A radical fluorosulfonyl arylation of alkynes with sulfuryl chlorofluoride as the FSO2 radical precursor via electron donor-acceptor photoactivation driven by daylight or a blue light-emitting diode is disclosed. A series of valuable benzo-fused carbocycles and heterocycles have been produced with simple operation under mild conditions in the absence of any external catalysts or additives. The synthetic potential of this protocol has further demonstrated excellent scalability, as well as diverse postderivatizations, including SuFEx reactions and other useful cascade reactions.
We disclose a deconstructive [5 + 1] annulation protocol for the synthesis of isoquinolones through a nitrogen insertion into abundant indanones. This method exploits photoredox-catalyzed ring-opening of oxime esters. The reaction proceeds smoothly with water as the reaction medium and tolerates a range of functional groups on diverse thiophenols, amines, or indanones. Moreover, the representative isoquinolones exhibit promising antifungal activities.
A radical hydro-fluorosulfonylation of propargyl alcohols with FSO2Cl is presented based on the photoactivation of the electron donor-acceptor (EDA) complex. The reaction avoids the requirement for photocatalysts, bases, hydrogen donor reagents, any other additives, and harsh conditions, enabling the facile synthesis of various functionalized γ-hydroxy (E)-alkenylsulfonyl fluorides. These multifunctional sulfonyl fluorides can be further diversified, providing access to various privileged molecules of biological relevance.
Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.
Neoplasms , Proto-Oncogene Proteins p21(ras) , Humans , Proto-Oncogene Proteins p21(ras)/genetics , Mutation , Oncogenes , Signal Transduction
An electrochemical approach to biheteroaryls through the coupling of diverse N-heteroarenes with heteroaryl phosphonium salts is reported. The reaction features pH and redox-neutral conditions and excellent regioselectivity, as well as exogenous air or moisture tolerance. Additionally, a one-pot, two-step protocol can be established to realize formal C-H/C-H coupling of heteroarenes, thereby greatly expanding the substrate availability. The utility of this method is demonstrated through late-stage functionalization, the total synthesis of nitraridine, and antifungal activity studies.
An electrochemical method is presented to construct 1,3-oxazines by the oxidative ring-opening of cyclopropylamides with alcohols. This method avoids the use of external oxidants and thus shows good functional group tolerance. The substrate scope covers primary, secondary, and tertiary alcohols as well as (hetero)aryl amide-substituted cyclopropanes.
An electroreductive strategy for radical hydroxyl fluorosulfonylation of alkenes with sulfuryl chlorofluoride and molecular oxygen from air is described. This mild protocol displays excellent functional group compatibility, broad scope, and good scalability, providing convenient access to diverse ß-hydroxy sulfonyl fluorides. These ß-hydroxy sulfonyl fluoride products can be further converted to valuable aliphatic sulfonyl fluorides, ß-keto sulfonyl fluorides, and ß-alkenyl sulfonyl fluorides. Further, some of these products showed excellent inhibitory activity against Botrytis cinerea or Bursaphelenchus xylophilus, which could be useful for potent agrochemical discovery. Preliminary mechanistic studies indicate that this transformation is achieved through rapid O2 interception by the alkyl radical and subsequent reduction of the peroxy radical, which outcompete other side reactions such as chlorine atom transfer, hydrogen atom transfer, and Russell fragmentation.
An unexpected deprotonative process of thiirenium ions is presented, which provides a new synthesis of aryl thioalkynes directly from terminal alkynes via the electrophilic activation of the carbon-carbon triple bonds. The conditions are well compatible with various functional-group-substituted aryl alkynes. The direct elimination from the thiirenium ion intermediate, or its tautomer, benzyl vinyl carbocation, is supported by control experiments and labeling reaction.
An electron donor-acceptor (EDA) complex photoactivation strategy for radical fluorosulfonylation is disclosed for the first time. Simply upon blue light irradiation, the FSO2 radical can be generated efficiently under catalyst-free, base-free, and additive-free conditions, which enables facile access to 6-keto alkenylsulfonyl fluorides from readily available propargyl alcohols and FSO2Cl. The 6-keto alkenylsulfonyl fluoride motif has been showcased as a versatile SuFEx hub with diverse follow-up derivatizations.
Transition metal-catalyzed divergent synthesis through alternation of the catalyst is appealing, as it provides an operationally simple way to access different valuable products, while using the same reactants as starting materials. Herein, a gold-catalyzed cascade reaction of conjugated diynamides with allylic alcohols is described. By variation of the catalysts, substituted allenes and furans could be obtained selectively. Mechanistic studies indicate that, after the addition of allylic alcohol to gold-activated diynamide, a [3,3]-sigmatropic rearrangement would take place and lead to the formation of a common reactive intermediate, which would further convert to the final products selectively. Further variation of the structure of diynamides has unveiled an additional reaction sequence involving intramolecular Himbert arene/allene Diels-Alder cycloaddition to afford a series of dearomatized products bearing bicyclo[2,2,2]octadiene core.
Gold , Propanols , Gold/chemistry , Catalysis
Sulfuryl chlorofluoride was first employed as a versatile reagent for controllable chlorination and chlorooxidation of simple unprotected indoles. Three types of products including 3-chloro-indoles, 3-chloro-2-oxindoles, and 3,3-dichloro-2-oxindoles could be selectively obtained in good to excellent yields by switching the reaction solvents. The present method features easy-to-operate, broad substrate scope, and mild reaction conditions.
