Synthesis of 6H-isoindolo[2,1-a]indol-6-ones through a sequential copper-catalyzed C-N coupling and palladium-catalyzed C-H activation reaction

Article abstract of DOI:10.1016/j.tet.2012.01.087

A series of 6H-isoindolo[2,1-a]indol-6-ones were synthesized through one-pot sequential coupling reactions, which were comprised of a copper-catalyzed C-N coupling cyclization and a palladium-catalyzed C-H activation course. General chemicals benzoyl chlorides and o-gem-dibromovinyl anilines were employed as the starting substrates.

Full text of DOI:10.1016/j.tet.2012.01.087

Tetrahedron 68 (2012) 3112e3116
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Synthesis of 6H-isoindolo[2,1-a]indol-6-ones through a sequential
copper-catalyzed C-N coupling and palladium-catalyzed CeH activation reaction
*
Hua-Feng He, Sheng Dong, Yi Chen, Yang Yang, Yueqin Le, Weiliang Bao
Department of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 6H-isoindolo[2,1-a]indol-6-ones were synthesized through one-pot sequential coupling re-
actions, which were comprised of a copper-catalyzed CeN coupling cyclization and a palladium-
catalyzed CeH activation course. General chemicals benzoyl chlorides and o-gem-dibromovinyl ani-
lines were employed as the starting substrates.
Received 3 November 2011
Received in revised form 5 January 2012
Accepted 31 January 2012
Available online 4 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Coupling reaction
CeH activation
Copper-catalysis
Palladium-catalysis
O-gem-Dibromovinyl aniline
Benzoyl chloride
1. Introduction
After ligands were introduced and the reaction temperature was
lowered, copper-catalyzed Ullmann condensation-type reactions
Indole and its derivatives are always the unremitting pursuit of
chemists due to their bio-active properties. Possessing charming
biological and pharmacological activities, they are scaffolds of
many important molecules in the field of biochemistry and me-
dicinal chemistry. For instance, indomethacin was found to have an
inverse correlation with the prevalence and severity of Alzheimer’s
disease (AD).1 Also they are very important scaffolds of many nat-
(formation of sp2 C-heteroatom bonds) have drawn considerable
attention for their efficiency and low cost.4 At the same time, in the
last decade CeH functionalization via CeH activation without the
pretreatment of substrates had aroused extensive revaluation of
synthetic chemistry for their economic facility and high efficiency.5
The tandem or domino methodology combining copper-catalyzed
CeC or CeX coupling reactions with transition-metal catalyzed
CeH activation in one-pot fashion would be even more attractive.
Our group has achieved some satisfactory results applying this
methodology. Pyrimido[1,6-a]indol-1(2H)-one derivatives were
synthesized via an addition/Cu-catalyzed N-arylation/CeH activa-
tion domino process in one-pot procedure from o-gem-dibromo-
vinylisocyanates and N-alkyl-anilines.6a Unsymmetrical 1,10-
carbonyl-2,20-biindolyl derivatives were also obtained from o-gem-
dibromovinylaniline and indole-1-carboxylic acid through a similar
procedure.6b
ural products and clinical substances. For example,
b-carbolines
were reported to be the basic scaffolds of the alkaloids existed in
Ailanthus altissima, which was widely used in Ayurveda and
evidence-based phytotherapy.2 Although there are plenty of
methods to synthesize indole derivatives,3 more convenient and
applicable access to these substances is still highly demanded.
COOH
R3
R
MeO
From our reported two examples andotherpioneering works,7,8 it
is obvious that the easily obtainable o-gem-dibromovinyl aniline was
a perfect precursor for indole derivatives synthesis. However, in the
synthesis of unsymmetrical 2,2-biindolyl derivatives, N-(2-(2,2-
dibromovinyl) phenyl)-1H-indole-1-carboxamide should be pre-
pared as the starting material. On the other hand, only indole-1-
carboxylic acids were applied. As the retrosynthetic analysis
showed (Scheme 1), we envisaged that these fused-cyclic com-
pounds could be obtained by the reaction of o-gem-dibromovinyl
N
N
NO
N
O
N
R1
O
O
R2
Cl
Indomethacin
β
-carbolines
* Corresponding author. Fax: þ86 571 88273814; e-mail address: wlbao@
css.zju.edu.cn (W. Bao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.087

H.-F. He et al. / Tetrahedron 68 (2012) 3112e3116
3113
aniline with the common chemicals acid chlorides via one-pot pro-
cedure. Herein, we report this one-pot tandem copper-catalyzed
CeN coupling/palladium-catalyzed CeC coupling reactions.
