N-Urethane protection of amines and amino acids in an ionic liquid

Article abstract of DOI:10.1039/c5ra12121c

An efficient, solvent-free protocol for the N-fluorenylmethoxycarbonylation and N-benzyloxycarbonylation of amines is described. The reaction of aliphatic and aromatic amines with FmocOSu and Cbz-Osu in [Bmim][BF₄] at room temperature afforded the corresponding N-urethane derivatives in excellent yields and do not require any further purification. The method has been extended to the N-Fmoc and N-Cbz protection of amino acids. Absence of bases, very short reaction times, high yields, selectivity and ease of product separation are some advantages of this protocol.

Full text of DOI:10.1039/c5ra12121c

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N-Urethane protection of amines and amino acids
in an ionic liquid†
Cite this: RSC Adv., 2015, 5, 63407
*
*
M. L. Di Gioia, A. Gagliardi, A. Leggio, V. Leotta, E. Romio and A. Liguori
An efficient, solvent-free protocol for the N-fluorenylmethoxycarbonylation and N-benzyloxycarbonylation of
amines is described. The reaction of aliphatic and aromatic amines with FmocOSu and Cbz-Osu in [Bmim]-
[BF4] at room temperature afforded the corresponding N-urethane derivatives in excellent yields and do
not require any further purification. The method has been extended to the N-Fmoc and N-Cbz protection
of amino acids. Absence of bases, very short reaction times, high yields, selectivity and ease of product
separation are some advantages of this protocol.
Received 23rd June 2015
Accepted 20th July 2015
DOI: 10.1039/c5ra12121c
www.rsc.org/advances
expensive catalysts, strong basic conditions, long reaction
times, the use of toxic (e.g. carcinogenic) solvents, chromato-
Introduction
graphic methods for the obtainment of the pure N-protected
amines.
Hence, a simple, mild and environmentally friendly method
for obtaining high yields in the urethane protection of amines
remains highly desirable.
Room temperature ionic liquids (ILs), especially those based
on the 1-N-alkyl-3-methylimidazolium cation, have shown great
promise as smart alternatives to conventional solvents because
of their unique features such as reasonable stability, low am-
mability, no miscibility with non-polar solvents.10
Due to their great potential as alternative reaction media for
catalytic processes, much attention has been focused on
organic reactions promoted by ionic liquids.11
In addition, ionic liquids show selectivity and enhancement
in reaction rates, compared to common organic solvents with
the added advantage of the ease of recovery and reuse of these
ionic solvents.12 Due to these benets, ionic liquids can make a
substantial contribution to green chemistry.
Recently, we reported on the use of 1-butyl-3-methylimidazolium
tetrauoroborate [Bmim][BF4] as the ionic liquid medium for the
clean removal of the 4-nitrobenzenesulfonyl (nosyl) protecting
group and for the easy subsequent tertbutyloxycarbonylation of
the free a-amino function of a-amino acid and dipeptide methyl
esters.13 Moreover, various ILs catalysts have been employed
for the preparation of N-Boc derivatives,14 and reports for the
N-Cbz protection are scanty and require chromatographic
purication;15 on the other hand there are no reports of using a
ionic medium for the synthesis of Fmoc-protected amines in the
literature.
The development of mild and selective protocols for the
protection and deprotection of amines continues to be an
essential tool in the eld of organic chemistry especially in
peptide, nucleoside, polymer or combinatorial synthesis.1
The presence of an amino group in various biologically active
compounds makes its protection a necessity during their
synthesis and transformation.1 Consequently, several kinds of
protecting groups have been successfully used in this regard.2
In this context, the carbamate derivatives occupy a prom-
inent position in the ranks of commonly used amine protecting
groups (PGs).3
Among them, the use of carbamates, such as tert-butyloxy-
carbonyl (Boc), carbobenzyloxy (Cbz), and 9-uorenylmethyloxy-
carbonyl (Fmoc), as protecting groups for amines has been
signicant because of the efficiency in the protection, inertness in
various reaction conditions as well as easiness in deprotection.1,2a,3
The Fmoc group has been notably used for orthogonal
protection of organic molecules for its important features of
lability in basic media and stability in acidic media.4 The Cbz
group is stable to basic and most aqueous acidic media and can
be easily removed by catalytic hydrogenation.5 The Boc group
enjoys popularity as a protecting group for amines due to its
stability toward nucleophilic attack, basic media as well as
catalytic hydrogenation.6
As a result of their importance, several methods for the
preparation of Fmoc-7 Cbz-8 or Boc-9 protected amines have
been developed to date. Nevertheless, all of these procedures
have their own particular drawbacks, such as the use of
In continuation of our efforts in green chemistry and to
explore the applicability of ionic liquids as reaction media, here
we report the successful use of [Bmim][BF4] as a solvent for the
selective Fmoc and Cbz-protection of various structurally
amines in a ionic liquid assisted process.
Dipartimento di Farmacia
e Scienze della Salute e della Nutrizione, Edicio
`
Polifunzionale, Universita della Calabria, 87030 Arcavacata di Rende, Cosenza,
Italy. E-mail: ml.digioia@unical.it; A.Liguori@unical.it; Fax: +39 0984 493265; Tel:
+39 0984 493095, +39 0984 493205
† Electronic supplementary information (ESI) available: Copy of 1H and 13C NMR
spectra for compounds 3a–o and 4a–o. See DOI: 10.1039/c5ra12121c
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activation of Fmoc-OSu, making the carbonyl group susceptible
to nucleophilic attack by the amine.
Results and discussion
At this point, we attempted to extend the generality of the
reaction by using [Bmim][BF4] as the reaction medium.
Different aliphatic (acyclic and cyclic) amines and various
aromatic and heteroaromatic amines were tested. The reaction
thus carried out in [Bmim][BF4] at room temperature afforded
the corresponding N-Fmoc derivatives in excellent yields and
with a short reaction time (3–9 min) (Table 1).
