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The preparation and reaction of enolates within micro reactors
Abstract
Over the past 5 years, interest in the miniaturisation of chemical synthesis has grown rapidly, however in order to facilitate transfer of the technology from its current position as a research tool to industrial applications, a core understanding of the challenges associated with transferring reactions from the macro to the micro domain is required. This paper therefore aims to broach this problem by investigating the application of micro reactors to a range of commonly employed synthetic reactions including acylation, aldol, alkylation, 1,4-conjugate addition (Michael addition) and the Knoevenagel condensation. Comparison of the results obtained with traditional batch techniques enable us to highlight some of the advantages associated with micro reaction technology.
... (m, 2H, H-3 The NMR spectra are in accordance with the literature, [419] except of the OH at 15.44 ppm, which is not mentioned. (Z )-4-Hydroxy-4-(4-nitrophenyl)but-3-en-2-one (24) [423] While the melting point is not in accordance with the literature, [424] the NMR spectra are in accordance. , 2H, H-3 : [339] 71 %) 29 as white solid and 1.7 g of the side-product 32. ...
Chimeric antigen receptors (CARs) are able to specifically direct T cells to tumor antigens and therapy with anti-CD19 CARs has already cured cancer patients with B-cell lymphomas who have undergone long-term therapy non-successful. Despite this impressive result, the therapy is currently only approved as a last treatment option for blood cancers due to its life-threatening deficiencies. For patient safety and to enable additional application such as the treatment of solid tumors, CAR-T cells must be controllable, e. g. by chemically programmable CARs (cpCARs) regulated by hapten-like compounds. This thesis reports the synthesis and characterization of such hapten-like compounds. In the first step, seven different warheads with two different spacers were bound to biotin in order to find a suitable warhead for programming the cpCAR. In a second step, synthetic routes for the three pharmacophores folate, c(RGD), and an RGD peptidomimetic were developed. The routes allow the modification of the pharmacophores with one of the warheads from the first step. CuAAC was chosen as a bioorthogonal approach to link pharmacophores and warheads. In total, three different pharmacophores were modified with the 1,3-diketone motif of compound 21 leading to 112, 113 and 128. Activation of the T-cell signaling cascade was tested after binding of these hapten-like compounds to the cpCAR in the presence of suitable target structures. For 112, only a slight, non-significant, activation of the T-cell signaling cascade was observed, whereas for 113 and 128, a significant activation of the T-cell signaling cascade was observed. The poor solubility of the folate compounds led to alternative strategies. Folic acid was exchanged by pteroic acid and the bifunctional, linear compounds were enlarged to trifunctional dendrimers. Besides the reported regioisomer in 112, a second one, which was not reported to date, occurred by the cyclization of the linear RGD pentapeptide leading to 113. After the reported synthesis of an RGD peptidomimetic analogous to 128 could not be reproduced, a new synthetic route was developed. It also consists of 17 steps, but reduces the number of linear steps from 13 to 10. Moreover, the developed route contains an asymmetric hydrogenation step and is, compared to the published one, more flexible by the use of the copper-catalyzed azide-alkyne cycloaddition (CuAAC). In addition, an unknown reaction was observed. Instead of the formation of a Schiff base in the reductive amination of 129, an insertion of propargylamine occurred forming 131. The reaction is almost quantitative and in high purity. After requiring no purification, it could be predestined for industrial purposes, such as the synthesis of N-functionalized 1,2-dihydroquinolines or as a building block with various orthogonal functional groups. Besides the sulfonamide 16, the diketone (21, 27, 31) and lactam compounds (39 – 41), experiments on adapter molecules with further warheads were performed. In the synthesis of a proadapter approach, in which the warhead is formed only after the retro-aldol reaction catalyzed by the mAb, 6 of 10 steps were successfully performed. A newly developed synthesis to keto-sulfonyl and keto-sulfoxide compounds could not be completed but was performed on a small scale to the point of keto-sulfonyl and keto-sulfoxide. Furthermore, a universal synthesis route was designed to allow the introduction of the warhead at the end of the synthesis by acylation. Thus, after 5 shared steps, 3 of them in quantitative yield, different warheads may be introduced. Moreover, this also facilitates the purification and the analysis of the compounds by the absence of tautomerism or labile groups. However, the acylation experiments were not successful with either the acid cyanide or the Weinreb amide. In summary, this thesis has proven that the 1,3-diketone motif is a suitable warhead for programming the cpCAR, which was developed by Hudecek et al. (unpublished data). The hapten-like compounds 112, 113 and 128 simultaneously bind to integrin and the cpCAR activating the T-cell signaling cascade. The modular synthesis strategy and the use of the bioorthogonal CuAAC allow straightforward access to these valuable immunotherapeutics but revealed the need for an additional purification step to remove copper ions.
... Therefore, considerable efforts have recently been devoted to the synthesis of this useful scaffold [1,4]. So far, several strategies have been developed for the synthesis of 1,3-diketones, including (a) Enolate strategy (Scheme 1a) [16][17][18][19][20][21][22], (b) Umpolung strategy (Scheme 1b) [23][24][25], and (c) carbonylation of ketones (Scheme 1c) [26]. Despite these advances, there are still some important challenges, such as the requirement of multistep preparation of precursors, the use of toxic or expensive reagents, and limited substrate scope, that need to be addressed for the synthesis of 1,3diketones. ...
An efficient protocol for the synthesis of asymmetric 1,3-diketones was reported through diacylation of 1,1-diborylalkanes using two different acyl sources. In this transformation, an enolate boron species was initially formed by introducing an acyl group, then it was trapped by another acyl group to form 1,3-diketone. This method not only provided the gateway to obtain a series of 1,3-diketones, but also afforded an operationally simple and efficient access to pyrazoles and isoxazoles.
... Meanwhile, a lot of review articles about this issue appeared in literature. [48][49][50][51][52][53][54][55] Next to this application, a wide variety of other applications is known, most of which are situated in the field of the analysis, especially for the development of micro total analysis systems (µ-TAS), [17,56] and the study of basic biology [57] such as the interaction between different cell types [58] . Generally, a µ-TAS includes the miniaturisation of an overall analytical process from sample preparation through reaction and separation to detection. ...
