A facile and convenient synthesis of 1H-isoindole-1,3(2H)-diones

Article abstract of DOI:10.3987/COM-06-10762

A facile synthesis of 1H-isoindole-1,3(2H)-diones (3a-h) has been developed by the reaction of the corresponding anhydrides (1a-h) with potassium cyanate (4a) or sodium thiocyanate (4b). The reactions were carried out in neutral media under reflux or under microwave irradiation without use of catalyst. Good to excellent yields of the products were obtained in high purity with very simple work-up.{A figure is presented}.

Full text of DOI:10.3987/COM-06-10762

HETEROCYCLES, Vol. 68, No. 8, 2006
1559
HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1559 - 1564. © The Japan Institute of Heterocyclic Chemistry
Received, 10th April, 2006, Accepted, 22nd June, 2006, Published online, 23rd June, 2006. COM-06-10762
A FACILE AND CONVENIENT SYNTHESIS OF
1H-ISOINDOLE-1,3(2H)-DIONES
Farzad Nikpour*, Samira Kazemi, and Davood Sheikh
Department of Chemistry, Faculty of Sciences, University of Kurdistan,
Sanandaj-Iran. fnikpour@uok.ac.ir & farzad_nikpour@yahoo.com
Abstract – A facile synthesis of 1H-isoindole-1,3(2H)-diones (3a-h) has been
developed by the reaction of the corresponding anhydrides (1a-h) with potassium
cyanate (4a) or sodium thiocyanate (4b). The reactions were carried out in neutral
media under reflux or under microwave irradiation without use of catalyst. Good
to excellent yields of the products were obtained in high purity with very simple
work-up.
Cyclic imides are extensively used in organic synthesis.1 Since many compounds containing this
heterocyclic nucleus are of biological or pharmacological interest,2-4 methods for the preparation of cyclic
imides skeletons, particularly 5-membered imides, have been extensively studied.5 Owing to their acidity
and the reactivity of secondary imides, the nitrogen atom of cyclic secondary imides may be easily
functionalized which makes cyclic tertiary imides versatile building blocks.6 In general, cyclic secondary
imides, most commonly 1H-isoindole-1,3(2H)-diones (phthalimides), are formed by the reaction of the
corresponding anhydrides (1) with ammonia or its salts. The reaction proceeds through phthalamic acid
intermediates (2), which in the second step cyclize to form the phthalimides (3) (Scheme 1).
O
O
O
NH3
or
- H2O
NH2
COOH
NH
O
+
(NH4 X -)
X
X
X
O
O
1
2
3
Scheme 1

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HETEROCYCLES, Vol. 68, No. 8, 2006
Here, we describe a practical and simple procedure for the synthesis of secondary phthalimide derivatives
(3) by reaction of phthalic anhydride derivatives (1) with potassium cyanate (4a) or sodium thiocyanate7
(4b). This method could also be utilized for the synthesis of a variety of cyclic secondary imides other
than five-membered imides. There is, so far, no report to use of metallic salts of cyanate or thiocyanate in
the synthesis of phthalimide derivatives. A plausible mechanism is shown in Scheme 2.
O
O
N
C
-
O
N
Y
Y
M+
O -
X
X
O
O
4a : KOCN
4b : NaSCN
5
1a-h
O
O
N -
O
-
N
O
H2O
- O=C=Y
C
Y
N H
X
X
X
O
O
O
6
3a-h
7
Scheme 2
We have found that when a mixture of phthalic anhydride derivatives (1a-h) and potassium cyanate (4a)
or sodium thiocyanate (4b) was refluxed in dimethylformamide (DMF), the corresponding imides (3a-h)
were generated in good yields. Extending of our previous works,5a, 8, 9 employing microwave-assisted
conditions, we carried out these reactions under microwave irradiations10 in DMF, which was recognized
as an excellent energy-transfer medium, to reduce the reaction time. As expected, the reaction proceeded
fastly to give the imides (3a-h) in good to excellent yields within 10 min. However, even under
microwave irradiation, the reaction did not proceed under solvent free or solid state conditions. The
reaction also proceeded in a green solvent, aqueous ethanol, in place of DMF in the presence of KOCN
(4a) under microwave irradiation. These facts indicated that microwave irradiations cause faster energy
transfer to chemical bonds relative to the classical heating (refluxing) to accelerate molecular rotation and,
thus, reaction rate leading to a significant time saving and often improving product yields. In all cases, the
products (3a-h) were isolated in neutral media with easy work-up. As it is observed, the cyanate (4a)
gives better yield than the thiocyanate (4b) probably because of stronger nucleophility of its nitrogen
atom in the former reagent7 (Table 1).

