3-Isochromanone: Synthetic Reactivity & Thermochemical Characterization

3-Isochromanone (3-ICN) is a naturally occurring heterocyclic aromatic compound that finds application in both scientific research and various industrial endeavors. Its versatility makes it a promising candidate for research and development, owing to its diverse biological effects. It has been reported to be isolated from the fungus Nigrospora sp. PSU-F12.  An improved Knoevenagel condensation of 3-isochromanone with aromatic aldehydes has been achieved by microwave irradiation on solid supports in the presence of various catalysts. Synthesis of this substance via Beayer-Villiger rearrangement has been reported. Additionally, this compound may act to interact with other enzymes involved in essential biochemical pathways, like cytochrome P450 enzymes. As research progresses, further insights into the potential of 3-Isochromanone and its applications in both scientific exploration and industry are likely to emerge. Its diverse effects and ability to interact with vital biochemical pathways continue to make it an intriguing subject for future investigations and development.

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones

The development of new applications of well-known reaction modes is of paramount importance in organic chemistry, which usually stems from the identification of new nucleophiles or electrophiles. When there is the necessity to develop catalytic reactions, a pronucleophile should have suitable Brønsted acidity to be deprotonated under relatively mild conditions to guarantee turnover during the reaction. At the same time, the deprotonated species should be sufficiently nucleophilic to react at a reasonable rate with the electrophilic reaction partner. In this context, monoesters, such as ethyl phenylacetate 1, have rarely been applied as pronucleophiles and required mostly the use of stoichiometric amounts of strong bases to undergo reactions. Differently, the structurally related lactones 3-isochromanone and 2-coumaranone (also known as benzofuran-2(3H)-one) have pKa(DMSO) values of 18.8 and 13.5, respectively, close to the C–H acidity level of methyl p-nitrophenylacetate (pKa = 15.1 in DMSO). A limited number of catalytic reactions of 3-substituted 2-coumaranones 3 have been reported. However, to our knowledge, the use of 3-isochromanones as pronucleophiles has so far almost been neglected. While SN2 alkylations at C-4 of 2a as well as Knoevenagel-type condensations with aldehydes have occasionally been studied, only one example for a conjugate addition to a Michael acceptor has been reported to date.[1]

The scope of the lactone–chalcone adduct formation was further explored under the optimized conditions. To assess the full extent of this reaction, we synthesized several substituted 3-isochromanones with a range of electronic properties incorporated on the aromatic ring. Several chalcones reacted with differently substituted 3-isochromanones with both reactants bearing halogens, electron-donating groups and EWGs in different positions on the aromatic rings, showing variable reaction time as detected by thin-layer chromatography (TLC) (used to monitor the disappearance of 3-isochromanones), obtaining 4-(3-Oxo-1,3-diphenylpropyl)­isochroman-3-one in moderate to excellent yields. Although the enolate of 2-coumaranone  is less nucleophilic than that of 3-isochromanone, it reacted successfully with chalcones under the conditions. Several substituted 2-coumaranones were reacted with chalcones bearing different substituents on both the aromatic rings as well, leading from good to high yields and from moderate to low diastereoselectivity.

Experimental and computational thermochemistry of 3-isochromanone

As a class of compounds, chromones and chromanones have been attracting much attention among chemists in different fields. Chromanone derivatives have been found to exhibit broad-spectrum biological activities, such as insecticidal, antifungal, antibacterial activities, and as perfuming ingredients. 6-Methyl-4-chromanone was found to exhibit strong activity in inhibiting in vitro cell growth of human K562 cells. The stabilizing effect of such delocalization interactions can be quantitatively obtained as second-order perturbative estimates of the corresponding bonding–anti-bonding interactions. By doing so, we were able to identify the leading donor–acceptor interactions which are responsible for the different stabilities of the chromanone isomers as being those involving the π lone-electronic pair of the ring oxygen and the anti-bonding π∗(Cdouble bondO), which contributes with a stabilization energy of about 36 kcal · mol−1 and 43 kcal · mol−1, respectively for dihydrocoumarin and for 3-isochromanone, and the π lone-electronic pair of the carbonyl oxygen and the anti-bonding σ∗(C–O) involving the carbon atom of the same group and the other oxygen atom, contributing with 36 kcal · mol−1 and34 kcal · mol−1, respectively for dihydrocoumarin and for 3-isochromanone. In this paper, we have reported experimental measurements of the standard molar energies of combustion of chromanone, dihydrocoumarin, and 3-isochromanone in oxygen at T = 298.15 K, obtained by combustion calorimetry, which, together with the corresponding standard molar enthalpies of sublimation and vaporization, obtained from Calvet microcalorimetry, provided the experimental estimates of their standard molar enthalpies of formation in the gaseous phase.[2]

References

[1]Mousavi MS, Di Mola A, Pierri G, Tedesco C, Hensinger MJ, Sun A, Wang Y, Mayer P, Ofial AR, Massa A. Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones. J Org Chem. 2024 May 17;89(10):6915-6928. doi: 10.1021/acs.joc.4c00277. Epub 2024 Apr 30. PMID: 38687827; PMCID: PMC11110064.

[2]Matos, M. A., Sousa, C. C. S., & Morais, V. M. F. (2009). Experimental and computational thermochemistry of the isomers: Chromanone, 3-isochromanone, and dihydrocoumarin. The Journal of Chemical Thermodynamics, 41(3), 308–314.

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