Pyridinium N-2′-pyridylaminide: radical cyclization for the synthesis of benzonaphthyridine derivatives

Article abstract of DOI:10.1016/j.tet.2007.04.077

The synthesis of benzonaphthyridine derivatives that incorporate a 2-aminopyridine moiety can be performed by intramolecular radical pyridylation of the appropriate substrates, obtained from pyridinium N-2′-pyridylaminide, using TTMSS and AIBN.

Full text of DOI:10.1016/j.tet.2007.04.077

Tetrahedron 63 (2007) 6774–6783
Pyridinium N-20-pyridylaminide: radical cyclization for the
synthesis of benzonaphthyridine derivatives
*
Araceli Nunez, Aranzazu Sanchez, Carolina Burgos and Julio Alvarez-Builla
*
ꢀ˜
ꢀ
ꢀ
Departamento de Quꢀımica Orgaꢀnica, Universidad de Alcalaꢀ, 28871 Alcalaꢀ de Henares, Madrid, Spain
Received 19 February 2007; revised 3 April 2007; accepted 23 April 2007
Available online 27 April 2007
Abstract—The synthesis of benzonaphthyridine derivatives that incorporate a 2-aminopyridine moiety can be performed by intramolecular
radical pyridylation of the appropriate substrates, obtained from pyridinium N-20-pyridylaminide, using TTMSS and AIBN.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
closure and, once again, Suzuki cross-coupling.6 Some
5,6-dihydrobenzo[c][1,8]naphthyridines II (Fig. 1) have
been prepared by thermolysis of the corresponding benzoan-
nulated enyne-carbodiimides through a biradical intermedi-
ate.7 Finally, benzo[c][1,8]naphthyridines III have been
synthesized by a variation of the classical Skraup method.8
Benzonaphthyridine derivatives are compounds of current
interest due to their diverse biological activities.1 These
compounds can also be considered as ‘aza-analogues’ of
phenanthridine derivatives, which are widely studied in the
field of medicinal chemistry.2
As part of our work on free-radical heteroarylations,9
using halogenated pyridinium N-20-pyridylaminides (i.e. 1,
Scheme 1) as starting materials, tris(trimethylsilyl)silane
and azobisisobutyronitrile (TTMSS/AIBN) under reductive
conditions we described an approach to 7-azaindoline deriv-
atives (i.e. 2, Scheme 1) via an intramolecular radical pro-
cess in which a pyridyl radical was added to an alkenyl
fragment.10 However, in the case outlined in Scheme 1, the
main product of the process was N-allyl-2-chloro-5H-ben-
zo[c][1,8]naphthyridin-6-one 3, thus showing the preference
of the pyridyl radical, in this case, to take part in a homolytic
aromatic substitution.
Among the different benzonaphthyridine isomers, we are
specifically interested in those that contain a 2-aminopyri-
dine moiety (see structures in Fig. 1). In recent years, partic-
ular attention has been devoted to the study of this class of
derivatives. For example, Ferraris and co-workers3 reported
the preparation and biological evaluation of a series of
aza-5[H]phenanthridin-6-ones, e.g., compound I (Fig. 1),
as potent, water-soluble inhibitors of poly ADP-ribose poly-
merase 1 (PARP1) for the treatment of ischemic injuries. The
preparation of these compounds, however, remains a difficult
area. The synthesis of 5H-benzo[c][1,8]naphthyridin-6-one
nucleus I (Fig. 1) has been performed by photoreaction
of 2-halo-N-pyridinylbenzamides4 or, alternatively, under
standard Suzuki conditions.3 Other related heterocyclic
structures have recently been synthesized through palla-
dium-catalyzed sequential aryl–aryl and N-aryl coupling,5
or by a two-step procedure that involves an anionic ring
O
Ph
N
N
Cl
2
O
N
N
H
N
H
N
N
N
O
N
N
N
N
+
-
N
Cl
O
N
N
Br
Cl
I
II
III
1
Cl
Figure 1. Some benzonaphthyridine derivatives containing a 2-aminopyri-
dine nucleus. I: 5H-benzo[c][1,8]naphthyridin-6-one; II: 5H-5,6-dihydro-
benzo[c][1,8]naphthyridine; III: benzo[c][1,8]naphthyridine.
3
(main product)
* Corresponding authors. Tel.: +34 91 885 4618; fax: +34 91 885 4686;
e-mail: carolina.burgos@uah.es
Scheme 1. Preliminary results in the synthesis of benzo[c][1,8]naphthyri-
din-6-one derivatives.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.077

A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
6775
H3C
Despite the fact that homolytic aromatic substitution has
O
been studied by various research groups,11 we wish to report
here the preparation of a series of compounds containing a 2-
aminopyridine fragment fused to a benzene ring. The route
starts from the appropriate pyridinium N-20-pyridylaminide
1 and proceeds through a pyridyl radical cyclization. It
should be borne in mind that electrophilic substitution on
the N-exocycle in 2-aminopyridine, using conventional
methods, to obtain suitable 2-aminopyridine derivatives,
occurs with difficulty—if at all.12
R1
N
N
N
O
N
iv
i
1
Cl
Cl
Br
16
R2
R2
13 (R1= Pyridinium)
14 (R1= H)
15 (R1= Ac)
H3C
ii
iii
N
N
R2= H, Me
Cl
17,18
R2
2. Results and discussion
17a R2= H
17b, 18b R2= Me
Our initial studies in this area started from the salts 4
(Scheme 2) obtained from N-aminide 1 by reaction with dif-
ferent acyl chlorides (R2¼H, CH3, OCH3, Cl). Reduction of
the N–N bond furnished unsubstituted amides 5 and methyl-
ation on the exocyclic nitrogen provided methylbenzamides
6, which are starting materials for the radical cyclization pro-
cess. Bearing in mind previous reports from Curran13 and
Ganguly,11c,14 and our own previous results,9 aryl radical
7, derived from 6, can cyclize at the ipso-position (path A)
to supply radical 8 or at the ortho-position (path B) to give
radical 9. Both radicals could be in equilibrium through a for-
mal 1,2-shift.13 Whereas oxidation of radical 9 could pro-
vide 9-substituted 5H-benzo[c][1,8]naphthyridin-6-ones 11
(R1¼CH3, R2¼H, CH3, OCH3, Cl), the other isomeric
5H-benzo[c][1,8]naphthyridin-6-ones 12 were observed in
all cases. The latter species should arise from the b-fragmen-
tation of spirocyclic radical 8 to provide, through a 1,4-aryl
migration, an amidoyl radical 10, which would eventually
Scheme 3. Preparation of starting material and radical cyclization from 15.
Reagents: (i) ArCH2Br/acetone 73–93%; (ii) TEAF/Pt/C 57–90%; (iii)
AcCl/Et3N, CH2Cl2 55–87%; (iv) TTMSS/AIBN/m-xylene, 21–32%.
afford the 8-substituted 5H-benzo[c][1,8]naphthyridin-6-
ones 12 (R1¼CH3, R2¼CH3, OCH3, Cl), or alternatively,
from the spirocyclic radical 8, through a formal 1,2-shift.11c
This class of 1,4-aryl migration has been previously reported
by Chuang et al.15 and by Ganguly et al.,11c,14b and has been
extensively studied by Studer16 on related substrates. How-
ever, when the cyclization process was tried on 4
(R1¼pyridinium, R2¼H, OCH3, Scheme 2) under similar
experimental conditions, only poor yields of 11 (R1¼H,
R2¼H, OCH3) were obtained (11e and 11f in 18% and
25%, respectively). When the procedure was attempted on
the benzyl derivative 15 (R1¼Ac, R2¼H, CH3) (Scheme
3)—obtained from amidine 1 by reaction with the corre-
sponding benzyl bromide, N–N fission and acetylation in
the presence of a base17—cyclized compounds were ob-
tained but only in low yield (21–32%).
R1
N
R1
O
N
O
N
N
iv
i
1
Cl
Cl
Br
7
Once again, when R2sH (for 15b R1¼Ac, R2¼CH3), two
isomeric compounds 17b and 18b were characterized, pre-
sumably due to 6-cyclization and 5-cyclization processes,
respectively.
