Iterative double cyclization reaction by SRN1 mechanism. A theoretical interpretation of the regiochemical outcome of diazaheterocycles

Article abstract of DOI:10.1039/c5ra04563k

In this report, we present a synthetic and mechanistic study of novel iterative double cyclization intramolecular S_RN1 reactions from diamides bearing two aryl iodide moieties. This cyclization affords aromatic diazaheterocyclic compounds in good yields. Two synthetic strategies were employed for their preparation: intramolecular S_RN1 and Homolytic Aromatic Substitution. The mechanism is non-trivial and we propose that radicals are intermediates. The regiochemistry was studied using computational calculations, employing the DFT method and the B3LYP functional. It was found that the distribution of products depends on the cyclization activation energies, proportion of neutral conformers, and the type of the electron transfer reaction.

Full text of DOI:10.1039/c5ra04563k

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: L. E. Peisino, G. P.
Camargo Solorzano, M. E. Budén and A. B. Pierini, RSC Adv., 2015, DOI: 10.1039/C5RA04563K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 11
RSC Advances
View Article Online
DOI: 10.1039/C5RA04563K
Journal Name
RSCPublishing
ARTICLE
Iterative double cyclization reaction by SRN1
mechanism. A theoretical interpretation of the
regiochemical outcome of diazaheterocycles
Cite this: DOI: 10.1039/x0xx00000x
a
a
a
a
Lucas E. Peisino, Gloria P. Camargo Solorzano, María E. Budén* and A. B. Pierini*
Received 00th January 2012,
Accepted 00th January 2012
In this report, we present a synthetic and mechanistic study of novel iterative double
cyclization intramolecular SRN1 reactions from diamides bearing two aryl iodide moieties.
This cyclization affords aromatic diazaheterocyclic compounds in good yields. Two
synthetic strategies were employed for their preparation: intramolecular SRN1 and Homolytic
Aromatic Substitution. The mechanism is non-trivial and we propose that radicals are
intermediates. The regiochemistry was studied using computational calculations, employing
the DFT method and B3LYP functional. It was found that the distribution of products
depends on the cyclization activation energies, proportion of neutral conformers, and the
type of the electron transfer reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
(
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
1
Introduction
2+
inorganic salts (i.e., Fe or SmI ) are needed to initiate the
Aromatic azaheterocycles present interesting pharmacological
properties related to the planarity of the system and
consequently to their DNA-chain intercalating abilities, which
make them suitable for anti-neoplastic or mutagenic
applications. Due to their significant biological activity, they
are an important class of heterocyclic compounds in medicinal
chemistry, being able to bind with high affinities to the aryl
hydrocarbon receptor (AhR), which activates the regulatory
protein. This effect was studied experimentally and using
QSAR methods.
In another context,
having more than one nitrogen atom have received an
increasing interest owing to the fact that their complexes with
transition-metal ions show interesting properties in harvesting
light and reemitting it at a wavelength that depends on the
2
1
2
reaction.
Several nucleophiles, for example carbanions and
heteroatomic anions, can be used for SRN1 reactions to form
new C–C or C–heteroatom bonds in good yields. However, an
exception to these is the reaction of phenyl amide anions with
haloaromatic substrates, where C–N and C–C bond formations
1
–4
1
3
were achieved instead. 2-Naphthylamide anions can react by
the photo SRN1 process with PhI, 4-MeOC H I and 1-
6
4
5
–8
iodonaphthalene in liquid ammonia. Here, 1-aryl 2-
naphthylamines were formed regioselectively in 45–63%
N-containing aromatic heterocycles
1
4
yields, with only 3–6% of
arylation has been previously achieved using
as a substrate with the anions of 2-naphtylamine and 9-
N–arylation. Moreover, double
p
-dihalobenzene
1
5
phenanthrylamine under irradiation in liquid ammonia.
synthetic strategy to obtain heterocyclic
9
,10
An SRN
1
metal ion used.
compounds was previously developed based on the
intramolecular cyclization of substrates bearing both the
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 been increased
considerably over recent decades, it has become an important
1
6
leaving group and the nucleophilic center. This methodology
has been recently applied to the synthesis of 1-phenyl-1-
1
7
1
1
oxazolinoindan derivatives and their related compounds;
synthetic strategy. The initiation step is by an electron transfer
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

RSC Advances
Page 2 of 11
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Journal Name
1
8
tetracyclic isoquinoline derivatives; a series of substituted 9
H
-
1
9–21
carbazoles and carbolines;
aporphine and homoaporphine
alkaloids; pyrroles, indoles, and pyrazoles; indazoles;
2
2
23
24
2
5
pyridio[1,2-a]benzimidazoles;
2-pyrrolyl and 2-indolyl
2
6,27
benzoxazoles,
SRN1 reaction of substituted iodobenzylamines with several
tetralones afforded a series of benzo[28]phenanthridines with
modest overall yields after several steps.
Recently, Rossi et. al. proposed a new approach for the
syntheses of phenanthridines and benzophenanthridines ( ) by
intramolecular ortho-arylation of (2-halobenzyl)- -arylamines
In these reactions, the cyclization of compounds
among others. Moreover, an intermolecular
c
2
N
2
9,30
(1) (eq 1).
such as
derivates
1
2
gaves very good yields of the phenanthridine
(44-85%). On other hand, by direct photolysis of the
C–I bond of
1, the synthesis of 2 was achieved with 30-95%
3
1,32
yields via Homolytic Aromatic Substitution (HAS).
Scheme 1 Synthesis of diamine
8
Following the same procedure, substrates
9
and 11 were
obtained in 26% and 65% isolated yields, from 4,4’-
diaminobiphenyl and 1,3-diaminopyridine, respectively
(
Scheme 2), using the new synthetic intermediates 10 and 12
It is worth noting in the literature an example reported of
double ring closure reactions by SRN1 where two 5-membered
1
9
rings are formed. In this case, two intramolecular consecutive
SRN1 of substrate were reported to give dicarbazol in 67%
3
4
yield (eq 2). However, there is no other reported example where
a double closure afforded two 6-membered rings. With this in
mind, in the present article we report a double cyclization
reaction to give 6-membered diazaheterocyclic compounds. In
order to explain their regiochemical outcome, a computational
study of the non-trivial mechanism is presented.
Scheme 2 Retrosynthetic preparation of diamines
.1 Intramolecular SRN1 Reactions
The results of the photostimulated reaction (180 min) of the
9 and 11
2
Results and discussion
2
The substrates were prepared through a three-step synthetic
strategy (Scheme 1). The first reaction was the formation of
diamines and 11 in the presence of excess -BuOK (5
8
,
9
t
acetamide derivate
excess of acetic anhydride. The dianion of amide
with NaH (2 equiv), after which -iodobenzyl chloride (2
equiv) was added and yielded the diacetylated dibenzyl amide
. Finally, acid hydrolysis of the acetamide group was carried
out and afforded in a 53% global yield.
