A convenient route to cyano derivatives of benzonaphthyridines

Article abstract of DOI:10.1007/s10593-011-0761-9

A smooth synthesis of benzo[c][1,5]naphthyridine-6-carbonitrile and benzo[h][1,6]naphthyridine-5-carbonitrile, starting from benzonaphthyridine N-oxides, is achieved by treatment with trimethylsilane carbonitrile (Me3SiCN) in CH2Cl2 at 0-5 °C. The resulting nitriles are then hydrolyzed to the corresponding acids by boiling in aqueous alkali.

Full text of DOI:10.1007/s10593-011-0761-9

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
A CONVENIENT ROUTE TO CYANO DERIVATIVES
OF BENZONAPHTHYRIDINES
1
B. Bachowska *
A smooth synthesis of benzo[c][1,5]naphthyridine-6-carbonitrile and benzo[h][1,6]naphthyridine-
5
-carbonitrile, starting from benzonaphthyridine N-oxides, is achieved by treatment with trimethylsilane
o
carbonitrile (Me SiCN) in CH Cl at 0–5 C. The resulting nitriles are then hydrolyzed to the
3
2
2
corresponding acids by boiling in aqueous alkali.
Keywords: benzonaphthyridine N-oxides, carbonitriles, carboxylic acids, cyanation.
A number of rearrangements starting with N-oxides may be used as convenient methods for the
introduction of substituents into aza-aromatic systems [1–4].
Most of these reactions involve addition of an A=B fragment to an equivalent of nitrone function to give
the structure 1 (possibly via 1,3-dipolar addition) followed by N–O bond cleavage and rearrangement of the
products thus formed.
+
N
H
N
products
O
A
A
B
O
B
1
The application of benzonaphthyridine N-oxides 2 and 3 for this purpose has been only rarely described.
It was found that the reactions of benzonaphthyridine N-oxides with phenyl isocyanate lead to
anilinobenzonaphthyridine [5]. Moreover, it has also been reported that benzonaphthyridine N-oxides with
chloromethyl-, phenyl-, and 4-tolylsulfone, chloro- and bromomethanesulfomorpholide, and neopentyl
chloromethanesulfonate undergo vicarious nucleophilic substitution of hydrogen, which offers another attractive
methodology for the introduction of substituents into benzonaphthyridine rings [6, 7].
In this paper, the cyanation of benzo[c][1,5]- and benzo[h][1,6]naphthyridines at C(6) and C(5),
respectively, is reported, starting with the corresponding benzonaphthyridine 5- and 6-oxides. The resulting
nitriles were then hydrolyzed to the corresponding acids.
_
*
______
To whom correspondence should be addressed, e-mail: b.bachowska@ajd.czest.pl.
1
Institute of Chemistry, Environmental Protection, and Biotechnology, Jan Długosz University, 13/15 Armii
Krajowei Ave, Częstochowa 42-200, Poland.
_
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, 406-409, March, 2011. Original article
received December 14, 2010. Revised version received January 12, 2011.
32 0009-3122/11/4703-0332©2011 Springer Science+Business Media, Inc.
3

