synthesis of 3,4-diarylsubstituted maleic anhydride maleimide by veeramaneni et al

LETTER 947

Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide via Unusual Oxidative Cyclization of Phenacyl Ester/Amide1

Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/MaleimideVijaya Raghavan Pattabiraman, Srinivas Padakanti, Venugopal Rao Veeramaneni, Manojit Pal,* Koteswar Rao YeleswarapuDiscovery Chemistry, Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500050, IndiaFax +91(40)3045438/3045007; E-mail: [email protected] 28 March 2002

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 YorkISSN 0936-5214

Abstract: A simple and general method has been developed for thesynthesis of 3,4-diarylsubstituted maleic anhydride and maleimidethrough tandem cyclization and oxidation reaction of phenacyl esteror amide. A wide variety of phenacyl esters or amides was treatedwith DBU under oxygen atmosphere to give the expected com-pounds in good to excellent yield. Mechanism of the reaction andapplication of the methodology have been discussed.

Key words: 3,4-diarylsubstituted maleic anhydride/maleimide, ox-idative cyclization, phenacyl ester/amide, oxygen

Tricyclic group of compounds are well known templatesfor the design of bioactive molecules in the field of newdrug discovery. This is exemplified by the development ofseveral pyridinylimidazoles as CSBP (p38) kinase inhibi-tors,2 pyrazolo[1,5-a]pyridines as potent and selectivenon-xanthine adenosine A1 receptor antagonists3 or thia-diazoles as functional M1 selective muscarinic agonists.4

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-onederivative7 (3) (Figure 1). These compounds are known tobe useful for the treatment of inflammation and other re-lated diseases with reduced gastrointestinal side effectswhen compared to traditional NSAIDs (non-steroidalanti-inflammatory drugs). All these compounds possess acommon structural feature i.e., a central ring having adiaryl stilbene-like moiety with a methanesulfonyl ormethanesulfamoyl group at the para position of one of thearyl rings. In connection with our studies on the synthesisof novel diaryl heterocycles as COX inhibitors8 we de-cided to explore the biological as well as pharmacologicalproperties of II having maleic anhydride or maleimidemoiety as central ring (Figure 2).

Maleic anhydrides are known to be useful for controllingmicrobial growth in water as well as preventing slime for-mation in various industrial manufacturing process.9

Apart from being well known dienophiles in Diels–Alderreactions, maleic anhydrides are useful intermediates invarious organic syntheses too. Diaryl substituted maleicanhydrides have been used to prepare correspondingphotodimers10 a as well as for the synthesis of biologically

active stilbene derivatives.10b Maleimides, on the otherhand, have been reported as rapid and time-dependent in-hibitors of PGHS (prostaglandin endoperoxide syn-thase)11a and selective inhibitors of PKC (protein kinaseC).11b They are also known to be useful for electrophoto-graphic photoreceptors.12

A wide range of chemistry including ring-closing met-athesis has been exploited for the preparation of oxygencontaining heterocycles.13 Amongst them, C–C bond for-mation in the presence of electrophile and base14 and/ortransition metal catalyst15 has assumed particular promi-nence for the synthesis of five membered rings. Althougha number of methods are available in the literature for thesynthesis of benzofurans, phthalides, furans, furanonesetc., only a few have been reported for the synthesis of di-aryl substituted maleic anhydrides.16 They are prepared byPerkin condensation of arylacetic acid either with ben-zoylformic acid in the presence of acetic anhydride10 orwith aryloxoacetyl chloride in the presence of triethyl-amine,11b multistep sequence from phenylacetonitriles16b

via 3-(�-cyanobenzylidene)-1-phenyltriazine or a threestep procedure17 starting from 3-aryl-2-hydroxybut-2-enedioates. 3,4-Diaryl substituted maleimides have beensynthesized11,12 from the corresponding maleic anhydrideand appropriate amine in the presence of acid or base cat-alyst or by the reaction of �-halohydrazides with 2-ami-

Figure 1 Examples of tricyclic compounds as selective COX-2 in-hibitor

N N

H2NO2S

H3C

CF3 O

H3CO2S

O

N

H3CO2S

O

C6H4F-p

2 (Rofecoxib)1 (Celecoxib) 3

Figure 2 Designing of new COX-2 inhibitor

H3CO2S

X

H3CO2S

O

O

central ring

I II X= O, NR

948 V. Raghavan Pattabiraman et al. LETTER

Synlett 2002, No. 6, 947–951 ISSN 0936-5214 © Thieme Stuttgart · New York

nopyridine.16c However, to the best of our knowledge nogeneral and direct method is available in the literature forthe synthesis of II. Here, in this report, we wish to disclosea very simple and convenient method for the preparationof II from readily available starting materials.

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 welldocumented in the literature.18 Application of this meth-odology for the preparation of biologically activecompounds6–8,19 has also been reported. Accordingly,when ester or amide III was treated with one equivalentof DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in a solventlike 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 wereformed as the exclusive product when the same reactionwas performed in the presence of three equivalents ofDBU 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 generalprotocol for the synthesis of 3,4-diaryl substituted maleicanhydride23 or maleimide. Our results are summarized inTable 1.

