Versatile and sustainable synthesis of cyclic imides from dicarboxylic acids and amines by Nb2O5 as a base-tolerant heterogeneous lewis acid catalyst

Article abstract of DOI:10.1002/chem.201404538

Catalytic condensation of dicarboxylics acid and amines without excess amount of activating reagents is the most atom-efficient but unprecedented synthetic method of cyclic imides. Here we present the first general catalytic method, proceeding selectively and efficiently in the presence of a commercial Nb₂O₅ as a reusable and base-tolerant heterogeneous Lewis acid catalyst. The method is effective for the direct synthesis of pharmaceutically or industrially important cyclic imides, such as phensuximide, N-hydroxyphthalimide (NHPI), and unsubstituted cyclic imides from dicarboxylic acid or anhydrides with amines, hydroxylamine, or ammonia.

Full text of DOI:10.1002/chem.201404538

DOI: 10.1002/chem.201404538
Communication
&
Organic Synthesis
Versatile and Sustainable Synthesis of Cyclic Imides from
Dicarboxylic Acids and Amines by Nb O as a Base-Tolerant
2
5
Heterogeneous Lewis Acid Catalyst
[a]
[b]
[a]
[a]
Md. Ayub Ali, S. M. A. Hakim Siddiki, Kenichi Kon, Junya Hasegawa, and Ken-
[a, b]
ichi Shimizu*
(
CO), no reusability of expensive catalysts, and difficulties in
[1a,15]
Abstract: Catalytic condensation of dicarboxylics acid and
amines without excess amount of activating reagents is
the most atom-efficient but unprecedented synthetic
method of cyclic imides. Here we present the first general
catalytic method, proceeding selectively and efficiently in
the presence of a commercial Nb O as a reusable and
catalyst/products separation. Hong et al.
reported the
atom-efficient synthesis of cyclic imides by dehydrogenative
coupling of diols and amines. However, the method has prob-
lems, such as limited substrate scope of diols and amines, no
catalyst reusability and the need of 0.2 equivalents of NaH.
Potentially, condensation of dicarboxylic acids with amines
can be a general synthetic route to cyclic imides. A few nonca-
talytic methods under harsh conditions (T=250-3808C, P=~
2
5
base-tolerant heterogeneous Lewis acid catalyst. The
method is effective for the direct synthesis of pharmaceut-
ically or industrially important cyclic imides, such as phen-
suximide, N-hydroxyphthalimide (NHPI), and unsubstituted
cyclic imides from dicarboxylic acid or anhydrides with
amines, hydroxylamine, or ammonia.
[5a,b]
330 bar) were reported.
Only one example of the catalytic
method using an organocatalyst is known, but the substrate
[5c]
scope is limited to only one example. The reaction might be
also catalyzed by Lewis acids, but co-presence of basic mole-
cules, amine and water (as byproduct), in the solution suppress
Lewis acidity by hindering coordination or irreversibly decom-
posing the catalyst. Recent reports showed that some metal
[16a]
Cyclic imides and their derivatives are an important class of
compounds with numerous applications in biological, medici-
oxides, such as Nb O ,
act as water-tolerant Lewis acid cata-
2
5
[16]
lysts. If a metal oxide acts as a Lewis acid catalyst even in
the presence of stronger base, such as amines, they can effec-
tively catalyze the condensation of dicarboxylic acids with
amines. In the course of our own studies into developing effi-
cient amide bond-forming reactions by metal oxides or Lewis
[
1,2]
nal, synthetic, and polymer chemistry
and are used as inter-
[
1a,b,2]
mediates in dyes and polymer industries.