R2
path A
R1
R2
path B
R1
4 (R1= Pyridinium)
5 (R1= H)
ii
iii
6 (R1= Me)
N
O
N
N
N
O
R2= H, Me, OMe, Cl
Unexpectedly, when the cyclization reaction was carried out
from 13 (R2¼H, CH3, OCH3, Cl), a complex mixture of
products was identified [19, 20, and 21, with a small amount
of tricyclic derivative 22 (z3%)] (Scheme 4 and Table 1), a
situation in agreement with previous reports.9b,c It would
seem that in 13, which is less reactive than 4, the N–N
bond reduction would occur at a slower rate and the forma-
tion of compounds 19 can be explained in terms of the
expected reaction pathway and subsequent elimination of
pyridine, as described for a related process.18 Additionally,
the well-documented stabilized radical 26, produced by
ipso-substitution of an aminomethyl group by an aryl radi-
cal, according to previous report by Renaud et al.,19 could
evolve to imine 27 or, alternatively, supply 20 by cyclization
at the ortho-position. Once again, the formation of 20 could
be explained also from 24 through a formal 1,2-shift.11c
However, compounds 21 were identified as 3-aryl-5-chloro-
pyridin-2-yl amines and imino derivatives were not detected:
probably 27 was converted into 21 in the chromatographic
process. In order to shed some light on this issue, a molar
Cl
Cl
H
9
8
R2
R2
N
R1
N
O
R1
N
Cl
O
N
10
R2
Cl
11
R1
N
R2
R2= H, Me, OMe, Cl
O
N
Cl
12
R2
R2= Me, OMe, Cl
Scheme 2. Preparation of starting material and radical cyclization from 6.
Reagents: (i) ArCOCl/acetone 80–95%; (ii) Et3B/EtOH 41–56%; (iii)
CH3I/acetone, K2CO3 78–90%; (iv) TTMSS/AIBN/m-xylene, 69–79%.

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A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
excess of sodium borohydride was added to the crude reac-
tion mixture, and the reaction was investigated by 1H NMR
spectroscopy and mass spectrometry. In this case, 3-aryl-2-
methylaminopyridines, corresponding to the reduction of
27, were identified. Other experiments are in progress to
clarify this unusual behavior.
involving the formation of the observed products are
suggested.
3. Experimental section
3.1. General
pyr
N
All experiments were carried out under a dry argon
atmosphere, with solvents freshly distilled under anhydrous
conditions, unless stated otherwise. All chemicals were
purchased from the Aldrich Chemical Company and Fluka,
N
N
N
Br –
N
i
N
N
+
Cl
Cl
N
1
and were used without further purification. H, 13C NMR,
23
22
Cl
Br
R2
and decoupled spectra were recorded on a Varian UNITY
300 MHz or VARIAN UNITY PLUS 500 MHz spectrome-
ter. Mass spectra were recorded on a VG AutoSpec (Micro-
mass Instruments). Elemental analysis was performed on
a LECO instruments CHNS-932. Compounds 1,17c 21a,20
and 229c have been described previously.
13
R2
pyr
N
pyr
N
N
N
Cl
Cl
H
25
24
R2
R2
3.2. General procedure for the preparation
of pyridinium salts 4
pyr
N
N
N
To a stirred solution of aminide 1 (284 mg, 1 mmol) in dry
acetone (7 mL), at room temperature, was added dropwise
the corresponding benzoyl chloride (1.1 mmol). The mixture
was stirred at the same temperature until all the starting
material had been consumed (TLC). The mixture was fil-
tered and the solid was washed with acetone and crystallized
from ethanol, yielding compounds 4a–d.
N
H2C
Cl
Cl
19
26
R2
R2
N
N
N
N
H2C
Cl
3.2.1. N-[Benzoyl-(3-bromo-5-chloro-pyridin-2-yl)-ami-
no]-pyridinium chloride 4a. The general procedure using
155 mg of benzoyl chloride gave a white solid (388 mg,
91%), mp 195–197 ꢀC; 1H NMR (300 MHz, CD3OD)
d 9.54 (d, 2H, J¼5.9 Hz), 8.94 (t, 1H, J¼7.8 Hz), 8.56
(d, 1H, J¼2.2 Hz), 8.47 (d, 1H, J¼2.2 Hz), 8.41 (at,
2H, J¼7.6 Hz), 7.75 (d, 2H, J¼8.6 Hz), 7.62 (t, 1H,
J¼7.5 Hz), 7.47 (at, 2H, J¼7.8 Hz); 13C NMR (75 MHz,
CD3OD) d 169.8, 150.4, 149.5, 149.2, 148.9, 144.8, 136.0,
134.7, 132.0, 130.7, 130.2, 130.0, 121.4; MS (ESI), m/z (rel-
ative intensity): 392, 390, 388 (M+, 35, 100, 91), 345, 343,
341 (1, 3.4, 2.6); Anal. Calcd for C17H12BrCl2N3O: C,
48.03; H, 2.85; N, 9.88%. Found: C, 48.40; H, 2.63; N,
9.91%.
Cl
20
R2
27
R2
H2N
N
Cl
21
R2
Scheme 4. Preparation of 19, 20, and 21 and suggested reaction pathway.
Reagents: (i) TTMSS/AIBN/m-xylene, 31–59%.
In conclusion, some results on the synthesis of benzo-
[c][1,8]naphthyridine derivatives by intramolecular radical
pyridylation of suitable substrates, obtained from pyridi-
nium N-20-pyridylaminide, through an easy, mild, and
selective approach are described. The methodology gener-
ally seems to be more flexible and efficient in the
preparation of 5H-benzo[c][1,8]naphthyridin-6-one deriva-
tives and should be complementary to conventional routes
in the preparation of fused pyridines. The method does, how-
ever, produce complex reaction mixtures and/or poor yields
for other derivatives. Although several reaction mechanisms
can explain these transformations, reasonable pathways
3.2.2. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-methyl-
benzoyl)-amino]-pyridinium chloride 4b. The general
procedure using 170 mg of 4-methylbenzoyl chloride gave
1
a white solid (416 mg, 95%), mp 135–136 ꢀC; H NMR
(300 MHz, CD3OD) d 9.51 (d, 2H, J¼5.8 Hz), 8.92 (t, 1H,
J¼7.7 Hz), 8.56 (d, 1H, J¼2.2 Hz), 8.47 (d, 1H, J¼
2.2 Hz), 8.39 (at, 2H, J¼7.1 Hz), 7.63 (d, 2H, J¼8.2 Hz),
7.29 (d, 2H, J¼8.2 Hz), 2.40 (s, 3H); 13C NMR (75 MHz,
CD3OD) d 169.6, 150.2, 149.6, 149.1, 148.7, 146.2, 144.7,
135.8, 130.6, 130.5, 130.2, 128.9, 121.2, 24.2; MS
(ESI), m/z (relative intensity): 406, 404, 402 (M+, 34, 100,
91), 359, 357, 355 (0.7, 2.6, 1.9); Anal. Calcd for
C18H14BrCl2N3O: C, 44.71; H, 2.92; N, 8.69%. Found: C,
44.53; H, 2.81; N, 8.30%.
Table 1. Results of the cyclization from compounds 13
Starting material
19 (%)
20 (%)
21 (%)
22 (%)
R2¼H, 13a
19
31
39
15
—
—
—
8
27
27
—
8
3
3
3
3
R2¼Me, 13b
R2¼OMe, 13c
R2¼Cl, 13d
3.2.3. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-methoxy-
benzoyl)-amino]-pyridinium chloride 4c. The general

A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
6777
procedure using 188 mg of 4-methoxybenzoyl chloride gave
2H, J¼8.2 Hz), 7.27 (d, 2H, J¼8.2 Hz), 2.40 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 164.7, 147.2, 146.0, 143.2,
140.5, 130.9, 129.4, 127.7, 127.5, 112.3, 21.5; MS (EI)
m/z (relative intensity): 328, 326, 324 (M+, 0.2, 1, 0.8),
247, 245 (4, 12), 119 (100), 91 (29); Anal. Calcd for
C13H10BrClN2O: C, 47.96; H, 3.10; N, 8.60%. Found: C,
47.67; H, 2.94; N, 8.42%.
1
a white solid (364 mg, 80%), mp 185–187 ꢀC; H NMR
(300 MHz, CD3OD) d 9.48 (d, 2H, J¼5.5 Hz), 8.92 (t, 1H,
J¼7.9 Hz), 8.57 (d, 1H, J¼2.4 Hz), 8.48 (d, 1H, J¼
2.4 Hz), 8.39 (at, 2H, J¼7.1 Hz), 7.72 (d, 2H, J¼8.9 Hz),
7.00 (d, 2H, J¼8.9 Hz), 3.86 (s, 3H); 13C NMR (75 MHz,
CD3OD) d 169.3, 165.6, 150.2, 150.0, 149.2, 148.9, 144.8,
135.8, 132.7, 130.6, 123.6, 121.2, 115.4, 56.2; MS
(ESI), m/z (relative intensity): 422, 420, 418 (M+, 29, 100,
71), 288, 286, 284 (2.5, 10, 7.5); Anal. Calcd for
C18H14BrCl2N3O2: C, 47.50; H, 3.10; N, 9.23%. Found: C,
47.40; H, 2.73; N, 9.41%.
