An easy access to 4-(1,2,3-triazolylalkyl)-1,2,3-triazole-fused dihydroisoquinolines and dihydroisoindoles

Article abstract of DOI:10.1016/j.tet.2012.10.005

A convenient synthesis of 4-(1,2,3-triazolylalkyl)-1,2,3-triazole fused dihydroisoquinolines and dihydroisoindoles is reported, starting from easily available (2-iodoaryl)alkyl azides and terminal alkynols. The procedure is based upon transition-metal cat

Full text of DOI:10.1016/j.tet.2012.10.005

Tetrahedron 68 (2012) 10310e10317
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An easy access to 4-(1,2,3-triazolylalkyl)-1,2,3-triazole-fused dihydroisoquinolines
and dihydroisoindoles
*
Vito Fiandanese , Isabella Marino, 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:
Received 25 May 2012
Received in revised form 13 September 2012
Accepted 2 October 2012
Available online 6 October 2012
A
convenient synthesis of 4-(1,2,3-triazolylalkyl)-1,2,3-triazole fused dihydroisoquinolines and
dihydroisoindoles is reported, starting from easily available (2-iodoaryl)alkyl azides and terminal
alkynols. The procedure is based upon transition-metal catalyzed coupling reactions followed by iterative
cycloaddition reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Coupling reactions
Click chemistry
Alkynols
Azides
Triazole-fused heterocycles
1. Introduction
In connection with our continuing interest in the development
of novel heterocyclic ring structures of biological signficance,10 we
The 1,2,3-triazole ring is considered an important pharmacophore
in drug discovery research, and is common amongst various com-
pounds of biological significance.1 These compounds were tradition-
ally synthesized by the Huisgen’s thermal 1,3-dipolar [3þ2]-
cycloaddition of azides with alkynes,2 but the original reactions
were seriously limited by the high reaction temperature and by the
low regioselectivityleading to 1,4- and 1,5-substituted-1,2,3-triazoles.
Significant advances have been obtained in this field by the copper(I)-
catalyzed 1,3-dipolar cycloaddition reaction of azides with alkynes
(CuAAC), the most prominent example of ‘click chemistry’, developed
by the groups of Sharpless3 and Meldal.4 Mild, efficient metal cata-
lyzed variants for both terminal- and internal alkynes are now avail-
able.5 These reactions can be conducted at room temperature and are
highly regioselective, leading exclusively to 4-substituted-1,2,3-
triazoles. The extraordinary success of click chemistry has led to
a wide number of publications over the last few years.6,7 In particular,
this methodology has been used by many research groups for the
synthesis of several bicyclic, as well as polycyclic fused triazoles het-
erocycles,8 compounds of great interest for their various biological
and pharmacological activities.8,9 Generally, fused triazoles are pre-
pared by an intramolecular 1,3-dipolar cycloaddition between azides
and alkynes8a,c,j and a one-pot copper-8d or palladium-catalyzed8f,g
coupling reaction followed by a [3þ2] cycloaddition.
have recently developed a general approach to novel un-
symmetrically substituted 4,40-bi-1,2,3-triazoles,11a an easy syn-
thesis of 1,2,3-triazole-fused heterocycles11b and NeC linked 1,2,3-
triazole oligomers,11c and a general procedure for the synthesis of
1,2,3-triazole-fused dihydroisoquinolines.11d On the basis of these
results, we now report the extensions of our initial discovery
dealing with 1,2,3-triazole fused-heterocycles, that have led to the
facile synthesis of 4-(1,2,3-triazolylakyl)-1,2,3-triazole-fused-het-
erocycles and of more complex derivatives containing additional
triazole rings. The methodology is based on the use of easily
available azides subjected to coupling reactions with several alky-
nols, leading to difunctional compounds bearing a hydroxyl group
as the site for azide substitution, followed by an iterative formation
of triazole rings.
2. Results and discussion
Our strategy is outlined in Scheme 1. We started with the coupling
reactions between 2-(2-iodoaryl)alkylazides 1, 2-iodobenzylazide
(m¼0) and 2-(2-iodophenyl)ethyl azide (m¼1) with several termi-
nal alkynols 2 (n¼1,2,3) leading to the corresponding coupled
products 3 that were easily transformed into the fused triazoles 4 by
means of a thermal intramolecular [3þ2] cycloaddition reaction in
toluene, without a catalyst. In order to obtain the desired final
products 8 it was necessary to convert the fused triazoles alcohols 4
into the corresponding azides 7. Thus the compounds 4 were easily
* Corresponding author. E-mail address: fianda@chimica.uniba.it (V. Fiandanese).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.005

V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
10311
OH
(
)
2 n=1,2,3n
N3
N3
(
)
(
)
(
)
(
)
PBr3, CH2Cl2, 50 °C
m
m
toluene
140 °C
m
m
N
N
or
Pd(PPh3)4, CuI
Et3N, 50 °C
I
N
OH
N
TsCl, KOH, THF, rt
(
)
n
N
N
1
m=0,1
3
( )n
( )n
OH
X
5 X = Br
4
6 X = OTs
(
)
(
)
m
m
NaN3
R
.
N
N
Cu(OAc)2 H2O
H2O, 100 °C
DMF, 100 °C
N
N
N
N
( )n
N3
( )n
N
N
N
7
R
8
Scheme 1.
transformed into bromoderivatives 5 or tosyl derivative 6, that, by
reactionwith NaN3 in DMF led to the azides 7. The final cycloaddition
reaction of the azides 7 with several aryl- and alkylalkynes afforded
the 4-(1,2,3-triazolylalkyl)-substituted-1,2,3-triazole-fused dihy-
droisoquinolines and dihydroisoindoles 8.
mass-spectrometry analysis was performed on a Shimadzu
GCeMS-QP5000 gas chromatograph-mass spectrometer equipped
with a Supelco SLBÔ-5 ms capillary column (30 mꢀ0.25 mm id). 1H
NMR spectra were recorded in deuterochloroform or DMSO-d6 on
a Varian Inova at 400 MHz. 13C NMR spectra were recorded in
deuterochloroform or DMSO-d6 on a Varian Inova at 100.6 MHz. IR
spectra were recorded on a PerkineElmer FT-IR Spectrum Bx. Ele-
mental analyses were recorded on a Carlo Erba EA 1108 elemental
analyzer. Melting points were determined on a Stuart Scientific
Melting point apparatus SMP3. Tetrahydrofuran was distilled from
sodium, N,N-dimethylformamide, toluene, and triethylamine were
used as supplied.
All results are depicted in Table 1. The products 3e7 were ob-
tained in fair to good yields. High yields were obtained in the cy-
cloaddition reactions, compounds 8a,b,d,f, (80e95%), whereas fair
to good yields (49e82%) were obtained for compounds 8c,e,g.
In order to demonstrate the versatility of our strategy, we de-
cided to increase the number of triazole rings linked to the fused
heterocycles by simple variation of the alkyne in the cyclization
reaction involving compound 7. As reported in Scheme 2, starting
from compound 7c and employing 4-bromo-1-butyne, the result-
ing product 9, obtained in 71% yield, was easily transformed into
azide 10 (98% yield) that was subjected to the cycloaddition re-
action with two alkynes leading to products 11a,b in high yields
(85% and 90%). It is worth noting that, following the same approach,
but starting from compound 10 and employing, in the cycloaddi-
tion reaction, instead of a simple alkyne, the bromoalkyne, we can,
in principle, considerably increase the number of triazole rings
linked to the fused heterocycles.
