Regio- and Stereoselective Electrophilic Cyclization Approach for the Protecting-Group-Free Synthesis of Alkaloids Lennoxamine, Chilenine, Fumaridine, 8-Oxypseudoplamatine, and 2- O-(Methyloxy)fagaronine

Article abstract of DOI:10.1021/acs.joc.8b02154

A unified strategy for protecting-group-free synthesis of alkaloids lennoxamine, chilenine, fumaridine, 8-oxypseudoplamatine, and 2-O-(methyloxy)fagaronine is reported. The core isoindolin-1-one and isoquinolin-1-one structures were built by a silver-cata

Full text of DOI:10.1021/acs.joc.8b02154

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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
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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†
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†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: yaotuanli@sust.edu.cn
Abstract: A unified strategy for protectingꢀgroupꢀfree synthesis of alkaloids lennoxamine,
chilenine, fumaridine, 8ꢀoxypseudoplamatine and 2ꢀOꢀmethyloxyfagaronine is reported. The
core isoindolinꢀ1ꢀone and isoquinolinꢀ1ꢀone structures were built by a silverꢀcatalyzed regioꢀ and
stereoselective cyclization of methyl 2ꢀalkynylbenzimidates. The regioselectiveity of cyclization
was achieved by utilizing the intrinsic functionality of alkaloids.
Introduction
Isoindolinꢀ1ꢀones1 and isoquinolinꢀ1ꢀones2 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 8ꢀ
oxypseudoplamatine (4), which inhibits cell proliferation, was found in Stephama suberosa,
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Forman
(Menispermaceae).5
2ꢀOꢀMethyloxyfagaronine
(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.
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Figure 1. Alkaloids containing isoindolinꢀ1ꢀone or isoquinolinꢀ1ꢀone skeleton
Previous synthesis of lennoxamine (1) and chilenine (2) could be classified as either first
assembly of the core isoindolinꢀ1ꢀone which was manipulated to form the benzazepine ring,7 or
the reversed sequence.8 The only reported synthesis of fumaridine (3) involved Hornerꢀ
WadsworthꢀEmmons (HWE) olefination between phosphorylated isoindolinone and substituted
benzaldehyde.9 Previous synthesis of 8ꢀoxypseudopalmatine (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 protectingꢀgroupꢀfree 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 isoindolinꢀ1ꢀone and isoquinolinꢀ1ꢀone motif could be constructed by the cyclization of 2ꢀ
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alkynylbenzimidates.15 However, a mixture of isoindolinꢀ1ꢀone and isoquinolinꢀ1ꢀone
derivatives was usually formed with isoquinolinꢀ1ꢀone derivatives as the major one.15a So the
underlying challenge was the regioꢀ (5ꢀexo to isoindoline vs 6ꢀendo to isoquinoline) and
stereoselectivity (E/Z isomers of 1ꢀmethyleneꢀ1Hꢀisoindoles) 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.
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Results and Discussion
We first investigated the steric and electronic effects of the silverꢀcatalyzed cyclization of
methyl 2ꢀalkynylbenzimidates (Scheme 1). When R is a proton, methyleneꢀ1Hꢀisoindole 7a (5ꢀ
exoꢀdig product) was obtained as the major product in a 53% yield, along with 44% of
isoquinoline 8a (6ꢀ
Scheme 1. Steric and Electronic Effects in the Silver Catalyzed Cyclization of Methyl 2ꢀ
Alkynylꢀbenzimidatesa
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aReaction conditions: 1 (0.25 mmol) and AgO2CCF3 (5 mol %), DCM (2.5 mL), rt, under air;
isolated yields
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8
9
endoꢀdig product). The reaction showed excellent stereoselectivity and only Z isomer of 7a was
obtained. When R is an electronꢀdonating pꢀmethoxy group, sixꢀmembered isoquinoline 8b was
the major product. On the other hand, when R is an electronꢀwithdrawing pꢀfluoro or pꢀester
group, fiveꢀmembered 3ꢀmethoxyꢀ1ꢀmethyleneꢀ1Hꢀisoindoles were isolated as the major
products (Scheme 1, 7c and 7d). Furthermore, when R is an oꢀester group, 1ꢀmethyleneꢀ1Hꢀ
isoindole was formed exclusively and no corresponding isoquinoline was observed (Scheme 1,
7e). Interestingly, when R is an oꢀalkyl group, the reactions mainly afforded 1ꢀmethoxyꢀ
isoquinolines (Scheme 1, 8f and 8g). While the presence of two methoxy groups on the 3ꢀ and 4ꢀ
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position of phenyl ring bearing imidate afforded a 1:1 mixture of 7h and 8h，placing two
methoxy groups on the 2ꢀ and 3ꢀposition led to exclusively generation of 1ꢀmethyleneꢀ1Hꢀ
isoindole 7i, which has reduced steric congestion compared with its isomeric 1ꢀmethoxyꢀ
isoquinoline product 8i.