6
from 1,4-diaminobenzene (
5) with an
was formed
equiv) under a nitrogen atmosphere are presented in Table 1.
Under these reaction conditions, and after oxidation with
6
o
MnO /CHCl , the diamine
8 afforded good yields of
2
3
diphenanthridines 13 (46%) and 14 (25%) using liquid
ammonia as the solvent (Table 1, entries 1-3 and eq 3).
7
8
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 11
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
abstraction from the solvent to afford 15, and with the Cbenzylic–N
fragmentation to give 17
.
Table 1 Photochemical reactions of compounds
8
,
9
, and 11 in
a
the presence of
t-BuOK.
-
b
Entry Substr
Solvent
Product Yields (%)
I (%)
Figure 1 Other products obtained in cyclization reaction of
diamine
1
2
8
8
8
8
8
8
8
8
9
NH3(l)
NH3(l)
NH3(l)
NH3(l)
NH3(l)
NH3(l)
DMF
Diglyme 13 (11)
NH3(l)
NH3(l)
13 (42)
13 (46)d
13 (46)
13 (--)
13 (3)
13 (18)
13 (21)
14 (20)
88
91
88
<5
32
79
73
90
42
94
c
8
14 (25)d
14 (17)
14 (--)
14 (<1)
14 (5)
3
e
In this work, the product yield of 13 was 46% (24% overall
yield) which is comparable, and in some cases better, than those
obtained by other synthetic strategies. Starting from analog
4
5
6
7
8
9
f
g
h
i
chloride derivative type
through a benzyne type mechanism using NaNH /THF and
8, a 4% yield of 13 was obtained
14 (8)
14 (5)
3
3
2
3
4
j
4
0% yield using KNH /NH3(liq).
However, there is no
specification for the preparation of the chloride derivative type
, which is not a single molecule. Furthermore, a comparable
yield of 13 (49% yield) was also reported using photochemical
-BuOK]. The substrate was previously methodology. However, these reactions were irradiated for 24-
18 (17)
19 (13) 20 (13)
(22)
Photostimulated reactions were performed with [substrate]=1.33 x 10
M and five times with [
dissolved in DMSO. Reaction times were 180 min, unless indicated 36 hours.
2
1
0
11
8
2
1
a
-3
t
3
5
otherwise. Irradiation was conducted in a reactor equipped with two
high pressure lamps of model Phillips HPI-T plus 400-W (air- and
water-refrigerated) with a maximum emission at 530 nm. Oxidation
Concerning the synthesis of 14, there is only one report in
which, after four consecutive reactions, the product was
36
obtained in 14% yield. This value is comparable to that
2
reactions were carried out by stirring the crude reaction with MnO in
1
obtained by the route where 14 was afforded with 9% overall
yield.
3
CHCl . Yields of the products was determined by H-NMR.
b
The halides were determined potentiometrically.
The substrate was not dissolved in DMSO.
Isolated yield.
c
d
e
f
Following the same methodology, the photostimulated
reaction of
diphenanthridine 18 was obtained in 17% yield (Table 1, entry
9 and eq 4). In this case, a 48% yield of unreacted substrate
9 was carried out in NH3(l) as the solvent, and the
Dark conditions. Only the substrate was detected (95% yield).
m-dinitrobenzene was added (30 mol %).
9
g
h
i
TEMPO was added (30 mol %).
was achieved, due to its very low solubility in the reaction
media. When the reaction was carried out in organic solvents
such as diglyme and DMF, no diazaheterocycle 18 was formed,
with only a reduced product being observed (results not
tabulated). Despite its regular yield, diazaheterocycle 18 has not
been described in the literature.
-3
-2
[
[
substrate] = 100 x 10 M and [
t
-BuOK] = 70 x 10 M.
-3
-3
substrate] = 20 x 10 M and [
t-BuOK] = 140 x 10 M.
j
Reaction time 240 min. Substrate was detected (48% yield).
In dark conditions, there was no reaction of
excess of -BuOK in liquid ammonia (Table 1, entry 4). The
reaction was partially inhibited by -dinitrobenzene ( -DNB),
8 with the
t
I
m
m
a well-known inhibitor of the SRN1 processes (Table 1, entry 5),
as well as being inhibited by radical traps such as TEMPO
NH
N
(
Table 1, entry 6). This indicates, for this system, that the
double cyclization is slow with respect to the single ring
closures previously reported, in which TEMPO caused no
inhibition.
The reaction was tested in the organic solvents DMF,
diglyme and DMSO. However, the yields of diphenanthridines
t-BuOK
MnO2
(
5 eq)
2
9,30
(4)
h , N2
1
3
and 14 were lower than in NH3(l), due to the greater
hydrogen–donor capacity of the media. For instance in DMF,
and 14 were formed in 21% and 8%, respectively (entry 7).
Using diglyme as the solvent, yields were 11% of 13 and 5% of
NH
N
1
3
I
9
18
In the same way, the photostimulated reaction of diamine 11
was carried out in NH3(l), and the double cyclization products
1
4
(entry 8), but only 5% of 13 being obtained in DMSO.**
In the HPLC/MS chromatogram profile of the selected
1
9
(C–C coupling) and 20 (C–N coupling) were both afforded
in 13%, together with the monocyclization–reduction product
in 22% yield (Table 1, entry 10 and eq 5). However, when
the reaction was carried out in DMF as the solvent, the yields of
the cyclic products 19 and 20 did not improve (results not
tabulated).
reaction (Table 1, entry 7; see ESI), the double-cyclization
products 13 and 14 were observed, together with the
monocyclization–reduction product 15, monocyclization with
iodo retention 16 and the monocyclization–fragmentation
2
1
(
Cbenzylic–N) product 17 (Figure 1). The absence of a double–
reduction product and the presence of 15 and 16 indicate that
the first cyclization was favored with respect to the second one.
The second cyclization reaction competed with the hydrogen–
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

RSC Advances
Page 4 of 11
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Journal Name
In contrast with the SRN1 conditions (Table 1, entry 9),
substrate was completely soluble in the direct photolysis
9
conditions. However, the yield of the double-cyclization
product 18 was less than 10% (Table 2, entries 3-5). A similar
behavior was observed in the reaction of 11, where the double-
cyclization products (19 and 20) were not obtained and only the
monocyclization–reduction product 21 was detected (Table 2,
entry 6).
a
Table 2 Photolysis reaction of compounds
8
,
9
and 11
.