In order to investigate the optimum model reaction, we
selected, aniline (2a), an aromatic amine, as model substrate
because of the low nucleophilicity of the amine nitrogen.
aniline (2a) was treated with 9-uorenylmethyloxycarbonyl
chloride (Fmoc-Cl) (1) (1 : 1 mmol) in 1 mL of [Bmim][BF4]. The
reaction was attempted at room temperature and in absence of
any organic solvent or bases. TLC analysis of the reaction
mixture showed aer only 1 minute the disappearance of the
FmocCl and the formation of a new spot on the TLC plate that
travels with the solvent front and assigned to dibenzofulvene: in
this case, it is more likely that the ionic liquid assists the b-
elimination to give quickly the dibenzofulvene and liberation of
the chlorine ion. Although the Fmoc-Cl (1) represents the
reagent of choice traditionally employed for the incorporation
of the Fmoc group, it has a series of drawbacks such as its
instability and the tendency to promote the formation of
undesirable by-products.16 Therefore, we decided to use a
commercially available reagent with a different leaving group
such as the 9-uorenylmethyl succinimidyl carbonate (Fmoc-
OSu) that has shown to be a more shelf-stable carbonate.17 We
repeated the same model reaction using 1 equiv. of FmocOsu to
add the Fmoc protecting group (Scheme 1). The reaction con-
ducted in [Bmim][BF4] (1 mL) at room temperature was
In most cases, the products were obtained in good to excel-
lent yields. Aniline and benzylamine derivatives were subjected
to the above described procedure affording the respective N-
protected amines in good yields (Table 1, entries 1–5). In
general, derivatives of benzylamine reacted faster than aniline
derivatives because of their better nucleophilic character.
We also explored a wide variety of aliphatic acyclic and cyclic
amines under the same standard reaction conditions. Notably,
in these case the reactions proceeded very fast and in nearly
quantitative yields (Table 1, entries 6 and 8–13). For instance,
when piperidine was used the desired product was obtained in
97% yield and in only 3 minutes (Table 1, entry 11): secondary
amines, in fact, generally took less reaction time due to better
nucleophilicity. The existence of a double bond in the starting
amine does not affect the protocol: when we used allylamine,
the corresponding product was delivered in 85% yields in 8
minutes (Table 1, entry 15). From these results, it is evident that
the studied IL, [Bmim][BF4], is a mild, highly efficient and a
green catalyst for N-Fmoc protection of amines.
Excellent chemoselectivity was observed in case of an ami-
noalcohol as the starting material: in fact, in the case of etha-
nolamine and of tyramine (Table 1, entry 14, and 7 respectively)
no bis Fmoc derivatives or mixture of O/N Fmoc-derivatives was
observed. N-Fmoc-ethanolamine (3n) and N-Fmoc-tyramine (3g)
were obtained in good yields (88 and 85%) and in fast reaction
rate.
It is well known that masking the a-amino function of amino
acids with urethane protecting groups has become topic of
fundamental importance in the preparation of building blocks
both in solution as well as solid phase peptide synthesis. So,
aer the effective results in the N-Fmoc protection of amines we
have further extended our study by applying the protocol to the
Fmoc protection of the a-amino group of amino acid methyl
esters.
completed in
5
minutes and the expected N-(9-uo-
renylmethoxycarbonyl)aniline (3a) was obtained in 86% yield
aer a simple extraction procedure with diethyl ether from the
ionic liquid and without the need for chromatographic puri-
cation. The use of larger amounts of the IL did not improve the
reaction yield or time.
These preliminary results were very promising as they clearly
showed evident advantages of the procedure with respect to
those reported in the literature: the Fmoc protection of the
amino group efficiently occurs in the ionic liquid without the
addition of bases, under solvent-free conditions and at room
temperature. Furthermore, the urethane protected amine is
afforded in very short time of reaction, aer a simple solvent
extraction procedure from the IL and without the need for
chromatography. So, the ionic liquid [Bmim][BF4] acts as the
solvent and probably as the catalyst by the electrophilic
Nevertheless, our protocol was not applicable for the Fmoc
protection of L-valine methyl ester hydrochloride (2r) due to the
lack of solubility and nucleophilicity of the amino acid methyl
ester as a HCl salt in the ionic medium. The best results were
obtained aer addition to the mixture of 0.5 mL of an aqueous
solution of sodium bicarbonate therefore allowing the libera-
tion of the amino group, which can then act as a good nucleo-
phile for the protection reaction. Under the optimized reaction
conditions, the Fmoc protection of valine methyl ester (2r) was
thus achieved in 8 minutes and in 86% yield (Table 1, entry 18).
Similarly, the treatment of other a-amino acid methyl esters
with FmocOsu in [Bmim][BF4] using NaHCO3 as an additive
provided the respective N-protected compounds in good to very
good yields (Table 1, entries 16, 17 and 19).
Scheme 1
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Table 1 N-Fmoc and N-Cbz protection of amines and -a-amino acid methyl esters in [Bmim][BF4]a,b
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
5
5
86
87
1
8
8
85
88
2
3
5
88
88
3
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
7
7
88
89
4
6
7
87
86
5
6
6
89
86
6
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
5
6
85
87
7
3
3
91d
95
8
4
4
93
92
9
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
3
3
96
95
10
3
3
97
95
11
5
5
89
87
12
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
4
4
87
91
13
9
8
88
86
14
8
6
85
92
15
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
9
9
90c
16
87c
9
7
85c
17
86c
8
8
86c
18
90c
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Table 1 (Contd.)
Entry
Amine (2)
Product (3 and 4)
Time (min)
Yield (%)
8
8
85c
88c
19
Reaction conditions: amine (1.0 mmol), FmocOSu (1.0 mmol), [Bmim][BF4] (1 mL), 25 ꢀC. b Isolated yields. c 0.5 mL of saturated NaHCO3 solution
a
d
was used as an additive. Yield of the rst of ve runs using the same recovered IL. Yields of the four subsequent runs were: 91, 89, 88, 86,
respectively.
Encouraged by these promising results, the developed protocol catalyst for the N-Fmoc and N-Cbz protection of the amino
was also attempted to introduce the Cbz urethane group, by group in amines and amino acid methyl esters.
using N-(benzyloxycarbonyloxy)succinimide (Cbz-Osu) (5).
The feasibility of any catalytic process is inuenced by the
Amines 2a–s were treated with 1 equiv. of CBz-Osu in [Bmim] possibility to reuse again and again the same catalyst. There-
[BF4] under solvent-free conditions at room temperature and fore, the reusability of [Bmim][BF4] was assessed by conducting
without the addition of bases (Scheme 2).
the N-Fmoc protection of cyclopentylamine (2h) over four
Also in this case, most of the aliphatic and aromatic amines successive runs. The results shown in Table 1 show no signi-
we checked gave high yields of carbamate (Table 1, products 4a– cant loss of activity of the IL.
