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

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.

Key words

cyclophanes - dimerizations - regioselectivity

References

• 1 Bartholomew GP. Bazan GC. Acc. Chem. Res.  2001,  34:  30 
• 2a Morisaki Y. Chujo Y. Macromolecules  2002,  35:  587 
• 2b Morisaki Y. Chujo Y. Chem. Lett.  2002,  194 
• 2c Morisaki Y. Ishida T. Chujo Y. Macromolecules  2002,  35:  7872 
• 3 Salhi F. Collard DM. Adv. Mater.  2003,  15:  81 
• 4 Gibson SE. Knight JD. Org. Biomol. Chem.  2003,  1:  1256 
• 5a Acetylation: Cram DJ. Allinger NJ. J. Am. Chem. Soc.  1955,  77:  6289 
• 5b Bromination: Cram DJ. Day AC. J. Org. Chem.  1966,  31:  1227 
• 5c Carbomethoxylation: Zitt H. Dix I. Hopf H. Jones PG. Eur. J. Org. Chem.  2002,  2298 
• 5d Formylation: Banfi S. Manfredi A. Montanari F. Pozzi G. Quici S. J. Mol. Catal. A: Chem.  1996,  133:  77 
• 5e Nitration: Lahann J. Höcker H. Langer R. Angew. Chem. Int. Ed.  2001,  40:  726 
• 6a Brink M. Synthesis  1975,  807 
• 6b Cipiciani A. Fringuelli F. Mancini V. Piermatti O. Pizzo F. Ruzziconi R. J. Org. Chem.  1997,  62:  3744 
• 6c Marshall JL. Hall L. Tetrahedron  1981,  37:  1271 
• 6d Rozenberg V. Dubrovina N. Sergeeva E. Antonov D. Belokon Y. Tetrahedron: Asymmetry  1998,  9:  653 
• 6e Minuti L. Taticchi A. Marrocchi A. Tetrahedron: Asymmetry  2000,  11:  4221 
• 7a Reich HJ. Cram DJ. J. Am. Chem. Soc.  1969,  91:  3505 
• 7b Reich HJ. Cram DJ. J. Am. Chem. Soc.  1969,  91:  3527 
• 7c Yeh YL. Gorham WF. J. Org. Chem.  1969,  34:  2366 
• 7d König B. Knieriem B. de Meijere A. Chem. Ber.  1993,  126:  1643 
• 7e Bartholomew GP. Bazan GC. J. Am. Chem. Soc.  2002,  124:  5183 
• 8a Winberg HE. Fawcett FS. Mochel WE. Theobald CW. J. Am. Chem. Soc.  1960,  82:  1428 
• 8b Winberg HE. Fawcett FS. Org. Synth., Coll. Vol. V   John Wiley and Sons, Ltd.; New York: 1973.  p.883-886  
• 9a Cram DJ. Dalton CK. Knox GR. J. Am. Chem. Soc.  1963,  85:  1088 
• 9b Longone DT. Chow HS. J. Am. Chem. Soc.  1964,  86:  3898 
• 9c Brown GW. Sondheimer F. J. Am. Chem. Soc.  1967,  89:  7116 
• 9d Hopf H. Angew. Chem., Int. Ed. Engl.  1972,  5:  419 
• 9e Otsubo T. Horita H. Misumi S. Synth. Commun.  1976,  6:  591 
• 10 Longone DT. Reetz MT. J. Chem. Soc., Chem. Commun.  1967,  46 
• 11a Szwarc M. J. Chem. Phys.  1948,  16:  128 
• 11b Errede LA. Landrum BF. J. Am. Chem. Soc.  1957,  79:  4952 
• 11c Errede LA. Hoyt JM. J. Am. Chem. Soc.  1960,  82:  436 
• 11d Errede LA. Gregorian RS. Hoyt JM. J. Am. Chem. Soc.  1960,  82:  5218 
• 17 Reich HJ. Cram DJ. J. Am. Chem. Soc.  1969,  91:  3534 

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.