Next, the bases employed in copper-catalyzed coupling reaction
were inspected, and K2CO3 was found to be the most suitable (Table
1, entries 3, 9e11). Furthermore, comparing with other solvents,
Br
R1
R1
Br
Br
N
O
N
O
NH
R1
X
R2
Br
R2
R2
O
R2
+
Br
NH2
O
R1
Scheme 1. Retrosynthetic analysis of 6H-isoindolo[2,1-a]indol-6-ones.
Benzoyl chloride (1a) and o-gem-dibromovinyl aniline (2a) were
chosen to investigate the reaction. The optimization of the reaction
conditions was performed stepwise for simplification. Based on our
previous works, the first step of the reaction, in which the indole
ring was formed via a nucleophilic substitution and a copper-
catalyzed intramolecular coupling cyclization, was conducted in
the presence of CuI (10%), N,N-dimethyl ethylenediamine (DMEDA)
(20%), and K2CO3 (1.0 equiv) in toluene at 120 ꢀC. The expected (2-
bromo-1H-indol-1-yl)(phenyl)methanone (3a) was obtained, but
the yield was only 48% (Table 1, entry 1). A lot of bromine-lost
product (4a) was observed. If the temperature was lowered to
100 ꢀC, trace of 3a could be obtained for the Cu(I)-catalyzed C-N
coupling was failed (Table 1, entry 2). As known, the existence of
iodine anion may accelerate the removal of bromine. Thus CuI was
replaced with CuBr to reduce the bromine-lost. To our delight, the
yield of 3a could be raised up to 91%. Other copper sources were
found less effective than CuBr (Table 1, entries 1, 3, 4, 5). Then, some
ligands were screened, and DMEDA was chosen as the most com-
patible one (Table 1, entries 3, 6, 7, 8).
toluene was the most effective to enhance the conversion (Table 1,
entries 3, 12e14). So the reaction condition shown in Table 1, entry
3 was chosen as the optimized one for the indole-ring formation
step.
With the best condition of the first step in hand, we sub-
sequently optimized the condition of palladium-catalyzed CeH
activation step. The product of the first step, 3a, was employed
directly to conduct this optimization. Meanwhile, in order to
complete the whole reaction in one-pot, the reaction conditions of
the first step were chosen to purchase the second step conversion.
Pd(dppf)Cl2 showed the best catalytic property among different
sources of palladium-catalyst (Table 2, entries 1e5). We screened
the bases used in this step and found that KOAc was the best one
(Table 2, entries 6e8).
Table 2
The optimization of palladium-catalyzed CeH activationa
Br
Palldium-cat.
N
N
base, toluene 120oC
Table 1
The optimization of copper-catalyzed intramolecular couplinga
5a
O
3a
O
O
Br
Br
Entry
Pd catalysis
Base
Yieldb [%]
Cu(I), ligand,
Cl R.T.
2h base, solv., 24h
N
N
Br
2
+
+
NH
1
2
3
4
5
6
7
8
PdCl2
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
Cs2CO3
TEA
15
47
13
82
10
43
27
25
O
O
1a
2a
Pd(PPh3)Cl2
Pd(allyl)2Cl2
Pd(dppf)Cl2
Pd(OAc)2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
4a
3a
Entry
Cu-cat
Ligands
Solvent
Base
Yieldb [%]
1
2c
3
4
5
6
7
CuI
CuI
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
1,10-Phenanthroline
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
48
Trace
91
13
61
CuBr
CuCl
Cu2O
CuBr
CuBr
a
Reaction condition: 0.5 mmol 3a, 0.05 mmol Pd-catalyst, and 0.75 mmol base in
3 mL solvent under nitrogen atmosphere.
b
<5
41
Isolated yield based on 3a.
