Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids

Article abstract of DOI:10.3390/molecules14125124

A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3- triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.

Full text of DOI:10.3390/molecules14125124

Molecules 2009, 14, 5124-5143; doi:10.3390/molecules14125124
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Chiral 1,4-Disubstituted-1,2,3-Triazole Derivatives
from Amino Acids
Michael Klein, Karin Krainz, Itedale Namro Redwan, Peter Dinér and Morten Grøtli *
Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg,
Sweden
* Author to whom correspondence should be addressed; E-Mail: grotli@chem.gu.se;
Tel.: +46-31-772 2905; Fax: +46-31-772 3840.
Received: 13 November 2009; in revised form: 26 November 2009 / Accepted: 7 December 2009 /
Published: 9 December 2009
Abstract: A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole
derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral
synthons is described. The amino acids were converted into azido alcohols, followed by
copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl
propiolate and subsequent ester aminolysis with primary and secondary amines furnished
the target compounds, which were obtained in excellent yields with no racemization.
Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-
triazoles derivatives has the potential of mimicking the binding mode of known purine
analogues.
Keywords: [3+2] cycloaddition; azido alcohols; 1,4-disubstituted-1,2,3-triazoles
1. Introduction
1,2,3-Triazoles are an important class of heterocycles due to their wide range of applications as
synthetic intermediates and pharmaceuticals [1,2]. Several therapeutically interesting 1,2,3-triazoles
have been reported, including anti-HIV agents [3–6], antimicrobial compounds [7], β3-selective
adrenergic receptor agonists [8], kinase inhibitors [9,10] and other enzyme inhibitors [11,12]. The

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1,2,3-triazole moiety is also present in a number of drugs, for example, the β-lactam antibiotic
tazobactam [13] and the cephalosporin cefatrizine [14].
In our search for synthetic non-natural frameworks that could mimic nucleosides, we wanted to
investigate the possibility of using 1,2,3-triazole moiety as a mimic of the imidazole part of the
adenine system (Figure 1). Imidazole and triazole based nucleoside derivatives have been reported as
potent enzyme inhibitors. Ribavarin [15], a 1,2,4-triazole based purine analogue, has high potency as
an antiviral agent and is currently used in the clinic to inhibit RNA virus infections. Furthermore,
imidazole based derivatives have been reported as potent adenosine deaminase (ADA) inhibitors
(Figure 1) [16–19]. Therefore, we wanted to investigate the possibility of the 1,2,3-triazole scaffold to
be docked into proteins that are inhibited of these nucleoside analogues and to develop efficient
synthesis protocols for the preparation of 1,4-disubstituted-1,2,3-triazoles.
Figure 1. (a) Docked binding mode of (R)-3 (yellow) compared to X-ray structure (1R6A)
of ribavirin-5’-triphosphate (blue) 1 in the active site of the NS5MTaseDV in the dengue
virus; (b) The docking shows that the NH2-groups of compound (R)-3 and ribavirin-5’-
monophosphate are almost superimposed and makes the same important interaction with
the carbonyl functions of Leu17 and Leu20 in the protein; (c) Docked binding mode of
(R)-3 (yellow) compared to x-ray structure (1v7a) of inhibitor 2 in the active site of the
ADA enzyme; (d) The imidazole part of compound (R)-3 is almost superimposed over
compound 2 and the phenyl ring points in (R)-3 in the same direction as the naphtyl ring in 2.
2. Results and Discussion
In order to explore the potential of the 1,4-disubstituted-1,2,3-triazoles as a possible scaffold for
nucleoside inhibitors, compound (R)-3 derived from D-phenylalanine, was docked into the nucleoside
binding pocket of a viral enzyme of the Dengue virus (NS5MTaseDV) [20] and adenosine deaminase

Molecules 2009, 14
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[16–19]. Initially, the triazole scaffold was compared with the ribavirin nucleotide that inhibits the
NS5MTaseDV enzyme. Upon entry into the cell, ribavirin gets converted to the 5’-triphosphate
derivative before it binds to the enzyme (Figure 1A). However, due to poor electron density in the
X-ray structure (1R6A) only the monophosphate has been modelled. Using Schrödinger’s Glide (XP
docking mode), compound (R)-3 docks into the same pose (yellow ligand) as the ribavirin
5’-monophosphate in the NS5MTaseDV enzyme suggesting that compound (R)-3 mimics the binding
mode of ribavirin (dark blue) (Figure 1B). The second example comes from the inhibition of the ADA
enzyme. In this case, several crystal structures have been reported with imidazole-based nano-molar
inhibitors [16–19].
Therefore, (R)-3 was also docked into the ADA system in order to investigate the similarity of the
1,4-disubstituted-1,2,3-triazoles to the imidazole-based nucleoside analogue 2 (Figure 1C). The
docking results from Glide (XP docking mode) show that our model compounds (yellow)
superimposes the imidazole of the inhibitor in the binding pocket of the X-ray structure (Figure 1D).
The docking results from NS5MTaseDV and adenosine deaminase (ADA) suggest that chiral 1,4-
disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known
purine analogues.
The 1 and 4 position of the triazole scaffold allow diversification and the 1,4-disubstituted-1,2,3-
triazoles should be easy accessible from [3+2] cycloaddition reactions between azides and alkynes
using the copper catalyzed procedure reported by Meldal [21] and Sharpless [22] (Figure 2). We
anticipated that by using azido alcohol derivatives, prepared from amino acids, a variety of different R-
groups could be introduced resulting in chiral 1,4-disubstituted-1,2,3-triazoles. Furthermore, by using
propiolate in the [3+2] cycloaddition reactions an ester functionality would be present in 4 position of
the disubstituted-1,2,3-triazoles and allow further derivatisation, for example by reactions with primary
or secondary amines.
Here, we report an efficient synthesis of compounds represented by structure 4 (Figure 2) by
performing [3+2] cycloaddition reactions followed by ester aminolysis. According to the general
strategy outlined in Figure 2, our synthesis of the 1,4-disubstituted-1,2,3-triazoles commenced with the
preparation of amino alcohols 10-14 by reduction of the corresponding amino acids 5-9 (Table 1).
Figure 2. Retrosynthetic strategy for the generation of chiral 1,4-disubstituted-1,2,3-
triazole derivatives.
Both L-Phe and D-Phe were selected in order to obtain the two different stereoisomers of 1,4-
disubstituted-1,2,3-triazoles containing an aromatic R-group. L-Homo-Phe was selected in order to

