Efficient and expeditious chemoselective BOC protection of amines in catalyst and solvent-free media

Article abstract of DOI:10.1007/s11164-016-2702-9

A green and eco-friendly route for the almost quantitative BOC protection of a large variety of aliphatic and aromatic amines, amino acids, and amino alcohols is reported in catalyst and solvent-free media under mild reaction conditions. The products were confirmed by ¹H, ¹³C NMR, IR spectroscopy, and in some cases, elemental analysis. This protocol does not require any water quenches, solvent separations, and purification steps, such as recrystallization and column chromatography.

Full text of DOI:10.1007/s11164-016-2702-9

Res Chem Intermed
DOI 10.1007/s11164-016-2702-9
Efficient and expeditious chemoselective BOC
protection of amines in catalyst and solvent-free media
Balaga Viswanadham1 Abdul S. Mahomed1
•
•
Holger B. Friedrich1 Sooboo Singh1
•
Received: 12 April 2016 / Accepted: 12 August 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A green and eco-friendly route for the almost quantitative BOC protec-
tion of a large variety of aliphatic and aromatic amines, amino acids, and amino
alcohols is reported in catalyst and solvent-free media under mild reaction condi-
tions. The products were confirmed by 1H, 13C NMR, IR spectroscopy, and in some
cases, elemental analysis. This protocol does not require any water quenches, sol-
vent separations, and purification steps, such as recrystallization and column
chromatography.
Keywords Protection Á N-BOC Á Catalyst and solvent-free Á Reaction temperature Á
Rotary evaporator
Introduction
It is universally recognized that there is increasing interest in more eco-friendly
practical approaches for pharmaceutical and fine chemical syntheses. This advanced
growth area is recognized as green chemistry/sustainable technology [1–4]. This
demands a paradigm shift from traditional concepts and focuses mainly on yield and
commercial value, whilst eliminating the usage of solvents and catalysts to enhance
green chemistry. In recent years, the amine functionality has been identified in a
broad range of biologically active molecules, and the protection of the amine
functionality is important in their synthetic applications. The nitrogen-containing
carbamate or BOC amine compounds, shown in Fig. 1, are frequently found in
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2702-9)
contains supplementary material, which is available to authorized users.
&
Sooboo Singh
singhso@ukzn.ac.za
1
School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4000, South Africa
123

B. Viswanadham et al.
O
O
O
OH
H
Cl
O
O
O
N
O
O
N
O
O
N
N
O
O
O
O
O
Fig. 1 Some important biologically active N-BOC amines
pharmaceutical and biologically active molecules in organic synthesis [5]. One of
the more significant routes to protection involves the use of BOC anhydride, which
has been studied over various catalytic and solvent systems [6–21]. Some examples
include DMAP, Lewis acid catalysts such as Zr(ClO4)2Á6H2O; Brønsted acid ionic
liquids [(HMIm)BF4]; functionalized silica, H3PW12O40, and montmorillonite K10.
The above studies showed that some processes required long reaction times, some
were carried out under harsh reaction conditions, and others required purification
steps such as column chromatography. In addition, these processes involving
catalysts and solvents sometimes required purification of the solvents, as well as
catalyst washing, post reaction. Chankeshwara and Chakraborti [22] studied the
N-BOC protection of amines in the absence of a catalyst, but used water as a
solvent. Raju et al. [23] reported N-BOC amine and hydrazine synthesis at room
temperature without a catalyst or solvent, and thereafter recrystallized the product
using a suitable solvent. Mojtahedi et al. [24] reported on N-BOC protection of
amines without a catalyst and under solvent-free conditions; however, the product
was isolated after purification by column chromatography. Jia et al. [25] also
reported, in a similar way, the synthesis of N-BOC amines without a catalyst and
solvent, but purification with column chromatography was carried out after reaction,
likely to remove the t-butanol from the reaction mixture considering that the
reactions were carried out mostly at room temperature.
Various routes to N-BOC protection are reported and shown in Scheme 1. Route
1 shows the reaction proceeding in an aqueous medium or in an organic solvent to
produce BOC amines after some purification technique [22, 26, 27]. Route 2
proceeds in the presence of a catalyst and solvent to obtain products after
purification such as column chromatography [11, 14, 15, 17, 18, 29, 30, 34, 35].
This route may require a catalyst washing step after the reaction. Route 3 proceeds
via the use of a catalyst to obtain a product but after some form of purification step
[28, 31–33]. The most attractive pathway, from an environmental perspective, is
route 4 where N-BOC protection takes place in the absence of a catalyst or solvent.
In keeping with this philosophy, we report a very simple and highly efficient
synthesis method for the protection of amines with BOC anhydride under catalyst
and solvent-free conditions. This reaction proceeds via a simple mixing of
stoichiometric amounts of the reactants to give products in quantitative yield, whilst
simultaneously removing the formed by-products.
123

