Novel formation of 1,3-oxazepine heterocycles via palladium-catalyzed intramolecular coupling reaction

Article abstract of DOI:10.1016/j.tet.2006.07.009

The oxazepine ring systems containing pyridazinone moiety were constructed via palladium-catalyzed intramolecular coupling reaction. The best conditions for this reaction were Pd(OAc)₂ as a palladium source, 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) as the ligand, and K₂CO₃ as base at 80 °C in toluene. The products have potential applications as biological and medicinal relevant compounds.

Full text of DOI:10.1016/j.tet.2006.07.009

Tetrahedron 62 (2006) 9002–9009
Novel formation of 1,3-oxazepine heterocycles via
palladium-catalyzed intramolecular coupling reaction
a
a
b
c,
Chen Ma,a, Shao-Jie Liu, Liang Xin, J. R. Falck and Dong-Soo Shin
*
*
aSchool of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
cDepartment of Chemistry, Changwon National University, Changwon 641-773, South Korea
Received 12 May 2006; revised 4 July 2006; accepted 5 July 2006
Available online 24 July 2006
Abstract—The oxazepine ring systems containing pyridazinone moiety were constructed via palladium-catalyzed intramolecular coupling
reaction. The best conditions for this reaction were Pd(OAc)2 as a palladium source, 1,10-bis(diphenylphosphino)-ferrocene (DPPF) as the
ligand, and K2CO3 as base at 80 ꢀC in toluene. The products have potential applications as biological and medicinal relevant compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The modification of the oxazepine nucleus is a versatile re-
search area due to its presence in some natural products and
biologically active substances.1 There are many methods for
the synthesis of oxazepine ring systems. However, new, sim-
ple, and efficient ways for constructing oxazepine rings are
still in great demand.2
To the best of our knowledge Buchwald and co-workers8
have prepared a seven-membered ring via an intramolecular
cycloamination, which is the first application of this cycliza-
tion to form these important tricyclic oxazepine ring systems.
As a part of our continuing interest in the development of
novel syntheses of heterocyclic systems,9 we report herein
our results in effecting an intramolecular Pd-catalyzed cou-
pling reaction of an aryl halide with an alcohol (Scheme 1).
Palladium-catalyzed cross-coupling reactions Ar–X with
carbon nucleophiles have found wide application in the syn-
thesis of complex organic molecules due to their mild reac-
tion conditions and high functional group compatibility.3
Successful extension of these reactions to heteroatom nucle-
ophiles including amines and thiols have been reported.4
Recent advances in the Pd-catalyzed aryl aminations have
extended the generality of this reaction to include a wide
variety of amines. In contrast, the Pd-catalyzed coupling
of Ar–X with alcohols still remains as an elusive goal in spite
of its potential application in organic synthesis.5 Aryl ethers,
including oxygen heterocycles, are prominent in a large
number of pharmacologically important molecules and are
found in numerous secondary metabolites.6 Available
methods for the synthesis of aryl ethers via direct nucleo-
philic substitution of an aryl halide with an alcohol typically
require harsh or restrictive conditions or a large excess of the
alcohol and are limited in substrate scope.7
R
R
Br
N
Pd(OAc)2, Ligand
N
O
N
O
N
HO
Base, Solvent, Heat
THP
N
N
O
THP
O
O
1
2
Scheme 1. The intramolecular Pd-catalyzed coupling reaction of an aryl
halide with an alcohol.
Preparation of Substrate 1 is shown in Schemes 2 and 3.
Substrate 1 was obtained from the corresponding pyrida-
zino-1,4-oxazine 8 by bromination and reduction. Pyrida-
zino-1,4-oxazine
8 was prepared by cyclization of
chloroacetamide 7 with pyridazinone 6. Chloroacetamide
7 was easily prepared by addition of various amines to
2-chloroacetyl chloride. Pyridazinone 6 was synthesized in
four steps from commercially available mucochloric acid.
Treatment of mucochloric acid with hydrazine sulfate in
refluxing ethanol/water (v/v ¼ 1:1) in the presence of
sodium acetate gave 4,5-dichloro-3(2H)-pyridazinone (3) in
excellent yields.10 The pyridazinone nitrogen of 4,5-di-
chloro-3(2H)-pyridazinone was protected by treatment of
Keywords: Oxazepine; Synthesis; Palladium catalyst; Intramolecular cou-
pling.
* Corresponding authors. Tel.: +86 531 88364464; fax:+86 531 88564464;
e-mail: chenma@sdu.edu.cn
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.009

C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
9003
compound 3 with excess dihydropyran and p-toluenesulfonic
acid in refluxing tetrahydrofuran to give 4,5-dichloro-2-
(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (4).11 The
compound 4 was followed by methoxide displacement to
produce 4-chloro-5-methoxy pyridazinone 5, which was
then hydrolyzed with potassium hydroxide in refluxing water
to give 4-chloro-5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-
3(2H)-pyridazinone (6) in good yield (Scheme 2).
(S)-(ꢁ)-2,20-bis(di-p-tolylphosphino)-1,10-bi-naphthyl (Tol-
BINAP) and 1,10-bis(diphenylphosphino)-ferrocene (DPPF)
ligands in place of P(o-tolyl)3, either NaOt-Bu or K2CO3 as
base and Pd(OAc)2 as the Pd source gave the desired cyclic
product 2 (Table 1).
The ligand DPPF proved to be more effective than DPPE,
DPPBz, BINAP, and Tol-BINAP. Optimization of NaOt-Bu
and K2CO3 as base showed that the use of a large excess
of K2CO3 instead of NaOt-Bu afforded products in higher
yields. Although it has been reported that the latter gives
faster reactions, its high basicity often causes problems. Ob-
served side products included dehalogenation of the aryl bro-
mides and oxidation of the alcohol to the ketone. A steric
effect was observed for Entry g, the increase of the steric
congestion on phenyl ring with trimethoxy groups obviously
reduced reaction yield. Under the conditions employed, ox-
azepine formation was not observed in toluene in the absence
of Pd-catalyst for any of the substrates examined in Table 1.
O
Cl
Cl
Cl
Cl
N
N
b
a
O
N
N
Cl
THP
Cl
H
O
4
O
OH
3
H3CO
HO
Cl
N
N
N
d
c
N
Cl
THP
THP
O
O
5
6
Scheme 2. (a) H2NNH2–H2SO4, AcONa, EtOH/H2O, reflux; (b) DHP,
PTSA, THF, reflux; (c) MeONa, MeOH, rt; and (d) KOH, H2O, reflux.
The proposed mechanism for the intramolecular Pd-cata-
lyzed coupling reaction of an aryl bromide with an alcohol
is shown in Scheme 4. The reaction occurs by oxidative
addition of the aryl bromide, subsequent generation of the
palladium oxametallacycle, and C–O bond-forming reduc-
tive elimination. Although aryl bromide intermediates were
generated independently and were shown to be kinetically
competent to be intermediates, the oxametallacycles could
not be observed or isolated.