De snel verminderende petroleumvoorraden en de lange procedure die nodig is voor de ontwikkeling en goedkeuring van een actieve substantie tot een geneesmiddel zijn drijvende krachten voor de verhoging van de synthetische efficiëntie in de organische scheikunde. De ontwikkeling van nieuwe technologieën is hierbij één van de mogelijke oplossingen. Sinds enkele decennia wordt een nieuwe technologie in de vorm van microreactoren geëvalueerd. Een betere massa- en warmtetransfer, minder opschalingproblemen en een veiliger gebruik van toxische componenten worden hierbij als voordelen naar voor geschoven. In deze thesis werd daarom intensief onderzoek verricht naar de toepasbaarheid van deze technologie voor multicomponentreacties. Hierbij werd gebruik gemaakt van een commercieel beschikbaar microreactor systeem. In een eerste luik werd de Baylis-Hillman reactie onderzocht. Deze driecomponentreactie, waarbij hoog gefunctionaliseerde β-hydroxy-α-methyleen componenten worden gesynthetiseerd, staat bekend als een trage reactie. De optimalisatie gebeurde aan de hand van een modelreactie. In dit specifiek geval werd een daling van 30 % in reactietijd bekomen. In een volgend luik werd een viercomponent-reactie voor de productie van tri- en tetragesubstitueerde imidazolen geëvalueerd. Hierbij werd de oplosbaarheid van de verschillende componenten als belangrijkste bottleneck waargenomen. Het gebruik van een solventsysteem was daarom noodzakelijk. Het type microreactor gebruikt in deze thesis is speciaal ontworpen om grotere hoeveelheden van een component te produceren. Daarom werd in een derde luik de synthese van α-aminofosfonaten, startende van het op voorhand geproduceerd imine, bestudeerd. Uitgaande van een conventionele synthesemethode werden deze α-aminofosfonaten, na een aantal modificaties, met succes geproduceerd. In de geoptimaliseerde procedure kon tot 250 g/dag geproduceerd worden. Overschakelen naar de driecomponentreactie, waarbij het imine in situ gevormd werd, gaf echter competitie met de vorming van de α-hydroxyfosfonaten. In een vierde deel werd de mogelijkheid onderzocht om met toxische reagentia te werken met deze technologie. Daarvoor werd de productie van 3-amino-4-arylamino-1H-isochromen-1-onen geëvalueerd waarbij in situ het uiterst toxische waterstofcyanide (HCN) gevormd wordt. Kwantitatieve studies toonden aan dat de HCN-vrijstelling veel lager was bij het gebruik van dit type microreactor in vergelijking met de conventionele reactiekolf. Problemen met de vroegtijdige kristallisatie van het eindproduct werden ook met succes opgelost. Een laatste luik bestond in de omzetting van de 3-amino-4-arylamino-1H-isochromen-1-onen tot 1H-isochromeno[3,4-d]imidazol-5-onen door middel van een ringsluitingsreactie. Na optimalisatie van de modelreactie bleken kleine modificaties noodzakelijk voor de algemene toepasbaarheid van de ringsluiting.
... Fine chemical synthesis strategies changed over the past decade when small-scale continuous-flow synthesis was developed using capillary and channel microreactors. The advantages of small-scale continuous-flow synthesis, over a batch approach, include: 1 greater control over the precision of reaction conditions (i.e., temperature, pressure, quality of mixing) [5,6]; 2 ability to use high temperature and pressure [7]; 3 suitability for in-line monitoring of reaction efficiency [8]; 4 automation capabilities [9,10]; 5 safer handling of hazardous reactions [11]; and, 6 simple scale-up strategies for larger product quantities [12,13]. ...
This year marks the 150th anniversary of the first continuous-flow chemistry (CFC) technique, developed by Ernest Solvay, which revolutionized industrial level synthesis. CFC is defined by multi-stage processes in which mixing and reacting of chemicals occur without interruption. A significant challenge of CFC lies in post-reaction purification. Free-flow electrophoresis (FFE) could be integrated with CFC. FFE separates chemicals by an electric field that is directed orthogonally to a pressure driven hydrodynamic flow. Although there are problems with FFE, both macro-scale and small-scale FFE are feasible for CFC integration, and realizing long-term steady-state continuous-flow purification can have significant benefits. In this review, we discuss (i) the progress of CFC, (ii) existing continuous-flow purification techniques, (iii) small-scale FFE limitations associated with steady-state continuous-flow purification, and (iv) advances in FFE performance.
... For example, benzoyl fluoride can be used to make Rifamycins, antibiotics used to treat tuberculosis as well as exhibiting anti-tumor and antiinflammatory activity [1]; to convert phosphoroazolides into phosophorofluorideates, potent enzymatic inhibitors [2]; and to acylate weakly basic aromatic amines to form analogs of the antitumor agent CC-1065 [3]. Benzoyl fluoride can also used for the production of ketones [4][5][6] and enolates [7,8], important intermediates in the pharmaceutical industry, and for the production of ionic liquids [9,10], as well as for a wide variety of other organic reactions [11][12][13][14][15]. ...
Several metals were found to catalyze the conversion of benzotrifluoride to benzoyl fluoride in the presence of carboxylic acids and sulfonic acids, together with the corresponding anhydride, and molecular oxygen. Nb2O5 exhibited the highest activity, and a conversion of ∼99.8% and a selectivity of ∼90% were obtained in 10min under mild conditions. The composition of the acid and anhydride was found to play two roles – as a proton source to activate the C–F bond and as an oxygen transfer agent to form benzoyl fluoride. Oxygen facilitated fluorine transfer but did not enter into the reaction products. A possible mechanism for the conversion of benzotrifluoride to benzoyl fluoride was proposed.
... The trimethylsilyl enol ethers, 4a-g, were prepared as described by Wiles et al. 42 starting with 20 mmol of the acetophenones. Compound 4h was prepared according to Schumacher and Reissig. ...
Para-Substituted α-fluoroacetophenones have been synthesized by three different routes. Electrophilic fluorination of trimethylsilyl enol ethers of acetophenones using Selectfluoro (F-TEDA-BF4, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate)) gave high to moderate yield depending on the electronic properties of the substituents. F-TEDA-BF4 mediated fluorination of acetophenones in methanol resulted in a mixt. of α-fluoroacetophenones and the corresponding 2-fluoro-1,1-dimethyl acetals. The di-Me acetals were hydrolyzed using trifluoroacetic acid in water to maximize the yield of the product. Nucleophilic fluorination of α-bromoacetophenones using tetrabutylammonium hydrogen bifluoride (TBABF) led to moderate yield when having electron-donating substituents, whereas low yields were experienced when more electron-withdrawing substituents were introduced. [on SciFinder(R)]
... Cyclopentanones 1a and 1b, and indanones 1i and 1j were purchased from Aldrich and used without purification. Substituted cyclopentanones 1c–h were prepared according to published procedures [18]. Urea–hydrogen peroxide complex was purchased from Acros. ...
Chemo-enzymatic oxidation of cyclopentanones and substituted cyclopentanones to the corresponding δ-valerolactones was investigated employing catalytic amount of Candida antarctica lipase-B in ethyl acetate and employing urea–hydrogen peroxide as the oxidant. In contrast to the smooth oxidation of cyclohexanones to the corresponding ɛ-caprolactones, the δ-valerolactones reacted further with the lipase delivering trans-esterified products and also acetylated alcohols, depending on the structural nature of the cyclopentanones.
