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A more direct method to convert 3 into 4 is the reaction of 3 with the enolate ion 5 of ethyl acetate followed by hydrolysis of the resultant ester. However, the generation of 5 from ethyl acetate quantitatively in high yield is not an easy task because the reaction requires a very strong base, such as LDA, and must be carried out at very low temperature under strictly anhydrous conditions. Malonic ester synthesis provides a more convenient alternative to convert 3 to 4.

Malonic ester synthesis can be adapted to synthesize compounds that have the general structural formula 6. Because Sodio Malonic Ester is an enolate, it can then be alkylated with alkyl halides. 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.

Steven Farmer Sonoma State University. Mechanism Malonic ester synthesis consists of four consecutive reactions that can be carried out in the same pot. Mechanism 1 Saponification 2 Decarboxylation 3 Tautomerization All of the steps together form the Malonic ester synthesis. From dimethylzinc 4 and simple alkyl chains 3 , 5 , 6 , 9 , 10 to derivatives harboring olefins 7 — 8 , alkynes 11 — 12 , acetals 16 , ethers 14 — 15 , and even alkyl halides 13 were tolerated.

The reaction was easily run on a gram scale as exemplified by 3 and could even be employed to produce isotopically labeled piperidine 4 - 13 C. In addition to 3 , this example highlights that a lower loading of dialkylzinc reagent 0. Secondary alkylzinc reagents such as cyclopropylzinc could also be accommodated as exemplified by Standard conditions: redox-active ester 1 equiv. Next, the scope of secondary alkyl carboxylic acids fifteen, Figure 2b was explored. Cyclic 18 , 19 , 21 , heterocyclic 20 , 22 , 26 — 28 , 31 , bridging 25 , indane 24 , acyclic 29 , and even fluorinated 23 , 30 alkyl carboxylic acids were all viable coupling partners.

Substrates 30 through 32 are particularly striking and open the door to access a vast array of fluorinated building blocks and optically pure tartrate-derived materials.

Malonic Ester Synthesis

Many of these products would be either inconvenient or chemically intractable to access from the corresponding alkyl halide starting materials 27 , 28 , 30 , 31 and Primary alkyl carboxylic acids, representing some of the most inexpensive organic materials available, could also be readily employed. Of the eight examples depicted in Figure 2c , most notable are the use of mono-methyladipic acid 34 , 2. Tertiary alkyl carboxylic acids Figure 2d could also be employed to generate quaternary centers. Although limited in scope, bridgehead systems such as adamantane 41 and 42 or bicyclo[2.

The classic Williamson ether synthesis is still the staple transform for constructing ethers but in many cases the SN2 reaction is either sluggish or unworkable due to steric hindrance. Redox-active esters enable the cross-coupling of alkylzinc reagents with high chemoselectivity Figure 2f even in complex contexts, reminiscent of that exhibited in classic amide-bond formation.

CAA1 - Preparation of higher alkyl esters of carboxylic acids - Google Patents

For example, a variety of sensitive fatty acids reacted smoothly to give the corresponding alkyl chains 50 , 57 and 58 without olefin isomerization or epoxide opening. Naturally occurring carboxylic acids such as biotin, cholic acid and dehydrocholic acid were also amenable to alkylation 54 — Pharmaceuticals such as pregabalin, 2,4-D, cetirizine and atorvastatin smoothly reacted with alkylzinc reagents to afford good yields of the alkyl coupling products 51—53 and In perhaps the most impressive feat of chemoselectivity for this methodology, the cross-coupling could be conducted on solid phase in the context of peptide synthesis.

Valuable synthetic handles including alkenes 60 and 62 and alkyl ethers 63 could be readily incorporated into resin-bound substrates Figure 3 , and the installation of an aliphatic side-chain 61 provides a facile approach to the modulation of peptide lipophilicity. This convenient approach to diversely functionalized peptides provides a tool for the construction of therapeutic peptide leads, stapled peptides 28 , 29 and for applications in bioconjugation. Returning to the limitations posed by tertiary systems, mechanistic studies involving 5- exo -dig cyclization, racemization and ring-strain opening experiments clearly point to the radical nature of this reaction see Figures S1 — S3.

