A convenient one-pot access to phenanthridinones via Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2013.05.022

A convenient one-step access to biologically important phenanthridinones 1 has been realized based upon Suzuki-Miyaura cross-coupling reaction. Reactions of 2-aminophenylboronic acid 2 with 2-halobenzoate 3 took place smoothly to afford substituted phenanthridinones 1 in excellent yields in the presence of palladium(II) acetate and 2-dicyclohexylphosphino-2′,6′- dimethoxybiphenyl (SPhos) as pre-catalysts. A natural product phenaglydon 1b was synthesized in one-pot manner from readily available starting materials in 95% yield.

Full text of DOI:10.1016/j.tetlet.2013.05.022

Tetrahedron Letters 54 (2013) 3712–3714
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient one-pot access to phenanthridinones via
Suzuki–Miyaura cross-coupling reaction
⇑
Kouichi Tanimoto, Naomichi Nakagawa, Kazutaka Takeda, Mitsunori Kirihata, Shinji Tanimori
Department of Bioscience and Informatics, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-step access to biologically important phenanthridinones 1 has been realized based
upon Suzuki–Miyaura cross-coupling reaction. Reactions of 2-aminophenylboronic acid 2 with 2-halo-
benzoate 3 took place smoothly to afford substituted phenanthridinones 1 in excellent yields in the pres-
ence of palladium(II) acetate and 2-dicyclohexylphosphino-2 ,6 -dimethoxybiphenyl (SPhos) as pre-
catalysts. A natural product phenaglydon 1b was synthesized in one-pot manner from readily available
starting materials in 95% yield.
Received 10 April 2013
Revised 30 April 2013
Accepted 7 May 2013
Available online 14 May 2013
0
0
Keywords:
Phenanthridinone
Ó 2013 Elsevier Ltd. All rights reserved.
Suzuki–Miyaura cross-coupling reaction
One-pot reaction
Heterocyclic compounds
Palladium catalyst
Phenanthridinone core 1a is one of the important structural
units for the development of therapeutic agents. Its derivatives dis-
play a variety of biological activities like protein kinase CK2 inhib-
itors for the treatment of cancer,1 pim kinase inhibitors with
commercially available 2-aminophenylboronic acid 2 with 2-halo-
benzoate 3 accompanying intramolecular amido-bond formation.
A naturally occurring phenanthridinone, phenaglydon (1b),10 has
been synthesized by this method in a single operation.
The reaction of 2-iodobenzoic acid 3a with 2-aminophenylbo-
ronic acid 2a was first investigated under various conditions
(Table 1). As shown in entries 1–5 in Table 1, these reactions were
found to be inefficient, probably due to the formation of possible
adduct formed from acid 3a with boronic acid 2a (B–O bond forma-
tion). By switching the acid 3a to ester 3b, the yield of the desired
product 1a was grown up to 76% after 24 h at 90 °C under the best
,2
3
potent cell antiproliferative activity, topoisomerase I (top1) inhib-
4
,5
5
itors, cytotoxity, inhibitors for human poly(ADP-ribose) poly-
6
merase-3 (Fig. 1). For these reasons, a number of synthetic
methods have been developed in the past decades. Traditional syn-
theses frequently require the multi-step sequences and harsh reac-
7
tion conditions.
Recently, the syntheses of phenanthridinones based upon C–H
bond functionalization have been reported.8 Although they avoid
pre-functionalization step of starting materials to realize atom eco-
nomical process, these methods frequently accompany the forma-
tion of regioisomeric products when they employ the substrates
with unsymmetrical aromatic substituents.
One of the practical syntheses would be a sequential Suzuki–
Miyaura coupling reaction followed by simultaneous amido-bond
formation to form phenanthridinone core 1 starting from 2-amin-
ophenylboronic acid 2 and 2-halobenzoic acid derivatives 3 (Fig. 2).
This method should afford substituted phenanthridinone deriva-
2
conditions with acid 3a (entry 4, Pd(OAc) and SPhos as pre-cata-
lysts in dioxane with K PO as a base) (entry 6). The reaction with
3
4
boronic acid ester 2b was found to be less effective (entry 7). For-
tunately, a better conversion was accomplished in the presence of
water (entry 8), which accelerated the formation of 1a to represent
an 86% yield after 3 h. A slightly better yield was also observed by
changing the leaving group from iodide 3b to bromide 3c, which
diminished the formation of an unknown by-product, to yield de-
sired phenanthridinone 1a in 94% isolated yield (entry 9). Again,
the conversion with acid 3a as the coupling partner under the con-
tives 1 with diverse structure in one-pot manner. Although such
ditions still afforded a lower yield (45%, entry 10). Thus, the origi-
methods have also been documented by three groups,2
,8f,9
their
nal conditions with the same strategy
2,8f,9
were dramatically
efficiencies still need to improve. In this Letter, we wish to describe
our preliminary results for the efficient formation of substituted
phenanthridinones 1 based on Suzuki–Miyaura cross-coupling of
improved by simply changing the catalyst system with lower cat-
alyst-loading and base (entry 6, Table 1), notably by the addition of
water as co-solvent (entries 8 and 9, Table 1), which would accel-
erate the reaction by increasing the solubility of boronic acid.
As the optimized conditions in hand, we next investigated the
scope and limitation of the transformation with a series of
⇑
Corresponding author. Tel./fax: +81 72 2549469.
E-mail address: tanimori@bioinfo.osakafu-u.ac.jp (S. Tanimori).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.022

