A greener, efficient and catalyst-free ultrasonic-assisted protocol for the n-fmoc protection of amines

Article abstract of DOI:10.5935/0103-5053.20150286

A simple, eco-sustainable method for the N-(9-fluorenylmethoxycarbonyl) (N-Fmoc) protection of various structurally amines under ultrasonic irradiation is reported. The corresponding N-Fmoc derivatives were obtained in good to excellent yields within short reaction time. The reaction proceeds without the formation of any side product. Mildness, efficiency and easier work are the main advantages of this new protocol.

Full text of DOI:10.5935/0103-5053.20150286

http://dx.doi.org/10.5935/0103-5053.20150286
J. Braz. Chem. Soc., Vol. 27, No. 3, 546-550, 2016.
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Article
A
A Greener, Efficient and Catalyst-Free Ultrasonic-Assisted Protocol for the N-Fmoc
Protection of Amines
Rachida Mansouri, Zineb Aouf, Salah Lakrout, Malika Berredjem and Nour-Eddine Aouf*
Laboratory of Applied Organic Chemistry (L.C.O.A.), Bioorganic Chemistry Group, Sciences
Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Box 12, 23000 Annaba, Algeria
A simple, eco-sustainable method for the N-(9-fluorenylmethoxycarbonyl) (N-Fmoc) protection
of various structurally amines under ultrasonic irradiation is reported. The corresponding N-Fmoc
derivatives were obtained in good to excellent yields within short reaction time. The reaction
proceeds without the formation of any side product. Mildness, efficiency and easier work are the
main advantages of this new protocol.
Keywords: N-Fmoc, protection, amines, ultrasound irradiations, green chemistry
derivatives, which include polymers,6 dimethoxytriazinyloxy
Introduction
moiety,7 triazoles,8 and water through photochemical
acylation.9 However, some of these procedures, although
effective, have several drawback, such as the use of expensive
catalysts, long reaction times, formation of the side-product
and use of toxic organic solvents.
In the last three years, several eco-sustainable
methodologies have been reported. In this context,
Gawande and Branco10 have used water as solvent for
the Fmoc protection of amines and lately, Braga and
co-workers11 described a solvent-free Fmoc protection
of amines under microwave conditions. More recently,
Nardi et al.12 described a new catalyst-free, water mediated
method for the protection of amines and amino acids with
di-tert-butyl dicarbonate, 9-fluorenylmethoxycarbonyl
chloride, acetyl chloride and tosyl chloride. The
protection is achieved in few minutes under microwave
irradiation.
The development of greener and eco-sustainable
methodologies for synthetic transformations is in great
demand.13 In this attention, sonochemistry has gained
considerable importance in organic chemistry.14 The
implementation of ultrasonic irradiations in organic
reactions provides a specific activation based on physical
proprieties, such as acoustic cavitation. Sonochemistry
offers a more versatile and facile pathway for a large variety
of reaction in comparison to conventional methods.
Continuing our interest towards the development
of green synthetic methods in chemistry of protecting
groups,15 we report the N-Fmoc protection of various
structurally amines in the absence of any solvent and
catalyst under ultrasonic irradiation.
The development of greener and simple methods for
protection of amines and amine derivatives is in great
demand in multi-step organic synthesis. Protecting groups
are used during organic synthesis to block temporarily
certain functional groups and prevent undesired reaction.
When the synthesis is complete and protection is no longer
necessary, the protective group is removed to restore the
functional group to its natural form.
Allyloxycarbonyl (Alloc), tert-butyloxycarbonyl (Boc),
(trichloroethyl) carbamate (Troc), benzyloxycarbonyl
(Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc) are
the most useful protecting groups for primary and
secondary amines and especially for amino acids.1
Among them, the Fmoc2 group is used extensively, as it
can be easily introduced by coupling an amine with an
activated 9-fluorenymethyl carbonate like Fmoc-chloride
(Fmoc-Cl),3 (9-fluorenylmethoxycarbonyloxy)succinimide
(Fmoc-OSu),4 or Fmoc benzotriazole-1-yl carbonate
(Fmoc-OBt).5 The main advantage of the Fmoc group is
its stability towards acidic conditions, which allows the
selective removal of other groups like Boc in presence
of acids. The Fmoc group is, in general, rapidly removed
by primary (i.e., cyclohexylamine, ethanolamine) and
secondary (i.e., piperidine, piperazine) and slowly cleaved
by tertiary amines.1
There are several protocols available for the protection of
amino groups as N-(9-fluorenylmethoxycarbonyl) (N-Fmoc)
*e-mail: noureddine.aouf@univ-annaba.dz, noureddineaouf@yahoo.fr

