A Facile Method for the Synthesis of 6-Aryl-1-(3-Chloropropanoyl)-4-[(E)-1-(2-Furyl)Methylidene)]-1,2,3,4-Tetrahydro-3-Pyridazinones and 2-(2-Chloroethyl)-5-[α-Aracyl-β-(2-Furyl)]-(E)-Vinyl-1,3,4-Oxadiazoles

Abstract

The 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetra-hydro-3-pyridazinones (6a-d) were synthesized by the reaction of acid chloride 3 with α-aracyl(β-2-furyl)acrylic acid hydrazides (2a-d) in a high yield, one pot reaction. On the other hand, 2-(2-chloroethyl)-5-[α-aracyl-β -(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d) were also prepared by cyclodehydration of N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloro-propanoyl] hydrazine derivatives (4a-d). The proposed structures of the products were confirmed by elemental analysis, spectral data and chemical evidence.

Introduction

We have previously reported [1,2] a synthetic approach to 5-aryl-3-furfurylidene-2-(3H)-furanones (1) via the condensation reactions of furan-2-carboxaldehyde with 3-aroylpropionic acids under Perkin conditions, which yield the corresponding E-lactones as the only product, with no detectable amount of the Z-isomers being identified by TLC and ¹H NMR [3]. This result was consistent with the reports of Awad et al. [5] and others' [6,7] concerning the condensation reaction of 5-methyl-furan-2-carbox-aldehyde and/or 5-methyl thiophene-2-carboxaldehyde with 3-aroylpropionic acids under Perkin condi-tions. The conversion of these 2(3H) furanones into benzofuran derivatives [1] and 5-oxo-2-pyrrolines [4] have also been described by one of us.

Dihydropyridazinone rings are of chemical and biological interest, having been reported as having antihypertensive activity [8]. In addition, Nannini et al. [9] has established that the pyridazinones display analgesic and anti-inflammatory activities. On the other hand, 1,3,4-oxadiazoles and N²(acyl)-benzoic hydrazides are reported to exhibit carcinostatic activity against several types of tumors [10] and antimi-crobial effects against Mycobacterium tuberculosis and Mycobacterium lapreae [11]. The amino-3-substituted propyl functionality is found in many compounds having vasodilator, antispasmodic, blood platelet aggregation inhibition [12], antiarrhythmic [13] and anticholesterolesmic [14] activities.

This reported biological importance of 2(3H)-furanones, 4,5-dihydropyridazinones and 1,3,4-oxadiazoles prompted us to attempt the conversion of 2(3H)-furanones (1a-d) into heterocyclic systems of potential synthetic and biological importance, for example, the acrylic acid hydrazides (2a-d), 3-pyridazinones (6a-d), N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloro propanoyl]hydrazine (4a-d) and 1,3,4-oxadiazole derivatives (7a-d), dihydropyridazinones (8a-d).

Results and Discussion

We report here a simple method for the synthesis of 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d) and 2-(2-chloroethyl)-5-[α-aracyl-β-(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d) in good yields via the interaction of hydrazides (2a-d) with acid chloride (3) and POCl₃ in a one pot reaction.

In this investigation, hydrazides (2a-d) proved to be useful precursors in the synthesis of several het-erocyclic systems. When the 2(3H)furanones (1a-d) were allowed to react with hydrazine hydrate in ethanol, ring opening occurs with the formation of the E-isomers of α-aracyl-β−(2-furyl)acrylic acid hydrazides (2a-d) as the only products. There was no detectable amount of the corresponding Z-isomers according to ¹H NMR [3]. The configurational structures of the 2(3H)-furanones (1a-d) as E-isomers were confirmed by ¹H and ¹³C NMR, as illustrated in Table 2 and Table 4. The infrared spectra of these products (2a-d) (cf. Table 1) show an absorption band at 3199.7-3104.2-3331 cm ^-1 (broad band) characteristic of the NH group, and bands at 1648-55 cm^-1 and 1668-97 cm^-1 for υC=O, characteristic of the amide carbonyl and ketone groups, respectively. On heating the hydrazides (2a-d) in 1.0 N HCl for 30-60 min, ring closure occurs, leading to the formation of the corresponding 3(2H)-pyridazinones, namely the 6-aryl-4-furylmethyl-3(2H)-pyridazinones (8a-d). The infrared spectra of compounds (8a-d) (cf. Table 1) show a broad absorption band at 3150-3300 cm ^-1 characteristic of the NH group and an absorption band at 1654-60 cm^-1 for υC=O, characteristic of the amide carbonyl group. The infrared spectra of these compounds are similar to those reported for other pyridazinone derivatives [15,16,17,18].

