Chemoselective: N-tert -butyloxycarbonylation of amines in glycerol

Article abstract of DOI:10.1039/c8nj01585f

A catalyst-free, efficient and green protocol has been developed for the chemoselective N-Boc protection of amines by using glycerol as a solvent at room temperature. A variety of functionalized amines, such as aliphatic, aromatic as well as heteroaromatic were protected using the developed protocol. N-tert-Butyloxycarbonylation derivatives were formed without the formation of isocyanate, urea, N,N-di-t-Boc, or oxazolidinone as side products. The operational simplicity, cleaner reaction, rapid reaction convergence, functional group tolerance, excellent yield, high selectivity, catalyst-free feature and solvent recyclability are the distinct advantages of this protocol. Owing to these merits, this protocol is feasible, economical and environmentally benign.

Full text of DOI:10.1039/c8nj01585f

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DOI: 10.1039/C8NJ01585F
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Chemoselective N-tert-butyloxycarbonylation of amines in
glycerol
Received 00th January 20xx,
Accepted 00th January 20xx
Ajit P Ingale,*ac Vishal K More,a Uddhav S Gangardea and Sandeep V Shindebc
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalyst-free, efficient and green protocol has been developed leads to the formation of side products such as isocyanates,
for chemoselective N-Boc protection of amines by using glycerol urea and N,N-Di-Boc derivatives5. Additionally, high toxicity,
solvent at room temperature. The varieties of functionalized unpleasant smell, nonrecyclability and requirement of excess
amines such as aliphatic, aromatic as well as heteroaromatic were amount catalyst make those protocols objectionable,
protected by using developed protocol. The N-tert- especially from standpoint of green chemistry.
butyloxycarbonylation derivatives were formed without any
Alternative protocols used for N-Boc protection of amines
isocyanate, urea, N,N-di-t-Boc, and oxazolidinone as side involves several Lewis or Brönsted acid catalyst, such as ZrCl4,6
products. The operational simplicity, cleaner reaction, rapid Zn(ClO4)26H2O,7 LiClO4,8 FeCl3,9 Cu(BF4)2H2O,10 La(NO3)36H2O,11
reaction convergence, functional group tolerance, excellent yield, Bi(NO3)35H2O,12 InCl3, InBr3,13 CsF,14 I2,15 Me2SBr2,16
high selectivity, catalyst-free and solvent recyclability are the (CF3)2CHOH,17
thiourea,18
thioglycoluril,19
guanidine
distinct advantages of this protocol. This makes the protocol hydrochloride,20 sulphamic acid,21 saccharin sulfonic acid22 and
feasible, economical and environmentally benign.
succinamide sulphonic acid23 has been reported. The various
heterogeneous catalysts, including amberlyst-15, sulfonic acid-
functionalized silica, sulfonic acid-functionalized nanoporous
titania, sulfonic acid-functionalized ordered nanoporous Na+-
montmorillonite, H3PW12O40, montmorillonite K-10 or KSF,
The amino functional group plays vital role in biological
functions as well as in organic synthesis. In most of the active
molecules amino functional groups are in active site and it is
difficult to stabilize at physiological pH. Protection and
deprotection of amino group's plays significant role in organic
transformation.1 There are number of reagents to protect the
amino functional groups, moreover an N-tert-butoxycarbonyl
(N-Boc) derivatives has becomes widely used strategy in the
synthesis of small organic to complex natural products2. The N-
Boc protection is easy to introduce with simple acid treatment
and has distinct stability and efficiency. The N-Boc is quite
stable in basic medium and also the carbamates are inert
mesoporous
silica
acid,
phenyl
sulfonic
acid,
tungstaophosphoric acid doped mesoporous silica, HClO4-SiO2,
poly(4-vinylpyridinium)perchlorate, nano-TiO2-HClO4, nano-
Fe2O3, and indion-190 resin24. Acidic ionic liquids, such as
[(HMIm)BF4], [TMG][Ac], [Py][OTf], [H-Suc]HSO4, an 1-alkyl-3-
methylimidazolium based ionic liquids, 1,3-disulfonic acid
imidazolium
hydrogen
sulfate,
and
imidazolium
trifluoroacetate have been used as catalyst for N-tert-
butoxycarbonylation of amines25. The catalyst-free protocols
including the use of β-cyclodextrin,26 water,27 ethanol28 and
PEG-40029 as well as solvent-free conditions with and without
microwave irradiation30 have been used for N-Boc protection
of amines. Many of these methods have some synthetic
advantages individually, but still suffer from certain limitation,
such as maintaining the anhydrous conditions, limited scope of
substrate, less yields, toxic catalysts and solvents, slow
reaction rate, tedious work-up and less recyclability of the
catalysts and solvents. Thus development of safe,
environmentally benign, mild, efficient, and high yielding rapid
catalyst-free protocol using cost effective and recyclable
solvent for N-Boc protection of amines is desirable.
towards
the
nucleophilic
reagents
and
catalytic
hydrogenation3. Furthermore, deprotection of the N-Boc
group could be easily carried out with acid treatment. Various
base catalyzed protocols were available for Boc protection of
amines in literature, for example, dimethylaminopyridine
(DMAP), NaHMDS, K2CO3, NaOH, triethyl amine and also Boc
activation of amides has emerged as a major strategy in
organic synthesis4. However, a base-catalyzed protocol often
Green and sustainable chemical processes with reduction or
even elimination of the use and production of hazardous
1

