A new, direct, and efficient synthesis of benzonaphthyridin-5-ones

Article abstract of DOI:10.1016/j.tet.2006.04.030

Microwave-assisted Suzuki cross-coupling reaction of 2-fluorophenylboronic acid with all orthochlorocyanopyridine isomers allowed the rapid syntheses of key intermediates for anionic ring closure, which was performed using potassium hydroxide under microwave irradiation to give benzonaphthyridin-5-ones in high yields.

Full text of DOI:10.1016/j.tet.2006.04.030

Tetrahedron 62 (2006) 5862–5867
A new, direct, and efficient synthesis of benzonaphthyridin-5-ones
*
´ ´
Thomas Cailly, Frederic Fabis and Sylvain Rault
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, U.F.R. des Sciences Pharmaceutiques,
´
Universite de Caen Basse-Normandie, 5 rue Vaubenard, 14032 Caen cedex, France
´
Received 28 February 2006; revised 6 April 2006; accepted 6 April 2006
Available online 5 May 2006
Abstract—Microwave-assisted Suzuki cross-coupling reaction of 2-fluorophenylboronic acid with all orthochlorocyanopyridine isomers
allowed the rapid syntheses of key intermediates for anionic ring closure, which was performed using potassium hydroxide under microwave
irradiation to give benzonaphthyridin-5-ones in high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
F
(N)
F
(N)
(N)
CN
Benzonaphthyridines are of great interest regarding to their
diverse biological activities1 and as ‘aza-analogues’ of
phenanthridines, which have been widely studied in the field
of medicinal chemistry.2 However their syntheses are not
scalable and suffer from a lack of diversity. To our point of
view, benzonaphthyridin-5-ones could be useful scaffolds
for the syntheses of diverse 5-substituted compounds. In
this paper, we wish to report a new and an efficient two-
step synthesis of the four benzonaphthyridin-5-one isomers
5a–d. Three of them have already been reported generally
with poor to low yield: 6H-benzo[f][1,7]naphthyridin-5-
one 5a,3 6H-benzo[c][2,7]naphthyridin-5-one 5b,3a,4 and
6H-benzo[h][1,6]naphthyridin-5-one 5c.3a,5 The synthesis
of 6H-benzo[c][2,6]naphthyridin-5-one 5d has not been
reported yet.
R
Li
N
Li
R
R
N
1
2
With R = Alkyl, Aryl and Amino.
Scheme 1. Anionic ring closure.
However, the scope of this sequence was still limited to the
variety of organometallic derivatives employed to achieve
the second step: alkyllithium and lithium amide reagents
mainly. In the benzonaphthyridine series, this reaction had
only been reported using lithium morpholide as a nucleo-
phile.7 This is the reason why in order to enlarge the scope
of this methodology we planned to prepare the lactam moi-
eties using, this time, the hydroxide ion as the nucleophile.
Before considering the improvement of the anionic ring
closure, it was necessary to have an easy access to biaryl
systems bearing a cyano group in position 2 and a fluorine
atom in position 20. These biaryl structures could be obtained
using the Suzuki–Miyaura cross-coupling reaction.8 Mean-
while four different partnerships were possible to achieve
the cross-coupling (Table 1). The pathway A using ortho-
fluoropyridylboronic derivatives was not usable for two
reasons. First these species, for which we described a synthe-
sis,9 remain very expensive. Second, no synthesis for a
4-fluoro-3-pyridylboronic or 3-fluoro-2-pyridylboronic spe-
cies is available. The B pathway using orthofluorobenzene
halides and orthocyanopyridylboronic acids or esters had
already been reported by Hansen and co-workers.7 But these
orthocyanopyridylboronic species are quite unstable10 and
no 2-pyridyl derivative has been described yet. The pathway
C was also limited (as pathways A and B) because of the
2. Results and discussion
2.1. Strategy
We hypothesized that a two-step procedure including an
anionic ring closure and Suzuki cross-coupling could lead
directly to benzonaphthyridinone systems. This strategy
was supported by the work of the Begtrup’s team6,7 who
demonstrated that anionic ring closure could be a powerful
method to synthesize 6-substituted phenanthridines and 5-
substituted benzonaphthyridines 2 by the attack of a lithiated
species on the nitrile function of biaryl 1 and subsequent
intramolecular nucleophilic aromatic substitution of the
fluorine atom (Scheme 1).
