Microwave solvent free regioselective 1,3 dipolar cycloaddition in the synthesis of 1,4 substituted [1,2,3]-triazoles as amide bond isosteres

Article abstract of DOI:10.1002/jhet.5570440410

(Chemical Equation Presented) 1,3 Dipolar cycloaddition of Fmoc-amino azides and acetylenic amides produces under solvent free irradiation a mixture of 1,4 or 1,5 substituted [1,2,3]-triazoles. The presence of copper (I) iodide, plays a central role on regioselectivity. Four Fmoc-amino azides characterized by different steric hindrance in side chains, and three different terminal alkynes, provided only the 1,4 substituted regioisomer under thermal microwave heating. Good yields, low consumption of organic solvents and short reaction times are the main aspects of our procedure. Reactions are compared to regioselective copper (I) catalysed solution synthesis performed at room temperature.

Full text of DOI:10.1002/jhet.5570440410

Jul-Aug 2007
815
Microwave Solvent Free Regioselective 1,3 Dipolar Cycloaddition in the
Synthesis of 1,4 Substituted [1,2,3]-Triazoles as Amide Bond Isosteres
Elisa Perissutti, Francesco Frecentese, Ferdinando Fiorino, Beatrice Severino,
Donatella Cirillo, Vincenzo Santagada* and Giuseppe Caliendo
Department of Medicinal Chemistry, University of Naples «Federico II»
Via D. Montesano, 49, 80131, Naples (Italy), santagad@unina.it
Received July 20, 2006
N
N
N
CuI /Alumina
MW
R1
R2 N3
R1
R2
1,3 Dipolar cycloaddition of Fmoc-amino azides and acetylenic amides produces under solvent free
irradiation a mixture of 1,4 or 1,5 substituted [1,2,3]-triazoles. The presence of copper (I) iodide, plays a
central role on regioselectivity. Four Fmoc-amino azides characterized by different steric hindrance in side
chains, and three different terminal alkynes, provided only the 1,4 substituted regioisomer under thermal
microwave heating. Good yields, low consumption of organic solvents and short reaction times are the
main aspects of our procedure. Reactions are compared to regioselective copper (I) catalysed solution
synthesis performed at room temperature.
J. Heterocyclic Chem., 44, 815 (2007).
13]. In fact, the application of microwave energy to organic
compounds for conducting synthetic reactions at highly
accelerated rates has become a well-known technique [14].
This paper describes the one pot regioselective and
environmentally friendly synthesis of 1,4 substituted
[1,2,3]-triazoles by application of microwave energy under
solvent free condition obtained by reaction of four Fmoc-
amino azides, characterized by different steric hindrance in
side chains, and three different terminal alkynes in presence
of copper (I) iodide and basic alumina.
INTRODUCTION
Replacement of the amide moiety by non hydrolysable
aromatic scaffolds and/or by isosters that introduce a
different orientation of the amino acids side chains is
currently an area of great interest in peptide and peptidom-
imetic chemistry [1]. 1,2,3-Substituted triazoles are
characterized by the described properties and can be
introduced in the syntheses of a great variety of peptides
[2]; in fact, they have been previously used as anti-HIV
agents [3], selective ꢀ3 adrenergic receptor agonists [4], as
antinflammatory agents [5] and more recently as inhibitors
on a recombinant cysteine protease [6]. These scaffolds can
be synthesized by linking propiolic acid to a N-terminal
amino group, followed by 1,3 dipolar cycloaddiction with
an Fmoc amino azide; the removal of the protecting group
allows the peptide synthesis to continue [7]. The synthesis
of 1,2,3-triazoles has been widely discussed in literature,
both in solution and on solid phase or under solvent free
conditions [7-8]. Thermal synthesis of 1,2,3-triazoles is
described as non-regioselective [9], while the use of
catalysts allows one to obtain a single isomer [10]. Copper
(I) iodide for example, either in solution or on solid phase
syntheses, generate 1,4 substituted triazoles without the
formation of the 1,5 isomer. The reaction takes place in
mild conditions and very high yields [11]. Since no
examples were described in literature for the generation of
just one isomer in a heated reaction, in order to reduce
reaction times and to confirm the regioselectivity of the
reaction, considering the importance of the described
heterocyclic moiety in peptide chemistry, our attention has
turned to improve the syntheses of these modified residues
by new synthetic methodologies [12]. Our interests were
mainly directed to the advances in the syntheses of
peptidomimetics and particularly to the application of
microwave irradiation in the field of peptide chemistry [12-
RESULTS AND DISCUSSION
The synthesis of Fmoc-amino azides, compounds 1a-1d,
was conducted through a nicotinoyl azide mediated
Mitsunobu reaction, in according to that already described in
literature [15], starting from the corresponding Fmoc amino
alcohol; reagents and conditions are reported in Scheme I.
