Pyridinium N-2′-pyridylaminide: radical cyclization in the synthesis of annulated 2-aminopyridines

Article abstract of DOI:10.1016/j.tetlet.2006.09.092

The synthesis of annulated 2-aminopyridines by intramolecular radical pyridylation of the appropriate substrates, obtained from pyridinium N-2′-pyridylaminide, can be performed using TTMSS and AIBN.

Full text of DOI:10.1016/j.tetlet.2006.09.092

Tetrahedron Letters 47 (2006) 8343–8346
Pyridinium N-20-pyridylaminide: radical cyclization in the
synthesis of annulated 2-aminopyridines
*
*
´
´
Aranzazu Sanchez, Araceli Nu´nez, Carolina Burgos and Julio Alvarez-Builla
˜
Departamento de Quı´mica Orga´nica., Universidad de Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
Received 17 July 2006; revised 14 September 2006; accepted 18 September 2006
Available online 9 October 2006
Dedicated to Professor Steven M. Weinreb on the occasion of his 65th birthday
Abstract—The synthesis of annulated 2-aminopyridines by intramolecular radical pyridylation of the appropriate substrates,
obtained from pyridinium N-20-pyridylaminide, can be performed using TTMSS and AIBN.
Ó 2006 Elsevier Ltd. All rights reserved.
Substituted 2-aminopyridines and their annulated deriva-
tives constitute an important class of organic compounds,
widely represented in the molecules of pharmacological
interest, in both therapeutic1 and recognition agent
fields.2
reaction. 1,2,3,4-Tetrahydro[1,8]naphthyridines are usu-
ally prepared by the selective catalytic hydrogenations of
the corresponding precursors, either prepared by Skra-
up,7 Friedla¨nder1d,e,8 or Friedel–Crafts6 approaches.
Moreover, Palukcki and co-workers.9 reported the prep-
aration of 1,2,3,4-tetrahydro[1,8]naphthyridine frag-
ments, using two different methods, one of which
relied, again, on variations of Friedla¨nder reaction,9a
the other being based in a double Suzuki–Miyaura
reaction and Chichibabin cyclization.9b,c Therefore, in
addition to more specific methodologies, a universal
synthetic method, which allows entry into these annu-
lated systems would be highly desirable. Accordingly,
Davies et al.10 recently described how the ortho
alkylation of Boc-protected 2-aminopyridines with a,x-
dihaloalkanes, followed by in situ cyclization, results in
the corresponding annulated pyridine derivatives in
good yields.
In recent years, particular attention has been devoted to
the development of synthetic methods that provide an
entry into this class of compounds. Thus, 7-azaindoline
I and 1,2,3,4-tetrahydro[1,8]naphthyridine II (Fig. 1)
derivatives which have been described as therapeutically
important compounds,3 remain a somewhat inaccessible
class of derivatives. Simple 7-azaindoline structures have
been prepared by the sluggish hydrogenations of azain-
doles.4 More recently, a free radical-mediated aryl-ami-
nation has been reported, whereby an aryl radical adds
to the nitrogen of an azomethine bond to supply the
required compound.5 Alternatively, Wijtmans et al.6
have described a new sequence based on Van der Plas’s
On the other hand, Zard and coworkers11 reported the
preparation of a series of compounds containing a 2-
aminopyridine nucleus fused to a saturated ring (7-aza-
oxindole, 7-azaindoline, tetrahydro[1,8]naphthyridine
and tetrahydro-5H-pyrido[2,3-b]azepin-8-one), starting
from various 2,6-dichloropyridines, through a radical
xanthate-mediated cyclization. Although this approach
is more general and flexible than previous traditional
routes, initial studies starting from the suitable 2-amino-
pyridines produced unwanted reactions on the cyclic
nitrogen, as a result of its higher nucleophilicity. In this
context, during the past few years our research group
has been interested in the chemistry of pyridinium
8
N
7
N
1
N
1
N
6
5
2
3
7
6
2
3
4
5
4
I
II
Figure 1. Compounds containing a pyridine nucleus fused to a
saturated nitrogen-containing ring. I: 7-azaindoline; II: 1,2,3,4-
tetrahydro[1,8]naphthyridine.
*
Corresponding authors. Tel.: +34 918854606; fax: +34 918854686
(C.B.); e-mail: carolina.burgos@uah.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.092

