Synthesis of 8-Alkoxy-5 H-isochromeno[3,4- c]isoquinolines and 1-Alkoxy-4-arylisoquinolin-3-ols through Rh(III)-Catalyzed C-H Functionalization of Benzimidates with 4-Diazoisochroman-3-imines and 4-Diazoisoquinolin-3-ones

Article abstract of DOI:10.1021/acs.joc.0c00283

Rh(III)-catalyzed C-H activation/annulation of benzimidates with 4-diazoisochroman-3-imines furnished 8-alkoxy-5H-isochromeno[3,4-c]isoquinolines in moderate to excellent yields with a broad range of substrate scope. The reaction was carried out under mild reaction conditions and could be scaled up with practical usage. Similar reaction between benzimidates and 4-diazoisoquinolin-3-ones provided 1-alkoxy-4-arylisoquinolin-3-ols in excellent yields. Moreover, the synthesized products could be conveniently transformed to the corresponding heterocycles with a 1,8-naphthyridinone or isochromenopyridinone core, which are privileged structures in medicinal chemistry.

Full text of DOI:10.1021/acs.joc.0c00283

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Article
Synthesis of 8-Alkoxy-5H-isochromeno[3,4-c]isoquinolines
and 1-Alkoxy-4-arylisoquinolin-3-ols through Rh(III)-
Catalyzed C-H Functionalization of Benzimidates with 4-
Diazoisochroman-3-imines and 4-Diazoisoquinolin-3-ones
Zhenmin Li, Jianwei Xie, Ping Lu, and Yanguang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00283 • Publication Date (Web): 23 Mar 2020
Downloaded from pubs.acs.org on March 23, 2020
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Synthesis of 8-Alkoxy-5H-isochromeno[3,4-c]isoquinolines and 1-Alkoxy-4-arylisoquinolin-3-
ols through Rh(III)-Catalyzed C-H Functionalization of Benzimidates with 4-
Diazoisochroman-3-imines and 4-Diazoisoquinolin-3-ones
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Zhenmin Li, Jianwei Xie, Ping Lu*, Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
N2
OR
OR
N2 SO2R3
N
R4
R2
O
N
N
RO
NH
R1
N
SO2R5
O
O
OH
R1
R1
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
AcOH, PhMe
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
HFIP, N2, 100 oC, 4 h
NH
SO2R5
R4
R2
27 examples
14 examples
up to 98% yield
air, 100 oC, 4 h
up to 97% yield
ABSTRACT: Rh(III)-catalyzed C-H activation/annulation of benzimidates with 4-
diazoisochroman-3-imines furnished 8-alkoxy-5H-isochromeno[3,4-c]isoquinolines in moderate to
excellent yields with a broad range of substrate scope. The reaction was carried out under mild reaction
conditions and could be scaled up with practical usage. Similar reaction between benzimidates and 4-
diazoisoquinolin-3-ones provided 1-alkoxy-4-arylisoquinolin-3-ols in excellent yields. Moreover, the
synthesized products could be conveniently transformed to the corresponding heterocycles with a 1,8-
naphthyridinone or isochromenopyridinone core, which are privileged structures in medicinal
chemistry.
INTRODUCTION
Diazo compounds are valuable reagents in modern organic synthesis because they can be
conveniently prepared and also be easily converted into more complicated compounds.1 They are also
versatile tools in chemical biology2 and material chemistry.3 By utilizing the copper(I)-catalyzed
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reaction of 2-ethynylanilines with sulfonyl azides or the Huisgen-type cycloaddition of indoles with
sulfonyl azides, we developed practical methods for thepreparation of 3-diazoindolin-2-imines in a
single step in 2014 (Figure 1).4 This class of cyclic α-diazo imidamides have been widely investigated
by us and other groups and a variety of indole-containing heterocycles were thus conveniently
synthesized.4,5 Encouraged by this success, we further prepared 4-diazoisochroman-3-imines by the
copper(I)-catalyzed reaction of (2-ethynylphenyl) methanols with sulfonyl azides in 2017.6 4-
Diazoisochroman-3-imines contain a cyclic α-diazo imidate substructure and could be used as metal
carbene precursors for cyclopropanation, transannulation7 and C-H functionalization of N-
methoxybenzamides8 and N-alkylbenzamidines.9 More significantly, we recently found that 4-
diazoisochroman-3-imines could be converted to cyclic α-diazo amides via Dimorth rearrangement.10
Thus, 4-diazoisoquinolin-3-ones appeared as more stable diazo reagents. In order to know the
reactivity of 4-diazo- isochroman-3-imines and 4-diazoisoquinolin-3-ones and their potential
applications in the synthesis of isochromans and isoquinolines which widely exist in the structures of
nature products,11 synthetic drugs,12 and organic materials,13 we studied the Rh(III)-catalyzed C-H
activation/annulation reaction of these two class of diazo compounds with benzimidates.
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N2
N2
N2
R2
R1
R1
O
N
N
SO2R
N
N
O
SO2R
SO2R
R1
-diazo imidamides
-diazo amides
4-diazoisoquinolin-3-ones
-diazo imidates
4-diazoisochroman-3-imines

(2019)

(2017)

(2014)
3-diazoindolin-2-imines
Figure 1. New Classes of Diazo Compounds Developed in Our Group
RESULTS AND DISCUSSION
Primarily, the reaction of ethyl benzimidate (1a) and diazo compound 2a was selected for screening
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the reaction conditions (Table 1). After the mixture of 1a (0.12 mmol), 2a (0.1 mmol), [Cp*RhCl2]2
(0.0025 mmol), AgSbF6 (0.01 mmol) and KOAc (0.02 mmol) in 1 mL of dichloroethane (DCE) reacted
under air atmosphere at 100 °C for 12 h, 3a, 4a14 and 5a were isolated by column chromatograph in
yields of 21%, 7% and 55%, respectively (Table 1, entry 1). Decreasing the reaction temperature and
extending the reaction time reduced the yields of these products (Table 1, entry 2). The yield of 3a was
significantly improved by changing the reaction atmosphere to nitrogen. In this way, 3a and 5a were
respectively isolated in 74% and 16% yields, while 4a could only be detected by TLC (Table 1, entry
3). Then, several solvents, such as toluene, 1,4-dioxane, 2,2,2-trifluoroethanol (TFE), and 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP), were screened and HFIP gave the best yield of 3a (Table 1, entries 4-
7). The optimal reaction time and temperature were respectively determined to be 4 h and 100 °C
(Table 1, entries 7-11). The reaction did not occur without the rhodium catalyst (Table 1, entry 12).
Silver salt was indicated to be essential to complete the reaction with excellent selectivity (Table 1,
entry 13). Higher yield of 3a was obtained when the reaction was performed without base (Table 1,
entry 14). When other silver salts were screened, no better results were observed (Table 1, entries 15-
17). Considering the simplicity, entry 14 in Table 1 was selected as the optimal reaction conditions for
the formation of 3a. Many efforts have been paid to obtain 4a in satisfactory yield were failed.
Table 1. Optimization of the Reaction Conditionsa
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OEt
OEt
NH
N
N
N2 Ts
N
[Cp*RhCl2]2
[Ag], KOAc
OEt
NH
Ts
OEt
O
N
+
+
+
solvent, N2,
temp, time
NHTs
O
O
1a
2a
3a
4a
5a
entry
1c
[Ag]
solvent
DCE
temp (°C)
time (h)
yield (%)b 3a/4a/5a
AgSbF6
100
12
21/7/55
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2c
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AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
-
DCE
60
16
12
12
12
12
12
4
7/2/48
DCE
100
100
100
100
100
100
100
80
74/trace/16
46/trace/26
68/0/20
80/0/12
89/0/0
4
PhMe
1,4-dioxane
TFE
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5
6
7
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
8
94/0/0
9
2
87/0/0
10
11
12d
13
14e
15e
16e
17e
18
4
85/0/trace
90/0/0
120
100
100
100
100
100
100
4
NR
4
79/trace/12
93/0/0
AgSbF6
AgOAc
AgBF4
AgOTf
4
4
83/0/0
4
84/0/0
4
80/0/0
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), [Cp*RhCl2]2 (2.5 mol %), [Ag] (10 mol %),
KOAc (20 mol %), solvent (1 mL), N2. b Isolated yield. c Under air atmosphere. d Without [Cp*RhCl2]2.
e Without KOAc.
