N-(4-fluorobenzyl)-N′-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide

Abstract

Herein, we present the synthesis of N-(4-fluorobenzyl)-N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide. The compound has been thoroughly characterized through melting-point determination, ¹H and ¹³C NMR spectroscopy and mass spectrometry. The structure was unequivocally determined by X-ray analysis. The comprehensive analytical data obtained from these techniques confirm the successful preparation and structural integrity of the newly synthesized molecule.

1. Introduction

N-tosylhydrazones are widely recognized as safe alternative reagents to diazo compounds. Characterized by excellent stability, facile preparation, operational safety and broad structural diversity, they can efficiently generate carbene coupling reagents in situ via the Bamford–Stevens reaction [1,2] to construct carbon–carbon and carbon–heteroatom bonds [3,4,5,6] and are commonly deployed in the synthesis of cyclic frameworks [7,8], bioactive pharmaceutical molecules [9,10] and other high-value compounds [11,12].

This work reports the successful preparation of N-(4-fluorobenzyl)-N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide. To confirm the structure of the target compound, comprehensive characterization was performed, covering melting-point determination and ¹H and ¹³C NMR spectroscopy, as well as full single-crystal X-ray diffraction structure determination and detailed structural analysis.

2. Results

The ¹H NMR spectrum confirms the presence of all 24 expected protons. The methyl groups appear at δ 2.39 ppm as a singlet integrating for three protons. A singlet signal at δ 4.76 ppm in the ¹H NMR spectrum was assigned to the methylene group belonging to the benzyl moiety formed during the N-alkylation reaction (see Supplementary Figure S1). The signal at δ 51.8 ppm in the ¹³C NMR spectrum, assigned to the methylene group, also supports this structural assignment (see Supplementary Figure S2). HRMS: m/z [M + H]⁺ calcd for C₂₁H₁₉F₂N₂O₂S⁺: 401.1130; found: 401.1129 (see Supplementary Figure S2).

N-(4-fluorobenzyl)-N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide was obtained as a crystalline solid from an ethyl acetate/n-hexane/acetone (v/v/v 6/1/1) solution through slow evaporation. Single-crystal X-ray crystallography was used to study it, allowing this compound to be unequivocally identified. Crystallographic data and structural refinement parameters of compound 2 are summarized in

Table 1. Crystallographic data for the structural analysis of compound 2.

Crystal Data	2
Empirical formula	C21H18F2N2O2S
Formula weight	400.43
Temperature/K	293.0
Crystal system	monoclinic
Space group	P21/c
a/Å	10.629(5)
b/Å	18.201(8)
c/Å	10.698(4)
α/°	90
β/°	113.245(15)
γ/°	90
Volume/Å3	1901.6(14)
Z	4
Density (calculated, Mg/m3)	1.399
Absorption coefficient µ (mm−1)	0.209
F(000)	832.0
Crystal size/mm3	0.25 × 0.22 × 0.21
Radiation	MoKα (λ = 0.71073)
2Θ range for data collection/°	4.476 to 52.462
Index ranges	−13 ≤ h ≤ 13, −22 ≤ k ≤ 22, −13 ≤ l ≤ 13
Reflections collected	13,758
Independent reflections	3790 [Rint = 0.0577, Rsigma = 0.0596]
Data/restraints/parameters	3790/0/255
Goodness-of-fit on F2	1.035
Final R indexes [I >= 2σ(I)]	R1 = 0.0534, wR2 = 0.1408
Final R indexes [all data]	R1 = 0.0719, wR2 = 0.1587
Largest diff. peak/hole/e Å−3	0.21/−0.31

and an ORTEP representation of the structure of compound 2 is shown in Figure 1.

Compound 2 crystallized in the monoclinic centrosymmetric P21/c space group, with four molecules in the asymmetric unit. The characteristic C=N bond angles were present in this molecule, displaying N(2)-C(15)-H(15) and N(2)-C(15)-C(16) angles of 120.03° and 119.93(12)°, respectively (see

Table 2. Selected bond distances (Å) and bond angles (deg) for compound 2.

