A novel one-pot pseudo-four-component isocyanide-based reaction: An unexpected approach for the synthesis of tetrahydrodiisoindoloquinoxalines and tetrahydrobenzodiisoindoloquinoxalines

Article abstract of DOI:10.1016/j.tet.2011.08.061

A novel isocyanide based one-pot pseudo-four-component strategy for the synthesis of tetrahydrodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloquinoxaline derivatives via the reaction of 1,2-diamines, 2-formylbenzoic acid, and an isocyanide at room t

Full text of DOI:10.1016/j.tet.2011.08.061

Tetrahedron 67 (2011) 8360e8366
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel one-pot pseudo-four-component isocyanide-based reaction: an
unexpected approach for the synthesis of tetrahydrodiisoindoloquinoxalines
and tetrahydrobenzodiisoindoloquinoxalines
,
a
a
a
b
Ahmad Shaabani a , Fatemeh Hajishaabanha , Mojtaba Mahyari , Hamid Mofakham , Seik Weng Ng
*
a Department of Chemistry, Shahid Beheshti University, G.C., PO Box 19396-4716, Tehran, Iran
b Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 May 2011
Received in revised form 3 August 2011
Accepted 22 August 2011
Available online 27 August 2011
A novel isocyanide based one-pot pseudo-four-component strategy for the synthesis of tetrahy-
drodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloquinoxaline derivatives via the reaction of
1,2-diamines, 2-formylbenzoic acid, and an isocyanide at room temperature in good yields without using
any catalyst and activation, is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Quinoxaline
Tetrahydroquinoxaline
Indoloquinoxaline
Multicomponent reaction
Isocyanide
R3
X
N
1. Introduction
Br
H
N
N
N
Cl
Cl
N
N
N
N
N
Quinoxalines are an excellent scaffold for drug development,
mainly due to their structural similarity to benzodiazepines. They
exhibit a wide variety of biological and medicinal activities in-
cluding: antidiabetic,1 anticancer, antibacterial,2 cytotoxic, and
antiviral effects, especially, against retroviruses, such as HIV.3 Some
of the compounds containing these heterocyclic cores have dem-
onstrated antidepressant I,4 excitatory amino acid antagonistic II,5
and antiglaucoma activities III (Fig.1).6 Quinoxalines with an indole
ring gave 5-substituted-2-bromoindolo[2,3-b]quinoxalines that
represent a broad spectrum of antitumor activity with two bio-
chemical mechanism-based screens (cdc2 kinase and cdc25 phos-
N
N
H
O
N
I
NR1R2
III
II
R1
H
R2
R3
N
O
N
R4
IV
phatase) with IC50 of 70 and 25 m
M.7 Also isoindoloquinoxalines are
Fig. 1. Examples of medicinal quinoxalines.
antihypertensive,8,9 and some of them, such as isoindolo[2,1-a]
quinoxaline derivatives IV showed antiproliferative activity.10
Multicomponent reactions (MCRs) are powerful tools for the
synthesis of complex biologically relevant molecules. The atom
economy of MCRs, their convergent character, operational sim-
plicity, and the structural diversity and complexity of the resulting
molecules make this chemistry exceptionally useful for discovery
and optimization processes in the pharmaceutical industry. MCRs
especially isocyanide-based MCRs (IMCRs) are fast and selective
methods for the synthesis of large libraries of organic molecules by
simply varying each component through a chain of consecutive
elementary transformations.11
Due to the biological and medicinal importance of the products
obtained from diamines, and in view of our current studies on
isocyanide-based multicomponent reactions (IMCRs) of diamines12
herein, we report a novel IMCR, which afford 5,12,16b,16c-tetra-
hydrodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamides 4aej
* Corresponding author. Tel.: þ982129902800; fax: þ982122431663; e-mail ad-
dress: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.061

A. Shaabani et al. / Tetrahedron 67 (2011) 8360e8366
8361
via an unexpected reaction between an isocyanide 1, formylbenzoic
acid13 2, and an aromatic 1,2-diamine 3. Alternatively, using
naphthalene-2,3-diamine 5 instead of aromatic 1,2-diamines pro-
duces 5,14,18b,18c-tetrahydrobenzo[g]diisoindolo[2,1-a:10,20-c]qui-
noxaline-18b-carboxamides 6aec in good yields at room
temperature (Scheme 1).
It is worth mentioning that in the present reaction three amides,
two CeC bonds, and two CeN bonds are newly formed. As indicated
in Fig. 2, the reaction is straightforward, and treatment of various
alkyl, aryl, and alicyclic isocyanides and various o-phenylenedi-
amines with formylbenzoic acid in methanol at room temperature
and under similar circumstances led to the formation of the
Scheme 1.
