Internal Nucleophile Research Articles

Electrochemical Synthesis of C(sp3)-Rich Heterocycles via Mesolytic Cleavage of Anodically Generated Aromatic Radical Cations.

Herein we report an electrochemical deconstructive functionalization approach for the synthesis of C(sp3)-rich heterocycles. The reaction proceeds via the mesolytic cleavage of anodically generated aromatic radical cations and the trapping of formed carbocation intermediates with internal nucleophiles. The method has been demonstrated across various arylalcohol substrates to access a diverse range of C(sp3)-rich heterocycles including tetrahydrofuran, tetrahydropyran, and pyrrolidine scaffolds (26 examples). The electrochemical method was demonstrated on a 5 mmol scale via single pass continuous flow, which utilized lower supporting electrolyte concentration and exhibited increased productivity in relation to the batch process.

Stereospecific Indium(III)‐Catalysed Tandem Cycloisomerization of Functionalized 1,6‐enynes: Scope and Mechanistic Insights

AbstractTandem cycloisomerization reactions of functionalized 1,6‐enynes under indium(III) catalysis are described. This atom‐economic transformation proceeds smoothly with 5‐exo‐dig regioselectivity using commercial In(III) halides and 1,6‐enynes furnished with alcohol, carboxylic acid or amine functional groups to give bicyclic structures in good yields and diastereoselectivities. The reaction with enynals involves a three–step mechanism to give an oxatricycle and a conjugated 1,3‐diene. In the absence of the internal nucleophile the enyne cycloisomerization evolves through a skeletal rearrangement or a cyclopropanation reaction after the regioselective 5‐exo‐dig cyclization. The 1,6‐enyne cycloisomerization is stereospecific and the stereoselectivity appears to be independent of the internal nucleophile. Experimental data support a common reaction mechanism involving an initial alkyne electrophilic π‐coordination of In(III) followed by Markovnikov electrophilic alkene addition and ring‐closure by nucleophilic attack. DFT studies hold up a stepwise mechanism involving the formation of a chiral non‐classical carbocation intermediate that determines the diastereoselectivity of this tandem cycloisomerization reaction.

Diverting the 5-exo-Trig Oxypalladation to Formally 6-endo-Trig Fluorocycloetherification Product through 1,2-O/Pd(IV) Dyotropic Rearrangement.

Pd-catalyzed cyclizative functionalization of γ-hydroxyalkenes affords tetrahydrofuran derivatives via a key 5-exo-trig oxypalladation step. Herein, we report a palladium(II)-catalyzed, Selectfluor-mediated formal 6-endo-trig fluorocycloetherification of γ-hydroxyalkenes for the synthesis of functionalized tetrahydropyrans. Mechanistically, an σ-alkyl-Pd(II) intermediate resulting from the 5-exo-trig oxypalladation process is isolated and characterized by X-ray crystallographic analysis. Its oxidation with Selectfluor to Pd(IV) triggers the chemoselective 1,2-O/Pd(IV) dyotropic rearrangement affording, after C-F bond-forming reductive elimination, the tetrahydropyrans with concurrent generation of a tertiary carbon-fluorine bond. The occurrence of this 1,2-positional interchange is further evidenced by trapping the rearranged quaternary C(sp3)-Pd bond by an internal nucleophile that is materialized by the development of a Pd(II)-catalyzed oxidative bis-heterocyclization of alkenes.

Synthesis of Tetrahydrofurans and Pyrrolidines by Copper-Catalyzed Oxy/Aminoarylation of Alkenes.

An efficient copper-catalyzed inter/intramolecular oxy/aminoarylation of γ-hydroxy/aminoalkenes with diaryliodonium triflates is reported. Simple activation of these arylating agents with copper(II) triflate in dichloromethane triggers a smooth activation of the alkene, which is simultaneously trapped by the internal nucleophile, yielding, depending upon its nature, a range of highly substituted tetrahydrofurans and pyrrolidines. The cyclization was moreover found to be stereospecific, with diastereoisomeric alkenes yielding diastereoisomers of the cyclized product, and could be extended to oxyalkynylation.

Asymmetric Fluorofunctionalizations with Carboxylate-Based Phase-Transfer Catalysts.

Fluorine is an attractive element in the field of pharmaceutical and agrochemical chemistry due to its unique properties. Considering the chiral environment in nature, where enantiomers often show different biological activities, the introduction of fluorine atom(s) into organic molecules to make chiral fluorinated compounds is an important subject. Herein, we describe the story of the development of our chiral carboxylate-based phase-transfer catalysts and their applications for asymmetric fluorocyclizations of alkenes bearing a carboxylic acid, an amide, and an oxime as an internal nucleophile with a dicationic fluorinating reagent, Selectfluor. We also describe dearomative fluorinations of indole derivatives, 2-naphthols, and resorcinols.

