Rapid and convenient microwave-assisted synthesis of aromatic imides and N-hydroxymethylimides

Article abstract of DOI:10.1081/SCC-120018768

Extremely simple high-yielding and rapid microwave-assisted synthesis of wide array of aromatic mono and diimides and mono- and bis-N-hydroxymethylimides is reported.

Full text of DOI:10.1081/SCC-120018768

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Rapid and Convenient Microwave-Assisted Synthesis of
Aromatic Imides and N-Hydroxymethylimides
a
Karol Kacprzak
a
Department of Chemistry, Adam Mickiewicz University, Poznań, Poland
Version of record first published: 16 Aug 2006.
To cite this article: Karol Kacprzak (2003): Rapid and Convenient Microwave-Assisted Synthesis of Aromatic Imides and N-
Hydroxymethylimides, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:9, 1499-1507
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 9, pp. 1499–1507, 2003
Rapid and Convenient Microwave-Assisted
Synthesis of Aromatic Imides and
N-Hydroxymethylimides
Karol Kacprzak*
Department of Chemistry, Adam Mickiewicz
University, Poznan, Poland
´
ABSTRACT
Extremely simple high-yielding and rapid microwave-assisted
synthesis of wide array of aromatic mono and diimides and
mono- and bis-N-hydroxymethylimides is reported.
Key Words: Imides; N-hydroxymethylimides; Microwaves.
*Correspondence: Karol Kacprzak, Department of Chemistry, Adam Mickie-
wicz University, Ul. Grunwaldzka 6 60-780 Poznan, Poland; Fax: +48 61
´
8
658008; E-mail: k.michal@mailcity.com.
499
1
DOI: 10.1081/SCC-120018768
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1
500
Kacprzak
In the course of our studies on various systems containing aromatic
1,2]
[
imides as the chromophores,
we needed a reliable method for the
preparation of imides and their various derivatives, e.g., N-hydroxy-
methylimides. In particular we were interested in convenient synthesis
of bifunctional imides and N-hydroxymethylimides derived from
1
1
,2,4,5-benzenetetracarboxylic anhydride (pyromellitic anhydride) and
,4,5,8-naphthalenetetracarboxylic anhydride. These imides found
[
3]
[4–7]
numerous applications in polymer and supramolecular
chemistry.
were used also as nucleophiles in the
Mitsunobu reaction as well as in the synthesis of N-carboethoxy-
[8]
[6,7,9]
Aromatic mono and diimides
[10,11]
[12]
imides
and N-alkylphthalimides.
Various N-hydroxymethyl-
imides were reported to have potentially interesting pharmacological
[13,14]
properties.
Surprisingly, only a few general methods are available for pre-
paration of unsubstituted imides. These include the reaction of anhydrides
with either ue ra ,
Although simple, these procedures have some disadvantages as tedious
[15]
[3,7,14,16]
[17,18]
aqueous ammonia
orf om ramide.
[
3,7,17]
[17]
work-up (e.g., long high-vacuum heating
Well-known procedure for the synthesis of N-hydroxymethylimides
) or difficult to reproduce.
based on aqueous formaldehyde solution, requires prolonged heat-
[
14,19]
ing,
the yields are variable and isolation of the products can be
difficult. Newer method of the preparation of N-hydroxymethylphthali-
[
20]
mides involves the use of ultrasounds.
Since all of these reactions are thermal processes, we expected that
they could be significantly accelerated by microwave heating. This well-
recognized technique was used successfully in organic synthesis, also
in the area of aromatic imides chemistry, e.g., in the synthesis of
[12]
[21]
[22]
N-alkylphthalimides
amino acids.
and N-phthaloyl
or tetrachlorophthaloyl
We now report a very simple and rapid route to a wide array of
aromatic mono and bifunctional imides and N-hydroxymethylimides,
based on microwave acceleration of the imidation reaction.
Synthesis of Imides
The results are shown in Table 1.