4o). In addition, the times required for derivatization were short
and no chromatographic purication was necessary. Further-
more, the protocol showed to be highly chemoselective as the in
Conclusions
the case of amino alcohols (Table 1, entries 4g–4n) the amine
group is only protected even in the presence of OH groups and
the N-Cbz protected compounds were obtained in excellent
yields as the sole product without the competitive formation of
the O-Cbz product. Again, esters of amino acids required 0.5 mL
of a sodium bicarbonate aqueous solution as additive in the IL
assisted protection process (Table 1, products 4p–4s).
In summary, we have reported a simple and convenient protocol
based on the use of [Bmim][BF4] for the preparation of Fmoc and
Cbz-protected amines and amino acid methyl esters. In partic-
ular, the absence of organic solvents or bases, the use of mild
conditions, short reaction times, the high yields, the simple work-
up procedure and nally the possibility to recycle the ionic liquid
represent important features and advantages of the method
providing a valuable contribution to the existing methodologies
for the introduction of urethane amine protecting groups.
The results of the presented protocol show that the ionic
liquid [Bmim][BF4] is an efficient reaction medium as well as a
Experimental section
General
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
Scheme 2
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standard procedures and distilled prior to use. All syntheses 6H, ArHFmoc and ArH), 7.62 (d, J ¼ 7.5 Hz, 2H, ArHFmoc), 7.71
were carried out in atmospheric conditions. All the a-amino (d, J ¼ 7.5 Hz, 2H, ArHFmoc). 13C NMR: (75 MHz, CDCl3) d 25.3,
acids were of the L-series. 1H NMR spectra were recorded at 300 47.1, 72.8, 120.1, 125.2, 127.0, 127.7, 128.2, 129.5, 141.2, 142.4,
MHz, while 13C NMR spectra were measured at 75 MHz. Spectral 143.7, 151.5.
analysis was performed at 293 K on diluted solutions of each
N-Fmoc-benzylamine (3c). White solid obtained in 88%
compound by using CDCl3 as the solvent. Chemical shis (d) are yield: 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 4.21 (t, J ¼ 6.3 Hz, 1H,
reported in ppm and referenced to CDCl3 (7.25 ppm for 1H and CHFmoc), 4.40 (d, J ¼ 6.0 Hz, 2H, CH2Ph), 4.48 (d, J ¼ 6.9 Hz,
77.0 ppm for 13C spectra). Coupling constants (J) are reported in 2H, CH2Fmoc), 5.07 (br s, 1H, NH), 7.25–7.47 (m, 9H, ArH), 7.60
Hertz (Hz). Reaction mixtures were monitored by thin layer (d, J ¼ 7.0 Hz, 2H, ArH), 7.78 (d, J ¼ 7.0 Hz, 2H, ArH). 13C-NMR:
chromatography (TLC) using Merck Silica gel 60-F254 precoated (75 MHz, CDCl3) d 45.0, 47.2, 67.7, 120.0, 121.0, 124.9, 126.9,
glass plates, and UV light (254 nm) or 0.2% ninhydrin in ethanol 127.4, 127.6, 128.9, 138.3, 141.2, 143.8, 155.4. ESI(+)-MS: calcd
and charring as visualizing agent. Evaporation of solvents was for ([C22H19NO2] + Na)+ [M + Na]+ 352.1313; found: 352.1314.
performed at reduced pressure using a rotary vacuum evapo-
N-Fmoc-1-phenylethylamine (3d). White solid obtained in
rator. LC-MS analysis was carried out using an Agilent UHPLC 88% yield: 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.53 (d, J ¼ 6.3 Hz,
instrument coupled to a QTOF mass spectrometer tted with an 3H, CHCH3), 4.20 (t, J ¼ 6.9 Hz, 1H, CHFmoc), 4.41 (d, J ¼ 7.0
electrospray ionization source (ESI) operating in positive ion Hz, 2H, CH2Fmoc), 4.88 (t, J ¼ 6.9 Hz, 1H, CHCH3), 5.03 (broad
mode. GC-MS analyses were performed using a 30 m ꢁ 0.25 s, 1H, NH), 7.20–7.46 (m, 9H, ArHFmoc and ArHPh), 7.60 (d, J ¼
mm, PhMesiloxane capillary column. The mass detector was 6.5 Hz, 2H, ArHFmoc), 7.77 (d, J ¼ 7.5 Hz, 2H, ArHFmoc). 13C-
operated in the electron impact ionization mode (EIMS) with an NMR: (75 MHz, CDCl3) d 22.3, 47.2, 50.6, 66.4, 119.9, 125.0,
electron energy of 70 eV. The injection port was heated to 125.9, 127.0, 127.3, 127.6, 128.6, 141.2, 143.9, 144.1, 155.5.
250 ꢀC. The oven temperature program was initially set at 70 ꢀC ESI(+)-MS: calcd for ([C23H21NO2] + Na)+ [M + Na]+ 366.1470;
with a hold of 1.5 min and ramped to 280 ꢀC at 20 ꢀC minꢂ1 with found: 366.1459.
a hold of 10 min. Electrospray ionization source-quadrupole
N-Fmoc-4-methoxybenzylamine
(3e). Colorless solid
1
time of ight (ESIQTOF) mass spectra, EIMS spectra, and H- obtained in 87% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.75
and 13C NMR spectra identied correct and pure samples. (s, 3H, OCH3), 4.25 (t, J ¼ 6.7 Hz, 1H, CHFmoc), 4.32 (d, J ¼ 6.1
Spectral data of all products agreed with those already reported Hz, 2H, CH2Ph), 4.45 (d, J ¼ 7.2 Hz, 2H, CH2Fmoc), 5.10 (broad
for the same compounds prepared as previously reported.
s, 1H, NH), 6.82 (d, J ¼ 8.3 Hz, 2H, ArH), 7.22 (d, J ¼ 8.3 Hz, 2H,
ArH), 7.27–7.47 (m, 4H, ArHFmoc), 7.61 (d, J ¼ 7.6 Hz, 2H,
ArHFmoc), 7.77 (d, J ¼ 7.4 Hz, 2H, ArHFmoc). 13C-NMR: (75
MHz, CDCl3) d 44.5, 47.2, 55.3, 66.6, 114.0, 119.9, 125.0, 127.0,
127.6, 128.9, 130.4, 141.3, 143.9, 156.3, 159.3. ESI(+)-MS: calcd
General procedure for the N-Fmoc and N-Cbz protection of
amines 2a–s in [Bmim][BF4]
To a magnetically stirred mixture of amine 2a–s (1 mmol) and for ([C23H21NO3] + Na)+ [M + Na]+ 382.1419; found: 382.1418.
