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 SVijaya ynthesi of3,4-DiarylsubstiutedMaleicAnhydride/Maleimide 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: [email protected] Received 28 March 2002

Abstract: 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. Key words: 3,4-diarylsubstituted maleic anhydride/maleimide, oxidative cyclization, phenacyl ester/amide, oxygen

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 inhibitors,2 pyrazolo[1,5-a]pyridines as potent and selective non-xanthine adenosine A1 receptor antagonists3 or thiadiazoles as functional M1 selective muscarinic agonists.4 They have also received particular attention in the development 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 related 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 diaryl stilbene-like moiety with a methanesulfonyl or methanesulfamoyl group at the para position of one of the aryl rings. In connection with our studies on the synthesis of novel diaryl heterocycles as COX inhibitors8 we decided to explore the biological as well as pharmacological properties of II having maleic anhydride or maleimide moiety as central ring (Figure 2). Maleic anhydrides are known to be useful for controlling microbial growth in water as well as preventing slime formation 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

H2NO2S N N

H3CO2S

H3CO2S

CF3

O

H 3C

O

1 (Celecoxib)

Figure 1 hibitor

N C6H4F-p O

2 (Rofecoxib)

3

Examples of tricyclic compounds as selective COX-2 in-

H3CO2S

H3CO2S O central ring

X O

I

Figure 2

II

X= O, NR

Designing of new COX-2 inhibitor

active stilbene derivatives.10b Maleimides, on the other hand, have been reported as rapid and time-dependent inhibitors of PGHS (prostaglandin endoperoxide synthase)11a and selective inhibitors of PKC (protein kinase C).11b They are also known to be useful for electrophotographic photoreceptors.12 A wide range of chemistry including ring-closing metathesis has been exploited for the preparation of oxygen containing heterocycles.13 Amongst them, C–C bond formation in the presence of electrophile and base14 and/or transition metal catalyst15 has assumed particular prominence for the synthesis of five membered rings. Although 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 diaryl substituted maleic anhydrides.16 They are prepared by Perkin condensation of arylacetic acid either with benzoylformic acid in the presence of acetic anhydride10 or with aryloxoacetyl chloride in the presence of triethylamine,11b multistep sequence from phenylacetonitriles16b via 3-(a-cyanobenzylidene)-1-phenyltriazine or a three step procedure17 starting from 3-aryl-2-hydroxybut-2enedioates. 3,4-Diaryl substituted maleimides have been synthesized11,12 from the corresponding maleic anhydride and appropriate amine in the presence of acid or base catalyst or by the reaction of a-halohydrazides with 2-ami-

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V. Raghavan Pattabiraman et al.

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 No.

Base promoted aldol-type cyclisation followed by dehydration of appropriately substituted phenacylester, leading to the formation of 3,4-diaryl furanones, has been well documented in the literature.18 Application of this methodology 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 anhydrides 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 literature on this unusual oxidative cyclization of III, we decided 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.

O IV

Scheme 1

O

4

77

2 Phenyl

4-Methoxyphenyl

O

5

81

3 Phenyl

4-Ethoxyphenyl

O

6

50

4 Phenyl

2-Fluorophenyl

O

7

75

5 Phenyl

3-Fluorophenyl

O

8

88

6 Phenyl

4-Fluorophenyl

O

9

70

7 Phenyl

3,4-Difluorophenyl O

10

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70 71

O

11

9 4-Methylphenyl Phenyl

O

1225

Phenyl

NC6H4F-p 13

61

IV was found to be the major product in most of the cases (entry 3–7, Table 2). Similarly the pyrrolin-2-one was detected 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 molar ratio of substrate III to DBU was found to be 1:3 to give a high yield of product V. All these results clearly indicate that the temperature, base and oxygen have combined influence on the nature of the product formed in this oxidative cyclization reaction. DBU, a well-known base in many organic transformations, was the base of our choice because of its poor nucleophilicity. However, use of other bases such as potassium hydroxide (powdered form), sodium hydride, diisopropylamine and triethylamine was also investigated. 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 unsatisfactory in other cases. Higher temperature (70–80 ºC) and longer time were required in those cases to drive the reaction in forward direction. The duration of the reaction was 6 hours. Reduced reaction time was found to be less effective (entry 8, Table 2). Acetonitrile was used as solvent in most of the cases.

