Total syntheses of menisporphine and daurioxoisoporphine c enabled by photoredox-catalyzed direct C-H arylation of isoquinoline with aryldiazonium Salt

Article abstract of DOI:10.1021/jo5020432

Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline alkaloids, menisporphine and daurioxoisoporphine C, through a mild and efficient photoredox-catalyzed direct C-H arylation of isoquinoline core with aryldiazonium salt. This new strategy is complementary to the conventional isoquinoline synthesis and would provide us a useful means to achieve a more convergent and flexible approach to access diverse isoquinoline structures.

Full text of DOI:10.1021/jo5020432

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Note
Total Syntheses of Menisporphine and Daurioxoisoporphine
C Enabled by Photoredox-Catalyzed Direct C–
H Arylation of Isoquinoline with Aryldiazonium Salt
Jing Zhang, Jie Chen, Xiaoyun Zhang, and Xiaoguang Lei
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5020432 • Publication Date (Web): 14 Oct 2014
Downloaded from http://pubs.acs.org on October 18, 2014
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Total Syntheses of Menisporphine and Daurioxoisoporphine
C Enabled by Photoredox-Catalyzed Direct C–H Arylation
of Isoquinoline with Aryldiazonium Salt
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Jing Zhang,†‡§ Jie Chen,†‡§ Xiaoyun Zhang,‡ and Xiaoguang Lei*‡ǁ
†School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China
‡National Institute of Biological Sciences (NIBS), Beijing, 102206, China
§These authors contributed equally.
ǁ
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College
of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and
Center for Life Sciences, Peking University, Beijing, 100871, China
xglei@pku.edu.cn
Table of Contents
Abstract
Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as
well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline
alkaloids menisporphine and daurioxoisoporphine
C
through
a
mild and efficient
photoredoxꢀcatalyzed direct C–H arylation of isoquinoline core with aryldiazonium salt. This new
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strategy is complementary to the conventional isoquinoline synthesis and would provide us a
useful means to achieve a more convergent and flexible approach to access diverse isoquinoline
structures.
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Isoquinoline alkaloids represent one of the vastest classes of natural products with striking
structural diversities as well as significant biological activities.1 For example, papaverine (Fig. 1)
is a wellꢀknown drug mainly used in the treatment of visceral spasm and vasospasm.2 Norruffscine
showed potent antiꢀHIVꢀ1 activity.3 Berberine has been used as an antibacterial drug in China
since the 1950s and was identified as a good hypolipidemic drug in 2004.4 Liriodenine exhibited a
wide range of pharmacological activities, including antibacterial, antifungal, antitumoral,
antiarrhythmic activities, etc.5 Recently, menisporphine (1), originally isolated from
Menispermum dauricum DC, was reported as a significant antiꢀangiogenic agent.6 Moreover, a
closely related natural product daurioxoisoporphine C (2) was also disclosed by Qin and
coworkers in 2001.7
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Figure1. Representative isoquinoline alkaloids.
Accordingly, complex and biologically active isoquinoline alkaloids have attracted longꢀterm
and broad attention from the synthetic community and have been the subjects of numerous
synthetic endeavors.1a,8 The traditional methods for construction of isoquinoline skeletons
including PictetꢀSpengler,9 BischlerꢀNapieralski,10 and PomeranzꢀFritsch reactions,11 have been
extensively employed for the total syntheses of isoquinoline alkaloids. However, these
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transformations typically required harsh reaction conditions, which provided poor functional
group tolerance. Recently, transition metal mediated isoquinoline syntheses12 opened new avenues
in the efficient preparation of complex isoquinoline natural products. Unfortunately, when applied
to the syntheses of isoquinoline alkaloids, most existing strategies involved preꢀinstallation of the
required functionalities before the construction of isoquinoline frameworks.
