Synthesis of 3,4-diarylsubstituted maleic anhydride/maleimide via unusual oxidative cyclization of phenacyl ester/amide

Article abstract of DOI:10.1055/s-2002-31901

A simple and general method has been developed for the synthesis of 3,4-diarylsubstituted maleic anhydride and maleimide through tandem cyclization and oxidation reaction of phenacyl ester or amide. A wide variety of phenacyl esters or amides was treated with DBU under oxygen atmosphere to give the expected compounds in good to excellent yield. Mechanism of the reaction and application of the methodology have been discussed.

Full text of DOI:10.1055/s-2002-31901

LETTER
947
Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide via Unusual
Oxidative Cyclization of Phenacyl Ester/Amide1
S
ynthesis of 3,4-D
i
iarylsu
j
a
d Maleic
A
y
nhydride/M
a
a
leimide Raghavan Pattabiraman, Srinivas Padakanti, Venugopal Rao Veeramaneni, Manojit Pal,*
Koteswar Rao Yeleswarapu
Discovery Chemistry, Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500050, India
Fax +91(40)3045438/3045007; E-mail: manojitpal@drreddys.com
Received 28 March 2002
H2NO2S
H3CO2S
H3CO2S
Abstract: A simple and general method has been developed for the
synthesis of 3,4-diarylsubstituted maleic anhydride and maleimide
N
through tandem cyclization and oxidation reaction of phenacyl ester
or amide. A wide variety of phenacyl esters or amides was treated
with DBU under oxygen atmosphere to give the expected com-
pounds in good to excellent yield. Mechanism of the reaction and
application of the methodology have been discussed.
N
CF3
O
N C6H4F-p
H3C
1 (Celecoxib)
O
O
2 (Rofecoxib)
3
Key words: 3,4-diarylsubstituted maleic anhydride/maleimide, ox-
idative cyclization, phenacyl ester/amide, oxygen
Figure 1 Examples of tricyclic compounds as selective COX-2 in-
hibitor
Tricyclic group of compounds are well known templates
for the design of bioactive molecules in the field of new
drug discovery. This is exemplified by the development of
several pyridinylimidazoles as CSBP (p38) kinase inhibi-
tors,2 pyrazolo[1,5-a]pyridines as potent and selective
non-xanthine adenosine A1 receptor antagonists3 or thia-
diazoles as functional M1 selective muscarinic agonists.4
H3CO2S
H3CO2S
O
central
ring
X
O
X= O, NR
I
II
Figure 2 Designing of new COX-2 inhibitor
They have also received particular attention in the devel-
opment of selective COX-2 inhibitors such as celecoxib5
(Celebrex) (1), rofecoxib6 (Vioxx) (2) or pyrrolin-2-one
derivative7 (3) (Figure 1). These compounds are known to
be useful for the treatment of inflammation and other re-
lated diseases with reduced gastrointestinal side effects
when compared to traditional NSAIDs (non-steroidal
anti-inflammatory drugs). All these compounds possess a
common structural feature i.e., a central ring having a
active stilbene derivatives.10b Maleimides, on the other
hand, have been reported as rapid and time-dependent in-
hibitors of PGHS (prostaglandin endoperoxide syn-
thase)11a and selective inhibitors of PKC (protein kinase
C).11b They are also known to be useful for electrophoto-
graphic photoreceptors.12
diaryl stilbene-like moiety with a methanesulfonyl or A wide range of chemistry including ring-closing met-
methanesulfamoyl group at the para position of one of the athesis has been exploited for the preparation of oxygen
aryl rings. In connection with our studies on the synthesis containing heterocycles.13 Amongst them, C–C bond for-
of novel diaryl heterocycles as COX inhibitors8 we de- mation in the presence of electrophile and base14 and/or
cided to explore the biological as well as pharmacological transition metal catalyst15 has assumed particular promi-
properties of II having maleic anhydride or maleimide nence for the synthesis of five membered rings. Although
moiety as central ring (Figure 2).
