Three-step one-pot synthesis of imidazo[2,1-b]chalcogenazoles via intramolecular cyclization of N-alkynylimidazoles

Article abstract of DOI:10.1002/adsc.201200075

Imidazo-chalcogenazoles are easily accessible from the corresponding N-alkynylimidazoles by a three-step, one-pot chalcogenation reaction. The generality of this reaction has been established with various substituted N-alkynylimidazoles as well as elemental chalcogens. By accessing the key intermediate 2-chalcogenolate-N-alkynylimidazole it was also possible to prepare dichalcogenide derivatives. Copyright

Full text of DOI:10.1002/adsc.201200075

FULL PAPERS
DOI: 10.1002/adsc.201200075
Three-Step One-Pot Synthesis of Imidazo[2,1-b]chalcogenazoles
G
via Intramolecular Cyclization of N-Alkynylimidazoles
Juliano Alex Roehrs,a Renan P. Pistoia,a Davi F. Back,b and Gilson Zenia,*
a
Laboratꢀrio de Sꢁntese, Reatividade, Avaliażo Farmacolꢀgica e Toxicolꢀgica de OrganocalcogÞnios, CCNE, UFSM,
Santa Maria, Rio Grande do Sul 97105-900, Brazil
Fax : (+55)-55-3220-8978; phone: (+55)-55-3220-9611; e-mail: gzeni@pq.cnpq.br
Laboratꢀrio de Materiais Inorgꢂnicos, CCNE, UFSM, Santa Maria, Rio Grande do Sul 97105-900, Brazil
b
Received: January 27, 2012; Published online: June 11, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200075.
Abstract: Imidazo-chalcogenazoles are easily accessi- ate 2-chalcogenolate-N-alkynylimidazole it was also
ble from the corresponding N-alkynylimidazoles by possible to prepare dichalcogenide derivatives.
a three-step, one-pot chalcogenation reaction. The
generality of this reaction has been established with Keywords: N-alkynylimidazoles; chalcogen-chalcoge-
various substituted N-alkynylimidazoles as well as el- nation; heterocycles; imidazoselenazoles; imidazo-
emental chalcogens. By accessing the key intermedi- thiazoles
Introduction
widely studied in view of their pharmacological prop-
erties which include antibacterial,[10] antiapoptotic,[11]
Nitrogen heterocycles are an important class of com- antitumoral,[12] hepatoprotective,[13] anticonvulsant,
pounds due to their variety of pharmacological prop- antioxidant,[14] antinociceptive and anti-allodynic ac-
erties, including antifungal, antiviral and antiprolifera- tivities.[15]
tive activities.[1] In addition, these compounds are
Although several procedures have been developed
very useful synthetic intermediates and can function for the synthesis of imidazo
AHCTUNGTRENNUNG
as suitable building blocks to synthesize some other amples involving the preparation of the correspinding
biologically active compounds, such as natural prod- selenium and tellurium derivatives have been report-
ucts.[2] Bicyclic nitrogen compounds have received ex- ed in the literature. The hydrochalcogenation of al-
tensive attention in particular in the natural products kynes is the most important and widely employed
and pharmaceutical fields.[3] More specifically, fused method for the preparation of vinylic chalcoge-
imidazo-systems have been used as antibacterial,[4] an- nides.[17] It differs from the other hydrometallation re-
tifungal[5] and antitumor[6] agents. The chemistry of se- actions, since it proceeds in an anti-fashion, as a result
lenium and tellurium compounds has emerged as of an anti-addition of an organochalcogenolate anion
a useful and convenient synthetic tool for the con- to the alkyne. This anti-addition leads to the Z-vinylic
struction of more elaborated structures. Consequently, chalcogenide, which is stereochemically stable and the
much effort has been spent to study the synthesis of isomerization to the E-isomer has not been reported
new classes of organochalcogen compounds as well as to date (Scheme 1, right). In continuation of our stud-
to study their application as intermediates in organic ies on the preparation of novel heterocycles contain-
synthesis. For example, the organochalcogen group is ing a chalcogen[18] and based on the fact that currently
able to be easily removed by using a transmetallation there are no reports in the literature concerning se-
reaction.[7]
There are also reports on the use of organochalco- were encouraged to examine if imidazoAHCUTNGTRENNUNG
quential chalcogenation reactions (Scheme 1, left), we
[2,1-b]chalco-
gens as substrates for new carbon-carbon, carbon- genazoles 2 could be prepared from N-alkynylimida-
metal, carbon-halogen and carbon-heteroatom bond zoles 1 via a three-step, one-pot chalcogenation se-
formation via lithium intermediates.[8] The organo- quence (Scheme 2).
