Electrophilic cyclization of N-alkynyl-2-(organochalcogen)imidazoles: An alternative access to imidazo[2,1-b]chalcogenazoles

Article abstract of DOI:10.1002/ejoc.201201692

We present here a practical synthesis of multifunctional imidazo[2,1-b]chalcogenazoles through electrophilic cyclization of N-alkynyl-2-(organochalcogen)imidazoles. The cyclization reaction proceeded cleanly and smoothly under mild reaction conditions in the presence of air. The methodology was highly regioselective: In a competition between the chalcogen and oxygen atoms, only S-, and Se-heterocycles were obtained. The resulting imidazo[2,1-b]chalcogenazoles proved to be versatile as precursors for the synthesis of more highly functionalized imidazoselenazoles through copper-catalyzed cross-coupling reactions with arene- and alkanethiols, leading to Ullmann-type products in good yields. We present here a practical synthesis of multifunctional imidazo[2,1-b]chalcogenazoles through electrophilic cyclization of N-alkynyl-2-(organochalcogen)imidazoles. The methodology was highly regioselective: In a competition between the chalcogen and oxygen atoms, only S- and Se-heterocycles were obtained. The resulting imidazo[2,1-b] chalcogenazoles proved to be versatile as precursors for the synthesis of more highly functionalized imidazoselenazoles. Copyright

Full text of DOI:10.1002/ejoc.201201692

FULL PAPER
DOI: 10.1002/ejoc.201201692
Electrophilic Cyclization of N-Alkynyl-2-(organochalcogen)imidazoles: An
Alternative Access to Imidazo[2,1-b]chalcogenazoles
Tamíris B. Grimaldi,[a] Benhur Godoi,[b] Juliano A. Roehrs,[a] Adriane Sperança,[a] and
Gilson Zeni*[a]
Keywords: Synthetic methods / Electrophilic cyclization / Alkynes / Heterocycles / Selenium / Chalcogens
We present here a practical synthesis of multifunctional imid-
azo[2,1-b]chalcogenazoles through electrophilic cyclization
of N-alkynyl-2-(organochalcogen)imidazoles. The cyclization
reaction proceeded cleanly and smoothly under mild reaction
conditions in the presence of air. The methodology was
highly regioselective: In a competition between the chalco-
gen and oxygen atoms, only S-, and Se-heterocycles were
obtained. The resulting imidazo[2,1-b]chalcogenazoles
proved to be versatile as precursors for the synthesis of more
highly functionalized imidazoselenazoles through copper-
catalyzed cross-coupling reactions with arene- and alka-
nethiols, leading to Ullmann-type products in good yields.
Introduction
structures in a stepwise manner.[12] The cyclization reaction
of an unsaturated substrate by an electrophilic source is one
of the most useful reactions in organic synthesis. Because
a halonium intermediate, which is attacked by an internal
nucleophilic heteroatom along an anti pathway, is involved
in these reactions, it becomes a versatile method for the
regio- and stereoselective preparation of a wide range of
heterocycles, such as indoles, furans, thiophenes, selenoph-
enes, benzo[b]furans, benzo[b]thiophenes, benzo[b]selenoph-
enes and pyrroles.[13] While various substituted heterocycles
have thus far been prepared by these methods, the synthesis
of imidazochalcogenazoles through the electrophilic cycli-
zation process has not been reported. Therefore, a simple,
general, and efficient procedure to prepare functionalized
imidazoles, which reduces the dependence on the condensa-
tion reactions, is extremely significant. This proposal be-
comes even more attractive, because this procedure was
conducted by using N-alkynyl-2-(organochalcogen)imid-
azole 1 for the preparation of 3-iodoimidazo[2,1-b]chalco-
genazoles 2, under mild reaction conditions by employing
EtOH as the solvent, at room temperature in the presence
of air (Scheme 1).
Nitrogen-containing heterocycles are known to present a
variety of biological and pharmaceutical properties.[1]
Among them, imidazole derivatives have attracted much at-
tention, because they are often found in natural and phar-
maceutical products and because of their wide-ranging
structural variations.[2] In particular, compounds containing
a fused imidazo nucleus have been used as antibacterial,[3]
antifungal[4] and antitumor[5] agents. They are also impor-
tant building blocks found in naturally occurring com-
pounds,[6] and are versatile precursors for the synthesis of
new fused N-heterocycles. On the basis of these important
properties, several methodologies have been described for
the preparation of imidazole derivatives.[7] Usually, they are
obtained from condensation reactions of halocarbonyl
compounds with thioureas or thioamides,[8] amino acids
with aldehydes,[9] diazo compounds with amides,[10] or
imines with thioamides.[11] The number of imidazoles that
could be synthesized by these procedures is limited by the
commercial availability of starting materials, low solubility
of compounds, difficulty of purification, complex workup,
use of toxic metal catalysts, and strongly acidic conditions.