a number of methods are available in the literature for the
synthesis of benzofurans, phthalides, furans, furanones
etc., only a few have been reported for the synthesis of di-
aryl substituted maleic anhydrides.16 They are prepared by
Perkin condensation of arylacetic acid either with ben-
zoylformic acid in the presence of acetic anhydride10 or
with aryloxoacetyl chloride in the presence of triethyl-
amine,11b multistep sequence from phenylacetonitriles16b
via 3-( -cyanobenzylidene)-1-phenyltriazine or a three
step procedure17 starting from 3-aryl-2-hydroxybut-2-
enedioates. 3,4-Diaryl substituted maleimides have been
synthesized11,12 from the corresponding maleic anhydride
and appropriate amine in the presence of acid or base cat-
alyst or by the reaction of -halohydrazides with 2-ami-
Maleic anhydrides are known to be useful for controlling
microbial growth in water as well as preventing slime for-
mation in various industrial manufacturing process.9
Apart from being well known dienophiles in Diels–Alder
reactions, maleic anhydrides are useful intermediates in
various organic syntheses too. Diaryl substituted maleic
anhydrides have been used to prepare corresponding
photodimers10 a as well as for the synthesis of biologically
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0947,0951,ftx,en;D10302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

948
V. Raghavan Pattabiraman et al.
LETTER
nopyridine.16c However, to the best of our knowledge no
general and direct method is available in the literature for
the synthesis of II. Here, in this report, we wish to disclose
a very simple and convenient method for the preparation
of II from readily available starting materials.
Table 1 Synthesis of 3,4-Diaryl Substituted Maleic Anhydride21 or
Maleimidea
En- Ar1
try
Ar2
X
Compd Yield
No.b of V
(%)c
No.
Base promoted aldol-type cyclisation followed by dehy-
dration of appropriately substituted phenacylester, lead-
ing to the formation of 3,4-diaryl furanones, has been well
documented in the literature.18 Application of this meth-
odology for the preparation of biologically active
compounds6–8,19 has also been reported. Accordingly,
when ester or amide III was treated with one equivalent
of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in a solvent
like acetonitrile under nitrogen atmosphere at 10–15 ºC,
furanones or pyrrolin-2-one derivatives (Method A,
Scheme 1) were obtained in good to excellent yields.
However, we have observed that disubstituted maleic an-
hydrides or 3,4-diaryl substituted maleimides were
formed as the exclusive product when the same reaction
was performed in the presence of three equivalents of
DBU under oxygen atmosphere at 25–30 ºC (Method B,
Scheme 1). Since no such report is available in the litera-
ture on this unusual oxidative cyclization of III, we decid-
ed to explore our new findings to establish it as a general
protocol for the synthesis of 3,4-diaryl substituted maleic
anhydride23 or maleimide. Our results are summarized in
Table 1.
As can be seen from Table 1, various substituents on Ar1
and Ar2 of the starting ester or amide III are well tolerated
during the course of the reaction. Good to excellent yields
of products were observed when an electron donating
group such as methoxy, ethoxy or fluoro (entry 2, 3 and 6)
occupied the p-position of Ar2. However, effect of an elec-
tron withdrawing group such as 4-nitrophenyl (entry 8)
and electron donating group i.e. 4-methylphenyl (entry 9)
was also investigated.
1
2
3
4
5
6
7
8
9
Phenyl
Phenyl
O
O
O
O
O
O
4
5
77
81
50
75
88
70
84
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Methoxyphenyl
4-Ethoxyphenyl
2-Fluorophenyl
3-Fluorophenyl
4-Fluorophenyl
6
7
8
9
3,4-Difluorophenyl O
10
4-Nitrophenyl Phenyl
4-Methylphenyl Phenyl
O
O
1124 70
1225 71
10 Phenyl
Phenyl
NC6H4F-p 13
61
a Reactions were carried out by using III (1.9 equiv) and DBU (5.9
equiv) in acetonitrile (8 mL).
b Identified by 1H NMR, IR, Mass.
c Isolated yields.
