1-Aminoisoindole as a useful π-system elongation unit

Article abstract of DOI:10.1016/j.tet.2009.03.072

Nitration of 4,7-ethanoisoindoles gave 1-nitro derivatives in moderate yields. Reduction of a nitro to amino group was successfully performed by sodium hydrosulfite in the case of ethyl 3-nitro-4,7-ethanoisoindole-1-carboxylate. The amino derivative was c

Full text of DOI:10.1016/j.tet.2009.03.072

Tetrahedron 65 (2009) 4345–4350
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1-Aminoisoindole as a useful
p
-system elongation unit
,
,
*
Taiji Akiyama a, Hiroki Uoyama b, Tetsuo Okujima a, Hiroko Yamada a c, Noboru Ono a, Hidemitsu Uno b
a Department of Chemistry and Biology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
b Division of Synthesis and Analysis, Department of Molecular Science, Integrated Center for Sciences, Ehime University, Matsuyama 790-8577, Japan
c PRESTO, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2009
Received in revised form 21 March 2009
Accepted 24 March 2009
Available online 1 April 2009
Nitration of 4,7-ethanoisoindoles gave 1-nitro derivatives in moderate yields. Reduction of a nitro to
amino group was successfully performed by sodium hydrosulfite in the case of ethyl 3-nitro-4,7-etha-
noisoindole-1-carboxylate. The amino derivative was converted to benzylidenaminoisoindoles based on
the retro Diels–Alder reaction. Their UV–vis spectra showed strong absorptions at 500–700 nm.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Phthalocyanine is one of the most common and important
pigments in our life and consists of four units of a 1-aminoisoindole
moiety. Two of them adopt a 1-amino-2H-isoindole structure and
others are 1-iminoisoindolenine (1-imino-1H-isoindole). In gen-
eral, the isoindole moiety can effectively expand its connecting
2.1. Preparation of arylidenaminoisoindole precursors
Ethyl 4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (1)
and 4,7-ethano-2H-isoindole (2) were prepared according to the
literature.6 We first attempted to prepare a 1-amino 3-bromo de-
p
-system compared with 1H-indole, because the
p
-system of iso-
rivative, which might be a useful building block for bicy-
indole is fully delocalized over the whole molecule.1 The isoindole
skeleton itself, however, is rarely found in pigments and dyes except
clo[2.2.2]octadiene-fused porphyrazine. Ethanoisoindole 2 was
nitrated with concd HNO3 in acetic anhydride to give 1-nitro-4,7-
dihydro-4,7-ethano-2H-isoindole (5) in 54% yield (Scheme 1). In
trifluoroacetic anhydride, concomitant trifluoroacetylation with
nitration occurred to give a 1-nitro 3-trifluoroacetyl derivative in
43% yield. Bromination of nitro derivative 5 with NBS gave 1-bromo-
4,7-ethano-3-nitro-2H-isoindole (6) in a 59% yield. Reduction of the
nitro group of 6 was attempted under several conditions by using
Na2S2O4 and LiAlH4. None of identifiable compounds was, however,
obtained probably due to very unstable nature of a 2-aminopyrrole
derivative under air.1 Since 2-aminopyrroles were successfully
prepared if they had electron-withdrawing groups,7 the starting
compound was changed to ester 1, reactivity of which was reduced
by the electron-withdrawing ester group. As an intractable mixture
was obtained in the conventional nitration of 1 using mixed acids
(HNO3, H2SO4), the milder nitration conditions were employed.
Thus, nitration of pyrrolecarboxylate ester 1 was carried out under
the similar conditions (HNO3, Ac2O, ꢀ10 ꢁC) as used in the nitration
of 2 to give nitropyrrolecarboxylate 3 in only a 16% yield. Reduction
of the nitro group in 3 was achieved by using Na2S2O4 to give ami-
nopyrrole 4. Isolation of the targeted compound 4 was rather diffi-
cult due to its intrinsic instability toward oxidation under air. Thus,
the isolated yield of 4 by column chromatography was low (10%),
although no obvious by-product formation was detected in the re-
action mixture. Therefore, the amino compound was used in the
next reaction without purification.
that the skeleton is implanted in other
p-ring system. The main
reasons are paucity of synthetic methods of isoindole derivatives
and their instability mainly due to easy tautomerism between
highly electron-rich 2H-isoindole and electrophilic isoindolenine
structures.2 Preparation of 2H-isoindole derivatives with electron-
donating substituents is extremely difficult, because such sub-
stituents as methoxy groups at
a positions of isoindole prompted to
shift the equilibrium exclusively to the isoindolenine structure.3 1-
Hydroxy-2H-isoindole and 1-amino-2H-isoindole without an N-
substituent usually existed as their keto and imino forms. Therefore,
no synthetic application using these compounds was so far repor-
ted. During our continuous studies for the preparation and appli-
cation of p
-expanded porphyrins and their analogues,4 we planned
to introduce an amino group into a bicyclo[2.2.2]octadiene-fused
(BCOD-fused) pyrrole derivative in order to prepare soluble pre-
cursors of phthalocyanine5 and meso-azatetrabenzoporphyrins. In
this paper, we will describe preparation of a 1-amino-4,7-ethano-
2H-isoindole derivative as the 1-aminoisoindole equivalent and its
conversion to arylmethylidenaminoisoindoles.
* Corresponding author. Tel.: þ81 89 927 9610; fax: þ81 89 927 9590.
