Synthesis of a new class of triazole-linked benzoheterocycles via 1,3-dipolar cycloaddition

Article abstract of DOI:10.1590/S0103-50532011000300025

A new series of 1,2,3-triazole derivatives have been synthesized from phthalimides and terminal alkynes in the presence of a catalytic amount of CuI. The present protocol affords 1,2,3-triazoles in moderate to good yields (44-89percent).

Full text of DOI:10.1590/S0103-50532011000300025

J. Braz. Chem. Soc., Vol. 22, No. 3, 592-597, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Short Report
S
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via
1,3-Dipolar Cycloaddition
Fernanda C. G. Barbosa and Ronaldo N. de Oliveira*
Departamento de Química, Laboratório de Síntese de Compostos Bioativos - LSCB, Universidade Federal
Rural de Pernambuco, Rua Dom Manoel de Medeiros s/n, Dois Irmãos, 52171-900 Recife-PE, Brazil
Uma nova série de derivados 1,2,3,-triazólicos foi sintetizada a partir de ftalimidas e alcinos
terminais na presença de quantidade catalítica de CuI. O presente protocolo forneceu 1,2,3-triazóis
em moderados a bons rendimentos (44-89%).
A new series of 1,2,3-triazole derivatives have been synthesized from phthalimides and terminal
alkynes in the presence of a catalytic amount of CuI. The present protocol affords 1,2,3-triazoles
in moderate to good yields (44-89%).
Keywords: benzoheterocycles, 1,2,3-triazole, phthalimide, copper-catalyst, cycloaddition
Introduction
order to reach this goal, we employed the 1,3-dipolar
cycloaddition reaction (1,3-DCRs) between an azide
function and a terminal alkyne via a cross-linking process
to afford the corresponding 1,2,3-triazoles, using a
copper(I)-based catalyst, specifically CuI. It is worth to
note that, in most cases explored in this work, there was
no need of any additional base in the reaction medium
as well as of any ligands for the catalytic system.15,16
The selected benzoheterocyclic alkynes are S-propargyl
derivatives of benzimidazole-2-thiol (1a), benzothiazole-
2-thiol (1b) and benzoxazole-2-thiol (1c), N-propargyl
derivatives of benzimidazole (1d) and phthalimide (1e).
N-(3-Azidopropyl- and 4-azidobutyl) phthalimides (2a,b)
were chosen as the phthalimide block. Furthermore,
we have used a retrosynthetic strategy to obtain the
desired products BTP (benzoheterocycle-1,2,3-triazole-
phthalimide), as shown in Figure 1.
The synthesis of small molecules libraries for biological
screening has gained impetus in the scientific community.
Among the different functional moieties employed for this
purpose, one commonly used is the nitrogen-containing
heterocyclic compounds, which exhibit diverse biological
and pharmacological activities. Compounds containing
such an aza-heterocycle were described as trypanocidal
agents,1 glycogen phosphorylase inhibitors,2 antitumor,3
antiviral,4 antimicrobial agents,5 antimycobacterial,6 among
others.7 In particular, two widely known classes have been
subject of investigation by our research group, namely the
benzoheterocyclic compounds and the triazoles.8 These
compounds have received much attention from medicinal
chemists, who search for a heterocyclic scaffold of drugs
in pharmacology, so that many efforts have been made in
the optimization of their preparation methods.8-11 Such
compounds are versatile molecules and their range of
applications is steadily increasing including, among
others, the areas of carbohydrates, materials sciences and
nanosciences.12-14 Still in this context and without loss of
structural simplicity, we have been attracted by the idea
of designing compounds built from different heterocyclic
blocks, seeking for an enhanced biological activity. In this
work, we performed the synthesis of novel compounds
based on 1,2,3-triazoles-linked benzoheterocycles. In
To our knowledge, these three-block conjugations were
not yet reported in the literature, which is surprising, in view
of the potential ready availability and the growing impact
of the triazole chemistry on organic synthesis.16
Results and Discussion
The starting materials (1a-e) were prepared via
nucleophilic substitution between propargyl bromide
(BrCH2C≡ CH) and the benzoheterocyclic compounds
in the presence of K2CO3. This protocol afforded the
corresponding terminal alkynes (1a-e) in 44-83% yields.
*e-mail: ronaldonoliveira@dq.ufrpe.br

