An easy synthetic approach to 1,2,3-triazole-fused heterocycles

Article abstract of DOI:10.1016/j.tet.2010.09.068

A convenient synthesis of 1,2,3-triazole-fused isoindolines and dihydroisoquinolines in good to excellent yield is reported, starting from easily available terminal alkynes and (2-haloaryl)alkylazides. The method is based upon a cycloaddition reaction, via click chemistry, followed by a transition metal-catalyzed functionalization of a C-H bond.

Full text of DOI:10.1016/j.tet.2010.09.068

Tetrahedron 66 (2010) 8846e8853
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An easy synthetic approach to 1,2,3-triazole-fused heterocycles
*
Vito Fiandanese , Giuseppe Marchese, Angela Punzi, Francesco Iannone, Giacomo G. Rafaschieri
Dipartimento di Chimica, Università di Bari, 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:
Received 30 June 2010
Received in revised form 1 September 2010
Accepted 20 September 2010
Available online 24 September 2010
A convenient synthesis of 1,2,3-triazole-fused isoindolines and dihydroisoquinolines in good to excellent
yield is reported, starting from easily available terminal alkynes and (2-haloaryl)alkylazides. The method
is based upon a cycloaddition reaction, via click chemistry, followed by a transition metal-catalyzed
functionalization of a CeH bond.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Click chemistry
Alkynes
Azides
Triazole-fused heterocycles
1. Introduction
copper-11c or palladium-catalyzed11d,e,l coupling reaction followed
by a [3þ2] cycloaddition. An alternative approach may involve an
Because of the widespread application of structurally novel
heterocycles in drug development, nitrogen heterocycles, such as
1,2,3-triazoles, have received considerable attention due to their
applications ranging from medicinal chemistry1 to material sci-
ence.2 In addition, several heterocycles containing the 1,2,3-triazole
ring system are reported to possess a broad spectrum of biological
properties, such as antibacterial,3 antiallergic,4 and anti-HIV activ-
ity.5 The most popular method for the synthesis of 1,2,3-triazoles is
the Huisgen 1,3-dipolar cycloaddition reaction of azides with
alkynes.6 However, the original reactions were severely limited by
the high reaction temperatures and the low regioselectivity. These
limitations have been overcome by the introduction of the copper
catalyzed 1,3-dipolar cycloaddition of terminal alkynes and azides,
so-called ‘click chemistry’.7,8 The cycloaddition reactions of terminal
alkynes with azides catalyzed by Cu(I) can be conducted at room
temperature and are highly regioselective leading exclusively to
4-substituted-1,2,3-triazoles. The number of publications dealing
with click chemistry has grown exponentially over the last few
years,9,10 and, in particular, this methodology has been widely used
by many research groups for the synthesis of several bicyclic, as well
as polycyclic fused triazoles heterocycles,11 compounds of great in-
terest for their various biological and pharmacological activities.11,12
Mainly, fused triazoles areprepared byan intramolecular 1,3-dipolar
cycloaddition between azides and alkynes11b,i and a one-pot
intramolecular direct transition metal-catalyzed arylation of 1,2,3-
triazoles by cleavage of CeH bonds with aryl halides,11g,h a meth-
odology which has been recently shown to be a powerful synthetic
tool for functionalization of heterocycles.13
Owing to our continuing interest in the synthesis of novel
structures of biological significance,14e16 we recently reported
a straightforward synthesis of a variety of heterocyclic compounds,
with an indole and benzofuran skeleton,14a,b and an easyand general
approach15 to more complex 4-substituted-1,2,3-triazoles,15a and to
unsymmetrically substituted 4,40-bi-1,2,3-triazoles,15b via click
chemistry. During our studies, we became interested in developing
an easy approach to 1,2,3-triazole-fused heterocycles. Herein we
wish to report on these studies, which enabled the synthesis of the
title compounds through a reaction sequence involving a pre-
liminary cycloaddition of easily available terminal alkynes and (2-
haloaryl)alkylazides, followed byan intramolecular direct transition
metal-catalyzed CeH arylation.
2. Results and discussion
Our strategy is depicted in Scheme 1. We started with the
cycloaddition reaction between (2-haloaryl)alkylazides, 2-iodo- or
2-bromobenzylazide (1, n¼0) and 2-(2-iodophenyl)ethylazide or 2-
(2-bromophenyl)ethylazide (2, n¼1) and several terminal alkynes
3. All reactions were performed in H2O at 100 ꢀC in the presence of
Cu(OAc)2$H2O as a catalyst15b (20 mol %), leading to functionalized
1,4-substituted-1,2,3-triazoles 4 (n¼0) and 5 (n¼1).
* Corresponding author. Tel./fax: þ39 080 5442075; e-mail address: fianda@
chimica.uniba.it (V. Fiandanese).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.068

V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
8847
N3
(
)
n
.
(
)
(
)
n
Cu(OAc)2 H2O
PdCl2(PPh3)2
n
+
R
N
N
H2O, 100 °C
n-Bu4NOAc, NMP
100 °C
X
X
N
N
N
N
6,7
3
4,5
R
1, 2
X = Br, I
R
n = 0, 1
R = alkyl, aryl
Scheme 1.
To obtain the annulated triazoles 6 and 7 we investigated the
catalytic activity of various Pd catalyst and we found17 that
compounds 4 and 5 were easily cyclized in the presence of
PdCl2(PPh3)2 (5 mol %), leading respectively to 1,2,3-triazole-fused
isoindolines 6 (n¼0) and dihydroiso-quinolines 7 (n¼1). It is
noteworthy that, relatively to compounds 6, there is only one
report regarding the synthesis of triazole-fused isoindolines,
obtained in fair yields employing the 2-iodobenzylazide and
various terminal alkynes, in a one-pot Pd-catalyzed coupling re-
action and cycloaddition.11l Our procedure is completely different
and, as reported in Table 1, the novel compounds 4 and the 1,2,3-
triazole-fused isoindolines 6 were obtained in high yields. More-
over, the reactions can be performed both with 2-iodobenzylazide
1a (entries 1, 4, and 6) and 2-bromobenzylazide 1b (entries 2, 3, 5,
and 7), and alkyl- (entries 1e3), aryl- (entries 4e6) and hetero-
aryl-acetylenes (entry 7) were used. With the same strategy we
were able to perform the synthesis of functionalized 1,2,3-tri-
azole-fused 5,6-dihydroisoquinolines,11g simply by employment of
2-(2-iodophenyl)ethylazide 2a and
2-(2-bromophenyl)ethyl azide 2b. We wish to emphasize that the
isoquinoline derivatives are an important class of alkaloids and
many biologically active natural products contain the isoquinoline
framework18 and their biological activities have made them useful
in pharmaceutical compounds.19 The overall results are reported
in Table 2. Also in this case we can use azide 2a (entries 1, 2, 4, 5,
and 7) or azide 2b (entries 3 and 6) obtaining the novel in-
termediates 5 in high yields, substituted in position 4 by alkyl-
(entries 1e3), or aryl- (entries 4e6), or 3-thienyl-group (entry 7).
The intramolecular direct Pd-catalyzed CeH arylation of novel
compounds 5 led to 1,2,3-triazole-fused 5,6-dihydroisoquinolines
7 in high yields.
3.2. General procedure for the synthesis of compounds
4 and 5
Alkyne 3 (1.2 equiv) and azide (1 equiv) were added at room
temperature to a solution (0.04 M) of Cu(OAc)2$H2O (0.2 equiv) in
H2O in a capped flask. The mixture was stirred at 100 ꢀC and, after
reaction completion (1e4 h), was quenched with a saturated
aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate
(3ꢁ30 mL). The organic extracts were washed with an aqueous
solution of NaCl (3ꢁ20 mL), dried over Na2SO4, and concentrated
under vacuum. The residue was purified by column chromatogra-
phy on silica gel and by crystallization.