4.2. General procedure for the synthesis of compounds 3
Alkyn-1-ol (2 equiv) was added at room temperature under
nitrogen to a stirred suspension (0.25e0.29 M) of 2-(2-iodophenyl)
ethylazide or 2-iodobenzylazide (1 equiv), Pd(PPh3)4 (0.04 equiv),
CuI (0.08 equiv) in Et3N. The mixture was heated at 50 ꢁC for 2 h,
then quenched with a saturated aqueous solution of NH4Cl (50 mL)
and extracted with ethyl acetate (3ꢀ60 mL). The organic extracts
were washed with an aqueous solution of NaCl (3ꢀ50 mL), dried
over Na2SO4, and concentrated under vacuum. The residue was
purified by column chromatography.
3. Conclusion
In summary, we have described an efficient and easy method for
the synthesis of 4-(1,2,3-triazolylakyl)-1,2,3-triazole-fused-hetero-
cycles 8, starting from readily available terminal alkynols and
azides and employing simple coupling reactions and appropriate
transformation of the alcoholic group in the azide function to ob-
tain the title compounds. Moreover, this procedure is greatly ver-
satile, as demonstred by the synthesis of compounds 11, with
additional triazole rings linked to the fused heterocycles.
4.2.1. 4-[2-(Azidomethyl)phenyl]but-3-yn-1-ol (3a). Compound 3a
was prepared from but-3-yn-1-ol (0.811 g, 11.58 mmol) and 2-
iodobenzylazide (1.500 g, 5.79 mmol) in accordance with the gen-
eral procedure. Purification by column chromatography, Rf (silica
gel, 30% ethyl acetate/hexane) 0.41, afforded 0.570 g of compound
3a (49% yield) as a yellow-orange oil. [Found: C, 65.70; H, 5.48; N,
20.93. C11H11N3O requires C, 65.66; H, 5.51; N, 20.88%]. nmax (neat)
3365, 3065, 2936, 2882, 2090, 1481, 1446, 1381, 1343, 1262, 1191,
1046, 760; dH (400 MHz, CDCl3) 7.44 (dd, J¼6.2, 1.8 Hz, 1H),
7.30e7.22 (m, 3H), 4.45 (s, 2H), 3.80 (t, J¼6.4 Hz, 2H), 2.75 (br s, 1H),
2.69 (t, J¼6.4 Hz, 2H); dC (100.6 MHz, CDCl3) 137.1, 132.4, 128.6,
128.2, 128.1, 123.2, 92.3, 79.7, 61.0, 53.5, 23.9; MS m/z 201 (Mþ, 14),
172 (29), 154 (25), 144 (90), 143 (71), 128 (18), 127 (19), 118
(100), 115 (85), 102 (12), 90 (77), 89 (52), 77 (24), 63 (36), 51 (26),
39 (66%).
4. Experimental section
4.1. 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-5 ms capillary column (30 mꢀ0.25 mm id). GC/
4.2.2. 3-[2-(2-Azidoethyl)phenyl]prop-2-yn-1-ol (3b). Compound
3b was prepared from prop-2-yn-1-ol (0.617 g, 10.99 mmol) and 2-

10312
V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
Table 1
Synthesis of compounds 8 according to Scheme 1
m
n
3 Yield (%)
4 Yield (%)
5 Yield (%)
6 Yield (%)
7 Yield (%)
8 Yield (%)
N
N
N
N
N
N
N
N
N
N
N
N
N3
0
2
OH
N
N
HO
Br
N3
3a
(49)
N
R
4a
5a (41)
7a (82)
(46)
8a R = Ph (80)
N
N
N3
N
N
N
N
N
N
N
N
N
1
1
N
N
N
OH
N
N3
Br
OH
(86)
(58)
3b
R
(61)
(89)
4b
5b
7b
8b R = p-Anisyl (87)
8c R = Cyclohexyl (49)
N
N
N3
N
N
N
N
N
N
N
N
N
N
1
2
OH
N
N
N3
7c
TsO
HO
(63)
(58)
3c
N
R
4c
6c (82)
(96)
8d R = Ph (81)
8e R = n-Pentyl (82)
1
3
N
N
N
N
N
N
N3
N
N
N
N
N
N
OH
N
N
3d
(59)
N
OH
4d (78)
Br
(46)
N3
R
(82)
5d
7d
8f R = p-Tolyl (95)
8g R = n-Pentyl (77)
(2-iodophenyl)ethylazide (1.500 g, 5.50 mmol) in accordance with
the general procedure. Purification by column chromatography, Rf
(silica gel, 30% ethyl acetate/hexane) 0.60, afforded 0.641 g of
compound 3b (58% yield) as a yellow oil. [Found: C, 65.71; H, 5.52;
N, 20.85. C11H11N3O requires C, 65.66; H, 5.51; N, 20.88%]. nmax
(neat) 3363, 3063, 2927, 2866, 2090, 1481, 1449, 1349, 1294, 1260,
1025, 953, 761; dH (400 MHz, CDCl3) 7.41 (d, J¼7.2 Hz, 1H),
7.26e7.20 (m, 1H), 7.19e7.11 (m, 2H), 4.50 (s, 2H), 3.46 (t, J¼7.2 Hz,
2H), 3.37 (br s, 1H), 3.02 (t, J¼7.2 Hz, 2H); dC (100.6 MHz, CDCl3)
139.6, 132.4, 129.1, 128.5, 126.6, 122.2, 91.4, 83.1, 51.2, 51.0, 33.8; MS
m/z 201 (Mþ, 54),172 (67),156 (19),144 (68),130 (41),115 (100),103
(34), 89 (24), 77 (58), 63 (31), 58 (24), 51 (39), 39 (57%).
4.2.3. 4-[2-(2-Azidoethyl)phenyl]but-3-yn-1-ol (3c). Compound 3c
was prepared from but-3-yn-1-ol (0.770 g, 10.99 mmol) and 2-(2-
iodophenyl)ethylazide (1.500 g, 5.50 mmol) in accordance with
the general procedure. Purification by column chromatography, Rf
(silica gel, 30% ethyl acetate/hexane) 0.48, afforded 0.685 g of
compound 3c (58% yield) as a yellow oil. [Found: C, 67.00; H, 6.12;
N, 19.63. C12H13N3O requires C, 66.96; H, 6.09; N, 19.52%]. nmax

V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
10313
N
N
N
N
N
N
N
N
N
N
N
R
NaN3
Br
N
.
.
Cu(OAc)2 H2O
H2O, 50 °C
DMF, 100 °C
Cu(OAc)2 H2O
H2O, 100 °C
N
N
N
N
N
N
N3
7c
N
N
N
Br
N
N3
R
N
10 (98%)
9 (71%)
N
11a R= p-Tolyl (90%)
11b R= n-Butyl (85%)
Scheme 2.
(neat) 3365, 3062, 2930, 2879, 2101, 1481, 1444, 1288, 1259, 1044,
757; dH (400 MHz, CDCl3) 7.42e7.37 (m,1H), 7.25e7.13 (m, 3H), 3.81
(t, J¼6.4 Hz, 2H), 3.49 (t, J¼7.4 Hz, 2H), 3.04 (t, J¼7.4 Hz, 2H), 2.70 (t,
J¼6.4 Hz, 2H), 2.30 (br s, 1H); dC (100.6 MHz, CDCl3) 139.6, 132.4,
129.2, 128.1, 126.7, 123.2, 90.9, 80.3, 61.2, 51.5, 34.2, 23.8; MS m/z
215 (Mþ, 25), 185 (100), 158 (41), 156 (39), 154 (19), 141 (18), 130
(63), 129 (55), 128 (62), 115 (59), 104 (21), 103 (21), 91 (11), 89 (11),
77 (51), 63 (18), 51 (26), 39 (28%).
