Monoalkylation Products Research Articles

Green Synthesis of Morpholines via Selective Monoalkylation of Amines.

Morpholines are common heterocycles in pharmaceutical and agricultural products, yet methods to synthesize them from 1,2-amino alcohols are inefficient. We report the simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and tBuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology is the identification of general conditions that allow for the clean isolation of monoalkylation products derived from a simple SN2 reaction between an amine and ethylene sulfate. Experiments suggest that the degree of selectivity is dependent upon the structure of reacting 1,2-amino alcohol as well as the unique properties of ethylene sulfate. This method can be used for the synthesis of a variety of morpholines containing substituents at various positions, including 28 examples derived from primary amines and multiple examples contained in known active pharmaceutical ingredients. We have conducted multiple examples on >50 g scale. We have also demonstrated the formal synthesis of a morpholine from a simple primary amine using ethylene sulfate. Overall, while this new methodology has many environmental and safety benefits relative to the traditional methods used to prepare morpholines from 1,2-amino alcohols, the most striking feature is the facile selective monoalkylation of a variety of primary amines. We have also explored various reactions beyond those related to the synthesis of morpholines, including obtaining proof-of-principle that ethylene sulfate can be used for the synthesis of piperazines and as a 2-carbon electrophile for fragment couplings.

Acidity-activity relationships in the solvent-free tert-butylation of phenol over sulfated metal oxides

Sulfated metal oxides have long been reported to exhibit enhanced acidity properties, which in turn affect reactivity. In this study, sulfated SnO2, TiO2 and ZrO2 of varying acidic properties were synthesized and utilized for the solvent-free alkylation of phenol with tert-butyl alcohol. Herein, it was observed that tert-butylation of phenol could be carried out at 120 °C with significant yield towards alkylated products; the majority was accounted for by the mono-alkylated products. Among the catalysts studied, SnO2 with high content of sulfation was found to be the more active. In-situ DRIFTS in the range of 25–500 °C was used to investigate the temperature evolution of sulfate species and differentiate between bidentate and tridentate configurations. By combining temperature-programmed desorption, in-situ DRIFTS and catalytic performance measurements a correlation between the ratio of Lewis to Brønsted acids and overall reactivity was observed.

Enhancing catalytic epoxide ring-opening selectivity using surface-modified Ti3C2T x MXenes

MXenes are a new family of two-dimensional carbides and/or nitrides. Their 2D surfaces are typically terminated by O, OH and/or F atoms. Here we show that Ti3C2T x —the most studied compound of the MXene family—is a good acid catalyst, thanks to the surface acid functionalities. We demonstrate this by applying Ti3C2T x in the epoxide ring-opening reaction of styrene oxide (SO) and its isomerization in the liquid phase. Modifying the MXene surface changes the catalytic activity and selectivity. By oxidizing the surface, we succeeded in controlling the type and number of acid sites and thereby improving the yield of the mono-alkylated product to >80%. Characterisation studies show that a thin oxide layer, which forms directly on the Ti3C2T x surface, is essential for catalysing the SO ring-opening. We hypothesize that two kinds of acid sites are responsible for this catalysis: In the MXene, strong acid sites (both Lewis and Brønsted) catalyse both the ring-opening and the isomerization reactions, while in the Mxene–TiO2 composite weaker acid sites catalyse only the ring-opening reaction, increasing the selectivity to the mono-alkylated product.

Study by NMR of Liquid-Phase Alkylation of Toluene with Hex-1-ene: Effect of Catalyst on Selectivity

In this work, the selectivity of different solid catalysts in the alkylation reaction of toluene with hex-1-ene has been studied in order to maximize mono-alkylated products. The reaction has been carried out in a fixed-bed reactor, at 120°C. An industrial alkylation catalyst has been used as a reference along with three commercial acid zeolites with difference structures (faujasite, mordenite and beta). All of catalysts achieved total conversion. Mono-alkyltoluenes selectivity was higher than 95% in all cases and formation of di-alkyltoluenes was less than 4.5%. The main products, mono-alkyltoluenes, were identified by Nuclear Magnetic Resonance spectroscopy. This work analyses the effect of physicochemical and structural properties of solid catalysts on the selectivity to the different alkylation products.