8344
A. Sa´nchez et al. / Tetrahedron Letters 47 (2006) 8343–8346
(8a from 1b and allyl bromide, 8c from 1b and 3,3-di-
methylallyl bromide and 8d from 1b and 2-methylallyl bro-
mide). Initial experiments on pyridyl radical cyclization
were then undertaken on 8a (Scheme 2) bearing in mind
our previous experience on the intramolecular process.13c
However, in agreement with previous results,12e the slow
dropwise addition (via syringe pump) of a solution of
TTMSS (2 equiv) and AIBN (2 equiv) to a solution of
8a in m-xylene/acetonitrile did not generate detectable
yields of annulated derivatives, and only poor yields of
tricyclic compound 2 were obtained.
N
N
H
N
+
-
N
N
N
+
-
.
Cl
N
N
N
X
Y
2
Cl
1a (X,Y=H)
1b (X= Br, Y= Cl)
R1
N
4
N
5
6
7
.
R4
Cl
R2
3
Cyclization of compound 8a did not seem to be an effi-
cient process, so N,N-reduction and acetylation in the
presence of the base were performed. The treatment of
10a under standard radical conditions,14 gave a mixture
of 7-azaindoline 4a, 1,2,3,4-tetrahydro[1,8]naphthyr-
idine 5a and pyrrolidin-2-one 6 (3:1:3). Careful examina-
tion of the reaction mixture by NMR spectroscopy
showed only half of the product arising from the direct
cyclization of the heteroaryl radical onto the allyl double
bond to give 4a and 5a (28% and 10% yield, respectively)
(Scheme 3).
R3
Scheme 1. Radical sequence plan.
N-20-pyridylaminide 1a (Scheme 1). Compound 1a is a
stable heterocyclic betaine in which the exocyclic nitrogen
anion is stabilized by the presence of a pyridinium moi-
ety.12 Moreover, the cyclic nitrogen is partially blocked
by an intramolecular hydrogen bond, making N-alkyl-
ation highly regioselective. This compound has proven
to be a versatile scaffold in a wide range of transforma-
tions, such as halogenations (for example, to supply 1b,
Scheme 1) or sulfonylations, and the final fission of the
N–N bond allows the synthesis of the corresponding
substituted 2-aminopyridine derivatives.12e
The main product 6, however, resulted from [1,5]-hydro-
gen transfer followed by a 5-exo trig cyclization, in pref-
erence to direct cyclization, despite the fact that this
route proceeds via a methyl radical intermediate 11
(Scheme 4). This kind of radical translocation has previ-
ously been studied by different authors for alternative
substrates.15 In order to avoid the unwanted [1,5]-hydro-
gen atom transfer process, 10b (Scheme 5) was prepared
and, under similar cyclization conditions, gave a mixture
(2:1, 49%) of N-allyl-2-chloro-5H-benzo[c][1,8]naph-
thyridin-6-one 7 and N-acetyl-5-chloro-3-methyl-7-aza-
indoline 4b. These results show the preference of the
pyridyl radical, in this case, to take part in homolytic
aromatic substitution.
As part of our work on free radical heteroaryl-
ations12e,13 using tris(trimethylsilyl)silane and azobis-
isobutyronitrile (TTMSS/AIBN) under reductive
conditions, we described an efficient approach to pyraz-
olopyridines 2 (Scheme 1) through an intramolecular
radical process. In this approach, a pyridyl radical was
added to the pyridinium nucleus, and the system was
subsequently rearomatized.13c Herein, we wish to report
an extension of the method to provide an improved
access to annulated aminopyridine derivatives (Scheme
1, compounds 4–7). In this method, a pyridyl radical 3
is intramolecularly added onto an alkenyl fragment
obtained from aminide 1b. This strategy could yield
the target compounds through a careful choice of alkene
intermediate.
H3C
O
H
i
ii
N
N
N
N
8a
Br
Cl
H3C
Br
10a
Cl
9a
Our initial studies started from salts 8, obtained from
N-aminide 1b by reaction with different allyl bromides
O
N
N
Cl
4a
H3C
H3C
O
R1
O
N
i
N
N
N
N
N
N
H
N
+
iii
+
(H2C)
N
- N
N
N
n
.
Cl
Cl
R2
Br
Cl
Br
Cl
Cl
5a
1b
8a
ii
N
N
N
N
Cl
O
Cl
6
N
2
Scheme 3. Preliminary results in the obtention of compounds 4 and 5.
(i) Et3B/EtOH, 64%; (ii) AcCl/Et3N, 51–80%; (iii) TTMSS/AIBN/
m-xylene, 70% (3:1:3).
Scheme 2. Initial radical studies from salt 8a. (i) Allyl bromide/
acetone, 68%; (ii) TTMSS/AIBN/m-xylene/acetonitrile.

