NMR investigations on the proline-catalyzed aldehyde self-condensation: Mannich mechanism, dienamine detection, and erosion of the aldol addition selectivity

The proline-catalyzed self-condensation of aliphatic aldehydes in DMSO with varying amounts of catalyst was studied by in situ NMR spectroscopy. The reaction profiles and intermediates observed as well as deuteration studies reveal that the proline-catalyzed aldol addition and condensation are competing, but not consecutive, reaction pathways. In addition, the rate-determining step of the condensation is suggested to be the C-C bond formation. Our findings indicate the involvement of two catalyst molecules in the C-C bond formation of the aldol condensation, presumably by the activation of both the aldol acceptor and donor in a Mannich-type pathway. This mechanism is shown to be operative also in the oligomerization of acetaldehyde with high proline amounts, for which the first in situ detection of a proline-derived dienamine was accomplished. In addition, the diastereoselectivity of the aldol addition is evidenced to be time-dependent since it is undermined by the retro-aldolization and the competing irreversible aldol condensation; here NMR reaction profiles can be used as a tool for reaction optimization.     

Cs/ZSM-35 分子筛催化甲缩醛和乙酸甲酯发生一步法羟醛缩合反应

丙烯酸及其酯是重要的化工原料, 广泛应用于涂料、粘结剂、纤维等领域, 目前工业上常采用丙烯两段氧化法进行制备. 然而该方法以石油基原料丙烯为源头, 采用 V/Mo/Bi 等金属催化剂, 不符合可持续发展理念, 且存在环境污染及氧气下产物易过度氧化等问题. 因此, 如何高效、安全、大规模工业化制备丙烯酸及其酯是研究者追求的目标. 以乙酸甲酯(MAc) 和甲醛为原料, 通过羟醛缩合一步制备丙烯酸及其酯是一条完全不同于丙烯氧化法的合成路径, 原料均可由煤基甲醇得到, 符合我国"富煤、贫油、少气"的基本能源结构, 且该方法碳原子利用率为 100%, 副产物仅为水, 属于绿色环保合成路径.羟醛缩合是典型的碳链增长反应, 可在酸性催化剂、碱性催化剂、以及酸碱双功能催化剂存在下发生. 碱性催化剂一般为负载型碱金属氧化物, 例如以 SiO2为载体的负载型 Na, K, Cs 氧化物催化剂等, 但都存在活性组分流失的问题, 进而导致催化剂的失活, 难以实现工业化. 酸碱双功能催化剂是目前研究的热点, 由于具有酸催化剂的高选择性和碱催化剂的高活性, 其反应性能要远优于单一酸性催化剂和单一碱性催化剂, 广大研究者对此进行了深入广泛的研究, 目前基本处于实验室阶段. 相对而言, 目前酸性催化剂上通过羟醛缩合反应制备丙烯酸及其酯的研究工作较少, 特别是以固体酸为催化剂进行乙酸甲酯和甲醛气固相反应研究非常少见.我们以甲缩醛为甲醛源, 创新性地采用固体硅铝分子筛为酸性催化剂, 催化甲缩醛 (DMM) 和 MAc 发生羟醛缩合反应来制备丙烯酸. 硅铝分子筛具有较高的活性, 可高效地催化羟醛缩合反应, 且由于分子筛催化剂具有很好的再生性能, 即使催化剂寿命较短, 也可采用流化床或移动床等反应器进行工业化, 因此存在良好的工业化前景. 为了进一步深入研究酸性位和碱性位各自对 DMM 和 MAc 羟醛缩合反应的影响, 本文以 HZSM-35 分子筛为载体, 采用浸渍法制备不同碱金属铯氧化物含量的催化剂, 利用氮气吸附/脱附方法和化学程序升温 (NH3-TPD) 方法对其孔结构和酸性质进行表征, 并进一步考察催化剂的性能. 结果表明, 微孔体积随着碱金属 Cs 负载量的增加而逐渐减小, 当 Cs 负载量增加至 10 wt% 时, 样品微孔体积从初始 0.105 cm3/g 降至 0.063 cm3/g. NH3-TPD 结果显示, 当 Cs 负载量为 1 wt%, 酸性催化剂载体上的强酸和弱酸活性位被大量碱性氧化物占据; 当负载量超过 5 wt% 时, 所有的酸性位均被覆盖. 随后考察负载不同碱金属含量分子筛的羟醛缩合反应性能, 发现碱金属氧化物的引入不利于羟醛缩合反应的进行, 这主要是由于作为甲醛源的 DMM 只有在酸中心上才能进行分解产生甲醛, 促使羟醛缩合反应顺利进行. 当采用 DMM 为甲醛源时, 体系中必须有酸性位存在. 同时得知, 分子筛 HZSM-35 中强酸和弱酸均是羟醛缩合反应的有效酸性位, 但强酸同时催化原料发生类甲醇制烯烃过程, 致使大量烃类副产物生成, 产生较重的积炭物种. 羟醛缩合反应在含有大量弱酸催化剂上 (如γ-Al2O3) 也可顺利进行, 且具有较高的活性和稳定性.     

