Synthesis of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines

Article abstract of DOI:10.1016/j.tet.2009.07.024

A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former step, the bulkiness of both starting nitropyridones an

Full text of DOI:10.1016/j.tet.2009.07.024

Tetrahedron 65 (2009) 7403–7407
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Synthesis of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines
,
b
b
b
Nagatoshi Nishiwaki a , Masataka Hisaki , Masaki Ono , Masahiro Ariga
*
a Center for Collaborative Research, Anan National College of Technology, Minobayashi, Anan, Tokushima 774-0017, Japan
b Department of Chemistry, Osaka Kyoiku University, Asahigaoka, Kashiwara, Osaka 582-8582, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is
demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former
step, the bulkiness of both starting nitropyridones and C2 reagents is found to be essential for avoiding
N-alkylation, which undergoes O-alkylation efficiently. The subsequent reductive cyclization affords
pyridoxazines with carbon substituents at both the 2- and the 6-positions that have not been available.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 May 2009
Received in revised form 7 July 2009
Accepted 7 July 2009
Available online 10 July 2009
Keywords:
Ring transformation
3-Nitro-2-pyridone
O-Alkylation
Reductive cyclization
Pyridoxazine
1. Introduction
Fused 1,4-oxazines are often seen as a partial structure in nat-
ural products and pharmaceuticals; however, most of the synthetic
Ring transformation that uses electron-deficient heterocyclic
compounds is one of the powerful methods for synthesizing
polyfunctionalized compounds that are not easily prepared by an
alternative procedure.1–3 3-Methyl-5-nitropyrimidin-4(3H)-one (1)
serves as an excellent substrate for this reaction, which proceeds
three components ring transformation with ketones in the pres-
ence of ammonium acetate to afford 6-substituted 3-nitropyridin-
2(1H)-ones 2 (Scheme 1).4–6 The vicinal functionalities of 2 are
considered to be useful for approaching for [b]-fused bicyclic pyr-
idines; thus, we focused on the construction of an 1,4-oxazine ring
whose oxygen atom is derived from a 2-oxo group and nitrogen
atom is derived from a 3-nitro group. Namely, the introduction of
a C2 unit on the oxo group and the subsequent reductive cyclization
are studied for synthesizing pyrido[2,3-b][1,4]oxazines (PyOAs).
studies are focused on benzo[1,4]oxazines,7–10 pyrido[3,2-b]oxa-
zines,11,12 and pyrimido[2,3-b][1,4]oxazines.13 On the contrary, only
several synthetic studies have been reported with regard to PyOAs.
One preparative method for PyOAs uses 3-amino-2-chloropyr-
idines14,15 or 3-nitro-2-chloropyridines16,17 as precursors by mod-
ifying a nitrogen substituent at the 3-position and by substituting
a 2-chloro group with nucleophilic alkoxide. 2-Bromo-3-hydroxy-
pyridines can be used as precursors although an oxygen atom is
substituted at the 3-position, in which Smile rearrangement pro-
ceeds after condensation of a 3-hydroxy group with
a-chloro-
acetamide.18 On the other hand, several other preparative methods
employing 2-pyridones as starting materials are also reported.
When 3-bis(2-chloroethyl)amino-2-pyridone is used, the oxo
group undergoes nucleophilic substitution at one of the chloro
atoms to yield PyOA having a 2-chloroethyl group at the 1-posi-
tion.19 In the case of 3,5-dinitropyridone, O-alkylation with 1,2-
dichloroethane followed by reductive cyclization leads to PyOA.20
These preparative methods are surely easy; however, the scarce
availability of multiple substituted pyridines significantly limits
substituents that can be introduced in the PyOA framework.
Namely, only oxy and oxo groups are seen at the 2-position of
PyOAs.14–20 With regard to the 6-position, carbon substituents
cannot be introduced except at a few instances.21–25
O
R6
NH4OAc
O
NO2
O
O2N
Me
6 = p-MeC6H4 2A 75%
i-Bu 2B 64%
N
R
R6
N
H
MeOH
reflux, 2 d
N
1
Scheme 1. Ring transformation affording nitropyridones 2.
