Sequential Aldol Research Articles

TfOH-Catalyzed Facile Access for One-Pot Synthesis of β-Acylamino Ketones by Avoiding the Usage of Acetyl Chloride

AbstractWe have developed a TfOH-catalyzed, highly efficient protocol for the synthesis of biologically active β-acylamino ketones from aldehyde, ketone, and nitrile by avoiding the use of acetyl chloride. The reaction proceeds through a sequential aldol reaction followed by a nucleophilic attack of nitrile and hydrolysis of nitrile in one pot. The attractive features of this tandem process are mild reaction conditions, high atom economy, broad substrate scope with 51–87% yield, gram-scale reaction, and ease of operation.

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

AbstractA reaction sequence of Diels–Alder cycloaddition and Tsuji–Trost allylation was examined in terms of its application to the synthesis of kopsinine and the related Kopsia alkaloids. Results of the studies in two synthetic directions are presented herein: 1) synthesis of the properly substituted diene, required for the Diels–Alder step; and 2) model studies and optimization of the key reaction sequence in the absence of side-chain. Details on the challenging introduction of the side-chain into tetrahydrocarboline ketone and its silylation, resulting in rare but unproductive vinylogous Claisen cyclization, and the successful Mannich/Mukaiyama aldol sequence are disclosed in the first direction. In the second direction, the endo-selective Diels–Alder reaction with allyl acrylate and Tsuji–Trost allylation providing incorrect stereochemistry are disclosed. Interaction of both dienes with an alkyne provides carbazoles via Alder–Rickert reaction.

Total Synthesis of des-Thiomethyllooekeyolide A.

The first asymmetric total synthesis and validation of the structural assignment of des-thiomethyllooekeyolide A (3) is described, which features a Shiina macrolactonization and a late-stage pyran-hemiketal formation. The eight stereogenic centers of the C16-polyketide chain were installed by sequential aldol and crotylation reactions.

Hf(OTf)4-Catalyzed Three-Component Synthesis of N-Carbamate-Protected β-Amino Ketones.

Hafnium(IV) triflate (Hf(OTf)4) has been identified as a potent catalyst for the direct three-component synthesis of β-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.

One Pot Sequential Aldol condensation - Michael Addition – Sonogashira, and Heck Arylation toward Highly Functionalized Quinolines

A facile Pd/Cu-cocatalyzed one-pot domino aldol condensation/Michael addition/Sonogashira coupling has been developed. The reaction of 2-chloro-3-formylquinolines (CFQs), 1 acetophenones (APs), 2 and terminal acetylenes, 3 by employing triethylamine as a base, solvent as well as a ligand under mild conditions gave highly functionalized 1,5-diphenyl-3-(2-(2-phenylethynyl)quinolin-3-yl)pentane-1,5-diones, 4a-j, Additionally accomplished Heck arylation using CFQs in the presence of Pd catalyst. The present methodology gave the desired synthetic building blocks in acceptable yields.

Transition metal-free functionalization of 2-oxindoles via sequential aldol and reductive aldol reactions using rongalite as a C1 reagent.

A sequential one-pot classical aldol, transition-metal and hydride-free reductive aldol reaction is reported here for C(sp3)- H functionalization of 2-oxindoles using the multifaceted reagent rongalite. Here, rongalite functions as a hydride-free reducing agent and double C1 unit donor. This protocol enables the synthesis of a wide range of 3-methylindoline-2-ones and 3-(hydroxymethyl)-3-methylindolin-2-ones from 2-oxindoles (65-95% yields), which are the synthetic precursors for many natural products. Some of the important aspects of this synthetic approach include one-pot methylation and hydroxymethylation, low-cost rongalite (ca. $0.03 per 1 g), mild reaction conditions and applicability to gram-scale synthesis.

