Electron-rich Aromatic Aldehydes Research Articles

Cascade Aza-Prins/Friedel-Crafts Reaction of Homocinnamyloxycarbamate and Aromatic Aldehydes Yielding Aromatic Ring-Annulated Hydrocyclopenta-1,2-oxazinane.

The cascade aza-Prins/Friedel-Crafts reaction of homocinnamyloxycarbamate with electron-rich aromatic aldehydes has been successfully established. Most of the aromatic aldehydes react with the carbamate stereoselectively to generate cis-hydroindeno-1,2-oxazinanes. However, the cascade reactions of benzaldehydes bearing two methoxy groups at the meta-positions exhibit a unique stereochemical profile. Furthermore, the cascade reaction of benzaldehyde bearing three methoxy groups at the meta- and para-positions proceeds along with a skeletal rearrangement. Additionally, the aza-Prins/Ritter reaction of cinnamyloxycarbamate with various aldehydes was found during the development of the cascade reaction. In contrast to the cascade aza-Prins/Friedel-Crafts reaction, the aza-Prins/Ritter reaction gave trans-disubstituted isoxazolidines. These stereochemical profiles for both reactions were considered on the basis of several transition-state models.

Ultrasound-assisted and Efficient Multicomponent Synthesis of 4H-Pyran Derivatives catalyzed by LiOH.H2O in Water.

It is well established that 4H-pyran derivatives hold a significant position in synthetic organic chemistry due to their diverse biological and pharmacological properties. This work aims to introduce a novel synthetic pathway for highly functionalized 4H-pyran derivatives, achieved through a 1,4-Michael addition followed by a cascade cyclization. This reaction is catalyzed by LiOH·H2O under ultrasonic irradiation in water, offering an efficient and environmentally friendly approach. In this study, lithium hydroxide monohydrate (LiOH·H2O) was used as the catalyst. To explore environmentally friendly methods, two novel approaches utilizing pure water were investigated (Method 1 and Method 2). The first method in-volves the use of alkylidene reagents malononitrile and ethyl acetoacetate in an aqueous medium. The second method features a multi-component cyclocondensation of aromatic aldehydes, malononitrile, and ethyl acetoacetate, activated by ultrasound waves and conducted in pure water. The impact of various substituents on the formation of 4H-pyrans, including both electron-poor and electron-rich aromatic aldehydes, was also evaluated. Most products were obtained in high yield and as very pure crystals with distinct colors. Generally, aromatic aldehydes with electron-withdrawing groups (Cl) exhibited greater reactivity than those with electron-donating groups (OMe). This trend is clearly demonstrated when comparing entries 3 and 4 with entries 5 and 6 in Tables 1-6. Compared to other procedures, this method is simple, fast, eco-compatible since it uses water as a solvent. In addition, the products are obtained in good yields in the pure state after simple recrystallization without the need for other purification techniques, such as column chromatography. These factors make this novel approach highly attractive for the synthesis of 4H-pyrans.

Knoevenagel reaction promoted by functional ionic liquids with primary and tertiary amines

ABSTRACT Functional ionic liquids have been widely used in the fields of synthetic chemistry, analytical chemistry, electrochemistry and material chemistry owing to their excellent properties such as easy structure modification and adjustable properties. In this work, a series of basic functionalized ionic liquids were prepared from 1, 4-diazabicyclo [2.2.2] octane (DABCO) or hexamethylenetetramine (HMTA) with various halogenated hydrocarbons, then these functional ionic liquids and water were used as solvent-catalyst system in the Knoevenagel reaction of various aldehydes with ethyl cyanoacetate or malononitrile, the influence of the structure of the ionic liquid and the content of water was investigated. The results showed that the composite solvent-catalyst system mixed by the functional ionic liquid N-(3-aminopropyl)-1,4-diazabicyclo [2.2.2] octane bromide with water can effectively promote the Knoevenagel reaction and the alkalinity of amine and hydrogen bond play an important role. Aromatic aldehydes with electron-donating or electron-withdrawing groups can obtain the target product at an excellent yield (79-99%). It is worth noting that the polycyclic aromatic aldehydes with high steric hindrance, 86%-95% yields of the object products were also obtained after 15 h-25 h. Furthermore, the catalyst could be reused for 6 times without any loss in its catalytic activity. The composite solvent-catalyst system mixed by the Functional ionic liquid N-(3-aminopropyl)-1,4-diazabicyclo[2.2.2]octane bromide with water can effectively promote the Knoevenagel reaction, even for the electron-rich aromatic aldehydes with poor reactivity, high yields of the target products and fast reaction rate were also obtained at room temperature.

