A general procedure for the synthesis of alkyl-and arylethynyl-1,2,3- triazole-fused dihydroisoquinolines

Article abstract of DOI:10.1039/c1ob06701j

A general procedure for the synthesis of the title compounds has been devised starting from the available 2-halophenylethyl azides, by means of click reactions with trimethylsilylacetylene or 1-trimethylsilyl-1,3-butadiyne followed by a transition metal-catalyzed functionalization of C-H bond. A further extension of this procedure led us to devise the synthesis of more complex 4,4′-bitriazole-fused dihydroisoquinolines. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c1ob06701j

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PAPER
A general procedure for the synthesis of alkyl- and
arylethynyl-1,2,3-triazole-fused dihydroisoquinolines
Vito Fiandanese,* Silvia Maurantonio, Angela Punzi and Giacomo G. Rafaschieri
Received 7th October 2011, Accepted 7th November 2011
DOI: 10.1039/c1ob06701j
A general procedure for the synthesis of the title compounds has been devised starting from the
available 2-halophenylethyl azides, by means of click reactions with trimethylsilylacetylene or
1-trimethylsilyl-1,3-butadiyne followed by a transition metal-catalyzed functionalization of C–H bond.
A further extension of this procedure led us to devise the synthesis of more complex
4,4¢-bitriazole-fused dihydroisoquinolines.
class of compounds, including more complex analogs possessing
substituted ethynyl chains easily transformed in additional 1,2,3-
triazole rings.
Introduction
An extensively studied reaction for the synthesis of 1,2,3-triazoles
is the Huisgen 1,3-dipolar cycloaddition reaction of azides with
alkynes.1 The limitations of the original reactions, due to the high
reaction temperature and to the low regioselectivity, have been
overcome by the copper(I)-catalyzed 1,3-dipolar cycloaddition
(CuAAC) reaction, which is the most prominent example of ‘click
chemistry’, developed by the groups of Sharpless2 and Meldal.3
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. Since its extraordinary success under different reaction
conditions,4,5 the click reaction has been applied widely in drug
discovery,6 bioconjugation,7 and materials science.8 In particular,
this methodology has been extensively used by many research
groups for the synthesis of several bicyclic, as well as polycyclic
fused triazole heterocycles,9 compounds of great interest for
their biological and pharmaceutical activities.9,10 Generally, fused
triazoles are prepared by an intramolecular [3 + 2] cycloadditon
between azides and alkynes9e,m and a one pot palladium-9g,h,n
or copper-catalyzed9f coupling reaction followed by 1,3-dipolar
cycloaddition. An alternative approach involves an intramolecular
direct transition metal-catalyzed arylation of 1,2,3-triazoles with
aryl halides,9k,l by functionalization of a C–H bond, a recent
methodology widely used for functionalization of heterocycles.11
Our previous studies have regarded the synthesis of several
heterocyclic compounds,12 and recently we have developed a
general approach for preparing a variety of novel unsymmetrically
substituted 4,4¢-bi-1,2,3-triazoles,13a several 1,2,3-triazole-fused
heterocycles13b and various N–C linked 1,2,3-triazole oligomers.13c
We now report some extensions of our initial discovery regarding
1,2,3-triazole fused heterocycles, that have led to the facile
synthesis of a number of novel members of this intriguing
Results and discussion
In accord with the plan outlined in Scheme 1 we started with
the cycloaddition reaction between (2-haloaryl)alkyl azides, 1-
(2-azidoethyl)-2-iodobenzene 1a with trimethylsilylacetylene 2
or 1-(2-azidoethyl)-2-bromobenzene 1b with 1-trimethylsilyl-1,3-
butadiyne 3 affording ingood yields the triazole derivatives 4 (86%)
and 8 (75%). In the case of compound 4 the intramolecular direct
C–H arylation of the triazole ring led easily to the silyl-substituted-
1,2,3-triazole-fused dihydroisoquinoline 5 (69% yield). A further
substitution of the silyl group with an iodine atom afforded
in 92% yield the compound 6 that, when subjected to cross-
coupling reactions with different aliphatic alkynes, led to a variety
of alkylethynyl-1,2,3-triazole-fused dihydroisoquinolines 7a–d in
high yields (Table 1). Whereas aryl- and heteroarylethynyl-1,2,3-
triazole-fused dihydroisoquinolines 10a–d were obtained from
compound 8, which was first subjected to cross-coupling reactions
with aryliodides, leading to compounds 9a–d and then to an
intramolecular direct C–H arylation that afforded in good yields
the arylethynyl-1,2,3-triazole-fused dihydroisoquinolines 10a–d
(Table 2). We wish to underline that we start from the bromo
azide 1b, instead of the iodo azide 1a, towards the compounds 10,
to avoid—in the cross-coupling reactions between the haloalkynyl
silane derivative and the aryl iodides, which lead to compounds
9—undesired coupling reactions.
Moreover, we were able to devise an alternative strategy leading
to the same compounds 7 and 10, as outlined in Scheme 2. Indeed,
compound 5, the intermediate for the synthesis of compounds 7,
was also obtained in high yield (91%) by a preliminary coupling of
trimethylsilylacetylene 2 with 1-(2-azidoethyl)-2-iodobenzene 1a
followed by a thermal intramolecular cycloaddition reaction14 in
toluene at 130 ◦C, without a catalyst, of the resulting coupled
product 11. It is noteworthy that this reaction represents an
Dipartimento di Chimica, Universita` di Bari “Aldo Moro”, via Orabona
4, 70126, Bari, Italy. E-mail: fianda@chimica.uniba.it; Fax: +39-080-
5442075; Tel: +39-080-5442075
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Scheme 1 Procedure for the synthesis of the title compounds 7 and 10.
Table 1 Synthesis of alkylethynyl-1,2,3-triazole-fused dihydroisoquino-
lines 7
Table 2 Synthesis of arylethynyl-1,2,3-triazole-fused dihydroisoquini-
lines 10
Halide 6
Alkyne
Products 7 (yields %)
Products 9
(yields %)
Products 10
(yields %)
Compound 8
Aryliodide
1-Heptyne
p-Iodoanisole
6
Ethynylcyclohexane
8
8
2-Iodothiophene
Iodobenzene
6
6
Prop-2-yn-1-
ylcyclopentane
1-Octyne
8
p-Iodotoluene
additional example of an intramolecular [3 + 2]cycloaddition of
azides on disubstituted alkynes9e,f without a catalyst.9e,15 The same
approach was followed for the synthesis of compounds 10c–f.
Indeed, a preliminary coupling reaction of the silyldiyne 3 with
the iodo azide 1a, followed by the thermal cycloaddition reaction
in toluene at 130 ◦C of the resulting coupling product 12, led
to the silylethynyl-1,2,3-triazole-fused dihydroisoquinoline 13 in
high yield (81%). The compound 13 was further elaborated to
give, by cross-coupling reactions with aryl- and heteroaryl iodides,
the series of arylethynyl-1,2,3-triazole-fused dihydroisoquinolines
10c–f (Table 3).
of bi-triazole derivatives by further cycloaddition reactions of
compound 13 with alkyl azides. We were pleased to find that these
cycloaddition reactions proceeded smoothly in our conditions
leading to the desired compounds 14a–f in high yields (Table 4).
Furthermore, we wish to emphasize that, as reported in Table 4, the
azides 1a and 1b were intentionally used to prepare the compounds
14d and 14e, with the aim of evaluating the possibility of obtaining
a new class of 4,4¢-bitriazole-fused dihydroisoquinoline derivatives
by a subsequent intramolecular C–H arylation of the compound
14d or of the compound 14e. We were delighted to find that the
desired compound 15 was obtained in good yield starting from
the compound 14e (eqn (1)).
Moreover, owing to our experience on the synthesis of unsym-
metrically substituted 4,4¢-bi-triazole derivatives,13a we decided
to explore the possibility of obtaining a new complex class
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Scheme 2 Alternative procedure for the synthesis of compounds 5 and 10.
Synthesis of products 7 according to the Scheme 1
Conclusions
1-[2-(2-Iodophenyl)ethyl]-4-(trimethylsilyl)-1H -1,2,3-triazole
(4). Trimethylsilylacetylene 2 (0.681 g, 6.93 mmol) was added
at room temperature under nitrogen to a stirred solution
of 2-iodophenylethyl azide 1a (1.262 g, 4.62 mmol), CuI
(0.880 g, 4.62 mmol) and 1,1,4,7,7-pentamethyldiethylenetriamine
(0.96 mL, 4.62 mmol) in THF (16 mL). The mixture was heated
at 50 ◦C for 2h, then quenched with a saturated aqueous solution
of NH4Cl (50 mL) and extracted with ethyl acetate (3 ¥ 60 mL).
