Synthesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline derivatives via trifluoroacetic acid-mediated cascade reactions

Article abstract of DOI:10.1016/j.tet.2021.132280

Condensation of methyl 2-acylbenzoates with 2-arylethanamines or 2-acylanilines in the presence of trifluoroacetic acid resulted in the formation of isoindolo[1,2-a]isoquinolines or isoindolo[2,1-a]quinolines, respectively, in moderate to excellent isolated yields.

Full text of DOI:10.1016/j.tet.2021.132280

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]
quinoline derivatives via trifluoroacetic acid-mediated cascade
reactions
Zhuo Huang 1, Yonggang Meng 1, Yangang Wu, Chuanjun Song*, Junbiao Chang**
College of Chemistry, And Green Catalysis Center, Zhengzhou University, Zhengzhou, 450001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Condensation of methyl 2-acylbenzoates with 2-arylethanamines or 2-acylanilines in the presence of
trifluoroacetic acid resulted in the formation of isoindolo[1,2-a]isoquinolines or isoindolo[2,1-a]quino-
lines, respectively, in moderate to excellent isolated yields.
Received 12 April 2021
Received in revised form
31 May 2021
Accepted 4 June 2021
Available online xxx
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
isoindolo[1,2-a]isoquinoline
isoindolo[2,1-a]quinoline
Cascade reaction
Trifluoroacetic acid
1. Introduction
reaction [11], Parham type [12] and aryne-mediated [13] cyclization
reactions. Synthetic methods concerning assembly of a five-
The isoindolo[1,2-a]isoquinoline structural motifs are widely
distributed in nature (Fig.1) [1e3]. These natural products and their
synthetic analogs have been reported to display a wide spectrum of
biological and pharmacological activities [4]. For instance, CRR-271
can act as a poly(ADP-ribose) polymerase-1 inhibitor [5]. Similarly,
molecules containing isoindolo[2,1-a]quinoline scaffolds have
shown protective effects against N2-induced hypoxia [6], as well as
inhibitory activities against DNA gyrase [7] and topoisomerase [8].
A variety of strategies have been developed toward the con-
struction of the isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]
quinoline frameworks. The most proven method for the synthesis
of the former involves a Lewis acid [9] or Brønsted acid [5,10]
promoted intramolecular cyclization of N-arylethylphthalimide or
N-arylethyl-3-hydroxyisoindolinone derivatives (Scheme 1a, 1b).
Other methods for joining a six-membered piperidine ring onto an
existing five-membered pyrrolidine ring to synthesize isoindolo
[1,2-a]isoquinolines include transition metal-catalyzed coupling
membered pyrrolidine ring onto an existing six-membered piper-
idine ring are less. These mainly include manipulation of 1-
aryltetrahydroisoquinolines [14], amide formation and Diels-
Alder reaction of 1-furanyltetrahydroisoquinolines [15], and
Parham-type
cyclization
of
2-(2-halobenzoyl)-dihy-
droisoquinolinones [16]. Likewise, isoindolo[2,1-a]quinolines are
mainly synthesized by construction of a six-membered piperidine
ring from substrates with an existing 5-membered pyrrolidine ring,
including BF3-mediated [4 þ 2] reaction of N-acyliminium cation
generated from 2-aryl-3-hydroxyisoindolinones with olefins
(Scheme 1c) [17], acid or transition metal catalyzed intramolecular
ring-closure of 3-substituted 2-arylisoindolinones [6,18,19]. Most of
these methods require multiple steps to access the substrates for
final ring closure. Therefore, some cascade reactions have been
developed. However, the requirement of microwave irradiation for
the synthesis of isoindolo[1,2-a]isoquinolines by condensation of 2-
formylbenzoic acids and 2-phenylethanamine restricts its
advancement [20], while the majority of methods for the synthesis
of isoindolo[2,1-a]quinolines suffer from drawbacks such as limited
substrate scope, harsh conditions and/or low product yield [7,8,21].
Herein, we report one-pot synthesis of isoindolo[1,2-a]isoquinoline
and isoindolo[2,1-a]quinoline analogues via trifluoroacetic acid-
mediated condensation of methyl 2-acylbenzoates with 2-
* Corresponding author.
** Corresponding author.
E-mail addresses: chjsong@zzu.edu.cn (C. Song), changjunbiao@zzu.edu.cn
(J. Chang).
1
These authors contributed equally.
https://doi.org/10.1016/j.tet.2021.132280
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Z. Huang, Y. Meng, Y. Wu et al., Synthesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline derivatives via
trifluoroacetic acid-mediated cascade reactions, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132280

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Fig. 1. Representative isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline alkaloids.
arylethanamines or 2-acylanilines, respectively (Scheme 1d, 1e).
reacted with methyl 2-formylbenzoate as expected to give 3l-r in
moderate to good isolated yields. To our delight, the reaction of
methyl (R)-tryptophanate with 2a gave 3s in 74% isolated yield as a
single diastereoisomer [22].
2. Results and discussion
To further demonstrate the application potential of this novel
chemistry, we carried out a gram-scale synthesis of 3a, which was
obtained in 91% isolated yield (Scheme 2).
3,4-Dimethoxyphenylethanamine
1a
and
methyl
2-
formylbenzoate 2a were used as substrates for the optimization
of reaction conditions, and the results were summarized in Table 1.
Initially, a 1:1 mixture of 1a and 2a was treated with an acid in
chloroform at 60 ꢀC. Large amount of unidentified polar substances
were formed in the presence of a Lewis acid such as BF3$Et2O, TiCl4,
or SnCl4, and the desired isoindolo[1,2-a]isoquinoline 3a was iso-
lated in low yield (Entries 1e3). Similar outcome was obtained with
methanesulfonic acid (Entry 4). Delightfully, 3a was isolated in 45%
yield when trifluoroacetic acid (TFA) was applied, together with
tetrahydroisoquinoline 4a in 21% isolated yield (Entry 5). The iso-
lated yield of 3a could be increased to 61% when 8 equivalents of
TFA was applied (Entry 7). However, further increase of acid loading
resulted in reduced product yield due to ammonium salt formation
and thus incomplete reaction (Entry 8). 4a was the sole product
obtained when acetic acid was used (Entry 6). With TFA as acid, the
solvents and reaction temperatures were screen (Entries 9e15). The
best result was obtained when the reaction was carried out in
dichloroethane at 70 ꢀC, which provide 3a in 96% isolated yield
(Entry 14).