From this viewpoint, nitropyridones 2 in Scheme 1 are suitable
precursors for PyOAs having an aryl and an alkyl group at the
6-position since the substituent at this position is modified easily by
changing ketone that is used for the ring transformation. In the
* Corresponding author. Tel./fax: þ81 884 23 7294.
E-mail address: nishiwaki@anan-nct.ac.jp (N. Nishiwaki).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.024

7404
N. Nishiwaki et al. / Tetrahedron 65 (2009) 7403–7407
present study, we employ pyridones 2A and 2B derived from
p-methylacetophenone and 4-methyl-2-pentanone, respectively,4–6
and unsubstituted pyridone 2C.26 Furthermore, we also attempt to
modify the 2-position of PyOA by using C2 reagents such as phenacyl
bromide 3a, chloroacetone 3b, bromoacetonitrile 3c, and ethyl
chloroacetate 3d. As a result, various PyOAs having substituents at the
2- and the 6-positions will be conveniently synthesized by changing
a combination of pyridones 2 and C2 reagents 3.
Next, reductive cyclization was studied. When O-phenacylated
pyridine 4Aa was treated with tin(II) chloride in ethyl acetate, the
reaction mixture was complicated; however, it was successful to
isolate the desired 2,6-disubstituted PyOA 6Aa in 27% yield from the
reaction mixture (Table 2, run 1). Further, PyOA 6Ba was isolated in
12% yield from 4Ba in a similar manner (run 2). The complication of
the reaction mixture could be avoided by using Raney nickel under
hydrogen atmosphere, and PyOAs 6Aa and 6Ba were afforded in
considerably improved 78% and 61% yields, respectively (runs 3 and
4). In cases of O-acetylmethyl derivatives 4Ab and 4Bb, PyOAs 7Ab
and 7Bb were obtained instead of 6Ab and 6Bb as a result of further
hydrogenation because the C]N bond is not conjugated with
a substituent at the 2-position (runs 5 and 6). On the other hand, the
reductive cyclizations of O-cyanomethylpyridines 4Ac and 4Bc
failed yielding complex mixtures without any detectable bicyclic
products formed via amidine intermediate37,38 under the employed
conditions. Since O-(ethoxycarbonyl)methylpyridines 4Ad and 4Bd
were less reactive than O-acylmethyl derivatives, only the reduction
of a nitro group occurred without cyclization leading to 3-amino-
pyridines 8Ad and 8Bd, respectively. The cyclizations of 8Ad and
8Bd were successfully performed upon treatment with p-toluene-
sulfonic acid to afford lactam-type PyOAs 9Ad and 9Bd in highyields
(Scheme 2).
2. Results and discussion
When pyridone 2A was allowed to react with phenacyl bromide
3a in the presence of triethylamine in acetonitrile, O-phenacylation
proceeded efficiently so as to afford 4Aa in 94% yield (Table 1, run 1).
Although N-phenacylation leading to 5Aa is also possible, the ob-
servation of only single absorption of a carbonyl group at 1697 cmꢀ1
in the IR spectrum indicated that the product was 4Aa. Similarly
isobutylpyridone 2B underwent the reaction to yield O-phenacy-
lated product 4Ba (run 2). Contrary to these results, unsubstituted
pyridone 2C (R6¼H) afforded N-phenacylated product 5Ca whose IR
spectrum exhibited two absorptions for carbonyl groups at 1692
and 1671 cmꢀ1 (run 3). In addition, the structure of 5Ca was sup-
ported by the observation of a correlation between a methylene
group and a proton at the 6-position in the 1H–1H NOESY 2D
spectrum. Other C2 reagents 3b–d also reacted with pyridones 2A
and 2B to afford corresponding O-alkylated products 4Ab–d and
4Bb–d, respectively, despite the necessity of reflux conditions (runs
4–9). In a combination of 2B and small C2 reagent 3c, two kinds of
cyanomethylated products were formed. The major product was
4Bc and the minor one was tentatively assigned to N-alkylated
product 5Bc by 1H NMR of a mixture with 4Bc because of difficult
isolation (run 7). In the present reaction, O-alkylation precedes
while alkylation of 2-pyridones27–31 or 2-quinolones32–34 tends to
afford more stable N-alkylated products.35,36 The formation of 5Ca
indicates congestion around a ring nitrogen and is necessary for
causing O-alkylation predominantly, which consequently enables
the subsequent construction of a [b]-fused oxazine ring.