Subsequently, the scope of benzimidates 1 was studied (Scheme 1). Methyl benzimidate and propyl
benzimidate provided 3b and 3c in 82% and 80%, respectively. The 4- position of benzimidate could
either be electron-withdrawing group (COCH3, CO2CH3, F, Cl, Br, CF3) for 3d-i and electron-donating
group (CH3, OCH3) for 3j and 3k. Excellent yields were observed for those with mild electron-
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withdrawing (F, Cl) and mild electron-donating groups (CH3). Both ethyl 2-fluorobenzimidate and
ethyl 3-methylbenzimidate provided products 3l and 3m in 83% yield. When ethyl 3-
chlorobenzimidate was used, isomers 3n and 3o14 were separated by column chromatograph in 18%
and 70% yields, respectively. The selectivity of more hindered 3o could be contributed to the stronger
acidity of 2-proton of 3-chlorobenzimidate, which is favored for the C−H bond activation. Ethyl 3,4-
dimethylbenzimidate regioselectively gave 3p in 72% yield.
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Scheme 1. Scope of Benzimidates 1
OR
N
OR
NH
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
N2 Ts
N
O
R1
R1
+
HFIP, N2
100 oC, 4 h
O
1
2a
3
OEt
N
OEt
OR
F
OEt
R1
O
Me
N
N
N
O
O
O
1
3d
, R = COMe, 70%
1
3e
, R = CO2Me, 72%
1
3f
, R = F, 91%
3m
, 83%
3a
, R = Et, 93%
3l
, 83%
1
3g
3h
, R = Cl, 90%
3b
3c
, R = Me, 82%
, R = n-Pr, 80%
1
, R = Br, 82%
1
3i
3j
, R = CF3, 79%
1
, R = Me, 92%
1
3k
, R = OMe, 76%
OEt
N
OEt
OEt
Me
Me
Cl
N
N
O
O
+
O
Cl
3o
, 70%
3p
, 72%
3n
, 18%
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The sulfonyl in 2 could be benzenesulfonyl, p-methoxybenzenesulfonyl, p-chlorobenzenesulfonyl,
p-fluorobenzenesulfonyl and 2-naphthalenesulfonyl as well (Scheme 2). The highest yield (97%) of
3a was obtained in the case where the sulfonyl is p-chlorobenzenesulfonyl. The 6-F-, 6-Cl-, 7-F-, 7-
Cl-, and 7-CF3-substituted 4-diazochroman-3-imines gave the corresponding products 3q-u in
excellent yields (88-97%), whereas 7-methoxy- and 6,7-methylenedioxy-substituted 4-diazochroman-
3-imines provided 3v (34%) and 3w (21%) in much lower yields.
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Scheme 2. Scope of Diazo Compounds 2
OEt
N
N2 SO2R3
N
OEt
NH
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
R2
O
+
HFIP, N2
100 oC, 4 h
O
R2
3
1a
OEt
2
OEt
N
OEt
N
N
3
3a
3a
3a
3a
3a
, R = C6H5, 86%
3
, R = 4-MeOC6H4, 77%
O
O
O
3
, R = 4-ClC6H4, 97%
3
, R = 4-FC6H4, 95%
3
, R = 2-naphthalenyl, 85%
F
Cl
3r
, 88%
3q
, 91%
OEt
OEt
2
3s
, R = F, 94%
N
2
N
3t
, R = Cl, 97%
O
2
3u
3v
, R = CF3, 96%
O
2
, R = OCH3, 34%
O
R2
3w
, 21%
O
Imine-directed Rh(III)-catalyzed ortho C-H functionalization of diarylmethanimines was also
comparatively investigated (Scheme 3). Under the same conditions for the preparation of 3 (Table 1,
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entry 14), diphenylmethanimine (6a) reacted with 2a to give 8-phenyl-5H-isochromeno[3,4-
c]isoquinoline 7a in 80% yield. In a similar way, 7b,14 7c and 7d were obtained in 58-70% yields.
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Scheme 3. Reactions of Diarylmethanimines
R
R
2a
(0.1 mmol)
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
N
R
O
NH
HFIP, N2
100 oC, 4 h
R
(0.12 mmol)
6a
6b
6c
6d
7a
7b
7c
7d
, R = H
, R = F
, R = Cl
, R = OCH3
, R = H, 80%
, R = F, 59%
, R = Cl, 58%
, R = OCH3, 70%
Delighted by these results, we then extended our method to the reaction of 4-diazoisoquinolinones
8. By using 1a and 8a as the reaction components, 9a was prepared in 75% yield.14 Because of the
structural unique and importance in medicinal chemistry,15 we further optimized the reaction
conditions in detail (Table S1, see Supporting Information). Optimal conditions were observed in the
o
case where the reaction was performed at 100 C in toluene using [Cp*RhCl2]2/AgSbF6/AcOH as
catalyst system under air atmosphere (Table S1, entry 16). Under these conditions, we tested the scope
of 1 (Scheme 4). Methyl benzimidate worked for the reaction and provided 9b in 94% yield. The
substituent on the 4-position of ethyl benzimidate could be methyl (9c, 95%), methoxy (9d, 93%),
bromo (9e, 81%), acetyl (9f, 78%) and ester (9g, 81%). Ethyl 3-methylbenzimidate afforded 9h in 98%
yield. The substituent on the 7-posision of diazo component could be electron-withdrawing (Cl, 9i,
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98%) or electron-donating (OMe, 9j, 59%). Excellent yields were also observed for 9k (94%) and 9l
(98%). Finally, 9m (92%) and 9n (74%) were prepared by changing the sulfonyl group.
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Scheme 4. Scope of Benzimidates 1
OR
R1
N2
N
R4
OR
NH
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
O
OH
R1
+
N
SO2R5
3 equiv. AcOH
PhMe, air, 100 oC, 4 h
NH
SO2R5
R4
8
1
9
OEt
OR
OEt
OEt
Me
N
N
N
N
R1
OH
OH
OH
OH
NH
Ts
NH
Ts
NH
NH
Ts
Ts
R4
1
9c
9d
9e
, R = Me, 95%
9a
9b
, R = Et, 96%
, R = Me, 94%
9h
, 98%
1
, R = OMe, 93%
4
9i
9j
, R = Cl, 98%
1
, R = Br, 81%
4
, R = MeO, 59%
1
9f
, R = COMe, 78%
1
9g
, R = CO2Me, 81%
OEt
OEt
OEt
N
N
N
OH
OH
OH
NH
SO2R5
NH
Ts
NH
Ts
Cl
O
O
5
9m
, R = 4-ClC6H4, 92%
5
9n
9k
, R = C6H5, 74%
, 94%
9l
, 98%
The rhodium-catalyzed reaction of diphenylmethanimine 6a with 8a was also tested. In this case,
10a was isolated in 82% yield (Scheme 5). Similar result was observed for the formation of 10b.
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Scheme 5. Reactions of Diarylmethane Imines
6
7
8
9
R
R
8a
(0.1 mmol)
2.5 mol % [Cp*RhCl2]2
10 mol % AgSbF6
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N
3 equiv. AcOH
PhMe, air, 100 oC, 4 h
NH
(0.12 mmol)
R
OH
Ts
R
N
H
6a
, R = H
10a
10b
, R = H, 82%
, R = MeO, 86%
6d
, R = MeO
Our methods are of practical usage. In the presence of [Cp*RhCl2]2 and AgSbF6, 0.482 g of 3a was
obtained in 87% isolated yield when 2.4 mmol of 1a and 2 mmol of 2a were used. In this case, 0.311
g of TsNH2 was simultaneously obtained in 91% yield after column chromatograph. Similarly, 0.399
g of 9a was prepared in 89% yield when 1.2 mmol of 1a and 1 mmol of 8a were used.
The further transformations of our products were also investigated. We demonstrated that the
imidate substructure in 3 could be converted to amide through an acid-catalyzed hydrolysis.16 As
shown in Scheme 6, treatment of 3a and 9a with conc. HCl in methanol gave isochromenopyridinone
11 and dibenzo[1,8]naphthyridinone 12 in excellent yields, respectively. Further treatment of 12 with
a strong base (e.g., potassium tert-butoxide)17 at 100 oC furnished dibenzo[1,8]naphthyridinone 13 in
almost quantitative yield.14 In consideration of 1,8-naphthyridinones and isochromenopyridinones
have been reported to possess strong pharmaceutical activities against cancer and inflammatory
diseases,18 our method should be valuable in medicinal chemistry.
