Facile Synthesis of Phenanthridinone Alkaloids via Suzuki–Miyaura Cross-coupling

Article abstract of DOI:10.1002/jhet.2725

Phenanthridinone alkaloids crinasiadine 1 and N-alkylcrinasiadines 6, 7, 8, 9, 10 have been synthesized based on palladium-catalyzed tandem C–C and C–N bond formation starting from 2-aminophenylboronic acid and 2-bromobenzoate in short steps. Related alka

Full text of DOI:10.1002/jhet.2725

Month 2016
Facile Synthesis of Phenanthridinone Alkaloids via Suzuki–Miyaura
Cross-coupling
*
Yoshiyuki Kuwata, Motohiro Sonoda, and Shinji Tanimori
Department of Applied Biological Sciences, Osaka Prefecture University, 1-1 Gakuencho, Nakaku, Sakai, Osaka
599-8531, Japan
*
E-mail: tanimori@bioinfo.osakafu-u.ac.jp
Received March 20, 2016
DOI 10.1002/jhet.2725
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Phenanthridinone alkaloids crinasiadine 1 and N-alkylcrinasiadines 6–10 have been synthesized based
on palladium-catalyzed tandem C–C and C–N bond formation starting from 2-aminophenylboronic acid
and 2-bromobenzoate in short steps. Related alkaloids, 5,6-dihydrobicolorine 2, trisphaeridine 3, and
bicolorine 12 have also been synthesized.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
conditions. The compound 3 named trisphaeridine has
been reported to display topoisomerase I inhibitory
activity [8]. Trisphaeridine 3 was transferred to bicolorine
12 by the treatment of excess iodomethane.
The structural unit of phenanthridinone is widespread
occurring in a variety of natural products and drugs (Fig. 1)
[1]. These compounds exhibit some important biological
activities like antitumor, antiviral, and cytotoxicity [2].
For these reasons, development of efficient and flexible
method for synthesizing phenanthridinones has been an
important subject in organic synthesis (Fig. 2) [3].
Previously, we reported the palladium-catalyzed one-pot
synthesis of phenanthridinones starting from 2-
aminophenylboronic acid and 2-halobenzoic acid esters
via tandem C–C and C–N bond formations (Fig. 3) [4].
In this paper, we report the facile preparation of naturally
occurring phenanthridinones and related alkaloids by
applying this protocol.
To further demonstrate the utility of this transformation,
phenanthridinone analogs 16–22 with various heterocyclic
ring systems have been synthesized from readily
available starting materials, methyl 2-bromonicotinate, 3-
bromoisonicotinate, 3-bromopicolinate, 3-bromothiophene-
2-carboxylate, 4-bromothiophene-3-carboxylate, 3-chlorobenzo
[b]thiophene-2-carboxylate, and 3-bromo-1H-indole-2-
carboxylate, respectively, in moderate yields (Table 1).
Fortunately, ethyl ester and chloride have found to be
acceptable for the transformation (entries 6 and 7).
CONCLUSIONS
RESULTS AND DISCUSSION
In conclusion, a facile method for the synthesis of
phenanthridinone and related alkaloids relying on
Suzuki–Miyaura cross-coupling has been accomplished to
afford a series of biologically active natural products. The
method has also been successfully applied to the synthesis
of rare phenanthridinone derivatives bearing heterocyclic
ring systems. As a consequence, these methods would
serve as combinatorial synthesis of phenanthridinone
derivatives for the development of pharmaceutical,
agrochemical, and material development.
Reaction of ester 5 [5] with 2-aminophenylboronic acid
4 under our previously reported conditions (Fig. 3) [4]
afforded an Amaryllidaceae alkaloid, crinasiadine (1) in
88% yield. Standard alkylation reactions of 1 with several
alkyl halides provided N-alkylcrinasiadines 6–10 [6] in
moderate yields (Scheme 1). The O-alkylation products
13–15 were also obtained along with the formation of 6,
8, and 9. Some of these compounds have been reported
to exhibit cytotoxic activity against human cancer cells
[7]. Hydride reduction of N-methylcrinasiadine (10) using
lithium aluminum hydride gave 5,6-dihydrophenanthridine
alkaloid, 5,6-dihydrobicolorine (2). Phenanthridine
alkaloid 3 has also been produced by the reaction of
aldehyde 11 with boronic acid 4 under the same reaction
EXPERIMENTAL
General information. Unless stated otherwise, reactions
were monitored by thin-layer chromatography on silica gel
© 2016 Wiley Periodicals, Inc.