Inspired by the results toward the successful synthesis of iso-
indolo[1,2-a]isoquinoline derivatives, we next turned our attention
to the construction of isoindolo[2,1-a]quinolines via TFA-mediated
condensation of 2-acylanilines with methyl 2-formlbenzoate and
the results were listed in Table 3. Delightfully, 2-acetylanilines
reacted with methyl 2-formylbenzoate to give the desired iso-
indolo[2,1-a]quinolines 6a-c in good to excellent isolated yields.
Reactions of the sterically more hindered 2-isobutyrylanilines were
less efficient, and the products 6d and 6e were obtained in 59% and
54% isolated yields, respectively. Interestingly, 2-propionylaniline
reacted with methyl 2-formylbenzoate to provide 6f in 96% iso-
lated yield, as a mixture of cis and trans isomers in a ratio of 1:10
(results based on 1H NMR integration). We managed to separate the
pure trans isomer and confirmed its relative stereochemistry by
NOE correlation (SI). The reaction of substrate with a sterically
more hindered pyridinyl moiety yielded 6g in 76% isolate yield,
solely as the trans isomer.
Having established the method toward the synthesis of isindolo
[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline analogues,
further transformations into other useful molecules were explored.
First, BBr3-mediated demethylation of 3a gave 7 which exhibited
anti-inflammatory activity (Scheme 3) [23]. Second, oxidation of 6f
with IBX, followed by bromination of the methyl group and sub-
sequent nucleophilic substitution with diethylamine enabled facile
access to compound 10 showing protective effect against N2-
induced hypoxia [6].
With the optimal conditions in hand, the substrate scope for the
TFA-mediated synthesis of a variety of isoindolo[1,2-a]isoquino-
lines and analogues were investigated (Table 2). While 2-
arylethylamines (either substituted or unsubstituted at the
aliphatic side chain) with activating methoxy group substituted
benzene ring reacted efficiently with methyl 2-formylbenzoates to
provide the desired products 3a-g in excellent isolated yields, it is
perhaps not surprising that reactions of 2-phenylethanamine and
2-(3-fluorophenyl)ethanamine were less satisfactory in which 3h
and 3i were obtained in 45% and 18% isolated yields, respectively.
The reactions of 2-(3,4-dimethoxyphenyl)ethanamine with methyl
2-acylbenzoates were also successful to give 3j and 3k in moderate
isolated yields, respectively. Because the efficiency of the reaction is
largely dependent on the electronic nature of the aryl group of the
ethanamine derivatives, subsequently, we explored the substrate
scope of heteroarylethanamines. Under the reaction conditions, a
3. Conclusion
In summary, we have developed efficient TFA-mediated syn-
thesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline
analogues. The former were obtained by cascade Pictet-Spen-
glereamidation formation reactions between methyl 2-
acylbenzoates and 2-arylethanamines, while the latter were
range
of
indolyl/benzofuranyl/benzothiophenylethanamines
2

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Scheme 1. Literature and present methods for the synthesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline derivatives.
accessed by condensation between methyl 2-formylbenzoate and
1-(2-aminophenyl)ethan-1-ones. Further transformations of iso-
indolo[1,2-a]isoquinoline 3a and isoindolo[2,1-a]quinoline 6f into
biologically active compounds 7 and 10, respectively, have also
been described.
quenched with 10% NaOH solution (5 mL). The separated aqueous
phase was extracted with DCM (3 x 10 mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and then
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel to afford 3a-s.
4. Experimental section
4.3. 2,3-Dimethoxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-
8(6H)-one (3a)
4.1. General
Eluent: 0.7% methanol in dichloromethane; white solid (142 mg,
Melting points were determined on a XT4A hot-stage apparatus
and are uncorrected. IR spectra were obtained using an Perki-
nElmer FT/IR spectrometer. 1H and 13C NMR spectra were obtained
on a Agilent AV400 instrument. High-resolution mass spectra were
recorded on a Micromass Q-TOF mass spectrometer.
96%); mp 175e177 ꢀC (lit. [10e], mp 172e173 ꢀC); 1H NMR
(400 MHz, CDCl3)
d
¼ 7.86 (d, J ¼ 7.6 Hz, 1H), 7.82 (dd, J ¼ 7.7, 0.9 Hz,
1H), 7.60 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.11 (s, 1H),
6.65 (s, 1H), 5.61 (s, 1H), 4.49 (ddd, J ¼ 12.9, 5.9, 3.4 Hz, 1H), 3.93 (s,
3H), 3.84 (s, 3H), 3.40 (ddd, J ¼ 12.9, 10.3, 4.6 Hz, 1H), 3.04e2.95 (m,
1H), 2.76 (dt, J ¼ 15.8, 4.0 Hz, 1H) ppm; HRMS (m/z) [M þ H]þ calcd
for C18H18NO3 296.1281, found 296.1279.
4.2. General procedure for the synthesis of isoindolo[1,2-a]
isoquinolines
4.4. 11-Bromo-2,3-dimethoxy-5,12b-dihydroisoindolo[1,2-a]
isoquinolin-8(6H)-one (3b)
To a stirred solution of 2-arylethanamine 1 (0.5 mmol) and
methyl 2-acyl benzoate 2 (0.5 mmol) in DCE (5 mL) at 0 ꢀC was
added TFA (4.0 mmol). The reaction was heated at 70 ꢀC until
completion (as monitored by TLC) and cooled. The reaction was
Eluent: 0.5% methanol in dichloromethane; reddish brown solid
(172 mg, 92%); mp 196e198 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.95
3

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of reaction conditions for the synthesis of isoindolo[1,2-a]isoquinoline 3a.a.
Entry
Acid (equiv.)
Solvent
Temp. (oC)
yield 3a (%)b
yield 4a (%)b
1
2
3
4
5
6
7
BF3$Et2O (4)
TiCl4 (4)
SnCl4 (4)
MsOH (4)
TFA (4)
AcOH (4)
TFA (8)
TFA (12)
TFA (8)
TFA (8)
TFA (8)
TFA (8)
TFA (8)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeCN
THF
DMF
DMSO
DCE
DCE
DCE
60
60
60
60
60
60
60
60
60
60
60
60
60
70
80
24
14
26
11
45
0
61
54
22
45
35
29
85
96
67
0
0
0
0
21
82
9
0
0
0
0
0
0
0
0
8c
9d
10e
11f
12g
13
14
15
TFA (8)
TFA (8)
a
All reactions were carried out using 0.5 mmol 1a and 0.5 mmol 2a to react for 5h.
b
c
d
e
f
Isolated yield.
13% 1a recovered.
23% 1a recovered.
17% 1a recovered.
21% 1a recovered.
