Copper nanoparticles catalyzed N-H functionalization: An efficient solvent-free N-tert-butyloxycarbonylation strategy

Article abstract of DOI:10.1016/j.tetlet.2016.12.091

A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives (NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate, mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino acid esters and amino alcohols were performed without racemization.

Full text of DOI:10.1016/j.tetlet.2016.12.091

Accepted Manuscript
Copper nanoparticles catalyzed N-H functionalization: an efficient solvent-free
N-tert-butyloxycarbonylation strategy
Barnali Deb, Sudipto Debnath, Anindita Deb, Dilip K. Maiti, Swapan Majumdar
PII:
S0040-4039(16)31758-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.091
TETL 48503
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 December 2016
29 December 2016
31 December 2016
Please cite this article as: Deb, B., Debnath, S., Deb, A., Maiti, D.K., Majumdar, S., Copper nanoparticles catalyzed
N-H functionalization: an efficient solvent-free N-tert-butyloxycarbonylation strategy, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.091
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Graphical Abstract
Copper nanoparticles catalyzed N-H functionalization: an
highly
Leave this area blank for abstract info.
efficient solvent-free N-tert-butyloxycarbonylation strategy
Barnali Deba, Sudipto Debnathb, Anindita Deba, Dilip K. Maiti*b and Swapan Majumdara
A chemoselective transformation of amines to tert-butyloxycarbonyl (Boc)
protected derivatives ( NBoc ) is demonstrated using copper nanoparticles
under solvent-free conditions. Simple method, mild conditions, rapid reaction
rate, tolerance of an wide range of functional groups and chiral centers, high
yield, ease recovery and high catalytic turn over are the salient features of this approach.

Tetrahedron Letters
1
Tetrahedron Letters
Copper nanoparticles catalyzed N-H functionalization: an efficient solvent-free
N-tert-butyloxycarbonylation strategy
Barnali Deba, Sudipto Debnathb, Anindita Deba, Dilip K. Maiti*b and and Swapan Majumdara
a Department of Chemistry, Tripura University, Suryamaninagar, 799 022, INDIA
b Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata 700 009, INDIA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives
(NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate,
mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high
catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino
acid esters and amino alcohols were performed without racemization.
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-tert-carbamate
copper nanoparticles
nanocatalysis
N-H functionalization
selectivity
Chemoselective protection of amines plays an important role in
various spheres of synthetic strategy particularly in the peptide
synthesis.1 Among the vast array of available amine protecting
groups, the tert-butoxycarbonyl (Boc) protecting group2 has
demonstrated to be the widely used strategy because of its easy
installation, stability in various reaction conditions and simple
deprotection to achieve the free amine functionality. The
commercially available di-tert-butyl dicarbonate (Boc2O) is