Vol. 22, No. 3, 2011
Barbosa and Oliveira
593
N–
O
+N
N
N
N
n
O
N
HET
N
O
N
n
+
O
HET
Benzoheterocyclic
Phthalimide Triazole
Figure 1. Retrosynthetic strategy of three-heterocyclic blocks conjugation.
The IR spectra of these compounds showed typical
bands at 2112-2121 cm-1, corresponding to C≡ C, and at
3176-3273 cm-1 to C≡ C-H stretching related to the alkyne.
The starting N-(azido-alkyl)phthalimide (2a) and (2b) were
prepared from N-(bromoalkyl)phthalimides by reaction
with NaN3 in DMF at 60 oC during 24 h. This procedure
afforded the azido-compounds (2a,b) as white solids which
were used without any purification.
the corresponding 1,2,3-triazoles (3) and (4) in 44-89%
yield after column chromatography or recrystallization
(Table 1). To our knowledge, such a cross-linking reaction
between alkyne and azide groups, using CuI as catalyst in
dichloromethane and in the absence of base, has not been
performed yet. In only one case, the addition of a base,
namely Et3N, was necessary to reduce the reaction time
(Table 1, entry 11).
In order to perform the cycloaddition reaction towards
three-heterocyclic blocks sequence BTP, we used the
most common cycloaddition protocol between N-(4-
azidobutyl)-phthalimide (2b) and the acetylene (1d) using
Cu(OAc)2 as Cu(II) source and sodium ascorbate in media
of tert-BuOH:H2O 50% at room temperature.10 However,
this methodology has provided low yields (ca. 23%).
Looking at this result, we turned to the following
modified protocol. The copper-catalyzed condensation
of 2-propargylsulfanylbenzothiazole (1b, 1.5 mol equiv.)
In order to test the applicability of the method
(CuI/CH2Cl2/rt) to a different substrate rather than the
benzoheterocyclic moiety, a different kind of functionality
was investigated. In this respect, we examined the
condensation reaction between N-3-azido-propyl (2a) or
N-4-azidobutylphthalimide (2b) and the ethynyl ketone
(1f), and checked the ready formation of 1,2,3-triazoles
(3f) and (4f) in excellent yields 92% and 91%, respectively
(Table 1, entries 6 and 12). These results are in agreement
with the literature, which can be justified by the fact that
α-carbonyl-alkynes are highly reactive.16
o
with azide (2b, 1 mol equiv.) in CH2Cl2 at 30 C
afforded 1,2,3-triazole (4b) in 84% yield after column
chromatography (Table 1, entry 8). Encouraged by this
positive result, we have focused our effort on the synthesis
of new derivatives of 1-[N-phthalimidoalkyl]-4-heteroaryl-
1H-1,2,3-triazoles (3) and (4) using this protocol (Scheme 1
and Table 1).
In summary, we have developed a convenient route,
with easy work up, for the synthesis of a new class of
1,2,3-triazole derivatives (3) and (4) in moderate to good
yields (44-92%). This new tris-heterocyclic sequence
(benzoheterocycles-triazole-phthalimide, BTP) represents
a set of potentially interesting compounds for biological
activity screening and we believe that applications for them
will be soon found in organic and medicinal chemistry.
Reaction of azidoalkylphthalimides (2a or 2b) with
benzoheterocycles (1a-e) provides easy conversion to
N
CuI/DCM
O
O
N
R
r.t./argon
N3
N
N
N
n
n
R
O
O
1a-f
3a-f (n =3)
4a-f (n =4)
2a (n =3)
2b (n =4)
O
O
N
O
N
N
N
S
SCH2
SCH2
N CH2
SCH2
R =
N
CH3
(f)
N
H
H2C
O
(e)
(b)
(a)
(c)
(d)
Scheme 1. Synthesis of the compounds 1,2,3-triazoles (3a-f) and (4a-f).