The organic extracts were washed with an aqueous solution of
NaCl (3 ¥ 40 mL), dried over Na2SO4 and concentrated under
vacuum. Purification by column chromatography, Rf 0.43 (30%
ethyl acetate/petroleum ether), afforded 1.474 g of compound 4
(86% yield). After crystallization from petroleum ether, compound
4 was obtained as a white solid, mp = 57–58 ◦C. Found: C, 42.15; H,
4.86; N, 11.38. C13H18IN3Si requires: C, 42.05; H, 4.89; N, 11.32%.
In summary, we have described an efficient method for the
synthesis of ethynyl substituted 1,2,3-triazole-fused dihydroiso-
quinolines 7 and 10 starting from readily available silyl alkynes
and 2-halophenylethyl azides and employing simple cycloaddition
reactions, cross-coupling reactions and finally intramolecular
cyclization by direct arylation of the C–H bond of the triazole ring.
Moreover, the versatility of this procedure is further demonstrated
by the possibility of an easy synthesis of more complex bitriazole-
fused dihydroisoquinoline derivatives.
Experimental
General
n
max/cm-1 (KBr) 3104, 2955, 2896, 1466, 1438, 1419, 1244, 1189,
Macherey-Nagel silica gel (60, particle size 0.040–0.063 mm) for
column chromatography and Macherey-Nagel 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 SLBTM-5 ms capillary column (30 m ¥ 0.25 mm id).
GC/mass spectrometry analysis was performed on a Shimadzu
GCMS-QP5000 gas chromatograph-mass spectrometer equipped
with a Supelco SLBTM-5 ms capillary column (30 m ¥ 0.25 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 Perkin-Elmer FT-IR
Spectrum Bx. Elemental 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, 1-methyl-2-
pyrrolidinone, acetonitrile, toluene and triethylamine were used as
supplied.
1114, 1099, 1050, 1009, 838, 749; dH (400 MHz, CDCl3) 7.79 (dd,
J = 7.6, 1.2 Hz, 1H), 7.21 (s, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 6.93
(dd, J = 7.6, 1.6 Hz, 1H), 6.89 (td, J = 7.6, 1.6 Hz, 1H), 4.56 (t, J =
7.4 Hz, 2H), 3.27 (t, J = 7.4 Hz, 2H), 0.24 (s, 9H); dC (100.6 MHz,
CDCl3) 146.2, 139.6, 139.6, 130.2, 129.3, 128.8, 128.5, 100.1, 49.1,
41.5, -1.2; MS m/z 328 (2%), 244 (44), 231 (73), 217 (5), 200 (4),
126 (15), 104 (86), 98 (14), 90 (16), 86 (21), 83 (15), 77 (25), 73
(100), 59 (34), 45 (34), 43 (36).
5,6-Dihydro-1-(trimethylsilyl)-[1,2,3]triazolo[5,1-a] isoquinoline
(5). To a solution of compound 4 (0.519 g, 1.40 mmol) in
NMP (10 mL) at room temperature under nitrogen PdCl2(PPh3)2
(0.049 g, 0.07 mmol) and n-Bu4NOAc (0.844 g, 2.80 mmol) were
successively added. The resulting mixture was stirred at 100 ◦C
for 1h, then was quenched with a saturated aqueous solution of
NH4Cl (40 mL) and extracted with ethyl acetate (3 ¥ 50 mL).
The organic extracts were washed with an aqueous solution of
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Table 3 Synthesis of arylethynl-1,2,3-triazole-fused dihydroisoquinilines
10 staring from compound 13
Table 4 Synthesis of products 14 starting from compound 13
Compound 13
Azides
Products 14 (yields %)
Compound 13
Aryliodide
Products 10 (yields %)
Iodobenzene
13
13
13
13
p-Iodotoluene
13
13
13
p-Nitroiodobenzene
3-Iodopyridine
13
NaCl (3 ¥ 40 mL), dried over Na2SO4 and concentrated under
vacuum. Purification by column chromatography, Rf 0.57 (60%
ethyl acetate/hexane), afforded 0.235 g of compound 5 (69%
yield). After crystallization from petroleum ether, compound 5
was obtained as a white solid, mp 82–83 ◦C. Found: C, 64.25; H,
7.10; N, 17.19. C13H17N3Si requires: C, 64.15; H, 7.04; N, 17.27%.
n
max/cm-1 (KBr) 3048, 2954, 2895, 1456, 1437, 1337, 1245, 837,
under nitrogen, NIS (2.180 g, 9.69 mmol) was added. The mixture
was heated at reflux for 2 h, then quenched with a saturated
aqueous solution of Na2S2O3 (50 mL) and extracted with ethyl
acetate (3 ¥ 50 mL). The organic extracts were washed with an
aqueous solution of NaCl (3 ¥ 40 mL), dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography, Rf 0.75 (60% ethyl acetate/petroleum ether),
leading to 0.883 g of compound 6 (92% yield). After crystallization
from ethyl acetate/petroleum ether, compound 6 was obtained as
a white solid, mp 137–138 ◦C. Found: C, 40.50; H, 2.76; N, 14.09.
C10H8IN3 requires: C, 40.43; H, 2.71; N, 14.14%. nmax/cm-1 (KBr)
3005, 2979, 2951, 2904, 1476, 1458, 1449, 1424, 1417, 1347, 1281,
1251, 1220, 1178, 1170, 1157, 1036, 994, 778, 758, 738, 713; dH
(400 MHz, CDCl3) 8.32 (dd, J = 7.8, 1.0 Hz, 1H), 7.43–7.30 (m,
3H), 4.58 (t, J = 7.0 Hz, 2H), 3.21 (t, J = 7.0 Hz, 2H); dC (100.6
756, 740, 727; dH (400 MHz, CDCl3) 7.62 (d, J = 7.6 Hz, 1H),
7.37–7.28 (m, 3H), 4.56 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 6.8 Hz,
2H), 0.43 (s, 9H); dC (100.6 MHz, CDCl3) 141.1, 138.7, 133.0,
128.9, 128.5, 127.4, 126.0, 125.8, 44.4, 29.2, -0.9; MS: m/z 243
(M+, 7%), 214 (28), 200 (11), 184 (5), 173 (14), 159 (4), 145 (13),
130 (11), 116 (28), 115 (32), 73 (100), 59 (25), 45 (44), 43 (30).
(1)
5,6-Dihydro-1-iodo-[1,2,3]triazolo[5,1-a]isoquinoline (6). To a
solution of compound 5 (0.785 g, 3.23 mmol) in CH3CN (20 mL)
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MHz, CDCl3) 133.4, 132.5, 129.7, 128.4, 127.6, 124.0, 123.7, 83.5,
45.2, 29.1; MS: m/z 297 (M+, 15%), 142 (13), 140 (12), 127 (8),
115 (100), 89 (9), 71 (11), 63 (10), 58 (10), 51 (9), 50 (8).
0.82 mmol) in accordance with general procedure. Purification
by column chromatography, Rf 0.65 (60% ethyl acetate/hexane),
afforded 0.092 g of compound 7c (81% yield) as a yellow oil.
Found: C, 77.85; H, 6.95; N, 15.20. C18H19N3 requires: C, 77.95;
H, 6.90; N, 15.15%. nmax/cm-1 (neat) 3057, 2947, 2865, 2236, 1474,
1457, 1425, 1369, 1350, 1235, 1047, 769, 745, 728; dH (400 MHz,
CDCl3) 8.16 (dd, J = 6.8, 2.2 Hz, 1H), 7.36–7.25 (m, 3H), 4.51
(t, J = 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 2.51 (d, J = 6.8 Hz,
2H), 2.17 (septet, J = 6.8 Hz, 1H), 1.90–1.80 (m, 2H), 1.70–1.48
(m, 4H), 1.43–1.30 (m, 2H); dC (100.6 MHz, CDCl3) 133.3, 131.9,
129.4, 128.1, 127.6, 126.5, 124.5, 124.1, 96.1, 71.0, 44.7, 38.8, 32.0,
28.7, 25.4, 25.2; MS: m/z 277 (M+, 10%), 248 (24), 220 (27), 208
(15), 206 (13), 182 (75), 180 (55), 168 (19), 152 (31), 103 (10), 89
(8), 77 (20), 69 (10), 67 (9), 63 (10), 51 (15), 41 (100), 39 (36).
General procedure for the synthesis of products 7
Alkyne (2 equiv) was added at room temperature under nitrogen
to a stirred suspension (0.1 N) of compound 6 (1 equiv), Pd(PPh3)4
(0.04 equiv) and CuI (0.02 equiv) in Et3N. The mixture was heated
at 50 ◦C and, after completion (5–7h), was quenched with a
saturated aqueous solution of NH4Cl (30 mL) and extracted with
ethyl acetate (3 ¥ 40 mL). The organic extracts were washed with
an aqueous solution of NaCl (3 ¥ 30 mL), dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel and by crystallization.
