Abstracts

ARTICLE

Preparation and reactions of 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionic acids¹

R.M. Srivastava*, and G.M. Seabra

Departamento de Química Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, 50.670-901 Recife - PE, Brazil

Received: October 28, 1996

Introduction

Although the synthesis of acids 3a-g have been described, their yields were rather low^2-4. In an attempt to improve the yields of these acids, we discovered that heating a mixture of arylamidoximes 1a-f and succinic anhydride 2 in a domestic microwave oven for 10 min provides 3a-f in high yield (Scheme 1). These acids are important because 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid (3a) has been found to possess significant peripheral analgesic and anti-inflammatory properties⁵. Compounds 3b-e, in a preliminary screening, showed some analgesic property; in fact, 3b and 3d have slightly better activity than dipyrone. Acid 3b also showed anti-inflammatory property but 30 percent less than indomethacine⁶.

During the preparation of 3a-g, we carefully investigated two minor products and identified them as 4a-f and 5a-f respectively. We synthesised 4a-f from 3a-f in order to verify their identities. The literature reports the synthesis of only 4a, from benzamidoxime and succinic anhydride⁷, and its spectroscopic properties^8,9. Besides this, no more information was available on this class of compounds. Next we transformed acids, 3a-g to their methyl esters, 6a-g. None of the methyl esters were known. Therefore, this paper describes the improved synthesis of 3a-f and the preparations of 4a-f from 3a-f, and of 6a-g from 3a-g, respectively.

Results and Discussion

The reaction of arylamidoximes 1a-f with succinic anhydride 2 was reported to yield 3a-f in poor to moderate yields⁴. Repeating this method under improved conditions and examining the products carefully by thin layer chromatography (TLC), we detected two fast running minor components. Their separation was achieved on a silica gel column. The products were identified as 3a-f (R_f = 0,1), 4a-f (R_f = 0,5) and 5a-f (R_f = 0,8) respectively. Acids 3a-f were the major products (70-75%) whereas 4a-f and 5a-f were the minor ones. If the quantities of all three products are summed up, a yield of 85% was obtained. Table 1 lists the yields of 3a-f obtained by heating 1 and 2 in a preheated oil bath (GPA), in dioxane (GPB) or in a microwave oven (GPC).

The yields of acids 3a-f have been slightly improved by refluxing the arylamidoxime and succinic anhydride in dioxane (GPB). This experiment also gave the two minor products.

Another fast and efficient synthesis of 3a-f was found. When an intimate mixture of an appropriate arylamidoxime and succinic anhydride was heated in a domestic microwave oven (80% potency) for 10 min (GPC), compound 3 was obtained as the major product and 4 and 5 as the minor products. Separation by column chromatography provided pure acids in high yields except in the case of 3b (Table 1). Thus, it is clear that microwave heating is more efficient than conventional heating for dry organic reactions¹⁰. The method allows rapid synthesis and cleaner products because of a shorter residence time.

The formation of a small quantity of 4 in the reaction of an arylamidoxime 1 and succinic anhydride 2 is interesting and requires comment. The acid 3 formed initially reacts with another molecule of amidoxime to give 4. This was proved experimentally by carrying out this preparation from 1 and 3, as shown in Scheme 1, item B. Either 7 or 8 could be the intermediate, which cyclizes to 4 on heating. However, intermediate 7 is more likely since, as has been established earlier,¹¹ the hydroxyl oxygen of arylamidoxime is more nucleophilic than the -NH₂ nitrogen, supporting the intermediate 7.

The formation of 5 is due to the reaction between two molecules of arylamidoximes under the reaction conditions. Compounds 5a-d,f were identical with authentic samples^12,13.Oxadiazole 5e was not found in the literature and, therefore, its properties are described in the experimental section.

Next, we tried to transform 3a-g to their methyl esters. Acids 3a-f were synthesised by the reported procedure^1b, and acid 3g was obtained likewise^1a. Addition of diazomethane to an ethereal solution of these acids afforded methyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionates 6a-g in almost quantitative yield. All seven esters were new.

The IR spectra of 6a-g showed a strong absorption around 1735 cm^-1 for the ester carbonyl function. The other absorptions were similar to those of the 1,2,4-oxadiazole ring reported earlier^14,15. The UV spectra had absorptions characteristic of a 1,2,4-oxadiazole ring¹⁶. Table 2 lists the UV spectra of compounds 6a-g.

