2. Results and Discussion
The synthesis of the tetramethylazepine
2 [
23] was carried out starting from the biphenylazepine
1 [11] following a two-step approach. First, two methyl groups were introduced in the benzylic positions by a double alkylation of the
N-nitroso azepine
3 (
Scheme 1); subsequently, the other two methyl groups were added in sequence by a repeated MeMgBr addition on azepine nitrones (
Scheme 2) [
24]. Accordingly, biphenylazepine
1 was first transformed in its
N-nitroso derivative
3 by reaction with aqueous NaNO
2 in acetic acid [
25]. After neutralization with 10 M NaOH, extraction with toluene, drying, and evaporation of solvent,
N-nitroso azepine
3 was obtained in a 90% yield. This compound was then deprotonated in THF by treatment with excess of KH, providing a dark red solution that was treated with MeI at reflux for 18 h, giving double alkylation at the benzylic positions. After quenching with water and neutralization, evaporation of solvent provided a yellow oil that, after washing with pentane, afforded (±)-
4 as an orange solid residue in an 88% yield. Notably, NMR spectra showed the presence of a single diastereomer of (±)-
4.
The
N-nitroso dimethylazepine
4 could not be deprotonated further even with a large excess of NaH [
24]. Therefore, the introduction of the other two methyl groups had to be obtained in a different way. Accordingly, the nitroso group was straightforwardly removed from the nitrogen of the azepine by treatment of the ethanolic solution of
4 with Raney Nickel under hydrogen atmosphere. After stirring overnight, dimethylazepine (±)-
5 [
21,
22] was obtained in an 80% yield after filtration of the mixture on celite and solvent removal. Analysis of the
1H NMR spectrum revealed a single set of signals allied to the phenyl and methyl moieties, indicating the presence of a C
2 symmetry of the molecule and, then, a
trans arrangement of the two methyl groups on the benzylic positions [
21,
22].
Afterwards, the second synthetic sequence allowed introduction of the other two methyl groups (
Scheme 2).
Accordingly, amine
5 was oxidized by treatment with Na
2WO
4·2H
2O and 35% aqueous H
2O
2 in a MeOH/H
2O mixture. After 6 h, the reaction was quenched with Na
2S
2O
5. After extraction, drying, and evaporation of solvent, dimethyl nitrone
6 was recovered in a 93% yield. The third methyl group was then introduced on nitrone
6 by a nucleophilic addition of MeMgBr in toluene. After quenching and treatment of the reaction mixture, trimethyl hydroxylamine
7 was recovered, which partially spontaneously oxidized to nitrone
8, as shown by both
1H NMR and GC–MS analyses (see
Supplementary Material). Therefore, compound
7 was not isolated but the mixture of
7 and
8 was directly oxidized to nitrone
8 by treatment with bleach (5% aqueous NaClO) overnight at room temperature [
26]. After reaction treatments, trimethyl nitrone
8 was recovered in a 94% yield. Finally, the fourth methyl group was introduced on nitrone
8 by repeating the MeMgBr nucleophilic addition. The resulting product, tetramethyl hydroxylamine
9, was not isolable because it spontaneously oxidized to provide the nitroxyl oxide
10 that was recovered in a 65% yield after chromatographic purification on silica gel column. Finally, the tetramethyl biphenylazepine
2 was obtained by indium-catalyzed reduction [
27], treating compound
10 with metal zinc (2 equiv) and indium (0.05 equiv) at reflux in an ethanol/NH
4Cl satd. solution (pH~6). After treatment of the reaction mixture, compound
2 was recovered in a 75% yield. Notably, this synthetic sequence appears particularly straightforward for the obtainment of biphenylazepine
2. In fact, most of the sequence reactions provided very high yields and only one step required chromatographic purification of the products. The desired title compound 5,5,7,7-tetrametyl-6,7-dihydro-5
H-dibenzo[
c,
e]azepine
2 was thus obtained from the starting biphenylazepine
1 in a 25% overall yield after eight steps.
To employ the biphenylazepine
2 as the probe of molecular chirality and as the
tropos moiety of the chiral ligands for asymmetric catalysis, it must be atropisomerically flexible, i.e., the aryl–aryl torsional barrier must be low enough (below 22 kcal/mol) to allow free interconversion between the
P or
M twist of the biphenyl at room temperature. Therefore, a VT-NMR study was undertaken to establish such torsional barrier (
Figure 1) in both the tetramethylated biphenylazepine
2 and the usubstituted precursor
1.