In recent years, synthetic methods for the formation of C–C bonds using silanes have been studied
extensively [8–11]. Fundamental work by Vorbrüggen on the cyanation of N-oxides of 6-membered
heterocycles using Me SiCN has opened new perspectives for the synthesis of cyano derivatives [12].
3
Following the methodology for cyanation of 2-unsubstituted 1H-imidazole 3-oxides [11], the solutions
of benzo[c][1,5]naphthyridine 5-oxide (2) and benzo[h][1,6]naphthyridine 6-oxide (3) in dry CH Cl in the
2
2
presence of Et N were treated with Me SiCN. The temperature of the mixture was kept at 0–5°C, and the
3
3
progress of the reaction was followed by TLC. After 2 h in the case of compound 2 and 6 h in the case of
compound 3, the starting material was consumed. After chromatographic workup, benzo[c][1,5]naphthyridine-
6
-carbonitrile (4) and benzo[h][1,6]naphthyridine-5-carbonitrile (5) were obtained in good yields.
Y
Y
Y
X
X
X
Me SiCN
3
+
N
+
N
H
Et N
3
–
N
CN
CN
OSiMe3
CH Cl2
2
O
OSiMe3
2
, 3
A
B
Y
Y
1
. aq. NaOH
X
X
2
. HCl
N
COOH
N
CN
6
, 7
4
, 5
2
, 4, 6 X = N, Y= CH; 3, 5, 7 X = CH, Y = N
The reaction mechanism for the formation of compounds 4 and 5 is analogous to that proposed for the
cyanation of azine N-oxides [11, 12]: silylation of the N-oxide leads to the benzonaphthyridinium ion A, which
adds a cyanide ion to give the intermediate B and which, in turn, eliminates Me SiOH.
3
The resulting nitriles 4 and 5 were then hydrolyzed to the corresponding acids 6 and 7 by boiling with
diluted sodium hydroxide and treatment of the resulting salt with diluted hydrochloric acid.
These results illustrate the interesting smooth conversion of benzo[c][1,5]naphthyridine 5-oxide and
benzo[h][1,6]naphthyridine 6-oxide into the corresponding benzonaphthyridine carbonitriles, which readily lead
to benzonaphthyridine carboxylic acids. The described method is highly recommended for the preparation of
benzonaphthyridine derivatives of the type 4–7. For further extension of these procedures and completion of the
series of compounds obtained previously in our laboratory [5–7, 13–17] the conversion of compounds 6 and 7
into functional derivatives of benzonaphthyridine carboxylic acids will be investigated.
EXPERIMENTAL
1
IR spectra were recorded on a Nexus Nicolet FTIR spectrometer in KBr. H NMR spectra were recorded
on a Bruker Avance III WB spectrometer at 400 MHz in CDCl , using TMS as the internal standard. Electron-
3
impact mass spectra were recorded on a AMD-604 instrument at 70 eV. Elemental analysis was performed on a
Perkin-Elmer 2400 CHN elemental analyzer. Melting points were determined on Boëtius apparatus.
3
33

