A facile synthesis of N-C linked 1,2,3-triazole-oligomers

Article abstract of DOI:10.1016/j.tet.2011.05.040

The synthesis of the title oligomers was performed by means of an iterative sequence of 1,3-dipolar cycloaddition reactions of appropriate azides, starting from commercial 4-bromo-1-butyne as a key intermediate.

Full text of DOI:10.1016/j.tet.2011.05.040

Tetrahedron 67 (2011) 5254e5260
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile synthesis of NeC linked 1,2,3-triazole-oligomers
*
Vito Fiandanese, Francesco Iannone, Giuseppe Marchese, Angela Punzi
ꢀ
Dipartimento di Chimica, Universita di Bari ‘Aldo Moro’, via Orabona 4, 70126 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the title oligomers was performed by means of an iterative sequence of 1,3-dipolar
cycloaddition reactions of appropriate azides, starting from commercial 4-bromo-1-butyne as a key
intermediate.
Received 17 February 2011
Received in revised form 21 April 2011
Accepted 9 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 14 May 2011
Keywords:
1,2,3-Triazoles
Nitrogen heterocycles
Click chemistry
Copper(I)-catalyzed alkyne-azide
cycloaddition
4-Bromo-1-butyne
1. Introduction
In connection with our previous studies dealing with the syn-
thesis of heterocyclic compounds,13 we have recently reported
Huisgen’s thermal 1,3-dipolar cycloaddition between azides and
alkynes is one of the most widely used methods for the synthesis of
1,2,3-triazoles.1 However, the harsh conditions of this uncatalyzed
cycloaddition lead to a mixture of 1,4-and 1,5-regioisomers. Sub-
sequently, Cu(I)-catalyzed azideealkyne cycloadditions (CuAACs)2,3
have been reported for the synthesis of 1,4-disubstituted-
1,2,3-triazoles from a wide range of substrates with excellent se-
lectivity.4 After this discovery, in the past decade CuAAC has gained
considerable attention as ‘click chemistry’, which proceeds in a va-
riety of solvents, including aqueous media, and in the presence of
numerous functional groups.5,6 The simplicity of these ‘click’ re-
actions offers several advantages from a synthetic point of view for
the functionalization or ligation of biological systems,7 in material
science8 and in combinatorial chemistry for drug discovery.9 In
particular, recently, many groups have extended the potential of
CuAAC by developing methods for multiple successive cycloaddi-
tions, which led to 1,2,3-triazole-oligomers.10e12 A common tactic
for the synthesis of higher order triazole cycloadducts involves the
repetition of a two-stage process consisting of the introduction of an
azido group in an appropriate substrate, followed by a CuAAC with
the suitable alkyne to obtain triazole-based biomimetic oligomers10
or triazole linked oligonucleotides analogues.11 Another approach is
based upon the successive CuAAC on a single scaffold, containing
both the azide and the alkyne moieties.12
a general approach to novel unsymmetrically substituted 4,40-bi-
1,2,3-triazoles14a and an easy synthesis of 1,2,3-triazole-fused
heterocycles.14b On the basis of these results, we decided to eval-
uate the possibility of devising an easy synthetic approach to new
triazole-based oligomers containing only triazole rings linked by
an alkyl chain in the 1,4-positions. Herein we wish to report on
these studies, which enabled the synthesis of the NeC type 1,2,3-
triazoles-linked oligomers. This strategy is based on the use of
commercially available 4-bromo-1-butyne 1, a difunctional com-
pound bearing both an alkyne moiety and a bromoalkyl group as
the site for azide substitution, which led to an iterative formation
of triazole rings.
2. Results and discussion
Our methodology is depicted in Scheme 1. We started with the
cycloaddition reaction between alkyl azides and compound 1. The
reactions were performed in H2O at room temperature in the
presence of Cu(OAc)2$H2O, leading regioselectively to 4-(2-
bromoethyl)-1,2,3-triazoles 2 in high yields. Subsequently, the
bromides were displaced by azide groups by treatment with so-
dium azide in DMF and compounds 2 were transformed in the
corresponding azides 3. A new cycloaddition reaction on the same
alkyne 1 led to the bis-triazoles 4 in good yields. The same iterative
sequence performed on triazoles 4 provided the azides 5 and 7 in
excellent yields (Table 1).
* Corresponding author. Tel.: þ39 080 5442464; fax: þ39 080 5442075; e-mail
address: punzi@chimica.uniba.it (A. Punzi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.040

V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
5255
N
N
N
N
N
N
NaN3, DMF
100 °C
RN3
1
N
NaN3, DMF
100 °C
Br
R
N
N
N
R
R
Cu(OAc)2·H2O
H2O, rt
Br
Cu(OAc)2·H2O
H2O, rt
Br
N3
N
N
1
2a,b
3a,b
4a,b
N
N
N
N
N
N
N
N
N
N
1
NaN3, DMF
100 °C
N
N3
R
N
N
R
N
N
N
R
Br
N3
Cu(OAc)2·H2O
H2O, rt
N
N
N
N
N
N
N
N
5a,b
6a,b
Scheme 1.
7a,b
Table 1
Yields (%) of compounds 2e7
(entries 2, 3, 5, 6, 8, 10, 12 and 13) and heteroaryl (entries 7 and 9)
alkynes. Thus, a variety of NeC type 1,2,3-bis-triazoles 9aeg,
bearing benzyl or alkyl groups on nitrogen and aryl or alkyl groups
on C-40 were obtained regioselectively from 4-(2-azidoethyl)-1,2,3-
triazoles 3. Moreover, trimeric cycloadducts 9hek and tetrameric
cycloadducts 9l,m containing a series of alkyl and aryl groups at the
end of the triazole oligomeric chain, were easily generated from
functionalized azides 5 and 7.
R
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
95
7a
7b
PhCH2
89
95
82
85
75
88
n-C8H17
96
96
92
97
86
Thus, in order to complete the formation of oligomeric chains
containing two, three and four triazole rings, these compounds
were reacted with different alkynes in the presence of
Cu(OAc)2$H2O in H2O at 100 ꢀC (Scheme 2).
3. Conclusion
In conclusion, starting from the easily available commercial
4-bromo-1-butyne1, wehavedevelopedadirectroutetoNeClinked
1,2,3-triazole-oligomers, using alternatively cycloaddition and azi-
dation reactions. Our procedure requires simple reaction conditions
for all steps, allows the efficient preparation of a series of NeC type
dimeric, trimeric and tetrameric cycloadducts and, in principle, the
methodology could be applied to the synthesis of other similar
oligomeric chains containing a higher number of triazole rings.
N
N
R'
8
N
N3
R
(
(
)
Cu(OAc)2·H2O
H2O, 100 °C
N
n
N
N
3,5,7
N
N
N
N
N
N
n
R
4. Experimental section
4.1. General
)
R'
N
N
N
9
MachereyeNagel silica gel (60, particle size 0.040e0.063 mm)
for column chromatography and MachereyeNagel aluminium
sheets with silica gel 60 F254 for TLC were used. GC analysis was
performed on a Varian 3900 gas chromatograph equipped with
a Supelco SLBÔ-5 ms capillary column (30 mꢁ0.25 mm id). GC/
Scheme 2.
