1-{(1S,2S,4R)-7,7-Dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo [2.2.1]heptan-2-yl}-1H-benzo[d]imidazole

Abstract

A three-step synthesis of 1-{(1S,2S,4R)-7,7-dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-yl}-1H-benzo[d]imidazole, prepared from camphor derived diamine, is disclosed. The absolute configuration at the chiral center bearing benzo[d]imidazole moiety was confirmed by NOESY. The structure of a newly synthesized compound was confirmed by ¹H- and ¹³C-NMR, 2D NMR, IR spectroscopy, and high resolution mass-spectrometry.

1. Introduction

In the last three decades, the field of asymmetric organocatalysis has experienced exponential growth, leading to numerous mechanistic studies and synthetic applications. The most attractive features of organocatalysis are easy-to-handle reaction conditions, environmentally friendly reagents without potentially toxic metal ions, and readily available tunable organocatalysts operating via different substrate activation modes. Nowadays, organocatalysis is an established methodology within asymmetric catalysis [1,2,3,4,5] and is increasingly used in the pharmaceutical and biotechnological industries [6,7].

Bifunctional hydrogen-bond donor organocatalysts are at the forefront of noncovalent organocatalysis. They allow simultaneous activation and coordination of both nucleophilic and electrophilic reactants. A typically used H-bond donor bifunctional organocatalyst is a derivative of a chiral 1,2-diamine scaffold such as cyclohexane-1,2-diamine or quinuclidine, which contains a tertiary amine functionality and a hydrogen-bond donor moiety. Thiourea and (thio)squaramide double hydrogen-bond donors are the most common and best [1,8,9,10,11]. Efficient bifunctional organocatalysts based on camphor-1,3-diamine were recently developed in our group [12,13]. Since the number of hydrogen bond donors used in organocatalysis is limited, the introduction of new hydrogen-bond donors would increase the number of available H-bond donor bifunctional organocatalysts and possibly broaden the substrate scope. In this context, we reported the synthesis of enaminone and benzenediamine hydrogen bond donors based on the chiral quinuclidine scaffold [14].

Continuing our research on the synthesis and application of camphor-derived organocatalysts in stereoselective synthesis [15], we report here an attempt to prepare an enaminone-benzenediamine organocatalyst based on camphor 4 using the developed synthesis protocols [14].

2. Results and Discussion

Recently, we reported the synthesis and catalytic activity of (S)-quininamine-based organocatalysts bearing enaminone and benzenediamine hydrogen bond donors [14]. In extension of this work, the developed three-step synthesis was used for the preparation of camphor-derived organocatalysts bearing benzenediamine hydrogen bond donor 4. Starting from diamine 1 [12], the nucleophilic aromatic substitution with 2-fluoronitrobenzene provided a nitroaniline derivative 2. The following catalytic hydrogenation of 2 furnished benzenediamine derivative 3, isolated as a salt solvates with acetic acid after column chromatography. Finally, treatment of the primary amino group of 3 with commercial 2-(ethoxymethylene)malononitrile was expected to provide the enaminone-benzenediamine derivative 4 with a Michael addition-elimination reaction. Instead, camphor-derived benzo[d]imidazole 5 was isolated in an 87% yield (Scheme 1). The formation of product 5 could be rationalized by the initial formation of the desired enamine 4, which in a 5-exo-trig cyclization gave imidazoline 4′. Elimination of the malononitrile provided the final aromatic benzo[d]imidazole 5. A closely similar reaction for the formation of benzo[d]imidazole systems, applying diethyl 2-(methoxymethylene)malonate, was reported by Pfizer in 2003 [16]. The benzimidazole core is usually prepared from ortho-phenylenediamine by cyclization with a carbonyl compound or its equivalent under various reaction conditions [17]. C1 reagents used include DMSO [18], aldehydes [19,20], orthoesters [21], formamides [22], carboxylic acids [23] and others [17].