2. Results and discussion
In pilot experiment, 3,4-diaminobenzophenone, for-
mylbenzoic acid, and cyclohexyl isocyanide in methanol were
stirred at room temperature. The progress of the reaction was
monitored by TLC. After 48 h, the reaction was completed and 9-
benzoyl-N-cyclohexyl-5,12-dioxo-5,12,16b,16c-tetrahydrodiisoindo
lo[2,1-a:10,20-c]quinoxaline-16b-carboxamide 4a was obtained in
90% yield (Scheme 1).
5,12,16b,16c-tetrahydrodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-
carboxamide derivatives 4aej in good yields. The results are sum-
marized in Table 1. The structure of compounds 4aej was deduced
from their IR, mass, 1H NMR, and 13C NMR spectral data. For ex-
ample, the 1H NMR spectrum of 4a exhibited a multiplet for the
a
cyclohexyl ring at
CHeNH of cyclohexyl, a singlet identified as CH proton at
d
¼0.77e1.35, a broad singlet at
d
¼3.15 for
d
¼5.21,
a multiplet at
d¼7.61e8.77 for H-aromatic and eNH of amide. The
1H-decoupled 13C NMR spectrum of 4a showed 30 distinct
O
O
O
O
O
O
N
N
N
O
O
O
Ph
Ph
Ph
Ph
N
H
N
H
N
H
N
N
N
O
O
O
4a
4b
4c
O
O
O
O
N
Cl
Cl
N
Cl
Cl
N
O
O
O
N
N
H
N
H
N
H
N
N
O
O
4e
O
4f
4d
O
O
O
Cl
Cl
N
N
Cl
Cl
N
O
H
O
N
N
N
H
O
H
N
N
N
O
O
4g O
4h
4i
O
O
O
N
N
N
N
O
O
O
N
H
N
N
N
H
H
N
4j O
O
O
6b
6a
O
N
N
O
N
H
6c
O
Fig. 2. The structure of compounds 4aej and 6aec.

8362
A. Shaabani et al. / Tetrahedron 67 (2011) 8360e8366
Table 1
Synthesis
expected product 14 was not obtained, but the reaction progressed
via a pseudo-four-component condensation reaction and afforded
a new class of bis(oxoisoindoline) derivatives 13aec compounds
(Fig. 4).13f,g This result shows, the successful isolation of the prod-
ucts 4aej and 6aec can be explained to the formation of cyclo-
of
tetrahydrodiisoindoloquinoxalines
4aej
and
R3
tetrahy-
Yield (%)
drobenzodiisoindoloquinoxalines 6aec
Product
R1
R2
4a
4b
4c
4d
4e
4f
4g
4h
4i
Cyclohexyl
tert-Butyl
1,1,3,3-Tetramethylbutyl
Benzyl
Cyclohexyl
tert-Butyl
1,1,3,3-Tetramethylbutyl
Benzyl
Cyclohexyl
Benzyl
Cyclohexyl
tert-Butyl
COPh
COPh
COPh
COPh
Cl
Cl
Cl
Cl
Me
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
90
88
90
82
78
88
86
75
75
74
87
75
70
adduct
8 via an electrocyclic reaction. Apparently, aliphatic
diamines do not have conjugated systems, which are necessary for
a pericyclic reaction.
So, we studied the reaction of 2,3-diaminomaleonitrile 15 with
cyclohexyl isocyanide 1 and formylbenzoic acid 2 (Scheme 4).
However, due to high stability of the generated imine 16 from re-
action of 2,3-diaminomaleonitrile and formylbenzoic acid, forma-
tion of cycloadduct 9, [1,5]-H shift reaction and nucleophilic attack
by isocyanide did not occur.12a
In summary, we have discovered a novel and efficient one-pot
pseudo-four-component condensation reaction leading to tetra-
hydrodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloqui
noxaline derivatives starting from simple and readily available
precursors. This novel protocol can be regarded as a new approach
for the preparation of synthetically and pharmaceutically relevant
isoindoloquinoxaline systems in good to excellent yields at room
temperature without using a catalyst. We hope that this approach
may be of value to others seeking novel synthetic fragments with
unique properties for medicinal chemistry.
4j
6a
6b
6c
Benzo
Benzo
Benzo
Benzyl
resonances in agreement with the proposed structure. The mass
spectra of these compounds displayed molecular ion peaks at the
appropriate m/z values.
It is important to note that compound 4a has two stereogenic
centers (C8 and C9) and therefore, two pairs of diastereoisomers
expected. The 1H NMR and 13C NMR spectra of the crude products
showed only one of two possible diastereomers (RR or SS) were
present in the reaction mixture. These structures were confirmed
by single-crystal X-ray analysis (Fig. 3).