To determine the free energy of the torsional inversion of biphenylazepine
2, several VT-NMR experiments were carried out. At room temperature,
1H NMR spectrum of
2 shows (
Figure 2 and
Figure S17 in the Supplementary Material), besides the biphenyl aromatic protons, two broad singlets at 0.92 and 1.55 ppm integrating six protons each. In fact, as a consequence of the not planarity of the twisted biphenyl system, the methyl groups on the benzylic positions are diastereotopic, so that the pseudo-axial and pseudo-equatorial methyls are anisochronous (
Figure 1, top). The conformational inversion through a planar transition state gives rise to the topoisomerization of methyls (a) and (b): if methyl (a) is pseudo-axial in the twisted conformer
M, it will be pseudo-equatorial in the
P twisted conformer and
vice versa for proton (b) (
Figure 1, top).
VT-NMR spectra (
Figure 2) show that these two broad singlets, which are visible at low temperature (up to +43 °C), coalesce merging in a single broad singlet at +45 °C (coalescence temperature). At +90 °C, fast interconversion between the two
M and
P conformers occurs and the spectrum shows only one singlet centered at 1.23 ppm, which is the average value of the chemical shift of the axial and equatorial methyl groups. A 14.9 Kcal/mol torsional barrier for the twist interconversion at the coalescence temperature T
c was computed by the Eyring equation [
28]. Such value indicates that, at room temperature, a free rotation around the aryl–aryl bond still occurs, thus making biphenylazepine
2 suitable as the chirality sensor and
tropos moiety in the chiral ligands.
To evaluate the effect of the four methyl substituents on the aryl–aryl torsional barrier of biphenylazepine
2, a comparison with the unsubstituted biphenylazepine
1 was carried out (
Figure 3). VT-NMR spectra on
1 show an analogous situation as in
2. However, in this case, the conformational inversion of the biphenyl twist exchanges the two benzyl hydrogens (a) and (b) (
Figure 1, bottom) instead of the methyl groups as in
2. If the exchange is fast (higher temperature), the
1H NMR signal of the benzyl protons appears as a singlet, while a slow conformational interconversion occurs at lower temperature, giving rise to two separate signals for the (a) and (b) protons coupled as an AB spin system. Benzyl protons coalesce at −65 °C; therefore, a ΔG* of 9.4 Kcal/mol can be calculated from the Eyring equation [
28].
In summary, although in biphenylazepine 2 the presence of four benzylic methyls increases the rotational barrier of about 5.5 kcal/mol in respect to the unsubstituted derivative 1, compound 2 is still conformational flexible at room temperature and then suitable to be employed as both the chirality probe and tropos unit.
3. Materials and Methods
NMR spectra were acquired on a Varian INOVA spectrometer running at 500 MHz for
1H and 125 MHz for
13C. Chemical shifts (δ) are reported in ppm relative to TMS signal.
13C NMR spectra were acquired in broad band decoupled mode. GC–MS analyses were carried out employing a HP 5 MS column, on a HP 6890 plus gaschromatograph equipped with HP 5973 mass detector. HRESI MS spectra were recorded on Agilent 6230B LC/MS TOF instrument [
29]. Melting points were measured with a Kofler hotstage Reichert-Thermovar apparatus and are uncorrected. Analytical thin-layer chromatography (TLC) was performed on silica gel plates (Merck, Kieselgel 60, F254, 0.25) and column chromatography was performed on silica gel (Merck, Kieselgel 60, 0.063–0.200 mm). 6,7-dihydro-5
H-dibenzo[
c,
e]azepine
1 was prepared as previously described [
11]. CH
2Cl
2 and triethylamine were freshly distilled over CaH
2 prior to their use. THF, toluene, and Et
2O were freshly distilled over sodium/benzophenone prior to their use. Unless otherwise specified, commercially available reagents and solvents were used without any purification.
6-Nitroso-6,7-dihydro-5H-dibenzo[c,e]azepine (3).
To a solution of 6,7-dihydro-5
H-dibenzo[
c,
e]azepine
1 (5.82 g, 30.0 mmol) in acetic acid (232 mL) was dropwise added under stirring, a solution of NaNO
2 (5.3 g, 77.0 mmol) in water (85.6 mL). The resulting yellow solution was stirred at room temperature for 4 h, then cooled at 0 °C in ice bath and treated with 10.0 M aqueous NaOH (120 mL) until the reaction was alkaline. The mixture was extracted with toluene, the two layers separated, and the organic phases washed with brine and dried over anhydrous Na
2SO
4. After filtration and evaporation of solvent under vacuum, the
N-nitroso derivative
3 was recovered as a yellow-orange solid (6.0 g, 26.8 mmol, 90% yield) and used without further purification. M.p. 109–111 °C.