commonly used for the introduction of the Boc group onto amines.
Conventional base-mediated methods3 for the N-Boc protection of
amines have been developed using N,N-dimethylaminopyridine
(DMAP), NaHMDS, K2CO3, NaOH, Et3N and DIPEA. However, the
protection reaction under basic conditions often leads to the
formation of undesirable side products such as isocyanate, urea and
N,N-di-Boc derivatives. Additionally, the unpleasant smell, high
toxicity, requirement of large excess amount and non-recyclability of
these reagents make the methods objectionable especially from the
stand point of sustainable development of chemistry. Recently, some
Lewis acids have also been applied as promoter for this protection
reaction.4 We and others have reported efficient processes for the
transformation of amines to their N-Boc protected derivatives
utilizing ionic liquids (IL) as catalysts.5 Major difficulty associated
with these processes is the less recyclability of the catalysts due to
low recovery of the highly water soluble ILs. In a continuous search
of eco-friendly recyclable catalyst for such transformation we
decided to take the advantages of copper-nanoparticles (Cu-NPs)
because of its ease fabrication, large reactive surface, highly
dispersed nature and simple recovery. Cu-NPs is one of the classic
metal nanomaterials6 that have received considerable attention in the
in many research and applied fields. Herein, we wish to disclose a
chemoselective and highly efficient nanocatalysis approach for the
tert-butylcarbamate (N-Boc) formation of amines under solvent-free
conditions using Cu-NPs as a recyclable catalyst (Scheme 1).
Scheme 1: Cu-NPs catalyzed N-Boc protection of amines
A number of methods are available for the preparation of Cu-
NPs such as in situ chemical synthesis,7 reduction of aqueous copper
salts,8 micro-emulsion,9 reverse micelles,10 hydro-thermal,11
electrolytic techniques by controlling electrode potential12 and the
polyol process13 or sonochemical method.14 However for our study
we have prepared Cu-NPs from copper sulphate solution using
ascorbic acid as reducing agent as well as capping agent with slight
modification of the fabrication protocol described by Liu et al.15 In a
typical experiment copper sulphate pentahydrate (6.25g, 25 mmol)
was dissolved in deionized water (15 mL) with stirring until a clear
blue solution was obtained, which was added to the solution of
ascorbic acid (9.685g, 55 mmol) in deionized water (25 mL) at once.
Instantly a deep greenish black colour was obtained. The resulting
solution was kept for 12h at room temperature or heated under inert
atmosphere for 10 min. The precipitated Cu-NPs were collected
through filtration, washed with deionized water and absolute alcohol
successively followed by drying under vacuum. Formation of the
NPs was verified by recording UV-Vis spectrum of material
dispersed in water, which showed the symbolic peak of the Cu-NPs
at 480.21nm (Fig. 1a). Dimension of the NPs was initially
past two decades due to its unusual properties and found applications
———
 Corresponding author. Tel: +91-381-237-9070; Fax: +91-381-2374802; e-mail: smajumdar@tripurauniv.in