3.3.3. N-(3-Bromo-5-chloro-pyridin-2-yl)-4-methoxy-
benzamide 5c. The general procedure starting from
227 mg of the corresponding pyridinium salt 4c gave, after
flash chromatography [silica gel, hexanes/EtOAc (80:20),
Rfz0.11] and crystallization, a white solid (70 mg, 41%),
1
3.2.4. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-chloro-
benzoyl)-amino]-pyridinium chloride 4d. The general
procedure using 193 mg of 4-chlorobenzoyl chloride gave
a white solid (391 mg, 85%), mp 51–52 ꢀC; 1H NMR
(300 MHz, CD3OD) d 9.53 (dd, 2H, J¼5.7, 1.1 Hz), 8.82
(tt, 1H, J¼7.9, 1.1 Hz), 8.58 (d, 1H, J¼2.2 Hz), 8.48 (d,
1H, J¼2.2 Hz), 8.41 (at, 2H, J¼7.5 Hz), 7.73 (d, 2H,
J¼8.8 Hz), 7.51 (d, 2H, J¼8.8 Hz); 13C NMR (75 MHz,
CD3OD) d 168.7, 150.4, 149.2, 148.6, 144.8, 140.8, 136.0,
131.7, 130.6, 130.5, 130.2, 129.6, 121.2; MS (ESI), m/z (rel-
ative intensity): 428, 426, 424, 422 (M+, 13, 82, 100, 93),
379, 379, 377, 375 (1.5, 3.3, 2.2), 288, 286, 284 (3.4, 13.9,
10.8); Anal. Calcd for C17H11BrCl3N3O: C, 44.43; H,
2.41; N, 9.14%. Found: C, 44.06; H, 2.31; N, 9.22%.
mp 161–162 ꢀC; H NMR (300 MHz, CDCl3) d 8.40 (br s,
1H), 8.36 (d, 1H, J¼2.2 Hz), 7.90 (d, 1H, J¼2.2 Hz), 7.88
(d, 2H, J¼8.8 Hz), 6.96 (d, 2H, J¼8.8 Hz), 3.86 (s, 3H);
13C NMR (75 MHz, CDCl3) d 164.6, 163.2, 147.6, 146.3,
140.8, 129.7, 127.9, 126.1, 114.3, 112.7, 55.7; MS (EI)
m/z (relative intensity): 344, 342, 340 (M+, 0.3, 1.1, 0.9),
263, 261 (2.3, 6.8), 135 (100); Anal. Calcd for
C13H10BrClN2O2: C, 45.71; H, 2.95; N, 8.20%. Found: C,
45.65; H, 2.82; N, 8.09%.
3.3.4. N-(3-Bromo-5-chloro-pyridin-2-yl)-4-chloro-benz-
amide 5d. The general procedure starting from 229 mg of
the corresponding pyridinium salt 4d gave, after flash chro-
matography [silica gel, hexanes/EtOAc (85:15), Rfz0.15]
and crystallization, a white solid (76 mg, 44%), mp 181–
1
3.3. General procedure for the preparation
of unsubstituted benzamides 5
182 ꢀC; H NMR (300 MHz, CDCl3) d 8.50 (br s, 1H),
8.34 (d, 1H, J¼2.3 Hz), 7.91 (d, 1H, J¼2.3 Hz), 7.85 (d,
2H, J¼8.5 Hz), 7.44 (d, 2H, J¼8.5 Hz); 13C NMR
(75 MHz, CDCl3) d 163.8, 146.9, 146.2, 140.7, 138.7,
132.1, 129.2, 128.9, 128.2, 112.5; MS (EI) m/z (relative in-
tensity): 350, 348, 346, 344 (M+, 0.6, 1, 0.8, 0.3), 319,
317, 315, 313 (2, 3.6, 2.2, 6.8), 139 (100), 111 (42); Anal.
Calcd for C12H7BrCl2N2O: C, 41.66; H, 2.04; N, 8.10%.
Found: C, 41.62; H, 1.97; N, 8.04%.
To a stirred solution of the corresponding pyridinium salt 4
(0.5 mmol) in ethanol (20 mL), at room temperature, was
added dropwise a solution of triethylborane in hexane
(1 mL, 1.0 M, 1 mmol). After stirring for 3 h at the same
temperature, air (1 mL) was passed with a syringe. After stir-
ring at the same temperature for a further 24 h, the same
amount of triethylborane and air were added again, until
the starting material had been consumed (TLC). Purification
by flash chromatography and crystallization from EtOAc/
hexanes furnished compounds 5a–d.
3.4. General procedure for the preparation
of methylbenzamides 6
To a stirred dispersion of the corresponding unsubstituted
benzamide
3.3.1. N-(3-Bromo-5-chloro-pyridin-2-yl)-benzamide 5a.
The general procedure starting from 213 mg of the corre-
sponding pyridinium salt 4a gave, after flash chromato-
graphy [silica gel, hexanes/EtOAc (90:10), Rfz0.15] and
crystallization, a white solid (87 mg, 56%), mp 186–
187 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.42 (d, 2H,
J¼2.4 Hz), 7.92 (m, 3H), 7.66 (tt, 1H, J¼7.3, 1.3 Hz),
7.50 (at, 2H, J¼7.3 Hz); 13C NMR (75 MHz, CDCl3)
d 164.8, 147.1, 146.0, 140.6, 133.7, 132.5, 128.8, 128.0,
127.4, 112.6; MS (EI) m/z (relative intensity): 314, 312,
310 (M+, 0.4, 2, 1.4), 231 (22), 105 (100), 77 (43); Anal.
Calcd for C12H8BrClN2O: C, 46.26; H, 2.59; N, 8.99%.
Found: C, 46.26; H, 2.57; N, 8.88%.
5
(0.4 mmol) and potassium carbonate
(110 mg, 0.8 mmol) in acetone (10 mL), at room tempera-
ture, was added iodomethane (4 mmol, 0.25 mL). The mix-
ture was stirred at the same temperature for 24 h until the
starting material had been consumed (TLC). Purification
by flash chromatography furnished products 6a–d.
3.4.1. N-(3-Bromo-5-chloro-pyridin-2-yl)-N-methyl-benz-
amide 6a. The general procedure using 5a (125 mg) as
starting material gave, after flash chromatography [silica
gel, hexanes/EtOAc (90:10), Rfz0.12], a yellow oil
1
(117 mg, 90%); H NMR (300 MHz, CDCl3) d 8.30 (d,
1H, J¼2.4 Hz), 7.79 (d, 1H, J¼2.4 Hz), 7.37 (d, 2H,
J¼7.4 Hz), 7.27 (t, 1H, J¼7.4 Hz), 7.18 (t, 2H, J¼7.4 Hz),
3.38 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.6, 153.5,
146.7, 141.5, 135.4, 130.7, 130.3, 128.2, 127.7, 119.0,
35.7; MS (EI) m/z (relative intensity): 328, 326, 324 (M+,
0.1, 0.3, 0.2), 247, 245 (8, 25), 105 (100), 77 (35).
3.3.2. N-(3-Bromo-5-chloro-pyridin-2-yl)-4-methyl-benz-
amide 5b. The general procedure starting from 219 mg of
the corresponding pyridinium salt 4b gave, after flash chro-
matography [silica gel, hexanes/EtOAc (90:10), Rfz0.11]
and crystallization, a white solid (75 mg, 46%), mp 163–
1
164 ꢀC; H NMR (300 MHz, CDCl3) d 8.49 (br s, 1H),
3.4.2. N-(3-Bromo-5-chloro-pyridin-2-yl)-4,N-dimethyl-
benzamide 6b. The general procedure using 5b (130 mg)
8.37 (d, 1H, J¼2.2 Hz), 7.90 (d, 1H, J¼2.2 Hz), 7.82 (d,

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A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
as starting material gave, after flash chromatography [silica
gel, hexanes/EtOAc (85:15), Rfz0.16], a white solid
(117 mg, 90%), mp 114–116 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.30 (d, 1H, J¼2.4 Hz), 7.78 (d, 1H, J¼2.4 Hz),
7.25 (d, 2H, J¼7.9 Hz), 6.97 (d, 2H, J¼7.9 Hz), 3.36 (s,
3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.6,
153.5, 146.6, 141.5, 140.5, 132.5, 130.4, 128.4, 128.3,
118.9, 35.6; MS (EI) m/z (relative intensity): 342, 340, 338
(M+, 0.1, 0.3, 0.2), 261, 259 (4, 13), 119 (100), 91 (25);
Anal. Calcd for C14H12BrClN2O: C, 49.51; H, 3.56; N,
8.25%. Found: C, 49.87; H, 3.52; N, 8.17%.
100), 218, 216 (27, 84); Anal. Calcd for C13H9ClN2O: C,
63.82; H, 3.71; N, 11.45%. Found: C, 63.50; H, 3.54; N,
11.12%.
