2
A.L. Belladona et al. / Tetrahedron Letters xxx (xxxx) xxx
However, no improvements were observed, and acetonitrile was
considered the most suitable solvent. Finally, we observed that
the presence of NaHCO3 as a weak base was important to reduce
the reaction time from 2.0 h to 0.5 h (Table 1, entry 8).
With the optimized reaction condition in hand (Table 1, entry
8), we explored the generality and scope of this methodology using
different diaryl diselenides 2 as well as (hetero)arenes 1 (Table 2).
In addition to diphenyl diselenide 2a, diaryl diselenides with the
electron-donating para-methoxy group, the electron-withdrawing
meta-trifluoromethane group and the sterically bulky substituent
2,4,6-trimethyl group were reacted with imidazo[2,1-b]thiazole
1a. In this regard, we observed that when the electron rich di(4-
methoxyphenyl)diselenide was employed,
a lower yield was
obtained when compared to the non-substituted diselenide 2a.
We propose that the presence of a strong donor group on the diaryl
diselenide hinders Se-Se bond cleavage and the generation of an
electrophilic selenium species. Conversely, we observed that the
presence of an electron-withdrawing group directly attached to
the benzene ring favors the formation of the coupling product 3c,
possibly by generating a stronger electrophilic selenium species.
When we turned our attention to the bulky di(2,4,6-trimethylphe-
nyl)diselenide, a good yield was obtained for product 3d. However,
this reaction shows evidence that steric hinderance can negatively
affect product formation (See Table 2).
In addition to 1a, 2-phenylimidazo[1,2-a]pyridine was also
reacted with the four diaryl diselenides under the same reaction
conditions. Products 3e-h were obtained in poor to excellent
yields. We observed that the electronic and steric effects associated
with the diselenides were consistent with the results described for
3a-d. The applicability of this protocol was further demonstrated
using different (hetero)arenes, including 1H-indole, 1H-pyrazole,
isoxazole and thiazole. The reaction of 1H-indole with diphenyl
diselenide in the presence of Selectfluor gave compound 3i in only
25% yield. This result is consistent with the strong interactions
between the electron rich 1H-indole and Selectfluor generating dif-
ferent fluorinated compounds and possibly resulting in its degra-
dation [22].
Fig. 1. Selected pharmacologically active selenium-containing heterocycles.
activate and functionalize double bonds through a selenenylation–
deselenenylation process [20].
In our study we focused on the selanylation reaction of different
(hetero)arenes mediated by Selectfluor under mild conditions.
Based on previously reported data [20,21], we proposed that an
electrophilic selenium species generated in situ, could be captured
by the electron rich (hetero)arene to form a new C-Se bond. Then,
hydrogen displacement would occur to allow rearomatization of
the (hetero)arene and generate the unsymmetrical selenide
product.
Results and discussion
Initially, the model substrates 6-phenylimidazo[2,1-b]thiazole
1a and diphenyl diselenide 2a were selected for optimization of
the reaction conditions. Selectfluor was employed as a mild and
safe oxidant, and various conditions were evaluated as depicted
in Table 1. Using Selectfluor (0.25 mmol) in acetonitrile at rt, 6-
phenyl-5-phenylselanyl-imidazo[2,1-b]thiazole 3a was obtained
in 98% yield after column chromatography (Table 1, entry 1). When
the reactions were conducted using 0.12 mmol or 0.05 mmol of
Selectfluor lower yields were obtained (Table 1, entries 2 and 3).
These results demonstrate the dependence of the yield on the
amount of Selectfluor. Other solvents such as PEG-400, ethanol,
DMSO and ethyl acetate were also tested (Table 1, entries 4–7).
Next, 1H-pyrazoles and isoxazoles were reacted with diaryl dis-
elenides to produce 4-selanyl-1H-pyrazoles 3j-n and 4-selanyl-
isoxazole 3o-p, respectively. Compounds 3j-m were obtained in
yields ranging from 21% to 60%. The reactions to give 3j and 3k
needed to be carried without NaHCO3, because the presence of a
base reduced the yield. When 5-methyl-3-isoxazolamine was used
product 3o was satisfactorily obtained in 61% yield. 5-Methyl-4-
(phenylselanyl)-3-isoxazolamine 3o has no precedent in the
Table 1
Optimization of the reaction conditions.a
Entry
Selectfluor (mmol)
Solvent
Time (h)b
Yield 3a (%)
1
2
3
4
5
6
7
8c
0.25
0.12
0.05
0.25
0.25
0.25
0.25
0.25
MeCN
MeCN
MeCN
PEG-400
DMSO
EtOH
2
3
98
77
27
45
12
50
17
98
12
12
5
23
12
0.5
AcOEt
MeCN
a
Reactions were conducted using 1a (0.25 mmol), 2a (0.13 mmol) in solvent (3.0 mL) at room temperature in air.
The consumption of 1a was monitored by TLC. 0.25 mmol of NaHCO3 was used.
b
c
Please cite this article as: A. L. Belladona, R. Cervo, D. Alves et al., CAH functionalization of (hetero)arenes: Direct selanylation mediated by Selectfluor,
Belladona, Andrei L.
