Efficient synthesis of isoindoles using supercritical carbon dioxide

Article abstract of DOI:10.1016/j.tetlet.2017.02.055

Bicyclopyrroles were efficiently converted to the corresponding isoindoles by a retro Diels-Alder reaction in supercritical carbon dioxide. By adding ethylene gas as an oxygen scavenger, the isoindole yield was further improved.

Full text of DOI:10.1016/j.tetlet.2017.02.055

Accepted Manuscript
Efficient synthesis of isoindoles using supercritical carbon dioxide
Satoshi Ito, Masayuki Akaki, Yasutaka Shinozaki, Yuuki Iwabe, Masaru
Furuya, Marina Tobata, Makoto Roppongi, Takafumi Sato, Naotsugu Itoh, Toru
Oba
PII:
S0040-4039(17)30235-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.055
TETL 48666
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 January 2017
9 February 2017
16 February 2017
Please cite this article as: Ito, S., Akaki, M., Shinozaki, Y., Iwabe, Y., Furuya, M., Tobata, M., Roppongi, M., Sato,
T., Itoh, N., Oba, T., Efficient synthesis of isoindoles using supercritical carbon dioxide, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.055
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient synthesis of isoindoles using
supercritical carbon dioxide
Leave this area blank for abstract info.
Satoshi Ito*, Masayuki Akaki, Yasutaka Shinozaki, Yuuki Iwabe, Masaru Furuya, Marina Tobata, Makoto
Roppongi, Takafumi Sato, Naotsugu Itoh, Toru Oba
Supercritical
Carbon Dioxide
20 MPa
CO2Et
CO2Et
N
X
N X
185 °C, 210 min
Y
Y

1
Tetrahedron Letters
journal homepage: www.els evier.com
Efficient synthesis of isoindoles using supercritical carbon dioxide
Satoshi Ito a,*, Masayuki Akaki a, Yasutaka Shinozaki a, Yuuki Iwabe a, Masaru Furuya a, Marina Tobata a,
Makoto Roppongi b, Takafumi Sato a, Naotsugu Itoh a, Toru Oba a
a Department of Applied Chemistry, Faculty of Engineering, Utsunomiya University, 7-1-2 Yoto, Utsunomiya, Tochigi 321-8585, Japan
b Collaboration Center for Research and Development of Utsunomiya University, 7-1-2 Yoto, Utsunomiya, Tochigi 321-8585, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Bicyclopyrroles were efficiently converted to the corresponding isoindoles by a retro Diels-
Alder reaction in supercritical carbon dioxide. By adding ethylene gas as an oxygen scavenger,
the isoindole yield was further improved.
Received in revised form
Accepted
2017 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Isoindole
Supercritical carbon dioxide
Bicyclopyrrole
retro Diels-Alder reaction
Introduction
However, unsubstituted isoindole decomposes rapidly in air at
room temperature because it has an exomethylene structure and
Isoindole has a simple skeleton in which benzene and pyrrole
are fused and is a structural isomer of indole, which is found
widely in nature. Isoindole derivatives and oligomers have been
investigated as various functional materials. Isoindole derivatives
are useful fluorescence labeling reagents1 or antihypertensive
agents. 2 For example, the oligomer benzopyrrolmethene has been
used for red organic electroluminescence. 3 Tetrabenzoporphyrins
have attracted attention as organic semi-conducting materials for
8
readily reacts with oxygen in the air. Therefore, introduction of
substituents directly to isoindole is difficult and the synthesis of
9
isoindole derivatives has been severely limited. We focused on
pyrrole fused with
a
bicyclo[2.2.2]octadiene skeleton
(bicyclopyrrole: 1). Bicyclopyrrole oligomers are converted
quantitatively to the corresponding π-conjugated extended
pyrrole oligomers by a retro Diels-Alder reaction. However,
bicyclopyrrole derivatives are obtained very low yields (less than
15%) because the isoindole derivative quickly reacts with trace
amounts of oxygen in high-boiling solvents. 10
field-effect transistors, 4 near-IR dyes, 5 solar cell materials, 6 and
7
photosensitizers for photodynamic therapy.
developing a method for synthesizing isoindoles is important
(Fig. 1).