HETEROCYCLES, Vol. 68, No. 8, 2006
1561
Table 1 : Synthesis of compounds (3a-h)a from the reaction of 1a-h with KOCN (4a) or NaSCN (4b)
Reflux in DMF
KOCN (4a) NaSCN (4b)
Time Yield Time Yield
(hour) 3 (%)b (hour) 3 (%)b
Microwave irradiation in DMF (or EtOH/H2O)
KOCN (4a)
NaSCN (4b)
Power
(watt)
Time
(min.) 3 (%)b
Yield
Power Time Yield
(watt) (min.) 3 (%)b
1
O
a
O
3
6
88
83
5
8
80
78
500
0.6
92
500
600
2
5
80
75
(500)c
(2)c
(90)c
O
Br
Br
O
Br
b
600
(600)c
3
(5)c
89
(80)c
O
Br
O
O
c
O
7
78
8
71
500
(500)c
2
(6)c
80
(68)c
500
3
72
O
NO2
O
d
e
O
7
5
80
85
8
6
74
79
700
2
77
600
600
3.5
5
67
62
HOOC
(600)c
(5)c
(73)c
O
O
O
600
(600)c
0.5
(5)c
75
(70)c
O
O
f
O
5
5
6
88
78
84
6
6
7
80
77
79
400
2
80
400
500
600
5
5
8
75
65
60
(500)c
(2)c
(65)c
O
O
g
h
O
500
(600)c
3
(4)c
78
(75)c
O
O
600
(700)c
8
(6)c
83
(74)c
O
O
a All products were identified and characterized by physical and spectral data. b Isolated yields. c In EtOH/H2O.
In conclusion, the synthesis of some cyclic secondary imides is developed by the reaction of
corresponding anhydrides with potassium cyanate or sodium thiocyanate in neutral media. This is a facile
and clean method for the synthesis of cyclic secondary imides, particularly phthalimide derivatives. The
reactions proceed without use of catalyst to produce good to excellent yields of the products in high
purity with very simple work-up.
ACKNOWLEDGEMENTS
We are thankful to the Kurdistan University Research Council for partial support of this work.
REFERENCES (AND NOTES)
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HETEROCYCLES, Vol. 68, No. 8, 2006
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7. Cyanates or thiocyanates are ambident nucleophiles. When the counter ions are Na+ and K+, A and C
are predominant and N-terminal has higher nucleophilicity than O-terminal and S-terminal. However,
+
when the counter ion is NH4 , the nucleophilicity is inversed. For example, see: (a) M. Moghadam, S.
Tangestaninejad, V. Mirkhani, and R. Shaibani, Tetrahedron, 2004, 60, 6105. (b) H. Sharghi, M. A.
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_
_
_
_
O
;
N
C
O
N
C
S
C
N
C
S
N
A
D
B
C
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Q.-X. Guo, Heterocycles, 2004, 63, 903. (c) A. de la Hoz, A. Diaz-Ortiz, and A. Moreno, Chem. Soc.
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Ellis, Curr. Org. Synth. 2005, 2, 333. (f) B. A. Roberts and C. R. Strauss, Acc. Chem. Res., 2005, 38,
653.
Microwave irradiations were carried out in a Butane oven Model MB310. The starting materials

