is critical for comprehensive chemical and biological studies. Our interest in synthesis promoted us to devise a convergent and protecting-group-free total synthesis of these alkaloids.13 None of the previous synthesis exploited the electrophilic cyclization of alkynes, which is a mild and efficient method for the construction of heterocycles.14 Previous work has demonstrated that the isoindolin-1-one and isoquinolin-1-one motif could be constructed by the cyclization of 2-


Page 3 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


alkynylbenzimidates.15 However, a mixture of isoindolin-1-one and isoquinolin-1-one derivatives was usually formed with isoquinolin-1-one derivatives as the major one.15a So the underlying challenge was the regio- (5-exo to isoindoline vs 6-endo to isoquinoline) and stereoselectivity (E/Z isomers of 1-methylene-1H-isoindoles) of the reaction. Because the regioselectivity is influenced by steric and electronic factors, we envisioned that the inherent functionality of alkaloids might be utilized as a handle to control the regioselectivity of the cyclization.

Results and Discussion We first investigated the steric and electronic effects of the silver-catalyzed cyclization of methyl 2-alkynylbenzimidates (Scheme 1). When R is a proton, methylene-1H-isoindole 7a (5exo-dig product) was obtained as the major product in a 53% yield, along with 44% of isoquinoline 8a (6Scheme 1. Steric and Electronic Effects in the Silver Catalyzed Cyclization of Methyl 2Alkynyl-benzimidatesa



Page 4 of 22

a

Reaction conditions: 1 (0.25 mmol) and AgO2CCF3 (5 mol %), DCM (2.5 mL), rt, under air; isolated yields

endo-dig product). The reaction showed excellent stereoselectivity and only Z isomer of 7a was obtained. When R is an electron-donating p-methoxy group, six-membered isoquinoline 8b was the major product. On the other hand, when R is an electron-withdrawing p-fluoro or p-ester group, five-membered 3-methoxy-1-methylene-1H-isoindoles were isolated as the major products (Scheme 1, 7c and 7d). Furthermore, when R is an o-ester group, 1-methylene-1Hisoindole was formed exclusively and no corresponding isoquinoline was observed (Scheme 1, 7e). Interestingly, when R is an o-alkyl group, the reactions mainly afforded 1-methoxyisoquinolines (Scheme 1, 8f and 8g). While the presence of two methoxy groups on the 3- and 4position of phenyl ring bearing imidate afforded a 1:1 mixture of 7h and 8h，placing two methoxy groups on the 2- and 3-position led to exclusively generation of 1-methylene-1Hisoindole 7i, which has reduced steric congestion compared with its isomeric 1-methoxyisoquinoline product 8i. The methylene-1H-isoindoles 7 have been distinguished from the isoquinolines 8 on the basis of their 1H NMR spectra. The five-membered ring products 7 have a vinyl hydrogen, which is observed as a singlet peak around 6.9 ppm, while in the six-membered products 8 the singlet peak is observed around 7.6 ppm (Figure 2).

OMe

OMe N

N

Ph H 6.9 ppm

Ph

H 7.67 ppm

Figure 2. 1H NMR Comparison of 7a and 8a

Plausible reaction pathways were shown in Scheme 2. The coordination of the triple bond of 6 to AgO2CCF3 enhances the electrophilicity of the triple bond, which induces a 5-exo-dig and/or 6-endo-dig cyclization of the imidate nitrogen onto the triple bond. Protonation of the resulting


Page 5 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


organosilver intermediate II and III affords product 7 and 8 and simultaneously regenerate the catalyst AgO2CCF3.

Scheme 2. Plausible Reaction Pathways

The retrosynthetic analysis followed our model studies in which substitutes on alkaloids can be used to control the regioselectivity of cyclization (Scheme 3). Serving as a common intermediate for the synthesis of lennoxamine (1), chilenine (2) and fumaridine (3), the key 3-methylene

Scheme 3. Retrosynthetic Analysis of Lennoxamine, Chilenine, Fumaridine and 8Oxypseudoplamatine



Page 6 of 22

isoindolin-1-one core would be prepared by a sequence of reactions involving Sonogashira coupling/imidate formation/cyclization/selective demethylation. The methoxy groups would be a handle to control the regioselectivity of the cyclization (5-exo to 3-methoxy-1-methylene-1Hisoindoline).

The

isoquinolin-1-one

core

of

8-oxypseudoplamatine

(4)

and

2-O-

methyloxyfagaronine (5) would be constructed by the same sequence, in which the regioselectivity of cyclization (6-endo to 1-methoxyisoquinoline) would be controlled by the acetate group. The synthesis of lennoxamine and chilenine was initiated from 2-iodobenzamide 912c which coupled with terminal alkyne 10, 16 led to 2-alkynylbenzamide 11 in an almost quantitative yield (Scheme 4). Treatment of 11 with Me3OBF4 afforded imidate 12, which was subjected to silver-

Scheme 4. Formal Synthesis of Lennoxamine and Chilenine


Page 7 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


catalyzed cyclization. As we envisioned, (Z)-3-methoxy-1-methylene-1H-isoindole 13 was obtained regio- and stereoselectively in a 61% yield. The (Z)-configuration of 13 was confirmed by X-ray diffraction analysis. LAH reduction, mesylation and selective demethylation provided 3-methylene-isoindolin-1-one 16. Finally, cyclization using NaH afforded dehydrolennoxamine 17 in a high yield, which could be converted to lennoxamine and chilenine by known procedures.7a,7c We initially planned to synthesize fumaridine (3) directly from intermediate 16 (Scheme 5). Unfortunately, the reaction of 16 with excess Me2NH only provided 10% yield of fumaridine (3) and dehydrolennoxamine 17 was obtained in a 52% yield. The planar structure and Z-double



bond of 3-methylene-isoindolin-1-one 16 facilitated the cyclization. Therefore, the reaction of 3methoxy-1-methylene-1H-isoindole 15 with Me2NH was performed instead, which followed by selective demethylation to provide fumaridine (3) in a good yield. All of the spectroscopic data were consistent with those reported in the literature.4,9 Scheme 5. Synthesis of Fumaridine

The synthesis of 8-oxypseudoplamatine (4) and 2-O-methyloxyfagaronine (5) started from 2iodobenzamide 19, which was coupled with terminal alkyne 20. The coupling product 21 was then subjected to imidate formation/cyclization (Scheme 6). As expected, 1-methoxyisoquinoline 22 was obtained as the major product. Selective demethylation of 22 led to isoquinlin-1-one 23, which could be converted to 8-oxypseudoplamatine (4) and 2-O-methyloxyfagaronine (5) according to known procedures.12c Scheme 6. Formal Synthesis of 8-Oxypseudoplamatine


Page 8 of 22

Page 9 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Conclusion In conclusion, we have developed a unified and protecting-group-free strategy for the synthesis of alkaloids lennoxamine (1), chilenine (2), fumaridine (3), 8-oxypseudoplamatine (4) and 2-Omethyloxyfagaronine (5). The core isoindolin-1-one or isoquinolin-1-one scaffold of these alkaloids was built by a silver-catalyzed regio- and stereoselective cyclization of methyl 2alkynylbenzimidates. The regioselectiveity of cyclization was achieved by utilizing the intrinsic functionality of alkaloids. Experimental Section General information. NMR spectra were recorded on a Bruker AM 400 MHz spectrometer and calibrated using residual undeuterated solvent as an internal reference (CDCl3 (1H): δ = 7.26 ppm; CDCl3 (13C): δ = 77.16 ppm; DMSO-d6 (1H): 2.50 ppm; DMSO-d6 (13C): 39.52 ppm). HPLC/MS analysis was carried out with gradient elution (5% CH3CN to 100% CH3CN) on an Agilent 1200 RRLC with a photodiode array UV detector and an Agilent 6224 TOF mass spectrometer (also used to produce high resolution mass spectra). Melting points were determined on a Stanford Research Systems OptiMelt apparatus. The infrared (IR) spectra were acquired as thin films using a universal ATR sampling accessory on a Bruker Vertex 80 FT-IR spectrometer and the absorption frequencies are reported in cm-1. Flash chromatography



separations were carried out using silica gel columns. The new compounds were characterized by 1

