A straightforward synthesis of benzofuran- and indole-substituted 1,2,3-triazoles via click chemistry

Article abstract of DOI:10.1055/s-0029-1217017

A convenient synthesis of benzofuran- and indole-substituted 1,2,3-triazoles has been devised starting from easily available 2-silylalkynyl-substituted benzofuran and indole derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217017

PAPER
3853
A Straightforward Synthesis of Benzofuran- and Indole-Substituted
1,2,3-Triazoles via Click Chemistry
Benzofuran-
a
nd In
i
dole-S
t
ubstitu
o
ted 1,2,3-TriazolesFiandanese,* Daniela Bottalico, Giuseppe Marchese, Angela Punzi, Maria Rosaria Quarta, Marianna Fittipaldi
Dipartimento di Chimica, Università di Bari, Via Orabona 4, 70126 Bari, Italy
Fax +39(80)5442075; E-mail: fianda@chimica.uniba.it
Received 11 May 2009; revised 6 June 2009
Table 1 Synthesis of 4-Benzofuran-Substituted Triazoles 2a–c
Abstract: A convenient synthesis of benzofuran- and indole-sub-
stituted 1,2,3-triazoles has been devised starting from easily avail-
able 2-silylalkynyl-substituted benzofuran and indole derivatives.
from Compound 1a
R
N
RN3
SiMe3
Key words: benzofurans, indoles, triazoles, cycloadditions, azides
N
CuI, TBAF
base, THF, r.t.
O
N
OTBDMS
1
2
1,2,3-Triazoles are nitrogen heterocycles which have
found a wide range of important applications in the phar-
maceutical, agrochemical, polymers and materials areas.1
In addition, a number of compounds of the 1,2,3-triazole
family have shown a broad spectrum of biological proper-
ties such as antibacterial,2 antiallergic,3 and anti-HIV ac-
tivity.4
Entry
R
Product
2a
Yield (%)
1
2
3
Bn
72
59
56
4-IC6H4CH2
Ph(CH2)2
2b
2c
a Base = 1,1,4,7,7-pentamethyldiethylenetriamine.
The Huisgen cycloaddition using azides and alkynes is an
important methodology for the synthesis of 1,2,3-tri-
azoles.5 However, the major limitations of the original re-
actions are the requirements for high reaction
temperatures and low regioselectivity. The introduction of
the copper-catalyzed 1,3-dipolar cycloaddition of azides
and terminal alkynes, the so-called ‘click chemistry’,
which was pioneered by Sharpless6 and Meldal,7 has over-
come these limitations. It was found that cycloadditions of
terminal alkynes with azides catalyzed by copper(I) can
be conducted at room temperature and these reactions are
highly regioselective leading exclusively to 4-substituted
1,2,3-triazoles. In addition, many new catalyst systems
have been reported in recent years and the number of pub-
lications dealing with click chemistry has grown exponen-
tially over the last few years.8
ring. Thus, we started to investigate the reactions of the
aryldiyne 1 with various azides and we found that the cy-
cloaddition promoted by a copper(I) salt8a led to the con-
current formation of the benzofuran and triazole rings
(Table 1) in compounds 2.
As reported in our previous work,12 the reaction of com-
pound 1 with the same fluoride source in tetrahydrofuran
at 55 °C led to 2-ethynylbenzofuran, so compound 2 prob-
ably was formed by a preliminary desilylation and ring
closure promoted by tetrabutylammonium fluoride lead-
ing to 2-ethynylbenzofuran, which subsequently reacted
with azide to form the heterocyclic benzofuran-triazole
system 2. Alternatively, the mechanism could also be dif-
ferent than a simple desilylation and ring-closure reaction.
The direct reactions of silylated alkynes with metals have
been suggested for copper14 and demonstrated for silver
by Pale and co-workers,15 and some of these reactions
have been recently reviewed.16 Moreover, cyclization un-
der basic conditions is also known.17
We have recently reported successful applications of our
methodology9 to the synthesis of a variety of naturally oc-
curring diacetylenic and polyacetylenic compounds.10,11
Moreover, more recently, a further application of our
method led to the straightforward synthesis of a variety of
bis-indolyl and bis-benzofuran derivatives,12 2-alkynylin-
doles, and 2-alkynylbenzofurans,13 starting from easily
available ortho-substituted aryldiynes.12,13
The same type of compound 2 can be also obtained start-
ing directly from 2-ethynylbenzofuran (3). After prelimi-
nary screening of copper salts as catalysts, we found that
the best results were obtained if the reactions were cata-
lyzed by copper(II) acetate in water8l at room temperature
(Table 2).
Thus, owing to the wide versatility of substituted si-
lyldiynes, we wished to explore the possible applications
of these substrates in click chemistry, with the aim of per-
forming the synthesis of more complex substituted 1,2,3-
triazoles linked both to the benzofuran and to the indole
The overall results are reported in Tables 1 and 2. The re-
actions of compound 1 with azides and with copper(I)
iodide (Table 1, entries 1–3) were performed in tetrahy-
drofuran, in the presence of an amine, 1,1,4,7,7-penta-
methyldiethylenetriamine, and of a solution of tetrabutyl-
SYNTHESIS 2009, No. 22, pp 3853–3859
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217017; Art ID: T09609SS
© Georg Thieme Verlag Stuttgart · New York

3854
V. Fiandanese et al.
PAPER
to obtain the same type of product 2 starting from three
different types of compounds (1, 3, and 4) and using two
different sets of reaction conditions.