Influence of the hydrogen bond on the iteroselective O-alkylation of calix[4]resorcinarenes

The effect of the hydrogen bond on the reactivity of hydroxyl groups of tetra( p -hydroxyphenyl)calix[4]resorcinarene with glycidyl methacrylate was studied. When the O -alkylation reaction was carried out with tetra( p -methoxyphenyl)calix[4]resorcinarene, the exposed hydroxyl groups of the upper rim did not react in the presence of NaOH or pyridine. When the O -alkylation reaction of tetra( p -hydroxyphenyl)calix[4]resorcinarene was carried out in the presence of NaOH, the expected tetraalkylation product in the lower rim was obtained, whereas the monoalkylation product in the lower rim was obtained, when the reaction was carried out with pyridine as base. Spectroscopic evidence showed that the reaction is selective for one hydroxyl group in the lower rim without affecting the hydroxyl groups in the upper rim. Suitable crystals of tetra( p -hidroxyphenyl)calix[4]resorcinarene in DMSO were obtained from the reaction and were characterized through an X-ray crystal structure determination and showed that asymmetric unit contains eight molecules of DMSO, and analysis indicated that calix[4]resorcinarene prefers a chair configuration in the solid state. In the crystal array, classical hydrogen bond O–H⋯O interactions and intermolecular contacts were observed. The formation of these crystals confirms the low reactivity of this conformer in the process. • O -Alkylation is regioselective. • Crown conformer is reactive. • Resorcinarene in chair conformation does not react.

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids.

(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.

Aluminium Oxide Supported on SBA-15 Molecular Sieves as Potential Lewis Acid Catalysts for Epoxide Ring Opening Using Aniline

A series of aluminium oxide (Al2O3)-supported SBA-15 molecular sieves were prepared using a one-step wet-impregnation method. Powder X-ray diffraction, nitrogen adsorption/desorption, infrared spectroscopy and ammonia TPD were used to investigate the structures and chemical natures of the surface-bound species. The FT-IR studies of metal-impregnated SBA-15 materials revealed strong covalent interaction of Al2O3 on SBA-15 materials with strong Lewis acidic properties, evident from ammonia-TPD studies. The metal oxide-supported SBA-15 catalysts are active for epoxide ring opening with aniline at room temperature, and showed remarkably high stability and selectivity towards mono-alkylated products (about 86%) viz., 1-(phenylamino)propan-2-ol and 2-(phenylamino)propan-1-ol. The catalytic activities remained intact after several recycles. The observed activities and selectivities were compared with other metal oxide-loaded SBA-15 catalysts obtained by similar preparation methods. Aluminium oxide supported SBA-15 molecular sieves were prepared using a one-step wet-impregnation method. The materials showed strong Lewis acidic sites and promising catalytic activity for epoxide ring opening with aniline at room temperature.

Improving the selectivity to 4-tert-butylresorcinol by adjusting the surface chemistry of heteropolyacid-based alkylation catalysts

Keggin tungstophosphoric acid (H3PW12O40, HPW) was immobilized onto Santa Barbara Amorphous (SBA-15) type silica to obtain selective catalysts for the resorcinol tert-butylation with methyl-tert-butyl ether. The challenge was to enhance the reaction selectivity to the mono-alkylated product i.e. 4-tert-butylresorcinol at the expenses of other more thermodynamically favored products as the 4,6-di-tert-butylresorcinol. Using HPW@SBA15 catalysts, remarkable selectivity to 4-tert-butylresorcinol was obtained, up to 42% (at 20% of resorcinol conversion). Our finding is that the change in the product distribution was dependent on the catalyst surface chemistry: 4TBR selectivity can be increased adjusting the fraction of Brønsted acid sites versus Lewis ones at the catalyst surface.

Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions

A simple procedure for the conversion of tertiary lactams to 2-monoalkylated cyclic amines is described. The reaction sequence involves conversion of a lactam to a thioiminium ion followed by reaction with an organocopper (RCu) reagent and final reduction with triacetoxyborohydride. The reaction is high yielding and shows an excellent functional group tolerance. Its utility is demonstrated by a rapid synthesis of indolizidine 167B. The excellent chemoselectivity of the process, where only monoalkylation products are formed, is rationalized by a mechanism involving the formation of a transient enamine.

Zn-loaded HY zeolite as active catalyst for iso-propylation of biomass-derived phenolic compounds: A comparative study on the effect of acidity and porosity of zeolites

Liquid bio-oil formed from pyrolysis of lignocellulosic biomass needs further upgradation by CC bond formation reaction between the phenolic compounds and small oxygenates to retain the maximum amount of carbon in the fuel range (C10C13), prior to hydrodeoxygenation step. In this contribution, we have explored the gas-phase alkylation of m-cresol with iso-propanol over zeolites like HZSM5, HBEA, HMCM22, HY, and ZnY solid acid catalysts. The fresh and spent catalysts were characterized by XRD, N2 sorption, ICP-MS, Py-FTIR, NH3-TPD, SEM, and TEM techniques. The time-on-stream and temperature studies were carried out over these catalysts at a WHSV value of 2.8h−1 to analyze the role of different active acidic sites as well as their pore dimensions on the catalytic activity and product distribution. Among all the catalysts, formation of thymol by C-alkylation was highly dominant over ZnY which has strong Lewis acid sites. Coke analysis revealed that HBEA was found to rapidly deactivate by coking (16.4% coke) and pore blocking. Time-on-stream study at 250°C showed that maximum conversion of m-cresol (92%) was obtained on fresh ZnY catalyst having strong Lewis acidity and moderate Bronsted acidity, confirming the fact that strong Lewis acidity in combination with Bronsted acidity improved the stability of iso-propyl cation and consequently, enhanced the conversion of m-cresol. Moreover, the presence of Zn2+ content in FAU zeolite framework was found to alter its acid site distribution and pore volume as compared to HY zeolite and resulted in predominant mono-alkylated product formation, especially thymol.

Synthesis of high-density biofuel with excellent low-temperature properties from lignocellulose-derived feedstock

Converting chemicals that can be derived from lignocellulose to cyclic hydrocarbons is a promising route for the synthesis of high-density biofuels. But the low-temperature properties of most synthesized fuels are not good, with high viscosity and freezing point. Herein, we presented the synthesis of cyclohexane derivatives by the alkylation of aromatic oxygenates (anisole, guaiacol and phenol) with furfural alcohol (furfuryl alcohol and 5-hydroxymethylfurfural), followed with hydrodeoxygenation. It is found that FeCl3 exhibits relatively high activity and selectivity for the alkylation of anisole (guaiacol), and AlCl3 is the best catalyst for phenol. The selectivity of mono-alkylation product is 71.0%, 92.4% and 84.3% for the alkylation of anisole, guaiacol and phenol with furfuryl alcohol when the reactant ratio is 10, respectively. A semi-continuous operation was adopted for the alkylation of furfuryl alcohol to improve the conversion of aromatic oxygenates. When furfuryl alcohol is replaced by 5-hydroxymethylfurfural, the selectivity reaches almost 100%, but the reaction is a little slower and longer time is needed to get full conversion. After hydrodeoxygenation by combination of Pd/C and HZSM-5, the alkylation product was converted to branched cyclohexane with density of 0.804g/cm3 at 20°C, kinematic viscosity of 34.4mm2/s at −60°C and freezing point lower than −80°C, which shows great potential as additive to promote the low-temperature properties of other fuels.

Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts.

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

Ruthenium-catalyzed direct N-alkylation of amines with carboxylic acids using methylphenylsilane as a hydride source

Direct N-alkylation of amines with carboxylic acids using a ruthenium catalyst with tris(pentafluorophenyl)phosphine as a ligand and methylphenylsilane as a reducing agent is described. Selective direct N-alkylation of amines was observed under these novel reaction conditions, and the corresponding mono-alkylated products were obtained in moderate to high yields with excellent selectivity. In addition, secondary amines were reacted with benzoic acid to afford the corresponding benzylated amines in moderate to high yields.