24% 1a recovered.
g
(s, 1H), 7.72 (d, J ¼ 8.1 Hz, 1H), 7.62 (dd, J ¼ 8.1, 1.5 Hz, 1H), 7.03 (s,
1H), 6.66 (s, 1H), 5.60 (s, 1H), 4.49 (ddd, J ¼ 13.0, 5.9, 3.2 Hz, 1H),
3.94 (s, 3H), 3.85 (s, 3H), 3.37 (ddd, J ¼ 13.0, 10.5, 4.5 Hz, 1H),
3.03e2.95 (m, 1H), 2.75 (dt, J ¼ 15.8, 3.9 Hz, 1H) ppm; 13C NMR
1.41 (s, 3H), 1.17 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 168.0,
148.7, 147.8, 144.7, 136.4, 132.6, 131.8, 128.6, 124.8, 124.3, 123.0,
109.1, 108.4, 59.7, 56.2, 56.1, 50.0, 37.1, 30.9, 26.8 ppm; IR (neat,
cmꢁ1
)
nmax 1679; HRMS (m/z) [M þ H]þ calcd for C20H22NO3
(100 MHz, CDCl3)
d
¼ 167.2, 148.7, 148.1, 146.6, 132.0, 131.8, 127.1,
324.1594, found 324.1596.
126.6, 126.4, 125.4, 125.3, 112.2, 108.8, 58.8, 56.5, 56.1, 38.4,
29.1 ppm; IR (neat, cmꢁ1
)
nmax 1670; HRMS (m/z) [M þ H]þ calcd for
4.7. 20,30-Dimethoxy-60H-spiro[cyclopropane-1,50-isoindolo[1,2-a]
isoquinolin]-80(12b0H)-one (3e)
79
C
H BrNO3 374.0386, found 374.0384.
18 17
4.5. 2,3-Dimethoxy-8-oxo-5,6,8,12b-tetrahydroisoindolo[1,2-a]
isoquinoline-11-carbonitrile (3c)
Eluent: 0.5% methanol in dichloromethane; white solid (155 mg,
96%); mp 187e188 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.88 (d,
J ¼ 7.6 Hz, 1H), 7.84 (d, J ¼ 7.6 Hz, 1H), 7.62 (td, J ¼ 7.6, 1.2 Hz, 1H),
7.50 (t, J ¼ 7.5 Hz, 1H), 7.16 (s, 1H), 6.31 (s, 1H), 5.78 (s, 1H), 3.94 (d,
J ¼ 13.0 Hz, 1H), 3.91 (s, 1H), 3.81 (s, 3H), 3.53 (d, J ¼ 13.0 Hz, 1H),
1.19e1.15 (m, 1H), 1.11e1.58 (m, 1H), 0.98e0.93 (m, 1H), 0.85e0.80
Eluent: 0.5% methanol in dichloromethane; yellow solid
(150 mg, 94%); mp 102e103 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.11
(s, 1H), 7.97 (dd, J ¼ 7.8, 0.7 Hz, 1H), 7.82e7.78 (m, 1H), 7.01 (s, 1H),
6.67 (s, 1H), 5.69 (s, 1H), 4.52 (ddd, J ¼ 13.1, 5.9, 3.2 Hz, 1H), 3.95 (s,
3H), 3.85 (s, 3H), 3.43 (ddd, J ¼ 13.1, 10.5, 4.5 Hz, 1H), 3.06e2.96 (m,
1H), 2.79 (dt, J ¼ 15.9, 3.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 168.0, 148.8, 147.5,
144.4, 133.0, 131.6, 131.5, 128.6, 126.8, 124.2, 123.3, 108.7, 106.0, 60.0,
56.3, 56.0, 47.2, 20.5, 16.7, 12.3 ppm; IR (neat, cmꢁ1
) nmax 1693;
d
¼ 166.0, 148.9, 148.3, 145.2, 136.7, 132.7, 127.1, 127.0, 124.9, 124.5,
HRMS (m/z) [M þ H]þ calcd for C20H20NO3 322.1438, found
118.4, 115.2, 112.3, 108.5, 59.1, 56.5, 56.1, 38.5, 29.2 ppm; IR (neat,
322.1434.
cmꢁ1
)
nmax 2331, 1689; HRMS (m/z) [M þ H]þ calcd for C19H17N2O3
321.1234, found 321.1236.
4.8. 20,30-Dimethoxy-60H-spiro[cyclobutane-1,50-isoindolo[1,2-a]
isoquinolin]-80(12b0H)-one (3f)
4.6. 2,3-Dimethoxy-5,5-dimethyl-5,12b-dihydroisoindolo[1,2-a]
isoquinolin-8(6H)-one (3d)
Eluent: 0.5% methanol in dichloromethane; white solid (153 mg,
91%); mp 191e193 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.89 (dt,
Eluent: 40% ethyl acetate in petroleum ether; white solid
J ¼ 7.6, 1.0 Hz, 1H), 7.84 (dq, J ¼ 7.7, 0.9 Hz, 1H), 7.61 (td, J ¼ 7.5,
1.2 Hz, 1H), 7.49 (tt, J ¼ 7.5, 0.8 Hz, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 5.63
(s, 1H), 4.70 (d, J ¼ 13.0 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.40 (d,
J ¼ 12.6 Hz, 1H), 2.61e2.49 (m, 1H), 2.37e2.19 (m, 2H), 2.17e1.96
(149 mg, 92%); mp 181e182 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.90
(d, J ¼ 7.6 Hz, 1H), 7.87 (d, J ¼ 7.6 Hz, 1H), 7.61 (td, J ¼ 7.5, 1.2 Hz, 1H),
7.50 (t, J ¼ 7.6 Hz, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 5.69 (s, 1H), 4.37 (d,
J ¼ 13.1 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.21 (d, J ¼ 13.1 Hz, 1H),
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 168.1, 148.9, 147.9,
4

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Table 2
Substrate scope for the synthesis of isoindolo[1,2-a]isoquinolines and analogues..
144.4, 134.7, 132.9, 131.7, 128.6, 125.2; 124.3, 123.2, 109.3, 108.4,
4.9. 3-Methoxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-
8(6H)-one (3g) [9e,10e]
59.5, 56.3, 56.2, 48.2, 43.3, 34.9, 30.9, 15.3 ppm; IR (neat, cmꢁ1
)
nmax
1677; HRMS (m/z) [M þ H]þ calcd for C21H22NO3 336.1594, found
336.1596.
Eluent: 0.6% methanol in dichloromethane; yellow solid
(114 mg, 86%); mp 62e65 ꢀC; 1H NMR (400 MHz, CDCl3)
J ¼ 7.5, Hz, 1H), 7.83 (dd, J ¼ 7.7, 0.9 Hz, 1H), 7.60 (td, J ¼ 7.5, 1.2 Hz,
1H), 7.53 (d, J ¼ 8.6 Hz, 1H), 7.48 (t, J ¼ 7.5 Hz, 1H), 6.83 (dd, J ¼ 8.5,
d
¼ 7.87 (d,
5

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Scheme 2. Grame-scale synthesis of 3a.
