Chemoselective cyclization of aminonicotinic acid derivatives to 1,8-napthyridin-2-ones via a potential intramolecular azadiene-ketene electrocyclization reaction

Full text of DOI:10.1021/jo0057553

J . Org. Chem. 2001, 66, 4413-4415
4413
Sch em e 1a
Ch em oselective Cycliza tion of
Am in on icotin ic Acid Der iva tives to
,8-Na p h th yr id in -2-on es via a P oten tia l
In tr a m olecu la r Aza d ien e-Keten e
Electr ocycliza tion Rea ction
1
Alexandros L. Zografos, Christos A. Mitsos, and
Olga Igglessi-Markopoulou*
National Technical University of Athens, Department of
Chemical Engineering, Laboratory of Organic Chemistry,
Zografou Campus, Athens 157 73, Greece
ojmark@orfeas.chemeng.ntua.gr
Received December 1, 2000
1
,8-Naphthyridinones are useful synthetic products
that were found to possess a variety of biological proper-
ties. Two classes of compounds, 1,8-naphthyridin-2-ones
and 1,8-naphthyridin-4-ones, have mainly attracted the
focus of the scientific community due to their unique
1
2
antibacterial, antiinflammatory, antiallergic, and anti-
secretory activities.3
3
-Substituted 1,8-naphthyridin-2-ones have been pre-
pared by treating substituted 2-aminonicotinic acid with
4
ethyl malonyl chloride or by reaction of 2-aminopyridines
5
with malonic esters. Similarly, the preparation of 2,3-
disubstituted 1,8-naphthyridin-4-ones was achieved by
cyclization of the appropriate substituted aminopyridine
derivatives.6
a
Key: (i) t-BuOK, THF.
One of the most common methods is that proposed by
Coppola, which involves reaction of aza-isatoic anhydride
with anions of â-keto esters. Although his method
appears to be general for the preparation of both 1,8-
naphthyridin-2-ones and 1,8-naphthyridin-4-ones, it pre-
sents disadvantages, such as the use of severe reaction
conditions and the formation of unequal amounts of both
products due to the intramolecular nucleophilic attack
of the aromatic amine on both the ester and ketone
carbonyl groups.7
attack by â-keto esters (2) under smooth reaction condi-
tions (Scheme 1).
Unexpectedly, the reaction of these activated systems
with nucleophiles does not give mixture of products in
contrast to Coppola’s method.
Thus, reaction of activated derivatives of aminonico-
tinic acid with 2 equiv of the appropriate â-ketoester
under basic solution of t-BuOK in THF gives only 2-alkyl-
3-alkoxycarbonyl 1,8-naphthyridin-4-one derivatives (4)
in good yields (Scheme 1).
7
In the course of our research on the synthesis of
heterocyclic systems comprising a â-dicarbonyl moiety,
we required a facile route to substituted 1,8-naphthyri-
dinones. To achieve the synthesis of 1,8-naphthyridin-
-ones, we have modified Coppola’s methodology by
Extending this method, we considered a versatile way
of preparing chemoselectively 1,8-naphthyridin-2-one
derivatives. The idea was to modify intermediate C-
acylation compound (I) in order to activate ester carbonyl
moiety.
8
4
making use of two new acylating agents, the N-succin-
imide ester of aminonicotinic acid (1) and azathio isatoic
anhydride (3). Both are excellent activating systems of
the carboxylic acid moiety and susceptible to nucleophilic
Thus, insertion of an electron-withdrawing group in
the amino functionality could give the desired activation
of ester group via a potential formation of a ketene
intermediate (II) (Figure 1).
Preparation of pyrido [2,3-d][3,1] oxazin-4-ones (5)
gives activation on the carboxylic acid moiety and the
desired protection for amino functionality. Reaction of 5
with anions of â-keto esters yields 1,8-naphthyridin-2-
ones (6) in a one-step route (Scheme 2). The protocol used
requires the reaction of 5 with 2 equiv of the anion of
the appropriate â-ketoester, generated with potassium
tert-butoxide. After acidification with 10% hydrochloric
acid, products of type 6 were obtained as pure solids.
The reaction is probably based on the formation of an
azadiene-ketene intermediate (IV), which is cyclized by
an intramolecular electrocyclization reaction. The deter-
minative factor in the formation of IV appears to be the
*
To whom correspondence should be addressed. Tel: +301 7723259,
301 7723074. Fax: +301 7723072.
1) Sherlock, M.; Kaminski, J .; Lee, T.; Wong, S.; Kreutner, W.;
Bryant, R.; McPhail, A. J . Med Chem. 1988, 31, 2108.
2) (a) Kuroda, T.; Suzuki, F. J . Heterocycl. Chem. 1991, 28, 2029.
b) Kuroda, T.; Suzuki, F. J . Med. Chem. 1992, 35, 1130.
3) Santilli, A.; Scotese, A.; Bauer, R.; Bell, S. J . Med. Chem. 1987,
0, 2270.