Table 2
Reductive cyclization leading to PyOAs 6 and 7
H
R2
N
R2
NO2
O
N
O
reductant
or
R2
AcOEt
rt
R6
N
R6
N
R6
N
O
O
6
7
4
Run
Nitropyridine
Reductant
Time/h
Product
R6
Yield/%
R2
1
2
3
4
5
6
4Aa
4Ba
4Aa
4Ba
4Ab
4Bb
SnCl2
SnCl2
Raney-Ni/H2
Raney-Ni/H2
Raney-Ni/H2
Raney-Ni/H2
24
24
3
3
3
p-Tol
i-Bu
p-Tol
i-Bu
p-Tol
i-Bu
Ph
Ph
Ph
Ph
Me
Me
6Aa
6Ba
6Aa
6Ba
7Ab
7Bb
27
12
78
61
58
79
Table 1
O-Alkylation of nitropyridones 2
3
NO2
O
X
FG
NO2
O
NO2
O
3
+
In summary, we have presented a novel preparative method for
R6
N
R6
N
FG
R6
N
H
NEt3
MeCN
PyOAs having substituents at the 2- and the 6-positions. The
2-position of PyOA can be modified by changing C2 reagents and
the 6-position can be modified by changing ketone in a step of the
ring transformation. Since all experiments require only simple
manipulations, this method is applicable for the preparation of
versatile 2,6-disubstituted PyOAs that are useful in the research of
new biologically active compounds.
FG
2
4
5
Run Nitropyridone
R6
C2 Reagent
Conditions
Temp/ꢁC Time/h
Yield/%
FG
X
4
5
1
2
3
4
5
6
7
8
9
p-Tol
i-Bu
H
p-Tol
i-Bu
p-Tol
i-Bu
p-Tol
i-Bu
2A
2B
2C
2A
2B
2A
2B
2A
2B
PhCO
PhCO
PhCO
MeCO
MeCO
CN
Br 3a rt
Br 3a rt
Br 3a rt
Cl 3b 80
Cl 3b 80
Br 3c 80
Br 3c 80
24
24
24
10
10
10
10
10
10
Aa
94
70
0
88
64
62
0
0
90
0
0
0
Ba
Ca
Ab
Bb
Ac
Bc
Ad
Bd
3. Experimental
3.1. General
CN
46a 28a
COOEt Cl 3d 80
COOEt Cl 3d 80
94
69
0
0
The melting points were determined on a Yanaco micro-melt-
ing-points apparatus, and were uncorrected. All the reagents and
solvents were commercially available and used as received. The 1H
Determined by 1H NMR.
a
H
NH2
O
NO2
O
Raney-Ni/H2
N
O
p-TsOH
OEt
OEt
AcOEt
rt, 3 h
MeOH
65 °C, 3 h
R6
N
R6
N
R6
N
O
O
O
4Ad
4Bd
8Ad 86%
8Bd 75%
9Ad 86%
9Bd 95%
Scheme 2. Synthesis of 6-subsitituted 2-oxo-PyOAs 9Ad and 9Bd.

N. Nishiwaki et al. / Tetrahedron 65 (2009) 7403–7407
7405
NMR spectra were measured on a Bruker DPX-400 with TMS as an
internal standard, and the 13C NMR spectra were measured on
a Bruker DPX-400 or JEOL AL-400 spectrometer at 100 MHz. As-
signments of 13C NMR spectra were performed by DEPT experi-
ments. The IR spectra were recorded on a JASCO FT/IR-4200
Spectrophotometer. The mass spectra were recorded on a JEOL JMS-
AX505HA. The elemental microanalyses were performed using
a Yanaco MT-6 CHN corder.
1334 cmꢀ1. Anal. Calcd for C15H14N2O4: C, 62.94; H, 4.90; N, 9.79.
Found: C, 62.88; H, 5.03; N, 9.86.
