Synthesis of enantiomerically pure α-[4-(1-substituted)-1,2,3-triazol-4-yl]-benzylacetamides via microwave-assisted click chemistry: towards new potential antimicrobial agents

Article abstract of DOI:10.1016/j.tetasy.2007.06.007

Chiral 1-phenyl-2-propynylamines are important building blocks for the synthesis of antifungal and antiaromatase agents related to bifonazole. In this report, a microwave-assisted Cu(I)-catalyzed 'click chemistry' approach has been employed to easily generate a small library of enantiomerically pure α-[4-(1-substituted)-1,2,3-triazol-4-yl]benzylacetamides starting from racemic propargylamines. These compounds could represent easily accessible intermediates for the synthesis of new antimicrobial agents.

Full text of DOI:10.1016/j.tetasy.2007.06.007

Tetrahedron: Asymmetry 18 (2007) 1345–1350
Synthesis of enantiomerically pure a-[4-(1-substituted)-1,2,3-
triazol-4-yl]-benzylacetamides via microwave-assisted click
chemistry: towards new potential antimicrobial agents
*
`
Daniele Castagnolo, Filippo Dessı, Marco Radi and Maurizio Botta
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Received 19 April 2007; accepted 6 June 2007
Abstract—Chiral 1-phenyl-2-propynylamines are important building blocks for the synthesis of antifungal and antiaromatase agents
related to bifonazole. In this report, a microwave-assisted Cu(I)-catalyzed ‘click chemistry’ approach has been employed to easily gen-
erate a small library of enantiomerically pure a-[4-(1-substituted)-1,2,3-triazol-4-yl]benzylacetamides starting from racemic propargylam-
ines. These compounds could represent easily accessible intermediates for the synthesis of new antimicrobial agents.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
N
N
Cl
Since the identification of clotrimazole 11 in 1972, a num-
ber of antifungal azole agents have been studied and are
now used in clinical practice. Miconazole 2 and related
derivatives, together with bifonazole 3, belong to the class
of imidazoles2 while fluconazole 4 represents an important
example of the triazole family (Fig. 1).3
N
N
Cl
O
Cl
Cl
Miconazole 2
Cl
Clortrimazole 1
Despite important advances in this field, there is a contin-
uing increase in the incidence of fungal infections, together
with a gradual rise in azole resistance. Moreover, further
studies have demonstrated that some of these antifungal
azoles effectively and rapidly inhibit the growth of chloro-
quine-resistant strains of P. falciparum in vitro.4
N
N
N
N
F
HO
F
N
N
N
N
Our interest in antifungal drugs,5 together with the experi-
ence acquired in the synthesis of chiral azoles and the re-
cent successes in the application of combinatorial
techniques and microwave-assisted procedures for the iden-
tification of novel lead compounds, brought us to investi-
gate the applicability of the ‘click chemistry approach’ to
generate a small library of novel chiral azole precursors.
Bifonazole 3
Fluconazole 4
Figure 1. Common antifungal agents.
‘near perfect’ reactions.6 The concept of click chemistry is
experiencing a growing popularity. This term, coined by
Sharpless, now refers to reactions yielding the product in
high yield without the need for further purification, gener-
ating inoffensive by-products, and operating in a benign
solvent, usually water. In this way, it is possible to reliably
generate a plethora of new compounds and thereby accel-
erate the process of drug discovery. The most powerful
In the last few years, click chemistry has emerged as a fast
and efficient approach for the synthesis of novel com-
pounds with desired functionality making use of selected
*
Corresponding author. E-mail: botta@unisi.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.007

1346
D. Castagnolo et al. / Tetrahedron: Asymmetry 18 (2007) 1345–1350
click reaction discovered to date is the CuI catalyzed vari-
ant of the Huisgen 1,3-dipolar cycloaddition of azides and
alkynes to afford 1,2,3-triazoles.7
R1
R1
i
CHO
5a-d
OH
Herein we turned our attention to the synthesis of enant-
6a-d
iopure
amides 9a–h, using
a-[4-(1-substituted)-1,2,3-triazol-4-yl]benzylacet-
microwave-assisted copper(I)-
a
ii
catalyzed click chemistry approach. These derivatives
could be interesting synthons for the synthesis of new
potential antifungal, antiaromatase and antimalarial
compounds related to bifonazole or letrazole.
