New Synthetic Method of Imides through Oxidative Photodecarboxylation Reaction of N-Protected α-Amino Acids with FSM-16

Article abstract of DOI:10.1246/cl.2000.542

FSM-16, a mesoporous silica, was found to promote the oxidative photodearboxylation of N-acyl-protected α-amino acids in hexane to afford the corresponding imides.

Full text of DOI:10.1246/cl.2000.542

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42
Chemistry Letters 2000
New Synthetic Method of Imides through Oxidative Photodecarboxylation Reaction
of N-Protected α-Amino Acids with FSM-16
†
Akichika Itoh, Tomohiro Kodama, Shinji Inagaki, and Yukio Masaki *
Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585
†
Toyota Central R & D Labs., Inc., Aichi 480-1192
(Received January 24, 2000; CL-000071)
FSM-16, a mesoporous silica, was found to promote the
oxidative photodecarboxylation of N-acyl-protected α-amino
acids in hexane to afford the corresponding imides.
tion, and it is thought to be necessary to mask the lone pair with
protecting groups in order for the reaction to proceed.
Imides have not only been used as the starting materials for
1
preparation of N-containing heterocycles, but also have been
2
focussed on from the view point of biological activity. In gen-
eral the preparation of imides involves acylation of amides with
3
2,4
5
anhydrides, acyl chlorides, or ketene, and, more recently,
6
with α,α,α-trichloromethyl carbonyl compounds and enol
esters; however, these methods involve some problems, such
7
as low yield or high environmental impact of the solvents used
or waste produced. On the other hand, we have been engaged
in applications of mesoporous zeolites, which have pores large
enough to incorporate usual molecules of low molecular
Furthermore, the pore size of the silica seems to be impor-
tant for this reaction. Table 1 shows the results of a study of
the pore size effect of FSMs. N-benzoylalanine (4b) was irradi-
ated for 36 h in the presence of FSM-8 (D < 1.5 nm; D, pore
diameter), FSM-12 (D = 2.0 nm), and FSM-16 (D = 2.7 nm).
Although a large amount of the starting 4b was recovered with
FSM-8 (entry 1), 76 and 70% of N-acetylbenzamide (5b) were
obtained in the presence of FSM-12 and FSM-16 respectively
(entries 2 and 3). These results show that FSM-16 is superior
for the substrates of similar or larger size than that of 4b to
other FSMs of small pore size, and that the reaction field is
actually inside the pores of FSMs, because the composition and
the chemical properties of FSMs are basically the same.
8
9
weight, to organic synthesis, and found that α-hydroxy car-
boxylic acids afforded the corresponding carbonyl compounds
through oxidative photodecarboxylation reaction in the pres-
ence of FSM-16,10 a mesoporous silica. The mechanism of
this reaction has not been elucidated yet; however, the sub-
stituent at the α-position of acids is thought to play an impor-
tant role in this reaction because usual aliphatic carboxylic
acids were intact under the reaction conditions. Accordingly, a
study of the substituent at the α-position is important to clarify
the mechanism and to apply this reaction to organic synthesis.
In the course of our investigation, we have found that N-pro-
tected α-amino acids with acyl groups afforded the correspon-
ding imides (Scheme 1). Now we report a new synthetic
method of imides through oxidative photodecarboxylation reac-
tion.
11
At first, glycine (1) and alanine (2) were examined for this
photodecarboxylation reaction. A suspension of 1 or 2 (50 mg)
and FSM-16 (100 mg) in dry hexane (7 mL) was irradiated at
room temperature in a pylex glass wear with a 400-W high-
pressure mercury lamp externally for 60 h; however, the start-
ing materials were recovered in both cases. Similarly with N-
benzylglycine (3), only the starting material was recovered. On
the other hand, N-benzoylglycine (4a) afforded N-formylbenz-
The solvents are also thought to play an important role in
this reaction. The reactivity of 4b in several organic solvents
was examined, and hexane proved to be a better solvent than
