Nucleophilic Vinylic Substitution Research Articles

Palladium-Catalyzed Defluorinative Alkylation of gem-Difluoroalkenes with Cyclopropanols: Stereoselective Synthesis of γ-Fluorinated γ,δ-Unsaturated Ketones.

A palladium-catalyzed defluorinative alkylation of gem-difluoroalkenes with cyclopropyl alcohols was developed. A range of γ-fluorinated γ,δ-unsaturated ketones were constructed in good yields with excellent stereoselectivities. In addition, by base-mediated intramolecular nucleophilic vinylic substitution (SNV), the products could be further transformed to 2,5-dimethylenetetrahydrofurans and analogues with excellent stereoselectivities.

Insights into the Friedel-Crafts Benzoylation of N-Methylpyrrole inside the Confined Space of the Self-Assembled Resorcinarene Capsule.

Friedel-Crafts benzoylation of N-methylpyrrole 2 can run inside the confined space of the hexameric resorcinarene capsule C. The bridged water molecules at the corner of C act as H-bonding donor groups to polarize the C-Cl bond of benzoyl chlorides 3a-f. Confinement effects on the regiochemistry of the FC benzoylation of N-methylpyrrole are observed. The nature of the para-substituents of 3a-f and their ability to establish H-bonds with the water molecules of C work synergistically with the steric constrictions imposed by the capsule to drive the regiochemistry of products 4a-f. QM investigations indicate that inside the cavity of C, the FC benzoylation of 2 has a bimolecular concerted SN2 mechanism, appropriately, above-plane nucleophilic vinylic substitution (SNVπ)─supported by H-bonding interactions between water molecules and both the leaving Cl atom and the carbonyl group.

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6' Steric Bulk of Cinchona Alkaloid.

A C6' bulky substituted quinine-catalyzed SNV reaction between 3-substituted oxindole and (E)-3-(nitromethylene)-oxindole was developed. This enantioselective C(sp3)-C(sp2) coupling furnished bisoxindole scaffolds featuring a vinyl-substituted all-carbon quaternary stereocenter with high stereoselectivities. In addition, the gram-scale synthesis and synthetic post-transformations were conducted to demonstrate the potential synthetic usefulness.

Nickel-Catalyzed Cross-Electrophile Ring Opening/gem-Difluoroallylation of Aziridines.

Herein we report a nickel-catalyzed regioselective cross-electrophile ring opening reaction of sulfonyl-protected aziridines with trifluoromethyl-substituted alkenes as the gem-difluoroallylating agents, providing a new and efficient entry to prepare gem-difluorobishomoallylic sulfonamides. Moreover, the scaffold of 6-fluoro-1,2,3,4-tetrahydropyridine can be constructed starting from the ring opening products via NaH-mediated intramolecular defluorinative nucleophilic vinylic substitution.

New synthesis of cycloalca[<i>с</i>]nicotinoamide and nitrile derivatives

Nitriles and amide of nicotinic acid were synthesized by Knoevenagel reactions, nucleophilic vinyl substitution (SNVin), and alkylation. The structure of (1-amino-5-phenyl-5,6,7,8-tetrahydrothieno[2,3- c ]isoquinolin-2-yl)(phenyl)methanone was studied by X-ray analysis.

A One-Pot Domino Reaction Providing Fluorinated 5,6-Dihydro-1,2-thiazine 1-Oxides from Sulfoximines and 1-Trifluoromethylstyrenes.

N-Trifluoroacetylated (N-TFA) sulfoximines react with 1-trifluoromethylstyrenes in a one-pot domino reaction to give fluorinated 5,6-dihydro-1,2-thiazine 1-oxides in good to high yields. The process involves three sequential reaction steps that can be characterized as (1) nucleophilic allylic substitution (SN2'), (2) hydrolysis, and (3) intramolecular nucleophilic vinylic substitution (SNV). The products can further be modified by defluorination. The molecular structure of the resulting product was confirmed by X-ray crystallographic analysis.

Preparation of Vinylphosphonates from Ketones Promoted by Tf2O.

An efficient triflic anhydride promoted phosphorylation of ketone was disclosed, and vinylphosphorus compounds were prepared under solvent- and metal-free conditions. Both aryl and alkyl ketones could perform smoothly to give vinyl phosphonates in high to excellent yields. In addition, the reaction was easy to carry out and easy to scale up. Mechanistic studies suggested that this transformation might involve nucleophilic vinylic substitution or a nucleophilic addition-elimination mechanism.