... A number of common C-C bondforming reactions have been demonstrated in flow, including Grignard reactions, 51,125,142 Wittig reactions, 85,143 addition of aryl and alkyl lithium salts, 85 Aldol reactions, 93 Claisen condensations, 144 Michael additions, 145 Diels-Alder and other cyclization reactions, 99 as well as alkylation of enolates. 146 Microreactors have also proven useful for the generation of carbon nucleophiles such as enolates, 85,147 enamines, 148 and Grignard reagents. 142 Watts and co-workers have improved a tricky reaction involving alkylation (Scheme 11). ...
The unique aspects of microreactor that make them efficient tools for organic chemistry on both small and large scale have been presented. The types of reactions that have been run in microreactors are also surveyed. These reactions include: stoichiometric reactions that include carbon-carbon bond-forming reactions, oxidations and reductions, heterocycle formations, carbon-nitrogen and carbon-oxygen bond-forming reactions, flouorinations, nitration reactions, reactions with diazo reagents, polymerizations, photochemical reactions, precipitate-forming reactions, and electrosynthesis; and the catalytic reactions like carbon-carbon bond-forming reactions, catalytic oxidations and reductions, organocatalysts reactions, and enzymatic reactions. The increased control over microreactor reactions in the form of thermal stability and mixing control means that new reactions can be made more reproducible from inception, and may offer better regioselectivity and chemical selectivity than traditional batch synthesis.
Pharmaceutical and fine chemical products are typically synthesised batchwise which is an anomaly since batch processes have a series of practical and economical disadvantages. On the contrary, flow continuous processes present a series of advantages leading to new ways to synthesise chemical products. Flow processes - * enable control reaction parameters more precisely (temperature, residence time, amount of reagents and solvent etc.), leading to better reproducibility, safer and more reliable processes * can be performed more advantageously using immobilized reagents or catalysts * improve the selectivity and productivity of the process and possibly even the stability of the catalyst * offer opportunities for heat exchange and energy conservation as well as an easy separation and recycling of the reactants and products by adequate process design * achieve multistep syntheses by assembling a line of reactors with minimum or no purification in between two reaction steps * can be assured by facile automation * scale-up can be easily conducted by number-up With all the new research activity in manufacturing chemical products, this comprehensive book is very timely, as it summarises the latest trends in organic synthesis. It gives an insight into flow continuous processes, outlining the basic concepts and explaining the terminology of, and systems approach to, process design dealing with both homogeneous and heterogeneous catalysis and mini- or micro-reactors. The book contains case studies, extensive bibliographies and reference lists in each chapter to enable the reader to grasp the contents and to go on to more detailed texts on specific subjects if desired. The book is written by both organic chemists and engineers giving a multidisciplinary vision of the new tools and methodologies in this field. It is essential reading for organic chemists (in industry or academia) working alongside chemical engineers or who want to undertake chemical engineering projects. It will also be of interest for chemical engineers to see how basic engineering concepts are applied in modern organic chemistry.
4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
A protocol for the reaction of ketone or ester enolates with aza‐o‐quinodimethanes (aza‐o‐QMs) formed in situ is reported via a 1,4‐elimination in the presence of tetramethylammonium fluoride (TMAF). The reaction partners were reacted to provide a wide variety of substituted 2‐(tosylamino)dihydrochalcones in 45–97% yield in a single reaction sequence in one pot under mild condition. Additionally, various 2‐(tosylamino)dihydrochalcones could be easily converted to form diverse heterocycles.
Examples of continuous flow reactions in the laboratory setting are becoming commonplace in pharmaceutical drug substance research. Developing these processes for robust commercialization and identifying the scale up parameters remains a challenge. An aldol reaction in the formation of an API intermediate was developed in flow at milliliter scale. Research focused on identifying conditions that led to robust and stable operating conditions. Desired reaction performance was achieved in various mixers across reactor scales by identifying conditions that led to similar flow regimes. Conditions from the lab were transferred to the pilot plant to successfully process ~200 kg of the starting material, and then later transferred to the commercial site.
Nucleophilic Substitution at Saturated Carbon Nucleophilic Substitution at Carbonyl Carbon Conclusion References
Isoquercitrin is a rare flavonol glycoside with a wide range of biological activities and is a key synthetic intermediate for the production of enzymatically modified isoquercitrin. In order to establish an ultrafast bioprocess for obtaining isoquercitrin, a novel continuous flow biosynthesis of isoquercitrin using the hesperidinase-catalyzed hydrolysis of rutin in a glass-polydimethylsiloxane (PDMS) microreactor was first performed. Using the developed microchannel reactor (200 μm width, 50 μm depth and 2 m length) with one T-shaped inlet and one outlet, the maximum yield of isoquercitrin (98.6%) was achieved in a short time (40 min) under the following optimum conditions: rutin concentration at 1 g L-1, hesperidinase concentration at 0.1 g mL-1, reaction temperature 40°C, and a flow rate of 2 μL min-1. The value of the activation energy, Ea, of the enzymatic reaction was 4.61 kJ mol-1, and the reaction rate and volume productivity were approximately 16.1-fold and 30% higher, respectively, than those in a batch reactor were. Thus, the use of a continuous-flow microreactor for the enzymatic hydrolysis of rutin is an efficient and simple approach to achieve a relatively high yield of isoquercitrin. (CC) 2015 SCS. All rights reserved.
(MeCOF) [557-99-3] C2H3FO (MW 62.04) InChI = 1S/C2H3FO/c1-2(3)4/h1H3 InChIKey = JUCMRTZQCZRJDC-UHFFFAOYSA-N (EtCOF) [430-71-7] C3H5FO (MW 76.07) InChI = 1S/C3H5FO/c1-2-3(4)5/h2H2,1H3 InChIKey = WMFABESKCHGSRC-UHFFFAOYSA-N (PhCOF) [455-32-3] C7H5FO (MW 124.11) InChI = 1S/C7H5FO/c8-7(9)6-4-2-1-3-5-6/h1-5H InChIKey = HPMLGNIUXVXALD-UHFFFAOYSA-N (precursors to acylium salts; acylating agents)Physical Data: MeCOF: mp −84 °C, bp 20–21 °C, d 1.032 g cm−3; EtCOF: bp 42–44 °C, d 0.972 g cm−3; PhCOF: mp −28 °C, bp 159–161 °C; d 1.140 g cm−3.Solubility: all reagents are miscible with all organic solvents, but react with some of them.Analysis of Reagent Purity: all reagents can be analyzed by 1H or 19F NMR.13Form Supplied in: acetyl, propionyl, and benzoyl fluorides are commercially available.Preparative Methods: acetyl fluoride (but not other acyl fluorides) is most conveniently prepared by addition of Acetyl Chloride to a solution of Potassium Fluoride in AcOH; reaction is immediate. Warming the solution and condensing the gas gives nearly quantitiative yields.1 Procedures applicable to the preparation of a variety of acyl fluorides include reaction of the acid chloride or anhydride with nucleophilic fluorides2 and fluorination of the carboxylic acid.3Handling, Storage, and Precautions: samples of acetyl fluoride sealed in glass ampoules slowly form a pyrylium salt.4 Acetyl fluoride is a corrosive lachrymator. All reagents are extremely hazardous. All possible precautions should be taken to avoid inhalation, ingestion, or absorption through the skin as they might cause severe burns. Use in a fume hood. Reagents are stable under normal conditions. Water, alcohol, oxidizing agents, and strong bases hydrolyze acyl fluorides generating an acidic gas, which in contact with metal surfaces can generate flammable and/or explosive hydrogen gas.