Scheme I
R1
O
R1
O
PPh3, DEAD,THF
0°C, 3h
N3
OH
O
NH
O
NH
O
1a-1d
N3
N
Compound
R1
1a
1b
1c
H
-CH3
1d

816
E. Perissutti, F. Frecentese, F. Fiorino, B. Severino, D. Cirillo, V. Santagada and G. Caliendo
Vol 44
The synthesis of the amido alkynes was conducted, on
were set as reported in Table 1. The main advantage of
our procedure, in comparison to those already reported in
literature [7-10], is that a short time of irradiation
provided the final compounds 3a-3l in good yields and
overall without the presence of the 1,5 isomer. The copper
(I) iodide catalyzed microwave assisted thermal synthesis
is regioselective and not dependent on steric effects that,
instead, play a central role in the uncatalyzed thermal
rection, where the hindrance of substituents in the amino
azide side chain can allow the obtaining of both the 1,4-
and 1,5-substituted triazoles or completely inhibit the
cycloaddition of the 1,5 substituted triazole. If the
application of microwave energy was performed for
longer time (> 20 min, Table 1) the reagents were not
completely transformed in the corresponding 1,2,3-
trizoles derivatives due to the decomposition of the
starting reagents. In the same way, no further yield
increasing was evidenced when the irradiation power was
increased from 800W to 1600W (Table 1); this is again
related to decomposition of the starting materials.
the other hand, by reaction of propiolic acid and the
desired amines following, with slight modifications of the
mixed anhydride method described by Coppola et al. [16]
yielding compounds 2a-2c; the described procedure is
summarized in Scheme II.
Scheme II
O
O
O
NaH
HC
C
O
O
HC
C
OH
ClCOOCH2CH3
THF
NH2-R2
O
R2
HC
C
NH
2a-2c
R2
Compound
2a
CONCLUSION
Final results obtained are summarized in Table 1.
Interestingly, the best results were obtained with
compounds 3i-3l both in solution then under microwave
solvent free synthesis; these results should probably be
addressed to the terminal alkyne used that resulted in a
liquid compound, considering its better distribution in the
solid matrix. In conclusion, we have shown that the
application of microwave irradiation in the solvent free
catalyzed synthesis of 1,4 substituted 1,2,3-triazoles
significantly reduces reaction times from 12-16 h to 20
minutes, without influencing significantly the obtained
yields, preserving the regioselectivity of the reaction.
Abbreviations and symbols. We have followed the
recommendations of the IUPAC-IUB Joint Commission on
Biochemical Nomenclature (Eur. J. Biochem., 138, 9
(1984)). In addition the following abbreviations are used:
DEAD, Diethyl azodicarboxylate; PPh3, Triphenylphosphin.
2b
2c
O
H2N
O
O
All synthesized compounds were obtained as white
powders, with exception of compound 2c that was
obtained as yellow oil. The syntheses of 1,2,3-triazoles,
summarized in Scheme 3, were performed using a
microwave oven (ETHOS 1600, Milestone®) especially
designed for organic synthesis. Fmoc amino-azides 1a-1d,
acetylenic amides 2a-2c, and copper (I) iodide were
mixed with the basic alumina in a 4:1 ratio.
EXPERIMENTAL
Scheme III
R1
O
R1
O
N
N
Microwave equipment and conditions. The synthetic steps
performed by microwave irradiation were carried out using a
microwave oven (ETHOS 1600, Milestone®) especially
designed for organic synthesis. The experimental conditions
used during microwave application were similar, with the same
concentration of starting materials, to those used in solvent
catalyzed reaction performed at room temperature. In this latter,
anyway, THF was used as solvent and N-ethyldiisopropylamine
was used instead of basic alumina. Basic alumina was selected
as solid support for the solvent free synthesis because of its basic
features, a necessary condition to the cycloaddition; on the other
hand, neat reaction was not successful. Microwave reactions
were performed in sealed tubes and a microwave program that
was composed by appropriate ramping and holding steps was
N
NH
N3
O
O
NH
NH
R2
1a-1d
O
CuI MW
Basic alumina
3a-3l
O
C
R2
HC
NH
2a-2c
The mixture was mixed for 5 min. The reaction mixture
was then transferred into a sealed tube and irradiated by
microwave for a total time of 20 min. The desired
parameters (microwave power, temperature and time)

Jul-Aug 2007
Microwave Solvent Free Regioselective 1,3 Dipolar Cycloaddition
817
Table 1
Solvent free microwave irradiationb
Room temperature
Compd
3a
R1
R2
Yield a
(%)
Time
(h)
Solid support
Time
(min.)
Temp.