3.2.1. 1-(2-Iodobenzyl)-4-octyl-1H-1,2,3-triazole (4a). Compound
4a was prepared from 2-iodobenzylazide (0.400 g, 1.54 mmol) and
1-decyne (0.256 g, 1.85 mmol) and the reaction was performed at
100 ꢀC in accordance with general procedure. Purification by col-
umn chromatography (silica gel, 30% ethyl acetate/petroleum
ether) afforded 0.446 g of compound 4a (73% yield). After crystal-
lization from ethyl acetate/petroleum ether, compound 4a was
obtained as a white solid, mp¼96e98 ꢀC. [Found: C, 47.42; H, 5.13;
N, 11.90. C14H18IN3 requires C, 47.34; H, 5.11; N, 11.83%.] nmax (KBr)
3108, 3057, 2949, 2919, 2849, 1463, 1458, 1436, 1219, 1054, 1012,
750, 742; dH (400 MHz, CDCl3) 7.88e7.84 (m, 1H), 7.30 (td, J¼7.6,
1.2 Hz, 1H), 7.26 (s, 1H), 7.04e6.98 (m, 2H), 5.55 (s, 2H), 2.68 (t,
J¼7.6 Hz, 2H), 1.62 (quintet, J¼7.6 Hz, 2H), 1.36e1.17 (m, 10H), 0.84
(t, J¼7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 148.9, 139.7, 137.6, 130.2,
129.4, 129.0, 120.9, 98.4, 58.2, 31.8, 29.4, 29.3, 29.2, 29.2, 25.7, 22.6,
14.1; MS m/z 397 (Mþ, 3), 299 (7), 270 (5), 217 (100), 186 (5), 152 (6),
90 (34), 69 (7), 55 (11), 43 (9), 41 (18%).
In summary, the procedure described here appears to be a useful
route to 1,2,3-triazole-fused heterocycles 6 and 7 and compares
favorably with other methodologies. We have shown that the title
compounds can be easily synthesized by simple cycloaddition re-
actions, via click chemistry, followed by an intramolecular direct
transition metal-catalyzed CeH arylation.
3.2.2. 1-(2-Bromobenzyl)-4-cyclohexyl-1H-1,2,3-triazole (4b). Com-
pound 4b was prepared from 2-bromobenzylazide (0.199 g,
0.94 mmol) and cyclohexylacetylene (0.122 g, 1.13 mmol) and the
reaction was performed at 100 ꢀC in accordance with general pro-
cedure. Purification by percolation (florisil, 50% ethyl acetate/petro-
leum ether) afforded 0.283 g of compound 4b (94% yield). After
crystallization from ethyl acetate/petroleum ether, compound 4b
was obtained as a white solid, mp¼120e121 ꢀC. [Found: C, 56.35; H,
5.70; N, 13.15. C15H18BrN3 requires C, 56.26; H, 5.67; N, 13.12%.] nmax
(KBr) 3109, 3057, 2919, 2849, 1448, 1209, 1044, 1026, 759, 744; dH
(400 MHz, CDCl3) 7.58 (dd, J¼7.6, 1.2 Hz, 1H), 7.30e7.24 (m, 2H), 7.18
(td, J¼7.6, 1.6 Hz, 1H), 7.05 (dd, J¼7.6, 1.6 Hz, 1H), 5.59 (s, 2H),
2.77e2.68 (m, 1H), 2.06e1.98 (m, 2H), 1.80e1.64 (m, 3H), 1.42e1.14
(m, 5H); dC (100.6 MHz, CDCl3) 154.1, 134.6, 133.0, 130.1, 130.0, 128.1,
123.2, 119.5, 53.5, 35.3, 32.9, 26.1, 26.0; MS m/z 321 (Mþ2, 3), 319
(Mþ, 3), 265 (4), 263 (4),184 (7), 171 (79), 169 (100), 122 (31), 95 (14),
90 (46), 89 (36), 80 (18), 67 (21), 63 (13), 55 (16), 53 (14), 51 (12%).
3. Experimental
3.1. General
MachereyeNagel silica gel (60, particle size 0.040e0.063 mm)
for column chromatography and MachereyeNagel aluminum
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-5ms capillary column (30 mꢁ0.25 mm id). GC/
mass-spectrometry analysis was performed on a Shimadzu GCMS-
QP5000 gas chromatograph-mass spectrometer equipped with
a Supelco SLBÔ-5ms capillary column (30 mꢁ0.25 mm id). 1H NMR
spectra were recorded in deuterochloroform, CD2Cl2 or acetone-d6
on a Varian Inova at 400 MHz. 13C NMR spectra were recorded in
deuterochloroform, CD2Cl2 or acetone-d6 on a Varian Inova at
100.6 MHz. IR spectra were recorded on a PerkineElmer FT-IR
Spectrum Bx. Elemental analyses were recorded on a Carlo Erba EA
1108 elemental analyzer. Melting points were determined on
a Reichert Microscope. NMP was used as supplied.
3.2.3. 1-(2-Bromobenzyl)-4-(cyclopentylmethyl)-1H-1,2,3-triazole
(4c). Compound 4c was prepared from 2-bromobenzylazide
(0.199 g, 0.94 mmol) and 3-cyclopentyl-1-propyne (0.123 g,
1.13 mmol) and the reaction was performed at 100 ꢀC in accordance
with general procedure. Purification by column chromatography
(silica gel, 50% ethyl acetate/petroleum ether) afforded 0.283 g of
compound 4c (94% yield). After crystallization from petroleum
ether, compound 4c was obtained as a white solid, mp¼62e63 ꢀC.

8848
V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
Table 1
Synthesis of 1,2,3-triazoles 4 and 1,2,3-triazole-fused isoindolines 6
Entry
Azides 1
Alkynes 3
Products 4a, yieldb (%)
Products 6c, yieldb (%)
N
N
N
N
N
N3
I
N
1
1-Decyne
C8H17
I
H
17C8
1a
(77)
6a
(73)
4a
N
N
N
N
N
N
N3
Br
2
Cyclohexylacetylene
Br
1b
(95)
N
6b
(94)
4b
N
N
N
N
N
Br
3
1b
3-Cyclopentyl-1-propyne
(87)
N
6c
(94)
4c
N
N
N
N
N
I
4
1a
Phenylacetylene
(68)
N
6d
(77)
4d
N
N
N
N
N
Br
5
1b
p-Tolylacetylene
Me
Me
(87)
N
6e
(95)
4e
N
N
N
N
N
I
6
1a
p-Methoxyphenylacetylene
OMe
MeO
(98)
N
6f
(90)
4f
N
N
N
N
N
Br
7
1b
3-Ethynyltiophene
S
S
(95)
6g
(96)
4g
a
All reactions were carried out in H2O in a capped flask at 100 ꢀC, according to a general procedure.
Yields of purified isolated products.
All reactions were carried out in NMP at 100 ꢀC, according to a general procedure.
b
c
[Found: C, 56.30; H, 5.73; N, 13.20. C15H18BrN3 requires C, 56.26; H,
169 (100), 144 (11), 122 (13), 95 (15), 90 (39), 89 (31), 80 (11), 79
(11), 67 (14), 54 (11), 41 (61%).
5.67; N, 13.12%.] nmax (KBr) 3115, 3063, 2936, 2862, 1439, 1212, 1141,
1046, 1031, 751, 739; dH (400 MHz, CDCl3) 7.58 (dd, J¼7.6, 1.2 Hz,
1H), 7.30e7.23 (m, 2H), 7.18 (td, J¼7.6, 1.6 Hz, 1H), 7.04 (dd, J¼7.6,
1.6 Hz,1H), 5.59 (s, 2H), 2.68 (d, J¼7.6 Hz, 2H), 2.14 (septet, J¼7.6 Hz,
1H), 1.76e1.65 (m, 2H), 1.64e1.42 (m, 4H), 1.25e1.10 (m, 2H); dC
(100.6 MHz, CDCl3) 148.3, 134.6, 133.1, 130.1, 129.9, 128.1, 123.2,
121.2, 53.5, 39.9, 32.4, 31.7, 25.1; MS m/z 253 (8), 251 (8), 171 (79),
3.2.4. 1-(2-Iodobenzyl)-4-phenyl-1H-1,2,3-triazole (4d). Compound
4d was prepared from 2-iodobenzylazide (0.300 g, 1.16 mmol) and
phenylacetylene (0.142 g, 1.39 mmol) and the reaction was per-
formed at 100 ꢀC in accordance with general procedure. Purifica-
tion by column chromatography (silica gel, 30% ethyl acetate/

V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
8849
Table 2
Synthesis of 1,2,3-triazoles 5 and 1,2,3-triazole-fused 5,6-dihydroisoquinolines 7
Entry
Azides 2
Alkynes 3
Product 5a, yieldb (%)
Product 7c, yieldb (%)
N3
N
N
I
N
N
1
1-Heptyne
N
N
I
H
H
11C5
H
11C5
(86)
2a
(94)
N
5a
7a
N
N
I
N
N
N
2
2a
1-Decyne
N
N
17C8
H17C8
(84)
(91)
7b
5b
N
N3
Br
N
N
N
3
Cyclohexylacetylene
Br
2b
(71)
I
5c
(87)
7c
N
N
N
N
N
N
4
2a
Phenylacetylene
(97)
I
(82)
5d
7d
N
N
N
N
N
N
5
2a
p-Tolylacetylene
Me
Me
(83)
7e
(84)
Br
5e
N
N
N
N
N
N
6
2b
p-Methoxyphenylacetylene
MeO
MeO
(74)
7f
(99)
I
5f
N
N
N
N
N
N
7
2a
3-Ethynylthiophene
S
S
(97)
(87)
5g
7g
a
All reactions were carried out in H2O in a capped flask at 100 ꢀC, according to a general procedure.