R1
NHR2
7a-d R2 = Ac
8a-d R2 = H
2. Results and discussion
iii
The retrosynthetic approach depicted in Scheme 1 shows
that the desired chiral compounds 9a–h could be easily ob-
tained via a 1,3-dipolar cycloaddition (click reaction) from
the corresponding propargylamides 8a–d, which could in
turn be obtained from the commercial aldehydes 5a–d
using an efficient procedure previously reported by us.5b,8
Scheme 2. Reagents and conditions: (i) ethynylmagnesium bromide, THF,
2 h, rt; (ii) H2SO4, CH3CN, rt; (iii) HCl, 70 ꢁC.
room temperature, the triazole products (S)-9e–h were
crystallized from the reaction mixture and then isolated
by simple filtration. In order to prepare N-phenyl triazole
derivatives 9a–d (n = 0), phenyl azide11 was used in place
of the in situ generated benzyl azide by applying the above
described procedure: compounds (S)-9a–d were crystallized
from the reaction mixture and then isolated by filtration.
(Scheme 3; Table 1).
Reacting aldehydes 5a–d with the appropriate Grignard re-
agent at room temperature for 2 h gave the corresponding
propargylic alcohols 6a–d. Racemic propargylamines 8a–d
were finally achieved in a good overall yield by hydrolysis
of acetamides 7a–d, which were in turn obtained from aryl
propargylic alcohols 6a–d via a Ritter reaction (aceto-
nitrile/sulfuric acid) (Scheme 2).
As expected, the new triazoles (S)-9a–h were formed in a
completely regioselective manner, with no contamination
by the 1,5-regioisomer as highlighted from NOE experi-
ments (Fig. 2a): in the case of compounds 9e–h (n = 1),
irradiation of the resonance arising from Hc resulted in
the observation of a strong NOE in the resonances arising
from Hb and the aromatic ortho protons while in the case
of compounds 9a–d (n = 0), irradiation of the resonance
arising from NH resulted in the observation of a strong
NOE in the resonances arising from Ha and Hb.
The kinetic enzymatic resolution of racemic propargylam-
ines 8a–d with CAL-B as the catalyst gave both (S)-amines
8a–d and (R)-acetamides 7a–d in good yields and high
enantiomeric excess; the absolute configurations were
determined by comparison with authentic samples (Scheme
3). The latter compounds (R)-7a–d were then submitted to
the microwave-assisted click reaction. In order to prepare
the N-benzyl triazole derivatives 9e–h (n = 1), a three com-
ponent copper(I)-catalyzed approach9 was used: alkynes
(R)-7a–d, benzyl chloride, and sodium azide were sus-
pended in a 1:1 mixture of t-BuOH and water, together
with the in situ generated Cu(I) catalyst (sodium ascor-
bate/Cu(SO)4),10 in a 10-mL sealed glass vial. After
10 min of irradiation at 125 ꢁC and subsequent cooling to
Unfortunately, the direct application of the previously de-
scribed click-chemistry protocol to the amines (S)-8a–d
recovered from the CAL-B catalyzed enzymatic resolution
never gave the expected triazole derivatives. The presence
of the free amino group proved detrimental to the outcome
of the 1,3-dipolar cycloaddition reaction most likely as a
consequence of the chelation of the copper ions: after filtra-
tion of the crude material, the isolated precipitate decom-
posed in a short time resulting in a complex reaction
mixture. Several attempts were made in order to optimize
the reaction conditions with compound (S)-8a; finally it
was found that the addition of aqueous ammonia to the
crude mixture after the click reaction allowed us to avoid
the decomposition of the desired triazole products. Unfor-
tunately, compounds (R)-10c,g, whose structure was con-
firmed by conversion into the corresponding amides (R)-
9c,g, needed to be recovered from the aqueous phase and
this procedure was therefore considered impractical for
the development of a click library (Scheme 3).
R1
R1
N
N
N
n
*
*
NHCOCH3
NHCOCH3
n = 0, 1
9a-h
8a-d
R1
CHO
5a-d
For this reason, in order to obtain the enantiopure triazoles
Scheme 1. Retrosynthetic approach.
(R)-9a–h, we considered it convenient to transform the

D. Castagnolo et al. / Tetrahedron: Asymmetry 18 (2007) 1345–1350
1347
R1
R1
R1
R1
N
N
i.
iii.
N
+
n
NH2
NH2
NHCOCH3
NHCOCH3
n = 0, 1
8a-d
(S)-8a-d
(R)-7a-d
(S)-9a-h
ii., iii.
iiii.