L-Proline
O
O
8
CuBr
Toluene
K2CO3
31
After the conditions of both steps were optimized, we tried to
carry out these two conversions in one-pot. When these two con-
versions were conducted step by step, the ultimate product was got
in 78% yield. When all the materials were put into the reaction tube
at the same time and the two conversions were conducted in one-
pot, the target product also could be got, though the yield was
down to 62%. Compared to the long time consumption and tedious
work-up in the separate procedure, we chose the one-pot pro-
cedure to explore the scope of the methodology. Also, the terminal
product 5a could be obtained without the addition of copper cat-
alyst, but the yield was lowered down drastically, only 21% of 5a
could be obtained.
OEt
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
Toluene
Toluene
Toluene
DMF
DMSO
Xylene
Cs2CO3
KOAc
TEA
K2CO3
K2CO3
K2CO3
20
<5
<5
trace
trace
18
10
11
12
13
14
a
Reaction condition: 0.5 mmol 1a, 0.6 mmol 2a, 0.05 mmol copper catalyst,
0.1 mmol ligands, and 0.5 mmol base in 3 mL solvent under nitrogen atmosphere at
120 ꢀC.
b
Isolated yield based on o-gem-dibromovinyl aniline.
This reaction was conducted at 100 ꢀC.
c

3114
H.-F. He et al. / Tetrahedron 68 (2012) 3112e3116
Next, we checked the scope and limitation of the reaction. The
2. Experimental section
electronic effect of the aromatic moiety of o-gem-dibromovinyl
aniline was firstly investigated. Generally, the substrates bearing
electron-withdrawing groups were more productive in the for-
mation of the indole rings in contrast to the ones with electron-
donating groups (compared the yields of 5a, 5b, 5c, and 5d,
Scheme 2). The electronic effect of the benzoyl chloride was then
examined, and the experimental results showed that electron-
donating groups could accelerate the palladium-catalyzed CeH
activation comparing with the electron-withdrawing groups. The
steric effect was also studied, as showed in Scheme 2. The steric
hindrance of ortho-methyl group of benzoyl chloride decreased the
yield of 5e drastically. When meta-methyl benzoyl chloride was
employed, one of the regioisomers 5f was solely obtained, which
exhibited the rather high regioselectivity of the CeH activation. On
2.1. Representative procedures for the synthesis of 6H-
isoindolo[2,1-a]indol-6-ones
To an oven-dried Schlenk tube charged with a magnetic stir bar,
o-gem-dibromovinyl aniline (0.5 mol) was added. The Schlenk tube
was capped with a Teflon screwcap, and then evacuated and
backfilled with N2 (with N2 baloon). Then 3 mL toluene was added
as the solvent. Benzoyl chloride of 0.5 mmol was dropped through
syringe. The reaction system was stirred for 2 h at room tempera-
ture. Then CuBr (0.05 mmol), DMEDA (0.1 mmol), K2CO3
(0.5 mmol), Pd(dppf)Cl2 (0.05 mmol), and KOAc (0.75 mmol) were
added under the protection of N2. Then the tube was put into 120 ꢀC
oil bath for 24 h. The reaction was monitored by TLC. If toluene or
xylene was used as the solvent, the combined filtrate was directly
concentrated by rotatory evaporation; if DMF or DMSO was used as
the solvent, 15 mL ethyl acetate was added and washed with sat-
urated brine (10 mLꢁ3). Dried over anhydrous sodium sulfate, the
filtrate was concentrated by rotatory evaporation. The residue was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (15:1e20:1 v/v) as eluent to give the corre-
sponding product.
the other hand, when methyl group was attached onto a-position of
o-gem-dibromovinyl aniline, the corresponding products were
afforded with relatively lower yields. Also, the electron-rich groups
would be benefit to this conversion, as the yields of 5l, 5m, 5n
showed.
2.1.1. 6H-Isoindolo[2,1-a]indol-6-one (5a).9 Yellow solid; yield:
62%; melting point: 123e124 ꢀC; IR (neat)
n
2920, 1722, 1607, 1442,
1377, 1137, 738, 690 cmꢂ1
.