(°C)
Yield
(%)
-H
-CH2C6H5
58
68
62
34
16
16
16
12
Basic alumina
5
10
5
5
10
5
5
10
5
60
100
100
60
100
100
60
100
100
50
48
3b
-CH3
Basic alumina
Basic alumina
Basic alumina
64
71
30
-CH2C6H5
-CH2C6H5
-CH2C6H5
3c
-CH2CH(CH3)2
-CH2C6H5
3d
5
10
5
85
85
5
10
5
60
3e
3f
-H
-CH3
50
57
30
42
16
16
16
12
Basic alumina
Basic alumina
Basic alumina
Basic alumina
46
68
26
38
O
O
O
O
100
100
H2N
H2N
H2N
H2N
5
10
5
60
100
100
5
10
5
60
3g
3h
-CH2CH(CH3)2
-CH2C6H5
100
100
5
10
5
50
85
85
5
10
5
50
85
85
3i
3j
3k
3l
-H
-CH3
O
O
66
50
56
61
12
12
12
12
Basic alumina
Basic alumina
Basic alumina
Basic alumina
58
55
60
60
O
O
5
10
5
50
85
85
5
10
5
50
85
85
-CH2CH(CH3)2
-CH2C6H5
O
O
5
10
5
50
85
85
O
O
a all the reactions were performed 3 times and the reaction time and yields given are the average valuesb the power used was 800 W
selected. The temperature of the stirred reaction mixture was
monitored directly by a microwave-transparent fluoroptic probe
inserted into the reaction mixture; irradiation time and power
were monitored with the “easyWAVE” software package.
Pressure was not monitored because the compounds in the
reaction were all solids.
instrument. Chemical shifts are given as ꢀ with references to
Me4Si. The following abbreviations are used to describe peak
patterns when appropriate: s (singlet), d (doublet), dd (double
doublet), t (triplet), q (quartet), m (multiplet). Mass spectra of
the final products were performed on LCQ Thermoquest-Ion
trap mass spectrometry.
Chemistry. All reactions were followed by thin layer
chromatography carried out on Merck silica gel 60 F254 plates
with fluorescent indicator and the plates were visualized with
UV light (254 nm). Preparative chromatographic purifications
were performed using silica gel column (Kieselegel 60).
Melting points were determined using a Kofler hot-stage
apparatus and are uncorrected. Elemental analyses were
carried out on a Carlo Erba model 1106. The structures were
verified spectroscopically by proton 1H-NMR and ESI-MS.
Spectra were recorded on a Varian Mercury Plus 400 MHZ
General procedure for the synthesis of 1,2,3-triazoles
derivatives under solvent free conditions. Fmoc-amino azide
(0.314 mmol), acetylenic amide (1 equiv.) and copper (I) iodide
(1 equiv.) were mixed with the neutral alumina in a 4:1 ratio.
The mixture was shaken for 5 min. The reaction mixture was
then transferred into a sealed vial and irradiated by microwave
for 20 min. The desired parameters (microwave power,
temperature and time) were set as reported in Table 1. After
irradiation the solid was extracted in dichloromethane and
purified by silica gel chromatography.

818
E. Perissutti, F. Frecentese, F. Fiorino, B. Severino, D. Cirillo, V. Santagada and G. Caliendo
Vol 44
(9H-fluoren-9-yl)methyl-2-(4-(benzylcarbamo-yl)-1H-1,2,3-
(d, 1H), 2.82 (m, 1H), 2.84 (d, 1H), 2.88 (d, 1H), 3.82 (t, 1H),
triazol-1-yl)ethylcarbamate (3a). White powder, mp 178-
180 °C; Rf 0.45 (dichlorometane/methyl alcohol 9.5/0.5); 1H
NMR (400 MHz, DMSO-d6): ꢀ 3.43 (t, 2H), 4.15 (t, 1H), 4.22
(d, 2H), 4.45 (d, 2H), 4.52 (t, 2H), 7.25 (m, 8H), 7.35 (t, 2H),
7.42 (s, NH), 7.62 (d, 2H), 7.84 (d, 2H), 8.51 (s, 1H), 8.89 (s,
NH); 13C NMR (DMSO-d6): ꢀ 38.0, 43.8, 47.0, 51.6, 67.4,
124.2, 126.8, 127.0, 128.2, 128.4, 128.6, 128.8, 131.9, 141.0,
141.7, 143.1, 143.6, 156.0, 161.1 ms: 468 (MH+), 490 (M-Na),
507(M-K). Anal. Calcd. for C27H25N5O3: C, 69.36; H, 5.39; N,
14.98; O, 10.27. Found: C, 69.51; H, 5.44; N, 14.94; O, 10.34.
