Temperature Stable Ion Exchange Resins as Catalysts for the Manufacturing of Vitamin Precursors by Aldol Reaction.

This study explores the potential of robust, strongly basic type I ion exchange resins-specifically, Amberlyst® A26 OH and Lewatit® K 6465-as catalysts for the aldol condensation of citral and acetone, yielding pseudoionone. Emphasis is placed on their long-term stability and commendable performance in continuous operational settings. The aldol reaction, which traditionally is carried out using aqueous sodium hydroxide as the catalyst, holds the potential for enhanced sustainability and reduced waste production through the use of basic ion exchange resins in heterogeneous catalysis. Density Functional Theory (DFT) calculations are employed to investigate catalyst deactivation mechanisms. The result of these calculations indicates that the active sites of Amberlyst® A26 OH are cleaved more easily than the active sites of Lewatit® K 6465. However, the experimental data show a gradual decline in catalytic activity for both resins. Batch experiments reveal Amberlyst® A26 OH's active sites diminishing, while Lewatit® K 6465 maintains relative consistency. This points to distinct deactivation processes for each catalyst. The constant count of basic sites in Lewatit® K 6465 during the reaction suggests additional factors due to its unique polymer structure. This intriguing observation also highlights an exceptional temperature stability for Lewatit® K 6465 compared to Amberlyst® A26 OH, effectively surmounting one of the prominent challenges associated with the utilization of ion exchange resins in catalytic applications.

Shedding Light on the Interactions of Hydrocarbon Ester Substituents upon Formation of Dimeric Titanium(IV) Triscatecholates in DMSO Solution.

The dissociation of hierarchically formed dimeric triple lithium bridged triscatecholate titanium(IV) helicates with hydrocarbyl esters as side groups is systematically investigated in DMSO. Primary alkyl, alkenyl, alkynyl as well as benzyl esters are studied in order to minimize steric effects close to the helicate core. The 1 H NMR dimerization constants for the monomer-dimer equilibrium show some solvent dependent influence of the side chains on the dimer stability. In the dimer, the ability of the hydrocarbyl ester groups to aggregate minimizes their contacts with the solvent molecules. Due to this, most solvophobic alkyl groups show the highest dimerization tendency followed by alkenyls, alkynyls and finally benzyls. Furthermore, trends within the different groups of compounds can be observed. For example, the dimer is destabilized by internal double or triple bonds due to π-π repulsion. A strong indication for solvent supported London dispersion interaction between the ester side groups is found by observation of an even/odd alternation of dimerization constants within the series of n-alkyls, n-Ω-alkenyls or n-Ω-alkynyls. This corresponds to the interaction of the parent hydrocarbons, as documented by an even/odd melting point alternation.

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion.

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described. The CCR generally requires dual Ni catalysis and MgBr2 promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr2 in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl2 as a precatalyst and MgBr2 with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh3 )2 Cl2 as a precatalyst and ZnPh2 does not require salt promotion and is stereoretentive. The reaction with Zn(CH2 SiMe3 )2 , however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh3 )2 Cl2 . Ni-Catalyzed and MgBr2 -promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh2 and Zn(CH2 SiMe3 )2 is stereoretentive with Ni(dppp)Cl2 and Ni(PPh3 )2 Cl2 . CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.

Organocatalytic Asymmetric Allylic Alkylations of Sulfoximines.

An enantio- and regioselective allylic alkylation of sulfoximines with Morita-Baylis-Hillman carbonates was developed. The asymmetric reaction is directed by a quinidine-derived organocatalyst providing a range of optically active α-methylene ß-sulfoximidoyl esters in high yields (up to 93%) with good to excellent enantiomeric excesses (up to 95%) under mild reaction conditions.

A Helicate-Based Three-State Molecular Switch.

The control of structural transformations triggered by external signals is important for the development of novel functional devices. In the present study, it is demonstrated that helicates can be designed to structurally respond to the presence of different counterions and to adopt either a compressed or an expanded structure. Reversible switching is not only possible between those two states, furthermore, the twist of the aggregate also can be controlled. Thus, three out of four possible states of a helicate (expanded/left-handed, expanded/right-handed, compressed/left-handed) based on an enantiomerically pure ester bridged dicatecholate ligand are specifically addressed by introduction, exchange, or removal of countercations. This approach is used to reversibly switch between the different states or to successively address them.