In addition, reaction of substituted phenylethyl amines with
chloroacetyl chloride in the presence of potassium carbonate
in refluxing dichloromethane afforded compound 7 in excel-
lent yields (Scheme 3). The reaction occurred at room tem-
perature for 12 h or at refluxing temperature for 2 h. The
compound 8 was synthesized by the reaction of various
substituted phenylethyl-2-chloroacetamides 7 with pyridazi-
none 6. The cyclization occurred smoothly in the presence of
cesium carbonate at refluxing acetonitrile in 63–79%
isolated yields via Smiles rearrangement.9
R2
R1
N
N R2
R1
R
R
OH
O
Br
2
1
Pd(0)
R
N
R
a
b
N
NH
Cl
R
O
NH2
N
O
R2
N
R2
R1
O
THP
R1
OH
O
N
O
7
8
R
Pd(II)
Pd(II)
Br
Br
R
Br
R
N
N
c
d
N
N
HO
R
O
N
N
R1
R2
O
THP
O
THP
N
OH
O
O
Base + HBr
9
1
Pd(II)
Br
Base
Scheme 3. (a) ClCH2COCl, K2CO3, CH2Cl2, reflux; (b) 6, Cs2CO3, CH3CN,
reflux; (c) NBS, DMF, rt, 100 ꢀC; and (d) NaBH4, CH3OH, rt.
R
According to literature procedure,12 bromination of 8 with
NBS in N,N-dimethyl formamide gave rise to compound 9
in good yield. Toward the end of subjection, reduction of
compound 9 in the present of sodium borohydride in meth-
anol at room temperature afforded the corresponding re-
duced product 1.
Scheme 4. The proposed mechanism for the intramolecular Pd-catalyzed
coupling reaction of an aryl bromide with an alcohol.
3. Conclusion
In summary, we have developed a useful synthetic method
for oxazepine ring systems. The best conditions for this re-
action were Pd(OAc)2 as a palladium source, 1,10-bis(diphe-
nylphosphino)-ferrocene (DPPF) as the ligand, and K2CO3
as base at 80 ꢀC in toluene. This approach may give access
to useful intermediates for the synthesis of natural products
and hitherto unknown pharmaceuticals.
The different conditions reported for the intramolecular cy-
cloamination to form seven-membered rings (Pd(PPh3)4,
NaOt-Bu, and toluene)8 resulted in poor yields of desired
product 2. Subjecting substrates 1 to the other reaction con-
ditions (Pd2(dba)3, P(o-tolyl)3, NaOt-Bu, and toluene)
afforded no desired cyclic product. However, the use of

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C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
Table 1. Pd-catalyzed synthesis of oxazepines containing pyridazinone moiety
Entry
a
Substrate 1
Ligand
DPPF
Base
Product 2
Yield (%)a
H3CO
H3CO
H3CO
H3CO
Br
N
N
O
N
N
N
N
K2CO3
62
HO
O
THP
THP
THP
O
THP
THP
THP
O
O
O
O
H3CO
H3C
H3CO
H3C
Br
Br
N
N
O
N
N
N
N
b
c
DPPF
DPPF
K2CO3
70
65
HO
O
O
O
H3CO
H3CO
N
O
N
O
N
N
N
N
K2CO3
HO
O
O
CH3
CH3
H3CO
H3C
H3CO
H3C
Br
N
O
d
DPPF
K2CO3
55
N
N
N
O
HO
O
N
THP
N
THP
O
O
O
O
O
Br
N
O
N
O
O
N
N
O
N
N
e
f
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
63
58
26
71
53
46
HO
THP
THP
THP
O
O
O
O
O
Br
N
N
O
N
O
N
N
HO
N
O
THP
O
O
O
H3CO
H3CO
H3CO
H3CO
Br
N
N
O
N
N
O
N
N
g
h
i
HO
OCH3
O
THP
THP
OCH3
O
O
O
O
H3CO
Cl
H3CO
Cl
Br
N
N
N
N
O
N
N
HO
O
THP
O
THP
(C2H5)2N
(C2H5)2N
Br
N
O
N
O
N
N
O
N
N
HO
HO
THP
THP
O
O
(C2H5)2N
C2H5
(C2H5)2N
C2H5
Br
N
O
N
O
N
N
O
N
N
j
THP
THP
O
O
a
Yields refer to the average of isolated yields for two or more runs.
1
4. Experimental
4.1. General
1H and 13C NMR spectra (300 MHz for H and 75 MHz
for 13C) were recorded in CDCl3 with CHCl3 as an internal
reference on a Varian spectrometer. IR spectra were recorded
on FTIR Nicolet Impect 410 spectrophotometer. Elemental
analyses were performed on a Perkin–Elmer 2400 elemental
analyzer. Thin layer chromatography (TLC) was performed
Melting points were determined on a Thomas–Hoover
capillary melting point apparatus and were uncorrected.

C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
9005
on Merck silica gel plates, with the compounds being iden-
tified in one or more of the following manners: UV (UL
listed 977c inspection equipment), 25% PMA solution
(phosphomolybdic acid and ethanol). Column chromato-
graphy was performed on Merck D-6100 silica gel 60 (70–
230 mesh, ASTM). All solvents were distilled before use.
Glassware was dried in an oven at 110 ꢀC overnight.
resulting solution was cooled to 0 ꢀC and 87% potassium
hydroxide (11.7 g, 181.7 mmol) was added in portions
over approximately 1 h. The mixture was heated to 40 ꢀC.
Following the addition, the mixture was allowed to stir for
an additional 3 h at ambient temperature. The reaction mix-
ture was partitioned with 120 mL of ethyl acetate and
120 mL of water. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with
brine and dried (MgSO4). The organic solution was clarified
by filtration and concentrated to give a dark semi-solid. The
crude material was equally divided and added to two 220-
mL flasks. The material was suspended and stirred in
120 mL hexane/ethyl ether (2:1). The washed material was
vacuum filtered on a Buchner funnel and air dried overnight
to give 34.1 g (77% over two steps) of 4-chloro-5-methoxy-
2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (5) as a
dark solid suitable for further transformations. The product
was purified by recrystallization from ethyl acetate/cyclo-
hexane to give a white solid. Mp 116–118 ꢀC; IR (KBr)
3062, 2933, 2860, 1678, 1556, 1400, 1365, 1230,
4.2. 4,5-Dichloro-3(2H)-pyridazinone (3)9b
To a 250-mL flask equipped with a magnetic stirrer was
added sodium acetate (27.2 g, 213 mmol) and hydrazine sul-
fate (17.7 g, 213 mmol) in ethanol/H2O (v/v:1/1) (120 mL).