Synthesis of β,β-Disubstituted Styrenes via Trimethylsilyl Trifluoromethanesulfonate-Promoted Aldehyde-Aldehyde Aldol Coupling-Elimination.

In the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine, α,α-disubstituted aldehydes condense with electron-rich aromatic aldehydes to yield β,β-disubstituted styrenes. More electron-rich aromatic aldehydes react more rapidly and in higher yield. Preliminary results suggest that the reaction may proceed via the ionization and formal deformylation of an aldol intermediate.

Selective PdII‐Catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin Analogues and Tolmetin

The PdII‐catalyzed C‐2 acylation of pyrrole with aldehydes in the presence of TBHP as oxidant has been studied for the synthesis of di(hetero)aryl ketones. The use of 2‐pyrimidine as directing group leads to 2‐acylpyrroles in moderate to good yields, although 2,5‐diacylpyrroles are obtained as by products. This side‐reaction could be avoided using 3‐methy‐2‐pyridine as directing group, obtaining selectively 2‐acylpyrroles. The reaction has been extended to a series of aromatic and heteroaromatic aldehydes, obtaining the best results with electron rich aromatic aldehydes. The methodology has been applied in the synthesis of pyrrolomycin alkaloid Celastramycin analogues and for an improved synthesis of Tolmetin, a nonsteroidal anti‐inflammatory drug.

Iodine mediated a simple strategy for the synthesis of β,γ-unsaturated-α-ketoesters and its application for the synthesis of 4,5-dihydropyrazole derivatives

Novel and efficient method for the synthesis of a series of β,γ-unsaturated-α-ketoesters under mild conditions was developed. This one-step protocol was achieved by the reaction of electron-rich aromatic aldehydes and pyruvates in the presence of 10 mol% of molecular iodine in solvent-free condition at 80 °C temperature. A wide variety of substrates bearing electron releasing groups on aromatic ring were well tolerated and delivered corresponding β,γ-unsaturated-α-ketoesters in moderate to good yields. These β,γ-unsaturated-α-ketoesters have been further utilized in the synthesis of 4,5-dihydropyrazole derivatives.

Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes.

Oxazolium salts were successfully employed for the first time as organocatalysts for benzoin, Stetter, and redox esterification reactions. An N-mesityl oxazolium salt catalyzed homobenzoin reaction of aromatic, heteroaromatic, and aliphatic aldehydes delivered α-hydroxy ketones in high yields. This new type of catalyst proved remarkably effective for the Stetter reaction of challenging substrates such as β-alkyl-α,β-unsaturated ketones and electron-rich aromatic aldehydes in comparison to common thiazolium and triazolium salts.

Direct Enantio- and Diastereoselective Oxidative Homocoupling of Aldehydes.

A novel strategy for the direct enantioselective oxidative homocoupling of α-branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon-carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines. Experimental mechanistic investigations based on competition experiments combined with computational studies indicate that the reaction proceeds through a radical cation intermediate and that reactivity and stereoselectivity follow different trends.

Utilization of Donor-Acceptor Interactions for the Catalytic Acceleration of Nucleophilic Additions to Aromatic Carbonyl Compounds.