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Scheme 6. Further Transformation of 3a and 9a
6
7
OEt
O
8
N
NH
9
HCl, EtOH
100 oC
O
O
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3a
OEt
11
, 99%
O
O
NH
NH
N
Ts
HCl, EtOH
100 oC
t-BuOK
PhMe, 100 oC
N
N
OH
NHTs
9a
13
12
, 96%
, 92%
Based on above results and literature reports,5b,19 a possible mechanism is proposed for the formation
of compounds 3a, 4a, 5a and 9a as shown in Scheme 7. Initially, 1a coordinates with rhodium and
C-H activation occurs to form intermediate A. The electron-deficient rhodium center reacts with 2a to
form Rh complex B along with the exclusion of nitrogen. A sequence of aryl migration/ligand
exchange/protonation generates intermediate D. Subsequently, D undergoes nucleophilic addition to
form E. Finally, aromatization furnishes 3a by elimination of TsNH2. The reaction of 8a processes
through a similar pathway to generate D', which undergoes nucleophilic addition-elimination to form
F. Tautomerism of F leads to a more stable product 9a. The by-products 4a and 5a may be formed
from intermediate D in the catalytic cycle. Thus, the release of the Rh (III) species from complex D
generates intermediate G, which tautomerizes to more stable 5a. On the other hand, G undergoes a
Dimroth rearrangement and intramolecular condensation sequence to give 4a.
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Scheme 7. Possible Mechanism for the Formation of 3a, 4a, 5a and 9a
6
7
8
9
OEt
OEt
NH
OEt
Dimroth
NH
H
Rearrangement
-H2O
N
OEt
NH
O
N
NHTs
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13
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NTs
Ts
O
O
N
Ts
G
5a
H
OEt
4a
NH
X
H+
-[Cp*RhX]+
Cp*
N
Rh
Ts
O
OEt
NH
OEt
NH
OEt
OEt
X
C
N
X
N
H
NHTs
O
Rh
Cp*
Rh Cp*
N
O
H
N
Ts
Ts
-TsNH2
O
X = SbF6
O
B
D
E
3a
N2
OEt
H+
1a
2a
2AgSbF6
NH
X
0.5 [Cp*RhCl2]2
[Cp*RhX]
2AgCl
C-H
activation
Rh
Cp*
8a
A
N2
OEt
OEt
OEt
OEt
X = SbF6 or AcO
N
X
Rh
N
NH
X
NH
Rh Cp*
O
Cp*
O
O
O
OEt
NHTs
NHTs
N
Ts
N
NH
X
Rh
Ts
D'
Cp*
O
B'
9a
F
N
H
Ts
C'
CONCLUSION
In conclusion, we have developed a facile and efficient protocol to construct 8-alkoxy-5H-
isochromeno[3,4-c]isoquinolines through a Rh(III)-catalyzed reaction of benzimidates and 4-
diazoisochroman-3-imines in moderate to excellent yields. Similar reaction between benzimidates and
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4-diazoisoquinolin-3-ones furnished 1-alkoxy-4-arylisoquinolin-3-ols. When diarylmethanimines
were used instead of benzimidates in these two transformations, 8-aryl-5H-isochromeno[3,4-
c]isoquinoline and 1-aryl-4-arylisoquinolin-3-ols were prepared in excellent yields, accordingly.
Furthermore, the synthesized isochromeno[3,4-c]isoquinolines and 4-arylisoquinolin-3-ols could be
conveniently converted into the corresponding heterocycles with a 1,8-naphthyridinone or
isochromenopyridinone core, which are privileged structures in medicinal chemistry.
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EXPERIMENTAL SECTION
1
13
1
General Information. NMR spectra were obtained at H 400 MHz and C 100 MHz. H NMR
chemical shifts were quoted in parts per million (ppm) referenced to 0.0 ppm of TMS or the center line
of a quintet at 2.50 ppm of DMSO-d6. 13C{1H} NMR chemical shifts were reported in ppm referenced
to the center line of a triplet at 77.00 ppm of CDCl3 or the center line of a heptet at 39.52 ppm of
DMSO-d6. Some abbreviations such as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet)
are used to describe peak patterns. J values were reported in Hz. HRMS data were recorded on ESI or
EI mass spectrometer. Flash column chromatography was performed employing 300-400 mesh silica
gel. Melting points were measured with a micro melting point apparatus without correction. Unless
otherwise mentioned, solvents and reagents were purchased from commercial sources and used as
received.
Substrates 1 and 6 were prepared according to literature reports.20,21 Diazo compounds 2 and 8
were synthesized by our previous methods.6, 8
Synthetic Procedures for Compounds 3 and 7. To an oven-dried Schlenk tube equipped with a
magnetic stirring bar was added sequentially 1a (0.12 mmol), 2a (0.1 mmol), [Cp*RhCl2]2 (0.0025
mmol), and AgSbF6 (0.01mmol). After vacuuming and backfilling with N2 three times, HFIP (1 mL)
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was injected by syringe. The reaction mixture was stirred at 100 °C (oil bath) for 4 h. After cooling to
room temperature, the resultant mixture was evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 30:1, v/v) to
give the products.
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Synthetic Procedures for Compounds 9 and 10: To an oven-dried round-bottom flask equipped
with a magnetic stirring bar was added sequentially 1a (0.12 mmol), 8a (0.1 mmol), AcOH (0.3 mmol)
and toluene (1 mL). The reaction mixture was stirred at 100 °C (oil bath) for 4 h. After cooling to room
temperature, the resultant mixture was evaporated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1, v/v) to give the
products.
Preparation of Compound 3a in 2 mmol Scale. To an oven-dried Schlenk tube equipped with a
magnetic stirring bar was added sequentially 1a (2.4 mmol), 2a (2 mmol), [Cp*RhCl2]2 (0.05 mmol),
and AgSbF6 (0.2 mmol). After vacuuming and backfilling with N2 three times, HFIP (22 mL) was
injected by syringe. The reaction mixture was stirred at 100 °C (oil bath) for 4 h. After cooling to room
temperature, the resultant mixture was evaporated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 30:1, v/v) to give 0.482
g of pure 3a (87% yield) and 0.311 g of TsNH2 as byproduct.
Preparation of Compound 9a in 1 mmol Scale. To an oven-dried round-bottom flask equipped
with a magnetic stirring bar was added sequentially 1a (1.2 mmol), 8a (1 mmol), AcOH (3 mmol) and
toluene (10 mL). The reaction mixture was stirred at 100 °C (oil bath) for 4 h. After cooling to room
temperature, the resultant mixture was evaporated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1, v/v) to give0.399
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g of pure 9a (89% yield).
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8
9
Synthetic Procedure for Compound 11. To a 25ml round bottom flask equipped with a magnetic
stirring bar was added 3a (0.1 mmol, 27.7 mg) and EtOH (3 mL). Hydrochloric acid (1 mL, 35%) was
slowly added to the solution. Then, the reaction solution was stirred at 100 °C (oil bath) for 12 hours.
After cooling down to room temperature, the mixture was washed with saturated aqueous NaHCO3
solution and extracted by DCM (3×15 mL). The organic phase was combined and dried over sodium
sulphate. The solvent was removed under reduced pressure and the residue was purified by
recrystallized from dichloromethane/n-hexane = 4:1 (v/v) to give pure 11.
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Synthetic Procedure for Compound 12. To a 25 mL round bottom flask equipped with a magnetic
stirring bar was added 9a (0.1 mmol, 44.8 mg) and EtOH (3 mL). Hydrochloric acid (1 mL, 35%) was
slowly added to the solution. Then, the solution was stirred at 100 °C (oil bath) for 12 hours. After
cooling down to room temperature, the mixture was washed with saturated aqueous sodium
bicarbonate and extracted by DCM (3×15 mL). The organic phase was combined and dried over
sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3:1, v/v) to give pure 12.
Synthetic Procedure for Compound 13. To a 25 mL round bottom flask equipped with a magnetic
stirring bar was added 12 (0.1 mmol, 40.2 mg), t-BuOK (4 equiv) and toluene (1 mL). The mixture
was stirred at 100 °C (oil bath) for 1 hour. After cooling down to room temperature, the mixture was
filtered through a pad of silica gel and washed with DCM. The solvent was removed under reduced
pressure and the residue was purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate/methanol = 6:1:0.7, v/v/v) to give pure 13.
8-Ethoxy-5H-isochromeno[3,4-c]isoquinoline (3a). White powder; petroleum ether /EtOAc (30/1)
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as eluent; Yield: 25.8 mg, 93%; M.p. 99 – 100 °C; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.4 Hz,
1H), 8.32 – 8.30 (m, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.45 – 7.40 (m, 2H), 7.3 –
7.29 (m, 2H), 5.19 (s, 2H), 4.61 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 160.8, 157.4, 136.2, 131.3, 131.2, 130.6, 128.2, 126.3, 125.2, 125.1, 124.7, 124.0, 123.4,
117.6, 102.4, 69.7, 62.8, 14.5. HRMS (EI) m/z: [M]+ Calcd for C18H15NO2 277.1103; Found 277.1101.