Table 3
Substrate scope for the synthesis of isoindolo[2,1-a]quinolines..
2.7 Hz, 1H), 6.72 (d, J ¼ 2.7 Hz, 1H), 5.62 (s, 1H), 4.43 (ddd, J ¼ 12.9,
6.0, 4.3 Hz, 1H), 3.77 (s, 3H), 3.47 (ddd, J ¼ 12.9, 9.6, 4.8 Hz, 1H), 3.04
(ddd, J ¼ 15.8, 9.6, 6.0 Hz, 1H), 2.85 (dt, J ¼ 15.8, 4.5 Hz, 1H) ppm;
HRMS (m/z) [M þ H]þ calcd for C17H16NO2 266.1176, found
266.1178.
4.11. 3-Fluoro-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one
(3i)
Eluent: 0.5% methanol in dichloromethane; white solid (22 mg,
18%); mp 154e155 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.89 (dt,
J ¼ 7.5, 1.0 Hz, 1H), 7.84 (dd, J ¼ 7.7, 1.0 Hz, 1H), 7.65e7.56 (m, 2H),
7.51 (t, J ¼ 7.5 Hz, 1H), 6.98 (td, J ¼ 8.5, 2.8 Hz, 1H), 6.92 (dd, J ¼ 9.2,
2.8 Hz, 1H), 5.64 (s, 1H), 4.43 (ddd, J ¼ 13.0, 6.0, 4.4 Hz, 1H), 3.49
(ddd, J ¼ 13.0, 9.4, 4.9 Hz, 1H), 3.07 (ddd, J ¼ 15.9, 9.4, 6.0 Hz, 1H),
2.89 (dt, J ¼ 15.9, 4.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
4.10. 5,12b-Dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one (3h)
Eluent: 0.7% methanol in dichloromethane; white solid (53 mg,
45%); mp 110e112 ꢀC (lit. [10e], mp 114e116 ꢀC); 1H NMR (400 MHz,
d
¼ 168.0, 161.9 (JF-C ¼ 245.0 Hz), 144.2, 137.3 (JF-C ¼ 8.0 Hz), 132.8,
CDCl3)
d
¼ 7.90e7.88 (m, 1H), 7.87e7.85 (m, 1H), 7.65e7.59 (m, 2H),
131.8, 130.3 (JF-C ¼ 3.0 Hz), 128.8, 127.0 (JF-C ¼ 8.0 Hz), 124.1, 123.5,
116.0 (JF-C ¼ 21.0 Hz), 114.0 (JF-C ¼ 21.0 Hz), 58.9, 38.0, 29.7 ppm; 19
F
7.53e7.47 (m, 1H), 7.29 (td, J ¼ 7.0, 2.0 Hz, 1H), 7.25e7.19 (m, 2H),
5.69 (s, 1H), 4.43 (ddd, J ¼ 12.9, 5.8, 4.6 Hz, 1H), 3.51 (ddd, J ¼ 12.9,
9.4, 4.8 Hz, 1H), 3.13e3.03 (m, 1H), 2.90 (dt, J ¼ 15.9, 4.6 Hz, 1H)
ppm; HRMS (m/z) [M þ H]þ calcd for C16H14NO 236.1070, found
236.1067.
NMR (376 MHz, CDCl3)
d
¼ 117.7 ppm; IR (neat, cmꢁ1
) nmax 1680;
HRMS (m/z) [M þ H]þ calcd for C16H13FNO 254.0976, found
254.0972.
6

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
Scheme 3. Synthesis of compounds 7 and 10.
4.12. 2,3-Dimethoxy-12b-methyl-5,12b-dihydroisoindolo[1,2-a]
isoquinolin-8(6H)-one (3j)
4.14. 7,8,13,13b-Tetrahydro-5H-benzo[1,2]indolizino[8,7-b]indol-5-
one (3l)
Eluent: 20% ethyl acetate in petroleum ether; white solid
Eluent: 0.7% methanol in dichloromethane; pale yellow solid
(84 mg, 54%); mp 179e181 ꢀC; 1H NMR (400 MHz, CDCl3)
(122 mg, 89%); mp 210e212 ꢀC (lit. [24], mp 212e214 ꢀC); 1H NMR
d
¼ 7.85e7.82 (m, 2H), 7.59 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.44 (td, J ¼ 7.5,
(400 MHz, DMSO‑d6)
d
¼ 11.37 (s, 1H), 8.30 (dd, J ¼ 7.5, 0.9 Hz, 1H),
0.8 Hz, 1H), 7.16 (s, 1H), 6.56 (s, 1H), 4.61 (ddd, J ¼ 13.3, 6.5, 1.4 Hz,
1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.35 (ddd, J ¼ 13.3, 12.1, 4.4 Hz, 1H),
3.02 (ddd, J ¼ 16.1, 12.1, 6.6 Hz, 1H), 2.70 (ddd, J ¼ 16.1, 4.4, 1.4 Hz,
7.76e7.69 (m, 2H), 7.55 (t, J ¼ 7.4 Hz, 1H), 7.43e7.38 (m, 2H), 7.10
(ddd, J ¼ 8.1, 7.1, 1.2 Hz, 1H), 6.99 (td, J ¼ 7.4, 1.0 Hz, 1H), 6.06 (s, 1H),
4.64e4.55 (m,1H), 3.41e3.33 (m, 1H), 2.88e2.78 (m,1H), 2.74e2.65
(m, 1H) ppm; HRMS (m/z) [M þ H]þ calcd for C18H15N2O 275.1179,
found 275.1176.
1H), 1.80 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 167.5, 150.8,
148.3,147.8,132.0,131.3,131.1,128.4,126.0,124.0,122.2,112.0,109.4,
63.7, 56.4, 56.0, 35.1, 29.4, 29.0 ppm; IR (neat, cmꢁ1
) nmax 1677;
HRMS (m/z) [M þ H]þ calcd for C19H20NO3 310.1438, found
4.15. 8,13b-Dihydrobenzo[40,5']thieno[20,3':3,4]pyrido[2,1-a]
isoindol-5(7H)-one (3 m)
310.1439.