Yields of purified isolated products.
All reactions were carried out in NMP at 100 ꢀC, according to a general procedure.
b
c
petroleum ether) afforded 0.322 g of compound 4d (77% yield).
1051, 1015, 764, 742, 694; dH (400 MHz, CDCl3) 7.89 (dd, J¼7.6,
1.2 Hz, 1H), 7.83e7.78 (m, 2H), 7.75 (s, 1H), 7.42e7.37 (m, 2H),
7.36e7.28 (m, 2H), 7.12 (dd, J¼7.6, 1.6 Hz, 1H), 7.04 (td, J¼7.6, 1.6 Hz,
1H), 5.65 (s, 2H); dC (100.6 MHz, CDCl3) 148.1, 139.9, 137.3, 130.4,
130.4, 129.6, 129.1, 128.8, 128.2, 125.7, 119.8, 98.6, 58.4; MS m/z 361
After crystallization from ethyl acetate/petroleum ether, compound
4d was obtained as a pale yellow solid, mp¼115e117 ꢀC. [Found: C,
49.95; H, 3.38; N, 11.70. C15H12IN3 requires C, 49.88; H, 3.35; N,
11.63%.] nmax (KBr) 3112, 3076, 3028, 1459, 1437, 1419, 1228, 1090,

8850
V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
(Mþ, 6), 332 (4), 217 (36), 206 (53), 178 (6), 128 (10), 116 (100), 102
(35), 90 (54), 89 (62), 77 (13), 63 (24), 51 (17%).
(86% yield) as a pale yellow oil. [Found: C, 48.70; H, 5.51; N, 11.49.
15H20IN3 requires C, 48.79; H, 5.46; N, 11.38%.] nmax (neat) 3131,
C
3063, 2953, 2927, 2856, 1466, 1459, 1436, 1217, 1048, 1013, 750; dH
(400 MHz, CDCl3) 7.80 (dd, J¼7.7, 1.2 Hz, 1H), 7.17 (td, J¼7.7, 1.2 Hz,
1H), 7.00 (s, 1H), 6.95 (dd, J¼7.7, 1.6 Hz, 1H), 6.89 (td, J¼7.7, 1.6 Hz,
1H), 4.50 (t, J¼7.4 Hz, 2H), 3.27 (t, J¼7.4 Hz, 2H), 2.62 (t, J¼7.6 Hz,
2H), 1.57 (quintet, J¼7.6 Hz, 2H), 1.35e1.18 (m, 4H), 0.84 (t, J¼7.0 Hz,
3H); dC (100.6 MHz, CDCl3) 148.1, 139.6, 139.6, 130.2, 128.9, 128.6,
120.9, 100.1, 49.5, 41.5, 31.2, 29.1, 25.5, 22.3, 13.9; MS m/z 242 (100),
231 (42), 217 (9), 170 (4), 158 (5), 124 (17), 117 (9), 104 (98), 95 (20),
90 (21), 77 (35), 68 (23), 55 (39), 41 (86%).
3.2.5. 1-(2-Bromobenzyl)-4-(4-methylphenyl)-1H-1,2,3-triazole (4e).
Compound 4e was prepared from 2-bromobenzylazide (0.199 g,
0.94 mmol) and 4-ethynyltoluene (0.131 g, 1.13 mmol) and the
reaction was performed at 100 ꢀC in accordance with general pro-
cedure. Purification bycolumn chromatography (silica gel, 40% ethyl
acetate/petroleum ether) afforded 0. 293 g of compound 4e (95%
yield). After crystallization from ethyl acetate/petroleum ether,
compound 4e was obtained as a white solid, mp¼133e134 ꢀC.
[Found: C, 58.50; H, 4.28; N, 12.75. C16H14BrN3 requires C, 58.55; H,
4.30; N,12.80%.] nmax (KBr) 3126, 3105, 2925,1458, 1442, 1427, 1350,
1222, 1046, 1026, 820, 748; dH (400 MHz, CDCl3) 7.72 (s, 1H),
7.71e7.67 (m, 2H), 7.60 (dd, J¼7.6, 1.2 Hz, 1H), 7.29 (td, J¼7.6, 1.2 Hz,
1H), 7.23e7.18 (m, 3H), 7.17e7.13 (m,1H), 5.67 (s, 2H), 2.35 (s, 3H); dC
(100.6 MHz, CDCl3) 148.2, 138.0, 134.3, 133.1, 130.3, 130.2, 129.5,
128.2,127.6,125.6,123.3,119.4, 53.8, 21.2; MS m/z 329 (Mþ2, 3), 327
(Mþ, 3), 300 (3), 298 (3), 220 (31), 171 (18), 169 (22), 130 (100), 110
(10), 103 (19), 90 (22), 89 (21), 77 (21), 63 (11), 51 (13%).
3.2.9. 1-[2-(2-Iodophenyl)ethyl]-4-octyl-1H-1,2,3-triazole (5b). Com-
pound 5b was prepared from 2-iodophenylethylazide (0.300 g,
1.10 mmol) and 1-decyne (0.183 g, 1.32 mmol) and the reaction was
performed at 100 ꢀC in accordance with general procedure. Purifi-
cation by column chromatography (silica gel, 30% ethyl acetate/pe-
troleum ether) afforded 0.380 g of compound 5b (84% yield). After
crystallization from petroleum ether, compound 5b was obtained as
a white solid, mp¼49e51 ꢀC. [Found: C, 50.72; H, 5.88; N, 10.70.
C18H2.6IN3 requires C, 50.78; H, 5.94; N, 10.77%.] nmax (KBr) 3125,
3060, 2923, 2848, 1466, 1454, 1438, 1208, 1054, 1014, 752; dH
(400 MHz, CDCl3) 7.81 (dd, J¼7.6, 1.2 Hz, 1H), 7.18 (td, J¼7.6, 1.2 Hz,
1H), 7.01 (s, 1H), 6.96 (dd, J¼7.6, 1.6 Hz, 1H), 6.91 (td, J¼7.6, 1.6 Hz,
1H), 4.52 (t, J¼7.2 Hz, 2H), 3.28 (t, J¼7.2 Hz, 2H), 2.63 (t, J¼7.6 Hz, 2H),
1.57 (quintet, J¼7.6 Hz, 2H), 1.32e1.17 (m,10H), 0.85 (t, J¼7.0 Hz, 3H);
dC (100.6 MHz, CDCl3) 148.2, 139.7, 139.7, 130.3, 128.9, 128.6, 121.0,
100.1, 49.5, 41.6, 31.8, 29.5, 29.3, 29.2, 29.1, 25.5, 22.6, 14.1; MS m/z
313 (4), 284 (100), 231 (60), 217 (11), 166 (10), 110 (32), 104 (98), 103
(23), 96 (20), 82 (15), 77 (26), 68 (21), 67 (17), 55 (30), 41 (77%).
3.2.6. 1-(2-Iodobenzyl)-4-(4-methoxyphenyl)-1H-1,2,3-triazole
(4f). Compound 4f was prepared from 2-iodobenzylazide (0.300 g,
1.16 mmol) and p-methoxyphenylacetylene (0.184 g,1.39 mmol) and
the reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography (silica gel, 40%
ethyl acetate/petroleum ether) afforded 0.408 g of compound 4f
(90% yield). After crystallization from ethyl acetate/petroleum ether,
compound 4f was obtained as a pale yellow solid, mp¼140e141 ꢀC.