IR (film): 3069, 2978, 1735, 1695, 1619, 1588, 1571, 1509, 1424, 1379, 1346, 1263, 1163, 1060, 942,
823, 794 cm-1.
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8-Methoxy-5H-isochromeno[3,4-c]isoquinoline (3b). White powder; petroleum ether /EtOAc (30/1)
as eluent; Yield: 21.6 mg, 82%; M.p. 160 – 161 °C; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.8 Hz,
1H), 8.29 – 8.26 (m, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.44 – 7.39 (m, 2H), 7.30 –
13
7.28 (m, 2H), 5.19 (s, 2H), 4.16 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 161.1, 157.4, 136.2,
131.35, 131.26, 130.5,128.2, 126.3, 125.13, 125.09, 124.8, 124.1, 123.4, 117.5, 102.7, 69.7, 54.3.
HRMS (EI) m/z: [M]+ Calcd for C17H13NO2 263.0946; Found 263.0948. IR (film): 3075, 2994, 1620,
1588, 1572, 1509, 1458, 1376, 1331, 1265, 1204, 1098, 989, 773 cm-1.
8-Propoxy-5H-isochromeno[3,4-c]isoquinoline (3c). Colorless liquid; petroleum ether /EtOAc
(30/1) as eluent; Yield: 23.3 mg, 80%; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.4 Hz, 1H), 8.31
(dd, J = 8.0, 1.2 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.44 – 7.38 (m, 1H), 7.29 –
7.27 (m, 2H), 5.18 (s, 2H), 4.50 (t, J = 6.6 Hz, 2H), 1.92 (h, J = 7.2 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 157.4, 136.2, 131.3, 131.2, 130.6, 128.2, 126.2, 125.14,
125.11, 124.7, 124.0, 123.4, 117.6, 102.4, 69.7, 68.5, 22.3, 10.6. HRMS (EI) m/z: [M]+ Calcd for
C19H17NO2 291.1259; Found 291.1260. IR (film): 3070, 2966, 1619, 1588, 1571, 1508, 1425, 1360,
1329, 1290, 1264, 1203, 1163, 1097, 1061, 1026, 968, 945, 774 cm-1.
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1-(8-Ethoxy-5H-isochromeno[3,4-c]isoquinolin-11-yl)ethan-1-one
(3d).
Yellow
powder;
6
7
8
9
°
1
petroleum ether /EtOAc (30/1) as eluent; Yield: 22.3 mg, 70%; M.p. 146 – 147 C; H NMR (400
MHz, CDCl3) δ 9.00 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 8.4, 1.6 Hz, 1H), 7.87
(d, J = 8.0 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.36 – 7.31 (m, 2H), 5.21 (s, 2H), 4.62 (q, J = 7.2 Hz, 2H),
2.73 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.2, 160.6, 158.0, 138.7,
135.8, 131.3, 130.1, 128.6, 126.7, 125.8, 125.4, 124.8, 124.6, 122.2, 119.4, 103.4, 69.8, 63.1, 27.0,
14.5. HRMS (EI) m/z: [M]+ Calcd for C20H17NO3 319.1208; Found 319.1209. IR (film): 2980, 1686,
1620, 1575, 1558, 1501, 1426, 1380, 1346, 1249, 1055, 950, 827, 789cm-1.
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Methyl 8-ethoxy-5H-isochromeno[3,4-c]isoquinoline-11-carboxylate (3e). Yellow powder;
°
1
petroleum ether /EtOAc (30/1) as eluent; Yield: 24.1 mg, 72%; M.p. 199 – 200 C; H NMR (400
MHz, CDCl3) δ 9.13 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.8, 1.6 Hz, 1H), 7.89
(d, J = 7.6 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.35 – 7.29 (m, 2H), 5.21 (s, 2H), 4.62 (q, J = 7.2 Hz, 2H),
4.00 (s, 3H), 1.52 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.9, 160.6, 157.9, 135.6,
132.3, 131.2, 130.1, 128.6, 126.6, 125.9, 125.5, 125.2, 124.9, 123.6, 119.5, 103.2, 69.8, 63.1, 52.5,
14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C20H18NO4 336.1230; Found 336.1231. IR (film): 3062,
2985, 1726, 1624, 1576, 1558, 1504, 1425, 1379, 1347, 1329, 1252, 1188, 1110, 1059, 766cm-1.
8-Ethoxy-11-fluoro-5H-isochromeno[3,4-c]isoquinoline (3f). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 26.9 mg, 91%; M.p. 143 – 144 °C; 1H NMR (400 MHz, CDCl3) δ 8.30
(dd, J = 9.2, 6.4 Hz, 1H), 8.00 (dd, J = 11.2, 2.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.44 – 7.40 (m,
1H), 7.32 – 7.27 (m, 2H), 7.14 (ddd, J = 8.8, 7.6, 2.4 Hz, 1H), 5.18 (s, 2H), 4.59 (q, J = 7.1 Hz, 2H),
1.50 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.8 (d, J = 249.0 Hz), 160.7, 158.4,
137.8 (d, J = 10.6 Hz), 131.1, 130.2, 128.4, 128.2 (d, J = 10.3 Hz), 126.5, 125.2, 124.1, 114.5, 113.6
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(d, J = 24.7 Hz), 107.8 (d, J = 23.2 Hz), 102.3 (d, J = 4.3 Hz), 69.7, 62.9, 14.5. HRMS (ESI) m/z: [M
+ H]+ Calcd for C18H15FNO2 296.1081; Found 296.1081. IR (film): 3062, 2985, 1630, 1592, 1575,
1513, 1425, 1408, 1348, 1330, 1252, 1202, 1145, 1094, 865, 780cm-1.
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11-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3g). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 28.0 mg, 90%; M.p. 152 – 153 °C; 1H NMR (400 MHz, CDCl3) δ 8.37
(d, J = 1.6 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.35 (dd,
J = 8.8, 2.0 Hz, 1H), 7.33 – 7.26 (m, 2H), 5.18 (s, 2H), 4.59 (q, J = 7.6 Hz, 2H), 1.50 (t, J = 7.6 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 158.3, 138.0, 137.1, 131.2, 130.0, 128.5, 126.9, 126.6,
125.2, 124.7, 124.4, 122.6, 115.8, 101.9, 69.7, 63.0, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for
C18H15ClNO2 312.0786; Found 312.0789. IR (film): 2980, 1615, 1587, 1570, 1498, 1416, 1380, 1344,
1284, 1248, 1190, 1102, 1056, 885, 776 cm-1.
11-Bromo-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3h). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 29.1 mg, 82%; M.p. 154 – 155 °C; 1H NMR (400 MHz, CDCl3) δ 8.54
(d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.8, 1.6 Hz, 1H),
7.46 – 7.42 (m, 1H), 7.33 – 7.27 (m, 2H), 5.18 (s, 2H), 4.59 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 158.2, 137.4, 131.2, 130.0, 128.5, 127.3, 126.9, 126.7,
126.6, 125.8, 125.2, 124.4, 116.0, 101.8, 69.8, 63.0, 14.5. HRMS (EI) m/z: [M]+ Calcd for
C18H14BrNO2 355.0208; Found 355.0210. IR (film): 3075, 2979, 1611, 1586, 1567, 1496, 1429, 1415,
1380, 1345, 1284, 1265, 1189, 1100, 886, 781 cm-1.
8-Ethoxy-11-(trifluoromethyl)-5H-isochromeno[3,4-c]isoquinoline (3i). Light yellow powder;
°
1
petroleum ether /EtOAc (30/1) as eluent; Yield: 27.3 mg, 79%; M.p. 172 – 173 C; H NMR (400
MHz, CDCl3) δ 8.69 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.8, 1.6
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Hz, 1H), 7.49 – 7.45 (m, 1H), 7.36 – 7.30 (m, 2H), 5.21 (s, 2H), 4.63 (q, J = 7.2 Hz, 2H), 1.53 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 158.3, 135.5, 132.6 (q, J =32.1 Hz), 131.3,
129.8, 128.7, 126.8, 126.5, 125.4, 124.5, 124.0 (q, J = 271.3 Hz), 120.9 (q, J = 4.4 Hz), 119.7 (q, J =
3.2 Hz), 118.9, 103.0, 69.8, 63.2, 14.4. HRMS (ESI) m/z: [M + H]+ Calcd for C19H15F3NO2 346.1049;
Found 346.1051. IR (film): 2985, 1579, 1555, 1509, 1434, 1408, 1380, 1349, 1314, 1286, 1251, 1111,
903, 832, 791 cm-1.