Eluent: 0.5% methanol in dichloromethane; yellow solid
(108 mg, 74%); mp 190e192 ꢀC (lit. [25], mp 193e195 ꢀC); 1H NMR
(400 MHz, CDCl3)
d
¼ 7.88 (dt, J ¼ 7.6, 1.0 Hz, 1H), 7.85e7.78 (m, 2H),
4.13. 12b-Ethyl-2,3-dimethoxy-5,12b-dihydroisoindolo[1,2-a]
isoquinolin-8(6H)-one (3k)
7.68e7.57 (m, 2H), 7.50 (t, J ¼ 7.5 Hz, 1H), 7.42e7.29 (m, 2H), 5.85 (s,
1H), 4.89 (ddd, J ¼ 13.4, 5.1, 2.4 Hz, 1H), 3.45 (ddd, J ¼ 13.4, 10.0,
6.3 Hz, 1H), 3.01e2.97 (m, 2H) ppm; HRMS (m/z) [M þ H]þ calcd for
Eluent: 40% ethyl acetate in petroleum ether; white solid
C
18H14NOS 292.0791, found 292.0789.
(69 mg, 43%); mp 142e143 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 7.85
(d, J ¼ 7.5 Hz, 1H), 7.77 (d, J ¼ 7.8 Hz, 1H), 7.60 (td, J ¼ 7.5, 1.2 Hz, 1H),
7.46 (td, J ¼ 7.5, 0.9 Hz, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 4.62 (ddd,
J ¼ 13.1, 6.7, 1.4 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.26 (ddd, J ¼ 13.1,
11.9, 4.5 Hz, 1H), 3.05 (ddd, J ¼ 16.2, 12.0, 6.7 Hz, 1H), 2.72 (ddd,
J ¼ 16.2, 4.5, 1.4 Hz, 1H), 2.31 (dq, J ¼ 14.5, 7.3 Hz, 1H), 2.20 (dq,
J ¼ 14.5, 7.3 Hz,1H), 0.50 (t, J ¼ 7.3 Hz, 3H) ppm; 13C NMR (100 MHz,
4.16. 8,13b-Dihydrobenzofuro[20,3':3,4]pyrido[2,1-a]isoindol-
5(7H)-one (3n)
Eluent: 13% ethyl acetate in petroleum ether; yellow solid
(99 mg, 72%); mp 197e198 ꢀC; 1H NMR (400 MHz, CDCl3)
CDCl3)
d
¼ 168.2, 148.4, 148.2, 147.7, 132.6, 131.9, 131.4, 128.4, 125.9,
d
¼ 7.97e7.94 (m, 1H), 7.88 (dt, J ¼ 7.5, 1.0 Hz, 1H), 7.63 (td, J ¼ 7.5,
124.0,122.2,112.0,109.4, 67.1, 56.4, 56.0, 35.0, 33.5, 29.2, 7.8 ppm; IR
1.2 Hz, 1H), 7.53e7.48 (m, 2H), 7.46e7.42 (m, 1H), 7.31e7.25 (m, 1H),
7.22 (td, J ¼ 7.4, 1.2 Hz, 1H), 5.78 (s, 1H), 4.88e4.83 (m, 1H), 3.38
(ddd, J ¼ 13.4, 11.2, 4.9 Hz, 1H), 2.96e2.87 (m, 1H), 2.83e2.77 (m,
(neat, cmꢁ1
)
nmax 1676; HRMS (m/z) [M þ H]þ calcd for C20H21NO3
324.1594, found 324.1597.
7

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
1H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 168.7, 155.1, 148.9, 141.9,
(m, 2H), 7.35 (d, J ¼ 8.0 Hz, 1H), 7.16 (td, J ¼ 8.0, 7.5, 1.4 Hz, 1H), 7.11
(td, J ¼ 7.5, 1.2 Hz, 1H), 6.28 (s, 1H), 5.81 (d, J ¼ 7.4 Hz, 1H), 3.71 (s,
3H), 3.49 (d, J ¼ 16.0 Hz, 1H), 3.25 (ddd, J ¼ 16.0, 7.4, 2.4 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) 171.8, 168.6, 143.7, 136.8, 132.5,
131.5, 129.5, 120.0, 126.6, 124.7, 122.8, 122.7, 120.1, 118.7, 111.3, 106.6,
132.3, 132.1, 129.1, 127.5, 124.5, 124.1, 123, 124.0, 119.5, 112.5, 111.5,
57.0, 37.8, 21.8; IR (neat, cmꢁ1
calcd for C18H14NO2 276.1019, found 276.1018.
)
nmax 1677; HRMS (m/z) [M þ H]þ
4.17. 5,6,7,13b-Tetrahydro-9H-benzo[1,2]indolizino[7,8-b]indol-9-
one (3ꢀ)
55.5, 52.8, 50.4, 24.6; IR (neat, cmꢁ1
) nmax 1721, 1677; HRMS (m/z)
[M þ H]þ calcd for C19H17N2O3 333.1234, found 333.1229.
Eluent: 1.4% methanol in dichloromethane; light yellow solid
4.22. General procedure for the synthesis of isoindolo[2,1-a]
quinolines
(107 mg, 78%); mp 126e128 ꢀC; 1H NMR (400 MHz, acetone-d6)
d
¼ 10.25 (s, 1H), 8.21 (dd, J ¼ 7.8, 0.9 Hz, 1H), 8.09e8.00 (m, 1H),
7.79e7.76 (m, 1H), 7.63 (td, J ¼ 7.6, 1.2 Hz,1H), 7.48 (t, J ¼ 7.5 Hz,1H),
7.40e7.34 (m, 1H), 7.17e7.07 (m, 2H), 6.04 (s, 1H), 4.71 (ddd,
J ¼ 13.0, 5.9, 1.2 Hz, 1H), 3.34 (ddd, J ¼ 13.0, 11.4, 4.5 Hz, 1H),
2.98e2.88 (m, 1H), 2.85e2.78 (m, 1H) ppm; 13C NMR (100 MHz,
To a stirred solution of 2-acylaniline 5 (0.5 mmol) and methyl 2-
formyl benzoate 2a (0.5 mmol) in DCE (5 mL) at 0 ꢀC was added TFA
(8.0 eq). The reaction was heat at 70 ꢀC until completion (as
monitored by TLC) and cooled. 10% NaOH solution (5 mL) was
added. The separated aqueous phase was extracted with DCM (3 x
10 mL). The combined organic extracts were dried over anhydrous
Na2SO4, filtered, and then concentrated in vacuo. The crude product
was purified by column chromatography on silica gel to afford 6a-f.
acetone-d6)
d
¼ 167.2, 143.7, 136.4, 131.9, 131.7, 130.9, 128.7, 126.2,
123.8, 123.2, 121.6, 118.9, 118.2, 111.3, 107.2, 56.7, 37.7, 21.4 ppm; IR
(neat, cmꢁ1
)
nmax 1668; HRMS (m/z) [M þ H]þ calcd for C18H15N2O
275.1179, found 275.1176.
