The first iodine improved 1,3-dipolar cycloaddition: Facile and novel synthesis of 2-substituted benzo[f]isoindole-4,9-diones

Article abstract of DOI:10.1016/j.tet.2013.08.029

The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hydrochlorides in the present of iodine at refluxing ac

Full text of DOI:10.1016/j.tet.2013.08.029

Tetrahedron 69 (2013) 9033e9037
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The first iodine improved 1,3-dipolar cycloaddition: facile and novel
synthesis of 2-substituted benzo[f]isoindole-4,9-diones
Huan-Ming Huang a, Jian-Rong Gao a, Li-Fen Hou b, Jian-Hong Jia a, Liang Han a, Qing Ye a,
,
Yu-Jin Li a
*
a State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, PR China
b College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2013
Received in revised form 23 July 2013
Accepted 15 August 2013
Available online 20 August 2013
The first novel protocol of the synthesis of 2-substituted benzo[f]isoindole-4,9-dione framework via the
one-pot, 1,3-dipolar cycloaddition of quinones, paraformaldehyde and N-substituted amino ester hy-
drochlorides in the present of iodine at refluxing acetonitrile was reported. All these reactions proceed
with good to excellent yields. The promising results obtained 1,3-dipolar cycloaddition will have the
potential application in natural product exhibiting important biological activities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2-Substituted benzo[f]isoindole-4,9-dione
1,3-Dipolar cycloaddition
Quinones
N-Substituted amino ester hydrochlorides
Iodine
1. Introduction
Pyrroles and their derivatives are one of the most important
heterocyclic compounds, found in common structural scaffolds in
natural products and bioactive molecules.1 2-Substituted benzo[f]
isoindole-4,9-diones are the core structure of natural product
exhibiting important biological activities.1c They exist in numerous
bioactive molecules, such as Azamonosporascone in Monosporascus
cannonballus,2 Reniera isoindole alkaloid in antimicrobial activity,3
GR30921 X for solid tumours,4 Bhimamycin C and Bhimamycin D
against human ovarian cancer cell lines1c,5 in Fig. 1. Additionally,
2-substituted benzo[f]isoindole-4,9-diones have been found fre-
quently in some anticancer compounds.5b
Interest in their chemistry continues unabated due to their wide
usefulness as biologically active agents and key intermediates in the
organic synthesis.6 The 1,3-dipolar azomethine ylide cycloaddition is
a powerful tool for the construction of five-membered heterocycles.7
Fig. 1. Representative examples of natural products.
and moisture, low-cost, ready availability, high catalytic activity and
so on.12
For instance, 2H-isoindole-4,7-diones,8
b-substituted meso-tetra-
phenylporphyrins,9 novel spirooxindoles.10 In recent years, the metal
(ion)-free catalysis of organic reactions are the challenge and get
more and more attention.3a,3c,11 For the last decade, the use of mo-
lecular iodine has become popular because of its high tolerance to air
To the best of our knowledge, there is no report in the literature
on the iodine participated in 1,3-dipolar cycloaddition of 1,4-
naphthoquinone with azomethine ylides generated in situ from
paraformaldehyde and N-substituted amino ester hydrochlorides.
These products contain one ester group, which can be converted
into useful building blocks. Interest in the functionalisation of qui-
none structures,13 we herein reported the first efficient synthesis
of novel 2-substituted benzo[f]isoindole-4,9-diones framework via
* Corresponding author. Tel.: þ86 0571 88320891; fax: þ86 0571 88320544;
e-mail address: lyjzjut@zjut.edu.cn (Y.-J. Li).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.029

9034
H.-M. Huang et al. / Tetrahedron 69 (2013) 9033e9037
Table 2
the one-pot, 1,3-dipolar cycloaddition of quinone, para-
Study of the reaction scope by variation of N-substituted amino esters
formaldehyde and N-substituted amino ester hydrochlorides.
2. Results and discussion
As indicated in Table 1, we started our novel methods for syn-
thesis of 2-substituted benzo[f]isoindole-4,9-diones through 1,3-
dipolar cycloaddition of 1,4-naphthoquinone 1a with sarcosine
ethyl ester hydrochloride 2a and paraformaldehyde 3a promoted
by iodine.