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8-Ethoxy-11-methyl-5H-isochromeno[3,4-c]isoquinoline (3j). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 26.8 mg, 92%; M.p.85 – 86°C; 1H NMR (400 MHz, CDCl3) δ 8.19 –
8.17 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.28 – 7.23 (m, 3H), 5.16 (s, 2H), 4.59 (q,
13
J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 160.7,
157.6, 141.6, 136.5, 131.3, 130.7, 128.1, 126.1, 126.0, 125.1, 125.0, 124.7, 122.7, 115.7, 102.0, 69.7,
62.6, 22.4, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO2 292.1332; Found 292.1333. IR
(film): 2978, 1625, 1577, 1505, 1421, 1345, 1290, 1257, 1166, 1099, 1062, 827, 787 cm-1.
8-Ethoxy-11-methoxy-5H-isochromeno[3,4-c]isoquinoline (3k). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 23.3 mg, 76%; M.p. 167 – 168 °C; 1H NMR (400 MHz, CDCl3) δ 8.20
(d, J = 9.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.30 – 7.27
(m, 2H), 7.03 (dd, J = 9.2, 2.4 Hz, 1H), 5.16 (s, 2H), 4.57 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 1.49 (t, J
13
= 7.2 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 162.1, 160.7, 158.2, 138.2, 131.3, 130.9, 128.2,
127.0, 126.1, 125.2, 123.9, 115.3, 112.4, 103.2, 102.1, 69.6, 62.6, 55.4, 14.6. HRMS (EI) m/z: [M]+
Calcd for C19H17NO3 307.1208; Found 307.1210. IR (film): 2988, 1620, 2590, 1579, 1508, 1422, 1381,
1345, 1261, 1225, 1151, 1062, 1026, 843, 781 cm-1.
8-Ethoxy-9-fluoro-5H-isochromeno[3,4-c]isoquinoline (3l). White powder; petroleum ether
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/EtOAc (30/1) as eluent; Yield: 24.5 mg, 83%; M.p. 165 – 166 °C; 1H NMR (400 MHz, CDCl3) δ 8.16
(d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61 – 7.55 (m, 2H), 7.44 – 7.37 (m, 2H), 7.32 – 7.28 (m,
2H), 7.04 (ddd, J = 8.8, 7.6, 0.8 Hz, 1H), 5.17 (s, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.4 (d, J = 259.4 Hz), 160.0 (d, J = 5.5 Hz), 157.7 (d, J =
1.1 Hz), 138.9 (d, J = 22.5 Hz), 131.5 (d, J = 9.7 Hz), 131.3, 130.6, 128.3, 126.5, 125.2, 124.7, 119.2
(d, J = 4.5 Hz), 110.0 (d, J = 21.8 Hz), 108.0 (d, J = 11.6 Hz), 102.0(d, J = 2.8 Hz), 69.7, 63.1, 14.4.
HRMS (ESI) m/z: [M + H]+ Calcd for C18H15FNO2 296.1081; Found 296.1083. IR (film): 2976, 2899,
1626, 1573, 1506, 1426, 1376, 1330, 1132, 1074, 1050, 879, 806, 759 cm-1.
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8-Ethoxy-10-methyl-5H-isochromeno[3,4-c]isoquinoline (3m). Light yellow liquid; petroleum
ether /EtOAc (30/1) as eluent; Yield: 24.2 mg, 83%; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.4
Hz, 1H), 8.07 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.52 (dd, J = 8.8, 2.0 Hz, 1H), 7.42 – 7.38 (m, 1H),
7.28 – 7.27 (m, 2H), 5.16 (s, 2H), 4.60 (q, J = 6.8 Hz, 2H), 2.52 (s, 3H), 1.51 (t, J = 6.8 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 156.8, 134.3, 133.7, 133.2, 131.3, 130.7, 128.1, 126.1,
125.1, 124.7, 124.1, 123.3, 117.7, 102.4, 69.6, 62.7, 21.3, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for
C19H18NO2 292.1332; Found 292.1335. IR (film): 3045, 2978, 1590, 1568, 1512, 1428, 1347, 1258,
1202, 1097, 1055, 1024, 944, 824, 760 cm-1.
10-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3n). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 5.6 mg, 18%; M.p. 134 – 135 °C; 1H NMR (400 MHz, CDCl3) δ 8.34
(d, J = 9.2 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 8.8, 2.4 Hz, 1H),
7.42 (ddd, J = 8.0, 6.0, 2.8 Hz, 1H), 7.33 – 7.28 (m, 2H), 5.19 (s, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.51
(t, J = 7.2 Hz, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 157.6, 134.5, 131.9, 131.3, 130.1, 129.6,
128.3, 126.6, 125.3, 125.1, 124.6, 124.3, 118.4, 102.5, 69.7, 63.1, 14.5. HRMS (ESI) m/z: [M + H]+
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Calcd for C18H15ClNO2 312.0786; Found 312.0789. IR (film): 2980, 1587, 1567, 1501, 1429, 1378,
1345, 1256, 1124, 1052, 941, 881, 821 cm-1.
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12-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3o). Yellow powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 21.8 mg, 70%; M.p. 150 – 151 °C; 1H NMR (400 MHz, CDCl3) δ 8.27
(dd, J = 8.2, 1.2 Hz, 1H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.34 – 7.30 (m, 1H), 7.27
– 7.20 (m, 3H), 5.30 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 11.6 Hz, 1H), 7.66 – 7.54 (m, 2H), 1.50 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 159.9, 134.0, 133.9, 130.5, 129.3, 128.7, 128.5,
126.9, 125.7, 124.3, 124.1, 124.0, 119.9, 101.3, 70.1, 63.3, 14.4. HRMS (ESI) m/z: [M + H]+ Calcd
for C18H15ClNO2 312.0786; Found 312.0787. IR (film): 3080, 2980, 1603, 1566, 1549, 1496, 1422,
1377, 1347, 1257, 1176, 1050, 1025, 894, 773 cm-1
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8-Ethoxy-10,11-dimethyl-5H-isochromeno[3,4-c]isoquinoline (3p). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 22.0 mg, 72%; M.p.175 – 177 °C; 1H NMR (400 MHz, CDCl3) δ 8.17
(s, 1H), 8.02 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.28 – 7.27 (m, 1H), 7.29 – 7.24 (m, 2H), 5.15 (s, 2H),
4.58 (q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 1.51 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 160.2, 156.9, 141.5, 134.9, 133.5, 131.3, 130.8, 128.1, 126.0, 125.0, 124.6, 124.5, 123.3,
116.2, 101.9, 69.6, 62.5, 20.9, 19.9, 14.6. HRMS (ESI) m/z: [M + H]+ Calcd for C20H20NO2 306.1489;
Found 306.1492. IR (film): 2976, 2922, 1630, 1588, 1569, 1499, 1426, 1377, 1343, 1257, 1155, 1059,
791 cm-1.
8-Ethoxy-2-fluoro-5H-isochromeno[3,4-c]isoquinoline (3q). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 26.9 mg, 91%; M.p. 124 – 125 °C; 1H NMR (400 MHz, CDCl3) δ 8.34
(d, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.4, 0.8 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.60 (dd, J = 10.4, 2.4 Hz,
1H), 7.46 – 7.41 (m, 1H), 7.24 (dd, J = 8.0, 5.6 Hz, 1H), 6.97 (td, J = 8.4, 2.4 Hz, 1H), 5.14 (s, 2H),
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4.61 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.8 (d, J =
242.6 Hz), 161.3, 157.7, 136.0, 132.6 (d, J = 8.9 Hz), 131.6, 126.7 (d, J = 2.8 Hz), 126.5, 126.4, 125.3,
124.2, 122.9, 117.6, 112.7 (d, J = 21.9 Hz), 111.7 (d, J = 24.0 Hz), 101.7 (d, J = 2.2 Hz), 69.1, 62.9,
14.5. HRMS (EI) m/z: [M]+ Calcd for C18H14FNO2 295.1009; Found 295.1007. IR (film): 2916, 1618,
1591, 1573, 1508, 1427, 1346, 1221, 1165, 1108, 1064, 1030, 947, 878, 770 cm-1.