As can be seen from Table 1, various substituents on Ar1

and Ar2 of the starting ester or amide III are well toleratedduring the course of the reaction. Good to excellent yieldsof products were observed when an electron donatinggroup 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.

The reactions were usually carried out at 25–30 ºC. Effectof 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 reactionwas carried out at lower temperature in the presence ofthree equivalent of DBU (entry 7, Table 2). On the otherhand either lower yields (10–15%) or formation of noproducts were observed when the reaction temperaturewas increased. It is evident from Table 2 that base has acrucial role in the formation of product V. Furanone IVwas isolated as the sole product even when the reactionwas carried out in the presence of oxygen using lesseramount of DBU (entry 1 and 2, Table 2). Indeed, furanone

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 threeequivalents of DBU at lower temperature but not at 25–30ºC (entry 12 vs. 13, Table 2). Thus, the most effective mo-lar ratio of substrate III to DBU was found to be 1:3 togive 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 thisoxidative 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 aspotassium hydroxide (powdered form), sodium hydride,diisopropylamine and triethylamine was also investigat-ed. Although the reaction proceeded at 25–30 ºC in thefirst two cases, leading to the formation of product V ingood 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 thereaction in forward direction.

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.

Table 1 Synthesis of 3,4-Diaryl Substituted Maleic Anhydride21 or Maleimidea

En-try No.

Ar1 Ar2 X Compd No.b

Yield of V (%)c

1 Phenyl Phenyl O 4 77

2 Phenyl 4-Methoxyphenyl O 5 81

3 Phenyl 4-Ethoxyphenyl O 6 50

4 Phenyl 2-Fluorophenyl O 7 75



7 Phenyl 3,4-Difluorophenyl O 10 84

8 4-Nitrophenyl Phenyl O 1124 70

9 4-Methylphenyl Phenyl O 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.

Scheme 1 Base promoted cyclization of Phenacyl ester (X = O) or amide (X = NR, R = aryl)

X

Ar1

Ar2

O

O

X

Ar1

Ar2

O

XAr1 Ar2

O

O

III

1equiv base, 10-15 °C

Inert atmosphere

3 equiv base, 25-30 °C

Oxygen atmosphere

(Method A) (Method B)IV V

LETTER Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide 949


However, use of other solvents such as dimethylforma-mide and dimethylsulfoxide was found to be equally ef-fective and the reaction proceeded well in these solventswhen inorganic bases such as potassium hydroxide wereused, leading to the formation of V as major product.

The oxidative cyclization reaction was found to be highlyselective in view of product formation because no otherside products were detected under the reaction conditionsemployed. All the products isolated were well character-ized by the 1H NMR, Mass and IR spectra (carbonylstretching frequencies in the region of 1830–1760 cm–1).

The mechanism of the reaction could be envisaged asshown in Scheme 2. The ester or amide III undergoesusual aldol-type cyclization reaction in the presence ofDBU leading to the formation of furanone or pyrrolin-2-one IV. Subsequent reaction with molecular oxygen can

yield product V by elimination of water. To gain furtherevidence regarding the intermediacy of IV, furanone 15was treated with DBU in acetonitrile under oxygen atmo-sphere and 4 was isolated in good yield (Scheme 3). In an-other study, 1-benzoylpropyl-2-phenylacetate 17 wastreated 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, wefailed 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 infurther oxidation reaction under the conditions employed.Thus, the oxidative cyclization reaction could proceedthrough the stepwise formation of furanone or pyrrolin-2-one followed by its oxidation to the corresponding prod-uct V.

Table 2 Effect of Reaction Condition on Product Distributiona

Entry Substrate (III): Base (DBU) (molar ratio)

Temp. (ºC) Conv.b (%) Product Distributionc (%)

154

1 1:0.5 10–15 24 100 0

2 1:0.5 25–30 31 100 0

3 1:1 10–15 53 96 3

4 1:1 25–30 58 82 11

5 1:2 10–15 92 85 13

6 1:2 25–30 90 55 35

7 1:3 10–15 94 67 24

8 1:3 25–30d – 21 42

9 1:3 25–30 98 0 77

10 1:3 25–30e – 0 60

11 1:3 25–30f – 0 69

1614

12 1:3 10–15 – 66 44

13 1:3 25–30 – 0 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.

OC6H5

C6H5 OOC6H5

C6H5 O

O

NC6H5 O

C6H5F

NC6H5 O

FC6H5

O

950 V. Raghavan Pattabiraman et al. LETTER


Scheme 3 a.O2, DBU (3 equiv), CH3CN, 25–30 °C, 6 h, 65%

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 methodologyhas been utilised for the synthesis8,22a of compounds of po-tential biological interest (Scheme 5). Compound 4 wasconverted to the corresponding maleimide according tothe known procedure.22b

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 maleimidevia oxidative cyclization of phenacyl ester or amide. Thepresent protocol is certainly superior to the existing meth-ods, particularly in the preparation of unsymmetricallysubstituted maleic anhydrides or maleimides. Further ap-plication of this methodology in organic synthesis is pres-ently under investigation.