Despite their
wide applicability, synthetic methods of cyclic imides from
readily available starting materials are limited. The typical
[
1,3–5]
[17]
methods
are the dehydrative condensation of an anhy-
acidic catalysts, we have found that Nb O shows “base-tol-
2
5
dride with an amine at high temperatures or in the presence
of an excess amount of promoter (Lewis acid, base, dehydrat-
erant” catalysis for this reaction. Herein, we report the first
general catalytic method of direct cyclic imide synthesis from
dicarboxylic acids with amines and ammonia under mild condi-
tions using Nb O catalyst prepared by calcination of a com-
[
3]
ing agent, or ionic liquids) and the cyclization of an amic acid
[
4]
with the help of acidic reagents, which suffer from low atom
efficiency and production of byproducts. Although new syn-
2
5
mercial niobic acid. The method is effective for the direct syn-
thesis of some industrially important cyclic imides, including N-
hydroxyphthalimide and unsubstituted cyclic imides.
[
6]
[7]
[8]
thetic routes from nitriles, halides, alkyne, pyridin-2-yl-
[
9]
[10]
[11,12a]
methylamines, aryl boronic acids,
aliphatic amides,
[
12b]
[13]
[14]
cyclic amines, isocyanates, and phthalimide using tran-
sition-metal catalysis (carbonylation, oxidation, etc.)
First, the reaction between an equimolar amount of succinic
acid and n-octylamine under reflux conditions in hexane was
tested as a model reaction to optimize the different parame-
ters (Table 1). Under the conditions in which the reaction
hardly proceeded in the absence of catalyst (Table 1, entry 1),
we screened 14 types of metal oxides (entries 2–14). In the
oxide catalysts tested, Nb O shows the highest yield (99%) of
[6–13]
or
[
14]
excess amounts of I(III) oxidant have been developed, these
homogeneous catalytic methods have drawbacks of narrow
substrate scope, needs of various additives or toxic reagents
2
5
[
a] M. A. Ali, Dr. K. Kon, Prof. J. Hasegawa, Dr. K.-i. Shimizu
Catalysis Research Center, Hokkaido University, N-21
W-10, Sapporo 001-0021 (Japan)
the corresponding imide. Conventional solid Lewis acids (TiO
2
[18]
and g-Al O )
show moderate yields (entries 4, 6). We also
2
3
Fax: (+81)11-706-9163
E-mail: kshimizu@cat.hokudai.ac.jp
tested water-tolerant Brønsted acidic heterogeneous cata-
[19]
lysts, including HZSM5 zeolite with a SiO /Al O ratio of 90
2
2
3
[
b] Dr. S. M. A. H. Siddiki, Dr. K.-i. Shimizu
(
entry 15), Cs-exchanged heteropoly acid (entry 16) and com-
Elements Strategy Initiative for Catalysis and Batteries
Kyoto University, Katsura, Kyoto 615-8520 (Japan)
mercial acidic resins (entries 17, 18), as well as water-tolerant
[20]
homogeneous Lewis acids, Sc(OTf) , Yb(OTf) , and HfCl (en-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404538.
3
3
4
tries 19-21). These catalysts gave small amounts of the product
Chem. Eur. J. 2014, 20, 1 – 6
1
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&
&
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The Lewis acid–base interaction depends on the HOMO
level of a nucleophile (base) and LUMO level of an electrophile
Table 1. Catalyst screening for the synthesis of cyclic imide.
(
acid); the smaller HOMO–LUMO gap results in a more stable
[20c,21]
Lewis acid–base complex.