3.7. 2-Acetylmethoxy-6-isobutyl-3-nitropyridine 4Bb
Pale yellow oil. 1H NMR (400 MHz, CDCl3)
d
0.90 (d, J¼6.7 Hz,
6H), 2.0–2.1 (m, 1H), 2.26 (s, 3H), 2.59 (d, J¼7.2 Hz, 2H), 5.02 (s, 2H),
6.88 (d, J¼8.1 Hz, 1H), 8.28 (d, J¼8.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 22.3 (CH3), 26.4 (CH), 28.7 (CH3), 47.0 (CH2), 70.7 (CH2),
3.2. O-Phenacylation of nitropyridone 2A
117.2 (CH), 131.3 (C), 135.9 (CH), 154.5 (C), 165.9 (C), 203.2 (C); IR
(neat) 1738, 1519, 1345 cmꢀ1; MS (FAB) 253 (Mþþ1, 100). Anal.
Calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10. Found: C, 57.20; H,
6.32; N, 11.02.
To a solution of pyridone 2A (114 mg, 0.5 mmol) in acetonitrile
(10 mL), phenacyl bromide (398 mg, 2 mmol), and triethylamine
(0.35 mL, 2.5 mmol) were added, and the resultant mixture was
stirred at room temperature for 1 day. After removal of the solvent
under reduced pressure, the residue was treated with column
chromatography on silica gel to afford O-phenacylated product 4Aa
(eluted with chloroform,164 mg, 0.47 mmol, 94% yield). Reactionsof
other pyridones and C2 reagents were performed in a similar way.
3.8. 2-Cyanomethoxy-6-(4-methylphenyl)-3-
nitropyridine 4Ac
Yellowsolid. Mp 185–186 ꢁC.1H NMR (400 MHz, DMSO-d6)
d 2.40
(s, 3H), 5.52 (s, 2H), 7.38 (d, J¼8.1 Hz, 2H), 7.93 (d, J¼8.4 Hz,1H), 8.17
(d, J¼8.1 Hz, 2H), 8.60 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-
3.3. 2-Benzoylmethoxy-6-(4-methylphenyl)-3-
nitropyridine 4Aa
d6) d 22.6 (CH3), 53.4 (CH2), 116.1 (CH), 118.0 (C), 129.2 (CH), 131.3
(CH),133.1 (C),134.5 (C),139.2 (CH), 143.0 (C), 154.5 (C), 159.8 (C); IR
(KBr) 1585,1335 cmꢀ1. Anal. Calcd for C14H11N3O3: C, 62.45; H, 4.09;
N, 15.61. Found: C, 62.63; H, 4.24; N, 15.47.
Pale yellow solid. Mp 148–149 ꢁC (dec).1H NMR (400 MHz, CDCl3)
d
2.35 (s, 3H), 5.81 (s, 2H), 7.13 (d, J¼8.2 Hz, 2H), 7.44 (d, J¼8.2 Hz,1H),
7.52 (dd, J¼8.2, 7.8 Hz, 2H), 7.66 (t, J¼7.8 Hz, 1H), 7.69 (d, J¼8.2 Hz,
3.9. 2-Cyanomethoxy-6-isobutyl-3-nitropyridine 4Bc
2H), 8.03 (d, J¼8.2 Hz, 2H), 8.43 (d, J¼8.2 Hz,1H); 13C NMR (100 MHz,
CDCl3)
d
21.4 (CH3), 68.7 (CH2),113.1 (CH),125.9(CH),127.4 (CH),128.0
Yellow solid. Mp 187–188 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.96
(CH), 128.9 (CH), 129.6 (CH), 133.6 (C), 133.8 (C), 134.8 (C), 136.8 (CH),
(d, J¼6.7 Hz, 6H), 2.1–2.4 (m, 1H), 2.71 (d, J¼7.2 Hz, 2H), 5.16 (s, 2H),
141.3 (C),154.9 (C),160.3(C),193.3(C); IR (KBr) 1697,1579,1373 cmꢀ1
;
7.01 (d, J¼8.1 Hz, 1H), 8.33 (d, J¼8.1 Hz, 1H); 13C NMR (100 MHz,
MS (FAB) 349 (Mþþ1, 100). Anal. Calcd for C20H16N2O4: C, 68.97; H,
CDCl3) d 22.4 (CH3), 28.7 (CH), 47.0 (CH2), 50.9 (CH2), 114.8 (C), 118.5
4.60; N, 8.05. Found: C, 68.80; H, 4.69; N, 8.01.