We were pleased to find that the cycloaddition reactions pro-
ceeded successfully with a variety of terminal alkynes. Indeed, as
reported in the Table 2, good to excellent yields of desired 1,2,3-
triazole derivatives 9 were obtained employing terminal alkynes
with different groups, including alkyl (entries 1, 4 and 11), aryl
mass-spectrometry analysis was performed on
a Shimadzu
GCMS-QP5000 gas chromatograph-mass spectrometer equipped
with a Supelco SLBÔ-5 ms capillary column (30 mꢁ0.25 mm id). 1H
NMR spectra were recorded in deuterochloroform, or DMSO-d6 on
Table 2
Synthesis of NeC type 1,2,3-triazole derivatives 9aem
Entry
1
Azides
Alkynes 8
Products 9, Yieldsa (%)
N
N
N
N
3a
N
9a (78)
9b (62)
N
N
N
N
N
2
3
3a
3a
N
N
Me
N
N
N
Me
N
9c (64)
N
N
(continued on next page)

5256
V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
Table 2 (continued )
Entry
Azides
Alkynes 8
Products 9, Yieldsa (%)
N
N
N
N
4
5
3b
N
N
9d (71)
9e (93)
N
N
N
N
3b
3b
N
N
OMe
N
N
N
N
6
7
8
MeO
N
N
9f (92)
N
N
N
N
3b
5a
N
N
N
N
9g (88)
N
N
N
N
N
N
N
N
N
9h (87)
N
N
N
N
N
N
9
5a
N
S
N
N
S
9i (90)
N
N
N
N
N
N
N
10
11
12
5b
5b
7a
N
N
N
9j (67)
N
N
N
N
N
N
N
N
9k (83)
N
N
N
N
N
N
N
N
N
N
N
N
9l (50)
OMe
N
N
N
N
N
13
7b
N
MeO
N
N
N
N
N
N
9m (72)
a
Yields of purified isolated products.
a Varian Inova at 400 MHz 13C NMR spectra were recorded in
deuterochloroform, or DMSO-d6 on a Varian Inova at 100.6 MHz 1H
and 13C NMR chemical shifts are reported in parts per million rel-
ative to the residual solvent peak in CDCl3 or in DMSO-d6. IR spectra
were recorded on a PerkineElmer FTIR Spectrum Bx. Elemental
analyses were recorded on a Carlo Erba EA 1108 elemental analyzer,
at the Centre CNR ICCOM, University of Bari. Melting points (un-
corrected) were determined on a Reichert Microscope.
4.2. General procedure for the synthesis of azides 3,5,7
4-Bromo-1-butyne 1 (1.2 equiv) and alkyl azide (1 equiv) were
added at room temperature to a solution (0.05e0.10 M) of
Cu(OAc)2$H2O (0.2 equiv) in H2O in a capped flask. The reaction
mixture was stirred at room temperature and, after completion
(1e6 h), was quenched with a saturated aqueous solution of NH4Cl
(30 mL) and extracted with ethyl acetate or CH2Cl2 (3ꢁ40 mL). The

V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
5257
organic extracts were washed with an aqueous solution of brine
(3ꢁ30 mL), dried over Na2SO4 and concentrated under vacuum. The
bromides 2,4,6 were purified by column chromatography on silica
gel and/or by crystallization. Sodium azide (1.2 equiv) was added to
a solution (0.4 M) of bromide (1 equiv) in DMF. The mixture was
warmed at 100 ꢀC and, after completion (3e4 h), was quenched
with a saturated aqueous solution of NH4Cl (30 mL) and extracted
with ethyl acetate or CH2Cl2 (3ꢁ40 mL). The organic extracts were
washed with an aqueous solution of NaCl (3ꢁ30 mL) and dried over
Na2SO4. After evaporation of the solvent at reduced pressure, pure
azides were isolated.
J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 144.0, 121.4, 50.6, 50.2, 31.6,
30.2, 28.9, 28.9, 26.4, 25.7, 22.5, 14.0; MS m/z 195 (2), 166 (3), 110
(3), 95 (4), 83 (7), 82 (6), 71 (16), 68 (14), 57 (51), 55 (28), 54 (31), 43
(89), 41 (100), 39 (29).
4.2.5. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-(2-bromoethyl)-
1H-1,2,3-triazole (4a). Compound 4a was prepared from 3a
(0.320 g, 1.40 mmol) and 4-bromo-1-butyne 1 (0.223 g, 1.68 mmol)
and the reaction was performed at room temperature in accordance
with general procedure. Purification by crystallization from CH2Cl2/
petroleum ether afforded 0.414 g of compound 4a (82% yield) as
a white solid, mp 160e161 ꢀC. [Found: C, 49.90; H, 4.78; N, 23.35.
C15H17BrN6 requires C, 49.87; H, 4.74; N, 23.26%.] nmax (KBr) 3133,
3074, 2952,1459,1448,1433, 1419, 1270,1207,1126, 1054, 1028, 821,
733, 710, 700; dH (400 MHz, CDCl3) 7.34e7.29 (m, 3H), 7.23 (s, 1H),
7.19e7.14 (m, 2H), 7.03 (s, 1H), 5.40 (s, 2H), 4.65 (t, J¼6.8 Hz, 2H),
3.53 (t, J¼6.8 Hz, 2H), 3.27 (t, J¼6.8 Hz, 2H), 3.15 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, CDCl3) 144.4, 143.4, 134.5, 129.0, 128.7, 127.9, 122.3,
121.9, 54.0, 49.3, 31.7, 29.2, 26.7.
4.2.1. 1-Benzyl-4-(2-bromoethyl)-1H-1,2,3-triazole (2a). Compound
2a was prepared from benzylazide (0.261 g, 1.96 mmol) and
4-bromo-1-butyne 1 (0.313 g, 2.35 mmol) and the reaction was
performed at room temperature in accordance with general pro-
cedure. Purification by column chromatography, Rf (silica gel, 30%
ethyl acetate/petroleum ether) 0.34, afforded 0.465 g of compound
2a (89% yield). After crystallization from ethyl acetate/petroleum
ether, compound 2a was obtained as a white solid, mp 78e79 ꢀC.
[Found: C, 49.70; H, 4.48; N, 15.70. C11H12BrN3 requires C, 49.64; H,
4.54; N, 15.79%.] nmax (KBr) 3130, 3067, 3032, 2952, 2921, 1455,
1449,1438,1262,1215,1205,1127, 1051, 815, 723, 696; dH (400 MHz,
CDCl3) 7.38e7.31 (m, 4H), 7.26e7.21 (m, 2H), 5.49 (s, 2H), 3.61 (t,
J¼6.8 Hz, 2H), 3.24 (t, J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 145.2,
134.6, 129.0, 128.6, 127.9, 121.6, 54.0, 31.4, 29.4; MS m/z 158 (1), 156
(1), 148 (1), 146 (1), 144 (1), 130(4), 104 (2), 91 (100), 65 (12), 51 (6).
4.2.6. 4-(2-Bromoethyl)-1-[2-(1-octyl-1H-1,2,3-triazol-4-yl)ethyl]-
1H-1,2,3-triazole (4b). Compound 4b was prepared from 3b
(0.250 g, 1.00 mmol) and 4-bromo-1-butyne (0.160 g, 1.20 mmol)
and the reaction was performed at room temperature in accordance
with general procedure. Purification by crystallization from ethyl
acetate/petroleum ether afforded 0.351 g of compound 4b (92%
yield) as a white solid, mp 104e105 ꢀC. [Found: C, 50.00; H, 7.08; N,
21.80. C16H27BrN6 requires C, 50.13; H, 7.10; N, 21.92%.] nmax (KBr)
3149, 3134, 3078, 2952, 2919, 2847, 1554, 1462, 1258, 1222, 1052,
1026, 827, 808; dH (400 MHz, CDCl3) 7.30 (s, 1H), 7.10 (s, 1H), 4.68 (t,
J¼6.4 Hz, 2H), 4.22 (t, J¼7.2 Hz, 2H), 3.59 (t, J¼6.6 Hz, 2H), 3.32 (t,
J¼6.4 Hz, 2H), 3.21 (t, J¼6.6 Hz, 2H),1.85e1.73 (m, 2H),1.35e1.15 (m,
10H), 0.83 (t, J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 144.5, 143.1,
122.5, 121.9, 50.3, 49.4, 31.8, 31.6, 30.2, 29.2, 29.0, 28.9, 26.7, 26.4,
22.5,14.0; MS m/z 273 (3), 245 (3),161 (7),147 (4),133 (13),106 (11),
96 (6), 82 (17), 80 (17), 71 (11), 68 (17), 57 (39), 55 (27), 54 (20), 53
(31), 43 (87), 41 (100).