A sustainable method for converting terminal alkynes into their corresponding carboxylic acids is reported using synthetic electrolysis in an undivided cell at room temperature. This protocol, avoiding transition metal catalysis and stoichiometric chemical oxidants, tolerates a variety of aryl, heteroaryl, and alkyl akynes. Preliminary mechanistic studies demonstrate that sodium nitrite serves a triple role as the electrolyte, nitryl radical precursor, and a nitrosating reagent.
Exploration of artificial aggregation-induced emission luminogens (AIEgens) has garnered extensive interest in the past two decades. In particular, AIEgens possessing natural characteristics (BioAIEgens) have received more attention recently due to the advantages of biocompatibility, sustainability and renewability. However, the extremely limited number of BioAIEgens extracted from natural sources have retarded their development. Herein, a new class of BioAIEgens based on the natural scaffold of chromene have been facilely synthesized via green reactions in a water system. These compounds show regiostructure-, polymorphism- and substituent-dependent fluorescence, which clearly illustrates the close relationship between the macroscopic properties and hierarchical structure of aggregates. Due to the superior biocompatibility of the natural scaffold, chromene-based BioAIEgens can specifically target the endoplasmic reticulum (ER) via the introduction of tosyl amide. This work has provided a new chromene scaffold for functional BioAIEgens on the basis of green and sustainable 'in-water' synthesis, applicable regiostructure-dependent fluorescence, and effective ER-specific imaging.
A new metal-free synthesis of pyrrole from allyl ketone and amine has been established. The reaction proceeds via an thiolative activation of the C-C double bond with dimethyl(methylthio)sulfonium trifluoromethanesulfonate, followed by a nucleophilic ring-opening addition of primary amine to the generated episulfonium intermediate, and then an internal condensation and aromatization. This mild procedure provides a novel strategy to the construction of substituted pyrroles through a formal [4 + 1] cycloaddition reaction.
Vinyl triflates are commonly employed as electrophilic vinyl sources in complex synthesis. The triflation of enolates is commonly required for the preparation of vinyl triflates, generally under strongly basic conditions. Herein, the reaction between alkynes and dimethyl(methylthio)sulfonium trifluoromethanesulfonate is presented, which leads to the development of a facile synthesis of ß-methylthio vinyl triflates in a chemo-, regio-, and stereoselective manner under neutral and extremely simple conditions.
Electrochemical synthesis of versatile ß-keto sulfonyl fluorides is accomplished by radical fluorosulfonylation of vinyl triflates with FSO2Cl as the fluorosulfonyl radical source. This electroreductive protocol uses inexpensive graphite felt as electrodes, thus avoiding the use of a sacrificial anode. Moreover, this protocol, featuring metal-free, mild conditions and easy scalability, allows expedient access to valuable ß-keto sulfonyl fluorides from readily available precursors, as well as the cyclic ones that are otherwise inaccessible using prior methods.
Trifluoromethyl carbinols and N-heteroarenes are both prevalent in bioactive molecules. However, access to high-value pharmacophores combining these two functional groups still remains a challenge. Herein, we report an electro-chemical redox-neutral coupling for the synthesis of N-heteroaryl trifluoromethyl carbinols from readily available N-heteroarenes and trifluoromethyl ketones. The reaction starts with reversing the polarity of ketones to nucleophilic ketyl radicals through an electrocatalytic proton-coupled electron transfer (PCET), followed by radical addition to heteroarenes and rearomatization to afford tertiary alcohol products. Importantly, the merging of paired electrolysis and cobalt catalysis is crucial to this regioselective C-H hydroxyalkylation of heteroarenes, and thus avoids several known competing pathways including the spin-center shift (SCS) process. Collectively, this protocol provides straightforward access to heteroaryl trifluoromethyl carbinols, featuring ideal atom economy, excellent regioselectivity, and paired redox-neutral electrolysis.
Radical fluorosulfonylation is emerging as an appealing approach for the synthesis of sulfonyl fluorides, which have widespread applications in many fields, in particular in the context of chemical biology and drug development. Here, we report the first investigation of FSO2 radical generation under electrochemical conditions, and the establishment of a new and facile approach for the synthesis of ß-keto sulfonyl fluorides via oxo-fluorosulfonylation of alkynes with sulfuryl chlorofluoride as the radical precursor and air as the oxidant. This electrochemical protocol is amenable to access two different products (ß-keto sulfonyl fluorides or α-chloro-ß-keto sulfonyl fluorides) with the same reactants. The ß-keto sulfonyl fluoride products can be utilized as useful building blocks in the synthesis of various derivatives and heterocycles, including the first synthesis of an oxathiazole dioxide compound. Furthermore, some ß-keto sulfonyl fluorides and derivatives exhibited notably potent activities against Bursaphelenchus xylophilus and Colletotrichum gloeosporioides.
Alkynes/chemistry , Sulfones/chemical synthesis , Animals , Anthelmintics/pharmacology , Antifungal Agents/pharmacology , Colletotrichum/drug effects , Electrochemical Techniques , Rhabditida/drug effects , Sulfones/pharmacology
A Cu-catalyzed coupling reaction of indanone oxime acetates with thiols has been developed for the synthesis of 2,3-functionalized 1-indenones. This protocol has several features including easy mild reaction conditions, stabilized enamine products, good tolerance of functional groups, and no external oxidants. This reaction enables direct derivatization on the indanone ring to provide valuable functionalized indenones at room temperature.
A novel selective fragmentation of cycloalkanones by NaNO2/HCl has been established. The C-C bond cleavage reaction proceeds smoothly under mild conditions, selectively affording versatile keto acids or oxime acids. The methodology can streamline the synthesis of valuable chiral molecules and isocoumarins from readily available feedstocks.