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obtain 1,4-disubstituted-1,2,3-triazoles with the phenyl group further away from the triazole ring.
These aromatic groups could potentially make interactions with hydrophobic pockets adjacent to the
nucleoside binding site in target proteins [23]. We also wanted to explore the use of amino acids with
alkyl side chains and selected L-Val and L-Ser. Although the copper(I)-catalyzed 1,3-dipolar
cycloaddition is insensitive to functional group interference, a benzyl ether derivative of L-Ser was
used in order to facilitate column chromatography of the target compound. The amino acids were
reduced using LiAlH4 and the resulting amino alcohols converted to the corresponding azides via
treatment with TfN3. In this way, a variety of azides derived from various amino alcohols were
obtained in good yields (70-76% yields) [24–29].
Table 1. Synthesis of azido alcohols.
Compound
R1
R2
Yield (%)
5
H
CH2Ph
-
6
CH2Ph
H
-
7
8
9
H
H
H
H
CH2CH2Ph
CH(CH3)2
CH2OCH2Ph
CH2Ph
-
-
-
10
11
12
13
14
15
16
17
18
19
79
91
92
96
97
76
72
74
70
73
CH2Ph
H
H
H
H
CH2CH2Ph
CH(CH3)2
CH2OCH2Ph
CH2Ph
H
CH2Ph
H
H
CH2CH2Ph
CH(CH3)2
CH2OCH2Ph
H
H
(i) LiAlH4, THF, 16 h, reflux. (ii) TfN3, DMAP, DCM, 15 h, RT.
In general, the copper(I)-catalyzed 1,3-dipolar cycloaddition is known as a mild reaction proceeding
well in aqueous solutions without protection from oxygen. A range of different reaction conditions
have been reported, particularly with respect to generation of the active CuI species. Sources of CuI
include CuI salts, most commonly copper iodide [21], in situ reduction of CuII salts, particularly CuII
sulfate [22], and comproportionation of Cu0 and CuII [30,31]. Recent reports suggest that nitrogen-
based ligands can stabilize the CuI oxidation state under aerobic, aqueous conditions and promote the
desired transformation [32].
We got very good results using 5 mol % of sodium ascorbate and 1 mol % of copper(II) sulphate in
a 1:1 mixture of water and tert-butyl alcohol (Table 2). The reaction between methylene propiolate and
15 or 18 using these reaction conditions furnished the two 1,4-disubstituted triazole products 24 and 25
in 71% and 74% isolated yields respectively, after stirring at RT in a capped vial. The reactions were

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monitored by TLC and showed complete conversion after 15 h. The product yields in the reactions
therefore reflect the efficiency of product purification rather than the coupling efficiency.
Table 2. Synthesis of 1,4-disubstituted-1,2,3-triazoles.
Compound
R1
R2
CH2Ph
R3
CH2Ph
CH2Ph
CH2Ph
Si(CH3)2C(CH3)3
H
R4
Yield (%)
20
21
22
23
24
25
26
27
28
29
H
-
87
91
92
67
71
74
97
83
90
82
CH2Ph
H
-
H
H
CH2CH2Ph
CH2OCH2Ph
CH2Ph
-
-
H
CO2CH3
CO2CH3
Ph
H
CH(CH3)2
CH2Ph
H
H
H
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CO2CH3
CO2CH3
CO2CH3
CH2Ph
H
H
CH2CH2Ph
(i) BnCl, NaH, TBAI, THF, 15 h, RT; or TBDMSiCl, imidazole, DMF, 15 h, RT; (ii) sodium
ascorbate, CuSO4 in H2O:t-BuOH (1:1 v/v), 15h, RT.
In order to improve the efficiency of purification of the products by column chromatography we
decided to block the hydroxyl function of the azido alcohols either as benzyl ethers (as in compounds
20-22) or as TBDMS ethers (as in compound 23). In addition, the benzyl ethers could make potential
interactions in the phosphate-and sugar binding area of the ATP binding site of target kinases [23].
The protected azido derivatives 20-22 were only partially soluble in water: t-BuOH (1:1 v/v) and
the cycloaddition reactions with methylene propiolate were attempted in water: THF (1:2 v/v) instead.
The corresponding 1,4-disubstituted triazole products 26-28 were obtained high yields (83–97%
yields). However, the reaction between methylene propiolate and the TBDMS-protected azido alcohol
did not proceed to completion, and the corresponding 1,4-disubstituted triazole 30 was only obtained
o
in 66% yield. Prolonged reaction times (30 h) or running the reaction at elevated temperature (50 C
for 15 h) did not improve the yield (data not shown). Steric interference of the bulky TBDMS ether in
the cycloaddition reaction is a possible explanation for this effect.
As well as high yields and prevention of by-product formation, it is essential to avoid racemization
when functionalizing enantiomerically pure compounds. Hence, a chiral HPLC system was used to
analyze the [3+2] cycloaddition products 27 and 28. The two enantiomers separated well on the chiral
HPLC column with retention times of 16.6 min (27) and 13.4 min (28) respectively. No racemization
could be detected.

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Scheme 1. Derivatisation of ester functionality with different amides. i. Amines, NaOMe,
MeOH, 15 h, RT.
The ester functionality of the disubstituted-1,2,3-triazoles was further derivatised by reaction with
primary and secondary amines. Compound 24 and 25 were reacted with 7N NH3 in MeOH for 15 h at
RT and the corresponding target compounds were obtained in 97% and 93% isolated yields
respectively. However, reacting 24 with other amines (3 eq) such as butylamine, benzylamine,
diethylamine, morpholine or ethanolamine in MeOH, resulted in sluggish reactions. Prolonged reaction
times (30 h), larger excess of amines (10 eq) or elevated temperature, either by classical thermal
heating (50 oC, 10 h) or by microwave assisted heating (100 oC, 10-60 min in a sealed vessel) had only
a marginal effect on the yield.
The reactions were repeated in the presence of 2 eq of sodium methoxide and TLC showed
complete conversion after 15 h at RT. Nevertheless, several products were formed and the target
compounds 31-35 were only isolated in low to moderate yields (4-58%). In general, the primary
amines gave the best result while the secondary amines proceeded more slowly (Table 3).
Table 3. Synthesis of 4-carbamoyl-1,2,3-triazoles.
Compound
R1
H
R2
CH2Ph
R3
R4
Yield (%)
(S)-3
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
H
NH2
97
58
4
H
CH2Ph
H
H
NH(CH2)3CH3
NH(CH2)2OH
NHCH2Ph
N(CH2CH3)2
N(CH2CH2)2O
NH2
H
CH2Ph
H
CH2Ph
H
35
12
30
35
92
93
81
87
8
H
CH2Ph
H
H
CH2Ph
H
H
CH(CH3)2
CH2Ph
H
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Si(CH3)2C(CH3)3
NH2
H
CH2Ph
NH(CH2)3CH3
NH(CH2)2OH
NHCH2Ph
N(CH2CH3)2
N(CH2CH2)2O
NH(CH2)3CH3
NH2
H
CH2Ph
H
CH2Ph
H
CH2Ph
H
CH2Ph
68
98
88
93
92
CH2Ph
H
H
CH2OCH2Ph
CH2OCH2Ph
CH2OCH2Ph
H
NH(CH2)3CH3
NH2
H