[1070-89-9] C6H18NNaSi2 (MW 183.42) InChI = 1S/C6H18NSi2.Na/c1-8(2,3)7-9(4,5)6;/h1-6H3;/q-1;+1InChIKey = WRIKHQLVHPKCJU-UHFFFAOYSA-N(useful as a sterically hindered base and as a nucleophile)Alternate Name: NaHMDS; sodium bis(trimethylsilyl)amide.Physical Data: mp 171–175 °C; bp 170 °C/2 mmHg.Solubility: soluble in THF, ether, benzene, toluene.1Form Supplied in: (a) off-white powder (95%); (b) solution in THF (1.0 M); (c) solution in toluene (0.6 M).Analysis of Reagent Purity: THF solutions of the reagent may be titrated using 4-phenylbenzylidenebenzylamine as an indicator.2Handling, Storage, and Precautions: the dry solid and solutions are flammable and must be stored in the absence of moisture. These should be handled and stored under a nitrogen atmosphere. Use in a fume hood.
The three-component reaction between an isoquinoline, a dialkyl acetylenedicarboxylate and 2,2,2-trifluoro-1-phenylethanone involving a 1,4-dipolar cycloaddition cascade approach is developed using a continuous-flow microreactor. The reaction conditions (solvent, flow rate and temperature) are optimized leading to the synthesis 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquinoline derivatives in 79-83% isolated yields, whilst eliminating the formation of 11bH-pyrido[2,1-a]isoquinoline-12,3,4-tetracarboxylate by-products. The continuous-flow method is also applied to similar reactions using aromatic aldehydes as the carbonyl component.
Das Konzept harter und weicher Säuren und Basen (HSAB) erwies sich als nützlich, um die Stabilitätskonstanten von Metallkomplexen zu erklären. Seine Anwendung auf organische Reaktionen, insbesondere zur Deutung ambidenter Reaktivität, hat jedoch exotische Blüten hervorgebracht. Beim Versuch, alle beobachteten Regioselektivitäten durch günstige Weich-weich- und Hart-hart-Wechselwirkungen sowie durch ungünstige Hart-weich-Wechselwirkungen zu erklären, wurden frühere Deutungen ambidenter Reaktivität ersetzt, die korrekt zwischen thermodynamischer und kinetischer Kontrolle sowie zwischen unterschiedlichen Koordinationsweisen ionischer Substrate unterschieden haben. Durch Nichtbeachtung widersprechender experimenteller Befunde und sogar Bezug auf nicht auffindbare experimentelle Daten erhielt die HSAB-Behandlung ambidenter Reaktivität unverdiente Popularität. In diesem Aufsatz zeigen wir, dass das HSAB-Konzept, wie auch das damit verwandte Klopman-Salem-Modell, nicht einmal das Verhalten der Prototypen ambidenter Nucleophile richtig beschreibt, sodass es eher irreführend denn ein nützlicher Wegweiser ist. Eine alternative Behandlung ambidenter Reaktivität auf der Basis der Marcus-Theorie wird vorgestellt.
Small-volume continuous-flow synthesis (small-volume CFS) offers a number of benefits for use in small-scale chemical production and exploratory chemistry. Typically, small-volume CFS is followed by discontinuous purification; however, a fully continuous synthesis-purification combination is more attractive. Milli free-flow electrophoresis (mFFE) is a promising continuous-flow purification technique that is well suited for integration with small-volume CFS. The purification stability of mFFE, however, needs to be significantly improved before it can be feasible for this combination. One of the major sources of instability of mFFE is attributed to the ions produced as a result of electrolysis. These ions can form pH and conductivity gradients in mFFE, which are detrimental to separation quality. The severity of these gradients has not been thoroughly studied in mFFE. In this paper, we have experimentally demonstrated that detrimental pH gradients occur at flow rates of 8 mL/min and less, and electric field strengths of 25 V/cm and greater. To decrease the pH gradients it is necessary to evacuate H+ and OH as soon as they are generated, this can be done by increasing local hydrodynamic flow rates. We calculated the necessary flow rate, to be applied at the electrode, which can effectively wash away both ions before they can cause a detrimental pH gradient. These optimized flow rates can be attained by designing a device that incorporates deep channels. We have confirmed the effectiveness of these channels using a prototyped device. The new design allows mFFE users to work over a wider range of flow-rate and electric-field conditions without experiencing significant changes in pH.
Selective reduction of three kinds of substrates were studied to evaluate the reducing abilities of N,N-dimethyl-benzimidazolidine (DMBI), 2-phenylbenzimidazoline (PBI) and 2-phenylbenzothiazoline (PBT). As hydride donors, these three five-membered heterocyclic compounds performed different reducing abilities depending on the substrates.
The introduction of alkyl substituents at C-2 of chromanones via conjugate addition of silyl enol ethers to a variety of chromenones is reported. In most cases racemic 2-alkyl chromanones were obtained in good yield in the presence of TMSOTf. The copper(II)-promoted conjugate addition of silyl enol ethers to chromenones was also carried out, albeit in low yields and no selectivity. Reliable syntheses of the chromenones via acylation of the corresponding β-diketo-compounds are also described.
A rapid and highly selective acylation of ferrocene with various acid anhydrides using microfluidic chip as the reactor is described. The pressure driven glass microreactor was fabricated by standard photolithography and wet etching techniques. High conversions of ferrocene to the corresponding acylferrocenes were achieved at 25°C and no diacylferrocene was observed in any case.
The reactions of 5-arylidene derivatives of Meldrum’s acid with ethyl vinyl ether or N-vinyl-2-oxazolidinone yielded trans-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, cis-trans-(2,4:4,7)-pyrano[4,3-b]pyrans, or diastereoisomeric mixtures of pyrano[4,3-b]pyrans and reactions with 3,4-dihydro-2H-pyran afforded Michael adducts. The reactions of 5-arylidene derivatives of Meldrum’s acid with cyanoacetic acid derivatives do not provide appropriate pyrans.
