Synthesis of phenanthridine and its analogues via aerobic ligand-free domino Suzuki coupling-Michael addition reaction catalyzed by in situ generated palladium-nanoparticles in water

Article abstract of DOI:10.1016/j.tetlet.2013.06.089

A convenient methodology has been developed towards the synthesis of substituted phenanthridines and analogous benzo[k] and benzo[i] derivatives via aerobic ligand-free domino Suzuki coupling-Michael addition reaction in the presence of Pd(OAc)₂ and K₃PO₄ as a catalytic system in H₂O at 90 C in good yields. Reaction was believed to be catalyzed by in situ generated palladium nanoparticles in water with the elimination of acetone.

Full text of DOI:10.1016/j.tetlet.2013.06.089

Accepted Manuscript
Synthesis of phenanthridine and its analogues via aerobic ligand-free domino
Suzuki coupling-Michael addition reaction catalyzed by in situ generated pal‐
ladium-nanoparticles in water
Munmun Ghosh, Atiur Ahmed, Shubhendu Dhara, Jayanta K. Ray
PII:
S0040-4039(13)01065-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.089
TETL 43142
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 March 2013
14 June 2013
18 June 2013
Please cite this article as: Ghosh, M., Ahmed, A., Dhara, S., Ray, J.K., Synthesis of phenanthridine and its analogues
via aerobic ligand-free domino Suzuki coupling-Michael addition reaction catalyzed by in situ generated palladium-
nanoparticles in water, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.089
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Synthesis of phenanthridine and its analogues via aerobic ligand-free domino Suzuki
coupling-Michael addition reaction catalyzed by in situ generated palladium-
nanoparticles in water
Munmun Ghosh, Atiur Ahmed, Shubhendu Dhara, Jayanta K. Ray*
Pd (OAc)2 (10 mol %)
K3PO4 (2 mmol)
B(OH)2
NH2
Br
+
N
TBAB (0.5 mmol)
water, 90 0C
60-85 %
MeCOMe
O
ꢀ

Synthesis of phenanthridine and its analogues via aerobic ligand-free domino Suzuki
coupling-Michael addition reaction catalyzed by in situ generated palladium-
nanoparticles in water
Munmun Ghosh, Atiur Ahmed, Shubhendu Dhara, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Corresponding author: Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in
Abstract: A convenient methodology has been developed towards the synthesis of
substituted phenanthridines and analogous benzo[k] and benzo[i] derivatives via aerobic
ligand-free domino Suzuki coupling-Michael addition reaction in presence of Pd(OAc)2 and
0
K3PO4 as catalytic system in H2O at 90 C in good yields. Reaction was believed to be
catalyzed by in situ generated palladium nanoparticles in water with the elimination of
acetone.
Keywords: Phenanthridine, Domino reaction, Suzuki coupling, Michael addition, Wittig
reaction, Palladium nanoparticles.
Transition-metal catalyzed C-C bond formation reactions have been extensively exploited
towards the synthesis of many important carbocycles and heterocycles over last few decades.1
Palladium-based methodologies have been used as an important synthetic tool2 because of
their functional group tolerance3, stereo- and regioselectivity4 and significant yields under
mild reaction conditions5.
Phenanthridines serve as the core structure of a number of biologically active natural
products demonstrating important pharmacological effects including antifungal, antibacterial,
antitumor, anticancer activities,6 and SPECT tracers.7 Figure 1 represents some
therapeutically promising compounds of this class.7-9 They are also receiving growing
attention in materials research because of their opto-electronic properties.10
O
OH
N
N
N
HO
O
125
I
O
O
O
N
MeO
F
Me
HSO4- . 2H2O
NK109
OH
7-Fluoro-5-{4-[3-(4-iodo-phenyl)-propyl]-
cyclohexylmethoxy}-benzo[h][1,6]naphthyridine
Lycorine
Figure 1. Bioactive molecules containing phenanthridine moieties
ꢁ

