Reactions >> Protecting Groups >> Stability

tert-Butyl carbamates

BOC-NR₂, BOC amines, BOC amino, BOC amide

T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis,
Wiley-Interscience, New York, 1999, 518-525, 736-739.

Stability

H₂O:	pH < 1, 100°C	pH = 1, RT	pH = 4, RT	pH = 9, RT	pH = 12, RT	pH > 12, 100°C
Bases:	LDA	NEt₃, Py	t-BuOK	Others:	DCC	SOCl₂
Nucleophiles:	RLi	RMgX	RCuLi	Enolates	NH₃, RNH₂	NaOCH₃
Electrophiles:	RCOCl	RCHO	CH₃I	Others:	:CCl₂	Bu₃SnH
Reduction:	H₂ / Ni	H₂ / Rh	Zn / HCl	Na / NH₃	LiAlH₄	NaBH₄
Oxidation:	KMnO₄	OsO₄	CrO₃ / Py	RCOOOH	I₂, Br₂, Cl₂	MnO₂ / CH₂Cl₂

General

The formation of Boc-protected amines and amino acids is conducted under either aqueous or anhydrous conditions, by reaction with a base and the anhydride Boc₂O. Active esters and other derivatives such as Boc-ONH₂ and Boc-N₃ can also be used.

The Boc group is stable towards most nucleophiles and bases. Therefore, an orthogonal protection strategy using a base-labile protection group such as Fmoc is possible. tert-Butyl carbamates are cleaved under anhydrous acidic conditions with the production of tert-butyl cations. Scavengers such as thiophenol may prevent nucleophilic substrates from being alkylated.

Protection of Amino Groups

Perchloric acid adsorbed on silica-gel (HClO₄–SiO₂) was found to be a new, highly efficient, inexpensive and reusable catalyst for chemoselective N-tert-butoxycarbonylation of amines at room temperature and under solvent-free conditions.
A. K. Chakraborti, S. V. Chankeshwara, Org. Biomol. Chem., 2006, 4, 2769-2771.

An efficient and practical protocol allows the protection of various aryl and aliphatic amines using (Boc)₂O in the presence of a catalytic amount of iodine under solvent-free conditions at ambient temperature.
R. Varala, S. Nuvula, S. R. Adapa, J. Org. Chem., 2006, 71, 8283-8286.

A catalyst-free N-tert-butyloxycarbonylation of amines in water gives N-t-Boc derivatives chemoselectively without any side products (such as isocyanate, urea, N,N-di-t-Boc). Chiral amines and esters of α-amino acids afforded optically pure N-t-Boc derivatives. Amino alcohols and 2-aminophenol afforded N-t-Boc protected derivatives without oxazolidinone formation.
S. V. Chankeshwara, A. K. Chakraborti, Org. Lett., 2006, 8, 3259-3262.

A stereoconservative protection and deprotection method of amino and carboxyl groups is reported.
D. M. Shendage, R. Froehlich, G. Haufe, Org. Lett., 2004, 6, 3675-3678.

E. A. Englund, H. N. Gopi, D. H. Appella, Org. Lett., 2004, 6, 213-215.

R. Moumne, S. Lavielle, P. Karoyan, J. Org. Chem., 2006, 71, 3332-3334.

New, stable amino-protecting reagents, Boc-DMT and Fmoc-DMT, were prepared, and found to be useful for the introduction of Boc and Fmoc groups into amines. Both the reagents can protect various amines including amino acids in good yield in aqueous media.
K. Hioki, M. Kinugasa, M. Kishimoto, M. Fujiwara, S. Tani, M. Kunishima, Synthesis, 2006, 1931-1933.

Other Syntheses of Boc-Protected Amino Groups

The reaction of di-tert-butyl dicarbonate or a chloroformate and sodium azide with an aromatic carboxylic acid produces the corresponding acyl azide. The acyl azide undergoes a Curtius rearrangement to form an isocyanate derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea.
H. Lebel, O. Leogane, Org. Lett., 2006, 8, 5717-5720.

Tert-butyl carbamates are produced in high yields at low temperature by the reaction of a carboxylic acid with di-tert-butyl dicarbonate and sodium azide, which leads to an acyl azide intermediate. Subsequent Curtius rearrangement in the presence of tetrabutylammonium bromide and zinc(II) triflate and trapping of the isocyanate derivative gives the desired product. This method tolerates various functional groups.
H. Lebel, O. Leogane, Org. Lett., 2005, 7, 4107-4110.

A nickel boride catalyzed reduction of nitriles allows the preparation of Boc protected amines. The catalytic use of nickel(II) chloride in combination with excess sodium borohydride is environmental benign and tolerates air and moisture. Although the yield is sometimes moderate, the cleanliness of the method is exceptional.
S. Caddick, D. B. Judd, A. K. de K. Lewis, M. T. Reich, M. R. V. Williams, Tetrahedron, 2003, 59, 5417-5423.

