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.

Amino groups are selectively protected in good yields by reaction with O-alkyl S-(pyridin-2-yl)carbonothiolates at room temperature in air. Even substrates with multiple hydroxyl groups such as glucosamine are selectively N-protected.
T. Suzuki, K. Tanaka III, Y. Hashimoto, N. Morita, O. Tamura, Synlett, 2020, 31, 899-902.

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

A copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue LEDs, achieves the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature.
J. M. Ahn, J. C. Peters, G. C. Fu, J. Am. Chem. Soc., 2017, 139, 18101-18106.

A highly efficient Ni(II)-catalyzed photoredox N-arylation of Cbz-amines/Boc-amines with aryl electrophiles at room temperature provides a wide variety of N-aromatic and N-heteroaromatic carbamate products that find use in the synthesis of several biologically active molecules. The reaction offers a viable alternative to traditional palladium-catalyzed Buchwald-Hartwig reaction.
L. R. Reddy, S. Kotturi, Y. Waman, V. R. Reddy, C. Patel, A. Kobarne, S. Kuttappan, J. Org. Chem., 2018, 83, 13854-13860.

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.

An intramolecular decarboxylation of readily prepared alkanoyloxycarbamates enables a general and effective synthesis of primary and secondary alkylamines. The reaction tolerates a broad range of functional groups and the corresponding products were obtained in good yields under mild conditions.
P. Li, N. Ma, Z. Wang, Q. Dai, C. Hu, J. Org. Chem., 2018, 83, 8233-8240.

A nickel boride catalyst prepared in situ from NiCl₂ and sodium borohydride allowed facile reductions of a wide range of nitroarenes, aliphatic nitro compounds, and organic azides. Addition of modified nanocellulose enabled lower catalyst loading in nitro reductions. The protocols are compatible with a one-pot Boc-protection to provide the corresponding carbamates.
G. Proietti, K. J. Prathap, X. Yu, R. T. Olsson, P. Dinér, Synthesis, 2022, 54, 133-146.

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.

An efficient synthesis of aryl carbamates - including major carbamate protecting groups - was achieved by introducing alcohols into the reaction of palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate. This methodology also provides direct access to S-thiocarbamates and diisocyanate precursors to polyurethane materials.
E. V. Vinogradova, N. H. Park, B. P. Fors, S. L. Buchwald, Org. Lett., 2013, 15, 1394-1397.

Primary and secondary allylic alcohols underwent a regioselective Mitsunobu reaction with readily accessible N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic amines. Subsequent N-methylation and Boc deprotection without chromatography yielded the amine products as hydrochloride salts.
B. C. van Veen, S. M. Wales, J. Clayden, J. Org. Chem., 2021, 86, 8538-8543.

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.

The combination of the tris-4-bromophenylamminium radical cation, commonly known as magic blue (MB^•+), and triethylsilane mediates a mild OtBu deprotection. Magic blue catalytically facilitates the cleavage of the C-O bond in tert-butyl carbamates, carbonates, esters, and ethers in a high isolated yield under mild conditions, and sacrificial triethylsilane accelerates the reaction.
D. Hidasová, Tomáš Slanina, J. Org. Chem., 2023, 88, 6932-6938.

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

A magnesium-catalyzed reduction of linear and cyclic carbamates, including N-Boc protected amines, provides N-methyl amines and amino alcohols which are of significant interest due to their presence in many biologically active molecules. Furthermore, the reduction can be extended to the formation of N-trideuteromethyl labeled amines.
M. Magre, M. Szewczyk, M. Rueping, Org. Lett., 2020, 22, 3209-3214.

In a practical one-pot synthesis of ureas, Boc-protected amines are transformed into nonsymmetrical and symmetrical disubstituted and trisubstituted ureas via in situ generation of isocyanates utilizing 2-chloropyridine and trifluoromethanesulfonyl anhydride. A variety of amines can be employed successfully, leading to high yields of isolated ureas.
C. Spyropoulos, C. G. Kokotos, J. Org. Chem., 2014, 79, 4477-4483.

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.

N-Boc- and N-Cbz-protected amines can be directly converted into amides by a novel rhodium-catalyzed coupling with arylboroxines. Both protected anilines and aliphatic amines are efficiently transformed into a wide variety of secondary benzamides, including sterically hindered and electron-deficient amides. The reaction tolerates acid-labile and reducible functional groups.
D. S. W. Lim, T. T. S. Lew, Y. Zhang, Org. Lett., 2015, 17, 6054-6057.

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.

α-Keto esters can be prepared via Mannich addition of ethyl diazoacetate to imines followed by oxidation of the diazo group with Oxone. Implementation of a recently developed dynamic kinetic resolution of β-substituted-α-keto esters via Ru(II)-catalyzed asymmetric transfer hydrogenation provides enantioenriched anti-α-hydroxy-β-amino acid derivatives in high diastereo- and enantioselectivity.
C. G. Goodman, D. T. Do, J. S. Johnson, Org. Lett., 2013, 15, 2446-2449.

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.