Here, we propose an alternative route to prepare imidazo-
chalcogenazoles by electrophilic cyclization of N-alkynyl-
imidazole derivatives. In this regard, electrophilic cycliza-
tion reactions represent an attractive alternative, because
simple substrates can be transformed in more elaborate
[a] Laboratório de Síntese, Reatividade, Avaliação Farmacológica
e Toxicológica de Organocalcogênios, CCNE, UFSM
Santa Maria, Rio Grande do Sul 97105-900, Brazil
Fax: +55-55-32208978
E-mail: gzeni@pq.cnpq.br
Homepage: www.ufsm.br
[b] Universidade Federal da Fronteira Sul, Cerro Largo,
Rio Grande do Sul 97900-000, Brazil
Scheme 1. General preparation of 3-iodoimidazo[2,1-b]chalco-
genazoles (2).
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201692.
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Access to Imidazo[2,1-b]chalcogenazoles
Table 1. Optimization of the cyclization conditions.[a]
Results and Discussion
For the preparation of the N-alkynyl-2-(organochal-
cogen)imidazole precursor 1, we chose the known reaction
of imidazole with bromoalkyne in 1,4-dioxane, using CuI
as the catalyst and Cs2CO3 as the base.[14] For the introduc-
tion of an organochalcogen group, we first generated the
lithium imidazole intermediate by treating N-alkynylimid-
azole with 1 equiv. of nBuLi, in THF at –78 °C for 30 min,
followed by reaction with an electrophilic chalcogen species
(Scheme 1. All details of the preparation of N-alkynyl-2-
(organochalcogen)imidazoles are found in the Supporting
Information. We first examined the cyclization reaction of
N-alkynyl-2-(butylselenyl)imidazole 1a in the presence of I2
(1.1 equiv.) using CH2Cl2 as solvent, under argon at room
temperature. The desired 3-iodo-2-phenylimidazo[2,1-b]-
selenazole 2a was obtained in 81% yield (Table 1, Entry 1).
This result was considered satisfactory; however, in order
to better understand the reaction behavior with respect to
the solvent, temperature, amount of iodine, and atmo-
sphere, we decided to carry out a full reaction parameter
screen as summarized in Table 1. The choice of the iodine
quantities had a crucial effect on the yield, and 1.1 equiv.
Entry
Electrophile [equiv.]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
I2 (1.1)
I2 (1.5)
I2 (2.0)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
CH2Cl2
CH2Cl2
CH2Cl2
THF
dioxane
MeCN
acetone
benzene
EtOH
81
78
71
n.r.[c]
n.r.[c]
59
64
81
81
10
11
EtOH
EtOH
91[d]
77[e]
[a] The reaction was performed in the presence of 1a (0.25 mmol),
solvent (5 mL) under argon at room temperature for 3 h. [b] Yields
were measured by GC analysis. [c] 1a was recovered quantitatively.
[d] The reaction was performed in the presence of air (open tube).
[e] The reaction was carried out at 78 °C.
was chosen as the best of those used. It should be noted not significantly influenced by the electronic effects of the
that the increase of iodine quantities to 1.5 and 2.0 equiv. substituents on the aromatic rings. Neutral, electron-donat-
corresponded to a decrease in the yields (Table 1, Entries 2 ing and electron-withdrawing groups bonded to the Csp
and 3). This could be explained by a competitive selenium atom led to the desired 3-iodoimidazo[2,1-b]selenazoles 2a–
halogenation reaction, a typical reaction for organoselen- h in good to excellent yields (Table 2, Entries 1–8). On the
ium compounds with the halogen excess that yields the sele- other hand, the presence of a naphthalene group directly
nium(IV) species and consumes the substrate in the reaction bonded to the triple bond in compound 1i led to a decrease
mixture.[15] With I2 (1.1 equiv.) as the electrophile source, in the cyclization efficiency, furnishing the corresponding
we screened other solvents as demonstrated in Table 1. No cyclized product 2i in 54% yield (Table 2, Entry 9). The ef-
trace of the cyclized product was obtained in the presence fect of changing aryl to alkyl substituents directly bonded
of THF or dioxane, while moderate yields were observed to the triple bond of the N-alkynylimidazole was also inves-
when reactions were carried out in acetonitrile or acetone tigated (Table 2, Entry 10). We were concerned that the ab-
(Table 1, Entries 4–7). Notably, benzene and ethanol were sence of pi (π) bonds next to the triple bond could result
found to be as effective as CH2Cl2, affording the product in decreased reactivity for the selenium nucleophilic attack.
