Regioselectivity in arene-catalyzed reductive lithiation of acetals of chlorobenzaldehydes

The regioselectivity of arene-catalyzed reductive lithiation of acetals of chlorobenzaldehydes strongly depends on the form of lithium metal employed as a reducing agent. According to previous findings, naphthalene catalyzed reductions run in the presence of lithium powder (high Na content) led to competitive metalations of both aromatic carbon-chlorine and benzylic carbon-oxygen bonds. At variance with these results, naphthalene catalyzed reductions run in the presence of lithium wire (either high or low Na content) led to highly regioselective metalation of aromatic carbon-chlorine bonds. These results disclose new possibilities of selective applications of arene-catalyzed reductive lithiation reactions.     

Copper-mediated chelation-assisted ortho nitration of (hetero)arenes

A novel copper-mediated chelation-assisted ortho C-H nitration of (hetero)arenes has been developed for the first time, which used dioxygen as terminal oxidant and 1,2,3-TCP as solvent, leading to the synthesis of nitroaromatics with excellent regioselectivity and in good yields. Mechanistic investigations indicate a mechanism involving a four-centered transition state, with simultaneous cleavage of an ortho C-H bond and a N-O bond of the nitrate anion on the 2-arylpyridine-coordinated copper(II) complex.     

New selectivity in peptide hydrolysis by metal complexes. Platinum(II) complexes promote cleavage of peptides next to the tryptophan residue

Tryptophan-containing N-acetylated peptides AcTrp-Gly, AcTrp-Ala, AcTrp-Val, and AcTrp-ValOMe bind to platinum(II) and undergo selective hydrolytic cleavage of the C-terminal amide bond; the N-terminal amide bond remains intact. In acetone solution, bidentate coordination of the tryptophanyl residue via the C(3) atom of indole and the amide oxygen atom produces complexes of spiro stereochemistry, which are characterized by (1)H, (13)C, and (195)Pt NMR spectroscopy, and also by UV-vis, IR, and mass spectroscopy. Upon addition of 1 molar equiv of water, these complexes undergo hydrolytic cleavage. This reaction is as much as 10(4)-10(5) times faster in the presence of platinum(II) complexes than in their absence. The hydrolysis is conveniently monitored by (1)H NMR spectroscopy. We report the kinetics and mechanism for this reaction between cis-[Pt(en)(sol)(2)](2+), in which the solvent ligand is water or acetone, and AcTrp-Ala. The platinum(II) ion as a Lewis acid activates the oxygen-bound amide group toward nucleophilic attack of solvent water. The reaction is unimolecular with respect to the metal-peptide complex. Because the tryptophanyl fragment AcTrp remains coordinated to platinum(II) after cleavage of the amide bond, the cleavage is not catalytic. Added ligand, such as DMSO and pyridine, displaces AcTrp from the platinum(II) complex and regenerates the promoter. This is the first report of cleavage of peptide bonds next to tryptophanyl residues by metal complexes and one of the very few reports of organometallic complexes involving metal ions and peptide ligands. Because these complexes form in nonaqueous solvents, a prospect for cleavage of membrane-bound and other hydrophobic proteins with new regioselectivity has emerged.     

Palladium(II) complexes, as synthetic peptidases, regioselectively cleave the second peptide bond "upstream" from methionine and histidine side chains

