Synthesis of novel fused azaheterocycles by photostimulated intramolecular SRN1 reactions with nitrogen nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2009.04.042

The synthesis of pyrrole, indole, and pyrazole fused azaheterocycles is presented. The anions of carboxamides (6 and 12) and pyrazolylamines (15a-b) react under photostimulation by an intramolecular S_RN1 process to yield fused azaheterocycles w

Full text of DOI:10.1016/j.tetlet.2009.04.042

Tetrahedron Letters 50 (2009) 3829–3832
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Tetrahedron Letters
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Synthesis of novel fused azaheterocycles by photostimulated
intramolecular SRN1 reactions with nitrogen nucleophiles
*
*
Victoria A. Vaillard, María E. Budén, Sandra E. Martín , Roberto A. Rossi
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de Torre y Medina Allende, 5000 Córdoba, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of pyrrole, indole, and pyrazole fused azaheterocycles is presented. The anions of carbox-
Received 10 March 2009
Revised 31 March 2009
Accepted 8 April 2009
Available online 14 April 2009
amides (6 and 12) and pyrazolylamines (15a–b) react under photostimulation by an intramolecular SRN
1
process to yield fused azaheterocycles with good to excellent yields. We report on an efficient two-step
synthesis of new fused azaheterocycles derived from pyrrole, indole, and pyrazole, as well as the synthe-
sis of their precursors. By the reaction of carboxamides (6 and 12) and pyrazolylamines (15a–b) with a
base, the corresponding anion could be formed. Then, by an intramolecular photostimulated SRN1 reac-
tion, the fused azaheterocycles were achieved (54–100%).
Ó 2009 Elsevier Ltd. All rights reserved.
Nitrogen-containing heterocycles constitute the main structure
within a large number of natural products and many pharmacolog-
ically active compounds. Primarily, condensed heterocyclic com-
pounds play increasingly important roles as synthetic building
blocks, and also as pharmacophores.1 Fused azaheterocycles com-
prise a family of biological agents with particularly interesting
pharmacological properties related to planarity of the system and
consequently to its DNA-chain intercalating ability, which make
them suitable for anti-neoplastic or mutagenic applications.2 Due
to their significant biological activity, azaheterocycles are an
important class of heterocyclic compounds in medicinal chemistry.
As a result of azaheterocycles intensive application in bio-or-
ganic chemistry, the search for new efficient methods for their syn-
thesis represents an active field of interest. Recent synthetic routes
to quinolinone heterocycles have involved strategies based on the
Baylis–Hillman adduct followed by a Friedel–Crafts cyclization
from Baylis–Hillman acid and arylamines3 or Diels–Alder cycliza-
tion of exo-diene lactams and followed by aromatization.4 Alterna-
tively, to obtain heterocycles derived from isoquinolines, aryl
iodide with bromoalkyl pirazole in a palladium-catalyzed reaction
was used.5 Triazolo-isoquinolines were synthesized by the reaction
of 2,3-diaminoisoquinolinium salts with aldehydes by a ring
closure.6
mechanism has broadened considerably over the last decades,
nowadays it serves as an important synthetic strategy.7 The initia-
tion 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 other sys-
tems light, electrons from alkali metals dissolved in liquid ammo-
nia or from a cathode, or inorganic salts (i.e., Fe+2 or SmI2) can
initiate the reaction. Several nucleophiles such as carbanions and
heteroatom anions can be used in 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, the formation of both C–N and C–C bonds is
achieved instead, and the regiochemistry of the reaction depends
on the substrates and nucleophiles.8,9
The anion of azaheterocycles such as pyrrole reacted with chlo-
roarenes by a cathode-induced reaction, to give mainly arylation in
the position two (52–67%) with a 3–14% arylation in position three
of the pyrrole moiety.10
Additionally, the anion of 4-methylimidazole also reacted with
chloroarenes in similar experimental conditions to afford 4-
methyl-5-aryl-1H-imidazole and 4-methyl-2-aryl-1H-imidazole
in a ratio of 4:1.11
Furthermore, to synthesize heterocyclic compounds by the SRN
1
On the other hand, the unimolecular radical nucleophilic substi-
tution, or SRN1 reaction, is a process through which an aromatic
nucleophilic substitution is achieved by a chain reaction with rad-
ical and radical anions as intermediates. Since the scope of this
reaction, a straightforward synthetic strategy was developed. Cyc-
lic products could be obtained by an intramolecular reaction, when
a substrate having both, the leaving group and the nucleophilic
center, was used.12 This method has been recently applied to the
synthesis of 1-phenyl-1-oxazolino-indan derivatives and related
compounds,13 to the synthesis of aporphine and homoaporphine
alkaloids by ortho-arylation of phenoxide ions,14 and to the synthe-
sis of phenanthridines and benzophenanthridines by intramolecu-
lar ortho-arylation of aryl amide ions with aryl halides.15
* Corresponding authors. Tel.: +54 351 4334170x151; fax: +54 351 4333030
(R.A.R.).
