(E)-1-(2,4-Dinitrophenyl)-2-(2-((1R,3R,5S,Z)-2-ethylidene-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)ethylidene)hydrazine

Abstract

The hydrovinylation of nopadiene gave a single 1,4-addition product (1) as an oil. A 3- step transformation of 3 gave 2,4-dinitrophenylhydrazone 6 as a crystalline compound. X-ray diffraction analysis of 6 confirmed the stereochemical assignments about the exocyclic olefin as well as at stereocenter C(3).

1. Introduction

Both β-pinene and myrtenal are chiral monoterpenes isolated from numerous terrestrial sources. While β-pinene is valued for its fragrance, myrtenal is an inhibitor of acetylcholinesterase [1]. Each of these monoterpenes can be used to prepare nopadiene, 1 [2,3]. Diene 1 is a starting material for the preparation of (1R)-9,9-dimethyltricyclo[6.1.1.0^2,6]deca-2,5-diene [4] which has been used to prepare a variety of transition metal complexes [5,6]. More recently, nopadiene has served as a chiral styrene substitute for elastomers [3].

The Ru-catalyzed hydrovinylation of nopadiene gave a single addition product (1) (Equation (1)) [7]. The structure of 3 was tentatively assigned based on its NMR spectral data, as well as based on the proposed structure of a π-allyl-Ru intermediate. To provide an unequivocal structural assignment, a crystalline 2,4-dinitrophenylhydrazone of 3 was prepared and its X-ray crystal structure was determined. While not the object of this study, some 2,4-dinitrophenylhydrazones have exhibited antifungal [8] and antimicrobial-resistant modulatory activity [9].

(1)

2. Results and Discussion

2.1. Synthesis

Hydroboration of (+)-3 with 9-borobicyclo[3.3.1]nonane (9-BBN) followed by oxidation gave a primary alcohol (4, Scheme 1). Swern oxidation of 4 yielded aldehyde 5. Finally, reaction of 5 with 2,4-dinitrophenylhydrazine afforded the title compound, (+)-6 as a yellow solid (Scheme 1). The overall composition of 6 was identified by ¹H and ¹³C NMR spectroscopy as well as combustion analysis.

2.2. Solid-State Structure

Recrystallization of the product from hot 95% ethanol gave yellow needles with a melting point of 143–145 °C. Figure 1 shows an ORTEP for each of the two unique structures in the unit cell, as determined by X-ray crystallography. Each of these molecules possesses the (Z)-stereochemistry of the exocyclic olefin and the (R)-configuration at the tertiary carbon adjacent to the exocyclic olefin. Notably, these stereochemical features of 6 corroborate the tentative structural assignment previously made for 3 [7]. The crystal belongs to the relatively rare triclinic, space group P1. There are significant conformational differences between two molecules within the unit cell with respect to certain torsional angles; the most striking difference is observed between C4–C12–C13–N1 = −14.8(4)° vs. C4A–C12A–C13A–N1A = −1.7(4)°. Due to these differences, the unit cell is chiral (in addition to each of the molecules being chiral, non-racemic).

The crystal packing for 6 is shown in Figure 2. There is intramolecular hydrogen bonding within a single molecule as well as intermolecular interactions between the two molecules (

Table 1. Hydrogen-bond geometry for 6.

D–H…A	D–H	H…A	D…A	D–H…A
N2–H2N…O1	0.79(4) Å	2.07(4) Å	2.617(3) Å	127(3)°
N2–H2N…O1A	0.79(4) Å	2.48(4) Å	3.210(3) Å	156(3)°
N2A–H2NA…O1A	0.89(4) Å	2.06(4) Å	2.624(3) Å	120(3)°
N2A–H2NA…O1	0.89(4) Å	2.45(4) Å	3.301(3) Å	161(3)°

). Hydrogens were treated by a mixture of independent and constrained refinement. For this reason, the N2–H distance for N2–H2N is shorter than is usually observed. Both intramolecular [10,11,12,13,14,15,16] as well as intermolecular [17,18,19] hydrogen bonding in the crystalline state of 2,4-dinitrophenylhydrazones has been reported.

