Claisen rearrangement

The Claisen rearrangement is an exothermic, concerted (bond cleavage and recombination) pericyclic reaction. Woodward–Hoffmann rules show a suprafacial, stereospecific reaction pathway. The kinetics are of the first order and the whole transformation proceeds through a highly ordered cyclic transition state and is intramolecular. Crossover experiments eliminate the possibility of the rearrangement occurring via an intermolecular reaction mechanism and are consistent with an intramolecular process.{{cite journal|year=1937|title=Observations on the Rearrangement of Allyl Aryl Ethers|journal=J. Am. Chem. Soc.|volume=59|page=107|doi=10.1021/ja01280a024|author1=Hurd, C. D.|author2=Schmerling, L.}}{{cite book|url=https://books.google.com/books?id=g5dYyJMBhCoC|title=Advanced Organic Chemistry: Part A: Structure and Mechanisms|publisher=Springer|year=2007|isbn=978-0-387-44897-8|pages=934–935|author1=Francis A. Carey|author2=Richard J. Sundberg}}

There are substantial solvent effects observed in the Claisen rearrangement, where polar solvents tend to accelerate the reaction to a greater extent. Hydrogen-bonding solvents gave the highest rate constants. For example, ethanol/water solvent mixtures give rate constants 10-fold higher than sulfolane.{{cite journal|year=1912|title=Über Umlagerung von Phenol-allyläthern in C-Allyl-phenole|url=http://babel.hathitrust.org/cgi/pt?id=mdp.39015026351380;view=1up;seq=325|journal=Chemische Berichte|volume=45|issue=3|pages=3157–3166|doi=10.1002/cber.19120450348|author=Claisen, L.}}{{cite journal|year=1925|title=Über den Mechanismus der Umlagerung der Phenol-allyläther|journal=Chemische Berichte|volume=58|issue=2|page=275|doi=10.1002/cber.19250580207|author1=Claisen, L.|author2=Tietze, E.}} Trivalent organoaluminium reagents, such as trimethylaluminium, have been shown to accelerate this reaction.{{cite journal|year=1958|title=A Kinetic Study of the ortho-Claisen Rearrangement1|journal=J. Am. Chem. Soc.|volume=80|issue=13|page=3277|doi=10.1021/ja01546a024|author1=Goering, H. L.|author2=Jacobson, R. R.}}{{cite journal|year=1970|title=The o-Claisen rearrangement. VIII. Solvent effects|journal=J. Org. Chem.|volume=35|issue=7|page=2196|doi=10.1021/jo00832a019|author1=White, W. N.|author2=Wolfarth, E. F.}}

The first reported Claisen rearrangement is the [3,3]-sigmatropic rearrangement of an allyl phenyl ether to intermediate 1, which quickly tautomerizes to a 2-allylphenol.

File:Aromatic_Claisen_1.svg

The Claisen rearrangement can occur in domino fashion with a Cope rearrangement, in which case the allyl group appears to attack the para position on the ring: File:Aromatic_Claisen_with_ortho-position_Substituted.png Meta-substitution affects the regioselectivity of this rearrangement.{{cite journal|last1=White|last2=Slater|first2=Carl D.|year=1961|title=The ortho-Claisen Rearrangement. V. The Products of Rearrangement of Allyl m-X-Phenyl Ethers|journal=The Journal of Organic Chemistry|volume=26|issue=10|pages=3631–3638|doi=10.1021/jo01068a004|first1=William N.}}{{cite journal|last1=Gozzo|last2=Fernandes|first2=Sergio Antonio|last3=Rodrigues|first3=Denise Cristina|last4=Eberlin|first4=Marcos Nogueira|last5=Marsaioli|first5=Anita Jocelyne|year=2003|title=Regioselectivity in Aromatic Claisen Rearrangements|journal=The Journal of Organic Chemistry|volume=68|issue=14|pages=5493–5499|doi=10.1021/jo026385g|pmid=12839439|first1=Fábio Cesar}} For example, electron withdrawing groups (such as bromide) at the meta-position direct the rearrangement to the ortho-position (71% ortho product), while electron donating groups (such as methoxy), direct rearrangement to the para-position (69% para product). Additionally, presence of ortho substituents exclusively leads to para-substituted rearrangement products.{{cite book|url=https://books.google.com/books?id=mjpJmiZ9OZ8C|title=Strategic Applications of Named Reactions in Organic Synthesis: Background And Detailed Mechanics: 250 Named Reactions|publisher=Academic Press|year=2005|isbn=978-0-12-429785-2|author1=László Kürti|author2=Barbara Czakó|access-date=27 March 2013}} If an aldehyde or carboxylic acid occupies the ortho or para positions, the allyl side-chain displaces the group, releasing it as carbon monoxide or carbon dioxide, respectively.{{cite book|url=https://www.scribd.com/doc/101455067/Organic-Reactions-v2|title=Organic Reactions, Volume II|last=Adams|first=Rodger|publisher=John Wiley & Sons, Inc.|year=1944|location=New York|pages=11–12}}{{cite journal|last=Claisen|first=L.|year=1913|title=Über die Umlagerung von Phenolallyläthern in die isomeren Allylphenole|journal=Justus Liebigs Annalen der Chemie|volume=401|issue=1|page=90|doi=10.1002/jlac.19134010103|author2=Eisleb, O.|url=https://zenodo.org/record/1427617}}