Rhodium-Catalyzed [4 + 3] Annulations of Sulfoximines with α,ß-Unsaturated Ketones Leading to 1,2-Benzothiazepine 1-Oxides.

A Cp*Rh(III) complex has been used as catalyst for the preparation of unprecedented 1,2-benzothiazepine 1-oxides by [4 + 3] cyclization of NH-sulfoximines with α,ß-unsaturated ketones. For a wide range of substrates with various functional groups, moderate to good product yields were obtained.

N-Heterocyclic carbene-catalyzed [4+2] annulation of ß-methyl enals and cyclic trifluoromethyl ketimines for the asymmetric synthesis of dihydroquinazolinone derivatives.

The enantioselective oxidative N-heterocyclic carbene-catalyzed [4+2] annulation reaction of ß-methyl enals and cyclic trifluoromethyl ketimines has been developed. A series of biologically interesting dihydroquinazolinone derivatives bearing a trifluoromethyl group and a tetrasubstituted stereocenter are efficiently prepared with very good yields and excellent stereoselectivities.

Experimental and Computational Studies of the Structure of Sulfonimidoyl Vinyllithiums.

tBuCH=C(Li)S(O)(NSO2 Tol)Ph⋅L (L=2THF, TMEDA) (1⋅L) in THF solution is a monomer with a C-Li bond according to NMR spectroscopy and cryoscopy. It was identified as CIP through the scalar 13 C,6 Li coupling and 6 Li,{1 H} NOE experiments. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure. 6 Li,1 H FUCOUP and 6 Li,1 H HMQC NMR experiments of 1⋅TMEDA revealed a scalar 6 Li,1 H coupling across the Li-C=C-H bonds. According to the NMR data the π-bond of 1⋅L is polarized by the negative charge of the anionic C atom. tBuCH=C(Li)S(O)(NMe)Ph (2⋅L) is most likely also a monomer with a C-Li bond. According to 6 Li,{1 H} NOE experiments it has a four-membered C-Li-N-S chelate ring structure. 13 C NMR spectroscopy showed the C-Li bonds of 1⋅L and 2⋅L to be fluxional. 1 H NMR spectroscopy and 1D TOCSY experiments of Ph2 C=C(Li)S(O)(NSO2 Tol)Ph revealed topomerization of the phenyl groups, which is attributed to a fast positional exchange of the Li atom and the sulfonimidoyl group. The fluxionality of the C-Li bond and the interchange of the Li atom and the sulfonimidoyl group at the anionic C atom of sulfonimidoyl vinyllithiums, which result in a low configurational stability, most likely involve the formation of O,Li and N,Li CIPs through heterolysis of the C-Li bond. Ab initio calculation of MeCH=C(Li)S(O)(NMe)Ph yielded an energy minimum structure with a C-Li bond, a four-membered C-Li-N-S chelate ring and a strongly expanded C=C-Li bond angle. According to calculation of MeCH=C(Li)S(O)(NMe)Ph, [MeCH=CS(O)(NMe)Ph]- and MeCH=C(H)S(O)(NMe)Ph deprotonation is not accompanied by a shortening of the C-S bond. Ab initio calculation of MeCH=C(Li)S(O)(NSO2 Me)Ph gave a structure with a C-Li bond and a six-membered C-Li-O-S-N-S chelate ring. 6 Li,1 H NOE experiments and cryoscopy of LiCH2 S(O)(NSO2 Tol)Ph (3) revealed a monomeric CIP with a C-Li bond. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure found in polymeric 3 in the crystal.

Synthesis of Sulfoximidoyl-Containing Hypervalent Iodine(III) Reagents and Their Use in Transition-Metal-Free Sulfoximidations of Alkynes.

Well-defined hypervalent iodine(III) reagents incorporating transferable sulfoximidoyl groups were obtained through ligand exchange reactions of methoxy(tosyloxy)iodobenzene (MTIB) with NH sulfoximines in good to excellent yields. The solid-state structure of a representative product was characterized by X-ray crystallography. Utilizing these reagents in synthesis provides a new, transition-metal-free approach towards N-alkynylated sulfoximines.

