Synthesis of 6H-isoindolo[2,1-a]indol-6-ones via Pd-catalyzed cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO

Article abstract of DOI:10.1016/j.tet.2017.12.058

An efficient method for preparation of substituted 6H-isoindolo[2,1-a]indol-6-ones (2) that are important structural components of a vast array of naturally occurring and pharmacologically active compounds, has been developed by the palladium-catalyzed in

Full text of DOI:10.1016/j.tet.2017.12.058

Accepted Manuscript
Synthesis of 6H-isoindolo[2,1-a]indol-6-ones via Pd-catalyzed
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO
Bin Liu, Chunbo Lai, Chunlei Zhang, Xigeng Zhou
PII:
S0040-4020(17)31351-0
10.1016/j.tet.2017.12.058
TET 29214
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 November 2017
Revised Date: 23 December 2017
Accepted Date: 29 December 2017
Please cite this article as: Liu B, Lai C, Zhang C, Zhou X, Synthesis of 6H-isoindolo[2,1-a]indol-6-ones
via Pd-catalyzed cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO, Tetrahedron
(2018), doi: 10.1016/j.tet.2017.12.058.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 6H-isoindolo[2,1-a]indol-6-ones
via Pd-Catalyzed Cycloaminocarbonylation
of 2-(1H-indol-2-yl)phenyl Tosylates with CO
Leave this area blank for abstract info.
Bin Liu,a,b Chunbo Lai,b Chunlei Zhang,b * and Xigeng Zhoua *
aDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan
University, Shanghai 200433, People’s Republic of China
bTechnology Research Institute of Shanghai Huayi (Group) Company, Shanghai 200241, People’s Republic of
China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 6H-Isoindolo[2,1-a]indol-6-ones via Pd-Catalyzed
Cycloaminocarbonylation of 2-(1H-Indol-2-yl)phenyl Tosylates with CO
Bin Liu,a,b Chunbo Lai,b Chunlei Zhang,b, and Xigeng Zhoua,
aDepartment of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, People’s Republic
of China
bTechnology Research Institute of Shanghai Huayi (Group) Company, Shanghai 200241, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for preparation of substituted 6H-isoindolo[2,1-a]indol-6-ones (2) that are
important structural components of a vast array of naturally occurring and pharmacologically
active compounds, has been developed by the palladium-catalyzed intramolecular
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates with CO. Significantly, 2-(1H-
indol-2-yl)benzamides resulting from intermolecular aminocarbonylation are formed when an
excess of amine is used in this reaction system. Alternatively, 2-(1H-indol-2-yl)benzamides can
also be synthesized by the in situ aminolysis of 2. Furthermore, treatment of 2 with hydrosilane
in the presence of KOH gave the unprecedented reducing products 2-(-1H-indol-2-yl)benzyl
alcohols in 75-86% yields. These results demonstrate that 6H-isoindolo[2,1-a]indol-6-ones are
versatile substrates for further synthetic elaboration.
Available online
Keywords:
Palladium
Cycloaminocarbonylation
C-O bond activation
6H-isoindolo[2,1-a]indol-6-ones
Ring-opening of lactam
2-(1H-indol-2-yl)phenyl tosylate
2009 Elsevier Ltd. All rights reserved
.
Given the easier synthesis and crystalline isolation of 2-(1H-
indol-2-yl)phenyl tosylates[8] from cheap 2-hydroxyphenyl alkyl
ketone precursors compared with o-(2-halophenyl)-1H-indoles,
we were interested in the synthesis of 6H-isoindolo[2,1-a]indol-
6-ones from 2-(1H-indol-2-yl)phenyl tosylates. Herein, we
describe a new method for preparation of 6H-isoindolo[2,1-
1. Introduction
Substituted 6H-isoindolo[2,1-a]indol-6-ones are important
structural components of a vast array of naturally occurring and
pharmacologically active compounds.[1] Such types of
heterocycles are valuable intermediates in organic synthesis,[2]
and can also be used as melatonin MT3 ligands,[3] potential
anticancer agents[4] and bacterial N or A efflux pump inhibitors [5]
Therefore, the importance of 6H-isoindolo[2,1-a]indol-6-ones
justifies a longstanding interest in the development of efficient
and versatile approaches to their synthesis and new structures.
a]indol-6-one
derivatives
by
the
Pd-catalyzed
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates
with CO.
