Syntheses of phenanthridines and benzophenanthridines by intramolecular ortho-arylation of aryl amide ions with aryl halides via SRN1 reactions

Article abstract of DOI:10.1016/j.tetlet.2007.10.009

The photostimulated reaction of N-(2-halo-benzyl)aryl amines with t-BuOK in liquid ammonia affords fused azaheterocycles by the S_RN1 mechanism. The starting materials are easily obtained by the reaction of 2-halo-benzyl chloride and aromatic amines to prepare the secondary amines. Through this approach, phenanthridine (90%), 4-phenylphenanthridine (87%), benzo[a]phenanthridine (98%), and benzo[c]phenanthridine (84%) were synthesized.

Full text of DOI:10.1016/j.tetlet.2007.10.009

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8739–8742
Syntheses of phenanthridines and benzophenanthridines by
intramolecular ortho-arylation of aryl amide ions with
aryl halides via SRN1 reactions
*
´
Maria E. Buden and Roberto A. Rossi
INFIQC, Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba,
Ciudad Universitaria, 5000 Co´rdoba, Argentina
Received 4 September 2007; revised 26 September 2007; accepted 2 October 2007
Available online 6 October 2007
Dedicated to Professor Miguel Yus on the occasion of his 60th anniversary
Abstract—The photostimulated reaction of N-(2-halo-benzyl)aryl amines with t-BuOK in liquid ammonia affords fused azahetero-
cycles by the SRN1 mechanism. The starting materials are easily obtained by the reaction of 2-halo-benzyl chloride and aromatic
amines to prepare the secondary amines. Through this approach, phenanthridine (90%), 4-phenylphenanthridine (87%),
benzo[a]phenanthridine (98%), and benzo[c]phenanthridine (84%) were synthesized.
Ó 2007 Elsevier Ltd. All rights reserved.
Fused azaheterocycles are a family of biological agents
with particularly interesting pharmacological properties
related to the planarity of the system and consequently
to its DNA-chain intercalating ability, which make them
suitable for anti-neoplastic or mutagenic applications.1
Nitroarylstannanes have been used as intermediates for
the preparation of phenanthridine and benzophenan-
thridine derivatives.6 Recently it has been reported that
aromatic aldehydes reacted with anilines and benze-
nediazonium-2-carboxylate to afford 6-aryl-phenanthr-
idines via a one-pot cascade process.7 A method to
synthesize benzo[c]phenanthridine was then developed
using nickel- or palladium catalyzed iminoannulation
of an internal alkyne.8
Due to their significant biological activity, these are an
important class of heterocyclic compounds in medicinal
chemistry.
Substituted phenanthridines and benzo[c]phenanthr-
idines, an important class of heterocyclic compounds in
medicinal chemistry, are attractive synthetic targets due
to their widespread occurrence in nature and broad
range of biological, including anti-tumor and anti-viral
activity.2–4 This has led to the search for new synthetic
methods that would facilitate the preparation of an
appropriate series of compounds.5 However, many of
the benzophenanthridine synthetic processes have shown
certain disadvantages: numerous steps, low yields, or
poor generality. Thus, a synthesis suitable for both these
compounds and also their analogues is required.
In the present study, we explore the synthesis of phenan-
thridines, benzophenanthridines and related derivatives
employing photostimulated coupling of suitable
precursors.
The radical nucleophilic substitution, or SRN1 reaction,
is a process through which an aromatic nucleophilic
substitution is achieved. Since the scope of this process
has increased considerably over the last decades, nowa-
days it serves as an important synthetic strategy.9 The
initiation step is an electron transfer (ET) from suitable
donors (i.e., the nucleophile or a base) to the substrate
to afford a radical anion. In some systems, the ET step
is spontaneous, however, in others light, electrons from
dissolved alkali metals in liquid ammonia, from a
cathode, or inorganic salts (i.e., Fe+2 or SmI2) can
initiate the reaction.
Keywords: SRN1; Phenanthridine; Benzophenanthridine; Photostimu-
lated reactions.
*
Corresponding author. Tel.: +54 351 4334170; fax: +54 351
4333030; e-mail: rossi@mail.fcq.unc.edu.ar
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.009

