NaIO4-mediated decarboxylative oxidation of γ-lactam carboxylic acids: A simple approach towards N -aryl maleimide derivatives

Article abstract of DOI:10.1055/s-0029-1218379

A simple methodology has been developed for the -synthesis of N-aryl maleimides from N-aryl γ-lactam-2-carboxylic acids by decaboxylative oxidation and dehydrogenation with the oxidant NaIO₄/LiBr in refluxing acetonitrile-water solvent. Georg T

Full text of DOI:10.1055/s-0029-1218379

LETTER
3333
NaIO4-Mediated Decarboxylative Oxidation of g-Lactam Carboxylic Acids:
A Simple Approach towards N-Aryl Maleimide Derivatives
A
Simple
A
pproac
o
h towards
N
-
A
ryl
M
aleim
a
ides Barman, Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: jkray@chem.iitkgp.ernet.in; E-mail: rayjayanta@hotmail.com
Received 11 September 2009
C–H activation at benzylic positions.14 When we treated
Abstract: A simple methodology has been developed for the
synthesis of N-aryl maleimides from N-aryl g-lactam-2-carboxylic
acids by decaboxylative oxidation and dehydrogenation with the
oxidant NaIO4/LiBr in refluxing acetonitrile–water solvent.
the g-lactam-carboxylic acids15 (1a–f) with NaIO4/LiBr in
acetonitrile–water (8:2; v/v) at 90 °C they furnished ex-
clusively the 1,3-diaryl maleimide derivatives (2a–f) in
high yields (Scheme 1, Table 1).
Key words: maleimides, decarboxylation, oxidation, g-lactam 2-
carboxylic acids, bromination
R2
R1
R2
R1
O
COOH
Maleimides have been used to design a variety of bioac-
tive materials. They react quickly with cysteine residues
and thus can be used as linkers for conjugation of mole-
cules with proteins.1 They also serve as a synthetic plat-
form in total synthesis, immuno conjugates for cancer
therapy, and solid-supported enzyme for synthetic appli-
cations.2 Fused and functionalized maleimides can be
used for the synthesis of polycyclic and fused pyridazine
derivatives.3 The reactivity of maleimides is largely based
on their Michael accepting ability and dienophilic nature.4
Zacchino et al. reported that N-phenyl- and N-phenylalkyl-
maleimides possess strong antifungal activities when test-
ed in agar dilution assays against a panel of 11 strains of
clinically important fungi including Candida spp.5 De-
spite this, there are few reports in the literature for the syn-
thesis of N-substituted maleimides, the majority of
methods reported being based on the reaction of the cor-
responding maleic anhydride with an amine or ammoni-
um acetate.6
N
N
NaIO4, LiBr
MeCN–H2O
O
O
2
1
Scheme 1
Table 1 Synthesis of N-Aryl Maleimides 2 from g-Lactam-2-
carboxylic Acids 1a
Entry Substrate
Product
Yield
N-aryl-g-lactam-2- carboxylic N-aryl-maleimides (%)
acid
1a
1b
1c
1d
1e
R1 = H, R2 = Cl
R1 = H, R2 = F
R1 = H, R2 = Br
R1 = R2 = F
2a
2b
2c
2d
2e
2f
87
76
70
81
76
52
R1 = Cl, R2 = F
R1 = H, R2 = OMe
Recently, we reported that decarboxylative oxidation of g-
lactam carboxylic acids by CAN/NaBrO3 in acetonitrile– 1f
water provides succinimide derivatives.7 A variety of ox-
idants including lead(IV), cobalt(III), silver(II), manga-
nese(III), thallium(III),8 and mercury(II)9 salts, Tungstate
(Na2WO4/H2O2),10 chromic acid, nonmetallic oxidants,
such as nitrosonium or nitronium salts11 and pyridine N-
oxide,12 have also been reported for the decarboxylation
of carboxylic acids. Herein, we wish to report a simple
methodology for the preparation of N-aryl maleimide de-
rivatives from N-aryl g-lactam carboxylic acids by using
a transition-metal-free oxidant.
a Reagents and conditions: All the reactions were carried out with cat-
alytic amount of NaIO4, and 3.5 equiv of LiBr in MeCN–H2O (8:2) at
90 °C for 5–8 h.
In order to gain insight into the mechanism, the reaction
was carried out (1) in the absence of NaIO4 in acetoni-
trile–water, (2) in the absence of LiBr in acetonitrile–wa-
ter, and (3) with NaIO4/LiBr in anhydrous acetonitrile. In
all cases we observed that no reaction occurred. From
these observations and following the concept of decarboxy-
lative oxidation7 and side-chain bromination in the pres-
ence of an oxidizing agent as reported13,14,16 a plausible
mechanism for the above reaction is depicted in
Scheme 2. We believe that NaIO4 oxidizes LiBr in the
presence of acid to liberate molecular bromine that decar-
boxylates the acid group and brominates the lactam ring.
After aqueous solvolysis in the acidic medium at elevated
temperature (90 °C) the alcohols produced would be con-
Sudalai et al. have reported that NaIO4/LiBr in the pres-
ence of acid oxidizes alkylarenes and benzylic bromides
or alcohols to carbonyl derivatives.13 They have also re-
ported that the same reagent system can also be used for
SYNLETT 2009, No. 20, pp 3333–3335
x
x
.x
x
.2
0
0
9
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218379; Art ID: D25509ST
© Georg Thieme Verlag Stuttgart · New York

