10a,11,11-Trimethyl-10a,11-dihydro-8H-benzo[e]imidazo[1,2-a]indol-9(10H)-one

Abstract

The alkylation of 1,1,2-trimethyl-1H-benzo[e]indole with 2-chloroacetamide, followed by work-up of the reaction mixture with a base and the subsequent treatment of a crude product with acetic acid gives 10a,11,11-trimethyl-10a,11-dihydro-8H-benzo[e]imidazo[1,2-a]indol-9(10H)-one. The structure assignments were based on data from ¹H, ¹³C, and ¹⁵N-NMR spectroscopy. The optical properties of the obtained compound were studied by UV–Vis and fluorescence spectroscopy.

1. Introduction

1,1,2-Trimethyl-1H-benzo[e]indole is an important precursor for the synthesis of building blocks that have wide application in the preparation of a number of near-infrared fluorescence emitting dyes. Alkylation of 1,1,2-trimethyl-1H-benzo[e]indole with various alkylating agents—such as iodomethane [1], iodoethane [2], 4-iodobutane [3], 1-iodo-3-phenylpropane [4], benzyl bromides [5,6], or 3-iodopropanoic acid [7] — affords the corresponding N-quaternary 1,1,2-trimethyl-1H-benzo[e]indolium salts. The reactions are usually performed in aprotic solvents such as acetonitrile or toluene with conventional or microwave heating [8]. Upon treatment with various electrophilic counterparts, these salts are converted into dyes, which have found wide application for the development of the near-infrared fluorescent probes [1,2,3,4,5,6,7]. Furthermore, organic squaraine dyes based on the N-quaternized 1,1,2-trimethyl-1H-benzo[e]indolium salts have been used for the preparation of dye-sensitized solar cells [9]. It was recently shown by us that the microwave-assisted reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylamide or acrylic acid gave functionalized benzo[e]indoline derivatives possessing intense fluorescence and significant Stokes shifts [10]. The aim of the present work is the synthesis of 10a,11,11-trimethyl-10a,11-dihydro-8H-benzo[e]imidazo[1,2-a]indol-9(10H)-one as a novel fluorescent building block, through the reaction of 1,1,2-trimethyl-1H-benzo[e]indole with 2-chloroacetamide. The structurally similar 9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives have found application in the preparation of optical molecular switches [11].

2. Results and Discussion

The reaction of 1,1,2-trimethyl-1H-benzo[e]indole 1 with 2-chloroacetamide was carried out in o-xylene at 140 °C (Scheme 1) and gave a solid, which was separated by filtration (Scheme 1). The obtained solid material, which constituted a complex product mixture, was dissolved in water, the solution was basified with solid sodium carbonate and the separated resinous substance was extracted with diethyl ether. After the solvent removal from the organic phase, the residue was dissolved in ethanol, acetic acid was added to the solution, and the mixture was refluxed for several minutes in order to perform ring-closure of the imidazolidine ring. The neutralization of the solution, followed by the extraction and purification of the crude product by column chromatography on silica gel gave the target compound 2 in 30% isolated yield.

The structure assignment of 2 was based on spectral data. The molecular formula of compound 2 was found to be C₁₇H₁₈N₂O by HRMS. The IR spectrum shows a broad band at 3157 cm⁻¹ for NH and a sharp band at 1698 cm⁻¹ for the C=O group. The broad-band decoupled ¹³C-NMR spectrum of compound 2, showed resonances for all 17 carbon atoms. The DEPT-90 and 135 spectra indicated the presence of 3 methyl, 1 methylene, and 6 methine carbon atoms. Comparison of the DEPT spectrum with the broad-band decoupled ¹³C-NMR spectrum, revealed the presence of seven quaternary carbons. The multiplicity edited ¹H-¹³C HSQC spectrum indicated that the methylene protons H-8, which are diastereotopic due to chirality of the molecule and seen as an AB-system with δ = 3.92 and 3.96 ppm in the ¹H-NMR spectrum, have one bond connectivities with the carbon C-8 at 55.3 ppm. The data from ¹H-¹³C HMBC spectrum revealed long range correlations of those methylene protons with the quaternary carbons C-6a (at 148.0 ppm), C-10a (at 92.1 ppm), and C-9 (174.1 ppm), respectively. The aforementioned protonated carbon C-8 showed correlation with carbonyl carbon C-9 in the 1,1-ADEQUATE spectrum, which revealed also correlations of C-6 with C-6a, and of 10a-CH₃ with C-10a, respectively. The ¹H-¹⁵N HSQC experiment (optimized for ¹J_NH = 90 Hz) indicated that the amide N-H proton at 7.83 ppm has one-bond connectivity with the N-10, which resonates at −243.3 ppm. The resonance for N-10 was also confirmed via the ¹H-¹⁵N HMBC experiment, which additionally revealed the data for N-7 (−288.7 ppm). Both nitrogen atoms showed appropriate strong couplings to the H-8 and 10a-CH₃ protons, and in the case of N-7 it had a weak coupling with the aromatic proton 6-H.

The optical properties of compound 2 were investigated by UV–Vis spectroscopy and fluorimetric measurement. The electronic absorption spectra of compound in THF did not have absorption bands in the visible part of the electronic spectra (Figure 1a). The fluorescence spectra of 2, measured in THF, displayed emission maximum at 418 nm with a Stokes shift of 74 nm (Figure 1b). The fluorescence quantum yield (Φ_f) of the solution was estimated by the integrating sphere method and gave the Φ_f value of 37.6%.

3. Materials and Methods

3.1. Materials

All reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification.