Sulfa-Michael addition initiated one-pot tandem sequence: Construction of highly substituted 2-cyclopentenones from allylic cyanohydrins

A practical and facile one-pot protocol to construct highly substituted 2-vinyl 2-cyclopentenone derivatives from O-unsaturated acyl-substituted allylic cyanohydrins through a SMA triggered tandem sequence is described. In this process, a SMA triggered intramolecular aldol sequence, followed by a DBU-catalyzed intramolecular Aldol reaction and subsequent dehydroxylation were involved. This one-pot transformation proceeded smoothly under mild reaction conditions with efficiency.

Catalyst Repurposing Sequential Catalysis by Harnessing Regenerated Prolinamide Organocatalysts as Transfer Hydrogenation Ligands.

A catalyst repurposing strategy based on a sequential aldol addition and transfer hydrogenation giving access to enantiomerically enriched α-hydroxy-γ-butyrolactones is described. The combination of a stereoselective, organocatalytic step, followed by an efficient catalytic aldehyde reduction induces an ensuing lactonization to provide enantioenriched butyrolactones from readily available starting materials. By capitalizing from the capacity of prolineamides to act as both an organocatalyst and a transfer hydrogenation ligand, catalyst repurposing allowed the development of an operationally simple, economic, and efficient sequential catalysis approach.

Graphene oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions

Graphene oxide (GO) in conjunction with tetra n-butyl ammonium bromide (TBAB) was found to function as an efficient catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones in a single reaction vessel. Benzaldehydes and acetophenone were coupled in situ to produce their corresponding chalcones which underwent a subsequent aza-Michael addition under solvent-free condition. This procedure avoids the use of precious metals and the heterogeneous nature of the GO simplifies purification and isolation of the products by simple filtration of the catalyst.

2‐Deoxyribose‐5‐phosphate aldolase from Thermotoga maritima in the synthesis of a statin side‐chain precursor: characterization, modeling and optimization

AbstractBACKGROUNDProducing statin side‐chains by sequential aldol condensation catalyzed by 2‐deoxyribose‐5‐phosphate aldolase (DERA) (EC 4.1.2.4) is the best‐known and most promising synthetic route. The advantage of this process is the formation of two stereocenters in a single step starting from inexpensive achiral components, acetaldehyde and chloroacetaldehyde. The limitation for the industrial‐scale application is enzyme inactivation caused by substrates as well by the intermediate produced by single aldol addition.RESULTSThe DERA enzyme from Thermotoga maritima (DERATm) was investigated extensively in this work. The influence of aldehydes on DERATm stability was studied in detail. Mathematical models in different reactor configurations were developed based on experimentally determined kinetic parameters of all reactions included in the synthesis of statin side‐chain. Models also included enzyme inactivation by all compounds with negative impact on its stability. Mathematical model‐based optimization enabled optimization of process conditions and reactor configuration. The fed‐batch reactor proved to be the most suitable choice achieving product concentration of 78 g L−1, productivity of 56 g L day−1 and yield of 95% under an optimal condition.CONCLUSIONThe validated mathematical model and applied methodology can be exploited for further process improvement and for process design of similar systems. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

An Efficient and Transition Metal-Free Base-Promoted Multi-Component Synthesis of Aza-Fused Polysubstituted Pyrido[2′,3′:3,4]Pyrazolo[1,5-a]Pyrimidine Derivatives

An efficient and concise practical protocol for the synthesis of novel aza-fused polysubstituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine derivatives from a readily available aromatic aldehyde, acetophenone and 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine in presence of Ba(OH)2, under transition metal-free conditions, has been established. This transformation presumably occurs through a sequential Aldol reaction, imine-formation, intramolecular N-cyclization, auto-oxidation sequence of reactions. This protocol, which includes the formation of new C–C and C–N bonds, features a wide substrate scope with a broad range of functional group tolerance.

Enantioselective Synthesis of ABCF Tetracyclic Framework of Daphniphyllum Alkaloid Calyciphylline N.

Efforts toward the enantioselective synthesis of Daphniphyllum alkaloid calyciphylline N which leads to efficient preparation of the ABCF tetracyclic framework containing three bridgehead all-carbon quaternary stereocenters are described. This synthetic work features the utilization of an asymmetric conjugate addition to install the C5 all-carbon quaternary center, an efficient successive inter/intramolecular aldol sequence to build the critical bicyclo[2.2.2]octanone BC core, and a ring closing metathesis reaction followed by stereoselective Nagata conjugate cyanation to deliver the functionalized F ring.

