Re-examination of microwave-induced synthesis of phthalimides

Article abstract of DOI:10.1016/S0040-4020(00)00445-2

Solvent-free microwave reactions between phthalic anhydride and amino compounds need at least one liquid phase. The reaction occurs after melting of anhydride and subsequent solubilisation in amines. So, reactions between two solids may not take place and need the use of a high boiling point solvent. In all cases, excellent yields are obtained within short reaction times with products of high purity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00445-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5473±5478
Re-examination of Microwave-Induced Synthesis of Phthalimides
a
Thierry Vidal, Alain Petit, Andre Loupy and Richard N. Gedye
a
a,
b
*
Â
a
  Á  à Â
Reactivite et Synthese Selective, UMR 8615, I.C.M.O., Bat. 410, Universite de Paris-Sud, 91405 Orsay Cedex, France
bDepartment of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada P3E 2C6
Received 16 December 1999; accepted 25 May 2000
AbstractÐSolvent-free microwave reactions between phthalic anhydride and amino compounds need at least one liquid phase. The reaction
occurs after melting of anhydride and subsequent solubilisation in amines. So, reactions between two solids may not take place and need the
use of a high boiling point solvent. In all cases, excellent yields are obtained within short reaction times with products of high purity. q 2000
Elsevier Science Ltd. All rights reserved.
Imide derivatives constitute an important class of organic
compounds with numerous uses in biology,1 synthetic2 and
polymer chemistry.3 Despite their wide applicability, avail-
able routes for their synthesis are limited. Generally most
methods involve Lewis acid mediated condensation of an
amine with maleic or phthalic anhydrides.4 These methods
are limited by low yields, by-product formation and harsh
reaction conditions.5
catalyst has been described for the preparation of imides
under microwave irradiation.10
Finally, Sandhu et al.9 advocated the use of a more eco-
friendly solvent-free system involving the reaction of
equal amounts of anhydride and amines or amino acids in
the absence of solvent in a domestic oven without any cata-
lyst. In the case of the reaction of the anhydride with amino
acids, a reaction between two solids was involved, for
example between phthalic anhydride and glycine (Scheme
4). Unfortunately, no temperature measurements were
reported.
Substantial improvements in amine additions to carbonyl
compounds have been described using microwave (MW)
irradiation6 and this technique has been used in the one-
pot synthesis of phthalimides by the condensation of func-
tionalised amines with maleic or phthalic anhydride using a
domestic microwave oven.7a,8,9 Bose et al.7a reported that N-
phthalimides of amino acids could be synthesized in good
yields within few minutes by the microwave-assisted reac-
tion of phthalic anhydride with amino acids in DMF. In
contrast, these reactions had been carried out conventionally
by re¯uxing the reagents in toluene for 1.5 h.7b It was
concluded that the large rate enhancement was not only
due to thermolysis implying that a speci®c (non-thermal)
microwave effect was involved. The reaction of phthalic
anhydride with glycine was later re-examined by Westaway
and Gedye,8 who found that the rate of the reaction was
actually the same when carried out by MW or conventional
heating in DMF at the same temperature. Hence it was
concluded that the rate increase observed by Bose was
due to a change in solvent and temperature when DMF
was substituted for toluene.
These results are unexpected since no liquid phase was
present. This prompted the present re-examination of the
reaction using a monomode reactor with focused micro-
waves11,12 and accurate temperature monitoring. To investi-
gate the possibility of speci®c (non-thermal) effects, the
microwave activated reactions would then be compared
with similar reactions using conventional heating strictly
under the same conditions.13,14 Special attention would be
given to:
(i) The effect of the physical state of the reactants by using
phthalic anhydride (mp 131±1348C) and several amino
compounds either liquid (benzylamine) or solids with low
melting point (6-amino-1-hexanol, mp 56±588C; n-octa-
decylamine, mp 55±578C) where a liquid phase would be
present, or with a rather high melting point (Glycine, mp
2408C) where no liquid phase would be expected.
(ii) The possibility of intervention of speci®c MW effects,
by comparing reaction rates under microwave and
conventional heating, using identical conditions except
for the heating mode. In particular, it would be kept in
mind that slower reactions are likely to show greater
microwave rate enhancements than faster ones.16
Recently, a solvent-free procedure using TaCl5±silica gel as
Keywords: phthalic anhydride; microwave reactions; DMF; solvent-free
reaction.
* Corresponding author. Tel.: 133-1-69-15-7650; fax: 133-1-69-15-
4679; e-mail: aloupy@icmo.u-psud.fr
Also, the reactions would be carried out in the absence or
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00445-2

