Di-tert-butyl dicarbonate

Di-tert-butyl dicarbonate
Names
IUPAC name
Di-t-butyl dicarbonate
Other names
di-tert-butyl pyrocarbonate
Boc anhydride
Boc2O
Identifiers
24424-99-5 YesY
ChEBI CHEBI:48500 YesY
ChemSpider 81704 YesY
Jmol 3D model Interactive image
PubChem 90495
Properties
C10H18O5
Molar mass 218.25 g·mol−1
Appearance colourless solid
Density 0.95 g·cm−3
Melting point 22 to 24 °C (72 to 75 °F; 295 to 297 K)
Boiling point 56 to 57 °C (133 to 135 °F; 329 to 330 K) (0.5 mmHg)
insol
Solubility in other solvents most organic solvents
Structure
0 D
Hazards
Main hazards toxic on inhalation T+
Related compounds
Related compounds
 ethyl chloroformate
phosgene
diethylpyrocarbonate
dimethyl dicarbonate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis.[1] 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 (FMOC-Cl) protection.

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:[2]

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.[3]

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.[4][5][6] 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.[7][8] Selective cleavage of the N-Boc group in the presence of other protecting groups is possible when using AlCl3.

Reaction with trimethylsilyl iodide in acetontrile followed by methanol is a mild and versatile method of deprotecting Boc-protected amines.[9][10][11][12]

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.[13]

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.[14] (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.

References

  1. ↑ M. Wakselman, "Di-t-butyl Dicarbonate" in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York. doi:10.1002/047084289.
  2. ↑ B. M. Pope, Y. Yamamoto, and D. S. Tarbell (1988). "Dicarbonic acid, bis(1,1-dimethylethyl) ester". Org. Synth.; Coll. Vol. 6, p. 418
  3. ↑ Yochai Basel, Alfred Hassner (2000). "Di-tert-butyl Dicarbonate and 4-(Dimethylamino)pyridine Revisited. Their Reactions with Amines and Alcohols". J. Org. Chem. 65: 6368–6380. doi:10.1021/jo000257f.
  4. ↑ R. M. Williams, P. J. Sinclair, D. E. DeMong, D. Chen, and D. Zhai (2003). "4-Morpholinecarboxylic acid, 6-oxo-2,3-diphenyl-, 1,1-dimethylethyl ester, (2S,3R)-". Org. Synth. 80: 18.
  5. ↑ E. A. Englund, H. N. Gopi, D. H. Appella (2004). "An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups". Org. Lett. 6 (2): 213–215. doi:10.1021/ol0361599. PMID 14723531.
  6. ↑ D. M. Shendage, R. Fröhlich, G. Haufe (2004). "Highly Efficient Stereoconservative Amidation and Deamidation of α-Amino Acids". Org. Lett. 6 (21): 3675–3678. doi:10.1021/ol048771l. PMID 15469321.
  7. ↑ Lundt, Behrend F.; Johansen, Nils L.; Vølund, Aage; Markussen, Jan (1978). "Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid". International Journal of Peptide and Protein Research 12 (5): 258–268. doi:10.1111/j.1399-3011.1978.tb02896.x. PMID 744685.
  8. ↑ 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.
  9. ↑ Michael E. Jung, Mark A. Lyster (1978). "Conversion of alkyl carbamates into amines via treatment with trimethylsilyl iodide". J. Chem. Soc., Chem. Commun.: 315–316. doi:10.1039/C39780000315.
  10. ↑ Richard S. Lott, Virander S. Chauhan, Charles H. Stammer (1979). "Trimethylsilyl iodide as a peptide deblocking agent". J. Chem. Soc., Chem. Commun.: 495–496. doi:10.1039/C39790000495.
  11. ↑ Olah, G; Narang, S. C. (1982). "Iodotrimethylsilane—a versatile synthetic reagent". Tetrahedron 38 (15): 2225. doi:10.1016/0040-4020(82)87002-6.
  12. ↑ Zhijian Liu, Nobuyoshi Yasuda, Michael Simeone, Robert A. Reamer (2014). "N-Boc Deprotection and Isolation Method for Water-Soluble Zwitterionic Compounds". J. Org. Chem. 79: 11792–11796. doi:10.1021/jo502319z.
  13. ↑ Anita Mehta, R. Jaouhari, T. J. Benson, K. T. Douglas (1992). Tetrahedron Letters 33 (37): 5441–5444. doi:10.1016/s0040-4039(00)79116-7. Missing or empty |title= (help)
  14. ↑ T. J. Harrison and G. R. Dake (2005). "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 (26): 10872–10874. doi:10.1021/jo051940a. PMID 16356012.

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