3.5.2. 2-Chloro-5,9-dimethyl-5H-benzo[c][1,8]naphthyr-
idin-6-one 11b and 2-chloro-5,8-dimethyl-5H-benzo-
[c][1,8]naphthyridin-6-one 12b. The general procedure
using 6b (170 mg) as the starting material gave a mixture
of products. After separation by flash chromatography [silica
gel, hexanes/EtOAc (90:10)], pure compounds 11b and 12b
were obtained (73%, 1.2:1). Analysis of the structures was
performed using NOE experiments.
3.4.3. N-(3-Bromo-5-chloro-pyridin-2-yl)-4-methoxy-N-
methyl-benzamide 6c. The general procedure using 5c
(137 mg) as starting material gave, after flash chromato-
graphy [silica gel, hexanes/EtOAc (80:20), Rfz0.23],
3.5.2.1. 2-Chloro-5,9-dimethyl-5H-benzo[c][1,8]naph-
thyridin-6-one 11b. White solid, Rfz0.27 (51 mg, EtOAc/
hexanes), mp 204–205 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.47 (d, 1H, J¼2.4 Hz), 8.43 (d, 1H, J¼2.4 Hz), 8.42 (d,
1H, J¼8.2 Hz), 7.93 (s, 1H), 7.46 (dd, 1H, J¼8.2, 1.6 Hz),
3.86 (s, 3H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 162.2, 146.7, 143.5, 130.8, 130.7, 130.4, 129.1, 129.0,
125.7, 123.7, 121.8, 115.7, 28.9, 22.0; MS (EI) m/z (relative
intensity): 260, 258 (M+, 31, 93), 232, 230 (32, 100), 166
(66); Anal. Calcd for C14H11ClN2O: C, 65.00; H, 4.29; N,
10.83%. Found: C, 65.21; H, 4.30; N, 10.51%.
1
a white solid (128 mg, 90%), mp 144–145 ꢀC; H NMR
(300 MHz, CDCl3) d 8.31 (d, 1H, J¼2.3 Hz), 7.78 (d, 1H,
J¼2.3 Hz), 7.30 (d, 2H, J¼8.8 Hz), 6.66 (d, 2H,
J¼8.8 Hz), 3.72 (s, 3H), 3.35 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 170.3, 161.0, 153.9, 146.7, 141.6, 130.4, 130.3,
127.7, 119.0, 113.0, 55.1, 35.8; MS (EI) m/z (relative inten-
sity): 358, 356, 354 (M+, 0.2, 0.9, 0.7), 277, 275 (4, 11), 135
(100); Anal. Calcd for C14H12BrClN2O2: C, 47.29; H, 3.40;
N, 7.88%. Found: C, 47.49; H, 3.34; N, 7.77%.
3.5.2.2. 2-Chloro-5,8-dimethyl-5H-benzo[c][1,8]naph-
thyridin-6-one 12b. White solid, Rfz0.30 (42 mg,
EtOAc/hexanes), mp 223–224 ꢀC; 1H NMR (500 MHz,
CDCl3) d 8.46 (d, 1H, J¼2.3 Hz), 8.40 (d, 1H, J¼2.3 Hz),
8.34 (br s, 1H), 8.03 (d, 1H, J¼8.2 Hz), 7.60 (dd, 1H,
J¼8.2, 1.9 Hz), 3.87 (s, 3H), 2.53 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 162.2, 146.7, 146.3, 139.9, 134.1,
130.2, 128.8, 128.2, 125.8, 125.7, 121.8, 115.9, 29.0, 21.6;
MS (EI) m/z (relative intensity): 260, 258 (M+, 33, 100),
232, 230 (25, 80), 135 (36); Anal. Calcd for C14H11ClN2O:
C, 65.00; H, 4.29; N, 10.83%. Found: C, 64.95; H, 4.14; N,
10.56%.
3.4.4. N-(3-Bromo-5-chloro-pyridin-2-yl)-4-chloro-N-
methyl-benzamide 6d. The general procedure using 5d
(138 mg) as starting material gave, after flash chromato-
graphy [silica gel, hexanes/EtOAc (85:15), Rfz0.33], a yel-
low oil (112 mg, 78%); 1H NMR (300 MHz, CDCl3) d 8.28
(d, 1H, J¼2.4 Hz), 7.78 (d, 1H, J¼2.4 Hz), 7.28 (d, 2H,
J¼8.4 Hz), 7.13 (d, 2H, J¼8.4 Hz), 3.34 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 169.5, 153.2, 146.8, 141.6,
136.3, 133.8, 130.9, 129.6, 128.0, 118.8, 35.6; MS (EI)
m/z (relative intensity): 364, 362, 360, 358 (M+, 0.3, 0.6,
0.2, 0.4), 279 (27), 141, 139 (33, 100).
3.5. Radical reaction on methylbenzamides 6: general
procedure for the preparation of 11a–d and 12b–d
3.5.3. 2-Chloro-9-methoxy-5-methyl-5H-benzo[c][1,8]-
naphthyridin-6-one 11c and 2-chloro-8-methoxy-5-
methyl-5H-benzo[c][1,8]naphthyridin-6-one 12c. The
general procedure using 6c (178 mg) as the starting material
gave a mixture of products. After separation by flash chro-
matography [silica gel, hexanes/EtOAc (90:10)], pure com-
pounds 11c and 12c were obtained (73%, 1.1:1). Analysis of
the structures was performed using NOE experiments.
A solution of TTMSS (248 mg, 1 mmol) and AIBN
(164 mg, 1 mmol) in m-xylene (10 mL) was added dropwise
by a syringe pump, during 13 h, to a stirred solution of the
corresponding methylbenzamide 6 (0.5 mmol) in m-xylene
(2 mL) at 80 ꢀC (bath temperature). Stirring was maintained
at the same temperature for further 12 h. The solution was
concentrated and the crude mixture separated by flash
chromatography, yielding the pure compounds 11a–d and
12b–d.
3.5.3.1.
2-Chloro-9-methoxy-5-methyl-5H-benzo-
[c][1,8]naphthyridin-6-one 11c. White solid, Rfz0.13
(52 mg, CH2Cl2), mp 217–220 ꢀC; 1H NMR (500 MHz,
CDCl3) d 8.48 (d, 1H, J¼2.3 Hz), 8.46 (d, 1H, J¼8.8 Hz),
8.36 (d, 1H, J¼2.3 Hz), 7.48 (d, 1H, J¼2.4 Hz), 7.20 (dd,
1H, J¼8.8, 2.4 Hz), 3.97 (s, 3H), 3.82 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 163.2, 161.8, 147.3, 146.9, 132.5,
131.1, 130.4, 125.5, 119.5, 117.1, 115.5, 104.6, 55.6, 28.7;
MS (EI) m/z (relative intensity): 276, 274 (M+, 33, 99),
248, 246 (33, 99), 202 (24), 168 (12), 140 (14); Anal. Calcd
for C14H11ClN2O2: C, 61.21; H, 4.04; N, 10.20%. Found: C,
61.60; H, 3.91; N, 10.17%.
3.5.1. 2-Chloro-5-methyl-5H-benzo[c][1,8]naphthyridin-
6-one 11a. The general procedure using 6a (163 mg) as
the starting material gave, after flash chromatography [silica
gel, hexanes/EtOAc (90:10), Rfz0.30] and crystallization,
a white solid (97 mg, 79%, EtOAc/hexanes), mp 118–
120 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.53 (dd, 1H,
J¼8.0, 1.3 Hz), 8.49 (d, 1H, J¼2.4 Hz), 8.43 (d, 1H, J¼
2.4 Hz), 8.14 (dd, 1H, J¼8.0, 1.1 Hz), 7.78 (dt, 1H, J¼8.0,
1.3 Hz), 7.65 (dt, 1H, J¼8.0, 1.1 Hz), 3.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 162.0, 146.8, 146.7, 132.7,
130.6, 130.4, 129.3, 129.0, 125.9, 125.8, 121.7, 115.6,
28.9; MS (EI) m/z (relative intensity): 246, 244 (M+, 33,
3.5.3.2.
2-Chloro-8-methoxy-5-methyl-5H-benzo-
[c][1,8]naphthyridin-6-one 12c. White solid, Rfz0.18
(48 mg, CH2Cl2), mp 219–220 ꢀC; 1H NMR (500 MHz,

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6779
CDCl3) d 8.43 (d, 1H, J¼2.4 Hz), 8.33 (d, 1H, J¼2.4 Hz),
8.04 (d, 1H, J¼8.8 Hz), 7.94 (d, 1H, J¼2.8 Hz), 7.35 (dd,
1H, J¼8.8, 2.8 Hz), 3.96 (s, 3H), 3.88 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 162.1, 160.8, 146.2, 145.8, 129.8,
127.6, 126.1, 124.1, 123.7, 122.8, 116.0, 109.7, 56.0, 29.3;
MS (EI) m/z (relative intensity): 276, 274 (M+, 34, 100),
248, 246 (12, 36), 202 (17); Anal. Calcd for C14H11ClN2O2:
C, 61.21; H, 4.04; N, 10.20%. Found: C, 61.60; H, 3.91; N,
10.17%.
