An efficient synthesis of [1,4]pyridazinooxazine[3,4-a]tetrahydro isoquinolines

Article abstract of DOI:10.1016/j.tet.2004.03.011

A series of fused isoquinoline-pyridazinooxazine chimera were prepared in good overall yield from phenethylamide 1 and 4,5-dichloropyridazin-3-one 2 via Smiles rearrangement and Pictet-Spengler cyclization.

Full text of DOI:10.1016/j.tet.2004.03.011

Tetrahedron 60 (2004) 3763–3773
An efficient synthesis of
[1,4]pyridazinooxazine[3,4-a]tetrahydro isoquinolines
Su-Dong Cho,a Yong-Dae Park,c Jeum-Jong Kim,c Woo-Hong Joo,b Motoo Shiro,d Lothar Esser,e
c
J. R. Falck,e Chuljin Ahn,b Dong-Soo Shinb and Yong-Jin Yoon
,
,
*
*
aResearch Institute of Basic Science, Changwon National University, Changwon 641-773, South Korea
bDepartments of Chemistry and Biology, Changwon National University, Changwon 641-773, South Korea
cDepartments of Chemistry and Research Institute of Life Science, Gyeongsang National University, Chinju 660-701, South Korea
dRigaku Corporation, 3-9-12 Matsubara-cho, Akishima-shi, Tokyo 196-8666, Japan
eDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Received 14 February 2004; revised 4 March 2004; accepted 4 March 2004
Abstract—A series of fused isoquinoline–pyridazinooxazine chimera were prepared in good overall yield from phenethylamide 1 and
4,5-dichloropyridazin-3-one 2 via Smiles rearrangement and Pictet–Spengler cyclization.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tives 3 via Smiles rearrangement of the initial adduct
between a-hydroxyphenethylamide 1 and 4,5-dichloro-2-
tetrahydropyranylpyridazin-3-one (2) (Scheme 1). Sodium
borohydride reduction of 3 in methanol gave the corre-
sponding 3-hydroxy derivative 4 in excellent yield. Boron
trifluoride-diethyl etherate induced cyclization in dichloro-
methane smoothly transformed 4 into 5, obtained as a single
stereoisomer. The configurations of 5a and 5b were
established by X-ray analysis (Fig. 1).13 These results
could describe the conversion of 4 into 5 via N-acyliminium
ion intermediate (Scheme 2).
Tetrahydroisoquinolines constitute a large and still growing
class of alkaloids that display diverse biological
activities.1–5 Not surprisingly, fusion of the tetrahydro-
isoquinoline skeleton with other heterocyclic ring systems
also leads to new entities showing significant biological
activities.6 Consequently, there has been a surge of interest
in the development of versatile synthetic methods for the
preparation of tetrahydroisoquinoline-heterocycle chimera,
inter alia, oxazines,7 thiazines,8 oxathiazine,9 benzoxazine10
and oxazaphosphorine.11 In the course of our development
of specific inhibitors of multi-drug resistant (MDR) pumps,
we needed a series of functionalized tetracycles derived
from the union of tetrahydroisoquinolines and
pyridazinoxazines. Herein, we wish to report a convenient,
high yield synthesis of several [1,4]pyridazinooxazino[3,4-
a]tetrahydroisoquinolines 6 and 7 from readily available
precursors.
Alkylation of 5 with alkyl halides afforded the correspond-
ing N-alklylated isoquinolines 6 and 7 in good yield. All
1
products were characterized by H, 13C NMR, IR, mass
spectroscopy and CHN analysis.
2.2. Synthesis of halotetrahydroisoquinolines
For access to 7,8-disubstituted analogs (isoquinoline
numbering), we sought to redirect the Pictet–Spengler
cyclization by introduction of a blocking group at the usual
site of annulation. While attempts to halogenate 3 under a
variety of conditions resulted in extensive decomposition,
9a was more amenable to functionalization (Scheme 3).
Specifically, 3 was deprotected using 6 N HCl14 and the
resultant pyridazino[4,5-b][1,4]oxazine-8-one (8) was
alkylated with benzyl chloride in the presence of potassium
carbonate in DMF to give 9a in good overall yield. The
halogenation of 9a was conducted in accordance with
literature procedures.15 To facilitate Pictet–Spengler
cyclization, the halogenation product 10, was firstly treated
2. Results and discussion
2.1. One-pot synthesis of pyridazino[4,5-b][1,4]oxazine
derivatives 3 via Smiles rearrangement
In a previous communication,12 we reported an efficient,
one-pot synthesis of pyridazino[4,5-b][1,4]oxazine deriva-
Keywords: Pyridazino[4,5-b][1,4]oxazine; Tetracyclic isoquinolines.
*
Corresponding author. Tel.: þ82-055-751-6019; fax: þ82-055-761-0244;
e-mail address: yjyoon@nongae.gsnu.ac.kr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.011

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S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
Scheme 1.
with NaBH4 in methanol and then boron trifluoride diethyl
etherate in methylene chloride leading to both cyclized
compounds 11 (39–92%) and 6g (1–48%). The distribution
of products depended on the identity of the blocking
substituent at C-2 on the aromatic moiety of dimethoxy
phenethyl group. The percentage of 11 increased in the
order H!I,Br,Cl, i.e., with increasing electrophilicity
(Table 1). It was gratifying to note that virtually complete
regiocontrol was achieved in the case of 9a and 10c.15
spectra were recorded on a Jeol AL-300 spectrometer with
chemical shift values reported in d units (ppm) relative to an
internal standard (TMS). IR spectra were obtained on a
Hitachi 270-50 spectrophotometer. Elemental analyses were
performed with a Perkin Elmer 240C. Open-bed UV-
chromatography was carried out on silica gel F254 (70–230
mesh, Merck) using gravity flow. The column was packed as
slurries with the elution solvent.
4.2. Synthesis of compound 5a and 5b
To a solution of compound 312 (50 mmol) in methanol
(50 mL) was added powdered sodium borohydride
(125 mmol) below 10 8C. The reaction mixture was
stirred for 6 h. After completion of the reaction as
determined by TLC, the mixture was evaporated in vacuo.
Dichloromethane and water were added sequentially. The
organic layer was separated, washed with brine, dried over
anhydrous magnesium sulfate, and evaporated in vacuo to
give crude 4. A solution of crude 4 in CH2Cl2 (50 mL) was
slowly added to BF3·OEt2 (155 mmol) at 10 8C. After
completion of the reaction as determined by TLC, water
added and the resulting mixture was neutralized using
saturated sodium bicarbonate. The organic layer was
separated, concentrated in vacuo, and the residue was
purified by column chromatography on silica gel with DMF/
diethyl ether (1/1, v/v) to give a white solid.
3. Conclusion
In conclusion, we report herein a convenient synthetic
strategy for the preparation of the title heterocycles
containing a fused tetrahydroisoquinoline-pyridazino[4,5-
b][1,4]oxazine chimera. The Pictet–Spengler cyclization of
9 was shown to depend on the identity of the substituent at
C-2 on the aromatic moiety of the dimethoxyphenylethyl
group. The percentage of 10 increased with increasing
electrophilicity of the substituent at C-2. Further studies on
the synthesis of related polyannular isoquinolines using this
methodology are in progress and will be reported in due
course.
4. Experimental
4.1. General
4.2.1. (10bS)-8,9-Dimethoxy-5,6,10b,11-tetrahydro-2H-
12-oxa-2,3,4b-triazachrysen-1-one (5a). 85%; mp 228–
229 8C; [a]2D0¼þ2.78 (c¼1, DMSO); IR (KBr) 3048, 2974,
2890, 1642, 1618, 1520, 1422, 1330, 1260, 1108, 1042,
Melting points were determined with a Thomas–Hoover
capillary apparatus and uncorrected. 1H and 13C NMR

S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3765
Figure 1. X-ray structure of 5a (up) and 5b (down)
836 cm21; 1H NMR (CDCl3) d 12.46 (s, 1H), 7.83 (s, 1H),
6.79 (s, 1H), 6.70 (s, 1H), 4.69–4.74 (dd, J¼2.70, 10.80 Hz,
1H), 4.42–4.44 (dd, J¼8.12, 11.00 Hz, 1H), 3.89–3.95 (dd,
J¼8.10, 10.80 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.78–
3.82 (m, 1H), 3.34–3.42 (m, 1H), 2.88–2.99 (m, 1H), 2.79–
2.84 (m, 1H); 13C NMR (CDCl3) d 27.68, 42.85, 52.86,
55.36, 55.67, 68.30, 108.71, 111.50, 122.17, 126.65, 129.75,
131.75, 134.42, 147.38, 147.85, 156.60; MS (m/z) 315
(Mþ); Anal. Calcd for C16H17N3O4: 60.94; H, 5.43; N,
13.33. Found: C, 60.92; H, 5.41; N, 13.29.
4.2.2. (10bS,11S)-8,9-Dimethoxy-11-methyl-5,6,10b,11-
tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (5b).
82%; [a]2D0¼251.98 (c¼1, DMSO); mp 214–215 8C; IR
(KBr) 3072, 2936, 1644, 1618, 1520, 1460, 1258, 1216,
1
1070, 1006, 902, 760 cm21; H NMR (CDCl3) d 7.69 (s,
1H), 6.67 (s, 1H), 6.66 (s, 1H), 4.68–4.71 (dd, J¼2.80,
10.85 Hz, 1H), 4.36–4.38 (dd, J¼2.05, 8.10 Hz, 1H), 3.93–
3.97 (dd, J¼8.20, 10.80 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
3.76 (s, 3H), 3.70–3.73 (m, 1H), 3.38–3.40 (m, 1H), 2.90–
2.94 (m, 1H), 2.81–2.85 (m, 1H); 13C NMR (CDCl3) d
28.35, 39.60, 43.58, 53.40, 56.01, 56.28, 69.16, 108.93,
111.91, 122.43, 126.93, 128.95, 131.54, 135.70, 148.23,
148.73, 156.27; MS (m/z): 329 (Mþ); Anal. Calcd for
C17H19N3O4: C, 62.00; H, 5.81; N, 12.76. Found: C, 62.02;
H, 5.78; N, 12.75.
Scheme 2.

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S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
Scheme 3.
Calcd for C17H19N3O4: C, 62.00; H, 5.81; N, 12.76. Found:
C, 62.02; H, 5.78; N, 12.75.
