A general synthesis of 8-hydroxy-6-substituted-1,7-naphthyridines

Article abstract of DOI:10.1002/jhet.5570430648

A general method for the synthesis of 8-hydroxy-6-substituted-1,7- naphthyridines is described using acylation of the dianion derived from tert-butylamide 1, followed by cyclization of the resulting intermediate ketones 2 with ammonium acetate.

Full text of DOI:10.1002/jhet.5570430648

Nov-Dec 2006
1725
A General Synthesis of 8-Hydroxy-6-substituted-1,7-naphthyridines
Xinglong Jiang, Guang-Pei Chen, Kapa Prasad,* Oljan Repiꢀ and Thomas J. Blacklock
Process Research & Development, Novartis Pharmaceuticals Corporation,
One Health Plaza, East Hanover, New Jersey 07936, USA
Received March 17, 2006
R
O
CH3
R
NH4OAc
LDA / -40 °C
RCO2Me
H
N
H
N
N
N
N
HOAc
110 °C
N
O
OH
O
1
2a-2f
3a-3f
A general method for the synthesis of 8-hydroxy-6-substituted-1,7-naphthyridines is described using
acylation of the dianion derived from tert-butylamide 1, followed by cyclization of the resulting
intermediate ketones 2 with ammonium acetate.
J. Heterocyclic Chem., 43, 1725 (2006).
The discovery of 1,7-naphthyridines as a novel class of
methylpyridine was converted initially to tert-
butylamide 1 via a Ritter reaction using tert-butyl
alcohol and sulfuric acid. The dianion of 1 formed
by treating with n-butyllithium was effectively
alkylated with m-chlorobenzyl chloride in very high
yield. Taking advantage of this finding we extended
the scope of this anion chemistry to acylations, and
the results obtained led to a general synthesis of 8-
hydroxy-6-substituted-1,7-naphthyridines that are
reported in this communication.
potent phosphodiesterase type 4 inhibitors [1] created
much interest in finding facile methods for preparing
these compounds. As the interest in this class of hetero-
cycles is rather new, not many methods are described in
the literature. One of the methods [1] started from 3-
pyridylacetonitrile-N-oxide employing trimethylsilyl-
cyanide and diethylcarbamyl chloride as reagents
(Scheme 1) to make the desired compounds. The workup
is tedious and the yields are low.
Following the literature procedure, 2-cyano-3-
methylpyridine was converted to tert-butylamide 1 in
92% yield using tert-butyl alcohol and sulfuric acid.
The dianion of 1 was readily prepared by adding 1 in
THF to freshly prepared LDA (prepared by adding n-
butyllithium to diisopropylamine in THF at ꢀ20 °C) at
Scheme 1
NH2
CN
CN
CN
Further
manipulations
N
N+
N
N
-
O
Br
Another method [2] that was tried starting from the
Scheme 3
easily available 2-cyano-3-methylpyridine is shown in
Scheme 2. Here the 8-hydroxy-1,7-naphthyridine was
prepared through the intermediacy of the corresponding
enamine, and the yield of the final product was only 5%
overall.
R
O
CH3
R
NH4OAc
LDA/-40 °C
RCO2Me
H
N
CH3
CH3
CH3
H
N
HOAc
110 °C
N
CH3
CH3
CH3
N
N
N
O
OH
3a-3f
O
1
2a-2f
Scheme 2
R
CH3
CH3
CH3
CN
ꢀ40 to ꢀ50 °C. Treatment of dianion of 1 with different
methyl esters followed by work up afforded the desired
functionalized ketones 2a-2f in good yields (Scheme
3). Theoretically, 2 equiv of LDA are needed for the
formation of dianion of 1, however, since the acylated
products 2a-2f are more acidic than 1, 2.3 equiv of
LDA were used in the reaction to avoid quenching of
the intermediate dianion of 1. As can be seen in the
Table, under these reaction conditions, the acylated
products 2a-2f were obtained in good yield.
N
N
OH
N
N
N
CN
The ready availability of 2-cyano-3-methyl-
pyridine made us think of different options for
transforming this material to the 1,7-naphthyridine
system. In this connection, the synthesis used in the
production of loratadine (a tricyclic antihistamine)
[3] became quite handy to us. Here the 2-cyano-3-

1726
X. Jiang, G.-P. Chen, K. Prasad, O. Repiꢀ and T. J. Blacklock
Vol 43
Table
3a and 3b an extractive work up with methylene chloride
was found to be necessary. The overall yield of 3 starting
from 1 was in the range of 52% to 84%.
