A general, simple and green process to access pyrrolo[2,1-a]isoquinolines using a KI/TBHP catalytic system

Article abstract of DOI:10.1039/c4ra03455d

A novel KI/TBHP-catalyzed 1,3-dipolar cycloaddition/oxidation/aromatization cascade reaction provided general, efficient and green access to biologically important pyrrolo[2,1-a]isoquinolines. The product pyrrolo[2,1-a]isoquinolines were obtained from rea

Full text of DOI:10.1039/c4ra03455d

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A general, simple and green process to access
pyrrolo[2,1-a]isoquinolines using a KI/TBHP
catalytic system†
Cite this: RSC Adv., 2014, 4, 27250
a
b
a
Huan-Ming Huang, Fang Huang, Yu-Jin Li, Jian-Hong Jia,a Qing Ye,a Liang Hana
*
a
*
and Jian-Rong Gao
A novel KI/TBHP-catalyzed 1,3-dipolar cycloaddition/oxidation/aromatization cascade reaction provided
general, efficient and green access to biologically important pyrrolo[2,1-a]isoquinolines. The product
pyrrolo[2,1-a]isoquinolines were obtained from reactions between simple, readily available dipolarophiles
and tetrahydroisoquinolines in moderate to excellent yields The reaction was environmentally benign in
the adoption of nontoxic KI as a catalyst and IOH was generated in situ from the oxidation reaction of KI
and TBHP.
Received 16th April 2014
Accepted 10th June 2014
DOI: 10.1039/c4ra03455d
www.rsc.org/advances
Introduction
Recently, various challenging metal-free reactions have been
developed via hypervalent iodine,1 molecular iodine,2 DDQ,3
strong base4 etc. as catalysts. Very recently, a novel class of
iodide-based oxidation catalysts was introduced by Ishihara and
co-workers,5 and the most important features of this catalytic
system are that the oxidation reactions require no metals and
that water or tert-butyl alcohol is the only by-product derived
from the co-oxidant. Comparing to molecular iodine, iodide is
cheaper, non-toxic and safe to the environment. This green and
efficient method has attracted various chemists to synthesize
Fig.
alkaloids.
1 Biologically important pyrrolo[2,1-a]isoquinoline lamellarin
abundant important compounds such as 2-acyl-2,3-dihy- cycloaddition/oxidation/aromatization cascade with hydrogen
drobenzofuran derivatives,5b 2-aminobenzoxazoles,6 N-nitrosa- peroxide as the terminal oxidant to pyrrolo[2,1-a]isoquinolines
mines,7 amides,8 2-aryl benzothiazoles,9 sulfonated oxindoles,10 was reported by our group (Scheme 1, eqn 1).19s As part of our
a-amino acid esters,11 tert-butyl peresters,12 allylic ester,13 N- ongoing research program the functionalized quinone struc-
sulfonyl formamidine,14 benzylic esters,15 highly functionalized tures19s,20 and inspired by the reported iodide-based oxidation
[6,6,5] tricyclic frameworks16 and iodophenols17 et al.
catalysts, we herein report a general, simple and green access to
The pyrrolo[2,1-a]isoquinoline structure occurs in lamellarin pyrrolo[2,1-a]isoquinolines using KI/TBHP catalytic system
alkaloids, a newly discovered family of marine natural products (Scheme 1, eqn 2). The reaction was environmentally benign in
that exhibit a wide spectrum of biological activities containing adoption of nontoxic KI as catalyst and IOH was generated in
potent inhibitor of human topoisomerase I, inhibition of HIV situ from the oxidation reaction of KI and TBHP.
integrase and potential antitumor activities (Fig. 1).18 So far,
various approaches to the synthesis of this useful carbon skel-
eton have been developed,19 especially the powerful 1,3-dipolar
cycloaddition.19m-s Very recently, iodine-catalyzed 1,3-dipolar
aState Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology, Hangzhou, 310014, P. R. China. E-mail: lyjzjut@
zjut.edu.cn; gdgjr@zjut.edu.cn; Fax: +86-0571-88320544; Tel: +86-0571-88320891
bDepartment of Pharmacology, School of Pharmaceutical Sciences, Southern Medical
University, Guangzhou 510515, China. E-mail: huangfang@263.net.cn
† Electronic supplementary information (ESI) available: Images of 1H and 13C
Scheme
1
Methods for the construction of pyrrolo[2,1-a]-
NMR of all products. See DOI: 10.1039/c4ra03455d
isoquinolines.