Table 2 Synthesis of 4-Benzofuran-Substituted Triazoles 2b,d,e
from Compound 3
R
N
RN3
At the same time and with the same procedure, we have
devised the synthesis of 1,2,3-triazol-4-yl- and 1,2,3-tria-
zol-4-ylethynyl-substituted indole derivatives. Naturally,
also in this case, it was necessary to start from 2-(silyl-
alkynyl)-substituted indole derivatives and for this pur-
pose we performed the synthesis of compounds 719 and 8.
When these compounds were subjected to the reactions
with the same azides (Table 4) all products 9 and 10 were
obtained in 62–92% yields.
N
Cu(OAc)2⋅H2O
H2O, r.t.
N
O
O
3
2
Entry
R
Product
2d
Yield (%)
1
2
3
2-IC6H4CH2
3-IC6H4CH2
4-IC6H4CH2
81
88
66
2e
2b
In conclusion, the procedure described here appears to be
a useful route to 1,4-disubstituted 1,2,3-triazoles. A spe-
cial advantage of our strategy is represented by the possi-
bility of synthesizing several triazole compounds linked
to the benzofuran or to the indole rings, starting from sim-
ilar intermediates and employing simple cyclization reac-
tions. Moreover, the simplicity of the operations involved,
the mild reactions conditions and the ready availability of
the silyl derivative employed are additional features mak-
ing the procedure very promising.
ammonium fluoride at room temperature.8a We have em-
ployed benzyl azide, 4-iodobenzyl azide, and 2-phenyl-
ethyl azide obtaining compounds 2a–c in fair to good
yields (56–72%). The reactions of compound 3 were per-
formed in water using copper(II) acetate as a catalyst
(20%) at room temperature8l leading to products 2
(Table 2, entries 1–3) in good yields (66–88%).
On the basis of these results, we planned to realize a con-
venient and general procedure for the synthesis of 1,2,3-
triazol-4-yl- or 1,2,3-triazol-4-ylethynyl-substituted ben-
zofuran derivatives. To realize this goal, we decided to
use in situ deprotection and the click approach starting
from 2-(silylalkynyl)-substituted benzofuran derivatives.
Indeed, we easily performed the synthesis of compound 4,
as reported in the literature18 and of compound 5, that,
when subjected to the reactions with several azides
(Table 3) led to the desired compounds 2 and 6 in fair to
high yields (55–89%). The overall results are reported in
Table 3. Aryl (entry 4) and different substituted alkyl
azides were used. We wish to emphasize that we were able
Column chromatography used Macherey-Nagel silica gel (60, par-
ticle size 0.040–0.063 mm) and TLC used Macherey-Nagel alumi-
num sheets with silica gel 60 F254. GC analysis was performed on a
Varian 3900 gas chromatograph equipped with a Supelco SLB-5ms
capillary column (30 m × 0.25 mm i.d.). GC/MS analysis was per-
formed on a Shimadzu GCMS-QP5000 GC-MS equipped with a
1
Supelco SLB-5ms capillary column (30 m × 0.25 mm i.d.). H
NMR (400 MHz) and 13C NMR (100.6 MHz) spectra of samples
were recorded in CDCl3 or DMSO-d6 on a Varian Inova spectrom-
eter. IR spectra were recorded on a Perkin-Elmer FT-IR Spectrum
Bx spectrophotometer. Elemental analyses were recorded on a
Carlo Erba EA 1108 elemental analyzer. Melting points (uncorrect-
ed) were determined on a Reichert Microscope or on a SMP3 Stuart
Table 3 Synthesis of 4-Benzofuran-Substituted Triazoles 2a–c,f,g and 6a,b Starting from Compounds 4 or 5a
R
RN3
N
N
SiMe3
SiMe3
O
N
CuI, TBAF
base, THF, r.t.
O
4
5
2
R
RN3
N
N
CuI, TBAF
base, THF, r.t.
O
O
N
6
Entry
Substrate
R
Product
2a
Yield (%)
1
2
3
4
5
6
7
4
4
4
4
4
5
5
Bn
77
72
55
89
83
60
66
4-IC6H4CH2
Ph(CH2)2
4-MeOC6H4
Me(CH2)7
Bn
2b
2c
2f
2g
6a
Ph(CH2)2
6b
a Base = 1,1,4,7,7-pentamethyldiethylenetriamine.
Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York

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Benzofuran- and Indole-Substituted 1,2,3-Triazoles
3855
Table 4 Synthesis of 4-Indole-Substituted Triazoles 9a–e and 10a,b Starting from Compounds 7 or 8a
R
RN3
N
N
SiMe3
CuI, TBAF
base, THF, r.t.
N
H
N
H
N
7
9
R
RN3
N
N
SiMe3
CuI, TBAF
base, THF, r.t.
N
H
N
N
10
8
H
Entry
Substrate
R
Product
9a
Yield (%)
1
2
3
4
5
6
7
7
7
7
7
7
8
8
Bn
82
63
92
66
67
78
62
4-IC6H4CH2
4-MeOC6H4
Ph(CH2)2
Me(CH2)7
Bn
9b
9c
9d
9e
10a
10b
Ph(CH2)2
a Base = 1,1,4,7,7-pentamethyldiethylenetriamine.