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chemicals are high demand. Therefore, the use of non-toxic 47% after 20 min of reaction. Increasing the amount of
solvent and catalyst-free protocols has a prime choice. In this glycerol to 1.5 mL the yield slightly increased to 77%. The best
context, the development of protocols using recyclable and result was attained in the presence of 2 mL (98%, Fig. 2).
environmentally friendly solvent has gained much interest Further increasing the quantity of glycerol had the opposite
recently because of the extensive uses of solvents in almost all effect and the yield of product decreased which could be
of the chemical industries, and of the predicted disappearance related to the dispersion of the reagents, when large quantity
of fossil oil.31 It has also observed that the catalysts employed of glycerol is used.
are not always ecofriendly and because of this, serious To understand the efficiency of our protocol with respect to
environmental pollution often results. In this regard, the use of others hydroxyl solvents methods like water, methanol,
glycerol as a promoting medium for organic reaction was ethanol and PEG-400 for N-tert-butyloxycarbonylation of p-
recently demostrated.32 Glycerol due to its unique combination toluidine, the results are collected and depicted in Table 1. The
of physical and chemical properties such as polarity, low results clearly indicates that the catalyst-free N-Boc protection
toxicity, no flammability, high boiling point, biodegradability, of amines in glycerol media reported here is the most efficient,
and easy availability from renewable feed stocks prompted us clean and green process as well as the present protocol offers
to extend its use as green solvent in organic synthesis.33 As a an advantage in terms of reaction conditions, reaction time
result, we have developed novel, efficient and chemoselective and yields.
catalyst-free protocol for N-Boc protection of amines using
Table 1 Efficiency of glycerol in comparison with reported methods
glycerol as recyclable solvent at room temperature. (Scheme
1)
for the N-tert-butyloxycarbonylation of p-toluidinea
.
Entry
Solvent
Water27
Time
1h
0.5h
0.5h
1.5h
30min
Isolated Yieldb
1
2
3
4
5
96
93
96
96
98
MeOH28
Ethanol28
PEG-40029
Glycerol
Scheme 1 Catalyst-free N-Boc Protection of amines in glycerol
a
Reaction conditions: 1mmol of p-toluidine, 1mmol of Boc2O,
2ml glycerol.
Results and Discussion
b Isolated yield of pure product.
In order to study the scope and limitations of this catalyst-
free N-tert-butyloxycarbonylation of amines in glycerol, we
began our investigation with a model reaction of aniline (1a)
with Di-tert-butyl carbonate (1:1mmol) in glycerol (2 mL)
under catalyst-free conditions to yield tert-butyl
phenylcarbamate (2a) (Scheme 2). The reaction was
completed in 10 min at room temperature and the
corresponding N-Boc protected amine obtained in 98% yield.
To understand the role of glycerol on the N-Boc protection of
amines, we have tested the reaction of aniline with di-tert-
butyl carbonate in solvent-free conditions at room
temperature. It should be noted that in solvent-free conditions
and after 12h, 2a was obtained in 25% yield whereas after 24 h
it was observed to increase to only 37%. All the attempts to
perform the reaction at room temperature (in solvent-and
catalyst-free conditions) were fruitless even after 24h.The N-
Boc protection of amine in glycerol showed a significant
improvement of yield as well as reaction time when compared
to the solvent-free reaction.
With the established optimal conditions, the scope of the
reaction was probed. As highlighted in Table 2 and 3 the N-Boc
protection of various amines (aromatic, aliphatic, cyclic and
heterocyclic), amino alcohols, amino phenols, chiral amines
and amino ester were carried out in excellent yields and
reduced time, between 2 min to 60 min. Generally, aniline and
aromatic amines bearing electron donating groups undergoes
the N-tert-butyloxycarbonylation in shorter reaction time with
excellent yields (Table 2, entries 1-9). However, the reaction is
somewhat sluggish at room temperature for the aromatic
amines bearing electron withdrawing groups but at 90oC the
amines reacted with Boc2O to furnish corresponding N-Boc
product in much improved yield (Table 2, entries 10-14). Other
aromatic amines such as 1-amino naphthalene, 2-amino
naphthalene, 2-amino pyridine, 2-amino thiazole, 2-amino
benzothiazole and 2-amino benzimidazole all are converted to
the corresponding N-Boc derivatives in excellent yield in
shorter reaction time (Table 2, entries 15-20). This protocol
was highly efficient for aliphatic primary, secondary or cyclic
amines which afforded corresponding N-Boc protected
derivatives at room temperature in excellent yield (Table 3,
entries 1-14). The aliphatic amine reacted faster than aromatic
amines and gave selectively monoprotected derivatives in
good to excellent yields. It is important to note that no side
reactions were observed in case of primary aliphatic amines,
such as formation of isocyanates or ureas, there was not any
bis-Boc derivatives observed.
Scheme 2 N-tert-butyloxycarbonylation of aniline in glycerol.
Also the amount of glycerol is crucial for the elapse of the
reaction. When using 0.5 mL of glycerol, 2a was obtained in
2