Yields of the Products
Compound
R
Yield (%)
For the sake of clarity, the 8-hydroxynaphthyridine
structure was proposed for 3a-3f. It is quite possible that
they exist in the corresponding lactam form as shown in
Scheme 5. For 3c and 3e we did study the structure in
solution by NMR. However, proton NMR in DMSO did
not give any conclusive evidence. By using 1H-15N
HMBC, the two forms can be distinguished. For
compound 3e (R = phenyl), the hydroxy proton at 11.8
ppm shows multiple-bond coupling to N-a at 156 ppm,
which clearly supports the enol form A. Also the H at
position 5 shows HMBC correlations to N-a. N-b was
observed at 315 ppm with HMBC correlations from H-3
No.
a
b
c
d
Product 2
Product 3
methyl
ethyl
isopropyl
cyclohexyl
phenyl
65
78
75
78
84
88
80
86
85
89
93
96
e
f
4-pyridinyl
It is worth noting that in the case of the condensation of
the dianion of 1 with methyl acetate, a byproduct (15% by
HPLC) was observed in addition to the desired 2a (65%
isolated yield). Based on LC-MS data this byproduct was
assigned the structure shown in the Figure,
1
and H-2. Whereas for compound 3c (R = isopropyl), H-
15N HMBC indicated one bond coupling (J = 88 Hz) from
N-a-H at 11.45 ppm to N-a at 160 ppm confirming the
lactam form in solution.
Figure
HO
N
N
Scheme 5
N
O
O
H
N
4
5
H
R
R
3
2
N
NH
a
resulting from further condensation of the product with
the starting anion of 1. With other methyl esters the
corresponding byproduct was not observed.
N
N
OH
b
O
B
A
The cyclization of 2a-2f was extensively investigated
and several reagents were tried. When 2d was treated
with 85% H3PO4 at 100 °C, the desired 3d was formed in
59% yield along with lactone 4 in 41% yield (Scheme 4).
With POCl3 at 105 °C, 5 was the major product (87%
yield), and lactone 4 was the minor product. However,
with 10 equiv of ammonium acetate in acetic acid at 108
°C for 5 h, 2d was quantitatively converted to the desired
3d, and it was isolated by quenching the reaction mixture
with water followed by filtration. Compounds 3c, 3e and
3f were also isolated in a similar fashion. In the case of
In conclusion, we have developed a simple and practical
synthetic route to 8-hydroxy-6-substituted-1,7-naphthy-
ridines starting from inexpensive raw materials.
EXPERIMENTAL
All chemicals were obtained from commercial suppliers and
used without further purification. 1H and 13C NMR spectra were
recorded at 500 or 300 ND at 125 and 75 MHz respectively.
Proton and carbon chemical shifts are expressed in ppm relative
Scheme 4
100 °C
H3PO4
+
NH
O
O
N
N
N
O
O
3d
4
O
105 °C
POCl3
+
N
N
H
N
O
O
N
O
5
4
2d
108 °C
NH
NH4OAc
N
O
3d

Nov-Dec 2006
A General Synthesis of 8-Hydroxy-6-substituted-1,7-naphthyridines
1727
to internal tetramethylsilane; coupling constants
expressed in Hertz. Melting points were measured on a Büchi
535 melting point apparatus.
(J) are
Anal. Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.63; H, 8.72; N, 9.36.
N-(1,1-Dimethylethyl)-3-[2-oxo-2-phenylethyl]-2-pyridinecar-
boxamide (2e).
Representative Procedure for 2.
A 100-mL flask was charged with 69 mmol of triethylamine
in 48 mL of anhydrous THF. The resulting solution was cooled
to ꢀ20 to ꢀ30 °C, and 34.5 mL of 2 M n-BuLi in hexanes was
slowly added while maintaining the temperature. Stirring was
continued for 30 min followed by cooling to ꢀ40 to ꢀ55 °C. A
solution containing 30 mmol of 1 in 30 mL of anhydrous THF
was slowly added while keeping the temperature below ꢀ40 °C.