Therefore,
To eliminate the adverse effect of oxygen in the reaction
system, we investigated using supercritical carbon dioxide.
Supercritical carbon dioxide (Tc=304.2 K, Pc=7.4 MPa) is a
special fluid that has both liquid and gas properties, and it is
generated when the temperature and pressure of carbon dioxide
11
are above its critical values. Supercritical carbon dioxide can
also dissolve organic compounds, making it useful as a reaction
12
solvent in organic synthesis. High-purity oxygen-free carbon
dioxide is easy to obtain and has low toxicity. Therefore, we
expected that isoindole derivatives could be synthesized
efficiently by thermal decomposition of bicyclopyrrole in
supercritical carbon dioxide.
Results and discussion
Figure 1. Isoindole and related compounds.
Bicyclopyrrole 1, which was the starting material, was
13
synthesized from cis-1, 2-dichloroethylene in five steps.
Bicyclopyrrole 1 was converted to α-bromobicyclopyrrole 2a by
reaction with N-bromosuccinimide. Bromobicyclopyrrole 2a was
also converted to α-phenylbicyclopyrrole 2b by Suzuki coupling
with phenylboronic acid. α-Bromobicyclopyrrole 2a was reacted
with copper cyanide to form α-cyanobicyclopyrrole 2c. α-
--------
∗ Corresponding author. Tel.: +81 28 689 7013; fax: +81 28 689
6009. E-mail address: s-ito@cc.utsunomiya-u.ac.jp (S. Ito).

2
Tetrahedron
Formylbicyclopyrrole 2d was synthesized from bicyclopyrrole
1 by a Vilsmeier formylation reaction. The ethyl ester group of
bicyclopyrrole 1 was decarboxylated by heating in ethylene
glycol in the presence of a strong base to obtain α-unsubstituted
bicyclopyrrole 3. The protons at the N-position of
bicyclopyrroles 1 and 3 were removed with NaH, and the
deprotonated bicyclopyrroles were treated with various halides to
obtain the corresponding N-substituted bicyclopyrroles 2e, 2f,
and 4 (Schemes 1 and 2).
The air in the reactor was gently purged with about 5 MPa of
CO2, and the pressure of the reactor was released to 0.1 MPa.
After that, all valves connected to the reactor were closed. The
heating was started from room temperature. When the
temperature was raised to the reaction temperature, the valve
connected to the compressor was opened and CO2 was introduced
to the reactor at the desired pressure, then the valve was closed
again and then the magnetic stirrer was rotated. We defined that
this time was the zero of reaction time. The pressure inside the
reactor was almost constant. After the reaction time, the reactor
was cooled and the CO2 in the reactor was slowly released
through the back pressure regulator. The products were purified
by silica gel column chromatography and HPLC.
First, we examined the reaction conditions for bicyclopyrrole 1
in detail. The highest isolation yield of isoindole 5 (68% yield)
was obtained when bicyclopyrrole 1 was heated in supercritical
carbon dioxide at 185 °C for 210 min. When the decomposition
reaction of bicyclopyrrole 1 was carried out at 220 ° C, the
isolated yield of isoindole 5 was greatly decreased, and the
reaction temperature was raised to 250 °C, black powder was
obtained and isoindole 5 could not be isolated. However, an
unexpected product, isoindole diester 9, was isolated under all
reaction conditions (yield of less than 1%). Next, bicyclopyrroles
2a–e were also reacted under the same conditions (185 °C, 210
min). The isoindole yields varied greatly depending on the
properties of the substituents. Bicyclopyrroles 2b–e with an
electron withdrawing group were converted to corresponding
isoindole derivatives 6b–e in high yields. In contrast, conversion
of α-bromobicyclopyrroles 2a and α-unsubstituted bicyclopyrrole
4 to isoindole were poorly controlled. In each of the reactions, α-
bromoisoindole 6a was obtained in extremely low yield, or a
black powder that could not be assigned was obtained. Although
the corresponding isoindoles were formed in the reaction system,
decomposition occurred due to instability of the exomethylenic
structure arising from the high electron density of the π-
conjugated systems (Scheme 3, Fig. 3).
