File Name: methods and applications of cycloaddition reactions in organic synthesis .zip
In organic chemistry , the Diels—Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene , commonly termed the dienophile , to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism. It was first described by Otto Diels and Kurt Alder in For the discovery of this reaction, they were awarded the Nobel Prize in Chemistry in Through the simultaneous construction of two new carbon—carbon bonds, the Diels—Alder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes.
The reaction has also been generalized to other ring sizes, although none of these generalizations have matched the formation of six-membered rings in terms of scope or versatility. The reaction is an example of a concerted pericyclic reaction.
A consideration of the reactants' frontier molecular orbitals FMO makes plain why this is so. The same conclusion can be drawn from an orbital correlation diagram or a Dewar-Zimmerman analysis.
However, the HOMO—LUMO energy gap is close enough that the roles can be reversed by switching electronic effects of the substituents on the two components.
Regardless of which situation pertains, the HOMO and LUMO of the components are in phase and a bonding interaction results as can be seen in the diagram below. Since the reactants are in their ground state, the reaction is initiated thermally and does not require activation by light.
The "prevailing opinion"     is that most Diels—Alder reactions proceed through a concerted mechanism; the issue, however, has been thoroughly contested. Despite the fact that the vast majority of Diels—Alder reactions exhibit stereospecific, syn addition of the two components, a diradical intermediate has been postulated  and supported with computational evidence on the grounds that the observed stereospecificity does not rule out a two-step addition involving an intermediate that collapses to product faster than it can rotate to allow for inversion of stereochemistry.
There is a notable rate enhancement when certain Diels—Alder reactions are carried out in polar organic solvents such as dimethylformamide and ethylene glycol,  and even in water. The geometry of the diene and dienophile components each propagate into stereochemical details of the product. For intermolecular reactions especially, the preferred positional and stereochemical relationship of subtituents of the two components compared to each other are controlled by electronic effects.
However, for intramolecular Diels—Alder cycloaddition reactions, the conformational stability of the structure the transition state can be an overwhelming influence. Frontier molecular orbital theory has also been used to explain the regioselectivity patterns observed in Diels—Alder reactions of substituted systems.
Calculation of the energy and orbital coefficients of the components' frontier orbitals  provides a picture that is in good accord with the more straightforward analysis of the substituents' resonance effects, as illustrated below.
In general, the regioselectivity found for both normal and inverse electron-demand Diels—Alder reaction follows the ortho-para rule , so named, because the cyclohexene product bears substituents in positions that are analogous to the ortho and para positions of disubstituted arenes. Pairing these two coefficients gives the "ortho" product as seen in case 1 in the figure below.
A diene substituted at C2 as in case 2 below has the largest HOMO coefficient at C1, giving rise to the "para" product. Similar analyses for the corresponding inverse-demand scenarios gives rise to the analogous products as seen in cases 3 and 4.
Examining the canonical mesomeric forms above, it is easy to verify that these results are in accord with expectations based on consideration of electron density and polarization. In general, with respect to the energetically most well-matched HOMO-LUMO pair, maximizing the interaction energy by forming bonds between centers with the largest frontier orbital coefficients allows the prediction of the main regioisomer that will result from a given diene-dienophile combination.
The maximization of orbital interaction correctly predicts the product in all cases for which experimental data is available. For instance, in uncommon combinations involving X groups on both diene and dienophile, a 1,3-substitution pattern may be favored, an outcome not accounted for by a simplistic resonance structure argument.
Diels—Alder reactions, as concerted cycloadditions, are stereospecific. Stereochemical information of the diene and the dienophile are retained in the product, as a syn addition with respect to each component. For example, substituents in a cis trans , resp.
Likewise, cis , cis - and trans , trans -disubstitued dienes give cis substituents at these carbons of the product whereas cis , trans -disubstituted dienes give trans substituents:  . Diels—Alder reactions in which adjacent stereocenters are generated at the two ends of the newly-formed single bonds imply two different possible stereochemical outcomes. This is a stereoselective situation based on the relative orientation of the two separate components when they react with each other.
In the alternative exo transition state, it is oriented away from it. There is a more general usage of the terms endo and exo in stereochemical nomenclature. In these "normal demand" Diels—Alder scenarios, the endo transition state is typically preferred, despite often being more sterically congested. This preference is known as the Alder endo rule. As originally stated by Alder, the transition state that is preferred is the one with a "maximum accumulation of double bonds.