R1
Br
N
N
N
N
ii
N
N
n
n = 0, 1
n
NH2
(R)-10c,g
NHCOCH3
n = 0, 1
(R)-9a-h
Scheme 3. Reagents and conditions: (i) AcOEt, CAL-B, Et2O, rt; (ii) Ac2O, Et3N, CH2Cl2, rt, 2 h; (iii) (For n = 1): NaN3, benzyl chloride, sodium
ascorbate/Cu(SO)4, H2O/t-ButOH, MW, 125 ꢁC, 10 min; (For n = 0): PhN3, sodium ascorbate/Cu(SO)4, H2O/t-ButOH, MW, 120 ꢁC, 10 min.
Table 1. a-[4-(1-Substituted)-1,2,3-triazol-4-yl]-benzylacetamides 9a–h
produced via Scheme 3
(a): 1,4-regioisomers
(b): 1,5-regioisomers
20
c
Entry
Compound
R
eea (%) Yieldb (%) ½aꢀD
H
R1
N
R1
Hb
Ha
N
N
H
n
N
N
Ha
N
H
Hc'
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(S)-9a
H
0
0
0
0
1
1
1
1
0
0
0
0
1
1
1
1
95
95
89
79
91
93
95
99
95
95
89
96
91
93
95
99
80
75
77
85
90
92
92
94
76
78
78
79
92
89
87
92
ꢁ9.4 (c 1.0 CHCl3)
ꢁ6.6 (c 0.9 CHCl3)
ꢁ6.8 (c 1.7 CHCl3)
ꢁ9.8 (c 1.0 CHCl3)
ꢁ9.2 (c 0.6 MeOH)
ꢁ7.9 (c 1.1 CHCl3)
ꢁ10.0 (c 0.6 CHCl3)
ꢁ10.9 (c 1.0 CHCl3)
+9.1 (c 1.0 CHCl3)
+6.9 (c 1.0 CHCl3)
+6.6 (c 1.7 CHCl3)
+9.9 (c 1.0 CHCl3)
+9.4 (c 0.6 MeOH)
+7.8 (c 1.1 CHCl3)
+9.9 (c 0.6 CHCl3)
+10.8 (c 1.0 CHCl3)
Hc
Hc
(S)-9b 4-F
(S)-9c 4-Br
(S)-9d 4-Cl
Hb
O
NH
Hc'
O
NH
H
CH3
9e-h
CH3
9e-h
(S)-9e
H
(S)-9f 4-F
(S)-9g 4-Br
(S)-9h 4-Cl
(R)-9a
H
R1
R1
N
N
Hb
Ha
N
(R)-9b 4-F
(R)-9c 4-Br
(R)-9d 4-Cl
N
N
Ha
N
H
Hb
O
NH
CH3
9a-d
(R)-9e
H
O
NH
H
(R)-9f 4-F
(R)-9g 4-Br
(R)-9h 4-Cl
CH3
9a-d
a Determined by chiral HPLC–MS using an (S,S)-Whelk-O1 column
(methanol/water 95:5, flow rate 0.8 mL/min, UV-254 nm).
b Refers to isolated and purified materials.
Figure 2. (a) Experimentally found NOE correlation for the 1,4-regio-
isomers, protons in bold represent the irradiated frequency; (b) expected
NOE for the 1,5-regioisomers.
c Measured in CHCl3 solution, except 9e measured in MeOH.
useful and readily accessible intermediates for the synthesis
of enantiopure azole analogues as potential antimicrobial
agents.
amines (S)-8a–d in the corresponding amides (S)-7a–d. The
latter compounds were directly submitted to the copper(I)-
catalyzed 1,3-dipolar cycloaddition reaction without the
need of any purification to give the desired compounds
(R)-9a–h as a pure product after simple filtration (Scheme
3, Table 1).
Further studies on the application of the reported interme-
diate for the synthesis of new potential antimicrobial
agents are ongoing and will be published in due course.
3. Conclusion
4. Experimental
In conclusion, a microwave-assisted Cu(I)-catalyzed ‘click
chemistry’ approach has been applied to the synthesis of
a small library of enantiopure pure a-[4-(1-substituted)-
1,2,3-triazol-4-yl]benzylacetamides 9a–h. These triazole
derivatives were obtained after a few minutes, in good
yields and high enantiomeric excess (Table 1) making them
Reagents were obtained from commercial suppliers and
used without further purification. THF was dried over
Na/benzophenone prior to use. Anhydrous reactions were
run under a positive pressure of dry N2 or Ar. Merck silica
gel 60 was used for flash chromatography (23–400 mesh).