(9H-Fluoren-9-yl)methyl-1-(4-(benzylcarbamo-yl)-1H-1,2,3-
triazol-1-yl)propan-2-ylcarbamate (3b). White powder, mp 228-
4.15 (q, 1H), 5.73 (d, 2H), 7.12 (s, NH2), 7.16 (d, 2H), 7.18 (d,
2H), 7.22 (t, 1H), 7.28 (m, 8H), 7.32 (s, NH), 8.21 (s, 1H), 8.88
(s, NH); 13C NMR (DMSO-d6): ꢀ 17.8, 31.3, 37.3, 42.4, 47.0,
53.5, 55.5, 55.7, 67.4, 126.0, 126.8, 127.8, 128.2, 128.4, 128.7,
128.8, 131.9, 139.5, 141.0, 143.1, 143.6, 155.7, 160.8, 177.4
ms: 581 (MH+), 603 (M-Na), 619 (M-K). Anal. Calcd. for
C33H36N6O4:C, 68.26; H, 6.25; N, 14.47; O, 11.02 Found: C,
68.44; H, 6.13; N, 14.88; O,11.32.
(9H-Fluoren-9-yl)methyl-1-(4-(1-carbamoyl-2-phenyl-
ethyl-carbamoyl)-1H-1,2,3-triazol-1-yl)propan-2-yl-carbamate
(3g). White powder, mp 154-156 °C; Rf 0.26 (ethyl acetate/
1
hexane 9/1); H NMR (400 MHz, DMSO-d6): ꢀ 0.80 (d, 3H),
1
230 °C; Rf 0.15 (ethyl acetate/hexane 1/1); H NMR (400 MHz,
0.84 (d, 3H), 1.18 (dd, 2H), 1.38 (m, 1H), 3.15 (d, 1H), 3.18 (d,
1H), 3.62 (m, 1H), 4.16 (d, 1H), 4.18 (d, 1H), 4.24 (d, 1H), 4.76
(q, 1H), 5.09 (d, 2H), 7.04 (s, NH), 7.26 (m, 8H), 7.47 (t, 2H),
7.62 (d, 2H), 7.82 (d, 2H), 8.04 (s, NH), 8.45 (s, 1H); 13C NMR
(DMSO-d6): ꢀ 18.5, 37.3, 43.2, 47.0, 55.5, 60.7, 67.4, 126.0,
126.8, 127.8, 128.2, 128.4, 128.7, 128.8, 131.9, 139.5, 141.0,
143.1, 143.6, 155.7, 160.8, 177.4 ms: 538 (MH+), 560 (M-Na),
576 (M-K). Anal. Calcd. for C30H30N6O4: C, 66.90; H, 5.61; N,
15.60; O, 11.88. Found: C, 66.78; H, 5.73; N, 15.32; O, 11.57.
(9H-Fluoren-9-yl)methyl-1-(4-(1-carbamoyl-2-phenyl-
ethyl-carbamoyl)-1H-1,2,3-triazol-1-yl)-3-phenyl-propan-2-
ylcarbamate (3h). White powder, mp 212-214 °C; Rf 0.35
(chloroform/ethyl alcohol 9,5/0,5); 1H NMR (400 MHz, DMSO-
d6): ꢀ 2.64 (d,1H), 2.68 (d, 1H), 2.84 (d, 1H), 2.88 (d, 1H), 3.01
(m, 1H), 3.16 (d, 1H), 3.21 (d, 1H), 3.82 (d, 1H), 3.86 (d, 1H),
4.42 (t, 1H), 4.48 (q, 1H), 5.02 (d, 2H), 7.02 (s, NH2), 7.26 (m,
14H), 7.47 (t, 2H), 7.82 (d, 2H), 8.04 (s, NH), 8.45 (s, 1H); 13C
NMR (DMSO-d6): ꢀ 37.3, 40.6, 47.0, 48.8, 55.5, 58.1, 67.4,
126.1, 126.2, 126.8, 127.8, 127.9, 128.2, 128.4, 128.7, 128.8,
130.1, 131.9, 138.1, 139.5, 141.0, 143.1, 143.6, 155.7, 160.8,
177.4 ms: 615 (MH+), 637 (M-Na), 653 (M-K). Anal. Calcd. for
C36H34N6O4: C, 70.34; H, 5.58; N, 13.67; O, 10.41 Found: C,
70.56; H, 5.73; N, 13.46; O, 10.51.
DMSO-d6): ꢀ 1.05 (d, 3H), 3.18 (d, 2H), 3.88 (m, 1H), 4.18 (t,
1H), 4.20 (d, 1H), 4.24 (d, 1H), 4.42 (d, 2H), 7.15 (s, NH), 7.25
(m, 8H), 7.42 (t, 1H), 7.58 (d, 2H), 7.84 (d, 2H), 8.48 (s, 1H), 8.88
(s, NH); 13C NMR (DMSO-d6): ꢀ 18.5, 43.1, 43.6, 44.2, 47.0,
60.7, 67.4, 125.6, 126.8, 127.1, 128.0, 128.5, 128.8, 129.2, 131.9,
141.0, 141.7, 143.6, 155.7, 161.1 ms: 482 (MH+), 504 (M-Na),
520 (M-K). Anal. Calcd. for C29H29N5O3: C, 70.28; H, 5.90; N,
14.13; O, 9.69. Found: C, 70.35; H, 5.98; N, 14.16; O, 9.83.
