Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Tetrahedron Lett. Author manuscript; available in PMC 2010 May 27.
Published in final edited form as:
Tetrahedron Lett. 2009 May 27; 50(21): 2462–2463.
doi:  10.1016/j.tetlet.2009.03.010
PMCID: PMC2701705

One Carbon Homologation of Halides to Benzyl Ethers


An external file that holds a picture, illustration, etc.
Object name is nihms112286u1.jpg

The preparation of one carbon homologated benzyl ethers from alkyl and aromatic halides is reported. The coupling reaction is rapid and efficient at room temperature.

Often in organic synthesis, removing unwanted steps in a synthetic route is convenient from both a time and material standpoint. Adding a step for protection of an alcohol after homologation can be circumvented by the approach presented here. This reduces both the time and the solvent costs needed to purify products, minimizing waste.

As the starting point for a total synthesis, we needed the benzyl ether 2a. Although a multi step preparation had been reported,1 we thought (Eq. 1) that a one-step assembly might be possible, by coupling the Grignard reagent derived from the commercial bromide 1a with commercial benzyl chloromethyl ether (BOM-Cl).24 We were pleased to observe that the homologation proceeded in good yield (Table 1, entry 1). We have expanded upon this observation to prepare an array of products derived from commercial bromides and Grignard reagents (Table 1, entries 2–6).

Table 1
Homologation of Halides to Benzyl Ethers.
equation image

This coupling shows a good range of scope. Both sp3 (entries 1, 3, 4, and 6) and sp2-hybridized Grignard reagents (entries 2 and 5) participated efficiently. The work-up was easy, and the products were readily purified. The yields in Table 1 are for products purified by silica gel chromatography, but on scale distillation worked as well.

We anticipate many uses for the products from this facile homologation. For example, 2c has been used in a range of useful transformations, inter alia for epoxidation,8a as the starting material for the synthesis of 3,5 dihydroxypentyl nucleoside analogues,8b and as a metathesis substrate.8c

In conclusion, we have developed a rapid and efficient procedure for the one-carbon homologation of halides to benzyl ethers. We anticipate that this coupling will useful in a wide range of applications.

Experimental Section

Procedure for the preparation of 2c: To a solution of commercial allyl magnesium chloride (4.0 mmol) in THF (8 mL) at 0°C was added all at once a solution of benzyl chloromethylether (3.8 mmol) in 2 mL of THF. The reaction mixture was held at 0°C for 30 min, and then was partitioned between saturated aqueous NH4Cl and ether. The combined organic extract was dried (Na2SO4) and concentrated, and the residue was chromatographed. Yields are based on benzyl chloromethyl ether charged. 2c: Clear oil (73% yield), TLC Rf = 0.64 (MTBE/petroleum ether 1:10); 1H NMR (400 MHz, CDCl3) δ 2.4 (m, 2H), 4.07 (t, J =6.8 Hz, 2H), 4.54 (s, 2H), 5.04m (d, J =12.3 Hz, 1H), 5.14 (d, J=17.2Hz, 1H), 5.84 (m, 1H), 7.34 (m, 5H); 13C NMR (100 MHz, CDCl3) δ d9 135.2, 128.3, 127.6, 127.5 u 138.2, 116.3, 72.9, 69.6, 34.2.

Supplementary Material



We thank the National Institutes of Health (GM42056) for support of this work. We thank Dr. John Dykins for mass spectrometric measurements, supported by the NSF (0541775).


Supporting Information Available. General experimental procedures, experimental procedures and spectra for all products.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Shimojo M, Matsumoto K, Hatanaka M. Tetrahedron. 2000;56:9281.
2. For the one recorded example of a Grignard reagent (derived from propargyl bromide) coupling with BOM-Cl, see Aliev AK, Karaev SF, Gasanov KG. Nauch Tr Azerb In-ta Nefti i Khimii. 1979;59
3. Several instances of enolate alkylation with BOM-Cl have been reported: (a) Kende AS, Chen J. J Am Chem Soc. 1985;107:7184. (b) Lee BH, Biswas A, Miller MJ. J Org Chem. 1986;51:106. (c) Brooks DW, Kellogg RP, Cooper CS. J Org Chem. 1987;52:192. (d) Fujisawa T, Fujimura A, Sato T. Bull Chem Soc Jpn. 1988;61:1273. (e) Corey EJ, Yuen PW. Tetrahedron Lett. 1989;30:5825. (f) Soti F, Kajtar-Peredy M, Keresztury G, Incze M, Kardos-Balogh Z, Szantay C. Tetrahedron. 1991;47:271. (g) Mata EG, Thomas EJ. J C S Perkin I. 1995:785. (h) Blakemore PR, Browder CC, Hong J, Lincoln CM, Nagornyy PA, Robarge LA, Wardrop DJ, White JD. J Org Chem. 2005;70:5449. [PubMed]
4. For the alkylation of the anion derived by deprotonation of a methyl pyridine with BOM-Cl, see Leighton P, Sanders JKMJCS. Perkin I. 1987:2385.
5. For the conversion of BOM-Cl into the Grignard reagent and coupling with an electrophile, see Crich D, Banerjee A. J Am Chem Soc. 2006;128:8078. [PubMed]
6. For a previous preparation of 2c, see Smith EH, Jeropoulos S. J Chem Soc, Chem Commun. 1986:1621.
7. For a previous preparation of 2d, see Barluenga J, Alonso-Cires L, Campos P, Asensio G. Synthesis. 1983:53.
8. For synthetic applications of 2c, see (a) Poulter CD, Muehlbacher M. J Org Chem. 1988;53:1026. (b) Legraverend M, Boumchita H, Zerial A, Huel C, Lemaitre M, Bisagni E. J Med Chem. 1990;33:2476. [PubMed] (c) Chan K, Ling YH, Loh T. Chem Commun. 2007:939. [PubMed]
9. 13C multiplicities were determined with the aid of a JVERT pulse sequence, differentiating the signals for methyl and methine carbons as “d” and for methylene and quaternary carbons as “u”.