PhICl2-Mediated Regioselective and Electrophilic Oxythio/Selenocyanation of o-(1-Alkynyl)benzoates: Access to Biologically Active S/SeCN-Containing Isocoumarins

Abstract

The application of PhICl2/NH4SCN and PhICl2/KSeCN reagent systems to the synthesis of the biologically active S/SeCN-containing isocoumarins via a process involving thio/selenocyanation, enabled by thio/selenocyanogen chloride generated in situ, followed with an intramolecular lactonization was realized. Gram-scale synthesis, further derivatization to access C4 thio/selenocyanated Xyridin A and anti-tumor activities of the obtained products highlight the potential use of this method.

Construction of the 2-Amino-1,3-selenazole Skeleton via PhICl2/KSeCN-Mediated Selenocyanation/Cyclization

“…This result might indicate that Cl-SeCN (SI) might not be the reactive intermediate as the reaction of an equal number of equivalents of PhICl 2 and KSeCN would produce Cl-SeCN as an intermediate. 22 However, a significant increase in reaction yield could be observed when 1.0 mmol of PhICl 2 and 2.0 mmol of KSeCN were employed (Scheme 2d). This result should be result from the in situ generation of (SeCN) 2 (SI) from the reaction of 1.0 mmol of PhICl 2 and 2.0 mmol of KSeCN.…”

“…The reaction of enamino ester 1e (0.5 mmol) with 1.0 mmol of PhICl 2 and 1.0 mmol of KSeCN afforded the desired product 2e in only 15% yield (Scheme d). This result might indicate that Cl-SeCN (SI) might not be the reactive intermediate as the reaction of an equal number of equivalents of PhICl 2 and KSeCN would produce Cl-SeCN as an intermediate . However, a significant increase in reaction yield could be observed when 1.0 mmol of PhICl 2 and 2.0 mmol of KSeCN were employed (Scheme d).…”

“…Organic selenocyanates are versatile building blocks for the synthesis of various selenium-containing compounds, − because the selenocyano group contains an intriguing cyano moiety with facile convertibility. Recently, our group realized the synthesis of the biologically interesting SeCN-containing isocoumarins via the PhICl 2 /KSeCN-mediated electrophilic selenocyanation of o -(1-alkynyl)­benzoates . On the contrary, enaminones are also important building blocks that can undergo various β-functionalization/cyclizations, allowing for the construction of a series of heterocyclic skeletons, including 2 H -azirine, − oxazole, − thiazole, , pyridine, and pyrrolone. , Inspired by the enriched convertibility of the selenocyano group combined with our continuous impetus for developing a novel method for β-functionalization of enaminones, we were interested in investigating the reaction between enaminones with PhICl 2 and KSeCN, for the purpose of finding a new way to access the pharmaceutically interesting 1,3-selenazole skeleton (Scheme d).…”

“…On the basis of the control experiments and previous literature reports, ,,, a plausible mechanism for the selenocyanative cyclization processes was proposed, taking the reaction of 1a as a model example (Scheme ). Initially, the reaction of PhICl 2 with KSeCN in EtOH afforded the reactive electrophilic species (SeCN) 2 in situ , through the Cl-SeCN intermediate . Then, the electrophilic addition of (SeCN) 2 to the alkene moiety of enamino ester 1a furnished imine A , by expelling the SeCN anion as the leaving group.…”

“…Initially, the reaction of PhICl 2 with KSeCN in EtOH afforded the reactive electrophilic species (SeCN) 2 in situ, through the Cl-SeCN intermediate. 22 Then, the electrophilic addition of (SeCN) 2 to the alkene moiety of enamino ester 1a furnished imine A, by expelling the SeCN anion as the leaving group. Next, the formed imine A was tautomerized into the stable enamino ester isomer B with the cis arrangement of carbonyl and amino groups, stabilized by the intramolecular hydrogen bond (Figure 2a).…”