A Greener Approach for the Chemoselective Boc Protection of Amines Using Sulfonated Reduced Graphene Oxide as a Catalyst in Metal- And Solvent-Free Conditions

Article abstract of DOI:10.1055/s-0039-1690239

Sulfonated reduced graphene oxide (SrGO) has displayed great potential as a solid acid catalyst due to its efficiency, cost-effectiveness, and reliability. In this study, SrGO was synthesized by the introduction of sulfonic acid-containing aryl radicals onto chemically reduced graphene oxide using ultrasonication. The SrGO catalyst was characterized by Fourier Transform Infrared (FTIR) spectroscopy, Raman spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM). Further, SrGO was effectively utilized as a metal-free and reusable solid acid catalyst for the chemoselective N - t -Boc protection of various aromatic and aliphatic amines under solvent-free conditions. The N - t -Boc protection of amines was easily achieved under ambient conditions affording high yields (84-95percent) in very short reaction times (5 min-2 h). The authenticity of the approach was confirmed by a crystal structure. The catalyst could be easily recovered and was reused up to seven consecutive catalytic cycles without any substantial loss in its activity.

Full text of DOI:10.1055/s-0039-1690239

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–K
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R. Mittal et al.
Paper
Synthesis
A Greener Approach for the Chemoselective Boc Protection of
Amines Using Sulfonated Reduced Graphene Oxide as a Catalyst in
Metal- and Solvent-Free Conditions
Rupali Mittal
Anupam Mishra
Satish K. Awasthi*
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Chemical Biology Laboratory, Department of Chemistry,
University of Delhi, Delhi 110007, India
satishpna@gmail.com
This research article is dedicated to Prof. S. Chandrasekaran,
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India on the occasion of his 74th birthday
Received: 07.08.2019
Accepted after revision: 14.10.2019
Published online: 06.11.2019
(Boc)2 is popularly used for masking amines with tert-bu-
toxycarbonyl (Boc) group. Conventionally, several base-me-
diated strategies like the reaction of amine with (Boc)2 in
the presence of DMAP,5 2-tert-butyloxycarbonyloxyimino-
2-phenylacetonitrile in the presence of Et3N in H2O–1,4-di-
oxane,6 4-dimethylamino-1-tert-butoxycarbonylpyridini-
um chloride/tetrafluoroborate in aqueous NaOH,7 tert-
butyl-2-pyridyl carbonate in the presence of Et3N in H2O–
DMF,8 and tert-butyl-1-chloroalkyl carbonates in the pres-
ence of K2CO3 in H2O–THF9 have been used. These proce-
dures are associated with several setbacks such as toxicity
of DMAP,10 particular efforts required for the preparation of
tert-butoxycarbonylation reagents,6–9 formation of side
products like urea,5d isocyanates11 and N,N-di-Boc deriva-
tives.12 There have been reports where catalysts like -cy-
clodextrin in water13 and NaI in THF14 have been used. Also,
in the past few years, several Lewis acid mediated proce-
dures15 have been reported. Lewis acid mediated protocols
have a major problem of non-recoverability and non-reus-
ability. Recently, heterogeneous catalysts like sulfonic-acid-
functionalized silica,16 Montmorillonite K10 and Montmo-
rillonite KSF,17 ZnO nanorods,18 Amberlyst® A21,19
V2O5/SnO2,20 etc. have been used for the N-t-Boc protection
of amines. These catalysts can be easily recovered and recy-
cled. There have also been reports where solvent-free18–
DOI: 10.1055/s-0039-1690239; Art ID: ss-2019-m0442-op
Abstract Sulfonated reduced graphene oxide (SrGO) has displayed
great potential as a solid acid catalyst due to its efficiency, cost-effec-
tiveness, and reliability. In this study, SrGO was synthesized by the intro-
duction of sulfonic acid-containing aryl radicals onto chemically re-
duced graphene oxide using ultrasonication. The SrGO catalyst was
characterized by Fourier Transform Infrared (FTIR) spectroscopy, Raman
spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric
analysis (TGA), scanning electron microscopy (SEM), energy dispersive
spectroscopy (EDS) and transmission electron microscopy (TEM). Fur-
ther, SrGO was effectively utilized as a metal-free and reusable solid
acid catalyst for the chemoselective N-t-Boc protection of various aro-
matic and aliphatic amines under solvent-free conditions. The N-t-Boc
protection of amines was easily achieved under ambient conditions af-
fording high yields (84–95%) in very short reaction times (5 min–2 h).
The authenticity of the approach was confirmed by a crystal structure.
The catalyst could be easily recovered and was reused up to seven con-
secutive catalytic cycles without any substantial loss in its activity.
Key words Boc protection, sulfonated reduced graphene oxide, sol-
vent-free, metal-free, heterogeneous catalysis
A wide range of biologically active compounds contain
amine groups, which makes their protection and deprotec-
tion an attractive and widely used strategy in organic and
medicinal chemistry.1 With the discovery of peptide nucleic
acids (PNAs) by Nielsen, protecting groups that are compat-
ible with Fmoc-mediated solid-phase synthesis and which
can be removed under acidic or neutral conditions are re-
quired.2 Boc protection strategy fits this criterion perfectly,
because it can withstand mild acidic as well as neutral con-
ditions, also it is stable against nucleophiles under basic
conditions.3 It can be further extended to the synthesis of
DNA-peptide conjugates.4 The commercially available
or catalyst-free23,24 conditions have been employed.