Entry
1
2
4
Yield of 4 (%)a
R1
R2
1
2
3
4
5
6
7
8
9
Me
Et
n-Pr
n-Bu
PhCH2
Me
Me
Me
Me
Ph
Et
Et
Et
Et
4a
4b
4c
4d
4g
4e
4f
4h
4i
4j
93.4
95.1
98.1
92.3
91.8
61.5
53.9
58.7
50.6
N.R.
Table 1
Et
Optimization of the reaction conditionsa
n-Pr
n-Bu
Isoamyl
i-Pr
Et
10
11
12
13
14
15
16
17
18
19
Me
Et
n-Pr
n-Bu
PhCH2
Me
Me
Me
Me
Et
Et
Et
Et
4k
4l
78.0
70.3
68.2
51.7
88.5
51.8
55.3
36.6
47.4
Entry
2a (equiv)
Iodine
(equiv)
Solvent
Base
Yield of
4a (%)b
4m
4n
4o
4p
4q
4r
1
2
3
4
5
6
7
8
3
1
3
3
3
3
2
1
3
3
3
3
3
3
3
3
0
0
0.1
0.5
0.7
1
1
1
1
1
1
1
1
1
1
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
50.0
18.1
55.0
70.0
87.1
93.4
69.6
35.1
86.1
82.0
71.5
87.7
76.7
51.4
47.5
92.0
Et
n-Pr
n-Bu
Isoamyl
i-Pr
4s
9
20
Me
Me
Et
Et
4tþ4t0
50.1
52.6
10
11
12
13
14
15
16
DBU
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
THF
C2H5OH
1,4-Dioxane
Toluene
DMF
21
4uþ4u0
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0e3.0 mmol), 3a (1.1 mmol), Iodine
(0e1.0 mmol), base (3.0 mmol), and solvent (10.0 mL), was stirred for 8 h under
refluxing temperature under air condition.
a
Isolated yield.
b
Yield of the isolated product based on 1a.
Initially, the corresponding product 4a was obtained in 50%
yield after refluxing for 8 h in acetonitrile in the absence of iodine,
the yield of 4a was obviously improved along with the increase of
iodine (Table 1, entries 3e6). As the quantity of 2a decreased, the
yield of 4a was also cut down correspondingly (Table 1, entries
6e8). Several bases were employed instead of Sodium bicarbonate,
the yield of 4a didn’t obtain in better yield (Table 1, entries 9, 10).
Then efforts were made to optimize other reaction parameters in-
cluding solvents and reaction temperatures. Thus, the reaction was
studied in different solvents, including CHCl3, THF, eEtOH, 1,4-di-
oxane, toluene, DMF (Table 1, entries 10e16). Finally, to our satis-
faction, the reaction in acetonitrile led to the desired product in
excellent yield (93.4%, Table 1, entry 6).
With the optimal reaction conditions in hand, the scope of this
iodine participated in 1,3-dipolar cycloaddition reaction was ex-
plored with a variety of N-substituted amino ester hydrochlorides,
and the results were summarized in Table 2. To our delight, good
yields were obtained in several cases (Table 2, entries 1e9, 11e19).
Unfortunately, when N-phenylglycine ethyl ester hydrochloride 2j
took into the reaction, the corresponding product wasn’t obtained
because of its lower activity (Table 2, entry 10). The structure of
product 4d was unambiguously established by X-ray crystallo-
graphic analysis (Fig. 2).14
Fig. 2. X-ray structure of 4d.
1,4-naphthoquinones. Unfortunately, product 4t was afforded in
50.1% total yield with two isomers and the ratio of 4t and 4t0 was 1:1
determined by 1H NMR when 5-hydroxy-1,4-naphthoquinone1cwas
employed (Table 2, entry 20). Similar result was obtained in 52.6%
total yield in the case of 5-nitro-1,4-naphthoquinone 1d (Table 2,
entry 21).