in 81% yield (Table 1, Entries 8 and 9). Due to environmen- However, this synthetic method was efficient in promoting
tal and health concerns associated with benzene and the cyclization of the substrate 1j, affording the expected
CH2Cl2, we selected ethanol as the best solvent. To make 3-iodo-2-pentylimidazo[2,1-b]selenazole 2j in 78% yield
our methodology more attractive from an economic stand- (Table 2, Entry 10). Like nucleophilic selenium groups, thi-
point, we tested the cyclization reaction in the absence of ols showed good reactivity in the present cyclization reac-
an inert gas by running the reaction in contact with atmo- tion, and 3-iodo-2-phenylimidazo[2,1-b]thiazole 2l and 3-
sphere using an open tube. By using this reaction system, iodo-2-(2-methoxyphenyl)imidazo[2,1-b]thiazole 2m were
the selenazole derivative 2a was obtained in 91% yield efficiently obtained in 85 and 87% yields, respectively
(Table 1, Entry 10). Finally, it was found that if the reaction (Table 2, Entries 12 and 13). We observed that as well as
temperature is elevated to 78 °C the reaction yield decreased iodine, PhSeBr was efficient as a cyclizing agent. We found
(Table 1, Entry 11). On the basis of the above investigation, that reaction with PhSeBr, an electrophilic selenium species,
the optimal conditions for this intramolecular cyclization promoted the cyclization of N-alkynyl-2-(organochalcogen)-
reaction were: N-alkynyl-2-(butylselenyl)imidazole 1a imidazole 1a, producing the highly substituted 3-(phenyl-
(0.25 mmol), I2 (1.1 equiv.) as the electrophile source, EtOH selenyl)imidazoselenazole 2n in 68% yield (Table 2, En-
(5 mL) as solvent, at room temperature under air.
try 14). Although it is known that Br2, NBS, CuBr2 and
As summarized in Table 2, the electrophilic cyclization BuTeBr can act as efficient electrophile donors to the
of various N-alkynyl-2-(organochalcogen)imidazoles 1 was alkyne triple bond, under our conditions no cyclized prod-
carried out smoothly to afford the corresponding 3-iodoim- ucts were isolated when we used these electrophile sources.
idazo[2,1-b]chalcogenazoles 2 in moderate to good yields It is important to point out that our cyclization approach
under the optimum reaction conditions. The analysis of was highly regioselective regarding a possible nucleophilic
these experiments showed that the cyclization process was competition between the selenium and oxygen atoms, and
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T. B. Grimaldi, B. Godoi, J. A. Roehrs, A. Sperança, G. Zeni
FULL PAPER
Table 2. Scope and generality of the electrophilic cyclization of N-alkynyl-2-(organochalcogen)imidazoles 1.[a]
[a] The reaction was carried out in the presence of 1 (0.25 mmol), I2 (1.1 equiv.), EtOH (5 mL) as solvent, at room temperature in the
presence of air (open tube). [b] Isolated yield after column chromatography. [c] PhSeBr was used as electrophile source.
between sulfur and oxygen atoms. The electrophilic cycliza-
We believe that this cyclization reaction follows a typical
tion reaction of 1g and 1m, which have methoxy groups, electrophilic cyclization pathway.[17] Thus, a plausible
could lead to the formation of undesired benzofuran deriva- mechanism for this process is shown in Scheme 3. The coor-
tives [Scheme 2, Equations (1) and (2)]. Gratifyingly, in dination of the electrophile source to the carbon–carbon
these two cases, our method afforded the desired imidazo- triple bond generates the iodonium intermediate A. Subse-
chalcogenazole heterocycles 2g and 2m as single regioiso- quent anti nucleophilic attack from the lone pair of the
mers. These results suggest that the higher nucleophilicity chalcogen atom to the activated carbon–carbon triple bond
of the selenium and sulfur atoms compared with the oxygen leads to the cationic species B, which affords the cyclized
atom strongly affects the cyclization mode.[16]
product 2 after facile removal of the alkyl group bonded to
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Access to Imidazo[2,1-b]chalcogenazoles
Scheme 2. Regioselectivity of the cyclization reaction.
Scheme 4. Copper-catalyzed cross-coupling reactions of 2a with
different thiols.
readily available precursors, the incorporation of two dif-
ferent useful functionalities in the structure, and that the
reactions were carried out under ambient conditions. An-
other feature of this protocol is the high regioselectivity
with respect to a possible nucleophilic competition between
the selenium or sulfur and the oxygen atoms. In our case,
only chalcogen heterocycles were obtained. Additionally,
the resulting 3-iodoimidazochalcogenazoles proved to be
quite versatile as synthetic intermediates for the preparation
of more highly functionalized heterocycle units. In this way,
the copper-catalyzed Ullmann coupling reactions of the im-
idazochalcogenazole 2a with different arene- and alkane-
thiols furnished the corresponding 3-(organosulfenyl)imid-
azochalcogenazoles 3 in moderate to excellent yields.
Scheme 3. Plausible electrophilic cyclization mechanism.
the chalcogen atom by SN2 displacement by the iodide pres-
ent in the reaction mixture (Scheme 3).