* Corresponding author. Tel.: +33 (0)2 31 93 41 69; fax: +33 (0)2 31 93 11
88; e-mail: rault@pharmacie.unicaen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.030

T. Cailly et al. / Tetrahedron 62 (2006) 5862–5867
Table 2. Microwave-assisted cross-coupling reactiona
5863
Table 1. Cross-coupling partnerships
CN
F
Boronics
Halides
Cross-coupling
partnerships
F
N
Cl
B(OH)2
+
N
F
CN
CN
B(OR)2
X
3a-d
4a-d
A
B
N
Starting materials
Products
Yields (%)b
CN
F
CN
F
X
X
X
B(OR)2
B(OR)2
B(OR)2
Cl
N
N
N
67
85
4a
4b
4c
3a
CN
N
CN
F
CN
Cl
F
F
C
D
N
3b
N
CN
F
CN
CN
Cl
N
N
71c
3c
N
CN
N
CN
Cl
expensiveness of fluoropyridine derivatives and the instabil-
ity of orthocyanophenylboronic species during the cross-
coupling reaction.11 The last partnership D consisted in
fusing 2-fluorophenylboronic and orthochlorocyanopyridine
3. Since we had described a general method for the ortho-
lithiation of cyanopyridines12 that permitted to synthesize
all isomers of orthochlorocyanopyridine 3, we first decided
to apply this last strategy using commercial 2-fluorophenyl-
boronic acid, which was able to furnish the four isomers of
benzonaphthyridin-5-one 5a–d in good conditions.
F
77
4d
3d
N
CN
a
Reaction conditions: 1 equiv of aromatic halide, 2 equiv of 2-fluoro-
phenylboronic acid, 5% mol of Pd(PPh3)4, 2.5 equiv of K3PO4, DMF,
150 ꢀC, microwave heating, sealed tube, 30 min.
Isolated yields.
b
c
CsF (2.5 equiv) was used instead of K3PO4.
obtained in 98% yield. The use of microwave heating con-
ditions reduced the reaction time to 10 min maintaining
the same yield (Scheme 2). We then tested the reactivity
of the carboxamide 6 under our microwave conditions. Its
total conversion into the benzonaphthyridin-5-one 5d was
observed, with no formation of the corresponding carboxylic
acid. In the absence of KOH, the carboxamide 6 did not react
and only the starting material was recovered. Therefore
these experiments showed that the formation of an anion
intermediate was needed to achieve the cyclization.
2.2. Cross-coupling reaction of orthochlorocyanopyri-
dines with 2-fluorophenylboronic acid
Our first attempt of cross-coupling at 100 ꢀC in DMF with
K3PO4 and Pd(PPh3)4 starting from 3b was disappointing.
However, using 2 equiv of 2-fluorophenylboronic acid in
order to compensate the protodeboronation side reaction
and increasing the reaction time from 24 to 36 h, we ob-
tained a 80% yield. Finally, taking into account the recent
results of several groups13 who had demonstrated that the use
of microwave energy could shorten the reaction time in this
reaction, we conducted an assisted microwave reaction in
a sealed tube. These latter conditions permitted the isolation
of 4b with a good 85% yield after 30 min at 150 ꢀC (Table 2).
N
N
F
F
i
65%
CN
O
NH2
6
We then applied these reaction conditions to the isomers
3a and 3d, which gave 4a and 4d with 67 and 77% yield,
respectively. In the case of 3c it was necessary to avoid the
side reaction of the chlorine atom in aromatic nucleophilic
substitutions, we therefore replaced the K3PO4 by CsF to
obtain 4c with a 71% yield.
4d
ii
99%
N
ii or iii
98%
N
H
O
5d
2.3. Anionic ring closure
Scheme 2. Anionic ring closure using various temperatures under micro-
wave or conventional heating conditions (isolated yields): (i) KOH 5 equiv,
MeOH, reflux, conventional heating, 24 h, (ii) KOH 5 equiv, MeOH,
150 ꢀC, conventional heating, sealed tube, 1 h, and (iii) KOH 5 equiv,
MeOH, 150 ꢀC, microwave heating, sealed tube, 10 min.