+
(
(
(
(
3
(
(
(
(
4) Paudler, W.; Kress, T. Adv. Heterocycl. Chem. 1970, 11, 123.
5) Schober, B.; Kappe, T. J . Heterocycl. Chem. 1988, 25, 1231.
6) Paudler, W.; Sheets, R. Adv. Heterocycl. Chem. 1983, 33, 147.
7) Coppola, G.; Fraser, J .; Hardtmann, G.; Shapiro, M. J . Heterocycl.
Chem. 1985, 22, 193.
8) Zografos, A.; Mitsos, C.; Igglessi-Markopoulou, O. Org. Lett. 1999,
, 1953. (b) Mitsos, C.; Zografos, A.; Igglessi-Markopoulou, O. J . Org.
Chem. 2000, 65, 5852.
(
1
1
0.1021/jo0057553 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/17/2001

4
414 J . Org. Chem., Vol. 66, No. 12, 2001
Notes
Ta ble 1. 1,8-Na p h th yr id in -2-on es Obta in ed w ith th e
P r op osed Meth od ology
starting material product method reaction time (h) yield (%)
5
5
5
5
5
5
5
5
5
5
5
5
5
a
a
a
a
a
a
b
b
b
b
b
b
b
6a
6a
6b
6b
6c
6c
6d
6d
6e
6e
6f
A
A
A
A
A
A
A
B
A
B
A
B
A
2
24
2
24
2
24
2
2
2
2
2
2
7
62
8
50
10
53
99
75
98
76
85
80
80
F igu r e 1.
Sch em e 2a
6f
6g
2
Further research on the elucidation of the reaction
mechanism providing chemoselectively 1,8-naphthyridin-
2
-ones is currently carried out in order to confirm the
existence of azadiene-ketene intermediate.
Exp er im en ta l Section
Gen er a l Meth od s. All the commercially available starting
materials were used without further purification. The â-keto
esters used were either purchased from Fluka or prepared by a
literature procedure.9 Commercially available THF was dried
prior to use by refluxing over sodium. Melting points are
uncorrected. Chemical shifts are quoted in ppm and J values in
Hz (t ) triplet, dd ) doublet of doublets, m ) multiplet, br )
broad).
N-Su ccin im id e Ester of Am in on icotin ic Acid (1). To a
solution of 2-aminonicotinic acid (7.2 mmol, 1.00 g) and N-
hydroxysuccinimide (0.014 mol, 1.67 g) in THF (70 mL) was
added DCC (7.2 mmol, 1.49 g), and the mixture was stirred for
2
4 h at room temperature. The mixture was filtered, and the
filtrate was evaporated in vacuo to give the title compound (0.80,
7%). Mp: 167-169 °C. Anal. Calcd for C10 : C, 51.06;
H, 3.86; N, 17.87. Found: C, 51.04; H, 3.84; N, 17.83. H NMR
300 MHz, DMSO-d
4
9 4 3
H O N
1
(
8
6
): δ 2.85 (4H, s), 6.71 (1H, dd, J ) 4, 8),
3
.18 (1H, dd, J ) 2, 8), 8.35 (1H, dd, J ) 2, 4). 1 C NMR (75
6
MHz, DMSO-d ): δ 170.7, 162.0, 160.1, 156.8, 139.9, 112.5, 99.0,
2
5.5.
Aza th ioisa toic An h yd r id e (3). In a dispersion of 2-ami-
nonicotinic acid (0.011 mol, 1.52 g) in carbon tetrachloride was
added thionyl chloride (0.22 mol, 2.61 g), and the mixture was
stirred for 2 h under reflux. The mixture was cooled and
evaporated under vacuo to give the title compound (1.66 g, 82%).
Mp: 192-194 °C. Anal. Calcd for C
N, 16.67; S, 19.04. Found: C, 42.80; H, 2.39; N, 18.91. H NMR
300 MHz, DMSO-d ): δ 6.97 (1H, dd J ) 6, 8), 8.28 (1H, dd J
2, 7), 8.55 (1H, dd J ) 2, 7). C NMR (75 MHz, DMSO-d
δ 112.1, 124.6, 141.6, 147.6, 153.8, 165.8.
6 4 2 2
H O N S: C, 42.86; H, 2.38;
a
Key: (i) method A: t-BuOK, THF; method B: t-BuOK,
1
t-BuOH.
(
)
6
1
3
6
):
substituent bonded on the nitrogen. Powerful electron-
withdrawing groups lead spontaneously to the formation
of IV. 2-Pentylpyrido[2,3-d]oxazin-4-one (5a) gives smaller
yields in contrast to 2-(4-nitrophenyl)pyrido[2,3-d][3,1]-
oxazin-4-one (5b), which is in accordance with the
hypothetical mechanism (Table 1).