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Excellent chemoselectivity was observed in case of amino
alcohol, amino phenol and aromatic as well as aliphatic
diamines, no bis-Boc derivatives or mixture of O/N Boc-
derivatives was observed. The amine group was exclusively
protected in comparatively good yields in the presence of
phenolic or alcoholic hydroxy group (Table 2, entries 6-7 and
Table 3, entry 2, 14). Aliphatic and aromatic diamines were
converted to exclusively mono-Boc protected derivatives in
shorter reaction time with excellent yields (Table 2, entries 8-9
and Table 3, entries 3-4). It is 100% mono-selective we did not
observe di-protection of aliphatic amines and diamines. No
comparative side reactions leading to formation of isocyanate,
urea of N,N-di-Boc derivatives were detected by thin layer
4
5
30
25
30
98
98
96
1d
1e
2d
2e
1
chromatography, H NMR and 13C NMR analyses of the crude
products. Chiral amines, esters of amino acids and amino
alcohol were efficiently protected to give optically pure N-Boc
derivatives without racemization in good to excellent yield
(Table 3, entry 11-14).
6
7
1f
2f
The solvent recycling and its reusability is an important
feature of this protocol. We also investigate the recycling
efficiency of the glycerol under catalyst-free conditions at
room temperature. After the completion of reactions, the
reaction mixture was diluted and extracted with mixture of pet
ether/ethyl aceate (9:1). The upper phase was dried and the
solvent evaporated. The glycerol phase was dried under
vacuum and directly reused. Glycerol maintained its good level
of efficiency even after being reused three times. The product
2a was obtained in 98%, 97% and 96% yields after the
successive cycles.
40
20
95
97
1g
2g
8
9
1h
1i
2h
2i
Table 2 Substrate scope for N-Boc protection of aromatic
amines in glycerola
40
55
92
89
10
1j
2j
Amine
(1a-1t)
Product
(2a-2t)
Time Yieldb
Entry
(Min)
(%)
720
45c
37
87
11
1
20
98
1a
1b
2a
2b
1k
2k
2
3
60
40
96
97
720
65c
23
84
12
13
1l
2l
720
90c
16
81
1c
2c
1m
2m
3