On the basis of the above results, a possible mechanism of the
present reaction is depicted in Scheme 1. Firstly, with molecular
iodine activated the carbonyl group,16 paraformaldehyde 3a was
attacked by N-substituted amino ester to give the initial addition
product A. Then the 1,3-dipole B was formed by removal of H2O and
reacted with quinones 1 to product intermediate C together with its
isomer D through aromatization. The final product 4 was obtained
by co-oxidation of molecular iodine and oxygen.17
Considering many natural products and bioactive molecules
have substituentgroupsonthestructureof1,4-naphthoquinone,1c,5,15
we try to expand the reaction with several substituted

H.-M. Huang et al. / Tetrahedron 69 (2013) 9033e9037
9035
(s, 1H), 4.52 (q, J¼8.0 Hz, 2H), 3.95 (s, 3H), 1.50 (t, J¼7.0 Hz, 3H); 13
C
NMR (CDCl3, 125 MHz):
d
(ppm) 180.1, 178.7, 160.9, 135.9, 134.3,
133.4, 133.1, 128.0, 127.4, 126.6, 125.8, 123.6, 122.6, 62.1, 37.5, 14.2;
GCeMS m/z 283.9 [MþH]þ, 283.0, 239.2, 211.2, 183.0, 170.1, 113.2,
50.0; Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C,
67.71; H, 4.73; N, 4.75.
4.1.2. Ethyl 2-ethy-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
(4b). Yield 95.1%, mp 143e144 ꢀC; 1H NMR (500 MHz, CDCl3):
8.26e8.21 (m, 2H), 7.73e7.71 (m, 2H), 7.55 (s, 1H), 4.52 (q, J¼6.5 Hz,
2H), 4.31 (q, J¼7.0 Hz, 2H), 1.53e1.49 (m, 6H); 13C NMR (CDCl3,
125 MHz): 180.3, 178.9, 161.1, 136.0, 134.4, 133.4, 133.0, 127.4(2C),
126.6, 126.0, 123.3, 122.7, 62.2, 45.1, 16.5, 14.1; GCeMS: m/z 298.2
(Mþ1), 297.2 (M,100%), 268.3, 253.3, 225.3,197.2,140.2,113.2; Anal.
Calcd for C17H15NO4: C, 68.68, H, 5.09, N, 4.71. Found: C, 68.41; H,
5.18, N, 4.48.
Scheme 1. Proposed mechanism.
3. Conclusion
In summary, we have reported a novel protocol of the synthesis
of 2-substituted benzo[f]isoindole-4,9-diones framework via the
one-pot, 1,3-dipolar cycloaddition 1,4-naphthoquinone, para-
formaldehyde and N-substituted amino ester hydrochlorides in the
present of iodine at refluxing acetonitrile, which to the best of our
knowledge has no precedents. We have shown that these reactions
proceed with good yields and the promising results obtained 1,3-
dipolar cycloaddition will have the potential application in natu-
ral product exhibiting important biological activities. These prod-
ucts contain one ester group, which can be converted into useful
building blocks. Further work aimed at the optimization, func-
tionalization of these exciting molecular scaffolds and will be
published in due course.
4.1.3. Ethyl 2-propy-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
(4c). Yield 98.1%, mp 115e116 ꢀC; 1H NMR (500 MHz, CDCl3):
d
(ppm) 8.25e8.21 (m, 2H), 7.74e7.69 (m, 2H), 7.52 (s, 1H), 4.52 (q,
J¼8.0 Hz, 2H), 4.23 (q, J¼7.5 Hz, 2H), 1.91e1.84 (m, 2H), 1.50 (t,
J¼6.5 Hz, 3H), 0.97 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 180.2, 178.9, 161.0, 135.9, 134.4, 133.4, 133.1, 127.4, 126.8,
126.6, 125.6, 123.3, 122.5, 62.2, 51.6, 24.5, 14.1, 11.0; GCeMS m/z
311.8 [MþH]þ, 310.8, 281.8, 265.9, 264.0, 250.0, 238.2, 224.0, 211.1;
HRMS (ESI-TOF) m/z Calcd for C18H17NO4Na [MþNa]þ 334.1050,
found 334.1052.