The mixture was heated to 60 ꢀC for 1 h, then, mucochloric
acid (30 g, 178 mmol) was added to the warm solution. The
solution was stirred under reflux for 4 h, followed by cooling
to room temperature, then, filtered. The residue was washed
with water, dried at room temperature to obtain slight yellow
product 3 in 92% yield. Mp 198–200 ꢀC; IR (KBr) 3250,
3200, 3031, 2864, 1653 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 8.07 (br s, 1H), 7.60 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 129.5, 137.2, 139.4, 167.5; Anal. Calcd for
C4H2Cl2N2O: C, 29.12; H, 1.22; N, 16.98. Found: C,
29.16; H, 1.32; N, 17.06%.
1116 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.89 (s, 1H),
1
6.08 (d, J¼10.8 Hz, 1H), 4.10–4.19 (m, 1H), 4.08 (s, 3H),
3.71–3.82 (m, 1H), 2.03–2.17 (m, 2H), 1.60–1.72 (m, 4H);
13C NMR (75 MHz, CDCl3) d 21.5, 25.1, 28.2, 66.8,
68.3, 73.5, 111.4, 129.2, 134.0, 155.2; Anal. Calcd for
C10H13N2O3Cl: C, 49.09; H, 5.36; N, 11.45. Found: C,
49.23; H, 5.33; N, 11.51%.
4.3. 4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-
pyridazinone (4)
4,5-Dichloro-3(2H)-pyridazinone (30 g, 181.8 mmol), dihy-
dropyran (19.4 g, 230.8 mmol), p-toluenesulfonic acid
monohydrate (2.83 g, 14.9 mmol), and 160 mL of tetrahy-
drofuran were added to a 500-mL round bottomed flask
equipped with a beating mantle, reflux condenser, and a
mechanical stirrer. The mixture was stirred at reflux for
29 h. Additional dihydropyran was added at 6 h (13.3 g,
157.9 mmol) and at 21 h (7.8 g, 92.5 mmol). The reaction
mixture was allowed to cool to room temperature overnight.
The mixture was concentrated in vacuo to an oily residue.
The residue was taken up in 160 mL of ethyl acetate and
washed with 2 N sodium hydroxide. The organic solution
was dried (MgSO4) and concentrated in vacuo to give 4,5-di-
chloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone(4),
which was a black oily solid, which was used without further
purification in the next step. The product was purified by
filtration through silica gel with ethyl acetate followed
by evaporation and recrystallization from ethyl acetate/
cyclohexane to give a white solid. Mp 75–77 ꢀC; IR (KBr)
3078, 2923, 2853, 1670, 1573, 1460, 1382, 1320, 1235,
4.5. 4-Chloro-5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-
3(2H)-pyridazinone (6)
To a 500-mL flask was added 4-chloro-5-methoxy-2-(tetra-
hydro-2H-pyran-2-yl)-3(2H)-pyridazinone (5) (45 g, 184
mmol) and potassium hydroxide (12.4 g, 220.8 mmol) in
water (150 mL). The mixture solution was heated to reflux
for 3 h, then, cooled to room temperature and 1 N HCl aque-
ous solution was added dropwise to cooled solution (pH¼
5–6). The mixture solution was filtered and residue was
washed with water. The crude product was purified by re-
crystallization from methanol/hexane to give 4-chloro-5-hy-
droxy-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone (6)
as a white solid in 86.5% yield. Mp 135–137 ꢀC; IR (KBr)
3397, 2967, 2865, 2569, 1638, 1588, 1410, 1301, 1205,
1
1092 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.82 (s, 1H),
7.45–7.56 (m, 1H), 6.03 (d, J¼10.5 Hz, 1H), 4.12 (d,
J¼13.2 Hz, 1H), 3.72–3.80 (m, 1H), 2.03–2.17 (m, 2H),
1.63–1.71 (m, 4H); 13C NMR (75 MHz, CDCl3) d 21.3,
24.9, 28.2, 66.7, 73.5, 111.5, 129.1, 133.8, 155.3; Anal.
Calcd for C9H11N2O3Cl: C, 46.87; H, 4.81; N, 12.15. Found:
C, 46.95; H, 4.78; N, 12.10%.
1
1092 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.85 (s, 1H),
6.01 (d, J¼10.8 Hz, 1H), 4.13 (d, J¼13.5 Hz, 1H), 3.70–
3.81 (m, 1H), 2.03–2.17 (m, 2H), 1.58–1.76 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 21.2, 24.9, 28.0, 66.7, 73.3,
112.0, 129.7, 132.8, 155.4; Anal. Calcd for C9H10N2O2Cl2:
C, 43.40; H, 4.05; N, 11.25. Found: C, 43.28; H, 4.16; N,
11.07%.
4.6. N-(3,4-Dimethoxyphenethyl)-2-chloroacetamide (7a)
A solution of chloroacetyl chloride (3.6 g, 32.6 mmol) in
CH2Cl2 (20 mL) was added dropwise to a solution of (3,4-
dimethoxyphenyl)ethyl amine (5.3 g, 29.6 mmol) and
K2CO3 (4.5 g, 32.6 mmol) in CH2Cl2 (150 mL) at room
temperature. The mixture solution was refluxed for 2 h,
cooled to room temperature and H2O was added. The phases
were separated and aqueous layer was extracted with
CH2Cl2. The organic phase was dried over MgSO4 and
evaporated in vacuo. The crude product was purified by flash
column chromatography using CH2Cl2 as eluent to afford
4.4. 4-Chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)-
3(2H)-pyridazinone (5)
4,5-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazi-
none (4) from the previous step and 170 mL of methanol
were added to a 500-mL round bottomed flask equipped
with a glycol cooling jacket and a mechanical stirrer. The

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C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
product 7 as a white solid with 92.1% yield. Mp 101–
103 ꢀC; IR (KBr) 3326, 3053, 2945, 1632, 1528, 1271,
147.7, 148.6, 159.3, 164.8; Anal. Calcd for C21H24BrN3O6:
C, 51.02; H, 4.89; N, 8.50. Found: C, 50.95; H, 4.97; N,
8.58%.
1
842 cmꢁ1; H NMR (300 MHz, CDCl3) d 6.67–6.82 (m,
3H), 6.53 (s, 1H), 4.23 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H),
3.26 (q, J¼6.6 Hz, 2H), 2.55 (t, J¼6.9 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 35.2, 40.4, 45.8, 57.2, 58.0, 112.7,
115.4, 120.1, 133.6, 146.3, 147.8, 166.3; Anal. Calcd for
C12H16ClNO3: C, 55.93; H, 6.26; N, 5.43. Found: C,
56.02; H, 6.19; N, 5.42%.
4.9. 4-(2-Bromo-4,5-dimethoxyphenethyl)-3,4-dihydro-
7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-pyrid-
azino[4,5-b][1,4]oxazin-8(7H)-one (1a)
To a 100-mL flask equipped with a magnetic stirrer was
added compound 9a (2.47 g, 5 mmol) in CH3OH (50 mL).
