Deprotection/reprotection of the amino group in α-amino acids and peptides. A one-pot procedure in [Bmim][BF4] ionic liquid

Article abstract of DOI:10.1039/c3ra46599c

This paper presents an efficient one-pot protocol for the sequential deprotection/reprotection of the α-amino group in α-amino acid and dipeptide methyl esters. [Bmim][BF₄] is used as the solvent in the entire process. In particular, the use of the ionic liquid allows for rapid and clean removal of the 4-nitrobenzenesulfonyl (nosyl) group and for facile subsequent tert-butyloxycarbonylation of the free α-amino function under very mild conditions. N-Boc-α-amino acid as well as peptide derivatives are isolated in excellent yields, and do not require any further purification. Absolute configurations of the precursors are totally preserved during the process.

Full text of DOI:10.1039/c3ra46599c

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PAPER
Deprotection/reprotection of the amino group in
a-amino acids and peptides. A one-pot procedure
in [Bmim][BF4] ionic liquid†
Cite this: RSC Adv., 2014, 4, 2678
a
M. L. Di Gioia, A. Barattucci,b P. Bonaccorsi,b A. Leggio,a L. Minuti,c E. Romio,a
*
A. Temperinid and C. Sicilianoa
This paper presents an efficient one-pot protocol for the sequential deprotection/reprotection of
the a-amino group in a-amino acid and dipeptide methyl esters. [Bmim][BF4] is used as the solvent in
the entire process. In particular, the use of the ionic liquid allows for rapid and clean removal of the
4-nitrobenzenesulfonyl (nosyl) group and for facile subsequent tert-butyloxycarbonylation of the free
a-amino function under very mild conditions. N-Boc-a-amino acid as well as peptide derivatives are
isolated in excellent yields, and do not require any further purification. Absolute configurations of the
precursors are totally preserved during the process.
Received 12th September 2013
Accepted 22nd November 2013
DOI: 10.1039/c3ra46599c
www.rsc.org/advances
useful for the N-protection of amino acids.3 In particular, the 4-
nitrobenzenesulfonyl (nosyl) group covers a key role due to its
Introduction
extreme ability in protecting and simultaneously activating the
NH2 moiety of amines and a-amino acids.4,5 In fact, nosyl
protection is successfully used for site-specic alkylation of
amino acids both in solution and on solid phase;6–10 therefore,
this group is exceptional for the preparation of N-alkylated
amino acids and peptides.11 Another important advantage of
nosyl against Fmoc amino acids is that the former do not form
oxazolones and thus nosyl-amino acyl chlorides can be used in
difficult couplings with less possibility of racemization.12
Despite the conditions used to insert the nosyl group, its
removal, especially in the case of deblocking of primary amines,
is complicated by harsh reaction conditions (elevated temper-
atures and strong bases).2 A further drawback consists in the
difficult separation of the deprotected products from the adduct
formed by the nucleophile and the aromatic derivative.13 The
selection of mild reaction conditions for the removal of
protective groups, in order to prevent the eventual degradation
and to preserve the stereochemical integrity either of the amino
acids or during the peptide chain elongation, is a crucial seek of
the contemporary synthetic chemistry. Therefore, the develop-
ment of an efficient and versatile methodology for the removal
of nosyl group is still a challenging task.
The presence of an amine functionality in a wide range of bio-
logically active compounds makes protection of amines an
important and frequently required exercise in synthetic organic
chemistry.1 In particular, protection of the a-amino function-
ality of amino acids is one of the most important issues in
peptide synthesis and it is mandatory to prevent polymerization
of the amino acid once it is activated. On the other hand,
peptide synthesis, both in solution and on solid phase, is
preferentially carried out in the C to N direction, and a-amino
temporary protecting groups are removed several times during
the synthesis; therefore, removal must be done in mild condi-
tions that do not affect the remaining protecting groups or even
the peptide chain.2
Although there are hundreds of protective groups that can be
introduced and removed by a variety of methods, new and
milder strategies continue to be developed for both introduc-
tion and cleavage of many of the existing protective groups.
Among the different means of masking of amino function, great
efforts have been dedicated to the arylsulfonyl moiety which is
aDipartimento di Farmacia
e Scienze della Salute e della Nutrizione, Edicio
`
Polifunzionale, Universita della Calabria, 87030 Arcavacata di Rende, Cosenza,
The use of ionic liquids (ILs) in organic synthesis has
received great attention due to their unusual properties as non-
conventional solvents.14 In fact, they are characterized by
reasonable stability, low ammability, no miscibility with non
polar solvents.15 In addition, ILs offer the possibility to carry out
the organic reactions with excellent improvement in
product yields and selectivity with respect to classical condi-
tions and enable an easy recover of the reaction products by
simple extraction procedures.16 Recently, the successful use of
Italy. E-mail: ml.digioia@unical.it; Fax: +39 0984 493265; Tel: +39 0984 493095
b
`
Dipartimento di Scienze Chimiche, Universita di Messina, Viale F. Stagno d'Alcontres
31, 98166 Messina, Italy
c
`
Dipartimento di Chimica, Universita di Perugia, via Elce di Sotto 8, 06123 Perugia,
Italy
d
`
Dipartimento di Chimica e Tecnologia del Farmaco, Universita di Perugia, via del
Liceo 1, 06123 Perugia, Italy
† Electronic supplementary information (ESI) available: Copy of 1H and 13C NMR
spectra for compounds 4a–d, 5a–h, 8, 9, 11. Copy of 1H and 13C NMR spectra for
N-Boc-N-methyl-valine methyl ester. See DOI: 10.1039/c3ra46599c
2678 | RSC Adv., 2014, 4, 2678–2686
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1,3-dialkylimidazolium cation based ILs it has been reported for derivative 4a which was obtained pure in 96% yield. The
the chemoselective protection of the NH2 functionality.17 In amount of the acetylated product was consistent with the
particular, ILs have demonstrated to serve as excellent catalysts complete removal of the nosyl group from 1a. Compound 4a
1
for the N-tert-butyloxycarbonylation of various amines and was completely characterized by GC/MS and H and 13C NMR
amino acids.18 All these considerations prompted us to inves- spectroscopy. The results obtained from these preliminary
tigate the use of ILs in the removal of nosyl group and the experiments were very promising, since they clearly showed that
sequential introduction of Boc moiety into amino acid and the removal of the nosyl group from N-protected amino acid
peptides.