5,6-Dihydro-1-(oct-1-yn-1-yl)-[1,2,3]triazolo[5,1-a]isoquinoline
(7d). Compound 7d was prepared from compound 6 (0.122 g,
0.41 mmol) and 1-octyne (0.090 g, 0.82 mmol) in accordance with
general procedure. Purification by column chromatography, Rf
0.63 (50% ethyl acetate/hexane), afforded 0.084 g of compound
7d (73% yield). After crystallization from hexane, compound 7d
was obtained as a pale brown solid, mp 42–43 ◦C. Found: C, 77.45;
H, 7.55; N, 15.20. C18H21N3 requires: C, 77.38; H, 7.58; N, 15.04%.
1-(Hept-1-yn-1-yl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoquinoline
(7a). Compound 7a was prepared from compound 6 (0.071 g,
0.24 mmol) and 1-heptyne (0.046 g, 0.48 mmol) in accordance
with general procedure. Purification by column chromatography,
Rf 0.71 (60% ethyl acetate/petroleum ether), afforded 0.053 g
of compound 7a (84% yield). After crystallization from ethyl
acetate/hexane, compound 7a was obtained as a pale yellow
solid, mp 54–56 ◦C. Found: C, 77.00; H, 7.25; N, 15.90. C17H19N3
requires: C, 76.95; H, 7.22; N, 15.84%. nmax/cm-1 (KBr) 3064,
2950, 2927, 2857, 2233, 1473, 1457, 1423, 1364, 1346, 1232, 1186,
775, 745, 727; dH (400 MHz, CDCl3) 8.16 (dd, J = 6.8, 2.0 Hz,
1H), 7.40–7.25 (m, 3H), 4.52 (t, J = 7.0 Hz, 2H), 3.19 (t, J =
7.0 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 1.65 (quintet, J = 7.0 Hz,
2H), 1.51–1.41 (m, 2H), 1.40–1.29 (m, 2H), 0.89 (t, J = 7.2 Hz,
3H); dC (100.6 MHz, CDCl3) 133.3, 131.9, 129.5, 128.1, 127.6,
126.5, 124.5, 124.2, 96.6, 71.0, 44.7, 31.1, 28.7, 28.0, 22.2, 19.6,
13.9; MS: m/z 265 (M+, 14%), 236 (8), 222 (14), 208 (23), 196
(35), 194 (30), 182 (100), 180 (48), 169 (54), 168 (39), 155 (30),
152 (43), 139 (14), 128 (18), 115 (32), 103 (12), 89 (12), 77 (29), 63
(16), 55 (14), 51 (22), 41 (48), 39 (39).
n
max/cm-1 (KBr) 3064, 2953, 2926, 2856, 2237, 1474, 1458, 1429,
1369, 1350, 1234, 1187, 769, 742, 728; dH (400 MHz, CDCl3) 8.14
(dd, J = 7.2, 1.8 Hz, 1H), 7.38–7.22 (m, 3H), 4.50 (t, J = 7.0 Hz,
2H), 3.17 (t, J = 7.0 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 1.63 (quintet,
J = 7.0 Hz, 2H), 1.50–1.41 (m, 2H), 1.33–1.23 (m, 4H), 0.85 (t, J =
7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 133.2, 131.9, 129.4, 128.1,
127.6, 126.4, 124.4, 124.1, 96.6, 71.0, 44.7, 31.2, 28.7, 28.6, 28.3,
22.5, 19.6, 14.0; MS: m/z 279 (M+, 13%), 250 (22), 236 (7), 222
(57), 210 (23), 208 (28), 194 (27), 183 (57), 182 (100), 180 (54), 168
(39), 152 (48), 140 (10), 128 (19), 115 (31), 103 (13), 89 (11), 77
(30), 63 (14), 55 (20), 51 (21), 43 (29), 41 (65), 39 (40).
Synthesis of products 10 according to Scheme 1
1-(Cyclohexylethynyl)-5,6-dihydro-[1,2,3]triazolo[5,1-a]isoqu-
inoline (7b). Compound 7b was prepared from compound 6
(0.071 g, 0.24 mmol) and cyclohexylacetylene (0.052 g, 0.48 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.74 (60% ethyl acetate/hexane), afforded
0.057 g of compound 7b (85% yield). After crystallization from
ethyl acetate/hexane, compound 7b was obtained as a pale yellow
solid, mp 94–96 ◦C. Found: C, 77.90; H, 6.98; N, 15.30. C18H19N3
requires: C, 77.95; H, 6.90; N, 15.15%. nmax/cm-1 (KBr) 3054, 2922,
2852, 2234, 1475, 1447, 1424, 1371, 1347, 1232, 948, 777, 746, 730;
1-[2-(2-Bromophenyl)ethyl]-4-(trimethylsilylethynyl)-1H-1,2,3-
triazole (8). 1-Trimethylsilyl-1,3-butadiyne
3
(0.580 g,
4.75 mmol) and 2-bromophenylethyl azide 1b (0.716 g,
3.17 mmol) were added at room temperature to a solution of
Cu(OAc)2·H2O (0.127 g, 0.63 mmol) in H2O (15 mL) in a capped
flask. The mixture was stirred at room temperature for 7 h, then
quenched with a saturated aqueous solution of NH4Cl (50 mL)
and extracted with ethyl acetate (3 ¥ 50 mL). The organic extracts
were washed with an aqueous solution of NaCl (3 ¥ 40 mL), dried
over Na2SO4 and concentrated under vacuum. Purification by
column chromatography, Rf 0.72 (30% ethyl acetate/petroleum
ether), afforded 0.827 g of compound 8 (75% yield). After
crystallization from ethyl acetate/petroleum ether, compound 8
d
H (400 MHz, CDCl3) 8.19 (dd, J = 6.8, 2.0 Hz, 1H), 7.40–7.26 (m,
3H), 4.53 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.76–2.65
(m, 1H), 1.98–1.89 (m, 2H), 1.82–1.70 (m, 2H), 1.66–1.50 (m, 3H),
1.42–1.30 (m, 3H); dC (100.6 MHz, CDCl3) 133.3, 132.0, 129.5,
128.2, 127.7, 126.6, 124.5, 124.3, 100.4, 71.0, 44.7, 32.3, 29.8, 28.8,
25.8, 24.8; MS: m/z 277 (M+, 19%), 248 (84), 234 (12), 220 (100),
206 (49), 194 (23), 193 (21), 192 (24), 191 (22), 180 (25), 178 (29),
168 (48), 165 (34), 155 (24), 154 (23), 152 (27), 139 (22), 130 (24),
115 (43), 103 (24), 102 (22), 89 (23), 82 (21), 77 (43), 63 (24), 51
(30), 41 (65), 39 (65).
◦
was obtained as a white solid, mp 127–128 C. Found: C, 51.85;
H, 5.30; N, 12.15. C15H18BrN3Si requires: C, 51.72; H, 5.21; N,
12.06%. nmax/cm-1 (KBr) 3136, 3044, 2961, 2177, 1472, 1458,
1436, 1352, 1250, 1220, 1055, 1026, 865, 841, 752, 655, 648; dH
(400 MHz, CDCl3) 7.54 (dd, J = 7.6, 1.2 Hz, 1H), 7.41 (s, 1H),
7.17 (td, J = 7.6, 1.2 Hz, 1H), 7.10 (td, J = 7.6, 1.6 Hz, 1H), 6.97
(dd, J = 7.6, 1.6 Hz, 1H), 4.58 (t, J = 7.2 Hz, 2H), 3.31 (t, J =
7.2 Hz, 2H), 0.21 (s, 9H); dC (100.6 MHz, CDCl3) 135.8, 133.1,
131.1, 130.7, 129.1, 127.9, 126.5, 124.2, 98.6, 93.4, 49.6, 37.0,
-0.4; MS m/z 268 (3%), 240 (7), 185 (55), 183 (60), 169 (13), 150
1-(3-Cyclopentylprop-1-yn-1-yl)-5,6-dihydro-[1,2,3]triazolo [5,1-
a]isoquinoline (7c). Compound 7c was prepared from compound
6 (0.122 g, 0.41 mmol) and 3-cyclopentyl-1-propyne (0.089 g,
1190 | Org. Biomol. Chem., 2012, 10, 1186–1195
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(47), 137 (6), 122 (11), 107 (23), 104 (100), 97 (22), 86 (36), 77
(45), 73 (89), 59 (81), 53 (23), 43 (51).