The mixture was cooled to 0 ꢀC in an ice bath and NaBH4
(0.22 g, 6 mmol) was added. The reaction mixture was
stirred at room temperature for 2 h and then CH3OH was
removed under reduced pressure. CH2Cl2 was added to the
residue and stirred for 10 min, then filtered and washed
with CH2Cl2. The solvent was evaporated in vacuo. The
crude product was purified by flash column chromatography
using EtOAc/CH2Cl2 as eluent to afford the product 1a as
a thin yellow solid with 89.6% yield. Mp 223–225 ꢀC; IR
(KBr) 3310, 3012, 2973, 2860, 1645, 1612, 1530, 1273,
4.7. 4-(3,4-Dimethoxyphenethyl)-7-(tetrahydro-2H-
pyran-2-yl)-2H-pyridazino[4,5-b][1,4]oxazine-
3,8(4H,7H)-dione (8a)
To a 250-mL flask equipped with a magnetic stirrer was
added 4-chloro-5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)-
3(2H)-pyridazinone (6) (4.24 g, 18.4 mmol), N-(3,4-di-
methoxyphenethyl)-2-chloroacetamide (7a) (3.6 g, 18.4
mmol), and Cs2CO3 (7.2 g, 22.1 mmol) in CH3CN
(100 mL). The mixture was heated to reflux for 60 h, moni-
tored by TLC. Then CH3CN was removed under reduced
pressure and CH2Cl2/H2O was added. The phases were sepa-
rated and aqueous layer was extracted with CH2Cl2. The
combined organic phases were dried over MgSO4 and evapo-
rated in vacuo. The crude product was separated by flash
column chromatography using EtOAc/CH2Cl2 (30%) as elu-
ent to afford the product 8a as a thin yellow solid with 83.7%
yield. Mp 181–183 ꢀC; IR (KBr) 3020, 2940, 2861, 1702,
1659, 1625, 1532, 1430, 1376, 1315, 1276, 1245,
1
1120 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.70 (s, 1H),
6.67–6.82 (m, 2H), 6.10 (d, J¼10.8 Hz, 1H), 4.42–4.49
(m, 2H), 4.06–4.17 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H),
3.58–3.82 (m, 4H), 2.88–2.92 (m, 2H), 2.01–2.17 (m, 2H),
1.60–1.71 (m, 4H), 1.42–1.49 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 22.5, 25.1, 29.1, 34.1, 43.6, 47.0, 55.8,
67.4, 69.7, 74.2, 83.6, 109.5, 112.4, 121.6, 126.3, 127.9,
129.2, 136.2, 147.5, 149.3, 163.9; Anal. Calcd for
C21H26BrN3O6: C, 50.82; H, 5.28; N, 8.47. Found: C,
50.77; H, 5.35; N, 8.42%.
1
1110 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.71 (s, 1H),
6.69–6.80 (m, 3H), 6.10 (d, J¼10.8 Hz, 1H), 4.74–4.87 (m,
1H), 3.96–4.15 (m, 3H), 3.73–3.86 (m, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 2.87 (t, J¼7.2 Hz, 2H), 2.02–2.12 (m, 2H),
1.61–1.74 (m, 4H), 1.57 (d, J¼4.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 22.6, 24.8, 28.9, 33.7, 43.0, 55.8, 68.8,
74.3, 76.6, 82.7, 108.1, 111.3, 111.7, 120.7, 124.9, 127.2,
129.2, 147.7, 149.0, 160.2, 164.4; Anal. Calcd for
C21H25N3O6: C, 60.71; H, 6.07; N, 10.11. Found: C, 60.62;
H, 6.16; N, 10.03%.
4.10. 4-(2-Bromo-5-methoxy-4-methylphenethyl)-3,4-
dihydro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-
pyridazino[4,5-b][1,4]oxazin-8(7H)-one (1b)
Mp 215–218 ꢀC; IR (KBr) 3321, 3018, 2957, 2845, 1643,
1550, 1272, 1115 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.74 (s, 1H), 6.73–6.84 (m, 2H), 6.12 (d, J¼10.8 Hz,
1H), 4.38–4.47 (m, 2H), 4.05–4.16 (m, 1H), 3.85 (s, 3H),
3.63–3.79 (m, 4H), 2.82–2.90 (m, 2H), 2.31 (s, 3H), 2.05–
2.18 (m, 2H), 1.63–1.75 (m, 4H), 1.40–1.48 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 21.6, 25.8, 28.4, 32.5, 36.5,
44.3, 47.6, 57.2, 67.9, 71.3, 84.1, 107.9, 115.3, 119.5,
124.8, 126.9, 129.4, 137.5, 148.1, 149.7, 162.5; Anal. Calcd
for C21H26BrN3O5: C, 52.51; H, 5.46; N, 8.75. Found: C,
52.54; H, 5.51; N, 8.67%.
4.8. 4-(2-Bromo-4,5-dimethoxyphenethyl)-7-(tetra-
hydro-2H-pyran-2-yl)-2H-pyridazino[4,5-b][1,4]oxa-
zine-3,8(4H,7H)-dione (9a)
A solution of NBS (1.78 g, 10 mmol) in dry DMF (20 mL)
was added to a solution of substrate 8a (4.15 g, 10 mmol)
in dry DMF (20 mL) and stirred at room temperature for
48 h. The mixture was poured into water (100 mL) and ex-
tracted with dichloromethane (200 mL). The extract was
washed with water, dried over MgSO4, and evaporated in
vacuo to yield crude monobromide. The crude product
was separated by flash column chromatography using
EtOAc/CH2Cl2 (20%) as eluent to afford the product 9a
as a thin yellow solid with 82.2% yield. Mp 175–177 ꢀC;
IR (KBr) 3034, 2952, 2863, 1705, 1650, 1542, 1421,
4.11. 4-(2-Bromo-5-methoxyphenethyl)-3,4-dihydro-
7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-pyrid-
azino[4,5-b][1,4]oxazin-8(7H)-one (1c)
Mp 219–221 ꢀC; IR (KBr) 3332, 3026, 2961, 2845, 1631,
1
1547, 1132 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.73 (s,
1H), 6.64–6.81 (m, 3H), 6.04 (d, J¼10.5 Hz, 1H), 4.35–
4.46 (m, 2H), 4.11–4.18 (m, 1H), 3.87 (s, 3H), 3.60–3.78
(m, 4H), 2.85–2.94 (m, 2H), 1.97–2.13 (m, 2H), 1.65–
1.72 (m, 4H), 1.44–1.52 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 23.2, 24.1, 30.6, 34.3, 44.2, 47.7, 56.4, 65.1,
74.8, 85.0, 110.6, 113.9, 121.3, 127.0, 129.1, 131.2,
135.5, 146.3, 148.7, 164.2; Anal. Calcd for C20H24BrN3O5:
C, 51.51; H, 5.19; N, 9.01. Found: C, 51.61; H, 5.22; N,
8.93%.