methyl esters could indeed occur in an IL. Further advantages of
the procedure against the classical methodologies need to be
pointed here: (i) use of room temperature; (ii) reduced amount
of base; (iii) very short reaction time; (iv) expeditious recovery of
the product by simple solvent extraction; (v) complete separa-
tion of the desired product from the by-product coming from
the unblocking; (vi) complete conversion of the starting mate-
rial and excellent yields in recovered product. The practicability
of the deprotection protocol was next demonstrated with a
series of lipophilic nosyl protected a-amino acid methyl esters
prepared as elsewhere reported4b (Table 1). The treatment of the
precursors 1b–d as previously described for the preliminary test
effectuated with 1a gave the corresponding N-acetylated deriv-
atives 4b–d in excellent yields. The molecular structure of each
Results and discussion
The study of our protocol began selecting N-nosyl-L-valine
methyl ester (1a), prepared as previously described,4b as a model
substrate. Compound 1a was treated with the reagent system
mercaptoacetic acid/sodium methoxide used in our already
reported protocol for the removal of nosyl group.4a The depro-
tection reaction was conducted at room temperature and in
[bmim][BF4] (1-butyl-3-methylimidazolium tetrauoroborate)
as the ionic liquid medium. TLC analysis of the reaction
mixture showed that the starting material remained totally
unchanged with respect to the standard used for the analysis
over 24 h of treatment. Moreover, no different spots related to
the formation of the unmasked amino acid methyl ester 2a and
the by-product 2-[(4-nitrophenyl)thio]acetic, coming from the
removal of the nosyl group, were observed. Upon the conditions
adopted in the above described experiment the basic reagent
sodium methoxide was not soluble, hampering the formation of
the S-nucleophile required for the removal of the nosyl group.
These preliminary data indicated us the need for searching
different basic media to successfully conduct the reaction. The
same experiment was thus repeated replacing sodium meth-
oxide with triethylamine (Scheme 1).
A reduced amount of base (only 5 equiv.) was used instead of
the high excess of sodium methoxide required in the precedent
protocol. The homogenous reaction mixture was monitored by
TLC revealing that starting material disappeared aer only 5
min of stirring. The complete removal of the nosyl group was
denitively assessed by the ninhydrin test. The free amino acid
methyl ester 2a was recovered through a simple extraction with
diethyl ether from [bmim][BF4]. In order to demonstrate the
successful removal of the nosyl group in IL, 2a was character-
ized aer its conversion into the corresponding N-acetyl deriv-
ative 4a by treatment with acetic anhydride under Schotten–
Baumann conditions. The reaction afforded the N-acetylated
1
compound 4b–d was denitively assigned by H and 13C NMR
spectroscopy. In all cases, the amount of the obtained N-acetyl
amino acid methyl esters agreed with the initial amount of the
corresponding amino acid precursor, indicating that nosyl
removal proceeded quantitatively. The easy and clean removal
of the nosyl group in IL and the introduction of the acetyl
moiety which was considered a suitable model for another N-
protecting group, suggested us that the same IL could be used
as the unique solvent medium in one-pot protocols for deno-
sylation/reprotection of the same amino function.
Acylation is an easy method of protection but the harsh
reaction conditions required to regenerate the amine from the
acylated derivative are not suitable for multifunctional
substrates such as amino acids and peptides.19 Conversely, the
N-tert-butyloxycarbonylation is one of the most commonly used
strategies to protect the a-amino function of amino acids under
the mild conditions required by solution phase peptide
synthesis. A number of procedures for Boc introduction are
already reported in the literature.20 Nevertheless, all method-
ologies show drawbacks mainly due to the long reaction times
and side-products formation.21 Thus the design of a highly
efficient protocol for Boc protection of amino acids under
mild and eco-friendly conditions could be advantageous and
still continues to draw attention. Recently, it has been
reported that various amines can be protected with Boc group in
Table 1 Preparation of 2a–d in [Bmim][BF4] and their N-acetylation
Entry
R1
R2
Timea (min)
Yield of 4b (%)
a
b
c
CH(CH3)2
CH2Ph
CH2CH(CH3)2
CH(CH3)CH2CH3
H
H
H
H
5
5
4
6
96
92
89
90
d
a
b
Scheme 1 Removal of nosyl group from 1a–d in [Bmim][BF4] and N-
acetylation of the free amino function of 2a–d.
Referred to the deprotection step in IL. Isolated yield based on
starting 1a–d.
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subsequent Boc reprotection of the free amino acid methyl
esters proceeded in very short times (Table 2). In all cases, yields
in recovered products were excellent ranging from 92% up to
96%. Differently from other procedures already reported for the
Boc protection of amines in ILs,18a no chromatography needed
to recover the nal products. In fact, compounds 5a–h were
obtained in high purity as veried by 1H and 13C NMR spec-
troscopy. As expected, the spectroscopic characteristics of each
compound matched those published for the same molecules
produced by other methodologies.22
Scheme
function of 1a–h in IL.
2 One-pot deprotection/reprotection of the a-amino
IL.18 N-tert-butyloxycarbonylation of amines is efficiently con-
ducted in 1-alkyl-3-methyl-1-imidazolium cation based ILs with
excellent chemoselectivity.17 Thus, we exploited a one-pot nosyl
deprotection and Boc reprotection of the a-NH2 group of amino
acid derivatives in [bmim][BF4]. The rst experiment was per-
formed selecting again 1a as case of study. The removal of nosyl
group was accomplished by treating 1a with the reagent system
mercaptoacetic acid/triethylamine using [bmim][BF4] as the
solvent. The resulting N-deprotected intermediate was not iso-
lated from the IL and directly treated with an equimolar amount
of di-tert-butyl dicarbonate (Boc2O) to reprotect the free a-
amino function (Scheme 2).
The reprotection reaction was conducted at room tempera-
ture without further addition of base. TLC monitoring demon-
strated that the entire process was complete within 10 min.
Extraction with diethyl ether and acidic washing of the organic
layers afforded the corresponding N-Boc-valine methyl ester 5a
which was recovered in an excellent yield referred to the initial
amount of the N-nosyl protected precursor (Table 2). As expec-
ted 1H and 13C NMR spectroscopy clearly conrmed the
molecular structure of 5a. The data obtained conrmed the
feasibility of a one-pot procedure which can straightforwardly
be used in a sequential deprotection/reprotection of the a-
amino function in a-amino acid methyl esters.