4.18. 6,13b-Dihydrobenzo[40,5']thieno[30,2':3,4]pyrido[2,1-a]
isoindol-9(7H)-one (3p)
4.23. 6,6a-Dihydroisoindolo[2,1-a]quinoline-5,11-dione (6a)
Eluent: 11% ethyl acetate in petroleum ether; white solid
Eluent: 17% ethyl acetate in petroleum ether; yellow solid
(111 mg, 89%); mp 175e177 ꢀC (lit. [6], mp 172e173 ꢀC); 1H NMR
(111 mg, 76%); mp 132e135 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.18
(400 MHz, CDCl3)
d
¼ 8.56 (dd, J ¼ 8.4, 0.6 Hz, 1H), 8.06 (dd, J ¼ 7.9,
(d, J ¼ 8.1 Hz, 1H), 8.03 (dd, J ¼ 7.7, 1.0 Hz, 1H), 7.93e7.91 (m, 1H),
7.82 (dt, J ¼ 8.0, 0.9 Hz,1H), 7.55e7.45 (m, 3H), 7.38 (ddd, J ¼ 8.2, 7.2,
1.1 Hz, 1H), 6.09 (s, 1H), 4.87 (ddd, J ¼ 12.9, 5.4, 1.3 Hz, 1H), 3.24
(ddd, J ¼ 12.9, 11.4, 3.6 Hz, 1H), 3.09e3.00 (m, 1H), 2.90e2.84 (m,
1.6 Hz, 1H), 8.00 (d, J ¼ 7.7 Hz, 1H), 7.71e7.64 (m, 2H), 7.60e7.55 (m,
1H), 7.53e7.50 (m, 1H), 7.29e7.21 (m, 1H), 5.28 (dd, J ¼ 14.2, 3.6 Hz,
1H), 3.32 (dd, J ¼ 16.3, 3.6 Hz, 1H), 2.69 (dd, J ¼ 16.3, 14.2 Hz, 1H)
ppm; HRMS(m/z) [M þ H]þ calcd for C16H12NO2 250.0863, found
250.0861.
1H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 169.6, 144.8, 139.0, 137.4,
137.3,132.5,132.1,128.7,126.9,124.5,124.3,124.1,124.0,123.0,121.6,
59.2, 38.9, 27.1 ppm; IR (neat, cmꢁ1
)
nmax 1685; HRMS (m/z) [M þ
4.24. 3-Bromo-6,6a-dihydroisoindolo[2,1-a]quinoline-5,11-dione
(6b)
H]þ calcd for C18H14NOS 292.0791, found 292.0793.
4.19. 6,13b-Dihydrobenzofuro[30,2':3,4]pyrido[2,1-a]isoindol-
9(7H)-one (3q)
Eluent: 14% ethyl acetate in petroleum ether; brown solid
(113 mg, 69%); mp 166e167 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.46
(d, J ¼ 8.8 Hz,1H), 8.15 (d, J ¼ 2.4 Hz,1H), 7.97 (dt, J ¼ 7.6,1.0 Hz,1H),
7.73 (dd, J ¼ 8.8, 2.4 Hz, 1H), 7.68 (td, J ¼ 7.5, 1.2 Hz, 1H), 7.60e7.55
(m, 1H), 7.52e7.50 (m, 1H), 5.26 (dd, J ¼ 14.3, 3.6 Hz, 1H), 3.32 (dd,
J ¼ 16.4, 3.6 Hz, 1H), 2.68 (dd, J ¼ 16.4, 14.3 Hz, 1H) ppm; 13C NMR
Eluent: 0.5% methanol in dichloromethane; pale yellow solid
(95 mg, 69%); mp 187e190 ꢀC (lit. [26], mp 183e185 ꢀC); 1H NMR
(400 MHz, CDCl3)
d
¼ 7.99 (dd, J ¼ 7.7,1.0 Hz,1H), 7.94e7.86 (m, 2H),
7.61 (td, J ¼ 7.6,1.2 Hz,1H), 7.51e7.44 (m, 2H), 7.34 (td, J ¼ 7.5,1.4 Hz,
1H), 7.29 (td, J ¼ 7.7, 1.6 Hz, 1H), 5.88 (s, 1H), 4.90 (dd, J ¼ 13.3,
6.1 Hz, 1H), 3.37 (ddd, J ¼ 13.2, 11.3, 4.6 Hz, 1H), 3.11e3.02 (m, 1H),
2.84 (dd, J ¼ 16.6, 4.7 Hz, 1H) ppm; HRMS (m/z) [M þ H]þ calcd for
C18H14NO2 276.1019, found 276.1016.
(100 MHz, CDCl3)
d
¼ 191.0, 165.8, 143.6, 140.0, 138.7, 133.3, 131.9,
130.5, 129.6, 125.1, 123.7, 122.2, 122.1, 117.7, 58.6, 42.9 ppm; IR (neat,
79
cmꢁ1
)
nmax 1705, 1692; HRMS (m/z) [M þ H]þ calcd for C16
H BrNO2
11
327.9968, found 327.9967.
4.25. 3-Iodo-6,6a-dihydroisoindolo[2,1-a]quinoline-5,11-dione (6c)
4.20. 14-Methyl-6,7-dihydroisoindolo[10,2':3,4]pyrazino[1,2-a]
indol-9(13bH)-one (3r)
Eluent: 6% ethyl acetate in petroleum ether; reddish brown solid
(133 mg, 71%); mp 157e159 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.35
Eluent: 25% ethyl acetate in petroleum ether; yellow solid
(s, 1H), 8.34 (d, J ¼ 6.8 Hz, 1H), 7.98 (d, J ¼ 7.6 Hz, 1H), 7.93 (dd,
J ¼ 8.8, 2.1 Hz, 1H), 7.68 (td, J ¼ 7.5, 1.2 Hz, 1H), 7.60e7.56 (m, 1H),
7.52e7.49 (m, 1H), 5.26 (dd, J ¼ 14.3, 3.6 Hz, 1H), 3.31 (dd, J ¼ 16.3,
3.6 Hz, 1H), 2.67 (dd, J ¼ 16.3, 14.3 Hz, 1H) ppm; 13C NMR (100 MHz,
(65 mg, 46%); mp 155e157 ꢀC (lit. [27], mp 173 ꢀC decomposition);
1H NMR (400 MHz, CDCl3)
d
¼ 7.94e7.90 (m, 2H), 7.64e7.55 (m, 2H),
7.50 (t, J ¼ 7.4 Hz, 1H), 7.24e7.12 (m, 3H), 6.16 (s, 1H), 4.85 (dd,
J ¼ 13.4, 3.8 Hz, 1H), 4.20 (dd, J ¼ 11.7, 3.6 Hz, 1H), 4.03 (td, J ¼ 11.7,
4.3 Hz, 1H), 3.45 (ddd, J ¼ 13.5, 11.7, 4.1 Hz, 1H), 2.67 (s, 3H) ppm;
HRMS (m/z) [M þ H]þ calcd for C19H17N2O 289.1335, found
289.1333.
