Diels-alder reaction of 2-(cyclic amino)-substituted 3-furancarbonitriles with maleimides to phthalimides

Article abstract of DOI:10.3987/COM-08-S(F)34

An efficient Diels-Alder reaction is described in the furan series, leading to phthalimides in high yields. Thermal treatment of 2-(4-morpholinyl, 1-piperidinyl, and l-pyrrolidinyl)-3-furancarbonitriles with maleimide derivatives, e.g. maleimide, N-methyl

Full text of DOI:10.3987/COM-08-S(F)34

HETEROCYCLES, Vol. 77, No. 1, 2009
617
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 617 - 628. © The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2008, Accepted, 6th August, 2008, Published online, 7th August, 2008.
DOI: 10.3987/COM-08-S(F)34
DIELS-ALDER REACTION OF 2-(CYCLIC AMINO)-SUBSTITUTED
3-FURANCARBONITRILES WITH MALEIMIDES TO PHTHALIMIDES
Hiroshi Maruoka,* Fumi Okabe, Yoshimichi Koutake, Toshihiro Fujioka,
and Kenji Yamagata
Faculty of Pharmaceutical Sciences, Fukuoka University, 8−19−1 Nanakuma,
Jonan−ku, Fukuoka 814−0180, Japan
E-mail: maruoka@fukuoka-u.ac.jp
Abstract – An efficient Diels-Alder reaction is described in the furan series,
leading to phthalimides in high yields. Thermal treatment of 2-(4-morpholinyl,
1-piperidinyl, and 1-pyrrolidinyl)-3-furancarbonitriles with maleimide derivatives,
e.g. maleimide, N-methylmaleimide, N-benzylmaleimide, N-phenylmaleimide and
N-(4-nitrophenyl)maleimide, in boiling acetic acid caused a [4 + 2] cycloaddition
reaction to give the corresponding phthalimide derivatives.
INTRODUCTION
Synthetic cyclic imides, such as succinimides, maleimides, glutarimides, phthalimides and related
compounds, possess structural features, which confer potential biological activity and pharmaceutical use.
Their molecules contain an imide ring so that they are hydrophobic and neutral, and can therefore cross
biological membranes in vivo. Thalidomide is one of them, which was introduced as a sedative drug, was
removed from the market because of its teratogenicity.1,2 Recently, thalidomide proved its activity as
potential inhibitor of TNF-α production3 and this immunosuppressive property led to its use in the
treatment of graft-versus-host disease, leprosy, Behcet’s disease, lupus erythematosus, and other related
diseases.4−9 Furthermore, a new pharmacologically interesting compound within the series of phthalimides,
10
NAN-190, is reported as a well-recognized antagonist of postsynaptic receptors 5-HT1A (Figure 1). On
the basis of these findings, many laboratories are engaged in the synthesis of various phthalimide
derivatives.11−23 For the reasons given above, the synthesis of cyclic imides, especially phthalimide
derivatives, is now receiving considerable interest.
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Dihydrofuran and furan derivatives widely occur as important structural units in a variety of natural
products that can be applied as pharmaceuticals, flavor and fragrance compounds.24−26 Because they are
useful and versatile synthetic intermediates for heterocyclic compounds, the development of
methodologies for the synthesis of such compounds are of significant interest. Among the most
significant examples in the furan chemistry, Diels-Alder cycloadditions using this heterocycle as the 4π
diene are of particular interest.27−29 This pericyclic process is one of the most employed strategies for the
construction of six-membered rings. There are only a few cases in the literature where [4 + 2]
cycloadditions of 2-aminofurans have been investigated. 2-Aminofurans revealed especially useful
partners in the preparation of cyclohexadiene derivatives and polysubstituted anilines. However, the
preparation of 2-aminofurans is only scarcely reported and mainly requires several steps such as
cyclopropenone ring opening in the presence of carbonyl metals,30 preparation of nitrofuroate followed by
Pd-catalyzed reduction,31 dinitration of furan and subsequent displacement of one nitro group by an
amine,32 or metal-free amination of bromoheterocycles.33 In the course of our studies on heterocyclic
β-enaminonitriles, we have already reported the synthesis of 2-(cyclic amino)-substituted
4,5-dihydro-3-furancarbonitriles 1−4.34,35 In this context, we planned the synthesis of a series of 4-(cyclic
amino)-substituted phthalimide derivatives in order to expand the scope application of the Diels-Alder
reaction of maleimides by using 2-(cyclic amino)-substituted 3-furancarbonitriles as starting materials.
O
O
Me
N
O
N
O
NH
NH
O
O
O
O
Thalidomide
Methylthalidomide
O
N
N
N
O
MeO
NAN-190
Figure 1. Chemical structures of thalidomide, methylthalidomide, and NAN-190.
RESULTS AND DISCUSSION
In the first step, we tried the dehydrogenation of dihydrofurans 1−4 to furans using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). As a consequence, when 1−4 were treated with DDQ
in refluxing 1,4-dioxane, the expected 2-(cyclic amino)-substituted 3-furancarbonitriles 5−8 were
obtained in moderate to good yields (5: 92%, 6: 90%, 7: 96%, 8: 55%, Scheme 1). Elemental analyses,

HETEROCYCLES, Vol. 77, No. 1, 2009
619
1
mass spectra, H and 13C NMR spectra of 5−8 are consistent with the assigned structures (see
experimental section).