.
Transition metal-catalyzed carbonylative coupling reactions
of organic substrates with CO have become a powerful tool in
organic synthesis.[6] In 2016, Cho[7a] and Fan[7b] reported the Pd-
catalyzed cyclocarbonylation of 2-(2-bromophenyl)-1H-indoles
for preparing 6H-isoindolo[2,1-a]indol-6-ones (Scheme 1, paths
a and b). Huang and co-workers[7c] reported the synthesis of
substituted 6H-isoindolo[2,1-a]indol-6-ones by Pd-catalyzed
carbonylation of 2-(2-iodophenyl)-1H-indoles with CO (Scheme
1, path c). The preparation of 6H-isoindolo[2,1-a]indol-6-ones
via rhodium-catalyzed intramolecular C-H carbonylation of 2-
aryindoles with carbon monoxide has also been achieved, but the
reaction needs 3 equivalents of AgOAc as oxidant (Scheme 1,
path d).[7d]
Scheme 1. Comparison of the previous cycloaminocarbonylative
work to the current work.
———
Corresponding author. Tel.: (+86)-21-6564-3769; (+86)-21-6564-3769; e-mail: xgzhou@fudan.edu.cn (X. Zhou).

2
Tetrahedron
2. Results and discussion
Table 2. Cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl
ACCEPTED MANUSCRIPT
tosylates[a,b]
Our initial screening of reaction conditions focused on the
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylate
(1a) with CO in the presence of 1,3-
bis(diphenyphosphino)propane (dppp) and different Pd catalyst
(Table 1). In a series of preliminary screening of Pd catalysts
(Table 1, entries 1-3), it was found that Pd(TFA)2 showed the
highest catalytic activity. Screening several different bases such
as K2CO3, DBU, AcONa, K3PO4, Na3PO4, K2HPO4 and PhONa,
2 equivalents of K3PO4 gave the best result with 50% yield
(Table 1, entries 4-11). Compared with dppp, 1,2-
Cl
N
N
N
O
O
O
2b 62%
2a 73%
2c 45%
bis(diphenylphosphino)ethane
(dppe),
2-
(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl
(X-
F
phos) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos), were less effective (Table 1, entries 12-14). The
yield could be improved to 54% by using the more amount of
Pd(TFA)2 (Table 1, entry 15). Replacement of CH3CN with 1,4-
dioxane as solvent led to the decrease of the yield (Table 1, entry
16). Additionally, increasing the reaction temperature up to 150
N
N
N
O
O
O
2f 50%
2e 30%
2d 51%
F
o
oC or 160 C gave a higher yield, while reducing the reaction
N
N
N
temperature or using less amount of Pd(TFA)2 and dppp led to a
decrease of yields (Table 1, entries 17-22).