4.2.2. 4-(2-Bromoethyl)-1-octyl-1H-1,2,3-triazole (2b). Compound
2b was prepared from n-octylazide (0.300 g, 1.93 mmol) and
4-bromo-1-butyne 1 (0.309 g, 2.32 mmol) and the reaction was
performed at room temperature in accordance with general pro-
cedure. Purification by crystallization from petroleum ether affor-
ded 0.536 g of compound 2b (96% yield) as a white solid, mp
37e38 ꢀC. [Found: C, 49.95; H, 7.58; N, 14.60. C12H22BrN3 requires C,
50.01; H, 7.69; N, 14.58%.] nmax (KBr) 3151, 2952, 2921, 2847, 1463,
1256, 1215, 1144, 1052, 916, 817; dH (400 MHz, CDCl3) 7.40 (s, 1H),
4.29 (t, J¼7.2 Hz, 2H), 3.61 (t, J¼6.8 Hz, 2H), 3.25 (t, J¼6.8 Hz, 2H),
1.90e1.80 (m, 2H), 1.35e1.15 (m, 10H), 0.83 (t, J¼6.8 Hz, 3H); dC
(100.6 MHz, CDCl3) 144.7, 121.4, 50.3, 31.6, 31.6, 30.2, 29.4, 29.0,
28.9, 26.4, 22.5, 14.0; MS m/z 273 (1), 271 (1), 232 (1), 230 (1), 204
(4), 202 (4), 140 (4), 96 (4), 82 (9), 80 (10), 71 (21), 57 (61), 55 (25),
54 (33), 43 (100), 41 (80).
4.2.7. 4-(2-Azidoethyl)-1-[2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl]-
1H-1,2,3-triazole (5a). Compound 5a was prepared from 4a
(0.400 g, 1.11 mmol) and sodium azide (0.087 g, 1.33 mmol). The
reaction was performed at 100 ꢀC accordance with general pro-
cedure leading to 0.305 g (85% yield) of azide 5a. After crystalli-
zation from ethyl acetate/petroleum ether, a white solid was
obtained, mp 103e104 ꢀC. [Found: C, 55.66; H, 5.40; N, 38.90.
C15H17N9 requires C, 55.72; H, 5.30; N, 38.99%.] nmax (KBr) 3132,
3069, 2960, 2108, 1458, 1449, 1439, 1261, 1209, 1124, 1096, 1054,
1030, 811, 734; dH (400 MHz, CDCl3) 7.34e7.30 (m, 3H), 7.22 (s, 1H),
7.19e7.15 (m, 2H), 7.06 (s, 1H), 5.41 (s, 2H), 4.65 (t, J¼6.8 Hz, 2H),
3.49 (t, J¼6.8 Hz, 2H), 3.27 (t, J¼6.8 Hz, 2H), 2.86 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, CDCl3) 143.7, 143.4, 134.5, 129.0, 128.7, 127.9, 122.3,
121.9, 54.0, 50.4, 49.2, 26.7, 25.5.
4.2.3. 4-(2-Azidoethyl)-1-benzyl-1H-1,2,3-triazole (3a). Compound
3a was prepared from 2a (0.460 g, 1.73 mmol) and sodium azide
(0.135 g, 2.08 mmol). The reaction was performed at 100 ꢀC in ac-
cordance with general procedure leading to 0.375 g (95% yield) of
azide 3a as a pale yellow oil. [Found: C, 57.91; H, 5.38; N, 36.95.
C11H12N6 requires C, 57.88; H, 5.30; N, 36.82%.] nmax (neat) 3135,
3060, 3032, 2935, 2873, 2099, 1668, 1451, 1296, 1260, 1219, 1128,
1053, 729; dH (400 MHz, CDCl3) 7.36e7.31 (m, 3H), 7.30 (s, 1H),
7.25e7.21 (m, 2H), 5.47 (s, 2H), 3.56 (t, J¼6.8 Hz, 2H), 2.94 (t,
J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 144.6, 134.6, 129.0, 128.6,
127.9,121.6, 54.0, 50.5, 25.7; MS m/z 200 (1),173 (8),144 (4),143 (3),
104 (4), 91 (100), 65 (23), 39 (21).
4.2.8. 4-(2-Azidoethyl)-1-[2-(1-octyl-1H-1,2,3-triazol-4-yl)ethyl]-
1H-1,2,3-triazole (5b). Product 5b was prepared from compound 4b
(0.340 g, 0.89 mmol) and sodium azide (0.070 g, 1.07 mmol). The
reaction was performed at 100 ꢀC in accordance with general
procedure leading to 0.298 g (97% yield) of azide 5b. After crys-
tallization from ethyl acetate/petroleum ether, a white solid was
obtained, mp 80e81 ꢀC. [Found: C, 55.66; H, 7.79; N, 36.55.
C16H27N9 requires C, 55.63; H, 7.88; N, 36.49%.] nmax (KBr) 3146,
3120, 3069, 2954, 2914, 2847, 2131, 1461, 1279, 1222, 1053, 1027,
810; dH (400 MHz, CDCl3) 7.26 (s, 1H), 7.11 (s, 1H), 4.63 (t, J¼6.8 Hz,
2H), 4.19 (t, J¼7.2 Hz, 2H), 3.50 (t, J¼6.8 Hz, 2H), 3.26 (t, J¼6.8 Hz,
2H), 2.86 (t, J¼6.8 Hz, 2H), 1.80e1.70 (m, 2H), 1.28e1.10 (m, 10H),
0.79 (t, J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 143.7, 142.9, 122.3,
4.2.4. 4-(2-Azidoethyl)-1-octyl-1H-1,2,3-triazole (3b). Compound
3b was prepared from 2b (0.525 g, 1.83 mmol) and sodium azide
(0.143 g, 2.20 mmol). The reaction was performed at 100 ꢀC in ac-
cordance with general procedure leading to 0.436 g (96% yield) of
azide 3b as a pale yellow oil. [Found: C, 57.61; H, 8.75; N, 33.50.
C12H22N6 requires C, 57.57; H, 8.86; N, 33.57%.] nmax (neat) 3136,
2927, 2856, 2099, 1458, 1374, 1290, 1258, 1217, 1054; dH (400 MHz,
CDCl3) 7.36 (s, 1H), 4.28 (t, J¼7.4 Hz, 2H), 3.57 (t, J¼6.8 Hz, 2H), 2.96
(t, J¼6.8 Hz, 2H), 1.89e1.80 (m 2H), 1.33e1.15 (m, 10H), 0.83 (t,

5258
V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
121.6, 50.4, 50.1, 49.2, 31.5, 30.1, 28.8, 28.7, 26.6, 26.2, 25.5, 22.4,
13.9.
122.3, 122.2, 121.6, 50.4, 50.1, 49.2, 49.1, 31.5, 30.1, 28.8, 28.7, 26.5,
26.5, 26.2, 25.5, 22.4, 13.9 (one coincident peak not observed).