After 30 min at this temperature, a solution containing 31.5
mmol of methyl ester substrate in 10 mL of anhydrous THF was
added fast. The reaction mixture was stirred for 30 min followed
by quenching with 10 mL of saturated ammonium chloride and
30 mL of water. The crude mixture was extracted with 60 mL of
ethyl acetate, and the organic layer was dried over MgSO4. The
evaporation of organic solvent afforded the desired 2, which can
be further purified by either by recrystallization or column
chromatography on silica gel as needed.
1H NMR (CDCl3): ꢀ 1.410 (s, 9 H), 4.97 (s, 2 H), 7.36 (dd, J
= 4.7 Hz, 7.7 Hz, 1 H), 7.47 (m, 2 H), 7.56 (m, 2 H), 7.99 (b, 1
H), 8.05 (m, 2 H), 8.47 (dd, J = 4.6 Hz, 1.5 Hz, 1 H); 13C NMR
(CDCl3) ꢀ 29.05, 43.56, 51.17, 125.68. 128.70, 128.93, 131.86,
133.34, 137.58, 141.48, 146.70, 149.47, 165.50, 197.44; MP:
106-107 °C; MS (M+H+): m/z 297.
Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45.
Found: C, 73.13; H, 7.09; N, 9.40.
N-(1,1-Dimethylethyl)-3-[2-oxo-(4-pyridinyl)-ethyl]-2-pyridine-
carboxamide (2f).
1H NMR (CDCl3): ꢀ 1.39 (s, 9 H), 4.86 (s, 2 H),), 7.39 (dd, J
= 4.7 Hz, 7.7 Hz, 1 H), 7.58 (dd, J = 1.7 Hz, 7.7 Hz, 1 H), 7.84
(dd, J = 1.5 Hz, 4.4 Hz, 2 H), 8.06 (brs, 1 H), 8.49 (dd, J = 1.7
Hz, 4.7 Hz, 1 H), 8.82 (dd, J = 1.5 Hz, 4.5 Hz, 2 H), 11.97 (brs,1
H); 13C NMR (CDCl3) ꢀ 29.01, 44.21, 51.17, 121.71, 125.87,
130.92, 141.82, 143.86, 147.11, 148.96, 151.19, 165.17, 197.02;
mp: 133.5-134.6 °C; MS (M+ H+): m/z 298.
N-(1,1-Dimethylethyl)-3-(2-oxopropyl)-2-pyridine-carboxamide (2a).
1H NMR (CDCl3): ꢀ 1.40 (s, 9 H), 2.32 (s, 3 H), 4.28 (s, 2
H), 7.32 (m, 1 H), 7.47 (m, 1 H), 8.03 (s, 1 H), 8.42 (m, 1 H);
Anal. Calcd for C17H19N3O2: C, 68.67; H, 6.44; N, 14.13.
Found: C, 68.64; H, 6.25; N, 14.12.
13C NMR (CDCl3)
ꢀ
29.08, 30.58, 48.38, 51.12, 125.77,
Representative Procedure for 3.
131.68, 141.78, 142.88, 146.78, 148.39, 165.30; MP: 78-79 °C;
MS (M+H+): m/z 235.
Anal. Calcd for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96.
Found: C, 66.47; H, 7.76; N, 11.76.
A 100-mL flask was charged with 10 mmol of 2, 7.7 g of
ammonium acetate and 10 mL of acetic acid. The resulting
suspension was heated to 108 °C and stirred at this temperature
for 8 h. The reaction was monitored by HPLC, and after the
reaction was completed, 10 mL of water was added, and the pH
of the reaction mixture was adjusted to 6-7 by adding 1 N NaOH
solution. If solids precipitated out, the desired product 3 was
collected by filtration, washed and dried in the oven. If the
desired product 3 was not precipitated, the reaction mixture was
extracted with CH2Cl2, followed by drying of the organic phase
and evaporation to dryness to afford 3, which can be further
purified by recrystallization.
N-(1,1-Dimethylethyl)-3-(2-oxobutyl)-2-pyridine-carboxamide (2b).