Scientific apparatus. THF was distilled from Na. PE = petroleum
ether.
IR (neat): 3407, 3058, 2960, 2198, 2096, 1351, 1307, 1250, 932,
850, 799, 755, 645 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.18 (br s, 1 H), 7.56 (dd, J = 8.0,
0.8 Hz, 1 H), 7.31–7.22 (m, 2 H), 7.11 (ddd, J = 8.0, 6.8, 1.2 Hz, 1
H), 6.88 (dd, J = 2.2, 1.0 Hz, 1 H), 0.23 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): d = 136.2, 127.2, 124.4, 121.1,
120.8, 116.9, 112.0, 110.9, 93.0, 87.4, 77.9, 69.0, –0.46.
MS (EI, 70 eV): m/z (%) = 237 (M+, 68), 222 (100), 206 (7), 192 (6),
168 (7), 165 (6), 154 (7), 111 (23), 97 (11), 84 (12), 77 (7), 67 (5),
63 (4), 53 (12), 43 (20).
2-[4-(Trimethylsilyl)buta-1,3-diynyl]benzofuran (5)
To a stirred soln of 1-(trimethylsilyl)buta-1,3-diyne9 (1.175 g, 9.63
mmol), 2-iodobenzofuran18 (1.959 g, 8.03 mmol), PdCl2(PPh3)2
(0.112 g, 0.16 mmol), and Et3N (16.8 mL) under N2, at r.t., CuI
(0.015 g, 0.08 mmol) was added. The mixture was heated at 60 °C
for 3 h, then quenched with sat. aq NH4Cl soln (50 mL) and extract-
ed with EtOAc (3 × 50 mL). The combined organic extracts were
washed with H2O (3 × 40 mL), dried (Na2SO4), and concentrated
under vacuum. The residue was purified by percolation (florisil col-
umn, PE) leading to 5 (1.586 g, 83%) as a brown oil.
Anal. Calcd for C15H15NSi: C, 75.90; H, 6.37; N, 5.90. Found: C,
75.85; H, 6.36; N, 5.88.
IR (neat): 3066, 2959, 2899, 2198, 2104, 1448, 1252, 1162, 1142,
1024, 919, 848, 749, 643 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.53 (ddd, J = 7.8, 1.2, 0.7 Hz, 1
H), 7.43–7.40 (m, 1 H), 7.34 (ddd, J = 8.3, 7.2, 1.2 Hz, 1 H), 7.23
(ddd, J = 7.8, 7.2, 1.0 Hz, 1 H), 7.05 (d, J = 1.0 Hz, 1 H), 0.24 (s, 9
H).
13C NMR (100.6 MHz, CDCl3): d = 155.1, 137.5, 127.1, 126.4,
123.5, 121.4, 114.7, 111.3, 94.9, 86.9, 80.2, 66.3, –0.56.
MS (EI, 70 eV): m/z (%) = 238 (M+, 38), 223 (100), 193 (4), 163 (7),
112 (21), 97 (6), 77 (8), 63 (5), 53 (10), 43 (20).
Conversion of Silylacetylenes 1, 4, 5, 7, 8 with Azides; General
Procedure
A THF soln (0.3–0.5 M) of the silyl derivative (1 equiv) was added
at r.t., under N2, to a stirred suspension (0.6–0.9 M) of azide (2
equiv) and CuI (1 equiv) in THF, then 1,1,4,7,7-pentamethyldieth-
ylenetriamine (2 equiv) and soon afterwards 1 M TBAF in THF (2
equiv) were added. The mixture was stirred at r.t. until completion
(1–1.5 h, 20 h for product 2f), then the reaction was quenched with
sat. aq NH4Cl soln (20 mL) and extracted with EtOAc (3 × 20 mL).
The combined organic extracts were washed with H2O (3 × 20 mL),
dried (Na2SO4), and concentrated under vacuum. The residue was
purified by column chromatography (silica gel, PE–EtOAc) and by
crystallization (EtOAc–PE).
Anal. Calcd for C15H14OSi: C, 75.58; H, 5.92. Found: C, 75.50; H,
5.88.
2-[4-(Trimethylsilyl)buta-1,3-diynyl]-1H-indole (8)
Conversion of 2-Ethynylbenzofuran (3) with Azides; General
Procedure
To a soln of 1-(trimethylsilyl)buta-1,3-diyne9 (0.300 g, 2.46 mmol),
2-iodo-1H-indole20 (0.299 g, 1.23 mmol), PdCl2(PPh3)2 (0.042 g,
0.06 mmol), and Et3N (0.3 mL, 1.85 mmol) in THF (8 mL), under
N2, at r.t., CuI (0.010 g, 0.05 mmol) was added. The mixture was
stirred at r.t. for 6 h, then quenched with sat. aq NH4Cl soln (20 mL)
and extracted with EtOAc (3 × 20 mL). The organic combined ex-
tracts were washed with H2O (3 × 20 mL), dried (Na2SO4), and con-
centrated under vacuum. The residue was purified by column
chromatography (silica gel, EtOAc–PE, 9.5:0.5) leading to 8 (0.157
g, 54%) as a brown viscous oil.
