If the debromination of Br-SPINOL were completed, it would be possible to access SPINOL from 3-hydroxybenzaldehyde in fewer steps than the equivalent synthesis from 3-methoxybenzaldehyde. Early attempts have been made, but an extensive testing of conditions has not been completed. If this were not possible, the most crucial step to improve would be the demethylation from SPINOMe to SPINOL, due to the hazardous nature of BBr3 and the low-yielding procedure.
The ‘chiral diols’ approach held promise. The related results from the Zhou group6 need to be verified and compared to this route. The ‘indanone/alkene’
approach requires successful synthesis of the alkene intermediate, followed by cyclisation.
Chapter 9
Experimental
9.1 1,1’-Spirobiindane-7,7’-diol (o-SPINOL), Compound 1-42
OH OH 1 2 4 3
6 5 7 8 9
Chemical Formula: C17H16O2 Exact Mass: 252.12
10
Procedure:69
7,7’-Dimethoxy-1,1’-spirobiindane (o-SPINOMe, 1-57) (0.080 g, 0.29 mmol) was charged to an oven-dried 50 mL RBF, which was then fitted with a stirrer bar and septum. Dry DCM (2.0 mL) was charged to the RBF, which was then flushed with N2. The solution was cooled to -78◦C and stirred for 10 mins. BBr3in DCM (1.0 mL) was charged to the RBF, which was allowed to warm to RT and stirred for 18 h. The solution was diluted with DCM (10 mL) and washed with H2O until the washings were neutral (approximately 200 mL H2O). The pale yellow organic solution was dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow film.
Isolated yield: 0.027 g (0.11 mmol, 38%)
1H NMR (700 MHz, CDCl3): δ/ppm 2.16-2.22 (2 H, m, H2), 2.29-2.32 (2 H, m, H2), 2.98-3.08 (4 H, m, H3), 4.63 (2 H, br s, H10), 6.68 (2 H, d, J = 8.0 Hz, H7), 6.89 (2 H, d, J = 8.1 Hz, H9), 7.17 (2 H, t, J = 7.7 Hz, H8);
13C NMR (176 MHz, CDCl3): δ/ppm 31.2 (C3), 37.4 (C2), 57.5 (C1), 114.3 (C7), 117.7 (C9), 129.9 (C8), 130.5 (C4), 145.8 (C5), 152.9 (C6).
IR (neat) ν = 3327.2 (OH, br), 1230.6 (C-O, s), 997.4 (m), 778.1 (s) cm−1.
LC-MS: Rt = 3.16 min, m/z 253.2 [MH]+; HR-MS calculated for C17H17O2 at 253.1229, found 253.1227 (∆ = -0.8 ppm).
Reference6,69,85
9.2 1,5-Bis(3-methoxyphenyl)penta-1,4-dien-3-one, Compound
1-53
OMe O
OMe Chemical Formula: C19H18O3
Exact Mass: 294.13 2 1 3 4
5 6 7 8 9
Procedure:67–69
NaOH (25.033 g, 625.8 mmol) was charged to a 1 L RBF fitted with a stirrer bar, followed by H2O (250 mL) and the resulting solution was stirred until all the base had dissolved. EtOH (200 mL) was charged to the RBF, and the mixture was heated to 25 ◦C. Next 3-methoxybenzaldehyde (1-52, 15.23 mL, 125.0 mmol) followed by acetone (4.60 mL, 62.6 mmol) were charged to the RBF and the solution was stirred for 15 mins, after which time formation of a yellow oil was observed. A second aliquot of 3-methoxybenzaldehyde (1-52, 15.23 mL, 125.0 mmol) then acetone (4.60 mL, 62.6 mmol) were charged to the RBF and the solution was again stirred for 2.5 h. The solution was extracted with DCM (100 mL x 3), and the resulting organic layers were combined and washed with H2O (100 mL x 3). The organic solution was dried over Na2SO4, filtered, and the solvent removed in vacuo to give a yellow oil which was 97% product by1H NMR spectroscopy. Purification by flash column chromatography (Hex:EtOAc 80:20 to 0:100) gave the product as a bright yellow oil.