IV was found to be the major product in most of the cases
(entry 3–7, Table 2). Similarly the pyrrolin-2-one was de-
tected in appreciable quantity in the presence of three
equivalents of DBU at lower temperature but not at 25–30
ºC (entry 12 vs. 13, Table 2). Thus, the most effective mo-
lar ratio of substrate III to DBU was found to be 1:3 to
give a high yield of product V. All these results clearly in-
dicate that the temperature, base and oxygen have com-
bined influence on the nature of the product formed in this
oxidative cyclization reaction.
DBU, a well-known base in many organic transforma-
tions, was the base of our choice because of its poor nu-
cleophilicity. However, use of other bases such as
potassium hydroxide (powdered form), sodium hydride,
diisopropylamine and triethylamine was also investigat-
ed. Although the reaction proceeded at 25–30 ºC in the
first two cases, leading to the formation of product V in
good yields (entry 10, 11, Table 2) it was found to be un-
satisfactory in other cases. Higher temperature (70–80 ºC)
and longer time were required in those cases to drive the
reaction in forward direction.
The reactions were usually carried out at 25–30 ºC. Effect
of temperature and concentration of base (DBU) on prod-
uct distribution is shown in Table 2. A mixture of fura-
none IV and furandione V was isolated when the reaction
was carried out at lower temperature in the presence of
three equivalent of DBU (entry 7, Table 2). On the other
hand either lower yields (10–15%) or formation of no
products were observed when the reaction temperature
was increased. It is evident from Table 2 that base has a
crucial role in the formation of product V. Furanone IV
was isolated as the sole product even when the reaction
was carried out in the presence of oxygen using lesser
amount of DBU (entry 1 and 2, Table 2). Indeed, furanone
The duration of the reaction was 6 hours. Reduced reac-
tion time was found to be less effective (entry 8, Table 2).
Acetonitrile was used as solvent in most of the cases.
O
Ar1
Ar1
O
1equiv base, 10-15 °C
3 equiv base, 25-30 °C
Ar1
Ar2
X
X
X
Ar2
Inert
atmosphere
Oxygen
atmosphere
(Method B)
Ar2
O
O
O
V
(Method A)
IV
III
Scheme 1 Base promoted cyclization of Phenacyl ester (X = O) or amide (X = NR, R = aryl)
Synlett 2002, No. 6, 947–951 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide
949
Table 2 Effect of Reaction Condition on Product Distributiona
Entry
Substrate (III): Base
Temp. (ºC)
Conv.b (%)
Product Distributionc (%)
(DBU) (molar ratio)
C6H5
C6H5
O
O
C6H5
O
O
O
C6H5
15
4
1
2
1:0.5
1:0.5
1:1
10–15
25–30
10–15
25–30
10–15
25–30
10–15
25–30d
25–30
25–30e
25–30f
24
31
53
58
92
90
94
–
100
100
96
82
85
55
67
21
0
0
0
3
3
4
1:1
11
13
35
24
42
77
60
69
5
1:2
6
1:2
7
1:3
8
1:3
9
1:3
98
–
10
11
1:3
0
1:3
–
0
C6H5
C6H5
O
N
O
C6H5
C6H5
N
O
F
F
16
14
12
13
1:3
1:3
10–15
25–30
–
–
66
0
44
61
a The reaction was carried out in acetonitrile under oxygen atmosphere for 6 h.
b Conversion was determined on the basis of the isolated yield of product and recovered starting material.
c Product distributions were calculated based on the isolated yield of each product.
d The reaction was carried out in acetonitrile under oxygen atmosphere for 2 h.
e KOH was used as base.
f NaH was used as base.