The methyleneꢀ1Hꢀisoindoles 7 have been distinguished from the isoquinolines 8 on the basis
of their 1H NMR spectra. The fiveꢀmembered ring products 7 have a vinyl hydrogen, which is
observed as a singlet peak around 6.9 ppm, while in the sixꢀmembered products 8 the singlet
peak is observed around 7.6 ppm (Figure 2).
OMe
N
OMe
N
Ph
Ph
H
H
6.9 ppm
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
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organosilver intermediate II and III affords product 7 and 8 and simultaneously regenerate the
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catalyst AgO2CCF3.
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Scheme 2. Plausible Reaction Pathways
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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 3ꢀmethylene
Scheme 3. Retrosynthetic Analysis of Lennoxamine, Chilenine, Fumaridine and 8ꢀ
Oxypseudoplamatine
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isoindolinꢀ1ꢀone 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 (5ꢀexo to 3ꢀmethoxyꢀ1ꢀmethyleneꢀ1Hꢀ
isoindoline). The isoquinolinꢀ1ꢀone core of 8ꢀoxypseudoplamatine (4) and 2ꢀOꢀ
methyloxyfagaronine (5) would be constructed by the same sequence, in which the
regioselectivity of cyclization (6ꢀendo to 1ꢀmethoxyisoquinoline) would be controlled by the
acetate group.
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The synthesis of lennoxamine and chilenine was initiated from 2ꢀiodobenzamide 912c which
coupled with terminal alkyne 10, 16 led to 2ꢀalkynylbenzamide 11 in an almost quantitative yield
(Scheme 4). Treatment of 11 with Me3OBF4 afforded imidate 12, which was subjected to silverꢀ
Scheme 4. Formal Synthesis of Lennoxamine and Chilenine
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catalyzed cyclization. As we envisioned, (Z)ꢀ3ꢀmethoxyꢀ1ꢀmethyleneꢀ1Hꢀisoindole 13 was
obtained regioꢀ and stereoselectively in a 61% yield. The (Z)ꢀconfiguration of 13 was confirmed
by Xꢀray diffraction analysis. LAH reduction, mesylation and selective demethylation provided
3ꢀmethyleneꢀisoindolinꢀ1ꢀone 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 Zꢀdouble
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bond of 3ꢀmethyleneꢀisoindolinꢀ1ꢀone 16 facilitated the cyclization. Therefore, the reaction of 3ꢀ
methoxyꢀ1ꢀmethyleneꢀ1Hꢀisoindole 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
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Scheme 5. Synthesis of Fumaridine
The synthesis of 8ꢀoxypseudoplamatine (4) and 2ꢀOꢀmethyloxyfagaronine (5) started from 2ꢀ
iodobenzamide 19, which was coupled with terminal alkyne 20. The coupling product 21 was
then subjected to imidate formation/cyclization (Scheme 6). As expected, 1ꢀmethoxyisoquinoline
22 was obtained as the major product. Selective demethylation of 22 led to isoquinlinꢀ1ꢀone 23,
which could be converted to 8ꢀoxypseudoplamatine (4) and 2ꢀOꢀmethyloxyfagaronine (5)
according to known procedures.12c
Scheme 6. Formal Synthesis of 8ꢀOxypseudoplamatine
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Conclusion
In conclusion, we have developed a unified and protectingꢀgroupꢀfree strategy for the synthesis
of alkaloids lennoxamine (1), chilenine (2), fumaridine (3), 8ꢀoxypseudoplamatine (4) and 2ꢀOꢀ
methyloxyfagaronine (5). The core isoindolinꢀ1ꢀone or isoquinolinꢀ1ꢀone scaffold of these
alkaloids was built by a silverꢀcatalyzed regioꢀ and stereoselective cyclization of methyl 2ꢀ
alkynylbenzimidates. 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; DMSOꢀd6 (1H): 2.50 ppm; DMSOꢀd6 (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 FTꢀIR
spectrometer and the absorption frequencies are reported in cmꢀ1. Flash chromatography
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separations were carried out using silica gel columns. The new compounds were characterized by
1H NMR,13C NMR, HRMS, and IR. The structure of known compounds were further confirmed
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by comparing their H NMR and 13C NMR data with those of literature. All reagents and
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solvents were used as received from commercial sources without further purification.
Compounds 2ꢀ(phenylethynyl)benzamide,17 2ꢀ((4ꢀmethoxyphenyl)ethynyl)benzamide,17 2ꢀ((4ꢀ
fluorophenyl)ethynyl) benzamide,17 methyl 2ꢀ((2ꢀcarbamoylphe nyl)ethynyl)benzoate,18 and 4,5ꢀ
dimethoxyꢀ2ꢀ(phenylethynyl) benzamide17 were prepared by following literature procedure.