A new route to produce chitosan derivatives: nucleophilic vinylic substitution with ethoxymethylenemalononitrile

AbstractChitosan (Ch) is a polysaccharide obtained from chitin: a renewable, nontoxic, biocompatible biomolecule that constitutes the second most abundant natural polymer on the planet. The presence of amino groups in the chitosan polymer chains allows one to change the physicochemical properties of the natural polymer. In this work, we prepared a chitosan derivative (ChMM) with ethoxymethylenemalononitrile (EMM) through a nucleophilic vinylic substitution (SNV), changing the experimental conditions of stoichiometry, solvent (ethanol, dimethylsulfoxide (DMSO)) and reaction time (3 and 6 h). ChMM was characterized by Fourier transform infrared spectroscopy (FTIR), solid‐state 13C NMR, elemental analysis (EA), thermogravimetry (TG), scanning electron microscopy (SEM) and X‐ray diffraction (XRD). The FTIR and 13C NMR results confirm the success of the reaction, showing a sharp peak at 2213 cm−1 corresponding to the stretching of the C–N bond and additional signals at 52 and 166 ppm, respectively. The degree of substitution (DS) was calculated from EA and the results obtained show that sample modified with a [Ch]/[EMM] molar ratio of 1:2 over 3 h in DMSO presented the better result (DS = 0.91). ChMM did not show a considerable change in morphology (SEM) and thermal stability (TG). The insertion of methylenemalononitrile groups led to a decrease in the crystallinity index of chitosan derivatives (XRD). ChMM showed good ability to remove dyes in acidic and basic media (pH 5, 7, 9), and for crystal violet and safranin dyes the removal percentage surpassed 70%. © 2022 Society of Industrial Chemistry.

One-pot synthesis of cyclobutenecarboxylate derivatives via olefinic C-F bond functionalization of gem-difluoroalkenes

A one-pot approach which provides a series of cyclobutenecarboxylates in moderate to excellent yields has been developed. This strategy involves visible light-induced [2+2]-photocycloaddition of quinolinones with 1-bromo-1-trifluoromethylethene, followed by tandem sodium alkoxide-promoted elimination, nucleophilic vinylic substitution and hydrolysis. The in-situ generated gem-difluoroalkene is the key intermediate to achieve this transformation. Excellent functional group compatibility and high regioselectivity render the method flexibility and practicability. It is worthy to note that cyclobutenecarboxylic acid can be easily obtained in this protocol, further demonstrating the synthetic potential of this strategy.

Nucleophilic Vinylic Substitution (SNV) of Trisubstituted Monofluoroalkenes for the Synthesis of Stereodefined Trisubstituted Alkenes and Divinyl Ethers.

We herein describe a nucleophilic vinylic substitution (SNV) of trisubstituted monofluoroalkenes with excellent stereocontrol (d.r. > 99:1). Starting from (E)-β-monofluoroacrylates, various trisubstituted (E)-alkenes containing O/N/S-substituent groups at the vinylic position can be obtained under simple conditions. Furthermore, (E,E)-divinyl ethers can be generated through dimerization of the monofluoroalkenes, triggered by adventitious water in the reaction mixture.

β-chlorovinylaldehydes as intermediates in the synthesis of new substituted β–fluoroalkoxyvinyl aldehydes and corresponding alcohols

A convenient synthesis of a series of new β-fluoroalkoxyvinyl aldehydes and their corresponding alcohols from β-chloro-α,β-unsaturated aldehydes was developed. The etherification reaction and the carbonyl reduction were successfully achieved, affording the desired products in good yields. The mechanism of the nucleophilic vinylic substitution reaction of the 3-chloro-3-phenylacrylaldehyde has been studied using DFT methods. IRC analysis shows the presence of a hidden intermediate, in agreement with a one kinetic step two-stage process. The isomerization of hidden intermediate Z-3-chloro-3-phenylacrylaldehyde (IntZ) into hidden intermediate E-3-chloro-3-phenylacrylaldehyde (IntE) was explained in terms of the small energy gap difference between the two intermediates IntZ and IntE and the thermodynamic stability of stereoisomer E compared to Z.

Preparation, Structure, and Reactivity of Pseudocyclic β‐Trifluorosulfonyloxy Vinylbenziodoxolone Derivatives

AbstractPseudocyclic β‐trifluorosulfonyloxy vinylbenziodoxolones were prepared starting from hydroxybenziodoxolones and alkynes in the presence of trifluoromethanesulfonic acid. The reaction of these compounds with azide anion leads to β‐azido vinylbenziodoxolones as products of vinylic nucleophilic substitution in which addition‐elimination reactions occur and the double bond configuration is retained. The structures of β‐trifluorosulfonyloxy vinylbenziodoxolone and β‐azido vinylbenziodoxolone were established by single crystal X‐ray diffraction.magnified image

Disrotatory Ring-Opening of Furans Gives Stereocontrol.

The ring-opening of 2-methylfuran and 2,3-dihydro-5-methylfuran catalyzed by the Lewis acid catalyst tris(pentafluorophenyl)borane in the presence of hydrosilanes was studied using quantum chemical methods. In a previous study, it was suggested that the stereoselective formation of the product is due to a nucleophilic vinylic substitution (SNV) during the reaction. Our calculations show that the pathway involving the SNV reaction is energetically not accessible. Instead, the intramolecular C-O bond cleavage is found to be much more favorable in energy for the ring opening reaction. The experimentally observed excellent stereoselectivity toward the Z-isomer product originates from an intrinsic preference of the furan ring to couple the C-O bond cleavage with a disrotatory motion of the oxygen and carbon fragments. This stereoselective feature is naturally programmed into the furan ring manifold and should be generally exploitable for engineering stereoselective ring-opening processes of bioderived furans.

