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. 2024 Jun 7;25(12):6327.
doi: 10.3390/ijms25126327.

Superelectrophilic Activation of Phosphacoumarins towards Weak Nucleophiles via Brønsted Acid Assisted Brønsted Acid Catalysis

Alena V Zalaltdinova  1 , Yulia M Sadykova  1 , Almir S Gazizov  1 , Atabek K Smailov  2 , Victor V Syakaev  1 , Daria P Gerasimova  1 , Elena A Chugunova  1 , Nurgali I Akylbekov  3   4 , Rakhmetulla U Zhapparbergenov  3   5 , Nurbol O Appazov  3   4 , Alexander R Burilov  1 , Michail A Pudovik  1 , Igor V Alabugin  6 , Oleg G Sinyashin  1
Affiliations

Superelectrophilic Activation of Phosphacoumarins towards Weak Nucleophiles via Brønsted Acid Assisted Brønsted Acid Catalysis

Alena V Zalaltdinova et al. Int J Mol Sci. .

Abstract

The electrophilic activation of various substrates via double or even triple protonation in superacidic media enables reactions with extremely weak nucleophiles. Despite the significant progress in this area, the utility of organophosphorus compounds as superelectrophiles still remains limited. Additionally, the most common superacids require a special care due to their high toxicity, exceptional corrosiveness and moisture sensitivity. Herein, we report the first successful application of the "Brønsted acid assisted Brønsted acid" concept for the superelectrophilic activation of 2-hydroxybenzo[e][1,2]oxaphosphinine 2-oxides (phosphacoumarins). The pivotal role is attributed to the tendency of the phosphoryl moiety to form hydrogen-bonded complexes, which enables the formation of dicationic species and increases the electrophilicity of the phosphacoumarin. This unmasks the reactivity of phosphacoumarins towards non-activated aromatics, while requiring only relatively non-benign trifluoroacetic acid as the reaction medium.

Keywords: acid catalysis; arenes; electrophilicity; phosphacoumarins.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Scheme 1
Scheme 1
Some examples of common superelectrophilic species [10,11,12,13,14,15,16,17,18,19] (A), the reactions of organophosphorus superelectrophiles reported thus far [20,21,22,23,24,25,26,27] (B), the known arylation of phosphacoumarins (C) and the superelectrophilic activation of phosphacoumarins reported in this work (D).
Scheme 2
Scheme 2
Synthesis of 4-aryl-substituted phosphaflavanoids in TFA medium.
Figure 1
Figure 1
Structure determination of the compound 2j. Key cross-peaks in the 1H-13C HMBC spectrum are indicated by arrows.
Scheme 3
Scheme 3
Selected examples highlighting the preferred substitution site of 2-naphthol in acid- [43,44,45] and superacid-catalyzed reactions [46,47,48] (A) and the tentative reaction mechanism in superacidic medium (B).
Scheme 4
Scheme 4
Possible reaction pathways and free energy profiles (kcal/mol) for the interaction of the monocationic phosphacoumarin electrophile with toluene as obtained from quantum chemistry calculations (ωB97X-V/def2-TZVPD//PBE/def2-TZVPD, C-PCM(TFA), Orca 5.0.3).
Scheme 5
Scheme 5
Possible reaction pathways and free energy profiles (kcal/mol) for the interaction of the dicationic phosphacoumarin electrophile with toluene as obtained from quantum chemistry calculations (ωB97X–V/def2-TZVPD//PBE/def2–TZVPD, C–PCM(TFA), Orca 5.0.3).
Scheme 6
Scheme 6
Free energies for the protonation of monocationic organophosphorus electrophiles as obtained from quantum chemistry calculations (ωB97X–V/def2–TZVPD//PBE/def2–TZVPD, C–PCM(TFA), Orca 5.0.3).
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