1376, 1257, 1215, 1106 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 7.76 (s, 1H), 6.72–6.78 (m, 2H), 6.12 (d,
J¼10.8 Hz, 1H), 4.75–4.86 (m, 1H), 3.99–4.16 (m, 3H),
3.74–3.86 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.84 (t,
J¼7.5 Hz, 2H), 2.00–2.11 (m, 2H), 1.62–1.74 (m, 4H),
1.55 (d, J¼5.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 22.6, 25.2, 28.8, 34.0, 43.2, 55.8, 68.6, 73.8, 75.5,
83.5, 106.3, 112.5, 119.8, 126.0, 128.2, 129.4, 135.6,

C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
9007
4.12. 4-(6-Bromo-3-methoxy-2,4-dimethylphenethyl)-
3,4-dihydro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-
2H-pyridazino[4,5-b][1,4]oxazin-8(7H)-one (1d)
4.16. 4-(2-Bromo-4-chloro-5-methoxyphenethyl)-3,4-di-
hydro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-
pyridazino[4,5-b][1,4]oxazin-8(7H)-one (1h)
Mp 210–212 ꢀC; IR (KBr) 3301, 3014, 2961, 2849, 1637,
Mp 211–213 ꢀC; IR (KBr) 3322, 3016, 2965, 2855, 1638,
1
1540, 1273, 1114 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
1546, 1120 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.76 (s,
d 7.76 (s, 1H), 6.80 (s, 1H), 6.12 (d, J¼10.2 Hz, 1H),
4.43–4.52 (m, 2H), 4.12–4.19 (m, 1H), 3.85 (s, 3H), 3.61–
3.75 (m, 4H), 2.80–2.91 (m, 2H), 2.37 (s, 3H), 2.25 (s,
3H), 2.07–2.15 (m, 2H), 1.63–1.74 (m, 4H), 1.42–1.49 (m,
3H); 13C NMR (75 MHz, CDCl3) d 22.0, 26.4, 29.1, 32.3,
33.6, 38.2, 43.8, 47.5, 59.7, 68.3, 71.8, 82.9, 109.1, 116.6,
118.9, 125.0, 127.2, 133.4, 137.2, 147.2, 148.6, 163.7;
Anal. Calcd for C22H28BrN3O5: C, 53.45; H, 5.71; N,
8.50. Found: C, 53.39; H, 5.72; N, 8.44%.
1H), 6.64–6.78 (m, 2H), 6.06 (d, J¼10.5 Hz, 1H), 4.30–
4.41 (m, 2H), 4.13–4.20 (m, 1H), 3.89 (s, 3H), 3.60–3.73
(m, 4H), 2.88–2.97 (m, 2H), 1.99–2.13 (m, 2H), 1.62–1.71
(m, 4H), 1.45–1.54 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 23.4, 24.3, 30.1, 35.2, 45.6, 46.7, 57.7, 65.2, 75.1, 84.6,
110.8, 114.9, 121.4, 126.8, 129.3, 134.5, 135.8, 145.3,
147.9, 164.6; Anal. Calcd for C20H23BrClN3O5: C, 47.97;
H, 4.63; N, 8.39. Found: C, 48.05; H, 4.65; N, 8.48%.
4.17. 4-(2-Bromo-5-(diethylamino)phenethyl)-3,4-dihy-
dro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-pyrid-
azino[4,5-b][1,4]oxazin-8(7H)-one (1i)
4.13. 4-(2-(6-Bromo-2,3-dihydrobenzo[b][1,4]dioxin-
7-yl)ethyl)-3,4-dihydro-7-(tetrahydro-2H-pyran-2-yl)-
3-hydroxy-2H-pyridazino[4,5-b][1,4]oxazin-8(7H)-one
(1e)
Mp 202–204 ꢀC; IR (KBr) 3309, 3036, 2951, 2855, 1636,
1
1542, 1118 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.70 (s,
Mp 220–222 ꢀC; IR (KBr) 3296, 3021, 2963, 2842, 1633,
1H), 6.67–6.84 (m, 3H), 6.04 (d, J¼10.5 Hz, 1H), 4.30–
4.41 (m, 2H), 4.10–4.19 (m, 1H), 3.62–3.77 (m, 4H),
2.74–2.99 (m, 6H), 1.98–2.14 (m, 2H), 1.65–1.75 (m, 4H),
1.43–1.55 (m, 3H), 1.19 (t, J¼6.6 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 14.2, 23.7, 25.0, 31.8, 34.6, 43.1, 48.4,
56.7, 65.2, 73.3, 85.5, 112.6, 113.2, 123.0, 127.8, 131.1,
132.5, 135.2, 146.2, 148.6, 164.6; Anal. Calcd for
C23H31BrN4O4: C, 54.44; H, 6.16; N, 11.04. Found: C,
54.28; H, 6.19; N, 10.87%.
1614, 1537, 1118 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.68 (s, 1H), 6.72–6.82 (m, 2H), 6.14 (d, J¼10.8 Hz,
1H), 4.40–4.48 (m, 2H), 4.06–4.28 (m, 5H), 3.62–3.80
(m, 4H), 2.87–2.96 (m, 2H), 2.05–2.16 (m, 2H), 1.63–
1.73 (m, 4H), 1.42–1.50 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 22.8, 25.4, 28.6, 34.7, 44.7, 47.2, 57.9, 68.3,
69.9, 76.1, 84.6, 107.8, 111.6, 120.5, 127.2, 127.8, 131.5,
136.1, 145.4, 148.0, 163.5; Anal. Calcd for C21H24BrN3O6:
C, 51.02; H, 4.89; N, 8.50. Found: C, 50.95; H, 4.96; N,
8.45%.
4.18. 4-(2-Bromo-5-(diethylamino)-4-ethylphenethyl)-
3,4-dihydro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-
2H-pyridazino[4,5-b][1,4]oxazin-8(7H)-one (1j)
4.14. 4-(2-(5-Bromobenzo[d][1,3]dioxol-6-yl)ethyl)-3,4-
dihydro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-
pyridazino[4,5-b][1,4]oxazin-8(7H)-one (1f)
Mp 196–199 ꢀC; IR (KBr) 3317, 3024, 2956, 2847, 1628,
1
1544, 1115 cmꢁ1; H NMR (300 MHz, CDCl3) d 7.65 (s,
Mp 223–225 ꢀC; IR (KBr) 3282, 3027, 2953, 2849, 1621,
1H), 6.72–6.86 (m, 2H), 6.08 (d, J¼10.5 Hz, 1H), 4.31–
4.44 (m, 2H), 4.05–4.13 (m, 1H), 3.64–3.77 (m, 4H),
2.72–2.95 (m, 6H), 1.99–2.23 (m, 4H), 1.63–1.75 (m, 4H),
1.46–1.56 (m, 3H), 1.16–1.23 (m, 9H); 13C NMR
(75 MHz, CDCl3) d 13.5, 14.4, 23.9, 25.6, 29.4, 32.3, 34.2,
41.7, 48.1, 57.5, 67.3, 72.8, 85.4, 111.5, 113.0, 122.6,
127.9, 131.5, 133.4, 136.1, 145.2, 147.9, 164.3; Anal. Calcd
for C25H35BrN4O4: C, 56.08; H, 6.59; N, 10.46. Found: C,
56.13; H, 6.45; N, 10.40%.