Isolated yield: 31.702 g (107.8 mmol, 86%)
1H NMR (700 MHz, CDCl3): δ/ppm 3.85 (6 H, s, H10), 6.96 (2 H, dd, J = 2.5, 8.2 Hz, H8), 7.06 (2 H, d, J = 15.9 Hz, H2), 7.13 (2 H, m, H5), 7.21 (2 H, d, J
= 7.6 Hz, H9), 7.32 (2 H, t, J = 7.9 Hz, H7), 7.70 (2 H, d, J = 15.9 Hz, H3);
13C NMR (176 MHz, CDCl3): δ/ppm 55.4 (C10), 113.3 (C5), 116.4 (C8), 121.1 (C9), 125.7 (C2), 130.0 (C7), 136.2 (C4), 143.3 (C3), 160.0 (C6), 188.9 (C1).
IR (neat) ν = 1620.7 (m, C=O), 1578.0 (s), 1593.0 (s), 1256.6 (s, C-O), 1043.3 (m, C-O), 985.0 (s), 859.8 (s), 763.8 (s), 705.8 (s), 665.6 (s) cm−1.
LC-MS: Rt = 3.77 min, m/z 295.2 [MH]+; HR-MS calculated for C19H19O3 at 295.1334, found 295.1341 (∆ = +2.4 ppm).
Reference69,86–89
9.3 1,5-Bis(3-methoxyphenyl)pentan-3-one, Compound 1-54
OMe O
OMe Chemical Formula: C19H22O3
Exact Mass: 298.16 2 1 3 4
5 6 7 8 9
Flow procedure:
A stock solution was prepared from 1,5-bis(3-methoxyphenyl)penta-1,4-dien-3-one (1-53, 12.048 g, 40.96 mmol) was dissolved in EtOAc (410 mL, 0.100 mol dm−3). The yellow solution was passed twice through the Thales Nano H-Cube R reactor (Raney Ni, 3.0 mL min−1, 60 ◦C, full H2) to give 100% conversion by 1H NMR spectroscopy. The solvent was removed in vacuo to give the product as a pale yellow oil.
Isolated yield: 11.786 g (39.53 mmol, 97%) Batch procedure:69
First, 1,5-bis(3-methoxyphenyl)penta-1,4-dien-3-one (1-53, 0.980g, 3.33 mmol) was charged to a 3-necked 100 mL RBF fitted with an overhead stirrer and two septa. Acetone (20 mL) was charged to the RBF, and the solution was degassed with N2. Raney Ni was charged to the flask, which was then stirred for 20 mins at RT under N2. An H2 balloon was fitted to the flask, which was then stirred at RT for 20 h. The flask was flushed with N2, then filtered through Celite over a scinter and rinsed with acetone. The solution was concentrated in vacuo to give a pale yellow oil, which was 100% pentanone by 1H NMR spectroscopy, with no over-reduced alcohol present.
Isolated yield: 0.851 g (2.85 mmol, 86%).
1H NMR (700 MHz, CDCl3): δ/ppm 2.71 (4 H, t, J = 7.6 Hz, H2), 2.87 (4 H, t, J = 7.6 Hz, H3), 3.79 (6 H, s, H10), 6.75 (6 H, m, H7/8/9), 7.20 (2 H, t, J = 7.8 Hz, H5);
13C NMR (176 MHz, CDCl3): δ/ppm 29.8 (C3), 44.4 (C2), 55.1 (C10), 111.4 (C7/8/9), 114.1 (C7/8/9), 120.6 (C7/8/9), 129.5 (C5), 142.6 (C4), 159.7 (C6), 209.0 (C1).