K. Tanimoto et al. / Tetrahedron Letters 54 (2013) 3712–3714
3713
Figure 1. Phenanthridinone (1) and related pharmaceuticals.
Figure 2. One-pot phenanthridinone formation based on Suzuki–Miyaura coupling.
Table 1
a
Optimization of reaction conditions
X
R2
conditions
+
NH
COOR1
H N
2
O
3
3
3
a: X=I, R =H
2a: R =B(OH)
2 2
2b: R2=B(OCMe2)2
1
b: X=I, R1=Me
1a
c: X=Br, R =Me
1
Entry
X
R
1
R
2
Pd cat.
PdCl c
Pd (dba)
PdCl (dppf)
Ligand
PPh d
Base
Solvent
Temp (°C)
Time (h)
Yieldb (%)
1
2
I
I
I
I
I
I
I
I
H
H
H
H
B(OH)
B(OH)
B(OH)
B(OH)
B(OH)
B(OH)
2
2
2
2
2
2
2
3
NaHCO
3
Dioxane
Dioxane
DMF
Dioxane
MeOH/MeCN
Dioxane
80
80
120
80
70
90
24
24
24
24
24
24
24
3
3
14
17
27
17
76
49
86
94
45
c
d
2
3
SPhos
—
Cs CO
2 3
2
c
3
2
NaOAc
c
SPhosd
—
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
K
3
K
2
K
3
K
3
K
3
K
3
K
3
PO
CO
4
c
c
c
H
/Ag
2
O
3
Me
Me
Me
Me
H
SPhosd
SPhosd
SPhos
SPhos
SPhos
PO
PO
PO
PO
PO
4
4
4
4
4
B(OCMe
2
)
2
Dioxane
90
B(OH)
B(OH)
B(OH)
2
2
2
Dioxane/H
Dioxane/H
Dioxane/H
2
2
2
O (5:1)
O (5:1)
O (5:1)
100
100
100
Br
I
24
24
1
0
a
Reaction conditions: 2-halobenzoic acid and/or ester 3 (0.58 mmol, 1 equiv), 2-aminophenylboronic acid 2 (96.3 mg, 0.703 mmol, 1.2 equiv), Pd catalyst (0.0058 mmol,
1
mol %), ligand (0.017 mmol, 3 mol %), and base (1.15 mmol, 2 equiv) in solvent (5 mL) under argon atmosphere.
b
Isolated yields.
c
1
2
0 mol % Pd catalyst was used.
0 mol % ligand was used.
d
Table 2
a
Palladium-catalyzed synthesis of phenanthridinone derivatives
Entry
1
3
1
Yieldb (%)
94
2
3
96
92
(
continued on next page)