Merging Rh-Catalyzed C-H Functionalization and Cascade Cyclization to Enable Propargylic Alcohols as Three-Carbon Synthons.

Reported herein is a reactivity of propargyl alcohols as "Three-Carbon Synthons" in a Rh(III)-catalyzed C-H functionalization of acetanilides, leading to the synthesis of core structures of isocryptolepine, γ-carbolines, dihydrochromeno[2,3-b]indoles, and diindolylmethanes (DIM) derivatives. The transformation involves a rhodium(III)-catalyzed C-H functionalization and heteroannulation to yield indoles followed by a cascade cyclization with both external and internal nucleophiles to afford diverse products. The role of the hydroxy group, the key function of the silver additive, the origin of the reverse regioselectivity and the rate-determining step, are rationalized in conformity with the combination of experimental, noncovalent interaction analysis and DFT studies. This protocol is endowed with several salient features, including one-pot multistep cascade approach, exclusive regioselectivity, good functional group tolerance and synthesis of variety of molecular frameworks.

Synthesis of Phenanthrene‐Based Polycycles by Gold(I)‐Catalyzed Cyclization of Biphenyl‐Embedded Trienynes

AbstractGold(I)‐catalyzed cyclization of o‐alkenyl‐o’‐alkynylbiaryls in the presence of external or internal nucleophiles provides a straightforward access to phenanthrene‐based polycycles, which are of considerable interest in materials science. Thus, their reactions with alcohols yield functionalized dihydrophenanthrenes, in a process that can also be carried out intramolecularly, to provide phenanthrene‐derived heteropolycyclic compounds. Moreover, benzo[b]triphenylenes can be synthesized from o‐methoxyvinyl‐o’‐alkynylbiaryls, in a reaction in which an (hetero)aryl substituent at the triple bond acts as an internal nucleophile.magnified image

Disulfide Isomerization in nDsbD-DsbC Complex - Exploring an Internal Nucleophile Mediated Reaction Pathway.

The disulfide bond redox chemistry of proteins is believed to be mostly governed by the proton motive force. The nucleophilic and α-elimination mechanisms are also found to supplement the formation and scission of the S-S bonds. On these grounds, the possibility for an internal nucleophile assisted disulfide bond formation in the nDsbD-DsbC complex was proposed way back. Using QM/MM MD metadynamics simulations, we explore the feasibility of the proposed mechanism. Our simulations highlight the formation of the internal nucleophile Tyr42 O- and Tyr40 O- which further generates Cys103 S- necessary for the disulfide bond formation in nDsbD. Our results illustrate how the isomerase DsbC is functionally activated by nDsbD in gram-negative bacteria. Also, we foresee that the results will be important for modelling anti-bacterial compounds based on nDsbD.

A Visible Light Ru-Catalyzed Photoredox Access to Substituted Dihydrofurans.

An efficient, visible light Ru(bpy)3Cl2-catalyzed method for the preparation of 2,3-dihydrofurans is reported. This approach employs 2-bromoketoesters as radical precursors and alkyl enol ethers as acceptors. The photoredox cycle furnishes an oxonium ion that is captured by an internal nucleophile to render the corresponding dihydrofurans. Moreover, the obtained products contain a versatile acetal moiety at C-2, allowing its transformation into a diverse variety of heteroaromatic and nonaromatic compounds. This method could serve as an important tool in the synthesis of complex tetrahydro- and dihydrofurans as well as heteroaromatic structures.

Towards solvent regulated self-activation of N-terminal disulfide bond oxidoreductase-D.

N-terminal disulfide bond oxidoreductase-D (nDsbD), an essential redox enzyme in Gram-negative bacteria, consists of a single disulfide bond (Cys103-Cys109) in its active site. The enzymatic functions are believed to be regulated by an electron transfer mediated redox switching of the disulfide bond, which is vital in controlling bacterial virulence factors. In light of the disulfide bond's inclination towards nucleophilic cleavage, it is also plausible that an internal nucleophile could second the existing electron transfer mechanism in nDsbD. Using QM/MM MD metadynamics simulations, we explore different possibilities of generating an internal nucleophile near the nDsbD active site, which could serve as a fail-over mechanism in cleaving the disulfide bond. The simulations show the formation of the internal nucleophile Tyr42O- (F ≈ 9 kcal mol-1) and its stabilization through the solvent medium. The static gas-phase calculations show that Tyr42O- could be a potential nucleophile for cleaving the S-S bond. Most strikingly, it is also seen that Tyr42O- and Asp68OH communicate with each other through a proton-hole like water wire (F ≈ 12 kcal mol-1), thus modulating the nucleophile formation. Accordingly, we propose the role of a solvent in regulating the internal nucleophilic reactions and the subsequent self-activation of nDsbD. We believe that this could be deterministic while designing enzyme-targeted inhibitor compounds.