2-Ethynylbenzofuran (3; 1.5 equiv) and azide (1 equiv) were added
at r.t. to a soln (0.12 M) of Cu(OAc)2·H2O (0.2 equiv) in H2O in a
capped flask. The mixture was stirred at r.t. and on completion (20
h) the reaction was quenched with sat. aq NH4Cl soln (20 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with sat. NaCl (3 × 20 mL), dried (Na2SO4), and con-
centrated under vacuum. The residue was purified by column chro-
Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York

3856
V. Fiandanese et al.
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matography (silica gel, PE–EtOAc, 4:1) and by crystallization
(EtOAc–PE).
MS (EI, 70 eV): m/z (%) = 289 (M+, 50), 260 (35), 233 (34), 219
(14), 170 (89), 143 (72), 142 (48), 115 (100), 105 (45), 91 (49), 79
(49), 77 (73), 65 (45), 63 (41), 51 (62).
4-(Benzofuran-2-yl)-1-benzyl-1H-1,2,3-triazole (2a)
Anal. Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C,
74.65; H, 5.15; N, 14.50.
Starting from 1 (0.20 g, 0.61 mmol) and BnN3 (0.162 g, 1.22 mmol)
gave 2a; yield: 0.121 g (72%); from 4 (0.150 g, 0.70 mmol) and
BnN3 (0.186 g, 1.40 mmol) gave 2a ; yield: 0.148 g (77%).
4-(Benzofuran-2-yl)-1-(2-iodobenzyl)-1H-1,2,3-triazole (2d)
Starting from 3 (0.400 g, 2.82 mmol) and 2-iodobenzyl azide (0.487
g, 1.88 mmol) gave 2d as a pale yellow-golden solid; yield: 0.611 g
(81%); mp 154–155 °C.
White solid; mp 174–175 °C.
IR(KBr): 3108, 1438, 1420, 1260, 1232, 1070, 1049, 799, 744, 720,
692 cm–1.
IR (KBr): 3119, 1438, 1313, 1256, 1238, 1180, 1068, 1046, 1014,
809, 746, 730 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.91 (dd, J = 7.9, 1.2 Hz, 1 H),
7.88 (s, 1 H), 7.63–7.57 (m, 1 H), 7.49–7.44 (m, 1 H), 7.35 (td like,
J = 7.6, 1.2 Hz, 1 H), 7.30–7.21 (m, 3 H), 7.18 (dd, J = 7.7, 1.7 Hz,
1 H), 7.06 (td like, J = 7.7, 1.7 Hz, 1 H), 5.69 (s, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 154.5, 147.9, 140.4, 140.0,
136.9, 130.6, 129.8, 129.1, 128.5, 124.5, 123.1, 121.2, 120.6, 111.0,
102.9, 98.8, 58.5.
1H NMR (400 MHz, CDCl3): d = 7.78 (s, 1 H), 7.59 (dd, J = 7.2, 0.8
Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.42–7.36 (m, 3 H), 7.34–7.30
(m, 2 H), 7.29–7.21 (m, 2 H), 7.20 (s, 1 H), 5.59 (s, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 154.5 148.0, 140.6, 134.2,
129.2, 128.9, 128.6, 128.2, 124.5, 123.1, 121.2, 120.3, 111.0, 102.8,
54.3.
MS (EI, 70 eV): m/z (%) = 275 (M+, 30), 246 (34), 219 (57), 191 (9),
170 (11), 156 (35), 115 (16), 101 (40), 91 (100), 77 (17), 75 (26), 65
(58), 63 (25), 51 (40).
MS (EI, 70 eV): m/z (%) = 246 (100), 217 (58), 191 (12), 189 (14),
156 (42), 109 (29), 101 (42), 91 (60), 90 (83), 89 (60), 77 (25), 75
(31), 63 (45), 51 (42).
Anal. Calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C,
74.25; H, 4.80; N, 15.30.
4-(Benzofuran-2-yl)-1-(4-iodobenzyl)-1H-1,2,3-triazole (2b)
Starting from 1 (0.200 g, 0.61 mmol) and 4-iodobenzyl azide (0.317
g, 1.22 mmol) gave 2b; yield: 0.144 g (59%); from 3 (0.300 g, 2.11
mmol) and 4-iodobenzyl azide (0.365 g, 1.41 mmol) gave 2b; yield:
0.373 g (66%); from 4 (0.150 g, 0.70 mmol) and 4-iodobenzyl azide
(0.363 g, 1.40 mmol) gave 2b; yield: 0.202 g (72%).
Anal. Calcd for C17H12IN3O: C, 50.89; H, 3.01; N, 10.47. Found: C,
50.99; H, 2.96; N, 10.38.
4-(Benzofuran-2-yl)-1-(3-iodobenzyl)-1H-1,2,3-triazole (2e)
Starting from 3 (0.310 g, 2.18 mmol) and 3-iodobenzyl azide (0.376
g, 1.45 mmol) gave 2e as a yellow-orange solid; yield: 0.512 g
(88%); mp 164–165 °C.
Pale yellow solid; mp 218–220 °C.
IR (KBr): 3101, 1437, 1421, 1310, 1257, 1230, 1178, 1077, 1048,
803, 752, 737 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.82 (s, 1 H), 7.73–7.67 (m, 2 H),
7.60 (d, J = 7.8 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.33–7.20 (m, 4
H), 7.12 (t, J = 7.7 Hz, 1 H), 5.53 (s, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 154.6, 147.7, 140.7, 138.0,
136.9, 136.4, 130.8, 128.5, 127.3, 124.6, 123.2, 121.3, 120.4, 111.0,
103.0, 94.8, 53.4.