H NMR,13C NMR, HRMS, and IR. The structure of known compounds were further confirmed

by comparing their 1H NMR and

13

C NMR data with those of literature. All reagents and

solvents were used as received from commercial sources without further purification. Compounds 2-(phenylethynyl)benzamide,17 2-((4-methoxyphenyl)ethynyl)benzamide,17 2-((4fluorophenyl)ethynyl) benzamide,17 methyl 2-((2-carbamoylphe nyl)ethynyl)benzoate,18 and 4,5dimethoxy-2-(phenylethynyl) benzamide17 were prepared by following literature procedure. General procedure for synthesis of 2-iodobenzamides 9 and 19. 6-Iodo-2,3dimethoxybenzamide (9). A solution of 6-iodo-2,3-dimethoxy benzoic acid19 (3.08 g, 10.0 mmol, 1.0 equiv) in thionyl chloride (30 mL) was refluxed for 2h. After cooling down to room temperature, excess thionyl chloride was removed under reduced pressure. THF (18 mL) was added and the resulting suspension was cooled to 0 °C, to which aqueous ammonia (25 wt %, 30 mL) was added drop-wise. After addition, the reaction was slowly warmed up to room temperature and stirred for 16 h. The precipitate was collected by filtration, washed with H2O (30 mL) and dried under air to afford 9 as a white solid (2.68 g, 87%). The spectral data was identical with literature.12c 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.81 (br, 1H), 5.72 (br, 1H), 3.85 (s, 3H), 3.84 (s, 3H).

2-Iodo-4,5-dimethoxybenzamide (19). This product was prepared by following the same procedure as in the synthesis of 9 and was obtained as white solid (2.77 g, 90%): m.p. 189-192 °C; 1H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 7.39 (s, 1H), 7.29 (s, 1H), 6.97 (s, 1H), 3.77 (s, 3H), 3.76 (s, 3H). 13C{1H} NMR (101 MHz, DMSO) δ 170.1, 149.8, 148.4, 134.6, 122.0, 111.9, 81.8, 56.0, 55.7; IR (neat) 3361, 3195, 1628, 1609, 1407, 1255, 1209; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C9H11INO3 307.9778; Found 307.9773.

General procedure for the synthesis of 2-alkynylbenzamides. Ethyl 4-((2carbamoylphenyl)ethynyl)benzoate. To a solution of 2-iodobenzamide (0.37 g, 1.5 mmol,1.0 equiv) in MeCN (10 mL) were added PdCl2(PPh3)2 (0.053 g, 0.075 mmol, 0.05 equiv), ethyl 4-ethynylbenzoate (0.313 g, 1.8 mmol, 1.2 equiv), and Et3N (0.455 g, 4.5 mmol, 3.0 equiv). The resulting mixture was stirred at 80 °C under argon. The progress of the reaction was monitored by TLC analysis to establish its completion. After cooling to room temperature, the reaction was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated. The residue was purified by column chromatography (Silica Gel, petroleum ether / ethyl acetate) to afford ethyl 4-((2-carbamoylphenyl)ethynyl)benzoate as a white solid (0.295 g, 67%): m.p. 167169 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 – 8.00 (m, 3H), 7.62 (dd, J = 6.1, 2.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.52 – 7.43 (m, 2H), 7.17 (br, 1H), 6.14 (br, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 166.0, 135.4, 133.8, 131.6, 131.2, 130.9, 130.3, 129.8, 129.5, 126.8, 119.9, 94.8, 90.4, 61.5, 14.5; IR (neat) 3182, 2983, 1717, 1480 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H15NO3 294.1125; Found 294.1126.


Page 10 of 22

Page 11 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2-(o-Tolylethynyl)benzamide. This product was prepared by following the same procedure as in the synthesis of ethyl 4-((2-carbamoylphenyl)ethynyl)benzoate and was obtained as a colorless oil (0.315. g, 89%). The spectral data was identical with literature.20 1H NMR (400 MHz, CDCl3) δ 8.16 – 8.03 (m, 1H), 7.62 (dd, J = 7.4, 1.5 Hz, 1H), 7.54 – 7.39 (m, 4H), 7.33 – 7.24 (m, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.02 (br, 1H), 2.50 (s, 3H).

2-((2-Isopropylphenyl)ethynyl)benzamide. This product was prepared by following the same procedure as in the synthesis of ethyl 4-((2-carbamoylphenyl)ethynyl)benzoate and was obtained as a white solid (0.293 g, 74%): m.p. 121-123 °C; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.55 – 7.37 (m, 5H), 7.34 – 7.28 (m, 2H), 7.15 (t, J = 7.1 Hz, 1H), 3.51 (dt, J = 13.7, 6.8 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); 13

C{1H} NMR (101 MHz, CDCl3) δ 169.1, 150.7, 134.8, 133.6, 132.5, 130.9, 130.1, 129.6, 128.7, 125.8, 125.2,

120.9, 120.6, 94.9, 91.1, 31.8, 23.3 (one carbon missing due to overlap); IR (neat) 3180, 2963, 2209, 1669, 1593, 1380 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17NO 264.1383; Found 264.1385.

2,3-Dimethoxy-6-(phenylethynyl)benzamide. This product was prepared by following the same procedure as in the synthesis of ethyl 4-((2-carbamoylphenyl)ethynyl)benzoate and was obtained as a yellow solid (0.331 g, 78%): m.p. 137-140 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 4.1 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.31 – 7.26 (m, 4H), 6.89 (d, J = 8.6 Hz, 1H), 6.00 (br, 2H), 3.882 (s, 3H), 3.879(s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 153.3, 146.1, 133.7, 131.8, 129.3, 128.5, 123.4, 113.7, 113.3, 91.9, 86.7, 62.2, 56.2 (one carbon missing due to overlap); IR (neat) 3328, 3188, 2940, 2375, 1669, 1593, 1365 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C17H15NO3 304.0944; Found 304.0943.

General procedure for the synthesis of methyl 2-alkynylbenzimidates 6a-6i. Methyl 2(phenylethynyl)benzimidate (6a). To a solution of 2-(phenylethynyl)benzamide (0.11 g, 0.5 mmol,1.0 equiv) in DCM (6 mL) at 0 °C was added trimethyloxonium tetrafluoroborate (0.111 g, 0.75 mmol, 1.5 equiv). The reaction mixture was slowly warmed up to room temperature and stirred overnight. Methanol (1.5 mL) was added to quench excess trimethyloxonium tetrafluoroborate. After stirring for 5 minutes, the reaction was concentrated under reduced pressure. The residue was purification by column chromatography (deactivated Silica Gel, DCM/MeOH) to afford 6a as a yellow oil (0.062 g, 53 %): 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.78 – 7.73 (m, 1H), 7.63 – 7.58 (m, 1H), 7.57 – 7.51 (m, 2H), 7.42 – 7.31 (m, 5H), 3.94 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 134.2, 133.8, 131.9, 130.1, 129.1, 128.64, 128.59, 128.2, 122.7, 121.3, 95.7, 87.4, 53.6; IR (neat) 2944, 1539, 1494, 1342, 1077 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C16H13NO 258.0889; Found 258.0881.

Methyl 2-((4-methoxyphenyl)ethynyl)benzimidate (6b). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.090 g, 68%): 1H NMR (400 MHz, CDCl3) δ 8.84 (br, 1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (dd, J = 7.6, 1.3 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.37 (td, J = 7.5, 1.6 Hz, 1H), 7.32 (td, J = 7.6, 1.5 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.93 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 160.3, 133.7, 133.6, 133.4, 130.0, 128.2, 121.7, 114.7, 114.3, 96.0, 86.2, 55.5, 53.6 (one carbon missing due to overlap); IR (neat) 3327, 2209, 1509, 1441, 1343 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO2 266.1176; Found 266.1176.