A conceptually new method for the catalytic electrophilic activation of aromatic carbonyl substrates, by utilizing donor-acceptor interactions between an electron-deficient macrocyclic boronic ester host ([2+2]BTH-F ) and an aromatic carbonyl guest substrate, was realized. In the presence of a catalytic amount of [2+2]BTH-F , dramatic acceleration of the nucleophilic addition of a ketene silyl acetal towards either electron-rich aromatic aldehydes or ketones was achieved. Several control experiments confirmed that inclusion of the aromatic substrates within [2+2]BTH-F , through efficient donor-acceptor interactions, is essential for the acceleration of the reaction.

Passerini/Friedel–Crafts Route towards Indole Derivatives

The Passerini adducts of various electron-rich aromatic aldehydes with pivalic acid were used as electrophiles towards indoles in a Friedel–Crafts-type reaction. The Friedel–Crafts step was performed under microwave conditions using a catalytic amount of FeCl3.

Piperazine as Leaving Group in A3 Adducts: Fast Access to Alkynyl Indoles

The A3 coupling between N-ethylpiperazine and electron-rich aromatic aldehydes forms adducts that may be easily used as electrophiles towards electron-rich heterocycles such as indoles. The removal of the piperazine moiety is triggered by the addition of 1,2-dibromoethane. Overall, the reaction provides efficient access to alkynyl indoles and pyrroles.

A CuAAC-Hydrazone-CuAAC Trifunctional Scaffold for the Solid-Phase Synthesis of Trimodal Compounds: Possibilities and Limitations.

We present a trifunctional scaffold designed for the solid-phase synthesis of trimodal compounds. This scaffold holds two alkyne arms in a free and TIPS-protected form for consecutive CuAAC (copper(I)-catalyzed azide–alkyne cycloaddition), one Fmoc-protected hydrazide arm for reaction with aldehydes, and one carboxylic acid arm with CF2 groups for attachment to the resin and 19F-NMR quantification. This scaffold was attached to a resin and derivatized with model azides and aliphatic, electron-rich or electron-poor aromatic aldehydes. We identified several limitations of the scaffold caused by the instability of hydrazones in acidic conditions, in the presence of copper during CuAAC, and when copper accumulated in the resin. We successfully overcame these drawbacks by optimizing synthetic conditions for the derivatization of the scaffold with aromatic aldehydes. Overall, the new trifunctional scaffold combines CuAAC and hydrazone chemistries, offering a broader chemical space for the development of bioactive compounds.

A Facile Synthesis ofN-H- andN-Substituted Acridine-1,8-diones under Sonic Condition

Synthesis of an assembly of structurally important N-H- and N-substituted acridine-1,8-diones by CAN (ceric ammonium nitrate) catalysed one-pot four-component reaction of electron-deficient and electron-rich aromatic aldehydes and aromatic amines or ammonium acetate and dimedone or cyclohexyl-1,3-diones at 26°C under sonic condition is reported. The method is clean and energy efficient as it uses a greener method and an eco-friendly catalyst.

“Extreme” Ugi Reactions With Some Complex α-Amino Acids

The Ti(IV)-catalyzed Ugi condensation of α-amino acids with electron-rich aromatic aldehydes performs adequately even with sterically demanding α-amino carboxylate salts. The reaction occurs diastereoselectively, in some cases with virtually complete diastereoselectivity. A stereochemical rationale for the reaction is proposed.

A tandem olefin migration and Prins cyclization using Cu(OTf)2–bisphosphine complexes: an improved synthesis of functionalized tetrahydropyrans

In situ-generated (bis-DPPMB)–Cu(OTf)2 complex has been examined to catalyze a tandem olefin migration and Prins cyclization of an alkenol with various aldehydes. The reaction proceeded with electron-rich aromatic aldehydes at room temperature and provided functionalized tetrahydropyrans in good yields. An efficient synthesis of the bis-DPPMB ligand has also been described.

ChemInform Abstract: AlCl3‐Promoted Highly Regio‐ and Diastereoselective [3 + 2] Cycloadditions of Activated Cyclopropanes and Aromatic Aldehydes: Construction of 2,5‐Diaryl‐3,3,4‐trisubstituted Tetrahydrofurans.