IR (KBr): 3097, 1437, 1423, 1404, 1314, 1259, 1182, 1046, 1006,
991, 822, 808, 798, 748 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.78 (s, 1 H), 7.72 (d like, J = 8.4
Hz, 2 H), 7.61–7.57 (m, 1 H), 7.46–7.42 (m, 1 H), 7.29–7.21 (m, 2
H), 7.20 (d, J = 1.2 Hz, 1 H), 7.05 (d like, J = 8.4 Hz, 2 H), 5.52 (s,
2 H).
13C NMR (100.6 MHz, CDCl3): d = 154.6, 147.8, 140.8, 138.4,
133.9, 129.9, 128.5, 124.6, 123.2, 121.3, 120.3, 111.1, 103.0, 94.8,
53.7.
MS (EI, 70 eV): m/z (%) = 372 (14), 345 (14), 246 (66), 219 (40),
218 (34), 217 (47), 191 (22), 189 (22), 170 (17), 156 (54), 123 (30),
109 (54), 101 (52), 90 (100), 89 (87), 75 (42), 63 (55), 51 (50).
MS (EI, 70 eV): m/z (%) = 373 (13), 372 (13), 345 (14), 246 (57),
217 (60), 191 (16), 189 (18), 170 (13), 156 (55), 123 (30), 109 (30),
101 (50), 90 (100), 89 (83), 75 (36), 63 (54), 51 (47).
Anal. Calcd for C17H12IN3O: C, 50.89; H, 3.01; N, 10.47. Found: C,
50.95; H, 2.97; N, 10.40.
Anal. Calcd for C17H12IN3O: C, 50.89; H, 3.01; N, 10.47. Found: C,
51.00; H, 3.00; N, 10.35.
4-(Benzofuran-2-yl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole
(2f)
Starting from 4 (0.150 g, 0.70 mmol) and 4-methoxyphenyl azide
(0.209 g, 1.40 mmol) gave 2f as a brown solid; yield: 0.181 g (89%);
mp 149–152 °C.
4-(Benzofuran-2-yl)-1-(2-phenylethyl)-1H-1,2,3-triazole (2c)
Starting from 1 (0.200 g, 0.61 mmol) and 2-phenylethyl azide
(0.179 g, 1.22 mmol) gave 2c; yield: 0.099 g (56%); from 4 (0.150
g, 0.70 mmol) and 2-phenylethyl azide (0.202 g, 1.40 mmol) gave
2c; yield: 0.112 g (55%).
IR (KBr): 3118, 1518, 1243, 1037, 836, 814, 745 cm–1.
White solid; mp 149–152 °C.
1H NMR (400 MHz, CDCl3): d = 8.19 (s, 1 H), 7.64 (d like, J = 9.0
Hz, 2 H), 7.61–7.56 (m, 1 H), 7.50–7.45 (m, 1 H), 7.30–7.19 (m, 3
H), 6.99 (d like, J = 9.0 Hz, 2 H), 3.82 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 159.9, 154.6, 147.8, 140.5,
130.1, 128.6, 124.6, 123.2, 122.1, 121.3, 118.5, 114.8, 111.1, 103.1,
55.6.
MS (EI, 70 eV): m/z (%) = 291 (M+, 6), 263 (100), 248 (42), 220
(65), 191 (9), 165 (16), 156 (17), 142 (10), 130 (14), 102 (27), 63
(10).
IR (KBr): 3121, 3061, 3028, 1438, 1429, 1367, 1257, 1227, 1177,
1072, 1048, 801, 735, 725, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.63 (s, 1 H), 7.61–7.57 (m, 1 H),
7.48–7.44 (m, 1 H), 7.32–7.20 (m, 5 H), 7.17 (d, J = 0.8 Hz, 1 H),
7.15–7.10 (m, 2 H), 4.64 (t, J = 7.4 Hz, 2 H), 3.25 (t, J = 7.4 Hz, 2
H).
13C NMR (100.6 MHz, CDCl3): d = 154.5, 148.0, 139.9, 136.7,
128.9, 128.6, 128.6, 127.2, 124.4, 123.1, 121.2, 120.7, 111.1, 102.6,
51.8, 36.7.
Anal. Calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C,
70.00; H, 4.53; N, 14.39.
Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York

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Benzofuran- and Indole-Substituted 1,2,3-Triazoles
3857
4-(Benzofuran-2-yl)-1-octyl-1H-1,2,3-triazole (2g)
Starting from 4 (0.150 g, 0.70 mmol) and n-octyl azide (0.217 g,
1.40 mmol) gave 2g as a white solid; yield: 0.173 g (83%); mp 115–
117 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.63 (s, 1 H), 8.51 (s, 1 H),
7.51 (d, J = 7.6 Hz, 1 H), 7.45–7.32 (m, 6 H), 7.07 (t like, J = 7.5
Hz, 1 H), 6.98 (t like, J = 7.5 Hz, 1 H), 6.78 (br s, 1 H), 5.69 (s, 2 H).
13C NMR (100.6 MHz, DMSO-d6): d = 141.2, 136.7, 136.1, 129.4,
129.1, 128.5, 128.4, 128.3, 121.7, 121.6, 120.2, 119.6, 111.7, 98.8,
53.2.