The 90 MHz ¹H-NMR Spectrum of 6a showed a multiplet between d 2.70-3.43 ppm for the methylene protons (2CH₂), but the 200 MHz proton magnetic resonance spectrum produced two well defined triplets at d 2.94 and 3.25 ppm respectively, the J values in both cases were 7.0 Hz. The former and latter are assigned as a and b methylene protons respectively. This assumption is based on our work for 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid.⁴ The other products 6b-g showed similar triplets having almost the same chemical shifts (Table 3).

¹³C-NMR spectra

In 1989, the methyl substituent effects on the phenyl ring of 3-phenyl- and 5-methyl-3-phenyl-1,2,4-oxadiazoles were studied¹⁷. This paper describes the study of methyl, methoxy, chloro and bromo substituent effects on the phenyl ring of methyl 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionates, 6a-g. The ¹³C substituent effects of monosubstituted benzenes were obtained from the published data¹⁸, and the values added to the phenyl carbons of 6a. The additivity holds good for all compounds except in the case of 6b especially for 2' and 6' carbons. This kind of discrepancy has been observed earlier17 (Table 4). Initially, we faced some difficulty in assigning the C-6 and C-7 signals. However, we overcame this problem in the following manner.

As described in the section dealing with the proton spectra of these compounds, we assigned the a and b methylene protons at d 2.94 and 3.25ppm respectively. Selective irradiation of the triplet at d 3.27 ppm of 6b changed the methylene carbon as a singlet at 30.31 ppm confirming it as C-6. Similarly, irradiation of the triplet at d 2.94 produced a singlet at 21.95 ppm indicating clearly that it is due to C-7. In the totally proton decoupled spectrum of 6b, it was difficult to locate C-1'. However, the Attached Proton Test (APT) technique indicated that C-1' had almost the same chemical shift as C-5'. Varying the delay time of the pulse sequence of the APT experiment gave the all quaternary carbon spectrum where C-1' appeared at d 126.04 ppm, thus confirming its identity.

There seems to be no effect on C-3 of the 1,2,4-oxadiazole ring when the substituent changes from phenyl to m-, p-tolyl or p-anisyl. However, a small downfield shift (~ +0.65 ppm) is observed when the subsitituent at C-3 is a o-tolyl group. A p-chlorophenyl or p-bromophenyl substituent at C-3 produced a small uplield shift (-0.73 & -0.64 ppm).

In summary, the additivity rule for the substituents on the phenyl ring holds good in all compounds except in 6b. Table 4 lists the ¹³C chemical shifts of compounds 6a-g.

Appearance of C-3 (d 167.19-168.88 ppm) and C-5 (d 176.19-178.53) signals in the ¹³C spectrum of compounds 6a-g can be correlated with the calculated charges of these carbons obtained for 6a (Table 5). The positive charges are 0.146548 e.u. and 0.231096 e.u. for C-3 and C-5. The former is lower than the latter and, therefore, the chemical shifts and the calculated values agree with the assignment. This can be justified by considering the electronegativity of two nitrogens attached on C-3 vs. one nitrogen and one oxygen on C-5.

Computational Method

The ab initio Hartree-Fock Self-Consistent Field (HF-SCF) molecular orbital calculations were performed by using the Gaussian 92 Program¹⁹ on an IBM RISC 6000 computer of our Department.

Ab initio calculations

In order to gain more insight about these molecules, we carried out ab initio molecular orbital calculations of compounds 3a, 4a, 5a and 6a using STO-3G basis set for geometry optimisation. It was not possible to do calculations for all compounds because of the computer time. The literature doesn't record any theoretical work on these molecules. The results obtained are discussed in the following paragraphs, and the principal values are listed in Tables 5 and 6. Figure 1 shows a schematic picture of the most stable conformations found for each molecule.

First, we examined the acid 3a. Although, semi-empirical calculations have been performed on the oxadiazoles^20,21,no work was found in the literature on 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid 3a. The calculations show that both phenyl and oxadiazole rings are coplanar. Further, C-6, C-7 and carbonyl carbon are in the plane of the oxadiazole ring. We did not examine the dimer of this acid. The dimer might show a somewhat different conformation of the side-chain. The calculated bond lengths and bond angles are very close to the experimental values for 2-(3-p-chlorophenyl[1,2,4]-oxadiazol-5-yl)-3,4-dihydro-1-naphthylaminoformaldehyde oxime 9 obtained by X-ray crystallography²². The bond distances, bond angles and electronic charges on each atom of the heterocyclic ring are given in Table 5. Dipole moments and HOMO energies are listed in Table 6.

