3-phenylphthalide

Structural formula
General
Surname	3-phenylphthalide
other names	3-phenyl-2-benzofuran-1 (3 H ) -one ( IUPAC ) 3-phenyl-1,3-dihydro-2-benzofuran-1-ones 3-phenyl-1 (3 H ) -isobenzofuranone
Molecular formula	C 14 H 10 O 2
Brief description	beige to white crystal powder
External identifiers / databases
CAS number 5398-11-8 EC number 226-426-9 ECHA InfoCard 100.024.024 PubChem 95365 ChemSpider 86062 Wikidata Q43685481
properties
Molar mass	210.22 g mol −1
Physical state	firmly
Melting point	115-119 ° C
solubility	soluble in many organic solvents, such as B. tetrahydrofuran and toluene , 1,4-dioxane or 1,2-dichloroethane
safety instructions
GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

3-Phenylphthalide is an aromatic γ- lactone with an isobenzofuran backbone and the simplest representative of the 3-arylphthalide, some of which have interesting pharmacological properties. The conventional synthesis routes produce the chiral 3-phenyl-1 (3 H ) -isobenzofuranone as a racemate .

Occurrence and representation

Synthesis from 2-carboxybenzaldehyde (phthalaldehyde acid)

According to a publication from 1908, 3-phenylphthalide is obtained from the reaction of 2-carboxybenzaldehyde (as 3-hydroxyphthalide) with a large excess of the Grignard compound phenylmagnesium iodide.

The reaction of phthalaldehyde acid with benzene in the presence of concentrated sulfuric acid at room temperature produces 3-phenyl-1 (3 H ) -isobenzofuranone within one hour in a practically quantitative crude yield and 86% pure yield.

The undemanding reaction conditions and high yields make this synthesis a useful route for the preparation of racemic 3-phenylphthalide.

Synthesis from 2-formylbenzoic acid esters

Instead of phthalaldehyde acid, 3-phenylphthalide can also be prepared from its esters, the so-called 2-formylbenzoic acid esters, by means of a palladium -catalyzed arylation of up to 97% or by rhodium -catalyzed arylation with aromatic boronic acids in up to 94% yield become.

In the presence of the catalyst allyl palladium (II) chloride dimer - [Pd (allyl) Cl] ₂ - and a thioether-imidazolium chloride ligand, and the base cesium fluoride , yields of racemic 3-phenyl are obtained in the reaction of methyl 2-formylbenzoate with phenylboronic acid in dioxane -1 (3 H ) -isobenzofuranone achieved up to 99%.

Because of the expensive catalysts and ligands, and sometimes questionable solvents such. B. 1,4-Dioxane, these reaction variants are more worthwhile for the construction of more complicated 3-arylphthalides.

The rhodium (I) -catalyzed addition of phenylboronic acid to 2-formylbenzoates in the presence of chiral phosphite ligands also leads to chiral 3-phenylphthalide in high yield (94%) but relatively low enantiomeric excess (71% ee).

Synthesis from 2-benzoylbenzoic acid

As early as 1876, Theodor Zincke reported the preparation of 3-phenylphthalide, which at that time was still known as β-benzhydrylbenzoic anhydride - from the anthraquinone precursor 2-benzoylbenzoic acid by reduction with zinc and hydrochloric acid , which is easily accessible by Friedel-Crafts acylation of benzene with phthalic anhydride .

An improvement in this reaction is the use of glacial acetic acid instead of hydrochloric acid, suggested by Fritz Ullmann , in which a quantitative yield of 3-phenylphthalide is achieved.

When the batch is enlarged ten times, a pure yield of 77% is obtained.

The first enantioselective synthesis of 3-phenyl-1 (3 H ) -isobenzofuranone with the chiral borane diisopinocampheylborane (+) - di-3-pinanylborane was reported from the working group of Herbert Charles Brown .

After oxidative cleavage of the borane compound and treatment with dimethyl sulfate , the R-isomer of 3-phenylphthalide is obtained with a very high enantiomeric excess (ee> 96%) with a product yield of 71% .