The pyrolysis reaction of bicyclopyrroles 1 and 2a–e in
supercritical carbon dioxide was performed with the following
reaction apparatus. 14 The experiments were conducted in a high-
pressure reactor made from 316 stainless steel. The internal
volume of the reactor was 50 cm3. For the reaction, the
bicyclopyrrole (50 mmol) and a magnetic stirrer were added to
the reactor. The loaded reactor was placed in
chromatography oven (GC-7A, Shimadzu) and connected to the
a gas
gas inlet line and gas outlet line (Fig. 2).
Figure 3. X-ray crystallographic analysis of isoindole 5; a) front view, b) side view, c) crystal packing.

3
To confirm the formation of isoindole derivatives in the reaction
15
system,
a retro Diels-Alder reaction of N-tosylated
bicyclopyrrole 4 was performed by adding N-phenylmaleimide as
a trapping agent for isoindole. As expected, Diels-Alder adduct 7
of N-tosylisoindole and N-phenylphthalimide was obtained in
72% yield and was found to be an exo Diels-Alder adduct by X-
ray crystal structure analysis (Scheme 4).
When N-tosylbicyclopyrrole 2f was thermally decomposed in
supercritical carbon dioxide, the expected isoindole was not
obtained. Instead, only unexpected isoindole 8 was isolated and
the structure of 8 was identified by X-ray crystal structure
analysis. The sulfone of bicyclopyrrole 2f was rearranged from
the N-position to the α-position and reduced to a sulfide. The
reaction mechanism is unknown (Scheme 5, Fig. 4).
Figure 5. X-ray crystallographic analysis of isoindole diester 9; a) front view, b) side view, c) crystal
packing.
Conclusions
Bicyclopyrroles were transformed into isoindoles in good yield
by a retro Diels-Alder reaction in supercritical carbon dioxide.
Oxidative decomposition of the product was prevented by adding
ethylene gas as an oxygen scavenger, greatly increasing the
isolation yield of isoindoles. This synthesis method provides a
new methodology for the synthesis of isoindole derivatives and
contributes to the development of new functional organic
materials with π-conjugated systems. We also demonstrated that
supercritical carbon dioxide is useful as a reaction solvent for
synthesizing sensitive organic compounds.
Acknowledgments
This work was partially supported by Cooperative Research
Program of ‘Network Joint Research Center for Materials and
Devices’ (No. 20161186: to S.I.), and JSPS KAKENHI Grant
Number JP16K05892 (to S.I.). We would also like to thank, Mr.
Tomokichi Onoda (Shimamura Tech. Co.: Preparative HPLC
Systems).
References and notes
Figure 4. X-ray crystallographic analysis of isoindole 8; a) front view, b) side view, c) crystal packing.
1. Roth, M.; Anal. Chem., 1971, 43, 880.
2. Press, J. B.; Wright Jr., W. B.; , Chan, P. S.; Marsico, J. W.; Haug,
M. F.; Tauber, J.; Tomcufcik, A. S, J. Med. Chem., 1986, 29, 816.
3. Wada, M.; Ito, S.; Uno, H.; Murashima, T.; Ono, N.; Urano, T.;
Urano, Y.; Tetrahedron Lett., 2001, 42, 6711; Urano, Y.; Ohno-
Okumura, E.; Sakamoto, K.; Wada, M.; Ito, S.; Ono, N.; Imag.
Sci., J., 2001, 48, 147.
Even though the amount of oxygen in the reaction system was
small, the yield of isoindole was very low. To remove residual
oxygen, a small amount of ethylene gas was added as an oxygen
scavenger and the thermal decomposition reaction of
16
4. Aramaki, S.; Sakai, Y.; Ono, N. Appl. Phys. Lett. 2004, 84, 2085.
5. 5. Ito, S.; Murashima, T.; Uno, H.; Ono, N.; Chem. Commun.,
1998, 1661; Ito, S.; Ochi, N.; Murashima, T.; Uno, H., Ono, N.,
Heterocycles, 2000, 52, 399.