3. Experimental
3.1. General
Melting points were measured on an Electrothermal 9200 ap-
paratus. Mass spectra were recorded on a Finnigan-MAT 8430
mass spectrometer operating at an ionization potential of 70 eV. IR
spectra were recorded on a Shimadzu IR-470 spectrometer. 1H
NMR Spectra were recorded on a Bruker DRX-300 Avance spec-
trometer 300.13 MHz; chemical shifts (d scale) are reported in
parts per million (ppm). 1H NMR Spectra are reported in order:
number of protons, multiplicity, and approximate coupling con-
stant (J value) in hertz (Hz); signals were characterized as s (sin-
glet), d (doublet), t (triplet), m (multiplet), br s (broad signal), and
Ar (aryl). The 13C NMR spectra were recorded at 75.47 MHz;
chemical shifts (d scale) are reported in parts per million (ppm).
The elemental analyses were performed with an Elementar Ana-
lysensysteme GmbH VarioEL. All the products are new compounds,
which were characterized by IR, 1H NMR and 13C NMR spectra, and
Mass spectral data.
Fig. 3. ORTEP diagram for 4a.
In view of the success of the above mentioned reaction, we
explored the scope of this promising reaction with naphthalene-
2,3-diamine, formylbenzoic acid and isocyanides. As indicated in
Table 1, the reactions proceed efficiently and led to tetrahy-
drobenzodiisoindoloquinoxaline derivatives 6aec in good yields.
The suggested mechanism for the formation of products 4aej
and 6aec is illustrated in Scheme 2. It is conceivable that, the initial
event is the formation of diimine 7 from condensation reaction of 3
or 5 and aldehyde moiety of formylbenzoic acid 2.13h Then cyclo-
adduct 9 was formed by a 4nþ2 electrocyclic reaction of 7 and
a [1,5]-H shift of 8. On the basis of the well established chemistry of
isocyanides with imines,11 intermediate 10 was produced by nu-
cleophilic attack of isocyanide 1 to activated iminium 9 and a clo-
sure of the five-membered indole ring followed by nucleophilic
attack of an H2O molecule on the nitrilium moiety and production
of compound 11. Finally, tautomerization of intermediate 11 pro-
duces compounds 4aej or 6aec.
3.2. Typical procedure for preparation of 9-benzoyl-N-
cyclohexyl-5,12-dioxo-5,12,16b,16c-tetrahydrodiisoindolo[2,1-
a:10,20-c]quinoxaline-16b-carboxamide (4a)
A solution of 3,4-diaminobenzophenone (0.21 g, 1 mmol), 2-
formylbenzoic acid (0.30 g, 2 mmol), and cyclohexyl isocyanide
(0.22 g, 2 mmol) in methanol (3 mL) was stirred for 48 h at
ambient temperature. After completion of the reaction, as in-
dicated by TLC (ethyl acetate/n-hexane, 3/1), the precipitate was
filtered off and washed with methanol and the residue was
crystallized from acetone to give 4a as colorless needles crystals
(0.51 g, yield 90%); mp 232e235 ꢀC; Rf (33% n-hexane/AcOEt)
0.73. IR (KBr) cmꢁ1: 3300, 3065, 2924, 2845, 1710, 1591, 1518,
1440, 1352, 1283, 1152. 1H NMR (300.13 MHz, DMSO-d6)
d:
0.77e1.35 (10H, m, 5CH2 of cyclohexyl), 3.15 (1H, s, CHeNH), 5.21
(1H, s, CH), 7.61e8.77 (17H, m, HeAr and NHeCO). 13C NMR
(75.47 MHz, DMSO-d6) d: 24.6, 25.4, 31.4, 31.7, 48.3, 63.5, 69.0,
For clarifying the proposed mechanism, we have also in-
vestigated this reaction using various aliphatic diamines 12 under
the same reaction conditions. As can be seen from Scheme 3, the
118.6, 123.6, 124.1, 124.6, 124.8, 125.0, 125.2, 126.9, 129.0, 130.2,
131.0, 131.2, 131.8, 132.0, 133.0, 133.7, 137.7, 140.4, 142.2, 164.2,
166.5, 167.1, 194.9. MS m/z: 441 (Mþꢁ126, 13), 413 (10), 337 (68),

A. Shaabani et al. / Tetrahedron 67 (2011) 8360e8366
8363
O
H
O
O
HO
HO
N
O
NH2
NH2
N
N
OH
[4+2]
N
O
HO
HO
O
8
3 or 5
2
7
O
O
O
O
HO
HO
N
H+
N
N
[1,5]
-H2O
R1
N
1
C
H-shift
N
N
H
N
O
O
HO
O
9
O
O
O
HO
H
N
N
N
+H2O
R1
N
-H2O
R1
4 or 6
N
N
OH
N
N
O
R1
N
O
O
11
10
Scheme 2. Possible mechanism.
O
HN
N
O
O
R4
NH2
NH2
N
CO2H
,
H
H
C
3O rt
O
N
NC
N
H
2
+
+
3-4 day
R4
N
,
H
H rt
C
3O
R4
CHO
O
O
13a-c
NH
O
1
2
12
14
R4 = H, CH3
Scheme 3. Clarification of the mechanism.