Rf 0.87 (70% ethyl acetate/petroleum ether), afforded 0.144 g
of compound 9c (95% yield). After crystallization from ethyl
acetate/petroleum ether, compound 9c was obtained as a yellow
solid, mp 86–88 ◦C. Found: C, 61.45; H, 3.95; N, 11.98. C18H14BrN3
requires: C, 61.38; H, 4.01; N, 11.93%. nmax/cm-1 (KBr) 3145, 3055,
2923, 1439, 1229, 1201, 1052, 1031, 808, 753, 746, 691; dH (400
MHz, CDCl3) 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.52–7.48 (m, 2H),
7.46 (s, 1H), 7.34–7.29 (m, 3H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 7.11
(td, J = 7.6, 1.6 Hz, 1H), 6.99 (dd, J = 7.6, 1.6 Hz, 1H), 4.63 (t,
J = 7.2 Hz, 2H), 3.35 (t, J = 7.2 Hz, 2H); dC (100.6 MHz, CDCl3)
135.9, 133.1, 131.6, 131.1, 130.8, 129.1, 128.7, 128.3, 127.9, 126.1,
124.2, 122.3, 92.4, 78.4, 49.7, 37.1; MS: m/z 244 (50%), 217 (23),
202 (22), 185 (53), 183 (53), 169 (12), 166 (12), 154 (20), 142 (8),
127 (100), 113 (14), 104 (88), 90 (22), 77 (71), 63 (27), 51 (34).
General procedure for the synthesis of products 9
To a solution (0.2 M) of aryl iodide (1 equiv) and compound
8 (1 equiv) in DMF at room temperature under nitrogen were
successively added Pd(PPh3)4 (0.05 equiv), AgCl (0.2 equiv),
K2CO3 (8 equiv) and MeOH (8 equiv). The mixture was stirred at
40 ◦C and, after reaction completion (2–3 h), was quenched with a
saturated aqueous solution of NH4Cl (40 mL) and extracted with
ethyl acetate (3 ¥ 50 mL). The organic extracts were washed with
an aqueous solution of NaCl (3 ¥ 40 mL), dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel and by crystallization.
1-[2-(2-Bromophenyl)ethyl]-4-[(4-methylphenyl)ethynyl]-1H-1,2,
3-triazole (9d). Product 9d was prepared from compound 8
(0.150 g, 0.43 mmol) and p-iodotoluene (0.094 g, 0.43 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.67 (40% ethyl acetate/petroleum ether),
afforded 0.126 g of compound 9d (80% yield). After crystallization
from ethyl acetate/petroleum ether, compound 9d was obtained
as a pale yellow solid, mp 138–139 ◦C. Found: C, 62.40; H, 4.25;
N, 11.55. C19H16BrN3 requires: C, 62.31; H, 4.40; N, 11.47%.
1-[2-(2-Bromophenyl)ethyl]-4-[(4-methoxyphenyl)ethynyl]-1H-
1,2,3-triazole (9a). Compound 9a was prepared from compound
8 (0.150 g, 0.43 mmol) and p-iodoanisole (0.101 g, 0.43 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.75 (60% ethyl acetate/petroleum ether),
afforded 0.142 g of compound 9a (86% yield). After crystallization
from ethyl acetate/petroleum ether, compound 9a was obtained as
a yellow solid, mp 117–119 ◦C. Found: C, 59.80; H, 4.20; N, 10.94.
C19H16BrN3O requires: C, 59.70; H, 4.22; N, 10.99%. nmax/cm-1
(KBr) 3147, 3007, 2959, 2923, 2836, 2226, 1604, 1544, 1502, 1458,
1440, 1292, 1248, 1232, 1171, 1033, 835, 810, 754; dH (400 MHz,
CDCl3) 7.55 (dd, J = 7.6, 1.2 Hz, 1H), 7.46–7.41 (m, 3H), 7.18 (td,
J = 7.6, 1.2 Hz, 1H), 7.10 (td, J = 7.6, 1.6 Hz, 1H), 6.99 (dd, J =
7.6, 1.6 Hz, 1H), 6.86–6.81 (m, 2H), 4.61 (t, J = 7.2 Hz, 2H), 3.79
(s, 3H), 3.33 (t, J = 7.2 Hz, 2H); dC (100.6 MHz, CDCl3) 159.9,
135.9, 133.1, 131.1, 131.1, 129.1, 127.9, 127.6, 125.8, 124.2, 114.3,
114.0, 92.4, 77.1, 55.3, 49.7, 37.0; MS: m/z 274 (68%), 259 (29),
247 (39), 231 (29), 185 (26), 183 (28), 169 (61), 157 (77), 141 (64),
127 (27), 113 (63), 104 (100), 90 (38), 89 (35), 77 (84), 63 (42), 51
(47).
n
max/cm-1 (KBr) 3151, 3042, 2945, 2916, 1456, 1438, 1233, 1204,
1050, 1030, 820, 808, 755; dH (400 MHz, CDCl3) 7.55 (dd, J =
7.6, 1.2 Hz, 1H), 7.44 (s, 1H), 7.42–7.37 (m, 2H), 7.18 (td, J = 7.6,
1.2 Hz, 1H), 7.15–7.08 (m, 3H), 6.99 (dd, J = 7.6, 1.6 Hz, 1H),
4.62 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H);
dC (100.6 MHz, CDCl3) 138.9, 135.9, 133.1, 131.4, 131.1, 131.0,
129.1, 129.1, 127.9, 125.9, 124.2, 119.2, 92.6, 77.8, 49.7, 37.0,
21.5; MS: m/z 258 (47%), 243 (20), 231 (23), 216 (19), 215 (17),
185 (35), 183 (38), 167 (36), 153 (13), 141 (59), 139 (64), 127 (20),
115 (53), 104 (100), 90 (28), 89 (31), 77 (69), 63 (26), 51 (39).
General procedure for the synthesis of products 10a–d
1-[2-(2-Bromophenyl)ethyl]-4-[(thiophen-2-yl)ethynyl]-1H-1,2,3-
triazole (9b). Product 9b was prepared from compound 8
(0.150 g, 0.43 mmol) and 2-iodothiophene (0.091 g, 0.43 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.48 (40% ethyl acetate/petroleum ether),
afforded 0.094 g of compound 9b (61% yield). After crystallization
from ethyl acetate/petroleum ether, compound 9b was obtained
as a pale yellow solid, mp 124–126 ◦C. Found: C, 53.75; H, 3.45;
N, 11.80; S, 8.90. C16H12BrN3S requires: C, 53.64; H, 3.38; N,
11.73; S, 8.95%. nmax/cm-1 (KBr) 3131, 3095, 2952, 2932, 1437,
1231, 1218, 1182, 1050, 1042, 1016, 1009, 850, 836, 755, 707, 655;
To a solution (0.1 M) of triazole 9 (1 equiv) in NMP at room
temperature under nitrogen were successively added PdCl2(PPh3)2
(0.05 equiv) and n-Bu4NOAc (2 equiv). The resulting mixture
◦
was stirred at 100 C and, after reaction completion (2–3h), was
quenched with aqueous NH4Cl (40 mL) and extracted with ethyl
acetate (3 ¥ 40 mL). The organic extracts were washed with an
aqueous solution of NaCl (3 ¥ 30 mL), dried over anhydrous
Na2SO4 and concentrated under vacuum. The residue was purified
by column chromatography on silica gel and by crystallization.
5,6-Dihydro-1-[(4-methoxyphenyl)ethynyl]-[1,2,3]triazolo[5,1-
a]isoquinoline (10a). Compound 10a was prepared from 9a
(0.130 g, 0.34 mmol) in accordance with general procedure.
Purification by column chromatography, Rf 0.56 (60% ethyl
acetate/petroleum ether), afforded 0.072 g of compound 10a (70%
yield). After crystallization from ethyl acetate/petroleum ether
and washing with ethyl acetate, compound 10a was obtained as a
d
H (400 MHz, CDCl3) 7.51 (dd, J = 7.6, 1.2 Hz, 1H), 7.45 (s, 1H),
7.27–7.22 (m, 2H), 7.14 (td, J = 7.6, 1.2 Hz, 1H), 7.07 (td, J =
7.6, 1.6 Hz, 1H), 6.98–6.92 (m, 2H), 4.59 (t, J = 7.2 Hz, 2H), 3.30
(t, J = 7.2 Hz, 2H); dC (100.6 MHz, CDCl3) 135.7, 133.0, 132.5,
131.0, 130.4, 129.0, 127.8, 127.8, 127.0, 126.2, 124.1, 122.0, 85.7,
82.0, 49.6, 36.9; MS: m/z 250 (54%), 223 (31), 217 (30), 185 (21),
169 (22), 160 (39), 133 (100), 116 (26), 104 (74), 89 (85), 77 (78),
69 (28), 63 (30), 51 (37), 45 (73), 39 (48).