Palladium(II) complexes promote hydrolysis of natural and synthetic oligopeptides with unprecedented regioselectivity; the only cleavage site is the second peptide bond upstream from a methionine or a histidine side chain, that is, the bond involving the amino group of the residue that precedes this side chain. We investigate this regioselectivity with four N-acetylated peptides as substrates: neurotransmitter methionine enkephalin (Ac-Tyr-Gly-Gly-Phe-Met) and synthetic peptides termed Met-peptide (Ac-Ala-Lys-Tyr-Gly-Gly-Met-Ala-Ala-Arg-Ala), His-peptide (Ac-Val-Lys-Gly-Gly-His-Ala-Lys-Tyr-Gly-Gly-Met(OX)-Ala-Ala-Arg-Ala), in which a Met is oxidized to sulfone, and HisMet-peptide (Ac-Val-Lys-Gly-Gly-His-Ala-Lys-Tyr-Gly-Gly-Met-Ala-Ala-Arg-Ala). While maintaining protein-like properties, these substrates are suitable for quantitative study since their coordination to Pd(II) ion can be determined (by NMR spectroscopy), and the cleavage fragments can be separated (by HPLC methods) and identified (by MALDI mass spectrometry). The only peptide bonds cleaved were the Gly3-Phe4 bond in methionine enkephalin, Gly4-Gly5 bond in Met-peptide, Gly3-Gly4 in His-peptide, and Gly3-Gly4 and Gly9-Gly10 bonds in HisMet-peptide. We explain this consistent regioselectivity of cleavage by studying the modes of Met-peptide coordination to the Pd(II) ion in [Pd(H(2)O)(4)](2+) complex. In acidic solution, the rapid attachment of the Pd(II) complex to the methionine side chain is followed by the interaction of the Pd(II) ion with the peptide backbone upstream from the anchor. In the hydrolytically active complex, Met-peptide is coordinated to Pd(II) ion as a bidentate ligand - via sulfur atom in the methionine side chain and the first peptide nitrogen upstream from this anchor - so that the Pd(II) complex approaches the scissile peptide bond. Because the increased acidity favors this hydrolytically active complex, the rate of cleavage guided by either histidine or methionine anchor increased as pH was lowered from 4.5 to 0.5. The unwanted additional cleavage of the first peptide bond upstream from the anchor is suppressed if pH is kept above 1.2. Four Pd(II) complexes cleave Met-peptide with the same regioselectivity but at somewhat different rates. Complexes in which Pd(II) ion carries labile ligands, such as [Pd(H(2)O)(4)](2+) and [Pd(NH(3))(4)](2+), are more reactive than those containing anionic ligands, such as [PdCl(4)](2)(-), or a bidentate ligand, such as cis-[Pd(en)(H(2)O)(2)](2+). When both methionine and histidine residues are present in the same substrate, as in HisMet-peptide, 1 molar equivalent of the Pd(II) complex distributes itself evenly at both anchors and provides partial cleavage, whereas 2 molar equivalents of the promoter completely cleave the second peptide bond upstream from each of the anchors. The results of this study bode well for growing use of palladium(II) reagents in biochemical and bioanalytical practice.     

Solvent-dependent regioselectivity of hydrogen chloride-mediated ring opening of alkylidenecyclopropanone acetal

Ring opening reactions of 2-cyclohexylidene-3,3-dimethylcyclopropanone acetal (1) are readily induced by treatment of hydrogen chloride in various solvents. Bond cleavage takes place at the C1-C2 or C2-C3 bond, and the ratio of C1-C2/C2-C3 cleavages changes from >99/1 to <1/99 depending on the solvent. The two modes of bond cleavage must be initiated by protonations at the carbon-carbon double bond and the acetal oxygen, respectively. The regioselectivity can be rationalized by the rate-determining protonation at carbon and the equilibrium protonation at oxygen.     

Microwave assisted fluorination: an improved method for side chain fluorination of substituted 1-arylethanones

A two-step, one-pot microwave (MW) assisted fluorination of 1-arylethanones to their corresponding 1-aryl-2-fluoroethanones has been developed. The first step utilises Selectfluor™ as a fluorinating agent in methanol forming 1-aryl-2-fluoroethanones and their corresponding dimethyl acetals. In the second step, water is added and Selectfluor™ acts as a Lewis acid in the hydrolytic cleavage of the dimethyl acetals. Compared to the thermal synthesis, the MW assisted method leads to a reduction in reaction time both in the fluorination and for the dimethyl acetal cleavage. Moreover, the one-pot procedure reduces reagent and solvent consumption. The method is best suited for the preparation of 1-aryl-2-fluoroethanones containing substituents that deactivates electrophilic aromatic substitution, however highly electron deficient ketones such as 1-(3,5-dinitrophenyl)ethanone reacts more slowly. Reactions using electron rich aromatic ketones had a low regioselectivity, and also produced fluoroaromatic products.     

Remote substituent effects on the oxymercuration of 2-substituted norbornenes: an experimental and theoretical study.

