An Effective Synthesis of N,N-Diphenyl Carbazolium Salts

Published as part of the Special Section 9^th EuCheMS ­Organic Division Young Investigator Workshop

Abstract

Tetraaryl ammonium salts are a synthetic challenge, since there is no general method for the arylation of triaryl amines. Contrary to other quaternary ammonium salts, tetraaryl ammonium salts should be very chemically stable. The ipso carbons are not very electrophilic, since the positive charge is distributed throughout the pi systems and they have no acidic β hydrogens. Here we demonstrate a simple approach to N,N-diphenyl carbazolium salts using only three synthetic steps, allowing for an easy production of these salts in large amounts and in a relatively short time. In addition, we study the Cu(I) catalyzed multi-arylation of 2,2’-diaminobiphenyl, focusing on the regioselectivity of each step. Finally, we characterize, for the first time, the solid state structure of a tetraaryl ammonium salt.

Key words

Quaternary ammonium salt - diazonium salt - selective arylation - copper catalysis - Ullmann reaction

• References and Notes

• 1 Jennings MC. Minbiole KP. C. Wuest WM. ACS Infect. Dis. 2015; 1: 288
• 2 Kuang M. Shiyi Z. Lei J. Li Q. J. Appl. Polym. Sci. 2008; 109: 3887
• 3 Corey EJ. Xu F. Noe MC. J. Am. Chem. Soc. 1997; 119: 12414
• 4 Dekel DR. Amar M. Willdorf S. Kosa M. Dhara S. Diesendruck CE. Chem. Mater. 2017; 29: 4425
• 5 Varcoe JR. Atanassov P. Dekel DR. Herring AM. Hickner MA. Kohl PA. Kucernak AR. Mustain WE. Nijmeijer K. Scott K. Xu T. Zhuang L. Energy Environ. Sci. 2014; 7: 3135
• 6 Gottesfeld S. Dekel DR. Page M. Bae C. Yan Y. Zelenay P. Kim YS. J. Power Sources 2018; 375: 170
• 7 von Hofmann AW. Ann. Chem. Pharm. 1851; 78: 253
• 8 Marino MG. Kreuer KD. ChemSusChem 2015; 8: 513
• 9 Dekel D. In Encyclopedia of Applied Electrochemistry . Kreysa G. Ota K. Savinell RF. Springer; New York, NY: 2014: 26
• 10 Arava S. Diesendruck CE. Synthesis 2017; 49: 3535
• 11 Hartwig JF. Acc. Chem. Res. 2008; 41: 1534
• 12 Ruiz-Castillo P. Buchwald SL. Chem. Rev. 2016; 116: 12564
• 13 Ullmann F. Bielecki J. Eur. J. Inorg. Chem. 1901; 34: 2174
• 14 Lam PY. Clark CG. Saubern S. Adams J. Winters MP. Chan DM. Combs A. Tetrahedron Lett. 1998; 39: 2941
• 15 Li S. Yang F. Lv T. Lan J. Gao G. You J. Chem. Commun. 2014; 50: 3941
• 16 Hirsch M. Dhara S. Diesendruck CE. Org. Lett. 2016; 18: 980
• 17 Cui CM. Zhou HP. Zhu CH. Wu JY. Acta Crystallogr., Sect. E: Struct. Rep. Online 2006; 62: o1762
• 18 Sobolev AN. Belsky VK. Romm IP. Chernikova NY. Guryanova EN. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1985; 41: 967
• 19 Nesmeyanov AN. Tolstaia TP. Grib AV. Dokl. Akad. Nauk SSSR 1963; 153: 608
• 20 Hellwinkel D. Seifert H. Eur. J. Inorg. Chem. 1972; 105: 880
• 21 Shchepina NE. Nefedov VD. Toropova MA. Avrorin VV. Lewis SB. Mattson B. Tetrahedron Lett. 2000; 41: 5303
• 22 Patil NM. Kelkar AA. Chaudhari RV. J. Mol. Catal. A: Chem. 2004; 223: 45
• 23 Tseng K.-C. Acta Chim. Sin. 1966; 32: 107
• 24 Buschman O. Grosjean M. Nasielski J. Martin RH. Helv. Chim. Acta 1964; 47: 2037
• 25a Hansch C. Leo A. Hoekman D. Exploring QSAR: Hydrophobic, Electronic, and Steric Constants . American Chemical Society; Washington, DC: 1995: 254
• 25b Hansch C. Leo A. Hoekman D. Exploring QSAR: Hydrophobic, Electronic, and Steric Constants . American Chemical Society; Washington, DC: 1995: 273