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On the other hand, when the 4-carboxy methyl ester-triazole 27 was reacted with 7N NH3 in MeOH
or amines in the presence of sodium methoxide the 4-carbamoyltriazoles 37-42 were obtained in high
yields. Ammonia and primary amines gave excellent yields (81–92%) while diethyl amine and
morpholine did not go to completion and gave the corresponding 4-carbamoyltriazoles in 8 and 68%
yields respectively. The 4-carbamoyltriazoles 43-46 were also obtained in excellent yields (88–98%).
In all cases TLC showed clean reactions with only formation of target compounds. The results clearly
show that it is essential to block the primary alcohol in order to prevent side-reaction and to secure
high yields of the 4-carbamoyltriazoles.
The two enantiomers 38 and 43 were analyzed by chiral HPLC to determine if any racemization
occurred in the amination step. The two enantiomers separated well on the chiral HPLC column with
retention times of 21.2 min (38) and 14.9 min (43) respectively. No racemization could be detected.
3. Experimental
3.1. General
(S)-2-Amino-3-phenylpropionic acid, (S)-2-amino-3-methylbutyric acid, (R)-2-amino-3-phenyl-
propionic acid, (S)-2-amino-4-phenylbutyric acid and (S)-2-amino-3-benzyloxypropionic acid (40)
were obtained from Sigma Aldrich and Bachem. Trifluoromethanesulfonic anhydride was obtained
1
from Acros. All other chemicals were reagent grade or better obtained from reputable suppliers. H-
and 13C-NMR spectra were recorded on a JEOL JNM-EX 400 spectrometer at 400 and 100 MHz,
respectively. Optical rotation was measured with a Perkin Elmer Polarimeter 341 LC. The reactions
were monitored by TLC, on silica plated aluminium sheets (Silica gel 60F254, E. Merck) in case of
flash chromatography, Merck silica gel CC (230-400 mesh) was used. Elemental analyses were
performed at H Kolbe Mikroanalytisches Laborium, Mühlheim an der Ruhr, Germany.
Chiral HPLC analysis was performed on a Varian system (9012 pump, flow 1 mL min−1; 9050
detector at 254 nm) using a Chiralpac AD column (250 × 4.6 mm) and isocratic elution with 10%
i-PrOH/n-hexane (method A) or 5% i-PrOH/n-hexane (method B).
3.2. General procedure for preparation of amino alcohols
A solution of lithium aluminium hydride (1.4 eq) in dry THF (2 mL/mmol amino acid) was stirred
and cooled in an ice bath. The amino acid (1 eq) was added and the mixture was stirred at 0 oC for 1 h,
warmed to room temperature, and stirred for an additional 1 h. The reaction mixture was then heated at
reflux for 16 h. The solution was cooled in an ice bath and diluted slowly with ether (30 mL). Water
(7.5 mL) and 15% NaOH (2.5 mL) were added dropwise to the solution in succession. The mixture
was filtered through Celite to remove the aluminium salts. The Celite was washed with ether
(2 × 15 mL). The filtrate was collected and the solvent was removed under reduced pressure affording
the amino alcohol. The amino alcohols were used in the following steps without further purification.

Molecules 2009, 14
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(S)-2-Amino-3-phenylpropan-1-ol (10): The target compound was prepared from 5 (24.2 mmol, 4 g)
using the general procedure described above and obtained as a yellow solid (2.9 g, 79% yield).
Analytical data was consistent with the literature [33].
(R)-2-Amino-3-phenylpropan-1-ol (11): The target compound was prepared from 6 (18.2 mmol,
3.00 g) using the general procedure described above and obtained as a yellow oil (2.49 g, 91% yield).
The amino alcohol was used for the following steps without further purification [34].
(S)-2-Amino-4-phenylbutan-1-ol (12): The target compound was prepared from 7 (5.5 mmol, 1.00 g)
using the general procedure described above and obtained as a yellow oil (50 mg, 92% yield).
Analytical data was consistent with the literature [34].
(S)-2-Amino-3-methylbutan-1-ol (13): The target compound was prepared from 8 (8.23 mmol, 965 mg)
using the general procedure described above and obtained as a yellow oil (805 mg, 96% yield).
Analytical data was consistent with the literature [35].
(R)-2-Amino-3-benzyloxypropan-1-ol (14): The target compound was prepared from 9 (10.24 mmol,
2.00 g) using the general procedure described above and obtained as an oil (1.80 g, 97% yield). The
1
amino alcohol was used for the following steps without further purification. H-NMR (CDCl3)
δ 3.03–3.10 (1H, m), 3.37–3.62 (2H, m), 3.43–3.50 (2H, m), 4.49 (2H, s), 7.24–7.37(5H, m).
Analytical data was consistent with the literature [35].
3.3. General procedure for preparation of azido alcohols by diazo transfer
To a solution of amino alcohol (1 eq) and DMAP (2.5 eq) in CH2Cl2 (1mL/mmol amino alcohol)
triflyl azide solution (4.4 eq) was added dropwise with stirring and exclusion of moisture. The reaction
mixture was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure and
purified by flash chromatography.
(S)-2-Azido-3-phenylpropan-1-ol (15): The target compound was prepared from 10 (19.27 mmol,
2.91 g) using the general procedure described above and purified by flash chromatography on silica gel
using EtOAc/hexane(1:2 v/v) as eluent. The target compound was obtained as a yellow oil (2.45 g,
66% yield). Analytical data was consistent with the literature [28].
(R)-2-Azido-3-phenylpropan-1-ol (16): The target compound was prepared from 11 (16.4 mmol,
2.49 g) using the general procedure described above and purified by flash chromatography on silica gel
using EtOAc/hexane (1:2 v/v) as eluent. The target compound was obtained as a yellow oil (2.10 g,
72% yield). 1H-NMR (CDCl3) δ 2.76–3.14 (2H, m), 3.55–3.69 (2H, m), 3.77–3.85 (1H, m), 7.20–7.35
(5H, m); 13C-NMR (CDCl3) δ 36.79 (-), 62.9 (+), 70.51 (-), 127.43 (+), 128.59 (+), 128.91 (+), 141.05
(q); Anal. Calc. for C8H11N3O: C, 64.39; H, 7.45; N, 28.17. Found: C, 64.44; H, 7.46; N, 28.28.
(S)-2-Azido-4-phenylbutan-1-ol (17): The target compound was prepared from 12 (5.03 mmol,
830 mg) using the general procedure described above and purified by flash chromatography on silica