The Bellus–Claisen rearrangement is the reaction of allylic ethers, amines, and thioethers with ketenes to give γ,δ-unsaturated esters, amides, and thioesters.{{cite journal|year=1978|title=A New Type of Claisen Rearrangement Involving 1,3-Dipolar Intermediates. Preliminary communication|journal=Helv. Chim. Acta|volume=61|issue=8|pages=3096–3099|doi=10.1002/hlca.19780610836|author1=Malherbe, R.|author2=Bellus, D.}}{{cite journal|year=1983|title=Reactions of haloketenes with allyl ethers and thioethers: A new type of Claisen rearrangement|journal=J. Org. Chem.|volume=48|issue=6|pages=860–869|doi=10.1021/jo00154a023|author1=Malherbe, R.|author2=Rist, G.|author3=Bellus, D.}}{{cite journal|year=2004|title=The Belluš–Claisen Rearrangement|journal=Angew. Chem. Int. Ed.|volume=43|issue=27|pages=3516–3524|doi=10.1002/anie.200301718|pmid=15293240|author=Gonda, J.}} This transformation was serendipitously observed by Bellus in 1979 through their synthesis of an intermediate to an insecticide, pyrethroid. Halogen substituted ketenes (R₁, R₂) are often used in this reaction for their high electrophilicity. Numerous reductive methods for the removal of the resulting α-haloesters, amides and thioesters have been developed.{{Cite journal|last=Edstrom|first=E|date=1991|title=An unexpected reversal in the stereochemistry of transannular cyclizations. A stereoselective synthesis of (±)-epilupinine|journal=Tetrahedron Letters|volume=32|issue=41|pages=5709–5712|doi=10.1016/S0040-4039(00)93536-6}}{{Cite journal|last=Bellus|date=1983|title=Reactions of haloketenes with allyl ethers and thioethers: a new type of Claisen rearrangement|journal= The Journal of Organic Chemistry|volume=48|issue=6|pages=860–869|doi=10.1021/jo00154a023}} The Bellus-Claisen offers synthetic chemists a unique opportunity for ring expansion strategies.

File:Claisen Bellus Rearrangement.png

The Eschenmoser–Claisen rearrangement proceeds by heating allylic alcohols in the presence of N,N-dimethylacetamide dimethyl acetal to form a γ,δ-unsaturated amide. This was developed by Albert Eschenmoser in 1964.{{cite journal|year=1964|title=CLAISEN'sche Umlagerungen bei Allyl- und Benzylalkoholen mit Hilfe von Acetalen des N, N-Dimethylacetamids. Vorläufige Mitteilung|journal=Helv. Chim. Acta|volume=47|issue=8|pages=2425–2429|doi=10.1002/hlca.19640470835|author1=Wick, A. E.|author2=Felix, D.|author3=Steen, K.|author4=Eschenmoser, A.}}{{cite journal|year=1969|title=CLAISEN'sche Umlagerungen bei Allyl- und Benzylalkoholen mit 1-Dimethylamino-1-methoxy-äthen|journal=Helv. Chim. Acta|volume=52|issue=4|pages=1030–1042|doi=10.1002/hlca.19690520418|author1=Wick, A. E.|author2=Felix, D.|author3=Gschwend-Steen, K.|author4=Eschenmoser, A.}} Eschenmoser-Claisen rearrangement was used as a key step in the total synthesis of morphine.{{Cite journal|last=Guillou|first=C|date=2008|title=Diastereoselective Total Synthesis of (±)-Codeine|journal=Chem. Eur. J.|volume=14|issue=22|pages=6606–6608|doi=10.1002/chem.200800744|pmid=18561354}}