594
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Table 1. Cu-Catalyzed formation of (3a-f) and (4a-f)
Products
Products
O
O
N
N
N
N
R
R
aYields / %
(time)
bYields / %
(time)
N
N
N
entry
entry
N
3
4
O
O
3a-f
4a-f
H
N
H
N
a =
S
a =
S
1
65 (19 h)
7
86 (24 h)
N
N
H2C
H2C
S
N
S
N
S
S
b =
c =
b =
c =
2
3
78 (21 h)
55 (28 h)
8
9
84 (23 h)
68 (22 h)
H2C
H2C
O
N
O
N
S
S
H2C
H2C
H2C
H2C
4
89 (27 h)
10
49 (19 h)
d =
N
N
d =
N
N
H2
C
H2
C
O
O
N
N
42 (5 days)
44 (18 h)c
5
6
71 (25 h)
92 (24 h)
11
12
e =
e =
O
O
O
O
f =
91 (24 h)
f =
CH3
CH3
aYields after recrystallization in dichloromethane/hexane. bYields after column chromatography and crystallization; cWhen added 10% of Et3N.
Experimental
Typical procedure for the synthesis of 1,4-disubstituted
1,2,3-triazoles
All commercially available reagents were used as
received.All organic solvents used for the synthesis were of
analytical grade. Column chromatography was performed
on Merck silica gel 60 (70-230 mesh). All reactions were
monitored by TLC analysis contained GF254. IR spectra
were recorded on a IFS66 Bruker spectrophotometer
using KBr discs. 1H and 13C NMR spectra were obtained
on Varian unity plus-300, 400 and 500 spectrometer
using tetramethylsilane as internal reference. Elemental
analyses were carried out on a EA1110 CHNS-O analyzer.
High resolution mass spectra HRMS were recorded on
a Shimadzu Liquid Chrom MS LCMS-IT-TOF using
acetonitrile or methanol as solvent. Air- and moisture-
sensitive reactions were performed under inert atmosphere
of argon. Melting points were determined on a PFM II
BioSan apparatus and are uncorrected.
In a round-bottom flask, the azide-compound (2a)
(100 mg, 0.43 mmol, 1 equiv. of azide function) was
charged with the terminal alkyne (1a) (113 mg, 0.60 mmol,
1.4 equiv.), the solvent (5 mL of DCM) and the copper
catalyst based on either CuI 10 mol% (12 mg, 0.063 mmol
each according to the alkyne-compound). The reaction
was performed by stirring at room temperature under
argon atmosphere, during 18-28 h. The resulting mixture
was washed with NH4OH and then extracted with
dichloromethane. The combined organic layers were dried
with over anhydrous sodium sulfate and then the solvent
was removed in vacuum. Purification of the crude material
by column chromatography using hexane-EtOAc (8:2)
as eluent or recrystallization in CH2Cl2/hexane mixture
afforded the title compound (3a).

