(Z)-1-(3,5-Dichloro-2H-pyrrol-2-ylidene)-N,N-dimethylmethanamine

Abstract

The Vilsmeier–Haack reaction is a convenient method for the formylation of electron-rich aromatic compounds. However, this interaction sometimes gives specific side products. We report the isolation and structural characterization of a novel compound (Z)-1-(3,5-dichloro-2-pyrrolylidene)-N,N-dimethylmethanamine obtained as a side product during the formylation of 2-chloropyrrole. The product was characterized using NMR spectroscopy and X-ray crystallography.

1. Introduction

The Vilsmeier–Haack reaction (VHR) plays a crucial role in modern organic synthesis [1,2]. It facilitates the introduction of a formyl group into the core of electron-rich aromatic molecules such as phenols, pyrrole [3], pyrazoles [4] and other [5]. Additionally, Vilsmeier reagent (VR) could interact with nonaromatic compound like alkenes, ketones, aldehydes and heterocycles [6]. Formylpyrroles are important intermediates in the synthesis of pyrrole-containing molecules, e.g., difluoroboron dyes like BODIPY, BOPHY, etc. [7]. Using halogenated 2-formylpyrroles enables the preparation of halogenated pyrrole-containing intermediates. Commonly, halogenated 2-formylpyrroles could be obtained by formylation of 2-halopyrroles with VR [8]. However, yields of this reaction are often low. It is well known that VHR can lead to the formation of different unexpected products, depending on substrate and reaction conditions. Herein, we report the isolation and characterization of (Z)-1-(3,5-dichloro-2-pyrrolylidene)-N,N-dimethylmethanamine from the reaction mixture of 2-chloropyrrole VHR.

2. Results

2.1. Synthesis of (Z)-1-(3,5-Dichloro-2-pyrrolylidene)-N,N-dimethylmethanamine

Typical procedures for 5-chloro-2-formylpyrrole preparation include chlorination of pyrrole and further VHR without purification of 2-chloropyrrole. The reaction yielded a complex mixture of products, from which (Z)-1-(3,5-dichloro-2-pyrrolylidene)-N,N-dimethylmethanamine was isolated by flash-chromatography with a moderate yield (Scheme 1). 5-Chloro-2-formylpyrrole and 1-(3-chloro-2-pyrrolylidene)-N,N-dimethylmethanamine were also identified by GC-MS in the crude products mixture as main components. However, only 5-chloro-2-formylpyrrole was isolated by chromatography.

The obtained product was characterized using ¹H and ¹³C NMR spectroscopy, HRMS and X-ray crystallography. In ¹H NMR spectrum singlet signals of methyl groups were observed at 3.36 and 3.72 ppm, singlet signals were also observed at 6.21 (=CHNMe₂) and 7.22 ppm (CH of pyrrole fragment). In ¹³C NMR, all signals of alkene fragments are observed at 113–145 ppm for heterocyclic and vinylidene carbons, and methyl groups gave signals at 40.5 and 47.5 ppm.

A plausible mechanism of formation of product 1 is shown in Scheme 2. We propose that the reaction of 2-chloropyrrole with VR leads to the formation of cation 2, which could undergo alkaline hydrolysis to yield 2-formyl-5-chloropyrrole. Apparently, due to the presence of the electron-withdrawing chlorine atom at position 5, cation 2 has sufficient electrophilicity to attach a chloride anion and form compound 3 or its isomer. Oxidation of compound 3 with atmospheric oxygen during work-up process leads to the isolated product 1.

2.2. XRD Studies

Single crystal X-ray studies were performed. The obtained substance in crystal has monoclinic P2₁/n space group with two molecules in the asymmetric unit M1 and M2. The structure of M1 and M2 with corresponding labeling scheme is shown in Figure 1. The conformation of molecules is planar with intramolecular C-H···N interactions (C⁶-H···N² (d_H···N² = 2.20 Å) and C¹³-H···N⁴ (d_H···N⁴ = 2.22 Å)).

M1 molecules form dimer connected by C⁶-H···Cl¹ and C⁷-H···π¹ interactions (π¹ is N²-C¹-C²-C³-C⁴ ring), and dimers are packing into the chain along the a-axis (Figure 2a,b). M2 molecules also form dimers and chains along the a-axis, but intermolecular interactions are absent. Chains M1 and M2 are connected to each other by C²-H···Cl³ interactions (Figure 2c).