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Aromatic Imides and N-Hydroxymethylimides
1501
Table 1. Microwave-assisted synthesis of aromatic imides.
Nucleophile/
solvent
Product
Power, time
Yield (%)
1
.1
.2
Formamide
Urea/DMF
650 W, 3 min
650 W, 3 min
90
80
1
Formamide
650 W, 3 min
64
1
1
.3
.4
Formamide
Formamide
650 W, 4 min
650 W, 3 min
96
79
1
.5
.6
Formamide
Urea/DMF
650 W, 4 min
650 W, 4 min
90
99
1
Formamide
85
1
1
1
.7
.8
.9
Formamide
Formamide
Formamide
600 W, 2.5 min
700 W, 5 min
700 W, 5 min
84
85
96

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1
502
Kacprzak
It was found that formamide is most universal, serving both as
a reagent and as a solvent and can be used in small quantities. In a
few cases urea in DMF or DMF/H O was also successfully used
2
(
see Table l).
Synthesis of N-hydroxymethylimides:
The results are shown in Table 2.
Hydroxymethylation was carried out with either aqueous
formaldehyde or with paraformaldehyde, the latter giving the products
with higher yields. These reactions were carried out in DMF
solution but with more soluble phthalimides water can also be used
as a solvent.
0
Attempts to synthesize N,N -bis-hydroxymethyl-1,4,5,8-naphthalene-
tetracarboxylic diimide by this method failed, probably due to the
extremely low solublility of the parent diimide.
EXPERIMENTAL
All reactions were performed in commercial microwave oven
Phillips/Whirlpool Model M600). Commercially available phthalic,
(
pyromellitic, 1,8-naphthalenedicarboxylic, 1,4,5,8-naphthalenetetra-
0
0
0
0
carboxylic, 3,3 ,4,4 -biphenyltetracarboxylic and 3,3 ,4,4 -benzophenone-
tetracarboxylic anhydrides (Aldrich) were used as received.
Other anhydrides were obtained from the corresponding diacids
1
by refluxing with acetic anhydride and crystallization. H NMR spectra
(
all in DMSO) were registered on a Varian or Bruker 300 MHz
spectrometer, with TMS as an internal reference. FT-IR spectra were
taken in KBrpellets on B ru kerIFS 113 v spect ro mete r. Melting points
¨
were determined on a Buchi melting point instrument B-545 and were
uncorrected. Note that melting points of N-hydroxymethylimides
are almost identical with the melting points of the corresponding
imides, due to thermal loss of formaldehyde, which can be determined
[3]
by DSC.

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Aromatic Imides and N-Hydroxymethylimides
1503
Table 2. Microwave-assisted synthesis of N-hydroxymethylimides.
a
Method , power, time
(min)
Yield
(%)
Product
2
.1
.2
A, 650 W, 7 min, H
A, 650 W, 5 min
B, 650 W, 4 min
2
O
97
97
80
2
A, 600 W, 2 min,
69
43
2
DMF–H O (3:1)
B, 600 W, 2 min
2
2
.3
.4
A, 650 W, 5 min
88
92
A, 650 W, 4 min
A, 750 W, 4 min
2
.5
92–98
80
B, 750 W, 4 min, aqueous
Formaldehyde–DMF (1:1)
2
.6
.7
A, 650 W, 4 min
A, 700 W, 4 min
83
98
2
2
.8
A, 600 W, 6 min,
92–98
2
DMF–H O (1:1)
a
Method A: paraformaldehyde/DMF, Method B: aqueous formaldehyde.