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With the optimal reaction conditions established, we then
examined the substrate scope of this KI/TBHP catalytic system
to construct pyrrolo[2,1-a]isoquinolines (Scheme 2).
Results and discussion
Initially, we focused on examining the feasibility of the reaction
of 1,4-naphthoquinone (1a) with ethyl 2-(3,4-dihy-
droisoquinolin-2(1H)-yl)acetate (2a) and optimizing the reac-
tion conditions. Excitingly, the proposed reaction between 1a
and 2a did indeed occur in the presence of KI (20 mol%) and
70% aqueous TBHP (3 equiv.) in DMF (80 ꢀC) for 10 h to afford
the corresponding product (3a) in 60% yield (Table 1, entry 1).
This result was due to iodine generated in situ from the oxida-
tion reaction of iodide with TBHP. Several other solvents were
also examined, but the yield of 3a was not improved in all these
tested solvents comparing with DMF (entry 2–6). The yield of 3a
was still not increased when the amount of KI was up to 30
mol% (entry 7). However, the yield of 3a was increased slightly
when the amount of 70% aqueous TBHP was increased to 6
equiv. (entry 8). When the amount of 2a increased to 1.5 equiv.,
the yield of 3a was up to 73% (entry 9). Encouraged by these
results, we further increased the amount of 2a to 1.7 equiv., the
yield of 3a was obtained in 87% (entry 10). However, the yield of
3a decreased slightly when the amount of 2a increased to 2
equiv. (entry 11). To further improve the economy of the reac-
tion, the amount of KI decreased to 0.1 equiv., 3a was only
obtained in 70% yield (entry 12). Another oxidant (35% aqueous
H2O2) was added instead of 70% aqueous TBHP, we only
obtained 3a in 50% yield (entry 13). Finally, the best yield of 3a
(87%) was obtained from the reaction of 1a (1 mmol), 2a (1.7
mmol), KI (20 moꢀl %), and 70% aqueous TBHP (3 mmol) in
DMF (5 mL) at 80 C for 9 h (entry 10).
As the reaction of 1a, 1,4-anthraquinone (1b) was also reacted
smoothly with 2a and the corresponding products (3b) was yiel-
ded in 93%. However, when N-phenyl maleimides (1c) was
employed under the optimal condition, the corresponding
product (3c) was only obtained in 70% yield. When the amount of
TBHP was up to 6 equiv., the yield of 3c increased to 94%. Then
several other N-substituted maleimides (1d–1h) reacted with 2a in
the presence of 6 equiv. TBHP and the corresponding products
(3d–3h) were obtained in good yields (74–94%). More importantly,
other dipolarophiles, such as activated alkynes and acrylates, also
reacted smoothly with 2a to afford the desired products in
moderate yields 78% and 50%. To further evaluate the substrate
scope, we examined various tetrahydroisoquinoline derivatives 2.
Excitingly, 3k was obtained in 90% yield when ethyl 2-(6,7-dime-
thoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetate (2b) was employed.
Similarly, the desired products 3l and 3m were both obtained in
80% when 1,4-anthraquinone (1b) and N-phenylmaleimide (1c)
reacted with 2b. Encouraged by these results, we prepared some
tetrahydroisoquinoline derivatives containing various ester
groups (methyl, ethyl, tertiary butyl, and benzyl) and allowed them
to react with 1,4-naphthoquinone (1a) or N-phenylmaleimide (1c).
The corresponding products 3m–3r were also obtained in good
yields, except the lower yield of 3p and 3q in 61% and 58% due to
the steric of tert-butyl group. The yields obtained using the
protocol described here were comparable to those reported in ref.
19s (Scheme 2, yields in parentheses), indicating that the products
can be synthesized effectively via 1,3-dipolar cycloaddition/
Table 1 Optimization of reaction conditionsa
Entry
Solvent
Temp (ꢀC)
Time (h)
KI (equiv.)
1a : 2a
Yield of 3ab (%)
1
2
3
4
5
6
DMF
80
10
15
30
28
17
16
10
10
9
9
9
14
12
0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.2
0.2
0.2
0.2
0.1
0.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.2
1 : 1.5
1 : 1.7
1 : 2.0
1 : 1.7
1 : 1.7
60
57
51
47
54
57
57
61
73
87
86
70
50
EtOH
CH3CN
CHCl3
THF
1,4-Dioxane
DMF
DMF
DMF
DMF
DMF
Reux
Reux
Reux
Reux
Reux
80
80
80
80
80
7
8c
9
10
11
12
13d
DMF
DMF
80
80
a
Compound 1a (1.0 mmol), 2a (1.2–2.0 mmol), KI (10–30 mol%) and 70% aqueous TBHP (3–6 equiv.) in solvent (5 mL) were stirred for several hours
at the specied temperature until 1a was consumed. b Isolated yield. c The amount of 70% aqueous TBHP was increased to 6 equiv. d 3 equiv. 35%
aqueous H2O2 was added instead of 70% aqueous TBHP.