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General procedure for synthesis of 2-iodobenzamides 9 and 19. 6-Iodo-2,3-
dimethoxybenzamide (9). A solution of 6ꢀiodoꢀ2,3ꢀdimethoxy 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 dropꢀwise. 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
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the synthesis of 9 and was obtained as white solid (2.77 g, 90%): m.p. 189ꢀ192 °C; H 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 (ESIꢀTOF) m/z: [M+H]+ calcd for C9H11INO3 307.9778; Found 307.9773.
General procedure for the synthesis of 2-alkynylbenzamides. Ethyl 4-((2-
carbamoylphenyl)ethynyl)benzoate. To a solution of 2ꢀiodobenzamide (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 4ꢀethynylbenzoate (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 4ꢀ((2ꢀcarbamoylphenyl)ethynyl)benzoate as a white solid (0.295 g, 67%): m.p. 167ꢀ
169 °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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H15NO3 294.1125;
Found 294.1126.
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2-(o-Tolylethynyl)benzamide. This product was prepared by following the same procedure as in the
synthesis of ethyl 4ꢀ((2ꢀcarbamoylphenyl)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).
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2-((2-Isopropylphenyl)ethynyl)benzamide. This product was prepared by following the same procedure
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as in the synthesis of ethyl 4ꢀ((2ꢀcarbamoylphenyl)ethynyl)benzoate and was obtained as a white solid (0.293 g,
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74%): m.p. 121ꢀ123 °C; H 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);
13C{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 cmꢀ1; HRMS (ESIꢀTOF) 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 4ꢀ((2ꢀcarbamoylphenyl)ethynyl)benzoate and was obtained as a yellow solid
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(0.331 g, 78%): m.p. 137ꢀ140 °C; H 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 cmꢀ1; HRMS (ESIꢀTOF) 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 2ꢀ(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
cmꢀ1; HRMS (ESIꢀTOF) 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
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same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.090 g, 68%): H 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 cmꢀ1；HRMS (ESIꢀTOF) 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
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same procedure as in the synthesis of 6a and was obtained as a yellow oil (0.096 g, 76%): H 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 cmꢀ1；HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C16H12FNO 254.0976; Found 254.0977.
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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 4ꢀ
((2ꢀcarbamoylphenyl)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 cmꢀ1；
HRMS (ESIꢀTOF) 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 2ꢀ
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((2ꢀcarbamoylphenyl)ethynyl)benzoate (0.0240g, 17%) was recovered. H 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); 13C{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 cmꢀ1；HRMS (ESIꢀTOF) 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%). 2ꢀ(oꢀTolylethynyl)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 cmꢀ1；HRMS (ESIꢀTOF) 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%). 2ꢀ((2ꢀIsopropylphenyl)
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 cmꢀ1；HRMS (ESIꢀTOF) 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%). 4,5ꢀDimethoxyꢀ2ꢀ
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(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 cmꢀ1；HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H17NO3 296.1281; Found 296.1283.
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Methyl 2,3-dimethoxy-6-(phenylethynyl)benzimidate (6i). This product was prepared by following
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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 cmꢀ1；HRMS
(ESIꢀTOF) 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 2ꢀalkynylbenzimidate 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 0.5ꢀ4 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. 94ꢀ96 °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 (ESIꢀTOF) 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.
41ꢀ42 °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 (ESIꢀTOF) 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. 143ꢀ145 °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 cmꢀ1；HRMS
(ESIꢀTOF) 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. 58ꢀ59 °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 =
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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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C17H15NO2
266.1176; Found 266.1178.
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(Z)-1-(4-Fluorobenzylidene)-3-methoxy-1H-isoindole (7c). This product was obtained as a white
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solid (0.035 g, 55%): m.p. 88ꢀ89 °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 cmꢀ1; HRMS (ESIꢀTOF) 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. 81ꢀ83 °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 cmꢀ1; HRMS (ESIꢀTOF) 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. 94ꢀ96 °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 cmꢀ1; HRMS (ESIꢀTOF) 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. 56ꢀ58 °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 cmꢀ1; HRMS (ESIꢀTOF) 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. 65ꢀ66 °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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H15NO3 294.1125; Found 294.1126.
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(Z)-3-Methoxy-1-(2-methylbenzylidene)-1H-isoindole (7f). This product was obtained as a white
solid (0.011 g, 17%): m.p. 70ꢀ71 °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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C17H15NO 250.1226; Found 250.1224.
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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 cmꢀ1; HRMS (ESIꢀTOF) 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. 51ꢀ53 °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 cmꢀ1;
HRMS (ESIꢀTOF) 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 cmꢀ1; HRMS (ESIꢀTOF) 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. 140ꢀ143 °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 cmꢀ1; HRMS (ESIꢀTOF) 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. 170ꢀ171 °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);
13C{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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C18H17NO3 296.1281; Found 296.1287.
