Abstract
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).2–4 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.
| Entry | Substrate | Product | Yield (%)a |
|---|---|---|---|
| 1 |
 1ab |
 2ac |
90 |
| 2 |
 1bd |
 2be |
84 |
| 3 |
 1cd |
 2cf |
73 |
| 4 |
 1db |
 2dg |
64 |
| 5 |
 1eb |
 2ee |
98 |
| 6 |
 1fd |
 2f |
98 |
Yields are reported for pure products.
The Grignard was prepared from the bromide.
Product had previously been prepared by alternate route: Ref 1.
Commercial Grignard reagent was used.
Products are commercially available.
Product had previously been prepared by an alternate route: Ref 6.
Product had previously been prepared by an alternate route: Ref 7.
 |
(1) |
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
Acknowledgments
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).
Footnotes
Supporting Information Available. General experimental procedures, experimental procedures and spectra for all products.
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References
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