E-mail address: uno@dpc.ehime-u.ac.jp (H. Uno).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.072

4346
T. Akiyama et al. / Tetrahedron 65 (2009) 4345–4350
R
CO2Et
CO2Et
iii)
CO2Et
NH
ii)
vi-viii)
NH
NH
NH
NH2
3
1: R = CO2Et
2: R = H
4
NO2
i)
N
R
iv)
v)
7a: R = Ph
7b: R = C6H4-p-CN
7c: R = C6H4-p-NO2
x)
ix)
NO2
NH
5
H
N
H
N
H
N
N
N
CO2Et
EtO2C
NO2
NH
EtO2C
N
N
CO2Et
N
H
N
H
8
9
6
Br
Scheme 1. Reagents, conditions, and yields: (i) KOH, ethylene glycol, 175 ꢁC, 81%; (ii) HNO3, Ac2O, ꢀ10 ꢁC, 16%; (iii) Na2S2O4, aq EtOH, 40 ꢁC, 10%; (iv) HNO3, Ac2O, ꢀ10 ꢁC, 54%; (v)
NBS, DMF/CH2Cl2, ꢀ10 ꢁC, 59%; (vi) PhCHO, toluene, 120 ꢁC, 19% (from 3); (vii) p-NCC6H4CHO, toluene, 120 ꢁC (from 3), 38%; (viii) p-O2NC6H4CHO, toluene, 120 ꢁC, 35% (from 3); (ix)
p-C6H4(CHO)2, toluene, 120 ꢁC, 29% (from 3); (x) 4,7-ethano-2H-isoindole-1,3-dicarbaldehyde, toluene, 120 ꢁC, 64% (from 3).
In order to extend the chromophore of 4, the amino group of 4
was transformed into an imino group. The crude aminopyrrole 4
was reacted with aromatic aldehydes to give imino derivatives 7 in
moderate yields. These imino compounds were considered as good
precursors giving the targeted 1-benzylidenaminoisoindole de-
rivatives by heat treatment. Amino derivative 4 also reacted with
aromatic dialdehydes such as p-phthalaldehyde and 4,7-dihydro-
4,7-ethano-2H-isoindole-1,3-dicarbaldehyde6a to give bis-imino
derivatives 8 and 9 in respective yields of 29 and 64%.
hydrogen bonds (Fig. 1; N–H/O: N/O distance, 2.927(3) Å; N–H,
0.826 Å; H/O, 2.156 Å; :N–H/O, 155.1ꢁ). The dimeric pairs were
stacked at the nitro group by the static electronic attraction be-
tween positively charged nitrogen and negatively charged oxygen
atoms (3.010(2) Å). Contrarily to 3, a zigzag cyclic tetrameric motif
was observed in the crystal structure of 6 (Fig. 2). The hydrogen-
bonding angle of :N–H/O was 127.1ꢁ and the N/O distance was
2.970(4) Å.
Molecular compositions of BCOD-fused benzylidenamino-
pyrroles 7, 8, and 9 were determined by combustion analysis. One-
eighth to half water molecule per a pyrrole molecule was contained
in the samples of 7 and 8 and one toluene molecule was included in
the sample of 9. Thermal behavior of BCOD-fused benzylidenami-
nopyrroles was then examined by thermogravimetric (TG) analysis
(10 ꢁC/min) and the results are summarized in Table 1.
2.2. Thermal behavior of BCOD-fused
arylmethylidenaminopyrroles
Before examination of the thermal conversion of BCOD-fused
compounds, X-ray crystallographic analysis was tried because we
often experienced co-crystallization of BCOD-fused compounds
with solvent molecules. Unfortunately, no suitable single crystal of
BCOD-fused benzylidenaminopyrrole 7, 8, or 9 was obtained, al-
though X-ray analysis was successfully done in two of BCOD-fused
nitro compounds 3 and 6.8 Hydrogen-bonding network of these
crystal structures were worthy to note (Figs.1 and 2). In both crystal
structures, mean planes of five pyrroles and three nitro atoms were
almost coplanar: 8.04(6)ꢁ for 3 and 3.07(10)ꢁ for 6. In the case of 3,
the pyrrole and carboxyl planes were also coplanar (2.39(7)ꢁ) and
this pyrrole-2-carboxylate moiety formed a planar dimer by two
In all cases except for 9, extrusion of ethylene from the BCOD
moiety started around 170 ꢁC with concomitant loss of water. In
the case of 9, co-solvent toluene was first lost during two tem-
perature ranges (114–151 and 151–180 ꢁC) and then ethylene was
Figure 1. Ortep drawing of two pairs of dimeric hydrogen-bonding molecules 3. N/
O]C distance, 2.927(3) Å; :N–H/O angle, 155.1ꢁ.
Figure 2. Ortep drawing of four hydrogen-bonding molecules of 6. Dihedral angle of
pyrrole mean planes, 106.29(15)ꢁ; N/O distance, 2.970(4) Å; :N–H/O angle, 127.1ꢁ.

T. Akiyama et al. / Tetrahedron 65 (2009) 4345–4350
4347
Table 1
Thermal behavior of BCOD-fused arylmethylidenaminopyrroles
Samplea
Decomp./ꢁC
Weight loss
Assignment
Start
167
End
275d
Obsdb/%
31.5
Calcdc/%
33.1
7a$1/2H2O
7b$1/8H2O
2CH2]CH2, CO2, 1/2H2O
171
252e
328d
13.5
31.8(18.3)
8.7
28.4(20.7)
CH2]CH2, 1/8H2O
CH2]CH2, CO2
252e
7c$1/4H2O
8$1/4H2O
170
245
245
8.5
29.7(21.2)
8.8
28.3(19.5)
CH2]CH2, 1/4H2O
CH2]CH2, CO2
289d
170
281
248
320e
410d
10.9
24.5(12.5)
36.6(12.1)
10.7
23.4(12.7)
36.1(12.7)
2CH2]CH2, 1/4H2O
CH2]CH2, CO2
CH2]CH2, CO2
320e
9$C7H8
114
151e
180e
255e
151e
180e
255e
318d
6.4
6.4
1/2C7H8
1/2C7H8
3CH2]CH2, CO2
CH2]CH2, CO2
12.4(6.0)
32.2(19.8)
42.3(10.1)
12.8(6.4)
30.6(17.8)
40.6(10.0)
a
The sample composition was determined by combustion analysis.