20,21,22
Looking at the environmental concerns attached with the
use of metals, some metal-free13,19,25 protocols have been
reported in the literature. Interestingly, Chakraborti and co-
workers reported organocatalysis by ionic liquids based on
1-alkyl-3-methylimidazolium cation for chemoselective
N-tert-butyloxycarbonylation of amines.25 Though, these
methods have proven to be valuable but keeping in per-
spective the frequent applications of N-tert-butyloxycarbo-
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R. Mittal et al.
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nylation in the preparation of small molecules and pep-
tides, and usefulness in biochemistry, there is still a re-
quirement of new and finer catalytic systems.
SO3H
GO
O
O
H
N
O
R
NH2
+
R
O
O
O
solvent-free, RT
5 min–2 h
O
amine (1)
Boc anhydride (2)
N-t-Boc protected
amine (3)
Since 2004, articles on graphene research have prolifer-
ated indefinitely. Graphene- and graphene oxide (GO)-
based materials have displayed interesting mechanical, op-
tical, and physical properties.26,27 Besides, because of their
large specific surface area, high surface-to-volume ratio,28
thermal and chemical stability, they have been successfully
utilized as supports for organic transformations. Over the
years, solid acid catalysts have become quite popular envi-
ronment-friendly replacements for conventional homoge-
neous liquid acid catalysts.29 In this regard, sulfonated car-
bon-based materials have been significantly put to use for
many organic syntheses.30 Thus, the current popularity of
GO-based materials inspired us to exploit solid acid poten-
tial of sulfonated reduced graphene oxide (SrGO) as a met-
al-free catalyst for the N-t-Boc protection of amines. In lit-
erature, there is no report that discusses the use of
graphene- or GO-based material as a catalyst for the N-t-
Boc protection of amines.
In this article, we report an efficient method for metal-
andsolvent-free, chemoselectiveN-tert-butyloxycarbonyla-
tion of amines using sulfonated reduced graphene oxide
(SrGO) as a heterogeneous solid acid catalyst at room tem-
perature (Scheme 1).
The sulfonated reduced graphene oxide (SrGO) was syn-
thesized by grafting sulfonic acid-containing aryl radicals
onto chemically reduced graphene oxide through ultrasonic
irradiation (Figure 1). The detailed synthetic procedures can
be found in the experimental section. SrGO catalyst was
characterized by Fourier transform infrared (FTIR) spec-
troscopy, Raman spectroscopy, powder X-ray diffraction
R = aromatic or
aliphatic
Scheme 1 Boc protection of amines using SrGO as catalyst
(PXRD), thermogravimetric analysis (TGA), scanning elec-
tron microscopy (SEM), energy dispersive spectroscopy
(EDS) and transmission electron microscopy (TEM).
The chemical environment over SrGO was characterized
using FTIR spectroscopy. For comparison, Figure 2 (a) de-
picts FTIR spectra of GO, SrGO, and reused SrGO. The FTIR
spectrum of GO shows peaks at 3429, 1729, 1633, and 1084
cm–1, which can be attributed to O–H stretching mode, C=O
for carbonyl and carboxylic acid, C=C stretching mode, and
C–O (epoxy) stretching mode, respectively. The FTIR spec-
trum of SrGO suggests chemical changes during the sulfon-
ation process. The increased intensity of O–H peak suggests
increase in hydroxyl groups due to SO3H groups.31,32 Fur-
ther, the decreased intensity of carbonyl peak at 1729 cm–1
in SrGO depicts partial reduction of GO during sulfonation
process.33 The peak at 1633 cm–1 in SrGO indicates partial
restoration of aromatic network of GO during chemical
modification.31,32 The emergence of sharp peaks at 1383
and 1204 cm–1 due to S=O symmetric and asymmetric
stretching modes, respectively, verifies the existence of sul-
fonic groups on the surface of SrGO. Moreover, the peaks at
630 and 616 cm–1 due to S–O and S–C stretching modes, re-
spectively, confirms the presence of covalent sulfonic acid
Figure 1 Schematic diagram for the preparation of GO and SrGO
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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Figure 2 (a) FTIR spectra of GO, SrGO, and reused SrGO; (b) Raman spectra of GO, SrGO, and reused SrGO; (c) XRD pattern of GO, SrGO, and reused
SrGO; (d) TGA curves of GO and SrGO.
groups on the SrGO surface.33 Further, no modifications
were observed in the FTIR spectrum of SrGO reused for sev-
en consecutive catalytic cycles.
26.8° with interlayer spacing of 0.56 nm was observed. The
narrower interlayer spacing upon sulfonation implies
restacking of GO nanosheets more tightly through – in-
teractions.36 The XRD pattern for SrGO reused for seven
consecutive catalytic cycles was similar to that of SrGO, im-
plying no modifications in its crystalline structure.
Raman spectroscopy is one of the most significant char-
acterization for carbon materials. The Raman spectra for
GO, SrGO, and reused SrGO is depicted in Figure 2 (b). The
two characteristic peaks at 1350 and 1595 cm–1 for GO and
at 1312 and 1544 cm–1 for SrGO correspond to the D and G
band, respectively. The D band arises due to the vibration of
sp3 carbon atoms of defects as well as disorder, whereas the
G band is a result of the vibration of sp2 carbon atoms in
graphitic hexagonal lattices.34,35 The ID/IG ratio for SrGO
(1.18) > GO (1.16), implying that some of the oxygenated
groups were removed by NaBH4 during ultrasonication. The
ID/IG ratio for SrGO reused for seven consecutive catalytic
cycles was found to be 1.165.