R
R1
N
CN
CN
R
DDQ
C6H5
1, 5
2, 6
3, 7
4, 8
N
N
N
O
R1
R1
N
R
R
N
R
R
O
O
1,4-dioxane
C6H5
C6H5
Me
1!4
5!8
N
O
Scheme 1
In the next step, we examined the cycloaddition reaction of 2-(cyclic amino)-substituted
3-furancarbonitriles 5−8 with maleimides 9a−e to phthalimide derivatives 10−13. The best results are
shown in Scheme 2 and Table 1. Indeed, when a mixture of 5−8 and maleimides 9a−e in acetic acid was
refluxed for 8 h, the desired phthalimides 10a−e, 11a−e, 12a−e, and 13a−e were obtained in moderate to
good yields. The IR spectra of 10−13 display bands near 2220 cm-1 due to a conjugated cyano group, and
in the range of 1770−1702 cm-1 due to two imido carbonyl groups. The 13C NMR spectra of 10−13 show a
signal near δ 116 due to the cyano carbon, and two signals near δ 166 due to the imido carbonyl carbon.
By comparison of the IR spectra, NMR spectra, mass spectra and elemental analyses of 10−13, it seems
that the structural assignments given to these compounds are correct.
These Diels-Alder reactions are assumed to proceed through the formation of the oxabridged
cycloadducts A. The literature has only a few examples of the isolation of the oxabridged
cycloadducts.32,36,37 In this reaction, such intermediates A were not observed. In all cases, aromatization
into phthalimide derivatives 10−13 spontaneously results from a ring-opening reaction of cycloadducts A
with an acid and subsequent dehydration of the ring-opening intermediates B. It is a fact that when these
cycloadditions were carried out under the milder reaction conditions, the intermediary of [4 + 2]
cycloadducts A and/or B could not be isolated but instead 2-(cyclic amino)-substituted
3-furancarbonitriles 5−8 were recovered unchanged. It makes us believe that the ring-opening reaction of
cycloadducts A and dehydration of the ring-opening intermediates B can be promoted by using acetic acid
not only as a solvent but also as a catalyst.
In conclusion, the Diels-Alder reaction of 2-(cyclic amino)-substituted 3-furancarbonitriles with
maleimides proceeds smoothly to furnish the corresponding phthalimide derivatives. Functionalized
phthalimide derivatives are important synthons in organic synthesis and for the preparation of
biologically active compounds with interest in medicinal chemistry.

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HETEROCYCLES, Vol. 77, No. 1, 2009
R
R
O
CN
O
N
NC
AcOH
H
R2
+
N
R1
N
R
R
H
O
R1
O
O
N
R
O
5!8
9a!e
R2
A
R
R
R
N
O
N
OH
NC
NC
4
7
3
5
6
N
R2
2
O
!H2O
1
H
R1
N
O
R1
R2
O
10a!e, 11a!e, 12a!e, 13a!e
B
R
R1
N
9!13 R2
R
a
H
C6H5
5,10
6,11
7,12
8,13
N
N
N
O
b
c
Me
C6H5
C6H5
Me
CH2C6H5
C6H5
d
e
4-NO2-C6H4
N
O
Scheme 2
Table 1. Synthesis of phthalimide derivatives 10!13 according to Scheme 2.
Entry
Sustrate
Product
Yield (%)
Entry
Sustrate
Product
Yield (%)
1
2
5
5
5
5
5
6
6
6
6
6
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
91
90
78
73
85
86
94
92
88
77
11
12
13
14
15
16
17
18
19
20
7
7
7
7
7
8
8
8
8
8
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
62
82
77
81
52
80
88
75
81
82
3
4
5
6
7
8
9
10

HETEROCYCLES, Vol. 77, No. 1, 2009
621
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer.
The 1H and 13C NMR spectra were measured with a JEOL JNM-A500 spectrometer at 500.00 and 125.65
1
13
MHz, respectively. The H and C chemical sifts (δ) are reported in parts per million (ppm) relative to
tetramethylsilane as internal standard. Positive FAB mass spectra were obtained on a JEOL JMS-700T
spectrometer. Elemental analyses were performed on YANACO MT-6 CHN analyzer. The starting
compounds, 2-(cyclic amino)-substituted 4,5-dihydro-3-furancarbonitriles 1-4, were prepared in this
laboratory according to the procedure reported in literature.34,35
General procedure for the preparation of 2-(cyclic amino)-substituted 3-furancarbonitriles 5−8.
A mixture of 1-4(20 mmol) and DDQ (4.99 g, 22 mmol) in 1,4-dioxane (40 mL) was refluxed for 1 h (in
the case of the preparation of 5−7) or 30 min (in the case of the preparation of 8). The solid was removed
by filtration and washed with 1,4-dioxane. The combined filtrates were concentrated in vacuo. The
residue was purified by column chromatography on alumina with CH2Cl2 as the eluent to give 5−8.
2-(4-Morpholinyl)-5-phenyl-3-furancarbonitrile (5)
Colorless columns (4.65 g, 92%), mp 107−108 °C (acetone/petroleum ether); IR (KBr): 2202 (CN) cm-1;
1H NMR (CDCl3): δ 3.64 (t, J = 4.9 Hz, 4H, 2NCH2), 3.84 (t, J = 4.9 Hz, 4H, 2OCH2), 6.58 (s, 1H, 4-H),
13
7.21−7.25 (m, 1H, aryl H), 7.32−7.36 (m, 2H, aryl H), 7.44−7.47 (m, 2H, aryl H); C NMR (CDCl3):
δ 46.4 (2NCH2), 66.0 (2OCH2), 70.4 (C-3), 106.8 (C-4), 116.4 (CN), 122.9, 127.4, 128.8, 129.2 (C aryl),
144.5 (C-5), 161.3 (C-2); MS: m/z 255 [M+H]+; Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02.
Found: C, 70.93; H, 5.59; N, 11.02.