[Bmim][BF4] (1 mL) (for amines 2p–s 0.5 mL of NaHCO3 N-Fmoc-2-phenylethylamine (3f). White solid obtained in
aqueous solution were added), Fmoc-OSu or Cbz-Osu (1 mmol) 89% yield: 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 2.82 (t, J ¼ 6.6 Hz,
was added and the mixture was stirred at ambient temperature 2H, NHCH2CH2), 3.45 (m, 2H, NHCH2CH2), 4.22 (t, J ¼ 6.6 Hz,
for 3–9 min. The reaction was monitored by TLC. Aer the 1H, CHFmoc), 4.42 (d, J ¼ 6.6 Hz, 2H, CH2Fmoc), 4.82 (br s, 1H,
completion of reaction, diethyl ether was added, and the IL NH), 7.14–7.46 (m, 9H, ArHFmoc and ArHPh), 7.60 (d, J ¼ 6.7
settled at the bottom. The supernatant was decanted off and the Hz, 2H, ArHFmoc), 7.78 (d, J ¼ 7.4 Hz, 2H, ArHFmoc). 13C-NMR:
IL was washed with Et2O (3 ꢁ 2 mL). The combined Et2O (75 MHz, CDCl3) d 36.1, 42.2, 47.2, 66.5, 119.9, 125.0, 126.5,
extracts were washed once with a 1 N aqueous solution of HCl (3 126.9, 127.6, 128.6, 128.8, 138.7, 141.3, 143.9, 156.2. ESI(+)-MS:
mL), dried over Na2SO4 and ltered. The products were isolated calcd for ([C23H21NO2] + Na)+ [M + Na]+ 366.1470; found:
aer evaporation of the diethyl ether to yield the highly pure N- 366.1467.
Fmoc derivatives 3a–s in 85–97% yields or the N-Cbz-derivatives
N-Fmoc-tyramine (3g). White solid obtained in 85% yield:
1
1
4a–s in 85–95% yields. H NMR and 13C NMR were consistent
H-NMR: (300 MHz, DMSO-d6, 25 C): 2.57 (t, J ¼ 7.3 Hz, 2H,
ꢀ
with the assigned structures.
NHCH2CH2), 3.11–3.14 (m, 2H, NHCH2CH2), 4.21 (m, 1H,
N-Fmoc-aniline (3a). Solid pale brown, obtained in 86% CHFmoc), 4.27 (d, J ¼ 6.9 Hz, 2H, CH2Fmoc), 6.65 (d, J ¼ 8.4 Hz,
yield. 1H NMR (300 MHz, CDCl3) d 4.30 (t, J ¼ 6.4 Hz, 1H 2H, ArH), 6.95 (d, J ¼ 8.1 Hz, 2H, ArH), 7.29–7.43 (m, 5H,
CHFmoc), 4.59 (d, J ¼ 6.4 Hz, 2H, CH2Fmoc), 6.70 (br s, 1H, ArHFmoc + NH), 7.66 (d, J ¼ 7.5 Hz, 2H, ArHFmoc), 7.88 (d, J ¼
NH), 7.09 (t, J ¼ 7.1 Hz, 1H, ArH), 7.24–7.48 (m, 8H, ArH), 7.63 7.5 Hz, 2H, ArHFmoc), 9.18 (s, 1H, OH). 13C-NMR: (75 MHz,
(d, J ¼ 7.6 Hz, 2H, ArH), 7.80 (d, J ¼ 7.4 Hz, 2H, ArHFmoc). 13
C
DMSO-d6): 35.4, 42.6, 47.3, 67.9, 115.5, 120.5, 121.9, 127.7,
NMR: (75 MHz, CDCl3) d 47.1, 66.8, 118.8, 120.1, 123.6, 124.9, 129.4, 129.8, 137.9, 139.8, 142.9, 156.0, 157.6. ESI(+)-MS: calcd
127.1, 127.8, 129.1, 138.3, 141.4, 143.8, 153.9. ESI(+)-MS: calcd for ([C23H21NO3] + Na)+ [M + Na]+ 382.1419; found: 382.1420.
for ([C21H17NO2] + Na)+ [M + Na]+ 338.1157; found: 338.1151.
N-Fmoc-cyclopentylamine (3h). White solid obtained in 91%
N-Fmoc-4-methylaniline (3b). Colorless solid obtained in yield: 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.31–1.48 (m, 2H,
85%: 1H NMR (300 MHz, CDCl3, 25 ꢀC): 2.79 (s, 3H, CH3), 4.33 (t, HNCHCH2CH2), 1.52–1.77 (m, 4H, HNCHCH2CH2 and
J ¼ 7.5 Hz, 1H, CHFmoc), 4.57 (d, J ¼ 7.5 Hz, 2H, CH2Fmoc), HNCHCH2CH2), 1.91–2.06 (m, 2H, HNCHCH2CH2), 3.96–4.05
6.74 (br s, 1H, NH), 7.09 (d, J ¼ 7.7 Hz, 2H, ArH), 7.30–7.49 (m, (m, 1H, NHCH), 4.20–4.30 (m, 1H, CHFmoc), 4.42 (d, J ¼ 6.6 Hz,
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2H, CH2Fmoc), 4.75 (broad s, 1H, NH), 7.30–7.53 (m, 4H, 2H, ArHFmoc), 7.76 (d, J ¼ 7.7 Hz, 2H, ArHFmoc). 13C-NMR: (75
ArHFmoc), 7.59 (d, J ¼ 6.9 Hz, 2H, ArHFmoc), 7.80 (d, J ¼ 6.9 Hz, MHz, CDCl3) d 43.4, 47.2, 62.3, 66.7, 119.9, 124.9, 127.0, 127.7,
2H, ArHFmoc). 13C-NMR: (75 MHz, CDCl3) d 23.5, 29.7, 33.2, 141.3, 143.8, 158.1. ESI(+)-MS: calcd for ([C17H17NO3] + Na)+ [M
47.3, 66.4, 119.9, 125.0, 127.0, 127.7, 141.3, 144.1, 155.1. ESI(+)- + Na]+ 306.1106; found: 306.1111.
MS: calcd for ([C20H21NO2] + Na)+ [M + Na]+ 330.1470; found:
330.1470.
