Development of a novel protocol for chemoselective deprotection of N/O-benzyloxycarbonyl (Cbz) at ambient temperature

Article abstract of DOI:10.1007/s00706-018-2276-x

Abstract: A novel protocol for the deprotection of N-benzyloxycarbonyl and O-benzyloxycarbonyl groups by nickel boride generated in situ from NaBH₄ and NiCl₂·6H₂O in methanol at room temperature has been developed to give the corresponding amines and phenols. This protocol is chemoselective as groups like chloro, bromo, amide, ester, pyridine, and tert-butyloxycarbonyl moiety are unaffected under these conditions. The deprotection has also been validated in gram scale reactions, to establish the wider appropriateness of this protocol. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2276-x

Monatshefte für Chemie - Chemical Monthly
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ORIGINAL PAPER
Development of a novel protocol for chemoselective deprotection
of N/O-benzyloxycarbonyl (Cbz) at ambient temperature
Mohit Saroha1 Komal Aggarwal1 Gaurav Bartwal1 Jitender M. Khurana1
•
•
•
Received: 15 June 2018 / Accepted: 24 July 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
A novel protocol for the deprotection of N-benzyloxycarbonyl and O-benzyloxycarbonyl groups by nickel boride generated
in situ from NaBH4 and NiCl2Á6H2O in methanol at room temperature has been developed to give the corresponding
amines and phenols. This protocol is chemoselective as groups like chloro, bromo, amide, ester, pyridine, and tert-
butyloxycarbonyl moiety are unaffected under these conditions. The deprotection has also been validated in gram scale
reactions, to establish the wider appropriateness of this protocol.
NaBH4
Graphical abstract
NiCl2.6H2
O
XH
O
X
O
R
R
X = NH, O
33 Examples
MeOH, rt
15 min
R = -F, -Cl, -Br, -OH, -OR, -COOMe,
-CONH2, -NH2, -NBoc, -Cbz
Wide functional group tolerance
Mild reaction condition No column chromatography
Less reaction time
Keywords Hydrogenation Á Deprotection Á Heterogeneous catalysis
Introduction
carbohydrates [7]. Benzyloxycarbonyl (Cbz) group is the
most appropriate amine-protecting group and is stable in
both mild acidic as well as in basic conditions. The N-
benzyloxycarbonyl group can be easily introduced gener-
ally by reaction of benzyl chloroformate in presence of a
mild base at room temperature [8]. It reduces the nucle-
ophilic character of the heteroatom and can be deprotected
when required. Several methods have been employed for
the deprotection of Cbz, e.g., palladium-catalysed
hydrogenolysis [9], Bu4NF in THF [10], solvated electrons
[11], BBr3 [12], strong basic hydrolysis [13], zinc/iodine in
methanol [14], catechol boron halides [15], and
trimethylsilyl iodide [16]. Each of these methods has their
own specific applications and there are certain drawbacks
also such as harsh conditions, tedious workup, long reac-
tion time, and expensive reagents.
Protection/deprotection approaches are often mandatory in
synthetic sequences. Amino and phenolic groups are pre-
sent in many starting materials and require protection/de-
protection to achieve the desired goals [1–3]. They have
application in organic synthesis, especially in the fields of
pharmaceuticals [4, 5], peptides [6], nucleotides, and
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-018-2276-x) contains
supplementary material, which is available to authorized
users.
Nickel boride can be readily prepared in situ from
nickel(II) chloride and sodium borohydride in a variety of
solvents and has been used as a reagent in a number of
important reductions. In continuation of our efforts to
& Jitender M. Khurana
jmkhurana1@yahoo.co.in; jmkhurana@chemistry.du.ac.in
1
Department of Chemistry, University of Delhi, Delhi 110007,
India
123

