2-(Fluoromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole

Abstract

Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) substitutes the TEMPO free radical with fluorine on 4,7-dimethoxy-1-methyl-2-{[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]methyl}-1H-benzimidazole to give the title compound in a 77% yield. A mechanism is proposed for the formation of this novel methylene fluoride.

1. Introduction

Traditionally, an alkoxyamine undergoes homolysis thermally to give the reactive carbon-centered radical and the stable free radical, nitroxide [1]. TEMPO-Vis is one of a new class of alkoxyamines that releases reactive quinone methide radicals and the nitroxide, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) upon exposure to visible-light at room temperature (Figure 1) [2]. Light-insensitive 4,7-dimethoxy-1-methyl-2-{[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]methyl}-1H-benzimidazole 1 is the synthetic precursor to TEMPO-Vis and photoactive bis-alkoxyamines.

Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) is an inexpensive and hazard-free source of electrophilic fluorine [3]. Selectfluor is reported to have fluorinated activated aromatic positions on anisoles [4], phenols [4], naphthols [4,5], and benzamides [5,6]. More recently, the enamine-activated position of benzotriazinones was fluorinated using Selectfluor [7]. As part of our attempts to fluorinate at the activated 4,7-dimethoxybenzene part of alkoxyamine 1 to give 2, an alternative to electrophilic aromatic substitution was discovered, and is now disclosed (Scheme 1).

2. Results and Discussion

Treatment of alkoxyamine 1 with Selectfluor (1.2 equiv) at 0 °C led to the rapid liberation of the TEMPO free radical, as indicated by GC-MS (Figure 2), and benzylic fluorination, to give 2-(fluoromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole 3. The novel methylene fluoride 3 was isolated in a 77% yield. 2-Fluoromethylbenzimidazole (without the dimethoxy groups) was previously prepared by condensation of 1,2-phenylenediamine with fluoroacetic acid [8]. The expected electrophilic aromatic fluorination at the electron-rich p-dimethoxybenzene part of 1 to give 2 was not observed (Scheme 1).

The displacement of TEMPO is apparent when comparing the ¹H NMR spectra (Figure 3). There are no TEMPO-based peaks in the spectrum of isolated 3, and the methylene signal shifted downfield to 5.61 ppm with splitting into a doublet (²J_H-F = 48.2 Hz) due to ¹H-¹⁹F coupling. The location and multiplicity of the methylene signal is in good agreement with signals reported for 2-(fluoromethyl)-1H-benzimidazole (5.64 ppm, d, ²J_H-F = 47.5 Hz) [8].

The methylene signal split into a doublet (¹J_C-F = 165.5 Hz) in the ¹³C NMR spectrum of 3 at 76.8 ppm (see Supplementary Materials for NMR spectra). ¹³C-¹⁹F NMR coupling also gave doublets for benzimidazole-C-2 at 147.1 ppm (²J_C-F = 19.0 Hz), and for the N-CH₃ at 32.6 ppm (⁴J_C-F = 2.5 Hz). The former is in good agreement with the literature data on 2-(fluoromethyl)-1H-benzimidazole C-2 (148.6 ppm, d, ²J_CF = 19.7 Hz) [8].

The ¹⁹F NMR signal for 3 at −214.93 ppm is similar to the literature value of −213.92 ppm for 2-(fluoromethyl)-1H-benzimidazole [8]. The signal appeared as a triplet (²J_F-H = 48.0 Hz), due to ¹⁹F-¹H coupling with the two ¹H atoms of the adjacent methylene group.

Alkoxyamine 1 is stable to visible-light and the reaction was performed at 0 °C, therefore ruling out bond homolysis as a pathway to formation of methylene fluoride 3. Assuming Selectfluor is a source of F⁺ or F^• and not fluoride, this rules out S_N2 displacement of the TEMPO residue [3,9]. Incompatible polarization of the alkoxyamine C–O bond also prevents a simple S_H2 mechanism. A single electron transfer (SET) pathway is now proposed, and is supported by the electrochemical oxidations of TEMPO-based alkoxyamines (TEMPO-R) with mesolytic cleavage of the alkoxyamine bond forming TEMPO⁺ and R^• [10]. In this case (Scheme 2), SET is proposed to induce mesolytic cleavage of ‘benzylic alkoxyamine’ 1 to produce TEMPO⁺ and a methylene radical 4. Abstraction of F^• by 4 gives reaction product 3, while reduction of the oxoammonium cation 5 by the Selectfluor-derived DABCO derivative 6 gives the TEMPO free radical detected by GC-MS (Figure 2). A plausible alternative to the mesolytic cleavage is initial S_N2 on the fluorine of Selectfluor by the N-3 of benzimidazole 1 to give an imidazolium fluoride [9]. The subsequent generation of 3 eliminates a TEMPO⁺ species that would undergo reduction by 6 (as in Scheme 2) to give a TEMPO free radical.