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Scheme 2 Reaction of different dipolarophiles with tetrahydroisoquinolines.
oxidation/aromatization cascade reaction. This approach could
According to the above experimental results and previous
therefore be considered a proper alternative to the reported reports,5,7,8b,11–14,19s,21 a plausible mechanism was proposed
process catalyzed by iodine reported in ref. 19s. Moreover, the (Scheme 3). Initially tertiary amine (2a) was oxidized to iso-
paper's merit lay in the adoption of environmentally benign quinolinium salt A by IOH, which was oxidized from KI by
catalyst (KI) which was favorable and highly pursued nowadays.
TBHP.22 Then 1,3-dipole B was formed by elimination of HI with
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Scheme 3 Proposed mechanism.
2a served as tertiary amine base, and then the 1,3-dipolar HRMS were measured in EI or ESI mode and the mass analyzer
cycloaddition reaction between B and 1a to afford the addition of the HRMS was TOF. Thin layer chromatography was per-
intermediate D. Finally, 3a was formed through sequential formed on pre-coated glass back plates and visualized with UV
oxidation. At the same time, intermediate C was reoxidized to light at 254 nm. Flash column chromatography was performed
IOH and 2a in the presence of excess TBHP.23
on silica gel.
Conclusions
Representative procedure for the synthesis of 3a
A dipolarophile 1a (1.0 mmol) was added to a mixture of a tet-
rahydroisoquinoline 2a (1.7 mmol), 70% aqueous TBHP (3–6
mmol), and potassium iodide (0.2 mmol) in DMF (5.0 mL). The
solution was stirred for 9 h at 80 ꢀC. Aer 1a was completely
consumed (as indicated by TLC and GC-MS), the reaction
mixture was washed with aqueous Na2S2O3, dried over magne-
sium sulfate, and concentrated in vacuo. Purication of the
crude product by ash chromatography on silica gel with
CH2Cl2 as the eluent provided desired products 3a.
In summary, we have developed a novel protocol for the
synthesis of pyrrolo[2,1-a]isoquinolines using KI/TBHP catalytic
system. The reaction is environmentally benign in adoption of
nontoxic KI as catalyst and IOH is generated in situ from the
oxidation reaction of KI and TBHP. This novel KI/TBHP-cataly-
zed 1,3-dipolar cycloaddition/oxidation/aromatization cascade
reaction provides a general, efficient and green access to bio-
logically important pyrrolo[2,1-a]isoquinolines and more
transformations by this useful catalytic system are currently
underway in our laboratory.
Experimental
General information
All solvents were puried and dried using standard methods
prior to use. Commercially available reagents were used without
Ethyl 9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]-
further purication. 1H NMR spectra were recorded on an NMR isoquinoline-8-carboxylate (3a).19m Yellow solid, yield 87%
1
ꢀ
instrument operated at 500 MHz. Chemical shis are reported (0.323 g), mp 144–145 C; H NMR (500 MHz, CDCl3): d (ppm)
in ppm with the solvent resonance as the internal standard 9.01 (d, J ¼ 8.0 Hz, 1H), 8.31–8.30 (m, 1H), 8.23–8.21 (m, 1H),
(CDCl3: d 7.26 ppm). 13C NMR spectra were recorded on an NMR 7.75–7.69 (m, 2H), 7.46 (t, J ¼ 8.0 Hz, 1H), 7.39 (t, J ¼ 6.5 Hz, 1H),
instrument operated at 125 MHz with complete proton decou- 7.29–7.27 (m, 1H), 4.56 (q, J ¼ 7.0 Hz, 2H), 4.30 (t, J ¼ 6.5 Hz,
pling. Chemical shis are reported in ppm with the solvent 2H), 3.12 (t, J ¼ 6.5 Hz, 2H), 1.51 (t, J ¼ 7.0 Hz, 3H); IR n/cmꢁ1
resonance as the internal standard (CDCl3: d 77.1 ppm). MS and (KBr) 1704, 1660, 1524, 1465, 1413, 1384, 1311, 1268, 1227, 1141,
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1108, 1047, 1010, 984, 790, 729, 711; GC-MS m/z 372.0 [M + 1]+,
326.7, 301.0, 243.6, 77.8, 51.0.