Entry
Substrate Time (min) Yield (%)
1
2
3
4
5
6
8
8
9
9
9
60
120
60
120
180
60
13 (28) 14 (<5)
13 (36) 14 (5)
18 (6)
18 (6)
18 (6)
11
19 (--) 20 (--) 21 (32)
a
Photostimulated reactions were performed with [substrate] = 1 mg/mL
with acetonitrile as solvent (7 mL) in a quartz tube, under a nitrogen
atmosphere and bubbling during all the reaction time. The reaction
mixture was previously degassed by nitrogen bubbling and sonication
Although, diazaheterocycle 19 was obtained in 68 % yield for 20 minutes. Irradiation was conducted in a photochemical reactor
in two consecutive reactions (diiodination of 2,6- equipped with nine Hg high pressure lamps (254 nm). Oxidation
2
diaminopyridine followed by a double Suzuki coupling with 2- reactions were carried out by stirring the crude reaction with MnO in
1
3
CHCl . Product yields were determined by H-NMR.
formylphenyl boronic acid and spontaneous cyclization and
aromatization), our strategy did not include the use of a
3
7
transition metal. This is important because impurities can be 2.3 Mechanism and Theoretical Calculations
avoided and the products used directly in pharmaceutical and
other industries. In addition, for compounds 20 and 21 there are
no precedent in the literature of their preparation.
2
.3.1 Diamine 8 The experimental behavior of the system was
modeled using the DFT methodology and the B3LYP
functional. A systematic inspection of the conformational
potential energy surface (PES) of diamine
that principally two conformers, s-cis and 8
present under the conformational equilibrium (eq 6). The
Boltzmann distribution of conformers (T =240 K) showed that
Taking into account that in all reactions double cyclization
products were formed, and considering the results presented in
8
led us to conclude
s-trans, are
2
9,30
8
Table 1 and those previously reported,
we suggest that SRN1
is the operating mechanism. Furthermore, the results in dark
conditions, the inhibition exerted by TEMPO and another
their conformer distribution ratio is 1.2:1 for
8
s-cis
:
8
s-trans.
inhibitor (
m-DNB), and the presence of monocyclization–
reduction product 15, are consistent with aryl radicals and
2
6,27
radical anions as intermediates.
2
.2 Intramolecular HAS Reactions
In order to explore other possible reaction patterns of the
substrates described above, we used the direct photolysis
reaction of compounds
8
,
9
and 11 to obtain the
diazaheterocycles. These reactions were carried out in a quartz
tube using anhydrous acetonitrile as the solvent.
2-
In the superbasic reaction medium, the dianions
8
s-cis and
Photostimulation was achieved by irradiating with
a
2-
8
s-trans can be formed. The s-cis/s-trans isomerization
barrier for the anions is high, because it involves rotation
wavelength of 254 nm. In this cyclization reaction, the presence
of a base is not required because initiation takes place through
the homolytic C–I breaking bond. The aryl radicals thus formed
around C3(phenyl) and the N bond, which has a partial double-
2
2-
bond character. Thus, the distribution of the anions
8
s-cis
s-trans).
The initiation step involves a photoinduced ET to
followed by fragmentation of a C–I bond to give the distonic
:8 s-
2
-
can be added to the
π system of the central aromatic ring to
trans is directly related to its neutrals (8 s-cis:8
2
-
yield a cyclohexadienyl radical. Possibly, this radical transfers
the tertiary hydrogen atom to other radical intermediates
present in the reaction media (i.e. iodine atom) to give the
8
‡
-
•-
-
radical dianion [
). The intermediate radical dianion [
intramolecular C–C cyclization, to afford the monocyclic
8 ] (s-cis and s-trans) and I anion (Scheme
3
1
-
•-
neutral cyclic product.
3
8
]
adds quickly, via
†
After a screening of conditions, the best results were found
to be obtained when degassing the reaction media by nitrogen
bubbling and sonication. Results of photolysis reactions in
these conditions for the three substrates studied are presented in
-
•-
conjugated radical dianion [22 ] (s-cis and s-trans), which is
separated from the second -iodoaryl moiety by a Csp3 atom.
The radical dianion [22 ] may follow either an intramolecular
Scheme 4) or an intermolecular ET reaction pathway (Scheme
).
o
-
•-
Table 2. In the photostimulated reaction (120 minutes) of 8, the
(
5
cyclic product 13 was obtained in 36% yield, and traces of
isomer 14 were also obtained (Table 2, entry 2). Although the
SRN1 reaction gave a higher yield of both products (Table 1,
entry 2), the direct photolysis was more selective towards
product 13
.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 11
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Scheme 3 Possible initiation step and first ring closure reaction
2
-
of
8
•
-
Following the intramolecular pathway, 23
(s-cis and s-
trans) can be formed (Scheme 4). However, cyclization to give
•-
•-
•-
radical anion 24 is favored from 23 s-cis because in 23 the
negative charge is localized in the C vecinal to Csp3 of the
•
-
central ring (Figure 2). After ring closure radical anion 24 is
2
-
•
-
yielded. This transfers the extra electron to
8
to afford 24 and
] , with the latter propagating the reaction cycle. Ultimate
tautomerization of 24 in the basic media, and subsequent
Figure 2 A) Resonance structures for radical anion 23 . B)
Electrostatic potential of radical anions 23 and [26 ] .
-
•-
•
-
- •-
[
8
•
-
-
•-
2-
oxidation will afford 13. Thus, the 23 s-trans isomer cannot
cyclize, and reduction of this radical anion by hydrogen-
abstraction from the solvent occurs to finally yield the
monocyclization–reduction product 15 (Scheme 4). Under this
intramolecular ET pathway, only the cis product 13 and
reduced product 15 will be observed.
On the other hand, if intermolecular ET from [22 ] to
8 is
can be afforded
Scheme 5). The anion 22 in the basic medium rearomatizes
(s-cis and s-trans), which can
initiate a second SRN1 cycle through the formation of the
(s-cis and s-trans). Given the
electronic distribution of [26 ] , both ortho positions to the
-
- •-
followed, 22
(
(
s-cis and s-trans) and [
8
]
-
2
-
the central ring to give 25
-
•-
distonic radical anion [26
]
-
•-
amide group are favored to couple with aryl radicals (Figure
-
•-
2
B). Following this reactive pathway, [26 s-cis ] and [26 s-
-
•-
trans ] can cyclize to give products 13 and 14. Experimentally,
we observed that both products are formed together with
products 15 and 16 (Figure 1). Moreover, product 16 is formed
2
-
through intermediate 25 , via protonation–oxidation reactions.
Therefore, intermolecular ET is operating in the cyclization of
2
-
8
.
-
•-
Scheme 4 Intramolecular ET from [22
]
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 11
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Journal Name
I
I
ET pathway, but also the intramolecular ET pathway is taking
place in this system.