Molecules 2009, 14
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gel using EtOAc/hexane (1:2 v/v) as eluent. The target compound was obtained as a clear oil (710 mg,
74% yield). 1H-NMR (CDCl3) δ 1.78–1.85 (2H, m), 2.67–2.85 (2H, m), 3.42–3.49 (1H, m), 3.55–3.73
(2H, m), 3.68–3.72 (2H, m), 7.18–7.34 (5H, m); 13C-NMR (CDCl3) δ 32.3 (-), 32.4 (-), 63.5 (+),
65.5 (-), 126.4 (+), 128.6 (+), 128.8 (+), 141.0 (q); Anal. Calc. for C10H13N3O: C, 62.81; H, 6.85; N,
21.97. Found: C, 62.69; H, 6.79; N, 21.88.
(S)-2-Azido-3-methylbutan-1-ol (18): The target compound was prepared from 13 (7.8 mmol, 805 mg)
using the general procedure described above and purified by flash chromatography on silica gel using
EtOAc/hexane (1:3 v/v) as eluent, affording the target compound as a yellow oil (698 mg, 70% yield).
Analytical data was consistent with the literature [35].
(R)-2-Azido-3-benzyloxypropan-1-ol (19): The target compound was prepared from 14 (10.7 mmol,
1.8 g) using the general procedure described above and purified by flash chromatography on silica gel
using EtOAc/hexane (1:2 v/v) as eluent. The target compound was obtained as an oil (1.51 g, 73%
yield). Analytical data was consistent with the literature [36].
3.4. General procedure for benzylation of the hydroxyl functionality
The azido alcohol (1 eq) was dissolved in dry THF (10 mL), NaH (suspension in mineral oil 60%,
2 eq) was added and the suspension was stirred 5 min at rt. Benzyl bromide (2 eq) and TBAI (0.05 eq)
were added and the reaction mixture stirred for 15 h. The reaction was quenched with sat. NH4Cl aq
(15 mL) at which the reaction mixture became clear, and was then extracted with EtOAc (2 × 30 mL).
The organic phases were pooled and washed once with brine, dried with MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by column chromatography on silica
gel using hexane and hexane/EtOAc (95:5 v/v) as eluents.
(S)-2-Azido-1-benzyloxy-3-phenylpropane (20): The target compound was prepared from 15
(12.18 mmol, 2.16 g) using the general procedure described above and obtained as a yellow oil (2.8 g,
87% yield). 1H-NMR (CDCl3) δ 2.83–2.99 (2 H, m), 3.54–3.59 (2H, m), 3.63–3.68 (1H, m), 4.63 (2H,
13
m), 7.24–7.45 (10 H, m); C-NMR (CDCl3) δ 37.30 (-), 62.81 (+), 71.91 (-), 73.46 (-), 126.90 (+),
127.73 (+), 127.89 (+), 128.52 (+), 128.68 (+), 129.38 (+), 137.43 (q), 137.91 (q); Anal. Calc. for
C16H17N3O: C,71.87; H, 6.42; N, 15.72. Found: C, 71.90; H, 6.44; N, 15.75.
(R)-2-Azido-1-benzyloxy-3-phenylpropane (21): The target compound was prepared from 16
(5.64 mmol, 1.00 mg) using the general procedure described above and was obtained as a yellow oil
1
(1.37 g, 91% yield). H-NMR (CDCl3) δ 2.82–3.01 (2 H, m), 3.54–3.62 (2H, m), 3.79–3.88 (1H, m),
4.65–4.72 (2H, m), 7.29–7.48 (10 H, m); 13C-NMR (CDCl3) δ 37.24 (-), 62.75 (+), 71.86 (-), 73.39 (-),
126.84 (+), 127.68 (+), 127.84 (+), 128.53 (+), 128.63 (+), 129.34 (+), 137.39 (q), 137.88 (q); Anal.
Calc. For C16H19N3O: C, 72.57; H, 6.81; N, 14.93. Found: C, 71.67; H, 6.72; N, 15.04.
(S)-2-Azido-1-benzyloxy-4-phenylbutane (22): The target compound was prepared from 17
(3.32 mmol, 635 mg) using the general procedure described above and was obtained as a yellow oil
1
(861 mg, 92% yield). H-NMR (CDCl3) δ 1.82–1.92 (2H, m), 2.68–2.91 (2H, m), 3.53–3.68 (3H, m),
4.62 (2H, s), 7.23–7.48 (10 H, m); 13C-NMR (CDCl3) δ 32.27 (-), 32.63 (-), 61.08 (+), 72.96 (-), 73.44

Molecules 2009, 14
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(-), 126.25 (+), 127.6 (+), 127.8 (+), 128.5 (+), 128.6 (+), 128.8 (+), 137.9 (q), 141.0 (q), Anal. Calc.
for C17H19N3O: C, 72.57; H, 6.81; N, 14.93. Found: C, 72.59; H, 6.77; N, 15.00.
((S)-2-Azido-3-benzyloxypropoxy)-tert-butyl-dimethylsilane (23): Compound 19 (2.59 mmol, 538 mg)
was dissolved in DMF (5 mL), TBDMS-Cl (3.38 mmol, 506 mg) and imidazole (6.5 mmol, 441 mg)
were added and the mixture stirred 15 h at rt. The reaction mixture was concentrated under reduced
pressure, extracted with EtOAc and NH4Claq and purified by column chromatography on silica gel
using hexane/EtOAc (99:1 v/v) as eluent. The target compound was obtained as an oil (775 mg, 93%
yield). 1H-NMR (CDCl3) δ 0.13 (6H, s), 0.95 (9H, s), 3.54–3.85 (5H, m), 4.60 (2H, s), 7.29–7.43 (5H,
m); 13C-NMR (CDCl3) δ -5.39 (+), 18.35 (q), 25.93 (+), 62.50 (N3CHCH2), 63.40 (+), 69.37 (-),
73.59 (-), 127.80 (+), 127.90 (+), 128.59 (+), 137.93 (q); Anal. Calc. for C16H27N3O2Si: C, 59.78; H,
8.47; N, 13.07. Found: C, 59.74; H, 8.42; N, 13.02.
3.5. General procedure for copper catalyzed cycloaddition reactions
The unprotected azido alcohol (1eq) and the alkyne (1.5 eq) were suspended in a 1:1 mixture of
water and tert-butyl alcohol (5 mL/mmol azido alcohol). Benzyl protected azido alcohol (1 eq) and the
alkyne (1.5 eq) were suspended in H2O/THF (1:2, v/v). Sodium ascorbate (0.1 eq as a 1 M solution in
water) was added, followed by copper(II) sulfate (0.01 eq as a 0.1 M solution in water). The reaction
mixture was stirred at rt for 15 h. The solvents were removed under reduced pressure and the residue
adsorbed on silica gel and purified by column chromatography.
1-((S)-1-Hydroxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (24): The target
compound was prepared from 15 (14.9 mmol, 2.64 g) and methyl propiolate (22.35 mmol, 1.87 g)
using the general procedure described above. The product was purified by column chromatography on
silica gel (2:1 EtOAc/hexane) affording the target compound as a pale oil (3.15 g, 81% yield).
1H- NMR (CDCl3) δ 3.28 (2H, d, J = 7.7 Hz), 3.89 (3H, s), 4.04–4.17 (2H, m), 4.75–4.81 (1H, m),
7.05–7.27 (5H m), 7.95 (1H, s); 13C-NMR (CDCl3) δ 37.35 (-), 52.15 (+), 63.50 (+), 65.56 (+), 127.25
(+), 128.46 (q), 129.10 (2x+), 135.89 (q), 139.06 (q), 161.03 (q); Anal. Calc. for C13H15N3O3: C,
59.76; H, 5.79; N, 16.08. Found: C, 59.87; H, 5.74; N, 15.93.
1-((S)-1-Hydroxymethyl-2-methylpropyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (25): The
target compound was prepared from 18 (5.43 mmol, 700 mg) and methyl propiolate (8.14 mmol, 684
mg) using the general procedure described above. The product was purified by column
chromatography on silica gel (2:1 EtOAc/hexane) affording the target compound as a pale oil (984 mg,
1
85% yield). H-NMR (CDCl3) δ 0.76 (3H, d, 6.6 Hz), 1.08 (3H, d, 6.6 Hz), 2.30–2.43 (1H, m),
3.92 (3H, s), 4.00–4.07 (1H, m), 4.17–4.25 (1H, m), 8.17 (1H, s); 13C-NMR (CDCl3) δ 19.33 (+),
19.61 (+), 29.73 (+), 52.31 (+), 62.35 (-), 70.24 (+), 128.15 (+), 139.73 (q), 161.31 (q); Anal. Calc. for
C9H15N3O3: C, 50.69; H, 7.09; N, 19.71; Found: C, 50.90; H, 6.92; N, 19.84.
1-((S)-(1-Hydroxymethyl-2-phenethyl)-4-phenyl-1H,1,2,3-triazole (26): The target compound was
prepared from 15 (2 mmol, 365 mg) and phenylacetylene (2.5 mmol, 275 μL) using the general