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In order to achieve more convergent and flexible synthesis, we envisioned that direct C–H
functionalization of the isoquinoline core might offer a promising alternative means to access
complex isoquinoline alkaloids. Over the past decade, a number of remarkable synthetic methods
have been developed for the direct C–H functionalization of heterocycles.13 Recently, König
group,14 and Martín and Carrillo group15 reported two elegant photocatalytic approaches16,17 for
direct C–H arylation of electronꢀrich (hetero)arenes with aryldiazonium salts or anilines nitrosated
in situ. With regard to electronꢀdeficient Nꢀheterocycles, direct C–H arylation was still a synthetic
challenge. Very recently, Xue et al disclosed the direct C–H arylation of pyridines with good
functional group tolerance utilizing aryldiazonium salts, but the reactivity of isoquinoline was
undiscussed.17j As reported by Baran et al, although a number of Nꢀheterocycles showed excellent
reactivity, only 33% yield was obtained when isoquinoline was used to react with arylboronic
acids.18 All of these previous landmark works inspired us to further develop a more efficient
method to achieve the direct CꢀH arylation of isoquinoline, which should ultimately enable us to
accomplish the efficient synthesis of diverse isoquinoline natural products. Here, we report our
endeavors in developing a mild and efficient photoredoxꢀcatalyzed direct C–H arylation of
isoquinoline core with aryldiazonium salt as well as the concise total syntheses of menisporphine
(1) and daurioxoisoporphine C (2) applying this newly developed chemistry.
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Our synthetic plan for 1 and 2 is depicted in Scheme 1. We envisioned that the methylamino
group of 2 could be installed through a biomimetic amination of 1. The C11a–C11b and C7a–C7
bonds of 1 could be derived through a Minisciꢀtype19 direct C–H arylation of methyl ester 3 with
4ꢀmethoxybenzenediazonium tetrafluoroborate 4 and an intramolecular FriedelꢀCrafts acylation
reaction, respectively. The methyl ester 3 could be prepared from the known bromide 5.20
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Scheme 1. Retrosynthetic analysis.
We first examined the crucial direct C–H arylation of isoquinoline 6 with aryldiazonium salt 4.
Several metal catalysts and solvents were carefully investigated, and the results were displayed in
Table 1. The control reaction suggested a catalyst was required for this reaction system (Table 1,
entry 1). Through the screen of various catalysts, we were pleased to find that the photoredox
catalyst Ru(bpy)3Cl2•6H2O gave us the best results (38% yield, entry 12) when the reaction was
conducted in DMSO utilizing a 40W compact fluorescent bulb. Among other nonꢀphotoreaction
catalysts, 20% CuCl gave the highest yield (35%) in DMSO (entry 4). Trifluoroacetic acid was
required for this reaction (entry 4, 5), most likely because it could protonate the heterocycles and
increase their reactivities. Further screening of different solvent showed that the yield was
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improved to 55% when MeOH was employed (entry 14). Other commonly used photoredox
catalysts like eosin Y and Ir(ppy)3 reduced the yield of the arylated product 7 (entry 11, 16).
Remarkably, we observed that the photoredoxꢀcatalyzed reaction could proceed smoothly at
roomꢀtemperature, which provided us a very mild reaction condition to facilitate the synthesis of
highly functionalized isoquinolines.
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Table 1. Initial reaction screeninga
Entry
11
Catalyst
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yieldb
trace
trace
12%
35%
20%c
25%
24%
13%
27%
11%
5%d
none
22
3
20% AgNO3
20% CoCl2
20% CuCl
20% CuCl
20% CuBr
20% CuI
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20% Fe(OAc)2
20% Mn(OAc)3
1% Eosin Y
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2.5% Ru(bpy)3Cl2•6H2O DMSO
38%e
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2.5% Ru(bpy)3Cl2•6H2O MeCN
2.5% Ru(bpy)3Cl2•6H2O MeOH
2.5% Ru(bpy)3Cl2•6H2O MeOH
29%e
55%e
NRf
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2.5% Ir(ppy)3
MeOH
28%e
a General conditions: isoquinoline (0.1 mmol), 4 (0.4 mmol), TFA (0.1 mmol), solvent (1 mL), 25
c
d
oC, 48 h. b Isolated yields. The reaction was conducted without TFA. König’s conditions14:
e
isoquinoline (1.0 mmol), 4 (0.1 mmol), 530 nm, 1 W LED bulb as the light source. A 40 W
compact fluorescent light bulb was used as the light source. f no light. DMSO = dimethylsulfoxide,
TFA
=
trifluoroacetic acid, bpy
=
2,2'ꢀbipyridine, NR
=
no reaction, ppy
=
2ꢀphenylpyridinatoꢀC2,N.