3334
G. Barman, J. K. Ray
LETTER
H+
LiBr
+
I–
Na+
NaIO4
Br2
+
H2O
+
+
+
O
Ar1
O
Ar1
O–
OH
H+
Br
Ar1
O
N
N
N
N
H2O
Br2
Na+
I–
H O HBr
+
+
+
+
2
O
NaIO4
Ar2
– CO2
– HBr
Ar2
Ar2
H
Ar1
O
+ O
H
O
OH
O
H
O
Ar1
Ar1
O
_
O
Na+
I
N
O
N
O
I
H+
O
O
Ar2
O
Ar2
Ar2
3
O
Ar1
O
O
Ar1
Br2
N
N
+
2 HBr
– HIO3
O
Ar2
Ar2
Scheme 2
which was purified by column chromatography [PE (60–80 °C)–
EtOAc] to afford the pure product.
verted into the maleimide derivatives by reaction with
NaIO4/LiBr.
In the above mechanistic path we see that by decarboxy-
lative hydroxylation the g-lactam carboxylic acids 1 were
converted to the 5-hydroxy g-lactam derivatives 3, which
were then converted into the maleimides 2.
1-(4-Chlorophenyl)-3-phenyl-pyrrole-2,5-dione (2a)
Deep brown solid; mp 123–126 °C. 1H NMR (200 MHz, CDCl3):
d = 6.75 (s, 1 H), 7.34–7.76 (m, 7 H), 7.95–7.98 (m, 2 H). 13C NMR
(50 MHz, CDCl3): d = 123.95, 127.59 (2 C), 128.35, 129.02 (2 C),
129.14 (2 C), 129.22 (2 C), 129.99, 131.46, 133.47, 143.83, 168.76,
169.07. ESI-HRMS: m/z calcd for C16H10NO2Cl [M + H+]:
284.0490; found: 284.0488.
To prove the generality of the mechanism we performed
the reaction on trans-5-hydroxy-1,4-diaryl g-lactam de-
rivative 4 (Scheme 3) and, under the same conditions, we
obtained the maleimide derivative, supporting our pro-
posed mechanism as depicted in Scheme 2.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
F
F
Acknowledgment
F
F
OH
Financial support from DST and CSIR (New Delhi) is gratefully
acknowledged.
O
N
N
NaIO4,LiBr
MeCN–H2O
O
O
4
2d
References
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Scheme 3
In conclusion, we have disclosed that NaIO4/LiBr can be
used for decarboxylative oxidation of g-lactam carboxylic
acids. This procedure demonstrates that N-aryl-maleimide
derivatives can be synthesized from g-lactam carboxylic
acids in good yield.
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General Procedure
To a flask containing the g-lactam-2-carboxylic acid 1 (1 mmol) in
MeCN (8 mL) and H2O (2 mL), LiBr (3.5 mmol), and NaIO4 (25
mol%) were added and reaction mixture was heated to 90 °C. The
reaction mixture was then refluxed for 6–8 h until completion of re-
action (monitored by TLC) and then cooled to r.t. (25–30 °C). The
mixture was extracted with CH2Cl2, the combined organic layers
were washed with a dilute solution of Na2S2O3, 5% NaHCO3, and
brine then dried over anhyd Na2SO4. After filtration, the solution
was concentrated under reduced pressure to give the crude product,
Synlett 2009, No. 20, 3333–3335 © Thieme Stuttgart · New York

LETTER
A Simple Approach towards N-Aryl Maleimides
3335
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Synlett 2009, No. 20, 3333–3335 © Thieme Stuttgart · New York

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