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research strategy more reliable and immense applica- carboxylative alkylselenation reaction was proposed
tion prospects. This protocol was also further applied (Scheme 6). The decarboxylation of the alkynyl
to the late-stage selenation of bioactive molecules, carboxylic acid with the copper catalyst appears first to
alkynyl carboxylic acid from estrone, which is one of produce alkynylcopper species A with the release of
the major mammalian estrogens, which has shown equivalent CO2. Then, this intermediate A undergoes
selective decarboxylative alkylselenation to give the the ligand exchange with Se2À and disproportionation
corresponding product in good yield.
to form the key intermediate C,[9,13] and reductive
A series of controlled experiments were designed to elimination and recoordination of alkynylselenyl
elucidate the reaction mechanism and the sequence of anions with copper salt to generate alkynylselenylcop-
multi-component cascade reactions (Scheme 5). With per species D. Finally, the critical complex D under-
the addition of 3.0 equivalents of TEMPO to perform a goes nucleophilic ring-opening reactions with
radical-probing experiment (eq. 1), it was found that epoxide[14] to provide the target compounds and release
the efficiency of the reaction was not significantly the copper catalyst.
affected, which excluded the radical-mediated prog-
ress. Two sets of blank tests were conducted and
investigated by GC-MS, and a mixture of phenyl
Conclusion
propionic acid with selenium powder under the The first example of copper-catalyzed decarboxylative
standard reaction condition (eq. 2), a certain amount of alkylselenation of alkynyl carboxylic acids with Se
1,4-diphenylbuta-1,3-diyne
and
cis-5-phenyl-2- powder and epoxides were described. It provides a
(phenylmethylene)-1,3-diselenole[12] were detected. It concise and distinct protocol to access a variety of
is worth noting that the reaction of epoxides with Se functionalized alkynyl selenides. Meanwhile, cheap
powder under the optimized reaction conditions and readily available elemental selenium was used as a
(eq. 3), only gave the vicinal diol product via selenating reagent. Moreover, copper catalyst playing a
nucleophilic ring-opening reactions. This result sug- multi-role in this reaction, effectively broadened the
gested that the possibility in situ formation of alkynyl- scope of difunctionlization of Se atom with the
copper intermediate could undergo the selenium formation of two CÀ Se bonds. Furthermore, this
insertion reaction. When using 10 mol% phenylethynyl transformation’s apparent feature was the use of water
copper as catalyst (eq. 5), 61% yield of corresponding as solvent, sustainable catalytic system, excellent func-
product was isolated, which suggested the alkynylcop- tional group compatibility and late-stage alkynylsele-
per may be the key intermediate, which was further nation of small bioactive compounds, which would
supported by the stoichiometric reactions (eq. 4). advance the synthetic applications and new drug
Furthermore, cesium 3-phenylpropiolate reacted with development.
Se powder and epoxide under the standard reaction
condition to give the target compound in good yield
(eq. 6). This reaction showed that cesium carbonate
Experimental Section
General experimental procedures of copper-catalyzed decarbox-
ylative alkylselenation of propiolic acids with Se powder and
epoxides: in a 25 mL Schlenk tube equipped with a stir bar
were placed propiolic acids (0.2 mmol), Se (0.6 mmol), epox-
ides (0.6 mmol), CuCl2 (0.02 mmol), 1,10-phen (0.02 mmol),
TBAI (0.4 mmol), Cs2CO3 (0.6 mmol) in H2O (2 mL), then the
Schlenk tube was plugged with a Teflon screwcap. The reaction
played an essential role in the deprotonation of alknyl
acids and promoted the activation of selenium with
copper salts.
Based on the above experimental results and
relevant works of literature, a plausible reaction
mechanism for copper-catalyzed three-component de-
°
mixture was stirred at 50 C for 24 h. After it was cooled, the
reaction mixture was diluted with 10 mL of ethyl acetate, and
filtered through diatomaceous earth, followed by washing the
pad of silica gel with the same solvent (20 mL). The organic
Scheme 5. Preliminary mechanism investigation.
Scheme 6. Proposed mechanism.
Adv. Synth. Catal. 2021, 363, 1930–1934
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