Table 1. The yield and ratio of 11/6g by Pictet–Spengler cyclization of 9a
and 11
4.3.2. (10bS)-2-Ethyl-8,9-dimethoxy-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6b). 91%;
mp 195–196 8C; IR (KBr) 3064, 2952, 2926, 1640, 1608,
X
Ratio of 11 and 6ga
Yield (%)b
of 11/6g
11
6g
1
1514, 1450, 1420, 1256, 1020, 896, 748 cm21; H NMR
H
I
Br
Cl
0
100
57
20
1
0/89
(CDCl3) d 7.72 (s, 1H), 6.67 (s, 1H), 6.66 (s, 1H), 4.68–4.71
(dd, J¼2.75, 10.80 Hz, 1H), 4.36–4.38 (dd, J¼2.10,
8.10 Hz, 1H), 4.18–4.22 (q, 2H), 3.92–3.96 (dd, J¼8.30,
10.75 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.70–3.73 (m,
1H), 3.38–3.40 (m, 1H), 2.89–2.94 (m, 1H), 2.83–2.85 (m,
1H), 1.34–1.37 (t, 3H); 13C NMR (CDCl3) d 13.70, 28.40,
43.52, 46.39, 53.40, 56.00, 56.27, 69.19, 108.95, 111.91,
122.47, 126.95, 129.08, 131.28, 135.71, 148.22, 148.71,
155.74; MS (m/z): 343 (Mþ); Anal. Calcd for C18H21N3O4:
C, 62.96; H, 6.16; N, 12.24. Found: C, 62.92; H, 6.15; N,
12.25.
43
80
99
37/48
69/17
92/1
a
Determined via GC–MS.
Isolated yield after flash chromatography.
b
4.3. Synthesis of compounds 6 and 7
A solution of compound 5 (30 mmol), organic halide
(33 mmol), K2CO3 (35 mmol) in DMF was stirred for
14 h at room temperature. After completion of the reaction
by TLC, the reaction mixture was concentrated in vacuo.
Dichloromethane (50 mL) and then water (50 mL) were
added to the mixture. The organic layer was separated and
subsequently washed with brine. Organic layer was dried
over anhydrous magnesium sulfate, and the resultant was
evaporated to give the crude product 6 and 7. The residue
was purified by column chromatography on silicagel with
CH2Cl2/EtOAc (10/1, v/v) to give the product.
4.3.3. (10bS)-2-Propyl-8,9-dimethoxy-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6c). 93%;
mp 166–167 8C; IR (KBr) 3062, 2940, 2872, 1646, 1618,
1514, 1462, 1258, 1028, 830, 764 cm21; 1H NMR (CDCl3)
d 7.71 (s, 1H), 6.67 (s, 1H), 6.66 (s, 1H), 4.69–4.72 (dd,
J¼2.75, 10.75 Hz, 1H), 4.36–4.38 (dd, J¼2.10, 8.10 Hz,
1H), 4.01–4.13 (m, 2H), 3.92–3.95 (dd, J¼8.30, 10.75 Hz,
1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.70–3.73 (m, 1H), 3.37–
3.39 (m, 1H), 2.89–2.94 (m, 1H), 2.83–2.85 (m, 1H), 1.79–
1.86 (m, 2H), 0.94–0.97 (t, 3H); 13C NMR (CDCl3) d 11.13,
21.84, 28.41, 43.48, 52.78, 53.37, 55.99, 56.24, 69.22,
108.9, 111.90, 122.46, 126.95, 128.88, 131.18, 135.63,
148.21, 148.69, 155.92; MS (m/z): 357 (Mþ); Anal. Calcd
for C19H23N3O4: C, 63.85; H, 6.49; N, 11.76. Found: C,
63.83; H, 6.46; N, 11.75.
4.3.1. (10bS)-8,9-Dimethoxy-2-methyl-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6a). 89%;
mp 214–215 8C; IR (KBr) 3072, 2936, 1644, 1618, 1520,
1460, 1258, 1216, 1070, 1006, 902, 760 cm21; H NMR
(CDCl3) d 7.69 (s, 1H), 6.67 (s, 1H), 6.66 (s, 1H), 4.68–4.71
(dd, J¼2.80, 10.85 Hz, 1H), 4.36–4.38 (dd, J¼2.05,
8.10 Hz, 1H), 3.93–3.97 (dd, J¼8.20, 10.80 Hz, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.76 (s, 3H), 3.70–3.73 (m, 1H), 3.38–
3.40 (m, 1H), 2.90–2.94 (m, 1H), 2.81–2.85 (m, 1H); 13C
NMR (CDCl3) d 28.35, 39.60, 43.58, 53.40, 56.01, 56.28,
69.16, 108.93, 111.91, 122.43, 126.93, 128.95, 131.54,
135.70, 148.23, 148.73, 156.27; MS (m/z): 329 (Mþ); Anal.
1
4.3.4. (10bS)-2-Isopropyl-8,9-dimethoxy-5,6,10b,11-
tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6d).
91%; mp 207–208 8C; IR (KBr) 3100, 3002, 2968, 2876,
1640, 1622, 1528, 1450, 1338, 1270, 1236, 1216, 1160,
1124, 1042, 1020, 920, 876, 844, 790 cm21 1H NMR
;

S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3767
(CDCl3) d 7.77 (s, 1H), 6.67 (s, 1H), 6.66 (s, 1H), 5.31–5.35
(m, 1H), 4.68–4.71 (dd, J¼2.75, 10.80 Hz, 1H), 4.36–4.38
(dd, J¼1.95, 8.15 Hz, 1H), 3.92–3.96 (dd, J¼8.25,
10.75 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.72–3.74
(m, 1H), 3.38–3.39 (m, 1H), 2.90–2.95 (m, 1H), 2.80–2.85
(m, 1H), 1.34 (d, J¼1.85 Hz, 3H), 1.33 (d, J¼1.85 Hz
3H); 13C NMR (CDCl3) d 20.96, 21.05, 28.41, 43.40,
48.59, 53.40, 55.99, 56.26, 69.20, 108.94, 111.91,
122.55, 126.99, 128.79, 130.86, 135.27, 148.19, 148.68,
155.62; MS (m/z): 357 (Mþ); Anal. Calcd for C19H23N3O4:
C, 63.85; H, 6.49; N, 11.76. Found: C, 63.83; H, 6.46; N,
11.75.
4.3.8. (10bS)-2-(4-Fluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6h). 93%; mp 203–204 8C; IR (KBr) 3072, 2926,
2850, 1654, 1622, 1520, 1450, 1268, 1222, 1058 cm21; 1H
NMR (CDCl3) d 7.71 (s, 1H), 7.40–7.45 (m, 2H), 6.95–
7.01 (m, 2H), 6.65 (s, 2H), 5.20–5.34 (dd, J¼13.50,
30.30 Hz, 2H), 4.67–4.71 (dd, J¼2.70, 11.10 Hz, 1H),
4.35–4.38 (dd, J¼2.00, 8.10 Hz, 1H), 3.88–3.93 (m, 4H),
3.87 (s, 3H), 3.68–3.75 (m, 1H), 3.31–3.39 (m, 1H), 2.87–
2.95 (m, 1H), 2.77–2.84 (m, 1H); 13C NMR (CDCl3) d
28.36, 43.28, 53.26, 53.69, 55.95, 56.21, 69.30, 108.77,
111.78, 115.17, 115.45, 122.20, 126.85, 129.40, 130.56,
130.67, 131.36, 132.61, 132.65, 135.44, 148.14, 148.61,
156.87; MS (m/z): 423 (Mþ); Anal. Calcd for C23H22FN3O4:
C, 65.24; H, 5.24; N, 9.92. Found: C, 65.22; H, 5.20; N,
9.88.
4.3.5. (10bS)-2-Butyl-8,9-dimethoxy-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6e). 94%;
mp 150–152 8C; IR (KBr) 3058, 2950, 2864, 1644, 1618,
1516, 1456, 1360, 1320, 1260, 1218, 1114, 1078, 1028, 906,
1
830, 760 cm21; H NMR (CDCl3) d 7.70 (s, 1H), 6.66 (s,
4.3.9. (10bS)-2-(3-Fluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6i). 92%; mp 208–209 8C; IR (KBr) 3096, 2952,
2H), 4.69–4.72 (dd, J¼2.80, 10.75 Hz, 1H), 4.36–4.37 (dd,
J¼2.15, 8.10 Hz, 1H), 4.12–4.17 (m, 2H), 3.91–3.95 (dd,
J¼8.10, 10.80 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.69–
3.73 (m, 1H), 3.35–3.38 (m, 1H), 2.90–2.94 (m, 1H), 2.84–
2.86 (m, 1H), 1.75–1.79 (q, 2H), 1.36–1.40 (q, 2H),
0.93–0.96 (t, 3H); 13C NMR (CDCl3) d 13.79, 19.89, 28.43,
30.63, 43.50, 51.02, 53.39, 56.01, 56.27, 69.22, 108.96,
122.47, 126.95, 128.89, 131.17, 135.70, 148.23, 148.72,
155.98; MS (m/z): 371 (Mþ); Anal. Calcd for C19H23N3O4:
C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N,
11.32.
1
1640, 1524, 1466, 1280, 780 cm21; H NMR (CDCl3) d
7.73 (s, 1H), 7.19–7.31 (m, 2H), 7.10–7.14 (m, 1H), 6.92–
6.99 (m, 1H), 6.65 (s, 2H), 5.24–5.38 (dd, J¼14.60,
18.48 Hz, 2H), 4.68–4.73 (dd, J¼2.78, 10.78 Hz, 1H),
4.37–4.40 (dd, J¼2.25, 8.21 Hz, 1H), 3.89–3.94 (dd,
J¼8.32, 10.77 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.64–
3.77 (m, 1H), 3.32–3.41 (m, 1H), 2.88–2.98 (m, 1H), 2.77–
2.85 (m, 1H); 13C NMR (CDCl3) d 28.38, 43.28, 53.27,
53.83 (C–F), 55.96, 56.21, 69.35, 108.74, 111.76, 114.50
(C–F), 114.78 (C–F), 115.36 (C–F), 115.65 (C–F),
122.17, 124.24 (C–F), 124.28 (C–F), 126.83, 129.50,
129.93 (C–F), 130.04 (C–F), 131.39, 135.41, 139.10
(C–F), 139.20 (C–F), 148.14, 148.62, 155.92; MS (m/z):
423 (Mþ); Anal. Calcd for C23H22FN3O4: C, 65.24; H, 5.24;
N, 9.92. Found: C, 65.22; H, 5.20; N, 9.90.