To achieve the second step we first evaluated the feasibility
of the anionic ring closure with KOH from 4-cyano-3-(2-
fluorophenyl)pyridine 4d. The first attempt with 5 equiv of
KOH in refluxing methanol for 24 h only led to the carbox-
amide 6. When the temperature was raised to 150 ꢀC in
a sealed tube for 1 h, the benzonaphthyridin-5-one 5d was
We further investigated this reaction regarding the quantity
and the nature of the base employed (Table 3). With 1 equiv

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T. Cailly et al. / Tetrahedron 62 (2006) 5862–5867
Table 3. Microwave-assisted anionic ring closure varying nature and quan-
Because our methodology was not described in the corre-
sponding phenanthridinic system our anionic ring closure
was finally tested on the 20-fluorobiphenyl-2-carbonitrile 7
(Scheme 3). The 5H-phenanthridin-6-one 8 was obtained
in a good 80% yield but the reaction time has to be increased
to 30 min. The p-deficient nature of the pyridine nucleus
could explain the milder condition needed to achieve the
transformation in benzonaphthyridin-5-one.
tity of basea
Bases
Equivalents
Reaction times
(min) mW
Products molar
ratiob
4d
6
5d
KOH
KOH
KOH
KOH
KOH
NaOH
1
1
3
3
5
5
10
20
10
20
10
10
23
16
3
3
0
47
42
9
3
0
30
42
88
94
100
95
F
4
1
a
Reaction conditions: MeOH, 150 ꢀC, microwave heating, and sealed tube.
Molar ratio determined by analysis of the crude 1H NMR spectra.
iv
b
CN
80%
N
H
O
8
7
of KOH, the reaction was not completed even after increas-
ing the reaction time from 10 to 20 min. With 3 equiv of
KOH the ratio of the benzonaphthyridin-5-one 5d was
increased, but the reaction was still not finished yet after
10 min. The same reaction conducted within 20 min did
not allow a total conversion of 4d into 5d. The use of 5 equiv
of KOH in a 10 min experiment showed us a total conversion
of 4d into 5d without formation of 6. The same reactive con-
ditions conducted with NaOH appeared to be less efficient
for this reaction. Finally, the best conditions to achieve the
reaction were: 5 equiv of KOH, 150 ꢀC, and 10 min under
microwave heating.
Scheme 3. Anionic ring closure using 20-fluorobiphenyl-2-carbonitrile 7
(isolated yields): (iv) KOH 5 equiv, MeOH, 150 ꢀC, microwave heating,
sealed tube, 30 min.
3. Conclusion
In conclusion, we have developed a very efficient micro-
wave-assisted synthesis of the benzonaphthyridin-5-ones
5a–d in a two-step procedure involving Suzuki cross-cou-
pling reaction followed by original KOH promoted anionic
ring closure. The benzonaphthyridin-5-ones 5a–d were
obtained in 63–84% overall yields starting from 3a–d.
Both nitrile and carboxamide groups were reactive under
these conditions and could allow an easy scalable access to
benzonaphthyridine scaffolds with a potential interest in the
field of medicinal chemistry. Finally, a new access to the
5H-phenanthridin-6-one enlarges the scope of our reaction
to benzenic derivatives. Furthermore, we are currently
exploring the use of our approach to synthesize aza-hetero-
cyclic systems.
Then, the three fluorophenylcyanopyridines 4a–c were sub-
jected to these best conditions to give the three correspond-
ing benzonaphthyridin-5-ones 5a–c in nearly quantitative
yields (Table 4).
Table 4. Microwave-assisted anionic ring closurea
N
F
N
4. Experimental
4.1. General
N
H
O
CN
4a-d
5a-d
Starting
materials
Products
Yieldsb (%)
Product
number
All commercial reagents were used as received except THF,
which was distilled from Na/benzophenone. Melting points
were determined on a kofler melting point apparatus. IR
1
N
O
spectra were recorded with a Perkin–Elmer BX FTIR. H
and 13C NMR spectra were recorded, respectively, at 400
and 100 MHz with a Jeol Lambda 400 NMR spectrometer.