IR (KBr): 3114, 2954, 2920, 2847, 1458, 1438, 1429, 1369, 1258,
1230, 1174, 1073, 1049, 911, 797, 753, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.86 (s, 1 H), 7.59 (d, J = 7.2 Hz,
1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.30–7.15 (m, 3 H), 4.40 (t, J = 7.2
Hz, 2 H), 2.00–1.87 (m, 2 H), 1.43–1.15 (m, 10 H), 0.85 (t, J = 6.6
Hz, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 154.8, 148.4, 140.3, 128.9,
124.7, 123.3, 121.5, 120.5, 111.3, 102.8, 50.8, 31.9, 30.5, 29.2,
29.1, 26.7, 22.8, 14.2.
MS (EI, 70 eV): m/z (%) = 297 (M+, 23), 185 (57), 184 (29), 170
(11), 157 (41), 144 (58), 131 (24), 115 (26), 102 (13), 101 (11), 69
(13), 55 (26), 43 (50), 41 (100).
MS (EI, 70 eV): m/z (%) = 274 (M+, 49), 245 (100), 218 (44), 169
(43), 155 (29), 128 (34), 101 (39), 91 (75), 77 (25), 65 (48), 51 (32).
Anal. Calcd for C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C,
74.40; H, 5.16; N, 20.38.
2-[1-(4-Iodobenzyl)-1H-1,2,3-triazol-4-yl]-1H-indole (9b)
Starting from 7 (0.200 g, 0.94 mmol) and 4-iodobenzyl azide (0.307
g, 1.88 mmol) gave 9b as a beige solid; yield: 0.237 g (63%); mp
274–277 °C (dec).
IR (KBr): 3329, 3115, 2922, 1457, 1405, 1324, 1217, 1054, 1009,
802, 787, 744 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.62 (s, 1 H), 8.50 (s, 1 H),
7.78 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0
Hz, 1 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.11–7.05 (m, 1 H), 6.98 (t like,
J = 7.2 Hz, 1 H), 6.78 (d, J = 1.2 Hz, 1 H), 5.66 (s, 2 H).
13C NMR (100.6 MHz, DMSO-d6): d = 141.7, 138.3, 137.1, 136.3,
131.0, 129.7, 128.8, 122.2, 122.1, 120.7, 120.0, 112.1, 99.2, 95.3,
53.1.
MS (EI, 70 eV): m/z (%) = 400 (M+, 60), 371 (74), 245 (29), 244
(43), 243 (38), 217 (85), 169 (68), 155 (45), 128 (47), 122 (37), 101
(52), 90 (100), 89 (82), 77 (35), 63 (46), 51 (40).
Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found: C,
72.75; H, 7.78; N, 14.18.
4-(Benzofuran-2-ylethynyl)-1-benzyl-1H-1,2,3-triazole (6a)
Starting from 5 (0.193 g, 0.81 mmol) and BnN3 (0.216 g, 1.62
mmol) gave 6a as a pale yellow-orange solid; yield: 0.145 g (60%);
mp 138–139 °C.
IR (KBr): 3116, 2227, 1457, 1448, 1247, 1230, 1169, 1061, 944,
820, 750, 732 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.65 (s, 1 H), 7.54 (br d, J = 7.6
Hz, 1 H), 7.46–7.18 (m, 8 H), 7.01 (d, J = 0.8 Hz, 1 H), 5.53 (s, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 154.9, 137.9, 133.8, 130.3,
129.2, 129.0, 128.1, 127.4, 126.6, 125.9, 123.3, 121.3, 112.6, 111.3,
84.2, 83.0, 54.4.
Anal. Calcd for C17H13IN4: C, 51.02; H, 3.27; N, 14.00. Found: C,
51.00; H, 3.25; N, 13.97.
2-[1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]-1H-indole (9c)
Starting from 7 (0.200 g, 0.94 mmol) and 4-methoxyphenyl azide
(0.280 g, 1.88 mmol) gave 9c as a pale brown solid; yield: 0.251 g
(92%); mp 243–247 °C (dec).
MS (EI, 70 eV): m/z (%) = 299 (M+, 13), 270 (36), 244 (40), 215
(33), 153 (15), 121 (10), 99 (14), 91 (100), 75 (17), 65 (49), 63 (22),
51 (27).
Anal. Calcd for C19H13N3O: C, 76.24; H, 4.38; N, 14.04. Found: C,
76.20; H, 4.40; N, 14.00.
IR (KBr): 3426, 3113, 1520, 1507, 1253, 1227, 1044, 1034, 840,
796, 736 cm–1.
4-(Benzofuran-2-ylethynyl)-1-(2-phenylethyl)-1H-1,2,3-tri-
azole (6b)
Starting from 5 (0.250 g, 1.05 mmol) and 2-phenylethyl azide
(0.309 g, 2.10 mmol) gave 6b as a pale yellow solid; yield: 0.217 g
(66%); mp 118–120 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.74 (s, 1 H), 9.08 (s, 1 H),
7.86 (d like, J = 9.0 Hz, 2 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.44 (d,
J = 8.0 Hz, 1 H), 7.19 (d like, J = 9.0 Hz, 2 H), 7.14–7.09 (m, 1 H),
7.05–6.98 (m, 1 H), 6.86–6.84 (m, 1 H), 3.85 (s, 3 H).
13C NMR (100.6 MHz, DMSO-d6): d = 159.3, 141.4, 136.5, 129.9,
128.7, 128.1, 121.8, 121.6, 120.0, 119.5, 119.4, 114.9, 111.5, 98.9,
55.5.
