PIDA-mediated N-N bond formation to access pyrazolidine-3,5-diones: a novel process for uricosuric agents G-25671 and sulfinpyrazone.

Traditionally, toxic and expensive hydrazine building blocks are required to construct pharmaceutically important pyrazolidine-3,5-diones. Herein, we have described a novel method for their synthesis based on metal-free oxidative dehydrogenative N-N bond formation by PIDA-mediated reaction of easily accessible dianilide precursors. The developed mild reaction protocol features a good functional group tolerance and scalability. The application of this method is demonstrated by offering a unique route for the synthesis of uricosuric agents G-25671 and sulfinpyrazone from inexpensive starting material aniline via smooth functionalization of the well-designed diversity-oriented cyclopropyl key intermediate.

Enantioselective Intramolecular Decarboxylative C-H Bond Func-tionalization of Quinazolinones with Amino Acids by Visible Light Photoredox Catalysis.

The direct visible light-mediated intramolecular decarboxylative C-H functionalization of Csp2 -H bond adjacent to the nitrogen of a heteroarene has been achieved by iridium-catalyzed photodecarboxylative radical cyclization. This method offers rapid entry to the synthesis of quinazolinone scaffolds from easily accessible starting materials. The newly developed protocol is mild, operationally simple, oxidant free and general. The utility of this unique Csp3 -Csp2 bond forming reaction has been demonstrated in the syntheses of Circumdatin, Sclerotigenine and Benzomalvin A class of quinazolinone natural products and their congeners. The present work represents an interesting example of use of memory of chirality in decarboxylative C-C bond forming enantioselective photoredox reaction.

Nickel-Catalyzed Direct Synthesis of N-Substituted Indoles from Amino Alcohols and Alcohols.

A one-pot cascade approach for the synthesis of N-substituted indoles from amino alcohols and alcohols under additive and base-free conditions with the liberation of water as the only stoichiometric byproduct is reported. The commercially available bench-stable Ni(OTf)2 salt in combination with 1,2-bis(dicyclohexylphosphino)ethane (dcype) is very effective for this unprecedented catalytic transformation. A broad range of substrates including aromatic and aliphatic primary alcohols, cyclic and acyclic secondary alcohols, and various substituted 2-aminophenyl ethyl alcohols are employed in the reaction conditions to provide a diverse range of N-alkylated indoles. Mechanistic studies revealed that the reaction proceeds through tandem N-alkylation via hydrogen autotransfer followed by the cyclization of N-alkylated alcohol intermediate.

Annulation of Enals with Carbamoylpropiolates via NHC-Catalyzed Enolate Pathway: Access to Functionalized Maleimides/Iso-maleimides and Synthesis of Aspergillus FH-X-213.

Herein we report the N-heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation of α,ß-unsaturated aldehydes with carbamoylpropiolates via an unusual enolate pathway leading to the construction of highly functionalized maleimides or isomaleimides. The electronic effect imposed by the alkyl/aryl group present on the amide nitrogen of carbamoylpropiolates plays a crucial role in the selective formation of these important five-membered heterocyclic building blocks. The developed protocol is mild and tolerates a wide range of substituents on both substrates. The application of this protocol in the synthesis of the antibacterial natural product Aspergillus FH-X-213 has also been demonstrated.

Construction of unique SCF3-containing building blocks via allylic alkylation of Morita-Baylis-Hillman adducts.

Lewis base-catalyzed allylic alkylation of Morita-Baylis-Hillman adducts with α-SCF3 ketones has been demonstrated. The developed strategy provides efficient access to a series of highly functionalized scaffolds featuring trifluoromethanesufinyl motif on a stereogenic carbon.

para-Selective copper-catalyzed C(sp2)-H amidation/dimerization of anilides via a radical pathway.

Copper-catalyzed amidation/dimerization of anilides via regioselective C(sp2)-H functionalization is achieved. The para-selective amidation is accomplished on the anilide aromatic ring via a radical pathway leading to C-N bond formation in the presence of ammonium persulfate as a radical source/oxidant for the copper catalyst. The developed protocol tolerates a wide range of anilide substrates. The regioselectivity is confirmed by single-crystal X-ray studies.

Photoactivatable prodrug for simultaneous release of mertansine and CO along with a BODIPY derivative as a luminescent marker in mitochondria: a proof of concept for NIR image-guided cancer therapy.