[Found: C, 49.08; H, 3.58; N, 10.75. C16H14IN3O requires C, 49.12; H,
3.61; N, 10.74%.] nmax (KBr) 3125, 3102, 2925, 1498, 1458, 1438, 1246,
1222,1174,1028,1012, 830, 750; dH (400 MHz, CDCl3) 7.88 (dd, J¼7.7,
1.2 Hz,1H), 7.75e7.70 (m, 2H), 7.67 (s,1H), 7.31 (td, J¼7.7,1.2 Hz,1H),
7.09 (dd, J¼7.7, 1.6 Hz, 1H), 7.03 (td, J¼7.7, 1.6 Hz, 1H), 6.94e6.89 (m,
2H), 5.62 (s, 2H), 3.81 (s, 3H); dC (100.6 MHz, CDCl3) 159.6, 148.0,
139.8, 137.4, 130.3, 129.5, 129.0, 127.0, 123.1, 119.0, 114.2, 98.5, 58.4,
55.3; MS m/z 391 (Mþ, 18), 236 (74), 221 (18), 217 (21), 193 (19), 165
(12),146 (100),128 (9),119 (34),103 (21), 90 (64), 89 (62), 76 (30), 65
(21), 63 (30), 51 (26), 50 (25%).
3.2.10. 1-[2-(2-Bromophenyl)ethyl]-4-cyclohexyl-1H-1,2,3-triazole
(5c). Compound 5c was prepared from 2-bromophenylethylazide
(0.149 g, 0.66 mmol) and cyclohexylacetylene (0.086 g, 0.79 mmol)
and the reactionwas performed at 100 ꢀC in accordancewith general
procedure. Purification by column chromatography (silica gel, 30%
ethyl acetate/petroleum ether) afforded 0.157 g of compound 5c
(71% yield). After crystallization from ethyl acetate/petroleum ether,
compound 5c was obtained as a white solid, mp¼81e82 ꢀC. [Found:
C, 57.53; H, 6.10; N, 12.65. C16H20BrN3 requires C, 57.49; H, 6.03; N,
12.57%.] nmax (KBr) 3109, 3062, 2917, 2849, 1460, 1447, 1434, 1215,
1058, 1039, 1024, 752; dH (400 MHz, CDCl3) 7.53 (dd, J¼7.6, 1.2 Hz,
1H), 7.16 (td, J¼7.6, 1.2 Hz, 1H), 7.08 (td, J¼7.6, 1.6 Hz, 1H), 6.98e6.92
(m, 2H), 4.54 (t, J¼7.2 Hz, 2H), 3.29 (t, J¼7.2 Hz, 2H), 2.74e2.65 (m,
1H), 2.00e1.90 (m, 2H), 1.79e1.62 (m, 3H), 1.43e1.13 (m, 5H); dC
(100.6 MHz, CDCl3) 153.5,136.5,133.0,131.2,128.8,127.7,124.2,119.7,
49.3, 37.3, 35.2, 33.0, 26.1, 26.0; MS m/z 254 (78), 226 (8), 185 (29),
183 (30),169 (9),136 (63),109 (33),104 (73), 91 (25), 80 (38), 79 (38),
77 (56), 67 (64), 55 (29), 41 (100%).
3.2.7. 1-(2-Bromobenzyl)-4-(thiophen-3-yl)-1H-1,2,3-triazole
(4g). Compound 4g was prepared from 2-bromobenzylazide
(0.199 g, 0.94 mmol) and 3-ethynylthiophene (0.122 g, 1.13 mmol)
and the reaction was performed at 100 ꢀC in accordance with
general procedure. Purification by column chromatography (silica
gel, 40% ethyl acetate/petroleum ether) afforded 0.289 g of com-
pound 4g (96% yield). After crystallization from ethyl acetate/pe-
troleum ether, compound 4g was obtained as an ivory-white solid,
mp¼99e100 ꢀC. [Found: C, 48.91; H, 3.22; N, 13.15; S, 10.05.
C13H10BrN3S requires C, 48.76; H, 3.15; N, 13.12; S, 10.01%.] nmax
(KBr) 3123, 3094, 2923, 1436, 1216, 1044, 1029, 850, 824, 784, 739,
711, 615; dH (400 MHz, CDCl3) 7.66 (s, 1H), 7.65 (dd, J¼3.0, 1.2 Hz,
1H), 7.61 (dd, J¼7.6, 1.2 Hz, 1H), 7.41 (dd, J¼5.0, 1.2 Hz, 1H), 7.34 (dd,
J¼5.0, 3.0 Hz, 1H), 7.28 (td, J¼7.6, 1.2 Hz, 1H), 7.21 (td, J¼7.6, 2.0 Hz,
1H), 7.14 (dd, J¼7.6, 2.0 Hz, 1H), 5.67 (s, 2H); dC (100.6 MHz, CDCl3)
144.3, 134.2, 133.1, 131.6, 130.3, 130.1, 128.2, 126.3, 125.7, 123.3, 121.1,
119.6, 53.7; MS m/z 321 (Mþ2, 4), 319 (Mþ, 4), 292 (3), 290 (3), 212
(44), 184 (6), 171 (21), 169 (24), 122 (100), 106 (14), 95 (16), 90 (36),
89 (29), 63 (16), 51 (13), 45 (79%).
3.2.11. 1-[2-(2-Iodophenyl)ethyl]-4-phenyl-1H-1,2,3-triazole
(5d). Compound 5d was prepared from 2-iodophenylethylazide
(0.150 g, 0.55 mmol) and phenylacetylene (0.067 g, 0.66 mmol) and
the reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography (silica gel, 30%
ethyl acetate/petroleum ether) afforded 0.200 g of compound 5d
(97% yield). After crystallization from ethyl acetate/petroleum
ether, compound 5d was obtained as a white solid, mp¼115e117 ꢀC.
[Found: C, 51.19; H, 3.80; N, 11.25. C16H14IN3 requires C, 51.22; H,
3.76; N, 11.20%.] nmax (KBr) 3116, 3089, 3055, 2958, 2930, 1466,
1436, 1221, 1076, 1015, 767, 751, 694; dH (400 MHz, CDCl3) 7.85 (dd,
J¼7.6, 1.2 Hz, 1H), 7.78e7.73 (m, 2H), 7.51 (s, 1H), 7.42e7.36 (m, 2H),
7.33e7.28 (m, 1H), 7.21 (td, J¼7.6, 1.2 Hz, 1H), 7.03 (dd, J¼7.6, 1.8 Hz,
1H), 6.94 (td, J¼7.6, 1.8 Hz, 1H), 4.62 (t, J¼7.2 Hz, 2H), 3.37 (t,
J¼7.2 Hz, 2H); dC (100.6 MHz, CDCl3) 147.3, 139.6, 139.3, 130.4, 130.1,
128.9, 128.6, 128.5, 127.9, 125.5, 119.9, 100.1, 49.7, 41.3; MS m/z 375
3.2.8. 1-[2-(2-Iodophenyl)ethyl]-4-pentyl-1H-1,2,3-triazole
(5a). Compound 5a was prepared from 2-iodophenylethylazide
(0.150 g, 0.55 mmol) and 1-heptyne (0.064 g, 0.66 mmol) and the
reaction was performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography (silica gel, 30%
ethyl acetate/petroleum ether) afforded 0.175 g of compound 5a

V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
8851
(Mþ, 2), 248 (41), 231 (19), 220 (13), 142 (5), 130 (25), 117 (28), 104
(100), 89 (32), 77 (51), 63 (22), 51 (31%).
(0.05 equiv) and n-Bu4NOAc (2 equiv). The resulting mixture was
stirred at 100 ꢀC and, after reaction completion (1e5 h), was
quenched with aqueous NH4Cl (20 mL) and extracted with ethyl
acetate (3ꢁ30 mL). The organic extracts were washed with an
aqueous solution of NaCl (3ꢁ20 mL), dried over anhydrous Na2SO4,
and concentrated under vacuum. The residue was purified by col-
umn chromatography on silica gel and by crystallization.
3.2.12. 1-[2-(2-Iodophenyl)ethyl]-4-(4-methylphenyl)-1H-1,2,3-tri-
azole (5e). Compound 5e was prepared from 2-iodophenylethyla-
zide (0.200 g, 0.73 mmol) and 4-ethynyltoluene (0.102 g, 0.88 mmol)
and the reactionwas performed at 100 ꢀC in accordance with general
procedure. Purification by column chromatography (silica gel, 30%
ethylacetate/petroleumether)afforded0.239gofcompound5e(84%
yield). After crystallization from ethyl acetate/petroleum ether,
compound 5e was obtained as a pale yellow solid, mp¼118e120 ꢀC.