(84), 143 (64), 130 (20), 118 (100), 115 (85), 90 (71), 77 (22), 63
(36), 51 (26), 39 (64%).
4.3.2. (5,6-Dihydro-[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)methanol
(4b). Compound 4b was prepared from 3b (0.637 g, 3.17 mmol) in
accordance with the general procedure. The reaction mixture was
cooled and crude product was recovered by filtration under vac-
uum. Purification by crystallization from ethyl acetate/hexane
afforded 0.547 g of compound 4b (86% yield) as a white solid,
mp¼137e139 ꢁC. [Found: C, 65.68; H, 5.47; N, 20.91. C11H11N3O
requires C, 65.66; H, 5.51; N, 20.88%]. nmax (KBr) 3255, 3047, 2934,
2856, 1483, 1430, 1341, 1188, 1150, 1116, 1034, 1022, 758, 729, 677,
629; dH (400 MHz, CDCl3þD2O) 7.86 (d, J¼7.6 Hz, 1H), 7.39e7.22 (m,
3H), 4.92 (s, 2H), 4.48 (t, J¼6.8 Hz, 2H), 3.14 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, CDCl3) 142.1, 132.3, 131.2, 129.2, 128.2, 128.1, 125.8,
124.5, 56.4, 44.8, 29.0; MS m/z 201 (Mþ, 56), 172 (69), 156 (19), 144
(68), 130 (41), 115 (100), 103 (35), 89 (23), 77 (60), 63 (31), 57 (24),
51 (40), 39 (57%).
4.2.4. 5-[2-(2-Azidoethyl)phenyl]pent-4-yn-1-ol (3d). Compound
3d was prepared from pent-4-yn-1-ol (0.925 g, 11.00 mmol) and 2-
(2-iodophenyl)ethylazide (1.500 g, 5.50 mmol) in accordance with
the general procedure. Purification by column chromatography, Rf
(silica gel, 30% ethyl acetate/hexane) 0.40, afforded 0.743 g of
compound 3d (59% yield) as a yellow oil. [Found: C, 68.15; H, 6.63;
N,18.43. C13H15N3O requires C, 68.10; H, 6.59; N,18.33%]. nmax (neat)
3365, 3062, 2931, 2872, 2085, 1481, 1442, 1381, 1349, 1294, 1261,
1052, 757; dH (400 MHz, CDCl3) 7.40e7.34 (m, 1H), 7.23e7.12 (m,
3H), 3.78 (t, J¼6.2 Hz, 2H), 3.47 (t, J¼7.4 Hz, 2H), 3.03 (t, J¼7.4 Hz,
2H), 2.55 (t, J¼7.0 Hz, 2H), 2.28 (br s, 1H), 1.89e1.80 (m, 2H); dC
(100.6 MHz, CDCl3) 139.2, 132.3, 129.2, 127.9, 126.6, 123.3, 93.6,
78.9, 61.4, 51.3, 34.1, 31.3, 15.9; MS m/z 229 (Mþ, 14), 199 (43), 198
(32), 185 (100), 172 (24), 170 (25), 156 (40), 145 (36), 144 (36), 130
(52), 129 (42), 128 (56), 115 (70), 103 (23), 91 (17), 89 (16), 77 (56),
63 (19), 51 (31), 39 (48%).
4.3.3. 2-(5,6-Dihydro-[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)ethanol
(4c). Compound 4c was prepared from 3c (0.683 g, 2.19 mmol) in
accordance with the general procedure. Purification by column
chromatography, Rf (silica gel, 10% hexane/ethyl acetate) 0.34,
afforded 0.430 g of compound 4c (63% yield). After crystallization
from ethyl acetate, compound 4c was obtained as a white solid,
mp¼99e101 ꢁC. [Found: C, 66.98; H, 6.13; N, 19.53. C12H13N3O
requires C, 66.96; H, 6.09; N, 19.52%]. nmax (KBr) 3304, 2946, 2914,
2861, 1469, 1434, 1191, 1151, 1047, 1017, 776, 742, 682; dH (400 MHz,
CDCl3þD2O) 7.60 (d, J¼7.6 Hz, 1H), 7.32e7.21 (m, 3H), 4.45
(t, J¼6.8 Hz, 2H), 4.02 (t, J¼6.2 Hz, 2H), 3.20e3.07 (m, 4H); dC
(100.6 MHz, CDCl3) 140.4, 132.3, 129.7, 128.7, 128.4, 127.6, 124.9,
124.1, 60.8, 44.6, 29.3, 29.0; MS m/z 215 (Mþ, 22), 185 (100),
158 (38), 156 (37), 154 (17), 141 (16), 130 (59), 129 (53), 128 (59), 115
(57), 104 (20), 103 (20), 91 (11), 89 (10), 77 (44), 63 (18), 51 (25),
39 (23%).
4.3. General procedure for the synthesis of compounds 4
A solution (0.23e0.50 M) of compound 3 in toluene was
heated at 140 ꢁC for 24e30 h in a capped flask. Compound 4b was
recovered by filtration, then purified by crystallization. For com-
pounds 4a,c,d, the reaction mixture was quenched with a satu-
rated aqueous solution of NH4Cl (30 mL) and extracted with ethyl
acetate (3ꢀ40 mL). The organic extracts were washed with an
aqueous solution of NaCl (3ꢀ30 mL), dried over Na2SO4, and
concentrated under vacuum. The residue was purified by column
chromatography.
4.3.4. 3-(5,6-Dihydro-[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)propan-
1-ol (4d). Compound 4d was prepared from 3d (0.743 g,
3.25 mmol) in accordance with the general procedure. Purification
by column chromatography, Rf (silica gel, ethyl acetate) 0.27,
afforded 0.580 g of compound 4d (78% yield). After crystallization
from ethyl acetate/hexane, compound 4d was obtained as a pale
yellow solid, mp¼71e72 ꢁC. [Found: C, 68.16; H, 6.61; N, 18.37.