O
O
O
2h 63%
2i 80%
2g 75%
Table 1. Palladium, Ligand, and Base Effects[a]
MeO
Cl
N
N
N
O
O
O
2k 60%
2j 61%
2l 52%
Yield
Et
Et
Entry
[Pd] (mol%)
Ligand (mol%)
Base (equiv)
K CO (1.2)
(%)[b]
F
Pd(OAc) (5)
1
2
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppe (10)
19
2
2
3
N
N
N
Pd(TFA) (5)
K CO (1.2)
2 3
21
16
2
F
O
O
O
Pd(PhCN)Cl (5)
K CO (1.2)
2 3
3
2
2n 91%
2o 77%
2m 62%
Pd(TFA) (5)
4
DBU (1.2)
trace
15
2
Et
N
Et
N
Et
Et
Pd(TFA) (5)
5
AcONa (1.2)
K PO (1.2)
2
Pd(TFA) (5)
N
6
39
2
3
4
Pd(TFA) (5)
Na PO (1.2)
3 4
7
35
O
O
O
2
2q 78%
2r 52%
2p 80%
Pd(TFA) (5)
K HPO (1.2)
2 4
8
25
2
Et
Et
Et
Pd(TFA) (5)
9
PhONa (1.2)
K PO (2)
18
2
Cl
Pd(TFA) (5)
10
11
12
13
14
15
50
2
3
4
N
N
N
Pd(TFA) (5)
K PO (3)
3 4
30
2
F
Cl
O
O
O
Pd(TFA) (5)
K PO (2)
3 4
5
2
2t 48%
2u 30%
2s 61%
Pd(TFA) (5)
K PO (2)
3 4
X-phos (10)
Xantphos (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
dppp (10)
trace
trace
54
2
Bn
Bn
Et
F
Pd(TFA) (5)
K PO (2)
3 4
MeO
2
Pd(TFA) (10)
K PO (2)
3 4
N
N
N
2
c
Pd(TFA) (10)
K PO (2)
3 4
trace
28
16
O
O
2
O
d
2w 71%
2x 65%
2v 40%
Pd(TFA) (10)
K PO (2)
3 4
17
2
18e
Bn
Pd(TFA) (10)
K PO (2)
3 4
72
2
f
Pd(TFA) (10)
K PO (2)
3 4
73
19
2
N
N
N
20f
21f
22f
Pd(TFA) (7.5)
K PO (2)
3 4
54
2
O
O
O
K PO (2)
－
3
4
2z 55%
2aa 30%
2y 52%
Pd(TFA) (10)
K PO (2)
3 4
trace
2
[a]
Conditions: substrate (1 mmol), Pd(TFA)2 (10 mol %), dppp (10 mol %),
K3PO4 (2 mmol), CO (1 MPa), CH3CN (30 mL), 160 C, 12 h.
yields.
[a] Conditions: substrate (1 mmol ), [Pd], Ligand, Base, CO (1 MPa), CH3CN,
140 C, 12 h. Isolated yield. 1,4-Dioxane instead of CH3CN as solvent.
o
[b]
Isolated
o
[b]
[c]
[d] 130 oC. [e] 150 oC. [f] 160 oC.

3
a
Based on the above observations and previous reports,[7b, 9]
With the optimum reaction conditions in hand, we
ACCEPTED MANUSCRIPT
subsequently investigated the scope of the Pd-catalyzed
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates
(Table 2). In general, the presence of substituents such as CH3,
Cl or F at the 5-position of the indole unit has a slightly negative
impact on the catalytic reaction, giving the desirable products in
relatively lower yields (Table 2, 2b - 2d). When the substituent
is located at the 7-position of the indole units, it leads to a more
significant decrease of yields due to the sterical effect (2e, 2b vs
2f, 2h vs 2l, 2i vs 2m, 2o vs 2t, 2s vs 2u). Surprisingly, the
presence of CH3 or Et substituent at the 3-position of the indole
ring has promotive impact on the catalytic reaction, giving the
corresponding 6H-isoindolo[2,1-a]indol-6-one derivatives in
satisfactory to excellent yields (Table 2, 2g - 2s). Significantly,
the catalytic system is tolerant to the chlorine substituent (Table
2, 2c, 2k, 2s, 2u). The presence of a benzyl substituent at the 3-
position of the indole ring can also give the corresponding 6H-
isoindolo[2,1-a]indol-6-one derivatives in moderate yields
(Table 2, 2w - 2y). 9-Methyl-6H-isoindolo[2,1-a]indol-6-one
and 7-Methyl-6H-isoindolo[2,1-a]indol-6-one were synthesized
from the corresponding tosylates in satisfactory yields (Table 2,
2z, 2aa).
plausible mechanism for the formation of 2a is shown in Scheme
3. The oxidative addition of the in situ generated Pd0 species with
1a leads to the formation of the key aryl palladium complex A,
which undergoes the CO insertion into a Pd-C bond to afford the
aroyl complex B. Under the promotion of a base, intermediate B
undergoes the intramolecular ligand exchange to afford
intermediate C. Finally, the reductive elimination forms the
cycloaminocarbonylation product and regenerates the active Pd0
species for the next catalytic cycle (Scheme 3).