We then examined the scope of aryldiazonium salts for the arylation of isoquinoline 6 under the
optimal conditions, and the results were summarized in Scheme 2. In general, the electronꢀrich
aryldiazonium salts showed better reactivity than the electronꢀdeficient ones. The reaction system
tolerated several functional groups including OMe, CF3 and Br (12–15). However, we also
observed that the reactivities of singleꢀsubstituted aryldiazonium salts unfortunately decreased as
follows: paraꢀ > metaꢀ > orthoꢀsubstitution (e.g., 9–11), which was probably attributed to the
steric hindrance effect. As a result, nearly half of the starting material was recovered when
2ꢀmethylbenzenediazonium tetrafluoroborate (11) was used for this reaction. Interestingly, we
found that some other types of heterocycles also exhibited good reactivity. Quinolines (16, 17),
acridine (18), phthalazine (19), pyridine (20) and pyrazine (21) could be directly C–H arylated
using this method in moderate to good yields. The regioꢀselectivity for quinolines tended to favor
the 2ꢀposition over the 4ꢀposition.
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Scheme 2. Substrate scopea
5
6
7
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9
N2BF4
R
1.0 equiv TFA
N
2.5% Ru(bpy)3Cl2 6H2O
+
N
40 W lightbulb
MeOH (0.1 M), 25 oC, 48 h
R
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1.0 equiv
6
4.0 equiv
N
N
N
N
Me
Me
Me
8
42%
10
11
9
21%b
30%
57%
N
N
N
N
OMe
OMe
CF3
Br
OMe
15
43%c
12
48%
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41%
14
33%
N
Me
N
4
OMe
2
N
OMe
16
80%
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41%
OMe
18
49%
(1.6:1:0.4 C2:C4:bis)c
N
N
COOMe
N
N
N
OMe
OMe
OMe
19
51%c,d
21
20
64%
70%d
a Reactions were conducted at 0.4 mmol scale under the reaction conditions in Table 1, entry 13.
b
c
Yields are of the isolated products. 42% starting material was recovered. The reaction was
conducted at 0.1 mmol scale. d 2.0 equiv of TFA was added to the reaction mixture.
Our proposed mechanism for the rutheniumꢀcatalyzed photoreaction is described in Scheme 3
which is based on our experimental results and the known catalytic cycle.14,17j,21 The photocatalyst
Ru(Ⅱ) first turns to the excited state with the visible light, followed by single electron transfer
(SET) from the excited state of Ru(Ⅱ) to aryldiazonium salt, which would afford the aryl radical
22. Subsequently the aryl radical 22 adds to the protonated isoquinoline 23 to give the radical
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cation intermediate 24, which is further transformed to the protonated target molecule 25 by two
possible pathways: (a) oxidation of the radical cation intermediate 24 by the Ru(Ⅲ) and followed
by deprotonation to yield 25 or (b) oxidation of 24 by aryldiazonium salt and then deprotonation
to afford 25 to complete the catalytic cycle of SET. However, no reaction occurred without light
according to the light “on/off” experiment (Table 1, entry 14, 15), indicating that pathway b, a
radical chain propagation pathway, was less possible.
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Scheme 3. The proposed mechanism for the photocatalytic direct C–H arylation of isoquinoline.
Scheme 4. Total syntheses of menisporphine and daurioxoisoporphine Ca
a Reagents and conditions: (a) CO (45 atm), MeOH, Et3N, 1,3ꢀDPPP, Pd(OAc)2, DMSO, 80 oC, 18
o
h; (b) KOH, EtOH/H2O, microwave, 100 oC, 2 h; (c) TFAA, 80 C, 13 h; (d) MeNH2, CH2Cl2,
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sealed tube, 100 oC, 8 h. 1,3ꢀDPPP = 1,3ꢀbis(diphenylphosphino)propane, TFAA = trifluoroacetic
anhydride.
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After establishing the key C–H arylation reaction, we then set out to investigate its synthetic
application in the total syntheses of isoquinoline alkaloids 1 and 2 (Scheme 4). The readily
available bromide 5 was converted into the methyl ester 3 in 87% yield through a
palladiumꢀcatalyzed methoxycarbonylation22 utilizing carbon monoxide and methanol. Then 3 was
subjected to the newly developed direct C–H arylation condition. It was interesting to find that in
this case higher yield of compound 26 (47%, 62% brsm) was obtained when DMSO was
employed as the solvent than methanol was used as the solvent previously. After extensive
screening of reaction conditions, hydrolysis of the ester 26 under a basic and microwave condition
afforded the acid 27, which was subsequently cyclized by the treatment of trifluoroacetic
anhydride through an intramolecular FriedelꢀCrafts acylation reaction to furnish the desired
natural product menisporphine (1) in 57% yield over two steps. Compared with the classic
approaches for isoquinoline syntheses, the current strategy offered us a more concise (only 4
steps) and convergent synthetic route with good total yield (23%, 31% brsm). With menisporphine
(1) in hand, we further investigated the biomimetic transformation from menisporphine to
daurioxoisoporphine C (2). To our delight, the direct amination was smoothly realized by the
treatment of 1 with methylamine23 to complete the first total synthesis of daurioxoisoporphine C
(2) in good yield (82%). The spectroscopic data of the synthetic compounds 1 and 2 fully matched
the data reported previously for the natural products.
