One-pot synthesis of pyridazino[1,4]oxazin-3-ones

Article abstract of DOI:10.1081/SCC-120030689

Pyridazino[1,4]oxazin-3-ones were conveniently prepared in a one-pot condensation of N-substituted 2-chloroacetamides with various 5-chloro-pyridazin-6-ones via rearrangement of a spiro-aminoketal intermediate.

Full text of DOI:10.1081/SCC-120030689

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One‐Pot Synthesis of Pyridazino[1,4]oxazin‐3‐ones
Chen Ma a , Su‐Dong Cho b , J. R. Falck c & Dong‐Soo Shin b
a School of Chemistry and Chemical Engineering, Shandong University, Jinan, China
b Department of Chemistry, Changwon National University, Changwon, South Korea
c Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas,
Texas, USA
Version of record first published: 21 Aug 2006.
To cite this article: Chen Ma, Su‐Dong Cho, J. R. Falck & Dong‐Soo Shin (2004): One‐Pot Synthesis of
Pyridazino[1,4]oxazin‐3‐ones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:8, 1399-1405
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 8, pp. 1399–1405, 2004
One-Pot Synthesis of Pyridazino[1,4]oxazin-
3-ones
2
3
2
Chen Ma,1, Su-Dong Cho, J. R. Falck, and Dong-Soo Shin
*
1School of Chemistry and Chemical Engineering, Shandong University,
Jinan, China
2Department of Chemistry, Changwon National University,
Changwon, South Korea
3Department of Biochemistry, University of Texas Southwestern Medical
Center, Dallas, Texas, USA
ABSTRACT
Pyridazino[1,4]oxazin-3-ones were conveniently prepared in a one-
pot condensation of N-substituted 2-chloroacetamides with various
5-chloro-pyridazin-6-ones via rearrangement of a spiro-aminoketal
intermediate.
Key Words: One-pot synthesis; Multi-drug resistant; X-ray analysis;
Pyridazino[1,4]oxazin-3-ones.
*
Correspondence: Chen Ma, School of Chemistry and Chemical Engineering,
Shandong University, Jinan, China; E-mail: chenma@ust.hk.
1399
DOI: 10.1081/SCC-120030689
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Ma et al.
INTRODUCTION
The widespread occurrence of fused [1,4]oxazin-3-ones in bioactive natu-
ral products and pharmaceuticals has made them important targets for
synthetic chemists.[1] While several protocols are available for the construc-
tion of [1,4]oxazin-3-ones, most involve multiple steps, require highly corros-
ive reagents and afford poor yields.[2–7] Consequently, there is still
considerable demand for more economic and versatile syntheses of fused
[1,4]oxazin-3-ones. In the course of our studies related to the development
of novel inhibitors of multi-drug resistant (MDR)[8] pumps, we identified
the pyridazino[1,4]oxazin-3-ones ring system 3 as a critical pharmacophore.
Herein, we report a convenient, one-pot route to 3 via condensation of N-sub-
stituted 2-chloroacetamides 1 with readily available 5-chloro-pyridazin-6-
ones 2 (Sch. 1) and the likely annulation mechanism.
Acetamides 1 were easily prepared in 97% yield by addition of the appro-
priate amine to 2-chloroacetyl chloride in CH2Cl2. The other precursor,
4-hydroxy-5-chloro-pyridazin-6-one 2,[9] was obtained in three steps from
commercially available 4,5-dichloropyridazin-6-one.[10] Notably, the choice
of base for the union of 1 and 2 proved to be very important. Strong bases,
e.g., NaOH, NaH, and KOt-Bu, did not give cyclized product regardless of
temperature. However, K2CO3 in acetonitrile solvent at reflux proved suitable.
In any conditions, 30 was not found. The scope of the reaction was investigated
with a variety of substitutions and the results are summarized in Table 1.
n-Aliphatic (entries 1 and 2), cyclo-aliphatic (entries 3–6), heterocyclic
(entries 7 and 8), and aromatic (entries 9–16) N-substituents on 2-chloroace-
tamide 1 were well tolerated. In contrast, changing R1 ¼ H to R1 ¼ Me at the
C2-position of 2 slowed the reaction rate and generally resulted in a modest
decrease in yield. This is consistent with an initial SN2 addition of the C4-
oxygen of 2 to the C2-position on 1 (Sch. 2). Any increase in the steric
congestion at this center would retard the reaction rate.
A mechanistic scenario consistent with the preceding observations and
products is outlined in Sch. 2. Following the initial SN2 nucleophilic substi-
tution of the hydroxyl group of 2 intermediate 4 undergoes subsequent
Scheme 1.