Methyl 2-((4-fluorophenyl)ethynyl)benzimidate (6c). This product was prepared by following the



same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.096 g, 76%): 1H NMR (400 MHz, CDCl3) δ 8.72 (br, 1H), 7.77 – 7.68 (m, 1H), 7.62 – 7.55 (m, 1H), 7.54 – 7.47 (m, 2H), 7.40 – 7.31 (m, 2H), 7.05 – 6.99 (m, 2H), 3.92 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 163.0 (d, J = 251.5 Hz), 134.2, 133.8 (d, J = 8.1 Hz), 133.7, 130.1, 128.6, 128.2, 121.1, 118.8 (d, J = 3.0 Hz), 116.0 (d, J = 22.2 Hz), 94.6, 87.1, 53.6; IR (neat) 2984, 2215, 1600, 1436 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H12FNO 254.0976; Found 254.0977.

Ethyl 4-((2-(imino(methoxy)methyl)phenyl)ethynyl)benzoate (6d). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.0861 g, 56%). Ethyl 4((2-carbamoylphenyl)ethynyl)benzoate (0.0470 g, 32%) was recovered. 1H NMR (400 MHz, CDCl3) δ 8.66 (br, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.76 – 7.69 (m, 1H), 7.63 – 7.54 (m, 3H), 7.42 – 7.33 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 166.1, 134.6, 133.9, 131.7, 130.5, 130.1, 129.7, 129.1, 128.3, 127.2, 120.7, 94.6, 90.0, 61.4, 53.7, 14.5; IR (neat) 3337, 2981, 1718, 1443, 1343 cm-1； HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17NO3 308.1281; Found 308.1288.

Methyl 2-((2-(imino(methoxy)methyl)phenyl)ethynyl)benzoate (6e). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.097 g, 66%). Methyl 2((2-carbamoylphenyl)ethynyl)benzoate (0.0240g, 17%) was recovered. 1H NMR (400 MHz, CDCl3) δ 9.06 (br, 1H), 8.00 (dd, J = 7.9, 1.0 Hz, 1H), 7.82–7.76 (m, 1H), 7.69–7.65 (m, 2H), 7.50 (td, J = 7.6, 1.4 Hz, 1H), 7.44–7.35 (m, 3H), 3.95 (s, 3H), 3.93 (s, 3H);

13

C{1H} NMR (101 MHz, CDCl3) δ 166.32, 166.27, 134.3, 134.1, 133.8, 132.0,

131.6, 130.7, 130.0, 128.7, 128.5, 128.2, 123.2, 121.3, 94.5, 92.0, 53.4, 52.4; IR (neat) 3333, 2947, 1724, 1491, 1441 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H15NO3 294.1125; Found 294.1124.

Methyl 2-(o-tolylethynyl)benzimidate (6f). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.064 g, 51%). 2-(o-Tolylethynyl)benzamide (0.0318 g, 25%) was recovered. 1H NMR (400 MHz, CDCl3) δ 8.76 (br, 1H), 7.74 (dd, J = 7.6, 1.5 Hz, 1H), 7.64 – 7.59 (m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.42 – 7.32 (m, 2H), 7.27 –7.19 (m, 2H), 7.16 (td, J = 7.2, 1.9 Hz, 1H), 3.93 (s, 3H), 2.52 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 140.4, 134.0, 133.9, 132.4, 130.1, 129.8, 129.1, 128.5, 128.2, 125.9, 122.5, 121.5, 94.8, 91.0, 53.7, 21.1 (one carbon missing due to overlap); IR (neat) 3335, 3018, 2209, 1343 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO 250.1226; Found 250.1227.

Methyl 2-((2-isopropylphenyl)ethynyl)benzimidate (6g). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a red oil (0.051 g, 37%). 2-((2-Isopropylphenyl) ethynyl)benzamide (0.0395g, 30%) was recovered. 1H NMR (400 MHz, CDCl3) δ 8.72 (br, 1H), 7.73 (dd, J = 7.6, 1.5 Hz, 1H), 7.60 (dd, J = 7.6, 1.4 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.43 – 7.33 (m, 2H), 7.33 – 7.27 (m, 2H), 7.19 – 7.13 (m, 1H), 3.93 (s, 3H), 3.52 (hept, J = 6.9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.2, 150.8, 134.1, 133.8, 132.9, 130.1, 129.5, 128.5, 128.2, 125.9, 125.3, 121.6, 121.5, 9.64, 90.8, 53.7, 31.9, 23.5 (one carbon missing due to overlap); IR (neat) 3336, 3062, 2874, 2208, 1343 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H19NO 278.1539; Found 278.1539.

Methyl 4,5-dimethoxy-2-(phenylethynyl)benzimidate (6h). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.111 g, 76%). 4,5-Dimethoxy-2-


Page 12 of 22

Page 13 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(phenylethynyl)benzamide (0.028 g, 20%) was recovered. 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.51 (m, 2H), 7.36 – 7.32 (m, 3H), 7.31 (s, 1H), 7.05 (s, 1H), 3.95 (s, 3H), 3.93 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.2, 150.1, 149.1, 131.7, 128.8, 128.6, 127.0, 122.7, 115.6, 114.2, 110.8, 94.7, 87.6, 56.2, 56.2, 53.5; IR (neat) 3333, 2937, 1518, 1445, 1360 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17NO3 296.1281; Found 296.1283.

Methyl 2,3-dimethoxy-6-(phenylethynyl)benzimidate (6i). This product was prepared by following the same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.087 g, 59%): 1H NMR (400 MHz, CDCl3) δ 7.51 (br, 1H), 7.44 – 7.39 (m, 2H), 7.30 – 7.25 (m, 3H), 7.22 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.2, 153.3, 145.9, 133.3, 131.6, 128.6, 128.5, 128.4, 123.3, 113.9, 113.0, 91.6, 86.7, 61.7, 56.1, 53.7; IR (neat) 3411, 2941, 1563, 1481, 1341 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17NO3 296.1281; Found 296.1282.

General procedure for the silver catalyzed cyclization of methyl 2-alkynylbenzimidates. To a solution of methyl 2-alkynylbenzimidate 6 (0.25 mmol,1.0 equiv) in DCM (2.5 mL) was added AgO2CCF3 (0.05 equiv). The resulting mixture was stirred at room temperature for 0.5-4 h. The completed reaction was concentrated under reduced pressure. The residue was purification by column chromatography (Silica Gel, petroleum ether/ethyl acetate) to afford product 7 and/or 8.

(Z)-1-Benzylidene-3-methoxy-1H-isoindole (7a). This product was obtained as a white solid (0.031 g, 53%): m.p. 94-96 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 – 8.18 (m, 2H), 7.76 (dt, J = 7.6, 0.9 Hz, 1H), 7.56 (dt, J = 7.5, 1.0 Hz, 1H), 7.47 – 7.38 (m, 3H), 7.35 (td, J = 7.4, 1.0 Hz, 1H), 7.29 (ddd, J = 7.4, 4.1, 1.3 Hz, 1H), 6.90 (s, 1H), 4.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.4, 145.5, 143.2, 136.3, 131.4, 130.2, 129.5, 128.7, 128.3, 127.7, 120.4, 120.0, 119.7, 56.4; IR (neat) 2940, 1641, 1537, 1431, 1375, 761; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14NO 236.1070; Found 236.1066..

1-Methoxy-3-phenylisoquinoline (8a). This product was obtained as a white solid (0.026 g, 44%): m.p. 41-42 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 8.3, 0.5 Hz, 1H), 8.18 – 8.14 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.66 – 7.60 (m, 1H), 7.52 – 7.44 (m, 3H), 7.40 – 7.34 (m, 1H), 4.23 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 148.0, 139.7, 139.0, 130.7, 128.8, 128.6, 126.8, 126.6, 124.4, 119.2, 110.6, 53.8 (one carbon missing due to overlap); IR (neat) 2922, 2852, 1626, 1574, 1372, 1332; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H14NO 236.1070; Found 236.1066.

(Z)-3-Methoxy-1-(4-methoxybenzylidene)-1H-isoindole (7b). This product was obtained as a light yellow solid (0.0146 g, 22%): m.p. 143-145 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.87 (s, 1H), 4.26 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.7, 159.9, 143.7, 143.4, 133.0, 129.9, 129.4, 129.3, 127.3, 120.3, 120.0, 119.5, 114.3, 56.2, 55.5; IR (neat) 2853, 1645, 1597, 1455, 1373 cm-1；HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO2 266.1176; Found 266.1174.