[Found:C, 52.53;H, 4.17;N,10.85. C17H16IN3 requiresC, 52.46;H, 4.14;
N, 10.80%.] nmax (KBr) 3082, 3057, 2942, 1459, 1436, 1219, 1188, 1086,
1047, 1014, 814, 761, 744, 530; dH (400 MHz, CDCl3) 7.83 (dd, J¼7.6,
1.2 Hz,1H), 7.67e7.62(m, 2H), 7.48 (s,1H), 7.23e7.16 (m, 3H), 7.02(dd,
J¼7.6,1.6 Hz,1H), 6.92 (td, J¼7.6,1.6Hz,1H), 4.60 (t, J¼7.4Hz, 2H), 3.35
(t, J¼7.4 Hz, 2H), 2.35 (s, 3H); dC (100.6 MHz, CDCl3) 147.6,139.7,139.5,
137.9, 130.3, 129.4, 129.0, 128.7, 127.7, 125.5, 119.6, 100.1, 49.8, 41.5,
21.2; MS m/z 389 (Mþ, 7), 262 (23), 234 (29), 231 (29), 144 (39), 130
(18),117 (54),115 (64),104 (100), 91 (27), 90 (25), 89 (22), 77 (46), 65
(13), 63 (17), 51 (25%).
3.3.1. 3-Octyl-8H-[1,2,3]triazolo[5,1-a]isoindole (6a). Compound 6a
was prepared from 4a (0.151 g, 0.38 mmol) in accordance with
general procedure. Purification by column chromatography (silica
gel, 40% ethyl acetate/petroleum ether) afforded 0.079 g of com-
pound 6a (77% yield). After crystallization from petroleum ether,
compound 6a was obtained as a pale yellow solid, mp¼79e80 ꢀC.
[Found: C, 75.87; H, 8.55; N, 15.70. C17H23N3 requires C, 75.80; H,
8.61; N, 15.60%.] nmax (KBr) 2947, 2914, 2850, 1474, 1458, 1437, 1310,
1166, 765, 726; dH (400 MHz, CDCl3) 7.58 (br d, J¼7.6 Hz, 1H),
7.49e7.41 (m, 2H), 7.35 (td, J¼7.6, 1.2 Hz, 1H), 5.27 (s, 2H), 2.92 (t,
J¼7.6 Hz, 2H), 1.78 (quintet, J¼7.6 Hz, 2H), 1.44e1.17 (m, 10H), 0.84
(t, J¼6.8 Hz, 3H); dC (100.6 MHz, CDCl3) 140.6, 139.3, 139.3, 128.7,
128.5, 127.6, 124.1, 120.8, 50.9, 31.8, 29.5, 29.3, 29.2, 29.2, 25.9, 22.6,
14.1; MS m/z 269 (Mþ, 5), 240 (14), 198 (9), 184 (22), 170 (100), 156
(44), 144 (30), 143 (25), 131 (22), 130 (26), 129 (22), 128 (21), 115
(32), 89 (16), 77 (7), 63 (7), 51 (7), 43 (22), 41 (51%).
3.2.13. 1-[2-(2-Bromophenyl)ethyl]-4-(4-methoxyphenyl)-1H-1,2,3-
triazole (5f). Compound 5f was prepared from 2-bromophenyle-
thylazide (0.149 g, 0.66 mmol) and 4-ethynylanisole (0.104 g,
0.79 mmol) and the reaction was performed at 100 ꢀC in accordance
with general procedure. Purification by column chromatography
(silica gel, 30% ethyl acetate/petroleum ether) afforded 0.234 g of
compound 5f (99% yield). After crystallization from ethyl acetate/
petroleum ether, compound 5f was obtained as a white solid,
mp¼114e115 ꢀC. [Found: C, 57.05; H, 4.45; N, 11.70. C17H16BrN3O
requires C, 57.00; H, 4.50; N, 11.73%.] nmax (KBr) 3088, 3044, 2952,
2932, 2834, 1502, 1472, 1443, 1435, 1248, 1081, 1026, 827, 758; dH
(400 MHz, CDCl3) 7.69e7.65 (m, 2H), 7.56 (dd, J¼7.6,1.2 Hz,1H), 7.41
(s, 1H), 7.16 (td, J¼7.6, 1.2 Hz, 1H), 7.09 (td, J¼7.6, 1.8 Hz, 1H), 7.02
(dd, J¼7.6, 1.8 Hz, 1H), 6.94e6.89 (m, 2H), 4.62 (t, J¼7.2 Hz, 2H), 3.80
(s, 3H), 3.35 (t, J¼7.2 Hz, 2H); dC (100.6 MHz, CDCl3) 159.5, 147.4,
136.3, 133.0, 131.2, 128.9, 127.8, 126.9, 124.3, 123.3, 119.1, 114.2, 55.3,
49.6, 37.2; MS m/z 359 (Mþ2, 12), 357 (Mþ, 13), 250 (32), 183 (15),
160 (74), 146 (29), 145 (27), 133 (100), 117 (60), 104 (82), 90 (40), 89
(68), 78 (22), 77 (80), 76 (23), 63 (36), 51 (40), 50 (24%).
3.3.2. 3-Cyclohexyl-8H-[1,2,3]triazolo[5,1-a]isoindole
(6b). Com-
pound 6b was prepared from 4b (0.150 g, 0.47 mmol) in accordance
with general procedure. Purification by column chromatography
(silica gel, 50% ethyl acetate/petroleum ether) afforded 0.107 g of
compound 6b (95% yield). After crystallization from ethyl acetate/
petroleum ether, compound 6b was obtained as a pale brown solid,
mp¼124e125 ꢀC. [Found: C, 75.30; H, 7.20; N, 17.63. C15H17N3 re-
quires C, 75.28; H, 7.16; N, 17.56%.] nmax (KBr) 3072, 2919, 2849,
1448, 1421, 1340, 1258, 1156, 994, 773, 754, 729; dH (400 MHz,
CD2Cl2) 7.69 (d, J¼8.0 Hz, 1H), 7.53e7.43 (m, 2H), 7.38 (td, J¼7.6,
1.2 Hz, 1H), 5.27 (s, 2H), 3.00 (tt, J¼12.0, 3.6 Hz, 1H), 2.08e2.00 (m,
2H), 1.94e1.85 (m, 2H), 1.84e1.65 (m, 3H), 1.55e1.31 (m, 3H); dC
(100.6 MHz, CD2Cl2) 144.4, 141.1, 138.5, 128.7, 128.6, 127.5, 124.2,
121.4, 50.9, 36.3, 32.8, 26.5, 26.1; MS m/z 239 (Mþ, 8), 210 (64), 196
(15), 182 (100), 168 (36), 156 (13), 144 (15), 130 (22), 117 (15), 115
(13), 89 (19), 77 (19), 63 (14), 51 (15), 41 (33%).
3.2.14. 1-[2-(2-Bromophenyl)ethyl]-4-(thiophen-3-yl)-1H-1,2,3-tri-
azole (5g). Compound 5g was prepared from 2-iodophenylethyla-
zide (0.200 g, 0.73 mmol) and 3-ethynylthiophene (0.095 g,
0.88 mmol) and the reaction was performed at 100 ꢀC in accordance
with general procedure. Purification by column chromatography
(silica gel, 30% ethyl acetate/petroleum ether) afforded 0.270 g of
compound 5g (97% yield). After crystallization from ethyl acetate/
petroleum ether, compound 5g was obtained as a white solid,
mp¼92e94 ꢀC. [Found: C, 50.35; H, 3.60; N, 12.62; S, 9.63.
C14H12BrN3S requires C, 50.31; H, 3.62; N,12.57; S, 9.59%.] nmax (KBr)
3099, 3077, 2954, 2930, 1438, 1217, 1074, 1017, 853, 788, 754, 717,
624; dH (400 MHz, CDCl3) 7.83 (dd, J¼7.6, 1.2 Hz,1H), 7.61 (dd, J¼2.8,
1.2 Hz, 1H), 7.42 (s, 1H), 7.38 (dd, J¼5.0, 1.2 Hz, 1H), 7.34 (dd, J¼5.0,
2.8 Hz,1H), 7.21 (td, J¼7.6,1.2 Hz,1H), 7.02 (dd, J¼7.6,1.6 Hz,1H), 6.93
(td, J¼7.6, 1.6 Hz, 1H), 4.60 (t, J¼7.4 Hz, 2H), 3.35 (t, J¼7.4 Hz, 2H); dC
(100.6 MHz, CDCl3) 143.7,139.7,139.5,131.8,130.3,129.1,128.7,126.2,
125.8,121.0,119.7,100.1, 49.8, 41.5; MS m/z 381 (Mþ, 8), 254 (35), 231
(16), 226 (17), 217 (7),142 (15),136 (56),122 (23),109 (67),104 (100),
90 (32), 77 (53), 65 (24), 63 (25), 51 (33), 45 (90%).