N-Fmoc-allylamine (3o). Pale yellow solid obtained in 85%
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.82 (t, J ¼ 5.4 Hz, 2H,
N-Fmoc-morpholine (3i). Colorless solid obtained in 93% NHCH2), 4.22 (t, J ¼ 6.9 Hz, 1H, CHFmoc), 4.44 (d, J ¼ 6.9 Hz,
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.40–3.54 (m, 4H, 2H, CH2Fmoc), 4.96 (broad s, 1H, NH), 5.19 (t, J ¼ 14.5 Hz, 2H,
CH2NCH2), 3.60–3.72 (m, 4H, CH2OCH2), 4.25 (t, J ¼ 6.6 Hz, 1H, CH2]CHCH2), 5.83–5.95 (m, 1H, CH2]CHCH2), 7.30–7.48 (m,
CHFmoc), 4.48 (d, J ¼ 6.6 Hz, 2H, CH2Fmoc), 7.30–7.48 (m, 4H, 4H, ArHFmoc), 7.61 (d, J ¼ 7.1 Hz, 2H, ArHFmoc), 7.79 (d, J ¼
ArHFmoc), 7.58 (d, J ¼ 7.5 Hz, 2H, ArHFmoc), 7.78 (d, J ¼ 7.2 Hz, 7.1 Hz, 2H, ArHFmoc). 13C-NMR: (75 MHz, CDCl3) d 43.5, 47.3,
2H, ArHFmoc). 13C-NMR: (75 MHz, CDCl3) d 44.4, 47.4, 66.5, 66.7, 116.1, 120.0, 125.1, 127.1, 127.7, 134.5, 141.4, 144.0, 156.3.
67.3, 120.0, 124.9, 127.1, 127.8, 141.4, 143.9, 155.2. ESI(+)-MS: ESI(+)-MS: calcd for ([C18H17NO2] + Na)+ [M + Na]+ 302.1157;
calcd for ([C19H19NO3] + Na)+ [M + Na]+ 332.1263; found: found: 302.1151.
332.1259.
N-Fmoc-glycine methyl ester (3p). White solid obtained in
N-Fmoc-pyrrolidine (3j). White solid obtained in 96% yield. 90% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.76 (s, 3H,
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.82–1.96 [m, 4H, OCH3), 4.01 (d, J ¼ 5.4 Hz, 2H, NHCH2), 4.23 (t, J ¼ 7.2 Hz, 1H,
NCH2(CH2)2], 3.39–3.48 (m, 4H, CH2NCH2), 4.25 (t, J ¼ 7.2 Hz, CHFmoc), 4.42 (d, J ¼ 7.2 Hz, 2H, CH2Fmoc), 5.40 (br s, 1H,
1H, CHFmoc), 4.39 (d, J ¼ 7.2 Hz, 2H, CH2Fmoc), 7.30–7.43 (m, NH), 7.27–7.42 (m, 4H, ArH), 7.61 (d, J ¼ 7.2 Hz, 2H, ArH), 7.77
4H, ArH), 7.63 (d, J ¼ 7.2 Hz, 2H, ArH), 7.77 (d, J ¼ 7.5 Hz, 2H, (d, J ¼ 7.5 Hz, 2H, ArH). 13C-NMR: (75 MHz, CDCl3) d 42.6, 47.0,
ArH). 13C-NMR: (75 MHz, CDCl3) d 24.9, 25.8, 45.8, 46.2, 47.3, 52.4, 67.1, 120.0, 125.0, 127.0, 127.7, 141.2, 143.7, 156.3, 170.5.
67.0, 119.9, 125.5, 126.9, 127.6, 141.2, 144.1, 154.9. ESI(+)-MS: ESI(+)-MS: calcd for ([C18H17NO4] + Na)+ [M + Na]+ 334.1055;
calcd for ([C19H19NO2] + Na)+ [M + Na]+ 316.1313; found: found: 334.1049.
316.1310.
N-Fmoc-alanine methyl ester (3q). Pale yellow solid obtained
N-Fmoc-piperidine (3k). Pale yellow solid obtained in 97% in 85% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.45 (d, J ¼ 7.2
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.49–1.53 [m, 6H, Hz, 3H, CHCH3), 3.77 (s, 3H, OCH3), 4.22 (t, J ¼ 6.7 Hz, 1H,
NCH2(CH2)3], 3.36–3.47 (m, 4H, NCH2), 4.22 (t, J ¼ 6.9 Hz, 1H, CHFmoc), 4.32–4.48 (m, 3H, CH2Fmoc and CHCH3), 5.38 (d, J ¼
CHFmoc), 4.39 (d, J ¼ 6.9 Hz, 2H, CH2Fmoc), 7.27–7.45 (m, 4H, 7.5 Hz, 1H, NH), 7.30–7.48 (m, 4H, ArHFmoc), 7.58–7.62 (m, 2H,
ArHFmoc), 7.59 (d, J ¼ 7.4 Hz, 2H, ArHFmoc), 7.78 (d, J ¼ 7.5 Hz, ArHFmoc), 7.78 (d, J ¼ 7.5 Hz, 2H, ArHFmoc). 13C-NMR: (75
2H, ArHFmoc). 13C-NMR: (75 MHz, CDCl3) d 25.5, 25.7, 44.8, MHz, CDCl3) d 18.7, 30.2, 47.1, 52.5, 66.9, 119.9, 125.0, 127.0,
47.3, 67.1, 119.9, 125.0, 126.9, 127.6, 141.2, 144.1, 155.2. ESI(+)- 127.7, 136.6, 141.8, 158.0, 172.1. ESI(+)-MS: calcd for
MS: calcd for ([C20H21NO2] + Na)+ [M + Na]+ 330.1470; found: ([C19H19NO4] + Na)+ [M + Na]+ 348.1212; found: 348.1200.
330.1473.