1H NMR (CDCl3): ꢀ 1.09 (t, J = 3.54 Hz, 3 H), 1.44 (s, 9 H),
2.66 (q, J = 7.35 Hz, 2 H), 4.26 (s, 2 H), 7.32 (dd, J = 5.3 Hz,
6.21 Hz, 1 H), 7.48 (dd, J = 6.21 Hz, 1.5 Hz, 1 H), 7.99 (brs, 1
H), 8.24 (dd, J = 5.3 Hz, 3.0 Hz, 1 H); 13C NMR (CDCl3)
ꢀ
8.10, 29.03, 36.36, 47.24, 51.08, 125.7, 131.8, 141.8, 146.6,
149.0, 165.4, 208.4; MP: 62-63 °C; MS (M+H+): m/z 249.
Anal. Calcd for C14H20N2O2: C, 67.71; H, 8.12; N, 11.28.
Found: C, 67.50; H, 8.40; N, 11.03.
8-Hydroxy-6-methyl-1,7-naphthyridine (3a).
1H NMR (CDCl3): ꢀ 2.240 (s, 3 H), 6.308 (s, 1 H), 7.672 (m,
1 H), 7.979 (m, 1 H), 8.694 (m. 1 H), 11.561 (brs, 1 H); 13C
NMR (CDCl3) ꢀ 19.8, 103.58, 127.18, 134.33, 135.36, 140.33,
140.48, 149.21, 164.43; MP: 233-234 °C; MS (M+H+): m/z
161.
N-(1,1-Dimethylethyl)-3-(2-oxo-3-methylbutyl)-2-pyridinecar-
boxamide (2c).
1H NMR (CDCl3): ꢀ 1.17 (d, J = 6.96 Hz, 6 H), 1.43 (s, 9 H),
2.90 (p, J = 6.96 Hz, 1 H), 4.36 (s, 2 H), 7.32 (dd, J = 4.7 Hz, 6.2
Hz, 1 H), 7.48 (dd, J = 6.21 Hz, 1.50 Hz, 1 H), 7.93 (s, 1 H),
8.42 (dd, J = 4.7 Hz, 1.5 Hz, 1 H); 13C NMR (CDCl3) ꢀ 18.24,
28.66, 40.86, 45.20, 50.75, 125.2, 131.6, 141.4, 146.1, 148.8,
165.0, 211.5; MP: 90-91 °C; MS (M+H+): m/z 263.
Anal. Calcd for C9H8N2O: C, 67.49; H, 5.03; N, 17.49.
Found: C, 67.21; H, 5.14; N, 17.29.
8-Hydroxy-6-ethyl-1,7-naphthyridine (3b).
Anal. Calcd for C15H22N2O2: C, 68.67; H, 8.45; N, 10.68.
Found: C, 68.84; H, 8.31; N, 10.71.
1H NMR (DMSO): ꢀ 1.21 (t, J = 7.53 Hz, 3 H), 2.52 (q, J =
7.53 Hz, 2 H), 6.33 (s, 1 H), 7.62 (dd, J = 4.32 Hz, 6.42 Hz, 1 H),
8.01 (dd, J = 1.68 Hz, 4.32 Hz, 1 H), 11.52 (brs, 1 H); 13C NMR
(DMSO) ꢀ 12.98, 25.79, 100.08, 127.07, 134.52, 134.89, 140.81,
145.51, 148.41, 161.58; MP: 188-189 °C; MS (M+H+): m/z 175.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08.
Found: C, 68.87; H, 5.72; N, 16.11.
N-(1,1-Dimethylethyl)-3-[2-oxo-2-cyclohexylethyl]-2-pyridine-
carboxamide (2d).
1H NMR (CDCl3): ꢀ 1.30 (m, 5 H), 1.4 (s, 9 H), 1.68 (m, 1
H), 1.80 (m, 2 H), 1.98 (m, 2 H),2.61 (m, 1 H), 4.36 (s, 2H),
7.31 (m, 1 H), 7.46 (dd, J = 1.5 Hz, 7.3 Hz, 1 H), 7.93 (brs, 1 H),
8.41 (dd, J = 1.7 Hz, 4.6 Hz, 1 H); 13C NMR (CDCl3) ꢀ 26.07,
26.32, 28.82, 29.05, 45.74, 51.00, 51.12, 125.59, 131.97, 141.79,
146.51, 149.30, 165.47, 210.82. MP: 99-100 °C; MS (M+H+):
m/z 303.