1H NMR (500 MHz, CDCl
3): δ (ppm) 4.60 (br s, 2H), 5.20 (br s, 2H), 7.30 ÷ 7.45 (m, 3H), 7.45 ÷ 7.60 (m, 5H).
13C NMR (125 MHz, CDCl
3) δ (ppm) 47.50, 53.88, 128.35, 128.51, 128.67, 128.82, 129.14, 129.31, 129.46, 130.28, 130.77, 132.13, 139.56, 140.58. MS (EI):
m/z 224 (M
+, 87), 194 (100), 179 (24), 166 (60), 165 (62), 152 (18). Spectroscopic data matched those already reported for compound
3 [
25].
5,7-Dimethyl-6-nitroso-6,7-dihydro-5H-dibenzo[c,e]azepine (4).
A mineral oil dispersion of KH (5.0 g) was washed with hexane, then suspended in anhydrous THF (150 mL) and a solution of N-nitroso azepine 3 (2.8 g, 12.5 mmol) in anhydrous THF (50 mL) was added under stirring at room temperature. After 30 min, CH3I (8.5 mL, 17.0 mmol) was added to the dark brown mixture. The mixture was heated at reflux overnight, then cooled at 0 °C in ice bath and water was added until complete dissolution of the white precipitate. The layers were separated and the aqueous phase was washed twice with Et2O. The collected organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration and solvent evaporation under vacuum, a dark orange liquid was recovered which, after washing with pentane provided 4 as an orange solid residue (2.78 g, 11.0 mmol, 88% yield). M.p. 108–110 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 0.89 (d, J = 7.3 Hz, 3H), 1.22 (d, J = 7.3 Hz, 3H), 5.93 (q, J = 6.7 Hz, 1H), 6.03 (q, J = 6.7 Hz, 1H), 7.27 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.40÷7.60 (m, 4H). 13C NMR (125 MHz, CDCl3) δ (ppm) 18.92, 22.45, 55.05, 64.30, 128.64, 128.82, 129.41, 129.64, 129.67, 129.82, 130.16, 130.30, 136.07, 136.55, 139.18, 140.05. MS (EI): m/z 252 (M+, 44), 222 (74), 207 (66), 193 (40), 180 (100), 165 (76).
5,7-Dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepine (5).
To a solution of
N-nitroso azepine
4 (2.0 g, 7.9 mmol) in anhydrous ethanol (50 mL), under nitrogen, activated Raney Nickel (400 mg) was added and hydrogen was bubbled overnight. The resulting white cloudy solution was filtered over celite and the filtrated washed with ethanol. The collected organic solution was concentrated under vacuum providing dimethyl amine
5 (1.40 g, 6.3 mmol, 80% yield) as a yellow viscous liquid which solidified on standing as pale yellow needles. M.p. 59–60 °C.
1H NMR (500 MHz, CDCl
3): δ (ppm) 1.34 (d,
J = 6.6 Hz, 6H), 1.82 (br s, 1H), 3.49 (q,
J = 6.6, 2H), 7.40 ÷ 7.60 (m, 8H).
13C NMR (125 MHz, CDCl
3) δ (ppm) 18.81, 50.77, 124.42, 127.68, 128.03, 128.36, 139.85, 141.43. MS (EI): m/z 223 (M
+, 7), 208 (100), 191 (11), 178 (10), 165 (24). Spectroscopic data matched those already reported for compound (
S)-
5 [
21,
22].
5,7-Dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepine-N-oxide (6).
To a solution of amine 5 (1.33 g, 6.0 mmol) in ethanol (30 mL) under nitrogen atmosphere Na2WO4·2H2O (216 mg, 0.65 mmol, 11 mol%) and water (4.7 mL) were added. The solution was cooled at 0 °C in ice bath and 35% aqueous H2O2 (2.8 mL, 90.5 mmol) was added under stirring. After 30 min, the solution was left warming at room temperature and stirred overnight. The mixture was then concentrated under vacuum, diluted with CH2Cl2 and brine. The mixture was treated with Na2S2O5 and the two layers separated. The aqueous phase was washed three times with CH2Cl2 and the collected organic phases were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The nitrone 6 was recovered as a waxy residue (1.31 g, 5.5 mmol, 92% yield). 1H NMR (500 MHz, CDCl3): δ (ppm) 1.80 (d, J = 7.0 Hz, 3H), 2.3 (s, 3H), 4.50 ÷ 4.70 (m, 1H), 7.20 ÷ 7.50 (m, 5H), 7.50 ÷ 7.70 (m, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 12.90, 19.16, 63.35, 123.97, 127.68, 127.94, 128.14, 128.44, 128.68, 128.85, 129.50, 129.66, 134.24, 138.19, 139.51, 141.45. MS (EI): m/z 237 (M+, 50), 220 (20), 207 (59), 192 (100), 179 (40), 165 (48), 152 (12).