Image:Eschenmoser-Claisen Rearrangement Scheme.png

Mechanism:

File:Eschenmoser Claisen Mechanism.png

{{main|Ireland–Claisen rearrangement}}

The Ireland–Claisen rearrangement is the reaction of an allylic carboxylate with a strong base (such as lithium diisopropylamide) to give a γ,δ-unsaturated carboxylic acid.{{Cite journal|last2=Mueller|first2=R. H.|year=1972|title=Claisen rearrangement of allyl esters|journal=Journal of the American Chemical Society|volume=94|issue=16|page=5897|doi=10.1021/ja00771a062|first1=R. E.|last1=Ireland}}{{cite journal|year=1975|title=The stereoselective generation of ester enolates|journal=Tetrahedron Lett.|volume=16|issue=46|pages=3975–3978|doi=10.1016/S0040-4039(00)91213-9|author1=Ireland, R. E.|author2=Willard, A. K.}}{{Cite journal|last2=Mueller|first2=R. H.|last3=Willard|first3=A. K.|year=1976|title=The ester enolate Claisen rearrangement. Stereochemical control through stereoselective enolate formation|journal=Journal of the American Chemical Society|volume=98|issue=10|page=2868|doi=10.1021/ja00426a033|last1=Ireland|first1=R. E.}} The rearrangement proceeds via silylketene acetal, which is formed by trapping the lithium enolate with chlorotrimethylsilane. Like the Bellus-Claisen (above), Ireland-Claisen rearrangement can take place at room temperature and above. The E- and Z-configured silylketene acetals lead to anti and syn rearranged products, respectively.{{Cite journal|last1=Ireland|first1=R. E. |first2= Peter |last2= Wipf |first3= Joseph D. |last3= Armstrong III |date=1991|title=Stereochemical control in the ester enolate Claisen rearrangement. 1. Stereoselectivity in silyl ketene acetal formation |journal= J. Org. Chem. |volume=56|issue=2|pages=650–657|doi=10.1021/jo00002a030}} There are numerous examples of enantioselective Ireland-Claisen rearrangements found in literature to include chiral boron reagents and the use of chiral auxiliaries.{{Cite journal|last=Enders|first=E|date=1996|title=Asymmetric [3,3]-sigmatropic rearrangements in organic synthesis|journal=Tetrahedron: Asymmetry|volume=7|issue=7|pages=1847–1882|doi=10.1016/0957-4166(96)00220-0}}{{Cite journal|last=Corey|first=E|date=1991|title=Highly enantioselective and diastereoselective Ireland-Claisen rearrangement of achiral allylic esters|journal= Journal of the American Chemical Society|volume=113|issue=10|pages=4026–4028|doi=10.1021/ja00010a074}}

File:TOC_for_IC.jpg

The Johnson–Claisen rearrangement is the reaction of an allylic alcohol with an orthoester to yield a {{no wrap|γ,δ-unsaturated}} ester.{{Cite journal|last1=Johnson|first1=William Summer|last2=Werthemann|first2=Lucius|last3=Bartlett|first3=William R.|last4=Brocksom|first4=Timothy J.|last5=Li|first5=Tsung-Tee|last6=Faulkner|first6=D. John|last7=Petersen|first7=Michael R.|date=1970-02-01|title=Simple stereoselective version of the Claisen rearrangement leading to trans-trisubstituted olefinic bonds. Synthesis of squalene|journal=Journal of the American Chemical Society|volume=92|issue=3|pages=741–743|doi=10.1021/ja00706a074|issn=0002-7863}} Weak acids, such as propionic acid, have been used to catalyze this reaction. This rearrangement often requires high temperatures (100–200 °C) and can take anywhere from 10 to 120 hours to complete.{{Cite journal|last=Fernandes|first=R. A.|date=2013|title=The Orthoester Johnson–Claisen Rearrangement in the Synthesis of Bioactive Molecules, Natural Products, and Synthetic Intermediates – Recent Advances|journal=European Journal of Organic Chemistry |volume=2014|issue=14|pages=2833–2871|doi=10.1002/ejoc.201301033}} However, microwave assisted heating in the presence of KSF-clay or propionic acid have demonstrated dramatic increases in reaction rate and yields.{{Cite journal|last=Huber|first=R. S.|date=1992|title=Acceleration of the orthoester Claisen rearrangement by clay catalyzed microwave thermolysis: expeditious route to bicyclic lactones|journal= The Journal of Organic Chemistry|volume=57|issue=21|pages=5778–5780|doi=10.1021/jo00047a041}}{{Cite journal|last=Srikrishna|first=A|date=1995|title=Application of microwave heating technique for rapid synthesis of γ,δ-unsaturated esters|journal=Tetrahedron|volume=51|issue=6|pages=1809–1816|doi=10.1016/0040-4020(94)01058-8}}

