A transition metal-free tandem process to pyrrolopyrazino[2,3-d]pyridazine- diones

Article abstract of DOI:10.1016/j.tet.2011.11.021

A transition metal-free tandem process for the synthesis of pyrrolopyrazino[2,3-d]pyridazine-diones is described. The process is an efficient construction of this tricyclic system by a one-pot coupling/Smiles rearrangement/cyclization approach. This methodology has potential applications in the synthesis of biologically and medicinally relevant compounds.

Full text of DOI:10.1016/j.tet.2011.11.021

Tetrahedron 68 (2012) 906e912
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A transition metal-free tandem process to pyrrolopyrazino[2,3-d]
pyridazine-diones
,b,
Aiping Huang a, Zhi Qiao a, Xinhai Zhang a, Wei Yu a, Qingqing Zheng a, Ying Ma a, Chen Ma a
*
a School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2011
Received in revised form 18 October 2011
Accepted 8 November 2011
Available online 15 November 2011
A transition metal-free tandem process for the synthesis of pyrrolopyrazino[2,3-d]pyridazine-diones is
described. The process is an efficient construction of this tricyclic system by a one-pot coupling/Smiles
rearrangement/cyclization approach. This methodology has potential applications in the synthesis of
biologically and medicinally relevant compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolopyrazino[2,3-d]pyridazine-dione
Smiles rearrangement
Tandem reaction
Synthesis
X-ray crystallographic analysis
1. Introduction
Tandem reactions now serve as efficient strategies in synthetic
organic chemistry,25e27 because they can complete several chem-
Pyridazinone moiety is found in various natural products and
biologically active compounds. Many pyridazinones exhibit a wide
range of activities,1e4 such as antimicrobial,5 analgesic,6 anti-in-
flammatory,7 herbicidal,8 antihypertensive,9 antitumor10 proper-
ties. Pyrrolo[1,2-a]pyrazin-1(2H)-ones are known as excellent PARP
inhibitors, and inhibitors against proliferation of BRCA deficient
cells.11 Heterocyclic compounds possessing a pyrrolo[1,2-a]pyr-
azin-1(2H)-one moiety show important biological activities,12e20
including anti-HIV,21 antimalarial,22 antiviral,23 and anticancer24
properties. We envision that pyrrolopyrazino[2,3-d]pyridazine-
diones would be biologically active molecules and intermediates
(Fig. 1).
ical processes in one-pot. There are many important advantages of
tandem reactions, such as atom economy, higher yield, decrease of
the cost of isolating and purifying intermediates. Smiles rear-
rangement is a direct and facile approach for the formation of many
heterocyclic compounds.28e32
Herein we report a simple and effective synthesis of pyrrolopyr-
azino[2,3-d]pyridazine-dione derivatives for constructing a tricyclic
system via a coupling/Smiles rearrangement/cyclization tandem re-
action. We used 2-tetrahydropyranyl-4,5-dichloropyridazin-3-one
and pyrrole-2-carboxamides33e36 as substrates, cesium carbonate
as the base, and acetonitrile as the solvent in one-pot.
2. Results and discussion
We optimized the reaction conditions using N-ethyl-1H-pyr-
role-2-carboxamide 1a and 2 as the model substrates, and we
found that Cs2CO3 in CH3CN was the most efficient system (Table 1).
We started by screening various bases in CH3CN, and Cs2CO3 pro-
vided the highest yields (entries 1e3). We then investigated the
effect of solvents, and CH3CN was the most efficient solvent (entries
2, 4e7). The reaction was also investigated by using K2CO3 as the
base and DMF as the solvent, but yields of the products were much
lower. As shown in Table 1, NaH in CH3CN, K2CO3 in DMF could
afford 3a much more than 4a (entries 3, 8), but yields of them were
much lower. Yields of 3a and 4a under other conditions were
Fig. 1. The structure of pyrrolopyrazino[2,3-d]pyridazine-dione.
* Corresponding author. Tel.: þ86 531 8836 4464; fax: þ86 531 8856 4464;
e-mail address: chenma@sdu.edu.cn (C. Ma).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.021

A. Huang et al. / Tetrahedron 68 (2012) 906e912
907
Table 1
Effects of base and solvent on the yields of 3a and 4aa
Entry
Base
Solvent
T (ꢀC)
Time (h)
Yieldb (%) (3aþ4a)
3a
4a
Total
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
NaH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CH3CN
CH3CN
CH3CN
DMF
NMP
DMSO
THF
Reflux
Reflux
Reflux
80
80
80
d
22
4
0
48
22
20
6
45
24
8
0
30
9
13
4
32
19
4
0
78
31
33
10
77
43
12
9
20
10
23
20
Reflux
80
DMF
a
Reaction conditions: N-ethyl-1H-pyrrole-2-carboxamide 1a (1.0 equiv), 2 (1.2 equiv), Cs2CO3 (3.5 equiv), reflux.
Isolated yield.
b
similar (entries 2, 4e7). Consequently, all following reactions were
It is possible that in compound 3a there was an intramolecular
hydrogen bonding between hydrogen atom on the pyrrole ring and
oxygen atom on the pyridazinone, and they can form a six-centered
structure.
A possible mechanism for the results was proposed in Scheme 1.
Nucleophilic substitution of compound 2 by 1 provided compound
5. Then carboxamide 5 formed carboxamide anion 6. Subsequently,
6 followed two paths a and b. Path b led to 4 by direct cyclization,
conducted with cesium carbonate in refluxing acetonitrile.
To explore the scope of this methodology, a variety of amines
were studied under the reaction conditions, which were optimized
above. The experimental results are collected in Table 2. As ob-
served in Table 2, a variety of pyrrole-2-carboxamides ranging from
aliphatic to aromatic afforded moderate to good yields of tricyclic
products. These all gave a mixture containing 3 and 4 (Table 2).
Table 2
Synthesis of pyrrolopyrazino[2,3-d]pyridazine-dionesa
Entry
R1
Time (h)
Yieldb (%)
Total (3þ4)
4
3
1
2
3
4
5
6
7
8
Et
Pr
i-Pr
c-Hex
13
22
19
14
18
12
13
12
9
30
35
27
38
31
23
36
29
14
27
28
31
4a
4b
4c
4d
4e
4f
4g
4h
4i
48
59
54
51
47
40
57
66
74
64
70
54
3a
3b
3c
3d
3e
3f
3g
3h
3i
78
94
81
89
78
63
93
95
88
91
98
85
Bn
3,4-(MeO)2eC6H3(CH2)2
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
9
10
11
12
7
14
12
4j
4k
4l
3j
3k
3l
a
Reaction conditions: pyrrole-2-carboxamide 1 (1.0 equiv), 2-tetrahydropyranyl-4,5-dichloropyridazin-3-one 2 (1.2 equiv), Cs2CO3 (3.5 equiv), reflux.
Isolated yield.
b
As shown in Table 2, the reactions of 2-tetrahydropyranyl-4,5-
whereas path a led to intermediate 7 via Smiles rearrangement.