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In conclusion, we have accomplished the concise total syntheses of two isoquinoline alkaloids
menisporphine and daurioxoisoporphine C (4 and 5 steps, respectively). The synthesis featured a
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newly developed photoredoxꢀcatalyzed direct C–H arylation of isoquinoline core with
aryldiazonium salts and a late stage biomimetic amination of menisporphine. The direct C–H
arylation of isoquinoline proceeds at room temperature and can also be applied to other
electronꢀdeficient heteroarenes with good functional group tolerance. Further investigations of its
synthetic application in other complex isoquinoline natural product synthesis are currently
underway and will be reported in due course.
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EXPERIMENTAL SECTION
General Methods. Organic solutions were concentrated under reduced pressure on a Büchi rotary
evaporator (Rꢀ3). Dimethylsulfoxide (DMSO) were distilled from anhydrous CaSO4/calcium
hydride; acetonitrile were distilled from calcium hydride; trifluoroacetic acid (TFA) were distilled
from trifluoroacetic anhydride; methanol were distilled from magnesium; acetone were distilled
from K2CO3/KMnO4 prior to use. Analytical thin layer chromatography (TLC) was performed
using 0.25 mm silica gel 60ꢀF plates and the visualization was accomplished with short wave UV
light (254 nm) and phosphomolybdic acid. Chromatographic purification of products was
accomplished using forceꢀflow chromatography on basic aluminum oxide (200ꢀ300 mesh) or
silica gel (200ꢀ400 mesh). 1H NMR spectra were recorded on a 400 MHz spectrometer at ambient
temperature with CDCl3 as the solvent unless otherwise stated. 13C NMR spectra were recorded on
a 100 MHz spectrometer (with complete proton decoupling) at ambient temperature. Chemical
1
shifts are reported in parts per million relative to chloroform (1H, δ7.26; 13C, δ77.0). Data for H
NMR are reported as follows: chemical shift(ppm), integration, multiplicity (s = singlet, d =
doublet, t = triplet, q =quartet, dd = doubleꢀdoublet, dq = double quartet, ddd= double double
doublet, sept = septet, m = multiplet, br = broad, and app = apparent) and coupling constants (Hz).
High resolution mass spectra (HRMS) were recorded by FTMS spectrometer. All reactions were
carried out in ovenꢀdried glassware under an argon atmosphere unless otherwise noted.
General procedure for the preparation of aryl diazonium tetrafluoroborates.24 The
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appropriate aniline (10 mmol) was dissolved in a mixture of 50% hydrofluoroboric acid (3.4 mL)
and distilled water (4 mL). After cooling to 0 °C with ice bath. Sodium nitrite (0.69 g) in distilled
water (1.5 mL) was added dropwise in a period of 5 minutes. The resulting mixture was stirred for
a period of 30 minutes and the precipitate was collected by filtration and redissolved in minimum
amount of acetone. Diethyl ether was added until the precipitation of diazonium tetrafluoroborate,
which was filtered, washed with diethyl ether several times and dried under vacuum.
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General procedure for the reaction of heterocycle with aryl diazonium tetrafluoroborate. An
ovenꢀdried 10 mL vial equipped with a magnetic stir bar was taken into the glove box. To the vial
was added Ru(bpy)3Cl2•6H2O (7.5 mg, 0.01 mmol), aryl diazonium tetrafluoroborate (1.6 mmol)
and MeOH (2 mL). A solution of heterocycle (0.4 mmol) and trifluoroacetic acid (30.6 µL, 0.4
mmol) in MeOH (2 mL) was added into the reaction vial. The vial was sealed with a septum
before removed from the glove box and placed approximately 2 cm from a 40 W compact
fluorescent light bulb. The reaction mixture was stirred at room temperature for 48 h. Then the
solution was evaporated to remove MeOH and the resulting residue was dissolved in CH2Cl2 (4
mL) and washed with saturated aqueous sodium bicarbonate (2 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3×4 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Purification of the crude
product was performed by aluminum oxide or silica gel chromatography with petroleum
ether/ethyl acetate or dichloromethane/methanol (depending on different substrates) as the eluent.