(CH), 125.9 (C), 136.2 (CH), 152.9 (C), 166.2 (C); IR (KBr) 1597,
1347 cmꢀ1. Anal. Calcd for C11H13N3O3: C, 56.17; H, 5.53; N, 17.87.
Found: C, 55.92; H, 5.96; N, 17.67.
3.4. 2-Benzoylmethoxy-6-isobutyl-3-nitropyridine 4Ba
Colorless oil. 1H NMR (400 MHz, CDCl3)
d
0.77 (d, J¼6.6 Hz, 6H),
3.10. 1-Cyanomethyl-6-isobutyl-3-nitro -2-pyridone 5Bc
1.8–2.0 (m, 1H), 2.47 (d, J¼7.1 Hz, 2H), 5.75 (s, 2H), 6.83 (d, J¼8.1 Hz,
1H), 7.51 (dd, J¼7.3, 7.1 Hz, 2H), 7.62 (tt, J¼7.3, 1.4 Hz, 1H), 7.97 (dd,
J¼7.1, 1.4 Hz, 2H), 8.27 (d, J¼8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
Brown oil. 1H NMR (400 MHz, CDCl3)
d
1.08 (d, J¼6.6 Hz, 6H),
2.0–2.1 (m,1H), 2.70 (d, J¼7.3 Hz, 2H), 5.05 (s, 2H), 6.26 (d, J¼8.0 Hz,
1H), 8.37 (d, J¼8.0 Hz, 1H); IR (neat) 1682, 1551, 1335 cmꢀ1. Since
separation with 4Bc could not be performed enough, sufficient
analytical data were not obtained.
d
22.2 (CH3), 28.5 (CH), 46.8 (CH2), 68.3 (CH2), 117.1 (CH), 127.8 (CH),
128.8 (CH), 131.3 (C), 133.7 (CH), 134.6 (C), 135.8 (CH), 154.6 (C),
165.7 (C), 193.1 (C); IR (neat) 1705, 1519, 1344 cmꢀ1; MS (FAB) 315
(Mþþ1, 100). Anal. Calcd for C17H18N2O4: C, 64.97; H, 5.73; N, 8.92.
Found: C, 65.64; H, 5.73; N, 8.29.
3.11. 2-(Ethoxycarbonyl)methoxy-6-(4-methylphenyl)-
3-nitropyridine 4Ad
3.5. 1-Benzoylmethyl-3-nitro-2-pyridone 5Ca
Pale yellow solid. Mp 134–135 ꢁC. 1H NMR (400 MHz, CDCl3)
Yellowish brown needles. Mp 143–144 ꢁC (dec). 1H NMR
d
1.25 (t, J¼7.1 Hz, 3H), 2.43 (s, 3H), 4.24 (q, J¼7.1 Hz, 2H), 5.11 (s,
(400 MHz, DMSO-d6)
d
5.70 (s, 2H), 6.55 (dd J¼7.7, 6.6 Hz, 1H), 7.62
2H), 7.29 (d, J¼8.1 Hz, 2H), 7.50 (d, J¼8.4 Hz, 1H), 7.90 (d, J¼8.1 Hz,
(dd, J¼7.6, 7.3 Hz, 2H), 7.75 (t, J¼7.6 Hz, 1H), 8.08 (d, J¼7.3 Hz, 1H),
2H), 8.43 (d, J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.2 (CH3),
8.18 (dd, J¼6.6, 2.0 Hz, 1H), 8.51 (dd, J¼7.7, 2.0 Hz, 1H); 13C NMR
21.4 (CH3), 61.3 (CH2), 63.7 (CH2), 113.0 (CH), 127.4 (CH), 129.7 (CH),
132.5 (C), 133.4 (C), 136.8 (CH), 141.6 (C), 154.8 (C), 159.1 (C), 168.2
(C); IR (KBr) 1754, 1583, 1339 cmꢀ1. Anal. Calcd for C16H16N2O5: C,
60.76; H, 5.06; N, 8.86. Found: C, 60.66; H, 5.18; N, 8.89.
