Requirements for an effective chiral auxiliary enolate alkylation 1. The kinetic enolate is not as stable, but it is the one that forms that fastest. Enolate anions and enamines university of texas at austin. The journal of organic chemistry 1996, 61 7, 24282440. The cleavage of xc from the substrate must occur under mild enough conditions. When this proton is not returned at the end of the stepwise process, the result is an anion termed an enolate see images at right. Alkylation of carbonyl compounds in the ticl4promoted reaction of trimethylsilyl enol ethers with epoxides gojko lalic. It was anticipated that the hydroxyl moiety, r2, would perform a crucial role, via enolate chelation, in establishing an enantiotopic bias in the alkylation of enolate 2. The number on the icon gives the page number in chemistry 3, third edition, where you can read more about the topic if you do not own a copy of the textbook you can obtain one from.
Aldehydes are too reactive and cannot usually be alkylated in this manner. Nov 01, 2015 this organic chemistry video tutorial discusses the reaction mechanism of the enolate ion and how it can be used for direct alkylation, acylation, carboxylation, michael addition, and how it can. Remember that enolates are sources of nucleophilic c and react with electrophiles. Once again, you can control which one of these enolates you form depending on the base that you use. Enolates are good nucleophiles and reaction with alkyl halides via s n2 type reactions. The more importants reaction of enolates are summarised below. The enol tautomer is nucleophilic and reacts with electrophiles.
Carbonyl condensation reactions as a result of the large dipole of the carbonyl group. In alkylation with alkyl halides, the electrophile is a relatively soft lewis acid. Enolates in organic synthesis 2 recall enolate alkylation, aldol addition and condensation can provide access to a wide variety of multifunctional compounds, which can lend themselves to further functionalization in multistep organic synthesis 3. The course of these reactions can be rationalized by considering the accessibility of both faces of the three possible enolates to the backside of each carbon of the epoxide. Enolates are ambident nucleophiles and can re soft electrophiles e. Aldehydes and ketones generate enolates by treating the bases which may participate in s n 2 alkylation reactions with suitable alkyl halides, forming a new carboncarbon bond in the process. You have probably reached this page by clicking the cover icon on another page.
Citations are the number of other articles citing this article, calculated by crossref and updated daily. Hydroxy ketones by the alkylation of pseudoephedrine amides with. The method is based on the generation of lithium enolate intermediates from the esters and in situ delivered lda. Disodium salts of pseudoephedrinederived myers enolates. To achieve this, the ketone is first enolized with a strong base like lithium diisopropylamide under conditions of kinetic control, and the alkylation is performed on the enolate solution. Oxygen is more electronegative than n enolates, enols and enamines structure, reactivity, general formation enolate enamine enol order of decreasing nucleophilic reactivity. This results in the attachment of an alkyl group to the carbon in a process termed alkylation.
Sn2 reaction, inversion of electrophile stereochemistry m. Alkylation of carbonyl compounds in the ticl 4 promoted reaction of trimethylsilyl enol ethers with ethylene oxide dedicated to professor zivorad cekovic, on the occasion of his 65th. The cleavage of xc from the substrate must occur under mild enough conditions so that racemization is avoided. If the two carbons differ in their degree of substitution, it may be possible to control which of the two regioisomers predominates. Dedicated to professor siegfried blechert on the occasion of his 65th birthday. The intramolecular alkylation of a ketone by three epoxide stereoisomers of 1 has been studied. Ring opening of epoxides with c nucleophiles springerlink. Alkylation with a reactive alkylating agent dialkyl sulfates, triethyloxonium fluoroborate in an aprotic polar solvent e.
The generation and alkylation of such nucleophiles are described in this chapter. The alkylation of carbon nucleophiles by s n 2type processes is an important transformation in the synthesis of organic compounds. Adding a ketone to strong base removes the alphaproton, and allows the enolate ion to nucleophilicattack rx. Kinetic and thermodynamic enolates video khan academy. Because sodio malonic ester is an enolate, it can then be alkylated with alkyl halides.