5-Phenyl-2-(1-piperidinyl)-3-furancarbonitrile (6)
Colorless prisms (4.54 g, 90%), mp 117−118 °C (CH2Cl2/petroleum ether); IR (KBr): 2195 (CN) cm-1; 1H
NMR (CDCl3): δ 1.64−1.75 (m, 6H, 3CH2), 3.58−3.66 (m, 4H, 2NCH2), 6.56 (s, 1H, 4-H), 7.19−7.22 (m,
1H, aryl H), 7.31−7.35 (m, 2H, aryl H), 7.45−7.47 (m, 2H, aryl H); 13C NMR (CDCl3): δ 23.9 (piperidine
C-4), 25.2 (piperidine C-3, 5), 47.5 (2NCH2), 68.9 (C-3), 107.1 (C-4), 117.2 (CN), 122.7 127.0, 128.7,
129.5 (C aryl), 143.4 (C-5), 161.7 (C-2); MS: m/z 253 [M+H]+; Anal. Calcd for C16H16N2O: C, 76.16; H,
6.39; N, 11.10. Found: C, 76.14; H, 6.41; N, 11.06.
5-Phenyl-2-(1-pyrrolidinyl)-3-furancarbonitrile (7)
Colorless columns (4.58 g, 96%), mp 133−134 °C (acetone/petroleum ether); IR (KBr): 2194 (CN) cm-1;
1H NMR (CDCl3): δ 2.01−2.04 (m, 4H, 2CH2), 3.68−3.71 (m, 4H, 2NCH2), 6.56 (s, 1H, 4-H), 7.17−7.21
(m, 1H, aryl H), 7.30−7.35 (m, 2H, aryl H), 7.43−7.46 (m, 2H, aryl H); 13C NMR (CDCl3): δ 25.4 (2CH2),
47.8 (2NCH2), 66.9 (C-3), 107.0 (C-4), 117.5 (CN), 122.5 126.7, 128.7, 129.7 (C aryl), 143.3 (C-5),
160.5 (C-2); MS: m/z 239 [M+H]+; Anal. Calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C,
75.67; H, 6.03; N, 11.67.

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5-Methyl-2-(4-morpholinyl)-3-furancarbonitrile (8)
1
Colorless columns (2.11 g, 55%), mp 56−57 °C (Et2O/petroleum ether); IR (KBr): 2204 (CN) cm-1; H
NMR (CDCl3): δ 2.15 (s, 3H, CH3), 3.05−3.51 (m, 4H, 2NCH2), 3.78−3.80 (m, 4H, 2OCH2), 5.91−5.92
13
(m, 1H, 4-H); C NMR (CDCl3): δ 12.9 (CH3), 46.6 (2NCH2), 66.0 (2OCH2), 68.8 (C-3), 107.0 (C-4),
116.8 (CN), 142.7 (C-5), 161.3 (C-2); MS: m/z 193 [M+H]+; Anal. Calcd for C10H12N2O2: C, 62.49; H,
6.29; N, 14.57. Found: C, 62.46; H, 6.31; N, 14.51.
General procedure for the preparation of phthalimide derivatives 10-13 from 5-8 and maleimides 9.
A mixture of 5-8 (5 mmol) and maleimide (0.97 g, 10 mmol), N-methylmaleimide (1.11 g, 10 mmol),
N-benzylmaleimide (1.87 g, 10 mmol), N-phehylmaleimide (1.73 g, 10 mmol), or N-(4-
nitrophenyl)maleimide (2.18 g, 10 mmol) in acetic acid (5 mL) was refluxed for 8 h. After removal of the
solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed
with water, dried and recrystallized from an appropriate solvent to yield 10-13.
2,3-Dihydro-4-(4-morpholinyl)-1,3-dioxo-7-phenyl-1H-isoindole-5-carbonitrile (10a)
Yellow needles (1.52 g, 91%), mp 310−311 °C (acetone); IR (KBr): 3160 (NH), 2224 (CN), 1766, 1722
(CO) cm-1; 1H NMR (DMSO-d6): δ 3.48−3.52 (m, 4H, 2NCH2), 3.78−3.81 (m, 4H, 2OCH2), 7.39−7.44 (m,
13
3H, aryl H), 7.45−7.52 (m, 2H, aryl H), 7.98 (s, 1H, 6-H), 11.39 (s, 1H, NH); C NMR (DMSO-d6): δ
51.9 (2NCH2), 66.7 (2OCH2), 111.1 (C aryl), 117.6 (CN), 123.9, 127.7, 128.2, 129.4, 132.8, 134.0, 134.8
(C aryl), 142.8 (C-6), 148.9 (C aryl), 166.5, 167.1 (CO); MS: m/z 334 [M+H]+; Anal. Calcd for
C19H15N3O3: C, 68.46; H, 4.54; N, 12.61. Found: C, 68.49; H, 4.62; N, 12.62.
2,3-Dihydro-2-methyl-4-(4-morpholinyl)-1,3-dioxo-7-phenyl-1H-isoindole-5-carbonitrile (10b)
Yellow prisms (1.56 g, 90%), mp 192−193 °C (acetone); IR (KBr): 2224 (CN), 1761, 1712 (CO) cm-1; 1H
NMR (DMSO-d6): δ 2.97 (s, 3H, CH3), 3.51 (t, J = 4.6 Hz, 4H, 2NCH2), 3.81 (t, J = 4.6 Hz, 4H, 2OCH2),
13
7.42−7.44 (m, 3H, aryl H), 7.50−7.53 (m, 2H, aryl H), 8.00 (s, 1H, 6-H); C NMR (DMSO-d6): δ 23.8
(CH3), 51.9 (2NCH2), 66.7 (2OCH2), 111.1 (C aryl), 117.6 (CN), 123.0, 127.7, 128.2, 129.4, 132.6, 133.3,
134.7 (C aryl), 142.9 (C-6), 148.5 (C aryl), 165.4, 165.9 (CO); MS: m/z 348 [M+H]+; Anal. Calcd for
C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.16; H, 5.03; N, 12.07.