8-Hydroxy-6-isopropyl-1,7-naphthyridine (3c).
1H NMR (DMSO): ꢀ 1.24 (d, J = 6.96 Hz, 6 H), 2.81 (p, J =
6.96 Hz, 1 H), 6.36 (s, 1 H), 7.62 (dd, J = 4.32 Hz, 8.10 Hz, 1

1728
X. Jiang, G.-P. Chen, K. Prasad, O. Repiꢀ and T. J. Blacklock
Vol 43
126.02, 128.45, 129.06, 132.60, 133.49, 133.78, 139.72, 140.17,
148.44, 161.44; MP: 238-240 °C; MS (M+ H+): m/z 223.
Anal. Calcd for C14H10N2O: C, 75.66; H, 4.54; N, 12.60.
Found: C, 75.52; H, 4.51; N, 12.57.
H), 8.04 (dd, J = 8.10 Hz, 1.5 Hz, 1 H), 8.69 (dd, J = 4.32 Hz,
1.5 Hz, 1 H), 11.50 (s, 1 H); 13C NMR (DMSO)
31.37, 98.38, 127.27, 134.74, 134.85, 140.87, 148.49, 149.58,
161.69; MP: 245-246 °C; MS (M+H+): m/z 189.
Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88.
Found: C, 70.31; H, 6.53; N, 15.00.
ꢀ 21.59,
8-Hydroxy-6-(4-pyridinyl)-1,7-naphthyridine 3f.
1H NMR (DMSO): ꢀ 7.16 (s, 1 H), 7.75 (dd, J = 4.3 Hz, 7.9
Hz, 1 H), 7.84 (d, J = 5.8 Hz, 2 H), 8.20 (d, J = 8.1Hz, 1 H), 8.72
(d, J = 5.8 Hz, 2 H), 8.83 (d, J = 3.0 Hz, 1 H), 11.96 (brs, 1 H);
13C NMR (DMSO) ꢀ 103.93, 121.21, 127.54, 134.07, 135.81,
138.47, 140.69, 141.96, 150.01, 150.54, 161.60; MP: >250 °C;
MS (M+H+): m/z 224.
8-Hydroxy-6-cyclohexyl-1,7-naphthyridine (3d).
1H NMR (DMSO): ꢀ 1.22 (m, 1 H), 1.38 (m. 5 H), 1.69 (m,
1 H), 1.78 (m, 2 H), 1.99 (m, 2 H), 2.54 (m, 1 H), 6.18 (s, 1 H),
6.44 (dd, J = 4.3 Hz, 8.1 Hz, 1 H), 7.77 (dd, J = 1.5 Hz, 7.2 Hz,
1 H), 8.74 (dd, J = 1.7 Hz, 4.3 Hz, 1 H), 10.156 (brs, 1 H); 13C
Anal. Calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82.
Found: C, 69.78; H, 4.09; N, 18.93.
NMR(DMSO)
ꢀ 25.01, 27.66, 31.07, 40.62, 99.10, 125.68,
133.24, 133.83, 139.76, 147.00, 147.49, 162.00; MP: >250 °C;
MS (M+ H+): m/z 229.
Anal. Calcd for C14H16N2O: C, 73.66; H, 7.06; N, 12.27.
Found: C, 73.49; H, 7.29; N, 12.17.
REFERENCES
[1] R. Hersperger, K. Bray-French, L. Mazzoni, T. Muller. J.
Med. Chem., 43, 675-682 (2000).
8-Hydroxy-6-phenyl-1,7-naphthyridine 3e.
[2] J. J. Baldwin, K. Mensler, G. S. Ponticello. J. Org. Chem.,
43, 4878 (1978).
[3] D. P. Schumacher, B. L. Murphy, J. E. Clark, P. Tahbaz, T.
A. Mann. J. Org. Chem., 54, 2242 (1989).
1H NMR (DMSO): ꢀ 6.64 (s, 1 H), 7.46 (m, 4 H), 7.65 (m,
2H), 7.88 (dd, J = 1.5 Hz, 8.2 Hz, 1 H), 8.78 (dd, J = 1.5 Hz, 5.4
Hz, 1 H), 1.15 (brs, 1 H); 13C NMR (DMSO) ꢀ 101.50, 125.09,