(d, 1H, J¼7.9 Hz), 8.51 (d, 1H, J¼1.9 Hz), 8.31 (d, 1H,
J¼7.9 Hz), 7.89 (t, 1H, J¼7.9 Hz), 7.72 (t, 1H, J¼7.9 Hz);
13C NMR (75 MHz, DMSO-d6) d 162.3, 148.1, 147.5,
133.9, 132.6, 132.1, 130.0, 128.2, 126.5, 125.5, 124.4,
115.2; MS (EI) m/z (relative intensity): 232, 230 (M+, 33,
100), 204, 202 (18, 58), 140 (34); Anal. Calcd for
C12H7ClN2O: C, 62.49; H, 3.06; N, 12.15%. Found: C,
62.61; H, 3.21; N, 12.88%.
3.6.2. 2-Chloro-9-methoxy-5H-benzo[c][1,8]naphthyri-
din-6-one 11f. The general procedure using 4c (227 mg)
as the starting material gave, after purification by flash chro-
matography [silica gel, hexanes/EtOAc (80:20)], a white
solid (32 mg, 25%, EtOAc/hexanes), mp>300 ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 12.00 (s, 1H), 9.05 (br s,
1H), 8.50 (d, 1H, J¼1.8 Hz), 8.21 (d, 1H, J¼8.8 Hz), 7.99
(br s, 1H), 7.26 (dd, 1H, J¼8.8, 1.8 Hz), 3.98 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) d 162.7, 160.7, 146.9, 146.6,
133.6, 131.2, 129.0, 124.0, 118.7, 117.3, 113.9, 105.5,
55.5; MS (EI) m/z (relative intensity): 262, 260 (M+, 33,
100), 219, 217 (10, 30), 189 (17); Anal. Calcd for
C13H9ClN2O2: C, 59.90; H, 3.48; N, 10.75%. Found: C,
60.10; H, 3.11; N, 10.79%.
3.5.4. 2,9-Dichloro-5-methyl-5H-benzo[c][1,8]naphthyri-
din-6-one 11d and 2,8-dichloro-5-methyl-5H-benzo-
[c][1,8]naphthyridin-6-one 12d. The general procedure
using 6d (180 mg) as the starting material gave a mixture
of products. After separation by flash chromatography
[silica gel, hexanes/EtOAc (95:5)], pure compounds 11d
and 12d were obtained (69%, 1.4:1). Assignment and
analysis of the structures were performed using NOE
experiments.
3.5.4.1. 2,9-Dichloro-5-methyl-5H-benzo[c][1,8]naph-
thyridin-6-one 11d. White solid, Rfz0.15 (56 mg,
CH2Cl2), mp 237–240 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.52 (d, 1H, J¼2.3 Hz), 8.48 (d, 1H, J¼8.6 Hz), 8.37 (d,
1H, J¼2.3 Hz), 8.11 (d, 1H, J¼1.9 Hz), 7.60 (dd, 1H,
J¼8.6, 1.9 Hz), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 161.7, 147.9, 139.9, 132.4, 131.1, 131.0, 130.0, 126.3,
124.6, 122.0, 114.9, 104.6, 29.3; MS (EI) m/z (relative inten-
sity): 282, 280, 278 (M+, 11, 66, 100), 253, 251, 249 (14, 66,
88); Anal. Calcd for C13H8Cl2N2O2: C, 55.94; H, 2.89; N,
10.04%. Found: C, 55.60; H, 2.98; N, 10.18%.
3.7. General procedure for the preparation of pyridi-
nium salts 13
The corresponding benzyl bromide (3.5 mmol) was added
dropwise to a stirred solution of aminide 1b (284 mg,
1 mmol) in dry acetone (11 mL) at room temperature. The
mixture was stirred at the same temperature until the starting
material had been consumed (TLC). The resulting solid was
filtered off, washed with EtOAc, and crystallized from
ethanol, yielding compounds 13a–d.
3.5.4.2. 2,8-Dichloro-5-methyl-5H-benzo[c][1,8]naph-
thyridin-6-one 12d. White solid, Rfz0.16 (40 mg,
CH2Cl2), mp 257–259 ꢀC; 1H NMR (300 MHz, CDCl3)
d 8.51 (d, 1H, J¼2.2 Hz), 8.50 (d, 1H, J¼2.2 Hz), 8.39 (d,
1H, J¼2.2 Hz), 8.08 (d, 1H, J¼8.6 Hz), 7.73 (dd, 1H,
J¼8.6, 2.2 Hz), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 161.3, 147.4, 147.0, 136.0, 133.5, 130.8, 129.3, 128.9,
127.5, 126.3, 123.8, 115.3, 29.4; MS (EI) m/z (relative inten-
sity): 282, 280, 278 (M+, 11, 65, 100), 253, 251, 249 (13, 57,
79); Anal. Calcd for C13H8Cl2N2O2: C, 55.94; H, 2.89; N,
10.04%. Found: C, 56.00; H, 2.98; N, 10.22%.
3.7.1. N-[Benzyl-(3-bromo-5-chloro-pyridin-2-yl)-ami-
no]-pyridinium bromide 13a. The general procedure using
598 mg of benzyl bromide furnished 13a as a white solid
(374 mg, 82%), mp 140–141 ꢀC; 1H NMR (300 MHz,
CD3OD) d 9.28 (d, 2H, J¼5.7 Hz), 8.66 (t, 1H, J¼7.8 Hz),
8.55 (d, 1H, J¼2.2 Hz), 8.40 (d, 1H, J¼2.2 Hz), 8.13 (at,
1H, J¼7.3 Hz), 7.50 (m, 2H), 7.35 (m, 3H), 5.21 (s, 2H);
13C NMR (75 MHz, CD3OD) d 153.3, 148.8, 148.2, 147.3,
144.5, 134.3, 132.9, 130.6, 130.2, 130.1, 129.9, 116.9,
61.4; MS (ESI) m/z (relative intensity): 378, 376, 374 (M+,
21, 77, 55), 331, 329, 327 (25, 100, 76); Anal. Calcd for
C17H14Br2ClN3: C, 44.82; H, 3.10; N, 9.22%. Found: C,
45.11; H, 3.43; N, 9.16%.
3.6. Radical reaction of pyridinium salts 4: general
procedure for the preparation of 11e,f
A solution of TTMSS (248 mg, 1 mmol) and AIBN
(164 mg, 1 mmol) in m-xylene (1 mL) and MeCN (9 mL)
was added dropwise by a syringe pump, during 13 h, to
a stirred solution of the corresponding salt 4 (0.5 mmol) in
MeCN (2 mL) at 80 ꢀC (bath temperature). Stirring was
maintained at the same temperature for further 12 h. The re-
sulting solid was filtered off and washed with cold MeCN.
Purification by flash chromatography and crystallization fur-
nished products 11e,f.
3.7.2. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-methyl-
benzyl)-amino]-pyridinium bromide 13b. The general
procedure using 647 mg of 4-methylbenzyl bromide gave
1
a white solid (436 mg, 93%), mp 169–170 ꢀC; H NMR
(300 MHz, CD3OD) d 9.26 (dd, 2H, J¼7.0, 1.2 Hz), 8.66
(tt, 1H, J¼7.8, 1.2 Hz), 8.54 (d, 1H, J¼2.3 Hz), 8.38 (d,
1H, J¼2.3 Hz), 8.13 (dd, 2H, J¼7.8, 7.0 Hz), 7.36 (d, 2H,
J¼7.9 Hz), 7.16 (d, 2H, J¼7.9 Hz), 5.16 (s, 2H), 2.13 (s,
3H); 13C NMR (75 MHz, CD3OD) d 153.2, 148.6, 148.1,
147.1, 144.3, 140.3, 132.7, 131.1, 130.6, 130.5, 129.8,
116.7, 61.2, 21.2; MS (ESI), m/z (relative intensity): 392,
390, 388 (M+, 43, 100, 96), 345, 343, 341 (2, 9, 6); Anal.
Calcd for C18H16Br2ClN3: C, 46.04; H, 3.43; N, 8.95%.
Found: C, 46.21; H, 3.52; N, 8.81%.
3.6.1. 2-Chloro-5H-benzo[c][1,8]naphthyridin-6-one 11e.