To explore the versatility of the methodology, we studied the
effect of amine additive on the chemoselectivity. Gratifyingly, it
was found that when ten equivalents of primary amine was
presented, the intermolecular aminocarbonylation products 2-
(1H-indol-2-yl)-benzamide (3a - 3d) were selectively obtained in
moderate yields (Scheme 4). However, treatment of 1a with CO
in the presence of bulky t-BuNH2 instead of n-BuNH2, gave only
the intra- rather than intermolecular aminocarbonylation product
2a (60% yield). In order to reveal the mechanism for the
formation of 3, we made an attempt to isolate the intermediates
of the reaction of 1n with CO and n-BuNH2 (10 equiv) under
standard conditions. When the reaction time was reduced from 12
h to 6 h, a mixture of 3b (30%) and 2n (25%) was obtained.
In addition, 2,11-dimethyl-6H-isoindolo[2,1-a]indol-6-one,
However,
attempt
to
prepare
the
intermolecular
2-fluoro-11-methyl-6H-isoindolo[2,1-a]indol-6-one
and
2-
aminocarbonylation product from the N-methyl-protected
substrate was unsuccessful. Furthermore, 3 could also be
synthesized by the in situ aminolysis of 6H-isoindolo[2,1-
a]indol-6-ones (2) (Scheme 5). These results demonstrated that
the formation of compounds 3 might be from the aminolysis of
the newly formed 2, rather than directly from the competing
intermolecular aminocarbonylation of 1 with CO and amine.
chloro-11-methyl-6H-isoindolo[2,1-a]indol-6-one, which have
the pharmacologically activities against hepatocellular liver
carcinoma cells as potential anticancer agents,[4] could also be
synthesized in 60-80% yields by applying the protocol (Table 2,
2h, 2i, 2k). However, attempts to synthesize the corresponding
cyclocarbonylation products at the 3-position of the indole ring
by protecting the -NH moiety with the t-butoxycarbonyl or
methyl substituent were unsuccessful.
To gain some preliminary understanding of the reaction
mechanism,
a
13CO(g) labeling reaction was carried out.
Replacement of CO (1 MPa) with 13CO(g) (0.5 MPa), [13C]-6H-
isoindolo[2,1-a]indol-6-one (2a*) was successfully obtained
from 2-(1H-indol-2-yl)phenyl tosylate in 50% yield, and the
corresponding product (2a*) was characterized by H NMR, 13C
1
NMR and HRMS (Scheme 2).
Scheme 4. Preparation of compound 3 from 1 with CO.
Scheme 2. Preparation of [13C]-6H-isoindolo[2,1-a]indol-6-one
(2a*) with 13CO.
Scheme 5. Preparation of compound 3 from 2 via aminolysis.
Scheme 6. Preparation of compound 4 from 2.
Scheme 3. Proposed reaction mechanism for the formation of
substituted 6H-isoindolo[2,1-a]indol-6-one.

4
Tetrahedron
ACCEPTED MANUSCRIPT
2-(-1H-Indol-2-yl)benzyl
alcohols
are
valuable
(s, 3H). 13C NMR (CDCl3, 100MHz): δ 161.8, 156.6, 136.7,
intermediates in organic synthesis.[2b,3,5,10] To our delight,
treatment of 2 with PhSiH3 in the presence of 1 equivalent of
KOH in dry THF at refluxing temperature for 1 h allowed the
formation of the desirable reduced products 4 in 75-86% yields
(Scheme 6), providing a new method for synthesis of 2-(-1H-
Indol-2-yl)benzyl alcohols.