4.2.9. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-{2-[4-(2-
bromoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-1H-1,2,3-triazole
(6a). Compound 6a was prepared from 5a (0.295 g, 0.91 mmol)
and 4-bromo-1-butyne 1 (0.195 g, 1.09 mmol) and the reaction
was performed at room temperature in accordance with general
procedure. Purification by crystallization from CH2Cl2/petroleum
ether afforded 0.312 g of compound 6a (75% yield) as a white solid,
mp 183e184 ꢀC (CH2Cl2/ethyl acetate). [Found: C, 49.95; H, 4.78;
N, 27.70. C19H22BrN9 requires C, 50.01; H, 4.86; N, 27.62%.] nmax
(KBr) 3126, 3074, 2951, 2922, 1458, 1448, 1435, 1261, 1211, 1226,
1055, 1026, 837, 820, 805, 739, 716, 698; dH (400 MHz, DMSO-d6)
7.91 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.40e7.28 (m, 3H), 7.27e7.21
(m, 2H), 5.55 (s, 2H), 4.66e4.55 (m, 4H), 3.71 (t, J¼6.8 Hz, 2H),
3.21e3.12 (m, 6H); dC (100.6 MHz, DMSO-d6) 143.8, 143.0, 142.5,
136.0, 128.6, 127.9, 127.6, 122.7, 122.6, 122.5, 52.6, 48.7, 48.6, 32.6,
28.8, 26.2, 26.1.
4.3. General procedure for the synthesis of compounds 9
Alkyne (1.2 equiv) and azide (1 equiv) were added at room
temperature to
a solution (0.02e0.04 M) of Cu(OAc)2$H2O
(0.2 equiv) in H2O in a capped flask. The mixture was warmed at
100 ꢀC and, after completion (1e2 h), was quenched with a satu-
rated aqueous solution of NH4Cl (30 mL) and extracted with ethyl
acetate or CH2Cl2 or CHCl3 (3ꢁ40 mL). The organic extracts were
washed with an aqueous solution of NaCl (3ꢁ30 mL), dried over
Na2SO4 and concentrated under vacuum. The residue was purified
by column chromatography on silica gel and/or by crystallization.
4.3.1. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-octyl-1H-1,2,3-
triazole (9a). Compound 9a was prepared from 3a (0.200 g,
0.88 mmol) and 1-decyne (0.146 g, 1.06 mmol) and the reaction was
performed at 100 ꢀC in accordance with general procedure. Puri-
fication by crystallization from ethyl acetate afforded 0.251 g of
compound 9a (78% yield) as a white solid, mp 126e127 ꢀC. [Found:
C, 68.91; H, 8.30; N, 23.00. C21H30N6 requires C, 68.82; H, 8.25; N,
22.93%.] nmax (KBr) 3111, 3063, 2950, 2917, 2849, 1466, 1457, 1436,
1221, 1214, 1051, 1028, 720, 694; dH (400 MHz, DMSO-d6) 7.83 (s,
1H), 7.74 (s, 1H), 7.39e7.29 (m, 3H), 7.26e7.20 (m, 2H), 5.54 (s, 2H),
4.58 (t, J¼7.2 Hz, 2H), 3.20 (t, J¼7.2 Hz, 2H), 2.54 (t, J¼7.6 Hz, 2H),
1.58e1.48 (m, 2H), 1.32e1.18 (m, 10H), 0.85 (t, J¼6.8 Hz, 3H); dC
(100.6 MHz, DMSO-d6) 146.6, 143.1, 136.0, 128.5, 127.8, 127.5, 122.7,
121.6, 52.5, 48.4, 31.1, 28.8, 28.6, 28.5, 28.4, 26.1, 24.9, 21.9, 13.8; MS
m/z 268 (3), 187 (8), 173 (9), 110 (5), 97 (9), 96 (11), 91 (100), 65 (9),
55 (7), 41 (27), 39 (10).
4.2.10. 4-{2-[4-(2-Bromoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-1-[2-(1-
octyl-1H-1,2,3-triazol-4-yl)ethyl]-1H-1,2,3-triazole (6b). Compound
6b was prepared from 5b (0.299 g, 0.87 mmol) and 4-bromo-1-
butyne 1 (0.138 g, 1.04 mmol) and the reaction was performed at
room temperature in accordance with general procedure. Purifi-
cation by crystallization from ethyl acetate afforded 0.394 g of
compound 6b (95% yield) as a white solid, mp 174e175 ꢀC. [Found:
C, 50.11; H, 6.78; N, 26.40. C20H32BrN9 requires C, 50.21; H, 6.74; N,
26.35%.] nmax (KBr) 3145, 3116, 3071, 2954, 2919, 2849, 1462, 1453,
1259, 1216, 1055, 1034, 814, 805; dH (400 MHz, CDCl3) 7.32 (s, 1H),
7.14 (s, 1H), 7.07 (s, 1H), 4.68e4.54 (m, 4H), 4.23 (t, J¼7.2 Hz, 2H),
3.56 (t, J¼6.8 Hz, 2H), 3.28e3.12 (m, 6H), 1.84e1.70 (m, 2H),
1.30e1.10 (m, 10H), 0.79 (t, J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3)
144.5, 142.8, 122.4, 122.2, 121.6, 50.2, 49.3, 49.2, 31.7, 31.5, 30.1, 29.2,
28.9, 28.8, 26.6, 26.6, 26.3, 22.4, 13.9 (one coincident peak not
observed).
4.3.2. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-phenyl-1H-
1,2,3-triazole (9b). Compound 9b was prepared from 3a (0.100 g,
0.44 mmol) and phenylacetylene (0.053 g, 0.53 mmol) and the
reaction was performed at 100 ꢀC and extracted with ethyl acetate
in accordance with general procedure. Purification by column
chromatography, Rf (silica gel, 10% petroleum ether/ethyl acetate)
0.36, afforded 0.090 g of compound 9b (62% yield). After crystalli-
zation from ethyl acetate/petroleum ether, compound 9b was
obtained as a white solid, mp 186e187 ꢀC. [Found: C, 68.98; H, 5.44;
N, 25.40. C19H18N6 requires C, 69.07; H, 5.49; N, 25.44%.] nmax (KBr)
3130, 3109, 3080, 3028, 2965, 2933, 1458, 1437, 1218, 1210, 1199,
1128, 1089, 1052, 863, 811, 761, 725, 697, 688; dH (400 MHz, DMSO-
d6) 8.50 (s, 1H), 7.89 (s, 1H), 7.79 (d, J¼7.2 Hz, 2H), 7.48e7.40 (m,
2H), 7.37e7.25 (m, 4H), 7.24e7.16 (m, 2H), 5.54 (s, 2H), 4.70 (t,
J¼7.2 Hz, 2H), 3.29 (t, J¼7.2 Hz, 2H); dC (100.6 MHz, DMSO-d6) 146.0,
142.9, 136.0, 130.7, 128.7, 128.5, 127.8, 127.6, 127.5, 125.0, 122.9,
121.3, 52.5, 48.8, 26.0; MS m/z 246 (6), 183 (6), 173 (5), 156 (5), 130
(8), 116 (6), 103 (11), 91 (100), 77 (11), 65 (13), 39 (16).
4.2.11. 4-{2-[4-(2-Azidoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-1-[2-(1-
benzyl-1H-1, 2, 3-triazol-4-yl)ethyl]-1H-1, 2, 3-triazole
(7a). Compound 7a was prepared from 6a (0.310 g, 0.68 mmol) and
sodium azide (0.053 g, 0.82 mmol). The reaction was performed at
100 ꢀC in accordance with general procedure leading to 0.250 g
(88% yield) of azide 7a. After crystallization from ethyl acetate/
petroleum ether, a white solid was obtained, mp 176e177 ꢀC.