1-Methoxy-3-(4-methoxyphenyl)isoquinoline (8b). This product was obtained as a white solid (0.034 g, 51%): m.p. 58-59 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.2 Hz, 1H), 8.16 – 8.08 (m, 2H), 7.73 (d, J =



8.2 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.49 – 7.43 (m, 1H), 7.05 – 6.98 (m, 2H), 4.23 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 160.3, 147.9, 139.2, 132.5, 130.6, 128.1, 126.6, 126.1, 124.3, 118.8, 114.2, 109.4, 55.6, 53.7; IR (neat) 2931, 1613, 1574, 1448, 1368 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO2 266.1176; Found 266.1178.

(Z)-1-(4-Fluorobenzylidene)-3-methoxy-1H-isoindole (7c). This product was obtained as a white solid (0.035 g, 55%): m.p. 88-89 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 – 8.17 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.5, 0.9 Hz, 1H), 7.35 (td, J = 7.4, 0.6 Hz, 1H), 7.13 – 7.05 (m, 2H), 6.84 (s, 1H), 4.25 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.4, 162.7 (d, J = 249.5 Hz), 145.0, 143.1, 133.1 (d, J = 7.1 Hz), 132.6, (d, J = 4.1 Hz), 130.1, 129.6, 127.8, 120.5, 119.6, 118.7, 115.7 (d, J = 22.2 Hz), 56.4; IR (neat) 2925, 2853, 1640, 1596, 1380 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H12FNO 254.0976; Found 254.0975.

3-(4-Fluorophenyl)-1-methoxyisoquinoline (8c). This product was obtained as a white solid (0.018 g, 28%): m.p. 81-83 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H), 8.17 – 8.09 (m, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.67 – 7.58 (m, 2H), 7.53 – 7.44 (m, 1H), 7.19 – 7.11 (m, 2H), 4.21 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.4 (d, J = 248.5 Hz), 160.7, 147.1, 139.0, 135.8, 130.8, 128.6, 128.5, 126.7 (d, J = 10.1 Hz), 124.4, 119.0, 115.7 (d, J = 21.2 Hz), 110.3, 53.8; IR (neat) 3061, 2945, 1633, 1506, 1375 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H12FNO 254.0976; Found 254.0977.

Ethyl (Z)-4-((3-methoxy-1H-isoindol-1-ylidene)methyl)benzoate (7d). This product was obtained as a white solid (0.050 g, 65%): m.p. 94-96 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 6.85 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.25 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.1, 166.7, 147.4, 142.9, 140.7, 131.0, 130.4, 129.8, 129.3, 128.2, 120.5, 119.9, 118.5, 61.1, 56.5, 14.5 (one carbon missing due to overlap); IR (neat) 2984, 1710, 1640, 1539, 1377 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H17NO3 308.1281; Found 308.1284.

Ethyl 4-(1-methoxyisoquinolin-3-yl)benzoate (8d). This product was obtained as a white solid (0.009 g, 12%): m.p. 56-58 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 – 8.19 (m, 3H), 8.16 – 8.10 (m, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.68 – 7.62 (m, 1H), 7.55 – 7.49 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.23 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.8, 160.7, 146.7, 143.8, 138.7, 130.9, 130.2, 130.1, 127.1, 127.0, 126.6, 124.4, 119.5, 111.7, 61.2, 53.9, 14.6; IR (neat) 3049, 1715, 1573, 1452, 1364 cm-1; HRMS (ESI-TOF) m/z: C19H17NO3 [M+H]+ calcd for 308.1281; Found 308.1281.

Methyl (Z)-2-((3-methoxy-1H-isoindol-1-ylidene)methyl)benzoate (7e). This product was obtained as a yellow solid (0.052 g, 71%): m.p. 65-66 °C; 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 7.8 Hz, 1H), 7.94 (dd, J = 7.9, 1.2 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.45 (td, J = 7.5, 0.9 Hz, 1H), 7.34 (m, 2H), 4.21 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.9, 168.3, 146.5, 143.2, 136.8, 133.5, 131.8, 130.6, 130.4, 130.1, 129.6, 128.0, 127.5, 120.3, 120.2, 117.6, 56.4, 52.3; IR (neat) 3069, 1718, 1640, 1540, 1376 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H15NO3 294.1125; Found 294.1126.


Page 14 of 22

Page 15 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Z)-3-Methoxy-1-(2-methylbenzylidene)-1H-isoindole (7f). This product was obtained as a white solid (0.011 g, 17%): m.p. 70-71 °C; 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.29 (dt, J = 8.1, 4.3 Hz, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 4.25 (s, 3H), 2.51 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 145.3, 143.1, 137.6, 134.5, 132.1, 130.3, 130.2, 129.4, 128.2, 127.7, 126.3, 120.3, 119.6, 116.9, 56.4, 20.5; IR (neat) 3049, 2937, 1724, 1540, 1371 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO 250.1226; Found 250.1224.

1-Methoxy-3-(o-tolyl)isoquinoline (8f). This product was obtained as colorless oil (0.047 g, 75%): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 8.0, 7.1 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.36 (s, 1H), 7.32 (m, 3H), 4.19– 4.17 (m, 3H), 2.53 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.0, 151.0, 140.7, 138.6, 136.6, 131.1, 130.6, 130.1, 128.1, 126.6, 126.7, 126.0, 124.3, 118.5, 114.6, 53.9, 21.2; IR (neat) 3055, 2936, 1574, 1450, 1371 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C17H15NO 250.1226; Found 250.1229.

(Z)-1-(2-Isopropylbenzylidene)-3-methoxy-1H-isoindole (7g). This product was obtained as a white solid (0.017 g, 25%): m.p. 51-53 °C; 1H NMR (400 MHz, CDCl3) δ 8.65 (dd, J = 6.8, 2.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.1 Hz, 1H), 7.42 – 7.26 (m, 5H), 4.25 (s, 3H), 3.49 (hept, J = 6.8 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 147.8, 145.5, 143.2, 133.2, 132.7, 130.3, 129.4, 128.5, 127.7, 125.9, 125.1, 120.3, 119.6, 116.9, 56.4, 29.7, 23.9; IR (neat) 3050, 2926, 1663, 1540, 1449 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H19NO 278.1539; Found 278.1540.

3-(2-Isopropylphenyl)-1-methoxyisoquinoline (8g). This product was obtained as colorless oil (0.047 g, 67%): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.54 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.49 – 7.38 (m, 3H), 7.32 (s, 1H), 7.28 (td, J = 7.4, 1.4 Hz, 1H), 4.15 (s, 3H), 3.42 (hept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.9, 151.6, 147.6, 140.1, 138.6, 130.6, 130.3, 128.5, 126.6, 126.5, 126.1, 125.7, 124.3, 118.5, 114.8, 54.1, 29.6, 24.5; IR (neat) 3058, 2962, 1575, 1450, 1371 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C19H19NO 278.1539; Found 278.1537.

(Z)-1-Benzylidene-3,5,6-trimethoxy-1H-isoindole (7h). This product was obtained as a yellow solid (0.036 g, 49%): m.p. 140-143 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.4 Hz, 2H), 7.42 – 7.36 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 4.24 (s, 3H), 3.99 (s, 3H), 3.92 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 151.4, 149.8, 145.5, 136.9, 136.4, 131.2, 128.7, 128.1, 123.1, 119.1, 102.4, 100.2, 56.4, 56.4, 56.3; IR (neat) 3067, 2934, 1642, 1536, 1372 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17NO3 296.1281; Found 296.1285.

1,6,7-Trimethoxy-3-phenylisoquinoline (8h). This product was obtained as a white solid (0.036 g, 49%): m.p. 170-171 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 – 8.08 (m, 2H), 7.57 (s, 1H), 7.49 (s, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.07 (s, 1H), 4.22 (s, 3H), 4.02 (s, 3H), 4.01 (s, 3H); 13

C{1H} NMR (101 MHz, CDCl3) δ 159.6, 153.1, 149.7, 146.9, 139.9, 135.3, 128.8, 128.2, 126.6, 113.8, 109.9,

105.7, 103.1, 56.3, 56.2, 53.7; IR (neat) 3004, 2950, 1624, 1584, 1461 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C18H17NO3 296.1281; Found 296.1287.