◦
white solid, mp 132–134 C. Found: C, 75.80; H, 5.09; N, 13.85.
C19H15N3O requires: C, 75.73; H, 5.02; N, 13.94%. nmax/cm-1 (KBr)
3063, 3002, 2978, 2934, 2836, 2205, 1602, 1512, 1489, 1285, 1250,
1239, 1181, 1023, 1013, 836, 770, 763, 734, 535; dH (400 MHz,
CDCl3) 8.24 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.44–
7.28 (m, 3H), 6.90 (d, J = 8.4 Hz, 2H), 4.59 (t, J = 7.0 Hz, 2H), 3.82
1-[2-(2-Bromophenyl)ethyl]-4-(phenylethynyl)-1H-1,2,3-triazole
(9c). Compound 9c was prepared from compound 8 (0.150 g,
0.43 mmol) and iodobenzene (0.088 g, 0.43 mmol) in accordance
with general procedure. Purification by column chromatography,
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(s, 3H), 3.24 (t, J = 7.0 Hz, 2H); dC (100.6 MHz, CDCl3) 160.0,
133.7, 133.2, 132.1, 129.7, 128.3, 127.9, 126.4, 124.8, 124.2, 114.6,
114.1, 95.0, 78.5, 55.3, 44.8, 28.8; MS: m/z 301 (M+, 21%), 273
(83), 258 (27), 245 (17), 242 (21), 241 (22), 240 (23), 230 (36), 215
(25), 202 (54), 141 (18), 136 (16), 123 (20), 115 (100), 108 (22), 101
(55), 88 (58), 77 (17), 75 (22), 63 (17), 51 (23), 39 (34).
(60), 241 (56), 227 (35), 215 (70), 202 (22), 189 (13), 141 (22), 127
(79), 121 (46), 115 (100), 101 (62), 88 (27), 77 (22), 63 (25), 51 (35).
Alternative procedure for the synthesis of product 5 according to
the Scheme 2
1-(2-Azidoethyl)-2-(trimethylsilylethynyl)benzene (11). Trime-
thylsilylacetylene 2 (0.719 g, 7.32 mmol) was added at room
temperature under nitrogen to a stirred suspension of 2-
iodophenylethyl azide 1a (1.000 g, 3.66 mmol), Pd(PPh3)4 (0.169
g, 0.15 mmol), CuI (0.055 g, 0.29 mmol) in Et3N (15 mL).
The mixture was heated at 50 ◦C for 2h, then quenched with
a saturated aqueous solution of NH4Cl (50 mL) and extracted
with ethyl acetate (3 ¥ 60 mL). The organic extracts were washed
with an aqueous solution of NaCl (3 ¥ 40 mL), dried over
Na2SO4 and concentrated under vacuum. Purification by column
chromatography, Rf 0.39(1% ethylacetate/hexane), afforded 0.623
g of compound 11 (70% yield) as a pale yellow oil. Found: C,
64.28; H, 7.15; N, 17.20. C13H17N3Si requires: C, 64.15; H, 7.04;
N, 17.27%. nmax/cm-1 (neat) 3066, 3022, 2959, 2930, 2898, 2874,
2154, 2101, 1481, 1458, 1448, 1343, 1284, 1249, 1106, 867, 842,
758, 644; dH (400 MHz, CDCl3) 7.47–7.42 (m, 1H), 7.28–7.22 (m,
1H), 7.21–7.15 (m, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.06 (t, J =
7.4 Hz, 2H), 0.25 (s, 9H); dC (100.6 MHz, CDCl3) 140.1, 132.6,
129.4, 128.8, 126.7, 122.8, 103.0, 98.7, 51.2, 34.3, -0.1; MS: m/z
243 (M+, 5%), 214 (21), 200 (8), 173 (12), 145 (10), 130 (8), 116
(24), 115 (25), 73 (100), 59 (21), 45 (36), 43 (27).
5,6-Dihydro-1-[(thiophen-2-yl)ethynyl]-[1,2,3]triazolo[5,1-a]iso-
quinoline (10b). Compound 10b was prepared from 9b (0.096 g,
0.27 mmol) in accordance with general procedure. Purification by
column chromatography, Rf 0.41 (40% ethyl acetate/petroleum
ether), afforded 0.045 g of compound 10b (60% yield). After
crystallization from ethyl acetate/petroleum ether, compound 10b
◦
was obtained as a pale yellow solid, mp 138–140 C. Found: C,
69.35; H, 4.05; N, 15.28; S, 11.60. C16H11N3S requires: C, 69.29;
H, 4.00; N, 15.15; S, 11.56%. nmax/cm-1 (KBr) 3095, 2963, 2927,
2207, 1261, 1223, 1095, 1079, 1035, 1009, 851, 803, 775, 732, 699;
d
H (400 MHz, CDCl3) 8.16 (dd, J = 7.8, 2.0 Hz, 1H), 7.42–7.30 (m,
5H), 7.03 (dd, J = 5.2, 3.6 Hz, 1H), 4.58 (t, J = 7.0 Hz, 2H), 3.24
(t, J = 7.0 Hz, 2H); dC (100.6 MHz, CDCl3) 134.2, 132.7, 132.1,
129.9, 128.3, 128.1, 127.9, 127.2, 125.7, 124.9, 123.8, 122.3, 88.2,
83.3, 44.8, 28.7; MS: m/z 277 (M+, 26%), 249 (93), 248 (100), 221
(49), 216 (17), 204 (22), 189 (23), 176 (24), 163 (16), 151 (16), 141
(15), 124 (25), 115 (43), 110 (45), 96 (30), 89 (31), 77 (24), 69 (18),
63 (25), 51 (32), 45 (65), 39 (49).
5,6-Dihydro-1-(phenylethynyl)-[1,2,3]triazolo[5,1-a]isoquinoline
(10c). Compound 10c was prepared from 9c (0.102 g, 0.29 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.74 (70% ethyl acetate/petroleum ether), af-
forded 0.075 g of compound 10c (95% yield). After crystallization
from ethyl acetate/petroleum ether, compound 10c was obtained
as a pale yellow solid, mp 101–103 ◦C. Found: C, 79.60; H, 4.92; N,
15.58. C18H13N3 requires: C, 79.68; H, 4.83; N, 15.49%. nmax/cm-1
(KBr) 3050, 3024, 2922, 2844, 1486, 1472, 1438, 1373, 1344, 910,
766, 755, 738, 724, 686, 599; dH (400 MHz, CDCl3) 8.24 (dd, J =
7.6, 1.2 Hz, 1H), 7.63–7.56 (m, 2H), 7.44–7.30 (m, 6H), 4.57 (t,
J = 7.0 Hz, 2H), 3.24 (t, J = 7.0 Hz, 2H); dC (100.6 MHz, CDCl3)
134.0, 132.1, 131.6, 129.8, 128.8, 128.4, 128.3, 127.9, 125.9, 124.8,
124.0, 122.4, 94.9, 79.8, 44.8, 28.7; MS: m/z 271 (M+, 17%), 243
(88), 242 (80), 228 (34), 227 (28), 215 (99), 202 (16), 189 (15), 140
(17), 139 (18), 121 (67), 115 (66), 108 (66), 107 (58), 94 (100), 89
(21), 81 (19), 77 (21), 63 (30), 51 (38).
5,6 - Dihydro - 1 - (trimethylsilyl) - [1,2,3]triazolo[5,1-a]isoquinol-
ine (5). A solution of compound 11 (0.756 g, 3.11 mmol) in
toluene (20 mL) was heated at 130 ◦C for 2 h, then quenched with
a saturated aqueous solution of NH4Cl (40 mL) and extracted
with ethyl acetate (3 ¥ 50 mL). The organic extracts were washed
with an aqueous solution of NaCl (3 ¥ 40 mL), dried over
Na2SO4 and concentrated under vacuum. Purification by column
chromatography, Rf 0.57 (60% ethyl acetate/hexane), afforded
0.688 g of compound 5 (91% yield).
Alternative procedure for the synthesis of products 10 according to
the Scheme 2
1-(2-Azidoethyl)-2-(4-trimethylsilylbuta-1,3-diyn-1-yl)- benzene
(12). A solution of 1-trimethylsilyl-1,3-butadiyne 3 (0.536 g,
4.39 mmol) in Et3N (5 mL) was added at room temperature under
nitrogen to a stirred suspension of 2-iodophenylethyl azide 1a
(0.800 g, 2.93 mmol), Pd(PPh3)4 (0.139 g, 0.12 mmol), CuI (0.011
g, 0.06 mmol) in Et3N (10 mL). 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 (3 ¥ 50 mL).