We thus envisaged to investigate a larger number of N-nosyl
protected a-amino acid methyl esters. Therefore, the reactivity
of other lipophilic as well as some selected polar amino acid
systems was tested. Starting from the N-nosyl-a-amino acid
methyl esters 1b–h (Table 2), the corresponding N-Boc protected
derivatives 5b–h were uniquely formed. Despite the methods
already reported, the new protocol required only 10–15 min of
stirring at room temperature for the complete removal of
the nosyl group as checked by TLC and GC/MS analysis of the
reaction mixtures. Also the treatment with Boc2O for the
Due to the effectiveness of the method, we considered very
attractive the investigation of its versatility by exploiting the
reactivity of N-nosyl-a-amino acid methyl esters having side-
chain functional groups protected with suitable masking
moieties, which should survive the conditions of deprotection
and reprotection of the “one-pot” protocol. Thus, N-nosyl-
Tyr(OBn) and N-nosyl-Cys(SBn) methyl esters, 1g and 1h
respectively, were used (Table 2). The choice of an O- and
S-benzyl protection was motivated by the fact that the Bn
(benzyl) group has largely been used for the solution and solid-
phase synthesis of a number of relevant peptides using the so-
called “Boc/Bn strategy”.23 In both cases the “one-pot” strategy
afforded the corresponding N-Boc-protected derivatives 5g and
5h in almost quantitative yields referred to the initial amounts
of the respective precursors. Also in these cases, the expected
molecular structure of 5g and 5h was conrmed by 1H and 13
C
NMR, demonstrating the full compatibility of Bn group with the
adopted experimental conditions.
Retention of conguration is a fundamental consideration
in amino acid chemistry. It is well known, in fact, that basic
media could induce racemization of the a-carbon atom. Our
protocol uses a weak base, such as triethylamine; although the
deprotection/reprotection steps are performed at room
temperature in very short times, we decided to check the
stability of the conguration of amino acid skeleton during the
entire process. Firstly we subjected to the protocol N-nosyl-
isoleucine methyl ester 1d. The proton and carbon spectra of
the corresponding Boc-derivative 5d showed only one set of
resonances which was diagnostic for the absence of racemiza-
tion, at least within the sensibility limits of the spectroscopic
techniques. Isoleucine and phenylalanine scaffolds are gener-
ally prone to racemization in polar solvents. Thus, the retention
of conguration was denitively assessed by preparing N-Boc-
phenylalanine methyl ester 1b and its enantiomer 1f by the one-
pot protocol in [bmim][BF4]. Both compounds were then used
as obtained to synthesize the diastereomeric pair of N-Boc-
dipeptides 8 and 9 (Scheme 3). To this aim, compounds 1b and
1f were demethylated11e to afford the corresponding acids which
in turn were immediately reacted with alanine methyl ester
hydrochloride 6 under typical conditions of a 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride/1-hydroxy-
benzotriazole (EDCI/HOBt) assisted coupling for the peptide
synthesis.24 Samples of the crude dipeptides 8 and 9 were
analyzed by 1H and 13C NMR. The complete spectroscopic
analysis of 8 did not exhibit residual signals attributable to the
other diastereomer 9 Furthermore, the proton as well as the
carbon spectrum of 8 and 9 were both characterized by unique
Table 2 Preparation of N-Boc-a-amino acid methyl esters 5a–h in IL
Entry
R1
R2
Timea (min)
Yield of 5b (%)
a
b
c
d
e
f
CH(CH3)2
CH2Ph
CH2CH(CH3)2
CH(CH3)CH2CH3
CH3
H
H
H
H
H
CH2Ph
H
H
10
15
12
10
10
15
15
15
94
96
95
94
94
96
93
92
H
g
h
CH2C6H4OBn
CH2SBn
a
Referred to the total one-pot process. b Isolated yield based on starting
1a–h.
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Scheme 4 One-pot protocol for the preparation of N-Boc-dipeptide
methyl esters 8, 9, 11 in IL.
by mixing approximately equimolar amounts of 8 and 9 (Fig. 1).
In particular, the methyl protons of the alanine residue showed
well distinguishable resonances in the spectra recorded for
both diastereomers. Different chemical shis were observed
also for the amide NH and OCH3 protons.
The preparation of the N-Boc-L-Leu-L-Ala-OMe 11 allowed us
to further explore the possible extension of the one-pot protocol
to deprotect and directly reprotect the amino function of
N-nosyl dipeptides. The previously reported methods required
unfavorable reaction conditions (a large excess of base, long
reaction times, reux) for the removal of the nosyl group from
dipeptidic systems.4a The model dipeptide N-nosyl-L-Leu-L-Ala-
OMe 10c was prepared as previously reported and subjected to
the treatment in [bmim][BF4] (Scheme 4).
Scheme 3 Synthesis of the diastereomeric pair of N-Boc-protected
dipeptide methyl esters 8 and 9 by EDCI/HOBt mediated coupling.
Table 3 N-Boc-protected dipeptide methyl esters 8 and 9 by EDCI/
HOBt mediated coupling
Entry
R1
R2
R3
R4
Yielda (%)
8
9
CH2Ph
H
H
CH2Ph
H
H
CH3
CH3
92
91
The removal of the nosyl group was monitored by TLC;
surprisingly, we noticed that reaction was complete in only 3
min at room temperature, demonstrating the highly efficient
role of the IL in this protocol. Reprotection with Boc2O required
5 min, and the work up conducted on the ethereal extracts of
the reaction mixture afforded the desired N-Boc dipeptide
derivative 11 in a 94% overall yield (Table 4) and isolated in high
purity grade, without the need for chromatographic purica-
a
Yields in recovered products referred to 1b and 1f.
series of signals, demonstrating that the congurations of each
single enantiomer 1b and 1f was preserved during the depro-
tection/reprotection process in [bmim][BF4] (Table 3).
The chemical shi differences between the most signicant
signals of the two diasteromeric dipeptides resulted evident
from the spectroscopic analysis recorded for a sample prepared
1
tion. H and 13C NMR conrmed the structure of 11. Spectra
were characterized by the presence of a unique pattern of
resonance suggesting that no diastereomeric dipeptides were
formed. The preparation of 11 offered us also the opportunity to
check the reusability of [bmim][BF4] in the one-pot protocol.
The results reported in Table 4 clearly indicate that no signi-
cant loss of efficiency of the IL was observed regarding both
yields in recovered product and reaction times.
To conrm the hypothesis of the complete retention of
conguration also when the protocol is applied to preformed
dipeptides, we synthesized the couple of diastereomeric N-nosyl
protected dipeptides 10b and 10c in which the two L- and D-
optical forms of phenylalanine were inserted. Also in the case of
dipeptidyl derivatives 10b and 10c the deprotection/repro-
tection protocol in IL gave the corresponding Boc-protected
analogues in very short time at room temperature and in
excellent overall yields and purity grade (Scheme 4 and Table 4).
1H NMR of 8 and 9, prepared following the one-pot protocol,
conrmed the presence of a single diastereomer in each
sample. The comparison between their 1H NMR spectra with
those recorded for the same compounds obtained via EDCI/
HOBt assisted coupling as previously described, indicated that
the protocol was also epimerization free.