4.3.6. (10bS)-2-Allyl-8,9-dimethoxy-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6f). 92%;
mp 172–173 8C; IR (KBr) 3082, 3026, 2948, 2850, 1638,
1620, 1520, 1458, 1420, 1360, 1328, 1266, 1220, 1108,
1078, 1040, 1008, 968, 916, 870, 770 cm21 1H NMR
;
(CDCl3) d 7.73 (s, 1H), 6.66 (s, 1H), 6.65 (s, 1H), 5.98–6.01
(m, 1H), 5.21–5.27 (m, 2H), 4.72–4.81 (m, 2H), 4.69–4.72
(dd, J¼2.75, 10.80 Hz, 1H), 4.37–4.39 (dd, J¼1.96,
8.10 Hz, 1H), 3.91–3.95 (dd, J¼8.30, 10.80 Hz, 1H), 3.89
(s, 3H), 3.87 (s, 3H), 3.70–3.74 (m, 1H), 3.36–3.41 (m,
1H), 2.91–2.97 (m, 1H), 2.81–2.85 (m, 1H); 13C NMR
(CDCl3) d 28.40, 43.50, 53.40, 53.43, 56.01, 56.28, 69.26,
108.92, 111.90, 118.09, 122.39, 126.92, 129.36, 131.35,
132.46, 135.67, 148.25, 148.73, 155.82; MS (m/z): 355
(Mþ); Anal. Calcd for C19H21N3O4: C, 64.21; H, 5.96; N,
11.82. Found: C, 64.21; H, 5.92; N, 11.79.
4.3.10. (10bS)-2-(2-Fluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6j). 90%; mp 195–196 8C; IR (KBr) 3070, 2950,
2906, 2840, 1642, 1616, 1516, 1458, 1360, 1262, 1218,
1
1050, 764 cm21; H NMR (CDCl3) d 7.74 (s, 1H), 7.31–
7.37 (m, 1H), 7.20–7.28 (m, 1H), 7.01–7.10 (m, 2H), 6.66
(s, 2H), 5.35–5.46 (dd, J¼14.59, 18.50 Hz, 2H), 4.69–4.73
(dd, J¼2.76, 10.78 Hz, 1H), 4.37–4.41 (dd, J¼2.02,
8.14 Hz, 1H), 3.89–3.95 (dd, J¼8.30, 10.75 Hz, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.69–3.76 (m, 1H), 3.32–3.40 (m,
1H), 2.88–2.98 (m, 1H), 2.77–2.85 (m, 1H); 13C NMR
(CDCl3) d 28.36, 43.25, 47.86 (C–F), 47.91 (C–F), 53.27,
55.96, 56.21, 69.33, 108.74, 111.77, 115.17 (C–F), 115.46
(C–F), 122.21, 123.68 (C–F), 123.88 (C–F), 124.12
(C–F), 124.17 (C–F), 126.85, 129.30 (C–F), 129.41
(C–F), 129.47, 130.60 (C–F), 130.65 (C–F), 131.32,
135.31, 148.12, 148.60, 156.10; MS (m/z): 423 (Mþ);
Anal. Calcd for C23H22FN3O4: C, 65.24; H, 5.24; N, 9.92.
Found: C, 65.21; H, 5.24; N, 9.89.
4.3.7. (10bS)-2-Benzyl-8,9-dimethoxy-5,6,10b,11-tetra-
hydro-2H-12-oxa-2,3,4b-triazachrysen-1-one (6g). 95%;
mp 208–210 8C; IR (KBr) 3048, 2936, 1634, 1620, 1520,
1460, 1414, 1320, 1264, 1220, 1160, 1112, 1080, 836, 776,
738 cm21; 1H NMR (CDCl3) d 7.70 (s, 1H), 7.25–7.44 (m,
5H), 6.65 (s, 1H), 6.64 (s, 1H), 5.26–5.38 (dd, J¼13.95,
44.80 Hz, 2H), 4.68–4.70 (dd, J¼2.75, 10.80 Hz, 1H),
4.35–4.37 (dd, J¼2.10, 8.20 Hz, 1H), 3.88–3.92 (dd,
J¼8.30, 10.75 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.68–
3.71 (m, 1H), 3.34–3.37 (m, 1H), 2.90–2.92 (m, 1H), 2.78–
2.83 (m, 1H); 13C NMR (CDCl3) d 28.05, 43.39, 53.34,
54.36, 55.99, 56.26, 69.28, 108.92, 111.89, 12235, 126.91,
127.70, 128.50, 128.76, 129.37, 131.28, 135.63, 136.88,
148.22, 148.70, 155.99; MS (m/z): 405 (Mþ); Anal. Calcd
for C23H23N3O4: C, 68.13; H, 5.72; N, 10.36. Found: C,
68.11; H, 5.69; N, 10.37.
4.3.11. (10bS)-2-(2,3-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6k). 91%; mp 200–201 8C; IR (KBr) 3070, 2942,
1
1648, 1616, 1520, 1482, 1360, 1260, 1056, 768 cm21; H
NMR (CDCl3) d 7.74 (s, 1H), 6.96–7.13 (m, 3H), 6.66 (s,
2H), 5.36–5.47 (dd, J¼14.70, 19.20 Hz, 2H), 4.69–4.73
(m, 1H), 4.37–4.41 (m, 1H), 3.91–3.95 (m, 1H), 3.89 (s,

3768
S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3H), 3.88 (s, 3H), 3.71–3.78 (m, 1H), 3.33–3.41 (m, 1H),
2.88–2.98 (m, 1H), 2.79–2.85 (m, 1H); 13C NMR (CDCl3)
d 28.29, 43.13, 47.57, 53.18, 55.89, 56.13, 69.31, 108.62,
111.66, 116.38 (C–F), 116.61 (C–F), 122.05, 123.89
(C–F), 123.95 (C–F), 124.04 (C–F), 125.17, 126.04
(C–F), 126.19 (C–F), 126.75 (C–F), 129.50, 131.35,
135.35, 148.05, 148.53, 155.96; MS (m/z): 441 (Mþ);
Anal. Calcd for C23H21F2N3O4: C, 62.58; H, 4.80; N, 9.52.
Found: C, 62.60; H, 4.79; N, 9.49.
148.04, 148.50, 155.78; MS (m/z): 441 (Mþ); Anal. Calcd
for C23H21F2N3O4: C, 62.58; H, 4.80; N, 9.52. Found: C,
62.56; H, 4.79; N, 9.48.
4.3.15. (10bS)-2-(3,4-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6o). 90%; mp 165–166 8C; IR (KBr) 3050, 2924,
1
2832, 1640, 1618, 1516, 1438, 1260, 1102, 762 cm21; H
NMR (CDCl3) d 7.73 (s, 1H), 7.04–7.13 (m, 1H), 7.16–
7.20 (m, 1H), 7.24–7.31 (m, 1H), 6.66 (s, 2H), 5.18–5.32
(dd, J¼13.99, 30.38 Hz, 2H), 4.68–4.73 (dd, J¼2.77,
10.79 Hz, 1H), 4.37–4.41 (dd, J¼2.14, 8.16 Hz, 1H),
3.89–3.94 (dd, J¼8.33, 10.83 Hz, 1H), 3.88 (s, 3H), 3.87
(s, 3H), 3.68–3.78 (m, 1H), 3.33–3.41 (m, 1H), 2.88–2.98
(m, 1H), 2.78–2.86 (m, 1H); 13C NMR (CDCl3) d 28.36,
43.24, 53.25, 53.50, 55.95, 56.20, 69.37, 108.69, 111.73,
117.06 (C–F), 117.29 (C–F), 117.72 (C–F), 117.95 (C–F),
122.09 (C–F), 124.91 (C–F), 124.96 (C–F). 125.00 (C–F),
125.04 (C–F), 126.79, 129.54, 131.45, 133.58 (C–F),
133.65 (C–F), 135.33, 148.13, 148.60, 155.83; MS (m/z):
441 (Mþ); Anal. Calcd for C23H21F2N3O4: C, 62.58; H,
4.80; N, 9.52. Found: C, 62.56; H, 4.79; N, 9.47.
4.3.12. (10bS)-2-(2,4-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6l). 89%; mp 220–221 8C; IR (KBr) 3082, 3026,
2960, 2926, 2850, 1656, 1620, 1520, 1454, 1470, 1270,
1
1222, 1060, 976 cm21; H NMR (CDCl3) d 7.73 (s, 1H),
7.36–7.41 (m, 1H), 6.77–6.84 (m, 2H), 6.66 (s, 2H), 5.29–
5.41 (dd, J¼14.10, 19.80 Hz, 2H), 4.68–4.73 (dd, J¼3.00,
10.50 Hz, 1H), 4.37–4.41 (dd, J¼2.10, 8.10 Hz, 1H), 3.90–
3.95 (dd, J¼8.10, 10.80 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H),
3.70–3.78 (m, 1H), 3.32–3.41 (m, 1H), 2.88–2.98 (m, 1H),
2.77–2.85 (m, 1H); 13C NMR (CDCl3) d 28.28, 43.17,
47.41 (C–F), 47.46 (C–F), 53.19, 55.89, 56.14, 69.28, 103.31
(C–F), 103.65 (C–F), 103.98 (C–F), 108.67, 111.08 (C–F),
111.13 (C–F), 111.36 (C–F), 111.41 (C–F), 111.71, 119.57
(C–F), 119.62 (C–F), 119.77 (C–F), 119.82 (C–F), 122.09,
126.76, 129.39, 131.30, 131.76 (C–F), 131.82 (C–F), 131.88
(C–F), 131.96 (C–F), 135.20, 148.08, 148.56, 155.96; MS
(m/z): 441 (Mþ); Anal. Calcd for C23H21F2N3O4: C, 62.58; H,
4.80; N, 9.52. Found: C, 62.56; H, 4.79; N, 9.50.
4.3.16. (10bS)-2-(3,5-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6p). 91%; mp 208–209 8C; IR (KBr) 3100, 2950,
1638, 1520, 1462, 1324, 1274, 1124, 992, 836, 778 cm21
;
1H NMR (CDCl3) d 7.74 (s, 1H), 6.90–6.94 (m, 2H), 6.66–
7.72 (m, 3H), 5.20–5.34 (dd, J¼14.40, 26.10 Hz, 2H),
4.69–4.73 (dd, J¼2.40, 10.50 Hz, 1H), 4.37–4.41 (dd,
J¼2.10, 8.10 Hz, 1H), 3.89–3.94 (dd, J¼8.40, 10.80 Hz,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.72–3.79 (m, 1H), 3.34–
3.42 (m, 1H), 2.89–2.97 (m, 1H), 2.78–2.85 (m, 1H); 13C
NMR (CDCl3) d 28.30, 43.17, 53.19, 53.54, 55.89, 56.14,
69.32, 102.73 (C–F), 103.07 (C–F), 103.40 (C–F), 108.68,
111.15 (C–F), 111.25 (C–F), 111.37 (C–F), 111.48 (C–F),
111.71,122.03,126.75,129.56,131.42, 135.20,139.10(C–F),
140.35 (C–F), 140.26 (C–F), 148.10, 148.58, 155.79; MS
(m/z): 441 (Mþ); Anal. Calcd for C23H21F2N3O4: C, 62.58;
H, 4.80; N, 9.52. Found: C, 62.57; H, 4.81; N, 9.49.