Often, as with highly substituted dienes, very bulky dienophiles, or reversible reactions as in the case of furan as diene , steric effects can override the normal endo selectivity in favor of the exo isomer. The diene component of the Diels—Alder reaction can be either open-chain or cyclic, and it can host many different types of substituents;  it must, however, be able to exist in the s- cis conformation, since this is the only conformer that can participate in the reaction.
A bulky substituent at the C2 or C3 position can increase reaction rate by destabilizing the s- trans conformation and forcing the diene into the reactive s- cis conformation. Dienes with bulky terminal substituents C1 and C4 decrease the rate of reaction, presumably by impeding the approach of the diene and dienophile. An especially reactive diene is 1-methoxytrimethylsiloxy-buta-1,3-diene, otherwise known as Danishefsky's diene.
Other synthetically useful derivatives of Danishefsky's diene include 1,3-alkoxytrimethylsiloxy-1,3-butadienes Brassard dienes  and 1-dialkylaminotrimethylsiloxy-1,3-butadienes Rawal dienes. Unstable and thus highly reactive dienes, of which perhaps the most synthetically useful are o - quinodimethanes , can be generated in situ.
On the contrary, stable dienes are rather unreactive and undergo Diels—Alder reactions only at elevated temperatures: for example, naphthalene can function as a diene, leading to adducts only with highly reactive dienophiles, such as N -phenyl- maleimide. In a normal demand Diels—Alder reaction, the dienophile has an electron-withdrawing group in conjugation with the alkene; in an inverse-demand scenario, the dienophile is conjugated with an electron-donating group.
The dienophile undergoes Diels—Alder reaction with a diene introducing such a functionality onto the product molecule. A series of reactions then follow to transform the functionality into a desirable group. The end product cannot not be made in a single DA step because equivalent dienophile is either unreactive or inaccessible. This is a "masked functionality" which can be then hydrolyzed to form a ketone.
Diels—Alder reactions involving at least one heteroatom are also known and are collectively called hetero-Diels—Alder reactions. Chlorosulfonyl isocyanate can be utilized as a dienophile to prepare Vince lactam. Lewis acids such as zinc chloride, boron trifluoride, tin tetrachloride, aluminum chloride, etc.
The complexed dienophile becomes more electrophilic and more reactive toward the diene, increasing the reaction rate and often improving the regio- and stereoselectivity as well. Lewis acid catalysis also enables Diels—Alder reactions to proceed at low temperatures, i. Many methods have been developed for influencing the stereoselectivity of the Diels—Alder reaction, such as the use of chiral auxiliaries, catalysis by chiral Lewis acids ,  and small organic molecule catalysts.
In the hexadehydro Diels—Alder reaction , alkynes and diynes are used instead of alkenes and dienes, forming an unstable benzyne intermediate which can then be trapped to form an aromatic product. This reaction allows the formation of heavily-functionalized aromatic rings in a single step. The retro Diels—Alder reaction is used in the industrial production of cyclopentadiene.
Cyclopentadiene is a precursor to various norbornenes , which are common monomers. The Diels—Alder reaction is also employed in the production of vitamin B6. The work by Diels and Alder is described in a series of 28 articles published in the Justus Liebigs Annalen der Chemie and Berichte der deutschen chemischen Gesellschaft from to The first 19 articles were authored by Diels and Alder, while the later articles were authored by Diels and various contributors.
The first application of Diels—Alder reaction in total synthesis was illustrated by R. Woodward 's syntheses of the steroids cortisone and cholesterol. Thus activation by strongly Lewis acidic cupric tetrafluoroborate was required to allow for the reaction to take place.
Samuel J. Danishefsky used a Diels—Alder reaction to synthesize disodium prephenate ,  a biosynthetic precursor of the amino acids phenylalanine and tyrosine, in This sequence is notable as one of the earliest to feature 1-methoxysiloxybutadiene, the so-called Danishefsky diene, in total synthesis. In their synthesis of reserpine ,  Paul Wender and coworkers used a Diels—Alder reaction to set the cis-decalin framework of the D and E rings of the natural product. The initial Diels-Alder between 2-acetoxyacrylic acid and the 1,2-dihydropyridinecarboxylate shown below put the newly installed carboxyl group in a position to rearrange exclusively to the cis-fused rings after conversion to the isoquinuclidene shown below.