The unique operational characteristics of microreactors are described in this article, with particular reference to their use as tools for chemical synthesis. With reference to the future automation, an example is presented to illustrate how microreactors can be readily integrated into current HPLC systems, to enable fully integrated chemical synthesis and product analysis to be performed.
Intramolecular [2 + 2] and [2 + 3] photocycloadditions of 2-(2-alkenyloxymethyl)naphthalene-1-carbonitriles and their photocycloreversion using glass-made microreactors were investigated in comparison with photoreactions under conventional batch conditions. Both the efficiency and regioselectivity were improved by use of glass-made microreactors. These results can be explained by thorough absorption of light and outflow of primary product from the reaction system.
Bubble and sweep: Free-flow electrophoresis (FFE) could allow continuous-flow purification of products from continuous-flow microsynthesis. However, gas bubbles distort the separation. An open-electrolyte FFE system avoids this problem. Electrodes placed in chimneys open to the atmosphere mean bubbles are vented directly from the system and cannot enter the separation channel.
K2CO3 and NaOPh promoted the rate of benzylic carbon−hydrogen bond activation (BnCHA) of toluenes with iridium(III) porphyrin carbonyl chloride (Ir(ttp)Cl(CO)) to give iridium porphyrin benzyls in high yields. Mechanistic studies suggested that K2CO3 initially converted Ir(ttp)Cl(CO) to Ir(ttp)X (X = OH−, KCO3−), which reacted very fast with toluenes to yield Ir(ttp)H. Ir(ttp)H then reduced the carbonyl ligand in unreacted Ir(ttp)Cl(CO) to yield Ir(ttp)Me. Ir(ttp)H also dimerized dehydrogenatively to give [Ir(ttp)]2, especially promoted in the presence of base, which further reacted with toluenes to yield iridium benzyls. Weaker base of NaOPh converted Ir(ttp)Cl(CO) to Ir(ttp)OPh, which selectively promoted BnCHA to yield iridium benzyls.
The concept of hard and soft acids and bases (HSAB) proved to be useful for rationalizing stability constants of metal complexes. Its application to organic reactions, particularly ambident reactivity, has led to exotic blossoms. By attempting to rationalize all the observed regioselectivities by favorable soft-soft and hard-hard as well as unfavorable hard-soft interactions, older treatments of ambident reactivity, which correctly differentiated between thermodynamic and kinetic control as well as between different coordination states of ionic substrates, have been replaced. By ignoring conflicting experimental results and even referring to untraceable experimental data, the HSAB treatment of ambident reactivity has gained undeserved popularity. In this Review we demonstrate that the HSAB as well as the related Klopman-Salem model do not even correctly predict the behavior of the prototypes of ambident nucleophiles and, therefore, are rather misleading instead of useful guides. An alternative treatment of ambident reactivity based on Marcus theory will be presented.
o-Benzenedisulfonimide, a new strong bench-stable Brønsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions.
Applications of microsystems (microreactors) in continuous-flow chemistry have expanded rapidly over the past two decades, with numerous reports of higher conversions and yields compared to conventional batch benchtop equipment. Synthesis applications are enhanced by chemical information gained from integrating microreactor components with sensors, actuators, and automated fluid handling. Moreover, miniaturized systems allow experiments on well-defined samples at conditions not easily accessed by conventional means, such as reactions at high pressure and temperatures. The wealth of synthesis information that could potentially be acquired through use of microreactors integrated with physical sensors and analytical chemistry techniques for online reaction monitoring has not yet been well explored. The increased efficiency resulting from use of continuous-flow microreactor platforms to automate reaction screening and optimization encourages a shift from current batchwise chemical reaction development to this new approach. We review advances in this new area and provide application examples of online monitoring and automation.
Les recherches que nous présentons dans ce mémoire portent sur les contacteurs membranaires en phases liquide/liquide appliqués à la précipitation. Le principe du contacteur à membrane, pour une réaction chimique, est le suivant : un réactif A circule tangentiellement à la surface de la membrane et un réactif B est introduit à travers les pores de la membrane. Le mélange et la réaction entre A et B se produisent à l'intérieur du module membranaire.
Un modèle numérique a été développé pour simuler l'écoulement et l'évolution des concentrations des réactifs. Les simulations montrent que l'utilisation de fibres creuses de faible rayon interne permet d'optimiser le mélange. A partir de ces résultats, un pilote a été conçu utilisant des modules fibres creuses pour une réaction modèle : la précipitation de BaSO4 à partir d'une solution de BaCl2 (A) et de K2SO4 (B). L'analyse d'images des cristaux obtenus permet de déterminer leur morphologie, leur taille et le taux de conversion du produit.
This review offers an overview of the relatively young research area of continuous flow lab-on-a-chip for synthetic applications. A short introduction on the basic aspects of lab-on-a-chip is given in the first part. Subsequently, the effects of downscaling reaction vessels as well as the advantages of the continuous flow microfluidic approach over conventional chemical laboratory batch methodologies are illustrated by a number of examples of organic reactions carried out in microfluidic devices. The last part deals with a key issue of the lab-on-a-chip approach, viz. the integration of the microreactor with the analytical instrumentation to achieve high-throughput reaction monitoring.
Although in its infancy, the field of micro reaction technology is growing rapidly, with many research groups investigating the practical advantages associated with reaction miniaturisation. With this in mind, the following Feature Article aims to provide an overview of the progress made in the past decade, paying particular attention to the field of synthetic organic chemistry.
Organic synthesis in microreactors is a novel way of performing reactions in a highly controlled way. The benefits of microreactors result from their physical properties, such as enhanced mass and heat transfer as well as regular flow profiles leading to improved yields with increased selectivities.
This review focuses on the use of micro reactors as tools in synthetic organic chemistry, aiming to highlight the many advantages associated with their use, in particular their ability to synthesise products in high yield, purity and, where relevant, selectivity.
Micro reaction technology offers a safe, controllable and information rich technique suitable for the long-term production of pharmaceutical agents and fine chemicals. To date however, few of the syntheses performed using this technology have addressed the problems associated with product purification. With this in mind, we report herein the incorporation of multiple supported reagents into EOF-based miniaturized flow reactors for the two-step synthesis of analytically pure compounds. Using this approach, the successful synthesis of 20 alpha,beta-unsaturated compounds in excellent yields (>99.1%) and purities (>99.9%) has been achieved, illustrating significant improvements compared to traditional batch techniques.