M. Saroha et al.
broaden the scope of nickel boride as an efficient depro-
tection/reducing reagent [17–27], we have investigated the
deprotection of N-benzyloxycarbonyl (Cbz) with nickel
boride generated in situ.
of 1a was then attempted with lower ratio using 1:4:12
molar ratio of 1a:NiCl2Á6H2O:NaBH4 in methanol but was
incomplete even after 60 min and gave 56% of 4-anisidine
after work up and separation (Table 1, entry 7). No
deprotection of 1a to 4-anisidine was observed when the
reactions were performed with nickel chloride or sodium
borohydride separately (Table 1, entries 8, 9). Reaction of
1a was when attempted with equimolar ratio of NiCl2-
6H2O:NaBH4 (1:5:5) in methanol but was incomplete even
after 60 min and gave 18% of 4-anisidine (2a) after work
up and separation (Table 1, entry 10).
Results and discussion
In this paper, we have reported a simple, efficient, and
inexpensive procedure for the deprotection of benzyloxy-
carbonyl (Cbz) protected amines and phenols to the cor-
responding amines and phenols with nickel boride
generated in situ from nickel chloride and sodium boro-
hydride in methanol at ambient temperature. Benzyl
4-methoxyphenylcarbamate (1a) was chosen as the model
reactant to investigate the appropriate conditions for
deprotection of N-benzyloxy carbamates (Table 1). Ini-
tially, the reaction of 1a was carried out with nickel boride
using 1:5:15 molar ratio (reactant:NiCl2Á6H2O:NaBH4) in
different solvents such as dioxane, tetrahydrofuran, ace-
tonitrile, and ethanol. The reactions were sluggish and
resulted in mixture of products after 60 min (Table 1,
entries 1–4). No reaction of 1a was observed in dichlor-
omethane (DCM) using same molar ratio of nickel boride
(Table 1, entry 5). However the reaction of 1a using 1:5:15
molar ratio of 1a:NiCl2Á6H2O:NaBH4 in methanol was
complete in 15 min at room temperature and gave 88% of
4-anisidine (2a) after work up (Table 1, entry 6). Reaction
Therefore, it can be inferred from above results that N-
benzyloxycarbonyl group could be deprotected with nickel
boride generated in situ using 1:5:15 molar ratio of reac-
tant:NiCl2:NaBH4 in methanol at room temperature.
Subsequently, reactions of different Cbz-protected
amines have been investigated with nickel boride in
methanol at room temperature. All the compounds 1a–1x
underwent deprotection successfully using 1:5:15 molar
ratio of reactant:nickel chloride:sodium borohydride. The
reactions were complete in 15 min in methanol at ambient
temperature and gave the corresponding amines 2a–2x in
high yields. All results are listed in Scheme 1.
It is inferred from the above results that the halo groups
(2d–2h), amide group (2v), ester group (2s), methoxy and
methylene dioxy groups (2a, 2r), and pyridine rings (2n,
2o) remained unaffected under these conditions making
this reductive deprotection chemoselective. It can also be
Table 1 Deprotection of 4-methoxyphenyl carbamate (1a) using nickel boride at ambient temperature
Entry
Molar ratio 1a:NiCl2Á6H2O:NaBH4
Solvent
Time/min
Isolated yield of 1a/%
a
1
2
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:4:12
1:5:0
Dioxane
THF
60
60
60
60
60
15
60
60
60
60
–
a
–
a
3
CH3CN
EtOH
–
a
4
–
b
5
DCM
–
6
MeOH
MeOH
MeOH
MeOH
MeOH
88c
56c
7
b
8
–
b
9
1:0:15
1:5:5
–
10
18c
aReaction incomplete and a mixture of products was obtained
bNo reaction
cYield of corresponding aniline
123