Asymmetric alkylation of aldehydes, ketones, and carboxylic acids. When forming the enolate for an alkylation process, the choice of base is important in order to avoid. The thermodynamic enolate is the more stable enolate. The ketone tautomer is electrophilic and reacts with nucleophiles. Alkylation of enolate anions formation of enol ethers. For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the absence of other strong nucleophiles and bases. The light hydrocarbons consist of olefins such as propylene and butylene and isoparaffins such as isobutane. It is known that the ratio of co alkylation depends significantly on various factors, including the type of enolate, alkylating agent, site of alkylation, and solvent environment. Ethers readily formed by trapping a lithium enolate with tmscl. An early milestone in the use of a chiral auxiliary for asymmetric alkylation. Alkylation of enolates condensation of enolates with alkyl halides and epoxides. Enolates are good nucleophiles and reaction with alkyl halides via s n 2 type reactions this allows alkyl groups to be introduced in the.
Reactions of alcohols, ethers, epoxides, amines, and sulfurcontaining compounds 10 chemists search the world for plants and berries and the ocean for flora and fauna that might be used as the source of a lead compound for the development of a new drug. Cc bond formation 72 carbon carbon bond formation 1. Reactions of epoxides with ester, ketone and amide enolates. A chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. Ring opening of epoxides has been an area of interest for organic chemists, owing to their reactivity toward nucleophiles. It is striking that 0alkyl and silylprotected enolates. The alkylation of carbonyl compounds at the a position is an important reaction for forming the carboncarbon bond. Some basics in most cases the equilibrium lies almost completely on the side of the ketone. These results predict that c alkylation is the preferred product for the same reasons concluded for iiia. Alkylation, in petroleum refining, chemical process in which light, gaseous hydrocarbons are combined to produce highoctane components of gasoline. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of simple carbonyl compounds are formed in. Aldehyde enolates cannot usually be prepared and used in this way because selfcondensation is too fast.
Diastereoselective reactions of ester enolates with epoxides. Alkylation of carbonyl compounds in the ticl4promoted reaction of trimethylsilyl enol ethers with ethylene oxide g. Enolate is nucleophilic due to oxygens small atomic radius formal negative charge detractors to nucleophilicity. The pifacial selectivity of electrophile attack on the enolate will be dictated by sterics. The evans oxazolidone chiral auxiliary has been the beststudied and most successful of the many that have been used to control faceselectivity in enolate reactions. This textbook aims to provide a comprehensive set of basic notes in organic chemistry, which will be suitable for undergraduate students taking chemistry, chemistry related. Reactions of epoxides ethers are not normally susceptible to attack by nucleophiles. Alkylation of carbonyl compounds in the ticl4promoted reaction of trimethylsilyl enol ethers with epoxides. Article views are the countercompliant sum of full text article downloads since november 2008 both pdf and html across all institutions and individuals. Regioselective ring opening of epoxides by chelated amino acid esters enolates uli kazmaier and ameer f. Scheme 2 intramolecular ester enolate alkylation in the synthesis of geijerone 4. Thermodynamic enolates an asymmetric ketone with hydrogens at both carbons can form two regioisomeric enolates.
Reactions of enolates act at either oxygen or carbon terminus. Asymmetric aalkylation of aldehydes, ketones, and carboxylic. The usefulness of epoxides in sn2 reactions has been studied and important. In practice, however, the reaction can be complicated and difficult to control. Cucatalyzed alkylation of organomagnesium reagents by rbr and ri in the. Chiral imide enolate alkylation uwmadison chemistry. The enolates can also be formed by conjugate reduction reactions.
Feb 25, 2000 read reactions of epoxides with ester, ketone and amide enolates, tetrahedron on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Cc bond formation 75 o a lda, thf, 78c b mei o me rate of alkylation is increased in more polar solvents or addition of additive me 2 n 3 p o hmpa r nme 2 o r h dmf rch 3 dma h 3 c s ch 3 o dmso ch 3 n o ch 3 n nch 3 o me 2 n nme 2 tmeda mechanism of enolate alkylation. Requirements for an effective chiral auxiliary enolate alkylation. Chemistry 3 alkylation of enolates introduction youtube. These c nucleophiles are useful for making new carboncarbon bonds.