N-Fmoc-valine methyl ester (3r). Pale yellow solid obtained
N-Fmoc-propylamine (3l). White solid obtained in 89% yield. in 86% yield. 1H-NMR (300 MHz, CDCl3, 25 ꢀC): 0.93 [d, J ¼ 6.9
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 0.95 (t, J ¼ 7.3 Hz, 3H, CH3), Hz, 3H, CH(CH3)2], 0.99 [d, J ¼ 6.6 Hz, 3H, CH(CH3)2], 2.09–2.49
1.48–1.57 (m, 2H, CH2CH3), 3.14–3.22 (m, 2H, NHCH2), 4.23 (t, J [m, 1H, CH(CH3)2], 3.77 (s, 3H, OCH3), 4.25 (t, J ¼ 7.2 Hz, 1H,
¼ 6.7 Hz, 1H, CHFmoc), 4.41 (d, J ¼ 6.9 Hz, 2H, CH2Fmoc), 4.82 CHFmoc), 4.38 (m, 1H, a-CH), 4.42 (d, J ¼ 7.2 Hz, 2H, CH2-
(br s, 1H, NH), 7.26–7.45 (m, 4H, ArHFmoc), 7.61 (d, J ¼ 7.5 Hz, Fmoc), 5.38 (d, J ¼ 9.9 Hz, 1H, NH), 7.31–7.44 (m, 4H, ArHF-
2H, ArHFmoc), 7.77 (d, J ¼ 7.5 Hz, 2H, ArHFmoc). 13C-NMR: (75 moc), 7.62 (d, J ¼ 7.2 Hz, ArHFmoc), 7.78 (d, J ¼ 7.2 Hz,
MHz, CDCl3) d 11.1, 23.2, 42.7, 47.3, 66.4, 119.9, 124.9, 126.9, ArHFmoc). 13C-NMR: (75 MHz, CDCl3) d 17.7, 18.9, 31.3, 47.2,
127.6, 141.3, 143.9, 156.4. ESI(+)-MS: calcd for ([C18H19NO2] + 52.2, 59.0, 67.0, 120.0, 125.1, 127.1, 127.7, 141.3, 143.8, 156.3,
Na)+ [M + Na]+ 304.1313; found: 304.1311.
N-Fmoc-octylamine (3m). Pale yellow solid obtained in 87% 376.1525; found: 376.1516.
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 0.87–0.98 (m, 3H,
N-Fmoc-isoleucine methyl ester (3s). Yellow solid obtained
172.6. ESI(+)-MS: calcd for ([C21H23NO4] + Na)+ [M + Na]+
1
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CH3), 1.18–1.37 [m, 10H, (CH2)5CH3], 1.39–1.58 (m, 2H, in 85% yield. H-NMR: (300 MHz, CDCl3, 25 C): 0.90–0.99 [m,
NHCH2CH2), 3.15–3.28 (m, 2H, NHCH2), 4.21 (t, J ¼ 6.6 Hz, 1H, 6H, CH(CH3)CH2CH3 and CH(CH3)CH2CH3], 1.20–1.40 (m, 1H,
CHFmoc), 4.42 (d, J ¼ 6.9 Hz, 2H, CH2Fmoc), 4.81 (br s, 1H, CH(CH3)CH2CH3), 1.44–1.51 (m, 1H, CH(CH3)CH2CH3), 1.90–
NH), 7.28–7.41 (m, 4H, ArHFmoc), 7.60 (d, J ¼ 6.9 Hz, 2H, 2.03 (m, 1H, CH(CH3)CH2CH3), 3.75 (s, 3H, OCH3), 4.24 (t, J ¼
ArHFmoc), 7.78 (d, J ¼ 7.75 Hz, 2H, ArHFmoc). 13C-NMR: (75 7.2 Hz, 1H, CHFmoc), 4.36–4.43 (m, 3H, CH2Fmoc and a-CH),
MHz, CDCl3) d 14.1, 22.6, 26.7, 29.2, 29.9, 31.7, 41.1, 47.3, 66.4, 5.37 (d, J ¼ 9.3 Hz, 1H, NH), 7.30–7.48 (m, 4H, ArHFmoc), 7.68
119.9, 124.9, 126.9, 127.6, 141.3, 143.9, 156.4. ESI(+)-MS: calcd (d, J ¼ 6.3 Hz, 2H, ArHFmoc), 7.76 (d, J ¼ 6.3 Hz, 2H, ArHFmoc).
for ([C23H29NO2] + Na)+ [M + Na]+ 374.2096; found: 374.2093.
13C-NMR: (75 MHz, CDCl3) d 11.6, 15.4, 25.3, 37.9, 47.1, 52.1,
N-Fmoc-ethanolamine (3n). Colorless solid obtained in 88% 58.3, 66.9, 119.9, 125.2, 127.0, 128.1, 141.2, 143.8, 156.0, 172.6.
1
yield. H-NMR: (300 MHz, CDCl3, 25 C): 1.90 (br s, 1H, OH), ESI(+)-MS: calcd for ([C22H25NO4] + Na)+ [M + Na]+ 390.1681;
ꢀ
3.30–3.46 (m, 2H, CH2NH), 3.69–3.84 (m, 2H, CH2OH), 4.21 (t, J found: 390.1695.
¼ 6.7 Hz, 1H, CHFmoc), 4.43 (d, J ¼ 6.7 Hz, 2H, CH2Fmoc), 5.19
N-Cbz-aniline (4a). Pale brown solid obtained in 87% yield.
(br s, 1H, NH), 7.27–7.45 (m, 4H, ArHFmoc), 7.58 (d, J ¼ 8.1 Hz, 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 5.3 (s, 2H, OCH2), 6.84 (br s,
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1H, NH), 7.10 (t, J ¼ 7.2 Hz, 1H, ArH), 7.30–7.48 (m, 9H, ArH).
13C-NMR: (75 MHz, CDCl3) d 67.1, 118.8, 123.6, 128.3, 128.4,
128.6, 129.1, 136.1, 137.8, 153.4. EIMS m/z (%), 227 (18, M+c),
183 (16), 119 (42), 108 (17), 91 (100), 79 (18), 77 (16), 65 (9).
N-Cbz-4-methylaniline (4b). Pale yellow solid obtained in
88% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 2.30 (s, 3H, CH3),
5.19 (s, 2H, OCH2), 6.68 (br s, 1H, NH), 7.10 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.20–7.45 (m, 7H, ArH). 13C-NMR: (75 MHz, CDCl3) d 20.7,
66.7, 118.7, 128.3, 128.6, 129.2, 129.5, 132.2, 135.1, 136.1, 168.6.
EIMS m/z (%) 241 (16, M+c), 197 (15), 133 (37), 91 (100), 79 (16),
77 (15), 65 (8).
N-Cbz-benzylamine (4c). Pale yellow solid obtained in 88%
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 4.40 (d, J ¼ 6.0 Hz, 2H,
NHCH2), 5.08 (br s, 1H, NH), 5.14 (s, 2H, O–CH2), 7.20–7.40 (m,
10H, ArH). 13C-NMR: (75 MHz, CDCl3) d 45.0, 66.7, 125.4, 127.4,
127.6, 127.9, 128.4, 128.5, 136.9, 138.2, 156.2. EIMS m/z (%) 241
(2, M+c), 150(88), 133 (19), 108 (39), 91 (100), 79 (32), 77 (30), 65
(15), 51 (10).