However, use of other solvents such as dimethylforma- yield product V by elimination of water. To gain further
mide and dimethylsulfoxide was found to be equally ef- evidence regarding the intermediacy of IV, furanone 15
fective and the reaction proceeded well in these solvents was treated with DBU in acetonitrile under oxygen atmo-
when inorganic bases such as potassium hydroxide were sphere and 4 was isolated in good yield (Scheme 3). In an-
used, leading to the formation of V as major product.
other study, 1-benzoylpropyl-2-phenylacetate 17 was
treated with DBU under the conditions of oxidative cy-
clization reaction where 5-hydroxyfuranone 18 was iso-
lated as the sole product (Scheme 4).20 However, we
failed to isolate the corresponding 5-hydroxyfuranones21
in other cases (entry 1–10, Table 1) even after several at-
tempts, probably because of its immediate participation in
further oxidation reaction under the conditions employed.
Thus, the oxidative cyclization reaction could proceed
through the stepwise formation of furanone or pyrrolin-2-
one followed by its oxidation to the corresponding prod-
uct V.
The oxidative cyclization reaction was found to be highly
selective in view of product formation because no other
side products were detected under the reaction conditions
employed. All the products isolated were well character-
1
ized by the H NMR, Mass and IR spectra (carbonyl
stretching frequencies in the region of 1830–1760 cm–1).
The mechanism of the reaction could be envisaged as
shown in Scheme 2. The ester or amide III undergoes
usual aldol-type cyclization reaction in the presence of
DBU leading to the formation of furanone or pyrrolin-2-
one IV. Subsequent reaction with molecular oxygen can
Synlett 2002, No. 6, 947–951 ISSN 0936-5214 © Thieme Stuttgart · New York

950
V. Raghavan Pattabiraman et al.
LETTER
Ar1
HO
O
Ar1
Ar2
BH+
Ar1
B
Ar2
B
X
X
X
Ar2
O
O2
BH+
O
O
III
IV
Ar1
Ar2
O OH
O
Ar1
Ar2
(ionic
mechanism)
H
X
+ H2O
X
O
O
HO.
V
O.
(free
radical
mechanism)
Ar1
Ar2
H
X
O
Scheme 2 Mechanism of the base promoted oxidative cyclization reaction
O
C6H5
Acknowledgement
C6H5
C6H5
a
O
O
The authors would like to thank Dr. A. Venkateswarlu, Dr. R.
Rajagopalan and Prof. J. Iqbal for their constant encouragement and
the Analytical Department for spectral support. The authors also
thank Dr. Bidhan C. Roy, Department of Chemistry, North Dakota
State University for literature help.
C6H5
O
O
15
4
Scheme 3 a.O2, DBU (3 equiv), CH3CN, 25–30 °C, 6 h, 65%
References
HO
C6H5
C6H5
O
a
(1) DRF Publication No. 185.
C6H5
O
C6H5
O
(2) Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.;
Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-
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Bioorg. Med. Chem. 1997, 5, 49.
O
O
17
18
Scheme 4 a. O2, DBU (3 equiv), CH3CN, 25–30 °C, 6 h, 89%
We have demonstrated that the phenylacyl esters are use-
ful precursors for the synthesis of a variety of diarylsub-
stituted maleic anhydride or maleimide. The methodology
has been utilised for the synthesis8,22a of compounds of po-
tential biological interest (Scheme 5). Compound 4 was
converted to the corresponding maleimide according to
the known procedure.22b
(3) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.;
Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.;
Shiokawa, Y. J. Med. Chem. 1999, 42, 779.
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J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
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Veenhuizen, A. M.; Zhang, Y. Y.; Jackson, P. C. J. Med.
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H3CO2S
O
SO2CH3
O
a
O
O
O
(6) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Cromlish, W.; Either, D.; Evans, J. F.; Ford-Hutchinson, A.