Finally, intermediate 7 underwent an intramolecular nucleophilic
with loss of chlorine atom to yield 3.
dichloropyridazin-3-one 2 with aromatic pyrrole-2-carboxamides
(Table 2, entries 7e12) gave higher yields of 3 compared to aliphatic
pyrrole-2-carboxamides (Table 2, entries 1e6). However, aromatic
amines with an electron-withdrawing group (Table 2, entries 8e10)
gave higher yields than the ones with an electron-donating group
(Table 2, entry 12).
To demonstrate this mechanism, we used N-ethyl-1-methyl-1H-
pyrrole-2-carboxamide 8 and 2 as substrates and cesium carbonate
as the base in acetonitrile (Scheme 2). However, there was not any
new product 9 even the reaction was refluxed for 8 h. This result
suggested that the first step of the reaction of 1 and 2 was the re-
placement of chlorine anionwith pyrrolyl anion and then proceeded
through path a or b to give 3 or 4, respectively. The configuration of
3b was determined by X-ray crystallographic analysis (Fig. 2).
In the 1H NMR spectrum of 3 and 4, the signals of pyrrol protons
were different. These signals of the protons on the pyrrole ring in
compound 4a were 6.80, 7.28, 7.57 ppm, and in compound 3a were
6.74, 7.35, 8.97 ppm. One signal shifted to 8.97 ppm from 7.57 ppm.

908
A. Huang et al. / Tetrahedron 68 (2012) 906e912
4. Experimental section
Cl
Cl
N
s
C
CO CH CN
N
N
,
N
N
2
3
3
+
NHR1
CO
N
H
reflux
4.1. General
NH
R1
THP
O
THP
l
C
O
2
O
1
5
Pyrrole-2-carboxamides, N-ethyl-1-methyl-1H-pyrrole-2-carbox-
amide,33e36 and indole-2-carboxamides37 were prepared accordingto
literature procedures. Acetonitrile was distilled from calcium hydride
prior to use. Other reagents were commercially available and were
used without further purification. All reactions were monitored by
thin-layer chromatography (TLC). 1H NMR spectra were recorded on
a Bruker Avance 400 or 300 spectrometer at 400 or 300 MHz, using
CDCl3 or DMSO-d6 as solvent and tetramethylsilane (TMS) as internal
standard. 13C NMR spectra were run in the same instrument at 100 or
75 MHz. Melting points were determined on an XD-4 digital micro
melting point apparatus. IR spectra were recorded with an IR spec-
trophotometer VERTEX 70 FTIR (Rruker Optics). HRMS spectra were
determined on a Q-TOF6510 spectrograph (Agilent).
s
C
2CO3
R1
N
O
N
N
N
N
N
a
a
b
THP
N
THP
O
N
Cl
Cl
O
O
R1
7
6
-
b
Cl
-
l
C
O
N
THP
N
N
N
N
+
N
N
N
O
THP
O
O
R1
4.2. General procedure for the synthesis of compounds 3 and 4
R1
3
4
A mixture of pyrrolamide 1 (1.0 mmol), 2-tetrahydropyranyl-4,5-
dichloropyridazin-3-one 2 (1.2 mmol), and Cs2CO3 (3.5 mmol) in
acetonitrile (15 mL) was refluxed, and TLC monitored the end of the
reaction. Then the mixture was cooled to room temperature and
diluted with brine (60 mL) and extracted with dichloromethane
twice (2ꢁ30 mL). The combined organic layers were dried with
MgSO4 and the solvent was removed in vacuo to afford a residue. The
residue was purified by column chromatography on silica gel to af-
ford 3 and 4.
Scheme 1. Proposed mechanism for formation of 3 and 4.
Scheme 2. Reaction of N-ethyl-1-methyl-1H-pyrrole-2-carboxamide 8 with 2.
4.2.1. 5-Ethyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]pyr-
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3a). White solid. Mp
206e207 ꢀC. 1H NMR (300 M, CDCl3):
d
8.97 (1H, q, J¼1.5 Hz), 8.15
(1H, s), 7.35 (1H, dd, J¼3.9, 1.5 Hz), 6.74 (1H, dd, J¼4.2, 3.0 Hz), 6.21
(1H, dd, J¼10.8, 2.1 Hz), 4.2e4.4 (2H, m), 4.17 (1H, m), 3.81 (1H, m),
2.03e2.32 (2H, m), 1.57e1.86 (4H, m), 1.39 (3H, t, J¼7.2 Hz); 13C
NMR (75 M, CDCl3): d 13.70, 22.88, 24.96, 28.86, 36.69, 68.98, 83.22,
113.96, 114.19, 115.70, 123.20, 123.66, 127.53, 127.62, 154.39, 154.71;
IR (KBr, cmꢂ1): 3179, 3147, 3094, 2962, 2843, 1672, 1563, 1209;
HRMS calcd for C16H18N4O3 314.1379; found: 314.1368.
4.2.2. 5-Ethyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]pyr-
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4a). Orange solid. Mp
180e182 ꢀC. 1H NMR (300 M, CDCl3):
d 8.30 (1H, s), 7.57 (1H, q,
J¼1.5 Hz), 7.28 (1H, dd, J¼3.9, 1.2 Hz), 6.80 (1H, dd, J¼3.9, 3.0 Hz),
6.11 (1H, dd, J¼10.5, 1.8 Hz), 4.80 (2H, m), 4.12 (1H, m), 3.75 (1H, m),
2.01e2.17 (2H, m),1.55e1.80 (4H, m),1.41 (3H, t, J¼6.9 Hz); 13C NMR
(75 M, CDCl3):
d 15.66, 22.93, 24.97, 29.06, 39.86, 69.00, 83.81,
Fig. 2. X-ray structure of compound 3b.
113.58, 115.80, 116.00, 120.32, 122.92, 124.17, 127.08, 154.72, 155.68;
IR (KBr, cmꢂ1): 3121, 3049, 2933, 2874, 1650, 1241; HRMS calcd for
C16H18N4O3 314.1379; found: 314.1358.
To expand the scope of this methodology, we studied the re-
action of indole-2-carboxamides37 10 and 2 under the same con-
ditions. The results are shown in Table 3. The reactions of 2 with
different indole-2-carboxamides, 5-fluoro-, and 5-methoxy-indole-
2-carboxamides proceeded well to afford the products 11 and 12.
4.2.3. 5-Propyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]-pyr-
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3b). White solid. Mp
181e182 ꢀC. 1H NMR (300 M, CDCl3):
d
8.97 (1H, q, J¼1.5 Hz), 8.13
(1H, s), 7.35 (1H, dd, J¼3.9, 1.5 Hz), 6.74 (1H, dd, J¼3.9, 3.0 Hz), 6.21
(1H, dd, J¼10.8, 2.1 Hz), 4.11e4.32 (3H, m), 3.81 (1H, m), 2.04e2.32
(2H, m), 1.57e1.86 (6H, m), 1.04 (3H, t, J¼7.2 Hz); 13C NMR (75 M,
3. Conclusion
CDCl3): d 11.10, 21.90, 22.88, 24.96, 28.86, 42.97, 68.98, 83.19, 114.02,
In summary, we have developed a transition metal-free tandem
processforthe synthesisofpyrrolopyrazino[2,3-d]pyridazine-diones.
