Broad Scope Research Articles

Gold(I)-Catalyzed 6-exo-dig Hydroamination/7-endo-dig Cycloisomerization Domino Approach to 3,7a-Diazacyclohepta[jk]fluorene Derivatives.

A series of 3,7a-diazacyclohepta[jk]fluorene derivatives were synthesized via a gold(I)-catalyzed 6-exo-dig hydroamination/7-endo-dig cycloisomerization domino method. The method exhibits a broad substrate scope, and a plausible mechanism has been proposed. The efficacy of this strategy is further validated by the successful derivatization of 3,7a-diazacyclohepta[jk]fluorene.

Catalytic Asymmetric Synthesis of Inherently Chiral Eight-Membered O-Heterocycles through Cross-[4+4] Cycloaddition of Quinone Methides.

Inherently chiral eight-membered rings embedded in tetraphenylene derivatives and hetero-analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. In this study, we describe the stereoselective cross-[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa-analogues of tetraphenylene with exceptional chemo-, diastereo-, and enantioselectivity. The structures of these novel rigid eight-membered O-heterocycles were explored via single-crystal X-ray diffraction and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross-[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expanded the inherently chiral library of medium-sized rings and also contributed to the advancement of asymmetric cross-[4+4] cycloadditions of quinone methides.

In-Situ Electrolyte for Electrosynthesis: Scalable Anodically-Enabled One-Pot Sequence from Aldehyde to Isoxazol(in)es.

Electrochemical transformations are considered a green alternative to classical redox chemistry as it eliminates the necessity for toxic and waste producing redox reagents. Typical electrochemical reactions require the addition of a supporting electrolyte - an ionic compound to facilitate reaction medium conductivity. However, this is often accompanied by an increase in the amount of produced waste. Here, we report an "in-situ electrolyte" concept for facile, transition-metal-free, additive-free one-pot electrochemical preparation of isoxazol(in)es, important scaffolds for biologically active natural and synthetic molecules, from the respective aldehydes. The protocol utilizes no halogenated solvents and no external oxidants, while salt side-products provide the ionic conductivity necessary for the electrosynthesis. The electrolysis is performed in an undivided cell, using the state-of-the-art electrodes for the chlor-alkali industry dimensionally stable and scalable mixed metal oxide anode and platinized titanium cathode of high durability. The cascade transformation comprises the condensation of aldehyde to oxime followed by its anodic oxidation and subsequent intra- and/or intermolecular [3+2] cycloadditions with an appropriate dipolarophile. Chemical yields up to 97 %, and good Faradaic efficiency, scalability, and stability are observed for most substrates in a broad scope.

Dual C2 Synthon Strategy for the Synthesis of Pyrimidines: Copper‐Catalyzed Aerobic α,β‐C(sp3)−H Bond Difunctionalization of Tertiary Alkylamines

AbstractHerein, we describe a two‐component methodology developed for the synthesis of pyrimidine derivatives using tertiary alkylamines and amidines. Tertiary alkylamines serve as dual C2 synthons through copper‐catalyzed aerobic difunctionalization of the α,β−C(sp3)−H bonds. The process operates under mild conditions and uses atmospheric oxygen as the oxidant. Notably, by this methodology yields up to 85% yields are obtained and a broad substrate scope is shown. Mechanistic studies indicate that the annulation proceeds via a radical‐mediated oxidation and C−N bond coupling process. This approach provides a pathway for synthesizing various heterocycles by employing tertiary alkylamines as dual C2 synthons.

Cu-Catalyzed Hydrodechlorination of Unactivated Alkyl Chlorides Using Diisobutylaluminum Hydride.

A copper-catalyzed hydrodechlorination of primary, secondary, and tertiary alkyl chlorides using diisobutylaluminum hydride is reported. This catalytic system offers a broad substrate scope, high yields, and good functional group tolerance. Mechanistic investigations indicated that the reaction predominantly proceeds via a radical pathway, as supported by radical clock experiments. Importantly, this study provides a new approach for the selective hydrodechlorination of unactivated alkyl chlorides and expands the utility of Cu-hydride catalysis in sustainable chemical synthesis.

Photoredox-Catalyzed Multicomponent α-Sulfonylation of Terminal Alkynes.