Percentage of weight loss was calculated from the initial weight and the ob-
b
served weight at the end temperature. Numerals in parentheses were percentage of
weight loss during the start and end temperatures versus the initial weight.
Figure 3. UV–vis spectra of BCOD-fused pyrroles in CHCl3.
c
Calculated percentage of weight loss was based on the assignment molecules.
d
Slow weight loss continued after the end temperature probably due to de-
2.3. UV–vis measurement of BCOD-fused pyrroles
and isoindoles
composition of the isoindole moiety.
e
The start and end temperatures were determined by differential TG diagram.
UV–vis spectra of the BCOD-fused pyrroles and the corre-
sponding isoindoles were measured in CHCl3 and are shown in
Figures 3 and 4. From Figure 3, broad absorption bands of mono-
benzylidenaminopyrroles 7a–c in the visible region showed
extruded. Decomposition of the ester group of 7a occurred al-
most simultaneously with loss of ethylene from the BCOD moiety,
while the ester group of 7c and 8 started to decompose com-
pletely after the extrusion of ethylene. In the TG curves of 7b and
9, there was no obvious rate change during the weight-losing
temperature ranges. These decomposition temperatures, how-
ever, could be obviously distinguished by differential TG data.
From these TG data, we concluded that extrusion of ethylene
from the BCOD-fused moiety was hardly affected by the sub-
stituent at the pyrrole ring and the starting temperature was
around 170 ꢁC as previously reported.9 On the other hand, de-
composition temperature of the ester group was quite sensitive
to the electronic structure of the pyrrole ring. The more electron-
withdrawing the substituent at
a-position was, the higher the
decomposition temperature became.
Bulk conversion of BCOD-fused pyrroles 7c, 8, and 9 were suc-
cessfully performed at 230, 240, and 220 ꢁC under a reduced
pressure (ca. 0.05 mmHg) for 30 min. Benzylidenaminoisoindoles
10c, 11, and 12 were obtained in quantitative yields (Chart 1). In the
thermal treatment of 7a and 7b, however, we failed to obtain pure
samples of 10a and 10b probably due to the partial decomposition
of ester group mentioned above, partial sublimation, and oxidative
decomposition.
H
R
N
EtO2C
N
CO2Et
N
N
CO2Et
N
H
N
H
10a: R = Ph
11
10b: R = C6H4-p-CN
10c: R = C6H4-p-NO2
H
H
N
N
EtO2C
N
N
CO2Et
N
H
12
Chart 1. Arylmethylidenaminoisoindoles.
Figure 4. UV–vis spectra of BCOD-fused pyrroles and the corresponding isoindoles in
CHCl3: (a) spectra of 7c and 10c; (b) spectra of 8 and 11; and (c) spectra of 9 and 12.

4348
T. Akiyama et al. / Tetrahedron 65 (2009) 4345–4350
a sequential bathochromic shift corresponding to electron-with-
drawing nature of the p-substituents on aryl groups (7a: 375 nm,
7b: 397 nm, and 7c: 427 nm) and their molecular extinction co-
efficients were almost similar. This is well understood by consid-
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was chromatographed on silica gel (CH2Cl2) to give 1.18 g (16%) of
the title compound as pale yellow crystals: mp 150–151 ꢁC; 1H NMR
(CDCl3, 400 MHz)
2H, J¼7.1 Hz), 4.41 (m, 1H), 4.58 (m, 1H), 6.47–6.56 (m, 2H), 9.37 (br,
1H); 13C NMR (CDCl3, 100 MHz)
14.23, 25.44, 25.62, 33.04, 33.38,
d
1.42 (t, 3H, J¼7.1 Hz), 1.47–1.66 (m, 4H), 4.40 (q,
ering strong electron-donating nature of
a-aminopyrrole. In the
spectrum of p-xylene-
a
,a
0-bis(ylidenaminopyrrole) 8, the molecu-
d
lar extinction coefficients of the absorption bands were nearly
doubled compared to the mono-benzylidenaminopyrroles and the
absorption maxima (281 and 442 nm) are similar to that of 7c. A
further bathochromic shift and obvious splitting (456, 484, and
519 nm) were observed in the spectrum of pyrrole-2,5-bis(methy-
lidenaminopyrrole) 9.
In Figure 4, spectra of isoindoles are shown with the corre-
sponding BCOD-fused pyrroles. Conversion of BCOD-fused pyrrole
to isoindole (Fig. 4a, 7c to 10c) brought about 65 nm bathochromic
shift. In the cases of 8 to 11 and 9 to 12, larger bathochromic shifts
61.48, 115.88, 130.65, 131.90, 134.41, 135.34, 136.89, 160.44; IR (KBr)
nmax 3273 (NH), 1693, 1588, 1520, 1364, 1307, 1293, 1242 cmꢀ1; MS
(EI) 262 (Mþ, 3%), 235 (12), 234 (100), 206 (10). Anal. Calcd for
C13H14N2O4þ1/8H2O: C, 59.03; H, 5.43; N, 10.59%. Found: C, 58.87;
H, 5.27; N, 10.51%. The single crystals were obtained by slow vapor
diffusion of methanol into a solution of 3 in CHCl3. Crystal formula,
C13H14N2O4, 0.30ꢂ0.25ꢂ0.20 mm, triclinic, space group P-1,
a¼7.7064(8), b¼8.4775(6), c¼11.1885(12) Å,
a
¼69.979(12)ꢁ,
b
¼75.454(13)ꢁ,
g
¼67.811(12)ꢁ, V¼629.65(12) Å3, Mo K
, T¼296 K,
a
Z¼2, rcalcd¼1.383 g cmꢀ3
,
m
¼0.104 mmꢀ1
,
F(000)¼276. 11,480
were recorded corresponding to the multiple
p-system expansion
measured, 2874 unique, 2146 observed [I>2s
[I>2
(I)]; R1¼0.0625
of pyrrole to isoindole. Especially, the absorption end of 12 excee-
ded the visible range and reached to 1000 nm. These isoindole dyes
were stable under air and no special precaution was needed al-
though slow decomposition was observed in protic solvents.