3. Materials and Methods

3.1. General

All ¹H NMR and ¹³C NMR spectra were recorded at Varian 300 MHz spectrometer in CDCl₃. ¹H spectra were calibrated according to the residual signal of CHCl₃ (δ 7.26 ppm) and ¹³C spectra were calibrated to the central peak for CDCl₃ (δ 77.0 ppm). Optical rotations were recorded on a Perkin Elmer 341 optical polarimeter at 589 nm wavelength (20 °C). Melting points were obtained in open capillaries on a Mel-Temp melting point apparatus and were uncorrected. Elemental analysis was obtained from Midwest Microlabs, Ltd. (Indianapolis, IN, USA).

Crystal data for 6 were measured on a Bruker APEX2 diffractometer (Cu Kα radiation, CCD detector, ω-scanning). The structure was solved using the XS/SHELXTL v6.12 [20] and refined using SHELXL97 v. 97.2 [21] programs. Full-matrix least-squares refinement against F² in anisotropic approximation was used for the non-hydrogen atoms. The weighted R-Factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². Hydrogens were treated by a mixture of independent and constrained refinement.

Crystal data: C₁₉H₂₄N₄O₄, a = 6.7643(2) Å, b = 8.3316(2) Å, c = 19.5719(6) Å, α = 79.330(2)^o, β = 87.964(3)^o, γ = 84.861(2)^o, V = 949.84(5) ų, triclinic, space group P1, Mr = 372.42, T = 100 K, Z = 2. R[F² > 2σ(F²)] = 0.035, wR(F2) = 0.098, S = 1.00, Flack parameter = 0.2(2).

Final atomic coordinates, geometrical parameters, and crystallographic data have been deposited to the Cambridge Crystallographic Data Centre, 11 Union Road, Cambridge, CB2 1EZ, UK; URL accessed 23 July 2024 (https://www.ccdc.cam.ac.uk/structures/) and are available on request quoting the deposition number CCDC 1903584.

3.2. (1R,3R,5S,Z)2-(2-Ethylidene-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol (4)

To a solution of 3 (0.380 g, 2.16 mmol) in THF (15 mL) at room temperature under N₂, was added a solution of 9-BBN (0.5 M in THF, 4.4 mL, 2.2 mmol). The reaction mixture was stirred for 18 h, and then 30% H₂O₂ (2.5 mL) was cautiously added followed by 1 M aqueous KOH (4.4 mL). The mixture was stirred for a further 30 min and partitioned between ether and brine and the organic extract was dried (Na₂SO₄) and concentrated. The residue was purified by column chromatography to afford 4 as a colorless oil (0.310 g, 74%). R_f = 0.35 (hexanes–ether = 2:1). ¹H-NMR (300 MHz, CDCl₃) δ = 5.26 (dq, J = 1.5, 6.0 Hz, 1H, C=CHMe), 3.80–3.65 (m, 2H, CH₂OH), 2.84 (t, J = 5.7 Hz, 1H), 2.52–2.40 (m, 1H), 2.36–1.60 (m, 7H), 1.53 (dd, J = 1.0, 6.3 Hz, 3H, C=CHMe), 1.27 (s and m, 4H), 0.70 (s, 3H, CH₃). ¹³C-NMR (75 MHz, CDCl₃) δ = 145.6, 117.1, 61.4, 46.3, 44.5, 41.3, 40.7, 32.1, 31.2, 27.4, 26.1, 21.5, 12.6 ppm. Anal. Calcd for C₁₃H₂₂O (194.31): C, 80.36; H, 11.41. Found: C, 79.82; H, 11.05.