5,5,7-Trimetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-6-ol (7).
To a solution of nitrone 6 (1.14 g, 4.8 mmol) in anhydrous toluene (80 mL) cooled at 10 °C was dropwise added, under nitrogen atmosphere, MeMgBr (5.5 mL, 16.4 mmol, 3.0 M in Et2O). After 15 min, the solution was left warming at room temperature and stirred for 5 h. Then the solution was quenched with saturated aqueous NH4Cl and solid NaCl until saturation. The layers were separated, and the aqueous layer was extracted twice with CH2Cl2. The collected organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum, providing 1.15 g of a crude mixture containing hydroxylamine 7 and nitrone 8 as revealed by GC–MS analysis. The mixture was not separated but directly oxidized to nitrone 8 in the following step. MS (EI): m/z 235 (M+-H2O, 2), 222 (100), 205 (10), 178 (11), 165 (12), 103 (8).
5,5,7-Trimetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-N-oxide (8).
To a 0.5 M solution in CH2Cl2 of the crude mixture (600 mg) coming from the previous reaction and containing both hydroxylamine 7 and nitrone 8 was dropwise added at 0 °C a solution of 5% aqueous NaClO (6 mL). After 30 min, the solution was left warming at room temperature and stirred overnight. Then the solution was diluted with CH2Cl2 and the two layers separated. The aqueous layer was extracted three times with CH2Cl2 and the collected organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The trimethyl nitrone 8 was recovered as a brown solid (560 mg, 2.23 mmol, 94% yield). M.p. 110–113 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 1.22 (s, 3H), 2.19 (s, 3H), 2.43 (s, 3H), 7.45 (m, 5H), 7.64 (m, 3H). 13C NMR (125 MHz, CDCl3) δ (ppm) 14.46, 21.75, 25.16, 26.60, 125.34, 128.00, 128.40, 128.55, 128.64, 128.74, 129.01, 130.48, 133.92, 137.12, 139.25, 141,97, 142.89. MS (EI): m/z 251 (M+, 8), 234 (8), 220 (12), 210 (16), 193 (100), 178 (50), 165 (11), 152 (8).
5,5,7,7-Tetramety-6,7-dihydro-5H-dibenzo[c,e]azepin-6-ol (9).
To a solution of nitrone 8 (510 mg, 2.0 mmol) in anhydrous toluene (40 mL) cooled at 4 °C under nitrogen atmosphere, MeMgBr (2.5 mL, 7.4 mmol, 3.0 M) was added. After 15 min, the solution was left warming at room temperature and stirred for 5 h, then quenched with saturated aqueous NH4Cl and solid NaCl was added until saturation. The two layers were separated and the aqueous layer extracted three times with CH2Cl2. The collected organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The recovered crude was purified by column chromatography (SiO2; petroleum ether:diethyl ether 1:1) providing hydroxylamine 9, which spontaneously oxidized to nitroxyl oxide 10 as dark green crystals (322 mg, 1.3 mmol, 65% yield). M.p. 123–125 °C. This compound is paramagnetic; therefore, its 1H NMR spectrum provided very broad bands that prevented any further characterization. The compound was used in the subsequent step without any purification.
5,5,7,7-Tetrametyl-6,7-dihydro-5H-dibenzo[c,e]azepine (2).
Nitroxyl oxide 10 (612 mg, 2.4 mmol) was dissolved in a 2:1 solution of ethanol and 10% aqueous NH4Cl (33 mL; pH ≈ 6), and zinc powder (298 mg, 4.6 mmol) and indium (13 mg, 0.11 mmol) were added. The mixture was heated 10 h at reflux, then cooled at room temperature, filtered over celite and extracted with ethyl acetate. To the organic solution saturated aqueous Na2CO3 (15 mL) was added and the two layers separated. The organic phase was died over anhydrous Na2SO4, filtered, and concentrated under vacuum. Biphenylazepine 2 was recovered as pale yellow crystals (450 mg, 1.8 mmol, 75% yield). M.p. 70–71 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 0.92 (br s, 6H), 1.55 (br s, 6H), 2.2 (br s, 1H), 7.33 (m, 2H), 7.37 (m, 4H), 7.46 (d, J = 8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ (ppm) 26.22, 28.63, 50.66, 120.33, 123.00, 123.09, 125.40, 137.70, 139.20. MS (EI): m/z 251 (M+, 8), 236 (100), 219 (13), 194 (30), 179 (48), 110 (15). HRESIMS (+) m/z 251.1669 [M + H]+ (calculated for C18H22N 251.1674).