Figure S3 (Supporting Informa-
tion) shows distributions and energy levels of the HOMOs for
succinic acid, n-octylamine, and water. As expected, the elec-
trons in the HOMO of succinic acid are located on the oxygen
atom of the carbonyl group, and those of n-octylamine are lo-
[
a]
Entry
Catalyst
Yield [%]
1
2
3
4
5
6
7
8
9
no catalyst
<1
[
b]
[c]
[d]
[e]
[f]
Nb
niobic acid
TiO
ZnO
2
O
5
99, 99, 98, 95, 96, 85
67
61
58
52
51
33
20
12
9
cated on the nitrogen atom of the NH group. The HOMO
2
2
energy of succinic acid (À7.45 eV) is lower than that of n-octyl-
amine (À6.23 eV). This indicates that a Lewis acid can interact
with nitrogen atom of n-octylamine in preference to the car-
bonyl oxygen atom of succinic acid. This theoretical result was
consistent with the kinetic results for the reaction of succinic
acid and n-octylamine by Nb O (Table 2). The reaction order
2 3
g-Al O
CeO
2
ZrO
2
WO
3
10
SnO
2
11
2
Ta O
5
2
5
1
1
1
1
1
1
1
1
2
2
2
3
4
5
6
7
8
9
0
1
SiO
MoO
MgO
2
8
4
3
3
3
11
4
5
4
with respect to succinic acid (nacid =0.3) was larger than that
with respect to n-octylamine (namine =À0.3), which indicates
that preferential adsorption of the amine over succinic acid on
the surface active site inhibits the catalytic reaction. The namine
value of Nb O was larger than those of conventional solid
3
HZSM5 zeolite
Cs2.5
H
0.5PW12
O
40
Amberlyst-15
Nafion-SiO
Sc(OTf)
Yb(OTf)
HfCl
2
5
2
Lewis acids, TiO (n
=À1.2) and g-Al O (n
=À1.6). This
2
amine
2
3
amine
3
suggests that the inhibition effect by the strong base (n-octyla-
mine) on Nb O is weaker than those on TiO and g-Al O . We
3
4
5
2
5
2
2
3
also studied the kinetic study in the co-presence of water in
the initial reaction mixture. The reaction order with respect to
water (nH2O) was negative for all the catalysts, which indicated
that water inhibits the reaction. The inhibition effect by water
for Nb O (n =À0.8) was less significant than those for TiO
[
a] GC yields. [b] Cycle 2. [c] Cycle 3. [d] Cycle 4. [e] Cycle 5. [f] Cycle 6.
2
5
H2O
2
Table 2. Summary of IR and kinetic results.
(
nH2O =À1.4) and g-Al O (n =À2.0). From these results, it is
2
3
H2O
[
a]
À1
[b]
À1
[c]
[d]
[e]
[f]
Catalyst [LA] [mmolg
]
n
C=O [cm
]
n
acid
n
amine
n
H2O
TON
concluded that Lewis acid site of Nb O has higher tolerance
2 5
to basic molecules (amines and water) than conventional solid
Lewis acids, which results in higher activity for cyclic imide syn-
thesis from dicarboxylic acids with amines. As listed in Table 2,
Nb
TiO
g-Al
Sc(OTf)
2
O
5
0.058
0.083
0.148
1686
1695
1697
–
0.3
0.4
0.4
–
À0.3
À1.2
À1.6
–
À0.8 341
À1.4 147
2
2
O
3
À2.0
70
0.5
[
g]
3
2.0
–
=
the nC IR band of the adsorbed acetic acid on Nb O ap-
O 2 5
[
a] The number of Lewis acid sites on the surface of oxides estimated by
peared at a lower wavenumber than those on TiO (n=
2
pyridine adsorption at 2008C (from ref. [18]). [b] Position of nC=O IR band
of adsorbed acetic acid (see Figure S1 in the Supporting Information).
[
À1
À1
1
695 cm ) and g-Al O (n=1697 cm ). This indicates that
2 3
Lewis acid sites on Nb O activate carboxyl groups more effec-
c] Reaction order with respect to succinic acid (see Figure S2a in the Sup-
2
5
porting Information). [d] Reaction order with respect to n-octylamine (Fig-
ure S2b in the Supporting Information). [e] Reaction order with respect to
water (Figure S2c in the Supporting Information). [f] TON with respect to
tively than the conventional solid Lewis acids, which can cause
effective activation of carboxylic acids.
We studied the reusability of Nb O . After the reaction, the
2
5
3
Lewis acid site. [g] Based on the molecular weight of Sc(OTf) .
catalyst was separated from the mixture by centrifugation, fol-
lowed by washing with acetone, and by drying at 908C for 3 h.