The auxiliary can then be typically recovered for future use. Stereoselective reactions of ester enolates with epoxides. Or reaction of the enolates with alkyl halides and epoxides. Similarly, generation of the enol often is accompanied by trapping or masking of the hydroxy group as an ether, such as a silyl enol ether. Much of this work has focused on the development of strategies for the asymmetric alkylation of monocarbonyl compounds. Unusual regioselectivity in the opening of epoxides by. Indeed, enolate chemistry has provided much of the foundation for the advancement of synthetic organic chemistry to its present state. Hydroxy ketones by the alkylation of pseudoephedrine amides with epoxides and their derivatives. More commonly it is important that a single regioisomer is formed, and that only a single alkylation occurs. Many carboncarbon bondforming processes involve reaction between a nucleophilic carbon and an electrophilic one. Enolate formation and reactivity princeton university. Alkylation of carbonyl compounds in the ticl4promoted. The alkylation of silyl enol ethers with sn1unreactive.
In chapter 17 you saw epoxides acting as electrophiles in s n2 reactions. Asymmetric alkylation of aldehydes, ketones, and carboxylic. Alkylation of cyclononanone enolate with propylene oxide according to screiber. Synthesis of cyclic carbonates and polycarbonates from epoxides and carbon dioxide. Hr 140 kjmol for ethylene carbonate synthesis scheme 1, r h, 4 yet current. As long as you can draw an enolate, you can do an enolate alkylation because all it is is that youre either exposing an enolate to an alkyl halide or youre exposing an enolate to an acid chloride. Treatment of aldehydes and ketones with a suitable base can lead to the formation of a nucleophilic species called an enolate that reacts with electrophiles. The enolates react usefully with s n 2reactive alkyl halides, aldehydes, acylating agents, and michael acceptors, as well as other electrophiles. Suggested solution alkylation of the enolate with the epoxide gives and alkoxide that cyclises to give the lactone. Enolate alkylation evans oxazolidinone enolates the basis for the most commonly employed chiral enolates involves an nacyl oxzolidinone that enantiomerically pure in the heterocycle. We observed a reversal of stereochemistry in the epoxide addition, as previously reported by myers in the context of the lithium enolates eq 3. Links to chemistry3 3rd edition oup by andy burrows. Overview of enolate alkylations uwmadison chemistry.
Enolate and other carbon nucleophile alkylation reactions using 1. Enantioretentive alkylation of oxazolidinone aluminum. The synthesis of cyclic carbonates from epoxides and carbon dioxide is a highly exothermic process. Requirements for an effective chiral auxiliary enolate. This manuscript describes a continuous flow protocol for the.
Instant notes organic chemistry pdf free download books overview. Regioselective ring opening of epoxides by chelated amino. Synthesis of enols and enolates chemistry libretexts. Intramolecular alkylation of a ketone by 1,2epoxide. Alkylation and acylation of nucleophilic carbon species by other mechanisms are discussed in. Siteselective dna alkylation of gg steps by naphthaldiimide derivatives possessing enantiomeric epoxide article in organic letters 221. The emphasis in this chapter is on enolate ions and enamines, two of the most useful kinds of carbon nucleophiles, and on their reactions with alkylating agents. Structural studies reveal that unaged disodium enolate 8 is tetrameric, with either an octagonal prismatic or a stackedcube core chart 1, 6 or 7. Alkylation of carbonyl compounds in the ticl promoted. Indeed, enolate chemistry has provided much of the foundation for the. Read more instant notes organic chemistry pdf notes free download. Reaction of enols and enolates contd 3 reactions with alkyl, allyl, and benzyl halides exclusive c alkylation enols are not nucleophilic enough to have reactions with these halides. Alkylation of enolates condensation of enolates with alkyl. Aldol reactions are useful in organic chemistry synthesis for creating new carbon to carbon bonds.