Fig. 1 1H NMR spectrum of a mixture of 8 and 9 (approx. 1 : 1). Spectral
windows: 6.50 ppm, signals of BocNH protons; 3.65 ppm, signals of
OCH3 protons; 1.20–1.30 ppm, signals of CH3 protons of the Ala
residue. (Colors: blue, resonances of 9; green: resonances of 8).
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Table 4 N-Boc-dipeptide methyl esters from [bmim][BF4] and reus-
ability of the IL
thin layer chromatography (TLC) using Merck Silica gel 60-F254
precoated glass plates, and UV light (254 nm) or 0.2% ninhydrin
in ethanol and charring as visualizing agent. GC-MS analyses
were performed using a 30 m ꢀ 0.25 mm, PhMesiloxane capil-
lary column. The mass detector was operated in the electron-
impact ionization mode (EIMS) with an electron energy of 70 eV.
The injection port was heated to 250 ꢁC. The oven temperature
program was initially set at 100 ꢁC with a hold of 2 min and
ramped to 280 ꢁC at 14 ꢁC minꢂ1 with a hold of 10 min. Methane
gas at a pressure of ca. 2 Torr was used as the CI reagent gas.
Evaporation of solvents was performed at reduced pressure
using a rotary vacuum evaporator. N-Nosyl a-amino acid methyl
esters 1a–h and N-nosyl dipeptide methyl esters 8, 9 and 11 were
prepared according to previously published protocol.4 Spectral
data of 1a–h agreed with those already reported for the same
compounds prepared as previously reported.4
R1
R2
H
Entry Product Time (min) Yielda (%)
CH2Ph
H
CH2CH(CH3)2
10a
8
9
9
8
8
96
CH2Ph 10b
10c
95
H
11
94b
a
b
Based on isolated products. Yield of the rst of ve runs using the
same recovered IL. Yields of the four subsequent runs were: 91, 92,
90, 89, respectively.
The validity of this method was further investigated by
preparing N-Boc-N-methyl-valine methyl ester. N-Methyl-a-
amino acids, in fact, cover an important role in medicinal
chemistry, and many efforts have been directed at optimizing
synthetic methods for their preparation and use in peptide
chemistry.2 N-Nosyl-N-methyl-valine methyl ester, prepared as
previously reported,4b was subjected to the one pot protocol in
[bmim][BF4]. The complete removal of nosyl group was
observed aer 30 min at room temperature. The subsequent
reprotection of the free amino group provided N-Boc-N-methyl-
valine methyl ester in 5 min and in 90% yield.
Deprotection of 1a–d and N-acetylation of 2a–d
General procedure. Mercaptoacetic acid (3 mmol) and Et3N
(5 mmol) were added to a solution of 1a–d (1 mmol) in [bmim]-
[BF4] (1 mL). Aer the addition, the reaction mixture was stirred
magnetically at room temperature. The consumption of the
starting materials was monitored by TLC (diethyl ether–petro-
leum ether 60 : 40) and was complete in 4–6 min. The reaction
mixture was then extracted with Et2O (5 ꢀ 4 mL) and the
combined Et2O extracts were concentrated in vacuo. The crude
residue, containing the respective free a-amino acid methyl
esters 2a–d, was solubilized in dry CH2Cl2 (5 mL). Acetic anhy-
dride (1 mL) and a 9% aqueous solution of NaHCO3 (5 mL) were
then added and the mixture was maintained under stirring at
room temperature for 4 h. The organic layer was separated and
the aqueous phase was extracted with three additional portions
of methylene chloride (3 ꢀ 10 mL). The combined organic
layers were washed twice a 9% aqueous solution of NaHCO3,
twice with aqueous HCl 1 N, once with brine and nally dried
(Na2SO4). Filtration and concentration under reduced pressure
gave 4a–d as colorless oils in 89–96% overall yields referred to
the starting materials 1a–d.
Conclusions
In summary, we have described here a one-pot procedure for the
sequential deprotection/reprotection of the amino function of
amino acid and peptide methyl esters in an IL. In particular, the
process was performed in [bmim][BF4] to remove nosyl group and
introduce the acid-labile Boc moiety. Mild conditions, room
temperature, reduced amount of base, very short reaction time,
the ease of extraction of products from IL, excellent yields and
purities, absence of racemization/epimerization and the IL recy-
clability were the distinct advantages of the protocol. The process
appears charming and highly versatile, representing a valuable
tool for the easy removal of 4-nitrobenzenesulfonyl group as well
as for the introduction of the Boc moiety. Finally the synthesis of
N-Boc-N-methyl-valine methyl ester indicates that the method
could be widespread used in amino acid and peptide chemistry.
N-Acetyl-L-valine methyl ester (4a)
Following the general procedure, compound 4a was prepared
from N-nosyl-L-valine methyl ester 1a. Obtained as a colorless oil
(104.6 mg, 96% yield): 1H NMR (300 MHz, CDCl3) d 0.88 [d, J ¼
6.9 Hz, 3H, CH(CH3)2], 0.91 [d, J ¼ 6.9 Hz, 3H, CH(CH3)2], 2.01
(s, 3H, CH3CO), 2.12 [m, 1H, CH(CH3)2], 3.71 (s, 3H, OCH3), 4.54
(dd, J ¼ 8.7 and 5.1 Hz, 1H, a-CH), 6.15 (d, J ¼ 6.9 Hz, 1H, NH);
13C NMR (75 MHz, CDCl3) d 17.8, 18.8, 23.1, 31.2, 52.0, 57.0,
169.9, 172.7. GC/MS (CI): m/z (%) 214 (17), 202 (27) [(M +
C2H5)+], 174 (65) [(M + H)+], 156 (8), 142 (64), 132 (49), 114 (100),
101 (6). Anal. calcd for C8H15NO3: C, 55.47; H, 8.73; N, 8.09.
Found: C, 55.32; H, 8.75; N, 8.06%.
Experimental
Materials and methods
Commercially available reagents were purchased from Sigma-
Aldrich Chemical Co. (Milano, Italy) and used as supplied
unless stated otherwise. Solvents were puried and dried by the
standard procedures and distilled prior to use. All syntheses
were carried out in atmospheric conditions. All the a-amino
acids were of the L-series. In the case of phenylalanine, both the
L- and D-enantiomers were used. 1H NMR spectra were recorded
at 300 MHz, while 13C NMR spectra were measured at 75 MHz.