The cis-fusion allowed for the establishment of the stereochemistry at C17 and C first by cleavage of the acetate group at C18 to give a ketone that can modulate the stereochemistry of the methoxy group C17, and then by reduction of the ketone at C18 from the exo face to achieve the stereochemistry of the final product. In Stephen F. Martin 's synthesis of reserpine ,  the cis-fused D and E rings were also formed by a Diels—Alder reaction.
A pyranone was similarly used as the dienophile by K. Nicolaou 's group in the total synthesis of taxol. The stereospecificity of the Diels—Alder reaction in this instance allowed for the definition of four stereocenters that were carried on to the final product. The Diels—Alder cycloaddition with bromoquinone was followed by a spontaneous dehydrohalogenation to re-form the aromatic ring.
The diene in this instance is notable as a rare example of a cyclic derivative of Danishefsky's diene. Viresh Rawal and Sergey Kozmin , in their synthesis of tabersonine,  used a Diels—Alder to establish cis relative stereochemistry of the alkaloid core. Conversion of the cis-aldehyde to its corresponding alkene by Wittig olefination and subsequent ring-closing metathesis with a Schrock catalyst gave the second ring of the alkaloid core.
The diene in this instance is notable as an example of a 1-aminosiloxybutadiene, otherwise known as a Rawal diene. The [2,3]-sigmatropic rearrangement of the thiophenyl group to give the sulfoxide as below proceeded enantiospecifically due to the predefined stereochemistry of the propargylic alcohol. In this way, the single allene isomer formed could direct the Diels-Alder to occur on only one face of the generated 'diene'. Andrew Myers' synthesis of - -tetracycline  achieved the linear tetracyclic core of the antibiotic with a Diels—Alder reaction.
Thermally initiated, conrotatory opening of the benzocyclobutene generated the o-quinodimethane, which reacted intermolecularly to give the tetracycline skeleton; the diastereomer shown was then crystallized from methanol after purification by column chromatography. The authors note that the dienophile's free hydroxyl group was integral to the success of the reaction, as hydroxyl-protected variants did not react under several different reaction conditions.
Takemura et al. Synthetic applications of the Diels—Alder reaction have been reviewed extensively. From Wikipedia, the free encyclopedia. Organic Reactions. Angewandte Chemie International Edition. Polymer Chemistry. Modern Organic Synthesis: An Introduction. Freeman and Co. Journal of the American Chemical Society. Mechanism of methylmagnesium bromide addition to benzonitrile".
In organic chemistry , the Diels—Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene , commonly termed the dienophile , to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism. It was first described by Otto Diels and Kurt Alder in For the discovery of this reaction, they were awarded the Nobel Prize in Chemistry in Through the simultaneous construction of two new carbon—carbon bonds, the Diels—Alder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes. The reaction has also been generalized to other ring sizes, although none of these generalizations have matched the formation of six-membered rings in terms of scope or versatility.
The dienophile. Hetero-dienophiles - aldehydes, thiocarbonyl compounds, N-sulphinylsulphonamides, imines, nitroso compounds. The diene. Reactions in water. Reactions under high pressure. Catalysis by Lewis acids. Asymmetric reactions.
China E-mail: hfding zju. This article is organized by reaction types, aiming to provide a clear clue to the latest research trends. If you are not the author of this article and you wish to reproduce material from it in a third party non-RSC publication you must formally request permission using Copyright Clearance Center. Go to our Instructions for using Copyright Clearance Center page for details. Authors contributing to RSC publications journal articles, books or book chapters do not need to formally request permission to reproduce material contained in this article provided that the correct acknowledgement is given with the reproduced material.
Advanced tools for developing new functional materials and applications in chemical research, pharmaceuticals, and materials science Cycloadditions are among the most useful tools for organic chemists, enabling them to build carbocyclic and heterocyclic structures. These structures can then be used to develop a broad range of functional materials, including pharmaceuticals, agrochemicals, dyes, and optics. With contributions from an international team of leading experts and pioneers in cycloaddition chemistry, this book brings together and reviews recent advances, trends, and emerging research in the field. The book not only features cutting-edge topics, but also important background information, such as the contributors process for developing new methodologies, to help novices become fully adept in the field. References at the end of each chapter lead to original research papers and reviews for facilitating further investigation of individual topics. Covering the state of the science and technology, Methods and Applications of Cycloaddition Reactions in Organic Syntheses enables synthetic organic chemists to advance their research and develop new functional materials and applications in chemical research, pharmaceuticals, and materials science. Other formats.
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