• 26 Ran C. Dai Q. Harvey RG. J. Org. Chem. 2005; 70: 3724
• 27 Alcalde E. Dinarés I. Rodríguez S. Garcia de Miguel C. Eur. J. Org. Chem. 2005; 1637
• 28 Shaughnessy KH. Ciganek E. DeVasher RB. Denmark SE. Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles . John Wiley and Sons; Hoboken: NJ: 2014: 6
• 29 Cristau H.-J. Cellier PP. Spindler J.-F. Taillefer M. Chem. Eur. J. 2004; 10: 5607
• 30 Allen FH. Kennard O. Watson DG. Brammer L. Orpen AG. Taylor R. J. Chem. Soc., Perkin Trans. 2 1987; S1
• 31 Avendaño C. Espada M. Ocaña B. García-Granda S. Díaz M. delR. Tejerina B. Gómez-Beltrán F. Martínez A. Elguero J. J. Chem. Soc., Perkin Trans. 2 1993; 1547
• 32 Mantina M. Chamberlin AC. Valero R. Cramer CJ. Truhlar DG. J. Phys. Chem. A 2009; 113: 5806
• 33 Bissantz C. Kuhn B. Stahl M. J. Med. Chem. 2010; 53: 5061
• 34 Representative Experimental Procedures and Characterization Data 2,2′-Diaminobiphenyl (A) In a 3 L beaker flask, glacial acetic acid (190 mL) is added to a stirred solution of 2,2′-dinitro biphenyl (13.00 g, 53.23 mmol) in absolute ethanol (1.9 L), followed by portionwise addition of zinc powder (75.00 g, 1147 mmol) during 2 min. Once the exothermic reaction subsides (10 min) the beaker is left stirring for additional 5 min after which it is allowed to reach RT. The yellow-green reaction mixture is filtered, the unreacted zinc powder is washed with small amounts of ethanol, and the filtrate is concentrated to a thick syrup, which is dissolved in 16% hydrochloric acid (80 mL). The aqueous phase is extracted with CHCl₃ (5 × 20 mL), until no color is observed in the organic phase, and then added slowly to 25% NH₄OH (1 L), for liberation of the amine and complexation of zinc(II). The free amine is extracted with CHCl₃ (4 × 100 mL), and the organic phase is washed with water (40 mL) and dried over Na₂SO₄. After the solvent is removed in vacuo, A is obtained as a light brown oil which solidifies to an off-white solid (9.23 g, 94%). 2-Amino,2′-(N,N-diphenylamino)biphenyl (B) In a 250 mL flame-dried Schlenk flask, A (9.00 g, 48.9 mmol) is deoxygenated (see Supporting Information). Xylenes (135 mL) are transferred via a syringe, and to the resulting solution KO^tBu (12.09 g, 107.7 mmol) is added under argon. The mixture is stirred for 10 min at RT, during which a brown-yellow color develops. PhI (20.93 g, 102.6 mmol) is injected to the Schlenk flask under argon, followed by addition of CuI (1.86 g, 9.77 mmol) and o-phenanthroline (1.76 g, 9.77 mmol). The mixture is stirred at 125 °C for 3.5 h, after which it is allowed to reach RT. The mixture is filtered, and the filtration cake washed with small amounts of CHCl₃ (ca. 70 mL). The solids are dissolved in 25% NH₄OH (200 mL), and the dark green-blue aqueous phase is extracted with CHCl₃ (2 × 30 mL) which is added to the filtrate. The filtrate is concentrated to a dark paste, which is dissolved in CHCl₃ (200 mL) and extracted with small amounts of 25% NH₄OH, until the aqueous phase is free from the copper complexes color. The organic phase is then extracted with 0.1 M HCl (3 × 250 mL) for separation of the unreacted A and phenanthroline, which can be recycled. The organic phase is washed with aq sat. NaHCO₃, water, dried over Na₂SO₄, filtered, and the solvent is removed in vacuo to give a dark paste, consisting of a mixture of B and