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6
5
5
5
98
96
95
720
47
85
14
50c
40
45
1f
1g
1h
2f
2g
2h
NH2
1n
2n
7
8
N
N
15
95
94
NH2
1o
2o
2p
16
1p
9
3
3
94
96
1i
1j
2i
2j
17
30
30
35
96
95
93
1q
2q
2r
10
18
1r
11
12
13
5
98
93
92
19
1s
2s
1k
1l
2k
2l
20
40
91
20
20
1t
2t
aAll the products were characterized by IR, 1H NMR, 13C
NMR. bIsoltaed yield of pure product. Reaction carried at
c
90OC.
Table 3 Substrate scope for N-Boc protection of aliphatic
amines in glycerola
1m
1n
2m
14
20
92
2n
aAll the products were characterized by IR, 1H NMR, 13C
NMR. bIsoltaed yield of pure product.
Amine
(1a-1n)
Product
(2a-2n)b
Time
Yieldb
(%)
Entry
The role of glycerol for the N-tert-butyloxycarbonylation of
amines is presented in Scheme 3. Hydrogen bond formation
between glycerol and the carbonyl oxygen atoms of Boc2O
causes “electrophilic activation" making the carbonyl group
more susceptible to nucleophilic attack. Due to hydrogen
bonding established by the glycerol the two compounds, the
di-tert-butylcarbonate and amines will be in the vicinity of
each other and the outcome will be an enhancement of
electrophilicity of carbonyl group and increased nucleophilicity
of the amines nitrogen. Intramolecular nucleophilic attack by
nitrogen atom on the carbonyl carbon followed by elimination
(Min)
1
2
98
1a
1b
1c
1d
2a
2
3
4
2
96
2b
2c
3
3
97
96
2d
2e
t
of CO2, BuOH, and the product N-Boc protected amine. A
similar mechanism for activation carbonyl compounds through
the hydrogen bonding has been reported in water27, alcoholic
solvents28 and in thioglycoluril19.
5
5
98
1e
4

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61.99, 56.53, 28.29, 14.03, HRMS (ESI): Calculated [M + H]+:
310.16, Found: 310.16.
1
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4
Scheme 3 Plausible mechanism for N-Boc protection of amines
Conclusions
In conclusion, a very efficient and catalyst-free methodology
for N-tert-butyloxycarbonylation of amines in glycerol is
reported. The method is highly efficient and environmentally
benign owing to the mild conditions, high yields, excellent
chemoselectivity, easy of product isolation and purification
which fulfil the criterion for a green chemistry practice.
5
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Conflicts of interest
“There are no conflicts to declare”.
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A mixture of amine (1 mmol) and (Boc)2O (1mmol) in glycerol
(2.0 ml) was vigorously stirred at room temperature for
appropriate time (Table 2 and 3) until complete disappearance
of amines was observed in the TLC monitoring. After the
completion of reactions, the reaction mixture was extracted
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1H), 4.57(bs, 1H), 4.16-4.08 (m, 2H), 2.94-2.93(d, J = 6.4 Hz),
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CDCl3): δ 171.84, 154.94, 128.34, 128.07, 127.40, 79.84, 73.15,
3

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New Journal of Chemistry
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DOI: 10.1039/C8NJ01585F
Graphical Abstract
Chemoselective N-tert-butyloxycarbonylation of amines in glycerol
Ajit P Ingale,*ac Vishal K More, a Uddhav S Gangarde a and Sandeep V Shinde bc