AbstractThe reaction with electron‐rich aromatic aldehydes allows facile and selective access to 2,4‐trans‐2,5‐trans‐pentasubstituted tetrahydrofurans.

Controlled Diastereo- and Enantioselection in a Catalytic Asymmetric Aziridination

Chiral polyborate based Brønsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.

Fluorinated 1-phenyl-1H-tetrazol-5-yl sulfone derivatives as general reagents for fluoroalkylidene synthesis.

Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation followed by electrophilic fluorination. Although metalation-fluorination of n-propyl, 5-hexenyl, and (cyclopropyl)methyl PT-sulfones proceeded under homogeneous conditions, fluorination of 2-methyl-2-propenyl PT-sulfone required heterogeneous fluorination conditions. Condensation reactions of fluoro PT-sulfones with aldehydes resulted in fluoroalkylidenes in high yields. Screening of olefination conditions showed that stereoselectivity depended on reagent and carbonyl structure and can in many cases be tuned either toward E- or Z-selectivity. For example, LHMDS-mediated condensations of 1-fluoropropyl PT-sulfone in the presence of MgBr(2) x OEt(2) were Z-selective with electron-rich aromatic aldehydes, a hindered aromatic aldehyde, and cinnamaldehyde. Low-temperature KHMDS-mediated condensations were E-selective with electron-rich and electron-deficient aromatic aldehydes and Z-selective with n-octanal. Dialkyl, aryl alkyl, and diaryl ketones reacted as well to give fluoro olefin products in 71-99% yields.

Catalytic Asymmetric Aziridination with Catalysts Derived from VAPOL and VANOL

This Account describes the discovery and development of the catalytic asymmetric aziridination reaction (AZ reaction) that has been the subject of efforts in our laboratory over the last 12 years. The optimized catalyst system involves catalysts generated from either the VAPOL or VANOL ligand and triphenyl borate. These catalysts are effective for formation of aziridines from the reac­tion of imines that bear a N-benzhydryl substituent with stabilized diazo compounds including the commercially available ethyl diazoacetate (EDA). The reaction is general for N-benzhydryl im­ines prepared from electron-rich and electron-poor aromatic aldehydes, as well as from primary, secondary and tertiary aliphatic aldehydes. This reaction is highly enantioselective and diastereo­selective giving cis-3-substituted aziridine-2-carboxylates in excellent yields. This Account presents the scope of the AZ reaction as defined by the work that has been done in our laboratory up to the present time, as well as applications of the resulting aziridines that have been demonstrated to date.

P(PhCH2NCH2CH2)3N: An Efficient Lewis Base Catalyst for the Synthesis of Propargylic Alcohols and Morita−Baylis−Hillman Adducts via Aldehyde Alkynylation

Proazaphosphatrane P(PhCH(2)NCH(2)CH(2))(3)N (1a) is an efficient catalyst for the addition of aryl trimethylsilyl alkynes to a variety of aromatic, aliphatic, and heterocyclic aldehydes in THF at room temperature. The reaction conditions are mild and employ a low catalyst loading (ca. 5 mol %). Only propargylic alcohols were isolated in good to excellent isolated yields when electron-rich, electron-neutral, heterocyclic, and aliphatic aldehydes were employed, whereas beta-branched Morita-Baylis-Hillman (MBH) type adducts were isolated with electron-deficient aromatic aldehydes after conventional acid hydrolysis of the TMS ether products. Alkynes containing heterocyclic and aromatic groups bearing electron-withdrawing or -donating substituents underwent clean addition to cyclohexanecarboxaldehyde and to electron-rich aromatic aldehydes to give propargylic alcohols in excellent isolated yields. beta-Branched Morita-Baylis-Hillman (MBH) type adducts were isolated when electron-deficient aromatic aldehydes were employed. Reaction pathways to both types of products are proposed.