We gratefully acknowledge the Swedish Research Council Formas for generous financial support.

1. Gram-scale Synthesis of Methyl 6-oxo-3,4,6-triphenylhexanoate
<ol>
	<li>Dry 1-ethyl-3-methyl imidazolium acetate (EMIMAc) in a round bottom flask on a rotary evaporator at 10 mBar, 40 &#176;C for 1 hr.</li>
	<li>Add 2.1 g of dry EMIMAc and 1.0 g of 1,3-diphenyl-2-propen-1-one to a 100 ml round bottom flask equipped with a magnetic stirrer.</li>
	<li>Add 2.019 ml of methanol and 2.3 g of cinnamaldehyde to the flask.</li>
	<li>At room temperature (22 &#176;C) dissolve the mixture in 60 ml of dichloromethane by stirring for 1 min.</li>
	<li>Subsequently add 0.37 ml of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the stirring mixture (step 1.4) and cap the round bottom flask.</li>
	<li>Stir with a magnetic stir bar at a speed of 500 rpm at room temperature (22 &#176;C).</li>
	<li>Check completion of the reaction with 1H NMR.24 Look for disappearance of double bond of the chalcone in the 7.8 ppm area.</li>
	<li>When the reaction has reached completion remove the volatiles on a rotary evaporator at 10 mBar, 20 &#176;C for 15 min.</li>
	<li>Add 50 ml methanol to the residue to dissolve the EMIMAc by stirring with a magnetic stir bar.</li>
	<li>Remove the solids from the walls of the flask by stirring violently with a magnetic stir bar at a speed of 750 rpm for 30 min. If necessary, use a spatula to remove remaining solids from the walls.</li>
	<li>Filter the mixture on a frit (pore size 3).</li>
	<li>Wash with additional 20 ml of methanol. If recycling of the EMIMAc is desired evaporate the methanolic filtrate. (step 2.1).</li>
	<li>Still on the frit, gently divide the filter cake (from step 1.11) into smaller pieces with a spatula and transfer the solids via a powder funnel to a pre-weighed round bottom flask and dry the solids under vacuum.</li>
	<li>Weigh the flask and calculate the yield.</li>
	<li>Analyze the product by 1H NMR (step 1.7). Compare with reported spectra.24</li>
</ol>
2. Recycling of EMIMAc
<ol>
	<li>Remove the volatiles from the methanolic mixture (from step 1.12) under reduced pressure of 10 mBar, at 40 &#176;C for 30 min.</li>
	<li>Analyze the resulting oil by 1H NMR and 13C NMR to check that EMIMAc is present.24</li>
	<li>Use the recycled EMIMAc starting from step 1.2.</li>
</ol>
3. Gelation
<ol>
	<li>Preparation of a Stock Solution
	<ol>
		<li>Add 200 mg of Methyl 6-oxo-3,4,6-triphenylhexanoate (the product from step 1.15) and a magnetic stir bar to a vial. Add 2.0 ml dichloromethane to dissolve the ketoester. Stir until everything has dissolved.</li>
	</ol>
	</li>
	<li>Gelation
	<ol>
		<li>Add 50 ml of heptane to a 500 ml beaker. Add 1.5 ml of the stock solution to the heptane. Stir swiftly to ensure adequate mixing and let stand without stirring at ambient temperature until gelation occurs.</li>
	</ol>
	</li>
</ol>

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The authors have nothing to disclose.