The organic extracts were washed with an aqueous solution of
NaCl (3 ¥ 40 mL), dried over Na2SO4 and concentrated under
vacuum. Purification by column chromatography, Rf 0.59 (2%
ethyl acetate/hexane), afforded 0.642 g of compound 12 (82%
yield) as a pale yellow oil. Found: C, 67.45; H, 6.45; N, 15.68.
C15H17N3Si requires: C, 67.37; H, 6.41; N, 15.71%. nmax/cm-1 (neat)
3066, 3023, 2959, 2202, 2100, 1450, 1280, 1250, 1014, 845, 757; dH
(400 MHz, CDCl3) 7.48 (br d, J = 7.6 Hz, 1H), 7.33–7.26 (m, 1H),
7.25–7.16 (m, 2H), 3.52 (t, J = 7.0 Hz, 2H), 3.04 (t, J = 7.0 Hz, 2H),
0.22 (s, 9H); dC (100.6 MHz, CDCl3) 141.5, 133.8, 129.6, 129.5,
126.9, 121.1, 91.7, 87.5, 78.0, 74.6, 51.4, 34.1, -0.4; MS: m/z 267
5,6-Dihydro-1-[(4-methylphenyl)ethynyl]-[1,2,3]triazolo[5,1-a]is-
oquinoline (10d). Compound 10d was prepared from 9d (0.100 g,
0.27 mmol) in accordance with general procedure. Purification by
column chromatography, Rf 0.55 (60% ethyl acetate/petroleum
ether), afforded 0.071 g of compound 10d (91% yield). After
crystallization from ethyl acetate/petroleum ether, compound 10d
◦
was obtained as a pale yellow solid, mp 150–153 C. Found: C,
79.88; H, 5.42; N, 14.68. C19H15N3 requires: C, 79.98; H, 5.30; N,
14.73%. nmax/cm-1(KBr) 3024, 2914, 1485, 1473, 1463, 1371, 1348,
1338, 1235, 1042, 1012, 819, 774, 736, 528; dH (400 MHz, CDCl3)
8.23 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.40–7.27
(m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 4.56 (t, J = 7.0 Hz, 2H), 3.22 (t,
J = 7.0 Hz, 2H), 2.36 (s, 3H); dC (100.6 MHz, CDCl3) 139.0, 133.8,
132.0, 131.4, 129.7, 129.1, 128.2, 127.8, 126.1, 124.7, 123.9, 119.3,
95.0, 79.1, 44.7, 28.7, 21.5; MS: m/z 285 (M+, 21%), 257 (83), 242
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(M+, 11%), 252 (4), 239 (94), 238 (100), 224 (43), 197 (12), 195
(11), 180 (12), 169 (11), 167 (13), 155 (14), 152 (13), 115 (27), 109
(21), 105 (19), 98 (26), 86 (14), 84 (16), 83 (15), 77 (17), 59 (67), 53
(24), 45 (26), 43 (68).
3069, 2935, 2217, 1591, 1508, 1489, 1336, 1103, 852, 818, 767; dH
(400 MHz, DMSO-d6) 8.30 (d, J = 8.2 Hz, 2H), 8.14 (d, J = 7.2 Hz,
1H), 7.94 (d, J = 8.2 Hz, 2H), 7.55–7.44 (m, 3H), 4.65 (t, J = 7.0 Hz,
2H), 3.29 (t, J = 7.0 Hz, 2H); dC (100.6 MHz, DMSO-d6) 147.1,
134.7, 133.4, 132.5, 130.3, 128.7, 128.2, 127.8, 124.1, 123.9, 123.5,
122.9, 92.7, 84.8, 44.4, 27.7; MS: m/z 288 (56%), 241 (100), 240
(70), 227 (59), 215 (61), 213 (56), 202 (33), 121 (24), 120 (22), 115
(79), 107 (49), 94 (39), 89 (22), 88 (20), 77 (20), 75 (18), 63 (34), 51
(33), 39 (50).
5,6-Dihydro-1-(trimethylsilylethynyl)-[1,2,3]triazolo[5,1-a]iso-
quinoline (13). A solution of compound 12 (0.488 g, 1.83 mmol)
◦
in toluene (20 mL) was heated at 130 C for 8h, then quenched
with a saturated aqueous solution of NH4Cl (40 mL) and extracted
with ethyl acetate (3 ¥ 50 mL). The organic extracts were washed
with an aqueous solution of NaCl (3 ¥ 40 mL), dried over
Na2SO4 and concentrated under vacuum. Purification by column
chromatography, Rf 0.71 (60% ethyl acetate/petroleum ether),
afforded 0.395 g of compound 13 (81% yield). After crystallization
from ethyl acetate/hexane, compound 13 was obtained as a white
solid, mp 69–70 ◦C. Found: C, 67.55; H, 6.47; N, 15.68. C15H17N3Si
requires: C, 67.37; H, 6.41; N, 15.71%. nmax/cm-1 (KBr) 3062, 2982,
2952, 2893, 2166, 1473, 1350, 1338, 1250, 1232, 1083, 861, 837, 768,
756; dH (400 MHz, CDCl3) 8.20–8.15 (m, 1H), 7.39–7.26 (m, 3H),
4.53 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H), 0.28 (s, 9H);
dC (100.6 MHz, CDCl3) 134.4, 132.1, 129.8, 128.2, 127.7, 125.9,
124.7, 123.9, 101.4, 95.0, 44.7, 28.7, -0.4; MS: m/z 267 (M+, 10%),
239 (96), 238 (100), 224 (45), 197 (13), 195 (12), 180 (12), 169 (11),
167 (14), 155 (16), 153 (10), 152 (13), 115 (24), 109 (20), 104 (16),
98 (24), 86 (15), 84 (19), 83 (16), 77 (15), 67 (10), 59 (73), 53 (26),
45 (26), 43 (64).
5,6-Dihydro-1-(pyridin-3-ylethynyl)-[1,2,3]triazolo[5,1-a]isoqui-
noline (10f). Compound 10f was prepared from 13 (0.130 g,
0.49 mmol) and 3-iodopyridine (0.100 g, 0.49 mmol) in accordance
with general procedure. Purification by column chromatography,
Rf 0.41 (80% ethyl acetate/hexane), afforded 0.089 g of compound
10f (67% yield). After crystallization from ethyl acetate/hexane,
compound 10f was obtained as a white solid, mp 169–171 ◦C.
Found: C, 74.88; H, 4.42; N, 20.68. C17H12N4 requires: C, 74.98;
H, 4.44; N, 20.58%. nmax/cm-1(KBr) 3029, 2952, 2227, 1638, 1480,
1454, 1420, 1374, 1342, 1183, 1011, 802, 766, 724, 698; dH (400
MHz, CDCl3) 8.75 (d, J = 1.2 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz,
1H), 8.12 (dd, J = 7.4, 2.0 Hz, 1H), 7.85–7.77 (m, 1H), 7.39–7.23
(m, 4H), 4.53 (t, J = 7.0 Hz, 2H), 3.20 (t, J = 7.0 Hz, 2H); dC (100.6
MHz, CDCl3) 151.9, 148.9, 138.3, 134.3, 132.1, 130.0, 128.3, 127.8,
125.1, 124.6, 123.5, 123.0, 119.5, 91.3, 83.1, 44.7, 28.5; MS: m/z
272 (M+, 16%), 243 (100), 229 (22), 216 (41), 189 (22), 163 (15),
140 (11), 122 (12), 115 (43), 109 (20), 108 (24), 94 (57), 81 (49), 77
(13), 75 (14), 63 (20), 51 (21), 39 (31).
General procedure for the synthesis of compounds 10c–f
To a solution (0.1–0.15 N) of aryliodide (1 equiv.) and compound
13 (1 equiv.) in DMF at room temperature under nitrogen were
successively added Pd(PPh3)4 (0.05 equiv.), AgCl (0.2 equiv.),
K2CO3 (8 equiv.) and MeOH (8 equiv.). The mixture was stirred at
40 ◦C and, after reaction completion (2–4h), was quenched with a
saturated aqueous solution of NH4Cl (40 mL) and extracted with
ethyl acetate (3 ¥ 40 mL). The organic extracts were washed with
an aqueous solution of NaCl (3 ¥ 30 mL), dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel and by crystallization.