N
N
N
N
ETinter
82
H
t-BuO
22
t-BuOH
8
252
22
N
N
N
h
-I
2
52
+
ET
N
2
6 s-cis
26 s-trans
N
N
N
•
-
2
6 s-cis
H
Figure 3 PES to cyclization of 26 radical anion.
2
.3.2 Diamine 11 Following the same procedure as that for
diamine , the reaction mechanisms for diamine 11 were
analyzed. A systematic inspection of the conformational PES of
led us to conclude that principally the two conformers 11 s-
cis and 11 s-trans are present under conformational equilibrium
N
8
13
2
7 s-cis
1
1
N
N
(
eq 8) in a relationship 1:1.8, respectively (T = 240 K).
2
6 s-trans
H
N
N
2
7-trans
14
-
•-
Scheme 5 Intermolecular ET from [22
]
Considering that the electronic structure of radical dianion
-
•-
[
26 ] (s-cis and s-trans) corresponds to a conjugated species
and that the evaluated energy for its cyclization is high (see
ESI), we propose that cyclization to occurs via the distonic
As mentioned above, the presence of product 21 (see eq 5)
•-
indicate that the first cyclization (C–C coupling) is favored with
respect to the second one (C–C or C–N coupling).
radical anion 26
(s-cis and s-trans), which can be present
under the reaction conditions (eq 7).
-
•-
In principle, once radical dianion [28
]
is formed, two
N
N
reactive pathways may be followed: intramolecular ET
(Scheme 6) and intermolecular ET (Scheme 7).
H+
(7)
Similar to
8, if the reaction takes place by intramolecular
ET (Scheme 6), only product 20 (C–N coupling) will be
•
-
obtained from the 29 s-trans . This behavior can be explained
N
NH
due to the negative charge being localized on the N atom of the
•
-
pyridine central ring for the radical anion 29 (Figure 4). Thus,
2
6
26
•-
the 29 s-cis isomer cannot cyclize, and reduction of this
•
-
The PES for cyclization of radical anions 26
(s-cis and s- radical anion (by hydrogen-abstraction from the solvent) will
trans) presented in Figure 3 shows that both conformers cyclize occur to finally yield the monocyclization–reduction product
with similar energies to give the s-cis and s-trans cyclic 21. Under this intramolecular pathway, product 19 will not be
products. Considering that the kinetics of ring closure are formed.
similar and that the interconversion between the s-cis and s-
trans conformers is very slow because it implies a rotation
§
around C-N bond with a double-bond character, then the
product distribution for this path is governed by this
conformational distribution and should be close to 1.2:1.
Taking into account that the experimental ratio of s-cis
:s-trans
products is 1.8:1, we propose that not only the intermolecular
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 11
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
-
•-
Scheme 6 Intramolecular ET from [28
]
-
•-
Scheme 7 Intermolecular ET from [28
]
Taking this into account, the second cyclization path was
theoretically investigated. The PES for this system shows that
the activation energy for C–N coupling is 10.4 kcal/mol, while
for the C–C coupling is only 2.0 kcal/mol (Figure 5). On the
other hand, the activation energy for hydrogen–abstraction of
-
•-
[
32 ] to yield 21 is 6.5 kcal/mol. This indicates that hydrogen–
abstraction competes with C–N coupling, and thus only the
monocyclation–reduction product 21 is obtained from [32- s-
-
•-
•-
trans
]
and only product 19 is formed from [32 s-cis ] .
Accordingly, product 20 is formed by the intramolecular ET
pathway (Scheme 6). Similarly to
pathways are present.
8
, in this system both ET
•
-
Figure 4 A) Resonance structures for radical anion 29 . B)
Electrostatic potential of radical anions 29 and [31 ] .
•
-
- •-
If intermolecular ET is in play (Scheme 7), the formation of
2
-
both products 19 and 20 is possible. As the relationship of 11
s-cis s-trans conformers is 1:1.8, the ratio of the radical anions
s-cis to 32 s-trans will remain constant as well as the ratio
:
•
-
•-
3
2
*
**
of products.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

RSC Advances
Page 8 of 11
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Journal Name
effect of the solvent through Tomasi’s polarized continuum
4
2-44
model (PCM)
as implemented in Gaussian09. The effect of
NH3(l) was evaluated using methanol as the model polar
3
0
solvent. The TS and intermediates were localized by a scan of
the distinguished reaction coordinate. Then, after refinement, a
characterization of stationary points was made by Hessian
matrix calculations, with all positive eigenvalues for a
minimum and only one negative eigenvalue for the TSs. The
energy reported for all species includes zero-point corrections.
4
.2 General Methods
1
The products were quantified by H-NMR. All NMR spectra
1
were obtained on a 400 MHz Spectrometer ( H-NMR (400
1
3
MHz), C-NMR (100 MHz), COSY, HSQC, HMBC and NOE)
using CDCl as the solvent unless otherwise indicated. The
3
coupling constants (J) are given in hertz. The HPLC/MS
analyses were carried out on a HPLC equipment with a reverse
C-18 stationary phase (15 cm x 4.6 x 5 micron) and
MeCN:water mixtures as the mobile phase; coupled to high-
resolution mass spectra on a TOF analyzer, using an ESI ion
source, with nitrogen as the nebulizing and drying gas. High-
resolution mass spectra were recorded on a TOF analyzer, using
an ESI source in a positive mode, with nitrogen as the
nebulizing and drying gas, and sodium formiate (10 mM) as the
internal calibrant.
•
-
Figure 5 PES to cyclization of radical anion 32
4
.3 Materials
3
Conclusions
Acetic anhydride, sodium hydride (60% on mineral oil), 2-
In this article, we have presented the synthesis of novel
diazaheterocycles by intramolecular SRN1 reactions. This is the
first study that explores in detail reactions where two ring
closures occur consecutively. Considering that during the
reaction two new junctions C–C or C–N are formed to result in
the formation of two new heterocycles within the same
molecule, it is ensured that the diazaheterocycles have good
yields (13, 46%; 14, 25%; 18, 17%; 19, 13% and 20, 13%).
iodobenzyl chloride and potassium -butoxide were obtained
t
from commercial sources. DMSO was stored over 4°A
molecular sieves. DMF was distilled from Na metal and stored
under nitrogen over 4°A molecular sieves. Diglyme was
distilled from Na metal and stored with Na wires. To prepare
the substrates, commercially available 1,4-diaminobenzene,
4
,4’-diaminobiphenyl and 2,6-diaminopyridine were used.
Silica gel (0.063-0.200 mm) was used in column
chromatography and on 2 mm plates (silica gel 60 PF254) in
radial thin-layer chromatography purification. All solvents were
of analytical grade and used as received from the supplier.