2
À
chalcogen class, mainly those with a C
G
bond, can also be applied as electrophiles, similar to
vinylic halides, in palladium cross-coupling reac-
tions.[9] Moreover, chalcogen heterocycles are agents
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Scheme 1. Chalcogen-chalcogenation (left) versus hydrochalcogenation reactions (right).
zoles with elemental sulfur, selenium and tellurium.
In most cases, N-alkynylimidazoles were found to
work more effectively than N-alkynylbenzoimida-
zoles. For example, compound 2a was obtained in
84% yield while the corresponding reaction with the
benzimidazole derivative gave the cyclized product 2i
in 76% yield. The reaction was not sensitive to either
electronic factors or the effective bulk of the aryl
group directly bonded to the alkyne. For instance, 2c
having an electron-donating p-methoxy group, 2e
having an electron-withdrawing group and 2b having
a hindered o-methoxy group showed the same behav-
Scheme 2. Optimized conditions to prepare imidazo
b]chalcogenazoles.
ACHTUNGTNER[NUNG 2,1-
Results and Discussion
The starting N-alkynylimidazoles 1 were prepared ior in this reaction. By contrast, in the case of an
using previously reported procedures.[19] At first, the alkyl group directly bonded to the selenium atom, it
anionic 2-lithium-N-alkynylimidazole, generated in was observed that decreasing the length of the alkyl
situ by reaction of substrate 1a (0.5 mmol) with n- group caused a decrease in the yields (Table 1, com-
BuLi (1.1 equiv.) in THF at À788C for 30 min, was pounds 2a and 2k). Compounds 2m–2x in Table 1 il-
treated with elemental selenium (2.0 equiv.) at lustrate the results of the cyclization using elemental
À788C. After the mixture had warmed to room tem- sulfur with several N-alkynylimidazoles. Compared
perature, 1-bromobutane (1.2 equiv.) was added and with the selenium derivatives the reaction employing
stirring was continued for 2 h. This reaction condi- sulfur was somewhat similar giving the cyclized prod-
tions provided the desired product 2a in 70% yield. A uct in equally good yield. By contrast, the optimized
variety of temperatures for the addition of elemental reaction conditions applied to elemental tellurium
selenium was tested, and we found that 08C gave the failed to afford the desired Te-heterocycle derivatives.
product 2a in 45% yield, while at room temperature In attempts to optimize the reaction conditions for
the product failed to form. Control experiments indi- tellurium derivatives, the reaction time, after the addi-
cate that the reaction temperature was an important tion of tellurium, was increased by 5 min until 30 min,
factor, because the 2-lithium-N-alkynylimidazole at which point samples were taken and analyzed.
anion was unstable at above À788C. In an effort to When the reaction time had reached 30 min the prod-
better understand the formation of 2a the amount of uct was obtained in 50% yield. Further increases in
elemental selenium was increased to 2.5 and the reaction time or changes of the other parameters
3.0 equiv. By using this alteration, 1a was converted led to decomposition without any improvement in the
to 2a in 84% yield. A prolonged reaction time only yields (Table 1, compound 2z).
led to a decrease in yield. These findings suggest that
A plausible mechanism for the formation of imida-
the optimum yield of this three-step, one-pot reaction zo-chalcogenazoles 2a–z is shown in Scheme 3. We
was obtained by reacting N-alkynylimidazole with n- believe that (i) the removal of hydrogen with n-BuLi
BuLi (1.1 equiv.) in THF at À788C for 30 min, fol- from N-alkynylimidazole gives the 2-lithium-N-alkyn-
lowed by the addition of elemental selenium
ACHTUNGTRENyNUGN limidazole a; (ii) the reaction of lithium intermediate
(2.5 equiv.) at À788C. After that, the mixture was a with elemental chalcogen affords the chalcogenolate
warmed to room temperature and 1-bromobutane species b; (iii) the increase of the reaction tempera-
(1.2 equiv.) was added and the reaction was stirred for ture leads to the addition of the chalcogenate anion
2 h (Scheme 2).
onto the triple bond of the alkyne and the subsequent
The results in Table 1 indicate the scope and limita- attack to the other chalcogen atom gives the chalco-
tions of the cyclization reaction of N-alkynylimida- genolate species c; (iv) trapping of chalcogenolate
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Adv. Synth. Catal. 2012, 354, 1791 – 1796

Three-Step One-Pot Synthesis of ImidazoACTHNUTRGNE[NUG 2,1-b]chalcogenazoles via Intramolecular Cyclization
Table 1. Scope and generality of the cyclization reaction.[a]
Scheme 3. Proposed mechanism for the synthesis of imidazo-
AHCTUNGTERG[NNUN 2,1-b]chalcogenazoles 2.
anion c with an electrophile source affords the desired
cyclized product 2 (Scheme 3).