(100 MHz, DMSO-d6)
d 58.9 (CH2), 106.5 (CH), 131.0 (CH), 132.0
(CH), 132.2 (C), 137.2 (CH),141.0 (CH), 142.5 (C), 150.1 (CH),156.6 (C),
195.0 (C); IR (KBr) 1692, 1671, 1536, 1349 cmꢀ1; MS (FAB) 259
(Mþþ1, 100). Anal. Calcd for C13H10N2O4: C, 60.47; H, 3.88; N, 10.85.
Found: C, 60.41; H, 3.91; N, 10.92.
3.12. 2-(Ethoxycarbonyl)methoxy-6-isobutyl-3-
nitropyridine 4Bd
3.6. 2-Acetylmethoxy-6-(4-methylphenyl)-3-
nitropyridine 4Ab
Pale yellow oil. 1H NMR (400 MHz, CDCl3)
d
0.91 (d, J¼6.7 Hz,
6H), 1.26 (t, J¼7.2 Hz, 3H), 2.0–2.2 (m, 1H), 2.59 (d, J¼7.2 Hz, 2H),
Yellow solid. Mp 166–167 ꢁC. 1H NMR (400 MHz, CDCl3)
d 2.31 (s,
4.21 (q, J¼7.2 Hz, 2H), 5.03 (s, 2H), 6.88 (d, J¼8.1 Hz, 1H), 8.28 (d,
3H), 2.42 (s, 3H), 5.11 (s, 2H), 7.29 (d, J¼8.2 Hz, 2H), 7.49 (d,
J¼8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.1 (CH3), 22.3 (CH3),
J¼8.4 Hz,1H), 7.84 (d, J¼8.2 Hz, 2H), 8.44 (d, J¼8.4 Hz,1H); 13C NMR
28.6 (CH), 46.9 (CH2), 61.2 (CH2), 63.3 (CH2), 117.3 (CH), 131.3 (C),
135.9 (CH), 154.5 (C), 165.7 (C), 168.2 (C); IR (neat) 1759, 1596,
1348 cmꢀ1; MS (FAB) 283 (Mþþ1, 100). Anal. Calcd for C13H18N2O5:
C, 55.31; H, 6.43; N, 9.92. Found C, 54.93; H, 6.46; N, 9.72.
(100 MHz, CDCl3)
d 21.4 (CH3), 26.5 (CH3), 71.1 (CH2), 113.2 (CH),
127.4 (CH), 129.8 (CH), 131.4 (C), 133.5 (C), 133.8 (C), 136.8 (CH),
141.6 (C), 154.7 (C), 159.5 (C), 203.6 (C); IR (KBr) 1722, 1582,

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N. Nishiwaki et al. / Tetrahedron 65 (2009) 7403–7407
3.13. Reductive cyclization of 4Aa leading to PyOA 6Aa
CDCl3) d 14.2 (CH3), 21.2 (CH3), 61.0 (CH2), 62.7 (CH2), 113.9 (CH),
121.8 (CH),125.4 (CH),129.2 (CH),129.4 (C),136.1 (C),137.1 (C),142.9
(C), 150.3 (C), 169.7 (C); IR (KBr) 3435, 3342, 1742, 1199 cmꢀ1; MS
(FAB) 287 (Mþþ1, 56), 286 (100). Anal. Calcd for C16H18N2O3: C,
67.13; H, 6.29; N, 9.79. Found: C, 67.28; H, 6.38; N, 9.68.
To a solution of O-phenacylpyridine 4Aa (296 mg, 0.85 mmol) in
ethyl acetate (50 mL), Raney-Ni was added, which was prepared
from 50 wt % Ni–Al (1.46 g, 12.4 mmol) and 20% NaOH aq. A hy-
drogen balloon was equipped and the mixture was stirred at room
temperature for 2 h. After filtration of Raney-Ni, the filtrate was
concentrated. Recrystallization of the residue from ethyl acetate
afforded PyOA 6Aa (200 mg, 0.66 mmol, 78%) as yellow needles.