Synthesis from phthalaldehyde

A more recent alternative route to 3-phenylphthalide and 3-arylphthalides starts from phthalaldehyde, which with phenylboronic acid, cyclooctadiene-rhodium chloride dimer as a catalyst, the diphosphine ligand dppb and the base potassium carbonate gives the product in 83% yield.

A variant of this is the cobalt -catalyzed reaction with cobalt (II) iodide , the diphosphine ligand 1,2-bis (diphenylphosphino) ethane and the base K ₂ CO ₃ , the 3-phenyl-1 (3 H ) -isobenzofuranone gives in 89% yield.

These transition-metal-catalyzed synthesis variants also seem to be more suitable for the construction of more complicated 3-arylphthalides, in which sensitive functional groups do not tolerate the harsh reaction conditions of the older processes.

properties

3-Phenylphthalide is a white, crystalline solid that is virtually insoluble in water, but dissolves in a wide variety of organic solvents. The chiral compound is obtained as a racemate in older synthesis routes without the use of chiral catalysts.

Applications

The carbanion formed in the reaction with potassium amide in liquid ammonia with 3-phenyl-1 (3 H ) -isobenzofuranone reacts with carbon dioxide (dry ice) to form the lactonecarboxylic acid 3-phenylphthalide-3-carboxylic acid in 87% yield. The carbanion reacts with benzyl chloride to form the 3-benzyl derivative and with benzoyl chloride to form the 3-benzoyl derivative and adds acrylonitrile to the corresponding cyanoethylation product .

The reaction of the 3-phenylphthalide precursor 2-benzoylbenzoic acid with thionyl chloride produces 3-chloro-3-phenylphthalide, which reacts with tert-butyl hydroperoxide to form 3-tert-butylperoxy-3-phenylphthalide.

The peroxy compound is used as a radical initiator in radical initiated polymerizations and as a crosslinker for polymers.

A classic multi-stage synthesis of some model substances for CNS- active benzazepines starts from 3-phenylphthalide, which reacts with acetonitrile and sodium amide to form lactol , which in turn is ring-opened with dimethylformamide-dimethylacetal (DMF-DMA). The reaction with guanidine forms a 2-aminopyrimidine . The secondary alcohol group on the benzene ring is oxidized to the ketone with manganese dioxide and the benzazepine ring is closed by hydrogenating cyclization.

