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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


1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently catalyze N-tert-butyloxycarbonylation of amines with excellent chemoselectivity. The catalytic role of the ionic liquid is envisaged as electrophilic activation of di-tert-butyl dicarbonate (Boc2O) through bifurcated hydrogen bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimidazolium cation.
A. Sarkar, S. R. Roy, N. Parikh, A. K. Chakraborti, J. Org. Chem., 2011, 76, 7132-7140.


The use of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as solvent and catalyst allows a simple and efficient, chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butyl dicarbonate. The catalyst can be readily recycled. No competitive side reactions such as formation of isocyanates, ureas, and oxazolidinones from α-amino alcohols were observed.
A. Heydari, S. Khaksar, M. Tajbakhsh, Synthesis, 2008, 3126-3130.


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 simple and efficient protection procedure is general and regioselective for the preparation of mono-N-Boc, N-Cbz, N-Fmoc or N-Alloc aromatic amines in high yield without affecting aliphatic amino groups and other functionalities.
V. Perron, S. Abbott, N. Moreau, D. Lee, C. Penney, B. Zacharie, Synthesis, 2009, 283-289.


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.


Stable Fmoc-, Boc-, and Alloc-benzotriazoles react with various amino acids including unprotected serine and glutamic acid, in the presence of triethylamine at 20˚C to afford Fmoc-, Boc-, and Alloc-protected amino acids in very good yields free of dipeptide and tripeptide impurities. Fmoc-, and Alloc-Gly-Gly-OH dipeptides were prepared in excellent yields by N-acylation of glycylglycine.
T. S. Ibrahima, S. R. Tala, S. A. El-Feky, Z. K. Abdel-Samii, A. R. Katritzky, Synlett, 2011, 2013-2016.


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 new mild method allows the removal of carbamates using TBAF in THF. Selectivity and mechanism are discussed.
U. Jacquemard, V. Beneteau, M. Lefoix, S. Routier, J.-Y. Merour, G. Coudert, Tetrahedron, 2004, 60, 10039-10047.


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 can 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


SmCl3 is an excellent catalyst for chemoselective esterifications and selective removal of acid sensitive hydroxyl protecting groups such as Boc, THP, and TBDMS. Chemoselective deprotection is demonstrated through suitable examples.
P. Gopinath, S. Nilaya, K. M. Muraleedharan, Org. Lett., 2011, 13, 1932-1935.


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.


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.


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.


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.


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.