2-Coumaranone

In 1884, Adolf von Baeyer and Paul Fritsch disclosed the synthesis of 2-coumaranone, which they described as the lactone of o-oxyphenylacetic acid, through the distillation "over free fire" of (2-hydroxyphenyl)acetic acid.{{citation|author1=A. Baeyer |author2=P. Fritsch|date=1884|doi=10.1002/cber.188401701258|issue=1|pages=973–975|periodical=Chem. Ber.|title=Ueber die o-Oxyphenylessigsäure und ihre Derivate|volume=17}}

File:2-Cumaranon Synthese aus 2-Hydroxyphenylessigsäure.svg

The lactone 3H-benzofuran-2-one forms in this process under intramolecular water splitting at high temperature and in an impure state.

A similar fragmentation by oxidative intramolecular ring closure from phenylacetic acid also yields only modest returns (< 20%) due to the oxidation sensitivity of the methylene group and the formation of several by-products 2-coumaranone.{{citation|author1=T. Fukagawa |author2=Y. Fujiwara |author3=H. Taniguchi|date=1982|doi=10.1021/jo00133a055|issue=12|pages=2491–2493|periodical=J. Org. Chem.|title=Palladium-catalyzed intramolecular aromatic nuclear acyloxylation: preparation of 2-coumaranone|volume=47}}

File:2-Cumaranon Synthese aus Phenylessigsäure.svg

The Ozonolysis of 2-allylphenol obtained by the alkylation of phenol with 3-bromopropene to produce phenylallyl ether and subsequently its Claisen rearrangement, gives rise to 2-hydroxyphenylacetic acid, which, through water splitting, yields 2-coumaranone. Despite this method having good yields, its economic and safety considerations make it unsuitable for an industrial process.{{Cite patent|country=EP |number=1481959 |title=Verfahren zur Herstellung von Lactonen und von aromatischen Hydroxycarbonsäuren |pubdate=2004-12-01 |fdate=2004-04-28 |invent1=W. Jary |assign=DSM Fine Chemicals Austria Nfg GmbH & CO., KG }}

File:2-Cumaranon via Ozonolyse.svg

On an industrial scale, the well-filtered starting materials cyclohexanone and glyoxylic acid are first transformed in an acid-catalyzed aldol condensation to form the (predominantly) cis-2-oxocyclohexylidene acetic acid (A). This then, in a second step, is transformed into the so-called enollactone (B) through water elimination (90% yield). The enollactone is continuously dehydrogenated at 250 °C in the vapor phase on a palladium catalyst to form 2-coumaranone (C) dehydrogenation (yield approximately 67%).{{citation|author1=N. Carmona |author2=P. Gallezot |author3=A. Perrard |author4=L. Carmona |author5=G. Mattioda |author6=J.-C. Vallejos|date=1998|isbn=0-8247-1929-8|location=New York, NY, U.S.A.|pages=381–390|publisher=Marcel Dekker, Inc.|title=Synthesis of 2-Coumaranone by Catalytic Dehydrogenation of α-Carboxymethylidene Cyclohexanone, in Catalysis of Organic Reactions, Frank E. Herkes, editor}}{{Cite patent|country=US |number=5616733 |Code= |title=Preparation method for 2-coumaranone |pubdate=1997-4-1 |fdate=1995-6-7 |invent1=J.-C. Vallejos |invent2=A. Perrard |invent3=Y. Christidis |invent4=P. Gallezot |assign=Société Française Hoechst }}{{Cite patent|country=EP |number=0818451 |title=Procédé de préparation de l'énollactone de l'acide 2-oxocyclohexylidène acétique et application à la préparation de la 2-coumaranone |pubdate=1998-01-14 |fdate=1997-07-02 |invent1=N. Carmona |invent2=L. Carmona |invent3=A. Perrard |invent4=J.-C. Vallejos |assign=Clariant Chimie S.A. }}

File:2-Cumaranon Industrielle Synthese.svg

An alternative process that uses glyoxylic acid methyl ester methylhemiacetals rather than glyoxylic acid as a starting material has not gained widespread acceptance.{{Cite patent|country=EP |number=149838 |title=Verfahren zur Herstellung von 2-Coumaron und substituierten 2-Coumaronen |pubdate=2004-08-25 |fdate=2001-05-09 |invent1=M. Stanek |invent2=P. Hildebrand |invent3=C. Zimmermann |invent4=M. Castelijns |assign=DSM Fine Chemicals Austria Nfg GmbH & CO., KG }}

Pure 2-coumaranone manifests as an off-white to pale yellow solid with an aromatic odor. On purification by distillation, "a colorless oil passes which solidifies in the receiver into splendid, transparent, well-formed crystals".{{citation |author=S. Czaplicki |author2=Stanislaus von Kostanecki |author3=V. Lampe |date=1909|doi=10.1002/cber.190904201133|issue=1|pages=827–838|periodical=Chem. Ber.|title=Versuche zur Synthese des Chromenols und seiner Derivate|volume=42|url=https://zenodo.org/record/2308760 }} 3H-benzofuran-2-one is soluble in hot water, diethyl ether and acetonitrile. The lactone hydrolyzes slowly in hot water and rapidly in aqueous alkalis to form 2-hydroxyphenylacetic acid or its alkali salt.