[Found: C, 54.49; H, 5.37; N, 40.25. C19H22N12 requires C, 54.53; H,
5.30; N, 40.17%.] nmax (KBr) 3129, 3073, 2923, 2850, 2103, 1547,
1449, 1435, 1261, 1210, 1125, 1056, 1029, 836, 810, 739, 718, 697; dH
(400 MHz, DMSO-d6) 7.89 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.40e7.28
(m, 3H), 7.27e7.21 (m, 2H), 5.55 (s, 2H), 4.62e4.54 (m, 4H), 3.58 (t,
J¼6.8 Hz, 2H), 3.22e3.12 (m, 4H), 2.88 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, DMSO-d6) 143.3, 143.0, 142.5, 136.0, 128.6, 127.9, 127.6,
122.7, 122.6, 122.5, 52.6, 49.8, 48.6, 48.6, 26.2, 26.1, 24.9.
4.3.3. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-p-tolyl-1H-1,2,3-
triazole (9c). Compound 9c was prepared from 3a (0.200 g,
0.88 mmol) and p-tolylacetylene (0.123 g, 1.06 mmol) and the re-
action was performed at 100 ꢀC in accordance with general pro-
cedure. Purification by column chromatography, Rf (silica gel, 10%
petroleum ether/ethyl acetate) 0.44, afforded 0.194 g of compound
9c (64% yield). After crystallization from ethyl acetate/petroleum
ether, compound 9c was obtained as a white solid, mp 170e171 ꢀC.
[Found: C, 69.88; H, 5.84; N, 24.45. C20H20N6 requires C, 69.75; H,
5.85; N, 24.40%.] nmax (KBr) 3129, 3087, 3060, 3046, 3032, 2972,
2933, 1458, 1437, 1216, 1197, 1129, 1088, 1052, 817, 724, 697; dH
(400 MHz, CDCl3) 7.60 (d, J¼8.4 Hz, 2H), 7.52 (s, 1H), 7.26e7.15 (m,
5H), 7.13e7.08 (m, 2H), 7.06 (s, 1H), 5.39 (s, 2H), 4.71 (t, J¼6.8 Hz,
2H), 3.31 (t, J¼6.8 Hz, 2H), 2.34 (s, 3H); dC (100.6 MHz, CDCl3) 147.4,
143.4, 137.9, 134.4, 129.4, 129.0, 128.6, 127.7, 127.6, 125.5, 122.0,
4.2.12. 4-{2-[4-(2-Azidoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-1-[2-(1-
octyl-1H-1,2,3-triazol-4-yl)ethyl]-1H-1,2,3-triazole (7b). Product 7b
was prepared from compound 6b (0.218 g, 0.46 mmol) and sodium
azide (0.036 g, 0.55 mmol). The reaction was performed at 100 ꢀC in
accordance with general procedure leading to 0.175 g (86% yield) of
azide 7b. After crystallization from ethyl acetate a white solid was
obtained, mp 158e159 ꢀC. [Found: C, 54.49; H, 7.37; N, 38.20.
C20H32N12 requires C, 54.53; H, 7.32; N, 38.15%.] nmax (KBr) 3145,
3120, 3069, 2954, 2923, 2848, 2110, 1458, 1450, 1261, 1217, 1055,
1031, 806; dH (400 MHz, CDCl3) 7.30 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H),
4.65e4.55 (m, 4H), 4.22 (t, J¼7.2 Hz, 2H), 3.50 (t, J¼6.8 Hz, 2H), 3.21
(t, J¼6.8 Hz, 4H), 2.88 (t, J¼6.8 Hz, 2H), 1.80e1.72 (m, 2H), 1.28e1.10
(m, 10H), 0.78 (t, J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 143.8, 142.7,

V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
5259
119.9, 54.0, 49.3, 26.7, 21.2; MS m/z 260 (6), 197 (6), 144 (6), 130 (7),
115 (12), 103 (4), 91 (100), 77 (5), 65 (11), 39 (10).
1469, 1420, 1216, 1202, 1055, 1048, 788; dH (400 MHz, CDCl3) 8.48
(d, J¼3.6 Hz, 1H), 8.05 (d, J¼7.8 Hz, 1H), 7.96 (s, 1H), 7.69 (t, J¼7.8 Hz,
1H), 7.19e7.10 (m, 2H), 4.72 (t, J¼6.8 Hz, 2H), 4.18 (t, J¼7.2 Hz, 2H),
3.34 (t, J¼6.8 Hz, 2H), 1.79e1.68 (m, 2H), 1.25e1.08 (m, 10H), 0.79 (t,
J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 150.0, 149.2, 148.0, 142.7,
136.6, 122.6, 122.4, 121.6, 119.9, 50.1, 49.5, 31.5, 30.0, 28.8, 28.7, 26.6,
26.2, 22.4, 13.9; MS m/z 209 (7), 198 (6), 184 (11), 171 (17), 169 (9),
158 (7), 157 (7), 131 (57), 118 (9), 104 (20), 82 (17), 78 (27), 68 (16),
57 (35), 55 (30), 43 (82), 41 (100), 39 (23).
4.3.4. 1-[2-(1-Octyl-1H-1,2,3-triazol-4-yl)ethyl]-4-pentyl-1H-1,2,3-
triazole (9d). Compound 9d was prepared from 3b (0.200 g,
0.80 mmol) and 1-heptyne (0.092 g, 0.96 mmol) and the reaction
was performed at 100 ꢀC in accordance with general procedure.
Purification by crystallization from ethyl acetate/petroleum ether
afforded 0.197 g of compound 9d (71% yield) as a white solid, mp
97e98 ꢀC. [Found: C, 65.88; H, 9.84; N, 24.35. C19H34N6 requires C,
65.86; H, 9.89; N, 24.25%.] nmax (KBr) 3146, 3114, 3065, 2954, 2925,
2848, 1459, 1220, 1217, 1052, 1029; dH (400 MHz, DMSO-d6) 7.75 (s,
1H), 7.74 (s, 1H), 4.58 (t, J¼7.2 Hz, 2H), 4.26 (t, J¼7.2 Hz, 2H), 3.19 (t,
J¼7.2 Hz, 2H), 2.55 (t, J¼7.6 Hz, 2H), 1.79e1.68 (m, 2H), 1.59e1.50
(m, 2H), 1.35e1.10 (m, 14H), 0.90e0.81 (m, 6H); dC (100.6 MHz,
DMSO-d6) 146.5, 142.6, 122.3, 121.6, 49.1, 48.5, 31.1, 30.7, 29.6, 28.5,
28.4, 28.2, 26.1, 25.6, 24.8, 21.9, 21.7, 13.8, 13.7; MS m/z 261 (3), 208
(3), 180 (4), 177 (3), 149 (4), 124 (43), 110 (14), 97 (10), 96 (10), 95
(10), 82 (17), 68 (19), 57 (29), 55 (31), 43 (72), 41 (100), 39 (19).
4.3.8. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-[2-(4-phenyl-
1H-1,2,3-triazol-1-yl)ethyl]-1H-1,2,3-triazole (9h). Compound 9h
was prepared from 5a (0.150 g, 0.46 mmol) and phenylacetylene
(0.056 g, 0.55 mmol) and the reaction was performed at 100 ꢀC in
accordance with general procedure. Purification by column chro-
matography, Rf (silica gel, 2% CH3OH/CH2Cl2) 0.24, afforded 0.170 g
of compound 9h (87% yield). After crystallization from CH2Cl2/pe-
troleum ether, compound 9h was obtained as a white solid, mp
193e195 ꢀC. [Found: C, 64.85; H, 5.50; N, 29.73. C23H23N9 requires
C, 64.92; H, 5.45; N, 29.63%.] nmax (KBr) 3144, 3118, 3082, 3069,
2956, 2927, 1457, 1449, 1438, 1222, 1207, 1054, 1048, 1028, 763, 735,
694; dH (400 MHz, DMSO-d6) 8.56 (s, 1H), 7.85e7.80 (m, 3H), 7.77 (s,
1H), 7.47e7.41 (m, 2H), 7.39e7.29 (m, 4H), 7.26e7.22 (m, 2H), 5.54
(s, 2H), 4.66 (t, J¼7.2 Hz, 2H), 4.59 (t, J¼7.2 Hz, 2H), 3.25 (t, J¼7.2 Hz,
2H), 3.17 (t, J¼7.2 Hz, 2H); dC (100.6 MHz, DMSO-d6) 146.1, 143.0,
142.5, 136.0, 130.7, 128.8, 128.6, 127.9, 127.7, 127.6, 125.0, 122.7,
122.6, 121.3, 52.5, 49.0, 48.6, 26.1, 26.0.