Heterogeneous para-phenylamino sulfonic acid ligand functionalized on MCM-41 derived from rice husk ash: Selective mono-alkylated products of tert-butylation of phenol

A new organo-inorganic hybrid material was prepared by immobilizing 3-(4-aminophenylamino)propane-1-sulfonic acid onto functionalized mesoporous MCM-41 via simple post-synthesis method. The hybrid organo MCM-41 preserved its hexagonal honey-comb configuration after both surface chemical modification and immobilization of sulfonic acid ligand. XRD analysis exhibited three well-resolved diffraction peaks corresponding to the highly ordered mesostructure. The five intense carbon peaks of solid-state CP-MAS 13CNMR spectroscopy confirmed the grafting of sulfonic acid ligand onto the well-structured MCM-41. Surface properties of the material revealed a pore size of 1.98nm and surface area of 468m2g−1. The catalytic performance of this hybrid material was tested in the alkylation of phenol with tert-butanol (TBA) and showed a high catalytic activity leading to 99.5% conversion of tert-butyl alcohol and high selectivity to monoalkylated products.

Synthesis of di(Imdazolium) and di(Pyrazolium) Salts as Precursors for N-heterocyclic Dicarbene Complexes

Alpha,omega-bis(pyrazol-1-yl)alkanes and alpha,omega-bis(imidazol-1-yl)alkanes with spacers consisting of four to ten methylene groups have been prepared from pyrazole, 3,5-dimethylpyrazole or imidazole and corresponding dibromoalkanes in a superbasic medium KOH-DMSO. The proposed method of synthesis allowed the preparation of new flexible bidentate ligands without the need to use toxic solvents and tedious workup procedures. Bis(pyrazol-1-yl)alkanes were further functionalized for their use as precursors for “non-classical” mesoionic N-heterocyclic carbene ligands. One the first step, iodine atoms were introduced to positions 4 of pyrazole rings by oxidative iodination using I2-HIO3 system. On the next step, nitrogen atoms in positions 2 of pyrazole rings were alkylated using several agents. Reaction with methyliodide unexpectedly led to the formation of only mono-alkylated products even after 7 days of refluxing in a neat alkyliodide. Methylation by trimethyloxonium tetrafluoroborate or methyltriflate led to dimethylated products in high yields. Bis(imidazol-1-yl)alkanes were easily alkylated by methyliodide to give di(imidazolium) salts – precursors to “classic” N-heterocyclic dicarbenes.

Phenyl-amino sulfonic solid acid-MCM-41 complex: A highly active and selective catalyst for the synthesis of mono-alkylated products in the solvent free tert-butylation of phenol

A simple post synthesis route was established for heterogenizing 3-(3-aminophenylamino)propane-1-sulfonic acid onto functionalized mesoporous MCM-41 to give an inorganic–organic hybrid, MCM-3-NHPhSO3H. The XRD analysis of the hybrid material exhibited three well-resolved diffraction peaks for the (100), (110) and (200) planes, which indicates the retention of the mesostructure. The 13C CP-MAS NMR spectroscopy of the hybrid material showed four intense carbon peaks from 107 to 131ppm, corresponding to the aromatic ring of the grafted ligand. Surface properties of the material revealed a pore size of 1.84nm and a specific surface area of 572m2g−1. The TEM images of the hybrid showed a well-ordered honey-comb structure after the series of modifications. The catalytic performance of MCM-3-NHPhSO3H resulted in 99% conversion of tert-butylphenol (TBA) with selectivity to only mono-alkylated products. The initial selectivity yield of 98% tert-butylphenol ether (TBPE) had decreased until a product distribution of 64% 2-(tert-butyl)phenol (2-TBP), 32% 4-(tert-butyl)phenol (4-TBP), 3% (TBPE) and 1% isobutene (IBE) was obtained. The catalyst could be regenerated without significant loss in reactivity.