The ¹H NMR spectra of compounds (2a-d) exhibit singlet signals at 4.41 for (CH₂COAr), a singlet at δ 6.67 for olefinic protons, triplet signals at δ 7.07 for (-NH-NH₂) and two signals dd for (-NH-NH₂) due to the strong electrical quadrupole moment effect [19]. In compounds (8a-d) the CH₂ adjacent to the furan ring exhibited a singlet at δ 3.92, the olefinic proton of the unsaturated double bond showed a doublet signal at δ 7.56 and the (-NH-) group a singlet at δ13.23 ppm.

The interaction of α-aracyl-β-(2-furyl)acrylic acid hydrazides (2a-d) with 3-chloropropanoyl chloride was studied also under different conditions at 0-15°C and 80°C. When the reaction took place at 0-15°C over 4-5 h, it gave a 85% yield of N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloropropanoyl]-hydrazine compounds (4a-d), but when the reaction took place at 80°C over 30-60 min, HCl was liberated to give an 80-92% yield of 6-aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d) as illustrated in Scheme 1.

Scheme 1.

Scheme 1.

In a parallel experiment using benzene solvent in the presence of acid catalyst (1.0 N HCl) at 80°C the hydrazine compounds (4a-d) cyclised and only formation of products (6a-d) was noted, as evi-denced by TLC after 1h. We believe the liberation of HCl aided the ring closure of the hydrazine de-rivatives compounds (4a-d) under the reaction conditions at 80°C to provide compounds (6a-d). These compounds were shown by direct comparison (m.p and mixed m.p) and also by TLC to be identical in all aspects with the authentic products obtained by the action of 1.0 N HCl in benzene solvent with N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloropropionyl]hydrazine compounds (4a-d). Acid catalysis proved to be essential and reaction was essentially complete after 30-60 min at 80°C (ca. 92% yield). The ¹H NMR spectra of (4a-d) exhibited singlet signals for the CH₂ protons at δ 4.41 ppm and also show two doublet signals at 9.8 and 10.11 ppm for the hydrazine (-NH-NH-) group.