6. Matsuo, Y.; Sato, Y.; Niinomi, T.; Soga, I.; Tanaka, H.;
Nakamura, E. J. Am. Chem. Soc., 2009, 131, 16048.
bicyclopyrrole 1 was carried out. The ethylene gas prevented
the decomposition of the product and the yield of isoindole 5 was
greatly improved (81%). In addition, the yield of isoindole
diester 9 also increased significantly (11%). We anticipate that
added ethylene gas traps residual oxygen in the reaction system,
but mechanism is unknown. We are conducting research to
elucidate this reaction mechanism (Scheme 6, Fig. 5).
7. Hammerer, F.; Achelle, S.; Baldeck, P.; Philippe, M.; Fichou, M.
P. J., Phys. Chem., 2011, 115, 6503.
8. Bonnett, R.; Brown, R. F. C.; Chem. Commun., 1972, 393;
Bornstein, J.; Remy, D. E.; Shields, J. E.; Chem. Commun., 1972,

4
Tetrahedron
1149; Priestley, G. M.; Warrener, R. N., Tetrahedron Lett.,
1972, 42, 4295.
NMR (CDCl3, 125 MHz) δ 144.3, 136.7, 136.3, 135.1, 134.6,
129.8, 129.3, 127.5, 126.4, 110.6, 108.1, 33.2, 32.7, 27.6, 26.6,
21.6; MS (ESI-TOF) m/z 300 [M+H]+; HRMS (ESI-TOF) m/z
calcd for C17H18NO2S [M+H]+: 300.1053. Found: 300.0867.
9. Theilacker, W.; Bluhm, H. J.; Heitmann, W.; Kalenda, H.; Meyer,
H. J.; Ann. Chem., 1964, 96, 673; Emmett, J. C.; Veber, D. F.;
Lwowski, W.; Chem. Commun., 1965, 272; Emmett, J. C.;
Lwowski, W.; Tetrahedron, 1966, 22, 1011; Fryer, R. I.; Earley,
J. V.; Sternbach, L. H.; J. Am. Chem. Soc., 1966, 88, 3173;
Ahmed, I.; Cheeseman, G. W. H.; Jaques, B.; Wallace, R. G.,
Tetrahedron, 1977, 33, 2255; Murashima. T, Tamai. R, Nishi. K,
Nomura. K, Fujita. K, Uno. H, Ono. N, J. Chem. Soc., Perkin
Trans. 1, 2000, 995; Ohmura, T.; Kijima, A.; Suginome, M., Org.
Lett., 2011, 13, 1238; Chrostowska, A.; Mazière, A.; Dargelos, A.;
Graciaa, A.; Darrigan, C.; Weber, L.; Halama, J., Eur. J. Inorg.
Chem., 2013, 5672; Green, A. P.; Turner, N. J.; O Reilly, E.,
Angew. Chem. Int. Ed. 2014, 53, 10714.
18. Selected experimental data for isoindole 5; Colorless crystal, m.p.
= 132-136 °C; 1H NMR (CDCl3, 500 MHz) δ 11.5 (brs, 1H), 8.09-
8.07 (m, 1H), 7.68 (m, 1H), 7.49 (d, 1H, J = 3.0 Hz), 7.29-7.26
(m, 1H), 7.12-7.09 (m, 1H), 4.50-4.45 (t, 2H, J = 7.1 Hz), 1.49-
1.46 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ 162.2,
126.9, 125.8, 125.5, 122.2, 121.1, 120.6, 116.0, 111.6, 60.3, 14.7;
MS (ESI-TOF) m/z 190 [M+H]+; HRMS (ESI-TOF) m/z calcd for
C11H12NO2 [M+H]+: 190.0863. Found: 190.0845. For 6b;
Colorless crystal, m.p. = 138-139 °C; 1H NMR (CDCl3, 500 MHz)
δ 10.82 (brs, 1H), 8.12 (d, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.54 (t,
1H), 7.09 (t, 1H), 7.41 (t, 1H), 7.33 (t, 1H), 7.18 (t, 1H), 4.41 (q,
2H, J = 7.1 Hz), 1.44 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125
MHz) δ 159.8, 131.6, 129.4, 128.1, 128.0, 127.4, 126.0, 125.9,