1348
D. Castagnolo et al. / Tetrahedron: Asymmetry 18 (2007) 1345–1350
1H NMR and 13C NMR spectra were measured at
200 MHz on a Brucker AC200F spectrometer and at
400 MHz on a Brucker Avance DPX400. Chemical shifts
are reported relative to CDCl3 at d 7.24 ppm and tetra-
methylsilane at d 0.00 ppm. Elemental analyses (C, H, N)
were performed in-house.
at room temperature for 2 h. The mixture was diluted with
water and extracted with AcOEt two times. The combined
organic layers were washed with brine, dried (Na2SO4), fil-
tered and evaporated to give the crude phenylazide. Then
alkyne (1.1 mmol) and freshly synthesized phenylazide
(1.1 mmol) were suspended in a 1:1 mixture of water and
tert-BuOH (1.5 mL each) in a 10 mL glass vial equipped
with a small magnetic stirring bar. To this, was added so-
dium ascorbate (0.1 equiv) and copper(II) sulfate pentahy-
drate (0.01 equiv), and the vial was tightly sealed with an
aluminum/Teflonꢂ crimp top. The mixture was then irradi-
ated for 10 min at 125 ꢁC, using an irradiation power of
100 W. After completion of the reaction, the vial was
cooled to 50 ꢁC by gas jet cooling before it was opened.
The mixture was then diluted with water (20 mL) and fil-
tered. The residue was washed with cold water (20 mL),
0.1 M NaOH (10 mL) and finally with petroleum ether
(50 mL) to furnish triazoles 9a–d as pure compounds.
HPLC and MS analyses were performed using a mass spec-
trometer (Agilent series 1100 LC/MSD) with a UV detec-
tor at k = 254 nm and an electrospray ionization source
(ESI). All solvents were of HPLC grade (Fluka). Mass
spectral (MS) data were obtained using an Agilent 1100
LC/MSD VL system (G1946C) with a 0.4 mL/min flow
rate using a binary solvent system of 95:5 methyl alcohol/
water. UV detection was monitored at 254 nm. Mass spec-
tra were acquired by using electrospray ionization in posi-
tive mode scanning over the mass range of 50–1500. The
following ion source parameters were used: drying gas
flow, 9 mL/min; nebulize pressure, 40 psig; drying gas tem-
perature, 350 ꢁC.
4.2.1. (S)-N-[Phenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-meth-
1
yl]-acetamide 9a. Yield: 80%. H NMR (CDCl3): d 7.74
The purity and enantiomeric excess of the compounds were
assessed by reverse-phase liquid chromatography (S,S-
Whelk-O1 chiral column) with a mobile phase composed
of methanol/water (95:5) and a flow rate of 0.8 mL/min.
(1H, s, CCHNPh), 7.62 (2H, d, J = 7.9 Hz, Ph), 7.46–
7.22 (8H, m, Ph and CCHNPh), 6.78 (1H, br s, NH),
6.34 (1H, s, CHN), 2.01 (3H, s, CH3). IR (KBr): 1664,
1496 cmꢁ1
.
MS: 293.1 (M+H)+, 315.1 (M+Na)+.
20
½aꢀD ¼ ꢁ9:4 (c 1.0, CHCl3). Anal. Calcd for C17H16N4O:
C, 69.85; H, 5.52; N, 19.17. Found: C, 69.98; H, 5.78; N,
19.43.
Microwave irradiation experiments were conducted using a
CEM Discover Synthesis Unit (CEM Corp., Matthews,
NC). The machine consists of a continually focused micro-
wave power delivery system with an operator-selectable
power output from 0 to 300 W. The temperature of the
contents of the vessels was monitored using a calibrated
infrared temperature control mounted under the reaction
vessel. All the experiments were performed using a stirring
option whereby the contents of the vessel were stirred by
means of a rotating magnetic plate located below the floor
of the microwave cavity and a Teflon-coated magnetic stir
bar in the vessel.
