A Bench-Stable Organic Salt for the Benzylation of Alcohols

Abstract

2-Benzyloxy-1-methylpyridinium triflate (Bn-OPT) effects the benzylation of alcohols in the absence of acidic or basic promoters. Solutions of Bn-OPT and primary, secondary, or tertiary alcohols give rise to the corresponding benzyl ethers upon mild heating. Acid scavengers are generally included in the reaction mixture. Bn-OPT is crystalline and bench-stable.

synthesis - benzyl ethers - protecting groups - alcohols

References

<A NAME="RS08705ST-1A">1a</A> Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons; New York: 1999. 

<A NAME="RS08705ST-1B">1b</A> Kocienski PJ. Protecting Groups   3rd ed.:  Thieme; Stuttgart: 2003. 

<A NAME="RS08705ST-2">2</A>

TfOH is generally required, whereas milder acids will promote the formation of p-methoxybenzyl ethers; see ref. 1.

<A NAME="RS08705ST-3">3</A>

Scattered literature reports provided the foundation for this work. In particular, alkoxypyridinium bromides decompose to pyridones and alkyl bromides via nucleophilic attack of the bromide ion (ref. 4), whereas alkoxypyridinium sulfonates are isolable (ref. 5). Note that Mukaiyama’s reagent (ref. 6) has been employed to convert alcohols into thioesters and azides.

<A NAME="RS08705ST-4">4</A> Joshi RA. Ravindranathan T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1984,  23:  260 

<A NAME="RS08705ST-5A">5a</A> Beattie DE. Crossley R. Dickinson KH. Dover GM. Eur. J. Med. Chem.  1983,  18:  277 

<A NAME="RS08705ST-5B">5b</A> See also: Kornblum N. Coffey GP. J. Org. Chem.  1966,  31:  3449 

For leading references, see:

<A NAME="RS08705ST-6A">6a</A> Hojo K. Yoshino H. Mukaiyama T. Chem. Lett.  1977,  437 

<A NAME="RS08705ST-6B">6b</A> Hojo K. Kobayashi S. Soai K. Ikeda S. Mukaiyama T. Chem. Lett.  1977,  635 

<A NAME="RS08705ST-7A">7a</A> Serio AJ. Duggan E. Grabowski JJ. Russ WK. Synthesis  1980,  573 

<A NAME="RS08705ST-7B">7b</A> Cherng Y.-J. Tetrahedron  2002,  58:  4931 

<A NAME="RS08705ST-7C">7c</A>

(c) We prepared 1 by the following procedure, which is a modification of that reported in ref. 7a: A toluene solution of benzyl alcohol (0.5 M, 1.0 equiv), 2-chloro-pyridine (1.2 equiv), KOH (3.2 equiv, powdered with a mortar and pestle), and 18-crown-6 (0.05 equiv) was heated at reflux for 1 h with azeotropic removal of water. Routine aqueous workup and purification on silica gel afforded 1 in 96% yield.

<A NAME="RS08705ST-8">8</A> Widmer U. Synthesis  1987,  568