The XRD patterns acquired for GO, SrGO, and reused
SrGO are shown in Figure 2 (c). For GO, single diffraction
peak at 2θ = 10.8° corresponding to (001) plane with inter-
layer spacing of 0.79 nm is observed. This confirms the for-
mation of GO by oxidation of graphite using Hummer’s
method.32 After partial reduction of GO with NaBH4 fol-
lowed by grafting of sulfonic acid containing aryl radicals,
the characteristic peak corresponding to (002) plane at 2θ =
The thermal stability of both GO and SrGO was explored
using thermogravimetric analysis. The obtained thermo-
gravimetric analysis curves for both GO and SrGO are illus-
trated in Figure 2 (d). For GO, an overall weight loss of 58% is
observed in three successive steps. First, due to vaporiza-
tion of adsorbed water molecules, a steady weight loss of 9%
occurs at around 100 °C. Then, due to the decomposition of
oxygen-containing groups, a rapid weight loss of 29% oc-
curs in the temperature range of 100–210 °C. Finally, due to
pyrolysis of carbon skeleton of GO, a weight loss of 20% oc-
curs in the temperature range of 210–800 °C. For SrGO, in
the same temperature range an overall weight loss of ca.
25% occurs in four successive steps. First, a weight loss of
14% occurs at around 280 °C, followed by slower decrease in
weight loss of total 11% in three successive steps, over a
temperature range of 280–800 °C. The weight loss due to
the decomposition of sulfonated groups of SrGO could be
observed in the temperature range of 400–600 °C.31
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Synthesis
Figure 3 (a), (b), and (c) TEM images of GO, SrGO, and reused SrGO, respectively; (d) and (e) SEM images of GO and SrGO, respectively; (f) EDX analysis
spectra of SrGO.
The morphological characteristics of GO and SrGO were
tested through TEM and SEM analysis, depicted in Figure 3
(a,b and d,e, respectively). The TEM image of GO illustrated
in Figure 3 (a) shows the overlapped sheet-like morphology.
The SEM image of GO depicted in Figure 3 (d) shows the
wrinkled sheet-like morphology. Both TEM and SEM analy-
sis suggest that the microstructure of GO nanosheets was
preserved even after the sulfonation process, depicted in
Figure 3 (b and e, respectively). The TEM image of SrGO re-
used for seven consecutive catalytic cycles depicted in Fig-
ure 3 (c) shows no morphological modifications.
The EDS elemental analysis of both GO (Figure S1 in SI)
and SrGO [Figure 3 (f)] was performed. The sulfur content
of 7.24 atomic% or 14.66 wt% in SrGO suggests the success-
ful grafting of sulfonic acid groups on the surface of GO.
After the successful characterization of GO and SrGO,
the catalytic potential of the as synthesized SrGO was eval-
uated for the Boc protection of amines. Morpholine was se-
lected as the model substrate. To achieve the optimum reac-
tion conditions, influence of different criterions like the
amount of catalyst, solvent, temperature, and reaction time
were studied for N-t-Boc protection of morpholine in the
presence of SrGO catalyst. The results are summarized in
Table 1.
To test the role of the catalyst in the N-t-Boc protection
of amines, the reaction was carried out in the presence of
GO (5 mg) and SrGO (5 mg) at room temperature under sol-
vent-free condition; the obtained N-t-Boc protected mor-
pholine was isolated in 72% and 89% yield in 1 hour and 10
minutes, respectively (Table 1, entries 5, 6). The comparison
between entries 1, 5, and 6 clearly indicates the vital role of
SrGO as a catalyst in N-t-Boc protection of morpholine be-
Table 1 Optimization of Reaction Conditionsa
Entry Catalyst amount (mg) Conditions
Time
Yield (%)b
1
2
–
Solvent-free, RT
DCM, RT
48 h
42
54
45
51
72
89
87
85
79
78
83
64
93
94
–
48 h
3
–
CH3CN, RT
48 h
4
–
CH3CN, reflux
solvent-free, RT
solvent-free, RT
DCM, RT
48 h
5
GO (5)
SrGO (5)
SrGO (5)
SrGO (5)
SrGO (5)
SrGO (5)
SrGO (5)
SrGO (2.5)
SrGO (7.5)
SrGO (10)
1 h
6
10 min
11 min
30 min
40 min
25 min
12 min
25 min
10 min
10 min
7
8
EtOH, RT
9
1,4-dioxane, RT
CH3CN, RT
10
11
12
13
14
First, the reaction performed between morpholine (1
mmol) and (Boc)2O (1 mmol) in the absence of catalyst at
room temperature under solvent-free condition, in di-
chloromethane (DCM), in acetonitrile, and under reflux in
acetonitrile, could afford the corresponding N-t-Boc pro-
tected morpholine in only 42%, 54%, 45%, and 51% yield af-
ter 48 hours, respectively (Table 1, entries 1–4).
CH3CN, reflux
solvent-free, RT
solvent-free, RT
solvent-free, RT
a Reaction conditions: morpholine (1 mmol), (Boc)2O (1 mmol), solvent (2
mL), and catalyst (mg).