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2-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3r). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 27.4 mg, 88%; M.p. 123 – 124 °C; 1H NMR (400 MHz, CDCl3) δ 8.34
(d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.4, 0.8 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.75 – 7.71 (m, 1H), 7.46
– 7.42 (m, 1H), 7.26 – 7.24 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.13 (s, 2H), 4.60 (q, J = 7.2 Hz, 2H),
1.51 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.3, 157.8, 135.9, 134.1, 132.4, 131.7,
129.4, 126.3, 126.0, 125.3, 124.5, 124.3, 123.0, 117.6, 101.5, 69.1, 62.9, 14.5. HRMS (EI) m/z: [M]+
Calcd for C18H14ClNO2 311.0713; Found 311.0714. IR (film): 3073, 2979, 1619, 1584, 1570, 1508,
1426, 1378, 1346, 1320, 1265, 1198, 1164, 1100, 1063, 1030, 944, 832, 805, 771 cm-1.
8-Ethoxy-3-fluoro-5H-isochromeno[3,4-c]isoquinoline (3s). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 27.7 mg, 94%; M.p. 139 – 140 °C; 1H NMR (400 MHz, CDCl3) δ 8.35
– 8.27 (m, 2H), 7.85 (dd, J = 8.8, 5.2 Hz, 1H), 7.71 – 7.67 (m, 1H), 7.44 – 7.40 (m, 1H), 7.11 (td, J =
8.4, 2.8 Hz, 1H), 7.01 (dd, J = 8.0, 2.4 Hz, 1H), 5.14 (s, 2H), 4.60 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.2 (d, J = 245.2 Hz), 160.6, 156.9 (d, J = 0.8 Hz),
135.9, 133.4 (d, J = 7.1 Hz), 131.3, 126.7 (d, J = 3.4 Hz), 126.1 (d, J = 7.7 Hz), 125.2, 124.1, 123.1,
117.6, 114.9 (d, J = 21.2 Hz), 112.4 (d, J = 22.2 Hz), 101.8, 69.1 (d, J = 2.2 Hz), 62.8, 14.5. HRMS
(EI) m/z: [M]+ Calcd for C18H14FNO2 295.1009; Found 295.1008. IR (film): 3074, 2979, 1620, 1595,
1566, 1509, 1441, 1419, 1379, 1346, 1330, 1992, 1262, 1198, 1163, 1097, 1060, 965, 865, 771 cm-1.
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3-Chloro-8-ethoxy-5H-isochromeno[3,4-c]isoquinoline (3t). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 30.2 mg, 97%; M.p. 169 – 170 °C; 1H NMR (400 MHz, CDCl3) δ 8.31
(d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.37
(dd, J = 8.4, 2.4 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 5.13 (s, 2H), 4.60 (q, J = 7.1 Hz, 2H), 1.51 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.0, 157.4, 136.0, 132.9, 131.7, 131.4, 129.2, 128.2,
125.8, 125.3, 124.2, 123.1, 117.9, 101.7, 69.0, 62.9, 14.5. HRMS (EI) m/z: [M]+ Calcd for
C18H14ClNO2 311.0713; Found 311.0715. IR (film): 3071, 2980, 1618, 1585, 1570, 1508, 1432, 1417,
1377, 1345, 1265, 1199, 1163, 1102, 1060, 944, 872, 769 cm-1.
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8-Ethoxy-3-(trifluoromethyl)-5H-isochromeno[3,4-c]isoquinoline (3u). White powder; petroleum
ether /EtOAc (30/1) as eluent; Yield: 33.1 mg, 96%; M.p. 123 – 124 °C; 1H NMR (400 MHz, CDCl3)
δ 8.34 – 8.31 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (s,
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1H), 7.47 – 7.43 (m, 1H), 5.20 (s, 2H), 4.61 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H). C{1H}
NMR (100 MHz, CDCl3) δ 161.7, 158.2, 136.1, 134.2, 131.7, 131.4, 127.9 (q, J = 32.5 Hz), 125.4,
125.2 (q, J =3.8 Hz), 124.6, 124.4, 124.1 (q, J = 270.0 Hz), 123.0, 122.0 (q, J = 3.6 Hz), 117.7, 101.5,
69.2, 63.1, 14.5. HRMS (EI) m/z: [M]+ Calcd for C19H14F3NO2 345.0977; Found 345.0979. IR (film):
3075, 2982, 1617, 1590, 1572, 1512, 1421, 1381, 1329, 1290, 1263, 1198, 1166, 1121, 1076, 1009,
948, 887, 774 cm-1.
8-Ethoxy-3-methoxy-5H-isochromeno[3,4-c]isoquinoline (3v). White powder; petroleum ether
/EtOAc (30/1) as eluent; Yield: 10.4 mg, 34%; M.p. 138 – 139 °C; 1H NMR (400 MHz, CDCl3) δ 8.37
(d, J = 8.8 Hz, 1H), 8.30 (dd, J = 8.4, 1.2 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.43
– 7.39 (m, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 5.15 (s, 2H), 4.60 (q, J = 7.1
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Hz, 2H), 3.87 (s, 3H), 1.51 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 160.0, 158.3,
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156.5, 136.0, 133.1, 131.0, 126.0, 125.2, 123.9, 123.4, 123.3, 117.6, 113.5, 111.0, 102.4, 69.7, 62.7,
55.4, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C19H18NO3 308.1281; Found 308.1283. IR (film):
2977, 1619, 1588, 1572, 1509, 1419, 1378, 1346, 1263, 1162, 1097, 1059, 1029, 952, 866, 770 cm-1.
5-Ethoxy-8H-[1,3]dioxolo[4',5':6,7]isochromeno[3,4-c]isoquinoline (3w). Yellow powder;
petroleum ether /EtOAc (30/1) as eluent; Yield: 6.7 mg, 21%; M.p. 144 – 146 °C; 1H NMR (400 MHz,
CDCl3) δ 8.32 – 8.28 (m, 2H), 7.70 – 7.66 (m, 1H), 7.43 – 7.39 (m, 2H), 6.79 (s, 1H), 6.02 (s, 2H),
5.07 (s, 2H), 4.59 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
160.3, 156.7, 147.7, 145.9, 135.8, 131.1, 125.2, 124.9, 124.6, 123.9, 123.1, 117.5, 106.1, 105.8, 102.6,
101.2, 69.5, 62.7, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C19H16NO4 322.1074; Found 322.1075.
IR (film): 2979, 1621, 1567, 1506, 1486, 1427, 1377, 1322, 1237, 1162, 1106, 1042, 937, 885, 770
cm-1.
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8-Ethoxy-6-tosyl-5,6-dihydrodibenzo[c,f][1,8]naphthyridine (4a). White powder; petroleum ether
/EtOAc (15/1) as eluent; Yield: 3.0 mg, 7%; M.p. 109 – 110 °C; 1H NMR (400 MHz, CDCl3) δ 8.32
(d, J = 8.4 Hz, 1H), 8.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.69 – 7.65 (m, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.51
– 7.47 (m, 1H), 7.39 (dd, J = 7.2, 1.6 Hz, 1H), 7.35 – 7.28 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 4.95 (s,
2H), 4.47 (q, J = 7.8 Hz, 2H), 2.31 (s, 3H), 1.46 (t, J = 7.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 159.3, 143.7, 142.9, 138.1, 135.4, 133.4, 131.0, 130.6, 128.9, 127.5, 126.92, 126.87, 126.5, 126.0,
125.5, 124.9, 124.3, 118.6, 111.0, 63.0, 50.4, 21.4, 14.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C25H22N2NaO3S 453.1243; Found 453.1246. IR (film): 3187, 2962, 1787, 1727, 1705, 1586, 1572,
1524, 1446, 1345, 1262, 1175, 1094, 1010, 802, 678 cm-1.
Ethyl 2-(3-((4-methylphenyl)sulfonamido)-1H-isochromen-4-yl)benzimidate (5a). White powder;
petroleum ether /EtOAc (5/1) as eluent; Yield: 24.6 mg, 55%; M.p. 105 – 106 °C; 1H NMR (400 MHz,
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CDCl3) δ 8.17 – 8.14 (m, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.55 – 7.52 (m, 1H),
7.49 – 7.46 (m, 1H), 7.46 – 7.42 (m, 1H), 7.32 – 7.36 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.17 (dd, J =
7.6, 1.6 Hz, 1H), 6. 99 – 6.97 (m, 2H), 4.33 (s, 2H), 4.29 – 4.20 (m, 2H), 2.42 (s, 3H), 1.84 (s, 1H),
1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 143.4, 141.0, 140.8, 138.7, 138.4,
132.0, 131.6, 131.1, 129.5, 129.25, 129.16, 128.9, 127.5, 124.8, 124.4, 123.7, 116.4, 108.7, 63.0, 62.7,
21.5, 14.4. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H24N2NaO4S 471.1349; Found 471.1347. IR
(film): 3262, 3066, 2925, 1770, 1705, 1619, 1590, 1573, 1452, 1423, 1338, 1160, 1096, 1011, 814,
768 cm-1.