5474
T. Vidal et al. / Tetrahedron 56 (2000) 5473±5478
Scheme 1. Reaction with benzylamine 2a.
thermal behaviour induced by MW absorption, which is
mainly dependent on the polarity of the system.17 It is note-
worthy that a sharp increase in heating rate occurs around
the melting points of the products, presumably due to an
increase in polarity associated with the change from the
solid to the liquid phase. Thus, the thermal MW effect is
more pronounced with liquids than with solids. Reaction
with benzylamine 2a (Scheme 1).18
In the reaction of benzylamine with phthalic anhydride, both
reactants are of low polarity and therefore slightly MW
absorbent. As the polarity increases during the reaction19
due to development of partial charges in the transition
state compared with initial one, the solvent-free reaction
shows a rapid rise in temperature to 1508C in less than
2 min (Fig. 1).
Figure 1. Thermal behaviour of 1 and 2a alone and their mixture under
MW irradiation.
After 5 min of irradiation, a crude yield of 95% of 3a was
obtained (90% of pure product after recrystallisation from
ethanol). Similar results were obtained under conventional
heating (D) using a thermostated oil bath (5 min, 1508C).
Therefore, in this case, there is no need for a solvent for the
reaction and there is no evidence for a speci®c microwave
effect (Entry 1, Table 1). Reaction with 6-amino-1-hexanol
2b (Scheme 2).
presence of a solvent, either polar or non-polar. In the case
of a polar solvent, although faster rates might be expected,
any speci®c or non-thermal microwave effects would be
masked due to absorption of microwaves by the solvent. On
the other hand, the possibility of speci®c effects would appear
to be greater in the presence of a non-polar solvent where
only the reactants would absorb microwave irradiation.15
The reaction with equivalent amounts of 1 and 2b under
MW activation in solvent-free conditions leads to a nearly
quantitative yield (97% based on isolated products) within
2 min with a ®nal temperature of 1608C (Fig. 2a). Heating in
an oil bath gave only 47% yield under similar conditions of
temperature and reaction time. The temperature±time
Results and Discussion
Prior to carrying out the reactions, the heating rate of each
reactant was studied under MW irradiation to evaluate the
Table 1. Synthesis of phthalimides 3a±3d under microwave activation (MW) or by conventional heating (D)
Entry
Compound
Solvent
Final temperature (8C)
Reaction time (min)
Yield (%) 3a
MW
D
1
2a
2b
None
150
5
95 (90)
95 (90)
2
3
4
None
None
Mesitylene
160
160
160
2
10
10
99 (97)
99 (97)
97
60 (47)
85
60
5
6
7
2c
None
None
Xylenes
150
120
120
15
15
15
95 (90)
75
75
93 (92)
73
71
8
9
10
11
2d
None
85
10
10
10
10
0
0
(90)
(81)
Toluene
Xylenes
DMF
110
135
150
(89)
(77)
a Yield evaluated by GC using an internal standard; yield in isolated product in brackets.

T. Vidal et al. / Tetrahedron 56 (2000) 5473±5478
5475
Scheme 2. Reaction with 6-amino-1-hexanol 2b.
Figure 2. (a) Thermal behaviour of 1 and 2b alone and their mixture under MW irradiation and in oil bath. (b) Thermal behaviour of the mixture of 1 and 2b in
mesitylene under MW irradiation and in oil bath.
pro®les for the reactions of 1 and 2b under solvent-free
conditions and in mesitylene are shown in Fig. 2a and b.
Under classical heating, the yield can be enhanced up to
85% by increasing the reaction time to 10 min. The yields
of reactions conducted in mesitylene are lower particularly
under classical heating (Entry 4, Table 1).
It is noteworthy that the reaction is chemoselective and
occurs speci®cally with the amino moiety. The starting
materials are completely converted into products in a very
short time (less than 2 min). When yields are not quantita-
tive, the complement to 100% is constituted by the inter-
mediate 4b. This compound was characterised by its H
NMR spectrum and by its easy transformation into its meth-
yl ester by reaction with diazomethane.
In this case, a solvent is not necessary and there is a
substantial rate enhancement in the MW heated reaction
(Entry 2, Table 1), presumably because of the higher polar-
ity of the amino alcohol 2b and its ability to interact strongly
with the microwaves. Thus there appears to be evidence for
1
Scheme 3. Reaction with n-octadecylamine 2c.