Direct photolysis reactions of the amines
8, 9 and 11 were
carried out and dual-closure rings were observed. However, a
lower percentage of products than that obtained by SRN1 were
found. This may have been due to the instability of
intermediates and products formed under the irradiation
conditions used in the photolysis reactions.
Radicals and radical anions are intermediates of these
reactions. The mechanism in the presence of a base was studied
using DFT calculations, with the product distribution depending
not only on the ratio of conformers of the neutral species, but
also on the type of the ET reaction and the relative energies of
the coupling. After the first cyclization, the reduction of the aryl
radical was always in competition with the second cyclization
reaction. Finally, we suggest that for these systems both
intramolecular and intermolecular ET were present.
1
4
N ,N -bis(2-iodobenzyl)benzene-1,4-diamine (8). 1,4-
Diaminobenzene (9.25 mmol, 1g) was added to a round-
bottomed flask equipped with a reflux condenser and magnetic
stirring. Next, an excess of acetic anhydride was added to give
the diacetylated intermediate
6, and this mixture was stirred for
1
5 minutes. Then, water was added and the reaction was
refluxed for one hour before the mixture was left to cool at rt.
The solid was filtered off, washed with cold water and dried.
DMSO (10 mL) and compound
6 (5.2 mmol) were added to a
dried shlenk tube (50 mL) with an N atmosphere and magnetic
2
stirrer. NaH (10.5 mmol) was then added in small parts, and
between each addition, a vacuum was applied to the reaction to
favor gas evolution. When an anion was formed, 2-iodobenzyl
chloride (1 mmol) was added and the mixture was stirred for 24
4
Experimental
hours. The precipitated
was filtered off and washed with cold water. To carry out
hydrolysis of the acetyl group, (1 mmol) was poured into a
round-bottomed flask equipped with a reflux condenser and
magnetic stirring. Then, ethanol (20 mL), 37% hydrochloric
acid (10 mL) and 98% sulphuric acid (10 drops) were added,
and the mixture was boiled for 24 hours. The mixture was left
to cool at rt and the precipitated hydrochloride was filtered off
7 was favored by water addition, which
4
.1 Computational Procedure
7
The conformational search was carried out using a Vconf
program. Calculations were performed using the Gaussian09
program, the B3LYP
basis set. The B3LYP functional and the 6-31+G*,
†
†
3
8,39
DFT functional and the 6-31++G**
3
0,40
6-
and 6-311+G** basis sets have been previously
2
1,41
40
3
11+G*,
tested for similar systems. All determinations were carried out
with full geometry optimization, including for all cases the
and washed with cold ethanol. To obtain free amine
8 (53%
global yield), basic medium extractions were carried out. The
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 11
Journal Name
RSC Advances
View Article Online
DOI: 10.1039/C5RA0
A
4
R
5
T
6
I
3
C
K
LE
products
7
and
8
were characterized by standard spectroscopic
Reactions of diamines 8, 9 and 11 in NH3(l). First, 150mL
techniques as follows.
The compound
of NH3(l) were condensed, previously dried with Na metal under
was isolated by crystalization as nitrogen in a three-necked, 250 mL round-bottomed flask
8
hydrochloride from acid ethanol and basic medium extraction. equipped with a cold finger condenser charged with ethanol, a
1
H-NMR (400 MHz, CDCl3),
.53 (s, 4H); 6.95 (td, 2H,
δ
H: 3.82 (br s, 2H); 4.24 (s, 4H); nitrogen inlet, and a magnetic stirrer.
=7.5Hz, 1.6Hz); 7.29 (td, 2H, then added. The diamine (0.25 mmol) were dissolved in 0.5 mL
=7.7Hz, 1.6Hz); 7.83 (dd, 2H, of DMSO and added to the solution. The reaction mixture was
=7.9Hz, 1.1Hz). C-NMR (100 MHz, CDCl3)
C: 54.3; 98.6; irradiated for indicate time and then quenched by adding
14.8; 128.4; 128.8; 129.0; 139.4; 140.3; 141.5. ESI-HRMS ammonium nitrate in excess. The ammonia was allowed to
t-BuOK (1.25 mmol) was
6
J
J
1
J
=7.5Hz, 1.1Hz); 7.39 (dd, 2H, J
1
3
δ
+
m/z [M + H] calcd for C H I N 540.9632, found 540.9638.
evaporate and water (50 mL) was added. The aqueous phase
was extracted with dichloromethane (3 x 50 mL), the organic
2
0
19 2
2
N,N’-(1,4-phenylene)bis(N-(2-iodobenzyl)acetamide) (7):
white solid. Isolated by precipitation from the reaction media as phase was dried (magnesium sulphate) and the solvent was
intermediate. H-NMR (400 MHz, DMSO-d ),
6
7
1
evaporated in vacuum. The crude was dissolved in chloroform
δ
H: 1.83 (s,
6
(
20 mL) and excess of MnO was added (1 g), the mixture was
H); 4.81 (s, 4H); 6.97 (td, 2H,
.32 (br d, 4H, =4.3Hz); 7.77 (d, 2H,
C: 22.9; 56.9; 99.5; 128.8; 129.4;
J
=7.8Hz, 4.6Hz); 7.26 (s, 4H);
2
1
3
stirred for 24 hours at rt. Then solid was filtered off and
products were purified as indicated. In other similar
J
J=7.7Hz). C-NMR
(
100 MHz, DMSO-d6)
29.6; 139.4; 139.5; 142.0; 169.8. ESI-HRMS m/z [M + Na]
calcd for C H I N O Na 646.9663, found 646.9689.
δ
1
+
experiments, the products were quantified by H-NMR by using
1
an internal standard. The yield of halide ions in the aqueous
solution was determined potentiometrically. For inhibited
reactions we procedure in similar manner, but after substrate
2
4
22 2
2
2
4
4´
N
,
N
-bis(2-iodobenzyl)-[1,1’-biphenyl]-4,4’-diamine
9). This reaction was carried out using a procedure similar to
that described for , but the substrate utilized was 4,4’-
diaminobiphenyl (10 mmol). Compound (430 mg, 26% global
yield) was separated as yellow solid by column
chromatography using petroleum ether:dichloromethane, 30:70.
(
addition
was added.
m-dinitrobenzene (30 mol %) or TEMPO (30 mol %)
8
9
Reactions of diamines 8, 9 and 11 in organic solvents. In
a 15 mL Shlenk tube with a magnetic stirrer and nitrogen
a
1
atmosphere,
t-BuOK (1.25 mmol) was added. The substrates
H-NMR (400 MHz, CDCl3),
.64 (br d, 4H, =6.5Hz); 6.98 (td, 2H,
td, 2H, =7.6Hz, 1.1Hz); 7.35 (br d, 4H,
=7.7Hz, 1.6Hz); 7.86 (dd, 2H, =7.9Hz, 1.1Hz). C-NMR
C: 53.4; 98.5; 113.3; 127.2; 128.4; 128.8;
δ
H: 4.21 (br s, 2H); 4.35 (s, 4H);
=7.6Hz, 1.6Hz); 7.31
=8.0Hz); 7.1 (dd,
(
0.25 mmol) were added to the solution. The reaction mixture
6
(
2
J
J
was irradiated for indicate time and then quenched by adding
ammonium nitrate in excess. Water (50 mL) was added. The
aqueous phase was extracted with dichloromethane (3 x 50
mL), the organic phase was washed with brine (3 x 50 mL),
dried (magnesium sulphate) and the solvent was evaporated in
vacuum.
