Domino Suzuki coupling and condensation reaction: An efficient strategy towards synthesis of phenanthridines

Article abstract of DOI:10.1016/j.tetlet.2014.11.092

A short and convenient hetero-annulation protocol has been developed for the synthesis of substituted phenanthridines via domino Suzuki coupling and condensation between N-(2-iodo-aryl)-formamide derivatives and 2-formylphenylboronic acid in the presence of Pd(OAc)₂, Cs₂CO₃ and PPh₃ as catalytic system in dry DMF at 85-90 °C for 6-7 h. The intermediate after Suzuki coupling and deprotection of nitrogen under the same catalytic system, furnishes the corresponding phenanthridines in good yields after immediate condensation and dehydration.

Full text of DOI:10.1016/j.tetlet.2014.11.092

Accepted Manuscript
Domino Suzuki coupling and condensation reaction: an efficient strategy to-
wards synthesis of phenanthridines
Munmun Ghosh, Atiur Ahmed, Raju Singha, Jayanta K. Ray
PII:
S0040-4039(14)01996-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.092
TETL 45476
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 October 2014
19 November 2014
20 November 2014
Please cite this article as: Ghosh, M., Ahmed, A., Singha, R., Ray, J.K., Domino Suzuki coupling and condensation
reaction: an efficient strategy towards synthesis of phenanthridines, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.11.092
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Graphical Abstract
Domino Suzuki coupling and condensation reaction: an efficient strategy
towards synthesis of phenanthridines
Munmun Ghosh, Atiur Ahmed, Raju Singha, Jayanta K. Ray*
Pd (OAc)2 (5 mol %)
OH
PPh3 (0.25 eq.)
B
I
OH
Cs2CO3 (2 eq.)
DMF (4 mL)
R
R
CHO
NH
N
85-90
°C, 6-7 h
66-85 %
CHO

Domino Suzuki coupling and condensation reaction: an efficient strategy towards
synthesis of phenanthridines
Munmun Ghosh, Atiur Ahmed, Raju Singha, 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 short and convenient hetero-annulations protocol has been developed for the
synthesis of substituted phenanthridines via domino Suzuki coupling and condensation
between N-(2-iodo-aryl)-formamide derivatives and 2-formylphenylboronic acid in presence
of Pd (OAc)2, Cs2CO3 and PPh3 as catalytic system in dry DMF at 85-90 °C for 6-7 h. The
intermediate after Suzuki coupling and deprotection of nitrogen under the same catalytic
system, furnishes the corresponding phenanthridines in good yields after immediate
condensation and dehydration.
Keywords: phenanthridine, domino reaction, Suzuki coupling, N-(2-iodo-aryl)-formamide,
palladium acetate.
Phenanthridines frequently occur as an important structural scaffold in a diverse array of
compounds including significant natural products demonstrating biological and therapeutical
activities such as antiprotozoal, antiviral, antitumor and anticancer.1Ligands based on
phenanthridine skeleton have emerged out as important tool for molecular imaging
techniques.2 They are also important in terms of materials applications.3 Figure 1 shows some
molecules containing phenanthridine motif which have received considerable attention in
medicinal as well as material applications.4
C9H19
O
O
NH2
N
C6H13
OH
H3CO
H3CO
OCH3
H2N
N
Ph
I
N
C6H13
N
CH3
Et
MeO
Me
fagaronine iodide
Ethidium
poly(phenanthridine-co-p-phenylene)
luminescent chemosensor material
OH
HSO4- . 2H2O
antiplasmodial
antileukaemic
antitumor
used in fluorescence assays
with nucleic acids
NK109
anticancer
antitumor
trypanocidal drugs
photoinduced charge donor in DNA
Figure 1. Phenananthridine-based compounds with potential medicinal and material
applications.
Such significant clinical and material applications prompted a number of chemists to target
the synthesis of phenanthridines over the last few decades. A considerable list of transition-
metal catalyzed5 as well as metal-free annulation strategies6 has been extensively employed
for the construction of phenanthridine and substituted phenanthridine derivatives. A previous
report from our group describes a single-step synthesis of highly substituted phenanthridines
from ortho-bromoaldehydes using ortho-aminobenzeneboronic acid via Suzuki coupling and