4.3.5. 1-[2-(1-Octyl-1H-1,2,3-triazol-4-yl)ethyl]-4-phenyl-1H-1,2,3-
triazole (9e). Compound 9e was prepared from 3b (0.200 g,
0.80 mmol) and phenylacetylene (0.098 g, 0.96 mmol) and the
reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography, Rf (silica gel, 2%
CH3OH/CH2Cl2) 0.29, afforded 0.262 g of compound 9e (93% yield).
After crystallization from ethyl acetate, compound 9e was obtained
as a white solid, mp 135e136 ꢀC. [Found: C, 68.28; H, 7.94; N, 23.80.
C20H28N6 requires C, 68.15; H, 8.01; N, 23.84%.] nmax (KBr) 3140,
3107, 3082, 2953, 2921, 2846, 1464, 1449, 1222, 1196, 1081, 1048,
1026, 837, 762, 694; dH (400 MHz, CDCl3) 7.74e7.69 (m, 2H), 7.61 (s,
1H), 7.36e7.31 (m, 2H), 7.28e7.22 (m, 1H), 7.11 (s, 1H), 4.72 (t,
J¼6.8 Hz, 2H), 4.18 (t, J¼7.4 Hz, 2H), 3.33 (t, J¼6.8 Hz, 2H), 1.78e1.66
(m, 2H), 1.25e1.10 (m, 10H), 0.80 (t, J¼6.8 Hz, 3H); dC (100.6 MHz,
CDCl3) 147.2, 142.8, 130.4, 128.7, 128.0, 125.4, 121.8, 120.3, 50.1, 49.3,
31.5, 30.1, 28.8, 28.7, 26.6, 26.2, 22.4, 13.9; MS m/z 295 (4), 268 (5),
197 (8),180 (6),156 (7),130 (8),116 (7),103 (13),102 (11), 82 (18), 68
(17), 57 (41), 55 (29), 43 (91), 41 (100), 39 (20).
4.3.9. 1-[2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl]-4-{2-[4-(thiophen-
3-yl)-1H-1,2,3-triazol-1-yl]ethyl}-1H-1,2,3-triazole (9i). Compound
9i was prepared from 5a (0.145 g, 0.45 mmol) and 3-
ethynylthiophene (0.058 g, 0.54 mmol) and the reaction was per-
formed at 100 ꢀC in accordance with general procedure. Purification
by crystallization from CHCl3/petroleum ether afforded 0.175 g of
compound 9i (90% yield) as a white solid, mp 186e187 ꢀC. [Found: C,
58.60; H, 4.98; N, 29.33; S, 7.38. C21H21N9S requires C, 58.45; H, 4.91;
N, 29.21; S, 7.43%.] nmax (KBr) 3129, 3087, 3062, 2922, 2850, 1458,
1447, 1220, 1056, 1028, 830, 785, 732; dH (400 MHz, DMSO-d6) 8.40
(s, 1H), 7.84e7.80 (m, 2H), 7.77 (s, 1H), 7.63 (dd, J¼4.8, 2.8 Hz, 1H),
7.49 (d, J¼4.8 Hz, 1H), 7.39e7.28 (m, 3H), 7.26e7.21 (m, 2H), 5.54 (s,
2H), 4.65 (t, J¼7.0 Hz, 2H), 4.59 (t, J¼7.0 Hz, 2H), 3.23 (t, J¼7.0 Hz, 2H),
3.18 (t, J¼7.0 Hz, 2H); dC (100.6 MHz, DMSO-d6) 143.0, 142.6, 142.5,
136.0,132.0,128.6,127.9,127.6,126.9,125.6,122.7,122.6,121.0,120.6,
52.5, 48.9, 48.6, 26.1, 26.1.
4.3.6. 4-(4-Methoxyphenyl)-1-[2-(1-octyl-1H-1,2,3-triazol-4-yl)
ethyl]-1H-1,2,3-triazole (9f). Compound 9f was prepared from 3b
(0.200 g, 0.80 mmol) and p-methoxyphenylacetylene (0.127 g,
0.96 mmol) and the reaction was performed at 100 ꢀC in accordance
with general procedure. Purification by column chromatography, Rf
(silica gel, 2% CH3OH/CH2Cl2) 0.34, afforded 0.281 g of compound 9f
(92% yield). After crystallization from ethyl acetate, compound 9f
was obtained as a white solid, mp 157e158 ꢀC. [Found: C, 66.00; H,
7.94; N, 21.88. C21H30N6O requires C, 65.94; H, 7.91; N, 21.97%.] nmax
(KBr) 3140, 3088, 2953, 2919, 2846, 1620, 1561, 1502, 1462, 1442,
1253, 1221, 1030, 823; dH (400 MHz, CDCl3) 7.64 (d, J¼8.6 Hz, 2H),
7.51 (s, 1H), 7.12 (s, 1H), 6.87 (d, J¼8.6 Hz, 2H), 4.70 (t, J¼6.8 Hz, 2H),
4.19 (t, J¼7.2 Hz, 2H), 3.77 (s, 3H), 3.32 (t, J¼6.8 Hz, 2H), 1.79e1.68
(m, 2H), 1.16e1.10 (m, 10H), 0.81 (t, J¼6.8 Hz, 3H); dC (100.6 MHz,
CDCl3) 159.5, 147.2, 143.0, 126.8, 123.2, 121.9, 119.5, 114.1, 55.2, 50.2,
49.3, 31.6, 30.1, 28.9, 28.7, 26.6, 26.3, 22.4, 13.9.
4.3.10. 1-[2-(1-Octyl-1H-1,2,3-triazol-4-yl)ethyl]-4-[2-(4-phenyl-
1H-1,2,3-triazol-1-yl)ethyl]-1H-1,2,3-triazole (9j). Compound 9j
was prepared from 5b (0.150 g, 0.435 mmol) and phenylacetylene
(0.053 g, 0.52 mmol) and the reaction was performed at 100 ꢀC in
accordance with general procedure. Purification by column chro-
matography, Rf (silica gel, 4% CH3OH/CH2Cl2) 0.31, afforded 0.130 g
of compound 9j (67% yield). After crystallization from ethyl acetate,
compound 9j was obtained as a white solid, mp 180e181 ꢀC.
[Found: C, 64.50; H, 7.50; N, 28.28. C24H33N9 requires C, 64.40; H,
7.43; N, 28.16%.] nmax (KBr) 3138, 3132, 3081, 2954, 2919, 2847,1462,
1445,1224,1048,1026, 762, 694; dH (400 MHz, CDCl3) 7.76e7.71 (m,
2H), 7.67 (s, 1H), 7.40e7.32 (m, 2H), 7.30e7.24 (m, 1H), 7.08 (s, 1H),
7.00 (s, 1H), 4.72 (t, J¼6.8 Hz, 2H), 4.60 (t, J¼6.8 Hz, 2H), 4.18 (t,
J¼7.2 Hz, 2H), 3.28 (t, J¼6.8 Hz, 2H), 3.19 (t, J¼6.8 Hz, 2H), 1.80e1.68
(m, 2H), 1.30e1.12 (m, 10H), 0.82 (t, J¼6.8 Hz, 3H); dC (100.6 MHz,
CDCl3) 147.3, 142.8, 130.5, 128.8, 128.1, 125.5, 122.5, 121.7, 120.2,
50.2, 49.4, 49.2, 31.6, 30.2, 28.9, 28.8, 26.7, 26.6, 26.3, 22.5, 14.0 (one
coincident peak not observed).