Selective Hydrodefluorination of Hexafluoropropene to Industrially Relevant Hydrofluoroolefins

AbstractThe selective hydrodefluorination of hexafluoropropene to HFO‐1234ze and HFO‐1234yf can be achieved by reaction with simple group 13 hydrides of the form EH3 ⋅ L (E=B, Al; L=SMe2, NMe3). The chemoselectivity varies depending on the nature of the group 13 element. A combination of experiments and DFT calculations show that competitive nucleophilic vinylic substitution and addition‐elimination mechanisms involving hydroborated intermediates lead to complementary selectivities.magnified image

Regio‐, Diastereo‐, and Enantioselective Organocatalytic Addition of 4‐Substituted Pyrazolones to Isatin‐Derived Nitroalkenes

Hydroquinine 2,5‐diphenyl‐4,6‐pyrimidinediyl diether [(DHQ)2Pyr] catalyzed the regio‐, diastereo‐, and enantioselective addition of 4‐substituted pyrazolones to isatin‐derived nitroalkenes, providing a variety of chiral alkenylpyrazolone adducts containing a tetrasubstituted stereocenter bearing an oxindole moiety with excellent yields, regioselectivity, and diastereoselectivity, as well as a moderate enantioselectivity (up to 98 % yield, > 20:1 E/Z ratio dr and 78 % ee). The reaction harnesses a nitroalkene as an alkenylating agent through a Nucleophilic Vinylic Substitution (SNV) reaction.

Regio‐ and Stereoselective Synthesis of 3‐Pyrazolylidene‐2‐oxindole Compounds by Nucleophilic Vinylic Substitution of (E)‐3‐(Nitromethylene)indolin‐2‐one

AbstractA highly regio‐ and stereoselective synthesis of 3‐alkylidene‐2‐oxindoles has been described through a nucleophilic vinylic substitution (SNV) of (E)‐3‐(nitromethylene)indolin‐2‐one using pyrazol‐3‐ones as nucleophiles and Et3N as a base. The reaction affords selectively the Z‐isomer when pyrazol‐3‐ones without substituents at the 4 position are used. While the reaction is E‐selective with 4‐substituted pyrazolones. The stereoselectivity (up to >20:1) and the yields (up to 98%) are very high under mild reaction conditions.magnified image

New Syntheses of Naphthostyryl Derivatives via Nucleophilic Vinylic Substitution

New substituted naphthostyryl derivatives have been synthesized by nucleophilic vinylic substitution reactions and converted to the corresponding N-alkyl derivatives by treatment with alkyl halides.

Organocatalytic C-F Bond Activation with Alanes.

Hydrodefluorination reactions (HDF) of per- and polyfluorinated olefins and arenes by cheap aluminum alkyl hydrides in non-coordinating solvents can be catalyzed by O and N donors. TONs with respect to the organocatalysts of up to 87 have been observed. Depending on substrate and concentration, high selectivities can be achieved. For the prototypical hexafluoropropene, however, low selectivities are observed (E/Z≈2). DFT studies show that the preferred HDF mechanism for this substrate in the presence of donor solvents proceeds from the dimer Me4 Al2 (μ-H)2 ⋅THF by nucleophilic vinylic substitution (SN V)-like transition states with low selectivity and without formation of an intermediate, not via hydrometallation or σ-bond metathesis. In the absence of donor solvents, hydrometallation is preferred but this is associated with inaccessibly high activation barriers at low temperatures. Donor solvents activate the aluminum hydride bond, lower the barrier for HDF significantly, and switch the product preference from Z to E. The exact nature of the donor has only a minimal influence on the selectivity at low concentrations, as the donor is located far away from the active center in the transition states. The mechanism changes at higher donor concentrations and proceeds from Me2 AlH⋅THF via SN V and formation of a stable intermediate, from which elimination is unselective, which results in a loss of selectivity.

ChemInform Abstract: One‐Pot Syntheses of N‐(α‐Fluorovinyl)azole Derivatives from N‐(Diphenylmethylene)‐2,2,2‐trifluoroethanamine.

AbstractN‐(α‐fluorovinyl)azoles are prepared in moderate to good yield by the reaction of N‐(diphenylmethylene)‐2,2,2‐trifluoroethanamine with various N—H‐containing heterocycles in the absence of any metal catalyst under mild conditions via vinylic nucleophilic substitution reaction.

Alkyl-and arylsulfanyl-substituted unsaturated carbonyl compounds

ABSTRACTA method for the synthesis of captodative sulfanyl enals, enones and enoates via nucleophilic vinylic substitution of corresponding halogen-bearing derivatives has been developed. The one-pot treatment of the haloenoates, haloenones or haloenals with thiols in the presence of organic base leads either to vicinal dithiosubstituted carbonyl-bearing compound or captodative systems with good to excellent yield. The major reaction direction strongly depends on the type of base used.