The alternative mode of ring closure of N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloropropionyl]-hydrazine compounds (4a-d), that is attack by the N¹, would lead to the formation of the corresponding N-(3-chloropropionyl)aminopyrrolines (5a-d) as intermediates. But these N-aminopyrrolines (5) are not formed, and the pyridazinones (6a-d) are the only isolable products obtained from this reaction. We be-lieve that the N-aminopyrrolines (5a-d) are unstable under the acid catalyzed reaction conditions and if formed, they might undergo ring expansion [1b] yielding the corresponding 3(2H) pyridazinones (6a-d). This behavior is in accordance with the reported rearrangements of N-aminophthalimides in acid me-dium to the corresponding phthalaza-1,4-diones [15]. The structure of compounds (6a-d) was con-firmed by ¹H NMR (300 MHz), microanalysis and infrared spectral data. The IR spectra show an ab-sorption band for the υC=O stretching vibrations of cyclic carboxamides at 1666-1678 cm^-1, character-istic of the 3(2H) pyridazinone ring, and in the 1725-1733 cm^-1 region for the C=O of the open alkyl-carboximide, as well as a broad band at 3227-3337 cm^-1 characteristic of the NH group. The spectra of compounds (6a-d) (cf, Table 1) are similar to those of 1-benzoyl-6-aryl-4-thienylidene-1,6-dihydropyridazin-3-(2H)ones [20]. The ¹H and ¹³C NMR data showed evidence for the formation of a bicyclic structure as shown in Table 2 and Table 3. In compounds (6a-d), as expected, the two olefins (=C-H) have different chemical shifts both in the ¹H and ¹³C NMR spectra. These highly conjugated struc-tures show a typical two singlet signal for the C-H in the ¹H NMR spectrum at δ 6.6-6.7 and 7.08-7.13 for CH=C-Ar and Fur-CH=C-respectively, because in the case of Fur-CH=C-there is a long range coupling with the furan-H and this evidence can be obtained from the coupling constants between H(7) and furan-H(9) as illustrated in Table 2. Further evidence to support our assignments was obtained from the ¹³C NMR spectrum of compound (6b) that showed the carbons of the highly conjugated system at C(5) and C(7) to be at δ 118.7 and 126.25 respectively as shown in Table 3. It is clear also from the ¹H NMR spectrum of the compounds (6a-d) that in the ClCH₂CH₂CO-system, the CH₂ adjacent to the carbonyl appears as a triplet at δ 3.722 ppm and the other CH₂ adjacent to the chlorine nuclei are com-pletely decoupled from directly attached protons, and appear as two triplet signals at 2.54-2.77 ppm, due to the strong electrical quadrupole moment effect [19].

Figure 1. MM2 Calculations for compound 6b.

Figure 1. MM2 Calculations for compound 6b.

Another piece of evidence to support our assignment the structure of compound (6b) was obtained through MM2 calculations for the minimum and total steric energy, as illustrated in Figure 1. It is im-portant to point out that we have examined steric energies from 68.479 kcal/mole to the lowest energy structure at 8..86 kcal/mole over 392 iterations. Minimization terminated normally because the gradient norm was less than the minimum gradient norm.

The interaction of hydrazides (2a-d) with POCl₃ provided 2-(β-chloroethyl)-5-[α-aracyl-β-(2-furyl)](E)-vinyl-1,3,4-oxadiazoles (7a-d) as the only products in 75-83% yield.. The infrared spectra (IR) of these products (cf. Table 1) show an absorption band at 1695-1698 cm^-1 for υC=O, character-istic of the ketone carbonyl group, and 1578-1617 cm^-1 for υC=N. The ¹H NMR spectrum of com-pounds (7a-d) exhibit singlet signals at δ 4.37 for (CH₂COAr) and a singlet signal at δ 6.65 for the ole-finic proton and the disappearance the signals of the hydrazo group as illustrated in Table 2.

Table 1. Infrared (IR) and ¹H NMR (300 MHz) spectral data for compounds 1a-8d.

Experimental

General

¹H NMR spectra were recorded on Varian Plus 300 (300 MHz) or Bruker XL 300 (300 MHz) in-struments, the ¹³C NMR spectra (with DEPT 135) on a Bruker WP80 or XL 300 instrument. Infrared spectra listed as recorded ‘neat’ refer to a thin film of material on NaCl disks, and were taken on a Per-kin Elmer 1600 FT-IR spectrometer. Mass spectra were recorded on a Kratos Concept instrument. Melting points were measured on an Electrothermal digital melting point apparatus and are uncorrected. The TLC analyses were carried out using Macherey-Nagel 0.25mm layer fluorescent UV₂₅₄ plates with the indicated solvent system. Elemental analyses were performed by M-H-W Laboratories (Phoenix, AZ) at University of Minho, Braga, Portugal.

α-(2-Furyl)methylidene-(E)-γ-aryl-2(3H)-furanones (1a-d)

2(3H)-Furanones (1a-d) were prepared following the literature method [2]. The structures of the products were confirmed by ¹H and ¹³C NMR spectral data as listed in Table 1 and Table 2.