Y. Kuwata, M. Sonoda, and S. Tanimori
Vol 000
Figure 1. Examples of natural products and drug with phenanthridinone core.
Figure 2. Synthetic approach to phenanthridinone alkaloids based on cascade process.
Figure 3. Our one-pot phenanthridinone synthesis [4].
plates (60Å, F254), visualizing with ultraviolet light or
iodine spray. Column chromatography was performed on
silica gel (60–120 meshes) using hexane and ethyl acetate.
1H and 13C NMR spectra were determined in CDCl3 or
DMSO-d6 solution using 400 and 100MHz spectrometers,
respectively. Proton chemical shifts (δ) are relative to
tetramethylsilane (δ=0.0) as the internal standard and
expressed in parts per million. Spin multiplicities are given
as s (singlet), d (doublet), t (triplet), m (multiplet), and
br (broad). Coupling constants (J) are given in hertz.
Infrared spectra were recorded on an Fourier transform
infrared spectrometer. Melting points were determined by
using a Büchi melting point B-540 apparatus and are
uncorrected. Mass spectrometry (MS) spectra were
obtained on a mass spectrometer. High-resolution MS was
determined using JEOL JMS-700 mass spectrometer
(JEOL Ltd., Tokyo, Japan).
Phenanthridin-6(5H)-ones 1, 16–22, and phenanthridine (3);
general procedure. A pressure-resistant tube, which was
equipped with a magnetic stir bar and fitted with a teflon
septum, was charged with Pd(OAc)2 (1.3 mg, 5.8 μmol,
1 mol%) and SPhos ligand (7.1 mg, 0.017 mmol, 3 mol%),
and 1,4-dioxane (1mL) and H2O (1 drop) were added via
syringe. The vessel was evacuated and back-filled with
argon (this process was repeated a total of three times).
The resulting solution was stirred for 20min. A round
bottom flask was charged with methyl 2-bromobenzoate
(0.58 mmol,
1
equiv.), 2-aminophenylboronic acid
(0.70 mmol, 1.2 equiv.), K3PO4 (245 mg, 1.15mmol,
2 equiv.), 1,4-dioxane (1 mL), and H2O (1 mL). The
mixture was transferred into the first reaction vessel, and
then additional 1,4-dioxane (3mL) was added. The vessel
was evacuated and back-filled with argon (this process
was repeated a total of three times). The vessel was
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Synthesis of Phenanthridinone Alkaloids
Scheme 1. Short-step synthesis of phenanthridinones and related alkaloids.
sealed with a screw cap, and the solution was heated at
100°C for 24h. The reaction mixture was allowed to
cool to room temperature, then diluted with water
(10 mL), and cooled to 0 °C. The precipitated product
was collected by filtration, washed with water, and dried
in vacuo to give 1, 16–22, and 3.
7.43 (d, J= 8.0 Hz, 1H), 7.33 (ddd, J = 8.0, 7.7, 1.0 Hz,
1H). 13C NMR (100MHz, DMSO-d6) δ 160.9, 154.2,
150.6, 137.9, 135.8, 131.3, 124.1, 123.4, 122.5, 121.3,
118.9, 116.0.
Benzo[c][2,6]naphthyridin-5(6H)-one (17) [9].
General
procedure was followed, using 2.0 equivalent of 2-
aminophenylboronic acid, 5 mol% of Pd(OAc)2, and
15mol% of Sphos. Yield: 62.1mg (69%); white solid;
mp 279 À281 °C (lit. [9] 300 À320°C (dec)); Rf = 0.26
Crinasiadine (1) [6].
Yield: 123.9mg (88%); white
solid; mp 340 À 343°C; Rf = 0.14 (hexane/EtOAc= 7/3).