123.4, 123.1, 123.0, 121.1, 121.0, 60.5, 14.84; MS (ESI-TOF) m/z
266 [M+H]+; Anal. calcd for C17H15NO2: C, 76.96; H, 5.70; N,
5.28. Found: C, 76.75; H, 5.50; N, 5.18. For 6c; Colorless crystal ,
m.p. = 193-194 °C; 1H NMR (CDCl3, 500 MHz) δ 11.03 (brs, 1H),
8.17-8.13 (m, 1H), 7.80-7.77 (m, 1H), 7.40-7.35 (m, 2H), 4.56-
4.52 (q, 2H, J = 7.1 Hz), 1.52-1.49 (t, 3H, J = 7.1 Hz); 13C NMR
(CDCl3, 125 MHz) δ 161.6, 131.1, 126.6, 126.1, 125.7, 121.7,
119.2, 117.2, 113.2, 97.0, 62.3, 14.6; MS (EI) m/z 214 [M+];
Anal. calcd for C14H14N2O2: C, 67.28; H, 4.71; N, 13.08. Found:
C, 67.06; H, 4.53; N, 13.01. For 6d; Colorless crystal, m.p. = 163-
165 °C; 1H NMR (CDCl3, 500 MHz) δ 11.29 (brs, 1H), 10.14 (s,
1H), 8.19-8.18 (d, 1H), 8.08-8.07 (d, 1H), 7.44-7.36 (m, 2H),
4.54-4.49 (q, 2H, J = 7.1 Hz), 1.50-1.47 (t, 3H, J = 7.3 Hz); 13C
NMR (CDCl3, 125 MHz) δ 178.1, 161.6, 129.9, 127.7, 127.6,
126.9, 124.8, 122.5, 119.7, 119.2, 62.2, 15.0; MS (ESI-TOF) m/z
218 [M+H]+; Anal. calcd for C12H11NO3: C, 66.35; H, 5.10; N,
6.45. Found: C, 66.07; H, 5.07; N, 6.04. For 6e; Colorless oil, 1H
NMR (CDCl3, 500 MHz) δ 8.14-8.11 (m, 1H), 7.60-7.58 (m, 1H),
7.40 (s, 1H), 7.31-7.23 (m, 4H), 7.15-7.13 (m, 2H), 7.10-7.07 (m,
1H), 5.91 (s,2H), 4.40-4.36 (q, 2H, J = 7.0 Hz), 1.44-1.41 (t, 3H, J
= 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 162.1, 138.6, 137.7,
129.1, 128.7, 128.1, 128.0, 127.9, 127.5, 125.7, 122.5, 121.6,
120.6, 60.1, 54.1, 14.9; MS (ESI-TOF) m/z 280 [M+H]+; HRMS
(ESI-TOF) m/z calcd for C18H18NO2 [M+H]+: 280.1332. Found:
280.1146. For Diels-Alder adduct 7; Colorless crystal, m.p. >250
°C; 1H NMR (CDCl3, 500 MHz) δ 7.50-7.47 (m, 2H), 7.45-7.42
(m, 2H), 7.40-7.38 (m,2H), 7.23-7.21 (m, 2H), 7.14-7.14 (m, 2H),
7.05-7.04 (m, 2H), 7.05-7.04 (m, 2H), 7.00-6.99 (m, 2H), 5.48 (s,
2H), 3.05 (s, 2H), 2.30 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
174.2, 143.7, 141.9, 135.0, 131.6, 129.3, 129.33, 129.29, 129.1,
127.8, 127.7, 126.4, 121.1, 66.3, 49.5, 21.5; MS (EI) m/z 444
[M+]; Anal. calcd for C25H20N2O4S: C, 67.55; H, 4.54; N, 6.30.
Found: C, 67.34; H, 4.35; N, 6.32. For 8; Colorless crystal, mp
149-151 °C; 1H NMR (CDCl3, 500 MHz) δ 10.33 (brs, 1H), 8.10-
8.09 (d, 1H), 7.74-7.72 (m, 1H), 7.32-7.30 (m, 1H), 7.20-7.16 (m,
1H), 7.01 (s, 4H), 4.47-4.43 (q, 2H, J = 7.1 Hz), 2.26 (s, 3H),
1.47-1.44 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ
136.6, 132.5, 130.1, 129.6, 128.0, 125.9, 123.6, 121.1, 120.2,
114.2, 60.6, 20.9, 14.6; MS (EI) m/z 311 [M+]; Anal. calcd for
C18H17NO2S: C, 69.43; H, 5.50; N, 4.50. Found: C, 69.33; H, 5.39;
10. Uno, H.; Ito, S.; Wada, M.; Watanabe, H.; Nagai, M.; Hayashi, A.;
Murashima, T.; Ono, N., J. Chem. Soc., Perkin Trans. 1, 2000,
4347-4355.