4.2.2. (R)-N-[Phenyl-(1-phenyl-1H-[1,2,3]triazol-4-yl)-meth-
1
yl]-acetamide 9a. Yield: 76%. H NMR (CDCl3): d 7.74
(1H, s, CCHNPh), 7.62 (2H, d, J = 7.9 Hz, Ph), 7.46–
7.22 (8H, m, Ph and CCHNPh), 6.78 (1H, br s, NH),
6.34 (1H, s, CHN), 2.01 (3H, s, CH3). IR (KBr): 1664,
1496 cmꢁ1
.
MS: 293.1 (M+H)+, 315.1 (M+Na)+.
20
½aꢀD ¼ þ9:1 (c 1.0 CHCl3). Anal. Calcd for C17H16N4O:
C, 69.85; H, 5.52; N, 19.17. Found: C, 69.98; H, 5.78; N,
19.43.
Compounds 7a–d and 8a–d have been synthesized follow-
ing a procedure previously reported by us and fully charac-
terized by comparison with an authentic sample.5b
4.2.3. (S)-N-[4-Fluorophenyl-(1-phenyl-1H-[1,2,3]triazol-4-
yl)-methyl]-acetamide 9b. Yield: 75%. H NMR (CDCl3):
1
d 7.85 (1H, s, CCHNPh), 7.67–6.98 (9H, m, Ph), 6.39 (1H,
s, CHN), 2.04 (3H, s, CH3). IR (KBr): 1661, 1494 cmꢁ1
.
4.1. General procedure for the acetylation of propargyl-
amines (S)-8a–d
20
MS: 311.1 (M+H)+, 333.1 (M+Na)+. ½aꢀD ¼ ꢁ6:6 (c 0.9,
CHCl3). Anal. Calcd for C17H15FN4O: C, 65.80; H, 4.87;
N, 18.05. Found: C, 65.69; H, 4.65; N, 18.34.
To a stirred solution of (S)-1-aryl-2-propynylamines (S)-
8a–d (2 mmol) in dry CH2Cl2 (4 mL), Et3N (3 mmol) was
added slowly at 0 ꢁC. After 5 min, (AcO)2O (2.2 mmol)
was added dropwise and the reaction was stirred under
inert atmosphere at room temperature for 2 h. The mixture
was washed with a solution of NaHCO3 (2 · 4 mL) and
brine. The organic layer was dried over Na2SO4, filtered
and concentrated. The crude amides (S)-7a–d were used
in the next click reaction without the need for any further
purification.
4.2.4. (R)-N-[4-Fluorophenyl-(1-phenyl-1H-[1,2,3]triazol-4-
1
yl)-methyl]-acetamide 9b. Yield: 78%. H NMR (CDCl3):
d 7.85 (1H, s, CCHNPh), 7.67–6.98 (9H, m, Ph), 6.39 (1H,
s, CHN), 2.04 (3H, s, CH3). IR (KBr): 1661, 1494 cmꢁ1
.
20
MS: 311.1 (M+H)+, 333.1 (M+Na)+. ½aꢀD ¼ þ6:9 (c 1.0,
CHCl3). Anal. Calcd for C17H15FN4O: C, 65.80; H, 4.87;
N, 18.05. Found: C, 65.69; H, 4.65; N, 18.34.
4.2.5. (S)-N-[4-Bromophenyl-(1-phenyl-1H-[1,2,3]triazol-4-
1
4.2. General procedure for the synthesis of triazoles 9a–d
yl)-methyl]-acetamide 9c. Yield: 77%. H NMR (CDCl3):
d 7.87 (1H, s, CCHNPh), 7.63–7.13 (9H, m, Ph), 6.80 (1H,
Aniline (2 mmol) was dissolved in HCl and cooled at 0 ꢁC.
NaNO2 (2 mmol) was added and the mixture stirred at 0 ꢁC
for 10 min. NaN3 was then added and the mixture stirred
br s, NH), 6.35 (1H, s, CHN), 2.01 (3H, s, CH3). IR (KBr):
1660, 1496 cmꢁ1. MS: 371.0 (M+H)+, 393.0 (M+Na)+.
20
½aꢀD ¼ ꢁ6:8 (c 1.7, CHCl3). Anal. Calcd for C17H15BrN4O:

D. Castagnolo et al. / Tetrahedron: Asymmetry 18 (2007) 1345–1350
1349
C, 55.00; H, 4.07; N, 15.09. Found: C, 55.32; H, 4.28; N,
15.29.
C18H18N4O: C, 70.57; H, 5.92; N, 18.29. Found: C,
70.68; H, 5.78; N, 18.45.