A generality-oriented and adaptive α-sulfonylation of alkynes via photoinduced multicomponent radical cross-coupling of terminal alkynes with sulfinates and a variety of alcohols, thiophenols, or selenophenols has been explored. This protocol features mild conditions, good functional group tolerability, broad substrate scope, excellent chemo-, site-, and stereoselectivity, and applicability to late-stage functionalization. It provides a modular platform for the synthesis of value-added structurally diverse α-sulfonyl-containing multisubstituted alkenes from simple precursors.

Cu(I)-Catalyzed C(sp3)-H Functionalization of Amino Acids with Benzimidate and Reactive Oxygen Species (ROS) To Synthesize Triazines and 2-Pyrrolidinones.

An easily accessible Cu(I)-catalyzed regioselective oxidative C-N/C-O cross-coupling organic transformation has been disclosed for the syntheses of variably functionalized triazines and N-benzoylpyrrolidin-2-ones through the involvement of C(sp3)-H bond functionalization, which is unknown in the literature. This general synthetic method is extended for decarboxylative oxidation of amino acids to install carbonyl functionality. It facilitates the formation of 2-3 new bonds through the cross-coupling strategy involving benzimidates, amino acids, and in situ-generated reactive oxygen species (ROS) from the aerial O2 as the sole oxidant. The key utilities of the new reactions are demonstrated by its operational simplicity, regioselectivity, robustness, and broad substrate scope with high yields.

Enantioselective Electrocatalysis for the Cross-Dehydrogenative Heteroarylation of Indoles, Pyrroles, and Furans.

Oxidative cross-dehydrogenative C-H/C-H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α-heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2-acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene-assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni-bound α-carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero-compounds. The consequential α-heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (-)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

Precisive Incorporation of Multiple Nitrogen Sources into Benzoxazoles via an Iodine-Mediated Electrochemical Four-Component Reaction.

An iodine-mediated electrochemical four-component reaction was developed to construct aromatic C-N bonds by making use of a simple nitrogen source, such as NH4+ and formamide. By virtue of this reaction, a variety of benzoxazoles bearing different substituents can be selectively modulated by using different bases. This protocol features a broad substrate scope and good scalability, is transition metal-free and chemical oxidant-free, and exhibits controlled product distribution. Additionally, it also enables a versatile platform for various isotope-labeled (15N and CD3) benzoxazoles.

Synthesis of Trifluoromethylselenolated Spiro[5.5]trienones/Spiro[4.5]trienones via Electrophilic Trifluoromethylselenolation Cyclization and Dearomatization

AbstractAn expedient strategy for the construction of trifluoromethylselenolated spiro[5.5]trienones/spiro[4.5]trienones through a cascade electrophilic trifluoromethylselenolation cyclization and dearomatization has been developed. This sequential process was induced by N‐trifluoromethylselenophthalimide (Phth‐SeCF3), which was an efficient electrophilic trifluoromethylselenolation reagent. This approach has the feature of mild conditions, broad substrate scope, and high functional group tolerance.

EnantioselectiveSynthesis ofspiro[indoline-3,4- pyrrolo [3,4-b]pyridines] via Organocatalysed Three-Component Cascade Reaction.

Asymmetric synthesis of spiro[indoline-3,4-pyrrolo [3,4-b]pyridines] derivatives was first developed through organocatalytic cascade Knoevenagel/Michael/cyclization reaction using a quinidine -derived squaramide. Under the optimized conditions, the three-component reaction of isatins, cyanoacetates, and 3-aminomaleimides yield the desired heterocycle-fused spirooxindoles in good yields (78-91%) with 53-99% enantiomer excess (ee). Notably, this reaction enabled a broad substrate scope under mild conditions, and provided a convenient method for enantioselective construction of diverse spirooxindoles combined with dihydropyridine and maleimide skeleton, which brought great potential to build new bioactive chemical entities.