Considering the important role of diorganoyl dise-
lenides[20] and disulfides[21] in biological processes and
as synthetic intermediates in organic synthesis, we
extend this approach to the synthesis of diselenides
and disulfides 2aa–ad (Scheme 4 and Scheme 5).
After having shown that the chalcogenolate species
c (Scheme 3) leads to cyclized product 2 via trapping
with an electrophile source, we set out to trap the lith-
Scheme 4. Synthesis of diselenides 2aa–ac.
[a]
Yields of isolated products.
Scheme 5. Synthesis of disulfide 2ad.
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Juliano Alex Roehrs et al.
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zole with elemental sulfur, selenium or tellurium to
prepare imidazoACTHNUTRGNEUNG[2,1-b]chalcogenazoles. In addition,
when the reaction was carried out using a proton
source instead of organohalides as electrophile
source, we obtained dichalcogenides as the products.
These results are significant since by using the same
reaction conditions we obtained two classes of
imidazo
ACHTUNGTREN[NUNG 2,1-b]chalcogenazoles. For instance, imidazo-
AHCTUNGTREG[NNNU 2,1-b]selenazoles were treated under selenium/lithi-
um exchange conditions with n-BuLi, and trapping
the lithium intermediates with aldehydes provided the
corresponding secondary alcohols. We have described
here a methodology to prepare a new class of organo-
chalcogen compounds. The results of this paper dem-
onstrate that once prepared, the organochalcogen
route is a useful and attractive strategy for studies on
both synthetic methodology and biologically active
Scheme 6. Reaction of the intermediate 3-lithium-imidazo-
ACHTUNGTRENNUNG[2,1-b]selenazole 3 with aldehydes.
compounds. All compounds prepared were character-
1
ium chalcogenolate intermediate c with an aqueous ized by H and 13C NMR spectroscopy, and the struc-
solution of NH4Cl. The chalcogenol species formed ture of 2i was elucidated by X-ray crystallography[23]
could then be oxidized under air to give the dichalco- (See Supporting Information) which confirmed the
genides. We have been successful with our strategy formation of the five-membered heterocycle via a 5-
and diselenides derivatives 2aa--ac were obtained in endo-dig cyclization process.
moderate to good yields (Scheme 4); however, none
of the corresponding disulfides were detected. Grati-
fyingly, disulfide 2ad was isolated in 68% yield when
the lithium thiolate anion d was allowed to react with
Experimental Section
molecular iodine (0.5 equiv.) for 2 h at room tempera-
ture (Scheme 5).
General Procedure for the One-Pot Synthesis of
Imidazo[2,1-b]selenazoles and Imidazo[2,1-b]-
thiazoles
G
ACHTUNGTRENNUNG
The 3-chalcogen imidazoACTHNUTRGNE[NUG 2,1-b]selenazoles obtained
appear highly promising as intermediates for the
preparation of more highly substituted heterocyclic
compounds. To further prove the utility of our meth-
odology, we carried out the selenium-lithium ex-
change reaction of product 2a using n-butyllithium to
prepare the lithium intermediate 3, which would be
To
a solution of the appropriate N-alkynylimidazole
(0.5 mmol) in THF (5 mL) under argon at À788C was
added n-BuLi (0.22 mL of 2.5M solution in hexane,
0.55 mmol). The reaction mixture was stirred for 30 min at
À788C prior to the addition of elemental chalcogen
(1.25 mmol). After that, the reaction mixture was allowed to
trapped with electrophiles. Lithium-selenium ex- stir at room temperature to complete consumption of the
chalcogen. The intermediate anionic chalcogenolate was
then trapped with an appropriate alkyl electrophile
(0.6 mmol). The reaction mixture was stirred at room tem-
perature for 2 h. After this time, the mixture was diluted
with ethyl acetate (20 mL) and washed with saturated
NH4Cl solution (3ꢄ20 mL). The organic phase was separat-
ed, dried over MgSO4, and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel
using ethyl acetate/hexane as the eluent.