CF3 : An Electron-Withdrawing Substituent for Aromatic Anion Acceptors? "Side-On" versus "On-Top" Binding of Halides.

The ability of multiple CF3 -substituted arenes to act as acceptors for anions is investigated. The results of quantum-chemical calculations show that a high degree of trifluoromethyl substitution at the aromatic ring results in a positive quadrupole moment. However, depending on the polarizability of the anion and on the substitution at the arene, three different modes of interaction, namely Meisenheimer complex, side-on hydrogen bonding, or anion-π interaction, can occur. Experimentally, the side-on as well as a η(2) -type π-complex are observed in the crystal, whereas in solution only side-on binding is found.

Asymmetric, Three-Component, One-Pot Synthesis of Spiropyrazolones and 2,5-Chromenediones from Aldol Condensation/NHC-Catalyzed Annulation Reactions.

A novel one-pot, three-component diastereo- and enantioselective synthesis of spiropyrazolones has been developed involving the aldol condensation of an enal to generate α,ß-unsaturated pyrazolones, which react with a second equivalent of enal through an N-heterocyclic carbene (NHC)-catalyzed [3+2] annulation. The desired spirocyclopentane pyrazolones are obtained in moderate to good yields and good to excellent stereoselectivities. Alternatively, starting from cyclic 1,3-diketones, 2,5-chromenediones are available through [2+4] annulation.

Organocatalytic Kinetic Resolution of Sulfoximines.

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

A Supramolecular Chiral Auxiliary Approach: "Remote Control" of Stereochemistry at a Hierarchically Assembled Dimeric Helicate.

Dimeric hierarchically-assembled titanium(IV) helicates are in solvent-dependent equilibrium with the corresponding monomers. Statistically formed mixtures of such complexes bearing chiral stereocontrolling ligands and achiral diene-substituted ligands show high diastereoselectivity and reasonable enantioselectivity in the Diels-Alder reaction with maleimides if the reaction proceeds with the dimer but not with the monomer. Thus, solvent dependent switching between the monomer and dimer enables on/off switching of the enantioselectivity.

Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and Silver Catalysis.

A stereoselective one-pot synthesis of spiropyrazolones through an organocatalytic asymmetric Michael addition and a formal Conia-ene reaction has been developed. Depending on the nitroalkene, the 5-exo-dig-cyclization could be achieved by silver-catalyzed alkyne activation or by oxidation of the intermediate enolate. The mechanistic pathways have been investigated using computational chemistry and mechanistic experiments.

Chiral Lithiated Allylic α-Sulfonyl Carbanions: Experimental and Computational Study of Their Structure, Configurational Stability, and Enantioselective Synthesis.

X-ray crystal structure analysis of the lithiated allylic α-sulfonyl carbanions [CH2 CHC(Me)SO2 Ph]Li⋅diglyme, [cC6 H8 SO2 tBu]Li⋅PMDETA and [cC7 H10 SO2 tBu]Li⋅PMDETA showed dimeric and monomeric CIPs, having nearly planar anionic C atoms, only OLi bonds, almost planar allylic units with strong CC bond length alternation and the s-trans conformation around C1C2. They adopt a C1S conformation, which is similar to the one generally found for alkyl and aryl substituted α-sulfonyl carbanions. Cryoscopy of [EtCHCHC(Et)SO2 tBu]Li in THF at 164 K revealed an equilibrium between monomers and dimers in a ratio of 83:17, which is similar to the one found by low temperature NMR spectroscopy. According to NMR spectroscopy the lone-pair orbital at C1 strongly interacts with the CC double bond. Low temperature (6) Li,(1) H NOE experiments of [EtCHCHC(Et)SO2 tBu]Li in THF point to an equilibrium between monomeric CIPs having only OLi bonds and CIPs having both OLi and C1Li bonds. Ab initio calculation of [MeCHCHC(Me)SO2 Me]Li⋅(Me2 O)2 gave three isomeric CIPs having the s-trans conformation and three isomeric CIPs having the s-cis conformation around the C1C2 bond. All s-trans isomers are more stable than the s-cis isomers. At all levels of theory the s-trans isomer having OLi and C1Li bonds is the most stable one followed by the isomer which has two OLi bonds. The allylic unit of the C,O,Li isomer shows strong bond length alternation and the C1 atom is in contrast to the O,Li isomer significantly pyramidalized. According to NBO analysis of the s-trans and s-cis isomers, the interaction of the lone pair at C1 with the π* orbital of the CC double bond is energetically much more favorable than that with the "empty" orbitals at the Li atom. The C1S and C1C2 conformations are determined by the stereoelectronic effects nC -σSR * interaction and allylic conjugation. (1) H DNMR spectroscopy of racemic [EtCHCHC(Et)SO2 tBu]Li, [iPrCHCHC(iPr)SO2 tBu]Li and [EtCHC(Me)C(Et)SO2 tBu]Li in [D8 ]THF gave estimated barriers of enantiomerization of ΔG(≠) =13.2 kcal mol(-1) (270 K), 14.2 kcal mol(-1) (291 K) and 14.2 kcal mol(-1) (295 K), respectively. Deprotonation of sulfone (R)-EtCHCHCH(Et)SO2 tBu (94 % ee) with nBuLi in THF at -105 °C occurred with a calculated enantioselectivity of 93 % ee and gave carbanion (M)-[EtCHCHC(Et)SO2 tBu]Li, the deuteration and alkylation of which with CF3 CO2 D and MeOCH2 I, respectively, proceeded with high enantioselectivities. Time-dependent deuteration of the enantioenriched carbanion (M)-[EtCHCHC(Et)SO2 tBu]Li in THF gave a racemization barrier of ΔG(≠) =12.5 kcal mol(-1) (168 K), which translates to a calculated half-time of racemization of t1/2 =12 min at -105 °C.