4.3.7. 2-{1-[2-(1-Octyl-1H-1,2,3-triazol-4-yl)ethyl]-1H-1,2,3-triazol-
4-yl}pyridine (9g). Compound 9g was prepared from 3b (0.200 g,
0.80 mmol) and 2-ethynylpyridine (0.099 g, 0.96 mmol) and the
reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography, Rf (silica gel, 3%
CH3OH/CH2Cl2) 0.21, afforded 0.248 g of compound 9g (88% yield).
After crystallization from ethyl acetate/petroleum ether, compound
9g was obtained as a pale brown solid, mp 115e116 ꢀC. [Found: C,
64.60; H, 7.74; N, 27.83. C19H27N7 requires C, 64.56; H, 7.70; N,
27.74%.] nmax (KBr) 3121, 3104, 3082, 2953, 2919, 2850, 1604, 1595,
4.3.11. 1-[2-(1-Octyl-1H-1,2,3-triazol-4-yl)ethyl]-4-[2-(4-pentyl-1H-
1,2,3-triazol-1-yl)ethyl]-1H-1,2,3-triazole (9k). Compound 9k was

5260
V. Fiandanese et al. / Tetrahedron 67 (2011) 5254e5260
prepared from 5b (0.150 g, 0.435 mmol) and 1-heptyne (0.050 g,
0.52 mmol) and the reaction was performed at 100 ꢀC and extracted
with CH2Cl2 in accordance with general procedure. Purification by
crystallization from ethyl acetate afforded 0.159 g of compound 9k
(83% yield) as a white solid, mp 165e166 ꢀC. [Found: C, 62.50; H,
8.80; N, 28.48. C23H39N9 requires C, 62.55; H, 8.90; N, 28.55%.] nmax
(KBr) 3141, 3074, 2955, 2923, 2852, 1549, 1463, 1450, 1212, 1056,
1028, 838, 812; dH (400 MHz, CDCl3) 7.15 (s, 1H), 7.11 (s, 1H), 7.08 (s,
1H), 4.60e4.51 (m, 4H), 4.21 (t, J¼6.8 Hz, 2H), 3.25e3.15 (m, 4H),
2.55 (t, J¼7.4 Hz, 2H), 1.85e1.70 (m, 2H), 1.60e1.45 (m, 2H),
1.30e1.05 (m, 14H), 0.85e0.70 (m, 6H); dC (100.6 MHz, CDCl3) 148.1,
142.9, 142.8, 122.2, 121.6, 120.9, 50.1, 49.2, 48.9, 31.5, 31.2, 30.0, 28.9,
28.8, 28.7, 26.5, 26.5, 26.2, 25.4, 22.3, 22.3, 13.8, 13.7.
References and notes
1. (a) Huisgen, R. Pure Appl. Chem. 1989, 61, 613e628; (b) Huisgen, R. In 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, NY, 1984; pp 1e176.
2. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40,
2004e2021; (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596e2599.
3. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057e3064.
4. For detailes on the CuAAC mechanism, see: (a) Buckley, B. R.; Dann, S. E.;
Heaney, H. Chem.dEur. J. 2010, 16, 6278e6284; (b) Hein, J. E.; Fokin, V. V. Chem.
Soc. Rev. 2010, 39, 1302e1315; (c) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.
V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127,
210e216; (d) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2210e2215.
5. Selected reviews: (a) Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem. Rev. 2009, 109,
4207e4220; (b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952e3015; (c)
ꢁ
ꢁ
ꢁ
Gil, M. V.; Arevalo, M. J.; Lopez, O Synthesis 2007, 1589e1620; (d) Angell, Y. L.;
Burgess, K. Chem. Soc. Rev. 2007, 36, 1674e1689; (e) Moses, J. E.; Moorhouse, A.
D. Chem. Soc. Rev. 2007, 36, 1249e1262.
4.3.12. 1-(2-(1-Benzyl-1H-1,2,3-triazol-4-yl)ethyl)-4-(2-(4-(2-(4-
phenyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)ethyl)-1H-
1,2,3-triazole (9l). Compound 9l was prepared from 7a (0.150 g,
0.36 mmol) and phenylacetylene (0.044 g, 0.43 mmol) and the
reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography, Rf (silica gel,
2% CH3OH/CH2Cl2) 0.14, afforded 0.094 g of compound 9l (50%
yield). After crystallization from CH2Cl2/petroleum ether, com-
pound 9l was obtained as a white solid, mp 227e228 ꢀC.; [Found:
C, 62.35; H, 5.40; N, 32.35. C27H28N12 requires C, 62.29; H, 5.42; N,
32.29%.] nmax (KBr) 3119, 3085, 3066, 2950, 1449, 1438, 1211, 1125,
1054, 1028, 848, 838, 762, 738, 694; dH (400 MHz, DMSO-d6) 8.55
(s, 1H), 7.84e7.78 (m, 4H), 7.70 (s, 1H), 7.46e7.40 (m, 2H),
7.37e7.27 (m, 4H), 7.26e7.21 (m, 2H), 5.55 (s, 2H), 4.68 (t, J¼7.2 Hz,
2H), 4.57 (t, J¼7.2 Hz, 2H), 4.54 (t, J¼7.2 Hz, 2H), 3.26 (t, J¼7.2 Hz,
2H), 3.17 (t, J¼7.2 Hz, 2H), 3.12 (t, J¼7.2 Hz, 2H); dC (100.6 MHz,
DMSO-d6) 146.1, 143.0, 142.6, 142.5, 136.0, 130.7, 128.7, 128.6, 127.9,
127.7, 127.6, 125.0, 122.7, 122.6, 122.5, 121.3, 52.5, 49.0, 48.7, 48.6,
26.2, 26.1, 26.0.
6. (a) Xu, M.; Kuang, C.; Wang, Z.; Yang, Q.; Jiang, Y. Synthesis 2011, 223e228; (b)
ꢁ
ꢁ
Vala, C.; Chretien, F.; Balentova, E.; Lamande-Langle, S.; Chapleur, Y. Tetrahedron
Lett. 2011, 52, 17e20; (c) Friscourt, F.; Boons, G.-J. Org. Lett. 2010, 12,
4936e4939; (d) James, D.; Escudier, J.-M.; Amigues, E.; Schulz, J.; Vitry, C.;
Bordenave, T.; Slozek-Pinaud, M.; Fouquet, E. Tetrahedron Lett. 2010, 51,
1230e1232; (e) Montagnat, O. D.; Lessene, G.; Hughes, A. B. J. Org. Chem. 2010,
75, 390e398; (f) Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. J. Org. Chem.