In conclusion, ethyl 1-amino-4,7-dihydro-4,7-ethano-iso-
indolecarboxylate (4) as a 1-aminoisoindole equivalent was pre-
pared and was derivatized to benzylidenamino compounds, which
were converted to benzylidenaminoisoindoles by the retro-Diels–
Alder reaction. The isoindole moiety was shown to be a good
s
(I)], wR2¼0.1997 (all); GOF¼1.094. CCDC no. 721549.
3.3. Ethyl 3-amino-4,7-dihydro-4,7-ethano-2H-isoindole-1-
carboxylate (4)
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 50 mg,
0.191 mmol) in 60% aq EtOH (10 mL) was added Na2S2O4 (143 mg,
0.82 mmol) at room temperature. After being stirred at 40 ꢁC for
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The res-
idue was chromatographed on silica gel (CH2Cl2/EtOAc¼2/1) to give
4.4 mg (10%) of the title compound as a brown oil. This compound
was very labile. Therefore, no satisfactory analytical data were
p-elongating moiety. In the case of isoindole-1,3-bis(methyliden-
aminoisoindole) 12, the absorption end went beyond the visible
region.
3. Experimental
3.1. General
obtained. 1H NMR (CDCl3, 400 MHz)
d
1.35 (t, 3H, J¼7.1 Hz), 1.44–
1.55 (m, 4H), 3.64 (br, 2H), 3.73 (m, 1H), 4.25 (q, 2H, J¼7.1 Hz), 4.28
(m, 1H), 6.43–6.50 (m, 2H), 8.72 (br, 1H).
Melting points were measured on a Yanagimoto micromelting
point apparatus and are uncorrected. NMR spectra were obtained
with a JEOL AL-300, JEOL AL-400 or EX-400 spectrometer at ambient
temperature. IR spectra were measured with a Horiba FT-720 in-
frared spectrophotometer. EI and FAB spectra were measured with
a JEOL JMS-700. The MALDI-TOF MS spectrum was measured with
a Voyager DE Pro instrument. Elemental analyses were performed
with a Yanaco MT-5 elemental analyzer. UV–vis spectra were mea-
sured with a HITACHI U-2810 spectrophotometer. All solvents and
chemicals were reagent grade quality, obtained commercially, and
used without further purification except as noted. Dry dichloro-
methane and THF were purchased from Kanto Chemical Co. Toluene,
triethylamine, and pyridine were distilled from calcium hydride and
then stored on appropriate Molecular Sieves 4 Å. Solvents for chro-
matography were purified by distillation. For spectral measure-
ments, spectral grades of chloroform were purchased from Nacalai
Tesque Co. Thin-layer (TLC) and column chromatography were per-
formed on Art. 5554 (Merck KGaA) and Silica Gel 60N (Kanto
Chemical Co.), respectively. Ethyl 4,7-dihydro-4,7-ethano-2H-iso-
indole-1-carboxylate (1),6 4,7-dihydro-4,7-ethano-2H-isoindole
(2),6 and 4,7-dihydro-4,7-ethano-2H-isoindole-1,3-dicarbaldehyde6a
were prepared according to the literature procedures.
3.4. 1-Nitro-4,7-dihydro-4,7-ethano-2H-isoindole (5)
To a stirred solution of ethanoisoindole (2; 4.00 g, 27.5 mmol) in
Ac2O (500 mL) was added slowly concd HNO3 (1.93 mL) at ꢀ10 ꢁC
under argon and the mixture was stirred for 7 h. The mixture was
poured into ice-water. The mixture was extracted with CH2Cl2. The
organic extract was successively washed with a satd NaHCO3 solu-
tion, water, and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was chromatographed on silica gel (CH2Cl2) to give
2.85 g (54%) of the title compound as pale yellow crystals: mp 108–
109 ꢁC; 1H NMR (CDCl3, 400 MHz)
4.56 (m, 1H), 6.42–6.51 (m, 2H), 6.64 (d, 1H, J¼2.9 Hz), 9.45 (br, 1H);
13C NMR (CDCl3,100 MHz)
25.42, 26.17, 33.09, 33.20,114.50,129.84,
d 1.38–1.61 (m, 4H), 3.90 (m, 1H),
d
132.54, 133.24, 133.89, 135.84; IR (KBr) nmax 3386 (NH), 2955, 1586,
1363, 1092, 915, 846, 816, 680, 612 cmꢀ1; MS (EI) 190 (Mþ, 41%),162
(100),132 (83),116 (63), 89 (73). Anal. Calcd for C10H10N2O2: C, 63.15;
H, 5.30; N, 14.73%. Found: C, 63.06; H, 5.28; N, 14.77%.