Acknowledgement

The authors would like to thank Dr. A. Venkateswarlu, Dr. R.Rajagopalan and Prof. J. Iqbal for their constant encouragement andthe Analytical Department for spectral support. The authors alsothank Dr. Bidhan C. Roy, Department of Chemistry, North DakotaState University for literature help.

References

(1) DRF Publication No. 185.(2) Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.;

Blumenthal, M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-Thompson, S. M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.; Hall, R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.; Korg, A. J.; Hofmann, G. A.; Sheldrake, P. L.; McDonnell, P. C.; Kumar, S.; Young, P. R.; Adams, J. L. Bioorg. Med. Chem. 1997, 5, 49.

(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.

(4) Sauerberg, P.; Olesen, P. H.; Nielsen, S.; Treppendahl, S.; Sheardown, M. J.; Honore, T.; Mitch, C. H.; Ward, J. S.; Pike, A. J.; Bymaster, F. P.; Sawyer, B. D.; Shannon, H. E. J. Med. Chem. 1992, 35, 2274.

(5) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor, S.; Granto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. M.; Zhang, Y. Y.; Jackson, P. C. J. Med. Chem. 1997, 40, 1347.

(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.; Lagunas, C.; Fernandez, A. G.; Miquel, I.; Fernandez-Serrat, A.; Farrerons, C. Bioorg. Med. Chem. Lett. 2000, 10, 1745.

(8) Pal, M.; Rao, Y. K.; Rajagopalan, R.; Misra, P.; Kumar, P. M.; Rao, C. S. World Patent WO 01/90097, 2001; Chem. Abstr. 2002, 136, 5893.

(9) Yokoyama, Y. Jpn. Kokai Tokkyo Koho JP 01050803 A2 27, 1989; Chem. Abstr. 1989, 111, 227229r.

O

C6H5

C6H5O

O

O

C6H5

C6H5O

15 4

a

O

C6H5

C6H5O

HO

OC6H5 C6H5

O

O

17 18

a

O

O

O

O

OO

SO2CH3

H3CO2S

19 20

a

Scheme 2 Mechanism of the base promoted oxidative cyclization reaction

X

Ar1

Ar2

O

O.

X

Ar1

Ar2

O

XAr1 Ar2

O

OX

Ar1

Ar2

O

HO

X

Ar1

Ar2

O

O OHH

X

Ar1

Ar2

O

O

H

III

V

B

IV

BH+ B

O2

HO.

(ionic mechanism)

(freeradicalmechanism)

+ H2O

BH+

LETTER Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide 951


(10) (a) Fields, E. K.; Behrend, S. J. J. Org. Chem. 1990, 55, 5165. (b) Atkinson, J. G.; Wang, Z. World Patent WO 9613483 A1, 1996; Chem. Abstr. 1996, 125, 114294.

(11) (a) Kalgutkar, A. S.; Crews, B. C.; Marnett, L. J. J. Med. Chem. 1996, 39, 1692. (b) Davis, P. D.; Bit, R. A.; Hurst, S. A. Tetrahedron Lett. 1990, 31, 2353; and references cited therein.

(12) Ichikawa, Y.; Shiyoji, M. Jpn. Kokai Tokkyo Koho JP 08231502 A2 10, 1996; Chem Abstr. 1996, 125, 300818.

(13) For an excellent review see: Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377.

(14) (a) Rousset, S.; Thibonnet, J.; Abarbri, M.; Duchene, A.; Parrain, J.-L. Synlett 2000, 260. (b) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857.

(15) (a) Kotora, M.; Negishi, E.-i. Synthesis 1997, 121; and references cited therein. (b) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem. Soc., Perkin. Trans. 1 1998, 561.

(16) (a) Koelsch, C. F.; Wawzonek, S. J. Org. Chem. 1941, 6, 684. (b) Smith, P. A. S.; Friar, J. J.; Resemann, W.; Watson, A. C. J. Org. Chem. 1990, 55, 3351. (c) Florac, C.; Baudy-Floc’h, M.; Robert, A. Tetrahedron 1990, 46, 445.

(17) Beccalli, E. M.; Gelmi, M. L.; Marchesini, A. Eur. J. Org. Chem. 1999, 6, 1421.

(18) (a) Dikshit, D. K.; Shing, S.; Sing, M. M.; Kamboj, V. P. Ind. J. Chem. 1990, 29B, 950. (b) Vijayaraghavan, S. T.; Balasubramanian, T. R. Ind. J. Chem. 1986, 25B, 760.

(19) Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med. Chem. 2001, 44, 3039.

(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.

(21) A useful method for the synthesis of 3,4-diaryl-5-hydroxyfuranones has been developed by us and will be reported elsewhere.

(22) (a) A detailed study on the synthesis of compounds of biological interest and their biological activity is under investigation. (b) Davis, P. D.; Bit, R. A. Tetrahedron Lett. 1990, 31, 5201.

(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.

synthesis of 3,4-diarylsubstituted maleic anhydride maleimide by veeramaneni et al

Documents