Vol. 27, No. 3, 2016
Mansouri et al.
547
Results and Discussion
resonance (NMR), mass spectrometry (MS) and infrared
spectroscopy (IR) and comparison with known compounds.
The different 1H NMR spectra showed two characteristic
signals between 4 and 5 ppm; a doublet corresponding to the
methylene protons (OCH2) and a triplet corresponding to
the methine (CH) group. In the IR spectra, the compounds
exhibit characteristic absorption at 1678-1700 cm−1
(CO carbamate).
In our initial attempt, we initiated our study by
evaluating the protection reaction of aniline 1 with
Fmoc-Cl 2 in dichloromethane (CH2Cl2), as solvent,
under ultrasonic irradiation. The reaction was completed
in three minutes and the N-Fmoc product was obtained in
95% yield. We also achieved the reaction in the absence
of solvent and got the same yield (Scheme 1). Thus, we
concluded that the ultrasonic irradiations plays an essential
role and the solvent did not affect the result of the reaction.
After exploiting the scope of various solvents, such
as CH2Cl2, chloroform (CHCl3), acetonitrile (CH3CN),
ethanol (EtOH), tetrahydrofuran (THF) and water (H2O)
for the reaction, we found no significant difference with
solvent free conditions.
Encouraged by these preliminary experimental results
and to increase the scope of this reaction, a series of
diverse structurally primary and secondary amines were
treated with Fmoc-Cl to synthesize a wide range of
Fmoc carbamates under ultrasound-assisted solvent-free
conditions (Table 1, entries 1-17).
Conclusions
In conclusion, we have developed a new, efficient,
simple and catalyst-free chemoselective N-Fmoc protection
of various amines, using ultrasound irradiation. The protocol
is an offering potential and should find many applications
in organic synthesis, especially peptides chemistry. The
methodology has also several other advantages such as:
excellent isolated yields, simple experimental procedure,
solvent-less conditions and the absence of any competitive
or side reactions. Further work is in progress to explore this
process for use in other protecting groups.
In all cases, the substrate underwent smooth conversion
to the corresponding N-Fmoc amines in good to excellent
yields.As it can be seen in Table 1, the nature of substituents
on the aromatic rings did not affect the yield.
In order to exploit the chemoselectivity of this
methodology, we also attempted the N-Fmoc protection
of β-amino alcohols under the same reaction conditions
(Table 2, entries 18-22). The corresponding N-Fmoc
derivatives were obtained as the only product in excellent
yields,withoutformationoftheO-fluorenylmethoxycarbonyl
(O-Fmoc) side produc.
Due to their importance in peptide synthesis, protection
of amino acids and their derivatives is of great interest, we
decided to extend our study to a series of amino acid esters,
N-Fmoc amino acid esters (Table 3, entries 23-27). As can
be seen in Table 3, the isolated yields of products were in
the range of 85-92% after 2 min of reaction.
The structure of all N-Fmoc carbamates were
unambiguously confirmed by usual spectrometric methods,
i.e., proton (1H ) and carbon 13 (13C) nuclear magnetic
Experimental
All commercial chemicals were used without further
purification. Sonication was performed in a FUNGILAB
ultrasonic bath (Spain) with a frequency of 40 kHz and
a power of 250 W. All reactions were monitored by thin
layer chromatography (TLC) on silica Merck 60 F254
percolated aluminum plates (Germany). Melting points
were measured in open capillary tubes on an electro-
1
thermal apparatus. H spectra were recorded on a
400 MHz Bruker spectrometer (USA). Chemical shifts are
reported in d units (ppm) with tetramethylsilane (TMS)
as a reference. All coupling constants (J) are reported on
Hz. Multiplicity is indicated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet).
13C NMR spectra were recorded on a 100 MHz Bruker
spectrometer (USA). Chemical shifts are reported on
d units (ppm) with chloroform (CDCl3) as a reference.
Infrared spectra were recorded on a PerkinElmer FT-600
spectrometer (USA). Mass spectra were recorded on a
O
O
NH2
r.t.,)))
O
+
HN
Cl
O
Neat
1
2
Scheme 1. N-(9-Fluorenylmethoxycarbonyl) protection of aniline.