NHC-catalyzed activation of α,ß-unsaturated N-acyltriazoles: an easy access to dihydropyranones.

An N-heterocyclic carbene catalyzed activation of α,ß-unsaturated N-acyltriazoles is described. The in situ generated α,ß-unsaturated acylazolium intermediates allowed an enantioselective formal [3+3] cycloaddition with 1,3-dicarbonyl compounds. The resulting dihydropyranones are formed in good to excellent yields and with high enantioselectivities.

NHC-Catalyzed Asymmetric Synthesis of Functionalized Succinimides from Enals and α-Ketoamides.

The efficient asymmetric synthesis of highly substituted succinimides from α,ß-unsaturated aldehydes and α-ketoamides via NHC-catalyzed [3+2] cycloaddition has been developed. The new scalable protocol significantly expands the utility of NHC catalysis for the synthesis of heterocycles and provides easy access to assemble a wide range of succinimides from simple starting materials.

Combining silver- and organocatalysis: an enantioselective sequential catalytic approach towards pyrano-annulated pyrazoles.

A one-pot asymmetric Michael addition/hydroalkoxylation sequence, catalyzed by a sequential catalytic system consisting of a squaramide and a silver salt, provides a new series of chiral pyrano-annulated pyrazole derivatives in excellent yields (up to 95%) and high enantioselectivities (up to 97% ee).

An organocatalytic Mannich/denitration reaction for the asymmetric synthesis of 3-ethylacetate-substitued 3-amino-2-oxindoles: formal synthesis of AG-041R.

The highly enantioselective organocatalytic addition of ethyl nitroacetate to isatin-derived N-Boc ketimines (Boc = tert-butoxycarbonyl), followed by the removal of the nitro group, is described. The scalable reaction sequence leads to the title compounds as important intermediates of pyrroloindoline alkaloids and related drugs in excellent yields and enantioselectivities. The synthesis of the hexahydrofurano[2,3-b]indole skeleton, the spirocarbamate oxindole unit, and the formal synthesis of AG-041R have been carried out to demonstrate the synthetic utility of this protocol.

Organocatalytic one-pot 1,4-/1,6-/1,2-addition sequence for the stereocontrolled formation of six consecutive stereocenters.

An unprecedented stereoselective organocatalytic one-pot 1,4-/1,6-/1,2-addition sequence between ß-dicarbonyl compounds, ß-nitroalkenes and 4-nitro-5-styrylisoxazoles sequentially catalyzed by low loading of a squaramide catalyst and an achiral base has been developed. The protocol opens an efficient entry to isoxazole bearing cyclohexanes with six consecutive stereogenic centers including one tetrasubstituted carbon in good yields and excellent diastereo- and enantioselectivities.