Synlett 2005(14): 2130-2134  
DOI: 10.1055/s-2005-872270
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Improved Method for the Regiospecific Synthesis of Polysubstituted [2.2]Paracyclophanes

Hak-Fun Chow*a, Kam-Hung Lowa, King Y. Wongb
a Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR
Fax: +852(2603)5057; e-Mail: hfchow@cuhk.edu.hk;
b Department of Physics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR
Further Information

Publication History

Received 11 June 2005
Publication Date:
03 August 2005 (online)

Abstract

4,16-Disubstituted, 4,7,12,15-tetrasubstituted, 4,8,12,16-tetrasubstituted and 4,5,7,8,12,13,15,16-octasubstituted [2.2]paracyclophanes can be prepared in significantly improved yields and excellent regiospecificities via the Winberg 1,6-elimination-dimerization reaction from substituted (4-methylbenzyl)tri­methylammonium hydroxides. Using 2-chloro-phenothiazine instead of phenothiazine as a polymerization inhibitor results in a doubling of product yields.

12

Typical Procedure for the Preparation of Substituted (4-Methylbenzyl)trimethylammonium Bromides 13.
In a 250-mL three-necked flask equipped with a stirrer, a gas outlet connected to an acid trap, and a gas inlet tube directed to about 1 cm above the surface of the liquid was placed a solution of the substituted benzyl bromide 12 (ca. 10 g) in Et2O (100 mL). The flask was cooled in an ice-water bath with stirring. Et3N was generated by heating an aqueous solution of Et3N (45% w/w, 50 mL) and passed into the inlet tube for 2 h. The product began to precipitate as a white solid. The resulting mixture was then allowed to stand overnight at r.t. and the ammonium salt 13 was collected on a Büchner funnel and dried under reduced pressure.
Data for compounds 13b: highly hygroscopic solid. 1H NMR (D2O): δ = 2.33 (3 H, s, ArCH 3), 3.11 and 3.16 [total 9 H, s, N(CH3)3], 4.46 and 4.62 (total 2 H, s, ArCH 2), 7.30-7.72 (total 3 H, m, ArH). 13C NMR (D2O): δ = 21.4, 23.3, 53.3, 53.8, 68.4, 68.6, 124.9, 125.6, 127.5, 127.7, 130.0, 132.3, 132.8, 135.0, 135.8, 136.7, 141.3, 144.3. MS (FAB):
m/z (%) = 242 (100) [M - Br]+. HRMS: m/z calcd for C11H17N79Br: 242.0539; found: 242.0540.
Data for compound 13e: mp >230 °C (dec.). 1H NMR (D2O): δ = 2.37 (3 H, s, ArCH 3), 3.18 [9 H, s, N(CH3)3], 4.63 (2 H, s, ArCH 2), 7.68 (1 H, s, ArH), 7.81 (1 H, s, ArH). 13C NMR (D2O): δ = 22.7, 53.6, 67.8, 124.5, 126.3, 126.9, 136.3, 138.3, 144.0. MS (FAB) m/z (%) = 322 (80) [M - Br]+. HRMS: m/z calcd for C11H16N79Br2: 319.9644; found: 319.9636.
Data for compound 13g: mp >230 °C (dec.). 1H NMR (D2O): δ = 2.52 (3 H, s, ArCH 3), 3.10 [9 H, s, N(CH3)3], 4.44 (2 H, s, ArCH 2), 7.74 (2 H, s, ArH). 13C NMR (D2O): δ = 23.8, 53.1, 60.2, 68.3, 125.8, 128.2, 136.2, 141.2. MS (FAB): m/z (%) = 322 (70) [M - Br]+. HRMS: m/z calcd for C11H16N79Br2: 319.9644; found: 319.9652.
Data for compound 13h: mp >210 °C (dec.). 1H NMR (DMSO-d 6): δ = 2.85 (3 H, s, ArCH 3), 3.26 [9 H, s, N(CH3)3], 5.15 (2 H, s, ArCH 2). 13C NMR (DMSO-d 6):
δ = 29.8, 54.1, 71.3, 129.3, 130.1, 131.4, 144.3. MS (FAB) m/z (%) = 480 (100) [M - Br]+. HRMS: m/z calcd for C11H14N79Br4: 475.7854; found: 475.7848.

13

Synthesis of Substituted 4-Methylbenzyl Bromides 12 from Substituted p -Xylenes.
A mixture of the substituted p-xylenes (ca. 10 g), N-bromosuccinimide (1 equiv) and benzoyl peroxide (0.01 g) in CCl4 (100 mL) was heated to reflux. After 3 h, the reaction mixture was cooled to 0 °C and the precipitated succinimide was removed by filtration and washed with CHCl3. The combined filtrates were evaporated under reduced pressure to give an oil that was purified by flash chromatography on silica gel (eluent: hexane) to afford the bromides 12 as a single compound or a regioisomeric mixture.
Data for 12b: colorless oil; R f = 0.68 (hexane). 1H NMR (CDCl3): δ = 2.32 and 2.38 (total 3 H, s, ArCH 3), 4.41 and 4.58, (total 2 H, s, ArCH 2Br), 7.07-7.56 (total 3 H, m, ArH). 13C NMR (CDCl3): δ = 20.8, 22.6, 32.1, 33.5, 124.2, 124.8, 127.8, 128.7, 130.9, 131.0, 132.6, 133.7, 133.9, 137.0, 138.1, 140.5. MS (EI): m/z (%) = 264 (23) [M+]. HRMS: m/z calcd for C8H8 79Br2: 261.8987; found: 261.8990. Anal. Calcd for C8H8Br2: C, 36.40; H, 3.05. Found: C, 36.16; H, 2.97.
Data for 12f: colorless oil; R f = 0.65 (hexane). 1H NMR (CDCl3): δ = 2.35 (3 H, s, ArCH 3), 4.51 (2 H, s, ArCH 2), 7.26 (1 H, s, ArH), 7.41 (1 H, s, ArH). 13C NMR (CDCl3): δ = 19.7, 29.5, 131.2, 131.9, 132.1, 133.0, 134.2, 138.3. MS (EI): m/z (%) = 254 (50) [M+]. HRMS: m/z calcd for C8H7 79Br35Cl2: 251.9103; found: 251.9110. Anal. Calcd for C8H7BrCl2: C, 37.84; H, 2.78. Found: C, 37.78; H, 2.91.