The microwave reactions were performed using a Biotage
Initiator microwave oven. Temperatures were measured
with an IR-sensor and the reactions are given as hold times.
4a
4b
95
5a
N
H
N
4.2. General procedure for the synthesis of ortho-
chlorocyanopyridines (3a, 3c, and 3d)
99
95
5b
5c
N
H
O
N
To a stirred solution under N2 of 2,2,6,6-tetramethylpiperi-
dine (20.2 mmol, 3.4 mL) in THF (40 mL) was added at
ꢁ30 ꢀC 2.5 M n-butyllithium (19.2 mmol, 7.7 mL). The
solution was allowed to reach 0 ꢀC, kept under stirring during
15 min and cooled to ꢁ80 ꢀC. A solution of the chosen
cyanopyridine (9.6 mmol, 1 g) in THF (20 mL) was slowly
added to the mixture over 15 min. After stirring 30 min at
ꢁ80 ꢀC, a solution of hexachloroethane (20.2 mmol,
4.78 g) in THF (10 mL) was slowly added over 15 min and
4c
N
H
O
a
Reaction conditions: KOH 5 equiv, MeOH, 150 ꢀC, microwave heating,
sealed tube, 10 min.
Isolated yields.
b

T. Cailly et al. / Tetrahedron 62 (2006) 5862–5867
5865
the resulting mixturewas stirred for 30 min. The solution was
then allowed to warm slowly to room temperature. The
mixturewas quenched with 40 mL of a saturated NH4Cl solu-
tion. The solution was extracted with EtOAc (3ꢂ100 mL),
the combined organic layers were washed with brine
(2ꢂ100 mL), dried with MgSO4, filtered, and evaporated
under reduced pressure. The products were purified by silica
gelchromatographyusingEtOAc/cyclohexane(1/4)aseluent.
1H NMR (400 MHz, CDCl3) d¼7.23 (m, 1H), 7.31 (td,
J¼7.5 and 1.2 Hz, 1H), 7.43–7.55 (m, 2H), 7.60 (dd,
3J¼8.0 Hz, 3J¼4.6 Hz, 1H), 7.88 (dd, 3J¼8.0 Hz,
4J¼1.4 Hz, 1H), 8.73 (dd, 3J¼4.7 Hz, 4J¼1.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) d¼116.3 (d, JC–F¼22 Hz), 116.5,
123.1 (d, JC–F¼15 Hz), 124.8 (d, JC–F¼4 Hz), 126.4, 131.2
(d, JC–F¼2 Hz), 131.8 (d, JC–F¼8 Hz), 133.5, 136.6, 138.7
(d, JC–F¼2 Hz), 150.0, 159.5 (d, JC–F¼248 Hz); IR (KBr)
3066, 3050, 2236 (CN), 1835, 1615, 1579, 1496, 1457,
4.2.1. 3-Chloropyridine-2-carbonitrile 3a. Starting from
2-cyanopyridine and following the general procedure, the
product was obtained as a pale yellow powder (0.99 g,
75%). 1H NMR (400 MHz, CDCl3) d¼7.51 (dd,
3J¼4.6 Hz, 3J¼8.5 Hz, 1H), 7.88 (dd, 4J¼1.4 Hz,
1416, 1217, 1111, 1001, 811, 775, 689, 551 cmꢁ1
mp 88 ꢀC. Lit.7
;
4.3.2. 2-(2-Fluorophenyl)nicotinonitrile 4b. Starting from
2-chloro-3-cyanopyridine and following the general proce-
dure, the product was obtained as a white powder (1.22 g,
3J¼8.5 Hz, 1H), 8.63 (dd, 4J¼1.4 Hz, 3J¼4.6 Hz, 1H); 13
C
1
NMR (100 MHz, CDCl3) d¼114.6, 127.5, 133.5, 135.9,
85%). H NMR (400 MHz, CDCl3) d¼7.21 (m, 1H), 7.25
137.6, 148.7; IR (KBr) 3437, 3049, 2970, 2238 (CN),
;
(td, J¼7.5 and 1.1 Hz, 1H), 7.38 (dd, 3J¼4.8 Hz,
3J¼7.8 Hz, 1H), 7.41–7.47 (m, 1H), 7.52 (td, J¼7.5 and
1563, 1421, 1062, 1041, 813, 746, 676, 559, 507 cmꢁ1
3
4
mp 84 ꢀC. Anal. Calcd for C6H3ClN2 (%): C, 52.01; H,
2.18; N, 20.22. Found: C, 52.39; H, 1.95; N, 19.98.