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Table 1. Formation of N-substituted [1,4]-oxazin-3-ones via intermediate 4.
Entry
R
R1
Amide 1
Time (hr)
3 Yielda (%)
1
2
H
CH3
1a
1b
49
48
65 (3a)
21 (3b)
3
4
H
CH3
1c
1d
42
48
53 (3c)
33 (3d)
5
6
H
CH3
1e
1f
72
61
62 (3e)
40 (3f)
7
8
H
CH3
1g
1h
60
72
68 (3g)
36 (3h)
9
H
1i
1j
48
72
55 (3i)
46 (3j)
10
CH3
11
12
H
CH3
1k
1l
48
60
66 (3k)
45 (3l)
13
14
H
1m
1n
43
59 (3m)
CH3
116
40 (3n)
61b (3o)
33c (3p)
15
16
H
CH3
1o
1p
52
60
aIsolated yield based on 1.
b[a]2D3þ105.46 (c1.10, CH2Cl2).
c[a]2D3242.69 (c2.6, CH2Cl2).
intramolecular Michael addition to give the spiro-aminoketal 5. Migration of
the spiro-oxygen, possibly assisted by the nitrogen lone pair, with concomitant
displacement of the adjacent chloride and subsequent aromatization with loss
of a proton evolves 3. In all cases (especially, entry 3), intermediate 4 could be
isolated. Subjecting 4 to the same reaction condition then afforded oxazine 3
in excellent yield.
Scheme 2.

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Ma et al.
X-ray analysis of crystal structure of 4-[2-(3,4-dimethoxy-phenyl)-ethyl]-7-
(tetrahydro-pyran-2-yl)-4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione (3m)
(entry 13) and 2-[5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyrida-
zin-4-yloxy]-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (4m) are shown in
Fig. 1.
Figure 1. The stereo ORTEP drawing of compound 3m and 4m (entry 13).

