G Model
CCLET-5863; No. of Pages 5
J.-Y. Chen, C.-T. Zhong, Q.-W. Gui et al.
Chinese Chemical Letters xxx (xxxx) xxx–xxx
investigated by employing methylthiazoltetrazolium assay on
human cervical cancer cells (HeLa), with 5-fluorouracil (a well-
known anticancer drug) as the positive control. We are pleased to
find that compound 3a exhibits strong cytotoxicity against HeLa
with the IC50 = 13.39 mg/mL (See Supporting information). The in-
depth research of the pharmacological activitives of 5-organylse-
lanyl uracils is being studied in our laboratory.
Since both tedious post-processing and purification were need
for the previous works to remove the excess amount of reagents
and byproducts that will restrain the directly subsequent trans-
formations, the present selenylation reaction has obvious advan-
tages for its excellent atom economy, and it only generates the
harmless hydrogen as the sole byproduct. In order to further prove
the advantage of the current method, a one-pot transformation
starting from substrate 1a was carried out. Naproxen, a famous
nonsteroidal anti-inflammatory drug, its corresponding uracil
analogue was easily obtained in excellent yield through one-pot
sequential selenylation and amidation from unprotected 6-amino-
uracil (1a → 3af, Scheme 5).
Fig. 2. The reusability of catalytic reaction.
It is well known that the reusability of catalytic system is of
great importance from the views of industry and green chemistry.
As a consequence, the reusability of the electrochemical system
was next investigated by the template reaction using substrate 1a
(
5 mmol) under the optimal reaction conditions. After completion
Scheme 6. Comparison of green metrics.
of the first selenylation reaction, the product 3a was collected via
water precipitation and simple filtration. The KI/DMSO filtrate was
re-used directly after drying under vacuum. As depicted in Fig. 2,
the KI/DMSO system could be facilely re-used, and no significant
reduction in activity has been observed after five consecutive runs.
To evaluate the environmental friendliness of the present
electrochemical reaction, both the atom economy and Eco-scale
value [9] were calculated (Scheme 6). The present method not only
presented 2.7-fold increase in atom economy and 2.1-fold increase
in Eco-scale value, but also greatly simplified the process for
isolating and purifying.
To elucidate the mechanism of the present electrochemical
selenylation reaction, some control experiments were conducted.
When 2 equiv. of TEMPO (a well-known radical scavenger) were
added to the reaction system, the selenylation reaction proceeded
as normal, indicating that the free-radical is not involved in the
current reaction (Scheme 7a). Performing the reaction under
nitrogen atmosphere afforded the product 3a in 95% NMR yield
Scheme 7. Control experiments.
(
Scheme 7b). This result indicated the current system is not
associated with ambient molecular oxygen. Cyclic voltammetric
analysis was also carried out to understand the possible mecha-
nism. As shown in Fig. 3, uracil (1a) could not be oxidized up to
3
(
1
.5 V, whereas diselenide (2a) was found to be oxidized at 2.97 V
vs. Ag/AgCl). In addition, KI gave two obvious oxidation peaks at
.15 V and 1.62 V (vs. Ag/AgCl), which indicated that the iodide ion
was easier to oxidize at the surface of the anode to form iodine
cation, which promoted the formation of oxidation state of
diselenide (2a). The similar results were also can be observed in
Fig. 3. The cyclic voltammetry experiment.
the cyclic voltammetry experiment of reaction mixture of KI, uracil
(1a) and diselenide (2a).
According to the above observations and relevant literature
reports [5d], a plausible reaction mechanism for the current
reaction is proposed in Scheme 8. Firstly, the anodic oxidation of an
+
iodide ion could produce the iodine cation (I ) or molecular iodine
2
(I ), which could react with a diselenide (2) to generate the highly
reactive selenium cation intermediate A. Next, the electrophilic
addition of uracil (1) and intermediate A led to a seleranium cation
Scheme 5. One-pot transformation.
4