Stereoselectivity in the Triose Aldol Condensation and the Aldol Condensation Between Glyceraldehyde and Glycolaldehyde

Abstract

Hydroxides of various alkali and alkaline earth metals have been investigated as catalysts in the triose aldol condensation and the aldol condensation between glyceraldehyde and glycolaldehyde. The proportions of diastereomers are very similar in the different product mixtures. Mechanistic models, previously suggested for other aldol condensations, have been considered for the reaction, and the observed diastereoselectivity is in accordance with a pericyclic transition state formed from a cis-enediolate-attack on the aldehyde.     

Direct Asymmetric Aldol Type Reaction with Ethyl Diazoacetate: Stereoselective Synthesis of α, β-Dihydroxy Esters

Enantioselective aldol condensation under catalytic condition remains a challenging task in modern organic synthesis, and numerous efforts have been directed to this area. In particular, the direct catalytic asymmetric aldol reaction is very attractive considering the requirement of atom efficiency. This has been studied only recently, and several very practical processes have been developed. We have recently initiated a study on the direct asymmetric aldol type reaction with ethyl diazoacetate as nucleophile. Moderate enantioselectivities (65% ～91% ee ) were achieved in the condensation of aldehydes with ethyl diazoacetate catalyzed by the chiral complex of BINOL derivatives-Zr (OBu- t )4. [1]     

Studies Toward Synthesis of Tetracyclic Core of Daphmanidin A–Type Alkaloids

A stereoselective approach to spiro-annulated bicyclo[2.2.2]octane ring system related to the tetracyclic skeleton of daphmanidin A–type alkaloids is described. Ring-closing metathesis, Wacker oxidation, and aldol condensation are key features ofour approach. An interesting steric effect on aldol condensation has also been observed.     

Efficient regioselective aldol condensation of methyl ketones promoted by organoaluminum compounds,and its application to muscone synthesis

Regioselective aldol condensation of 2-octanone and 2-butanone at the methyl side proceeded in high yields using a system of dialkylaluminum phenoxide/tertiary amine. The intramolecular aldol condensation of 2,15-hexadecanedione was carried out by the same system, especially di-i-butylaluminum phenoxide/pyridine, to give dehydromuscone in 65% yield. Its hydrogenation afforded muscone (3-methylcyclopentadecanone).     

Enantioselective aldol reaction of chiral acyl thiazolidine thione derived boron enolates

The compatability of an acyl thiazolidine thione as a chiral auxillary in boron enolate chemistry has been demonstrated by an enantioselective aldol condensation. The aldol products provide direct access to chiral β-lactams.     

氧化铝催化双子丙酮缩合反应的机理

为了研究2,15－十六烷二酮在氧化铝表面的环合机理,选择小分子丙酮为模型化合物,用量子化学半经验AM1方法研究双分子丙酮在氧化铝表面的醛醇缩合机理,给出了反应过程中的5个过渡态和4个中间体的结构和几何参数,该催化反应可以认为是氧化铝分子与两分子丙酮分子发生静电络合作用,然后借助氧原子的负电荷导致脱氢并实现缩合,根据中间体的能量变化,推测有较稳定的铝复合物生成。     

Stereoselective aldol condensation of 3,4-dihydro-3-oxo-2H-1,4-benzothiazines: X-ray determination of the aldol stereostructure

3,4-Dihydro-2-methyl-3-oxo-2$\text{H}$-1,4-benzothiazines (1) give erythro-stereoselective aldol condensation. The stereochemistry was determined by single crystal X-ray diffraction. The aldol condensation takes place under kinetic control. The reasons for the observed stereoselectivity are discussed.     

Review of the aldol reaction

Aldol condensation is an important synthetic method widely used in organic synthesis. Development of catalytic methods that avoids the production of stoichiometric by-products while maintaining high levels of control available from stoichiometric processes provides an atom-economical alternative for these important transformations. Indeed, numerous catalysts for the aldol reaction have been reported in recent years, including enzymes, catalytic antibodies, organometals, organocatalysts, and small molecules. The direct aldol reaction is the most important reaction employed by synthetic chemists and is common in nature. Recently, various Lewis acids have been examined as catalysts for aldol reactions, but aldol condensation in a micellar medium has not been studied in detail so far. Because of stronger environmental concerns, organic reactions in green media, especially in water, have attracted more attention. It is believed that micelles act as nano reactors to enhance the reaction rates and give very good to excellent yields of end products.     