1-(4-Methoxyphenyl)isoquinoline (7). The General Procedure was followed but at 0.1 mmol
scale to afford 1ꢀ(4ꢀmethoxyphenyl)isoquinoline (7) as a light yellow solid (13.0 mg, 55%). The
spectroscopic data for this compound were identical to those reported in the literature.25
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1-Phenylisoquinoline (8). The General Procedure was followed to afford 1ꢀphenylisoquinoline (8)
as a yellow oil (34.4 mg, 42%). The spectroscopic data for this compound were identical to those
reported in the literature.26
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1-(p-Tolyl)isoquinoline (9). The General Procedure was followed to afford 1ꢀ(pꢀtolyl)isoquinoline
(9) as a yellow oil (50.0 mg, 57%). The spectroscopic data for this compound were identical to
those reported in the literature.26
1-(m-Tolyl)isoquinoline (10). The General Procedure was followed to afford
1ꢀ(mꢀtolyl)isoquinoline (10) as a white solid (26.0 mg, 30%): mp 76.9 – 78.7 ºC; 1H NMR (400
MHz, CDCl3) δ 8.61 (d, J = 5.7 Hz, 1H), 8.15 – 8.10 (m, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.69 (ddd,
J = 8.2, 6.9, 1.2 Hz, 1H), 7.64 (dd, J = 5.7, 0.7 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.48 (d, J = 7.6 Hz,
1H), 7.44 – 7.39 (m, 1H), 7.31 (d, J = 7.5 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
160.9, 142.2, 139.5, 138.1, 136.8, 130.5, 129.9, 129.3, 128.1, 127.7, 127.1, 127.0, 126.9, 126.7,
119.8, 21.5; IR (neat) ν = 3047, 2918, 1619, 1581, 1555, 1498, 1384, 1354, 1275, 1162, 1137, 872,
826, 781, 751, 707, 633 cmꢀ1; HRMS (ESI) [M + H]+ calculated for C16H14N: 220.1121, found:
220.1118.
1-(o-Tolyl)isoquinoline (11). The General Procedure was followed to afford
1ꢀ(oꢀtolyl)isoquinoline (11) as a light yellow oil (18.4 mg, 21%) and the starting material
isoquinoline as a colorless oil (21.6 mg, 42%) . The spectroscopic data for this compound were
identical to those reported in the literature.27
1-(3-Methoxyphenyl)isoquinoline (12). The General Procedure was followed to afford
1ꢀ(3ꢀmethoxyphenyl)isoquinoline (12) as a yollow oil (47.0 mg, 48%). The spectroscopic data for
this compound were identical to those reported in the literature.28
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1-(4-(Trifluoromethyl)phenyl)isoquinoline (13). The General Procedure was followed to afford
1ꢀ(4ꢀ(trifluoromethyl)phenyl)isoquinoline (13) as a white solid (44.0 mg, 41%): mp 130.4 –
132.4 ºC; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.7 Hz, 1H), 8.03 (dd, J = 8.5, 0.9 Hz, 1H),
7.92 (d, J = 8.2 Hz, 1H), 7.86 – 7.78 (m, 4H), 7.75 – 7.69 (m, 2H), 7.57 (ddd, J = 8.3, 6.9, 1.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 159.1, 143.1, 142.3, 136.9, 130.7 (q, J = 32.5 Hz), 130.3,
130.3, 127.6, 127.2, 126.9, 126.5, 125.3 (q, J = 3.7 Hz), 124.2 (q, J = 270.6 Hz), 120.6; IR (neat) ν
= 3058, 1618, 1582, 1555, 1404, 1332, 1158, 1114, 1070, 839, 831, 756, 681, 610 cmꢀ1; HRMS
(ESI) [M + H]+ calculated for C16H11F3N: 274.0838, found: 274.0839.