b Isolated yields.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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Synthesis
cause substantial decrease in reaction time with increase in
yield was observed. Moreover, better catalytic activity of
SrGO over GO was expected because of the enhanced acidic
character of SrGO due to the presence of sulfonic acid
groups on its surface. Next, the reaction was performed us-
ing SrGO (5 mg) at room temperature in DCM, ethanol, 1,4-
dioxane, acetonitrile, and under reflux in acetonitrile; tert-
butyl morpholine-4-carboxylate was obtained in 87%, 85%,
79%, 78%, and 83% yield after 11 minutes, 30 minutes, 40
minutes, 25 minutes, and 12 minutes, respectively (entries
7–11). The comparison between entries 6–11 indicates that
the best conditions for the reaction to take place are at
room temperature under solvent-free condition. Further, to
optimize the amount of catalyst, the reaction was tested us-
ing lower amount of SrGO (2.5 mg) at room temperature
under solvent-free condition, which gave the desired prod-
uct in only 64% yield after 25 minutes (entry 12). Next,
higher amounts of SrGO (7.5 mg and 10 mg) was tested at
room temperature under solvent-free condition, which re-
sulted in 93% and 94% yield after 10 minutes, respectively
(entries 13, 14). Increasing the amount of SrGO from 7.5 mg
to 10 mg did not have any significant influence on the reac-
tion time and product yield, therefore, it could be concluded
that 7.5 mg of SrGO was the required amount of catalyst to
yield the best results. Thus, by summing up the above re-
sults, 7.5 mg of SrGO catalyst at room temperature under
solvent-free condition were found to be the optimal condi-
tions for the N-t-Boc protection of amines.
In the present study, the scope of the reaction was ex-
panded to aromatic and aliphatic secondary amines
(Scheme 1) to produce the corresponding N-t-Boc protected
amines under the optimized reaction conditions (Table 1,
entry 13). The results are summarized in Table 2. The sub-
strates readily produced N-t-Boc protected derivatives with
sufficiently high yields in 5 minutes to 2 hours without the
formation of any side or waste products. The aromatic sub-
strates with electron-donating groups 3d,e, 3l–n readily at-
tained N-t-Boc protected derivatives in excellent yields (87–
95%) whereas for the aromatic substrates with electron-
withdrawing groups 3i–k, the reaction was sluggish and af-
forded the N-t-Boc protected derivatives in slightly lower
yields (84–88%). This might be because of the introduction
of electron-withdrawing group, which rendered amine less
nucleophilic. The aliphatic secondary amines 3a–c smooth-
ly produced the corresponding N-t-Boc protected deriva-
tives in good yields (91–93%). The chemoselectivity was
demonstrated by the substrates containing sensitive groups
like phenol and thiophenol 3o and 3p, which also success-
fully yielded N-t-Boc protected derivatives in desirable yield
of 93% and 87%, respectively, without the formation of O/S-
t-Boc protected products. Further, the substrates containing
two primary amine groups 3f–h resulted in N-t-Boc protec-
tion of a single amine group in excellent yields (94–95%).
We tested the selectivity of SrGO for mono-N-t-Boc protec-
tion in the case of ethylenediamine by increasing the
amount of (Boc)2 to 1.2, 1.5, and 2.0 mmol. Interestingly, in
all the cases, mono-N-t-Boc protected product 3f was
Table 2 SrGO-Catalyzed N-t-Boc Protection of Aminesa,b
SO3H
GO
H
O
O
N
O
R
NH2
+
R
O
O
O
solvent-free, RT
O
O
O
O
O
O
O
NH
O
H
O
N
N
HN
N
N
O
H2N
NH
O
O
O
O
3b
3c
3d
3f
3a
10 min, 93%
3e
15 min, 87%
15 min, 92%
20 min, 91%
8 min, 93%
5 min, 94%
O
O
H
N
O
O
NH
O
H2N
NH
O
NC
NH
O
O
H3C
O
O
O
N
H
O
NH2
3g
3h
3i
3j
3k
7 min, 95%
12 min, 94%
24 h, N.R.
2 h, 84%
3 h, 88%
S
NH
O
NH
O
N
HO
NH
O
NH
H3CO
NH
O
NH
HS
O
N
O
O
O
O
O
O
O
O
3l
30 min, 95%
3m
30 min, 89%
3n
1 h, 90%
3o
1 h, 93%
3p
1 h, 87%
3q
2 h, 91%
Crystal Structure
a Reaction conditions: Amine (1 mmol), (Boc)2O (1 mmol), SrGO (7.5 mg), RT.
b Isolated yields. Products were characterized using 1H NMR, 13C NMR, mass, and IR spectroscopy.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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achieved. It was observed that the reaction between 2′-ami-
noacetophenone and (Boc)2O could not afford the corre-
sponding N-t-Boc protected derivative 3i even after the re-
action time was extended upto 24 hours whereas the reac-
tion between 4′-aminoacetophenone and (Boc)2O readily
produced the corresponding N-t-Boc protected derivative 3j
with adequate yield (84%) in 2 hours. This is anticipated due
to the steric hindrance caused by the bulky acetyl group at
the ortho-position.
The obtained N-t-Boc protected derivatives were ana-
lyzed by 1H NMR, 13C NMR, mass, and IR spectroscopy.
Moreover, the authenticity of this approach was confirmed
by the X-ray analysis of compound 3q. For the current
study, X-ray quality single crystals of compound 3q were
grown in ethyl acetate at room temperature by slow evapo-
ration of solution growth method. Figure 4 shows the OR-
TEP diagram and unit cell packing of the compound 3q. The
compound 3q crystallized in monoclinic cell and space
group P21/c with the following lattice parameters: a =
6.2520 (9) Å, b = 22.958 (4) Å, c = 8.8269 (12) Å,  = 90°,  =
94.667° (14),  = 90°, V = 1262.8 (3) Å3, and  (calculated) =
1.317 g cm–3.