C13H15N3O requires C, 68.10; H, 6.59; N, 18.33%]. nmax (KBr) 3395,
3193, 2929, 2863, 1470, 1442, 1372, 1346, 1193, 1150, 1058, 1044,
764, 734; dH (400 MHz, CDCl3þD2O) 7.57 (d, J¼7.6 Hz, 1H),
7.30e7.18 (m, 3H), 4.43 (t, J¼6.8 Hz, 2H), 3.67 (t, J¼6.0 Hz, 2H), 3.10
(t, J¼6.8 Hz, 2H), 3.01 (t, J¼7.4 Hz, 2H), 2.04e1.95 (m, 2H); dC
(100.6 MHz, CDCl3) 142.5, 132.3, 129.0, 128.5, 128.3, 127.6, 125.1,
124.1, 61.4, 44.6, 31.2, 29.0, 22.8; MS m/z 229 (Mþ, 14), 199 (43), 198
(32), 185 (100), 172 (24), 170 (26), 156 (40), 145 (37), 144 (37), 130
4.3.1. 2-(8H-[1,2,3]Triazolo[5,1-a]isoindol-3-yl)ethanol
(4a). Compound 4a was prepared from 3a (0.509 g, 2.53 mmol) in
accordance with the general procedure. Purification by column
chromatography, Rf (silica gel, ethyl acetate) 0.23, afforded 0.234 g
of compound 4a (46% yield). After crystallization from ethyl ace-
tate, compound 4a was obtained as
a
white solid,
mp¼130e132 ꢁC. [Found: C, 65.73; H, 5.54; N, 20.93. C11H11N3O
requires C, 65.66; H, 5.51; N, 20.88%]. nmax (KBr) 3306, 2924, 2858,
1446, 1440, 1429, 1408, 1145, 1047, 1010, 768, 731; dH (400 MHz,
CDCl3þD2O) 7.63 (d, J¼7.6 Hz, 1H), 7.48e7.38 (m, 2H), 7.37e7.31
(m, 1H), 5.23 (s, 2H), 4.01 (t, J¼6.0 Hz, 2H), 3.13 (t, J¼6.0 Hz, 2H); dC
(100.6 MHz, CDCl3) 140.5, 140.1, 136.2, 128.7, 128.1, 127.9, 124.0,
121.0, 61.4, 51.0, 28.9; MS m/z 201 (Mþ, 14), 172 (24), 154 (19), 144

10314
V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
(57), 129 (42), 128 (58), 115 (76), 103 (24), 91 (15), 89 (16), 77 (57),
63 (20), 51 (31), 39 (48%).
compound 6c (82% yield). After crystallization from ethyl acetate/
hexane, compound 6c was obtained as white solid,
a
mp¼105e106 ꢁC. [Found: C, 61.80; H, 5.23; N, 11.43; S, 8.75.
C19H19N3O3S requires C, 61.77; H, 5.18; N, 11.37; S, 8.68%]. nmax (KBr)
3042, 2957, 2915,1591,1481,1352,1169,1096, 978, 857, 767, 662, 548;
dH (400 MHz, CDCl3) 7.67 (d, J¼8.0 Hz, 2H), 7.52 (d, J¼7.2 Hz, 1H),
7.34e7.21 (m, 5H), 4.45 (t, J¼6.8 Hz, 2H), 4.40 (t, J¼7.2 Hz, 2H), 3.30 (t,
J¼7.2 Hz, 2H), 3.11 (t, J¼6.8 Hz, 2H), 2.36 (s, 3H); dC (100.6 MHz,
CDCl3) 144.9, 137.5, 133.3, 132.8, 130.4, 130.0, 129.2, 128.8, 128.1,
128.0, 125.0, 124.3, 68.8, 45.0, 29.4, 26.8, 21.7; MS m/z 281 (4), 207
(10),197 (36),168 (100),154 (39), 141 (35),127 (21),115 (70),103 (8),
89 (13), 84 (50), 77 (24), 70 (23), 63 (15), 51 (16), 39 (31%).
4.4. General procedure for the synthesis of compounds 5a,b,d
PBr3 (2 equiv) was added at room temperature to a solution
(0.20e0.35 M) of compounds 4a,b,d (1 equiv) in CH2Cl2. The mixture
was heated at 50 ꢁC and, after completion (2e5 h), was quenched
with a saturated aqueous solution of NaHCO3 (30 mL) and extracted
withethyl acetate (3ꢀ40 mL). The organicextractswerewashedwith
an aqueous solution of NaCl (3ꢀ30 mL), dried over Na2SO4, and
concentratedundervacuum. The residuewaspurifiedby percolation.
4.4.1. 3-(2-Bromoethyl)-8H-[1,2,3]triazolo[5,1-a]isoindole
(5a). Compound 5a was prepared from 4a (0.234 g, 1.17 mmol) and
PBr3 (0.638 g, 2.34 mmol) in accordance with the general pro-
cedure. Purification by percolation, Rf (florisil, ethyl acetate) 0.68,
afforded 0.127 g of compound 5a (41% yield). After crystallization
from ethyl acetate/hexane, compound 5a was obtained as a white
solid, mp¼131e132 ꢁC. [Found: C, 50.15; H, 3.90; N, 15.94.
C11H10BrN3 requires C, 50.02; H, 3.82; N, 15.91%]. nmax (KBr) 3069,
2958, 2856, 1454, 1429, 1273, 1256, 1272, 1256, 1166, 1092, 1165,
1092, 1023, 771, 726; dH (400 MHz, CDCl3) 7.64 (d, J¼7.6 Hz, 1H),
7.48e7.39 (m, 2H), 7.35 (td, J¼7.6, 1.0 Hz, 1H), 5.24 (s, 2H), 3.73 (t,
J¼7.0 Hz, 2H), 3.46 (t, J¼7.0 Hz, 2H); dC (100.6 MHz, CDCl3) 140.7,
140.3, 135.5, 128.7, 128.1, 127.8, 124.1, 121.1, 51.0, 31.7, 29.6.
4.6. General procedure for the synthesis of compounds 7
Sodium azide (1.2 equiv) was added to a solution (0.17e0.29 M)
of compounds 5a,b,d or 6c (1 equiv) in DMF. The mixture was
warmed to 100 ꢁC for 2e5 h, then quenched with an aqueous so-
lution of NaCl (40 mL) and extracted with ethyl acetate (3ꢀ50 mL).
The organic extracts were washed with an aqueous solution of NaCl
(3ꢀ40 mL) and dried over Na2SO4. After evaporation of the solvent
at reduced pressure, pure azides were isolated.
4.6.1. 3-(2-Azidoethyl)-8H-[1,2,3]triazolo[5,1-a]isoindole
(7a). Compound 7a was prepared from 5a (0.120 g, 0.455 mmol) and
sodium azide (0.036 g, 0.55 mmol) in accordance with the general
procedure leading to 0.084 g (82% yield) of azide 7a as a viscous pale
yellow oil. [Found: C, 58.43; H, 4.50; N, 37.10. C11H10N6 requires C,
58.40; H, 4.46; N, 37.15%]. nmax (neat) 3059, 2932, 2861, 2095, 1459,
1442,1365,1296,1270,1170,1087,1023, 779, 729;dH (400 MHz, CDCl3)
7.65 (d, J¼7.6 Hz, 1H), 7.50e7.41 (m, 2H), 7.37 (t, J¼7.6 Hz,1H), 5.27 (s,
2H), 3.71 (t, J¼6.8 Hz, 2H), 3.18 (t, J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3)
140.7, 140.4, 134.8, 128.8, 128.1, 127.9, 124.1, 120.9, 51.0, 50.9, 26.0; MS
m/z 226 (Mþ, 13), 169 (33), 143 (54), 142 (92), 116 (61), 115 (100), 89
(50), 77 (16), 71 (26), 63 (36), 57 (17), 51 (24), 39 (66%).
4.4.2. 1-(Bromomethyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquino-
line (5b). Compound 5b was prepared from 4b (0.547 g,
2.72 mmol) and PBr3 (1.484 g, 5.44 mmol) in accordance with the
general procedure. Purification by percolation, Rf (florisil, 50% ethyl
acetate/CH2Cl2) 0.73, afforded 0.440 g of compound 5b (61% yield)
as a white solid, mp¼93e95 ꢁC. [Found: C, 50.10; H, 3.88; N, 15.95.