5476
T. Vidal et al. / Tetrahedron 56 (2000) 5473±5478
Figure 4. Thermal behaviour of 1 and 2d alone and their mixture under
MW irradiation.
Figure 3. Thermal behaviour of the mixture of 1 and 2c under MW irradia-
tion and in oil bath.
and 2d does not occur in the absence of solvent even after
10 min (Entry 8, Table 1). This could explain the much
lower melting point of Sandhu's product compared with
literature value for phthaloylglycine (mp9 110±1118C
instead of 1958C21) (Scheme 4). The mixture remains
solid since the temperature of the two reactants reaches
only 558C for 1 and 658C for 2d (Fig. 4).
a speci®c microwave in solvent-free media or in mesitylene
which could be explained either by modi®cations of acti-
vation parameters (DS#) or hot-spots in the reaction mixture.
It should be noted, however, that it was dif®cult to achieve
an identical temperature pro®le under MW and oil-bath
heating. Typically, as shown in Fig. 2a and b, the heating
rate of the MW reaction is initially lower than that of the oil-
bath reaction, but then increases rapidly to reach a tempera-
ture of about 408C, higher than the classically heated
mixture after about 80 s. Hence it is also possible that the
microwave effect could be a thermal one. Reaction with n-
octadecylamine 2c (Scheme 3).
Adding a high boiling point solvent, either polar (DMF) or
non-polar (xylenes) allows a rise in temperature up to
melting point of phthalic anhydride (131±1348C) (Fig. 5a
and b). This causes the reactants to dissolve in the solvent
and the reaction can occur in homogeneous medium with
satisfactory yields (Entries 10 and 11; Table 1) (Fig. 4).
N-Octadecylphthalimide 3c is obtained in 90±92% yield by
heating at 1508C in solvent-free conditions, whatever the
activation mode is (Entry 5, Table 1) (Fig. 3).
Some attempts were performed with maleic anhydride
(mpˆ54±568C) either in the absence or in the presence of
solvent (xylene, tetralin). Within 3 min under MW (max.
temperatureˆ1888C), the conversion is total. N-Carboxy-
methylmaleimide 5 is contaminated with more polar by-
products dif®cult to be separated after extraction with metha-
nol. The treatment indicated by Sandhu9 is not appropriated
as 5 is effectively insoluble in chloroform (Scheme 5).
At lower temperature (1208C), yields decrease to 73±75%
without any speci®c in¯uence of microwave or solvent
(Entries 6 and 7, Table 1). Conversions are total and the
complement to 100% is constituted by the amide acid 4c,
which is characterized by 1H NMR.
Conclusion
This study has established that the solvent-free MW reac-
tions need at least one liquid reactant. This is possible if a
liquid reactant (case 2a) or a solid with low melting point
able to melt rapidly (cases 2b and 2c) is used, giving a polar
liquid which is more prone to MW absorption. In these
Reaction with glycine 2d (Scheme 4). In contrast with
Sandhu's observation, the reaction between the solids 1
Scheme 4. Reaction with glycine 2d.

T. Vidal et al. / Tetrahedron 56 (2000) 5473±5478
5477
Figure 5. Thermal behaviour of solvent and phthalic anhydride in this solvent under MW irradiation: (a) xylenes; (b) DMF.
Crude products were analysed by capillary gas chroma-
tography (column CP Sil 5CB, 25 m) and the data are
shown in Table 2.
In a typical reaction, 9.15 mmol of benzylamine 2a (1 ml)
and 9.15 mmol of phthalic anhydride 1 (1.35 g) were intro-
duced into a Pyrex ¯ask, and then submitted to microwave
irradiation under conditions of time and temperature as indi-
cated. At the end of the irradiation, the reaction mixture was
cooled to room temperature. The crude solid was recrystal-
lised from ethanol to afford 1.95 g (8.23 mmol, 90%) of
pure 3a as white crystals.
Scheme 5. Reaction of maleic anhydride with glycine.
cases, the temperature may be over 1358C and the reaction
can occur after melting and solubilisation of phthalic anhy-
dride in the amines. If this situation is not involved (i.e. in
reactions between two solids) the reaction may not take
place and requires the use of a high boiling point solvent.
In all cases, excellent yields of phthalimides (.90%) are
obtained from the reaction of phthalic anhydride with amino
compounds within short reaction times (5±10 min) giving
products of high purity.
In the case of 2b, 2c and 2d, the same amounts of starting
materials were used. For the reactions carried out with
solvent, 2 mL of this solvent was used. At the end of
irradiation, the reaction mixtures were cooled and extracted
with acetone. The extracts were evaporated under reduced
pressure, analysed by GC (with internal standard) and puri-
®ed by chromatography on silica gel using pentane/diethyl
ether as eluant. Details of the NMR analysis of the products
are as follows:
Experimental
Microwave experiments were performed in a Synthewave
402w monomode reactor from Prolabo Company. All reac-
tions were conducted in a specially adapted cylindrical
Pyrex vessel. The mixtures were heated into the monomode
reactor at temperatures and for reaction times as indicated in
the table or in the ®gures. Continuous mechanical stirring
provided a good homogeneity of materials. The temperature
was controlled throughout the reaction and evaluated by an
infrared detector that indicated the surface temperature (IR
detector was calibrated by according the emissivity factor
using an optical ®bre inside the reaction mixture). A com-
puter system was used for automatic control of the irradia-
tion (power and temperature) as well as data processing.
N-Benzylphthalimide 3a: mp 118±1208C (lit.22 mp 110±
1168C); 1H NMR d (CDCl3, 250 MHz) 4.83 (s, 2H,
PhCH2N), 7.24±7.33 (m, 3H, ArH), 7.39±7.46 (m, 2H,
ArH), 7.66±7.77 (m, 2H, ArH (Pht)), 7.79±7.85 (m, 2H,
ArH (Pht)); 13C NMR d (CDCl3, 62.9 MHz) 41.5
(PhCH2N), 123.3, 127.8, 128.6, 133.9 (C Ar), 168.2 (CvO).
6-Phthalimidohexan-1-ol 3b: mp 46±488C (from: ethyl
1
acetate/hexane) (lit.23 mp 43±458C); H NMR d (DMSO
d6, 250 MHz) 1.30 (m, 4H, C4H and C3H), 1.40 and 1.58
(2 m, 4H, C5H and C2H), 3.37 (dt, 2H, C1H, J1-2
ˆ
J1-OHˆ6.4 Hz), 3.56 (t, 2H, C6H, Jˆ7.2 Hz), 4.38 (t, 1H,
OH), 7.77±7.94 (m, 4H, ArH (Pht)); 13C NMR d (CDCl3,
62.9 MHz) 25.1, 26.4, 28.4 (C5, C4 and C3), 32.4 (C2), 37.7
(C6), 62.4 (C1), 123.0, 133.8 (C Ar), 168.4 (CvO).
NMR spectra were recorded on Bruker AC 250 in solutions
with TMS as reference. Melting points were determined on
a BuÈchi melting point apparatus and are uncorrected.
Table 2. GC analysis
Compound
Temperature programation
Retention time (min)
Internal standard
Retention time of the
internal standard (min)
3b
3c
140±2608C with 108C/min
2808C
8.4
6.3
Diethyl phthalate
2-Ethylhexyl phthalate
3.7
3.0