1.7 Hz, 1H), 8.02 (dd, J¼7.8 Hz, J¼1.7 Hz, 1H), 8.85
(dd, 3J¼4.8 Hz, 4J¼1.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d¼110.4, 116.3 (d, JC–F¼21 Hz), 116.4, 122.1,
124.5 (d, JC–F¼4 Hz), 125.5 (d, JC–F¼14 Hz), 131.2 (d,
JC–F¼2.5 Hz), 132.1 (d, JC–F¼8 Hz), 140.7, 152.6, 157.3,
159.7 (d, JC–F¼249 Hz); IR (KBr) 3066, 2226 (CN), 1613,
1577, 1556, 1493, 1459, 1433, 1219, 1110, 835, 809, 760,
687, 621, 552 cmꢁ1; mp 76 ꢀC. Lit.7
4.2.2. 4-Chloronicotinonitrile 3c. Starting from 3-cyano-
pyridine and following the general procedure, the product
1
was obtained as a pale yellow powder (0.5 g, 37%). H
NMR (400 MHz, CDCl3) d¼7.51 (d, J¼5.3 Hz, 1H), 8.71
3
3
(d, J¼5.3 Hz, 1H), 8.86 (s, 1H); 13C NMR (100 MHz,
CDCl3) d¼111.4, 113.8, 124.6, 146.5, 153.4, 153.8; IR
(KBr) 3426, 3091, 2926, 2236 (CN), 1572, 1549, 1473,
;
4.3.3. 4-(2-Fluorophenyl)nicotinonitrile 4c. Starting from
3c according to the general procedure and replacing
K3PO4 by CsF (18 mmol, 2.73 g), the product was obtained
as a white powder (1.01 g, 71%). 1H NMR (400 MHz,
CDCl3) d¼7.32 (td, J¼9.0 and 0.8 Hz, 1H), 7.32 (td,
J¼7.6 and 0.8 Hz, 1H), 7.45–7.55 (m, 3H), 8.86 (d,
J¼4.8 Hz, 1H), 9.00 (s, 1H); 13C NMR (100 MHz, CDCl3)
d¼110.1, 115.9, 116.5 (JC–F¼21 Hz), 123.2 (JC–F¼13 Hz),
124.9 (JC–F¼4 Hz), 125.0, 130.6 (JC–F¼2 Hz), 132.2
(JC–F¼7 Hz), 147.1, 152.6, 153.5, 159.1 (JC–F¼249 Hz);
IR (KBr), 3056, 2233 (CN), 1615, 1585, 1474, 1447, 1398,
1257, 1210, 1109, 1040, 846, 826, 775, 756, 620, 587,
551, 529; mp 101 ꢀC. Lit.7
1404, 1291, 1187, 1101, 844, 798, 728, 700, 571, 476 cmꢁ1
mp 86 ꢀC. Anal. Calcd for C6H3ClN2 (%): C, 52.01; H,
2.18; N, 20.22. Found: C, 52.31; H, 2.07; N, 19.93.