2,3-Dihydro-4-(4-morpholinyl)-1,3-dioxo-7-phenyl-2-(phenylmethyl)-1H-isoindole-5-carbonitrile
(10c)
Orange needles (1.65 g, 78%), mp 183−184 °C (acetone); IR (KBr): 2221 (CN), 1760, 1706 (CO) cm-1;
1H NMR (DMSO-d6): δ 3.53 (t, J = 4.6 Hz, 4H, 2NCH2), 3.80 (t, J = 4.6 Hz, 4H, 2OCH2), 4.70 (s, 2H,
CH2C6H5), 7.24−7.32 (m, 5H, aryl H), 7.42−7.44 (m, 3H, aryl H), 7.51−7.53 (m, 2H, aryl H), 8.03 (s, 1H,
6-H); 13C NMR (DMSO-d6): δ 41.0 (CH2C6H5), 51.9 (2NCH2), 66.7 (2OCH2), 111.1 (C aryl), 117.6 (CN),
122.5, 127.3, 127.4, 127.7, 128.3, 128.4, 129.4, 132.7, 132.9, 134.6, 136.4 (C aryl), 143.2 (C-6), 148.8 (C
aryl), 165.1, 165.7 (CO); MS: m/z 424 [M+H]+; Anal. Calcd for C26H21N3O3: C, 73.74; H, 5.00; N, 9.92.

HETEROCYCLES, Vol. 77, No. 1, 2009
623
Found: C, 73.74; H, 5.09; N, 9.93.
2,3-Dihydro-4-(4-morpholinyl)-1,3-dioxo-2,7-diphenyl-1H-isoindole-5-carbonitrile (10d)
Orange prisms (1.50 g, 73%), mp 197−198 °C (acetone); IR (KBr): 2222 (CN), 1768, 1717 (CO) cm-1; 1H
NMR (DMSO-d6): δ 3.55−3.58 (m, 4H, 2NCH2), 3.79−3.82 (m, 4H, 2OCH2), 7.38−7.45 (m, 6H, aryl H),
13
7.47−7.51 (m, 2H, aryl H), 7.56−7.58 (m, 2H, aryl H), 8.08 (s, 1H, 6-H); C NMR (DMSO-d6): δ 52.0
(2NCH2), 66.7 (2OCH2), 110.8 (C aryl), 117.6 (CN), 122.5, 127.5, 127.7, 128.0, 128.3, 128.6, 129.5,
131.7, 132.8, 133.0, 134.7 (C aryl), 143.3 (C-6), 148.9 (C aryl), 164.4, 164.9 (CO); MS: m/z 410 [M+H]+;
Anal. Calcd for C25H19N3O3: C, 73.34; H, 4.68; N, 10.26. Found: C, 73.71; H, 4.79; N, 10.22.
2,3-Dihydro-4-(4-morpholinyl)-2-(4-nitrophenyl)-1,3-dioxo-7-phenyl-1H-isoindole-5-carbonitrile
(10e)
Orange needles (1.91 g, 85%), mp 234−235 °C (acetone); IR (KBr): 2222 (CN), 1770, 1722 (CO) cm-1;
1H NMR (DMSO-d6): δ 3.58 (t, J = 4.6 Hz, 4H, 2NCH2), 3.82 (t, J = 4.6 Hz, 4H, 2OCH2), 7.43−7.46 (m,
3H, aryl H), 7.57−7.60 (m, 2H, aryl H), 7.73−7.75 (m, 2H, aryl H), 8.11 (s, 1H, 6-H), 8.35−8.38 (m, 2H,
aryl H); 13C NMR (DMSO-d6): δ 52.0 (2NCH2), 66.7 (2OCH2), 110.8 (C aryl), 117.6 (CN), 122.3, 123.9,
127.8, 127.9, 128.3, 129.4, 132.8, 134.6, 137.5 (C aryl), 143.6 (C-6), 146.2, 149.0 (C aryl), 163.8, 164.3
(CO); MS: m/z 455 [M+H]+; Anal. Calcd for C25H18N4O5: C, 66.08; H, 3.99; N, 12.33. Found: C, 66.09; H,
4.11; N, 12.27.
2,3-Dihydro-1,3-dioxo-7-phenyl-4-(1-piperidinyl)-1H-isoindole-5-carbonitrile (11a)
Orange needles (1.44 g, 86%), mp 256−257 °C (acetone); IR (KBr): 3186 (NH), 2222 (CN), 1767, 1715
(CO) cm-1; 1H NMR (DMSO-d6): δ 1.60−1.75 (m, 6H, 3CH2), 3.40−3.48 (m, 4H, 2NCH2), 7.40−7.43 (m,
13
3H, aryl H), 7.49−7.51 (m, 2H, aryl H), 7.93 (s, 1H, 6-H), 11.31 (s, 1H, NH); C NMR (DMSO-d6): δ
23.2 (piperidine C-4), 26.1 (piperidine C-3, 5), 53.0 (2NCH2), 111.1 (C aryl), 117.6 (CN), 123.3, 127.6,
128.0, 129.4, 131.9, 134.1, 134.9 (C aryl), 142.8 (C-6), 149.9 (C aryl), 166.4, 167.1 (CO); MS: m/z 332
[M+H]+; Anal. Calcd for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.48; H, 5.23; N, 12.64.
2,3-Dihydro-2-methyl-1,3-dioxo-7-phenyl-4-(1-piperidinyl)-1H-isoindole-5-carbonitrile (11b)
Orange needles (1.62 g, 94%), mp 189−190 °C (acetone); IR (KBr): 2224 (CN), 1763, 1713 (CO) cm-1;
1H NMR (DMSO-d6): δ 1.69−1.74 (m, 2H, piperidine 4-CH2), 1.81−1.86 (m, 4H, piperidine 3, 5-CH2),
13
3.09 (s, 3H, CH3), 3.53−3.56 (m, 4H, 2NCH2), 7.41−7.44 (m, 5H, aryl H), 7.74 (s, 1H, 6-H); C NMR
(DMSO-d6): δ 23.8 (piperidine C-4), 24.0 (CH3), 26.6 (piperidine C-3, 5), 53.9 (2NCH2), 111.8 (C aryl),
117.9 (CN), 122.1, 128.1, 128.7, 129.3, 132.8, 133.5, 134.9 (C aryl), 143.5 (C-6), 150.6 (C aryl), 165.9,
166.4 (CO); MS: m/z 346 [M+H]+; Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17. Found: C,
73.01; H, 5.59; N, 12.18.