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504
Kacprzak
General Procedure for the Synthesis of Aromatic Imides
Well-powdered mixture of anhydride (1 mmol) with formamide
3–4 mL) or with urea (2 mmol of urea for monoanhydrides or 3 mmol
of urea for dianhydrides) in DMF (3–4 mL), (see Table 1), was placed in
50 mL Erlenmeyer flask covered with watch glass. The mixture was
(
2
irradiated in two intervals for total time and power as indicated in
Table 1. Usually the imides spontaneously crystallize at room temp-
erature (if not, water is added slowly for the precipitation). The products
were filtered, washed with water and dried. The purity of the imides is
high but if necessary they could be crystallized from dioxane, DMF or
DMSO-H O.
2
This procedure was used also for the preparation of gram quantities
of imides 1.5 and 1.9 (10 mL formamide for 4 g of pyromellitic
anhydride). In this case the use of fume hood is recommended due to
intensive formation of gases.
General Procedure for the Synthesis of
Aromatic N-Hydroxymethylimides
Well-powdered mixture of imide (0.4 mmol) and paraform-
aldehyde (1 equiv. formonoimides and 3 equiv. fordiimides) in
DMF (3–4 mL) was placed in 250 mL Erlenmeyer flask covered
with watch glass. The mixture was irradiated in two intervals for
total time and poweras indicated in Table 2 (an additional 2 mL
of DMF can be added if the solvent evaporates). Usually the product
spontaneously crystallize at room temperature (if not, water is added
slowly forthe p er cipitation). The p or duct was filte er d, washed with
water and dried. In some cases the crude products contained small
amount (ꢀ4%) of the substrate. If necessary pure N-hydroxymethyl-
imides can be obtained by crystallization form dioxane, DMF or
DMSO-H O.
2
Paraformaldehyde can be replaced by 2 mL of formaldehyde solution
for 1 mmol scale preparation of imides.
1
Phthalimide (1.1): H NMR ꢀ 11.4 (bs, 1H), 7.84 (s, 4H); IR ꢁ 3202,
À1
ꢁ
3
062, 1774, 1751, 1605, 1388, 1308, 1053, 715 cm , m.p. 230–233 C
ꢁ
(
lit. 234 C); yield 80–90%.
1
-Nitrophthalimide (1.2): H NMR ꢀ 11.8 (bs, 1H), 8.28 (m, 1H), 8.14
3
m, 1H), 8.11 (m, 1H); IR ꢁ 3173, 3075, 1771, 1708, 1615, 1538, 1357,
(
1
À1
ꢁ ꢁ
313, 1072, 846, 802 cm ; m.p. 217–219 C (lit. 215 C); yield 64%.

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Aromatic Imides and N-Hydroxymethylimides
1505
1
,4-Dichlorophthalimide (1.3): H NMR ꢀ 11.64 (bs, 1H), 8.13 (s, 2H);
3
IR ꢁ 3257, 3094, 1781, 1724, 1674, 1386, 1342, 1170, 1060, 903, 746 cm
À1
,
ꢁ
ꢁ
m.p. 218–220 C (lit. 221 C); yield 96%.
2
212, 3078, 1788, 1772, 1708, 1381, 1367, 1087, 754, 714 cm
1
,3,4,5-Tetrachlorophthalimide (1.4): H NMR ꢀ 11.9 (bs, 1H); IR ꢁ
À1
3
m.p. 341–343 C (lit. 340 C); yield 79%.
;
ꢁ
ꢁ
1
Pyromellitic diimide (1.5): H NMR ꢀ 11.8 (bs, 2H), 8.10 (s, 2H); IR ꢁ
À1
3198, 3068, 1772, 1698, 1378, 1357, 1156, 1061, 860, 727 cm ; does
not melt below 410 C (lit. 450 C); yield 99%.
ꢁ
ꢁ
0
0
1
,3 ,4,4 -Biphenyltetracarboxylic diimide (1.6): H NMR ꢀ 11.5
3
bs, 2H), 8.3 (m, 4H), 8.0 (m, 2H); IR ꢁ 3208, 1768, 1736, 1716, 1616,
(
1
À1
ꢁ
425, 1348, 1308, 1112, 1054, 853 cm ; does not melt below 400 C;
yield 85%.
0
0
1
3
,3 ,4,4 -Benzophenonetetracarboxylic diimide (1.7): H NMR ꢀ 11.7
(
bs, 2H), 8.18 (dd, J ¼ 1.6 Hz, J ¼ 7.7 Hz, 2H); 8.05 (m, 4H); IR ꢁ 3228,
À1
3070, 1782, 1728, 1703, 1667, 1362, 1247, 1102, 1045, 749, 721 cm
m.p. 380–385 C; yield 84%.
;
ꢁ
1
,8-Naphthalenedicarboxylic imide (1.8): H NMR ꢀ 11.7 (bs, 1H),
1
.47 (m, 4H), 7.89 (m, 2H); IR ꢁ 3176, 3061, 2827, 1701, 1683, 1348,
8
8
À1
ꢁ
ꢁ
44, 778 cm ; m.p. 300–302 C (lit. 299–300 C); yield 85%.
1
,4,5,8-Naphthalenetetracarboxylic diimide (1.9): H NMR ꢀ 12.1
1
bs, 2H), 8.63 (s, 4H); IR ꢁ 3170, 3069, 2854, 1701, 1678, 1374, 1338,
(
À1
ꢁ
8
64, 764 cm ; does not melt below 410 C; yield 96%.
1
N-Hydroxymethylphthalimide (2.1): H NMR ꢀ 7.95–7.87 (m, 4H),
6
1
.44 (t, J ¼ 7.1 Hz, IH), 4.99 (d, J ¼ 7.1 Hz, 2H); IR ꢁ 3445, 1774, 1726,
À1
ꢁ
ꢁ
468, 1053, 978, 713 cm ; m.p. 137–139 C (lit. 138–140 C); yield 97%.
N-Hydroxymethyl-3-nitrophthalimide (2.2):
1
H NMR
ꢀ
8.68
(
dd, 1H, J ¼ 2.2 Hz, J ¼ 8.2 Hz), 8.55 (d, J ¼ 0.5 Hz, 1H), 8.20 (m, 1H),
6
1
4
.60 (t, lH, J ¼ 7.1 Hz), 5.02 (d, 2H, J ¼ 6.8 Hz); IR ꢁ 3542, 1776, 1712,
-
1
ꢁ ꢁ
537, 1460, 1064, 987 cm ; m.p. 159–161 C (lit. 162–163 C); yield
3–69%.
1
N-Hydroxymethyl-3,4-dichlorophthalimide (2.3): H NMR ꢀ 8.25
(
1
9
s, 2H), 6.53 (t, J ¼ 7.1 Hz, 1H), 4.97 (d, J ¼ 7.1 Hz, 2H); IR ꢁ 3468,
780, 1707, 1456, 1409, 1388, 1357, 1191, 1143, 1047, 1104, 996,
15 cm ; m.p. 217–220 C; yield 88%.
N-Hydroxymethyl-2,3,4,5-tetrachlorophthalimide(2.4): H NMRꢀ6.62
À1
ꢁ
1
(
1
t, J ¼ 7.1 Hz, 1H), 4.98 (d, J ¼ 7.4 Hz, 2H); IR ꢁ 3520, 1786, 1713, 1460,
À1
ꢁ
080, 1004, 759, 737 cm ; m.p. 340 C; yield 92%.
0
1
N,N -bis-Hydroxymethylpyromellitic diimide (2.5): H NMR ꢀ 8.31
(
1
(
s, 2H), 6.59 (t, J ¼ 7.1 Hz, 2H), 5.03 (d, J ¼ 7.1 Hz, 4H); IR ꢁ 3477,
Àl
ꢁ
770, 1712, 1455, 1054, 977, 800, 744 cm ; does not melt below 410 C
ꢁ
lit. 146 C, DSC); yield 92–98%.