In the context of copper-catalyzed cross coupling reac-
tions, the Ullmann-type reaction is widely known as a clas-
sical method for carbon–heteroatom bond formation.[18]
Although a great variety of haloheteroaryl compounds have
been used as substrates in this reaction, up to now it has
not been applied to the 3-iodoimidazoselenazoles. In order
to expand the scope of Ullmann cross-coupling and to dem-
onstrate the applicability of 3-iodoimidazo[2,1-b]chalco-
genazoles, we briefly investigated the reaction of 2a with
arene- and alkanethiols in a copper-catalyzed cross-cou-
pling reaction (Scheme 4). The reaction of 3-iodo-2-phenyl-
imidazoselenazole 2a (0.25 mmol) with an appropriate thiol
(0.75 mmol) in the presence of CuI (0.025 mmol) and 1,10-
phenanthroline (0.05 mmol) in DMSO (0.5 mL) gave the 3-
Experimental Section
General Remarks: 1H NMR spectra were obtained at 200 MHz
with a DPX-200 NMR spectrometer or at 400 MHz with a DPX-
400 NMR spectrometer. Spectra were recorded in CDCl3 solutions.
13C NMR spectra were obtained either at 50 MHz with a DPX-
200 NMR spectrometer or at 100 MHz with a DPX-400 NMR
spectrometer. Spectra were recorded in CDCl3 solutions. Column
chromatography was performed by using Merck Silica Gel (230–
400 mesh). Thin layer chromatography (TLC) was performed by
using Merck Silica Gel GF254 (0.25 mm thickness). For visualiza-
tion, TLC plates were either placed under UV light, or stained with
(organosulfenyl)imidazoselenazole derivatives in good iodine vapour or acidic vanillin. Most reactions were monitored
by TLC for disappearance of starting material. Mass spectra were
recorded with a Shimadzu GC–MS-2010P. Elemental analyses were
performed with a Vario EL III elemental analysis instrument.
HRMS data were recorded with a Shimadzu LC-MS-IT-TOF spec-
trometer.
yields (Scheme 4).
Conclusions
We have described an electrophilic cyclization reaction
that provides an efficient tool for the selective synthesis of
3-iodoimidazoselenazoles from N-alkynyl-2-(organochal-
cogen)imidazoles. The main advantages of this methodol-
General Procedure for the Preparation of N-Alkynyl-2-(organochal-
cogen)imidazoles 1: To a solution of the appropriate N-alkynylimid-
azole (1 mmol) in THF (10 mL) under argon at –78 °C was added
nBuLi (2.5 m in hexane, 0.48 mL, 1.2 mmol). The reaction mixture
ogy are the easy assembly of the starting materials from was stirred at this temperature for 30 min. At the same time, in
Eur. J. Org. Chem. 2013, 2646–2652
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T. B. Grimaldi, B. Godoi, J. A. Roehrs, A. Sperança, G. Zeni
FULL PAPER
another reaction vessel, to a solution of (BuSe)2 (0.6 mmol) in THF
(5 mL) under argon at 0 °C was added bromine (0.7 mmol) in benz-
ene (3 mL). The reaction mixture was stirred at this temperature
for 30 min. After this time, with the assistance of a syringe, this
content was added to the first one. The reaction mixture was
warmed to room temperature, quenched with a saturated NH4Cl
solution (5 mL), and extracted with EtOAc (3ϫ20 mL). The com-
bined organic layers were dried with MgSO4, concentrated, and
subjected to flash chromatography (0–25% EtOAc/hexane).
126.1, 116.7, 68.6, 20.2 ppm. MS (EI, 70 eV): m/z (%) = 388 (23)
[M + 1], 207 (67), 181 (45), 154 (17), 127 (28), 115 (40), 102 (34),
73 (100). C12H9IN2Se (387.08): calcd. C 37.24, H 2.34, N 7.24;
found C 37.39, H 2.39, N 7.31.
3-Iodo-2-(4-methoxyphenyl)imidazo[2,1-b][1,3]selenazole (2e): Ob-
tained as a pale yellow solid, yield 0.082 g (81%); m.p. 185.5 °C.
1H NMR ([D6]DMSO, 400 MHz): δ = 7.78 (d, J = 1.2 Hz, 1 H,
NCH), 7.52 (d, J = 8.8 Hz, 2 H, =CH), 7.27 (d, J = 1.4 Hz, 1 H,
NCH), 7.07 (d, J = 8.8 Hz, 2 H, =CH), 3.84 (s, 3 H, CH3) ppm.
13C NMR (CDCl3, 100 MHz): δ = 160.4, 131.9, 131.0, 130.8, 125.8,
116.9, 114.3, 100.0, 65.5, 55.4 ppm. MS (EI, 70 eV): m/z (%) = 404
(29) [M + H]+, 341 (11), 281 (37), 253 (25), 207 (100), 191 (21), 147
(19), 133 (23), 73 (95). HRMS: calcd. for C12H9IN2OSe 403.8925;
2-(Butylselenyl)-1-(phenylethynyl)-1H-imidazole (1a): Obtained as a
1
yellow oil, yield 0.167 g (55%). H NMR (CDCl3, 200 MHz): δ =
7.55–4.50 (m, 2 H, =CH), 7.40–7.34 (m, 3 H, =CH), 7.25 (d, J =
1.6 Hz, 1 H, NCH), 7.07 (d, J = 1.5 Hz, 1 H, NCH), 3.23 (t, J =
7.4 Hz, 2 H, CH2), 1.80 (quint, J = 7.8 Hz, 2 H, CH2), 1.46 (sext, found 403.8937.
J = 7.5 Hz, 2 H, CH2), 0.92 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
3-Iodo-2-(3-methoxyphenyl)imidazo[2,1-b][1,3]selenazole (2f): Ob-
NMR (CDCl3, 100 MHz): δ = 140.7, 131.6, 130.2, 128.8, 128.4,
123.4, 121.2, 102.3, 74.0, 32.2, 28.1, 22.8, 13.5 ppm. MS (EI,
70 eV): m/z (%) = 303 (11) [M + H]+, 303 (1), 247 (38), 167 (100),
141 (35), 123 (65), 96 (70).