Conversion of propionic acid and 3-pentanone to hydrocarbons on ZSM-5 catalysts: Reaction pathway and active site

Conversion of propionic acid to gasoline-range molecules was investigated at 350°C on a series of ZSM-5 catalysts with varying density of Brønsted acid sites (BAS), achieved by ion exchange of proton with Na+. Ketonization of propionic acid to 3-pentanone is the primary reaction, with the sequential aldol condensation to dipentanone alcohol being the secondary. The major reaction pathway for forming the aromatics involves dehydration, cyclization, dehydration and hydride transfer from dipentanone alcohol, leading to the formation of C10 aromatics before being dealkylated to lighter aromatics. Temperature programmed desorption of propionic acid indicates that the reaction initiates with acylium cation formation on BAS through dehydration. Comparing the turnover frequencies of ketonization and aldol condensation on ZSM-5 with varying density of BAS indicates that BAS is the active site for both reactions. The propionic acid feed deactivates the catalyst faster than the 3-pentantone feed due to a stronger adsorption of propionic acid on the acid sites of ZSM-5.

Sequential Catalysis of Phosphine Oxide for Stereoselective Synthesis of Stereopentads

An efficient method for accessing enantiomerically pure stereopentads via a catalytic asymmetric sequential aldol reaction has been developed for the first time. The enantioselective sequential aldol reaction produces a wide range of chiral stereopentad precursors in good yields with excellent enantioselectivities. The key to success is the use of the sequential catalytic system involving a chiral phosphine oxide catalyst and trichlorosilyl triflate.

Recyclable Organocatalysts for a One‐Pot Asymmetric Synthesis of 2‐Fluorocyclohexanols Bearing Six Contiguous Stereocenters

AbstractA recyclable fluorous bifunctional Cinchona alkaloid/thiourea‐catalyzed quadruple fluorination/Michael/Michael/aldol sequence has been developed for the one‐pot synthesis of cyclohexanols bearing six contiguous stereocenters including a fluorinated tertiary carbon. By using readily available starting materials including β‐keto esters, β‐nitrostyrenes, and α,β‐unsaturated aldehydes, fully functionalized cyclohexanols were synthesized in 52–80% yields with up to 99% ee and >20:1 dr. The fluorous catalyst could be easily recovered by fluorous solid‐phase extraction in 94–97% yield and >98% purity. In addition to the high synthetic efficiency achieved through the pot economic reactions, other green techniques such as transition metal‐free catalysis and catalyst recovery are also employed.magnified image

Self-Terminated Cascade Reactions That Produce Methylbenzaldehydes from Ethanol

2- and 4-Methylbenzaldehyde, which are useful precursors for phthalic anhydride and terephthalic acid, form by sequential aldol condensations between acetaldehyde and enals and subsequent dehydrocyclization during ethanol upgrading reactions on hydroxyapatite catalysts. The selectivities for methylbenzaldehydes exceed 30%, as a result of rapid cyclization reactions and steric protection that hinders further growth. Such pathways compete with a set of alternating condensation and hydrogenation steps, known as the Guerbet reaction, which produces broad distributions of n- and iso-alcohols. The selectivities to C8 aromatic products increase in proportion to the ratio of the acetaldehyde to ethanol concentrations. These reactions provide new pathways for the selective conversion of bioethanol to value-added chemicals.

