Cis,exo-1,2,3,4,4a,13b-hexahydro-1,4-methano-5-isopropoxy-9H-tribenzo[b,f]azepine

Abstract

The title compound—cis,exo-1,2,3,4,4a,13b-hexahydro-1,4-methano-5-isopropoxy-9H-tribenzo[b,f]azepine—was synthesized in 83% isolated yield by a palladium-catalyzed one-pot strategy from 1-iodo-2-isopropoxybenzene and ortho-bromoaniline. The azepine derivative was fully characterized (FT-IR, MS, ¹H and ¹³C-NMR, elemental analysis) and all proton and carbon signals have been completely assigned by 2D NMR experiments.

1. Introduction

The selective activation and functionalization of inert C-H bonds is a great challenge in synthetic chemistry [1,2,3,4,5]. In 1997 Marta Catellani discovered an innovative strategy aimed at the derivatization of both the ortho and ipso positions of aryl halides [6]. Over the years, this palladium/norbornene-catalyzed C-H activation and functionalization reaction has been proven to be a powerful tool for the construction of complex molecules in a one-pot fashion [7,8]. In this context, we have successfully applied this methodology to the synthesis of many compounds, including natural product derivatives [9,10,11,12,13,14,15,16,17,18,19,20]. Notably, in 2011, we enriched the versatility of the Catellani reaction by the synthesis of dibenzo[b,f]azepines [21].

A dibenzo[b,f]azepine scaffold is essential for the construction of important therapeutic agents, exhibiting a variety of biological activities including anticancer, antidepressant, and antiepileptic properties [22,23,24,25].

In this Note, we report the preparation of azepine 3—that is, cis,exo-1,2,3,4,4a,13b-hexahydro-1,4-methano-5-isopropoxy-9H-tribenzo[b,f]azepine—by employing the abovementioned palladium-catalyzed methodology [21] (Scheme 1). The structure of compound 3 was confirmed by NMR, MS, and FT-IR, and all data are in concordance with the assumed structure.

2. Results and Discussion

As shown in Scheme 1, cis,exo-1,2,3,4,4a,13b-hexahydro-1,4-methano-5-isopropoxy-9H-tribenzo [b,f]azepine (3) was synthesized in 83% isolated yield. The reaction was carried out using 1-iodo-2-isopropoxybenzene (1), o-bromoaniline (2), and norbornene, in the presence of a catalytic amount of Pd(OAc)₂ (5 mol %), PPh₃ (12.5 mol %), and Cs₂CO₃ as a base in DMF at 105 °C for 24 h. Notably, the isopropoxy group, which can be easily converted to a hydroxyl group [26], is well tolerated by this protocol.

A plausible reaction mechanism is shown in Scheme 2. At first, the oxidative addition of 1 to palladium(0) affords the palladium(II) complex I, which, after stereoselective norbornene insertion, leads to intermediate II. The intramolecular C-H bond activation provides the arylnorbornyl palladacycle III, which is able to react with 2-bromoaniline 2, giving intermediate IV. Finally, an intramolecular C-N coupling affords compound 3 and palladium(0), which can start a new catalytic cycle. Contrary to many other Catellani-type reactions, norbornene is a reagent here since it is incorporated in the final product.

Compound 3 was characterized by NMR (¹H and ¹³C-NMR in Figure 1 and Figure 2), FT-IR, and MS. In addition, all proton and carbon signals were assigned by 2D and ¹³C-DEPT-NMR experiments (Figures S1–S11, Supplementary Materials) and protons on the norbornene bridge were unequivocally assigned by NOESY-2D-NMR (Figure S12, Supplementary Materials). As expected, diagnostic NOE correlations appear between H13 and H13b (green circle, Figure S12), and H1′ and H6 (blue circle, Figure S12). Furthermore, the proton marked as H14 anti has a strong NOE correlation with H2/H3 protons (red circle in Figure S12), while no correlation signals are present between H2/H3/H4a/H13b protons and H14 syn. In summary, the signal at 1.62 ppm, which accounts for H2/H3 (both endo and exo) protons, presents typical NOE correlations with H4a, H13b (orange circle in Figure S12), H4, H1 (grey circle in Figure S12), and H14 anti (red circle in Figure S12), as expected for the presented stereochemistry.