Dibromo-BODIPY as an Organic Photocatalyst for Radical-Ionic Sequences.

A new dibrominated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is reported as a new metal-free photocatalyst. This BODIPY showed similar optoelectronic, electrochemical, and performance properties to those of Ru(bpy)3Cl2, one of the most common photocatalysts in a known radical-ionic transformation, such as the formation of 1,4-dicarbonyl compounds. Moreover, additional sequences in which the generated oxonium ion is trapped by an internal nucleophile were developed using this BODIPY photocatalyst. These new sequences allowed the straightforward preparation of γ-alkoxylactones, monoprotected 1,4-ketoaldehydes, and dihydrofurans. This new catalyst, the methodology, and the forged functional groups could be important tools in organic synthesis.

Synthesis of 6-Membered-Ring Fused Thiazine-Dicarboxylates and Thiazole-Pyrimidines via One-Pot Three-Component Reactions.

A facile and efficient one-pot three-component reaction method for the synthesis of thiazine-dicarboxylates is reported. Reaction of an isocyanide and dialkyl acetylenedicarboxylate with 2-amino-4H-1,3-thiazin-4-one derivatives containing both an acidic proton and an internal nucleophile gave the products in good yields of 76–85%. The reactivity of dialkyl acetylenedicarboxylates was further tested in the synthesis of thiazole-pyrimidines where a two-component reaction of 2-aminothiazole with dialkyl acetylenedicarboxylates was successfully converted to a more efficient three-component reaction of a thiourea, α-haloketone and dialkyl acetylenedicarboxylate (DMAD/DEtAD) to give thiazole-pyrimidines in good yields of 70–91%.

Azetidiniums: Ring‐Expansion to Pyrrolidines, Piperidines, Azepanes, and Azocanes

The 4‐membered ring in bicyclic azetidiniums, e.g. 1‐azabicyclo[2.n.0]alkanes (n = 1–4), can be efficiently transformed to larger rings. This minireview focuses on the ring‐expansion of these azetidiniums to five‐ and eight‐membered nitrogen containing heterocycles (pyrrolidines, piperidines, azepanes and azocanes). The ring‐expansion is induced by nucleophiles which can be internal nucleophiles (leaving groups), or external nucleophiles.

Selenophosphoramide-catalyzed diamination and oxyamination of alkenes.

A new selenophosphoramide-catalyzed diamination of terminal- and trans-1,2-disubstituted olefins is presented. Key to the success of this transformation was the introduction of a fluoride scavenger, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to prevent a competitive syn-elimination pathway, as was the use of a phosphoramide ligand on selenium to promote the desired substitution reaction. A screen of catalysts revealed that more electron-rich phosphine ligands resulted in higher yields of the desired product, with selenophosphoramides giving the optimal results. A broad range of substrates and functional groups were tolerated and yields were generally good to excellent. For (E)-1,2-disubstituted olefins, diastereoselectivities were always high, giving exclusively anti products. The conditions were also applied to substrates bearing internal nucleophiles such as esters and carbonates, giving rise to 1,2-aminoesters and cyclic carbonates, respectively.

Intramolecular 6-endo-dig-Cyclization of Ethyl 5-Aminomethyl-4-(1,2,3-thiadiazol-4-yl)furan-2-carboxylate

The reaction of 5-aminomethyl-4-(1,2,3-thiadiazol-4-yl)furan-2-carboxylic acid ethyl ester with bases has given ethyl 5-sulfanylidene-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-carboxylate as a result of intramolecular 6-endo-dig-cyclization of thioketene generated in situ with an internal CH2NH2 nucleophile. The obtained ester has been alkylated with iodomethane at the sulfur atom to form ethyl 5-methylsulfanyl-4,7-dihydrofuro[2,3-c] pyridine-2-carboxylate. The Hantzsch reaction with ω-bromoacetophenone has resulted in the formation of 7-ethoxycarbonyl-3-phenylfuro[3,2-d[1,3]thiazolo[3,2-a]pyridin-4-ium bromide.

The Effect of the ortho Nitro Group in the Solvolysis of Benzyl and Benzoyl Halides.