4.1.4. Ethyl 2-butyl-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
(4d). Yield 92.3%, mp 162e163 ꢀC; 1H NMR (500 MHz, CDCl3):
d
(ppm) 8.26e8.22 (m, 2H), 7.74e7.69 (m, 2H), 7.52 (s, 1H), 4.52 (q,
4. Experimental section
4.1. General
J¼7.0 Hz, 2H), 4.26 (t, J¼7.5 Hz, 2H), 1.85e1.79 (m, 2H), 1.50 (t,
J¼7.0 Hz, 3H), 1.41e1.33 (m, 2H), 0.97 (t, J¼7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz):
d (ppm) 180.2, 178.9, 161.1, 136.0, 134.4, 133.4,
133.1, 127.4, 126.66 (2C), 125.7, 123.3, 122.5, 62.2, 49.8, 33.2, 19.8,
14.1, 13.6; GCeMS m/z 326.6 [MþH]þ, 325.7, 279.8, 251.8 (100%),
210.0; HRMS (ESI-TOF) m/z Calcd for C19H19NO4Na [MþNa]þ
348.1206, found 348.1209.
All chemicals were purchased from commercial vendors and
were used as received without further purification; any exceptions
are noted within the text and the vendors are noted within the
context of use. The 1H and 13C NMR spectra were recorded at 500
and 125 MHz, respectively, in CDCl3 using TMS as internal standard
4.1.5. Ethyl 2-benzyl-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
with a Bruker AM 500 spectrometer. Chemical shifts (
d) were re-
(4e). Yield 91.8%, mp 100e101 ꢀC; 1H NMR (500 MHz, CDCl3):
ported as parts per million (ppm) and the following abbreviations
were used to identify the multiplicities: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, b¼broad and all combinations
thereof can be explained by their integral parts. The GCeMS was
taken on Agilent (GC431eMS210) and elementary analysis was on
Thermo Electron Corporation Flash EA 1112, HRMS were recorded
on a Bruker MicroTOF-QII mass instrument (ESI).
d (ppm) 8.25e8.21 (m, 2H), 7.74e7.69 (m, 2H), 7.53 (s, 1H),
7.38e7.32 (m, 3H), 7.21 (d, J¼6.5 Hz, 2H), 5.45 (s, 2H), 4.43 (q,
J¼7.0 Hz, 2H), 1.37 (t, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 180.1, 178.8,161.0, 135.9,135.1, 134.4, 133.5 (2C), 129.1, 128.6
(2C), 127.7, 127.3 (2C), 127.0, 126.7, 125.9, 123.4, 122.6, 62.2, 53.2,
13.9; GCeMS m/z 360.2 [MþH]þ, 359.2 [M]þ, 330.2, 314.3, 313.2,
135.2, 91.2, 65.1; HRMS (ESI-TOF) m/z Calcd for C22H17NO4Na
[MþNa]þ 382.1050, found 382.1059.
4.1.1. Typical procedure for the preparation of ethyl 2-methyl-2H-
benzo[f]isoindole-4,9-dione-1-carboxylate (4a). Typically, a mixture
of 1,4-naphthoquinone (1a, 1.0 mmol, 0.158 g, 1.0 equiv), sarcosine
ethyl ester hydrochloride (2a, 3.0 mmol, 0.4605 g, 3.0 equiv),
paraformaldehyde (3a, 1.1 mmol, 0.0330 g, 1.1 equiv), Iodine
(1.0 mmol, 0.2540 g, 1.0 equiv), sodium bicarbonate (3.0 mmol,
0.2520 g, 3.0 equiv) in acetonitrile (10.0 mL), was stirred at
refluxing temperature under air condition until the staring material
was consumed, as determined by GCeMS and TLC. The reaction
mixture was poured into 8 mL saturated aqueous sodium thiosul-
fate and was extracted (3*10 mL) with CH2Cl2. The combined ex-
tracts were dried over MgSO4. The solvent was removed under
vacuum, and the resulting crude product was purified by chroma-
tography on silica gel eluted with CH2Cl2 to afford the desired
product 4a as yellow solid (0.2643 g, yield 93.4%, mp 149e150 ꢀC).