HETEROCYCLES, Vol. 68, No. 8, 2006
1563
were purchased (Merck) and used.
Caution! For more safety, especially when DMF are used in microwave oven, all experiments should
be performed in an efficient hood in order to avoid the contact of vapors.
General procedure:
A mixture of 1 mmol carboxylic anhydrides (1a-h), 0.08 g (1 mmol) of KOCN and 0.5 mL of DMF
or 1 mL of EtOH/H2O contained in a 15 mL beaker (equipped with a simple funnel) was placed in
the microwave oven and irradiated as indicated in Table 1. After completion of the reaction, the
precipitate was cooled to room temperature, then, 3 mL of ice-water was added and mixed with the
contents and filtered (three times). In reflux conditions, after completion of the reaction, the solvent
was removed under reduced pressure and then, the mixture was washed with ice-water (three times).
o
The products were collected and dried first in air and then in oven (50 C). The raw products were
recrystallized from EtOH, n-hexane/ EtOH or EtOH /AcOH.
Compound 2a: mp 236-238 oC [238 oC11].
Compound 2b: mp >330 oC [>370 oC12].
Compound 2c: mp 215-216 oC [214-215 oC13].
Compound 2e: mp 135-137 oC [136-137 oC14].
Compound 2d: White crystals from EtOH, mp 223-230 oC.
IR (KBr): ν = 3215-2540, 1781, 1709, 1684 cm-1.
1H NMR (200.1 MHz) in DMSO-d6: δ (ppm) = 7.87 (d, 3JHH = 7.7 Hz, 1H, arom. H), 8.18 (s, 1H, arom.
H), 8.31 (d, 3JHH = 7.7 Hz, 1H, arom. H), 11.48 (s, 1H, NH), 12.23 (bs, 1H, COOH)
13C NMR (50.3 MHz) in DMSO-d6: δ (ppm) = 173.23, 170.71, 167.34, 141.16, 140.78, 139.98, 137.91,
128.09, 128.03.
EI-MS (70 eV): m/z (%) = 191 (M+˙, 90), 174 (M+ - OH, 100), 146 (M+ - CO2H, 58), 104 (C7H4O+,
67), 76 (C6H4+, 78).
Compound 2f: White crystals from n-hexane/ EtOH, mp 96-98 oC.
IR (KBr): ν = 3215, 1764, 1711 cm-1.
1H NMR (200.1 MHz) in CDCl3: δ (ppm) = 1.72 (s, 3H, CH3), 2.38-2.14 (m, 2H, CH2), 2.56-2.40 (m,
2H, CH2), 3.16-3.01 (m, 2H, 2CH), 5.54 (dd, 3JHH = 2.8 Hz, 3JHH = 1.6 Hz, 1H, =CH), 8.82 (bs, 1H,
NH).
13C NMR (50.3 MHz) in CDCl3: δ (ppm) = 181.45, 177.2, 136.09, 119.81, 40.49, 40.00, 28.13, 23.67,
23.21.
+
+
EI-MS (70 eV): m/z (%) = 165 (M+˙, 94), 94 (M+ - CO - HNCO, 70), 93 (C7H9 , 88), 91 (C7H7 , 38),
79 (C6H7 , 100), 77 (C6H5 , 3).
+
+
Compound 2g: White crystals from n-hexane/EtOH, mp 120-123 oC.
IR (KBr): ν = 3210, 1774, 1751, 1718 cm-1.
1H NMR (200.1 MHz) in CDCl3: δ (ppm) = 1.49-1.43 (m, 4H, 2CH2), 1.84-1.79 (m, 4H, 2CH2),
2.96-2.84 (m, 2H, 2CH), 8.37 (bs, 1H, NH).

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HETEROCYCLES, Vol. 68, No. 8, 2006
13C NMR (50.3 MHz) in CDCl3: δ (ppm) = 179.74, 40.75, 23.45, 21.51.
EI-MS (70 eV): m/z (%) = 153 (M+˙, 39), 82 (M+ - CO - HNCO, 97), 67 (C5H7 , 100), 54 (C4H6 ˙,
+
+
51).
Compound 2h: White crystals from n-hexane/EtOH, mp 135-138 oC.
IR (KBr): ν = 3216, 1779, 1704, 1693 cm-1.
1H NMR (200.1 MHz) in CDCl3: δ (ppm) = 1.48-1.39 (m, 2H, CH2), 1.79 (s, 3H, CH3), 2.78-2.68 (m,
2H, 2CH), 3.00 (s, 1H, CH), 3.19 (s, 1H, CH), 5.77 (s, 1H, =CH), 8.70 (bs, 1H, NH).
13C NMR (50.3 MHz) in CDCl3: δ (ppm) = 178.51, 178.34, 147.72, 129.95, 50.71, 49.31, 48.23, 44.84,
42.15, 14.90.
+
+
+
+
EI-MS (70 eV): m/z (%) = 177 (M+˙, 9), 91 (C7H7 , 11), 80 (C6H8 ˙, 100), 79 (C6H7 , 35), 77 (C6H5 ,
3).
11. W. A. Noyes and P. K. Porter, Org. Synth. Coll. Vol., 1941, 1, 457.
12. H. A. Cyba, US Patent, 3873567, 1975, (Int. Cl. C07d 27/52).
13. N. Rabjohn, M. F. Drumm, and R. L. Elliott, J. Am. Chem. Soc., 1956, 78, 1631.
14. T. Nagase, Bull. Chem. Soc. Jpn, 1964, 37, 1175.