(9H-Fluoren-9-yl)methyl-1-(4-(benzylcarbamo-yl)-1H-1,2,3-
triazol-1-yl)-4-methylpentan-2-ylcarbamate (3c). White
1
powder, mp 167-169°C; Rf 0.20 (ethyl acetate/hexane 1/1); H
NMR (400 MHz, DMSO-d6): ꢀ 1.02 (dd, 2H), 1.05 (m, 1H), 1.21
(m, 1H), 1.35 (d, 6H), 4.14 (m, 1H), 4.42 (d, 1H), 4.46 (d, 1H),
4.60 (d, 2H), 4.78 (d, 2H), 7.18 (s, NH), 7.28 (m, 8H), 7.37 (t,
1H), 7.40 (d, 2H), 7.68 (d, 2H), 8.02 (s, 1H), 8.12 (s, NH); 13
C
NMR (DMSO-d6): ꢀ 23.5, 25.4, 30.9, 40.4, 42.0, 47.0, 48.1, 67.4,
126.8, 127.7, 128.2, 128.4, 128.8, 129.3, 129.7, 131.0, 134.0,
135.7, 141.0, 143.6, 156.0, 169.9 ms: 524 (MH+), 546 (M-Na),
572 (M-K). Anal. Calcd. for C32H35N5O3: C, 71.49; H, 6.56; N,
13.03; O, 8.93. Found: C, 71.63; H, 6.71; N, 13.07; O, 8.99.
(9H-Fluoren-9-yl)methyl-1-(4-(benzylcarbamo-yl)-1H-
1,2,3-triazol-1-yl)-3-phenylpropan-2-ylcarbamate (3d). White
1
powder, mp 235-237 °C; Rf 0.43 (ethyl acetate/ hexane 6/4); H
(9H-Fluoren-9-yl)methyl-2-(4-(benzyl-2-carbamoyl-3-
phenyl-propanoate)-1H-1,2,3-triazol-1-yl)ethyl-carbamate
(3i). White powder, mp 173-175 °C; Rf 0.41 (ethyl acetate/
NMR (400 MHz, DMSO-d6): ꢀ 2.85 (d, 1H), 2.88 (d, 1H), 3.15
(d, 1H), 3.18 (d, 1H), 3.78 (m, 1H), 4.22 (t, 1H), 4.62 (d, 2H), 5.09
(d, 2H), 7.02 (s, NH), 7.28 (m, 12H), 7.47 (t, 2H), 7.61 (d, 2H),
7.83 (d, 2H), 8.47 (s, 1H), 8.75 (s, NH); 13C NMR (DMSO-d6): ꢀ
35.8, 40.4, 41.3, 47.0, 47.4, 67.4, 125.6, 126.8, 127.7, 127.9,
128.2, 128.4, 128.6, 128.8, 129.3, 129.8, 131.0, 134.0, 135.7,
140.4, 141.0, 143.6, 156.0, 169.9 ms: 558 (MH+), 580 (M-Na),
596 (M-K). Anal. Calcd. for C34H31N5O3: C, 73.23; H, 5.60; N,
12.56; O, 8.61. Found: C, 73.34; H, 5.73; N, 12.65; O, 8.72.
(9H-Fluoren-9-yl)methyl-2-(4-(1-carbamoyl-2-phenyl-ethyl-
carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl-carbamate (3e). White
powder, mp 242-244 °C; Rf 0.71 (dichlorometane/methyl
alcohol 9.5/0.5); 1H NMR (400 MHz, DMSO-d6): ꢀ 3.02
(d,1H), 3.08 (d, 1H), 3.42 (d, 2H), 4.18 (t, 1H), 4.23 (d, 2H),
4.43 (t, 2H), 4.65 (q, 1H), 7,29 (m, 10H), 7.38 (t, 2H), 7.52 (t,
1H), 7.58 (s NH2), 7.83 (d, 2H), 8.45 (s, 1H); 13C NMR (DMSO-
d6): ꢀ 37.3, 38.0, 47.0, 51.6, 55.5, 67.4, 126.0, 126.8, 127.8,
128.2, 128.4, 128.8, 129.0, 131.9, 139.5, 141.0, 143.1, 143.6,
156.0, 160.8, 177.4 ms: 525 (MH+), 547 (M-Na), 563(M-K).