5-Nitro-3H-benzofuran-2-one is formed during the nitration of 2-coumaranone with nitrating acid.{{cite web|access-date=2022-06-20|author=Christopher E. Malmberg|date=2015|page=14|publisher=Central Washington University Central Washington University|title=Total Synthesis of Clavatadine A Analogs to Produce a Viable Reversible Inhibitor for Factor XIa|url=https://core.ac.uk/download/pdf/51140415.pdf|website=MS Thesis}}{{Cite patent|country=US |number=7070630 |title=Primary intermediates für oxidative coloration of hair |pubdate=2006-4-7 |fdate=2004-5-3 |invent1=M.-I. Lim, Y.-G. Pan |assign=The Procter & Gamble Co. }}

File:2-Cumaranon Nitro+Amino.svg

The 5-amino-3H-benzofuran-2-one can be obtained from the nitro compound using catalytic hydrogenation at a palladium catalyst.

Lactones such as 2-coumaranone ('I) are readily cleaved by nucleophiles, leading to ring opening. Thus, 5-nitro-3H-benzofuran-2-one reacts with secondary amines to form 2-hydroxyphenylacetic acid amides. Through hydrogenation, these transform into corresponding 3-amino-6-hydroxyphenylethylamines, which are useful precursors for hair dyeing.

File:2-Cumaranon Haarfarbstoff-Vorstufe.svg

Condensation of 5-nitro-3H-benzofuran-2-one (II) with a mixture of valeric acid (III) and valeric anhydride (IV) results in the enollactone (V), which upon heating rearranges to the substituted benzofurancarboxylic acid (VI), a key precursor for the antiarrhythmic drug Dronedarone.{{Cite patent|country=EP |number=2508517 |title=Process for the preparation of N-alkyl-2(hydroxy-4-benzoyl)-3-benzofurans and its intermediates thereof |pubdate=2012-10-10 |fdate=2004-12-15 |invent1=A. Shoutteeten, F. Bleger, F. Mordacq, J. Piron |assign=Clariant Specialty Fine Chemicals (France) }}

File:2-Cumaranon Dronedaron-Vorstufe.svg

The basic structure of 2-coumaranone also underlies a class of antioxidants and radical scavengers, especially for stabilizing polypropylenes. In the synthesis of a model compound, glyoxylic acid reacts with 2 moles of 4-tert-butylphenol in the presence of methanesulfonic acid CH₃SO₃H to form a phenolic intermediate and is then esterified with benzoic acid.{{Cite patent|country=EP |number=2500341 |title=Benzofuranone derivatives and application of the same |pubdate=2013-06-26 |fdate=2011-09-06 |invent1=C.-F. Chiu, C.-Y. Su, S. Lee |assign=Chitec Technology Co., Ltd., Double Bond Chemical Ind., Co., Ltd., FDC, Lees Chemical Industry Co. Ltd. }}

File:2-Cumaranon Antioxidantien.svg

A one-pot reaction, carried out as a Tscherniak-Einhorn reaction of fluorophenols (X), glyoxylic acid (Y), and carbamates, such as carbamic acid methyl ester{{citation |author=R. Krieg |author2=B. Hoffmann |author3=D. Weiß |author4=C. Biskup |date=2019|doi=10.1002/hlca.201800243|issue=6|pages=e1800243|journal=Helv. Chim. Acta|title=First synthesis of highly chemiluminescent benzo[b]furan-2(3H)-ones bearing a urea substructure|volume=102|s2cid=107893512 }} or carbamic acid mesityl ester (Z), yields 2-coumaranones with carbamide side chains. These compounds react with strong bases such as diazabicycloundecene or potassium tert-butanolate, and show pronounced chemiluminescence in the presence of oxygen.{{citation|author=S. Schramm|display-authors=etal|date=2013|pages=174–188|periodical=Arkivoc|title=Investigations on the synthesis and chemiluminescence of novel 2-coumaranones|url=http://www.arkat-usa.org/get-file/47206/|volume=3}}{{citation|author=S. Schramm|display-authors=etal|date=2015|pages=44–59|periodical=Arkivoc|title=Investigations on the synthesis and chemiluminescence of novel 2-coumaranones – II|url=https://www.arkat-usa.org/get-file/52793/|volume=5}}{{cite web|access-date=2022-06-20|format=PDF; 170 kB|language=en|publisher=Cayman Chemical Co.|title=2-Coumaranone-1-L|url=https://cdn.caymanchem.com/cdn/insert/27389.pdf|website=caymanchem.com}}

File:2-Cumaranon Chemilumineszenz.svg

The most notable application of 2-coumaranone by volume is as a starting material for the synthesis of the fungicide azoxystrobin{{Cite patent|country=WO |number=199208703 |title=Process for the preparation of pyrimidine compounds |pubdate=1992-5-29 |fdate=1991-11-12 |invent1=J.D. Jones, G.A. DeBoos, P. Wilkinson, B.G. Cox, J.M. Fielden |assign=Imperial Chemical Industries PLC }} (known as Amistar from Syngenta) in the class of strobilurins.

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Category:Lactones

Category:Heterocyclic compounds with 2 rings