3. Materials and Methods

Compound 3 was synthesized according to the procedure described in the literature [21]. Other chemicals were obtained from commercial sources and were used without further purification. Gas chromatography analyses were performed with an Agilent Technology 7820A instrument (Agilent Technologies, Santa Clara, CA, USA) using a 30 m SE-30 capillary column. Column chromatography was carried out on silica gel (Merck, Darmstadt, Germany, 0.063–0.200 mm) and Thin-Layer Chromatography (TLC) on Merck 60F254 plates. Electron ionization (EI) mass spectra were obtained with an Agilent Technology instrument (Agilent Technologies, Santa Clara, CA, USA) working at 70 eV ionization energy. NMR spectra were recorded in CDCl₃, using the solvent residual signals as internal reference (7.26 and 77.00 ppm, respectively, for ¹H and ¹³C) on a Bruker AVANCE 400 spectrometer (Bruker, Milan, Italy). Data for ¹H-NMR and ¹³C-NMR are reported as follows: chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, hept = heptet), integration and coupling constant (Hz). IR spectrum was run on a Nicolet FT-IR 5700 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) paired with a Diamond Smart Orbit accessory. Melting point was determined with an electrothermal apparatus. Elemental analysis was performed with a Carlo Erba EA 1108-Elemental Analyzer (Carlo Erba, Milan, Italy).

The reaction in Scheme 1 was carried out in a 20-mL Schlenk-type flask under a controlled atmosphere. The Schlenk-type flask, equipped with a magnetic stirring bar, was charged under nitrogen with Cs₂CO₃, dried at 110 °C for 2 h (326 mg, 1.0 mmol), PPh₃ (14 mg, 0.055 mmol) and Pd(OAc)₂ (5 mg, 0.022 mmol) in DMF (5 mL). After 10 min stirring, a DMF solution (5 mL) of 1-iodo-2-isopropoxybenzene (1, 126 mg, 0.48 mmol), o-bromoaniline (2, 76 mg, 0.44 mmol) and norbornene (50 mg, 0.53 mmol) was added. The resulting mixture was stirred in an oil bath at 105 °C for 24 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and washed with a saturated solution of NaCl (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄; the solvent was removed under reduced pressure and the product was isolated by flash column chromatography on silica gel using a hexane–EtOAc mixture (98:2) as eluent. Compound 3 was obtained as a white solid in 83% of yield (116 mg, 0.36 mmol). Mp 158–159 °C. IR (KBr, cm⁻¹): ν 3373, 2970, 2953, 2864, 1584, 1492, 1467, 1449, 1240, 1121, 1050, 743.

¹H-NMR (400 MHz, CDCl₃) δ 7.23 (dd, J = 7.7, 0.9 Hz, 1H, H13), 7.08 (td, J = 7.6, 1.5 Hz, 1H, H11), 7.00 (t, J = 8.0 Hz, 1H, H7), 6.93 (td, J = 7.4, 1.0 Hz, 1H, H12), 6.79 (dd, J = 7.7, 0.9 Hz, 1H, H10), 6.56 (d, J = 8.1 Hz, 1H, H6), 6.43 (d, J = 7.9 Hz, 1H, H8), 5.13 (s, 1H, NH), 4.59 (hept, J = 5.9 Hz, 1H, H1′), 3.84 (d, J = 9.7 Hz, 1H, H4a), 3.15 (d, J = 9.7 Hz, 1H, H13b), 2.66 (d, J = 9.6 Hz, 1H, H14 syn), 2.34 (s, 1H, H4), 2.26 (s, 1H, H1), 1.62 (s, 4H, H2 endo, H2 exo, H3 endo, H3 exo), 1.43 (d, J = 6.0 Hz, 3H, H2′), 1.40 (d, J = 6.0 Hz, 3H, H2′), 1.16 (d, J = 9.6 Hz, 1H, H14 anti). ¹³C-NMR (101 MHz, CDCl₃) δ 156.92 (C5), 145.23 (C4b), 144.09 (C13a), 133.82 (C10a), 132.57 (C13), 126.40 (C11), 126.03 (C7), 123.89 (C8a), 121.63 (C12), 119.60 (C10), 112.27 (C8), 106.56 (C6), 70.14 (C1′), 52.79 (C13b), 49.81 (C4), 48.58 (C1), 42.42 (C4a), 37.93(C14), 31.18 (C3), 30.20 (C2), 22.32 (C2′), 22.31 (C2′). GC-MS (EI): m/z 319 (M⁺, 100), 276 (12), 252 (54), 238 (65), 210 (36), 196 (72), 180 (25), 167 (13). Anal. Calcd. for C₂₂H₂₅NO: C, 82.72; H, 7.89; N, 4.38. Found: C, 82.49; H, 7.78; N, 4.31.