Based on the anti-configuration determined by X-ray analysis of ketoester 3 and on the mechanistic investigation proposed by Bode and co-workers30 the following reaction path is suggested (Figure 5). Deprotonation of the IL generates NHC species; the NHC reacts with the unsaturated aldehyde to form the Breslow intermediate I. The Breslow intermediate and the chalcone react in a cross-benzoin reaction to form diene II. Intermediate II undergoes an oxy-Cope rearrangement via boat transition state (TS), setting the anti-oriented stereogenic centers III. After tautomerization, acyl azolium IV reacts with methanol to deliver the product and regenerating the catalyst.
<img alt="Figure 5" src="/files/ftp_upload/53213/53213fig5.jpg" /> 
Figure 5: Catalytic cycle of the NHC-catalyzed addition of chalcone to cinnamaldehyde (R = Me, Et). Re-print with permission from reference 24.
Critical step of importance is the addition sequence of the reagents. If DBU is not added as the last reagent the reaction yields tend to become very low. It is also recommended to evaporate the EMIMAc before usage since residual amount of volatile material present in EMIMAc may lead to byproducts. In the washing step (1.12) the large chunks of product must be crushed in order to obtain sufficiently pure material.
Troubleshooting
The gel state is a metastable state and the gels inevitably become grainy over time. However, if the gels are grainy directly after formation a possible reason could be that the gelation is conducted at a to high gelator concentration.
At present, the reactions need to be conducted with excess amounts of EMIMAc, aldehyde and methanol in order to achieve a high conversion. From efficiency perspective this is not optimal but lower loadings of either reagents result in decreased reaction yields.
The synthesis of the 1,6-ketoesters is highly stereoselective, proceeds in good to excellent yields. In addition, an efficient washing protocol renders a pure ketoester end product without the need for solvent-demanding chromatography. Alternative methods to selectively access the highly functionalized 1,6-ketoesters are considerably more laborious.
Given the easy synthesis of 1 via a three-component reaction, the methodology presented offers a fast way to generate molecular diversity. Combined with the potency of 1 as an organogelator, this technique can thus be used for a rapid evaluation of the 1,6-ketoesters as a new class of LMWG. The method allows production of tailored gelators with desirable properties, enabling access to new materials.

<img alt="TOC 1" src="/files/ftp_upload/53213/53213TOC.jpg" />
(Above) Three-component synthesis of 1,6-ketoesters: a new class of low molecular weight gelators.

Ionic liquids (ILs) have high stability, low volatility, non-flammability and have therefore rendered attention as safe reaction media and ideal solvents for recycling.1-3 Dialkyl imidazoliums are a certain type of ionic liquids that, in the presence of a base, can be deprotonated to render an N-heterocyclic carbene (NHC).4 In the field of organocatalysis, NHCs, operating under distinct reaction paths, have found widespread usage in a broad range of generic reactions.5-11
Despite this, the connection between ILs and C-C bond forming NHC&#8211;catalysis is relatively unexplored. Nevertheless, NHCs derived from ILs have been reported to catalyze C-C bond forming reactions such as the benzoin condensation and the Stetter reaction.12-22 For example, Davis et al. have shown that ILs derived from N-alkyl thiazoliums serve as precatalysts in the formation of benzoin from benzaldehyde.12
More recently, Chen and co-workers expanded this concept using an imidazolium based IL, 1-ethyl-3-methyl imidazolium acetate (EMIMAc), to perform the benzoin condensation on 5-hydroxymethylfurfural (HMF) to generate 5,5&#8217;-di(hydroxymethyl)furoin (DHMF).23 Given that ILs are commercially available and offer an inexpensive way of generating NHCs, we were interested in investigating what other types of reactions ILs could perform. To this end, we found that dialkyl imidazoliums could efficiently be used as precatalysts in the formal conjugate addition of unsaturated aldehydes to chalcones (Figure 1) giving 1,6-ketoesters. The most efficient IL, EMIMAc, promotes a highly stereoselective reaction between cinnamaldehyde and chalcone. The reaction occurs with high preference for the anti-diastereomer and the 1,6-ketoesters can be isolated in yields up to 92%.24,25,26
<img alt="Figure 1" src="/files/ftp_upload/53213/53213fig1.jpg" /> 
Figure 1: IL-mediated three-component, stereoselective addition of cinnamaldehyde to chalcone.