1604, 1538, 1112 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d 7.66 (s, 1H), 6.73–6.82 (m, 2H), 6.10 (d, J¼10.5 Hz,
1H), 4.37–4.46 (m, 2H), 4.14–4.27 (m, 3H), 3.55–3.72 (m,
4H), 2.83–2.95 (m, 2H), 2.02–2.15 (m, 2H), 1.63–1.71 (m,
4H), 1.38–1.46 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 23.1, 25.2, 28.7, 35.3, 46.0, 47.7, 56.1, 72.4, 76.5, 83.6,
108.5, 113.0, 121.3, 126.1, 127.9, 132.8, 135.9, 146.2,
148.6, 164.4; Anal. Calcd for C20H22BrN3O6: C, 50.01; H,
4.62; N, 8.75. Found: C, 50.10; H, 4.61; N, 8.63%.
4.19. 9,10-Dimethoxy-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2a)
4.15. 4-(2-Bromo-3,4,5-trimethoxyphenethyl)-3,4-dihy-
dro-7-(tetrahydro-2H-pyran-2-yl)-3-hydroxy-2H-pyrid-
azino[4,5-b][1,4]oxazin-8(7H)-one (1g)
A round bottom flask was flushed with nitrogen and charged
with 5 mol % Pd(OAc)2, 10 mol % DPPF, and toluene. The
mixture was stirred under nitrogen for 10 min. In another
round bottom flask substrate 1 and K2CO3 were weighed.
Then, Pd(OAc)2/DPPF solution was added, and the flask
was rinsed with an additional toluene. The resulting mixture
was heated to 80 ꢀC under N2 with vigorous stirring until
the starting substrate 1 had disappeared as judged by
TLC. After cooling down, the solid material was filtered
off and washed with CH2Cl2. The solvent was evaporated
and the crude product was purified by flash column chroma-
tography using EtOAc/CH2Cl2 (30%) as eluent to afford the
Mp 225–226 ꢀC; IR (KBr) 3332, 3017, 2946, 2862, 1640,
1617, 1535, 1275, 1113 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 7.72 (s, 1H), 6.86 (s, 1H), 6.13 (d, J¼10.5 Hz,
1H), 4.43–4.52 (m, 2H), 4.07–4.16 (m, 1H), 3.90 (s, 3H),
3.87 (s, 3H), 3.86 (s, 3H), 3.62–3.80 (m, 4H), 2.87–2.95
(m, 2H), 2.00–2.14 (m, 2H), 1.62–1.71 (m, 4H), 1.41–1.51
(m, 3H); 13C NMR (75 MHz, CDCl3) d 23.1, 25.6, 30.2,
34.5, 42.2, 47.9, 54.4, 67.5, 69.9, 71.6, 73.8, 84.0, 108.6,
112.2, 122.7, 127.3, 128.5, 129.8, 135.5, 146.1, 148.8,
163.3; Anal. Calcd for C22H28BrN3O7: C, 50.20; H, 5.36;
N, 7.98. Found: C, 50.33; H, 5.47; N, 7.91%.

9008
C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
product as a white solid in 62% yield. Mp 195–197 ꢀC; IR
(KBr) 3069, 2980, 2938, 2860, 1645 cmꢁ1 1H NMR
4.23. 3-(Tetrahydro-pyran-2-yl)-6,6a,10,11,14,15-hexa-
hydro-3H-5,7,9,12-tetraoxa-2,3,15a-triaza-cyclo-
hepta[1,2-a;4,5-b’]dinaphthalen-4-one (2e)
;
(300 MHz, CDCl3) d 7.83 (s, 1H), 6.82 (s, 1H), 6.67 (s,
1H), 6.17–6.25 (m, 1H), 6.08 (d, J¼10.8 Hz, 1H), 4.40–
4.46 (m, 2H), 4.10–4.15 (m, 1H), 3.86 (s, 3H), 3.85 (s,
3H), 3.73–3.78 (m, 1H), 3.58–3.67 (m, 2H), 2.87 (t,
J¼7.2 Hz, 2H), 2.08–2.17 (m, 2H), 1.61–1.72 (m, 4H);
13C NMR (75 MHz, CDCl3) d 22.6, 24.8, 28.9, 33.7,
43.0, 55.8, 68.8, 74.3, 76.6, 82.7, 85.3, 111.3, 111.7,
120.7, 124.9, 127.2, 129.2, 148.0, 148.7, 155.2, 167.4;
Anal. Calcd for C21H25N3O6: C, 60.71; H, 6.07; N, 10.11.
Found: C, 60.76; H, 6.11; N, 10.02%.
Prepared as a white solid in 63% yield. Mp 205–207 ꢀC; IR
(KBr) 3066, 2983, 2948, 2849, 1632 cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 7.88 (s, 1H), 6.80 (s, 1H), 6.71 (s,
1H), 6.19–6.27 (m, 1H), 6.09 (d, J¼10.2 Hz, 1H), 4.22–
4.45 (m, 6H), 4.08–4.15 (m, 1H), 3.73–3.80 (m, 1H),
3.56–3.65 (m, 2H), 2.85 (t, J¼6.9 Hz, 2H), 2.10–2.19 (m,
2H), 1.60–1.71 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 22.3, 24.8, 28.9, 34.1, 43.3, 56.2, 68.3, 74.1, 76.0, 82.1,
84.7, 111.4, 111.7, 121.3, 125.6, 127.3, 129.9, 146.3,
149.6, 155.1, 167.5; Anal. Calcd for C21H23N3O6: C,
61.01; H, 5.61; N, 10.16. Found: C, 60.95; H, 5.71; N,
10.13%.