3
The synthesis and properties of the N-oxides 2 and 3 have been described previously [18]. Me SiCN is a
commercial reagent (Aldrich) distilled prior to use and stored in refrigator.
Cyanation of Benzonaphthyridine N-oxides (General Method). To the solution of compound 2 or 3
(
392 mg, 2 mmol) in dry CH Cl (10 ml) freshly activated molecular sieves (4 Å, 200 mg) were added. The
2
2
mixture was stirred in a 50 ml flask closed with septum at room temperature for 1 h and then placed in a
water/ice cooling bath. Subsequently, a solution of Me SiCN (398 mg, 0.52 ml, 4 mmol) and Et N (303 mg,
3
3
0
.42 ml, 3 mmol) in CH Cl (3 ml) was slowly added through the septum using a syringe. The stirring was
2 2
continued for 2 h (compound 2) or 6 h (compound 3) at 0–5°C. Then the brown mixture was diluted with CH Cl
2
2
(
20 ml) and extracted with H O (4  30 ml), the organic layer was dried (MgSO ) and the solvent was evaporated.
2
4
The crude products were purified by column chromatography using dichloromethane as eluent, followed by
recrystallization from benzene.
Benzo[c][1,5]naphthyridine-6-carbonitrile (4). Yield 300 mg (73%); mp 154-155°C. IR spectrum, ,
cm : 2215 (C≡N). H NMR spectrum, δ, ppm (J, Hz): 8.92 (1H, dd, J = 7.8, J = 1.7, H-10); 8.77-8.71 (2H, m,
-
1
1
H-2,4); 8.51 (1H, dd, J = 8.4, J = 1.25, H-7); 7.95 (1H, dd, J = 8.4, J = 6.9, H-8); 7.85 (1H, dd, J = 8.3, J = 4.15,
+
+
H-3); 7.70 (1H, dd, J = 7.8, J = 6.9, H-9). Mass spectrum, m/z (I , %): 205 [M] (100), 178 [M–HCN] (15).
rel
Found, %: C 76.20; H 3.45; N 20.35. C H N . Calculated, %: C 76.09; H 3.43; N 20.47.
13
7
3
Benzo[h][1,6]naphthyridine-5-carbonitrile (5). Yield 307 mg (75%); mp 165–166°C (mp
-
1
1
1
63-164.5°C [19]). IR spectrum, , cm : 2231 (C≡N). H NMR spectrum, δ, ppm (J, Hz): 9.27 (1H, dd, J = 4.4,
J = 1.8, H-2); 9.19 (1H, dd, J = 8.1, J = 1.65, H-10); 8.71 (1H, dd, J = 8.25, J = 1.8, H-4); 8.29 (1H, dd, J = 8.4, J
+
=
(
1.8, H-7); 7.98-7.89 (2H, m, H-8,9); 7.79 (1H, dd, J = 8.25, J = 4.4, H-3). Mass spectrum, m/z (I , %): 205 [M]
rel
+
100), 178 [M-HCN] (12). Found, %: C 75.98; H 3.40; N 20.23. C H N . Calculated, %: C 76.09; H 3.43; N
13 7 3
2
0.47.
Hydrolysis of Benzonaphthyridine Carbonitriles (General Method). Compound 4 or 5 (300 mg,
.5 mmol) was stirred and heated at 100°C in aqueous sodium hydroxide (6 ml, conc. 20%) for 6 h. After
1
cooling to room temperature, the precipitated salt was filtered off, and the aqueous phase was washed with ethyl
ether and then acidified with diluted hydrochloric acid (conc. HCl–water, 1:1) to pH ~4. The precipitated pale-
yellow crystals were separated and recrystallized from benzene.
Benzo[c][1,5]naphthyridine-6-carboxylic Acid (6). Yield 237 mg (72%); mp 191-192°C. IR spectrum,
, cm : 3000 (O–H), 1690 (C=O), 1264 (C–O), 920 (O–H). H NMR spectrum, δ, ppm (J, Hz): 10.50 (1H, s,
-
1
1

COOH); 9.05 (1H, dd, J = 4.45, J = 1.8, H-2); 8.60 (1H, dd, J = 7.9, J = 1.8, H-10); 8.43 (1H, dd, J = 8.45,
J = 1.3, H-7); 8.30 (1H, dd, J = 8.35, J = 1.8, H-4); 7.82 (1H, dd, J = 8.45, J = 6.9, H-8); 7.72 (1H, dd, J = 4.45,
+
J = 8.35, H-3); 7.58 (1H, dd, J = 7.9, J = 6.9, H-9). Mass spectrum, m/z (I , %): 224 [M] (100), 179
rel
+
[
M-COOH] (15). Found, %: C 69.46; H 3.42; N 12.37. C H N O . Calculated, %: C 69.64; H 3.60; N 12.49.
1
3
8
2
2
Benzo[h][1,6]naphthyridine-5-carboxylic Acid (7). Yield 229 mg (70%); mp 185–187°C. IR spectrum,
, cm : 2890 (O–H), 1680 (C=O), 1307, 1263 (C–O), 940 (O–H). H NMR spectrum, δ, ppm (J, Hz): 10.31 (1H, s,
-1
1

COOH); 9.69 (1H, dd, J = 8.25, J = 1.35, H-10); 9.12 (1H, dd, J = 4.75, J = 1.75, H-2); 8.69 (1H, dd, J = 8.1, J =
1
.4, H-7); 8.47 (1H, dd, J = 8.45, J = 1.75, H-4); 8.01 (1H, dd, J = 8.25, J = 6.9, H-9); 7.69 (1H, dd, J = 4.75, J =
+
+
8.45, H-3); 7.54 (1H, dd, J = 6.9, J = 8.1, H-8). Mass spectrum, m/z (I , %): 224 [M] (100), 179 [M-COOH] (17).
rel
Found, %: C 69.37; H 3.48; N 12.35. C H N O . Calculated, %: C 69.64; H 3.60; N 12.49.
13
8
2
2
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