C11H10BrN3 requires C, 50.02; H, 3.82; N, 15.91%]. nmax (KBr) 2952,
2921, 2851, 1469, 1425, 1260, 1194, 1094, 1034, 1017, 768, 733, 677,
582; dH (400 MHz, CDCl3) 7.76 (d, J¼8.0 Hz, 1H), 7.44e7.38 (m, 1H),
7.37 (m, 2H), 4.80 (s, 2H), 4.53 (t, J¼6.8 Hz, 2H), 3.18 (t, J¼6.8 Hz,
2H); dC (100.6 MHz, CDCl3) 139.0, 132.7, 130.8, 129.5, 128.5, 128.1,
125.4, 124.0, 44.7, 28.9, 23.5.
4.6.2. 1-(Azidomethyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(7b). Compound 7b was prepared from 5b (0.440 g, 1.67 mmol)
and sodium azide (0.130 g, 2.00 mmol) in accordance with the
general procedure leading to 0.337 g (89% yield) of azide 7b as
a viscous yellow oil. [Found: C, 58.45; H, 4.52; N, 37.18. C11H10N6
requires C, 58.40; H, 4.46; N, 37.15%]. nmax (neat) 3058, 2952, 2926,
2090, 1480, 1470, 1465, 1454, 1441, 1432, 1380, 1302, 1255, 1089,
1039, 1020, 802, 774; dH (400 MHz, CDCl3) 7.68e7.63 (m, 1H),
7.40e7.31 (m, 3H), 4.65 (s, 2H), 4.56 (t, J¼6.8 Hz, 2H), 3.20 (t,
J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 137.0,132.6,131.4,129.5, 128.5,
128.0, 125.0, 124.0, 46.0, 44.8, 28.9; MS m/z 226 (Mþ, 41), 184 (41),
156 (91),142 (24),130 (85),129 (63),128 (49),115 (100),103 (54), 89
(27), 77 (83), 63 (43), 51 (55), 39 (75%).
4.4.3. 1-(3-Bromopropyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquino-
line (5d). Compound 5d was prepared from 4d (0.580 g,
2.53 mmol) and PBr3 (1.380 g, 5.06 mmol) in accordance with the
general procedure. Purification by percolation, Rf (florisil, ethyl
acetate) 0.73, afforded 0.338 g of compound 5d (46% yield) as a pale
yellow viscous oil. [Found: C, 53.40; H, 4.88; N, 14.43. C13H14BrN3
requires C, 53.44; H, 4.83; N, 14.38%]. nmax (neat) 3053, 2952, 2930,
2856, 1480, 1434, 1370, 1243, 1195, 1045, 770; dH (400 MHz, CDCl3)
7.61 (d, J¼7.6 Hz, 1H), 7.36e7.23 (m, 3H), 4.49 (t, J¼6.8 Hz, 2H), 3.51
(t, J¼6.6 Hz, 2H), 3.15 (t, J¼6.8 Hz, 2H), 3.10 (t, J¼7.4 Hz, 2H),
2.40e2.31 (m, 2H); dC (100.6 MHz, CDCl3) 141.2, 132.4, 129.2, 128.6,
128.4, 127.7, 125.1, 124.0, 44.6, 33.3, 31.3, 29.1, 24.8.
4.6.3. 1-(2-Azidoethyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(7c). Compound 7c was prepared from 6c (0.800 g, 2.17 mmol) and
sodium azide (0.169 g, 2.60 mmol) in accordance with the general
procedure leading to 0.500 g (96% yield) of azide 7c as a pale yellow
oil. [Found: C, 60.03; H, 5.10; N, 34.90. C12H12N6 requires C, 59.99;
H, 5.03; N, 34.98%]. nmax (neat) 3053, 2931, 2872, 2107, 1480, 1434,
1374, 1341, 1291, 1256, 1196, 771, 732; dH (400 MHz, CDCl3) 7.59 (d,
J¼7.2 Hz, 1H), 7.36e7.26 (m, 3H), 4.49 (t, J¼6.8 Hz, 2H), 3.73 (t,
J¼7.2 Hz, 2H), 3.20 (t, J¼7.2 Hz, 2H), 3.15 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, CDCl3) 138.9, 132.6, 129.9, 128.8, 128.5, 127.7, 125.0,
123.9, 50.1, 44.7, 29.1, 26.5; MS m/z 240 (Mþ, 8), 212 (20), 185 (34),
156 (100), 141 (10), 130 (33), 129 (35),128 (42), 115 (27), 103 (19), 89
(9), 77 (39), 63 (20), 51 (29), 39 (29%).
4.5. Synthesis of compound 6c
4.5.1. 2-(5,6-Dihydro-[1,2,3]triazolo[5,1-a]isoquinolin-1-yl)ethyl 4-
methylbenzenesulfonate (6c). A solution of compound 4c (0.364 g,
1.69 mmol) in THF (15 mL) was added at room temperature under
a nitrogen atmosphere to KOH (0.182 g, 5.08 mmol), followed by the
addition of tosyl chloride (0.644 g, 3.38 mmol) in one portion. The
mixture was stirred at room temperature for 16 h, then quenched
with a saturated aqueous solution of NH4Cl (30 mL) and extracted
with ethyl acetate (3ꢀ40 mL). The organic extracts were washed
with an aqueous solution of NaCl (3ꢀ30 mL), dried over Na2SO4, and
concentrated under vacuum. Purification by column chromatogra-
phy, Rf (silica gel, 30% hexane/ethyl acetate) 0.50, afforded 0.512 g of
4.6.4. 1-(3-Azidopropyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquino-
line (7d). Compound 7d was prepared from 5d (0.338 g, 1.16 mmol)

V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
10315
and sodium azide (0.091 g, 1.39 mmol) in accordance with the
general procedure leading to 0.242 g (82% yield) of azide 7d as
a pale yellow oil. [Found: C, 61.45; H, 5.52; N, 33.18. C13H14N6 re-
quires C, 61.40; H, 5.55; N, 33.05%]. nmax (neat) 2928, 2867, 2102,
1480, 1469, 1450, 1444, 1348, 1262, 1193, 1017, 771; dH (400 MHz,
CDCl3) 7.56 (d, J¼7.6 Hz, 1H), 7.36e7.22 (m, 3H), 4.48 (t, J¼6.8 Hz,
2H), 3.39 (t, J¼6.8 Hz, 2H), 3.14 (t, J¼6.8 Hz, 2H), 3.02 (t, J¼7.4 Hz,
2H), 2.12e2.02 (m, 2H); dC (100.6 MHz, CDCl3) 141.4, 132.4, 129.1,
128.6, 128, 127.7, 125.1, 123.9, 50.7, 44.6, 29.1, 27.7, 23.4; MS m/z 226
(53), 199 (59), 198 (100), 197 (66), 182 (20), 170 (27), 156 (26), 154
(24), 141 (24), 130 (78), 128 (66), 115 (74), 103 (43), 89 (24), 77 (85),
63 (31), 51 (50), 42 (44), 41 (45), 39 (77%).
compound 8c was obtained as a white solid, mp¼168e169 ꢁC.