<table><tbody><tr><td>1-ethyl-3-methyl imidazolium acetate</td><td>Aldrich</td><td>51053-100G-F</td><td>Produced by BASF &amp;ge;90%, dried on a rotary evaporated before use (10 mBar, 40 &amp;deg;C, 1 hr)&lt;br/&gt; CAS NUMBER: 143314-17-4</td></tr><tr><td>1,3-diphenyl-2-propen-1-one</td><td>Aldrich</td><td>11970-100G</td><td>98.0%&lt;br/&gt; CAS NUMBER: 94-41-7</td></tr><tr><td>trans-cinnamaldehyde&amp;nbsp;</td><td>Aldrich</td><td>C80687-25G</td><td>99%, stored under nitrogen prior to use&lt;br/&gt; CAS NUMBER: 14371-10-9</td></tr><tr><td>1,8-Diazobicyclo[5.4.0]undec-7-ene</td><td>Aldrich</td><td>139009-25G</td><td>98%&lt;br/&gt; CAS NUMBER: 6674-22-2</td></tr><tr><td>Methanol</td><td>Sigma-Aldrich</td><td>32213N-2.5L</td><td>puriss. P.a., ACS reagent, reag. ISO, reag. Ph. Eur. &amp;ge;99.8% (GC)&lt;br/&gt; CAS NUMBER: 67-56-1</td></tr><tr><td>Dichloromethane</td><td>Fischer Chemical</td><td>D/1852/17X</td><td>Analytic reagent grade, stabilized with amylene&lt;br/&gt; CAS NUMBER: 9/2/1975</td></tr><tr><td>n-Heptane</td><td>Fischer Chemical</td><td>H/0160/17X</td><td>Analytic reagent grade&lt;br/&gt; CAS NUMBER: 142-82-5</td></tr></tbody></table>

highly stereoselective synthesis of 1,6-ketoesters mediated by ionic liquids: a three-component reaction enabling rapid access to a new class of low molecular weight gelators

In organic chemistry ionic liquids (ILs) have emerged as safe and recyclable reaction solvents. In the presence of a base ILs can be deprotonated to form catalytically active N-Heterocyclic Carbenes (NHCs). Here we have used ILs as precatalysts in the addition of &#945;,&#946;-unsaturated aldehydes to chalcones to form 1,6-ketoesters, incorporating an anti-diphenyl moiety in a highly stereoselective fashion. The reaction has a broad substrate scope and several functional groups and heteroaromatics can be integrated into the ketoester backbone in generally good yields with maintained stereoselectivity. The reaction protocol is robust and scalable. The starting materials are inexpensive and the products can be obtained after simple filtration, avoiding solvent-demanding chromatography. Furthermore, the IL can be recycled up to 5 times without any loss of reactivity. Moreover, the 1,6-ketoester end product is a potent gelator in several hydrocarbon based solvents. The method enables rapid access to and evaluation of a new class of low molecular weight gelators (LMWGs) from recyclable and inexpensive starting materials.