We reasoned that the steric limitations encountered could be overcome by engaging these reactive species with a radical trap that could subsequently combine with an organozinc reagent. Remarkably, such a conjunctive cross-coupling could be realized as shown in Figure 4.

One-Step Synthesis of Nitriles from Acids, Esters and Amides Using DIBAL-H and Ammonium Chloride

This reaction is scalable as exemplified by 76 , generates 2 new C—C bonds, and is a rare example of a multicomponent cross coupling reaction that forms quaternary centers in high yield. All the products shown were obtained in a racemic form. As with any methodology there are obvious drawbacks.


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For example, the atom-economy is low due to the use of an activating group. We do note, however, that such considerations are ignored in the enormous field of peptide chemistry where expensive coupling agents are regularly employed to make a simple amide bond. The use of two equivalents of the dialkylzinc reagent is another disadvantage in cases where the zinc-derived fragment is valuable. The data presented herein suggests that the advantages associated with this method far outweigh its limitations.

Without exception, the carboxylic acids employed represent the most inexpensive sources of these carbon frameworks; in fact all of these were commercially available. In contrast, in the cases where an alkyl halide would be chemically stable, only a handful are commercially available. Conceptually, carboxylic acids can perhaps be considered as Nature's version of a boronic acid.

For the past seven decades these ubiquitous functional groups have usually been dehydrated with incorporation of a nucleophile such as an amine to make an amide. This method extends the native diversification of this functional group, 33 to allow for the addition of a new carbon framework via extrusion of CO2.

As such it is anticipated that this technique will greatly expand planning options in retrosynthetic analysis. China Scholarship Council postdoctoral fellowship to C. We thank Dr. Huang and Dr. Pasternack for assistance with NMR spectroscopy; Dr.

Supplementary files

Collins for providing samples of atorvastatin, cetirizine and pregabalin; Mr. Riley Mills for experimental assitance; Dr. Rheingold, Dr. Moore, and Dr. Galella for x-ray crystallographic analysis; and Dr.


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Chen for helpful discussions. Europe PMC requires Javascript to function effectively. Recent Activity. Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study demonstrates how the same activating principles used for decades to make simple C-N amide bonds from carboxylic acids with loss of water can be used to make C-C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. The snippet could not be located in the article text.

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This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Author manuscript; available in PMC Nov PMID: Malins , 1 Jacob T. Edwards , 1 Shuhei Kawamura , 1 Brad D. Maxwell , 2 Martin D. Eastgate , 3 and Phil S. Lara R.

Jacob T. Brad D. Martin D. Phil S. Copyright notice. The publisher's final edited version of this article is available at Science. See other articles in PMC that cite the published article. Abstract Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers and represent an ideal starting material with which to forge new connections. Open in a separate window.

Figure 1. Development of a Ni-catalyzed decarboxylative alkyl-alkyl cross-coupling A Activation of carboxylic acids in organic synthesis. Figure 2. Scope of the Ni-catalyzed decarboxylative alkyl-alkyl cross-coupling Standard conditions: redox-active ester 1 equiv. Figure 3. Figure 4.

Scope of the Ni-catalyzed three-component conjunctive cross-coupling Standard conditions: redox-active ester 1 equiv. Supplementary Material Supplemental Click here to view.

Fischer esterification - Carboxylic acids and derivatives - Organic chemistry - Khan Academy

References and Notes 1. Diederich F, Stang PJ. Metal-catalyzed Cross-coupling Reactions. Jolibois P. Compt Rend Acad Sciences. J Org Chem. J Am Chem Soc. Tamura M, Kochi J.