4.2.6. (R)-N-[4-Bromophenyl-(1-phenyl-1H-[1,2,3]triazol-4-
yl)-methyl]-acetamide 9c. Yield: 78%. H NMR (CDCl3):
d 7.87 (1H, s, CCHNPh), 7.63–7.13 (9H, m, Ph), 6.80 (1H,
1
4.3.3. (S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-fluorophen-
yl)-methyl]-acetamide 9f. Yield: 92%. H NMR (CDCl3):
d 7.33–6.94 (10H, m, Ph and CCHNPh), 6.90 (1H, br s,
1
br s, NH), 6.35 (1H, s, CHN), 2.01 (3H, s, CH3). IR (KBr):
1660, 1496 cmꢁ1. MS: 371.0 (M+H)+, 393.0 (M+Na)+.
NH), 6.30 (1H, s, CHN), 5.46 (2H, s, NCH2Ph), 1.97
(3H, s, CH3). IR (KBr): 1661, 1494 cmꢁ1. MS: 325.1
20
½aꢀD ¼ þ6:6 (c 1.7, CHCl3). Anal. Calcd for C17H15BrN4O:
20
(M+H)+, 347.1 (M+Na)+. ½aꢀD ¼ ꢁ7:9 (c 1.1 CHCl3).
C, 55.00; H, 4.07; N, 15.09. Found: C, 55.32; H, 4.28; N,
15.29.
Anal. Calcd for C18H17FN4O: C, 66.65; H, 5.28; N,
17.27. Found: C, 66.87; H, 5.46; N, 17.45.
4.2.7. (S)-N-[(4-Chlorophenyl)(1-phenyl-1H-[1,2,3]triazol-4-
yl)methyl]acetamide 9d. Yield: 85%. 1H NMR (300 MHz,
CDCl3): d 8.01 (1H, br s, NH), 7.85 (1H, s, CCHN), 7.63–
6.97 (9H, m, Ph), 6.38 (1H, s, PhCHC), 2.01 (3H, s, CH3)
4.3.4. (R)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-fluorophen-
yl)-methyl]-acetamide 9f. Yield: 89%. H NMR (CDCl3):
d 7.33–6.94 (10H, m, Ph and CCHNPh), 6.90 (1H, br s,
1
IR (KBr): 1660, 1496 cmꢁ1. MS: 327.1 (M+H)+, 349.1
NH), 6.30 (1H, s, CHN), 5.46 (2H, s, NCH2Ph), 1.97
20
(M+Na)+. ½aꢀD ¼ ꢁ9:8 (c 1.0 CHCl3). Anal. Calcd for
(3H, s, CH3). IR (KBr): 1661, 1494 cmꢁ1. MS: 325.1
20
(M+H)+, 347.1 (M+Na)+. ½aꢀD ¼ þ7:8 (c 1.1 CHCl3).
C17H15BrN4O: C, 55.00; H, 4.07; N, 15.09. Found: C,
55.32; H, 4.28; N, 15.29.
Anal. Calcd for C18H17FN4O: C, 66.65; H, 5.28; N,
17.27. Found: C, 66.87; H, 5.46; N, 17.45.
4.2.8. (R)-N-[(4-Chlorophenyl)(1-phenyl-1H-[1,2,3]triazol-4-
yl)methyl]acetamide 9d. Yield: 79%. 1H NMR (300 MHz,
CDCl3): d 8.01 (1H, br s, NH), 7.85 (1H, s, CCHN), 7.63–
6.97 (9H, m, Ph), 6.38 (1H, s, PhCHC), 2.01 (3H, s, CH3)
4.3.5.
(S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-bromo-
phenyl)-methyl]-acetamide 9g. Yield: 92%. 1H NMR
(CDCl3): d 7.41–7.17 (10H, m, Ph and CCHNPh), 6.21
(1H, s, CHN), 5.46 (2H, s, NCH2Ph), 2.00 (3H, s, CH3).
IR (KBr): 1660, 1496 cmꢁ1. MS: 327.1 (M+H)+, 349.1
20
(M+Na)+. ½aꢀD ¼ þ9:9 (c 1.0 CHCl3). Anal. Calcd for
C17H15BrN4O: C, 55.00; H, 4.07; N, 15.09. Found: C,
55.32; H, 4.28; N, 15.29.
