58
K. Chinni Mahesh et al. / Tetrahedron Letters 48 (2007) 55–59
Table 2. Selective Cbz-protection of mixtures of amines
Entry Mixture of amines
Products (% of isolated yield)
NH-Cbz
NH2
+
NH2
+
NH-Cbz
1
(95)
(95)
(3)
+
+
1 equivalent of CBzCl
2 equivalents of CBzCl
(98)
NH-Cbz
NH-Cbz
NH2
NH2
+
+
2
(99)
(0 )
(39)
+
+
1 equivalent of CBzCl
2 equivalents of CBzCl
(99)
La(NO3)3.6H2O
R'NH-Cbz
85-98%
R'NH2
1
R''NH2
Cbz-Cl
R''NH-Cbz
0-3%
+
+
+
r.t. 5 min
:
:
1
1
1
2
98%
39-98%
:
1
:
Scheme 2.
(86–98%, Table 1). The times required for derivatization
were short (4–15 min). This method was compatible
with various amines including aliphatic, aromatic and
heteroaromatic examples.
tives in good yields. Chiral substrates were resistant to
racemization and labile functionalities such as esters
were compatible in this conversion. The protocol is
highly chemoselective, involves simple experimental pro-
cedures, mild reaction conditions and gives excellent
yields of Cbz-protected amines.
Amino groups with different chemical natures further
demonstrated the chemoselectivity of the reaction. Thus,
in piperinyl indazoles only the aliphatic amino group
was protected (Table 1, entries 25 and 26). In the case
of tryptamine only the aliphatic amino group was pro-
tected (Table 1, entry 11). Similarly, in the case of an
amino alcohol (Table 1, entry 15) and an amino phenol
(Table 1, entry 10), only the amino groups were pro-
tected. In a separate experiment, a mixture of primary
(1 mmol) and secondary (1 mmol) amines was treated
with Cbz–Cl (1 mmol) in the presence of lanthanum(III)
nitrate hexahydrate to give predominantly primary-Cbz-
protected amine (95%) (Table 2, entry 1). However, if
the reaction was carried out with 2 equiv of Cbz–Cl,
both the primary and secondary amines were protected
to give the corresponding carbamates. (Table 2, entry
1). In the case of a mixture of aliphatic and aromatic
amines (1 mmol each), the reaction with Cbz–Cl
(1 mmol) in the presence of lanthanum(III) nitrate hexa-
hydrate, only the aliphatic amine was derivatized; how-
ever, if 2 mmol of Cbz–Cl was used, the aromatic amine
was also partly converted (Scheme 2 , Table 2, entries 1
and 2).
Typical experimental procedure: To a mixture of amine
(1 mmol) and benzyloxycarbonyl chloride (Cbz–Cl)
(1.2 mmol) was added finely powdered La(NO3)3Æ6H2O
(5 mol %) and the reaction was stirred under solvent-free
conditions at room temperature for an appropriate
amount of time (Table 1). After completion of the reac-
tion as monitored by TLC, water was added to the reac-
tion mixture and the product was extracted into ethyl
acetate (3 · 20 mL). The combined organic layer was
washed with brine, dried over anhydrous sodium sulfate
and concentrated under reduced pressure to give a crude
product which was purified by silica gel column chroma-
tography to afford the corresponding N-benzyloxy-
carbonyl protected amines.
Acknowledgements
The authors thank DOD, DBT and CSIR, New Delhi,
India, for the financial support and to the Director,
IICT for his constant encouragement.
In conclusion, we have described for the first time,
lanthanum(III) nitrate hexahydrate as a remarkably
efficient catalyst for Cbz-protection of a wide range of
amines using Cbz–Cl. Aromatic amines containing elec-
tron-withdrawing groups also gave the desired deriva-
References and notes
1. Fieser, L. F.; Fieser, M. In Reagents in Organic Synthesis;
John Wiley & Sons: New York, 1967; Vol. 1, p 109.
Chinni Mahesh