3.3.3. 3-(Cyclopentylmethyl)-8H-[1,2,3]triazolo[5,1-a]isoindole
(6c). Compound 6c was prepared from 4c (0.150 g, 0.47 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 40% ethyl acetate/petroleum ether) afforded
0.098 g of compound 6c (87% yield). After crystallization from ethyl
acetate/petroleum ether, compound 6c was obtained as a pale
brown solid, mp¼104e105 ꢀC. [Found: C, 75.32; H, 7.21; N, 17.60.
C15H17N3 requires C, 75.28; H, 7.16; N,17.56%.] nmax (KBr) 2941, 2919,
2855, 1447, 1261, 1169, 1093, 1025, 798, 771, 744, 722; dH (400 MHz,
CDCl3) 7.59 (br d, J¼7.6 Hz, 1H), 7.50e7.41 (m, 2H), 7.35 (td, J¼7.6,
1.2 Hz,1H), 5.28 (s, 2H), 2.92 (d, J¼7.6 Hz, 2H), 2.35 (septet, J¼7.6 Hz,
1H), 1.82e1.72 (m, 2H), 1.70e1.59 (m, 2H), 1.58e1.48 (m, 2H),
1.36e1.22 (m, 2H); dC (100.6 MHz, CDCl3) 140.7, 139.5, 138.8, 128.7,
128.6, 127.6, 124.1, 120.8, 50.9, 40.5, 32.3, 31.7, 25.0; MS m/z 239
(Mþ,17), 210 (58), 196 (13), 182 (81),168 (63),144 (25),143 (34),142
(42), 130 (49), 115 (56), 89 (33), 77 (15), 63 (19) 51 (18), 41 (100%).
3.3.4. 3-Phenyl-8H-[1,2,3]triazolo[5,1-a]isoindole (6d)11l. Compound
6d was prepared from 4d (0.152 g, 0.42 mmol) in accordance with
general procedure. Purification by column chromatography (silica
gel, 40% ethyl acetate/petroleum ether) afforded 0.067 g of com-
pound 6d (68% yield). After crystallization from ethyl acetate/pe-
troleum ether, compound 6d was obtained as a pale brown solid,
mp¼153e155 ꢀC. [Found: C, 77.30; H, 4.80; N, 17.93. C15H11N3
3.3. General procedure for the synthesis of compounds 6 and 7
To a solution (0.1 N) of triazole (1 equiv) in NMP at room tem-
perature under nitrogen were successively added PdCl2(PPh3)2

8852
V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
requires C, 77.23; H, 4.75; N, 18.01%.] nmax (KBr) 3058, 3034, 2964,
2922, 2850, 1609, 1448, 1359, 985, 760, 699, 668; dH (400 MHz,
CDCl3) 7.95e7.90 (m, 2H), 7.88 (br d, J¼7.2 Hz,1H), 7.54e7.37 (m, 6H),
5.35 (s, 2H); dC (100.6 MHz, CDCl3) 141.1, 139.3, 139.0, 131.2, 128.9,
128.8, 128.4, 128.1, 128.1, 126.9, 124.2, 121.3, 50.9; MS m/z 233 (Mþ, 7),
205 (54), 204 (100), 190 (14), 176 (20), 151 (11), 102 (68), 89 (39), 88
(39), 76 (44), 63 (25), 51 (25), 50 (19%).
J¼7.6,1H), 7.38e7.25 (m, 3H), 4.52 (t, J¼6.8 Hz, 2H), 3.17 (t, J¼6.8 Hz,
2H), 2.94 (t, J¼7.6 Hz, 2H),1.78 (quintet, J¼7.6 Hz, 2H),1.46e1.30 (m,
4H), 0.88 (t, J¼7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 143.5, 132.4, 128.8,
128.5, 128.4, 127.7,125.6, 124.0, 44.7, 31.7, 29.3, 28.6, 26.5, 22.4, 14.0;
MS m/z 241 (Mþ, 16), 212 (23), 198 (25),185 (100), 184 (59),170 (47),
156 (45),143 (20),130 (35),129 (48), 128 (53), 127 (21), 115 (57), 103
(20), 91 (10), 89 (10), 77 (34), 63 (12), 51 (23), 41 (41%).
3.3.5. 3-(4-Methylphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindole (6e).
Compound 6e was prepared from 4e (0.148 g, 0.45 mmol) in ac-
cordance with general procedure. Purification by column chro-
matography (silica gel, 40% ethyl acetate/petroleum ether)
afforded 0.098 g of compound 6e (87% yield). After crystallization
from ethyl acetate/petroleum ether, compound 6e was obtained as
a white solid, mp¼160e162 ꢀC. [Found: C, 77.80; H, 5.35; N, 17.03.
C16H13N3 requires C, 77.71; H, 5.30; N, 16.99%.] nmax (KBr) 3067,
3024, 2963, 2918, 2853, 1437, 1413, 1354, 1176, 1128, 984, 829, 810,
764, 714; dH (400 MHz, acetone-d6) 7.95 (d, J¼7.2 Hz, 1H),
7.88e7.83 (m, 2H), 7.72e7.68 (m, 1H), 7.55e7.49 (m, 1H), 7.47 (td,
J¼7.6, 1.2 Hz, 1H), 7.39e7.34 (m, 2H), 5.50 (s, 2H), 2.40 (s, 3H); dC
(100.6 MHz, acetone-d6) 144.1, 140.4, 140.2, 139.5, 131.4, 130.9,
130.4, 130.1, 129.9, 128.5, 126.5, 122.8, 52.6, 22.3; MS m/z 247 (Mþ,
14), 219 (89), 218 (100), 204 (88), 203 (38), 189 (18), 176 (15), 166
(10), 116 (10), 109 (39), 102 (37), 95 (42), 94 (33), 89 (21), 82 (46),
76 (26), 63 (26), 51 (30), 50 (22%).
3.3.9. 1-Octyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline (7b). Com-
pound 7b was prepared from 5b (0.189 g, 0.46 mmol) in accordance
with general procedure. Purification by column chromatography
(silica gel, 50% ethyl acetate/petroleum ether) afforded 0.118 g of
compound 7b (91% yield) as a pale yellow oil. [Found: C, 76.27; H,
8.87; N, 17.50. C18H25N3 requires C, 76.28; H, 8.89; N, 17.63%.] nmax
(neat) 2923, 2854, 1476, 1466, 1439, 1371, 1190, 767, 739, 729, 682; dH
(400 MHz, CDCl3) 7.57 (d, J¼7.6, 1H), 7.37e7.24 (m, 3H), 4.51 (t,
J¼6.8 Hz, 2H), 3.16 (t, J¼6.8 Hz, 2H), 2.93 (t, J¼8.0 Hz, 2H), 1.76
(quintet, J¼8.0 Hz, 2H), 1.47e1.37 (m, 2H), 1.36e1.16 (m, 8H), 0.84 (t,
J¼7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 143.4, 132.4, 128.8, 128.5, 128.4,
127.7, 125.6, 124.0, 44.7, 31.8, 29.4, 29.3, 29.2, 29.1, 28.9, 26.5, 22.6,
14.0; MS m/z 283 (Mþ, 14), 254 (18), 240 (10), 212 (10), 198 (39), 185
(100), 184 (60), 170 (42), 156 (35), 143 (16), 130 (27), 129 (29), 128
(33), 115 (35), 103 (14), 77 (14), 55 (8), 51 (8), 41 (39%).