4.1.6. Propyl 2-methy-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
(4f). Yield 61.5%, mp 121e122 ꢀC; 1H NMR (500 MHz, CDCl3):
d
(ppm) 8.26e8.24 (m, 1H), 8.23e8.21 (m, 1H), 7.74e7.69 (m, 2H),
7.49 (s, 1H), 4.41 (t, J¼7.0 Hz, 2H), 4.00 (s, 3H), 1.94e1.86 (m, 2H),
1.09 (t, J¼8.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d (ppm) 180.1,
178.7, 161.0, 136.0, 134.3, 133.5, 133.1, 128.0, 127.5, 126.6, 125.8,
123.6, 122.7, 67.7, 37.6, 22.0, 10.5; GCeMS m/z 298.1 [MþH]þ, 297.1,
255.1, 239.3, 238.3, 211.2, 170.2, 41.0; HRMS (ESI-TOF) m/z Calcd for
C
17H15NO4Na [MþNa]þ 320.0893, found 320.0898.
4.1.7. Butyl 2-methyl-2H-benzo[f]isoindole-4,9-dione-1-carboxylate
(4g). Yield 53.9%, mp 120e121 ꢀC; 1H NMR (500 MHz, CDCl3):
d
(ppm) 8.25e8.23 (m, 1H), 8.21e8.20 (m, 1H), 7.73e7.68 (m, 2H),
7.48 (s, 1H), 4.44 (t, J¼7.0 Hz, 2H), 3.94 (s, 3H), 1.87e1.82 (m, 2H),
Yield 93.4%, mp 152e153 ꢀC; 1H NMR (500 MHz, CDCl3):
8.26e8.24 (m, 1H), 8.23e8.21 (m, 1H), 7.74e7.69 (m, 2H), 7.48
d (ppm)
1.56e1.48 (m, 2H), 1.01 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 180.0, 178.6, 160.9, 135.9, 134.3, 133.4, 133.0, 128.0, 127.4,

9036
H.-M. Huang et al. / Tetrahedron 69 (2013) 9033e9037
126.6, 125.8, 123.5, 122.6, 65.9, 37.5, 30.6, 19.2, 13.7; GCeMS m/z
312.4 [MþH]þ, 311.5, 239.5, 238.5, 211.5, 170.5, 113.5, 41.2; HRMS
(ESI-TOF) m/z Calcd for C18H17NO4Na [MþNa]þ 334.1050, found
334.1052.
161.3, 135.0, 134.8, 132.4, 131.2, 130.0 (2C), 129.5, 129.1 (2C), 128.8,
126.8, 126.0, 124.1, 123.5, 62.2, 49.8, 33.2,19.8, 14.2, 13.6; GCeMS m/
z 376.0 [MþH]þ, 375.1, 304.2, 302.2 (100%), 274.2, 190.2, 155.2,
126.3; HRMS (ESI-TOF) m/z Calcd for C23H21NO4Na [MþNa]þ
398.1363, found 398.1371.
4.1.8. Isopentyl 2-methyl-2H-benzo[f]isoindole-4,9-dione-1-
carboxylate (4h). Yield 58.7%, mp 119e120 ꢀC; 1H NMR (500 MHz,
4.1.14. Ethyl 2-benzyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
CDCl3):
d
(ppm) 8.26e8.24 (m, 1H), 8.23e8.21 (m, 1H), 7.75e7.69
carboxylate (4o). Yield 88.5%, mp 149e150 ꢀC; 1H NMR
(m, 2H), 7.49 (s, 1H), 4.48 (t, J¼7.0 Hz, 2H), 3.95 (s, 3H), 1.87e1.81
(500 MHz, CDCl3):
d
(ppm) 8.74 (d, J¼8.5 Hz, 2H), 8.05e8.03 (m,
(m, 1H), 1.79e1.75 (m, 2H), 1.01 (d, J¼6.5 Hz, 6H); 13C NMR (CDCl3,
2H), 7.65e7.63 (m, 2H), 7.58 (s, 1H), 7.38e7.24 (m, 3H), 7.23 (d,
J¼7.5 Hz, 2H), 5.46 (s, 2H), 4.45 (q, J¼7.0 Hz, 2H), 1.40 (t, J¼7.0 Hz,
125 MHz):
d (ppm) 178.0, 178.5, 160.9, 135.9, 134.2, 133.4, 133.0,
128.0, 127.4, 126.5, 125.7, 123.5,122.5, 64.7, 37.5, 37.1, 25.1, 22.5 (2C);
GCeMS m/z 326.2 [MþH]þ, 325.3, 256.2, 238.3, 170.3, 113.2, 41.0;
HRMS (ESI-TOF) m/z Calcd for C19H19NO4Na [MþNa]þ 348.1206,
found 348.1216.