change reactions have great importance in synthetic
organic chemistry, particularly with respect to the for-
[22]
À
mation of new C C bonds. The lithium intermedi-
ate 3 was prepared according to the literature method
by deprotonation of 3-(phenylselenyl)-imidazoACTHUNTGRNEUNG[2,1-
b]selenazole 2a using n-butyllithium (1.0 equiv.) in
THF (5 mL) at À788C.[7a] We found that quenching
the resulting lithium intermediate 3 with EtOH af-
forded the corresponding hydrogenated product in
3-(Butylselenyl)-2-phenylimidazoACTHNUTRGENN[UG 2,1-b]AHCTUNGTRENN[UNG 1,3]selenazole
1
78% yield. We attempted to extend this reaction to (2a): Yield: 0.160 g (84%); mp 63–648C. H NMR (CDCl3,
400 MHz): d=7.71 (s, 1H), 7.57–7.54 (m, 2H), 7.44–7.38 (m,
3H), 7.30 (s, 1H), 2.73 (t, J=7.3 Hz, 2H), 1.47 (quin, J=
7.3 Hz, 2H), 1.22 (sex, J=7.3 Hz, 2H), 0.77 (t, J=7.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz): d=136.0, 133.7, 132.6,
130.0 (2C), 128.9, 128.5, 115.4, 111.8, 32.0, 28.6, 22.4, 13.3;
MS (EI, 70 eV): m/z (relative intensity)=384 (7), 328 (19),
248 (5), 168 (100), 89 (36); anal. (%) calcd. for C15H16N2Se2:
C 47.14, H 4.22, N 7.33; found: C 47.31, H 4.29, N 7.40.
use an aldeyde as the electrophile source. The reac-
tion with p-chlorobenzaldeyde and p-tolyl aldehyde
took place giving the expected secondary alcohols 4
in 60 and 65% yields, respectively (Scheme 6).
Conclusions
3-(Butylthio)-2-phenylimidazo
ACHTUNGTNER[NUNG 2,1-b]thiazole (2m): Yield:
0.105 g (73%); oil. 1H NMR (CDCl3, 200 MHz): d=7.70–
In conclusion, we have succeeded in the development
of a three-step, one-pot reaction of N-alkynylimida- 7.65 (m, 2H), 7.58 (s, 1H), 7.50–7.39 (m, 3H), 7.36 (s, 1H),
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Three-Step One-Pot Synthesis of ImidazoACTHNUTRGNE[NUG 2,1-b]chalcogenazoles via Intramolecular Cyclization
2.72 (t, J=7,0 Hz, 2H), 1.40 (quin, J=7.3 Hz, 2H), 1.23
(sex, J=7.3 Hz, 2H), 0.75 (t, J=7.3 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): d=135.0, 133.6, 131.2, 129.3 (2C), 129.0,
128.5, 118.0, 111.9, 34.0, 31.2, 21.2, 13.3. MS (EI, 70 eV): m/z
(relative intensity)=288 (57), 232 (100), 168 (25), 121 (74),
89 (32); anal. (%) calcd. for C15H16N2S2: C 62.46, H 5.59, N
9.71; found: C 62.60, H 5.64, N 9.80.
70 eV): m/z (relative intensity)=652 (4), 571 (15), 493 (10),
325 (22), 169 (84), 89 (100); HR-MS: m/z=676.7781, calcd.
for C22H14N4Se4 (M+Na+): 676.7776.
General Procedure for the Reaction of Intermediate
2-Phenyl-3-lithioimidazo
Aldehydes
ACHTUNGERTN[NUNG 2,1-b]selenazole with
To a two-necked, round-bottomed flask, under argon, con-
taining a solution of 2a (0.25 mmol) in THF (5 mL) at
À788C was added n-BuLi (0.5 mmol, of a 2.5M solution in
hexane) in one portion. The reaction mixture was stirred for
15 min, and then a solution of appropriated aldehyde
(0.3 mmol) in THF (2 mL) at À788C was added. The reac-
tion mixture was allowed to stir at room temperature for
1 h. After this, the mixture was diluted with ethyl acetate
(20 mL) and washed with saturated solution of NH4Cl
(20 mL). The organic phase was separated, dried over
MgSO4 and concentrated under vacuum. The residue was
purified by flash chromatography and eluted with ethyl ace-
tate/hexane.