The role of sulfonated reduced graphene oxide as a cata-
lyst for the N-t-Boc protection of amines can be explained
through the proposed mechanism in Scheme 2. The hydro-
gen bond formation between the sulfonic acid groups of the
SrGO catalyst and oxygen atoms of the carbonyl groups of
(Boc)2O lead to the ‘electrophilic activation’ of the carbonyl
Figure 4 ORTEP diagram and unit cell packing of compound 3q
groups. This electrophilic activation makes carbonyl groups
more susceptible to the nucleophilic attack by the amine
groups. This causes elimination of tert-butanol and carbon
dioxide gas as by-products, eventually resulting in the for-
mation of desired N-t-Boc protected amine derivatives.
Recyclability and reusability of a heterogeneous catalyst
determines its feasibility and application. When looking
from the industrial application point of view, recyclability
and reusability are significant parameters. In the present
study, the recyclability of SrGO catalyst was investigated
under the optimal reaction conditions (Table 1, entry 13).
The catalyst was recovered by vacuum filtration, washed
with ethanol (3 × 5 mL) and subsequently dried in an air
O
O
GO
GO
S
S
O
O
O
O
H
H
SO3H
O
O
GO
O
O
O
O
O
O
O
O
O
O
O
O
H
O
H
N
R
H
N
H
R
O
GO
S
O
H
O
H
N
O
O
O
+
R
+
CO2 (g)
OH
O
O
H
O
H
O
N
R
carbon
dioxide
gas
tert-butanol
Boc protected
amine
(product)
SO3H
GO
Formation of by-products:
O
+
CO2 (g)
OH
HO
O
Scheme 2 Proposed mechanism for the Boc protection of amines using SrGO
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

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R. Mittal et al.
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Synthesis
oven at 70 °C for 3 h and reused for further reactions. The
isolated yield (%) for 7 cycles is plotted in Figure 5 [the fig-
ure has been drawn from 85% to clearly differentiate be-
tween the isolated yields (%) for each cycle]. The catalytic
activity of SrGO decreased slightly for the first five cycles,
eventually becoming constant. The isolated yield (%) was
more than 85% even after reusing the catalyst consecutively
for 7 cycles. Conclusively, SrGO holds a great potential as a
catalyst in organic syntheses because of advantages like the
high temperature tolerance, easy recovery, and the reus-
ability without inactiveness.
The comprehensive literature survey suggests that the
use of SrGO as a catalyst for the Boc protection of amines
has several advantages over earlier work (Table 3). This is
the first report where a graphene- or GO-based heteroge-
neous catalyst has been employed for the N-t-Boc protec-
tion of amines. The SrGO was found to be superior because
most of the earlier methods required purification through
column chromatography. Many of the catalysts that have
been reported earlier are homogeneous in nature, which
means they deteriorate/decompose after the reaction and
thus cannot be recovered. Moreover, some of the reported
catalysts that could be recovered, showed catalytic activity
only up to 4 cycles whereas SrGO is superior in terms of its
recyclability and reusability. It could be easily reused up to
7 cycles with excellent catalytic activity. Thus, the present
methodology is an interesting alternative for the N-t-Boc
protection of amines.
In conclusion, we have demonstrated a metal-free and
chemoselective Boc protection of amines using sulfonated
reduced graphene oxide as a catalyst under solvent-free
conditions at room temperature. This method has displayed
great applicability to a wide range of amine substrates,
which could be prepared under two hours at room tem-
perature. Boc protection of amines is a common and im-
portant practice in the field of organic and medicinal chem-
istry. The superior recyclability and reusability of SrGO
makes this methodology even more interesting. Besides,
looking at the current popularity and easy preparation of
graphene-based materials, this protocol is an appealing al-
ternative for the preparation of N-t-Boc protected amine
derivatives. This approach can further be exploited in the
natural products and total synthesis.
Figure 5 Recyclability test of the SrGO catalyst
Table 3 Comparison with Previous Work
Entry
Catalyst
Reusability
Ref.
15a
1
2
yttria-zirconia
reusable
-cyclodextrin
reusable
13
3
–
–
23
4
HClO4-SiO2
up to 4 cycles
21
5
molecular I2
–
22
6
sulfonic acid functionalized silica
up to 3 cycles
16
7
ZnO nanorods
reusable
18
8
1-alkyl-3-methylimidazolium cation-based IL
up to 5 cycles
25
9
–
–
24
10
11
12
13
14
Amberlyst® A21
reusable
19
MgBr2·OEt2
–
15g,f
14
NaI
–
V2O5/SnO2
reusable
20
sulfonated reduced graphene oxide
up to 7 cycles
This work
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

H
R. Mittal et al.
Paper
Synthesis
Boc Protection of Amines; General Procedure
All the chemicals were purchased from Sigma–Aldrich or Alfa Aesar.
The graphite powder was obtained from Central Drug House (P) Ltd.,
New Delhi, India. Double-distilled H2O was used for the preparation
of all aqueous solutions. All solvents and reagents were obtained
commercially and used as received.
To a magnetically stirred solution of (Boc)2 (1 mmol, 218.25 mg) and
SrGO (7.5 mg), was added the respective amine (1 mmol) and stirred
for the appropriate time (Table 2) at RT. The progress of the reaction
was monitored by TLC. After the completion of the reaction, DCM (2
mL) was added to the reaction mixture and the catalyst was separated
by vacuum filtration. The catalyst was washed with EtOH (3 × 5 mL)
and subsequently dried in an air oven at 70 °C for 3 h and reused for
further reactions. The solvent was concentrated under reduced pres-
sure to yield N-t-Boc protected amine derivatives. The products were
characterized by 1H NMR, 13C NMR, MS, and IR spectroscopy.