Enolate and other carbon nucleophile alkylation reactions using 1,2cyclic sulfates as. For that reason, c alkylation of the enolate is favored, as, due to carbons lower electronegativity, the enolate s carbon position is a much softer lewis base than the oxygen position. For instance, in the case of carboxylate, aldehyde, and symmetrical ketone derivatives, a general and widely applicable asymmetric method has to control aspects of the reaction, including the geometry about the carboncarbon bond of the enolate, as well as the facial approach of the electrophile to the enolate. Bu w1 02 a literature search provided no precedent for the alkylation of 1,3oxazolidin5one enolates with epoxides. The b3lyp density functional studies on the mechanism of the sn2substitution reaction of methyl halides and epoxides with lithium organocupratesi, ch32culilicl and ch32culi2, revealed the energetics and the geometries of important transition states and intermediates along the reaction pathway. O o o co2et o o oet o o o now sn2 opening of the protonated lactone with the soft nucleophile bromide ion gives the. Pdf regioselective ring opening of epoxides by chelated amino.
The carbonyl carbon is electrophilic and is the site of addition reactions by nucleophiles. These metrics are regularly updated to reflect usage leading up to the last few days. Either enantiomeric series is readily available either from natural amino acids valinol or related aminoalcohols or from ephedrine. The use of highthroughput screening allowed for the optimization of reaction conditions for the palladiumcatalyzed asymmetric decarboxylative alkylation reaction of enolate stabilized enol carbonates. After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the carboxylic acids can be removed through a decarboxylation step. Rate and computational studies reveal the mechanism of alkylation. Synthesis of cyclic carbonates from epoxides and carbon. Cc bond formation 80 the aldol reaction is an equilibrium which can be driven to completion. With regard to the yield of these alkylation reactions, li. Just to catch you up, in the ketones and aldehydes section of your textbook, theres a reaction that ketones and aldehydes can undergo with amines that forms imines and enamines. In this video, i want to discuss enolate alkylations and acylations. Alkylation of carbonyl compounds in the ticl 4promoted reaction of trimethylsilyl enol ethers with epoxides. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. Xc must be low cost, and available in both enentiomeric forms 2.
Since the reaction is an s n2 reaction, methyl and primary halides are most suitable for alkylation reactions. Enolate ion reaction mechanism formation alkylation. Zahoor institut fur organische chemie, universitat des saarlandes, d66123 saarbrucken, germany email. This is an important example of substrate control by formation of a chiral auxiliary. The aqueous base conditions used for the aldol condensation are not suitable because the enolate anions of. Although a variety of products are possible a priori, in tertbuohh 2 okoh each reaction yields a preponderant product. Instant notes organic chemistry pdf notes free download. Introduction to the reactions of enols and enolates chemgapedia. Such reactions yield important products depending on the type of nucleophiles used. Alkylation of enolates condensation of enolates with alkyl halides and epoxides comprehensive organic synthesis 1991, vol. In payne rearrangement, the epoxide functions solely as an electrophile, whereas in alkylatrve epoxide rearrangement it possesses latent nudeophilic character that is revealed upon nucleophilic attack 8t c1.
This organic chemistry video tutorial discusses the reaction mechanism of the enolate ion and how it can be used for direct alkylation, acylation, carboxylation, michael addition, and how it can. Enolates in organic synthesis university of nairobi. Jul 25, 2014 alkylation of enolates, an introduction. Over the years, an enormous amount of effort has gone into the study of enolate chemistry. Alkylation of enolates the alkylation of relatively acidic substances such as. Dedicated to professor siegfried blechert on the occasion of. Enamine alkylation and acylation organic chemistry video. Read reactions of epoxides with ester, ketone and amide enolates, tetrahedron on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Enolate alkylation and acylation organic chemistry video. Alkylation of carbon via enolates and enamines springerlink. Reactions of epoxides with ester, ketone and amide. Because of the strain associated with the threemembered ring, epoxides readily undergo a variety of ringopening reactions.