5-Chloro-4-iodo-1,3-dimethyl-1H-pyrazole

Abstract

Reaction of 5-chloro-1,3-dimethyl-1H-pyrazole with I₂/HIO₃ in refluxing acetic acid gives the title compound in good yield. Detailed spectroscopic data (¹H NMR, ¹³C NMR, ¹⁵N NMR, IR, MS) are presented.

(Hetero)aryl halides are valuable starting materials for different transition-metal-catalyzed cross coupling reactions. In the recent past, these reactions have emerged as extraordinaryly important methods for C–C and also C–X (X = O, N, S) bond formation in organic chemistry [1,2].

In the Sonogashira coupling, terminal acetylenes react with, for instance, (hetero)aryl halides or triflates to afford the corresponding (hetero)aryl alkynes [3,4]. Comparing the reactivity of the possible aryl reactants, the general order of reactivity is aryl iodides > aryl triflates ≥ aryl bromides >> aryl chlorides [4]. Accordingly, the best results in many reactions can be obtained with aryl iodides. This is also confirmed for pyrazolyl halides, in which a clear preference for iodides over bromides and chlorides is evident [5].

In the course of a synthetic program dedicated to the functionalization of halogenopyrazoles [6,7,8,9], we were interested in 4-iodopyrazole 2, which was – amongst others – considered as a possible precursor in Sonogashira-type couplings. The synthesis of compound 2 was achieved by reaction of commercially available 5-chloro-1,3-dimethyl-1H-pyrazole (1) with I₂/HIO₃ in refluxing acetic acid (Scheme 1). Thus, the desired iodopyrazole 2 was obtained in 75% yield after flash chromatography.

Experimental

The melting point was determined on a Reichert–Kofler hot-stage microscope and is uncorrected. Mass spectrum: Shimadzu QP 1000 instrument (EI, 70 eV). IR spectrum: Perkin-Elmer FTIR Spectrum 1000 instrument (KBr-disc). The elemental analysis was performed at the Microanalytical Laboratory, University of Vienna. ¹H and ¹³C NMR spectra were recorded on a Varian UnityPlus 300 spectrometer at 28 °C (299.95 MHz for ¹H, 75.43 MHz for ¹³C). The centre of the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm (¹H in CDCl₃) and δ = 77.0 ppm (¹³C in CDCl₃). The digital resolutions were 0.2 Hz/data point in the ¹H and 0.4 Hz/data point in the ¹H-coupled ¹³C-NMR spectra (gated decoupling). The ¹⁵N NMR spectrum (50.68 MHz, refocused and decoupled INEPT) was obtained on a Bruker Avance 500 instrument with a ‘directly’ detecting broadband observe probe (BBFO) and was referenced against external nitromethane.

5-Chloro-4-iodo-1,3-dimethyl-1H-pyrazole (2)

To a solution of 5-chloro-1,3-dimethyl-1H-pyrazole (1) (2.500 g, 19.15 mmol) in glacial acetic acid (10 mL) was added HIO₃ (674 mg, 3.8 mmol) and the mixture was stirred for 10 minutes. Then I₂ (3.884 g, 15.3 mmol) was added and the mixture was heated to reflux for 4 h. After cooling, the mixture was treated with 2N NaOH until the dark color disappeared, then some drops of Na₂S₂O₃ solution were added to obtain a colorless solution. The mixture was exhaustively extracted with dichloromethane, the combined organic layers were washed with water, dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: light petroleum–ethyl acetate, 10:1) to afford 3.683 g (75%) of 2 as colorless crystals, mp 64–65 °C.

IR (KBr) ν (cm^-1): 2923, 1497, 1350, 1271, 1107, 1053, 1022, 638.

MS (EI, 70 eV): (m/z, %) 256/258 (M⁺, 19/7), 160 (14), 128 (24), 96 (18), 64 (100).

¹H NMR (CDCl₃): δ (ppm) 2.22 (s, 3H, 3-Me), 3.84 (s, 3H, 1-Me).

¹³C NMR (CDCl₃): δ (ppm) 14.4 (3-Me, ¹J = 128.3 Hz), 37.1 (1-Me, ¹J = 141.1 Hz), 60.8 (C-4, ³J(C4,3-Me) = 4.3 Hz), 131.3 (C-5, ³J(C5,1-Me) = 2.4 Hz), 150.4 (C-3, ²J(C3,3-Me) = 6.9 Hz).

¹⁵N NMR (CDCl₃): δ (ppm) −186.1 (N-1), −77.5 (N-2).

Anal. Calcd for C₅H₆ClIN₂: C, 23.42%; H, 2.36%; N, 10.92%. Found: C, 23.76%; H, 2.34%; N, 10.81%.