As exemplified above, EMIMAc serve as a precatalyst in the formal conjugate addition of &#945;,&#946;-unsaturated aldehyde to chalcones. Other commercially available imidazolium based ILs such as 1-ethyl-3-methylimidazolium chloride (EMIMCl) and 1-butyl-3-methylimidazolium chloride (BMIMCl) were also investigated, however, these reactions proceeded in lower yields indicating that the acetate anion may be important for reactivity (Table 1, entry 1-3).27,28*
* The role of the anion in this reaction is at the moment unclear. For studies on the role of the anion in NHC-catalysis see, references 27 and 28.
<img alt="Table 1" src="/files/ftp_upload/53213/53213table1highres.jpg" width="700" />
Table 1: Optimization of reaction conditions for the synthesis of 1.
Other commonly used NHC precatalysts such as A and B were less efficient than EMIMAc and gave ketoester 1 in 33% and 46% yields, respectively (Table 1, entry 4 and 6). In addition, to achieve an efficient reaction the use of a co-solvent is necessary, where the co-solvent provides a homogeneous phase reaction by both dissolving the IL and end product. As a co-solvent, dichloromethane provided the best result with regard to reaction yield. Efforts to find a more benign solvent were made; methanol and acetonitrile are also possible to use as co-solvents but at the expense of lower yields (Table 1, entry 7 and 8). The choice of base is also important, without added base no reaction can be observed (Table 1, entry 9). DBU was found to be the optimal base (Table 1, entry 1) but carbonate bases were also viable giving full conversion within 1.5 hr but with a higher degree of byproduct formation (Table 1, entry 11, 72% yield). Milder bases such as triethylamine only gave trace amounts of product (Table 1, entry 10). Furthermore, the individual components of the IL mediated three-component reaction can be varied to introduce several functional groups to the ketoester backbone. Chalcones bearing electron donating groups and halogen substituents are well tolerated and proceed in high dr and good yields (Figure 2, entries 2-10). For example, ketoester 6 bearing a bromo-substituent on the aromatic ring, a convenient scaffold for cross-coupling chemistry, can be isolated in 75% yield. The &#945;,&#946;-unsaturated aldehyde can also be altered allowing the introduction of a chloro-, methyl- and methoxy-group on the ketoester backbone without affecting the selectivity or yield (Figure 2, entries 11-13). Moreover, different primary alcohols such as ethanol and benzyl alcohol can also be introduced (Figure 2, entries 14 and 15).
<img alt="Figure 2" src="/files/ftp_upload/53213/53213fig2.jpg" /> 
Figure 2: Reaction scope of the formal conjugate addition of &#945;,&#946;-unsaturated aldehydes to chalcones. (a) Reactions performed at RT, dichloromethane, DBU (0.5 equiv.), IL (2.5 equiv.), aldehyde (3 equiv.), chalcone (1 equiv. 0.08 M), alcohol (10 equiv.). (b) Yields refer to isolated yields after purification. Modified from reference 24.
Notably the reactions are extremely stereoselective and only the anti-diastereoisomer is obtained. The anti-oriented vicinal diphenylethylene was determined by X-ray analysis on compound 3 (Figure 3).
<img alt="Figure 3" src="/files/ftp_upload/53213/53213fig3.jpg" /> 
Figure 3: ORTEP drawing of ketoester 3. Re-print with permission from reference 24.
As shown the pure ketoester 1 can be obtained after a simple workup and washing protocol. The IL can then be recycled after evaporation of the methanolic solution. The IL has been recycled up to five times with no decrease in reaction yield.24
Moreover, the 1,6-ketoesters are also potent gelators in hydrocarbon solvents such as hexane and heptane (Figure 4).29 The gelation is concentration dependent and ketoester 1 gelates already at a concentration of 2 mg/ml within 10 min. At higher concentrations the gelation occurs within a min. The gelation is reversible and addition of dichloromethane or heating will re-dissolve the ketoester.
<img alt="Figure 4" src="/files/ftp_upload/53213/53213fig4.jpg" /> 
Figure 4: Gelation in heptane. (a and b) organogel of gelator 1 in heptane (5 mg/ml). (c) Gel removed from the beaker.

Watch this Scientific Journal Video about Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular

Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

Ionic liquids (ILs) mediate fast, simple and cheap access to 1,6-ketoesters in high diastereoselectivities and good yields. The reaction protocol is robust and the 1,6-ketoesters can be obtained in gram scale after a simple filtration protocol. Moreover, the 1,6-ketoesters are potent gelators in hydrocarbon solvents.

In organic chemistry ionic liquids (ILs) have emerged as safe and recyclable reaction solvents. In the presence of a base ILs can be deprotonated to form ...

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Nanyang Technological University

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JoVE Journal

Chemistry

9.4K Views.  Chalmers University of Technology. Ionic liquids (ILs) mediate fast, simple and cheap access to 1,6-ketoesters in high diastereoselectivities and good yields. The reaction protocol is robust and the 1,6-ketoesters can be obtained in gram scale after a simple filtration protocol. Moreover, the 1,6-ketoesters are potent gelators in hydrocarbon solvents. 

Video: Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to &#62;95%).

Chiral amino alcohols are versatile molecules for use as scaffolds in organic synthesis. Starting from L-lysine, we synthesize amino alcohols by an enzymatic cascade reaction combining diastereoselective C-H oxidation catalyzed by dioxygenase followed by cleavage of the carboxylic acid moiety of the corresponding hydroxyl amino acid by a decarboxylase.

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. ...