Spectral analysis was performed at 293 K on diluted solutions of
each compound by using CDCl3 as the solvent. Chemical shis
N-Acetyl-L-phenylalanine methyl ester (4b)
(d) are reported in ppm and referenced to CDCl3 (7.25 ppm for Following the general procedure, compound 4b was prepared
1H and 77.0 ppm for 13C spectra). Coupling constants ( J) are from N-nosyl-L-phenylalanine methyl ester 1b. Obtained as a
reported in Hertz (Hz). Reaction mixtures were monitored by colorless oil (111.3 mg, 92% yield): 1H NMR (300 MHz, CDCl3) d
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1.98 (s, 3H, CH3CO), 3.03–3.18 (m, 2H, CH2Ph), 3.71 (s, 3H, the reaction mixture over a period of 15 min. The nal solution
OCH3), 4.88 (m, 1H, a-CH), 6.08 (d, J ¼ 6.9 Hz, 1H, NH), 7.06– was stirred overnight at room temperature. The mixture was
7.11 (m, 2H, ArH), 7.22–7.32 (m, 3H, ArH); 13C NMR (75 MHz, thus evaporated to dryness under vacuum and the residue dis-
CDCl3) d 23.1, 37.8, 52.6, 53.1, 127.2, 128.4, 129.2, 135.8, 169.8, solved in AcOEt (5 mL). The organic solution was washed with
172.1. GC/MS (CI): m/z (%) 262 (13), 250 (31) [(M + C2H5)+], 222 5% aqueous NaHSO4 (3 ꢀ 5 mL), 5% aqueous NaHCO3 (3 ꢀ
(100) [(M + H)+], 190 (38), 180 (69), 162 (76), 120 (8). Anal. calcd 5 mL) and once with brine (5 mL). The organic layer was dried
for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.38; H, over Na2SO4, ltered and evaporated to dryness under vacuum
6.80; N, 6.35%.
to give 8 (228.2 mg, 91% yield) or 9 (232.4 mg, 93% yield). Each
product displayed 1H and 13C NMR characteristics that matched
those observed for the same compound from the [bmim][BF4]
procedure.
N-Acetyl-L-leucine methyl ester (4c)
Following the general procedure, compound 4c was prepared
from N-nosyl-L-leucine methyl ester 1c. Obtained as a colorless
oil (101.1 mg, 89% yield): H NMR (300 MHz, CDCl3) d 0.91 [d,
1
One pot synthesis of Boc-amino acid methyl esters 5a–h and
Boc-dipeptide methyl esters 8, 9, 11 in [bmim][BF4]
J ¼ 6.3 Hz, 6H, CH2CH(CH3)2], 1.41–1.69 [m, 3H, CH2CH(CH3)2,
CH2CH(CH3)2], 2.01 (s, 3H, CH3CO), 3.71 (s, 3H, OCH3), 4.61 (m,
General procedure. Mercaptoacetic acid (3 mmol) and Et3N
1H, a-CH), 6.07 (d, 1H, J ¼ 7.8 Hz, NH); 13C NMR (75 MHz, (5 mmol) were added to a solution of 1a–h, 8, 9, 11 (1 mmol) in
CDCl3) d 21.9, 22.7, 24.8, 41.6, 50.7, 52.3, 169.9, 173.7; GC/MS [bmim][BF4] (1 mL). The solution was magnetically stirred for
(CI): m/z (%) 228 (26), 216 (41) [(M + C2H5)+], 188 (100) [(M + H)+], 3–7 min at room temperature, until the complete denosylation
170 (7), 156 (58), 146 (54), 128 (100), 86 (7). Anal. calcd for of starting compounds, as monitored by TLC (diethyl ether–
C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.58; H, 9.18; N, petroleum ether 60 : 40). Boc2O (1 mmol) was then added and
7.46%.
the stirring was further maintained for 5–10 min at room
temperature and the progress of the reaction was monitored by
TLC and GC/MS. Aer a total time of 8–15 min the reaction
mixture was diluted with Et2O and the IL settled at the bottom.
The supernatant was decanted off and the IL was washed with
Et2O (5 ꢀ 2 mL). The combined Et2O extracts were washed twice
with a 5% aqueous solution of NaHSO4 and once with brine
(10 mL), dried over Na2SO4 and ltered. Evaporation of the
solvent to dryness under reduced pressure conditions afforded
5a–h in 92–96% yields. Compounds 5a–h displayed NMR
spectral characteristics similar to those elsewhere published for
the same compounds obtained by other methods.20
N-Acetyl-L-isoleucine methyl ester (4d)
Following the general procedure, compound 4d was prepared
from N-nosyl-L-isoleucine methyl ester 1d. Obtained as a
colorless oil (102.3 mg, 90% yield): 1H NMR (300 MHz, CDCl3) d
0.85–0.95 [m, 6H, CH(CH3)CH2CH3, CH(CH3)CH2CH3], 1.20 [m,
1H, CH(CH3)CH2CH3], 1.44 [m, 1H, CH(CH3)CH2CH3], 1.83 [m,
1H, CH(CH3)CH2CH3], 2.01 (s, 3H, CH3CO), 3.72 (s, 3H, OCH3),
4.57 (dd, J ¼ 8.7 and 5.1 Hz, 1H, a-CH), 6.12 (d, J ¼ 8.7 Hz, 1H,
NH); 13C NMR (75 MHz, CDCl3) d 11.5, 15.3, 23.2, 24.9, 37.9,
52.0, 56.4, 169.8, 172.6. GC/MS (CI): m/z (%) 228 (21), 216 (35)
[(M + C2H5)+], 188 (79) [(M + H)+], 170 (5), 156 (51), 146 (31), 128
(100), 86 (5). Anal. calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48.
Found: C, 57.82; H, 9.17; N, 7.46%.
N-Boc-L-valine methyl ester (5a)
Following the general procedure, compound 5a was prepared
from N-nosyl-L-valine methyl ester 1a. Obtained as a viscous
colorless oil (137.2 mg, 94% yield): 1H NMR (300 MHz, CDCl3) d
0.83 [d, J ¼ 6.9 Hz, 3H, CH(CH3)2], 0.90 [d, J ¼ 6.9 Hz, 3H,
CH(CH3)2], 1.39 (s, 9H, t-Bu), 2.07 [m, 1H, CH(CH3)2], 3.68 (s,
3H, OCH3), 4.16 (dd, J ¼ 8.7 and 4.9 Hz, 1H, a-CH), 5.05 (d, J ¼
8.7 Hz, 1H, NH); 13C NMR (75 MHz, CDCl3) d 17.6, 18.9, 27.3,
28.2, 54.4, 58.4, 79.6, 155.6, 173.1. GC/MS (EI): m/z (%) 231 (2),
172 (24), 158 (4), 130 (21), 116 (61), 88 (25), 72 (100), 57 (99).