IR (KBr): 1661, 1494 cmꢁ1. MS: 385.1 (M+H)+, 407.1
20
(M+Na)+. ½aꢀD ¼ ꢁ10:0 (c 0.6 CHCl3). Anal. Calcd for
C18H17BrN4O: C, 56.12; H, 4.45; N, 14.54. Found: C,
56.34; H, 4.67; N, 14.75.
4.3. General procedure for the synthesis of triazoles 9e–h
Benzyl chloride (1.0 mmol), alkyne (1.1 mmol) and sodium
azide (1.1 mmol) were suspended in a 1:1 mixture of water
and tert-BuOH (1.5 mL each) in a 10 mL glass vial
equipped with a small magnetic stirring bar. To this were
added sodium ascorbate (0.1 equiv) and copper(II) sulfate
pentahydrate (0.01 equiv) and the vial was tightly sealed
with an aluminum/Teflonꢂ crimp top. The mixture was
then irradiated for 10 min at 125 ꢁC, using an irradiation
power of 100 W. After completion of the reaction, the vial
was cooled to 50 ꢁC by gas jet cooling before it was opened.
The mixture was then diluted with water (20 mL) and fil-
tered. The residue was washed with cold water (20 mL),
0.1 M NaOH (10 mL) and finally with petroleum ether
(50 mL) to furnish product triazoles 9e–h.
4.3.6. (R)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-bromophen-
yl)-methyl]-acetamide 9g. Yield: 87%. 1H NMR
(CDCl3): d 7.41–7.17 (10H, m, Ph and CCHNPh), 6.21
(1H, s, CHN), 5.46 (2H, s, NCH2Ph), 2.00 (3H, s, CH3).
IR (KBr): 1661, 1494 cmꢁ1. MS: 385.1 (M+H)+, 407.1
20
(M+Na)+. ½aꢀD ¼ þ9:9 (c 0.6 CHCl3). Anal. Calcd for
C18H17BrN4O: C, 56.12; H, 4.45; N, 14.54. Found: C,
56.34; H, 4.67; N, 14.75.
4.3.7. (S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)(4-chlorophen-
yl)methyl]-acetamide 9h. Yield: 94%. 1H NMR
(300 MHz, CDCl3): d 7.70 (1H, br s, NH), 7.32–6.72
(10H, m, Ph and CCHN), 6.19 (1H, s, PhCHC), 5.43
(2H, s, NCH2 Ph), 1.96 (3H, s, CH3) IR (KBr): 1661,
20
1494 cmꢁ1. MS: 341.1 (M+H)+, 363.1 (M+Na)+. ½aꢀD
¼
4.3.1. (S)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenyl-meth-
yl]-acetamide 9e. Yield: 90%. H NMR (CDCl3): d 7.33–
7.24 (11H, m, Ph and CCHNPh), 6.82 (1H, br s, NH), 6.27
1
ꢁ10:9 (c 1.0 CHCl3). Anal. Calcd for C18H17BrN4O: C,
56.12; H, 4.45; N, 14.54. Found: C, 56.34; H, 4.67; N,
14.75.
(1H, s, CHN), 5.45 (2H, s, NCH2Ph), 2.00 (3H, s, CH3). IR
(KBr): 1666, 1496 cmꢁ1. MS: 307.1 (M+H)+, 329.1
20
(M+Na)+. ½aꢀD ¼ ꢁ9:2 (c 0.6 MeOH). Anal. Calcd for
C18H18N4O: C, 70.57; H, 5.92; N, 18.29. Found: C,
70.68; H, 5.78; N, 18.45.
4.3.8. (R)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)(4-chlorophen-
yl)methyl]-acetamide 9h. Yield: 92%. 1H NMR
(300 MHz, CDCl3): d 7.70 (1H, br s, NH), 7.32–6.72
(10H, m, Ph and CCHN), 6.19 (1H, s, PhCHC), 5.43
4.3.2. (R)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenyl-meth-
1
yl]-acetamide 9e. Yield: 92%. H NMR (CDCl3): d 7.33–
(2H, s, NCH2 Ph), 1.96 (3H, s, CH3) IR (KBr): 1661,
20
7.24 (11H, m, Ph and CCHNPh), 6.82 (1H, br s, NH), 6.27
1494 cmꢁ1. MS: 341.1 (M+H)+, 363.1 (M+Na)+. ½aꢀD
¼
(1H, s, CHN), 5.45 (2H, s, NCH2Ph), 2.00 (3H, s, CH3). IR
þ10:8 (c 1.0 CHCl3). Anal. Calcd for C18H17BrN4O: C,
56.12; H, 4.45; N, 14.54. Found: C, 56.34; H, 4.67; N,
14.75.