1H NMR (400 MHz, DMSO-d6): δ 11.64 (brs, 1H), 8.29
(d, J= 7.8Hz, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 7.42 (dd,
J =7.8, 7.6Hz, 1H), 7.32 (d, J= 7.9 Hz, 1H), 7.20 (dd,
J =7.9, 7.6Hz, 1H), 6.22 (s, 2H). MS (EI): m/z =239 [M]+.
1
(hexane/EtOAc =1/1). H NMR (400 MHz, DMSO-d6): δ
12.00 (brs, 1H), 9.86 (s, 1H), 8.79 (d, J= 5.1Hz, 1H),
8.54 (d, J= 7.9 Hz, 1H), 8.08 (d, J= 5.1 Hz, 1H), 7.52
(dd, J =7.9, 7.6 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.29
(dd, J= 7.9, 7.6 Hz, 1H).13C NMR (100MHz, DMSO-d6)
δ 159.7, 147.9, 146.5, 136.9, 130.8, 130.4, 128.5, 123.1,
122.8, 119.7, 116.4, 115.7.
Trisphaeridine (3) [6].
Yield: 48.7 mg (50%); pale
yellow solid; mp 137 À 140°C; Rf = 0.35 (hexane/
EtOAc = 7/3). 1H NMR (400 MHz, CDCl3) δ 9.09
(s, 1H), 8.37 (dd, J= 8.0, 1.5 Hz, 1H), 8.14 (dd, J = 8.3,
1.2Hz, 1H), 7.91 (s, 1H), 7.69 (ddd, J = 8.3, 8.0, 1.5 Hz,
1H), 7.63 (ddd, J= 8.3, 8.0, 1.2 Hz, 1H), 7.33 (s, 1H),
6.17 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 151.8,
151.4, 148.2, 144.0, 130.2, 130.0, 128.0, 126.7, 124.2,
123.0, 122.0, 105.5, 101.9, 99.9.
Benzo[f][1,7]naphthyridin-5(6H)-one (18) [9].
General
procedure was followed, using 2.0 equivalent of 2-
aminophenylboronic acid, 5 mol% of Pd(OAc)2, and
15mol% of Sphos. After 24 h, the reaction mixture was
allowed to cool to room temperature, then diluted with
brine (10 mL), and extracted with CHCl3 (15 mL × 3).
The organic layer was washed with brine and dried over
Na2SO4. The filtrate was concentrated in vacuo and
diluted with a small amount of CHCl3. The precipitated
product was collected by filtration and washed with
CHCl3. The filtrate was concentrated in vacuo and
Benzo[c][2,5]naphthyridin-1(2H)-one (16) [9].
General
procedure was followed, using 2.0 equivalent of
2-aminophenylboronic acid, 5 mol% of Pd(OAc)2, and
15mol% of SPhos. Yield: 42.6mg (47%); white solid;
mp 273 À 275°C (lit. [9] 295–300 °C); Rf =0.24 (hexane/
1
EtOAc = 1/1). H NMR (400 MHz, DMSO-d6): δ 11.96
(brs, 1H), 9.07 (dd, J = 4.5, 1.8 Hz, 1H), 8.63 (dd, J = 8.0,
1.0Hz, 1H), 8.62 (dd, J = 7.9, 1.8 Hz, 1H), 7.69 (dd,
J =7.9, 4.5 Hz, 1H), 7.60 (ddd, J= 8.0, 7.7, 1.5 Hz, 1H),
purified
by
column
chromatography
(Hexane/
CHCl3 = 95/5) to give desired product. Yield: 39.5mg
(44%); beige solid; mp 306À 307°C (lit. [9] 300–310 °C);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Kuwata, M. Sonoda, and S. Tanimori
Vol 000
Table 1
Synthesis of rare phenanthridinone analogs with heterocyclic ring systems
Entry
1
2-X-HetAr-CO2R
Product 1
Yield (%)a
47
2
3
69
44
4
5
46
54
6
7
49
53
aIsolated yield.