4.3.13. (10bS)-2-(2,5-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6m). 87%; mp 215–216 8C; IR (KBr) 3098, 2950,
1
1638, 1520, 1264 cm21; H NMR (CDCl3) d 7.77 (s, 1H),
6.93–7.28 (m, 3H), 6.67 (s, 2H), 5.33–5.44 (dd, J¼14.93,
18.70 Hz, 2H), 4.71–4.75 (dd, J¼2.78, 10.78 Hz, 1H),
4.40–4.44 (dd, J¼2.20, 8.19 Hz, 1H), 3.91–3.96 (dd,
J¼8.31, 10.75 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.73–
3.80 (m, 1H), 3.35–3.43 (m, 1H), 2.90–3.00 (m, 1H), 2.79–
2.87 (m, 1H); 13C NMR (CDCl3) d 28.37, 43.22, 47.74,
53.25, 55.95, 56.20, 69.41, 108.69, 111.74, 115.45 (C–F),
115.57 (C–F), 115.77 (C–F), 115.88 (C–F), 116.12 (C–F),
116.23 (C–F), 116.44 (C–F), 116.53 (C–F), 116.81 (C–F),
116.86 (C–F), 122.10, 125.27 (C–F), 125.38 (C–F), 125.51
(C–F), 125.61 (C–F), 126.81, 129.66, 131.21, 135.21,
148.13, 148.61, 156.03; MS (m/z): 441 (Mþ); Anal. Calcd
for C23H21F2N3O4: C, 62.58; H, 4.80; N, 9.52. Found: C,
62.55; H, 4.78; N, 9.50.
4.3.17. (10bS)-8,9-Dimethoxy-2-(4-trifluoromethyl-
benzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (6q). 92%; mp 215–216 8C; IR (KBr) 3072,
2948, 1620, 1522, 1464, 1430, 1340, 1260, 1120, 838,
758 cm21; 1H NMR (CDCl3) d 7.73 (s, 1H), 7.52–7.58 (m,
4H), 6.65 (s, 2H), 5.29–5.43 (dd, J¼13.80, 28.80 Hz, 2H),
4.68–4.72 (dd, J¼2.70, 10.80 Hz, 1H), 4.37–4.40 (dd,
J¼1.80, 8.10 Hz, 1H), 3.89–3.94 (dd, J¼8.40, 10.80 Hz,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.70–3.77 (m, 1H), 3.32–
3.41 (m, 1H), 2.88–2.98 (m, 1H), 2.77–2.85 (m, 1H); 13C
NMR (CDCl3) d 28.38, 43.28, 53.28, 53.95, 55.97, 56.22,
69.37, 108.75, 111.78, 122.13, 125.39 (C–F), 125.45
(C–F), 125.50 (C–F), 125.54 (C–F), 126.81, 128.99,
129.58, 131.44, 135.39, 140.65, 148.19, 148.66, 155.94;
MS (m/z): 473 (Mþ); Anal. Calcd for C24H22F3N3O4: C,
60.89; H, 4.68; N, 8.88. Found: C, 60.86; H, 4.68; N, 8.85.
4.3.14. (10bS)-2-(2,6-Difluorobenzyl)-8,9-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (6n). 93%; mp 206–207 8C; IR (KBr) 3092, 2950,
1650, 1624, 1520, 1480, 1278, 1256, 1056, 840, 794 cm21
;
1H NMR (CDCl3) d 7.68 (s, 1H), 7.21–7.31 (m, 1H), 6.85–
6.94 (m, 2H), 6.65 (s, 1H), 6.64 (s, 1H), 5.42 (s, 2H), 4.68–
4.72 (dd, J¼2.70, 10.80 Hz, 1H), 4.36–4.40 (dd, J¼2.10,
8.10 Hz, 1H), 3.89–3.95 (dd, J¼8.40, 11.10 Hz, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.63–3.73 (m, 1H), 3.30–3.38 (m,
1H), 2.86–2.96 (m, 1H), 2.75–2.83 (m, 1H); 13C NMR
(CDCl3) d 28.32, 41.97 (C–F), 42.01 ( (C–F), 43.18, 53.21,
55.90, 56.14, 69.26, 108.65, 111.03 (C–F), 111.12 (C–F),
111.26 (C–F), 111.37 (C–F), 111.67, 112.13 (C–F),
122.20, 126.78, 129.18 (C–F), 129.76, 131.13, 135.09,
4.3.18. (10bS)-8,9-Dimethoxy-2-(3-trifluoromethyl-
benzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (6r). 92%; mp 155–156 8C; IR (KBr) 3076,
2952, 2846, 1638, 1610, 1512, 1320, 1258, 1168, 1120,
1
760 cm21; H NMR (CDCl3) d 7.74 (s, 1H), 7.68 (s, 1H),

S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3769
7.63–7.65 (d, 1H), 7.51–7.54 (d, 1H), 7.40–7.45 (t, 1H),
6.65 (s, 2H), 5.29–5.43 (dd, J¼14.40, 27.90 Hz, 2H), 4.68–
4.73 (dd, J¼2.70, 10.50 Hz, 1H), 4.37–4.41 (dd, J¼1.80,
8.10 Hz, 1H), 3.89–3.94 (dd, J¼8.40, 10.80 Hz, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.70–3.78 (m, 1H), 3.33–3.41 (m,
1H), 2.88–2.98 (m, 1H), 2.77–2.85 (m, 1H); 13C NMR
(CDCl3) d 28.38, 43.26, 53.27, 53.94, 55.96, 56.22, 69.39,
108.76, 111.78, 122.15, 124.59 (C–F), 124.64 (C–F),
125.40 (C–F), 125.45 (C–F), 125.50 (C–F), 126.85,
129.00, 129.58, 131.45, 132.29, 132.30, 135.35, 137.65,
148.16, 148.65, 155.91; MS (m/z): 473 (Mþ); Anal. Calcd
for C24H22F3N3O4: C, 60.89; H, 4.68; N, 8.88. Found: C,
60.86; H, 4.67; N, 8.85.
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7c). 92%; mp 198–199 8C; IR (KBr) 3050, 2976,
2948, 1648, 1622, 1526, 1430, 1260, 1218, 1104, 1040,
1010, 842 cm21; 1H NMR (CDCl3) d 7.68 (s, 1H), 6.76 (s,
1H), 6.62 (s, 1H), 4.25–4.31 (m, 1H), 4.01–4.12 (m, 3H),
3.88 (s, 3H), 3.87 (s, 3H), 3.82–3.86 (m, 1H), 3.36–3.49
(m, 1H), 2.88–3.00 (m, 1H), 2.65–2.73 (m, 1H), 1.75–1.87
(m, 2H), 1.50 (d, J¼6.30 Hz, 3H), 0.92–0.97 (t, J¼7.20 Hz,
3H); 13C NMR (CDCl3) d 11.07, 18.53, 21.72, 27.43,
45.61, 52.70, 55.84, 56.04, 59.10, 73.07, 110.68, 111.43,
123.75, 127.60, 129.54, 130.65, 135.26, 147.49, 148.50,
155.95; MS (m/z): 371 (Mþ); Anal. Calcd for C20H25N3O4:
C, 64.67; H, 6.78; N, 11.31. Found: C, 64.66; H, 6.76; N,
11.30.
4.3.19. (10bS)-8,9-Dimethoxy-2-(2-trifluoromethyl-
benzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (6s). 93%; mp 220–221 8C; IR (KBr) 3062,
4.3.23. (10bS,11S)-2-Isopropyl-8,9-dimethoxy-11-
methyl-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (7d). 91%; mp 242–243 8C; IR (KBr) 3074,
2962, 2924, 1626, 1600, 1510, 1418, 1248, 1200, 1180,
1
2942, 1646, 1618, 1516, 1312, 1100, 770 cm21; H NMR
(CDCl3) d 7.77 (s, 1H), 7.65–7.68 (d, 1H), 7.31–7.47 (m,
2H), 7.07–7.09 (d, 1H), 6.68 (s, 1H), 6.67 (s, 1H), 5.57 (s,
2H), 4.72–4.77 (dd, J¼3.00, 11.10 Hz, 1H), 4.42–4.46 (dd,
J¼2.00, 8.10 Hz, 1H), 3.92–3.97 (dd, J¼8.40, 11.10 Hz,
1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.74–3.81 (m, 1H), 3.35–
3.43 (m, 1H), 2.91–3.01 (m, 1H), 2.78–2.86 (m, 1H); 13C
NMR (CDCl3) d 28.28, 43.12, 50.11, 53.19, 55.87, 56.13,
69.35, 108.67, 111.71, 122.06, 127.77 (C–F), 125.84
(C–F), 125.91 (C–F), 126.76, 127.12, 128.08, 129.66,
131.39, 131.96, 135.09, 135.34, 148.08, 148.56, 156.27; MS
(m/z): 473 (Mþ); Anal. Calcd for C24H22F3N3O4: C, 60.89;
H, 4.68; N, 8.88. Found: C, 60.87; H, 4.66; N, 8.87.
1
1086, 1020, 990, 824 cm21; H NMR (CDCl3) d 7.74 (s,
1H), 6.76 (s, 1H), 6.62 (s, 1H), 5.27–5.36 (m, 1H), 4.30–
4.38 (m, 1H), 4.07 (d, J¼5.10 Hz, 1H), 3.88–3.91 (m, 1H),
3.87 (s, 3H), 3.86 (s, 3H), 3.36–3.46 (m, 1H), 2.88–3.01
(m, 1H), 2.65–2.73 (m, 1H), 1.50 (d, J¼6.60 Hz, 3H),
1.30–1.35 (t, J¼6.60 Hz, 6H); 13C NMR (CDCl3) d 18.66,
20.95, 21.07, 27.45, 45.64, 48.54, 55.93, 56.13, 59.13,
72.95, 110.60, 111.54, 124.05, 127.66, 129.48, 130.36,
135.00, 147.60, 148.57, 155.70; MS (m/z): 371 (Mþ); Anal.
Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found:
C, 64.63; H, 6.77; N, 11.29.
4.3.20. (10bS,11S)-8,9-Dimethoxy-2,11-dimethyl-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7a). 94%; mp 183–184 8C; IR (KBr) 3100, 2976,
1642, 1620, 1520, 1422, 1220, 1110, 1018, 980, 838,
4.3.24. (10bS,11S)-2-Butyl-8,9-dimethoxy-11-methyl-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7e). 88%; mp 126–127 8C; IR (KBr) 3074, 2952,
2874, 1640, 1620, 1522, 1428, 1360, 1278, 1216, 1104,
1012, 838, 778 cm21; 1H NMR (CDCl3) d 7.68 (s, 1H), 6.76
(s, 1H), 6.62 (s, 1H), 4.25–4.31 (m, 1H), 4.05–4.13 (m,
3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.78–3.84 (m, 1H),
3.37–3.49 (m, 1H), 2.89–3.01 (m, 1H), 2.66–2.73 (m,
1H), 1.73–1.80 (m, 2H), 1.50 (d, J¼6.00 Hz, 3H),
1.33–1.41 (m, 2H), 0.92–0.96 (t, J¼7.20 Hz, 3H); 13C
NMR (CDCl3) d 13.72, 18.53, 19.80, 27.44, 30.52,
45.62, 50.94, 55.84, 56.05, 59.12, 73.08, 110.70, 111.43,
123.76, 127.60, 129.55, 130.65, 135.29, 147.50, 148.51,
155.92; MS (m/z): 385 (Mþ); Anal. Calcd for C21H27N3O4:
C, 65.44; H, 7.06; N, 10.90. Found: C, 65.43; H, 7.05; N,
10.87.
