(1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one Oxime

1. Introduction

The Nazarov cyclization (NC), is a classical reaction reported firstly by Ivan Nikolaevich Nazarov in the 1940s [1]. This is a thermally-permitted 4π [2 + 2] electrocyclic type reaction that converts divinyl ketones 1 into 2-cyclopenten-1-ones (CPs) 2 by means of a conrotatory ring closure, catalyzed by acids, as shown in Scheme 1 [2].

This reaction has a stereospecific character, for which, disrotatory closure is not allowed within this pathway. Since its discovery, various modifications of the NC have been developed, using different acid catalysts and exploring precursors structurally different than those originally proposed divinyl ketones 1 [3,4]. These variations have demonstrated the versatility of the NC, consolidating it as an efficient strategy for the synthesis of functionalized CPs, compounds of notable interest in pharmaceutical chemistry due to their presence in different synthetic and naturally occurring molecules with recognized biological activity [5].

Thus, the 2-cyclopenten-1-one ring is a fundamental building block in organic synthesis due to its structural and chemical versatility. Its biological relevance is evidenced by its presence in various synthetic and naturally occurring compounds with recognized pharmaceutical activity, such as litseaverticillol A, (-)-nigrosporiones C and D, (-)-kjellmanianone, untenone A and pentenomicine, as shown in Scheme 3 [6]. Particularly, nigrosporiones C and D have been shown to possess potent antifungal properties and were isolated from an endophytic fungus from the insect Oxya chinensis Thunberg [7].

Figure 1. Several naturally occurring compounds of biological interest containing the 2-cyclopenten-1-one ring in their structures.

Figure 1. Several naturally occurring compounds of biological interest containing the 2-cyclopenten-1-one ring in their structures.

Likewise, 2-cyclopenten-1-one ring is also present in prostaglandins, among them, the cyclopentenone prostaglandins (cyPG’s) like PGA₁, PGA₂ and Δ¹²PGJ₂ series (Scheme 3). These structures are potent bioactive molecules and have a wide range of pharmaco-biological functions [8,9].

On the other hand, the α,β-unsaturated diaryl ketones (chalcones) have shown a wide spectrum of biological activities [10,11], but also have been used a key building blocks for constructing diverse more elaborated acyclic and cyclic organic compounds of practical interest [12,13]. Based on our vast expertise in the synthetic and practical utility of chalcone derivatives [14,15,16], the new divinyl ketone oxime 4, corresponding to an interesting aza-analog of divinyl ketones 1, was envisaged as a key precursor to further evaluate its suitability for conversion into the aza-2-cyclopenten-1-one derivative 5 through Nazarov cyclization conditions.

2. Results and Discussion

The target compound (1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one oxime (4) was synthesized in a two-steps reaction sequence (Scheme 2).

Initially, the precursor (1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one (1a) was obtained in excellent yield from a 2.2:1 ratio of 2,4-dichlorobenzaldehyde 3 and acetone via a Claisen-Schmidt condensation reaction [17], as shown in Scheme 2. Reaction proceeded in methanol at room temperature and catalyzed by aqueous 20% NaOH. After simple work-up procedure and recrystallization in aqueous ethanol, the divinyl ketone precursor (1a) was obtained in 92% yield. Analytical and spectroscopic techniques confirmed its formation. Particularly, the C=O absorption band at 1653 cm^-1 in the IR spectrum (Supplementary Figure S1), five different signals (integrating for ten protons, including two doublets for the two equivalent protons of the α,β-unsaturated system with J_trans = 16.0 Hz) in the ¹H NMR (Supplementary Figure S2), nine different carbon signals (including the C=O group at 188.4 ppm) in the ¹³C NMR, agree with the symmetry and structure proposed for precursor 1a (Supplementary Figure S3). Additionally, and based on the presence of four chlorine atoms, a complex profile of five even molecular ion peaks in the range of m/z 378–370 agrees the isotopic chlorine rule [18,19] (Supplementary Figure S4), confirming the obtained structure for 1a.

The following step consisted in the condensation of precursor 1a with hydroxylamine hydrochloride to afford the target product 4. Thus, precursor 1a was treated with NH₂OH∙HCl (2.0 equiv.) in the presence of AcOH at 70 ^oC. Upon consumption of the starting materials by four days of heating (monitored by TLC), and after a work-up procedure and purification by column chromatography using DCM as the eluent, the target product 4 was obtained in 87% yield. The structure of 4 was verified by IR, NMR, MS, and microanalysis data.

Infrared spectrum showed a weak and broad stretching band at 3271 cm^-1, a medium stretching band at 1732 cm^-1 and a strong stretching band at 964 cm^-1 (Supplementary Figure S5). This finding corresponds the characteristic bands of the =NO-H, C=N- and N-O functionalities, respectively, of the oxime group [20]. The ¹H NMR spectrum showed a complex profile in the aromatic region in the range of 7–8 ppm (integrating for 10H), suggesting a complete asymmetry of the structure contrary to that observed in the ¹H NMR spectrum of its precursor 1a. The existence of a thin singlet at 12.00 ppm (integrating for 1H) assigned to =NO-H proton indicates formation of the expected oxime functionality. Four doublets at ~7.43 (d, J = ~16.8 Hz, 1H), ~7.38 (d, J = ~16.2 Hz, 1H), ~7.35 (d, J = ~16.8 Hz, 1H) and 7.15 (d, J = 16.3 Hz, 1H) ppm, corresponding to the α,β-vinylic protons of the aliphatic C=C bonds, confirm the loss of symmetry of 1a after the formation of the oxime functionality in 4, passing from two to four α,β-vinylic protons with trans configuration, among other confirming protonic signals (Supplementary Figure S6), Figure 2.