Molecules 2009, 14
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procedure described above. The crude product was purified by column chromatography on silica gel
(2:3 EtOAc/hexane) affording the desired product as a colourless solid (512 mg, 98% yield). 1H-NMR
(CDCl3) δ 3.22–3.35 (2H, m), 4.05–4.25 (2H, m), 4.67–4.73 (1H, m), 7.07–7.12 (2H, m), 7.19–7.39
13
(6H, m), 7.50 (1H, s), 7.61–7.67 (2H, m); C-NMR (CDCl3) δ 37.97(+), 64.19 (-), 65.55 (+), 120.70
(+), 125.75 (+), 127.30 (+), 128.30 (+), 128.96 (+), 129.00 (+), 129.21 (+), 130.46 (q), 135.76 (q),
136.77 (q); Anal. Calc. for C17H17N3O: C, 73.10; H, 6.13; N, 15.04. Found: C, 72.94; H, 6.09; N,
14.98.
1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (27): The
target compound was prepared from 20 (5.6 mmol, 1.50 g) and methyl propiolate (8.4 mmol, 711 mg)
using the general procedure described above. The crude product was obtained as a pale oil (1.63 g,
1
83% yield). H-NMR (CDCl3) δ 3.21–3.32 (2H, m), 3.75–3.84 (2H, m), 3.92 (3H, s), 4.41–4.51 (2H,
m), 4.84–4.98 (1H, m), 7.01–7.05 (2H, m), 7.16–7.36 (8H, m), 8.08 (1H, s); 13C-NMR (CDCl3) δ
37.81 (-), 52.30 (+), 63.59 (+), 70.13 (-), 73.66 (-), 127.38 (+), 127.96 (+), 128.23 (+), 128.71 (+),
128.96 (+), 129.04 (+), 135.94 (q), 137.19 (q), 139.51 (+), 161.31 (q); Anal. Calc. for: C20H21N3O3: C,
68.36; H, 6.02; N, 13.66. Found: C, 68.29; H, 5.98; N, 13.55; Optical rotation: [α]20D= +53,33 (c 1,06
in CHCl3); tR (method A): 16.3.
1-((R)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (28): The
target compound was prepared from 21 (3.7 mmol, 1.00 g) and methyl propiolate (5.6 mmol, 474 mg)
using the general procedure described above. The crude product was obtained as a yellow oil (1.18 mg,
1
90% yield). H-NMR (CDCl3) δ 3.21–3.33 (2H, m), 3.75–3.84 (2H, m), 3.93 (3H, s), 4.41–4.52 (2H,
m), 4.89–4.97 (1H, m), 7.01–7.06 (2H, m), 7.17–7.37 (8H, m), 8.08 (1H, s); 13C-NMR (CDCl3)
δ 37.85 (-), 52.30 (+), 63.56 (+), 70.16 (-), 73.68 (-), 127.39 (+), 127.98 (+), 128.24 (Ph), 128.73 (Ph),
128.98 (Ph), 129.06 (Ph), 135.98 (q), 137.21 (q), 139.47 (+), 161.40 (q); Anal. Calc. for C20H21N3O3:
C, 68.36; H, 6.02; N, 11.96. Found: C, 68.30; H, 5.99; N, 11.87; Optical rotation: [α]20D= -50,94 (c
1,02 in CHCl3); tR (methode A): 13.4.
1-((S)-1-Benzyloxymethyl-3-phenylpropyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (29): The
target compound was prepared from 22 (1.49 mmol, 400 mg) and methyl propiolate (2.14 mmol, 180
mg) using the general procedure described above. The crude product was obtained as a yellow oil
1
(473 mg, 88% yield). H-NMR (CDCl3) δ 1.85–2.02 (2H, m), 2.57–2.71 (2H, m), 3.44–3.55 (2H, m),
3.84 (3H, s), 4.18–4.28 (2H, m), 4.46–4.59 (1H, m), 7.13–7.19 (2H, m), 7.23–7.37 (8H, m), 7.82 (1H,
s); 13C-NMR (CDCl3) δ 32.62 (-), 33.98 (-), 49.67 (+), 52.54 (+), 71.75 (-), 73.38 (-), 126.06 (+),
127.86 (+), 128.58 (+), 138.36 (q), 139,81 (q), 141.84 (q), 161.38 (q); Anal. Calc. for C21H23N3O3: C,
68.82; H, 6.34; N, 11.74. Found: C, 69.03; H, 6.39; N, 11.85.
1-[(S)-1-Benzyloxymethyl-2-(tert-butyl-dimethylsilanyloxy)-ethyl]-1H-1,2,3-triazole-4-carboxylic acid
methyl ester (30): The target compound was prepared from 23 (1.21 mmol, 390 mg) and methyl
propiolate (1.82 mmol, 153 mg) using the general procedure described above. The crude product was
purified by column chromatography on silica gel (1:3 EtOAc/hexane) affording the product as an oil