X O III

3 equiv base, 25-30 °C

© Thieme Stuttgart · New York

Ar1

Ar2

O X

Oxygen atmosphere (Method B)

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

Synlett 2002, No. 6, 947–951

84 24

Phenyl

O Ar1

Inert atmosphere (Method A)

Phenyl

Compd Yield No.b of V (%)c

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.

1equiv base, 10-15 °C X

1 Phenyl

10 Phenyl

The reactions were usually carried out at 25–30 ºC. Effect of temperature and concentration of base (DBU) on product distribution is shown in Table 2. A mixture of furanone 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

Ar2

X

8 4-Nitrophenyl

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 electron withdrawing group such as 4-nitrophenyl (entry 8) and electron donating group i.e. 4-methylphenyl (entry 9) was also investigated.

Ar1

Ar2

Ar2 O V

LETTER Table 2 Entry

949

Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide

Effect of Reaction Condition on Product Distributiona Substrate (III): Base (DBU) (molar ratio)

Temp. (ºC)

Conv.b (%)

Product Distributionc (%)

C6H5

O O

C6H5

C6H5

O

O

15

C6H5

1

1:0.5

10–15

24

100

4 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

d

8

1:3

25–30

–

21

42

9

1:3

25–30

98

0

77

e

–

0

60

–

0

69

10

1:3

25–30

11

1:3

25–30f

C6H5 N C6H5

F

O

C6H5

16

O N

C6H5

O

F

O

12

1:3

10–15

–

66

14 44

13

1:3

25–30

–

0

61

a

The reaction was carried out in acetonitrile under oxygen atmosphere for 6 h. 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. b

However, use of other solvents such as dimethylformamide and dimethylsulfoxide was found to be equally effective and the reaction proceeded well in these solvents when inorganic bases such as potassium hydroxide were used, leading to the formation of V as major product. 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 characterized by the 1H 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-2one IV. Subsequent reaction with molecular oxygen can

yield product V by elimination of water. To gain further evidence regarding the intermediacy of IV, furanone 15 was treated with DBU in acetonitrile under oxygen atmosphere and 4 was isolated in good yield (Scheme 3). In another study, 1-benzoylpropyl-2-phenylacetate 17 was treated with DBU under the conditions of oxidative cyclization reaction where 5-hydroxyfuranone 18 was isolated 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 attempts, 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-2one followed by its oxidation to the corresponding product V.

Synlett 2002, No. 6, 947–951

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© Thieme Stuttgart · New York

950

LETTER

V. Raghavan Pattabiraman et al. Ar1 HO

O Ar1

B

Ar2

X

BH+

O2

Ar2

BH+

III

B X

Ar2

O

Ar1

X O

O IV

O OH H X

Ar1

(ionic mechanism)

O

Ar1

X

Ar2

+ H2O

Ar2 O

O (free radical mechanism)

Ar1

HO.

O.

V

H X

Ar2 O

Scheme 2

Mechanism of the base promoted oxidative cyclization reaction

C6H5

O

C6H5

a

Acknowledgement

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

C6H5

O

O 15

4

Scheme 3

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

O C6H5

O

C6H5

a

O

C6H5 C6H5

O 17

Scheme 4

References

HO

O

18

a. O2, DBU (3 equiv), CH3CN, 25–30 °C, 6 h, 89%

We have demonstrated that the phenylacyl esters are useful precursors for the synthesis of a variety of diarylsubstituted maleic anhydride or maleimide. The methodology has been utilised for the synthesis8,22a of compounds of potential biological interest (Scheme 5). Compound 4 was converted to the corresponding maleimide according to the known procedure.22b H3CO2S O SO2CH3

O

O

a

O

O O 20

19

Scheme 5

a. Method B (Scheme 1)

To conclude, the present method using DBU in the presence of oxygen in acetonitrile provides a convenient synthesis of diarylsubstituted maleic anhydride or maleimide via oxidative cyclization of phenacyl ester or amide. The present protocol is certainly superior to the existing methods, particularly in the preparation of unsymmetrically substituted maleic anhydrides or maleimides. Further application of this methodology in organic synthesis is presently under investigation.

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(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.; FierThompson, 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.

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Synthesis of 3,4-Diarylsubstituted Maleic Anhydride/Maleimide

(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.; BaudyFloc’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.

951

(21) A useful method for the synthesis of 3,4-diaryl-5hydroxyfuranones 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): d = 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): d = 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.

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