NMR and DFT Insight into the Synergistic Role of Bovine Serum Albumin–Ionic Liquid for Multicomponent Cascade Aldol/Knoevenagel–thia‐Michael/Michael Reactions in One Pot

AbstractThe synergistic combination of two catalysts is an emerging strategy towards the formation of unprecedented complex molecules, and herein bovine serum albumin (BSA) and the neutral ionic liquid 1‐butyl‐3‐methylimidazolium bromide ([bmim]Br) are used together for the first time towards multiple C−C and C−S bond‐formation reactions in one pot under metal‐free, acid‐free, and base‐free conditions by merging two classical named reactions, that is, aldol condensation (AC) and thia‐Michael addition (TMA) for the cascade chemoselective generation of β‐aryl‐β‐sulfido carbonyl compounds from aliphatic ketones, aromatic aldehydes, and thiols. NMR spectroscopy and DFT calculations studies provided insight into the synergism, progress, and mechanism of the reaction, and control experiments highlighted that the single catalysts (BSA or IL) alone did not allow even the first AC step to proceed. Moreover this synergistic BSA–[bmim]Br catalytic system offers the step‐economical synthesis of the anticoagulant warfarin through sequential aldol–Michael addition reactions and potent pyridine analogues through a Knoevenagel–Michael route. Besides, the recyclability of the catalytic system (up to 5 times) with the generation of water as a byproduct makes our one‐pot protocol more economically efficient and synthetically attractive than traditional methods.

Total synthesis of atropurpuran.

Due to their architectural intricacy and biological significance, the synthesis of polycyclic diterpenes and their biogenetically related alkaloids have been the subject of considerable interest over the last few decades, with progress including the impressive synthesis of several elusive targets. Despite tremendous efforts, conquering the unique structural types of this large natural product family remains a long-term challenge. The arcutane diterpenes and related alkaloids, bearing a congested tetracyclo[5.3.3.04,9.04,12]tridecane unit, are included in these unsolved enigmas. Here we report a concise approach to the construction of the core structure of these molecules and the first total synthesis of (±)-atropurpuran. Pivotal features of the synthesis include an oxidative dearomatization/intramolecular Diels-Alder cycloaddition cascade, sequential aldol and ketyl-olefin cyclizations to assemble the highly caged framework, and a chemoselective and stereoselective reduction to install the requisite allylic hydroxyl group in the target molecule.

Selective ketonization of acetic acid over HZSM-5: The importance of acyl species and the influence of water

The ketonization of acetic acid over HZSM-5 is investigated via a combination of temperature-programmed techniques (TP), IR, and reaction kinetics. TP experiments demonstrate the generation of stable acyl intermediates that require higher temperatures to facilitate C–C coupling with a second acetic acid molecule. Near-exclusive selectivities for the ketonization reaction devoid of significant sequential aldol condensation are observed at temperatures ranging from 270 to 330°C. The rate-determining step is proposed to involve the interaction of an acyl group with a second acid, with an apparent reaction order of 1.6. This order can be explained by a second-order rate-determining step that is reduced as a result of acid-derived surface species. Isotope labeling experiments reveal that the rate-determining step is the formation of the C–C bond rather than the activation of the second acid. The ketonization reaction exhibits a −0.46 order with respect to water, but this loss in activity is accompanied by a significant increase in catalyst stability.

One-Pot Sequential Aldol Condensation and Hydrogenation of n-Butyraldehyde to 2-Ethylhexanol

2-Ethylhexanol (2EHO) is an important organic chemical. The industrial production of 2EHO comprises three units: propylene hydroformylation to n-butyraldehyde, n-butyraldehyde self-condensation to 2-ethyl-2-hexenal (2E2H), and 2E2H hydrogenation to 2EHO. In the present work, 2EHO was synthesized by one-pot sequential aldol condensation and hydrogenation of n-butyraldehyde. Among a series of metal–solid acid bifunctional catalysts, Ni/La–Al2O3 showed a better catalytic performance. The effect of reaction conditions on the one-pot sequential synthesis of 2EHO catalyzed by Ni/La–Al2O3 was investigated, and the suitable reaction conditions were obtained as follows: weight percentage of Ni/La–Al2O3 = 15%, self-condensation reaction conducted at 180 °C for 8 h, and then hydrogenation reaction conducted at 180 °C for 6 h under 4 MPa H2 pressure. Under the above reaction conditions, n-butyraldehyde conversion attained 100% at a 2EHO selectivity of 67.0%. The inhibition of Ni to n-butyraldehyde self-condensation r...