IR (KBr): 3116, 2959, 2924, 2227, 1447, 1259, 1100, 1050, 1022,
798, 744, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.58–7.54 (m, 1 H), 7.47–7.42 (m,
2 H), 7.36–7.21 (m, 5 H), 7.10–7.06 (m, 2 H), 7.03 (d, J = 0.8 Hz, 1
H), 4.62 (t, J = 7.2 Hz, 2 H), 3.22 (t, J = 7.2 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 290 (M+, 32), 262 (100), 247 (58), 219
(63), 191 (21), 155 (50), 129 (70), 128 (36), 110 (36), 102 (42), 96
(21), 77 (33), 64 (43), 63 (42), 51 (31).
13C NMR (100.6 MHz, CDCl3): d = 154.9, 137.9, 136.5, 129.6,
128.9, 128.6, 127.4, 127.3, 126.9, 125.9, 123.4, 121.4, 112.6, 111.3,
84.3, 82.8, 51.9, 36.5.
Anal. Calcd for C17H14N4O: C, 70.33; H, 4.86; N, 19.30. Found: C,
70.30; H, 4.89; N, 19.38.
2-[1-(2-Phenylethyl)-1H-1,2,3-triazol-4-yl]-1H-indole (9d)
Starting from 7 (0.200 g, 0.94 mmol) and 2-phenylethyl azide
(0.276 g, 1.88 mmol) gave 9d as a white solid; yield: 0.179 g (66%);
mp 212–214 °C.
MS (EI, 70 eV): m/z (%) = 313 (M+, 40), 284 (72), 257 (58), 167
(89), 166 (86), 139 (95), 138 (51), 126 (34), 105 (98), 103 (37), 91
(100), 79 (67), 77 (93), 65 (55), 63 (46), 51 (69).
Anal. Calcd for C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found: C,
76.70; H, 4.79; N, 13.38.
IR (KBr): 3308, 3113, 3028, 1456, 1418, 1326, 1216, 1084, 1053,
794, 738 cm–1.
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1H-indole (9a)
Starting from 7 (0.200 g, 0.94 mmol) and BnN3 (0.250 g, 1.88
mmol) gave 9a as a beige solid; yield: 0.211 g (82%); mp 259–261
°C (dec).
1H NMR (400 MHz, DMSO-d6): d = 11.60 (s, 1 H), 8.40 (s, 1 H),
7.51 (br d, J = 7.6 Hz, 1 H), 7.38 (dd like, J = 8.0, 0.8 Hz, 1 H),
7.31–7.18 (m, 5 H), 7.07 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 6.98 (ddd,
J = 8.0, 7.2, 1.2 Hz, 1 H), 6.72–6.70 (m, 1 H), 4.69 (t, J = 7.2 Hz, 2
H), 3.22 (t, J = 7.2 Hz, 2 H).
IR (KBr): 3329, 3134, 3117, 3032, 1455, 1413, 1324, 1216, 1055,
800, 744, 717 cm–1.
Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York

3858
V. Fiandanese et al.
PAPER
13C NMR (100.6 MHz, DMSO-d6): d = 140.6, 137.8, 136.6, 129.5,
128.9, 128.7, 128.4, 126.9, 121.6, 121.5, 120.1, 119.5, 111.6, 98.6,
50.9, 35.9.
Acknowledgment
This work was financially supported by the University of Bari.
MS (EI, 70 eV): m/z (%) = 288 (M+, 34), 259 (10), 232 (16), 218 (7),
169 (100), 155 (11), 142 (24), 130 (13), 115 (28), 105 (16), 91 (17),
79 (18), 77 (29), 65 (14), 63 (12), 51 (20).
References
(1) (a) Morales-Sanfrutos, J.; Ortega-Munoz, M.; Lopez-
Jaramillo, J.; Hernandez-Mateo, F.; Santoyo-Gonzalez, F.
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Int. Ed. 2007, 46, 1018. (c) Such, G. K.; Quinn, J. F.; Quinn,
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(e) Löber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett.
2003, 5, 1753.
Anal. Calcd for C18H16N4: C, 74.98; H, 5.59; N, 19.43. Found: C,
75.00; H, 5.62; N, 19.39.
2-(1-Octyl-1H-1,2,3-triazol-4-yl)-1H-indole (9e)
Starting from 7 (0.200 g, 0.94 mmol) and n-octyl azide (0.290 g,
1.88 mmol) gave 9e as a white solid; yield: 0.186 g (67%); mp 164–
166 °C.
IR (KBr): 3252, 3109, 2959, 2919, 2850, 1457, 1413, 1329, 1319,
1216, 1051, 1013, 800, 742, 722 cm–1.
(2) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn,
M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega,
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(5) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984.
1H NMR (400 MHz, DMSO-d6): d = 11.61 (s, 1 H), 8.47 (s, 1 H),
7.51 (br d, J = 8.0 Hz, 1 H), 7.39 (dd like, J = 8.0, 0.8 Hz, 1 H), 7.07
(ddd, J = 8.0, 7.2, 1.2 Hz, 1 H), 6.98 (ddd, J = 8.0, 7.2, 1.2 Hz, 1 H),
6.74 (dd, J = 2.0, 0.8 Hz, 1 H), 4.41 (t, J = 7.0 Hz, 2 H), 1.91–1.80
(m, 2 H), 1.35–1.15 (m, 10 H), 0.83 (t, J = 6.8 Hz, 3 H).