The effect of a remote substituent on regioselectivity in the oxymercuration of 2-substituted norbornenes has been investigated experimentally and theoretically using density functional theory (DFT). Regioselectivities of 1:1 to 14:1 were observed with various 2-substituted norbornenes. Exo-2-substituted norbornenes always gave greater regioselectivities compared to the corresponding endo-2-substituted norbornenes. The effects of solvents on the regioselectivity have also been examined, and ethereal solvents were found to be the best choice giving the optimal yield and regioselectivity. The relative rate of oxymercuration was estimated by competition experiments. The least reactive substrate (X = OAc) gave the highest regioselectivity. According to DFT predictions, the increased difference between the reaction barriers that results in the greater regioselectivity is correlated directly with the larger polarity of the C=C double bond, which is attacked by the mercury and oxygen. A number of stable exo and endo conformers were predicted. All exo conformers show the same polarity of the double bond, while some endo conformers have a reversal of this polarity. All the conformers except those with the OAc substituent are very close in energy and thus should react. The existence of a mixture of endo conformers with the C=C double bond of opposite polarity clearly explains a decrease in regioselectivity for the endo species. The origin of the greatest regioselectivity for the OAc-2-norbornenes lies in the fact that the conformer with the largest polarity is notably lower in energy than others due to an internal C-H-O hydrogen bond.     

Mechanistic investigation of a novel vitamin B(12)-catalyzed carbon [bond] carbon bond forming reaction, the reductive dimerization of arylalkenes

In the presence of catalytic vitamin B(12) and a reducing agent such as Ti(III)citrate or Zn, arylalkenes are dimerized with unusual regioselectivity forming a carbon [bond] carbon bond between the benzylic carbons of each coupling partner. Dimerization products were obtained in good to excellent yields for mono- and 1,1-disubstituted alkenes. Dienes containing one aryl alkene underwent intramolecular cyclization in good yields. However, 1,2-disubstituted and trisubstituted alkenes were unreactive. Mechanistic investigations using radical traps suggest the involvement of benzylic radicals, and the lack of diastereoselectivity in the product distribution is consistent with dimerization of two such reactive intermediates. A strong reducing agent is required for the reaction and fulfills two roles. It returns the Co(II) form of the catalyst generated after the reaction to the active Co(I) state, and by removing Co(II) it also prevents the nonproductive recombination of alkyl radicals with cob(II)alamin. The mechanism of the formation of benzylic radicals from arylalkenes and cob(I)alamin poses an interesting problem. The results with a one-electron transfer probe indicate that radical generation is not likely to involve an electron transfer. Several alternative mechanisms are discussed.     

Reactions of triflate esters and triflamides with an organic neutral super-electron-donor

The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with (18)O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.     

A new germanium-based linker for solid phase synthesis of aromatics: synthesis of a pyrazole library

An efficient synthesis of chlorogermane linker 12 is described. Economic introduction of germanium into this linker is accomplished by insertion of dichlorogermylene [from germanium(IV) chloride] into the homobenzylic C-Cl bond of 4-(2-chloroethyl)phenol 1. Using linker 12, transmetalation with lithiated 4-acetophenone, 3-acetophenone, and 4-(4'methoxy)biphenyl followed by Mitsunobu-type coupling to Argogel gives functionalized resins 14, 16, and 18, respectively. Treatment of resin 18 with TFA, ICl, Br2, or NCS effects clean ipso-degermylation releasing biphenyls 19-22, respectively. Resins 14 and 16 are employed for the parallel synthesis of a library of pyrazoles by enaminone formation (using Bredereck's reagent), condensative ring-closure (using a series of monosubstituted hydrazines), and cleavage (using TFA and Br2). Analysis of this library reveals the influence of the hydrazine substituent on both the regioselectivity of ring-closure and the propensity for electrophilic substitution at the 4-position of the pyrazoles during ipso-degermylative cleavage.     