1
746 cm21; H NMR (CDCl3) d 7.68 (s, 1H), 6.76 (s, 1H),
6.61 (s, 1H), 4.39–4.47 (m, 1H), 4.09 (d, J¼4.20 Hz, 1H),
3.88–3.91 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.68–3.77 (s,
3H), 3.37–3.49 (m, 1H), 2.91–3.01 (m, 1H), 2.65–2.72 (m,
1H), 1.50 (d, J¼6.60 Hz, 3H); 13C NMR (CDCl3) d 18.48,
27.11, 39.49, 45.63, 55.79, 55.98, 58.84, 72.69, 110.24,
111.45, 123.99, 127.37, 129.41, 130.86, 135.24, 147.49,
148.45, 156.20; MS (m/z): 343 (Mþ); Anal. Calcd for
C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.92;
H, 6.17; N, 12.24.
4.3.21. (10bS,11S)-2-Ethyl-8,9-dimethoxy-11-methyl-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7b). 90%; mp 150–151 8C; IR (KBr) 3094, 2984,
2950, 1636, 1620, 1526, 1440, 1264, 1220, 1200, 1106,
4.3.25. (10bS,11S)-2-Allyl-8,9-dimethoxy-11-methyl-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7f). 91%; mp 195–196 8C; IR (KBr) 3142, 3026,
2986, 2800, 1646, 1618, 1260, 1100, 1030, 1002, 836,
1
1038, 1016, 840 cm21; H NMR (CDCl3) d 7.70 (s, 1H),
6.76 (s, 1H), 6.62 (s, 1H), 4.30–4.38 (m, 1H), 4.11–4.24
(m, 2H), 4.07 (d, J¼5.10 Hz, 1H), 3.88–3.91 (m, 1H), 3.87
(s, 3H), 3.86 (s, 3H), 3.37–3.49 (m, 1H), 2.88–3.01 (m,
1H), 2.66–2.73 (m, 1H), 1.50 (d, J¼6.60 Hz, 3H), 1.32–
1.37 (t, J¼7.50 Hz, 3H); 13C NMR (CDCl3) d 15.56, 18.49,
27.29, 45.58, 46.25, 55.79, 55.99, 58.98, 72.89, 110.50,
111.42, 123.81, 127.51, 129.64, 130.68, 135.23, 147.46,
148.45, 155.67; MS (m/z): 357 (Mþ); Anal. Calcd for
C19H23N3O4: C, 63.85; H, 6.49; N, 11.76; N, 12.24. Found:
C, 63.82; H, 6.47; N, 11.74.
1
780 cm21; H NMR (CDCl3) d 7.71 (s, 1H), 6.76 (s, 1H),
6.62 (s, 1H), 5.93–6.04 (m, 1H), 5.19–5.28 (m, 2H), 4.66–
4.80 (m, 2H), 4.28–4.34 (m, 1H), 4.07 (d, J¼5.1 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.82–3.84 (m, 1H), 3.36–3.46
(m, 1H), 2.88–3.00 (m, 1H), 2.66–2.73 (m, 1H), 1.50 (d, J
¼6.60 Hz, 3H); 13C NMR (CDCl3) d 18.61, 27.47, 45.71,
53.43, 55.94, 56.13, 59.17, 73.15, 110.68, 111.54, 118.08,
123.84, 127.63, 130.09, 130.89, 132.49, 135.37, 147.61,
148.61, 155.86; MS (m/z): 369 (Mþ); Anal. Calcd for
C20H23N3O4: C, 65.03; H, 6.28; N, 11.37. Found: C, 65.01;
H, 6.26; N, 11.38.
4.3.22. (10bS,11S)-8,9-Dimethoxy-11-methyl-2-propyl-

3770
S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
4.3.26. (10bS,11S)-2-Benzyl-8,9-dimethoxy-11-methyl-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (7g). 92%; mp 183–184 8C; IR (KBr) 3072, 2950,
1634, 1612, 1516, 1458, 1410, 1354, 1260, 1208, 1100,
47.80 (C–F), 55.81, 56.03, 59.18, 73.34, 110.82, 111.40,
115.01 (C–F), 115.30 (C–F), 123.45, 123.61 (C–F), 123.80
(C–F), 123.99 (C–F), 124.04 (C–F), 135.05, 147.46, 148.50,
156.05; MS (m/z): 437 (Mþ); Anal. Calcd for C24H24F1N3O4:
C, 65.89; H, 5.53; N, 9.61. Found: C, 65.87; H, 5.50; N, 9.61.
1
1006, 736 cm21; H NMR (CDCl3) d 7.67 (s, 1H), 7.41–
7.45 (m, 2H), 7.22–7.32 (m, 3H), 6.74 (s, 1H), 6.61 (s, 1H),
5.21–5.37 (dd, J¼14.10, 33.30 Hz, 2H), 4.15–4.23 (m,
1H), 4.02 (d, J¼5.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
3.76–3.83 (m, 1H), 3.31–3.41 (m, 1H), 2.85–2.96 (m, 1H),
2.62–2.70 (m, 1H), 1.49 (d, J¼6.30 Hz, 3H); 13C NMR
(CDCl3) d 18.60, 27.60, 45.59, 54.34, 55.91, 56.13, 59.27,
73.37, 110.92, 111.50, 123.58, 127.64, 127.75, 128.44,
128.82, 130.21, 130.92, 135.31, 136.87, 147.53, 148.59,
156.01; MS (m/z): 419 (Mþ); Anal. Calcd for C24H25N3O4: C,
68.72; H, 6.01; N, 10.02. Found: C, 68.69; H, 6.00; N, 10.01.
4.3.30. (10bS,11S)-2-(2,3-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7k). 91%; mp 190–192 8C;
IR (KBr) 3050, 2948, 1638, 1516, 1500, 1460, 1274, 1100,
1
1032, 830, 768 cm21; H NMR (CDCl3) d 7.71 (s, 1H),
6.96–7.15 (m, 3H), 6.74 (s, 1H), 6.63 (s, 1H), 5.39 (d,
J¼3.30 Hz, 2H), 4.17–4.25 (m, 1H), 4.06 (d, J¼5.40 Hz,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81–3.84 (m, 1H), 3.35–
3.44 (m, 1H), 2.88–2.99 (m, 1H), 2.66–2.72 (m, 1H), 1.48
(d, J¼6.30 Hz, 3H); 13C NMR (CDCl3) d 18.54, 27.61,
45.52, 47.60, 55.87, 56.07, 59.26, 73.48, 110.81, 111.39,
116.36 (C–F), 116.59 (C–F), 123.39, 124.03 (C–F), 125.40
(C–F), 125.43 (C–F), 126.23 (C–F), 127.67, 130.41,
131.01, 135.04, 138.26, 147.51, 156.18; MS (m/z): 455
(Mþ); Anal. Calcd for C24H23F2N3O4: C, 63.29; H, 5.09; N,
9.23. Found: C, 63.26; H, 5.07; N, 9.24.
4.3.27. (10bS,11S)-2-(4-Fluorobenzyl)-8,9-dimethoxy-11-
methyl-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (7h). 90%; mp 186–187 8C; IR (KBr) 3098,
2970, 1640, 1622, 1520, 1436, 1362, 1280, 1238, 1210,
1102, 1036, 1020, 826, 780 cm21; 1H NMR (CDCl3) d 7.68
(s, 1H), 7.41–7.46 (m, 2H), 6.94–7.01 (m, 2H), 6.74 (s,
1H), 6.61 (s, 1H), 5.17–5.33 (dd, J¼13.80, 35.40 Hz, 2H),
4.14–4.23 (m, 1H), 4.03 (d, J¼5.40 Hz, 1H), 3.87 (s, 3H),
3.86 (s, 3H), 3.78–3.83 (m, 1H), 3.33–3.42 (m, 1H), 2.86–
2.97 (m, 1H), 2.64–2.71 (m, 1H), 1.48 (d, J¼6.30 Hz, 3H);
13C NMR (CDCl3) d 18.53, 27.56, 45.52, 53.64, 55.84,
56.04, 59.21, 73.37, 100.49 (C–F), 110.80, 111.36, 115.06
(C–F), 115.34 (C–F), 123.42, 127.64, 130.20, 130.60
(C–F), 130.72 (C–F), 130.91 (C–F), 132.57 (C–F),
132.60, 135.22, 147.46, 148.51, 155.86; MS (m/z): 437
(Mþ); Anal. Calcd for C24H24F1N3O4: C, 65.89; H, 5.53; N,
9.61. Found: C, 65.85; H, 5.50; N, 9.58.
4.3.31. (10bS,11S)-2-(2,4-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7l). 90%; mp 190–191 8C; IR
(KBr) 3058, 2948, 1638, 1518, 1430, 1264, 1020 cm21; 1H
NMR (CDCl3) d 7.63 (s, 1H), 7.37–7.42 (m, 1H), 6.69–
6.82 (m, 2H), 6.67 (s, 1H), 6.62 (s, 1H), 5.36 (d, J¼3.30 Hz,
2H), 4.22–4.32 (m, 1H), 4.05 (d, J¼5.68 Hz, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.76–3.82 (m, 1H), 3.34–3.43 (m, 1H),
2.82–2.94 (m, 1H), 2.61–2.74 (m, 1H), 1.47 (d, J¼6.50 Hz,
3H); 13C NMR (CDCl3) d 18.55, 27.61, 45.53, 47.48, 55.88,
56.08, 59.26, 73.46, 103.31 (C–F), 103.65 (C–F), 103.98
(C–F), 110.82, 111.10 (C–F), 111.16 (C–F), 111.24 (C–F),
111.40 (C–F), 111.56, 119.63 (C–F), 123.43, 127.67, 130.32
(C–F), 130.98, 132.06, 147.52, 148.57, 156.08; MS(m/z):455
(Mþ); Anal. Calcd for C24H23F2N3O4: C, 63.29; H, 5.09; N,
9.23. Found: C, 63.28; H, 5.05; N, 9.22.
4.3.28. (10bS,11S)-2-(3-Fluorobenzyl)-8,9-dimethoxy-11-
methyl-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (7i). 94%; mp 202–203 8C; IR (KBr) 3096,
2952, 1642, 1520, 1460, 1280, 1258, 1102, 1030, 776 cm21
;
1H NMR (CDCl3) d 7.69 (s, 1H), 7.19–7.30 (m, 2H), 7.10–
7.14 (m, 1H), 6.92–6.98 (m, 1H), 6.74 (s, 1H), 6.62 (s, 1H),
5.20–5.36 (dd, J¼13.80, 32.70 Hz, 2H), 4.14–4.22 (m,
1H), 4.04 (d, J¼5.70 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H),
3.79–3.84 (m, 1H), 3.34–3.44 (m, 1H), 2.89–2.98 (m, 1H),
2.66–2.72 (m, 1H), 1.48 (d, J¼6.30 Hz, 3H); 13C NMR
(CDCl3) d 18.55, 27.63, 45.55, 53.83 (C–F), 53.85 (C–F),
55.88, 56.08, 59.28, 73.48, 110.88, 111.41, 114.42 (C–F),
114.70 (C–F), 115.42 (C–F), 115.71 (C–F), 123.41, 124.31
(C–F), 124.35 (C–F), 127.69, 129.85 (C–F), 129.95 (C–F),
130.35(C–F),131.00,135.22,139.18, 147.52, 148.57, 155.93;
MS(m/z): 437 (Mþ); Anal. CalcdforC24H24F1N3O4: C, 65.89;
H, 5.53; N, 9.61. Found: C, 65.86; H, 5.52; N, 9.59.