The catalyst was analyzed by various techniques. Fourier Transform
IR spectra were recorded on PerkinElmer FTIR spectrophotometer us-
ing ATR method with a scanning range of 4000–400 cm–1. The X-ray
diffractograms were obtained using Bruker high-resolution X-ray dif-
fractometer with a scan rate of 5° min–1 in the 2θ range of 5–40°. The
Raman spectra were recorded on Renishaw Laser Raman Spectrome-
ter using a laser of wavelength 514 nm over the wavenumber from
1000–2000 cm–1. The thermal stability of the catalyst was assessed
using PerkinElmer, Pyris diamond TGA/DTA by heating the sample
under N2 atmosphere from RT to 800 °C at a constant heating rate of
10 °C/ min and a gas flow of 200 mL/min. The SEM images and Ele-
mental analysis was obtained using Jeol Scanning Electron Micro-
scope with EDX. TEM images were acquired on Technai 200 Kv Trans-
mission Electron Microscope by dispersing nanoparticles in EtOH and
casting them onto copper grid coated with an amorphous carbon
film.
tert-Butyl Morpholine-4-carboxylate (3a)
White solid; yield: 0.174 g (93%); mp 64–66 °C.
FTIR: 3006, 2967, 2864, 1684, 1454, 1416, 1361, 1273, 1246, 1163,
1112, 1073, 860 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.59–3.61 (4 H, t, J = 4.5 Hz), 3.36–3.38
(4 H, t, J = 4.9 Hz), 1.43 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 154.85, 80.01, 66.74, 44.53, 28.44.
HRMS (ESI): m/z calcd for C9H17NO3: 187.1208 [M + H]+; found:
The synthesized organic compounds were characterized using mass
spectra recorded on Agilent LCMS with Quadruple time of flight. 1H
and 13C NMR spectra were obtained on Jeol 400 MHz spectrometer
with CDCl3 as solvent and chemical shift is reported in ppm with re-
spect to TMS (internal standard). Fourier Transform IR spectra of the
synthesized compounds were recorded on PerkinElmer FTIR spectro-
188.1290.
tert-Butyl Piperazine-1-carboxylate (3b)
White solid; yield: 0.171 g (92%); mp 44–46 °C.
FTIR: 2979, 1688, 1418, 1366, 1244, 1159, 870 cm–1
1H NMR (400 MHz, CDCl3):  = 3.60–3.63 (4 H, t, J = 4.9 Hz), 3.37–3.40
(4 H, t, J = 4.9 Hz), 1.76 (NH, br), 1.44 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 154.77, 80.11, 50.79, 43.51, 28.45.
.
photometer using KBr pellets with a scanning range of 4000-400 cm–1
.
X-ray analysis results were collected on Crysalis PRO (Oxford Diffrac-
tion) with graphite mono75 chromate Mo K radiation ( = 0.71073Å)
and the structure was elucidated by direct method using SHELXL-97.
HRMS (ESI): m/z calcd for C9H18N2O2: 186.1387 [M + H]+; found:
187.1459.
Sulfonated Reduced Graphene Oxide (SrGO)
The reaction scheme for the preparation of graphene oxide (GO) and
sulfonated reduced graphene oxide (SrGO) is shown in Figure 1. First,
graphene oxide (GO) was synthesized according to the known litera-
ture.36a Subsequently, sulfonated reduced graphene oxide (SrGO) cat-
alyst was also prepared according to a previously reported proce-
dure.30g–i,36b with minor modifications. Initially, GO powder (100 mg)
was added to deionized H2O (100 mL) in a glass flask and mixed uni-
formly using a magnetic stirrer at RT for 10 min. The resulting disper-
sion was sonicated in an ultrasonic bath (20 kHz with 100% output)
for 1 h. Then, a freshly prepared solution of NaBH4 (0.8 g) in deionized
H2O (20 mL) was added dropwise into the above dispersion while ad-
justing pH to 10 using 5 wt% Na2CO3 solution. The dispersion was
then heated at 100 °C for 45 min during which time brown GO disper-
sion turned black. The dispersion was then centrifuged (8000 rpm for
10 min) and washed with deionized H2O three times to get partially
reduced graphene oxide (rGO). Thus, obtained rGO was dispersed in
deionized H2O (100 mL) using ultrasonic bath for 40 min and then
cooled. A diazonium salt was prepared by the reaction of sulfanilic
acid (100 mg) and 1 N HCl (1.1 mL) in H2O (15 mL) at 0 °C, followed by
addition of NaNO2 (35 mg) in H2O (15 mL). This diazonium salt was
added into rGO dispersion at 0 °C and stirred overnight at RT. The re-
sulting black precipitate was centrifuged (8000 rpm for 10 min) and
washed with deionized H2O (5 × 3 mL) and with absolute EtOH (1 × 3
mL). Finally, the precipitate was dried in a vacuum oven at 70 °C for
8 h.
tert-Butyl Piperidine-1-carboxylate (3c)
Colorless liquid; yield: 0.169 g (91%).
FTIR: 2976, 2933, 2856, 1687, 1416, 1364, 1250, 1120, 1069, 758 cm–1
1H NMR (400 MHz, CDCl3):  = 3.25–3.28 (4 H, m), 1.40–1.47 (6 H, m),
1.36 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 155.03, 79.17, 44.89, 27.47, 24.57.
HRMS (ESI): m/z calcd for C10H19NO2: 185.1418 [M + H]+; found:
.
186.1491.
tert-Butyl Benzylcarbamate (3d)
Light yellow solid; yield: 0.193 g (93%); mp 57–59 °C.
FTIR: 3461, 3360, 3013, 2978, 1698, 1504, 1453, 1391, 1366, 1245,
1219, 1164, 1027, 745 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.22–7.33 (5 H, m), 4.30 (2 H, s), 1.45
(9 H, s).
