(Z)-2-(Bromomethyl)-3-(hydroxymethylene)-7-methoxy-5-methyl-2-(tribromomethyl)-4-chromanone

Abstract

An attempt to achieve the deprotonative bromination of a 2-methyl-3-formyl-chromenone with tetrabromomethane led to an unexpected bromo-tribromomethylation product. We report the synthesis and characterization of the title compound.

1. Introduction

Brominated heterocycles display a range of bioactivities [1] and serve as versatile intermediates in nucleophilic substitution and catalytic cross-coupling reactions, facilitating the rapid exploration of chemical space [2]. Therefore, incorporating bromo groups into heterocyclic frameworks is pivotal in synthetic and medicinal chemistry [3]. Among numerous approaches, deprotonative bromination has been widely applied to carbonyl-containing heterocycles, wherein an enolizable position is activated by a base and subsequently trapped by an electrophilic bromine source [4]. Common brominating agents include N-bromosuccinimide, molecular bromine, and tetrabromomethane, the latter being less commonly used than the former, yet displaying an unconventional reactivity mode under suitable conditions [5].

In parallel, a tribromomethyl group has attracted growing interest for its role as both a synthetic handle and a property-modulating motif [6]. Notably, tribromomethylated heterocycles are relevant in developing agrochemicals and pharmaceuticals, particularly where metabolic stability or halogen-bonding interactions are desired. Furthermore, the CBr₃ group serves as a masked functionality that can be transformed into carbonyl derivatives [7], making it strategically valuable for the planning of multistep synthesis. Bromoform or tetrabromomethane is commonly employed for the transfer of tribromomethyl.

Despite the aforementioned features of bromo and tribromomethyl groups, the bromo-tribromomethylation reaction, wherein both a bromine atom and a tribromomethyl group are incorporated into the substrate, has been sporadically reported in the literature [8]. The methodology could be advantageous in synthesizing densely brominated compounds. Herein, we describe our observation of a bromotribromomethylation product obtained from the attempted deprotonative bromination of a 2-methyl-3-formyl-chromenone using tetrabromomethane. The synthesis and structural characterization of the title compound are reported.

2. Results and Discussion

Our initial plan was to introduce a bromo group at the 2-methyl position of 7-methoxy-2,5-dimethyl-4-oxo-4H-chromene-3-carbaldehyde (1) [9] through deprotonative bromination. Compound 1 was treated with LiHMDS in THF at −78 °C for 10 minutes under an argon atmosphere, and the resulting reactive species was quenched with a THF solution of tetrabromomethane. As shown in Scheme 1, (Z)-2-(bromomethyl)-3-(hydroxymethylene)-7-methoxy-5-methyl-2-(tribromomethyl)-4-chromanone (2), instead of 3, was obtained in good yield.

The structure of 2 was unambiguously assigned based on X-ray crystallography analysis (Figure 1), indicating that a bromo and a tribromomethyl group were installed at 2-methyl and C2 of the chromanone core, respectively. We presumed that the overall transformation commenced with a distal bromination of the deprotonated chromenone with CBr₄, giving the brominated chromenone 3 and a tribromomethyl anion; the tribromomethyl anion counterattacked the β-carbon of compound 3 through a Michael reaction [10] to furnish the title compound. This result showcases an unusual reactivity mode for CBr₄ and provides new insight into the halogenation chemistry of chromenone-based substrates.

3. Materials and Methods

3.1. General Experimental Information

The reaction was carried out with flame-dried glassware under an Ar atmosphere with the Schlenk line technique. Tetrahydrofuran was purified using a commercial solvent purification system. Tetrabromomethane was purchased from a commercial source and used without further purification. The reaction was monitored by thin-layer chromatography (TLC) on silica gel 60 Å F254 plates and visualized with 254 nm UV and KMnO₄ as a color development agent. The reaction residue was purified via flash column chromatography with silica gel (230–400 mesh). The melting point was uncorrected. ¹H NMR (600 MHz) and ¹³CNMR (150 MHz) spectra were recorded at 25 °C in CDCl₃. Chemical shifts are reported in ppm to the high frequency of the reference, and coupling constants J are reported in Hz. High-resolution mass spectroscopy (HRMS) was performed on a TOF instrument with ESI in positive ionization mode.

3.2. Preparation of the Title Compound

A 50 mL round-bottom flask equipped with a magnetic stir bar was charged with 7-methoxy-2,5-dimethyl-4-oxo-4H-chromene-3-carbaldehyde (325 mg, 1.4 mmol, 1 equiv.), LiHMDS (1.0 M solution in toluene) (1.4 mL, 1.4 mmol, 1.0 equiv.) and THF (10.0 mL) under argon at −78 °C. After 10 minutes, a solution of CBr₄ (465 mg, 1.4 mmol, 1.0 equiv.) in THF (5.0 mL) was added, and the mixture was stirred at the same temperature for 12 h. After the starting material was consumed as judged by TLC analysis; 2.0 N HCl_(aq) (2 mL) was added dropwise to quench the reaction. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were sequentially washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, and filtered. The mixture was concentrated in vacuo and purified through flash column chromatography (R_f 0.8; n-hexane/EtOAc = 3:1), to give the chromanone compound (679 mg, 1.2 mmol, 86% yield) as a brown solid. Note: X-ray quality crystals were grown by the slow evaporation of a dichloromethane–methanol (v/v = 1:1) solution of 2. m.p. 67–68 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.71 (d, J = 5.4 Hz, 1H), 6.41 (m, 2H), 4.45 (d, J = 11.4 Hz, 1H), 4.22 (d, J = 11.4 Hz, 1H), 3.85 (s, 3H), 2.65 (s, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 181.3, 181.1, 165.1, 161.1, 143.2, 113.5, 108.9, 100.0, 98.8, 88.3, 55.6, 54.8, 35.6, 23.4. HRMS (ESI, [M+H]⁺) m/z (%) Calcd. for C₁₄H₁₂Br₄O₄ 560.7547, found 560.7548.

3.3. X-Ray Structure Determination

X-ray diffraction data were collected at 200(2) K using a Bruker D8 Venture Dual Single Crystal X-ray Diffractometer in NTNU. Crystal data for C₁₄H₁₂Br₄O₄, M = 563.88 g mol⁻¹, space group P 2₁/n, a = 8.3907(9) Å, b = 19.815(2) Å, c = 9.7637(12) Å, β = 94.456(4)^◦, V = 1618.5(3) ų, Z = 4, Dcalc = 2.314 g∙cm⁻³. The final R1 [I > 2σ(I)] was 0.0567 and wR2 (all data) was 0.1486, with a goodness of fit on F2 of 1.027. Data have been deposited at the Cambridge Crystallographic Data Centre as CCDC 2445640. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/structures, accessed on 11 June 2025.

4. Conclusions

In summary, we present the vicinal bromo-tribromomethylation reaction of a 2-methyl-3-formyl-chromenone under basic conditions. Tetrabromomethane served as a novel counterattack reagent [11] for preparing a polybrominated heterocyclic framework.