Vol. 22, No. 3, 2011
Barbosa and Oliveira
595
4-(Benzimidazol-2-ylsulfanyl)methyl-1-(3-phthalimido-
1703, 1614, 1399, 1042, 722. 1H NMR (300 MHz, CDCl3):
d 2.26 (q, 2H, CH2), 3.66 (t, 2H, J 6.8 Hz, NCH2), 4.34 (t,
2H, J 7.2 Hz, NCH2), 5.49 (s, 2H, NCH2), 7.28 (m, 2H,
Harom), 7.64 (s, 1H, N=CH in benzimidazole), 7.67-7.71 (m,
5H, Phth, Harom), 7.79 (s, 1H, NCH= in triazole). 13C NMR
(75.5 MHz, CDCl3): d 29.2, 34.7, 47.8, 104.9, 110.0, 122.5,
122.9, 123.3, 123.1, 131.7 (C in triazole), 134.1 (NCH= in
triazole), 142.4, 168.2 (C=O in phthalimide). Anal. Calc.
C21H18N6O2(2.5H2O): C, 58.46; H, 5.37. Found: C, 57.79;
H, 4.66.
propyl)-1,2,3-triazole (3a)
Yield 65%; mp 102-103 C; Rf = 0.5 (CH2Cl2-EtOAc,
9:1);IRnmax/cm-1:3452, 3140, 2940, 1766, 1706, 1464, 1430,
o
1
1396, 1359, 996, 750, 717. H NMR (300 MHz, CDCl3):
d 2.28 (q, 2H, CH2), 2.90 (bs, 1H, NH), 3.69 (t, 2H, J 6.6 Hz,
NCH2), 4.35 (t, 2H, J 6.9 Hz, NCH2), 4.67 (s, 2H, SCH2),
7.29 (t, 1H, J 7.5Hz, Harom), 7.41 (t, 1H, J 7.5Hz, Harom),
7.71-7.84 (m, 6H, Phth, NCH=, Harom), 7.92 (d, 1H, J 8.1Hz,
Harom). 13C NMR (75.5 MHz, CDCl3): d 27.7, 29.3, 34.9,
47.9, 121.1, 121.5, 123.4, 124.3, 126.0, 131.8 (C in triazole),
134.2 (NCH= in triazole), 135.4, 143.6, 152.8 and 165.9 (C
in benzimidazole), 168.2 (C=O in phthalimide). m/z LC-MS
[M(C21H18N6O2S)+H]+ calc.: 419.1290; found: 419.2774.
4-(N-Phthalimidomethyl)-1-(3-phthalimidopropyl)-1,2,3-
triazole (3e)
Yield 71% (Lit.17 96%); Rf = 0.4 (CH2Cl2-EtOAc, 9:1);
IR nmax/cm-1: 3589, 3150, 2953, 1767, 1706, 1467, 1429,
1
4-(Benzothiazol-2-ylsulfanyl)methyl-1-(3-phthalimido-
1396, 714. H NMR (300 MHz, CDCl3): d 2.29 (q, 2H,
propyl)-1,2,3-triazole (3b)
CH2), 3.73 (t, 2H, J 6.3 Hz, NCH2), 4.36 (t, 2H, J 7.2 Hz,
NCH2), 4.97 (s, 2H, PhthCH2), 7.68-7.75 (m, 5H, NCH=
and Phth), 7.80-7.85 (m, 4H, Phth). 13C NMR (75.5 MHz,
CDCl3): d 29.4, 32.9, 34.9, 47.9, 123.3, 123.4, 131.8, 132.0,
134.0, 134.2, 167.6 and 168.3 (C=O in phthalimide). m/z
LC-MS [M(C22H18N5O4)+H]+ calc.: 416.1359. Found:
416.1305.
o
Yield 78%; mp 103-105 C; Rf = 0.4 (CH2Cl2-EtOAc,
9:1); IR nmax / cm-1: 3140, 2940, 1767, 1706, 1464, 1430,
1397, 1360, 994, 717. 1HNMR(300MHz, CDCl3):d2.27(q,
2H, CH2), 3.69 (t, J 6.6 Hz, 2H, NCH2), 4.34 (t, J 6.9 Hz, 2H,
NCH2), 4.66 (s, 2H, SCH2), 7.29 (ddd, 1H, J 7.5, 7.5, 1.2 Hz,
Harom), 7.42 (ddd, 1H, J 7.5, 7.5, 1.2 Hz, Harom), 7.72-7.77 (dd,
3H, J 5.4, 3.0, Phth and Harom), 7.81-7.85 (m, 3H, Phth and
NCH=), 7.91 (dd, 1H, J 7.5 Hz, Harom). 13C NMR (75.5 MHz,
CDCl3): d 27.6, 29.3, 34.8, 47.8, 121.0, 121.5, 123.3, 124.3,
125.9, 131.7 (C in triazole), 134.1, 135.4, 143.7, 152.9 (Carom
