Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis. This
carbonate ester reacts with amines to give N-tert-butoxycarbonyl or so-called
Boc derivatives. These derivatives do not behave as amines, which allows
certain subsequent transformations to occur that would have otherwise affected
the amine functional group. The Boc can later be removed from the amine using
acids. Thus, Boc serves as a protective group, for instance in solid phase
peptide synthesis. It is unreactive to most bases and nucleophiles, allowing
for an orthogonal Fluorenylmethyloxycarbonyl chloride
protection. Preparation
Di-tert-butyl dicarbonate is inexpensive, so it is usually purchased.
Classically, this compound is prepared from tert-butanol, carbon dioxide,
phosgene, using DABCO as a base: This route is currently employed
commercially by manufacturers in China and India. European and Japanese
companies use the reaction of sodium tert-butylate with carbon dioxide,
catalysed by p-toluenesulfonic acid or methanesulfonic acid. This process
involves a distillation of the crude material yielding a very pure grade.
Boc anhydride is also available as a 70% solution in toluene or THF. As boc
anhydride may melt at ambient temperatures, its storage and handling
is sometimes simplified by using a solution.
Protection and deprotection of amines The Boc group can be added to the amine
under aqueous conditions using di-tert-butyl dicarbonate in the
presence of a base such as sodium bicarbonate. Protection of the amine can
also be accomplished in acetonitrile solution using 4-dimethylaminopyridine
as the base. Removal of the Boc in amino acids can be
accomplished with strong acids such as trifluoroacetic acid neat or in
dichloromethane, or with HCl in methanol. A complication may be the
tendency of the t-butyl cation intermediate to alkylate other
nucleophiles; scavengers such as anisole or thioanisole may be used. Selective
cleavage of the N-Boc group in the presence of other protecting groups is
possible when using AlCl3. The use of triethylsilane as a
carbocation scavenger in the presence of trifluoroacetic acid in dichloromethane
has been shown to lead to increased yields, decreased reaction times, simple
work-up and improved selectivity for the deprotection of t-butyl ester and
t-butoxycarbonyl sites in protected amino-acids and peptides in the presence
of other acid-sensitive protecting groups such as the benzyloxycarbonyl,
9-fluorenylmethoxycarbonyl, O- and S-benzyl and t-butylthio groups.
Other uses The synthesis of
6-acetyl-1,2,3,4-tetrahydropyridine, an important bread aroma compound from
2-piperidone was accomplished using t-boc anhydride.. The first step in this
reaction sequence is the formation of the carbamate from the reaction of the
secondary amine with boc anhydride in acetonitrile with DMAP as a catalyst.
References ^ M. Wakselman, "Di-t-butyl Dicarbonate"
in Encyclopedia of Reagents for Organic Synthesis 2004, J. Wiley & Sons, New
York. doi:10.1002/047084289. ^ B. M. Pope, Y. Yamamoto, and D. S.
Tarbell. "Dicarbonic acid, bis(1,1-dimethylethyl) ester". Org.
Synth. ; Coll. Vol. 6, p. 418 ^ R. M. Williams, P. J. Sinclair, D. E.
DeMong, D. Chen, and D. Zhai. "4-Morpholinecarboxylic acid,
6-oxo-2,3-diphenyl-, 1,1-dimethylethyl ester,-". Org. Synth. 80: 18.
^ E. A. Englund, H. N. Gopi, D. H. Appella. "An Efficient Synthesis of a
Probe for Protein Function: 2,3-Diaminopropionic Acid with
Orthogonal Protecting Groups". Org. Lett. 6: 213–215. doi:10.1021/ol0361599.
PMID 14723531. ^ D. M. Shendage, R. Fröhlich, G. Haufe.
"Highly Efficient Stereoconservative Amidation and Deamidation of α-Amino
Acids". Org. Lett. 6: 3675–3678. doi:10.1021/ol048771l. PMID 15469321.
^ Lundt, Behrend F.; Johansen, Nils L.; Vølund, Aage; Markussen, Jan. "Removal
of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic
acid". International Journal of Peptide and Protein Research 12: 258–268.
doi:10.1111/j.1399-3011.1978.tb02896.x. PMID 744685.
^ Andrew B. Hughes. "1. Protection Reactions". In Vommina V. Sureshbabu,
Narasimhamurthy Narendra. Amino Acids, Peptides and Proteins in Organic
Chemistry: Protection Reactions, Medicinal Chemistry, Combinatorial
Synthesis 4. doi:10.1002/9783527631827.ch1.
^ Anita Mehta, R. Jaouhari, T. J. Benson, K. T. Douglas. Tetrahedron
Letters 33: 5441–5444. doi:10.1016/s0040-4039(00)79116-7.
^ T. J. Harrison and G. R. Dake. "An Expeditious, High-Yielding Construction
of the Food Aroma Compounds 6-Acetyl-1,2,3,4-tetrahydropyridine and
2-Acetyl-1-pyrroline". J. Org. Chem. 70: 10872–10874. doi:10.1021/jo051940a. PMID
16356012. External links
Protection or deprotection conditions - Synthetic protocols from
organic-reaction.com Basel, Yochai; Hassner, Alfred.
"Imidazole and Trifluoroethanol as Efficient and Mild Reagents for
Destruction of Excess Di-tert-butyl Dicarbonate [(BOC)2O]". Synthesis 2001:
0550. doi:10.1055/s-2001-12350.