8740
M. E. Bude´n, R. A. Rossi / Tetrahedron Letters 48 (2007) 8739–8742
Table 1. Synthesis of fused azaheterocyclesa
Expta Substrate Conditions X ꢀb (%) Productsc,a
Several nucleophiles such as carbanions and heteroatom
anions can be used for SRN1 reactions to form new C–C
or C-heteroatom bonds in good yields. An exception to
this is the reaction of aromatic amide ions with aromatic
substrates. In these cases, C–N and C–C bond forma-
tion is achieved instead. For instance, the reaction of
phenylamide with PhI initiated by K metal in liquid
ammonia affords diphenylamine (19%), and 2- (11%)
and 4-biphenyl amines (11%).10
(yield %)
d
1
2e
3
4f
5g
6h
7i
8
9
10 j
1
1
Dark, 180 min
hm, 30 min
—
56
97
38
97
89
88
95
101
96
2 (56), 3 (2)
2 (90), 3 (9)
2 (32), 3 (2)
2 (68), 3 (18)
2 (85), 3 (8)
2 (88), 3 (4)
8 (87), 9 (10)
11 (98)
1
hm, 120 min
hm, 120 min
hm, 120 min
hm, 120 min
hm, 120 min
hm, 180 min
hm, 120 min
hm, 180 min
1
1
1
1
7
2-Naphthylamide ions initiate the photo SRN1 process
of PhI, 4-MeOC6H4I, and 1-iodonaphthalene in liquid
ammonia. Here, 1-aryl 2-naphthylamines are formed
regioselectively in 45–63% yields, with 3–6% of
N-arylation.11
10
12
13 (84), 14 (8)
a The substrate (1 equiv) and t-BuOK (2.5 equiv) in 200 mL of anhy-
drous liquid ammonia N2 atmosphere, unless otherwise indicated.
Irradiation was conducted in a photochemical reactor equipped with
two 400-W Hg lamps emitting maximally at 350 nm (air and water
refrigerated).
When a substrate has both the leaving group and the
nucleophilic center, the intramolecular reaction affords
a cyclic product.12 This method has been recently
applied to the synthesis of 1-phenyl-1-oxazolino-indan
derivatives and related compounds,13 and to the synthe-
sis of aporphine and homoaporphine alkaloids by ortho-
arylation of phenoxide ions.14
b The halides were determined potentiometrically.
c The products were determined by GLC, unless otherwise indicated.
d The substrate was recovered almost quantitatively.
e The substrate was recovered in 38%.
f p-DNB was added (27 mol %). The substrate was recovered in 39%.
g The solvent was DMSO.
h Di-tert-butyl nitroxide was added (30 mol %).
i TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) was added (38 mol %).
j The reduced product was observed (3%).
So far, there is no instance of the intramolecular aryla-
tion of the aromatic amide ions with a pendant aryl moi-
ety to obtain fused azaheterocycles. The starting
materials are easily obtained by the reaction of 2-halo-
benzyl chloride and aromatic amines to prepare the sec-
ondary amines.
I
–
2
I
N
hv
The substrate N-(2-iodobenzyl)benzenamine (1) was
prepared by standard procedures in 85% yield.15 In the
dark (180 min), there was no reaction of 1 and t-BuOK
in excess in liquid ammonia under a nitrogen atmo-
sphere. However, under irradiation (30 min), phenan-
thridine (2) was obtained in 56% yield, and the
reduced product N-benzyl-benzenamine (3) was
achieved in 2% yield (Eq. 1).
N
ET
–
2
1
1
.
N
N
–
2
1
H
- I
I
4
5
N
HN
hv
NH3,
N
t
-BuOK
–
2
1
5
+
1
+
1
ð1Þ
2
H
HN
+
5
N
HN
- H+
+ H+
3
[O]
5
2
After 120 min of irradiation, 2 and the reduced product
3 were obtained in 90% and 9% yields, respectively. The
reaction was partially inhibited by p-dinitrobenzene
(p-DNB), a well-known inhibitor of SRN1 processes
(Table 1), however, the reaction was not inhibited
by radical traps, such as di-tert-butyl nitroxide or
TEMPO.16 In DMSO as a solvent, 2 and the reduced
product 3 were obtained in 68% and 18% yields, respec-
tively. All these results indicate that the reaction occurs
by the SRN1 mechanism, as depicted in Scheme 1.
5
6
Scheme 1. Mechanism of the cyclization–oxidation processes.
tion of the C–I bond of 12ꢀÅ gives the distonic radical an-
ion 4ꢀÅ and Iꢀ ion. The intermediate radical anion 4ꢀÅ,
via an intramolecular process, yields the conjugated rad-
ical anion 5ꢀÅ.18 An ET from 5ꢀÅ to 1ꢀÅ affords the inter-
mediate
5 , which
and the radical dianion 12ꢀÅ
The reaction of 1 with t-BuOK in excess affords the
amide ions 1ꢀ. The initiation step is the photoinduced
propagates the reaction. The intermediate 5 gives anion
5ꢀ under these basic reaction conditions. Upon acidifi-
cation of the reaction media and work up, product 6
ET to 1ꢀ yielding the radical dianion 12ꢀÅ 17 Fragmenta-
.