A wide range of pyrrole-2-carboxamides with 2-tetrahydropyranyl-
4,5-dichloropyridazin-3-one worked well to afford the tricyclic
products. Indole-2-carboxamides were also compatible with this
method. Further studies on its application in the synthesis of bi-
ologically relevant compounds are currently in progress.
114.20, 115.70, 123.11, 123.65, 127.72, 127.80, 154.38, 154.95; IR (KBr,
cmꢂ1): 3178, 3139, 3090, 2962, 2859, 1673, 1651, 1260; HRMS calcd
for C17H20N4O3 328.1535; found: 328.1542.
4.2.4. 5-Propyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]-pyr-
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4b). White solid. Mp
169e171 ꢀC. 1H NMR (300 M, CDCl3):
d 8.30 (1H, s), 7.57 (1H, q,

A. Huang et al. / Tetrahedron 68 (2012) 906e912
909
Table 3
Reactions of indole-2-carboxamides 10 with 2a
Entry
R2
R3
Time (h)
Yieldb (%)
Total (11þ12)
11
12
1
2
3
4
5
H
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-FC6H4
Bn
16
19
13
15
20
54
45
43
46
44
11a
11b
11c
11d
11e
43
42
34
37
35
12a
12b
12c
12d
12e
97
87
77
83
79
5-MeO
5-F
H
5-MeO
a
Reaction conditions: 10 (1.0 equiv), 2-tetrahydropyranyl-4,5-dichloropyridazin-3-one 2 (1.2 equiv), Cs2CO3 (3.5 equiv), reflux.
Isolated yield.
b
J¼1.5 Hz), 7.28 (1H, dd, J¼3.9, 1.5 Hz), 6.80 (1H, dd, J¼3.9, 3.0 Hz),
159e160 ꢀC. 1H NMR (300 M, CDCl3):
d 8.27 (1H, s), 7.52 (1H, q,
J¼1.5 Hz), 7.20 (1H, dd, J¼3.9, 1.2 Hz), 6.75 (1H, dd, J¼3.6, 3.0 Hz),
6.14 (1H, dd, J¼10.5, 1.8 Hz), 5.20 (1H, m), 4.15e4.20 (1H, m), 3.80
(1H, m), 2.63 (2H, m), 2.09e2.24 (2H, m), 1.31e1.87 (12H, m); 13C
6.11 (1H, dd, J¼10.5, 2.1 Hz), 4.70 (2H, m), 4.19 (1H, m), 3.79 (1H, m),
2.06e2.28 (2H, m), 1.59e1.86 (6H, m), 1.01 (3H, t, J¼7.2 Hz); 13C
NMR (75M, CDCl3):
d 11.16, 22.89, 23.74, 24.96, 29.09, 45.65, 68.96,
83.68, 113.61, 115.77, 115.99, 120.26, 122.93, 124.10, 127.08, 154.73,
155.76; IR (KBr, cmꢂ1): 3119, 3048, 2931, 2854, 1648, 1156; HRMS
calcd for C17H20N4O3 328.1535, found: 328.1544.
NMR (75 M, CDCl3): d 22.89, 24.95, 25.35, 26.60, 26.63, 29.14, 29.95,
30.18, 60.66, 69.01, 83.64, 113.33, 115.67, 115.87, 120.95, 124.40,
125.26, 127.22, 155.27, 156.71; IR (KBr, cmꢂ1): 3233, 3133, 2931, 2851,
1648, 1610, 1196; HRMS calcd for C20H24N4O3 368.1848; found:
368.1851.
4.2.5. 5-Isopropyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3c). White solid. Mp
188e200 ꢀC. 1H NMR (300 M, CDCl3):
d
8.96 (1H, q, J¼1.5 Hz), 8.37
4.2.9. 5-Benzyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]-pyr-
(1H, s), 7.32 (1H, dd, J¼3.9, 1.5 Hz), 6.72 (1H, dd, J¼4.2, 3.0 Hz), 6.21
(1H, dd, J¼10.8, 3.0 Hz), 4.15e4.20 (1H, m), 3.81 (1H, m), 2.04e2.32
(2H, m), 1.57e1.86 (4H, m), 1.66 (3H, d, J¼3.0 Hz), 1.64 (3H, d,
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3e). White solid. Mp
207e208 ꢀC. 1H NMR (300 M, CDCl3):
d
9.01 (1H, q, J¼1.5 Hz), 8.07
(1H, s), 7.44 (1H, dd, J¼3.9, 1.5 Hz), 7.24e7.37 (5H, m), 6.78 (1H, dd,
J¼4.2, 3.0 Hz), 6.18 (1H, dd, J¼10.5, 2.1 Hz,), 5.65 (1H, d, J¼15.9 Hz),
5.34 (1H, d, J¼16.5 Hz), 4.10e4.15 (1H, m), 3.80 (1H, m), 2.04e2.23
J¼3.0 Hz); 13C NMR (75 M, CDCl3):
d 20.68, 20.71, 22.88, 24.97, 28.88,
69.00, 83.14, 114.01, 114.23, 116.36, 123.41, 123.56, 127.88, 128.44,
154.58, 155.35; IR (KBr, cmꢂ1): 3161, 3135, 2943, 2848, 1667, 1609,
1231; HRMS calcd for C17H20N4O3 328.1535; found: 328.1537.
(2H, m), 1.59e1.82 (4H, m); 13C NMR (75 M, CDCl3):
d 22.84, 24.91,
28.85, 45.10, 68.97, 83.20, 114.39, 114.77, 115.95, 122.93, 124.08,
126.60, 127.86, 128.10, 129.26, 135.35, 154.30, 155.26; IR (KBr,
cmꢂ1): 3173, 3132, 2945, 2864, 1678, 1645, 1210; HRMS calcd for
C21H20N4O3 376.1535; found: 376.1540.
4.2.6. 5-Isopropyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4c). White solid. Mp
167e169 ꢀC. 1H NMR (300 M, CDCl3):
d 8.27 (1H, s), 7.52 (1H, q,
J¼1.5 Hz), 7.23 (1H, d, J¼3.9 Hz), 6.76 (1H, t, J¼3.6 Hz), 6.11 (1H, dd,
4.2.10. 5-Benzyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1,6]-pyr-
J¼10.5, 1.8 Hz), 5.74 (1H, m), 4.19 (1H, m), 3.79 (1H, m), 2.06e2.28
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4e). Yellow solid. Mp
(2H, m), 1.65e1.79 (10H, m); 13C NMR (75M, CDCl3):
d
20.60, 20.71,
215e217 ꢀC. 1H NMR (300 M, CDCl3):
d 8.30 (1H, s), 7.58 (1H, q,
22.93, 24.94, 29.03, 52.20, 69.02, 83.95,113.33,115.71,115.96,120.90,
124.14, 125.12, 127.22, 130.21, 155.28; IR (KBr, cmꢂ1): 3128, 3115,
3048, 2922, 2851, 1649, 1269; HRMS calcd for C17H20N4O3 328.1535;
found: 328.1527.
