Di-tert-butyl Dicarbonate

Di-''tert''-butyl dicarbonate is a reagent widely used in organic synthesis. Since this compound can be regarded formally as the acid anhydride derived from a ''tert''-butoxycarbonyl (Boc) group, it is commonly referred to as Boc anhydride. This pyrocarbonate reacts with amines to give ''N''-''tert''-butoxycarbonyl or so-called Boc derivatives. These carbamate derivatives do not behave as amines, which allows certain subsequent transformations to occur that would be incompatible with the amine functional group. The Boc group can later be removed from the amine using moderately strong acids (e.g., trifluoroacetic acid). Thus, Boc serves as a protective group, for instance in solid phase peptide synthesis. Boc-protected amines are unreactive to most bases and nucleophiles, allowing for the use of the fluorenylmethyloxycarbonyl group (Fmoc) as an orthogonal protecting group.

Preparation

Di-''tert''-butyl dicarbonate is inexpensive, so it is usually purchased. Classically, this compound is prepared from ''tert''-butanol, carbon dioxide, and 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''-butoxide 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 (DMAP) 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.

Reaction with trimethylsilyl iodide in acetonitrile followed by methanol is a mild and versatile method of deprotecting Boc-protected amines.

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, starting from 2-piperidone was accomplished using ''t''-boc anhydride.
(See Maillard reaction). The first step in this reaction sequence is the formation of the carbamate from the reaction of the amide nitrogen with boc anhydride in acetonitrile using DMAP as a catalyst.

:

Di-''tert''-butyl dicarbonate also finds applications as a polymer blowing agent due to its decomposition into gaseous products upon heating.

Hazards

Bottles of di-''tert''-butyl dicarbonate buildup of internal pressure in sealed containers caused by its slow decomposition to di-''tert''-butyl carbonate and ultimately ''tert-''butanol and CO₂ in the presence of moisture. For this reason, it is usually sold and stored in plastic bottles rather than glass ones.

The main hazard of the reagent is its inhalational toxicity. Its median lethal concentration of 100 mg/m³ over 4 hours in rats is comparable to that of phosgene (49 mg/m³ over 50 min in rats).

References

External links

*

{{DEFAULTSORT:Di-Tert-Butyl Dicarbonate
Reagents for organic chemistry
Carbonate esters
Dicarbonates
Tert-butyl compounds