Low-energy electron attachment to 5'-thymidine monophosphate: modeling single strand breaks through dissociative electron attachment

Mechanisms of low-energy electron (LEE) attachment and subsequent single-strand break (SSB) formation are investigated by density functional theory treatment of a simple model for DNA, i.e., the nucleotide, 5'-thymidine monophosphate (5'-dTMPH). In the present study, the C5'-O5' bond dissociation due to LEE attachment has been followed along the adiabatic as well as on the vertical (electron attached to the optimized geometry of the neutral molecule) anionic surfaces using B3LYP functional and 6-31G* and 6-31++G** basis sets. Surprisingly, it is found that the PES of C5'-O5' bond dissociation in the anion radicals have approximately the same barrier for both adiabatic and vertical pathways. These results provide support for the hypothesis that transiently bound electrons (shape resonances) to the virtual molecular orbitals of the neutral molecule likely play a key role in the cleavage of the sugar-phosphate C5'-O5' bond in DNA resulting in the direct formation of single strand breaks without significant molecular relaxation. To take into account the solvation effects, we considered the neutral and anion radical of 5'-dTMP surrounded by 5 or 11 water molecules with Na+ as a counterion. These structures were optimized using the B3LYP/6-31G** level of theory. We find the barrier height for adiabatic C5'-O5' bond dissociation of 5'-dTMP anion radical in aqueous environment is so substantially higher than in the gas phase that the adiabatic route will not contribute to DNA strand cleavage in aqueous systems. This result is in agreement with experiment.     

Interplay of terminal amino group and coordinating side chains in directing regioselective cleavage of natural peptides and proteins with palladium(II) complexes

Palladium(II) ions anchored to side chains of histidine and methionine residues in peptides and proteins in weakly acidic aqueous solutions promote hydrolytic cleavage of proximate amide bonds in the backbone. In this study, we determine how attachment of Pd(II) ions to histidine and methionine anchors and also to the terminal amino group in six natural peptides (chains A and B of insulin, segment 11-14 of angiotensinogen, pentagastrin, angiotensin II, and segment 3-8 of angiotensin II) and two proteins (ubiquitin and cytochrome c) affects regioselectivity and rate of backbone cleavage. These Pd(II)-promoted reactions follow a clear pattern of regioselectivity, directed by the anchoring side chains. When the Pd(II) reagent is nonspecifically anchored to the terminal amino group, the ligating site that is present in almost all proteins, the cleavage is fortunately absent. When the reagent is anchored to a residue in positions 1, 2, or 3, cleavage is absent, because the terminal amino group and deprotonated amide nitrogen atom(s) interposed between it and the anchor "lock" the Pd(II) ion in hydrolytically inactive chelate complexes. When the reagent is anchored to residues in positions beyond 3, the second amide bond upstream from the anchor is regioselectively cleaved in all cases when the anchor was "isolated," that is, flanked by noncoordinating side chains. Segment 3-8 of angiotensin II undergoes additional cleavage, which we explain by determining the rate constants for the cleavage, identifying the rate-limiting displacement of ethylenediamine ligand from the Pd(II) ion, and detecting several intermediates. Experiments with cytochrome c demonstrate that the number of cleavage sites can be controlled by adjusting the mole ratio of the Pd(II) reagent to the substrate. Our inorganic peptidases are useful for biochemical applications because their regioselectivity and reactivity set them apart from proteolytic enzymes and organic chemical reagents.     

On the catalytic mechanism of choline oxidase

Choline oxidase catalyzes the four-electron oxidation of choline to glycine betaine, with betaine aldehyde as an intermediate. In this study, primary deuterium and solvent kinetic isotope effects have been used to elucidate the mechanism for substrate oxidation by choline oxidase using both steady-state kinetics and rapid kinetics techniques. The D(kcat/Km) value with 1,2-[2H4]-choline at saturating oxygen concentration was independent of pH in the range between 6.5 and 10, with a value of approximately 10.6, indicating that CH bond cleavage is not masked by other titratable kinetic steps belonging to the reductive half-reaction. In agreement with this conclusion, a Dkred value of approximately 8.9 was determined at pH 10 for the anaerobic reduction of the flavin by choline, irrespective of whether aqueous or deuterated solvent was used. At pH 10, both the D2(O)(kcat/Km) and the D2(O)kred values were not different from unity with choline or 1,2-[2H4]-choline, while the Dkcat and D2(O)kcat values were 7.3 and 1.1, respectively. The kcat and kred values were 133 s(-1) and 135 s(-1) with betaine aldehyde and 60 s(-1) and 93 s(-1) with choline. These data are consistent with a chemical mechanism in which the choline hydroxyl proton is not in flight in the transition state for CH bond cleavage and with chemical steps of flavin reduction by choline and betaine aldehyde being rate limiting for the overall turnover of the enzyme.     