M. E. Bude´n, R. A. Rossi / Tetrahedron Letters 48 (2007) 8739–8742
8741
Cl
was not isolated, whereas the oxidized aromatized prod-
uct 2 was.
N
HN
hv
NH3,
t-BuOK
A reaction that competes with the cyclization of the rad-
ical anion 4ꢀÅ is the reduction of this ion by hydrogen
abstraction from the solvent to yield 3.
13
H3C
HN
ð4Þ
12
+
With biphenyl-2-amine, substrate 7 was prepared (82%),
and in the photostimulated reaction, it afforded 87% of
4-phenylphenanthridine (8) and a small amount of the
reduced product 9 (Eq. 2). Employing the same proce-
dure, N-(2-iodobenzyl) naphthalen-2-amine (10) was
prepared (80% yield) with 2-naphthyl amine as a sub-
strate. In the photostimulated reaction (120 min) with
an excess of t-BuOK in liquid ammonia, benzo[a]phen-
anthridine (11) was obtained in 98% yield (Eq. 3).19
14
.
H2C
N
N
N
ð5Þ
o
o
15
16
17
I
We have shown that the photostimulated reactions of
several N-(2-halo-benzyl)aryl amines with t-BuOK in
liquid ammonia afford fused azaheterocycles with excel-
lent yields by the SRN1 mechanism. The starting
materials are easily obtained by the reaction of 2-halo-
benzyl chloride and aromatic amines to prepare the
secondary amines. Considering the availability and/or
simplicity of the starting materials, and the readiness and
mild conditions of the procedure, we have demonstrated
that this can be a general methodology for the synthesis
of this family of compounds. Further studies are in pro-
gress in order to optimize the synthesis of fused azahet-
erocycles with aromatic and heteroaromatic amines, and
also to examine the possibility of polysubstitution.
HN
N
hv
NH3,
Ph
Ph
t
-BuOK
ð2Þ
8
7
HN
+
Ph
9
With the substrate N-(2-chlorobenzyl)naphthalen-1-
amine (12), obtained in 91% yield, under 180 min of
irradiation, the expected ring closure product
benzo[c]phenanthridine (13) was formed in 84% yield,
and rearranged product 14 in a small amount (8%)
(Eq. 4). The same result was observed with N-(2-iodo-
benzyl)naphthalen-1-amine.
Acknowledgements
The rearranged product 14 may be obtained by the reac-
tion of the distonic radical anion intermediate 15ꢀÅ with
the nucleophilic N to form the radical anion 16ꢀÅ, which
by ring opening, yields the radical anion 17ꢀÅ, as a result
of the stability of the diaryl amide moiety and the benzyl
radical (Eq. 5). By H abstraction and after protonation,
17ꢀÅ affords the product 14 observed. There is a prece-
dent that cyclic radical anions can suffer ring opening
to give benzyl radicals and the nucleophilic center.20
´
This work was supported in part by the Agencia Cordo-
ba Ciencia, CONICET, SECYT, Universidad Nacional
de Cordoba, and FONCYT, Argentina. M.E.B. grate-
fully acknowledges the receipt of a fellowship from
CONICET.
´
Supplementary data
I
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.10.009.
hv
NH3,
NH
ð3Þ
N
t-BuOK
10
11
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