3.2.1. 9-Benzoyl-N-tert-butyl-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide (4b). Light
yellow powder (0.48 g, yield 88%); mp 252e255 ꢀC; Rf (33% n-
hexane/AcOEt) 0.71. IR (KBr) cmꢁ1: 3432, 3097, 3084, 3040, 2958,
2920, 2863, 1728, 1714, 1686, 1657, 1601, 1568, 1506, 1363, 1329,
NH
N
HN
O
HN
O
O
O
O
O
N
N
N
N
N
O
1297, 1256, 1159, 1093. 1H NMR (300.13 MHz, DMSO-d6)
d
: 0.83 (9H,
s, 3CH3), 5.18 (1H, s, CH), 7.13e8.75 (17H, m, HeAr and NHeCO). 13
NMR (75.47 MHz, DMSO-d6) : 28.1, 51.3, 64.0, 69.2, 118.6, 123.7,
HN
O
O
O
O
NH
O
NH
C
13c
13a
13b
d
product
yield (%) 45
13a
13b 13c
124.1, 124.9, 126.9, 129.1, 130.2, 131.0, 131.4, 131.9, 133.1, 133.6, 137.7,
140.2, 142.2, 164.1, 166.4, 167.0, 194.9. MS m/z: 542 (Mþþ1, 21), 442
(MþL100, 80), 413 (19), 337 (40), 279 (15), 105 (100), 77 (40), 57
(25). Anal. Calcd for C34H27N3O4: C, 75.40; H, 5.02; N, 7.76; found C,
75.62; H, 4.88; N, 7.54.
46
43
Fig. 4. The structure of bis(oxoisoindoline) derivatives.
309 (20), 280 (30), 279 (56), 251 (12), 177 (15), 151 (25), 105 (100),
77 (62), 55 (55). Anal. Calcd for C36H29N3O4: C, 76.17; H, 5.15; N,
7.40; found C, 76.33; H, 5.01; N, 7.29. ORTEP diagram for 4a;
summary of data: The Cambridge Crystallographic Data Centre
3.2.2. 9-Benzoyl-5,12-dioxo-N-(2,4,4-trimethylpentan-2-yl)-
5,12,16b,16c-tetrahydrodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-car-
boxamide (4c). Light yellow powder (0.54 g, yield 90%); mp
220e223 ꢀC; Rf (33% n-hexane/AcOEt) 0.68. IR (KBr) cmꢁ1: 3347,
3065, 2960, 2877, 1721, 1665, 1591, 1509, 1442, 1353, 1271, 1212,
(CCDC) no.: 808,449; unit cell parameters:
b 14.0031(13) c 14.2793(13) 78.0530(10)
a
8.5028(8)
a
b
90.0790(10)
g
1150, 1085. 1H NMR (300.13 MHz, DMSO-d6)
d
: 0.48 (9H, s, 3CH3),
0.82 (6H, s, 2CH3), 2.04 (2H, CH2), 5.12 (1H, s, CH), 7.00e8.70 (17H,
m, HeAr and NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
: 28.6, 29.3,
73.7420(10); space group Pꢁ1. (Fax: þ441 223 336 033; e-mail:
deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
d

8364
A. Shaabani et al. / Tetrahedron 67 (2011) 8360e8366
O
N
O
OH
CO2H
CHO
NC
NH2
NH2
NC
NC
N
O
+ 2
NC
+
NC
N
H
NC
NC
MeOH, 48 h
MeOH, 48 h
N
NH2
1
2
15
O
16
17
Scheme 4. Reaction of 2,3-diaminomaleonitrile with cyclohexyl isocyanide and formylbenzoic acid.
31.0, 31.4, 50.0, 55.2, 63.8, 69.3, 118.7, 123.6, 124.1, 124.7, 124.9,
125.2, 126.9, 129.0, 130.1, 130.9, 131.4, 131.8, 133.0, 133.4, 137.7, 140.1,
142.3, 164.0, 166.6, 167.0, 194.9. MS m/z: 441 (Mþꢁ156, 24), 337
(60), 280 (27), 279 (65), 177 (15), 151 (31), 105 (85), 77 (73), 57
(100), 41 (47). Anal. Calcd for C38H35N3O4: C, 76.36; H, 5.90; N, 7.03;
found C, 76.54; H, 5.69; N, 7.19.