Ethyl 10-(4-nitrophenyl)-9,11-dioxo-6,9,10,11-tetrahydro-5H-
pyrrolo-[30,40:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3e).19n
Yellow solid, yield 81% (0.349 g), mp 206–207 ꢀC; 1H NMR (500
MHz, CDCl3): d (ppm) 8.55 (d, J ¼ 8.5 Hz, 1H), 8.35 (d, J ¼ 9.0 Hz,
2H), 7.72 (d, J ¼ 9.5 Hz, 2H), 7.46–7.40 (m, 2H), 7.32 (d, J ¼ 7.0
Hz, 1H), 4.80 (t, J ¼ 6.5 Hz, 2H), 4.46 (q, J ¼ 7.5 Hz, 2H), 3.21 (t,
J ¼ 6.5 Hz, 2H), 1.49 (t, J ¼ 7.5 Hz, 3H); IR n/cmꢁ1 (KBr) 1761,
1713, 1524, 1384, 1321, 1277, 1194, 1138, 1109, 1040, 1011, 893,
853, 817, 777; GC-MS m/z 432.5 [M + 1]+, 400.2, 333.8, 263.9,
200.9, 184.5, 85.1.
Ethyl 9,16-dioxo-5,6,9,16-tetrahydronaphtho[5,6]isoindolo-
[1,2-a]isoquinoline-8-carboxylate (3b).19s Orange solid, yield 93%
(0.392 g), mp 234–235 ꢀC; 1H NMR (500 MHz, CDCl3): d (ppm) 9.00
(d, J ¼ 8.0 Hz, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 7.95–7.94 (m, 2H),
7.55–7.54 (m, 2H), 7.41 (t, J ¼ 7.5 Hz, 1H), 7.32 (t, J ¼ 8.0 Hz, 1H),
7.21 (d, J ¼ 7.5 Hz, 1H), 4.57 (q, J ¼ 7.0 Hz, 2H), 4.22 (t, J ¼ 6.5 Hz,
2H), 3.06 (t, J ¼ 6.5 Hz, 2H), 1.54 (t, J ¼ 7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d (ppm) 179.4, 179.2, 161.6, 135.5, 134.8, 134.6,
133.5, 132.1, 131.2, 129.9, 129.8, 129.7, 129.2, 129.0, 128.8, 128.7,
128.5, 127.3, 127.3, 126.4, 126.1, 124.0, 118.2, 62.5, 43.1, 29.1, 14.1;
IR n/cmꢁ1 (KBr) 1665, 1461, 1267, 1016, 751; HRMS (ESI-TOF) m/z
calcd for C27H20NO4 [M + H]+ 422.1392, found 422.1388.
Ethyl 10-(4-triuoromethylphenyl)-9,11-dioxo-6,9,10,11-tetra-
hydro-5H-pyrrolo-[30,40:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxy-
late (3f).19s White solid, yield 83% (0.377 g), mp 203–204 ꢀC; 1H
NMR (500 MHz, CDCl3): d (ppm) 8.49–8.47 (m, 1H), 7.72 (d, J ¼
8.5 Hz, 2H), 7.58 (d, J ¼ 8.5 Hz, 2H), 7.36–7.34 (m, 2H), 7.25 (t,
J ¼ 4.5 Hz, 1H), 4.70 (t, J ¼ 7.0 Hz, 2H), 4.39 (q, J ¼ 7.0 Hz, 2H),
3.13 (t, J ¼ 7.0 Hz, 2H), 1.47 (t, J ¼ 7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d (ppm) 162.2, 160.6, 159.1, 135.8, 134.2,
133.5, 132.3, 130.3, 127.7, 127.6, 127.5, 126.8, 125.7, 125.6,
125.5, 125.1, 124.5, 122.8, 118.8, 115.6, 61.5, 43.2, 27.9, 13.9;
IR n/cmꢁ1 (KBr) 1762, 1712, 1477, 1417, 1385, 1325, 1277,
1196, 1162, 1117, 1068, 1019, 947, 895, 845, 815; GC-MS m/z
454.7 [M + 1]+, 453.8, 371.0, 408.8, 381.8, 338.0, 139.0; HRMS
(ESI-TOF) m/z calcd for C24H18F3N2O4 [M + H]+ 455.1219,
found 455.1216.