3.5. 1-Bromo-3-nitro-4,7-dihydro-4,7-ethano-2H-
isoindole (6)
To
a stirred solution of the nitro compound (5; 1.00 g,
3.2. Ethyl 3-nitro-4,7-dihydro-4,7-ethano-2H-isoindole-1-
carboxylate (3)
5.26 mmol) in DMF (100 mL) was added NBS (0.936 g, 5.26 mmol)
at ꢀ10 ꢁC and the mixture was stirred for 30 min. After the mixture
was warmed up to 5 ꢁC, additional NBS (240 mg, 1.35 mmol) was
added. After 3 h, the mixture was poured into ice-water. The mix-
ture was extracted with CH2Cl2. The organic extract was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was successively chromatographed on silica gel (CH2Cl2)
and alumina (EtOAc) to give 830 mg (59%) of the title compound as
pale yellow crystals: mp>158 ꢁC (decomp.); 1H NMR (CDCl3,
To a stirred solution of ethyl pyrrolecarboxylate (1; 6.00 g,
27.6 mmol) in Ac2O (750 mL) was slowly added concd HNO3
(3.82 mL) at ꢀ10 ꢁC under argon and the mixture was stirred for
1 h. After being stirred overnight, the mixture was poured into ice-
water. The mixture was extracted with CH2Cl2. The organic extract
was successively washed with a satd NaHCO3 solution, water, and

T. Akiyama et al. / Tetrahedron 65 (2009) 4345–4350
4349
400 MHz)
d
1.41–1.64 (m, 4H), 3.85 (m, 1H), 4.58 (m, 1H), 6.44–6.53
25.30, 25.71,
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. To the
residue was added a solution of 4-cyanobenzaldehyde (91.8 mg,
0.7 mmol) in toluene (40 mL) and then the mixture was stirred at
120 ꢁC overnight. When the mixture was cooled to room temper-
ature, orange precipitates were formed. Filtration gave 100 mg
(38%) of the title compounds as orange crystals: mp>210 ꢁC
(m, 2H), 9.21 (br, 1H); 13C NMR (CDCl3, 100 MHz)
d
32.51, 33.52, 98.21, 130.26, 132.60, 133.91, 134.01, 135.44; IR (KBr)
nmax 3291 (NH), 2960,1588,1372,1063, 851, 746, 694, 558 cmꢀ1; MS
(EI) 270 (Mþþ1, 15%), 268 (15), 242 (99), 240 (100), 169 (11), 167
(11), 130 (43). Anal. Calcd for C10H9BrN2O2: C, 44.63; H, 3.37; N,
10.41%. Found: C, 44.57; H, 3.62; N, 10.43%. The single crystals were
obtained by slow vapor diffusion of methanol into a solution of 6 in
CHCl3. Crystal formula, C10H9BrN2O2, 0.30ꢂ0.20ꢂ0.20 mm, tetra-
gonal, space group I41/a, a¼19.359(3), b¼19.359(3), c¼10.845(2) Å,
(decomp.); 1H NMR (CDCl3, 400 MHz)
d
1.39 (t, 3H, J¼7.1 Hz), 1.52–
1.66 (m, 4H), 4.22 (m, 1H), 4.34 (q, 2H, J¼7.1 Hz), 4.40 (m, 1H), 6.54
V¼4064.4(12) Å3, Mo
Ka
,
T¼296 K, Z¼16, rcalcd¼1.759 g cmꢀ3
,
(m, 2H), 7.72 (m, 2H), 7.94 (m, 2H), 8.54 (br, 1H), 8.64 (s, 1H); 13C
m
¼4.025 mmꢀ1, F(000)¼2144. 10,465 measured, 2281 unique, 1838
NMR (CDCl3, 100 MHz) d 14.51, 26.03, 26.59, 33.37, 33.61, 60.25,
observed [I>2
s
(I)]; R1¼0.0471 [I>2
s
(I)], wR2¼0.1265 (all);
112.72, 113.76, 118.55, 124.27, 128.36, 132.48, 133.33, 135.30, 135.46,
138.22, 140.35, 153.14, 161.50; IR (KBr) nmax 3309 (NH), 2224, 1666,
1455, 1372, 1346, 1250, 1145, 551 cmꢀ1; UV–vis (CHCl3): lmax/nm
(log10 3): 397 (4.41), 280 (4.23); MS (EI) 345 (Mþ, 23%), 318 (22), 317
(100), 271 (33), 244 (19), 243 (84), 115 (21). Anal. Calcd for
C21H19N3O2þ1/8H2O: C, 72.55; H, 5.58; N, 12.09%. Found: C, 72.58;
H, 5.64; N, 11.88%.
GOF¼1.168. CCDC no. 721548.
3.6. 1-Nitro-3-trifluoroacetyl-4,7-dihydro-4,7-ethano-2H-
isoindole
To a stirred solution of ethyl pyrrolecarboxylate (1; 73 mg,
0.50 mmol) in trifluoroacetic anhydride (10 mL) was added slowly
concd HNO3 (0.035 mL) at ꢀ10 ꢁC under argon and the mixture was
stirred for 1 h. After being stirred for 1 h, the mixture was poured
into ice-water. The mixture was extracted with CH2Cl2. The organic
extract was successively washed with a satd NaHCO3 solution,
water, and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on silica gel (CH2Cl2) to give 61.5 mg
(43%) of the title compound as pale yellow crystals: mp 111–114 ꢁC;
3.9. Ethyl 3-p-nitrobenzylidenamino-4,7-dihydro-4,7-ethano-
2H-isoindole-1-carboxylate (7c)
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 400 mg,
1.53 mmol) in 60% aq EtOH (56 mL) was added Na2S2O4 (1.06 g,
6.09 mmol) at room temperature. After being stirred at 40 ꢁC for
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. To the
residue was added a solution of 4-nitrobenzaldehyde (211 mg,
1.40 mmol) in toluene (80 mL) and then the mixture was stirred at
120 ꢁC overnight. When the mixture was cooled to room temper-
ature, orange precipitates were formed. Filtration gave 192 mg
(35%) of the title compound as orange crystals: mp>225 ꢁC
1H NMR (CDCl3, 400 MHz)
(m, 1H), 6.48–6.59 (m, 2H), 9.80 (br, 1H); 13C NMR (CDCl3, 100 MHz)
25.04, 25.38, 32.78, 33.93, 114.69, 117.37, 117.55, 132.00, 133.24,
d 1.46–1.70 (m, 4H), 4.40 (m, 1H), 4.65
d
134.40, 134.60, 134.82, 136.15, 140.93, 170.24, 170.63, 171.02, 171.40;
IR (KBr) nmax; 3321 (NH), 1678, 1529, 1271, 1211, 1161, 1020,
930 cmꢀ1
;
MS (FAB) 287 (Mþþ1); HRMS (FAB) calcd for
C12H9F3N2O3þHþ: Mr¼287.0644. Found: 287.0645.
