Benzyl carbamates
Cbz-NR2 / Z-NR2
T. W. Green, P. G. M. Wuts,
Protective Groups in Organic
Synthesis,
Wiley-Interscience, New York, 1999, 531-537, 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 |
Protection of Amino Groups
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.
Deprotection
In situ preparation of an active Pd/C catalyst from Pd(OAc)2 and
charcoal in methanol enables a simple, highly reproducible protocol for the
hydrogenation of alkenes and alkynes and for the hydrogenolysis of O-benzyl
ethers. Mild reaction conditions and low catalyst loadings, as well as the
absence of contamination of the product by palladium residues, make this a
sustainable, useful process.
F.-X. Felpin, E. Fouquet, Chem. Eur. J., 2010,
12440-12445.
Cbz, Alloc, and methyl carbamate protected amines can be readily deprotected
by treatment with 2-mercaptoethanol in the presence of potassium phosphate in
N,N-dimethylacetamide at 75 °C. This nucleophilic deprotection protocol is
superior to the standard hydrogenolysis or Lewis acid-mediated deprotection
conditions for substrates bearing sensitive functionalities.
T. Scattolin, T. Gharbaoui, C.-y. Chen, Org. Lett.,
2022, 24, 3736-3740.
Ammonia, pyridine and ammonium acetate were extremely effective
as inhibitors of Pd/C catalyzed benzyl ether hydrogenolysis. While olefin, Cbz,
benzyl ester and azide functionalities were hydrogenated smoothly, benzyl ethers
were not cleaved.
H. Sajiki, Tetrahedron Lett., 1995,
36, 3465-3468.
A generally applicable method for the introduction of gaseous hydrogen into a
sealed reaction system under microwave irradiation allows the hydrogenation of
various substrates in short reaction times with moderate temperatures between 80
°C and 100 °C with 50 psi of hydrogen.
G. S. Vanier, Synlett, 2007, 131-135.
In situ generation of molecular hydrogen by addition of triethylsilane to
palladium on charcoal results in rapid and efficient reduction of multiple bonds,
azides, imines, and nitro groups, as well as deprotection of benzyl and allyl
groups under mild, neutral conditions.
P. K. Mandal, J. S. McMurray, J. Org. Chem.,
2007,
72, 6599-6601.
Various thioureas derived from primary amines and carbamoyl-protected
isothiocyanates react with the Burgess reagent to give the corresponding
guanidines via either a stepwise or one-pot procedure. A selective deprotection
of the N,N′-diprotected guanidines affords N-monoprotected
guanidines.
T. Maki, T. Tsuritani, T. Yasukata, Org. Lett., 2014,
16, 1868-1871.
Other Syntheses of Cbz-Protected Amino Groups
An efficient catalytic four-component reaction of carbonyl compounds, benzyl
chloroformate, 1,1,1,3,3,3-hexamethyldisilazane, and allyltrimethylsilane
provides Cbz-protected homoallylic amines in the presence of 5 mol% of iron(II)
sulfate heptahydrate as an inexpensive and environmentally friendly catalyst.
Q.-Y. Song, B.-L. Yang, S.-K. Tian, J. Org. Chem., 2007,
72, 5407-5410.
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.
Conversion of Cbz-protected Amines to other functional groups
Lanthanum triflate catalyzes a direct conversion of N-benzyloxycarbonyl-,
N-allyloxycarbonyl-, and N-trichloroethoxycarbonyl-protected
amines into nonsymmetric ureas in high yields. A variety of protected aromatic
and aliphatic carbamates reacted readily with various amines in the presence of
lanthanum triflate to generate the desired ureas.
T. T. Bui, H.-K. Kim, Synlett, 2020,
31,
997-1002.
Cbz-Protected Amino-Groups in Multi-step Syntheses
N-Cbz-protected amino acids reacted with various aryl amines in the
presence of methanesulfonyl chloride and N-methylimidazole in
dichloromethane to give the corresponding arylamides in high yields without
racemization under these mild conditions.
L. Mao, Z. Wang, Y. Li, X. Han, W. Zhou, Synlett, 2011,
129-133.