3.2. Instrumentation

For thin layer chromatography (TLC), Merck pre-coated TLC plates (Silica gel 60 F₂₅₄, Merck KgaA, Darmstadt, Germany) were employed. The purification of the products was performed using flash chromatography on a glass column with silica gel (high purity grade 9385, pore size 60 A, 230–400 mesh particle size). The melting points were determined on a Melt-Temp (Capillary Melting point Apparatus, Barnstead International, Dubuque, IOWA, USA) and are uncorrected. The ¹H, ¹³C and ¹⁵N-NMR spectra were recorded in CDCl₃ solutions at 25 °C on a Bruker Avance III 700 (Bruker BioSpin AG, Fallanden, Switzerland), (700 MHz for ¹H, 176 MHz for ¹³C, 71 MHz for ¹⁵N) spectrometer equipped with a 5 mm TCI ¹H-¹³C/¹⁵N/D z-gradient cryoprobe. The chemical shifts, expressed in ppm, were relative to tetramethylsilane (TMS). The ¹⁵N-NMR spectra were referenced to neat, external nitromethane (coaxial capillary). The full and unambiguous assignments of the ¹H, ¹³C, and ¹⁵N-NMR resonances were achieved using standard Bruker software (TopSpin 3.2.7) and a combination of standard NMR spectroscopic techniques, such as DEPT, COSY, TOCSY, NOESY, gs-HSQC, gs-HMBC, H2BC, and 1,1-ADEQUATE. The infrared spectra were recorded on a Bruker TENSOR 27 spectrometer (Bruker Optik GmbH, Ettlingen, Germany), using potassium bromide pellets. The UV–Vis spectra were recorded using 0.1 mM solutions of the compounds in THF on a Shimadzu 2600 UV-Vis spectrometer (Shimadzu EUROPA GmbH, Duisburg, Germany). The fluorescence spectra were recorded on a FL920 fluorescence spectrometer from Edinburgh Instruments (Edinburg Instruments Ltd, Livingston, UK). The PL quantum yields were measured from dilute solutions by an absolute method using Edinburgh Instruments (Edinburg Instruments Ltd, Livingston, UK)integrating sphere excited with a Xe lamp. Optical densities of the sample solutions were ensured to be below 0.1 to avoid reabsorption effects. All optical measurements were performed at rt under ambient conditions. HRMS spectra were recorded with a Bruker micrOTOF - QIII spectrometer (Bruker Daltonik GmbH, Bremen, Germany).

3.3. Synthesis

To a solution of 1,1,2-trimethyl-1H-benzo[e]indole (1) (1.0 g, 4.8 mmol) in o-xylene (5 mL), 2-chloroacetamide (0.51 g, 5.5 mmol) was added and the reaction mixture was heated at 140 °C for 4 h to afford a solid, which was separated by filtration. The solid was dissolved in ethanol (5 mL), the solution was diluted with water (15 mL) and treated with solid sodium carbonate till alkaline pH. The separated resinous substance was extracted with diethyl ether (3 × 15 mL), the organic layers were combined, and the organic solvent was removed under reduced pressure. The residue was dissolved in ethanol (5 mL), glacial acetic acid (2 mL) was added to the solution and the mixture was refluxed for 10 min. Upon cooling to rt, the reaction mixture was diluted with water (30 mL), neutralized with solid sodium carbonate and extracted with diethyl ether (3 × 15 mL). The residue was purified by flash chromatography on silica gel (dichloromethane/methanol, 20:1→ dichloromethane/methanol, 9:1, v/v) to yield the title compound 2.

Yield: 380 mg, (30%), brownish crystals, m. p. 225–226 °C. IR (KBr) ν(cm⁻¹): 3157 (NH), 3054 (CH_arom), 2966 (CH_aliph), 1698 (C=O), 1351, 1307, 811, 745. UV-Vis (THF) λ_max, nm (ε × 10³, dm³·mol⁻¹·cm⁻¹): 216 (34.98), 246 (59.49), 287 (7.08); 299 (5.89), 344 (2.49). ¹H-NMR (700 MHz, CDCl₃): δ_H ppm 1.40 (s, 3H, 11-CH₃), 1.58 (s, 3H, 10a-CH₃), 1.75 (s, 3H, 11-CH₃), 3.92 (d, J = 16.7 Hz, 1H, 8-CH_aH_b), 3.96 (d, J = 16.5 Hz, 1H, 8-CH_aCH_b), 7.02 (d, J = 8.7 Hz, 1H, 6-H), 7.30 (t, J = 7.4 Hz, 1H, 3-H), 7.44 (t, J = 7.6 Hz, 1H, 2-H), 7.71 (d, J = 8.7 Hz, 1H, 5-H), 7.80 (d, J = 8.2 Hz, 1H, 4-H), 7.83 (s, 1H, NH), 7.97 (d, J = 8.5 Hz, 1H, 1-H). ¹³C-NMR (176 MHz, CDCl₃): δ_C ppm 20.7 (10a-CH₃), 23.5 (11-CH₃), 25.3 (11-CH₃), 48.4 (C-11), 55.3 (C-8), 92.1 (C-10a), 114.3 (C-6), 122.0 (C-1), 123.2 (C-3), 126.7 (C-2), 129.0 (C-11a), 129.62 (C-4), 129.64 (C-5), 130.2 (C-11b), 131.2 (C-4a), 148.0 (C-6a), 174.1 (C=O). ¹⁵N-NMR (71 MHz, CDCl₃): δ_N ppm –288.7 (N-7), –243.3 (N-10). HRMS (ESI TOF): [M + Na⁺]⁺ found 289.1312. [C₁₇H₁₈N₂O + Na⁺]⁺ requires 289.1311.