3
714
K. Tanimoto et al. / Tetrahedron Letters 54 (2013) 3712–3714
Table 2 (continued)
Entry
3
1
Yieldb (%)
24 (65) c
4
5
89
80
6
7
8
9
88
84
82
1
0
95
a
All the reactions were performed with 2-bromobenzoate 3 (0.58 mmol, 1 equiv), 2-aminophenylboronic acid 2 (96.3 mg, 0.70 mmol, 1.2 equiv), Pd(OAc)
.0058 mmol, 1 mol %), SPhos (7.1 mg, 0.017 mmol, 3 mol %), and K PO (245.1 mg, 1.15 mmol, 2 equiv) in dioxane (5 mL) and H O (1 mL) at 100 °C for 24 h under argon
atmosphere.
2
(1.3 mg,
0
3
4
2
b
Isolated yields.
Without H O.
2
c
2
-bromobenzoate
3
and the results were summarized in
7. (a) Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69, 5147–5149; (b)
Dubost, E.; Magnelli, R.; Cailly, T.; Legay, R.; Fabis, F.; Rault, S. Tetrahedron 2010,
1
1,12
Table 2.
As a result, most of the reactions represented excellent
6
6, 5008–5016; (c) Lu, S.-M.; Alper, H. J. Am. Chem. Soc. 2005, 127, 14776–
4784; (d) Guy, A.; Guette, J.-P.; Lang, G. Synthesis 1980, 222–223.
8. (a) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. Angew. Chem., Int. Ed. 2011, 50, 1380–
383; (b) Nakamura, M.; Aoyama, A.; Salim, M. T. A.; Okamoto, M.; Baba, M.;
Miyachi, H.; Yuichi Hashimoto, Y.; Aoyama, H. Bioorg. Med. Chem. 2010, 18,
402–2411; (c) Ishida, N.; Nakanishi, Y.; Moriya, T.; Murakami, M. Chem. Lett.
2011, 40, 1047–1049; (d) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc.
006, 128, 9048–9049; (e) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J.
conversions to afford a variety of substituted phenanthridinones in
a range of 80–96% yields, in spite of the electronic nature of sub-
stituents (electron-withdrawing and/or electron-donating groups)
at several positions (entries 2, 3, 5–10). The only exception was
the case of benzoate with the nitro group as a substituent (entry
1
1
2
2
4
). The reason for this low yield has been unclear at present,
A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838–2841; (f) Lamba, J. J. S.; Tour, J.
M. J. Am. Chem. Soc. 1994, 116, 11723–11736.
although the same reaction without water provided even better
conversion (65%, entry 4).
9. Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911–2914.
10. Wurz, G.; Hofer, O.; Greger, H. Nat. Prod. Lett. 1993, 3, 177–182.
In conclusion, we have developed a convenient and rapid access
to phenanthridinone derivatives utilizing readily available starting
materials in one-pot process. This method would serve as the con-
struction of phenanthridinone libraries with diverse structures.
The reaction with substituted boronic acid under the conditions
has been under investigation and will be reported elsewhere.
11. General procedure for the synthesis of phenanthridinone derivatives 1: 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
SPhos ligand (7.1 mg, 0.017 mmol, 3 mol %), and the 1,4-dioxane (1 mL) and
O (1 drop) were added via syringe. The vessel was evacuated and backfilled
lmol, 1 mol %) and
H
2
with argon (this process was repeated a total of three times). The resulting
solution was stirred for 20 min. A round bottom flask was charged with methyl
2
-bromobenzoate
3
(0.580 mmol, 1 equiv), 2-aminophenylboronic acid
PO (245.1 mg, 1.154 mmol, 2 equiv),
O (1 mL). The mixture was transferred into the
2
(
96.3 mg, 0.703 mmol, 1.2 equiv),
K
3
4
Supplementary data
1,4-dioxane (1 mL) and H
2
first reaction vessel, and then additional 1,4-dioxane (3 mL) was added. The
vessel was evacuated and backfilled with argon (this process was repeated a
total of three times). The vessel was sealed with a screw cap, and the solution
was heated at 100 °C for 24 h. 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 the phenanthridin-6(5H)-one 1 as pure form.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
0
5.022.
References and notes
12. Spectral data of representative compounds, 9-methylphenanthridin-6(5H)-one (1b,
phenaglydon): From 3d (0.102 mg, 0.446 mmol), 2-aminophenylboronic acid 2a
1
2
3
4
5
6
.
.
.
.
.
.
Vangrevelinghe, E.; Zimmermann, K.; Schoepfer, J.; Portmann, R.; Fabbro, D.;
Furet, P. J. Med. Chem. 2003, 46, 2656–2662.
Pierre, F.; Chua, P. C.; O’Brien, S. E.; Siddiqui-Jain, A.; Bourbon, P.; Haddach, M.,
et al J. Med. Chem. 2011, 54, 635–654.
Pierre, F.; Stefan, E.; Nédellec, A.-S.; Chevrel, M.-C.; Regan, C. F.; Siddiqui-Jain,
A., et al Bioorg. Med. Chem. Lett. 2011, 21, 6687–6692.
Antony, S.; Agama, K. K.; Miao, Z.-H.; Takagi, K.; Mollie, H.; Wright, M. H., et al
Cancer Res. 2007, 67, 10397–10405.
Ruchelman, A. L.; Kerrigan, J. E.; Li, T.-K.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J.
Bioorg. Med. Chem. 2004, 12, 3731–3742.
Lehtiö, L.; Jemth, A.-S.; Collins, R.; Loseva, O.; Johansson, A.; Markova, N., et al J.
Med. Chem. 2009, 52, 3108–3111.
(0.070 mg, 0.51 mmol), Pd(OAc)
0.013 mmol, 3 mol %), K PO (0.18 mg, 0.86 mmol, 2 equiv), and in dioxane
(5 mL) and water (1 mL) at 100 °C for 24 h, product 1b was obtained as yellow
2
(1.0 mg, 4.45 mmol, 1 mol %), SPhos (5.5 mg,
3
4
10
solid in 95% isolated yield (0.079 g); white solid: mp 251.3–251.8 °C (lit.
ꢀ
1
;
1H
250–251 °C); IR (KBr) 3411, 3011, 2887, 1671, 1612, 1429, 1362, 749 cm
NMR (400 MHz, DMSO-d ) d 11.60 (1H, br s), 8.36 (1H, d, J = 8.0 Hz), 8.32 (1H,
br s), 8.20 (1H, d, J = 8.0 Hz), 7.50–7.44 (2H, m), 7.35 (1H, d, J = 8.0 Hz), 7.24
(1H, dd, J = 8.0, 8.0 Hz), 2.53 (3H, s); 13C NMR (100 MHz, DMSO-d
) d 160.8,
143.0, 136.7, 134.2, 129.4, 129.1, 127.5, 123.4, 123.2, 122.5, 122.1, 117.5, 116.1,
6
6
+
21.5; HRMS (EI) calcd for [C14H11NO] 209.0841, found 209.0842.