Synthesis of methyl 2-(2-ethynylphenyl)acetates 10 and 20. Methyl 2-(6ethynylbenzo[d][1,3]dioxol-5-yl)acetate (10). To a solution of 2-(benzo[d][1,3]dioxol-5-yl)acetic acid16 (4.0 g, 22.2 mmol, 1.0 equiv) in HOAc (60 mL), iodine monochloride (4.9 g, 30.2 mmol, 1.36 equiv) in HOAc (20 mL) was added dropwise via a dropping funnel. The reaction mixture was stirred for 2 h and poured into water (100 mL). Solid sodium thiosulfate was added with stirring till color changed from purple to light yellow. Water (160 mL) was added and the solid was collected by filtration, washed with water (100 mL) and dried under air to afford 2-(6iodobenzo[d][1,3]dioxol-5-yl)acetic acid as a light yellow solid (4.0 g, 59%), which was used as is in the next step. 1

H NMR (400 MHz, DMSO) δ 12.41 (br, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 6.03 (s, 2H), 3.63 (s, 2H); 13C{1H} NMR

(101 MHz, DMSO) δ 171.6, 147.8, 147.1, 131.8, 117.7, 111.1, 101.7, 89.6, 45.3. Thionyl chloride (1.12 g, 9.39 mmol, 1.69 equiv) was added dropwise to a solution of 2-(6-iodobenzo[d][1,3] dioxol-5-yl)acetic acid (1.70 g, 5.55 mmol, 1.0 equiv) in MeOH (39 mL) at 0 °C. The mixture was stirred at room temperature for 3 h and concentrated. The residue was purified by chromatography (Silica Gel, petroleum ether / ethyl acetate) to afford methyl 2-(6-iodobenzo[d][1,3]dioxol-5-yl)acetate (1.68 g, 95%) as a white solid: m.p. 8082 °C; 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 6.78 (s, 1H), 5.95 (s, 2H), 3.71 – 3.69 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.3, 148.7, 147.8, 130.9, 118.8, 110.6, 101.9, 89.0, 52.4, 46.0; IR (neat) 2996, 1737, 1635, 1487, 1238 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C10H9IO4 342.9438; Found 342.9415. To a solution of methyl 2-(6-iodobenzo[d][1,3]dioxol-5-yl)acetate (2.71 g, 8.41 mmol, 1.0 equiv) in THF (11 mL) were added PdCl2(PPh3)2 (0.178 g, 0.254 mmol, 0.03 equiv), CuI (0.048g, 0.254 mmol, 0.03eq), ethynyltrimethylsilane (0.998 g, 10.16 mmol, 1.2 equiv) and Et3N (11 mL). The resulting mixture was stirred at room temperature under argon for 3 h. The completed reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Silica Gel, petroleum ether / ethyl acetate) to afford methyl 2-(6((trimethylsilyl)ethynyl)benzo[d][1,3]dioxol-5-yl)acetate as a yellow solid (2.4 g, 98%): m.p. 69 -71 °C; 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 6.72 (s, 1H), 5.94 (s, 2H), 3.73 (s, 2H), 3.68 (s, 3H), 0.21 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.81, 148.4, 146.7, 131.8, 116.7, 111.8, 110.4, 103.2, 101.7, 97.8, 52.2, 39.7, 0.2; IR (neat) 2958, 2150, 1740, 1488, 1370 cm-1; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H18NaO4Si 313.0867; Found 313.0860. To a solution of methyl 2-(6-((trimethylsilyl)ethynyl)benzo[d][1,3]dioxol-5-yl)acetate (4.0 g, 13.8 mmol, 1.0 equiv) in CH2Cl2/MeOH (1 : 1, 108 mL) was added K2CO3 (7.61 g, 55.1 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature under argon for 1 h. The reaction was quenched with H2O (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (50 mL), dried (MgSO4) and concentrated to afford 10 as a yellow solid: (2.79 g, 93%): m.p. 63-65 °C. 1H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.74 (s, 1H), 5.95 (s, 2H), 3.76 (s, 2H), 3.68 (s, 3H), 3.17 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.7, 148.7, 146.8, 131.8, 115.5, 112.2, 110.3, 101.8, 81.9, 80.4, 52.3, 39.5; IR (neat) 3284, 2907, 1735, 1488, 1372 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C12H10O4 219.0652; Found 219.0657.

2-(2-Ethynyl-4,5-dimethoxyphenyl)acetate (20). This compound was prepared by following the same procedure as synthesis of 10. Methyl 2-(2-iodo-4,5-dimethoxyphenyl)acetate21 (2.17 g, 6.46 mmol) and ethynyltrimethylsilane (0.761 g, 7.75 mmol, 1.2 equiv) afforded methyl 2-(4,5-dimethoxy-2-


Page 16 of 22

Page 17 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


((trimethylsilyl)ethynyl)phenyl)acetate (1.96 g, 99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.75 (s, 2H), 3.68 (s, 3H), 0.22 (s, 9H); IR (neat) 2956, 2844, 2148, 1740, 1513 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H22O4Si 307.1360; Found 307.1377. 2-(4,5-Dimethoxy-2((trimethylsilyl)ethynyl)phenyl)acetate (1.56 g, 5.09 mmol) afforded methyl 2-(2-ethynyl-4,5dimethoxyphenyl)acetate (20) (1.14 g, 96%) as a light yellow solid: m.p. 89-90 °C; 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s, 2H), 3.69 (s, 3H), 3.18 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 150.0, 148.0, 130.2, 115.2, 114.5, 112.8, 82.1, 80.2, 56.2, 56.2, 52.2, 39.3; IR (neat) 3237, 1720, 1514, 1453, 1332 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H14O4 235.0965; Found 235.0965.

Methyl 2-(6-((2-carbamoyl-3,4-dimethoxyphenyl)ethynyl)benzo[d][1,3]dioxol-5-yl)acetate (11). This compound was prepared by following the general procedure for the synthesis of 2-alkynylbenzamide. 9 (2.8 g, 9.12 mmol) and 10 (2.79 g, 12.77 mmol, 1.4 equiv) afforded 11 (3.3g, 91%) as a white solid: m.p. 210212 °C; 1H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 7.43 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.93 (s, 2H), 6.07 (s, 2H), 3.85 (s, 3H), 3.82 (s, 2H), 3.74 (s, 3H), 3.61 (s, 3H); 13C{1H} NMR (101 MHz, DMSO) δ 171.2, 167.3, 152.9, 147.7, 146.2, 144.7, 135.9, 131.1, 127.9, 115.9, 112.8, 112.0, 110.6, 110.4, 101.7, 90.0, 88.4, 60.9, 55.9, 51.7, 38.5; IR (neat) 3386, 2953, 2370, 1732, 1488 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H19NO7 398,1234; Found 398.1234.

Methyl 2-(6-((2-(imino(methoxy)methyl)-3,4-dimethoxyphenyl)ethynyl)benzo[d][1,3]dioxol5-yl)acetate (12). This compound was prepared by following the general procedure for the synthesis of methyl 2alkynylbenzimidates, 11 (0.235 g, 0.591 mmol) was converted to 12 (0.180 g, 74%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (br, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.72 (s, 1H), 5.92 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.77 (s, 2H), 3.65 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.8, 167.1, 153.2, 148.2, 146.7, 145.8, 132.9, 130.9, 128.6, 116.5, 113.8, 113.0, 111.6, 110.2, 101.7, 89.6, 61.6, 56.1, 53.6, 52.2, 39.5 (one carbon missing due to overlap); IR (neat) 3323, 2941, 2560, 1738, 1493 cm-1; HRMS (ESITOF) m/z: [M+H]+ calcd for C22H21NO7 412.1391; Found 412.1388.