General procedure for the synthesis of compounds 14a–f
(Scheme 2)
A THF solution (0.2–0.3 M) of silylated derivative 13 (1 equiv.) was
added at room temperature, under nitrogen, to a stirred suspension
(0.2–0.3 M) of azide (1.2 equiv.) and CuI (1 equiv.) in THF, then
1,1,4,7,7-pentamethyldiethylene triamine (1.2 equiv.) and soon
afterwards TBAF (1 M in THF, 1.2 equiv.) were added. The
mixture was stirred at room temperature until reaction completion
(3–6 h), then was quenched with a saturated aqueous solution of
NH4Cl (30 mL) and extracted with CH2Cl2 (3 ¥ 50 mL). The
organic extracts were washed with an aqueous solution of NaCl
(3 ¥ 30 mL), dried over Na2SO4 and concentrated under vacuum.
The residue was purified by column chromatography on silica gel
and by crystallization.
5,6-Dihydro-1-(phenylethynyl)-[1,2,3]triazolo[5,1-a]isoquino-
line (10c). Compound 10c was prepared from 13 (0.099 g,
0.37 mmol) and iodobenzene (0.076 g, 0.37 mmol) in accordance
with general procedure. Purification by column chromatography
afforded 0.066 g of compound 10c (66% yield).
5,6-Dihydro-1-(1-octyl-1H-1,2,3-triazol-4-yl)-[1,2,3]triazolo- [5,
1-a]isoquinoline (14a). Product 14a was prepared from com-
pound 13 (0.136 g, 0.51 mmol) and n-octyl azide (0.095 g,
0.61 mmol) in accordance with general procedure. Purification
by column chromatography, Rf 0.69 (80% ethyl acetate/petroleum
ether), afforded 0.129 g of product 14a (72% yield) as a pale yellow
oil. Found: C, 68.65; H, 7.42; N, 23.88. C20H26N6 requires: C, 68.54;
H, 7.48; N, 23.98%. nmax/cm-1 (neat) 3115, 3065, 2949, 2923, 2854,
1465, 1458, 1436, 1261, 1221, 1048, 963, 771; dH (400 MHz, CDCl3)
8.89 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.39–7.30 (m, 1H), 7.29–7.20
(m, 2H), 4.55 (t, J = 7.0 Hz, 2H), 4.39 (t, J = 7.2 Hz, 2H), 3.17
(t, J = 7.0 Hz, 2H), 1.92 (quintet, J = 7.2 Hz, 2H), 1.38–1.15 (m,
10H), 0.81 (t, J = 7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 140.7,
134.6, 132.4, 130.4, 129.2, 127.8, 127.8, 127.6, 124.5, 122.3, 50.4,
45.0, 31.5, 30.1, 29.1, 28.9, 28.8, 26.4, 22.4, 13.9; MS: m/z 350
5,6-Dihydro-1-[(4-methylphenyl)ethynyl]-[1,2,3]triazolo[5,1-a]is-
oquinoline (10d). Compound 10d was prepared from 13 (0.100 g,
0.37 mmol) and p-iodotoluene (0.081 g, 0.37 mmol) in accordance
with general procedure. Purification by column chromatography
afforded 0.064 g of compound 10d (60% yield).
5,6-Dihydro-1-[(4-nitrophenyl)ethynyl]-[1,2,3]triazolo[5,1-a]iso-
quinoline (10e). Compound 10e was prepared from 13 (0.130
g, 0.49 mmol) and p-nitroiodobenzene (0.122 g, 0.49 mmol)
in accordance with general procedure. Purification by column
chromatography, Rf 0.77 (80% ethyl acetate/hexane), afforded
0.128 g of compound 10e (83% yield). After crystallization from
ethyl acetate, compound 10e was obtained as a yellow solid, mp
233–234 ◦C. Found: C, 68.40; H, 3.75; N, 17.68. C18H12N4O2
requires: C, 68.35; H, 3.82; N, 17.71%. nmax/cm-1 (KBr) 3099,
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The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 1186–1195 | 1193
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(M+, 17%), 294 (12), 251 (10), 237 (32), 209 (21), 195 (19), 182
(20), 169 (30), 154 (15), 141 (16), 127 (17), 115 (20), 77 (12), 55
(27), 43 (55), 41 (100).
1H), 7.10–7.05 (m, 2H), 4.68 (t, J = 7.2 Hz, 2H), 4.56 (t, J =
6.8 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H);
dC (100.6 MHz, CDCl3) 140.6, 136.0, 134.4, 133.0, 132.5, 131.0,
130.5, 129.3, 128.9, 127.8, 127.8, 127.8, 127.5, 124.5, 124.2, 122.8,
49.6, 45.0, 37.1, 29.1.
1-(1-Decyl-1H-1,2,3-triazol-4-yl)-[1,2,3]triazolo-5,6-dihydro- [5,
1-a]isoquinoline (14b). Product 14b was prepared from com-
pound 13 (0.110 g, 0.41 mmol) and n-decyl azide (0.090 g,
0.49 mmol) in accordance with general procedure. Purification by
column chromatography, Rf 0.75 (80% ethyl acetate/petroleum
ether), afforded 0.115 g of product 14b (74% yield). After
crystallization from ethyl acetate/petroleum ether, product 14b
was obtained as a white solid, mp 64–65 ◦C. Found: C, 69.65; H,
7.90; N, 22.30. C22H30N6 requires: C, 69.81; H, 7.99; N, 22.20%.
1-{1-[2-(2-Iodophenyl)ethyl]-1H-1,2,3-triazol-4-yl}-5,6-dihy-
dro-[1,2,3]triazolo[5,1-a]isoquinoline (14e). Product 14e was pre-
pared from compound 13 (0.198 g, 0.74 mmol) and 2-
iodophenylethyl azide 1a (0.242 g, 0.89 mmol) in accordance
with general procedure. Purification by column chromatography,
Rf 0.78 (90% ethyl acetate/petroleum ether), afforded 0.271 g
of compound 14e (78% yield). After crystallization from ethyl
acetate/petroleum ether, compound 14e was obtained as a white
solid, mp 127–129 ◦C. Found: C, 51.15; H, 3.75; N, 17.90.
C20H17IN6 requires: C, 51.30; H, 3.66; N, 17.95%. nmax/cm-1 (KBr)
3113, 3060, 2879, 2824, 1465, 1448, 1445, 1432, 1357, 1260, 1224,
1056, 1012, 962, 774, 734; dH (400 MHz, CDCl3) 8.86 (dd, J = 7.6,
1.2 Hz, 1H), 7.99 (s, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.39–7.24
(m, 3H), 7.18 (td, J = 7.6, 1.2 Hz, 1H), 7.07 (dd, J = 7.6, 1.6 Hz,
1H), 6.89 (td, J = 7.6, 1.6 Hz, 1H), 4.64 (t, J = 7.6 Hz, 2H), 4.56 (t,
J = 6.8 Hz, 2H), 3.37 (t, J = 7.6 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H);
dC (100.6 MHz, CDCl3) 140.6, 139.7, 139.3, 134.4, 132.5, 130.4,
130.1, 129.3, 129.0, 128.6, 127.8, 127.8, 127.4, 124.4, 122.8, 100.1,
49.8, 45.0, 41.4, 29.1.
n
max/cm-1 (KBr) 3116, 3065, 2921, 2854, 1466, 1458, 1434, 1351,
1261, 1221, 1048, 962, 770; dH (400 MHz, CDCl3) 8.90 (d, J =
7.6 Hz, 1H), 8.09 (s, 1H), 7.39–7.32 (m, 1H), 7.31–7.23 (m, 2H),
4.56 (t, J = 6.8 Hz, 2H), 4.40 (t, J = 7.2 Hz, 2H), 3.19 (t, J =
6.8 Hz, 2H), 1.93 (quintet, J = 7.2 Hz, 2H), 1.38–1.15 (m, 14H),
0.82 (t, J = 6.6 Hz, 3H); dC (100.6 MHz, CDCl3) 140.6, 134.5,
132.4, 130.4, 129.3, 127.8, 127.5, 124.4, 122.3, 50.4, 45.0, 31.7,
30.1, 29.3, 29.2, 29.1, 29.1, 28.9, 26.4, 22.5, 14.0 (one coincident
peak not observed); MS: m/z 378 (M+, 18%), 322 (15), 237 (32),
223 (18), 209 (24), 195 (19), 182 (20), 169 (36), 156 (19), 154 (18),
141 (16), 139 (16), 128 (16), 127 (16), 115 (18), 103 (7), 77 (11), 55
(32), 43 (70), 41 (100), 39 (18).
5,6-Dihydro-1-[1-(3-phenylpropyl)-1H-1,2,3-triazol-4-yl]-[1,2,
3]triazolo[5,1-a]isoquinoline (14f). Product 14f was prepared
from compound 13 (0.110 g, 0.41 mmol) and 3-phenylpropyl
azide (0.079 g, 0.49 mmol) in accordance with general procedure.