Studies on the double alkylation of 2,2-disubstituted-1,3-dithiacycloalkane-S-oxides: synthesis of tertiary thiol derivatives

Di-alkylation of 2,2-dimethyl-1,3-dithiacycloalkane-S-oxides has been achieved allowing the synthesis of two tertiary thiol centres. The diastereoisomers of the mono-alkylated products have been shown to react at different rates. The X-ray crystal structures of three substituted dithiane-S-oxides have been determined, and the conversion of the dialkylated products into cyclic disulfide derivatives of tertiary thiols (1,2-dithiolanes) has been achieved by treatment with acid.

Alkylation of amines with alcohols catalyzed by palladium nanoparticles

Palladium nanoparticles (PdNPs) generated in situ from the complex [(dippe)PdMe2] were used as efficient catalyst for the alkylation of amines by aliphatic alcohols using neat conditions, under hydrogen atmosphere. On using short chain alcohols, the reaction resulted in the generation of dialkylated and trialkylated amines in high yields (>80%). The use of bulky alcohols allowed the production of mono-alkylated products, also in high yield.

The synthesis, characterization, and alkylation of nacnac chromium triflate derivatives

A Cr(III) triflate coordinated by the bulky β-diketiminate MeL iPr ( MeL iPr = 2,4-pentane N, N′-bis(2,6-diisopropylphenyl)diketiminate) was synthesized from the corresponding bridging iodide complex [ MeL iPrCr(μ-I)] 2 by ligand substitution and subsequent oxidation with silver triflate (AgOTf). MeL iPr Cr III(OTf) 2 exhibits rare trigonal bipyramidal geometry about Cr(III). Attempts to alkylate this triflate synthon with 1,4-dilithiobutane (Li(CH 2) 4Li) led to reduction, while reaction with dimethylzinc (ZnMe 2) led to a mono-alkylated product; only the reaction with methyl lithium (MeLi) was successful in generating a dialkyl.

Influence of chain length on mono- versus di-alkylation in the reactivity of [Pt2(μ-S)2(PPh3)4] towards α,ω-dihalo-n-alkanes; a synthetic route to platinum(II) ω-haloalkylthiolate complexes

Abstract The reactions of [Pt2(μ-S)2(PPh3)4] with α,ω-dibromoalkanes Br(CH2)nBr (n = 4, 5, 6, 8, 12) gave mono-alkylated [Pt2(μ-S){μ-S(CH2)nBr}(PPh3)4]+ and/or di-alkylated [Pt2(μ-S(CH2)nS}(PPh3)4]2+ products, depending on the alkyl chain length and the reaction conditions. With longer chains (n = 8, 12), intramolecular di-alkylation does not proceed in refluxing methanol, with the mono-alkylated products [Pt2(μ-S){μ-S(CH2)nBr}(PPh3)4]+ being the dominant products when excess alkylating agent is used. The bridged complex [{Pt2(μ-S)2(PPh3)4}2{μ-(CH2)12}]2+ was accessible from the reaction of [Pt2(μ-S)2(PPh3)4] with 0.5 mol equivalents of Br(CH2)12Br. [Pt2(μ-S){μ-S(CH2)4Br}(PPh3)4]+ can be cleanly isolated as its BPh4− salt, but undergoes facile intramolecular di-alkylation at −18 °C, giving the known species [Pt2(μ-S(CH2)4S}(PPh3)4]2+. The reaction of I(CH2)6I with [Pt2(μ-S)2(PPh3)4] similarly gives [Pt2(μ-S){μ-S(CH2)6I}(PPh3)4]+, which is fairly stable towards intramolecular di-alkylation once isolated. These reactions provide a facile route to ω-haloalkylthiolate complexes which are poorly defined in the literature. X-ray crystal structures of [Pt2(μ-S){μ-S(CH2)5Br}(PPh3)4]BPh4 and [Pt2(μ-S(CH2)5S}(PPh3)4](BPh4)2 are reported, together with a study of these complexes by electrospray ionisation mass spectrometry. All complexes fragment by dissociation of PPh3 ligands, and the bromoalkylthiolate complexes show additional fragment ions [Pt2(μ-S){μ-S(CH2)n−2CH CH2}(PPh3)m]+ (m = 2 or 3; m ≠ 4), most significant for n = 4, formed by elimination of HBr.