Other reductive cyclizations were performed in a similar way.
3.19. 3-Amino-2-(ethoxycarbonyl)methoxy-6-
isobutylpyridine 8Bd
Pale yellow solid. Mp 39–40 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.86
(d, J¼6.6 Hz, 6H), 1.27 (t, J¼7.1 Hz, 3H), 1.9–2.1 (m, 1H), 2.38 (d,
J¼7.1 Hz, 2H), 3.4–3.7 (br, 2H), 4.21 (q, J¼7.1 Hz, 2H), 4.88 (s, 2H),
6.53 (d, J¼7.6 Hz, 1H), 6.84 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
3.14. 6-(4-Methylphenyl)-2-phenylpyrido[2,3-b]-
[1,4]oxazine 6Aa
CDCl3) d 14.2 (CH3), 22.4 (CH3), 28.7 (CH), 46.0 (CH2), 60.9 (CH2), 62.5
Yellow needles (from EtOAc). Mp 158–162 ꢁC (dec). 1H NMR
(CH2), 117.1 (CH), 121.8 (CH), 127.8 (C), 147.2 (C), 150.4 (C), 169.8 (C);
IR (neat) 3462, 3366,1752,1193 cmꢀ1. Anal. Calcd for C13H20N2O3: C,
61.90; H, 7.94; N, 11.11. Found: C, 61.95; H, 8.17; N, 11.29.
(400 MHz, CDCl3)
d
2.39 (s, 3H), 5.43 (s, 2H), 7.25 (d, J¼8.0 Hz, 2H),
7.45–7.5 (m, 4H), 7.74 (d, J¼7.8 Hz, 1H), 7.9–7.5 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d 20.4 (CH3), 64.3 (CH2), 114.4 (CH), 125.6 (CH),
125.8 (CH), 127.9 (CH), 128.5 (CH), 130.7 (CH), 133.7 (C), 134.3 (C),
135.3 (CH), 138.3 (C), 152.3 (C), 153.7 (C), 156.5 (C), 157.7 (C); MS
(FAB) 301 (Mþþ1, 100). Anal. Calcd for C20H16N2O: C, 80.00; H, 5.33;
N, 9.33. Found: C, 80.00; H, 5.27; N, 9.28.
3.20. Cyclization of 8Ad leading to PyOA 9Ad
To a solution of aminopyridine 8Ad (86 mg, 0.3 mmol) in
methanol (5 mL), p-toluenesulfonic acid (26 mg, 0.15 mmol) was
added. After heating the solution under reflux for 3 h, 0.1 M
Na2CO3aq (15 mL, 1.5 mmol) was added, and then the solution was
extracted with ethyl acetate (20 mLꢂ3). The organic layer was dried
over MgSO4 and concentrated to afford PyOA 9Ad (62 mg,
0.26 mmol, 86%) as a pale yellow solid.
3.15. 6-Isobutyl-2-phenylpyrido[2,3-b][1,4]oxazine 6Ba
Colorless needles. Mp 96–99 ꢁC. 1H NMR (400 MHz, CDCl3)
d
0.94 (d, J¼6.6 Hz, 6H), 2.0–2.2 (m, 1H), 2.63 (d, J¼7.2 Hz, 2H), 5.51
(s, 2H), 6.99 (d, J¼8.0 Hz, 1H), 7.45–7.55 (m, 3H), 8.24 (dd, J¼7.9,
1.7 Hz, 1H), 8.41 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 22.4
3.21. 1,2-Dihydro-6-(4-methylphenyl)-2-oxopyrido[2,3-b]-
[1,4]oxazine 9Ad
(CH3), 29.0 (CH), 47.1 (CH2), 65.1 (CH2), 118.9 (CH), 125.2 (C), 126.4
(CH), 128.8 (CH), 131.5 (CH), 134.7 (C), 135.7 (CH), 153.0 (C), 158.2
(C),159.7 (C); MS (FAB) 267 (Mþþ1, 100). Anal. Calcd for C20H16N2O:
C, 76.69; H, 6.77; N, 10.53. Found: C, 76.30; H, 6.28; N, 10.30.