1H NMR (400 MHz, CDCl3)
d
7.86 (d,
J¼8.2 Hz, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.47 (d, J¼3.8 Hz, 2H), 7.41 (d,
J¼8.0 Hz, 1H), 7.32e7.29 (m, 1H), 7.26e7.24 (m, 1H), 7.12 (t,
J¼7.4 Hz, 1H), 6.56 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d 162.6, 138.8,
134.6, 134.5, 133.8, 133.6, 133.5, 128.7, 126.2, 125.2, 123.8, 122.2,
121.2, 113.3, 103.4.
2.1.2. 2-Bromo-6H-isoindolo[2,1-a]indol-6-one (5b). Yellow solid;
yield: 56%; melting point: 170e171 ꢀC; IR (neat)
n 2921, 1723, 1610,
1433, 1376, 1137, 864, 754 cmꢂ1; HRMS (EI): [M]þ calculated for
C15H8BrNO: 296.9789, found: 296.9794. 1H NMR (400 MHz, CDCl3)
d
7.76e7.73 (m, 2H), 7.5 (d, J¼1.6 Hz, 1H), 7.52e7.51 (m, 2H),
7.38e7.36 (m, 2H), 6.53 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d
162.4,
139.9, 136.1, 134.3, 133.9, 133.6, 132.2, 129.2, 129.0, 125.4, 124.9,
121.5, 116.9, 114.4, 102.4.
2.1.3. 3-Bromo-6H-isoindolo[2,1-a]indol-6-one (5c). Yellow solid;
yield: 54%; melting point: 193e194 ꢀC; IR (neat)
n 2920, 1723, 1598,
1434, 1352, 1180, 757, 691 cmꢂ1; HRMS (EI): [M]þ calculated for
C15H8BrNO: 296.9789, found: 296.9790. 1H NMR (400 MHz, CDCl3)
d
8.04 (s, 1H), 7.76 (d, J¼7.6 Hz, 1H), 7.52e7.51 (m, 2H), 7.38e7.34
(m, 1H), 7.30e7.26 (m, 2H), 6.56 (s, 1H); 13C NMR (CDCl3, 100 MHz)
162.4, 139.2, 134.5, 134.14, 134.0, 133.5, 133.3, 129.1, 127.1, 125.5,
d
123.2, 121.4, 120.0, 116.5, 102.9.
2.1.4. 2,3-Dimethoxy-6H-isoindolo[2,1-a]indol-6-one (5d). Yellow
solid; yield: 61%; melting point: 160e161 ꢀC; IR (neat)
n 2929, 1725,
1613, 1483, 1284, 1062, 906, 756 cmꢂ1; HRMS (EI): [M]þ calculated
for C17H13NO3: 279.0895, found: 279.0897. 1H NMR (400 MHz,
CDCl3)
1H), 6.88 (s, 1H), 6.45 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H); 13C NMR
(CDCl3, 100 MHz) 162.7, 149.4, 146.9, 137.6, 135.1, 133.6, 133.5,
d
7.69 (d, J¼7.8 Hz, 1H), 7.46e7.39 (m, 3H), 7.25 (t, J¼6.2 Hz,
Scheme 2. Scope of the one-pot reaction. (a) Reaction condition: 0.5 mmol 1,
0.6 mmol 2, 0.05 mmol CuBr, 0.1 mmol DMEDA, 0.5 mmol K2CO3, 0.05 mmol Pa(dppf)
Cl2, and 0.75 mmol KOAc in 3 mL toluene under the protection of N2. Isolated yield
based on 1; bonly 0.4 mmol 2-(2,2-dibromovinyl)-4,5-dimethoxyaniline was used;
conly 0.43 mmol 2-methylbenzoyl chloride was used.
d
128.2, 128.0, 126.8, 125.2, 120.5, 104.5, 103.6, 97.0, 56.3, 56.2.
2.1.5. 7-Methyl-6H-isoindolo[2,1-a]indol-6-one (5e). Yellow solid;
yield: 43%; melting point: 157e158 ꢀC; IR (neat)
n 2918, 1714, 1608,
In conclusion, we have set-up a facile method for the straight-
forward synthesis of 6H-isoindolo[2,1-a]indol-6-ones from easily
obtainable chemicals benzoyl chlorides and o-gem-dibromovinyl
anilines in one-pot procedure. The products might have potential
importance in biochemistry and pharmacology.