3H); 13C NMR (CDCl3, 125 MHz):
d (ppm) 18.0, 178.7, 161.1, 135.1,
134.9, 134.6, 132.2, 131.0, 130.0 (2C), 129.5, 129.1 (3C), 129.0, 128.9,
128.6, 127.8 (2C), 127.1, 126.1, 124.1, 123.5, 62.2, 53.2, 13.9; GCeMS
m/z 410.1 [MþH]þ, 409.2 [M]þ, 380.2, 364.2, 363.3, 274.3, 91.0, 65.0;
HRMS (ESI-TOF) m/z Calcd for C26H19NO4Na [MþNa]þ 432.1206,
found 432.121.
4.1.9. Isopropyl 2-methyl-2H-benzo[f]isoindole-4,9-dione-1-
carboxylate (4i). Yield 50.6%, mp 133e134 ꢀC; 1H NMR (500 MHz,
CDCl3):
d
(ppm) 8.26e8.24 (m, 1H), 8.22e8.20 (m, 1H), 7.74e7.69
4.1.15. Propyl 2-methyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
(m, 2H), 7.46 (s, 1H), 5.39e5.34 (m, 1H), 3.94 (s, 3H), 1.49 (d,
carboxylate (4p). Yield 51.8%, mp 127e128 ꢀC; 1H NMR (500 MHz,
J¼6.0 Hz, 6H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 180.2, 178.7,
CDCl3):
d
(ppm) 8.71 (d, J¼3.5 Hz, 2H), 8.02 (dd, J1¼3.5 Hz,
160.4, 136.0, 134.8, 134.4, 133.5, 133.1, 127.7, 127.5, 126.7, 125.5,
123.4, 122.6, 70.3, 37.4, 21.8; GCeMS m/z 298.1 [MþH]þ, 297.1,
239.2, 211.2, 183.2, 170.3, 154.2, 43.0; HRMS (ESI-TOF) m/z Calcd for
J2¼6.0 Hz, 2H), 7.63 (dd, J1¼3.5 Hz, J2¼6.5 Hz, 2H), 7.51 (s, 1H), 4.42
(t, J¼7.0 Hz, 2H), 3.94 (s, 3H), 1.92 (q, J¼7.5 Hz, 2H), 1.12 (t, J¼8.0 Hz,
3H); 13C NMR (CDCl3, 125 MHz):
d (ppm) 179.9, 178.5, 161.1, 134.9,
C
17H18NO4 [MþH]þ 298.1074, found 298.1080.
134.6, 132.3, 130.9, 129.9 (2C), 129.5, 129.0 (2C), 128.6, 128.1, 125.9,
124.3, 123.5, 67.7, 37.5, 22.0, 10.5; GCeMS m/z 348.0 [MþH]þ, 347.1,
289.2, 275.3, 262.2, 261.3, 163.3, 41.0; HRMS (ESI-TOF) m/z Calcd for
4.1.10. Ethyl 2-methyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
carboxylate (4k). Yield 78.0%, mp 202e203 ꢀC; 1H NMR
C
21H17NO4Na [MþNa]þ 370.1050, found 370.1058.
(500 MHz, CDCl3):
d
(ppm) 8.73 (d, J¼13.5 Hz, 2H), 8.04e8.02 (m,
2H), 7.65e7.63 (m, 2H), 7.52 (s, 1H), 4.53 (q, J¼7.0 Hz, 2H), 3.95 (s,
4.1.16. Butyl 2-methyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
3H), 1.52 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d
(ppm)
carboxylate (4q). Yield 55.3%, mp 147e148 ꢀC; 1H NMR
179.9, 178.6, 160.9, 134.9, 134.6, 132.3, 139.9, 129.9 (2C), 129.5, 129.0
(2C), 128.7, 128.0, 125.9, 124.3, 123.5, 62.1, 37.5, 14.1; GCeMS m/z
333.1 [M]þ, 289.2, 262.2, 261.3 (100%), 220.2, 163.3, 42.1; HRMS
(ESI-TOF) m/z Calcd for C20H15NO4Na [MþNa]þ 356.0893, found
356.0900.