2
Tetrahedron Letters
determined as 1-2nm (Fig. 1b) using water solution of the
nanomaterials in the dynamic light scattering (DLS). Transmission
electron microscope (TEM) imaging (Fig. 1c) of the Cu-NPs showed
formation of spherical nanomaterials having maximum population at
2.2nm (Fig. 1d, histogram).
min at ambient temperature to achieve the desired N-Boc protected
aniline (2a) in 95% yield (Table 1, entry 1). The reaction was carried
out with the increase in amount of Cu-NPs (15 mol%), which did not
improve the yield (Table 1, entry 2). On decreases the quantity (8
mol%) of the catalyst slowed down the reaction rate (30 min) with
reduction of yield (92%, Table 1, entry 3). A little conversion was
observed even after longer period of time, when the reaction was
carried out in the absence of the catalyst (Table 1, entry 4). To our
surprise commercially available copper powder facilitated the N-Boc
protection reaction and afforded 2a in 43% yield after 1.5h (Table 1,
entry 5). Identity of N-Boc in 2a was ascertained by spectroscopic
analyses (NMR and FTIR). A symbolic absorption band at 1689 cm-1
(sharp peak) in the FTIR spectrum, proton NMR signal at  1.50
ppm (singlet) and 13C NMR signals at  152.8, 85.2/ 80.4 (rotomer)
and 28.3/27.4 (rotomer) were observed for the N-Boc group in 2a.
Next we investigated the catalytic turnover of the recovered Cu-NPs
from the post reaction mixture and reused for subsequent trial runs.
We have used the recovered up to four times. The results indicated
that the recycle Cu-NPs were very effective without noticeable loss
of catalytic activity (Table 1, entry 6).
480.21 nm
0.07
a
0.06
0.05
0.04
450
460
470
480
490
500
Wavelength (nm)
b
1.6nm
Table 1: Survey of N-Boc protection nanocatalysis using Cu-NPs
Entry Catalyst (mol%)
Time (min)
Yield (%)a
1
2
3
4
5
6
Cu-NPs (10)
Cu-NPs (15)
Cu-NPs (8)
None
10
10
30
90
90
10
95
95
92
21
43
Cu powder (10)
Cu-NPs (10)b
95, 94, 92, 92
c
aYields refer to isolated pure 2a; b recycled Cu-NPs.
With this optimized process in hand (Table 1, entry 1), the
efficacy of our nanocatalysis protocol was evaluated using various
amines (1) with Boc2O under solvent-free benign conditions. The
scope of the novel approach is illustrated in Scheme 2. The reaction
was general for amines bearing aromatic, heteroaromatic, aliphatic
and bi-functional residues. For aryl amines the reaction rate depends
on the nature of substitutions as well as their relative positions in the
aromatic rings. p-Toluidine reacted with Boc2O in a little slower rate
(25 min) at room temperature and yielded 84% of the desired product
o
2b (Scheme 2). While under heating conditions (70 C) yield (94%)
and reaction rate (10 min) were significantly improved. Similarly the
reaction of o-toluidine with Boc2O was afforded 2c in excellent yield
(96%) at 70 oC in a slower rate (25 min). It might be due to the steric
hindrance of the o-substituent present in the aromatic ring, which
prevented easy attack to one of the carbonyl group of Boc2O. Other
aromatic amines such as 1-amino naphthalene, N-phenyl-N-benzyl
amine, benzimidazole and 2-methyl benzimidzole were converted
into the corresponding N-Boc derivatives (2d, 2f, 2h-i) in high to
d
o
excellent yields at 70 C because of their very slow reaction rate at
room temperature. The reaction of imidazole, benzylamine,
dodecylamine and secondary aliphatic amines like pyrrolidine,
morpholine, dibenzyl amine and piperazine bearing one or two
amine groups rapidly provided the desired products 2g (99%), 2j
(87%), 2k (95%), 2l-p (80, 96%, 89% and 87%), respectively at
room temperature. Unfortunately sterically hindered diphenyl amine
failed to furnish any yield even after prolonged heating at 70 oC.
After successful exploration of efficient protocol for N-Boc
protection of various aromatic, hetero-aromatic as well as aliphatic
amines by the Cu-nano catalysis we turned our attention to the
Figure 1: Characterization of Cu-NPs: (a) UV-Vis spectrum, (b) DLS data;
(c) TEM image; (d) dimension histogram of the particle from TEM image.
Initially we have targeted aniline (1a) as a model substrate for the
N-Boc protection reaction with Boc2O in the presence of different
amount of Cu-NPs under solvent-free conditions. The results were
summarized in Table 1. Gratifyingly, reaction of aniline (1a) with
Boc2O was completed in the presence Cu-NPs (10 mol%) within 10