Anal. Calcd. for C29H28N6O4: C, 66.40; H, 5.38; N, 16.02; O,
12.20. Found: C, 66.51; H, 5.43; N, 16.12; O, 12.28.
1
hexane 6/4); H NMR (400 MHz, DMSO-d6): ꢀ 3.16 (t, 2H),
3.42 (d, 1H), 3.46 (d, 1H), 4.22 (t, 1H), 4.26 (t, 2H), 4.42 (d,
2H), 4.74 (q, 1H), 5.18 (d, 2H), 7.28 (m, 12H), 7.42 (t, 2H), 7.46
(s, NH), 7.62 (d, 2H), 7.82 (d, 2H), 8.64 (s, 1H), 8.77(s, NH);
13C NMR (DMSO-d6): ꢀ 37.0, 38.0, 47.0, 51.6, 53.1, 67.4, 68.5,
126.0, 126.8, 127.2, 127.7, 127.8, 128.2, 128.4, 128.7, 128.8,
129.0, 131.9, 139.5, 141.0, 141.2, 143.1, 143.6, 156.0, 160.8,
171.6 ms: 616 (MH+), 638 (M-Na), 654 (M-K). Anal. Calcd. for
C36H33N5O5: C, 70.23; H, 5.40; N, 11.38; O, 12.99 Found: C,
70.46; H, 5.68; N, 11.23; O, 13.12.
(9H-Fluoren-9-yl)methyl-1-(4-(benzyl-2-carbamoyl-3-phenyl-
propanoate)-1H-1,2,3-triazol-1-yl)propan-2-yl-carbamate (3j).
White powder, mp 182-184 °C; Rf 0.29 (ethyl acetate/hexane
1
1/1); H NMR (400 MHz, DMSO-d6): ꢀ 1.02 (d, 3H), 3.18 (d,
2H), 3.88 (t, 1H), 4.18 (d.1H), 4.22 (d,1H), 4.28 (m, 1H), 4.38
(d, 1H), 4.42 (d, 1H), 4.75 (q, 1H), 5.15 (d, 2H), 7.24, (s, NH),
7.28 (m, 12H), 7.58 (t, 2H), 7.62 (d, 2H), 7.84 (d, 2H), 8.44 (s,
1H), 8.78 (s, NH); 13C NMR (DMSO-d6): ꢀ 18.5, 37.0, 43.2,
47.0, 53.1, 60.7, 67.4, 68.5, 126.0, 126.8, 127.2, 127.7, 127.8,
128.2, 128.4, 128.8, 129.0, 131.9, 139.5, 141.0, 141.2, 143.1,
143.6, 155.7, 160.8, 171.9 ms: 630 (MH+), 652 (M-Na), 668
(M-K). Anal. Calcd. for C37H35N5O5: C, 70.57; H, 5.60; N,
11.12; O, 12.70 Found: C, 70.56; H, 5.49; N, 11.24; O, 12.42.
(9H-Fluoren-9-yl)methyl-1-(4-(1-carbamoyl-2-phenyl-
ethyl-carbamoyl)-1H-1,2,3-triazol-1-yl)propan-2-yl-carbamate
(3f). White powder, mp 137-139 °C; Rf 0.23 (ethyl acetate); 1H
NMR (400 MHz, DMSO-d6): ꢀ 1.02 (d, 3H), 2.64 (d, 1H), 2.68

Jul-Aug 2007
Microwave Solvent Free Regioselective 1,3 Dipolar Cycloaddition
819
[5] Maehr, H. Offmann-La Roche Inc., New Jersey, U.S.A. U.S.
patent no. US6232471 B1 ( 2001).
[6] Tornøe, C. W.; Sanderson, S. J.; Mottram, J. C.; Coombs, G.
H.; Meldal, M. J. Comb. Chem, 6, 312 ( 2004)
(9H-Fluoren-9-yl)methyl-4-methyl-1-(4-(benzyl-2-carba-
moyl-3-phenylpropanoate)-1H-1,2,3-triazol-1-yl)pentan-2-yl-
carbamate (3k). White powder, mp 179-181°C; Rf 0.52 (ethyl
1
acetate/hexane 1/1); H NMR (400 MHz, DMSO-d6): ꢀ 0.79 (d,
[7] (a) Tornøe, C. W.; Christenseer, C.; Meldal, M. J. Org.
Chem., 67, 3057 (2002). (b) Tornøe, C. W.; Sanderson, S. J.; Mottram, J.
C.; Coombs, G. H.; Morten, M. J. Comb. Chem, 6, 312 (2004)
[8] (a) Zhang, Z.; Fan, E. Tetrahedron Lett. 2006, 47, 665. (b)
Rostovtsev, V. V.; Green, L. G. Fokin, V. V., Sharpless, K. D. Angew.
Chem. Int. Ed., 41, 2596 (2002). (c) Katritzky, A. R.; Singh, S. K. J.