tained as a pale yellow solid, yield 0.081 g (80%); m.p. 162.4–
165.2 °C. 1H NMR (CDCl3, 400 MHz): δ = 7.60 (s, 1 H, NCH),
7.37 (t, J = 7.9 Hz, 1 H, =CH), 7.30 (s, 1 H, NCH), 7.13–7.09 (m,
2 H, =CH), 6.97 (dd, J = 8.5, 1.7 Hz, 1 H, =CH), 3.86 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.7, 134.7, 132.1,
130.6, 130.0, 122.0, 116.9, 115.2, 114.9, 65.9, 55.4 ppm. MS (EI,
70 eV): m/z (%) = 404 (44) [M + H]+, 403 (2), 324 (16), 281 (40),
253 (25), 207 (100), 191 (20), 156 (29), 147 (19), 133 (23), 73 (92).
HRMS: calcd. for C12H9IN2OSe 403.8925; found 403.8938.
General Procedure for the Preparation of Imidazo[2,1-b]chalcogen-
azoles 2: To a solution of the appropriate N-alkynyl-2-chalcogene-
imidazole (0.25 mmol) in ethanol (2 mL) was added iodine
(0.275 mmol) in ethanol (3 mL). The reaction mixture was stirred
at room temperature for 30 min. The reaction mixture was
quenched with a saturated Na2S2O3 solution (5 mL), and extracted
with EtOAc (3ϫ20 mL). The combined organic layers were con-
centrated and subjected to flash chromatography (0–50% EtOAc/
hexane).
3-Iodo-2-(2-methoxyphenyl)imidazo[2,1-b][1,3]selenazole (2g): Ob-
tained as a pale yellow solid, yield 0.070 g (69%); m.p. 160.5–
1
161.6 °C. H NMR (CDCl3, 400 MHz): δ = 7.58 (d, J = 1.5 Hz, 1
H, NCH), 7.48–7.39 (m, 2 H, =CH), 7.29 (d, J = 1.3 Hz, 1 H,
NCH), 7.08–6.97 (m, 2 H, =CH), 3.86 (s, 3 H, CH3) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 157.1, 132.2, 132.0, 131.2, 127.4,
3-Iodo-2-phenylimidazo[2,1-b][1,3]selenazole (2a): Obtained as a
pallid yellow solid, yield 0.080 g (86%); m.p. 197.5–200.5 °C. 1H
NMR (CDCl3, 400 MHz): δ = 7.60 (d, J = 1.2 Hz, 1 H, N-CH), 122.5, 120.7, 116.7, 111.6, 100.0, 62.8, 55.6 ppm. MS (EI, 70 eV):
7.55 (dd, J = 7.9 Hz, J = 2.0 Hz, 2 H, =CH), 7.48-7.41 (m, 3 H,
=CH), 7.30 (d, J = 1.2 Hz, 1 H, N-CH). 13C NMR (CDCl3, 100
MHz): δ = 143.8, 133.6, 132.1, 130.7, 129.7, 129.3, 128.9, 116.9,
65.9. MS (EI, 70 eV): m/z (%) = 374 [M + 1, (32)], 294 (20), 248
(6), 207 (33), 169 (86), 167 (100), 89 (55), 73 (29), 63 (19).
C11H7IN2Se: calcd. C 35.42, H 1.89, N 7.51; found C 35.59, H
1.94, N 7.57.
m/z (%) = 404 (25) [M + H]+, 281 (24), 253 (22), 207 (69), 197 (22),
135 (23), 118 (37), 91 (55), 73 (100). HRMS: calcd. for
C12H9IN2OSe 403.8925; found 403.8945.
2-(4-Chlorophenyl)-3-iodoimidazo[2,1-b][1,3]selenazole (2h): Ob-
tained as a pale yellow solid, yield 0.085 g (83%); m.p. 172.2 °C.