Methyl (Z)-2-(6-((3,4,5-trimethoxy-1H-isoindol-1-ylidene)methyl)benzo[d][1,3]dioxol-5yl)acetate (13). This compound was prepared by following the general procedure for silver-catalyzed cyclization. 12 (0.375 g, 0.91 mmol) was cyclized to 13 (0.229 g, 61%) as a yellow solid: m.p. 166-168 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.74 (s, 1H), 5.96 (s, 2H), 4.23 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.74 (s, 2H), 3.66 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 172.07, 172.05, 152.7, 147.5, 147.3, 144.1, 143.9, 137.7, 129.3, 128.0, 123.0, 115.2, 115.1, 114.4, 111.7, 110.9, 101.4, 62.4, 57.1, 56.9, 52.4, 39.8; IR (neat) 2928, 1706, 1493, 1365, 1268 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H21NO7 412.1391; Found 412.1392.

(Z)-2-(6-((3,4,5-Trimethoxy-1H-isoindol-1- ylidene)methyl)benzo[d][1,3]dioxol-5-yl)ethan1-ol (14). 13 (0.20 g, 0.486 mmol, 1.0 equiv) was dissolved anhydrous THF (6.0 ml) and cooled to 0 °C. LiAlH4 (2.5 M solution in THF, 0.29 mL, 1.5 equiv) was added dropwise, and the reaction was monitored by TLC. Upon



completion of the reaction, water (0.028 mL) was added while maintaining at 0 °C. Under vigorous stirring, aqueous NaOH (15 wt%, 0.028 mL) was added followed by water (0.028 mL). The mixture was filtered and washed with THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (Silica Gel, petroleum ether / ethyl acetate) to afford 14 as a yellow solid (0.146 g, 78%): m.p. 134-135 °C. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 6.67 (s, 1H), 5.92 (s, 2H), 4.21 (s, 3H), 3.93 (s, 3H), 3.86 (s, 3H), 3.79 (t, J = 6.6 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.16 (br, 1H); 13

C{1H} NMR (101 MHz, CDCl3) δ 171.8, 152.5, 147.5, 146.6, 143.8, 143.6, 137.5, 132.5, 128.6, 122.8, 115.1,

114.9, 114.8, 111.7, 110.2, 101.2, 63.6, 62.3, 56.9, 56.8, 37.0; IR (neat) 3310, 2843, 1611, 1538, 1486, 1370 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H21NO6 384.1442; Found 384.1447.

(Z)-2-(6-((3,4,5-Trimethoxy-1H-isoindol-1-ylidene)methyl)benzo[d][1,3]dioxol-5-yl)ethyl methanesulfonate (15). 14 (0.130 g, 0.339 mmol, 1.0 eq) and Et3N (0.1 mL) was dissolved in DCM (0.5 mL) and cooled to 0 °C, to which a solution of methanesulfonyl chloride (0.053 mL, 2.0 equiv) in DCM (0.35 mL) was added dropwise. After stirring for 2 h at room temperature, HCl (2N,10 mL) was added and extracted with DCM (20 mL). The organic phase was washed with satd. NaHCO3 (20 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated to afford 15 as a yellow solid (0.148 mg, 95%), which was used directly in next step without further purification. m.p. 139-140 °C. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 6.68 (s, 1H), 5.95 (s, 2H), 4.34 (t, J = 7.6 Hz, 2H), 4.22 (s, 3H), 3.94 (s, 3H), 3.89 (s, 3H), 3.22 (t, J = 7.6 Hz, 2H), 2.88 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 152.7, 147.6, 147.2, 144.4, 143.8, 137.4, 129.6, 129.1, 122.9, 115.5, 115.1, 113.8, 111.9, 110.3, 101.4, 70.0, 62.3, 57.0, 56.8, 37.7, 34.2; IR (neat) 2924, 1738, 1492, 1350, 1267 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H23NO8S 462.1217; Found 462.1218.

(Z)-2-(6-((4,5-Dimethoxy-3-oxoisoindolin-1-ylidene)methyl)benzo[d][1,3]dioxol-5-yl)ethyl methanesulfonate (16). 15 (0.060 g, 0.130mmol,1.0 equiv), NaBr (0.80 g, 7.80 mmol, 60 equiv) and pMeC6H4SO3H（0.335 g, 1.95 mmol, 12 equiv) were stirred in MeOH (18 mL) for 1 h at 50 °C. The completed reaction was concentrated, quenched with satd. NaHCO3 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried (MgSO4) and concentrated to afford 16 as a yellow solid (0.054 g, 93%), which used directly in next step without further purification. m.p.183-186 °C; 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 6.58 (s, 1H), 6.04 (s, 2H), 4.32 (t, J = 7.0 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.11 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (101 MHz, DMSO) δ 166.8, 152.8, 146.4, 146.2, 145.8, 132.8, 132.0, 129.1, 127.3, 120.7, 117.4, 116.0, 110.2, 109.8, 101.1, 70.1, 61.7, 56.5, 36.7, 32.5 (one carbon missing due to overlap); IR (neat) 2924, 1738, 1492, 1350, 1267 cm-1; HRMS (ESITOF) m/z: [M+H]+ calcd for C21H21NO8S 448.1061; Found 448.1055.

Dehydrolennoxamine (17). To a suspension of NaH (0.039 g, 60 wt % mineral oil suspension, 0.965 mmol, 10 equiv) in THF (10 mL) at 0 °C, was added a solution of 16 (0.040 g, 0.089 mmol, 1.0 equiv) in THF (4.0 mL) over 3 h. After stirring for 6 h, the completed reaction was quenched with satd. NH4Cl (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic phase was dried (MgSO4) and concentrated. The residue was purified by


Page 18 of 22

Page 19 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


column chromatography (Silica Gel, DCM / MeOH) to afford dehydrolennoxamine 17 (0.027 g, 86%) as a yellow solid: m.p. 211-213 °C (lit.7d 208-209 °C). The spectral data were consistent with literature. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.78 (s, 1H), 6.65 (s, 1H), 6.31 (s, 1H), 5.95 (s, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 3.08 – 2.93 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 153.2, 147.1, 146.8, 134.2, 133.5, 131.3, 128.0, 120.6, 116.6, 114.6, 110.5, 110.4, 105.2, 101.5, 62.7, 57.0, 42.1, 35.7 (one carbon missing due to overlap).

(Z)-N,N-dimethyl-2-(6-((3,4,5-trimethoxy-1H-isoindol-1-ylidene)methyl)benzo[d][1,3]dioxol -5-yl)ethan-1-amine (18). A mixture of 15 (0.069 g, 0.149 mmol, 1.0 equiv) and Me2NH (2M in THF, 4.0 mL, 8 mmol, 53 equiv) was heated at 60 °C overnight. The completed reaction was concentrated. The residue was purified by column chromatography (Silica Gel, DCM / MeOH / Et3N) to afford compound 18 as a yellow solid (0.049 g, 80%)：m.p.167-168 °C. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.65 (s, 1H), 5.95 (s, 2H), 4.22 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H), 3.36 – 3.23 (m, 2H), 3.00 – 2.94 (m, 2H), 2.73 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.1, 151.9, 146.8, 145.9, 143.1, 137.0, 132.8, 127.5, 122.2, 114.7, 114.4, 113.8, 111.1, 109.3, 100.5, 61.7, 60.5, 56.3, 56.1, 44.5, 31.3. (two carbon missing due to overlap); IR (neat) 2932, 1614, 1539, 1468 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C23H26N2O5 411.1914; Found 411.1919.

Fumaridine (3). To a solution of 18 (0.049 g, 0.119 mmol) in MeOH (17 mL) was add HCl (4.0 M, 0.15 µl, 5.0 equiv) and the resulting mixture was stirred at room temperature for 1 h. The completed reaction was concentrated, diluted with EtOAc (10 mL), washed satd. NaHCO3 (15 mL). The aqueous phase was back-extracted with EtOAc (3 x 20 mL). The combined organic phase was concentrated and the residue was purified by column chromatography (Silica Gel, DCM / MeOH / Et3N) to afford fumaridine (3) (0.038 g, 80%) as a yellow solid: m.p. 186-188 °C (lit.22 189-190 °C). The spectral data were consistent with literature.4 1H NMR (400 MHz, CDCl3) δ 8.07 (br, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.72 (s, 1H), 6.46 (s, 1H), 5.94 (s, 2H), 4.06 (s, 3H), 3.90 (s, 3H), 2.96 – 2.87 (m, 2H), 2.68 – 2.61 (m, 2H), 2.42 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.1, 153.5, 147.5, 147.2, 147.1, 133.4, 131.9, 127.2, 121.2, 117.4, 115.8, 110.5, 108.9, 101.9, 101.6, 62.6, 60.1, 57.0, 44.9, 31.2, 29.9.