Purification by column chromatography, Rf 0.64 (80% ethyl
acetate/petroleum ether), afforded 0.127 g of product 14f (87%
yield). After crystallization from ethyl acetate/petroleum ether,
compound 14f was obtained as a white solid, mp 119–120 ◦C.
Found: C, 70.70; H, 5.70; N, 23.62. C21H20N6 requires: C, 70.77;
H, 5.66; N, 23.58%. nmax/cm-1 (KBr) 3133, 3026, 2940, 2923, 2865,
2849, 1465, 1458, 1451, 1261, 1218, 1050, 965, 775, 757, 746, 699;
5,6-Dihydro-1-[1-(2-phenylethyl)-1H-1,2,3-triazol-4-yl]-[1,2,3]-
triazolo[5,1-a]isoquinoline (14c). Product 14c was prepared from
compound 13 (0.150 g, 0.56 mmol) and 2-phenylethyl azide (0.099
g, 0.67 mmol) in accordance with general procedure. Purification
by column chromatography, Rf 0.43 (60% ethyl acetate/petroleum
ether), afforded 0.165 g of product 14c (86% yield). After
crystallization from ethyl acetate/petroleum◦ether, compound 14c
was obtained as a white solid, mp 136–138 C. Found: C, 70.10;
H, 5.40; N, 24.62. C20H18N6 requires: C, 70.16; H, 5.30; N, 24.54%.
n
max/cm-1 (KBr) 3114, 3063, 3046, 3024, 2943, 2905, 2879, 2830,
1472, 1449, 1422, 1357, 1259, 1223, 1057, 1027, 963, 772, 711, 690;
H (400 MHz, CDCl3) 8.83 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.39–
d
H (400 MHz, CDCl3) 8.93 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.43–
d
7.35 (m, 1H), 7.34–7.25 (m, 4H), 7.24–7.15 (m, 3H), 4.58 (t, J =
6.8 Hz, 2H), 4.42 (t, J = 7.2 Hz, 2H), 3.21 (t, J = 6.8 Hz, 2H),
2.68 (t, J = 7.2 Hz, 2H), 2.30 (quintet, J = 7.2 Hz, 2H); dC (100.6
MHz, CDCl3) 140.7, 140.0, 134.5, 132.5, 130.4, 129.3, 128.5, 128.4,
127.9, 127.5, 126.2, 124.4, 122.5, 49.5, 45.0, 32.3, 31.5, 29.1 (one
coincident peak not observed).
7.34 (m, 1H), 7.33–7.17 (m, 5H), 7.13 (d, J = 7.2 Hz, 2H), 4.65
(t, J = 7.4 Hz, 2H), 4.55 (t, J = 6.8 Hz, 2H), 3.26 (t, J = 7.4 Hz,
2H), 3.18 (t, J = 6.8 Hz, 2H); dC (100.6 MHz, CDCl3) 140.5, 136.7,
134.4, 132.5, 130.4, 129.3, 128.7, 128.5, 127.9, 127.8, 127.4, 127.0,
124.4, 122.7, 51.6, 45.0, 36.5, 29.1; MS: m/z 342 (M+, 44%), 195
(84), 168 (100), 153 (27), 141 (79), 127 (30), 115 (50), 105 (23), 103
(27), 91 (89), 77 (59), 65 (35), 51 (52), 41 (22).
Synthesis of a symmetrical bi-1,2,3-triazole-fused
dihydroisoquinoline
1-{1-[2-(2-Bromophenyl)ethyl]-1H-1,2,3-triazol-4-yl}-5,6-dihy-
dro-[1,2,3]triazolo[5,1-a]isoquinoline (14d). Product 14d was pre-
pared from compound 13 (0.110 g, 0.41 mmol) and 2-
bromophenylethyl azide 1b (0.111 g, 0.49 mmol) in accordance
with general procedure. Purification by column chromatography,
Rf 0.61 (80% ethyl acetate/petroleum ether), afforded 0.138 g
of product 14d (80% yield). After crystallization from ethyl
acetate/petroleum ether, compound 14d was obtained as a white
solid, mp 147–148 ◦C. Found: C, 57.15; H, 4.15; N, 19.90.
C20H17BrN6 requires: C, 57.02; H, 4.07; N, 19.95%. nmax/cm-1
(KBr) 3115, 3062, 2952, 2889, 1467, 1449, 1437, 1262, 1224, 1057,
1044, 1024, 963, 775, 734; dH (400 MHz, CDCl3) 8.85 (dd, J =
7.6, 1.2 Hz, 1H), 7.97 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.36 (td,
J = 7.6, 1.6 Hz, 1H), 7.33–7.24 (m, 2H), 7.15 (td, J = 7.6, 1.2 Hz,
5, 5¢, 6, 6¢-Tetrahydro-1, 1¢-bi[1, 2, 3]triazolo[5, 1, a]isoquinoline
(15). To a solution of compound 14e (0.254 g, 0.54 mmol)
in NMP (6 mL) at room temperature under nitrogen were
successively added PdCl2(PPh3)2 (0.021 g, 0.03 mmol) and n-
Bu4NOAc (0.326 g, 1.08 mmol). The resulting mixture was stirred
◦
at 100 C for 23h, then was quenched with a saturated aqueous
solution of NH4Cl (30 mL) and extracted with CH2Cl2 (3 ¥
50 mL). The organic extracts were washed with an aqueous
solution of NaCl (3 ¥ 40 mL), dried over Na2SO4 and concentrated
under vacuum. Purification by column chromatography, Rf 0.66
(50% ethyl acetate/CH2Cl2), afforded 0.135 g of compound 15
(73% yield). After crystallization from CH2Cl2/petroleum ether,
1194 | Org. Biomol. Chem., 2012, 10, 1186–1195
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The Royal Society of Chemistry 2012
©

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compound 15 was obtained as a white solid, mp 238–240 ◦C.
Found: C, 70.52; H, 4.68; N, 24.62. C20H16N6 requires: C, 70.57;
H, 4.74; N, 24.69%. nmax/cm-1 (KBr) 3058, 3055, 2938, 1475, 1449,
1432, 1347, 1254, 1187, 1159, 1043, 991, 968, 760, 737, 714; dH
(400 MHz, CDCl3) 8.00 (d, J = 8.0 Hz, 2H), 7.30–7.18 (m, 6H),
4.65 (t, J = 6.8 Hz, 4H), 3.26 (t, J = 6.8 Hz, 4H); dC (100.6 MHz,
CDCl3) 134.3, 132.6, 132.0, 129.5, 128.1, 127.8, 126.2, 124.5, 45.1,
29.1; MS: m/z 340 (M+, 33%), 283 (92), 256 (26), 167 (24), 154
(18), 141 (27), 127 (100), 115 (29), 114 (39), 113 (38), 101 (31), 89
(15), 77 (42), 63 (17), 51 (28), 39 (31).
C. Tron, T. Pirali, R. A. Billington, P. L. Canonico, G. Sorba and A.
A. Genazzani, Med. Res. Rev., 2008, 28, 278; (g) A. D. Moorhouse, A.
M. Santos, M. Gunaratman, M. Moore, S. Neidle and J. E. Moses, J.
Am. Chem. Soc., 2006, 128, 15972.
7 (a) Z. Song, X.-P. He, X.-P. Jin, L.-X. Gao, L. Sheng, Y.-B. Zhou, J. Li
and G.-R. Chen, Tetrahedron Lett., 2011, 52, 894; (b) Q. Zeng, S. Saha,
L. A. Lee, H. Barnhill, J. Oxsher, T. Dreher and Q. Wang, Bioconjugate
Chem., 2011, 22, 58; (c) V. Araga˜o-Leoneti, V. L. Campo, A. S. Gomes,
R. A. Field and I. Carvalho, Tetrahedron, 2010, 66, 9475; (d) J. M.
Holub and K. Kirshenbaum, Chem. Soc. Rev., 2010, 39, 1325; (e) S.
K. Mamidyala and M. G. Finn, Chem. Soc. Rev., 2010, 39, 1252; (f) A.
H. El-Sagheer and T. Brown, Chem. Soc. Rev., 2010, 39, 1388; (g) X.
Jiang, M. C. Lok and W. E. Hennink, Bioconjugate Chem., 2007, 18,
2077; (h) P.-C. Lin, S.-H. Ueng, M.-C. Tseng, J.-L. Ko, K.-T. Huang,
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Acknowledgements
8 (a) X. Pang, L. Zhao, C. Feng and Z. Lin, Macromolecules, 2011, 44,
7176; (b) G. Franc and A. K. Kakkar, Chem. Soc. Rev., 2010, 39, 1536;
(c) A. Qin, J. W. Y. Lam and B. Z. Tang, Chem. Soc. Rev., 2010, 39,
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This work was financially supported by the University of Bari
“Aldo Moro”.
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