condensation.7 Recently, our group also reported a convenient method for the conversion of
o-iodoanilines to N-(2-iodo-aryl)-formamides under Vilsmeier–Haack reaction condition
using phosphorus tribromide.8 Following these two strategies, herein we report a convenient
and short hetero-annulation protocol for the construction of phenanthridine skeleton from N-
(2-iodo-aryl)-formamides (2a-2j) using 2-formylphenylboronic acid 3 via domino Suzuki
coupling-condensation. In this regard N-(2-iodo-aryl)-formamides (2a-2j) were synthesized
from the corresponding o-iodoanilines following the previous strategy (Scheme 1).8
2a : R1 = R2 = R3 = H (95%)
2b : R1 = Me, R2 = R3= H (94%)
2c : R1 = Br, R2 = R3 = H (92%)
2d : R1 = Cl, R2 = R3 = H (91%)
2e : R1 = F, R2 = R3 = H (84%)
2f : R1 = NO2, R2 = R3 = H (75%)
2g : R1 = R2 = Cl, R3 = H (81%)
2h : R1 = R2 = F, R3 = H (77%)
2i : R1 = F, R2 = Cl, R3 = H (79%)
2j : R1 = R3 = Me, R2 = H (92%)
R1
R2
R3
(1 eq.)
1a-1j
I
R1
R2
I
PBr3 (2.7 eq.)
DMF (3.0 eq.)
CHCl3 (0.80 mL)
0 °C-r.t., 1-2 h
NH2
NH
R3 CHO
2a-2j
Scheme 1. Synthesis of N-(2-iodo-aryl)-formamides
Table 1
Optimization Studiesa
CHO
I
catalyst, base
OH
B
ligand, solvent
85-90 °C, 6h
NH
OH
N
3
4b
2b
CHO
Entry
Catalyst
Ligand
Base
Et3N
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
Temperature (°C) Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
90
90
90
85
90
85
90
85
68
42
43
85
46
71
26
72
Na2CO3
K2CO3
Cs2CO3
NaOAc
KOtBu
HCOONa
CS2CO3

Table 1. continued....
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3
CS2CO3
DMSO
90
90
90
90
90
90
66
46
73
59
54
50
10
11
12
PPh3
CS2CO3 1,4-dioxan
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
PPh3
13 PdCl2(CH3CN)2
-
-
14
Pd(PPh3)4
a
Reagents and conditions: 2a (1 eq.), 2-formylphenylboronic acid (1.2 eq.), Pd catalyst (5
mol %), base (2 eq.), ligand (0.25 eq.) and solvent (4 mL) for 6h.
b Yields refer to the isolated yields after purification through column chromatography.
N-(2-iodo-4-methyl-phenyl)-formamide 2b was initially reacted with 2-formylphenylboronic
acid 3 in presence of Pd (OAc)2 catalyst, Et3N base and PPh3 ligand in DMF at 90 °C for 6 h
to give 2-Methyl-phenanthridine 4b in 68 % yield. After screening through a number of
catalysts, bases, ligands and solvents, the domino reaction was found to be most effective
with Pd (OAc)2 (5 mol %), Cs2CO3 (2 eq.), PPh3 (0.25 eq.) when 1 eq. of 2a was reacted with
1.2 eq. of 2- formylphenylboronic acid in DMF (4 mL) at 90 °C for 6 h resulting in the
formation of 2-Methyl-phenanthridine 4b (85 % isolated yield) (Table 1, Entry 4). Here, C-C
and C-N bond formation occur simultaneously in domino Suzuki coupling and deprotection
followed by condensation fashion with immediate dehydration leading to the formation of 2-
Methyl-phenanthridine (Scheme 2).
With this optimized condition, we tried to extend the scope of this methodology. For this
purpose, various formamides 2a-2j obtained from different substituted o-iodoanilines 1a-1j
were allowed to react with 2- formylphenylboronic acid 3 under the optimized reaction
condition. The results are summarized in Table 2.