Controlled and efficient activation is the crucial aspect of designing an effective prodrug. Herein we demonstrate a proof of concept for a light activatable prodrug with desired organelle specificity. Mertansine, a benzoansamacrolide, is an efficient microtubule-targeting compound that binds at or near the vinblastine-binding site in the mitochondrial region to induce mitotic arrest and cell death through apoptosis. Despite its efficacy even in the nanomolar level, this has failed in stage 2 of human clinical trials owing to the lack of drug specificity and the deleterious systemic toxicity. To get around this problem, a recent trend is to develop an antibody-conjugatable maytansinoid with improved tumor/organelle-specificity and lesser systematic toxicity. Endogenous CO is recognized as a regulator of cellular function and for its obligatory role in cell apoptosis. CO blocks the proliferation of cancer cells and effector T cells, and the primary target is reported to be the mitochondria. We report herein a new mitochondria-specific prodrug conjugate (Pro-DC) that undergoes a photocleavage reaction on irradiation with a 400 nm source (1.0 mW cm-2) to induce a simultaneous release of the therapeutic components mertansine and CO along with a BODIPY derivative (BODIPY(PPH3)2) as a luminescent marker in the mitochondrial matrix. The efficacy of the process is demonstrated using MCF-7 cells and could effectively be visualized by probing the intracellular luminescence of BODIPY(PPH3)2. This provides a proof-of-concept for designing a prodrug for image-guided combination therapy for mainstream treatment of cancer.

Stereoselective construction of deoxy-cruciferane alkaloids by NHC-catalyzed intramolecular annulation of homoenolate with quinazolinone.

Chiral N-heterocyclic carbene (NHC)-catalyzed intramolecular [3 + 2] annulation of enals with an unactivated imine moiety of quinazolinone via formal homoenolate cycloaddition has been demonstrated. It is an excellent approach for stereoselective syntheses of deoxy-cruciferane alkaloids comprising a biologically important pyrroloindoline scaffold. Notably, this is the first report on the NHC-catalyzed asymmetric intramolecular homoenolate annulation with cyclic N-acyl amidine.

Ru-Catalyzed Regioselective Cascade Annulation of Acrylamides with 2-Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters.

Ru-catalyzed regioselective cascade annulation of acrylamides with 2-alkynoates via aza-Michael/C-H activation sequence for the synthesis of various 6-oxo nicotinic acid esters is described. The regioselectivity of the protocol has been confirmed by performing silver mediated protodecarboxylation of the corresponding 6-oxo nicotinic acid to furnish 2-pyridone. The developed protocol is copper or silver salt-free and uses inexpensive, safe, and environmentally benign peroxide-based "oxone" as the sole oxidant. A redox-neutral version of the protocol is also demonstrated.

Transition-Metal-Free Regioselective One-Pot Synthesis of Aryl Sulfones from Sodium Sulfinates via Quinone Imine Ketal.

A novel, efficient, and regioselective transition-metal-free one-pot synthesis of aryl sulfones via the reactive quinone imine ketal intermediate is demonstrated using easily accessible bench-stable sulfinate salts. A broad range of functionality on p-anisidine substrates as well as sulfinate salts was tolerated under mild reaction conditions to provide the corresponding aryl sulfones in good to excellent yields.

Ruthenium-Catalyzed Regioselective Alkenylation/Tandem Hydroamidative Cyclization of Unmasked Quinazolinones Using Terminal Alkynes.

Ruthenium-catalyzed amide directed Csp2-H activation of the quinazolinone scaffold has been demonstrated, leading to the selective mono- or dialkenylation in moderate to good yields to achieve medicinally important stilbene containing quinazolinones. The terminal alkyne is utilized as a coupling partner, which resulted in the selective trans-alkene formation. Electron-deficient phenylacetylenes facilitate alkenylation followed by tandem hydroamidation of the newly generated trans-double bond to provide novel quinazolinone alkaloids related to the Luotonine class of natural products.

Silver-Mediated Oxidative Decarboxylative Intramolecular Asymmetric Radical Cyclization (Csp3-Csp2) via Memory of Chirality: Access to Circumdatin Alkaloids.

A novel silver-mediated oxidative decarboxylative intramolecular asymmetric radical cyclization has been developed to form a Csp3-Csp2 bond via memory of chirality. The application of the process has been demonstrated for the synthesis of the circumdatin class of alkaloids in high enantiopurity with retention of the configuration. The developed protocol is mild and works with an inexpensive silver catalyst in the absence of ligand, base, or additives. The involvement of a monoradical in the reaction has been established by trapping the radical intermediate.