4.20. 10-Methoxy-9-methyl-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2b)
Prepared as a thin yellow solid in 70% yield. Mp 189–
4.24. 9,10-Methylenedioxy-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2f)
1
191 ꢀC; IR (KBr) 3067, 2983, 2945, 2862, 1642 cmꢁ1; H
NMR (300 MHz, CDCl3) d 7.88 (s, 1H), 6.85 (s, 1H), 6.68
(s, 1H), 6.14–6.23 (m, 1H), 6.04 (d, J¼10.2 Hz, 1H),
4.37–4.45 (m, 2H), 4.11–4.15 (m, 1H), 3.87 (s, 3H), 3.70–
3.76 (m, 1H), 3.60–3.68 (m, 2H), 2.86 (t, J¼7.2 Hz, 2H),
2.31 (s, 3H), 2.05–2.16 (m, 2H), 1.64–1.75 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 22.3, 24.7, 28.7, 33.7, 42.6,
56.3, 68.9, 75.1, 76.3, 82.6, 85.4, 111.8, 111.9, 122.3,
124.7, 126.7, 129.2, 148.0, 148.7, 154.9, 167.5; Anal. Calcd
for C21H25N3O5: C, 63.14; H, 6.31; N, 10.52. Found: C,
63.26; H, 6.32; N, 10.45%.
Prepared as a white solid in 58% yield. Mp 209–211 ꢀC; IR
(KBr) 3058, 2976, 2943, 2862, 1640 cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 7.8 (s, 1H), 6.82 (s, 1H), 6.67 (s,
1H), 6.16–6.25 (m, 1H), 6.08 (d, J¼10.8 Hz, 1H), 4.95 (s,
2H), 4.39–4.46 (m, 2H), 4.07–4.13 (m, 1H), 3.71–3.79 (m,
1H), 3.60–3.68 (m, 2H), 2.92 (t, J¼7.5 Hz, 2H), 2.05–2.15
(m, 2H), 1.60–1.70 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 22.0, 24.7, 28.4, 33.5, 42.2, 56.7, 68.4, 76.2, 83.1, 85.3,
111.7, 112.5, 122.0, 124.4, 127.6, 130.2, 147.7, 150.2,
154.8, 167.6; Anal. Calcd for C20H21N3O6: C, 60.14; H,
5.30; N, 10.52. Found: C, 60.15; H, 5.43; N, 10.37%.
4.21. 10-Methoxy-3-(tetrahydro-pyran-2-yl)-6,6a,12,13-
tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-benzo[4,5]-
cyclohepta[1,2-a]naphthalen-4-one (2c)
4.25. 8,9,10-Trimethoxy-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2g)
Prepared as a white solid in 65% yield. Mp 202–205 ꢀC; IR
(KBr) 3072, 2985, 2947, 2870, 1641 cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 7.84 (s, 1H), 6.71–6.85 (m, 3H),
6.18–6.27 (m, 1H), 6.10 (d, J¼10.5 Hz, 1H), 4.40–4.47
(m, 2H), 4.08–4.14 (m, 1H), 3.86 (s, 3H), 3.71–3.77 (m,
1H), 3.59–3.69 (m, 2H), 2.83 (t, J¼6.9 Hz, 2H), 2.10–2.18
(m, 2H), 1.60–1.70 (m, 4H); 13C NMR (75 MHz, CDCl3)
d 22.4, 24.7, 29.1, 34.0, 42.7, 56.3, 68.8, 75.8, 82.5, 84.2,
111.5, 112.4, 115.4, 121.6, 124.95, 127.3, 128.3, 147.9,
148.7, 156.4, 168.0; Anal. Calcd for C20H23N3O5: C,
62.33; H, 6.01; N, 10.90. Found: C, 62.38; H, 6.07; N,
10.79%.
Prepared as a white solid in 26% yield. Mp 212–215 ꢀC; IR
(KBr) 3062, 2971, 2943, 2848, 1637 cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 7.89 (s, 1H), 6.68 (s, 1H), 6.15–6.23
(m, 1H), 6.06 (d, J¼10.2 Hz, 1H), 4.41–4.48 (m, 2H),
4.13–4.19 (m, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H),
3.70–3.76 (m, 1H), 3.53–3.62 (m, 2H), 2.85 (t, J¼7.5 Hz,
2H), 2.08–2.16 (m, 2H), 1.58–1.71 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 23.2, 24.9, 29.1, 33.5, 43.7, 57.0, 69.4,
71.2, 74.6, 77.3, 82.7, 85.1, 111.4, 121.8, 125.4, 128.0,
131.6, 138.3, 148.0, 149.6, 154.4, 167.7; Anal. Calcd for
C22H27N3O7: C, 59.32; H, 6.11; N, 9.43. Found: C, 59.46;
H, 6.17; N, 9.38%.
4.22. 10-Methoxy-9,11-dimethyl-3-(tetrahydro-pyran-2-
yl)-6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2d)
4.26. 9-Chloro-10-methoxy-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2h)
Prepared as a white solid in 55% yield. Mp 192–194 ꢀC; IR
1
(KBr) 3062, 2955, 2857, 1631 cmꢁ1; H NMR (300 MHz,
CDCl3) d 7.90 (s, 1H), 6.82 (s, 1H), 6.22–6.31 (m, 1H),
6.11 (d, J¼10.5 Hz, 1H), 4.36–4.43 (m, 2H), 4.10–4.15
(m, 1H), 3.88 (s, 3H), 3.68–3.75 (m, 1H), 3.60–3.67 (m,
2H), 2.84 (t, J¼7.5 Hz, 2H), 2.33 (s, 3H), 2.26 (s, 3H),
2.06–2.16 (m, 2H), 1.67–1.76 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 22.2, 24.8, 25.7, 29.5, 34.6, 42.7, 55.9,
68.8, 75.3, 76.3, 83.2, 85.4, 111.7, 122.2, 124.9, 126.6,
128.0, 135.3, 148.3, 149.5, 155.1, 167.7; Anal. Calcd for
C22H27N3O5: C, 63.91; H, 6.58; N, 10.16. Found: C,
63.82; H, 6.62; N, 10.11%.
Prepared as a white solid in 71% yield. Mp 202–204 ꢀC; IR
1
(KBr) 3053, 2948, 2855, 1632 cmꢁ1; H NMR (300 MHz,
CDCl3) d 7.96 (s, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 6.23–
6.30 (m, 1H), 6.05 (d, J¼10.8 Hz, 1H), 4.41–4.48 (m, 2H),
4.14–4.19 (m, 1H), 3.87 (s, 3H), 3.62–3.67 (m, 1H), 3.50–
3.58 (m, 2H), 2.72 (t, J¼7.5 Hz, 2H), 2.04–2.12 (m, 2H),
1.57–1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) d 23.6,
27.9, 34.2, 42.3, 58.1, 65.8, 74.3, 76.5, 81.4, 84.2, 111.5,
113.7, 121.8, 124.5, 128.2, 130.8, 146.1, 148.8, 155.0,

C. Ma et al. / Tetrahedron 62 (2006) 9002–9009
9009
Zara, E.; Mezei, A.; Behr, A.; Simay, A. Bioorg. Med. Chem.