Pale yellow solid. Mp 282–283 ꢁC. 1H NMR (400 MHz, DMSO-d6)
d
2.34 (s, 3H), 4.82 (s, 2H), 7.18 (d, J¼8.1 Hz, 2H), 7.26 (d, J¼8.0 Hz,
1H), 7.57 (d, J¼8.0 Hz, 1H), 7.85 (d, J¼8.1 Hz, 2H), 10.91 (br s, 1H,
exchangeable with D2O); 13C NMR (100 MHz, DMSO-d6)
20.7
3.16. 1,2-Dihydro-2-methyl-6-(4-methylphenyl)pyrido-
d
[2,3-b][1,4]oxazine 7Ab
(CH3), 66.8 (CH2), 114.4 (CH), 120.7 (C), 124.1 (CH), 125.7 (CH), 129.2
(CH), 134.9 (C), 137.8 (C), 147.7 (C), 150.0 (C), 163.9 (C); IR (KBr) 3179,
1690 cmꢀ1. Anal. Calcd for C14H12N2O2: C, 70.00; H, 5.00; N, 11.67.
Found: C, 70.00; H, 5.09; N, 11.57.
Colorless needles. Mp 148–152 ꢁC. 1H NMR (400 MHz, CDCl3)
d
1.12 (d, J¼6.4 Hz, 3H), 2.28 (s, 3H), 3.45–3.55 (m, 1H), 3.65–3.80
(br, 1H), 3.90 (dd, J¼10.7, 8.2 Hz, 1H), 4.29 (dd, J¼10.7, 2.7 Hz, 1H),
6.81 (d, J¼7.9 Hz, 1H), 7.1–7.2 (m, 3H), 7.75 (d, J¼8.1 Hz, 2H); 13C
3.22. 1,2-Dihydro-6-isobutyl-2-oxopyrido[2,3-b]-
[1,4]oxazine 9Bd
NMR (100 MHz, CDCl3)
d 17.5 (CH3), 21.2 (CH3), 44.8 (CH), 71.0
(CH2), 114.2 (CH), 122.5 (CH), 125.9 (CH), 127.6 (C), 129.2 (CH), 136.0
(C), 137.3 (C), 144.9 (C), 150.4 (C); IR (KBr) 3279 cmꢀ1; MS (FAB) 241
(Mþþ1, 100), 240 (69). Anal. Calcd for C15H16N2O: C, 75.00; H, 6.67;
N, 11.67. Found: C, 74.84; H, 6.86; N, 11.48.
Yellow solid. Mp 126–127 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.91
(d, J¼6.6 Hz, 6H), 2.0–2.1 (m,1H), 2.53 (d, J¼7.2 Hz, 2H), 4.83 (s, 2H),
6.77 (d, J¼7.7 Hz, 1H), 7.09 (d, J¼7.7 Hz, 1H), 9.3–9.6 (br, 1H); 13C
NMR (100 MHz, CDCl3)
d 22.3 (CH3), 29.0 (CH), 46.5 (CH2), 67.2
3.17. 1,2-Dihydro-6-isobutyl-2-methylpyrido[2,3-b]-
[1,4]oxazine 7Bb
(CH2), 118.1 (C), 118.4 (CH), 124.2 (CH), 150.1 (C), 155.2 (C), 165.6 (C);
IR (neat) 3195, 1716 cmꢀ1. Anal. Calcd for C11H14N2O2: C, 64.08; H,
6.80; N, 13.59. Found: C, 64.15; H, 7.00; N, 13.38.
Pale yellow solid. Mp 81–82 ꢁC. 1H NMR (400 MHz, CDCl3)
d 0.88
(d, J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H), 1.95–2.1 (m, 1H), 2.43 (d,
J¼7.0 Hz, 2H),3.5–3.6(m,1H), 3.6–3.8(br,1H),3.92(dd,J¼10.6, 8.4 Hz,
1H), 4.32 (dd, J¼10.6, 2.7 Hz, 1H), 6.55 (d, J¼7.7 Hz, 1H), 6.78 (d,
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