Molecules 2009, 14
5135
(382 mg, 82% yield). 1H-NMR (CDCl3) δ -0.11(3H, s), -0.10 (3H, s), 0.74 (9H, s), 3.77–3.88 (5H, m),
3.89–4.04 (2H, m), 4.37–4.46 (2H, m), 4.79–4.87 (1H, m), 7.11–7.25 (5H, m), 8.16 (1H, s); 13C-NMR
(CDCl3) δ -5.88 (+), -5.85 (+), 17.87 (Q), 25.50 (+), 51.80 (+), 61.99 (-), 62.64 (+), 67.74 (-),
73.24 (-), 125.56 (+), 127.79 (+), 128.31 (+), 137.01 (q), 139.15 (q), 161.03 (q); Anal. Calc. for
C20H31N3O4Si: C, 59.23; H, 7.70; N, 10.36. Found: C, 58.99; H, 7.79; N, 10.28.
3.6. General procedure for ester-amide conversion
Reaction with ammonia: The ester was dissolved in 7N NH3 in MeOH (1.5 mL) and stirred at rt
overnight. The solvent was removed under reduced pressure and the desired product was purified by
recrystallization or by column chromatography on silica gel.
Reaction with all other amines: Sodium (2 eq) was dissolved in MeOH (3 mL) under nitrogen
followed by addition of amine (3 eq). A solution of the ester (1 eq) dissolved in MeOH (0.5 mL) was
added to the reaction mixture. The reaction was stirred under nitrogen at rt for 15 h. The reaction was
quenched with 1M HCl aq (1 mL) and extracted with CHCl3 (2 x 20 mL). The organic layer was
washed with brine, separated, dried with MgSO4. The solvent was removed under reduced pressure
and the crude product purified by column chromatography on silica gel or by recrystallization.
1-((S)-1-Benzyl-2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxylic acid amide ((S)-3): The target
compound was obtained by reacting 24 (0.89 mmol, 233 mg) with NH3 following the procedure above.
The desired product was recrystallized from EtOH affording 3 as a white solid (184 mg, 97% yield).
1H- NMR (DMSO) δ 3.13–3.26 (2H, m), 3.75–3.84 (2H, m), 4.86–4.93 (1H, m), 5.16 (1H, t),
13
7.09–7.23 (5H, m), 7.40 (1H, s), 7.77 (1H, s), 8.53 (1H, s); C-NMR (DMSO) δ 36.53 (-), 63.10 (-),
64.62 (+), 125.96 (+), 126.49 (+), 128.43 (+), 128.80 (+), 137.12 (q), 142.46 (q), 161.65 (q); Anal.
Calc. for: C12H14N4O2: C, 58.53; H, 5.73; N, 22.75. Found: C, 58.39; H, 5.64; N, 22.78.
1-((S)-1-Benzyl-2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxylic acid butylamide (31): The target
compound was obtained by reacting 24 (0.76 mmol, 200 mg) with butyl amine (2.38 mmol, 230 μL)
following the procedure described above. The crude product was purified by column chromatography
on silica gel (2:3 EtOAc/hexane, then 2:1 EtOAc/hexane + 10% MeOH) affording compound 31 as a
1
white solid (100 mg, 58% yield). H-NMR (CDCl3) δ 0.87–0.95 (3H, m), 1.30–1.61 (4H, m),
3.19–3.28 (2H, m), 3.37–3.42 (2H, m), 3.98–4.05 (2H, m), 4.77–4.84 (1H, m), 7.06–7.10 (2H, m), 7,14
(1H, t), 7.18–7.28 (3H, m), 8.07 (1H, s); 13C-NMR (CDCl3) δ 13.95 (+), 20.29 (-), 31.71 (-), 37.73 (-),
39.12 (-), 63.61(-), 65.46 (+), 126.00 (+), 127.43 (+), 129.05 (+), 129.13 (+), 136.27 (q), 142.19 (q),
160.48 (q); Anal. Calc. for: C16H22N4O2: C, 63.56; H, 7.33; N, 18.53. Found: C, 63.51; H, 7.23; N,
18.41.
1-((S)-1-Benzyl-2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxylic acid (2-hydroxy-ethyl)-amide (32):
The target compound was obtained by reacting 24 (0.55 mmol, 145 mg) with ethanol amine
(1.6 mmol, 100 μL) following the procedure described above. The crude product was purified by
column chromatography on silica gel using CHCl3/MeOH (9:1 v/v) as eluent. The title compound was

Molecules 2009, 14
5136
1
obtained as an oil (7 mg, 4% yield). H-NMR (CD3OD) δ 3.18–3.36 (2H, m), 3.46–3.52 (2H, m),
3.66–3.71 (2H, m), 3.91–4.04 (2H, m), 4.64–4.69 (1H, m), 7.07–7.29 (5H, m), 8.27 (1H, s); 13C-NMR
(CDCl3) δ 38.14 (-), 42.46 (-), 61.37 (-), 64.40 (-), 66.84 (+), 126.99 (+), 127.73 (+), 129.43 (+),
129.81 (+), 136.31 (q), 142.67 (q), 160.52 (q); Anal. Calc. for C14H18N4O3: C, 57.92; H, 6.25; N,
19.30. Found: C, 58.18; H, 6.24; N, 19.32.
1-((S)-1-Hydroxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid benzylamide (33): The
target compound was obtained by reacting 24 (0.76 mmol, 200 mg) with benzylamine (2.3 mmol,
250 μL) following the procedure described above. The crude product was purified by column
chromatography on silica gel using EtOAc/hexane (2:3 v/v) and EtOAc/hexane + 10% MeOH) as
1
eluents to afford 33 as an oil (80 mg, 35% yield). H-NMR (CDCl3) δ 3.22–3.34 (2H, m), 3.99–4.10
(2H, m), 4.56–4.67 (2H, m), 4.76–4.85 (2H, m), 7.08–7.12 (2H, m), 7.21–7.38 (8H, m), 7.46 (1H, t),
8.06 (1H, s); 13C-NMR (CDCl3) δ 37.75(-), 43.46 (-), 63.71 (-), 65.46 (+), 126.23 (+), 127.51 (+),
127.85 (+), 128.08 (+), 128.97 (+), 129.11 (+), 136.15 (q), 137.93 (q), 142.66 (q), 160.27 (q); Anal.
Calc. for: C19H20N4O2: C, 67.84; H, 5.99; N, 16.65. Found: C, 67.68; H, 5.78; N, 16.47.
1-((R)-1-Hydroxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid diethylamide (34): The
target compound was obtained by reacting 24 (0.69 mmol, 180 mg) with diethyl amine (2.1 mmol,
220 μL) following the procedure described above. The crude product was purified by column
chromatography on silica gel using CHCl3/EtOAc (2:1 v/v) and, DCM/MeOH (9:1 v/v) as eluents to
1
afford 34 as an oil (25 mg, 12% yield). H-NMR (CDCl3) δ 0.98–1.48 (6H, m), 3.22–3.35 (2H, m),
3.88–3.92 (2H, m), 3.94–4.15 (2H, m), 4.78–4.85 (1H, m), 7.00–7.41 (5H, m), 8.05 (1H, s); 13C-NMR
(CDCl3) δ 12.92 (+), 14.76 (+), 37.61 (-), 41.56 (-), 43.34 (-), 63.61 (-), 65.81 (-), 127.31 (+), 128.12
(+), 128.25 (+), 128.79 (+), 128.91 (+), 129.1 (+), 136.38 (q), 144.51 (q), 160.90 (q); Anal. Calc. for
C16H22N4O2: C, 63.56; H, 7.33; N, 18.53; Found: C, 63.70; H, 7.36; N, 18.57.
[1-((S)-1-Benzyl-2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-morpholin-4-yl-methanone (35): The target
compound was obtained by reacting 24 (0.47 mmol, 124 mg) with morpholine (1.4 mmol, 125 μL)
following the procedure above. The crude product was purified by column chromatography on silica
gel using EtOAc/hexane (3:1v/v) and DCM/MeOH (9;1 v/v) as eluents affording the target compound
1
as an oil (52 mg, 30% yield). H-NMR (CDCl3) δ 3.22–3.33 (2H, m), 3.60–3.85 (4H, d), 3.91–4.04
(2H, m), 4.23–4.31 (4H, d), 4.72–4.83 (1H, m), 7.08–7.09 (2H, m), 7.15–7.26 (3H, m); 13C-NMR
(CDCl3) δ 37.61 (-), 43.22 (-), 47.48 (-), 63.51 (-), 65.34 (+), 66.97 (-), 67.29 (-), 127.34 (+), 128.95
(+), 129.08 (+), 136.28 (q), 143.24 (q), 160.15 (q); Anal. Calc. for: C16H20N4O3: C, 60.75; H, 6.37; N,
17.71. Found: C, 60.80; H, 6.39; N, 17.75.
1-((S)-1-Hydroxymethyl-2-methylpropyl)-1H-1,2,3-triazole-4-carboxylic acid amide (36): The target
compound was obtained by reacting 25 (0.49 mmol, 106 mg) with NH3 following the procedure above.
1
The crude product was obtained as an oil (32 mg, 35% yield). H-NMR (CD3OD) δ 0.75 (3H, d,
J = 6.6 Hz), 1.07 (3H,d, J = 6.6 Hz ), 2.24–2.37 (1H, m), 3.91–4.12 (2H, m), 4.32–4.44 (1H, m), 8.42
13
(1H, s); C-NMR (CD3OD) δ 19.31 (+), 19.90 (+), 31.08 (+), 62.83 (-), 71.49(+), 127.51 (+), 133.36