4.2.3. 3-Chloroisonicotinonitrile 3d. Starting from 4-cyano-
pyridine and following the general procedure, the product
was obtained as pale orange needles (0.99 g, 75%). 1H
3
NMR (400 MHz, CDCl3) d¼7.56 (d, J¼4.8 Hz, 1H), 8.68
(d, 3J¼4.8 Hz, 1H), 8.82 (s, 1H); 13C NMR (100 MHz,
CDCl3) d¼113.7, 120.9, 126.3, 133.1, 148.1, 150.4; IR
(KBr) 3016, 2953, 2475, 2238 (CN), 1573, 1471, 1401,
1384, 1280, 1162, 1036, 840, 795, 708, 576 cmꢁ1; mp
80 ꢀC. Anal. Calcd for C6H3ClN2 (%): C, 52.01; H, 2.18;
N, 20.22. Found: C, 52.39; H, 2.37; N, 20.32. Lit.14
4.3.4. 3-(2-Fluorophenyl)isonicotinonitrile 4d. Starting
from 3d and following the general procedure, the product
was obtained as a white powder (1.10 g, 77%). H NMR
1
4.3. General procedure for the microwave Suzuki cross-
coupling synthesis of 4a–d and 7
(400 MHz, CDCl3) d¼7.25–7.27 (m, 1H), 7.32 (td, J¼7.5
and 1.1 Hz, 1H), 7.46 (td, J¼7.5 and 1.8 Hz, 1H), 7.49–
7.52 (m, 1H), 7.65 (d, 3J¼5.1 Hz, 1H), 8.80 (d, 3J¼5.1 Hz,
1H), 8.84 (s, 1H); 13C NMR (100 MHz, CDCl3) d¼115.7,
116.4 (d, JC–F¼22 Hz), 120.5, 122.3 (d, JC–F¼15 Hz),
124.7 (d, JC–F¼4 Hz), 125.6, 131.1 (d, JC–F¼2 Hz), 131.8
(d, JC–F¼8 Hz), 133.3, 149.4, 151.6 (d, JC–F¼2 Hz), 159.5
(d, JC–F¼248 Hz); IR (KBr) 3064, 2233 (CN), 1614, 1577,
1500, 1472, 1450, 1402, 1260, 1219, 1199, 1074, 841,
828, 785, 763, 752, 586, 555 cmꢁ1; mp 50 ꢀC. Lit.7
In a microwave vial with a magnetic stir bar was introduced
K3PO4 (18 mmol, 3.8 g), 2-fluorophenylboronic acid
(14 mmol, 2 g), and Pd(PPh3)4 (5%, 0.4 g). The vial was
sealed and purged with argon through the septum inlet. A
solution of orthochlorocyanopyridine 3a–d (7 mmol, 1 g)
in DMF (15 mL) was degassed with argon and added with
a syringe through the vial’s septum. The suspension was
then heated at 150 ꢀC under microwave irradiation for half
an hour. The resulting mixture was poured into 100 mL of
water and extracted three times with EtOAc. The combined
organic layers were dried with MgSO4, filtered, and evapo-
rated. The products were purified by silica gel chromato-
graphy using EtOAc/cyclohexane (1/4) as eluent.
4.3.5. 20-Fluorobiphenyl-2-carbonitrile 7. Starting from 2-
bromobenzonitrile and following the general procedure, the
product was obtained as a white powder (0.92 g, 88%). H
1
NMR (400 MHz, CDCl3) d¼7.19–7.30 (m, 2H), 7.40–7.52
(m, 4H), 7.66 (ddd, J¼8.0, 7.3, and 1.3 Hz, 1H), 7.78
(ddd, J¼7.6, 1.5, and 1.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d¼112.9, 116.2 (d, JC–F¼22 Hz), 118.1, 124.3
(d, JC–F¼4 Hz), 125.8 (d, JC–F¼14.8 Hz), 128.2, 130.8
4.3.1. 3-(2-Fluorophenyl)pyridine-2-carbonitrile 4a.
Starting from 3a and following the general procedure,
the product was obtained as a white powder (0.96 g, 67%).

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T. Cailly et al. / Tetrahedron 62 (2006) 5862–5867
(d, JC–F¼8 Hz), 131.0 (d, JC–F¼2.5 Hz), 131.2 (d, JC–F
3.0 Hz), 132.5, 133.3, 139.6, 159.6 (JC–F¼248 Hz). Lit.6a
¼
3033, 2983, 2873, 1678 (CO), 1604, 1585, 1455, 1406,
1361, 1204, 1151, 884, 762, 731, 711, 668, 617, 496 cmꢁ1
;
mp>260 ꢀC. Anal. Calcd for C12H8N2O (%): C, 73.46; H,
4.4. Synthesis of 3-(2-fluorophenyl)isonicotinamide 6
4.11; N, 14.28. Found: C, 73.19; H, 4.11; N, 14.08. Lit.3a
3-(2-Fluorophenyl)isonicotinonitrile 4d (1 mmol, 0.2 g) and
KOH (5 mmol, 0.28 g) were solubilized in MeOH (5 mL) in
a sealed tube. The mixture was then heated at 65 ꢀC for 24 h.