in benzothiazole), 165.8, 168.2 (C=O in phthalimide).Anal.
Calc. C21H17N5O2S2: C, 57.91; H, 3.93; N, 16.08; S, 14.73.
Found: C, 58.18; H, 4.03; N, 15.93; S, 14.58.
4-Acetyl-1-(3-phthalimidopropyl)-1,2,3-triazole (3f)
Yield 92%; mp 188-190 oC; Rf = 0.7 (Hexane-EtOAc,
1:1); IR nmax/cm-1: 3106, 3048, 1776, 1701, 1680, 1384,
1177, 1030, 721. 1H NMR (300 MHz, CDCl3): d 2.37 (q,
2H, CH2), 2.66 (s, 3H, COCH3), 3.76 (t, J 6.9 Hz, 2H,
NCH2), 4.46 (t, J 6.9 Hz, 2H, NCH2), 7.73-7.77 (dd, J 3.3,
5.7, 2H, Phth), 7.84-7.87 (dd, J 3.3, 5.4, 2H, Phth), 8.26 (s,
1H, NCH=). NMR 13C (75.5 MHz, CDCl3): d 27.2, 29.3,
34.7, 48.2, 123.5, 131.7 (C in triazole), 134.3 (NCH= in
triazole), 168.2 (C=O in phthalimide), 192.7 (COCH3).
m/z LC-MS [M(C15H14N4O3)+H]+ calc.: 299.1144. Found:
299.1163.
4-(Benzoxazol-2-ylsulfanyl)methyl-1-(3-phthalimido-
propyl)-1,2,3-triazole (3c)
Yield 55%; mp 131-133 C; Rf = 0.6 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3150, 2939, 1765, 1709, 1495, 1454,
o
1
1433, 1397, 1362, 1216, 1134, 715. H NMR (400 MHz,
CDCl3): d 2.28 (q, 2H, CH2), 3.69 (t, 2H, J 6.3 Hz, NCH2),
4.35 (t, 2H, J 6.9 Hz, NCH2), 4.61 (s, 2H, SCH2), 7.19-7.29
(m, 2H, Harom), 7.43 (dd, 1H, J 7.5, 1.5 Hz, Harom), 7.62 (d,
1H, J 7.2 Hz, Harom), 7.70-7.75 (dd, 2H, J 5.7, 3.0, Phth),
7.78-7.84 (dd, 2H, J 5.1, 3.0, Phth), 7.93 (s, 1H, NCH=).
13C NMR (100 MHz, CDCl3): d 26.7, 29.3, 34.8, 47.8, 109.9
(Carom in benzoxazole), 118.4 (Carom in benzoxazole), 123.3,
123.9, 124.2, 131.8 (C in triazole), 134.2 (NCH= in triazole),
141.7, 152.0, 164.3, 168.2(C=Oinphthalimide).m/zLC-MS
[M(C21H17N5O3S) + H]+ calc.: 420.1130. Found: 420.1027.
4-(Benzimidazol-2-ylsulfanyl)methyl-1-(4-phthalimido-
butyl)-1,2,3-triazole (4a)
Yield 86%; mp 100-102 oC; Rf = 0.6 (Hexane-EtOAc,
7:3); IR nmax/cm-1: 3460, 3145, 3053, 2938, 2871, 1765,
1705, 1459, 1429, 1399, 1372, 1337, 1308, 1222, 1045,
1
996, 920, 747, 723. H NMR (400 MHz, CDCl3): d 1.67
(q, 2H, CH2), 1.90 (q, 2H, CH2), 2.81 (bs, 1H, NH), 3.68
(t, 2H, J 5.4 Hz, NCH2), 4.35 (t, 2H, J 5.4 Hz, NCH2), 4.69
(s, 2H, SCH2), 7.29 (t, 1H, J 6.0 Hz, Harom), 7.41 (t, 1H,
J 5.7 Hz, Harom), 7.64 (s, 1H, NCH=), 7.69-7.71 (dd, 2H,
J 2.4, 4.2, Phth), 7.74 (d, 1H, J 5.7 Hz, Harom), 7.78-7.82
(dd, 2H, J 2.4, 3.6, Phth), 7.90 (d, 1H, J 6.0 Hz, Harom).
13C NMR (100 MHz, CDCl3): d 25.5, 27.3, 27.7, 36.7, 49.5,
121.0, 121.4, 123.2, 124.3, 126.0, 131.8 (C in triazole),
4-(Benzimidazolemethyl)-1-(3-phthalimidopropyl)-1,2,3-
triazole (3d)
Yield 89%; mp 148-150 oC; Rf = 0.2 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3141, 3089, 3050, 3020, 2943, 1769,