F (ca. 7:3 mol ratio), which is used for the next step without further purification. Samples of pure B and F are obtained by column chromatography of this mixture. Analytical Data of Compound B Red-brown solid, 60%; R_f = 0.57 (CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.66, (d, J = 8.0 Hz, 1 H), 7.59, (d, J = 8.0 Hz, 1 H), 7.53 (dt, J = 8.0, 1.3 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.25 (t, J = 8.0 Hz, 4 H, Ph-m), 7.12 (t, J = 8.0 Hz, 2 H, Ph-p), 7.07–7.02 (m, 6 H), 6.75 (t, J = 8.0 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H), 3.38 (br s, 2 H, NH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 147.34 (C(Ph)–N, 2 C), 146.04 (C–N, 1 C), 143.35 (C–N, 1 C), 136.82 (C–C, 1 C), 132.46 (C–H(biphenyl), 1 C), 130.10 (C–H(biphenyl), 1 C), 128.86 (C–H (biphenyl), 1 C), 128.62 (C–H(biphenyl), 1 C), 128.50 (C–H(Ph), 4 C), 127.89 (C–H(biphenyl), 1 C), 125.25 (C–H(bi­phenyl), 1 C), 125.10 (C–C, 1 C), 122.02 (C–H(Ph), 4 C), 121.36 (C–H(Ph), 2 C), 118.03 (C–H(biphenyl), 1 C), 115.26 (C–H(biphenyl), 1 C). APCI-HRMS: m/z calcd for C₂₄H₂₁N₂ [M + H]⁺: 337.1699; found: 337.1719 (–5.8 ppm). N,N-Diphenylcarbazolium Hexafluorophosphate (C) In a 100 mL Erlenmeyer beaker, a mixture of B and F (4.36 g) is dissolved in glacial acetic acid (53 mL). The solution is cooled to 0–5 °C using an ice bath, and the solidified acetic acid solution was crushed by a steel spatula. A solution of NaNO₂ (4.15 g, 60.2 mmol) in water (5.5 mL) is added, and the resulting dark slurry stirred mechanically (using a spatula) for 20 min. Urea prills (3.32 g, 55.3 mmol) are then added, and the mixture stirred mechanically (using a spatula) for 1 h at 40 °C, during which a black tar appears. The reaction mixture is concentrated under reduced pressure and the residue dissolved in CHCl₃ (50 mL), filtered, and the filtration cake washed with small amounts of CHCl₃. The solvent is removed in vacuo, and the dark residue partitioned between diethyl ether (40 mL) and water (10 mL). The organic phase is further extracted with water (5 mL), and the volume of the united aqueous phase reduced to ca. 6 mL in vacuo, and extracted with small amounts of diethyl ether until no color is seen in the organic phase. Removal of water and acetic acid from the yellow aqueous phase by reduced pressure azeotropic distillation with toluene and freeze-drying affords the acetate salt as a highly hygroscopic yellow solid, which still contains acetic acid and water. Pure C is obtained by addition of 75% (w/v) NH₄PF₆ solution (5 mL) to the concentrated solution of acetate. The resulted light yellow precipitate is collected, washed with small amounts of water, and dried under reduced pressure. Analytical Data of Compound C Yellow solid, 857 mg, 22% from B; ¹H NMR (400 MHz, CD₃CN): δ = 8.21 (d, J = 8.0 Hz, 2 H, biphenyl), 7.81 (t, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.67–7.62 (m, 4 H), 7.56 (t, J = 8.0 Hz, 4 H, m-Ph), 7.47 (d, J = 8.0 Hz, 4 H, o-Ph). ¹³C NMR (75 MHz, CD₃CN): δ = 151.31 (2 C), 147.74 (2 C), 133.40 (C–H(biphenyl), 2 C), 132.53 (C–H(biphenyl), 2 C), 132.19 (C–H(biphenyl), 2 C), 131.88 (C–H (Ph), 4 C), 131.52 (C–C(biphenyl), 2 C), 124.53 (C–H(biphenyl), 2 C), 123.55 (C–H(Ph), 4 C). ¹⁹F NMR (377 MHz, CD₃CN): δ = –72.82 (d, J₁= 707 Hz, P–F). ESI-HRMS: m/z calcd for C₂₄H₁₈N [M – PF₆]⁺: 320.1439; found: 320.1420 (–5.9 ppm).