13C NMR (100 MHz, CDCl3):  = 156.03, 139.04, 128.67, 127.56,
127.39, 79.53, 44.74, 28.50.
HRMS (ESI): m/z calcd for C12H17NO2: 207.1258 [M + H]+; found:
208.1332.
tert-Butyl Phenethylcarbamate (3e)
Transparent solid; yield: 0.193 g (87%); mp 53–57 °C.
FTIR: 3346, 3027, 2975, 2933, 1691, 1503, 1452, 1391, 1364, 1247,
1163, 1039, 689 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

I
R. Mittal et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.15–7.28 (5 H, m), 3.33–3.35 (2 H, t,
J = 6.2 Hz), 2.75–2.78 (2 H, t, J = 6.9 Hz), 1.42 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 152.28, 142.95, 133.30, 119.25,
118.22, 105.47, 81.63, 28.29.
13C NMR (100 MHz, CDCl3):  = 156.06, 139.17, 128.89, 128.61,
HRMS (ESI): m/z calcd for C12H14N2O2: 218.1059 [M + H]+; found:
126.43, 79.07, 41.95, 36.31, 28.51.
219.1131.
HRMS (ESI): m/z calcd for C13H19NO2: 221.1427 [M + H]+; found:
222.1500.
tert-Butyl (4-Methoxyphenyl)carbamate (3l)
White solid; yield: 0.212 g (95%); mp 96–98 °C.
tert-Butyl (2-Aminoethyl)carbamate (3f)
FTIR: 3361, 2977, 1692, 1599, 1515, 1367, 1308, 1235, 1156, 1051,
Mustard solid; yield: 0.151 g (94%); mp 68–70 °C.
754 cm–1
.
FTIR: 3372, 2979, 2933, 1680, 1518, 1447, 1392, 1365, 1274, 1159,
1H NMR (400 MHz, CDCl3):  = 7.23–7.25 (2 H, m), 6.78–6.82 (2 H, m),
6.56 (NH, br), 3.74 (3 H, s), 1.48 (9 H, s).
870 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.13 (NH, br), 5.02 (NH2), 3.11–3.17 (2
H, m), 2.73–2.76 (2 H, t, J = 5.8 Hz), 1.38 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 155.69, 153.37, 131.59, 120.67,
114.23, 80.24, 55.55, 28.45.
13C NMR (100 MHz, CDCl3):  = 28.44, 40.83, 41.88, 79.40, 155.46.
HRMS (ESI): m/z calcd for C12H17NO3: 223.1221 [M + H]+; found:
224.1293.
HRMS (ESI): m/z calcd for C7H16N2O2: 160.1209 [M + H]+; found:
161.1282.
tert-Butyl (4-Phenoxyphenyl)carbamate (3m)
Dark brown solid; yield: 0.254 g (89%); mp 107–109 °C.
tert-Butyl (4-Aminophenyl)carbamate (3g)
Dark brown solid; yield: 0.198 g (95%); mp 114–116 °C.
FTIR: 3377, 2978, 2920, 2850, 1699, 1593, 1514, 1485, 1367, 1311,
1222, 1153, 1049, 1028, 825 cm–1
.
FTIR: 3364, 2978, 2934, 1690, 1623, 1600, 1515, 1426, 1392, 1366,
1310, 1232, 1155, 1052, 826 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.93–7.32 (9 H, m), 6.46 (NH, br), 1.50
(9 H, s).
1H NMR (400 MHz, CDCl3):  = 7.10–7.12 (2 H, d, J = 7.7 Hz), 6.60–6.62
(2 H, d, J = 8.7 Hz), 6.27 (NH2), 1.48 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 157.98, 153.05, 152.46, 134.06,
129.74, 122.86, 120.39, 120.06, 118.15, 80.65, 28.43.
HRMS (ESI): m/z calcd for C17H19NO3: 285.1365 [M + H]+; found:
13C NMR (100 MHz, CDCl3):  = 153.41, 142.45, 129.79, 120.96,
115.69, 80.11, 28.47.
286.1451.
HRMS (ESI): m/z calcd for C11H16N2O2: 208.1219 [M + H]+; found:
209.1292.
tert-Butyl Pyridin-4-ylcarbamate (3n)
White solid; yield: 0.175 g (90%); mp 143–147 °C.
tert-Butyl (2-Aminophenyl)carbamate (3h)
Light brown solid; yield: 0.196 g (94%); mp 110–112 °C.
FTIR: 3340, 2978, 1704, 1511, 1451, 1365, 1242, 1156, 1052, 742 cm–1
1H NMR (400 MHz, CDCl3):  = 6.64–7.23 (4 H, m), 6.45 (NH2), 1.50 (9
H, s).
13C NMR (100 MHz, CDCl3):  = 153.93, 140.02, 126.23, 124.84,
119.72, 117.70, 80.63, 28.41.
HRMS (ESI): m/z calcd for C11H16N2O2: 208.1219 [M + H]+; found:
209.1294.
FTIR: 1723, 1599, 1525, 1454, 1422, 1394, 1365, 1304, 1257, 1165,
1055, 763 cm–1
.
.
1H NMR (400 MHz, CDCl3):  = 8.39–8.41 (2 H, dd, J = 4.9, 1.4 Hz), 7.81
(NH, br), 7.34 (2 H, m), 1.48 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 152.32, 150.31, 146.25, 112.50, 81.54,
28.30.