Rf = 0.24 (CHCl3/MeOH =19/1). 1H NMR (400MHz,
DMSO-d6): δ 11.91 (brs, 1H), 8.95 (d, J = 8.3 Hz, 1H),
8.88 (d, J = 4.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.83
(dd, J = 8.3, 4.0 Hz, 1H), 7.52 (dd, J = 8.0, 7.3 Hz, 1H),
7.37 (d, J= 8.0 Hz, 1H), 7.27 (dd, J= 8.0, 7.3Hz, 1H).
13C NMR (100MHz, DMSO-d6)
159.5, 150.1,
141.7, 136.5, 131.4, 130.8, 130.3, 127.0, 123.7, 122.3,
δ
116.5, 115.9.
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Synthesis of Phenanthridinone Alkaloids
Thieno[2,3-c]quinolin-4(5H)-one (19) [10].
Yield:
(dd, J =7.8, 7.4 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.30
(dd, J= 8.0, 7.4 Hz, 1H), 6.13 (s, 2H), 3.80 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 160.9, 152.1, 148.4, 137.4,
130.4, 128.9, 122.9, 122.3, 121.3, 119.2, 115.0, 107.0,
101.9, 100.4, 30.0.
41.6mg (46%); beige solid; mp 283 À 284°C (lit. [10]
280°C); Rf = 0.31 (hexane/EtOAc = 1/1). 1H NMR
(400 MHz, DMSO-d6): δ 11.88 (brs, 1H), 8.17 À 8.15
(m, 2H), 8.06 (d, J = 4.4 Hz, 1H), 7.47 (d, J = 7.1Hz, 1H),
7.44 (dd, J= 8.3, 7.3 Hz, 1H), 7.26 (dd, J = 7.3, 7.1 Hz,
1H). 13C NMR (100 MHz, DMSO-d6) δ 157.7, 143.1,
137.4, 134.3, 130.0, 129.0, 124.2, 123.5, 122.2, 116.9,
116.1.
5,6-Dihydrobicolorine (2) [14].
A two-neck round-
bottomed flask was equipped with magnetic stirrer. The
reaction apparatus was evacuated and back-filled with
nitrogen (this process was repeated a total of three times).
LiAlH4 (23 mg, 0.60 mmol) and dry THF (6 mL) were
added. A solution of N-methylcrinasiadine (10, 50 mg,
0.20 mmol) in dry THF (10 mL) was added, and the
solution was stirred for 18h at reflux. The solution was
cooled to room temperature and was quenched with H2O
(1 mL). The mixture was filtered through a pad of celite
and dried over Na2SO4. The filtrate was concentrated
in vacuo; the residue was purified by column
Thieno[3,4-c]quinolin-4(5H)-one (20) [11].
Yield:
49.2mg (54%); beige solid; mp 252 À 254°C (lit. [11]
256°C); Rf = 0.38 (hexane/EtOAc = 1/1). 1H NMR
(400 MHz, DMSO-d6):
δ
11.19 (brs, 1H), 8.50
(d, J = 2.9Hz, 1H), 8.40 (d, J= 2.9 Hz, 1H), 8.06
(d, J = 7.8Hz, 1H), 7.36 (dd, J = 7.8, 7.6 Hz, 1H), 7.26
(d, J =8.0Hz, 1H), 7.16 (dd, J = 8.0, 7.6 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6) δ 158.2, 136.28, 136.25,
130.8, 130.2, 128.6, 124.1, 122.3, 119.3, 116.6, 116.0.
chromatography
(hexane/EtOAc= 6/1)
and
gave
Benzothieno[2,3-c]quinolin-6(5H)-one (21) [12].
Yield:
5,6-dihydrobicolorine (2). Yield: 33.1 mg (70%); yellow
solid; mp 85 À 87°C (lit. [12] 80 À 81°C); Rf = 0.41
(hexane/EtOAc =6/1). 1H NMR (400MHz, CDCl3):
δ 7.46 (d, J = 7.7 Hz, 1H), 7.17 (s, 1H), 7.12 (dd, J= 7.7,
7.3 Hz, 2H), 6.78 (dd, J =7.9, 7.3 Hz, 1H), 6.65
(d, J =7.9 Hz, 1H), 6.54 (s, 1H), 5.88 (s, 2H), 4.00
(s, 2H), 2.82 (s, 3H). 13C NMR (100MHz, CDCl3):
δ 147.5, 146.7, 146.5, 128.4, 127.2, 126.2, 123.6, 122.9,
118.7, 112.2, 106.1, 103.1, 100.9, 55.1, 38.5.