J
J
1
3
H,
J
J
(
1
100 MHz, CDCl3)
29.0; 131.1; 139.5; 141.0; 146.2. ESI-HRMS m/z [M + H]
calcd for C H I N 616.9945, found 616.9950.
δ
+
2
6
23 2
2
N
,
N
’-([1,1’-biphenyl]-4,4’-diyl)bis(
N-(2-iodobenzyl)
Reactions of diamines 8, 9 and 11 in acetonitrile.
Substrate (7 mg) was dissolved in anhydrous acetonitrile (7
acetamide) (10): white solid. Isolated by extraction with
CH Cl (3 x 75 mL) from reaction crude as intermediate. H-
1
2
2
45
mL) in a quartz flask. The mixture was irradiated [irradiation
NMR (400 MHz, CDCl3),
t, 2H, =7.5Hz); 7.13 (d, 4H,
.37 (dd, 2H, =7.6Hz, 1.6Hz); 7.50 (d, 4H,
δ
H: 1.98 (s, 6H); 5.02 (s, 4H); 6.92
=7.8Hz); 7.30 (t, 2H, =7.5Hz);
=8.5Hz); 7.74 (d,
=7.8Hz). C-NMR (100 MHz, CDCl3) C: 22.7; 57.0;
conditions:LuzChem or Rayonet photochemical reactor using
(
J
J
J
2
54 nm lamps (9 and 16 lamps respectivelly)] under an nitrogen
7
2
9
1
7
N
J
J
1
3
atmosphere for 2 h. The solvent was evaporated, and the crude
was dissolved in chloroform (10 mL) and excess of MnO was
added (0.5 g), the mixture was stirred for 24 hours at rt. Then
solid was filtered off and products were quantified by H-NMR
H,
J
δ
2
9.2; 128.1; 128.4; 128.5; 129.0; 129.5; 139.3; 134.5; 142.1;
46.3; 170.5. ESI-HRMS m/z [M + H] calcd for C H I N O
+
3
0
27 2
2
2
1
01.0156, found 701.0170.
2
6
by using an internal standard.
,
N
-bis(2-iodobenzyl)pyridine-2,6-diamine
(11).
This
33–35
Dibenzo[a,k][4,7]phenanthroline (13):
white solid.
reaction was carried out using a procedure similar to that
described for but the substrate utilized was 2,6-
diaminopyridine (10 mmol). Compound 11 (1.2 g, 65% global
yield) was isolated as a white solid by crystallization as
hydrochloride from acid ethanol and subsequent basic
extraction. H-NMR (400 MHz, CDCl3),
J
(
J
Isolated (89 mg, 48% yield) by radial thin-layer
chromatography eluted with pentane:ethyl acetate, 80:20. H-
8
,
1
NMR (400 MHz, CDCl3),
.4Hz); 7.67 (ddd, 2H, =8.0Hz, 7.0Hz, 1.0Hz); 8.13 (dd, 2H,
=8.0Hz, 0.8Hz); 8.29 (s, 2H); 8.51 (d, 2H, =8.5Hz); 9.43 (s,
C: 120.1; 126.6; 127.0;
27.6; 128.1; 129.0; 130.8; 132.9; 145.1; 153.4. ESI-HRMS
δH: 7.55 (ddd, 2H, J=8.5Hz, 7.0Hz,
1
J
2
1
J
1
J
δ
H: 4.44 (d, 4H,
=6.2Hz); 5.71 (d, 2H, =7.9Hz); 6.94
=7.6Hz, 1.7Hz); 7.18 (t, 1H, =7.9Hz); 7.25 (td, 2H,
=7.5Hz, 1.1Hz); 7.35 (br d, 2H, =7.7Hz); 7.82 (dd, 2H,
=7.9Hz, 1.2Hz). C-NMR (100 MHz, CDCl3) C: 51.1; 95.6;
8.6; 128.3; 128.7; 128.9; 139.1; 139.3; 141.5; 157.6. ESI-
13
H). C-NMR (100 MHz, CDCl3) δ
=6.3Hz); 4.81 (t, 2H,
J
J
td, 2H,
J
J
+
m/z [M + H] calcd for C H N 281.1073, found 281.1085.
2
0
13
2
J
3
6
1
3
Isoquinolino[3,4-
b
]phenanthridine (14)
:
white solid.
J
9
δ
Isolated (31 mg, 17% yield) by radial thin-layer
1
+
chromatography eluted with pentane:ethyl acetate, 80:20. H-
HRMS m/z [M + H] calcd for C H I N 541.9585, found
5
1
9
18 2
3
NMR (400 MHz, CDCl3),
H, =7.0Hz, 1.1Hz); 8.07 (d, 2H,
=8.2Hz); 9.32 (s, 2H); 9.33 (s, 2H). C-NMR (100 MHz,
CDCl3) C: 122.5; 123.4; 124.8; 126.2; 128.2; 129.0; 131.5;
32.4; 142.6; 154.9. ESI-HRMS m/z [M + H] calcd for
C H N 281.1073, found 281.1065.
δ
H: 7.78 (t, 2H,
J=7.5Hz); 7.94 (td,
41.9600.
’-(pyridine-2,6-diyl)bis(N-(2-iodobenzyl)acetamide)
12): yellow solid. Isolated by precipitation from the reaction
2
J
J
J
=7.9Hz); 8.79 (d, 2H,
N
,
N
13
(
1
δ
media as intermediate. H-NMR (400 MHz, CDCl ),
δ
H: 2.05
=7.6Hz, 1.4Hz); 7.10 (br d,
J=7.5Hz, 0.9Hz); 7.70 (t, 1H,
3
+
1
(
2
J
s, 6H); 4.97 (s, 4H); 6.89 (td, 2H,
H, =7.6Hz); 7.19 (td, 2H,
=8.0Hz); 7.73 (br d, 2H,
CDCl3) C: 23.5; 56.4; 97.7; 117.9; 127.8; 128.4; 128.9; 138.9;
39.4; 139.9; 153.3; 171.0. ESI-HRMS m/z [M + Na] calcd
for C H I N O Na 647.9615, found 647.9644.