Molecules 2009, 14
5137
(q), 164.94 (q); Anal. Calc. for C8H14N4O2: C, 48.46; H, 7.13; N, 28.27. Found: C, 48.68; H, 7.16; N,
28.35.
1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid amide (37): The target
compound was obtained by reacting 27 (0.51 mmol, 180 mg) with NH3 following the procedure above.
The product was recrystallized from EtOH affording the target compound as a white solid (158 mg,
92% yield). 1H-NMR (CDCl3) δ 3.20–3.30 (2H, m,, 3.73–3.82 (2H, m), 4.42–4.52 (2H, m), 4.89–4.98
(1H, m), 5.79 (2H, s), 6.99–7.10 (2H, m), 7.16–7.36 (8H, m), 8.11 (1H, s); 13C-NMR (CDCl3) δ 37.98
(-), 63.54 (+), 70.22 (-), 73.72 (-), 126.24 (+), 127.44 (+), 128.01 (+), 128.27(+), 128.77 (+), 129.00
(+), 129.09 (+), 136.0 (q), 137.2 4(q), 142.34 (q), 162.31 (q); Anal. Calc. for: C19H20N4O2: C, 67.84;
H, 5.99; N, 16.55. Found: C, 67.73; H, 5.93; N,16.49.
1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid butylamide (38): The
target compound was obtained by reacting 27 (0.56 mmol 200 mg) with butyl amine (1.7 mmol,
124 mg) following the procedure above. The target compound was obtained as an oil (207 mg, 93%
yield) without any purification. 1H-NMR (CDCl3) δ 0.92–0.98 (3H, m), 1.37–1.45 (2H, m), 1.55–1.65
(2H, m), 3.19–3.33 (2H, m), 3.40–3.48 (2H, m), 3.72–3.83 (2H, m), 4.41–4.53 (2H, dd), 4.89–4.99
(1H, m), 7.01–7.07 (2H, m), 7.17–7.37 (8H, m), 8.12 (1H, s); 13C-NMR (CDCl3) δ 13.87 (+), 20.19 (-),
31.78 (-), 37.87 (-), 38.94 (-), 63.33 (+), 70.22 (-), 73.56 (-), 125.51 (+), 127.28 (+), 127.89 (+), 128.12
(+), 128.64 (+), 128.87 (+), 128.99 (+), 136.05 (q), 137.21 (q), 143.10 (q), 160.24 (q); Anal. Calc. for:
C23H28N4O2: C, 70.38; H, 7.19; N, 14.27; Found: C, 70.34; H, 7.24; N, 14.36; tR (Method B): 21.2.
1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid (2-hydroxyethyl)-amide
(39): The target compound was obtained by reacting 27 (0.56 mmol, 200 mg) with ethanol amine
(1.7 mmol, 104 mg) following the procedure above. The target compound was obtained as an oil (170
1
mg, 81% yield) without any purification. H-NMR (CDCl3) δ 3.16–3.30 (2H, m), 3.55–3.61 (2H, m),
3.71–3.80 (4H, m), 4.39–4.50 (2H, m), 4.88–4.97 (1H, m), 7.00–7.04 (2H, m), 7.14–7.34 (8H, m), 7.87
(1H, m), 8.18 (1H, s); 13C-NMR (CDCl3) δ 37.77 (-) , 42.18 (-) , 61.88 (-), 63.31 (+), 70.19 (-),
73.47 (-), 125.86 (+), 127.23 (+), 127.84 (+), 128.08 (+), 128.59 (+), 128.82 (+), 128.94 (+), 135.97
(q), 137.17 (q), 142.72 (q), 161.1 (q); Anal. Calc. for: C21H24N4O3: C, 65.38; H, 6.31; N, 15.25; Found:
C, 65.45; H, 6.29; N, 15.23.
1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid benzylamide (40): The
target compound was obtained by reacting 27 (0.42 mmol, 150 mg) with benzyl amine (1.2 mmol,
137 mg) following the procedure above. The target compound was obtained as an oil (161 mg, 87%
yield) without any purification. 1H-NMR (CDCl3) δ 3.19–3.33 (2H, m), 3.73–3.82 (2H, m), 4.42–4.53
(2H, m), 4.56 (2H, d, J = 5.9 Hz), 4.89–4.98 (1H, m), 7.02–7.07 (2H, m), 7.18–7.38 (13H, m), 7.49
13
(1h, t, J = 5.9Hz), 8.12 (1H, s); C-NMR (CDCl3) δ 37.96 (-), 43.31 (-), 63.47 (+), 70.26 (-), 73.70
(+), 125.80 (+), 127.40 (+), 127.73 (+), 128.00 (+), 128.06 (+), 128.24 (+), 128.75 (+), 128.90 (+),
128.98 (+), 129.08 (+), 136.09 (q), 137.26 (q), 138.12 (q), 142.90 (q), 160.24 (q); Anal. Calc. for
C26H25N4O2: C: 73.22; H, 6.14; N, 13.14. Found: C, 73.28; H, 6.12; N, 13.19.