Because of such potential therapeutic and material properties, synthesis of phenanthridine
skeletons via novel and shorter synthetic methodology has become research interest over the
last few decades. Recently, Zhang et al. reported copper-catalyzed synthesis of
phenanthridine derivatives from biaryl-2-carbonitriles and Grignard reagents.11 Buden and
co-workers reported electron-transfer-mediated synthesis of phenanthridines by
intramolecular arylation of anions from N-(ortho-Halobenzyl)arylamines.12 Chattopadhyay et
al. synthesized phenanthridine skeleton from 2-allyl aniline derivatives via ring closing enyne
metathesis (RCEYM) followed by Diels-Alder aromatization.13 Li and co-workers
synthesized phenanthridine and benzo[i]phenanthridine derivatives from nitroarylstannanes
and 2-bromobenzaldehyde and/or 2-bromo-1-naphthaldehyde followed by reduction with
zinc dust in acetic acid.14 Our aim was to synthesize phenanthridine using environmentally
benign and mild reaction conditions. Recently our group reported aerobic ligand-free
palladium nanoparticle catalyzed synthesis of benzo[c]chromene derivatives via domino
Suzuki coupling-Michael addition reaction.15
Following this strategy, herein we report aerobic ligand-free synthesis of phenanthridine and
its analogues by the treatment of 2-aminophenylboronic acid on ꢀ-(2-bromoaryl)-ꢁ,ꢀ-
unsaturated carbonyl compounds (3a-3h) which were synthesized by Wittig reaction from 2-
bromocarboxaldehydes (1a-1h) using 1-(triphenylphosphoranylidene)-2-propanone 2 in dry
dichloromethane (DCM) at 0 0C to rt for 3h (Scheme 1)16. Aromatic ortho-
bromonaphthaldehydes were synthesized from the corresponding tetralones via Vilsmeier-
Haack type reaction followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
oxidation.17 Here C-C and C-N bonds are formed simultaneously in a domino Suzuki
coupling followed by Michael addition fashion in water with the elimination of acetone
leading to the formation of phenanthridine.
Ph3P
(1.5eq)
Br
O
2
Br
DCM, 0 0C-r.t.,3h
80-90 %
CHO
1a-1h
3a-3h
O
Scheme 1. Wittig reaction with 2-bromocarboxaldehydes.
ꢂ

5a
N
Br
Pd(OAc)2, K3PO4
TBAB, water
(HO)2B
H2N
Phenanthridine
90 0C
N
4
or
N
O
or
3a-3h
5g
5e
Benzo[k]phenanthridine
Benzo[i]phenanthridine
Scheme 2. Synthesis of phenanthridine and its analogues
Table 1
Optimazition studiesa,b
(HO)2B
H2N
catalyst, base
Br
N
ligand, water
TBAB
5a-5h
4
3a-3h
O
ꢃ

Base
Temp (oC)
Yield (%)c
Entry
1
Ligand
PPh3
PPh3
_
Catalyst
Pd(OAc)2
Pd(OAc)2
90
90
72
76
Et3N
K3PO4
2
3
4
75
85
65
Pd(OAc)2
Et3N
90
_
_
_
90
Pd(OAc)2
K3PO4
5
6
7
Pd(OAc)2
Pd(OAc)2
90
90
K2CO3
80
64
Cs2CO3
_
_
_
100
90
NaOAc
KOBut
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(CH3CN)2
PdCl2
73
59
62
52
8
9
100
Na2CO3
_
_
90
10
11
K3PO4
K3PO4
100
a Reagents and conditions: 3a (1 mmol), 2-aminophenylboronic acid (1.6 mmol), Pd catalyst
(10 mol %), base (2mmol), TBAB (0.5 mmol), and water (5 mL) for 5 h.
b Reaction was done in a two-necked round-bottomed flask fitted with condenser.
c Yields refer to the isolated yields after purification through column chromatography.
3a was initially reacted with 2-aminophenylboronic acid 4 in presence of Pd (OAc)2 catalyst,
Et3N base, PPh3 ligand, and tetrabutylammonium bromide (TBAB) in water at 90 0C for 5 h
to give phenanthridine 5a in 72% yield. After screening through a number of Pd catalysts and
bases, the domino reaction was found to be most effective with Pd (OAc)2 (10 mol %), K3PO4
(2 mmol), and TBAB (0.5 mmol) when 1 mmol of 3a was reacted with 1.6 mmol of 2-
aminophenylboronic acid in water at 90 0C for 5 h to give 85% isolated yield (Table 1, Entry
4). The reaction was observed to be faster and high yielding in the absence of ligand and
K3PO4 acted as a base as well as a stabilizer of Pd nanoparticles18.
With this optimized conditions, the methodology was generalized towards the synthesis of
various substituted phenanthridine and its analogous derivatives in good yield.
Table 2: Synthesis of phenanthridinesa
ꢄ

R1
R1
R2
R3
Br
Pd (OAc)2, K3PO4 R2
TBAB, water
(HO)2B
H2N
N
R3
90 0C
O
5a-5d
4
3a-3d
R1
Entry
1
R2
H
R3
H
Time (h)
5
Yield (%)b
85
Product
H
N
N
5a
MeO
MeO
65
8
8
OMe
H
OMe
F
H
H
2
3
5b
60
63
N
F
5c
Me
H
Me
H
6
4
N
5d
Table 3: Synthesis of benzo[k]phenanthridinesa
ꢅ

O
R4 Br
N
R4
Pd (OAc)2, K3PO4
R5
R6
(HO)2B
H2N
R5
R6
TBAB, water
90 0C
5e-5f
4
3e-3f
R6
H
Yield (%)b
R4
H
R5
Entry
5
Product
Time (h)
N
5
80
H
5e
N
74
H
OMe
H
5
6
MeO
5f
Table 4: Synthesis of benzo[i]phenanthridinesa
O
R7
N
R7
(HO)2B
R8
R9
Br
R8
R9
Pd (OAc)2, K3PO4
TBAB, water
90 0C
H2N
4
3g-3h
5g-5h
ꢆ