The recovered catalyst was reused five times without a marked
loss of its catalytic activity (Table 1, entry 2). ICP-AES analysis of
the solution confirmed that the content of Nb in the solution
was below the detection limit. The results indicate that Nb O
(
3–11%). As listed in Table 2, the turnover number (TON) with
respect to Lewis acid site of Nb O (341) was 680 times higher
2
5
than that of Sc(OTf) (0.5).
3
2
5
[23]
On the basis of the IR result of the CO adsorbed on the
acts as a reusable heterogeneous catalyst.
5
+
Nb
Lewis acid site on the prehydrated Nb O , Nakajima
Then, we studied condensation of succinic acid with differ-
ent amines (Table 3). Under mild conditions (ca. 688C) with
small amount of Nb O (0.29 mol% based on the number of
2
5
[
16a]
et al.
showed that the Nb site acted as a Lewis acid site in
the presence of water. To investigate the interaction of the Nb
site with the carbonyl oxygen of a carboxylic group, we mea-
sured the in situ IR spectrum of acetic acid adsorbed on Nb O .
2
5
[18]
Lewis acid sites on Nb O5 ), a variety of aliphatic and aromat-
2
ic amines with various functional groups reacted with equimo-
lar amounts of succinic acid to give the N-substituted succi-
nimde derivatives in good to high isolated yield. Linear-,
branched-, and cyclo-alkyl amines (Table 3, entry 1–4), aliphatic
amines with phenyl (entry 5), hydroxyl (entry 6), CꢀC- (entry 7)
groups, benzyl amines with electron-rich and -poor ring (en-
2
5
The spectrum (see Figure S1 in the Supporting Information)
shows the C=O stretching band of the adsorbed acetic acid
À1
(
nC
=
) at a lower wavenumber (n=1686 cm ) than that on
O
À1
non-Lewis acidic oxide, SiO (n=1703 cm ). This indicates the
2
5
+
activation of the carbonyl group by a Nb Lewis acid site.
&
&
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Communication
Table 3. Synthesis of succinimides from different amines by Nb
2
O
5
.
Table 3. (Continued)
[a]
[
a]
Entry
Amine
Product
Yield [%]
78
Entry
1
Amine
Product
Yield [%]
98
1
6
7
1
91
2
80
95
74
97
75
98
81
95
[
a] Isolated yields. [b] 18 h, reflux in n-octane. [c] 30 h. [d] 40 h.
[
b]
3
4
5
6
7
8
9
tries 9–11), heteroaromatic amines (entries 12,13), and anilines
with different substituents (CH OÀ, ClÀ, SHÀ) were tolerant, re-
3
sulting in a good to high isolated yield of the N-aryl imides
(
74–98%).
Next, we tested reactions of n-octylamine with various dicar-
boxylic acids, including less reactive ones (Table 4). Although
the reaction with glutaric acid under the standard conditions
gave 69% yield of the corresponding imide, the uses of
[
[
[
[
b]
Table 4. Cyclic imidation of dicarboxylic acids with n-octylamine by
b,c]
b,c]
d]
Nb O .
2
5
[
a]
Entry
Acid
Product
Yield [%]
84
[
b]
1
[
b]
10
85
2
68
77
91
98
88
[
b]
1
1
92
90
82
90
88
[
[
c]
c]
3
4
5
6
1
1
1
1
2
3
4
5
[
b,d]
[
b]
[
a] Isolated yields. [b] 1 mmol amine. [c] 45 h.
Chem. Eur. J. 2014, 20, 1 – 6
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&
&
These are not the final page numbers! ÞÞ

Communication
1
0
.2 equivalents of amine and
.2 g of 4 ꢁ molecular sieves
Table 5. Synthesis of cyclic imide derivatives by Nb
2
O
5
.