Chemical synthesis in microreactors is a novel way of conducting chemistry in a highly controlled way with improved yields at impressive selectivities and with reduced overall effort. This paper describes recent technological progress with the potential as well as the application of
the technology to chemical synthesis, discusses novel chemical optimization technology and reports on the transfer of the technology into production.
Infrared radiation promoted the synthesis of benzylidenemalononitriles, benzylidenecyanoacetamides and benzylidenecyanoacetic acids by condensation of aromatic aldehydes with the corresponding active methylene compound in the presence of Tonsil Actisil FF, without solvent. Mass of catalyst, solvent, and reaction time were assessed in order to improve the efficiency of this process.
A variety of N-substituted α-silylated-α,β-unsaturated amidate anions (2) have been found to be excellent Michael acceptors in charge-directed conjugate addition reactions with Grignard and organolithium reagents. The effects of olefin substitution, Si-substitution, N-substitution, and amidate counterion have been studied. Anionic acceptors may be prepared in situ by the addition of silylated vinyllithium reagents to isocyanates and then allowed to undergo conjugate addition reactions with subsequently added nucleophiles, but it was found to be more efficient to isolate neutral acceptors and regenerate the acceptor anion through the use of excess nucleophile. β-Substituted acceptors were found to react only with reactive organolithium reagents while a β,β-disubstituted acceptor failed to undergo conjugate addition reactions. A primary amide acceptor (14d) also undergoes addition reactions with larger quantities of nucleophiles suggesting that dianionic amidate acceptors (31) are involved. Diene acceptor 24 was found to undergo a 1,6-addition reaction with n-BuLi. Sodium and potassium amidate salts were found to be inferior to lithium and magnesium salts in addition reactions in keeping with the expectation that an increase in carbonyl-group charge burden retards conjugate reactions. Triphenylsilyl-containing acceptor 16 was found to be more reactive in reactions with n-BuMgCl but less reactive with bulkier tert-BuMgCl. Adduct dianions can be monoalkylated with alkyl iodides and used in Peterson olefination reactions.
-Butyldimethylsilyl enol ethers of pentane-2,4-dione and methyl acetoacetate react rapidly at room temperature to give high isolated yields of the t-butyldimethylsilyl ethers of a variety of alcohols.
Silyl-proton exchange reactions with ketene methyl trialkylsilyl acetals proceeded rapidly and quantitatively under mild conditions. The preparative silylation of alcohols, carboxylic acids, mercaptans, and amides is described.
The title reaction proceeds regiospecifically under mild conditions in high yield; an application in the synthesis of an alkaloid is described.
A new convenient route to silyl ethers and esters from alcohols and carboxylic acids using allylsilanes in the presence of an acid catalyst in acetonitrile was developed. The present method is also applicable to t-butyldimethylsilylation.
Among the large number of microfluidic components realized up to now, micropumps clearly represent the case of a 'long runner' in science. A brief literature review reveals, that one of the first scientific papers on a micropump dates from 1978, which is more than two decades ago. An increasing number of publications is found from that time on representing widespread research activities, and there seems to be no change of this trend. An astonishing diversity of micropump concepts and devices has emerged until today, reaching from peristaltic micropumps to a large number of micro diaphragm pumps to recent high-pressure devices without any moving parts. Electrohydrodynamic, electroosmotic, electrostatic, electromagnetic, magnetohydrodynamic, SMA, piezoelectric, thermopneumatic, hydraulic or pneumatic - almost every MEMS-based or mesoscopic actuation principle has been combined with micropumps. An outstanding diversity is also found in the fabrication technology - the span reaches from silicon-based devices over precision machining to injection moulding. This altogether makes it worth to summarize and also take a look into the future of micropumps - after the first two decades.
The fabrication and use of micro reactors in organic synthesis is reviewed.
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The formation of porous silica microstructures (frits) in capillaries with an internal diameter of 500 µm has been examined for inducing electroosmotic flow (EOF). Capillaries with this internal diameter are normally considered too large to support efficient EOF, but the discrete pumping devices reported here are able to overcome this limitation. The formation of these structures in the capillaries has been examined, with particular emphasis on identifying parameters within the preparation stage that might give rise to variation in the porosity of the frit. The initial results showed that the induced electroosmotic flow rate increased with frit length (to an optimum of 50 mm) with an applied potential of 700 V. The work offers an opportunity to extend electroosmotic pumping to capillaries of larger internal diameter than was previously thought ideal. It offers a number of potential advantages in the area of fluid propulsion, including the electric control of flow rates, the plug like nature of the flow, and the absence of moving parts. When this technology is applied to micro-reactors, the silica structures offer the dual advantages of providing a pumping mechanism while also retaining the catalyst in the micro-reactor.
A dual pump and a buffer pump have been integrated on a silicon wafer for chemical analyzing systems. These pumps realize constant and rippleless liquid flow of a small volume. The controllable flow rate of the pumps was up to about 40 μl/min and the maximum pumping pressure was about 1 mH2O. A sample injector made up of two three-way valves has also been fabricated with micromachining.
A silicon micropump, provided with piezoelectric valves, which can be manufactured by established integrated circuit techniques is the subject of this report. The micropump can be used to pump liquids or gases to a higher pressure, which can be relieved through a check valve. The body of the pump and the valves are made in silicon and contain piezoelectric material which allows opening and closing of the valves electrically.
A convenient synthesis of α, β-unsaturated cyanoesters in E-isomer exclusively promoted by tri-n-butylarsine under neutral condition is described.
Dolastatin 10 (1), isolated from the sea hare Dolabella auricularia, has proved to be an exceptionally promising antineoplastic substance. Synthesis of this new and important peptide has been achieved. However, a more convenient and stereoselective synthesis of its three chiral center dolaproine (2a) unit has become necessary. A practical solution to this challenging problem was realized by employment of the following key reaction steps. Chiral oxazolidinone 5 was condensed at -75°C with S-prolinal 4 using dibutylboron triflate to direct the stereochemical course of the aldol reaction. Methylation of the product (6, 60-80% yields) and cleavage of the amide, in 83 and 93% yields respectively, completed a facile route to N-Boc-dolaproine (2b). Pertinent aspects of the aldol reaction and cleavage of oxazolidinone amides are discussed.
By the reaction of Vilsmeier salts, derived from tetra-alkylureas or from tetra-alkylthioureas, with primary aliphatic amines, a series of sterically hindered penta-alkyl guanidines has been prepared. 2-t-Butyl-1′,1′,3″,3″-tetramethylguanidine and pentaisopropylguanidine combine ease of preparation with a range of resistance to alkylating agents. Preliminary experiments indicate that these inexpensive bases will be useful in organic synthesis.
Miniaturization of already existing techniques in on-line analytical chemistry is an alternative to compound-selective chemical sensors. Theory indicates higher efficiency, faster analysis time and lower reagent consumption. Micromachining, a well known photolithographic technique for structures in the micrometer range, is introduced and documented with structures as examples for flow injection analysis, electrophoresis and a detector cell.