Table 2
Synthesis of phenanthridinesa
Pd (OAc)2 (5 mol %)
PPh3 (0.25 eq.)
R1
R2
I
CHO
R1
R2
OH
B
Cs2CO3 (2 eq.)
DMF (4 mL)
NH
R3 CHO
2a-2j
OH
N
3
3 4a-4j
°C, 6-7h
85-90
R
Entry
1
R1
H
R2
H
R3 Temp (°C)
Time (h)
6
Product
Yield(%)b
83
H
85
N
4a
Me
2
3
4
5
6
7
Me
Br
H
H
H
H
H
Cl
H
85
6
85
79
74
69
66
70
N
4b
Br
Cl
H
90
85
90
90
7
N
4c
Cl
H
H
H
7
N
4d
F
F
7
N
4e
O2N
NO2
7
N
4f
Cl
Cl
H
90
7
Cl
N
4g

Table 2 continued…
8
F
F
H
90
7
68
68
F
F
N
4h
4i
F
9
F
Cl
H
90
7
Cl
Me
N
10
Me
H
Me
85
6
82
N
4j
Me
a Reagents and conditions: all the reactions were carried out under the following conditions:
substrates 2a–2j (1 eq.), 2-formylphenylboronic acid 3 (1.2 eq.), Pd (OAc) 2 (5 mol %), PPh3
(0.25 eq.), Cs2CO3 (2 eq.), and DMF (4 mL) at 85-90 °C for 6-7 h.
b Yields were determined after purification through column chromatography.
The reaction was found to be relatively faster and high yielding in case of formamides
containing electron-donating (2b and 2j) and/or weak electron-withdrawing groups (2c)
compared to the formamides with strong electron-withdrawing groups (2d-2i).
We then attempted to determine the correct sequence for cyclization. For this purpose,
formamide 2b was heated with 2-formylphenylboronic acid 3 without Pd catalyst keeping all
other conditions intact. All the reactants remained as such even after 5 h. From this
observation, it can be concluded that the reaction followed a sequence of Suzuki coupling and
simultaneous deprotection followed by condensation leading to the formation of intermediate
6 which after dehydration furnished the desired product 4b.
Pd (II)
PPh3
Cs2CO3
H2N
CHO
I
deprotection
Pd (0)
NH
2b
5
CHO
Pd(II)I
condensation
H
N
HO
NH
CHO
CHO
HN
CHO
(II)
Pd
6
CHO
dehydration
N
Cs2CO3
OH
OH
B
4b

Scheme 2. Plausible mechanism for the formation of phenanthridine
The intermediate 5 formed after Suzuki coupling and deprotection underwent intramolecular
condensation as soon as it was formed to give intermediate 6 (2-Methyl-5, 6-dihydro-
phenanthridin-6-ol) which was transformed to the final product 4b after immediate
dehydration. So, intermediate 5 and/or 6 could not be isolated. Aromaticity might be the
driving force for the sequential elimination of formaldehyde (deprotection) and water
(dehydration) leading to the formation of phenanthridine.
In summary, we have developed a short and efficient approach10 for the construction of
phenanthridine skeleton from N-(2-iodo-aryl)-formamides obtained easily from readily
available o-iodoanilines. Our synthetic strategy is advantageous with respect to high yield,
substrate versatility, and easily accessible starting materials. Our methodology also allows
easy conversion of –NH2 to -NHCHO and deprotection of –NHCHO under the same reaction
condition. Hope, our methodology can be usefully applied for the synthesis of
phenanthridine-containing compounds with promising pharmacological as well as material
activities.
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 2a-2j and
4a-4j) associated with this article can be found, in the online version, at
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10. General procedure for the synthesis of phenanthridines 4 : Substrate 2b (100 mg, 0.38
eq.), 2-formylphenylboronic acid 3 (68.94 mg, 0.46 eq.), Cs2CO3 (247.62 mg, 0.76 eq.), PPh3
(24.92 mg, 0.095 eq.) and Pd (OAc)2 (3.6 mg, 5 mol %) were taken in a two necked round-
bottomed flask in argon atmosphere. 4 mL of dry DMF was added to the reaction mixture and

heated at 85 °C for 6 h. Progress of the reaction was monitored by TLC. After the completion
of the reaction, the reaction mixture was cooled to r.t. 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 (4a) : Yellow solid; mp: 105-
1
106 °C (lit.9 mp: 104-106 °C); Yield: 83%; H NMR (400 MHz in CDCl3): δ = 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): δ = 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: 180.0812.