Efficient and expeditious chemoselective BOC protection…
Scheme 1 Synthesis of N-BOC amines by various routes
Experimental
The chemicals were procured in reagent grade and used without further purification.
1H NMR and 13C NMR spectra were recorded employing a Bru¨ker Advance
400 MHz instrument with CDCl3 as a solvent. The Fourier transformed infrared
spectra were recorded using the attenuated total reflectance (ATR) technique on a
Perkin Elmer Universal spectrometer at room temperature between 400 and
4000 cm-1. Elemental analyses were performed on a Thermal-Scientific Flash 2000
CHNS analyzer. The reactions were carried out in a 50 mL RB flask under reduced
pressure for 10 min at 80 °C unless reported differently. In a typical experiment,
5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was
allowed to proceed for 10 min. The desired product was obtained in a rotary
evaporator under vacuum conditions. In all cases, the products were found to be
pure (NMR) and did not require any further purification. As confirmation, we
carried out elemental analyses on some products, which are shown in Table 4. The
1
BOC products were characterized by H and 13C NMR and IR spectroscopy. The
results of these are presented in the supplementary information.
Result and discussion
The results of the N-BOC protection of various amines are shown in Table 1, and
the proposed mechanism for BOC protection of amines in catalyst and solvent-free
media is shown in Scheme 2 [24]. The reaction conditions enhance easy attack of
123

B. Viswanadham et al.
Table 1 Catalyst and solvent free BOC protection of various aminesa
Entry
1
Reactant
Product
Con.
(%)
100
Yield
(mol %)
99
O
H
NH2
N
O
NH2
O
2
100
99
H
N
O
Cl
Cl
N
NH2
O
O
3
4
5
100
100
100
99
98
98
H
H
O
O
Br
Br
N
NH2
I
I
O
NH2
H
N
O
I
I
NH2
Cl
O
6
7
100
100
99
98
H
H
N
N
O
Cl
O
NH2
O
CH3
CH3
CH3
O
CH3
NH2
8
9
100
100
98
98
H
N
O
O
H3
C
CH3
H3C
CH3
NH2
H
CH3
CH3
N
O
CH3
CH3
NH2
NH2
O
O
10
100
99
N
H
H
N
H
O
NH2
NH2
11
12
100
100
99
98
N
H
O
H
N
O
N
N
O
O
HO
HO
13
14
100
100
98
98
HO
NH2
N
H
O
O
NH2
O
HO
N
H
123

Efficient and expeditious chemoselective BOC protection…
Table 1 continued
Entry
15
Reactant
Product
Con.
(%)
Yield
(mol %)
NH2
O
100
99
HN
O
H
N
NH2
16
100
96
O
O
O
NH2
17
18
100
100
96
95
N
O
NH2
H
N
O
O
NH2
H
19
20
100
100
96
97
N
O
O
O
NH2
H
OH
NH2
N
O
OH
O
21
100
97
H
H2N
H2N
N
O
O
O
N
H
O
O
O
22
23
24
100
100
100
96
98
98
NH2
O
N
N
H
H
N
N
N
N
O
H
O
O
O
N
OH
N
H
OH
O
O
O
H
N
O
25
26
100
100
97
99
H2N
O
OH
OH
O
O
O
H
H
N
N
H
O
O
O
O
O
27
100
97
O
N
N
H
O
O
Reaction conditions: Amine (5 mmol), BOC anhydride (5 mmol) carried out using a
rotary evaporator at 80o
C
a
Reaction conditions: Amine (5 mmol), BOC anhydride (5 mmol) carried out using a rotary evaporator
at 80 °C
the electron deficient carbonyl carbon in BOC anhydride by the nucleophilic lone
pair on the nitrogen atom of the amine. The major advantage of our process involves
the efficient removal of by-products such as t-butanol and CO2 during the course of
the reaction without the need to purify the reaction products, thus giving analytically
123