3.3.10. 1-Cyclohexyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline
(7c). Compound 7c was prepared from 5c (0.130 g, 0.39 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 50% ethyl acetate/petroleum ether) afforded
0.086 g of compound 7c (87% yield). After crystallization from ethyl
acetate/petroleum ether, compound 7c was obtainedas awhite solid,
mp¼84e86 ꢀC. [Found: C, 75.90; H, 7.63; N,16.65. C16H19N3 requires
C, 75.85; H, 7.56; N, 16.59%.] nmax (KBr) 3060, 2927, 2850, 1474, 1443,
1338, 1190, 993, 778, 756, 730, 684; dH (400 MHz, CDCl3) 7.56 (d,
J¼7.6 Hz, 1H), 7.34 (td, J¼7.6, 2.0 Hz, 1H), 7.31e7.23 (m, 2H), 4.49 (t,
J¼6.8 Hz, 2H), 3.14 (t, J¼6.8 Hz, 2H), 3.01e2.91 (m,1H), 2.02e1.92 (m,
2H), 1.91e1.70 (m, 5H), 1.48e1.26 (m, 3H); dC (100.6 MHz, CDCl3)
147.9, 132.6, 128.4, 128.3, 127.9, 127.7, 125.7, 124.1, 44.6, 35.9, 32.2,
29.3, 26.6, 25.9; MS m/z 253 (Mþ, 36), 224 (100), 196 (83), 185 (49),
182 (72), 168 (26), 167 (28), 141 (15), 130 (21), 128 (25), 115 (44), 103
(20), 91 (24), 84 (18), 77 (41), 63 (13), 55 (16), 51 (23), 41 (55%).
3.3.6. 3-(4-Methoxyphenyl)-8H-[1,2,3]triazolo[5,1-a]isoindole (6f).
Compound 6f was prepared from 4f (0.149 g, 0.38 mmol) in ac-
cordance with general procedure. Purification by column chroma-
tography (silica gel, 40% petroleum ether/ethyl acetate) afforded
0.098 g of compound 6f (98% yield). After crystallization from ethyl
acetate/petroleum ether, compound 6f was obtained as a white
solid, mp¼154e156 ꢀC. [Found: C, 72.85; H, 5.02; N, 16.03.
C16H13N3O requires C, 72.99; H, 4.98; N, 15.96%.] nmax (KBr) 3064,
2961, 2922, 2850, 1615, 1508, 1454, 1420, 1356, 1298, 1246, 1174,
1100, 1031, 825, 803, 768; dH (400 MHz, acetone-d6) 7.93e7.86 (m,
3H), 7.69e7.65 (m, 1H), 7.52e7.47 (m, 1H), 7.44 (td, J¼7.6, 1.2 Hz,
1H), 7.13e7.07 (m, 2H), 5.47 (s, 2H), 3.87 (s, 3H); dC (100.6 MHz,
acetone-d6) 161.5, 144.0, 140.2, 139.8, 130.3, 130.0, 129.9, 129.9,
126.4, 126.1, 122.6, 116.2, 56.6, 52.6.
3.3.7. 3-(Thiophen-3-yl)-8H-[1,2,3]triazolo[5,1-a]isoindole (6g). Com-
pound 6g was prepared from 4g (0.150 g, 0.47 mmol) in accordance
with general procedure. Purification by column chromatography
(silica gel, 40% ethyl acetate/petroleum ether) afforded 0.107 g of
compound 6g (95% yield). After crystallization from ethyl acetate/
petroleum ether, compound 6g was obtained as a green solid,
mp¼178e180 ꢀC. [Found: C, 65.32; H, 3.85; N, 17.60; S, 13.35.
C13H9N3S requires C, 65.25; H, 3.79; N, 17.56; S, 13.40%.] nmax (KBr)
3101, 2963, 2924, 2848, 1420, 1402, 1319, 1171, 1121, 1070, 867, 856,
793, 773, 730, 708; dH (400 MHz, CDCl3) 7.85 (br d, J¼7.6 Hz, 1H), 7.74
(dd, J¼2.8, 1.2 Hz, 1H), 7.64 (dd, J¼4.8, 1.2 Hz, 1H) 7.53e7.49 (m, 1H),
7.49e7.43 (m, 2H), 7.40 (td, J¼7.6, 1.2 Hz, 1H), 5.33 (s, 2H); dC
(100.6 MHz, CDCl3) 140.9, 138.4, 135.0, 132.0, 128.7, 128.2, 127.8, 126.5,
126.3, 124.1, 122.0, 121.0, 50.9; MS m/z 239 (Mþ, 12), 211 (99), 210
(100), 184 (27), 166 (19), 152 (10), 139 (29), 105 (14), 102 (17), 92 (61),
79 (22), 63 (25), 51 (22), 45 (60%).
3.3.11. 1-Phenyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline
(7d). Compound 7d was prepared from 5d (0.139 g, 0.37 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 50% ethyl acetate/petroleum ether) afforded
0.075 g of compound 7d (82% yield). After crystallization from ethyl
acetate/petroleum ether, compound 7d was obtained as a yellow
solid, mp¼154e156 ꢀC. [Found: C, 77.80; H, 5.35; N, 16.95. C16H13N3
requires C, 77.71; H, 5.30; N, 16.99%.] nmax (KBr) 3057, 3044, 3032,
2972, 2947, 2913, 1478, 1466, 1448, 1365, 1340, 1232, 1191, 1152, 987,
784, 764, 750, 730, 705, 682; dH (400 MHz, acetone-d6) 7.72e7.67
(m, 2H), 7.56e7.53 (m, 1H), 7.52e7.41 (m, 4H), 7.33 (td, J¼7.6, 1.2 Hz,
1H), 7.25e7.19 (m, 1H), 4.60 (t, J¼6.8 Hz, 2H), 3.32 (t, J¼6.8 Hz, 2H);
dC (100.6 MHz, acetone-d6) 144.2, 135.6, 134.3, 130.9, 130.8, 130.6,
130.5, 130.2, 130.1, 129.0, 127.0, 125.8, 46.6, 30.8; MS m/z 247 (Mþ,
14), 219 (31), 218 (24), 204 (23), 189 (12), 165 (7), 141 (8), 116 (80),
115 (100), 109 (36), 96 (29), 94 (30), 82 (32), 63 (14), 51 (18%).
3.3.8. 1-Pentyl-5,6-dihydro[1,2,3]triazolo[5,1-a]isoquinoline
(7a).
3.3.12. 1-(4-Methylphenyl)-5,6-dihydro[1,2,3]triazolo [5,1-a]isoquino-
line (7e). Compound 7e was prepared from 5e (0.167 g, 0.43 mmol)
in accordance with general procedure. Purification by column
chromatography (silica gel, 50% ethyl acetate/petroleum ether)
afforded 0.093 g of compound 7e (83% yield). After crystallization
from ethyl acetate/petroleum ether, compound 7e was obtained as
a yellow solid, mp¼140e142 ꢀC. [Found: C, 78.20; H, 5.75; N, 16.05.
C17H15N3 requires C, 78.13; H, 5.79; N,16.08%.] nmax (KBr) 3055, 3016,
Compound 7a was prepared from 5a (0.173 g, 0.47 mmol) in ac-
cordance with general procedure. Purification by column chroma-
tography (silica gel, 50% ethyl acetate/petroleum ether) afforded
0.107 g of compound 7a (94% yield) as a pale yellow oil. [Found: C,
74.67; H, 7.87; N, 17.50. C15H19N3 requires C, 74.65; H, 7.94; N,
17.41%.] nmax (neat) 2953, 2923, 2857, 1476, 1466, 1456, 1373, 1351,
1338, 1306, 1196, 768, 740, 731, 682; dH (400 MHz, CDCl3) 7.58 (d,

V. Fiandanese et al. / Tetrahedron 66 (2010) 8846e8853
8853
3. Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.;
Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.;
Reischer, R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.;
Yagi, B. H. J. Med. Chem. 2000, 43, 953e970.
4. (a) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986, 29,
2262e2267; (b) Buckle, D. R.; Outred, D. J.; Rockell, C. J. M.; Smith, H.; Spicer, B. A.
J. Med. Chem. 1983, 26, 251e254.
5. Giffin, M. J.; Heaslet, H.; Brik, A.; Lin, Y.-C.; Cauvi, G.; Wong, C.-H.; McRee, D. E.;
Elder, J. H.; Stout, C. D.; Torbett, B. E. J. Med. Chem. 2008, 51, 6263e6270.
6. (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.
7. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596e2599.
2943, 2914,1514,1469,1366,1349,1342,1184, 991, 827, 773, 748, 738,
556; dH (400 MHz, CDCl3) 7.61e7.57 (m, 3H), 7.32e7.22 (m, 4H), 7.16
(td, J¼7.6,1.2 Hz,1H), 4.55 (t, J¼6.8 Hz, 2H) 3.22 (t, J¼6.8 Hz, 2H), 2.40
(s, 3H); dC (100.6 MHz, CDCl3) 143.0, 138.2, 132.7, 129.3, 129.0, 128.9,
128.7, 128.4, 128.3, 127.4, 125.1, 124.3, 44.9, 29.2, 21.3; MS m/z 261
(Mþ, 10), 233 (27), 218 (15), 203 (15), 189 (8), 141 (12), 116 (79), 115
(100), 109 (21), 103 (15), 102 (18), 101 (16), 94 (11), 89 (23), 77 (10), 76
(12), 63 (10), 51 (13%).