596
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
133.9 (NCH= in triazole), 135.4, 143.8, 152.9 and 165.8
(C in benzimidazole), 168.3 (C=O in phthalimide). Anal.
Calc.: C22H20N6O2S.0.8H2O: C, 59.13; H, 4.87. Found: C,
58.68; H, 4.33.
CDCl3): d 25.4, 27.3, 36.7, 40.7, 49.6, 109.9, 120.4, 122.0,
122.4, 123.2, 123.3, 131.9 (C in triazole), 134.1 (NCH= in
triazole), 143.0, 168.3 (C=O in phthalimide). m/z LC-MS
[(C22H20N6O2)+H]+ calc.: 401.1728. Found: 401.1714.
4-(Benzothiazol-2-ylsulfanyl)methyl-1-(4-phthalimido-
4-(N-Phthalimidomethyl)-1-(4-phthalimidobutyl)-1,2,3-
triazole (4e)
butyl)-1,2,3-triazole (4b)
Yield 84%; mp 92-94 C; Rf = 0.6 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 2972, 2854, 1770, 1710, 1613, 1465,
o
Yield 44%; mp 150-151 oC; Rf = 0.45 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3133, 2952, 1768, 1702, 1614, 1467,
1
1
1428, 1397, 1304, 1041, 757, 719. H NMR (300 MHz,
1428, 1397, 1089, 1030, 939, 715. H NMR (400 MHz,
CDCl3): d 1.68 (q, 2H, CH2), 1.91 (q, 2H, CH2), 3.68 (t,
2H, J 6.9 Hz, NCH2), 4.38 (t, 2H, J 7.2 Hz, NCH2), 4.70
(s, 2H, SCH2), 7.30 (dd, 1H, J 7.5, 7.5 Hz, Harom), 7.42
(ddd, 1H, J 7.7, 7.7 Hz, Harom), 7.69-7.78 (m, 4H, NCH=,
Phth, Harom), 7.80-7.83 (m, 2H, Phth), 7.92 (d, 1H, J 7.5 Hz,
Harom). 13C NMR (75.5 MHz, CDCl3): d 22.6, 25.4, 27.3,
27.3, 36.7, 109.9, 116.0, 118.4, 121.1, 122.4, 123.3, 129.5,
131.8, 134.0, 143.9, 155.2, 168.3 (C=O in phthalimide).
Anal. Calc. C22H19N5O2S2: C, 58.78; H, 4.26; N, 15.58;
S, 14.27. Found: C, 58.21; H, 4.43; N, 15.04; S, 14.27.
m/z LC-MS [M + H]+ calc.: 450.1058. Found: 450.1085.
CDCl3): d 1.70 (q, 2H, CH2), 1.92 (q, 2H, CH2), 3.70 (t,
2H, J 6.6 Hz, NCH2 in triazole), 4.37 (t, 2H, J 6.9 Hz,
NCH2 in phthalimide), 4.98 (s, 2H, PhthCH2), 7.63 (s, 1H,
NCH=), 7.68-7.73 (m, 4H, Phth), 7.79-7.86 (m, 4H, Phth).
13C NMR (100 MHz, CDCl3): d 25.5, 27.4, 32.9, 36.8, 49.6,
123.3, 123.4, 131.8, 132.0 (C in triazole), 134.0 (NCH=
in triazole), 167.6 and 168.3 (C=O in phthalimide). Anal.
Calc. C23H19N5O4.(1/2H2O): C, 63.01; H, 4.60; N, 15.97.
Found: C, 63.11; H, 4.09; N, 15.98.
4-Acetyl-1-(4-phthalimidobutyl)-1,2,3-triazole (4f)
Yield 91%; mp 151-153 oC; Rf = 0.6 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3138, 2923, 2851, 1709, 1681, 1537,
1400, 1216, 1035, 723. 1H NMR (500 MHz, CDCl3): d 1.72
(q, 2H, CH2), 1.96 (q, 2H, CH2), 2.66 (s, 3H, COCH3), 3.73
(t, J 6.5 Hz, 2H, NCH2 in triazole), 4.45 (t, J 6.5 Hz, 2H,
NCH2 in phthalimide), 7.70-7.72 (m, 2H, Phth), 7.82-7.84
(m, 2H, Phth), 8.04 (s, 1H, NCH=). 13C NMR-APT (125.6
MHz, CDCl3): d 25.5, 27.1(CH3), 27.3, 36.7, 49.9, 123.4
(CHarom), 132.0 (C in triazole), 134.1 (NCH= in triazole),
168.4 (C=O in phthalimide), 192.9 (COCH3). Anal. Calc.
for C16H16N4O3: C, 61.53; H, 5.16; N, 17.94. Found: C,
61.89; H, 5.22; N, 17.64. m/z L C-MS [M(C16H16N4O3) +
H]+ calc.: 313.1301. Found: 313.1305.
4-(Benzoxazol-2-ylsulfanyl)methyl-1-(4-phthalimidobutyl)-
1,2,3-triazole (4c)
o
Yield 67%; mp 68-70 C; Rf = 0.8 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3467, 3147, 3053, 2933, 2867, 1773,
1716, 1613, 1502, 1454, 1397, 1365, 1236, 1131, 1096,
1042, 740, 721. 1H NMR (400 MHz, CDCl3): d 1.70 (q, 2H,
CH2), 1.97 (q, 2H, CH2), 3.69 (t, 2H, J 7.2 Hz, NCH2), 4.35
(t, 2H, J 7.2 Hz, NCH2), 4.64 (s, 2H, SCH2), 7.22-7.7.30
(m, 2H, Harom), 7.44 (d, 1H, J 7.6 Hz, Harom), 7.62 (d, 1H, J
7.6 Hz, Harom), 7.70-7.73 (dd, 2H, J 5.6, 3.2, Phth), 7.75 (s,
1H, NCH=), 7.79-7.82 (dd, 2H, J 5.6, 3.2, Phth). 13C NMR
(100 MHz, CDCl3): d 25.5, 26.6, 27.3, 36.7, 49.8, 110.0,
118.4, 123.3, 124.1, 124.4, 131.9 (C in triazole), 134.0
(NCH= in triazole), 141.7, 152.0, 159.7, 168.3 (C=O in
phthalimide).Anal. Calc. C22H19N5O3S.(0.4H2O): C, 59.96;
H, 4.53; N, 15.89; S, 7.27. Found: C, 59.31; H, 4.45; N,
15.59; S, 7.92.
Supplementary Information
Supplementary data are available free of charge at
http://jbcs.sbq.org.br, as PDF file.
4-(Benzimidazolemethyl)-1-(4-phthalimidobutyl)-1,2,3-
triazole (4d)
Acknowledgments
Yield 49%; mp 103-105 oC; Rf = 0.3 (CH2Cl2-EtOAc,
9:1); IR nmax/cm-1: 3137, 3089, 2937, 1769, 1708, 1494,
1458, 1399, 1042, 747, 720. 1H NMR (300 MHz, CDCl3):
d 1.65 (q, 2H, CH2), 1.87 (q, 2H, CH2), 3.65 (t, 2H,
J 6.9 Hz, NCH2 in triazole), 4.32 (t, 2H, J 7.2 Hz, NCH2 in
phthalimide), 5.52 (s, 2H, NCH2), 7.26-7.31 (m, 3H, Harom),
7.49 (s, 1H, NCH= in benzimidazole), 7.68-7.72 (m, 2H,
dd, 2H, J 5.4, 3.0, Phth), 7.70-7.83 (m, 3H, Phth, Harom),
8.32 (s, 1H, NCH= in triazole). 13C NMR-APT (125.6 MHz,
TheauthorsaregratefultoPernambucoStateFoundation
of Science and Technology (FACEPE:APQ-0776-1.06/08)
for financial support and CNPq/PIBIC/UFRPE-Brazil for
providing a fellowship to one of us (F. C. G. B.). Our thanks
are also due to Central Analytical CENAPESQ-UFRPE
for facilities installation and DQF-UFPE for obtaining
the spectra data. We thank to Dr. Helcio José Batista for
his continuous support throughout the preparation of the
manuscript.