CDCl3)
d
¼ 190.9, 165.8, 144.1, 143.6, 140.6, 136.6, 133.3, 131.9, 129.6,
125.1, 123.9, 122.3, 122.1, 88.0, 58.6, 42.8 ppm; IR (neat, cmꢁ1
) nmax
1703, 1681; HRMS (m/z) [M þ H]þ calcd for C16H10INO2 375.9829,
found 375.9820.
4.21. Methyl (7R,13bS)-5-oxo-7,8,13,13b-tetrahydro-5H-benzo
[1,2]indolizino[8,7-b]indole-7-carboxylate (3s)
4.26. 6,6-Dimethyl-6,6a-dihydroisoindolo[2,1-a]quinoline-5,11-
dione (6d)
Eluent: 25% ethyl acetate in petroleum ether; yellow solid
Eluent: 11% ethyl acetate in petroleum ether; yellow solid
(123 mg, 74%); mp 182e183 ꢀC (lit. [22a], mp 166e168 ꢀC);
(82 mg, 54%); mp 144e145 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.53
20
[
a
]
¼ ꢁ138ꢀ (c ¼ 1.00 CHCl3); 1H NMR (400 MHz, CDCl3)
d
¼ 9.05
(dd, J ¼ 8.4, 0.6 Hz, 1H), 8.05 (dd, J ¼ 8.0, 1.6 Hz, 1H), 7.80e7.97 (m,
D
(s, 1H), 7.93 (t, J ¼ 8.3 Hz, 2H), 7.59 (td, J ¼ 7.5, 1.2 Hz, 1H), 7.51e7.45
1H), 7.67e7.53 (m, 4H), 7.23 (ddd, J ¼ 8.2, 7.3, 1.1 Hz, 1H), 4.95 (s,
8

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
1H), 1.63 (s, 3H), 0.66 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
water peak), 2.73e2.63 (m, 2H) ppm; HRMS (m/z) [M þ H]þ calcd
d
¼ 197.8, 166.3, 141.6, 140.4, 135.3, 133.3, 132.5, 129.3, 128.6, 124.9,
for C16H13NO3 268.0968, found 268.0967.
124.5, 123.6, 120.5, 120.1, 66.7, 46.7, 19.9, 17.9 ppm; IR (neat, cmꢁ1
)
nmax 1688, 1671; HRMS (m/z) [M þ H]þ calcd for C18H16NO2
4.31. 6-Methylisoindolo[2,1-a]quinoline-5,11-dione (8)
278.1176, found 278.1175.
To a solution of 6f (1.05 g, 4.0 mmol) in DMSO (5 mL) at room
temperature under argon was added dropwise a solution of IBX
(1.23 g, 4.4 mmol) in DMSO (5 mL). The reaction was stirred for 2 h
before being quenched with saturated aqueous NaHCO3 (5 mL). The
separated aqueous phase was extracted with EtOAc (3 x 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
over Na2SO4, filtered, and then concentrated in vacuo. The residue
was purified by column chromatography on silica gel (10% ethyl
acetate in petroleum ether) to give 8 (0.58 g, 55%) as yellow solid;
mp 249e251 ꢀC (lit. [6], mp 260e261 ꢀC); 1H NMR (400 MHz,
4.27. 3-Iodo-6,6-dimethyl-6,6a-dihydroisoindolo[2,1-a]quinoline-
5,11-dione (6e)
Eluent: 5% ethyl acetate in petroleum ether; brown solid
(119 mg, 59%), mp 109e111 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.39e8.31 (m, 2H), 8.00 (d, J ¼ 7.4 Hz, 1H), 7.92 (dd, J ¼ 8.8,
2.2 Hz, 1H), 7.66e7.57 (m, 3H), 4.95 (s, 1H), 1.64 (s, 3H), 0.67 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3)
¼ 196.6, 166.4, 143.7, 141.4, 139.9,
137.3, 133.1, 132.8, 129.5, 125.1, 123.7, 122.1, 122.1, 88.1, 66.5, 46.7,
d
19.9, 17.9 ppm; IR (neat, cmꢁ1
)
nmax 1708, 1671; HRMS (m/z) [M þ
CDCl3)
d
¼ 9.16 (dd, J ¼ 8.6, 1.0 Hz, 1H), 8.30 (dd, J ¼ 8.1, 1.7 Hz, 1H),
H]þ calcd for C18H14INO2 404.0142, found 404.0140.
8.03e7.97 (m, 2H), 7.76e7.67 (m, 2H), 7.61 (td, J ¼ 7.5, 0.9 Hz, 1H),
7.39 (ddd, J ¼ 8.2, 7.1,1.1 Hz,1H), 2.54 (s, 3H) ppm; HRMS (m/z) [M þ
H]þ calcd for C17H11NO2 262.0863, found 262.0861.
4.28. 6-Methyl-6,6a-dihydroisoindolo[2,1-a]quinoline-5,11-
dione (6f)
4.32. 6-(Bromomethyl)isoindolo[2,1-a]quinoline-5,11-dione (9)
Eluent: 3% ethyl acetate in petroleum ether; brown solid
(126 mg, 96%, trans:cis 10:1); the spectroscopic and analytical data
A solution of 8 (522 mg, 2.0 mmol) and AIBN (33 mg, 0.2 mmol)
in CCl4 (10 mL) was cooled to 0 ꢀC. NBS (392 mg, 2.2 mmol) was
added in portion. After addition, the mixture was heated at reflux
for 6 h and cooled. The bulk of solvent was removed in vacuo. The
residue was purified by column chromatography on silica gel (9%
ethyl acetate in petroleum ether) to afford 9 (537 mg, 74%) as yellow
solid; mp 230e231 ꢀC (lit [6]. 237e241 ꢀC); 1H NMR (400 MHz,
for the isolated trans isomer: 1H NMR (400 MHz, CDCl3)
d
¼ 8.53
(dd, J ¼ 8.4, 1.1 Hz, 1H), 8.09 (dd, J ¼ 7.9, 1.6 Hz, 1H), 8.07e8.03 (m,
1H), 7.72e7.59 (m, 4H), 7.30e7.25 (m, 1H), 4.93 (d, J ¼ 12.8 Hz, 1H),
2.66 (dq, J ¼ 12.8, 6.8 Hz 1H), 1.67 (d, J ¼ 6.8 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 194.8, 165.7, 143.5, 141.0, 135.4, 132.6, 132.6,
129.4, 128.0, 125.1, 124.6, 123.9, 122.19, 120.6, 64.1, 47.6, 11.0 ppm; IR
(neat, cmꢁ1
)
nmax 1684, 1667; HRMS (m/z) [M þ H]þ calcd for
CDCl3)
d
¼ 9.15 (d, J ¼ 8.5 Hz, 1H), 8.33 (dd, J ¼ 8.0, 1.4 Hz, 1H), 8.13
C
17H14NO2 264.1019, found 264.1019.