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1-(4-Bromophenyl)isoquinoline (14). The General Procedure was followed to afford
1ꢀ(4ꢀbromophenyl)isoquinoline (14) as a yellow solid (37.3 mg, 33%). The spectroscopic data for
this compound were identical to those reported in the literature.29
1-(3,4-Dimethoxyphenyl)isoquinoline (15). The General Procedure was followed but at 0.1
mmol scale to afford 1ꢀ(3,4ꢀdimethoxyphenyl)isoquinoline (15) as a light yellow solid (11.5 mg,
43%). The spectroscopic data for this compound were identical to those reported in the literature.30
2-(4-Methoxyphenyl)quinoline
(16-C2),
4-(4-methoxyphenyl)quinoline
(16-C4),
2,4-bis(4-methoxyphenyl)quinoline (16-C2C4). The General Procedure was followed but at 0.1
mmol scale to afford 2ꢀ(4ꢀmethoxyphenyl)quinoline (16-C2) as a light yellow solid (10.0 mg,
43%), 4ꢀ(4ꢀmethoxyphenyl)quinoline (16-C4) as
a yellow oil (6.3 mg, 27%), and
2,4ꢀbis(4ꢀmethoxyphenyl)quinoline (16-C2C4) as a light yellow oil (3.5 mg, 10%). For 16-C2 and
16-C4, the spectroscopic data were identical to those reported in the literature.31 For 16-C2C4:1H
NMR (400 MHz, CDCl3) δ 8.23 – 8.13 (m, 3H), 7.92 (dd, J = 8.4, 1.0 Hz, 1H), 7.75 (s, 1H), 7.71
(ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.45 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.12 –
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7.02 (m, 4H), 3.92 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 159.8, 156.4, 148.9,
148.7, 132.3, 130.8, 130.8, 129.9, 129.3, 128.9, 125.8, 125.7, 125.6, 118.8, 114.2, 114.0, 55.4,
55.4; IR (neat) ν = 3000, 2932, 2835, 2360, 2342, 1607, 1516, 1497, 1462, 1401, 1359, 1291,
1248, 1178, 1032, 833, 766 cmꢀ1; HRMS (ESI) [M + H]+ calculated for C23H20NO2: 342.1489,
found: 342.1481.
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2-(4-Methoxyphenyl)-4-methylquinoline (17). The General Procedure was followed to afford
2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀmethylquinoline (17) as a yellow oil (40.3 mg, 41%). The spectroscopic
data for this compound were identical to those reported in the literature.32
9-(4-Methoxyphenyl)acridine (18). The General Procedure was followed with the exception of
the way of work up: the solution of the reaction was evaporated to remove MeOH and the
resulting residue was diluted with CH2Cl2 (10 mL) and dry sodium bicarbonate solid (500 mg)
was added to the residue. The resulting mixture was stirred for 1 hour, filtered and the sodium
bicarbonate solid was washed with CH2Cl2 several times. The CH2Cl2 solutions were combined
and concentrated in vacuum. Purification of the crude product was performed by aluminum oxide
chromatography with petroleum ether/ethyl acetate as the eluent to afford
9ꢀ(4ꢀmethoxyphenyl)acridine (18) as a yellow solid (55.3 mg, 49%). The spectroscopic data for
this compound were identical to those reported in the literature.33
1-(4-Methoxyphenyl)phthalazine (19). The General Procedure was followed but at 0.1 mmol
scale and with the addition of 2.0 equiv of TFA to afford 1ꢀ(4ꢀmethoxyphenyl)phthalazine (19) as
o
1
a white solid (12.0 mg, 51%): mp 124.0 – 126.0 C; H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H),
8.14 – 8.11 (m, 1H), 8.04 – 7.96 (m, 1H), 7.88 (tdd, J = 9.6, 7.0, 1.4 Hz, 2H), 7.77 – 7.70 (m, 2H),
7.14 – 7.04 (m, 2H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 159.4, 150.2, 132.4,
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132.0, 131.5, 128.5, 127.1, 126.6, 126.2, 125.4, 114.0, 55.4；IR (neat) ν = 3052, 2961, 2932, 2838,
2359, 2341, 1722, 1611, 1518, 1489, 1367, 1253, 1176, 1034, 840, 738, 703 cmꢀ1; HRMS (ESI)
[M + H]+ calculated for C15H13N2O: 237.1022, found: 237.1023.