The general procedure using 4a (213 mg) as the starting ma-
terial gave, after purification by flash chromatography [silica
gel, hexanes/EtOAc (90:10)], a white solid (21 mg, 18%,
EtOAc/hexanes), mp>300 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 12.20 (s, 1H), 8.97 (d, 1H, J¼1.9 Hz), 8.60

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1
3.7.3. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-methoxy-
benzyl)-amino]-pyridinium bromide 13c. The general
procedure using 703 mg of 4-methoxybenzyl bromide gave
55 mg, 57%), mp 47–48 ꢀC; H NMR (300 MHz, CDCl3)
d 8.03 (d, 1H, J¼2.2 Hz), 7.62 (d, 1H, J¼2.2 Hz), 7.24 (d,
2H, J¼8.0 Hz), 7.10 (d, 2H, J¼8.0 Hz), 5.28 (br s, 1H),
4.59 (d, 2H, J¼5.5 Hz), 2.35 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 152.9, 145.0, 138.4, 137.0, 135.8, 129.3,
127.6, 118.9, 104.9, 45.6, 21.1; MS (EI) m/z (relative
intensity): 314, 312, 310 (M+, 4, 15, 12), 299, 297, 295 (2,
6, 5), 105 (100), 77 (13); Anal. Calcd for C13H12BrClN2:
C, 50.11; H, 3.88; N, 8.99%. Found: C, 50.21; H, 3.65; N,
9.17%.
1
a white solid (354 mg, 73%), mp 168–169 ꢀC; H NMR
(300 MHz, CD3OD) d 9.22 (dd, 2H, J¼6.9, 1.3 Hz), 8.66
(tt, 1H, J¼7.8, 1.3 Hz), 8.55 (d, 1H, J¼2.2 Hz), 8.39 (d,
1H, J¼2.2 Hz), 8.12 (dd, 2H, J¼7.8, 6.9 Hz), 7.37 (d, 2H,
J¼8.6 Hz), 6.88 (d, 2H, J¼8.6 Hz), 5.13 (s, 2H), 3.77 (s,
3H); 13C NMR (75 MHz, CD3OD) d 161.8, 153.4, 148.7,
148.2, 147.3, 144.5, 132.8, 132.1, 129.9, 125.9, 116.8,
115.4, 61.1, 55.7; MS (ESI) m/z (relative intensity): 408,
406, 404 (M+, 19, 69, 52), 361, 359, 357 (11, 44, 34), 329,
327, 325 (25, 100, 75); Anal. Calcd for C18H16Br2ClN3O:
C, 44.52; H, 3.32; N, 8.65%. Found: C, 44.11; H, 3.00; N,
8.78%.
3.9. General procedure for the preparation
of benzylacetamidopyridines 15
Et3N (1.1 mmol, 0.15 mL) and then acetyl chloride
(1 mmol, 71 mL) were added to a stirred solution of the cor-
responding unsubstituted benzylaminopyridine 14 (1 mmol)
in dry CH2Cl2 (15 mL) at room temperature. After
stirring for 8 h at the same temperature, further quantities
of Et3N (0.5 mmol, 70 mL) and acetyl chloride (0.5 mmol,
35 mL) were added. The mixture was stirred at the same
temperature for further 12 h until the starting material had
been consumed (TLC). Purification by flash chromato-
graphy [silica gel, hexanes/EtOAc (80:20)] furnished prod-
ucts 15a,b.
3.7.4. N-[(3-Bromo-5-chloro-pyridin-2-yl)-(4-chloro-
benzyl)-amino]-pyridinium bromide 13d. The general
procedure using 719 mg of 4-methoxybenzyl bromide gave
1
a white solid (441 mg, 90%), mp 156–157 ꢀC; H NMR
(300 MHz, CD3OD) d 9.34 (d, 2H, J¼5.7 Hz), 8.70 (t, 1H,
J¼7.8 Hz), 8.54 (d, 1H, J¼2.2 Hz), 8.38 (d, 1H, J¼
2.2 Hz), 8.18 (at, 2H, J¼7.3 Hz), 7.53 (d, 2H, J¼8.2 Hz),
7.36 (d, 2H, J¼8.2 Hz), 5.23 (s, 2H); 13C NMR (75 MHz,
CD3OD) d 153.0, 148.9, 148.1, 147.4, 144.5, 136.0, 133.2,
133.0, 132.3, 130.2, 130.1, 117.1, 60.6; MS (ESI) m/z (rela-
tive intensity): 414, 412, 410, 408 (M+, 8, 52, 100, 68), 365,
363, 361 (12, 44, 34); Anal. Calcd for C17H13BrCl2N3: C,
41.67; H, 2.67; N, 8.58%. Found: C, 42.01; H, 3.02; N,
8.38%.
3.9.1. N-Benzyl-N-(3-bromo-5-chloro-pyridin-2-yl)-acet-
amide 15a. The general procedure using 14a (297 mg) as
starting material gave, after flash chromatography, a white
1
solid (Rfz0.40, 187 mg, 55%), mp 65–67 ꢀC; H NMR
(300 MHz, CDCl3) d 8.37 (d, 1H, J¼2.2 Hz), 7.92 (d, 1H,
J¼2.2 Hz), 7.20 (s, 5H), 5.00 (br s, 2H), 1.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 169.5, 151.9, 147.1, 141.7,
136.1, 131.5, 129.0, 128.2, 127.5, 120.5, 50.9, 22.5; MS
(EI) m/z (relative intensity): 342, 340, 338 (M+, 1.5, 5.8,
4.4), 299, 297, 295 (16, 64, 48), 190 (8), 91 (100); Anal.
Calcd for C14H12BrClN2O: C, 49.51; H, 3.56; N, 8.25%.
Found: C, 49.21; H, 3.55; N, 8.37%.
3.8. General procedure for the preparation of unsub-
stituted benzylaminopyridines 14
Platinum on charcoal (5%) (75 mg) was suspended in
a stirred solution of the corresponding pyridinium salt 13
(0.31 mmol) in MeCN (3 mL) and cooled in an ice bath.
Formic acid (96%, 1.5 mL) in MeCN (1.5 mL) and then tri-
ethylamine (4.5 mL) in the same solvent (3 mL) were added
dropwise. The resulting suspension was stirred at room tem-
perature and filtered through Celite. The filtrate was evapo-
rated and the residue dissolved in water, made basic with
solid potassium carbonate, and extracted with EtOAc. The
combined organic phases were dried over Na2SO4, filtered,
and evaporated to dryness. The corresponding N-benzylami-
nopyridine was purified by flash chromatography [silica gel,
hexanes/EtOAc (95:5)].
3.9.2. N-(3-Bromo-5-chloro-pyridin-2-yl)-N-(4-methyl-
benzyl)-acetamide 15b. The general procedure using 14b
(311 mg) as starting material gave, after flash chromato-
1
graphy, a yellow oil (Rfz0.24, 307 mg, 87%); H NMR
(300 MHz, CDCl3) d 8.38 (d, 1H, J¼2.2 Hz), 7.93 (d, 1H,
J¼2.2 Hz), 7.10 (d, 2H, J¼7.8 Hz), 7.01 (d, 2H,
J¼7.8 Hz), 4.95 (br s, 2H), 2.03 (s, 3H), 1.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 169.5, 151.8, 146.9, 141.6,
136.9, 132.9, 131.3, 128.9, 128.8, 120.4, 50.4, 22.4, 21.0;
MS (EI) m/z (relative intensity): 342, 340, 338 (M+, 1.5,
5.8, 4.4), 299, 297, 295 (16, 64, 48), 190 (8).
3.8.1. N-Benzyl-(3-bromo-5-chloro-pyridin-2-yl)-amine
14a. The general procedure using 141 mg of 13a as the start-
ing material gave a yellow oil (Rfz0.35, 83 mg, 90%); H
1
NMR (300 MHz, CDCl3) d 8.04 (d, 1H, J¼2.3 Hz), 7.64
(d, 1H, J¼2.3 Hz), 7.32 (m, 5 H), 5.34 (br s, 1H), 4.65 (d,
2H, J¼5.7 Hz); 13C NMR (75 MHz, CDCl3) d 152.9,
152.0, 145.0, 138.9, 128.6, 127.5, 127.3, 119.0, 104.9,
45.8; MS (EI) m/z (relative intensity): 300, 298, 296 (M+,
9, 37, 28), 263, 261 (3, 3), 106 (49), 91 (100); Anal. Calcd
for C12H10BrClN2: C, 48.43; H, 3.39; N, 9.41%. Found: C,
48.21; H, 3.55; N, 9.37%.
3.10. Radical reaction on methylbenzamides 15: general
procedure for the preparation of 17a,b and 18b
A solution of TTMSS (248 mg, 1 mmol) and AIBN
(164 mg, 1 mmol) in m-xylene (10 mL) was added dropwise
by a syringe pump, during 13 h, to a stirred solution of the
corresponding benzyl acetamidopyridine 15 (0.5 mmol) in
m-xylene (2 mL) at 80 ꢀC (bath temperature). Stirring was
maintained at the same temperature for further 12 h. The so-
lution was concentrated and the crude mixture was separated
by flash chromatography [silica gel, hexanes/EtOAc
(80:20)], yielding the pure compounds 17 and 18.