[Found: C, 68.30; H, 6.59; N, 25.18. C19H22N6 requires C, 68.24; H,
6.63; N, 25.13%]. nmax (KBr) 3117, 3061, 2920, 2844, 1480, 1442, 1256,
1207, 1161, 1046, 812, 759, 726, 678; dH (400 MHz, CDCl3) 7.77 (d,
J¼7.2 Hz, 1H), 7.38 (s, 1H), 7.34e7.22 (m, 3H), 5.76 (s, 2H), 4.50 (t,
J¼6.8 Hz, 2H), 3.14 (t, J¼6.8 Hz, 2H), 2.69e2.55 (m, 1H), 1.99e1.86
(m, 2H), 1.75e1.55 (m, 3H), 1.36e1.20 (m, 4H), 1.19e1.05 (m, 1H); dC
(100.6 MHz, CDCl3) 154.1, 136.1, 132.5, 131.6, 129.6, 128.3, 128.2,
125.4, 123.5, 119.2, 45.4, 44.7, 35.1, 32.6, 28.8, 25.9, 25.8; MS m/z 334
(Mþ, 3), 306 (4), 185 (49), 156 (100), 130 (51), 129 (82), 128 (36), 103
(16), 77 (25), 41 (28), 39 (23%).
4.7.4. 5,6-Dihydro-1-[2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl]-
[1,2,3]triazolo[5,1-a]isoquinoline (8d). Compound 8d was prepared
from 7c (0.074 g, 0.31 mmol) and phenylacetylene (0.038 g,
0.37 mmol) and the reaction was performed at 100 ꢁC in accordance
with the general procedure. Purification by column chromatogra-
phy, Rf (silica gel,10% hexane/ethyl acetate) 0.56, afforded 0.085 g of
compound 8d (81% yield). After crystallization from ethyl acetate/
4.7. General procedure for the synthesis of compounds 8
Alkyne (1.2 equiv) and azide (1 equiv) were added at room
temperature to
a solution (0.03e0.06 M) of Cu(OAc)2$H2O
(0.2 equiv) in H2O in a capped flask. The mixture was warmed to
100 ꢁC and, after completion (1e5 h), was quenched with a satu-
rated aqueous solution of NH4Cl (30 mL) and extracted with ethyl
acetate or CH2Cl2 (3ꢀ50 mL). The organic extracts were washed
with an aqueous solution of NaCl (3ꢀ30 mL), dried over Na2SO4,
and concentrated under vacuum. The residue was purified by col-
umn chromatography on silica gel and by crystallization.
hexane, compound 8d was obtained as
a
white solid,
mp¼149e150 ꢁC. [Found: C, 70.08; H, 5.33; N, 24.48. C20H18N6 re-
quires C, 70.16; H, 5.30; N, 24.54%]. nmax (KBr) 3128, 3095, 3044,
2952, 1609, 1469, 1448, 1427, 1374, 1225, 1193, 1077, 1049, 913, 769,
747, 725, 691; dH (400 MHz, CDCl3) 7.78 (s, 1H), 7.71e7.67 (m, 2H),
7.42 (d, J¼7.2 Hz, 1H), 7.34e7.18 (m, 6H), 4.91 (t, J¼6.8 Hz, 2H), 4.44
(t, J¼6.8 Hz, 2H), 3.56 (t, J¼6.8 Hz, 2H), 3.07 (t, J¼6.8 Hz, 2H); dC
(100.6 MHz, CDCl3) 147.3, 138.1, 132.4, 130.6, 130.1, 128.9, 128.5,
128.4, 127.8, 127.8, 125.5, 124.5, 123.9, 120.5, 48.5, 44.7, 29.0, 27.6;
MS m/z 342 (Mþ, 39), 285 (57), 258 (67), 197 (25), 185 (65), 170 (55),
156 (35),154 (29), 143 (23), 141 (27), 130 (94), 128 (83), 115 (57), 103
(85), 89 (42), 77 (100), 63 (35), 51 (42), 39 (51%).
4.7.1. 3-[2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethyl]-8H-[1,2,3]triazolo
[5,1-a]isoindole (8a). Compound 8a was prepared from 7a (0.084 g,
0.37 mmol) and phenylacetylene (0.046 g, 0.45 mmol) and the re-
action was performed at 100 ꢁC in accordance with the general
procedure. Purification by column chromatography, Rf (silica gel,
ethyl acetate) 0.41, afforded 0.097 g of compound 8a (80% yield).
After crystallization from ethyl acetate/hexane, compound 8a was
obtained as a pale brown solid, mp¼173e175 ꢁC. [Found: C, 69.45;
H, 4.95; N, 25.68. C19H16N6 requires C, 69.50; H, 4.91; N, 25.59%].
nmax (KBr) 3132, 3053, 2941,1455,1448,1426,1350,1216,1177,1036,
760, 686; dH (400 MHz, CDCl3) 7.70 (s, 1H), 7.68e7.62 (m, 2H),
7.46e7.22 (m, 7H), 5.21 (s, 2H), 4.89 (t, J¼6.0 Hz, 2H), 3.59 (t,
J¼6.0 Hz, 2H); dC (100.6 MHz, CDCl3) 147.4, 140.5, 130.4, 128.8,
128.6, 128.2, 127.9, 127.3, 125.6, 124.0, 120.9, 120.6, 51.1, 49.2, 26.9
(two coincident peaks not observed).
4.7.5. 5,6-Dihydro-1-[2-(4-pentyl-1H-1,2,3-triazol-1-yl)ethyl]-[1,2,3]
triazolo[5,1-a]isoquinoline (8e). Compound 8e was prepared from
7c (0.072 g, 0.30 mmol) and 1-heptyne (0.035 g, 0.36 mmol) and
the reaction was performed at 100 ꢁC in accordance with the gen-
eral procedure. Purification by column chromatography, Rf (silica
gel, 10% hexane/ethyl acetate) 0.45, afforded 0.083 g of compound
8c (82% yield). After crystallization from ethyl acetate/hexane,
compound 8c was obtained as a white solid, mp¼94e95 ꢁC. [Found:
C, 67.90; H, 7.23; N, 24.91. C19H24N6 requires C, 67.83; H, 7.19; N,
24.98%]. nmax (KBr) 3120, 3069, 2952, 2927, 2854, 1457, 1374, 1339,
1214, 1128, 1049, 771; dH (400 MHz, CDCl3) 7.36e7.32 (m, 1H),
7.30e7.23 (m, 3H), 7.20 (s, 1H), 4.80 (t, J¼7.0 Hz, 2H), 4.48 (t,
J¼7.0 Hz, 2H), 3.51 (t, J¼7.0 Hz, 2H), 3.12 (t, J¼7.0 Hz, 2H), 2.54 (t,
J¼7.6 Hz, 2H),1.49 (quintet, J¼7.6 Hz, 2H),1.28e1.14 (m, 4H), 0.79 (t,
J¼7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 148.1, 138.2, 132.3, 130.1, 129.0,
128.4, 127.9, 124.4, 123.9, 121.3, 48.4, 44.7, 31.2, 29.0, 28.9, 27.7, 25.4,
22.2, 13.8; MS m/z 336 (Mþ, 12), 251 (15), 223 (31), 208 (14), 197
(100), 185 (49), 170 (38), 169 (35), 168 (35), 156 (21), 154 (21), 143
(14), 141 (16), 130 (48), 128 (50), 124 (58), 115 (31), 103 (29), 77 (33),
68 (19), 55 (20), 42 (30), 41 (88), 39 (41%).
4.7.2. 5,6-Dihydro-1-{[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]
methyl}-[1,2,3]triazolo[5,1-a]isoquinoline (8b). Compound 8b was
prepared from 7b (0.120 g, 0.53 mmol) and p-methox-
yphenylacetylene (0.084 g, 0.64 mmol) and the reaction was per-
formed at 100 ꢁC in accordance with the general procedure.
Purification by column chromatography, Rf (silica gel, ethyl acetate)
0.64, afforded 0.166 g of compound 8b (87% yield). After crystalli-
zation from ethyl acetate/hexane, compound 8b was obtained as
a white solid, mp¼178e180 ꢁC. [Found: C, 66.98; H, 4.99; N, 23.50.