1H NMR (CDCl3, 200 MHz): δ = 7.60 (d, J = 1.0 Hz, 1 H, NCH),
7.46 (d, J = 2.9 Hz, 4 H, =CH), 7.31 (s, 3 H, NCH) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 143.6, 135.4, 132.1, 132.0, 130.9,
3-Iodo-2-(p-tolyl)imidazo[2,1-b][1,3]selenazole (2b): Obtained as a
pale yellow solid, yield 0.075 g (78%); m.p. 195.0–196.8 °C. 1H 129.3, 129.2, 117.0 ppm. MS (EI, 70 eV): m/z (%) = 408 (19), 281
NMR (CDCl3, 400 MHz): δ = 7.59 (s, 1 H, NCH), 7.43 (d, J = (40), 253 (24), 207 (100), 191 (20), 147 (19), 133 (22), 123 (20), 96
7.9 Hz, 2 H, =CH), 7.30–7.25 (m, 3 H, =CH, NCH), 2.41 (s, 3 H,
CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.8, 139.5, 132.0,
130.9, 130.7, 129.6, 129.5, 116.9, 21.3 ppm. MS (EI, 70 eV): m/z
(%) = 388 (81) [M + H]+, 387 (6), 308 (38), 207 (28), 183 (75), 181
(100), 102 (35), 91 (29), 77 (24). HRMS: calcd. for C12H9IN2Se [M
+ H]+ 388.9048; found 388.9010.
(17), 73 (98). C11H6ClIN2Se (407.50): calcd. C 32.42, H 1.48, N
6.87; found C 32.59, H 1.53, N 6.94.
3-Iodo-2-(naphthalen-1-yl)imidazo[2,1-b][1,3]selenazole (2i): Ob-
tained as a pale yellow solid, yield 0.057 g (54%); m.p. 205.5–
208.0 °C. 1H NMR (CDCl3, 400 MHz): δ = 7.99–7.89 (m, 3 H,
=CH), 7.64 (d, J = 1.5 Hz, 1 H, NCH), 7.59–7.51 (m, 4 H, =CH),
7.36 (d, J = 1.5 Hz, 1 H, NCH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 144.8, 133.7, 132.2, 131.6, 130.8, 130.3, 129.6, 128.9,
3-Iodo-2-(m-tolyl)imidazo[2,1-b][1,3]selenazole (2c): Obtained as a
yellow solid, yield 0.060 g (62%); m.p. 166.3–168.9 °C. 1H NMR
(CDCl3, 400 MHz): δ = 7.60 (d, J = 1.1 Hz, 1 H, NCH), 7.36–7.26 128.5, 127.0, 126.6, 125.5, 125.2, 116.8, 69.7 ppm. MS (EI, 70 eV):
(m, 5 H, =CH, NCH), 2.43 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 143.8, 138.7, 133.4, 181.9, 130.9, 130.2, 130.0, 128.7,
126.7, 116.9, 65.7, 21.3 ppm. MS (EI, 70 eV): m/z (%) = 388 (7) [M
+ H]+, 207 (58), 183 (38), 181 (47), 127 (7), 102 (26), 91 (14), 77
(17), 73 (100). HRMS: calcd. for C12H9IN2Se [M + Na]+ 410.8868;
found 410.8894.
m/z (%) = 424 (17) [M + H]+, 423 (1), 297 (33), 281 (40), 217 (40),
207 (100), 191 (51), 139 (62), 73 (82). C15H9IN2Se (423.11): calcd.
C 42.58, H 2.14, N 6.62; found C 42.63, H 2.19, N 6.69.
3-Iodo-2-pentylimidazo[2,1-b][1,3]selenazole (2j): Obtained as a pale
yellow solid, yield 0.081 g (78%); m.p. 77.0–77.3 °C. 1H NMR
(CDCl3, 400 MHz): δ = 7.47 (d, J = 1.2 Hz, 1 H, NCH), 7.22 (d,
J = 1.2 Hz, 1 H, NCH), 2.78 (t, J = 7.6 Hz, 2 H, CH2), 1.67 (quint,
J = 7.3 Hz, 2 H, CH2), 1.44–1.35 (m, 4 H, CH2), 0.92 (t, J = 7.1 Hz,
3-Iodo-2-(o-tolyl)imidazo[2,1-b][1,3]selenazole (2d): Obtained as a
yellow solid, yield 0.069 g (71%); m.p. 156.7–158.8 °C. 1H NMR
(CDCl3, 400 MHz): δ = 7.56 (d, J = 1.2 Hz, 1 H, NCH), 7.38–7.24 3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.0, 133.4,
(m, 5 H, =CH, NCH), 2.30 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 144.6, 137.8, 132.9, 132.0, 131.0, 130.5, 130.4, 129.9,
131.8, 116.3, 65.9, 33.3, 31.0, 30.4, 22.3, 13.8 ppm. MS (EI, 70 eV):
m/z (%) = 368 (56) [M + H]+, 367 (1), 311 (100), 207 (57), 184 (59),
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Access to Imidazo[2,1-b]chalcogenazoles
104 (21), 95 (90), 73 (54), 52 (70). C10H13IN2Se (367.09): calcd. C 2-Phenyl-3-(p-tolylsulfenyl)imidazo[2,1-b][1,3]selenazole (3b): Ob-
32.72, H 3.57, N 7.63; found C 32.90, H 3.61, N 7.70.
tained as a yellow solid, yield 0.066 g (71%); m.p. 77.0–79.1 °C. 1H
NMR (CDCl3, 400 MHz): δ = 7.58 (s, 1 H, NCH), 7.53 (s, 1 H,
NCH), 7.42–7.31 (m, 5 H, =CH), 7.07–7.02 (m, 4 H, =CH), 2.27
(s, 3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 148.5, 141.2,
136.4, 134.0, 132.9, 132.2, 130.0, 129.1, 128.9, 126.9, 126.4, 115.1,
113.9, 20.9 ppm. MS (EI, 70 eV): m/z (%) = 370 (13) [M + H]+,
369 (1), 290 (60), 253 (25), 207 (100), 147 (26), 135 (36), 102 (43),
77 (13), 73 (78). C18H14N2SSe (369.34): calcd. C 58.53, H 3.82, N
7.58; found C 58.71, H 3.91, N 7.63.