Next, we examined the methyl ester 6a of acid 3a. To our surprise, the ester shows the same conformation as that of the parent acid, indicating that substitution of the hydrogen atom by the methyl group did not affect the conformation.

Oxadiazole 5a shows that all three rings lie in the same plane. The literature does not report any work about this compound. As expected the atomic charge at C-5 is slightly less than when there is an alkyl substituent. This also supports that the C-5 phenyl ring and the heterocyclic ring are conjugated.

Examination of 4a shows that the phenyl rings still remain in the same plane as the oxadiazole ring and the molecule as a whole, in it's most stable conformation, is practically planar, with a dihedral angle of 179.9^o between the two ring oxygens. A second stable structure was found with the phenyl-oxadiazol-5-yl groups connected via the ethylene function forming a torsion angle of about 66^o from one another. This structure was found to be about 0.22 kcal/mol higher in energy than the former. The values in Table 5 for compound 4a refer to the most stable conformation (the planar one). We can note, that the calculated values for 4a are also in good agreement with the available experimental data²².

Experimental

Melting points are uncorrected. IR spectra were recorded with a Perkin-Elmer spectrophotometer, model 237B grating instrument and UV spectra with a Beckman Model DB spectrophotometer. ¹H- and ¹³C-NMR spectra were obtained with a EM-390 90 MHz and with a Bruker AC 200 MHz spectrophotometers using TMS as an internal standard. A solution (0.3M) of compounds 6a-g in CDCl₃ in a 5 mm sample tube was used for measuring the ¹³C spectra. Sanyo microwave oven (2450 MHz and 1350 watts) was employed for the preparation of 3a-f. Dr. Luzia E. Narimatsu of the "Instituto de Química, Universidade de São Paulo, SP," performed the elemental analyses. Thin layer chromatography (TLC) was carried out on silica gel coated plates with fluorescent indicator (PF₂₅₄) and eluted with chloroform unless otherwise stated.

Reaction of Arylamidoximes 1a-f with Succinic Anhydride ⁴

General procedure A

The appropriate arylamidoxime (7.35mmol) and succinic anhydride (8.09 mmol) were triturated and put in a test tube. The test tube was dipped in a preheated oil bath at 130 °C. After 40 min, the same was removed. TLC showed four spots corresponding to compounds (CHCl₃,R_fvalues in parentheses): 5 (0.8), 4, (0.5), 1 (0.3), and 3 (0.1). The mixture was chromatographed over silica gel using initially n-hexane and then gradually increasing the polarity by adding chloroform. This separated compounds 5 and 4. Elution of 3 was possible only with a mixture of chloroform and ethyl acetate. A little of a polar compound remained on the column which could be eluted only with methanol. This product is presumably the impure succinic acid. The details are given below:

3,5-Bisaryl-1,2,4-oxadiazoles (5a-f, R_f » 0.8). Compounds 5a-d, f were identical with those prepared earlier.^12,13 Their yields are given in parentheses: 5a (6.1%), 5b (1.4%), 5c (11,2%), 5d (2.9%), and 5f (9.9%). The new product 5e melted at 179-8 °C, after recrystallization from ethanol-water, yield (11,5%). Its NMR data and elemental analysis are given below:

¹H-NMR (CDCl₃-DMSO-d₆, 9.9/0.1): d = 7.55 (d, 2H), 7.63 (d, 2H), 8.17 (d, 2H), and 8.27 (d, 2H). These doublets have J value of about 8.5 Hz.

C₁₄H₈C_l2N₂₀

Calc.

C 57.74

H 2.77

N 9.62

(291.10)

Found

57.45

2.62

9.32

Compounds with R_f value » 0,5. The TLC, mixture melting points and the NMR spectra of these products agreed with 4a-f, isolated earlier or prepared independently. The yields are given in parentheses: 4a (8.9%), 4b (12%), 4c (11.6%), 4d (4.4%), 4e (8.8%), 4f (10.5%).

3-[3-(Aryl)-1,2,4-oxadiazol-5-yl] propionic acids (3a-f). The melting points as well as the yields of compounds 3a-f are compiled in Table 1.

General procedure B

The appropriate arylamidoxime 1 (3.67 mmol) and succinic anhydride 2 (3.67 mmol) in dioxane (10 mL) were refluxed for 4 h under nitrogen atmosphere. TLC of the reaction mixture had the same R_f values as described above. Solvent removal followed by liquid chromatography over silica gel, using solvents as described in procedure A, afforded the desired products. The yields of 3a-f are summarised in Table 1.