3101, 2939, 2887, 1704, 1586, 1484, 1367, 1226, 1126. 1H NMR
(300.13 MHz, DMSO-d6) d: 0.51 (9H, s, 3CH3), 0.84 (3H, s, CH3), 0.88
(3H, s, CH3), 1.32 (2H, ABq, J¼14.4 Hz, CH2), 5.11 (1H, s, CH),
6.98e8.70 (11H, m, HeAr and NHeCO). 13C NMR (75.47 MHz,
DMSO-d6) d: 28.5, 29.3, 30.9, 31.4, 50.0, 55.4, 63.4, 69.4, 119.6, 123.6,
123.9,124.1,125.0, 125.2, 125.4, 126.9,127.6,129.0,131.0,131.4,131.7,
133.1, 133.7, 140.0, 142.2, 163.8, 166.5, 166.7. MS m/z: 407 (Mþꢁ156,
37Cl, 100), 405 (Mþꢁ156, 35Cl, 100), 377 (32), 349 (32), 314 (28), 57
(100), 41 (55). Anal. Calcd for C31H29Cl2N3O3: C, 66.19; H, 5.20; N,
7.47; found C, 66.40; H, 5.02; N, 7.29.
3.2.3. 9-Benzoyl-N-benzyl-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide (4d). Light
orange powder (0.47 g, yield 82%); mp 233e237 ꢀC; Rf (33% n-
hexane/AcOEt) 0.66. IR (KBr) cmꢁ1: 3326, 3060, 2918, 2845, 1688,
1591, 1513, 1435, 1351, 1271, 1168, 1090. 1H NMR (300.13 MHz,
3.2.7. N-Benzyl-8,9-dichloro-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide
(4h). Light orange needles crystals (0.40 g, yield 75%); mp
210e214 ꢀC; Rf (33% n-hexane/AcOEt) 0.67. IR (KBr) cmꢁ1: 3404,
3180, 3065, 2924, 2835, 1683, 1602, 1550, 1482, 1419, 1355, 1309,
DMSO-d6)
(1H, s, CH), 6.79e8.80 (22H, m, HeAr and NHeCO). 13C NMR
(75.47 MHz, DMSO-d6) : 42.0, 63.1, 69.1, 118.7, 123.7, 124.1, 125.1,
d: 3.75 (1H, br m, CHeNH), 4.04 (1H, br m, CHeNH), 5.30
d
125.3, 126.3,126.9,127.1,128.4,129.0,130.1,131.2,131.8,132.0,133.0,
133.2, 137.6, 138.9, 140.3, 142.0, 165.5, 166.4, 167.1, 194.8. MS m/z:
441 (MþL134, 52), 337 (50), 279 (16), 247 (15), 231 (17), 177 (17),
151 (19), 133 (22), 91 (100). Anal. Calcd for C37H25N3O4: C, 77.20; H,
4.38; N, 7.30; found C, 77.44; H, 4.20; N, 7.51.
1205, 1152, 1095. 1H NMR (300.13 MHz, DMSO-d6)
d
: 3.80 (1H, m,
CHeNH), 4.07 (1H, m, CHeNH), 5.30 (1H, s, CH), 7.03e8.80 (16H, m,
HeAr and NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
: 42.0, 62.8,
d
69.1, 119.7, 123.7, 124.0, 124.2, 125.1, 125.5, 126.3, 127.0, 128.3, 129.2,
131.3, 134.1, 138.8, 165.2, 166.2, 166.9. MS m/z: 407 (Mþꢁ134, 37Cl,
100), 405 (Mþꢁ134, 35Cl, 100), 376 (24), 326 (10), 299 (100), 273
(23), 239 (15), 202 (24), 177 (22), 158 (65), 130 (43), 91 (100), 65
(44), 39 (24). Anal. Calcd for C30H19Cl2N3O3: C, 66.68; H, 3.54; N,
7.78; found C, 66.47; H, 3.36; N, 7.69.
3.2.4. 8,9-Dichloro-N-cyclohexyl-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide
(4e). Colorless needles crystals (0.41 g, yield 78%); mp >270 ꢀC; Rf
(33% n-hexane/AcOEt) 0.70. IR (KBr) cmꢁ1: 3294, 2934, 2850, 1721,
1676, 1592, 1528, 1491, 1464, 1399, 1366, 1330, 1291, 1236. 1H NMR
(300.13 MHz, DMSO-d6)
3.11 (1H, s, CHeNH), 5.16 (1H, s, CH), 7.59e8.70 (11H, m, HeAr and
NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
: 21.2, 24.7, 25.3, 31.5,
31.8, 48.5, 63.1, 69.1, 119.6, 123.6, 123.8, 124.1, 124.9, 125.1, 125.3,
126.9, 127.4, 129.0, 131.1, 131.3, 131.8, 133.1, 134.0, 140.3, 142.0, 163.9,
166.4, 166.8. MS m/z: 407 (Mþꢁ126, 37Cl, 40), 405 (Mþꢁ126, 35Cl,
45), 377 (25), 349 (24), 314 (27), 277 (23), 176 (37), 151 (25), 130
(15), 102 (28), 83 (27), 55 (100). Anal. Calcd for C29H23Cl2N3O3: C,
65.42; H, 4.35; N, 7.89; found C, 65.21; H, 4.56; N, 7.68.