Anal. calcd for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C,
57.34; H, 9.12; N, 6.08%.
Synthesis of N-Boc-dipeptide methyl esters 8 and 9 via EDCI/
HOBt assisted coupling
General procedure.11e,24 To a solution of N-Boc-L-phenylala-
nine methyl ester 1b or N-Boc-D-phenylalanine methyl ester 1f
(1 mmol) in ethyl acetate (10 mL), LiI (5 mmol) was added and
the resulting solution was heated at reux for 24 h. Aer
complete conversion of the starting amino acid methyl ester, a
saturated aqueous Na2CO3 solution and the mixture was
extracted twice with EtOAc. The aqueous phase was made acidic
by adding 5% aq. KHSO4, then extracted three times with
EtOAc. The organic layers were collected, washed once with
N-Boc-L-phenylalanine methyl ester (5b)
brine, dried over Na2SO4 and evaporated to dryness. The crude Following the general procedure, compound 5b was prepared
residue, containing the free carboxylic acid derivatives, was from N-nosyl-L-phenylalanine methyl ester 1b. Obtained as a
1
directly used for the subsequent coupling reaction. To a solu- viscous colorless oil (147.8 mg, 96% yield): H NMR (300 MHz,
tion of N-Boc-L-Phe-OH or N-Boc-D-Phe-OH (1 mmol) in dry CDCl3) d 1.39 (s, 9H, t-Bu), 2.98–3.14 (m, 2H, CH2Ph), 3.69 (s,
methylene chloride (3 mL) HOBt monohydrate (1 mmol), EDCI 3H, OCH3), 4.57 (m, 1H, a-CH), 5.01 (d, J ¼ 7.9 Hz, 1H, NH), 7.10
(1 mmol) and DIEA (2.5 mmol) was added. The resulting (d, J ¼ 6.5 Hz, 2H, ArH), 7.18–7.31 (m, 3H, ArH); 13C NMR (75
mixture was maintained under magnetic stirring for 45 min at MHz, CDCl3) d 28.1, 38.0, 51.9, 54.4, 79.5, 126.7, 128.3, 129.1,
0
ꢁC. L-Alanine methyl ester hydrochloride (1 mmol) was dis- 136.1, 155.0, 172.2. GC/MS (EI): m/z (%) 279 (2), 223 (7), 206 (10),
solved in dry methylene chloride (2 mL) and added dropwise to 178 (6), 162 (100), 131 (7), 120 (26), 91 (37), 57 (56). Anal. calcd
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for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.24; H, 7.43 (m, 5H, Bn-ArH); 13C NMR (75 MHz, CDCl3) d 28.2, 37.3,
7.57; N, 5.02%.
52.0, 54.4, 69.9, 79.7, 114.8, 127.3, 127.8, 128.2, 128.4, 130.2,
136.9, 146.6, 157.8, 172.28. Anal. calcd for C22H27NO5: C, 68.55;
H, 7.06; N, 3.63. Found: C, 68.82; H, 7.04; N, 3.62%.
N-Boc-L-leucine methyl ester (5c)
Following the general procedure, compound 5c was prepared
from N-nosyl-L-leucine methyl ester 1c. Obtained as a viscous
colorless oil (139.4 mg, 95% yield): 1H NMR (300 MHz, CDCl3) d
0.83 [d, J ¼ 6.3 Hz, 3H, CH2CH(CH3)2], 0.85 [d, J ¼ 6.3 Hz, 3H,
CH2CH(CH3)2], 1.32 (s, 9H, t-Bu), 1.39–1.68 [m, 3H,
CH2CH(CH3)2, CH2CH(CH3)2], 3.64 (s, 3H, OCH3), 4.22 (dt, J ¼
8.7 and 6.9 Hz, 1H, a-CH), 4.98 (d, J ¼ 8.4 Hz, 1H, NH); 13C NMR
(75 MHz, CDCl3) d 21.6, 22.6, 24.5, 27.2, 28.1, 41.5, 51.9, 79.5,
155.3, 173.9. GC/MS (EI): m/z (%) 186 (15), 172 (2), 144 (12), 130
(57), 86 (100), 57 (73). Anal. calcd for C12H23NO4: C, 58.75; H,
9.45; N, 5.71. Found: C, 58.97; H, 9.43; N, 5.69%.
N-Boc-L-cysteine(SBn) methyl ester (5h)
Following the general procedure, compound 5h was prepared
from N-nosyl-L-cysteine(SBn) methyl ester 1h. Obtained as a
viscous colorless oil (147.1 mg, 92% yield): H NMR (300 MHz,
CDCl3) d 1.36 (s, 9H, t-Bu), 2.56 (dd, J ¼ 13.9 and 5.1 Hz, 1H,
CH2SBn), 2.61 (dd, J ¼ 13.9 and 5.1 Hz, 1H, CH2SBn), 3.62 (s, 2H,
SCH2Ph), 3.64 (s, 3H, OCH3), 4.43 (dt, J ¼ 7.8 and 5.1 Hz, 1H, a-
CH), 5.21 (d, J ¼ 7.8 Hz, 1H, NH), 7.08–7.28 (m, 5H, ArH). 13C
NMR (75 MHz, CDCl3) d 28.2, 33.5, 36.5, 52.6, 53.0, 80.0, 127.1,
128.5, 128.9, 137.6, 155.1, 171.5. Anal. calcd for C16H23NO4S: C,
59.05; H, 7.12; N, 4.30. Found: C, 59.27; H, 7.10; N, 4.29%.
1
N-Boc-L-isoleucine methyl ester (5d)
N-Boc-L-phenylalanyl-L-alanine methyl ester (8)
Following the general procedure, compound 5d was prepared
from N-nosyl-L-isoleucine methyl ester 1d. Obtained as a viscous
colorless oil (138.7 mg, 94% yield): 1H NMR (300 MHz, CDCl3) d
0.81 [t, J ¼ 7.2 Hz, 3H, CH(CH3)CH2CH3], 0.82 [d, J ¼ 6.9 Hz, 3H,
CH(CH3)CH2CH3], 1.08 (m, 1H, CH(CH3)CH2CH3], 1.32 [m, 1H,
CH(CH3)CH2CH3], 1.34 (s, 9H, t-Bu), 1.72 (m, 1H, CH(CH3)
CH2CH3], 3.63 (s, 3H, OCH3), 4.13 (m, 1H, a-CH), 5.01 (s broad,
1H, NH); 13C NMR (75 MHz, CDCl3) d 11.3, 15.3, 24.9, 28.1, 37.9,
51.7, 57.7, 79.5, 155.4, 172.6. GC/MS (EI): m/z (%) 186 (24), 172
(3), 144 (17), 130 (92), 86 (78), 57 (100). Anal. calcd for
Following the general procedure, compound 8 was prepared
from N-nosyl-L-phenylalanyl-L-alanine methyl ester 10a.
