Tert-Butyloxycarbonyl protecting group explained

The tert-butyloxycarbonyl protecting group or tert-butoxycarbonyl protecting group^[1] (BOC group) is an acid-labile protecting group used in organic synthesis.

The BOC group can be added to amines under aqueous conditions using di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide:

Protection of amines can also be accomplished in acetonitrile solution using 4-dimethylaminopyridine (DMAP) as the base.

Removal of the BOC group in amino acids can be accomplished with strong acids such as trifluoroacetic acid in dichloromethane, or with HCl in methanol.^{[2] [3]} 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.^{[4] [5]} Selective cleavage of the N-Boc group in the presence of other protecting groups is possible when using AlCl₃.

Sequential treatment with trimethylsilyl iodide then methanol can also be used for Boc deprotection,^{[6] [7]} especially where other deprotection methods are too harsh for the substrate.^[8] The mechanism involves silylation of the carbonyl oxygen and elimination of tert-butyl iodide, methanolysis of the silyl ester to the carbamic acid and finally decarboxylation to the amine .^[9]

Amine protection

The tert-butyloxycarbonyl (Boc) group is used as a protecting group for amines in organic synthesis.

Common amine protection methods

• Simple rapid stirring of a mixture of the amine and di-tert-butyl dicarbonate (Boc₂O) suspended in water at ambient temperature, an example of an on-water reaction.^[10]
• Heating a mixture of the amine to be protected and di-tert-butyl dicarbonate in tetrahydrofuran (THF) at 40 °C^[11]
• Add the amine to sodium hydroxide and di-tert-butyl dicarbonate in water and THF at 0 °C then warm to ambient temperature.^[12]
• Heating a mixture of the amine to be protected and di-tert-butyl dicarbonate in a biphasic mixture of chloroform and aqueous sodium bicarbonate at reflux for 90 minutes.^[13]
• Add the amine to di-tert-butyl dicarbonate, 4-dimethylaminopyridine (DMAP), and acetonitrile (MeCN) at ambient temperature^[14]

BOC-protected amines are prepared using the reagent di-tert-butyl-iminodicarboxylate. Upon deprotonation, this reagent affords a doubly BOC-protected source of NH, which can be N-alkylated. The approach is complementary to the Gabriel synthesis of amines.

Common amine deprotection methods

• Mix the protected carbamate to be deprotected with 3 M hydrochloric acid (HCl) in ethyl acetate for 30 min at ambient temperature^[15]
• Heat the carbamate in a mixture of aqueous hydrochloric acid and toluene at 65 °C^[16]
• Dissolving desired protected compound in a 50/50 mix of dichloromethane and trifluoroacetic acid^[17]

Notes and References

1. Web site: Rules for abbreviation of protecting groups. 2013. IUPAC. iupac.org.
2. 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 . . 2004 . 6 . 213–215 . 10.1021/ol0361599 . 14723531 . 2.
3. D. M. Shendage . R. Fröhlich . G. Haufe . Highly Efficient Stereoconservative Amidation and Deamidation of α-Amino Acids . . 2004 . 6 . 3675–3678 . 10.1021/ol048771l . 15469321 . 21.
4. 10.1111/j.1399-3011.1978.tb02896.x . Removal of t-Butyl and t-Butoxycarbonyl Protecting Groups with Trifluoroacetic acid . 1978 . Lundt . Behrend F. . Johansen . Nils L. . Vølund . Aage . Markussen . Jan . . 12 . 5 . 258–268 . 744685.
5. Book: 10.1002/9783527631827.ch1 . Protection Reactions . Andrew B. Hughes . Vommina V. Sureshbabu . Narasimhamurthy Narendra . 4 . Amino Acids, Peptides and Proteins in Organic Chemistry . Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis . . https://books.google.com/books?id=uZK2i-FkeAUC&pg=PP18 . 9783527641574 . XVIII – LXXXIV. 2011 .
6. Richard S. Lott . Virander S. Chauhan . Charles H. Stammer . Trimethylsilyl iodide as a peptide deblocking agent . . 11 . 1979 . 495–496 . 10.1039/C39790000495 .
7. 10.1016/0040-4020(82)87002-6 . Iodotrimethylsilane—a versatile synthetic reagent. 1982 . Olah . G . Narang . S. C. . . 38 . 15 . 2225–2277 .
8. Zhijian Liu . Nobuyoshi Yasuda . Michael Simeone . Robert A. Reamer . N-Boc Deprotection and Isolation Method for Water-Soluble Zwitterionic Compounds . . 2014 . 79 . 23 . 11792–11796 . 10.1021/jo502319z . 25376704 .
9. Michael E. Jung . Mark A. Lyster . Conversion of alkyl carbamates into amines via treatment with trimethylsilyl iodide . . 7 . 1978 . 315–316 . 10.1039/C39780000315 .
10. Chankeshwara. Sunay V.. Chakraborti. Asit K.. 2006. Catalyst-Free Chemoselective N-tert-Butyloxycarbonylation of Amines in Water. 10.1021/ol0611191. 16836380. Org. Lett.. 8. 15. 3259–3262.
11. Book: http://onlinelibrary.wiley.com/book/10.1002/0470053488. Greene's Protective Groups in Organic Synthesis. 4th. John Wiley & Sons. Wuts. Peter G. M.. Greene. Theodora W.. 10.1002/9780470053485.ch7. 9780471697541. Protection for the Amino Group. 696–926. 2006.
12. Fachao Yan. Hanbing Liang. Jian Song. Jie Cui. Qing Liu. Sheng Liu. Ping Wang. Yunhui Dong. Hui Liu. Palladium-Catalyzed Cyclization-Heck Reaction of Allenamides: An Approach to 3-Methylene-5-phenyl-1,2,3,4-tetrahydropyridine Derivatives. Org. Lett.. 2017. 19. 1. 86–89. 10.1021/acs.orglett.6b03364. 27966983.
13. Tarbell. D. Stanley. Yamamoto. Yutaka. Pope. Barry M.. 1972. New Method to Prepare N-t-Butoxycarbonyl Derivatives and the Corresponding Sulfur Analogs from di-t-Butyl Dicarbonate or di-t-Butyl Dithiol Dicarbonates and Amino Acids. Proc. Natl. Acad. Sci. U.S.A.. 69. 3. 730–732. 426545. 16591972. 10.1073/pnas.69.3.730. 1972PNAS...69..730T. free.
14. Englund. Ethan A.. Gopi. Hosahudya N.. Appella. Daniel H.. An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups. Org. Lett.. 6. 2. 213–215. 10.1021/ol0361599. 14723531. 2004.
15. Stahl. Glenn L.. Walter. Roderich. Smith. Clark W.. General Procedure for the Synthesis of Mono-N-Acylated 1,6-Diaminohexanes. J. Org. Chem.. 43. 11. 2285–2286. 10.1021/jo00405a045. 1978.
16. Prashad. Mahavir. Har. Denis. Hu. Bin. Kim. Hong-Yong. Girgis. Michael J.. Chaudhary. Apurva. Repič. Oljan. Blacklock. Thomas J.. Marterer. Wolfgang. Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist. Org. Process Res. Dev.. 8. 3. 330–340. 10.1021/op0341824. 2004.
17. Web site: Boc Deprotection - TFA.