Deprotection

Aqueous phosphoric acid is an effective, environmentally benign, selective and mild reagent for the deprotection of tert-butyl carbamates, tert-butyl esters, and tert-butyl ethers. CBZ carbamates, azetidine, benzyl and methyl esters, TBDMS, and methyl phenyl ethers are tolerated. The reactions are high yielding, and the workup is convenient.
B. Li, M. Berliner, R. Buzon, C. K.-F. Chiu, S. T. Colgan, T. Kaneko, N. Keene, W. Kissel, T. Le, K. R. Leeman, B. Marquez, R. Morris, L. Newell, S. Wunderwald, M. Witt, J. Weaver, Z. Zhang, Z. Zhang, J. Org. Chem., 2006, 71, 9045-9050.

A stereoconservative protection and deprotection method of amino and carboxyl groups is reported.
D. M. Shendage, R. Froehlich, G. Haufe, Org. Lett., 2004, 6, 3675-3678.

D. M. Shendage, R. Froehlich, G. Haufe, Org. Lett., 2004, 6, 3675-3678.

An efficient synthesis of N(α)-Boc₂-N(β)-Cbz-2,3-diaminopropionic acid is reported. The synthesis starts from commercially available N(α)-Boc-Asp(OBn)-OH and employs a Curtius rearrangement to establish the β-nitrogen. The success of the Curtius rearrangement depends on proper protection of the α-nitrogen.
E. A. Englund, H. N. Gopi, D. H. Appella, Org. Lett., 2004, 6, 213-215.

Diethyl N-Boc-iminomalonate, prepared on multi-gram scale, served as a stable and highly reactive electrophilic glycine equivalent which reacted with organomagnesium compounds affording substituted aryl N-Boc-aminomalonates. Subsequent hydrolysis produced arylglycines.
P. Cali, M. Begtrup, Synthesis, 2002, 63-64.

A base-catalyzed Michael-type addition of sodium diethyl malonate to N-Boc-α-amidoalkyl-p-tolyl sulfones in tetrahydrofuran followed by hydrolysis of the adducts in refluxing 6 M aqueous hydrochloric acid affords β³-amino acid hydrochlorides in high yield and excellent purity.
M. Nejman, A. Śliwińska, A. Zwierzak, Tetrahedron, 2005, 61, 8536-8541.

Enantioenriched propargyl mesylates or perfluorobenzoates react with α-(N-carbamoyl)alkylcuprates to afford scalemic α-(N-carbamoyl) allenes. Subsequent N-Boc deprotection and AgNO₃-promoted cyclization afford enantioenriched N-alkyl-3-pyrrolines.
R. K. Dieter, N. Chen, V. K. Gore, J. Org. Chem., 2006, 71, 8755-8760.

The reaction of Boc-protected ortho-aminostyrenes with alkyllithiums, followed by the addition of specific electrophiles sets up a cascade reaction process between the reacted electrophile and the ortho-amino substituent, facilitating an in situ ring closure and dehydration to generate an indole ring system.
C. M. Coleman, D. F. O'Shea, J. Am. Chem. Soc., 2003, 125, 4054-4055.

A direct preparation of O-substituted hydroxylamines from alcohols is described by O-alkylation of tert-butyl N-hydroxycarbamate with the methanesulfonates of respective alcohols, followed by acidic N-deprotection.
S. Albrecht, A. Defoin, C. Tarnus, Synthesis, 2006, 1635-1638.

Conversion of Boc-protected Amines to other functional groups

Carbamates may be converted into ureas using aluminum amide complexes. Bi-, tri- and tetra-substituted ureas were prepared from carbamate-protected primary or secondary amines by reaction with primary or secondary amines in the presence of stoichiometric quantities of trimethylaluminum.
S.-H. Lee, H. Matsushita, B. Clapham, K. D. Janda, Tetrahedron, 2004, 60, 3439-3443.

Acyl halide-methanol mixtures are efficient reagents for the one-pot transformation of t-butyl carbamates into amides. This transformation can be carried out in the presence of a benzyloxycarbonyl group.
A. Nazih, D. Heissler, Synthesis, 2002, 203-206.

Boc-Protected Amino-Groups in Multi-step Syntheses

An interesting example of selective deprotection of the tert-butyl esters in the presence of N-Boc protecting groups of several amino acids using cerium(III) chloride as a Lewis acid is reported.
E. Marcantoni, M. Massaccesi, E. Torregiani, G. Bartoli, M. Bosco, L. Sambri, J. Org. Chem, 2001, 66, 4430-4432.

Pd-catalyzed selective oxidation of Boc-protected N-methylamines with IOAc as the oxidant involves a Boc-directed C-H activation process.
D.-H. Wang, X.-S. Hao, D.-F. Wu, J.-Q. Yu, Org. Lett., 2006, 8, 3387-3390.