d
: 0.82e1.40 (10H, m, 5CH2 of cyclohexyl),
3.2.8. N-Cyclohexyl-9-methyl-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide
(4i). White powder (0.36 g, yield 75%); mp 254e258 ꢀC; Rf (33% n-
hexane/AcOEt) 0.69. IR (KBr) cmꢁ1: 3425, 2928, 2844, 1711, 1678,
d
1510,1467,1372,1082.1H NMR (300.13 MHz, DMSO-d6)
d: 0.79e1.35
(10H, m, 5CH2 of cyclohexyl), 2.36 (3H, s, CH3), 3.10 (1H, s, CHeNH),
5.02 (1H, s, CH), 7.08e8.41 (12H, m, HeAr and NHeCO). 13C NMR
(75.47 MHz, DMSO-d6) d: 21.6, 24.6, 25.4, 31.5, 31.7, 48.3, 63.7, 69.1,
118.6,119.0,122.5,122.7,123.5,123.7,124.6,124.8,125.0,125.2,128.8,
130.8, 132.2, 132.4, 132.8, 133.3, 140.6, 142.1, 164.4, 166.3, 166.6. MS
m/z: 351 (MþL126, 85), 323 (24), 293 (21), 280 (20), 190 (23), 165
(25),147 (16),102 (18), 83 (32), 55 (100). Anal. Calcd for C30H27N3O3:
C, 75.45; H, 5.70; N, 8.80; found C, 75.67; H, 5.59; N, 8.62.
3.2.5. N-tert-Butyl-8,9-dichloro-5,12-dioxo-5,12,16b,16c-tetrahy-
drodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-carboxamide (4f). Dark
blue powder (0.45 g, yield 88%); mp >270 ꢀC; Rf (33% n-hexane/
AcOEt) 0.73. IR (KBr) cmꢁ1: 3432, 3109, 3072, 3046, 2964, 2933,
2863,1718,1692,1600,1470,1404,1369,1329. 1H NMR (300.13 MHz,
3.2.9. N-Benzyl-5,12-dioxo-5,12,16b,16c-tetrahydrodiisoindolo[2,1-
a:10,20-c]quinoxaline-16b-carboxamide (4j). Yellow needles crystals
(0.35 g, yield 74%); mp 228e230 ꢀC; Rf (33% n-hexane/AcOEt) 0.64.
IR (KBr) cmꢁ1: 3378, 3070, 3033, 2918, 1720, 1698, 1673, 1612, 1550,
1518, 1500, 1455, 1377, 1356, 1326, 1304. 1H NMR (300.13 MHz,
DMSO-d6)
d
: 0.83 (9H, s, 3CH3), 5.19 (1H, s, CH), 7.15e8.76 (11H, m,
: 28.2, 51.4,
HeAr and NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d
63.5, 69.3, 119.6, 123.5, 124.1, 124.7, 124.9, 125.3, 127.5, 129.1, 130.0,
130.3,130.5,130.9,131.6,133.2,133.4,133.9,142.0,154.6,163.9,166.7,
168.8. MS m/z: 507 (Mþ, 37Cl, 20), 505 (Mþ, 35Cl, 22), 405 (Mþꢁ100,
63), 377 (23), 349 (15), 307 (31), 288 (11), 262 (50), 225 (13),102 (10),
76 (16), 57 (35). Anal. Calcd for C27H21Cl2N3O3: C, 64.04; H, 4.18; N,
8.30; found C, 63.81; H, 4.34; N, 8.16.
DMSO-d6)
d
: 4.02 (2H, br s, CH2), 5.23 (1H, s, CH), 7.00e8.90 (18H,
: 42.0, 63.2,
m, HeAr and NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d
69.3, 125.0, 126.1, 126.8, 128.2, 128.4, 128.8, 129.3, 132.0, 132.1, 132.7,
138.9, 140.8, 141.9, 161.7, 165.4, 166.3. MS m/z: 337 (MþL134, 52),
233 (27), 91 (100), 65 (23). Anal. Calcd for C30H21N3O3: C, 76.42; H,
4.49; N, 8.91; found C, 76.21; H, 4.67; N, 8.73.