(decomp.); 1H NMR (CDCl3, 300 MHz)
d
1.40 (t, 3H, J¼7.1 Hz), 1.48–
3.7. Ethyl 3-benzylidenamino-4,7-dihydro-4,7-ethano-2H-
isoindole-1-carboxylate (7a)
1.64 (m, 4H), 4.24 (m, 1H), 4.35 (q, 2H, J¼7.1 Hz), 4.41 (m, 1H), 6.53–
6.55 (m, 2H), 8.00 (m, 2H), 8.30 (m, 2H), 8.53 (br, 1H), 8.70 (s, 1H);
13C NMR (CDCl3, 100 MHz)
d 14.52, 26.04, 26.60, 33.43, 33.63, 60.31,
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 200 mg,
0.763 mmol) in 60% aq EtOH (28 mL) was added Na2S2O4 (532 mg,
3.06 mmol) at room temperature. After being stirred at 40 ꢁC for
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. To the
residue was added a solution of benzaldehyde (71.3 mg, 0.7 mmol)
in toluene (40 mL) and then the mixture was stirred at 120 ꢁC
overnight. When the mixture was cooled to room temperature,
yellow precipitates were formed. Filtration gave 45.4 mg (19%) of
the title compound as yellow crystals: mp 190 ꢁC; 1H NMR (CDCl3,
112.97, 124.04, 124.61, 128.58, 133.31, 135.27, 135.49, 138.26, 142.01,
148.86, 152.48, 161.48; IR (KBr) nmax 3314 (NH), 3277, 1671, 1518,
1450, 1335, 1245, 1100, 844, 748, 688 cmꢀ1; UV–vis (CHCl3): lmax
/
nm (log10 3): 427 (4.34), 283 (4.23); MS (EI) 365 (Mþ, 19%), 338 (21),
337 (100), 291 (28), 263 (31), 217 (26), 190 (17), 89 (12). Anal. Calcd
for C20H19N3O4þ1/4H2O: C, 64.94; H, 5.31; N, 11.36%. Found: C,
64.73; H, 5.09; N, 11.40%.
3.10. p-Xylene-a,a
0-bis(ylidenamino-3-ethoxycarbonyl-4,7-
dihydro-4,7-ethano-2H-isoindole) (8)
300 MHz)
d
1.38 (t, 3H, J¼7.1 Hz), 1.53–1.61 (m, 4H), 4.20 (m, 1H),
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 200 mg,
0.763 mmol) in 60% aq EtOH (28 mL) was added Na2S2O4 (532 mg,
3.06 mmol) at room temperature. After being stirred at 40 ꢁC for
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. To the
residue was added a solution of p-phthalaldehyde (33.5 mg,
0.25 mmol) in toluene (20 mL) and then the mixture was stirred at
120 ꢁC overnight. When the mixture was cooled to room temper-
ature, orange precipitates were formed. Filtration gave 40.8 mg
(29%) of the title compound as orange crystals: mp>210 ꢁC
4.33 (q, 2H, J¼7.1 Hz), 4.40 (m, 1H), 6.54 (m, 2H), 7.45–7.47 (m, 3H),
7.85 (m, 2H), 8.45 (br, 1H), 8.67 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d
14.55, 26.15, 26.72, 33.22, 33.66, 59.99, 111.53, 122.17, 128.28,
128.78, 131.17, 134.35, 135.36, 135.60, 136.37, 138.33, 156.92, 161.56;
IR (KBr) nmax 3274 (NH), 1667, 1444, 1371, 1345, 1250, 1153, 756,
693 cmꢀ1; UV–vis (CHCl3): lmax/nm (log10 3): 375 (4.33), 277 (4.20);
MS (EI) 320 (Mþ, 28%), 293 (20), 292 (100), 246 (27), 245 (12), 219
(19), 218 (89), 90 (14). Anal. Calcd for C20H20N2O2þ1/2H2O: C,
72.93; H, 6.43; N, 8.50%. Found: C, 72.75; H, 6.11; N, 8.63%.