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Methyl 2-(4-methoxyphenyl)isonicotinate (20). The General Procedure was followed to afford
methyl 2ꢀ(4ꢀmethoxyphenyl)isonicotinate (20) as a light yellow solid (62.0 mg, 64%): mp 68.5 –
o
70.5 C; 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J = 5.0, 0.8 Hz, 1H), 8.23 (dd, J = 1.4, 0.9 Hz,
1H), 8.04 – 8.00 (m, 2H), 7.70 (dd, J = 5.0, 1.5 Hz, 1H), 7.04 – 6.99 (m, 2H), 3.98 (d, J = 1.9 Hz,
3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 160.9, 158.1, 150.3, 138.0, 131.1, 128.3,
120.3, 118.9, 114.2, 55.4, 52.7；IR (neat) ν = 2953, 2838, 1731, 1606, 1556, 1515, 1435, 1303,
1251, 1176, 1111, 1031, 972, 836, 764, 684 cmꢀ1; HRMS (ESI) [M + H]+ calculated for C14H14NO3:
244.0968, found: 244.0967.
2-(4-Methoxyphenyl)pyrazine (21). The General Procedure was followed with the addition of
2.0 equiv of TFA to afford 2ꢀ(4ꢀmethoxyphenyl)pyrazine (21) as a yellow solid (52.0 mg, 70%).
The spectroscopic data for this compound were identical to those reported in the literature.34
Procedures for the syntheses of menisporphine and daurioxoisoporphine C
Methyl 6,7-dimethoxyisoquinoline-8-carboxylate (3). A mixture of bromide 5 (525 mg, 1.96
mmol), triethylamine (396 mg , 3.92 mmol), 1,3ꢀbis(diphenylphosphino)propane (143 mg, 0.35
mmol) and palladium acetate (78 mg, 0.35 mmol) in DMSO (2 mL) and MeOH (20 mL) was
placed in a pressure reactor and pressurized with carbon monoxide (45 atm).22 The mixture was
heated to 80 °C with stirring for 18 h, then cooled, filtered through a shortꢀpad of celite (eluting
with ethyl acetate), and concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL),
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and then washed with water (15 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by aluminum oxide chromatography (eluting with
petroleum ether/ethyl acetate = 3:1) to afford 3 as a white solid (421 mg, 87% yield): mp 78.2 –
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80.2 ºC; H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 7.52 (dd, J = 5.7,
0.7 Hz, 1H), 7.15 (s, 1H), 4.07 (s, 3H), 4.02 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
166.5, 155.3, 148.5, 147.9, 143.2, 134.1, 124.2, 121.2, 119.3, 107.1, 62.0, 56.0, 52.7; IR (neat) ν =
2948, 1729, 1616, 1472, 1426, 1336, 1303, 1249, 1212, 1045, 1014, 858, 757, 637 cmꢀ1; HRMS
(ESI) [M + H]+ calculated for C13H14NO4: 248.0917, found: 248.0913.
Methyl 6,7-dimethoxy-1-(4-methoxyphenyl)isoquinoline-8-carboxylate (26). An ovenꢀdried 10
mL vial equipped with a magnetic stir bar was taken into the glove box. To the vial was added
Ru(bpy)3Cl2•6H2O (9.2 mg, 0.0123 mmol), 4ꢀmethoxybenzenediazonium tetrafluoroborate 4 (431
mg, 1.94 mmol) and DMSO (2.45 mL). A solution of 3 (120 mg, 0.49 mmol) and trifluoroacetic
acid (73 µL, 0.98 mmol) in DMSO (2.45 mL) was added into the reaction vial. The vial was
sealed with a septum before removed from the glove box and placed approximately 2 cm from a
40 W compact fluorescent light bulb. The reaction mixture was stirred at room temperature for 48
h. Then the solution was diluted with CH2Cl2 (8 mL) and washed with saturated aqueous sodium
bicarbonate (5 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2
(3×6 mL). The combined organic layers were washed with water (3×10 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residue was purified by aluminum oxide
chromatography (eluting with petroleum ether/ethyl acetate = 19:1 to 9:1) to afford 26 as a yellow
solid (81 mg, 47%, 62% b.r.s.m.), together with the recovered starting material 3 (28 mg).