4.3.32. (10bS,11S)-2-(2,5-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7m). 92%; mp 204–205 8C;
IR (KBr) 3100, 2974, 1648, 1516, 1476, 1292, 1016, 1040,
842 cm21; 1H NMR (CDCl3) d 7.72 (s, 1H), 6.97–7.05 (m,
2H), 6.87–6.95 (m, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 5.32–
5.37 (dd, J¼2.03, 8.14 Hz, 2H), 4.16–4.24 (m, 1H), 4.06 (d,
J¼5.55 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81–3.85 (m,
1H), 3.36–3.45 (m, 1H), 2.91–3.00 (m, 1H), 2.66–2.73 (m,
1H), 1.49 (d, J¼6.31 Hz, 3H); 13C NMR (CDCl3) d 18.61,
27.71, 45.59, 47.78 (C–F), 47.83 (C–F), 55.94, 56.16,
59.37, 73.63, 110.99, 111.49, 115.43 (C–F), 115.55 (C–F),
115.76 (C–F), 115.87 (C–F), 116.08 (C–F), 116.19 (C–F),
116.40 (C–F), 116.52 (C–F), 116.68 (C–F), 116.73 (C–F),
117.01 (C–F), 117.06 (C–F), 123.43, 125.30 (C–F), 125.42
(C–F), 125.54 (C–F), 125.66 (C–F), 127.77, 130.59,
131.14, 135.14, 147.61, 148.67, 156.11; MS (m/z): 455
(Mþ); Anal. Calcd for C24H23F2N3O4: C, 63.29; H, 5.09; N,
9.23. Found: C, 63.28; H, 5.08; N, 9.21.
4.3.29. (10bS,11S)-2-(2-Fluorobenzyl)-8,9-dimethoxy-11-
methyl-5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triaza-
chrysen-1-one (7j). 93%; mp 177–178 8C; IR (KBr) 3078,
2970, 2900, 1644, 1620, 1522, 1470, 1438, 1364, 1280,
1240, 1214, 1100, 1032, 1018, 776 cm21; 1H NMR (CDCl3)
d 7.70 (s, 1H), 7.22–7.37 (m, 2H), 7.00–7.08 (m, 2H), 6.75
(s, 1H), 6.62 (s, 1H), 5.33–5.43 (dd, J¼15.00, 15.90 Hz,
2H), 4.19–4.23 (m, 1H), 4.04–4.06 (m, 1H), 3.87 (s, 3H),
3.86 (s, 3H), 3.80–3.83 (m, 1H), 3.35–3.42 (m, 1H), 2.87–
2.92 (m, 1H), 2.64–2.71 (m, 1H), 1.50 (d, J¼6.00 Hz, 3H);
13C NMR (CDCl3) d 18.49, 27.52, 45.47, 47.74 (C–F),
4.3.33. (10bS,11S)-2-(2,6-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7n). 92%; mp 240–241 8C;

S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3771
IR (KBr) 3100, 2998, 2954, 1664, 1624, 1522, 1480, 1250,
1
2.65–2.72 (m, 1H), 1.48 (d, J¼5.70 Hz, 3H); 13C NMR
(CDCl3) d 18.51, 27.60, 45.51, 53.92, 55.85, 56.07, 59.26,
73.51, 110.90, 111.42, 123.35, 125.33, 125.38, 127.66,
129.00, 130.42, 131.07, 135.15, 140.63, 147.54, 148.60,
155.93; MS (m/z): 487 (Mþ); Anal. Calcd for
C25H24F3N3O4: C, 61.60; H, 4.96; N, 8.62. Found: C,
61.59; H, 4.92; N, 8.60.
1038, 800 cm21; H NMR (CDCl3) d 7.64 (s, 1H), 7.21–
7.28 (m, 1H), 6.86–6.91 (m, 2H), 6.74 (s, 1H), 6.61 (s, 1H),
5.39 (s, 2H), 4.19–4.27 (m, 1H), 4.04 (d, J¼5.70 Hz, 1H),
3.87 (s, 3H), 3.86 (s, 3H), 3.77–3.83 (m, 1H), 3.32–3.41
(m, 1H), 2.87–2.97 (m, 1H), 2.63–2.70 (m, 1H), 1.48 (d,
J¼6.30 Hz, 3H); 13C NMR (CDCl3) d 18.52, 27.49, 42.09,
45.49, 55.84, 56.03, 59.17, 73.26, 110.71, 110.97 (C–F),
110.99 (C–F), 111.07 (C–F), 111.31, 111.38 (C–F), 111.86
(C–F), 112.11 (C–F), 123.58, 127.63, 129.56 (C–F),
129.69 (C–F), 129.83 (C–F), 129.98 (C–F), 130.74,
134.93, 147.46, 148.49, 155.82; MS (m/z): 455 (Mþ);
Anal. Calcd for C24H23F2N3O4: C, 63.29; H, 5.09; N, 9.23.
Found: C, 63.25; H, 5.08; N, 9.21.
4.3.37. (10bS,11S)-8,9-Dimethoxy-11-methyl-2-(3-tri-
fluoromethylbenzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7r). 90%; mp 145–147 8C; IR
(KBr) 3098, 2972, 1644, 1626, 1526, 1478, 1342, 1284,
1138, 1040, 780, 714 cm21; 1H NMR (CDCl3) d 7.40–7.70
(m, 5H), 6.74 (s, 1H), 6.62 (s, 1H), 5.26–5.41 (dd, J¼14.10,
30.60 Hz, 2H), 4.14–4.22 (m, 1H), 4.04 (d, J¼5.40 Hz,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81–3.84 (m, 1H), 3.35–
3.49 (m, 1H), 2.88–2.98 (m, 1H), 2.64–2.72 (m, 1H), 1.48
(d, J¼6.30 Hz, 3H); 13C NMR (CDCl3) d 18.54, 27.65,
45.53, 53.92, 55.87, 56.08, 59.29, 73.55, 110.89, 111.39,
123.35, 124.51 (C–F), 124.56 (C–F), 125.46 (C–F), 125.51
(C–F), 127.69, 128.93, 130.44, 131.07 (C–F), 132.38
(C–F), 137.59, 147.52, 148.58, 155.60; MS (m/z): 487
(Mþ); Anal. Calcd for C25H24F3N3O4: C, 61.60; H, 4.96; N,
8.62. Found: C, 61.58; H, 4.93; N, 8.60.
4.3.34. (10bS,11S)-2-(3,4-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7o). 91%; mp 143–144 8C; IR
(KBr) 3060, 2942, 2842, 1630, 1516, 1438, 1356, 1270,
1
1100, 1018, 826, 770 cm21; H NMR (CDCl3) d 7.69 (s,
1H), 7.25–7.32 (m, 1H), 7.16–7.21 (m, 1H), 7.03–7.12 (m,
1H), 6.74 (s, 1H), 6.62 (s, 1H), 5.14–5.30 (dd, J¼13.94,
34.11 Hz, 2H), 4.14–4.22 (m, 1H), 4.04 (d, J¼5.53 Hz,
1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.80–3.84 (m, 1H), 3.35–
3.44 (m, 1H), 2.87–2.98 (m, 1H), 2.65–2.72 (m, 1H), 1.48
(d, J¼6.31 Hz, 3H); 13C NMR (CDCl3) d 18.60, 27.69,
45.60, 53.54, 55.93, 56.15, 59.35, 73.57, 110.96, 111.47,
117.02 (C–F), 117.25 (C–F), 117.84 (C–F), 118.07 (C–F),
123.43, 125.02 (C–F), 125.07 (C–F), 125.11 (C–F), 125.16
(C–F), 127.74, 130.44, 131.11, 133.64 (C–F), 133.72
(C–F), 133.76 (C–F), 133.77 (C–F), 135.24, 147.60,
148.21 (C–F), 148.45 (C–F), 148.66, 151.60 (C–F),
151.73 (C–F), 151.85 (C–F), 155.89; MS (m/z): 455
(Mþ); Anal. Calcd for C24H23F2N3O4: C, 63.29; H, 5.09;
N, 9.23. Found: C, 63.28; H, 5.06; N, 9.22.
4.3.38. (10bS,11S)-8,9-Dimethoxy-11-methyl-2-(2-tri-
fluoromethylbenzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7s). 91%; mp 203–204 8C; IR
(KBr) 3048, 2974, 1656, 1624, 1522, 1440, 1330, 1286,
1
1050, 778 cm21; H NMR (CDCl3) d 7.74 (s, 1H), 7.65–
7.68 (d, J¼7.80 Hz, 1H), 7.31–7.47 (m, 2H), 7.0–7.11 (d,
J¼7.8 Hz, 1H), 6.76 (s, 1H), 6.64 (s, 1H), 5.55 (s, 2H),
4.18–4.27 (m, 1H), 4.09 (d, J¼5.40 Hz, 1H), 3.89 (s, 3H),
3.88 (s, 3H), 3.76–3.85 (m, 1H), 3.37–3.51 (m, 1H),
2.88–3.01 (m, 1H), 2.67–2.73 (m, 1H), 1.51 (d, J¼6.00 Hz,
3H); 13C NMR (CDCl3) d 18.56, 27.67, 45.52, 50.56
(C–F), 50.60 (C–F), 55.89, 56.09, 59.33, 73.63, 110.91,
111.42, 123.37, 125.84 (C–F), 125.91 (C–F), 127.12,
127.72 (C–F), 128.29 (C–F), 130.66, 131.10, 132.00
(C–F), 135.05, 135.46 (C–F), 147.55, 148.60, 156.40;
MS (m/z): 487 (Mþ); Anal. Calcd for C25H24F3N3O4: C,
61.60; H, 4.96; N, 8.62. Found: C, 61.57; H, 4.98; N,
8.61.