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Synthesis of methyl 2-(2-ethynylphenyl)acetates 10 and 20. Methyl 2-(6-
ethynylbenzo[d][1,3]dioxol-5-yl)acetate (10). To a solution of 2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)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 2ꢀ(6ꢀ
iodobenzo[d][1,3]dioxolꢀ5ꢀyl)acetic acid as a light yellow solid (4.0 g, 59%), which was used as is in the next step.
1H 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.
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Thionyl chloride (1.12 g, 9.39 mmol, 1.69 equiv) was added dropwise to a solution of 2ꢀ(6ꢀiodobenzo[d][1,3]
dioxolꢀ5ꢀyl)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 2ꢀ(6ꢀiodobenzo[d][1,3]dioxolꢀ5ꢀyl)acetate (1.68 g, 95%) as a white solid: m.p. 80ꢀ
82 °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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C10H9IO4 342.9438; Found 342.9415.
To a solution of methyl 2ꢀ(6ꢀiodobenzo[d][1,3]dioxolꢀ5ꢀyl)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 2ꢀ(6ꢀ
((trimethylsilyl)ethynyl)benzo[d][1,3]dioxolꢀ5ꢀyl)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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C15H18NaO4Si 313.0867; Found
313.0860.
To a solution of methyl 2ꢀ(6ꢀ((trimethylsilyl)ethynyl)benzo[d][1,3]dioxolꢀ5ꢀyl)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. 63ꢀ65 °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 cmꢀ1;
HRMS (ESIꢀTOF) 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 2ꢀ(2ꢀiodoꢀ4,5ꢀdimethoxyphenyl)acetate21 (2.17 g, 6.46 mmol) and
ethynyltrimethylsilane (0.761 g, 7.75 mmol, 1.2 equiv) afforded methyl 2ꢀ(4,5ꢀdimethoxyꢀ2ꢀ
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((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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C16H22O4Si 307.1360; Found 307.1377. 2ꢀ(4,5ꢀDimethoxyꢀ2ꢀ
((trimethylsilyl)ethynyl)phenyl)acetate (1.56 g, 5.09 mmol) afforded methyl 2ꢀ(2ꢀethynylꢀ4,5ꢀ
dimethoxyphenyl)acetate (20) (1.14 g, 96%) as a light yellow solid: m.p. 89ꢀ90 °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 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C13H14O4 235.0965; Found 235.0965.
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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 2ꢀalkynylbenzamide. 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. 210ꢀ
212 °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 cmꢀ1; HRMS (ESIꢀTOF) 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]dioxol-
5-yl)acetate (12). This compound was prepared by following the general procedure for the synthesis of methyl 2ꢀ
alkynylbenzimidates, 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 cmꢀ1; HRMS (ESIꢀ
TOF) 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-5-
yl)acetate (13). This compound was prepared by following the general procedure for silverꢀcatalyzed cyclization.
12 (0.375 g, 0.91 mmol) was cyclized to 13 (0.229 g, 61%) as a yellow solid: m.p. 166ꢀ168 °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 cmꢀ1; HRMS (ESIꢀTOF) 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)ethan-
1-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
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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. 134ꢀ135 °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);
13C{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 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C21H21NO6 384.1442; Found 384.1447.
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(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. 139ꢀ140 °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 cmꢀ1; HRMS (ESIꢀTOF) 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 pꢀ
MeC6H4SO3H（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.183ꢀ186 °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 cmꢀ1; HRMS (ESIꢀ
TOF) 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
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column chromatography (Silica Gel, DCM / MeOH) to afford dehydrolennoxamine 17 (0.027 g, 86%) as a yellow
solid: m.p. 211ꢀ213 °C (lit.7d 208ꢀ209 °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).
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(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.167ꢀ168 °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 cmꢀ1; HRMS (ESIꢀTOF) 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 backꢀextracted
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.
186ꢀ188 °C (lit.22 189ꢀ190 °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 2ꢀalkynylbenzamide. 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. 153ꢀ155 °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 (ESIꢀTOF)
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 2ꢀalkynylbenzimidates, amide 21 (0.235 g, 0.591 mmol)
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was converted to corresponding benzimidate, which was subjected to silverꢀcatalyzed 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 (ESIꢀTOF) m/z: [M+H]+ calcd for C23H26NO7 428.1704; Found
428.1706.
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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 pꢀMeC6H4SO3H
(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 Xꢀray crystallographic data
for compound 13 (PDF)
Acknowledgments
This work was financially supported by Shaanxi University of Science and Technology (BJ15ꢀ33)
and the Natural Science Foundation of Shaanxi Province of China (2017JM2004). Dr. Yifan
Kang (SUST) is acknowledged for assistance with Xꢀray di raction studies on compound 13.
References
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