The resulting solution was poured into 20 mL of water and
extracted three times with EtOAc. The combined organic
layers were dried with MgSO4, filtered, and evaporated.
The crude product was purified by silica gel chromatography
using CH2Cl2/EtOAc (1/1) and EtOAc as eluents to give
3-(2-fluorophenyl)isonicotinamide 6 as a yellow powder
(0.14 g, 65%).1H NMR (400 MHz, CDCl3) d¼5.72 (br s,
1H), 5.98 (br s, 1H), 7.17 (t, J¼8.5 Hz, 1H), 7.26 (t,
J¼7.6 Hz, 1H), 7.37–7.48 (m, 2H), 7.61 (d, 3J¼4.8 Hz,
1H), 8.63 (s, 1H), 8.71 (d, 3J¼4.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d¼116.1 (d, JC–F¼21 Hz), 121.8, 124.0
(d, JC–F¼15 Hz), 124.8 (d, JC–F¼3 Hz), 128.4, 130.8 (d,
4.5.3. 6H-Benzo[c][2,7]naphthyridin-5-one 5c. Starting
from 4c and following the general procedure, the product
was obtained as a white powder (0.46 g, 95%). H NMR
1
(400 MHz, DMSO) d¼7.30 (t, J¼7.1 Hz, 1H), 7.38 (d,
J¼8.2 Hz, 1H), 7.68 (t, J¼7.1 Hz, 1H), 8.41 (d, J¼5.7 Hz,
1H), 8.45 (d, J¼8.2 Hz, 1H), 8.90 (d, J¼5.7 Hz, 1H), 9.41
(s, 1H), 11.94 (br s, 1H); 13C NMR (100 MHz, DMSO)
d¼115.7, 116.1, 116.4, 120.3, 122.6, 124.0, 131.2, 138.2,
140.6, 150.2, 151.8, 160.2; IR (KBr) 3016, 2887, 1682
(CO), 1603, 1476, 1417, 1357, 1180, 1041, 1018, 752,
730, 667 cmꢁ1; mp>260 ꢀC. Anal. Calcd for C12H8N2O
(%): C, 73.46; H, 4.11; N, 14.28. Found: C, 73.36; H,
4.08; N, 14.36. Lit.3a,5
4.5.4. 6H-Benzo[c][2,6]naphthyridin-5-one 5d. Starting
from 4d and following the general procedure, the product
was obtained as a white powder (0.475 g, 98%). H NMR
JC–F¼8 Hz), 131.1 (d, JC–F¼15 Hz), 132.1 (d, JC–F
¼
1
10 Hz), 142.0, 149.8, 151.6, 159.7 (d, JC–F¼247 Hz),
168.5; IR (KBr) 3312 (NH), 3045, 1666 (CO), 1582, 1477,
;
(400 MHz, DMSO) d¼7.30 (t, J¼7.3 Hz, 1H), 7.38 (d, J¼
1451, 1388, 1257, 1203, 1111, 1082, 849, 763, 625 cmꢁ1
8.0 Hz, 1H), 7.54 (t, J¼7.3 Hz, 1H), 8.10 (d, J¼5.1 Hz,
3
mp 174 ꢀC; HRMS/ESI (g molꢁ1) Calcd for C12H10FN2O
[M+H]+ 217.0777; found 217.072.
1H), 8.56 (d, J¼8.0 Hz, 1H), 8.80 (d, 3J¼5.1 Hz, 1H),
9.88 (s, 1H), 12.07 (br s, 1H); 13C NMR (100 MHz,
DMSO) d¼115.7, 116.4, 119.6, 122.8, 123.0, 128.5, 130.4,
130.8, 136.9, 146.5, 147.8, 159.7; IR (KBr) 3024, 2997,
2874, 1669 (CO), 1609, 1549, 1469, 1432, 1411, 1368,
878, 748, 687, 639, 620, 508 cmꢁ1; mp>260 ꢀC. Anal.