NHC‐Catalyzed [3+3] Cycloaddition of 2‐(acetoxymethyl)buta‐2,3‐dienoates with 1 C,3O‐bisnucleophiles

AbstractDiverse transformations of allenoates catalyzed by Lewis bases have emerged as a powerful platform for generating new chemical entities in organic synthesis. Herein, an N‐heterocyclic carbene (NHC) catalyzed [3+3] cyclization of 2‐(acetoxymethyl)buta‐2,3‐dienoates with 1 C,3O‐bisnucleophiles has been developed. This approach provides a facile method to synthesize highly functionalized 4H‐pyran derivatives with a broad substrate scope (31 examples, up to 83 % yield).

Electron-Donor-Mediated Divergent Transformation of Br-RF via EDA Complex for the Synthesis of Fluorine-Containing Oxindoles and Amides.

We have developed an unprecedented electron-donor-controlled divergent reaction between N-alkylsulfonylated acrylamides and Br-RF, facilitated by an electron donor-acceptor (EDA) complex, for the synthesis of fluorine-containing oxindoles and amides. Key to this divergent transformation is the EDA complex generation by altering electron donors. This approach has several advantages, such as broad substrate scope, being metal-catalyst- and photocatalyst-free, and having good functional group tolerance.

Enantioselective Electrocatalysis for Cross‐Dehydrogenative Heteroarylation with Indoles, Pyrroles, and Furans

AbstractOxidative cross‐dehydrogenative C−H/C−H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α‐heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2‐acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene‐assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni‐bound α‐carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero‐compounds. The consequential α‐heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (−)‐COX‐2 inhibitor, (+)‐acremoauxin A, and (+)‐pemedolac.

Nitrogen-Nitrogen Radical Coupling-Enabled Precise Difunctionalization of Carbon-Nitrogen Double Bonds.

In this study, we have developed a metal-free, photoinduced energy transfer strategy for the efficient difunctionalization of carbon-nitrogen double bonds (C═N). Utilizing oxime ester-based bifunctional reagents, we have achieved direct radical difunctionalization of C═N bonds through nitrogen-nitrogen radical coupling, with over 35 examples and yields up to 96%. This method exhibits broad substrate scope, being compatible with a variety of carboxylic acids and biologically active molecules, thus offering a novel approach for the difunctionalization of heteroatom-containing unsaturated bonds in synthetic chemistry.

Oxoammonium-Catalyzed Oxidation of N-Substituted Amines.

We report the development of oxoammonium-catalyzed oxidation of N-substituted amines via a hydride transfer mechanism. Steric and electronic tuning of catalyst led to complementary sets of conditions that can oxidize a broad scope of carbamates, sulfonamides, ureas, and amides into the corresponding imides. The reaction was further demonstrated on a 100-g scale using a continuous flow setup.

Gold(I)‐Catalyzed Regioselective Cycloisomerization of Bis(indol‐3‐yl)‐ynamides to Access Five‐membered Ring Linked Bisindole Derivatives

A gold(I)‐catalyzed regioselective cycloisomerization of bis(indol‐3‐yl)‐ynamides for the rapid construction of five‐membered ring linked bisindole derivatives has been reported, affording the desired products in the range of 72% ‐ 94% yields under mild conditions along with broad substrate scope. Moreover, DFT calculation of the NBO (natural bond orbital) charge supports the origin of its regioselectivity.

Additive‐Free and Diastereoselective Synthesis for Trans‐Disubstituted‐2,3‐Dihydro‐Benzofurans via [4+1] Annulation between p‐QMs and TFISYs

AbstractAn additive‐free and diastereoselective [4+1] annulation between ortho‐hydroxyphenyl‐substituted para‐quinone methides and CF3‐substituted imidoyl sulfoxonium ylides is developed, providing a facile and practical route to diverse trans‐2,3‐dihydrobenzofurans with high efficiency. This protocol features mild conditions, broad substrate scope and easy to operate.

Access to Alkenyl Cyclobutanols by Ni‐Catalyzed Regio‐ and Enantio‐Selective syn‐Hydrometalative 4‐exo‐trig Cyclization of Alkynones

AbstractEnantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn‐hydrometalative 4‐exo‐trig cyclization of 1,4‐alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni−H species, with carbonyl‐directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

Access to Alkenyl Cyclobutanols by Ni-Catalyzed Regio- and Enantio-Selective syn-Hydrometalative 4-exo-trig Cyclization of Alkynones.

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.