3. Materials and Methods

3.1. Materials and Measurements

4,7-Dimethoxy-1-methyl-2-{[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]methyl}-1H-benzimidazole (1) was synthesized in an 83% yield by the base-mediated substitution on 2-(chloromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole by TEMPO hydroxylamine (prepared in situ via PtO₂ catalyzed hydrogenation of TEMPO (Sigma-Aldrich, 98%, St. Louis, MO, USA) [11]) [2]. 2-(Chloromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole was prepared in an 85% overall yield by N-methylation and chlorination of (4,7-dimethoxy-1H-benzimidazol-2-yl)methanol [2,12]. Selectfluor (Sigma-Aldrich, >95% F⁺ active), MeCN (Sigma-Aldrich, HPLC Plus, ≥99.9%), CH₂Cl₂ (Fischer Scientific, ≥99%, Hampton, NH, USA) and MgSO₄ (Alfa Aesar, 99.5%, Haverhill, MA, USA) were used as received. GC-MS analysis was performed on an Agilent 7890A GC system (Agilent Technologies, Santa Clara, CA, USA), equipped with an Agilent 5975C inert XL Mass Selective Detector (EI) and an RTX-1, 30 m, ID 0.25 mm, FD 0.25 µm column (Restek Corporation, Bellefonte, PA, USA). Helium was used as carrier gas at a flow rate of 0.7 mL/min. The injector was heated to 250 °C, and the oven temperature was increased from 75 to 250 °C at the rate of 10 °C/min, and was then further increased to 350 °C at 50 °C/min. Thin layer chromatography (TLC) was performed on Merck TLC silica gel 60 F₂₅₄ plates using a UV lamp (254 nm) for visualization. Flash chromatography was performed using silica gel, pore size 60 Å, 230–400 mesh, and particle size 40–63 μm (Sigma-Aldrich) using EtOAc (Fischer Scientific, ≥99%) and hexanes (Fischer Scientific, bp 40–60 °C). The melting point was measured on a Stuart Scientific melting point apparatus, SMP3. Infrared spectrum was recorded using a Perkin-Elmer Spec 1 (Perkin-Elmer, Waltham, MA, USA) with ATR attached. CDCl₃ (Sigma-Aldrich, 99.8% atom D + 0.03% Si(CH₃)₄ v/v) was used as received. NMR spectra were recorded using a Varian 500 MHz instrument (Varian Medical Systems, Palo Alto, CA, USA). The chemical shifts were in ppm relative to Si(CH₃)₄. NMR assignments were supported by DEPT and ¹H-¹³C correlation. ¹³C NMR with complete proton decoupling and ¹⁹F NMR spectra were collected at 125 and 470 MHz, respectively. HRMS was carried out using ESI time-of-flight mass spectrometer (TOFMS) in positive mode using a Waters LCT Mass Spectrometry instrument (Waters, Milford, MA, USA).

3.2. Synthesis of 2-(Fluoromethyl)-4,7-dimethoxy-1-methyl-1H-benzimidazole (3)

Selectfluor (0.118 g, 0.33 mmol) was added to alkoxyamine 1 (0.100 g, 0.28 mmol) in MeCN (5 mL) at 0 °C and stirred for 20 min. H₂O (10 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (MgSO₄), evaporated, and the residue purified by flash chromatography using EtOAc and hexanes, as eluent to yield 3 (48 mg, 77%) as a colorless solid; mp 90–92 °C; R_f 0.33 (1:1 EtOAc:hexanes); ν_max (neat, cm⁻¹) 3001, 2936, 2838, 1525, 1465, 1392, 1263, 1238, 1221, 1174, 1100, 1070; δ_H (500 MHz, CDCl₃) 3.89 (3H, s, OCH₃), 3.96 (3H, s, OCH₃), 4.10 (3H, s, NCH₃), 5.61 (2H, d, ²J_H-F = 48.2 Hz), 6.51 (1H, d, ³J_H-H = 8.5 Hz), 6.59 (1H, d, ³J_H-H = 8.5 Hz); δ_C (125 MHz, CDCl₃) 32.6 (d, ⁴J_C-F = 2.5 Hz, NCH₃), 55.8, 55.9 (both OCH₃), 76.8 (d, ¹J_C-F = 165.5 Hz, CH₂), 101.5, 104.0 (both CH), 127.0, 134.2, 141.8, 146.3 (all C), 147.1 (d, ²J_C-F = 19.0 Hz, C2); δ_F (470 MHz, CDCl₃) − 214.93 (t, ²J_F-H = 48.0 Hz); HRMS (ESI) m/z [M + H]⁺, C₁₁H₁₄N₂O₂F calcd. 225.1039, observed 225.1040.