E-mail addresses: martins@fcq.unc.edu.ar (S.E. Martín), rossi@fcq.unc.edu.ar
(R.A. Rossi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.042

3830
V. A. Vaillard et al. / Tetrahedron Letters 50 (2009) 3829–3832
So far, there has been no instance of the intramolecular aryla-
as a model of carboxamide 6, we can assume that the pyrrole
tion of pyrrole anion and related azaheterocycle ions with a pen-
dant aryl moiety which contain an appropriate leaving group to
obtain fused azaheterocycles through the SRN1 mechanism. The
methodology could be a useful tool for the preparation of novel
condensed azaheterocyles. The synthetic strategy involves the
reaction of suitable pyrrole containing substrate 1 with a base to
yield nitrogen anion 2ꢀ. Upon photostimulation and work-up in
acidic conditions, fused azaheterocyles may be obtained (com-
pound 3, Eq. 1).
hydrogen will be the first to be deprotonated by the base.
NH2
I
I
Cl
H
N
OH
O
H
N
H
N
HN
O
ð2Þ
SOCl2
O
Et3N
6 60 % overall yield
4
5
Therefore, when substrate 6 (1 equiv) was treated with t-BuOK
(2 equiv), anion 6ꢀ was formed, and under irradiation (2 h) the
new azaheterocycle 3H-pyrrolo[2,3-c]quinolin-4(5H)-one (7) was
obtained in 68% isolated yield (Eq. 3) (Table 1, entry 1). In the same
experimental conditions, however, after a 3 h irradiation, 7 was ob-
tained in 100% yield (Table 1, entry 2).
X
X
Base
hν
- X-
ð1Þ
Z
Y
Y
Y
Z
Z
N
H
N
N
H
-
H
1
2
3
I
N
O
Thus, herein we report on an efficient two-step synthesis of new
fused azaheterocycles derived from pyrrole, indole, and pyrazole,
and the synthesis of the precursors required.
HN
O
N
hv
NH
ð3Þ
As the pyrrole nucleus is present in many compounds with bio-
logical activities,16 we chose a derivative of this azaheterocycle
with suitable substituents to probe the synthetic strategy. In a
one-pot, two-step process, the precursor N-(2-iodophenyl)-1H-
pyrrole-2-carboxamide (6) was synthesized. From the commercial
1H-pyrrole-2-carboxylic acid (4) we prepared the 1H-pyrrole-2-
carbonyl chloride (5). After this, and by the reaction of 5 with 2-
iodoaniline, carboxamide 6 was obtained with 60% overall isolated
yield (Eq. 2).
Amide 6 has two acidic hydrogens, and since it is a new com-
pound, we did not know the pKa in liquid ammonia. However, con-
sidering that pyrrole has a pKa of 17.5 in DMSO, and taking 3,4-
dihydroquinolin-2(1H)-one, which has a pKa of 20.7 in DMSO,17
-
7
6
When the reaction was carried out in DMSO, azaheterocycle 7 was
obtained in 53% isolated yield (2 h) and 83% yield after 3 h of irra-
diation (Table 1, entries 3 and 4). The reaction did not occur in
the dark, and the photostimulated reaction was inhibited by 1,4-
dinitrobenzene, a well-known inhibitor of SRN1 reactions (Table 1,
entries 5 and 6). On the basis of the lack of formation of product
7 in dark conditions, as well as, when the irradiated reaction was
carried out in the presence of 1,4-dinitrobenzene, a SRN1 mecha-
nism can be proposed for this reaction (Scheme 1).