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. Recently, we have developed a two-step strategy for ketone enolate umpolung that has enabled the development of methods for chlorination, azidation, and amination using azoles. In addition, we have developed C-C bond&#8211;forming arylation and allylation reactions. At the heart of these methods is the preparation of the intermediate and highly reactive enolonium species prior to addition of a reactive nucleophile. This strategy is thus reminiscent of the preparation and use of metal enolates in classical synthetic chemistry. This strategy allows the use of nucleophiles that would otherwise be incompatible with the strongly oxidizing hypervalent iodine reagents. In this paper we present a detailed protocol for chlorination, azidation, N-heteroarylation, arylation, and allylation. The products include motifs prevalent in medicinally active products. This article will greatly assist others in using these methods.

A two step one-pot protocol for the umpolung of ketone enolates to enolonium species and addition of a nucleophile to the &#945;-position is described. Nucleophiles include chloride, azide, azoles, allyl-silanes, and aromatic compounds.

&#945;-Functionalization of ketones via umpolung of enolates by hypervalent iodine reagents is an important concept in synthetic organic chemistry. ...

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1&#176; and 2&#176; aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

Organocatalysis

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of organocatalysis by illustrating the proper setup of a reaction that utilizes enamine catalysis. Organocatalysis is a form of catalysis that uses substoichiometric amounts of small organic molecules to accelerate reactions. This type of catalysis is complementary to other forms of catalysis such as transition metal or biocatalysis. Transition metal catalysis involves transition metals as catalysts and biocatalysis uses enzymes as catalysts. Some advantages of organocatalysis include the low toxicity and cost of the organocatalysts in comparison to many metal catalysts. In addition, most organocatalysts are not sensitive to air and moisture, unlike metal catalysts. In contrast to enzymes found in living organisms, the small molecules that act as organocatalysts are typically easy to access. Furthermore, organocatalysis offers complementary and new reactivity not observed with other forms of catalysis.

Organocatalysis: Principles and Applications

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of ...

Education

JoVE Science Education

Organic Chemistry II

&alpha;-Alkylation of Ketones via Enolate Ions

Ketones with &#945; protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by resonance, and its hybrid structure exhibits negative charges on the carbonyl oxygen and the &#945; carbon. This ambident nucleophile can attack an electrophile via two possible sites: the carbonyl oxygen, known as O-attack, or the &#945;&nbsp;carbon, known as C-attack. The nucleophilic attack via the carbanionic site is preferred. This is due to the strong interaction of the positive counterpart of the base with the anionic oxygen, which restricts the approaching electrophile, making the reaction less favorable. Also, the product obtained through C-attack is more stable than that obtained through O-attack, as the stronger C=O &#960; bond is retained in the former, whereas a weaker C=C &#960; bond is preserved in the latter.
A subsequent reaction of the enolate with electrophiles such as alkyl halides produces an &#945;-alkylated ketone via the SN2 pathway. The &#945;-alkylation of ketones is achieved with the halides of primary alkyl, benzyl, and allylic groups. With secondary and tertiary alkyl halides, elimination predominates over substitution.

&#945;-Alkylation of Ketones via Enolate Ions

Ketones with &#945; protons are deprotonated by strong bases like lithium diisopropylamide (LDA) to form enolate ions. The anion is stabilized by ...

JoVE Core

Organic Chemistry

Unit 1

&alpha;-Carbon Chemistry: Enols, Enolates, and Enamines

KEY TERMS AND CONCEPTS

Alkylation of &beta;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide base that abstracts the acidic proton of the &beta;-keto esters. The step results in an enolate ion which is doubly stabilized. The enolate then reacts with an alkyl halide via the SN2 process to produce an alkylated ester intermediate with a new C&#8211;C bond. The hydrolysis of the intermediate, followed by acidification, results in an alkylated &beta;-keto acid. Under high-temperature conditions, the &beta;-keto acid undergoes decarboxylation to form a ketone. However, if the alkylation is repeated before hydrolysis and decarboxylation steps, a disubstituted ketone is obtained.

Alkylation of &#946;-Ketoester Enolates: Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and &beta;-keto esters. The reaction occurs in the presence of an alkoxide ...

Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

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