11. Charles, A. E., Nature, 1996, 383, 313.
12. Brennecke, J. F.; Chateauneuf, J. E., Chem. Rev., 1999, 99, 433;
Licence, P.; Ke, J.; Sokolova, M.; Ross, S. K.; Poliakoff, M.,
Green Chem. 2003, 5, 99.
13. Ito, S.; Murashima, T.; Ono, N., J. Chem. Soc., Perkin Trans. 1,
1997, 3161; Okujima, T.; Hashimoto, Y.; Jin, G.; Yamada, H.;
Uno, H.; Ono, N., Tetrahedron, 2008, 64, 2405.
14. Sato, T.; Ito, S.; Yajima, Y.; Itoh, N., J. Supercritical Fluids,
2009, 51, 217.
15. Solé, D.; Serrano, O., Org. Biomol. Chem., 2009, 7, 3382.
16. In the case of the experiment with ethylene, 0.1 MPa of ethylene
gas was introduced to the reactor through the other introduction
port before the introduction of CO2.
17. Selected experimental data for bicyclopyrrole 2a; Colorless
crystal: m.p. = 145-148 °C; 1H-NMR (CDCl3, 500 MHz): δ = 9.00
(brs, 1H), 6.51-6.45 (m, 2H), 4.36-4.31 (m, 1H, q, 2H, J = 7.1 Hz),
3.80 (m, 1H), 1.59-1.43 (m, 4H), 1.39-1.36 (t, 3H, J = 7.05 Hz);
13C-NMR (CDCl3, 125 MHz): δ = 161.1, 137.7, 135.7, 135.1,
130.7, 115.2, 95.8, 60.3, 34.0, 32.6, 26.4, 26.1, 14.5; Anal. calcd
for C13H14BrNO2: C, 52.72; H, 4.76; N, 4.73. Found: C, 52.57; H,
4.75; N, 4.71. For 2b; Colorless crystal, m.p. = 147-150 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.50 (brs, 1H), 7.51 (d, 2H), 7.42 (d,
2H), 7.28 (t, 1H), 6.54 (d, 2H), 4.41 (s, 1H), 4.33 (q, 2H, J = 7.1
Hz), 4.20 (s, 1H), 1.62-1.53 (m, 4H), 1.39 (t, 3H, J = 7.1 Hz); 13
C
NMR (CDCl3, 125 MHz) δ 161.9, 138.2, 136.1, 135.5, 132.2,
129.1, 128.9, 127.4, 126.3, 114.0, 60.1, 33.9, 33.5, 26.9, 26.4,
14.7; MS (FAB+) m/z 294 [M++1]; Anal. calcd for C19H19NO2: C,
77.79; H, 6.53; N, 4.77. Found: C, 77.69; H, 6.56; N, 4.69. For 2c;
Colorless crystal, m.p. = 127-129 °C; 1H NMR (CDCl3, 500 MHz)
δ 9.94 (brs, 1H), 6.51-6.46 (m, 2H), 4.44-4.37 (q, 2H, J = 7.1 Hz),
4.37 (s, 1H), 4.08 (s, 1H), 1.61-1.59 (d, 2H), 1.47-1.45 (d, 2H),
1.44-1.41 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ
161.1, 141.1, 136.0, 135.6, 134.9, 118.2, 113.1, 96.3, 61.5, 33.7,
33.1, 26.3, 26.0, 14.5; MS (FAB+) m/z 243 [M++1]; Anal. calcd
for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.26; H,
5.71; N, 11.47. For 2d; Colorless crystal, m.p. = 113-115 °C; 1H
NMR (CDCl3, 500 MHz) δ 9.74 (s, 1H), 9.10 (s, 1H), 6.57-6.49
(m, 2H), 4.42 (s, 1H), 4.39-4.34 (q, 2H, J = 7.1 Hz), 4.28 (s, 1H),
1.67-1.60 (d, 2H), 1.51-1.49 (d, 2H), 1.41-1.49 (t, 3H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) δ178.6, 161.1, 141.1, 136.9, 136.0,
134.7, 125.2, 119.4, 61.1, 33.4, 32.7, 26.5, 26.1, 14.5; MS (FAB+)
m/z 246 [M++1]; Anal. calcd for C14H15NO3: C, 68.56; H, 6.16; N,
5.71. Found: C, 68.66; H, 6.09; N, 5.72. For 2e; Colorless crystal,