Compound 26: mp 154.7 – 156.7 ºC; 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.2 Hz, 1H), 7.50
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(d, J = 5.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.20 (s, 1H), 6.96 (d, J = 8.1 Hz, 2H), 4.04 (s, 3H),
3.91 (s, 3H), 3.86 (s, 3H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 159.8, 158.5, 155.1,
148.5, 141.9, 136.3, 133.3, 130.9, 125.9, 119.3, 118.6, 113.2, 107.4, 62.1, 56.0, 55.4, 52.0; IR
(neat) ν = 2945, 1733, 1608, 1469, 1412, 1273, 1249, 1178, 1125, 1046, 1017, 837, 777 cmꢀ1;
HRMS (ESI) [M + H]+ calculated for C20H20NO5: 354.1336, found: 354.1332.
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Menisporphine (1). Compound 26 (22.8 mg, 0.065 mmol) was added to a solution of KOH (5 N)
in 2.2 mL of EtOH/H2O (1:10). The vial was capped and heated in the microwave reactor at 100
oC for 2 h, and then the alkaline solution was cooled to room temperature, neutralized to pH 7 with
1 N HCl, and extracted with nꢀBuOH (4×10 mL). The organic layers were dried over Na2SO4,
filtered and concentrated in vacuo to afford the crude acid 27, which was dissolved in 4 mL of
TFAA in a sealed tube. The tube was capped then stirred at 80 oC for 13 h. The reaction solution
was cooled to room temperature, added dropwise to iceꢀcold water (15 mL), neutralized to pH 7
with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×20 mL). The organic layers were
dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by aluminum
oxide chromatography (eluting with petroleum ether/ethyl acetate = 9:1) to afford menisporphine
1 as a yellow solid (11.8 mg, 57% over 2 steps): mp 205.3 – 206.8 ºC; 1H NMR (400 MHz, CDCl3)
δ 8.79 (d, J = 8.8 Hz, 1H), 8.66 (d, J = 5.5 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 5.5 Hz,
1H), 7.40 (s, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 4.15 (s, 3H), 4.08 (s, 3H), 3.98 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 182.6, 161.3, 156.4, 155.5, 147.3, 143.6, 134.8, 133.3, 129.7, 126.9, 122.0,
120.5, 119.0, 118.4, 111.5, 108.9, 61.5, 56.3, 55.7; IR (neat) ν = 2923, 2851, 2358, 1656, 1603,
1472, 1413, 1349, 1279, 1242, 1139, 1014, 839, 805, 627 cmꢀ1; HRMS (ESI) [M + H]+ calculated
for C19H16NO4: 322.1074, found: 322.1071.
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Daurioxoisoporphine C (2). To a solution of 1 (8.4 mg, 0.026 mmol) in CH2Cl2 (1 mL) was
added methylamine (27.0~32.0% in alcohol, 1 mL). The resulting mixture was stirred at 100 oC in
a sealed tube for 8 h, before cooled to room temperature.23 Then the reaction mixture was diluted
with water (3 mL), and extracted with CH2Cl2 (3×5 mL). The organic layers were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by aluminum oxide chromatography
(eluting with petroleum ether/ethyl acetate = 9:1) to afford daurioxoisoporphine C 2 as a yellow
solid (6.9 mg, 82%): mp 221.5 – 223.5 ºC;1H NMR (400 MHz, CDCl3) δ 12.83 (br s, 1H), 8.96 (d,
J = 8.8 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.38
(dd, J = 8.8, 2.8 Hz, 1H), 7.06 (s, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.57 (d, J = 5.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 181.5, 160.5, 153.2, 151.6, 142.3, 141.8, 134.4, 129.7, 126.5, 121.2,
118.9, 118.6, 110.5, 106.9, 105.9, 55.6, 34.0; IR (neat) ν = 2921, 2851, 1730, 1574, 1532, 1496,
1355, 1279, 1204, 1141, 845, 810, 742 cmꢀ1; HRMS (ESI) [M + H]+ calculated for C19H17N2O3:
321.1234, found: 321.1233.
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ASSOCIATED CONTENT
Supporting Information
Comparisons of natural and synthetic menisporphine and daurioxoisoporphine C, copies of NMR
spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: xglei@pku.edu.cn
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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We thank Prof. GuoꢀWei Qin (SIMM) for providing us the original HꢀNMR spectrum of
daurioxoisoporphine C, Ms. Mingyan Zhao (NIBS) for NMR, HPLCꢀMS and GCꢀMS analysis,
and Dr. Jiang Zhou (Peking University) for HRMS analysis. Financial support from the National
High Technology Projects 973 (2012CB837400) and NNSFC (21222209, 91313303) is gratefully
acknowledged.
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