Tetrahedron Letters
3
compatibility and selectivity of Cu-NP’s approach in the presence
R2
O
O
O
R2
of other functionalities such as alcohol, phenol, thiol and ester group.
In our earlier investigation5a we have reported that phenols, alcohols
or thiols proceeded for Boc protection using protic ionic liquid as
catalyst at elevated temperature. In contrast to it, our present studies
indicated that the Cu-NPs catalyzed Boc protection method is very
much selective to amine functional group only (Table 2). Phenol,
benzyl alcohol and benzyl thiol were inert to Boc2O under the
reaction conditions. Thus amine functional group can selectively
protected by Boc group in the presence of other functional group e.g.
3-amino phenol, 3-amino-1-propanol and 4-nitroaniline (entries 1-3,
Table 2), were efficiently converted in to the corresponding N-Boc
protected derivative without effecting the other potential functional
groups. To our delight one of the amino groups of o-
phenylenediamine can also be efficiently protected using 1
equivalent Boc2O and catalyst Cu-NPs under solvent-free conditions
to produce desired product in 90% yield (entry 4, Table 2). In any
cases, N,N- or N,O-di-Boc were not detected, which confirmed the
excellent chemoselective nature of the strategy. In the cases of chiral
amine such as amino alcohols (3e-g) and amino esters (3h-i) all
furnished N-Boc protected products (4e-i) without racemization at
the chiral centers under the mild reaction conditions (entries 5-9,
Table 2). The N,N-Di-Boc derivative of amine is useful for many
synthetic protocols. Thus, we examined our chemoselective
protection approach for N,N-Di-Boc formation reaction using
PhCH2NHBoc (2j) with Boc2O in the presence of Cu-NPs (10
Cu-NPs (10 mol%)
N
NH
+
Solvent-free, rt/70 0C,
5-120 min, 80-99%
R1
O
O
O
O
R1
1 (1 mmol)
2
1.2 mmol
NHBoc
2b
NHBoc
2b
NHBoc
2c
25 min, rt, 84%; 10 min, 70 oC, 94%;
25 min, 70 oC, 96%;
Ph
Boc
N
N
N
Ph
N
Boc
NHBoc
2e
2d
2g
2f
Boc
2 h, 70 oC, 98%; 2 h, 70oC, 90%; 1 h, 70 oC, 80%; 10 min, rt, 99%;
N
N
NHBoc
N
N
2i
2h Boc
2j
Boc
5min, 70 oC, 97%; 5min, 70 oC, 97%; 5min, rt, 87%; 5min, rt, 95%
Ph
O
N Boc
N Boc
2l
N
Boc
2m
2n
Ph
10 min, rt, 80%; 5 min, rt, 96% ; 5 min, rt, 89%.15 min, rt, 87%
Scheme 2: Cu-NPs catalyzed N-Boc protection of aromatic and
aliphatic amines
Table 2: Chemoselective Boc protection of phenols, amino alcohols, chiral aminoacids and esters
Entry
1
Substrate (3)
NH2
3a
Product (4)
NHBoc
4a
Temp. (oC)
Time (min.)
5
Yield (%)
86
70
HO
HO
HO
HO
2
rt
20
98
NH2
NHBoc
4b
3b
O2N
NH2
3c
O2N
NHBoc
4c
3
4
5
70
rt
600
60
60
90
NH2
NH2
NH2
NHBoc
OH
3d
4d
OH
rt
rt
10
10
87
96
NH2
NHBoc
4e
3e
OH
OH
6
NHBoc
4f
NH2
3f
OH
NHBoc
OH
4g
7
8
9
rt
rt
10
60
10
97
94
87
NH
3g
2
CO2Et
NH2
CO2Et
NHBoc
Ph
3h
Ph
4h
70
N
CO2Bn
N
CO2Bn
NHBoc
Boc
H
4i
3i
2j
10
70
60
NR
N(Boc)2
4j