A kinetic study was carried out on the solvolysis of o-nitrobenzyl bromide (o-isomer, 1) and p-nitrobenzyl bromide (p-isomer, 3), and o-nitrobenzoyl chloride (o-isomer, 2) in a wide range of solvents under various temperatures. In all of the solvents without aqueous fluoroalcohol, the reactions of 1 were solvolyzed at a similar rate to those observed for 3, and the reaction rates of 2 were about ten times slower than those of the previously studied p-nitrobenzoyl chloride (p-isomer, 4). For solvolysis in aqueous fluoroalcohol, the reactivity of 2 was kinetically more reactive than 4. The l/m values of the extended Grunwald–Winstein (G–W) equation for solvolysis of 1 and 2 in solvents without fluoroalcohol content are all significantly larger than unity while those in all the fluoroalcohol solvents are less than unity. The role of the ortho-nitro group as an intramolecular nucleophilic assistant (internal nucleophile) in the solvolytic reaction of 1 and 2 was discussed. The results are also compared with those reported earlier for o-carbomethoxybenzyl bromide (5) and o-nitrobenzyl p-toluenesulfonate (7). From the product studies and the activation parameters for solvolyses of 1 and 2 in several organic hydroxylic solvents, mechanistic conclusions are drawn.

Photocatalytic Cleavage of Aryl Ether in Modified Lignin to Non-phenolic Aromatics

Depolymerization of lignin meets the difficulty in cleaving the robust aryl ether bond. Herein, through installing an internal nucleophile in the β-O-4′ linkage, the selective cleavage of aryl ethe...

Regiochemistry Control by Bipyridine Substituents in the Deprotonation of ReI and MoII N-Alkylimidazole Complexes.

Compounds containing N-alkylimidazoles (N-RIm) and 4,4'-disubstituted 2,2'-bipyridines (4,4'-R'2 bipy) coordinated to cationic {Mo(η3 -C4 H7 )(CO)2 } and {Re(CO)3 } fragments undergo deprotonation of the C2-H group of the N-RIm ligands in their reactions with KN(SiMe3 )2 . The resulting internal nucleophile adds either to one pyridyl ring, which becomes dearomatized and can undergo ring opening in the subsequent reaction with excess MeOTf, or to the metal center, yielding imidazol-2-yl complexes, which in turn add HOTf or MeOTf, affording N-heterocyclic carbene complexes. Which pathway is followed is dictated by the metal and the nature of the imidazole (R) and bipyridine (R') substituents. For ReI compounds, addition to pyridine is found with R'=tBu and OMe, whereas for R=Me and R'=NMe2 , imidazolyl formation is preferred. Coordination of 4,7-Cl2 -1,10-phenanthroline to MoII favors C-C coupling, in contrast to the analogous parent bipy or phenanthroline complexes, for which formation of the imidazol-2-yl complexes had been found. DFT calculations showed the theoretically expected products in each case, and following their predictions new types of products were obtained experimentally.

Iron-Promoted Intramolecular Cascade Cyclization for the Synthesis of Selenophene-Fused, Quinoline-Based Heteroacenes.

Herein, we report the Fe(III)-promoted linear intramolecular cascade cyclization of 1,3-diyne and 1,3,5-triyne for the construction of selenophene-fused, quinoline-based heteroacene scaffolds. In one step, 1,3-diyne and 1,3,5-triyne were cyclized via diversified internal nucleophiles by using diorganyl diselenides. The diorganyl diselenide plays dual role, one as a cyclizing agent and second as insertion of one and/or two selenium atom and one R'-Se group in the final product. This is highly important in terms of atom economy. Diversified internal nucleophiles were used to afford quinoline- and acridine-based cores. The synthesized selenophene-fused derivatives showed λmax, Fmax, and Φf values in the range from 370-411 nm, 427-472 nm, and 0.003-0.059, respectively, in dichloromethane solvent.

Synthesis of Chiral Polyhydroxylated Benzimidazoles by a Tandem Radical Fragmentation/Cyclization Reaction: A Straight Avenue to Fused Aromatic-Carbohydrate Hybrids.

The synthesis of benzimidazole-fused iminosugars through a tandem β-fragmentation-intramolecular cyclization reaction is described. The use of the benzimidazole ring as the internal nucleophile and the use of phenyliodosophthalate (PhI(Phth)), a new metal-free and low toxic hypervalent iodine reagent, are the most remarkable novelties of this synthetic strategy. With this approach, we have demonstrated the usefulness of the fragmentation of anomeric alkoxyl radicals promoted by the PhI(Phth)/I2 system for the preparation of new compounds with potential interest for both medicinal and synthetic chemists.