Formation of Dimers of Some 2‐Substituted Indan‐1‐one Derivatives during Base‐Mediated Cross‐Aldol Condensation

Unexpected dimers of some 2‐substituted indan‐1‐one derivatives were isolated during aldol condensation of indan‐1‐one with various aldehydes in the presence of KOH (see Scheme). Monomeric products, usually expected from aldol condensation, further underwent a base‐catalyzed nucleophilic addition reaction to their dimeric form in some cases. The structures of these dimers were characterized by using various spectral techniques and in one case, structural details were determined from a high‐resolution crystallographic analysis.     

The Stereoselective Aldol Condensation of α-Fluoroacetates

2,6-Di-t-butyl-4-methylphenyl(BHT) and benzyl α-fluoroacetates were converted to their lithium enolates and were utilized in the aldol condensation. The improved diastereoselectivity found with the BHT esters is thought to arise from of equilibration of the aldol product rather than stereoselective enolate formation.     

Synthetic application of acylnitroso Diels-Alder derived aminocyclopentenols: total synthesis of (+)-streptazolin

Concise total syntheses of (+)-streptazolin 1 and its more stable dihydro derivative 2 were accomplished via an intramolecular aldol condensation strategy starting from readily available aminocyclopentenol (-)-7. The synthetic sequence included reductive amination, stereoselective epoxidation, intramolecular aldol (and condensation) reaction, and Wittig reaction. The overall yield for dihydro derivative 2 from aminocyclopentenol (-)-7 was about 7% for a total of 14 steps.     

Regioselective aldol condensations of a cholestanone-derived dialdehyde: new twists on a classic reaction

Methods have been developed for the regioselective formation of both aldol condensation products from a non-symmetrical dialdehyde derived from 5α-cholestan-3-one. The findings disclosed herein, as well as their mechanistic implications, should assist in achieving selective intramolecular aldol closures in other contexts.     

A new approach to sulfenylated enolates

Bissulfenylation followed by monodesulfenylation with a Grignard reagent cleanly provides magnesium enolates of α-phenylthiocarbonyl compounds for aldol condensation.     

Bimorpholine-mediated enantioselective intramolecular and intermolecular aldol condensation

Monosalts of N-substituted bimorpholine derivatives are efficient organocatalysts in intramolecular and intermolecular aldol reactions. The properties of the catalysts can be tuned either by the selection of an appropriate acid for the salt formation or by the change of a substituent at the nitrogen atom. In aldol condensation, i-Pr-substituted bimorpholine is the most stereoselective catalyst affording products in high yield with enantioselectivities up to 95% ee.     

Stereoselective Arene‐Forming Aldol Condensation: Synthesis of Configurationally Stable Oligo‐1,2‐naphthylenes

Structurally well‐defined oligomers are fundamental for the functionality of natural molecular systems and key for the design of synthetic counterparts. Herein, we describe a strategy for the efficient synthesis of individual stereoisomers of 1,2‐naphthylene oligomers by iterative building block additions and consecutive stereoselective arene‐forming aldol condensation reactions. The catalyst‐controlled atropoenantioselective and the substrate‐controlled atropodiastereoselective aldol condensation reaction provide structurally distinct ter‐ and quaternaphthalene stereoisomers, which represent configurationally stable analogues of otherwise stereodynamic, helically shaped ortho‐phenylenes.     

Regio- and diastereoselective boron-mediated aldol reactions of chiral α,β,γ,δ-unsaturated N-acyloxazolidinones

Chiral N-acyloxazolidinones derived from conjugated dienoic acids undergo boron-mediated aldol condensation in good yield and with high regio- and diastereoselectivity to provide a convenient method for introducing a 1,3-diene subunit. The condensation of a homologous triene derivative is also described.     

Direct asymmetric aldol reaction of hydroxyacetone promoted by chiral tertiary amines

The tertiary amine-catalyzed direct asymmetric aldol reaction of hydroxyacetone with a variety of aromatic aldehydes is developed. Using 5-10 mol % of quinidine as catalyst, the direct aldol condensation products were obtained in reasonable yields and with asymmetric induction (up to 47% ee). The present approach is extended to asymmetric organocatalytic strategies for the preparation of 1,2-diols.     

Acid catalyzed aldol condensation in the gas phase

The gas phase reaction of acetaldehyde with a Brønsted acid in a chemical ionization source yields protonated crotonaldehyde, as shown by its collisional activation mass spectrum. This is thus analogous to the well known aldol condensation in solution, in which the initial aldol adduct loses water to yield crotonaldehyde. The possibility of a common mechanism for the gas phase and solution reactions is discussed.