A series of benzyldimethylsulfonium - and related hydrogensulfate salts have been synthesized from the ternary system ArCH2OH:H2SO4: Me2S or tetrahydrothiophene. The salts are generally stable crystalline solids, but anomalously high reactivity is observed for 9-(anthrylmethyl)dimethylsulfonium hydrogensulfate. Selected sulfonium salts have been used for the O- and S-benzylation of phenol and thiophenol, respectively, in a two phase system under near-neutral conditions. The benzylation of oximes and benzimidazole under basic conditions is also described.
Mg–Al–O–t-Bu-hydrotalcite catalyst was found to be an efficient, environmentally attractive and selective solid base catalyst for 1,4 Michael addition. Mg–Al–O–t-Bu hydrotalcite is also effective for simple synthesis of α,β-unsaturated esters and nitriles by condensation of the corresponding activated carboxylic esters or nitriles with various aldehydes by Knoevenagel condensation. These reactions proceeded at room temperature at a greater rate in the presence of Mg–Al–O–t-Bu hydrotalcite than in the presence of any of the other catalysts examined.
The principle of physiochemical and chemical modulation in flow injection analysis is outlined. Advantageous properties of flow injection analyzers for chemical on-line process control are summarized. Three exampls of applications are presented. First, peak-width measurements enable chemical batch processes to be monitored over several orders of magnitude of analyte concentration whereas peak-height measurements are selected in the critical state of the process where very small changes of analyte concentration must be determined precisely. Secondly, exploitation of variable gradient dilution to match sample concentration to the needs of accurate analysis is combined with trapped-zone selective spectrophotometry. Finally, frequency-discriminated chemical analysis is feasible by combining sample gradient formation with reagent injection.
Unequivocal answers to the questions in the title are not possible yet, but the strongest stable uncharged base, the PS compound 1, is 28-29 pK units more basic than triethylamine. Compound 1 is easily prepared, readily soluble, and can be stored almost indefinitely at room temperature in the absence of moisture.
Bicyclic amidines, especially DBN and DBU, have recently become of interest, principally because of their use as dehydrohalogenation reagents. The use of these compounds in the introduction of double bonds, as well as in various base-catalyzed reactions, is the subject of this review. 1. Preparation of DBN and DBU 2. Dehydrohalogenation Reactions 2.1. Introduction of One Double Bond 2.2. Introduction of Multiple Double Bonds 2.3. Comparison of DBN and DBU in Dehydrohalogenation Reactions 3. Elimination of Sulfonic Acids 4. Phosphorus Ylids 5. Elimination of Hyponitrous Acid 6. Stereochemical Course of the Elimination Reactions 7. Aldol Condensations 8. Rearrangements 9. Reactions with Aromatic Isocyanates 10. Preparation of Carboxylic Acid Chlorides 11. Acylation of Phenols 12. Catalysts in the Synthesis of Macromolecules
Du to the constrained planarity and the extended charge delocalization of the cations 1‐H⊕ and 2‐H⊕ the konjugate tricyclic vinamidines 1 and 2 are very strong bases. They are therefore of interest as proton traps in aprotic solvents. The starting materials for their syntheses are inexpensive reagents such as triethylenetetramine, malonodinitrile, and ammonium chloride. (Figure Presented.)
Using a series of silica-supported bases, we demonstrate the synthesis of eight condensation products within an EOF-based flow reactor; in all cases, high yields (>99%) and product purity are obtained.
[Ru(μ-O2CH)(CO)2(PPh3)]2 in acetonitrile is an efficient catalyst precursor for the Michael addition of soft carbonucleophiles to butenone. The utilization of terminal alkynes as donors makes possible the selective formation of γ,δ-ynones.
A feature article describing the fundamental characteristics
and emerging applications of micro technology in the field of synthetic
chemistry.
The stereochemistry of the aldol condensation of preformed lithium enolates of a variety of ethyl ketones and propionic acid derivatives with aldehydes has been investigated. It is found that certain compounds give completely or nearly completely one diastereomeric enolate and that the stereostructure of the resulting aldol is correlated with the stereostructure of the enolate from which it is formed. The observed stereochemistry may be understood in terms of an ordered transition state in which both oxygens are oriented in more or less the same direction. It is shown that the observed stereochemistry is kinetically controlled. In many cases, the initial aldol adduct equilibrates to furnish predominantly a threo isomer. The rate of equilibration varies widely, ranging from very fast at -60°C with the propiophenone-benzaldehyde adduct to slow at 25°C for the ethyl tert-butyl ketone-benzaldehyde adduct. The equilibration behavior of lithium ketolates is compared with that of the zinc ketolates, and some differences are noted. A method for achieving erythro-threo equilibration via a chloral hemiacetal is presented. A new reagent is introduced (trimethylsilyloxy ketone 36) which may be used to stereoselectively homologate an aldehyde to an erythro α-methyl-β-hydroxy acid. As an application of the use of stereoselective aldol condensations in synthesis, (±)-ephedrine (48) has been synthesized from benzaldehyde in 71% overall yield.
Two procedures for the preparation of trimethylsilyl enol ethers from aldehydes and ketones are described. Reaction of the ketone with chlorotrimethylsilane and triethylamine in dimethylformamide solution usually affords an equilibrium mixture of the trimethylsilyl enol ethers. Successive reaction of the ketone with lithium diisopropylamide and with chlorotrimethylsilane in 1,2-dimethoxyethane solution normally produces a mixture in which the less highly substituted enol ether (from kinetically controlled enolate formation) is the principal product. A number of representative structurally and stereochemically isomeric trimethylsilyl enol ethers have been characterized (see Table II) and their physical properties have been studied.
The kinetics of the reactions of phenyl isocyanate with 2-ethylhexanol, methanol, and deuterium methoxide, in the presence of some amine catalysts, have been investigated. A new catalytic species, heptamethylisobiguanide, has been found to possess higher activity than any other amine-type catalyst. Its activity is attributed to its high base strength. The mechanism is explained in terms of an increasing contribution of an amine-isocyanate complex with increasing base strength of the amine. The possibility of proton removal by the amine catalyst appears remote after consideration of deuterium isotope effects.