A. Sa´nchez et al. / Tetrahedron Letters 47 (2006) 8343–8346
8345
O
Cl
N
R1
N
N
N
4
N
N
N
3
R1
N
5
.
H
O
Cl
Cl
6
Br
Cl
O
H
N
H
N
N
N
10a
4c (54%)
10c (R1= Ac)
H
1b
.
.
O
O
Cl
R1
Cl
H
H
6
11
N
N
4
N
N
3
5
Scheme 4. [1,5]-Hydrogen transfer and 5-exo trig cyclization.
.
N
N
Cl
R1
6
Cl
5b (70%)
Br
Cl
10d (R1= Ac)
R1
N
O
N
Ph
N
N
Cl
.
Cl
12
4b
Scheme 6. Obtention of compounds 4 and 5.
O
N
N
O
N
N
ii
Cl
i
priate substrates, obtained from pyridinium N-20-
pyridylaminide, can be performed using an easy, mild
and selective approach. The methodology seems to be
generally more flexible than conventional routes, and
should be complementary to other approaches in the
preparation of all the fused pyridines described.
9a
.
Cl
Br
10b
O
N
N
Cl
7
Acknowledgments
Scheme 5. Radical cyclization from 10b. (i) BzCl/CH2Cl2/Et3N 56%;
(ii) TTMSS/AIBN/m-xylene, 49% (1:2).
Financial support by the CICYT (Project CTQ2005-
08902/BQU) and two grants, by the Universidad de Al-
Finally, on the assumption that:16
´
´
cala (A.S.) and by Ministerio de Education y Ciencia
(Spain) (A.N.) are gratefully acknowledged.
(a) alkenylaryl radicals are systems in which the lack of
chain flexibility greatly increases the difference in
strain energy between the transition states for exo
and endo ring closures,
Supplementary data
(b) when the 3-position is occupied by a heteroatom (N
in the present case), both lengths and angles in the
transition state are modified, leading to a variation
of the rate of cyclization and regioselectivity (exo/
endo),
Available selected experimental procedures and selected
spectra. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.09.092.
(c) in the well-studied case of the hexenyl radical, the
presence of a substituent such as Me has a different
effect on the rate and the regioselectivity depending
on its position in the chain, additional experiments
were carried out using alkenylheteroarylderivatives
10c and 10d. These products have been obtained
from salts 8c and 8d, by N,N-reduction (to supply
compounds 9c and 9d) and acetylation, respec-
tively. The results of these experiments are summa-
rized in Scheme 6. Both azaindoline 4c and
tetrahydro[1,8]naphthyridine 5b were obtained with
satisfactory yields (54% and 70%, respectively) with
only traces of other isomeric compounds. It is,
however, to be emphasized that although the con-
trol of regioselectivity in compound 5b should be
due to a 6-endo cyclization, a rapid rearrangement
of radical 12, via a reversible 5-exo trig cyclization,
as occurs in related systems,17 cannot be excluded.
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