Vol. 22, No. 3, 2011
Barbosa and Oliveira
597
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Submitted: June 21, 2010
Published online: October 21, 2010

J. Braz. Chem. Soc., Vol. 22, No. 3, S1-S19, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Supplementary Information
SI
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via
1,3-Dipolar Cycloaddition
Fernanda C. G. Barbosa and Ronaldo N. de Oliveira*
Departamento de Química, Universidade Federal Rural de Pernambuco, Rua Dom Manoel de
Medeiros S/N, Dois Irmão, 52171-030 Recife-PE, Brazil
Synthesis of terminal alkynes (1a-e)
allowed to stir at 60 °C for 24 h under argon atmosphere.
The mixture was then cooled to room temperature and
extraction with dichloromethane was done. The combined
organic layers were dried over sodium sulfate anhydrous
and concentrated under reduced pressure.
1 mmol of benzoheterocyclic and 1 mmol of K2CO3
were suspended in anhydrous DMF (5 mL). Then,
1.5 equiv. of propargyl bromide (80% solution in toluene)
was added. The reaction mixture was stirred for 20 h at
room temperature. The mixture was then extracted with
dichloromethane/water. The combined organic layers were
dried over sodium sulfate anhydrous and concentrated
under reduced pressure, and the residue was purified by
chromatography on silica gel (hexane:EtOAc, 7:3) to afford
the corresponding propargylic benzoheterocycles (1a-e).
N-3-(azidopropyl)phthalimide (2a)
Yield 75%; white solid; IR nmax/cm-1: 2945, 2100
(N3), 1711 (C=O), 1399, 1040, 723. 1H NMR (300 MHz,
CDCl3): d 1.96 (q, 2H), 3.38 (t, 2H, J 6.9 Hz), 3.79 (t, 2H,
J 6.9 Hz), 7.73 (dd, 2H, J 5.7 and 3.0 Hz), 7.86 (dd, 2H,
J 5.7 and 3.0 Hz).
Synthesis of N-3-(azidopropyl)phthalimide (2a) or
N-4-(azidobutyl)phthalimide (2b)
N-4-(azidobutyl)phthalimide (2b)
Yield 61%; white solid; IR nmax/cm-1: 2950, 2096 (N3),
1709 (C=O), 1396, 719. 1H NMR (300 MHz, CDCl3): d
1.65 (m, 2H), 1.78 (m, 2H), 3.33 (t, 2H, J 6.6 Hz), 3.79 (t,
2H, J 6.9 Hz), 7.72 (dd, 2H, J 5.7 and 3.0 Hz), 7.85 (dd,
2H, J 5.7 and 3.0 Hz).
N-(bromoalkyl)phthalimide (500 mg) in 2.5 mL of DMF
was charged in a round-bottom flask. Then, 1.5 equiv. of
sodium azide was introduced and the reaction mixture was
*e-mail: ronaldonoliveira@dq.ufrpe.br