548
A Greener, Efficient and Catalyst-Free Ultrasonic-Assisted Protocol for the N-Fmoc Protection of Amines J. Braz. Chem. Soc.
Table 1. N-(9-Fluorenylmethoxycarbonyl) derivatives of primary and secondary amines under ultrasound irradiation
O
O
R1
r.t., )))
Neat
R1
NH
Cl
O
N
O
+
R2
R2
R1, R2 = Alkyl, Aryl
entry
1
Substrate
Product
Yield / %
95
time / min
5
m.p.a / °C
NH2
NHFmoc
191
191-19211
NH2
OCH3
NH2
NHFmoc
OCH3
2
3
93
91
4
5
189
NHFmoc
184
192-19311
H3CO
H3CO
NHFmoc
NH2
192-193
195-19711
4
5
6
94
90
91
5
4
4
H3C
H3C
Cl
NH2
NHFmoc
162
163-16510
Cl
NH2
NHFmoc
176
172-17410
F
F
NH2
7
NHFmoc
92
3
191
NHFmoc
NH2
8
92
88
85
3
3
3
192
175-179
137
NH2
9
NHFmoc
10
NH2
NH2
NH2
NHFmoc
NHFmoc
11
12
83
84
2
2
103-105
102
NHFmoc
13
14
15
77
72
75
5
5
5
121
NH
NFmoc
112
113-11511
FmocN
O
HN
O
Oil
NFmoc
NH
H
N
Fmoc
N
120
16
87
79
5
5
119-12011
N
NH
N
NFmoc
17
117
aMelting point.

Vol. 27, No. 3, 2016
Mansouri et al.
549
Table 2. N-(9-Fluorenylmethoxycarbonyl) of β-amino alcohols under ultrasound irradiation
R
R
r.t., )))
OH
Fmoc-Cl
OH
+
NH2
NHFmoc
Neat
entry
18
Substrate
Product
Yield / %
87
time / min
2
m.p.a / °C
NHFmoc
NH2
146
HO
HO
HO
OH
HO
OH
19
20
85
86
2
2
138
NH2
NHFmoc
OH
120-123
OH
NH2
NHFmoc
OH
OH
21
87
89
2
2
117-119
112
NHFmoc
NH2
OH
OH
22
NHFmoc
NH2
aMelting point.
Table 3. N-(9-Fluorenylmethoxycarbonyl) of α-amino acid esters under ultrasound irradiation.
O
O
r.t., )))
R
R
Fmoc-Cl
+
OEt
OEt
Neat
NHFmoc
NH2
entry
23
Substrate
Product
Yield / %
time / min
2
m.p.a / °C
O
O
90
85
91
88
92
108
OEt
OEt
NH2
NHFmoc
O
O
24
25
26
2
2
2
2
98-90
87
OEt
NH2
OEt
NHFmoc
O
O
OEt
OEt
NH2
NHFmoc
O
O
85-87
107
OEt
OEt
NH2
NHFmoc
O
O
27
OEt
OEt
NHFmoc
NH2
aMelting point.
Shimadzu QP 1100 Ex mass spectrometer (USA) operating
at an ionization potential of 70 eV.
placed in a glass tube under neat conditions and were
sonicated for a suitable time (as indicated in Tables 1, 2
and 3). All reactions were performed in a water bath at
room temperature. After completion of the reaction (as
indicated by TLC), 5 cm3 of diethyl ether was added to
the mixture. The N-Fmoc derivatives were crystallized and
were obtained in good to excellent yields.
General procedure of N-Fmoc protection on amines
derivatives promoted by ultrasound irradiations
Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were

550
A Greener, Efficient and Catalyst-Free Ultrasonic-Assisted Protocol for the N-Fmoc Protection of Amines J. Braz. Chem. Soc.
Purification of the product was accomplished by
recrystallization from diethyl ether.
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Acknowledgements
This work was supported financially by The General
Directorate for Scientific Research and Technological
Development (DG-RSDT),Algerian Ministry of Scientific
Research, Applied Organic Laboratory (FNR 2000).
We also thank Professor Jacques Lebreton (Université
de Nantes, France) for his help in the identification of
all products in NMR and MS and fruitful discussions
with Professor Carlos Afonso (Universidade de Lisboa,
Portugal). The authors are thankful to MSc Sara Boughaba
and MSc Meriem Saadi (Université Badji Mokhtar-Annaba,
Algeria) for their help in this work.
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Published online: October 30, 2015