Methyl 2-(2-((2-carbamoyl-4,5-dimethoxyphenyl)ethynyl)-4,5-dimethoxyphenyl)acetate (21). This compound was prepared by following the general procedure for the synthesis of 2-alkynylbenzamide. 19 (0.56 g, 1.82 mmol, 1.0 equiv) and 20 (0.512 g, 2.2 mmol, 1.2 equiv) afforded 21 (0.588 g, 78%) as a light yellow solid: m.p. 153-155 °C; 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.64 (s, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 6.83 (s, 1H), 5.79 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.83 (s, 2H), 3.69 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.9, 167.6, 151.0, 150.2, 149.6, 148.2, 129.7, 127.6, 115.4, 114.6, 114.5, 113.3, 112.99, 112.93, 93.2, 90.6, 56.3, 56.3, 56.3, 56.2, 52.4, 39.7; IR (neat) 3364, 3159, 1738, 1595, 1523, 1334, 1238; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H24NO7 414.1547; Found 414.1549.

Methyl 2-(4,5-dimethoxy-2-(1,6,7-trimethoxyisoquinolin-3-yl)phenyl)acetate (22). By following the general procedure for the synthesis of methyl 2-alkynylbenzimidates, amide 21 (0.235 g, 0.591 mmol)



was converted to corresponding benzimidate, which was subjected to silver-catalyzed cyclization without purification. 22 was obtained as a yellow oil (0.161 g, 64% over two steps): 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.26 (s, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 6.87 (s, 1H), 4.11 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H), 3.94 (s, 3H), 3.93 (s, 2H), 3.93 (s, 3H), 3.59 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.9, 159.1, 153.1, 149.7, 149.0, 148.8, 148.1, 135.0, 133.7, 124.9, 114.3, 113.7, 113.7, 113.1, 105.4, 103.0, 56.2, 56.2, 56.2, 56.2, 53.7, 51.9, 38.8; IR (neat) 2947, 1735, 1579, 1508, 1463, 1216, 1162; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C23H26NO7 428.1704; Found 428.1706.

Methyl 2-(2-(6,7-dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)-4,5-dimethoxyphenyl) acetate (23). 22 (0.028 g, 0.066 mmol, 1.0 equiv), NaBr (0.41 g, 3.96 mmol, 60 equiv) and p-MeC6H4SO3H (0.122 g, 0.792 mmol, 12 equiv) were stirred in MeOH (9 mL) at 80 °C for 4 h. The completed reaction was concentrated, quenched with satd. NaHCO3 (10 mL) and extracted with EtOAc (3 x 20mL). The combined organic phase was dried (MgSO4) and concentrated. The residue was purified by column chromatography (Silica Gel, DCM / MeOH ) to afford 23 as a yellow solid (0.022 g, 80%). The spectral data were consistent with literature.12c 1H NMR (500 MHz, CDCl3) δ 9.38 (s, 1H), 7.79 (s, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 6.81 (s, 1H), 6.42 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.93 (s, 3H), 3.91 (s, 3H), 3.77 (s, 3H), 3.63 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 173.2, 162.3, 153.9, 149.9, 149.3, 148.5, 137.9, 133.6, 128.2, 124.9, 119.1, 113.2, 112.7, 107.5, 106.5, 106.2, 56.4, 56.3, 56.2, 56.2, 52.9, 38.6.

Supporting Information Crystal data for 13 (CIF) Copies of the 1H and 13C NMR spectra for all new compounds and X-ray crystallographic data for compound 13 (PDF) Acknowledgments This work was financially supported by Shaanxi University of Science and Technology (BJ15-33) and the Natural Science Foundation of Shaanxi Province of China (2017JM2004). Dr. Yifan Kang (SUST) is acknowledged for assistance with X-ray diffraction studies on compound 13. References (1) (a) Li, E.; Jiang, L.; Guo, L.; Zhang, H.; Che, Y. Pestalachlorides A-C, Antifungal Metabolites from the Plant Endophytic Fungus Pestalotiopsis Adusta. Bioorg. Med. Chem. 2008, 16, 7894–7899. (b) Almeida, C.; Hemberger, Y.; Schmitt, S. M.; Bouhired, S.; Natesan, L.; Kehraus, S.; Dimas, K.; Gütschow, M.; Bringmann, G.; König, G. M. Marilines A-C: Novel Phthalimidines from the Sponge Derived Fungus Stachylidium sp. Chem. Eur. J. 2012, 18, 8827–8834. (c) Hu, X.; Xia, Q.-W.; Zhao, Y.-Y.; Zheng, Q.-H.; Liu, Q.-Y.; Chen, L.; Zhang, Q.-Q. Speradines B-E, Four Novel Tetracyclic Oxindole Alkaloids from the Marine-Derived Fungus Aspergillus oryzae. Heterocycles 2014, 89, 1662–1669. (d) Sovic, I.; Jambon, S.; Kraljevic Pavelic, S.; Markova-Car, E.; Ilic, N.; Depauw, S.; David-Cordonnier, M.-H.; Karminski-Zamola, G. Synthesis,