General procedure C

Arylamidoxime (3.7 mmol) and succinic anhydride (4.06 mmol) were intimately mixed, and heated initially in a microwave oven at 80% power for 5 min, and after a few minutes the same mixture was heated for an additional 5 min. TLC showed similar results as observed in procedures A or B. Compound 1b reacted poorly under these conditions. Therefore, this product was heated at maximum power for 10 min without interruption. The products were cromatographed by silica gel chromatography. The yields are given in Table 1.

Synthesis of 5,5'-(1,2-Ethanediyl)-bis[3-(aryl)-1,2,4 -oxadiazoles] (4a-f) from (3a-f) and (1a-f). The appropriate 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionic acid, 3a-f (1.92 mmol), dicyclohexylcarbodiimide (1.92 mmol) and the appropriate benzamidoxime 1a-f (1.92 mmol) in dried and freshly distilled dioxane (ca. 10 mL) were stirred at room temperature under nitrogen for 2h followed by 4 h of reflux. TLC (CHCl₃-Et0Ac, 1/1) showed four spots in each case. The R_f values of the reaction products of 3a and 1a were: 0.88 (DCC), 0.77 (4a), 0.47 (1a, trace), and 0.02 (dicyclohexylurea) respectively. The reaction of 1b-f and 3b-f gave similar TLC results, i.e. four spots in each case. Solvent evaporation afforded a solid mass, which was separated using a silica gel packed column. The details are given below:

5,5'-(1,2-Ethanediyl)-bis[3-(phenyl)-1,2,4-oxadiazole] (4a). After chromatography, the pure material weighed 0.49 g (81%). Recrystallization from ethanol-water gave a product, mp 163 °C (lit.⁷, m.p. 163-164 °C). ¹H-NMR (CDCl₃): d = 3.58 (s, 4H, 2CH₂), 7.27-7.70 (m, 6H, meta and para aromatic protons), 7.90-8.27 (m, 4H, ortho aromatic protons).

5,5'-(1,2-Ethanediyl)-bis[3-(o-tolyl)-1,2,4-oxadiazole] (4b). Column chromatography afforded 0.53 g (80%) of 4b. Crystallisation either from chloroform-n-hexane or ethanol-water provided crystals, mp 149-150 °C. ¹H-NMR (CDCl₃): d = 2.60 (s, 6H, 2CH₃), 3.53 (s, 4H, 2CH₂), 7.10-7.65 (m, 6H, meta and para protons), 7.78-8.20 (narrow multiplet, 2H, ortho protons).

C₂₀H₁₈N₄0₂

Calc.

C 69.35

H 5.24

N 16.17

(346.34)

Found

69.26

5.27

16.07

5,5'-(1,2-Ethanediyl)-bis[3-(m-tolyl)-1,2,4-oxadiazole] (4c). Recrystallization from ethanol gave 0.45 g of 4c (69%) m.p. 111-112^o. ¹H-NMR (CDCl₃): d = 2.4 (s, 6H, 2CH₃ ), 3.5 (s, 4H, 2CH₂), 6.98-7.45 (4H, unresolved narrow multiplet, meta and para protons), 7.61-8.00 (broad and unresolved ortho protons, 4H).

C₂₀H₁₈N₄0₂

Calc.

C 69.35

H 5.24

N 16.17

(346.34)

Found

69.09

5.09

15.99

5,5'-(1,4-Ethanediyl)-bis[3-(p-tolyl)-1,2,4-oxadiazole] (4d). After chromatographic separation, the compound was recrystallised from ethanol to give 0.51 g (77%) of 4d, m.p. 172-173 °C. ¹H-NMR (CDCl₃): d = 2.42 (s, 6H, 2CH₃), 3.57 (s,4H, 2CH₂), 7.65 (AA'BB' system, 8H).

C₂₀H₁₈N₄0₂

Calc.

C 69.35

H 5.24

N 16.17

(346.34)

Found

69.07

5.25

16.31

5,5'-(1,2-Ethanediyl)-bis[3-(p-chlorophenyl)-l,2,4-oxadiazole] (4e). Usual chromatography and work-up followed by crystallisation from ethyl acetate furnished 0.43 g (58%) of 4e, m.p. 234-236 °C. This compound is almost insoluble in most cold organic solvents. It is only sparingly soluble in a mixture of dimethylsulfoxide and acetone at room temperature. ¹H-NMR (CD₃COCD₃-DMSO-d_6, 1/1): d = 3.70 (s, 4H, 2CH₂), 7.80 (AA'BB' system, 8H).

C₁₈H₁₂C_l2N₄0₂

Calc.