Divergent Synthesis of Oxindolylidene Acetates and Spirooxindolopyrrolidones from Arynes.

A novel process for the preparation of various ( E)-oxindolylidene acetates using arynes and carbamoylpropiolates has been developed. The utility of this protocol is also further extended to the one-pot synthesis of complex spirooxindolopyrrolidones. This method provides a milder and transition-metal-free access to both of the target scaffolds in moderate to good yields.

Application of Sulfur Ylides in 1,2-Difunctionalization of Arynes via Insertion into a C-S σ-Bond.

A novel reactivity of sulfur ylides has been demonstrated in a transition-metal-free protocol to access ortho-substituted thioanisole derivatives by insertion of arynes into a C-S σ-bond in moderate to good yields. The reaction involves the formation of C-C and C-S bonds and consecutive breaking of two C-S bonds under operationally mild reaction conditions.

Diversification of Quinazolinones by Pd-Catalyzed C(sp3)-Acetoxylation.

The quinazolinone ring has been exploited as a directing group for C(sp3)-H functionalization for the first time. The proximal C-γ(sp3)-H bonds have been oxidized by palladium-catalyzed acetoxylation reaction. Various functional groups on the quinazolinone scaffold were tolerated to provide novel quinazolinone derivatives. The use of base was found to be crucial for the monoselective acetoxylations.

Synthesis of Methyl-Protected (±)-Chlorizidine A.

The first total synthesis of the methyl-protected (±)-chlorizidine A has been achieved in 10 steps. Pd-catalyzed decarboxylative coupling and late-stage oxidation were utilized to construct the 5H-pyrrolo[2,1-a]isoindol-5-one scaffold. Samarium(II) iodide mediated Reformatsky reaction and intramolecular Mitsunobu reactions were efficiently applied for the synthesis of the 2,3-dihydropyrrolizine ring system. Chlorizidine A is highly prone to degradation; hence, methyl-protected (±)-chlorizidine A was prepared.

Pd-Catalyzed Regioselective Mono-Arylation: Quinazolinone as the Inherent Directing Group for C(sp2)-H Activation.

The Pd-catalyzed quinazolinone-directed regioselective monoarylation of aromatic rings by C-H bond activation is developed. A broad substrate scope is demonstrated for both quinazolinone as well as diaryliodonium triflates. The use of a base was found to be crucial for this transformation, unlike for the known nitrogen-directed arylations. All of the novel quinazolinones of biological interest were synthesized by using the operationally simple Pd(II)-catalyzed arylation reaction.

Diversity-Oriented Synthesis of Spiroannulated Benzofuran-3-one Scaffold of Leptosphaerin C and Congeners via Aryne Insertion.

A concise synthesis of functionalized cyclohexenone-fused spirobenzofuran-3-ones under mild reaction conditions was developed. The reaction proceeds via insertion of aryne into the C-O bond followed by a regioselective intramolecular conjugate addition. The use of silyl-protected acid was crucial for the transformation. This protocol was successfully applied for the synthesis of leptosphaerin C core and its novel analogues.

Synthesis of o-Methyl Trifluoromethyl Sulfide Substituted Benzophenones via 1,2-Difunctionalization of Aryne by Insertion into the C-C Bond.

An efficient process for the preparation of valuable o-methyl trifluoromethyl sulfide substituted benzophenones has been developed. The transition-metal-free method features insertion of aryne into a C-C σ-bond under mild reaction conditions for the first time to achieve ortho-difunctionalized arenes containing a pharmaceutically important trifluoromethylthio functional group. A wide substrate scope has been demonstrated for the developed protocol.

Synthesis of Succinimide Derivatives by NHC-Catalyzed Stetter Reaction of Aromatic Aldehydes with N-Substituted Itaconimides.

An N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aromatic aldehydes with N-substituted itaconimides has been developed. A delicate balance between the Stetter reaction and the competing isomerization of the itaconimide double bond has been achieved in this operationally simple reaction to afford valuable new succinimide derivatives containing 1,4 and 1,5 dicarbonyl scaffolds in good to excellent yields. The reaction tolerates variable substituents on both aldehydes and N-substituted itaconimides.