3.3. (1R,3R,5S,Z)(2-Ethylidene-6,6-dimethyl-bicyclo[3.1.1]hept-3-yl)acetaldehyde (5)

To a solution of DMSO (0.40 g, 5.1 mmol) in CH₂Cl₂ (20 mL) at −60 °C, was added dropwise a 2.0 M solution of oxalyl chloride (0.39 g, 3.1 mmol) in CH₂Cl₂ (10 mL). The mixture was stirred for 20 min and then a solution of 4 (0.45 g, 2.3 mmol) was added dropwise. The mixture was stirred for 10 min and then triethylamine (1.76 mL) was slowly added dropwise. The mixture was warmed to room temperature, stirred for 30 min and then quenched with water (10 mL). The mixture was extracted several times with CH₂Cl₂. The combined extracts were concentrated, and the crude product was dissolved in hexanes–ether (1:1), filtered and concentrated. The residue was purified by column chromatography (SiO₂, hexanes–ethyl acetate, 10:1) to give 5 (0.38 g, 86%) as a colorless oil. R_f = 0.43 (hexanes–ether = 10:1). ¹H-NMR (300 MHz, CDCl₃) δ = 9.78 (t, J = 2.1 Hz, 1H), 5.24 (dq, J = 1.0, 6.7 Hz, 1H), 3.18–2.97 (m, 1H), 2.87 (t, J = 5.7 Hz, 1H), 2.80–2.63 (m, 2H), 2.43–2.20 (m, 3H), 2.20–1.95 (m, 1H), 1.53 (dd, J = 1.5, 6.9 Hz, 3H), 1.28 (s, 3H), 1.20 (d, J = 10.5 Hz, 1H), 0.74 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃) δ = 202.6, 144.5, 117.8, 57.9, 44.6, 41.2, 40.3, 32.0, 29.6, 27.8, 26.1, 21.6, 12.6 ppm. Anal. Calcd for C₁₃H₂₀O (192.30): C, 81.20; H, 10.48. Found: C, 80.78; H, 10.31.

3.4. (E)-1-(2,4-Dinitrophenyl)-2-(2-((1R,3R,5S,Z)-2-ethylidene-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)ethylidene)hydrazine (6)

Conc. HCl (1 mL) was added to a solution of 2,4-dinitrophenyl-hydrazine (0.50 g, 2.5 mmol) in 95% ethanol (12 mL). The mixture was heated to 80 °C for 10 min and then filtered through glass wool. A portion of this solution (4 mL) was added to a solution of 5 (0.15 g, 0.78 mmol) in 95% ethanol (2 mL) at 40 °C, where a yellow precipitate immediately began to form. After stirring for 30 min, the precipitate was collected by filtration and washed with 95% ethanol. The solid was recrystallized from hot 95% ethanol to afford 6 yellow needles (0.13 g, 44%). Mp 143–145 °C; [α]_D²⁰ = +4.6 (c = 0.5, CH₂Cl₂); ¹H-NMR (300 MHz, CDCl₃) δ = 11.06 (s, 1H, NH), 9.13 (d, J = 3.0 Hz, 1H, H-3 of DNP), 8.31 (dd, J = 2.7, 9.6 Hz, 1H, H-5 of DNP), 7.97 (d, J = 9.6 Hz, 1H, H-6 of DNP), 7.56 (t, J = 5.7 Hz, 1H, CH=N), 5.33 (q, J = 6.9 Hz, 1H, C=CHMe), 2.95–1.98 (m, 8H), 1.58 (dd, J = 0.6, 6.9 Hz, 3H, C=CHMe), 1.30 (s, 3H, Me-8), 1.26 (d, J = 9.9 Hz, 1H), 0.76 (s, 3H, Me-9). ¹³C-NMR (75 MHz, CDCl₃) δ = 152.2 (C=N), 145.0 (C=CHCH₃), 144.2 (C-1 of DNP), 137.6 (C-4 of DNP), 129.9 (C-2 of DNP), 128.7 (C-5 of DNP), 123.4 (C-3 of DNP), 118.2 (C=CHCH₃), 116.5 (C-6 of DNP), 45.5, 44.6, 41.3, 40.5 (C-6), 33.2, 30.8, 27.9, 26.1 (C=CHCH₃), 21.7 (CH₃), 12.6 (CH₃). Anal. Calcd for C₁₉H₂₄N₄O₄ (374.12): C, 61.28; H, 6.50; N, 15.04. Found: C, 61.25; H, 6.45; N, 15.00. (Supplementary Materials Figures S1 and S2).