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1
506
N,N -bis-Hydroxymethyl-3,3 ,4,4 -biphenyltetracarboxylic
Kacprzak
diimide
0
0
0
1
(
2.6): H NMR ꢀ 8.4 (m, 4H), 8.0 (m, 2H); 6.49 (t, J ¼ 7.1 Hz, 2H), 5.02
(
d, J ¼ 7.1 Hz, 4H); IR ꢁ 3481, 3215, 1768, 1716, 1617, 1450, 1425, 1346,
À1
ꢁ
067, 980 cm ; does not melt below 350 C; yield 83%.
1
0
0
0
N,N -bis-Hydroxymethyl-3,3 ,4,4 -benzophenonetetracarboxylic diimide
1
(
2
1
2.7): H NMR ꢀ 8.24–8.21 (m, 2H), 8.15 (m, 4H), 6.53 (t, J ¼ 7.1 Hz,
H), 5.03 (d, J ¼ 7.1 Hz, 4H); IR ꢁ 3517, 1776, 1715, 1457, 1416, 1247,
À1
ꢁ ꢁ
061, 990, 730 cm ; m.p. 195 C (lit. 146 C, DSC); yield 98%.
N-Hydroxymethyl-1,8-naphthalenedicarboxylic imide (2.8): H NMR
1
ꢀ
8.53 (m, 4H), 7.91 (t, J ¼ 7.1, 2H), 6.37 (t, J ¼ 7.1 Hz, 1H), 5.49 (d,
À1
J ¼ 7.1 Hz, 2H); IR ꢁ 3403, 1698, 1660, 1460, 1060, 990, 781 cm
;
ꢁ
ꢁ
m.p. 300–302 C (lit. 304–306 C); yield 92–98%.
ACKNOWLEDGMENTS
Support from Komitet Badan Naukowych (KBN) grant No 7 T09A
´
37 20, is kindly acknowledged.
1
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Received in the UK January 25, 2002

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