3-Iodo-2-phenylbenzo[d][1,3]selenazolo[3,2-a]imidazole (2k): Ob-
tained as a pale yellow solid, yield 0.041 g (39%); m.p. 203.7–
1
205.8 °C. H NMR (CDCl3, 400 MHz): δ = 8.60 (d, J = 8.3 Hz, 1
H, =CH), 7.78 (d, J = 8.1 Hz, 1 H, =CH), 7.54 (d, J = 6.4 Hz, 2
H, =CH), 7.46 (q, J = 5.9 Hz, 3 H, =CH), 7.37 (t, J = 7.6 Hz, 1
H, =CH), 7.27 (t, J = 8.1 Hz, 1 H, =CH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 154.6, 147.6, 134.2, 132.9, 130.2, 129.3, 128.9, 127.4,
123.6, 120.7, 119.1, 112.3, 65.3 ppm. MS (EI, 70 eV): m/z (%) =
424 (25) [M + H]+, 344 (9), 217 (32), 207 (27), 169 (100), 167 (48),
89 (63), 73 (27), 63 (16). C15H9IN2Se (423.11): calcd. C 42.58, H
2.14, N 6.62; found C 42.70, H 2.20, N 6.66.
3-(4-Methoxyphenylsulfenyl)-2-phenylimidazo[2,1-b][1,3]selenazole
(3c): Obtained as a yellow oil, yield 0.068 g (70 %). 1H NMR
(CDCl3, 400 MHz): δ = 7.61 (s, 1 H, NCH), 7.51 (s, 1 H, NCH),
7.43–7.32 (m, 5 H, =CH), 7.16 (d, J = 9.1 Hz, 2 H, =CH), 6.81 (d,
J = 8.8 Hz, 2 H, =CH), 3.75 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 158.9, 140.6, 133.0, 129.4, 129.2, 128.9, 126.5, 126.0,
115.0, 113.9, 55.4 ppm. MS (EI, 70 eV): m/z (%) = 386 (22) [M +
2 H]+, 384 (9), 306 (77), 281 (39), 253 (25), 207 (100), 151 (26), 133
(25), 102 (59), 77 (21), 73 (82). HRMS: calcd. for C18H14N2OSSe
385.9992; found 386.0017.
3-Iodo-2-phenylimidazo[2,1-b]thiazole (2l): Obtained as a yellow so-
lid, yield 0.069 g (85%); m.p. 195.0–197.9 °C. 1H NMR (CDCl3,
400 MHz): δ = 7.60 (dd, J = 7.3, 1.8 Hz, 2 H, =CH), 7.49–7.42 (m,
4 H, =CH, N-CH), 7.35 (s, 1 H, N-CH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 146.9, 133.0, 131.7, 130.7, 129.5, 128.9, 114.1,
64.6 ppm. MS (EI, 70 eV): m/z (%) = 326 (39), 199 (10), 172 (10),
121 (100), 89 (16), 77 (19). C11H7IN2S (326.15): calcd. C 40.51, H
2.16, N 8.59; found C 40.70, H 2.20, N 8.63.
3-(4-Chlorophenylsulfenyl)-2-phenylimidazo[2,1-b][1,3]selenazole
(3d): Obtained as a pale yellow solid, yield 0.089 g (91%); m.p.
118.4–118.8 °C. 1H NMR (CDCl3, 400 MHz): δ = 7.56 (s, 2 H,
NCH), 7.42–7.33 (m, 5 H, =CH), 7.22 (d, J = 8.5 Hz, 2 H, =CH),
7.03 (d, J = 8.8 Hz, 2 H, =CH) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 141.7, 134.5, 132.7, 132.3, 129.4, 129.2, 129.0, 127.6, 126.5,
113.6 ppm. MS (EI, 70 eV): m/z (%) = 390 (23) [M + H]+, 389 (4),
310 (84), 281 (39), 253 (25), 207 (100), 133 (31), 102 (94), 89 (32),
77 (13), 73 (82). C17H11ClN2SSe (389.76): calcd. C 52.39, H 2.84,
N 7.19; found C 52.62, H 2.91, N 7.24.