3.3.13. 1-(4-Methoxyphenyl)-5,6-dihydro[1,2,3]triazolo [5,1-a]isoqui-
noline (7f). Compound 7f was prepared from 5f (0.150 g, 0.42 mmol)
in accordance with general procedure. Purification by column chro-
matography (silica gel, 40% petroleum ether/ethyl acetate) afforded
0.086 g of compound 7f (74% yield). After crystallization from ethyl
acetate/petroleum ether, compound 7f was obtained as a pale yellow
solid, mp¼116e117 ꢀC. [Found: C, 73.68; H, 5.49; N,15.09. C17H15N3O
requires C, 73.63; H, 5.45; N, 15.15%.] nmax (KBr) 3067, 2956, 2923,
2838, 1610,1508,1466, 1458,1366, 1297, 1246, 1228,1190, 1178, 1023,
843, 769; dH (400 MHz, CDCl3) 7.62e7.57 (m, 2H), 7.56e7.53 (m, 1H),
7.30e7.26(m,1H), 7.23(td,J¼7.6,1.2Hz,1H), 7.14(td,J¼7.6, 1.2 Hz, 1H),
6.98e6.93 (m, 2H), 4.53 (t, J¼6.8 Hz, 2H), 3.82 (s, 3H), 3.20 (t, J¼6.8 Hz,
2H);dC (100.6MHz,CDCl3)159.6,142.7,132.7,129.7,128.8,128.7,128.4,
127.3, 125.1, 124.1, 123.9, 114.0, 55.2, 44.9, 29.2; MS m/z 277 (Mþ, 14),
249 (32), 234 (30), 219 (7), 218 (7), 206 (9), 204 (9), 178 (14), 152 (9),
141 (13),116 (77),115 (100),111 (20),103(11),102(18), 94(12), 89(19),
88 (14), 82 (10), 76 (23), 63 (16), 51 (14%).
8. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057e3064.
9. Selected reviewes: (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; Gil, M. V.; Arévalo, M. J.; López, O. Synthesis 2007,
1589e1620.
ꢀ
10. (a) James, D.; Escudier, J.-M.; Amigues, E.; Schulz, J.; Vitry, C.; Bordenave, T.;
Slozek-Pinaud, M.; Fouquet, E. Tetrahedron Lett. 2010, 51, 1230e1232; (b)
Montagnat, O. D.; Lessene, G.; Hughes, A. B. J. Org. Chem. 2010, 75, 390e398; (c)
Cravotto, G.; Fokin, V. V.; Garella, D.; Binello, A.; Boffa, L.; Barge, A. J. Comb.
Chem. 2010, 12, 13e15; (d) Jurícek, M.; Kouwer, P. H. J.; Rehák, J.; Sly, J.;
Rowan, A. E. J. Org. Chem. 2009, 74, 21e25; (e) Xia, Y.; Liu, Y.; Wan, J.; Wang, M.;
Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. J. Med. Chem. 2009, 52, 6083e6096; (f)
Broggi, J.; Díez-González, S.; Petersen, J. L.; Berteina-Raboin, S.; Nolan, S. P.;
Agrofoglio, L. A. Synthesis 2008, 141e148; (g) Li, P.; Wang, L.; Zhang, Y. Tetra-
hedron 2008, 64, 10825e10830; (h) Jlalia, I.; Elamari, H.; Meganem, F.;
Herscovici, J.; Girard, C. Tetrahedron Lett. 2008, 49, 6756e6758; (i) Wang, Z.-X.;
Zhao, Z.-G. J. Heterocycl. Chem. 2007, 44, 89e92; (j) Chassaing, S.; Kumarraja, M.;
Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett. 2007, 9, 883e886; (k) 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; (l) Bertrand, P.; Gesson, J. P. J. Org. Chem.
2007, 72, 3596e3599.
11. (a) Brawn, R. A.; Welzel, M.; Lowe, J. T.; Panek, J. S. Org. Lett. 2010, 336e339; (b)
Majumdar, K. C.; Ray, K.; Ganai, S.; Ghosh, T. Synthesis 2010, 858e862; (c) Hu, Y.-Y.;
Hu, J.; Wang, X.-C.; Guo, L.-N.; Shu, X.-Z.; Niu, Y.-N.; Liang, Y.-M. Tetrahedron 2010,
66, 80e86; (d) Chowdhury, C.; Mukherjee, S.; Das, B.; Achari, B. J. Org. Chem. 2009,
74, 3612e3615; (e) Chowdhury, C.; Sasmal, A. K.; Dutta, P. K. Tetrahedron Lett.
2009, 50, 2678e2681; (f) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I.
Bioorg. Med. Chem. Lett. 2009,19, 5241e5245;(g) Laleu, B.; Lautens, M. J. Org. Chem.
2008, 73, 9164e9167;(h) Chen, W. L.; Su, C. L.; Huang, X. Synlett 2006,1446e1448;
(i) Dolhem, F.; Thali, F. A.; Lièvre, C.; Demailly, G. Eur. J. Org. Chem. 2005,
5019e5023; (l) Chowdhury, C.; Mandal, S. B.; Achari, B. Tetrahedron Lett. 2005, 46,
8531e8534.
3.3.14. 1-(Thiophen-3-yl)-5,6-dihydro[1,2,3]triazolo [5,1-a]isoquino-
line (7g). Compound 7g was prepared from 5g (0.130 g, 0.34 mmol)
in accordance with general procedure. Purification by column
chromatography (silica gel, 50% ethyl acetate/petroleum ether)
afforded 0.075 g of compound 7g (87% yield). After crystallization
from ethyl acetate/petroleum ether, compound 7g was obtained as
a yellow solid, mp¼160e162 ꢀC. [Found: C, 66.32; H, 4.42; N,16.60; S,
12.72. C14H11N3S requires C, 66.38; H, 4.38; N, 16.59; S, 12.66%.] nmax
(KBr) 3095, 3073, 2929, 1484, 1474, 1466, 1458, 1400, 1348, 1321,
1288, 1240, 1184, 1133, 857, 802, 774, 743, 640; dH (400 MHz, CDCl3)
7.68e7.64 (m, 2H), 7.42e7.39 (m, 2H), 7.33e7.30 (m, 1H), 7.28 (td,
J¼7.6, 1.2 Hz, 1H), 7.21 (td, J¼7.6, 1.6 Hz, 1H), 4.55 (t, J¼6.8 Hz, 2H),
3.22 (t, J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 138.6,132.8,132.1,129.2,
129.1, 128.5, 127.6, 127.5, 126.0, 125.0, 124.3, 123.8, 44.9, 29.2; MS m/z
253 (Mþ, 16), 225 (38), 224 (20), 210 (17), 197 (8),191 (6),165 (8),152
(11), 141 (10), 116 (77), 115 (100), 112 (16), 98 (38), 89 (11), 85 (11), 77
(12), 76 (11), 63 (13), 51 (15), 45 (36%).
12. Shafran, E. A.; Bakulev, V. A.; Rozin, Y. A.; Shafran, Y. M. Chem. Heterocycl. Comp.
2008, 44, 1040e1069.
13. Selected reviewes: (a) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.dEur. J. 2010, 16, 2654e2672; (b) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792e9826; (c) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094e5115; (d)
Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074e1086.
14. (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2008, 64,
53e60; (b) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron
2008, 64, 7301e7306; (c) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.
Tetrahedron 2006, 62, 5126e5132; (d) Fiandanese, V.; Bottalico, D.; Cardellic-
chio, C.; Marchese, G.; Punzi, A. Tetrahedron 2005, 61, 4551e4556; (e)
Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. J. Organomet. Chem. 2005,
690, 3004e3008; (f) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tet-
rahedron 2004, 60, 11421e11425.
Acknowledgements
15. (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.; Quarta, M. R.;
Fittipaldi, M. Synthesis 2009, 3853e3859; (b) Fiandanese, V.; Bottalico, D.;
Marchese, G.; Punzi, A.; Capuzzolo, F. Tetrahedron 2009, 65, 10573e10580.
16. For a comprehensive review, see: Fiandanese, V.; Bottalico, D. Curr. Org. Chem.
2009, 13, 554e572.
This work was financially supported by the University of Bari
(Italy).
17. Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org. Lett. 2007, 9,
2333e2336.
References and notes
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