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8-Phenyl-5H-isochromeno[3,4-c]isoquinoline (7a). Yellow-green powder; petroleum ether /EtOAc
(20/1) as eluent; Yield: 24.7 mg, 80%; M.p. 86 – 87 °C; 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.4
Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.80 – 7.76 (m, 2H), 7.72 – 7.68 (m, 2H),
7.55 – 7.48 (m, 3H), 7.46 (dd, J = 7.6, 2.0 Hz, 1H), 7.43 – 7.40 (m, 1H), 7.39 – 7.36 (m, 1H), 7.34 (dd,
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J = 7.6, 2.0 Hz, 1H), 5.25 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 160.2, 157.8, 138.7, 135.4,
133.1, 130.7, 130.3, 129.9, 128.9, 128.8, 128.3, 128.2, 127.6, 126.3, 125.4, 124.8, 124.6, 124.0, 108.2,
69.5. HRMS (ESI) m/z: [M + H]+ Calcd for C22H16NO 310.1226; Found 310.1227. IR (film): 3058,
2850, 1614, 1585, 1561, 1540, 1451, 1435, 1390, 1324, 1292, 1206, 1146, 1025, 941, 775 cm-1.
11-Fluoro-8-(4-fluorophenyl)-5H-isochromeno[3,4-c]isoquinoline (7b). Light yellow solid;
°
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petroleum ether /EtOAc (20/1) as eluent; Yield: 20.4 mg, 59%; M.p. 225 – 227 C; H NMR (400
MHz, CDCl3) δ 8.15 (dd, J = 10.8, 2.8 Hz, 1H), 8.11 (dd, J = 9.6, 6.0 Hz, 1H), 7.97 (d, J = 7.6 Hz,
1H), 7.78 – 7.73 (m, 2H), 7.52 – 7.48 (m, 1H), 7.43 – 7.34 (m, 2H), 7.24 – 7.17 (m, 3H), 5.26 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 165.4 (d, J = 250.7 Hz), 163.4 (d, J = 247.8 Hz), 159.1, 158.5,
137.1 (d, J = 10.7 Hz), 134.5 (d, J = 3.5 Hz), 132.9, 132.1 (d, J = 8.2 Hz), 131.7 (d, J = 10.0 Hz),
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129.5, 128.5, 127.9, 125.6, 125.5, 122.0, 115.4 (d, J = 21.6 Hz), 114.9, 108.1 (d, J = 5.1 Hz), 108.0 (d,
J = 12.8 Hz), 69.5. HRMS (ESI) m/z: [M + H]+ Calcd for C22H14F2NO 346.1038; Found 346.1036. IR
(film): 3054, 1625, 1566, 1544, 1509, 1439, 1404, 1321, 1280, 1252, 1225, 1199, 1157, 1054, 991,
845, 786, 737 cm-1.
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11-Chloro-8-(4-chlorophenyl)-5H-isochromeno[3,4-c]isoquinoline (7c). Yellow-green solid;
petroleum ether /EtOAc (20/1) as eluent; Yield: 21.9 mg, 58%; M.p.225 – 227 °C; 1H NMR (400 MHz,
CDCl3) δ 8.52 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4
Hz, 2H), 7.53 – 7.50 (m, 3H), 7.44 – 7.40 (m, 1H), 7.38 – 7.35 (m, 2H), 5.26 (s, 2H). 13C{1H} NMR
(100 MHz, CDCl3) δ 158.8, 158.5, 137.7, 136.7, 136.2, 135.4, 133.0, 131.5, 130.0, 129.2, 128.65,
128.64, 128.1, 126.0, 125.8, 125.6, 123.1, 122.9, 107.9, 69.6. HRMS (ESI) m/z: [M + H]+ Calcd for
C22H14Cl2NO 378.0447; Found 378.0448. IR (film): 2920, 1609, 1553, 1537, 1493, 1398, 1320, 1285,
1182, 1088, 1049, 989, 844, 778 cm-1.
11-Methoxy-8-(4-methoxyphenyl)-5H-isochromeno[3,4-c]isoquinoline (7d). Light-yellow powder;
°
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petroleum ether /EtOAc (20/1) as eluent; Yield: 25.8 mg, 70%; M.p. 187 – 189 C; H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.48 – 7.44
(m, 1H), 7.38 – 7.34 (m, 2H), 7.06 – 7.03 (m, 3H), 5.22 (s, 2H), 3.97 (s, 3H), 3.89 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 161.5, 160.3, 159.4, 158.5, 137.5, 133.0, 131.6, 131.3, 130.7, 130.4, 128.2,
127.2, 125.5, 125.1, 120.4, 116.7, 113.7, 107.0, 102.6, 69.4, 55.43, 55.37. HRMS (ESI) m/z: [M + H]+
Calcd for C24H20NO3 370.1438; Found 370.1439. IR (film): 3062, 2934, 1619, 1565, 1542, 1514, 1452,
1399, 1323, 1288, 1249, 1225, 1178, 1058, 1031, 989, 840, 788 cm-1.
N-(2-(1-ethoxy-3-hydroxyisoquinolin-4-yl)benzyl)-4-methylbenzenesulfonamide
(9a).
White
powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 43.0 mg, 96%; M.p. 151 – 152 °C; 1H NMR
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(400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.47 – 7.44 (m, 1H), 7.42 – 7.35 (m, 5H), 7.29 (ddd, J
= 8.2, 6.8, 1.2 Hz, 1H), 7.18 – 7.16 (m, 1H), 7.02 (d, J = 7.6 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.46
(s, 1H), 4.86 (q, J = 7.5, 4.0 Hz, 1H), 4.57 – 4.46 (m, 2H), 3.90 (dd, J = 12.4, 7.6 Hz, 1H), 3.71 (dd, J
= 12.4, 4.0 Hz, 1H), 2.33 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.1,
152.4, 142.9, 140.0, 136.1, 135.9, 134.2, 131.9, 131.2, 130.3, 129.3, 128.6, 128.5, 126.8, 124.4, 123.4,
122.9, 115.6, 102.8, 62.7, 45.9, 21.4, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C25H25N2O4S
449.1530; Found 449.1525. IR (film): 3300, 2981, 2928, 1707, 1624, 1599, 1573, 1509, 1423, 1340,
1275, 1162, 1095, 1049, 941, 838, 771, 737, 676 cm-1.
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N-(2-(3-Hydroxy-1-methoxyisoquinolin-4-yl)benzyl)-4-methylbenzenesulfonamide (9b). Light
°
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yellow powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 40.8 mg, 94%; M.p. 88 – 89 C; H
NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 7.47 – 7.38 (m, 6H), 7.32 – 7.28 (m, 1H), 7.18 –
7.16 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.48 (s, 1H), 4.84 (dd, J = 7.6, 4.0 Hz,
1H), 4.11 (s, 3H), 3.90 (dd, J = 12.4, 7.2 Hz, 1H), 3.71 (dd, J = 12.0, 4.0 Hz, 1H), 2.34 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 160.4, 152.4, 143.0, 140.0, 136.0, 135.9, 134.1, 131.9, 131.3, 130.4, 129.3,
128.7, 128.6, 126.8, 124.3, 123.6, 123.0, 115.6, 103.0, 54.2, 45.9, 21.4. HRMS (ESI) m/z: [M + Na]+
Calcd for C24H22N2NaO4S 457.1192; Found 457.1194. IR (film): 3301, 2949, 1626, 1599, 1573, 1509,
1463, 1448, 1379, 1351, 1277, 1211, 1115, 1095, 1006, 980, 814, 771, 672 cm-1.
N-(2-(1-Ethoxy-3-hydroxy-6-methylisoquinolin-4-yl)benzyl)-4-methylbenzenesulf-onamide
(9c).
White powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 43.9 mg, 95%; M.p. 205 – 207 °C; 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 1H), 7.48 – 7.46 (m, 1H), 7.43 – 7.37 (m, 4H), 7.18 –
7.16 (m, 1H), 7.12 (dd, J = 8.4, 1.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.07 (s, 1H), 4.83
(dd, J = 7.6, 4.0 Hz, 1H), 4.56 – 4.45 (m, 2H), 3.91 (dd, J = 12.4, 7.6 Hz, 1H), 3.71 (dd, J = 12.8, 4.0
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Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.0,
152.5, 142.9, 141.8, 140.3, 136.1, 136.0, 134.4, 132.0, 130.3, 129.3, 128.6, 128.5, 126.8, 125.7, 124.2,
122.0, 113.8, 102.4, 62.5, 45.9, 22.1, 21.4, 14.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C26H26N2NaO4S 485.1505; Found 485.1506. IR (film): 3300, 2980, 1626, 1576, 1501, 1423, 1382,
1339, 1264, 1161, 1096, 1048, 810, 738, 665 cm-1.