The structure of compound 5 was confirmed by spectroscopic methods (¹H- and ¹³C-NMR, 2D-NMR, IR, and high-resolution mass spectrometry). The absolute configuration at the chiral center bearing benzo[d]imidazole moiety was confirmed by NOESY on the basis of the cross-peak between the methyl group and the exo-H(2) proton (Figure 1). The intermediate 2 was characterized by ¹H- and ¹³C-NMR, 2D-NMR, IR, and melting point while the intermediate 3 was characterized by ¹H- and ¹³C-NMR (In Supplementary Materials). Intermediates 4 and 4′ were not observed.

In conclusion, camphor-derived benzo[d]imidazole 5 was synthesized in three-steps from diamine 1. In view of the synthetic accessibility of benzo[d]imidazole 5, a small library can easily be prepared and studied further. In addition, alkylation of benzo[d]imidazole 5 could lead to camphor-based N-heterocyclic carbene precursors [15].

3. Materials and Methods

Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical grade anhydrous Na₂SO₄. Melting points were determined on a Kofler micro hot stage and on SRS OptiMelt MPA100—Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA). The NMR spectra were obtained on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for ¹H and 126 MHz for ¹³C nucleus, using CDCl₃ with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm (Sigma-Aldrich, St. Louis, MO, USA)). All the commercially available chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA). Catalytic hydrogenation was performed on a Parr Pressure Reaction Hydrogenation Apparatus (Moline, IL, USA). The optical rotation of optical active substances was measured on a Perkin Elmer 241 MC Polarimeter (PerkinElmer, Waltham, MA, USA) equipped with a Na lamp (sodium emission lines at 589.0 nm) at 20 °C.

(1S,2S,4R)-7,7-Dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-amine (1) [12] was prepared following the literature procedure.

3.1. Synthesis of (1S,2S,4R)-7,7-Dimethyl-N-(2-nitrophenyl)-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-amine (2)

A mixture of (1S,2S,4R)-7,7-dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-amine (1) (1.75 mmol, 343 mg), 1-fluoro-2-nitrobenzene (1.75 mmol, 0.185 mL), K₂CO₃ (1.75 mmol, 0.242 g), and DMF (5 mL) was stirred at 25 °C for 24 h. Volatile components were evaporated in vacuo. The residue was purified by column chromatography (EtOAc). Fractions containing the product 2 were combined and volatile components evaporated in vacuo. Yield: 553 mg (1.61 mmol, 92%) of yellow solid; mp = 83.5–85.3 °C. ¹H-NMR (500 MHz, CDCl₃): δ 0.95 (s, 3H); 1.02 (s, 3H); 1.01–1.06 (m, 1H); 1.24 (ddd, J = 4.4, 9.5, 12.3 Hz, 1H); 1.58–1.68 (m, 3H); 1.68–1.84 (m, 4H); 2.23 (ddd, J = 4.1, 9.5, 13.5 Hz, 1H); 2.38–2.49 (m, 4H); 2.69 (q, J = 7.3 Hz, 2H); 2.82 (d, J = 13.4 Hz, 1H); 3.81 (d, J = 10.1 Hz, 1H); 6.57 (ddd, J = 1.3, 6.9, 8.4 Hz, 1H); 6.71 (dd, J = 1.3, 8.9 Hz, 1H); 7.35 (ddd, J = 1.7, 6.9, 8.7 Hz, 1H); 8.14 (dd, J = 1.7, 8.7 Hz, 1H); 9.01 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.40, 20.23, 24.08, 26.66, 28.14, 38.28, 45.28, 48.43, 52.25, 56.73, 58.33, 58.48, 114.60, 115.41, 126.94, 132.46, 135.61, 145.90.