Development of a novel protocol for chemoselective deprotection of N/O-benzyloxycarbonyl…
Scheme 1
NH2
NHCbz
NiCl2.6H2O : NaBH4
MeOH, rt
R
R
1a-1x
2a-2x
NH2
NH2
NH2
NH2
N
R
2n, 75%
2l, 94%
NH2
2m, 78%
2a, R = 4-OMe, 88%
2b, R = 4-OH, 86%
2c, R = 4-Me, 79%
2d, R = 4-Br, 81%
2e, R = 4-Cl, 82%
2f, R = 3,4-F2, 83%
2g, R = 4-F,3-Cl, 86%
2h, R = 3,4-Cl2, 89%
2i, R = 4-H, 76%
NH2
NH2
N
2p, 74%
NH2
2q, 76%
2o, 78%
2j, R = 2-NH2, 81%
2k, R = 3,4-Me2, 83%
NH2
NH2
O
O
NH2
O
Me
O
NH2
2t, 72%b
2r. 81%
NH2
H2N
2s, 87%
2u, 86%b
NH2
NH2
NHBoc
= deprotected amino/ hydroxy group
O
HO
2w, 84%
= concomitantly reduced functional
group
NH2
2v, 85%
2x, 85%
inferred that nickel boride chemoselectively deprotected
only the -NCbz group in presence of N-tert-butyloxycar-
bonyl functional group (2x). However, nitro and cyano
underwent concomitant reduction (2t, 2u), and therefore,
required higher molar ratios. Furthermore, the reaction
proceeded very efficiently with aliphatic amines also (2p,
2q) under similar condition and gave the desired amine in
good yield. 4-Aminophenol having both N and O protected
with -Cbz group underwent simultaneous deprotection of
both -Cbz groups to give 4-aminophenol (2w). In case of
benzylamine-Cbz, the isolated product was identified as
benzylamine (2m) (Scheme 2).
deprotection in 15 min to give the corresponding phenols
in high yields. It can be inferred from the above results also
that the chlorine (4d), acetamide (4c), and methylene dioxy
group (4e) remained unaffected under these conditions.
The -OCbz functional group underwent chemoselective
deprotection in presence of N-tert-butyloxycarbonyl func-
tional group (4h). The deprotection seemed to proceed via
hydrogenolysis of benzyl C–O bond rather than a hydrol-
ysis mechanism.
Conclusion
Further, we investigated whether deprotection of phe-
nols protected with Cbz could also be achieved under these
conditions. Therefore, a reaction of benzyl oxycarbony-
lated 2-naphthol was attempted with nickel boride in 1:5:15
molar ratio (reactant:NiCl2:NaBH4) under identical condi-
tions. The reaction was complete in 15 min and gave 85%
of 2-naphthol (4a) after workup.
In conclusion, we have reported nickel boride as an effi-
cient reagent for the reductive deprotection of amine-Cbz
and O-Cbz to give the corresponding amines and phenols.
The conditions are mild, neutral, and tolerate a wide range
of functionalities, including methoxy, methylenedioxy,
ester, amide, and halo group. The deprotection is believed
to occur via hydrogenolysis.
Subsequently, reactions of other phenols protected with
-Cbz were also attempted under identical condition. All
the -Cbz protected phenols underwent complete
123

M. Saroha et al.
OCbz
Scheme 2
NiCl2.6H2O : NaBH4
MeOH, rt
OH
R
R
3a-h
4a-h
OH
OH
OH
HO
O
O
OH
O
N
H
Cl
4e, 88%
4d, 85%
4a, 85%
4b, 82%
4c, 85%
OH
OH
OH
= deprotected amino/ hydroxy group
= concomitantly reduced functional group
NH
O
N
H2N
4g, 89%b
O
4f, 81%
4h, 89%
filtered through a Celite pad (* 2.5 cm) and washed with
methanol (3 9 10 cm3). The solution was concentrated on
a rotavapor and diluted with water (* 50 cm3), followed
by extraction with dichloromethane (3 9 10 cm3). The
combined dichloromethane extract was washed with water
and dried over anhyd. K2CO3. The solvent was removed on
a rotary evaporator and the product was dried. 4-Anisidine
(2a) was obtained as colourless solid in 88% yield.
The products were identified by m.p., IR, and NMR
spectra. The products Scheme 1, entry 24 and Scheme 2,
entry 8 were purified by flash column chromatography on
silica gel using petroleum ether:ethyl acetate (95:5, v/v) as
eluent.
Experimental
All the chemicals were commercial and purchased from
Sigma-Aldrich or Merck and used as received. All the
-NCbz and -OCbz compounds were prepared. Thin layer
chromatography (GF254) was used to monitor reaction
progress. Melting points were measured on Buchi M-560
melting point apparatus. IR (neat) and IR (DCM) spectra
were recorded on a Shimadzu and Bruker FTIR spec-
trophotometer, respectively, and the values are expressed
1
as cm-1. The H NMR and 13C NMR spectra were recor-
ded on Jeol JNM ECX-400P at 400 and 100 MHz,
respectively, using TMS as internal standard. The chemical
shift values are recorded on d scale and the coupling
constants (J) are in Hz.
Acknowledgements M. S. and G. B. thank CSIR, New Delhi, India
for the Grant of SPM Fellowship and JRF and SRF, respectively.
Authors also acknowledge University of Delhi for providing us
University Grant and DST Purse Grant.
General procedure
References
In a typical experiment, benzyl 4-methoxyphenyl carba-
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place and the reaction mixture turned black due to in situ
formation of nickel boride. The progress of the reaction
was monitored by TLC (petroleum ether:ethyl acetate
80:20, v/v). After completion, the reaction mixture was
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