3.2.6. 8,9-Dichloro-5,12-dioxo-N-(2,4,4-trimethylpentan-2-yl)-
5,12,16b,16c-tetrahydrodiisoindolo[2,1-a:10,20-c]quinoxaline-16b-car-
boxamide (4g). Dark blue powder (0.48 g, yield 86%); mp
223e227 ꢀC; Rf (33% n-hexane/AcOEt) 0.75. IR (KBr) cmꢁ1: 3410,
3.2.10. N-Cyclohexyl-5,14-dioxo-5,14,18b,18c-tetrahydrobenzo[g]dii-
soindolo[2,1-a:10,20-c]quinoxaline-18b-carboxamide
(6a). Brown

A. Shaabani et al. / Tetrahedron 67 (2011) 8360e8366
8365
needles crystals (0.45 g, yield 87%); mp >270 ꢀC; Rf (33% n-hexane/
AcOEt) 0.79. IR (KBr) cmꢁ1: 3436, 3028, 2929, 2851, 1708, 1683,
1602, 1506, 1469, 1361, 1327, 1294, 1210. 1H NMR (300.13 MHz,
CH), 4.62 (1H, br m, CH), 5.35 (1H, s, CH), 5.41 (1H, s, CH), 7.33e7.51
(8H, m, HeAr), 8.75 (2H, s, 2 NHeCO). 13C NMR (75.47 MHz, DMSO-
d6) d: 15.8, 24.7, 24.9, 25.6, 32.3, 32.5, 32.7, 44.6, 46.3, 48.4, 48.5,
DMSO-d6)
CHeNH), 5.20 (1H, s, CH), 7.35e9.01 (15H, m, HeAr and NHeCO).
13C NMR (75.47 MHz, DMSO-d6)
: 24.6, 25.2, 31.2, 31.7, 36.2, 48.5,
63.7, 69.5, 116.0, 120.3, 123.6, 123.9, 124.7, 124.9, 126.1, 126.4, 126.9,
127.9, 128.9, 129.7, 130.6, 131.0, 132.0, 132.6, 133.5, 140.4, 142.0,
162.8, 164.3, 166.8. MS m/z: 513 (Mþ, 75), 387 (Mþꢁ126, 82), 359
(31), 331 (30), 126 (20), 83 (61), 55 (100). Anal. Calcd for
C33H27N3O3: C, 77.17; H, 5.30; N, 8.18; found C, 77.40; H, 5.13; N,
8.37.
d
: 0.65e1.30 (10H, m, 5CH2 of cyclohexyl), 3.09 (1H, s,
61.3, 63.5, 122.1, 122.7, 123.0, 123.1, 128.5, 128.6, 128.7, 131.4, 131.8,
132.1, 142.5, 143.4, 166.2, 167.8, 168.4, 169.3. MS m/z: 557 (Mþþ1,
25), 430 (MþL126, 7), 285 (24), 160 (100), 132 (40), 104 (12), 83
(25), 55 (48). Anal. Calcd for C33H40N4O4: C, 71.20; H, 7.24; N, 10.06;
found C, 71.41; H, 6.98; N, 10.31.
d
3.3.2. 2,20-(Propane-1,3-diyl)bis(N-cyclohexyl-3-oxoisoindoline-1-
carboxamide) (13c). White powder (0.24 g, yield 43%); mp
265e269 ꢀC; Rf (17% n-hexane/AcOEt) 0.61. IR (KBr) cmꢁ1: 3488,
3274, 3072, 2930, 2850, 1695, 1650, 1549, 1467, 1448, 1410. 1H NMR
3.2.11. N-tert-Butyl-5,14-dioxo-5,14,18b,18c-tetrahydrobenzo[g]dii-
(300.13 MHz, DMSO-d6) d: 1.15e1.65 (20H, m, 10CH2 of cyclohexyl),
soindolo[2,1-a:10,20-c]quinoxaline-18b-carboxamide
(6b). Light
2.00 (2H, m, CH2), 3.00 (2H, m, CH2), 3.50 (2H, s, 2CHeNH), 3.76
(2H, m, CH2), 5.22 (2H, s, 2CH), 7.53e7.70 (8H, m, HeAr), 8.56 (2H,
brown powder (0.37 g, yield 75%); mp >270 ꢀC; Rf (33% n-hexane/
AcOEt) 0.75. IR (KBr) cmꢁ1: 3420, 3054, 2966, 2939, 2898, 2861,
1772,1757,1724,1684,1602,1508,1474,1374,1322,1309,1284,1211.
d, J¼6.50 Hz, 2NHeCO). 13C NMR (75.47 MHz, DMSO-d6)
d: 24.8,
25.6, 26.9, 32.6, 48.5, 63.5, 122.4, 122.7, 123.2, 129.1, 132.2, 142.3,
166.0, 168.5. MS m/z: 556 (Mþ, 33), 431 (MþL125, 100), 306 (100),
243 (30), 215 (20), 172 (48), 146 (100). Anal. Calcd for C33H40N4O4:
C, 71.20; H, 7.24; N, 10.06; found C, 71.42; H, 7.11; N, 10.34.