(MS4A) pellets, placed at the
upper side of the reaction
vessel, resulted in an 84% yield
[
a]
Entry Acid/anhydride
amine
Product
Yield [%]
92
(
(
(
Table 4, entry 1). Mareic acid
entry 2), DL-tartaric acid
entry 3), trans-1,2-cyclohexane-
acid (entry 4),
[
b]
1
12M CH
3
NH
NH
2
in H
in H
2
O
O
dicarboxylic
phthalic acid (entry 5), and 4,5-
dichlorophthalic acid (entry 6)
were selectively transformed to
the corresponding cyclic imides
in moderate to high yields (68–
[b]
2
12M CH
3
2
2
81
78
92
98%).
The method was also effective
3
4
for direct synthesis of pharma-
ceutically or industrially impor-
tant cyclic imides from readily
available dicarboxylic acid or an-
hydrides (Table 5). Using an
aqueous solution of methyla-
mine, phensuximide (an anticon-
vulsant) and N-methylmaleimide
were prepared in high yield
[
c]
c]
5
6
7
95
95
85
(Table 5, entries 1, 2). A a-TNF in-
[
hibitor named PP-33 (entries 3,8),
N-(3-hydroxypropyl-pthalimide)
(entries 4,10), N-allylphthalimide
(entry 5), 1,8-naphthalimide
(entry 6), and 2-quinolinephthal-
[c]
2
NH OH·HCl
imide (entry 9) were synthesized
in good to high yields (78–95%).
NHPI is a well-established pro-
moter for the aerobic oxidation
8
80
[
22]
of organic substrates. We gave
the first example of the catalytic
synthesis of NHPI from hydroxyl-
[
c]
9
93
90
amine
entry 7).
Unsubstituted cyclic imides
and
phthalic
acid
(
1
0
were also synthesized from di-
carboxlic acids in n-octane under
3 2
[a] Isolated yields. [b] 4 mmol CH NH , 0.3 g MS4A. [c] No solvent, 36 h, 1508C.
3
bar NH at 1408C [Eq. (1)]. Suc-
3
cinic acid, glutaric acid, and
phthalic acid reacted with NH3
to give succinimide, glutarimide, and phthalimide in good to
excellent isolated yield (71–94%).
In conclusion, we have reported that cyclic imides can be
synthesized directly from various dicarboxylic acid or anhy-
drides with various amines, hydroxylamine, or ammonia by
using Nb O5 as reusable heterogeneous catalyst. This atom
2
economical and simple method will provide a practical and
convenient route to cyclic imides from readily available or bio-
mass-derived starting materials. Preliminary mechanistic stud-
ies suggest that the Lewis acid site of Nb O has a higher toler-
2
5
ance to basic molecules (amines and water) than conventional
solid Lewis acids, which results in higher catalytic activity.
Lewis acid catalysis of Nb O even in the presence of strong
2
5
&
&
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Communication
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[23] After 3 h of the standard reaction (Table 1, entry 2), the catalyst was re-
moved from the reaction mixture. Further heating of the filtrate in
reflux conditions did not increase the yield, which eliminated a homoge-
2 5
neous catalysis of soluble Nb species leached out of Nb O .
Received: July 23, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Organic Synthesis
M. A. Ali, S. M. A. H. Siddiki, K. Kon,
J. Hasegawa, K.-i. Shimizu*
&& – &&
A general catalytic method for the
direct cyclic imide synthesis from dicar-
method is effective for the synthesis of
some pharmaceutically or industrially
important cyclic imides, including N-hy-
droxyphthalimide and unsubstituted
cyclic imides.
Versatile and Sustainable Synthesis of
Cyclic Imides from Dicarboxylic Acids
boxylic acids with amines or NH under
3
and Amines by Nb O as a Base-
2
5
mild conditions using a reusable Nb O5
2
Tolerant Heterogeneous Lewis Acid
Catalyst
catalyst is reported (see scheme). The
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!