1471, 1379, 1177, 873, 741 cmꢂ1; HRMS (EI): [M]þ calculated for
C16H11NO: 233.0841, found: 233.0844. 1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼8.0 Hz, 1H), 7.45 (d, J¼8.0 Hz, 1H), 7.39e7.36 (m, 2H),
7.28 (t, J¼6.8 Hz, 1H), 7.14 (t, J¼7.6 Hz, 1H), 7.09 (d, J¼6.0 Hz, 1H),

H.-F. He et al. / Tetrahedron 68 (2012) 3112e3116
3115
6.58 (s, 1H), 2.68 (s, 3H); 13C NMR (CDCl3, 100 MHz)
138.6, 135.1, 134.5, 133.6, 133.3, 131.3, 130.8, 126.1, 123.7, 122.1, 118.9,
113.2, 102.7, 17.3.
d
163.6, 139.9,
7.51 (t, J¼7.2 Hz, 1H), 7.39 (d, J¼7.6 Hz, 1H), 7.33e7.26 (m, 2H), 7.17
(t, J¼7.2 Hz, 1H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 162.3,
135.8, 135.1, 134.7, 134.0, 133.6, 133.5, 128.1, 126.5, 125.3, 123.6,
121.2, 120.2, 115.4, 113.3, 9.5.
2.1.6. 8-Methyl-6H-isoindolo[2,1-a]indol-6-one (5f). Yellow solid;
yield: 67%; melting point: 146e147 ꢀC; IR (neat)
n
2917, 1724, 1603,
2.1.13. 9-Methoxy-11-methyl-6H-isoindolo[2,1-a]indol-6-one (5m).
1443, 1373, 1151, 813, 740 cmꢂ1; HRMS (EI): [M]þ calculated for
Yellow solid; yield: 62%; melting point: 191e192 ꢀC; IR (neat)
n
C16H11NO: 233.0841, found: 233.0843. 1H NMR (400 MHz, CDCl3)
2922, 1703, 1613, 1440, 1275, 1169, 856, 741 cmꢂ1; HRMS (EI): [M]þ
calculated for C17H13NO2: 263.0946, found: 263.0947. 1H NMR
d
7.86 (d, J¼7.6 Hz, 1H), 7.54 (s, 1H), 7.42e7.37 (m, 2H), 7.30e7.23
(m, 2H), 7.13 (t, J¼7.6 Hz, 1H), 6.52 (s, 1H), 2.39 (s, 3H); 13C NMR
(400 MHz, CDCl3)
d
7.85 (d, J¼8.0 Hz,1H), 7.68 (d, J¼8.4 Hz,1H), 7.39
(CDCl3, 100 MHz)
d
162.81, 139.2, 139.0, 134.6, 134.3, 134.1, 133.5,
(d, J¼7.6 Hz, 1H), 7.28 (t, J¼8.2 Hz, 1H), 7.15 (t, J¼7.8 Hz, 1H), 7.05 (s,
132.0, 126.0, 125.8, 123.7, 122.1, 121.0, 113.2, 102.7, 21.4.
1H), 6.79 (d, J¼9.2 Hz, 1H), 3.92 (s, 3H), 2.43 (s, 3H); 13C NMR
(CDCl3, 100 MHz)
d 164.3, 137.1, 135.5, 134.2, 133.6, 126.9, 126.5,
2.1.7. 9-Methyl-6H-isoindolo[2,1-a]indol-6-one (5g). Yellow solid;
126.4, 124.8, 123.3, 120.1, 115.1, 113.1, 113.0, 107.3, 55.8, 9.5.
yield: 75%; melting point: 170e171 ꢀC; IR (neat)
n 2919, 1724, 1618,
1443, 1372, 1133, 746, 652 cmꢂ1; HRMS (EI): [M]þ calculated for
C16H11NO: 233.0841, found: 233.0839. 1H NMR (400 MHz, CDCl3)
2.1.14. 9-Chloro-11-methyl-6H-isoindolo[2,1-a]indol-6-one
(5n).