W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.;
Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini,
J.; O Neil, G. P.; Oullet, M.; Percival, M. D.; Perrier, H.;
Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Visco, D.;
Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
(7) Bosch, J.; Roca, T.; Catena, J.-L.; Llorens, O.; Perez, J.-J.;
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A.; Farrerons, C. Bioorg. Med. Chem. Lett. 2000, 10, 1745.
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O
20
19
Scheme 5 a. Method B (Scheme 1)
To conclude, the present method using DBU in the pres-
ence of oxygen in acetonitrile provides a convenient syn-
thesis of diarylsubstituted maleic anhydride or maleimide
via oxidative cyclization of phenacyl ester or amide. The
present protocol is certainly superior to the existing meth-
ods, particularly in the preparation of unsymmetrically
substituted maleic anhydrides or maleimides. Further ap-
plication of this methodology in organic synthesis is pres-
ently under investigation.
(9) Yokoyama, Y. Jpn. Kokai Tokkyo Koho JP 01050803 A2
27, 1989; Chem. Abstr. 1989, 111, 227229r.
Synlett 2002, No. 6, 947–951 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide
(21) A useful method for the synthesis of 3,4-diaryl-5-
951
(10) (a) Fields, E. K.; Behrend, S. J. J. Org. Chem. 1990, 55,
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9613483 A1, 1996; Chem. Abstr. 1996, 125, 114294.
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Chem. 1996, 39, 1692. (b) Davis, P. D.; Bit, R. A.; Hurst, S.
A. Tetrahedron Lett. 1990, 31, 2353; and references cited
therein.
hydroxyfuranones has been developed by us and will be
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(23) Typical Procedure for the Synthesis of 3,4-Diaryl
Substituted Maleic Anhydride: Preparation of 4: To a
solution of 2-oxo-2-phenylethyl-2-phenylacetate (0.50 g,
1.968 mmol) in acetonitrile (8 mL) was added DBU (0.899
g, 5.905 mmol) slowly and dropwise at 25 °C in the presence
of atmospheric oxygen. The mixture was stirred for 6 h.
After completion of the reaction the mixture was poured into
ice-cold 3 N HCl solution (20 mL) with stirring. The solid
separated was filtered off, washed with water (2 10 mL)
followed by petroleum ether (2 5 mL). Compound 4 was
isolated in 77% yield as light yellow solid, mp 158–160 °C
(lit16 159–160 °C).
(24) Spectral data for 11: mp: 161.5–162 °C (1:9 EtOAc–
hexane); IRmax (KBr): 1833, 1766 cm–1; 1H NMR (200 MHz,
CDCl3): = 7.31–7.54 (m, 5 H), 7.74 (d, J = 8.74 Hz, 2 H),
8.27 (d, J = 8.79 Hz, 2 H); Mass (CI method, I-butane): m/z
(%) = 296(100) [MH+]; UV (MeOH): 268 nm. Elemental
analysis found: C, 64.81; H, 3.11; N, 4.62. C16H9NO5
requires C, 65.09; H, 3.07; N, 4.74.
(25) Spectral data for 12: mp: 121–122 °C (1:9 EtOAc–hexane);
IRmax (KBr): 1826, 1757 cm–1; 1H NMR (200 MHz, CDCl3):
= 2.38 (s, 3 H), 7.18–7.26 (m, 3 H), 7.39–7.56 (m, 6 H);
Mass (CI method, I-butane): m/z (%) = 265(100) [MH+]; UV
(MeOH): 355 nm. Elemental analysis found: C, 77.55; H,
4.32. C17H12O3 requires C, 77.26; H, 4.58.
(20) Formation of 18 could be accounted by the intermediacy of
a tertiary hydroperoxide. For a similar mechanistic sequence
see: Heaney, H.; Taha, M. O.; Slawin, A. M. Z. Tetrahedron
Lett. 1997, 38, 3051.
Synlett 2002, No. 6, 947–951 ISSN 0936-5214 © Thieme Stuttgart · New York