135.3, 134.8, 133.9, 133.1, 128.0, 127.8, 124.9, 120.9, 115.1,
113.7, 113.6, 104.0, 55.6, 9.4. HRMS (ESI) Calcd for C17H14NO2
[M+H]+: 264.1025; Found: 264.1026.
3.1.4. 4,11-Dimethyl-6H-isoindolo[2,1-a]indol-6-one (2l)
Yellow solid; 174.4 C; 1H NMR (CDCl3, 400MHz): δ 7.66
o
(d, J = 7.5 Hz, 1H), 7.47-7.42 (m, 2H), 7.25-7.22 (m, 1H), 7.11
(dd, J = 7.2, 1.4 Hz, 1H), 7.04-6.99 (m, 2H), 2.84 (s, 3H), 2.33 (s,
3H). 13C NMR (CDCl3, 100MHz): δ 161.7, 136.4, 135.5, 134.4,
134.1, 133.5, 133.3, 128.9, 127.8, 125.1, 124.7, 123.8, 120.5,
117.1, 115.2, 21.2, 9.3. HRMS (ESI) Calcd for C17H14NO
[M+H]+: 248.1075; Found: 248.1089.
In summary, we have developed an efficient method for the
synthesis of 6H-isoindolo[2,1-a]indol-6-one derivatives from the
corresponding 2-(1H-indol-2-yl)phenyl tosylates via the Pd-
catalyzed intramolecular cycloaminocarbonylation with carbon
monoxide in moderate to good yields. Furthermore, it is found
that the presence of an excess of primary amines can switch the
chemoselectivity of the aminocarbonylation from intramolecular
to intermolecular reaction, affording substituted 2-(1H-indol-2-
yl)benzamides. In addition, the direct transformation of
3.1.5. 4-Fluoro-11-methyl-6H-isoindolo[2,1-a]indol-6-one (2m)
o
1
Yellow solid; 223.6 C; H NMR (CDCl3, 400MHz): δ 7.73
(d, J = 7.5 Hz, 1H), 7.50-7.46 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H),
7.11-7.03 (m, 2H), 6.99-6.94 (m, 1H), 2.38 (s, 3H). 13C NMR
(CDCl3, 100MHz): δ 160.5, 149.9 (d, JCF = 250 Hz), 139.1,
135.7, 134.4, 133.5, 133.1, 128.3, 125.4, 124.3 (d, JCF = 5.7 Hz),
121.0, 120.6 (d, JCF = 13.6 Hz), 115.7 (d, JCF = 2.4 Hz), 114.9 (d,
JCF = 3.7 Hz), 113.2 (d, JCF = 18.5 Hz), 9.4. HRMS (ESI) Calcd
for C16H11FNO [M+H]+: 252.0825; Found: 252.0839.
isoindolo[2,1-a]indol-6-ones
into
2-(-1H-indol-2-yl)benzyl
alcohols is also achieved. The easy synthesis and crystalline
isolation of 2-(1H-indol-2-yl)phenyl tosylates from cheap 2-
hydroxyphenyl alkyl ketone precursors makes the present method
an attractive and practical alternative to those commonly used o-
(2-halophenyl)-1H-indoles
as
counterparts
in
cycloaminocarbonylation protocols. Further investigations on the
synthetic applications of this method are underway in our
laboratory.
3.1.6. 11-Ethyl-2-fluoro-6H-isoindolo[2,1-a]indol-6-one (2o)
1
Yellow solid; 136.6 oC; H NMR (CDCl3, 400MHz): δ 7.80-
7.68 (m, 2H), 7.53-7.45 (m, 2H), 7.29 (t, J = 6.9 Hz, 1H), 7.05 (d,
J = 8.9 Hz, 1H), 6.96 (t, J = 8.9 Hz, 1H), 2.81 (q, J = 7.6 Hz,
2H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100MHz): δ
162.0, 159.8 (d, JCF = 238 Hz), 135.9 (d, JCF = 9.0 Hz), 135.5,
134.6, 133.7, 133.5, 130.0, 128.3, 125.3, 121.4 (d, JCF = 3.9 Hz),
121.3, 113.9 (d, JCF = 9.3 Hz), 113.6 (d, JCF = 25 Hz), 106.6 (d,
JCF = 25 Hz), 18.0, 14.3. HRMS (ESI) Calcd for C17H13FNO
[M+H]+: 266.0981; Found: 266.0985.
