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.

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.

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.

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.

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.

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.

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.

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.

Asymmetric synthesis of fully substituted cyclopentane-oxindoles through an organocatalytic triple Michael domino reaction.

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three C-C bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.

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 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.

Stereocontrol in dinuclear triple lithium-bridged titanium(IV) complexes: solving some stereochemical mysteries.

Compounds 1 a-f-H2 form "monomeric" triscatecholate titanium(IV) complexes [Ti(1 a-f)3](2-), which in the presence of Li cations are in equilibrium with the triple lithium-bridged "dimers" [Li3(Ti(1 a-f)3)2](-). The equilibrium strongly depends on the donor ability of the solvent. Usually, in solvents with high donor ability, the stereochemically labile monomer is preferred, whereas in nondonor solvents, the dimer is the major species. In the latter, the stereochemistry at the complex units is "locked". The configuration at the titanium(IV) triscatecholates is influenced by addition of chiral ammonium countercations. In this case, the induced stereochemical information at the monomer is transferred to the dimer. Alternatively, the configuration at the metal complexes can be controlled by enantiomerically pure ester side chains. Due to the different orientation of the ester groups in the monomer or dimer, opposite configurations of the triscatecholates were observed by circular dichroism (CD) spectroscopy for [Ti(1 c-e)3](2-) or [Li3(Ti(1 c-e)3)2](-). A surprising exception was found for the dimer [Li3(Ti(1 f)3)2](-). Herein, the dimer is the dominating species in weak donor (methanol), as well as strong donor (DMSO), solvents. This is due to the bulkiness of the ester substituent destabilizing the monomer. Due to the size of the substituent in [Li3(Ti(1 f)3)2](-) the esters have to adopt an unusual conformation in the dimer resulting in a stereocontrol of the small methyl group. Following this, opposite stereocontrol mechanisms were observed for the central metal-complex units of [Li3(Ti(1 c-e)3)2](-) or [Li3(Ti(1 f)3)2](-).

Merging gold and organocatalysis: a facile asymmetric synthesis of annulated pyrroles.

The combination of cinchona-alkaloid-derived primary amine and Au(I) -phosphine catalysts allowed the selective C-H functionalization of two adjacent carbon atoms of pyrroles under mild reaction conditions. This sequential dual activation provides seven-membered-ring-annulated pyrrole derivatives in excellent yields and enantioselectivities.

Chiral fluorinated α-sulfonyl carbanions: enantioselective synthesis and electrophilic capture, racemization dynamics, and structure.

Enantiomerically pure triflones R(1) CH(R(2) )SO2 CF3 have been synthesized starting from the corresponding chiral alcohols via thiols and trifluoromethylsulfanes. Key steps of the syntheses of the sulfanes are the photochemical trifluoromethylation of the thiols with CF3 Hal (Hal=halide) or substitution of alkoxyphosphinediamines with CF3 SSCF3 . The deprotonation of RCH(Me)SO2 CF3 (R=CH2 Ph, iHex) with nBuLi with the formation of salts [RC(Me)SO2 CF3 ]Li and their electrophilic capture both occurred with high enantioselectivities. Displacement of the SO2 CF3 group of (S)-MeOCH2 C(Me)(CH2 Ph)SO2 CF3 (95 % ee) by an ethyl group through the reaction with AlEt3 gave alkane MeOCH2 C(Me)(CH2 Ph)Et of 96 % ee. Racemization of salts [R(1) C(R(2) )SO2 CF3 ]Li follows first-order kinetics and is mainly an enthalpic process with small negative activation entropy as revealed by polarimetry and dynamic NMR (DNMR) spectroscopy. This is in accordance with a Cα S bond rotation as the rate-determining step. Lithium α-(S)-trifluoromethyl- and α-(S)-nonafluorobutylsulfonyl carbanion salts have a much higher racemization barrier than the corresponding α-(S)-tert-butylsulfonyl carbanion salts. Whereas [PhCH2 C(Me)SO2 tBu]Li/DMPU (DMPU = dimethylpropylurea) has a half-life of racemization at -105 °C of 2.4 h, that of [PhCH2 C(Me)SO2 CF3 ]Li at -78 °C is 30 d. DNMR spectroscopy of amides (PhCH2 )2 NSO2 CF3 and (PhCH2 )N(Ph)SO2 CF3 gave NS rotational barriers that seem to be distinctly higher than those of nonfluorinated sulfonamides. NMR spectroscopy of [PhCH2 C(Ph)SO2 R]M (M=Li, K, NBu4 ; R=CF3 , tBu) shows for both salts a confinement of the negative charge mainly to the Cα atom and a significant benzylic stabilization that is weaker in the trifluoromethylsulfonyl carbanion. According to crystal structure analyses, the carbanions of salts {[PhCH2 C(Ph)SO2 CF3 ]Li⋅L}2 (L=2 THF, tetramethylethylenediamine (TMEDA)) and [PhCH2 C(Ph)SO2 CF3 ]NBu4 have the typical chiral Cα S conformation of α-sulfonyl carbanions, planar Cα atoms, and short Cα S bonds. Ab initio calculations of [MeC(Ph)SO2 tBu](-) and [MeC(Ph)SO2 CF3 ](-) showed for the fluorinated carbanion stronger nC →σ* SCF 3 and nO →σ* SCF 3 interactions and a weaker benzylic stabilization. According to natural bond orbital (NBO) calculations of [R(1) C(R(2) )SO2 R](-) (R=tBu, CF3 ) the nC →σ*SR interaction is much stronger for R=CF3 . Ab initio calculations gave for [MeC(Ph)SO2 tBu]Li⋅2 Me2 O an O,Li,Cα contact ion pair (CIP) and for [MeC(Ph)SO2 CF3 ]Li⋅2 Me2 O an O,Li,O CIP. According to cryoscopy, [PhCH2 C(Ph)SO2 CF3 ]Li, [iHexC(Me)SO2 CF3 ]Li, and [PhCH2 C(Ph)SO2 CF3 ]NBu4 predominantly form monomers in tetrahydrofuran (THF) at -108 °C. The NMR spectroscopic data of salts [R(1) (R(2) )SO2 R(3) ]Li (R(3) =tBu, CF3 ) indicate that the dominating monomeric CIPs are devoid of Cα Li bonds.

Bis(allyl)zinc revisited: sigma versus pi bonding of allyl coordination.

The reinvestigation of two allyl zinc compounds, parent bis(allyl)zinc [Zn(C(3)H(5))(2)] (1) and 2-methallyl chloro zinc [Zn(C(4)H(7))Cl] (2), revealed two new coordination modes in the solid state for the allyl ligand, viz cis- and trans-µ(2)-η(1):η(1). These results call for modification of the conventional interpretation of zinc-allyl interactions. Computational results indicate that the classical η(3)-bonding mode of the allyl ligand is not favored in zinc compounds. A rare case of a zinc-olefin interaction in the dimer of [Zn(η(1)-C(3)H(5))(OC(C(3)H(5))Ph(2))] was found in the monoinsertion product of 1 with benzophenone.

Organocatalytic, asymmetric synthesis of 3-sulfenylated N-Boc-protected oxindoles.

Sulfenylated oxindoles: The first asymmetric sulfenylation of N-Boc-protected oxindoles has been developed to provide products containing a tetrasubstituted stereogenic center in high to excellent yields (86-98 %) and, in most cases, excellent enantioselectivities (up to 96 % ee; see scheme).