Image:Johnson-Claisen Rearrangement Scheme.png

Mechanism:

File:Johnson Claisen Mechanism.png

The Kazmaier-Claisen rearrangement is the reaction of an unsaturated amino acid ester with a strong base (such as lithium diisopropylamide) and a metal salt at –78 °C to give a chelated enolate as intermediate.{{Cite journal|last1=Varghese|first1=V|last2=Hudlicky|first2=T|date=2013|title=Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Rearrangement and C-10/C-11 Closure Strategy|journal=Synlett|volume=24|issue=3|pages=369–374|doi=10.1055/s-0032-1318114}}{{Cite journal|author1=Ndungu, J |author2=X Gu |author3=D Gross |author4=J. Cain |author5=M Carducci |author6=V Hruby |date=2004|title=Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors|journal=Tetrahedron Letters|volume=45|issue=21|pages=4139–4142|doi=10.1016/j.tetlet.2004.03.146}} While different metal salts can be used to form the enolate, the use of zinc chloride results in the highest yield and gives the best stereospecificity.{{Cite journal|last=Kazmaier|first=U|date=1993|title=Stereoselective Synthesis of 2-(2'-Cycloalkenyl) Glycinates via [3,3] Sigmatropic Rearrangement of Chelated Ester-Enolates|journal=Tetrahedron|volume=50|pages=12895–12902|doi=10.1016/S0040-4020(01)81208-4}} The enolate species rearranges at –20 °C to form an amino acid with an allylic side chain in α-position. This method was described by Uli Kazmaier in 1993.{{Cite journal|last=Kazmaier|first=U|date=1993|title=Synthesis of Unsaturated Amino Acids by [3,3]-Sigmatropic Rearrangement of Chelate-Bridged Glycine Ester Enolates|journal=Angewandte Chemie International Edition|volume=104|issue=9|pages=1046–1047|doi=10.1002/anie.199409981}}

Image:Kazmaier-Claisen-rearrangement.svg

The Claisen rearrangement of aryl ethers can also be performed as a photochemical reaction. In addition to the traditional ortho product obtained under thermal conditions (the [3,3] rearrangement product), the photochemical variation also gives the para product ([3,5] product), alternate isomers of the allyl group (for example, [1,3] and [1,5] products), and simple loss of the ether group, and even can rearrange alkyl ethers in addition to allyl ethers. The photochemical reaction occurs via a stepwise process of radical-cleavage followed by bond-formation rather than as a concerted pericyclic reaction, which therefore allows the opportunity for the greater variety of possible substrates and product isomers.{{cite journal |journal= Journal of Photochemistry and Photobiology C: Photochemistry Reviews |volume= 6 |year= 2005 |pages= 123–138 |title= The photochemical rearrangement of aromatic ethers: A review of the Photo-Claisen reaction |first= Francisco |last= Galindo |doi= 10.1016/j.jphotochemrev.2005.08.001 }} The [1,3] and [1,5] results of the photo-Claisen rearrangement are analogous to the photo-Fries rearrangement of aryl esters and related acyl compounds.{{GoldBookRef|file=P04614|title=photo-Fries rearrangement}}

An iminium can serve as one of the pi-bonded moieties in the rearrangement.{{cite journal|author1=Kurth, M. J. |author2=Decker, O. H. W. |journal=J. Org. Chem.|year=1985|volume=50|pages= 5769–5775|doi=10.1021/jo00350a067|title=Enantioselective preparation of 3-substituted 4-pentenoic acids via the Claisen rearrangement|issue=26}}

Image:Aza-Claisen Rearrangement Example.png

The thio–Claisen rearrangement reacts an allyl vinyl sulfide with mercuric oxide.{{cite encyclopedia|doi=10.1002/047084289X.rm038|entry=Mercury(II) oxide|first1=Ellen M.|last1=Leahy|title=Mercury(II) Oxide |encyclopedia=Encyclopedia of Reagents for Organic Synthesis|date=2001 |publisher=Wiley|isbn=0-471-93623-5 }}