2,3-Dihydro-1,3-dioxo-7-phenyl-2-(phenylmethyl)-4-(1-piperidinyl)-1H-isoindole-5-carbonitrile
(11c)

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HETEROCYCLES, Vol. 77, No. 1, 2009
Orange prisms (1.93 g, 92%), mp 181−182 °C (acetone); IR (KBr): 2224 (CN), 1761, 1712 (CO) cm-1; 1H
NMR (DMSO-d6): δ 1.62−1.66 (m, 2H, piperidine 4-CH2), 1.70−1.76 (m, 4H, piperidine 3, 5-CH2),
3.45−3.48 (m, 4H, 2NCH2), 4.69 (s, 2H, CH2C6H5), 7.23−7.32 (m, 5H, aryl H), 7.40−7.44 (m, 3H, aryl H),
13
7.50−7.53 (m, 2H, aryl H), 7.98 (s, 1H, 6-H); C NMR (DMSO-d6): δ 23.2 (piperidine C-4), 26.1
(piperidine C-3, 5), 41.0 (CH2C6H5), 53.1 (2NCH2), 111.3 (C aryl), 117.6 (CN), 122.0, 127.3, 127.4,
127.7, 128.2, 128.4, 129.4, 132.0, 133.0, 134.7, 136.5 (C aryl), 143.2 (C-6), 149.8 (C aryl), 165.0, 165.7
(CO); MS: m/z 422 [M+H]+; Anal. Calcd for C27H23N3O2: C, 76.94; H, 5.50; N, 9.97. Found: C, 76.89; H,
5.57; N, 9.94.
2,3-Dihydro-1,3-dioxo-2,7-diphenyl-4-(1-piperidinyl)-1H-isoindole-5-carbonitrile (11d)
Orange needles (1.79 g, 88%), mp 200−201 °C (acetone); IR (KBr): 2223 (CN), 1767, 1718 (CO) cm-1;
1H NMR (DMSO-d6): δ 1.64−1.67 (m, 2H, piperidine 4-CH2), 1.71−1.76 (m, 4H, piperidine 3, 5-CH2),
3.49−3.51 (m, 4H, 2NCH2), 7.38−7.43 (m, 6H, aryl H), 7.47−7.51 (m, 2H, aryl H), 7.55−7.57 (m, 2H,
13
aryl H), 8.03 (s, 1H, 6-H); C NMR (DMSO-d6): δ 23.2 (piperidine C-4), 26.1 (piperidine C-3, 5), 53.1
(2NCH2), 111.0 (C aryl), 117.7 (CN), 122.0, 127.5, 127.7, 128.0, 128.1, 128.6, 129.4, 131.8, 132.1, 133.0,
134.8 (C aryl), 143.3 (C-6), 149.9 (C aryl), 164.4, 165.0 (CO); MS: m/z 408 [M+H]+; Anal. Calcd for
C26H21N3O2: C, 76.64; H, 5.19; N, 10.31. Found: C, 76.73; H, 5.27; N, 10.26.
2,3-Dihydro-2-(4-nitrophenyl)-1,3-dioxo-7-phenyl-4-(1-piperidinyl)-1H-isoindole-5-carbonitrile
(11e)
Orange needles (1.74 g, 77%), mp 192−193 °C (acetone/petroleum ether); IR (KBr): 2222 (CN), 1767,
1
1720 (CO) cm-1; H NMR (DMSO-d6): δ 1.63−1.69 (m, 2H, piperidine 4-CH2), 1.72−1.78 (m, 4H,
piperidine 3, 5-CH2), 3.51−3.54 (m, 4H, 2NCH2), 7.42−7.45 (m, 3H, aryl H), 7.56−7.59 (m, 2H, aryl H),
13
7.73−7.76 (m, 2H, aryl H), 8.07 (s, 1H, 6-H), 8.34−8.37 (m, 2H, aryl H); C NMR (DMSO-d6): δ 23.2
(piperidine C-4), 26.1 (piperidine C-3, 5), 53.1 (2NCH2), 111.0 (C aryl), 117.6 (CN), 121.7, 123.9, 127.7,
127.9, 128.2, 129.4, 132.1, 132.9, 134.7, 137.6 (C aryl), 143.6 (C-6), 146.1, 150.0 (C aryl), 163.7, 164.4
(CO); MS: m/z 453 [M+H]+; Anal. Calcd for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.01; H,
4.57; N, 12.27.
2,3-Dihydro-1,3-dioxo-7-phenyl-4-(1-pyrrolidinyl)-1H-isoindole-5-carbonitrile (12a)
Orange needles (0.98 g, 62%), mp 220−221 °C (acetone); IR (KBr): 3195 (NH), 2212 (CN), 1756, 1704
(CO) cm-1; 1H NMR (DMSO-d6): δ 1.92−1.96 (m, 4H, 2CH2), 3.79−3.83 (m, 4H, 2NCH2), 7.37−7.42 (m,
13
3H, aryl H), 7.47−7.49 (m, 2H, aryl H), 7.82 (s, 1H, 6-H), 11.14 (s, 1H, NH); C NMR (DMSO-d6): δ
25.4 (2CH2), 53.2 (2NCH2), 102.2 (C aryl), 116.8 (CN), 119.4, 127.6, 127.7, 127.8, 129.3, 134.3, 135.1
(C aryl), 143.9 (C-6), 145.5 (C aryl), 167.0, 167.2 (CO); MS: m/z 318 [M+H]+; Anal. Calcd for
C19H15N3O2: C, 71.91; H, 4.76; N, 13.24. Found: C, 71.87; H, 4.81; N, 13.26.