J¼1.5 Hz), 7.19e7.34 (6H, m), 6.84 (1H, dd, J¼3.9, 2.7 Hz), 6.14 (2H, d,
J¼3.6 Hz), 6.08 (1H, dd, J¼10.5, 2.1 Hz), 4.12e4.17 (1H, m), 3.76 (1H,
m), 2.03e2.23 (2H, m), 1.56e1.81 (4H, m); 13C NMR (75 M, CDCl3):
d
22.83, 24.94, 29.04, 46.17, 68.91, 83.69, 114.27, 115.91, 116.51,
120.55, 122.41, 123.91, 127.07, 127.48, 128.36, 138.34, 154.71, 155.91;
IR (KBr, cmꢂ1): 3123, 3111, 3051, 2928, 2855, 1647, 1233; HRMS
calcd for C21H20N4O3 376.1535; found: 376.1544.
4.2.7. 5-Cyclohexyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3d). White solid. Mp
163e165 ꢀC.1H NMR (300 M, CDCl3):
s), 7.31 (1H, dd, J¼3.9,1.5 Hz), 6.71 (1H, dd, J¼3.9, 3.0 Hz), 6.19 (1H, dd,
J¼10.5, 2.1 Hz), 5.65 (1H, d, J¼15.9 Hz), 5.34 (1H, d, J¼16.5 Hz), 5.02
(1H, s), 4.15e4.20 (m, 1H), 3.80 (1H m), 1.24e2.38 (16H m); 13C NMR
d
8.95 (1H, q, J¼1.5Hz), 8.47 (1H,
4.2.11. 5-(3,4-Dimethoxyphenethyl)-2-(tetrahydro-2H-pyran-2-yl)
pyrrolo[10,20:1,6]pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione
(3f). White solid. Mp 178e180 ꢀC. 1H NMR (300 M, CDCl3):
d 8.98
(75 M, CDCl3):
d
22.84, 24.95, 25.22, 26.41, 28.81, 30.04, 30.12, 68.87,
(1H, q, J¼1.5 Hz), 8.12 (1H, s), 7.38 (1H, J¼3.9,1.5 Hz), 6.81e6.84 (2H,
m), 6.75e6.78 (2H, m), 6.19 (1H, dd, J¼10.8, 2.1 Hz), 4.32e4.48 (2H,
m), 4.19e4.20 (1H, m), 3.86 (6H, d, J¼1.8 Hz), 3.81 (1H, m), 2.97 (2H,
m), 2.08e2.25 (2H, m), 1.61e1.81 (4H, m); 13C NMR (75M, CDCl3):
83.04, 113.83, 114.06, 116.17, 123.42, 123.47, 128.17, 128.60, 154.47,
155.39; IR (KBr, cmꢂ1): 3163, 3148, 2935, 2853, 1660, 1610, 1258;
HRMS calcd for C20H24N4O3 368.1848; found: 368.1843.
d
22.85, 24.95, 28.92, 34.34, 43.32, 55.92, 65.53, 68.97, 83.20, 111.55,
4.2.8. 5-Cyclohexyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4d). White solid. Mp
111.90, 114.10, 114.28, 115.54, 120.77, 123.07, 127.59, 127.65, 129.59,
148.18, 149.26, 154.24, 154.81; IR (KBr, cmꢂ1): 3193, 2925, 2850,

910
A. Huang et al. / Tetrahedron 68 (2012) 906e912
1727, 1653, 1263; HRMS calcd for C24H26N4O5 450.1903; found:
450.1906.
J¼2.9 Hz), 7.57e7.76 (2H, m), 7.47 (1H, s), 7.41 (1H, dd, J¼4.0,1.5 Hz),
7.24e7.30 (2H, m), 6.78 (1H, dd, J¼3.9, 3.0 Hz), 6.18 (1H, dd, J¼10.7,
2.2 Hz), 4.12e4.16 (1H, m), 3.81 (1H, m), 2.04e2.20 (2H, m),
4.2.12. 5-(3,4-Dimethoxyphenethyl)-3-(tetrahydro-2H-pyran-2-yl)
pyrrolo[10,20:1,6]pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione
1.57e1.77 (4H, m); 13C NMR (75 M, CDCl3):
d 22.82, 24.93, 28.67,
68.90, 83.28, 114.54, 115.16, 115.33, 123.06, 124.41, 128.48, 128.62,
130.37,130.48,130.60,133.09,136.07,154.34,154.75; IR (KBr, cmꢂ1):
3165, 3092, 3060, 2926, 2853, 1686, 1657, 1273; HRMS calcd for
C20H17ClN4O3 396.0989; found: 396.0977.
(4f). White solid. Mp 191e193 ꢀC. 1H NMR (300 M, CDCl3):
d 8.28
(1H, s), 7.57 (1H, q, J¼1.5 Hz), 7.30 (1H, dd, J¼3.9, 1.5 Hz), 6.91e6.94
(2H, m), 6.77e6.82 (2H, m), 6.13 (1H, dd, J¼10.5, 2.1 Hz,) 4.86e5.05
(2H, m), 4.16e4.20 (1H, m), 3.85 (6H, d, J¼6.0 Hz), 3.75 (1H, m), 3.02
(2H, dd, J¼15.9, 8.4 Hz), 2.08e2.27 (2H, m), 1.57e1.85 (4H, m); 13C
4.2.18. 5-(4-Chlorophenyl)-3-(tetrahydro-2H-pyran-2-yl)pyrrolo
NMR (75 M, CDCl3):
d
22.92, 24.96, 29.06, 35.93, 45.72, 55.83, 55.90,
[10,20:1,6]pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione (4i). Orange
68.99, 83.61, 111.17, 112.43, 113.72, 115.88, 116.19, 120.15, 121.18,
122.91, 124.05, 127.01, 131.33, 147.57, 148.78, 154.74, 155.83; IR (KBr,
cmꢂ1): 3116, 3044, 2927, 2852, 1645, 1236; HRMS calcd for
C24H26N4O5 450.1903; found: 450.1908.
solid. Mp 184e186 ꢀC. 1H NMR (300 M, CDCl3):
d 8.38 (1H, s), 7.66
(1H, d, J¼1.44 Hz), 7.43 (2H, d, J¼8.44 Hz), 7.36 (1H, d, J¼3.1 Hz),
7.21 (2H, d, J¼7.5 Hz), 6.84 (1H, t, J¼3.32 Hz), 5.96 (1H, dd, J¼10.5,
1.7 Hz), 4.10 (1H, m), 3.67 (1H, m), 1.98e2.15 (2H, m), 1.53e1.72 (4H,
m); 13C NMR (75 M, DMSO-d6):
d 22.84, 25.11, 28.65, 67.99, 83.19,
4.2.13. 5-Phenyl-2-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
114.33, 115.73, 120.02, 120.59, 122.50, 123.85, 128.31, 128.65, 130.75,
132.50, 138.13, 153.75, 155.44; IR (KBr, cmꢂ1): 3115, 3056, 2925,
2855, 1651, 1624, 1278; HRMS calcd for C20H17ClN4O3 396.0989;
found: 396.0968.