(500 MHz, CDCl3):
d
(ppm) 8.74 (s, J¼13.5 Hz, 2H), 8.05 (dd,
J1¼3.5 Hz, J2¼6.5 Hz, 2H), 7.65 (dd, J1¼3.5 Hz, J2¼6.5 Hz, 2H), 7.53 (s,
1H), 4.47 (t, J¼7.5 Hz, 2H), 3.96 (s, 3H), 1.91e1.85 (m, 2H), 1.59e1.51
(m, 2H), 1.03 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d (ppm)
180.0, 178.5, 161.1, 134.9, 134.6, 132.3, 130.9, 129.9 (2C), 129.5, 129.0
(2C), 128.7, 128.0, 126.0, 124.3, 123.5, 66.0, 37.5, 30.6, 19.2, 13.8;
GCeMS m/z 362.0 [MþH]þ, 361.0, 289.0, 262.2, 261.2, 220.2, 207.2,
4.1.11. Ethyl 2-ethyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
carboxylate (4l). Yield 70.3%, mp 187e188 ꢀC; 1H NMR (500 MHz,
73.0; HRMS (ESI-TOF) m/z Calcd for
C
22H19NO4Na [MþNa]þ
CDCl3):
(m, 2H), 7.61 (s, 1H), 4.55 (q, J¼7.0 Hz, 2H), 4.33 (q, J¼7.0 Hz, 2H),
1.55e1.52 (m, 6H); 13C NMR (CDCl3, 125 MHz):
(ppm) 179.8, 178.5,
161.0, 134.8, 134.5, 132.2, 130.9, 129.8, 129.8, 129.3, 128.9, 128.9,
128.6, 126.1, 125.5, 123.9, 123.4, 62.0, 44.8, 16.3, 14.0; GCeMS m/z
348.0 [MþH]þ, 347.1, 303.3, 286.3, 275.3, 247.3, 190.3, 163.3, 120.0;
HRMS (ESI-TOF) m/z Calcd for C21H17NO4Na [MþNa]þ 370.1050,
found 370.1058.
d
(ppm) 8.77 (d, J¼7.5 Hz, 2H), 8.07e8.05 (m, 2H), 7.68e7.64
384.1206, found 384.1215.
d
4.1.17. Isopentyl 2-methyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
carboxylate (4r). Yield 36.6%, mp 100e101 ꢀC;
(ppm) 8.75 (d,
d
J¼12.5 Hz, 2H), 8.06e8.05 (m, 2H), 7.66 (dd, J1¼3.0 Hz, J2¼6.0 Hz,
2H), 7.55 (s, 1H), 4.50 (t, J¼7.5 Hz, 2H), 3.97 (s, 3H), 1.88e1.83 (m,
1H), 1.82e1.77 (m, 2H), 1.02 (d, J¼6.5 Hz, 6H); 13C NMR (CDCl3,
125 MHz): d (ppm) 180.1,178.6,161.2,135.0,134.7,132.4,131.0,130.0
(2C), 129.6, 129.1 (2C), 128.8, 128.1, 126.1, 124.4, 123.6, 65.0, 37.6,
30.3, 25.3, 22.6 (2C); GCeMS: m/z 376.5 [MþH]þ, 375.5, 306.5,
289.7, 288.7, 261.8, 163.6, 41.3; HRMS (ESI-TOF) m/z Calcd for
4.1.12. Ethyl 2-propyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
carboxylate (4m). Yield 68.2%, mp 176e177 ꢀC; 1H NMR
(500 MHz, CDCl3):
d
(ppm) 8.78 (d, J¼6.5 Hz, 2H), 8.08e8.05 (m,
C
23H21NO4Na [MþNa]þ 398.1363, found 398.137.