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In conclusion, we have developed a novel and versatile procedure for pre-
paring pyridazino[1,4]oxazin-3-ones in one-pot. Further studies directed
towards the synthesis of oxazines containing the various heterocyclic moieties
using this method are currently being pursued.
TYPICAL EXPERIMENTAL PROCEDURE
2-Chloroacetamides (compound 1c). To a solution of cyclohexylamine
(5 g, 50.42 mmol), and K2CO3 (8.3 g, 60.05 mmol) in dichloromethane
(100 mL) was slowly added chloro acetylchloride (6.26 g, 55.46 mmol) for
30 min at room temperature. After 30 min, the mixture was refluxed for 4 hr.
Then, the resulting mixture was stirred at room temperature for 30 min. The
reaction mixture was poured into cold water and extracted twice with
dichloromethane. The combined organic extracts were washed with water
and dried over MgSO4. The solution was concentrated under reduced pressure
and the residue was purified by column chromatography on silica gel (eluent:
hexane/EtOAc, 1 : 1) to afford 1c (8.15 g, 92%) as a white solid (hexane/
EtOAc, 4 : 1): m.p. 97–998C; IR (KBr, cm21) 3413, 3054, 2934, 1670,
1268; 1H NMR (300 MHz, CDCl3) d 6.42 (bs, 1H), 4.03 (s, 2H), 3.79
(m, 1H), 1.18–1.94 (m, 9H); 13C NMR (150 MHz, CDCl3) d 24.7, 25.4,
32.8, 42.7, 48.6, 171.3; Anal. Calcd for C8H14ClNO: C, 54.70; H, 8.03; N,
7.79. Found: C, 54.67; H, 8.02; N, 7.82.
Annulation procedure (compound 3c). Method A: A solution of N-sub-
stituted halo acetamides 1c (2 g, 11.38 mmol), 4-hydroxy-5-chloro-pyridazin-
6-one 2 (2.76 g, 11.95 mmol), and K2CO3 (3.46 g, 25.05 mmol) in acetonitrile
(60 mL) was refluxed for 48 hr. After cooling to room temperature, the result-
ing mixture was stirred for 30 min and filtered, concentrated. Purification of
the crude material chromatography on silica gel (elution: hexane/EtOAc,
5 : 1) afforded the oxazine 3c (2.24 g, 53%) as a white solid (hexane/
EtOAc, 9 : 1): m.p. 183–1848C; IR (KBr, cm21) 3052, 2978, 1702, 1659,
1
1274; H NMR (300 MHz, CDCl3) d 8.04 (s, 1H), 6.07 (d, J ¼ 10.26 Hz,
1H), 4.68 (s, 2H), 4.31–4.39 (m, 1H), 4.11 (m, 1H), 3.73–3.80 (m, 1H),
1.18–2.16 (m, 16H); 13C NMR (300 MHz, CDCl3) d 22.7, 24.9, 25.1, 26.1,
28.9, 29.9, 30.0, 55.6, 68.3, 68.8, 82.7, 126.0, 128.6, 155.4, 163.3; Anal.
Calcd for C17H23N3O4: C, 61.25; H, 6.95; N, 12.60. Found: C, 61.16; H,
6.96; N, 12.67.
Method B: A solution of N-substituted halo-acetamides 1c (5 g,
28.46 mmol), 4-hydroxy-5-chloro-pyridazin-6-one 2 (7.23 g, 31.31 mmol), and
K2CO3 (9.05 g, 65.46 mmol) in acetonitrile (200mL) was refluxed for 24hr.
After cooling to room temperature, the resulting mixture was stirred
for 30min and filtered, concentrated. Purification of the crude material

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Ma et al.
chromatography on silica gel (elution: hexane/EtOAc, 5 : 1) afforded 3c (2 g,
19%) accompanied with intermediate 4c (2.66 g, 28%). 4c: m.p. 181–1828C;
1
IR (KBr, cm21) 3424, 3058, 2982, 1664, 1260; H NMR (300MHz, CDCl3)
d 7.82 (s, 1H), 6.49 (bs, 1H), 6.07 (d, J ¼ 10.51 Hz, 1H), 4.67 (s, 2H),
4.11–4.14 (m, 1H), 3.72–3.86 (m, 2H), 1.23–2.14 (m, 16H); 13C NMR
(300 MHz, CDCl3) d 22.7, 24.5, 24.8, 25.3, 28.9, 29.9, 32.7, 48.1, 68.5, 68.9,
84.0, 127.1, 152.8, 157.8, 164.4; Anal. Calcd for C17H24ClN3O4: C, 55.21; H,
6.54; N, 11.36. Found: C, 55.05; H, 6.56; N, 11.40.
A solution of intermediate 4c (2 g, 5.40 mmol) and K2CO3 (0.82 g,
5.95 mmol) in acetonitrile (30 mL) was refluxed for 28 hr. After 30 min, the
resulting mixture was filtered and concentrated. Purification of the crude
material chromatography on silica gel (elution: hexane/EtOAc, 5 : 1) afforded
3c (1.88 g, 95%) as a white solid.
ACKNOWLEDGMENT
This work was financially supported by the Korea Research Foundation
(KRF-2000-SP0743).
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Received in Japan August 18, 2003

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