C20H18N6O requires C, 67.02; H, 5.06; N, 23.45%]. nmax (KBr) 3132,
3013, 2968, 2936, 2895, 2824, 1614, 1556, 1492, 1457, 1246, 1172,
1022, 787, 759; dH (400 MHz, CDCl3) 7.86e7.81 (m, 2H), 7.69e7.62
(m, 2H), 7.35 (td, J¼7.6, 1.6 Hz, 1H), 7.32e7.23 (m, 2H), 6.89e6.82
(m, 2H), 5.86 (s, 2H), 4.52 (t, J¼6.8 Hz, 2H), 3.75 (s, 3H), 3.15 (t,
J¼6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 159.5, 148.1, 136.1, 132.6, 131.8,
129.8, 128.4, 128.3, 126.8, 125.5, 123.5, 123.0, 118.7, 114.1, 55.2, 45.7,
44.8, 28.9.
4.7.6. 5,6-Dihydro-1-[3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propyl]-
[1,2,3]triazolo[5,1-a]isoquinoline (8f). Compound 8f was prepared
from 7d (0.102 g, 0.40 mmol) and p-tolylacetylene (0.056 g,
0.48 mmol) and the reaction was performed at 100 ꢁC in accordance
with the general procedure. Purification by column chromatogra-
phy, Rf (silica gel, ethyl acetate) 0.42, afforded 0.141 g of compound
8f (95% yield). After crystallization from ethyl acetate/hexane,
compound 8f was obtained as a white solid, mp¼119e120 ꢁC.
[Found: C, 71.28; H, 5.93; N, 22.63. C22H22N6 requires C, 71.33; H,
5.99; N, 22.69%]. nmax (KBr) 3086, 3038, 2920, 2856, 1493, 1471,
1454, 1437, 1344, 1217, 1182, 1046, 816, 763; dH (400 MHz, CDCl3)
7.80 (s, 1H), 7.64 (d, J¼8.0 Hz, 2H), 7.39e7.34 (m, 1H), 7.26e7.19 (m,
3H), 7.14 (d, J¼8.0 Hz, 2H), 4.48 (t, J¼6.8 Hz, 2H), 4.43 (t, J¼6.8 Hz,
4.7.3. 1-[(4-Cyclohexyl-1H-1,2,3-triazol-1-yl)methyl]-5,6-dihydro-
[1,2,3]triazolo[5,1-a]isoquinoline (8c). Compound 8c was prepared
from 7b (0.217 g, 0.96 mmol) and cyclohexylacetylene (0.125 g,
1.15 mmol) and the reaction was performed at 100 ꢁC in accordance
with the general procedure. Purification by column chromatogra-
phy, Rf (silica gel, ethyl acetate) 0.61, afforded 0.157 g of compound
8c (49% yield). After crystallization from ethyl acetate/hexane,

10316
V. Fiandanese et al. / Tetrahedron 68 (2012) 10310e10317
2H), 3.09 (t, J¼6.8 Hz, 2H), 2.97 (t, J¼6.8 Hz, 2H), 2.43 (quintet,
J¼6.8 Hz, 2H), 2.29 (s, 3H); dC (100.6 MHz, CDCl3) 147.4, 140.9, 137.6,
132.3, 129.2, 128.6, 128.4, 127.7, 125.4, 124.8, 123.8, 119.7, 49.2, 44.6,
28.9, 28.7, 23.0, 21.1 (two coincident peaks not observed); MS m/z
370 (Mþ, 17), 313 (21), 212 (100), 198 (43), 185 (16), 182 (15), 169
(18),168 (18),156 (17),141 (16),130 (39),128 (32),115 (41),103 (28),
91 (15), 77 (43), 65 (12), 63 (12), 51 (16), 39 (27%).
2H), 4.44 (t, J¼6.8 Hz, 2H), 3.48 (t, J¼6.8 Hz, 2H), 3.40 (t, J¼6.8 Hz,
2H), 3.09 (t, J¼6.8 Hz, 2H), 2.80 (t, J¼6.8 Hz, 2H); dC (100.6 MHz,
CDCl3) 143.6, 138.0, 132.3, 130.0, 128.8, 128.3, 127.7, 124.4, 123.7,
122.3, 50.3, 48.4, 44.6, 28.9, 27.5, 25.3.
4.8.3. 5,6-Dihydro-1-(2-(4-(2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)
ethyl)-1H-1,2,3-triazol-1-yl)ethyl)-[1,2,3]triazolo[5,1-a]isoquinoline
(11a). Compound 10 (0.154 g, 0.46 mmol) and p-tolylacetylene
(0.064 g, 0.55 mmol) were added at room temperature to a solution
of Cu(OAc)2$H2O (0.018 g, 0.09 mmol) in H2O (3 mL) in a capped
flask. The mixture was warmed to 100 ꢁC and, after completion
(1 h), was quenched with a saturated aqueous solution of NH4Cl
(30 mL) and extracted with CH2Cl2 (3ꢀ40 mL). The organic extracts
were washed with an aqueous solution of NaCl (3ꢀ30 mL), dried
over Na2SO4, and concentrated under vacuum. Purification by col-
umn chromatography, Rf (silica gel, 10% CH3OH/CH2Cl2) 0.46,
afforded 0.187 g of compound 11a (90% yield). After crystallization
from CH2Cl2/hexane, compound 11a was obtained as a white solid,
mp¼213e214 ꢁC. [Found: C, 66.58; H, 5.53; N, 27.90. C25H25N9 re-
quires C, 66.50; H, 5.58; N, 27.92%]. nmax (KBr) 3127, 3063, 2946,
2917, 1545, 1474, 1448, 1434, 1380, 1218, 1053, 819, 764, 727; dH
(400 MHz, DMSO-d6) 8.47 (s, 1H), 7.91 (s, 1H), 7.70 (d, J¼8.2 Hz, 2H),
7.58e7.53 (m, 1H), 7.45e7.41 (m, 1H), 7.39e7.33 (m 2H), 7.22 (d,
J¼8.2 Hz, 2H), 4.74 (t, J¼7.4 Hz, 2H), 4.61 (t, J¼7.4 Hz, 2H), 4.51 (t,
J¼6.8 Hz, 2H), 3.47 (t, J¼7.4 Hz, 2H), 3.22 (t, J¼7.4 Hz, 2H), 3.16 (t,
J¼6.8 Hz, 2H), 2.31 (s, 3H); dC (100.6 MHz, DMSO-d6) 146.2, 142.6,
138.0, 137.0, 133.1, 129.3, 129.3, 128.7, 128.6, 128.0, 127.5, 125.0,
124.3, 123.8, 123.0, 120.9, 48.9, 48.1, 44.2, 28.3, 27.0, 26.1, 20.8.