In conclusion, we are reporting a synthetic route for
the preparation of 1,8-naphthyridin-4-ones based on the
reaction of two new acylating agents with â-ketoesters
under smooth reaction conditions. The proposed meth-
odology leads to the formation of pure 1,8-naphthyridin-
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr id o[2,3-
d ][3,1]oxa zin -4-on es (5a ,b). A solution of 2-aminonicotinic acid
(0.011 mol) in pyridine (20 mL) was cooled at 0 °C, and the
appropriate acid chloride (0.011 mol) was added dropwise over
a period of 15 min. The reaction mixture was stirred at room
temperature for 1.5 h. The protected aminonicotinic acid was
cyclized either with DCC or with other dehydrating reagents.
2
-P en tylp yr id o[2,3-d ][3,1]oxa zin -4-on e (5a ). A mixture of
2
1
-aminonicotinic acid (0.011 mol, 1.52 g), pyridine-benzene (1:
, 40 mL), and caproyl chloride (0.011 mol, 1.51 g) was stirred
for 1.5 h at room temperature. The mixture was quenched with
water, and the organic layer was separated and evaporated in
vacuo. The residue was dried, and its solution in dichlo-
romethane was stirred with an equivalent amount of DCC. The
mixture was stirred for 24 h at room temperature and filtered.
The filtrate was evaporated in vacuo to give the title compound
4
-ones without byproducts formed through the alternate
nucleophilic attack of aromatic amine to the esteric
carbonyl moiety. In our attempt to synthesize 1,8-
naphthyridin-2-ones, we have designed and applied a
new method involving a potential intramolecular elec-
trocyclization reaction of an azadiene-ketene intermedi-
ate. By this methodology, the chemoselective preparation
of 1,8-naphthyridin-2-ones is feasible in high yields.
(
1
1.61 g, 67%). Anal. Calcd for C12
2.84. Found: C, 66.08; H, 6.49; N, 12.80. H NMR (300 MHz,
14 2 2
H N O : C, 66.03; H, 6.47; N,
1
(
9) Oikawa, Y.; Yoshioka, K.; Sugano, K.; Yonemitsu, O Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p 359.

Notes
CDCl
J . Org. Chem., Vol. 66, No. 12, 2001 4415
3
): δ 0.90 (3H, t, J ) 8), 1.37 (4H, m), 1.87 (2H, qt, J ) 8),
.76 (2H, t, J ) 8), 7.47 (1H, dd, J ) 3, 7), 8.50 (1H, dd, J ) 2,
): δ 175.1,
To a solution of potassium tert-butoxide (4.5 mmol) in anhydrous
THF (25 mL) (method A) or in anhydrous t-BuOH (method B)
was added dropwise the appropriate â-keto ester 2 (4.5 mmol),
and after the mixture was stirred at room temperature for 30
min a clear solution resulted. The activated derivative of
aminonicotinic acid (1, 3, or 5) (2.2 mmol) was added at once in
the solution, and the mixture was stirred for 2 h (or 24 h for
2
5
1
1
), 8.96 (1H, dd, J ) 2, 5). 13C NMR (75 MHz, CDCl
67.7, 151.2, 145.2, 144.7, 118.6, 117.3, 38.1, 31.0, 24.5, 22.1,
3.6.
3
2
-(4-Nitr op h en yl)p yr id o[2,3-d ][3,1]oxa zin -4-on e (5b). A
mixture of 2-aminonicotinic acid (0.011 mol, 1.52 g), pyridine
20 mL), and 4-nitrobenzoyl chloride (0.011 mol, 2.04 g) was
(
4
a -c or 6a -c) and then quenched with water (10 mL). The
stirred for 1.5 h at room temperature. Benzoyl chloride (0.011
mol,1.54 g) was then added to the mixture and stirring continued
at room temperature for 1 h. The mixture was quenched with
water, filtered, and washed with water to give the title compound
mixture was concentrated in a rotary evaporator, and the aquatic
residue was washed with ether (5 mL). The aqueous solution
was acidified with 10% hydrochloric acid under cooling in an
ice-water bath to obtain the product in a solid form.
(
5
7 4 3
1.90 g, 64%). Mp: 235-237 °C. Anal. Calcd for C13H O N : C,
1
8.00; H, 2.62; N, 15.61. Found: C, 57.99; H, 2.62; N, 15.63. H
NMR (300 MHz, CDCl
(
NMR (75 MHz, CDCl ): δ 158.7, 158.0, 157.3, 150.9, 138.2, 135.1,
3
3
): δ 7.58 (1H, dd, J ) 3, 7), 8.40-8.60
4H, m), 8.61 (1H, dd, J ) 2, 5), 9.08 (1H, dd, J ) 2, 5). 13
Ack n ow led gm en t. We thank the Research Com-
mittee of the National Technical University of Athens
for a doctoral assistantship (A.L.Z.).
C
1
30.1, 129.1, 124.6, 124.1, 113.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,8-Na p h th y-
r id in -4-on es (4a -c) a n d 1,8-Na p h th yr id in -2-on es (6a -g).
J O0057553