Bond	Distance (Å)	Bond	Angle (°)
N(1)-N(2)	1.372(15)	N(2)-C(15)-H(15)	120.03
N(1)-C(8)	1.457(16)	N(2)-C(15)-C(16)	119.93(12)
N(2)-C(15)	1.277(19)	C(8)-N(1)-N(2)	123.28(11)
S(1)-C(5)	1.747(13)	C(15)-N(2)-N(1)	120.61(11)
S(1)-N(1)	1.649(12)	N(2)-N(1)-S(1)	111.10(8)
S(1)-O(1)	1.415(10)	C(8)-N(1)-S(1)	123.49(9)
S(1)-O(2)	1.422(10)	O(1)-S(1)-O(2)	120.21(6)
C(8)-H(8)	0.970	O(1)-S(1)-N(1)	107.05(6)
C(8)-C(9)	1.503(18)	O(1)-S(1)-C(5)	107.80(6)

). Furthermore, the N(1)-N(2) bond distance is 1.372(15) Å aligned with that reported for other hydrazides in the literature [13,14]. The crystal packing is depicted in Figure 2.

3. Materials and Methods

¹H NMR and ¹³C NMR spectra were collected on a Bruker NEO 400 MB spectrometer (Bruker, Billerica, MA, USA), with CDCl₃ as the solvent and Me₄Si as the internal standard. Mass spectra were acquired in electron ionization (EI) mode at 70 eV with 200 °C on a Shimadzu GCMS-QP2010 Plus instrument (Shimadzu, Kyoto, Japan) using a direct inlet probe. Only molecular and parent ion peaks (m/z) are reported.

All starting materials were purchased from Energy Chemical Company (Hefei, China). All solvents and reagents were of reagent grade and were used without further purification unless otherwise specified. Column chromatography was performed on a flash chromatography system with silica gel, using petroleum ether (60–90 °C) and ethyl acetate as the eluent. Pre-coated silica gel GF-254 plates (Qiwei, Hangzhou, China) were used for thin-layer chromatography (TLC).

For the X-ray diffraction studies, crystals of compound 2 were obtained by the slow evaporation of a dilute hexane solution, and the reflections were acquired with a Bruker APEX DUO (Bruker, Billerica, MA, USA) diffractometer equipped with an Apex II CCD detector (Bruker, Billerica, MA, USA), with Mo Kα radiation (λ = 0.71073 Å) at 100 K. Frames were collected using omega scans and integrated with SAINT, and multi-scan absorption correction (SADABS) was applied. Direct methods (SHELXS-97) were employed to solve the structure [15]. Subsequent difference-Fourier syntheses revealed the remaining atoms, which were then refined anisotropically against F2 by full-matrix least-squares fitting using SHELXL [16] and the ShelXle GUI [17]. The C-H hydrogen atoms were positioned geometrically at idealized locations.

N-(4-fluorobenzyl)-N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide 2

White solid (272 mg, 76% yield), mp = 131–133 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.3 Hz, 2H), 7.63 (s, 1H), 7.52 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 5.3 Hz, 1H), 7.29 (d, J = 5.3 Hz, 1H), 7.02 (t, J = 8.6 Hz, 4H), 4.76 (s, 2H), 2.44 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.0 (d, J = 250 Hz), 162.3 (d, J = 245 Hz), 147.3, 144.4, 134.3, 131.1 (d, J = 2.9 Hz), 130.1 (d, J = 3.4 Hz), 129.7, 129.4 (d, J = 8.5 Hz), 128.8 (d, J = 8.0 Hz), 128.3, 115.9 (d, J = 5.0 Hz), 115.7 (d, J = 5.2 Hz), 51.8, 21.6. HRMS: m/z [M + H]⁺ calc for C₂₁H₁₉F₂N₂O₂S⁺: 401.1130; found: 401.1129.

N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide (2 mmol 0.584 g) and NaOMe (1 mmol 0.054 g) were dissolved in methanol (6 mL). The mixture was heated at 60 °C for 18 h. After the reaction was complete, the resulting mixture was filtered to remove the solid, and the liquor was extracted with ethyl acetate (3 × 10 mL) and washed with saturated sodium chloride solution (3 × 10 mL). The resulting organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was isolated by column chromatography using ethyl acetate/petroleum ether (v/v 6/1) as the eluent for N’-(4-fluorobenzylidene)-4-methylbenzenesulfonohydrazide (Scheme 1).