13C NMR (100.6 MHz, DMSO-d6): d = 140.8, 136.7, 129.6, 128.4,
121.6, 121.4, 120.1, 119.5, 111.6, 98.6, 49.8, 31.4, 29.9, 28.8, 28.6,
26.1, 22.3, 14.2.
MS (EI, 70 eV): m/z (%) = 296 (M+, 16), 183 (9), 169 (100), 156
(12), 130 (12), 115 (8), 101 (6), 55 (10), 43 (21), 41 (43).
Anal. Calcd for C18H24N4: C, 72.94; H, 8.16; N, 18.90. Found: C,
72.90; H, 8.12; N, 18.80.
(6) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
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2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)ethynyl]-1H-indole (10a)
Starting from 8 (0.103 g, 0.435 mmol) and BnN3 (0.116 g, 0.87
mmol), and washing with PE, gave 10a as a pale golden solid; yield:
0.101 g (78%); mp 166–169 °C.
(8) (a) Jurícek, M.; Kouwer, P. H. J.; Rehák, J.; Sly, J.; Rowan,
A. E. J. Org. Chem. 2009, 74, 21. (b) Broggi, J.; Díez-
González, S.; Petersen, J. L.; Berteina-Raboin, S.; Nolan, S.
P.; Agrofoglio, L. A. Synthesis 2008, 141. (c) Li, P.; Wang,
L.; Zhang, Y. Tetrahedron 2008, 64, 10825. (d) Jlalia, I.;
Elamari, H.; Meganem, F.; Herscovici, J.; Girard, C.
Tetrahedron Lett. 2008, 49, 6756. (e) Wang, Z.-X.; Zhao,
Z.-G. J. Heterocycl. Chem. 2007, 44, 89. (f) Chassaing, S.;
Kumarraja, M.; Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett.
2007, 9, 883. (g) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae,
I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew. Chem.
Int. Ed. 2007, 46, 1730. (h) Bertrand, P.; Gesson, J. P.
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Angew. Chem. Int. Ed. 2006, 45, 8235. (l) Reddy, K. R.;
Rajgopal, K.; Kantam, M. L. Synlett 2006, 957.
IR (KBr): 3274, 3142, 2224, 1457, 1363, 1341, 1219, 1057, 808,
790, 753, 725, 695 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.80 (s, 1 H), 8.69 (s, 1 H),
7.56 (br d, J = 8.0 Hz, 1 H), 7.43–7.32 (m, 6 H), 7.19 (ddd, J = 8.0,
7.2, 1.0 Hz, 1 H), 7.05 (ddd, J = 8.0, 7.2, 1.0 Hz, 1 H), 6.86 (dd,
J = 2.0, 0.8 Hz, 1 H), 5.67 (s, 2 H).
13C NMR (100.6 MHz, DMSO-d6): d = 136.4, 135.6, 129.2, 128.8,
128.3, 128.2, 127.9, 127.0, 123.2, 120.5, 119.9, 117.2, 111.3, 108.2,
85.2, 81.7, 53.1.
Anal. Calcd for C19H14N4: C, 76.49; H, 4.73; N, 18.78. Found: C,
76.40; H, 4.76; N, 18.68.
2-{[1-(2-Phenylethyl)-1H-1,2,3-triazol-4-yl]ethynyl}-1H-indole
(10b)
Starting from 8 (0.141 g, 0.595 mmol) and 2-phenylethyl azide
(0.175 g, 1.19 mmol), and washing with PE, gave 10b as a pale yel-
low solid; yield: 0.115 g (62%); mp 139–141 °C.
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Tetrahedron 2004, 60, 11421. (b) Fiandanese, V.; Bottalico,
D.; Marchese, G.; Punzi, A. J. Organomet. Chem. 2005, 690,
3004. (c) Fiandanese, V.; Bottalico, D.; Cardellicchio, C.;
Marchese, G.; Punzi, A. Tetrahedron 2005, 61, 4551.
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Tetrahedron 2006, 62, 5126.
IR (KBr): 3403, 3129, 3050, 2224, 1457, 1363, 1340, 1291, 1275,
1224, 1052, 837, 796, 742, 728, 704 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.74 (s, 1 H), 8.39 (s, 1 H),
7.55 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.30–7.12 (m, 6
H), 7.04 (t, J = 7.6 Hz, 1 H), 6.85 (br s, 1 H), 4.66 (t, J = 7.0 Hz, 2
H), 3.17 (t, J = 7.0 Hz, 2 H).
(11) For a comprehensive review, see: Fiandanese, V.; Bottalico,
13C NMR (100.6 MHz, DMSO-d6): d = 137.6, 136.8, 129.1, 129.0,
128.8, 128.3, 127.4, 127.1, 123.7, 120.9, 120.4, 117.5, 111.7, 108.7,
85.5, 82.1, 51.2, 35.7.
D. Curr. Org. Chem. 2009, 13, 554.
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Tetrahedron 2008, 64, 53.
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Anal. Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.92; H, 5.18; N, 17.89.
Tetrahedron 2008, 64, 7301.
(14) Ito, H.; Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedron
Lett. 1997, 38, 3977.
Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York

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Benzofuran- and Indole-Substituted 1,2,3-Triazoles
3859
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Synthesis 2009, No. 22, 3853–3859 © Thieme Stuttgart · New York