IR (neat) ν = 1711.8 (C=O, m), 1583.9 (C=O, s), 1256.6 (C-O, s), 1152.5 (C-O, s), 1042.1 (m), 779.6 (m), 729.8 (m), 695.3 (s) cm−1.
LC-MS: Rt = 3.73 min, m/z 321 [M+Na]+; HR-MS calculated for C19H22O323Na at 321.1467, found 321.1477 (∆ = +3.1 ppm).
Reference69,87
9.4 1,5-Bis(2-bromo-5-methoxyphenyl)pentan-3-one, Compound
1-55
OMe O
OMe Chemical Formula: C19H20Br2O3
Exact Mass: 453.98 2 1 3 4
5 6 7 8 9
Br Br
Batch procedure with Br2:69
First, 1,5-bis(3-methoxyphenyl)pentan-3-one (1-54, 0.823 g, 2.76 mmol) then DCM (10 mL) were charged to a 100 mL RBF fitted with a stirrer bar. Pyridine (0.78 mL, 9.64 mmol) was charged to the RBF, which was cooled to -10 ◦C in an ice/ salt bath and stirred for 10 mins. A solution of Br2 (0.36 mL, 6.99 mmol) in DCM (3 mL) was added dropwise to the RBF, and an exotherm was observed.
The solution was warmed to RT, and stirred for 4 h. The reaction was quenched with 10% Na2S2O3 (10 mL), then washed with 1 M HCl (15 mL x 3). The orange organic extract was washed with H2O (20 mL x 2), dried over Na2SO4 and filtered.
The solvent was removed in vacuo to give an orange oil which solidified to a pale yellow wax overnight.
Isolated yield: 1.007 g (2.22 mmol, 80%) Batch procedure with NBS:
First, 1,5-bis(3-methoxyphenyl)pentan-3-one (1-54, 0.298 g, 0.99 mmol) was charged to a 50 mL RBF fitted with a stirrer bar. MeCN (4 mL) was charged to the RBF to give a pale yellow solution. NBS (0.360 g, 2.02 mmol) was charged to the RBF, which was stirred at RT for 30 mins. The reaction was quenched with 10% Na2S2O3 (10 mL), then extracted with Et2O (10 mL), 10% Na2S2O3 (10 mL) followed by H2O (10 mL). The organic extracts were combined and dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil.
Isolated yield: 0.228 g (0.50 mmol, 50%) Flow procedure:
1,5-Bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one (3-10, 0.0913 g, 0.203 mmol) was dissolved in EtOAc (6 mL, 0.034 mol dm−3) and passed through the Thales Nano H-Cube reactor (Raney Ni catalyst, 2.0 mL minR −1, 70 ◦C, 1 atm, full H2 mode) six times. The solution was concentrated in vacuo to give the product.
Isolated yield: 0.030 g (0.066 mmol, 33%)
1H NMR (700 MHz, CDCl3): δ/ppm 2.73 (4 H, t, J = 7.7 Hz, H2), 2.96 (4 H, t, J = 7.7 Hz, H3), 3.76 (6 H, s, H10), 6.63 (2 H, dd, J = 8.7, 3.1 Hz, H7), 6.77 (2 H, d, J = 3.0 Hz, H5), 7.39 (2 H, t, J = 8.7 Hz, H8);
13C NMR (176 MHz, CDCl3): δ/ppm 30.6 (C3), 42.5 (C2), 55.4 (C10), 113.6 (C7), 114.6 (C9), 116.2 (C5), 133.4 (C8), 141.2 (C4), 159.0 (C6), 208.4 (C1).
IR (neat) ν = 1700.6 (C=O, m), 1571.9 (C=O, m), 1471.0 (s), 1240.1 (C-O, s), 1163.2 (C-O, s), 790.7 (s), 599.5 (s) cm−1.
LC-MS: Rt = 4.18 min, m/z 477:479:481 (1:2:1) [M+Na]+; HR-MS calculated for C19H20O3Br223Na at 476.9677, found 476.9676 (∆ = -0.21 ppm).
Reference69