3.8.2. N-(3-Bromo-5-chloro-pyridin-2-yl)-(4-methylben-
zyl)-amine 14b. The general procedure using 146 mg of
13b as the starting material gave a white solid (Rfz0.39,

A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
6781
3.10.1. 1-(2-Chloro-6H-benzo[c][1,8]naphthyridin-5-yl)-
ethanone 17a. The general procedure using 15a (170 mg)
5H), 7.34 (d, 1H, J¼2.4 Hz), 4.68 (br s, 2H); 13C NMR
(75 MHz, CDCl3) d 154.2, 144.9, 137.5, 136.5, 129.3,
128.5, 128.4, 123.1, 121.1; MS (EI) m/z (relative intensity):
206, 204 (M+, 21, 65), 205, 203 (33, 100), 168 (30); Anal.
Calcd for C11H9ClN2: C, 65.56; H, 4.43; N, 13.69%. Found:
C, 64.31; H, 4.15; N, 13.87%.
as starting material gave
a white solid (Rfz0.47,
41 mg, 32%), mp 150–151 ꢀC; 1H NMR (300 MHz,
CDCl3) d 8.27 (d, 1H, J¼2.4 Hz), 8.02 (d, 1H, J¼2.4 Hz),
7.65 (dd, 1H, J¼6.6, 2.2 Hz), 7.35 (m, 3H), 5.02 (s,
2H), 2.37 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 170.4, 148.9, 145.2, 134.2, 131.6, 129.4, 129.2, 128.6,
128.2, 126.4, 124.4, 123.3, 44.7, 24.0; MS (EI) m/z
(relative intensity): 260, 258 (M+, 2, 6), 217, 215 (35,
100), 179 (8), 152 (16). Anal. Calcd for C14H11ClN2O: C,
65.00; H, 4.29; N, 10.83%. Found: C, 64.63; H, 4.42; N,
10.49%.
3.11.2. 2-Chloro-9-methyl-benzo[c][1,8]naphthyridine
19b and 5-chloro-3-p-tolyl-pyridin-2-ylamine 21b. The
general procedure using 235 mg of 13b as the starting mate-
rial gave a mixture of products. After separation by flash
chromatography [silica gel, hexanes/EtOAc (1:1)], pure
compounds 19b and 21b were obtained (59%, 1.1:1), to-
gether with a small amount (3%) of tricyclic derivative 22.
In this case, no traces of 5-cyclization compound 20b were
detected. Assignment and analysis of the structures were
performed using NOE experiments.
3.10.2. 1-(2-Chloro-9-methyl-6H-benzo[c][1,8]naphthyr-
idin-5-yl)-ethanone 17b and 1-(2-chloro-8-methyl-
6H-benzo[c][1,8]naphthyridin-5-yl)-ethanone 18b. The
general procedure using 15b (176 mg) as starting material
gave a mixture of products (17b and 18b) as a white solid
(Rfz0.30, 28 mg, 21%); 1H NMR (300 MHz, CDCl3)
d 8.26 (d, 1H, J¼2.3 Hz), 8.25 (d, 1H, J¼2.4 Hz), 8.02 (d,
1H, J¼2.3 Hz), 7.99 (d, 1H, J¼2.4 Hz), 7.53 (d, 1H,
J¼7.8 Hz), 7.50 (br s, 1H), 7.20 (m, 3H), 7.13 (br s, 1H),
4.98 (s, 4H), 2.38 (s, 3H), 2.36 (s, 3H).
3.11.2.1. 2-Chloro-9-methyl-benzo[c][1,8]naphthyri-
dine 19b. Yellow solid, Rfz0.15 (35 mg), mp 159–
1
161 ꢀC; H NMR (500 MHz, CDCl3) d 9.43 (s, 1H), 8.96
(d, 1H, J¼2.6 Hz), 8.82 (d, 1H, J¼2.6 Hz), 8.28 (br s,
w½¼0.9 Hz), 8.01 (d, 1H, J¼8.1 Hz), 7.63 (dd, 1H,
J¼8.1, 0.9 Hz), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 156.8, 152.1, 150.1, 142.7, 131.8, 130.7, 130.3, 129.7,
128.9, 124.7, 121.7, 119.4, 22.4; MS (EI) m/z (relative inten-
sity): 230, 228 (M+, 33, 100); Anal. Calcd for C13H9ClN2: C,
68.28; H, 3.97; N, 12.25%. Found: C, 67.97; H, 3.86; N,
12.36%.
3.11. Radical reaction on pyridinium salts 13: general
procedure for the preparation of 19, 20, and 21
A solution of TTMSS (0.248 g, 1 mmol) and AIBN (0.164 g,
1 mmol) in m-xylene (1 mL) and MeCN (9 mL) was added
dropwise by a syringe pump, during 13 h, to a stirred solu-
tion of the corresponding pyridinium salt 13 (0.5 mmol) in
MeCN (2 mL) at 80 ꢀC (bath temperature). Stirring was
maintained at the same temperature for further 12 h. The so-
lution was concentrated and the crude mixture was separated
by flash chromatography, yielding the pure compounds 19,
20, and 21. Assignments and analysis of the structures
were performed using NOE experiments.
3.11.2.2. 5-Chloro-3-p-tolyl-pyridin-2-ylamine 21b.
1
White solid, Rfz0.67 (31 mg), mp 157–158 ꢀC; H NMR
(300 MHz, CDCl3) d 7.99 (d, 1H, J¼2.4 Hz), 7.34 (d, 1H,
J¼2.4 Hz), 7.32 (d, 2H, J¼8.2 Hz), 7.26 (d, 2H,
J¼8.2 Hz), 4.64 (br s, 2H), 2.40 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 154.3, 144.7, 138.2, 137.4, 133.6,
129.9, 128.3, 123.1, 121.1, 21.2; MS (EI) m/z (relative inten-
sity): 220, 218 (M+, 22, 69), 219, 217 (41, 100), 182 (18);
Anal. Calcd for C12H11ClN2: C, 65.91; H, 5.07; N,
12.81%. Found: C, 65.71; H, 5.38; N, 12.68%.
3.11.1. 2-Chloro-benzo[c][1,8]naphthyridine 19a and 5-
chloro-3-phenyl-pyridin-2-ylamine 21a. The general
procedure using 228 mg of 13a as the starting material
gave a mixture of products. After separation by flash
chromatography [silica gel, hexanes/EtOAc (70:30)], pure
compounds 19a and 21a were obtained (46%, 1:1.4)
together with a small amount (3%) of tricyclic derivative
22.9c
3.11.3. 2-Chloro-9-methoxy-benzo[c][1,8]naphthyridine
19c. The general procedure using 243 mg of 13c as the start-
ing material gave a mixture of products. After separation by
flash chromatography [silica gel, hexanes/EtOAc (1:1)],
pure compound 19c was obtained (39%) together with a
small amount (3%) of tricyclic derivative 22. In this case,
neither 20c nor 21c was detected. Assignment and analysis
of the structures were performed using NOE experiments.
3.11.1.1. 2-Chloro-benzo[c][1,8]naphthyridine 19a.
1
1
Yellow solid, Rfz0.10 (20 mg), mp 231–233 ꢀC; H NMR
Yellow solid, Rfz0.15 (48 mg), mp 205–207 ꢀC; H NMR
(300 MHz, CDCl3) d 8.99 (br s, 1H), 8.98 (d, 1H,
J¼2.4 Hz), 8.84 (d, 1H, J¼2.4 Hz), 8.51 (d, 1H, J¼8.1 Hz),
8.12 (d, 1H, J¼8.1 Hz), 7.93 (t, 1H, J¼8.1 Hz), 7.80 (t, 1H,
J¼8.1 Hz); 13C NMR (75 MHz, CDCl3) d 157.2, 152.0,
150.3, 131.8, 131.7, 130.4, 130.0, 129.1, 129.0, 128.5,
122.1, 119.6; MS (EI) m/z (relative intensity): 216, 214
(M+, 32, 100), 179 (24); Anal. Calcd for C12H7ClN2: C,
67.15; H, 3.29; N, 13.05%. Found: C, 67.29; H, 2.91; N,
12.86%.
(300 MHz, DMSO-d6) d 9.42 (s, 1H), 9.31 (br s, 1H), 8.91
(br s, 1H), 8.24 (d, 1H, J¼8.5 Hz), 8.10 (br s, 1H), 7.43 (d,
1H, J¼8.5 Hz), 4.07 (s, 3H); 13C NMR (75 MHz, DMSO-
d6) d 163.8, 154.1, 150.1, 147.2, 134.8, 132.1, 132.0,
129.3, 120.2, 119.6, 119.3, 104.1, 56.2; MS (EI) m/z (relative
intensity): 246, 244 (M+, 33, 100), 203, 201 (13, 40); Anal.