Page 20 of 22

Page 21 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Antitumor Activity and DNA Binding Features of Benzothiazolyl and Benzimidazolyl Substituted Isoindolines. Bioorg. Med. Chem. 2018, 26, 1950–1960. (e) Afifi, S.; Michael, A.; Azimi, M.; Rodriguez, M.; Lendvai, N.; Landgren, O. Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat. Pharmacotherapy 2015, 35, 1173–1188. (f) Sorbera, L. A.; Leeson, P. A.; Silvestre, J.; Castaner, J. Pagoclone: Anxiolytic GABA-A/BZD Site Partial Agonist. Drugs Future 2001, 26, 651–657. (2) (a) Jagtap, P. G.; Baloglu, E.; Southan, G. J.; Mabley, J. G.; Li, H.; Zhou, J.; van Duzer, J.; Salzman, A. L.; Szabo, C. Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the Modification of Indeno[1,2-c]isoquinolinone. J. Med. Chem. 2005, 48, 5100–5103. (b) Torisawa, Y.; Aki, S.; Minamikawa, J. Conversion of Indanone Oximes into Isocarbostyrils. Bioorg. Med. Chem. Lett. 2007, 17, 453–455. (c) Pettit, G. R.; Meng, Y. H.; Herald, D. L.; Graham, K. A. N.; Pettit, R. K.; Doubek, D. L. Isolation and Structure of Ruprechstyril from Ruprechtia tangarana. J. Nat. Prod. 2003, 66, 1065–1069. (d) Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson, D. A.; Cottam, H. B. Substituted Isoquinolines and Quinazolines as Potential Antiinflammatory Agents. Synthesis and Biological Evaluation of Inhibitors of Tumor Necrosis Factor. J. Med. Chem. 1999, 42, 3860–3873. (e) Sunderland, P. T.; Dhami, A.; Mahon, M. F.; Jones, L. A.; Tully, S. R.; Lloyd, M. D.; Thompson, A. S.; Javaid, H.; Martin, N. M. B.; Threadgill, M. D. Synthesis of 4Alkyl-, 4-Aryl- and 4-Arylamino-5-aminoisoquinolin-1-ones and Identification of a New PARP-2 Selective Inhibitor. Org. Biomol. Chem. 2011, 9, 881–891. (3) (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. (±)-Nuevamine, an Isoindoloisoquinoline Alkaloid, and (±)-Lennoxamine, an Isoindolobenzazepine. Tetrahedron Lett. 1984, 25, 599–602. (b) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M. Chilenine: An Isoindolobenzazepine Alkaloid. Tetrahedron Lett. 1982, 23, 39–42. (4) Hussain, S. F.; Minard, R. D.; Freyer, A. J.; Shamma, M. New Alkaloids from Fumaria parviflora. J. Nat. Product. 1981, 44, 169–178. (5) Patra, A.; Montgomery, C. T.; Freyer, A. J.; Guinaudeau, H.; Shamma, M.; Tantisewie, B.; Pharadai, K. The Protoberberine Alkaloids of Stephania suberosa. Phytochemistry 1987, 26, 547–549. (6) Calder, E. D. D.; McGonagle, F. I.; Harkiss, A. H.; McGonagle, G. A.; Sutherland, A. Preparation of AminoSubstituted Indenes and 1,4-Dihydronaphthalenes Using a One-Pot Multireaction Approach: Total Synthesis of Oxybenzo[c]phenanthridine Alkaloids. J. Org. Chem. 2014, 79, 7633–7648. (7) (a) Kise, N.; Isemoto, S.; Sakurai, T. Electroreductive Intramolecular Coupling of Phthalimides with Aromatic Aldehydes: Application to the Synthesis of Lennoxamine. J. Org. Chem. 2011, 76, 9856–9869 and references cited therein. (b) Argade, N.; Wakchaure, P. Intramolecular Chemoselective Acylation of a Suitably Substituted Isoindole: Synthesis of (±)-Chilenine and (±)-Deoxychilenine. Synthesis 2011, 17, 2838–2842 and references cited therein. (c) Fang, F. G.; Danishefsky, S. J. The Total Synthesis of Chilenine: Novel Constructions of Cyclic Enamides. Tetrahedron Lett. 1989, 30, 2747–2750. (8) (a) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. Synthesis of Isoindolobenzazepine Alkaloids Based on Radical Reactions or Pd(0)-Catalyzed Reactions. J. Org. Chem. 2009, 74, 5486–5495. (b) Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. A Short Synthesis of Lennoxamine Using a Radical Cascade. Org. Lett. 2005, 7, 4389–4390. (c) Son, K.-H.; Min, J.-Y.; Kim, G. Benzazepine Ring Formation via an Intramolecular Heck Reaction: Synthetic Application to Chilenine. Bull. Korean Chem. Soc. 2014, 35, 985–986. (9) Rys, V.; Couture, A.; Deniau, E.; Grandclaudon, P. First Total Synthesis of Fumaridine. Tetrahedron. 2003, 59, 6615–6619. (10) (a) Lee, C.-S.; Yu, T.-C.; Luo, J.-W.; Cheng, Y.-Y.; Chuang, C.-P. Radical-initiated Cyclization as a Key Step for the Synthesis of Oxoprotoberberine Alkaloids. Tetrahedron Lett. 2009, 50, 4558–4562. (b) Suau, R.; López-Romero, J. M.; Ruiz, A.; Rico, R. Synthesis of Homoprotoberberines and 8-Oxoprotoberberines by Sequential Bicyclization of Phenylacetamides. Tetrahedron 2000, 56, 993–998. (c) Cobas, A.; Guitán, E.; Castedo, L. Cycloaddition Reactions of Isoquinoline-pyrroline-2,3-dione and Carboline-pyrroline-2,3-dione with Benzyne. Total Synthesis of 8-Oxypseudopalmatine and Decarbomethoxydihydrogambirtannine. J. Org. Chem. 1992, 57, 6765–6769. (11) (a) Stubba, D.; Lahm, G.; Geffe, M.; Runyon, J. W.; Arduengo, A. J. III; Opatz, T. Xylochemistry—Making Natural Products Entirely from Wood. Angew. Chem. Int. Ed. 2015, 54, 14187–14189. (b) Li, D. Y.; Shi, K. J.; Mao, X. F.; Chen, G. R.; Liu, P. N. Transition Metal-Free Cascade Reactions of Alkynols to Afford Isoquinolin-1(2H)-one and Dihydroisobenzofuran Derivatives. J. Org. Chem. 2014, 79, 4602–4614.



(12) (a) Chen, A.; Zhao, K.; Zhang, H.; Gan, X.; Lei, M.; Hu, L. Synthesis of 8-Oxoprotoberberines Using Acidmediated Cyclization or the Heck Reaction. Monatsh. Chem. 2012, 143, 825–830. (b) Van, H. T. M.; Yang, S. H.; Khadka, D. B.; Kim, Y.-C.; Cho, W.-J. Total Synthesis of 8-Oxypseudopalmatine and 8Oxypseudoberberine via Ring-Closing Metathesis. Tetrahedron 2009, 65, 10142–10148. (c) Beugelmans, R.; Bois-Choussy, M. A Common and General Access to Berberine and Benzo[c]phenanthridine Alkaloids. Tetrahedron 1992, 48, 8285–8294. (13) (a) Yao, T.; Liu, T.; Zhang, C. Palladium-Catalyzed Domino Heck/Intermolecular Cross-Coupling: Efficient Synthesis of 4-Alkylated Isoquinoline Derivatives. Chem. Commun. 2017, 53, 2386–2389. (b) Yao, T.; He, D. Palladium-Catalyzed Domino Heck/Aryne Carbopalladation/C-H Functionalization: Synthesis of Heterocycle-Fused 9,10-Dihydrophenanthrenes. Org. Lett. 2017, 19, 842. (c) Yao, T.; Zhang, H. Zhao, Y. Synthesis of 9,10-Phenanthrenes via Palladium-Catalyzed Aryne Annulation by o-Halostyrenes and Formal Synthesis of (±)-Tylophorine. Org. Lett. 2016, 18, 2532–2535. (14) (a) Godoi, B.; Schumacher, R. F.; Zeni, G. Synthesis of Heterocycles via Electrophilic Cyclization of Alkynes Containing Heteroatom. Chem. Rev. 2011, 111, 2937. (b) Rodriguez, F.; Fananas, F. J. Metal-catalyzed Electrophilic Cyclization Reactions in the Synthesis of Heterocycles. Targets Heterocycl. Syst., 2009, 13, 273–302. (15) (a) Preindl, J.; Jouvin, K.; Laurich, D.; Seidel, G.; Fürstner, A. Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects. Chem. Eur. J. 2016, 22, 237. (b) Li, J.; Chen, L.; Chin, E.; Lui, A. S.; Zecic, H.; Platinum(II)-catalyzed Intramolecular Cyclization of Alkynylbenzonitriles: Synthesis of 1-Alkoxyisoquinolines and Isoquinolones. Tetrahedron Lett. 2010, 51, 6422–6425. (c) Singh, R. M.; Kumar, R.; Sharma, N.; Asthana, M. Palladium-Catalyzed One-Pot Synthesis of Benzo[b][1,6]naphthyridines via Sonogashira Coupling and Annulation Reactions from 2-Chloroquinoline-3carbonitriles. Tetrahedron 2013, 69, 9443–9450. (16) Chouhan, G.; Alper, H. Palladium-Catalyzed Carboxamidation Reaction and Aldol Condensation Reaction Cascade: A Facile Approach to Ring-Fused Isoquinolinones. Org. Lett. 2008, 10, 4987–4990. (17) Brahmchari, D.; Verma, A. K.; Mehta, S. Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-Mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides. J. Org. Chem. 2018, 83, 3339–3347. (18) Mehta, S.; Waldo, J. P.; Larock, R. C. Competition Studies in Alkyne Electrophilic Cyclization Reactions. J. Org. Chem. 2009, 74, 1141–1147. (19) Antien, K.; Viault, G.; Pouysegu, L.; Peixoto, P. A.; Quideau, S. Asymmetric Dearomative Spirolactonization of Naphthols Using λ3-Iodanes under Chiral Phase-Transfer Catalysis. Tetrahedron 2017, 73, 3684–3690. (20) Li, J.; Chen, L.-J.; Chin, E.; Lui, A. S.; Zecic, H. Platinum(II)-Catalyzed Intramolecular Cyclization of Alkynylbenzonitriles: Synthesis of 1-Alkoxyisoquinolines and Isoquinolones. Tetrahedron Lett., 2010, 51, 6422–6425. (21) Qandil, A. M.; Miller, D. W.; Nichols, D. E. A Practical and Cost-Effective Synthesis of 6,7-Dimethoxy-2tetralone. Synthesis, 1999, 2033–2035. (22) Blasko, G.; Gula, D. J.; Shamma, M. The Phthalideisoquinoline Alkaloids. J. Nat. Product. 1982, 45, 105– 122.


Page 22 of 22

Regio- and Stereoselective Electrophilic Cyclization Approach for the

Recommend Documents