α-Aracycl-β-(2-furyl)acrylic acid hydrazides (2a-d) [2]

Hydrazine hydrate (1 mol) was added to a suspension of the 2-(3H)-furanones (1a-d) (1 mol) in ab-solute ethanol (20 mL). The reaction mixture was allowed to stand at room temperature with occasional shaking from time to time and then left overnight. The reaction was monitored by TLC and was shown to be complete after 2 days. Evaporation of the solvent by rotatory evaporator gave a colorless solid that was filtered off and recrystallized from a suitable solvent to give colorless crystals in 75-85% yield, as listed in Table 2.

4-Furylmethyl-6-aryl-3(2H)pyridazin-3-ones (8a-d)

1.0 N HCl (5 mL) was added dropwise with stirring at 25-35oC over 30-60 min to a solution of the α-aracycl-β-(2-furyl)acrylic acid hydrazides (2a-d) (1 mole) in benzene (20 mL); after completion of the addition the solid was continue stirring for 1h, then filtered off and washed thoroughly with water. The product obtained was recrystallized from a suitable solvent as shown in Table 2.

6-Aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (4a-d)

To a solution of the α-aracycl-β-(2-furyl)acrylic acid hydrazides (2a-d) (1 mol) in benzene (50 mL) was added 3-chloro-propionyl chloride (3) (1.01 mol) and the mixture stirred at 0-15o C for 5 h. The progress of the reaction was monitored by TLC and shown to be complete after 5-6 hrs and when the color become yellow. The solid separated out were collected and re-crystallized from ethanol to yield the title compounds in 80-92% yield (cf. Table 2).

6-Aryl-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d)

To a solution of the α-aracycl-β-(2-furyl)acrylic acid hydrazides (2a-d) (1 mol) in benzene (50 mL) was added 3-chloropropionyl chloride (3) (1.1 mol) and the reaction mixture was refluxed at 80°C for 30-60 min. The progress of the reaction was monitored by TLC during this time and the reaction was shown to be complete after 1h when the color become yellow. The solvent was removed by rotatory evaporator and the solids which separated out were collected and then recrystallized from ethanol to yield the products in 80-92% yield (cf. Table 2). In a parallel experiment with hydrazine derivatives (4a-d) in benzene solvent in the presence of acid catalyst (1.0 N HCl) using the same reaction conditions previously mentioned, the only products which could be identified by TLC after 30-60 min. were com-pounds (6a-d). These compounds were shown by direct comparison of m.p and mixed m.p, TLC and spectral data to be identical in all aspects with authentic samples.

2-(β-Chloroethyl)-5-[α-aracyl-β-(2-furyl)]-(E)-vinyl-1,3,4-oxadiazoles (7a-d)

A mixture of the N¹[α-aracyl-β−(2-furyl)acroyl-N²[3-chloropropionyl]hydrazine compounds (4a-d) (1 mol) and POCl₃ (10 mL) were stirred and heated at 106oC for 1 h., then allowed to cool, poured onto crushed ice and washed with aqueous 1.0 N NaHCO3. The yellowish solid precipitate was filtered off, washed with water and recrystallized from benzene-petroleum ether (b.p. 100-120oC) mixture to produce compounds (7a-d) (cf. Table 2). These experiments were repeated using Ac₂O as dehydrating agent instead of POCl₃ and there is no indication for any change in the yields.

Table 2. Physical data for compounds 1a-8d.

Table 2. Physical data for compounds 1a-8d.

Table 3. ¹³C Chemical shifts (dC[²H₆]DMSO) for 6-(4-methylphenyl)-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d).

Table 3. ¹³C Chemical shifts (dC[²H₆]DMSO) for 6-(4-methylphenyl)-1-(3-chloropropanoyl)-4-[(E)-1-(2-furyl)methylidene)]-1,2,3,4-tetrahydro-3-pyridazinones (6a-d).

Table 4. ¹³C Chemical shifts (dC[²H₆]DMSO) for a-(2-furyl)methylidene-(E)-g-aryl-2(3H)-furanones 1a and 1c.

Table 4. ¹³C Chemical shifts (dC[²H₆]DMSO) for a-(2-furyl)methylidene-(E)-g-aryl-2(3H)-furanones 1a and 1c.