Org. Chem., 67, 9077 (2002). (d) Biagi, G.; Giorgi, I.; Livi O.;
Lucacchini, A.; Martini, C.; Scartoni, V. J. Pharm. Sci., 82, 893 (1993).
(e) Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R. J. Org. Chem.,
23, 1051 (1958). (f) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A.;
Zh. Org. Khim 3, 968 (1967). (g) Mearnman, R. C.; Newall, C. E.;
Tonge, A. P. J. Antibiot., 37, 885 (1984).
[9] Bastide, J.; Henri-Rousseau, O. In the Chemistry of the
carbon-carbon triple bond, Ed. Interscience Publishers, London, 1978,
pp 447.
[10] (a) Zhao, Y. B.; Yan, Z.Y.; Liang, Y. M. Tetrahedron Lett.,
47, 1545 (2006). (b) Barr, L.; Lincoln, S. F.; Easton, C. J.
Supramolecular Chemistry, 17, 547 (2005).
3H), 0.82 (d, 3H), 1.19 (dd, 2H), 1.27 (m, 1H), 3.15 (d, 2H), 4.15
(d, 1H), 4.22 (d, 1H), 4.24 (t, 1H), 4.25 (d, 1H), 4.27 (d, 1H), 4.32
(dd, 1H), 4.75 (q, 1H), 5.09 (d, 2H), 7.28 (m, 12H), 7.60 (t, 2H),
7.64 (d, 2H), 7.82 (d, 2H), 8.20 (s, NH), 8.42 (s, 1H), 8.70 (s,
NH); 13C NMR (DMSO-d6): ꢀ 22.8, 23.2, 37.2, 42.4, 43.9, 47.0,
53.1, 58.8, 67.4, 68.5, 126.0, 126.8, 127.2, 127.7, 127.8, 128.2,
128.4, 128.7, 128.8, 129.0, 131.9, 139.5, 141.0, 141.2, 143.1,
143.6, 155.7, 160.8, 171.6 ms: 672 (MH+), 694 (M-Na), 710 (M-
K). Anal. Calcd. for C40H41N5O5: C, 71.52; H, 6.15; N, 10.43; O,
11.91 Found: C, 71.56; H, 6.22; N, 10.25; O, 13.36.
(9H-Fluoren-9-yl)methyl-3-phenyl-1-(4-(benzyl-2-carba-
moyl-3-phenylpropanoate)-1H-1,2,3-triazol-1-yl)propan-2-
ylcarbamate (3l). White powder, mp 199-201 °C; Rf 0.44 (ethyl
acetate/hexane 6/4); 1H NMR (400 MHz, DMSO-d6): ꢀ 2.85 (d,
1H), 2.88 (d, 1H), 3.07 (d, 1H), 3.10 (d, 1H), 3.15 (d, 1H), 3.18
(d, 1H), 3.22 (m, 1H), 4.22 (t, 1H), 4.75 (q, 1H), 4.87 (s, 2H),
5.02 (d, 2H), 7.04 (s, NH), 7.22 (t, 2H), 7.26 (d, 2H), 7.31 (m,
12H), 7.37 (t, 1H), 7.47 (t, 2H), 7.62 (d, 2H), 7.84 (d, 2H), 8.44
(s, 1H), 8.53 (s, NH); 13C NMR (DMSO-d6): ꢀ 37.0, 40.6, 47.0,
48.8, 53.1, 58.1, 67.4, 68.5, 126.0, 126.1, 126.8, 127.2, 127.7,
127.8, 128.2, 128.3, 128.4, 128.7, 128.8, 128.9, 129.0, 131.9,
138.1, 139.5, 141.0, 141.2, 143.1, 143.6, 155.7, 160.8, 171.6
ms: 706 (MH+), 728 (M-Na), 744 (M-K). Anal. Calcd. for
C43H39N5O5: C, 73.17; H, 5.57; N, 9.92; O, 11.33 Found: C,
73.06; H, 5.23; N, 9.60; O, 11.47.
[11] Bock. V. D.; Hiemstra, H. ; van Maarseveen, J. H. Eur. J.
Org. Chem., 51 (2006).
[12] (a) Santagada, V.; Frecentese, F.; Perissutti, E.; Favretto, L.;
Caliendo, G. QSAR & Combinatorial Science, 23, 919 (2004). (b)
Santagada, V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem., 9, 1251
(2002).