This reaction mechanism involved, in the first place, the reac-
tion of 6 with t-BuOK in excess, which afforded amide ions 6ꢀ.
Table 1
Intramolecular photostimulated reactions of carboxamides (6 and 12) and pyrazolylamines (15a–b)a
Entry
Substrate
Solvent
Substrate recoveredb (%)
Conditions
Product
Yieldb (%)
H
N
I
O
1
2
3
4
5
6c
NH3
NH3
DMSO
DMSO
DMSO
DMSO
25
—
27
–
95
100
hv, 2 h
hv, 3 h
hv, 2 h
hv, 3 h
Dark, 2 h
hv, 2 h
75 (68)
100
72 (53)
83
—
—
H
N
HN
O
NH
6
7
H
H
O
N
N
O
7d
8d
NH3
DMSO
—
—
hv, 2.5 h
hv, 2.5 h
83
94
Cl
HN
HN
12
13
H
N
I
H
N
N
N
N
9
NH3
—
hv, 3 h
54
HN
17a
N
15a
15b
I
H
N
Me
H
N
N
HN
Me
10
11
NH3
DMSO
—
—
hv, 3 h
hv, 3 h
56
25
N
17b
a
The reactions were run in 200 mL of liquid ammonia or 7 mL of DMSO, with 1 equiv of the substrate (0.25 mmol) and 2 equiv of t-BuOK (0.5 mmol) and irradiated.
Yields were determined by GC (internal standard method). Isolated yields are given in parentheses.
20 mol % of 1.4-dinitrobenzene was added. The substrate was 100% recovered.
b
c
d
1 equiv of 12 and 2.5 equiv of t-BuOK were used.

V. A. Vaillard et al. / Tetrahedron Letters 50 (2009) 3829–3832
3831
H
H
N
H
N
-
.
N
O
O
N
O
I
I
.
hv
+ H+
t-BuOK
Cl hν
HN
O
-
.
HN
N
HN
O
N
N
-
N
-
HN
ð5Þ
ET
t-BuOK
- Cl-
O
2
I-
-
.
-
6
8
6
-
-
12
13
13
N
O
N
.
O
H
N
R
Cl
NH
N
-
6
NH
H
H
N
H
R
I
NaHCO3
NH
ET
N
+
ð6Þ
9
I
- H+
.
NH2
14a: R = H
9
H
N
N
O
O
14b: R = Me
15a: R = H
+ H+
15b: R = Me
NH
NH
When the reaction mixtures were irradiated (3 h), the fused 2H-
pyrazolo[3,4-c]isoquinoline (17a) and 1-methyl-2H-pyrazolo[3,4-
c]isoquinoline (17b) were obtained (Table 1, entries 9 and 10). Upon
acidification of the reaction media and after the work-up, products
16 were not isolated, whereas the spontaneously oxidized aroma-
tized products 17 were obtained (Eq. 7).
9
7
Scheme 1.
The initiation step of the SRN1 reaction was the photoinduced ET to
6ꢀ yielding the radical dianion 62ꢀ 18
The subsequent fragmenta-
.
R
N
H
N
H
N
tion of the C–I bond of 62ꢀ gave the distonic radical anion 8ꢀand
Iꢀ ion. The intermediate radical anion 8ꢀ, via an intramolecular
process, yields the conjugated radical anion 9ꢀ.19 An ET from 9ꢀ
to 6ꢀ affords the intermediate 9 and the radical dianion 62ꢀ, which
propagates the chain reaction. Therefore, under the basic reaction
conditions, intermediate 9 led to anion 9ꢀ, which upon acidificat-
ion of the reaction media and work-up gives product 7.
