Synlett 2021; 32(02): 215-218
DOI: 10.1055/a-1315-1279
cluster
Modern Heterocycle Synthesis and Functionalization

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

Benjamin T. Boyle
,
J. Luke Koniarczyk
,
This work was supported by The National Institutes of Health (NIGMS) under Award Number R01 GM124094.


Abstract

Here we report that N-phosphonium pyridinium intermediates are unusually reactive for pyridine SNAr 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.

Supporting Information



Publication History

Received: 03 November 2020

Accepted after revision: 19 November 2020

Publication Date:
19 November 2020 (online)

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 15 Phosphonium Salts 1ar: 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.