3.8. Ethyl 3-p-cyanobenzylidenamino-4,7-dihydro-4,7-
ethano-2H-isoindole-1-carboxylate (7b)
(decomp.); 1H NMR (CDCl3, 300 MHz)
d
1.40 (t, 6H, J¼7.1 Hz), 1.56–
1.64 (m, 8H), 4.24 (m, 2H), 4.35 (q, 4H, J¼7.1 Hz), 4.41 (m, 2H), 6.53–
6.56 (m, 4H), 7.94 (s, 4H), 8.45 (br, 2H), 8.69 (s, 2H); 13C NMR (CDCl3,
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 200 mg,
0.763 mmol) in 60% aq EtOH (28 mL) was added Na2S2O4 (532 mg,
3.06 mmol) at room temperature. After being stirred at 40 ꢁC for
100 MHz, diastereomer mixture, typical signals) d 14.56, 26.12,
26.70, 33.38, 33.66, 38.12, 60.09, 112.05, 123.00, 128.55, 134.15,
135.42, 135.50, 138.70, 149.44, 149.75, 155.35, 166.51; IR (KBr) nmax

4350
T. Akiyama et al. / Tetrahedron 65 (2009) 4345–4350
3306 (NH), 1672, 1446, 1371, 1342, 1247, 1142, 1045, 953, 687,
526 cmꢀ1; UV–vis (CHCl3): lmax/nm (log10 3): 469 (4.60), 442 (4.73),
281 (4.41); MS (MALDI-TOF) 583 (Mþþ1). Anal. Calcd for
C34H34N4O4þ1/4H2O: C, 72.00; H, 6.13; N, 9.88%. Found: C, 71.98; H,
6.09; N, 9.65%.
120.58, 122.95, 125.84, 127.53, 128.49, 134.64, 138.65, 156.08,
160.58; IR (KBr) nmax 3203 (NH), 1654, 1484, 1407, 1358, 1269, 1232,
1193, 1901, 1307, 752 cmꢀ1; UV–vis (CHCl3): lmax/nm (log10 3): 544
(4.73), 512 (4.78), 365 (4.07), 284 (4.52); MS (FAB) 507 (Mþþ1), 506
(Mþ). Anal. Calcd for C30H26N4O4: C, 71.13; H, 5.17; N,11.06%. Found:
C, 70.55; H, 5.15; N, 10.95%.
3.11. 4,7-Dihydro-4,7-ethano-2H-isoindole-1,3-
bis(methylidenamino-3-ethoxycarbonyl-4,7-dihydro-4,7-
ethano-2H-isoindole) (9)
3.14. 2H-Isoindole-1,3-bis(methylidenamino-3-
ethoxycarbonyl-2H-isoindole) (12)
To a stirred solution of ethyl nitropyrrolecarboxylate (3; 1.00 g,
3.80 mmol) in 60% aq EtOH (140 mL) was added Na2S2O4 (2.66 g,
15.3 mmol) at room temperature. After being stirred at 40 ꢁC for
1 h, the mixture was poured into ice-water. The mixture was
extracted with CH2Cl2. The organic extract was washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. To the
residue was added a solution of 4,7-dihydro-4,7-ethano-2H-iso-
indole-1,3-dicarbaldehyde (250 mg, 1.25 mmol) in toluene
(105 mL) and then the mixture was stirred at 120 ꢁC overnight.
When the mixture was cooled to room temperature, orange pre-
cipitates were formed. The precipitates were collected by filtration
and then chromatographed on silica gel (EtOAc/hexane¼1/1) to
give 500 mg (64%) of the title compound as red crystals: mp 165 ꢁC;
Tris-isoindole derivative 9 (5 mg) was heated at 220 ꢁC under
a reduced pressure (ca. 0.05 mmHg) for 30 min to give the title
compound in quantitative yield: 235–238 ꢁC; 1H NMR (DMSO-d6,
400 MHz)
d
1.41 (t, 6H, J¼7.3 Hz), 4.38 (q, 4H, J¼7.3 Hz), 7.19 (m,
2H), 7.31 (m, 2H), 7.43 (m, 2H), 7.99 (m, 2H), 8.09 (m, 2H), 8.52 (m,
2H), 9.46 (s, 2H), 13.28 (br, 3H); IR (KBr) nmax 2360, 1654, 1446, 1207,
1186, 1088, 1030, 754 cmꢀ1; UV–vis (CHCl3): lmax/nm (log10 3): 684
(4.29), 632 (4.33), 426 (4.34); MS (FAB) 545 (Mþ); HRMS (FAB) calcd
for C32H27N5O4þHþ: Mr¼546.2141. Found: 546.2140.
Acknowledgements
1H NMR (CDCl3, 300 MHz)
d
1.35 (t, 6H, J¼7.1 Hz), 1.48–1.64 (m,
This work was partially supported by Grant-in-Aids for the
Scientific Research C (20550047) from the Japanese Ministry of
Education, Culture, Sports, Science and Technology.
12H), 4.14 (m, 4H), 4.33 (q, 4H, J¼7.1 Hz), 4.46 (m, 2H), 6.53–6.54
(m, 6H), 8.46 (m, 2H), 9.02 (br, 2H), 9.57 (br, 1H); 13C NMR (CDCl3,
100 MHz, diastereoisomer mixture, typical signals)
d 14.44, 25.62,
26.16, 26.22, 26.76, 26.90, 32.78, 33.47, 33.50, 33.70, 33.71, 60.10,
111.34, 120.58, 125.65, 135.25, 135.44, 135.52, 135.62, 135.85, 137.96,
139.08, 144.74, 161.94; IR (KBr) nmax 3293 (NH), 2952, 1659, 1433,
1245, 1145, 1044, 1024, 845, 689 cmꢀ1; UV–vis (CHCl3): lmax/nm
(log10 3): 519 (4.52), 484 (4.64), 456 (4.51), 357 (4.25), 339 (4.28),
325 (4.24), 281 (4.30); MS (FAB) 629 (Mþ). Anal. Calcd for
C38H39N5O4þC7H8: C, 74.87; H, 6.56%; N, 9.70. Found: C, 75.10; H,
6.62; N, 9.28%.
References and notes
1. For reviews, see: Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4; Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2.