3. Experimental Section
3.1
General
procedure
for
the
intramolecular
cycloaminocarbonylation of 2-(1H-indol-2-yl)phenyl tosylates
2-(1H-Indol-2-yl)phenyl tosylate (1 mmol), Pd(TFA)2 (10
mol%), dppp (10 mol%), anhydrous K3PO4 (2 mmol) and
CH3CN (30 mL) were charged in a 200 ml-autoclave. The
autoclave was flushed and then pressurized with carbon
3.1.7. 11-Ethyl-4-methyl-6H-isoindolo[2,1-a]indol-6-one (2q)
o
monoxide to 1 MPa, the mixture was stirred at 160 C for 12 h.
o
1
Yellow solid; 132.4 C; H NMR (CDCl3, 400MHz): δ 7.72
(d, J = 7.5 Hz, 1H), 7.56-7.45 (m, 2H), 7.30-7.27 (m, 1H), 7.21
(dd, J = 7.0, 1.5 Hz, 1H), 7.08-7.03 (m, 2H), 2.88-2.83 (m, 5H),
1.33 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100MHz): δ 161.9,
135.5, 135.0, 134.5, 134.4, 133.6, 133.4, 128.9, 127.9, 125.2,
125.0, 123.8, 121.9, 120.7, 117.3, 21.3, 17.8, 14.3. HRMS (ESI)
Calcd for C18H16NO [M+H]+: 262.1232; Found: 262.1233.
The mixture was cooled to room temperature and vented to
discharge the excess CO. After filtration, solvent was removed
under reduced pressure and the crude residue was purified by
column chromatography on silica gel with petroleum ether-ethyl
acetate as the eluent to afford the desired product.
3.1.1. [13C]-6H-Isoindolo[2,1-a]indol-6-one (2a*)
1
Yellow solid; 168.6 oC; H NMR (CDCl3, 400MHz): δ 7.86
3.1.8. 2,11-Diethyl-6H-isoindolo[2,1-a]indol-6-one (2r)
(d, J = 8.0 Hz, 1H), 7.72 (dd, J = 7.4, 3.3 Hz, 1H), 7.47 (d, J =
4.0 Hz, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.33-7.28 (m, 1H), 7.25 (d,
J = 3.7 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H). 13C NMR
(CDCl3, 100MHz): δ 162.6 (13C-enriched), 138.8 (d, J = 8.3 Hz),
134.6 (d, J = 4.1 Hz), 134.4 (d, J = 2.6 Hz), 134.1, 133.6, 133.5,
128.7 (d, J = 4.6 Hz), 126.3, 125.2 (d, J = 2.8 Hz), 123.8, 122.2,
121.2 (d, J = 3.2 Hz), 113.3, 103.4 (d, J = 1.8 Hz). HRMS (ESI)
Calcd for C1413CH10NO [M+H]+: 221.0796; Found: 221.0807.
o
1
Yellow solid; 125.0 C; H NMR (CDCl3, 400MHz): δ 7.73
(d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49-7.42 (m, 2H),
7.24-7.21 (m, 1H), 7.19 (s, 1H), 7.09 (dd, J = 8.1, 0.9 Hz, 1H),
2.83 (q, J = 7.6 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6
Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100MHz): δ
162.1, 139.7, 135.0, 134.9, 134.1, 133.9, 133.3, 132.0, 127.8,
126.4, 125.1, 122.0, 121.0, 119.3, 113.1, 29.0, 18.0, 16.1, 14.4.