Ethyl 9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo-
[30,40:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3c).19m White
1
ꢀ
solid, yield 94% (0.363 g), mp 190–191 C; H NMR (500 MHz,
CDCl3): d (ppm) 8.59 (d, J ¼ 8.5 Hz, 1H), 7.50 (t, J ¼ 7.0 Hz, 2H),
7.43–7.36 (m, 5H), 7.29 (d, J ¼ 7.5 Hz, 1H), 4.77 (q, J ¼ 8.0 Hz, 2H),
4.44 (q, J ¼ 7.0 Hz, 2H), 3.18 (t, J ¼ 7.0 Hz, 2H), 1.48 (t, J ¼ 8.0 Hz,
3H); IR n/cmꢁ1 (KBr) 1759, 1709, 1551, 1482, 1421, 1384, 1341,
1301, 1279, 1198, 1155, 1111, 1090, 1051, 945, 895, 862, 823, 759;
GC-MS m/z 386.8 [M + 1]+, 385.8, 339.9, 314.0, 270.1, 139.1.
Ethyl 10-(4-methoxyphenyl)-9,11-dioxo-6,9,10,11-tetrahydro-
5H-pyrrolo-[30,40:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate
(3d).19n White solid, yield 74% (0.308 g), mp 168–169 ꢀC; 1H
NMR (500 MHz, CDCl3): d (ppm) 8.57 (d, J ¼ 7.5 Hz, 1H), 7.41–
7.35 (m, 2H), 7.31 (d, J ¼ 8.5 Hz, 2H), 7.28–7.27 (m, 1H), 7.00 (d,
J ¼ 9.0 Hz, 2H), 4.75 (t, J ¼ 7.0 Hz, 2H), 4.42 (q, J ¼ 7.5 Hz, 2H),
3.84 (s, 3H), 3.17 (t, J ¼ 7.0 Hz, 2H), 1.47 (t, J ¼ 7.5 Hz, 3H); IR n/
cmꢁ1 (KBr) 1761, 1707, 1514, 1385, 1280, 1250, 1194, 1159, 1111,
1031, 809, 743; GC-MS m/z 417.3 [M + 1]+, 385.1, 325.6, 288.2,
236.1, 156.7, 71.1.
Ethyl 10-benzyl-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-
[30,40:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3g).19n White
1
ꢀ
solid, yield 88% (0.352 g), mp 200–201 C; H NMR (500 MHz,
CDCl3): d (ppm) 8.49 (d, J ¼ 7.5 Hz, 1H), 7.45 (d, J ¼ 7.0 Hz, 2H),
7.38–7.30 (m, 3H), 7.27–7.23 (m, 1H), 7.20 (d, J ¼ 7.0 Hz, 1H),
4.77 (s, 2H), 4.68 (t, J ¼ 7.0 Hz, 2H), 4.43 (q, J ¼ 7.0 Hz, 2H),
3.10 (t, J ¼ 7.0 Hz, 2H), 1.49 (t, J ¼ 7.0 Hz, 3H); GC-MS m/z 401.0
[M + 1]+, 400.0, 371.0, 353.9, 325.9, 224.2, 195.1.
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Ethyl
2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydrobenzo-
[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3k).19s Orange
1
ꢀ
solid, yield 90% (0.388 g), mp 194–195 C; H NMR (500 MHz,
CDCl3): d (ppm) 8.88 (s, 1H), 8.23 (t, J ¼ 2.0 Hz, 1H), 8.12–8.10
(m, 1H), 7.66–7.60 (m, 2H), 6.67 (s, 1H), 4.51 (q, J ¼ 7.0 Hz, 2H),
4.21 (t, J ¼ 7.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.01 (t, J ¼ 7.0
Hz, 2H), 1.48 (t, J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
(ppm) 179.5, 179.4, 161.5, 150.2, 147.6, 136.2, 135.8, 134.6,
133.1, 132.7, 127.3, 126.9, 126.4, 125.9, 122.9, 119.1, 116.3,
112.4, 110.2, 62.4, 54.3, 55.9, 43.3, 28.5, 14.0; IR n/cmꢁ1 (KBr)
1718, 1657, 1479, 1385, 1282, 1257, 1217, 1152, 1132, 1045,
1015, 705; HRMS (ESI-TOF) m/z calcd for C25H22NO6 [M + H]+
432.1447, found 432.1444.
