Synthesis of phenanthridines and analogues via suzuki coupling and condensation

Article abstract of DOI:10.1055/s-0033-1339793

A convenient and short methodology has been developed towards the synthesis of highly substituted phenanthridines and their analogous benzo[k] and benzo[i] derivatives in a single step via Suzuki coupling and condensation between suitably substituted aromatic ortho-bromoaldehydes and ortho-aminobenzeneboronic acids in good to excellent yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339793

LETTER
▌2263
lSetyternthesis of Phenanthridines and Analogues via Suzuki Coupling and
Condensation
Synthesis of Phenanthridines
Shubhendu Dhara, Munmun Ghosh, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Fax +91(3222)282252; E-mail: jkray@chem.iitkgp.ernet.in
Received: 11.07.2013; Accepted after revision: 18.08.2013
wave-assisted cyclotrimerization–aromatization ap-
proach. Yanada et al.8 constructed benzo[k]-
phenanthridines via Lewis acid catalyzed tandem cycliza-
Abstract: A convenient and short methodology has been developed
towards the synthesis of highly substituted phenanthridines and
their analogous benzo[k] and benzo[i] derivatives in a single step
via Suzuki coupling and condensation between suitably substituted tion of ortho-alkynylanilines and ortho-alkynylbenzalde-
aromatic ortho-bromoaldehydes and ortho-aminobenzeneboronic hydes. However, most of the reported procedures
acids in good to excellent yields.
involved several steps, and the starting materials are often
Key words: Suzuki coupling, palladium acetate, condensation, not readily accessible. Our aim was to develop a one-step
boronic acid
protocol for the synthesis of phenanthridines, and we en-
visaged that a Suzuki coupling could be an effective ap-
proach (Scheme 1).
Phenanthridines are important structural motifs in a large
number of naturally occurring and bioactive compounds
showing extensive pharmacological activities and appli-
Br
(HO)2B
H2N
1
cations. Important compounds in this class include ethid-
+
ium salts (1), that act as DNA intercalators and stains,2
and alkaloids such as nitidine (2), chelerythrine (3), san-
N
CHO
Scheme 1 Retrosynthesis of phenanthridine
3
guinarine (4, Figure 1).
Herein, we wish to report a single-step strategy to access
phenanthridines and their analogous benzo[k] and ben-
zo[i] derivatives via Suzuki coupling of suitably substitut-
NH2
O
O
MeO
MeO
N
Me
Table 1 Screening of Catalysts
H2N
N
Et
Ph
nitidine 2
catalyst
ligand
ethidium 1
Br
(HO)2B
H2N
+
O
O
solvent
temp
O
N
CHO
O
Entry Catalyst
Base
Solvent Time Temp Yield
N
(%)a
N
(h)
(°C)
MeO
Me
Me
O
OMe
O
1
2
3
4
5
6
7
8
9
0
1
Pd(PPh3)4
Pd (dba)
Et N
DMF
DMF
DMF
DMA
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
DMA
5
5
5
5
5
5
5
5
3
3
3
3
80
80
80
80
80
80
90
90
90
90
90
90
60
41
72
80
63
50
74
75
80
90
51
45
3
sanguinarine 4
chelerythrine 3
Et N
2
3
3
Figure 1
Pd(OAc)2
Pd(OAc)2
PdCl2
Et N
3
Et N
3
Development of synthetic procedures to such structures
remains a source of interest, and the literature contains
various reports of methods to construct these heterocy-
cles. Among them, the Bischler–Napieralski cycliza-
tion has been extensively used to synthesize
phenanthridine derivatives. Wang et al. reported a cas-
cade approach to 6-arylphenanthridines from aromatic al-
dehydes, anilines, and benzenediazonium-2-carboxylate.
Et N
3
4
,5,9
Pd(MeCN)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
2
Cl
2
Et N
3
Na CO
2
3
6
7
K CO
2
3
Cs CO
2
3
2
Deiters et al. described a ruthenium-catalyzed and micro-
1
1
Cs CO
2
3
3
Cs CO
2
SYNLETT 2013, 24, 2263–2265
Advanced online publication: 26.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
12
NaOAc
DOI: 10.1055/s-0033-1339793; Art ID: ST-2013-D0641-L
Georg Thieme Verlag Stuttgart · New York
a
Isolated yields after purification by column chromatography.
©