2010, 75, 7002e7005; (g) Cravotto, G.; Fokin, V. V.; Garella, D.; Binello, A.; Boffa,
L.; Barge, A. J. Comb. Chem. 2010, 12, 13e15; (h) Jurícek, M.; Kouwer, P. H. J.;
ꢁ
Rehak, J.; Sly, J.; Rowan, A. E. J. Org. Chem. 2009, 74, 21e25; (i) Xia, Y.; Liu, Y.;
Wan, J.; Wang, M.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. J. Med. Chem. 2009,
ꢁ
52, 6083e6096; (j) Broggi, J.; Díez-Gonzalez, S.; Petersen, J. L.; Berteina-Raboin,
S.; Nolan, S. P.; Agrofoglio, L. A. Synthesis 2008, 141e148; (k) Li, P.; Wang, L.;
Zhang, Y. Tetrahedron 2008, 64, 10825e10830; (l) Jlalia, I.; Elamari, H.; Mega-
nem, F.; Herscovici, J.; Girard, C. Tetrahedron Lett. 2008, 49, 6756e6758; (m)
Wang, Z.-X.; Zhao, Z.-G. J. Heterocycl. Chem. 2007, 44, 89e92; (n) Chassaing, S.;
Kumarraja, M.; Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 883e886; (o)
Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S.
Angew. Chem., Int. Ed. 2007, 46, 1730e1733; (p) Bertrand, P.; Gesson, J. P. J. Org.
Chem. 2007, 72, 3596e3599.
7. (a) Song, Z.; He, X.-P.; Jin, X.-P.; Gao, L.-X.; Sheng, L.; Zhou, Y.-B.; Li, J.; Chen, G.-
R. Tetrahedron Lett. 2011, 52, 894e898; (b) Zeng, Q.; Saha, S.; Lee, L. A.; Barnhill,
H.; Oxsher, J.; Dreher, T.; Wang, Q. Bioconjugate Chem. 2011, 22, 58e66; (c)
~
Aragao-Leoneti, V.; Campo, V. L.; Gomes, A. S.; Field, R. A.; Carvalho, I. Tetra-
hedron 2010, 9475e9492; (d) Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010,
39, 1325e1337; (e) Mamidyala, S. K.; Finn, M. G. Chem. Soc. Rev. 2010, 39,
1252e1261; (f) El-Sagheer, A. H.; Brown, T. Chem. Soc. Rev. 2010, 39, 1388e1405;
(g) Jiang, X.; Lok, M. C.; Hennink, W. E. Bioconjugate Chem. 2007, 18, 2077e2084;
(h) Lin, P.-C.; Ueng, S.-H.; Tseng, M.-C.; Ko, J.-L.; Huang, K.-T.; Yu, S.-C.; Adak, A.
K.; Chen, Y.-J.; Lin, C.-C. Angew. Chem., Int. Ed. 2006, 45, 4286e4290.
8. (a) Franc, G.; Kakkar, A. K. Chem. Soc. Rev. 2010, 39, 1536e1544; (b) Qin, A.; Lam,
J. W. Y.; Tang, B. Z. Chem. Soc. Rev. 2010, 39, 2522e2544; (c) Johnson, J. A.; Finn,
M. G.; Koberstein, J. T.; Turro, N. J. Macromolecules 2007, 40, 3589e3598; (d)
Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018e1025; (e) Ornelas, C.; Aranzaes,
J. R.; Cloutet, E.; Alves, S.; Astruc, D. Angew. Chem., Int. Ed. 2007, 46, 872e877.
9. (a) He, R.; Yu, Z.; He, Y.; Zeng, L.-F.; Xu, J.; Wu, L.; Gunawan, A. M.; Wang, L.;
Jiang, Z.-X.; Zhang, Z.-Y. ChemMedChem 2010, 5, 2051e2056; (b) Colombo, M.;
Peretto, I. Drug Discovery Today 2008, 13, 677e684; (c) Moorhouse, A. D.; Moses,
J. E. ChemMedChem 2008, 3, 715e723; (d) Tron, G. C.; Pirali, T.; Billington, R. A.;
Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res. Rev. 2008, 28, 278e308; (e)
Moorhouse, A. D.; Santos, A. M.; Gunaratman, M.; Moore, M.; Neidle, S.; Moses,
J. E. J. Am. Chem. Soc. 2006, 128, 15972e15973.
10. (a) Angelo, N. G.; Arora, P. S. J. Org. Chem. 2007, 72, 7963e7967; (b) Zhang, Z.;
Fan, E. Tetrahedron Lett. 2006, 47, 665e669; (c) Angelo, N. G.; Arora, P. S. J. Am.
Chem. Soc. 2005, 127, 17134e17135.
11. (a) Pourceau, G.; Meyer, A.; Vasseur, J. J.; Morvan, F. J. Org. Chem. 2009, 74,
1218e1222; (b) Lucas, R.; Zerrouki, R.; Granet, R.; Krausz, P.; Champavier, Y.
Tetrahedron 2008, 64, 5467e5471; (c) Nuzzi, A.; Massi, A.; Dondoni, A. QSAR
Comb. Sci. 2007, 26, 1191e1199.
12. (a) Valverde, I. E.; Delmas, A. F.; Aucagne, V. Tetrahedron 2009, 65, 7597e7602;
(b) Montagnat, O. D.; Lessene, G.; Hughes, A. B. Tetrahedron Lett. 2006, 47,
6971e6974.
4.3.13. 4-(2-(4-(2-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)
ethyl)-1H-1,2,3-triazol-1-yl)ethyl)-1-(2-(1-octyl-1H-1,2,3-triazol-4-
yl)ethyl)-1H-1,2,3-triazole (9m). Compound 9m was prepared from
7b (0.175 g, 0.40 mmol) and p-methoxyphenylacetylene (0.063 g,
0.48 mmol) and the reaction was performed at 100 ꢀC and extracted
with CH2Cl2 in accordance with general procedure. Purification by
column chromatography, Rf (silica gel, 5% CH3OH/CH2Cl2) 0.31,
afforded 0.165 g of compound 9m (72% yield). After crystallization
from CH2Cl2/petroleum ether, compound 9m was obtained as
a white solid, mp 239e240 ꢀC. [Found: C, 60.90; H, 7.15; N, 29.45.
C29H40N12O requires C, 60.82; H, 7.04; N, 29.35%.] nmax (KBr) 3144,
3119, 3089, 3064, 2953, 2923, 2849, 1459, 1448, 1251, 1220, 1207,
1053, 1033, 826; dH (400 MHz, DMSO-d6, 70 ꢀC) 8.34 (s, 1H), 7.78 (s,
1H), 7.73 (d, J¼8.4 Hz, 2H), 7.69 (s,1H), 7.67 (s, 1H), 7.00 (d, J¼8.4 Hz,
2H), 4.67 (t, J¼7.0 Hz, 2H), 4.63e4.51 (m, 4H), 4.28 (t, J¼7.0 Hz, 2H),
3.80 (s, 3H), 3.28 (t, J¼7.0 Hz, 2H), 3.23e3.07 (m, 4H), 1.73e1.61 (m,
2H), 1.35e1.15 (m, 10H), 0.85 (t, J¼6.8 Hz, 3H); dC (100.6 MHz,
DMSO-d6, 70 ꢀC) 158.7, 145.8, 142.4, 142.3, 126.1, 123.2, 122.2, 122.1,
121.9, 119.9, 114.0, 54.8, 48.9, 48.6, 48.4, 48.4, 30.7, 29.2, 28.0, 27.9,
25.9, 25.4, 21.5, 13.3 (three coincident peaks not observed).
13. (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Quarta, M. R.; Fitti-
paldi, M. Synthesis 2009, 3853e3859; (b) Fiandanese, V.; Bottalico, D.; Mar-
chese, G.; Punzi, A. Tetrahedron 2008, 64, 7301e7306; (c) Fiandanese, V.;
Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2008, 64, 53e60.
14. (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Capuzzolo, F. Tetra-
hedron 2009, 65, 10573e10580; (b) Fiandanese, V.; Marchese, G.; Punzi, A.;
Iannone, F.; Rafaschieri, G. G. Tetrahedron 2010, 66, 8846e8853.
Acknowledgements
This work was financially supported by the University of Bari
‘Aldo Moro’.