HRMS (ESI) Calcd for C19H18NO [M+H]+: 276.1388; Found:
276.1394.
3.1.2. 2,4-Dimethyl-6H-isoindolo[2,1-a]indol-6-one (2e)
o
1
Yellow solid; 121.8 C; H NMR (CDCl3, 400MHz): δ 7.70
(d, J = 7.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.32-7.28 (m, 1H), 7.00
(s, 1H), 6.84 (s, 1H), 6.52 (s, 1H), 2.83 (s, 3H), 2.33 (s, 3H). 13C
NMR (CDCl3, 100MHz): δ 162.2, 140.0, 135.5, 134.3, 133.7,
133.6, 133.5, 132.5, 130.0, 128.5, 125.1, 124.4, 120.5, 119.5,
103.7, 21.0, 21.0. HRMS (ESI) Calcd for C17H14NO [M+H]+:
248.1075; Found: 248.1089.
3.1.9. 2-Chloro-11-ethyl-6H-isoindolo[2,1-a]indol-6-one (2s)
o
Yellow solid; 142.0 C; 1H NMR (CDCl3, 400MHz): δ 7.75-
7.70 (m, 2H), 7.50-7.47 (m, 2H), 7.34-7.28 (m, 2H), 7.21-7.18
(m, 1H), 2.81 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.7 Hz, 3H). 13C
NMR (CDCl3, 100MHz): δ 162.0, 136.0, 135.2, 134.5, 133.6,
131.9, 129.1, 128.4, 126.2, 125.4, 121.4, 121.0, 120.1, 114.1,
99.9, 17.9, 14.3. HRMS (ESI) Calcd for C17H13ClNO [M+H]+:
282.0686; Found: 282.0683.
3.1.3. 2-Methoxy-11-methyl-6H-isoindolo[2,1-a]indol-6-one (2j)
o
1
Yellow solid; 178.4 C; H NMR (CDCl3, 400MHz): δ 7.65
(t, J = 7.2 Hz, 2H), 7.45-7.38 (m, 2H), 7.24-7.21 (m, 1H), 6.81
(d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 3.82 (d, J = 1.5 Hz, 3H), 2.31
3.1.10. 11-Ethyl-4-fluoro-6H-isoindolo[2,1-a]indol-6-one (2t)
o
1
Yellow solid; 190.2 C; H NMR (CDCl3, 400MHz): δ 7.74
(d, J = 7.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.30 (t, J = 7.3 Hz, 1H),

5
Gadge, S. T.; Gautam, P.; Bhanage, B. M. Chem. Rec. 2016, 16,
835-856.
7.16 (d, J = 7.7 Hz, 1H), 7.09-7.04 (m, 1H), 7.00-6.95 (m, 1H),
2.86 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR
(CDCl3, 100MHz): δ 160.6, 150.1 (d, JCF = 251 Hz), 138.2 (d, JCF
= 4.9 Hz), 135.2, 134.4, 133.6, 133.1, 128.4, 125.5, 124.3 (d, JCF
= 6.1 Hz), 121.5, 121.1, 120.8, 115.8 (d, JCF = 3.3 Hz), 113.1 (d,
JCF = 18.5 Hz), 17.9, 14.3. HRMS (ESI) Calcd for C17H13FNO
[M+H]+: 266.0981; Found: 266.0989.
ACCEPTED MANUSCRIPT
7. (a) Yoo, J. M.; Ho, S. L.; Cho, C. S. Synlett 2016, 27, 1383-1386;
(b) Guo, S.; Tao, L.; Wang, F.; Fan, X. Chem. Asian J. 2016, 11,
3090-3096; (c) Han, Q.; Fu, S.; Zhang, X.; Lin, S.; Huang, Q.
Tetrahedron Lett. 2016, 57, 4165-4169; (d) Huang, Q.; Han, Q.;
Fu, S.; Yao, Z.; Su, L.; Zhang, X.; Lin, S.; Xiang, S. J. Org. Chem.