2,3-Dihydro-2-methyl-1,3-dioxo-7-phenyl-4-(1-pyrrolidinyl)-1H-isoindole-5-carbonitrile (12b)

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625
Orange needles (1.37 g, 82%), mp 185−186 °C (acetone); IR (KBr): 2214 (CN), 1752, 1702 (CO) cm-1;
1H NMR (DMSO-d6): δ 1.93−1.96 (m, 4H, 2CH2), 2.93 (s, 3H, CH3), 3.81−3.84 (m, 4H, 2NCH2),
13
7.38−7.42 (m, 3H, aryl H), 7.48−7.50 (m, 2H, aryl H), 7.85 (s, 1H, 6-H); C NMR (DMSO-d6): δ 23.8
(CH3), 25.4 (2CH2), 53.2 (2NCH2), 102.6 (C aryl), 115.9 (CN), 119.3, 127.6, 127.8, 127.9, 129.3, 133.6,
135.0 (C aryl), 143.9 (C-6), 145.4 (C aryl), 165.9, 166.1 (CO); MS: m/z 332 [M+H]+; Anal. Calcd for
C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.51; H, 5.24; N, 12.73.
2,3-Dihydro-1,3-dioxo-7-phenyl-2-(phenylmethyl)-4-(1-pyrrolidinyl)-1H-isoindole-5-carbonitrile
(12c)
1
Red needles (1.57 g, 77%), mp 161−162 °C (acetone); IR (KBr): 2216 (CN), 1754, 1706 (CO) cm-1; H
NMR (DMSO-d6): δ 1.93−1.96 (m, 4H, 2CH2), 3.82−3.85 (m, 4H, 2NCH2), 4.67 (s, 2H, CH2C6H5),
13
7.23−7.32 (m, 5H, aryl H), 7.38−7.41 (m, 3H, aryl H), 7.48−7.50 (m, 2H, aryl H), 7.88 (s, 1H, 6-H); C
NMR (DMSO-d6): δ 25.4 (2CH2), 40.9 (CH2C6H5), 53.3 (2NCH2), 102.8 (C aryl), 115.4 (CN), 119.2,
127.2, 127.3, 127.6, 127.8, 128.0, 128.4, 129.4, 133.2, 134.9, 136.6 (C aryl), 144.2 (C-6), 145.5 (C aryl),
165.6, 165.7 (CO); MS: m/z 408 [M+H]+; Anal. Calcd for C26H21N3O2: C, 76.64; H, 5.19; N, 10.31.
Found: C, 76.74; H, 5.34; N, 10.23.
2,3-Dihydro-1,3-dioxo-2,7-diphenyl-4-(1-pyrrolidinyl)-1H-isoindole-5-carbonitrile (12d)
1
Red needles (1.59 g, 81%), mp 216−217 °C (acetone); IR (KBr): 2216 (CN), 1758, 1712 (CO) cm-1; H
NMR (DMSO-d6): δ 1.94−1.97 (m, 4H, 2CH2), 3.85−3.88 (m, 4H, 2NCH2), 7.37−7.41 (m, 6H, aryl H),
13
7.46−7.49 (m, 2H, aryl H), 7.53−7.56 (m, 2H, aryl H), 7.94 (s, 1H, 6-H); C NMR (DMSO-d6): δ 25.4
(2CH2), 53.4 (2NCH2), 102.6 (C aryl), 115.5 (CN), 119.3, 127.5, 127.7, 127.8, 128.1, 128.6, 129.4, 131.9,
133.2, 135.0 (C aryl), 144.2 (C-6), 145.7 (C aryl), 164.9, 165.0 (CO); MS: m/z 394 [M+H]+; Anal. Calcd
for C25H19N3O2: C, 76.32; H, 4.87; N, 10.68. Found: C, 76.38; H, 5.01; N, 10.60.
2,3-Dihydro-2-(4-nitrophenyl)-1,3-dioxo-7-phenyl-4-(1-pyrrolidinyl)-1H-isoindole-5-carbonitrile
(12e)
Orange prisms (1.13 g, 52%), mp 177−178 °C (acetone); IR (KBr): 2212 (CN), 1749, 1702 (CO) cm-1; 1H
NMR (DMSO-d6): δ 1.95−1.98 (m, 4H, 2CH2), 3.86−3.89 (m, 4H, 2NCH2), 7.39−7.44 (m, 3H, aryl H),
13
7.55−7.57 (m, 2H, aryl H), 7.72−7.75 (m, 2H, aryl H), 7.96 (s, 1H, 6-H), 8.32−8.36 (m, 2H, aryl H); C
NMR (DMSO-d6): δ 25.4 (2CH2), 53.4 (2NCH2), 102.5 (C aryl), 115.1 (CN), 119.2, 123.9, 127.69,
127.72, 127.9, 128.1, 129.4, 133.1, 134.9, 137.7 (C aryl), 144.5 (C-6), 145.8, 145.9 (C aryl), 164.1, 164.5
(CO); MS: m/z 439 [M+H]+; Anal. Calcd for C25H18N4O4: C, 68.49; H, 4.14; N, 12.78. Found: C, 68.42; H,
4.42; N, 12.86.