63.0mg (53%); white solid; mp >310°C (lit. [10] >310 °C);
Rf = 0.3 (hexane/EtOAc= 1/1). 1H NMR (400MHz,
DMSO-d6): δ 12.31 (s, 1H), 8.94 (dd, J = 6.1, 3.2 Hz,
1H), 8.79 (d, J= 8.0 Hz, 1H), 8.27 (dd, J= 6.1, 3.2 Hz,
1H), 7.70 À7.68 (m, 2H), 7.65 À7.53 (m, 2H),
7.51À 7.35 (m, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 157.8, 141.2, 137.5, 135.8, 135.4, 132.1, 128.8, 127.4,
125.8, 125.7, 124.1, 123.5, 122.6, 117.2, 116.6. MS (EI):
m/z= 251 [M]+.
Bicolorine (12). To a solution of trisphaeridine (30 mg,
0.13 mmol) in acetone (5mL) was added MeI (0.17mL,
2.69 mmol, 20 equiv.) at room temperature. The mixture
was refluxed for 3h. The reaction mixture was quenched
with Et2O. The precipitate was filtered with Et2O and
dried to give bicolorine (iodide). Yield: 34.8mg (71%);
yellow solid; mp 308 À310 °C; Rf = 0.13 (CHCl3/MeOH,
5H-Indolo[2,3-c]quinolin-6(7H)-one (22) [13].
Yield:
42.8mg (49%); pale white solid; mp 312 À 315°C
1
(lit. [11] 294 À298 °C); Rf = 0.1 (hexane/EtOAc = 1/1). H
NMR (400 MHz, DMSO-d6): δ 12.41 (brs, 1H), 11.93
(brs, 1H), 8.50 (d, J= 8.0 Hz, 1H), 8.47 (d, J= 7.8 Hz,
1H), 7.67 (d, J= 8.0 Hz, 1H), 7.54 (d, J =8.0 Hz, 1H),
7.49 (t, J = 7.7Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36
(t, J = 8.0Hz, 1H), 7.34 (t, J= 8.0 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 155.6, 138.7, 134.9, 127.5,
125.8, 125.6, 122.9, 122.28, 122.26, 122.16, 120.6,
118.1, 118.0, 116.0, 113.0.
1
9/1). H NMR (400MHz, CDCl3) δ 9.89 (s, 1H), 9.00
(d, J = 8.2 Hz, 1H), 8.62 (s, 1H), 8.43 (d, J =7.9 Hz, 1H),
8.08 (dd, J =8.2, 7.3 Hz, 1H), 8.00 (dd, J= 7.9, 7.3 Hz,
1H), 7.87 (s, 1H), 6.48 (s, 2H), 4.56 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157.2, 121.9, 150.0, 134.4, 133.7,
131.6, 129.5, 125.0, 124.8, 120.4, 120.0, 107.1, 104.3,
101.3, 45.3.
N-methylcrinasiadine (10) [3f].
To a suspension of
cesium carbonate (684 mg, 2.10mmol) and crinasiadine 1
(100 mg, 0.42 mmol) in dry tetrahydrofuran (THF)
(10 mL) was added MeI (0.08 mL, 1.25 mmol) at room
temperature. The mixture was refluxed for 3 h. The
reaction mixture was concentrated in vacuo, quenched
with H2O (10 mL), and extracted with EtOAc
(10 mL × 3). The organic layer was washed with brine
and dried over Na2SO4. The filtrate was concentrated
in vacuo, and the residue was purified by column
N-Alkylcrinasiadines 6–9; general procedure.
To a
suspension of cesium carbonate (1.05–1.10 mmol,
5 equiv.), NaI (0.21 mmol, 1 equiv.), and 1 (50 mg,
0.21 mmol) in dimethylformamide (6 mL) was added
alkyl bromide (0.63 mmol, 3 equiv.) at room temperature.