N-Cbz-morpholine (4i). Colorless oil obtained in 92% yield.
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.48–3.53 (m, 4H, CH2NCH2),
3.60–3.73 (m, 4H, CH2OCH2), 5.15–5.19 (s, 2H, OCH2), 7.30–7.41
(m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 44.2, 66.5, 67.2,
127.9, 128.1, 128.5, 136.4, 155.2. EIMS m/z (%) 221 (20, M+c), 176
(2), 146 (5), 130 (4), 91 (100), 77 (3), 65 (6).
N-Cbz-pyrrolidine (4j). Colorless oil obtained in 95% yield.
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.80–1.93 [m, 4H,
NCH2(CH2)2], 3.33–3.47 (m, 4H, CH2NCH2), 5.12 (s, 2H, PhCH2),
7.30–7.42 (m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 24.9, 25.6,
45.7, 46.2, 72.8, 127.8, 128.6, 128.7, 137.0, 154.9. EIMS m/z (%)
205 (19, M+c), 160 (9), 114 (2), 91 (100), 77 (3), 65 (5).
N-Cbz-piperidine (4k). Pale yellow oil obtained in 95% yield.
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.42–1.63 [m, 6H,
NCH2(CH2)3], 3.44 (t, J ¼ 6.1 Hz, 4H, CH2NCH2), 5.13 (s, 2H,
OCH2), 7.29–7.40 (m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d
24.3, 44.8, 65.9, 126.9, 127.4, 127.5, 128.3, 136.1, 158.3. EIMS
m/z (%) 219 (15, M+c), 174 (16), 128 (15), 91 (100), 77 (3), 65 (8).
N-Cbz-propylamine (4l). Colorless oil obtained in 87% yield.
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 0.92 (t, J ¼ 7.3 Hz, 3H, CH3),
1.46–1.58 (m, 2H, CH2CH3), 3.12–3.19 (m, 2H, NHCH2), 4.83 (br
s, 1H, NH), 5.10 (s, 2H, OCH2), 7.32–7.38 (m, 5H, ArH). 13C-NMR:
(75 MHz, CDCl3) d 11.1, 23.1, 42.7, 66.5, 128.0, 128.1, 128.5,
136.6, 156.4. EIMS m/z (%) 193 (3, M+c), 164 (2), 108 (79), 91
(100), 79 (14), 65 (13).
N-Cbz-octylamine (4m). White solid obtained in 91% yield.
1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 0.87 (t, J ¼ 6.5 Hz, 3H, CH3),
1.19–1.32 (m, 10H, (CH2)5CH3), 1.39–1.56 (m, 2H, NHCH2CH2),
3.25–3.45 (m, 2H, NHCH2), 4.80 (br s, 1H, NH), 5.10 (s, 2H,
OCH2), 7.37 (s, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 14.0, 22.6,
26.7, 29.2, 29.6, 31.7, 41.1, 66.5, 126.9, 128.0, 128.4, 136.6, 156.3.
EIMS m/z (%) 263 (4, M+c), 234 (3), 172 (6), 108 (99), 91 (100), 79
(15), 77 (13), 65 (7).
N-Cbz-1-phenylethylamine (4d). Pale yellow solid obtained in
89% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.50 (d, 3H, J ¼ 6.6
Hz, CHCH3), 4.88 (m, 1H, CHCH3), 5.00–5.13 (m, 3H, OCH2 and
NH), 7.20–7.40 (m, 10H, ArH).13C-NMR: (75 MHz, CDCl3) d 24.4,
50.6, 66.7, 125.8, 127.3, 128.0, 128.4, 128.5, 128.6, 136.4, 142.1,
158.1. EIMS m/z (%) 255 (1, M+c), 240 (11), 196 (16), 164 (98), 147
(14), 132 (10), 120 (28), 105 (25), 91 (100), 79 (14), 77 (15), 65 (8).
N-Cbz-4-methoxybenzylamine (4e). Pale yellow solid
1
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obtained in 89% yield. H-NMR: (300 MHz, CDCl3, 25 C): 3.78
(s, 3H, OCH3), 4.30 (d, J ¼ 5.7 Hz, 1H, NHCH2), 5.00–5.18 (m, 3H,
NH and OCH2), 6.88 (d, J ¼ 8.7 Hz, 2H, ArH), 7.21 (d, J ¼ 8.6 Hz,
2H, ArH), 7.28–7.46 (m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d
44.6, 55.2, 66.7, 113.9, 128.1, 128.5, 128.8, 130.4, 135.8, 136.5,
156.3, 158.9. EIMS m/z (%) 271 (1, M+c), 240 (2), 180 (83), 121
(100), 91 (37), 79 (28), 77 (27), 65 (12).
N-Cbz-2-phenylethylamine (4f). Pale yellow solid obtained in
86% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 2.83 (t, J ¼ 6.9 Hz,
2H, NHCH2CH2), 3.46 (q, J1 ¼ 20.0 Hz, J2 ¼ 6.6 Hz, 2H,
NHCH2CH2), 4.82 (br s, 1H, NH), 5.12 (s, 2H, OCH2), 7.14–7.42
(m, 10H, ArH). 13C-NMR: (75 MHz, CDCl3) d 36.0, 42.2, 66.6,
126.5, 128.1, 128.5, 128.6, 128.7, 128.8, 136.5, 138.6, 156.3. EIMS
m/z (%) 255 (1, M+c), 147 (16), 120 (5), 108 (15), 91 (100), 79 (16),
77 (14), 65 (8).
N-Cbz-ethanolamine (4n). White solid obtained in 86%
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.13 (br s, 1H, OH),
3.25–3.37 (m, 2H, NHCH2), 3.65–3.71 (m, 2H, CH2OH), 5.07 (s,
2H, OCH2), 5.46 (br s, 1H, NH), 7.32 (s, 5H, ArH). 13C-NMR: (75
MHz, CDCl3) d 43.4, 61.9, 66.8, 128.2, 128.4, 128.5, 136.3, 157.1.
EIMS m/z (%) 195 (2, M+c), 176 (2), 146 (3), 108 (100), 91 (93), 79
(75), 77 (50), 65 (13), 51 (11).