J
2
0
13
2
J
1
3
2,2’-Biphenanthridine (18): white solid. Isolated (25 mg,
7% yield) by radial thin-layer chromatography eluted with
J=7.7Hz). C-NMR (100 MHz,
1
δ
1
+
dichloromethane:methanol, 98:2. H-NMR (400 MHz, CDCl
3
),
1
δ
H: 7.76 (t, 2H, =7.4Hz); 7.92 (td, 2H, =7.7Hz, 1.1Hz); 8.10
J
J
2
3
21 2
3
2
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

RSC Advances
Page 10 of 11
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
Journal Name
*
**
(
J
(
1
d, 2H,
=8.5Hz); 8.76 (d, 2H,
J
=7.9Hz); 8.16 (dd, 2H,
=8.3Hz); 8.92 (d, 2H,
s, 2H). C-NMR (100 MHz, CDCl3) C: 121.1; 122.0; 124.5;
26.7; 127.8; 128.4; 129.0; 130.8; 131.2; 132.6; 139.6; 144.1;
J
=8.5Hz, 1.9Hz); 8.33 (d, 2H,
The rotation barrier is ca. 23 kcal/mol, from AM1 calculations.
http://www.verachem.com/products/vconf/
J
J
=1.6Hz); 9.32
††
1
3
δ
+
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
1
53.8. ESI-HRMS m/z [M + H] calcd for C H N 357.1386,
26 17 2
found 357.1399.
Benzo[
3
7
f
]isoquinolino[3,4-
b][1,8]nafthiridine (19):
purple 10.1039/b000000x/
solid. Isolated (3 mg) by radial thin-layer chromatography
1
eluted with dichloromethane:methanol, 99:1 to 91:9. HNMR
1
2
3
B. P. Hudson and J. K. Barton, J. Am. Chem. Soc., 1998, 120, 6877-
888.
S. W. Fewell and J. L. J. Woolford, Mol. Cell. Biol., 1999, 19, 826-
34.
(
J
(
400 MHz, CDCl3),
=7.6Hz); 8.20 (d, 2H,1
δ
H: 7.87 (t, 2H,
J
=7.5Hz); 8.05 (t, 2H,
=8.3Hz); 9.67
s, 2H); 10.17 (s, 1H). C-NMR (100 MHz, CDCl3) C: 118.5;
22.4; 126.3; 127.4; 128.9; 129.6; 132.1; 132.4; 153.7; 159.7.
6
J=7.8Hz); 8.90 (d, 2H, J
3
δ
8
1
+
H.-L. Chan, H.-Q. Liu, B.-C. Tzeng, Y.-S. You, S.-M. Peng, M.
ESI-HRMS m/z [M + Na] calcd for C H N Na 304.0848,
1
9
11
3
found 304.0851.
-Benzo[5,6][1,8]nafthiridin[1,2-
Yang and C.-M. Che, Inorg. Chem., 2002, 41, 3161-3171.
2
H
a
]quinazoline (20): orange
solid. Isolated (3 mg) by preparative thin-layer chromatography
eluted with dichloromethane:methanol, 98:2 to 97:3. H-NMR
4
5
C. Bailly, Curr. Med. Chem., 2000,
E. Lo Piparo, K. Koehler, A. Chana and E. Benfenati, J. Med. Chem.
006, 49, 5702-5709.
C. L. Waller and J. D. McKinney, Chem. Res. Toxicol., 1995,
58.
7, 39-58.
,
1
2
(
J
400 MHz, acetone-d6),
=7.5Hz); 7.28 (d, 1H,
.340 (br t, 1H, =7.9Hz); 7.43 (br d, 1H,
=7.1Hz, 7.5Hz); 7.92 (cplx. t, 1H,
=8.1Hz); 8.67 (br d, 1H, =8.3Hz); 9.04 (d, 1H,
δ
H: 5.30 (s, 2H); 7.00 (br t, 1H,
=7.2Hz); 7.338 (br d, 1H, =8.6Hz);
=7.6Hz); 7.71 (br t,
=7.7Hz); 8.22 (br d,
=8.9Hz);
6
7
8
8
, 847-
J
J
8
7
1
1
9
δ
1
1
2
J
J
J
M. Gillner, J. Bergman, C. Cambillau, M. Alexandersson, B.
Fernström and J. A. Gustafsson, Mol. Pharmacol., 1993, 44, 336-345.
U. Rannug, M. Sjögren, A. Rannug, M. Gillner, R. Toftgard, J. A.
Gustafsson, H. Rosenkranz and G. Klopman, Carcinogenesis, 1991,
H,
H,
J
J
J
J
1
3
.47 (s, 1H). C-NMR (from HSQC and HMBC, acetone-d6)
C: 59.6; 109.0; 109.4; 112.0; 120.9; 121.0; 121.3; 125.3;
26.0; 128.0; 128.7; 130.9; 131.3; 133.5; 151.3; 153.9; 154.0;
12, 2007-2015.
+
55.2; 156.3. ESI-HRMS m/z [M + H] calcd for C H N
1
9
14
3
9
1
K. E. S. Phillips, T. J. Katz, S. Jockusch, A. J. Lovinger and N. J.
Turro, J. Am. Chem. Soc., 2001, 123, 11899-11907.
0 D. Waghray, A. Cloet, K. Van Hecke, S. F. L. Mertens, S. De Feyter,
L. Van Meervelt, M. Van der Auweraer and W. Dehaen, Chem. Eur.
J., 2013, 19, 12077-12085.
84.1182, found 284.1191.
-Benzylbenzo[ ][1,8]nafthiridin-3-amine (21): yellow
N
c
solid. Isolated (6 mg) by preparative thin-layer chromatography
1
eluted with dichloromethane:methanol, 98:2 to 97:3. HNMR
(
6
400 MHz, CDCl3),
.81 (d, 1H, =8.9Hz); 7.30 (br d, 1H,
=7.3Hz); 7.44 (br d, 2H, =7.7Hz); 7.59 (td, 1H,
.8Hz); 7.80 (ddd, 1H, =8.3Hz, 7.0Hz, 1.3Hz); 8.02 (br d, 1H,
=8.0Hz); 8.34 (d, 1H, =8.4Hz); 8.57 (d, 1H, =8.9Hz); 9.36
C: 46.1; 110.4; 111.1;
δ
H: 4.81 (d, 2H,
J
=5.4Hz); 5.81 (br s, 1H);
=7.3Hz); 7.35 (br t, 2H,
=7.1Hz,
J
J
1
1
1 J. I. Bardagí, V. A. Vaillard and R. A. Rossi, in Encyclopedia of
Radicals in Chemistry, Biology and Materials, ed. C. Chatgilialoglu
and A. Studer, John Wiley & Sons, Ltd, 2012, ch. The SRN1 Reaction,
pp. 1505-1519.