other typical ones (Table 2). In our previous paper on the oxida-
tive photodecarboxylation of α-hydroxycarboxylic acids, the
1
1
real oxidant assumed to be the oxygen in air. The solvents in
1
3
Table 2 are arranged in the order of the solubility of oxygen.
Although hexane of the highest solubility of oxygen among the
typical organic solvents examined afforded 5b in highest yield,
the yields of 5b generally does not correlate to the order.
1
2
amide (5a) in 45% yield after 60 h irradiation. These results
suggest that the basicity of the nitrogen atom inhibits the reac-
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
543
respectively in higher yields than 4a did. These results suggest
that not only the shape of the substrates, but also the electronic
effect of the substituents participate in the direction of this reac-
tion.
In conclusion, this new synthetic method of imides is
thought to be more environmentally friendly than previous
methods, because easily available α-amino acids are used as the
starting materials, and organic solvents of high environmental
impact, such as halogenated solvents or benzene, are not used.
Furthermore, the reaction is operationally simple from the view
point of the convenience of the work-up in which FSM-16 can
be removed only by filtration of the reaction mixture.
References and Notes
1
2
W. Flitsch and M. Hohenhorst, Liebigs Ann. Chem., 1990,
97; W. Flitsch, K. Pandl, and P. Russkamp, Liebigs Ann.
Chem., 1983, 529.
Irreversible inhibition of mammalian and insect peptidyl-
glycine α-hydroxylating monooxygenases (PHMs), which
are peptide amidating enzymes, by N-formyl amides was
reported, see: M. Klinge, H. Cheng, T. M. Zabriskie, and J.
C. Vederas, J. Chem. Soc., Chem. Commun., 1994, 1379.
K. Baburao, A. M. Costello, R. C. Petterson, and G. E.
Sander, J. Chem. Soc. C, 1968, 2779.
Table 3 shows the results for the reaction with several α-
amino acids which are protected with a variety of acyl groups.
The results that without FSM-16 or irradiation, only the starting
material was recovered (entries 1 and 2) show the necessity of
both FSM-16 and irradiation for this reaction. N-Benzoyl- (4a),
N-benzyloxycarbonyl- (4f), and N-phenylacetylglycine (4g)
took a longer time to complete the reaction (entries 4, 8, and 9),
on the other hand, conversions of N-benzoyl- (4b), N-benzyl-
oxycarbonyl- (4e), and N-tert-butoxycarbonylalanine (4h) to
the corresponding imides completed in relatively short time
3
3
4
5
6
7
8
R. T. Lalonde and C. B. Davis, J. Org. Chem., 35, 771
(entries 3, 7, and 10). N-Benzoylleucine (4c) afforded the prod-
(
1970).
R. E. Dunbar and W. M. Swenson, J. Org. Chem., 23, 1793
1958).
uct 5c in a moderate yield (entry 5). The best yield in our study
was attained by the reaction with N-benzoylphenylglycine (4d)
(
(entry 6). From these results, the suitable protective group for
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IUPAC recommends classification of pores to micropore
each α-amino acid seems to be different. Although the sub-
strate 4a is smaller than 4b, 4c and 4d, the yield was lower than
that of the others (entries 3-6). Furthermore 4f and 4g, which
are thought to be more bulky than 4a, afforded 5f and 5g
(D < 2 nm; D, pore diameter) and mesopore (2 nm < D <
50 nm), see: IUPAC Manual of Symbols and Terminology,
appendix 2, Part 1, Colloid and Surface Chemistry. D. H.
Everett, Pure Appl. Chem., 31, 578 (1972).
9
1
A. Itoh, T. Kodama, S. Maeda, and Y. Masaki,
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11 A. Itoh, T. Kodama, S. Inagaki, and Y. Masaki, Org. Lett.,
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12 A typical procedure follows: A suspension of N-protected
amino acid (4, 50 mg) and FSM-16 (100 mg) in dry hexane
(7 mL) was irradiated at room temperature with a 400-W
high-pressure mercury lamp externally for the indicated
time. FSM-16 was then filtered off and washed with ethyl
acetate, and the filtrate was concentrated under reduced
pressure. Pure product 5 was obtained after purification by
preparative TLC.
13 Y. Che, K. Tokuda, and T. Ohsaka, Bull. Chem. Soc. Jpn.,
71, 651 (1998).