Calcd for C12H8N2O (%): C, 73.46; H, 4.11; N, 14.28.
Found: C, 73.13; H, 4.08; N, 13.96.
4.5. General procedure for microwave anionic ring
closure synthesis of 5a–d
A biaryl 4a–d (2.4 mmol, 0.49 g) and KOH (12 mmol,
0.69 g) were solubilized in MeOH (7 mL) in a microwave
vial. The suspension was then heated at 150 ꢀC under micro-
wave irradiation for 10 min. The resulting mixture was
poured into 20 mL of water and extracted three times with
EtOAc. The combined organic layers were dried with
MgSO4, filtered, and evaporated to give analytically pure
products 5a–d.
4.5.5. 5H-Phenanthridin-6-one 8. Starting from 7 and fol-
lowing the general procedure, the product was obtained
as a white powder (0.39 g, 80%). 1H NMR (400 MHz,
DMSO) d¼7.30 (t, J¼7.5 Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H),
7.53 (t, J¼7.5 Hz, 1H), 7.69 (t, J¼7.5 Hz, 1H), 7.90 (t,
J¼7.5 Hz, 1H), 8.37 (d, J¼8.0 Hz, 1H), 8.42 (d, J¼8.0 Hz,
1H), 8.54 (d, J¼8.0 Hz, 1H) 11.73 (br s, 1H); 13C NMR
(100 MHz, DMSO) d¼116.1, 117.5, 122.2, 122.6, 123.2,
125.6, 127.4, 127.9, 129.5, 132.7, 134.2, 136.5, 160.8; IR
(KBr) 3435, 3047, 1663 (CO), 1608, 1557, 1510, 1469,
1424, 1369, 1153, 1037, 943, 748, 726 cmꢁ1; mp>260 ꢀC.
Anal. Calcd for C12H8N2O (%): C, 79.98; H, 4.65; N, 7.17.
Found: C, 79.84; H, 4.52; N, 6.72. Lit.15
4.5.1. 6H-Benzo[f][1,7]naphthyridin-5-one 5a. Starting
from 4a and following the general procedure, the product
was obtained as a white powder (0.46 g, 95%). H NMR
1
(400 MHz, DMSO) d¼7.28 (td, J¼7.3 and 1.2 Hz, 1H),
7.37 (dd, J¼8.2 and 0.7 Hz, 1H), 7.52 (td, J¼8.2 and
1.2 Hz, 1H), 7.83 (dd, 3J¼4.4 Hz, 3J¼8.3 Hz, 1H), 8.40 (d,
4
3
J¼7.3 Hz, 1H), 8.88 (dd, J¼1.5 Hz, J¼4.4 Hz, 1H), 8.95
(dd, 4J¼1.5 Hz, 3J¼8.3 Hz, 1H), 11.97 (br s, 1H); 13C
NMR (100 MHz, DMSO) d¼115.9, 116.5, 122.3, 123.7,
127.0, 130.3, 130.8, 131.4, 136.4, 141.6, 150.1, 159.4; IR
(KBr) 3178, 3127, 3043, 2857, 1677 (CO), 1588, 1549,
Acknowledgements
1460, 1270, 1221, 1158, 867, 809, 160, 751, 671, 629 cmꢁ1
;
´
We thank the Servier Laboratories, The ‘Conseil Regional
mp>260 ꢀC. Anal. Calcd for C12H8N2O (%): C, 73.46; H,
de Basse-Normandie’ and ‘Les Sapins de l’Espoir’ for their
financial support and Dr. R. Legay for helpful discussions in
NMR spectroscopy.
4.11; N, 14.28. Found: C, 73.22; H, 3.85; N, 14.30. Lit.3a
4.5.2. 6H-Benzo[h][1,6]naphthyridin-5-one 5b. Starting
from 4b and following the general procedure, the product
was obtained as a white powder (0.48 g, 99%). H NMR
1
References and notes
(400 MHz, DMSO) d¼7.30 (t, J¼7.3 Hz, 1H), 7.38 (d,
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