[13] (a) Santagada, V.; Frecentese, F.; Perissutti, E.; Fiorino, F.;
Severino, B.; Cirillo, D.; Terracciano, S.; Caliendo, G. J. Comb. Chem.,
7, 618 (2005). (b) Santagada, V.; Frecentese, F.; Perissutti, E.; Cirillo,
D.; Terracciano, S.; Caliendo, G. Bioorg. Med. Chem. Lett., 14, 4491
(2004). (c) Santagada, V.; Frecentese, F.; Fiorino, F.; Cirillo, D.;
Perissutti, E.; Severino, B.; Terracciano, S.; Caliendo, G. QSAR &
Combinatorial Science, 23, 899 (2004). (d) Severino, B.; Santagada,
V.; Frecentese, F.; Perissutti, E.; Terracciano, S.; Fiorino, F.; Cirillo, D.;
Salvadori, S.; Balboni, G.; Caliendo, G. Synthesis , 18, 3011 (2004). (e)
Santagada, V.; Fiorino, F.; Perissutti, E.; Severino, B.; Terracciano, S.;
Cirino, G.; Caliendo, G. Tetrahedron Lett., 44, 1145 (2003). (f)
Santagada, V.; Fiorino, F.; Perissutti, E.; Severino, B.; De Filippis, V.;
Vivenzio, B.; Caliendo, G. Tetrahedron Lett., 42, 5171 (2001).
[14] (a) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathe, D. Synthesis, 1213 (1998). (b) Galema, S.A. Chem.
Soc. Rev., 26, 233 (1997). (c) Caddick, S. Tetrahedron, 51, 10403 (1995).
(d) Larhed, M.; Hallberg, A. Drug Discov. Today, 6, 406 (2001) (e) Kappe,
C. O. Angew. Chem. Int. Ed., 43, 6250 (2004) (f) De La Hoz, A.; Diaz-
Ortiz, A.; Moreno, A. Curr. Org. Chem., 8, 903 (2004). (g) Das, S. K.
Synlett , 6, 915 (2004). (h) Loupy, A. Actualite Chimique , 272, 18
(2004) (i) Kaval, N.; Dehaen, W.; Van der Eycken, E. J. Comb. Chem., 7,
90 (2005). (k) Kappe, C.O., Dallinger, D. Nature Reviews Drug Discovery,
5, 51 (2006). j) Luopy, A. Microwaves in Organic Synthesis, Wiley-VCH,
Weinheim, 2002. k) Brittany L. Hayes Microwave Synthesis, CEM
Publishing, USA, 2002. l) Tierney, J. P.; Lidström, P. Microwave Assisted
Organic Synthesis, Blackwell Publishing Ltd, Oxford, UK, 2005. m)
Kingston, H. M.; Haswell, S. J. Microwave-Enhanced Chemistry,
American Chemical Society, Washington DC, 1997
REFERENCES
[1] (a) Zanotti, G. C.; Campbell, B. E.; Easwaran, K. R. K.;
Blont, E. R. Int. J. Pept. Protein Res., 32, 527 (1988). (b) Barbeau, D.;
Guay, S.; Escher, E. J. Med. Chem., 35, 151 (992). (c) Manning, M.;
Stoev, S.; Bonkowsky, K.; Masicka, A.; Lammek, B. J. Med. Chem., 35,
382 (1992). (d) Aubry, A.; Marraud, M. Biopolymers, 28, 109 (1989).
(e) El Masdauri, L.; Aubry, A.; Sakarellos C.; Gomez E.J.; Cung M.T.;
Marraud M. Int.J.Pept. Protein Res., 31, 420 (1998). (f) Marraud M.;
Dupont V.; Grand V.; Zerkout A.; Lecoq G.; Boussard G.; Vidal J.;
Collet A.; Aubry A. Biopolymers, 33, 1135 (1993). (g) Jensen R.T.; Coy
D.H. Trends Pharm. Sci , 12,13 (1991). (h) Coy D.H.; Heinz-Erian P.;
Jiang N.Y.; Sasaki Y.; Taylor J.; Moreau J.P.; Wolfrey W.T.; Gardner
J.D.; Jensen R.T. J. Biol .Chem., 263, 5056 (1988). (i) Hudson D.;
Sharpe R.; Szelke M. Int. J. Pept. Protein Res., 15, 122 (1980).
[2] Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem. Soc.,
125, 9372 (2003).
[3] (a) Alvarez, R.; Velazquez, S.; San, F.; Aquaro, S.; De, C.;
Perno, C. F.; Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem.,
37, 4185 (1994). (b) Velazquez, S.; Alvarez, R.; Perez, C.; Gago, F.; de
Clercq, E.; Balzarini, J.; Camarasa, M. J. Antiviral Chemother., 9,
481(1998).
[4] Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M.
R.; Cascieri, M. A.; Collwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M.
J.; Hom, G. J.; MacIntyre, D. E.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.;
Weber, A. E. Bioorg. Med. Chem. Lett., 10, 2111 (2000).
[15] Papeo, G.; Posteri, H.; Vinello, P. Varasi, M. Synthesis, 17,
2886 (2004).
[16] Coppola, G. M.; Damon, R. E. Synthetic Communications,
23, 2003 (1993).