Obtained asa viscous colorless oil (148.1 mg, 92% yield): 1H NMR
(300 MHz, CDCl3) d 1.28 (d, 3H, J ¼ 7.2 Hz, CHCH3), 1.33 (s, 9H,
tBu), 2.88–3.09 (m, 2H, CH2Ph), 3.63 (s, 3H, OCH3), 4.38 (m, 1H,
a-CHPhe), 4.47 (quintet, J ¼ 7.2 Hz, a-CHAla), 5.29 (d, 1H, J ¼ 8.2
Hz, NHCHCH3), 6.84 (s broad, 1H, OCONH), 7.10–7.23 (m, 5H,
ArH); 13C NMR (75 MHz, CDCl3) d 17.8, 28.1, 38.3, 47.9, 52.1, 55.7,
79.8, 126.6, 128.3, 129.2, 136.6, 155.4, 171.0, 172.7. GC/MS (EI):
m/z (%) 294 (5), 277 (3), 233 (10), 174 (11), 164 (37), 159 (21), 120
(90), 91 (19), 77 (4), 57 (100). Anal. calcd for C18H26N2O5: C, 61.70;
H, 7.48; N, 7.99. Found: C, 61.48; H, 7.50; N, 7.97%.
C
12H23NO4: C, 58.75; H, 9.45; N, 5.71. Found: C, 58.53; H, 9.49;
N, 5.72%.
N-Boc-L-alanine methyl ester (5e)
N-Boc-D-phenylalanyl-L-alanine methyl ester (9)
Following the general procedure, compound 5e was prepared
from N-nosyl-L-alanine methyl ester 1e. Obtained as a viscous
colorless oil (132.1 mg, 94% yield): 1H NMR (300 MHz, CDCl3) d
1.35 (d, J ¼ 7.2 Hz, 3H, CHCH3), 1.41 (s, 9H, t-Bu), 3.71 (s, 3H,
OCH3), 4.27 (quintet, J ¼ 7.2 Hz, 1H, a-CH), 5.05 (s broad, 1H,
NH); 13C NMR (75 MHz, CDCl3) d 18.4, 28.1, 48.1, 52.1, 79.6,
155.2, 172.8. GC/MS (EI): m/z (%) 144 (52), 130 (9), 116 (6), 102
(16), 88 (40), 59 (36), 57 (100). Anal. calcd for C9H17NO4: C,
53.19; H, 8.43; N, 6.89. Found: C, 53.39; H, 8.44; N, 6.87%.
Following the general procedure, compound 9 was prepared
from N-nosyl-D-phenylalanyl-L-alanine methyl ester 10b.
Obtained as a viscous colorless oil (151.3 mg, 95% yield): 1H
NMR (300 MHz, CDCl3) d 1.21 (d, 3H, J ¼ 7.3 Hz, CHCH3), 1.34
(s, 9H, tBu), 2.93–3.07 (m, 2H, CH2Ph), 3.64 (s, 3H, OCH3), 4.35
(m, 1H, a-CHPhe), 4.46 (quintet, J ¼ 7.3 Hz, 1H, a-CHAla), 5.31
(d, J ¼ 8.1 Hz, NHCHCH3, 1H), 6.58 (d, J ¼ 7.3 Hz, 1H, OCONH),
7.11–7.24 (m, 5H, ArH); GC/MS (EI): m/z (%) 294 (5), 277 (3), 233
(11), 174 (12), 164 (41), 159 (20), 120 (92), 91 (21), 77 (4), 57 (100).
13C NMR (75 MHz, CDCl3) d 17.8, 28.1, 38.3, 47.9, 52.0, 55.6,
79.9, 126.6, 128.4, 129.2, 136.7, 155.2, 170.8, 172.8. Anal. calcd
for C18H26N2O5: C, 61.70; H, 7.48; N, 7.99. Found: C, 61.60; H,
7.46; N, 8.01%.
N-Boc-D-phenylalanine methyl ester (5f)
Following the general procedure, compound 5f was prepared
from N-nosyl-D-phenylalanine methyl ester 1f. Obtained as a
viscous colorless oil (148 mg, 96% yield). Anal. calcd for
C
15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.70; H, 7.56;
N, 5.00%.
N-Boc-L-leucyl-L-alanine methyl ester (11)
Following the general procedure, compound 11 was prepared
N-Boc-L-tyrosine(OBn) methyl ester (5g)
from N-nosyl-L-leucyl-L-alanine methyl ester 10c. Obtained as a
1
Following the general procedure, compound 5g was prepared viscous colorless oil (185.4 mg, 94% yield): H NMR (300 MHz,
from N-nosyl-L-tyrosine(OBn) methyl ester 1g. Obtained as a CDCl3) d 0.90 [d, J ¼ 6.2 Hz, 3H, CH2CH(CH3)2], 0.91 [d, J ¼ 6.2
1
viscous colorless oil (150.4 mg, 93% yield): H NMR (300 MHz, Hz, 3H, CH2CH(CH3)2], 1.39 (d, J ¼ 7.5 Hz, 3H, CHCH3), 1.49
CDCl3) d 1.39 (s, 9H, t-Bu), 3.02 (m, 2H, CHCH2), 3.69 (s, 3H, (s, 9H, tBu), 1.52–1.73 [m, 3H, CH2CH(CH3)2, CH2CH(CH3)2],
OCH3), 4.55 (m, 1H, a-CH), 5.02 (s, 2H, CH2Ph), 6.89 (d, J ¼ 8.7 3.73 (s, 3H, OCH3), 4.40–4.49 (m, 1H, a-CHLeu), 4.52 (quintet,
Hz, 2H, o-OBnArH), 7.03 (d, J ¼ 8.7 Hz, 2H, m-OBnArH), 7.27– J ¼ 7.5 Hz, 1H, a-CHAla), 6.73 (m, 2H, OCONH, NHCHCH3);
2684 | RSC Adv., 2014, 4, 2678–2686
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13C NMR (75 MHz, CDCl3) d 18.1, 21.8, 23.0, 24.7, 28.1, 40.5,
48.1, 51.8, 52.4, 79.8, 155.2, 171.1, 173.0. Anal. calcd for
Acknowledgements
C
15H28N2O5: C, 56.94; H, 8.92; N, 8.85. Found: C, 57.15; H,
This work was supported by grants from MIUR (Ministero
8.90; N, 8.88%.
`
Italiano dell'Universita e della Ricerca, ex-60% funds).