azino[2,3-d]pyridazine-1,6(2H,5H)-dione (3g). White solid. Mp
154e156 ꢀC. 1H NMR (300M, CDCl3):
d
9.04 (1H, q, J¼1.5 Hz), 8.37
(1H, s), 7.54e7.63 (3H, m), 7.46 (1H, s), 7.42 (2H, dd, J¼4.2, 1.5 Hz),
7.29e7.35 (2H, m), 6.78 (1H, dd, J¼3.9, 3.0 Hz), 6.18 (1H, dd, J¼10.8,
2.1 Hz), 4.09e4.16 (1H, m), 3.81 (1H, m), 2.04e2.20 (2H, m),
4.2.19. 5-(4-Bromophenyl)-2-(tetrahydro-2H-pyran-2-yl)pyrrolo
1.61e1.78 (4H, m); 13C NMR (75 M, CDCl3):
d
22.84, 24.94, 28.72,
[10,20:1,6]pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione
(3j). White
9.04 (1H, q,
68.90, 83.19, 114.41, 114.85, 115.17, 123.30, 124.18, 128.82, 128.96,
129.06, 129.90, 130.33, 134.67, 154.41, 154.91; IR (KBr, cmꢂ1): 3170,
3064, 2924, 2855, 1696, 1662, 1207; HRMS calcd for C20H18N4O3
362.1379; found:362.1387.
solid. Mp 144e147 ꢀC. 1H NMR (300 M, CDCl3):
d
J¼1.5 Hz), 7.72e7.76 (2H, m), 7.47 (1H, s), 7.41 (1H, dd, J¼3.9,1.5 Hz),
7.17e7.26 (2H, m), 6.78 (1H, dd, J¼3.9, 2.7 Hz), 6.18 (1H, dd, J¼10.5,
2.1 Hz), 4.09e4.16 (1H, m), 3.81 (1H, m), 2.04e2.24 (2H, m),
1.57e1.82 (4H, m); 13C NMR (75M, CDCl3):
d 22.82, 24.93, 28.66,
4.2.14. 5-Phenyl-3-(tetrahydro-2H-pyran-2-yl)pyrrolo[10,20:1, 6]pyr-
68.90, 83.28, 114.54, 115.18, 115.33, 123.05, 124.13, 124.41, 128.41,
128.60, 130.65, 130.77, 133.63, 154.34, 154.67; IR (KBr, cmꢂ1): 3164,
3089, 2927, 2852, 1687, 1658, 1209; HRMS calcd for C20H17BrN4O3
440.0484; found: 440.0484.
azino[2,3-d]pyridazine-4,6(3H,5H)-dione (4g). Orange solid. Mp
204e207 ꢀC. 1H NMR (300 M, CDCl3):
d 8.37 (1H, s), 7.65 (1H, q,
J¼1.5 Hz), 7.47e7.49 (3H, m), 7.35 (1H, dd, J¼3.9, 1.5 Hz), 7.24e7.28
(2H, m), 6.84 (1H, dd, J¼3.6, 2.7 Hz), 5.96 (1H, dd, J¼10.5, 2.1 Hz),
4.06e4.10 (1H, m), 3.63 (1H, m), 1.96e2.18 (2H, m), 1.50e1.73 (4H,
4.2.20. 5-(4-Bromophenyl)-3-(tetrahydro-2H-pyran-2-yl)pyrrolo
m); 13C NMR (75 M, CDCl3):
d
22.82, 24.87, 29.12, 29.70, 68.91, 83.13,
[10,20:1,6]pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione
(4j). White
114.98, 115.99, 116.99, 120.05, 122.62, 124.06, 127.10, 128.39, 128.56,
138.00, 153.75, 155.58; IR (KBr, cmꢂ1): 3112, 3055, 2923, 2853, 1661,
1278; HRMS calcd for C20H18N4O3 362.1379; found: 362.1382.
solid. Mp 169e172 ꢀC. 1H NMR (300M, CDCl3):
d 8.38 (1H, s), 7.65
(1H, q, J¼1.5 Hz), 7.58 (2H, d, J¼8.7 Hz), 7.36 (1H, dd, J¼3.9, 1.2 Hz),
7.13 (2H, d, J¼8.1 Hz), 6.84 (1H, dd, J¼3.6, 2.7 Hz), 5.96 (1H, dd,
J¼10.5, 1.7 Hz), 4.10 (1H, m), 3.67 (1H, m), 1.98e2.15 (2H, m),
4.2.15. 5-(4-Fluorophenyl)-2-(tetrahydro-2H-pyran-2-yl)pyrrolo-
1.53e1.72 (4H, m); 13C NMR (75 M, DMSO-d6):
d 27.59, 29.87, 33.32,
[10,20:1,6]pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione
(3h). White
9.01 (1H, q,
72.69, 87.87, 119.11, 120.50, 122.27, 124.79, 125.76, 128.58, 130.68,
133.41, 135.90, 137.37, 143.02, 146.85, 160.79; IR (KBr, cmꢂ1): 3112,
3054, 2925, 2854, 1651, 1614, 1276; HRMS calcd for C20H17BrN4O3
440.0484, 440.0478.
solid. Mp 216e218 ꢀC. 1H NMR (300 M, CDCl3):
d
J¼1.5 Hz), 7.46 (1H, s), 7.37 (1H, dd, J¼3.9,1.5 Hz), 7.25e7.35 (4H, m),
6.76 (1H, dd, J¼3.6, 2.7 Hz), 6.18 (1H, dd, J¼10.5, 2.1 Hz), 4.11e4.16
(1H, m), 3.81 (1H, m), 2.04e2.21 (2H, m), 1.67e1.77 (4H, m); 13C
NMR (75 M CDCl3):
d
22.77, 24.91, 28.61, 68.72, 83.14, 114.21, 114.57,
4.2.21. 2-(Tetrahydro-2H-pyran-2-yl)-5-(p-tolyl)pyrrolo[10,20:1,6]
114.94, 117.28 (d, J¼23.2 Hz), 122.94, 124.07, 128.60, 130.45 (d,
J¼3.7 Hz), 130.95 (q, J¼5.3 Hz), 154.12, 154.66, 161.23, 164.54; IR
(KBr, cmꢂ1): 3166, 3070, 2927, 2856, 1690, 1660, 1222; HRMS calcd
for C20H17FN4O3 380.1285; found: 380.1263.
pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione (3k). White solid. Mp
186e188 ꢀC. 1H NMR (300 M, CDCl3):
d
9.02 (1H, q, J¼1.5 Hz), 7.49
(1H, s), 7.37e7.41 (3H, m), 7.15e7.23 (2H, m), 6.78 (1H, t, J¼4.0 Hz),
6.18 (1H, dd, J¼10.5, 2.1 Hz), 4.12e4.16 (1H, m), 3.81 (1H, m), 2.46
(3H, s), 2.04e2.20 (2H, m), 1.57e1.77 (4H, m); 13C NMR (75 M,
4.2.16. 5-(4-Fluorophenyl)-3-(tetrahydro-2H-pyran-2-yl)pyrrolo-
CDCl3): d 21.29, 22.82, 24.94, 28.64, 68.80, 83.14, 114.22, 114.54,
[10,20:1,6]pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione (4h). White
114.97, 123.27, 123.97, 128.62, 128.70, 128.92, 129.11, 130.91, 131.92,
139.94, 154.33, 154.94; IR (KBr, cmꢂ1): 3164, 3145, 2922, 2851,
1696, 1658, 1215; HRMS calcd for C21H20N4O3 376.1535; found:
376.1534.
solid. Mp 269e271 ꢀC. 1H NMR (300 M, CDCl3):
d 8.38 (1H, s), 7.66
(1H, q, J¼1.5 Hz), 7.35 (1H, dd, J¼3.9, 1.2 Hz), 7.13e7.26 (4H, m), 6.85
(1H, q, J¼3.9, 2.7 Hz), 5.96 (1H, dd, J¼10.8, 2.1 Hz), 4.07e4.13 (1H,
m), 3.66 (1H, m), 1.98e2.21 (2H, m), 1.55e1.76 (4H, m); 13C NMR
(75 M, CDCl3):
d
22.80, 24.85, 29.11, 68.96, 83.19, 115.21, 115.62 (d,
4.2.22. 3-(Tetrahydro-2H-pyran-2-yl)-5-(p-tolyl)pyrrolo[10,20:1,6]
J¼24.4 Hz), 116.12, 117.10, 120.14, 122.46, 123.91, 127.08, 129.83 (d,
J¼21.8 Hz), 133.75 (d, J¼3.0 Hz), 153.79, 155.62, 160.58, 163.86; IR
(KBr, cmꢂ1): 3120, 3053, 2950, 2873, 1653, 1277; HRMS calcd for
C20H17FN4O3 380.1285; found: 380.1295.
pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione (4k). White solid. Mp
279e282 ꢀC. 1H NMR (300 M, CDCl3):
d 8.38 (1H, s), 7.65 (1H, q,
J¼1.2 Hz), 7.33 (1H, dd, J¼3.9, 1.2 Hz), 7.26e7.29 (2H, m), 7.15 (2H, d,
J¼7.2 Hz), 6.84 (1H, dd, J¼3.9, 3.0 Hz), 5.96 (1H, dd, J¼10.8, 2.1 Hz),
4.10 (1H, m), 3.67 (1H, m), 2.43 (3H, s), 1.98e2.15 (2H, m), 1.53e1.72
4.2.17. 5-(4-Chlorophenyl)-2-(tetrahydro-2H-pyran-2-yl)pyrrolo
(4H, m); 13C NMR (75 M, CDCl3):
d 21.46, 22.82, 24.87, 29.15, 68.91,
[10,20:1,6]pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione
(3i). White
9.03 (1H, q,
83.07, 114.89, 115.96, 116.92, 120.01, 122.70, 124.08, 127.15, 127.42,
solid. Mp 161e163 ꢀC. 1H NMR (300 M, CDCl3):
d
127.79, 129.37, 135.36, 138.14, 153.79, 155.74; IR (KBr, cmꢂ1): 3112,

A. Huang et al. / Tetrahedron 68 (2012) 906e912
911
3054, 2924, 2870, 1654, 1626, 1276; HRMS calcd for C21H20N4O3
376.1535; found: 376.1528.
(12b). Brown solid. Mp 313e315 ꢀC. 1H NMR (300 M, CDCl3): 9.04
(1H, s), 7.98 (1H, d, J¼9.3 Hz), 7.61 (1H, s), 7.26e7.31 (2H, m),
7.17e7.24 (4H, m), 6.01 (1H, dd, J¼10.5, 1.8 Hz), 4.07e4.11 (1H, m),
3.92 (3H, s), 3.60e3.73 (2H, m), 2.44 (1H, s), 1.99e2.22 (2H, m),
4.2.23. 5-(4-Methoxyphenyl)-2-(tetrahydro-2H-pyran-2-yl)pyrrolo
[10,20:1,6]pyrazino[2,3-d]pyridazine-1,6(2H,5H)-dione
(3l). White
9.02 (1H, q,
1.51e1.73 (4H, m); 13C NMR (100 M, CDCl3):
d 21.35, 23.04, 25.14,
solid. Mp 186e187 ꢀC. 1H NMR (300 M, CDCl3):
d
28.98, 56.02, 68.89, 82.88, 109.09, 112.56, 113.32, 118.80, 119.35,
124.05, 128.56, 129.55, 129.72, 129.80, 130.89, 133.19, 134.15, 134.82,
140.13, 155.10, 158.26; IR (KBr, cmꢂ1): 3157, 2937, 2861, 1653, 1276;
HRMS calcd for C26H24N4O4 456.1798, 456.1774.
J¼1.2 Hz), 7.52 (1H, s), 7.40 (1H, dd, J¼3.9,1.2 Hz), 7.18e7.25 (2H, m),
7.06e7.11 (2H, m), 6.78 (1H, dd, J¼3.9, 3.0 Hz), 6.18 (1H, dd, J¼10.5,
1.8 Hz), 4.10e4.16 (1H, m), 3.89 (3H, s), 3.81 (1H, m), 2.04e2.26 (2H,
m), 1.57e1.83 (4H, m); 13C NMR (75 M, CDCl3):
d 22.84, 24.94, 28.68,
55.61, 68.85, 83.17, 114.29, 114.64, 115.06, 115.45, 115.57, 123.32,
124.04, 126.96, 129.13, 129.18, 129.97, 130.04, 154.38, 155.18, 160.37;
IR (KBr, cmꢂ1): 3165, 2923, 2852, 1686, 1658, 1250; HRMS calcd for
C21H20N4O4 392.1485; found: 392.1479.
4.2.29. 9-Fluoro-2-(tetrahydro-2H-pyran-3-yl)-5-(p-tolyl)pyridazino
[40,50:5,6]pyrazino[1,2-a]indole-1,6(2H,5H)-dione (11c). Brown solid.
Mp 296e298 ꢀC. 1H NMR (300 M, CDCl3):
d 11.13 (1H, s), 8.86 (1H, s),
7.83 (1H, d, J¼8.1 Hz), 7.38 (3H, d, J¼7.8 Hz), 7.22 (3H, d, J¼6.9 Hz),
5.99 (1H, d, J¼9.6 Hz), 4.08e4.18 (1H, m), 3.38e3.81 (1H, m), 2.52
(1H, s), 2.01e2.25 (2H, m), 1.52e1.75 (4H, m); 13C NMR (100 M,
4.2.24. 5-(4-Methoxyphenyl)-3-(tetrahydro-2H-pyran-2-yl)pyrrolo
[10,20:1,6]pyrazino[2,3-d]pyridazine-4,6(3H,5H)-dione
(4l). Brown
8.37 (1H, s), 7.64
CDCl3): d 22.35, 24.64, 28.04, 29.91, 67.53, 82.39, 111.49, 113.86,
solid. Mp 206e207 ꢀC. 1H NMR (300 M, CDCl3):
d
114.83 (d, J¼5.0 Hz), 116.79, 120.26, 122.64 (d, J¼3.0 Hz), 128.72 (q,
J¼15.0 Hz), 130.53 (d, J¼24.5 Hz), 131.51 (d, J¼21.0 Hz), 133.27,
134.30, 136.49, 139.13, 154.92, 157.55, 166.85; IR (KBr, cmꢂ1): 3135,
3080, 2927, 2855, 1673, 1655, 1270; HRMS calcd for C25H21FN4O3
444.1589; found: 444.1592.