2. Donohoe, T. J. 1H- and 2H-Isoindoles. In Hetarenes and Related Ring Systems,
Fused Five-membered Hetarenes with One Heteroatom; Thomas, E. J., Ed.; Science
of Synthesis; George Thieme: Stuttgart, 2001; Vol. 10, Chapter 14, pp 653–692.
3. Chacko, E.; Bornstein, J.; Sadella, D. J. Tetrahedron 1979, 35, 1055–1058.
4. For recent examples, see: Okujima, T.; Hashimoto, Y.; Jin, G.; Uno, H.; Ono, N.
Tetrahedron 2008, 64, 2405–2411; Mack, J.; Bunya, M.; Shimizu, Y.; Uoyama, H.;
Komobuchi, N.; Okujima, T.; Uno, H.; Ito, S.; Stillman, M. J.; Ono, N.; Kobayashi, N.
Chem.dEur. J. 2008, 14, 5001–5020; Uno, H.; Shimizu, Y.; Uoyama, H.; Tanaka, Y.;
Okujima, T.; Ono, N. Eur. J. Org. Chem. 2008, 87–98; Yamada, H.; Kuzuhara, D.;
Takahashi, T.; Shimizu, Y.; Uota, K.; Uno, H.; Ono, N. Org. Lett. 2008, 10,
2947–2950.
5. Akiyama, T.; Hirao, A.; Okujima, T.; Yamada, H.; Uno, H.; Ono, N. Heterocycles
2007, 74, 835–842; Hirao, A.; Akiyama, T.; Okujima, T.; Yamada, H.; Uno, H.;
Sakai, Y.; Aramaki, S.; Ono, N. Chem. Commun. 2008, 4714–4716.
6. (a) Ito, S.; Ochi, N.; Murashima, T.; Uno, H.; Ono, N. Heterocycles 2000, 52,
399–411; (b) Okujima, T.; Komobuchi, N.; Uno, H.; Ono, N. Heterocycles 2006, 67,
255–267; (c) Okujima, T.; Jin, G.; Hashimoto, Y.; Uno, H.; Ono, N. Heterocycles
2006, 70, 619–626.
3.12. Ethyl 3-p-nitrobenzylidenamino-2H-isoindole-1-
carboxylate (10c)
p-Nitrobenzylidenaminoisoindole 7c (5 mg) was heated at
230 ꢁC under a reduced pressure (ca. 0.05 mmHg) for 30 min to give
the title compound in quantitative yield: mp 261–264 ꢁC; 1H NMR
(DMSO-d6, 400 MHz)
7.23 (m, 1H), 7.33 (m, 1H), 8.02 (m, 2H), 8.12 (m, 4H), 9.29 (s, 1H),
13.53 (br, 1H); 13C NMR (DMSO-d6, 100 MHz)
14.52, 59.78, 110.59,
d
1.39 (t, 3H, J¼6.8 Hz), 4.38 (q, 2H, J¼6.8 Hz),
d
120.60, 120.62, 120.73, 123.62, 124.15, 125.95, 127.56, 128.79, 133.97,
142.45, 148.20, 153.91, 160.72; IR (KBr) nmax 3209 (NH), 1662, 1508,
1450, 1330, 1205, 1099, 838, 744 cmꢀ1; UV–vis (CHCl3): lmax/nm
(log10 3): 492 (4.42), 366 (3.86), 282 (4.31); MS (FAB) 338 (Mþþ1),
337 (Mþ). Anal. Calcd for C18H15N3O4: C, 64.09; H, 4.48; N, 12.46%.
Found: C, 63.16; H, 4.48; N, 12.23%.
7. Pantos¸, G. D.; Rodrı´guez-Morgade, M. S.; Torres, T.; Lynch, V. M.; Sessler, J. L.
Chem. Commun. 2006, 2132–2134 and references cited therein.
8. X-ray data were processed by CrystalClear Ver. 1.3.6. The processed data were
treated with the WinGX program. Structures were solved by SIR-97, expanded
by DIRDIF, and then refined by SHELXL-97. The final structures were validated by
the PLATON cif check. WinGX 1.80.03: Suite for small-molecule single-crystal
crystallography, University of Glasgow, Farrugia, L. J. J. Appl. Crystallogr. 1999, 32,
837–838; SIR-97: A package for crystal structure solution and refinement, Isti-
tuto di Gristallografia, Italy; Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl.
Crystallogr. 1999, 32, 115–119; SHELXL-97: Program for the refinement of crystal
structures from diffraction data, University of Go¨ttingen, Go¨ttingen, Germany; ‘A
short history of SHELX’ Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122;
DIRDIF2008 program system: Beurskens, P. T.; Beurskens, G.; de Gelder, R.;
Garcia-Granda, S.; Gould, R. O.; Smits, J. M. M. Crystallography Laboratory,
3.13. p-Xylene-a,a
0-bis(ylidenamino-3-ethoxycarbonyl-2H-
isoindole) (11)
p-Xylylidenamino compound 8 (5 mg) was heated at 240 ꢁC
under a reduced pressure (ca. 0.05 mmHg) for 30 min to give the
title compound in quantitative yield: mp 284–286 ꢁC; 1H NMR
University of Nijmegen: The Netherlands, 2008. PLATON:
Crystallographic Tool, Utrecht University, Utrecht, The Netherland; Spek, A. L.
J. Appl. Crystallogr. 2003, 36, 7–13.
9. 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.
A Multipurpose
(DMSO-d6, 400 MHz)
7.20 (m, 4H), 7.32 (m, 4H), 8.03 (m, 4H), 9.25 (s, 2H), 13.47 (br, 2H);
13C NMR (DMSO-d6, 100 MHz)
14.62, 59.60, 109.31, 120.23, 120.39,
d
1.40 (t, 6H, J¼7.1 Hz), 4.38 (q, 4H, J¼7.1 Hz),
d