Individual evidence

1. ↑ ^{a b c} data sheet tert-Butyl carbamate from Sigma-Aldrich , accessed on September 10, 2017 ( PDF ).
2. ↑ ^{a b} Entry on 3-phenylphthalide at TCI Europe, accessed on September 20, 2017.
3. ↑ ^{a b c} C.-H. Xing, Y.-X. Liao, P. He, Q.-S. Hu: Transition metal-catalyzed addition reactions of arylboronic acids with alkyl 2-formylbenzoates: efficient access to chiral 3-substituted phthalides . In: Chem. Commun. tape 46 , 2010, p. 3010-3012 , doi : 10.1039 / c001104e .
4. ↑ ^{a b} M. Kuriyama, N. Ishiyama, R. Shimazawa, R. Shirai, O. Onomura: Efficient synthesis of 3-arylphthalides using palladium-catalyzed arylation of aldehyde with organoboronic acids . In: J. Org. Chem. Band 74 , no. 23 , 2009, p. 9210-9213 , doi : 10.1021 / jo901964k .
5. ↑ ^{a b} Z. Ye, G. Lv, W. Wang, M. Zhang, J. Cheng: Rhodium-catalyzed cascade reaction: Aryl addition / intramolecular esterification to access 3-aryl and 3-alkenyl phthalides . In: Angew. Chem. Band 122 , 2010, p. 3753-3756 , doi : 10.1002 / anie.201000302 .
6. ↑ P. Nahini, Y. Poonam: Synthesis and biological activities of some new phthalide . In: Res. J. Chem. Sci. tape 2 , no. 8 , 2012, p. 57-61 ( isca. In [PDF]).
7. ↑ R. Karmarkar, P. Pahari, D. Mal: Phthalides and phthalans: Synthetic methodologies and their applications in the total synthesis . In: Chem. Rev. Band 114 , no. 12 , 2014, p. 6213-6284 , doi : 10.1021 / cr400524q .
8. ↑ E. Mermod, H. Simonis: About some phthalides and mekonins . In: Chem. Ber. tape 41 , no. 1 , 1908, p. 982-985 , doi : 10.1002 / cber.190804101191 .
9. ↑ VW Floutz: Notes - Condensation reactions of phthalaldehydic acid . In: J. Org. Chem. Band 25 , no. 4 , 1960, p. 643-645 , doi : 10.1021 / jo01074a608 .
10. ^ N. Miyaura: Celebrating 20 Years of SYNLETT - Special Account On Palladium (II) -Catalyzed Additions of Arylboronic Acids to Electron-Deficient Alkenes, Aldehydes, Imines, and Nitriles . In: Synlett . tape 13 , 2009, p. 2039-2050 , doi : 10.1055 / s-0029-1217555k .
11. ↑ Louis F. Fieser: Experiments in Organic Chemistry, 2nd Edition . DC Heath & Co., Boston, MA, USA 1941, p. 184-187 .
12. ↑ F. Rotering, T. Zincke: About β- Benzhydrylbenzoic anhydride and about β-benzylbenzoic acid . In: Chem. Ber. tape 9 , no. 1 , 1876, p. 631-640 , doi : 10.1002 / cber.187600901193 .
13. ↑ F. Ullmann: Ueber Reduction der o-Benzoylbenzoic acid . In: Liebigs Ann. Chem. Band 291 , no. 1 , 1896, p. 17-25 , doi : 10.1002 / jlac.18962910105 .
14. ↑ ^{a b} C.R. Hauser, MT Tetenbaum, DS Hoffenberg: Condensations Involving the Metalation of the 3-Position of 3-Phenylphthalide by Means of Alkali Amides. Carbonation of Phthalide . In: J. Org. Chem. Band 23 , no. 6 , 1958, pp. 861-865 , doi : 10.1021 / jo01100a026 .
15. ^ RK Dhar et al .: Diisopinocampheylborane . In: e-EROS Encyclopedia of Reagents for Organic Synthesis . 2015, doi : 10.1002 / 047084289X.rd248.pub3 .
16. ↑ PV Ramachandran, G.-M. Chen, HC Brown: Efficient general asymmetric syntheses of 3-substituted 1 (3 H ) -Isobenzofuranones in very high enantiomeric excess . In: Tetrahedron Lett. tape 37 , no. 13 , 1996, pp. 2205-2208 , doi : 10.1016 / S0040-4039 (96) 00260-2 .
17. ↑ J. Karthikeyan, K. Parthasarathy, C.-H. Cheng: Synthesis of biarylketones and phthalides from organoboronic acids and aldehydes catalyzed by cobalt complexes . In: Chem. Commun. tape 47 , 2011, p. 10461-10463 , doi : 10.1039 / C1CC13771A .
18. ^ FN Jones, CR Hauser: Synthesis of 3-substituted 3-phenylphthalides . In: J. Org. Chem. Band 27 , no. 9 , 1962, pp. 3364-3365 , doi : 10.1021 / jo01056a540 .
19. ↑ Patent US3654315 : Organic pseudo peresters. Registered June 3, 1969 , published April 4, 1972 , Applicant: Reichhold Chemicals, Inc., Inventor: YG Chang, PS Bailey. ‌
20. ↑ Patent US4322273 : Process for cross-linking shaped non-polar synthetic resins and electrical insulation containing such resins. Applied on August 27, 1979 , published March 30, 1982 , applicant: Akzona Inc., inventor: JD van Drumpt. ‌
21. ^ JV Earley, RI Fryer, NW Gilman: 2-Benzazepines. 7. Synthesis of pyrimido [5,4-d] [2] benzazepines . In: J. Heterocyclic Chem. Volume 20 , 1983, p. 1195-1197 , doi : 10.1002 / jhet.5570200512 .