Yellow solid; yield: 52%; melting point: 210e211 ꢀC; IR (neat)
n
d
7.87 (d, J¼8.0 Hz, 1H), 7.62 (d, J¼7.6 Hz, 1H), 7.43 (d, J¼7.6 Hz, 1H),
7.31 (s, 1H), 7.27 (t, J¼7.4 Hz, 1H), 7.13 (t, J¼7.8 Hz, 1H), 6.56 (s, 1H),
2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz)
162.8, 144.7, 138.9, 134.9,
2921, 1710, 1606, 1374, 1296, 1099, 890, 743 cmꢂ1; HRMS (EI): [M]þ
calculated for C16H10ClNO: 267.0451, found: 267.0454. 1H NMR
d
(400 MHz, CDCl3)
d
7.84 (d, J¼8.4 Hz,1H), 7.66 (d, J¼8.0 Hz,1H), 7.51
134.4, 133.6,131.3, 129.6, 126.2, 125.1, 123.7, 122.2, 121.9, 113.2, 103.1,
22.0.
(d, J¼1.2 Hz, 1H), 7.38 (d, J¼8.0 Hz, 1H), 7.30 (t, J¼7.2 Hz, 1H), 7.26
(dd, J1¼8.4 Hz, J2¼1.2 Hz, 1H), 7.17 (t, J¼8.4 Hz, 1H), 2.42 (s, 3H); 13
C
NMR (CDCl3, 100 MHz)
d 161.2, 139.9, 136.4, 135.5, 133.6, 133.3,
2.1.8. 9-Chloro-6H-isoindolo[2,1-a]indol-6-one (5h). Yellow solid;
132.2, 128.1, 127.0, 126.3, 123.8, 121.4, 120.4, 116.6, 113.4, 9.5.
yield: 62%; melting point: 236e237 ꢀC; IR (neat)
n 2920, 1718, 1611,
1421, 1376, 1142, 826, 729 cmꢂ1; HRMS (EI): [M]þ calculated for
C15H8ClNO: 253.0294, found: 253.0295. 1H NMR (400 MHz, CDCl3)
2.1.15. 3-Bromo-9-chloro-6H-isoindolo[2,1-a]indol-6-one
(5o).
Yellow solid; yield: 52%; melting point: 210e211 ꢀC; IR (neat)
n
d
7.88 (d, J¼7.8 Hz, 1H), 7.68 (d, J¼8.0 Hz, 1H), 7.50 (s, 1H), 7.46 (d,
J¼8.4 Hz, 1H), 7.32e7.29 (m, 2H), 7.17 (t, J¼7.6 Hz, 1H), 6.64 (s, 1H);
13C NMR (CDCl3, 100 MHz)
161.6, 140.2, 137.4, 136.1, 134.2, 133.7,
2921, 1710, 1606, 1374, 1296, 1099, 890, 743 cmꢂ1; HRMS (EI): [M]þ
calculated for C15H7BrClNO: 330.9400, found: 330.9402. Because
5o can not dissolve in almost all the solvents, we did not get the
data of 1H NMR and 13C NMR.
d
132.1, 128.9, 126.8, 126.4, 124.1, 122.5, 121.6, 113.4, 104.6.
2.1.9. 9-Methoxy-6H-isoindolo[2,1-a]indol-6-one (5i). Yellow solid;
Acknowledgements
yield: 58%; melting point: 149e150 ꢀC; IR (neat)
n 2927, 1726, 1604,
1444, 1333, 1017, 818, 744 cmꢂ1; HRMS (EI): [M]þ calculated for
C16H11NO2: 249.0790, found: 249.0793. 1H NMR (400 MHz, CDCl3)
This work was financially supported by the Natural Science
Foundation of China (No. 21072168).
d
7.88 (d, J¼8.0 Hz, 1H), 7.67 (d, J¼8.4 Hz, 1H), 7.45 (d, J¼7.6 Hz, 1H),
7.28 (t, J¼7.8 Hz, 1H), 7.14 (t, J¼7.4 Hz, 1H), 7.02 (d, J¼1.4 Hz, 1H),
Supplementary data
6.82 (dd, J1¼8.4 Hz, J2¼1.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
164.5, 162.5, 138.4, 136.9, 134.2, 133.7, 126.9, 126.3, 126.1, 123.5,
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.01.087.
122.2, 114.1, 113.1, 107.1, 103.2, 55.8.
2.1.10. 3-Bromo-9-methoxy-6H-isoindolo[2,1-a]indol-6-one
(5j).