2H), 7.68e7.65 (m, 2H), 7.58 (s, 1H), 4.55 (q, J¼7.0 Hz, 2H), 4.25 (t,
J¼6.5 Hz, 2H), 1.94e1.86 (m, 2H), 1.53 (t, J¼7.0 Hz, 3H), 0.99 (t,
4.1.18. Isopropyl 2-methyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 180.2, 178.8,
carboxylate (4s). Yield 47.4%, mp 192e193 ꢀC; 1H NMR (500 MHz,
161.2, 135.0, 134.7, 132.4, 131.1, 130.0 (2C), 129.5, 129.1, 129.0, 128.8,
126.8, 125.9, 124.1, 123.4, 62.2, 51.6, 24.5, 14.1, 11.0; GCeMS m/z
362.5 [MþH]þ, 361.5, 317.7, 290.5, 289.8, 261.8, 190.5, 163.5, 126.5;
HRMS (ESI-TOF) m/z Calcd for C22H19NO4Na [MþNa]þ 384.1206,
found 384.1208.
CDCl3): 1H NMR (500 MHz, CDCl3):
d (ppm) 8.79 (s, 1H), 8.76 (s, 1H),
8.07 (dd, J1¼3.5 Hz, J2¼6.0 Hz, 2H), 7.66 (dd, J1¼3.5 Hz, J2¼6.0 Hz,
2H), 7.54 (s, 1H), 1.52 (d, J¼6.5 Hz, 6H); 13C NMR (CDCl3, 125 MHz):
d
(ppm) 179.9, 178.4, 160.5, 134.9, 134.6, 132.2, 130.9, 129.9 (2C),
129.4, 129.0, 128.9, 128.6, 127.8, 126.5, 124.0, 123.3, 70.2, 37.3, 21.7
(2C); GCeMS m/z, 348.0 [MþH]þ, 346.9, 289.0, 261.2 (100%), 220.2,
4.1.13. Ethyl 2-butyl-2H-naphtho[2,3-f]isoindole-4,11-dione-1-
41.0; HRMS (ESI-TOF) m/z Calcd for
370.1050, found 370.1057.
C
21H17NO4Na [MþNa]þ
carboxylate (4n). Yield 51.7%, mp 156e157 ꢀC; 1H NMR (500 MHz,
CDCl3):
d
(ppm) 8.74 (d, J¼7.0 Hz, 2H), 8.05e8.04 (m, 2H), 7.65e7.63
(m, 2H), 7.56 (s, 1H), 4.54 (q, J¼7.0 Hz, 2H), 4.26 (t, J¼7.5 Hz, 2H),
4.1.19. Ethyl 8-hydroxy-2-methyl-2H-benzo[f]isoindole-4,9-dione-1-
carboxylate (4t) and ethyl 5-hydroxy-2-methyl-2H-benzo[f]iso-
indole-4,9-dione-1-carboxylate (4t0). Yield 50.1%; 1H NMR (500 MHz,
1.90e1.80 (m, 2H), 1.52 (t, J¼7.0 Hz, 3H), 1.41e1.34 (m, 2H), 0.97 (t,
J¼3.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d (ppm) 183.9, 180.2,

H.-M. Huang et al. / Tetrahedron 69 (2013) 9033e9037
9037
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d (ppm) 12.94 (s, 1H), 12.67 (s, 1H), 7.77e7.74 (m, 2H),
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125 MHz): d (ppm) 185.7, 185.0, 179.1, 177.9, 162.9, 162.4, 160.5, 160.5,
136.0, 135.9, 135.6, 134.5, 128.1, 128.0, 126.3, 126.1, 124.1, 123.4 (2C),
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1.52e1.49 (m, 3H), 1.45e1.42 (m, 3H); 13C NMR (CDCl3, 125 MHz):
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125.1, 123.1, 122.6, 122.2, 121.7, 121.3, 62.3, 62.2, 37.8, 37.6, 14.1, 13.8;
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Acknowledgements
We gratefully acknowledge the financial supported by the Nat-
ural Science Foundation of China (21176223) and the National
Natural Science Foundation of Zhejiang (LY13B020016) and the Key
Innovation Team of Science and Technology in Zhejiang Province
(2010R50018).
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.029.
13. (a) Huang, H.-M.; Li, Y.-J.; Dai, Y.-P.; Yu, W.-B.; Ye, Q.; Gao, J.-R. J. Chem. Res. 2013,
37, 34; (b) Huang, H.-M.; Li, Y.-J.; Yang, J.-R.; Jia, J.-H.; Ye, Q.; Han, L.; Gao, J.-R.
Tetrahedron 2013, 69, 5221.
References and notes
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