(dt, J ¼ 8.0, 0.9 Hz, 1H), 8.02 (dt, J ¼ 7.4, 1.0 Hz, 1H), 7.83 (td, J ¼ 7.6,
1.2 Hz, 1H), 7.76e7.68 (m, 2H), 7.43 (ddd, J ¼ 8.2, 7.1, 1.1 Hz,1H), 4.93
79
4.29. trans-6-(Pyridin-2-yl)-6,6a-dihydroisoindolo[2,1-a]
quinoline-5,11-dione (6g)
(s, 2H) ppm; HRMS (m/z) [M þ H]þ calcd for C17
H BrNO2 339.9968,
10
found 339.9969.
Eluent: 15% ethyl acetate in petroleum ether; yellow solid
4.33. 6-((Diethylamino)methyl)isoindolo[2,1-a]quinoline-5,11-
dione (10)
(124 mg, 76%); mp 169e171 ꢀC; 1H NMR (400 MHz, CDCl3)
d
¼ 8.76
(ddd, J ¼ 4.9, 1.9, 0.9 Hz, 1H), 8.57 (d, J ¼ 8.3 Hz,1H), 8.08 (dd, J ¼ 7.9,
1.6 Hz, 1H), 7.96 (d, J ¼ 7.7 Hz, 1H), 7.79 (td, J ¼ 7.7, 1.8 Hz, 1H), 7.70
(ddd, J ¼ 8.6, 7.3, 1.7 Hz, 1H), 7.46 (t, J ¼ 7.5 Hz,1H), 7.39 (ddd, J ¼ 7.7,
4.8, 1.1 Hz, 1H), 7.30 (td, J ¼ 7.6, 1.2 Hz, 1H), 7.28e7.21 (m, 2H), 6.18
(dd, J ¼ 7.7, 0.9 Hz, 1H), 6.06 (d, J ¼ 12.8 Hz, 1H), 3.88 (d, J ¼ 12.8 Hz,
To a solution of compound 9 (272 mg, 0.8 mmol) in 1,4-dioxane
(5 mL) was added potassium carbonate (138 mg, 1.0 mmol) and
diethylamine (176 mg, 2.4 mmol). The resulting mixture was
heated at reflux for 1 and cooled. The bulk of 1,4-dioxane was
removed on a rotary evaporator. The residue was partitioned be-
tween ethyl acetate (20 mL) and water (5 mL). The separated
organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (9% ethyl acetate in petroleum ether) to
afford 10 (178 mg, 67%) as yellow solid; mp 147e149 ꢀC (lit [6].
1H); 13C NMR (100 MHz, CDCl3)
d
¼ 192.6, 166.0, 155.5, 150.2, 143.4,
141.1, 136.9, 135.8, 132.5, 132.3, 129.2, 128.4, 126.7, 124.7, 124.5,
123.3, 123.1, 122.6, 120.6, 62.0, 60.6 ppm; IR (neat, cmꢁ1
) nmax 1700,
1670; HRMS (m/z) [M þ H]þ calcd for C21H15N2O2 327.1128, found
327.1129.
4.30. 2,3-Dihydroxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-
8(6H)-one (7)
153e155 ꢀC); 1H NMR (400 MHz, CDCl3)
d
¼ 9.17 (d, J ¼ 8.6 Hz, 1H),
8.31e8.26 (m, 2H), 7.95 (dt, J ¼ 7.5, 1.0 Hz, 1H), 7.75e7.69 (m, 2H),
7.64e7.60 (m, 1H), 7.41 (ddd, J ¼ 8.1, 7.1, 1.1 Hz, 1H), 3.98 (s, 2H), 2.67
(q, J ¼ 7.1 Hz, 4H), 1.07 (t, J ¼ 7.1 Hz, 6H) ppm; HRMS (m/z) [M þ H]þ
calcd for C21H20N2O2 333.1598, found 333.1597.
To a stirred solution of 3a (295 mg, 1.0 mmol) in dry DCM
(10 mL) at ꢁ78 ꢀC was added BBr3 (1.0 M in DCM, 4.0 mL, 4.0 mmol)
dropwise. The resulting mixture was stirred for 1 h at ꢁ78 ꢀC before
being allowed to warm to room temperature and stirred for a
further 1 h. The reaction was quenched with water (3 mL). The
separated aqueous phase was extracted with DCM (3 x 10 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
filtered and then concentrated in vacuo. The residue was purified
by column chromatography on silica gel (50% ethyl acetate in pe-
troleum ether) to afford 7 (80 mg, 30%) as red solid; mp 110e112 ꢀC
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgement
(lit. [10a], mp 114e115 ꢀC); 1H NMR (400 MHz, DMSO‑d6)
d
¼ 8.98
(s, 1H), 8.89 (s, 1H), 7.96e7.93 (m, 1H), 7.73e7.68 (m, 2H), 7.54 (t,
J ¼ 7.4 Hz, 1H), 7.09 (S, 1H), 6.56 (s, 1H), 5.69 (s, 1H), 4.17 (ddd,
J ¼ 12.7, 5.6, 4.1 Hz,1H), 3.36 (m, 1H, this signal was obscured by the
We are grateful to NSFC-Henan (U1804283) and Postgraduate
Education Reform and Quality Improvement Project of Henan
Province (YJS2021KC03) for financial support.
9

Z. Huang, Y. Meng, Y. Wu et al.
Tetrahedron xxx (xxxx) xxx
A.M. Maharramov, Alexey V. Varlamov, Tetrahedron 65 (2009) 3789‒3803;
(b) F.I. Zubkov, I.K. Airiyan, J.D. Ershova, T.R. Galeev, V.P. Zaytsev, E.V. Nikitina,
A.V. Varlamov, RSC Adv. 2 (2012) 4103‒4109.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2021.132280.
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