With similar approach, from the commercial 1H-indole-2-car-
boxylic acid (10) bromide acid 11 was prepared. Then, by the reac-
tion of 11 with 2-chloroaniline in a one-pot two-step process, N-(2-
chlorophenyl)-1H-indole-2 (12) was obtained in 40% overall iso-
lated yield (Eq. 4).
R
R
N
work-up
[O]
hv
N
N
NH
NH
N
ð7Þ
I
16a: R = H
16b: R = CH3
17a: R = H
17b: R = CH3
15a-: R = H
15b-: R = CH3
When the photostimulated reaction of 15b was carried out in
DMSO, the yield was only 25% (Table 1, entry 11). It is important
to notice that in all reactions with pyrazole derivatives remained
substrate were not found, and the dehalogenation was complete
(100% of Iꢀ ions), which indicated the total conversion of the sub-
strate. As the nucleus of pyrazole is quite sensitive to light,21 we
believe that precursor 15- and/or products 16 are partially de-
stroyed by the irradiation. Nevertheless, yields of 54–56% of fused
azaheterocycles 17 were obtained.
NH2
H
O
N
O
Br
O
HO
HN
Cl
PPh3
NBS
Cl
HN
HN
ð4Þ
Et3N
We have shown that the photostimulated intramolecular reac-
tions of anions derived from pyrrole, indole, and pyrazole with a
pendant aromatic moiety with a suitable leaving group in liquid
ammonia afford novel fused azaheterocycles in good to excellent
yields by the SRN1 mechanism. The starting materials to prepare
the precursors of the fused azaheterocycle products are easily ob-
tained. Considering the availability and/or simplicity of the starting
materials, and the readiness and mild conditions of the procedures,
we have demonstrated that this can be a general methodology for
the synthesis of this family of compounds.
10
11
12 40 % overall yield
As with the pyrrole precursor 6, the pKa of the indole (pKa = 16.9
in DMSO)17 seems to be smaller than the pKa of the corresponding
amide. Thus, the indole hydrogen will be the first to be deproto-
nated by the base. In the photostimulated reaction of anion 12ꢀ
(2.5 h), formed by the acid base reaction of 12 with t-BuOK
(2.5 equiv) in liquid ammonia, 83% of the ring closure product
5H-indolo[2,3-c]quinolin-6(7H)-one (13) was formed after the
acidification of the reaction mixture (Eq. 5) (Table 1, entry 7). Sim-
ilarly, the photostimulated reaction of anion 12ꢀ in DMSO (2.5 h)
afforded 94% yield of fused heterocycle 13 (Table 1, entry 8).
Since the pyrazole nucleus is an important heterocyclic system
with a wide variety of biological activities,20 we extended the
application of the synthetic strategy developed to fused heterocy-
cle derivatives of pyrazole. The approach involved the reaction of
the commercial 1H-pyrazol-3-amine (14a) and 5-methyl-1H-pyra-
zol-3-amine (14b) with 1-(chloromethyl)-2-iodobenzene to give
N-(2-iodobenzyl)-1H-pyrazol-3-amines 15 (Eq. 6), but with an iso-
lated yield of 30% for both.
Acknowledgments
We thank ACC, CONICET, FONCYT, and SECYT for their continu-
ous support to our work. V.A.V. and M.E.B. thank CONICET for the
fellowships provided.
Supplementary data
The pKa of pyrazole is 28.8 in DMSO,17 and probably more acidic
than the benzyl-pyrrolylamine moiety. Thus, when substrates 15
were treated with 2 equiv of t-BuOK in liquid ammonia, anions
15- were formed (Eq. 7).
Supplementary data (general experimental details and proce-
dures, and also characterization of 6, 7, 12, 13, 15 and 17) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.04.042.

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V. A. Vaillard et al. / Tetrahedron Letters 50 (2009) 3829–3832
O. A., Spinelli, D., Eds.; Soc. Chimica. Italiana: Rome, Italy, 1999; Vol. 3, pp 215–
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