2016, 81, 12135-12142.
8. (a) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754-2755; (b) Reeves, D. C.; Rodriguez, S.; Lee,
H.; Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett.,
2011, 13, 2495-2497; (c) Chung, S.; Sach, N.; Choi, C.; Yang, X.;
Drozda, S. E.; Singer, R. A.; Wright, S. W. Org. Lett. 2015, 17,
2848-2851.
9. (a) Odell, L. R.; Savmarker, J.; Larhed, M. Tetrahedron Lett.
2008, 49, 6115-6118; (b) Liu, B.; Wang, Y.; Liao, B.; Zhang, C.;
Zhou, X. Tetrahedron Lett. 2015, 56, 5776-5780; (c) Liu, B.;
Zhang, C.; Zhou, X. Tetrahedron 2016, 72, 8282-8286.
10. (a) Kiruthika, S. E.; Nandakumar, A.; Perumal, P. T. Org. Lett.
2014, 16, 4424-4427; (b) Dalton, L.; Humphrey, G. L.; Cooper, M.
M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1, 1983, 2417-2422.
3.1.11. 4-Chloro-11-ethyl-6H-isoindolo[2,1-a]indol-6-one (2u)
o
1
Yellow solid; 159.6 C; H NMR (CDCl3, 400MHz): δ 7.73
(d, J = 7.6 Hz, 1H), 7.51 (q, J = 7.6 Hz, 2H), 7.33-7.27 (m, 2H),
7.21 (d, J = 7.9 Hz, 1H), 7.04 (td, J = 7.8, 1.6 Hz, 1H), 2.85 (q, J
= 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3,
100MHz): δ 160.7, 137.5, 135.9, 134.0, 133.7, 133.3, 132.3,
128.4, 127.8, 125.5, 124.3, 120.9, 120.9, 119.4, 118.2, 17.7, 14.2.
HRMS (ESI) Calcd for C17H13ClNO [M+H]+: 282.0686; Found:
282.0683.
3.1.12. 11-Ethyl-2-methoxy-6H-isoindolo[2,1-a]indol-6-one (2v)
o
Yellow solid; 158.0 C; 1H NMR (CDCl3, 400MHz): δ 7.70
(d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.46-7.41 (m, 2H),
7.25-7.22 (m, 1H), 6.87-6.78 (m, 2H), 3.83 (s, 3H), 2.80 (q, J =
7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3,
100MHz): δ 161.9, 156.5, 135.8, 134.8, 134.7, 133.9, 133.2,
128.2, 127.9, 125.0, 121.7, 121.0, 113.8, 113.4, 104.4, 55.7, 17.9,
14.3. HRMS (ESI) Calcd for C18H16NO2 [M+H]+: 278.1181;
Found: 278.1179.
3.1.13. 11-Benzyl-2-fluoro-6H-isoindolo[2,1-a]indol-6-one (2x)
o
1
Yellow solid; 174.2 C; H NMR (CDCl3, 400MHz): δ 7.80-
7.77 (m, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.34-
7.27 (m, 6H), 7.25-7.21 (m, 1H), 6.99-6.91 (m, 2H), 4.17 (s, 2H).
13C NMR (CDCl3, 100MHz): δ 162.0, 159.8 (d, JCF = 239 Hz),
138.2, 136.8, 136.0 (d, JCF = 9.4 Hz), 134.5, 133.8, 133.7, 129.9,
128.8, 128.6, 128.4, 126.8, 125.4, 121.4, 117.7 (d, JCF = 3.9 Hz),
113.9, 113.8 (d, JCF = 17.7 Hz), 107.0 (d, JCF = 24.5 Hz), 30.7.
HRMS (ESI) Calcd for C22H15FNO [M+H]+: 328.1138; Found:
328.1136.
Acknowledgements
We thank the National Natural Science Foundation of
China (grant nos 21372047, 21572034, 21732007), and 973
program (2015CB856600) for financial support.
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