B. Viswanadham et al.
Table 2 Protection of aniline derivatives with BOC2O at various reaction temperatures
Reaction
temperature (°C)
Yield (mol%)
Aniline- 4-Chloro
BOC
4-Bromo
aniline-BOC
4-Iodo
aniline-BOC
3,4-Dimethyl
aniline-BOC
aniline-BOC
RTa
50a
80b
a
60
78
99
3
10
99
10
40
99
55
72
98
95
99
99
Yield based on 1H NMR analysis
Isolated yields
b
pure products in almost quantitative yield. We also studied selected indole
compounds using the same reaction conditions and found them to produce a
quantitative yield towards the desired product (Table 1). However, we found them
less reactive, based on the longer reaction time (30 min) required to obtain
quantitative yields.
In respect to the reaction mechanism, the rate of the reaction can be favoured by
influencing the nucleophilicity of the lone pair on the nitrogen atom. Hence,
electron donating groups enhance the rate, whereas, in the case of electron
withdrawing groups, a decrease in rate would be favored. This effect would be
pronounced for aryl amines as demonstrated by the results shown in Table 2. In
order to compare the rate of the reaction as a function of the substituent, we studied
the protection of several amines at various reaction temperatures including room
temperature, 50, and 80 °C. When the reaction was carried out at room temperature,
the electron withdrawing substituents clearly show a lower rate when compared to
the electron donating groups. In comparison, the un-substituted aniline gave a rate
that is in between activating and deactivating aniline derivatives (Table 2).
Reaction mechanism
The same trend was observed when the temperature was increased to 50 °C.
However, increasing the temperature further to 80 °C showed no influence of the
substituents, with the rates being almost the same. These results show that the rate of
reaction can be tuned by controlling the reaction temperature. The order of the rate
is as follows, CH3 [ H [ I [ Br [ Cl (Table 2), and these results correlate well
with the inductive effect of these substituents, Cl [ Br [ I [ H [ CH3.
The purity of compounds was confirmed by NMR analyses, and this was sufficient
for the work presented; however, as an extra measure, we also carried out CHN
analyses for some products obtained at 80 °C, as shown in Table 3. These results
confirm the analytical purity of the products.
In order to compare the results obtained with those reported, we present several
studies
in
Table 4
where
aniline
was
N-BOC
protected
[11, 14, 15, 17, 18, 21, 28–35]. It can be seen from the data in the Table that the
present protocol is highly efficient, albeit at 80 °C, and very expeditious when
123

Efficient and expeditious chemoselective BOC protection…
O
O
H
O
O
O
N
O
O
N
O
O
O
O
O
H
O
O
O
H
H
H
H
N
R
R
OH
+ CO2
R
R= X, CH3
R
O
N
O
H
Scheme 2 Reaction pathway for BOC amine formation under mild reaction conditions
Table 3 Elemental analysis of selected BOC amines
Compound
Theoretical (%)
Founda (%)
H N
C
H
N
C
O
H
68.37 7.82 7.25 67.37 7.46 7.16
N
O
O
58.03 6.2 6.15 57.03 5.85 5.91
H
N
O
Cl
N
O
O
O
41.4 4.42 4.39 41.24 4.16 4.15
48.55 5.19 5.15 48.20 4.80 4.79
70.56 8.65 6.33 69.57 7.91 6.26
H
H
H
O
O
I
N
Br
N
O
CH3
CH3
a
Deviation for some compounds due to adsorbed water (0.1–0.15 wt%)
compared to most. It must also be highlighted that all, but one, of the reported
methods required purification to obtain the final product. As a result, the
methodology reported here makes the process cost effective, efficient, and
environmentally friendly, whilst giving excellent yields toward the product.
123

B. Viswanadham et al.
Table 4 Comparison of N-BOC protection of aniline with (BOC)2O—literature results with the present
study
S.
no.
Catalyst
Solvent
Reaction time
(min)/room
temperature
Yield (%)/purification cc References
(column
chromatography)
1
2
Yttria-zirconia
Sulfonic acid-
functionalized silica
b-cyclodextrin
Thiourea
CH3CN 840/RT
90/cc
83/cc
[11]
[14]
CH2Cl2
45/RT
3
4
5
6
7
8
9
H2O
150/RT
75/cc
95/cc
85/cc
95
[15]
[17]
[18]
[21]
[25]
[28]
[29]
[30]
[31]
Toluene 40/70 °C
H3PW12O40
Water
CH2Cl2
Water
Neat
8/RT
30/35 °C
30/RT
60/RT
720/RT
60/RT
5/RT
No catalyst
FeCl3
95/cc
89/cc
92/cc
97/cc
93/cc
Neat
Zn(ClO4)2Á6H2O
CH2Cl2
10 Saccharin sulfonic acid Hexane
11 N-Sulfonic acid poly(4- Neat
vinylpyridinium)
chloride
12 Pyridinium 2,2,2-
trifluoroacetate ionic
liquid
Neat
25/RT
95/cc
[32]
13 I2
Neat
30/RT
2/RT
98/cc
98/cc
[33]
[34]
14 1,3-Disulfonic acid
imidazolium hydrogen
sulfate
Ethyl
acetate
15 [H-Suc]HSO4
16 No catalyst
17 No catalyst
a
Ethyl
acetate
6/RT
93/cc
60a
[35]
Neat
10/RT
10/80 °C
Present
work
Neat
99b
Present
work
Yield based on 1H NMR analysis
Isolated yield
b
Conclusions
In the present investigation, a very simple method and green protocol is reported for
a catalyst and solvent-free BOC protection of amines. This methodology is highly
efficient and eco-friendly, chemoselective, with excellent yields and easy product
isolation. We also show that at 80 °C the inductive effects of substituents have no
effect on the rate of the BOC protection whilst at the lower temperatures, a higher
rate was observed for the electron donating groups.
123

Efficient and expeditious chemoselective BOC protection…
Acknowledgments Dr. B. Viswanadham thanks the University of KwaZulu-Natal for the award of an
AES Postdoctoral Fellow.
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