General Procedure for the One-Pot Synthesis of
ImidazoACHTUNGTRENNUNG[2,1-b]tellurazole 2z
To
a
solution of 1-(phenylethynyl)-1H-imidazole 1a
(0.5 mmol) in THF (5 mL) under argon at À788C was
added n-BuLi (0.22 mL of 2.5M solution in hexane,
0.55 mmol). The reaction mixture was stirred for 30 min at
À788C prior to the addition of elemental tellurium
(1.25 mmol). After the 30 min at À788C, the reaction mix-
ture was allowed to stir at room temperature to complete
consumption of the tellurium. The intermediate anionic tel-
lurolate generated in situ was then trapped with 1-bromobu-
tane (0.6 mmol). The reaction mixture was stirred at room
temperature for 2 h. After this time, the mixture was diluted
with ethyl acetate (20 mL) and washed with saturated
NH4Cl solution (3ꢄ20 mL). The organic phase was separat-
ed, dried over MgSO4, and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel
using ethyl acetate/hexane as the eluent. Obs.: The use of
tellurium - 200 mesh was required.
(4-Chlorophenyl)(2-phenylimidazoACTHNUTRGENN[GU 2,1-b]HCATUNGTRENN[UGN 1,3]selenazol-3-
yl)methanol (4a): Yield: 0.058 g (60%); mp 228–2308C.
NMR (DMSO-d6, 400 MHz): d=7.61(d, J=8.2 Hz, 2H),
7.54–7.45ACTHUNGTREN(NGUN m, 3H), 7.40–7.34ACHTUNGTREG(NNUN m, 5H), 7.09ACHTGUNTREN(NUGN s, 1H), 6.70(d,
J=2.4 Hz, 1H), 5.98 (s, 1H); 13C NMR (DMSO-d6,
100 MHz): d=143.1, 138.8, 132.4, 132.3, 132.0, 129.5, 129.3,
129.1, 128.9, 128.4, 127.3, 127.2, 115.7, 65.5; MS (EI, 70 eV):
m/z (relative intensity))=388 (99), 249 (24), 168 (56), 139
(54), 77 (100); HR-MS: m/z=388.9891, calcd for
C18H13ClN2OSe (M+H+): 388.9955.
3-(Butyltelluronyl)-2-phenylimidazoACTHNUTRGENNUG[2,1-b]ACHTUNGTRNE[NUGN 1,3]tellurazole
(2z): Yield: 0.119 g (50%); mp 126–1288C. 1H NMR
(CDCl3, 200 MHz): d=7.99 (s, 1H), 7.39 (s, 5H), 7,27 (s,
1H), 2.72 (t, J=7.3 Hz, 2H), 1.57 (quin, J=7.3 Hz, 2H),
1.20 (sex, J=7.3 Hz, 2H), 0.79 (t, J=7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d=139.2, 131.4, 130.8, 130.0 (2C), 128.4,
128.3, 121.7, 99.2, 33.4, 24.6, 13.2, 10.8; MS (EI, 70 eV): m/z
(relative intensity)=480 (22), 424 (22), 298 (64), 168 (100),
89 (72); HR-MS: m/z=506.9352, calcd. for C15H16N2Te2
(M+Na+): 506.9335.
Acknowledgements
We are grateful to FAPERGS (PRONEX-10/0005-1),
CAPES (SAUX) and CNPq (CNPq/INCT-catalise) for the fi-
nancial support. CNPq is also acknowledged for the fellow-
ships.
General Procedure for the One-Pot Synthesis of 1,2-
Bis
N
ACHTUNGTRENNUNG[1,3]selenazol-3-yl)diselenides
To
a
(0.5 mmol) in THF (5 mL) under argon at À788C was
added n-BuLi (0.22 mL of 2.5M solution in hexane,
0.55 mmol). The reaction mixture was stirred for 30 min at
À788C prior to the addition of elemental selenium
(1.25 mmol). After that, the reaction mixture was allowed to
stir at room temperature to complete consumption of the
chalcogen. The reaction mixture was quenched with 5 mL of
a saturated NH4Cl solution and allowed to oxidize under air
for 2 h. After this time, the mixture was diluted with ethyl
acetate (20 mL) and washed with saturated NH4Cl solution
(3ꢄ20 mL). The organic phase was separated, dried over
MgSO4, and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel using ethyl
acetate/hexane as the eluent.
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Adv. Synth. Catal. 2012, 354, 1791 – 1796