S2
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S1. 1H (300 MHz) and 13C (75.5 MHz) NMR spectrum of compound 3a in CDCl3.

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Barbosa and Oliveira
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Figure S2. 1H (300 MHz) and 13C (75 MHz) NMR spectrum of compound 3b in CDCl3.

S4
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S3. 1H (400 MHz) and 13C (100 MHz) NMR spectrum of compound 3c in CDCl3.

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Figure S4. 1H (400 MHz) and 13C (100 MHz) NMR spectrum of compound 3d in CDCl3.

S6
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S5. 1H (300 MHz) and 13C (75.5 MHz) NMR spectrum of compound 3e in CDCl3.

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Figure S6. 1H (300 MHz) and 13C (75.5 M Hz) NMR spectrum of compound 3f in CDCl3.

S8
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S7. 1H (400 MHz) and 13C (100 MHz) NMR spectrum of compound 4a in CDCl3.

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Figure S8. 1H (300 MHz) and 13C (75.5 MHz) NMR spectrum of compound 4b in CDCl3.

S10
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S9. 1H (400 MHz) and 13C (100 MHz) NMR spectrum of compound 4c in CDCl3.

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Figure S10. 1H (300 MHz) and 13C-APT (125 MHz) NMR spectrum of compound 4d CDCl3.

S12
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S11. 1H (400 MHz) and 13C (100 MHz) NMR spectrum of compound 4e CDCl3.

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Figure S12. 1H (500 MHz) and 13C-APT (125 MHz) NMR spectrum of compound 4f in CDCl3.

S14
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S13. IR spectrum of compound 3a.
Figure S14. IR spectrum of compound 3b.
Figure S15. IR spectrum of compound 3c.

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Figure S16. IR spectrum of compound 3d.
Figure S17. IR spectrum of compound 3e.
Figure S18. IR spectrum of compound 3f.

S16
Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S19. IR spectrum of compound 4a.
Figure S20. IR spectrum of compound 4b.
Figure S21. IR spectrum of compound 4c.

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Figure S22. IR spectrum of compound 4d.
Figure S23. IR spectrum of compound 4e.
Figure S24. IR spectrum of compound 4f.

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Synthesis of a New Class of Triazole-Linked Benzoheterocycles via 1,3-Dipolar Cycloaddition
J. Braz. Chem. Soc.
Figure S25. m/z LC-MS spectrum graph of the compounds 3a, 3c, 3e and 3f.

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Figure S26. m/z LC-MS spectrum graph of the compounds 4b, 4d and 4f.