Molecules 2009, 14
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1-((S)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid diethylamide (41): The
target compound was obtained by reacting 27 (0.56 mmol, 200 mg) with diethylamine (1.7 mmol,
125 mg) following the procedure above. The crude product was purified by column chromatography
on silica gel (hexane, then 1:1 EtOAc/hexane) to afford the desired amide as an oil (17 mg, 8% yield).
1H- NMR (CDCl3) δ 1.18–1.35 (6H, m), 3.20–3.36 (2H, m), 3.46–3.58 (2H, m), 3.70–3.98 (4H, m),
4.42–4.55 (2H, m), 4.87–4.97 (1H, m), 7.00–7.39 (10H, m, Ph), 8.09 (1H, s, CCHN); 13C-NMR
(CDCl3) δ 13.04 (+), 14.81 (+), 38.08 (-), 41.35 (-), 43.27 (-), 63.14 (+), 70.34 (-), 73.69 (-), 127.33
(+), 127.9 (+), 128.1 (+), 128.2 (+), 128.7 (+), 129.1 (+), 136.3 (q), 137.18 (q), 144.5(q), 160.9 (q);
Anal. Calc. for C23H28N4O2: C, 70.38; H, 7.19; N, 14.27. Found: C, 70.40; H, 7.16; N, 14.28.
[1-((S)-1-Benzyloxymethyl-2-phenyethyl)-1H-1,2,3-triazol-4-yl]-morpholin- 4-yl-methanone (42): The
target compound was obtained by reacting 27 (0.56 mmol, 200 mg) with morpholine (1.7 mmol, 148
mg) following the procedure above. The target compound was obtained as an oil (182 mg, 82% yield)
1
without any purification. H-NMR (CDCl3) δ 3.18–3.32 (2H, m), 3.71–3.78 (8H, m), 4.27–4.33 (2H,
13
m), 4.36–4.49 (2H, m), 4.88–4.96 (1H, m), 6.97–7.32 (10H, m), 8.13 (1H, s); C-NMR (CDCl3) δ
37.84 (-), 43.07 (-), 47.35 (-), 63.14 (+), 66.95 (-), 67.28 (-), 70.16 (-), 73.52 (-), 127.25 (+), 127.83
(+), 128.08 (+), 128.61 (+), 128.67 (+),128.82 (+), 128.99 (+), 136.07 (q), 137.23 (q), 143.65 (q),
160.01 (q); Anal. Calc. for C22H23N4O3: C, 67.96; H, 6.45; N, 13.78. Found: C, 68.04; H, 6.41; N,
13.72.
1-((R)-1-Benzyloxymethyl-2-phenethyl)-1H-1,2,3-triazole-4-carboxylic acid butylamide (43): The
target compound was obtained by reacting 28 (0.56 mmol, 200 mg) with butyl amine (1.7 mmol,
124 mg) following the procedure above. The target compound was obtained as an oil (220 mg, 98%
yield) without any purification. 1H-NMR (CDCl3) δ, 0.96 (3H, t, J = 7.3Hz), 1.37–1.47 (2H, m), 1.56–
1.65 (2H, m), 3.19–3.34 (2H, m), 3.41–3.47 (2H, m), 3.72–3.83 (2H, m), 4.42–4.57 (2H, dd, J = 11.9
13
Hz, J = 25.5Hz), 4.90–4.98 (1H, m), 7.03–7.07 (2 H, m), 7.17–7.38 (8H, m), 8.13 (1H, s); C-NMR
(CDCl3) δ 13.88 (+), 20.21 (-), 31.79 (-), 37.88 (-), 38.96 (-), 63.34 (+), 70.25 (-), 73.59 (-), 125.53 (+),
127.30 (+), 127.90 (+), 128.12 (+), 128.66 (+), 128.89 (+), 129.01 (+), 136.06 (q), 137.22 (q), 143.10
(q), 160.25 (q); Anal. Calc. for C23H28N4O2: C, 70.38; H, 7.19; N, 14.27. Found: C, 70.46; H, 7.16; N,
14.21; tR (Method B): 14.9.
1-((S)-1-Benzyloxymethyl-3-phenylpropyl)-1H-1,2,3-triazole-4-carboxylic acid amide (44): The target
compound was obtained by reacting 29 (0.15 mmol, 57 mg) with NH3 following the procedure above.
The crude product was purified by column chromatography using EtOH/hexane (1:1 v/v) as eluent.
The target compound was obtained as a white solid (44 mg, 88% yield). 1H-NMR (CDCl3) δ 2.15–2.28
(1H, m), 2.33–2.57 (3H, m), 3.68–3.79 (2H, m), 4.38–4.52 (2H, dd, J = 12.1 Hz, J = 30.0 Hz),
13
4.67–4.75 (1H, m), 7.05–7.34 (10H, m), 8.22 (1H, s); C-NMR (CDCl3) δ 31.90 (-), 33.08 (-), 61.41
(+), 71.39 (-), 73.63 (-), 126.04 (+), 126.64 (+), 127.93 (+), 128.24 (+), 128.59 (+), 128.75 (+), 128.85
(+), 137.27 (q), 140.01 (q), 142.65 (q), 162.47 (q); Anal. Calc. for C20H22N4O2: C, 68.55; H, 6.33; N,
15.99. Found: C, 68.48; H, 6.26; N, 15.88.

Molecules 2009, 14
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1-((S)-1-Benzyloxymethyl-3-phenylpropyl)-1H-1,2,3-triazole-4-carboxylic acid butylamide (45): The
target compound was obtained by reacting 29 (0.3 mmol, 113 mg) with butylamine (0.9 mmol, 67 mg)
following the procedure above. The target compound was obtained as an oil (113 mg, 93% yield)
1
without any purification. H-NMR (CDCl3) δ 0.95 (3H, t, J = 7.3 Hz), 1.37–1.47 (2H, m), 1.56–1.67
(2H, m), 2.15–2.56 (4H, m), 3.44–3.49 (2H, m), 3.67–3.77 (2H, m), 4.43 (2H, dd, J = 12.1 Hz,
13
J = 29.3 Hz), 4.65–4.73 (1H, m), 7.04–7.35 (10H, m), 8.18 (1H, s); C-NMR (CDCl3) δ 13.89 (+),
20.22 (-), 31.82 (-), 31.82 (-), 33.03 (-), 38.98 (-), 61.24 (-), 71.39 (-), 73.52 (-),125.30 (+), 126.52 (+),
127.82 (+),128.11 (+), 128.51 (+), 128.64 (+), 128.75 (+), 137.24 (q), 140.01 (q), 143.33 (q), 160.30
(q); Anal. Calc. for C24H30N4O2: C, 70.91; H, 7.44; N, 13.78. Found: C, 71.05; H, 7.39; N, 13.86.
1-[(S)-1-Benzyloxymethyl-2-(tert-butyl-dimethylsilanyloxy)-ethyl]-1H-1,2,3-triazole-4-carboxylic acid
amide (46): The target compound was obtained by reacting 30 (0.23 mmol, 95 mg) with NH3
following the procedure above. The product was recrystallized from EtOH affording 46 as a white
1
solid (88 mg, 92% yields). H-NMR (CDCl3) δ -0.09(3H, s), -0.01 (3H, s), 0.82 (9H, s), 3.81–4.03
13
(5H, m), 4.41–4.52 (2H, m), 4.81–4.87 (1H, m), 7.11–7.25 (5H, m), 8.16 (1H, s); C-NMR (CDCl3)
δ -5.48 (+), -5.42 (+), 18.31 (q), 62.10 (-), 62.64 (+), 67.74 (-), 73.24 (-), 125.56 (+), 127.79 (+),
128.31 (+), 128.73 (+), 137.01 (q), 142.23 (q), 161.03 (q); Anal. Calc. for C19H30N4O3Si: C, 58.43; H,
7.74; N, 14.35. Found: C, 58.58; H, 7.79; N, 14.42.
3.7. Docking
X-ray structures with inhibitors were used as starting point for all dockings. The enzymes were
prepared according to the standard procedure in the Schrödinger package. Docking was performed by
using Glide (Schrödinger) [37–39] with extra precision (XP) settings and standard parameters for
ligand docking.
4. Conclusions
An efficient synthetic route was developed for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole
derivatives starting from D-or L-amino acids. The target compounds were obtained in excellent yields
with no racemization. This straight forward and flexible strategy allow the synthesis of novel, 4-
disubstituted-1,2,3-triazole derivatives with desired properties and is currently being explored in our
laboratory for the development of kinase inhibitors.
Acknowledgements
Financial support was obtained from the European Commission (the QUASI project, contract
LSHG-CT2003-503230 and the CELLCOMPUTE project, contract 040451).

Molecules 2009, 14
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Sample Availability: Samples of the compounds are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).