Lett. 1997, 7, 2857; (c) Hallinan, E. A.; Hagen, T. J.;
Tsymbalov, S.; Stapelfeld, A.; Savage, M. A. Bioorg. Med.
Chem. 2001, 9, 1.
166.4; Anal. Calcd for C20H22ClN3O5: C, 57.21; H, 5.28; N,
10.01. Found: C, 57.26; H, 5.32; N, 10.08%.
4.27. 10-Diethylamino-3-(tetrahydro-pyran-2-yl)-
6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2i)
2. (a) Allaway, C. L.; Daly, M.; Nieuwenhuyzen, M.; Saunders,
G. C. J. Fluorine Chem. 2002, 115, 91; (b) Chelucci, G.;
Saba, A.; Valenti, R.; Bacchi, A. Tetrahedron: Asymmetry
2000, 11, 3449; (c) Ouyang, X.; Tamayo, N.; Kiselyov, A. S.
Tetrahedron 1999, 55, 2827.
Prepared as a thin yellow solid in 53% yield. Mp 182–
1
184 ꢀC; IR (KBr) 3058, 2961, 2945, 2850, 1638 cmꢁ1; H
3. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b)
Martin, A. R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221; (c)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (d)
Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003,
103, 1875; (e) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009.
NMR (300 MHz, CDCl3) d 7.91 (s, 1H), 6.72–6.83 (m,
3H), 6.14–6.21 (m, 1H), 6.06 (d, J¼10.2 Hz, 1H), 4.36–
4.41 (m, 2H), 4.06–4.12 (m, 1H), 3.70–3.77 (m, 1H), 3.56–
3.65 (m, 2H), 3.32 (q, J¼6.6 Hz, 4H), 2.83 (t, J¼6.9 Hz,
2H), 2.10–2.18 (m, 2H), 1.60–1.70 (m, 4H), 1.22 (t,
J¼6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 14.2, 23.3,
24.8, 28.9, 33.8, 42.7, 45.7, 56.6, 75.4, 82.0, 83.9, 111.6,
112.1, 116.4, 122.7, 124.8, 127.4, 128.3, 146.7, 148.3,
158.2, 167.3; Anal. Calcd for C23H30N4O4: C, 64.77; H,
7.09; N, 13.14. Found: C, 64.67; H, 7.07; N, 13.02%.
4. (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969; (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36,
3609; (c) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc.
1995, 117, 2937; (d) Arnould, J. C.; Didelot, M.; Cadilhac,
C.; Pasquet, M. J. Tetrahedron Lett. 1996, 37, 4523.
5. (a) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 11695;
(b) Ito, A.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236;
(c) Ito, A.; Ono, Y.; Tanaka, K. Angew. Chem., Int. Ed. 2000,
39, 1072; (d) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere,
G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027; (e)
Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
6. (a) Ellis, G. P. The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, NY,
1977; Vol. 31; (b) Mustafa, A. The Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley:
New York, NY, 1974; Vol. 29.
4.28. 10-Diethylamino-9-ethyl-3-(tetrahydro-pyran-2-
yl)-6,6a,12,13-tetrahydro-3H-5,7-dioxa-2,3,13a-triaza-
benzo[4,5]cyclohepta[1,2-a]naphthalen-4-one (2j)
Prepared as a thin yellow solid in 46% yield. Mp 186–
1
187 ꢀC; IR (KBr) 3046, 2957, 2843, 1636 cmꢁ1; H NMR
(300 MHz, CDCl3) d 7.95 (s, 1H), 6.79 (s, 1H), 6.67 (s,
1H), 6.16–6.26 (m, 1H), 6.04 (d, J¼9.9 Hz, 1H), 4.37–4.44
(m, 2H), 4.05–4.11 (m, 1H), 3.68–3.76 (m, 1H), 3.55–3.63
(m, 2H), 3.36 (q, J¼6.6 Hz, 4H), 2.86 (t, J¼6.9 Hz, 2H),
2.43 (q, J¼5.4 Hz, 2H), 2.11–2.18 (m, 2H), 1.62–1.71 (m,
4H), 1.25 (t, J¼6.3 Hz, 6H), 1.15 (t, J¼5.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 13.1, 14.2, 17.6, 22.9, 24.7,
29.8, 35.2, 42.7, 46.3, 57.8, 74.3, 82.1, 84.2, 111.3, 117.1,
122.4, 125.7, 127.7, 129.7, 133.5, 145.3, 148.0, 157.8,
167.4; Anal. Calcd for C25H34N4O4: C, 66.06; H, 7.54; N,
12.33. Found: C, 65.95; H, 7.49; N, 12.36%.
7. (a) Keeggstra, M. A.; Peters, T. H.; Brandsma, L. Tetrahedron
1992, 48, 3633; (b) Yeager, G. W.; Schissel, D. N. Synthesis
1991, 63, 193; (c) Pearson, A. J.; Gelormini, A. M. J. Org.
Chem. 1994, 59, 4561; (d) Lee, S.; Frescas, S. P.; Nichols,
D. E. Synth. Commun. 1995, 25, 2775.
8. Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525.
9. (a) Cho, S.-D.; Park, Y.-D.; Kim, J.-J.; Lee, S.-G.; Ma, C.;
Song, S.-Y.; Joo, W.-H.; Falck, J. R.; Shiro, M.; Shin, D.-S.;
Yoon, Y.-J. J. Org. Chem. 2003, 68, 7918; (b) Ma, C.; Cho,
S.-D.; Falck, J. R.; Shin, D.-S. Heterocycles 2004, 63, 75; (c)
Cho, S.-D.; Song, S.-Y.; Park, Y.-D.; Kim, J.-J.; Joo, W.-H.;
Shiro, M.; Falck, J. R.; Shin, D.-S.; Yoon, Y.-J. Tetrahedron
Lett. 2003, 44, 8995.
10. (a) Mowry, D. T. J. Am. Chem. Soc. 1953, 75, 1909; (b)
Niedballa, C.; Vorbruggen, H. J. Org. Chem. 1974, 36, 3672;
(c) Dury, J.; Meier, K.; Eichenberger, K. Helv. Chim. Acta
1954, 37, 121; (d) Kuraishi, T. Pharm. Bull. 1956, 5, 376.
11. Bryant, R. D.; Kunng, F. A.; South, M. S. J. Heterocycl. Chem.
1995, 32, 1473.
Acknowledgements
The project was sponsored by the Scientific Research
Foundation for the Returned Overseas Chinese Scholars,
State Education Ministry (2004-527) and Excellent Young
Scientist Awarded Foundation of Shandong Province
(2005BS11007).
References and notes
1. (a) Serrano-Wu, M. H.; Laurent, D. R. S.; Chen, Y. Bioorg.
Med. Chem. Lett. 2002, 12, 2757; (b) Matyus, P.; Varga, I.;
12. Outten, R. A.; Daves, G. D., Jr. J. Org. Chem. 1987, 52, 5064.