4
Tetrahedron
1. Aromatic 1o vs Aliphatic 1o
may be explained due to the highly chemoselective nature of the
polarized surface of the Cu-NPs. Although commercially available
bulk copper powder showed some activity towards N-Boc protection
under solvent-free conditions, but the progress of the reaction is not
satisfactory due to lack of highly polarized reactive surface, which is
the signature of Cu-NPs.
NHBoc
NH2
NH2
NHBoc
Boc2O (1mmol)
(1)
+
+
Cu-NP's (10 mol%)
rt
2j (100%)
1j (1mmol)
2a (0%)
1a (1mmol)
2. Aromatic 1o vs Aromatic 2o
NH2 NHBn
General procedure for N-tert-butoxycarbonylation of amines
To a mixture of amine (1.0 mmol) and (Boc)2O (1.2 mmol) copper
nano particles (0.1 mmol) was added with vigorous stirring at room
N(Boc)Bn
NHBoc
+
Boc2O (1mmol)
(2)
+
o
temperature or 70 C for the appropriate time (Scheme 2 and Table
Cu-NP's (10 mol%)
rt
2) until total disappearance of the amines was observed in the TLC
monitoring. After completion, the reaction mixture was diluted with
dry ether (5 mL) and catalyst was separated by centrifugation and the
residue was washed with ether. The combined filtrate was
evaporated to dryness and dried under vacuum. The N-Boc product
was essentially pure but for getting analytical data the sample was
passed through silica-gel (100-200 mesh) column using 10-30%
ethyl acetate in hexane as eluent. The physical data (m. p., FTIR,
NMR, optical rotation) of the known compounds were found to be
identical with those reported in the literature (ESI).
1f (1mmol)
1a (1mmol)
2a (100%) 2f (0%)
3. Aliphatic 1o vs Aliphatic 2o
NHBn
Boc2O (1mmol)
NH2
NHBoc
+
N(Boc)Bn
(3)
+
Cu-NP's (10 mol%)
rt
2j (100%)
1j (1mmol) 1n (1mmol)
2n (0%)
Scheme 3: Competitive N-Boc protection reaction
Acknowledgments
mol%) at 70 oC for 1h, but no reaction was occurred (entry 10, Table
2).
Financial supports by Council of Scientific and Industrial
Research (CSIR), Govt. of India is gratefully acknowledged
(Project no. 02(0235)/15/EMR-II).
The chemoselectivity of the process was also established by
conducting competitive N-Boc protection reactions using a mixture
of compounds bearing two non-identical amine groups of different
chemical nature. For example, a mixture (1:1) of aromatic primary
amine, aniline (1a) and aliphatic primary amine, benzylamine (1j)
was exposed to Boc2O (1 mol) in the presence of Cu-NPs catalyst at
room temperature (eq. 1, Scheme 3). Surprisingly it produced the
product 2j (Scheme 1) through 100% conversion of 1j keeping intact
the other aromatic amine 1a. The reaction was highly chemoselective
to aromatic primary amine (1a) for the N-Boc protection at ambient
temperature with respect to aromatic secondary amine, N-
benzylaniline 1f (eq. 2, Scheme 3). Similarly treatment of a mixture
(1:1) of aliphatic 1o amine (1j) and aliphatic 2o amine, dibenzyl-
amine (1n) with Boc2O (1 mol), only the primary amine 1j was
derivatized, where as the secondary one (1n) of slightly different
chemical nature remained unreacted (eq. 3, Scheme 3).
Notes and references
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R1
N H
R2
R1
R1
H
Cu-NP
N
R2
O
O
N
O
O
R2
O
O
O
O
+
H
O
H
O
O
O
Boc-OH
O
R1
O
O
Boc2O
N
R2
CO2 + t-BuOH
Scheme 4: Possible catalytic cycle for N-Boc protection
The catalytic pathway for the highly chemoselective Boc
derivatization of amines is unknown to us. However it is expected
that the strongly polarized and reactive surface of Cu-NPs first
performs the N-H insertion of Cu(0) on the catalytic surface of the
small NPs (Scheme 4). The reactive Cu-N bond immediately inserted
in to one of the Boc2O-carbonyl center. Subsequent release of the N-
Boc protected product and BocOH with regeneration of Cu-NPs
complete the catalytic cycle. Selectivity of this protection strategy

Tetrahedron Letters
5
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6
Tetrahedron
Title of the manuscript: Copper
nanoparticles catalyzed N-H
functionalization: an efficient solvent-free
N-tert-butyloxycarbonylation strategy”
Authors: Barnali Deb, Sudipto Debnath,
Anindita Deb, Dilip K. Maiti and Swapan
Majumdar
Submitted to Tetrahedron Letters
HIGHLIGHTS
 Cu-NP’s catalyzed N-H
functionalization to t-
butyloxycarbamate synthesis.
 Highly chemoselective method for t-
butyloxycarbonyl protection of
amines
 Polarized and reactive surface of Cu-
NP’s mediated Boc protection of
amines.