1H NMR (300.13 MHz, DMSO-d6)
d
: 0.74 (9H, s, 3CH3), 5.22 (1H, s,
CH), 7.25e9.03 (15H, m, HeAr and NHeCO). 13C NMR (75.47 MHz,
DMSO-d6) : 28.1, 51.2, 69.7, 87.3, 116.0, 119.9, 123.9, 124.3, 124.7,
d
124.9, 126.8, 127.7, 129.1, 129.7, 130.6, 130.8, 132.1, 132.5, 132.9,
133.5, 139.9, 141.9, 164.2, 165.4, 168.6. MS m/z: 387 (MþL100, 100),
359 (62), 330 (72), 301 (10), 270 (49),133 (35), 105 (100), 77 (46), 57
(27). Anal. Calcd for C31H25N3O3: C, 76.37; H, 5.17; N, 8.62; found C,
76.14; H, 5.32; N, 8.43.
3.4. Typical procedure for preparation of 2-((E)-((Z)-2-amino-
1,2-dicyanovinylimino)methyl)benzoic acid (16)
A solution of 2,3-diaminomaleonitrile (0.10 g, 1 mmol), 2-
formylbenzoic acid (0.30 g, 2 mmol), and cyclohexyl isocyanide
(0.22 g, 2 mmol) in methanol (3 mL) was stirred for 48 h at ambient
temperature. After completion of the reaction, as indicated by TLC
(ethyl acetate/n-hexane, 6/1), the precipitate was filtered off and
washed with methanol and the product 16 was obtained as orange
powder; mp 194e199 ꢀC; Rf (17% n-hexane/AcOEt) 0.69. IR (KBr)
cmꢁ1: 3476, 3444, 3313, 2233, 2205, 1683, 1619, 1556, 1384, 1300,
3.2.12. N-Benzyl-5,14-dioxo-5,14,18b,18c-tetrahydrobenzo[g]dii-
soindolo[2,1-a:10,20-c]quinoxaline-18b-carboxamide
(6c). Orange
powder (0.36 g, yield 70%); mp 250e252 ꢀC; Rf (33% n-hexane/
AcOEt) 0.76. IR (KBr) cmꢁ1: 3399, 3060, 3033, 2960, 2924, 2851,
1707, 1680, 1602, 1560, 1507, 1466, 1374, 1330, 1246. 1H NMR
(300.13 MHz, DMSO-d6)
CH), 6.39e9.14 (20H, m, HeAr and NHeCO). 13C NMR (75.47 MHz,
DMSO-d6) : 41.9, 63.2, 69.6, 116.1, 120.6, 123.7, 124.8, 125.0, 126.0,
d
: 4.01 (2H, ABq, J¼7 Hz, CH2), 5.34 (1H, s,
1265, 1077. 1H NMR (300.13 MHz, DMSO-d6)
HeAr and NH2), 9.05 (1H, s, CH), 13.50 (1H, m, OH). 13C NMR
d: 7.50e8.45 (6H, m,
d
126.7, 127.0, 127.8, 128.1, 129.0, 129.7, 131.2, 132.5, 132.7, 133.6,140.2,
165.6, 166.2, 166.8. MS m/z: 521 (Mþ, 25), 387 (MþL134, 40), 359
(16), 331 (15), 91 (100), 65 (18). Anal. Calcd for C34H23N3O3: C,
78.30; H, 4.44; N, 8.06; found C, 78.52; H, 4.26; N, 8.34.
(75.47 MHz, DMSO-d6) d: 103.3, 114.3, 114.8, 127.9, 128.7, 130.7,
131.3, 132.1, 132.3, 135.6, 154.5, 168.5. MS m/z: 241 (Mþþ1, 23), 133
(100). Anal. Calcd for C12H8N4O2: C, 60.00; H, 3.36; N, 23.32; found
C, 59.90; H, 3.54; N, 23.14.
3.3. Typical procedure for preparation of 2,20-(ethane-1,2-
diyl)bis(N-cyclohexyl-3-oxoisoindoline-1-carboxamide) (13a)
Acknowledgements
We gratefully acknowledge financial support from the Iranian
Vice-President for Science and Technology.
A solution of ethylenediamine (0.06 g,1 mmol), 2-formylbenzoic
acid (0.30 g, 2 mmol), and cyclohexyl isocyanide (0.22 g, 2 mmol) in
methanol (3 mL) was stirred for 72 h at ambient temperature. After
completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane, 6/1), the precipitate was filtered off and washed with
methanol and the product 13a was obtained as white powders
(0.24 g, yield 45%); mp >270 ꢀC; Rf (17% n-hexane/AcOEt) 0.63. IR
(KBr) cmꢁ1: 3343, 3264, 3084, 2934, 2854, 1706, 1683, 1651, 1555,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.061.
References and notes
1518, 1467, 1404. 1H NMR (300.13 MHz, DMSO-d6)
d: 1.16e1.65
(20H, m, 10CH2 of cyclohexyl), 3.44 (2H, s, 2CHeNH), 4.02 (4H, m,
2CH2), 5.23 (2H, s, 2CH), 7.50e7.70 (8H, m, HeAr), 8.50 (2H, br s,
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