5478
T. Vidal et al. / Tetrahedron 56 (2000) 5473±5478
N-(6-Hydroxy-hexyl)phthalamic acid 4b: 1H NMR d
(DMSO d6, 250 MHz) 1.30 (m, 4H, C4H and C3H), 1.40
and 1.58 (2 m, 4H, C5H and C2H), 2.78 (dt, 2H, C6H,
Tetrahedron Lett. 1999, 40, 3957±3960. (g) Seijas, J. A.; Vazquez-
Tato, P.; Montserrat-Martinez, M.; Nunez-Corredoira, G. J. Chem.
Res. (S) 1999, 420±421.
J6-5ˆJ6-NHˆ6.9 Hz), 3.37 (dt, 2H, C1H, J1-2ˆJ1-OH
ˆ
7. (a) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei,
K.; Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30, 741±744.
(b) Bose, A. K. Organic Synthesis, Collective Vol 5, 1973, pp
973±975.
7.1 Hz), 4.38 (t, 1H, OH), 6.12 (s, 1H, NH), 7.50 and 8.16
(m, 4H, ArH (Pht)).
N-Octadecylphthalimide 3c: mp 82±838C (lit.20 mp 78±
818C); H NMR d (CDCl3, 250 MHz) 0.85 (t, 3H, C18H,
8. Westaway, K. C.; Gedye, R. N. J. Microwave Power Electro-
magnetic Energy 1995, 30, 219±230.
1
Jˆ6.0 Hz), 1.17±1.42 (m, 28H, C3H to C17H), 1.65 (m,
2H, C2H), 3.68 (t, 2H, C1H, Jˆ7.4 Hz), 7.67±7.78 (m,
2H, ArH (Pht)), 7.8±7.9 (m, 2H, ArH (Pht)).
9. Borah, N. H.; Boruah, R. C.; Sandhu, J. S. J. Chem. Res. (S)
1998, 272±273.
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Raza, A. Synlett 1999, 1597±1599.
N-Octadecylphthalamic acid 4c: 1H NMR d (CDCl3,
250 MHz) 0.85 (t, 3H, C18H, Jˆ6.0 Hz), 1.17±1.42 (m,
30H, C3H to C17H), 1.65 (m, 2H, C2H), 3.35 (dt, 2H, C1H,
J1-NHˆJ1-2ˆ7.4 Hz), 6.60 (t, 1H, NH), 7.42 and 7.91 (m, 4H,
ArH (Pht)).
11. Grillo, A. C. Spectroscopy 1989, 4, 16±21.
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Â
Jacquault, P.; Mathe, D. Synthesis 1998, 1213±1234.
1
acetate/hexane) (lit.21 mp 1958C); H NMR d (Acetone d6,
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124.0, 132.8 and 135.3 (C Ar), 168.0 and 168.9 (COOH
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