C-H arylation of pyridines: high regioselectivity as a consequence of the electronic character of C-H bonds and heteroarene ring

We report a new catalytic protocol for highly selective C-H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO(2), CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C-H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C-H bond) in combination with steric effects (sensitivity to bulky substituents).     

Mass spectral studies of meso-dialkyl, alkyl aryl and cycloalkyl calix(4)pyrroles under positive and negative ion electrospray ionization conditions

A series of meso-dialkyl, alkyl aryl and cycloalkyl calix(4)pyrroles (1-15) are studied under positive and negative ion electrospray ionization (ESI) conditions. The positive ion spectra show abundant [M + H](+) and [M + Na](+) ions and the negative ion spectra show the [M + Cl](-) (the Cl(-) ions from the solvent) and [M - H](-) ions. The collision induced dissociation (CID) spectra of [M + H](+), [M + Na](+), [M + Cl](-) and [M - H](-) ions are studied to understand their dissociation pathway and compared to that reported for M(+) under electron ionization (EI) conditions. The beta-cleavage process that was diagnostic to M(+) is absent in all the CID spectra of the ions studied under ESI. Dissociation of all the studied ions resulted in the fragment ions formed by sequential elimination of pyrrole (A) and/or dialkyl/alkyl aryl/cycloalkyl (B) groups involving hydrogen migration to pyrrole ring at each cleavage of A--B bond, which clearly reveals the arrangement of A and B groups in the calix(4)pyrroles. The source of hydrogen that migrates to pyrrole ring during A--B bond cleavage is investigated by the experiments on deuterated compounds and [M + D](+) ions; and confirmed that the hydrogen attached to pyrrole nitrogen, hydrogen on alpha-carbon of alkyl group and the H(+)/Na(+) ion that added during ESI process to generate [M + H](+)/[M + Na](+) ions involve in the migration. The yields of [M + Na](+) ions are found to be different for the isomeric meso-cycloalkyl compounds (cycloheptyl, and 2-, 3- and 4-methyl cyclohexyl) and for normal and N-confused calix(4)pyrroles. The isomeric methyl and 3-hydroxy/4-hydroxy phenyl calix(4)pyrroles show specific fragmentation pattern during the dissociation of their [M - H](-) ions.     

A theoretical study of rhodium(I) catalyzed carbonylative ring expansion of aziridines to beta-lactams: crucial activation of the breaking C-N bond by hyperconjugation

The regioselectivity and enantiospecificity of the [Rh(CO)2Cl]2-catalyzed carbonylative ring expansions of N-tert-butyl-2-phenylaziridine to yield 2-azetidinone and the lack of reactivity of N-tert-butyl-2-methylaziridine along this process were investigated at the B3LYP/6-31G(d) (LANL2DZ for Rh) theory level taking into account solvent effects. According to our results, the regioselectivity in the ring expansion of N-tert-butyl-2-phenylaziridine and the unreactivity of N-tert-butyl-2-methylaziridine experimentally observed are determined by the different degree of activation of the breaking C-N bond in the initial aziridine-Rh(CO)2Cl complex due to its hyperconjugation interaction with the substituent on the carbon atom. When a phenyl substituent is present its hyperconjugation interaction with the C(alpha)-N bond facilitates the insertion of the metal atom into this bond. On the other hand, when the substituent is a methyl group, a larger stability of the initial complex along with a lower stabilization through hyperconjugation of the TS for insertion of the Rh atom into the C(alpha)-N bond make the ring expansion of N-tert-butyl-2-methylaziridine unviable. The enantiospecificity experimentally observed is also reproduced by our calculations given that the stereogenic center is never perturbed to change its configuration.     

Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid

Nonenzymatic peptide bond cleavage at asparagine (Asn) and glutamine (Gln) residues has been observed during peptide deamidation experiments; cleavage has also been reported at aspartic acid (Asp) and glutamic acid (Glu) residues. Although peptide backbone cleavage at Asn is known to be slower than deamidation, fragmentation products are often observed during peptide deamidation experiments. In this study, mechanisms leading to the cleavage of the carboxyl-side peptide bond of Asn and Asp residues were investigated using computational methods (B3LYP/6-31+G**). Single-point solvent calculations at the B3LYP/6-31++G** level were carried out in water, utilizing the integral equation formalism-polarizable continuum (IEF-PCM) model. Mechanism and energetics of peptide fragmentation at Asn were comparatively analyzed with previous calculations on deamidation of Asn. When deamidation proceeds through direct hydrolysis of the Asn side chain or through cyclic imide formationvia a tautomerization routeit exhibits lower activation barriers than peptide bond cleavage at Asn. The fundamental distinction between the mechanisms leading to deamidationvia a succinimideand backbone cleavage was found to be the difference in nucleophilic entities involved in the cyclization process (backbone versus side-chain amide nitrogen). If deamidation is prevented by protein three-dimensional structure, cleavage may become a competing pathway. Fragmentation of the peptide backbone at Asp was also computationally studied to understand the likelihood of Asn deamidation preceding backbone cleavage. The activation barrier for backbone cleavage at Asp residues is much lower (approximately 10 kcal/mol) than that at Asn. This suggests that peptide bond cleavage at Asn residues is more likely to take place after it has deamidated into Asp.     

Theoretical Study on the Hetero-Diels-Alder Reactions between 3-Pyridinedithioesters and 1-Phenylsulfanylbutadiene

The mechanism, catalytic effect and solvent effect of the hetero-Diels-Alder reac- tions between 3-pyridinedithioesters and 1-phenylsulfanylbutadiene have been studied theoretically using density functional theory (DFT) at the B3LYP/6-31G(d) level. The results show that all of these reactions proceed in a concerted but asynchronous way. In some reactions the formation of C-S bond is prior to that of C-C bond and the opposite results are found in other reactions. The BF3 catalyst may lower the activation barriers by changing the energies of LUMO for 3-pyridine- dithioester. THF solvent has trivial influence on the potential energy surface of these reactions. With the BF3-catalyzed reactions, regioselectivity and stereoselectivity observed experimentally were predicted correctly by calculations and these results originate probably from C-H···F interaction in two transition states.     

Theoretical investigation on regioselectivity of aromatic ketones in the addition with olefin catalyzed by RuH2(CO)(PPh3)3

Ab initio method is employed to study the structures of twelve aromatic ketones at HF/3-21G, HF/6-31G and HF/6-31G levels, respectively. A theoretical analysis is also carried out to study the regioselectivity and reactivity of aromatic ketones in the addition with olefin catalyzed by RuH2(CO)(PPh3)3. The results indicate that a U shape LUMO conjugation of aromatic ketones in a plane plays an important role in regioselectivity on the cleavage of p C-H bond and is a nec-essary factor to success of addition with olefin, and that sterle effect is an indispensable factor in forming additional ortho-product. Meanwhile, electronic effect may influence the rate of addition for the structures alike which only have different replacements in the same site of aromatic ring, such as furan, thiophene and pyrole. A possible catalytic reaction mechanism is proposed that the addition of C-H bond may be carried out by a coordination of aromatic ketones with Ru complex.     

Reductive lithiation of 1,3-dimethyl-2-arylimidazolidines

Naphthalene catalyzed lithiation of 1,3-dimethyl-2-phenylimidazolidine led to cleavage of the benzylic carbon-nitrogen bond, with formation of an intermediate dianion. Under similar conditions, 1,3-dimethyl-2-(4-chlorophenyl)imidazolidine underwent regioselective cleavage of the aromatic carbon-chlorine bond, leading to a 4-formylphenyllithium equivalent, whilst 1,3-dimethyl-2-(4-methoxymethylphenyl)imidazolidine underwent regioselective cleavage of the benzylic carbon-oxygen bond, leading to a 4-formylbenzyllithium equivalent.