The presence of the C=N signal at 152.4 ppm of the oxime functionality added to sixteen sp²-carbon atom signals in the range of 120.9–134.3 ppm are the most relevant features in the ¹³C NMR spectrum of 4 (Supplementary Figure S7). Additionally, a complex profile of five odd molecular ion peaks with m/z 393/391/389/387/385 (accomplishing the Cl- and N-rules) [21,22], and four base peaks with m/z 356/354/352/350 (M – Cl) in the mass spectrum (Supplementary Figure S8), also agrees with the proposed structure for oxime 4.

3. Materials and Methods

3.1. General Information

All reagents and solvents are commercially available (Merck, Kenilworth, NJ, USA) and were used without further purification. The progress of the reaction was monitored by TLC with 0.2 μm precoated plates of silica gel 60GF254 (Merck, Kenilworth, NJ, USA). Melting points were determined on a Stuart SMP3 melting point apparatus (Cole-Parmer, Staffordshire, UK) and are uncorrected. IR spectra were recorded on a Shimadzu IRAffinity⁻¹ (Shimadzu, Kyoto, Japan) with ATR probe. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance II spectrophotometer (Bruker, Bruker BioSpin GmbH, Rheinstetten, Germany) operating at 400 MHz and 100 MHz, respectively, and using CDCl₃ and DMSO-d₆ as solvents and TMS as internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are given in Hz. The following abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, and m = multiplet. Mass spectra were run on a SHIMADZU GCMS-QP2010 spectrometer (Shimadzu, Kyoto, Japan) operating at 70 eV (equipped with a direct inlet probe) operating at 70 eV. Microanalyses were performed on an Agilent CHNS elemental analyzer (Thermo Fischer Scientific Inc., Madison, WI, USA) and the values are within ± 0.4% of the theoretical values.

3.2. Synthesis of (1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one (1a)

A mixture of 2,4-dichlorobenzaldehyde 3 (2.65 g, 2.2 equiv.), acetone (0.5 mL, 1.0 equiv.), aqueous 20% NaOH (0.2 mL) and methanol (4 mL) was subjected to stirring at room temperature for 2 h. The solid formed was filtered and washed with cold methanol. Recrystallization from 96% ethanol afforded 3 (2.36g, 92% yield, yellow solid, m.p. 165‒166 ^oC; 166‒167 ^oC [23]). FTIR (ATR): ν = 1653 (C=O), 1584, 1470 cm^-1. ¹H NMR (400 MHz, CDCl₃) δ: 8.05 (d, J_trans = 16.0, 2H), 7.65 (d, J_ortho = 8.5 Hz, 2H), 7.47 (d, J_meta = 2.0 Hz, 2H), 7.31 (dd, J_ortho = 8.5 Hz, J_meta = 1.8 Hz, 2H), 7.03 (d, J_trans = 16.0, 2H) ppm. ¹³C NMR (100 MHz, CDCl₃) δ: 188.4 (C=O), 138.5, 136.8 (Cq), 136.2 (Cq), 131.7 (Cq), 130.3, 128.6, 127.9, 127.8 ppm. MS (EI, 70 eV) m/z (%): 378/376/374/372/370 (0.2/1/5/11/9) [M⁺], 341/339/337/335 (4/30/95/100) [M ‒ Cl].

3.3. Synthesis of (1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one oxime (4)

A mixture of (1E,4E)-1,5-bis(2,4-dichlorophenyl)penta-1,4-dien-3-one 1a (0.2 g, 1.0 equiv.), hydroxylamine hydrochloride (0.75 g, 2.0 equiv.), and AcOH (5 mL) was subjected to heating at 70 °C for 4 days. The resulting crude was neutralized with solid NaHCO₃ until pH = 9, filtering under vacuum the solid formed and washing with cold acetic acid. The solid was subsequently purified by column chromatography using DCM as the eluent to afford the target product 4 (0.18g, 87% yield, beige solid, m.p. 162‒163 ^oC). FTIR (ATR): ν = 3271 (O-H), 3152, 1732 (C=N), 1467, 978, 964 cm^-1. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.00 (s, 1H, OH), 7.99 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.43 – 7.32 (m, 3H), 7.15 (d, J = 16.3 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 152.4 (C=N), 134.4 (Cq), 134.1 (Cq), 133.8 (Cq), 133.7 (Cq), 133.5 (Cq), 133.4 (Cq), 130.5, 129.7, 129.6, 129.1, 128.9, 128.4, 128.3, 127.1 (x 2C), 120.9 ppm. Anal. calcd. for C₁₇H₁₁Cl₄NO (387,08): C, 52.75; H, 2.86; N, 3.62. Found: C, 52.86; H, 3.01; N, 3.49. MS (EI, 70 eV) m/z (%): 393/391/389/387/385 (0.6/6/28/59/43) [M⁺], 356/354/352/350 (8/61/100/99) [M ‒ Cl].