HRMS (ESI): m/z calcd for C10H14N2O2: 194.2349 [M + H]+; found:
195.2422.
tert-Butyl (4-Hydroxyphenyl)carbamate (3o)
tert-Butyl (4-Acetylphenyl)carbamate (3j)
Pink solid; yield: 0.195 g (93%); mp 146–148 °C.
White solid; yield: 0.198 g (84%); mp 148–150 °C.
FTIR: 3360, 2980, 2929, 1693, 1612, 1519, 1436, 1369, 1226, 1159,
FTIR: 3312, 2980, 1723, 1669, 1594, 1527, 1406, 1362, 1317, 1271,
1055, 827 cm–1
.
1234, 1157, 1047, 837 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.11–7.13 (2 H, d, J = 8.4 Hz), 6.68–6.72
(2 H, m), 6.36 (OH, br), 1.49 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 153.83, 152.33, 130.76, 121.76,
115.86, 80.61, 28.46.
HRMS (ESI): m/z calcd for C11H15NO3: 209.1052 [M – H]–; found:
208.0977.
1H NMR (400 MHz, CDCl3):  = 7.88–7.90 (2 H, d, J = 8.8 Hz), 7.42–7.44
(2 H, d, J = 8.7 Hz), 6.71 (NH, br), 2.54 (3 H, s), 1.51 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 197.01, 152.22, 142.96, 131.92,
129.93, 117.46, 81.40, 28.35, 26.47.
HRMS (ESI): m/z calcd for C13H17NO3: 235.2634 [M + H]+; found:
236.2706.
tert-Butyl (4-Mercaptophenyl)carbamate (3p)
tert-Butyl (4-Cyanophenyl)carbamate (3k)
Light brown solid; yield: 0.196 g (87%); mp 148–152 °C.
White solid; yield: 0.192 g (88%); mp 116–120 °C.
FTIR: 3385, 2256, 1651, 1499,.1310, 1235, 1166, 1020, 994, 824, 762
FTIR: 3327, 3019, 2980, 2225, 1721, 1597, 1516, 1405, 1363, 1316,
cm–1
.
1225, 1154, 1053, 745 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.91 (NH), 7.15–7.24 (4 H, m), 3.22
(SH), 1.33 (9 H, s).
1H NMR (400 MHz, CDCl3):  = 7.46–7.52 (4 H, m), 7.11 (NH, br), 1.47
(9 H, s).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–K

J
R. Mittal et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 152.96, 139.36, 130.97, 129.92,
118.95, 80.16, 28.38.
HRMS (ESI): m/z calcd for C11H15NO2S: 225.0816, [M – H]–; found:
224.0744.
(7) (a) Guibé-Jampel, E.; Wakselman, M. J. Chem. Soc. D 1971, 267.
(b) Guibé-Jampel, E.; Wakselman, M. Synthesis 1977, 772.
(8) Kim, S.; Lee, J. I. Chem. Lett. 1984, 237.
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thesis 1986, 627.
(10) Registry of Toxic Effects of Chemical Substances 1985-86, U.S.
Department of Health and Human Services; U.S. Government
Printing Office: Washington DC, 1988.
tert-Butyl Benzo[d]thiazol-2-ylcarbamate (3q)
White solid; yield: 0.228 g (91%); mp 98–100 °C.
FTIR: 3131, 3056, 2971, 2931, 2801, 1709, 1603, 1558, 1455, 1363,
(11) (a) Knölker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37, 5861.
(b) Knölker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew.
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1280, 1185, 1052, 861, 755, 669 cm–1
.
1H NMR (400 MHz, CDCl3):  = 11.76 (NH, br), 7.91–7.93 (1 H, d, J = 8.2
Hz), 7.77–7.78 (1 H, d, J = 7.8 Hz), 7.36–7.40 (1 H, t, J = 7.8 Hz), 7.24–
7.28 (1 H, t, J = 7.3 Hz), 1.58 (9 H, s).
13C NMR (100 MHz, CDCl3):  = 161.91, 153.05, 148.73, 131.53,
125.73, 123.45, 121.12, 120.94, 83.32, 28.47.
(13) Reddy, M. S.; Narender, M.; Nageswar, Y. V. D.; Rama Rao, K.
Synlett 2006, 1110.
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Kumar, P. ARKIVOC 2002, (vii), 28. (b) Bartoli, G.; Bosco, M.;
Locatelli, M.; Marcantoni, E.; Massaccesi, M.; Melchiorre, P.;
Sambri, L. Synlett 2004, 1794. (c) Sharma, G. V. M.; Reddy, J. J.;
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2006, 47, 1087. (f) Chankeshwara, S. V.; Chakraborti, A. K.
Synthesis 2006, 2784. (g) Schechter, A.; Goldrich, D.; Chapman, J.
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HRMS (ESI): m/z calcd for C12H14N2O2S: 250.0790 [M + H]+; found:
251.0862.
Acknowledgment
S.K.A. acknowledges the financial support from the University of
Delhi, Delhi, India and DST Purse Grant Phase-II for the research grant.
R.M. acknowledges the award of Research fellowship from UGC, New
Delhi, India and University Science Instrumentation Centre (USIC)
and Department of Chemistry, University of Delhi, Delhi, India for
providing instrumentation facilities. We are grateful to Sophisticated
Analytical Instrument Facility (SAIF)-AIIMS, New Delhi, India for pro-
viding TEM facility.
(17) Chankeshwara, S. V.; Chakraborti, A. K. J. Mol. Catal. A: Chem.
2006, 253, 198.
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2011, 8, 38.
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58, 1619.
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Res. 2017, 9, 128.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690239.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
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gInformati
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