(KBr): 1666, 1496 cmꢁ1. MS: 307.1 (M+H)+, 329.1
20
(M+Na)+. ½aꢀD ¼ þ9:4 (c 0.6 MeOH). Anal. Calcd for

1350
D. Castagnolo et al. / Tetrahedron: Asymmetry 18 (2007) 1345–1350
2. Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J.
J. Med. Chem. 1979, 22, 1003–1005.
4.4. (R)-N-[4-Bromophenyl-(1-phenyl-1H-[1,2,3]triazol-4-
yl)-methyl]-amine (10c)
3. Koltin, Y. Annu. Rep. Med. Chem. 1990, 25, 141–148.
4. Huy, N. T.; Kamei, E.; Kondo, Y.; Serada, S.; Kanaori, K.;
Takano, R.; Tajima, K.; Hara, S. J. Biochem. 2002, 131, 437–
444.
1
Yield: 78%. H NMR (CDCl3): d 7.73–7.07 (10H, m, Ph
and CCHNPh), 5.21 (1H, s, PhCHC), 2.27 (2H, br s,
20
D
NH2). MS: 313.1 (MꢁNH2)+, 351.1 (M+Na)+. ½aꢀ
¼
5. (a) Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta,
M. J. Org. Chem. 1995, 60, 2008–2015; (b) Messina, F.; Botta,
M.; Corelli, F.; Schneider, M. P.; Fazio, F. J. Org. Chem.
1999, 64, 3767–3769; (c) Botta, M.; Corelli, F.; Gasparrini,
F.; Messina, F.; Mugnaini, C. J. Org. Chem. 2000, 65, 4736–
4739; (d) Messina, F.; Botta, M.; Corelli, F.; Paladino, A.
Tetrahedron: Asymmetry 2000, 11, 4895–4901; (e) Tafi, A.;
Costi, R.; Botta, M.; Di Santo, R.; Corelli, F.; Massa, S.;
Ciacci, A.; Manetti, F.; Artico, M. J. Med. Chem. 2002, 45,
2720–2732; (f) Di Santo, R.; Tafi, A.; Costi, R.; Botta, M.;
Artico, M.; Corelli, F.; Forte, M.; Caporuscio, F.; Angio-
lella, L.; Palamara, A. T. J. Med. Chem. 2005, 48, 5140–
5153.
ꢁ15:8 (c 1.0 CHCl3). Anal. Calcd for C15H13BrN4: C,
54.73; H, 3.98; N, 17.02. Found: C, 54.68; H, 4.04; N,
17.00.
4.5. (R)-N-[(1-Benzyl-1H-[1,2,3]triazol-4-yl)-(4-bromophen-
yl)-methyl]-amine (10g)
1
Yield: 75%. H NMR (CDCl3): d 7.37–7.09 (10H, m, Ph
and CCHNPh), 5.37 (1H, s, PhCHC), 5.23 (2H, s,
NCH2Ph), 2.00 (2H, br s, NH2). MS: 326.2 (MꢁNH2)+,
20
365.1 (M+Na)+. ½aꢀD ¼ ꢁ14:5 (c 2.2 CHCl3). Anal. Calcd
for C16H15BrN4: C, 55.99; H, 4.41; N, 16.32. Found: C,
55.92; H, 4.40; N, 16.38.
6. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2001, 40, 2004–2021; (b) Kolb, H. C.; Sharpless, K. B.
Drug Discovery Today 2003, 8, 1128–1137; (c) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006,
51–68.
Acknowledgments
7. Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984.
8. Castagnolo, D.; Renzulli, M. L.; Galletti, E.; Corelli, F.;
Botta, M. Tetrahedron: Asymmetry 2005, 16, 2893–
2896.
This study was partially supported by grants from the
European TRIoH Consortium (LSHB-2003-503480).
Fondazione Monte dei Paschi di Siena and the University
of Siena are also gratefully acknowledged for the financial
support.
9. Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken,
E. Org. Lett. 2004, 6, 4223–4225.
10. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
11. Pagliai, F.; Pirali, T.; Del Grosso, E.; Di Brisco, R.; Tron, G.
C.; Sorba, G.; Genazzani, A. A. J. Med. Chem. 2006, 49, 467–
470.
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