1
N-Cbz-allylamine (4o). Yellow oil obtained in 92% yield. H-
N-Cbz-tyramine (4g). White solid obtained in 87% yield. 1H-
NMR: (300 MHz, CDCl3, 25 ꢀC): 2.72 (t, 2H, J ¼ 6.9 Hz,
NHCH2CH2), 3.46 (q, J1 ¼ 20.0 Hz, J2 ¼ 6.6 Hz, 2H, NHCH2), 4.84
(br s, 1H, NH), 5.12 (s, 2H, OCH2), 6.15 (br s, 1H, OH), 6.75 (d,
2H, ArH), 6.98 (d, 2H, ArH), 7.38 (s, 5H, ArH). 13C-NMR: (75 MHz,
CDCl3) d 35.1, 42.4, 66.8, 115.5, 128.1, 128.5, 129.7, 129.8, 136.3,
140.1, 154.6, 156.5. EIMS m/z (%) 271 (5, M+c), 239 (4), 163 (13),
107 (100), 91 (40), 79 (16), 77 (17), 65 (6).
N-Cbz-cyclopentylamine (4h). Colorless oil obtained in 95%
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.40–1.49 (m, 2H,
HNCHCH2CH2), 1.56–1.77 (m, 4H, HNCHCH2CH2 and
HNCHCH2CH2), 1.90–2.05 (m, 2H, HNCHCH2CH2), 4.02 (m, 1H,
HNCH), 4.72 (br s, 1H, NH), 5.10 (s, 2H, OCH2), 7.30–7.40 (m,
5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 23.4, 29.3, 33.1, 52.7,
66.5, 127.7, 128.1, 128.5, 136.6, 155.8. EIMS m/z (%) 219 (2, M+c),
190 (2), 146 (5), 128 (6), 108 (63), 91 (100), 79 (5), 77 (4), 65 (5).
NMR: (300 MHz, CDCl3, 25 ꢀC): 3.70–3.90 (m, 2H, NHCH2), 4.93–
5.26 (m, 5H, NH, OCH2, CH]CH2), 5.82 (m, 1H, CH]CH2), 7.38
(s, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 43.5, 66.8, 116.1,
127.9, 128.1, 128.5, 134.5, 136.6, 156.3. EIMS m/z (%) 191 (3,
M+c), 150 (2), 130 (16), 108 (68), 91 (100), 79 (15), 77 (14), 65 (7).
N-Cbz-glycine methyl ester (4p). White solid obtained in 87%
yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 3.72 (s, 3H, OCH3), 4.01
(d, J ¼ 5.7 Hz, 2H, NHCH2), 5.12 (s, 2H, OCH2), 5.40 (br s, 1H,
NH), 7.30–7.40 (m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 42.6,
52.4, 67.1, 127.9, 128.3, 128.6, 136.1, 156.3, 170.5. EIMS m/z (%)
223 (8, M+c), 164 (2), 120 (2), 108 (86), 91 (100), 79 (18), 77 (15),
65 (8).
N-Cbz-alanine methyl ester (4q). Colorless solid obtained in
86% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 1.36 (d, J ¼ 7.2 Hz,
3H, CHCH3), 3.75 (s, 3H, OCH3), 4.30–4.50 (m, 1H, CHCH3), 5.11
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(s, 2H, OCH2), 5.34 (br s, 1H, NH), 7.30–7.40 (m, 5H, ArH). 13C-
NMR: (75 MHz, CDCl3) d 18.6, 49.5, 52.4, 66.9, 127.7, 128.3,
128.6, 136.2, 155.5, 173.4. EIMS m/z (%) 237 (3, M+c), 178 (8),
134 (12), 108 (45), 91 (100), 79 (21), 77 (16), 70 (35), 65 (7).
N-Cbz-valine methyl ester (4r). Colorless solid obtained in
90% yield. 1H-NMR: (300 MHz, CDCl3, 25 ꢀC): 0.89 [d, J ¼ 6.9 Hz,
3H, CH(CH3)2], 0.95 [d, J ¼ 6.9 Hz, 3H, CH(CH3)2], 2.10–2.20 [m,
1H, CH(CH3)2], 3.72 (s, 3H, OCH3), 4.25–4.35 (m, 1H, NHCH),
5.12 (s, 2H, OCH2), 5.32 (br s, 1H, NH), 7.32–7.42 (m, 5H, ArH).
13C-NMR: (75 MHz, CDCl3) d 17.5, 18.9, 25.4, 52.2, 58.9, 67.0,
128.1, 128.6, 129.3, 136.1, 156.2, 172.5. EIMS m/z (%) 265 (5,
M+c), 206 (14), 162 (21), 116 (21), 108 (24), 91 (100), 79 (13), 77
(10), 65 (5).
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N-Cbz-isoleucine methyl ester (4s). Colorless solid obtained
1
ꢀ
in 88% yield. H-NMR: (300 MHz, CDCl3, 25 C): 0.83–0.97 [m,
6H, CH(CH3)CH2CH3 and CH(CH3)CH2CH3], 1.16–1.22 (m, 1H,
CH(CH3)CH2CH3), 1.40–1.49 (m, 1H, CH(CH3)CH2CH3), 1.90–
1.95 (m, 1H, CH(CH3)CH2CH3), 3.75 (s, 3H, OCH3), 4.30–4.50
(m, 1H, a-CH), 5.10 (s, 2H, OCH2), 5.32 (d, J ¼ 8.4 Hz, 1H, NH),
5.33–5.47 (m, 5H, ArH). 13C-NMR: (75 MHz, CDCl3) d 11.5, 15.4,
24.9, 37.9, 52.1, 58.3, 66.9, 127.9, 128.1, 128.5, 136.2, 156.0,
172.5. EIMS m/z (%) 279 (2, M+c), 220 (25), 176 (36), 162 (5), 108
(20), 91 (100), 79 (8), 77 (7), 65 (6).
Recycling of [Bmim][BF4] in the synthesis of 3h
At the end of the rst experiment and aer the recovery of the N-
Fmoc-cyclopentylamine, the IL was treated with a saturated
aqueous solution of NaHCO3 (2 mL) and subjected to consec-
utive extractions with ethyl acetate and diethyl ether. The ionic
liquid was recovered by removing water under vacuum. The IL
was nally dried at 80 ꢀC for 1 h and reused for the next run. The
IL was reused for consecutive four times without loss in its
efficiency (91, 89, 88 and 86% yields, respectively).
Acknowledgements
This work was supported by grants from MIUR (Ministero Ital-
`
iano dell' Universita e della Ricerca, ex-60% funds).
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