The mixture was stirred for 4 h at 110 °C. The reaction
mixture was quenched with H2O (6mL) and filtered with
EtOAc. The filtrate was extracted with EtOAc
(20 mL ×2). The organic layer was washed with H2O
(three times) and brine and dried over Na2SO4. The
filtrate was concentrated in vacuo, and the residue was
purified by column chromatography (hexane/CHCl3 =1/1)
to give N-alkylcrinasiadine 6–9.
chromatography
(hexane/CHCl3 = 1/1)
to
give
N-methylcrinasiadine (10). Yield: 68.8mg (65%); white
solid; mp 243 À245 °C (lit. [3f] 294 À298°C); Rf = 0.27
(hexane/CHCl3 = 1/1). 1H NMR (400 MHz, CDCl3): δ
8.08 (d, J= 7.8Hz, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 7.51
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Y. Kuwata, M. Sonoda, and S. Tanimori
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N-Isopentylcrinasiadine (6) [7]. Yield: 37.9 mg (57%);
white solid; mp 121 À 124°C; Rf =0.21 (CHCl3/
EtOAc = 2/1). 1H NMR (400 MHz, CDCl3): δ 8.08
(d, J= 7.8Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.50
(dd, J= 7.8, 7.3 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.27
(dd, J = 7.9, 7.3 Hz, 1H), 6.11 (s, 2H), 4.40 À 4.36
(m, 2H), 1.90 À 1.76 (m, 1H), 1.70 À 1.64 (m, 2H), 1.06
(d, J = 6.6Hz, 6H). 13C NMR (100MHz, CDCl3): δ 160.5,
152.1, 148.3, 136.5, 130.4, 128.9, 123.1, 122.0, 121.3,
119.4, 114.9, 106.8, 101.9, 100.3, 41.4, 36.0, 26.6, 22.6.
(dd, J= 7.6, 7.3 Hz, 1H), 6.12 (s, 2H), 4.46 À 4.42
(m, 2H), 4.17 (q, J= 7.1 Hz, 2H), 2.53 (t, J =7.0 Hz, 2H),
2.20 À2.05 (m, 2H), 1.28 (t, J =7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 173.2, 160.7, 152.2, 148.3, 136.4,
130.5, 129.0, 122.2, 121.1, 119.3, 115.2, 106.8, 123.0,
102.0, 100.3, 60.5, 42.0, 31.4, 22.5, 14.2.
O-ethoxycarbonylpropylcrinasiadine
(15).
Yield:
21.3 mg (29%); white solid; mp 118 À121°C; Rf = 0.45
1
(hexane/EtOAc, 7/3); H NMR (400MHz, CDCl3) δ 8.22
(d, J = 7.9 Hz, 1H), 7.82 (d, J= 7.7 Hz, 1H), 7.81 (s, 1H),
7.65 (s, 1H), 7.56 (ddd, J= 7.9, 7.6, 1.4 Hz, 1H), 7.43
(ddd, J = 7.7, 7.6, 1.3 Hz, 1H), 4.69 À4.61 (t, J =6.1 Hz,
2H), 4.16 (q, J =7.1 Hz, 2H), 2.59 (t, J =7.6 Hz, 2H),
2.32 À2.19 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H).
O-isopentylcrinasiadine (13).
Yield: 16.2mg (24%);
white solid; mp 92 À94 °C; Rf = 0.67 (hexane/EtOAc,
2/1); 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 8.1,
1.2Hz, 1H), 7.76 (dd, J = 8.0, 1.0 Hz, 1H), 7.69 (s, 1H),
7.57 (s, 1H), 7.48 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.33
(ddd, J= 8.0, 7.0, 1.0 Hz, 1H), 4.54 (t, J =6.6 Hz, 2H),
1.93À 1.88 (m, 1H), 1.73 (q, J= 6.6 Hz, 2H), 0.95
(d, J = 6.6Hz, 6H).
Acknowledgments. This work was financially supported by JSPS
KAKENHI grant number 25410051.
N-ethoxycarbonylethylcrinasiadine (7) [7].