3.2. Synthesis of N¹-{(1S,2S,4R)-7,7-Dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-yl}benzene-1,2-diamine (3)

A mixture of (1S,2S,4R)-7,7-dimethyl-N-(2-nitrophenyl)-1-[(pyrrolidin-1-yl)methyl]bicyclo-[2.2.1]heptan-2-amine (2) (0.83 mmol, 285 mg), Pd-C (ω = 10%, 20 mg), and MeOH (5 mL) was shaken in a Paar shaker hydrogenation apparatus in H₂ atmosphere (3 bar) at 25 °C for 6 h. The reaction mixture was filtrated to remove Pd-C, volatile components were evaporated in vacuo. The residue was purified by column chromatography (Silica Gel 60; EtOAc/MeOH/AcOH = 4:1:0.1). Fractions containing the product 3 were combined and volatile components evaporated in vacuo. Yield: 262 mg (0.70 mmol, 85%, acetic acid to amine 3 in a 1:1 ratio) of colorless oil. ν_max 3378, 2954, 2877, 2791, 1616, 1571, 1507, 1441, 1416, 1389, 1354, 1323, 1254, 1231, 1156, 1069, 1037, 910, 868, 777, 740, 695, 670 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.95 (s, 3H); 0.98–1.03 (m, 1H); 1.02 (s, 3H); 1.33 (ddd, J = 4.6, 9.5, 12.4 Hz, 1H); 1.62–1.69 (m, 1H); 1.71 (t, J = 4.6 Hz, 1H); 1.79–1.88 (m, 5H); 1.99 (s, 3H); 2.41–2.57 (m, 2H); 2.88 (d, J = 2.5 Hz, 2H); 2.94 (br s, 2H); 3.12 (br s, 2H); 3.71 (ddd, J = 1.8, 3.9, 9.6 Hz, 1H); 6.18 (br s, 4H); 6.49 (dd, J = 1.3, 7.6 Hz, 1H); 6.62–6.67 (m, 2H); 6.71 (ddd, J = 2.7, 6.2, 7.7 Hz, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.33, 20.16, 22.93, 23.76, 26.34, 28.27, 38.34, 45.03, 49.77, 51.13, 56.93, 57.01, 60.65, 112.16, 115.23, 118.59, 119.04, 136.11, 136.25, 176.69.

3.3. Synthesis of 1-{(1S,2S,4R)-7,7-Dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-yl}-1H-benzo[d]imidazole (5)

A mixture of N¹-{(1S,2S,4R)-7,7-dimethyl-1-[(pyrrolidin-1-yl)methyl]bicyclo[2.2.1]heptan-2-yl}benzene-1,2-diamine (3) (157 mg, 0.42 mmol; acetic acid to amine 3 in a 1:1 ratio) and 2-(ethoxymethylene)malononitrile (61 mg, 0.50 mmol) in dichloromethane (2 mL) was stirred at 25 °C for 24 h. Volatile components were evaporated in vacuo. The residue was purified by column chromatography (Silica Gel 60; EtOAc/petroleum ether = 3:1). Fractions containing the product 5 were combined and volatile components evaporated in vacuo. Yield: 118 mg (0.365 mmol, 87%) of colorless semisolid. [α]_D^r.t. = −55.9 (0.16, MeOH). EI-HRMS: m/z = 324.2429 (MH⁺); C₂₁H₂₉N₃ requires: m/z = 324.2434 (MH⁺); ν_max 2958, 2781, 2192, 1613, 1562, 1482, 1456, 1420, 1390, 1370, 1351, 1329, 1284, 1225, 1196, 1111, 1073, 1009, 907, 888, 797, 783, 766, 737, 643 cm⁻¹. ¹H-NMR (500 MHz, CDCl₃): δ 0.98–1.10 (m, 2H); 1.06 (s, 3H); 1.17 (s, 3H); 1.17–1.26 (m, 2H); 1.56–1.66 (m, 2H); 1.73–1.83 (m, 1H); 1.86 (t, J = 4.5 Hz, 1H); 1.89–2.01 (m, 3H); 2.03–2.09 (m, 1H); 2.14–2.24 (m, 2H); 2.36 (d, J = 13.1 Hz, 1H); 2.59–2.69 (m, 1H); 2.78 (d, J = 13.2 Hz, 1H); 4.86 (ddd, J = 2.4, 5.0, 11.9 Hz, 1H); 7.19–7.25 (m, 2H); 7.39–7.44 (m, 1H); 7.71–7.77 (m, 1H); 8.17 (s, 1H). ¹³C-NMR (126 MHz, CDCl₃): δ 19.41, 20.79, 23.50, 27.00, 28.52, 37.42, 45.03, 50.85, 54.00, 55.64, 57.07, 59.81, 111.64, 119.62, 121.82, 121.96, 135.87, 142.22, 142.72.