Ethyl 10-propyl-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-
[30,40:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3h).19s White
1
ꢀ
solid, yield 91% (0.321 g), mp 188–189 C; H NMR (500 MHz,
CDCl3): d (ppm) 8.53 (d, J ¼ 8.5 Hz, 1H), 7.42–7.39 (m, 1H), 7.38–
7.34 (m, 1H), 7.27 (d, J ¼ 8.5 Hz, 1H), 4.72 (t, J ¼ 7.0 Hz, 2H), 4.43
(q, J ¼ 7.0 Hz, 2H), 3.59 (t, J ¼ 7.0 Hz, 2H), 3.15 (t, J ¼ 7.0 Hz,
2H), 1.72–1.67 (m, 2H), 1.49 (t, J ¼ 7.0 Hz, 3H), 0.96 (t, J ¼ 7.5 Hz,
3H); 13C NMR (CDCl3, 125 MHz): d (ppm) 164.2, 162.7, 159.7,
132.8, 132.4, 130.1, 127.9, 127.9, 127.6, 125.9, 125.7, 118.1,
116.7, 61.5, 43.3, 39.9, 28.4, 22.0, 14.2, 11.4; IR n/cmꢁ1 (KBr)
1752, 1700, 1471, 1385, 1330, 1280, 1199, 1123, 1012, 779, 746;
GC-MS m/z 353.0 [M + 1]+, 352.0, 323.1, 278.1, 266.2, 222.2,
139.2, 103.0; HRMS (ESI-TOF) m/z calcd for C20H21N2O4 [M + H]+
353.1501, found 353.1498.
Ethyl 2,3-dimethoxy-9,16-dioxo-5,6,9,16-tetrahydronaphtho-
[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3l).19s Orange
solid, yield 80% (0.433 g), mp 271–272 ꢀC; 1H NMR (500 MHz,
CDCl3): d (ppm) 8.98 (s, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 8.04–
8.00 (m, 2H), 7.63–7.61 (m, 2H), 6.73 (s, 1H), 4.57 (q, J ¼ 7.5
Hz, 2H), 4.26 (t, J ¼ 7.0 Hz, 2H), 4.13 (s, 3H), 3.93 (s, 3H), 3.06
(t, J ¼ 7.0 Hz, 2H), 1.54 (t, J ¼ 7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz): d (ppm) 179.6, 179.4, 161.8, 150.2, 147.7, 136.3, 134.9,
134.6, 132.4, 131.3, 129.83, 129.77, 129.3, 128.82, 128.76,
128.4, 127.0, 126.1, 123.8, 119.3, 117.2, 112.6, 110.2, 62.5,
56.3, 56.0, 43.3, 28.6, 14.1; IR n/cmꢁ1 (KBr) 1719, 1659, 1479,
1384, 1271, 1240, 1222, 1186, 1133, 1038, 914, 763;
HRMS (ESI-TOF) m/z calcd for C29H24NO6 [M + H]+ 482.1604,
found 482.1600.
3-Ethyl 1,2-diethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-
1,2,3-tricarboxylate (3i).19s White solid, yield 78% (0.301 g), mp
1
ꢀ
112–113 C; H NMR (500 MHz, CDCl3): d (ppm) 8.20–8.18 (m,
1H), 7.32–7.30 (m, 2H), 7.25–7.24 (m, 1H), 4.54 (t, J ¼ 7.0 Hz,
2H), 4.38 (q, J ¼ 7.0 Hz, 2H), 4.34–4.30 (m, 4H), 3.00 (t, J ¼ 7.0
Hz, 2H), 1.41 (t, J ¼ 7.0 Hz, 3H), 1.37–1.32 (m, 6H); 13C NMR
(CDCl3, 125 MHz): d (ppm) 166.0, 163.4, 159.9, 136.6, 134.3,
129.2, 128.5, 127.3, 126.9, 126.9, 126.5, 119.0, 110.8, 61.4, 61.0,
60.7, 42.6, 29.4, 14.12, 14.09, 14.05; IR n/cmꢁ1 (KBr) 1673, 1581,
1431, 1366, 1155, 1043, 886; GC-MS m/z 385.5 [M]+, 384.7, 339.7,
312.8, 265.7, 221.9, 139.0, 129.9; HRMS (ESI-TOF) m/z calcd for
C
21H24NO6 [M + H]+ 386.1604, found 386.1598.
Ethyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahy-
dro-5H-pyrrolo[30,40:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxy-
late (3m).19n Orange solid, yield 80% (0.357 g), mp 230–231 ꢀC;
1H NMR (500 MHz, CDCl3): d (ppm) 8.24 (s, 1H), 7.49–7.47 (m,
2H), 7.40–7.36 (m, 3H), 6.75 (s, 1H), 4.73 (t, J ¼ 7.0 Hz, 2H),
4.41 (q, J ¼ 7.0 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.11 (t, J ¼ 7.0
Hz, 2H), 1.46 (t, J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
(ppm) 163.46, 161.59, 159.59, 150.67, 148.57, 134.01, 132.60,
128.97 (2C), 127.84, 127.28 (2C), 125.55, 125.03, 118.29,
118.08, 114.75, 110.48, 110.26, 61.48, 56.14, 55.97, 43.42,
27.81, 14.12; GC-MS m/z 447.1 [M + 1]+, 445.0, 411.3, 385.4,
301.9, 254.3, 100.1, 56.4.
Diethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxy-
late (3j).19n Yellow solid, yield 50% (0.157 g), mp 100–101 ꢀC; 1H
NMR (500 MHz, CDCl3): d (ppm) 8.45 (d, J ¼ 8.5 Hz, 1H), 7.50 (s,
1H), 7.36–7.30 (m, 2H), 7.25 (d, J ¼ 6.0 Hz, 1H), 4.61 (t, J ¼ 6.5
Hz, 2H), 4.37–4.32 (m, 4H), 3.03 (t, J ¼ 6.5 Hz, 2H), 1.41–1.38 (m,
6H); GC-MS m/z 314.2 [M + 1]+, 312.9, 283.5, 155.9, 73.5.
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1141, 1010, 714; HRMS (ESI-TOF) m/z calcd for C25H21NO4Na [M
+ Na]+ 422.1369, found 422.1365.
Methyl 2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydrobenzo-
[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3n).19s Orange
1
ꢀ
solid, yield 92% (0.329 g), mp 205–206 C; H NMR (500 MHz,
CDCl3): d (ppm) 8.95 (s, J ¼ 8.0 Hz, 1H), 8.27–8.25 (m, 1H), 8.17–
8.16 (m, 1H), 7.71–7.65 (m, 2H), 7.42 (t, J ¼ 6.5 Hz, 1H), 7.36–
7.33 (m, 1H), 7.23 (s, J ¼ 7.0 Hz, 1H), 4.26 (t, J ¼ 6.5 Hz, 2H), 4.06
(s, 3H), 3.08 (t, J ¼ 6.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz): d
(ppm) 179.51, 179.47, 161.8, 135.8, 135.6, 134.6, 133.7, 133.3,
132.9, 130.1, 128.9, 127.4 (2C), 127.2, 126.5, 126.3, 125.4, 123.4,
117.5, 53.0, 43.2, 29.0; IR n/cmꢁ1 (KBr) 1712, 1656, 1466, 1412,
1385, 1314, 1269, 1224, 1140, 1113, 1060, 1012, 799, 734; GC-MS
m/z 358.1 [M + 1]+, 356.8, 333.6, 276.5, 139.8, 73.9; HRMS (ESI-
TOF) m/z calcd for C22H16NO4 [M + H]+ 358.1079, found
358.1077.
tert-Butyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetra-
hydro-5H-pyrrolo [30,40:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxy-
late (3q).19s Orange solid, yield 58% (0.240 g), mp 234–235 ꢀC; 1H
NMR (500 MHz, CDCl3): d (ppm) 8.59 (dd, J1 ¼ 1.5 Hz, J2 ¼ 8.0 Hz,
1H), 7.50 (t, J ¼ 8.0 Hz, 2H), 7.43–7.35 (m, 5H), 7.28 (t, J ¼ 6.5 Hz,
1H), 4.75 (t, J ¼ 6.5 Hz, 2H), 3.16 (t, J ¼ 6.5 Hz, 2H), 1.68 (s, 9H);
13C NMR (CDCl3, 125 MHz): d (ppm) 163.2, 161.6, 159.0, 133.0,
132.8, 132.4, 130.1, 128.9 (2C), 127.9, 127.9, 127.7, 127.6, 127.3
(2C), 125.7, 124.7, 120.2, 116.0, 83.4, 43.3, 28.4, 28.3 (3C); IR
n/cmꢁ1 (KBr) 1759, 1703, 1481, 1415, 1385, 1349, 1305, 1289,
1154, 1135, 1112, 1089, 1051, 950, 889, 843, 762; HRMS (ESI-TOF)
m/z calcd for C25H22N2O4Na [M + Na]+ 437.1478, found 437.1475.
Methyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahy-
dro-5H-pyrrolo[30,40:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate
(3o).19s Orange solid, yield 71% (0.264 g), mp 217–218 ꢀC; 1H NMR
(500 MHz, CDCl3): d (ppm) 8.58–8.57 (m, 1H), 7.49 (t, J ¼ 7.5 Hz,
2H), 7.43–7.36 (m, 5H), 7.29–7.28 (m, 1H), 4.77 (t, J ¼ 7.0 Hz, 2H),
3.98 (s, 3H), 3.18 (t, J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d
(ppm) 163.0, 161.5, 160.0, 133.6, 132.6, 132.4, 130.4, 128.8 (2C),
128.0, 127.9, 127.70, 127.65, 127.0 (2C), 125.5, 125.3, 118.2, 116.3,
52.3, 43.4, 28.3; IR n/cmꢁ1 (KBr) 1497, 1385, 1199, 756, 694, 620;
GC-MS m/z 373.6 [M + 1]+, 372.1, 348.6, 303.2, 256.4, 202.1, 154.1,
54.6; HRMS (ESI-TOF) m/z calcd for C22H17N2O4 [M + H]+
373.1188, found 373.1184.
Benzyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahy-
dro-5H-pyrrolo[30,40:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate
(3r).19s Orange solid, yield 90% (0.390 g), mp 198–199 ꢀC; 1H NMR
(500 MHz, CDCl3): d (ppm) 9.00 (d, J ¼ 7.5 Hz, 1H), 8.30 (dd, J1 ¼
2.5 Hz, J2 ¼ 6.0 Hz, 1H), 8.24 (dd, J1 ¼ 3.0 Hz, J2 ¼ 6.5 Hz, 1H),
7.74–7.70 (m, 2H), 7.57 (d, J ¼ 6.5 Hz, 2H), 7.47–7.36 (m, 5H), 7.27
(d, J ¼ 8.5 Hz, 1H), 5.53 (s, 2H), 4.26 (t, J ¼ 6.5 Hz, 2H), 3.08 (t, J ¼
6.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz): d (ppm) 179.8, 179.5,
161.4, 135.9, 135.8, 135.2, 134.9, 133.7, 133.4, 133.1, 130.2, 129.0,
128.8 (2C), 128.7 (2C), 128.7, 127.5, 127.5, 127.3, 126.7, 126.4,
125.5, 123.7, 117.7, 68.4, 43.3, 29.2; IR n/cmꢁ1 (KBr) 1642,
1384, 1262, 1097, 802; HRMS (ESI-TOF) m/z calcd for C28H20NO4
[M + H]+ 434.1392, found 434.1390.
Acknowledgements
This work was supported by the Natural Science Foundation of
China (Grant no. 21176223), the National Natural Science
Foundation of Zhejiang (Grant no. LY13B020016), and the Key
Innovation Team of Science and Technology in Zhejiang Prov-
ince (Grant no. 2010R50018).
tert-Butyl
2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydro-
(3p).19s
benzo[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate
Orange solid, yield 61% (0.244 g), mp 170–171 ꢀC; 1H NMR (500
MHz, CDCl3): d (ppm) 9.02 (d, J ¼ 7.5 Hz, 1H), 8.30 (dd, J1 ¼ 2.0
Hz, J2 ¼ 6.5 Hz, 1H), 8.23 (dd, J1 ¼ 2.0 Hz, J2 ¼ 6.5 Hz, 1H), 7.72–
7.69 (m, 2H), 7.45 (t, J ¼ 7.5 Hz, 1H), 7.37 (t, J ¼ 7.5 Hz, 1H), 7.27
(d, J ¼ 8.5 Hz, 1H), 4.27 (t, J ¼ 7.0 Hz, 2H), 3.11 (t, J ¼ 7.0 Hz,
2H), 1.72 (s, 9H); 13C NMR (CDCl3, 125 MHz): d (ppm) 179.8,
179.3, 160.6, 135.8, 135.0, 134.9, 133.5, 133.1, 132.9 (2C), 129.9,
128.8, 127.7, 127.4, 127.4, 127.2, 126.5, 122.4, 117.2, 84.1, 43.0,
29.1, 28.1 (3C); IR n/cmꢁ1 (KBr) 1660, 1467, 1385, 1266, 1229,
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