2
264
S. Dhara et al.
LETTER
R1
R1
chloro-5,6-dicyano-1,4-benzoquinone)
(Scheme 3).
aromatization
R2
R2
R3
Br
Pd(OAc)2 (5 mol%)
The key coupling step was found to be most effective us-
ing Pd(OAc) /Ph P (Table 1) as catalyst with Cs CO in
Ph3P
N
R3
or
CHO
2
3
2
3
Cs2CO3, dry DMA
phenanathridine
H2N
dry DMA at 90 °C (Table 1, entry 10).
90 °C, 52–90%
+
Using the optimized coupling conditions [Pd(OAc) (5
2
(
HO)2B
R7
mol%), Ph P (0.25 equiv), Cs CO (1.5 equiv), dry DMA
3
2
3
Br/CHO
R6
(3 mL), 90 °C, 3 h] we generalized our methodology by
synthesizing a range of highly substituted phenanthridines
in good to excellent yields (Table 2 and Table 3).
R7
CHO/Br
N
benzo[i]phenan- R7
R5
thridine
R6
R4
R5
R4
The reaction course is proposed to follow initial Suzuki
coupling then condensation. Support for this came from
the fact that no imine was isolated during the reaction
course.
N
benzo[k]phenanthridine
Table 3 Synthesis of Phenanthridine Analogues
Scheme 2
CHO
R7
Br
ed aromatic ortho-bromoaldehydes and ortho-
aminobenzenboronic acids in good to quantitative yields
R6
R7
(
Scheme 2).
R5
R4
N
Aromatic 1-bromo-naphthalene-2-carbaldehyde deriva-
tives were synthesized by Vilsmeier–Haack reaction upon
corresponding ketones and followed by DDQ (2,3-di-
Pd(OAc)2 (5 mol%)
Ph3P
H2N
benzo[i]phenanthridine
or
+
or
R6
Cs2CO3, dry DMA
(
HO)2B
R5
R7
90 °C
Br
R4
R7
CHO
Table 2 Synthesis of Phenanthridines
R1
R1
R6
R2
R3
Br
Pd(OAc)2 (5 mol%)
Ph3P
R2
R3
R5
R4
H2N
N
+
benzo[k]phenanthridine
N
Cs2CO3
dry DMA
CHO
(
HO)2B
Entry R4 R5
R6
H
R7
Product
Yield
(
90 °C
phenanthridine
%)a
Entry R1
R2
R3
H
Product
Yield (%)a
1
2
H
H
H
OMe
52
84
OMe
1
H
H
H
90
N
N
OMe
MeO
MeO
2
3
4
OMe OMe
85
78
73
75
OMe H
H
N
N
OMe
MeO
MeO
OMe OMe OMe
N
3
Me
H
H
H
H
75
88
N
H
H
H
H
F
OMe
N
MeO
F
4
H
OMe OMe
5
NO2
N
N
O2N
a
a
Isolated yields after purification by column chromatography.
Isolated yields after purification by column chromatography.
Synlett 2013, 24, 2263–2265
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Phenanthridines
2265
(
3) (a) Clement, B.; Weide, M.; Wolschendorf, U.; Kock, I.
Angew. Chem. Int. Ed. 2005, 44, 635. (b) Treus, M.; Estevez,
J. C.; Castedo, L.; Esteves, R. J. Tetrahedron Lett. 2002, 43,
Br
O
Br
PBr3, DMF
CHCl3
CHO
CHO
DDQ
5
323. (c) Lunch, M. A.; Duval, O.; Pochet, P.; Waigh, R. D.
0
6
°C–r.t.
5–85%
benzene
reflux
12–16 h
Bioorg. Med. Chem. Lett. 2001, 11, 2643.
overnight
(4) Messmer, W. M.; Tin-Wa, M.; Fong, H. H. S.; Bevelle, C.;
Farnsworth, N. R.; Abraham, J.; Trojanek, D. J. J. Pharm.
Sci. 1972, 61, 1858.
70–90%
Scheme 3
(
5) (a) Li, D.; Zhao, B.; LaVoie, E. J. J. Org. Chem. 2000, 65,
802. (b) Some, S.; Ray, J. K.; Banwell, M. G.; Jones, M. T.
2
Tetrahedron Lett. 2007, 48, 3609. (c) Candito, D. A.;
Lautens, M. Angew. Chem. Int. Ed. 2009, 48, 6713.
In conclusion we have developed an efficient and very
short route towards the synthesis of highly substituted
phenanthridines and their benzo[k] and benzo[i] deriva-
tives in good yields via palladium-mediated Suzuki cou-
pling. Our synthetic strategy is general, tolerates a variety
of substituents, and proceeds under mild reaction condi-
(
d) Pawlas, J.; Begtrup, M. Org. Lett. 2002, 16, 2687.
6) (a) Mamalis, P.; Petrow, V. J. Chem. Soc. 1950, 703.
b) Buu-Hoï, N. P.; Jaquignon, P.; Long, C. T. J. Chem. Soc.
957, 505.
(
(
1
(7) Shou, W.-G.; Yang, Y.-Y.; Wang, Y.-G. J. Org. Chem.
2006, 71, 9241.
8) Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.;
Minami, H.; Yanada, K.; Ishikura, M.; Takemoto, Y. J. Org.
Chem. 2008, 73, 5135.
9) Linsenmeier, A. M.; Williams, C. M.; Bräse, S. J. Org.
Chem. 2011, 76, 9127.
10) Representative Procedure for Suzuki Coupling
o-Bromobenzaldehyde (50 mg, 0.273 mmol.), o-
1
0
tions.
(
Acknowledgement
(
S. D. thanks CSIR, New Delhi for a Fellowship. The DST, India is
also thanked for providing funds for the project and creating a 400
MHz NMR facility under the IRPHA programme.
(
aminobenzeneboronic acid (53.5 mg, 1.2 equiv), Pd(OAc)2
(
5 mol%), Ph P (0.25 equiv), and Cs CO (133.5 mg, 1.5
3
2
3
Supporting Information for this article is available online at
equiv) were added to a two-necked round-bottom flask
under an argon atmosphere. Dry DMA (3 mL) was added to
the reaction mixture, and the solution was degassed with
nitrogen and heated at 90 °C for 3 h. Progress of the reaction
was monitored by TLC. On completion, the reaction mixture
was cooled to r.t. and diluted with H O. It was then extracted
with EtOAc (3 × 50 mL), and the combined organic phases
were washed with brine and dried over anhydrous Na SO .
The solution was filtered and evaporated under reduced
pressure, and the crude product was purified by column
chromatography on silica eluting with PE–EtOAc (5:1);
yellow solid; mp 102–104 °C (lit. 104–106 °C); yield 90%.
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
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References and Notes
(
1) (a) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981,
8, 223. (b) Ishikawa, T. Med. Res. Rev. 2001, 21, 61.
c) Borst, P. IUBMB Life 2005, 57, 745. (d) Denny, W. A.
2
1
(
2
4
Curr. Med. Chem. 2002, 9, 1655.
(2) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem.
2008, 6, 263.
9
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2263–2265

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