14

Synthesis of Substituted 4-Methylbenzyl Bromides 12 from Substituted 4-Methylbenzyl Alcohols.
A mixture of the substituted 4-methylbenzyl alcohol (30 mmol), CBr4 (14.92 g, 45 mmol) and PPh3 (11.80 g, 45 mmol) was stirred in THF at r.t. for 4 h. The reaction mixture was filtered through Celite and the filtrate was concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel (eluent: hexane) to give the target bromide.
Data for 12d: white solid, mp 43-45 °C; R f = 0.75 (hexane). 1H NMR (CDCl3): δ = 2.25 (6 H, s, ArCH 3), 4.47 (2 H, s, ArCH 2Br), 7.11-7.17 (3 H, m, ArH). 13C NMR (CDCl3): δ = 19.5, 19.7, 33.9, 126.4, 130.0, 130.3, 135.2, 137.1. MS (CI): m/z (%) = 198 (23) [M+]. HRMS: m/z calcd for C9H11 79Br: 198.0039; found: 198.0039. Anal. Calcd for C8H11Br: C, 54.30; H, 5.57. Found: C, 54.11; H, 5.61.
Data for 12g: white solid, mp 99-100 °C; R f = 0.75 (hexane). 1H NMR (CDCl3): δ = 2.54 (3 H, s, ArCH 3), 4.33 (2 H, s, ArCH 2Br), 7.52 (2 H, s, ArH). 13C NMR (CDCl3): δ = 23.5, 30.7, 125.2, 132.2, 137.7, 138.0. MS (EI): m/z (%) = 342 (15) [M+]. HRMS: m/z calcd for C8H7 79Br3: 339.8092; found: 339.8090. Anal. Calcd for C8H7Br3: C, 28.03; H, 2.06. Found: C, 27.88; H, 2.12.

15

General Procedure for the Synthesis of Substituted [2.2]Paracyclophanes.
Ag2O (23.0 g, 0.10 mol) was added to an aqueous solution (75 mL) of the substituted ammonium bromide(s) 13 (0.10 mol) and the mixture was stirred at r.t. for 1.5 h. The mixture was filtered and the solid was washed with H2O (40 mL). The combined aqueous layers were placed in a 500-mL three-necked round-bottom flask equipped with a stirrer and a Dean-Stark water separator attached to a reflux condenser. Toluene (300 mL) and phenothiazine (0.50 g, 2.5 mmol) or 2-chlorophenothiazine (0.59 g, 2.5 mmol) was then added to the solution and the mixture was heated under reflux for 3 h. When all the water had been removed, Et3N began to evolve and a pale yellow solid (p-phenyleneethylene polymer) began to precipitate. Heating and stirring were continued for another 1.5 h, after which time the evolution of Et3N had ceased. The mixture was cooled and the solid was filtered and washed with toluene (10 mL × 3). The filtrates were combined and concentrated under reduced pressure to give the target compound as a solid that was further washed with acetone (10 mL × 3). Analytically pure samples were obtained from recrystallization from an organic solvent.
Data for 14e: white solid, mp >280 °C (dec.). 1H NMR (CDCl3): δ = 2.92-3.07 (4 H, m, CH2), 3.15-3.35 (4 H, m, CH2), 7.20 (4 H, s, ArH). 13C NMR (CDCl3): δ = 32.6, 125.2, 134.3, 140.2. MS (EI): m/z (%) = 524 (1) [M+]. HRMS: m/z calcd for C16H14 79Br4: 523.7628; found: 523.7634.
Data for 14g: white solid, mp >280 °C (dec.). 1H NMR (CDCl3): δ = 2.93-2.98 (4 H, m, CH2), 3.40-3.45 (4 H, m, CH2), 7.17 (4 H, s, ArH). 13C NMR (CDCl3): δ = 31.0, 34.8, 127.2, 132.8, 137.5, 141.7. MS (EI): m/z (%) = 523 (54) [M+]. HRMS: m/z calcd for C16H12 79Br4: 523.7667; found: 523.7658. Anal. Calcd for C16H12Br4: C, 36.68; H, 2.31. Found: C, 36.59; H, 2.37.
Data for 14h: white powder, mp >280 °C (dec.). 1H NMR (PhNO2-d 5): 3.39 (8 H, s, ArCH 2). MS (EI): m/z (%) = 839 (22) [M+]. HRMS: m/z calcd for C16H8 79Br8: 831.4088; found: 831.4078.

16

The yields reported were the average of two or more runs.

18

We wish to point out that there were only two aromatic 13C signals instead of three for this compound in the paper reported by de Meijere (see ref. 7d). We also noted that the atom numbering system used in de Meijere’s paper was different from ours.

19

CCDC-274514 contains the crystallographic data of compound 14g. The data can be obtained via www.ccdc.cam.ac.uk/conts/retrieving.html.

20

CCDC-274513 contains the crystallographic data of compound 14h. The data can be obtained via www.ccdc.cam.ac.uk/conts/retrieving.html.