4.7.7. 5,6-Dihydro-1-[3-(4-pentyl-1H-1,2,3-triazol-1-yl)propyl]-
[1,2,3]triazolo[5,1-a]isoquinoline (8g). Compound 8g was prepared
from 7d (0.182 g, 0.72 mmol) and 1-heptyne (0.084 g, 0.87 mmol)
and the reaction was performed at 100 ꢁC in accordance with the
general procedure. Purification by column chromatography, Rf
(silica gel, ethyl acetate) 0.43, afforded 0.194 g of compound 8g (77%
yield). After crystallization from ethyl acetate/hexane, compound
8g was obtained as a white solid, mp¼114e115 ꢁC. [Found: C, 68.50;
H, 7.53; N, 24.00. C20H26N6 requires C, 68.54; H, 7.48; N, 23.98%].
nmax (KBr) 3125, 3063, 2947, 2920, 2852, 1544, 1471, 1464, 1440,
1360, 1340, 1211, 1046, 1015, 823, 808, 767, 726; dH (400 MHz,
CDCl3) 7.40e7.34 (m, 2H), 7.30e7.23 (m, 3H), 4.48 (t, J¼7.0 Hz, 2H),
4.42 (t, J¼7.0 Hz, 2H), 3.14 (t, J¼7.0 Hz, 2H), 2.93 (t, J¼7.0 Hz, 2H),
2.63 (t, J¼7.7 Hz, 2H), 2.38 (quintet, J¼7.0 Hz, 2H), 1.59 (quintet,
J¼7.7 Hz, 2H), 1.32e1.20 (m, 4H), 0.81 (t, J¼7.2 Hz, 3H); dC
(100.6 MHz, CDCl3) 148.1, 141.0, 132.3, 129.2, 128.7, 128.4, 127.7,
124.8, 123.8, 120.9, 49.0, 44.6, 31.2, 29.0, 29.0, 28.8, 25.4, 23.0, 22.2,
13.8; MS m/z 350 (Mþ, 7), 212 (23), 198 (100), 185 (18), 168 (9), 156
(9), 130 (14), 128 (15), 103 (10), 77 (14), 68 (10), 54 (9), 41 (44%).
4.8. Synthesis of compounds 11 according to Scheme 2
4.8.4. 1-(2-(4-(2-(4-Butyl-1H-1,2,3-triazol-1-yl)ethyl)-1H-1,2,3-
triazol-1-yl)ethyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(11b). Compound 10 (0.120 g, 0.36 mmol) and 1-hexyne (0.036 g,
0.43 mmol) were added at room temperature to a solution of
Cu(OAc)2$H2O (0.014 g, 0.07 mmol) in H2O (3 mL) in a capped flask.
The mixture was warmed to 100 ꢁC and, after completion (2 h), was
quenched with a saturated aqueous solution of NH4Cl (30 mL) and
extracted with CH2Cl2 (3ꢀ40 mL). The organic extracts were
washed with an aqueous solution of NaCl (3ꢀ30 mL), dried over
Na2SO4, and concentrated under vacuum. Purification by column
chromatography, Rf (silica gel, 5% CH3OH/CH2Cl2) 0.28, afforded
0.127 g of compound 11b (85% yield). After crystallization from
ethyl acetate, compound 11b was obtained as a white solid,
mp¼148e149 ꢁC. [Found: C, 63.35; H, 6.53; N, 30.12. C22H27N9 re-
quires C, 63.29; H, 6.52; N, 30.19%]. nmax (KBr) 3135, 3067, 2941,
2925, 2861,1546,1476,1453,1435,1382,1212,1130,1052,1044, 846,
766; dH (400 MHz, CDCl3) 7.39e7.34 (m,1H), 7.32e7.25 (m, 3H), 7.20
(s, 1H), 7.14 (s, 1H), 4.80 (t, J¼7.0 Hz, 2H), 4.54 (t, J¼7.0 Hz, 2H), 4.50
(t, J¼7.0 Hz, 2H), 3.50 (t, J¼7.0 Hz, 2H), 3.19 (t, J¼7.0 Hz, 2H), 3.15 (t,
J¼7.0 Hz, 2H), 2.59 (t, J¼7.6 Hz, 2H), 1.54 (quintet, J¼7.6 Hz, 2H),
1.34e1.22 (m, 2H), 0.84 (t, J¼7.2 Hz, 3H); dC (100.6 MHz, CDCl3)
148.1, 142.9, 138.0, 132.4, 130.1, 129.0, 128.5, 127.8, 124.5, 123.8,
122.6, 121.0, 49.0, 48.5, 44.7, 31.4, 29.0, 27.6, 26.6, 25.1, 22.1, 13.7.
4.8.1. 1-{2-[4-(2-Bromoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-5,6-
dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(9). 4-Bromo-1-butyne
(0.213 g, 1.60 mmol) and azide 7c (0.320 g, 1.33 mmol) were
added at room temperature to a solution of Cu(OAc)2$H2O (0.054 g,
0.27 mmol) in H2O (5 mL). The mixture was warmed at 50 ꢁC for 1 h
in a capped flask, then quenched with a saturated aqueous solution
of NH4Cl (40 mL) and extracted with ethyl acetate (3ꢀ50 mL). The
organic extracts were washed with an aqueous solution of NaCl
(3ꢀ40 mL), dried over Na2SO4, and concentrated under vacuum.
Purification by column chromatography, Rf (silica gel, 10% hexane/
ethyl acetate) 0.32, afforded 0.353 g of compound 9 (71% yield).
After crystallization from ethyl acetate/hexane, compound 9 was
obtained as a white solid, mp¼110e111 ꢁC. [Found: C, 51.53; H,
4.55; N, 22.57. C16H17BrN6 requires C, 51.49; H, 4.59; N, 22.52%]. nmax
(KBr) 3132, 3081, 2952, 2904, 1555, 1476, 1426, 1253, 1212, 1166,
1124, 1053, 1014, 915, 823, 763, 724; dH (400 MHz, CDCl3) 7.39 (s,
1H), 7.32e7.22 (m, 4H), 4.84 (t, J¼6.8 Hz, 2H), 4.47 (t, J¼6.8 Hz, 2H),
3.51 (t, J¼6.8 Hz, 2H), 3.45 (t, J¼6.8 Hz, 2H), 3.12 (t, J¼6.8 Hz, 4H); dC
(100.6 MHz, CDCl3) 144.4, 138.1, 132.3, 130.1, 128.9, 128.4, 127.8,
124.5, 123.8, 122.4, 48.6, 44.7, 31.3, 29.2, 29.0, 27.6.
4.8.2. 1-{2-[4-(2-Azidoethyl)-1H-1,2,3-triazol-1-yl]ethyl}-5,6-
dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(10). Sodium
azide
(0.096 g, 1.48 mmol) was added to a solution of compound 9
(0.461 g, 1.24 mmol) in DMF (9 mL). The mixture was warmed to
100 ꢁC for 3 h, then quenched with an aqueous solution of NaCl
(30 mL) and extracted with ethyl acetate (3ꢀ40 mL). The organic
extracts were washed with an aqueous solution of NaCl (3ꢀ30 mL)
and dried over Na2SO4. After evaporation of the solvent at reduced
pressure, 0.407 g of pure azide 10 (98% yield) were isolated. After
crystallization from ethyl acetate/hexane, compound 10 was ob-
tained as a white solid, mp¼84e85 ꢁC. [Found: C, 57.28; H, 5.19; N,
37.63. C16H17N9 requires C, 57.30; H, 5.11; N, 37.59%]. nmax (KBr)
3117, 3064, 2938, 2869, 2095, 1542, 1470, 1431, 1379, 1349, 1305,
1212, 1115, 1049, 1011, 964, 808, 771, 729, 676; dH (400 MHz, CDCl3)
7.36 (s, 1H), 7.32e7.28 (m, 1H), 7.26e7.19 (m, 3H), 4.80 (t, J¼6.8 Hz,
Acknowledgements
This work was financially supported by the University of Bari
‘Aldo Moro’.
References and notes
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