(1H, q, J¼1.2 Hz), 7.33 (1H, dd, J¼3.9, 1.5 Hz), 7.17 (2H, d, J¼6.9 Hz),
6.98 (2H, d, J¼9.0 Hz), 6.83 (1H, dd, J¼3.9, 3.0 Hz), 5.96 (1H, dd,
J¼10.5, 1.8 Hz), 4.10 (1H, m), 3.86 (3H, s), 3.67 (1H, m), 2.01e2.20
(2H, m), 1.26e1.72 (4H, m); 13C NMR (75 M, CDCl3):
d 22.82, 24.87,
29.16, 55.31, 68.94, 83.11, 113.87, 114.89, 115.97, 116.84, 119.97,
122.77, 124.11, 127.09, 128.63, 129.01, 130.53, 153.83, 155.90, 159.23;
IR (KBr, cmꢂ1): 3109, 3059, 2924, 2852, 1727, 1654, 1246; HRMS
calcd for C21H20N4O4 392.1485; found: 392.1486.
4.2.30. 9-Fluoro-3-(tetrahydro-2H-pyran-2-yl)-5-(p-tolyl)pyridazino
[40,50:5,6]pyrazino[1,2-a]indole-4,6(3H,5H)-dione (12c). White solid.
Mp 367e369 ꢀC. 1H NMR (300 M, CDCl3):
d 9.04 (1H, s), 8.07 (1H,
dd, J¼9.6, 4.2 Hz), 7.66 (1H, s), 7.55 (1H, dd, J¼8.4, 2.4 Hz), 7.38 (1H,
d, J¼2.7 Hz), 7.35 (1H, d, J¼2.4 Hz), 7.30 (1H, d, J¼8.7 Hz), 7.18 (2H, d,
J¼8.4 Hz), 6.01 (1H, dd, J¼10.5, 1.8 Hz), 4.08e4.11 (1H, m),
3.62e3.69 (1H, m), 2.44 (3H, s), 2.00e2.23 (1H, m), 1.50e1.74 (4H,
4.2.25. 2-(Tetrahydro-2H-pyran-3-yl)-5-(p-tolyl)pyridazino[40,50:
5,6]pyrazino[1,2-a]indole-1,6(2H,5H)-dione (11a). White solid. Mp
289e292 ꢀC.1H NMR (300 M, DMSO-d6):
d 12.906 (1H, s), 9.33 (1H, s),
8.58 (1H, d, J¼7.8 Hz), 7.69 (1H, t, J¼9.0 Hz), 7.58 (1H, t, J¼7.8 Hz), 7.39
(1H, t, J¼7.2 Hz), 7.12e7.25 (4H, m), 5.76 (1H, dd, J¼9.0, 5.1Hz), 3.92
(1H, d, J¼11.7 Hz), 3.42e3.58 (1H, m), 2.41 (3H, s),1.92e2.24 (2H, m),
m); 13C NMR (100 M, CDCl3):
d 21.46, 22.83, 24.93, 29.16, 68.95,
83.08, 108.34, 108.58, 109.38 (d, J¼4.0 Hz), 115.14 (d, J¼9.0 Hz),
115.48, 115.74, 121.71, 123.12, 127.27 (d, J¼7.0 Hz), 129.46 (d,
J¼8.0 Hz), 130.66, 131.02 (d, J¼10.0 Hz), 135.34, 138.25, 153.89,
156.53, 160.68; IR (KBr, cmꢂ1): 3122, 2927, 2849, 1644, 1257; HRMS
calcd for C25H21FN4O3 444.1589; found: 444.1584.
1.49e1.64 (4H, m); 13C NMR (100 M, DMSO-d6):
d 21.27, 23.02, 25.25,
28.86, 68.00, 83.06, 113.92, 115.30, 115.85, 122.03, 122.27, 123.34,
127.44, 128.10, 128.31, 128.88, 128.99, 130.78, 133.63, 137.02, 138.02,
140.17, 153.58, 156.33; IR (KBr, cmꢂ1): 3192, 3048, 2919, 2849, 1674,
1653, 1211; HRMS calcd for C25H22N4O3 426.1692; found: 426.1682.
4.2.31. 5-(4-Fluorophenyl)-2-(tetrahydro-2H-pyran-3-yl)pyridazino
[40,50:5,6]pyrazino[1,2-a]indole-1,6(2H,5H)-dione (11d). White solid.
4.2.26. 3-(Tetrahydro-2H-pyran-2-yl)-5-(p-tolyl)pyridazino[40,50:
Mp 276e278 ꢀC. 1H NMR (400 M, CDCl3):
d 11.05 (1H, s), 9.00 (1H, s),
5,6]pyrazino[1,2-a]indole-4,6(3H,5H)-dione (12a). White solid. Mp
8.21 (1H, d, J¼8.12 Hz), 7.56 (1H, t, J¼7.60 Hz), 7.41e7.46 (2H, m),
7.24e7.34 (4H, m), 6.04 (1H, dd, J¼10.52, 1.56 Hz), 4.12 (1H, d,
J¼11.04 Hz), 3.68 (1H, t, J¼11.40 Hz), 2.01e2.30 (2H, m), 1.53e1.75
345e347 ꢀC. 1H NMR (300 M, CDCl3):
d 9.12 (1H, s), 8.10 (1H, d,
J¼8.7Hz), 7.93 (1H, d, J¼8.1 Hz), 7.62 (1H, s), 7.60 (1H, t, J¼8.1 Hz), 7.47
(1H, t, J¼7.5 Hz), 7.29 (2H, d, J¼8.1 Hz), 7.19 (2H, d, J¼8.4 Hz), 6.02 (1H,
q, J¼10.8, 2.1 Hz), 4.10 (1H, d, J¼11.1 Hz), 3.67 (1H, t, J¼12.0 Hz), 2.44
(3H, s),1.99e2.20 (2H, m),1.26e1.79 (4H, m); 13C NMR (75 M, DMSO-
(4H, m); 13C NMR (100 M, DMSO-d6):
d 22.98, 25.25, 28.86, 68.00,
83.07, 113.94, 115.10 (d, J¼5.0 Hz), 115.28, 115.36 (d, J¼7.0 Hz),
115.92, 122.03, 122.33, 127.50, 128.31, 130.44 (q, J¼8.0 Hz), 130.72,
133.69, 136.81 (d, J¼3.0 Hz), 140.19, 153.66, 156.32, 160.61, 163.02;
IR (KBr, cmꢂ1): 3222, 3145, 2920, 2850, 1673, 1656, 1208; HRMS
calcd for C24H19FN4O3 430.1441; found: 430.1444.
d6):
d 21.25, 22.88, 25.18, 28.73, 68.04, 83.08, 108.84, 115.79, 123.61,
123.72, 124.15, 126.86, 128.22, 128.60, 128.88, 129.71, 134.12, 136.63,
137.06, 153.85, 156.79; IR (KBr, cmꢂ1): 3181, 2925, 2857, 1656, 1274;
HRMS calcd for C25H22N4O3 426.1692; found: 426.1680.