From a spectroscopic examination of metal enolates, the mercury(II) salts of ketones are found to exist as α-metalated ketones 2, but salts with the metals lithium, sodium, zinc, and magnesium exist as enolate structures in which either contact ion pairs 4b or solvent-separated ions 3 may be present. The existence of these metal enolates as solvent-separated ion pairs is favored (1) in a polar or a good solvating solvent, such as DME or DMF rather than ether; (2) by the presence of a metal cation such as lithium, sodium, or zinc rather than magnesium; and (3) by use of the trans (1b) rather than the cis (1a) stereoisomer of the enolate. In kinetically controlled reactions of metal enolates with acetylating agents, O-acylation is the favored reaction with α-metalated ketones 2 and with solvent-separated ion pairs 3. The amount of of C-acylation is increased and may become the predominant reaction with metal enolates that exist as contact ion pairs 4b. When the solvent and metal cation are kept constant, more C-acylation is obtained when acetyl chloride or acetyl bromide is used as the acylating agent rather than acetic anhydride or ketene.
The alkylation of specific structural isomers of lithium enolates derived from 1-decalone (1), 2-methylcyclohexanone (2), 2-benzylcyclohexanone (3), cyclohexanone, and 2-heptanone (23) has been studied. The more highly substituted enolate isomers are best obtained by reaction of the corresponding enol acetates or enol trimethylsilyl ethers with methyllithium. The advantage gained with the silyl enol ethers in avoiding dialkylation is offset by the frequent difficulty in obtaining a single structural isomer of the silyl ether. The less highly substituted lithium enolates of unsymmetrical ketones are best obtained by a kinetically controlled deprotonation of the ketone with the hindered base, lithium diisopropylamide. Although the less hindered lithium enolates from cyclic ketones can be alkylated with good structural specificity, this procedure was not satisfactory for alkylation at the methyl group of 2-heptanone because of a combination of an unfavorable position of enolate equilibria and, especially, an unfavorable ratio of alkylation rates for the structurally isomeric enolates.
Independent enantioselective synthesis of (R)- and (S)-thiophan (1) via a six-step sequence has been completed. The pivotal step in the establishment of absolute stereochemistry in the enantiomeric target structures was the alkylation of the oxazolidyl carboximide-derived enolates 6 and 7 with bromomethyl benzyl sulfide (5b). The diastereoselection observed in these bond constructions was in excess of 95%.
Alkylation of 4-amino-1-azabutadiene derivatives 1 with different alkyl halides followed by acid hydrolysis gives mono-C-alkylated 1,3-diketones 3 in excellent yields. In contrast acylation of 1 occurs at the imine nitrogen.
Trimethylsilyl enol ethers of ketones are acylated by a variety of acid chlorides in the presence of zinc chloride or antimony trichloride. The major product of this reaction is the 1,3-diketone resulting from C-acylation. Some O-acylation is observed in most cases. Yields of 1,3-diketones varied but were usually good to excellent.
A variety of N-substituted alpha-silylated-alpha,beta-unsaturated amidate anions (2) have been found to be excellent Michael acceptors in charge-directed conjugate addition reactions with Grignard and organolithium reagents. The effects of olefin substitution, Si-substitution, N-substitution, and amidate counterion have been studied. Anionic acceptors may be prepared in situ by the addition of silylated vinyllithium reagents to isocyanates and then allowed to undergo conjugate addition reactions with subsequently added nucleophiles, but it was found to be more efficient to isolate neutral acceptors and regenerate the acceptor anion through the use of excess nucleophile. Beta-Substituted acceptors were found to react only with reactive organolithium reagents while a beta,beta-disubstituted acceptor failed to undergo conjugate addition reactions. A primary amide acceptor (14d) also undergoes addition reactions with larger quantitites of nucleophiles suggesting that dianionic amidate acceptors (31) are involved. Diene acceptor 24 was found to undergo a 1,6-addition reaction with n-BuLi. Sodium and potassium amidate salts were found to be inferior to lithium and magnesium salts in addition reactions in keeping with the expectation that an increase in carbonyl-group charge burden retards conjugate reactions. Triphenylsilyl-containing acceptor 16 was found to be more reactive in reactions with n-BuMgCl but less reactive with bulkier tert-BuMgCl. Adduct dianions can be monoalkylated with alkyl iodides and used in Peterson olefination reactions.
The chloro, bromo and iodo 2-(α-hydroxy-p-halobenzyl)-cyclohexanones, the bromo and iodo α-cyclohexyl-p-halobenzyl alcohols, the chloro and bromo 2-(p-halobenzyl)-cyclohexanones and the chloro, bromo and iodo 2-(p-halobenzylidene)-cyclohexanones have been made. The infrared spectra of the 2-(α-hydroxy-p-halobenzyl)-cyclohexanones, the α-cyclohexyl-p-halobenzyl alcohols, the 2-(p-halobenzyl)-cyclohexanones, the ultraviolet spectra and the dipole moments of the 2-(α-hydroxy-p-halobenzyl)-cyclohexanones have been measured. Two fractions were obtained for the bromo and iodo 2-(α-hydroxy-p-halobenzyl)-cyclohexanones. The higher melting fractions are shown to have the hydroxybenzyl groups in the equatorial position and it has been demonstrated that these compounds have an intramolecular hydrogen bond present both in dilute solution in carbon tetrachloride and in mulls. The hydrogen bonded OH in these compounds gives rise to a sharp narrow band of high extinction at 2.78 to 2.79 μ when measured in dilute solution. The band is shifted only 0.02 to 0.08 μ when measured in the solid. The evidence indicates the low melting fraction is a mixture of diastereoisomers having the hydroxybenzyl group also in an equatorial position. The 2-(α-hydroxy-p-halobenzyl)-cyclohexanones have a higher extinction at 290 mμ than does a simple ketone. The reason for the enhancement in this case appears not to be an interaction between the carbonyl and the phenyl, but an interaction between the carbonyl and the hydroxyl groups.
Die Verfasser zeigen an der Silylierung von verschiedenen Ketonen und Alkoholen mit Äthyl-trimethylsilylacetat (II) in Gegenwart katalytischer Mengen an Tetra-n-butylammoniumfluorid, daß das Silylacetat ein ausgezeichnetes Silylierungsmittel bei milden Reaktionsbedingungen ist.
Die bei der Reaktion der enolisierbaren Oxazolidonketone (II), (V) bzw. (VII) mit Dibutylboryltriflat (III) in Gegenwart von N,N-Diisopropylethylamin entstehenden Boronenolate gehen mit den Aldehyden (I) chirale, erythro-selektive Aldolkondensation ein unter Bildung der Ketole (IV), (VI) bzw. (VIII) und (IX) (Aufarbeitung der Reaktionsgemische mit Phosphatpuffer pH7, nachfolgend H2O2-Oxidation in Methanol bei 0 ?C).
This paper is a theoretical study of electrokinetic flow in narrow cylindrical capillaries. It is concerned with the dependence of the usual electrokinetic phenomena on the electrokinetic radius. The results obtained for this dependence must, however, be treated with caution for the higher values of the interface potential due to the use of the Debye-Hückel approximation. Of interest is the prediction of a maximum in the electroviscous effect.