The Chen–Mapp reaction, also known as the [3,3]-phosphorimidate rearrangement or Staudinger–Claisen reaction, installs a phosphite in the place of an alcohol and takes advantage of the Staudinger reduction to convert this to an allylic amine. The subsequent Claisen is driven by the fact that a P=O double bond is more energetically favorable than a P=N double bond.{{Cite journal| last1 = Chen | first1 = B.| last2 = Mapp | first2 = A.| title = Thermal and catalyzed [3,3]-phosphorimidate rearrangements| journal = Journal of the American Chemical Society| volume = 127| issue = 18| pages = 6712–6718| year = 2005| pmid = 15869293 | doi = 10.1021/ja050759g}}

Image:MappReaction.png

{{main|Overman rearrangement}}

The Overman rearrangement (named after Larry Overman) is a Claisen rearrangement of allylic trichloroacetimidates to allylic trichloroacetamides.{{Cite journal| last1 = Overman | first1 = L. E.| title = Thermal and mercuric ion catalyzed [3,3]-sigmatropic rearrangement of allylic trichloroacetimidates. 1,3-Transposition of alcohol and amine functions| journal = Journal of the American Chemical Society| volume = 96| issue = 2| pages = 597–599| year = 1974 | doi = 10.1021/ja00809a054}}{{Cite journal| last1 = Overman | first1 = L. E.| title = A general method for the synthesis of amines by the rearrangement of allylic trichloroacetimidates. 1,3-Transposition of alcohol and amine functions| journal = Journal of the American Chemical Society| volume = 98| issue = 10| pages = 2901–2910| year = 1976 | doi = 10.1021/ja00426a038}}{{cite journal |doi=10.15227/orgsyn.058.0004|title=Allylically Transposed Amines from Allylic Alcohols: 3,7-Dimethyl-1,6-Octadien-3-Amine|journal=Organic Syntheses|volume=58|pages=4|year=1978|first1= L. A. |last1= Clizbe |first2= L. E. |last2= Overman}}

Image:Overman Rearrangement scheme.svg

The Overman rearrangement is applicable to the synthesis of vicinal diamino compounds from 1,2-vicinal allylic diols.

Unlike typical Claisen rearrangements which require heating, zwitterionic Claisen rearrangements take place at or below room temperature. The acyl ammonium ions are highly selective for Z-enolates under mild conditions.{{cite journal|author1=Yu, C.-M. |author2=Choi, H.-S. |author3=Lee, J. |author4=Jung, W.-H. |author5=Kim, H.-J. |journal=J. Chem. Soc., Perkin Trans. 1|year=1996|pages= 115–116|doi=10.1039/p19960000115|title=Self-regulated molecular rearrangement: Diastereoselective zwitterionic aza-Claisen protocol|issue=2}}{{cite journal|author=Nubbemeyer, U. |journal=J. Org. Chem.|year=1995|volume=60|pages= 3773–3780|doi=10.1021/jo00117a032|title=1,2-Asymmetric Induction in the Zwitterionic Claisen Rearrangement of Allylamines|issue=12}}

Image:Zwitterionic Claisen Rearrangement Scheme.png

The enzyme chorismate mutase (EC 5.4.99.5) catalyzes the Claisen rearrangement of chorismate to prephenate, an intermediate in the biosynthetic pathway towards the synthesis of phenylalanine and tyrosine.{{cite journal|author=Ganem, B. |journal=Angew. Chem. Int. Ed. Engl.|year=1996|volume=35|pages= 936–945|doi=10.1002/anie.199609361|title=The Mechanism of the Claisen Rearrangement: Déjà Vu All over Again|issue=9}}

Image:Chorismate Mutase Scheme.png

Discovered in 1912, the Claisen rearrangement is the first recorded example of a [3,3]-sigmatropic rearrangement.{{cite journal|author=Claisen, L. |journal=Chemische Berichte|year=1912|volume=45|pages=3157–3166|url=http://babel.hathitrust.org/cgi/pt?id=mdp.39015026351380;view=1up;seq=325|doi=10.1002/cber.19120450348|title=Über Umlagerung von Phenol-allyläthern in C-Allyl-phenole|issue=3}}{{cite journal|author1=Claisen, L. |author2=Tietze, E. |journal=Chemische Berichte|year=1925|volume=58|page=275|doi=10.1002/cber.19250580207|title=Über den Mechanismus der Umlagerung der Phenol-allyläther|issue=2}}{{cite journal|author1=Claisen, L. |author2=Tietze, E. |journal=Chemische Berichte|year=1926|volume=59|page=2344|doi=10.1002/cber.19260590927|title=Über den Mechanismus der Umlagerung der Phenol-allyläther. (2. Mitteilung)|issue=9}}

• Carroll rearrangement
• Cope rearrangement

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