Calcd for C13H9ClN2O: C, 63.82; H, 3.71; N, 11.45%.
Found: C, 64.12; H, 3.51; N, 11.53%.
3.11.4. 2,9-Dichloro-benzo[c][1,8]naphthyridine 19d, 2,8-
dichloro-benzo[c][1,8]naphthyridine 20d, and 5-chloro-
3-(4-chlorophenyl)-pyridin-2-ylamine 21d. The general
procedure using 245 mg of 13d as the starting material
3.11.1.2. 5-Chloro-3-phenyl-pyridin-2-ylamine 21a.20
1
Yellow solid, Rfz0.45 (28 mg), mp 93–95 ꢀC; H NMR
(300 MHz, CDCl3) d 8.00 (d, 1H, J¼2.4 Hz), 7.42 (m,

6782
A. Nuꢀn˜ez et al. / Tetrahedron 63 (2007) 6774–6783
Luo, T.; Lu, K.; Xu, Z.; Chen, J.; Yang, Z. J. Comb. Chem.
2006, 8, 696–704; (c) Ruchelman, A. L.; Houghton, P. J.;
Zhou, N.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem.
2005, 48, 792–804; (d) Hinschberger, A.; Butt, S.; Lelong,
V.; Boulouard, M.; Dumuis, A.; Dauphin, F.; Bureau, R.;
Pfeiffer, B.; Renard, P.; Rault, S. J. Med. Chem. 2003, 46,
138–147.
gave a mixture of products. After separation by flash chro-
matography [silica gel, hexanes/EtOAc (60:40)], pure com-
pounds 19d, 20d, and 21d were obtained (31%, 2:1:1)
together with a small amount (3%) of tricyclic derivative
22. Assignment and analysis of the structures were per-
formed using NOE experiments.
2. For recent examples in phenanthridine series, see: (a) Parenty,
A. D. C.; Smith, L. V.; Guthrie, K. M.; Long, D.; Plumb, J.;
Brown, R.; Cronin, L. J. Med. Chem. 2005, 48, 4504–4506;
(b) Ferraris, D.; Ficco, R. P.; Pahutski, T.; Lautar, S.; Huang,
S.; Zhang, J.; Kalish, V. Bioorg. Med. Chem. Lett. 2003, 13,
2513–2518.
3. Ferraris, D.; Ko, Y.-S.; Pahutski, T.; Fico, R. P.; Serdyuk, L.;
Alemu, C.; Bradford, C.; Chiou, T.; Hoover, R.; Huang, S.;
Lautar, S.; Liang, S.; Lin, Q.; Lu, M. X.-C.; Mooney, M.;
Morgan, L.; Qian, Y.; Tran, S.; Williams, L. R.; Wu, Q. Y.;
Zhang, J.; Zou, Y.; Kalish, V. J. Med. Chem. 2003, 46, 3138–
3151.
3.11.4.1.
2,9-Dichloro-benzo[c][1,8]naphthyridine
1
19d. White solid, Rfz0.10 (19 mg), mp 242–243 ꢀC; H
NMR (500 MHz, CDCl3) d 9.45 (s, 1H), 9.01 (d, 1H,
J¼2.5 Hz), 8.78 (d, 1H, J¼2.5 Hz), 8.48 (d, 1H,
J¼1.8 Hz), 8.06 (d, 1H, J¼8.4 Hz), 7.75 (dd, 1H, J¼8.4,
1.8 Hz); 13C NMR (75 MHz, CDCl3) d 156.4, 152.1,
151.0, 138.6, 132.9, 130.5, 130.4, 130.3, 129.8, 124.2,
121.9, 118.5; MS (EI) m/z (relative intensity): 252, 250,
248 (M+, 11, 64, 100), 215, 213 (10, 30); Anal. Calcd for
C12H6Cl2N2: C, 57.86; H, 2.43; N, 11.25%. Found: C,
57.57; H, 2.39; N, 11.57%.
4. Park, Y.-T.; Jung, C.-H.; Kim, M.-S.; Kim, K.-W.; Song, N. W.;
Kim, D. J. Org. Chem. 2001, 66, 2197–2206.
5. Ferraccioli, R.; Carenzi, D.; Rombola, O.; Catellani, M. Org.
Lett. 2004, 6, 4759–4762.
6. Cailly, T.; Fabis, F.; Rault, S. Tetrahedron 2006, 62, 5862–
5867.
7. Li, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2003, 68,
5512–5518.
3.11.4.2.
2,8-Dichloro-benzo[c][1,8]naphthyridine
1
20d. White solid, Rfz0.15 (10 mg), mp 262–243 ꢀC; H
NMR (500 MHz, CDCl3) d 9.42 (s, 1H), 9.00 (d, 1H,
J¼2.4 Hz), 8.80 (d, 1H, J¼2.4 Hz), 8.45 (d, 1H,
J¼8.7 Hz), 8.10 (d, 1H, J¼2.0 Hz), 7.87 (dd, 1H, J¼8.7,
2.0 Hz); 13C NMR (75 MHz, CDCl3) d 156.2, 152.1,
150.9, 135.4, 132.7, 130.8, 130.6, 130.3, 128.4, 127.6,
124.1, 119.4; MS (EI) m/z (relative intensity): 252, 250,
248 (M+, 11, 64, 100), 215, 213 (10, 29); Anal. Calcd for
C12H6Cl2N2: C, 57.86; H, 2.43; N, 11.25%. Found: C,
57.99; H, 2.22; N, 10.85%.
8. Silwa, W. Pr. Nauk. Inst. Chem. Org. Fiz. Politech. Wroclaw.
1978, 13, 1–167; Chem. Abstr. 1979, 90, 186830g.
ꢀ
9. (a) Nꢀun˜ez, A.; Sanchez, A.; Burgos, C.; Alvarez-Builla, J.
ꢀ
Tetrahedron 2004, 60, 6217–6224; (b) Sanchez, A.; Nun˜ez,
A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004, 60,
ꢀ
3.11.4.3. 5-Chloro-3-(4-chlorophenyl)-pyridin-2-yl-
amine 21d. Yellow solid, Rfz0.36 (10 mg), mp 140–
141 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.02 (d, 1H,
J¼2.4 Hz), 7.45 (d, 2H, J¼8.6 Hz), 7.37 (d, 2H,
J¼8.6 Hz), 7.32 (d, 1H, J¼2.4 Hz), 4.56 (br s, 2H); 13C
NMR (75 MHz, CDCl3) d 154.3, 145.2, 137.6, 135.2,
134.7, 130.1, 129.7, 121.9, 121.5; MS (EI) m/z (relative in-
tensity): 242, 240, 238 (M+, 7, 41, 64), 204, 202 (11, 32),
168 (18); Anal. Calcd for C11H8Cl2N2: C, 55.26; H, 3.37;
N, 11.72%. Found: C, 55.60; H, 3.01; N, 11.91%.
ꢀ˜
ꢀ
11843–11850; (c) Nunez, A.; Garcıa de Viedma, A.; Martinez-
Barrasa, V.; Burgos, C.; Alvarez-Builla, J. Synlett 2002, 1093–
ꢀ
1096; (d) Martinez-Barrasa, V.; Garcıa de Viedma, A.; Burgos,
C.; Alvarez-Builla, J. Org. Lett. 2000, 2, 3933–3935.
ꢀ
ꢀ
10. Sanchez, A.; Nun˜ez, A.; Burgos, C.; Alvarez-Builla, J.
Tetrahedron Lett. 2006, 47, 8343–8346.
11. For some examples of homolytic aromatic substitution, see: (a)
Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun.
2004, 2228–2229; (b) Zhang, W.; Pugh, G. Tetrahedron 2003,
59, 3009–3018; (c) Ganguly, A. K.; Wang, C. H.; David, M.;
Bartner, P.; Chan, T. M. Tetrahedron Lett. 2002, 43, 6865–
6868; (d) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53,
8287–8294.
Acknowledgements
12. (a) El Qacemi, M.; Ricard, L.; Zard, S. Z. Chem. Commun.
2006, 4422–4424; (b) Bacque, E.; El Qacemi, M.; Zard, S. Z.
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Financial support from the CICYT (project CTQ2005-
ꢀ
08902/BQU) and two grants from the Universidad de Alcala
(A.S) and the Ministerio de Educacion y Ciencia (Spain)
ꢀ
ꢀ
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13. Gonzalez-Lopez de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7,
(A.N.) are gratefully acknowledged.
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Tetrahedron Lett. 2004, 45, 883–886.
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Supplementary data
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet.2007.04.077.
References and notes
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17. (a) Martınez-Barrasa, V.; Delgado, F.; Burgos, C.; Garcıa-
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ꢀ
ꢀ
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