4.3.35. (10bS,11S)-2-(3,5-Difluorobenzyl)-8,9-
dimethoxy-11-methyl-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7p). 91%; mp 230–231 8C;
IR (KBr) 3076, 2950, 1640, 1522, 1464, 1278, 1126, 1032,
780 cm21; 1H NMR (CDCl3) d 7.70 (s, 1H), 6.90–7.00 (m,
2H), 6.78 (s, 1H), 6.65–6.74 (m, 1H), 6.63 (s, 1H), 5.17–
5.32 (dd, J¼2.02, 8.14 Hz, 2H), 4.14–4.22 (m, 1H), 4.05 (d,
J¼5.70 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.81–3.84 (m,
1H), 3.36–3.45 (m, 1H), 2.88–2.99 (m, 1H), 2.66–2.73 (m,
1H), 1.49 (d, J¼6.60 Hz, 3H); 13C NMR (CDCl3) d 18.54,
27.65, 45.53, 53.60, 55.87, 56.07, 59.30, 73.57, 102.73
(C–F), 103.07 (C–F), 103.40 (C–F), 110.89, 111.28,
111.38 (C–F), 111.51 (C–F), 111.62 (C–F), 123.30,
127.68, 130.50, 131.10, 135.11, 140.24 (C–F), 140.36
(C–F), 147.52, 148.58, 155.86; MS (m/z): 455 (Mþ); Anal.
Calcd for C24H23F2N3O4: C, 63.29; H, 5.09; N, 9.23. Found:
C, 63.24; H, 5.07; N, 9.21.
4.4. Synthesis of compound 8
To a solution of compound 3 (30 mmol) in methanol was
added 6 N hydrochloric acid (120 mmol). The mixture was
warmed to 40 8C for 10 min and heated to reflux for 4 h. The
reaction mixture was slowly cooled to 30 8C. The mixture
was made basic (pH 7.5) by addition of 50% sodium
hydroxide in portion. The product in the mixture was
filtered, and dried at 50 8C.
4.3.36. (10bS,11S)-8,9-Dimethoxy-11-methyl-2-(4-tri-
fluoromethylbenzyl)-5,6,10b,11-tetrahydro-2H-12-oxa-
2,3,4b-triazachrysen-1-one (7q). 89%; mp 130–131 8C;
IR (KBr) 3072, 2948, 1622, 1520, 1466, 1430, 1338, 1260,
1140, 1120, 1076, 1030, 836, 776 cm21; 1H NMR (CDCl3)
d 7.70 (m, 1H), 7.55–7.62 (m, 4H), 6.74 (s, 1H), 6.62 (s,
1H), 5.26–5.42 (dd, J¼13.80, 33.30 Hz, 2H), 4.17–4.19
(m, 1H), 4.06 (d, J¼5.40 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H),
3.81–3.84 (m, 1H), 3.35–3.42 (m, 1H), 2.90–2.94 (m, 1H),
4.4.1. 4-[2-(3,4-Dimethoxyphenyl)ethyl]-4H,7H-pyri-
dazino[4,5-b][1,4]oxazine-3,8-dione (8a). 92%; mp 234–
235 8C; IR (KBr) 3270, 3100, 3064, 3022, 2908, 2840,
1700, 1658, 1630, 1510, 1418, 1374, 1320, 1250, 1228,
1134, 1018, 984, 802, 760 cm21; 1H NMR (CDCl3) d 13.04
(s, 1H), 7.96 (s, 1H), 6.71–6.84 (m, 3H), 4.73 (s, 2H), 4.07–
4.12 (t, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 2.78–2.83 (t, 2H);
13C NMR (CDCl3) d 32.90, 41.87, 55.29, 55.36, 66.78,
111.57, 112.53, 120.74, 125.72, 128.60, 129.92, 136.65,

3772
S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
147.39, 148.51, 155.91, 162.00; MS (m/z): 331 (Mþ); Anal.
Calcd for C16H17N3O5: C, 58.00; H, 5.17; N, 12.68. Found:
C, 57.98; H, 5.15; N, 12.65.
4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione(10c). 91%;
mp 178–179 8C; IR (KBr) 3082, 3046, 2962, 2850, 1718,
1664, 1636, 1510, 1422, 1384, 1368, 1260, 1234, 1170, 1036,
858, 708 cm21; 1H NMR (CDCl3) d 7.83 (s, 1H), 7.26–7.41
(m, 5H), 7.18 (s, 1H), 6.72 (s, 1H), 5.32 (s, 2H), 4.76 (s, 2H),
4.01–4.04 (t, J¼7.43 Hz, 2H), 3.82(s, 3H), 3.81(s, 3H), 3.00–
3.03 (t, J¼7.70 Hz, 2H); 13C NMR (CDCl3) d 38.40, 41.75,
55.09, 56.13, 56.24, 67.50, 87.87, 112.90, 121.86, 125.26,
127.25, 128.09, 128.65, 128.80, 132.44, 135.88, 137.23,
148.93, 149.90, 155.35, 162.11; MS (m/z): 547 (Mþ); Anal.
Calcd for C23H22IN3O5: C, 50.47; H, 4.05; N, 7.68. Found: C,
50.48; H, 4.04; N, 7.62.
4.4.2. (11S)-4-[2-(3,4-Dimethoxyphenyl)ethyl]-2-methyl-
4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione (8b). 90%;
mp 180–182 8C; IR (KBr) 3320, 2974, 2850, 1642,
1620, 1514, 1450, 1408, 1360, 1266, 1222, 1094, 1016,
1
950, 926, 884, 820, 782, 762 cm21; H NMR (CDCl3) d
12.67 (s, 1H), 7.71 (s, 1H), 6.71–6.81 (m, 3H), 4.79–4.85
(m, 1H), 4.00–4.18 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H),
2.87–2.92 (t, 2H), 1.62 (d, J¼6.90 Hz, 3H); 13C NMR
(CDCl3) d 16.72, 33.73, 43.31, 55.97, 55.99, 74.51, 111.55,
112.00, 120.91, 126.83, 128.66, 129.32, 136.56, 148.25,
149.23, 157.89, 164.67; MS (m/z): 487 (Mþ); Anal. Calcd
for C17H19N3O5: C, 59.12; H, 5.55; N, 12.17. Found: C,
59.11; H, 5.53; N, 12.15.
4.4.7. (10bS)-2-Benzyl-7-chloro-9,10-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (11a). 90%; mp 178–179 8C; IR (KBr) 3004, 2946,
2844, 1638, 1600, 1480, 1450, 1332, 1298, 1230, 1156,
1100, 1070, 1044, 942, 782 cm21; 1H NMR (CDCl3) d 7.68
(s, 1H), 7.26–7.44 (m, 5H), 6.95 (s, 1H), 5.28–5.40 (dd,
J¼13.90, 48.20 Hz, 2H), 4.92–4.95 (dd, J¼2.50, 10.15 Hz,
1H), 4.41–4.43 (dd, J¼2.15, 8.30 Hz, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 3.59–3.63 (dd, J¼8.45, 10.10 Hz, 1H),
3.41–3.43 (m, 1H), 3.34–3.38 (m, 1H), 2.95–3.00 (m,
1H), 2.78–2.83 (m, 1H); 13C NMR (CDCl3) d 26.45, 44.25,
51.56, 54.40, 56.14, 60.72, 66.79, 113.28, 125.31, 125.57,
127.72, 128.41, 128.51, 128.76, 131.26, 131.28, 136.86,
137.34, 145.34, 151.19, 156.26; MS (m/z): 440 (Mþ); Anal.
Calcd for C23H22ClN3O4: C, 62.80; H, 5.04; N, 9.55. Found:
C, 62.78; H, 5.04; N, 9.52.
4.4.3. 7-Benzyl-4-[2-(3,4-dimethoxyphenyl)ethyl]-
4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione (9a). 89%;
mp 164–165 8C; IR (KBr) 3100, 3020, 2952, 2848, 1706,
1656, 1630, 1522, 1430, 1394, 1350, 1270, 1240, 1184,
1140, 1030, 1000, 836, 816, 760, 706 cm21 1H NMR
;
(CDCl3) d 7.53 (s, 1H), 7.19–7.35 (m, 5H), 6.71 (d, 1H),
6.61–6.65 (m, 2H), 5.25 (s, 2H), 4.68 (s, 2H), 3.96–3.99 (t,
J¼7.52 Hz, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 2.78–2.81 (t,
J¼7.71 Hz, 2H); 13C NMR (CDCl3) d 34.10, 43.29, 55.40,
56.35, 56.37, 67.85, 111.91, 112.29, 121.23, 125.43, 127.23,
128.55, 129.07, 129.28, 129.71, 136.22, 137.64, 148.65,
149.66, 155.77, 162.27; MS (m/z): 421 (Mþ); Anal. Calcd
for C23H23N3O5: C, 65.55; H, 5.50; N, 9.97. Found: C,
65.53; H, 6.49; N, 9.96.
4.4.8. (10bS)-2-Benzyl-7-bromo-9,10-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (11b). 87%; mp 167–168 8C; IR (KBr) 3014, 2920,
2858, 1636, 1480, 1444, 1430, 1348, 1298, 1220, 1090,
4.4.4. 7-Benzyl-4-[2-(2-chloro-4,5-dimethoxyphenyl)-
ethyl]-4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione
(10a). 89%; mp 175–176 8C; IR (KBr) 3028, 2960, 2850,
1700, 1660, 1626, 1506, 1422, 1388, 1348, 1256, 1210,
1
1036, 830 cm21; H NMR (CDCl3) d 7.67 (s, 1H), 7.24–
7.44 (m, 5H), 7.13 (s, 1H), 5.27–5.40 (dd, J¼13.90,
47.30 Hz, 2H), 4.91–4.94 (dd, J¼2.40, 10.15 Hz, 1H),
4.41–4.43 (dd, J¼2.00, 8.36 Hz, 1H), 3.87 (s, 3H), 3. 86 (s,
3H), 3.58–3.62 (dd, J¼8.50, 10.05 Hz, 1H), 3.41–3.44 (m,
1H), 3.34–3.37 (m, 1H), 2.94–2.96 (m, 1H), 2.78–2.81 (m,
1H); 13C NMR (CDCl3) d 29.33, 44.51, 51.57, 54.40, 56.17,
60.67, 66.80, 116.41, 118.45, 125.86, 127.09, 127.71,
128.50, 128.76, 131.22, 131.26, 136.86, 137.32, 145.94,
151.33, 156.25; MS (m/z): 484 (Mþ); Anal. Calcd for
C23H22BrN3O4: C, 57.04; H, 4.58; N, 8.68. Found: C, 57.03;
H, 4.54; N, 8.66.
