Benzyl (Bn) Protective Group

• General Characteristics

-Benzyl group (Bn) is stable towards both acids and bases and is a highly general protecting group.

-Base sensitive compounds can be protected using BnOC(=NH)CCl₃ under acidic conditions.

-Deprotection is usually done under reductive conditions (H₂-Pd/C, Na/NH₃(l), electrolytic reduction, etc). Alternatively, benzyl groups can be deprotected by RuCl₃/NaIO₄ oxidation-then-hydrolysis or by the combination of a Lewis acid and a nucleophile (such as Me₂BBr).

• General References

・Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 17, 3535. doi:10.1016/S0040-4039(00)71351-7
・White, J. D.; Reddy, G. N.; Spessard, G. O. J. Am. Chem. Soc. 1988, 110, 1624. DOI: 10.1021/ja00213a047

• Reaction Mechanism

1. Protection

Follows the mechanism of Williamson ether synthesis.

2. Deprotection (reductive conditions)

• Examples

Typical protection and deprotection examples^[1]: Benzyl group is stable, therefore protection is often done during the early stage of syntheses.

Selective cleavage of N-Bn in the presence of O-Bn is possible.^[2]

The Dudley reagent^[3]: This bench stable reagent is easy to handle and capable of benzylation under nearly neutral conditions.

• Experimental Procedure

-The substrate is reacted with BnCl or BnBr in DMF with NaH as a base. Benzylated products are generally obtained in high yield.

-The catalytic addition of Bu₄NI (TBAI) or NaI accelerates benzylation (through in situ formation of reactive BnI).

• Experimental Tips

-Benzyl bromide is a lachrymator. Handle it inside a fume hood.

-Quenching the reaction with methanol/potassium carbonate instead of water is a nice way to destroy unreacted benzyl bromide. This procedure is recommended as it makes extraction easier.

• References

[1] Oguri, H.; Hishiyama, S.; Oishi, T.; Hirama, M. Synlett 1995, 1252. DOI: 10.1055/s-1995-5259
[2] Kroutil, J.; Tmka, T.; Cemy, M. Synthesis 2004, 446. DOI: 10.1055/s-2004-815937
[3] (a) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923. DOI: 10.1021/jo0602773 (b) Poon, K. W. C.; House, S. E.; Dudley, G. B. Synlett 2005, 3142. DOI: 10.1055/s-2005-921898

• Related Books

[amazonjs asin=”0471697540″ locale=”US” title=”Greene’s Protective Groups in Organic Synthesis”]

[amazonjs asin=”0865779937″ locale=”US” title=”Protecting Groups (Foundations of Organic Chemistry)”]

[amazonjs asin=”0198502753″ locale=”US” title=”Protecting Group Chemistry (Oxford Chemistry Primers)”]

protection of alcohol, protective group