m.p. = 78-82 °C; 1H NMR (CDCl3, 500 MHz) δ 8.23-8.21 (m,
2H), 7.31 (m, 2H), 7.26-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.00-
6.97 (m, 2H), 6.59 (s, 2H), 4.43-4.39 (q, 4H, J = 7.1 Hz), 1.44-
1.41 (t, 6H, J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) δ 161.2,
138.2, 128.4, 127.9, 126.9, 126.0, 125.5, 121.7, 118.3, 60.8, 50.6,
14.3; MS (ESI-TOF) m/z 352 [M+H]+; HRMS (ESI-TOF) m/z
calcd for C21H22NO4 [M+H]+: 352.1543. Found: 352.1542. For 2f;
Colorless crystal, m.p. = 127-129 °C; 1H NMR (CDCl3, 500 MHz)
δ 7.84 (m, 2H), 7.29-7.27 (m,1H), 7.28 (m, 2H), 6.48-6.45 (m,
1H), 6.42-6.39 (m, 1H), 4.25 (m, 1H), 4.24-4.19 (m, 2H), 3.83 (m,
1H), 2.40 (s, 3H), 1.57-1.47 (m, 4H), 1.30-1.28 (t, 3H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) δ 159.6, 144.2, 143.9, 136.9, 134.5,
131.1, 129.3, 127.8, 118.3, 116.4, 60.4, 33.9, 26.4, 25.5, 21.7,
14.3; MS (ESI-TOF) m/z 372 [M+H]+; Anal. calcd for
C21H20NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.46; H, 5.68;
N, 3.82. For 4; Colorless crystal, m.p. = 146-148 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.67 (d, 2H), 7.23 (d, 2H), 6.75 (s, 2H), 6.38-
6.35 (m, 2H), 3.71 (m, 2H), 2.36 (s, 3H), 1.52-1.42 (m, 4H); 13C
1
N, 4.52. For 9; Gray crystal, m.p. = 118-120 °C; H NMR (CDCl3,
500 MHz) δ 10.91 (brs, 1H), 8.15-8.12 (m, 2H), 7.33-7.30 (m,
2H), 4.51-4.46 (q, 4H, J = 7.1 Hz), 1.49-1.46 (t, 6H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) δ 160.8, 127.0, 125.7, 121.3, 115.9,
61.1, 14.5; MS (ESI-TOF) m/z 262 [M+H]+; Anal. calcd for
C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.60; H, 5.86;
N, 5.30.
19. All measurements were made on a Bruker SMART-APEX II CCD
plate detector with graphite monochromated Mo-Kα radiation.
The data were collected at a temperature of −173 °C and
processed using the APEX II programs from Bruker.
20. Shelx-2013: Program for the refinement of crystal structures from
diffraction data, University of Göttingen, Göttingen, Germany;
"Crystal structure refinement with SHELXL". M. G. Sheldrick,
Acta
org/10.1107/S2053229614024218.
Cryst.,
2015,
C71,
3–15,
DOI:
21. CCDC 1526462 (2a), CCDC 1526461 (2f), CCDC 1526460 (4),
CCDC 1526456 (5), CCDC 1526455 (7), CCDC 1526454 (8), and
CCDC 1526453 (9) contain the crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data centre via
www.ccdc.cam.ac.uk/data_request/cif.

5
Click here to remove instruction text...
Highlighits
Bicyclopyrroles were efficiently converted to the corresponding isoindoles by a retro
Diels-Alder reaction in supercritical carbon dioxide.
By adding ethylene gas as an oxygen scavenger, the isoindole yield was further
improved.
This synthesis method provides a new methodology for the synthesis of isoindole
derivatives.