3. Materials and Methods

All chemicals were purchased from commercial sources and used without additional purification unless otherwise noted. The progress of reactions was monitored by thin-layer chromatography (TLC) on Sorbfil Silica 60 F254 on aluminum sheets with UV visualization. Column chromatography was performed by using 100–200 mesh silica gel. NMR spectra were recorded on Bruker Avance-400 (400.13 MHz for ¹H, 100.62 MHz for ¹³C) spectrometer; chemical shifts of ¹H and ¹³C{¹H} are provided in ppm, with solvent signals serving as the internal standard (¹H = 7.24 ppm and ¹³C = 77.16 ppm for CDCl₃). The masses of molecular ions were determined by high-resolution mass spectrometry (HRMS) by means of a DFS Thermo Scientific instrument (EI, 70 eV). X-ray diffraction data for compound was collected at 296 K using a Bruker KAPPA APEX II diffractometer with graphite monochromated MoK_α radiation. Absorption corrections were applied using SADABS [9]. The structure was solved by SHELXT [10]. Refinement was carried out by the full-matrix least-squares technique with SHELXL [10] using OLEX2 [11] software. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were calculated at idealized positions according to the riding model.

Synthesis of 2-chloro-1H-pyrrole.

A mass of 5.00 g (75 mmol) of pyrrole was added to 200 mL of dry CH₂Cl₂. The solution was cooled to −20 °C. Then, a 10.46 g (78 mmol) of NCS was added to the cooled mixture. The obtained mixture was stirred for 10 min and was kept at the temperature −20 °C for 2 h. A mass of 9.87 g (78 mmol) of Na₂SO₃ was added, and the resulting mixture was stirred for 10 min. After that, 150 mL water and 100 mL CH₂Cl₂ were added, the organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic phase was washed with water (3 × 100 mL) and dried over Na₂SO₄. Evaporation under reduced pressure at room temperature gave 4.80 g of crude 2-chloro-1H-pyrrole. The product was used without purification.

¹H NMR (δ, 400.13 MHz, CDCl₃): 6.11 (m, 1H, NH-CH=CH), 6.21 (t, 1H, J = 3.4 Hz, NH-CCl=CH), 6.66 (m, 1H, NH-CH=CH), 8.08 (s, 1H, NH).

Synthesis of (Z)-1-(3,5-dichloro-2H-pyrrol-2-ylidene)-N,N-dimethylmethanamine (1) (Supplementary Materials).

To an ice-cooled solution of 4.86 mL (52 mmol) POCl₃, 4.03 mL (52 mmol) DMF was added dropwise in an Ar atmosphere. After the addition, 70 mL of dry CH₂Cl₂ was added, then a solution of 4.80 g (47 mmol) 2-chloro-1H-pyrrole in 50 mL dry CH₂Cl₂ was added dropwise in 30 min while cooling to 0 °C in an Ar atmosphere. The resulting mixture was stirred for 20 h at RT. After that, a solution of 25 g Na₂CO₃ in 100 mL water was added, and the mixture was stirred for 50 min. Then, the organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic phase was washed with water (3 × 100 mL), dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, with EtOAc/Hex (1:1) as eluent, R_f = 0.48. Light yellow solid. Yield = 2.27 g (16% based on pyrrole). M. p.: 69–71 °C.

¹H NMR (δ, 400.13 MHz, CDCl₃): 3.36 (s, 3H, Me₁), 3.72 (s, 3H, Me₂), 6.21 (s, 1H, Cy C-H), 7.22 (s, 1H, -C=CH-NMe₂).

¹³C NMR (δ, 100.6 MHz, CDCl₃): 40.5, 47.5, 113.1, 126.3, 131.7, 144.2, 144.4.

HRMS (EI, m/z): calculated for C₇H₈³⁵Cl₂N₂—190.0059, found—190.0063.

Next, 2-chloro-5-formylpyrrole was eluted, 1.37 g (14% based on pyrrole), colorless crystals.

¹H NMR (δ, 400.13 MHz, CDCl₃): 6.20 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 4.0, Hz, 1H), 9.35 (s, 1H), 10.86 (br. s, 1 H, NH). NMR spectrum identical with [8,12].

X-ray structure determination: crystal data for C₇H₈Cl₂N₂, M = 191.05 g mol^–1, colorless elongated prism, crystal dimensions 1.00 × 0.62 × 0.18 mm, monoclinic, space group P2₁/n, a = 7.3574(3), b = 15.7753(6), c = 15.4311(6) Å, β = 100.599(2)°, V = 1760.46(12) ų, Z/Z’ = 8/2, D_calc = 1.442 g cm^–3, R1 = 0.037, wR2 = 0.109, R_int = 0.036, S = 1.05. Data have been deposited at the Cambridge Crystallographic Data Centre as CCDC 2360994.