Benzyl Chloromethyl Ether1

[3587-60-8]  · C8H9ClO  · Benzyl Chloromethyl Ether  · (MW 156.61)

(protecting group for alcohols2 and amines;3 electrophile in alkylation of carbanions;4 and source of nucleophilic benzyloxymethyl anion5)

Physical Data: bp 53-56 °C/1.5 mmHg; 96-99 °C/11 mmHg; d 1.13 g cm-3; nD20 1.5268-1.5279.

Solubility: sol THF, ether, dioxane, dichloromethane, chloroform, benzene, toluene, DMF, DMSO, and acetonitrile.

Form Supplied in: liquid.

Analysis of Reagent Purity: NMR, GC.

Preparative Methods: benzyl alcohol plus aqueous formaldehyde and hydrogen chloride gas;1,6,7 reaction of benzyl methyl ether with boron trichloride;8 cleavage of benzyloxymethyl methyl sulfide with sulfuryl chloride.9

Purification: distillation.

Handling, Storage, and Precautions: stable indefinitely when kept dry but destroyed by water and other nucleophilic reagents.

Alcohol Protecting Group.

The foremost use for this reagent is as a protecting group for the alcohol functional group. This can be illustrated in a step utilized in the total synthesis of kijanolide (eq 1).10 An enantioselective synthesis of the taxol side chain used the benzyloxymethyl (BOM) ether for protection of an alcohol group (eq 2).11

Ethyl lactate can be protected as a BOM ether for subsequent nucleophilic additions to the corresponding aldehyde with high diastereoselectivity.12 A synthesis of zoapatanol used selective protection of a diol (eq 3).13 Primary alcohols can be protected selectively in the presence of secondary hydroxy groups,14 and secondary hydronyls react more quickly than tertiary ones with benzyl chloromethyl ether and base.15 Removal of this protecting group can be carried out by hydrogenolysis over Pd.

Amine Protecting Group.

2,3,5-Triiodoimidazole reacts with Potassium Carbonate in DMF followed by benzyl chloromethyl ether to give the 1-BOM derivative in 83% yield.3 A substituted purine undergoes protection with benzyl chloromethyl ether and Sodium Hydride (eq 4).16 Imide nitrogens can be protected in the presence of lactam nitrogens because of the difference in acidity.17

Alkylation of Carbanions.

Methyl 2-phenylpropionate can be deprotonated with LDA and alkylated on carbon with benzyl chloromethyl ether.4 Introduction of the BOM group in both chiral amides (eq 5)18 and dianions (eq 6)19 gives good yields. Removal of the benzyl group by hydrogenolysis completes the hydroxymethylation process.

Benzyloxymethyl Anion.

Both Grignard and organolithium reagents of the benzyloxymethyl anion can be prepared. The Grignard reagent is formed by reaction with Magnesium.20 Trapping this species with Tri-n-butylchlorostannane and reaction of the stannane with n-Butyllithium gives the organolithium.20 Addition to electrophiles is predictable (eq 7).5 Removal of the benzyl group via hydrogenolysis reveals that the ether anion is a masked methanol dianion.

1. Connor, D. S.; Klein, G. W.; Taylor, G. N. OS 1972, 52, 16.
2. Stork, G.; Isobe, M. JACS 1975, 97, 6260.
3. Groziak, M. P.; Wei, L. JOC 1991, 56, 4296.
4. Miyamoto, K.; Tsuchiya, S.; Ohta, H. JACS 1992, 114, 6256.
5. Wipf, P.; Kim, Y. JOC 1993, 58, 1649.
6. Hill, A. J.; Keach, D. T. JACS 1926, 48, 257.
7. Paraformaldehyde can be used in place of formalin: Guedin-Vuong, D.; Yoichi, N. BSF 1986, 245.
8. Goff, D. A.; Harris, R. N., III; Bottaro, J. C.; Bedford, C. D. JOC 1986, 51, 4711.
9. Benneche, T.; Strande, P.; Undheim, K. S 1983, 762.
10. Roush, W. R.; Brown, B. B. JOC 1993, 58, 2162.
11. Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J. JOC 1986, 51, 46.
12. Banfi, L.; Bernardi, A.; Colombo, L.; Gennari, C.; Scolastico, C. JOC 1984, 49, 3784.
13. Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E. JACS 1980, 102, 6611.
14. McCarthy, P. A. TL 1982, 4199.
15. Bender, S. L.; Widlanski, T.; Knowles, J. R.; B 1989, 28, 7560.
16. Shimada, J.; Suzuki, F. TL 1992, 33, 3151.
17. Yamagishi, M.; Yamada, Y.; Ozaki, K.; Asao, M.; Shimizu, R.; Suzuki, M.; Matsumoto, M.; Matsuoka, Y.; Matsumoto, K. JMC 1992, 35, 2085.
18. Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. JACS 1990, 112, 8215.
19. Fang, C.; Suganuma, K.; Suemune, H.; Sakai, K. JCS(P1), 1991, 1549.
20. Still, W. C. JACS 1978, 100, 1481.

Harold W. Pinnick

Bucknell University, Lewisburg, PA, USA

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