Yield:
35.2mg (50%); white solid; mp 114 À 116°C; Rf = 0.34
(hexane/EtOAc= 7/3). 1H NMR (400 MHz, CDCl3): δ
8.08 (d, J= 8.0Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 7.51
(dd, J= 8.0, 7.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.28
(dd, J= 8.3, 7.6Hz, 1H), 6.12 (s, 2H), 4.67 (t, J= 7.8 Hz,
2H), 4.19 (q, J= 7.1 Hz, 2H), 2.81 (t, J= 7.8Hz, 2H),
1.26 (t, J = 7.1Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 171.3, 160.6, 152.3, 148.4, 136.0, 130.5, 129.0, 123.3,
122.4, 120.9, 119.4, 114.5, 106.7, 102.0, 100.4, 60.8,
38.6, 32.1, 14.1.
REFERENCES AND NOTES
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N-phenylethylcrinasiadine (8) [7].
Yield: 10.2mg
(14%); white solid; mp 154 À 157°C; Rf = 0.24 (hexane/
EtOAc = 6/1). 1H NMR (400 MHz, CDCl3): δ 8.11
(d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.63 (s, 1H), 7.59 À 7.50
(m, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.43 À7.21 (m, 6H),
6.13 (s, 2H), 4.60 À4.55 (m, 2H), 3.10À 3.06 (m, 2H).
13C NMR (100 MHz, CDCl3): δ 160.6, 152.3, 148.4,
138.5, 136.4, 130.5, 129.0, 128.8, 128.7, 126.6, 123.3,
122.3, 121.2, 119.4, 114.8, 106.8, 101.9, 100.4, 44.3, 33.7
O-phenethylcrinasiadine (14).
Yield: 6.2 mg (9%);
white solid; mp 138 À 140°C; Rf =0.49 (hexane/EtOAc,
1
6/1); H NMR (400 MHz, CDCl3) δ 8.20 (d, J= 7.6 Hz,
1H), 7.83 (d, J =8.0 Hz, 1H), 7.80 (s, 1H), 7.63 (s, 1H),
7.56 (dd, J= 7.6, 7.1 Hz, 1H), 7.43 (dd J =8.0, 7.1 Hz,
1H), 7.40 À7.30 (m, 4H), 7.29 À 7.19 (m, 1H), 6.13
(s, 2H), 4.82 (t, J = 6.8 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 158.1, 151.1, 147.7,
142.9, 138.8, 132.1, 129.1 (2C), 128.4 (2C), 128.0,
127.8, 126.3, 124.1, 122.5, 121.8, 115.8, 102.8, 101.7,
100.2, 66.6, 35.6.
[3] Recent
synthesis
of
phenanthoridinone
alkaroids:
(a) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O.
Org Lett 2004, 6, 16 2741; (b) Cahiez, G.; Chaboche, C.;
Mahuteau-Betzer, F.; Ahr, M. O. Org Lett 2005, 7, 1943; (c) Karthikeyan, J.;
Cheng, C.-H. Angew Chem Int Ed 2011, 50, 9880; (d) Rajeshkumar, V.;
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Wu, Y.-S.; Jhan, Y.-H.; Hsieh, J.-C. Org Chem Front 2014, 1, 253;
(f) Pimparkar, S.; Masilamani Jeganmohan, M. Chem Commun 2014,
50, 12116; (g) Feng, M.; Tang, B.; Wang, N.; Xu, H.-X.; Jiang, X. Angew
Chem Int Ed 2015, 54, 14960.
[4] Tanimoto, K.; Nakagawa, N.; Takeda, K.; Kirihata, M.;
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[5] Constance, G.; Sylvie, M.; Francois, T.; Francois-Hugues, P.
Tetrahedron 2009, 65, 10009.
N-ethoxycarbonylpropylcrinasiadine (9) [7].
Yield:
47.2mg (64%); white solid; mp 116 À 119°C; Rf = 0.18
(hexane/EtOAc= 7/3). 1H NMR (400 MHz, CDCl3):
δ 8.09 (d, J= 8.0 Hz, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 7.60
(d, J = 7.6Hz, 1H), 7.53 (dd, J = 8.0, 7.6 Hz, 1H), 7.29
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Phenanthridinone Alkaloids
[6] Mishra, S.; De, S.; Kakde, B. N.; Dey, D.; Bisai, A. Indian J
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet