Alkylation Products Research Articles

Regioselective alkylation reaction of purines under microwave irradiation

AbstractThe alkylation of purines which is generally carried out after anion formation by treatment with a base and alkyl halide is complicated and in the best cases, mixtures of N‐alkylated compounds are obtained. Purine derivatives can be acquired from alkylation at N‐7 and N‐9. In this work, the reaction conditions have been optimized to obtain the alkylation products of N‐9 regioselectively. Different bases have been tried and tetrabutylammonium hydroxide has led to the best results. The reaction depends on the type of base and solvent used and improves considerably when the aid of microwave irradiation is used, which also considerably reduces the reaction time by reducing the formation of secondary products.

Cover Feature: Understanding the Alkylation Mechanism of 3‐Chloropiperidines – NMR Kinetic Studies and Isolation of Bicyclic Aziridinium Ions (Eur. J. Org. Chem. 44/2021)

The Cover Feature shows the NMR kinetic analysis of the DNA alkylation mechanism of 3-chloropiperidines. The structure of the bicyclic aziridinium ion proposed as the reaction intermediate was confirmed by single crystal XRD and is shown in the center. These highly electrophilic intermediates are readily attacked by nucleophiles such as DNA bases, resulting in an alkylation product shown in the bottom right corner. An alkylated DNA double strand, containing a single strand break, as well as the corresponding depurination products are depicted on the top. In the background multiple stacked NMR spectra of a kinetic analysis in aqueous solution are shown. More information can be found in the Full Paper by R. Göttlich et al.

Enantioselective Radical SN2-Type Alkylation of Morita-Baylis-Hillman Adducts Using Dual Photoredox/Palladium Catalysis.

An enantioselective radical alkylation of 4-alkyl-1,4-dihydropyridines with Morita-Baylis-Hillman (MBH) adducts has been reported. The SN2-type products are predominant. This reaction is enabled by dual photoredox/palladium catalysis. The alkylation products are provided in good yields with good regio- and enantioselectivity. The use of Ding's spiroketal-based bis(phosphine) (SKP) ligand is crucial to achieving satisfactory regio- and enantioselectivity. The resultant α,β-unsaturated ester can be easily reduced to a synthetically useful chiral allyl alcohol.

PH-Mediated Selective Synthesis of N-Allylic Alkylation or N-Alkylation Amines with Allylic Alcohols via an Iridium Catalyst in Water.

Amination of allylic alcohols is an effective approach in the facile synthesis of N-allylic alkylation or N-alkylation amines. Recently, a series of catalysts were devised to push forward this transformation. However, current synthetic methods are typically limited to achieve either N-allylic alkylation or N-alkylation products via a certain catalyst. In this article, a pH-mediated selective synthesis of N-allylic alkylation or N-alkylation amines with allylic alcohols via an iridium catalyst with water as the environmental benign solvent is revealed, enabling the miscellaneous synthesis of N-allylic alkylation and N-alkylation products in outstanding yields. Furthermore, a gram-scale experiment with low catalyst loading offers the potential to access a distinct entry for the synthesis of the antifungal drug naftifine.

Manganese(I) catalyzed cross-coupling of secondary allylic alcohols and primary alcohols

Cross-coupling of alcohols to value-added products by using sustainable catalytic reactions has gained attention in recent years. Isomerization of secondary allylic alcohol to the corresponding enolizable ketone is an atom economical and known transformation. Herein, a selective cross-coupling of secondary allylic alcohol and primary alcohol is reported to afford the corresponding α-alkenyl or alkylation products. These catalytic protocols proceed via acceptorless dehydrogenative coupling (ADC) or borrowing hydrogen (BH) strategies, which liberates water and/or hydrogen as the only byproducts. Highly abundant manganese-based pincer catalysts catalyze the reactions.

Front Cover: Ruthenium(II)‐Catalyzed Direct Ortho Functionalization of 1‐Arylpyrazoles with Maleimides: A Condition Controlled Installation of Succinimides and Maleimides on Arenes (Asian J. Org. Chem. 9/2021)

Ruthenium(II)-catalyzed switchable ortho C−H activation of 1-arylpyrazoles with maleimides has been achieved. This divergent reaction selectively installs various succinimide and maleimide substituents on the aromatic ring of 1-arylpyrazoles. Depending on the acidic or basic reaction conditions, a wide range of alkylation and alkenylation products are obtained, without the formation of bis-adducts. More information can be found in the Full Paper by Y. R. Lee and co-workers.

Experimental and Computational Studies on the Ruthenium-Catalyzed Dehydrative C-H Coupling of Phenols with Aldehydes for the Synthesis of 2-Alkylphenol, Benzofuran, and Xanthene Derivatives.

The cationic Ru-H complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1) was found to be an effective catalyst for the dehydrative C-H coupling reaction of phenols and aldehydes to form 2-alkylphenol products. The coupling reaction of phenols with branched aldehydes selectively formed 1,1-disubstituted benzofurans, while the coupling reaction with salicylaldehydes yielded xanthene derivatives. A normal deuterium isotope effect was observed from the coupling reaction of 3-methoxyphenol with benzaldehyde and 2-propanol/2-propanol-d8 (kH/kD = 2.3 ± 0.3). The carbon isotope effect was observed on the benzylic carbon of the alkylation product from the coupling reaction of 3-methoxyphenol with 4-methoxybenzaldehyde (C(3) 1.021(3)) and on both benzylic and ortho-arene carbons from the coupling reaction with 4-trifluorobenzaldehdye (C(2) 1.017(3), C(3) 1.011(2)). The Hammett plot from the coupling reaction of 3-methoxyphenol with para-substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H, F, Cl, CF3) displayed a V-shaped linear slope. Catalytically relevant Ru-H complexes were observed by NMR from a stoichiometric reaction mixture of 1, 3-methoxyphenol, benzaldehyde, and 2-propanol in CD2Cl2. The DFT calculations provided a detailed catalysis mechanism featuring an electrophilic aromatic substitution of the aldehyde followed by the hydrogenolysis of the hydroxy group. The calculations also revealed a mechanistic rationale for the strong electronic effect of the benzaldehdye substrates p-X-C6H4CHO (X = OMe, CF3) in controlling the turnover-limiting step. The catalytic C-H coupling method provides an efficient synthetic protocol for 2-alkylphenols, 1,1-disubstituted benzofurans, and xanthene derivatives without employing any reactive reagents or forming wasteful byproducts.

The shape selectivity of zeolites in isobutane alkylation: An investigation using CBMC and MD simulations

The adsorption and diffusion behaviors of C8 isomers and C9 component as main products of the isobutane alkylation catalyzed by zeolites with different topologies were investigated using configurational bias Monte Carlo (CBMC) and MD simulations in this work. The adsorption capacity of zeolites at 353 K and 2.0 MPa relies on their pore volume with the order of FAU > BEA > LTL > MOR. The diffusion coefficient of C8 and C9 molecules increases with the decrease of loading and the increase of temperature, and the more compact molecules diffuse slower than the slimmer ones at low loadings while quicker at higher loadings. It was found that for zeolites, small adsorption heat of C8 isomers, or large molecular diffusion coefficient would correspond to a high selectivity of target alkylates. Particularly, BEA zeolite with large RPLD/LCD shows high reaction selectivity, rendering it a good candidate catalyst for C4 alkylation.

Direct, Catalytic α-Alkylation of N-Heterocycles by Hydroaminoalkylation: Substrate Effects for Regiodivergent Product Formation.

Saturated N-heterocycles are prevalent in pharmaceutical and agrochemical industries, yet remain challenging to catalytically alkylate. Most strategies for C-H activation of these challenging substrates use protected amines or high loadings of precious metal catalysts. We report an early transition-metal system for the broad, robust, and direct alkylation of unprotected amine heterocycles with simple alkenes. Short reaction times are achieved using an in situ generated tantalum catalyst that avoids the use of bases, excess substrate, or additives. In most cases, this catalyst system is selective for the branched reaction product, including examples of products that are generated with excellent diastereoselectivity. Alkene electronic properties can be exploited for substrate-modified regioselectivity to access the alternative linear amine alkylation product with a group 5 catalyst. This method allows for the facile isolation of unprotected N-heterocyclic products, as useful substrates for further reactivity.

Molecular Dosimetry of Temozolomide: Quantification of Critical Lesions, Correlation to Cell Death Responses, and Threshold Doses.

Temozolomide (TMZ) is a DNA-methylating agent used in cancer chemotherapy, notably for glioblastoma multiforme (GBM), where it is applied as a front-line drug. One of the DNA alkylation products of TMZ is the minor lesion O6 -methylguanine (O6 MeG), which is responsible for nearly all genotoxic, cytotoxic, and cytostatic effects induced in the low-dose range relevant for cancer therapy. Here, we addressed the question of how many O6 MeG adducts are required to elicit cytotoxic responses. Adduct quantification revealed that O6 MeG increases linearly with dose. The same was observed for DNA double-strand breaks (DSB) and p53ser15. Regarding apoptosis, hockeystick modeling indicated a possible threshold for A172 cells at 2.5 μmol/L TMZ, whereas for LN229 cells no threshold was detected. Cellular senescence, which is the main cellular response, also increased linearly, without a threshold. Using a dose of 20 μmol/L, which is achievable in a therapeutic setting, we determined that 14,000 adducts give rise to 32 DSBs (γH2AX foci) in A172 cells. This leads to 12% cell death and 35% of cells entering senescence. In LN229 cells, 20 μmol/L TMZ induced 20,600 O6 MeG adducts, 66 DSBs (γH2AX foci), 24% apoptosis, and 52% senescence. The linear dose response and the genotoxic and cytotoxic effects observed at therapeutically relevant dose levels make it very likely that the TMZ target concentration triggers a significant cytotoxic and cytostatic effect in vivo Despite a linear increase in the O6 MeG adduct level, DSBs, and p53 activation, the low curative effect of TMZ results presumably from the low rate of apoptosis compared to senescence.

C2-selective alkylation of pyridines by rhodium–aluminum complexes

A C2- and mono-selective alkylation of various pyridines and azines with unactivated alkenes and vinylarenes using a heterobimetallic Rh–Al catalyst is reported. The use of aliphatic alkenes exclusively affords the linear alkylation products, while vinylarenes mainly afford branched alkylation products. The details of the reaction mechanism are revealed by DFT calculations: the reductive elimination of the products is rate-determining, which is consistent with the experimental results. The origin of the linear/branched selectivity is elucidated based on deformation/interaction analysis.

Coalescence-adsorption coupling treatment instead of alkaline washing-water washing process for efficient removal of sulfuric acid and sulfates

C4 alkylate oil is an ideal blending component of automotive gasoline, and the green removal of sulfuric acid and sulfates from the high-temperature sulfuric acid alkylation reaction products (SAARP) has always been a hot issue in the field of clean alkylation production. In this paper, a novel coalescence separation-depth adsorption (CS-DA) coupling dry separation technique is introduced to efficiently separate acid-hydrocarbon emulsions, with the aim to supersede the alkaline washing-water washing (AW-WW) process in alkylation unit. Lateral line tests were conducted on the coupling treatment of the alkylation reaction products (ARP) produced in the STRATCO alkylation unit of Sinopec Tianjin Branch. The sulfur morphology analysis shows that the sulfides in the ARP mainly come from C4 feedstocks and alkylation reaction, including mercaptans, thioethers, thiophenes, trace hydrogen sulfide and sulfur dioxide. The mechanism of coalescence separation reveals that the efficient removal process of sulfuric acid by fiber coalescence separation also has a function similar to "pickling extraction" to remove sulfates. In addition, we investigated the influence of CS-DA coupling treatment on the total sulfur and sulfuric acid content in the ARP and performed the copper corrosion and water-soluble acid assays. The research findings indicated that the back sideline of the acid coalescer had the most outstanding separation effect relative to the front and rear lateral lines of the heat exchanger. The total sulfur content in the ARP after separation can be reduced to less than 5 mg/L, without water-soluble acid and copper corrosion (1a). The industrial application shows that the CS-DA coupling dry separation technique can completely replace the AW-WW process, which makes the various indicators of alkylate oil strictly controlled and the sulfur content up to the industrial standard. The novel dry separation technique provides a promising alternative for solving the difficulties in the emulsion treatment of high-temperature sulfuric acid alkylation and promoting the clean production of alkylation.

Deuterium-Labeling Studies on the C–H/Olefin Coupling of Aromatic Ketones Catalyzed by Fe(PMe3)4

AbstractDeuterium-labeling experiments were performed for the Fe(PMe3)4-catalyzed C–H/olefin coupling using a deuterium-labeled aromatic ketone with various alkenes. While the reactions with a variety of alkenes provided the linear alkylation products formed via 1,2-insertion of alkene into an Fe–H bond, the reversible 2,1-insertion proceeded during the reaction highly depends on the choice of the alkene. No H/D scrambling resulting from 2,1-insertion/β-elimination was detected for the reactions with a vinylsilane and N-vinylcarbazole, but the reactions­ with styrenes are considered to involve rapid 2,1-insertion/ β-elimination processes to cause significant levels of H/D scrambling.

Rh(II)-Catalyzed C-H Alkylation of Benzylamines with Unactivated Alkenes: The Influence of Acid on Linear and Branch Selectivity.

The Rh-catalyzed C-H alkylation of benzylamine derivatives with unactivated 1-alkenes that proceeds via a picolinamide directing group is reported. The crucial role of an acid additive in this transformation is confirmed. Aromatic acids showed high linear selectivity, and aliphatic acids provided branched alkylation products as the major product. The reaction has a broad scope for benzylamines and alkenes. Deuterium labeling experiments suggest that a Rh-carbene intermediate is involved in the case of linear product formation. A different reaction pathway, however, appears to be involved in the case of branched alkylation products, and this pathway also appeared to be a minor pathway in linear-selective reactions.

One-Pot Reductive Alkylation of 2,4-Dihydroxy Quinolines and Pyridines.

A one-pot, Hantzsch ester-mediated Knoevenagel condensation-reduction reaction has been developed for alkylation of a wide range of substituted 2,4-quinoline diols and 2,4-pyridine diols with aldehydes. The process is operationally simple to perform, scalable, and provides highly useful C-3 alkylated quinoline and pyridine diols in yields of 58-92%. The alkylation products can be converted to 2,4-dihaloquinoline and pyridine substrates for further functionalization.

A journey into metal–carbon bond homolysis

This article surveys the current knowledge in metal alkyl complexes with homolytically weak metal–carbon bonds, therefore prone to thermally produce alkyl radicals. It outlines the role of a metal complex as a moderator to control the radical reactivity (“persistent radical effect”). It describes the methods that have been used so far (as well as others that are potentially available) to investigate the metal–carbon bond cleavage thermodynamic and kinetic parameters, including their caveats and limitations. A number of systems scrutinized in the author’s own laboratory and in those of collaborators are presented and discussed. These investigations have combined metal complexes and alkyl radicals, with guidance and understanding provided by DFT calculations, to achieve higher performance in the controlled radical polymerization of challenging monomers (vinyl acetate, vinylidene fluoride) and in olefin radical cross-coupling, and have brought to light mechanistic questions of more general relevance.

Acid- and Base-Switched Palladium-Catalyzed γ-C(sp3)-H Alkylation and Alkenylation of Neopentylamine.

The functionalization of remote unactivated C(sp3)-H and the reaction selectivity are among the core pursuits for transition-metal catalytic system development. Herein, we report Pd-catalyzed γ-C(sp3)-H-selective alkylation and alkenylation with removable 7-azaindole as a directing group. Acid and base were found to be the decisive regulators for the selective alkylation and alkenylation, respectively, on the same single substrate under otherwise the same reaction conditions. Various acrylates were compatible for the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. The alkenylation protocol could be further extended to acrylates with natural product units and α,β-unsaturated ketones. The preliminary synthetic manipulation of the alkylation and alkenylation products demonstrates the potential of this strategy for structurally diverse aliphatic chain extension and functionalization. Mechanistic experimental studies showed that the acidic and basic catalytic transformations shared the same six-membered dimer palladacycle.

Octane compositions in sulfuric acid catalyzed isobutane/butene alkylation products: experimental and quantum chemistry studies

Octanes in alkylation products obtained from industrial alkylation were studied by batch experiments. More than eight octane isomers were identified and quantified by gas chromatography-mass spectrometry. Based on a classic carbenium ion mechanism, the carbocation transition states in concentrated sulfuric acid catalyzed alkylation were investigated using quantum-chemical simulations and predicted the concentration and octane isomerization products including trimethylpentane and dimethylhexane as well as the formation of heavier compounds that resulted from the oligomerization of octane and butene. The agreement between model calculations and experimental data was quite satisfactory. Calculation results indicated that composition and content of trimethylpentanes in the alkylation products were 2,2,4-trimethylpentane > 2,3,3-trimethylpentane > 2,3,4-trimethylpentane > 2,2,3-trimethylpentane whether the 2-butene or i-butene acts as olefin. Heavier compounds in the alkylate were primarily formed by the oligomerization of dimethylhexane with 1-butene. Hopefully, the carbocation transition state models developed in this work will be useful for understanding the product distributions of octane in alkylation products.

Ruthenium-catalyzed stereospecific benzylic alkylation of optically active benzyl esters with malonate nucleophiles

The transition metal-catalyzed stereospecific benzylic alkylation of optically active benzyl esters with active methylene compounds remains extremely rare. Herein, we describe the study for the ruthenium-catalyzed benzylic alkylation of chiral benzyl esters with malonates as a carbon nucleophile. A combination of [Cp*RuCl2]2 and picolinic acid found to be effective for the title reaction, providing the chiral benzylic alkylation products with retention of stereochemistry of the starting material. We proposed that the ruthenium catalysis would proceed via a double inversion mechanism.

Polycyclic aromatic hydrocarbons in the Mukundpura (CM2) Chondrite

Soluble polycyclic aromatic hydrocarbons (PAHs) have been measured in Mukundpura (MK) CM2 carbonaceous chondrite using Gas Chromatography-Mass Spectrometry (GC-MS). The data show high yields of PAHs with the presence of 2, 3, and 4 ring polycyclic aromatic hydrocarbons along with heterocyclic nitrogen and sulfur-containing compounds. MK also shows the presence of significant amount of alkylation products. The distribution and relative abundances of PAHs in the MK are discussed in context of its petrographic grade and correlation with aqueous alteration.