Facile Pyridine S _N Ar Reactions via N-Phosphonium–Pyridinium Intermediates

Abstract

Here we report that N-phosphonium pyridinium intermediates are unusually reactive for pyridine S_NAr reactions. Specifically, forming phosphonium salts from halopyridines typically requires elevated temperatures and Lewis acid additives. The alternative activation mode described in this paper permits C–P bond formation to occur at ambient temperatures in many cases, and functions across a broad range of substrates.

Key words

pyridines - S _N Ar reaction - phosphonium salts - pyridinium salts

Publication History

Received: 03 November 2020

Accepted after revision: 19 November 2020

Accepted Manuscript online:
19 November 2020

Article published online:
09 December 2020

• References and Notes

• 1a Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265
• 1b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 1c Eicher T, Hauptmann S. The Chemistry of Heterocycles: Structures, Reactions, Synthesis and Applications, 2nd ed. Wiley-VCH; Weinheim: 2003
• 2a Zafar MN, Atif AH, Nazar MF, Sumrra SH, Gul-E-Saba Gul-E-Saba, Paracha R. Russ. J. Coord. Chem. 2016; 42: 1
• 2b Wurz RP. Chem. Rev. 2007; 107: 5570
• 2c Leclerc N, Sanaur S, Galmiche L, Mathevet F, Attias A.-J, Fave J.-L, Roussel J, Hapiot P, Lemaître N, Geffroy B. Chem. Mater. 2005; 17: 502
• 3 Suh MP, Cheon YE, Lee EY. Coord. Chem. Rev. 2008; 252: 1007
• 4 Campeau L.-C, Fagnou K. Chem. Soc. Rev. 2007; 36: 1058
• 5a Hilton MC, Dolewski RD, McNally A. J. Am. Chem. Soc. 2016; 138: 13806
• 5b Anderson RG, Jett BM, McNally A. Angew. Chem. Int. Ed. 2018; 57: 12514
• 5c Patel C, Mohnike M, Hilton MC, McNally A. Org. Lett. 2018; 20: 2607
• 5d Koniarczyk JL, Hesk D, Overgard A, Davies IW, McNally A. J. Am. Chem. Soc. 2018; 140: 1990
• 5e Zhang X, McNally A. ACS Catal. 2019; 9: 4862
• 5f Zhang X, McNally A. Angew. Chem. Int. Ed. 2017; 56: 9833
• 5g Che Y.-Y, Yue Y, Lin L.-Z, Pei B, Deng X, Feng C. Angew. Chem. Int. Ed. 2020; 59: 16414
• 6a Hilton MC, Zhang X, Boyle BT, Alegre-Requena JV, Paton RS, McNally A. Science 2018; 362: 799
• 6b Boyle BT, Hilton MC, McNally A. J. Am. Chem. Soc. 2019; 141: 15441
• 7 Dolewski RD, Fricke PJ, McNally A. J. Am. Chem. Soc. 2018; 140: 8020
• 8 Mečiarová M, Toma Š, Loupy A, Horváth B. Phosphorus, Sulfur Silicon Relat. Elem. 2007; 183: 21
• 9 Modern Nucleophilic Aromatic Substitution . Terrier F. Wiley-VCH; Weinheim: 2013
• 10 Cotton FA, Kibala PA. J. Am. Chem. Soc. 1987; 109: 3308
• 11 Albayer M, Dutton JL. J. Coord. Chem. 2019; 72: 1307
• 12 Weigand JJ, Burford N, Decken A, Schulz A. Eur. J. Inorg. Chem. 2007; 4868
• 13 Aycock RA, Wang H, Jui NT. Chem. Sci. 2017; 8: 3121
• 14 Georgiou DC, Butler P, Browne EC, Wilson DJ. D, Dutton JL. Aust. J. Chem. 2013; 66: 1179
• 15 Phosphonium Salts 1a–r: General Procedure An oven-dried 8 mL vial (<1.0 mmol) or 16 mL vial (1.0–4.0 mmol) equipped with a stirrer bar was charged with the appropriate iodopyridine (1.0 equiv), (p-anisole)₃P (1.0 equiv), and CHCl₃ (0.5 M). The mixture was then stirred at rt, 50 °C, or 80 °C for the appropriate time. The mixture was then diluted with CHCl₃, and the product was precipitated with Et₂O (100 mL per 1.0 mmol) at rt. (3-Chloropyridin-4-yl)[tris(4-methoxyphenyl)]phosphonium Iodide (1b) Prepared according to general procedure from 3-chloro-4-iodopyridine (72 mg, 0.30 mmol) and (p-anisole)₃P (106 mg, 0.30 mmol) in CHCl₃ (0.6 mL) at rt for 36 h to give a light-brown solid; yield: 174 mg (98%, 0.3 mmol); mp 91–93 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.12–8.59 (m, 2 H), 7.58 (dd, J = 12.7, 8.9, 6 H), 7.48–7.10 (m, 7 H), 3.95 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃) δ = 165.40 (d, J = 3.0), 151.98 (d, J = 5.0), 150.11 (d, J = 9.8), 136.35 (d, J = 12.4), 134.75 (d, J = 2.2), 130.32 (d, J = 8.4), 129.29 (d, J = 88.3), 117.02 (d, J = 14.5), 105.78 (d, J = 100.0), 56.51. ³¹P NMR (162 MHz, CDCl₃) δ = 21.08. LRMS (ESI + APCI): m/z [M – I]⁺ calcd for C₂₆H₂₄ClNO₃P: 464.1; found: 464.2.