Mixture of 8 and 9
Notes and references
Mixture of diastereomers (1 : 1 ratio): 1H NMR (300 MHz,
CDCl3) d 1.20 (d, J ¼ 7.2 Hz, 3H, CHCH3), 1.28 (d, J ¼ 7.2 Hz, 3H,
CHCH3), 1.33 (s, 9H, tBu), 1.34 (s, 9H, tBu), 2.96–3.11 (m, 4H,
CH2Ph), 3.63 (s, 3H OCH3), 3.64 (s, 3H, OCH3), 4.28–4.41 (m, 2H,
a-CHPhe), 4.41–4.55 (m, 2H, a-CHAla), 5.12 (m, 2H, NHCHCH3),
6.40 (d, J ¼ 7.3 Hz, 1H, OCONH), 6.55 (d, J ¼ 7.3 Hz, 1H,
OCONH), 7.10–7.23 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3) d
17.8, 18.0, 28.1, 38.2, 38.6, 47.8, 47.9, 52.1, 55.7, 55.8, 79.9,
126.7, 128.4, 129.2, 136.5, 136.6, 155.2, 170.6, 170.8, 172.6,
172.8.
1 T. W. Greene and P. G. M. Wuts, Protecting Group in Organic
Synthesis, John Wiley and Sons, New York, 1999.
´
2 A. Isidro-Llobet, M. Alvarez and F. Albericio, Chem. Rev.,
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3 (a) R. De Marco, M. L. Di Gioia, A. Liguori, F. Perri,
C. Siciliano and M. Spinella, Tetrahedron, 2011, 67, 9708–
9714.
4 (a) A. Leggio, M. L. Di Gioia, A. Liguori and F. Perri,
Tetrahedron, 2007, 63, 8164–8173; (b) M. L. Di Gioia,
A. Leggio, A. Le Pera, A. Liguori, A. Napoli, C. Siciliano and
G. Sindona, J. Org. Chem., 2003, 68, 7416–7421.
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1995, 36, 6373–6374.
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2690–2691.
7 E. Biron and H. Kessler, J. Org. Chem., 2005, 70, 5183–
5189.
Recycling of [Bmim][BF4] in the synthesis of 11
General procedure. At the end of the rst experiment and
aer the product recovery, the resultant orange paste-like IL
thus obtained, was treated with 5% aqueous HCl (2 mL) and
subjected to consecutive extractions with methylene chloride.
The ionic liquid was recovered by removing water under
vacuum. The IL was nally dried at 100 ꢁC for 1 h and reused for
next run without any signicant loss of efficiency (91, 92, 90 and
89% yields).
8 T. Kan and T. Fukuyama, Chem. Commun., 2004, 353–359.
9 M. L. Di Gioia, A. Leggio and A. Liguori, J. Org. Chem., 2005,
70, 3892–3897.
10 M. L. Di Gioia, A. Leggio, A. Liguori and F. Perri, J. Org.
Chem., 2007, 72, 3723–3728.
One pot synthesis of N-Boc-N-methyl-L-valine methyl ester in
11 (a) S. C. Miller and T. S. Scanlan, J. Am. Chem. Soc., 1997, 119,
2301–2302; (b) E. Biron, J. Chatterjee and H. Kessler, J. Pept.
Sci., 2006, 12, 213–219; (c) A. Leggio, A. Liguori, A. Napoli,
C. Siciliano and G. Sindona, J. Org. Chem., 2001, 66, 2246–
2250; (d) E. Belsito, M. L. Di Gioia, A. Greco, A. Leggio,
A. Liguori, F. Perri, C. Siciliano and M. C. Viscomi, J. Org.
Chem., 2007, 72, 4798–4802; (e) E. Belsito, R. De Marco,
M. L. Di Gioia, A. Liguori, F. Perri and M. C. Viscomi, Eur.
J. Org. Chem., 2010, 4245–4252; (f) M. L. Di Gioia,
A. Leggio, A. Liguori, F. Perri, C. Siciliano and
M. C. Viscomi, Amino Acids, 2010, 38, 133–143.
[bmim][BF4]
Mercaptoacetic acid (3 mmol) and Et3N (5 mmol) were added
to a solution of N-nosyl-N-methyl-L-valine methyl ester (1
mmol) in [bmim][BF4] (1 mL). The solution was magnetically
stirred for 30 min at room temperature, until the complete
denosylation of starting compounds, as monitored by TLC
(diethyl ether–petroleum ether 60 : 40). Boc2O (1 mmol) was
then added and the stirring was further maintained for 5 min
at room temperature and the progress of the reaction was
monitored by TLC and GC/MS. The reaction mixture was
diluted with Et2O and the IL settled at the bottom. The 12 E. Vedejs, S. Lin, A. Klapars and J. Wang, J. Am. Chem. Soc.,
supernatant was decanted off and the IL was washed with 1996, 118, 9796–9797.
Et2O (5 ꢀ 2 mL). The combined Et2O extracts were washed 13 R. De Marco, M. L. Di Gioia, A. Leggio, A. Liguori and
twice with a 5% aqueous solution of NaHSO4 and once with M. C. Viscomi, Eur. J. Org. Chem., 2009, 3795–3800.
brine (10 mL), dried over Na2SO4 and ltered. Evaporation of 14 (a) P. Wasserscheid and T. Welton, Ionic Liquids in Synthesis,
the solvent to dryness under reduced pressure conditions
afforded N-Boc-N-methyl-L-valine methyl ester as a viscous
colorless oil in 90% yield: 1H NMR (300 MHz, CDCl3, a
Wiley-VCH, 2004; (b) M. A. P. Martins, C. P. Frizzo,
D. N. Moreira, N. Zanatta and H. G. Bonacorso, Chem. Rev.,
2008, 108, 2015–2050.
mixture of rotamers) d 0.87 [d, J ¼ 6.9 Hz, 3H, CH(CH3)2], 15 (a) M. J. Earle and R. A. Sheldon, Pure Appl. Chem., 2000, 72,
0.98 [d, J ¼ 6.9 Hz, 3H, CH(CH3)2], 1.43 (s, 9H, tBu), 1.99–2.21
[m, 1H, CH(CH3)2], 2.78 and 2.82 (s, 3H, NCH3), 3.69 (s, 3H,
OCH3), 4.08 and 4.42 (d, J ¼ 10.6 Hz, 1H, a-CH); 13C NMR (75
MHz, CDCl3) d 19.1, 27.8, 28.3, 30.3, 51.5 and 51.6, 70.9, 79.7,
155.3, 171.5. GC/MS (EI): m/z (%) 245 (2), 186 (15), 144 (17),
130 (79), 102 (49), 86 (92), 57 (100), 41 (34). Anal. calcd for
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