J
J
J
0
J
J
J
J
1
3
(
s, 1H). C-NMR (100 MHz, CDCl3)
δ
2 R. A. Rossi, A. B. Pierini and A. B. Peñéñory, Chem. Rev., 2003,
103, 71-167.
1
1
20.7; 125.1; 125.9; 127.5; 127.8; 128.8; 129.0; 131.3; 133.1;
33.4; 138.8; 153.5; 156.4; 158.3. ESI-HRMS m/z [M + H]
+
calcd for C H N 286.1339, found 286.1352.
1
9
16
3
13 J. F. Bunnett and J. K. Kim, J. Am. Chem. Soc., 1970, 92, 7464-7466.
1
1
1
4 A. Pierini, M. Baumgartner, and R. Rossi, Tetrahedron Lett., 1987,
, 4653-4656.
Acknowledgements
28
This work was supported in part by the Consejo Nacional de
Investigaciones Cientificas y T´ecnicas (C O N I C E T), the
Agencia Nacional de Promoci´on Cient´ıfica y T´ecnica
5 L. B. Jimenez, N. V. Torres, J. L. Borioni and A. B. Pierini,
Tetrahedron, 2014, 70, 3614-3620.
6 R. A. Rossi and M. T. Baumgartner, Synthesis of Heterocycles by the
(
(
ANPCyT) and the Secretaria de Ciencia y T´ecnologia
Universidad Nacional de C´ordoba), Argentina. L.E.P and
S
RN1Mechanism in Targets in Heterocyclic System: Chemistry and
Properties, Soc. Chimica. Italiana: Rome, Italy, 1999, vol. 3, pp. 215-
43.
G.P.C.S. gratefully acknowledge the receipt of a fellowship
from C O N I C E T.
2
1
1
1
2
2
2
7 L. J. Marshall, M. D. Roydhouse, A. M. Z. Slawin and J. C. Walton,
J. Org. Chem., 2007, 72, 898-911.
Notes and references
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias
a
8 M. D. Roydhouse and J. C.Walton, Eur. J. Org. Chem., 2007, 1059-
Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, 5000
Córdoba, X5000HUA, Argentina. Tel:+54-03515353867; E-mail:
eugebuden@yahoo.com.ar and adriana@fcq.unc.edu.ar
1
063.
9 M. E. Budén, V. A. Vaillard, S. E. Martín and R. A. Rossi, J. Org.
Chem., 2009, 74, 4490-4498.
0 J. K. Laha, S. M. Barolo, R. A. Rossi and G. D. Cuny, J. Org. Chem.
,
*
* In DMSO and DMF several concentrations of diamine 8 and base
2
011, 76, 6421-6425.
were explored, but the yield of cyclic products does not improve.
1 W. D. Guerra, R. A. Rossi, A. B. Pierini and S. M. Barolo, J. Org.
Chem., 2015, 80, 928-941.
†
For full optimization reaction see ESI.
‡
In the distonic specie, the negative charge is in
π system meanwhile
2 S. M. Barolo, X. Teng, G. D. Cuny and R. A. Rossi, J. Org. Chem.
,
the radical is in
σ system.
2
006, 71, 8493-8499.
§
The rotation barrier is ca. 17 kcal/mol, from AM1 calculations.
1
0 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 11 of 11
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C5RA04563K
2
2
2
2
2
2
2
3
3
3
3
3
3
3 V. A. Vaillard, M. E. Budén, S. E. Martín and R. A. Rossi,
Tetrahedron Lett., 2009, 50, 3829-3832.
4 Thomé, I., Besson, C., Kleine, T. and Bolm, C., Angew. Chem. Int.
Ed, 2013, 52, 7509-7515.
5 S. M. Barolo, Y. Wang, R. A. Rossi and G. D. Cuny, Tetrahedron
013, 69, 5487-5494.
,
2
6 V. A. Vaillard, J. F. Guastavino, M. E. Budén, J. I. Bardagí, S. M.
Barolo and R. A. Rossi, J. Org. Chem., 2012, 77, 1507-1519.
7 V. A. Vaillard, R. A. Rossi and J. E. Argüello, Org. Biomol. Chem.
012, 10, 9255-9261.
,
2
8 R. Beugelmans, J. Chastanet, H. Ginsburg, L. Quintero-Cortes and G.
Roussi, J. Org. Chem., 1985, 50, 4933-4938.
9 M. E. Budén and R. A. Rossi, Tetrahedron Lett., 2007, 48, 8739-
8
742.
0 M. E. Budén, V. B. Dorn, M. Gamba, A. B. Pierini and R. A. Rossi,
J. Org. Chem., 2010, 75, 2206-2218.
1 A. M. Linsenmeier, C. M. Williams and S. Bräse, J. Org. Chem.
011, 76, 9127-9132.
2 A. M. Linsenmeier, C. M. Williams and S. Bräse, Eur. J. Org. Chem.
013, 3847-3856.
,
2
,
2
3 T. Caronna, S. Gabbiadini, A. Mele and F. Recupero, Helv. Chim.
Acta, 2002, 85, 1-8.
4 S. V. Kessar, Y. P. Gupta, P. Singh, V. Jain and P. S. Pahwa, J.
Chem. Soc. Pakistan, 1979, 1, 129-130.
5 C. Bazzini, S. Brovelli, T. Caronna, C. Gambarotti, M. Giannone, P.
Macchi, F. Meinardi, A. Mele, W. Panzeri, F. Recupero, A. Sironi, R.
Tubino, Eur. J. Org. Chem. 2005, 1247-1257.
3
3
6 L. H. Klemm and A. Weisert J. Heterocyclic Chem., 1965,
43.
2, 140-
1
7 S. Djurdjevic, D. A. Leigh, H. McNab, S. Parsons, G. Teobaldi and
F. Zerbetto, J. Am. Chem. Soc., 2007, 129, 476-477.
3
3
4
4
4
4
4
8 C. Lee, W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.
9 A. D. Becke, Phys. Rev. A, 1988, 38, 3098-3100.
0 L. E. Peisino and A. B. Pierini, J. Org. Chem., 2013, 78, 4719-4729.
1 A. B. Pierini and D. M. A. Vera, J. Org. Chem., 2003, 68, 9191-9199.
2 S. Miertus, E. Scrocco and J. Tomasi, J. Chem. Phys., 1981, 55, 117.
3 S. Miertus and J. Tomasi, J. Chem. Phys., 1982, 65, 239-245.
4 M. Cossi, V. Barone, R. Cammi and J. Tomasi, J. Chem. Phys. Lett.
996, 255, 327-335.
5 D. B. G. Williams and M. Lawton, J. Org. Chem., 2010, 75, 8351-
354.
,
1
4
8
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 11