References and notes
Yellow solid; yield: 58%; melting point: 224e225 ꢀC; IR (neat)
n
2939, 1714, 1610, 1439, 1242, 1068, 831, 784 cmꢂ1; HRMS (EI): [M]þ
1. (a) Dvir, E.; Friedman, J. E.; Lee, J. Y.; Koh, J. Y.; Younis, F.; Raz, S.; Shapiro, I.;
Hoffman, A.; Dahan, A.; Rosenberg, G.; Angel, I.; Kozak, A.; Duvdevani, R. J.
Pharmacol. Exp. Ther. 2006, 318, 1248e1256; (b) Boussard, M.-F.; Truche, S.;
Rousseau-Rojas, A.; Briss, S.; Desamps, S.; Droual, M.; Wierzbicki, M.; Ferry, G.;
Audinot, V.; Delagrange, P.; Boutin, J. A. Eur. J. Med. Chem. 2006, 41, 306e320; (c)
calculated for C16H10BrNO2: 326.9895, found: 326.9892. 1H NMR
(400 MHz, CDCl3)
J¼8.4 Hz, 1H), 7.25 (d, J¼7.6 Hz, 1H), 7.02 (s, 1H), 6.83 (d, J¼8.0 Hz,
1H), 6.56 (s, 1H), 3.91 (s, 3H); 13C NMR (CDCl3, 100 MHz)
164.7,
d
8.05 (s, 1H), 7.68 (d, J¼8.4 Hz, 1H), 7.30 (d,
d
ꢀ
ꢀ
Guillaumel, J.; Leonce, S.; Pierre, A.; Renard, P.; Pfeiffer, B.; Arimondo, P. B.;
ꢀ
162.3, 138.7, 136.7, 134.1, 133.0, 127.2, 126.7, 125.7, 123.2, 119.9, 116.3,
114.3, 107.3, 102.8, 55.9.
Monneret, C. Eur. J. Med. Chem. 2006, 41, 379e386; (d) Guillaumel, J.; Leonce, S.;
ꢀ
Pierre, A.; Renard, P.; Pfeiffer, B.; Peruchon, L.; Arimondo, P. B.; Monneret, C.
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L.; Williams, A. R.; Swain, C. J. Bioorg. Med. Chem. Lett. 2001, 11, 1237e1240.
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Ogura, M.; Fransworth, N. R. Lloydia 1978, 41, 166e168; (c) Aono, H.; Koike, K.;
Kaneko, J.; Ohmoto, T. Phytochemistry 1994, 37, 579e584; (d) Khan, S. A.;
Shamsuddin, K. M. Phytochemistry 1981, 20, 2062e2063; (e) Koike, K.; Ohmoto,
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2.1.11. 9-Chloro-2,3-dimethoxy-6H-isoindolo[2,1-a]indol-6-one (5k).
Yellow solid; yield: 60%; melting point: 190e191 ꢀC; IR (neat)
n
2969, 1728, 1612, 1481, 1286, 1217, 932, 841 cmꢂ1; HRMS (EI): [M]þ
calculated for C17H12ClNO3: 313.0506, found: 313.0501. 1H NMR
(400 MHz, CDCl3)
d
7.63 (d, J¼8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (d,
J¼7.8 Hz, 1H), 6.92 (s, 1H), 6.51 (s, 1H), 3.98 (s, 3H), 3.92 (s, 3H); 13C
NMR (CDCl3, 100 MHz) d 161.7, 150.0, 147.2, 140.2, 136.7, 136.1, 131.8,
128.5, 128.1, 126.6, 126.3, 120.9, 104.8, 104.5, 97.1, 56.4, 56.3.
2.1.12. 11-Methyl-6H-isoindolo[2,1-a]indol-6-one (5l). Yellow solid;
yield: 57%; melting point: 169e170 ꢀC; IR (neat)
n 2919, 1708, 1608,
1446, 1360, 1124, 738, 694 cmꢂ1; HRMS (EI): [M]þ calculated for
C16H11NO: 233.0841, found: 233.0846. 1H NMR (400 MHz, CDCl3)
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d
7.87 (d, J¼8.0 Hz, 1H), 7.76 (d, J¼7.8 Hz, 1H), 7.57 (d, J¼7.2 Hz, 1H),

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