2,3-Dihydro-7-methyl-4-(4-morpholinyl)-1,3-dioxo-1H-isoindole-5-carbonitrile (13a)
Yellow needles (1.09 g, 80%), mp 227−228 °C (acetone); IR (KBr): 3168 (NH), 2225 (CN), 1761, 1720
(CO) cm-1; 1H NMR (DMSO-d6): δ 2.51 (d, J = 0.6 Hz, 3H, CH3), 3.39−3.41 (m, 4H, 2NCH2), 3.75−3.77

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13
(m, 4H, 2OCH2), 7.94 (q, J = 0.6 Hz, 1H, 6-H), 11.47 (s, 1H, NH); C NMR (DMSO-d6): δ 15.9 (CH3),
51.6 (2NCH2), 66.7 (2OCH2), 111.4 (C aryl), 117.7 (CN), 123.6, 130.3, 134.7 (C aryl), 143.2 (C-6), 148.3
(C aryl), 166.7, 168.5 (CO); MS: m/z 272 [M+H]+; Anal. Calcd for C14H13N3O3: C, 61.99; H, 4.83; N,
15.49. Found: C, 61.99; H, 4.93; N, 15.42.
2,3-Dihydro-2,7-dimethyl-4-(4-morpholinyl)-1,3-dioxo-1H-isoindole-5-carbonitrile (13b)
Yellow needles (1.26 g, 88%), mp 183−184 °C (acetone); IR (KBr): 2220 (CN), 1755, 1704 (CO) cm-1;
1H NMR (DMSO-d6): δ 2.53 (d, J = 0.6 Hz, 3H, 7-CH3), 2.29 (s, 3H, 2-CH3), 3.42 (t, J = 4.6 Hz, 4H,
13
2NCH2), 3.77 (t, J = 4.6 Hz, 4H, 2OCH2), 7.97 (q, J = 0.6 Hz, 1H, 6-H); C NMR (DMSO-d6): δ 16.0
(7-CH3), 23.7 (2-CH3), 51.6 (2NCH2), 66.6 (2OCH2), 111.3 (C aryl), 117.6 (CN), 122.7, 130.1, 134.0 (C
aryl), 143.3 (C-6), 148.0 (C aryl), 165.6, 167.2 (CO); MS: m/z 286 [M+H]+; Anal. Calcd for C15H15N3O3:
C, 63.15; H, 5.30; N, 14.73. Found: C, 63.12; H, 5.29; N, 14.63.
2,3-Dihydro-7-methyl-4-(4-morpholinyl)-1,3-dioxo-2-(phenylmethyl)-1H-isoindole-5-carbonitrile
(13c)
Yellow needles (1.36 g, 75%), mp 146−147 °C (acetone); IR (KBr): 2221 (CN), 1762, 1712 (CO) cm-1;
1H NMR (DMSO-d6): δ 2.54 (d, J = 0.6 Hz, 3H, CH3), 3.43 (t, J = 4.6 Hz, 4H, 2NCH2), 3.76 (t, J = 4.6
13
Hz, 4H, 2OCH2), 4.73 (s, 2H, CH2C6H5), 7.24−7.34 (m, 5H, aryl H), 8.00 (q, J = 0.6 Hz, 1H, 6-H); C
NMR (DMSO-d6): δ 16.0 (CH3), 40.8 (CH2C6H5), 51.7 (2NCH2), 66.6 (2OCH2), 111.4 (C aryl), 117.6
(CN), 122.2, 127.28, 127.34, 128.4, 130.3, 133.6, 136.4 (C aryl), 143.6 (C-6), 148.2 (C aryl), 165.2, 167.0
(CO); MS: m/z 362 [M+H]+; Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.84; H,
5.34; N, 11.48.
2,3-Dihydro-7-methyl-4-(4-morpholinyl)-1,3-dioxo-2-phenyl-1H-isoindole-5-carbonitrile (13d)
Yellow columns (1.40 g, 81%), mp 171−172 °C (acetone); IR (KBr): 2219 (CN), 1765, 1711 (CO) cm-1;
1H NMR (DMSO-d6): δ 2.58 (d, J = 0.6 Hz, 3H, CH3), 3.47 (t, J = 4.6 Hz, 4H, 2NCH2), 3.77 (t, J = 4.6
Hz, 4H, 2OCH2), 7.40−7.46 (m, 3H, aryl H), 7.50−7.54 (m, 2H, aryl H), 8.05 (q, J = 0.6 Hz, 1H, 6-H); 13C
NMR (DMSO-d6): δ 16.2 (CH3), 51.7 (2NCH2), 66.6 (2OCH2), 111.0 (C aryl), 117.7 (CN), 122.2, 127.5,
128.1, 128.7, 130.3, 131.6, 133.7 (C aryl), 143.7 (C-6), 148.3 (C aryl), 164.6, 166.3 (CO); MS: m/z 348
[M+H]+; Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N, 12.10. Found: C, 69.32; H, 5.04; N, 12.01.
2,3-Dihydro-7-methyl-4-(4-morpholinyl)-2-(4-nitrophenyl)-1,3-dioxo-1H-isoindole-5-carbonitrile
(13e)
Orange needles (1.60 g, 82%), mp 204−205 °C (acetone); IR (KBr): 2219 (CN), 1764, 1715 (CO) cm-1;
1H NMR (DMSO-d6): δ 2.59 (d, J = 0.6 Hz, 3H, CH3), 3.49 (t, J = 4.6 Hz, 4H, 2NCH2), 3.78 (t, J = 4.6
Hz, 4H, 2OCH2), 7.74−7.78 (m, 2H, aryl H), 8.08 (q, J = 0.6 Hz, 1H, 6-H), 8.37−8.40 (m, 2H, aryl H); 13C
NMR (DMSO-d6): δ 16.2 (CH3), 51.7 (2NCH2), 66.6 (2OCH2), 111.1 (C aryl), 117.7 (CN), 121.9, 124.0,
127.9, 130.4, 133.6, 137.4 (C aryl), 144.0 (C-6), 146.2, 148.4 (C aryl), 163.9, 165.6 (CO); MS: m/z 393

HETEROCYCLES, Vol. 77, No. 1, 2009
627
[M+H]+; Anal. Calcd for C20H16N4O5: C, 61.22; H, 4.11; N, 14.28. Found: C, 61.27; H, 4.15; N, 14.25.