3-Iodo-2-(2-methoxyphenyl)imidazo[2,1-b]thiazole (2m): Obtained
as a pale yellow solid, yield 0.077 g (87%); m.p. 160.5–161.6 °C. 1H
NMR (CDCl3, 400 MHz): δ = 7.45–7.37 (m, 3 H, =CH, NCH),
7.33 (d, J = 1.2 Hz, 1 H, NCH), 7.05–6.98 (m, 2 H, =CH), 3.84 (s,
3 H, CH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 157.2, 147.7,
132.7, 132.4, 131.3, 127.6, 120.6, 120.1, 113.8, 111.4, 67.9,
55.5 ppm. MS (EI, 70 eV): m/z (%) = 356 (100), 229 (12), 214 (37),
170 (14), 151 (33), 111 (32), 91 (38), 77 (11). HRMS: calcd. for
C12H9IN2OS [M + H]+ 356.9553; found 356.9521.
2-Phenyl-3-(propylsulfenyl)imidazo[2,1-b][1,3]selenazole (3e): Ob-
tained as a yellow oil, yield 0.036 g (45 %). 1H NMR (CDCl3,
400 MHz): δ = 7.77 (s, 1 H, NCH), 7.49–7.33 (m, 6 H, =CH,
NCH), 2.63 (t, J = 7.3 Hz, 2 H, CH2), 1.59 (sext, J = 7.3 Hz, 2 H,
CH2), 1.00 (t, J = 7.3 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 147.3, 140.1, 133.5, 133.1, 129.2, 128.8, 126.4, 117.6,
114.0, 39.0, 23.0, 12.9 ppm. MS (EI, 70 eV): m/z (%) = 322 (13) [M
+ H]+, 281 (42), 275 (3), 253 (22), 207 (100), 135 (17), 133 (22), 102
(61), 77 (5), 73 (76). HRMS: calcd. for C14H14N2SSe 322.0043;
found 322.0065.
2-Phenyl-3-(phenylselenyl)imidazo[2,1-b][1,3]selenazole (2n): Ob-
tained as a yellow solid, yield 0.068 g (68%); m.p. 71 °C. H NMR
1
(CDCl3, 400 MHz): δ = 7.55–7.52 (m, 2 H, =CH), 7.48 (d, J =
1.2 Hz, 1 H, NCH), 7.43–7.40 (m, 3 H, =CH), 7.22 (s, 5 H, =CH),
7.20 (d, J = 1.0 Hz, 1 H, NCH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 138.1, 133.2, 132.5, 129.9, 129.8, 129.7, 129.2, 128.9,
128.6, 127.8, 127.4, 115.5, 111.3 ppm. MS (EI, 70 eV): m/z (%) =
404 (17) [M + 2 H]+, 402 (15), 281 (38), 207 (100), 191 (22), 169
(48), 167 (35), 89 (56), 73 (87), 51 (21). C17H12N2Se2 (402.22):
calcd. C 50.76, H 3.01, N 6.96; found C 50.89, H 3.08, N 7.02.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental methods and characterization data, including
1H and 13C NMR spectra.
General Procedure for the Copper-Catalyzed Coupling Reaction of
2a with Different Thiols: A Schlenk flask under argon was charged
with 3-iodo-2-phenylimidazo[2,1-b][1,3]selenazole (0.25 mmol),
CuI (0.025 mmol), 1,10-phenanthroline (0.05 mmol) and the appro-
priate thiol (0.75 mmol) in DMSO (0.5 mL). The reaction mixture
was stirred at room temperature for 10 min, and then was kept at
100 °C for 24 h. The reaction mixture was quenched with a satu-
rated aqueous NH4Cl solution (5 mL), and the organic phase was
extracted with EtOAc (3ϫ20 mL). The combined organic layers
were dried with MgSO4 and concentrated under vacuum. The resi-
due was purified by flash chromatography (0–50% EtOAc/hexane).
Acknowledgments
The authors are grateful to the Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq/INCT-catalise), the Coord-
enação de Aperfeiçoamento de Pessoal de Nível Superior (SAUX)
and to the Fundação de Amparo à Pesquisa do Estado do Rio
Grande do Sul (FAPERGS) (PRONEX-10/0005-1) for fellowships
and financial support.
2-Phenyl-3-(phenylsulfenyl)imidazo[2,1-b][1,3]selenazole (3a): Ob-
tained as a pale yellow solid, yield 0.077 g (86%); m.p. 145.5–
147.2 °C. 1H NMR (CDCl3, 400 MHz): δ = 7.58 (s, 1 H, NCH),
7.55 (s, 1 H, N-CH), 7.41–7.30 (m, 5 H, =CH), 7.26–7.22 (m, 2 H,
=CH), 7.16–7.10 (m, 3 H, =CH) ppm. 13C NMR (CDCl3,
100 MHz): δ = 148.7, 141.5, 136.0, 134.1, 132.8, 129.3, 129.1, 128.9,
126.4, 126.3, 126.2, 114.4, 113.9 ppm. MS (EI, 70 eV): m/z (%) =
356 (31) [M + H]+, 355 (6), 276 (100), 134 (21), 121 (22), 102 (74),
89 (18), 77 (21), 73 (25), 63 (7). C17H12N2SSe (355.32): calcd. C
57.46, H 3.40, N 7.88; found C 57.62, H 3.48, N 7.93.
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