C 55.83

H 3.13

N 14.16

(387.18)

Found

55.57

3.14

14.23

5,5'-(1,2-Ethanediyl)-bis[3-(p-bromophenyl)-1,2,4-oxadiazole (4f). This product 0.59 g (69%) was obtained as colourless crystals. A similar solubility problem, as observed for 4e, was encountered. Because of this, the ¹H-NMR spectrum was not obtained. Crystallisation and recrystallization from a large quantity of hot ethyl acetate provided crystals, m.p. 222-223 °C.

C₁₈H₁₂Br₂N₄0₂

Calc.

C 45.39

H 2.54

N 11.76

(476.28)

Found

45.63

2.63

12.02

Methyl 3-[3-(Aryl)-1,2,4-oxadiazol-5-yl] propionates. (6a-g). To the appropriate acid 3a-g in ether, a freshly prepared ethereal solution of diazomethane²³ was added dropwise until the nitrogen evolution ceased and the yellow colour of diazomethane persisted. Solvent removal, after half hour of standing at room temperature, provided an almost quantitative yield of 6a-g. The details of the individual compounds are given below:

Methyl 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionate (6a). Recrystallisation from ethanol-water afforded colourless crystals, m.p. 49 °C.

C₁₂H₁₂N₂0₃

Calc.

C 62.06

H 5.21

N 12.06

(232.09)

Found

62.41

5.35

12.17

Methyl 3-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl] propionate (6b). The ester obtained was yellow in colour. Liquid chromatography over a short silica gel column removed the coloured impurities. This compound could not be crystallised, but the colourless oil analysed correctly for 6b.

C₁₃H₁₄N₂0₃

Calc.

C 63.41

H 5.73

N 11.37

(246.24)

Found

63.46

6.14

11.19

Methyl 3-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl] propionate (6c). The liquid obtained was purified as described for 6b. The spectral results agreed with the structure of 6c.

C₁₃H₁₄N₂0₃

Calc.

C 63.41

H 5.73

N 11.37

(246.24)

Found

63.43

5.88

11.73

Methyl 3-[3-p-tolyl)-1,2,4-oxadiazol-5-yl] propionate (6d). Crystallisation and recrystallization of the product from ethanol-water gave colourless crystals m.p. 63-64 °C.

C₁₃H₁₄N₂0₃

Calc.

C 63.41

H 5.73

N 11.37

(246.24)

Found

63.88

5.92

11.17

Methyl 3-[3-(p-chlorophenyl)-1,2,4-oxadiazol-5-yl] propionate (6e). Crystallisation from ethanol afforded a colourless solid, m.p. 92 °C. The spectroscopic data confirmed the structure as 6e.

C₁₂H₁₁N₂0₃Cl

Calc.

C 54.07

H 4.16

N 10.63

(266.66)

Found

53.92

4.01

10.63

Methyl 3-[3-(p-bromophenyl)-1,2,4-oxadiazol-5-yl] propionate (6f). The compound after recrystallization from ethanol-water melted at 100 °C.

C₁₂H₁₁N₂0₃Br

Calc.

C 46.31

H 3.57

N 9.00

Br 25.71

(311.21)

Found

46.48

3.89

8.74

25.62

Methyl 3-[3-(p-anisyl)-1,2,4-oxadiazol-5-yl] propionate (6g). This compound was also crystallised from ethanol-water, and melted at 59.5 °C.

C₁₃H₁₄N₂0₄

Calc.

C 59.53

H 5.38

N 10.67

(262.24)

Found

59.36

5.30

10.43

Acknowledgment

Our thanks are due to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for financial support. We are thankful to Prof. Orlando E. da Silva for the ¹H-NMR spectra. The authors are grateful to Prof. G. Descotes for his help in getting the ¹³C-NMR spectrum of compound 6b done by Madam Marie-France-Cadot and Dr. Jean-Pierre Praly.

References

1. This work was published earlier as two separate articles: a) Srivastava, R.M.; de Oliveira, M.L.; de Albuquerque, J.F.C. J. Braz. Chem.Soc. 1992, 3, 117 and b) Srivastava, R.M.; da Silva, A.J.C.N.; de Oliveira, M.L. J. Braz. Chem Soc. 1993, 4, 84. Unfortunately, there were many printing mistakes and even omission of certain parts. Therefore, both articles have been combined and published again. This paper also contains additional preliminary information about the pharmacological activity tests of compounds 3b-c and the detailed results of the ab initio molecular orbital calculations of compounds 3a, 4a, 5a and 6a, respectively.

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