REFERENCES
1. F. O. Kelsey, Teratology, 1988, 38, 221.
2. Y. Shibata, K. Sasaki, Y. Hashimoto, and S. Iwasaki, Chem. Pharm. Bull., 1996, 44, 156.
3. E. P. Sampaio, E. N. Sarno, R. Galilly, Z. A. Cohn, and G. Kaplan, J. Exp. Med., 1991, 173, 699.
4. T. Randall, J. Am. Med. Assoc., 1990, 263, 1467.
5. M. Siadak and K. M. Sullivan, Blood. Rev., 1994, 8, 154.
6. R. Feldmann, D. Salomon, and J.-H. Saurat, Dermatology, 1994, 189, 425.
7. Y. Hashimoto, Chemistry Today, 1994, 283, 38.
8. G. Kaplan, Immunobiol., 1994, 191, 564.
9. P. M. Parker, N. Chao, A. Nademanee, M. R. O’Donnell, G. M. Schmidt, D. S. Snyder, A. S. Stein,
E. P. Smith, A. Molina, D. E. Stepan, A. Kashyap, I. Planas, R. Spielberger, G. Somlo, K. Margolin,
K. Zwingenberger, K. Wilsman, R. S. Negrin, G. D. Long, J. C. Niland, K. G. Blume, and S. J.
Forman, Blood, 1995, 86, 3604.
10. R. K. Raghupathi, L. Rydelek-Fitzgerald, M. Teitler, and R. A. Glennon, J. Med. Chem., 1991, 34,
2638.
11. Y. Shibata, M. Shichita, K. Sasaki, K. Nishimura, Y. Hashimoto, and S. Iwasaki, Chem. Pharm.
Bull., 1995, 43, 177.
12. M. S. Khajavi, F. Nikpour, and M. Hajihadi, J. Chem. Res. (S), 1996, 96.
13. D. Bogdal, J. Pielichowski, and A. Boron, Synlett, 1996, 873.
14. H. Miyachi, A. Azuma, A. Ogasawara, E. Uchimura, N. Watanabe, Y. Kobayashi, F. Kato, M. Kato,
and Y. Hashimoto, J. Med. Chem., 1997, 40, 2858.
15. H. Miyachi, A. Ogasawara, A. Azuma, and Y. Hashimoto, Bioorg. Med. Chem., 1997, 5, 2095.
16. Y. Peng, G. Song, and X. Qian, Synth. Commun., 2001, 31, 1927.
17. B. Martin, H. Sekljic, and C. Chassaing, Org. Lett., 2003, 5, 1851.
18. L. M. Lima, P. Castro, A. L. Machado, C. A. M. Fraga, C. Lugnier, V. L. G. de Moraes, and E. J.
Barreiro, Bioorg. Med. Chem., 2002, 10, 3067.
19. K. Kacprzak, Synth. Commun., 2003, 33, 1499.
20. K. Mogilaiah and G. R. Reddy, Indian J. Chem., 2004, 43B, 882.
21. F. Nikpour, S. Kazemi, and D. Sheikh, Heterocycles, 2006, 68, 1559.
22. E. P. S. Falcão, S. J. de Melo, R. M. Srivastava, M. T. J. A. Catanho, and S. C. D. Nascimento, Eur.
J. Med. Chem., 2006, 41, 276.
23. S. H. L. Kok, R. Gambari, C. H. Chui, M. C. W. Yuen, E. Lin, R. S. M. Wong, F. Y. Lau, G. Y. M.

628
HETEROCYCLES, Vol. 77, No. 1, 2009
Cheng, W. S. Lam, S. H. Chan, K. H. Lam, C. H. Cheng, P. B. S. Lai, M. W. Y. Yu, F. Cheung, J. C.
O. Tang, and A. S. C. Chan, Bioorg. Med. Chem., 2008, 16, 3626.
24. F. M. Dean, ‘Advances in Heterocyclic Chemistry: Recent Advances in Furan Chemistry. Part II,’
Vol. 31, ed. by A. R. Katritzky, Academic Press, Inc., New York, 1982, pp. 237−344.
25. M. V. Sargent and F. M. Dean, ‘Comprehensive Heterocyclic Chemistry: Furans and their Benzo
Derivatives: (ii) Reactivity,’ Vol. 4, eds. by C. W. Bird and G. W. H. Cheeseman, Pergamon Press,
Oxford, 1984, pp. 599−656.
26. H. Heaney and J. S. Ahn, ‘Comprehensive Heterocyclic Chemistry II: Furans and their Benzo
Derivatives: Reactivity,’ Vol. 2, eds. by A. R. Katritzky, C. W. Rees, and E. F. V. Scriven,
Pergamon Press, Oxford, 1996, pp. 297−350.
27. J. L. Isidor, M. S. Brookhart, and R. L. McKee, J. Org. Chem., 1973, 38, 612.
28. A. O. Abdelhamid, A. M. Negm, and I. M. Abbas, J. Prakt. Chem., 1989, 331, 31.
29. R. Medimagh, S. Marque, D. Prim, S. Chatti, and H. Zarrouk, J. Org. Chem., 2008, 73, 2191.
30. N. Chatani and T. Hanafusa, J. Org. Chem., 1987, 52, 4408.
31. J. E. Cochran, T. Wu, and A. Padwa, Tetrahedron Lett., 1996, 37, 2903.
32. A. Padwa, M. Dimitroff, A. G. Waterson, and T. Wu, J. Org. Chem., 1997, 62, 4088.
33. D. Prim and G. Kirsch, Tetrahedron, 1999, 55, 6511.
34. K. Yamagata, M. Takaki, and M. Yamazaki, Liebigs Ann. Chem., 1992, 1109.
35. K. Yamagata, K. Akizuki, and M. Yamazaki, J. Prakt. Chem., 1998, 340, 51.
36. R. H. Schlessinger, T. R. R. Pettus, J. P. Springer, and K. Hoogsteen, J. Org. Chem., 1994, 59, 3246.
37. R. H. Schlessinger, and C. P. Bergstrom, Tetrahedron Lett., 1996, 37, 2133.