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N-(2-(1-ethoxy-3-hydroxy-6-methoxyisoquinolin-4-yl)benzyl)-4-methylbenzene-sulfonamide (9d).
°
1
White powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 44.5 mg, 93%; M.p. 84 – 85 C; H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 1H), 7.50 – 7.47 (m, 1H), 7.43 – 7.35 (m, 4H), 7.19 –
7.17 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.90 (dd, J = 9.2, 2.4 Hz, 1H), 6.71 (s, 1H), 6.23 (d, J = 2.4 Hz,
1H), 4.89 (dd, J = 8.0, 4.0 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.92 (dd, J = 12.4, 7.6 Hz, 1H), 3.70 (dd,
J = 12.4, 3.6 Hz, 1H), 3.64 (s, 3H), 2.33 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.0, 159.9, 153.2, 142.9, 142.2, 136.1, 135.9, 134.4, 131.8, 130.3, 129.3, 128.7, 128.5,
126.8, 126.3, 115.1, 110.5, 102.5, 102.1, 62.6, 55.2, 45.9, 21.4, 14.6. HRMS (ESI) m/z: [M + H]+
Calcd for C26H27N2O5S 479.1635; Found 479.1633. IR (film): 3288, 2981, 1621, 1582, 1504, 1422,
1340, 1235, 1158, 1027, 909, 813, 733, 672 cm-1.
N-(2-(6-bromo-1-ethoxy-3-hydroxyisoquinolin-4-yl)benzyl)-4-methylbenzenesulf-onamide (9e).
White powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 42.6 mg, 81%; M.p. 205 – 206 °C; 1H
NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.44 – 7.36 (m, 4H),
7.16 – 7.12 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.08 (s, 1H), 4.84 (dd, J = 7.6, 3.6 Hz, 1H), 4.52 (q, J =
7.2 Hz, 2H), 3.93 (dd, J = 12.8, 7.6 Hz, 1H), 3.72 (dd, J = 12.8, 3.6 Hz, 1H), 2.36 (s, 3H), 1.53 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.2, 153.3, 143.0, 141.3, 136.2, 136.1, 133.3, 131.9,
130.3, 129.3, 128.82, 128.76, 126.9, 126.7, 126.1, 125.2, 114.2, 102.1, 62.9, 45.7, 21.5, 14.5. HRMS
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(ESI) m/z: [M + Na]+ Calcd for C25H23BrN2NaO4S 549.0454; Found 549.0437. IR (KBr): 3402, 3249,
2978, 1620, 1600, 1566, 1494, 1464, 1417, 1336, 1289, 1154, 1097, 1051, 872, 815, 778, 693 cm-1.
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N-(2-(6-acetyl-1-ethoxy-3-hydroxyisoquinolin-4-yl)benzyl)-4-methylbenzenesulf-onamide
(9f).
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Yellow powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 38.2 mg, 78%; M.p. 172 – 173 °C; 1H
NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 8.8, 1.6 Hz, 1H), 7.59 (d, J = 1.6
Hz, 1H), 7.48 – 7.37 (m, 5H), 7.19 – 7.17 (m, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.28 (s, 1H), 4.95 (dd, J
= 8.0, 3.6 Hz, 1H), 4.54 (q, J = 7.2 Hz, 2H), 3.94 (dd, J = 12.8, 8.0 Hz, 1H), 3.71 (dd, J = 12.8, 4.0 Hz,
1H), 2.48 (s, 3H), 2.35 (s, 3H), 1.54 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 198.2,
160.0, 153.3, 143.1, 139.7, 138.8, 136.1, 133.3, 131.9, 130.3, 129.3, 128.9, 128.7, 126.9, 125.1, 124.3,
121.6, 117.5, 103.8, 63.0, 45.7, 26.8, 21.5, 14.5. HRMS (ESI) m/z: [M + Na]+ Calcd for
C27H26N2NaO5S 513.1455; Found 513.1453. IR (film): 3285, 2981, 1684, 1625, 1577, 1498, 1425,
1384, 1336, 1246, 1159, 1103, 911, 732, 672 cm-1.
Methyl 1-ethoxy-3-hydroxy-4-(2-(((4-methylphenyl)sulfonamido)methyl)phenyl)-isoquinoline-6-
carboxylate (9g). Light yellow powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 41.0 mg, 81%;
M.p. 185 – 186 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 8.4, 1.6 Hz,
1H), 7.71 (d, J = 0.8 Hz, 1H), 7.47 – 7.37 (m, 5H), 7.18 – 7.15 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.18
(s, 1H), 4.88 (dd, J = 7.5, 3.9 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 3.92 (dd, J = 12.6, 7.6 Hz, 1H), 3.87
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(s, 3H), 3.71 (dd, J = 12.5, 3.8 Hz, 1H), 2.35 (s, 3H), 1.55 (t, J = 7.1 Hz, 3H). C{1H} NMR (100
MHz, CDCl3) δ 166.6, 159.9, 153.3, 143.0, 139.4, 135.97, 135.95, 133.4, 132.3, 131.9, 130.4, 129.3,
128.8, 128.7, 126.9, 125.3, 124.8, 122.9, 117.4, 103.7, 63.0, 52.4, 45.7, 21.4, 14.5. HRMS (ESI) m/z:
[M + Na]+ Calcd for C27H26N2NaO6S 529.1404; Found 529.1403. IR (film): 3300, 2981, 1724, 1628,
1577, 1502, 1427, 1336, 1248, 1160, 1112, 1050, 814, 768, 668 cm-1.
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N-(2-(1-ethoxy-3-hydroxy-7-methylisoquinolin-4-yl)benzyl)-4-methylbenzenesulf-onamide
(9h).
White powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 45.3 mg, 98%; M.p. 160 – 161 °C; 1H
NMR (400 MHz, CDCl3) δ 7.94 (d, J = 1.2 Hz, 1H), 7.46 – 7.44 (m, 1H), 7.41 – 7.34 (m, 4H), 7.25
(dd, J = 8.8, 2.0 Hz, 1H) (m, 1H), 7.17 – 7.15 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.4 Hz,
1H), 6.42 (s, 1H), 4.87 (s, 1H), 4.56 – 4.45 (m, 2H), 3.90 (dd, J = 12.4, 6.8 Hz, 1H), 3.70 (dd, J = 12.4,
3.2 Hz, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
159.6, 151.7, 142.9, 138.2, 136.1, 136.0, 134.4, 133.3, 133.2, 131.9, 130.3, 129.2, 128.6, 128.5, 126.8,
123.3, 122.9, 115.7, 102.7, 62.6, 45.9, 21.4, 21.3, 14.6. HRMS (ESI) m/z: [M + Na]+ Calcd for
C26H26N2NaO4S 485.1505; Found 485.1508. IR (film): 3299, 2980, 1629, 1615, 1599, 1570, 1427,
1332, 1280, 1206, 1160, 1024, 909, 814, 733, 668 cm-1.
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N-(5-chloro-2-(1-ethoxy-3-hydroxyisoquinolin-4-yl)benzyl)-4-methylbenzenesulf-onamide
(9i).
Light yellow powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 47.2 mg, 98%; M.p. 92 – 93 °C;
1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.48 – 7.41 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H),
7.34 – 7.29 (m, 2H), 7.18 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.39
(s, 1H), 4.88 (dd, J = 7.6, 4.0 Hz, 1H), 4.57 – 4.48 (m, 2H), 3.87 (dd, J = 12.8, 7.6 Hz, 1H), 3.68 (dd,
J = 12.8, 3.6 Hz, 1H), 2.34 (s, 3H), 1.53 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.4,
152.4, 143.1, 139.7, 136.1, 136.0, 134.8, 134.1, 131.8, 131.5, 129.3, 128.6, 126.9, 124.5, 123.7, 122.7,
115.7, 101.6, 62.8, 45.2, 21.4, 14.5. HRMS (ESI) m/z: [M + Na]+ Calcd for C25H23ClN2NaO4S
505.0959; Found 505.0958. IR (film): 3294, 2981, 1624, 1572, 1509, 1425, 1338, 1277, 1161, 1100,
1044, 909, 814, 771, 676 cm-1.
N-(2-(1-ethoxy-3-hydroxyisoquinolin-4-yl)-5-methoxybenzyl)-4-methylbenzene-sulfonamide (9j).
White powder; petroleum ether /EtOAc (4/1) as eluent; Yield: 28.2 mg, 59%; M.p. 188 – 189 °C; 1H
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