R8
H
R9
Product
N
R7
H
Yield (%)b
70
Entry
7
Time (h)
5
H
5g
N
MeO
68
OMe
H
5
H
8
5h
a Reagents and conditions: all the reactions were carried out under the following conditions:
substrates 3a–3h (1 mmol), 2-aminophenylboronic acid (1.6 mmol), Pd (OAc)2 (10 mol %),
TBAB (0.5 mmol), K3PO4 (2 mmol), and water (5 mL) at 90 0C.
b Yields were determined after purification through column chromatography.
Next, the correct sequence for cyclization was determined by heating 3a with 2-
aminophenylboronic acid without Pd catalyst keeping all other conditions intact. No reaction
was observed. This might be due to the bulkiness of the Michael donor and acceptor (Scheme
3).
O
B(OH)2
NH O
NH-K+
NH2
K3PO4
(HO)2B
(HO)2B
Br
Br
Scheme 3. Reaction without Pd catalyst
Hence, the reaction course can be concluded to proceed through Suzuki coupling followed by
intramolecular Michael addition and elimination of acetone molecule (Scheme 4). Here, 2-
aminophenylboronic acid itself acted as the reducing agent.19 On heating a solution of 2-
aminophenylboronic acid in water with Pd (OAc)2 in absence of ꢀ-(2-bromoaryl)-ꢁ,ꢀ-
unsaturated carbonyl compound, TBAB or PPh3, the solution turned black immediately
indicating the formation of Pd(0).

PdII
NH2
+
K3PO4
O
K
B(OH)2
O
NH
Pd 0
Br
Intramolecular
Michael addition
6
O
O
O
H
N
NH-K+
PdII
BrPdII
HO
N
O
NH2
K3PO4
+
B(OH)2
5a
Scheme 4. Plausible rationale for the formation of Phenanthridine
The intermediate after Suzuki coupling 6, being a very reactive system because of the close
proximity of NH- ion and the ꢀ-carbon of the ꢁ,ꢀ-unsaturated ketone, underwent
intramolecular Michael addition immediately. So, 6 could never be isolated. The cross
coupling step was catalyzed by in situ generated Pd-nanoparticles. Finally, acetone was
eliminated to furnish the product 5a. Aromaticity might be the driving force for the
elimination of acetone.
In summary, we have developed an efficient method21 for the synthesis of phenanthridine
and its benzo[k] and benzo[i] analogues via ligand-free domino Suzuki coupling-Michael
addition catalyzed by in situ generated palladium nanoparticles in water. Our synthetic
strategy is short and involves easily available starting materials and mild reaction conditions.
Hopefully, our methodology can be utilized for the synthesis of phenanthridine containing
natural products of promising pharmaceutical characteristics.
ꢇ

Acknowledgement:
M.G. thanks CSIR, New Delhi for the fellowship. The DST, India is also thanked for
providing funds for the project and creating 400 MHz NMR facility under the IRPHA
programme.
Supplementary data
Supplementary data (experimental procedure and spectral data for the compounds 3a and 5a-
5h) associated with this article can be found, in the online version, at
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21. General procedure for the synthesis of phenanthridine: Compound 3a (0.05 g, 0.22
mmol), 2-aminophenylboronic acid 4 (0.048 g, 0.35 mmol), K3PO4 (0.093 g, 0.44 mmol),
TBAB (0.035 g, 0.11 mmol), and Pd (OAc)2 (10 mol %) were taken in a two-necked round
bottom flask fitted with a condenser. 5 ml water was added and the reaction mixture was
heated at 90 0C. Progress of the reaction was monitored by TLC. After the completion of the
reaction the reaction mixture was cooled to rt and extracted with EtOAc (3x20ml).Combined
organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated
under reduced pressure and the crude product was purified through column chromatography
using silica gel (60-120 mesh) and pet ether:EtOAc (5:1) as eluent.
Spectral data of representative compound, Phenanthridine (5a): Yellow solid; mp: 105-
106 0C (lit.20 mp: 104-106 0C); Yield: 85%; 1H NMR (400 MHz in CDCl3): ꢂ = 9.28 (1H, s),
ꢀꢀ

8.61-8.56 (2H, m), 8.21 (1H, d, J = 8.0 Hz), 8.04 (1H, d, J = 8.0 Hz), 7.86 (1H, t, J = 7.8 Hz),
7.77-7.66 (3H, m); 13C NMR (50 MHz in CDCl3): ꢂ = 153.8, 144.6, 132.8, 131.3, 130.3,
129.0 (2C), 128.9, 127.7, 127.3, 126.6, 122.5, 122.1; Anal. Calcd for C13H9N: C: 87.12; H:
5.06; N: 7.82 %; Found: C: 86.97; H: 5.11; N: 7.69 %; HRMS Calcd for C13H10N+ [M+ H]+:
180.0808; Found: 180.0823.
ꢀꢁ