1
1170, 1038, 960, 820, 700 cm21; H NMR (CDCl3) d 7.76
(s, 1H), 7.26–7.41 (m, 5H), 6.84 (s, 1H), 6.69 (s, 1H), 5.32
(s, 2H), 4.76 (s, 2H), 4.03–4.06 (t, J¼7.52 Hz, 2H), 3.83 (s,
3H), 3.82 (s, 3H), 2.98–3.01 (t, J¼7.72 Hz, 2H); 13C NMR
(CDCl3) d 31.78, 41.31, 55.06, 56.22, 56.32, 67.47, 112.79,
113.56, 124.91, 125.18, 126.40, 126.89, 128.09, 128.66,
128.81, 135.88, 137.21, 148.38, 149.02, 155.36, 162.05; MS
(m/z): 456 (Mþ); Anal. Calcd for C23H22ClN3O5: C, 60.59;
H, 4.86; N, 9.22. Found: C, 60.55; H, 4.85; N, 9.20.
4.4.5. 7-Benzyl-4-[2-(2-bromo-4,5-dimethoxyphenyl)-
ethyl]-4H,7H-pyridazino[4,5-b][1,4]oxazine-3,8-dione
(10b). 92%; mp 176–177 8C; IR (KBr) 3050, 3012, 2952,
2846, 1698, 1644, 1618, 1510, 1420, 1388, 1344, 1260,
1214, 1164, 1030, 880, 820, 712 cm21; 1H NMR (CDCl3) d
7.73 (s, 1H), 7.19–7.35 (m, 5H), 6.91 (s, 1H), 6.64 (s, 1H),
5.24 (s, 2H), 4.69 (s, 2H), 3.95–3.99 (t, J¼7.44 Hz, 2H),
3.76 (s, 3H), 3.75 (s, 3H), 2.92–2.95 (t, J¼7.71 Hz, 2H);
13C NMR (CDCl3) d 34.50, 41.83, 55.45, 56.62, 67.85,
113.99, 114.55, 116.13, 125.60, 127.42, 128.46, 128.76,
129.02, 129.16, 136.24, 137.57, 149.33, 149.42, 155.74,
162.45; MS (m/z): 500 (Mþ); Anal. Calcd for
C23H22BrN3O5: C, 55.21; H, 4.43; N, 8.40. Found: C,
55.19; H, 4.40; N, 8.41.
4.4.9. (10bS)-2-Benzyl-7-iodo-9,10-dimethoxy-
5,6,10b,11-tetrahydro-2H-12-oxa-2,3,4b-triazachrysen-
1-one (11c). 89%; mp 225–226 8C; IR (KBr) 3048, 2944,
2868, 1648, 1620, 1482, 1422, 1320, 1256, 1106, 1036,
1
1002, 836, 740 cm21; H NMR (CDCl3) d 7.72 (s, 1H),
7,22–7.44 (m, 5H), 6.73 (s, 1H), 5.27–5.36 (dd, J¼13.90,
30.20 Hz, 2H), 4.66–4.69 (dd, J¼2.75, 10.90 Hz, 1H),
4.35–4.37 (dd, J¼1.85, 7.90 Hz, 1H), 3.96–4.00 (dd,
J¼8.00, 10.90 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H),
3.69–3.72 (m, 1H), 3.30–3.33 (m, 1H), 2.87–2.92 (m,
1H), 2.78–2.84 (m, 1H); 13C NMR (CDCl3) d 34.40, 44.16,
53.54, 54.45, 56.36, 60.29, 68.92, 100.99, 110.38, 127.76,
128.11, 128.52, 128.79, 129.34, 130.32, 131.01, 135.94,
136.75, 148.79, 151.29, 155.92; MS (m/z): 531 (Mþ); Anal.
Calcd for C23H22IN3O4: C, 51.99; H, 4.17; N, 7.91. Found:
C, 51.96; H, 4.15; N, 7.88.
4.4.6. 7-Benzyl-4-[2-(2-iodo-4,5-dimethoxyphenyl)ethyl]-

S.-D. Cho et al. / Tetrahedron 60 (2004) 3763–3773
3773
´ ´
El-Gharib, M. S. A.; Sohajda, A.; Bernath, G.; Kobor, J.;
¨
Dombi, G. Heterocycles 1983, 20, 1325. (d) Fu¨lop, F.;
Acknowledgements
´ ´ ´
Bernath, G.; El-Gharib, M. S. A.; Kobor, J.; Sohar, P.; Pelczer,
´
This work was supported by Korea Research Foundation
Grant (KRF-2002-C00008).
´
I.; Argay, G.; Kalman, A. Chem. Ber. 1990, 123, 803.
´
´ ´ ´
(e) Sohar, P.; Lazar, L.; Fu¨lop, F.; Bernath, G.; Kobor, J.
´
¨
Tetrahedron 1992, 48, 4937.
8. (a) Rozwadowska, M. D.; Sulima, A. Tetrahedron 2003, 59,
1173. (b) Rozwadowska, M. D.; Sulima, A. Tetrahedron 2001,
57, 3499.
References and notes
1. For tropoloisoquinolines: (a) Morita, H.; Matsumoto, K.;
Takeya, K.; Itokawa, H.; Iitaka, Y. Chem. Pharm. Bull. 1993,
41, 1418. (b) Morita, H.; Matsumoto, K.; Takeya, K.; Itokawa,
H. Chem. Pharm. Bull. 1993, 41, 1478. (c) Morita, H.; Takeya,
K.; Itokawa, H. Bioorg. Med. Chem. Lett. 1995, 5, 597.
2. For jamtine: Rao, K. V. J.; Rao, L. R. C. J. Sci. Ind. Res. 1981,
125.
´ ´ ´ ´ ´
9. Sohar, P.; Forro, E.; Lazar, L.; Bernath, G.; Sillanpaa, R.;
¨¨
¨
Fu¨lop, F. J. Chem. Soc., Perkin Trans. 2 2000, 287.
10. Senthilvelan, A.; Ramakrishnan, T. V. Tetrahedron Lett. 2002,
43, 8379.
´
¨¨
11. (a) Martinek, T.; Forro, E.; Gu¨nther, G.; Sillanpaa, R.; Fulop,
¨ ¨
F. J. Org. Chem. 2003, 65, 316. (b) Fu¨lop, F.; Forro, E.;
´
¨
¨¨
Martinek, T.; Gu¨nther, G.; Sillanpaa, R. J. Mol. Struct. 2000,
554, 119.
3. For Erythrina alkaloids: (a) Jackson, A. H. In The chemistry
and biology of isoquinoline alkaloids; Phillipson, J. D.,
Roberts, M. F., Zenk, M. H., Eds.; Springer: Berlin, 1985;
p 62. (b) Decker, M. W.; Anderson, D. J.; Brioni, J. D.;
Donnelly-Roberts, D. L.; Kang, C. H.; O’Neill, A. B.; Piattoni-
Kaplan, M.; Swanson, S.; Sullivan, J. P. Eur. J. Pharmacol.
1995, 280, 79.
12. 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.
13. Crystal data for 5a: C16H17N3O4, FW¼315.32, monoclinic,
˚
˚
space group P1 (No. 2), a¼9.725 (6) A, b¼9.870 (5) A,
˚
c¼10.034 (4) A, a¼113.69 (2)8, b¼103.18 (3)8, g¼99.22 (3)8,
4. For dihydroindeno[1,2-c]isoquinolines: (a) Strumberg, D.;
Pommier, Y.; Paull, K.; Jayaraman, M.; Nagafuji, P.;
Cushman, M. J. Med. Chem. 1999, 42, 446. (b) Jayaraman,
M.; Fox, B. M.; Hollingshead, M.; Kohlhagen, G.; Pommier,
Y.; Cushman, M. J. Med. Chem. 2002, 45, 242.
3
3
˚
V¼823.8 (8) A ; Z¼2, Dc¼1.449 g/cm , F000¼380.00, m
(Mo Ka)¼1.07 cm21, Temperature¼2180 8C. Data were
collected on a Rigaku RAXIS-RAPID Imaging Plate diffract-
ometer using 2umax¼60.18 with graphite monochromated
˚
Mo Ka radiation (l¼0.71075 A). Of 8700 reflections
5. For protoberberines: (a) Bhakuni, D. S.; Jain, S. Proto-
berberine aAlkaloids. The alkaloids; Brossi, A., Ed.;
Academic: New York, 1986; Vol. 28, Chapter 2. (b) Bentley,
K. W. Berberines and tetrahydroberberines. The isoquinoline
alkaloids; Ravindranath, B., Ed.; Harwood: Bangalore, 1998;
Vol. 1, p 219.
collected, 4627 reflections with I.23.00s (I), 2u,60.078
were used in the solution. Structure refined to R¼0.087,
R1¼0.046 and Rw¼0.091., Crystal data for 5b: C17H19N3O4,
FW¼329.35, orthorhombic, space group P212121 (No. 19),
˚
˚
˚
a¼7.9375 (5) A, b¼8.2717 (6) A, c¼23.9023 A, V¼1569.3
3
3
˚
(2) A , Z¼4, Dc¼1.394 g/cm , F000¼696.00, ( (Mo Ka)¼8.37
cm21, Temperature¼23.0 8C. Data were collected on a Rigaku
RAXIS-RAPID Imaging Plate diffractometer using
2umax¼136.48 with graphite monochromated Mo Ka radiation
6. (a) Rao, A. K.; Gadre, J. N.; Pednekar, S. Indian J. Chem.
1997, 36, 410. (b) Augelli-Szafran, C. E.; Jaen, J. C.;
Moreland, D. W.; Nelson, C. B.; Penvose-Yi, J. R.; Schwarz,
¨
R. D. Bioorg. Med. Chem. Lett. 1994, 4, 1991. (c) Bohme,
˚
(l¼1.54186 A). Of 18088 reflections collected, 1676 reflec-
T. M.; Augelli-Szafran, C. E.; Hallak, H.; Pugsley, T.; Serpa,
K.; Schwarz, R. D. J. Med. Chem. 2002, 45, 3094.
(d) Hassanein, H.; El Nahal, H. M.; Gerges, F. R. Eur.
J. Med. Chem. 1995, 30, 525.
tions with 2s.136.398 were used in the solution. Structure
refined to R¼0.064, R1¼0.033 and Rw¼0.077..
14. Bryant, R. D.; Kunng, F.-A.; South, M. S. J. Heterocycl.
Chem. 1995, 32, 1473.
7. (a) Nair, V.; Vinod, A. U.; Nair, J. S.; Sreekanth, A. R.; Rath,
N. P. Tetrahedron Lett. 2003, 44, 729. (b) Heydenreich, M.;
15. Cho, S.-D.; Song, S.-Y.; Hur, E.-J.; Chen, M.; Joo, W.-H.;
Falck, J. R.; Yoon, Y.-J.; Shin, D.-S. Tetrahedron Lett. 2001,
41, 6251.
´ ´ ´
¨¨
Koch, A.; Lazar, L.; Szatmari, I.; Sillanpaa, R.; Kleinpeter, E.;
¨
¨ ¨
Fu¨lop, F. Tetrahedron 2003, 59, 1951. (c) Fulop, F.;