4.2.32. 5-(4-Fluorophenyl)-3-(tetrahydro-2H-pyran-2-yl)pyridazino
4.2.27. 9-Methoxy-2-(tetrahydro-2H-pyran-3-yl)-5-(p-tolyl)pyr-
idazino[40,50:5,6]pyrazino[1,2-a]indole-1,6(2H,5H)-dione
[40,50:5,6]pyrazino[1,2-a]indole-4,6(3H,5H)-dione
(12d). Brown
9.87 (1H, s), 9.55
solid. Mp 324e327 ꢀC. 1H NMR (400 M, CDCl3):
d
(11b). White solid. Mp 288e291 ꢀC. 1H NMR (300 M, CDCl3):
d
11.46
(1H, d, J¼8.48 Hz), 7.53 (3H, d, J¼6.64 Hz), 7.27e7.41 (5H, m), 6.32
(1H, d, J¼10.48 Hz), 4.17 (1H, d, J¼11.44 Hz), 3.85 (1H, t, J¼11.48 Hz),
2.01e2.22 (2H, m), 1.59e1.81 (4H, m); 13C NMR (100 M, CDCl3):
(1H, s), 8.95 (1H, s), 7.53 (1H, d, J¼2.1 Hz), 7.39 (2H, d, J¼8.1 Hz),
7.20e7.25 (3H, m), 7.15 (1H, dd, J¼9.0, 2.1 Hz), 6.08 (1H, dd, J¼10.5,
1.8 Hz), 4.07e4.18 (1H, m), 3.94 (3H, s), 3.63e3.71 (1H, m), 2.53 (3H,
s), 1.99e2.37 (2H, m), 1.51e1.76 (4H, m); 13C NMR (100 M, CDCl3):
d
23.05, 25.11, 29.04, 68.99, 83.16, 111.88, 113.65, 117.35 (d,
J¼22.0 Hz), 119.09, 121.91, 123.41, 128.01, 128.71 (q, J¼7.0 Hz),
129.07, 129.30, 130.76 (d, J¼3.0 Hz), 136.57, 139.59, 155.62, 158.09,
163.58, 164.79; IR (KBr, cmꢂ1): 3196, 3087, 2935, 2847, 1676, 1235;
HRMS calcd for C24H19FN4O3 430.1441; found: 430.1434.
d
21.52, 22.95, 25.01, 29.30, 55.79, 68.87, 82.83, 102.87, 114.77,
115.56, 116.72, 118.47, 122.31, 127.14, 127.62, 129.44, 130.42, 133.69,
135.24, 137.19, 138.08, 153.94, 155.69, 157.06; IR (KBr, cmꢂ1): 3231,
2938, 2850,1652,1626,1221; HRMS calcd for C26H24N4O4 456.1798;
found: 456.1776.
4.2.33. 5-Benzyl-2-(tetrahydro-2H-pyran-3-yl)pyridazino[40,50: 5,6]
pyrazino[1,2-a]indole-1,6(2H,5H)-dione (11e). White solid. Mp
4.2.28. 9-Methoxy-3-(tetrahydro-2H-pyran-2-yl)-5-(p-tolyl)pyr-
idazino[40,50:5,6]pyrazino[1,2-a]indole-4,6(3H,5H)-dione
264e267 ꢀC.1H NMR (400 M, CDCl3):
(1H, d, J¼1.60 Hz), 7.29 (4H, d, J¼4.24 Hz), 7.22e7.24 (2H, m), 7.12 (1H,
d
10.97 (1H, s), 8.93 (1H, s), 7.53

912
A. Huang et al. / Tetrahedron 68 (2012) 906e912
ꢀ
ꢀ
ꢀ
Chem. Lett. 2000, 10, 1767; (f) Beres, M.; Timari, G.; Hajos, G. Tetrahedron Lett.
2002, 43, 6035.
dd, J¼9.00, 2.04 Hz), 6.50 (2H, d, J¼15.76 Hz), 6.18 (1H, d, J¼9.00 Hz),
4.16 (1H, d, J¼11.04 Hz), 3.93 (3H, s), 3.79 (1H, t, J¼11.32 Hz),
2.07e2.28 (2H, m),1.56e1.82 (4H, m); 13C NMR (100 M, CDCl3) 23.03,
25.12, 29.28, 48.61, 55.83, 68.94, 83.53, 103.12, 114.60, 115.41, 117.31,
118.56, 122.28, 126.66, 126.95, 127.68, 128.54, 130.54, 133.67, 135.13,
138.52,154.87,155.74,156.95; IR (KBr, cmꢂ1): 3140, 3006, 2934, 2853,
1689, 1644, 1215; HRMS calcd for C26H24N4O4 456.1798, 456.1772.
3. (a) Russell, R. K.; Press, J. B.; Rampulla, R. A.; McNally, J. J.; Falotico, R. J.; Keiser,
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idazino[40,50:5,6]pyrazino[1,2-a]indole-4,6(3H,5H)-dione
(12e). Brown solid. Mp 339e342 ꢀC. 1H NMR (400 M, CDCl3):
d 8.62
(1H, d, J¼9.48 Hz), 8.04 (1H, s), 7.73 (1H, s), 7.24e7.36 (5H, m), 7.16
(1H, d, J¼2.56 Hz), 7.12 (1H, dd, J¼9.52, 2.64 Hz), 6.22 (1H, dd,
J¼10.56, 1.96 Hz), 5.65 (1H, d, J¼16.20 Hz), 5.37 (1H, d, J¼16.12 Hz),
4.13e4.16 (1H, m), 3.91 (3H, s), 3.77e3.84 (1H, m), 2.04e2.16 (2H, m),
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1.55e1.79 (4H, m); 13C NMR (100 M, CDCl3):
d 22.91, 24.98, 29.16,
45.49, 55.62, 69.03, 83.55, 101.75, 110.53, 116.54, 119.19, 121.46,
126.59, 127.20, 128.13, 128.18, 128.31, 128.44, 129.34, 130.41, 131.14,
135.16, 153.94, 156.39; IR (KBr, cmꢂ1): 3192, 3077, 2935, 2870, 1653,
1222; HRMS calcd for C26H24N4O4 456.1798; found: 456.1746.
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We are grateful to National Science Foundation of China (No.
20872079), the Natural Science Foundation of Shandong Province
(2009ZRB019YA), IIFSDU (No. 2010TS052) and State Key Laboratory
of Natural and Biomimetic Drugs of Peking University (K20090205)
for financial support of this research.
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